Ortner's identification of pathological conditions in human skeletal remains [3rd. ed.] 9780128097380

Table of contents :
Ortner’s Identification of Pathological Conditions in Human Skeletal Remains
Copyright
List of Contributors
Preface
A Tribute to Don Ortner
References
1 Introduction
History of the First Edition From Donald J. Ortner
Acknowledgments for the First Edition
History of the Second Edition From Donald J. Ortner
Acknowledgments for the Second Edition
Objectives of the First and Second Editions
History of the Third Edition From Jane E. Buikstra
Acknowledgments for the Third Edition
Objectives of the Third Edition
Format of the Volume
Abbreviations
References
2 A Brief History and 21st Century Challenges
A Brief History of Paleopathology
21st Century Paleopathology
Paleoepidemiology
Epidemiology and Paleoepidemiology
The Relationship Between Paleoepidemiology and Paleopathology
Paleoepidemiology and the Osteological Paradox
References
3 Themes in Paleopathology
Social and Identity Theory
Feminist and Gender Theory
The Intersectionality of Sex, Gender, and Age
Structural Violence
Ancient Humans and Impairment, Disability, and Care
Osteobiography in Paleopathology
References
4 Fundamentals of Human Bone and Dental Biology: Structure, Function, and Development
Skeletal Structure, Function, and Cellular Basis of Bone Biology
Evolution of the Vertebrate Skeleton
Gross Function and Anatomy
Bone Tissue: Composition and Organization
Cartilaginous Tissue
Bone Cells
Molecules and Signaling Pathways: Master Control Mechanisms
Skeletogenesis and Bone Modeling
Embryological and Developmental Processes
Bone Modeling
Endochondral Ossification
Intramembranous Ossification
The Facial Skeleton
Bone Remodeling
The Basic Multicellular Unit
Tooth Structure and Formation
Enamel
Dentin
Periodontal Ligament and Cementum
Tooth Morphogenesis
Conclusions
References
5 Abnormal Bone: Considerations for Documentation, Disease Process Identification, and Differential Diagnosis
Abnormal Bone: General Considerations and Gross Appearance
Description of Abnormal Bone
Differential Diagnosis
Cases of Abnormal Bone: Modeling Description, Identification, and Differential Diagnoses
Conclusion
References
6 Histomorphology: Deciphering the Metabolic Record
Introduction
Visualization of Histological Structures in Dry Bone
Histomorphology: Deciphering the Metabolic Record
The Cellular Basis of Bone Formation and Resorption
Remodeling and the Morphology of the BMU
Calculation of Remodeling Parameters From BSUs
Application of Remodeling Parameters to Pathological Cases and Archeological Skeletal Populations
Why Bones Break: Histomorphometric Assessment of Bone Strength and Fragility
Mechanical Loading Shapes the Material and Structural Properties of Bone Tissue
Bone Functional Adaptation
Mechanical Loading Modes Experienced by Bone
Material Properties and Bone Strength
Trade-Offs Between Strength and Toughness in Fracture Resistance
Normal Trajectory of Remodeling Rate Over the Lifespan
Describing Osteopenia and Osteoporosis in Modern Populations
Describing Bone Loss in Past Populations
Bone Strength at the Microscale: Microdamage as an Energy-Dissipating Mechanism
Morphology of Microdamage Depends on Loading Mode
Diffuse Microdamage as an Energy-Dissipating Mechanism
Microdamage Tends to Initiate at Stress-Concentrating Voids
Changes With Age: Increased Mineralization Accelerates Microdamage Accumulation
Changes With Age: Older Tissue Loses Osteocyte Sensitivity to Microdamage
Intraskeletal Variability in Microdamage Accumulation
Bone Strength at the Microscale: Lacunar-Canalicular Architecture Reflects Osteocyte Activity
Osteocyte Lacunar Density and Volume Increases With Higher Strain
Changes With Age: Osteocyte Lacunar Density Decreases
Changes With Age: Percent Occupied Lacunae Decreases
Changes With Age: Altered Lacunar-Canalicular Architecture
Osteocytic Osteolysis and Pathology
Bone Strength at the Microscale: Vascular Porosity Reflects Resorption Activity
Vascular Porosity Reflects Regional Mechanical Strain
Changes With Age: Increased Vascular Porosity Weakens Bone
Bone Strength at the Microscale: Secondary Osteon Size and Shape as Toughening Mechanisms
Small, Circular Osteons Are Associated With Higher Mechanical Strain
Mechanical Strain Directs Three-Dimensional Secondary Osteon Orientation
Changes With Age: Secondary Osteons Become Smaller and More Circular
Structural Properties of Whole Bone in Cross-Section
Radial Expansion of the Cross-Section Results From Growth in Bone Length
Sexual Dimorphism in Radial Expansion During Growth and Senescence
Sexual Dimorphism in Trabecular Bone Loss With Age
Estrogen Deficiency Also Contributes to Bone Loss in Elderly Men
Cortical Drift During Growth Alters Cross-Sectional Shape
Assessment of Axial Loading Differences Through the Relative Cortical Area
Cross-Sectional Shape as a Metric of Loading Direction
The Parabolic Index: An Overlooked Cross-Sectional Indicator of Osteoporosis
Pathology and Histomorphometry
Remodeling Processes Commonly Disrupted by Pathology
Pathological Alteration of Remodeling Rate Over the Lifespan
Pathological Alteration of Mineralization
Pathological Alteration of Collagen Deposition
Infection: Osteomyelitis
Cancer: Metastatic Bone Disease
Cancer: Osseous Bone Tumors
Imbalances of Bone Remodeling: Paget’s Disease of Bone (PDB)
Imbalances of Bone Remodeling: Osteopetrosis
Disorders of Bone Mineral Homeostasis: Rickets/Osteomalacia
Disorders of Bone Mineral Homeostasis: Hyperparathyroidism
Disorders of Bone Mineral Homeostasis: Hyperthyroidism
Disorders of Bone Mineral Homeostasis: Diabetes mellitus
Disorders of Bone Mineral Homeostasis: Glucocorticoid Excess
Collagen Disorders: Osteogenesis Imperfecta
Conclusion
References
7 The Role of Imaging in Paleopathology
Why Is Medical Imaging Important?
A Brief History of Radiology in Paleopathology
Basic Principles and Terminology
Radiographic Appearance of Pathologic Conditions
Mummies, Paleopathology, and Radiography
Other Bone Changes and Radiography
Harris Lines
Body Mass Calculations
Osteoporosis
Taphonomic Alterations
Other Imaging Modalities
Microcomputed Tomography
Magnetic Resonance Imaging
Conclusion
References
8 Ancient DNA in the Study of Ancient Disease
Introduction to Ancient DNA
History/Trajectory of the Field
Current Methods
DNA Preservation
Sample Preparation and DNA Extraction
NGS Analyses
Microbiome Analyses
Applications of Ancient DNA
Ancient DNA of Pathogens That Can Leave Bony Changes: Leprosy, Tuberculosis, Brucellosis, Malaria, Syphilis
Leprosy
Tuberculosis
Brucellosis
Malaria
Syphilis
Mass Graves and “Invisible” Pathogens: Smallpox, Plague, Cholera, Enteric Dysentery, and Flu
Yersinia pestis
Smallpox
Food and Waterborne Outbreaks
Influenza
“Invisible” Pathogens (to the Paleopathological Record)
Parasites and Commensals (Lice, Worms, and the Microbiome)
Lice
Parasites in Feces
The Gut Microbiome
The Oral Microbiome
Future Prospects for Ancient Pathogen Research
References
9 Trauma
Introduction
Trauma
Pathology
Classification of Fractures
Fracture Mechanisms
Fracture Healing
Bony Sequelae of Trauma
Dental Trauma
Subluxation and Dislocation
Recording Trauma
Paleopathology
Introduction
Trauma Resulting From Intentional Violence
Fractures Resulting From Accidental Events
Fracture Treatment
Complications of Fracture
Dislocation (Luxation) and Subluxation
Trauma, Mortality, and Violence in Past Societies
Mortality Patterns in the Past
Organized Violence
Structural Violence
Child Abuse
Elder Abuse
Intimate Partner Abuse
Violence Directed Toward Bodies
Traumatic Surgical Interventions
Amputation
Trepanation
Sincipital T-Mutilation
Trauma to the Skeleton Through Cultural Modifications
Cranial Modification
Foot Binding
Waist Training
Dental Modification
Summary and Conclusions
References
10 Infectious Disease: Introduction, Periostosis, Periostitis, Osteomyelitis, and Septic Arthritis
Introduction
Humoral Versus Cellular Responses to Infectious Agents
Vascular Changes in Response to Infectious Agents
The Biology of Infection
Periostitis or Periostosis
Pathology
Periostosis in Particular Parts of the Skeleton
Paleopathology
Osteomyelitis
Pathology
Hematogenous Osteomyelitis
Infant Osteomyelitis
Adult Osteomyelitis
Changes in Specific Bones
Skull
Spine
Short Tubular Bones
Cancellous Bones
Paleopathology of Osteomyelitis
The Skull
Postcranial Osteomyelitis
Septic Arthritis
Pathology
Paleopathology
Summary
References
11 Bacterial Infections
Introduction
Tuberculosis
Introduction
Pathology
Statistical Data
General Pattern of Bone and Joint Tuberculosis
The Spine
The Hip
The Knee
The Ankle (Distal Tibia and Fibula) and Tarsal Bones
The Tubular Bones of the Hands and Feet
The Shoulder
The Elbow
The Wrist and Carpal Bones
The Shaft of Long Bones
Ribs
Sternum
The Skull
Cranial Vault
Cranial Base
Facial Bones
Paleopathology
Old World Evidence
New World Evidence
Was There Pre-Columbian Tuberculosis?
Phylogeography of American Tuberculosis
Skeletal Examples
Leprosy
Introduction
Pathology
Direct Effects of M. leprae
Indirect Effects of M. leprae
Periostosis of Limb Bones
Other Bone Changes Associated With Leprosy
Diagnosis of Leprosy in Skeletal Remains
Paleopathology
Naestved, Denmark
Chichester, England
Treponematosis, Treponemal Infection, or Treponemal Disease (TD)
Introduction
Pathology
Yaws
Bejel (or Endemic Syphilis or Treponarid)
Venereal Syphilis (VS)
The Skull
The Spine
The Long Bones
The Joints
Congenital Syphilis (CS)
Paleopathology
Historical Documents
Skeletal Remains
Theories of Disease Evolution
Molecular Evidence
Skeletal Examples
Congenital Syphilis
Adult Treponemal Disease
Brucellosis
Introduction
Pathology
Paleopathology
Glanders
Pathology
Actinomycosis and Nocardiosis
Pathology
Plague
Introduction
Paleopathology
References
12 Fungal, Viral, Multicelled Parasitic, and Protozoan Infections
Fungal Infections
Introduction
Pathology
North American Blastomycosis
Paracoccidioidomycosis
Cryptococcosis
Coccidioidomycosis
Histoplasmosis
Mucormycosis (Phycomycosis and Zygomycosis)
Mycetoma (Maduromycosis)
Sporotrichosis
Aspergillosis
Paleopathology of Fungal Infections
Viral Infections
Introduction
Pathology
Smallpox (Variola)
Rubella
Poliomyelitis
Paget’s Disease
Skull
Long Bones
Spine
Flat Bones
Paget’s Disease Sarcoma
Paleopathology of Viral Infections
Smallpox
Poliomyelitis
Paget’s Disease
Multicelled Parasitic Infections
Introduction
Pathology
Echinococcosis
Paleopathology of Multicelled Parasitic Infections
Protozoan Infections
Pathology
Leishmaniasis
Malaria
Paleopathology of Protozoan Infections
Leishmaniasis
Malaria
Sarcoidosis
Introduction
Pathology
References
13 Parasitology
Bringing Ortner Forward in Time and Application: Echinococcus granulosus
Archeological Data Violating Clinical Predictions Signal Fruitful Areas of Investigation: The Case of Enterobius vermicularis
Chagas Disease, Mummies, and Molecular Biology: Adjusting Clinical Perspectives
Lice Reflect Social Organization, Interaction, and Privation
Medicines and Dietary Analysis
Cemetery Studies: Korea and Central Russia AD 1500–1800
Conclusion
References
14 Circulatory, Reticuloendothelial, and Hematopoietic Disorders
Circulatory Disorders
Blood Supply of Bones
Osteonecrosis
Paleopathology
Necrosis of the Femoral Head
Paleopathology
Legg–Calvé–Perthes Disease and Slipped Femoral Capital Epiphysis
Paleopathology
Other Disorders Associated With Osteonecrosis
Köhler’s Disease of the Tarsal Navicular
Freiberg’s Disease of a Metatarsal Head
Other Diseases Associated With Trauma and Vascular Deficiency
Osteochondritis Dissecans
Paleopathology
Osgood–Schlatter Disease
Paleopathology
Scheuermann’s Disease
Paleopathology
Hypertrophic (Pulmonary) Osteoarthropathy
Paleopathology
Aneurysmal Erosion
Paleopathology
Reticuloendothelial Disorders
Lipid Storage Diseases
Gaucher’s Disease
Niemann–Pick Disease
Other Lipidoses
Langerhans Cell Histiocytosis (Histiocytosis X)
Paleopathology
Hematopoietic Disorders
Anemias
Thalassemia
Sickle Cell Anemia and Its Genetic Variants
Hereditary Spherocytosis (Congenital Hemolytic Anemia)
Iron-Deficiency Anemia
Erythroblastosis Fetalis
Paleopathology of Anemia
Thalassemia and Sickle Cell Anemia
Iron-Deficiency Anemia
Leukemia
Myeloma
Paleopathology
References
15 Metabolic Disease
Introduction
Vitamin C Deficiency
Subadult Scurvy
Paleopathology
Adult Scurvy
Paleopathology
Vitamin D Deficiency
Rickets
Paleopathology
Osteomalacia
Paleopathology
Co-occurrence of Rickets and Scurvy
Osteoporosis
Methods in the Study of Osteoporosis in Paleopathology
Measurement of Bone Quantity
Measurement of Bone Quality
Paleopathology
Conclusion
Fluorosis
Paleopathology
Hyperostosis Frontalis Interna
Paleopathology
References
16 Endocrine Disturbances
Introduction
Pituitary Disturbances
Pathology
Pituitary Gigantism
Acromegaly
Hypopituitarism
Pituitary Dwarfism
Paleopathology
Gigantism
Acromegaly
Pituitary Dwarfism
Other Endocrine Disturbances
Introduction
Pathology
Hypothyroidism
Hyperthyroidism
Cushing’s Disease
Hypogonadism
Hypergonadism
Hypoparathyroidism
Albright’s Hereditary Osteodystrophy
Hyperparathyroidism
Primary Hyperparathyroidism (Osteitis Fibrosa Cystica Generalisata)
Secondary Hyperparathyroidism
Paleopathology
Hypothyroidism
Albright’s Hereditary Osteodystrophy
Hyperparathyroidism
References
17 Congenital and Neuromechanical Abnormalities of the Skeleton
Introduction
Skull
Pathology
Anencephaly
Cleft Lip and/or Palate
Congenital Herniations
Premature Suture Closure
Hydrocephalus
Paleopathology
Cleft Lip and Cleft Palate
Congenital Herniation
Hydrocephalus
Biparietal Fenestra
Premature Fusion of Sutures
Spine
Pathology
Spina Bifida
Congenital Kyphosis and Lordosis
Scoliosis
Sacralization and Lumbarization
Klippel–Feil Syndrome
Spondylolysis
Postparalytic Deformities of the Spine
Paleopathology
Scoliosis
Spina Bifida
Klippel–Feil Syndrome
Spondylolysis
Ribs and Sternum
Pathology and Paleopathology
Pelvis
Pathology
Paleopathology
Extremities
Pathology
Postparalytic Deformities of the Appendicular Skeleton
Paleopathology
Postparalytic Deformities
References
18 Skeletal Dysplasias and Related Conditions
Introduction
Defects in Endochondral Bone Formation
Achondroplasia
Pathology
Thanatophoric Dwarfism
Paleopathology
Multiple Epiphyseal Dysplasias
Paleopathology
Acromesomelia
Léri–Weill Dyschondrosteosis
Paleopathology
Mucopolysaccharidosis
Pathology
Defects in Intramembranous Bone Formation
Osteogenesis Imperfecta
Pathology
Type I (A and B) Osteogenesis Imperfecta
Type II Osteogenesis Imperfecta
Types III and IV Osteogenesis Imperfecta
Paleopathology
Cleidocranial Dysplasia
Pathology
Osteopetrosis
Pathology
Malignant Osteopetrosis
Metaphyseal Dysplasia (Pyle’s Disease)
Pathology
Paleopathology
Progressive Diaphyseal Dysplasia (Camurati–Engelmann’s Disease)
Pathology
Palaeopathology
Melorheostosis (Leri’s Disease)
Pathology
Osteopoikilosis
Pathology
Osteopathia Striata
Pathology
Paleopathology
References
19 Tumors of Bone
Introduction
Principles of Diagnosis
Paleopathology
Primary Benign Tumors
Pathology
Osteogenic Tumors
Osteoma
Osteoid Osteoma
Osteoblastoma
Chondrogenic Tumors
Chondroma
Osteochondroma
Chondroblastoma
Bizarre Parosteal Osteochondromatous Proliferation and Subungual Exostosis
Chondromyxoid Fibroma
Fibrogenic, Fibrohistiocytic, and Fibro-Osseous Lesions
Desmoplastic Fibroma
Nonossifying Fibroma and Benign Fibrous Histiocytoma
Fibrous Dysplasia
Osteofibrous Dysplasia
Osteoclastic Giant Cell-Rich Tumors
Giant Cell Tumor of Bone
Vascular Tumors
Hemangioma and Vascular Malformations
Epithelioid Hemangioma
Meningioma
Cystic Lesions
Simple Bone Cysts
Aneurysmal Bone Cyst
Intraosseous Epidermal Cyst and Dermoid Cyst
Paleopathology
Osteogenic Tumors
Osteoma
Osteoid Osteoma and Osteoblastoma
Chondrogenic Tumors
Chondroma
Osteochondroma
Chondroblastoma
Fibrogenic, Fibrohistocytic, and Fibro-Osseous Lesions
Nonossifying Fibroma
Fibrous Dysplasia
Osteoclastic Giant Cell-Rich Tumors
Giant Cell Tumor of Bone
Vascular Tumors
Hemangioma and Vascular Anomalies
Meningioma
Cystic Lesions
Primary Malignant Bone Tumors
Pathology
Osteosarcoma
Chondrosarcoma
Ewing Sarcoma of Bone
Chordoma
Adamantinoma
Paleopathology
Bone Metastases
Pathology
Biology of Bone Metastases
Diagnostic Features
Paleopathology
Abbreviations
Carina Marques
References
20 Joint Disease
Osteoarthritis
A Note on Nomenclature
Pathophysiology of Osteoarthritis
Types of Osteoarthritis
Precipitants of Osteoarthritis
Paleopathological Diagnosis
The Distribution of Osteoarthritis in the Skeleton
Particular Features of Osteoarthritis in Different Joints
Effects of Osteoarthritis During Life
Osteoarthritis and Occupation
Other Conditions With Proliferation or Eburnation
The Erosive Arthropathies
Rheumatoid Arthritis
The Sero-Negative Arthropathies
Ankylosing Spondylitis
Reactive Arthropathy
Psoriatic Arthropathy
Enteropathic Arthropathy
Some General Comments on the Sero-Negative Arthropathies
Erosive Osteoarthritis
The Crystal Arthropathies
Gout
Septic Arthropathy
References
21 The Dentition: Development, Disturbances, Disease, Diet, and Chemistry
Introduction
Dental Development
Dentin
Enamel
Disturbances in Dental Development
Abnormal Quality of Teeth: Disturbance of Dentin Development
Pathology
Paleopathology
Abnormal Quality of Teeth: Disturbance of Enamel Development
Pathology
Palaeopathology
Abnormal Quality of Teeth: The Effects of Disease
Pathology
Paleopathology
Abnormal Quantity of Teeth and Dental Crowding
Pathology
Paleopathology
Abnormal Size of Teeth
Pathology
Paleopathology
Dental Anomalies
Pathology
Paleopathology
Dental Discoloration
Pathology
Paleopathology
Identifying Dental Wear and Oral Disease
Dental Wear
Pathology
Paleopathology
Caries
Pathology
Paleopathology
Alveolar Lesions
Pathology
Paleopathology
Other Miscellaneous Conditions of the Oral Cavity
Pathology
Odontogenic Cysts: Pathology and Paleopathology
Odontogenic Tumors: Pathology and Paleopathology
Nonodontogenic Cysts and Tumors: Pathology and Paleopathology
Hyperostosis/Tori: Pathology and Paleopathology
Antemortem Tooth Loss
Pathology
Paleopathology
Periodontal Disease
Pathology
Paleopathology
Interpreting Oral Health
Sex Differences in Oral Health
Oral Health and Demographic Transitions
Dental Chemistry
Introduction
Paleodietary Reconstruction: Bulk Stable Isotope Analysis Background
Paleodietary Reconstruction: Bulk Stable Isotope Analysis in Bioarcheological Research
Paleodietary Reconstruction: Compound-Specific Isotope Analysis Background
Paleodietary Reconstruction: Compound-Specific Isotope Analysis in Bioarcheological Research
Paleodietary Reconstruction: Trace Elements Background
Paleodietary Reconstruction: Trace Elements in Bioarcheological Research
Patterns of Breastfeeding and Weaning: Background
Patterns of Breastfeeding and Weaning: The Bioarcheological Research
Understanding Stress and Disease From Chemical Analyses: Background
Understanding Stress and Disease From Chemical Analyses: The Bioarcheological Research
Human Mobility and Migration: Background
Human Mobility and Migration: The Bioarcheological Research
Dental Calculus
Pathology: Dental Calculus Formation
Paleopathology: Microparticle Analyses of Dental Calculus in Bioarcheology
Paleopathology: Chemical Analyses of Dental Calculus for Bioarcheological Research
Paleopathology: aDNA and Protein Analyses of Dental Calculus for Bioarcheological Research
References
22 Mummies and Paleopathology
Paleopathological Examination of Mummies
Endoscopy
Tissue Histology
Mummy Paleopathology
Neoplasms
Infectious Diseases
Parasitic and Helminth Diseases (See Also Chapter 14)
Other Diseases of Visceral Organs
Lesions, Trauma, and Cause of Death
Conclusion
References
23 Nonhuman Animal Paleopathology—Are We so Different?
Introduction
Research Foci Within Nonhuman Animal Paleopathology
Areas of Departure
Areas of Commonality
Toward Closer Integration
Acknowledgments
References
24 Postscript
The Future of Paleopathology
References
Index

Citation preview

Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

Ortner’s Identification of Pathological Conditions in Human Skeletal Remains Third Edition

Edited by

Jane E. Buikstra Arizona State University, Tempe, AZ, United States

Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom Copyright r 2019 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN: 978-0-12-809738-0 For Information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Stacy Masucci Acquisition Editor: Elizabeth Brown Editorial Project Manager: Pat Gonzalez Production Project Manager: Bharatwaj Varatharajan Cover Designer: Matthew Limbert Cover photo by Haagen D. Klaus and courtesy of the Smithsonian Institution National Museum of Natural History. Typeset by MPS Limited, Chennai, India

List of Contributors Amanda M. Agnew, School of Health and Rehabilitation Sciences, The Ohio State University, Columbus, OH, United States Megan B. Brickley, Department of Anthropology, McMaster University, Hamilton, ON, Canada Jane E. Buikstra, Arizona State University, Tempe, AZ, United States; Arizona State University, Phoenix, AZ, United States Morgana Camacho, Pathoecology Laboratory, School of Natural Resources, University of Nebraska - Lincoln, United States Mary E. Cole, Department of Anthropology, The Ohio State University, Columbus, OH, United States Sharon DeWitte, University of South Carolina, SC, United States Bruno Frohlich, Department of Anthropology, Smithsonian Institution, Washington, DC, United States; Department of Anthropology, Dartmouth College, Hanover, NH, United States Anne L. Grauer, Loyola University Chicago, Chicago, IL, United States Rebecca Kinaston, Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand Haagen D. Klaus, Department of Sociology and Anthropology, George Mason University, Fairfax, VA, United States Mary Lewis, University of Reading, Reading, United Kingdom Niels Lynnerup, Department of Forensic Medicine, University of Copenhagen, Copenhagen, Denmark

Justyna J. Miszkiewicz, School of Archaeology & Anthropology, Australian National University, Canberra, ACT, Australia Marc F. Oxenham, School of Archaeology & Anthropology, Australian National University, Canberra, ACT, Australia Andrew T. Ozga, Center for Evolution and Medicine, Tempe, AZ, United States; Institute for Human Origins, Tempe, AZ, United States Rebecca Redfern, Centre for Human Bioarchaeology, Museum of London, London, United Kingdom Karl Reinhard, Pathoecology Laboratory, School of Natural Resources, University of Nebraska - Lincoln, United States Charlotte A. Roberts, Department of Archaeology, Durham University, Durham, United Kingdom Anne C. Stone, School of Human Evolution and Social Change, Tempe, AZ, United States; Center for Evolution and Medicine, Tempe, AZ, United States; Institute for Human Origins, Tempe, AZ, United States Samuel D. Stout, Department of Anthropology, The Ohio State University, Columbus, OH, United States Richard Thomas, School of Archaeology and Ancient History, University of Leicester, Leicester, United Kingdom Monica Tromp, Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand; Department of Archaeology, Max Planck Institute for the Science of Human History, Jena, Germany

Carina Marques, Research Centre for Anthropology and Health (CIAS), Department of Life Sciences, University of Coimbra, Coimbra, Portugal; Department of Anthropology, William Paterson University, Wayne, NJ, United States

Tony Waldron, University College London, London, United Kingdom

Simon Mays, Historic England, Portsmouth, United Kingdom

Anna Willis, College of Arts, Society & Education, James Cook University, Townsville, QLD, Australia

Chiara Villa, Department of Forensic Medicine, University of Copenhagen, Copenhagen, Denmark

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Preface One of the last times I saw Don Ortner in his office at the Department of Anthropology of the Natural History Museum, he gestured to the shelves and filing cabinets where he had been beginning to accumulate sources for the third edition of Identification of Pathological Conditions in Human Skeletal Remains. As we who mourn him know only too well, he died unexpectedly on April 29, 2012, and this task remained undone. Hoping that at least a partial manuscript existed, I asked Bruno Frohlich, a close colleague of Don’s at the National Museum of Natural History, about evidence of the volume’s progress. As the person who assumed the challenging task of sorting Don’s office, Bruno indicated that there was nothing of substance, no outline, no negotiations with a press. Thus, it was obvious that organizing a new edition would require starting with the Ortner (2003) volume and revising. The alternative, letting the fine second edition become increasingly out of date, a piece of history but not a useful teaching and research aid, seemed an unhappy choice. New volumes by other authors would no doubt appear, but in my opinion that energy and expertise could be better directed toward advancing knowledge in other ways rather than “reinventing the wheel.” Following discussions with colleagues in paleopathology and the Ortner family, primarily Don’s widow Joyce and son, Don, Jr., I agreed to explore publication options and consider how the volume might be revised to reflect new knowledge and the further integration of the study of health into perspectives on the past. After discussions with several presses, it seemed prudent to choose Elsevier, as they could readily provide the text and image files from the second edition. I wish to thank them most sincerely for their support and patience throughout this protracted process. There have been many decisions along the way. Initially, and with sage advice from many colleagues, such as Anne Grauer and Charlotte Roberts, I generated a proposal for Elsevier, which included an outline of the volume, as it appears here. Recognizing that a collaborative effort would be needed to update the core chapters on pathological conditions, specialists in the paleopathology

of specific conditions were invited to take Don’s (and Walter Putschar’s) chapters and rework them to reflect new knowledge. Each invited author accepted, which is a measure of their professionalism and their respect for Don. In creating the current organization, I have deleted information about basic osteological methods, such as estimating age-at-death and biological sex. These are now covered in much greater detail in a variety of basic and advanced osteology texts. We have introduced distinctive chapters on normal and abnormal bone development, imaging, radiology, and ancient pathogen DNA and microbiomes. The chapter on dental disease now also includes biochemical methods for estimating diet (paleodiet). In some cases, conditions have been shuffled between chapters, their realignment reflecting contemporary thought. Faced with deciding whether to follow my vision of paleopathology in the 21st century or to attempt to guess what Don might have wanted 15 years after the previous edition and 6 years after his death, I have chosen the former. In reflecting upon the many stimulating and open discussions that Don and I have had about the field, I am convinced that he would approve. I have therefore deemphasized “classification” in the diagnostic process, and I have added a chapter that recognizes social theoretical approaches to interpreting pathological conditions. In addition, attempting to recognize related specialties, chapters on mummy science and animal paleopathology have also been added. It is my personal view that the 21st century will witness remarkable new knowledge of disease histories and disease transmission that unites the study of zoonotic and human infections, facilitated by molecular studies. The biomolecular “revolution,” however, will continue to complement and augment our studies of human remains, which will continue to be as fundamentally important to the study of ancient disease as Don and Walter recognized in their 1981 volume. A final word should be added about authorship. Several chapter authors asked that Don be included as a co-author, as I also felt appropriate for the volume as a whole. As there are prohibitions against attributing posthumous authorship, I decided to follow the biomedical

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model and entitle this volume Ortner’s Identification of Pathological Conditions in Human Skeletal Remains, 3rd edition. So here it is! It wouldn’t have been possible without Don’s (and Walter’s) exemplary prototype, as well as the many colleagues who so willingly contributed revisions

and original chapters. I sincerely hope that you find it useful in your research and teaching, as you advance the vibrant field of paleopathology during the 21st century. Jane E. Buikstra Arizona State University

A Tribute to Don Ortner It is a great honor to be asked to write this tribute for the third edition of Don’s Identification of Pathological Conditions in Human Skeletal Remains. Charlotte had attended Don’s 1985 Short Course in Paleopathology at the Smithsonian Institution, Washington, DC (the fifth and final one there), and we both met Don at the Paleopathology Association European Meeting in Madrid in 1986. He indicated that he was “looking for a hook on which to hang his hat” in Europe and do research and teaching. We proposed the University of Bradford, and he accepted the University’s invitation to be an Honorary Visiting Professor. Thus began a long and enduring relationship and collaboration with the Smithsonian Institution, and a long and close friendship between the Ortners and the Manchesters, and Charlotte and family. This friendship has endured to the present, long past Don’s untimely tragic death, and is exemplified by the endearing label applied to Don, with typical Yorkshire bluntness, by Keith’s wife’s aunt: “the Big Bug from America.” Research collaborations at the University developed, especially in tuberculosis and leprosy, and in 1988 the first (Bradford) Short Course in Paleopathology was run. It ran seven times, with the final one in 2008. Don’s involvement at Bradford had continued for several years by then, and during that time he and his wife Joyce had explored much of the county of Yorkshire, and become the owners of “Yorkshire passports”! Don started his career with an undergraduate degree (BA) in Zoology with a minor in chemistry. This is interesting when compared to the late Don Brothwell, whose first degree was a BSc in Anthropology and Archaeology (including zoology and geology), and the fact that Don Ortner was inspired by a primatologist to move into looking at past disease. A Masters degree in Anthropology followed at Syracuse University, where he also did the physical anthropology course taught by Gordon Bowles, who had studied under EA Hooton. He then completed a PhD in 1969 at the University of Kansas (the effects of ageing and disease on the micromorphology of human compact bone). He worked for some time as a Museum Technician in the Department of Anthropology at the National Museum of Natural History at the Smithsonian Institution, Washington, DC (with JL Angel and TD Stewart), and then was

recruited as an Assistant Curator in 1969, becoming Curator of Physical Anthropology in 1976. Following a strongly influential meeting with Adolph Schultz at the University of Zurich in Switzerland who studied wild shot primate pathology, he was convinced that “paleopathology could make a valuable contribution to science if the research was founded on a thorough knowledge of anatomy, physiology and the mechanisms of disease processes” (Powell, 2012: 91). The rest is history. This set the stage for the rest of his career. His meeting with pathologist Walter Putschar led to Ortner and Putschar (1981) and Don’s considerable work for that first edition benefited from his experience working with pathology reference collections in European museums. Highlighting these collections as beneficial to understanding how disease processes affect bones has led to much more work on documented skeletal collections in paleopathological research. Don was deeply involved with paleopathology at many levels, including service to the field, and he headed up the Paleopathology Association (PPA) as President from 1999 to 2001. In terms of research, Don has contributed much to the literature beyond his books. He was particularly proud of his achievements in developing diagnostic criteria for scurvy and rickets, and documenting the effect of the early stages of leprosy on the facial bones. He was open to debates in paleopathology, and welcomed interactions with younger scholars where he could help. He was always willing to talk to anybody about paleopathology, young, old, amateur or highly experienced. In particular, we would like to emphasize Don’s commitment to research-led education in paleopathology, epitomized by many activities. Three are prominent. Firstly, the hugely successful short courses in paleopathology with a worldwide participation helped many “graduates” along the road to successful careers, including one of the authors (Ortner et al., 2012). Secondly, these courses ran alongside the many workshops in paleopathology Don led at the annual meetings of the PPA, starting in 1985, and gave people the opportunity to engage with different pathological conditions at theoretical and practical levels. There is no underestimating the time Don (and his compatriot Bruce Ragsdale, a pathologist) spent putting the workshops together. They remain a legacy for PPA xvii

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meetings today. Thirdly, this volume has become the mainstay for scholars working in paleopathology. The first edition of this book had been published in 1981, well before his link with Bradford began (“Don’s Bible”). This marked a turning point in the global evolution and development of paleopathology. Previous publications, whilst important in establishing paleopathology as a discipline and documenting global evidence for disease in antiquity, lacked the scientific and clinical rigor of Don’s book in elucidating diagnostic and differential diagnostic paleopathological criteria for different diseases. The second edition was produced in the prime years of his involvement at Bradford (Ortner, 2003). In that edition Don wrote 20 of the 23 chapters; authoring virtually all the chapters was no mean achievement. These two editions had focused on a classificatory system of disease, whilst incorporating and integrating clinical and epidemiological aspects. His writings on the basic biology of bone, on pathological processes, and on clinical and scientific methodology create a baseline for this third edition which, whilst maintaining a classificatory base, has diversified and expanded into broader aspects and concepts of paleopathology. This appropriately includes methodological developments. We believe that this edition is a just and fitting tribute to Don’s immense and unequaled contribution to the totality of paleopathology, making it an accepted and important component of anthropology, archeology, and clinical medicine. The chapters of the current edition, by necessity, have been reworked by a range of authors from both the Old and New Worlds, but the work Don put into the chapters of the previous volumes provided a very strong base with which the new chapter authors could work. We are sure that Don would

have been incredibly pleased to see this new edition and the developments the volume has taken, and happy to see Jane head it up. This new edition of Don’s seminal work in paleopathology will clearly take us well into the 21st century and set the stage for research and teaching in this field. In so doing, it takes into account developments in the field over the last 15 years, showing particularly how nonhuman paleopathology, paleoparasitology, and biomolecular analyses have an increasing part to play in the reconstruction of the origin, evolution, and history of disease. It also illustrates that paleopathology is rapidly progressing as a multimethod-driven discipline fit for the future, and one that embraces other disciplines across the arts, humanities, social sciences, and sciences. Charlotte Roberts and Keith Manchester

REFERENCES Ortner, D.J., 2003. Identification of Pathological Conditions in Human Skeletal Remains, second ed. Smithsonian Institution Press, Washington, DC. Ortner, D.J., Putschar, W.G.J., 1981. Identification of Pathological Conditions in Human Skeletal Remains. Smithsonian Institution Press, Washington, DC. Ortner, D.J., Knu¨sel, C., Roberts, C.A., 2012. Special courses in human skeletal paleopathology. In: Buikstra, J.E., Roberts, C.A. (Eds.), The Global History of Paleopathology. Pioneers and Prospects. University Press, Oxford, pp. 684 693. Powell, M.L., 2012. Donald J. Ortner. In: Buikstra, J.E., Roberts, C.A. (Eds.), The Global History of Paleopathology. Pioneers and Prospects. University Press, Oxford, pp. 89 96.

Chapter 1

Introduction Jane E. Buikstra Arizona State University, Tempe, AZ, United States

This third edition of the Identification of Pathological Conditions in Human Skeletal Remains updates and expands upon the topical coverage of earlier works published by Ortner and Putschar (1981) and Ortner (2003). In this chapter, we develop a “roadmap” for the structure and organization of this volume. First, we present the history of this landmark volume from the perspectives of Donald J. Ortner (first and second editions) and Jane E. Buikstra (third edition). In these sections, and elsewhere, our goals have included retaining Don’s voice, so there are many portions of the second edition that are retained throughout the volume. We also acknowledge those individuals and institutions who have contributed to its development over the past 30 1 years. We then introduce the objectives for this third edition, outlining those chapters that have been reorganized as well as those chapters that have been added to this edition, which cover a new range of related fields integral to the development of 21st century paleopathology. Finally, we will introduce and review the format of the volume and its organization.

HISTORY OF THE FIRST EDITION FROM DONALD J. ORTNER The first edition of this book was the result of a joint collaboration between Dr. Walter G. J. Putschar and me. Dr. Putschar was an internationally known, consultant pathologist at Massachusetts General Hospital in Boston, MA, who had a special interest in diseases of the human skeleton. We began our professional relationship in 1970 when he accepted my invitation to be the principal lecturer in a seminar series on human skeletal paleopathology that I was organizing at the Smithsonian Institution. The first Paleopathology Seminar Series was held in 1971 and brought several leading authorities on skeletal disease, paleopathology, and related subjects to the Smithsonian Institution to present a series of lectures to a select group of scholars interested in skeletal paleopathology.

The seminar series was held yearly through 1974. By that time the logistics of obtaining funds to offer the series, arranging for students to come from many universities, including those outside the United States, and assembling an outstanding faculty for the 10-week series of lectures and laboratory sessions raised serious questions about whether this was the most cost-effective method for enhancing the quality and direction of research in skeletal paleopathology. It also highlighted the need for a comprehensive reference work on diseases of the skeleton that might be encountered in archeological skeletal remains. I discussed this issue with Dr. Putschar and we decided that many more scholars interested in skeletal paleopathology would have access to the substance of the seminar series if the information in the lectures and laboratory sessions was incorporated into a well-illustrated and comprehensive reference work on pathological conditions that affect the human skeleton. In the summer of 1974, with the support of a grant from the Smithsonian Research Foundation (now the Smithsonian Scholarly Studies Program), Dr. Putschar and I, accompanied by our wives, Florence Putschar and Joyce E. Ortner, and my three children, traveled extensively in Great Britain and several European countries for more than three months visiting educational and research centers that had significant collections of documented human skeletal pathology. In selecting these centers, we leaned heavily on the advice of the late Dr. Cecil J. Hackett, a physician who had worked for several years in Uganda where he had treated hundreds of patients suffering from yaws. This experience led to a research interest in treponematosis, and Dr. Hackett wrote his doctoral dissertation on the clinical, radiological, and anatomical manifestations of yaws (Hackett, 1947). Following his career in Uganda, Dr. Hackett settled in England where he continued his research on treponematosis, its history and skeletal manifestations. As part of this research he visited many of the major European collections of anatomical pathology that contained documented cases of

Ortner’s Identification of Pathological Conditions in Human Skeletal Remains. DOI: https://doi.org/10.1016/B978-0-12-809738-0.00001-6 © 2019 Elsevier Inc. All rights reserved.

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2 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

syphilis. Hackett’s research on these cases resulted in the publication of his classic monograph (Hackett, 1976) on the skeletal manifestations of syphilis, yaws, and treponarid (bejel). His knowledge of these collections and which ones were likely to serve the objectives Dr. Putschar and I had set out to achieve was an invaluable asset. During our visit to these institutions, Dr. Putschar and I studied and photographed hundreds of cases of skeletal disease. In addition to the photographic record we made of these cases, we often were able to obtain autopsy or museum records that provided descriptive details and a diagnosis for the cases. Radiographic films were acquired for some of the cases. Dr. Putschar dictated his observations about each case and these observations were subsequently transcribed and organized by Mrs. Putschar. In some cases, Dr. Putschar’s diagnostic opinions were at variance with the diagnosis given in the catalog and this difference was duly noted in his observations. Most often, however, the diagnosis given in the catalogs was plausible if not reasonably certain. We began the task of writing the book shortly after completing our European research in 1974. In 1979, we submitted the completed manuscript to the Smithsonian Institution Press for publication as part of the Smithsonian Contributions to Anthropology series. The manuscript was reviewed by the Department of Anthropology, external reviewers, the Director’s office of the National Museum of Natural History, and the Press. After approval on all levels, editing and production took an additional several months and the book was published in December of 1981 as Smithsonian Contributions to Anthropology, Number 28. A hard-cover edition was published in 1985 that was identical to the first edition except for the addition of an index.

Acknowledgments for the First Edition The initial research conducted for the first edition of this book was an extensive survey in 1974 by Dr. Putschar and me of documented skeletal pathology in 16 European pathology and anthropology collections in six countries. This survey was supported by the Smithsonian Research Foundation and Hrdliˇcka Fund. The following list of these institutions and the staff members who assisted our survey of their collections is inadequate recognition of the many courtesies extended during our work. Sadly, many colleagues who provided this assistance have since retired or died. Furthermore, some of the collections have been moved from the site where we studied them and some probably no longer exist. However, it remains appropriate to acknowledge the contribution they have made to both editions of this book. Austria: Federal PathologicAnatomy Museum, Vienna (Dr. Karl von Portele and Dr.

Alexander Mu¨ller); Pathology Museum of the University of Graz (Prof. Dr. Max Ratzenhofer); Pathology Museum of the University of Innsbruck (Prof. Dr. Albert Probst and Prof. Dr. Josef Thurner, Salzburg, Austria). Czechoslovakia: National Museum, Department of Anthropology, Prague (Dr. Emanuel Viˇck, Dr. Milan Sfloukal and Dr. H. Han¯akov¯a). England: The Natural History Museum, London (Dr. Theya Molleson and Rosemary Powers); Guy’s Hospital Medical School, Gordon Pathology Museum, London; The Royal College of Surgeons of England, Wellcome Museum, London (Dr. Martin S. Israel); The Royal College of Surgeons of England, Hunterian Museum, London (Elizabeth Allen); St. George’s Hospital Medical School, Pathology Museum, London; Westminster Hospital School of Medicine, Pathology Museum, London. France: (Prof. Y. Le Gal and Prof. Andre` Batzenchlager). Scotland: The Royal College of Surgeons of Edinburgh (Prof. Eric C. Mekie, Dr. Andrew A. Shivas, Violette Tansy, Turner, McKenzy). Switzerland: Anthropological Institute of the University of Zurich (Dr. Wolfgang Scheffrahn); Historical Museum, Chur (Dr. H. Erb); Institute of Pathological Anatomy of the University of Zurich (Prof. Dr. Erwin Uehlinger, Prof. Dr. Christoph E. Hedinger, and Aschwanden); Natural History Museum, Bern (Prof. Dr. Walter Huber). Dr. Cecil J. Hackett, an associate of the Royal Orthopaedic Hospital, did much to expedite our work in London, England, and offered several helpful suggestions regarding collections in other countries that proved valuable to our study. The product of this 1974 survey was more than 1200 photographs, both black and white and color (taken by me) of approximately 500 pathological specimens jointly studied. For some cases, we were able to obtain x-ray films as well. Dr. Putschar described the specimens in detail on tape, and included original autopsy and clinical data where available. This collection of photographs, radiographs, and the transcripts of case descriptions is available for study at the Department of Anthropology, National Museum of Natural History, Smithsonian Institution, Washington, DC. Many of them are used as illustrations in this book. A number of people made significant contributions during the preparation of the manuscript. Paula Cardwell, Elenor Haley, and particularly Katharine Holland typed initial drafts. Marguerite (Monihan) Guthrie and Elizabeth Beard typed the final draft. Marcia Bakry prepared some of the drawings. A special note of appreciation goes to Jacqui Schulz for the many unpaid hours spent preparing the remaining drawings and getting the photographic illustrations ready for publication. Photographic enlargements were prepared by H.E. Daugherty and Agnes I. Stix. Stix also assisted in editing and typing the manuscript. David Yong, Edward Garner, and Dwight Schmidt

Introduction Chapter | 1

provided valuable technical assistance. The staff of the library of the Smithsonian Institution, particularly Janette Saquet, was most helpful. Dr. J. Lawrence Angel, Dr. T. Dale Stewart, and Dr. Douglas H. Ubelaker, members of the Department of Anthropology, Smithsonian Institution, have made valuable suggestions, as have Dr. Saul Jarcho (New York City) and Dr. George Armelagos (University of Massachusetts, Amherst, MA). The staff of the Smithsonian Institution Press, particularly Albert L. Ruffin, Jr., managing editor, series publications, and, Joan B. Horn, senior editor, deserve special recognition for their assistance from the conceptualization through publication of the book. Finally, the wives of both authors have been intimately involved with the preparation of the book. Florence Putschar spent hundreds of volunteer hours organizing photographs, typing, preparing the bibliography, editing, and otherwise making her remarkable abilities available to the project. Joyce Ortner has also assisted in obtaining illustrative material and skeletal specimens.

HISTORY OF THE SECOND EDITION FROM DONALD J. ORTNER Since Dr. Putschar and I completed the manuscript for the first edition, much has changed in the study of ancient skeletal diseases. The Paleopathology Association, established in 1973 with fewer than two dozen members, is now a thriving international scientific association with more than 600 members worldwide that holds annual meetings in the United States and biennial meetings in Europe. There is now a scientific journal devoted to paleopathology1 and another new journal in which this subject is an important emphasis. A bibliography of paleopathology (both the published edition and the supplements) contains more than 26,000 citations, many of which were published in the last 20 years (Tyson, 1997). My own research interest and experience has developed as well. In 1984 I received a 3-year grant from the National Institutes of Health (NIH; grant AR 34250) to conduct a survey of pathological cases in the human skeletal collections at the National Museum of Natural History (NMNH). This survey was superimposed on a major effort by the Museum to create an electronic data base of our catalog that required that the anthropological collections be inventoried. Several people were involved in this inventory, but three members of the technical staff deserve particular mention: Marguerite (Monihan) Guthrie, who typed much of the manuscript of the first edition of this book, was responsible for creating, editing, 1. Refers to the Journal of Paleopathology, founded by Luigi Capasso, which has been published by the Abruzzo Anthropological Association since 1987.

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and maintaining the data base. Dwight Schmidt and Stephen Hunter were responsible for doing the actual inventory of the human skeletal collection. This inventory required that all human remains in the collection be compared with the catalog record to ensure that the skeleton had been cataloged and that the catalog record was accurate. This meant opening thousands of drawers and handling more than 36,000 partial to complete human skeletons. While they were engaged in this task, Schmidt and Hunter were encouraged to identify any cases of skeletal pathology and bring them to my attention. Both Schmidt and Hunter were enthusiastic and highly motivated. They became skilled at identifying pathological cases and this added immeasurably to the quality and quantity of archeological and anatomical cases of skeletal disease in the human skeletal collection of the NMNH. One of the frustrating aspects of the research Dr. Putschar and I had conducted on the NMNH pathological materials was the lack of accessible and reliable information on the archeological dating of the human remains. The grant from NIH provided funding to hire an archeologist, Dr. James Krakker, to review the archeological field records and publications to determine as accurately as possible the archeological dates for much of the human skeletal collection. After a cluster of pathological cases had been identified, Dr. Putschar would come to the Museum for several days and the two of us would review each one, and he would dictate his observations on the pathogenesis and differential diagnosis. During these visits, Mrs. Putschar would transcribe the dictation and organize the notes. The result was the identification and documentation of many additional cases of skeletal paleopathology that added greatly to our knowledge of disease in antiquity and our ability to diagnose diseases encountered in archeological remains. One of the interesting dimensions of this exercise was the enthusiasm with which Dr. Putschar reviewed these cases. Virtually every pathological specimen brought new knowledge and insight about pathogenesis to both of us. Because of Dr. Putschar’s vast previous experience with skeletal disease in many countries, it surprised me that he was still finding new insights as he studied these cases. The lesson he repeatedly emphasized was that archeological remains offer the potential to see the expression of disease in an entire skeleton and usually in the untreated state. This is rarely possible in a modern clinical context. He also stressed that careful observation of the type and distribution pattern of lesions within the skeletal specimen provided insight regarding pathogenesis that complemented other sources of information about the disease process. Since 1979, research methodology has also benefitted from some major breakthroughs in technology. Computed tomography has brought new understanding to our knowledge of skeletal radiology and pathology. Archeological

4 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

skeletal tissue has been found to be a remarkably good substrate for the preservation of ancient biomolecules, including DNA. Recovery of identifiable genetic material from pathogens has been reported (e.g., Kolman et al., 1999) and this is only the early stage of this research. The remarkable power of the personal computer has provided new ways to manage data and visualize the patterns of pathology that we encounter in archeological skeletal remains. The first edition of this book was prepared using an electric typewriter. I am using a computer word processing system for this edition and I often listen to the music of Mozart being played through my computer while I work. I doubt that Dr. Putschar would have approved of listening to Mozart while writing. Among many other interests, he had a passionate enthusiasm for classical music and especially the music of Mozart, a fellow Austrian by birth. Mozart, in his view, must be listened to and appreciated without distractions. We also know much more about the skeletal manifestations of disease in archeological human remains and this has led to greater diagnostic certainty for many pathological conditions. Medical knowledge has continued to grow, with new insight about the causes of and relationships between skeletal diseases. Not surprisingly the terminology in medicine and paleopathology has continued to change to reflect the new knowledge acquired about skeletal diseases. All of these changes argue for a revision of the first edition that will address the new knowledge about both skeletal pathology and paleopathology that has developed in the last 20 years. Regrettably, Dr. Putschar did not live to see the development of many of these innovations or to participate in this revision. While attending professional meetings in Scotland in early October 1985 he and Mrs. Putschar visited a medieval castle site near Edinburgh. During the visit he fell and hit his head on the stone ruins. He developed a hematoma on the brain that subsequently required surgery. On their return to the United States he and Mrs. Putschar received more bad news when she was diagnosed with terminal cancer. Despite these health problems they both insisted that before Dr. Putschar’s surgery he go ahead with the lectures he had promised to deliver on skeletal disease for the last seminar series on skeletal paleopathology held at the Smithsonian Institution from October 21 through November 8, 1985. Although his balance was affected by his injury, and he was deeply troubled by Mrs. Putschar’s illness, his lectures were models of clarity and provided a remarkable learning experience for all who heard him. Mrs. Putschar died on December 31, 1985. The Putschars had a wonderful marriage and her death was a devastating loss for him. Dr. Putschar’s health declined following two surgeries to control the bleeding in his brain and he died on April 5, 1987 at the age of 83.

Inevitably the progress made in both medical knowledge and paleopathology during the past 20 years means that the revisions for this edition are substantial. However, much of the insight and understanding of pathology that Dr. Putschar brought to the first edition remains relevant and wherever possible I have retained his language and perspectives on skeletal disease. This second edition owes much to his knowledge and experience.

Acknowledgments for the Second Edition In the first edition of this book, I acknowledged the assistance of those who contributed so substantially to its preparation. Some of these people have since died, but the kindness of all who gave of their time and expertise remains a wonderful memory. Since the publication of the first edition many additional people have shared their knowledge and made collections and many additional cases of pathology available for my research. These include the following institutions and people. Australia: The Shellshear Museum, Sydney (Prof. Jonathan Stone and Kenneth Parsons); The Australian Museum, Sydney (Phillip Gordon and Dr. Ronald Lampert); The South Australian Museum, Adelaide (Dr. Graeme Pretty). Denmark: The Danish National Museum, Cophenhagen (Prof. Vilhelm Møller-Christensen). England: The Department of Archaeological Sciences, The University of Bradford, Bradford (Arnold Aspinall, Dr. Keith Manchester, Dr. Charlotte Roberts, Anthea Boylston, Jason Maher, Prof. Mark Pollard, and Dr. Carl Heron); The Rheumatology Unit, Bristol University, Bristol (Dr. Juliet Rogers and Prof. Paul Dieppe); The Canterbury Archaeological Trust, Canterbury (Paul Bennett and Trevor Anderson); English Heritage, Ancient Monuments Laboratory, London (Dr. Simon Mays). Norway: The Department of Anatomy, University of Oslo (Prof. Dr. Per Holck and Inger Saelebakke); The Leprosy Museum of Bergen (Prof. Lorentz M. Irgens). Scotland: The Royal College of Surgeons of Edinburgh (Dr. I. S. Kirkland). Switzerland: The Institute of Pathological Anatomy, University of Zurich (Prof. Dr. Ph. U. Heitz and Prof. A. R. von Hochstetter). United States: The Bishop Museum, Honolulu, Hawaii (Dr. Donald Duckworth, Dr. Yosiniko H. Sinoto, and Toni Han); The Peabody Museum, Harvard University (Dr. David Pilbeam and Dr. Lane Beck); The San Diego Museum of Man (Rose Tyson); The Lowie Museum (now the Phoebe Apperson Hearst Museum of Anthropology), University of California, Berkeley, California. In 1987 I was appointed Visiting Professor of Paleopathology at the University of Bradford, Bradford, England. Since 1988, I have been in residence in the Department of Archaeological Sciences at the University for varying lengths of time almost every year. This has

Introduction Chapter | 1

been a remarkably valuable experience and I am very grateful for the wonderful collegial relationships that have developed over the years and the generous hospitality extended to me and my family. These colleagues include Arnold Aspinall, the Chairman of the Department when I was first appointed, Dr. Keith Manchester, Dr. Charlotte Roberts (now at the University of Durham), Prof. Mark Pollard, who followed Mr. Aspinall as Department Chairman, and Dr. Carl Heron, the current Department Chairman. The skeletal collection in the department, particularly the remarkable collection of human remains from the medieval cemetery in Chichester, England, associated with the Hospital of St. James and St. Mary Magdalene have been of great help in furthering my knowledge of human skeletal paleopathology. Many of the people buried in this cemetery were lepers and their skeletons provide crucial insight regarding the skeletal manifestations of this dreaded disease. In 1992 I had a casual conversation about my research with a friend of many years, David Malin, a sales representative for Siemens Medical Systems, Inc. He offered to try and arrange access to CT equipment at a Siemens facility. His efforts put me in contact with Matthew Riemann (now retired), the director of the Training and Development Center for Siemens Medical Systems, Inc. in Iselin, NJ. Riemann was supportive and asked two members of his staff, Valere Choumitsky and Blaise Falkowski, to do what they could to assist my research. At that time Mr. Falkowski was the senior instructor for technical training of engineers and service technicians who service Siemens CT scanners in North America. When the facility was not being used for training we were able to use the equipment to scan paleopathological cases. Eventually the Training and Development Center moved to Cary, North Carolina, and I and my Smithsonian colleague, Dr. Bruno Frohlich, continued to use the equipment at no cost during windows in the training schedule. Access to this equipment proved to be a powerful research tool and most of the CT images included in this edition were generated on Siemens equipment. CT scanning equipment at the Siemens training facility is upgraded periodically to the newest models manufactured by Siemens. On one occasion Dr. Frohlich learned that a Siemens Somatom AR-T scanner was to be replaced with a new model. He suggested that Siemens donate the older model to the Smithsonian. After approval on all relevant levels the equipment was given to the Museum and is now used in support of the research endeavors of the museum staff. The expertise and the many hours of assistance provided by Mr. Falkowski and his colleagues at Siemens continues to be of major value to my research. Agnes Stix, Museum Specialist, and Janet Beck, Volunteer Research Assistant, Department of Anthropology, National Museum of Natural History,

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Smithsonian Institution, have invested countless hours in organizing bibliographic source materials and illustrations for this book. They have created computer data bases for the references and photographs that greatly facilitated my work. Stix in particular has had the responsibility of organizing the various electronic files of figures, tables, text, figure legends and references and keeping changes in one file congruent with the other. Their contributions to this edition are substantial and I am in their debt. Marcia Bakry, Scientific Illustrator, Department of Anthropology, National Museum of Natural History, Smithsonian Institution, is responsible for preparing the digitized figures for the book. Using the powerful software available today for manipulating digitized photographic images, she has been able to improve significantly the quality of the figures used in this edition and deserves my deepest thanks and that of the reader who will benefit from her skilled work. Dr. Margaret R. Dittemore, Branch Librarian, Anthropology Branch Library, Smithsonian Institution Libraries, and her colleagues in the library were crucial in identifying and obtaining source materials used in the book. I am also indebted to Roxie Walker and the Institute of Bioarchaeology (formerly the Bioanthropology Foundation) for grants that partially supported the preparation of this edition.

OBJECTIVES OF THE FIRST AND SECOND EDITIONS There are many sources of information on the history of disease, including ancient medical documents, historical records, art, and the physical remains of ancient people including both soft tissues and skeletons. Undoubtedly, human skeletons represent the most ubiquitous source of information on ancient diseases. This fact must be tempered with the knowledge that relatively few morbid conditions affect the skeleton in a way that leaves visible changes in dry bones. In spite of this limitation, the study of skeletal pathology in archeological materials can provide time depth to our understanding of disease and contribute to our knowledge regarding the role of disease in human adaptation. In addition, skeletal paleopathology may also broaden our understanding of disease as it affects bone tissue. The paleopathologist often has access to all portions of the skeleton, a situation rarely realized in modern pathology or radiology. This means that the gross pattern and distribution of the morbid condition in all areas of the skeleton can be studied in detail. To provide reliable standard specimens for dry bone diagnosis, the reference cases used as a basis for the first two editions of this book were primarily from the period between AD 1750 and 1930. Ortner felt that earlier than this range the medical data were too ambiguous and later,

6 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

the pathologic manifestations were too altered by surgery, chemotherapy, radiation therapy, and, above all, by the use of antibiotics. For this reason, the first two editions turned to the great medical and anatomical collections of Great Britain and of continental Europe. The British collections proved in many ways to be the most useful, because they were made by physicians and surgeons, who were at all times interested in documenting clinical and historical data. Yet even this material is not necessarily identical to manifestations seen in archeological specimens. As Ortner noted, his compiling these editions highlighted the fact that even the great pathological anatomists of earlier times made mistakes in differential diagnosis. This book was intended mainly to serve as a text and atlas of dry bone pathology, regardless of whether or not each entity had been identified in paleopathology. For that reason, as many aspects as possible of documented, dry bone pathology were illustrated, especially because the original skeletal collections can never be duplicated and may ultimately disappear. In the paleopathological discussions in these earlier editions, emphasis was laid on careful and critical study of published reports and of actual specimens, bringing a variety of types of evidence to bear on arriving at a reasonable diagnostic assumption. Even so, multiple possibilities and uncertainties often remained. Not the least of these problems was the ambiguous and confusing terminology about the nature of pathological conditions and the chronology of archeological specimens in published reports. This book was written primarily with the needs of the biological anthropologist and archeologist in mind, with the hope that they would be able to recognize the abnormalities seen in archeological human skeletal material they excavate or study. This book was also meant to highlight the importance of recovering all mineralized tissues, including the small bones of the hands and feet, during excavation of a burial. Ortner also was interested in generating a broader readership with different backgrounds, though, and emphasized the importance of including historians of medicine and disease, orthopedic surgeons, radiologists, pathologists, and physicians, who may be called upon to interpret skeletal lesions in dry specimens or who are interested in extending their understanding to the more detailed gross expressions of skeletal disease.

HISTORY OF THE THIRD EDITION FROM JANE E. BUIKSTRA Don Ortner was just embarking upon the third edition of this important volume at the time of his unanticipated death on April 29, 2012, following a brief illness. For those of us who had been close to Don professionally and/or personally, our grief was profound. For example,

I—who had enjoyed so many pleasant lunches with Don when I could sneak away from meetings of the National Museum of Natural History’s Repatriation Committee or other Washington responsibilities—could not bear to walk by his office door for nearly a year, finding other circuitous routes to reach the Rose Seminar room of the NMNH’s Anthropology Department. Don’s achievements were celebrated both at the Smithsonian, during an event held during the autumn of 2012, and at the annual meeting of the Paleopathology Association, held during the 2013 annual meeting, April 9 and 10. Fortunately, Powell (2012) had been able to convince Don to be interviewed for a chapter in the Global History of Paleopathology (Buikstra and Roberts, 2012), wherein details of his life and scholarly contributions may be found. I can add only that he was an enthusiastic supporter of the fledgling International Journal of Paleopathology, ably contributing one of the Inaugural Essays and serving as an Associate Editor. He rolled up his sleeves upon many occasions to review articles and offer sage advice to junior colleagues. In discussions with Don’s family, especially his partner Joyce and Don Jr., who sounds remarkably like his father, it became clear that they would be supportive of a third edition of Identification of Pathological Conditions in Human Skeletal Remains, under my editorship. Discussions with Bruno Frohlich, who was helping the Department of Anthropology in archiving the materials from Don’s office, made it clear that Don had only just embarked on the project. No publisher had been identified, nor was there a proposal. Given this situation, I began plans for the project. In creating the proposal, first discussed with the Smithsonian Press, who were not enthusiastic about the project due to concerns with copyright issues, I reflected upon the many productive discussions in which I had engaged with Don. These convinced me that he would have wanted the volume revision not to second guess “what Don might have wanted,” but rather to reflect the status of paleopathology at the time the revision appeared. This meant continuing to emphasize the basic empirical evidence upon which paleopathological identifications are based, but also to reflect the dynamic nature of paleopathology today. Given the mentorship and encouragement that Don had so freely provided to so many of us, I also believe that he would have wanted our generation(s) to leave our imprint upon the work—giving it our best effort. It is with this spirit that we have approached the volume. When I approached Elizabeth Brown, Senior Acquisitions Editor at Elsevier, about the project, she was enthusiastic in support. We have tried to maintain the many strengths of the earlier editions, while also adding new methodological advances (molecular and parasitology), mentioning closely related and increasingly convergent

Introduction Chapter | 1

research topics (animal paleopathology; mummy science) and emphasizing the interdisciplinarity of paleopathology in exploring themes based in the social sciences and humanities. When approached, colleagues in paleopathology and related disciplines signed on enthusiastically, bringing their special expertise to this important initiative. Don and I agreed about most aspects of paleopathology, especially the need for detailed descriptions of pathological changes, for standard terminology, to appreciate limitations of early clinical accounts as well as those of the antibiotic era, and for rigorous applications of differential diagnostic methods. I am less concerned than he about classification, and therefore this topic will be less visible in this third edition. I sincerely hope that we have done justice to Don’s fundamental contributions to the discipline of paleopathology, while recognizing key developments since his seminal 2003 publications.

Acknowledgments for the Third Edition First and foremost, I would like to acknowledge the Ortner family in their support of this initiative. The Department of Anthropology, especially its Chair during the period of project development, Torben Rick, along with Don’s long-term collaborator, Bruno Frohlich have been immensely reassuring. The editor is extremely appreciative of the enthusiasm and expertise of the collaborators, whose wisdom is represented here. The editorial and content editorial assistance of Katelyn Bolhofner has improved clarity and accuracy throughout the development of the volume. Additional polish has been added by the skills of Sylvia Cheever in final stages of the process. Anne Grauer’s careful proof-reading and apt suggestions have improved the final production, which is deeply appreciated. Many of the authors wish to express their gratitude to Don Brothwell for his scholarship and personal encouragement of our research, both in human and in animal paleopathology. Finally, the assistance and encouragement from Elsevier, including Elizabeth Brown, Pat Gonzalez, and the production team have been essential to the success of the project.

OBJECTIVES OF THE THIRD EDITION More than 30 years have passed since the landmark Identification of Pathological Conditions in Human Skeletal Remains (Ortner and Putschar, 1981) was published, followed by the second edition (Ortner, 2003) over a decade ago. The field and the profession of paleopathology have changed markedly over this period, in no small part due to the influence of these volumes. Ortner had planned but not begun writing a third edition at the time of his sudden death, and this volume represents the completion of this project, reflecting his (and Walter

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Putschar’s) core contributions in bone disease through revised and new chapters that manifest the contemporary breadth and depth of the discipline of paleopathology. This third edition updates the previous volumes through the addition of recent medical information on skeletal disorders and the latest relevant literature on human skeletal paleopathology. This work also adds chapters on current methods being used in research on skeletal paleopathology. These include increased reliance on imaging, including CT methods, histology, and analysis of ancient DNA. In addition, chapters covering closely related subjects, such as diet (including isotopes, microwear, colon contents, (macro/micro fossils; pollen), dental calculus, dental caries), mummy science, animal paleopathology, and paleoparasitology have been added. Given the contemporary availability of numerous texts covering basic osteology, in this edition chapters on biological profiling and osteobiographical methods have been deleted. These topics are now introduced briefly in Chapter 3, and Chapter 2 now offers an extended history of paleopathology, current issues in the field, and the importance of rigorous differential diagnosis. The volume is further framed by an expanded discussion of important themes for consideration in this paleopathological research (Chapter 3). As was the case for the first two editions of this volume, the most fundamental objective of this third edition is to provide an integrated, detailed discussion of the gross pathology of the human skeleton to facilitate rigorous differential diagnosis of these pathologies in human skeletal remains from archaeological contexts. In addition to this foundation, the objectives of this third edition include: emphasizing careful consideration of contemporary clinical literature in diagnosis, encouraging knowledge in epidemiology, animal paleopathology, parasitology, and molecular and chemical advances in contextualizing skeletal analyses, and presenting advances in imaging, data collection, and diagnostic approaches arising from such related fields as forensic science, dental anthropology, biogeochemistry, and molecular science.

FORMAT OF THE VOLUME While texts in paleopathology all agree that classification is an important aspect of disease diagnosis, there is no general agreement upon the number of classes of disease. As Ortner (2012) notes, Reznick’s orthopedic radiology text recognizes 17 categories. Aufderheide and Rodrı´guezMartı´n (1998)’s paleopathology text recognizes 13, while both editions of the Ortner volumes focus upon 12. Influenced by Lent Johnson, Ragsdale and various coworkers (Ragsdale and Miller, 1996; Ragsdale and Lehmer, 2012) have asserted the utility of seven basic disease categories, readily recalled through the use of the acronym VITAMIN (see Table 1.1, adapted from Ragsdale and

8 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

TABLE 1.1 Ragsdale’s Seven Basic Disease Categories 1

V

Vascular

2

I

Innervation/mechanical

3

T

Trauma/repair

4

A

Anomaly

5

M

Metabolic

6

I

Inflammatory/immune

7

N

Neoplasms

Lehmer, 2012: 230). Roberts and Manchester (third edition, 2010) also organize their discussion in The Archaeology of Disease into seven categories. After emphasizing the need for histology and recognition of disease processes, Ragsdale and Lehmer (2012: 247) close with the assertion, “that only through detailed descriptions and diagnoses to general disease categories, will a stronger methodological basis for comparative research in paleopathology be reached.” They argue, based upon evidence from four workshops held at the paleopathology meetings (Miller et al., 1996) that assignments to disease categories are more accurate than specific diagnoses. While these conclusions do reflect the empirical data from the Workshops, questions about the relative experience of the participants remains. In addition, the degree to which comparisons across 7, 12, 13, or 1 categories are meaningful in interpreting the past must, of course, depend upon the research question addressed or the hypothesis posed. Further, the issue of contexts—environmental, temporal, cultural—must be considered. As Ortner (2012) emphasizes, disease classifications emphasize cause or pathogenesis of a disease. In that, e.g., bacterial pathogenesis can be a cause, pathogenesis would seem to be the overarching category. Many diseases have multiple causes, and classifications become complex. Metabolic diseases, due to disturbances in osteoid formation and mineralization, are often associated with nutritional deficiencies. Similarly, erosive arthropathies are typically classified as joint disorders, even though an infection may trigger the response. This volume will follow the previous editions in its classification of disease conditions: trauma, infectious diseases, circulatory disorders, reticuloendothelial and hematopoietic disorders, metabolic disorders, endocrine disorders, congenital and neuromechanical disorders, dysplasias, tumor and tumor-like disorders, joint disorders, dental and jaw disorders, and miscellaneous disorders. A few specific disorders have been moved to more completely reflect contemporary knowledge of pathogenesis. In reference to the process of classification, Ortner

(2012: 263) emphasized that the important point “is the need to understand the pathogenesis and, where possible, the cause of the disorder and not let the assignment to a specific category of disease obscure our understanding of the basic bone biology of disease.”

ABBREVIATIONS The illustrations in this book are of specimens from many institutions. The following abbreviations are used in the legends to avoid repetition of lengthy institutional names and locations. This list includes institutions that had pathological cases used in both the first and second editions. AFIP AIUZ ANM BMNH CGH CISC

DPUS FM FPAM HM IEC

IPAZ LLACMUHNAC MGH NHMB NMNH PMES WM

Armed Forces Institute of Pathology, Washington, DC, United States Anthropological Institute, University of Zurich, Zurich, Switzerland National Museum of Anthropology, Prague, Czech Republic British Museum, The Natural History Museum, London, England Department of Pathology, Charleston General Hospital, Charleston, WV, United States Coimbra Identified Skeletal Collection, Departamento de Cieˆncias da Vida, Universidade de Coimbra, Portugal Department of Pathology, University of Strasbourg, Strasbourg, France Field Museum of Natural History, Chicago, IL, United States Federal Pathologic-Anatomy Museum, Vienna, Austria Hunterian Museum, The Royal College of Surgeons of England, London, England International Exchange Collection, Departamento de Cieˆncias da Vida, Universidade de Coimbra, Coimbra, Portugal Institute of Pathological Anatomy, University of Zurich, Zurich, Switzerland Luı´s Lopes Anthropological Collection, Museu Bocage, Museu Nacional de Histo´ria Natural e da Cieˆncia, Lisbon, Portugal Department of Pathology, Massachusetts General Hospital, Boston, MA, United States Natural History Museum, Bern, Switzerland National Museum of Natural History, Smithsonian Institution, Washington, DC, United States Pathology Museum, The Royal College of Surgeons of Edinburgh, Edinburgh, Scotland Wellcome Museum, The Royal College of Surgeons of England, London, England

REFERENCES Aufderheide, A.C., Rodrı´guez-Martı´n, C., 1998. The Cambridge Encyclopedia of Human Paleopathology. Cambridge University Press, Cambridge.

Introduction Chapter | 1

Buikstra, J.E., Roberts, C.A. (Eds.), 2012. The Global History of Paleopathology: Pioneers and Prospects. Oxford University Press, New York. Hackett, C., 1947. The Bone Lesions of Yaws in Uganda. Thesis. University of London, London. Hackett, C., 1976. Diagnostic criteria of syphilis, yaws and treponarid (treponematoses) and of some other diseases in dry bones. Sitzungsberichte der Heidelberger Akademie der Wissenschaften Mathematisch-naturwissenschaftliche Klasse, Abhandlung 4. Springer-Verlag, Berlin. Kolman, C., Centurion-Lara, A., Lukehart, S., Owsley, D., Tuross, N., 1999. Identification of Treponema pallidum subspecies pallidum in a 100-year-old skeletal specimen. J. Infect. Diseases 180, 2060 2063. Miller, E., Ragsdale, B.D., Ortner, D.J., 1996. Accuracy in dry bone diagnosis: a comment on palaeopathological methods. Int. J. Osteoarchaeol. 6 (3), 221 229. Ortner, D.J., 2003. Identification of Pathological Conditions in Human Skeletal Remains. Academic Press, New York. Ortner, D.J., 2012. Differential diagnosis and issues in disease classification. In: Grauer, A. (Ed.), A Companion to Paleopathology. WileyBlackwell, New York, pp. 250 267.

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Ortner, D.J., Putschar, W.J.P., 1981. Identification of Pathological Conditions in Human Skeletal Remains. Smithsonian Institution Press, Washington, DC. Powell, M.L., 2012. Donald J. Ortner (1938 ). In: Buikstra, J.E., Roberts, C.A. (Eds.), The Global History of Paleopathology: Pioneers and Prospects. Oxford University Press, New York, pp. 89 96. Ragsdale, B.D., Lehmer, L.M., 2012. A knowledge of bone at the cellular (histological) level is essential to paleopathology. In: Grauer, A. (Ed.), A Companion to Paleopathology. Wiley-Blackwell, New York, pp. 227 259. Ragsdale, B.D., Miller, E., 1996. Workshop A. Skeletal Disease Workshop VIII: several of the seven basic categories of disease. In: Cockburn, E. (Ed.), Papers on Paleopathology Presented at the 23rd Annual Meeting of the Paleopathology Association, Durham, North Carolina. Paleopathology Association, Detroit, p. 1. Roberts, C.A., Manchester, K., 2010. The Archaeology of Disease. Cornell University Press, New York. Tyson, R. (Ed.), 1997. Human Paleopathology and Related Subjects. An International Bibliography. San Diego Museum of Man, San Diego.

Chapter 2

A Brief History and 21st Century Challenges Jane E. Buikstra1 and Sharon DeWitte2 1

Arizona State University, Tempe, AZ, United States, 2University of South Carolina, SC, United States

In this chapter, we consider the history of paleopathology and a few of the fundamental issues faced by practitioners in the development of this field. We then turn to a discussion of the current state of paleopathology, reviewing methodological and theoretical issues encountered in 21st century paleopathology. In this regard, we discuss the differential diagnosis of pathological conditions in archeological skeletal remains, suggesting avenues by which paleopathologists may pursue more rigorous diagnosis. Finally, we discuss the important contribution of paleoepidemiology in the advancement of this field, as well as considering the ramifications of the osteological paradox in such work.

A BRIEF HISTORY OF PALEOPATHOLOGY Paleopathology has been defined in recent decades as the study of disease, both human and nonhuman, in antiquity using a variety of different sources, including human mummified and skeletal remains, ancient documents, illustrations from early books, painting and sculpture from the past, and analysis of coprolites (Ortner, 2003: 8) More recently, this definition has been reevaluated and expanded to reflect the crucial interplay of biomedical and social sciences and the humanities in the development and future of the field (Buikstra et al., 2017). A comprehensive history of paleopathology has recently been written (Buikstra and Roberts, 2012), and there are several other older summaries of this history that readers who have a specific interest in the subject may wish to consult (e.g., Jarcho, 1966; Angel, 1981; Ubelaker, 1982; Armelagos, 1997; Aufderheide and Rodriguez-Martin, 1998). Thus, a detailed history of paleopathology that includes research using all the varied sources of potential information is beyond the scope of this book. Here, we offer a brief summary of the history of paleopathology,

highlighting some of the issues and major developments in the field over the past 200 years. The history of paleopathology in many ways parallels the development of most other scientific disciplines. The early publications consist of a body of descriptive literature in which abnormalities encountered by an observer are described against the background of what is normal. Much of this early research was no more than an anatomical account of these abnormal conditions with little if any attempt to explore the biological or pathological significance of what was being described. The earliest work focused on nonhuman paleontological specimens (e.g., Esper, 1774; Cuvier, 1820). Warren (1822) included a discussion of artificial cranial deformation in human skulls of indigenous North Americans in his book titled, A Comparative View of the Sensorial and Nervous Systems in Man and Animals. In 1861 in Paris, Gosse published another study of artificial cranial deformation. In the following decades, the question of the origin of syphilis began to be debated with intensity (e.g., Jones, 1876; Virchow, 1898). This debate marks one of the earliest attempts to use archeological human remains to resolve an important biomedical problem. And toward the end of the 19th century, R.W. Shufeldt proposed that the term “paleopathology” be used to describe “all diseased or pathological conditions found fossilized in the remains of extinct or fossil animals” (Shufeldt, 1892: 679). As the term “paleopathology” began to be used in the early 20th century, this period witnessed a marked expansion of published reports on ancient disease. Particularly notable is the work of Sir Marc Armand Ruffer (1910) on Egyptian mummies, and the studies on Nubian skeletal material by Wood-Jones (1908, 1910) and Elliot-Smith and Wood-Jones (1910). In the United States, Aleˇs Hrdliˇcka (1914) published some observations on the pathology of ancient Peruvian skulls. In 1923, Moodie’s

Ortner’s Identification of Pathological Conditions in Human Skeletal Remains. DOI: https://doi.org/10.1016/B978-0-12-809738-0.00002-8 © 2019 Elsevier Inc. All rights reserved.

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Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

introduction to the study of ancient disease, which emphasized nonhuman paleontological specimens, appeared. A brief, general review of human paleopathology was published by Williams in 1929. This review included observations on bones and teeth as well as on mummy tissue and ancient art. Pales (1930) followed with his book on paleopathology and comparative pathology. Most of his cases and discussions concerned European human specimens. In the same year, Hooton (1930) published his classic study of North American Indian skeletal material from Pecos in which he included an extensive description of pathological specimens. Hooton’s study is notable in its descriptive detail, in the statistical treatment of different types of disease in the skeletal population, and in his efforts to show trends in disease frequency through the time period of human occupation at the site. In the 1960s, Wells (1964) published a review of evidence of human paleopathology from skeletal material, mummies, and art that brought paleopathology to the attention of a more general audience. But in the preceding decades, paleopathological studies had fallen into a pattern of inclusion in archeological research as descriptive addenda or appendices. Thus, calls for further advances in the field of paleopathology were made (Jarcho, 1966; Brothwell and Sandison, 1967; see also Grmek, 1983/1989), resulting in the establishment of professional organization, international journals, and professional meetings and training seminars (Buikstra and Roberts, 2012). Throughout the development of human skeletal paleopathology as a scholarly discipline there have been recurring problems in both theory and methodology. In the early stages of paleopathology, most of the research was conducted by physicians who had little knowledge of archeology, thus context often was overlooked. As studies of pathological skeletal specimens began to be conducted primarily by biological anthropologists, whose formal training and experience in skeletal pathology and radiology may be deficient, pathological conditions were at risk of being attributed incorrectly to the wrong time period by those unfamiliar with the complexities of archeological dating. Further, bone lesions were incorrectly diagnosed through ignorance of anatomy and the total range of diseases that affect bone (see Stewart’s comments on this problem in Jarcho, 1966: 43). These problems were complicated further due to the slow formulation of a theoretical context for interpreting the meaning of paleopathological data. [See, e.g., the debate (Wood et al., 1992; Goodman, 1993) about what can and cannot be said about prevalence data and the inferences made about the health of past human populations.] In 1988, Ortner and Aufderheide (1991) organized a symposium held as part of the International Congress of Anthropological and Ethnological Sciences in Zagreb,

Yugoslavia (now Croatia) that attempted to assess (1) how far paleopathology had developed as a scientific discipline, (2) some of the theoretical and methodological problems that needed to be resolved, and (3) directions that research might take in the future. Methodological issues included an inconsistent descriptive terminology that precluded comparison between published reports, and the lack of diagnostic criteria that fully utilized the information available in archeological human skeletons (Ortner, 1991). Theoretical issues included the need for greater understanding of what skeletal disease meant in terms of the general morbidity that existed within the living population in which the person with skeletal disease lived (Ortner, 1991). Much of the emphasis in paleopathology until fairly recently has been on descriptions of pathological specimens, and there had been little effort to relate the evidence of disease to the broader problems of human adaptation. Early hints of such an emphasis exist in Hooton’s Pecos Pueblo monograph (1930), in the consideration of epidemiological factors in evaluating the data on pre-Columbian tuberculosis in the New World (Morse, 1969), and in discussions on the origin of treponemal diseases (Hackett, 1963; Hudson, 1965). But not until recently has the trend toward population studies of ancient disease become a significant part of the literature on paleopathology as these methodological and theoretical problems are resolved (e.g., Larsen, 1997). Much of the descriptive literature in skeletal paleopathology depended upon the scholar’s knowledge of gross bone pathology. Unfortunately, where this knowledge was inadequate there were few reference sources that could be of assistance. Jarcho (1966) organized a symposium on human paleopathology that addressed this problem, among others. The participants called for the establishment of a paleopathology registry and improved diagnostic methodology to partially correct these problems. Steinbock’s reference book (1976) on diagnosis of ancient bone disease represented the first integrated attempt to establish diagnostic criteria for the paleopathologist that addressed the broad range of diseases that affect the human skeleton. The first two editions of this volume (Ortner and Putschar, 1981 and slightly revised in 1985; Ortner, 2003) provided a complimentary treatment of skeletal disease. Both these reference works represented important steps in improving the knowledge regarding the types of diseases that affect bone and the morphological features associated with the disease. Since the publication of the first two editions of this book, there has been a substantial increase in research on broader scientific problems, particularly those related to paleoepidemiology, as we will review later in this chapter. There has also been significant progress made on several crucial methodological problems. One of the most

A Brief History and 21st Century Challenges Chapter | 2

important of these has been the improvement in our application of differential diagnosis, which we will discuss in detail in the following section. As we face a new suite of issues and advances in the 21st century, we argue that paleopathology should be an interdisciplinary endeavor, incorporating expertise from the humanities, the social sciences, and the biomedical sciences (Buikstra et al., 2017).

21ST CENTURY PALEOPATHOLOGY Our vision of 21st century paleopathology is of a profoundly interdisciplinary endeavor, drawing knowledge and professionals from the biomedical and social sciences, as well as the humanities. We use knowledge about past health to address the coevolution of humans and pathogens, and we anticipate much more knowledge about both human and animal disease will soon be reviewed through molecular study. This volume therefore is meant to be an entry point for knowledge that necessarily extends well beyond these pages. First of all, we must recognize that paleopathology proceeds primarily through scientific methods. Our observations of ancient remains should be drawn carefully, follow standard descriptive terminology, and be designed to minimize both intra- and interobserver error. A general overview of terminology appears on the Paleopathology Association’s website (https://paleopathology-association. wildapricot.org/Nomenclature-in-Paleopathology). While this overview generally follows medical terms, methodological and application issues arise due to the fact that most of our observations are made upon materials that emerged from a burial environment. Taphonomic changes are frequently described in terms also used for vital processes, “abraded” and “eroded” being two apt examples. Therefore, when using such terms, the observer should be careful to indicate whether the process occurred ante- or postmortem. We continue to follow Ragsdale and colleague’s (1981) descriptions of periosteal bone reactions (see also Weston, 2012), familiar to those of us who have been humbled during Ortner/Ragsdale and Ragsdale workshops at the annual meetings of the Paleopathology Association. It is crucial not only to describe, but also to understand, the processes that have led to the observed change. As we consider our observations, we should report whether or not the process was active at the time of death, or quiescent. There are published standards (Buikstra and Ubelaker, 1994) and freely available databases (Osteoware) for recording pathological changes in human bones. Whatever system is used, an explicit key that explains the coding system is crucial. While this issue may not seem so important to those starting their research careers, its

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significance will become apparent as the need for consistency across years of data collection and comparative approaches emerge. Observing pathological changes and distinguishing these from postmortem alterations is one crucial step in assessing ancient disease (see Chapter 5: Abnormal Bone: Considerations for Documentation, Disease Process Identification, and Differential Diagnosis). Once these have been coded by individual, and then across a skeletal sample, the identification of a condition assumes significance. Remembering that observations may be complicated by comorbidities, i.e., that two or more diseases may affect a given individual, the survey of possible conditions should begin. In most cases, this assessment can begin with this volume, but it should not necessarily end here. To fully appreciate the manner in which bones (and other tissues) may react to a given insult requires an appreciation of the variable manner in which a person may be affected and the fact that the person may have died prior to the most extreme manifestation of the disease, as recorded here or in the clinical literature. Certainly medical interventions, especially antibiotics and chemotherapy, have changed the course of disease over the past century profoundly. Earlier medical procedures, such as treating venereal syphilis with mercury or malaria with high-temperature baths, may or may not have altered the course of disease. Such treatments, however, may have introduced their own diagnostic sequelae. Earlier editions of this volume have recommended clinical diagnoses found in books and medical museums between 1750 and 1930. We are inclined to a more conservative perspective, particularly in reference to infectious diseases. The most reliable sources, in our experience, have been clinical reports from the period following the identification of the pathogen causing the condition and prior to the development of effective interventions. In the absence of documented collections, of course, autopsies and radiographic records are seldom sufficiently complete to provide the desirable, complete skeletal record. Even those practitioners using documented collections should be careful to read all the supporting documentation to discern the degree to which the “diagnosis” was based upon clinical observations rather than posthoc skeletal observations. Again, we emphasize that, in most cases, this book should be considered a secondary source. Anyone wishing to develop a definite differential diagnosis should consult the primary literature, which engages the clinical literature. Web-based searches are important, especially in discovering primary source documents from an earlier era. Identifying a disease process in archeologically recovered human remains is only part of the process of interpreting past lives. A practitioner of paleopathology needs to appreciate concepts drawn from the social sciences

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Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

(Buikstra et al., 2017; Chapter 3: Themes in Paleopathology) and the humanities (Mitchell, 2011, 2012, 2017). Given the myriad branches of knowledge required for most studies of ancient disease, collaborations are crucial and training in professional cooperation and respect are important for paleopathologists. Among other essential considerations are ethical issues relating to patients and descendent groups (Lambert, 2012). These are an essential part of any training program and any development of a project involving peoples from the past. In closing, we will more closely examine the potential contribution of paleoepidemiology to 21st century paleopathology research.

PALEOEPIDEMIOLOGY Epidemiology and Paleoepidemiology Epidemiology is the study of the distribution of healthrelated states or events (including, but not limited to, disease) within populations and of the factors that affect them, and the application of this information in efforts to control diseases and other health problems (WHO, 2018). Paleoepidemiology is the study of population-wide patterns of human health and disease in the past, typically done using data derived from skeletal or mummified remains excavated from archeological sites or from documented skeletal collections. For many populations, skeletal data provide the only remaining evidence of health in the past, and paleoepidemiology thus provides invaluable insights into how human health has varied within and between populations or subpopulations throughout human prehistory and history. Hooton’s (1930) examination of pathology in Pecos Pueblo is often credited as the first paleoepidemiological study, providing a model for the application of quantitative analyses of paleopathological data that became more widely used in bioarcheological research beginning in the 1960s (Armelagos, 2003; Mendonc¸a de Souza et al., 2003). Since then, paleoepidemiologists have addressed such topics as the Neolithic and the second epidemiological transitions (e.g., Armelagos and Cohen, 1984; Wilson, 2014; Zuckerman, 2014), the effects of European contact on indigenous populations (e.g., Klaus and Tam, 2009; Larsen et al., 2001), and mortality patterns during and health patterns following infectious disease epidemics (e.g., DeWitte, 2018; DeWitte and Wood, 2008). Though the ultimate goal of paleoepidemiology— understanding how and why health-related states vary within a population—is shared with epidemiology, and though both fields focus on groups rather than individuals as the fundamental units of analysis, the data and analytical methods available to scholars in these fields are quite different. Epidemiologists use experimental or

observational data derived from longitudinal or crosssectional studies of living populations; however, only cross-sectional data are available to paleoepidemiologists. Because paleoepidemiologists work with samples of the dead, they cannot follow individuals over time to determine how their health-related states change in response to exposure to a particular variable. It is possible for paleoepidemiologists to examine the within-individual effects of variables over time (i.e., the life course) in a typical archeological skeletal sample by assessing later-life outcomes associated with developmental stress markers or isotopic signature of diet or mobility that form relatively early in life and can be assigned ages-at-formation. Alternatively, paleoepidemiologists can study documented skeletal collections for which they have information both about exposures early in life and later health or mortality outcomes. With respect to the former approach, there are unfortunately a limited number of developmental skeletal stress markers (e.g., enamel hypoplasia, neural canal dimensions, tooth size, cribra orbitalia, stature), and they generally suffer from low specificity. Further complicating paleoepidemiological studies is the fact that skeletal samples are typically accumulated over multiple generations, and often it is difficult or impossible to determine more precisely, within the general period of use of a cemetery, the date of death of each individual in the sample (Mendonc¸a de Souza et al., 2003). This is even further complicated by the lack of accuracy and precision associated with adult skeletal age-estimation methods (BocquetAppel and Masset, 1982; Milner and Boldsen, 2012). As a consequence of these issues, paleoepidemiologists rarely examine true cohorts of individuals (a cohort is a group of individuals who all experience a particular event at the same time; e.g., a birth cohort is a group of people who were all born at the same time) as is possible for epidemiologists. Thus, paleodemographic studies might be confounded by temporal changes in exposure variables that cannot be detected and thus which cannot be controlled for. Epidemiologists are interested in and generally capable of measuring health-related states and disease outcomes relative to a particular population at risk. That is, epidemiologists can identify not only those individuals who have the specific conditions of interest, but also those alive at the same time (and at the same age) who do not have those conditions or who do not develop them over the course of a study. Combined with good temporal control, information about the population at risk allows epidemiologists to better contextualize, among other things, the incidence and prevalence of conditions. Incidence is the number of new or newly diagnosed cases of a condition within a specified period of time, and prevalence is the actual number of individuals with the condition alive at a particular point or during a particular

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period of time. In theory, paleoepidemiologists share an interest in these phenomena with respect to past populations. However, paleoepidemiologists have much more limited information about past populations at risk, as they observe only those individuals who died and ultimately became part of excavated skeletal samples (see more about selective mortality below), not the actual onceliving populations to which they originally belonged. Paleoepidemiological reconstructions of past populations at risk, incidence, prevalence, and other measures are thus, at best, biased. Epidemiologists are also better able to identify healthrelated states or diseases of interest because they have at their disposal data collected from living people using a variety of diagnostic tools (the nature of which depends on the condition of interest), including physical examinations of living patients or decedents, health history and behavior questionnaires, immunoassays, histological analyses, and cell cultures. Diagnostic criteria or tests for identifying diseases or conditions are typically described in terms of their sensitivity and specificity. Sensitivity, which is also referred to as the true positive rate, is the proportion of people with a condition who are correctly identified by a test as having the condition, i.e., the extent to which true positives are not overlooked by the test (Boldsen, 2001; Waldron, 2007). Diagnostic tests with high sensitivity produce few false negatives, so if people test negative for the disease of interest, it is likely that they do not, in fact, have that disease. Specificity (also called the true negative rate) is the proportion of people without a condition who are correctly identified by the test as not having it (Boldsen, 2001; Waldron, 2007); i.e., specificity is the extent to which people who test positive really represent the condition of interest. Diagnostic tests with high specificity produce few false positives, so if people test positive for a condition, it is likely that they actually have the condition. Because of controlled laboratory and field experiments, it is possible to accurately assess the sensitivity and specificity of diagnostic criteria used in living populations, so epidemiologists know how confident they can be in their diagnoses and research findings based thereon. Though epidemiologists often work with data derived from tests having relatively low sensitivity and specificity, they are at an advantage in knowing something about the level of uncertainty they face in their research. Paleoepidemiologists, on the other hand, most often rely solely upon skeletal lesions or stress markers to assess health-related states, which provide relatively limited information about health and disease (compared to the data available to epidemiologists) and for which there is often limited, if any, information about sensitivity and specificity. The specificity of skeletal lesions for diagnostic purposes is limited in large part by the fact that bone

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can respond to disease and trauma in just a few general ways: bone is deposited, removed, or deformed in response to these deviations from normal physiology or structural integrity. Paleoepidemiologists are faced with the dilemma that many diseases can lead to the production of skeletal lesions that look similar, if not identical, across those etiologies. For example, Weston (2008) assessed periosteal new bone formation macroscopically and using radiographs from individuals with known metabolic, infectious, and other conditions, such as chronic osteomyelitis, fracture, syphilis, and rickets. She did not identify any location, size, shape, or form characteristics of the lesions that were specific to those conditions, which indicates that responses to diseases are determined by the nature of the affected bone and the periosteum rather than by the diseases themselves (Weston 2008: 56). Even in cases of diseases that produce pathognomonic lesions (many examples of which are provided in this volume), differential diagnosis can be severely hampered if the preservation of the relevant elements is poor. The sensitivity of skeletal lesions is limited because not everyone with conditions that have the potential to affect the skeleton will, in fact, develop skeletal lesions in response (Milner and Boldsen, 2017). For example, tuberculosis can cause the production of diagnostic bony lesions, but only approximately 3% 5% of people with untreated tuberculosis develop such lesions (Resnick and Niwayama, 1995). This low proportion means that many people with tuberculosis in skeletal samples will not be diagnosed based on skeletal pathology alone. As has been discussed elsewhere (see, e.g., Mays, 2018; Zuckerman et al., 2016), few paleoepidemiological studies have estimated the sensitivity and specificity of skeletal lesions. For example, Smith-Guzma´n (2015) assessed the sensitivity and specificity of a suite of skeletal lesions with respect to malaria-associated anemia using clinical samples of individuals with known cause of death or malaria exposure. Boldsen (2001) estimated the sensitivity and specificity of skeletal indicators of leprosy based, in part, on samples drawn from medieval cemeteries associated with lepers’ hospitals. Konigsberg and Frankenberg (2013) illustrate the general approach to estimation using a hypothetical example. Often, however, paleoepidemiologists face an unquantified level of uncertainty regarding how many false negatives and false positives with respect to a particular condition exist within their samples. As emphasized in Chapter 8, it is increasingly possible to use ancient biomolecular approaches to identify diseases such as bubonic plague, tuberculosis, leprosy, malaria, hepatitis, and enteric fever (Salmonella) in skeletal or mummified tissue samples (Bos et al., 2011, 2014, 2016; Donoghue et al., 2015; Marciniak et al., 2016; Patterson Ross et al., 2018; Va˚gene et al., 2018).

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Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

However, these approaches are not without their own problems; e.g., they are expensive (prohibitively so for many scholars) and destructive, and it can be difficult to interpret negative findings given the myriad factors that interfere with DNA and other biomolecule preservation, extraction, or amplification. As a result, ancient biomolecule studies tend to yield small sample sizes of individuals who test positive for the pathogens of interest, and thus, to date, few paleoepidemiological studies have been based solely on ancient bimolecular data. Despite the issues associated with identifying specific conditions in skeletal samples, paleoepidemiological studies have examined a variety of specific infectious, metabolic, and degenerative conditions in past populations, including leprosy (Boldsen, 2001), syphilis (Harper et al., 2011), tuberculosis (Buikstra, 1999), vitamin D deficiency (Snoddy et al., 2016), developmental dysplasia (Blatt, 2015), and degenerative joint disease (Klaus et al., 2009). The existence of documented historical plague burials has also facilitated paleoepidemiological studies of bubonic plague in the absence of diagnostic skeletal pathology (DeWitte and Wood, 2008; Kacki, 2017). By choice or necessity, however, rather than attempt to diagnose specific etiologies, many paleoepidemiologists use skeletal lesions as general (i.e., nonspecific) indicators of exposure to physiological stress or developmental disturbance. Thus, many paleoepidemiological studies focus on the general health of populations using nonspecific indicators rather than attempt to assess health in the context of specific diseases. This approach skirts some of the issues associated with low sensitivity and specificity, but still must contend with the fundamental issue that skeletal samples are inherently biased and that the presence or absence of lesions can be difficult to interpret (as framed by the osteological paradox, described below).

The Relationship Between Paleoepidemiology and Paleopathology With its focus on skeletal pathology, paleoepidemiology is clearly aligned with its sister discipline, paleopathology. Both fields focus on health, disease, or well-being in the past, and both make use of the same skeletal pathologies and stress markers (and thus both ultimately grapple with the same limitations associated with these data). However, paleopathology is primarily concerned with the differential diagnosis of pathologies in individual skeletons, establishing the antiquity of specific diseases, or documenting the presence of particular conditions in past populations via case studies of one or a few individuals (Boldsen and Milner, 2012). Paleoepidemiology, as detailed above, focuses on populations as the unit of analysis, and though some practitioners might not entirely

agree with Goodman’s (1993: 282) claim that “paleoepidemiologists are rarely interested in individuals,” it is certainly true that from an analytical and interpretive perspective, individuals are of interest because they contribute to the observed aggregate patterns (Milner and Boldsen, 2017). Because of these different scales of focus, paleopathology and paleoepidemiology typically use different analytical approaches. Paleopathology tends to be more descriptive, whereas paleoepidemiology applies quantitative analyses to a greater extent (indeed, quantitative analyses are impossible to apply to paleopathological case studies involving isolated individuals). Like epidemiology, paleoepidemiology is inherently comparative; in order to interpret the broader implications of the presence of pathologies, rates of pathological lesions are compared in paleoepidemiological studies between groups, such as male versus female, urban versus rural, or high status versus low status. Paleopathology, however, can be successfully done without the application of a comparative framework. Milner and Boldsen (2017) emphasize the unique paleoepidemiological focus on estimating the risks of death associated with skeletal pathologies. Their definition of paleoepidemiology is inherently demographic. Informative paleopathological research does not necessarily require information beyond the presence (or absence) of pathology, and thus paleopathology can be done independently of demographic data.

Paleoepidemiology and the Osteological Paradox The focus on population-level health and disease dynamics in paleoepidemiology provides scholars in the field the opportunity to actively engage with and attempt to resolve some of the issues associated with the osteological paradox, which was described over 25 years ago by Wood et al. (1992). The osteological paradox centers around two important phenomena: heterogeneous frailty and selective mortality. Frailty, in this context, refers to the age-standardized relative risk of death (Vaupel et al., 1979). Variation in frailty (i.e., heterogeneous frailty) exists in populations because of a variety of factors, such as differences in immune competence (associated with nutritional status, genetic variation in regions of the genome associated with immunity or disease susceptibility, the effect of sex hormones, etc.), differences in risktaking behavior (e.g., smoking or heavy drinking) or exposure to occupational hazards, or variation in exposure to disease vectors or environmental pollution. Wood et al. emphasized the potential for “hidden” heterogeneity in frailty to complicate reconstructions of health from skeletal samples. Epidemiologists, because they have access to

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observational, interview, and clinical data from living people, can potentially identify and control for numerous factors known or suspected to influence frailty. However, even in living populations, not all sources of variation in frailty are known and thus controlled for in studies of population health. This problem of hidden heterogeneity is exacerbated when we rely on biased samples of the dead for whom behavioral and clinical information is nearly or (more often) totally nonexistent. Without the ability to control for many potential sources of variation in frailty in skeletal samples, we cannot be certain that the aggregate patterns we observe in these samples accurately represent the health or disease experiences of all of the subgroups that comprise the larger sample. Heterogeneous frailty strongly influences the composition of the skeletal samples. With respect to many causes of death, mortality does not behave indiscriminately, killing all individuals at each particular age at the same rate. Instead, mortality is often selective: disproportionately affecting individuals with the highest frailty at each particular age. It is these individuals, with the highest frailty, who are most likely to become part of the skeletal samples that are eventually available to paleoepidemiologists. This phenomenon makes it difficult, if not impossible, to estimate the prevalence of conditions in once-living populations based on the observed frequencies of associated pathologies in a skeletal sample, particularly if those conditions are associated with elevated risks of mortality. Using this approach would tend to result in the overestimation of the prevalence of the causative conditions. Because of the potential effects of heterogeneous frailty and selective mortality, Wood et al. urge caution in the interpretation of health from observations of skeletal pathologies or stress markers, particularly avoiding the conventional assumption that the presence of skeletal pathologies is an indicator of poor health and a lack thereof reflects good health. As had previously been addressed by Angel (1975), Ortner (1991,1992), and Harpending (1990), Wood et al. discussed the relationship between skeletal lesion formation and survivorship. Specifically, they raise the possibility that because skeletal pathologies take time to form, they might, at least in some cases, indicate relatively good health rather than high frailty. That is, the presence of a skeletal pathology reflects survival, at least temporarily, with or beyond the causative condition. The absence of pathology might indicate relatively poor health if individuals without skeletal lesions succumbed to illness, trauma, or malnutrition and died before the lesions could form. Wood et al. (1992) do not argue that stress markers are necessarily or even typically reflective of good health; instead they urge scholars to consider multiple, equally plausible, interpretations rather than uncritically hewing to conventional interpretations that might not be appropriate.

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One way to address these fundamental difficulties is to leverage aggregate demographic data to assess the effects of skeletal pathologies (Milner and Boldsen, 2017). Rather than making assumptions about how pathologies reflect health, paleoepidemiologists can establish whether (in a particular context) a positive association exists at the population level between a skeletal pathology and risk of death (or a negative association exists between the pathology and survival). Such an association would support interpretations of the pathology as an indicator of poor health. This approach reduces uncertainty about what skeletal pathologies indicate about health at the population level, but we must still be cautious about the inferences we make for individuals in the sample. Estimation of survivorship or the risk of death associated with pathologies is only possible using paleoepidemiological data; it cannot be done using isolated individuals. This approach requires a comparative approach and access to information about the demographic outcomes for people with and without pathologies. With structured aggregate data, paleoepidemiologists are also in a position to directly assess heterogeneous frailty, as least with respect to those factors that are detectable in the skeleton or burial context, such as age, sex, social status, or nutritional status. Being able to compare mortality outcomes across these and similar categories does not entirely alleviate the problem of hidden heterogeneity in frailty, but at the very least, paleoepidemiologists can, with large enough samples, control for some sources of heterogeneity that might otherwise confound reconstructions of population health. Examples of paleoepidemiological research that have addressed the osteological paradox include Boldsen’s (2005) study of the association of skeletal indicators of leprosy and risk of mortality in medieval Denmark; Wilson’s (2010, 2014) assessment of the health and demographic effects of the intensification of maize agriculture, the adoption of Mississippian lifeways, and increased interpersonal violence and warfare in Illinois; and DeWitte and colleagues’ evaluation of selective morality during the medieval Black Death in London (DeWitte and Hughes-Morey, 2012; DeWitte and Wood, 2008).

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Mendonc¸a de Souza, S.M.F., Carvalho, D.Md, Lessa, A., 2003. Paleoepidemiology: is there a case to answer? Mem. Inst. Oswaldo Cruz 98, 21 27. Milner, G.R., Boldsen, J.L., 2012. Transition analysis: a validation study with known-age modern American skeletons. Am. J. Phys. Anthropol. 148, 98 110. Milner, G.R., Boldsen, J.L., 2017. Life not death: epidemiology from skeletons. Int. J. Paleopathol. 17, 26 39. Mitchell, P.D., 2011. Retrospective diagnosis and the use of historical texts for investigating disease in the past. Int. J. Paleopathol. 1, 81 88. Mitchell, P.D., 2012. Integrating historical sources with paleopathology. In: Grauer, A.L. (Ed.), A Companion to Paleopathology. WileyBlackwell, Chichester, West Sussex, UK, pp. 310 323. Mitchell, P.D. 2017. Improving the use of historical written sources in paleopathology. In Rigor in Paleopathology: Perspectives from across the Discipline, J. E. Buikstra, ed., International Journal of Paleopathology 19, 88 95. Moodie, R., 1923. Paleopathology: An Introduction to the Study of Ancient Evidences of Disease. University of Illinois Press, Urbana. Morse, D., 1969. Ancient disease in the Midwest. Springfield, Illinois State Museum Reports of Investigations, No. 15. Ortner, D.J., 1991. Theoretical and methodological issues in paleopathology. In: Ortner, D.J., Aufderheide, A.C. (Eds.), Human Paleopathology: Current Syntheses and Future Options. Smithsonian Institution Press, Washington, DC, pp. 5 11. Ortner, D.J., 1992. Skeletal paleopathology: probabilities, possibilities, and impossibilities. In: Verano, J.W., Ubelaker, D.H. (Eds.), Disease and Demography in the Americas. Smithsonian Institution Press, Washington, DC, pp. 5 13. Ortner, D.J., 2003. Identification of pathological conditions in human skeletal remains. Academic Press, San Diego, CA. Ortner, D.J., Aufderheide, A. (Eds.), 1991. Human Paleopathology: Current Syntheses and Future Options. Smithsonian Institution Press, Washington, D. C. Ortner, D.J., Putschar, W.G.J., 1981. 1985 Identification of pathological conditions in human skeletal remains. Smithsonian Institution Press. Pales, L., 1930. Paleopathologie et Pathologie Comparative. Masson et Cie, Paris. Patterson Ross, Z., Klunk, J., Fornaciari, G., Giuffra, V., Ducheˆne, S., Duggan, A.T., et al., 2018. The paradox of HBV evolution as revealed from a 16th century mummy. PLoS Pathog. 14, e1006750. Ragsdale, B.D., Madewell, J.E., Sweet, D.E., 1981. Radiologic and Pathologic Analysis of Solitary Bone Lesions, Part II: Periosteal Reactions. Radiologic Clinics of North America 19, 749 783. Resnick, D., Niwayama, G., 1995. Osteomyelitis, septic arthritis, and soft tissue infection: organisms. In: Resnick, D. (Ed.), Diagnosis of Bone and Joint Disorders, third ed. W. B. Saunders, Edinburgh, pp. 2467 2474. Ruffer, M., 1910. Remarks on the histology and pathological anatomy of Egyptian mummies. Cairo Sci. J. 1 5. Shufeldt, R.W., 1892. Notes on paleopathology. Popular Science Monthly 42, 679 684. Smith-Guzma´n, N.E., 2015. The skeletal manifestation of malaria: an epidemiological approach using documented skeletal collections. Am. J. Phys. Anthropol. 158, 624 635. Snoddy, A.M.E., Buckley, H.R., Halcrow, S.E., 2016. More than metabolic: considering the broader paleoepidemiological impact of vitamin d deficiency in bioarchaeology. Am. J. Phys. Anthropol. 160, 183 196.

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Steinbock, R., 1976. Paleopathological Diagnosis and Interpretation. Charles C. Thomas, Springfield, IL. Ubelaker, D.H., 1982. The Development of Human Paleopathology. In: Spencer, F. (Ed.), A History of American Physical Anthropology 1930-1980. Academic Press, New York, pp. 337 356. ˚ .J., Herbig, A., Campana, M.G., Robles Garcı´a, N.M., Va˚gene, A Warinner, C., Sabin, S., et al., 2018. Salmonella enterica genomes from victims of a major sixteenth-century epidemic in Mexico. Nat. Ecol. Evol. 2, 520 528. Vaupel, J.W., Manton, K.G., Stallard, E., 1979. The impact of heterogeneity in individual frailty on the dynamics of mortality. Demography 16, 439 454. Virchow, R., 1898. Knochen aus Alten Gra¨bern von Tennessee. Verhandlungen der Berliner Gesellschaft fu¨r Anthropologie 30, 342 344. Waldron, T., 2007. Paleoepidemiology: The Measure of Disease in the Human Past. Left Coast Press Inc, Walnut Creek, CA. Warren, J., 1822. A Comparative View of the Sensorial and Nervous Systems in Man and Animals. Ingraham, Boston. Wells, C., 1964. Bones, Bodies and Disease. Thames and Hudson, London. Weston, D.A., 2008. Investigating the specificity of periosteal reactions in pathology museum specimens. Am. J. Phys. Anthropol. 137, 48 59. Weston, D.A., 2012. Nonspecific Infection in Paleopathology: Interpreting Periosteal Reactions. In: Grauer, A.L. (Ed.), A Companion to Paleopathology. Wiley-Blackwell, Chichester, West Sussex, UK, pp. 492 512. Williams, H.U., 1929. Human paleopathology, with some original observations on symmetrical osteoporosis of the skull. Arch. Pathol. 7, 839 902. Wilson, J.J., 2010. Modeling Life Through Death in Late Prehistoric West-Central Illinois: An Assessment of Paleodemographic and Paleoepidemiological Variability [PhD]. Binghamton University, SUNY, Binghamton, NY. Wilson, J.J., 2014. Paradox and promise: Research on the role of recent advances in paleodemography and paleoepidemiology to the study of “health” in Precolumbian societies. Am. J. Phys. Anthropol. 155, 268 280. Wood-Jones, F., 1908. The pathological report. Archaeological Survey of Nubia Bulletin 2, 55 69. Wood-Jones, F., 1910. Anatomical variations, and the determination of the age and sex of skeletons. In: Elliot-Smith, G., Wood-Jones, F. (Eds.), The Archaeological Survey of Nubia Report for 1907 1908, Vol II: Report on the Human Remains. National Printing Department, Cairo, pp. 221 262. Wood, J.W., Milner, G.R., Harpending, H.C., Weiss, K.M., 1992. The osteological paradox: Problems of inferring prehistoric health from skeletal samples. Curr. Anthropol. 33, 343 370. World Health Organization, 2018. Health Topics: Epidemiology. ,http://www.who.int/topics/epidemiology/en/. (accessed 15.01.18.). Zuckerman, M.K., 2014. Modern Environments and Human Health: Revisiting the Second Epidemiological Transition. Wiley-Blackwell, Hoboken, NJ. Zuckerman, M.K., Harper, K.N., Armelagos, G.J., 2016. Adapt or die: three case studies in which the failure to adopt advances from other fields has compromised paleopathology. Int. J. Osteoarchaeol. 26, 375 383.

Chapter 3

Themes in Paleopathology Anne L. Grauer1 and Jane E. Buikstra2 1

Loyola University Chicago, Chicago, IL, United States, 2Arizona State University, Phoenix, AZ, United States

The identification and diagnosis of pathological conditions in human skeletal remains is a key component of paleopathology. As discussed in Chapters 1 and 5, detailed descriptions of lesions and the application of differential diagnoses have allowed researchers to more closely align skeletal lesions with the clinical manifestations of disease. A number of themes emanate from interpretations of pathological lesions, which extend beyond diagnosis. In Chapter 1, we discussed the need for paleopathologists to appreciate perspectives and theories drawn from the social sciences and humanities. Especially important are cautions about attributing social status based exclusively on counts of grave wealth without consideration of broader contextual issues. This approach became popular, especially in American archeology, during the 1960s with the work of Louis Binford, Arthur Saxe, and James Brown. Binford (1971), working within a cross-cultural processual paradigm (see also Carr, 1995) and using subsistence as a proxy for social complexity, argued that dimensions of mortuary behavior correlated predictably with social status. Arthur Saxe’s (1970) unpublished dissertation also interrogated the funereal ethnographic record cross-culturally. His “Hypothesis 8,” which explores the relationship between the presence of formal cemeteries and resource ownership has been expanded and applied by researchers, including Charles and Buikstra (1983), Goldstein (1980), and Morris (1991). During the 1980s, a “postprocessual” rebuttal of processual archeology, including mortuary studies (Hodder, 1982, 1984), led to diminished visibility for funerary archeology (Rakita and Buikstra, 2005), in spite of its important role in paleopathological analyses. Despite cautionary tales, some researchers continue to equate the quality and quantity of grave goods with levels of social status, and tie these closely to the presence of pathological conditions, often without considering other contextual factors (Grauer, 2019). However, research such as that conducted on the Andean Chiribaya peoples of Peru (AD 800 1350), serves as a great example of the importance of nuanced interpretations of funerary

behavior. Here, we find elaborate subsurface tombs with metals, feathers, and other material culture in sites such as Chiribaya Alta (Buikstra, 1995). Contemporary inland Chiribaya sites at higher elevations, such as Yaral (1000 m above sea level), present far less elaborate tombs with small numbers of ceramics and other vessels. Before beginning to assume greater economic wealth (and thus, status) among coastal Chiribaya, however, we need to appreciate the presence of elaborate public buildings at Yaral, where public rituals likely took place. Rather than Yaral graves serving as symbols of wealth or status, perhaps the grand public spaces are where social differences were displayed. Hence, we must avoid embracing counts of material items within tombs as reflecting the status of the dead. As with the dedicatory offerings to the Maya woman in the “Margarita” tomb at Copa´n, grave accompaniments may reflect pilgrimages of mourners, who—in this case—elevated and probably changed the status of the decedent from a biological to a primordial progenitor of the Copa´n royal dynasty during the Classic period (BAD 400 800). Clearly, the interpretation of social status requires careful and nuanced interpretations of archeological and historical contexts. Social status is only one aspect of human identity that impacts and informs paleopathological analysis. Gender, age, religion, ethnicity, and disability, inferred from bioarcheological data, also play important roles in paleopathological research (Grauer, 2018). In the following sections we discuss social attributes increasingly synthesized with paleopathological research: sex, gender, and age; and discuss research into structural violence, disability, and care, and the role of individual and populational studies within paleopathology.

SOCIAL AND IDENTITY THEORY For paleopathologists and bioarcheologists, bones serve as the nexus of interpretation, as pathological, biomechanical, and physiological factors acting upon and within the

Ortner’s Identification of Pathological Conditions in Human Skeletal Remains. DOI: https://doi.org/10.1016/B978-0-12-809738-0.00003-X © 2019 Elsevier Inc. All rights reserved.

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individual are evaluated alongside psychological and social responses. Whether viewed within the fields of sociology, psychology, or anthropology, identity studies share a common goal: to explore and understand intersectionality between an individual and larger social spheres.

Feminist and Gender Theory A key dimension in the integration of social and identity theory in paleopathological and bioarcheological research is the influence of feminist and gender theory on skeletal analysis (Grauer, 2018). Similar to the effects of processual and postprocessual paradigms (discussed earlier), which profoundly influenced the interpretation of skeletal remains, feminist and gender theories have evoked changes to the definitions and the operationalization of our concepts of sex and gender. Feminist theory is argued to have developed in three waves. The first wave, stemming from entrenched political and economic inequities of the 19th and early 20th centuries that denied women the right to vote, sought to fight for basic rights (Sanders, 2006; Sharlach, 2009). Its influence on skeletal analyses would be felt decades later as women such as Mildred Trotter, Lucille St. Hoyme, and Alice Brues, became pioneers in the growing field of physical anthropology (Buikstra and Roberts, 2012). The second wave of the feminist movement focused on social empowerment (Baxandall and Gordon, 2005). Concepts of sex (based on biological determinants) and gender (argued to be the social role adopted by an individual based on sex) were disentangled as a means to draw attention to and end repression. This perspective deeply influenced skeletal analyses, as it established binary definitions of sex and gender: i.e., that there are two discrete biological sexes that can be identified skeletally, and based on ascribed sex, there are two polemical social roles (one masculine, one feminine) that become socially enacted. Investigation into skeletal manifestations of sexual dimorphism bolstered this perspective. As osteologists isolated key anatomical features, such as the sciatic notch and subpubic angle, which qualitatively differed in adults, and developed quantifiable measures of variance to test predictability, the perceived chasm between female and male widened. Paleopathological studies increasingly mapped the presence of lesions onto female and male skeletons. As a careful control, skeletons in too poor condition for adequate evaluation, or morphologically falling into the “undeterminate,” category, were often excluded from analyses as a means to clearly discern patterns of disease by sex. This approach proved productive. Cribra orbitalia and porotic hyperostosis, for instance, often associated with

the presence of iron-deficiency anemia (Stuart-Macadam, 1987), were predicted and found to be common in female skeletons. The cause, it was asserted, was females’ fluctuating physiological need for iron due to pregnancy, lactation, and menstruation (e.g., Cybulski, 1977; Webb, 1984). Social roles of females were also argued to contribute to sex-demarcated patterns of skeletal lesions. Biological differences between females and males were expected to be exacerbated by an assumed ubiquitous gender hierarchy, whereby males held power and maintained access to resources (Cohen and Bennett, 1993), leaving females vulnerable to fluctuating access to nutrition. Blood loss, alongside disruption to dietary iron acquisition and absorption, would therefore contribute to higher rates of iron-deficiency anemia in females. The entangled effects of sex and gender have also been explored using nonspecific indicators of stress, such as enamel hypoplasias. The presence of childhood growth disruption, mapped onto sex in adult skeletons, might infer differential treatment of children based on sex, but varying rates of enamel hypoplasias have alternatively been used to explore the axiom of male biological vulnerability (Stinson, 1985) The argument here is that females, due to demands of pregnancy and lactation, have evolutionarily been selected to physiologically buffer the effects of fluctuating environments, rendering males, in comparison, more vulnerable. Tackling this precept headon, Guatelli-Steinberg and Lukacs (1999), in their metaanalysis of human and nonhuman primates conclude that “in most studies, sex differences in EH prevalence are statistically nonsignificant. However, when sex differences are significant, there is a slight trend for them to be greater in males than in females, suggesting a weak influence of greater male vulnerability. Cultural practices of sex-biased investment in children appear to have greater impact on EH expression than does male vulnerability/ female buffering” (Guatelli-Steinberg and Lukacs, 1999: 73). Innate differences between females and males, and their consequences for the paleopathological record, played a prominent role in Ortner’s second edition of this volume (2003: 114 118). Focus was placed on skeletal indicators of infectious disease and human immune reactivity. Ortner asserted that bearing children posed an undeniable biological risk for women that was exacerbated by the effects of agriculture: i.e., sedentism and its concomitant increase in infection. Culturally determined differential access to food, especially during times of famine, placed women in a particularly precarious position. What were the skeletal outcomes of these conditions? Ortner’s model predicting paleopathological ramifications of differing male and female immune reactivity tackled

Themes in Paleopathology Chapter | 3

these issues of sex, gender, and the skeletal record. Ortner (2003: 115 116) contended that:

Frequency

1. “If all factors were equal,” meaning that social and/or environment variables influencing health were the same for women and men, then “women might be expected to survive to the chronic stage of infectious disease more often than men.” 2. “Given the known sex difference in immune reactivity, the male and female subsamples of the population might be arranged as two partially superimposed, normal distributions (Fig. 3.1). The mean (X1) of the male subsample would be positioned more toward the poor end of the scale than the female mean (X2).” 3. “An additional variable is the hypothetical range on the immune response scale where skeletal involvement occurs. At the poor end of the scale we may designate as R1 the point below which skeletal involvement does not occur and death is the typical event with R2 as the point on the other end of the scale beyond which skeletal manifestations do not occur because of complete recovery from infectious disease.” 4. “If, for the moment, we assume that all other variables (most particularly, exposure to infectious agents) that affect the expression of infectious disease in the human skeleton are constant and the distribution approximates normality, it is apparent that the position and range of X1 and X2 and R2 on the scale will affect the sex ratios for the prevalence of infectious disease in the skeletal sample.” 5. When modern clinical male/female ratios in various infectious diseases are evaluated, “they do tend to cluster and consistently show greater male morbidity for infection.” When the prevalence of periostitis is

R1

Poor

X1

R2X2

Immune response

Good

FIGURE 3.1 Graph showing hypothetical male and female distributions on an immune response scale from poor to good. X 1 designates the mean of the male distribution and X 2 the mean of the female distribution. R1 is a theoretical point below which skeletal manifestations of disease do not occur and death is a typical event. R2 is the point on the other end of the scale where no skeletal disease occurs because of complete recovery from infectious disease. R1 and R2 are positioned to create a male/female ratio of approximately 3:1, similar to what one finds in the clinical ratio of infectious disease.

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examined within archeological populations, males frequently display higher rates of morbidity compared to women (p. 116). Ortner’s model crystallized the perceived dichotomy between biological sex and socially established notions of gender. His conclusions, however, extend beyond sex- or gender-based determinism. For instance, he asserted that, “males have higher morbidity than females. One question is whether this is simply the result of greater exposure to infectious agents among males or a more effective immune response among females. In some infectious diseases, such as mycotic infection, a case can be made for greater exposure to infectious agents by males in at least some agricultural societies. However, in at least some cultural contexts and in some age ranges, males and females seem to have equal exposure to infectious agents but males seem more vulnerable to disease” (p. 116). Hence, while Ortner implies that sex and gender can be independently isolated, he does not depend on codified gender roles based on sex to explain differential morbidity. He recognizes social complexity and its impact on disease. So perhaps the perceived complexity of social roles, along with definitions and applications of our concepts of “sex” and “gender” need revision. Enter third-wave feminist, gender, and queer theory. These paradigms focus on dispelling heteronormative assumptions, and often refocus attention onto experiences of the individual. The paradigms assert that biological sex is not inextricably linked to an immutable gender role, and gender roles are neither binary nor absolute. For instance, Sofaer argues that “collapsing sex and gender renders associations between bodies and objects unproblematic. . .” (Sofaer, 2006: 101) and that “in practice the classification of gender often tends to assume that gender is stable thereby precluding the fluidity that is a particularly useful element of the concept and that is inherent in understanding it as culturally dependent. . .” (Sofaer, 2006: 100). Gender, it is asserted, is an element of identity, and is malleable and continually negotiated throughout the life course of the individual. Adding to an even greater complexity, gender identity is simultaneously personal and social. An individual’s emic gender identity (an internalized identity) is shaped and may differ from their etic identity (attitudes, views, or interpretations of the individual made by others). Paleopathological research is impacted by these paradigmatic shifts, with studies of skeletal trauma leading the change due to the perceived direct role that behavior plays in its etiology. Although interpersonal aggression, violence, and warfare have long been viewed as direct manifestations of gendered behavior (Holliman, 2011), the promise of the new theoretical direction lies in the reinterpretation of the causes and cultural meaning of traumatic lesions. Notable contributions include Knu¨sel

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(2011), whose rigorous archeological contextual analysis of British medieval warfare and differential diagnosis of humeral medial epicondylar avulsion fractures is accompanied by careful exploration of the construction and effects of masculinity from childhood to adulthood. Work by Bengtson and O’Gorman (2017) warns us against adopting the deterministic view of sex and gender roles, as warfare need not be limited to men and inextricably tied to masculinity. Their analysis of mortuary data, subsistence, and skeletal data from prehistoric sites in the Central Illinois River Valley suggests that “Morton Village women may have regularly and actively participated in violent encounters as part of their engagement with the broader socio-politics of the region without being formally celebrated as warriors in their mortuary disposition” (Bengtson and O’Gorman, 2017). The constructed dichotomy between victim and assailant is also being reevaluated in light of feminist and gender theory. Tung (2014), in her analysis of gender-based violence against women during Wari imperial rule (AD 600 1100) and post-Wari rule (AD 1100 1400) of southern Peru, argues that “a temporal view of the frequency and patterning of violence among males and females may illuminate how social norms related to violence may have changed from one cultural era to the next, if they changed at all. In particular, a bioarchaeological study that considers the role of gender in when and how violence is enacted can further clarify how one’s sex structured the likelihood that one might become a victim of violence and whether or not the violence would be deadly” (Tung, 2014: 335). Martin et al. (2010) and Harrod and Martin (2014) operationalize this approach by closely examining the types and patterns of traumatic injury in ancestral Pueblo skeletal remains from La Plata (AD 850 1150) and integrating their data with a carefully constructed model that reflects proposed social, economic, environmental, demographic, and archeological manifestations of human subordination and captivity. They, like a growing number of paleopathologists and bioarcheologists, are leading the way toward the development of nuanced and highly contextual interpretations of engendered violence and aggression (see discussion of structural violence below). New feminist and gender paradigms also impact research into the paleopathology of infectious disease. As emphasized by Zuckerman and Crandall (unpublished manuscript), “stigmatized and morally-loaded diseases, including syphilis and leprosy (Hansen’s Disease), present profound opportunities for detecting the play of sex, gender, and sexuality in the spaces between biological, historical, and archaeological data,” and “in some instances, using a biocultural approach and embedding skeletal data into a highly specific archaeological and historical interpretive framework can reveal inconsistencies that generate novel, otherwise inaccessible insights into the effects of

past ideologies into the lived experiences of disease, sex, gender, and sexuality.” In DeWitte and Stojanowski’s (2015) evaluation of the impact and reaction within paleopathology to the osteological paradox (Wood et al., 1992), they argue that “frailty—and its causes and consequences—is actually one of the more intriguing topics in the health sciences today, one to which researchers across a number of domains contribute. Furthermore, understanding the nature of human frailty and how it relates to social inequality and social complexity is a highly relevant topic that crosscuts disciplinary boundaries” (DeWitte and Stojanowski, 2015: 428). Applying this dictate, Yaussy et al. (2016) examine the effects of famine and its influence on frailty using attritional and famine burials denoted in the medieval cemetery of St. Mary Spital in London. They conclude that “the significant association between sex and periosteal lesions suggests that some aspects of life were different for the two sexes, resulting in different exposures to traumas, infections, or other stressors” (Yaussy et al., 2016: 279). Moving beyond the common binary construction of sex and gender, they warn that confounding factors must be taken into account. These include socioeconomic and genderbased decisions of medieval men and women to migrate to urban centers, which influences the sex ratios of skeletal populations and statistical decisions made by researchers which render the detection of sex differences in mortality across the human life span impossible.

The Intersectionality of Sex, Gender, and Age When the biological and social ramifications of sex and gender are examined, the inextricable variable of age becomes evident. Most recently, this recognition has been manifested in the development of a life course approach in paleopathology (see Gilchrist, 2000; Gowland and Knusel, 2006). Since, as Sofaer (2011) asserts, humans embody both a chronological and socially defined age, the life course approach seeks to address the intersectionality of sex, gender, multidimensionally defined age, and health and disease. Focusing on childhood, for instance, has allowed researchers interested in human disease to appreciate the complex interactions between childhood biological development and children’s dynamic social spaces and roles (see Halcrow and Tayles, 2008, 2011; Perry, 2008; Lewis, 2007; Mays et al., 2017; Gowland and Penny-Mason, 2018). Penny-Mason and Gowland (2014: 185), for instance, in their assessment of over 4600 British medieval skeletons determined to be less than 16 years old at time of death, find that “those aged 6 11 years exhibited similar levels of disease and trauma to 0 5 year olds, suggesting that although children were

Themes in Paleopathology Chapter | 3

developing into adult roles, the majority were likely to have experienced an extended period of childhood roles into puberty.” Conversely, Barrett and Blakey (2011) find that childhood mortality rates were high for enslaved Africans buried in the 18th century New York African Burial Ground and that in 1731, an 11-year-old enslaved African was categorized as an “adult,” thereby profoundly affecting children’s exposure to trauma and pathogens. Adopting a life course approach has also been influential in the exploration of the relationships between age, sex, gender, and disease in adults. Grauer et al. (1999) for instance, noted in their inquiry into the interplay between sex, gender, and the detectable presence of disease in skeletons from the 19th-century Dunning Poorhouse Cemetery, that no statistical differences appeared between adult females and males in the frequencies of lesions such as porotic hyperostosis, periosteal reaction, enamel hypoplasias, and fractures. However, when lesions were mapped onto age at death, and social history was carefully interwoven, different results emerged. “Young women, it appears, were not entering and dying in the poorhouse with a legacy of childhood anemia, bouts of infections, evidence of enduring severe nonspecific stress, and poor dental health. More likely, they were dying of acute conditions contracted shortly before their deaths. Their presence in the cemetery sample suggests that poor health and difficult childhoods did not bring them to the facility, and that regardless of reasonable health upon entering, their prolonged (if not eternal) residency put their lives in jeopardy” (Grauer et al., 1999: 161). As Agarwal asserts, “it must be understood that sociocultural influences on the body are not layered on top of the primary influences of sex and age; rather, they mold and determine the sex- and age-related trajectory of bone health. Although this makes the analysis of skeletal variation in bone maintenance and loss harder to complete, it widens the potential to visualize skeletons and bodies that are the result of developmental processes that have acted at the level of the individual, generations, or entire communities. This has great relevance for how bioarchaeologists observe variation in not only bone maintenance but also all aspects of bone morphology, as well as how we reconstruct age and gendered identity in the past” (Agarwal, 2012: 331). Skeletal studies evaluating disease frequency or lesion susceptibility based on sex appear to rely on two competing premises: human females are more susceptible to some diseases such as hematopoietic disorders and generalized bone loss due to reproductive demands (pregnancy, lactation, menstruation) and fluctuating hormone levels, while simultaneously being more “naturally” resistant to infectious diseases due to greater immune responsivity. Key variables, however, are often overlooked: changing social and biological effects of the life course and negotiated gender identity. Recent work seeks to tackle these inextricable associations. Agarwal and Beauchesne (2011)

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and Agarwal (2016), for instance, examine the plasticity of bone development and maintenance using variables such as body build, diet and activity, production of sex hormones, and hereditary factors, and overlay them onto the human life course: fetal life, childhood and adolescence, young adulthood, and middle-older adulthood. Qualitative and quantitative aspects of vertebral trabecular bone microstructure were assessed from a British rural medieval skeletal population and from two urban medieval sites dated from approximately the 11th 16th centuries. Young women in rural environments, where higher parity appears to occur, display greater bone loss during reproductive years. Nevertheless, this does not appear to impact long-term bone maintenance, perhaps due to the physical demands of rural life, as witnessed by similar bone density in older males and females. Hence, the complexities of age, biology, sex, social and gender roles, and environment, force us to recognize that skeletally determined sex cannot alone predict health outcomes. To further confound us, current gender theories suggest that inadvertent effects of second-wave feminist theory, which emphasized differences between women and men and led skeletal analysts to hone their ability to accurately differentiate female and male skeletons, actually limited our understanding of health and disease in the past. Agarwal argues that “if gender is dynamic over the life course, the reading of gendered patterns of bone loss in past populations will inevitably be obscured by a static mapping of gender to biological sex in skeletal analysis” (Agarwal, 2012: 323). Can skeletons that fall between our discrete sex categories provide us with information about the past? The Developmental Origins of Health and Disease Hypothesis (DOHaD), which focuses on phenotypic plasticity would have us saying, “Yes!” Built upon Barker’s work (2002), which examined the influences of fetal development and prenatal conditions on postnatal health and disease, the DOHaD forces us to reevaluate the biological and social precursors to sexual dimorphism. Morphological differences between female and male skeletons may be influenced by many developmental and epigenetic factors. Removing from analysis adult skeletons that emerge in-between morphological expectations of female/male differences denies us the opportunity to explore roles that fetal, childhood, and adolescent life experiences may play upon the later life course (Armelagos et al., 2009; Watts, 2013). Kirkpatrick (2000) and Hollimon (2006, 2011) show us that there are numerous ethnographic examples of social groups that include labile third or fourth genders which are navigated, negotiated, and performed throughout the life course. Hence, adult skeletons whose sex cannot be morphologically determined, and individuals whose social roles are not heteronormative, are essential contributors to our understanding of health and disease in the past.

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Indeed, Ortner’s (2003) ground-breaking model predicting paleopathological ramifications of differing male and female immune reactivity can serve as a foundation for new research informed by current feminist and gender paradigms. Predicted disparities between female and male immune reactivity can be tested. Do, for instance, skeletons with well-delineated sexual dimorphic features comply with the expected immune responses? If so, does this mean that ascribed biological sex is the cause of the correlation? Might social, environmental, genetic, and developmental variables play key roles or even obscure variation from the prediction? Do individuals falling toward the center of the morphological spectrum between female and male display similar patterns of periosteal reaction? Might social, environmental, genetic, and developmental variables be key in interpreting these results? How might interpretations of immune responses be influenced by life course analyses? How might detailed and highly contextualized understandings of human interactions and experiences influence our interpretation of the skeletal record? Clinical data indicate that immune responses vary greatly over the human life span and in reaction to the life course (Boraschi et al., 2013; GiefingKro¨ll et al., 2015), rendering Ortner’s ubiquitous snapshot of sex differences a model from which new hypotheses can be drawn.

STRUCTURAL VIOLENCE Structural violence is a term that originated in peace studies (Galtung, 1969; see also Farmer et al., 2006; Klaus, 2012). It refers to social circumstances, frequently aspects of social structures or institutions that keep individuals from meeting basic needs—from a healthy existence. The intimate relationship between structural and behavioral violence is underscored by Gilligan (1996: 196), who argues that the “question as to which of the two forms of violence—structural or behavioral—is more important, dangerous, or lethal is moot, for they are inextricably related to each other, as cause to effect.” While much has been published about behavioral violence detected by the presence of fractures and trauma in past populations, only recently has the concept of structural violence been integrated into paleopathological research. Its incorporation into skeletal analysis is an important one, as it allows us to move beyond the recognition of interpersonal aggression and begin to witness the life-long and postmortem effects of social inequity (Klaus, 2012). One growing body of research explores the ramifications of human exploitation and marginalization (Tegtmeyer and Martin, 2017). For instance, while the term “structural violence” was not expressly used, enslavement, low socioeconomic status, and other structural issues have figured heavily in de la Cova’s (2011,

2017) studies of documented collections. She began using the term formally in 2012. Examining the skeletal remains of individuals retained in the Hamann-Todd Human Osteological Collection, the Terry Collection, and the William Montague Cobb Collection, she argues that skeletal health disparities are evident between 19th-centuryborn African Americans and Euro-Americans due to “environmental conditions related to enslavement, postliberation migration to the industrialized North, crowded urban living conditions, and poor sanitation” (de la Cova, 2011: 536). Such richly embedded studies hold excellent promise for nuanced perspectives on the complex nature of human health in situations wherein individuals are disadvantaged in circumstances beyond their control (de la Cova, 2017). The effects of structural violence are also revealed in the postmortem treatment and disposition of human remains. Blakely and Harrington (1997), Mitchell (2012), and Nystrom (2017a: 16), are just a few of the researchers who have explored the “systemic political, economic, and social inequalities” that clearly influenced the bodies chosen for autopsy or dissection, and the means by which medical colleges, individuals, and organizations obtained human remains. Autopsy was performed to understand the cause of death or conditions impacting an individual. Dissection was performed on individuals stripped of their identity, rendering their bodies material objects, subjected to experimentation and display. Adding to the complex effects of structural violence is the fact that the racially and socially biased use and collection of skeletal remains in the past inherently affects our analyses today. These individuals, who suffered the effects of structural violence during and after their lives, problematically serve as the baseline skeletal series long assumed to be representative of human variability, and thus used for the development of standards used today for estimating age-at-death and sex (Nystrom 2014, 2017b).

ANCIENT HUMANS AND IMPAIRMENT, DISABILITY, AND CARE The presence of bone change associated with trauma or disease tells us much about human life in the past by providing insight into the actions or force needed to fracture bone, or the presence of pathogens responsible for lesions. More recently, the presence of bone change has become the foundation upon which evidence for impairment, disability, and care is extrapolated. Solecki, for instance, in 1971, concluded that Shanidar I, classified as Homo sapiens neandertalensis, with “sustained injuries to the right frontal squama, the left lateral orbit, the right humerus and right fifth metatarsal. . . hypoplasia or atrophy of the right clavicle, scapula, and humerus, osteomyelitis of the

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right clavicle, degenerative joint disease at the right knee, ankle, and first tarsometatarsal joint, and remodeling of the left tibia” (Trinkhaus and Zimmerman, 1982: 61), was “crippled” and at a “distinct disadvantage” in the harsh Middle Paleolithic environment of modern-day Iraq (Solecki, 1971). His ability to thrive was attributed to group compassion and cooperation. As another example, Stirland (1997: 588) argued that the presence of two “remarkable examples of disabled individuals,” one displaying juvenile polyepiphyseal disease and the other a neuromuscular disorder with paraplegia, buried in a poor medieval parish churchyard in England, implicitly suggested that “care in the community” was not a modern precept, as neither of the individuals would have survived into adulthood unaided. Emphasis in these and many ensuing studies is placed on situating the individual within a larger social context. Hence, these rising themes succeed in shifting emphasis away from case study descriptions of lesions toward complex social interactions and the surmised implications of trauma and disease on the individual and community. Important issues arise from paleopathological and bioarcheological research into impairment, disability, and care. The first involves definitions. What exactly constitutes “impairment” or “disability”? In many published works, the terms are used interchangeably. However, the amalgamation assumes that there are universal cultural norms which predicate our understanding of the terms. Do both terms imply lack of mobility or the presence of pain? Are they quantifiable? Tilley (1999: 3) asserts that “‘Disability’ refers to a state (temporary or longer-term) arising from an impairment in body function or structure that is associated with activity limitations and/or participation restrictions. This state is given meaning by both the individual and the community in relation to the lifeways in which it is experienced.” Hence, the term “impairment” may be used to explain the types or extent of change in the body of an individual, such as the discordant endochondral and intramembranous bone formation of achondroplasia leading to alterations in body proportions and subsequent morphological and biomechanical complications. For the paleopathologist, types of movement, ramifications of bone changes, and visual appearance of the individual might be used to qualify and quantify the term “impairment.” The term “disability,” however, can then be used to posit ways in which skeletal changes impacted the individual’s social interactions, or identity. Cross (1999) offers further points of distinction between the terms in her construction of two models: the medical model and the social model of disability. “According to the medical model, disability is viewed as a personal, individual medical tragedy amenable to either a medical intervention, cure, or control. . . the medical condition, illness, or disease is seen as being ‘the

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disability’. . .” (Cross, 1999: 181). In contrast, the social model emphasizes the social response to impairment, which both creates and frames the notion of disability. The concept of “disability,” therefore, is highly contextual and relational. It is formed and manipulated by the social actors: the individual and the community being researched by the paleopathologist, and the paleopathologists her/ himself. As Roberts (2000: 48) astutely points out, “deformity does not always lead to disability.” “Health, disease and disability are perceived very differently in different cultures, and in many situations caregiving can only be inferred with reference to what is known about the contemporary social, cultural, economic and physical environments, and only when indicators of a serious challenge to functioning ability are present” (Tilley, 1993: 3). The constructed meanings of the terms “impairment” and “disability” might be operationalized best by appreciating their inextricable connections within careful archeological contexts (Byrnes and Muller, 2017; Tilley and Schrenk, 2017). Kieffer’s recent work (2015) with an assemblage of apparently sacrificial skeletal remains pointedly seeks to “connect the physical condition of two ancient Maya individuals who suffered from Klippel-Feil syndrome with how they may have been treated differently, excluded from society and ultimately documenting a condition that may have led to them being chosen for ritual sacrifice.” Similarly, Boutin (2016), offering a careful assessment of pathological conditions in a skeleton of a young woman from the Early Dilmun period (c.2050 1800 BCE) from modern Bahrain, interprets the complexity of her life through careful integration of archeological context and the development of the “Bioarchaeology of Personhood” model. Tenets of this model include “(bio)archaeologists should not expect fixed conceptions of self across history and prehistory,” “identity cannot be parsed finely into gender or religion or class (or disability, for that matter),” and that an “openness to alternative modes of interpretation,” is essential (Boutin, 2016: 18). “Consequently,” assert Buikstra and Scott (2009: 42), “through the study of human remains and their archaeological contexts, we may be able to address societal definitions of disability for those individuals who register infirmities skeletally.” Defining the term “care” has been equally challenging to paleopathologists. Tilley (2015: 1) argues that “care provision is a conscious and purposive practice that involves caregiver(s) and care recipient(s), and it does not take place in a void. In any community, at any point in time, the perception of what constitutes ‘health’ and ‘disease’ and the related response . . . are shaped by a combination of cultural norms, values and belief systems; traditions; collective skills and experience; political, social and economic organization; environmental variables; and access to recourses.” In the paleopathological

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literature, the recognition of skeletal conditions deemed to have been incapacitating to an individual are often assumed to denote the presence of “care.” The argument is framed something like this: if an individual with a serious impairment lives longer than might be expected, then she/ he must have been cared for by others. Lebel et al. (2001), for instance, argue that the recovery of a partial Middle Pleistocene mandible from France exhibiting substantial antemortem tooth loss thrived, in part, due to provisioning and actions by others. Similarly, Oxenham et al. (2009) document the presence of ankylosed vertebrae, significantly reduced diaphysial diameters of postcranial long bones, and morphological superior inferior compression of hand phalanges in a Southeast Asian Neolithic skeleton (known as M9) from modern Vietnam. The proposed differential diagnosis of “congenital segmentation disorder as a child, leading to fusion of his cervical spine and concomitant or subsequent severe neurological impairment (likely quadriparesis or quadriplegia)” led the authors to unequivocally assert that “this would have left M9 completely dependent on others for every aspect of daily living” (Oxenham et al., 2009: 111). The fact that an individual might have required assistance during their life is not necessarily the contested issue in these and other studies. Rather, the issue is how “care” is interpreted. In most instances, the term “care” implies that the recipient is a “less functioning” individual. The subtext being that healthy, “normal” individuals are self-reliant and independent. But humans, like most social animals, require care and cooperation throughout their lives in order to survive. Is an infant abnormal if she/he requires constant care? Is a woman or man abnormal if intense focus on the production of material goods renders them reliant on others for food acquisition? Is it unusual for a relative to assist a family member who has a fractured limb? No. What, then, does survival of a physically incapacitated individual really tell us? Ironically, it may simply tell us that humans in the past were remarkably similar to humans today and to a wide range of nonprimate mammals (Fashing and Nguyen, 2011). Our interest in “care,” therefore, ought to extend beyond the assertion that care was provided in the past, and explore the plasticity of complex, context-dependent social interactions and/ or strategies adopted (whether successful or not) that influence the lives of others. The paleopathological focus on recognizing “compassion” in the archeological record further complicates the skeletal interpretation of “care.” Like the terms “impairment” and “disability,” the terms “compassion” and “care” are often treated as synonyms. They are not. While the term “care” denotes “attending to” and provisioning, the term “compassion” involves emotional responses including sympathy, empathy, and an awareness of suffering. In her astute and unsettling critique of paleopathological research

supporting evidence of prehistoric compassion, Dettwyler (1991) lays bare a number of assumptions that underlie inferences of compassion. She argues that one assumption, that most people within a population are productive and self-sufficient, overlooks the changing roles of children and the elderly, and ignores that “illness and injury probably incapacitate most members of a population occasionally. . .” (Dettwyler, 1991: 380). Disability is not, therefore, abnormal or unusual. Assuming that the survival of an incapacitated individual indicates the presence of compassion is also misleading, as “cruelty and indifference leave few traces in the archaeological record” (Dettwyler, 1991: 382). Similarly, Dettwyler directly refutes the assumption that caring for or facilitating the survival of an incapacitated individual is always a “compassionate” act, since cultures that practice infanticide of impaired or deformed children emically frame compassion as sparing their child from hardship. Another key component of impairment, disability, and care research involves the need for clinical correlates. Paleopathologists rely (or certainly ought to rely) on the integration of clinical research in order to develop differential diagnoses of archeological specimens (Mays, 2011). Often neglected, however, is the use of clinical data to interpret the ramifications of bone changes. There is a tendency to equate lesions appearing macroscopically severe with the in vivo presence of pain or debilitation. This association is problematic. Roberts (1988) and Grauer and Roberts (1996) point out that long bone fractures, some displaying considerable angulation (up to 35 degrees) or overlap (up to 35 mm) impacting alignment and creating shortening, are clinically considered “successful” and can thus be used to interpret the presence of healing and the presence of treatment in the archeological record. Visually, a femur displaying 35 degrees angulation is alarming. The impact on the individual might intuitively appear great, as mobility is likely impacted. But the association between visual deformity (variation from normal) and the psychosocial impact on the individual is not straightforward. Clinical research into the correlation between tissue damage and pain finds varying association in, for instance, patients with osteoarthritis of the knee (Torres et al., 2006). Torres et al. found that pain severity, measured in 143 patients, was not statistically correlated with the presence of osteophytes and bone cysts, but was statistically significant when bone attrition and bone marrow lesions were observed. Further complicating the association between pathological conditions and pain, Summers et al. (1991), and later Wollaars et al. (2007) found positive and statistically significant associations between pain in patients with spinal cord injuries and “negative cognitions” such as anger or isolation, as well as in those “less accepting” of their disability. “Level of lesion, completeness of injury,

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surgical fusion and/or instrumentation. . . were not associated with pain severity” (Summers et al., 1991: 183). More recently, Neogi (2013: 1147) argued that “pain is a subjective experience, influenced by a number of factors, including genetic predisposition, prior experience. . . current mood, coping strategies and catastrophizing, and sociocultural environment . . ..” Hence, without taking into account psycho-social-economic and other factors that contribute to personal differences, assessments of the relation between pathological structure and symptoms will be confounded. Our take-away is that assertions of impairment or disability in the archeological record that are based on the presence of pathological lesions invariably associated with pain are naive, and that, indeed, impairment and disability are best evaluated as inextricably linked to all aspects of human life. Asserting the presence of biomechanical incapacitation or functional outcomes of pathological conditions from skeletal remains is being increasingly addressed by paleopathologists. Morphological changes to joints, for instance, can have predictable consequences for mobility. Joint fusion caused by arthroses or trauma leads to changes in gait, posture, and movement, depending on the location and etiology of the condition. The clinical record bears witness to these associations. Correlations between joint change and functional outcomes of osteoarthritis have been a particular focus of the National Institutes of Health, as an enormous initiative known as the Osteoarthritis Initiative, seeks to document and make public osteoarthritis status and outcome measures in patients throughout the United States (http://www.oai.ucsf.edu/). Young and Lemaire (2014, 2017) offer an ordinal grading system of severity of osteoarthritis based on these data. Their resulting COAS (Clinical Archaeological Osteoarthritis Scale) is intended to allow researchers to model functional outcomes of OA based on dependent variables such as age, sex, and type of movement. Functional limitations of OA patients, such as climbing stairs, bending, etc., might have archeological correlates such as traversing mountainous terrain or squatting, allowing paleopathologists to explore links between lesions and impairment. Hence, the integration of the clinical record with archeological or mummified specimens has much to offer.

OSTEOBIOGRAPHY IN PALEOPATHOLOGY In what might appear to be an ironic twist in skeletal analyses, researchers are rethinking current emphases on population approaches. Discussed in detail in Chapter 1, paleopathological research fomenting from social theory of the 1960s, redirected attention away from case studies toward population analyses. Concentration on skeletal

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populations, advocated by “new archeology,” allowed broad evolutionary and epidemiological questions to be posed. These cast light on changing human pathogen interactions, and the effects of variables such as environment, subsistence strategies, time, and inclusion into biosocial groups (whether defined geographically or as status, sex, or age). Lost, however, was the appreciation for highly contextualized studies of individuals. To be clear, case studies are not the same as osteobiographies. Case studies center attention on particular lesions, diagnostic issues, or on finite details of a circumscribed population. On the other hand, osteobiographies, a term first coined by Frank Saul (1976), and later redefined by Robb (2002), currently seek to emphasize multidimensional aspects of the life of an individual. As such, osteobiographies draw heavily on archeological and historical context and interpretation (see Stodder and Palkovich, 2012), as well as identity theory and the life course approach in order to understand the life of an individual. Stodder (2012) offers a compelling segue into osteobiographical research in her evaluation of data and data analysis in paleopathology. Our decades-old emphasis on building large databases and statistically testing hypotheses with large sample sizes, she argues, compels us to ignore outliers (Stodder, 2012: 352). It might also lead to disregarding statistically insignificant results. Outliers, however, provide us with pertinent information. If, as Stodder points out, stature is being investigated (which might be used as a proxy for the presence of childhood stressors in the population), the statistical mean along with measures of population differences become the tools of analysis. Individuals who fall outside the circumscribed standard deviation are rendered inconsequential to the study. But studying these individuals might be key to our mapping population dynamics such as migration, genetic and epigenetic bases for phenotypic variation, environmental change, and interpersonal interactions. These aspects of human life profoundly impact host pathogen relationships, and thus warrant attention. The geographical movement and social interactions of a single individual can influence the spread of disease and influence the evolutionary course of a disease. Social and identity theory has greatly impacted the osteobiological approach, as individuals stand at the core of evaluation. The individual is evaluated and understood in light of the presence and implications of paleopathological lesions, which gain meaning within complex historical and mortuary contexts. As Sofaer (2011: 285 286) points out, “the need to better integrate knowledge from the natural and social sciences, as well as the humanities, is of increasing importance if we wish to understand the challenges facing human existence in the past, present and future.” “The skeletal body is employed as a means of underpinning interpretations rather than as a source for

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generating them” (Sofaer, 2006: 2). This call to reflect on the intersectionality of human life created by time, place, and interpersonal relationships serves as the foundation for Watkins and Muller’s (2015) initiative to closely integrate documentary evidence with the African American remains in the W. Montague Cobb skeletal collection. They assert that repositioning the Cobb Human Archive involves assessing the repercussions of using a skewed skeletal sample when exploring population distributions, as the dearth of infants and very old individuals might be supplemented by documentary sources. Limitations created by the statistical construct of cohort evaluation, in the presence of a chronologically skewed skeletal sample that includes individuals who lived in Washington, DC for a few days or up to a lifetime, may be eased in part by the inclusion of census data and other records that provide temporal perspectives. And very personal and very political concepts of “ethnicity” and “race” might be used to “disrupt narratives that position the collection as a resource for exploring ‘unique’ features of African descendant populations that can be taken out of context” (Watkins and Muller, 2015: 49). Hence, the integration “opens up analytical and interpretive possibilities that are reflected in the most recent scholarship that focuses on anatomical collections as well as skeletal remains from cemeteries and other burial sites. This includes studying individual experiences of health and disease in the larger context of social issues, experiential interpretations of skeletal remains that may include fictional narrative, different ways of theorizing connections between the past and the present, and denaturalizing and complicating notions of gender and age” (Watkins and Muller, 2015: 46 47). Bringing complexity to the evaluation and life of the individual has led some researchers to contest the boundaries of scientific inquiry. Boutin (2016), for instance, situates a skeleton of a young female from c.2050 to 1800 BCE Bahrain, displaying idiopathic coxa valga with femoral anteversion, and humerus varus deformity with reduced bone length firmly within archeological and mortuary contexts by offering a fictive osteobiographical narrative of the individual’s life. Through the eyes of the mother, and writing in the first person, Boutin recreates the life events of the impacted young woman. The impaired child is given a name, Beltani. Her life is appreciated through a model of personhood where constructs of identity and individuality are not seen as universals, are deeply complex and comprised of many entangled facets, and is informed by the life course paradigm. Her mother’s thoughts and actions are thus offered based on known clinical repercussions of the deformities and nuanced assessments of the mortuary context within which the individual was recovered. “. . .as she grew,” Boutin pens in the voice of Beltani’s mother, “she helped as much as

my other daughters, never complaining about the awkward positions into which she sometimes had to contort her upper body, or the stares she had to endure as her twisted legs carried her down the street. . .” (Boutin, 2016: 25). Readers of these new directions in paleopathological research are often struck by the subjective interpretations. Some might discount them. But the approaches present two important points: close and careful synthesis of paleopathological lesions within archeological, mortuary, and documentary context is essential, and all science is subjective. Attending to the first point, it is clear that interpreting the etiology along with the repercussions of pathological conditions requires the integration of as many data points and pieces of information as possible. Traumatic lesions result from human actions and reactions, whether they be physical, physiological, or pathogenic. Similarly, the etiological complexity of metabolic disorders might best be appreciated alongside complex social interactions between humans, humans and their environments, and varying physiological needs throughout the life course. Hence, understanding human skeletal responses requires an appreciation for the complexity of human life. The second point, that all science is subjective, has deep roots in intellectual and philosophical inquiry (Reiss and Sprenger, 2016). Published scientific articles from the early to mid 20th century comfortably employed the first person or subjective narrative to report data, analyses, and conclusions, only to become more sterile and impersonal in later decades (Sheffield, 2010). Growing numbers of reports written in the passive and third person have led to readers’ interpretations that the words on the page are truth; that there is a single understanding or interpretation to be shared by all. But, argue Jahn and Dunne (1997: 201), “over the greater portion of its scholarly history, the particular form of human observation, reasoning, and technical deployment we properly term ‘science’ has relied at least as much on subjective experience and inspiration as it has on objective experiments and theories.” The new themes driving paleopathology in exciting directions, such as social science and identity theories, feminist and gender theories, and disability and impairment theories, support this contention. They converge on the point that human experiences are unique and multidimensional and are understood through many lenses, none more important or “real” than the next. Denying the subjectivity of our work within paleopathology removes the humanity from the humans we seek to understand. As Zee (1975: 417) so poignantly points out, “. . . the question we asked ourselves still remains: what is it that so readily impels us to gather facts from a suffering person to diagnose a disease rather than into a more mutual exploration to learn more about the personal meanings and causes of what a

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person experiences?” These are the new directions bringing new understandings to human health and disease. Multiscalar studies hold great promise in offering nuanced understandings of the past and the complex relationship between human biological and social lives. For instance, Torres-Rouff and Knudson (2017: 381) combine multiple lines of evidence that reflect “identities in the past” —individual and group, mutable and immutable, in order to offer insights into a period of marked change in the Andes. Focusing upon the oases of San Pedro de Atacama and the Loa Valley, they investigate the “tumultuous” period of transition between the Middle Horizon (AD 500 1100) and the Late Intermediate Period (AD 1100 1400). Mutable aspects of identity include those inscribed upon the body and cultural practices related to funerary ritual. Immutable are those relating to geographic origins and heredity. The changes inscribed upon the body include cranial modification, discussed here in Chapter 9. Biological age and sex are used as proxies for social age and gender. Inherited measurable features of the skeleton and nonmetric traits assist in interpreting ancestry inferring ethnicity, while biogeochemistry provides indications of geographic origins. Their research, and that of a growing number of other paleopathologists and bioarchaeologists, clearly supports the promise of incorporating numerous lines of evidence and social theory with skeletal analyses.

REFERENCES Agarwal, S.C., Beauchesne, P., 2011. It is not carved in bone: Development and plasticity of the aged skeleton. In: Agarwal, S.C., Glencross, B.A. (Eds.), Social Bioarchaeology. Wiley-Blackwell, Malden, MA, pp. 312 332. Agarwal, S.C., 2012. The past of sex, gender, and health: bioarchaeology of the aging skeleton. Am. Anthropol. 114 (2), 322 335. Agarwal, S.C., 2016. Bone morphologies and histories: life course approaches in bioarchaeology. Yearb. Phys. Anthropol. 159 (Suppl. S61), 130 149. Armelagos, G.J., Goodman, A., Harper, K., Blakey, M., 2009. Enamel hypoplasia and early mortality: bioarchaeological support for the Barker Hypothesis. Evol. Anthropol. 18, 261 271. Barker, D.J., 2002. Fetal programming of coronary heart disease. Trends Endocrinol. Metab. 13, 364 368. Barrett, A.R., Blakey, M.L., 2011. Life histories of enslaved Africans in colonial New York. In: Agarwal, S.C., Glencross, B.A. (Eds.), Social Bioarchaeology. Wiley-Blackwell, Malden, MA, pp. 212 251. Baxandall, R., Gordon, L., 2005. Second-wave feminism. In: Hewitt, N. A. (Ed.), A Companion to American Women’s History. Blackwell Publ, Malden, MA, pp. 414 431. Bengtson, J., O’Gorman, J., 2017. Women’s participation in prehistoric warfare: A Central Illinois River Valley case study. IJO 27 (2), 230 244. Binford, L.R., 1971. Mortuary practices: their study and their potential. Mem. Soc. Am. Archaeol. 25, 6 29.

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Blakely, R.L., Harrington, J.M., 1997. Bones in the Basement: Postmortem Racism in Nineteenth-Century Medical Training. Smithsonian Institution Press, Washington, DC. Boraschi, D., Aguado, M.T., Dutel, C., Goronzy, J., Louis, J., GrubeckLoebenstein, B., et al., 2013. The gracefully ageing immune system. Sci. Transl. Med. 5 (185), 1 9. Boutin, A.T., 2016. Exploring the social construction of disability: an application of the bioarchaeology of personhood model to a pathological skeleton from ancient Bahrain. Intl. J. Paleopath. 12, 17 28. Buikstra, J.E., 1995. Tombs for the living . . . or for the dead: The Osmore Ancestors. In: Dillehay, T. (Ed.), Tombs for the Ancestors. Dumbarton Oaks Research Library and Collection, Washington, DC, pp. 229 280. Buikstra, J.E., Scott, R.E., 2009. Key concepts in identity studies. In: Knudson, K.J., Stojanowski, C.M. (Eds.), Bioarchaeology and Identity in the Americas. University Press of Florida, Gainesville, pp. 25 55. Buikstra, J.E., Roberts, C.R., 2012. The Global History of Paleopathology: Pioneers and Prospects. Oxford University Press, Oxford. Byrnes, J.F., Muller, J.L., 2017. Bioarchaeology of Impairment and Disability: Theoretical, Ethnohistorical, and Methodological Perspectives. Springer, New York. Carr, C., 1995. Mortuary practices: their social, philosophical-religious, circumstantial, and physical determinants. J. Archaeol. Method Theory 2 (2), 105 200. Charles, D.K., Buikstra, J.E., 1983. Archaic mortuary sites in the central Mississippi drainage: distribution, structure, and behavioral implications. In: Phillips, J.L., Brown, J.A. (Eds.), Archaic Hunters and Gatherers in the American Midwest. Academic Press, New York, NY, pp. 117 145. Cohen, M., Bennett, S., 1993. Skeletal evidence for sex roles and gender hierarchies in prehistory. In: Miller, B.D. (Ed.), Sex and Gender Hierarchies. Cambridge University Press, Cambridge, pp. 273 296. Cross, M., 1999. Accessing the inaccessible: disability and archaeology. Archaeol. Rev. Cambridge 15 (2), 7 30. Cybulski, J.S., 1977. Cribra orbitalia, a possible sign of anemia in early historic native populations of the British Columbia coast. Am. J. Phys. Anthropol. 47, 31 39. de la Cova, C., 2011. Race, health, and disease in 19th-century-born males. Am. J. Phys. Anthropol. 144, 526 537. de la Cova, C., 2017. Fractured lives: structural violence, trauma, and recidivism in urban and industrialized 19th-century-born African Americans and Euro-Americans. In: Tegtmeyer, C.E., Martin, D.L. (Eds.), Broken Bones, Broken Bodies: Bioarchaeological and Forensic Approaches for Accumulated Trauma and Violence. Lexington Books, London, p. 153. Dettwyler, K.A., 1991. Can paleopathology provide evidence for “compassion”? Am. J. Phys. Anthropol. 84 (4), 375 384. DeWitte, S.N., Stojanowski, C.M., 2015. The osteological paradox 20 year later: past perspectives, future directions. J. Archaeol. Res. 23, 397 450. Farmer, P.E., Nizeye, B., Stulac, S., Keshavjee, S., 2006. Structural violence and clinical medicine. PloS Medicine 3 (10), e449. Available from: https://doi.org/10.1371/journal.pmed.0030449. Fashing, P.J., Nguyen, N., 2011. Behavior toward the dying, diseased, or disabled among animals and its relevance to paleopathology. Int. J. Paleopath. 1, 128 129. Galtung, J., 1969. Violence, peace, and peace research. J Peace Res 6 (3), 167 191.

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Giefing-Kro¨ll, C., Berger, P., Lepperdinger, G., Grubeck-Loebenstein, B., 2015. How sex and age affect immune responses, susceptibility to infections, and response to vaccination. Aging Cell 14, 309 321. Gilchrist, R., 2000. Archaeological biographies: realizing human life cycles, -courses and histories. World Archaeol. 31 (3), 325 328. Gilligan, J., 1996. Violence: Reflections on a National Epidemic. Vintage Books, New York, NY. Goldstein, L., 1980. Mississippian mortuary practices: a case study of two cemeteries in the lower Illinois Valley. Northwestern University Archaeology Program Scientific Papers #4. Gowland, R., Knu¨sel, C., 2006. Social Archaeology of Funerary Remains. Oxbow Books, Oxford. Gowland, R.L., Penny-Mason, B., 2018. Overview: archaeology and the medieval life-course. In: Gerrard, C., Gutierrez, A. (Eds.), Oxford Handbook of Later Medieval Archaeology in Britain. Oxford University Press, Oxford, pp. 759 773. Grauer, A.L., McNamara, E., Houdek, D., 1999. A history of their own: Health and disease in a 19th-century poorhouse. In: Grauer, A.L., Stuart-Macadam, P. (Eds.), Sex and Gender in Paleopathological Perspective. Cambridge University Press, Cambridge, pp. 149 164. Grauer, A.L., 2018. A century of paleopathology. Am. J. Phys. Anthropol. 165, 904 914. Grauer, A.L., 2019. Paleopathology: from bones to behavior. In: Katzenberg, M.A., Grauer, A.L. (Eds.), Biological Anthropology of the Human Skeleton, third ed. Wiley-Blackwell, New York, pp. 447 465. Grauer, A.L., Roberts, C.A., 1996. Paleoepidemiology, healing, and possible treatment of trauma in the medieval cemetery population from St. Helenon-the-Walls, York, England. Am. J. Phys. Anthropol. 100, 531 544. Guatelli-Steinberg, D., Lukacs, J.R., 1999. Interpreting sex differences in enamel hypoplasia in human and non-human primates: developmental, environmental, and cultural considerations. Yearb. Phys. Anthropol. 42, 73 126. Halcrow, S.E., Tayles, N., 2008. The bioarchaeological investigation of childhood and social age: problems and prospects. J. Archaeol. Method Theory 15 (2), 190 215. Halcrow, S.E., Tayles, N., 2011. The bioarchaeologial investigation of children and childhood. In: Agarwal, S.C., Glencross, B.A. (Eds.), Social Bioarchaeology. Wiley-Blackwell, Chicester, pp. 333 360. Harrod, R.P., Martin, D.L., 2014. Signatures of captivity and subordination on skeletonized human remains: a bioarchaeological case study from the ancient Southwest. In: Martin, D.L., Anderson, C.P. (Eds.), Bioarchaeological and Forensic Perspectives on Violence: How Violent Death in Interpreted from Skeletal Remains. Cambridge University Press, Cambridge, pp. 103 119. Hodder, I. (Ed.), 1982. Symbolic and Structural Archaeology. University Press, Cambridge. Hodder, I., 1984. Burials, houses, men and women in the European Neolithic. In: Miller, Tilley (Eds.), Ideology, Power and Prehistory. Cambridge University Press, Cambridge, pp. 51 68. Hollimon, S., 2006. The archaeology of nonbinary genders in Native North American Societies. In: Nelson, S.M. (Ed.), Handbook of Gender Archaeology. AltaMira Press, Walnut Creek, pp. 435 450. Hollimon, S., 2011. Sex and gender in bioarcheological research. In: Agarwal, S., Glencross, B. (Eds.), Social Bioarchaeology. Wiley Blackwell, New York, pp. 149 182. Jahn, R.G., Dunne, B.J., 1997. Science of the subjective. J. Sci. Explor. 11 (2), 201 224.

Kieffer, C.L., 2015. Sacrifice of the social outcasts: two cases of Klippel-Feil Syndrome at Midnight Terror Cave, Belize. IJO. Available from: https://doi.org/10.1002/oa.2456. Kirkpatrick, R.C., 2000. The evolution of human homosexual behavior. Curr. Anthropol. 41, 385 398. Klaus, H.D., 2012. The bioarchaeology of structural violence: a theoretical model and a case study. In: Martin, D.L., Harrod, R.P., Perez, V. R. (Eds.), The Bioarchaeology of Violence. University of Florida Press, Gainesville, FL, pp. 29 62. Knu¨sel, C., 2011. Men take up arms for war: sex and status distinctions of humeral medial epicondylar avulsion fractures in the archaeological record. In: Baadsgaard, A., Boutin, A.T., Buikstra, J.E. (Eds.), Breathing New Life into the Evidence of Death: Contemporary Approaches to Bioarchaeology. School for Advanced Research Press, Santa Fe, pp. 221 251. Lebel, S., Trinkaus, E., Faure, M., Fernandez, P., Gue´rin, C., Richter, D., et al., 2001. Comparative morphology and paleobiology of Middle Pleistocene human remains from the Bau de l’Aubesier, Vaucluse, France. Proc. Natl. Acad. Sci. U.S.A. 98, 11097 11102. Lewis, M.E., 2007. The Bioarchaeology of Children: Perspectives from Biological and Forensic Anthropology. Cambridge University Press, Cambridge. Martin, D.L., Harrod, R.P., Fields, M., 2010. Beaten down and worked to the bone: bioarchaeological investigations of women and violence in the ancient Southwest. Landscapes Violence 1 (1), 1 19. Mays, S., 2011. The relationship between paleopathology and the clinical sciences. In: Grauer, A. (Ed.), Companion to Paleopathology. Wiley, New York, pp. 285 309. Mays, S., Gowland, R., Halcrow, S., Murphy, E., 2017. Child bioarchaeology: perspectives on the past 10 years. Child. Past 10 (1), 38 56. Mitchell, P., 2012. Anatomical Dissection in Enlightenment England and Beyond: Autopsy, Pathology, and Display. Ashgate, Farnham. Morris, I., 1991. The archaeology of ancestors: the Saxe/Goldstein hypothesis revisited. Cambridge Archaeol. J. 1 (2), 147 169. Neogi, T., 2013. The epidemiology and impact of pain in osteoarthritis. Osteoarthritis Cartilage 21, 1145 1153. Nystrom, K.C., 2014. The bioarchaeology of structural violence and dissection in the 19th-century United States. Am. Anthropol. 116 (4), 765 779. Nystrom, K.C., 2017a. Introduction. In: Nystrom, K.C. (Ed.), The Bioarchaeology of Dissection and Autopsy in the United States. Springer, New York, pp. 1 22. Nystrom, K.C., 2017b. The Bioarchaeology of Dissection and Autopsy in the United States. Springer, New York. Ortner, D.J., 1998. Male/female immune reactivity and its implications for interpreting evidence in human skeletal paleopathology. In: Grauer, A.L., Stuart-Macadam, P. (Eds.), Sex and Gender in Paleopathological Perspective. Cambridge University Press, Cambridge, pp. 79 93. Ortner, D.J., 2003. Identification of Pathological Conditions in Human Skeletal Remains, second ed Academic Press, New York. Oxenham, M.F., Tilley, L., Matsumura, H., Nguyen, L.C., Nguyen, K.T., Nguyen, K.D., et al., 2009. Paralysis and severe disability requiring intensive care in Neolithic Asia. Anthropol Sci. 117. Available from: https://www.jstage.jst.go.jp/article/ase/117/2/117_081114/_html/-char/ja. Penny-Mason, B.J., Gowland, R.L., 2014. The children of the reformation: childhood palaeoepidemiology in Britain, AD 1000 1700. Medieval Archaeol. 58, 162 194.

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Perry, M., 2008. Redefining childhood through bioarchaeology: toward an archaeological and biological understanding of children in antiquity. In: Baxter, J.E. (Ed.), Children in Action: Perspectives on the Archaeology of Childhood, Number 15 (1). Archaeological Papers of the American Anthropological Association, pp. 89 111. Rakita, G.F.M., Buikstra, J.E., 2005. Introduction. In: Rakita, G.F.M., Buikstra, J.E., Beck, L.A., Williams, S.R. (Eds.), Interacting with the Dead: Perspectives on Mortuary Archaeology for the New Millennium. University Press of Florida, Gainesville, FL. Reis, J., Sprenger J., 2016. Scientific objectivity. In: Zalta, N., (Ed.), The Stanford Encyclopedia of Philosophy, Summer 2016 edition. ,http:// plato.stanford.edu/archives/sum2016/entries/scientific-objectivity/.. Robb, J., 2002. Time and biography. In: Hamilakis, Y., Pluciennik, M., Tarlow, S. (Eds.), Thinking Through the Body. Springer, Boston, MA, pp. 153 171. Roberts, C.A., 1988. Trauma and Its Treatment in Medieval British Antiquity. PhD dissertation. Bradford University, Bradford. Roberts, C.A., 2000. Did they take sugar? The use of skeletal evidence in the study of disability in past populations. In: Hubert, J. (Ed.), Madness, Disability, and Social Exclusion: The Archaeology and Anthropology of “Difference”. Routledge, Abingdon, pp. 46 59. Sanders, V., 2006. First wave feminism. In: Gamble, S. (Ed.), The Routledge Companion to Feminism and Postfeminism. Routledge, London, pp. 15 24. Saul, F.P., 1976. Osteobiography: life history recorded in bone. In: Giles, E., Friedlander, J.S. (Eds.), The Measures of Men. Peabody Museum Press, Cambridge, MA, pp. 372 382. Saxe, A., 1970. Social Dimensions of Mortuary Practices. University of Michigan. Sharlach, L.B., 2009. First wave feminism. In: Ness, I. (Ed.), The International Encyclopedia of Revolution and Protest. https://doi. org/10.1002/9781405198073.wbierp0556. Sheffield, N., 2010 2011. Duke Graduate School Scientific Writing Resource. ,https://cgi.duke.edu/web/sciwriting/index.php.. Sofaer, J.R., 2006. The Body as Material Culture: A Theoretical Osteoarchaeology. Cambridge University Press, Cambridge. Sofaer, J.R., 2011. Towards a social bioarchaeology of age. In: Agarwal, S.C., Glencross, B.A. (Eds.), Social Bioarchaeology. WileyBlackwell, Malden, MA, pp. 285 311. Solecki, R.S., 1971. Shanidar: The First Flower People. Knopf Publ, New York. Stinson, S., 1985. Sex differences in environmental sensitivity during growth and development. Yearb. Phys. Anthropol. 28, 123 147. Stirland, A.J., 1997. Care in the medieval community. Int. J. Osteoarch. 7, 587 590. Stodder, A.L.W., 2012. Data and data analysis: Issues in paleopathology. In: Grauer, A.L. (Ed.), Companion to Paleopathology. WileyBlackwell, New York, pp. 339 356. Stodder, A.L.W., Palkovich, A.M., 2012. The Bioarchaeology of Individuals. University of Florida Press, Gainesville. Stuart-Macadam, P., 1987. Porotic hyperostosis: new evidence to support the anemia theory. Am. J. Phys. Anthropol. 74 (4), 521 526. Summers, J.D., Rapoff, M.A., Varghese, G., Porter, K., Palmer, R.E., 1991. Psychosocial factors in chronic spinal cord injury pain. Pain 47 (2), 183 189.

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Chapter 4

Fundamentals of Human Bone and Dental Biology: Structure, Function, and Development Niels Lynnerup1 and Haagen D. Klaus2 1

Department of Forensic Medicine, University of Copenhagen, Copenhagen, Denmark, 2Department of Sociology and Anthropology, George Mason

University, Fairfax, VA, United States

The average adult human skeleton contains 206 bones and 32 teeth; in subadults, there are more than twice that number of bones, in addition to a set of deciduous teeth. A range of intrinsic and extrinsic parameters and biologic states guide the normal growth, maintenance, repair, metabolic functioning, and optimization of bone form and strength. Yet, these tissues are subject to a diverse spectrum of developmental, metabolic, infectious, reticuloendothelial, hematopoietic, degenerative, metastatic, and endocrine influences. These conditions may disrupt or manipulate underlying bone physiology. Accordingly, detailed knowledge of bone and tooth biology is a fundamental baseline in the practice of paleopathology. This chapter provides a relevant overview concerning current understandings regarding how human bone and dental tissue form, grow, and function—crosscutting gross anatomy, bone microstructure, and cellular and molecular levels.

SKELETAL STRUCTURE, FUNCTION, AND CELLULAR BASIS OF BONE BIOLOGY Evolution of the Vertebrate Skeleton Bone was once thought of as a relatively simple tissue type when compared to the overt complexity of the nervous system, for example. This view of bone was reinforced further by the fact that skeletal phenotypes are varyingly biologically and evolutionarily constrained, such that a diverse range of pathophysiological processes can evoke only a specific range of possible forms of abnormal bone phenotypes. Additionally, bone is characterized by a rather slow tissue turnover rate compared to

other tissue types, resulting in much longer time intervals between disease onset and morphological alterations. Yet, such simplistic notions of the skeletal system have been increasingly shown to be deeply flawed. Human bones are a product of approximately three-quarters of a billion years of evolution (Donoghue and Aldridge, 2001; Ota and Kuratani, 2009). An evolutionary view is the starting point to understand the skeleton today. Vertebrates are a relatively small branch on the tree of life and appear in the fossil record relatively recently. Fossil data and comparative morphologic, genomic, and embryological evidence suggest the long-term evolutionary pathway likely involved a common ancestor that was invertebrate chordate—either a complex annelid-like worm or a more basic enteropneusta-like marine worm (Holland et al., 2015). Ancestral chordates appear to have been filter feeders that possessed a notochord, gill slits, an endostyle, and a post-anal tail (Gee, 1996; Lowe et al., 2015). In time, prismatic mineralized cartilage developed around the notochord and brain and a bilateral body plan emerged. Crown-group vertebrates (the last common ancestor to all living vertebrates and their fossil ancestors) emerged in the Cambrian epoch and were jawless, fishlike animals (Janvier, 2015). Interestingly, various lines of evidence suggest more than 80% of the basic relationships and components of the vertebrate skeleton were established within 15 million years after the emergence of true vertebrates (Hall, 2002, 2015)—underscoring the degree of adaptive advantage that bones conferred as well as the conserved nature of underlying bone form and function. All vertebrates possess a bony vertebral column and joints. The vertebral column is key to maintaining specific

Ortner’s Identification of Pathological Conditions in Human Skeletal Remains. DOI: https://doi.org/10.1016/B978-0-12-809738-0.00004-1 © 2019 Elsevier Inc. All rights reserved.

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postures, and joints permit forms of locomotion beginning with movement of the early vertebral column. Subsequent evolution of a cranium, mandible, and appendicular skeleton allowed vertebrates an opportunity to develop a more complex central nervous system, face, limbs, and tissues regulating hematopoiesis and mineral homeostasis. The first vertebrates lacked jaws, but one branch of this diverse and now mostly extinct group, known as gnathostomes, indeed developed a mandible and paired appendages during the late Ordovician period or early Silurian period (Brazeaum and Friedman, 2015). Between 423 and 419 million years ago (mya), mandibulated bony fish and tetrapod ancestors began to undergo remarkable diversification. By the close of the Devonian at 360 mya, adaptations for terrestriality were present (Clack, 2012; also see Dial et al., 2015). Today, more than 99% of all living vertebrates are gnathostomes. Over this history and within the deeply conserved elements of bone biology, significant complexity developed and accumulated. In the last 200 years of scientific study, many of the biological complexities of the skeleton have come to light, but it seems that for every new fact gained, two more questions arise. Bone has been revealed to be a highly complex organ system, involving specialized intercellular signaling and tightly coordinated systems of information exchange that precisely regulate turnover, growth, repair, and disease response, offering direct bridges between bone and the central nervous system and neuropeptides, the deep synergisms between bone and the immune system, endocrine and paracrine system influences, the gut microbiome, and deeply embedded life history traits (e.g., Gosman et al., 2011; Baldock, 2013; Lorenzo et al., 2015; Yan et al., 2016; Okamoto et al., 2017; Martin and Sims, 2018; Wei and Karsenty, 2018).

carpal and tarsal bones. This tripartite approach to classification not only reflects a straightforward way to start sorting and identifying commingled bones, but it also directly reflects differences in how bones are vascularized, form and grow, and highlights varying biomechanical properties, metabolic functions, and locomotor functions. For example, flat bones are often enriched with red marrow, generating new blood cells, and they are therefore also highly vascularized. In turn, they represent ideal microenvironments for various kinds of bloodborne cancers or iron-loving pathogens to metastasize and colonize (e.g., Wilbur et al., 2008; Klaus, 2017). Conversely, the tubular long bones possess load-bearing capabilities that reflect not only long-term patterns of physical activity and adaptation, but also risk specific kinds of fractures. Long bones share a common gross anatomy (Fig. 4.1). Most of their mass is comprised of a relatively long, cylindrical tube- or shaft-like structure called the diaphysis.

Gross Function and Anatomy Functionally, the skeleton offers protection for vital soft tissue structures, such as the brain, spinal cord, heart, and lungs. The senses of sight, smell, hearing, and taste reside within the skull. Bone also provides the underlying architecture for ligament and muscle attachments to facilitate locomotion. It is a principal organ maintaining mineral homeostasis, including its role as a reservoir for bioavailable calcium and phosphate, and bone is the factory for the production of blood cells and cells of the innate immune system (Favus and Goltsman, 2013; Frisch and Calvi, 2013). On a gross anatomical level, the bones of the skeleton can be classified as: (1) long, tubular bones of the extremities, (2) flat bones, which form parts of the “walls” of adjacent body cavities (e.g., braincase, thoracic and pelvic cavities), and (3) irregular bones, such as the geometrically complex vertebrae, bones of the facial skeleton, and

FIGURE 4.1 Gross anatomy of the exterior of a long bone (in this case a right adult femur) denoting the diaphysis (primary center of ossification), the proximal distal epiphyses (secondary centers of ossification, an apophysis (relatively rare tertiary centers of ossification), and both proximal and distal metaphyses and articular surfaces (29-year-old female, Terry Anatomical Collection, NMNH P000171R; photo: HDK).

Fundamentals of Human Bone and Dental Biology: Structure, Function, and Development Chapter | 4

A diaphysis is the product of the primary center of ossification (see section on Embryological and Developmental Processes below) and internally, it features a medullary cavity, or marrow space. Long bones tend to gradually increase in width toward the ends in the region termed the metaphysis. At the end of a long bone is its epiphysis, which represents a secondary center of ossification. During the process of bone growth, epiphyses are separated from metaphyses by a cartilaginous growth plate that ossifies and unites the two following the completion of bone growth. Tertiary centers of growth are termed apophyses and form at the site of tendinous insertions, such as the greater and lesser trochanters of the femur. The external surface of every bone is covered in a thin, wax-like membrane called the periosteum. The space between the periosteum and the bone itself is termed the periosteal envelope. The periosteum is highly vascularized and highly osteogenic (Ragsdale and Lehmer, 2012). Arterial vessels penetrate the periosteum and the surface of the bone through numerous microscopic nutrient foramina (Fig. 4.2). In long bones, a major artery supplies

Articular cartilage Epiphyseal artery

Epiphysis

Metaphyseal artery Metaphysis

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the bone marrow, and the nutrient foramen is correspondingly much larger and can be seen macroscopically. This major artery, penetrating the diaphysis, divides into two branches traveling toward each epiphysis, with a further division between a primary epiphyseal and a metaphyseal branch. Veins follow the arteries, although the vertebrae have distinct venous foramina on the lateral aspects of vertebral bodies. Periosteal blood vessels are very important for bone growth (see below), as well as for bone repair after fracture and responses to infection. If the periosteum is removed, the underlying bone will die and necrotize. The high degree of vascularization also means that bloodborne pathogens, emanating from elsewhere in the body, may be spread with relative ease to bone, resulting in periosteal inflammatory reactions (Weston, 2012; Klaus, 2014). The periosteum also carries the greatest number of peripheral nerves associated with bone, such that pain associated with fracture is mostly due to periosteal nerve signaling. In contrast, a deeper, chronic infection of bone may result in less physical discomfort. The periosteum is comparatively thick and also serves as an anchor for fibers that facilitate muscle attachments (Sharpey’s fibers). These fibers penetrate the outer surface of the bone and thus form a very strong anchor for the membrane. Bone morphology at these sites of attachment may be influenced further by mechanical loads, resulting in new bone formation if there is an increased strain on the muscle attaching at the site. Macroscopically, these form roughened and topographically rugose areas called entheses.

Bone Tissue: Composition and Organization Periosteal arteries Diaphysis

Nutrient artery

Compact bone FIGURE 4.2 Diagram showing the blood supply of an adult long bone. The nutrient artery and the epiphyseal arteries enter the bone through nutrient foramina. These openings in the bone arise developmentally as the pathways of the principal vessels of periosteal buds. Metaphyseal arteries arise from periosteal vessels that become incorporated into the metaphysis as the bone grows in diameter. Reproduced with permission from Ross, M.H., Pawlina W., 2011. Histology: A Text and Atlas with Correlated Cell and Molecular Biology. Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia, p. 222.

Bone is one of the hardest materials synthesized by any biological process. Bone is a composite material—part mineral, part collagen—and therefore possesses the optimal qualities of both—simultaneously rigid and flexible and lightweight (amounting to only about 30% of the weight of the human body). As a composite, the skeleton is made up of inorganic mineral content (B60%), organic components (B25%), and water (B15%). Chemically, the inorganic component of bone tissue is hydroxyapatite (Ca10 (PO4)6 (OH)2), which is a specialized crystalline form of calcium phosphate. These plate-shaped crystals have a very large surface area (about 100 m2 per 1 g of hydroxyapatite crystals). Bone matrix also incorporates organic tensile collagen fibers (type I), which are alkaline-soluble polypeptides. The combination of organic collagen fibers and inorganic crystals is suspended in an intercellular matrix of proteoglycans giving bone unique mechanical and physical properties. Bone possesses a

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high tensile strength—1100 kg/cm2 parallel to the bone’s axis—more than twice that of porcelain and other ceramic fabrics. Due to the crystalline nature of bone mineral, the longitudinal compressive strength is also very high, exceeding 2000 kg/cm2. Indeed, bone tissue is often compared to fiberglass plastic: a flexible but strong fiberglass weave (collagen) surrounded by hard but fragile, epoxy resin (mineral). Bone is comparable to all connective tissues in that it consists of cells and an intercellular substance. In bone, the intercellular matrix consists of collagen fibers and mineral salts, mostly calcium phosphate (85%), but also calcium carbonate (10%), in addition to magnesium and alkali salts (5%). Almost the entire body’s calcium store is maintained within the skeleton, which therefore serves as a calcium reservoir (Favus and Goltsman, 2013). There is a tightly regulated exchange of calcium between blood and the skeleton in order to maintain an allostatic balance. Calcium is important for muscle function, and even small deviations in blood calcium can result in spasmodic cramps. Due to its importance, the body may be forced to draw upon calcium deposits in the skeleton if there is insufficient dietary calcium intake. For any single bone there are two types of tissue: an external compact lamellar tissue, which forms a smooth surface (or “cortex,” hence the alternate term cortical bone) and an internal spongy or cancellous substance (trabecular bone). Compact bone covers all parts of the skeletal surface. Macroscopically, it has a homogeneous appearance and is most pronounced in the diaphyses of the largest long bones, where it surrounds the marrow space in a cylindrical wall up to several millimeters thick. A layer of compact bone also covers joint surfaces, although they are considerably thinner. Cancellous bone is most prolific in irregular and flat bones, such that it occupies the space between the external and internal surfaces of flat bones, including the parietal bones where it is termed diploe¨. Cancellous bone forms a fine network of thin bone beams (trabeculae). The total internal cancellous bone surface area of the skeleton therefore is very large. Trabeculae also play a biomechanical role, perhaps most clearly seen in longitudinal sections of the femoral neck, where the orientation of trabecular networks reflects the optimal directional transmission of force (including stretching, torsional, and compressive forces) and underscores how bone architecture elegantly maximizes strength with a minimum of material. The internal surface of a long bone diaphysis is composed of the medullary cavity and the endosteal envelope that is best described as cellular membrane (Hall, 2015). The medullary cavity contains bone marrow that fills the internal bone cavity beneath the cortical surface. In adult

long bones, this cavity is cylindrical. Marrow space is also found continuing onward into the metaphyses where it is interwoven into trabecular space. Marrow spaces are filled with both red and yellow bone marrow. The red marrow is hematopoietic and is the main blood-forming organ after birth. Hematopoietic marrow red blood cells, white blood cells, and platelets are produced in marrow tissue that is nourished from the blood vessels that pass through the nutrient foramen (Kumar et al., 2014; also see Chotinantakul and Leeanansaksiri, 2012). The term red bone marrow refers to the mainly hematopoietic cells, or blood stem cells, responsible for forming the different cellular components of blood. In children, all bone marrow is red due to the demands of blood cell formation in a growing body. From about the fifth year of life onwards, areas of red marrow (for instance, in the cranial vault) are gradually replaced by yellow fat cells. This process begins at the center of the bone and expands outward. After skeletal growth has ended (from the age of 20 25), there is usually only red bone marrow in the proximal aspects of femora and humeri and in various flat bones (sternum, ribs, clavicles, scapulae, and the pelvic bones). In older adults, these bones may eventually contain only yellow bone marrow. In rare cases of unusually severe or chronic anemia or another increased need for blood cells, yellow bone marrow can be converted to red bone marrow.

Cartilaginous Tissue The cartilage of the joint surfaces consists of hyaline cartilage, which covers them with no intervening periosteal membrane (for excellent overviews, see Resnick, 2002; Lories and Luyten, 2018). Hyaline cartilage possesses a very smooth, strong, and elastic quality. This smoothness, combined with synovial joint fluid, minimizes friction in the joints. These biomechanical properties of hyaline cartilage make a joint highly resistant to wear despite the enormous strain and compressional forces to which is exposed (e.g., up to 300 kg in the hip joint). Cartilage may vary in thickness from 1 to 7 mm. On convex joints, the cartilage is thickest in the middle, whereas on concave surfaces, the thickest portions are distributed to the joint edges. As with bone, hyaline cartilage consists of cells surrounded by an intercellular matrix. These cells are called chondrocytes, and produce a proteoglycan matrix as well as collagen fibers. The fibers are usually oriented in ways that maximize their biomechanical efficiency vis-a`-vis joint movements. A simple and consistent fiber orientation is easiest to achieve if the joint has one axis of motion (e.g., a simple hinge joint between phalanges). Unsurprisingly, joints with more axes of movement are also more prone to

Fundamentals of Human Bone and Dental Biology: Structure, Function, and Development Chapter | 4

cartilage damage (e.g., shoulder, elbow, hip, knee). Hyaline cartilage (as elastic and fibrous cartilage) lacks blood vessels and nerves, and thus regenerates slowly or not at all if the tissue is damaged. This may result in the underlying joint bone surface being directly exposed in severe cases of osteoarthritis. If adjacent joint surfaces are thus denuded, they may interact directly, leading to pathological eburnation and surface grooving. The two other kinds of cartilage are elastic cartilage, found in the epiglottis, pharynx, and the outer ear. Fibrous cartilage (fibrocartilage) is found in the vertebral discs, the intraarticular components of major joints (e.g., the menisci of the knee joints), and symphyses. Interestingly, the sacroiliac joint has hyaline cartilage on the sacral joint surface and fibrocartilage on the iliac joint surface. Overall, the three cartilage types differ in relative amounts of collagen, elastic fibers, and proteoglycan matrix. Elastic cartilage is yellowish in color due to a higher content of elastic fibers, while the latter is more whitish and less elastic (Ross and Pawlina, 2011; Standring, 2015).

Bone Cells The growth, regulation, repair, and other functions of skeletal tissue are driven by the behavior of just three kinds of cells: osteoblasts, osteoclasts, and osteocytes. Osteoblasts are bone-producing cells derived from osteoprogenitor cells that are products of mesenchymally derived cell lines. Osteoblasts are mononuclear cells and possess copious ribosomes and mitochondria that reflect their intensive protein synthesis duties in the production of new bone. Osteoblasts were once envisioned solely as bone-producing cells, but we now know that their activities range from the synthesis and deposition of an unmineralized collagen mass (osteoid), to the secretion of calcium phosphate, osteoclast regulation, hematopoiesis, and immune functions (Gosman, 2012). In particular, there appear to be fundamental interactions between blood and osteoblasts as they continuously “talk” to each other as osteoblasts provide critical regulatory support of the hematopoietic stem cell line (Wu et al., 2009). Osteoblasts are plump and polygonal in shape and genetically are a sophisticated derived fibroblast (Ducy et al., 2000). Osteoblasts produce a mucoprotein matrix mainly consisting of highly structured layers of collagen fibers (type I fibrils). This is followed by deposition of solid particles of calcium phosphate as hydroxylapatite crystals are embedded upon and between the collagen fibers. Their ultimate fate resides in becoming either osteocytes or bone-lining cells (Fig. 4.3). Osteoclasts are cells that remove bone. They are large, multinucleated cells that arise from the fusion of usually

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Osteoblast lineage Stem cell ?

Preosteoblast

Osteoblast

Osteocyte

Bone-lining cell

FIGURE 4.3 A schematic representation of the origin and fate of osteoblasts. Osteblasts share a stem cell source in common with fibroblasts. When the stem cell differentiates into a preosteoblast, its daughter cells are committed to osteoblasts development. Ultimately, they may undergo apoptosis, serve as BLCs, or become trapped in matrix and further develop as an osteocyte. Reproduced with permission from Garner, S.C., Anderson J.J.B., 2012. Skeletal tissues and Mineralization. In: Anderson, J.J.B., Garner S.C., Klemmer P.J. (Eds.). Diet, Nutrients, and Bone Health. CRC Press, Boca Raton, FL., p. 36.

between 10 and 20 mononuclear phagocytes, which themselves are macrophage-related hematopoietic precursor cells in bone marrow (Boyle et al., 2003) (Fig. 4.4). Osteoclasts possess a ruffled border that facilitates a tight seal between cell and bone surface (Teitelbaum, 2000; Ross, 2013). Under this seal, the osteoclast creates its own microenvironment. Osteoclasts possess electrogenic proton pumps (H1-ATPase) and a Cl channel that allows the cell to secrete hydrochloric acid and collagen-degrading proteolytic enzymes. Under the seal, local pH drops to around 4.5 and is sufficient to dissolve bone matrix (Ross, 2013). Exposed collagen fragments are then broken down by the enzyme cathepsin K and the mineral and protein remains are expelled into the surrounding intracellular fluid (Stenbeck and Horton, 2004). Just like osteoblasts, osteoclasts are mobile and can move along a surface between 95 and 115 μm/h (Hall, 2015) (Fig. 4.5). Osteocytes are osteoblasts that became trapped in bone matrix deposited by other surrounding osteoblasts. The trapped cell then differentiates into an osteocyte, decreasing in size and organelle volume. They occupy ovoid-shaped cavities in the bone matrix called lacunae.

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Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

Osteoclast lineage CFU-GM

(+) GM-CSF Promonocyte IL-1; IL-6; TGF-α

(+)

(+)

Early pre-osteoclast

Monocyte

(+)

PTH; 1,25D

Tissue macrophage

Late pre-osteoclast

(+)

PTH; 1,25D IL-6 Osteoblast (+)

TGF-β

Giant cell

Osteoclast

(+) (+)

(–)

CT

Active osteoclast

PTH; 1,25D; IL-1; TGF-α

FIGURE 4.4 A schematic representation of the origin and fate of osteoclasts. Osteoclasts orginate from a stem cell population of colonyforming-unit-granulocyte-macrophages (CFU-GM) that can either give rise to osteoclasts or monocytes/macrophages. CFU-GMs are stimulated by the granulocyte-macrophage colony stimulating factor and differentiate into premonocytes. This cell will then commit to either a osteoclastic or monocytic pathway under the stimuli from varying local factors including the influence of various interleukins (e.g., IL-1, IL-6) along with transforming growth factor-α (TGF-α) for the osteoclast linage and transforming growth factor-β (TGF-β) for the monocyte linage(s). Additional influences of parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D (1,25D) and other cytokines, either acting alone or via osteoblast mediation, further develops the cell and regulates the behavior of a mature osteoclast throughout its life. Reproduced with permission from Garner, S.C., Anderson J.J.B., 2012. Skeletal tissues and Mineralization. In: Anderson, J.J.B., Garner S.C., Klemmer P.J. (Eds.). Diet, Nutrients, and Bone Health. CRC Press, Boca Raton, FL., p. 38.

It was once commonly held that osteocytes were simply unlucky osteoblasts that found themselves at the wrong place at the wrong time and when trapped in the matrix they entered into a passive state, retired from all meaningful and functional roles. Currently emerging understanding demonstrates the opposite.

Osteocytes appear to be proverbial “control freaks” (Gosman, 2012) that are the primary regulators of bone mass as they integrate mechanical and hormonal signals (Dallas and Bonewald, 2008; Bonewald, 2013; Hall, 2015; and see below). An emerging consensus portrays osteocytes as the master mechanosensory cell in bone. Osteocytes retain thread-like cytoplasmic extensions from their earlier lifetime as osteoblasts. These pass through small channels in the bone matrix called canaliculi. These specialized extensions connect to one another via gap junctions that allow osteocytes to form a functional and communicative syncytium that links all cells within bone. Together, they all function in a way that can be seen as a single mineral regulatory endocrine gland (Bonewald, 2013; Qing et al., 2008). More than 90% of all cells within mature bone are osteocytes. Most critical to an understanding of bone cells is that they do not operate independently of each other. Osteocytes appear to first assess mechanical signals and then regulate bone shape and density by targeting osteoblast and osteoclast functions. Basically, it is the balanced actions of osteoblasts and osteoclasts that secure bone growth and maintenance. The balance between osteoblastic and osteoclastic activity is equally fundamental for understanding the pathophysiology of all diseases affecting bones (see Chapter 5). Some disease processes give rise to greatly enhanced osteoblastic activity, while others are characterized by an elevated osteoclastic response. Others feature mixed responses or begin with elevated osteoclast activity but are later eclipsed by new bone formation. Ultimately, these cells are not behaving autonomously, but are responding to a yet deeper level of control: molecular signaling mechanisms.

Molecules and Signaling Pathways: Master Control Mechanisms Since the late 1980s, advances in molecular biology and genetics have progressively revealed the major molecules, cell signaling pathways, and genes that drive and regulate bone cell behavior. These insights hold myriad implications for paleopathological problem-solving (e.g., Crespo et al., 2017). Osteoblast-mediated bone production is fundamentally controlled by a group of proteins called Wnt (named after the wingless gene in Drosophila) via Wnt cell surface coreceptor LRP5 (low-density lipoprotein-related protein 5). The Wnt/b-catenin pathway is commonly called the canonical pathway, as it activates gene expression in cell nuclei to incite osteoblasts to form new bone (Fig. 4.6). Osteoblasts

HCO3–

Chloride-bicarbonate exchanger

CO2 Cl– HCO3– H2CO3 CA II H2O + CO2

H+

RER

ADP + Pi

ATP Chloride channel

Golgi

Proton pump Cl–

H+

FIGURE 4.5 Osteoclasts are bone-resorbing cells. This multinucleated cell froms a “sealing zone” with the bone surface that allows for the area within the zone to exposed to a low pH microenvironment. This is created by active pumping of hydrogen ions and proteolytic enzymes into the resorption zone. Reproduced with permission from Garner, S.C., Anderson J.J.B., 2012. Skeletal tissues and Mineralization. In: Anderson, J.J.B., Garner S.C., Klemmer P.J. (Eds.). Diet, Nutrients, and Bone Health. CRC Press, Boca Raton, FL., p. 39.

dr

og

e ne

sis

Chondrocyte

Bone marrow

Ch

WNT

on

Osteoblast progenitor

MSC

Osteogenesis

HSC WNT

RANK

Adipocyte

sis gene ipo d A

Apoptosis

Committed osteoblast progenitor

RANKL

? DKK1 SOST

Preosteoblast

Matrix mineralization

WNT

Lining cell

WNT

Monocyte Osteoid WNT

RANKL OPG

Mature osteoblast

New bone SOST DKK1

Osteoclast

Old bone Osteocyte

FIGURE 4.6 Osteoblasts derive from pluripotent mesenchymal stem cells. Wnt β-catenin signaling commits these cells to the osteoblast lineage and prevents adipogenic and chondrogenic cell fate. Once commitment is ensured, canonical Wnt signaling is essential for osteoblast precursor proliferation and differentiation. Wnt β-catenin signaling appears to downregulate osteoblast apoptosis in some instances. Further, Wnt β-catenin signaling for the osteoblast lineage inhibits osteoclastic bone resorption. Wnt β-catenin signaling is required for osteoblast and osteocyte expression of the antiosteoclastic factor OPG, the decoy receptor for RANKL. Reproduced with permission from Baron, R., Kneissel, M., 2013. WNT Signalling bone homeostatis and disease: from human mutations to treatments. Nat. Med. 19, 179 192.

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Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

might theoretically continue differentiating from pluripotent mesenchymal stem cells and produce more and more bone if it were not for the downregulating effects of molecules in the Dickkopf protein family (Dkk1 and 2) and the glycoprotein sclerostin. Sclerostin is produced by the SOST AQ5 gene in osteocytes and is an antagonist to Wnt and other bone morphogenic proteins (BMPs; Datta et al., 2008). Another deep level of control over bone formation involves the number of osteoblasts that are produced and active at any given time. The transcription factor Runx2 (Runt-related transcription factor 2) is a master switch for osteoblast differentiation (de Gorter and ten Tijke, 2013). Interaction with many different coregulatory proteins determines if Runx2 positively or negatively modulates expression of several osteoblast specific genes (de Gorter and ten Tijke, 2013). Runx2 also controls expression of the transcription factor Osterix that down the line controls expression of the genes osteopontin, osteocalcin, osteonectin, and collagen-1 (Nakashima et al., 2002; Koga et al., 2005). BMPs are derived from the tumorgrowth factor-β (TGF-β) family and are fundamental for bone development, maintenance, and fracture repair. BMPs activate a range of functions that lead to osteoblast differentiation (Robinson, 2012), not least of which is induction of Runx2 in a positive feedback loop (de Gorter and ten Tijke, 2013). TGF-β by itself appears to have up- and downregulating effects depending on the concentration of this cytokine in skeletal tissue (Takayanagi, 2005). Additional key regulatory factors that can either upregulate or downregulate osteoblast activity are parathyroid hormone (PTH), vitamin D, calcitonin, Hedgehog gene signaling, IGF-1 (insulin-like growth factor-1) and FGF (fibroblast growth factors), Notch protein signaling, and sex hormones (de Gorter and ten Tijke, 2013). Estrogen plays a role in upregulating osteoblast activity via receptors ERα and ERβ in osteoblasts and osteoclasts to shape critical roles in mechanotransduction and the osteogenic response to biomechanical stress. In addition to Wnt, Leptin, a product of adipose tissue, appears to be another “master regulator” of bone formation via interfaces with the sympathetic nervous system to inhibit osteoblast activity (Ducy et al., 2000). Osteoclast differentiation and activity are driven by a separate series of unique molecules and signaling pathways. Osteoclasts all appear to begin as macrophages in bone marrow. Osteoclastogenesis is instigated by two master cytokines: RANKL (receptor activator of nuclear

factor κB ligand) and M-CSF (macrophage-colony stimulating factors) with RANKL (a member of the tumor necrosis factor superfamily) being the most important. RANKL’s effects are dependent on the presence of receptor molecules on the surface of osteoclast precursor cells called RANK, and osteoprotegerin (OPG)—the soluble, high-affinity inhibitor receptor protein for RANKL. RANKL is expressed in osteoblasts and their immediate precursor cells. RANK is activated by RANKL, thus allowing for the differentiation and activation of osteoclasts. Key to this is that effects of RANKL are inhibited by OPG. This decoy receptor for RANKL is produced by diverse kinds of tissues to prevent osteoclast differentiation. Should bone resorption need to be slowed, or perhaps even be overtaken by relatively greater osteoblastic activity, one manner to achieve this end is increased production of OPG. With more of these molecules in circulation, more RANKL molecules are intercepted before they can reach their target cells. All bone resorption is coordinated by this RANKL/RANK/ OPG regulatory axis and the RANKL:OPG ratio (Porth, 2011; Gosman, 2012; also see Henriksen et al., 2011; various chapters in Burr and Allen, 2014). Additional secondary factors influencing osteoclast differentiation and activity include interferon-γ (INFγ) as a major suppressor of osteoclasts, TNF-α (tumor necrosis factor-α), IL-1 (interleukin-1), vitamin D, prostaglandins, estrogen levels, and possibly even lymphocytes (see review in Ross, 2013). As noted earlier and elaborated upon in the discussion of remodeling in this chapter, the activity of these cells is tightly integrated and balanced in a healthy skeleton. This coupling and cross-talk is very intricate and still not fully understood (Fig. 4.7). What is apparent is paradoxical: bone-forming osteoblasts appear to receive, translate, and mediate the signals that activate osteoclasts. Major factors and signaling pathways that maintain this coupling are TGF-β, PTH, OPG, and RANKL (see Hall, 2015: 241 246). Thus, osteoblasts aid in mobilizing osteoclasts as the osteocytes orchestrate the entire show. RANKL is expressed along osteocyte dendritic filaments that stimulate osteoclast differentiation quite some distance away deep in the marrow (Bonewald, 2013). Osteocytes are also capable of positively affecting the activation state of osteoclasts by promoting factors such as SOST, Sclerotin, and MEPE/OF45, but they also can drive new bone formation by expressing DMP1, Phex, and other factors (Bonewald, 2013; also Gosman, 2012).

Fundamentals of Human Bone and Dental Biology: Structure, Function, and Development Chapter | 4

43

WNT3a LRP5/6

Osteoblast

WNT10b

FZD FZD

LRP5/6

PTH1R

DKK1

WNT10b

SOST

β-catenin PTH1R

PKA

PKA Cilia BMPR

FZD

OPG BMPR

ROR2 BMP

RANKL

OPG

Fluid shear stress

WNT5a RANKL RANK FZD ROR2 NFATc1

Osteoclast marker genes

Osteocyte

Osteoclast

FIGURE 4.7 Cross-talk between bone cells is remarkably elaborate and not yet fully understood. Minimally, though, osteocytes control bone formation through the secretion of the Wnt antagonists sclerostin (SOST) and DKK1, the expression of which is modulated by mechanical signaling, PTH, and BMP. PTH represses, whereas BMP signaling induces, the expression of these antagonists. Wnt signaling in osteocytes controls the production of OPG, which is the decoy receptor for the key osteoclast differentiation factor RANKL. Osteoblast-expressed Wnt 5a stimulates differentiation of osteoclast precursors as a result of binding to the FZD ROR2 receptor complex. Osteoclasts stimulate the local differentiation of osteoblasts at the end of the resorption phase by secreting Wnt ligands serving as something of a remodeling feedback loop. The activation of PTH1R-mediated signaling in osteoblasts and osteocytes leads to β-catenin stabilization and, thus, activation of Wnt signaling. Reproduced with permission from Baron, R., Kneissel, M., 2013. WNT Signalling bone homeostatis and disease: from human mutations to treatments. Nat. Med. 19, 179 192.

SKELETOGENESIS AND BONE MODELING

Embryological and Developmental Processes

The growth and development of the skeletal system represents an objectively fascinating process worthy of study on its own merits, but it also holds keys for understanding the interplay between underlying biology and disease states. For greater depth and further reading on developmental and evolutionary dimensions of skeletal growth and development, we highly recommend Hall (2015) and chapters in Percival and Richtsmeier (2017).

The early embryo, consisting at first of a blastocyst, develops into a disc formed of two layers of cells (the bilaminar germ disc) during the second week of development. In the third week, this two-layered structure differentiates into a three-layered structure (the trilaminar germ disc) at the onset of organogenesis. The three distinct layers of the ectoderm, mesoderm, and endoderm each give rise to specific cells, tissues, and organs. The ectoderm

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Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

becomes skin tissue and tooth enamel (see below). The mesoderm differentiates into the various connective tissues such as bone, cartilage, dentin, and cementum. Skeletogenesis initiates in the vertebrate embryo as pluripotent mesenchymal cells arise from the ectoderm and mesoderm. These cells migrate to specific locations in the body and commit to a skeletal fate via a complex and still not fully understood process (Cardew and Goode, 2001; Lefebvre and Bhattaram, 2010; Hall, 2015). Most skeletogenic cells later develop into chondrocytes, osteoblasts, or articular chondrocytes and synovial cells, while others remain as mesenchymal stem cells throughout life. The origins of skeletogenic cells can be found in the ectoderm-derived neural tube, the paraxial mesoderm, and lateral plate mesoderm. When the neural crest peels away from the neural tube, its cells assume a mesenchymal identity and proceed to migrate to numerous locations in the embryo, giving rise to neurons, melanocytes, and skeletogenic cells (Hall, 2015; Sauka-Spengler and BronnerFraser, 2008; Limura et al., 2009). Cells derived from the neural tube provide for some craniofacial elements, while the lateral plate mesoderm gives rise to others, as well as the appendicular skeleton and sternum. The paraxial mesoderm generates somites, or paired segmented blocks of mesodermal tissue, that form the axial skeleton (vertebral column and ribs) (Lefebvre and Bhattaram, 2010). Approximately 42 44 pairs of somites form paraxially around the central longitudinal neural groove and notochord. By the fourth week of development, neural crest and mesodermal cells have settled into skeletal sites as influenced by the establishment of complex morphogenic fields in the mesenchyme (for a review, see Hall, 2015: 545 561). Skeletal initiation now begins. The cells begin to produce a matrix of collagen-1, fibronectin, and hyaluronan as they proliferate and die in a tightly choreographed process (Shum et al., 2003). This activity establishes mesenchymal structures that prefigure future skeletal structures. Mesenchyme has the potential to differentiate into various forms of connective tissues, such as with the formation of fibroblasts that can form reticular, collagenous, and elastic fibers, chondroblasts that can form cartilage, and osteoblasts that can form bone. These cells together are known as osteochondroprogenitor cells. Driving this elaborate process of skeletogenesis is an even more complex suite of dynamic networks of genes and cell signaling factors. Master transcription factors such as Sox4, Sox11, and Sox12, and Runx2 appear to play clear roles (Bhattaram et al., 2010), and these are influenced yet deeper by morphogens such as Sonic Hedgehog (Shh), FGFs, Wnt ligands, BMPs, and retinoic acid (Butterfield et al., 2010). Later in development, the number of somites declines and the mesenchyme, along with other stem cells of the

ectoderm and endoderm, starts differentiating the upper and lower extremities. This takes place during the second month of development. Disturbance of the development at this point may lead to malformations or complete agenesis of the extremities.

Bone Modeling Bone modeling is the principal expression of normal bone cell coordination in a growing skeleton (Parfitt, 2002). Bone modeling occurs as either intramembranous or endochondral ossification. This discussion provides an overview of the general processes of bone modeling and the key known and suspected molecular signaling, transcription factors, and morphogens involved in ossification and osteoblast activity (for further details, see Lefebvre and Bhattaram, 2010; Hall 2015, and references therein). Hogg et al. (2017) have hypothesized that a fundamental biorhythm known as Havers Halber oscillation (HHO) is expressed in the increments of mineralized tissues (bone lamellae, striae of Rezius in teeth). This circadian rhythm represents oscillations between the sympathetic nervous system and long-term rhythms of bone growth. The development and growth of bones are further dependent on a variety of factors and substances, such as calcium, phosphorus, vitamins C and D, and hormones from the pituitary gland, thyroid, and parathyroid glands. A lack of these substances, hormonal disorders, or underlying genetic errors may lead to pathological growth and development of the skeleton.

Endochondral Ossification Much of the human skeleton is produced from endochondral ossification. Most skeletogenic cells become chondrocytes to construct cartilage anlagen that constitutes the primary skeleton of the vertebrate embryo. In a two-step process regulated at least in part by TGF-β and Wnt signaling, skeletogenic cells condense and begin to rapidly proliferate a cartilaginous matrix—the skeletal primordea. Mesenchyme is transformed into hyaline cartilage “models” of many distinct bones. The most characteristic forms of endochondral ossification can be found in long bones, where the structure is initially shaped into a proportionally long shaft with undifferentiated globular ends (for further perspectives on bone modeling, ontogeny, and development, consult Burr and Organ, 2017; Percival et al., 2017; Ryan et al., 2017; Wallace et al., 2017). Cartilaginous growth plates first develop in the globular ends to become epiphyses. This process is driven by diverse signaling instructions at different points, including PTH and parathyroid hormone-related peptide (Ppr), Indian hedgehog (Ihh), the Sox trio, and Runx2 and

Fundamentals of Human Bone and Dental Biology: Structure, Function, and Development Chapter | 4

Runx3 (Lefebvre and Bhattaram, 2010). When chondrocytes begin to undergo programmed death at the end of growth plates, teams of osteoclasts invade the space to remove the cartilage matrix. They are followed in a coordinated fashion by osteoblasts that produce bone, endothelial cells that generate a vascular supply, and hematopoietic and stromal cells that give rise to bone marrow. Ossification begins in the diaphysis between the 4th and 5th weeks of gestation. Chondrocytes in the perichondrium are activated primarily by Ihh and differentiate into osteoblasts. The osteoblasts initially form a broad ring of osteoid, resulting in a kind of perichondral “cuff” or “sleeve” around the center of the diaphysis and the primary center of ossification is formed. By mineralizing the intercellular matrix of the osteoblasts, osteoblasts proliferate within the bone and, once trapped in the matrix, differentiate into osteocytes. At the same time, there is a transformation of the inner, original hyaline structure with the formation of more or less continuous medullary cavity for the future bone marrow formation. Simultaneously, ossification begins in the interior of the cartilage model. A blood vessel proliferates into the cartilage through the perichondral sleeve, forming the nutrient foramen. Mesenchymal cells migrate along with the blood vessel and differentiate into cells that break down the intracellular matrix of the cartilage, while others become osteoblasts that begin to secrete osteoid. In this way, the remaining hyaline cartilage component of the bone diaphysis, surrounded by bone marrow, is gradually removed and transformed into an internal, spongy, trabecular bone structure.

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In long bone ossification, there are also independent ossification centers at the epiphyses, termed secondary ossification centers (Figs. 4.8 and 4.9). However, since the cartilage of the epiphysis lacks a perichondrium, perichondral ossification cannot achieve longitudinal growth. Instead, a separate, secondary endochondral bone core forms and grows radially. Importantly, hyaline cartilage retains the ability to grow and does so especially at the ends of the bone cuff. Ultimately, the primary and secondary ossification centers meet with only a thin layer of cartilage remaining between the ossification centers. This is the epiphyseal disc, or growth plate. As long as the epiphyseal disc is intact, the bone can grow in length because the disc continuously forms new cartilage. This in turn produces new bone on the end of the diaphysis, thus pushing the epiphyses further away from each other and extending the diaphysis. As the primary ossification center grows, eventually the entire diaphysis of the long bone is surrounded by an osteogenic perichondral sleeve. The thickness of the diaphysis is determined by the balance between osteoblast and osteoclast activity in the periosteal and endosteal envelopes (Fig. 4.10). Ultimately, epiphyseal cartilage stops growing and is completely replaced by bone (Fig. 4.11). This terminates the endochondral growth process. Of the original complete hyaline model, only that covering the joint surface remains.

Epiphysis Growth plate Metaphysis

Diaphysis

Metaphysis FIGURE 4.8 Histological features of endochondral ossification. Cartilage (C) is at the top of the field; the zone of hypertrophic and calcifying cartilage is seen at the middle level of the field, and bone formation (B) is occurring in the lower portion of the image. The perichondral collar (or sleeve bone (SB)) marks the lateral margin of the growth plate to the left. Femur, 5-month human fetus, approximately 50 3 magnification.

Growth plate Epiphysis FIGURE 4.9 A cross-sectional representation of the major components of a growing long bone.

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Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 4.12 A cross-sectional representation along the mid-sagittal plane of a 4-month-old human fetus. Stippled areas indicate the approximate region of intramembranous ossification of the cranial vault, while horizontal lines represent the approximate extent of endochondral ossification in the facial skeleton. FIGURE 4.10 Remodeling dynamics at the ends of a growing long bone are represented in this schematic illustration. The conical end represents the metaphysis and growth plate. The hatched zones represent areas produced from earlier stages of growth, and the cross-hatched areas are those that are removed (in essence, sculpted by osteoclasts) as the bone grows (arrows).

FIGURE 4.11 Proximal epiphysis and greater trochanter of the right femur seen at the very end of the endochondral growth process. The epiphyseal cartilage has stopped proliferating, the epiphyses are increasingly attached to the bone, and the remaining cartilage between the epiphysis/apophysis and the bone is progressively ossified until the epiphyseal and apophyseal lines (arrows) are remodeled and disappear (approximately 18 20-year-old individual; Huntington Anatomical Collection, NMNH; photo: HDK).

Intramembranous Ossification A second mode of ossification occurs when connective tissue ossifies directly without formation of hyaline cartilage as an intermediary stage. Such de novo bone formation occurs in the membranous structure seen in most of the flat bones of the facial skeleton, cranial vault, and within the initial sections of the clavicle (Fig. 4.12). Intramembranous ossification initiates with a conglomeration and compaction of mesenchymal cells that transform into osteoblasts and produce osteoid. Primary ossification centers then form as the osteoid is calcified in a radial fashion, projecting outward from the centerpoint of each future bone (Opperman, 2000). This primary ossification process produces a trabecular appearance, merging into a spongy network surrounded by mesenchymal tissue that becomes bone marrow. For the neurocranium, particularly pronounced bone formation in the inner and outer surfaces of the bone results in compressed and highly laminated compact bones (the internal and external tables of the cranium, for example), while the space between retains a spongy appearance (the diploe¨). The mesenchymal, nonossified membrane surrounding the centers of ossification is ultimately transformed into periosteal and endosteal membranes on the outer and inner surfaces of the cranial bone, respectively. At birth, much of the basicranium is still composed of cartilage, and the flat bones of the neurocranium are separated by relatively wide membranous zones covered with periosteal membrane (Fig. 4.13). These zones are widest where several cranial

Fundamentals of Human Bone and Dental Biology: Structure, Function, and Development Chapter | 4

47

FIGURE 4.13 Two views of the cranium of a perinatal individual demonstrating an open anterior (or bregmatic) fontanelle. Brain growth coordinated with the cranium’s elaborate spatiotemporal and modular approach to growth, and these membranous zones between help permit the outward growth of the cranium (NMNH 380385; photo: HDK).

bones meet. The largest of these are the bregamatic fontanelle (between the frontal bone and the parietal bones) and the posterior fontanelle (between the parietal bones and the occipital bone). Brain growth is intertwined and coordinated with the cranium’s dynamically elaborate spatiotemporal and modular approach to growth (Kawasaki and Richtsmeier, 2017). The membranous zones between the cranial bones gradually close by ossification, until only a narrow, irregularly shaped suture remains. The cranium grows in an outward direction due to osteoblastic activity in the connective tissue of the sutures and in the outer periosteal layer of the neurocranial bones. At the same time, corresponding osteoclast activity occurs on the inside of the neurocranial bones that further refines and contours the shape of the growing structure. Intramembranous cranial bone growth is tightly coordinated with brain growth. Thus, significant abnormalities or disturbances in brain growth (e.g., missing structures) result in pathologically altered crania such as with anencephaly. Conversely, disorders such as hydrocephaly produce abnormal expansion of cranial bones. In the cranial base, growth takes place especially in the cartilage plate that lies between the occipital and sphenoid bones (spheno-occipital synchondrosis). As with the long bone epiphyseal growth plates, cartilage stops growing around 15 18 years of age, arresting any further growth of the basicranium. Premature closure of the spheno-occipital synchondrosis or any of the other sutures will result in cranial shape abnormalities. In cases of scaphocephaly, premature fusion of the sagittal suture prevents any additional lateral directional growth to produce an elongated, hyperdolicocephalic vault morphology (Fig. 4.14) (see Lieberman, 2011: 96 143).

The Facial Skeleton Unlike long bones, where the fusion of the epiphyseal growth plate means that the long bone cannot grow further in length, the elements of the facial skeleton retain the ability to grow, partially owing to the many small sutures between the many bones of the facial skeleton. The gradual growth and accumulation of bone mass in the facial skeleton also leads to increased osteoclast activity within the bones, which is in part related to the formation of sinuses, or major open internal spaces of the single bones (e.g., the frontal sinus, sphenoid sinus, ethmoid sinus, maxillary sinus). These sinuses form during the first years of life. The mandible is quite gracile at birth and consists of separate left and right halves held together by a fibrous symphysis along the midline. For most gnathostomes, the symphysis that unites the left and right hemimandible is retained through life. Among anthropoids, the left and right mandibles eventually fuse, occurring for humans around one year after birth. Growth and development of the mandible result from a complex confluence of ontogenetic and biomechanical signals (Dechow, 2017). The greatest facial growth activity in childhood takes place around the mandibular condyles, whereby the mandible grows to project inferiorly and anteriorly (Hall, 2015: 515 541; also see Freidline et al., 2017). Fields of resorption and recontouring transform face and mandible morphology. Also, the distance between the left and right temporomandibular joints increases along with the size of the cranium, such that the mandibular angle relative to the mandibular body decreases from around 140 to 120 100 or less. While

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Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 4.14 Errors in cranial growth can result in cranial shape abnormalities such as scaphocephaly where premature fusion of the sagittal suture prevents further lateral directional growth. The result is an atypically narrow neurocranium assuming an elongated, hyperdolicocephalic form—the result of the cranium growing in the only direction that it still can (18-year-old female, Terry Anatomical Collection, NMNH P000800R; photo: HDK).

the rami grow most in childhood, the mandibular corpus sees its greatest size increase in adolescence. If the growth of the cranial base and mandible does not occur at the same rate, this may lead to problems with occlusion (see Lieberman, 2011, and references therein).

BONE REMODELING Osteoblasts and osteoclasts work in concert, linked by complex molecular and mechanical signaling cues. The previously discussed process of bone modeling can be understood in terms of osteoblasts and osteoclasts shaping bone in a coordinated fashion via an unfolding of ontogenetic processes and mechanical inputs (Ryan et al., 2017). Osteoblasts lay down bone in one location, while osteoclasts in other locations quite literally sculpt and refine morphology via resorption (Martin et al., 1998) (Fig. 4.15). Following this process, bone will also be maintained, repaired, and biomechanically optimized via a process of remodeling involving bone replacement or turnover (Parfitt, 2002, 2003; Wallace et al., 2017). When extended to bone remodeling, Hogg et al. (2017)’s aforementioned HHO oscillation hypothesis would understand remodeling as a profoundly embedded life history trait. There are two modes of remodeling: conservation and disuse. Conservation mode encompasses the repair of damage and the functional adaptation to biomechanical loading. Mechanically, remodeling provides a mechanism to optimize bone strength to specific mechanical environments. Structurally, remodeling serves a repair function, removing microcracks and other accumulated fatigue

FIGURE 4.15 A schematic representation of the process of modeling drift. During growth, with changes in the axis of mechanical loading, bone is added to the anteromedial periosteal and posterolateral endosteal surfaces while bone is removed from the anteromedial and posterolateral endosteal surfaces.

damage (Burr, 2002; Parfitt, 2002). This mode is a lifelong process that nominally resorbs and forms bone in equal amounts while the skeleton is developing and throughout the remainder of life (Martin et al., 1998).

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Metabolically, conservation-mode remodeling contributes directly to calcium allostasis via the exchange of calcium ions at the bone surface. While conservation remodeling may not result in dramatically different bone morphology, it fundamentally alters the density of bone tissue. Disuse mode remodeling results in a net loss of bone mass, and can also be a response to decreased habitual mechanical loading, various disease states, osteopenia, and senescence. First observed in the 1960s (Frost, 1963; Takahasi et al., 1964), the cellular behavior and signaling processes of remodeling, including the roles of PTH, estrogen, and calcitonin that modulate the ratio of RANKL:OPG coordinating osteoclast and osteoblast activity leading to either net bone gain or loss, are now relatively well understood.

The Basic Multicellular Unit Bone remodeling is accomplished by teams of osteoclasts and osteoblasts that produce a temporary microanatomical Osteonal artery Collagen fibers

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structure called the basic multicellular unit (BMU) (Frost, 1969). BMUs are three-dimensional cylindrical structures in cortical bone and hemicylindrical structures in trabecular bone or on periosteal or endosteal surfaces. The end result of a BMU is the histological feature known as an osteon (Figs. 4.16 4.19). Adults may produce some 3 million BMUs annually, with around one million active at any given time. A mature osteon is the smallest structural unit comprising either mineralized cortical or trabecular bone tissue. An osteon is made up of concentrically arranged layers (lamellae) of bone tissue akin to the rings of a tree, around which a pair of capillaries and nerve fibers occupy the central Haversian canal. These canals are usually less than 100 μm in diameter and are more or less parallel to the long axis of a bone (Hall, 2015) but can also “drift” if the BMU proceeded at another angle. An osteon typically has 5 7 (and sometime up to 20) layers of lamellae. Embedded in the lamellae are individual osteocytes,

Inner circumferential lamellae Endosteum

Interstitial lamellae

Osteon

Volkmann’s canal Lamellae of bone Osteonal endosteum Haversian canal

Outer circumferential lamellae

Osteocyte and lacuna Periosteum

FIGURE 4.16 A diagram of a section of cortical bone from a long bone. The concentric lamellae and the Haversian system that they surround comprise an osteon or Haversian system. One of the osteons is represented as an elongated cylindrical structure rising above the plane of the cross-section. This helps visualize the several concentric lamellae and perpendicular orientation of the collagen fibers in adjacent layers. Also note the structure of the vascular supply to the osteon. Reproduced with permission from Ross, M.H., Pawlina W., 2011. Histology: A Text and Atlas with Correlated Cell and Molecular Biology. Wolters Kluwer/ Lippincott Williams & Wilkins, Philadelphia, p. 222.

FIGURE 4.17 Microscopic view of osteons in various stages of formation. (A) A resorption space (RS) is seen in the center right of the field, while a forming osteon (FO) is seen to the lower left. Most of the remaining osteons have completed protein matrix synthesis as indicated by their small central Haversian canals. (B) A microradiograph of the same view reveals both the variation in osteon density and degrees of mineralization (more completely mineralized structures are lighter). Approximately 45 3 magnification.

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FIGURE 4.19 Backscattered electron-scanning electron microscope view of two osteons observed in the process of formation.

FIGURE 4.18 A small osteon (arrow) entirely within a larger osteon— also known as a type II osteon. Adult human cortical bone. Approximately 150 3 magnification.

former members of the BMU caught up in their own matrix. The osteocytes communicate with a central arteriole and nerve, as well as other osteocytes via canaliculi, gap junctions, and the functional syncytium. No osteocyte lies more than 0.2 mm from a Haversian canal. In trabecular bones, Haversian canals are absent as the cells are fed directly from the surrounding bone marrow. Triggering BMU formation and the remodeling process is multifactorial. In some cases, the calcium reservoir may need to be tapped in a nontargeted fashion to release its mineral content (e.g., lactation; Agarwal and Macadam, 2003). In other cases, targeted remodeling may be triggered by mechanical strain or to repair microdamage induced from repetitive or excessive mechanical loading. For years, the sensory mechanism behind targeted remodeling was unknown and referred to as the presumed “mechanostat.” Today, it is clear that osteocytes are the all-important mechanosensory mechanism. They appear to sense variations in streaming electric potentials caused by the movement of ions along with loading-induced fluid

FIGURE 4.20 Backscattered electron-scanning electron microscope of an osteon in formation, traveling obliquely through the bone. This view captures the scalloped border of the resorption bays (Howship’s lacunae) to the left, while the bone on the right is undergoing active formation.

flow through the canaliculi (Salzstein et al., 1987; also, Klein-Nulend et al., 2013), in addition to sensory aspects of osteocyte shape (van Oers et al., 2015). Subsequently, osteocytes orchestrate modeling and remodeling linking Wnt and PTH signaling pathways, upregulated mRNA expression, β-catenin, and DKK1. Bone remodeling involves a process known as the ARF cycle (activation, resorption, and formation) (Figs. 4.20 and 4.21). A fully mature BMU is composed of a team of osteoclasts that remove bone at the leading edge of the structure, or the cutting cone. In the wake of the cutting cone is a resorptive bay with highly irregular margins. When the osteoclasts conclude their activities, a reversal event occurs in the temporal and spatial patterning of the RANKL:OPG ratio, promoting a team of osteoblasts to deposit new bone and filling in the resorptive

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Osteoclast precursors

Osteoblast recruitment Fusion

Chemical signals?

Apoptosis Bone lining cells

Bone lining cells Osteoclasts

Unmineralized osteoid

Osteoblasts

Mechanical stimulus Osteocytes Mature bone

Activation

Resorption

Reversal

Formation/mineralization

Quiescence

FIGURE 4.21 A schematic and simplified representation of the formation of a basic multicellular unit (BMU) and the ARF cycle progressing from left to right.

FIGURE 4.22 The process of remodeling for trabecular bone follows a different path than that of cortical bone. This image illustrates the process in the proximal femur, and the far greater surface area available in trabecular tissue results in higher turnover rates. On one hand, this is advantageous for rapid adaptation to mechanical loading, but on the other hand, it promotes greater susceptibility to pathological conditions involving net resorptive bone loss.

bay. At the center of it all is a proliferating capillary, key to coordinating the ARF cycle as it brings osteoclast and osteoblast precursor cells to the BMU. An active BMU travels through tissue space excavating approximately 200 μm of bone at an average 10 μm per day for some 90 100 days (Fig. 4.22). van Oers (2008) suggests that strain-induced osteocyte signaling literally steers the BMU by directionally inhibiting osteoclasts to ensure the BMU travels through three-dimensional tissue space exactly where it is needed (Fig. 4.23) (and for more on the spatial and temporal characteristics of a BMU, including the roles of RANK, RANKL, OPG, and bidirectional interactions between Wnt, TGF-β, IGF-1, sclerostin, and Ephrin-eph signaling, see Henricksen et al. (2009)). It takes approximately 100 days to complete a BMU in a human, but the lifespan of the osteoclasts and osteoblasts is 10 12 days to a few weeks, respectively. Thus, the supporting capillary provides circulating monocytes that deliver osteocyte and osteoblast precursor cells (see Parfitt, 2002; Gosman, 2012), which is necessary to keep the process going as veteran members of the BMU perish via apoptosis. Osteoblasts, evidently stimulated principally by sclerostin signaling molecules (Winkler et al., 2003) ultimately seal up the closing cone to terminate the BMU that closes around the capillary to form the Haversian canal and a completed osteon.

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Haversian system of cortical bone

Osteoclasts

Cutting cone

Osteoblasts

Bone formation

Bone lining cells

Mature osteon

Haversian canal

Lamellar bone

FIGURE 4.23 A cross- section of the spatial organization and cellular activity during BMU formation. The cutting cone is formed by teams of osteoclasts excavating and dissolving bone. Teams of osteoblasts that deposit new bone populate the reversal zone immediately behind the osteoclasts. In their wake, a new blood vessel forms in the Haversian canal which itself is lined with osteoblasts that differentiate into quiescent BLCs. Reproduced with permission from Garner, S.C., Anderson, J.J.B., 2012. Skeletal tissues and mineralization. In: Anderson, J.J.B., Garner, S.C., Klemmer, P.J. (Eds.), Diet, Nutrients, and Bone Health. CRC Press, Boca Raton, FL, p. 43.

TOOTH STRUCTURE AND FORMATION Teeth are the one element of the skeletal system that interfaces directly with the external environment. These are multifunction structures most commonly relied upon for speech sound production and mastication and mechanical digestion of food. As mammals, humans produce two sets of teeth. A deciduous dentition is replaced by a larger and more numerous permanent set when body growth accelerates. Here, we provide an overview of tooth anatomy, structure, and formation, and for further reading on these topics, Ten Cate’s Oral Histology (Nanci, 2017) is an outstanding reference. A tooth consists of a crown that is exposed to the oral cavity and a root that is anchored in alveolar bone (Fig. 4.24). The transition between the crown and root is the cementoenamel junction). A tooth consists of three different hard tissues: enamel, dentin, and cementum. Enamel covers the dental crown and cementum covers the root surface. Under the enamel and cementum, dentin provides a structural backing for hard but fragile enamel and encloses the tooth’s soft tissue component, the pulp chamber, which fills the inner cavity of the tooth. The pulp consists of blood vessels and nerves connected to the rest of the body’s vascular and nervous networks through the apical foramen at the root’s apex.

FIGURE 4.24 A schematic representation of the major anatomical components of a human tooth.

Enamel Enamel is the hardest material produced by biological processes. It is derived from the epithelium and forms the anatomical crown of a tooth. Composed of approximately 96% inorganic apatite crystals and 4% organic material and water, this highly mineralized, acellular, and avascular tissue has been shaped by natural selection for its abrasion-resistant properties. To these ends, enamel apatite crystals are packed together as parallel alternating crystallite enamel rods and inter-rod enamel (Nanci, 2017). Enamel thickness varies on the dental crown, being thickest on the buccal surfaces (about 2.5 mm) and thinner toward the cervix. Enamel is translucent and varies in color from yellowish to grayish white. Ameloblasts, or enamel-forming cells, eventually disappear as the development completes. Accordingly, enamel cannot be repaired or remodeled. An enamel defect or chipping/spalling damage is permanent. Therefore, diseases that have an impact on enamel formation may leave permanent “scars” in the enamel structure.

Dentin Dentin is a yellowish, somewhat elastic but mineralized avascular tissue that supports the enamel and encloses the

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pulp chamber. Approximately 60% of the dentin is inorganic apatite, while the remaining 40% is a fibrillar protein collagen all arranged in tubular structures radially, oriented from the pulp chamber and toward enamel and cementum boundaries. Odontoblasts are dentin-producing cells that remain active at the ends of these tubules, located at the innermost edges of the dentin. Dentin can be remodeled to a degree as odontoblasts can produce new tissue (secondary dentin) if required (e.g., excessive tooth wear that exposes the dentin).

Periodontal Ligament and Cementum A tooth is anchored in its alveolar socket by a pair of highly specialized connective structures that form a functional unit consisting of the periodontal ligament and cementum. The periodontal ligament is a mass of collagen fiber bundles. One side of the ligament is woven into alveolar bone, and the other side embedded into the cementum that covers the root surface. The periodontal ligament resembles a spliced rope, wherein individual strands can be continuously remodeled and adapted to resist mechanical stress without the overall structure losing its form or function (Nanci, 2017). Cementum is the mineralized medium between the tooth and the periodontal ligament. It is an avascular connective tissue with a mineral content equivalent to bone. Primary, or acellular, cementum covers the cervical portion of the root nearest the CEJ. Secondary, or cellular, cementum can be found on the apical half of the root. Cement can contain cementoblasts, and during the course of life, cement thickness increases. Akin to osteoblasts, cementoblasts can become trapped in their own matrix and differentiate into cementocytes. The embryological origin of cementum is the same as bone. The formation of teeth has a developmental origin mostly in the ectodermal layer of the early trilaminatephase embryo. Later, the folding of the embryo into two planes promotes the formation of a primitive oral cavity (the stomatodeum) as ectoderm is warped inward to line the stomatodeum. As the neural tube forms, the aforementioned neural crest separation and migration event occurs, likely driven by Wnt and FGF signaling (Nanci, 2017). This is the next critical step in tooth formation from which is derived and position established for the primordial dentin and acellular cementum (along with much of the facial skeleton).

Tooth Morphogenesis Complex arrays and cascades of molecular signaling events drive tooth morphogenesis. After around 35 days of development, U-shaped bands of thickening epithelium begin to form the putative maxillary and mandibular arches. Each primary epithelial band divides quickly,

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differentiating into the dental lamina and vestibular lamina. Cell division associated with the anterior dental lamina begins to form a series of epithelial outgrowths at the positions of future deciduous teeth. Following this, tooth development occurs over the bud, cap, and bell stage to again involve a diverse range of transcription factors and secreted proteins (e.g., Wnt, BMP, Shh, homobox domain genes, zinc-fingered glioma-associated oncogene homolog, and many more (Nanci, 2017)). Determination of tooth type is also achieved at this early stage. Overall, some 300 genes are implicated in tooth development, and the variable timing and differential expression in tissue space result in cusp number, size, and final tooth form (Thesleff, 2006; also see Edgar and Ousley, 2016; Townsend et al., 2012). Traditionally, field theory and clone theory were advocated. Field theory asserted that factors shaping tooth form were present in ectomesenchyme that created distinct but overlapping morphologic fields for each tooth type. Clone theory argued that each tooth class is derived from a clone of ectomesenchymal cells programmed to produce a particular type of tooth. Elements of both models may find some validity in homeobox code (field) theory. This third explanation has increasingly good experimental support to suggest that spatially circumscribed expression of homeobox genes in the jaw primordia, such as Msx and the Dlx families, are responsible for the formation of single and multicusp teeth, respectively (and see Nanci, 2017, for additional details). Deciduous and permanent teeth undergo the same formation steps, though their timing is obviously staggered (Fig. 4.25). Permanent teeth that develop under deciduous teeth are equally derived from the dental lamina, produced as a second tooth bud at the deepest portion of the lamina and medioinferior to a deciduous bud. Molars have no deciduous analogs and arise from a posterior burrowing of the dental laminae that produces epithelial outgrowths to give rise to adult molars. At this point, all the preconditions for tooth formation are set and the bud stage is initiated. Here, the undifferentiated epithelial cells make their initial incursion into the jaw mesenchyme. Soon after, modulation of various homeobox genes, including Shh, BMPs, and Pax-9 provide the queues for the bud to transition to the cap stage where distinct tooth morphologies begin to emerge. The cap stage is characterized by a ball of condensed ectomesenchyme that forms the dental papilla (future dentin and pulp), the dental follicle (support tissues), and the enamel organ that sits atop the papilla like a cap. Enamel knots also emerge at this time, and the multiples of knots that form in premolar and molar caps are key to multicusp morphogenesis (Nanci, 2017). Continued cell division along the internal surface of the enamel epithelium of enamel organ gives way to the bell stage. Progressive cessation of cell division in the constituent rings of cells in

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the enamel organ causes the bell to buckle and form an apex (Hillson, 2014: 90). This process permits a tooth crown to assume its final shape. The dental lamina disintegrates and the tooth becomes a separate entity from the oral epithelium (Fig. 4.26). Enamel and dentin formation is initiated in the latter portions of the bell stage. Ameloblasts are a class of epithelial cells that experience a truly unique life cycle in the range of progressive phenotypes and activities they exhibit in the stages of enamel formation. Enamel formation can last as long as 5 years for some teeth. It involves a three-step process that begins in the inner enamel epithelium at the tips of the cusp outline and progressively spreads downward to the rest of the crown. First, the presecretory stage involves ameloblasts differentiating from the outer enamel epithelium, dental follicle, and dental papilla cells in the bell. At this time, ameloblasts begin to acquire a unique set of structures. Their internal organization begins to physically shift with the nucleus and mitochondria shifting proximally and the number and volume of Golgi bodies and endoplasmic reticulum increase. A distal extremity forms from the cell known as a Tomes’ process. The secretory stage is coeval with crown initiation as the ameloblasts produce a highly organized enamel matrix involving primary enamel prisms and inter-rod enamel. The ribosomes produce enamel proteins packaged into secretory granules, further modified by the Golgi complexes and which migrate into the Tomes’ process. The Tomes’ processes release the granules to first create an initial layer of enamel lacking enamel rods. Then, ameloblasts begin to migrate away from the dentin as the

FIGURE 4.25 Deciduous and permanent teeth undergo the same formation steps, though their timing is staggered. With the exception of the molars, permanent teeth that develop under deciduous teeth are also derived from the dental lamina, produced as a second, deeper tooth bud. Dental development in a subadult between 4 and 5 years of age can be seen in this cutaway view (NMNH; photo: HDK).

Dental lamina Ameloblastic layer Dental papilla Permanent tooth bud

Gum

FIGURE 4.26 A schematic representation of a developing human incisor at approximately 2.5 months following fertilization.

Outer enamel organ epithelium Stellate reticulum

Lip Lip sulcus

Odontoblastic layer Mesodermal follicular sheath Mandibular ossification Meckel’s cartilage

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FIGURE 4.27 Tooth bud in a 5-month-old human fetus. (A) Seen at low magnification (85 3 ), the enamel is the dark layer at the apex of the crown. (B) A higher magnification (400 3 ) shows the detail and organization of the dentin and enamel, with the boundary between the two indicated by the arrow. Odontoblasts (OD) are seen with their elongated processes expanding into dental tubules. Ameloblasts (AM) line the outer surface of the tooth bud actively forming the enamel.

second extension of the Tomes’ process materializes. These two processes allow for a staggered secretion of enamel proteins that produce prismatic and inter-rod enamel (Nanci, 2017). Tooth enamel at this point is about 30% mineralized tissue (Fig. 4.27). The maturation stage precedes tooth eruption. Again, ameloblasts undergo a phenotypic restructuring as they prepare to mineralize the enamel to its fullest extent. Ameloblasts alternate between a smooth apical border to one that is highly ruffled and invaginated. This modulation moves as waves through the tooth from areas of least maturity to the most mature enamel (from the apical to the incisal portion of the tooth). As this occurs, ameloblasts extensively dehydrate the enamel matrix and remove nearly all of the organic material in the enamel matrix that is further enriched and mineralized with greater proportions of carbonatoapatite crystal. Maturation concludes when the crown is completed. Dentin formation also begins at the bell stage of tooth germ development in the spaces adjacent to inner enamel epithelium, and once again, Nanci (2017) provides a detailed synthesis of the process. In summary, odontoblasts differentiate from the ectomesenchymal

cells of the dental papilla and start to produce dentinal matrix not long after they arise. They first begin to manufacture large collagen type III and smaller type I fibers that will prefigure the interface at the dentin enamel junction. They also produce a complex protein-rich ground substance. At this point, the dentin matrix is completely organic. At the same time, odontoblast cell membranes project short processes that form an extracellular matrix while small matrix vesicles bud off near the basal lamina. Apatite crystals are then seeded in the vesicles and mineralized to increase in size until they rupture the vesicle and eventually fuse with other clusters until they form a continuous structure that is approximately 60% mineral by weight. Odontoblasts can be understood as having a matrixforming surface directly atop the cell while its zone of mineralization is some 10 40 μm beneath that. Root dentin formation is somewhat different from that of coronal dentin. In the bell stage, the cervical loop plunges downwards in a tube that prefigures the shape of the root in Hertwig’s epithelial root sheath. Differentiation of odontoblasts within the structure then carries on dentin formation from the crown and continues until closure of the root apex.

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CONCLUSIONS This chapter has provided a succinct overview of normal human bone biology and that of abnormal bone, from gross anatomy to its functional, organizational, and ontogenetic bases. An understanding of normal bone biology is necessary to recognize, describe, and identify the presence of disease in skeletal remains. In other words, a detailed engagement with bone biology and physiology is central to rigorous practice of paleopathology and bioarcheology (e.g., Buikstra et al., 2017, Gosman, 2012; Klaus, 2014; Mays, 2018; Ragsdale and Lehmer, 2012; see also Chapter 5). To be certain, the ever-quickening pace and depth of discovery in the fields of human bone biology hold increasingly important keys for a sophisticated, nuanced, and accurate approach and philosophy in the study of disease in human skeletal remains.

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Clack, J.A., 2012. Gaining Ground: The Origin and Evolution of Tetrapods, second ed. Indiana University Press, Bloomington, IN. Crespo, F.A., Klaes, C.K., Switala, A.E., DeWitte, S.N., 2017. Do leprosy and tuberculosis generate a systemic inflammatory shift? Setting the ground for a new dialogue between experimental immunology and bioarchaeology. Am. J. Phys. Anthropol. 162 (1), 143 156. Dallas, S., Bonewald, L., 2008. Osteocytes play to standing room only: meeting report from the 30th annual meeting of the American Society for Bone and Mineral Research. IBMS BoneKey 5, 441 445. Datta, H., Ng, W.F., Walker, J.A., Tuck, S.P., Varanasi, S.S., 2008. The cell biology of bone metabolism. J. Clin. Pathol. 61, 577 587. Dechow, P.C., 2017. Changes in mandibular cortical bone density and elastic properties during growth. In: Percival, C.J., Richtsmeier, J.T. (Eds.), Building Bones: Bone Formation and Development in Anthropology. Cambridge University Press, Cambridge, pp. 128 147. de Gorter, D.J.J., ten Tijke, P., 2013. Signal transduction cascades controlling osteoblast differentiation. In: Rosen, C.J., Bouillon, R.J., Compston, J.E., Rosen, V. (Eds.), Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, eighth ed. WileyBlackwell, Ames, IA, pp. 15 24. Dial, K.P., Shubin, N., Brainerd, E.L. (Eds.), 2015. Great Transformations in Vertebrate Evolution. University of Chicago Press, Chicago, IL. Donoghue, P.C.J., Aldridge, R.J., 2001. Origin of a mineralized skeleton. In: Ahlberg, P.E. (Ed.), Early Vertebrate Evolution: Paleontology, Phylogeny, Genetics, and Evolution. Taylor Francis, London, pp. 85 105. Ducy, P., Amling, M., Takeda, S., Priemel, M., Schilling, A.F., Beil, F.T., et al., 2000. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 100, 197 207. Edgar, H.J.H., Ousley, S.D., 2016. Dominance in dental morphological traits: implications for biological distance studies. In: Piloud, M.A., Hefner, J.T. (Eds.), Biological Distance Analysis: Forensic and Bioarchaeological Perspectives. Academic Press, Amsterdam, pp. 317 332. Favus, M.J., Goltsman, D., 2013. Regulation of calcium and magnesium. In: Rosen, C.J., Bouillon, R.J., Compston, J.E., Rosen, V. (Eds.), Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, eighth ed. Wiley-Blackwell, Ames, IA, pp. 173 179. Freidline, S.E., Martinez-Maza, C., Gunz, P., Hublin, J.-J., 2017. Exploring modern human facial growth at the micro- and macroscopic levels. In: Percival, C.J., Richtsmeier, J.T. (Eds.), Building Bones: Bone Formation and Development in Anthropology. Cambridge University Press, Cambridge, pp. 104 127. Frisch, B., Calvi, L.M., 2013. Hematopoeisis and bone. In: Rosen, C.J., Bouillon, R.J., Compston, J.E., Rosen, V. (Eds.), Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, eighth ed. Wiley-Blackwell, Ames, IA, pp. 1028 1035. Frost, H., 1963. Bone Remodeling Dynamics. University of Michigan Press, Ann Arbor, MI. Frost, H., 1969. Tetracycline-based histological analysis of bone remodeling. Calcif. Tissue Res. 3, 211 237. Gee, H., 1996. Before the Backbone: Views on the Origin of the Vertebrates. Chapman and Hall, London. Gosman, J.H., 2012. The molecular biological approach in paleopathology. In: Grauer, A.L. (Ed.), A Companion to Paleopathology. Wiley-Blackwell, Chichester, pp. 76 96.

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Gosman, J.H., Stout, S.D., Larsen, C.S., 2011. Skeletal biology over the lifespan: a view from the surfaces. Yearb. Phys. Anthropol. 54, 86 98. Hall, B.K., 2002. Paleontology and evolutionary developmental biology: a science of the 19th and 21st centuries. Palaeontology 45, 647 669. Hall, B.K., 2015. Bone and Cartilage: Developmental and Evolutionary Skeletal Biology, second ed. Elsevier, Amsterdam. Henricksen, K., Neutzsky-Wulff, A., Bonewald, L., Karsdale, M., 2009. Local communication on and within bone controls bone remodeling. Bone 44, 1026 1043. Henriksen, K., Bollerslev, J., Everts, V., Karsdal, M.A., 2011. Osteoclast activity and subtypes as a function of physiology and pathology-implications for future treatments of osteoporosis. Endocr. Rev. 32 (1), 31 63. Hillson, S., 2014. Tooth Development in Human Evolution and Bioarchaeology. Cambridge University Press, Cambridge. Hogg, R.T., Bromage, T.G., Goldman, H.M., Katris, J.A., Clement, J.G., 2017. The Havers-Halberg oscillation and bone metabolism. In: Percival, C.J., Richtsmeier, J.T. (Eds.), Building Bones: Bone Formation and Development in Anthropology. Cambridge University Press, Cambridge, pp. 254 280. Holland, N.D., Holland, L.Z., Holland, P.W.H., 2015. Scenarios for the making of vertebrates. Nature 520, 450 455. Janvier, P., 2015. Facts and fancies about early fossil chordates and vertebrates. Nature 520, 483 489. Kawasaki, K., Richtsmeier, J.T., 2017. Association of the chondrocranium and dermatocranium in early skull formation. In: Percival, C. J., Richtsmeier, J.T. (Eds.), Building Bones: Bone Formation and Development in Anthropology. Cambridge University Press, Cambridge, pp. 52 78. Klaus, H.D., 2014. Frontiers in the bioarchaeology of stress and disease: cross-disciplinary perspectives from pathophysiology, human biology, and epidemiology. Am. J. Phys. Anthropol. 155 (1), 295 308. Klaus, H.D., 2017. Possible prostate cancer in northern Peru: differential diagnosis, vascular anatomy, and molecular signaling in the paleopathology of metastatic bone disease. Int. J. Paleopathol. Available from: https://doi.org/10.1016/j.ijpp.2016.11.004. Klein-Nulend, J., Bakker, A.D., Bacabac, R.G., Vatsa, A., Weinbaum, S., 2013. Mechanosensation and transduction in osteocytes. Bone 54 (2), 182 190. Koga, T., Matsui, Y., Asagiri, M., Kodama, T., de Crombrugghe, B., Nakashima, K., et al., 2005. NFAT and Osterix cooperatively regulate bone formation. Nat. Med. 11 (8), 880 885. Kumar, V., Abbas, A.K., Aster, J.C., 2014. Robbins & Cotran Pathologic Basis of Disease, ninth ed. Saunders, New York. Lefebvre, V., Bhattaram, P., 2010. Vertebrate skeletogenesis. Curr. Top. Dev. Biol. 90, 291 317. Lieberman, D.E., 2011. Evolution of the Human Head. Belknap, Harvard University Press, Cambridge, MA. Limura, T., Denans, N., Pourquie´, O., 2009. Establishment of Hox vertebral identities in the embryonic spine precursors. Curr. Top. Dev. Biol. 88, 201 234. Lorenzo, J., Choi, Y., Horowitz, M., Takayanagi, H. (Eds.), 2015. Osteoimmunology: Interactions of the Immune and Skeletal Systems. second ed. Elsevier, Amsterdam. Lories, R.J., Luyten, F.P., 2018. Overview of joint and cartilage biology. In: Thakker, R.V., Whyte, M.P., Eisman, J.A., Igarashi, I. (Eds.), Genetics of Bone Biology and Skeletal Disease, second ed. Elsevier, London, pp. 209 226.

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Townsend, G., Bockmann, M., Hughes, T., Brook, A., 2012. Genetic, environmental and epigenetic influences on variation in human tooth number, size and shape. Odontology 100 (1), 1 9. van Oers, R.F., 2008. A unified theory for osteonal and hemi-osteonal remodeling. Bone 42 (2), 250 259. van Oers, R.F., Wang, H., Bacabac, R.G., 2015. Osteocyte shape and mechanical loading. Curr. Osteoporos. Res. 13 (2), 61 66. Wallace, I.J., Demes, B., Judex, S., 2017. Ontogenetic and genetic influence son bone’s responsiveness to mechanical signals. In: Percival, C.J., Richtsmeier, J.T. (Eds.), Building Bones: Bone Formation and Development in Anthropology. Cambridge University Press, Cambridge, pp. 233 253. Wei, J., Karsenty, G., 2018. The cross talk between the central nervous system, bone, and energy metabolism. In: Thakker, R.V., Whyte, M.P., Eisman, J.A., Igarashi, I. (Eds.), Genetics of Bone Biology and Skeletal Disease, 2nd ed. Elsevier, London, pp. 317 328. Weston, D.A., 2012. Nonspecific infection in paleopathology: interpreting periosteal reactions. In: Grauer, A.L. (Ed.), A Companion to Paleopathology. Wiley-Blackwell, Chichester, pp. 492 512. Wilbur, A.K., Farnbach, A.W., Knudson, K.J., Buikstra, J.E., 2008. Diet, tuberculosis, and the paleopathological record. Curr. Anthropol. 49, 963 991. Winkler, D., Sutherland, M., Geoghegan, J.C., Yu, C., Hayes, T., Skonier, J.E., et al., 2003. Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J. 22 (23), 6267 6276. Wu, J.Y., Scadden, D.T., Kronenberg, H.M., 2009. Role of osteoblast lineage in the bone marrow and hematopoietic niches. J. Bone Miner. Res. 24, 759 764. Yan, J., Herzog, J.W., Tsang, K., Brennan, C.A., Bower, M.A., Garrett, W.S., et al., 2016. Gut mircrobiota induce IGF-1 and promote bone formation and growth. Proc. Natl. Acad. Sci. U.S.A. 113 (47), E7554 E7563.

Chapter 5

Abnormal Bone: Considerations for Documentation, Disease Process Identification, and Differential Diagnosis Haagen D. Klaus1 and Niels Lynnerup2 1

Department of Sociology and Anthropology, George Mason University, Fairfax, VA, United States, 2Department of Forensic Medicine, University of

Copenhagen, Copenhagen, Denmark

The overview of normal bone biology in Chapter 4 provides a context for considering pathological alterations to the human skeleton. Many, if not all, of these phenomena can be understood in terms of alterations, transformations, or deviations of underlying mechanisms involving normal osteoblast osteoclast coordination, bone growth, maintenance, and metabolic functions. Here, discussion moves to an overview of key issues surrounding abnormal bone tissue. This chapter outlines the basics of abnormal bone, from gross appearance to documentation, disease process identification, and differential diagnoses of skeletal abnormalities.

ABNORMAL BONE: GENERAL CONSIDERATIONS AND GROSS APPEARANCE As noted in Chapter 4, bone is paradoxical—remarkably complex in its biology but evolutionarily and functionally constrained in its phenotypic responses to many diseases. Bones can only respond in three ways to pathological processes: formation of abnormal tissue, abnormal loss of tissue, or a combination of formation/loss. In some syndromes, these responses are nonspecific, while in others the patterns of bone alteration can lead to a possible or probable differential diagnosis (Appleby et al., 2015; Aufderheide and Rodrı´guez-Martı´n, 1998; Buikstra et al., 2017; Lewis, 2018; Ortner, 2003, 2012; Ragsdale and Lehmer, 2012; Roberts and Manchester, 2007; Weston, 2012). Linking gross appearance and molecular signaling mechanisms are the osteoblasts and osteoclasts discussed in Chapter 4. The behavior of these cells produce skeletal

lesions that characterize many disease states (Schinz et al., 1951 1952; Resnick, 2002: 609 651). Local and systemic factors interacting with bacteria, viruses, protozoa, multicellular parasites, fungi, external nutritional factors, and innate genetic disorders can all pathologically modify normal osteoblast and osteoclast functioning and behavior (see below, and Chapter 4; also see chapters in Anderson et al., 2011). In human skeletal paleopathology, a crucial first step in the study of disease is distinguishing normal from abnormal bone, which necessitates understanding the full range of normal (or otherwise nonpathological) anatomical variation and physiological functions that produce differences of size, shape, and morphology that do not lead to functional impairment. Within this “range of normal,” some examples include anomalies such as cranial ossicles, persistence of the metopic suture into adulthood, the septal aperture of the olecranon fossa, or the presence of sesamoid bones in the hands and feet. A definitive source to consult on nonpathological nonmetric cranial and postcranial variation is Mann et al. (2016; also Hauser and De Stephano, 1989). Such normal variation also changes throughout the life course. For instance, the presence of highly vascular and porous new bone formation is normal in a fetal and infant skeleton and reflects the rapid pace of growth (Lewis, 2018). However, bone tissue of a similar gross appearance in an individual over the age of two is likely indicative of a pathological process. In another example involving the need to carefully distinguish normal from abnormal, a slight degree of superficial porosity may often be present on the ectocranial surfaces of the parietal and frontal bones in adulthood. Such features represent fine arrays of nonpathological nutrient foramina

Ortner’s Identification of Pathological Conditions in Human Skeletal Remains. DOI: https://doi.org/10.1016/B978-0-12-809738-0.00005-3 © 2019 Elsevier Inc. All rights reserved.

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FIGURE 5.1 Postmortem damage to bones can often resemble perimortem or antemortem pathological processes. In these cases, careful observation of margin morphology and coloration demonstrates a range of postmortem features including: (A) depressed parietal bone fracture; (B) incomplete postmortem breakage of a proximal ulna resulting from a torsional force; (C) penetrating puncture wound to a parietal bone; (D) penetrating chop damage to a lumbar vertebral body; and (E) oblique chop/slicing damage to the diaphysis of a humerus. These bones were damaged in antiquity as their respective skeletons were exhumed and placed in a large collective secondary burial (Mo´rrope, Peru, Middle/Late Colonial Period; photos: HDK).

and are not necessarily healed porotic hyperostosis lesions. To evaluate the possibility of porotic hyperostosis, further observations regarding the location, morphology, density, and size of porous features are required. Paleopathologists must also distinguish between changes in bone produced during life and the range of pseudopathological postmortem alterations that can mimic disease conditions. These are produced either by factors within the immediate depositional environment or through excavation. Within a burial setting, various biotic processes can alter bone, and include the growth of plant roots around and through bones, burrowing insects or

rodents, and the action of fungi (Henderson, 1987; Child, 1995). Abiotic factors are typically geological, which can include variations in temperature, salinity, pH, pressure of the overburden, and so forth. For example, growth of salt crystals within bone can produce damage at first glance quite similar to gummatous caries sicca lesions produced by treponemal disease. Careful observation, however, can rule out disease (Verano, 2012). Also, the chemistry of specific soil microenvironments even within a single burial can produce variations in preservation that might be confused with abnormal bone tissue. For example, bone in contact with wood from a coffin tends to break

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down faster than other elements in a burial, leading to erosion on the anterior aspect of vertebral bodies that has been confused with the influence of infectious disease. Careless excavation can produce alterations to bone that may be confused with pathological processes. Socalled examples of “trowel trauma” resemble, and must be differentiated from, sharp force injuries. The accidental swipe of a shovel might produce damage analogous to a wound from a bladed weapon. Natural taphonomic forces, such as the pressure exerted by the overburden on a skeleton or precipitation of salt crystals, can also break bone in a wide variety of ways (Fig. 5.1A E). At least three criteria can be considered to distinguish genuine pathological processes from postmortem artifacts. First, postmortem destructive processes generally produce jagged, sharp, or otherwise highly irregular edges. Second, the coloration of the defect margin is especially important to consider. In virtually any kind of postmortem bone breakage, the edges of the defect are often more lightly colored than the outer cortical bone surface. More recently exposed inner surfaces of the bone have not been in contact with the surrounding depositional environment for the same amount of time. Therefore, they are lighter in color. While wooden digging tools are optimal when excavating skeletons, subtle examples of damage can occur when a fine-tipped implement (such as a bamboo skewer) comes into contact with bone and produce features resembling cut-marks. The postmortem nature of such damage can be discerned as postmortem due to the shiny or slightly reflective bone surface within the defect, particularly evident at low magnification. Authentic, perimortem cut-marks display no such polish. Along these lines, key features to look for on the edge of “cuts include evidence that the bone at the edge of the cut has been altered in color to resemble external bone surface color. Bright, lightcolored edges are evidence of recent taphonomic events. Third, biologic processes experienced in life, especially those involving chronic conditions promoting bone loss, will demonstrate comparatively greater degrees of smoothed or rounded margins. With the exception of only the most aggressive osteoclastic chronic diseases, bone destruction is commonly accompanied by reparative new bone formation surrounding the margins of the defect that involves an inflammatory/reparative axis in response to bone destruction. Still, in the case of aggressive disease processes such as certain metastasized cancers, careful examination of lesion characteristics, distribution of lesions in the skeleton, and its radiographic appearance are required to distinguish it from any pseudopathological process (Fig. 5.2; see Chapters 15 and 20). Additionally, when describing postmortem taphonomic changes, Manchester et al. (2016) offer an outstanding set of structured lists of descriptive terminology including

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FIGURE 5.2 Some types of skeletal lesions require extremely careful examination to include the distribution of lesions in the skeleton and radiographic characterization to distinguish it from pseudopathological or taphonomic processes, such as this case of metastatic cancer (primary site unknown) affecting the vertebral column and os coxae (left superoposterior ilium pictured here) (34 year-old male, Terry Anatomical Collection, NMNH P0001606; photo: HDK).

taphonomic changes. Of course, when applying their taphonomic terms, using the additional adjective “postmortem” is quite important (Buikstra et al., 2017). Incorrect identification of a postmortem artifact of taphonomy as an antemortem process is bad science and certainly embarrassing. That said, some cases of altered bone present significant challenges, even for experienced paleopathologists. Very careful and nuanced observation may be required, and further use of tools such as microscopy or medical imaging technologies (e.g., radiographs, CT scanning) can often provide definitive diagnostic information. Sometimes, even after all that effort, a case may still be ambiguous. Still, a few guidelines can be considered that can assist in the macroscopic differentiation between a postmortem pseudopathological condition and an abnormality that arose in living bone (Ortner, 2003, 2012).

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DESCRIPTION OF ABNORMAL BONE When an antemortem or perimortem bone abnormality has been identified, goals turn to reconstructing pathological processes and the most likely causes of the abnormality. In paleopathology, traditional reliance is placed upon visual (gross) examination of bone that is the focus of this chapter. Of course, the more lines of available evidence, the better, and gross examination is often best complemented by radiography (Chapter 7; Wanek et al., 2012), various forms of microscopy (e.g., Schultz, 2001; Ragsdale and Lehmer, 2012), chemical or isotopic analyses (Koon, 2012), and increasingly, ancient pathogen and microbiome DNA analysis (Chapter 8; Bos et al., 2014; Rasmussen et al., 2015; Va˚gene et al., 2018; Warinner et al., 2014). Description in paleopathology. Best practices in 21st century paleopathology rely on a multitiered logical framework that first describes an abnormality. Second, these features are used to identify diseases most likely to have caused this change. Third, one engages in differential diagnosis. Of course, in many cases, it may be impossible to determine the ultimate cause or exact disease (e.g., Weston, 2008). For example, while there are more than 100 known conditions that can produce enamel hypoplasias (Schultz et al., 1998), they are nonetheless among the most valuable windows on early life stress and physiological disruption. While the exact trigger for hypoplasia formation is not observable in skeletal tissue alone, the fact that a stress-induced physiological state occurred is what matters. In other situations, a combination of careful description and differential diagnosis can identify a disease process, especially when the types and patterns of bone involvement tend toward unique patterning. As Ortner (1991, 2003, 2011, 2012) and others (Buikstra and Ubelaker, 1994) have emphasized, a clear and detailed description is one of the most important and fundamental elements to proper practice of paleopathology. Ortner defined four key components to a descriptive system for abnormal bone conditions. First, standardized and unambiguous terminology must be used. Second, a complete inventory of all skeletal material observed must be made. Third, abnormalities are then precisely described in terms of the size, shape, and other morphologic characteristics such as the characteristics of the defect margins. Fourth, the location(s) and distribution of the pathological features are described. Ortner framed description as being conceptually anchored by thinking about bone abnormalities in terms of altered osteoclast and osteoblast activity. The strength of any descriptive system is only as good as its descriptive terminology. In a very concrete sense, words matter. Ortner (2011, 2012) argued that in

paleopathological description and differential diagnosis, the terms we use “. . .often make a big difference between confusion and understanding. Indeed, a basic component of any scientific discipline is rigor in defining and using terms” (Ortner, 2012: 250). Critiques from both within and outside our discipline have aimed at improving our descriptive terminological rigor (Manchester et al., 2016). Particularly those who work in the anatomical sciences provide good models for paleopathologists to follow, as their exacting and rigorous use of terminology helps in getting the highest achievable precision in the observation and description of anatomical structures. Specifically, the foundation of a common descriptive system in paleopathology can and should consistently embrace the international terminological standards established by the Nomina Anatomica (NA) and its successor, the Terminologica Anatomica (TA). These works are the officially approved nomenclature for anatomy as designated by the International Congress of Anatomists. The NA had its origins in 1955 and represented an effort to better standardize the earlier Basle Nomina Anatomica. The NA was continuously revised in 5-year intervals until 1985. Technically, the yet further streamlined TA succeeded the NA in 1998, although the NA is still very widely used (International Anatomical Nomenclature Committee, 1989). For example, a paleopathologist using the TA or NA would not varyingly use any of the multiple, imprecise, or confusing terms for the orbit seen in paleopathological literature (referred to as many things, such as the eye orbit, ocular orbit, orbital plate). Beyond the simple fact that the TA/NA identify this structure as the orbit, there is a consistent logic to this: there is only one structure in the skeleton that is an anatomical orbit, so the use of any other adjectives is redundant or misleading. Likewise, according to these standards, there are no such structures in the human body as “the frontal,” “the parietal,” or “the sphenoid” as is so often written in paleopathological descriptions. As named structures, these features do not exist in the natural world. However, the sphenoid bone (the os spehnoidale), along with the frontal bone (os frontale), and the parietal bone (os paretale) are recognized. Other descriptive terminological errors are even more common, such as the surprisingly frequent misuse of the term skull when the anatomical cranium is being explicitly described (and see Knu¨sel (2014) for more on this issue, including thoughtful perspectives derived from funerary archaeology). Using the human anatomical terminology in the Terminologica Anatomica (1998) as its foundation, Manchester et al. (2016) developed systematic terminological conventions tailored specifically to paleopathological documentation and interpretation. They drew upon

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the experiences and lessons learned from a series of workshops hosted by Donald Ortner and Bruce Ragsdale beginning in 1985 (Powell, 2012; Ragsdale, 1992). This effort initially involved the need to counter the use of inconsistent or inappropriate terms when describing normal and abnormal structures, as well as the fundamental importance of the correct use of widely held descriptive conventions. Manchester and colleagues (2016) add to this further refinement and systemization of terms to the ends of increasing consensus, replicability of observation, and accuracy in paleopathology. Their schema spans general terms, systemic and functional anatomy and physiology, systematic anatomy (bones, joints, muscles, cardiovascular, lymphoid, and neural), pathological, clinical, radiological, and taphonomic descriptive categories. The broader point is that the use of anatomical descriptive standards lends greater precision, reduces ambiguity and interobserver error, and builds cross-disciplinary credibility. Further, we would argue even further that such terminological rigor enhances how we observe and document anatomical structures and their deviations from normal anatomy. The language that we use directly shapes our thinking and perception. Descriptive terminological quality is not just about a state of mind, but it helps foster better practice, tying together the description process recognition differential diagnosis process. Rooted within a rigorous terminological foundation (see Chapter 2; Buikstra et al., 2017; PPA Website) the initial descriptive analysis then attempts to determine whether a skeletal abnormality is: (1) a solitary abnormality possessing a single or solitary focus; (2) a bilateral multifocal abnormality in which abnormal bone is located in two or more sites of the skeleton; (3) a randomly distributed multifocal pathological phenomenon; (4) a diffuse abnormal reduction of bone mass throughout the skeleton (but not necessarily equally reduced in all areas, and; (5) a local or generalized disturbance of normal size and shape of bone that may be accompanied by abnormal bone (Ortner, 2003: 49). In the case of solitary lesions, the lesion itself should be described minimally in terms of size, shape, depth or height, bone quality (e.g., reactive new bone, remodeled bone), and characteristics of the margins of the abnormality. In the case of bilateral multifocal abnormalities, the contralateral lesion may be of a perceptively different size, shape, and position. In this case, it is best to measure each lesion and discuss the variation in size. Of course, more than one pathological condition may be at play in a skeleton, and beginning with the process of documentation and description, the potential of comorbid conditions must always be considered. Further, a descriptive analysis of an abnormal skeleton should be highly specific in regard to the bones involved

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and the location of the abnormalities within the skeleton. Basic directional terminology drawn from the TA/NA should always be used consistently when describing defect locations (e.g., anterior, posterior, anterolateral, inferoposterior, distal, proximal, and so forth). Then, observations are to be mapped onto an anatomical organizational framework. This framework provides a systematic nomenclature and can be expanded with as much anatomic specificity as required or dictated by preservation, research design, or other factors (Buikstra and Ubelaker, 1994; Ortner, 2003; Wilczak and Dudar, 2011). Process recognition in paleopathology. Once the abnormality is described, the work then turns to distinguishing the potential biological process or processes responsible for the abnormality. Abnormal bone can be described in terms of possibilities of altered bone formation, bone loss, bone size, or bone shape. Again, all of this comes back to basic bone biology and variations of abnormally elevated or depressed osteoblast or osteoclast activity. Another option involves normal osteoclast function but depressed osteoblast activity that cannot mineralize normally osteoid matrix. Since unmineralized osteoid decomposes along with the rest of the soft tissue, this last phenomenon might visually appear as a case of elevated osteoclastic responses. Again, the following categories again are not intended to be comprehensive but to serve as a framework than can be expanded upon as needed: 1. Abnormal bone size a. Abnormally small size for age and/or sex b. Abnormally large size for age and/or sex 2. Abnormal bone or bone group shape a. Abnormal shape resulting from defects in growth and development b. Abnormal shape resulting from poorly mineralized bone or biomechanical loading c. Abnormal shape resulting from poor alignment following fracture 3. Abnormal bone formation a. Abnormal new bone formation i. Immature reactive new bone (no discernable pattern or organization of vascular pores or striations) ii. Porous bone iii. Striated bone iv. Spiculated bone b. Abnormal formation of compact (lamellar) bone i. Smooth compact bone (nonplaque-like formations (e.g., osteomas)) ii. Porous compact bone iii. Striated compact bone

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iv. Spiculated compact bone v. Plaque-like formations (relatively thin and flat formations of smooth compact new bone atop a normal bone surface) 4. Abnormal bone destruction a. No margin or clearly defined border b. Clear border but no evidence of repair (marginal new bone formation absent) c. Clear border with evidence of repair (marginal new bone formation present) d. Defined focus with centralized destruction accompanied by marginal new bone formation e. Repair of defined focus with centralized destruction accompanied by marginal new bone formation f. Focal porous destruction g. Generalized porous destruction h. Destructive remodeling i. Osteopenia j. Fracture Pathophysiology and disease processes—defining mechanisms of abnormal bone. The pathological variations of abnormal bone size, shape, formation, and destruction varyingly span several biologic phenomenon: vascular disturbances, innervation/biomechanical disease, trauma/repair, errors in growth, metabolic diseases, inflammatory processes, and neoplastic disorders (see Chapters 10 23). For an additionally key overview of this topic, we recommend Ragsdale and Lehmer (2012). Further, Donald Resnick’s (2002) five-volume Diagnosis of Bone and Joint Disorders, Fourth Edition, is a vital reference work. While Resnick’s emphasis is skeletal radiology, it also provides excellent coverage on the pathogenesis and patterning of skeletal diseases extending down to the cellular level and should be a standard reference for anyone engaging in the study of ancient disease. The broader message here is that integrating these explicitly biological perspectives encourages rigorous and informed disease process identification, and thus, differential diagnosis (Mays, 2018). Pathophysiology is the holistic study of disease physiology, at the center of which are the structural and functional changes to the body caused by disease or anatomical alteration. Key components to the broader perspectives pursued by pathophysiology are its additional foci involving defining various etiologies and the progression of disease pathogenesis—the sequence of nested or contingent causalities spanning cellular, tissue-level, system-wide, and body-level events beginning with the initial exposure or manifestation of a disease state to its conclusion (Kumar et al., 2014; Porth, 2014). These events influence morphological changes to underlying tissues that are often

characteristic or diagnostic of specific disorders which themselves are products of yet more fundamental molecular or genetic phenomena. The human body can endure a range of abnormal or altered physiological stimuli that can produce diverse phenomena. Many states reflect physiological plasticity and are reversible. They can be identified as consistent with a few broad pathophysiologic categories that then are progressively narrowed down to specific conditions (see Kumar et al., 2014). For example, an increased demand or tissue-level stimulation can promote hypertrophy or hyperplasia. Hypertrophy involves an increase in the size of cells as more cellular protein is synthesized to meet a functional demand. In contrast, hyperplasia is an increase in the number of cells to similarly meet a perceived functional demand, resulting in increased tissue or organ mass. Abnormal production of hormones or growth factors is one driver, while compensatory hyperplasias generate increased tissue mass following tissue damage (e.g., a bone callous following fracture). Atrophy represents an opposite process where tissue or organ size decreases due to an abnormal loss of cells or a reduction of cell size. Atrophy can be subdivided into several pathologic categories such as disuse atrophy, denervation atrophy (damage to nerve fibers that affect muscles and bone mass), inadequate blood supply (ischemia), inadequate protein/calorie nutrition (cachexia), depressed endocrine signaling, and tissue compression (pressure) (Kumar et al., 2014). Cell injury and death can relate to either acute or chronic reduced oxygen supply (hypoxia), microbial infection (fungal, parasitic, bacterial, and viral agents), external physical causes (mechanical trauma, thermal trauma), and chemical insults (excess fluoride, poisons, drugs, pollutants). These produce myriad forms of cell injury that may be varyingly reversible or irreversible. Generally, they all involve changes to cell morphology, from initial exposure to crossing over so-called “points of no return” leading to cell death (Kumar et al., 2014). Cellular swelling is a near universal feature of cell injury and occurs when ion pumps in the plasma membrane can no longer maintain fluid homeostasis. This produces fatty swelling of the endoplasmic reticulum and mitochondria as well as swollen outpouchings of the cell membrane (blebs). Persistent or excessive injury or cell death may produce necrosis spanning coagulative, liquefactive, gangrenous, caseous, fatty, and fibrinoid forms (Kumar et al., 2014: 15, 16). An inflammatory response, degradation of the cell membrane, and leakage of the cellular contents all characterize necrosis. Apoptosis is another reaction involving a regulated form of preprogrammed, noninflammatory cell death. For a look at the nature, processes, and variations of inflammatory responses, we direct the reader

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to Kumar and colleagues’ (2014) overview of acute and chronic inflammation. Another component of pathophysiology is to consider how cellular responses play out on larger tissue- or organlevel scales. This is not only intrinsically valuable to the study of disease progression but further assists paleopathology in the identification and differential diagnosis of skeletal lesions. That is to say the combination of an understanding of cell and tissue-level physiology and related anatomical features is important to rigorous paleopathological practice. For example, it was long held that porotic hyperostosis lesions were a product of chronic childhood iron-deficiency anemia (e.g., Stuart-Macadam, 1987, 1992). Walker and colleagues (2009) took a pathophysiological approach to the behavior of marrow cells and the process of erythropoiesis and suggest that megaloblastic anemias (vitamin B9 and B12 deficiencies) are at the roots of its etiology, though iron deficiency or comorbidity between megaloblastic and iron-deficiency anemia

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still remain as possible interpretations (Oxenham and Cavill, 2010; McIlvaine, 2015). Abnormal size and shape. Based on these pathophysiological mechanisms outlined above, disease processes can produce abnormal bone sizes, shapes, formation, and loss (Fig. 5.3). A spectrum of abnormalities in bone size can be linked to genetic, developmental, mechanical, or environmental factors. Errors in growth, or dysplasias, involve abnormal bone size and shapes, and are often found in developmental disorders occurring in embryological development and that play out over development, such as scoliosis (Fig. 5.4). Skeletal dysplasias can be seen as a spectrum of connective tissue disorders (Chapter 19). Rubin (1964) proposed that the various disorders could be organized according to the anatomic site of the potential defect: epiphyseal, metaphyseal, and diaphyseal. Some errors are triggered by environmental cues, such as the link between maternal folate deficiency and neural tube defects (spina bifida) (Pitkin, 2007). Likewise, chronic

FIGURE 5.3 Examples of abnormal bone shape. Left: distinctive anterior pseudo-bowing of the tibia produced by pathological apposition of new bone on the anterior surfaces of the diaphysis in a clinically documented case of venereal syphilis (79-year-old female, Terry Anatomical Collection, NMNH P0000172). Right: medial bowing and marked anteroposterior flattening of a left tibial diaphysis possibly attributable to rickets or osteomalacia (adult individual; Huntington Anatomical Collection 850, NMNH; photo: HDK).

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FIGURE 5.4 Scoliosis of the vertebral column resulting from developmental errors producing wedge-shaped vertebral bodies and characteristic abnormal spinal curvature; also note fusion of right inferior rib (59-yearold female, Terry Anatomical Collection, NMNH P0001636; photo: HDK).

vitamin D deficiency (rickets in children and osteomalacia in adults) where elements such as the long bones, cranial base, and pelvic girdle bow or flattened due to their inability to resist normal weight-bearing owing to insufficiently mineralized osteoid content (Fig. 5.5). Other size abnormalities have genetic origins such as improper expression of Wnt3 in tetra-amelia syndrome that inhibits the formation of the appendicular skeleton (Niemann et al., 2004). Achondroplasia (Fig. 5.6) is another example resulting from a mutation of the fibroblast growth factor receptor gene FGFR3. This leads to a failure of normal endochondral ossification at the level of proliferating and maturing cartilage, along with impacts to intramembranous ossification (DiRocco et al., 2014), but most of the axial skeleton forms and develops relatively normally. Such errors may be understood less as a “malfunction” of chondroblasts, osteoblasts, and osteoclasts, but as those cells faithfully executing impaired instructions. Abnormal bone size can also result from elevated osteoblast activity in a range of morphological forms of hypertrophy (Fig. 5.7). These conditions may relate to a state where there is disequilibrium between bone formation and bone resorption in a bone environment where: (1) osteoblast and osteoclast formation are both elevated; (2) osteoblast activity is elevated while osteoclast functioning is normal; and (3) osteoblast activity is either normal or elevated while osteoclast functioning is depressed. Importantly, size/shape variations and abnormal new bone production do not represent mutually exclusive phenomena. Hypertrophic conditions can be products of pathologic processes producing abnormal new bone, including alteration of the shape of the anterior tibia in treponemal disease, or localized hyperostosis of the cranium under conditions of chronic anemia, or the generalized skeleton-wide hyperostosis of the skeleton in pachydermia. The other side of this coin included osteopetrosis, or Albers Scho¨nberg disease. This features normal osteoblast functioning but virtually nonexistent osteoclast activity. Extensive abnormal bone formation in the endosteal envelope (Fig. 5.8) formed as osteoclasts fails to remove bone enlarging the marrow cavity during growth. Anatomical factors may produce pathological size and shape variations. Altered or insufficient vascular supply to bone can produce necrosis or ischemia. A compromised arterial blood supply to bone in CalveLegg-Perthe disease involves the idiopathic blockage of arterial supply to the femoral head, which is delivered almost exclusively from major arteries running by the neck of the femur (the circumflex arteries). The growing femoral head cannot receive enough blood from the auxiliary artery that passes through the round ligament of

FIGURE 5.5 Medial bowing of the left and right femoral diaphyses (left) (48-year-old male, Terry Anatomical Collection, NMNH P0000828; photo: HDK) and tibial diaphyses (right) (65year-old female, Terry Anatomical Collection, NMNH P0000770 characteristic of healed (inactive) rickets. Photo: HDK).

FIGURE 5.6 Normal adult femur size and morphology (left) and achondroplastic femoral (right). Also note the flaring distal femoral metaphyses and epiphyses, which is also characteristic of achondroplastic dysplasias (37-year-old female, Terry Anatomical Collection, NMNH P0000512 (left), and 59year-old female, Terry Anatomical Collection, NMNH P0001636; photo: HDK).

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FIGURE 5.7 Hypertrophy of the left and right femoral diaphyses attributable to Paget’s disease. Contralateral lesions on the right femur are clearly not as severe but abnormal bone formation is still clearly present (75-yearold male, Terry Anatomical Collection, NMNH P0000531; photo: HDK).

FIGURE 5.9 Skeletal disuse atrophy (humerus, left; femur; right) associated with quadriplegic paralysis for at least the final 16 years of this individual’s life (21-year-old male, NMNH 6087; photo: HDK).

FIGURE 5.8 An example of abnormal bone formation in the endosteal envelope of a right proximal femoral diaphysis leading to near total obliteration of the medullary cavity (Huntington Anatomical Collection, NMNH; photo: HDK).

the head of the femur. The shape of the femoral head progressively changes as bone tissue necrotizes and adjacent bone atrophies. Additional size and shape abnormalities relate to innervation and biomechanical disease. These alterations generally follow Wolff’s law. These can involve a spectrum of abnormally hypertrophied bone emerging from excessive strain from high levels of physical activity to a pathological loss of bone mass/strength and resultant atrophy in contexts of disuse or paralysis (Fig. 5.9). Traumatic injuries span a wide array of abnormal bone shape/size, bone formation, and bone loss stemming from fractures, dislocations, cuts, blunt force injuries, dismemberment, trepanations, cranial deformation, and burn

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FIGURE 5.10 Complete fracture of the distal femoral diaphysis. While poorly reduced (aligned), the bone demonstrates very advanced healing (enlarged view, right) (adult male, NMNH (169) Huntington Anatomical Collection 321053; photo: HDK).

injuries (Redfern, 2016) (Figs. 5.10 5.17). Immediately following sublethal bone fractures, a repair process begins with the formation of a hematoma and a cascade of molecular signaling mechanisms including the master organizer Runx2 that begin to direct the organization of the clot into a semistable fibrous mass that is further organized into bone as repair proceeds (Fig. 5.18) (Lieberman and Friedlaender, 2005). Abnormal bone formation and destruction. Abnormal new bone formation may occur as both periosteal and endosteal envelopes. On the molecular level, a host of

bone-forming signaling mechanisms can be at play, from Wnt expression to RANK and OPG ratios. On a tissue level, conditions that produce passive hyperemia elevate blood oxygen tension such that the locally negatively charged environment stimulates osteoblasts (MacGintie et al., 1993). Abnormal periosteal new bone formation can be morphologically quite variable (Ragsdale et al., 1981; Resnick, 2002). While the timing of response is variable, injury or inflammation to the periosteum will activate its osteogenic potential such as with treponemal disease, localized trauma, staphylococcal or

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FIGURE 5.11 Femoral diaphyseal fracture exhibiting a large and relatively well-organized and extensively remodeled bony callous that originated as a hematoma surrounding the traumatic injury (48-year-old female, Terry Anatomical Collection, NMNH P0000016R; photo: HDK).

streptococcal infection, or scurvy (Figs. 5.19 and 5.20) as new, reactive bone is rapidly formed. It is initially highly vascularized and poorly organized but is destined for remodeling (Figs. 5.21 and 5.22). Contrary to common use in paleopathology, it is probably incorrect to refer to such new bone formation as “woven bone” since usage of that term should be based on histological identification. The faster new bone formation occurs, the less organized the new tissue will be (Figs. 5.23 and 5.24). Socalled “sunburst” formations of spiculated new bone produced by an adrenoneuroblastoma, for instance, represent high-velocity abnormal new bone formation when

compared to plaque-like periostosis. New bone formation typically produces defects with persistent well-defined borders. New bone formation may also be fundamentally reparative in function, from callous formation in fracture repair to inflammation or bone destruction in osteoarthritis, vertebral tuberculosis, or intervertebral disk herniation (osteophytosis) (Fig. 5.25). In that sense, abnormal new bone formation in degenerative joint disease is not produced by the disorder, but rather, it is an attempted reparative response to the underlying pathological condition. Neoplasms represent accelerated proliferation of abnormal cells (Brothwell, 2012; Resnick, 2002) that may be either localized and benign or systemic and malignant

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FIGURE 5.13 Well-healed depressed cranial fracture affecting the right posteroinferior parietal bone (adult individual; Huntington Anatomical Collection, NMNH; photo: HDK).

FIGURE 5.12 Complete fracture of the right humerus characterized by successful union and significant remodeling of the callous (79-year-old female, Terry Anatomical Collection, NMNH P0000047R; photo: HDK).

FIGURE 5.14 Crush fracture affecting the left lateral aspect of the L-5 vertebral body; subsequent remodeling and fusion to the bony sacrum can be observed (adult individual; Huntington Anatomical Collection 213, NMNH; photo: HDK).

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FIGURE 5.15 Abnormal bone loss owing to a surgical intervention seen here in an example of trepanation; little to no remodeling can be observed and it is likely this individual did not survive long after the procedure was concluded (adult male individual, pre-Hispanic Peru, NMNH 204254; photo: HDK).

(Figs. 5.26 and 5.27). Neoplasms or osteopenia can also compromise normal bone size, shape, or strength. Bone tumor types are numerous (Ragsdale and Lehmer, 2012: Fig. 13.1) but generally can be characterized by the location of the types of cells in which they arise (chondroblasts, osteoblasts, and osteoclasts) and by their products (cartilage, fibrous tissue, or bone). Metastatic cancer, especially breast, prostate, lung, and kidney tumors have a special affinity for bone (Resnick, 2002; and see below in Case Study 2: Abnormal Bone Destruction and Formation discussed at the end of this chapter). Depending on the neoplasm, resulting bone involvement can be lytic (e.g., multiple myeloma), blastic (e.g., sarcomas), or mixed (leukemia, prostate/pancreatic/bladder/carcinoid metastases) (e.g., Klaus, 2016, 2018b). Other more exotic neoplasms can include bone- and tooth-forming teratomas that arise from errors in embryological development (Wasterlain et al., 2017), and depending on their size, can become malignant (Charlier et al., 2009; Klaus and Ericksen, 2013). Abnormal bone loss can relate to either a failure of formation or the destruction of preexisting tissue. The former can include embryological errors such as an epidermal inclusion cyst (Ortner, 2003), where epidermal tissue is improperly sequestered in the mesoderm and bone cannot form. Destruction or removal of preexisting bone occurs far more commonly as seen in pathogenic processes including the fine vascular response to scurvy in the sphenoid bone to more wide-ranging and larger volumes of bone loss seen in brucellosis, tuberculosis, and various metastatic diseases. In these processes, there

FIGURE 5.16 Abnormal bone size resulting from bilateral amputation of the lower limbs approximately at the midpoint in the tibia and fibula associated with clinically documented chronic syphilis (right side shown here) (approximately 42-year-old female, Terry Anatomical Collection, NMNH P0000745; photo: HDK).

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FIGURE 5.17 Pronounced fronto-occipital style of artificial cranial deformation produced by application of chronic low-grade pressure during childhood when the cranium is incompletely ossified (adult female individual, pre-Hispanic Bolivia, NMNH 390818; photo: HDK).

FIGURE 5.18 Abnormal periosteal new bone formation on the anterior diaphysis of a right femur; size, shape, and sharply defined margin characteristics, along with the abnormal medial angulation of the superior diaphysis, are together suggestive of the abnormality’s origin as subperiosteal bleeding is associated with a fracture (adult male individual; Huntington Anatomical Collection (144) 318956, NMNH; photo: HDK).

FIGURE 5.19 Abnormal periosteal new bone formation located on the anterior crest of the tibia, exhibiting fine, highly vascularized new bone formation and associated sclerotic activity. Abnormal periosteal new bone formation (adult individual; Huntington Anatomical Collection, NMNH; photo: HDK).

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FIGURE 5.20 New bone formation present on the right zygomatic bone indicative of an abnormal osteoblastic phenomenon (63-year-old female, Terry Anatomical Collection, NMNH P0000240R; photo: HDK).

again is a spectrum of predicable responses in relation aggressiveness and speed of progression. Slowly progressive lytic lesions can feature partially remodeled and relatively regular borders, whereas more acute and destructive processes will produce highly irregular, “punched-out,” or “moth-eaten” lesions in appearance that do not elicit marginal inflammation (Fig. 5.28). Bone destruction can be seen as a net increase in osteoclastic activity, itself a downstream state of the fundamental cellular signaling mechanisms that emerge during a chronic inflammatory event in or around bone (Gosman, 2012). Simply stated, inflammation causes bone to destroy itself. Related active hyperemia increases tissue oxygen tension and positively charged solutes in blood are optimal for osteoclast activity (MacGintie et al., 1993). Inflammatory disorders are the result of an immune response to infectious agents such as bacteria, viruses, parasites, fungi, and autoimmune disorders (Ward and Lentsch, 1999; Straub and Schradin, 2016). The inflammatory process begins with a standard, coordinated vascular cellular response, but bone itself is incapable of swelling (one of the three biologic manifestations of inflammation). Inflammation involves an exaggerated form of normal cell turnover, encompassing elaborate cascades of cell signaling factors and pro- and antiinflammatory signals. Inflammation triggers the recruitment of leukocytes, activation of macrophages, neutrophils, phagocytes, regulatory interleukins, and other factors that may ultimately conclude inflammatory and healing processes. Importantly, inflammation-driven bone destruction and reactive new bone formation can coexist in bone, and represent two adjacent bone microenvironments with contrasting osteoblast and osteoclast activity. This is discussed further later in this chapter. Many such inflammatory disorders follow these patterns, though a few exceedingly rare osteoclastic disorders follow their

FIGURE 5.21 Abnormal periosteal new bone formation affecting much of the diaphysis of this right tibia. Bottom closeup image demonstrates the presence of newer, more vascularized tissue (A) and lesion surfaces exhibiting a greater degree of age and remodeling (B) (63-year-old female, Terry Anatomical Collection, NMNH P0000240R; photo: HDK).

FIGURE 5.22 As abnormal periosteal new bone is progressively remodeled, impressions of blood vessels in the periosteal membrane may form as the remodeling processes occurs around the adjacent vasculature (adult male individual; Huntington Anatomical Collection (448) 132316, NMNH; photo: HDK).

FIGURE 5.23 Exuberant, relatively poorly organized, and generally rapid idiopathic new bone formation and partial ossification of the interosseous membrane affecting the left tibia and fibula (60-year-old male, Terry Anatomical Collection, NMNH P0000868; photo: HDK).

FIGURE 5.24 Manifestations of periosteal new bone formation on the same tibial diaphysis, demonstrating a highly vascularized active state of new bone formation on the left anterior aspect of the bone (A) simultaneously accompanied by a more inactive, healing, and remodeling surface on the left posterior aspect (B) (adult male individual; Huntington Anatomical Collection (1556) 227958, NMNH; photo: HDK).

FIGURE 5.25 Examples of abnormal joint morphology. Left: Extensive vertebral osteophytosis and partial fusion between the T12 and L1 vertebral bodies can often be understood in terms of the pathophysiological response and reparative attempt in response to underlying inflammatory disorders (Burial 2007-2 DIST, 35 45-year-old individual of indeterminate sex, late pre-Hispanic Peru). Right: similarly, marginal lipping can be observed in the superior and anterior borders of the glenoid fossa, while purely lytic joint surface porosity of the joint surface itself is related to subchondral bone death (adult individual; Huntington Anatomical Collection (22.2) ‘93-‘4. NMNH). Photos: HDK).

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own unique rules, such as Gorham Stout syndrome. Also known as vanishing bone disease or progressive massive osteolysis, a still-unknown mechanism(s) abnormally stimulates osteoclasts in the absence of an inflammatory trigger whereby bone is resorbed and replaced by hypervascular connective and lymphatic tissue (Nickolaou et al., 2014) (Fig. 5.29). The five modes of inflammation are septic, granulomatous, angiitic, toxic, and reactive (Ragsdale and

FIGURE 5.26 A benign and localized neoplasm in the form of a welldefined and circumscribed “button” osteoma observed on the anterior aspect of the right parietal bone (70-year-old male, Terry Anatomical Collection, NMNH P00000061; photo: HDK).

Lehmer, 2012). Septic inflammation is dominated by polymorphonuclear immune cells that rapidly produce exudate (pus) that can fill a marrow cavity, strip periosteum, and kill bone. Septic inflammation, such as that seen in osteomyelitis (Fig. 5.30), can generate swelling and edema in the medullary cavity with increasing pressure, promoting infarction of cortical tissue. The result is a sequestrum (necrotic bone destined for resorption) and accompanying involucrum (a shell of new, reparative periosteal bone). Granulomatous inflammation is a slower, histiocyte-moderated mode of inflammatory response. It involves the accumulation of rounded aggregates of macrophages and lymphocytes around a necrotic focus that spread and can lead primarily to bone destruction such as with tuberculosis. Angiitic inflammation is driven by antibody-producing cells (plasma cells, lymphocytes) that accumulate around blood vessels and produce a necrotizing gumma as seen in treponemal diseases. Toxic inflammation includes rheumatoid arthritis when fluid effusion in a joint triggers an inflammatory response. Reactive inflammation, associated with viruses and parasitic infection, tends to be the most localized and least severe in skeletal tissue (Ragsdale and Lehmer, 2012). Other disorders feature both abnormal bone loss and formation. These are associated with biphasic hyperemia with the disease beginning as active hyperemia but later transitioning to a passive state such as chronic

FIGURE 5.27 Aggressive and purely osteolytic processes affecting the ilium (A) and scapula (B) associated with clinically identified metastasized breast cancer (48-year-old female, Terry Anatomical Collection, NMNH P0000016R; photo: HDK).

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FIGURE 5.28 Contrasting processes: (A) an example of a chronic and inflammatory condition involving both bone destruction and new bone formation, particularly notable along the margins of the destructive focus attributable to tertiary syphilis (adult individual, NMNH (1263) Huntington Anatomical Collection 317848; photo: HDK); (B) a more acute and purely lytic phenomenon producing so-called “moth-eaten” irregular margins in a case of probable subadult tuberculosis (Burial U10 05-29, Middle/Late Colonial Period, Mo´rrope, Peru; photo: HDK).

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FIGURE 5.29 Radiographic view of Gorham Stout syndrome (also known as vanishing bone disease or progressive massive osteolysis). This rare osteoclastic disorder involves abnormally stimulated osteoclasts in the absence of an inflammatory trigger whereby bone (in this case, the entire mandible) is resorbed and replaced by hypervascular connective and lymphatic tissue (image courtesy of Dr. Aditya Shetty, Radiopaedia. org).

osteomyelitis, Paget’s disease, or pulmonary hypertrophic osteoarthropathy. In the case of gummatous treponemal lesions, a region of reactive abnormal periosteal new bone formation surrounds a central destructive focus. Tuberculosis lesions in vertebral bodies produce significant bone loss and mechanical fragility. Reparative new bone attempts to offset the destruction (Fig. 5.31), but since osteoclastic activity is far more rapid, greater net bone loss always occurs, leading to Pott’s disease and kyphosis. Recognizing a biphasic phenomenon may be very valuable to disease process identification, such as with Paget’s disease (Fig. 5.32) and metastasized prostate cancer both featuring initial lytic activity that later switches over to abnormal new bone formation. Metabolic diseases also produce a host of atypical bone phenotypes through abnormal production, mineralization, maintenance, or as secondary sequellae to metabolic deficiencies. For instance, rickets and ostemalacia stem from chronic vitamin D deficiency in subadults and adults, respectively. Improper mineralization of osteoid leads to mechanically insufficient bone that can bend,

flatten, or otherwise become distorted under conditions of normal loading. Rachitic bone may also feature “slit/strut” morphology in metaphyseal regions. These formations represent parallel zones of alternatingly mineralized and unmineralized osteoid that provide both greater resistance to bending and a basis for rapid mineralization when sufficient vitamin D becomes available (Ortner and Mays, 1998: 53). Skeletal signs of scurvy can be understood as a manifestation of vitamin C deficiency that leads to poorquality type-I collagen, which produces weakened blood vessels prone to tearing and hemorrhage. With bleeding occurring in the periosteal envelope, various osteoblastic and osteoclastic-related responses occur, including the removal of bone to make way for new blood vessels and the formation of new bone from subperiosteal hematomas (see papers in Crandall and Klaus, 2014). Beyond traditionally recognized nutritional, hormonal, and environmental factors, other deeper systemic and genetic factors may underlie generalized disorders of the skeleton are considered “metabolic” regardless of immediate cause, including hereditary diseases such as osteogenesis imperfecta or osteopetrosis. Yet, a metabolic disorder such as osteoporosis is probably best understood as a syndrome or group of diseases resulting in a reduction of bone mass. Similarly, drawing distinctions between endocrine diseases, nutritional deficiencies, and hereditary syndromes can logically organize and distinguish such disorders and is advantageous in terms of diagnostic logic; the underlying pathophysiological processes of systemic skeletal diseases very much form a continuum. Ultimately, all pathological variations of bone size, shape, formation, and loss are multicomponent phenomena. To understand them in the most complete way possible, cultural/behavioral influences to the physiological components of inflammation, hyperemia, and osteoblast and osteoclast activity must also be considered. An understanding of these conditions ultimately must rest with the body of knowledge regarding: molecular signaling mechanisms and gene expressions—and how particular disease states change, alter, or manipulate osteoblast and osteoclast signaling to their own ends (see examples at the end of this chapter). The fundamental factor is the behavior of the RANKL/RANK/OPG regulatory axis, the RANKL:OPG ratio, and the expressions of Wnt/β-catenin pathway (also known as the canonical pathway) (Porth, 2014; Gosman, 2012; also see Chapter 4 and various chapters in Rosen et al., 2014). This is critical to how paleopathologists think about identifying and understanding disease processes. Classify with caution (see Chapter 1). Classification systems are useful tools but also involve perils. While

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FIGURE 5.30 Fracture of the left femur demonstrating advanced yet incomplete healing with swelling of the diaphysis and extensive reparative new bone formation (left); posterior close-up view of the fracture with a single, large draining cloaca resulting from chronic osteomyelitis (21-year-old male, Terry Anatomical Collection, NMNH P000128; photo: HDK).

they can minimize ambiguity and error in assigning a given disorder to any of the categories in the system, they are typologies and do not guarantee unambiguous assignment (Ortner, 2012). Therefore, the most prudent way to pursue the necessary classification of abnormal

bone is considering causation and pathogenesis at the center as the guiding principles for understanding the disease process (see examples below). The pathologic and radiographic features of skeletal disorders at various stages of a disease known from living patients are vital

FIGURE 5.31 Two views of osteoclast-driven bone destruction and osteoblast-mediated responses, including putative attempts at stabilization via ossification of adjacent connective tissue, are seen here in a case of extensive chronic tuberculosis affecting the T7 L5 vertebral bodies (23-year-old male, Terry Anatomical Collection, NMNH P000468; photo: HDK).

FIGURE 5.32 Bone destruction and formation can be observed in cases of Paget’s disease, which is a biphasic disorder. Initial and persistent bone loss affecting the posterior cranium (right) can be contrasted with subsequent abnormal bone formation that has altered the geometry of the facial skeleton (adult male, NMNH, Historic New York; photos: HDK).

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factors in differential diagnosis, but paleopathology can only reconstruct disease processes in bone most often confined only to the last moments of a person’s affliction and may or may not be the immediate cause of death (Ortner, 2011). Also, while we depend on analogies with clinical literature for interpreting skeletal evidence of disease, we must recognize that we are making a uniformitarian assumption (Buikstra et al., 2017). That is, we would be wise to question whether or not a pathologic process unfolded in the past as it does in the clinically observed present, especially when there are significant discontinuities in ecogeographic space and evolutionary time. This gives us at least some critical understandings to evaluate the strengths of any classificatory analogies we may draw.

DIFFERENTIAL DIAGNOSIS The process of description and process identification in paleopathology builds toward the final goal—the differential diagnosis of abnormal skeletal tissue. Quick visual examination is never sufficient to securely identify a pathological process. Given the multitude of distinct diseases that can produce similar or overlapping patterns of pathological bone formation or destruction, the method of differential diagnosis is a necessary tool in the study of abnormal bone. A survey of the literature uncovers multiple “styles” of differential diagnosis. As Buikstra et al. (2017) emphasize, there are clinical approaches that focus upon individual skeletons, while in other cases, a population-based approach may be followed. In the latter case, key diagrams or pattern-fit methods may be applied. Modern paleopathology aims to practice rigorous differential diagnosis (Buikstra et al., 2017; Klaus, 2017; Mays, 2018). Some investigators have sought confirmation of what they deem is a likely diagnosis. Others conduct what could be called “snap” diagnoses, drawing on intuition or appealing to “expert opinion.” Instead, the most advisable approach is to adapt the methods and epistemology using the hypothetico-deductive method of differential diagnosis as used in clinical practice. The relationship between disease and skeletal lesions is not isomorphic. Accordingly, differential diagnosis is by nature a probabilistic endeavor. First, one gathers all available information in the description of a pathological condition. Second, possible etiological and pathogenic conditions are identified. Third, the observed abnormal bone is compared to known disease patterns and contrasting forms of disease are systematically removed from consideration. Diagnostic options are thus progressively narrowed down in an exclusionary fashion. As in hypothesis testing, the most likely diagnostic option(s) is that which cannot be ruled out or rejected. In other words,

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differential diagnosis is a method that involves a process of elimination that reduces the probability of candidate conditions until one or more conditions are concordant with observations and cannot be excluded. Plurality, creativity, and differing opinions should always be encouraged in science, but when it comes to differential diagnosis, there is arguably less flexibility regarding best practice. An increasingly rigorous, streamlined, and systematic approach can reduce interobserver error, enhance comparability across studies, and produce more certain and accurate differential diagnoses of skeletal disease. This can be possible through operationalizing a few different elements. First, it is key to comparatively and visually map the anatomical distribution of lesions in an individual or across a sample. Then, process identification and pattern matching can make equal use of this framework or rubric to rank potential differential diagnoses to the progressive exclusion of unlikely diagnostic options. Once again, the use of rigorous and explicit terminology plays a key role in differential diagnosis and the confidence of the assessment. A review of the literature reveals a wide range of often-ambiguous terminology used in diagnosis, from considerations of a lesion being perhaps a likely candidate condition to claims of pathognomonic certainty. For the sake of both standardization and logical rigor, we concur with Appleby et al. (2015) and find great value in their recommendation to adapt the logic and organization of the Istanbul Protocol Manual on the Effective Investigation and Documentation of Torture and other Cruel, Inhuman or Degrading Treatment or Punishment (UN, 2004). Appleby et al. (2015: 20) replaced the Istanbul Protocol’s use of “trauma” with “condition(s)” and proposed the following criteria: G

G

G

G

G

Not consistent: the abnormality could not have been caused by the condition(s) described; Consistent with: the abnormality could have been caused by the condition(s) described, but it is nonspecific and there are many other possible causes; Highly consistent: the abnormality could have been caused by the condition(s) described, and there are few other possible causes; Typical of: the abnormality is usually found with this type of condition(s), but there are other possible causes; Diagnostic of: the abnormality could not have been caused in any way other than by the condition(s) described (i.e., it is pathognomonic).

This system possesses several advantages, including making the degree of diagnostic confidence overt. Naturally, we seek the most specific identification of ancient disease. Ortner (2011, 2012) always stressed that differential diagnoses must always be restrained—never to exceed the evidence. Ragsdale and Lehmer (2012) also

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emphasized the need for a conservative practice of differential diagnosis. For them, the greatest diagnostic confidence and comparability can be found in the level of disease identification (see also Miller et al., 1996). In one example, Klaus and Ortner’s (2014) study of treponemallike lesions in a skeleton from early postcontact Peru are highly concordant with those produced by known cases of venereal syphilis. Still, there is highly significant overlap with lesions produced by yaws (another treponemal manifestation) with no one specific feature to argue the lesions were diagnostic of either candidate condition. Therefore, the differential diagnosis can reject a variety of abnormal proliferative and lytic conditions but can only say the lesions are either typical of yaws or venereal syphilis. It is also equally important to avoid careless diagnostic comparisons between an archeological skeletal abnormality and radiographic or gross images of clinical patients with skeletal disorders. The legendary American orthopedic pathologist Lent Johnson, M.D., decried what he called “ribbon matching” in which he referred to diagnostic efforts that attempted to match either a pathological gross specimen or a radiograph with an image in an orthopedic pathology or skeletal radiology text (Ortner, 2011: 6). Instead, Johnson urged paleopathologists to base their diagnoses in the reconstruction of the pathological history of a skeletal disorder and then to seek an understanding of the pathogenesis of the abnormality. Ortner (2011) extended this excellent advice to all possible analyses of archaeological examples of skeletal pathology. When examining a lesion in dry bone, close examination will allow the observed to identify the progress of a disease. As part of differential diagnosis, one should consider the disease process in both soft and hard tissue, as it culminates in the observed lesion. While this will not always be possible in every skeleton, it should still be attempted based upon a reasonably comprehensive knowledge of basic osteoblastic and osteoclastic processes. We end this section by considering a number of epistemological and theoretical observations regarding differential diagnosis offered by Mays (2018). Ultimately, differential diagnosis involves an attempt to bridge unknown to known, but we must always question and improve the ways in which we generate this knowledge. These include the relationships between heuristic (intuitive) and formal analogies, the limitations of comparability of archaeological material with the medical, clinical, and paraclinical literature, and the benefits and shortcomings from comparisons with anatomical reference samples (Mays, 2018). In particular, Mays (2018: 17) argues for a greater metacognizance that can prevent “the unthinking empiricism that reliance on a reference/target sample methodology can engender.” Of course, reference data and collections will always be useful, but combining them

with other lines of information is often wise. At the same time, we need to increase the explicit biological (pathophysiological) emphasis in understanding of skeletal lesions, further practical and philosophical evaluation regarding our uses of analogy, and the potential of Bayesian methods to reduce diagnostic ambiguity. Further thinking regarding any uniformitarian notions should be critically assessed. Continuing advances in genomics, metagenomics, and proteomics are permitting increasingly unambiguous forms of direct identification, which may eventually transcend many of the challenges that currently face paleopathological differential diagnosis.

CASES OF ABNORMAL BONE: MODELING DESCRIPTION, IDENTIFICATION, AND DIFFERENTIAL DIAGNOSES We close this chapter with a summary of two abbreviated case studies involving archeological examples of ancient bone from a site in Peru that attempts to apply examples of the frameworks described in this chapter. We review one case dominated by abnormal bone loss and one case featuring abnormal bone destruction and formation. Case Study 1: Abnormal Bone Destruction. The archeological site of Ventarro´n is located in the Lambayeque Valley Complex on the arid north coast of Peru. Ventarro´n was a prominent monumental site during Peru’s precocious Formative era beginning around 2800 BCE (Alva Meneses, 2012). Though abandoned for millennia, the complex was seen as a sacred locus by later societies who continued to bury their dead among the ruins (Klaus, 2018a). Burial 2007-2 DIST-A was a 35 45-year-old individual of indeterminate sex. This context likely dates to the late pre-Hispanic Middle Sica´n culture (AD 900 1050/1100). The vertebral column demonstrated significant bone destruction between the sixth and eighth thoracic vertebrae (Fig. 5.33). The greatest degree of destruction was centralized at the T7 vertebrae. More than 95% of the vertebral body had been destroyed, leaving only small intact portions of the superior vertebral endplates anterior to the left and right pedicles. The T8 vertebra demonstrated a large defect present in the anterior aspect of the vertebral body that had extended anteriorly to destroy nearly all of the superior vertebral endplate. Well-organized sclerotic new bone formation was present on the remaining anterior, left lateral, and right lateral surfaces of the T8 vertebral body. The left lateral side of the T6 vertebral body was missing as a large cavity-like defect exposed the trabecular structure all the way to the anatomical center of the vertebral body. Well-organized sclerotic new bone formation was similarly present on the remaining anterior and right lateral surfaces of the T6 vertebral body.

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FIGURE 5.33 Two views of affected vertebrae diagnostic of pre-Hispanic tuberculosis on the north coast of Peru, with a detailed view of the extent of bone destruction and osteoclastic activity affecting the T6, T7, and T8 vertebral bodies (right) (Burial 2007-2 DIST, 35 45-year-old individual of indeterminate sex, late pre-Hispanic Peru; photo: HDK).

Before the differential diagnosis can proceed, we must evaluate whether these defects are taphonomic in nature. We can reject the pseudopathological options. These features are not consistent with patterns of salt crystal precipitation in bone in the region (Verano, 2012; Klaus and Ortner, 2014). They do not conform to any form of postdepositional damage caused by looting. There is no evidence of fungal growth, bioturbation (animal or root activity), or other geological cause (e.g., high water table, high acidity). These abnormalities were from a biological process incurred during life. New bone formation on the T6 and T8 vertebral bodies further validates this interpretation. Disease process identification involves these defects narrowed down to that of a primarily osteoclastic phenomenon of the vertebral column that can be accompanied by some reactive bone. The lack of more extensive reparative or reactive new bone appears to reflect a rapidly progressing, though chronic, condition. Within this category, the most likely diagnostic options are brucellosis, echinococcosis, paracoccidoidomycosis, and tuberculosis (see Resnick, 2002; Ortner, 2003, this volume). Brucellosis is a zoonosis caused by ingesting the milk or meat of an animal infected by one of three species of

this Gram-negative bacteria. Pulmonary infection frequently disseminates to the skeleton, mainly affecting noncontiguous vertebrae and frequently destroying vertebral endplates and the intervertebral disc. Brucellosis is not a consistent diagnostic option due to the involvement of contiguous vertebrae and that endplate destruction here appears as collateral damage due to the progression of an osteoclastic process focused in vertebral bodies. Echinococcosis tapeworms are transmitted to humans via contaminated meat, crops, or drinking water. Infection generally begins in the liver with disseminated cases involving the growth of cysts in bone as part of the parasite’s lifecycle. Here, these lesions are highly inconsistent with echinococcosis, including lesion size, the presence of marginal repair, and the fact that vertebral transverse processes and neural arches were spared. Paracoccidoidomycosis is a fungal infection that produces either singular or multiple destructive lesions in marrow spaces. Again, this condition is inconsistent with these observations, as paracoccidoidomycosis tends to produce relatively rounded lesions that are far more numerous, better defined, and distributed on noncontiguous vertebrae. Tuberculosis is acquired by either aerosolized transmission or via consumption of infected animal

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meat or milk. Disease progression consists of primary infection and later reactivation with the potential of hematogenous dissemination to hematopoietic marrow. Vertebral lesions associated with tuberculosis are predominantly osteoclastic but as the infection persists and progresses, increased venous blood flow with reduced oxygen tension produces a contrasting anoxic bone microenvironment around the margins of a destructive focus. Thus, osteoblasts can be stimulated to produce reactive or reparative new bone around and within the margins of lytic foci (Resnick, 2002). Using the modified Istanbul Protocol (Appleby et al., 2015), we would argue that lesions in Ventarro´n Burial 2007-2 DIST-A are diagnostic of tuberculosis. Mycobacterial infection cannot be ruled out. It is the most probable diagnostic option. Still, much of the skeleton of this individual was missing, and one of the bases for a confident differential diagnosis involves evaluation of lesion distribution throughout the entire skeleton. The missing elements here prohibit this broader perspective, so we may state the lesions are tentatively diagnostic of tuberculosis. It is, however, always better to err on the side of caution. In general, however, this set of changes is consistent with findings from prior, rigorously established differential diagnoses of tuberculosis (Buikstra, 1981; Buikstra et al., 2017; Roberts and Buikstra, 2003). If the differential diagnosis leads to tuberculosis, it is useful to evaluate the degree of consistency between these lesions and the known pathophysiology and molecular signaling mechanisms of mycobacterial disease. Here, we find high consistency. When tuberculosis disseminates from the lungs, the bacilli take a hematogenous route aided by the venous plexus of Baston to the vertebrae. As an iron-loving bacterium, the rich hematopoietic marrow inside the vertebral bodies represents the most optimal environment for bacilli colonization and growth (Wilbur et al., 2008). A granuloma then forms around infectious foci in the bone marrow microenvironment. The granuloma is surrounded by numerous multinucleated osteoclast-like and osteoclast precursor cells. These and other innate immune cells are activated to manage the infection. They release multiple inflammatory factors such as IFN-γ, TNF-α, and IL-1. In particular, the cytokines TNF-α and IL-1 locally disregulate the normal balance between osteoclasts and osteoblasts. The RANKL-OPG ratio is altered in the context of tuberculosis infection (OPG downregulated; RANKL upregulated). In fact, osteoblasts are in charge of the downstream effect of increased osteoclastogenesis (Li et al., 2016; Zhang et al., 2015). Pathological bone loss then follows. Further, experimental evidence suggests that bone destruction in tuberculosis goes beyond the release of inflammatory factors. Tuberculosis reprograms osteoclasts. Hoshino et al. (2014) infected cultured osteoclasts with

tuberculosis bacilli. Their results showed that intracellular infection of multinucleated osteoclasts resulted in a rapid advance of tuberculosis infection and prompted an osteolytic response. Tuberculosis bacteria were also able to escape from the infected osteoclast. This triggered an abnormal pattern of osteoclast activation rooted in the bacteria’s manipulation of the osteoclast itself, with development via dysregulation of cytokine and chemokine expression—the purposes of which require additional investigation. Of course, abnormal new bone formation also occurs in tuberculosis immediately adjacent to the margins of destructive foci. This means that pathogenic and molecular signaling pathways within a lytic lesion are more or less the diametric opposite of what is occurring just beyond its margins as an attempt at sclerotic repair is made. Certainly, we may suspect responsible agents are upregulated Wnt, BMP, and related signaling involving the RANKL-OPG axis. This also helps highlight the fact that disease processes may not be characterized in terms of binary molecular signaling processes (also see Chapter 8). Case Study 2: Abnormal Bone Destruction and Formation. One of the other structures at the Ventarro´n Archaeological Complex involved another Middle Sica´n occupation at the truncated pyramid of Zarpa´n (Alva Meneses, 2012). There, 43 funerary contexts were documented. Zarpa´n Burial 9 possessed abnormal patterns of bone loss and bone formation on their L5 vertebra and S1 sacral segment (Klaus, 2018b). This adult male was 40 45 1 years old at the time of death and was generally very well preserved and complete except for the missing left and right feet. A complex mixture of bone resorption and new bone formation were observed on the anterior and lateral surfaces of the L5 vertebra and S1 segment of the bony sacrum (Figs. 5.34 and 5.35). These abnormalities featured a mixed reaction involving bone loss and bone formation. On the anterior aspect of the L5 and S1, dozens of focal points of bone loss involved wellcircumscribed oval or circular defects, some of the smallest examples of which could be mistaken for enlarged nutrient foramina. A larger area of contiguous bone loss destroyed the right anteroinferior margin of the L5 vertebra. These lytic loci were accompanied by areas of fine reactive new bone formation initiated on the right anterior aspect of the L5, more advanced spiculated bone formation on the left anterior aspect of the L5, and areas of fine new abnormal bone formation on the S1 sacral segment, especially on the left side. The inferior portion of the L5 vertebra exhibited bone destruction affecting most of the inferior vertebral endplate. Anteriorly, substantial irregular areas of bone had been resorbed, and were generally surrounded by erratically distributed additional circular or oval foci of penetrating bone loss. Additional vertebral margin bone loss

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FIGURE 5.34 Mixed abnormal bone resorption and new bone formation on anterior and lateral surfaces of the L5 vertebra and S1 segment of the bony sacrum, highly consistent with metastatic prostate cancer (adult male, Zarpa´n Burial 9; photo: HDK).

FIGURE 5.35 (a) Detailed left anterolateral view of the L5 lumbar vertebrae; (b) abnormal multifocal bone loss affecting the inferior vertebral endplate of the L5 vertebral body; and (c) abnormal multifocal bone loss affecting the superior vertebral endplate of the S1 vertebral segment of the bony sacrum (adult male, Zarpa´n Burial 9; photo: HDK).

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was present on the left posteroinferior aspect of the L5 body. This lytic process extended into the superior endplate of the S1 segment of the bony sacrum. There, the most significant destruction was again localized on the left side, and extended into the superior left wing of the bony sacrum. Vertebral endplate destruction of the L5 and S1 sacral segment was not associated with marginal new bone formation. The only other pathological processes in this individual’s skeleton included well-healed cribra orbitalia and porotic hyperostosis lesions, as well as active periodontal disease. Pseudopathology can be convincingly excluded, as there are clearly multiple antemortem processes of de novo bone proliferation and bone resorption. Process identification of these lesions falls into the range of disorders that can produce mixed blastic and lytic phenomena in the inferior vertebral column. These lesions are inconsistent with osteomyelitis due to the lack of necrotizing foci or cloaca. Nonspecific periostosis is equally inconsistent as anterior vertebrae are an extraordinarily rare anatomical location for nonspecific lesions. Brucellosis should be considered but can be ruled out as not consistent the basis that brucellosis is intensely osteolytic, has a predilection for thoracic vertebrae, and rarely involves new bone formation (Ortner, 2003). Tuberculosis is inconsistent due to the inferior anatomical location, lack of large destructive foci, and the presence of endplate involvement. Chronic fungal infections such as coccidoidomycosis or paracoccidoidomycosis are rejected as they are characterized by welldefined lytic foci, often coupled with sclerotic margins on noncontiguous vertebrae, clavicles, ribs, and long bones (Long and Merbs, 1981; Ortner, 2003; Temple, 2006). An evaluation of sclerosing bone disorders, such as hypertrophic (pulmonary) osteoarthropathy, melorheostosis, and fluorosis can each be ruled out on the basis of a clear mismatch of lesion morphology, distribution, and cooccurrence of lytic foci. Metastatic disorders, however, can produce a variety of mixed blastic and lytic bone involvement (Johnson and Sterling, 2013). Most metastases, such as metastasized breast cancer, are highly osteolytic (Resnick, 2002). Potential diagnostic options such as multiple myeloma, leukemia, and Hodgkin’s and nonHodgkin’s lymphomas can be rejected based on differing lesion morphology and distribution (Resnick and Haghighi, 2002). Of all metastatic diseases, prostate cancer is by far the most likely to produce osteoblastic lesions (Resnick, 2002). The distribution of metastatic prostate cancer is distinct from the majority of hematogenous metastases, as this condition has a clear anatomical preference for the lumbar vertebrae, bony sacrum, and ossa coxae (Resnick, 2002; Ortner, 2003; Coleman, 2006). Related osteosclerotic new bone formation may possess radial, sunburst-like formations. Single or multiple vertebrae may be involved,

and when lesions are confluent over multiple vertebrae, intervertebral disk spaces may be invaded by cancer cells (Resnick, 2002: 4304). Clinical findings of abnormal sclerosing bone formation on vertebral bodies of older adult men are nearly always correlated to metastasized prostate cancer (Resnick, 2002: 4293). New bone proliferation on the os coxae is highly unique though not quite diagnostic for disseminated prostate cancer (Ortner, 2003), and diagnosis does not oblige pelvic involvement. Any related bone destruction is characterized by poorly defined, highly irregular loci (Resnick, 2002; Johnson and Sterling, 2013). On these bases, we argue that these lesions are highly consistent with metastatic prostate cancer. We are cautious because bladder, pancreatic, and carcinoid caners may not be differentiated from prostate metastases via either visual or radiographic means. However, differential diagnosis is a probabilistic exercise, and bone involvement in these other cancers is far less common, especially for carcinoid and pancreatic malignancies. Even further, the former tends to be predominantly lytic, while the latter preferentially involves both thoracic and lumbar vertebrae (see discussion in Resnick, 2002). The solitary lesion in the T4 vertebra is very likely to represent another kind of disease process such as tuberculosis. Thus, comorbidity is possible, if not likely, in this individual (independent differential diagnosis of that abnormality is required, but is a bit beyond the scope and space that we have here). Again, we can check our most probable differential diagnosis of metastasized prostate cancer against anatomical, clinical, and molecular factors. Anatomical structure is consistent. In the case of a primary prostate cancer tumor, the paravertebral plexus of Baston is the most likely vascular intake point for prostate cancer cells that seed them directly to lumbar vertebral bodies (Resnick, 2002). The rich hematopoietic marrow, large capillary networks, and sluggish blood flow in lumbar vertebrae represent an appealing environment for tumor metastases. Experimental and therapeutic perspectives demonstrate disseminated prostate cancer lesions likely begin with a strong bone resorption component, and as the disease progresses, the formation/resorption control axis flips dramatically (Johnson and Sterling, 2013). The pathophysiology of sustained metastasized prostate tumor growth requires secretion of osteoblast-derived growth factors. Prostate cancer cells themselves appear to secrete multiple Wnt ligands to activate the canonical Wnt pathway along with multiple other bone-forming factors within the cancer microenvironment (Klaus, 2018b). In other words, once the cancer establishes a foothold, osteoblasts become the “master switches” manipulated by the malignant cells for their survival and growth. Also, disseminated cancer cells likely home-in toward specific organs that provide the most ideal microenvironments for

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tumor development. The anatomical specificity for lumbar, sacral, or pelvic lesions associated with prostate carcinomas may reveal the existence of unique and preexisting molecular “addresses” in these bones for prostate metastases—following the evolving theoretical concept of the premetastatic niche (Clines, 2013).

CONCLUSION This chapter has provided an overview of key paleopathological considerations of abnormal bone. The discussion examined considerations of terminology, the abnormal behavior of bone cells, general mechanisms of pathology, and systems for the rigorous description, disease process identification, and differential diagnosis of skeletal abnormalities. Our discipline is grounded by long-established core competencies involving observational/diagnostic proficiency and the ability to study disease across broad geographic, temporal, and evolutionary contexts. Simultaneously, new developments including clinical, theoretical, and methodological advances are emergent (Crespo et al., 2017; Gosman et al., 2011; Lorenzo et al., 2015; Thakker et al., 2018). It is hard to envision that in the future, at least in the near term, where aDNA or proteomic analyses will truly render obsolete the fundamental competencies of description, identification, and differential diagnosis. These new frontiers represent complementary and synergistic domains for human skeletal paleopathology, pointing toward diverse new horizons in the study of abnormal bone.

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Klaus, H.D., 2018b. Possible prostate cancer in northern Peru: differential diagnosis, vascular anatomy, and molecular signaling in the paleopathology of metastatic bone disease. Int. J. Paleopathol. 21, 147 157. https://doi.org/10.1016/j.ijpp.2016.11.004. Klaus, H.D., Ericksen, C.M., 2013. Paleopathology of an ovarian teratoma: description and diagnosis of an exotic abdominal bone and tooth mass in a historic Peruvian burial. Int. J. Paleopathol. 3, 294 301. Klaus, H.D., Ortner, D.J., 2014. Treponemal infection in Peru’s Early Colonial period: a case of complex lesion patterning and unusual funerary treatment. Int. J. Paleopathol. 4, 25 36. Knu¨sel, C., 2014. Crouching in fear: terms of engagement for funerary remains. J. Soc. Archaeol. 14, 26 58. Koon, H.E., 2012. A biochemical marker for scurvy in archaeological bones. Am. J. Phys. Anthropol. 147, 184 185. Kumar, V., Abbas, A.K., Aster, J.C., 2014. Robbins & Cotran Pathologic Basis of Disease, ninth ed. Saunders, New York. Lewis, M., 2018. Paleopathology of Children: Identification of Pathological Conditions in the Human Skeletal Remains of NonAdults. Elsevier/Academic, London. Li, Z., Jiang, H., Yang, X., Shi, L., Liu, J., Zhang, X., 2016. The role of TNF-α and IFN-γ in the formation of osteoclasts and bone absorption in bone tuberculosis. Int. J. Clin. Exp. Pathol. 9 (8), 8406 8414. Lieberman, J.R., Friedlaender, G.E. (Eds.), 2005. Bone Regeneration and Repair: Biology and Clinical Applications. Humana Press, Totwa, NJ. Long, J.C., Merbs, C.F., 1981. Coccidioidomycosis: a primate model. In: Buikstra, J.E. (Ed.), Prehistoric Tuberculosis in the Americas. Northwestern University Archaeological Program, Evanston, pp. 69 83. Lorenzo, J., Choi, Y., Horowitz, M., Takayanagi, H. (Eds.), 2015. Osteoimmunology: Interactions of the Immune and Skeletal Systems. second ed. Elsevier, Amsterdam. MacGintie, L.A., Wu, D.D., Cochran, G.V., 1993. Streaming potentials in healing, remodeling and intact cortical bone. J. Bone Miner. Res. 8 (11), 1323 1335. Manchester, K., Ogden, A., Storm, R., September 2016. Nomenclature in Palaeopathology. Paleopathology Association Newsletter. Mann, R.W., Hunt, D.R., Lozanoff, S., 2016. Photographic Regional Atlas of Non-Metric Traits and Anatomical Variants in the Human Skeleton. Thomas, Springfield, IL. Mays, S., 2018. How should we diagnose disease in palaeopathology? Some epistemological considerations. Int. J. Paleopathol. 20, 12 19. McIlvaine, B.K., 2015. Implications of reappraising the iron deficiency anemia hypothesis. Int. J. Osteoarchaeol. 25 (6), 997 1000. Miller, E., Ragsdale, B.D., Ortner, D.J., 1996. Accuracy in dry bone diagnosis: a comment on palaeopathological methods. Int. J. Osteoarchaeol. 6, 221 229. Niemann, S., Zhao, C., Pascu, F., Stahl, U., Aulepp, U., Niswander, L., et al., 2004. Homozygous WNT3 mutation causes tetra-amelia in a large consanguineous family. Am. J. Hum. Genet. 74 (3), 558 563. Nikolaou, V.S., Chytas, D., Korres, D., Efstathopoulos, N., 2014. Vanishing bone disease (Gorham-Stout syndrome): a review of a rare entity. World J. Orthop. 5 (5), 694 698. Ortner, D.J., 1991. Theoretical and methodological issues in paleopathology. In: Auferheide, A.C., Ortner, D.J. (Eds.), Human Paleopathology: Current Syntheses and Future Options. Smithsonian Institution Press, Washington, DC, pp. 5 11.

Ortner, D.J., 2003. Identification of Pathological Conditions in Human Skeletal Remains, second ed. Academic, New York. Ortner, D.J., 2011. Human skeletal paleopathology. Int. J. Paleopathol. 1, 4 11. Ortner, D.J., 2012. Differential diagnosis and issues in disease classification. In: Grauer, A.L. (Ed.), A Companion to Paleopathology. Wiley-Blackwell, Chichester, pp. 250 267. Ortner, D.J., Mays, S., 1998. Dry-bone manifestations of rickets in early infancy and childhood. Int. J. Osteoarchaeol. 8, 45 55. Oxenham, M.F., Cavill, I., 2010. Porotic hyperostosis and cribra orbitalia: the erythropoietic response to iron deficiency anaemia. Anthropol. Sci. 118, 199 200. Pitkin, R.M., 2007. Folate and neural tube defects. Am. J. Clin. Nutr. 85 (1), 285S 288S. Porth, C.M., 2014. Essentials of Pathophysiology, fourth ed. Wolters Kluwer/Lippincott, Philadelphia, PA. Powell, M.L., 2012. Donald J. Ortner (1938 ). In: Buikstra, J.E., Roberts, C.A. (Eds.), The Global History of Paleopathology: Pioneers and Prospects. Oxford University Press, Oxford, pp. 89 96. Ragsdale, B.D., Madewell, J.E., Sweet, D.E., 1981. Radiologic and pathologic analysis of solitary bone lesions, part II: periosteal reactions. Radiol. Clinics N. Am. 19, 749 783. Ragsdale, B.D., 1992. Task Force on Terminology: Provisional Word List. Paleopathology Association Newsletter 78, pp. 7 8. Ragsdale, B.D., Lehmer, L.M., 2012. A knowledge of bone at the cellular (histological) level is essential to paleopathology. In: Grauer, A. L. (Ed.), A Companion to Paleopathology. Wiley-Blackwell, Chichester, pp. 227 249. Rasmussen, S., Allentoft, M.A., Nielsen, K., Orlando, L., Sikora, M., Sjo¨gren, K.-G., et al., 2015. Early divergent strains of Yersinia pestis in Eurasia 5,000 years ago. Cell 163 (3), 571 582. Redfern, R., 2016. Injury and Trauma in Bioarchaeology: Interpreting Violence in Past Lives. Cambridge University Press, Cambridge. Resnick, D.J. (Ed.), 2002. Diagnosis of Bone and Joint Disorders, fourth ed. 5 vols. W.B. Saunders, Philadelphia, PA. Resnick, D., Haghighi, P., 2002. Myeloproliferative disorders. In: Resnick, D. (Ed.), Diagnosis of Bone and Joint Disorders. Saunders, Philadelphia, PA, pp. 2247 2266. Roberts, C.A., Buikstra, J.E., 2003. The bioarchaeology of tuberculosis: a global view on a reemerging disease. University Press of Florida, Gainesville. Roberts, C.A., Manchester, K., 2007. The Archaeology of Disease. Cornell University Press, Cornell. Rosen, C.J., Bouillon, R.J., Compston, J.E., Rosen, V. (Eds.), 2014. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. eighth ed. Wiley-Blackwell, Ames, IA. Rubin, P., 1964. Dynamic Classification of Bone Dysplasias. Year Book, Chicago, IL. Schinz, H., Baensch, W., Friedel, E., Uehlinger, E., 1951 1952. Rotengen Diagnostics: Skeleton, vols. 1 and 2. Grune and Stratton, New York. Schultz, M., 2001. Paleohistology of bone: a new approach to the study of ancient diseases. Yearb. Phys. Anthropol. 44, 106 147. Schultz, M., Carlie-Thiele, P., Schmidt-Schultz, T.H., Keirdof, H., Teegen, W.R., Kreutz, K., 1998. Enamel hypoplasias in archaeological skeletal remains. In: Alt, K.W., Ro¨sing, F.W., Teschler-Nicola, M. (Eds.), Dental Anthropology: Fundamentals, Limits, and Prospects. Springer-Verlag, New York, pp. 293 311.

Considerations for Documentation, Disease Process Identification, and Differential Diagnosis Chapter | 5

Straub, R.H., Schradin, C., 2016. Chronic inflammatory systemic diseases: an evolutionary trade-off between acutely beneficial but chronically harmful programs. Evol. Med. Public Health 2016 (1), 37 51. Stuart-Macadam, P., 1987. Porotic hyperostosis: new evidence to support the anemia theory. Am. J. Phys. Anthropol. 74, 521 526. Stuart-Macadam, P., 1992. Porotic hyperostosis: a new perspective. Am. J. Phys. Anthropol. 87, 39 47. Temple, D.H., 2006. A possible case of coccidioidomycosis from the Los Muertos site, Tempe, Arizona. Int. J. Osteoarchaeol. 16, 316 327. Thakker, R.V., Whyte, M.P., Eisman, J.A., Igarashi, I. (Eds.), 2018. Genetics of Bone Biology and Skeletal Disease. second ed Elsevier, London. UN, 2004. Istanbul Protocol Manual on the Effective Investigation and Documentation of Torture and Other Cruel, Inhuman or Degrading Treatment or Punishment. Office of The United Nations High Commissioner for Human Rights, New York/Geneva. ,http://www. ohchr.org/documents/publications/training8rev1en.pdf.. Va˚gene, A., Herbig, A., Campana, M.G., Robles Garcı´a, N.M., Warinner, C., Sabin, S., et al., 2018. Salmonella enterica genomes from victims of a major sixteenth-century epidemic in Mexico. Nat. Ecol. Evol. 2, 520 528. Verano, J.W., 2012. Appendix 3: Human skeletal remains from Chotuna. In: Donnan, C.B. (Ed.), Chotuna and Chornancap: Excavating an Ancient Peruvian Legend. Cotsen Institute of Archaeology Press, Los Angeles, CA, pp. 185 194. Walker, P.L., Bathhurst, R.R., Richman, R., Gjerdrum, T., Andrushko, V.A., 2009. The causes of porotic hyperostosis and cribra orbitalia: a reappraisal of the iron deficiency anemia hypothesis. Am. J. Phys. Anthropol. 139, 109 125.

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Wanek, J., Papageorgeopoulou, C., Ru¨hli, F., 2012. Fundamentals of paleoimaging techniques: bridging the gap between physicists and anthropologists. In: Grauer, A.L. (Ed.), A Companion to Paleopathology. Wiley-Blackwell, Chichester, pp. 324 338. Ward, P.A., Lentsch, A.B., 1999. The acute inflammatory response and its regulation. Arch. Surg. 134 (6), 666 669. Warinner, C., Rodrigues, J.F.M., Vyas, R., Trachsel, C., Shved, C., Grossmann, J., et al., 2014. Pathogens and host immunity in the ancient human oral cavity. Nat. Genet. 46, 336 344. Wasterlain, S.N., Alves, R.V., Garcia, S.J., Marques, A., 2017. Ovarian teratoma: a case from 15th-18th century Lisbon, Portugal. Int. J. Paleopathol. 18, 38 43. Weston, D.A., 2008. Investigating the specificity of periosteal reactions in pathology museum collections. Am. J. Phys. Anthropol. 137, 48 59. Weston, D.A., 2012. Nonspecific infection in paleopathology: interpreting periosteal reactions. In: Grauer, A.L. (Ed.), A Companion to Paleopathology. Wiley-Blackwell, Chichester, pp. 492 512. Wilbur, A.K., Farnbach, A.W., Knudson, K.J., Buikstra, J.E., 2008. Diet, tuberculosis, and the paleopathological record. Curr. Anthropol. 49, 963 991. Wilczak, C.A., Dudar, C., 2011. Osteoware Software Manual, vol. I. Smithsonian Institution, Washington, DC. ,https://osteoware.si.edu/ sites/default/files/content-pdfs/Osteoware_Vol-1_Feb2012.pdf.. Zhang, Y., Liu, X., Li, K., Bai, J., 2015. Mycobacterium tuberculosis 10kDa co-chaperonin regulates the expression levels of receptor activator of nuclear factor-κB ligand and osteoprotegerin in human osteoblasts. Exp. Ther. Med. 9, 919 924.

Chapter 6

Histomorphology: Deciphering the Metabolic Record Samuel D. Stout1, Mary E. Cole1 and Amanda M. Agnew2 1

Department of Anthropology, The Ohio State University, Columbus, OH, United States, 2School of Health and Rehabilitation Sciences, The Ohio

State University, Columbus, OH, United States

INTRODUCTION Bone is “a metropolis of highways and freeways, turnpikes and underground railways: a house of many rooms and corridors, with fluid-filled canals and canaliculi, wired with nerve fibers, fed with a vasculature no less complex than that of the hepatobiliary, pulmonaryalveolar or renal glomerulotubular systems” (Ego Seeman, 2007). Ortner noted in his second edition of Identification of Pathological Conditions in Human Skeletal Remains (2003) that skeletal remains are the most abundant source of information on ancient diseases. Fortunately for those interested in health and disease in past human populations, bone is a durable, metabolically active tissue that can persist long after death. Moreover, the organic and inorganic material composition of bone and its distribution allow enduring evidence of cellular activity associated with metabolic processes and functional adaptations of a bone to be inscribed within its microstructure (see Chapter 4 for a discussion of basic bone development). Pathological macroscale changes to bone are fundamentally derived from nanoscale cellular processes, which are recorded in bone tissue at the microscale. Such modifications begin to deform bone by altering the stimulation, sensitivity, or capability of bone cells at the nanoscale. These dysregulated cells subsequently modify the normal frequency, rate, or quality of cellular activities such as bone formation (modeling), bone resorption, or bone turnover (remodeling). Such changes to the quantity or quality of bone tissue first appear at the microscale. With significant progression of the disease, changes to bone tissue quantity may be observed at the macroscale as surfacelevel apposition, loss, or porosity. Microscopic analysis of bone tissue is therefore an important supplement to the typical macroscopic

diagnosis of pathological conditions in skeletal remains. Tissue-level changes accumulate until they manifest at the macroscale, so microscopic analysis can identify pathology at earlier or less severe stages. Bone tissue also more precisely reflects the cellular source of the pathology. Due to the interconnectedness (or “coupling”) of cellular activity in bone, even a single type of physiological dysregulation (e.g., availability of parathyroid hormone (PTH)) induces a cascade of cellular reactions that produce a suite of histological pathologies (see Table 6.4). These histomorphological features (e.g., mineralization, lacunar-canalicular or vascular porosity, lamellar structure, trabecular architecture) do not have an obvious macrolevel correlate. Additionally, all histomorphological features change in frequency, distribution, and/or morphology due to the senescence of cellular function and biomechanical or physiological stimulation with age. By understanding the normal trajectory of cellular activity and its histological evidence over the lifespan, one can more specifically and accurately identify pathological deviations in this life course. In this chapter, we discuss how tissue-level (histological) analysis of bone can be employed in paleopathology and related fields, such as bioarcheology and skeletal biology, to assess skeletal health and disease. In the previous edition of this chapter, Schultz (2003b) discussed pathological changes at or near the surface of the cortical bone. He focused on new bone proliferation on external periosteal and endocranial surfaces, and on porotic hyperostosis of the skull vault and orbital roof (cribra orbitalia). This previous chapter used histology to describe the microstructure of reactions that are often macroscopically visible on the cortical bone surface. In this edition, we build on Schultz’s (2003b) work by moving inside the cortical bone to examine the healthy,

Ortner’s Identification of Pathological Conditions in Human Skeletal Remains. DOI: https://doi.org/10.1016/B978-0-12-809738-0.00006-5 © 2019 Elsevier Inc. All rights reserved.

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aged, and pathological presentation of its histological components. More specifically, we consider how histomorphological and histomorphometric analyses of bone remodeling activity can be used to evaluate bone metabolism and its biomechanical consequences. We begin with methodological advances, expanding on Schultz’s (2003b) description of two-dimensional histological thin sections by discussing emerging technologies for threedimensional microscopic imaging. The subsequent material is divided into three sections. The first three sections focus, respectively, on the rate of bone turnover (remodeling), the biomechanical stimuli of remodeling, and the morphology of cortical bone (osteocyte lacunae, vascular porosity, lamellar structure, whole bone cross-sectional shape) resulting from metabolic processes (e.g., modeling and remodeling). These three sections describe the normal trajectory and histological remnants of these processes, with consideration for typical variation due to biomechanical differences, sexual dimorphism, and aging. This baseline knowledge is essential for the fourth section, which describes pathological changes to cortical microstructure. Pathological interference with cellular processes alters histology in a predictable pattern, which becomes evident once one understands the link between cellular activity and histomorphometry in healthy individuals.

Visualization of Histological Structures in Dry Bone Most studies rely on modern human or animal bone to describe the prevalence and shape of histological structures in relation to mechanical loading, aging, and pathology. However, the histology of dry archeological bone may be visualized using the same techniques of brightfield or polarized light microscopy. Sample preparation mirrors that of modern bone tissue. Transmitted light microscopy requires ground or microtome-cut thin sections, while reflected light microscopy involves polishing the bone surface (reviewed in Schultz, 2011). Taphonomic processes related to burial conditions do sometimes cause diagenetic changes to bone tissue. Fungi, bacteria, and algae can erode bone microstructure (bioerosion), and staining, inclusions, infiltrations, and cracking can similarly obscure histological structures (Hollund et al., 2012). Special consideration for sample cleaning is recommended (Schultz, 2011). Diagenetic processes may also hamper uptake and tissue coloration by histological stains (Schultz, 2011). However, some staining methods have been developed for dry archeological bone that can enhance visualization of osteocyte lacunae, radiating canaliculi, and cortical pores, and the cement lines demarcating secondary osteons can also increase in visibility (de Boer et al., 2012).

Other microscopic imaging techniques may extract additional information from archeological bone, although these methods are typically more costly and require more extensive sample preparation. For example, in both archeological and fossil bone, scanning electron microscopy can distinguish osteocyte lacunae that are empty from those still occupied by mineralized osteocytes. Cellular structures indicative of apoptosis can also be distinguished in archeological bone using transmission electron microscopy (Bell et al., 2008). Three-dimensional imaging techniques are also finding increasing application in archeological bone. Confocal laser scanning microscopy (CLSM) is a type of fluorescence microscopy that uses a precise laser and a pinhole to block out-of-focus light. This precision produces two-dimensional images with higher contrast and better lateral and axial resolution than traditional wide-field epifluorescence microscopy. Images at successive two-dimensional depths can be stacked into a three-dimensional image (Maggiano et al., 2009). CLSM has been advanced as a technique for visualizing and quantifying the three-dimensional structures of cortical pores, osteocyte lacunae and canaliculi, and microcracks in archeological bone (Papageorgopoulou et al., 2006, 2007, 2010; Maggiano et al., 2009). CLSM can also identify tetracycline labeling in well-preserved archeological bone, following osteons and lamellae through three-dimensional space (Maggiano et al., 2006, 2009). Microcomputed tomography (micro-CT, see Chapter 7) reconstructs three-dimensional structures from X-ray images taken at multiple angles (Cooper et al., 2004). Although desktop/laboratory micro-CT typically cannot achieve the resolution required to distinguish osteocyte lacunae or lamellar structures, it has been increasingly used to visualize and measure the three-dimensional cortical pore network in modern human bone (e.g., Stout et al., 1999; Cooper et al., 2003, 2004, 2006, 2007a,b; Dechow et al., 2008; Chen et al., 2010; Hennig et al., 2015). The higher resolution and phase contrast capabilities of synchrotron micro-CT can additionally display and quantify three-dimensional osteocyte lacunae (e.g., Hannah et al., 2010; Carter et al., 2013a,b, 2014; BachGansmo et al., 2016) and lamellar structures, including osteon cement lines (Cooper et al., 2011; Maggiano et al., 2016). Desktop and synchrotron micro-CT have been used to distinguish fragments of Paleolithic animal bone, ivory, and antler based on the size, shape, and distribution of Haversian canals and their association with osteocyte lacunae (Reiche et al., 2011b). Synchrotron micro-CT has also found application in comparing pore volumes of bovine compact bone between modern and Neolithic archeological contexts (Reiche et al., 2011a). Like CLSM, micro-CT of human bone tissue has been methodologically developed in recent years but has not yet been broadly applied in practical archeological contexts.

Histomorphology: Deciphering the Metabolic Record Chapter | 6

HISTOMORPHOLOGY: DECIPHERING THE METABOLIC RECORD In the 1985 Yearbook of Physical Anthropology, Harold Frost discusses the “new bone” paradigm, and its potentials for anthropological research (Frost, 1985). A crucial component of this new bone biology is recognition of the importance of the intermediary organization of the skeletal system (Frost, 1983), which is a tissue-level phenomenon that bridges the gap between bone cells and whole bones. Based upon this understanding, histomorphological features observed in bone are products of the physiological process of remodeling, and as such, provide a foundation for paleohistopathological analysis. This model came together initially at the University of Utah’s Hard Tissue Workshops (Jee, 2000) and is also referred to as the “Utah Paradigm.” Several decades later, this paradigm remains a centerpiece of modern musculoskeletal research (Pivonka et al., 2018). In this model, patterns of histological features within bone tissue represent patterns of bone formation, resorption, and turnover (remodeling) during life. This cellular activity is triggered by biomechanical demands on the bone during life (Frost, 2003) and augmented by physiological needs of the body (Rauch and Schoenau, 2001). For paleopathologists, bioarcheologists, and other researchers undertaking analyses of skeletal remains, a thorough understanding of the normal trajectory of bone remodeling is essential for interpreting apparent skeletal anomalies, lesions and stress markers, and offering plausible diagnoses. In this section, we describe the cellular activity underlying the bone remodeling process and the histomorphological features that it produces. Since many pathological conditions alter bone formation or resorption through direct or indirect interference with normal cellular activity (Table 6.5), we begin with a brief outline of the roles of bone cells in tissue production. We then provide a worked example of how histomorphometric analysis can be use to describe bone formation rates for skeletal remains. We also describe how variation in remodeling parameters has been linked to age, sex, behavior (physical activity/diet), and pathological conditions in modern and archeological populations.

The Cellular Basis of Bone Formation and Resorption Remodeling is a life-long metabolic process by which teams of specialized cells, basic multicellular units (BMUs), resorb and replace defined packets of bone, leaving behind distinct histomorphological features, named basic structural units (BSUs). This turnover of tissue plays important roles in the physiology of bone, including mineral homeostasis and mobilization, and

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biomechanical repair and adaptation (Rosen, 2008). Bones change in mass and shape drastically during subadult growth, but the amount and distribution of bone mass continues to change throughout the lifetime in response to mechanical and physiological demands. Modeling refers to formation of bone on a bone surface, uncoupled to resorption. Remodeling is a coupled process, in which preexisting bone is resorbed and then replaced by new bone formation (Frost, 2003). There are two forms of remodeling: targeted and stochastic. In targeted remodeling, bone responds to a specific, localized mechanical need for bone resorption or repair. In stochastic remodeling, physiological needs of the body regulate bone formation and resorption (Martin, 2002; Eriksen, 2010). Modeling and remodeling are carried out by osteoblasts, the bone-forming cells, and osteoclasts, the bone-resorbing cells. Bone cell recruitment and activity are regulated by the local presence of paracrine factors (produced by nearby cells) and autocrine factors (produced by the cell itself) (Plotkin and Bivi, 2014). The production of local factors is influenced by mechanical demand and physiological demand on the body. Local mechanical demand changes when the mechanical loading environment of the bone is altered or when the bone accumulates microscopic damage (microdamage) that compromises its previous strength. Osteocytes, which are terminally differentiated osteoblasts embedded in preexisting bone during formation, sense these alterations (reviewed in Seeman, 2006). They produce local factors that activate osteoblast bone formation and/or osteoclast bone resorption, reshaping and repairing bone to withstand the new mechanical loading environment. Levels of local factors are also regulated by endocrine factors (produced by distant cells), particularly systemic hormone levels. These hormonal signals are not the direct consequence of mechanical demand, but a physiological response to other processes in the body (Martin, 2003; Eriksen, 2010).

Remodeling and the Morphology of the BMU Modeling occurs on the surface of bone and does not require synchrony between osteoclast and osteoblast activity. However, remodeling requires osteocytes to coordinate action between osteoclasts and osteoblasts through the formation of a BMU. The transition from osteoclast bone resorption to osteoblast bone formation is known as “coupling.” It is propagated by the release of local factors from resorbed bone, as well as a complex array of signals within and between osteoclasts and osteoblasts (Sims and Martin, 2014). In cortical bone, the BMU tunnels into the cortex, with osteoclasts resorbing bone in a “cutting cone,” and osteoblasts following behind in a “closing cone” to form new bone. Osteoblasts

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Bone lining cells Complete osteon

Forming osteon

Osteoblasts Capillary Osteoclasts

Resorptive bay

FIGURE 6.1 In cortical bone, the morphology of a basic structural unit (BSU) depends on the progress of the basic multicellular unit (BMU) in the cross-sectional plane. Near the active cutting cone, the BSU appears as a resorptive bay (Howship’s lacuna). When the periphery of the resorptive bay has been filled by new bone, the BSU appears as a secondary osteon with a central Haversian canal. Drawing based on Parfitt (1994: 277).

leave a central Haversian canal for the central blood vessel (Eriksen, 2010) (Fig. 6.1). This structure is called a secondary osteon, in contrast to the primary osteons that form when modeled bone surrounds a blood vessel on the surface of the bone (Burr and Akkus, 2014). Secondary osteons are distinguished by a cement line, the highly mineralized border that marks remodeling reversal, where osteoclast resorption ends and osteoblast resorption begins (Skedros et al., 2005). In trabecular bone, the BMU sits on the exposed surface of the trabecula. Osteoclasts resorb bone, forming a trench, which is then filled with bone by osteoblasts (Sims and Martin, 2014). This structure is called a hemiosteon. In very thick trabeculae, complete osteons can form by tunneling through the trabecula (Burr and Akkus, 2014).

Calculation of Remodeling Parameters From BSUs The BSUs resulting from remodeling indicate how far a particular remodeling event has progressed both at the

FIGURE 6.2 Cortical tissue from midshaft of a femur from a 71-yearold female (modern) demonstrating osteon types. A primary osteon (A), created by modeling, lacks a cement line (bright field). Interstitial lamellae (polarized light) flow around the primary osteon. Remodeling begins with the formation of a resorption bay (B). Osteoblasts lay down circumferential lamellae starting at the periphery of the resorption bay, leaving a central vascular pore. These secondary osteons, most commonly classified as type I (C), are demarcated by a cement line (bright field) and disrupt the flow of interstitial lamellae (polarized light). Type II (embedded) secondary osteons (D
F) represent new remodeling events that occur within existing secondary osteons. Their reversal/cement lines (bright field) and circumferential lamellae (polarized light) are discontinuous with the surrounding osteon. If the cement line of a secondary osteon is disrupted by a later remodeling event, it is considered a fragmentary osteon (G). Image taken under bright field light (left), and linear polarization (right), scale included. Photo credit: Mary Cole.

time of death, and at the level of the cutting cone visible in the plane of cross-section. In cortical bone, BSUs take the form of resorptive bays (Howship’s lacunae) and osteons (Haversian systems) (Figs. 6.2 and 6.3).1 The relationship between these BSUs and the remodeling process that created them provides a unique opportunity to 1. These osteons are sometimes referred to as secondary osteons to distinguish them from primary osteons, which are not a product of bone remodeling.

Histomorphology: Deciphering the Metabolic Record Chapter | 6

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remodeling events, and number of resorptive bays (N.Rs. Vd), all divided by the section area (Sa.Ar) (Eq. (6.1)). OPD 5 ½N:On 1 N:On:Fg 1 N:Rs:Vd  Sa:Ar21 OPD 5 20:0mm22

FIGURE 6.3 Cortical tissue (modern) distinguishing secondary osteon types. Type II (embedded) osteons represent later, distinct remodeling events that occur within an existing secondary osteon. The circumferential lamellae and reversal/cement lines of the two osteons are not aligned. In contrast, double zonal osteons represent an arrest and later continuation of the same remodeling event. There is alignment between the circumferential lamellae of the internal and peripheral regions of the osteon, and between the arrest and reversal/cement line of the osteon. Drifting osteons represent lateral movement of the three-dimensional secondary osteon during remodeling. Photo credit: Sam Stout.

extract information about normal and abnormal cortical bone remodeling from skeletal remains, because the remodeling rate and amount of bone turnover are recorded in their number and size. Resorptive bays (Howship’s lacunae), distinguished by their scalloped border (Fig. 6.2), are evidence of the initiation (activation) of a BMU, and the amount of bone that was resorbed. Osteons (Haversian systems) represent forming and completed BMUs. An algorithm is available that employs these static histological features to estimate bone remodeling rates without the use of in vivo tissue time markers (Frost and Wu, 1967; Wu et al., 1970; Stout and Paine, 1994). Although the algorithm was developed using the rib, several studies have modified it and applied it to the femur (Martin, 1983; Abbott et al., 1996; Robling and Stout, 2003; Streeter et al., 2010). However, use of the rib is recommended, since many of the modifications required for application to bones other than the rib have yet to be validated. The following example, based upon a rib sample from a female from the prehistoric Peruvian site at La Paloma, illustrates the application of the algorithm. Osteological analysis estimated age at death to have been late 3rd to early 4th decade of life (Benfer, 1990). For the purpose of this analysis, an age of 30 years is used. Number of osteonsðN:OnÞ 5 20:0 mm22 Visible evidence of bone remodeling is represented by osteon population density (OPD), comprised of the sum of numbers of complete osteons (N.On) and fragmentary osteons (N.On.Fg), those partially removed by subsequent

(6.1)

As the number of osteons per unit area increases due to continuous activations of BMUs, evidence of some osteons is completely removed. Therefore, accumulated osteon creations (OPD.cd), representing all evidence of BMU activation events, must be estimated. OPD.cd (Eq. (6.2)) is estimated from OPD using a derived scaling factor β (Frost, 1987c). A packing factor (k) of 1.70, that accounts for the overlapping distribution of osteons and osteon fragments in a typical unit of area of cortical bone, has been calculated empirically by Stout and Paine (1994). OPD:Cd 5 OPD  β
21 β 5 12α3:5
21 α 5 OPD  k On:Ar  4π21
21 19:99 α5  1:7 0:0386  4π21 mm2 α 5 0:576 OPD:Cd 5 19:99mm2  1:787 23:6 OPD:Cd 5 mm2

(6.2)

OPD.Cd can be used to estimate the activation rate (Ac.f) of BMUs per unit area/year (Eq. (6.3)). To determine Ac.f, 12.5 years is subtracted from the estimated chronological age to obtain the mean tissue age for the specimen. This is necessary because increased size and expansion of the marrow cavity, and transverse cortical modeling drift during growth, remove histomorphological evidence of earlier bone remodeling activity. OPD, therefore, does not represent accumulated evidence of bone remodeling activity from birth, but rather a later age subsequent to the period of active growth and cortical modeling drift, referred to as the effective age of the birth of adult compacta. The effective age of the birth of adult compacta has been reported to be B12.5 6 3 years for the midshaft of the human rib (Frost and Wu, 1967). Ac:f 5 OPD:Cd  t21 Ac:f 5 23:6ð30 2 12:5yearsÞ Ac:f 5 1:34=mm2 =year

(6.3)

It should be noted that this is the activation rate based upon the number of BSUs occurring in a plane of a section, rather than the true activation frequency based upon BMU activations per mm, and referred to as origination frequency (Or.f) (Martin et al., 2015). It is the activation rate that has the greatest effect on the rate of bone remodeling and the amount of bone turned over (Martin et al.,

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TABLE 6.1 Activation Rates Reported in the Rib for Selected Diseases Disease

BMU/mm2/year (Ac.f)

Normal

2.01

Postmenopausal osteoporosis (females)

2.81

Senile osteoporosis (females)

1.90

Senile osteoporosis (males)

2.19

Osteomalacia

4.74

Rheumatoid arthritis

0.58

Cushing’s disease

0.18

Osteogenesis imperfect

9.12

Source: Modified from Martin (1991).

2015). Estimation of the activation rate, therefore, can provide valuable information regarding skeletal health (Table 6.1). The validity of the algorithm is demonstrated by agreement between tetracycline-based and osteon accumulation values (Wu et al., 1970; Stout and Paine, 1994). Bone formation rate (BFR) (Eq. (6.4)) is calculated as: BFR 5 Ac:fUOn:Ar BFR 5 1:34=mm2 =year U0:039 mm2 BFR 5 0:052 mm2 =mm2 =year

(6.4)

where On.Ar is the mean osteon area, including the Haversian canal, contained within B30 complete osteons chosen at random, defined as osteons for which their perimeter has not been encroached upon by subsequent bone remodeling.

Application of Remodeling Parameters to Pathological Cases and Archeological Skeletal Populations For paleopathology, it is important to understand the factors that can influence bone remodeling rates determined using this algorithm. Table 6.2 lists examples of some of these factors. Table 6.3 compares the osteon population-based estimated parameters of bone remodeling for the rib from the 30-year-old and additional comparative samples from the prehistoric archeological site of La Paloma, Peru, with comparable values derived from a modern autopsy sample by Stout and Paine (1994). All bone remodeling parameters for the archeological population sample from La Paloma, Peru, are consistent with those derived from the comparative modern sample, providing evidence that the

average bone remodeling rate has not changed significantly between modern and archeological populations some five millennia apart (Quilter, 1989). These results validate the use of the algorithm to compare these parameters between populations from various time periods to assess skeletal health. Wu et al. (1970) provide examples of data for OPDderived bone remodeling rates for select pathological conditions, including osteoporosis, osteogenesis imperfecta (OI), and diabetes mellitus. For osteoporotic samples, bone formation rates were 81% (0.065 mm2/mm2/year) compared to age-matched controls, and On.Ar was smaller (0.029 mm2). In addition, a greater proportion of OPD was fragmentary osteons, which may reflect the relatively smaller cortical areas (Ct.Ar) observed for osteoporotic ribs (Fig. 6.4) (Sedlin, 1964; Takahashi and Frost, 1965), which would lead to a greater fragmentary fraction of OPD. Similarly, osteon area (On.Ar) has been shown to have a relationship with cortex availability (Ct.Ar), and therefore, could relate to osteoporotic bone loss (Dominguez and Agnew, 2016) (Figs. 6.5 and 6.6). Table 6.4 provides examples of bone remodeling parameters for two different diagnosed pathological conditions in two modern autopsy samples of similar ages to Table 6.3, for comparison. The relatively higher parameters of bone turnover in the person with metastatic breast cancer is interesting, given that hypercalcemia often accompanies this disease, and metastasis can cause a regional acceleratory phenomenon (Frost, 1983). Several studies have applied the algorithm to archeological skeletal populations. Stout and Lueck (1995) utilized it to estimate and compare bone remodeling rates in ribs from three archeological skeletal populations and a

Histomorphology: Deciphering the Metabolic Record Chapter | 6

97

TABLE 6.2 Pathological Factors Affecting Osteon-Based Remodeling Rates (Frost, 1987b,c) Hormone Disorders

Trauma (Regional)

Paralysis

Electrolyte disorders

Metabolic disorders

Genetic disorders

Toxic agents

Regional acceleratory phenomenon

Tumors

Acute mechanical disuse

Nutrition and diet

Microdamage

Anemias

Paget’s disease

Metabolic alkalosis

Metabolic acidosis

Genetic structural disorders

Vitamin disorders

TABLE 6.3 Comparison of Rib Bone Remodeling Parameters for the Archaeological Sample from La Paloma, Peru (Robling, 1998; Robling and Stout, 2003) with Comparable Autopsy Data (Stout and Paine, 1994) Samples

Mean age (years)

OPD (N/ mm2)

OPD.Cd (N/ mm2)

Ac.f (N/mm2/ year)

On.Ar (mm2)

BFR (mm2/ mm2/year)

La Paloma example

30

20

23.6

1.34

0.039

0.052

La Paloma comparativea

28.8

19.5

22.4

1.5

0.036

0.054

Modern comparative sampleb

26

17.9

23.7

1.8

0.043

0.075

a

Means for the comparative La Paloma samples are based upon 37 individuals in their 3rd and 4th decades. Means for the modern comparative samples are based upon 11 individuals in their 3rd and 4th decades.

b

TABLE 6.4 Comparative Bone Remodeling Parameters for Modern Pathological Samples Condition

Mean Age (years)

OPD (N/ mm2)

OPD.Cd (N/ mm2)

Ac.f (N/mm2/ year)

On.Ar (mm2)

BFR (mm2/mm2/ year)

Cancera

27

26.3

45.4

3.1

0.039

0.124

Neurological diseaseb

26

18.8

26.3

1.9

0.049

0.0962

a

Metastatic breast cancer (Fig. 6.4). Neurofibromatosis and wheelchair-bound (Fig. 6.5).

b

modern autopsy sample. Compared to the modern autopsy sample, the archeological samples, representing intensive foraging and incipient maize agriculture, showed a trend toward increased bone remodeling rates over time, with the older intensive foraging populations being lowest. However, further analysis revealed this trend cannot be

attributed to differences in bone remodeling rates among the populations due to older effective ages of adult compacta in the archeological populations. Robling and Stout (2003) estimated bone remodeling rates using the algorithm in conjunction with biomechanical analysis of rib and femur samples from the Peruvian site of

98

Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 6.4 Complete cross-section from midshaft of a fifth rib from a 92-year-old female (modern) who suffered from osteoporosis and had been entirely immobile for at least 1 year prior to death. The excessive intracortical porosity in all cortices results in almost complete trabecularization of the existing cortex. Image taken under bright field light, basic fuchsin stained, scale included. Photo credit: Victoria Dominguez.

FIGURE 6.6 Complete cross-section from midshaft of a sixth rib from a 26-year-old male (modern) who suffered from neurofibromatosis and was confined to a wheelchair. Large areas of primary bone are present on all cortices indicating modeling drift was recently or may still be active. Table 6.4 provides comparative analysis of remodeling rates and associated age estimates for this individual. Image taken under bright field light, basic fuchsin stained, scale included. Photo credit: Victoria Dominguez.

from the Isola Sacra necropolis (AD 100
300) associated with the ancient city of Portus Romae, with modern African American and European American samples. Bone remodeling rates for ribs from the Isola Sacra and modern African American samples are similar, and lower than those observed in the modern European American samples. These results raise interesting questions in light of the higher frequency of osteopenia and greater risk of bone fracture associated with individuals of European descent, especially females (Johnell and Kanis, 2006). Miszkiewicz and Mahoney (2016) highlight 11 additional studies linking remodeling rate to sex, physical activity, or diet in archeological skeletal populations FIGURE 6.5 Complete cross-section from midshaft of a sixth rib from a 27-year-old female (modern) who was diagnosed with malignant neoplastic breast cancer 3 years prior to death. She chose to receive little to no treatment for the condition. Abnormal excessive bone formation and infilling is evident throughout the medullary region with high concentrations of vascular canals. Periosteal apposition is seen on the pleural cortex only. Table 6.4 provides comparative analysis of remodeling rates and associated age estimates for this individual. Image taken under bright field light, basic fuchsin stained, scale included. Photo credit: Victoria Dominguez.

La Paloma dating between 5800 and 2600 BC, and spanning a shift in subsistence economy from hunting and gathering to a local sedentary maritime economy. Both remodeling rates and geometric properties decreased over time, reflecting the effects of this subsistence change on skeletal morphology and histomorphology. Cho and Stout (2003) compared rib bone remodeling rates between an Imperial Roman skeletal population

WHY BONES BREAK: HISTOMORPHOMETRIC ASSESSMENT OF BONE STRENGTH AND FRAGILITY Between about 1900 and 1960, the coupling of boneforming cells (osteoblasts) and bone-resorbing cells (osteoclasts) in their recruitment and activity by osteocytes in response to mechanical signals was not understood. Bone cells were thought to respond to genetic and hormonal signals alone (Frost, 2003). However, a purely physiological perspective faces what Rauch and Schoenau (2001) call the “blind steering” problem. Hormones and other physiological influences increase and decrease bone mass in the same way that the wheels move a car backwards and forwards, but cannot steer its direction. Physiological influences cannot tell how much bone mass

Histomorphology: Deciphering the Metabolic Record Chapter | 6

already exists. They cannot detect how much more or less bone is needed, or where it should be positioned, to make bone strong enough to withstand typical mechanical demands on the skeleton. They do not detect when bone has mechanically failed at a microscopic level and is in need of repair (Rauch and Schoenau, 2001). According to the new bone biology paradigm, the primary function of bone is biomechanical, and a major function of bone remodeling is to maintain bone strength by structurally altering bone during life in order to optimize its strength given the mechanical loads it must endure. The sensitivity of osteocytes to local biomechanical changes “steers” bone formation, resorption, and repair to the tissue locations where it is most needed. Physiological processes move or expand the range of mechanical stimuli for these processes (Rauch and Schoenau, 2001). For example, disorders of bone mineral homeostasis that will be discussed (rickets/osteomalacia, hyperparathyroidism, hyperthyroidism, diabetes mellitus, glucocorticoid excess) stimulate cellular activity outside of the range associated with mechanical loading (see Table 6.5). The previous section described the cellular processes driving modeling and remodeling, and demonstrated algorithms for quantifying the activation and rate of remodeling. In this section, we examine the normal morphology of the histological features created by modeling and remodeling. We begin here with the theoretical concepts of bone functional adaptation and the mechanostat. Given a directional change in mechanical strain, these models predict whether bone modeling or remodeling will occur, and in turn what histological features should be observed. Next, we describe common types of mechanical loading experienced by bone, and their association with relatively higher or lower mechanical strain. We can use the mechanical loading mode of a tissue region (e.g., compression) as a proxy of mechanical strain (e.g., high strain) to predict patterns in bone modeling and remodeling, and predict the resulting histomorphometry of these regions. Cellular processes that remove, add, or repair bone to match recent mechanical demands, also alter bone’s material properties in preparation for future mechanical damage through the formation of “toughening mechanisms.” These tissue adaptations range from resistance to regional or local mechanical loads exerted at the nanoscale (tissue structure or “ultrastructure”) and microscale (histomorphometry), to the mechanical loads exerted on the whole bone by body structure and movement. We describe how the material properties of bone ultrastructure and microstructure are organized to resist elastic (temporary), but especially plastic (permanent), deformation.

99

These material properties are largely determined by remodeling rates, so we trace the normal trajectory of stochastic remodeling over the lifespan as cellular processes undergo senescence and dysregulation. We also consider the lifetime trajectory of targeted remodeling in response to microdamage. Bone is adapted to plastically dissipate energy through the formation and subsequent targeted repair of microdamage, but these processes also become uncoupled with age (Frost, 2003; Burr and Martin, 1993; Li et al., 2001). We conclude this section with an overview of normal bone histomorphometry and changes expected with age. The distribution and shape of these histological features can often be predicted by considering both the remodeling rate in response to previous mechanical strain and the toughening mechanisms needed to resist future mechanical damage. Lacunar-canalicular architecture provides information about regional osteocyte sensitivity to mechanical demands and local physiological needs. Vascular pore architecture reflects the flexibility of tissue regions to accommodate stress-concentrating voids that compromise bone strength. Secondary osteon size and shape are similarly a proxy for regional mechanical loading, as these histological units reflect both previous remodeling and toughening against propagating microdamage. The structural properties of the whole bone in cross-section are specifically mathematically linked to whole-bone mechanical demands. We consider changes in cross-sectional size associated with aging and sexual dimorphism, and alterations in cross-sectional shape during growth and adaptation to physical activity patterns.

Mechanical Loading Shapes the Material and Structural Properties of Bone Tissue Bone Functional Adaptation Bone is a mechanical organ, and the cellular processes that create its histological components are primarily driven by mechanical stimuli. In order to distinguish pathological bone, one must first understand the impact of mechanical loading on the variability of these histological features. Pathological conditions drive cellular activity and its histomorphometric products outside of this normal variation. In this subsection, we discuss the theoretical basis for interpreting histomorphometry that links biomechanical inputs to cellular activity outputs. Bone functional adaptation is a theoretical concept that explains how bone adjusts the amount and distribution of its mass to withstand that bone’s typical mechanical loads. While this concept is regularly applied to the

TABLE 6.5 Pathological Alteration of Remodeling Rates

Aging and osteoporosis

Osteomyelitis

Metastatic bone disease

Cause

Localization /Progression

Effect on Bone Cells

Bone Turnover

Bone Fragility

Remodeling rate increases after age 35,1 combined with cellular senescence2

Higher remodeling rates generally seen in bones and tissue regions under less mechanical loading3

Osteoclasts: Activated by decline in muscle and physical activity4; microdamage5

Net bone loss as capacity for bone formation increasingly lags6

Osteoporotic fracture in 1 in 3 women and 1 in 5 men over age 50 7

Bacterial infection, most commonly Staphylococcus aureus,8 from blood, infected tissue, or direct implantation9

Usually originates in long bone metaphyses.10 Spreads from periosteum to cortical bone to medullary cavity, ending with marrow fibrosis11

Osteoclasts: Activated by inflammation9

Resorption increased and formation of woven bone increased9

Fracture risk increased by formation of sinus tracts11

Osteolytic: Metastases most commonly breast,12 as well as lung, kidney, and thyroid13

Commonly spreads to axial skeleton and limb girdles via blood flow through vertebralvenus plexus.14 Cancer cells circulating in blood home to bone marrow13

Osteoclasts: Differentiation increased by tumor inflammatory response13,15

Resorption increased overall, but some woven bone formation13

Fractures common in breast (53%), lung (8%), kidney (11%), thyroid (4%), and lymphoma (4%)19

Formation increases overall, with local resorption20

Fractures in B3% of cases.19 Fragility increased by heterogeneity of resorption and woven bone formation20

Osteoblastic: Metastases from prostate cancer12

Osteoblasts: Senescence of sensitivity to signaling and capacity for differentiation 2

Osteoblasts: Activated by bone resorption9

Osteoblasts: Tumor releases antagonists to differentiation.16,17 Melanoma releases antagonists and is purely osteolytic18 Osteoclasts: Tumor promotes osteoblastogenesis13 but not its antagonists15 Osteoblasts: Releases cytokines that promote osteoblastogenesis, but attenuates them with proteases16

Osseous tumors

Malignant mesodermal cells21

Typically arise in medullary cavity of growing tubular bones, but less commonly in the cortex, bone surface, or extraskeletally21

Osteoblasts: Malignant mesodermal cells produce osteoid, chondroid, and/or fibrous tissue21

Tumors can be osteoblastic, osteolytic, or a mixed pattern21

Fractures spontaneously or with minor trauma22 most often through the tumor23

Paget’s disease

Unknown, but may be viral.24 Genetic susceptibility in 4% of cases25

Present in single or multiple bones, 26 commonly in the axial skeleton,27 targets sites of mechanical loading26

Osteoclasts: Genetic mutations in osteoclast differentiation, autophagy.28 Osteoclasts larger, more numerous (5 3 ), more nuclei (12 1 ).29,30 Increased osteoclast expression of factors for activation and resorbing31
33

Resorption increased30 with compensatory formation of “pagetoid” woven bone36 and fibrotic osteoid37

Can be asymptomatic (22% of cases), but weak woven bone can cause pathological fracture (5.7%)38

Osteoblasts: More numerous (5
10 3 ) 34,35

Osteopetrosis

Genetic in 70% of cases, mostly affecting osteoclast ability to resorb bone through modifying extracellular pH39

ARO: congenital; usually fatal in first year ADO: late childhood or adolescence onset; asymptomatic to (rarely) fatal XLO: X-linked39 (del)

Osteoclasts: Usually “osteoclast rich,” with increased numbers, size, and nuclei.39
41 Unable to form ruffled border for resorption.39
40 Can be “osteoclast poor” due to mutations in osteoclastogenesis signaling42

Impaired bone resorption. Bone formation can be increased by reaction to fracture, subperiosteal hemorrhage, or impairment of cross-talk with osteoclasts39,40

Dense, brittle bone interrupted by thickened cement lines41 is at high risk of transverse fracture.44 Occluded marrow lowers white blood cell count, risking osteomyelitis39

Unmineralized cortex cannot be remodeled, but is covered by a thick osteoid seam (hyperosteoidosis)46,48

Contributes to osteopenia and fracture risk in adults and children, especially in weightbearing regions49,50

Bone resorption triggers compensatory formation of a fibrous matrix containing woven bone (peritrabecular fibrosis)50

Fractures of the long bones, clavicles, pelvis, and ribs are common56

Lowering TSH reduces its suppression of osteoclastogenesis and osteoblastogenesis.61 Resorption and formation increased. Net bone loss due to shortened formation 60,63

Long term fracture risk increased two- to threefold in hip64,65 and fourfold in vertebrae66

Osteoblasts: Subset of ARO patients have few osteoblasts and reduced bone formation43 Rickets Osteomalacia

Hyperparathyroidism

Hyperthyroidism

Reduced availability of serum calcium, phosphate, or alkaline phosphatase.45 X-linked hypophosphatemia is caused by abnormal phosphate processing

Poor bone mineralization, primarily due to vitamin D deficiency, resulting in decreased absorption of calcium and phosphate in the small intestine, and decreased calcium reclamation from resorbed bone. 45

Osteoclasts: Cannot remove the unmineralized osteoid deposited normally by osteoblasts46

Excessive parathyroid hormone (PTH) secretion due to parathyroid gland over activity (primary), calcium deficiency (secondary) or autonomous gland function (tertiary)51

Resorption and fracture risk attenuated in regions that bear weight (e.g., tibia vs. radius).52
55 Early resorption of phalangeal margins50

Osteoclasts: Increased osteoclastogenesis51

Excessive thyroid hormone can be endogenous (e.g. Grave’s disease, toxic thyroid nodule or multinodular goiter) or exogenous (thyroid hormone treatment)57

Overt: excessive secretion of thyroid hormones Subclinical: low levels of thyroid stimulating hormone (TSH)58

Osteoblasts: Normal osteoid formation.46 Lack of vitamin D reduces expression of factors that promote osteoclast differentiation and activity47

Osteoblasts: PTH triggers osteoblast and osteocyte secretion of factors for osteoclastogenesis.51 Increased activity in response to bone resorption50 Osteoclasts: Thyroid hormone triggers osteoblast secretion of factors for osteoclastogenesis and increases these factors in serum.58
60 Osteoblasts: Thyroid hormone promotes lifecycle from proliferation to differentiation to apoptosis 60

(Continued )

TABLE 6.5 (Continued)

Diabetes Mellitus

Cause

Localization /Progression

Effect on Bone Cells

Bone Turnover

Bone Fragility

Inadequate insulin secretion produces a delayed but increased inflammatory response67

Type 1 (T1DM): autoimmune destruction of β-cells of pancreas, resulting in absolute insulin secretion deficiency Type 2 (T2DM): resistance to insulin action and inadequate secretion of insulin to compensate68

Osteoclasts: Osteoclastogenesis increased by elevated and prolonged expression of proinflammatory factors in both T1DM69 and T2DM.70,71 High fatty acid levels induce and mediate osteoclastogenesis.72 Extracellular sugar production of advanced glycation end products (AGEs)74,74 induces osteoclastogenesis directly75,76 and through osteocyte stimulation.77,78 Apoptosis increased in T1DM79,80 and T2DM79,81,82

T1DM: Bone resorption increased71,79,82,89 and bone formation decreased90
93 T2DM: Bone resorption found both to decrease94,95 and increase96,97

Bone brittleness increased98
100 by minimal matrix production83 and by AGEs forming nonenzymatic cross-links in collagen.101 Skeletal fracture risk increased Btwofold.83 Fracture healing impaired and prolonged102
105

Bone mass is lost rapidly in an early phase due to increased resorption, and then lost slowly in a later phase due to insufficient bone formation.117,123 Bone formation is suppressed within hours of elevation.124 Osteoblast inhibition plays the primary role, compared to osteoclast activity107

Fractures occur in 30%
50% of long-term cases, often in the vertebrae (typically asymptomatic) and femoral neck125
127

Osteoblasts: Osteoblastogenesis suppressed in T1DM83
86 and T2DM.87 T1DM suppresses mature osteoblast expression of factors67 and collagen88 for ossification. Osteoblast apoptosis increased in T1DM79,80 and T2DM81 Glucocorticoid Excess

Glucocorticoids administered exogenously or through endogenous stimulation (e.g. inflammation, burn, or a tumor of the hypothalamic
pituitary
adrenal axis as in Cushing’s syndrome)106

Main effect is directly on bone cells.107 Bone quality also inhibited by indirect action of glucocorticoids on calcium secretion and suppressed secretion of growth hormone, gonadotropin releasing hormone, and PTH.108 Concentrated in trabecular bone109

Osteoclasts: Early phase promotes osteoclastogenesis110
112 and inhibits apoptosis.113 Late phase disrupts cytoskeleton organization,114 reduces precursor proliferation,115 and triggers attenuation of reactive oxygen species needed for osteoclastogenesis.116 This reduces numbers118 and resorbing activity114 Osteoblasts: Osteoblastogenesis suppressed by inhibition of signaling pathways, release of antagonists,118
120 and transcription factors (FOXO) released to counter oxidative stress.122 Significantly increased apoptosis of osteoblasts and osteocytes117

Osteogenesis imperfecta

Autosomal dominant mutations in pro-1 or pro-2 chain of type 1 collagen in 90% of cases (OI types I
IV)128

Collagen destabilized by exclusion (OI type I) or inclusion (OI types II, III, IV) of mutant chain. Mutations in posttranslational collagen modification enzymes (OI types VII, VIII)128

Osteoclasts: Numbers reduced in OI type II129 Resorption decreased 11%/cycle in OI types I
IV130 Osteoblasts: All types have organelles swollen by retained mutant collagen. Numbers reduced in OI type II.129 Formation decreased 14%/ cycle OI types I
IV131

OI types I
IV: Net bone loss; activation frequency increased 60%.130 OI types V
VII: delayed mineralization creates a higher relative osteoid surface.131
133 OI type VIII: scattered focal osteoid accumulation134

Spontaneous fracture risk increases with disease severity: type I , types IV, V, VI, VII , type III , type II (perinatal lethal)133

[1] Martin (1993); [2] Pearson and Lieberman (2004); [3] Gocha and Agnew (2016); [4] Thomas et al. (2005); [5] Ebacher et al. (2007); [6] Seeman and Delmas (2006); [7] Kanis et al. (2000); [8] Bruder et al. (2009); [9] Keel (2015); [10] Elgazzar and Shehab (2006); [11] Rosenberg (2010); [12] Perez et al. (1990); [13] Buijs and van der Pluijm (2009); [14] Rubens (1998); [15] Schwaninger et al. (2007); [16] Chappard et al. (2011); [17] Chappard et al. (1978); [18] Tian et al. (2003); [19] Higinbotham and Marcove (1965); [20] Roudier et al. (2008); [21] Klein and Siegal (2006); [22] Jaffe et al. (1987); [23] Haynes et al. (2017); [24] Singer (1999); [25] Eekhoff et al. (2004); [26] Langston and Ralston (2004); [27] Valenzuela and Pietschmann (2017); [28] Lucas et al. (2006); [29] Hosking (1981); [30] Meunier et al. (1980); [31] Hoyland and Sharpe (1994); [32] Hoyland et al. (1994); [33] Teramachi et al. (2014); [34] Pestka et al. (2012); [35] Seitz et al. (2009); [36] Vallet and Ralston (2016); [37] Meunier (1975); [38] Tan and Ralston (2014); [39] Del Fattore et al. (2008); [40] Shapiro et al. (1980); [41] Semba et al. (2000); [42] Sobacchi et al. (2007); [43] Helfrich et al. (1991); [44] Kuo and Davis (1981); [45] Holick (2007); [46] Oppenheimer and Snodgrass (1980); [47] Khosla (2001); [48] Teitelbaum (1980); [49] Perez-Rossello et al. (2012); [50] McCarthy (2016); [51] Fraser (2009); [52] Hansen et al. (2010); [53] Stein et al. (1999); [54] Vu et al. (2013); [55] Unnanuntana et al. (2011); [56] Khosla et al. (1998); [57] Mankin (1995); [58] Greenspan and Greenspan (1999); [59] Zaidi et al. (2010); [60] Lakatos et al. (1997); [61] Bassett and Williams (2003); [61] Zaidi et al. (2009); [62] Zaidi et al. (2006); [63] Harvey et al. (2002); [64] Wejda et al. (1995); [65] Bauer et al. (2001); [66] Vestergaard (2007); [67] Retzepi et al. (2018); [68] American Diabetes (2014); [69] Silva et al. (2012); [70] Duarte et al. (2007); [71] Bastos et al. (2012); [72] Drosatos-Tampakaki et al. (2014); [73] Yamamoto et al. (2008); [74] Schwartz et al. (2009); [75] Giacco and Brownlee (2010); [76] Ha et al. (2004); [77] Ding et al. (2006); [78] Nyman et al. (2007); [79] Pacios et al. (2012); [80] Coe et al. (2011); [81] Andriankaja et al. (2012); [82] Mahamed et al. (2005); [83] Verhaeghe et al. (1994); [84] Maor and Karnieli (1999); [85] Lu et al. (2003); [86] Anagnostou and Shepherd (2008); [87] Chang et al. (2009); [88] Gooch et al. (2000); [89] Santos et al. (2010); [90] Kemink et al. (2000); [91] Verhaeghe et al. (1989); [92] Verhaeghe et al. (1990a); [93] Verhaeghe et al. (1990b); [94] El Miedany et al. (1999); [95] Erbagci et al. (2002); [96] Isaia et al. (1999); [97] Krakauer et al. (1995); [98] Hou et al. (1991); [99] Einhorn et al. (1988); [100] Reddy et al. (2001); [101] Ruppel et al. (2008); [102] Loder (1988); [103] Folk et al. (1999); [104] Choi et al. (2014); [105] Liuni et al. 2015; [106] Klein (2015); [107] Henneicke et al. (2011); [108] Canalis et al. (2007); [109] van Staa et al. (2000); [110] Rubin et al. (1998); [111] Hofbauer et al. (1999); [112] Sivagurunathan et al. (2005); [113] Weinstein et al. (2002); [114] Kim et al. (2006); [115] Kim et al. (2007); [116] Bartell et al. (2014); [117] Weinstein et al. (1998); [118] Pereira et al. (2002); [119] Yao et al. (2008); [120] Hayashi et al. (2009); [121] Mak et al. (2009); [122] Iyer et al. (2013); [123] LoCascio et al. (1990); [124] Kauh et al. (2012); [125] Cohen et al. (1999); [126] Wallach et al. (2000); [127] Angeli et al. (2006); [128] Basel and Steiner (2009); [129] Sarathchandra et al. (2000); [130] Rauch et al. (2000); [131] Glorieux et al. (2000); [132] Glorieux et al. (2002); [133] Rauch and Glorieux (2004); [134] Fratzl-Zelman et al. (2016b).

104 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

external size and shape of the bone, tissue within the bone cortex also adapts. Bone functional adaptation is a feedback-based model in which increasing mechanical strain leads to bone deposition, while decreasing mechanical strain leads to bone resorption. Equilibrium strains that fall within a range of “optimum customary strain level” do not produce a net change in bone deposition (Lanyon et al., 1982). The strain level perceived to be “optimal” by bone during its typical mechanical loading likely is determined by a combination of factors, including skeletal location, genetics, hormonal, and other physiological influences, and the breakdown of these influences with senescence and disease (Heaney et al., 2000; Ruff et al., 2006; Robling et al., 2014). More specifically, bone is known to adapt to regional strains, not total strains (Lanyon et al., 1982; Ruff et al., 2006). Lanyon et al. (1982) found that when strain is distributed regionally, bone forms preferentially on the periosteal surface of the region under higher strain, rather than uniformly around the circumference of the bone. Frost’s (1987a) mechanostat provides a strain-based mathematical model for how this feedback might occur. Strains falling below a disuse threshold result in bone resorption, strains within the equilibrium range produce remodeling to repair and maintain bone, and strains above the equilibrium range stimulate modeling, meaning the formation of new bone where it was previously absent. Higher strains produce the accumulation of fatigue damage, and ultimately result in failure (Frost, 1987a). Mechanical studies on bone allowed Frost to update his model with quantifiable strain magnitudes for these thresholds (Frost, 2003). See Pearson and Lieberman (2004) for an overview of alternative models for bone functional adaptation.

Mechanical Loading Modes Experienced by Bone How can we infer mechanical strain without destructive mechanical testing of bone tissue? The type or “mode” of mechanical loading experienced by bone can be used as a proxy of relatively higher or lower strain, allowing comparisons to other tissue regions or skeletal elements. The mechanical loading mode can be inferred from how the bone is loaded by body weight and/or physical activity, as described in this subsection. Additionally, spontaneous fractures tend to concentrate at specific anatomical sites (e.g., vertebrae, femoral neck) that experience heavy mechanical demand from dynamic loading or body weight. These sites are more vulnerable to changes in bone quality that increase bone fragility with age. Pathological fractures may be distinguished

by their occurrence at less common anatomical sites, dissociated from the usual life conditions and age-associated changes that typically predict traumatic fractures (see “Bone Fragility” in Table 6.5). Understanding how the biomechanical configuration of a bone affects mechanical demand and eventual fracture risk can help identify pathological sources of fracture. Bone is loaded uniformly along its long axis during axial loading. In axial compression, the ends of bones are pushed together and length decreases. For example, vertebrae in humans are compressed axially by body weight during upright posture and during daily activities such as bending or lifting with the back (Cooper et al., 1992). The vertebrae, especially in the thoracolumbar spine, are a common site of traumatic axial compression injuries (Gertzbein, 1991). These fractures are more common in patients with bones weakened by osteoporosis or certain cancers, as the compression fracture can occur with minimal loading (Wood et al., 2014). Between 12% and 23.5% of individuals over age 50, both male and female, have at least one vertebral fracture related to osteoporosis, as quantified in American, European, and Canadian populations (Cooper et al., 1992; Melton et al., 1993; O’Neill et al., 1996; Jackson et al., 2000). In axial tension, the ends of bones are pulled apart and length increases. Bone is weaker in tension than compression (Reilly and Burstein, 1974; Reilly and Burstein, 1975). That is, when cyclically loaded to the same magnitude, bone fails more quickly in tension than compression (Caler and Carter, 1989; Pattin et al., 1996). Lanyon and Baggott (1976) observed that, in bending, compressed regions of bone have higher strain ( 3 1.9) than tensed regions. Since compression exerts comparatively higher magnitude loads than tension, there is rarely a net tensile strain in bone. Tensile strains can occur regionally, as in bending, or due to pull from muscle attachments, as violently demonstrated in evulsion fractures (Currey, 1962; Einhorn, 1992). Over 70% of longitudinal forces in bone are due to bending (Biewener and Bertram, 1993). In bending, cortical regions are tensed and compressed by the same applied load. Compressive and tensile stresses in the plane of bending decrease toward the neutral axis, and the net stress is zero where they meet (Robling et al., 2014). Since bone will be formed or resorbed regionally at the periosteal or endosteal surface in relation to these regional strains, quantifying cross-sectional geometry (the distribution of bone in a cross-section) can help infer the causative direction of nonaxial loading (Ruff et al., 2006). Other forces exerted during locomotion include torsion, in which the ends of bones are twisted relative to each other, and shear, in which the ends of bones move in

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parallel but opposite directions due to a transverse load. Most forces exerted during locomotion result from bending, torsion, shear, or a combination of these forces, placing different regions of a given cross-section into different strain modes (Skedros, 2011). Additionally, bone is anisotropic, meaning that its resistance to a force depends on the direction of force (Melton et al., 1988). For example, vertebrae are most resistant to compression (Galante et al., 1970), while the proximal femur is resistant to loads parallel to its trabecular architecture (Brown and Ferguson, 1978) and is more resistant to longitudinal rather than transverse loading (Burstein et al., 1976; Einhorn, 1992). Falls provide an example of how mechanical loading modes combine to exert force on and fracture bone regions. Approximately 80%
90% of all fractures in older adults (age 65 1 ) occur during falls (Sjo¨gren and Bjo¨rnstig, 1989; Kannus et al., 1999). Forearm fractures, commonly of the distal radius or ulna from a “fall onto an outstretched hand,” comprise an estimated 18.5% of osteoporotic fractures worldwide, with a high prevalence in women (80%) (Johnell and Kanis, 2006). Most distal radius fractures occur when the hand strikes the ground with wrist in dorsiflexion (palm-first). The palmar aspect first fails in tension, further bending the wrist in dorsiflexion and compressing the dorsal aspect. Compaction at the metaphysis and shear at articular surfaces complicate the injury (Meena et al., 2014). Between 21% and 61% of distal radius fractures present alongside a fracture of the ulnar styloid process. The distal ulna can also fracture at the head, neck, or distal shaft, almost always alongside a distal radial shaft fracture, unless the ulna has been directly injured (Logan and Lindau, 2008).

Material Properties and Bone Strength The theoretical concept of bone functional adaptation, as modeled by the mechanostat, explains changes in bone quantity as a reaction to recent mechanical demand. Remodeling also alters bone quality, adapting its material properties to resist mechanical damage in the future. The strength of bone is a function of both structural and material strength. As Martin (1993) notes, structural properties are the consequence of modeling the external shape (geometry and size) of bone, while material properties are associated with remodeling and the resulting organization of the internal structures of bone tissue. Tissue organization includes bone’s mineralized matrix, but also the absence of tissue in the spaces formed by Volkmann’s and Haversian canals, lacunae and canaliculi, and the marrow surrounding trabecular architecture (Martin, 1993; Allen and Burr, 2008). This subsection introduces

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the components of a stress
strain curve, which represent the bone’s material properties, normalized for mass and geometry. Stress is the force of the applied load divided by area, while strain is the corresponding net change in length (Einhorn, 1992). The initial part of the curve is linear, with stress and strain increasing proportionally. In this elastic (or preyield) region, bone is not permanently deformed and can return to zero displacement with no energy lost (Einhorn, 1992), while its slope, Young’s modulus of elasticity, corresponds to stiffness or rigidity of a whole structure (Einhorn, 1992; Burr, 2011). Following the yield point, stress and strain are not proportional, and the material enters the plastic (postyield) deformation region, where energy is lost, and the material is permanently deformed (Einhorn, 1992; Robling et al., 2014). The strength of bone is defined as the ultimate stress before the bone fails (Einhorn, 1992; Burr, 2011). Brittle materials such as chalk have minimal or no postyield deformation, but fail soon after reaching the yield point (Einhorn, 1992). This reduced plastic deformation is also seen in pathologically brittle bone, as in osteopetrosis (Einhorn, 1992) and osteogenesis imperfecta (Carriero et al., 2014a,b). The total area under the stress
strain curve is called toughness, which represents the total energy that the material absorbs before failing (Einhorn, 1992).

Trade-Offs Between Strength and Toughness in Fracture Resistance Bone cannot maximize both its elastic resistance and its resistance to fracture and crack propagation within the plastic region (toughness) (Ritchie, 2011). A brittle material has high stiffness and strength but low toughness because it fails early in plastic deformation (Einhorn, 1992). For example, overly mineralized osteopetrotic bones are very dense and strong. However, these bones are fragile because they can absorb little energy before failure. Conversely, osteoporotic bones are less strong and stiff, but can absorb more energy before failure. Osteoporotic bones resist fracture less than a normal bone, but more than an osteopetrotic bone (Burr, 2011). Due to a high remodeling rate that keeps mineralization low, juvenile bones are less brittle and can plastically deform more than healthy adult bone (Martin, 1993; Agnew et al., 2013). Bone’s resistance to fracture is defined not simply by the energy it can absorb before failure (Burr, 2011). Tough materials such as bone release energy in the form of limited plastic deformations that do not fully fracture the bone, and are thereby able to dissipate more energy

106 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

before failure. As a fracture grows, bone actually develops greater resistance to fracture (toughness) (Wang and Gupta, 2011). Intrinsic toughening mechanisms elongate plastic deformation, allowing a bone to deform more before it initiates or propagates a crack. Extrinsic toughening mechanisms cannot stop crack initiation, but they can slow or stop an initiated crack (Ritchie, 2011). Mineralized tissue toughness is mostly derived from extrinsic toughening mechanisms, including dissipation of energy through microdamage, crack deflection at secondary osteon cement lines, and crack bridging (Nalla et al., 2005). Microdamage is actually an advantage to bone in small amounts because it dissipates energy in the plastic deformation region that would fracture a more brittle material (Martin, 2003). Even though microdamage does weaken bone, mechanosensory osteocytes allow bone to target and remodel the damaged area. Microdamage threatens bone when it accumulates quicker than it can be repaired, due to high strains (Frost, 2003) or senescence of bone’s cellular targeting and remodeling mechanisms.

Normal Trajectory of Remodeling Rate Over the Lifespan Variation in remodeling rate depends not only on mechanical stimuli, but on changes in cellular activity over the lifespan, particularly during growth and senescence. Knowledge of the life trajectory of remodeling is essential for distinguishing pathological deviations in cellular activity. For example, woven bone signifying rapid turnover is a normal occurrence in growing young juveniles, but represents pathology or fracture repair in adults (Teitelbaum, 1980). A driving force behind toughening mechanisms in bone is their hierarchal structure, with organization from the molecular level to the macroscale (Allen and Burr, 2008; Ritchie, 2011; Wang and Gupta, 2011). Since material properties of bone are most strongly associated with remodeling (Martin, 1993), the rate of remodeling is a major determinant of bone strength, as it relates to these properties. Children have high remodeling rates during growth, which slow with adulthood. Remodeling rates reach a minimum at about age 35 and then begin to increase again (Martin, 1993). One reason for this increase in the remodeling rate in individuals over 35 years of age is a decline in muscle strength and physical activity (Thomas et al., 2005). This decline can trigger increasing amounts of disuse remodeling, in which more bone is resorbed than is formed in its place (Frost, 2003). A second driving force behind the increase in remodeling rate is that stimuli for remodeling (such as fatigue

damage) continue, but bone’s cellular capacity to form new bone declines. High remodeling rates in youth lead to a positive bone balance, but high remodeling rates in age lead to a net bone loss (Seeman and Delmas, 2006). In growth and adulthood, estrogen promotes endosteal bone formation, while testosterone promotes periosteal bone formation. As hormone levels decline with age, osteoblasts are no longer driven by these additional signals for bone formation (Pearson and Lieberman, 2004). Osteoblasts and their progenitors also undergo senescence with age, evidenced by a decline in production of alkaline phosphatase (an enzyme that is a byproduct of bone formation) and osteoprotegerin (a protein produced by osteoblasts that inhibits osteoclastogenesis), which indicate a decline in capacity for differentiation and a reduced sensitivity both to chemical and mechanical signaling pathways (Tanaka and Liang, 1996; Nishida et al., 1999; Makhluf et al., 2000; Batge et al., 2000). Researchers are still debating why this senescence occurs and have considered hypotheses such as the accumulation of reactive oxygen species, irreversible epigenetic modifications, and telomere shortening (Pearson and Lieberman, 2004). Biocultural factors can also modify age-associated bone loss. In both modern and archeological populations, bone loss is associated with inadequate nutrition (e.g., calcium and vitamin D deficiency, increased animal protein and phosphorus, and malnutrition). Reproductive stress (pregnancy, lactation) and lifestyle choices (lack of physical activity, smoking, drinking) also appear to be risk factors for osteoporosis (reviewed in Agarwal, 2008). Remodeling in old age does not reap the mechanical benefits of remodeling in youth due to the net loss of bone (Martin, 1993).

Describing Osteopenia and Osteoporosis in Modern Populations Throughout this chapter, cortical bone microstructure will be described both as it appears in healthy individuals and as it changes due to age-associated declining bone mass. These senescent changes are most noticeable when they are exacerbated in osteopenia and osteoporosis, which will be defined here. Age-associated changes in bone mass are typically clinically quantified in terms of bone mineral density (BMD) through dual-energy X-ray absorptiometry (DXA or DEXA) at sites such as the proximal femur, lumbar spine, and forearm (Kanis et al., 2008). In 1994, the World Health Organization (WHO) published diagnostic criteria for low or decreased BMD in postmenopausal women through comparison with the BMD of young, healthy women. Osteopenia describes

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BMD between 1.0 and 2.5 standard deviations (T-score of
1.0 to
2.5) below this standard. Osteoporosis describes BMD more than 2.5 standard deviations (T-score less than or equal to
2.5) below this standard (WHO, 2007). The International Osteoporosis Foundation (Kanis and Glu¨er, 2000) and the International Society of Clinical Denistometry (Binkley et al., 2006) recommend that the young adult standard for BMD be the femoral neck measurements of white women aged 20
29, as collected in the NHANES III (Third National Health and Nutrition Examination Survey) reference database (Looker et al., 1997, 1998). Kanis et al. (2008) argue that these standards can accommodate white and nonwhite postmenopausal women and men over age 50. Osteoporosis increases the risk of “low force” or “fragility” fractures in response to mild or moderate trauma. In severe cases, normal physical activities can result in spontaneous fractures (Dolinak, 2008). Falls are responsible for approximately 80%
90% of all fractures in older adults (Sjo¨gren and Bjo¨rnstig, 1989; Kannus et al., 1999). Despite its clinical prevalence, BMD is underpredictive of actual fracture risk. For example, a study of hip fracture patients in the United States found that 54% were not defined as osteoporotic at the hip (T-score .
2.5) and 6% were not even diagnostically osteopenic (Tscore .
1.0) (Wainwright et al., 2005). BMD only explains a doubling of the fracture risk between ages 60 and 80, when fracture risk actually increases 13-fold (De Laet et al., 1997). This metric cannot quantify ageassociated changes in the three-dimensional structure of cortical or trabecular bone tissue, which independently reduce bone strength and increase fracture risk (Chen et al., 2010). The National Bone Health Alliance (NBHA), composed of clinicians and clinical scientists from the National Osteoporosis Foundation and the American Society for Bone and Mineral Research, recommends an expanded toolkit for diagnosing osteoporosis in postmenopausal women and men over age 50. Even when BMD does not indicate osteoporosis (T-score . 2.5), a diagnosis may be made if an individual is at increased risk for future fractures. Risk factors include a prior lowtrauma fracture at the hip for all patients, and a prior lowtrauma fracture located in the vertebrae, proximal humerus, pelvis, or (in some cases) the distal forearm for patients diagnosed with osteopenia (Siris et al., 2014). The NBHA also recommend the use of the FRAX (Kanis, 2008), a tool sponsored by the WHO that aggregates epidemiological data from large patient cohorts in North America, Europe, Australia, and Asia. FRAX algorithms provide the 10-year probability of experiencing hip fracture or any major osteoporotic fracture (hip, spine, forearm, or shoulder). This risk is calculated based on a

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combination of demographic data (age, sex, nationality, ethnicity), clinical risk factors (e.g., prior fracture, medical conditions, smoking, and drinking), and femoral neck or total hip BMD.

Describing Bone Loss in Past Populations The diagnostic challenges seen in modern populations are exacerbated in bioarcheological contexts, which lack these patient data. Beauchesne and Agarwal (2017) note that, in contrast to surveys of modern Western populations, bioarcheological studies often find bone loss at younger ages for both sexes, similarities between sexes in age-associated bone loss, and a low frequency of fragility fractures. One explanation for this unexpected scarcity of fragility fractures may be the survival of healthier individuals to older ages in archeological populations (Brickley and Agarwal, 2003), also described as the osteological paradox or the hidden heterogeneity of frailty (Wood et al., 1992). Beauchesne and Agarwal (2017) suggest that literature inconsistency may also be due to sampling at dissimilar skeletal sites, which differ in the rate or extent of bone loss because they vary in mechanical loading or tissue type (e.g., cortical or trabecular bone). While fractures are visible in macroscopic examination, it is difficult to distinguish fragility-related fractures from traumatic fractures, or even postmortem fractures (Agarwal, 2008). Like clinicians, bioarcheologists have turned to methods than can detect a decline in the structural or material properties of bone tissue prior to fracture. However, methodological differences in describing bone loss can contribute to literature inconsistency regarding patterns of bone loss in the past. A method’s quantification of bone loss is specific to the skeletal site being analyzed and the bone type (cortical or trabecular) targeted. The measurement used as a proxy of bone quality also differs between methods, with the most common metrics including cortical geometry (radiogrammetry), BMD (bone densitometry, typically DXA), trabecular structure (micro-CT or peripheral quantitative computed tomography (pQCT)), and histological markers of remodeling (cortical bone histomorphometry) (Agarwal, 2008; Beauchesne and Agarwal, 2017). In radiogrammetry, radiographs are taken of a bone to measure its cortical thickness, which can be converted to its cortical index (percentage of total bone width) (Beauchesne and Agarwal, 2017). The second metacarpal is commonly chosen for radiogrammetry in archeological studies (e.g., Pfeiffer and King, 1983; Ekenman et al., 1995; Mays, 1996, 2001; Lazenby, 2002; Ives and Brickley, 2004; Glencross and

108 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

Agarwal, 2011; Beauchesne and Agarwal, 2014, 2017) due to its circular shape and nearly central medullary cavity, although it is not a common site of osteoporotic fracture (Ives and Brickley, 2004). Other bioarcheological studies have applied radiogrammetry to the femur (Ericksen, 1976; Ekenman et al., 1995; Mays et al., 1998), radius (Ekenman et al., 1995; McEwan et al., 2005), humerus (Ericksen, 1976), and lumbar vertebrae (Pfeiffer and King, 1983). In modern clinical contexts, densitometric analyses of BMD have replaced radiogrammetry (Beauchesne and Agarwal, 2017). Bone densitometry has also seen application in archeological contexts at common clinical sites such as the proximal femur (Mays et al., 1998; Ekenman et al., 1995; Lees et al., 1993; Mays et al., 2006), femoral neck (Hammerl et al., 1990; Poulsen et al., 2001; Turner Walker et al., 2001; Lees et al., 1993; McEwan et al., 2004; Holck, 2007), midshaft and distal radius (Perzigian, 1973; McEwan et al., 2004, 2005), lumbar vertebrae (Agarwal and Grynpas, 2009), as well as the midshaft humerus and tibia (Ekenman et al., 1995). The emergence of threedimensional imaging technology, such as micro-CT and pQCT, has popularized the analysis of changes in trabecular bone architecture in archeological populations. Highly trabecular regions chosen for analysis include the fourth lumbar vertebra (Kneissel et al., 1997; Agarwal et al., 2004; Agarwal, 2012; Beauchesne and Agarwal, 2017), the proximal femur (Ryan and Shaw, 2015), and the epiphyses of appendicular bones (Chirchir et al., 2015). Cortical bone histomorphometry, which is the focus of this chapter, has largely been applied to quantify bone loss in archeological studies of the femur (Martin and Armelagos, 1979, 1985; Richman et al., 1979; Ericksen, 1980; Thompson et al., 1981; Thompson and Gunness-Hey, 1981; Burr et al., 1990), rib (Stout and Teitelbaum, 1976; Stout, 1983; Stout and Lueck, 1995; Mulhern, 2000; Beauchesne and Agarwal, 2017), or femur and rib comparatively (Pfeiffer, 1998; Cho and Stout, 2003, 2011; Robling and Stout, 2003; Pfeiffer et al., 2006).

Bone Strength at the Microscale: Microdamage as an Energy-Dissipating Mechanism Using histomorphometry to infer remodeling activity and its mechanical stimulus appears straightforward with the setpoints outlined in the mechanostat model. However, as Martin (2000) identifies, the remodeling range of the mechanostat model does not have a high enough setpoint to target microdamage. Remodeling is initiated both at low strains, in response to disuse, and high strains, in response to microdamage. Attempts to infer mechanical

demand from histomorphometry must consider whether the remodeling is likely to represent stochastic bone turnover or targeted bone repair. Martin (2000) notes that placing remodeling and its adaptive window out of the range of microdamage repair implies that targeted remodeling is not adaptive. However, microdamage serves as a toughening mechanism to resist bone failure. Bone trades some of its elastic stiffness for toughness. While it yields earlier, it can deform plastically and resist fracture for increasing amounts of strain (Ritchie, 2011). Bone dissipates energy without failure through forming small diffuse cracks under tension and larger microcracks under compression. This energy release increases the total energy required to break the bone (Martin, 2003). Microdamage also is an important consideration for predicting histomorphometry because it both initiates and is initiated by histological features. Microcracks are removed through targeted remodeling bone (Burr and Martin, 1993; Li et al., 2001), creating the secondary osteons, vascular pores, and lacunar-canalicular architecture associated with remodeled bone. However, microdamage can also be initiated by these same vascular pores and osteocyte lacunae (Ebacher et al., 2007). Microdamage has not been examined commonly in archeological bone, although Papageorgopoulou and colleagues (2006, 2007, 2010) have demonstrated its threedimensional visualization and quantification with CLSM in bone from a Swiss medieval (11th
15th century AD) population. However, microdamage is an important consideration for interpreting the mechanical loading environment of bone tissue. The concept of microdamage appends Frost’s mechanostat model of bone turnover, such that remodeling activity can be triggered both at moderate strains and at strains high enough to induce microdamage (Burr and Martin, 1993; Li et al., 2001). Microdamage accumulation also helps explain the increased fragility of bone in association with age and pathologies that increase mineralization, accumulate vascular porosity, and promote osteocyte apoptosis or death. In particular, vascular porosity is created by microdamage-targeted remodeling, and subsequently this stress-concentrating porosity becomes a risk factor for initiation propagation of microcracks into fracture (Ebacher et al., 2007).

Morphology of Microdamage Depends on Loading Mode While diffuse microdamage and linear cracks are visible at the microscale, they begin with nanoscale-level structural changes in the bonds between collagen, mineral, and noncollagenous proteins. Osteoporotic bone has reduced mean collagen fibril diameter, which may explain some

Histomorphology: Deciphering the Metabolic Record Chapter | 6

of its increased fragility (Kafantari et al., 2000; Tzaphlidou and Kafantari, 2000). Fibers with a similar banding pattern have been reported for relatively ancient bone (Ascenzi, 1955; Wyckoff and Doberenz, 1965), suggesting that collagen fibers are preserved for analysis in such bone. When subjected to cyclic bending, bone tends to fail through interlamellar debonding in tensed regions and through oblique or longitudinal cracking in compressed regions (Carter and Hayes, 1977). Many of bone’s material properties are anisotropic, meaning they accumulate differently based on direction, and microdamage is no exception (Burr et al., 1998). Tension and compression loading differ in the strain threshold and resulting morphology of microdamage in bone. Pattin et al. (1996) observed modulus degradation and an increase in the cyclic dissipation of energy starting at 2500 με in cadaveric femoral cortical bone loaded under tension, compared to a damage threshold of 4000 με under compression. Diab and Vashishth (2005) found that tensed regions accumulate four-fold more diffuse microdamage than compressed regions, while compressed regions accumulate twice as much linear microcracking as tensed regions. Regions under tension preferentially develop diffuse damage, a mesh of many small cracks B2
10 μm wide oriented transversely to the tensile stress (Schaffler et al., 1994; Zioupos and Currey, 1994; Boyce et al., 1998; Reilly and Currey, 1999, 2000; Vashishth et al., 2000; Ebacher et al., 2007). However, this microdamage does not coalesce into large ( . 100 μm) microcracks that are capable of penetrating Haversian systems until high strains are reached, just prior to failure. Bone tissue regions under compression first begin to develop microcracks at high strains, but these cracks are likely to continue growing and lead to bone fracture (Reilly and Currey, 1999). Linear microcracks are 40
100 μm long and 1
2 μm wide in cross-section, but can run 300
500 μm in the longitudinal plane of the bone (Burr and Martin, 1993; Taylor and Lee, 1998). Burr et al. (1998) found that tensile cortices had significantly more (25%) damage than compressed cortices, since diffuse microdamage begins in tensed regions at lower strains than microcracks begin in compressed regions.

Diffuse Microdamage as an Energy-Dissipating Mechanism Since bone is weaker and deforms under lower strain in tension, it is able to dissipate energy by forming diffuse cracks that are less likely to propagate into fracture than those formed under compression. This mechanism increases the fatigue life of the bone (Reilly and Currey, 1999; Diab et al., 2005; Green et al., 2011). Reilly and

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Curry (1999; 2000) found that diffuse microdamage appears even before the yield point in the load/deformation curve signifying any loss of stiffness. Until a 15% loss of stiffness, only these small, isolated cracks appear in bone (Burr et al., 1998). Up to a stiffness loss of 20%, bone does not suffer significant changes in the energy it can absorb before failing (Boyce et al., 1998; Martin et al., 1997; Reilly and Currey, 2000). Energy dissipation through microdamage was also found in Ebacher et al.’s (2007) study of four-point bending of machined cortical sections and whole cadaveric tibiae. After the bone yields to plastic deformation in tension, the neutral axis shifts toward the compressive surface, redistributing longitudinal (axial) strains toward the tensile surface. Due to this redistribution, the compressive surface experiences higher stress, while the tensile surface is pulled further apart and experiences higher strain. Therefore, compression is a key determinant of the maximum stress that bone can withstand prior to failure (Wang and Gupta, 2011). However, transverse strains are redistributed toward the compressive surface. This is because the tensile surface expands in volume in the transverse plane (as measured by Poisson’s ratio) through the formation of cracks and voids, while volume is largely conserved on the compressive surface (Ebacher et al., 2007). This concept of diffuse microdamage as an adaptive energy-dissipating mechanism was challenged by the finding that diffuse microdamage does not stimulate remodeling. Herman et al. (2010) found that loading the rat ulna produced osteocyte apoptosis and activated remodeling at sites of linear microcracks but not diffuse microdamage. Seref-Ferlenguez et al. (2014) used creep loading to generate in vivo diffuse damage in the rat ulna. They found that diffuse damage was reduced and the 15% loss in stiffness recovered within 14 days after loading. SerefFerlenguez et al. (2015) hypothesize that diffuse damage is repaired through mineral deposition regulated by osteocyte-produced proteins, and through the repair of ionic bonds in the matrix. In trabecular bone, complete fractures of trabeculae (microfractures) remodel through endochondral ossification (Burr, 2011).

Microdamage Tends to Initiate at StressConcentrating Voids Early researchers recognized that microdamage could initiate at stress concentrators such as vascular canals and osteocyte lacunae (e.g., Currey, 1962). Ebacher et al. (2007) observed that tensile diffuse microdamage can initiate both within Haversian systems and throughout interstitial bone. However, they found that compressive microcracks preferentially initiated within Haversian systems during bending. Crack initiation has been linked

110 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

both to the concentration of stress within these canals and to their low shear strength as a consequence of low mineralization, resulting in a low elastic modulus within the Haversian system (Ascenzi and Bonucci, 1972; Reilly and Currey, 1999). A microcrack would have to pass into an older, stiffer bone region in order to escape the Haversian system (He and Hutchinson, 1989). This interface increases resistance to cracking outside of the Haversian system, such that microdamage often remains restricted to the system in which it initiated (Ebacher et al., 2007). Ebacher et al. (2007) argue that microdamage and fracture are highly influenced by pore number, size, and canal geometry in regions under compression, but not tension. Since compressive microdamage largely is restricted to Haversian systems surrounding vascular canals, the amount of porosity in an individual should influence bone failure in compressed regions. Tensed regions can initiate microdamage in interstitial bone, so they should not be as sensitive to individual differences in porosity. In Ebacher et al.’s (2007) study of four-point bending of machine cortical sections and whole cadaveric tibiae, compression regions from different individuals did indeed show variance in the shape and magnitude of their stress
strain curves. Tension regions showed very uniform stress
strain curves between individuals, supporting the argument that failure under tension is not very sensitive to interindividual variation porosity. Even though tensed regions accumulate significantly more porosity than compressed regions (e.g., Frost, 1990; Skedros et al., 1994b, 2005), they are not very sensitive to microdamage and failure as a direct consequence of this porosity.

Changes With Age: Increased Mineralization Accelerates Microdamage Accumulation In mechanical testing, microdamage reduces both stiffness (Burr et al., 1998) and overall strength of bone (Carter and Hayes, 1977). The cracked region of bone cannot be recracked to release energy unless it is remodeled. This effect decreases bone’s capacity to resorb energy (toughness) (Burr, 2011). While large amounts of microdamage can be induced in mechanical testing, these levels are rarely, if ever, found in vivo (Burr, 2011). In experimental animal models, increased microdamage does reduce toughness, but not at the levels of physiologically normal microdamage accumulation (Allen et al., 2006; Mashiba et al., 2000, 2001; Komatsubara et al., 2003). Burr (2011) argues that microdamage typically accrued in vivo is not a significant mechanical detriment to bone unless it is not remodeled, due to turnover suppression or failure to detect the damage. Microdamage does eventually become mechanically compromising if allowed to accumulate (Ebacher et al., 2007). Microdamage is known to accumulate with age in

the cortex of the weight-bearing femoral mid-diaphysis, proximal femoral head, femoral neck, and tibial diaphyses (Mori et al., 1997; Norman and Wang, 1997; Schaffler et al., 1995). Trabecular microfractures have also been found to increase with age in human femoral heads (Koszyca et al., 1989) and human vertebral bodies (Vogel et al., 1993). Preferential formation of less damaging diffuse microdamage in vivo also shifts with age (Diab and Vashishth, 2007). Younger individuals form many localized diffuse cracks, while older individuals form fewer, longer linear microcracks (Allen and Burr, 2008). Age and pathology alter mineral content and quality, inviting microdamage accumulation in brittle tissue regions. Higher mineralization promotes stiffness, while lower mineralization promotes energy dissipation (Burr, 2011; Donnelly et al., 2010). Increasing mineralization decreases the yield strain of bone before plastic deformation, which helps explain why microdamage is highly localized to these brittle regions (Norman and Wang, 1997; Schaffler et al., 1995; Wasserman et al., 2005; Ebacher et al., 2007). Wasserman et al. (2005) used Raman microspectroscopy to determine that microcracks significantly colocalized with regions of comparatively high mineralization in human midshaft femora. Most microdamage accordingly accumulates in older, interstitial regions of bone tissue (Norman and Wang, 1997; Schaffler et al., 1995). Microcrack length and orientation are the strongest predictors of the decline in stiffness. Burr et al. (1998) found that microdamage to less than 0.1% of the cortex, on average, was sufficient to cause stiffness losses in excess of 15%. Akkus et al. (2003) found that a metric incorporating crack length and orientation had a stronger association with elastic modulus degradation than the number of microcracks (66% greater) or the sum of crack lengths (33% greater). Bone can slow this decline in stiffness by deflecting the crack away from its propagating force, or by shortening the length of the crack. Norman and Wang (1997) found that in the human midshaft tibia and proximal femur, 62.4% of all microcracks are deflected around osteons in the border between the cement line (which marks remodeling reversal) and the interstitial bone. Similarly, Schaffler et al. (1995) found that in human femora, 87% of microcracks either initiated in interstitial bone, presumably due to high mineralization, or intersected with cement lines.

Changes With Age: Older Tissue Loses Osteocyte Sensitivity to Microdamage Due to continual remodeling throughout life, regions of bone tissue vary in tissue age and do not match the chronological age of an individual. However, interstitial regions that do persist for decades will eventually lose

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osteocyte sensitivity, allowing microdamage to accumulate without detection and repair. Interstitial regions are remnants of primary circumferential lamellar bone or old osteons that have not been recently remodeled, and are therefore more mineralized (Wasserman et al., 2005). Primarily lamellar bone adjacent to the endosteum is resorbed with age, and much of the intracortical bone is replaced with secondary osteonal bone through remodeling. However, primary lamellar bone can remain as interstitial bone near the periosteal surface across the lifespan. Therefore, aged individuals do retain regions of old tissue even if their remodeling rate has increased, as in postmenopausal osteoporosis (Akkus et al., 2003). Simmons et al. (1991) note that individuals over age 60 have increased numbers of new, mineralized secondary osteons relative to 40
45-year-olds, due to increases in remodeling rate with senescence. However, individuals over age 60 also retain more of their older, more highly mineralized bone, which was previously targeted for remodeling. Osteocyte activity is essential for microdamage detection and repair. After depositing osteoid, approximately 10%
30% of the bone-forming osteoblast cells become trapped in the new matrix and differentiate into osteocytes (Banks, 1974; Parfitt, 1993; Aubin and Liu, 1996). Osteocyte cell bodies are housed in lacunae, and they extend their approximately 50 dendrites through fluidfilled channels called canaliculi to communicate with other osteocytes (Himeno-Ando et al., 2012). Osteocytes sense local changes in mechanical strain and trigger cellular pathways for bone modeling and remodeling to compensate for these changes (Komori et al., 2013). However, they can also sense microdamage in their environment and signal for local repair. The mechanism for this “targeted” remodeling is likely osteocyte apoptosis. Linear microcracks disrupt lacunar-canalicular fluid transport between osteocytes (Tami et al., 2002). This break in fluid flow impairs nutrient transport and cell
cell signaling, causing hypoxic stress followed by osteocyte apoptosis (Martin, 2003; Herman et al., 2010). Osteocyte activity is highly localized, as the cells must be active within B100 μm of microdamage to activate targeted remodeling (Verborgt et al., 2000). Osteocytes were originally estimated by Frost (1960a) to have a lifespan of approximately 20 years. Bonewald (2017) notes that osteocytes in regions with slow bone turnover may survive for decades, compared to the dayslong lifespan of osteoclasts and weeks-long lifespan of osteoblasts. However, empty osteocyte lacunae do accumulate with age. In aged individuals, microdamage may accumulate both because the interstitial tissue has declined in mechanical quality, and because osteocytes in that region are dead and cannot target remodeling (Schaffler et al., 1995; Burr, 2011).

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Intraskeletal Variability in Microdamage Accumulation Under models of bone functional adaptation, such as Frost’s (1987a) mechanostat, high strain suppresses remodeling activity related to routine bone turnover. Yet, strains high enough to induce microdamage also trigger targeted remodeling activity, composing an estimated 10%
30% of all remodeling activity (Burr and Martin, 1993; Li et al., 2001). Considering both models, in circumstances of higher mechanical strain, the routine remodeling rate might be suppressed, but the targeted remodeling rate might be accelerated in response to more frequent microdamage. Perhaps in part due to methodological variation, this uncertainty regarding remodeling rate is also reflected to some degree in the literature. Some have hypothesized that skeletal elements experiencing higher mechanical loads accrue more microscopic damage, triggering more frequent remodeling for repairs. For example, Robling and Stout (2003) found that the femur exceeds the rib in remodeling rates. They link this conclusion to dynamic loading, which is produced by movement in the femur but is relatively uncommon in the rib. However, other studies conversely claim higher remodeling rates in the rib compared to the femur (Hattner and Frost, 1963; Frost, 1969; Cho and Stout, 2011; Mulhern, 2000; Mulhern and Van Gerven, 1997). Similarly, other authors have found denser secondary osteon populations in skeletal elements or tissue regions under low strain, which the authors attribute to more frequent remodeling for bone renewal (e.g., Portigliatti et al., 1983; Mason et al., 1995; Skedros et al., 1996; Gocha and Agnew, 2016). If the remodeling rate varies between skeletal elements, microdamage accumulation may similarly vary. For example, Frost (1960c) did not find a significant relationship between microdamage and age in his sample of human ribs. Schaffler et al. (1995) attribute this difference from results of their femoral study to the relatively higher remodeling rate in the rib. They argue that the rib can minimize microdamage accumulation over the lifespan through its high turnover rate. Cho and Stout (2011) hypothesize that the rib accumulates more microdamage than the femur due to loading cycles induced by respiration. This microdamage produces greater rates of targeted remodeling in the rib. Frost (1963) stated that the high remodeling rate in ribs also causes them to reflect changes in bone mass from disease and aging earlier than appendicular bones. Relative to long bones, the human rib is isolated from irregular dynamic loading, being similarly loaded between individuals by the musculature associated with breathing (Bellemare et al., 2003). Agnew et al. (2017) found that in the human sixth rib midshaft, linear microcrack length, density, and surface density

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significantly varied between elderly individuals. This suggests that interindividual metabolic variations in remodeling rate can cause significant differences in microdamage accumulation, even between similarly aged individuals. However, as Agnew et al. (2015) note, the relationship between age, microdamage, and mechanical properties is still not firmly established in the rib, and is the subject of ongoing study.

Bone Strength at the Microscale: LacunarCanalicular Architecture Reflects Osteocyte Activity The preceding section discussed the bone remodeling process, how histomorphological features relate to it, and how histomorphometric analysis can be used to assess aspects of this important metabolic process, e.g., bone formation rate, in skeletal remains. The following section addresses how an often overlooked aspect of the microarchitecture of bone, lacunar-canalicular architecture, can provide useful information about bone strength.

Osteocyte Lacunar Density and Volume Increases With Higher Strain Osteocyte lacunae concentrate stress and have been observed to serve as initiation points for microscopic cracks (Reilly and Currey, 2000). Osteocyte lacunar density has been shown to weaken deer calcanei and equine third metatarsals because it is negatively correlated with stiffness, ultimate stress, and yield and elastic energy (Skedros et al., 2003). While these elastic properties are important, osteocytes are necessary for continually sensing and repairing bone’s plastic deformation microdamage. Qiu et al. (2005) found that the likelihood of microdamage was 3.8 3 higher in bone with osteocyte lacunar density less than 728 mm
2. They examined ribs from women aged 50
60 and found that about 73% of the microcracks were associated with interstitial bone fragments without osteocyte lacunae. Two-dimensional counts of osteocyte lacunae do not consistently reflect mechanical predictions for osteocyte activity. New osteocyte lacunae are created through modeling or remodeling in a region. Osteocyte lacunae are removed if the surrounding tissue is resorbed, or if the osteocyte dies and the lacuna is filled in (Carter et al., 2014). Some pericellular modification of the lacuna may also be possible (Qing and Bonewald, 2009; Tang et al., 2012). Theoretically, compressed regions should contain a higher density of osteocyte lacunae than tensed regions. Compressed regions are under higher strain, so more osteocytes should be present to detect and repair fatigue damage (Skedros et al., 2005). This pattern has been confirmed in compressed and tensed regions of adult equine

radii, equine calcani, and artiodactyl calcani (Hunt and Skedros, 2001; Skedros et al., 2004, 2005). However, the inverse pattern is found in equine third metacarpals, where osteocyte lacunae have a denser population in the tensed region compared to the compressed region (Skedros et al., 2005). Notably, osteocyte lacunar density is a quantification of the number of lacunae in the two-dimensional area of a cross-section, and does not consider the volume of lacunae or their canalicular connections. Two-dimensional methods for quantifying osteocyte lacunar density rely largely on point-counts of the osteocyte lacunae seen in cross-section, sometimes with geometric extrapolations to three dimensions. These methods cannot detect variations along the thickness of the cross-section (Hannah et al., 2010). Three-dimensional analysis of osteocyte lacunar volume with confocal microscopy and synchrotron μCT suggests osteocytes in regions of higher strain trend toward denser concentrations, higher lacunar volume, and larger surface area (Carter et al., 2013a, 2013b, 2014; Hannah et al., 2010; Himeno-Ando et al., 2012). The increase in lacunar volume appears to be related to metabolic activity, as cytoplasm volume is increased but nuclear volume is not (Himeno-Ando et al., 2012).

Changes With Age: Osteocyte Lacunar Density Decreases Osteocyte lacunar density generally decreases with age, as reviewed in Hunter and Agnew (2016). In cortical bone, age-associated declines in osteocyte lacunar density have been observed significantly (Busse et al., 2010; Vashishth et al., 2000; Hunter and Agnew, 2016) or insignificantly (Carter et al., 2013a) in the midshaft femur, and insignificantly in the distal radius and midshaft rib (Hunter and Agnew, 2016). In trabecular bone, osteocyte lacunar density declines significantly with age in the femoral head (Mori et al., 1997) and the iliac crest (Mullender et al., 1996; Qiu et al., 2002; Bach-Gansmo et al., 2016). Osteocyte lacunar density also declines with age in the parietal bone (Torres-Lagares et al., 2010). Cortical porosity increases with age due to the same factors that drive osteocyte apoptosis: increased targeted remodeling and resorption and cellular senescence in osteoblast functionality (Thomas et al., 2005; Pearson and Lieberman, 2004). As osteocyte lacunar density decreases with age, it shows a significant association with increasing cortical porosity, a relationship seen in the cortices of the midshaft femur (Vashishth et al., 2000, 2002; Dong et al., 2014; Hunter and Agnew, 2016), femoral neck (Power et al., 2004), distal radius, midshaft rib (Hunter and Agnew, 2016), and in the trabecular bone of the vertebral body (Vashishth et al., 2005).

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This decline in osteocyte lacunar density may be attributed to several age-associated challenges to osteocyte survival and function. First, as previously discussed, osteocytes in unremodeled tissue may exceed their lifespan, precluding future local remodeling triggered by mechanical strain changes or microdamage (Schaffler et al., 1995; Burr, 2011). Osteocyte lacunae can remain empty after death, or else become filled with hypermineralized matrix through a process known as micropetrosis (Frost, 1960b). Second, as previously discussed, osteocytes may also die through apoptosis in response to microdamage, which is increasingly common with age. Older bone tissue is more vulnerable to microdamage because it is brittle due to age-associated changes in mineral size, shape, and composition (Wasserman et al., 2005). A microcrack’s disruption of lacunar-canalicular fluid flow causes apoptosis of local osteocytes (Martin, 2003; Herman et al., 2010), releasing proinflammatory cytokines that recruit osteoclasts for bone resorption (Lotze and Tracey, 2005; Kennedy et al., 2014). Third, osteocyte apoptosis also increases systemically with age, without triggering remodeling activity, in response to increased levels of reactive oxygen species and decreased lysosomal function (Noble et al., 1997; Jilka et al., 2013), as reviewed by Jilka and O’Brien (2016). Mechanical loading promotes osteocyte survival (Hamrick et al., 2006), so declining physical activity and increasing muscle weakness with age may be another factor driving osteocyte apoptosis. Accordingly, Hunter and Agnew (2016) found that osteocyte lacunar density declined with age at the highest rate and with the greatest interindividual variability in the midshaft femur, followed by the distal radius and then the midshaft rib. The femur and distal radius are dynamically loaded, making their microstructure more sensitive to interindividual and ageassociated variation in physical activity, while the rib is cyclically loaded by breathing throughout life (Hunter and Agnew, 2016). Age-associated declines in osteocyte survival appear in many bones of the human body, but the extent can vary widely between individuals and sampling sites, as explored by Frost (1960a). Dunstan et al. (1993) found that osteocyte viability (showing lactate dehydrogenase activity) decreases with age in the trabecular bone of the femoral head, but not that of the second lumbar vertebra. The femoral head has a low remodeling rate compared to the lumbar vertebrae, so osteocytes are more likely to exceed their lifespan before replacement. Dunstan et al. (1993) and Wong et al. (1987) noted that in osteonecrosis and osteoarthritis cases complete loss of osteocyte viability is localized to deep trabecular bone in the femoral head, which is particularly susceptible to this pathology. Wong et al. (1985) found that in the trabecular bone of

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the femoral head nearly all osteocytes are viable before age 25. Viability significantly decreases with age, especially in the older tissue deep in trabeculae, similarly in healthy individuals, cases of degenerative joint disease, and chronic alcoholism. Osteocyte survival is also reduced with age in the ilium (Delling, 1973). Even in the parietal bone, which has low bone turnover, osteocyte lacunar density and percentage of occupied lacunae both decline with age in cortical and trabecular bone (TorresLagares et al., 2010).

Changes With Age: Percent Occupied Lacunae Decreases Osteocyte lacunar density approximates osteocyte survival (Hunter and Agnew, 2016). However, the distinction between a lacuna and its osteocyte occupant is important in some pathological cases. Osteocyte lacunar density can decline because the osteocytes are formed in fewer numbers, or because the osteocytes die more frequently and their empty lacunae are filled by micropetrosis (Qiu et al., 2003). For example, in Qiu et al.’s (2003) study of the trabecular bone of the iliac crest, healthy patients experienced increasing osteocyte apoptosis with age, declining both in osteocyte lacunar density and percent occupied lacunae. Yet patients with vertebral fractures experienced decreased osteocyte formation with age, perhaps due to premature osteoblast apoptosis, causing a decline in osteocyte lacunar density while percent occupied lacunae remained stable. These changes were localized to deep (older) trabecular bone in healthy individuals, but targeted both superficial and deep bone in fracture patients (Qiu et al., 2003). Osteoporosis can alter the rate at which osteocyte lacunar density declines with age, although reports are not consistent. Mori et al. (1997) found that femoral neck fracture predicted an B30% (insignificant) lower osteocyte lacunar density in the trabecular bone of the femoral head, compared to healthy controls. Qiu et al. (2003) similarly found that vertebral fracture predicted a 34% (significant) lower osteocyte lacunar density in the trabecular bone of the iliac crest, compared to healthy controls. Conversely, Mullender et al. (1996) found that osteoporotic individuals experienced significantly less of a decline in osteocyte lacunar density with age in the trabecular bone of the iliac crest, compared to healthy controls. They did not see a significant correlation of percent empty lacunae with age in either healthy or osteoporotic individuals, leading them to suggest that osteoporosis does not accelerate osteocyte apoptosis. McCreadie et al. (2004) similarly found no significant difference in osteocyte lacunar density between fracture cases and controls in the trabecular bone of the femoral head.

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Changes With Age: Altered LacunarCanalicular Architecture The absolute number of osteocyte lacunae may be less important than the volume and connectivity of the whole network in fluid flow and intercellular communication (Robling and Turner, 2002; Skedros et al., 2005). Canaliculi appear to be thinner, but more branched and numerous, in more highly loaded bone (Himeno-Ando et al., 2012). Milovanovic et al. (2013) found that aged individuals have B30% fewer canaliculi per lacuna, and that aging decreases canalicular number, connectivity, and extent, a phenomenon also seen in mice (Kobayashi et al., 2015). Age and pathology can also alter osteocyte lacunar size and shape, although reports are not always consistent. Lacunar size has been found to both decrease with age (Mullender et al., 1996; Carter et al., 2013a) and increase with age (Bach-Gansmo et al., 2016). Osteoporosis has been described variably as increasing (Wright et al., 1978; van Hove et al., 2009), decreasing (Mullender et al., 1996), or causing no change (McCreadie et al., 2004) in osteocyte lacunar size. Osteopenic osteocytes are reported to be relatively large and elongated, osteopetrotic osteocytes are small and discoid, and osteoarthritic osteocytes are smallest and round (van Hove et al., 2009). Smaller and more spherical osteocytes are more sensitive to small strains, producing more nitrous oxide (NO) in response to mechanical loading and thereby inhibiting osteoclast activity (Bacabac et al., 2008). Smaller osteocytes, with their high mechanosensitivity, might contribute to the osteoclast inhibition and high BMD that characterizes osteopetrosis. Enlarged osteocytes, being less sensitive to mechanical loading, could permit the excessive osteoclastic resorption seen in osteopenia and osteoporosis (van Hove et al., 2009).

Osteocytic Osteolysis and Pathology Another potential mechanism for altering lacunar dimensions is osteocytic osteolysis, in which osteocytes exchange calcium with their lacunar-canalicular shells. The concept of osteocytic osteolysis in humans became unfavorable in the 1970s. This was due to its association with the erroneous mechanism of bone flow, which posited that osteocytes, not osteoclasts, were the main bone resorbers (Wysolmerski, 2012). If osteocytic osteolysis does occur in humans, it probably has a minor role in calcium balance compared to exchange across quiescent surfaces (Skedros et al., 2005). PTH stimulates enlargement of osteocyte lacunae in bats, squirrels, hamsters, snakes, rats, and mice. This stimulation creates osteocytes with enlarged lacunae, irregular and rough borders, and perilacunar demineralization (reviewed in Wysolmerski, 2012). PTH also stimulates osteocytes to express tartrate-

resistant acid phosphatase, which is associated with bone resorption (Tazawa et al., 2004; Ardeshirpour et al., 2010; Qing et al., 2012). The osteocyte lacunar area also enlarges with lactation, but returns to normal after forced weaning in mice. This suggests that osteocytes can supplement calcium during times of high demand, such as lactation (Qing et al., 2012). Due to the association of osteocytic osteolysis with pathological conditions, Dallas et al. (2013) suggest that the term “perilacunar remodeling” be applied to this normal osteocyte functioning.

Bone Strength at the Microscale: Vascular Porosity Reflects Resorption Activity Vascular Porosity Reflects Regional Mechanical Strain Pores related to the vascularization of bone, including resorption bays and Haversian canals, are the product of mechanically induced modeling and remodeling. Bone modeling involves concentric lamellae of bone surrounding a blood vessel, producing a primary osteon with a central pore containing vasculature (Stout et al., 1999; Burr and Akkus, 2014). Bone remodeling begins with osteoclasts tunneling through the bone, forming a “cutting cone” that, in cross-section, appears as a large, irregularly shaped pore called a “resorption bay” (Stout and Crowder, 2011; van Oers et al., 2008). If mechanical strain and physiological capacity are sufficient to induce the formation of new bone, the resorption bay is filled in with concentric lamellae of bone, producing a secondary osteon with a central pore called a “Haversian canal” (Burr and Akkus, 2014). If bone formation is not complete, the resorption bay will remain as a large pore. Adjacent resorption bays near the marrow cavity can coalesce into huge “trabecularized” pores if their interstitial regions are resorbed (Zebaze et al., 2009). Individual vascular pores form a complex threedimensional network interconnected by branching events and transverse canals, sometimes called “Volkmann’s canals” (Tappen, 1977; Stout et al., 1999). While transverse canals and Volkmann’s canals are sometimes used as interchangeable terms, Maggiano et al. (2016) notes the historical distinction. Volkmann’s (1863) original description referred to vascular canals that formed during osteomyelitis, breaking out of their Haversian system to canalize adjacent bone. Therefore, these Volkmann’s canals lack surrounding lamellae (Jaffe, 1929; Cooper et al., 1966). Tappen (1977) describes transverse canals that are surrounded by lamellae because they are contiguous with a remodeling event, either the cutting cone “breaking out” laterally from an existing BMU or “swinging around” during remodeling. Maggiano et al. (2016) used synchrotron μCT to determine that transverse canals

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generally emerge through one of the following processes: (1) lateral branching of a smaller diameter canal from a larger diameter canal, (2) dichotomous branching, wherein a canal splits into two canals similar in size to produce a “dumbbell” shaped osteon, or (3) intraosteonal remodeling, involving a younger Haversian system remodeling an existing, older Haversian system and potentially reusing its blood vessel. Branching events have been reported to occur on average every 2.5 mm (Beddoe, 1977) to 3 mm (Koltze, 1951) along a canal. According to Frost’s (1990) mechanostat model, high strain represses bone resorption and should reduce bone porosity, while low strain is permissive to bone resorption and should increase bone porosity. Since porosity is the product of remodeling, intraskeletal variance in porosity should reflect intraskeletal variance in the remodeling rate (Cho and Stout, 2011). For example, due to their high turnover rates, ribs are thought to lose bone earlier than more dynamic and weight-bearing skeletal elements (Epker et al., 1965; Agnew and Stout, 2012). However, Hunter and Agnew (2016) did not find significant differences in percent porosity between the distal radius, midshaft rib, and midshaft femur of the same individuals. Similarly, Cole and Stout (2015) did not observe significant differences in percent porosity at the midshafts of the femur, tibia, and rib of the same individuals in a small sample. However, they found that the rib displayed significantly greater trabecularized porosity than the femur or tibia, which preferentially formed cortical pores (Cole and Stout, 2015). The rib experiences extensive trabecularization of the cortex with age, as pores adjacent to the endosteum coalesce with each other and the marrow cavity. Since these pores are united with the marrow cavity, they are likely to be excluded from pore quantification during analysis, obscuring the true relationship of porosity to aging and bone strength (Hunter and Agnew, 2016; Dominguez and Agnew, 2014). Zebaze et al. (2009) found that exclusion of the trabecularized cortex underestimates porosity by B2.5-fold. In the midthoracic (4
7) ribs, subtraction of porous voids makes the cortical area a better predictor of the peak force, structural stiffness, and total energy required to fracture the rib. These improvements are significant but small, suggesting that bone loss at the endosteum reflected in measures of cross-sectional bone quantity is more important for predicting bone strength in ribs (Dominguez et al., 2016). Similarly, in the distal radius, the total reduction in bone mass between ages 50 and 80 is due largely to porous trabecularization at the endosteum (47%), followed by trabecular bone thinning (32%), and then formation of pores within the cortex (21%) (Zebaze et al., 2010). The primacy of this “invisible” trabecularized porosity in some skeletal elements helps explain why certain pathological conditions appear to accelerate

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intracortical pore formation in some bones but not others. For example, Villanueva et al. (1966) found that osteoporotic ribs had normal intracortical porosity, but experienced an expansion of the marrow cavity with associated cortical thinning. Conversely, Jowsey (1964) described extensive intracortical remodeling with increasing numbers of incomplete osteons in osteoporotic femora. Porosity has been shown to vary within a crosssectional plane according to regional strain differences. Endosteal skeletal regions experience lower-magnitude strains compared to regions located closer to the periosteum and consequently are more porous. Skeletal biologists have long recognized that porosity increases from the periosteum to the endosteum in various long bones (e.g., Jowsey, 1960; Atkinson, 1965; Martin et al., 1980; Martin and Burr, 1984a; Thomas et al., 2005; Zebaze et al., 2010). Strains are lowest at the endosteum because these regions are closest to the neutral axis, where strain is minimized (Martin, 1993; Thomas et al., 2005). While females do lose bone preferentially at the endosteum with age, porosity is highest at the femoral endosteum across the lifespan in both sexes (Bousson et al., 2001). Similarly, compressed regions of a cross-section experience high strain and are less porous, while tensed regions experience low strain and are more porous, as demonstrated in the calcanei of Rocky Mountain mule deer (Skedros et al., 1994b). Two-dimensional studies of the midshaft rib have found that the cutaneous region is significantly more porous and trabecularized than the pleural region (Agnew and Stout, 2012; Agnew et al., 2013; Cole and Stout, 2015; Dominguez and Agnew, 2016). However, it is unknown if this difference is related to regional strain patterning, thus it may not reflect the true loading environment of the rib or its effects on threedimensional pore structure (Dominguez and Agnew, 2016).

Changes With Age: Increased Vascular Porosity Weakens Bone About 70% of age-related bone loss in appendicular bones is cortical bone loss, which primarily occurs through the accelerated formation of pores (Power et al., 2004; Cooper et al., 2004; Zebaze and Seeman, 2015). It is well established that intracortical porosity increases with age as resorption rate outpaces formation rate and capacity (Jowsey, 1960, 1964; Bell et al., 2001). Osteoblasts’ capacity for bone formation slows with age, decreasing their ability to keep pace filling resorption bays (Pearson and Lieberman, 2004). Bone resorption also increases in response to the lowered strains of weakening muscles and declining physical activity (Thomas et al., 2005). After age 60, porosity increases 31%
33% per decade in the femoral neck (Chen et al., 2010). Pore diameter increases

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while pore number and spacing decrease, suggesting that pores are coalescing (Chen and Kubo, 2014; Milovanovic et al., 2014). These changes are exacerbated in women due to declining estrogen levels at menopause that increase bone resorption (Chen and Kubo, 2014). Expansion and coalescence of existing pores is a key driver of age-associated increases in porosity. Pore size plays a central role in variation in porosity in general. Thomas et al. (2005) found that mean pore area explained B81% of regional variation in porosity in the midshaft femur, with only 12%
16% additionally explained by pore density. With age, pore expansion and coalescence further eclipses pore density as a driver of porosity. Bousson et al. (2001) and Cooper et al. (2007a) both noted that, in the midshaft femur, pore number increases up to age 60. After this threshold, pore number declines as canals increase in size and decrease in spacing, indicating that these canals are coalescing and interconnecting. Chen et al. (2010) similarly found that, in the femoral neck, cortical porosity increases twofold, canal diameter increases 65%
77%, and canal number decreases 16%
17% between middle-aged and elderly groups of men and women. Percent porosity increases with age even as the absolute number of pores decreases because formerly distinct pores are combining through resorption of their prior tissue boundaries. For example, Bell et al. (2001) found that in individuals older than 75 years, giant coalesced canals ( . 385 μm in diameter) accounted for 27% of femoral neck porosity, despite being 1% of the number of canals. Sex differences in age-associated porosity also appear to be driven by pore size. In the anterior femoral midshaft, the significantly higher porosity seen in women is derived from their significantly larger canal diameter (Cooper et al., 2007a). The higher porosity seen in the femoral neck in women can also be attributed to their significantly larger canals, but not to significant differences in canal number or spacing. Large canals are concentrated at the endosteum of the femoral neck in elderly men, but also occur at the periosteum in elderly women (Chen et al., 2010). Variation in where this coalescence occurs may help explain interindividual variation in fracture risk, as described by Bell et al. (1999a,b) for the human femoral neck. In this region, the superior cortex is least compressed and experiences the lowest strain during gait, while the inferior cortex is the most compressed and experiences the highest strain. Accordingly, in individuals without femoral neck fractures, porosity decreases as strain increases along this superior
inferior axis. However, in women with femoral neck fractures, this gradient is disrupted as porosity increases by 41% in the anterior cortex. This concentration is related to a doubling of pore coalescence into “giant canals” ( . 385 μm) in

this region. Age-associated restriction of physical activities that load the anterior cortex, such as hip extension and adduction, may contribute to the increased porosity of this region in fracture cases. This coalescence weakens the femoral neck along the inferoanterior to superoposterior axis, the same direction that deformation occurs during a sideways fall (Bell et al., 1999a,b). Despite this age-associated increase in porosity, the extent of vascular pore accumulation is highly individualized. Age explains only 12.1% of the variation in porosity between individuals, even when controlled for height, weight, and sex (Stein et al., 1999). Agnew and Stout (2012) found that elderly individuals displayed vascular porosity covering between 6.24% and 41.95% of the cortex at the midpoint of sixth ribs. Individual factors such as severe osteoporosis, poor diet, and low physical activity can contribute to higher percentages of porosity in a given age category (Cho and Stout, 2011; Thomas et al., 2005; Agnew and Stout, 2012). Porosity reflects the biological age of tissue, rather than the chronological age of the individual (Thomas et al., 2005). Pathological conditions that alter remodeling rates can also affect the prevalence and shape of vascular porosity (Fig. 6.7). Increases in vascular porosity compromise bone’s resistance to elastic and plastic deformation. Vascular porosity is associated either with the complete resorption of a mineralized bone region, or its partial replacement with less mineralized new bone. Therefore, vascular porosity causes declines in stiffness and hardness, which are associated with mineralization as previously discussed. Currey (1999) compared 67 compact tissues from 32 species and found that most samples with low mineral (,220 m/g) had high porosity ( . 8%) and lower values of Young’s modulus. Changes in porosity in the human femur account for 76% in the reduction of strength (ultimate stress) in tension with age (McCalden et al., 1993). An increase in porosity from 4% to 10% reduces peak stress before fracture by more than half. An increase in porosity from 4% to 20% reduces bone’s ability to deform without cracking by threefold (Martin and Burr, 1989). Since vascular pores concentrate stress, they also serve as initiation and propagation sites for microcracks (Ebacher et al., 2007). Ex vivo experiments show that a 4% increase in vascular porosity decreases initiation toughness by 4% and increases crack propagation by 84% in bone tissue (Ural and Vashishth, 2007; Diab and Vashishth, 2005). The secondary osteons that form around vascular pores have a cement line that deflects microcracks and serves as a toughening mechanism. However, these interfaces will still be weaker against catastrophic failure (Martin, 1993). Secondary bone is 80%
90% as strong and 87%
91% as stiff as primary bone (Reilly and Burstein, 1974; Vincentelli and Grigorov, 1985).

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FIGURE 6.7 Complete cross-section from midshaft of a 6th rib from a 95-year-old male (modern). The cutaneous cortex (top) especially shows pathological areas of excessive intracortical porosity. The gross irregular margins of the porous areas (not the normal scalloping referred to as Howship’s lacunae) indicate this is not the result of a typical lack of osteon infilling in the remodeling process seen in osteoporotic individuals, however it is unknown what the cause of these pathological changes is. Image taken under bright field light, basic fuchsin stained, scale included. Photo credit: Victoria Dominguez.

Bone Strength at the Microscale: Secondary Osteon Size and Shape as Toughening Mechanisms Small, Circular Osteons Are Associated With Higher Mechanical Strain Secondary osteon size also varies according to mechanical strain differences within single skeletal elements. High strain represses remodeling activity, which should theoretically result in a smaller osteon area (Abbott et al., 1996). A finite element model from van Oers et al. (2008) suggests that relatively small changes in strain are sufficient to cause large variations in osteon diameter. Smaller osteons also allow bone to pack more osteons into the same space, taking advantage of their toughening mechanisms to resist high strain. Regions with smaller osteons have higher fracture toughness in tension and shear, as seen in the human femur (Yeni et al., 1997). Within a cross-section, compressed regions experience higher strain and tend to produce smaller osteons than tensed regions. This pattern is see in the human femur (Yeni et al., 1997) and in the calcaneus of adult elk, sheep (Skedros et al., 1997), horse (Skedros et al., 1994b, 1997), and mule deer (Skedros et al., 1994a, 2001, 2004). However, size differences were not detected between compressed and tensed regions of the horse radius (Mason et al., 1995) or human tibia (Yeni et al., 1997). In the mule deer calcaneus, osteons are also smaller in the endocortical region, where strain is lowest, compared to

the middle and pericortical regions (Skedros et al., 1994b), although this pattern was not detected in the elk, sheep, or horse calcaneus (Skedros et al., 1997). Higher strain from increased mobility and body weight can also reduce osteon size in the same skeletal element. Schlecht et al. (2012) found that individuals with normal mobility have smaller osteons than quadriplegic individuals in the femur, tibia, humerus, and radius. In the ulna and fibula, which are not so highly loaded by body weight or limb use, osteon area falls within the same range for mobile and quadriplegic individuals, although mobile individuals still have slightly smaller osteons. Robust Pleistocene humans have significantly smaller (B25%) osteons in the femur and tibia compared to modern humans (Abbott et al., 1996). Osteons near the periosteum of the anterior midshaft femur significantly decrease in size as body weight increases (Britz et al., 2009). Sexual dimorphism in osteon size is likely a proxy for higher physical activity and body weight in males, which tends to produce smaller osteons in weight-bearing bones, such as the femur (Dominguez and Agnew, 2016). For example, males were observed to have significantly smaller osteons than females in the anterior midshaft femur of the 14th
19th century Pecos Pueblo population (Burr et al., 1990) and throughout the midshaft femoral cortex in a late medieval Nubian population (Mulhern and Van Gerven, 1997). However, this Nubian population did not display the same sexual dimorphism in osteon size in the rib, which lacks the weight-bearing and dynamic loading

118 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

environment of the femur (Mulhern, 2000). Similarly, sex differences in osteon size were not detected in the rib at the Early Archaic Windover, Middle Woodland Gibson, and Late Woodland Ledders sites (Stout and Lueck, 1995), or in modern individuals (Dominguez and Agnew, 2016). Even in the femur, osteon size is not consistently correlated with sex. Pfeiffer (1998; Pfeiffer et al., 2006) observed no significant sex differences in osteon size in the femur or rib of 18th-century English Huguenots (Spitalfields), 19th-century British Canadians (St. Thomas), or Later Stone Age or 20th-century South Africans (University of Capetown). Britz et al. (2009) found that females in a modern Australian population unexpectedly have significantly smaller osteons than males in the anterior midshaft femur, but these differences are due to outlier individuals. Dominguez and Crowder (2015) suggest an endocrine role due to their observation that, in the anterior femur, younger females have larger osteons and older females have smaller osteons compared to age-matched males. Intraskeletal comparisons do not maintain the pattern of high mechanical strain and smaller osteon size seen regionally within skeletal elements. The weight bearing and dynamic loading in the femur might be predicted to produce smaller osteons than those seen in the rib. However, the femur has significantly larger osteons than the rib in both modern (Goliath et al., 2016) and archeological (Pfeiffer, 1998; Pfeiffer et al., 2006) populations. The smaller cross-sectional area of ribs compared to femora may favor a smaller osteon size (Goliath et al., 2016), especially given that even within the ribs Dominguez and Agnew (2016) noted a relationship between osteon size and the amount of available cortex (Ct.Ar) for remodeling to occur. The more variable loading experienced by the femur could also contribute to its greater variability in osteon size (Pfeiffer et al., 2006). The smaller osteons that form under higher mechanical strain also tend to be more circular in shape. The circularity index of an osteon is measured as 4π (area/ perimeter2), where values approaching zero represent more elongated osteons and where those approaching one represent more circular osteons (Goliath et al., 2016). In the mule deer calcaneus, osteons are smallest and most circular in the high-strain regions under compression and near the periosteum (Skedros et al., 1994b). Near the periosteum of the anterior midshaft femur, increased body weight is associated with increased circularity, as well as smaller size (Britz et al., 2009). Sex differences and intraskeletal differences in circularity are not significant in the rib, humerus, and femur (Britz et al., 2009; Crescimanno and Stout, 2012; Goliath et al., 2016). Hennig et al. (2015) caution that the circularity index is highly sensitive to minor variations in perimeter, such as errors in closure of a digital outline of an osteon. They

recommend substituting the inverse of the osteon aspect ratio, quantified as (major axis/minor axis)21, where zero is infinitely elongated and one is perfectly circular.

Mechanical Strain Directs Three-Dimensional Secondary Osteon Orientation The tunneling orientation of the cutting cone during bone remodeling appears to be mechanically directed. Like the vascular pores they contain, secondary osteons tend be longitudinally oriented (90 degrees) in long bones to align with the principal direction of loading. For example, the femur has a mean osteon orientation of 79 degrees (Hennig et al., 2015). Tappen (1977) traced BMUs through serial sections and found that osteons commonly tunnel both proximally and distally, forming a structure described by Johnson (1964) as a “double-ended osteon.” In dogs, the proximal
distal tunnel comprises 34.7% of Haversian systems in the tibia and 42.1% of Haversian systems in the humerus, not considering osteons that extended beyond the serial sectioned volume (Tappen, 1977). van Oers et al. (2008) used a finite element model of bone remodeling to demonstrate that proximal
distal tunneling emerges from the strain environment around the initial resorption cavity. During longitudinal loading, strains around the resorption bay are high in the transverse direction, inhibiting osteoclast resorption, while strains in the longitudinal direction are low, permitting osteoclast resorption proximally and distally. As the osteon tunnels longitudinally, it can also “drift” laterally (Fig. 6.8). The drifting osteon morphotype results from continuous resorption on one side and continuous formation on the opposing side of a lateral plane through the osteon. In the cross-sectional plane, this osteon morphotype appears as a Haversian canal surrounded by four to eight concentric lamellae, which continue on one side of the osteon as a “tail” of semicircular lamellae (Robling and Stout, 1999). Robling and Stout (1999) comprehensively examined drifting osteons in serial sections of two baboon midshaft fibulae, a human third metatarsal, and a human proximal phalanx. They found that most drifting osteons do not consistently trend in a single direction, but change direction slightly (e.g., 3 degrees) or even significantly (e.g., 188 degrees). The finite element model of van Oers et al. (2008) predicts that the drifting osteon morphotype emerges when a steep lateral gradient of strain permits resorption on the lesser-strained side and inhibits resorption on the higher-strained side. Robling and Stout (1999) observed substantial changes in drift direction occurred between adjacent osteons and within single osteons at the same cross-sectional level, so strain gradients would need to be highly localized and change direction frequently to “steer” this drift. Cooper et al. (2011) suggest that microcracks may provide such a

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terminating in resorption bays on the endosteal surface (Koltze, 1951; Cohen and Harris, 1958; Maggiano, 2011). More rarely, osteons narrow to end in a “blind” or “sealed” osteon. The prevalence of this secondary osteon morphotype has been reported as ,0.1% in nonprimate bone (Henrie et al., 2014), 1%
2.2% in healthy human femora and tibiae (Pazzaglia et al., 2013; Henrie et al., 2014), and 4%
5% in tibia following traumatic amputation (Congiu and Pazzaglia, 2011). Due to its higher prevalence in trauma cases, sealed osteons may be related to a reduction or severance of blood supply (Henrie et al., 2014).

Changes With Age: Secondary Osteons Become Smaller and More Circular

FIGURE 6.8 Cortical tissue from midshaft of an ulna femur from a 71year-old female (modern). Drifting osteons can be identified by the “tail” of semicircular lamellae visible in the contour of the cement line (bright field) and especially in collagen fiber orientation (polarized light). Note that while overall drift trends toward the endosteum (top), pathways are highly variable. Image taken under bright field light (top), and linear polarization (bottom), scale included. Photo credit: Mary Cole.

temporary localized stimuli for targeted remodeling, causing the cutting cone to drift toward and remodel the damaged region. Osteons do generally exhibit an overall drift toward the lower strains at the endosteum (Koltze, 1951; Cohen and Harris, 1958; Epker and Frost, 1965; Burton et al., 1989; Maggiano, 2011). Drifting osteons have been reported to form across the lifespan (Robling and Stout, 1999), but with a significant reduction in frequency of formation with age (Sedlin et al., 1963; Coutelier, 1976; Streeter, 2011). Most of the BMUs observed by Tappen (1977) originated as lateral “breakout zones” from existing BMUs before tunneling proximally and distally. Maximum Haversian system length has been reported as ranging from 5.4 to 10 mm (Filogamo, 1946; Johnson, 1964; Cooper et al., 2006). Osteons have been described as

Age-associated declines in physical activity and muscle strength might be expected to relieve high strains and thereby produce larger, more elliptical osteons. However, the literature supports an opposite trend toward smaller, more circular osteons with age. Smaller osteons have long been noted in human bones such as the femur (Currey, 1964; Singh and Gunberg, 1970; Evans, 1976; Thompson, 1980; Martin et al., 1980; Watanabe et al., 1998; Burr et al., 1990; Ericksen, 1991; Pfeiffer, 1998; Britz et al., 2009; Hennig et al., 2015; Goliath et al., 2016), tibia (Singh and Gunberg, 1970; Ortner, 1975; Evans, 1976; Thompson and Galvin, 1983), fibula (Evans, 1976), humerus (Iwamoto et al., 1978; Martin et al., 1980; Yoshino et al., 1994), metacarpal (Martin et al., 1980), rib (Pfeiffer, 1998; Dominguez and Agnew, 2016; Goliath et al., 2016), and mandible (Singh and Gunberg, 1970). Osteon area also decreases with age in animal models, including the femora of rhesus macaques (Burr, 1992; Havill, 2004) and the rat femur, tibia, and mandible (Singh and Gunberg, 1971). As a caveat, a statistically significant decrease of osteon area with age has not been upheld in some case studies of these same human bones (Jowsey, 1964; Black et al., 1974; Mulhern and Van Gerven, 1997; Pfeiffer, 1998; Pfeiffer et al., 2006). Osteons have also been observed to increase in circularity with age in the femur (Currey, 1964; Britz et al., 2009; Goliath et al., 2016) and rib (Goliath et al., 2016). Histological studies of osteon geometry have historically relied on two-dimensional cross-sections. Yet osteons form complex, interconnected three-dimensional networks, much like the vascular pores they contain (Maggiano et al., 2016). Hennig et al. (2015) wondered whether Haversian systems were altering their threedimensional shape with age, or whether they were merely changing in orientation, thereby skewing their twodimensional cross-section. If a Haversian system does not change its three-dimensional geometry, but alters its orientation relative to the plane of section, it can alter its

120 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

cross-sectional area and circularity. Hennig et al. (2015) matched three-dimensional μCT reconstructions of vascular canal orientation to the two-dimensional inverse osteon aspect ratio of the surrounding osteons. More obliquely oriented osteons would be expected to appear more elongated in cross-section. However, as vascular canals became more obliquely oriented with age due to interconnection and convergence, their surrounding osteons actually become more circular in cross-section. Increasing obliqueness perpendicular to the major axis of the osteon could theoretically increase circularity, but this would also increase cross-sectional area, contrary to the observed ageassociated reduction of osteon size (Hennig et al., 2015). Britz et al. (2009) similarly reject an orientation-based explanation for increased circularity because osteon diameter decreases with age. Osteons with similar canal orientations also display a large variation in cross-sectional shape. These results suggest that osteons are actually altering their three-dimensional size and shape with age, becoming smaller and more circular, rather than merely altering their orientation (Hennig et al., 2015). Do age-associated changes in osteon size and shape stem from senescence, adaptation, or continuation of normal remodeling activity? Supporting a senescent explanation, Martin et al. (1980) propose that osteoclasts decline in their capacity to extend the borders of the cutting cone, producing smaller osteons. Takahashi et al. (1965) and Seeman (2013) suggest that larger osteons have a higher probability of being removed by remodeling as OPD increases with age. An adaptive argument advanced by Burr et al. (1990) is that changes in osteon shape and size help compensate for age-associated reductions in bone quality. Specifically, smaller osteons can accommodate a higher OPD, increasing the cement line interfaces for toughening mechanisms such as microcrack deflection and osteon pullout (Dominguez and Agnew, 2016). Smaller osteons would also require smaller resorption bays, reducing the size of temporary but stressconcentrating defects (Goliath et al., 2016). Conversely, Hennig et al. (2015) argue that the thinning, porous cortex can interact with weight gain during aging to inflict higher strain on skeletal elements. In this scenario, the trend toward smaller, more circular osteons is a continuation of the relationship with high strain seen in youth.

Structural Properties of Whole Bone in Cross-Section Remodeling alters the material properties of bone by reorganizing its internal structures, such as its lacunarcanalicular architecture, vascular porosity, and lamellar organization. The structural properties of bone are altered by changes to its external size and shape produced by

modeling or resorption on periosteal or endosteal surfaces (Martin, 1993). The size and shape of cortical bone in cross-section is largely established by modeling during growth. However, periosteal apposition and endosteal resorption accelerate during senescence, and can either preserve or compromise bone strength, depending on their balance.

Radial Expansion of the Cross-Section Results From Growth in Bone Length During growth, increases in bone length impose more strain on the bone during bending. Modeled as a beam, the deflection of a bone is given by the equation ML2/ 8EI, where M is the bending moment (combination of forces and moments on a region), L is length, E is Young’s modulus, and I is the area moment of inertia. In other words, bone deflection increases with the square of its length (Turner, 2006). Bones grow in length before they grow in mass during the pubertal growth spurt in both sexes, during which they have a higher rate of fracture (Rauch and Schoenau, 2001). This strain drives radial expansion of the whole bone in cross-section. Hollow tubes are more resistant to bending and torsion when their mass is distributed further from the neutral axis (Ruff and Hayes, 1983; Einhorn, 1992). For a given bending moment, bone can decrease its deflection by increasing the area moment of inertia (I). For a tubular bone, I 5 π4 (rp4
re4), where rp is the periosteal (outer) radius and re is the endosteal (marrow cavity) radius. In mammals, the periosteal radius is about 1.8 times the endosteal radius, so I  0.71rp4. In other words, bone can compensate for the deformation induced by its increasing length by increasing its periosteal radius (Turner, 2006). For example, an 8% increase in periosteal radius is associated with a 36% increase in bone rigidity (stiffness) (Turner, 2006). During periosteal expansion, the endosteum is resorbed, maintaining the ratio between their radii (Martin, 2003). Cortical area, the amount of cortical bone in a transverse cross-section, is also proportional to resistance to axial compression loads caused by body weight (Skedros, 2011). Increasing body mass during growth also contributes to the mechanical demand for radial expansion through modeling (Rauch and Schoenau, 2001).

Sexual Dimorphism in Radial Expansion During Growth and Senescence Testosterone increases periosteal bone formation and estrogen increases endosteal bone formation (Turner et al., 1989, 1990). Frost (1992) hypothesized that estrogen lowers the mechanostat setpoint for modeling, so that more endocortical bone is formed than is mechanically necessary. During fetal growth, placental estrogen levels are high, inhibiting endosteal resorption. When this estrogen

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supply is cut off at birth, the setpoint is raised, and mechanically unnecessary endocortical bone is resorbed. As the marrow cavity expands, bone density decreases by about 30% within the first six postnatal months (Trotter and Hixon, 1974). In females, the mechanically driven endosteal expansion associated with radial growth is reversed by high levels of estrogen expression at the end of puberty. Bone is added at the endosteum (Martin, 2003; Robling et al., 2014). During the reproductive period, females store more mineral than men of the same age and lean body mass (Ferretti et al., 1998). When estrogen levels decline through the menopause, the mechanostat setpoint is raised again, and cortical bone resorption increases at the endosteum (Robling et al., 2014). The activation frequency of resorption increases by 33%, substantially increasing erosion of the marrow cavity (Han et al., 1997). Testosterone increases bone strength by promoting periosteal expansion, distributing mass further from the neutral axis. In males, the periosteal and endosteal radii increase steadily during growth and then stay fairly constant until middle age. During senescence, male periosteal and endosteal radii slowly expand again (Martin, 2003). Due to their enhanced periosteal formation, males have larger bone diameters at peak bone mass compared to females (Burr and Akkus, 2014). For example, in a modern Australian population, midshaft femoral cross-sectional dimensions are comparable between young males and females when adjusted for height. Femora became larger and more circular with age in both sexes, expanding significantly in height-normalized mediolateral diameter (B18% male, B10% female) and anteroposterior diameter (B6% male and female). However, male bone dimensions exceed those of females during and after menopause (Feik et al., 2000). Schlecht et al. (2015) found that young women (20
35 years old) have significantly less (6%
25%) cortical area than expected from their body size and external bone size (robustness). In males, this periosteal apposition compensates for age-associated endosteal resorption. Periosteal apposition needs to restore only B30% of the bone resorbed at the endosteum to preserve resistance to bending or torsion, since distribution of mass further from the neutral axis is more mechanically effective (Martin, 1993). For example, in the femur, males and females decline equally in material strength related to bone composition, but female structural strength declines with age, while male structural strength is preserved by periosteal apposition (Martin and Atkinson, 1977). Males, but not females, similarly preserve or expand cortical area and its associated cross-sectional measurements of resistance to bending or torsion in the tibia (Ruff and Hayes, 1988), radius (Burr and Martin, 1983), and vertebral body (Mosekilde and Mosekilde, 1990). Loss of cross-sectional robustness is associated with decreased stiffness and reduced resistance to fracture, as

121

demonstrated in the tibia (Armstrong et al., 2004; Jepsen et al., 2013), femur, humerus, radius, second metacarpal (Schlecht et al., 2014), and rib (Murach et al., 2017). Aging males still experience reduced bone strength and increased fracture risk due to previously discussed declines in bone quality (Martin, 1993). One in three women and one in five men over age 50 will experience an osteoporotic fracture (Melton et al., 1992, 1998; Kanis et al., 2000). However, male preservation of structural properties of bone strength helps explain their lower overall incidence of osteoporotic fracture. Females experience 1.6 times as many osteoporotic fractures as males, or 61% of the worldwide incidence of all fractures. Prevalence is particularly high in females for osteoporotic fractures of the forearm (80%), humerus (75%), hip (70%), and vertebrae (58%) (Johnell and Kanis, 2006).

Sexual Dimorphism in Trabecular Bone Loss With Age Unlike the cortical bone loss associated with aging, trabecular loss begins during sex hormone sufficiency in early adulthood. Riggs et al. (2008) compared cortical and trabecular bone loss across the lifespan in the distal radius, distal tibia, and lumbar spine. They found that before age 50, women have already lost 37% and men have lost 42% of the total amount of trabecular bone they will lose over their lifetimes. One potential cause of this early trabecular bone loss is a decline in serum IGF-I (56% in women, 24% in men) and serum IGFBP3, a sign of growth hormone (GH) secretion (10% in women, 15% in men) between ages 20 and 50. Trabecular bone loss also accelerates at periomenopause in women, as estrogen levels decline, and after age 65 in men, as sex steroid levels decline. In comparison, only 6% of lifetime cortical bone loss occurs before age 50 in women, and only 15% in men (Riggs et al., 2008). Trabecular bone loss in early adulthood has also been detected in the proximal femur (Riggs et al., 2004) and lumbar spine (Meier et al., 1984; Kalender et al., 1989; Yu et al., 1999; Riggs et al., 2004). Men tend to lose cancellous bone through trabecular thinning, while women decline in trabecular number. This variation may contribute to the lower fracture risk in males. In their study of the distal radius, Khosla et al. (2005) found that cortical thickness and cortical volumetric bone mineral density (vBMD) decline largely after age 50 in both men and women. However, age-associated changes in trabecular bone structure begin earlier. Trabecular bone volume/tissue volume (BV/TV) decreases similarly in women (
27%) and men (
26%) between ages 20 and 90. Young men have thicker trabecular bone than young women. Between ages 20 and 49, trabeculae become thinner and more numerous in men. In contrast, aging women experience trabecular loss, signified by

122 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

decreased trabecular number and increased trabecular spacing (Khosla et al., 2005). The iliac crest displays similar patterns of female trabecular loss as opposed to trabecular thinning (Parfitt et al., 1983; Han et al., 1996). For the same loss of trabecular volume, a reduction in trabecular number reduces bone strength and Young’s modulus two to five times more than trabecular thinning (Silva and Gibson, 1997). This structural compensation for trabecular volume loss in aging men may contribute to their lower fracture risk (Khosla et al., 2005).

Estrogen Deficiency Also Contributes to Bone Loss in Elderly Men In men, approximately 50% of cases of osteoporosis have a direct cause, and are termed secondary osteoporosis (Pietschmann et al., 2001). Approximately 85% of cases of secondary osteoporosis in men are endocrine-related (corticosteroid excess in Cushing’s syndrome, testosterone deficiency in primary or secondary hypogonadism) or behaviorally induced (exogenous corticosteroid use, alcoholism, tobacco use, inadequate calcium or vitamin D intake) (reviewed in Ebeling, 2008; Sim and Ebeling, 2013). When no secondary cause is discerned, the osteoporosis is termed primary or idiopathic (Pietschmann et al., 2001). Estrogen, particularly estradiol (E2), plays a key role in primary osteoporosis in elderly men. After age 70, declining bioavailability of estradiol is associated with accelerated cortical bone loss (Khosla et al., 2005; Riggs et al., 2008), increased markers of bone turnover (Szulc et al., 2001; Khosla et al., 2001; Gennari et al., 2003; van Pottelbergh et al., 2003), and decreased BMD (Bourdel et al., 1989; Slemenda et al., 1997; Greendale et al., 1997; Khosla et al., 1998, 2001, 2005; Ongphiphadhanakul et al., 1998; Center et al., 1999; Amin et al., 2000; Szulc et al., 2001; van Pottelbergh et al., 2003). Khosla et al. (2001, 2005), in particular, demonstrated that older men can fall below the threshold of bioavailable estrogen needed to protect against bone loss. Total levels of testosterone and the estrogen hormone estradiol (E2) remain largely constant over male lifespan (Khosla et al., 2001). However, bioavailable testosterone declines 26% in middle-aged men (40
59 years) and 60% in older men ( . 60 years) compared to young men. Similarly, bioavailable estradiol declines 9% in middle-aged men and 38% in older men compared to young men. This shrinking bioavailability appears to be due largely to an age-associated increase of the sex-hormone binding globulin (SHBG), which binds estradiol. SHBG is 16% higher in middle-aged men and 76% higher in older men (Khosla et al., 2005). Pietschmann et al. (2001) similarly found that men diagnosed with primary osteoporosis have significantly lower serum estradiol and free androgen, and significantly higher SHBG concentrations, compared to controls.

Bioavailable testosterone affects bone mass indirectly through its aromatization to estrogen. In men, over 80% of estrogen is produced in the adipose tissue by aromatase conversion from androgens. A small amount is also produced by the testes (Weaver and Fuchs, 2014). Men’s ability to aromatize testosterone to estradiol may actually increase with age. However, the decline in bioavailable testosterone as a substrate for this process further reduces bioavailable estradiol (Khosla et al., 2001). In a nursing home study of elderly men, up to 66% of hip fractures and 20% of spinal fractures occurred in hypogonadal men with abnormally low serum testosterone (Abbasi et al., 1995). Gennari et al. (2003) also found that aromatase activity increased with age, but was lower in osteoporotic men compared to controls. Compared to other estrogens and testosterone, bioavailable estradiol is the most significant predictor of bone resorption markers and BMD in elderly men (Khosla et al., 2001). The level of bioavailable estradiol also shows a significant positive association with cortical and trabecular vBMD in the male lumbar spine, femoral neck, distal radius, and distal tibia, even after adjusting for age (Khosla et al., 2005). Khosla et al. (2001) found that elderly men with Bio-E2 level above the sample median lost minimal or no bone at the radius and ulna, while men falling below this median threshold lost bone at a progressively higher rate as Bio-E2 levels decreased. Khosla et al. (2005) similarly found that men with Bio-E2 levels below the sample median significantly declined in trabecular vBMD and cortical vBMD at several skeletal sites. In their sample of subjects from Rochester, MN, B90% of postmenopausal women, B50% of elderly men, and B25% of middle-aged men fell below this median threshold, suggesting that they were at risk of developing osteoporosis (Khosla et al., 2001). Gennari et al. (2003) also observed that men above a sample median threshold of bioavailable estradiol were relatively protected from bone loss, while men below this threshold were at risk for bone loss.

Cortical Drift During Growth Alters CrossSectional Shape Strain-responsive modeling is not uniform within a crosssection, but instead varies between planes, such as the anterior
posterior or medial
lateral axes. Within a given plane, resistance to bending is also approximated by area Ð moment of inertia (I). The equation I 5 y2δA2 integrates small units of area (δA) along the plane of interest with their perpendicular distance (y) from the neutral axis (Skedros, 2011). The need for resistance to bending in a given plane determines the distribution, and therefore shape, of bone in a given cross-section (Ruff and Hayes,

Histomorphology: Deciphering the Metabolic Record Chapter | 6

FIGURE 6.9 Complete cross-section from midshaft of a fifth rib from a 15-year-old male (modern). The cutaneous cortex (top) contains many porous areas while the pleural cortex (bottom) contains more primary circumferential lamellae, reflecting the process of cortical (modeling) drift. Additionally, the high turnover rate seen during development results in the disproportionate amount of intracortical porosity in the cutaneous cortex. Although these changes are not pathological, and are normal during growth, the resulting lack of bone can increase fracture risk in adolescents. Image taken under bright field light, scale included. Photo credit: Victoria Dominguez.

1983). During growth, bones use cortical (modeling) drift to adapt their shape to the mechanical demands of a changing body structure and capacity for physical activity. In this modeling process, bone is formed on the periosteum and resorbed from the endosteum to shift a region of cortex in a given plane (Frost, 2003). This high activation frequency creates large concentrations of intracortical porosity as the periosteal cortex is resorbed and the endosteal cortex is trabecularized in the direction of drift (Frost, 1969; Agnew et al., 2013) (Fig. 6.9). The actively drifting cortex results in extreme tissue heterogeneity that may indicate whether a bone is more or less likely to resist loading. Agnew et al. (2013) found that in growing human ribs, the percentage of Haversian bone in a crosssection, as opposed to primary bone, has a positive relationship with elastic modulus. During aging, changes in gait can again activate cortical drift. In Feik et al.’s (2000) modern Australian population, the anterior cortex expands with age in both females (9.3% increase) and males (3.1% increase). They attribute this anterior drift to a stooping posture during aging, which thrusts the hips, head, and thorax forward. The endosteal lamellar pocket (ELP), so named by Maggiano et al. (2011), is a histological remnant of cortical drift during growth that remains in the adult crosssection. ELPs are large regions of primary bone that form at the endosteum as hemicircumferential lamellae. In the adult femur, they border approximately one-sixth to onehalf of the medullary cavity and commonly cover half of the cortical thickness in this region. ELPs have few

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longitudinally oriented secondary osteons marking remodeling activity, and are instead vascularized by radially oriented transverse canals (Maggiano et al., 2011). For example, the midshaft femur drifts rapidly posteriorly and medially in toddlers and slowly anteriorly and laterally starting in childhood (Goldman et al., 2009). To move the femur laterally, the lateral cortex forms bone on its periosteal surface and resorbs bone on its endosteal surface. The medial cortex also moves laterally through the reverse pattern of periosteal resorption and endosteal formation. The primary bone formed on the medial endocortex forms an ELP that persists in the adult femur, although its anterior or posterior positioning varies between individuals (Maggiano et al., 2011). These ELPs are more prominent in the distal femur (Maggiano et al., 2015). ELPs in the adult humerus, instead, reflect torsional loading during growth. The midshaft and distal diaphysis display clockwise drift, wherein the periosteal bone rotates from posterior-medial to posterior, and the endosteal bone rotates from anterio-medial to anteriolateral (Maggiano et al., 2015).

Assessment of Axial Loading Differences Through the Relative Cortical Area Cross-sectional size and shape are modeled by mechanical loading, primarily during growth. Physical activity patterns, diet, health, and aging can alter typical mechanical loading, so groups that vary in these biocultural circumstances will also vary in cross-sectional size and shape. Over the last few decades, bioarcheologists and paleoanthropologists have used population and group differences in cross-sectional geometry to make inferences about the evolution of bipedalism, along with shifting patterns of subsistence, division of labor, and mobility (reviewed in Ruff and Larsen, 2014). Relative cortical area (RCA), also called percent cortical area (%Ct.Ar), can be used to infer changes in bone mass between groups or over time (Sladek et al., 2006). %Ct.Ar is measured as cortical area (Ct.Ar)/total area (Tt. Ar), and therefore describes the proportion of total area of a cross-section that contains cortical bone. For example, a %Ct.Ar of 0.5 indicates that 50% of the total area (i.e., transverse size) of a cross-section contains cortical bone (Peck and Stout, 2007). %Ct.Ar is not standard for an individual, but varies intraskeletally. For example, Auerbach and Ruff (2006) determined that the humerus shows a right-side bias in midshaft diaphyseal breadth. They attribute this difference to the human prevalence of right-handedness. Similarly, skeletal samples of the upper limb from Neandertals to the present show significant variability in upper limb asymmetry along the shaft

124 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

(Trinkaus et al., 1994). Peck and Stout (2007) and Stewart et al. (2015) both found that the midshaft rib has significantly lower %Ct.Ar than the dynamically loaded long bones of the upper and lower limbs. In the upper limb, humeri have a relatively low %Ct.Ar, while radii and ulnae have a relatively high %Ct.Ar, reflecting more diverse limb use. Potentially due to their shared and constant role in bipedalism, the femur and tibia have very similar %Ct.Ar, grouping with (Stewart et al., 2015) or without (Peck and Stout, 2007) the nonweight-bearing fibula. Two immobilized quadriplegic individuals had extremely low femoral %Ct.Ar compared to a mobile group (Peck and Stout, 2007), providing evidence for reduction in bone with pathological disuse. %Ct.Ar does not quantify the absolute magnitude of axial load, but is simply used to compare the relative values between individuals. For example, Sladek et al. (2006) inferred that Late Eneolithic and Early Bronze Age central Europeans had similar patterns of mobility due to their similar tibial %Ct.Ar values. Diet also contributes to the capacity of bone to form and retain mass. Cho and Stout (2011) detected higher cortical bone turnover and loss in females compared to males in an Imperial Roman population. While female bone loss is probably partially due to menopause and lactation, Cho and Stout (2011) also implicate lesser access to calciumrich marine foods in this population.

Cross-Sectional Shape as a Metric of Loading Direction Since most loading during locomotion is not axial, differences in physical activity and limb use between groups are better inferred by relative cross-sectional shape than by relative cross-sectional size (Ruff and Larsen, 2014). Cross-sectional shape analysis quantifies the distribution of bone along planes of bending within the cross-section. Area moment of inertia (I), also called second moment of area, essentially measures the distribution of bone around the neutral axis, as previously described (Ruff and Hayes, 1983). It is often used to measure resistance to bending perpendicular to anatomical planes, or around the principal axes in a cross-section. Bending about the planes of shortest distribution of tissue (the minor axis) gives the greatest resistance to bending (Imax), whereas bending about the longest distribution of tissue (the major axis) gives the least resistance to bending (Imin) (Ruff and Hayes, 1983). Circularity of the bone is given by the ratio of any two perpendicular area moments of inertia, most typically Imax/Imin. When the bone is more circular, Imax and Imin are closer in value, so the circularity ratio is closer to 1 (Ruff and Hayes, 1983). Several additional calculations may be derived from area moment of inertia (I) to summarize the section’s overall resistance to bending. The polar moment of inertia

(J), often used as an estimate of resistance to torsion, is given by the sum of two perpendicular area moments of inertia, such as Imax 1 Imin (Ruff and Hayes, 1983). The section modulus (Z) is calculated as Imax/c, where I is the area moment of inertia and c is the maximum radius of the cross-section (Juvinall and Marshek, 1991). Z approximates the cross-section’s resistance to loading best by considering the distribution of tissue. It has been shown to be strongly correlated with the strength of bone in mechanical tests of bending or torsion (Klenerman et al., 1967; Martin and Burr, 1984b; Murach et al., 2017). Over the last few decades, anthropologists have used these estimates of mechanical loading history to make inferences about past behavior and physical activities (Ruff and Larsen, 2014). In paleoanthropology, cross-sectional geometry has been broadly applied to fossil remains to track changes in the bending environment associated with shifting locomotion patterns, limb length, and body size (e.g., Endo and Kimura, 1970; Lovejoy and Trinkaus, 1980; Kennedy, 1983; Trinkaus and Ruff, 1989, 1999a,b; Abbott et al., 1996; Ruff, 1993, 1999, 2009; Trinkaus et al., 1998, 1999; Ruff et al., 1999; Kuperavage and Eckhardt, 2009; Bleuze, 2012). In bioarcheology, cross-sectional geometry has been shown to shift at the population level with changes in subsistence, division of labor, mobility, and tool use (reviewed in Ruff and Larsen, 2014).

The Parabolic Index: An Overlooked CrossSectional Indicator of Osteoporosis Cross-sectional geometry calculations are not intended to accurately represent absolute values of bending or torsional resistance for individuals (Ruff et al., 2006). Absolute values are generally only reported in depth for individual fossil hominins, due to the small sample size. Even then, these hominins are almost always contextualized by crosssectional measurements from larger populations of other hominin fossils, primates, and/or anatomically modern humans (e.g., Gruss, 2007; Ruff, 2009; Bleuze, 2012). Most bioarcheological analyses look for broader population or subpopulation patterns and distributions in cross-sectional shape and size, since individuals are not guaranteed to be representative of the entire population. Conversely, the parabolic index is an old but largely overlooked cross-sectional measurement that does have potential for assessing bone strength in individuals. First proposed by Epker and Frost (1964), this metric incorporates both the percentage of bone mass in the crosssection and its distribution around the centroid. The parabolic index (Y) is a ratio of the RCA to the relative marrow area, also written as follows (Eq. (6.5)): Y 5 ðCortical area  Marrow areaÞ=ðTotal area2 Þ

(6.5)

Regardless of their individual percentages, RCA and relative marrow area sum to 1.00, meaning 100% of the

Histomorphology: Deciphering the Metabolic Record Chapter | 6

total area of the cross-section. The parabolic index (Y) reaches a maximum value of 0.25 when RCA and relative marrow area are both equal to 0.5, each composing 50% of the total area. Epker and Frost (1964) derived the parabolic index from the mechanics of hollow cylinders loaded slightly off center, wherein the “parabolic formula for nominally concentrically loaded columns” has an optimal wall-to-lumen ratio of 0.5
0.5 (Olsen, 1956; Popov, 1952, cited in Epker and Frost, 1964: 472). Hollow cylinders closer to this ratio better withstand longitudinal compression loads (Takahashi and Frost, 1966). The parabolic index also incorporates a nonaxial loading component because “it is assumed that the column is loaded slightly off center so that there is a definite bending or buckling tendency” (Epker and Frost, 1964: 472). Both Epker and Frost (1964) and Takahashi and Frost (1966) found that metabolically normal ribs approached the maximum parabolic index of 0.25, while osteoporotic ribs did not exceed a parabolic index threshold of 0.19. Takahashi and Frost (1966) noted that, in their modern population, males steadily decline in the parabolic index after age 35. Females remain near the maximum parabolic index until a rapid postmenopausal drop after age 50. Males and females both approach an osteoporotic parabolic index after age 70. In contrast, Cho and Stout (2003) and Beauchesne and Agarwal (2017) do not detect sex differences in Imperial Roman populations at Isola Sacra and Velia, respectively. However, the Velia population also lacks the significant sex differences seen in modern populations for other cortical geometric measurements (metacarpal cortical index, rib RCA), as well as rib cortical histomorphometry and vertebral trabecular BV. While no ribs in the Velia population fall below the parabolic index threshold for osteoporosis (0.19), the parabolic index does decline significantly with age in both males and females (Beauchesne and Agarwal, 2017). Frost (1963) argues that, due to their high remodeling rate, ribs reflect physiological changes in bone biology due to age and disease earlier then appendicular bones. This suggests that different skeletal elements within an individual might differ in the parabolic index. The threshold indicative of osteopenia or osteoporosis might also vary between types of bones. A comprehensive study of intraskeletal variability in the parabolic index in metabolically normal and pathological individuals would improve the applicability of this metric in archeological and forensic contexts. Preliminary examination of a small sample from Cole and Stout (2016) suggests that the midshaft femur, tibia, and rib of the same individuals do significantly differ in their parabolic index. However, correcting for cortical porosity brings these skeletal elements into greater agreement as to whether an individual falls above or below the 0.19 threshold for osteoporosis.

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PATHOLOGY AND HISTOMORPHOMETRY Pathological conditions can alter the balance of bone formation and resorption by acting directly or indirectly on cellular processes, including remodeling rate, mineralization, and collagen deposition. This section highlights a selection of pathological conditions known to alter bone histomorphometry. Types of pathology discussed here include infection (osteomyelitis), cancer (metastatic bone disease, osseous bone tumor), imbalances of bone remodeling (Paget’s disease of bone, osteopetrosis), disorders of bone mineral homeostasis (rickets/osteomalacia, hyperparathyroidism, hyperthyroidism, diabetes mellitus, glucocorticoid excess), and collagen disorders (OI). These descriptions demonstrate how pathological interference with one or more aspects of cellular activity can dysregulate or uncouple bone formation and resorption. The histomorphological consequences are predictable, given an understanding of the normal stimuli and trajectory of these cellular activities.

Remodeling Processes Commonly Disrupted by Pathology Pathological Alteration of Remodeling Rate Over the Lifespan Pathological conditions often alter the timing, frequency, or quality of bone formation and resorption. Uncoupling the normal balance of formation and resorption can cause abnormal bone accumulation or loss, sometimes enough to alter structural properties such as bone size and geometry. For example, a relative increase in activation rate can lead to higher bone turnover and a transient porosity from a proportional increase in forming BSUs (osteons). Alternatively, a decrease in activation rate can lead to an accumulation of microdamage. Thus, intraskeletal differences in histomorphometry between bones are largely derived from remodeling. Altered remodeling functionality, such as in senescence, trauma, and disease can lead to an increase in bone’s fragility and an altered ability to withstand normal mechanical loading. Pathological interruption of normal modeling and remodeling processes also changes the material properties associated with bone’s internal histological structures. Table 6.5 describes how several pathological conditions act on osteoclast and osteoblast activity to alter bone formation and resorption, ultimately increasing bone fragility. Histological changes to mineralization, the lacunarcanalicular architecture, vascular porosity, and lamellar structure will be discussed under the relevant sections. Table 6.6 summarizes pathological changes to histology discussed in this chapter.

TABLE 6.6 Notable Histological Changes Associated With Pathology

Aging/osteopenia/ osteoporosis

Mineralization

Osteocytes

Vascular Porosity

Lamellar Structure

Trabecular

Whole Bone

Older, more highly mineralized bone increasing retained1

Lacunar density decreases with age,2 Osteoporotic osteocytes are large and elongated3 but may4,5 or may not6,7 have increased density

Increased porosity through coalescence (diameter increases, number and spacing decrease).8
10 May be abnormally regionally concentrated in osteoporosis10,12,13

Secondary osteons become smaller14 and more circular15,16 with age

Trabecular bone mass declines beginning in early adulthood
17 through trabecular thinning in men and trabecular loss in women18

Declining estrogen promotes endosteal bone resorption in women and to a lesser degree in men.19 Testosterone promotes periosteal apposition throughout life20

Lacunae may be empty due to necrosis.21,22 Lacunae and canaliculi enlarged23

Blurred necrotic lamellae,22 “pagetoid” woven bone with irregular reversal lines23

Trabecular fragmentation and necrosis21

Periosteal lifting and apposition22

Lacunae may be small, empty,25 or absent.26 Osteocytic osteolysis near osteolytic metastases27

Regional heterogeneity in resorption and woven bone formation28

Scalloped resorption and woven bone formation creates “candelabra” appearance27

Endosteal resorption27; factors diffuse through Haversian systems to form woven bone at periosteum29

Osteomyelitis

Metastatic bone disease

Hypercalcemia due to calcium released by bone resorption24

Osseous bone tumors

Malignant tissue may have increased and disorganized mineralization30

Paget’s disease of bone

Localized osteomalacia due to high bone turnover33

Osteopetrosis

Osteopetrorickets: Lack of resorption restricts serum

Increased osteocyte lacunar density and lacunae size34

Haversian canals may be empty31 or absent30 in malignant tissue

Can produce woven or differentiated bone matrix based on timing of cell malignancy.32 Differentiated malignant matrix lacks reversal lines31

Penetration of tumors through Haversian canals lifts the periosteum and causes detached periosteal apposition32

Deep “swallowtail” resorption fronts.35 Increased porosity36 with complex network37

Patchwork of lamellar bone and woven bone.38 Random collagen fiber orientation.35 Osteons rarely complete, with scalloped “polycyclic” cement lines38

Twofold increase due to more numerous trabeculae with less separation, although thickness does not change.35,39 Fibrous tissue covers B50% of surface35

Bones thicken and elongate38

Organized Haversian system is largely absent

Thickened cement lines containing osteoblastic products

Primary trabeculae are thickened and densely packed due to woven

ARO (congenital): No marrow cavity because calcified cartilage is not

(ARO)41 or sparse (ADO)43

calcium-phosphorus available for mineralization of new osteoid40

Rickets / osteomalacia

Not enough calciumphosphate product for normal bone mineralization46

Osteocytic osteolysis47 with halo defects48

Hyperparathyroidism

Hypercalcemia due to calcium released by bone resorption52

Osteocytic osteolysis53,54 with irregularly shaped lacunae, mineral intrusion, and appearance in unmineralized regions55,56

Hyperthyroidism

Significant negative calcium balance in response to hypercalcemia63

Diabetes mellitus

Reduced bone mineralization, especially trabecular65

Reduced osteocyte lacunar density and narrowed canaliculi66

Glucocorticoid excess

Reduced bone mineralization71

Osteocytic osteolysis.72 Commonly apoptotic in necrotic tissue73

Significant cortical porosity and extensive trabecularization.57
60 Deep, irregular subperiosteal resorption55

and degraded collagen fibers42
44

or lamellae apposition on retained cartilage core43

resorbed during growth. Thickened metaphyses and diaphysis as lamellar or woven bone forms on cartilage core.43 Longitudinal bone growth impaired.44 ADO (adult onset): Rugger jersey spine (dense bands parallel to vertebral end plate)45

Thickened osteoid seams cover almost all bone surfaces,49 including Haversian surfaces48

Coarse trabeculae50 with a mineralized core and osteoid periphery51

Rickets: thin cortices, widened metaphyses, stunting, bone bowing50

Compensatory formation of fibrous matrix containing woven bone. 49Brown tumors form in severe primary hyperparathyroidism61

Tunneling and perforation of trabeculae.49 Reduced trabecular volumetric density due to reduced trabecular number, increased trabecular spacing, and trabecular thinning. Inhibited changes at weight-bearing sites59,60,62

Reduced cortical area and cortical thickness, but inhibited at weightbearing sites59,62

Porosity increased, primarily in cortical bone64

Increased porosity due to increased number and density of canals74,75

Net 10% loss of mineralized bone per remodeling cycle63 Trabecular core increased at the expense of cortical bone67

Bone formation is reduced or absent on all surfaces68
70

More resorption than cortical bone. Trabeculae thin and perforate,76,77 increasing spacing and number75

Decreased osteoid area and width75

(Continued )

TABLE 6.6 (Continued)

Osteogenesis imperfecta

Mineralization

Osteocytes

Vascular Porosity

Lamellar Structure

Trabecular

Whole Bone

Mineral platelets are smaller, thinner, and more numerous. High bone mineralization due to increased packing density.78 Poor mineral organization inhibits stiffness79

Multiple osteocytes per lacunae (OI type II) or increased osteocyte numbers (OI types I, II, III).82 Lacunae are spherical and less aligned with bone axis79

Porosity increased with more numerous and more connected canals79
81

OI type I and IV: Lamellae thin but normally organized82
84 OI type II: Significantly smaller diameter collagen fibrils,85,86 woven bone predominates with patches of lamellar bone and osteoid82 OI type III: Mixed lamellar and woven bone82,84 with poorly aligned mineral crystals87 OI type V: Abrupt changes in collagen fibril width, coarse and mesh-like lamellae with irregular organization under polarized light88 OI type VI: Fish-scale pattern under polarized light suggests disordered mineral deposition89 OI type VIII: Collagen fibrils abnormally large (fused) or small (fragmented)90

OI types I
IV: Reduced trabecular production and absent or insufficient thickening84,91 OI type II: Few, discontinuous trabeculae82 OI type VI: Trabeculae thin but maintain number83,89 OI type VII: Trabeculae maintain thickness but decrease in number83,89 OI type VIII: Trabeculae half as thick as OI types I and VII; reduced in number90,92

Bones can be shortened or deformed93 Reduced cortical width.91,84 Osteoid seams are thickened by increased activation frequency OI types I, III, and IV and by delayed mineralization in OI types V, VI, and VII.91 Osteoid accumulates in scattered foci in OI type VIII90

[1] Simmons et al. (1991); [2] Hunter and Agnew (2016); [3] van Hove et al. (2009); [4] Mori et al. (1997); [5] Qiu et al. (2003); [6] Mullender et al. (1996); [7] McCreadie et al. (2004); [8] Chen and Kubo (2014); [9] Milovanovic et al. (2014); [10] Chen et al. (2010); [11] Bell et al. (2001); [12] Bell et al. (1999a); [13] Bell et al. (1999a); [14] Dominguez and Agnew (2016); [15] Goliath et al. (2016); [16] Hennig et al. (2015); [17] Riggs et al. (2008); [18] Khosla et al. (2005); [19] Han et al. (1997); [20] Martin (2003); [21] Tiemann et al. (2014); [22] Keel (2015); [23] Bruder et al. (2009); [24] Rubens (1998); [25] Adler (2000); [26] Hofstaetter et al. (2013); [27] Chappard et al. (1978); [28] Buijs and van der Pluijm 2009); [29] Wlodarski and Reddi (1987); [30] Hofstaetter et al. (2013); [31] Adler (2000); [32] Klein and Siegal (2006); [33] Williams et al. (1981); [34] Hernandez et al. (2004); [35] Seitz et al. (2009); [36] Vallet and Ralston (2016); [37] Chappard et al. (1984); [38] Meunier et al. (1980); [39] Pestka et al. (2012); [40] Kaplan et al. (1993); [41] Kuo and Davis (1981); [42] Semba et al. (2000); [43] Helfrich et al. (1991); [44] Shapiro et al. (1980); [45] Stark and Savarirayan (2009); [46] Holick (2006); [47] Dallas et al. (2013); [48] Teitelbaum (1980); [49] McCarthy (2016); [50] Perez-Rossello et al. (2012); [51] Unnanuntana et al. (2011); [52] Bilezikian and Potts (2002); [53] Bonucci et al. (1976); [54] Bonucci and Gherardi (1977); [55] Fadda et al. (1990); [56] Bonucci et al. (1978); [57] Christiansen et al. (1993); [58] van Doorn et al. (1993); [59] Hansen et al. (2010); [60] Vu et al. (2013); [61] Carlson (2010); [62] Stein et al. (1999); [63] Harvey et al. (2002); [64] Mosekilde and Melsen (1978); [65] Einhorn et al. (1988); [66] Lai et al. (2015); [67] Hou et al. (1991); [68] Verhaeghe et al. (1989); [69] Verhaeghe et al. (1990a); [70] Verhaeghe et al. (1990b); [71] Weinstein et al. (1998); [72] Lane et al. (2006); [73] Weinstein et al. (2000); [74] Vedi et al. (2005); [75] Weinstein et al. (1998); [76] Dalle Carbonare et al. (2001); [77] Dalle Carbonare et al. (2005); [78] Fratzl-Zelman et al. (2014); [79] Carriero et al. (2014a,b); [80] Carriero et al. (2011); [81] Albert et al. (2014); [82] Sarathchandra et al. (2000); [83] Rauch and Glorieux (2004); [84] Glorieux and Travers (1994); [85] Sarathchandra et al. (1999a); [86] Sarathchandra et al. (1999b); [87] Traub et al. (1994); [88] Glorieux et al. (2000); [89] Glorieux et al. (2002); [90] Fratzl-Zelman et al. (2016b); [91] Rauch et al. (2000); [92] Fratzl-Zelman et al. (2016a); [93] Basel and Steiner (2009).

Histomorphology: Deciphering the Metabolic Record Chapter | 6

Pathological Alteration of Mineralization Pathological conditions can alter serum mineral concentrations as well as mineral concentration within bone tissue. Hypercalcemia is a common consequence of abnormally increased osteoclastic resorption, which releases calcium from bone. Suppressed bone turnover can leave unremodeled bone dense and brittle, while increased bone turnover can deposit abnormal woven bone with irregular mineralization. Pathological changes in remodeling rate can affect both the mean degree of mineralization (DMB) and the overall heterogeneity of mineral distribution in bone tissue (Martin, 1993; Bala et al., 2013). When remodeling rate is low, there is more time for complete secondary mineralization. Mean DMB increases and bone becomes more homogeneously mineralized (Bala et al., 2013). For example, a low remodeling rate and associated increases in mineralization homogeneity are seen in anticatabolic (resorption-reducing) bisphosphonate osteoporosis treatment (Chavassieux et al., 1997; Boivin et al., 2000, 2003; Zoehrer et al., 2006; Borah et al., 2006; Misof et al., 2008; Boskey et al., 2009; Bala et al., 2011), osteopetrosis (Boskey and Marks, 1985; Chavassieux et al., 2007), and necrosis (He´mar et al., 2012), among other pathologies (Bala et al., 2013). When the remodeling rate is high, bone turnover occurs before full secondary mineralization. Mean DMB decreases and bone becomes more heterogeneously mineralized due to matrix in various stages of mineralization (Bala et al., 2013). This connection is upheld for the increased remodeling experienced during menopause (Recker et al., 2004), postmenopausal osteoporosis (Roschger et al., 2001, 2008a,b; Misof et al., 2003; Ciarelli et al., 2003; Zoehrer et al., 2006; Boivin et al., 2008), anabolic (bone-forming) PTH osteoporosis treatment (Misof et al., 2003; Paschalis et al., 2005), and mild primary hyperparathyroidism (PHPT) (Boivin and Meunier, 2002; Roschger et al., 2007). Either extreme of remodeling and mineralization is disadvantageous. Bone with high mineralization, such as osteopetrotic bone, is stronger (ultimate stress) and stiffer. However, it has a short plastic deformation region and is more likely to fracture. Additionally, its mineral homogeneity reduces its ability to stop or deflect cracks. Bone with low mineralization, such as osteoporotic bone, can deform more under strain, but has lower strength and stiffness (Ruppel et al., 2008). When bone is too flexible, it can crack even under normal loading (Seeman and Delmas, 2006).

Pathological Alteration of Collagen Deposition During normal modeling and remodeling, collagen is deposited in an orderly manner in uniform, parallel

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bundles. This creates the circumferential lamellae of primary bone and the concentric lamellae contained within secondary osteons. In contrast, rapid bone turnover is disordered and deposits woven bone, characterized by random collagen fiber orientation and nonuniform collagen bundle size (Teitelbaum, 1980). Osteocytes and their lacunae are enlarged in woven bone (Hernandez et al., 2004). Osteocytes in woven bone also have an irregular spherical shape, compared to the almond-like elliptical shape in lamellar bone (Marotti et al., 1985). Due to the rapid formation of woven bone, osteocytes enter the matrix quickly and have an irregular distribution of dense areas and nearly acellular areas (Marotti, 1990). In a rat model, osteocyte lacunar density is also increased in the woven bone created by endochondral ossification, being 40% higher in primary spongiosa compared to lamellar trabecular bone, and 100% higher in the gap region of a fracture callus compared to lamellar cortical bone. However, osteocyte lacunar density is not increased in woven bone associated with intramembranous ossification, such as fracture callus buttressing or periosteal apposition in response to severe mechanical overload (Hernandez et al., 2004). Pathological conditions involving rapid bone turnover can trigger woven bone deposition and further distort its histological presentation (Teitelbaum, 1980). This chapter will detail how some pathological conditions alter the quality of collagen or mineral deposited by bone cells, or reduce bone cell functionality, further distorting the associated histology. Nonpathological instances of woven bone are associated with constrained time periods of early bone growth or fracture healing. For example, Streeter’s (2010) age estimation method for the subadult rib indicates that woven bone comprises most of the rib cortex before age 5, but recedes to the periosteal region of the cutaneous cortex before disappearing around age 18. In adults, woven bone is created during the early stages of fracture repair, after which it is remodeled into lamellar bone. de Boer and colleagues (2013a, 2015) have developed a timeline for the microscopic histological appearance of a healing fracture or amputation in archeological dry bone. Following initial resorption of the lesion margins (4
7 days after fracture), primary woven bone is rapidly laid down to form a periosteal callus (formation visible after 7 days) and endosteal callus (formation visible after 10
12 days). Remodeling begins to convert this woven bone into secondary lamellar bone starting at 14 days. Polarized light microscopy and hematoxylin staining can improve histological detection of the transition from woven to lamellar bone. This remodeling is accompanied by the formation of cutting and closing cones (after 14
21 days), union of the cortex with the endosteal callus (after 17 days) and periosteal callus (after 6 weeks), bridging of the cortical bone by the callus (after 21
28 days), and

130 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

smoothing of the periosteal callus outline (after 2
3 months). Given successful healing, remodeling in the fracture region returns to a quiescent (resting) state after 1
2 years. This histological timeline of early fracture healing allows researchers to estimate how long an individual survived following a perimortem fracture (de Boer et al., 2013a, 2015). Additionally, Assis and Keenleyside (2016) note that a callus may appear healed macroscopically while retaining an immature microstructure, evidenced by disorganized lamellae, ongoing pockets of resorption, and enlarged Haversian canals. While this method was largely developed on tubular bones, it has also been applied to cranial trauma (Steyn et al., 2014).

Infection: Osteomyelitis Cause: Staphylococcus aureus is the most common cause (85%) of infection leading to osteomyelitis in long bones (Bruder et al., 2009). Bacteria can enter the bone through several routes: through the blood (hematogenous), contiguous spread from an adjacent infected tissue, direct implantation into the bone, or infection posttrauma (Keel, 2015). The acute hematogenous route of infection is the most common in children (Elgazzar and Shehab, 2006). Localization: Osteomyelitis occurs more frequently in long bone metaphyses due to their rich, slow blood flow and high bone porosity. The growth plate blocks spread to the epiphyses between the ages of 1 and 16, but is possible in its absence in infants and adults, allowing the infection to spread to adjacent joints. Osteomyelitis can also occur in the pelvis, calcaneus, and vertebrae, with the latter most common in adults aged 60
70. Osteomyelitis appears in the foot in 15% of adult diabetics (reviewed in Elgazzar and Shehab, 2006). Disease progression: The first stage of infection is infectious periostitis, which causes periosteal irritation, lifting, and bone formation (Keel, 2015; Elgazzar and Shehab, 2006). Blood supply to the bone is cut off at the periosteum and intramedullary pressure increases, further impairing blood flow and leading to bone necrosis (Keel, 2015). Necrosis is visible at microscopic levels after 48 hours (Vigorita, 2008; Keel, 2015). The infection then progresses through the periosteum to the cortical bone (infectious osteitis) and ultimately inflames the medullary cavity (osteomyelitis) (Keel, 2015; Elgazzar and Shehab, 2006). Acute osteomyelitis, characterized by marrow fibrosis, develops into chronic osteomyelitis without treatment in 5%
25% of cases (Rosenberg, 2010). Effect on bone turnover and lamellar organization: Fresh tissue shows evidence of tissue infection through the infiltration of white blood cells (granulocytes), fluid retention (edema), and necrosis. In dry bone, the evidence of this infection is destructive resorption of the adjacent

bone cortex, followed by reactive deposition of woven bone if the disease progresses (de Boer and van der Merwe, 2016). In osteomyelitis, osteoclasts are activated at the cortical surface in response to infection, resorbing a scalloped border (Keel, 2015). Necrotic lamellae appear blurred histologically (Bruder et al., 2009). Adjacent Howship’s lacunae create irregular trabecular contours (Bruder et al., 2009). This can lead to trabecular fragmentation, and necrotic trabeculae if the bone is segmented off from adjacent viable bone (sequestrum) (Tiemann et al., 2014). Osteoblasts then form woven bone to reinforce necrotic trabecular or lamellar bone, a process known as “creeping substitution” (Keel, 2015). Vascular channels signifying hypervascularization may be visible at the periosteal surface (de Boer et al., 2013b). However, subsequent remodeling of this new bone can make it difficult to distinguish from old bone (de Boer et al., 2013b; de Boer and van der Merwe, 2016). Osteomyelitis may also appear histologically similar to osteolytic metastatic cancers and malignant primary osseous tumors, which also induce destructive bone resorption and reactive bone formation (de Boer and van der Merwe, 2016). In chronic osteomyelitis, osteoclast activation and osteoblast deposition of woven bone lead to “pagetoid” irregular reversal lines resembling those of Paget’s disease (Bruder et al., 2009). Woven bone can also form in abnormal locations, such as periosteal apposition (involucrum) or in soft tissue regions (heterotopic ossification) (Keel, 2015). Effect on osteocyte lacunae: Empty lacunae both within cortical bone and lamellae indicate necrosis (Tiemann et al., 2014; Keel, 2015). Osteocytes undergo necrosis within 2 weeks of infection (Bruder et al., 2009). However, the postmortem loss of osteocytes removes evidence of this apoptosis in dry bone (de Boer and van der Merwe, 2016). Both osteocyte lacunae and canaliculi are enlarged in osteomyelitis (Bruder et al., 2009). Effect on bone fragility: Chronic osteomyelitis can lead to the formation of sinus tracts, increasing the risk of pathological fracture (Rosenberg, 2010). Histological case studies in paleopathology: These histological hallmarks of destructive bone resorption and reactive bone formation have provided evidence of nonspecific bone infections in archeological remains (e.g., Schultz, 2002; Weston, 2009; Flohr and Schultz, 2009a,b; van de Merwe et al., 2010; Schultz, 2011). Some paleopathological case studies combine histology with macroscopic evidence to suggest specific infections, such as leprosy (Blondiaux et al., 1994; Schultz and Roberts, 2002; Schultz, 2002), venereal syphilis (Hackett, 1981; von Hunnius et al., 2006; Schultz, 2002, 2011), tuberculosis (Wakely et al., 1991; Schultz, 2002, 2011; Nicklisch et al., 2012; Schultz and Schmidt-Schultz, 2015), and scurvy (Schultz, 2002, 2011; van de Merwe et al., 2010).

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Cancer: Metastatic Bone Disease Cause: Circulating cancer cells in the bloodstream initially adhere to the endothelium of marrow cavity. Buijs and van der Pluijm (2009) review factors in the affinity and homing of cancer cells to the bone marrow. Metastatic bone disease is generally osteolytic (bone destroying), including those derived from breast, lung, kidney, and thyroid cancers, as well as melanomas (Roudier et al., 2008; Chappard et al., 2011). Prostate cancer is osteoblastic/osteosclerotic (bone-forming). However, prostate cancer has an osteolytic presentation at the histological level even though bone formation increases overall (Roudier et al., 2008). Localization: Metastatic bone disease most commonly occurs in axial skeleton due to slow blood flow making it easier for metastases to attach (Rubens, 1998). Venous blood from the pelvis and breast flows into the vertebralvenous plexus, bypassing the pulmonary circulation, which is why breast, prostate, lung, kidney, and thyroid cancers have high incidences in the axial skeleton and limb girdles (Rubens, 1998). Breast cancer (65%
75%) and prostate cancer (68%) are the most common carcinomas to develop bone metastases (Perez et al., 1990). Breast and prostate cancers combined account for approximately 80% of metastases to bone (Rubens, 1998). Lung, kidney, and thyroid cancers develop bone metastases in approximately 30%
40% of cases (Rubens, 1998). Gastrointestinal tract carcinomas are rarer (,10%) (Buijs and van der Pluijm, 2009). Disease progression: In osteolytic cancers, PTHrP production by most solid cancers increases osteoclast differentiation by upregulating RANKL and downregulating OPG. The bone microenvironment appears to induce tumors to produce PTHrP, rather than tumors having an inherently higher level. As bone is resorbed in the vicinity of the tumor, TGF-β, IGF-I, and IGF-II are released, stimulating more tumor growth and more release of PTHrP in a vicious cycle (reviewed in Buijs and van der Pluijm, 2009 and Chappard et al., 2011). Tumors also release IL1, IL-6, IL-8, IL-11, and tumor necrosis factor (TNF)-α which cause osteoblasts to secrete RANKL and further induce osteoclast activity (reviewed in Virk and Lieberman 2007). Osteolytic cancers such as breast cancer also produce dickkopf-1 (DKK-1) and noggin to antagonize Wnt and BMP signaling, respectively, decreasing osteoblast differentiation (Schwaninger et al., 2007). Myeloma is a purely osteolytic cancer because its tumors strongly release the Wnt signaling antagonist DKK-1 to inhibit osteoblast activity (Tian et al., 2003). In osteoblastic prostate cancer, the prostate tumor promotes osteoblast activity through secretion of factors that promote osteoblast differentiation, such as BMPs, IGF-I, IGF-II, FGF-1, FGF-2, VEGF, PDGF-BB, and ET-1

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(reviewed in Buijs and van der Pluijm, 2009 and Chappard et al., 2011). Prostate cancer also lacks expression of DKK-1 and noggin antagonists to Wnt and BMP signaling (Schwaninger et al., 2007). Stimulated osteoblasts then release IL-6 in large amounts as well as IGF-I, FGF, TGF-β, PDGF-BB, and PTHrP, further stimulating tumor growth (Chappard et al., 2011). Somewhat paradoxically, prostate tumors also release cytokines that promote osteoclast differentiation (PTHrP, IL-1, IL-6, M-CSF). However, the simultaneous expression of proteases (uPA, cathepsin D, PSA) reduces the biologically active form of the highly expressed PTHrP, controlling osteoclast activity (Chappard et al., 2011). Effect on bone turnover and lamellar organization: In metastatic bone disease, osteolytic and osteoblastic cancers increase both cellular processes to some degree, due to the coupled nature of chemical triggers for bone formation and resorption. In osteolytic cancers, there is still usually local bone formation in an attempt at repair even though the overall effect is destructive (Buijs and van der Pluijm, 2009). For example, in breast cancer at least 15%
20% of cases have predominately osteoblastic lesions (Coleman and Seaman, 2001). Factors released from the bone by osteoclast resorption actually stimulate osteoblast activity, causing woven bone to form on trabeculae (Chappard et al., 1978). Trabecular destruction and endosteal scalloping (Rubens, 1998) combined with this woven bone formation create a “candelabra” appearance of trabeculae (Chappard et al., 1978). These factors can also diffuse through Haversian canals to reach the periosteum, causing woven bone to form at the periosteum (Wlodarski and Reddi, 1987). Bone formation has also been observed within Haversian canals following this diffusion, especially where they intersect with the bone surface (Anderson et al., 1992). Myeloma is a purely osteolytic cancer because its tumors strongly release an antagonist to osteoblastogenesis (Tian et al., 2003). In prostate cancer, despite being largely osteoblastic, markers of bone resorption are increased despite there being no increase in osteoclast number (Maeda et al., 1997). Even within the same biopsy, bone can appear osteodense and osteopenic. Woven bone forms on top of existing osteoid and trabeculae in regions where lamellar bone has been totally resorbed and de novo within the tumor stroma in the marrow cavity. This creates heterogeneous regions with varying degrees of bone resorption and woven bone (Roudier et al., 2008). Effect on mineralization: Hypercalcemia is common in patients with osteolytic metastatic bone disease because osteoclastic resorption releases calcium. Tumor production of PTHrP can induce hypercalcemia even when cancer is not metastatic to bone (Rubens, 1998). Hypercalcemia is most common in lung, hematologic, and breast cancers (Clines and Guise, 2005) and can occur

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in 3%
30% of cancer patients (Grill and Martin, 2000). See Mundy and Martin (1982) for specific frequencies of hypercalcemia for different malignancies. Effect on osteocyte lacunae: Enlarged osteocyte lacunae have been reported near skeletal metastases of lung cancer (Cramer et al., 1981) and in the woven bone formed on the trabeculae in osteolytic cancers (Chappard et al., 1978). This enlargement may be due to osteocytic osteolysis—direct resorption of the bone matrix surrounding the lacuna—which is triggered by PTH, since tumors produce PTHrP (Wysolmerski, 2012). In osteoblastic prostate cancer, osteoblasts are not well-differentiated (cuboidal) but are spindle-shaped and flat, and these become trapped in abnormal woven bone as osteocytes (Roudier et al., 2008). Effect on bone fragility: Cancers where osteolysis predominates (e.g., breast cancer) have a higher fracture risk than cancers that are osteoblastic/osteosclerotic (e.g., prostate cancer), although both types have regions of bone formation and resorption that contribute to fragility (Rubens, 1998). Fractures of long bones, ribs, or vertebrae occur in approximately 50% of all patients with metastases, with most fracture cases resulting from breast carcinoma (53%) and other common sources being kidney (11%), lung (8%), thyroid (4%), lymphoma (4%), and prostrate (3%) cancers (Higinbotham and Marcove, 1965). Fractures of long bones occur in B16% of patients with breast metastases to bone (Coleman and Rubens, 1987). Even though prostate cancer forms new bone, the heterogeneity of osteodense and osteopenic bone may contribute to high bone fragility (Roudier et al., 2008). The amount of bone compromised contributes to fracture risk. Pathological fracture is unusual when below twothirds of the diameter of a long bone is affected, but occurs in 80% of cases where above two-thirds are affected (Rubens, 1998). Histological case studies in paleopathology: In archeological contexts (reviewed in de Boer et al., 2013b), histology has helped identify primarily osteoblastic lesions associated with prostate cancer (Tkocz and Bierring, 1984; Anderson et al., 1992; de la Ru´a et al., 1995; Schultz et al., 2007; Molnar et al., 2009; Merczi et al., 2014), as well as primarily osteolytic lesions characteristics of lung cancer (Grupe, 1988), breast cancer (Schultz, 1993; Merczi et al., 2014), multiple myeloma (Wakely et al., 1998; Molnar et al., 2009), and unspecified metastatic carcinoma (Strouhal, 1991; Sefca´kova´ et al., 2001; Molnar et al., 2009).

Cancer: Osseous Bone Tumors Cause: Osseous bone tumors arise from mesodermal (connective tissue) malignant cells that produce bone or osteoid (Klein and Siegal, 2006).

Localization: Osteosarcomas typically occur in long bones, and presentation in the axial skeleton is uncommon and likely secondary (Mirra et al., 1989). They typically arise in the medullary cavity of growing tubular bones, but can also arise in the cortex, on the bone surface, or extraskeletally (Klein and Siegal, 2006). Disease progression: Malignant medullary tumors penetrate Haversian canals and thereby reach the periosteum. The periosteum is lifted, and its inner cambium layer produces new bone in response to being separated from bone. Unlike periosteal apposition in benign circumstances, this malignant periosteal apposition tends to be discontinuous, meaning that it may be detached from the bone surface at the middle or end of the new shell of bone (Kim et al., 2006). Effect on bone turnover and lamellar organization: Benign osseous bone tumors can form well-organized lamellar bone that is similar to normal bone (de Boer and van der Merwe, 2016). For example, osteoblastoma and osteoid osteoma produce differentiated bone matrix (Klein and Siegal, 2006). Benign tumors are also rarely osteolytic (de Boer et al., 2013b). Malignant osseous bone tumors can be osteoblastic/osteosclerotic (forming bone) or osteolytic (destroying bone) or a mixed pattern (Klein and Siegal, 2006). Malignant mesodermal cells deposit osteoid and also often chondroid and fibrous tissue, and are classified based on producing 50% or more of that tissue type. Classically, osteoblastic osteosarcoma appears as deposition of bone matrix in a “lacy” pattern into which the malignant cells are nested (Klein and Siegal, 2006). Osteosarcoma is histologically similar to fracture callus or fibrous dysplasia rather than normal bone, because cells become malignant prior to differentiation (Klein and Siegal, 2006). Chondroblastic osteosarcoma involves deposition of hyaline cartilage. Fibroblastic osteosarcoma creates spindle cells that look like atypical fibroblasts with minimal bone matrix (Klein and Siegal, 2006) in a chessboard pattern (Adler, 2000). Dry bone preserves evidence of chondroblastic or fibroblastic osteosarcoma through a secondary reaction of bone resorption, with variable bone formation (de Boer and van der Merwe, 2016). Effect on mineralization: A case study of a proximal tibia sclerotic osteosarcoma found that it was 20% more mineralized than normal bone. This would cause an increase in brittleness. The tumor did not have the advancing mineralization front seen in lamellar bone, but began with random mineral clusters similar to those seen in woven bone (Hofstaetter et al., 2013). Effect on osteocyte lacunae: Osseous bone tumors tend to form small and sometimes empty osteocyte lacunae (Adler, 2000). Osteocyte lacunae have been characterized as less numerous even in benign cases (Vyhna´nek et al., 1999; Eshed et al., 2002). A mineralized tumor

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matrix in a sclerotic (bone-forming) osteosarcoma was found to have no osteocyte lacunar canalicular network, even though this network is dense in woven bone (Hofstaetter et al., 2013). In osteosarcomas that are only sclerosing, excess bone matrix formation may cause tumor cells to become compressed and incorporated into the matrix, resembling osteocytes and making diagnosis difficult in a small biopsy. This “normalization” was first described by Jaffe (1960). Tumor cells with their enlarged size are more evident near the advancing edge of the tumor (Klein and Siegal, 2006). Effect on vascular porosity: It is possible for benign osteomas (e.g., osteoma eburneum) to produce mineralized, mature bone with Haversian systems, including empty Haversian canals, concentric lamellae, and osteocyte lacunae. However, these lack reversal lines (Adler, 2000). Eshed et al. (2002) also note poor vascularization in their extensive study of benign button lesions, in contrast to highly vascularized “ballooned” osteomas that form in response to trauma. Woven bone formed by malignant osteosarcomas has similarly been observed to lack Haversian systems (Suzuki, 1987; Vyhna´nek et al., 1999). For example, a highly mineralized osteosarcoma was found to lack BSU features such as cement lines, lamellar collagen fibrils, and osteocyte lacunae (Hofstaetter et al., 2013). Effect on bone fragility: Pathologic fractures can occur spontaneously or with minor trauma (Jaffe et al., 1987). Most fractures occur through the tumor (Haynes et al., 2017). However, pathologic fracture is a fairly uncommon complication of osteosarcoma (5%
10%) (Jaffe et al., 1987). Histological case studies in paleopathology: Histology has particular value in distinguishing between benign and malignant osseous bone tumors (de Boer et al., 2013b). Benign tumors growing without invasive or osteolytic activity have been observed in archeological dry bone (e.g., Strouhal et al., 1996; Strouhal et al., 1997; Strouhal and Nˇemeˇckova´, 2004; Herschkovitz et al., 1999; Vyhna´nek et al., 1999; Eshed et al., 2002). Osteolytic cavities (Schultz, 1991) and the irregular lamellar organization characteristic of malignant osteoblastic osteosarcoma are also preserved in archeological contexts (e.g., Suzuki, 1987 Strouhal et al., 1996; Strouhal et al., 1997; de Boer and van der Merwe, 2016).

Imbalances of Bone Remodeling: Paget’s Disease of Bone (PDB) Cause: Paget’s disease of bone (PDB) is a noninflammatory metabolic disorder characterized by accelerated osteoclastic resorption and compensating osteoblastic formation of disorganized woven bone (Valenzuela and

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Pietschmann, 2017). This causes bones to thicken and elongate (Meunier et al., 1980). The cause of PDB is unknown, but may be initiated by a virus (Singer, 1999). Localization: PDB rarely presents before age 55 and is more common in males (van Staa et al., 2002). It is the second most common metabolic bone disorder after osteoporosis (Ringe et al., 1984). PDB can present in a single bone (monostotic) or multiple bones (polyostotic) (Langston and Ralston, 2004). The axial skeleton is a common site of lesions (Valenzuela and Pietschmann, 2017), presenting frequently in the pelvis (70%), lumbar spine (53%), and skull (32%). The femur (55%) and tibia (32%) are also common sites (Kanis, 1992). The lumbar spine is a more common site than the cervical spine due to the tallness of the vertebral body. However, there are no significant differences in morphology between its presentation in the spine and the iliac crest (Pestka et al., 2012). Preference for dominant limbs (Kanis, 1992) and initiation at muscle insertion sites (Solomon, 1979) suggests that increased mechanical loading may help target presentation (Langston and Ralston, 2004). Disease progression: A family history of susceptibility occurs in 4% (Eekhoff et al., 2004) to 50% Morales-Piga et al., 1995) of cases, displaying autosomal dominance but incomplete penetrance in heritability (Morissette et al., 2006). Its highest rates are in Britain and countries with its migrants, being nearly absent in Africa (Cooper et al., 2006; Saraux et al., 2007). It is also rare in Asia and Scandinavian countries (Vallet and Ralston, 2016). Archeological studies suggest that susceptibility originated in England and spread via migration (Mays, 2010). Susceptibility is increased by mutations in the osteoclastic RANKL-NF-kappaB signaling pathway including SQSTM1, which is related to osteoclast autophagy, VCP, which regulates I-kappaB proteasomal degradation, TNFRSF11A, which encodes RANKL, and TNFRSF11B, which encodes OPG (Lucas et al., 2006). Effect on bone turnover and lamellar organization: The estimated resorption rate is increased sevenfold in transiliac bone (Meunier et al., 1980). Osteoclasts are larger, more numerous, and have more nuclei per cell (Hosking, 1981; Meunier et al., 1980), commonly displaying more than 12 nuclei per cell at the trabecular bone surface (Seitz et al., 2009). They have nuclear inclusions that may be paramyxoviruses or proteins that aggregate due to defects in autophagy (Hocking et al., 2010). Osteoclasts also have increased expression of factors related to activation and formation and increased resorbing capacity (Hoyland and Sharpe, 1994; Hoyland et al., 1994; Teramachi et al., 2014). Osteoblast numbers increase 10-fold in the iliac crest, although they display normal morphology (Seitz et al., 2009). There is a fivefold increase in both osteoclast and osteoblast number in the vertebrae (Pestka et al., 2012).

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“Chaotic” woven bone formation is consequently increased (Vallet and Ralston, 2016), creating a patchwork of lamellar bone and woven bone (Meunier et al., 1980). This woven bone has random collagen fiber orientation (Seitz et al., 2009). There are few complete osteons, but instead what Meunier et al. (1980) describes as “small patches, having scalloped contours and interlocked together by polycyclic cement lines.” In the cancellous bone of the iliac crest, an over twofold increase in BV can be attributed to increased trabecular number and decreased separation, with no change in trabecular thickness (Seitz et al., 2009). Similar results are seen in the vertebrae (Pestka et al., 2012). The accelerated synthesis also creates excess osteoid (Meunier, 1975), which was observed to cover B50% of the trabecular bone surface with fibrotic tissue compared to none in healthy patients (Seitz et al., 2009). However, this unmineralized osteoid is rarely preserved in archeological dry bone (Stout, 1978), even in cases of PDB (e.g., Aaron et al., 1992). Effect on mineralization: Pagetic woven bone has an increased calcification rate. However, the accelerated bone turnover rate leaves many patches unmineralized before resorption begins again (Meunier et al., 1980). This creates localized osteomalacia even in regions with a high bone formation rate (Williams et al., 1981). Effect on osteocyte lacunae: Osteocyte lacunae are significantly larger in regions of woven bone compared to regions of lamellar bone in the same patient. However, this is a characteristic of woven bone and is not specific to PDB (Meunier et al., 1980). Effect on vascular porosity: Enlarged osteoclasts form deep resorption lacunae in a “swallowtail pattern.” This is also seen at the periphery of a Paget sarcoma (Seitz et al., 2009). Resorption fronts extend irregularly in multiple directions and are unusually deep (Chappard et al., 1984). This increases vascularity (Vallet and Ralston, 2016) and creates channels with “complex scaffolding” (Chappard et al., 1984). Effect on bone fragility: Pagetic woven bone is mechanically weak (Vallet and Ralston, 2016). In a cohort of UK patients, the most common symptoms of PDB were bone pain (73.8%), bone deformity (18.1%), deafness (7.9%), and pathological fracture (5.7%), with no symptoms in 22% of patients (Tan and Ralston, 2014). Due to the mild early presentation of PDB, a cohort study of a Minnesota population found that a diagnosis did not significantly increase the risk of fracture compared to the general population. However, patients with PDB experienced fractures through their pagetic bone in 14% of all fracture cases, while only 2% of all fractures in the general population could be classified as pathological (Melton et al., 2000). Histological case studies in paleopathology: Other pathologies inducing rapid bone turnover may mimic

PDB’s first phase of osteoclastic resorption and the second phase of mixed osteoclastic and osteoblastic activity. However, the third phase forms the characteristic “pagetic” woven bone that can be discerned even in poorly preserved archeological remains (de Boer et al., 2013b; de Boer and van der Merwe, 2016). Several paleopathological case studies of suspected PDB note that resorption cavities and vascular canals are more prevalent and irregular, osteocyte lacunae are enlarged and misshapen, and pagetic woven bone, characterized by erratic cement lines, forms a mosaic with organized lamellar bone (Bell and Jones, 1991; Aaron et al., 1992; Mays and Turner-Walker, 1999; Roches et al., 2002).

Imbalances of Bone Remodeling: Osteopetrosis Cause: Osteopetrosis, also called “marble bone disease,” results from mature but nonresorbing osteoclasts combined with normal bone formation. The lack of resorption produces dense, brittle bone (Helfrich et al., 1991). A number of genetic defects inhibit osteoclast differentiation and/or resorption, and can be diagnosed in 70% of cases. Most are related to osteoclast control of pH inside and outside the cell, which is related to resorption (reviewed in Del Fattore et al., 2008). ARO (autosomal recessive) (also called malignant, infantile, or congenital) is the most severe type of osteopetrosis, with some intermediate forms (IRO). ADO (also called Albers
Scho¨nberg disease) is milder and more frequent in adults (Del Fattore et al., 2008). ARO occurs in the first few months of infancy, while ADO presents in late childhood or adolescence (Stark and Savarirayan, 2009). X-linked cases (XLO) are also possible (Del Fattore et al., 2008). Disease progression: In infantile osteopetrosis (ARO), the calcified cartilage formed during endochondral ossification is not resorbed. The metaphysis and then the diaphysis becomes filled with calcified cartilage, obliterating the marrow cavity in the most severe cases. These calcified cartilage cores are surrounded by woven or lamellar bone. Primary trabeculae are thickened and densely packed, retaining their cartilage core (Helfrich et al., 1991). Externally, metaphyses are widened and abnormally shaped, and diaphyses have a thickened cortex, due to lack of resorption (Shapiro et al., 1980). This produces funnel-shaped metaphysis, also called an Erlenmeyer flask deformity (Stark and Savarirayan,2009). Due to this impairment of longitudinal bone growth, individuals have short stature, as well as characteristic macrocephaly and frontal bossing of the skull (Stark and Savarirayan, 2009). When X-rayed, bones have a “bone in bone” appearance, with dense cores, less dense bone, and then a dense periphery (Del Fattore et al., 2008). Adult-onset

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osteopetrosis (ADO), when X-rayed, displays “sandwich vertebrae” with dense bands parallel to vertebral end plates. This is also called “rugger jersey spine” (Stark and Savarirayan, 2009). Effect on bone turnover and lamellar organization: The most common form of osteopetrosis is “osteoclastrich,” where osteoclasts are either normal or increased in number but are unable to form the ruffled border required for resorption of the bone matrix (Del Fattore et al., 2008). A case of ARO had five times the normal number of osteoclasts (Helfrich et al., 1991). In ARO, osteoclasts are huge, with as many as 80 nuclei, but they lack clear zones and ruffled borders (Shapiro et al., 1981). ADO type I was previously observed to have few, small osteoclasts (Semba et al., 2000), but this has now been reclassified as an osteoblast gain of function, not osteopetrosis (Del Fattore et al., 2008). ADO type II has large, numerous osteoclasts (Semba et al., 2000), and can range from asymptomatic to (rarely) fatal (Del Fattore et al., 2008). Osteopetrosis can also be “osteoclast-poor,” having few or no osteoclasts (Helfrich et al., 1991; Flanagan et al., 2002). This presentation is likely related to osteoclastogenesis signaling, as mutations in RANKL were observed in a subset of such patients (Sobacchi et al., 2007). The bone formation rate is generally normal, but bone is thickened because it is not resorbed and because fractures and subperiosteal hemorrhage trigger additional bone formation (Shapiro et al., 1980). However, several ARO patients with osteopetrosis were observed to have extremely low counts of osteoblasts, bone-lining cells, and stromal cells, as well as reduced bone formation, compared to controls (Helfrich et al., 1991). Impairment of normal cross-talk between osteoclasts and osteoblasts may contribute to osteoblasts forming increased amounts of low-quality bone (Del Fattore et al., 2008). Osteopetrotic bone contains thicker and more prominent cement lines (Shapiro et al., 1980; Semba et al., 2000) with a highly mineralized amorphous layer on bone surfaces and at cement lines (Helfrich et al., 1991; Semba et al., 2000). This layer is composed of osteoblastic products (e.g., osteocalcin) as well as degraded collagen fibers (Semba et al., 2000). These cement lines predispose the bone to frequent fractures due to discontinuity of the bone matrix (Semba et al., 2000). Effect on mineralization: Rickets is a common complication of osteopetrosis (osteopetrorickets) despite the highly mineralized bone that characterizes this pathology. Due to lack of resorption by osteoclasts, serum calciumphosphorus cannot mineralize newly forming osteoid. This is known as the “paradox of plenty” (Kaplan et al., 1993). Effect on osteocyte lacunae: Osteopetrotic osteocytes appeared small and discoid in a case study, compared to osteocytes in osteopenic bone. Smaller osteocytes have

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higher mechanosensitivity, which may contribute to osteoclast inhibition in this pathology. Additionally, osteocyte lacunae were less aligned to the principal direction of loading compared to lacunae observed in osteopenic and osteoarthritic bone. Osteopetrotic bone has a limited range of deformation in response to mechanical loading, which may inhibit osteocyte lacunar alignment with this loading (van Hove et al., 2009). Effect on vascular porosity: In congenital osteopetrosis (ARO), there is no organized Haversian system in lamellar bone. The occlusion of the medullary cavity prevents differentiation between cortical and medullary regions (Kuo and Davis, 1981). In adult-onset osteopetrosis (ADO type II), there is a sparse Haversian system in lamellar bone (Semba et al., 2000). Effect on bone fragility: Osteopetrotic bone is at high risk of low-trauma fracture (Del Fattore et al., 2008). The dense, brittle bone is especially vulnerable to transverse fracture (Kuo and Davis, 1981). Osteomyelitis is a complication occurring most frequently in the mandible (Semba et al., 2000). This bone infection is compounded by low white blood cell counts due to marrow occlusion (Del Fattore et al., 2008). Most infants with ARO die in the first year from infection or bleeding (Shapiro et al., 1980). Histological case studies in paleopathology: Reports of congenital and adult-onset osteopetrosis are rare in archeological contexts. Waldron et al. (1989) assesses osteopetrosis radiologically in an 18th-century English family, finding cases in two neonates (both approximately 15 days old), a 2.5-year-old boy, and two children under 3 years old. Osteopetrosis is also noted in a Nubian child’s mandible (Nielsen and Alexandersen, 1971). Favia et al. (2010) reports a Neolithic Italian case of osteopetrosis in an adult, which presents histologically with few Haversian canals, no resorptive bays or osteocyte lacunae, and maximal mineralization in the centers of osteons and trabeculae.

Disorders of Bone Mineral Homeostasis: Rickets/Osteomalacia Cause: Rickets (childhood) and osteomalacia (adulthood) result in poor bone mineralization due to reduced availability of serum calcium, phosphate, or alkaline phosphatase (Unnanuntana et al., 2011). Localization: Costochondral junctions, knees, and wrists are rapidly growing regions that show early evidence of rickets (Perez-Rossello et al., 2012). Disease progression: The primary cause is vitamin D deficiency from inadequate intake and/or absorption, resistance, impaired synthesis, or increased degradation of vitamin D. Vitamin D is essential for normal bone

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mineralization. After conversion to a biologically active form in the liver, vitamin D (1α,25-dihydroxyvitamin D or 1,25(OH)2D) increases the efficiency of calcium absorption (from 10%
15% to 30%
40%) and phosphate absorption (from 60% to 80%) in the small intestine (Holick, 2007). Vitamin D also induces osteoblasts to express alkaline phosphatase, osteocalcin (for osteoclast activity), and RANKL (for osteoclastogenesis). This resorption allows vitamin D to recruit calcium and phosphate from the skeleton (Khosla, 2001). This pathology can also be inherited via X-linked hypophosphatemia, which causes renal wasting (Unnanuntana et al., 2011). Effect on bone turnover and lamellar organization: In cases caused by vitamin D deficiency, osteoblast activity is normal, so osteoid is deposited. However, since it is not mineralized, it cannot be removed by osteoclasts. This creates a thickened cortex lacking remodeling activity and covered by an osteoid seam (Oppenheimer and Snodgrass, 1980). This excess osteoid due to decreased mineralization rate is called hyperosteoidosis. The interface between osteoid and mineralized bone is smooth (Teitelbaum, 1980). Unmineralized osteoid covers about 15% of bone surfaces in normal bone, but thick osteoid seams cover almost all bone surfaces (McCarthy, 2016), including Haversian and endosteal surfaces (Teitelbaum, 1980). Trabeculae have mineralized bone centrally but are covered with unmineralized osteoid (Unnanuntana et al., 2011). In X-linked hypophosphatemia, this osteosclerosis broadens trabeculae with wide osteoid seams that resist osteoclast resorption (Teitelbaum, 1980). Effect on mineralization: The decline in serum calcium resulting from inadequate vitamin D intake is sensed by the parathyroid gland, increasing PTH secretion and causing secondary hyperparathyroidism. PTH elevates serum calcium by increasing calcium resorption and stimulating vitamin D production in the kidneys. PTH also interacts with vitamin D to increase osteoblast expression of RANKL, ultimately releasing calcium from the skeleton through osteoclastic resorption. Serum calcium levels are thus usually normal. However, PTH also decreases kidney reabsorption of phosphorus, so it is lost in the urine. Consequently, there is not enough calcium-phosphate product to properly mineralize the skeleton (Holick, 2006). Effect on osteocyte lacunae: In rickets/osteomalacia, lacunae are enlarged (Recklinghausen, 1910), likely resulting from osteocytic osteolysis to reclaim calcium from the skeleton (Dallas et al., 2013). In the related X-linked hypophosphatemia, hypomineralized zones (halo defects) appear around osteocyte lacunae in newly formed osteocytes, although this disappears with aging (Teitelbaum, 1980). Effect on bone fragility: Rickets creates undermineralized bones with thin cortices, coarse trabeculae, and

widened metaphyses. Growing children can experience stunting, bone bowing, and fracture (Perez-Rossello et al., 2012). A study of infants and toddlers with radiographically diagnosed nutritional rickets found that 17.5% experienced long bone, rib, and metaphyseal fractures. These fractures appeared in older, mobile individuals (Chapman et al., 2010). Agarwal et al. (2009) similarly found fractures in 8% of toddlers with nutritional rickets. Osteomalacia can contribute to osteopenia in adults, particularly in elderly individuals who are already at risk due to age. Weight-bearing bones, such as the pelvis, may experience insufficiency fractures (McCarthy, 2016). Histological case studies in paleopathology: Although the osteoid seams are not well retained in dry bone (e.g., Schamall et al., 2003), unusual voids in remodeled regions can signify that this unmineralized tissue was present during life. Schamall and colleagues (2003) take a multimethod approach to the analysis of a collection of 19th-century lumbar vertebrae associated with rickets or osteomalacia. They use backscattered electron scanning electron microscopy (BSE-SEM) to visualize unfilled, resorbed regions of trabeculae and enlarged osteocyte lacunae. The secondary electron mode of SEM facilitates detection of undermineralized osteoid, which appears more translucent, surrounding trabecular centers. Light microscopy of demineralized, Goldner-stained thin sections indicates small amounts of osteoid remaining around trabeculae and at vertebral cartilaginous endplates. Changes in trabecular architecture detected with quantitative computed tomography indicate increased trabecular resorption. Brickley and colleagues (2007) also apply BSE-SEM to suspected 18th- and 19th-century cases of residual juvenile rickets and osteomalacia. They similarly detect large resorption cavities, enlarged osteocyte lacunae, and more translucent tissue regions of low mineralization. They also describe “defective cement lines” that create empty rings around osteons, separating their central lamellae from the surrounding interstitial bone (Brickley et al., 2007). This ring defect is visible both in clinical fresh bone and archaeological dry bone (Brickley et al., 2007; de Boer and van der Merwe, 2016). These histological indicators are confirmed by van der Mewre and colleagues (2018) in their study of four cases of osteomalacia around the turn of the 20th century. BSESEM detects defective cement lines, large resorption areas, enlarged osteocyte lacunae, and layers or islands of poorly mineralized bone adjacent to secondary osteons, Haversian canals, and osteocyte lacunae. The authors show that light microscopy of ground sections can detect these same features, with mineralization defects highlighted by a hematoxylin stain. These histological changes are more prevalent in ribs and vertebrae, which have higher rates of bone turnover, compared to femora.

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Disorders of Bone Mineral Homeostasis: Hyperparathyroidism Cause: In hyperparathyroidism, parathyroid gland secretion of PTH is increased, promoting osteoclastic resorption (Unnanuntana et al., 2011). Hyperparathyroidism has the highest incidence in postmenopausal women. In primary hyperparathyroidism (PHPT), PTH secretion increases due to parathyroid gland overactivity. Between 75% and 85% of patients have adenomas on a single parathyroid gland. In secondary hyperparathyroidism, PTH secretion increases in response to low calcium, as in vitamin D deficiency, chronic kidney disease, and liver failure. After extended secondary hyperparathyroidism, PTH secretion can no longer be suppressed by increasing calcium or vitamin D levels, a condition classified as tertiary hyperparathyroidism (Fraser, 2009). Localization: Weight bearing is protective against osteoclastic resorption. Subperiosteal resorption is common in the digits of the hands and feet (Unnanuntana et al., 2011), and resorption of phalangeal margins is the first radiological sign (McCarthy, 2016). In the radius, but not the tibia, cortical area and thickness are reduced, while trabeculae decrease in number and width and increase in spacing (Hansen et al., 2010; Stein et al., 1999; Vu et al., 2013). Disease progression: PTH signals through the PTH1R receptor to increase RANKL expression in osteocytes and decrease OPG expression in osteoblasts and osteocytes. Elevating the RANKL:OPG ratio favors osteoclastogenesis, leading to bone resorption (Bellido and Gallant, 2014). Effect on bone turnover and lamellar organization: Osteoclastic bone resorption manifests as significantly increased cortical porosity and extensive trabecularization of the cortex (Christiansen et al., 1993; van Doorn et al., 1993; Hansen et al., 2010; Vu et al., 2013). Osteoclasts first increase their number of resorption pits and then tunnel into the middle of trabeculae. As the disease progresses, a fibrous matrix containing woven bone forms in an attempt to compensate (peritrabecular fibrosis) (McCarthy, 2016). In severe PHPT, dysregulation of cellular resorption and repair cumulates in a giant cell reparative granuloma. These cysts are lined with osteoclasts and surrounded by fibrous tissue and woven bone. They are also called “brown tumors” because they tend to cluster around red blood cells and incorporate their brown hemosiderin waste products (Carlson, 2010; McCarthy, 2016). Brown tumors preferentially occur in craniofacial bones (especially mandible or maxilla), but are also seen in the rib and pelvis (Carlson, 2010). Dry bone preserves evidence of tunneling or “dissecting resorption” in the trabecular and subperiosteal regions. However, it does not retain compensatory soft-tissue production, such as

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fibrotic bone marrow or osteoid deposition (de Boer and van der Merwe, 2016). Robling and Stout (2003) also note that hyperparathyroidism increases activation frequency, increasing the number of osteons and active BMUs. Effect on mineralization: Due to excessive bone resorption, hypercalcemia is a symptom, and typically is how the disease is first detected in an individual (Bilezikian and Potts, 2002). Effect on osteocyte lacunae: In hyperparathyroidism, excessive PTH secretion stimulates osteocytic osteolysis in humans, just as in animals. Bonucci et al.’s (1978) iliac crest biopsy of a patient with PHPT shows enlarged, irregularly shaped lacunae and enlarged canaliculi. Lacunae sometimes seem to be coalescing. Electron microscopy shows that the irregular lacunar shape is caused by granular, filamentous, amorphous material, and sometimes calcified collagen fibrils filling the pericellular membrane. This debris is evidence of osteocytic osteolysis. Crystals also protrude irregularly from the bone matrix into the lacunar border. Moreover, the osteocytes themselves are irregularly shaped, with cytoplasmic processes that protrude into their peripheral membrane. Osteocytes also appear more frequently than controls, and are concentrated near sites of osteoclastic resorption. Osteocyte-like cells are additionally found in uncalcified osteoid and in irregular lacunae in incompletely calcified regions (Bonucci et al., 1978). Large, irregular lacunae are also reported by Meunier et al. (1971). Similarly, Fadda et al. (1990) used scanning electron microcopy to observe wide lacunae, small canaliculi, and irregular “calcospherites” in patients with PHPT. Increased lacunar size is seen in patients with renal osteodystrophy associated with secondary hyperparathyroidism (Bonucci and Gherardi, 1977; Bonucci et al., 1976). Effect on vascular porosity: Transiliac biopsy shows that women with PHPT have 30% more cortical porosity (Christiansen et al., 1993; van Doorn et al., 1993), more osteoclasts, and more Howship’s lacunae than controls (Bonucci et al., 1978). A 19% increase in porosity was similarly observed in the radius (Hansen et al., 2010). Significant increases in cortical porosity also occur in compact and transitional regions in the distal tibia (Vu et al., 2013). Scanning electron microscopy shows an endosteal surface with especially high bone turnover, creating deep Howship’s lacunae and leaving residual trabeculae (Fadda et al., 1990). Trabecularization of the cortex due to increased cortical porosity creates the impression that trabecular bone is increasing, to the degree that PHPT is often incorrectly assumed to be preserving trabecular bone (Vu et al., 2013). In fact, HR-pQCT studies have demonstrated reduced trabecular number, increased trabecular spacing, and thinner trabeculae in the radius (Hansen et al., 2010; Stein et al., 2013; Vu et al., 2013).

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In hyperparathyroidism associated with chronic renal failure, Meema and Oreopoulos (1983) observed that subperiosteal resorption of the phalanges is not due to osteoclastic activity on the periosteum, but rather enlargement of resorption spaces forming adjacent to the periosteum. This creates a “lace-like” serration of periosteal bone. Scanning electron microscopy shows large, deep, irregularly connected canals furrowing the periosteal surface (Fadda et al., 1990). Effect on bone fragility: Due to excessive bone resorption, hyperparathyroidism can lead to osteopenia (Unnanuntana et al., 2011). Fractures of the long bones, clavicles, pelvis, and ribs are common (Mankin, 1995). Histological case studies in paleopathology: Hyperparathyroidism is rarely reported in archeological contexts, potentially because it is conflated with other metabolic disorders that cause demineralization. Tunneling resorption, especially of the cortex, can help distinguish hyperparathyroidism from other pathologies (Mays et al., 2001, 2007). For example, an early Neolithic skeleton from Germany supports radiological evidence of PHPT with histological demonstration of tunneling resorption, including bite-like defects of vertebral trabeculae and enlarged Haversian canals (Zink et al., 2005). A Roman Period Egyptian skeleton similarly shows evidence of PHPT through tunneling resorption observed in the trabeculae and subperiosteal cortical bone of the midshaft femur. This trabecular resorption produces a low trabecular BV and high surface/volume ratio, and compensatory production of fibrous lamellae (Cook et al., 1988). A 15th
19th-century English skeleton has been diagnosed radiologically with PHPT, but also displays tunneling resorption in the femoral cortex, producing high porosity (Mays et al., 2001). The dietary calcium deficiency common in some past populations may trigger secondary hyperparathyroidism (Robling and Stout, 2003). For example, Weinstein and colleagues (1981) note “trabecular atrophy” in a transilial bone core of a Peruvian mummy, signified by decreased trabecular BV, surface density, and mean trabecular diameter. They attribute this suspected secondary hyperparathyroidism to the high phosphorus and low calcium content of a corn-heavy diet. Foldes and colleagues (1995) suggest secondary hyperparathyroidism as the source of osteopenia in a premenopausal female from the Negev Desert. This diagnosis is supported by extensive erosion on endosteal, periosteal, and trabecular bone surfaces of the iliac crest. This resorption produced extremely low trabecular BV and a thin, highly porous cortex. Mays and colleagues (2007) observe secondary hyperparathyroidism in a 19th-century English child as a complication of the calcium deficiency associated with rickets. Scanning electron microscopy reveals trabecular bite-like defects and internal tunneling, while Haversian canals are enlarged in cortical bone.

More translucent (darker) regions signify compensatory formation of less mineralized new bone, demarcated by cement lines. Renal disease can also cause secondary hyperparathyroidism, resulting in the mild osteoporosis observed in an Andean mummy, although this case study did not identify cortical tunneling (Blackman et al., 1991).

Disorders of Bone Mineral Homeostasis: Hyperthyroidism Cause: Hyperthyroidism or thyrotoxicosis involves net bone loss due to either the excessive secretion of thyroid hormones (overt hyperthyroidism) or low levels of thyroid stimulating hormone (TSH, subclinical hyperthyroidism) (Zaidi et al., 2009b). Both overt and subclinical hyperthyroidism can endogenously result from Grave’s disease or a toxic thyroid nodule or multinodular goiter. Thyroid hormone treatment can also exogenously cause subclinical hyperthyroidism (Greenspan and Greenspan, 1999). Disease progression: Both overt and subclinical hyperthyroidism increase osteoclast and osteoblast activity. Hyperthyroidism causes high serum levels of TNF-α and IL-6, which promote osteoclastogenesis through RANK-L (Lakatos et al., 1997). Thyroid hormone (T3) also directly stimulates osteoblasts to release IL-6, IL-8, PGE2, and RANK-L to induce osteoclastogenesis. At the same time, thyroid hormone promotes the osteoblast lifecycle from proliferation to differentiation and eventually apoptosis. It induces IGF-I for osteoblastogenesis and increases synthesis of osteoblast products such as osteocalcin, type I collagen, and alkaline phosphatase. Thyroid hormone may also promote osteoblast apoptosis by targeting FGFR1 (reviewed in Bassett and Williams, 2003 and Zaidi et al., 2009b). In subclinical hyperthyroidism, thyroid hormone levels are normal but TSH levels are low. TSH normally suppresses osteoclastogenesis through attenuating RANKL and TNF-α (Zaidi et al., 2006). When TSH levels are low, these pathways can promote more osteoclastogenesis. TSH may also normally suppress LRP5 and VEGF, which promote osteoblastogenesis (reviewed in Zaidi et al., 2009a). Effect on bone turnover and lamellar organization: In active thyrotoxicosis, remodeling frequency is increased, including bone resorption and formation. However, bone resorption largely retains its normal 50-day duration, while the normal 150-day span of bone formation is reduced by two-thirds (Bassett and Williams, 2003). The remodeling cycle is reduced by B50% from its normal 200 days, shortening the time for matrix deposition and mineralization. As the pace of bone formation lags behind bone resorption, a net 10% of mineralized bone is lost per remodeling cycle (Harvey et al., 2002). The reverse

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process occurs in hypothyroidism, but changes in bone mass are small because activation frequency is reduced (Mosekilde et al., 1990). Effect on mineralization: Net bone resorption elevates serum levels of calcium and phosphorus. Marked hypercalcemia is present in up to 5% of patients, while mild hypercalcemia occurs in up to 20% of patients (Harvey et al., 2002). PTH is suppressed, resulting in reduced renal conversion of vitamin D to its metabolically active form. Calcium is lost through decreased intestinal absorption and increased clearance in the urine and feces. Hypercalcemia thereby induces a significant negative calcium balance (Harvey et al., 2002; Bassett and Williams, 2003). BMD reductions are seen in the lumbar spine (12%
15%), hip (13%
17%), forearm (15%
20%), and calcaneus (25%) (Harvey et al., 2002). In postmenopausal females, active thyrotoxicosis corresponds to a 12%
15% reduction in BMD, primarily due to changes in cortical bone (Bassett and Williams, 2003). Effect on osteocyte lacunae: An absence of osteocytic osteolysis was noted in hyperthyroidism (Mosekilde and Melsen, 1978), which suppresses PTH levels by releasing calcium from bone (Harvey et al., 2002). Effect on vascular porosity: Hyperthyroidism results in net bone loss because activation frequency is increased, but the duration of bone formation is attenuated (Bassett and Williams, 2003). Increased cortical porosity compared to controls is observed in the iliac crest (Mosekilde et al., 1976, 1977; Mosekilde and Melsen, 1978). Mosekilde and Melsen (1978) observed that hyperthyroidism induced osteoclastic resorption primarily in cortical bone, while hyperparathyroidism stimulated osteoclastic resorption equally in trabecular and cortical bone. Effect on bone fragility: Long term, there is a two- to threefold increase in hip fracture risk, primarily postmenopause (Wejda et al., 1995; Bassett and Williams, 2003). Postmenopausal declines in TSH correspond to a threefold increase in hip fracture risk and a fourfold rise in vertebral fracture risk (Bauer et al., 2001). There is also an increased risk of any fracture 5 years after diagnosis of hyperthyroidism and 10 years after a diagnosis of hypothyroidism (Vestergaard, 2007). Histological case studies in paleopathology: Unlike hyperparathyroidism, hyperthyroidism cannot be confidently histologically distinguished from other endocrinerelated or metabolic causes of secondary osteoporosis (Schultz, 2003a; Ortner, 2003; Waldron, 2009). However, secondary osteoporosis derived from hyperthyroidism may manifest focally in unusual locations, such as the frontal bone of the skull, cervical vertebrae, ribs, pelvis, hands, and feet (Waldron, 2009; Lewis, 2017). Hypothyroidism has been more commonly reported in archeological contexts, as onset early in fetal or postnatal development can cause significant macroscopic changes.

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Delayed epiphyseal fusion reduces stature, even leading to severe dwarfism, and can also induce secondary osteoarthritis, particularly in the hip. Abnormal development of the skull, vertebrae, and ribs may also be observed. Endemic hypothyroidism results from a dietary deficiency of iodine, which is required for thyroid hormones, while sporadic hypothyroidism is caused by damage to the thyroid gland from genetic, infectious, or cancerous sources (Ortner and Hotz, 2005).

Disorders of Bone Mineral Homeostasis: Diabetes mellitus Cause: Type 1 diabetes mellitus (T1DM) involves the autoimmune destruction of beta cells (β-cells) of the pancreas, resulting in absolute insulin secretion deficiency. Type 2 diabetes mellitus (T2DM) refers to resistance to insulin action and inadequate secretion of insulin to compensate (American Diabetes, 2014). Diabetes mellitus is the most common chronic metabolic disease, affecting 8.5% of adults over 18 years of age (World Health Organization, 2016). Uncontrolled diabetes mellitus creates an inflammatory response that reduces wound healing, increases bone resorption, and decreases bone formation (Jiao et al., 2015). Disease progression: Uncontrolled diabetics have a delayed inflammatory response. Their NF-κB signaling cascade is downregulated, reducing expression of genes needed for inflammatory and mesenchymal cells to migrate and function. The activation of T-cells, leukocytes, lymphocytes, and mononuclear cells is delayed, but their response is also increased (reviewed in Retzepi et al., 2018). T1DM significantly increases proinflammatory cytokine expression in rats (Lee et al., 2017). T2DM patients similarly express significantly increased levels of the proinflammatory mediator TNF-α following bone fracture, along with other proinflammatory cytokines and chemokines (Sun et al., 2016). Increased and prolonged inflammation increases osteoclastogenesis in both T1DM and T2DM (reviewed in Jiao et al., 2015). T1DM elevates IL-17 and IL-23 (Silva et al., 2012), while T2DM significantly increases TNF-α, IL-1β, and IL-6 (Duarte et al., 2007; Bastos et al., 2012). These factors increase RANKL/OPG and TNF levels in diabetics, promoting bone resorption (Pacios et al., 2012; Bastos et al., 2012; Mahamed et al., 2005; Santos et al., 2010). High fatty acid levels will also induce osteoclastogenesis when mediated by TNF-α, and will enhance RANKL-stimulated osteoclastogenesis (DrosatosTampakaki et al., 2014). T2DM also increases osteoclast apoptosis, inhibiting the coupled transition from bone resorption to bone formation (Pacios et al., 2013). However, the relationship of T2DM to osteoclast activity

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may be more complicated, given that bone resorption has been found to both decrease (El Miedany et al., 1999; Erbagci et al., 2002) and increase (Isaia et al., 1999; Krakauer et al., 1995). T1DM may suppress factors associated with osteoblast proliferation and function during early healing (reviewed in Jiao et al., 2015). Wnt/β-catenin signaling involved in osteoblastogenesis is glucose-responsive and could be misregulated by hyperglycemia (Anagnostou and Shepherd, 2008). Similarly, T1DM rat chondrocytes and osteoblasts in ossifying regions have decreased IGF-1, IGF-1 receptors, and insulin receptors (Verhaeghe et al., 1994; Maor and Karnieli, 1999). Inadequate expression of transcription factors (Cbfa1/Runx-2, Dlx5) can prevent mature osteoblast differentiation, although this is reversed by insulin in T1DM rats (Lu et al., 2003). Factors involved in ossification (BMP-4, LTBP-4, THRA, CD276) are also significantly downregulated in uncontrolled T1DM (Retzepi et al., 2018). T1DM rats also delay the expression of type II and type X collagen mRNA transcripts and produce less type X collagen (Gooch et al., 2000). Consequently, T1DM is associated with reduced levels of bone formation markers, including plasma mean IGF-1, serum alkaline phosphatase, and serum osteocalcin (Kemink et al., 2000). The histology of uncontrolled T1DM rats in early fracture healing shows impaired formation of fibrin mesh and suppressed populations of inflammatory, mesenchymal, and osteoblastic cells (Retzepi et al., 2018). T2DM also shows reduced bone formation (Krakauer et al., 1995; El Miedany et al., 1999; Sarkar and Choudhury, 2013) in response to TNF, IL-1, IL-6, and IL7 stimulating NF-κB to suppress osteoblast function (Chang et al., 2009). Both T1DM (Pacios et al., 2012; Coe et al., 2011) and T2DM (Andriankaja et al., 2012; Pacios et al., 2012) also have increased osteoblast apoptosis related to TNF-α elevation. Diabetic formation of advanced glycation end products (AGEs) also promotes osteoclastogenesis and inhibits osteoblastogenesis. These condensations of arginine, lysine, and ribose accumulate in the extracellular matrix in association with extracellular sugars (Yamamoto et al., 2008; Schwartz et al., 2009). AGEs form nonenzymatic crosslinks between collagen molecules. These crosslinks reduce collagen elasticity and are associated with mechanical metrics of bone brittleness (Ruppel et al., 2008). Some AGEs bind to the RAGE receptor on osteocytes, stimulating the release of proinflammatory cytokines that enhance osteoclast activation (Ding et al., 2006; Nyman et al., 2007). In osteoblasts, AGE binding to the RAGE receptor inhibits osteoblast differentiation (McCarthy et al., 2001; Sanguineti et al., 2008) and induces osteoblast apoptosis (Alikhani et al., 2007; McCarthy et al., 2001; Kume et al., 2005). Additionally,

AGEs promote the formation of reactive oxygen species (ROS) (Giacco and Brownlee, 2010). ROS induce RANKL expression, promoting osteoclastogenesis. ROS also create a feedback loop by increasing expression of the RAGE receptor (Ha et al., 2004). Effect on bone turnover and lamellar organization: Uncontrolled diabetes mellitus creates an inflammatory response that reduces wound healing, increases bone resorption, and decreases bone formation (Jiao et al., 2015). T1DM rats have reduced or absent bone formation on trabecular, endocortical, and periosteal surfaces (Verhaeghe et al., 1989, 1990a,b). Diabetic rat femoral necks, accordingly, have less cortical bone and an increased core of trabecular bone (Hou et al., 1991). Effect on mineralization: Brittle diabetic bones result from suppression of osteoblast activity (Verhaeghe et al., 1994). Diabetic rats have low osteocalcin in plasma (20%
28% compared to controls) but normal osteocalcin and calcium in bone in the humerus. The plasma concentration reflects synthesis by osteoblasts, which is reduced in diabetes (Verhaeghe et al., 1994). Bending stiffness is accordingly increased in diabetic rat femora and tibiae (Reddy et al., 2001; Einhorn et al., 1988). Einhorn et al.’s (1988) study on diabetic rat tibiae also suggests that mineralization is preserved in weight-bearing cortical bone at the expense of trabecular bone. Relative to nondiabetic controls, the tibial metaphyses, which contains more trabecular bone, has a decreased mineral content (percent ash), CaP ratio, and hydroxyapatite crystal size and perfection, as well as increased osteocalcin. However, the tibial diaphysis, which has a thicker cortical wall, had an increased mineral content (percent ash) relative to controls. Meta-analyses show a trend toward increased fracture risk at most skeletal sites, generally with a higher risk for T1DM compared to T2DM. However, these metaanalyses also indicate that BMD generally decreases for T1DM but increases for T2DM (Vestergaard, 2007; Janghorbani et al., 2007; Thrailkill et al., 2005). Also, osteopenia and osteoporosis are frequent complications of T1DM, but are not typically associated with T2DM (Thrailkill et al., 2005). Several explanations have been advanced for why T2DM diabetics have increased fracture risk, despite their increased BMD, compared to nondiabetic controls. First, it is possible that bone resorption actually decreases in T2DM, as some studies have found (El Miedany et al., 1999; Erbagci et al., 2002). Thrailkill et al., (2005) note that T1DM represents insulinopenia, while T2DM represents hyperinsulinemia, with normal or increased concentrations. Hyperinsulinemia may preserve bone mass in T2DM by acting as an anabolic agent. Second, the higher BMI associated with T2DM may increase BMD through mechanical loading (Vestergaard, 2007). Third, comorbidities of T2DM may increase the risk of falls, leading to fracture. These risk factors include

Histomorphology: Deciphering the Metabolic Record Chapter | 6

impaired vision, peripheral neuropathy, lack of sensation in the lower extremities, and hypoglycemia unawareness or seizures (Janghorbani et al., 2007; Thrailkill et al., 2005). Fourth, T2DM may compromise bone structure in a manner not detected by BMD. In the spine, trabecular BV is lower in T2DM, compromising trabecular bone strength despite higher BMD (Parkinson and Fazzalari, 2003; Strotmeyer et al., 2004). Effect on osteocyte lacunae: T1DM, as induced in mice, results in a 10% lower osteocyte lacunar density in cortical bone compared to normal, age-matched mice. Diabetic rats also have significantly narrowed canaliculi, including a reduced canalicular wall area and cell process area. Suppression of osteoblast differentiation may contribute to these changes in density and morphology (Lai et al., 2015). Effect on bone fragility: The risk of skeletal fracture is increased about twofold in diabetic patients (Verhaeghe et al., 1994). Fracture healing is also impaired during the callus mineralization phase (Liuni et al., 2015). For displaced closed fractures of the lower extremity, fracture healing is prolonged by 87% (Loder, 1988), with a 3.4fold higher risk of complications in fracture union (Folk et al., 1999). Histological case studies in paleopathology: Diabetes mellitus is another metabolic disorder that cannot reliably be distinguished from many other metabolic or endocrine causes of secondary osteoporosis based on bone histology alone (Schultz, 2003a). The reduced bone formation and increased bone brittleness seen in untreated diabetes mellitus are not a unique histological indicator (Dupras et al., 2010). However, when diabetes mellitus is suspected from macroscopic evidence of comorbidities, histology has the potential to provide supporting evidence. For example, Dupras and colleagues (2010) describe a possible case of diabetes mellitus from a Middle Kingdom Egyptian site. They focus on macroscopic indicators, but also note a reduction of cortical bone in the foot, suggesting osteopenia. Diabetes mellitus is not reliably predicted by a single musculoskeletal disorder (Upson-Taboas, 2016), so multiple lines of evidence are important. The prolonged inflammatory response associated with untreated diabetes mellitus can induces osteoporosis, osteoarthritis, or osteolysis (resorption) especially around the joints, such as the shoulder and the metatarsal
phalangeal joints of the feet. Dental disease, including caries, periodontal abscesses, and antemortem tooth loss, is another diabetic indicator retained in archeological dry bone. An additional complication is diffuse idiopathic skeletal hyperostosis (DISH), which refers to vertebral fusion resulting from ossification of the anterior longitudinal ligament of the spine, and other spinal and extraspinal ligaments and entheses (Dupras et al., 2010; UpsonTaboas, 2016). Biocultural indicators, such as high social

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status or access to rich foods, may provide additional evidence for diabetes mellitus as a source of DISH. Rogers and Waldron (2001) suggest that the high prevalence (11.5%) of DISH in monastic burials in 13th-, 14th-, and 16th-century England may be a consequence of obesity and resulting type II diabetes mellitus, which correlates with historical accounts of a rich diet in monasteries. Burials in an abbey court in the Netherlands ranging from the 3rd to 11th centuries displayed evidence of DISH in 40.4% of cases (Verlaan et al., 2007). Janssen and Maat (1999) find DISH in all of the clergy examined in an 11th-century sample from the Netherlands. Jankauskas (2003) calculates a slight but significant prevalence of DISH among high-status burials (27.14%) compared to average/urban (11.86%) and poor/rural (7.14%) burials in 2nd- and 3rd-century Lithuania.

Disorders of Bone Mineral Homeostasis: Glucocorticoid Excess Cause: Endogenous glucocorticoid excess can be stimulated by inflammation, a burn injury, or a tumor of the hypothalamic-pituitary-adrenal axis. A prominent example of the latter cause is Cushing’s syndrome, where a pituitary tumor causes hypersecretion of adrenocorticotropic hormone (Klein, 2015). Disease progression: Glucocorticoids can act indirectly to inhibit bone quality by secreting calcium (through decreased renal and intestinal resorption), by suppressing GH secretion, by inhibiting gonadotropin release to suppress testosterone and estrogen, and by causing PTH to increase its pulsatile burst release over its tonic release (Canalis et al., 2007). However, the main effect is through direct action of glucocorticoids on bone cells (Henneicke et al., 2011). In both humans and mice, bone mass is lost rapidly in an early phase due to increased resorption. Bone mass is then lost slowly in a later phase due to insufficient bone formation (LoCascio et al., 1990; Weinstein et al., 1998). Glucocorticoid excess initially promotes osteoclastogenesis by inhibiting OPG and increasing expression of RANKL (Hofbauer et al., 1999; Sivagurunathan et al., 2005) and M-CSF (Rubin et al., 1998). Glucocorticoids are also antiapoptotic to mature osteoclasts in mice (Weinstein et al., 2002). However, prolonged glucocorticoid excess eventually suppresses osteoclast number and function by preventing M-CSF from activating factors (RhoA, Rac, and Vav3) that organize the osteoclast cytoskeleton (Kim et al., 2006). Glucocorticoids also suppress proliferation of bone-marrow macrophages that are osteoclast precursors (Kim et al., 2006, 2007). Mice given a high glucocorticoid dose had 65% fewer osteoclasts, although apoptosis was not observed (Weinstein et al.,

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1998). Osteocyte lifespans are still prolonged, but their resorbing activity is inhibited. This reduced resorption in turn reduces osteoblast bone formation (Kim et al., 2006). Glucocorticoid excess also inhibits bone formation by suppressing osteoblastogenesis (reviewed in Klein, 2015). Signaling pathways are inhibited and antagonists are increased for Wnt (antagonized by sFRP-1, DKK-1, and axin-2) and BMP-2 (antagonized by follistatin and Dan) (Yao et al., 2008; Mak et al., 2009; Hayashi et al., 2009). Glucocorticoid excess suppresses mRNA transcripts for osteoblast differentiation (osteocalcin, alkaline phosphatase, Cbfa1, and type I collagen) and promotes expression of transcripts for adipocytic differentiation (Pereira et al., 2002; Yao et al., 2008). Glucocorticoids also create oxidative stress in bone, activating nuclear transcription factors of the forkhead box O family (FOXO). These factors bind to β-catenin, suppressing the Wnt-β catenin signaling needed for osteoblastogenesis (Iyer et al., 2013). FOXO additionally inhibits osteoclastogenesis by attenuating reactive oxygen species accumulation in mitochondria of osteoclast precursors, which is important for their differentiation (Bartell et al., 2014). Long term, the effects of glucocorticoid excess on osteoclasts appear to minimally contribute to the loss of bone mass and strength, compared to effects on osteoblasts (Henneicke et al., 2011). Specifically, rodent studies show that protecting osteoclasts from glucocorticoid signaling does partially prevent increased osteoclast lifespan and bone resorption (Rauch et al., 2010; Jia et al., 2006; Kim et al., 2006), but compromised bone formation still reduces bone strength (Rauch et al., 2010; Kim et al., 2006). However, protecting osteoblasts from glucocorticoid signaling prevents osteoblast and osteocyte apoptosis, permits osteoblast function, preserves bone formation, and maintains bone strength and quality even at supraphysiological glucocorticoid levels (Rauch et al., 2010; O’Brien et al., 2004; Weinstein et al., 2010; Henneicke et al., 2011). Protecting osteoblasts and osteocytes actually prevents pathological increases in osteoclast number and activity (Henneicke et al., 2011). Effect on bone turnover and lamellar organization: Histological studies of glucocorticoid excess reflect a decline in bone mass due to early increased resorption and later decreased formation. Trabecular bone experiences more resorption than cortical bone, initially thinning and then perforating at higher doses (Dalle Carbonare et al., 2001, 2005). Consequently, vertebral and rib fractures are common in cases of glucocorticoid excess, with only moderate increases in hip and nonvertebral fractures (van Staa et al., 2000). For example, mice receiving a high glucocorticoid dose experienced a 40% decline in vertebral cancellous bone area and a 23% reduction in trabecular width. Increased spacing and number indicated that some trabeculae were totally resorbed

(Weinstein et al., 1998). Pharmacological glucocorticoid use in humans results in up to 20% trabecular volume bone loss in the first 5
7 months and 5% per year in following years (LoCascio et al., 1990). Long-term corticosteroid treatment for osteoporosis depresses the bone formation rate in the iliac crest, according to tetracycline double labeling (Bressot et al., 1979). A high dose of glucocorticoids in mice significantly decreased the rate of bone formation (53%), producing significant declines in vertebral osteoid area, perimeter, and width (Weinstein et al., 1998). Effect on mineralization: In addition to reducing bone formation rate, glucocorticoid excess hampers mineralization. Mineral apposition in vertebral trabecular bone declined 22% in mice given a low glucocorticoid dose and 40% in mice given a high glucocorticoid dose, compared to normal controls (Weinstein et al., 1998). Effect on osteocyte lacunae: Osteonecrosis occurs in 5%
25% of patients treated long term with glucocorticoids (Mankin, 1992). The femoral head is most commonly affected, often bilaterally (Weinstein et al., 2000). Osteocytes and lining cells are commonly apoptotic in human osteonecrotic femoral head. Once the mechanosensory network is disrupted, unrepaired microdamage causes the femoral head to collapse (Weinstein et al., 2000). In mice given a high glucocorticoid dose, 28% of osteocytes in the cortical bone of the femoral metaphysis were apoptotic, although no apoptosis was observed in vertebral cancellous bone (Weinstein et al., 1998). In glucocorticoid excess in mice, enlarged lacunae indicate osteocytic osteolysis (Lane et al., 2006). Lacunar size also increases moderately in humans undergoing long-term corticosteroid treatment for osteoporosis (Bressot et al., 1979). Effect on vascular porosity: Glucocorticoid excess is characterized by early increases in bone resorption and later decreases in bone formation. In the iliac crest, patients treated with glucocorticoids have significant increases in cortical porosity and in the number and density of Haversian canals. The Haversian canal area nonsignificantly trends toward increased size. The increase in porosity is due to increased canal number, reflecting the decline in resorption activity after the early phase and subsequent impaired formation over the long term ( . 1 year) (Vedi et al., 2005). Similarly, mice given a high glucocorticoid dose present with a threefold increase in empty erosion cavities, signifying delayed bone formation (Weinstein et al., 1998). Effect on fracture risk: Fractures occur in 30%
50% of patients undergoing long-term glucocorticoid use, often in the vertebrae (typically asymptomatic) and femoral neck (Cohen et al., 1999; Wallach et al., 2000; Angeli et al., 2006). Despite similar BMD, patients with glucocorticoid-induced osteoporosis have greater fracture risk than other causes of osteoporosis (Kanis et al., 2004;

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van Staa et al., 2000, 2003; Canalis et al., 2007). This suggests that a change in bone quality in addition to reduced BMD is responsible (Henneicke et al., 2011). In normal osteoporosis, resorption merely exceeds formation, while formation is actively suppressed in glucocorticoid-induced osteoporosis (Gennari, 1994). Histological case studies in paleopathology: Glucocorticoid excess, such as Cushing’s syndrome, is another endocrine cause of secondary osteoporosis that cannot be distinguished from other endocrine and metabolic causes based only on bone histology (Schultz, 2003a). However, histology has the potential to support emerging archeological methods for the assessment of normal and pathological levels of glucocorticoids, such as cortisol. Notably, archeological hair samples can preserve cortisol levels reflecting the last few months to years of an individual’s life. These cortisol levels can show high variation between individuals, suggesting their use as a marker of differential stress in archeological contexts (Webb et al., 2011). For example, in a study of Peruvian mummies by Webb and colleagues (2015), elevated hair cortisol levels serve as a proxy of increased stress. Cortisol elevation correlates with isotopic evidence of dietary changes due to local mobility, injury, or illness. Cushing’s syndrome also produces elevated cortisol levels in the hair of modern individuals, compared to controls (Thomson et al., 2009; Manenschijn et al., 2011, 2012; Hodes et al., 2017). In an archeological application of this technique, Thomson (2008) found extremely high cortisol levels in the hair of a mummified Nubian (AD 350
550) female aged approximately 35 years. The cortisol levels are comparable to modern patients with Cushing’s syndrome. A prior histological analysis of this individual by White and Armelagos (1997) notes extensive osteopenia, supporting a diagnosis of glucocorticoid excess. They histologically identify osteopenia based on increased resorption (low percent cortical area, high frequency of resorption spaces) and increased bone turnover (few intact osteons compared to fragmentary osteons) in the femur.

Collagen Disorders: Osteogenesis Imperfecta Cause: Osteogenesis imperfecta (OI) unites eight presentations of abnormal collagen. OI types I through IV are the original characterization by Sillence and Rimoin (1978), with OI types V through VIII being more recent discoveries. In 90% of cases, autosomal dominant mutations are located in COL1A1 (pro-1 chain of type 1 collagen) or CO1A2 (pro-2 chain of type 1 collagen). OI type I is milder and involves chain exclusion, where the abnormal collagen chain is not inserted into the triple helix, leaving collagen less structurally stable. OI types II, III, and IV are more severe and involve chain nonexclusion, where the abnormal collagen is inserted and destabilizes

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the triple helix. OI types V and VI presently have unknown genetic causes. OI type VII involves an autosomal recessive mutation in CRTAP (cartilage-associated protein), while OI type VIII is an autosomal recessive mutation in LEPRE1 (prolyl-3-hydroxylase-1). These proteins are involved in an enzyme complex that modifies COL1A1 posttranslationally (reviewed in Basel and Steiner, 2009). Disease progression: OI alters bone formation both quantitatively, typically by reducing production, and qualitatively, by distorting lamellar structure with abnormal collagen. All original classifications of OI (I
IV) have abnormal osteoblasts, with their mitochondria, rough endoplasmic reticulum, and Golgi apparatus swollen with retained mutant collagen. Osteoblast numbers are reduced and osteoclast numbers are increased in type II only, which is perinatal lethal. Osteoclasts are also increased in type II but normal in types I, III, and IV (Sarathchandra et al., 2000). Effect on bone turnover and lamellar organization: OI types I through IV suppress osteoclast activity slightly less than osteoblast activity, with 11% less bone resorbed and 14% less bone formed per remodeling cycle in the iliac crest. This produces a net bone loss (Rauch et al., 2000). Iliac crest biopsies indicate that OI types I through IV have lower cancellous bone mass due to reduced production of trabeculae and absent or insufficient trabecular thickening. Cortical width and mineral apposition rate are also reduced (Rauch et al., 2000; Glorieux and Travers, 1994). Despite less bone turnover in individual remodeling cycles, activation frequency is increased 60% above controls in the mildest OI type I. This is likely due to more frequent microdamage in the poor-quality lamellar bone, triggering more frequent remodeling (Rauch et al., 2000). Wu and colleagues (1970) found that elevated activation frequency creates more osteons per year in the human rib. However, ribs with OI sustain modeling drift into adulthood, removing old osteons and artificially lowering OPD. This increased activation frequency thickens osteoid seams in OI types I, III, and IV (Rauch et al., 2000). In OI types I through IV, iliac crest biopsies indicate that cortical width and mineral apposition rate are reduced. Cancellous bone mass is also reduced due to decreased production of trabeculae and absent or insufficient trabecular thickening (Rauch et al., 2000; Glorieux and Travers, 1994). Lamellae are thin, reflecting smaller-diameter collagen fibrils (Glorieux and Travers, 1994; Rauch and Glorieux, 2004; Sarathchandra et al., 1999a,b, 2000). Lamellar organization decreases with the severity of the disease, presenting as normal (OI types I and IV), mixed with woven bone (OI type III), or with predominate woven bone in a patchwork with mineralized bone and osteoid (OI type II) (Sarathchandra et al., 2000).

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OI types V through VIII are rarer and more recent discoveries. OI type V has normal remodeling activation. Bone formation at individual sites is prolonged but with decreased production, attributed to lower osteoblast quality. This reduces cortical width and cancellous BV. Polarized light microscopy shows coarse and mesh-like lamellae with irregular organization and abrupt changes in the width of collagen fibrils. Although osteoid seams are thinner than controls, a decreased mineral apposition rate creates a higher relative osteoid surface (Glorieux et al., 2000). Endochondral ossification is delayed (Bishop, 2016). OI type VI does not significantly differ from controls in resorption. However, a decreased mineral apposition rate significantly increases osteoid thickness and relative surface. Consequently, cortical width and trabecular thickness are diminished, but trabecular numbers mirror controls (Glorieux et al., 2002; Rauch and Glorieux, 2004). Polarized light microscopy shows a fish-scale pattern and tetracyclin labels are blurred, suggesting disordered mineral deposition (Glorieux et al., 2002). Endochondral ossification is not delayed (Bishop, 2016). OI type VII has increased bone formation and resorption compared to controls, with almost a twofold increase in turnover per year. However, increased osteoblast numbers cannot compensate for decreased osteoblast performance, and mineral apposition is decreased. Subsequently, cortical width is decreased by approximately half. Trabecular number decreases but thickness is preserved, the inverse pattern seen in OI type VI. Lamellar organization is similar to OI type I (Ward et al., 2002). OI type VIII has normal markers of bone formation. Case studies show normal or increased resorption despite substantially fewer osteoclasts observed on the bone surface. Mineral lag time is not increased. Cortical width is decreased, and osteoid surface area and volume are increased, compared to controls. Paradoxically, average osteoid thickness is slightly lower than controls. This is due to a unique pattern of “scattered focal osteoid accumulation,” where the osteoid appears in patches, creating heterogeneous regions of high and low mineralization in cortical and trabecular bone. These low levels of mineralization fall below those seen in OI type VII. A second distinguishing feature is the extreme thinness of the trabeculae, which are approximately half as thick as those formed in OI types I and VII, and are also reduced in number (Fratzl-Zelman et al., 2016b). Mouse models display a less severe reduction in trabecular thickness (Fratzl-Zelman et al., 2016a). Collagen fibrils have irregular cross-sections and a subpopulation is fused or fragmented. This produces abnormally large and small collagen fibrils (Fratzl-Zelman et al., 2016b).

Effect on microdamage: OI demonstrates how microdamage results from changes at bone’s nanoscale (collagen and mineral) and subsequently alters the histology of its microscale (vascular porosity). In mouse models of osteogenesis imperfecta (OIM), abnormal collagen fibrils reduce collagen content by 20% (Camacho et al., 1999). OIM mice also have 27% fewer enzymatic crosslinks (Sims et al., 2003) and, instead, form more nonenzymatic crosslinks (Carriero et al., 2014a,b). While nonenzymatic crosslinks typically increase stiffness, they are insufficient to compensate for the loss of bone strength. This abnormal crosslinking prevents collagen from sliding and/or stretching in response to large mechanical strains ( . 0.3%), such that they fail at smaller ultimate tissue strains (Carriero et al., 2014a,b). Additionally, mineral platelets are smaller, more densely packed, and disorganized in OI bone (Vanleene et al., 2012), reducing the ability of adjacent platelets to shear to dissipate energy. These changes to OI collagen and mineral energy dissipation make the bone less tough (Bishop, 2016). OIM bone almost completely lacks extrinsic toughening, indicating minimal resistance to a propagating crack. This can be partially explained by the reduced lamellar structure, which would normally deflect the crack (Carriero et al., 2014a,b). The increased activation frequency observed in OI may be triggered by the microdamage that accumulates in this brittle bone tissue (Rauch et al., 2000). The porosity produced by this remodeling further weakens OI bone to propagation of microcracks into fractures (Carriero et al. 2014a,b). Effect on mineralization: Abnormal collagen molecules are kinked and disorganized, restricting the Dspacing where mineral platelets nucleate and expand (Bart et al., 2014). Mineral platelets are smaller (Fratzl et al., 1996), more numerous, and thinner than normal platelets (Fratzl-Zelman et al., 2014). Average crystal size is normal for OI type I, but decreases with disease severity, becoming smaller from OI type IV to OI type III to OI type II. OIM mice have thinner and more variably aligned mineral crystals in cortical bone, which may contribute to brittleness (Fratzl et al., 1996; Vanleene et al., 2012). The abnormal lamellar organization seen in OI type V (“coarse mesh”) and OI type VI (“fish scale”) indicates a defective mineralization process resulting in hypermineralization. Endochondral ossification is delayed in OI type V but not OI type VI (Bishop, 2016). The increased packing density of these small crystals contributes to high mineralization and increased brittleness (Fratzl-Zelman et al., 2014). Bone mineralization density distribution shows that the cortical and trabecular bone matrix is highly mineralized in OI types I, III, IV, VII, and VIII (Roschger et al., 2008a,b; Fratzl-Zelman et al., 2014, 2016b). The looser organization of collagen allows more water and minerals to infiltrate between fibers

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(Bishop, 2016) and permits less alignment of mineral platelets within bone tissue (Fratzl et al., 1996). In OI types II, III, and IV, abnormal collagen fibrils are covered in small mineral crystals. Electron diffraction shows that these crystals are poorly organized apatite. Crystals are observed on top of normal mineralized fibrils, on loose unmineralized abnormal fibrils, and in their own crystal clusters (Traub et al., 1994). Despite higher mineralization, OIM mice are less stiff as the disease becomes more severe. Due to small, disorganized, reduced crystallinity of minerals, platelets may not be able to fuse into a continuous structure to provide stiffness (Carriero et al., 2014a,b). Effect on osteocyte lacunae: Several types of OI increase osteocyte lacunar density, shape, and alignment. OI type II often has two to three osteocytes per lacunae (hyperosteocytosis). This signifies woven bone and a lack of matrix mineralization. OI types I, II, and III, but not OI type IV, have increased osteocyte numbers (Sarathchandra et al., 2000). Synchrotron micro-CT of OIM mice shows a higher density of osteocyte lacunae, a more spherical and less elongated lacunar shape, and less alignment with the longitudinal bone axis. However, osteocyte lacunae have a similar mean volume to normal mice. Due to the high activation frequency in OI bone, osteocytes deposited rapidly may have less time to align with the principal loading direction. The increased osteocyte lacunar density and total lacunar volume were suggested to contribute to microcrack propagation (Carriero et al., 2014a). However, osteocyte lacunar density was not found to be significantly associated with mechanical properties in the cortical bone of children with OI (Albert et al., 2014). Effect on vascular porosity: OIM mice have a 4.5-fold increase in canal density compared to normal mice. Canals are small and highly branched, maintaining similar cortical porosity between OIM and normal mice (Carriero et al., 2011, 2014a,b). Increased vascular canal density and connectivity are also seen in human OI (Jameson et al., 2013). This may be because brittle OI bone invites microdamage and elevates the activation frequency of remodeling (Rauch et al., 2000). Carriero et al. (2014a,b) also suggest that the increased nutrient demand of this high bone turnover may demand an expanded vasculature. Synchrotron micro-CT indicates that, unlike OIM mice, human OI cortical bone has a much higher average porosity (21%) than typical values for children and young adults (3%
6%). Longitudinal properties (elastic modulus, yield strength, and maximum strength) of bone are significantly negatively associated with porosity (Albert et al., 2014). A 3-D fracture propagation model suggests that the many small canals disrupt bone continuity, reducing its ability to resist a propagating transverse crack. The crack was modeled as propagating 1.4 3 as fast. This is

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corroborated by mechanical testing, wherein OIM bone has less stable crack extension, such that small cracks quickly propagate to fracture and failure (Carriero et al., 2014a,b). OI type VIII is noted to have high cortical porosity and trabecularization in humans (Fratzl-Zelman et al., 2016a). Effect on bone fragility: Macroscopically, OI presents in bone with short stature or deformed bones, brittle and opaque teeth (dentinogenesis imperfecta), and progressive hearing loss in early adulthood as ossicles are damaged. OI bone fractures spontaneously or with minimal trauma (Basel and Steiner, 2009). In OI type I, fractures range from a few to more than a hundred over the lifespan. They decrease after puberty then increase around age 50, accounting for 25% of lifetime fractures. OI type III allows survival to adulthood, but more than 200 fractures are possible, and bone becomes progressively deformed. OI type II is perinatal lethal due to the deformed ribcage restricting breathing, All other OI types are intermediate between OI type I and OI type III (reviewed in Basel and Steiner, 2009). Histological case studies in paleopathology: In archeological remains, microscopic assessment can reinforce a diagnosis of OI when the more obvious macroscopic deformities are observed. Gray (1970) assesses OI in a 21st-dynasty (c.1000 BCE) Egyptian 2-year-old and notes that trabeculae appear radiographically as “scattered, amorphous wisps.” OI type II can be lethal between birth and 1 month of age (OI type IIa or IIc), or may be sustained for a few years (OI type IIb). Survival of this child for 2 years suggests OI type IIb, III, or IV (Cope and Dupras, 2011). Cope and Dupras (2011) suggest the same classification, based on macroscopic assessment, for a fetal skeleton (38 weeks gestation) from the Egyptian Romano-Byzantine period (AD 50
450). Cortical bone deposition is patchy and coarse on the metaphyseal surfaces of the ulna, radius, humerus, and tibia. The paleopathological literature also contains adolescent cases of OI. Wells (1965) describes an early medieval English female aged approximately 18 with a severely bent left femur and deep fossae eroded at the sharpest angle. Radiological examination reveals a highly reduced trabecular number and a thin, osteoporotic cortex. Ortner (2003) assigns this case to OI type I due to the survival to adulthood. Ortner (2003) also evaluates a late adolescent from the Maryland Juhle site (AD 1400
1500). Long bone diaphyses are abnormally restricted in diameter and materially fragile, but show no evidence of healed or unhealed fracture. A microradiograph also reveals a low OPD, as previously described by Wu et al. (1970). Adolescent survival suggests OI type IV, or OI type I that unusually lacks fractures (Ortner, 2003). Slender, unfractured long bone diaphyses with few osteons are also observed in five late adolescent or early adult cases from

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the Egyptian Romano-Byzantine period, as described by Sheldrick (1980, 1999). Vairamuthu and Pfeiffer (2018) make a case for OI type IV in a Late Archaic North American female aged approximately 16 years. The individual is severely stunted, making milder OI type I unlikely, but she does not display the bone deformities or fractures expected of other types of OI. Cortical thinning of the femoral neck and lumbar vertebral body reveal extensive cortical porosity and a porous “honeycomb” of thin trabeculae.

CONCLUSION Bone’s capacity to adapt to load is a trade-off between elastic and plastic behavior. Bone adapts to regional mechanical strains at the microscale, and to global mechanical strains in terms of cross-sectional shape and size. Toughening mechanisms, which allow bone to dissipate energy plastically before breaking, are major determinants of the distribution of microstructure within bone. Intraskeletal differences between bones are largely derived from remodeling rate, which determines how quickly bone’s strength will be restored after plastic deformation. As remodeling functionality enters senescence, remodeling repair lags behind deformation and decreases in quality. Pathological conditions can also alter the speed or organization of the remodeling process, with corresponding changes in tissue structure. Characterizing the frequency and rate of bone remodeling is important for identifying changes in these parameters related to mechanical loading, aging, and pathology. The first section of this chapter demonstrated the use of OPD and osteon area for calculating activation frequency and bone formation rate. These equations have been applied to modern populations, archeological groups, and pathological cases. The second section of this chapter described the close relationship between bone microstructure and regional mechanical loading, and the resulting contribution of these features to bone strength. Histological alterations in a number of pathological conditions were also considered. Rather than relying on resistance to elastic deformation, which requires a brittle material, human bone preferentially dissipates energy through plastic deformation, particularly microdamage. This is an effective strategy for preserving bone strength due to bone’s capacity to continually renew and repair itself through remodeling. However, microdamage targets tissue regions with high mineralization or stress-concentrating voids, such as vascular pores and osteocyte lacunae. As mineralization and porosity increase over the lifespan, or in certain pathological conditions, microdamage accumulation exceeds remodeling repair and negatively impacts bone strength. With age, remodeling also becomes detached from its close association with mechanical loading. Bone

resorption is increasingly triggered by declining muscle strength and physical activity, while bone formation lags due to senescence of osteoblast and osteocyte sensitivity and function. The three main structures observed at the microscale in cortical bone tissue are osteocyte lacunae, vascular porosity, and secondary osteons. The distribution and shape of these structures are also closely linked to mechanical loading. Regions of higher mechanical strain are thought to accumulate more microdamage, necessitating a larger osteocyte response. Increased mechanical loading corresponds to denser osteocyte populations and larger lacunar volume, suggesting increased cellular metabolic activity. Osteocyte lacunar density generally decreases with age as the cells exceed their lifespan or undergo apoptosis in response to microdamage and cellular senescence. Pathological conditions can reduce osteocyte survival or restrict their lacunar size and shape. Conditions that release excessive parathyroid hormone or diminish serum calcium can enlarge lacunae through osteocytic osteolysis, as osteocytes reclaim small amounts of calcium locally. Remodeling results in net bone loss through the formation of vascular pores, regardless of whether the process is triggered by routine bone turnover, mechanical strain changes, or microdamage. Vascular porosity is generally higher in regions of lower mechanical strain within a cross-section, as higher mechanical strain inhibits bone resorption. Porosity increases with age as bone formation lags behind increased bone resorption. Pore expansion and coalescence appear to play a primary role in this change, as resorption of interstitial regions unites adjacent pores with each other and with the marrow cavity (“trabecularization”). This increase in vascular porosity weakens bone because, in addition to reducing bone mass, pores concentrate stress and are targets for microdamage initiation and propagation into fracture. Porosity may be increased or decreased by pathological conditions that, respectively, increase or decrease resorption and bone turnover. The secondary osteons that surround vascular pores are also signatures of regional mechanical loading. Since higher mechanical strain inhibits bone resorption, secondary osteons in these regions tend to be smaller and more circular. In three dimensions, secondary osteons largely align with the principal direction of loading, but they can also “drift” laterally, potentially to target microdamage. Despite declining mechanical loading with age, secondary osteons tend to become even smaller and more circular. This may help compensate for age-associated declines in bone quality by preserving the toughening mechanisms inherent in secondary osteon structure. Pathological conditions frequently disrupt lamellar structure, both in cortical and trabecular bone. This can be caused by uncoupled

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rates of bone resorption, formation, and mineralization, or by diminished quality or availability of the collagen and mineral components of bone tissue. A common pathological presentation is the formation of weaker disorganized woven bone, or the persistence and expansion of unmineralized osteoid. While microstructure is sensitive to regional mechanical loading, the size and shape of the whole cross-section reflects body weight and physical activity. Sexual dimorphism is evident in the trajectory of cortical and trabecular bone apposition and loss over the lifespan, helping explain the greater bone fragility of postmenopausal women. Cross-sectional shape reflects the predominant direction of bone bending during life. The microstructural ELP records the cortical drift of the cross-section to its adult position. Cross-sectional geometry has been broadly applied to infer physical behaviors in fossil and archeological human populations. The parabolic index is an overlooked indicator of osteoporosis that could also lend interpretation to these contexts. Recent advances in microscopic imaging technology have produced a wealth of information about the connections between bone histomorphology and mechanical loading, aging, and pathology. Bone biologists have also significantly expanded the understanding of the cell signaling pathways driving the activation and coupling of bone formation and resorption. In pathological conditions, dysregulation of these cellular processes predictably alters bone turnover and causes logical consequences for bone tissue structure. These advances make it possible to use bone tissue to infer trends in mechanical loading, bone quality, and bone fragility. However, practical application of bone histomorphology remains largely concentrated in modern human populations and animal models. Recognition of the information available at the microstructural level should encourage the broader application of bone histomorphology in archeological populations and studies of paleopathology.

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1112.

Chapter 7

The Role of Imaging in Paleopathology Chiara Villa1, Bruno Frohlich2,3 and Niels Lynnerup1 1

Department of Forensic Medicine, University of Copenhagen, Copenhagen, Denmark, 2Department of Anthropology, Smithsonian Institution,

Washington, DC, United States, 3Department of Anthropology, Dartmouth College, Hanover, NH, United States

WHY IS MEDICAL IMAGING IMPORTANT? Radiographic techniques, such as X-rays and computed tomography (CT), are important diagnostic tools for examining mummified and skeletal remains. They are noninvasive and nondestructive approaches that facilitate visualizing the internal structures of a bone or a mummy. Radiological examinations can be complementary to the macroscopic analyses of bones but are indispensable when dealing with mummified remains. Radiography and CT scanning of bones should be performed whenever possible, both to help in the diagnosis of the disease and for a permanent documentation of the remains. Importantly, a permanent digital documentation of pathological samples can be shared among experts and can be used to establish pathology databases such as, “The IMPACT Radiological Mummy Database of mummies” (Nelson and Wade, 2015) or “Digitized diseases” (http://www.digitiseddiseases.org/). This chapter provides a brief history and discusses the basic technical principles and terminology regarding the use of radiography in paleopathology. It also illustrates how several diseases appear on X-rays and CT, including taphonomic alterations, as distinguished from vital changes. We also address certain borderline pathologic conditions, which are often considered when compiling a general health profile from a skeleton and which rely on radiography. Finally, the chapter will also address the use of certain other imaging modalities.

A BRIEF HISTORY OF RADIOLOGY IN PALEOPATHOLOGY The use of radiographic techniques in paleopathological studies has a long history, starting soon after the discovery of the X-rays in 1895 by the German physicist Wilhelm Conrad Ro¨ntgen (Ro¨ntgen, 1972; Thomas and Banerjee, 2013). Less than a year after the discovery of X-rays, Ko¨nig performed the first radiographies on

Egyptian mummies: a child and a cat (Ko¨nig, 1896). Many other radiographic examinations were performed in the following years, not only on mummies, but also on dry bones and hominid fossils (for a review of the early literature see Bo¨ni et al., 2004; Chhem, 2008). Entire collections of mummies were radiographed (Moodie, 1931; Harris and Weeks, 1973; Harris and Wente, 1980; Dawson and Gray, 1968). Even though the primary purpose of using X-rays was for documenting collections (Chhem, 2008), several pathological changes were described, including osteoarthritis, atheroma, healed fractures, dental disease, and parasite-induced changes (Brothwell and Sandison, 1967; Dawson and Gray, 1968; Christensen, 1969; Harris and Weeks, 1973; David, 1979; Harris and Wente, 1980; Bloomfield, 1985; Lynnerup, 2007 and references therein). The first X-ray studies with the aim of visualizing pathological changes in humans for diagnostic purposes are attributed to Eaton (1916), Means (1925), and Williams (1929). In the early 1970s, the introduction of CT greatly improved the capabilities of radiology (Hounsfield, 1973). Once again, anthropologists and paleopathologists immediately realized its importance for studying mummies and skeletal remains. The first CT scan was performed on an Egyptian mummy in 1979 (Harwood-Nash, 1979). Many others soon followed; for a detailed review of the early studies see Chhem (2008), Lynnerup and Ruhli (2015), Cox (2015), and references therein. Today, X-rays and CT scanning are routine research tools for studying mummies, fossils, and bones.

BASIC PRINCIPLES AND TERMINOLOGY This section is not intended to be exhaustive, but will introduce the reader to basic principles and provide a glossary for the most common terms (Table 7.1) associated with radiography and CT scanning. For a full presentation, please refer to, e.g., Bansal (2006), Buzug (2008),

Ortner’s Identification of Pathological Conditions in Human Skeletal Remains. DOI: https://doi.org/10.1016/B978-0-12-809738-0.00007-7 © 2019 Elsevier Inc. All rights reserved.

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170 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

TABLE 7.1 Glossary of Basic Radiology Terminology Term

Meaning

Artifact

A discrepancy between the reconstructed values in an image and the true attenuation coefficient of the object The reduction of X-ray intensities when passing through matter In or along the axis (midline) of the body. A plane that is parallel to both the left right and anterior posterior axes in the “patient-oriented” coordinate system The pack of primary X-rays emerging from the X-ray tube Mechanical device for defining the shape of an X-ray beam The contrast is defined as the difference in density (blackness) between various regions on a radiograph Ability to detect small differences in the attenuation coefficient of adjacent structures Coronal or frontal plane runs the length of the body and passes through it from side to side, thereby dividing it into anterior and posterior portions An intensity scale for CT images. The unit for CT attenuation is called the Hounsfield unit (HU). The numbers are set on a scale in which 1000 represents the attenuation of air and 0 is the attenuation of water The degree of darkening of a radiographic image: black areas (air spaces) have maximum density, while white areas (bones, metal objects) have minimum density A physical instrument to measure the intensity of the incident X-rays An image is underexposed, i.e., the object appears white or relatively featureless if insufficient X-rays reach the film during the exposure; an image is overexposed, i.e., the object is not distinguishable from the background if an elevated number of X-rays penetrate it during the exposure Area of the scan A CT scan mode in which the patient table travels continuously during the data acquisition The unit for the CT number scale (see also CT number) 2D picture element A mathematical process used to reconstruct the CT images from the measured attenuation profiles Material or structure that is easily penetrated by X-rays. Such an object appears dark on the radiography or CT image Material or structure that absorbs and scatters X-rays. Such an object appears light on the radiography or CT image The ability to differentiate objects The sagittal plane runs superiorly inferiorly along the dorsoventral axis. Section parallel to the median plan of the body Survey image used for orientation in the CT scanning. A projection image similar to an X-ray radiograph acquired with a stationary gantry and a continuously moving patient table Refers to the resolution of the CT scan (axial plane) Refers to the movement of the table/scanner for scanning the next slice 3D volume element, in a CT, is defined by the pixel and the slice thickness The parameter that determines the interval of gray tones that are visualized Source of X-rays. It consists of an anode and a cathode enclosed in a vacuum envelope

Attenuation Axial view Beam (X-rays beam) Collimator Contrast Contract resolution Coronal view CT number

Density Detector Exposition

Field of view (FoV) Helical (spiral) scan HU (Hounsfield unit) Pixel Reconstruction algorithm or convolution kernel Radiolucent/radiolytic Radiopaque/radiodense Resolution Sagittal view Scanogram (scout view, tomogram, project radiograph) Slice thickness Slice increment Voxel Window (or windowing) X-ray tube

Fleckenstein and Tranum-Jensen (1993), Goldman (2008), Hsieh (2009), Kalender (2011), Seibert (2004), and Seibert and Boone (2005). Radiographic techniques use X-rays to visualize the internal structures of the object. X-rays are electromagnetic waves able to penetrate materials. They interact with the atoms of the material and can be absorbed or scattered. The X-rays are said to be attenuated with a reduction in Xray intensity. Their absorption depends on the density, thickness, and atomic number of the material. The X-rays that pass through the examined object have a pattern of intensity that reflects the absorption characteristics of the

object, and this pattern is recorded to form an image (i.e., radiography). The image will be darkest where the greatest number of X-rays has reached the image detector (i.e., film, digital plate) and lightest where the greatest proportion of the X-rays is absorbed by the sample. The materials with a high density, such as compact bones and metal objects, inhibit passage of the X-ray, i.e., they are radiodense or radiopaque and are visualized in white or light gray. Less dense materials, e.g., soft tissues, allow a major number of X-rays to pass, i.e., they are more radiolucent and are visualized in black-gray. Empty space is rendered in black.

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An X-ray machine consists of: (1) a source of X-rays (an X-ray tube) and (2) a medium to record the attenuation of the X-rays and produce an image (i.e., an image detector). The image detector is a film in conventional radiography, or a digital plane in computed radiography (CR) and digital radiography (DR). A radiograph is a 2D visualization of attenuation variations in a 3D item. The main factors that can influence the quality of radiography are the tube voltage (kV) and the X-ray dose (mAs), which determine the energy and number of Xrays, respectively. The penetration power of X-rays is determined by their energy. Low-energy X-rays are more likely absorbed by the object and do not reach the image detector, while high-energy X-rays easily pass through material and are registered by the image detector. A good image is obtained when most the details of an object are visualized; thus a greater variation of X-rays should reach the film, such that a greater difference of shades of gray appears. Increasing the energy of X-rays (kV) is not always the solution. Indeed, if all the high-energy X-rays easily penetrate the object regardless of its composition, the resulting image is completely homogeneous, and thus the different structures cannot be distinguished. The number of X-rays (determined by mAs) reaching the film during the exposure can also determine the quality of the image. An image may be underexposed, i.e., the object appears white or relatively featureless, if insufficient Xrays reach the film during the exposure. Alternatively, an image may be overexposed, i.e., the object is not distinguishable from the background, if an elevated number of X-rays penetrate it during the exposure. Modern clinical X-ray equipment (CR and DR) is now fully digitized, so images can easily be manipulated such that brightness, contrast, and sharpness can be improved. The relative

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position of the object, the X-ray source, and the image detector can also have a great influence on the image, creating artifacts and distortions. The object should be directly under the center of the X-ray beam, parallel and close to the image detector (Seibert, 2004; Seibert and Boone, 2005; Saab et al., 2008). While a single image of the object is created using an X-ray machine, hundreds of slices may be produced during CT scanning. This is possible because the source of the X-rays rotates continuously around the object that moves through the CT scanner, and multiple image detectors simultaneously acquire the X-ray projections (Hsieh, 2009; Kalender, 2011). Thus, the CT images are the result of processing a large number of X-rays acquired from different angulations. The cross-sectional images (reconstructed slices) are usually represented in a 512 3 512 pixel matrix, with each pixel representing the X-ray attenuation coefficient in a small volume (voxel) determined by the underlying anatomy. The x and y (pixel dimensions) of each slice in the transverse plane are determined by the matrix size and the fields of view. The third voxel dimension (z) is perpendicular to the transverse plane and equals the slice thickness (Kalender, 2011). Exposure parameters, such as the tube voltage (kV) and the X-ray dose (mAs), can influence CT image quality, as well as slice thickness, slice increment, pitch, and the reconstruction algorithm (see Table 7.2 for further details). As a general guideline, we suggest that the sample should be scanned with the smallest thickness possible, and the pitch and slice increment values should be set lower than the values used for the thickness to reduce possible artifacts. For more in-depth technical considerations, see Hsieh (2009), Kalender (2011), and Zollikofer and Ponce de Leon (2005). In medical CT scanning, the

TABLE 7.2 Overview of the Most Typical Appearances of the Several Pathological Conditions as Observed by X-Rays and CT Scanning

Radiolytic lesions

Description

Examples

Radiodense lesions

Description Example

Inactive

Active

Aggressive

Confined or circumscribed and surrounded by a sclerotic rim of bone Osteomyelitis (Fig. 7.1), osteoblastoma

Confined or circumscribed without a rim, meaning that the lesion is still growing

No clear border, cortical expansion and destruction

Amorphous Calcification

Benign tumors

Malignant tumors, osteosarcoma, aneurysmal bone cyst, infectious diseases (Fig. 7.2), hematopoietic diseases (Fig. 7.3) New bone formation, which can be extraosseous and/or intraosseous Osteosarcoma (Fig. 7.4), metastases of carcinoma of the prostrate, fractures, osteochondroma (Fig. 7.5), cartilaginous exostoses (Fig. 7.6), osteomyelitis (Fig. 7.1)

The staging between “inactive,” “active,” and “aggressive” is best understood as a spectrum.

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FIGURE 7.1 Osteomyelitis on a left femur: (A) photograph; (B) radiograph; (C) coronal CT scan; (D F) axial CT images (the 3D visualization on the right indicates the slice position). Osteomyelitis has a complex development, and radiographically is characterized by both radiolytic and radiodense areas. In image (C), the sequestrum, highlighted by the lower arrows (white arrows in online version), is visualized as a regular radiolytic/radiolucent area, while the internal sclerosis, highlighted by the middle arrows (orange arrows in online version), is visualized as radiodense areas. Note that the increased thickness of the cortical bone due to elevated periosteum production is well visible on the CT images, highlighted by the upper arrows (light blue arrows in online version).

differences in X-ray attenuations of the tissues, i.e., the difference in material density, can be measured using the Hounsfield unit (HU) scale. The HU scale is calibrated arbitrarily according to the attenuation of water (HU 0) and air (HU 1000). Materials more radiopaque than water result in correspondingly higher positive values of HU; soft tissues have values around HU (20 100), while bones have HU over 200, with higher values for compact bones. X-ray and CT scanning examinations should ideally be seen as complementary examinations. CT scanning has

three main advantages: (1) it overcomes the superimposition problem that prevents one from clearly seeing deep areas or juxtaposed structures in plain radiography; (2) it better visualizes the contrast between the different bones and soft tissue; and (3) it generates 3D visualizations of single structures. However, ordinary X-rays are probably the most accessible technology for most anthropologists and paleopathologists, especially considering that there are portable X-ray machines that can be used in the field (Conlogue et al., 2004; Nystrom et al., 2004).

FIGURE 7.2 Femur with pronounced destruction (arrows) of the diaphysis due to syphilis: (A) photograph; (B) radiograph; (C) coronal CT scan.

FIGURE 7.3 Multiple lytic lesions (arrows) of a skull probably caused by multiple myeloma (hematopoietic disorder): (A) photograph; (B) lateral X-ray; (C) 3D visualization from CT scanning of the inside of the skull; (D) axial CT scan.

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FIGURE 7.4 Destruction of the frontal bone (lytic area) with sunburst appearance in the frontal bone due to an osteosarcoma.

FIGURE 7.5 Osteochondroma on a rib: (A) photograph; (B) lateral X-ray; (C and D) transverse CT images of the rounded formations (the 3D visualization on the right indicates the slice position). Note the nodular character of the mineralized portion of the tumor visualized as radiodense areas in the X-ray and the CT images.

RADIOGRAPHIC APPEARANCE OF PATHOLOGIC CONDITIONS The evaluation of pathological changes in radiographic images is not easy and requires experience. A thorough

knowledge of the normal anatomy, anatomical variations, and pathological conditions is essential. Abnormal bone changes can be broadly categorized as abnormal bone size, abnormal bone shape, abnormal bone formation, and abnormal bone destruction (see Chapter 5). The

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FIGURE 7.6 Cartilaginous exostoses between the fibula and the tibia: (A) photograph; (B) radiograph; (C) coronal CT scan. The bone formation on proximal epiphysis shows a marked bone sclerosis visualized as a radiodense area (white arrows).

radiographic findings of abnormal bone size and shape often correspond well with the macroscopic changes. Abnormal bone formation and bone destruction can be visualized as whiter (radiodense) or darker (radiolytic) areas. As emphasized for dry bones (Buikstra and Ubelaker, 1994; Ortner, 2012), a clear and detailed description of the radiographic images is fundamental. Table 7.2 provides an overview of the most typical appearances of the several pathological conditions as observed by X-rays and CT scanning. Aside from the basic diagnostic distinctions between bone remodeling (bone growth and bone destruction resulting in radiopaque and radiolytic areas, respectively, on X-ray and CT), it is equally important, for dry bone macroscopic study, to evaluate if these basic processes occur inside the bone (intraosseous/intramedullar), on the bone surface (extraosseous), or a combination thereof, and whether a lesion is superficial or involves more of the internal bone structure (see Chapters 4 and 5). Most of the pathological conditions affecting dry bone can be evaluated macroscopically. Radiography can

provide further information, but the procedure is not always essential for diagnosis. For example, osteoarthritis can be recognized by the presence of osteophytes, porosity of the joint surface, and eburnation; lingual hyperostosis of the mandible (torus mandibularis) can also be identified from a gross examination. Indeed, some pathological lesions are only visible on direct inspection of dry bones since the resolution of the radiography/CT images is not adequate. This would pertain to slight periosteal reactions on ribs, scorbutic changes (porous hypertrophic bone), or cribra orbitalia. On the other hand, there are pathologies such as osteoporosis, endosteal sclerosis, middle ear infection, and confirmation of suspected previous (well-healed) fractures, which are invisible by gross examination of the bone. Finally, there are cases where both a gross evaluation and radiographic examination provide excellent complementary information, e.g., in cases of lytic lesions, Paget’s disease (Mays, 2008), and tumors. Modern radiological imaging constitutes an important source of information (Ortner, 2005; Roberts and Manchester, 2007; Mays, 2011). Comparing radiological

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images of archeological specimens with those of living patients can help the paleopathologist reach a diagnosis. Indeed, paleopathologists can benefit from the large number of radiographic images available in the medical literature that present a great range of manifestations of various diseases. An example of this is “radiopaedia” (https://radiopaedia.org), a free resource with one of the web’s largest collections of radiology cases and reference articles. Additionally, paleopathology may contribute to modern medicine, as not all lesions visible on dry bones can be seen on radiological imaging, and notation of these allows a more complete overview of the manifestation of the disease (Ortner, 2005; Roberts and Manchester, 2007).

Mummies, Paleopathology, and Radiography Mummies and bog bodies are unique samples for studying ancient disease (refer to Chapter 22), as they allow for examination of pathological conditions affecting soft tissues and with a rapid onset and/or a short course (Cockburn et al., 1998). Outside of performing a destructive autopsy, pathological conditions of the bones in mummies can be investigated only through radiographic and endoscopic imaging. Several pathological conditions have been identified in mummies (refer to Chapter 22). Given the continuing progress in medical imaging, mummies previously examined by X-rays may yield much revised and additional information when CT scanning has been applied (Villa et al., 2015; Zesch et al., 2016) or when newer generations of CT scan equipment is used (e.g., an embedded arrow head in the shoulder region of a mummy was not seen until a later, second, CT scan, capable of smaller slice thickness, was used (Seiler et al., 2013)).

OTHER BONE CHANGES AND RADIOGRAPHY Aside from using radiography as a diagnostic tool for welldefined diseases, as discussed in the previous section, radiography may also be used to study changes in bone morphology and internal architecture, which may reflect changes related to diseases or perhaps be indicative of a more general health (or growth) insult. For instance, a macroscopic observation of bilateral, often distal diffuse periostitis of the lower limb bones may be indicative of a nonspecific, chronic disease or its effects. Equally, there are some observations that can only be observed radiographically. In this section, we briefly focus on Harris lines (HL), the estimation of body mass, and osteoporosis. While perhaps debatable in terms of diagnostic precision or evidence, these changes are nonetheless often reported and interpreted in a diagnostic discussion.

Harris Lines HL are bands of increased bone density that are seen as opaque lines across the diaphysis and metaphysis of long bones, parallel to the metaphyses (Harris, 1926, 1931a,b, 1933). They have been studied primarily in tibiae and femora, but they have also been observed in other long bones such as the radii (see Primeau et al., 2018 and references therein). Diverse terms have been used for HL: bone scars (Dreizen et al., 1964), Park lines or Park Harris lines (Lee and Mehlman, 2003), transverse lines (Mitchell, 1964; Garn and Schwager, 1967; Gindhart, 1969; Clark and Mack, 1988; Egawa et al., 2001), growth recovery lines or grow restart lines (Ecklund and Jaramillo, 2002; Sajko et al., 2011), growth arrest lines (Harris, 1931a; Blanco et al., 1974; Yao and Seeger, 1997; Khadilkar et al., 1998), radiopaque transverse lines (Blanco et al., 1974; Clarke, 1982; Hummert and Van Gerven, 1985; Byers, 1991), growth recovery zones (Siffert and Katz, 1983), and opaque transverse lines (Khadilkar et al., 1998). As will be noted, some of these terms reflect that radiography is needed to observe HL. HL arise from dissimilar reaction times between osteoblasts and osteoclasts in times during temporary cessation of growth, causing a band of increased bone density, which becomes evident once the individual resumes normal growth (refer to Chapter 4). Once the epiphyses have fused to the diaphysis, HL can no longer develop (Scheuer and Black, 2000). HL, caused by temporary growth arrest, are attributed to a broad array of etiologies such as malnutrition, metabolic diseases, childhood diseases such as measles, mumps, and chicken pox (Harris, 1931a; Hewitt et al., 1955; Park, 1964; Gindhart, 1969), diabetes (Harris, 1931b), hypoparathyroidism (Rosen and Deshmukh, 1985), children with psychosocial short stature (Khadilkar et al., 1998), juvenile chronic arthritis (Fiszman et al., 1981), consumption of ethanol (Gonzalez-Reimers et al., 1998), or repeated child abuse (Walker et al., 1997). There is little research in the form of longitudinal studies regarding the rate of disappearance and persistence of HL. Dreizen et al. (1964) and Gindhart (1969) found that some lines persisted, while others disappeared during developing years. On the other hand, HL have been confirmed in modern populations with known ages above 50 years (Ameen et al., 2005) and from cadaveric material with known ages above 60 years (Egawa et al., 2001). Plain radiography is the most commonly used method to evaluate HL (Brickley and McKinley, 2004) (Fig. 7.7). However, recent research suggests that CT scanning may also be a valid tool (Primeau et al., 2016).

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information to include in diagnostic deliberations (e.g., Kacki et al., 2018). Body mass can also be used to assess behavior-related changes due to activity. Alternative noninvasive methods to evaluate the crosssectional area have been suggested based on the use of radiographs (Runestad et al., 1993; Stock Jay, 2002; O’Neill and Ruff, 2004).

Osteoporosis

FIGURE 7.7 A radiographic of paired tibiae showing bilateral Harris lines (arrows). Image courtesy of Dr. M.L. Jørkov, University of Copenhagen.

Osteoporosis is a complex bone disorder of multifactor etiology. It is a frequent metabolic bone disorder that affects many postmenopausal women and elderly people of both sexes. Diagnostic determination of osteoporosis in past populations may, alongside specific underlying diseases, supplement the “osteobiography” of a skeleton, as osteoporosis may also reflect bone modifications related to age, menopausal status, or lifestyle (see Curate, 2014 for a review, and Chapter 16). Here we simply address the fact that radiography, along with dual X-ray absorptiometry, is probably the most commonly used technique to study osteoporosis in skeletons (Mays, 2008; Curate, 2014). Radiogrammetry quantifies the cortical bone in tubular bones and can be measured on a plain radiograph (usually by computing the ratio between the total width of diaphysis and the medullary cavity thickness, not unlike measurement for calculating body mass) (Ives and Brickley, 2004). Singh et al. (1970) proposed the “Singh index” as a score of the pattern of trabecular bone. For comprehensive guidelines for radiogrammetric analysis, the reader can refer to Meema and Meema (1987), Ives and Brickley (2004), and Brickley and Agarwal (2003). Radiogrammetry of the femur and the tibia has been applied to evaluate age-related cortical bone loss in skeletal remains (Gonzalez-Reimers et al., 1998; Mays et al., 1998). Also, many anthropological studies of cortical bone has used the second metacarpal (e.g., Ekenman et al., 1995; Lazenby, 1995; Mays, 2000, 2001, 2006; Robb et al., 2010; Beauchesne and Agarwal, 2011). No paleopathological radiographic studies appear to have been conducted on trabecular bone loss in lumbar vertebrae, which is diagnostic of osteoporosis in living patients.

Body Mass Calculations Several methods for deducing body mass are based on measuring the cortical cross-sectional area of the femur or determining diameters and thickness of the cortical, compact bone component of the femur, and other bones (e.g., Ruff, 2000; Ruff and Hayes, 1983; Torchia and Ruff, 1990; Lacoste Jeanson et al., 2017, and reference therein). In a paleopathological context, body mass may reflect growth stunting and may be used as ancillary

TAPHONOMIC ALTERATIONS Taphonomic and diagenetic processes can influence imaging and need to be considered carefully to avoid incorrect diagnoses. For example, soil intrusion within bones can be visualized as radiopaque areas and can be misinterpreted as pathological lesions (Fig. 7.8) such as sclerotic bone tumors (Mays, 2011).

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(A)

(B)

rendering technique are not always suitable for mummies, especially if the mummy is wrapped or inside a coffin or bundle. Bog bodies are an extreme case of postmortem alteration: the diagenetic changes are so massive in these mummies due to the acidic bog environment, that all tissues, including bones and teeth, show very similar values of HU (Villa and Lynnerup, 2012). In such cases, a manual segmentation process, i.e., manual slice-by-slice image editing, is necessary. The manual process of segmentation (delineation and extraction) is often very timeconsuming (Lynnerup, 2008), but it can result in accurate and precise 3D models. Software applications such as Mimics (http://www.materialise.com/en/medical/software/ mimics), Amira (https://www.fei.com/software/amira-forlife-sciences/), and 3D slicer (https://www.slicer.org/) allow postprocessing of the 2D images (surface rendering (SR)). In addition, the resulting 3D model obtained using SR can be exported as “.stl” for further analysis, e.g., to be 3D printed, and/or for virtual reconstruction. Threedimensional printed copies of bones can be used for teaching or, as recently demonstrated, they can be manipulated to overcome extensive diagenetic changes and help in the final diagnosis (Lynnerup et al., 2016).

OTHER IMAGING MODALITIES (C)

FIGURE 7.8 CT images of a left femur with radiopaque artifact resulting from soil embedded in the diaphysis (arrows): (A) sagittal view; (B) coronal view; transverse view (C). Note that the cortical and the trabecular bone does not present any pathological change.

Microcomputed Tomography Microcomputed tomography (micro-CT or µCT) is a CT scanning technique forfeiting FoV for the highest possible resolution. Objects can be scanned with a voxel resolution of 1 µm. A micro-CT is equipped with similar components to those present in a CT scanner but at a smaller size; e.g., the X-ray tube typically has a window of 1 50 µm; the field of view is around 1 100 mm. Different from CT scanning, a long acquisition time (from 10 to 300 minutes) is necessary (Kalender, 2011). Micro-CT has been used in bioarcheological contexts. Some examples include the study of taphonomical changes in bog body bones (Boel and Dalstra, 2007) and the investigation of fossil teeth to evaluate antemortem treatment of dental pathology (Oxilia et al., 2017).

Magnetic Resonance Imaging Postmortem alterations are usually more marked in soft tissues than in bones (Ruhli and Boni, 2000; Ruhli et al., 2004; Lynnerup, 2007; Lynnerup and Ruhli, 2015; Sydler et al., 2015). Unfortunately, these values cannot be applied directly to mummies or degraded dry bones. Though morphologically well preserved, mummified tissues display a different radio-opaque response (Ruhli et al., 2004; Lynnerup, 2007). Consequently, 3D visualizations created using the clinical ranges and the volume-

Magnetic resonance imaging (MRI) is a nonionizing imaging (not using X-rays) technique that provides detailed information of organs and soft tissues. MRI uses properties of the hydrogen atoms to “see” within a body. Hydrogen is the most abundant atom in the body and is commonly found in water and fat. The magnetic resonance (MR) activate nuclei of the hydrogen, i.e., nuclei where the number of protons is not equal to the number of neutrons align their axis of rotation to the magnetic field generated inside

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the MR. When the field is turned off, the hydrogen atoms gradually return to their normally random orientation. The return process produces a radio signal that can be measured by receivers in the scanner and rendered into an image (Rinck, 2001; Talbot et al., 2011). There are fewer hydrogen atoms in bones and in desiccated mummies, making MRI technique less efficient. Several attempts have been made, unfortunately, without success (Lewin and Notman, 1983; Notman et al., 1986; Hunt and Hopper, 1996). The first visualization was possible only after invasive rehydration of the tissues (Piepenbrink et al., 1986). Many studies have been conducted, and MR images have been obtained without invasive treatment of the sample (Ruhi et al., 2007; Giovannetti et al., 2016). For a comprehensive review, the readers can refer to Ruhli (2015) and Giovannetti et al. (2016).

CONCLUSION Radiographic technologies are outstanding diagnostic tools for the paleopathologist. They are not invasive and allow permanent documentation of the specimen. Having access to radiography is a must for any paleopathological laboratory, and serious consideration should be given to bringing along portable X-ray equipment in the field, if specimens cannot be removed from the site. Recently, concern has been raised about whether X-rays may be detrimental to ancient DNA, and thus whether X-raying or CT scaning should be avoided prior to sampling for ancient DNA (Immel et al., 2016). However, as far as we know, no studies have specifically tested effects of radiation at the level of ordinary diagnostic X-rays and CT scans on dry bone specimens. Wanek et al. (2013) performed a theoretical study and concluded that in mummified tissue, cell shrinkage caused by dehydration probably decreased the impact of X-ray radiation on mummified cells significantly, and that backscattered electrons in cortical bone protected deeper lying ancient cells from radiation damage. It should also be noted that advances in digital X-raying have decreased radiation levels, so that a normal X-ray of, e.g., a skull more or less equals the background radiation level over approximately 5 years (refer to the Report of United Nations Scientific Committee, 2010). Finally, along with laser surface scanning, CT scanning is an excellent source of 3D data, which may enable the production of 3D print copies of specimens and lesions. All these new modalities offer new and exciting ways for presenting and sharing diagnostic deliberations and pathological specimens, including for teaching purposes.

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Rosen, R.A., Deshmukh, S.M., 1985. Growth arrest recovery lines in hypoparathyroidism. Radiology 155, 61 62. Ruff, C.B., 2000. Body size, body shape, and long bone strength in modern humans. J. Hum. Evol. 38, 269 290. Ruff, C.B., Hayes, W.C., 1983. Cross-sectional geometry of Pecos Pueblo femora and tibiae a biomechanical investigation: I. Method and general patterns of variation. Am. J. Phys. Anthropol. 60, 359 381. Ruhi, F.J., Boni, T., Perlo, J., Casanova, F., Baias, M., Egarter, E., et al., 2007. Non-invasive spatial tissue discrimination in ancient mummies and bones in situ by portable nuclear magnetic resonance. J. Cult. Heritage 8, 257 263. Ruhli, F.J., 2015. Short Review: Magnetic resonance imaging of ancient mummies. Anat. Rec. (Hoboken) 298, 1111 1115. Ruhli, F.J., Boni, T., 2000. Radiological aspects and interpretation of post-mortem artefacts in ancient Egyptian mummies from Swiss collections. Int. J. Osteoarchaeol. 10, 153 157. Ruhli, F.J., Chhem, R.K., Boni, T., 2004. Diagnostic paleoradiology of mummified tissue: interpretation and pitfalls. Can. Assoc. Radiol. J. 55, 218 227. Runestad, J.Q., Ruff, C.B., Nieh, J.C., Thorington Jr., R.W., Teaford, M. F., 1993. Radiographic estimation of long bone cross-sectional geometric properties. Am. J. Phys. Anthropol. 90, 207 213. Saab, G., Chhem, R., Bohay, R.N., 2008. Paleoradiologic techniques. In: Chhem, R.K., Brothwell, D.R. (Eds.), Paleoradiology. Imaging Mummies and Fossils. Springer. Sajko, S., Stuber, K., Wessely, M., 2011. Growth Restart/Recovery Lines involving the vertebral body: a rare, incidental finding and diagnostic challenge in two patients. J. Can. Chiropr. Assoc. 55, 313 317. Scheuer, L., Black, S., 2000. Developmental Juvenile Osteology. Academic Press. Seibert, J.A., 2004. X-ray imaging physics for nuclear medicine technologists. Part 1: Basic principles of X-ray production. J. Nucl. Med. Technol. 32, 139 147. Seibert, J.A., Boone, J.M., 2005. X-ray imaging physics for nuclear medicine technologists. Part 2: X-ray interactions and image formation. J. Nucl. Med. Technol. 33, 3 18. Seiler, R., Spielman, A.I., Zink, A., Ruhli, F., 2013. Oral pathologies of the Neolithic Iceman, c.3,300 BC. Eur. J. Oral Sci. 121, 137 141. Siffert, R.S., Katz, J.F., 1983. Growth recovery zones. J. Pediatr. Orthop. 3, 196 201. Singh, M., Nagrath, A.R., Maini, P.S., 1970. Changes in trabecular pattern of the upper end of the femur as an index of osteoporosis. J. Bone Joint Surg. 52, 457 467. Stock Jay, T., 2002. A test of two methods of radiographically deriving long bone cross-sectional properties compared to direct sectioning of the diaphysis. Int. J. Osteoarchaeol. 12, 335 342. ¨ hrstro¨m, L., Rosendahl, W., Woitek, U., Ru¨hli, F., 2015. Sydler, C., O CT-Based assessment of relative soft-tissue alteration in different types of Ancient Mummies. Anat. Rec. (Hoboken) 298, 1162 1174. Talbot, J., Kaut Roth, C., Westbrook, C., 2011. MRI in Practice. John Wiley and Sons Ltd. Thomas, A.M.K., Banerjee, A.K., 2013. The History of Radiology. Oxford University Press. Torchia, M.E., Ruff, C.B., 1990. A quantitative assessment of crosssectional cortical bone remodeling in the femoral diaphysis following hip arthroplasty in elderly females. J. Orthop. Res. 8, 883 891.

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Villa, C., Lynnerup, N., 2012. Hounsfield units ranges in CT-scans of bog bodies and mummies. Anthropol. Anz. 69 (2), 127 145. Villa, C., Davey, J., Craig, P.J.G., Drummer, O.H., Lynnerup, N., 2015. The advantage of CT scans and 3D visualizations in the analysis of three child mummies from the Graeco-Roman Period. Anthropol. Anz. 72, 55 65. Walker, P.L., Cook, D.C., Lambert, P.M., 1997. Skeletal evidence for child abuse: a physical anthropological perspective. J. Forensic Sci. 42, 196 207. Wanek, J., Speller, R., Ruhli, F.J., 2013. Direct action of radiation on mummified cells: modeling of computed tomography by Monte Carlo algorithms. Radiat. environ. biophys. 52 (3), 397 410.

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Chapter 8

Ancient DNA in the Study of Ancient Disease Anne C. Stone1,2,3 and Andrew T. Ozga2,3 1

School of Human Evolution and Social Change, Tempe, AZ, United States, 2Center for Evolution and Medicine, Tempe, AZ, United States, 3Institute

for Human Origins, Tempe, AZ, United States

INTRODUCTION TO ANCIENT DNA As discussed in this volume, human skeletal remains can contain a multitude of clues about the impact of pathogens and chronic diseases on the overall health of past peoples. However, many pathogens are known to cause death quickly, resulting in limited, if any, skeletal manifestations, causing the remains to appear “healthy.” In addition, death often may be the result of multiple factors that can include early life insults that contribute to frailty (e.g., DeWitte, 2015, see also Chapter 2) or coinfections. For example, tuberculosis (TB) is the leading cause of death today for individuals with human immunodeficiency virus (HIV) (TB/HIV facts 2015, http://www.who. int/hiv/topics/tb/tbhiv_facts_2015/en/). Such complexities can be addressed through the use of ancient DNA analysis methods. The study of DNA from archeological remains, often referred to as molecular archeology or, more recently, paleogenomics, uses techniques from molecular and evolutionary biology to address an array of questions about the population history and evolution of past peoples, domesticates, and pathogens. Although ancient DNA research began in the 1980s (Hagelberg et al., 1989; Higuchi et al., 1984; Pa¨a¨bo 1985), the focus on ancient disease did not begin until the early 1990s. This initial research focused primarily on Mycobacterium tuberculosis and Mycobacterium leprae (Arriaza et al., 1995; Rafi et al., 1994; Salo et al., 1994; Spigelman and Lemma, 1993). In addition to infectious disease pathogens, some of the early work also examined immune loci, specifically HLA (Ivinson et al., 1992; Lawlor et al., 1991), and loci related to hemoglobinopathies (Be´raud-Colomb et al., 1995; Filon et al., 1995). The early era of ancient DNA (i.e., pre-next-generation

sequencing) was laborious and results often were contested due to difficulty in identifying contamination from modern DNA. In the last 10 years, the development of new extraction and sample preparation methods for ancient DNA analysis as well as the application of nextgeneration sequencing (NGS) has facilitated ancient genomics, including the investigation of ancient pathogen genomics. Regardless of methodology, the examination of past diseases through ancient DNA requires awareness of the evolutionary context of the pathogen and its host. To accomplish this, ancient DNA researchers need to be conversant in a number of related fields: population genetics, evolutionary biology, computational biology, human genetics, and pathogen genetics. In order to establish an appropriate evolutionary context, relevant modern genetic data must be included (including from closely related taxa) for comparison with sequences recovered from ancient samples. Thus, the initial design of the research project is crucial so that the data obtained are informative from an anthropological or evolutionary medicine perspective and so that the results are statistically robust. Ancient DNA, when successfully obtained, can address many questions about the host and the microbial (including pathogen) environments in which they lived. One basic goal in this research is confirming whether a specific pathogen is present, which is of particular interest to the paleopathologist who wants to know whether a particular skeletal lesion might be the result of a specific pathogen. Such analyses could also help indicate the range of phenotypes caused by the pathogen in question. Importantly, absence of evidence must not be interpreted as evidence of absence, since pathogen DNA may not be

Ortner’s Identification of Pathological Conditions in Human Skeletal Remains. DOI: https://doi.org/10.1016/B978-0-12-809738-0.00008-9 © 2019 Elsevier Inc. All rights reserved.

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preserved. In addition, the presence of a particular pathogen does not necessarily mean that it was the cause of death. From an evolutionary perspective, simply identifying the presence of a pathogen is not as interesting as placing the agent of disease into larger epidemiological or evolutionary contexts. For example (as discussed later in this chapter), recent analyses of both Justinian plague and Black Death victims have shown that the bacterium Yersinia pestis was indeed the cause of both pandemics (Bos et al., 2011; Schuenemann et al., 2011; Wagner et al., 2014). This research has laid to rest many debates about the cause of both plague events; however, it has also illustrated the power of evolutionary analyses to shed light on the course of pandemics over time, including changes in the pathogen itself. In addition, current and future work on the human host, specifically people living before and after these pandemics, may reveal adaptations that increased resistance to Y. pestis in the affected populations over time. Finally, ancient DNA analyses can offer information about some of the changes in the human microbiome over time, including how it has been impacted by changing subsistence patterns and the manner by which it contributes to health. In this chapter, we will discuss the current methods used to study ancient DNA along with some of the successes and challenges of this work.

History/Trajectory of the Field Ancient DNA analyses have been driven by technological advances in molecular biology as well as theoretical advances in population genetics and phylogenetics. During the 1980s, these advances were fostered by the invention of the polymerase chain reaction (PCR) (Mullis et al., 1986; Saiki et al., 1988). This method became the workhorse of ancient DNA research, as well as much of molecular biology in general, because this technique can copy a specific fragment of DNA (or RNA if reverse transcriptase PCR (RT-PCR) is used), essentially doubling the number of fragments for every “cycle” of amplification. This can be successful even if there are only a few of the relevant copies of the desired sequence in the initial extraction elution. PCR was followed by one of three primary techniques: DNA fragment analysis using restriction enzymes to analyze polymorphic sites, direct Sanger sequencing (which provides an “average” or consensus sequence of the DNA fragment), or cloning, whereby the PCR products were inserted into a bacterial vector (to separate and copy individual molecules of the pool of DNA products generated by PCR) followed by direct sequencing of some of the clones. The successful amplification of PCR products from ancient DNA is often influenced by coextracted inhibitors, the amount of starting template, DNA damage, and the size of the targeted

sequence (Handt et al., 1994; Ho¨ss et al., 1996; Pa¨a¨bo, 1989). In addition, the widespread use of PCR for the amplification of low template and/or damaged material (i.e., ancient DNA) revealed the challenges of contamination either during sample excavation, preparation, extraction, or during the PCR preparation itself, resulting in assessments of where during these processes contamination was likely and recommendations of how to prevent it (Champlot et al., 2010; Cooper and Poinar, 2000; Deguilloux et al., 2011; Leonard et al., 2007; Malmstrom et al., 2005; Richards et al., 1995). Many of the first-generation ancient DNA studies focused on mitochondrial DNA (mtDNA) (Hagelberg and Clegg, 1991; Higuchi et al., 1984; Pa¨a¨bo et al., 1988; Stone and Stoneking, 1993). mtDNA is found in the mitochondria, the energy-producing organelles typically present in hundreds or even thousands of copies within most cells. Thus, mtDNA is easier to obtain compared with nuclear DNA, considering it has a much higher copy number per eukaryotic cell (estimated at 1100 8800 copies/cell (Bogenhagen and Clayton, 1974)). A few studies targeted pathogen DNA though comparative pathogen data were often scarce since many pathogens of interest remained uncharacterized either without a complete genome sequence or in terms of their diversity (or both). As a result, the early ancient pathogen studies generally focused on identifying the presence of a single pathogen in a sample (Rafi et al., 1994; Salo et al., 1994; Spigelman and Lemma, 1993) rather than evolutionary analyses. Exceptions to this rule include studies of such viruses as the influenza virus and HIV, which possess genomes small enough to sequence completely (Taubenberger et al., 2005; Worobey et al., 2008). Another major challenge to PCR testing for the presence of a single pathogen is that these analyses were, in general, phylogenetically uninformative. In other words, while many of these studies may have in fact found the pathogen in question, it was often not possible to distinguish the result from contamination or a closely related nonpathogenic microbe found in the burial environment. For example, early research on ancient tuberculosis used the IS6110 element or short gene sequences to identify M. tuberculosis complex (MTBC) DNA (e.g., Arriaza et al., 1995; Salo et al., 1994; Spigelman and Lemma, 1993). Such sequences do not provide sufficient information to distinguish strains, and thus, target DNA contaminated by positive controls used in the laboratory cannot be clearly excluded. As a molecular technique, PCR is still common in genetics laboratories due to its low cost and ease of use. It is often a quick way to test samples for contamination or for the presence of host or pathogen DNA. In particular, a method known as quantitative PCR (qPCR), in which fluorescent probes adhere to specific DNA sequences, can be used to quantify directly the number of DNA molecules amplified during each cycle of the PCR process

Ancient DNA in the Study of Ancient Disease Chapter | 8

(Heid et al., 1996). The resulting amplification curve is an illustration of the number of DNA molecules present in each sample over the course of each PCR cycle. qPCR can be used for a number of purposes: to quantify the number of starting molecules (important for library preparation as discussed in the next section), to detect inhibition due to coextracting inhibitors, and to screen samples to assess whether they would be amenable to the newer, more timeconsuming and expensive NGS methods (Bunce et al., 2012; Enk et al., 2013; Harkins et al., 2015; King et al., 2009; Poinar et al., 2006). However, when testing for the presence of a pathogen, care must be taken in the design of the qPCR assays to avoid false positives from related environmental microbes. For example, Harkins et al. (2015) showed that the initial design of a qPCR assay using two primers and a probe that targeted a specific MTBC sequence in the rpoB gene was not, in fact, specific to the MTBC. This assay also showed a low signal for other mycobacteria outside of the complex. Unfortunately, damaged and/or inhibited ancient TB DNA can also show a low signal. After taking advantage of new rpoB sequences from mycobacteria deposited in NCBI’s sequence database, GenBank, the qPCR primers and probe were redesigned (resulting in fewer positive samples that were more in line with qPCR data from other markers as well as data from targeted capture and sequencing). Importantly, this qPCR process is used as a first evaluative step in determining sample quality and which would then be subjected to the next-generation methods described below to confirm the result and allow evolutionary analyses.

Current Methods One of the main challenges of working with ancient DNA compared to modern DNA is that, over time, DNA degrades into shorter and shorter fragments, eventually becoming too small to assemble properly into identifiable sequences even with the most advanced bioinformatic techniques. Early research analyzing ancient DNA used dried tissue (Higuchi et al., 1984; Pa¨a¨bo, 1985) and bone (Hagelberg et al., 1989). In recent years, additional materials have been shown to be reservoirs for the preservation of ancient genetic material including hair, coprolites (paleofeces), and dental calculus (Black et al., 2011; Bonnichsen et al., 2001; Poinar et al., 1998). The analysis of DNA from these ancient materials is feasible due to a number of advances in molecular genetics, the first of which was PCR (Mullis and Faloona, 1987; Saiki et al., 1988). More recently, new methods of DNA extraction, library construction, DNA capture, DNA sequencing (specifically NGS), and modern contamination quality control checks have allowed the field of ancient genomics to progress substantially.

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The first ancient DNA studies were aimed primarily at successfully extracting and then sequencing DNA using traditional Sanger sequencing, most commonly of fragments of mtDNA (e.g., Hagelberg and Clegg, 1991; Higuchi et al., 1984; Pa¨a¨bo, 1989). Newer studies that use NGS have generated complete mitochondrial and nuclear genome sequences from human samples and full microbial genomes as part of microbiome analyses (e.g., Green et al., 2010; Poinar et al., 2006; Rasmussen et al., 2010; Warinner et al., 2014b). While the methods for ancient DNA analysis have developed rapidly, due partly to studies of the ancient Homo lineage including the Neandertal and Denisovan genome projects (Green et al., 2010; Reich et al., 2010), basic techniques are common in most analyses. These include sample preparation and DNA extraction, which involve decontaminating the outer layer of the ancient material before extracting DNA through a variety of methods that include traditional phenol chloroform and silica-based filtration protocols. These are followed either by PCR and Sanger sequencing (common in older analyses) or by newer techniques such as DNA library preparation, targeted capture (also known as targeted enrichment), and NGS, which allows for deep, parallel sequencing of one or more samples on a single lane/ run of a DNA sequencer. Before briefly discussing each of these procedures, it is important to review the factors that are thought to affect DNA preservation in a sample.

DNA Preservation Many factors influence DNA preservation in biological materials, including the environment, the source material, and the characteristics of the genetic material itself. Typically, the quality and quantity of DNA isolated from ancient material is better from tooth roots than from bone, and better from bone than mummified soft tissue (Alonso et al., 2001; Kurosaki et al., 1993; O’Rourke et al., 1996; Stone et al., 2001). Recent research suggests that the petrous portion of the temporal bone and dental calculus may harbor the best-preserved host DNA (Ozga et al., 2016; Pinhasi et al., 2015). Environments with cooler mean annual temperatures, neutral or slightly alkaline pH, and dry conditions are best for DNA preservation, although samples found in wet anoxic conditions (with neutral pH) have also yielded DNA (Campos et al., 2012; Hagelberg and Clegg, 1991; Holland et al., 1993; Ho¨ss, 1994; Lawlor et al., 1991; Pru¨fer et al., 2014). Samples obtained from permafrost have yielded the oldest DNA sequences as well as the highest endogenous DNA content (Ho¨ss et al., 1994; Schwarz et al., 2009; Shapiro et al., 2004). In particular, permafrost has produced the oldest ancient genome to date, that of a 750,000-year-old Siberian horse (Orlando et al., 2013). DNA preservation also may depend on the characteristics of the DNA.

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Specifically, whether the DNA is mitochondrial, nuclear, or from pathogens with a lipid cell wall (such as TB) may impact preservation (Donoghue et al., 2004; Higgins et al., 2015; Nguyen-Hieu et al., 2012; Schuenemann et al., 2013; Zink et al., 2002). In very cold environments, theoretical analyses suggest that DNA as old as one million years of age could be recovered (Millar and Lambert, 2013). However, the presence or absence of the conditions for ancient DNA preservation noted here do not guarantee successful recovery, and poorly preserved biological materials, against all odds, can produce usable ancient genetic material. Discerning which skeletal tissue is best to sample in a specific environmental context is difficult, and results vary across studies. In research comparing DNA preservation in bone, dentin, and cementum in Neolithic humans excavated in Germany, Adler et al. (2011) found that cementum contained the highest quantities of DNA, and DNA extracted from teeth had a lower number of damaged sequences compared to bone. However, cementum covers the roots of teeth in a very thin layer; thus, most researchers undoubtedly include both cementum and dentin in DNA extractions from the tooth root. As an additional contamination control, many researchers remove the surface of the tooth root mechanically through abrasion or using diluted bleach (B5% sodium hypochlorite) prior to DNA extraction; this process likely removes much of the cementum and potentially reduces DNA yield (Higgins et al., 2013). Comparisons of tooth types within the mouth generally indicate that DNA is best preserved in roots of the larger molars (Rubio et al., 2009) and in teeth that have not been compromised by caries or other pathologies that damage enamel and would foster the entry of environmental microbes into the interior of the tooth (Higgins and Austin, 2013; Higgins et al., 2011). Recently, the petrous portion of the temporal bone was reported to yield more DNA than other skeletal elements, including teeth from archeological sites ranging in age from 800 to 10,000 years old (Gamba et al., 2014; Pinhasi et al., 2015). Newer methods of DNA extraction that recover small DNA fragments, as well as the use of petrous portions and dental calculus, have also increased success rates in older contexts and warmer climates (Glocke and Meyer, 2017; Meyer et al., 2016; Pinhasi et al., 2015). Differing microenvironments, even within the same burial or excavation site, may cause varying success for DNA analysis (Hagelberg and Clegg, 1991; Milos et al., 2007; Stone and Stoneking, 1999). The temperature of the surrounding environment and time since death are two variables thought to play major roles in the maintenance of DNA integrity (Ho¨ss et al., 1996; Lindahl, 1993; Rubio et al., 2009; Smith et al., 2001, 2003). For example, during the first 20 days postmortem, DNA in human tissues

decreases exponentially (Bar et al., 1988). To understand the rate at which DNA degrades over time, Allentoft et al. (2012) analyzed 158 radiocarbon-dated bones ranging in age from B600 to 8000 before present (BP) and found that the average DNA half-life was 521 years for a 242 base pair (bp) mtDNA sequence. However, this was in a relatively cool environment (burial temperature of 13.1 C/55.5 F), and temperature appeared to explain only 38% of the variance in success rate of DNA recovery. Relatively few studies have examined the rate of DNA degradation over time in different environments (Adler et al., 2011; Colotte et al., 2009; Marota et al., 2002). Instead, most have focused on theoretical expectations (Smith et al., 2003; Willerslev et al., 2004). Other environmental factors affecting DNA recovery include substances, such as fulvic acids, naturally found in soil, that can be coextracted with the DNA to inhibit downstream PCR and make DNA analysis difficult, though many protocols, such as silica-based purification columns address these issues (Poinar et al., 1998; Tuross 1994). These studies of DNA preservation have focused primarily on host DNA rather than pathogen DNA. The preservation of pathogen DNA within an individual is difficult to predict and is likely affected by pathogen type and load at the time of death of the host, as well as many of the environmental features noted above. Also, pathogen load can vary substantially across tissues. Examples of pathogen recovery from very old contexts include Helicobacter pylori from the Iceman (a 5300year-old frozen mummy from the Alps), Y. pestis from Eurasian Neolithic and Bronze Age individuals, and, recently, the presence of the periodontitis-associated “red complex” (Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola) in Neandertals (Andrades Valtuena et al., 2017; Maixner et al., 2014, 2016; Rasmussen et al., 2015; Weyrich et al., 2017). There is some indication that for chronic diseases that result in bony lesions, the pathogen may be easiest to obtain from the bony lesion itself or in nearby bone. However, the lesions themselves, if osteoclastic, may be comprised of fragile, less dense bone that results in poor DNA preservation. Systemic infections, such as Y. pestis, can be detected in tissues throughout the body, though tooth roots and the pulp cavity are typically used, since they demonstrate better DNA preservation in general (Bos et al., 2011; Devault et al., 2014b). To date, pathogen DNA has not been reported from petrous temporal samples even from systemic infections (Margaryan et al., 2018). DNA from pathogens found in the gastrointestinal system has been recovered from both dental calculus and coprolites (e.g., Cleeland et al., 2013; Iniguez et al., 2006; Loreille et al., 2001; Warinner et al., 2014b), though respiratory and systemic pathogens could be expected to be found in such samples as well. For example, M.

Ancient DNA in the Study of Ancient Disease Chapter | 8

tuberculosis can be detected in both modern fecal and calculus samples (Eguchi et al., 2003; Kokuto et al., 2015; Palakuru et al., 2012), though it has not yet been recovered from ancient fecal or calculus samples. Properties of the pathogens themselves may also promote preservation or make them less likely to be recovered. For example, parasitic eggs built to withstand environmental challenges after fecal deposition and mycobacteria with mycolic acid membranes may preserve better than many other pathogens (Loreille et al., 2001; Schuenemann et al., 2013), while RNA viruses would be less likely to be recovered because of the rapid degradation of RNA after death. To date the only “ancient” RNA analyses have been from the 1918 flu virus as discussed further below.

Sample Preparation and DNA Extraction One of the greatest concerns regarding ancient DNA analyses is contamination from modern sources and the surrounding environment. As such, proper collection, storage, and preparation of samples are each important for securing authentic DNA data. Ideally, samples should be recovered from the field with the utmost caution so as not to introduce any spurious modern genetic material. If possible, the sample should be deposited into a sterile collection container using gloved hands immediately upon discovery. However, since this is not always possible during field excavations, all samples must undergo further decontamination protocols in the laboratory. All preparation of biological materials should be carried out in a designated ancient DNA laboratory, one that is separate from any modern DNA laboratory and thus free of amplified DNA PCR products that could contaminate the extraction process (Fig. 8.1). This ancient laboratory should have an area designated for both sample preparation and extraction and have a filtered, enclosed airflow system and ultraviolet (UV) lighting. Sample preparation should be performed with gloves, masks, gowns, and sterile materials (including scalpels, saws, drills, and containers). These tools and workbenches should be cleaned regularly with bleach, ethanol, and molecular grade H2O and UV irradiated before and after each use. Samples should be stored in a constant temperature environment (preferably a cool dark place with low humidity), as DNA can degrade over time under poor storage conditions (Pruvost et al., 2007; Rubio et al., 2009). The removal of surface contaminants from samples should be carried out in a designated enclosed area (preferably an out-of-use PCR hood) in order to prevent any bone dust and debris from entering the extraction area. The surface of the sample should be removed by cutting or grinding away the exposed layers of bone or tooth root. Alternatively, the surface can be sterilized by irradiating the surface with UV light or by soaking the material in a hydrochloric acid

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or bleach solution. The sample should then be pulverized into dust or small pieces. This process can be carried out using a scalpel, a hammer, a bone mill, or a slow-speed drill (a dremel with a sterilized diamond wheel, for example). This step increases the surface area of the material, which improves the recovery of DNA during the extraction process. Because of the concerns about contamination and false results, the procedures used to prepare samples and prevent contamination have been the subject of considerable discussion and analysis in the ancient DNA community (e.g., Cooper and Poinar 2000; Malmstrom et al., 2007; Pilli et al., 2013). Once the samples have been prepared, the next step is the extraction of DNA from the material, whether that is tissue, bone, tooth roots, dental calculus, coprolites, soil, or hair (Adler et al., 2013; Gilbert et al., 2004; Hagelberg and Clegg, 1991; Ozga et al., 2016; Poinar et al., 1998; Rasmussen et al., 2011; Slon et al., 2017). The samples must first be treated with solutions that allow the DNA to be accessible and remove unwanted contaminants, including amino acids and proteins. Most techniques for ancient DNA extraction use ethylenediaminetetraacetic acid (EDTA) and proteinase K to inactivate DNases and digest proteins that may hinder proper extraction. The next steps of the extraction either take advantage of the fact that most proteins are hydrophobic (and DNA is hydrophilic) to successively separate the DNA from the other cell materials or make use of a binding agent to adhere the DNA to a filter and wash away all other elements. This first process references phenol chloroform extraction, while the second involves a silica-binding protocol, both of which are still used regularly within ancient DNA laboratories. The phenol chloroform extraction method separates the proteins and hydrophobic lipids from the nucleic acids and was first used for ancient DNA analyses (Hagelberg and Clegg, 1991; Higuchi et al., 1984). However, this method can also result in coextraction of inhibitors that can inhibit subsequent reactions; thus, the use of a silica column which is more efficient at removing inhibitors is a recommended next step. The silica-based extraction methods use chaotropic salts (primarily guanidinium isothiocyanate or guanidinium hydrochloride) to catalyze the adsorption of DNA to silica as well as help digest proteins (Dabney et al., 2013; Ho¨ss and Pa¨a¨bo, 1993; Rohland and Hofreiter, 2007; Yang et al., 1998). These methods employ either a silica column or silica-binding buffer and have been shown to maximize the recovery of endogenous DNA (Gamba et al., 2016). Of importance to particularly degraded samples, the method developed by Dabney et al. (2013) increases the yield of very short DNA fragments less than 80 bp in size. Extremely short fragments (B25 bp) have been recovered from Middle Pleistocene remains using both enhanced extraction and library preparation methods (Glocke and Meyer, 2017).

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FIGURE 8.1 A flow chart illustrating the ancient DNA methods pipeline up to sequencing. Samples arrive at the laboratory and are decontaminated using bleach and a UV crosslinker; the outer layer may also be shaved off using a Dremel at this point. Protective gear is donned by the researcher and the sample is pulverized. DNA is extracted from the sample depending on the chosen methodology. Samples are assessed for quality and go onto traditional PCR or qPCR probes, or alternatively single/double-stranded library builds. Samples are then indexed to a specific number of cycles as designated by qPCR output or the selected methodology. After another quality check the samples can be sequenced outright (referred to as shotgun sequencing) or captured using homemade/manufactured biotinylated baits which bind to amplified DNA and then to a magnet, allowing the nontarget DNA to be washed away. The target DNA can then undergo another round of quality control in order to determine whether more amplification cycles are necessary before sequencing.

Preprepared extraction kits from biotechnology companies can be used, but these typically are not calibrated to the low quantities and small fragment sizes of ancient DNA. It is also important to note that these methods will extract all of the DNA in the sample, which may include both host and pathogen DNA from the surrounding environment (Pedersen et al., 2015), along with the genetic material of any human handlers (Leonard et al., 2007). Generally, less than 1% of the DNA present in the extract is endogenous to the host in question, and a much smaller percentage belongs to any specific ancient pathogen. DNA extraction methods are also available for soil, and nondestructive methods have been developed for bones, teeth, and skin samples (Bolnick et al., 2012; Hofreiter, 2012; Rohland et al., 2004; Slon et al., 2017).

NGS Analyses NGS was developed in response to the human genome project in order to increase the throughput of DNA sequence analyses (Levy and Myers, 2016; Shendure et al., 2017; Shendure and Ji, 2008). Poinar et al. (2006) were the first to apply NGS to ancient DNA research, using it to obtain 13 million base pairs of DNA, including the complete mtDNA genome from a Siberian woolly mammoth approximately 28,000 years old. This analysis used shotgun sequencing, a process where the DNA is extracted, fragmented into sequences less than 200 300 base pairs in size (a step not necessary for ancient DNA), and sequenced using a high-throughput next-generation sequencer. NGS offers a number of advantages over

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traditional Sanger sequencing and is available from biotechnology companies such as Illumina, Pacific Biosciences, Thermo Fisher Scientific (Ion Torrent), and 454 Life Sciences (GS FLX). Specifically, NGS can sequence millions of DNA molecules in parallel, which decreases the overall time and cost of obtaining large amounts of genetic data. For ancient DNA, NGS allows the investigator to obtain many independent sequence reads (i.e., sequence fragments) for a given stretch of genome without the need for standard PCR and cloning. The average number of reads per base pair is known as the depth of coverage (so 10 3 depth of coverage means that a given base is covered on average by 10, nonduplicate independent sequences). Greater depth of coverage results in higher confidence in the true sequence of the genome, including better identification of errors caused by DNA damage. In turn, this impacts downstream genome reconstructions of host or microbial DNA, allowing for more accurate evolutionary analyses. Another common term used in the discussion of NGS genome sequencing is genome coverage or coverage that reflects the percentage of the reference genome that is covered by reads at a specific depth. Thus, a coverage of 98% is excellent, while low coverage of only 30% could indicate that DNA preservation was low or possibly that the reference genome was not appropriate. Finally, NGS can also sequence much smaller DNA fragments compared with standard Sanger sequencing, which is biased toward longer fragments to allow primers to anneal and copy properly. Typical workflow for ancient DNA NGS analyses follows one of two trajectories: the shotgun technique, which sequences all adapter-ligated DNA within a single sample without bias, and targeted capture, which uses a modern genome as “bait” to extract a taxonomically similar ancient genome (Knapp and Hofreiter, 2010; Marciniak et al., 2015). Both first require the construction of a DNA library, and there are several methods for creating libraries from ancient DNA (Briggs and Heyn, 2012; Gansauge et al., 2017; Gansauge and Meyer, 2013; Meyer et al., 2012; Rohland et al., 2015; Rohland and Reich, 2012). In general, the DNA is end-repaired and annealed to a set of adapters (one on each end) that are compatible with the NGS system (such as Illumina or Ion Torrent) that will be used for sequencing. Once the adaptors have been adhered, the resulting DNA library is usually checked for quality with qPCR in order to determine the extent to which DNA has been successfully recovered from the sample. This process also estimates the number of amplifications necessary to prepare the DNA for immediate sequencing (shotgun) or targeted capture. This number is important because insufficient amplification results in few copies of the fragments of interest, resulting in poor sequencing results, and too many amplification cycles

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may result in high clonality, in which a few sequences dominate an entire sample pool. The primers used in the library amplification process contain a series of unique indices (barcodes) that allow for many samples to be run in parallel on a single sequencing run (Kircher et al., 2012). The presence of unique barcode identifiers for each sample allows for them to be demultiplexed (i.e., separated) using bioinformatic techniques after sequencing has been completed. In other words, there is little to no crossover between different samples during this process because the unique tags allow users to differentiate and examine each sample independently. Depending on the quality of the DNA and the size of the genome in question, it may be necessary to sequence a single sample at a greater depth of coverage through multiple sequencing attempts. The creation of the DNA library is particularly useful because it can be amplified and used many times for different purposes (i.e., multiple sequencing runs or by targeting different parts of the library such as DNA from the host or a specific pathogen). After amplifying the library, samples are essentially ready for shotgun sequencing or targeted capture (after confirmation of quality and concentration through quality checks with qPCRs or fragment analyzers). Shotgun sequencing is completely untargeted, meaning that in addition to host DNA, a number of other sources may be detected including DNA from bacteria, fungi, and viruses found in the host or from the burial environment. The main challenge with shotgun sequencing is that if the endogenous DNA content is very low in any given sample, the vast majority of sequencing reads will be from environmental microbes. Archeological samples generally have less than 1% endogenous DNA (Skoglund et al., 2012). Exceptions include well-preserved samples, such as those found in permafrost or caves, where the endogenous DNA content can be higher (e.g., Poinar et al., 2006; Rasmussen et al., 2010; Reich et al., 2010). Most analyses, particularly of pathogens, use some form of targeted capture to enrich for the DNA of interest prior to sequencing. Usually the pathogen to be targeted is known to be present in the sample because of an initial shotgun sequencing run, qPCR results, or through the use of a microbial detection array. The latter use a type of targeted enrichment (with baits attached to a glass slide), but they target many microbes rather than just one to assess what is present in ancient samples (Bos et al., 2015; Devault et al., 2014b). In order to target a specific pathogen, several capture methods can be employed (Briggs et al., 2009a,b; Burbano et al., 2010; Carpenter et al., 2013; Fu et al., 2013; Stiller, 2012). At present, in-solution hybridization, using single-stranded DNA or RNA baits to “fish” for complementary sequences is the most common. Targeted capture can result in much higher coverage of the desired genome accompanied with lower sequencing

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costs due to the reduction of spurious/unwanted sequences. The sequencing process can be carried out in the laboratory where the samples were prepared, or shipped to a number of sequencing centers around the world. Operating and maintaining large sequencing machines can be costly and time-intensive, therefore many researchers choose to outsource their sequencing to an offsite center, which then returns the data to the laboratory for analysis. Depending on the sequencing method used and the samples being examined, this can take anywhere from hours to weeks to complete. Once sequencing is complete, the data must be filtered to remove the low-quality sequences, the duplicates generated during library amplification, and any contamination from modern DNA sources. The data are then mapped to reference sequences or de novo assembled (when there is no reference available) to produce a consensus sequence with identifiable variants needed for subsequent phylogenetic and population genetic analyses. These bioinformatics analyses typically require specialized computer programs and scripts as well as high-performance computing resources (Ginolhac et al., 2011; Jonsson et al., 2013; Louvel et al., 2016; Peltzer et al., 2016; Schubert et al., 2014). The majority of NGS analysis pipelines use command line scripting and prepackaged programs, though users can create scripts from the ground up in order to suit their data analysis needs. Samples may require multiple rounds of extraction, library construction, capture, and sequencing to obtain sufficiently high-quality sequences for subsequent genetic analyses. NGS, along with the methods for targeted capture, has transformed ancient DNA research, allowing host genomic analyses as well as the investigation of symbiotic and pathogenic microbes found in hosts.

Microbiome Analyses The methods discussed above outline the primary ways that ancient DNA is extracted and analyzed in the laboratory. However, another type of “targeted” analysis also benefiting from the technological advances associated with NGS focuses on the “microbiome”; recently, these methods have been applied to ancient human gut and oral microbiomes. The term “microbiome” was first coined in 2001 to refer to the pathogenic and commensal microorganisms within and on a particular host (Lederberg and McCray, 2001). In 2007, the National Institutes of Health initiated the Human Microbiome Project (HMP) with the goal of understanding and characterizing the many microbiota in and on humans from across the globe and assessing the influence these microbes have on overall host health (Group et al., 2009). Human microbiomes are implicated in a wide range of metabolic, immunological, and developmental processes including host metabolism

(Tremaroli and Backhed, 2012), vitamin production (LeBlanc et al., 2013), education of the immune system (Hooper and Macpherson, 2010), and defense against infection (Brotman, 2011). In combination with ancient DNA methods, the microbiome methods now allow for an investigation into the evolution of host microbiomes across species and over time. There are two primary methods for examining modern and ancient microbiomes: 16S ribosomal RNA (rRNA) targeted amplification, which allows for taxonomic identification of bacteria and archaea, and shotgun metagenomics, which is an untargeted amplification method that allows for sequencing of all DNA present within a sample regardless of its biological source. The first method targets a hypervariable region within the ubiquitous 16S rRNA gene in order to distinguish microbial taxa without the necessity of bacterial culturing (Woese and Fox, 1977). There are nine hypervariable regions of differing sizes within the 16S rRNA gene, and individual sample barcoding allows for multiplexing and pooling of many samples on a single sequencing run (Caporaso et al., 2010). These sequences (referred to as operational taxonomic units, OTUs) are then clustered based on similarity (97% or higher) which correlate to particular bacterial “species.” This method is very common in studies of modern human populations, but it is not without its flaws when used with ancient material, especially considering most ancient DNA sequences fall below the threshold (,200 bp on average) of 16S rRNA variable region detection. For example, the 16S V3 region has been shown not to properly reflect microbial taxa within ancient DNA samples (Ziesemer et al., 2015) when compared to shotgun metagenomic data. Despite these cautions, 16S analyses have still been used in a number of ancient microbiome studies, including the Neandertal oral cavity (Weyrich et al., 2017), the gut of Otzi, the Tyrolean iceman (Lugli et al., 2017), and 11th-century pre-Columbian mummies (Santiago-Rodriguez et al., 2015, 2016b). Most 16S rRNA data can be analyzed using command line custom scripts or through QIIME (Quantitative Insights into Microbial Ecology) (Caporaso et al., 2010). QIIME is an open-source bioinformatics pipeline that assists in analyzing raw data from 16S rRNA reads. Ancient DNA analysis using 16S rRNA sequences and QIIME remains a cost-effective, quick, and easy way to characterize microbial taxa from a particular environment if DNA preservation is good and the biases are considered. The second method, which is especially popular for degraded samples with average sequence lengths below 300 bp, is known as shotgun metagenomics. Although more cost-prohibitive, nontargeted shotgun metagenomics has several advantages: it goes beyond simple taxonomic identification, it identifies other nonmicrobial organisms

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including parasites, fungi, and viruses, and it allows for studies of gene function. One drawback of this method is that there is still debate regarding the best way to analyze and categorize the data. Whereas 16S rRNA can be binned into OTU groups, shotgun metagenomics is untargeted and therefore cannot give accurate taxonomic abundances. At present, QIIME is not properly tailored to examine shotgun reads, so a variety of methods are employed depending on the biological sources, laboratories, and the bioinformatics expertise of the user. Additionally, methods for determining bacterial, archaeal, and eukaryotic taxa can be computationally intensive with shotgun data and the results should be carefully examined so as not to incorporate environmental or host contamination. If a particular microbe is found to be present in the host through microbiome analyses, targeted capture can be used to increase coverage and depth as discussed earlier. To authenticate ancient microbiome analyses, whether generated via 16S, shotgun, or targeted capture, the overall damage patterns can be assessed (through MapDamage, if the target ancient genome has been mapped sufficiently to a reference) (Jonsson et al., 2013) and modern sequences can be removed through methods such as SourceTracker (within QIIME) (Caporaso et al., 2010).

APPLICATIONS OF ANCIENT DNA Ancient DNA of Pathogens That Can Leave Bony Changes: Leprosy, Tuberculosis, Brucellosis, Malaria, Syphilis A major focus of ancient pathogen genomics has been infectious agents for diseases identified through the study of diagnostic skeletal changes. Some bony changes, such as those caused by anemia, have multiple causes including infectious disease. Ancient DNA studies can confirm the diagnosis or identify potential pathogens as well as provide additional data about the spread of pathogens and their evolutionary history. Examples include the pathogens causing leprosy, tuberculosis, malaria, and syphilis. These examples also reveal some of the challenges for examining ancient DNA from pathogens.

Leprosy Leprosy or Hansen’s disease can be caused by one of two pathogens, M. leprae and Mycobacterium lepromatosis. Of these, M. leprae is the pathogen described by Hansen in 1874, while M. lepromatosis was recently identified in patients primarily in the Americas (Han et al., 2008; Hansen, 1874; Singh et al., 2015). Genome analyses show that these two mycobacteria diverged approximately 14 million years ago (Singh et al., 2015). Some of the clinical and histological signals appear similar (Scollard, 2016);

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M. lepromatosis appears to move more rapidly and diagnostic skeletal symptoms have not been recognized in this form. To date, M. lepromatosis has not been found in ancient individuals, while M. leprae has been detected using PCR assays (Haas et al., 2000; Rafi et al., 1994), SNP assays (Inskip et al., 2015; Watson and Lockwood, 2009), and full genome sequences (Mendum et al., 2014; Schuenemann et al., 2013). Other than confirming the diagnosis of leprosy in an individual, questions have included: When did M. leprae “jump” into humans (and from what)? How are ancient and modern strains in different regions of the world related to each other? And why did leprosy decline in frequency in Europe after the Medieval period? The last question is the most difficult to address, given that other factors unrelated to the biology of the pathogen may have played the largest role in the decline of leprosy in Europe (Boldsen, 2009; Manchester, 1986, 1991; O’Neill, 1993; Roberts, 1986; Steinbock, 1976). We do not see differences between the genomes of ancient and modern strains that could explain this decline (Benjak et al., 2018; Schuenemann et al., 2013). Ancient DNA analyses have helped identify the likely time period during which M. leprae began affecting humans. Specifically, Schuenemann et al. (2013) used the sequences from the ancient samples to calibrate the molecular clock. This calibration determined the mutation rate per time period, and thus, they could estimate the time to the most recent common ancestor (TMRCA) of all the M. leprae strains included in the analysis (both ancient and modern). The results showed that human M. leprae strains have a TMRCA of about 2800 BP and more recent phylogenetic analyses that include additional strains (as well as M. lepromatosis) have shifted that somewhat to B4000 years BP (Benjak et al., 2018; Schuenemann et al., 2018). To date, biogeographical analyses have been limited to ancient samples from Europe, while modern M. leprae samples have been obtained from around the world. Phylogenetic analyses of the ancient cases show multiple branches of strains in Europe, even within the same cemetery, but additional data from multiple time points and geographic regions are needed to discern the origin and assess how M. leprae subsequently spread. Data from extant strains point to an origin in Asia or Oceania, while Schuenemann et al. (2018) also suggest Europe as the potential geographic origin based on the diversity of ancient strains. DNA analyses of B150 extant human strains and three nonhuman primate strains revealed that the most basal lineages are found in the Philippines, New Caledonia, Japan, Korea, and China (Benjak et al., 2018; Honap et al., 2018; Schuenemann et al., 2013). Analyses of strains from other species indicate exchange with humans. For example, armadillos in the United States acquired leprosy from humans recently, and the genomic

192 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

analyses show that these strains are most closely related to branch 3I strains in Europe (Truman et al., 2011). An analysis of lesions in red squirrels on Brownsea Island in southern England suggests that humans gave M. leprae to them as well (also branch 3I), while the finding that red squirrels in several parts of the United Kingdom carry M. lepromatosis (which has not been identified in ancient or modern cases in Europe) is quite puzzling (Avanzi et al., 2016) and may suggest that rodents are the natural hosts of these pathogens. Genome analyses of strains of M. leprae found in nonhuman primates from Africa and the Philippines also suggest exchange with humans since they cluster with human strains from the same geographic region (Honap et al., 2018). Thus, a clear understanding of the reservoirs and/or original hosts of M. leprae and M. lepromatosis leading to human infection is currently not available.

Tuberculosis TB can be caused by any of the members of the MTBC but most cases in humans are caused by M. tuberculosis. The origins of TB have long been debated with early scholars concluding that humans likely acquired TB during the domestication of cattle since spatial proximity would have facilitated transfer of Mycobacterium bovis (see Roberts and Buikstra, 2003; Stone et al., 2009). However, the identification of TB lesions in precontact Native Americans who were not in contact with cattle cast doubt on this hypothesis (Buikstra, 1976; Daniel, 2000). More recently, molecular evidence showed that M. bovis is derived in comparison with M. tuberculosis (Brosch et al., 2002; Gordon et al., 1999). Ancient DNA analyses of tuberculosis first focused on confirming its diagnosis in skeletons in the Americas and elsewhere by amplifying a fragment of a repetitive element, IS6110, found in all members of the MTBC but absent from other mycobacteria (e.g., Arriaza et al., 1995; Donoghue et al., 1998; Salo et al., 1994; Taylor et al., 1996; Zink et al., 2001). More recent analyses of modern strains have shown that some lineage 1 strains have no copies of IS6110 (see Fig. 8.2 for an explanation of the TB lineages), and there is one example of IS6110 in a non-MTBC mycobacterial strain (Coros et al., 2008; Thierry et al., 1995; van Soolingen et al., 1993). Thus, this repeat element must be used with caution to identify ancient cases of TB. Additionally, care must be taken in the design of PCR primers or probes (for any pathogen) to be sure that related environmental pathogens are not amplified, thus giving a false-positive signal (Harkins et al., 2015; Mu¨ller et al., 2015). Genetic epidemiological analyses of TB from patients today often use analyses of the direct repeat locus (known as spoligotyping) or analyses of microsatellite repeats called mycobacterial

interspersed repetitive units-variable number of tandem repeats (Kamerbeek et al., 1997; Supply et al., 2001), but their use in evolutionary studies can be problematic because not all alleles are identical by descent and it is difficult to calculate accurate evolutionary rates for repeat elements. These loci have been assessed in a few ancient DNA studies (e.g., Zink et al., 2003), but one challenge for ancient DNA analyses is that it is difficult to discern whether the absence of a repeat is due to its actual absence in that TB strain or due to preservation issues. With the introduction of NGS, modern TB genome sequences and phylogenies confirmed that animal strains within the MTBC were derived and found that they were nested with human strains in lineages 5 and 6, common in West Africa (Hershberg et al., 2008). Hershberg et al. (2008) also proposed that human tuberculosis arose in Africa and that the early lineages (1, 5, and 6) likely dispersed out of Africa with modern humans, followed by the subsequent spread of “modern” lineages later through trade and colonization when human population densities were higher. Ancient DNA analyses of tuberculosis using NGS first focused on strains in Europe (Bouwman et al., 2012; Chan et al., 2013). Bouwman et al. (2012) used hybridization capture to target 260 regions in the TB genome, including 218 known SNPs, in DNA extracted from a late-19th-century burial in St. George’s Church Crypt, Leeds, England. The results showed that hybridization capture could be used to obtain genetic data from ancient tuberculosis strains and that this strain was closely related to H37Rv, a strain that was derived from a TB patient from New York state in 1905 (Kubica et al., 1972). Analyses of additional individuals from St. George’s Crypt as well as five other sites in the United Kingdom and one in France dating from the 2nd to 19th centuries assessed 11 SNPS (Muller et al., 2014). Of 34 samples tested, 6 individuals could be genotyped successfully and compared to extant strains. Though the number of SNPs examined was limited, the results showed that all of the ancient strains appear to fall into lineage 4 (as defined by Hershberg et al., 2008), common today in the Americas and Europe. Strains clustering in lineage 4 were also found in Hungarian burials from the 17th century (Chan et al., 2013; Kay et al., 2015). Importantly, Kay et al. (2015) also demonstrated that most individuals are infected by multiple strains, making analyses more challenging, and they estimate the TMRCA of lineage 4 strains to approximately AD 400. Questions about the source of ancient tuberculosis in the Americas and the timing of its origin in humans were addressed by Bos et al. (2014). Using targeted capture to recover the complete genome sequences of M. tuberculosis from three ancient individuals from the Osmore River Valley of Peru, they found that the ancient Peruvian strains (Fig. 8.2) are most closely related to strains

Ancient DNA in the Study of Ancient Disease Chapter | 8

M. tuberculosis L1-L7

L1

L5

L6

820–1571 1471–2286

L7 416–958

1210–2364

M. canettii 276

5–5

104

2659–4904

L4 1254–2343

2

MRCA 2951–5339

5

M. microti

02

–5

2 79

Chimpanzee bacillus

307–750 1014–1294 1439–2510 977–1183

2510–4576

M. pinnipedii

Ancient Peruvian humans

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FIGURE 8.2 A Bayesian maximum clade credibility tree of 261 MTBC genomes, with estimated divergence dates in years BP using a model of population expansion. The lineages are defined based on analyses of modern strains. Lineage 1 (L1) strains are typically found along the rim of the Indian Ocean and in the Philippines. L2 and L3 strains are found in East Asia and India/East Africa, respectively. L4 strains are found in Europe and the Americas today. L5 and L6 strains are found in West Africa, and L7 strains were recently identified in Ethiopia. Reproduced from Bos et al. (2014).

1779–3422 1653–3113

M. orygis

1271–2429 877–1717

L3

M. caprae M. bovis

L2

adapted to sea mammals (specifically Southern Hemisphere seals and sea lions which carry MTBC strains that are classified as Mycobacterium pinnipedii). This was unexpected, and it suggests that tuberculosis first arrived in the Americas by jumping from South American seals to humans, likely through transmission during butchering or consumption of undercooked seal meat. Phylogenetic analyses and mutation rate estimation, calibrated using the radiocarbon-dated samples, also allowed Bos et al. to estimate the TMRCA of the MTBC and showed that this ancestor was more recent (only B3000 6000 years old) than previous estimates, which ranged from B35,000 to B3 million years ago (Comas et al., 2013; Gutierrez et al., 2005; Hughes et al., 2002). Whether such pinnipedderived MTBC strains spread to inland parts of South America as well as North America by human-to-human transmission, or whether different strains spread into North America via another route, such as from Asia via the Bering Strait during the Inuit-Aleut expansion (introduction through both routes could have occurred), is not known. These findings demonstrate the ability of the MTBC to infect different mammalian hosts because, after the initial “jump” into humans 3000 6000 years ago, a human strain jumped back into other animals, ultimately including seals, who then eventually passed it back to humans in the Americas. How often this back and forth has occurred, as well as the selective pressures on the mycobacteria after such jumps, are open questions. Additional questions about tuberculosis include: What

was the pattern and pace of lineage 4 TB strain introduction in the Americas (and elsewhere) during colonization? What were the evolutionary forces that shaped tuberculosis diversity over time? And where (and from what species) did M. tuberculosis first jump into humans?

Brucellosis Brucellosis is a zoonotic infection transmitted by Brucella through direct contact with animals or their byproducts. This disease can leave skeletal changes in humans that may be confused with those left by tuberculosis, thus aDNA offers a particular advantage to paleopathologists seeking to definitively diagnose such cases. Brucellosis has been identified in a few geographical areas throughout the globe using ancient DNA techniques. Brucellosis DNA was detected in samples from the Middle Bronze Age Middle East (3500 BP), Butrint, Albania (800 1000 BP), and from Medieval Italy (700 BP) (Kafil et al., 2014; Kay et al., 2014; Mutolo et al., 2012). Additionally, Kay et al. used shotgun sequencing to recover a 6.5 3 Brucella melitensis genome. They reported that the Medieval strain from Sardinia is more closely related to Italian strains and suggest an initial zoonotic origin from sheep or goats (Kay et al., 2014). Brucellosis is a commonly ignored public health concern found across historical texts but usually impacts younger individuals and only leaves skeletal evidence in 20% 85% of cases (Geyik et al., 2002; Rossetti et al., 2017).

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Malaria Malaria, caused by several species of Plasmodium, has likely affected humans (and other primates) for millennia, though the environmental and settlement changes associated with the shift to agriculture likely intensified its impact on human populations. This is evidenced by estimates of the ages of alleles that confer resistance and estimates of when these parasites likely became humanspecific (Hedrick, 2011; Loy et al., 2017; Verrelli et al., 2002). While malaria itself does not cause bony changes in the skeleton, chronic anemia associated with malaria can leave nonspecific evidence detectable in the bioarcheological record. In addition, some of the alleles that confer resistance to malaria can also cause anemia (such as sickle cell anemia and thalassemia), and these can be assessed in ancient skeletons. For example, to examine whether a child with skeletal pathologies consistent with severe anemia from a 3800-year-old cemetery in Israel had beta-thalassemia, Filon et al. (1995) used PCR to amplify a fragment of the β-globin gene. Hemoglobin, which transports oxygen in the blood, is comprised of α-globin and β-globin chains. Individuals with thalassemia have a deficiency or complete lack of one of these two components. In this particular case, Filon et al. found that the child suffered from β-thalassemia major, since it was homozygous for a null mutation common in the Mediterranean that results in no production of the adult form of β-globin (most people begin producing the adult form early in childhood). This child also likely survived to the age of eight because of elevated levels of fetal hemoglobin production. Additional studies have searched for mutations causing β-thalassemia in the Mediterranean (Hughey et al., 2012; Sallares et al., 2004; Vigano et al., 2017). Direct testing for malaria in skeletons has been successful in only a few cases (Marciniak et al., 2016; Sallares et al., 2003). Marciniak et al. tested Imperial period skeletons dating to the 1st 2nd centuries AD from southern Italy and found that two individuals were infected with Plasmodium falciparum, which causes severe malaria. The authors were able to capture B51% of the P. falciparum mtDNA genome in order to identify the species causing disease, but, unfortunately, they were not able to obtain sufficient sequence for informative evolutionary analyses.

Syphilis The causative agent of syphilis (both venereal and congenital) as well as yaws and bejel (also known as endemic syphilis) is Treponema pallidum, typically with the different diseases being associated with different subspecies of T. pallidum (subspecies pallidum, pertenue, and endemicum, respectively). A fourth treponemal disease, pinta,

classified as Treponema carateum, only affects the skin and does not cause skeletal lesions. The debate about the origin of syphilis centers on three major hypotheses: whether syphilis originated in the Americas and then was brought to Europe by returning soldiers (the Columbian hypothesis), whether it arose in Europe or Africa and spread (the pre-Columbian hypothesis), or whether it is an “heirloom” pathogen that spread with humans out of Africa and thus was present everywhere prior to European contact (the Unitarian hypothesis which also posits that syphilis, yaws, and endemic syphilis are caused by variation in the same pathogen) (e.g., Baker and Armelagos, 1988; Cook and Powell, 2012; Gogarten et al., 2016; Harper et al., 2011). Early attempts to obtain ancient DNA from individuals with treponemal diseases used PCR followed by Sanger sequencing or analysis of restriction fragment length polymorphisms that identified a single SNP characteristic of T. pallidum subsp. pallidum. Specifically, Kolman et al. (1999) used both immunological and PCR analyses to confirm a case of syphilis in an individual from Easter Island. However, several subsequent studies were not successful in the recovery of T. pallidum from ancient bones (Barnes and Thomas, 2006; Bouwman and Brown, 2005; von Hunnius et al., 2007). For example, Barnes and Thomas (2006) noted the challenges in identifying both M. tuberculosis and T. pallidum given the available methods as well as the available comparative data from modern strains. In particular, since relatively few pathogen sequences were in the public databases and little variation had been identified, they pointed out the difficulty in distinguishing between contaminant vs. endogenous pathogen sequences. They tried to amplify and clone pathogen DNA from human remains with known causes of death due to syphilis or tuberculosis that were preserved in medical collections, but the fragments amplified were PCR artifacts or from other bacteria. In addition to testing medical and archeological bone samples with known syphilis or characteristic markers, von Hunnius et al. (2007) used rabbits at different stages of syphilis infection to test whether different tissues (including bone) showed evidence of the pathogen. Despite the use of five different PCR assays targeting T. pallidum, none of the human bone samples yielded positive results and only the bone from a rabbit in the acute state of infection (i.e., soon after initial infection) tested positive, while those from latent/chronic stages did not. Thus, by the time most people show skeletal lesions characteristic of syphilis, the amount of bacteria in bones is likely very low and thus, difficult to detect. More recently, Montiel et al. (2012) posited that infants with congenital syphilis who died soon after birth would have higher systemic bacterial loads and be the most likely to produce ancient syphilis DNA sequences. They tested individuals buried in a crypt

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dating from the 16th and 17th centuries and, using PCR, amplified two SNPs specific to T. pallidum subsp. pallidum. At present, the ancient genome data necessary to clarify the debate about the origin of syphilis are not yet available, and the data from modern pathogenic treponemes are also fairly limited, particularly for T. carateum, whose genome has not been sequenced (Arora et al., 2016; Gogarten et al., 2016). Data from modern strains indicate that T. pallidum subspecies pertenue and endemicum cluster with each other and that the TMRCA for T. pallidum pallidum is estimated to be AD 1611 1859, long after the first historical reports of syphilis (Arora et al., 2016). This late date may reflect the limitations in geographic strain diversity in the available data, particularly in strains from Africa, or it could reflect the success of a particular set of strains to the detriment of more virulent strains, since there is some indication of more severe disease in early reports of syphilis.

Mass Graves and “Invisible” Pathogens: Smallpox, Plague, Cholera, Enteric Dysentery, and Flu Many important diseases causing significant mortality in the past result in either relatively quick recovery or death, and thus, leave no mark on the skeleton. Most of the information about these “plagues” comes to us from historical records, particularly in years with pandemics, while archeological evidence is limited to occasional mass graves and suggestions of depopulation. Recently, ancient DNA from mass graves (as well as some individual graves) is helping to identify the source of specific historical pandemics, assess the evolution of strains over the course of a pandemic, and discern why particular strains were so virulent.

Yersinia pestis Three major historical plague pandemics have been identified: the first pandemic also known as the Justinian plaque (BAD 541 750), the second pandemic which began with the “Black Death” (BAD 1347 1351) and lasted until the early 18th century, and the third pandemic (AD 1855 1954) which generated the strains that persist today (Little, 2008). DNA data have confirmed that Y. pestis was indeed the cause of all three historical plague pandemics and also revealed that it impacted human populations as early as the Late Neolithic and Bronze Ages (Andrades Valtuena et al., 2017; Bos et al., 2011; Rasmussen et al., 2015; Wagner et al., 2014). These earliest strains of the plague were not identified from mass graves but from a general scan of the DNA extracted from individuals for the purpose of understanding human

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population history. Specifically, Rasmussen et al. (2015) screened shotgun sequences from over 100 Bronze Age individuals from Eurasia, and they found seven individuals, ranging in age from B2800 to 5000 years old and geographically from Poland to the Altai region of Siberia, with some DNA sequences from Y. pestis. After intensive shotgun sequencing, they were able to recover the complete genome sequences at a depth of 0.14 29.5 3 . In addition, Andrades Valtuena et al. (2017) found similaraged Y. pestis in other burials from Europe and the Caucasus using shotgun sequencing and targeted capture. These results were surprising because of the lack of historical or archeological evidence for plague during this period. Also, analyses of the Y. pestis genome sequences indicated an older TMRCA (5783 years) as well as an older divergence time (B55,000 years ago) between Y. pestis and its closest relative Yersinia pseudotuberculosis (Rasmussen et al., 2015). However, as noted by Wagner et al. (2014), there are significant challenges in accurately dating divergence in Y. pestis. Importantly, the genome data from Rasmussen et al. (2015) and Andrades Valtuena et al. (2017) also point to important aspects of the evolution of the pathogen. In particular, they show that the genetic changes that facilitate infection of and transmission by fleas were not present in the early strains of Y. pestis, but these changes are found after B3700 BP. For example, none of the Late Neolithic or Bronze Age strains have a mutation in the pla gene that is required for developing severe bubonic plague, though Andrades Valtuena et al. (2017) point out that a less severe form of bubonic plague may have been possible. Thus, cases of plague in this period were likely either pneumonic or septicemic and acquired either through a zoonotic route (i.e., rodents) or a less efficient and less severe transmission via fleas. The introduction of plague into Europe during the Late Neolithic may have been associated with the movement of people, such as Yamnaya pastoralists, from the Central Asian steppes (Andrades Valtuena et al., 2017; Rasmussen et al., 2015). The ancient DNA data from the first and second pandemics (i.e., the Justinian plague and Black Death, respectively) show conclusively that both were caused by Y. pestis strains that do not differ significantly from modern strains in terms of virulence and route of transmission (Bos et al., 2011; Harbeck et al., 2013; Schuenemann et al., 2011; Seifert et al., 2016; Spyrou et al., 2016; Wagner et al., 2014). These two pandemics had a severe effect on many populations, likely because of factors such as a lack of understanding about germ theory and basic sanitation, the impact of preceding famines on susceptibility to infectious disease, coinfection by other pathogens/ parasites, and changes in the ecology of vector species (e.g., DeWitte, 2015; Sallares, 2007). Analyses of Justinian plague strains show that this strain is distinct

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from the strain causing the Black Death, and it does not appear to have any living descendants (Feldman et al., 2016; Wagner et al., 2014). The dating of the emergence of these strains is difficult because the substitution rate varies, apparently speeding up during pandemics and then slowing during sylvatic cycles. This may be due to changes in selection patterns as the bacteria switch hosts, differences in the amount of replication during pandemic and endemic phases or other factors (Cui et al., 2013; Wagner et al., 2014). In addition, a high-coverage Justinian plague genome reconstructed by Feldman et al. (2016) enabled a clear assessment of plasmids, substitutions, and structural changes, some of which include loci that have been implicated in virulence. Unlike the first pandemic strains, the second pandemic strains are at the root of a branch that includes the strains causing the third pandemic which persist today (Bos et al., 2011, 2012; Spyrou et al., 2016; Wagner et al., 2014). SNP analyses of multiple individuals affected by strains during the second pandemic show that these strains were identical or very similar to one another, pointing to its rapid spread during the Black Death (AD 1346 1353) and subsequent persistence in Europe until the late 18th century (Bos et al., 2011, 2016; Haensch et al., 2010; Seifert et al., 2016). While there has been debate about whether the Y. pestis causing the second pandemic was introduced multiple times or once and subsequently persisted, these data suggest that the latter hypothesis is likely correct. In addition, the data suggest that the second pandemic strains ultimately spread back into central/east Asia and gave rise to the strains that started the third pandemic (Spyrou et al., 2016; Wagner et al., 2014).

Smallpox To date, the variola virus, which causes smallpox, is the only human pathogen to be eradicated as a result of vaccination efforts (Fenner et al., 1988). Although it is closely related to the viruses causing taterapox (found in African gerbils) and camelpox (found in camels), where and when the variola virus emerged as a human pathogen is unknown (Esposito et al., 2006; Gubser et al., 2004; Li et al., 2007). Because smallpox does leave a mark on the skin (i.e., pox), the ancient DNA research has focused on mummies with discernable evidence of disease. Specifically, analyses of European and Siberian cases, along with archived modern strains, show that the genetic diversity of strains is fairly low and point to a fairly recent origin (Biagini et al., 2012; Duggan et al., 2016; Pajer et al., 2017). For example, in an evolutionary analysis that also incorporated variola virus genome data from a Lithuanian mummy from the 17th century, Duggan et al. (2016) estimate the TMRCA of these strains to AD 1588 1645. Pajer et al. (2017) obtained genome data

from two undated medical human tissue samples from a museum in Czech Republic. Through amino acid racemization, they estimated that these viruses were 60 120 years old. They then used these estimated dates to calibrate the molecular clock, obtaining an older time of AD 1350 for the common ancestor. The accuracy of racemization for estimating dates that then were used for calibration, however, has been questioned (Porter et al., 2017). In addition to difficulties in dating historical samples for calibration, the pox viruses have many insertion deletion polymorphisms that make alignment complicated, and these can also impact the estimates of divergence times. By carefully considering the insertion deletion differences among strains and using a better reference genome, Smithson et al. (2017) created new genome alignments of modern as well as the Lithuanian mummy variola virus genomes. They then used these for new analyses that suggest that the common ancestor of the existing variola virus genomes dates to AD 1470 1563 and may diverge from the camelpox/taterapox clade around 1250 2000 years earlier. Interestingly, these studies point to the role of global trade in disseminating strains and also suggest that variolation and vaccination had a major impact on strain diversity. While the molecular data currently point to a recent origin, they are limited by the fact that these may not fully represent the diversity of past strains. This could account for the discrepancy between the molecular dates to a recent common ancestor and archeological and historical evidence pointing to older cases.

Food and Waterborne Outbreaks While there is great interest in the major epidemics that have affected humans, most deaths in the past were likely due to more mundane causes such as diarrhea and sepsis. In particular, water and foodborne bacteria and viruses were major causes of mortality and morbidity prior to modern water treatment and hygienic food preservation/ preparation practices. Many of these cases were likely limited to one or a few families in a community. However, severe outbreaks caused by pathogens such as Vibrio cholerae, Salmonella typhi, and Shigella dysenteriae, particularly in urban areas, can result in mass fatalities. Cholera is well-known for its impact on cities in the 19th century and for more recent outbreaks after natural disasters or civil conflict such as in Haiti and Yemen (Hendriksen et al., 2011; Johnson, 2006; Qadri et al., 2017). Cholera is commonly transmitted via infected water or food, and it can kill people extraordinarily quickly. Devault et al. (2014a) obtained DNA from a preserved intestinal sample from a victim of the second pandemic in Philadelphia and recovered the genome of V. cholera. Their analyses showed that this strain had all of the major regions associated with virulence in classical

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strains. In addition, despite some structural differences, the core genome was relatively conserved, pointing to selective constraints. Finally, they estimated the origin of the classical strains to between 1797 and 1813, in agreement with historical accounts of the first cholera pandemic in 1817. Analysis of cholera genomes is challenging because of the high rate of recombination and rapid mutation rate. As a result, estimating the origin of all pathogenic V. cholera is difficult, and Devault et al. suggest that it likely dates to the first epidemiological transition. Examples of waterborne and foodborne pathogens from the archeological record are currently limited, but recently Vagene et al. (2018) identified Salmonella enterica subspecies enterica serovar Paratyphi C in individuals from a contact period Mixtec epidemic burial ground at Teposcolula-Yucundaa in the state of Oaxaca, Mexico. They extracted DNA from the pulp cavity of teeth from 29 individuals (5 precontact and 24 postcontact). The postcontact burials were typically multiple burials, and they dated to the cocoliztli epidemic in AD 1545 1550. To discern the cause of the epidemic, Vagene et al. employed a screening approach using shotgun sequencing and the program MALT to identify possible pathogens. They found 10 individuals with sequences from S. enterica. Following targeted capture, they recovered five genomes that clustered with S. enterica subspecies enterica serovar Paratyphi C genomes in phylogenetic analyses. Of the five ancient genomes, two had higher coverage and depth, allowing robust comparisons with modern strains. The Paratyphi C strain of S. enterica causes enteric fever and was likely introduced by an asymptomatic carrier from Europe. Such analyses can help shed light on the epidemics that affected newly contacted populations, particularly in the Americas.

Influenza The influenza virus is another pathogen that can be the cause of a pandemic. Flu pandemics occur roughly every 40 years, at times when there is an antigenic shift in the virus. The first clearly identified flu pandemic occurred in 1580, though earlier cases and possible pandemics exist (Potter, 2001). Ancient DNA techniques have been used to sequence genomes of the flu virus from the 1918 (“Spanish” flu) pandemic, which was particularly virulent. The genome was stitched together over time using reverse transcription PCR, since the flu virus is an RNA virus, followed by Sanger sequencing. It was actually the first genome sequence from an “ancient” pathogen. The initial sequencing of fragments of several genes was performed on a preserved sample from a US serviceman who died during the epidemic (Taubenberger et al., 1997). Subsequent analyses focused on lung tissue from an

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Alaskan victim of the pandemic who was buried in permafrost and ultimately the sequences of the eight genes comprising the coding portion of the genome were obtained (Basler et al., 2001; Reid et al., 1999, 2000, 2004; Taubenberger et al., 1997, 2005). This in turn enabled the reconstruction of the virus so that it could be characterized (Tumpey et al., 2005). These analyses showed that the virus was very closely related to avian flu virus but with changes at key residues such that it could infect mammals. Interestingly, why the 1918 flu virus was so virulent is not completely understood. The hemagglutinin and neuraminidase genes, which are important for virus entry and exit from cells, do not show changes that indicate increased virulence. It may be the combination of changes in the different genes that resulted in such a severe impact. More recently, Xiao et al. (2013) extracted RNA from a formalin-fixed paraffin-embedded tissue sample dating to 1918 from a male who died at Camp Upton and used this to construct a cDNA library. A cDNA library is comprised of complementary DNA synthesized from RNA templates; thus the library should be complementary to RNA viruses and messenger RNA from the host and bacteria in the extract. This was then sequenced using NGS technology. They recovered the complete 1918 flu virus genome (at 3000 3 coverage) as well as gene expression sequences from bacteria, including Streptococcus pneumoniae, and from the host. S. pneumoniae causes pneumonia, which is commonly associated with influenza. The analyses of sequences associated with host gene expression showed an excess linked to inflammatory and cell death responses (Xiao et al., 2013). Analyses of this 1918 flu genome found seven nonsynonymous changes compared with the 1918 flu genome sequenced previously from Alaska. These analyses show some of the challenges in understanding exactly why a pathogen is so virulent, even in a well-studied pathogen.

“Invisible” Pathogens (to the Paleopathological Record) Most pathogenic infections leave no visible marks on human skeletal material, even under ideal preservation conditions, and many infections leave nondiagnostic skeletal lesions or only leave diagnostic lesions in some fraction of cases. As ancient DNA methods improve and the number of samples tested increases, these hidden pathogens are sometimes revealed. For example, sepsis, which is a body response that occurs as result of an infection, can be caused by a number of factors including the presence of bacteria in the blood. Although soft tissue is unlikely to preserve in the fossil record outside of anoxic permafrost conditions, abscesses can sometimes calcify and maintain within the skeletal record. Devault et al. (2017)

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sequenced genetic material recovered from two mineralized “nodules” on the ribs of a Late Byzantine era female from Troy, Anatolia (present day Turkey, dated to 790 860 BP). These nodules tested positive for Gardnerella vaginalis, which is found in modern-day pregnancy infections, and Staphylococcus saprophyticus, which is commonly present in urinary tract infections, suggesting this individual suffered from maternal sepsis (Devault et al., 2017). Another example of a pathogen that does not leave any skeletal evidence is H. pylori, a bacterium which is found in the stomach of a majority of the world’s population (Atherton, 2006). However, it has been detected in mummified soft tissue. Specifically, H. pylori genome sequences have been obtained from two individuals who were recovered from receding glaciers: Kwa¨day Da¨n Ts’ı`nchi (Long Ago Man Found) dating to AD 1670 1850, who was recovered in British Columbia ¨ tzi dating to the Cooper (Swanston et al., 2011) and O Age (B5300 BP) who was recovered in the Italian Alps (Maixner et al., 2016). In addition, H. pylori has been detected and characterized at the vacA gene in wellpreserved mummified individuals from 17th-century Korea (Shin et al., 2018). Analyses of worldwide strains of H. pylori show that it is geographically structured, likely jumped into humans in Africa roughly 85,000 120,000 BP, and dispersed with humans out of Africa (Falush et al., 2003; Moodley et al., 2012). ¨ tzi have Interestingly, both Kwa¨day Da¨n Ts’ı`nchi and O H. pylori genomes that inform us about contact and admixture between populations. Kwa¨day Da¨n Ts’ı`nchi carried H. pylori that was a recombinant of strains from ¨ tzi’s H. pylori shows the Americas and Europe, while O that the admixture between central Asian and northeast African strains that produced the strains found in Europe today occurred much more recently than previously thought (Maixner et al., 2016; Swanston et al., 2011). Finally, another example of a pathogen that does not leave skeletal evidence is hepatitis B virus (HBV). This virus was recovered from a well-preserved child mummy from Naples, Italy, dating to AD 1509 1629, a Korean mummy dating to AD 1612 1752, and from Neolithic and medieval individuals from archeological sites in Germany (Kahila Bar-Gal et al., 2012; Krause-Kyora et al., 2018; Patterson Ross et al., 2018). The genome sequence from the Italian mummy, as well as previously published HBV data, indicate that the sequence changes found in the data do not have a predictable rate; in other words, the mutations are not clock-like so molecular clock methods cannot be used to estimate divergence times (Patterson Ross et al., 2018). Because the child died in the 16th century, the virus clearly diversified before then. The lack of temporal signal also makes authenticating the ancient data more challenging. The ancient

sequence looks very similar (rather than ancestral) to modern HBV strains found in the Mediterranean basin, so authentication relies on DNA damage patterns and the lack of HBV in controls (Patterson Ross et al., 2018). The medieval HBV genome from Petersberg, Germany, also clustered with strains found in the Mediterranean basin (group D), while the Korean HBV sequence clusters with modern group C strains (Kahila Bar-Gal et al., 2012; Krause-Kyora et al., 2018). However, the sequences from Neolithic individuals show that HBV has been in Europe at least 7000 years, and these strains do not have close modern relatives (falling between modern human and nonhuman primate HBV strains) (Krause-Kyora et al., 2018).

Parasites and Commensals (Lice, Worms, and the Microbiome) Initial ancient DNA analyses of parasites focused primarily on worms found in coprolites and on ectoparasites found on mummies or preserved clothing. More recently, the gut and oral microbiomes have also been of interest, providing insights into dietary differences across human populations and time periods as well as identifying common oral or gut commensals and pathogens. This section will specifically examine the parasites on us (ectoparasites), within us (using dental calculus), and excreted from us (coprolites or colon contents). For decades, the standard method of detection for ancient parasites within or derived from host organisms was microscopy. Some fossils date back millions of years including marine lice (Urda rostrata) dated to 168 million years ago (Nagler et al., 2017) and even a tongue worm (Invavita piratica) found within microscopic crustaceans which dated back to 425 million years ago (Siveter et al., 2015). However, many organisms cannot be identified by physical features alone and many parasite eggs were later found to be misclassified (Cleeland et al., 2013).

Lice Evolutionary analyses indicate that many parasites, including lice, have been present throughout human history. For example, Pediculus humanus has fed on human blood since at least 5 7 million years ago, diverging from chimpanzee lice (Pthirus pubis) (Reed et al., 2004). More recently, the human louse diverged into two groups: the head louse (P. humanus capitis) and body louse (P. humanus humanus). Early molecular studies showed three distinct clades of body lice on humans diverging 0.7 to 1 million years ago (Reed et al., 2004). Additional studies, including samples derived from Pre-Columbian mummies (Raoult et al., 2008), demonstrated the presence of three phylotypes distinguished by location on the human body

Ancient DNA in the Study of Ancient Disease Chapter | 8

instead of geography. Improved genetic methods resulted in the renaming of these “types” as “clades” and teased out the relationship between ancient lice retrieved from Roman Period combs (1st century AD to 6th century BC) found at sites in Israel (Amanzougaghene et al., 2016). They confirmed that clade B lice existed in the Middle East and thus questioned the hypothesis that clade B had an American origin since these combs dated prior to AD 1492. Additional samples show a third Clade C that originated in Africa and Asia and can even be traced along paths of human migration (Boutellis et al., 2014; Drali et al., 2015). Interestingly, pubic lice (P. pubis) belong to a different clade that is more closely related to lice found in gorillas (Reed et al., 2007).

Parasites in Feces Fossilized fecal material, better known as coprolites, have been found at many archeological sites across the globe (Appelt et al., 2016) and date back as far as the Paleozoic era (270 million years ago) (Dentzien-Dias et al., 2013). Fecal samples have also been analyzed after removal from the intestinal tracts of mummies. Initial studies of fecal material involved macroscopic/microscopic analysis and identification of species through phenotypic characteristics. Prior to gut microbiome investigations, feces were examined mainly in order to explore parasite distribution across populations (Araujo et al., 2015; Leles et al., 2014). Coprolites from Rio Zape, Mexico (1400 BP), underwent additional microscopic and 18S rRNA examination to detect Ascaris parasites (Cleeland et al., 2013). Ascaris and other worms have been found in many other fecal samples, including those from pre-Columbian South America, Spanish mummies, Medieval burials from Belgium, and late-17th-century Koreans (Iniguez et al., 2006; Jaeger et al., 2016; Leles et al., 2008; Loreille et al., 2001; Oh et al., 2015; Shin et al., 2009). Many of these studies moved beyond microscopy to other highthroughput methods which allow for the genotyping of ancient human gut parasites (Cote et al., 2016). New methods may even allow for DNA from these parasites to be recovered from soil in future studies, as was the case for ancient human DNA recovered from environmental samples in Siberia (Slon et al., 2017).

The Gut Microbiome Fecal samples are also increasingly valuable for understanding the ancient microbiome. In particular, how the microbiome has changed over time and across space is important for understanding microbial, parasitic, and viral pathogenicity and the trajectory of human evolution (Schnorr et al., 2016). This topic has been addressed through examination of modern remote indigenous human communities and nonhuman primates (Contreras et al.,

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2010; Obregon-Tito et al., 2015; Schnorr et al., 2014; Yatsunenko et al., 2012) as well as through ancient DNA analyses of past people. Presently, the absence of processed foods and antibiotics in the diet of indigenous communities is thought to reflect the preindustrial/metropolitan human microbiome. A number of studies have examined the differences between traditional and industrialized communities in both oral and gut bacterial taxonomies. One such example is the examination of the genus Treponema, which has been detected in extant hunter-gatherers and 1000-year-old Mexican coprolites, but is missing from healthy urban populations (Schnorr et al., 2014; Tito et al., 2012). The precise reason behind its absence is still not fully understood. It is currently thought that the microbiota within the mammalian gut coevolved with their respective hosts and have involvement in both metabolism and immune response (Groussin et al., 2017), but the manner by which microbes first come to inhabit the human gut is still up for debate. Additionally, through comparisons of the human microbiome to those of other primates, Moeller and colleagues have been able to estimate divergence times of bacterial genomes during hominid evolution (Moeller et al., 2013, 2014, 2016). Studies suggest that although there are taxonomic overlaps in gut microbiota based on host geography, many strains have been vertically transmitted for an unknown amount of time and evolved with the host itself. One of the earliest ancient microbiome studies examined a 1300 BP coprolite from Durango, Mexico (Tito et al., 2008). The resultant taxonomy showed that its microbiome resembled modern feces both taxonomically and functionally. This shotgun analysis was complemented later by 16S rRNA V3 analyses of other archeological coprolites from Hinds Cave (8000 BP, USA), Caserones (1600 BP, Chile), and Rio Zape (Tito et al., 2012). The coprolites were shown to preserve DNA sufficiently well to allow Tito and colleagues to make comparisons with modern rural and cosmopolitan fecal microbiota communities. They found that the Hinds Cave coprolite microbiome did not resemble modern feces, while that from Caserones was similar to organic compost matter, indicating that it did not preserve the original microbiome characteristics. Subsequent studies of paleofeces discovered in Puerto Rico (AD 5 1170) showed that microbial and fungal sequences can be used to identify unique cultural affiliations (Huecoid and Saladoid) as well as preserve parasites from raw fish that were considered a dietary staple for both communities (Cano et al., 2014). The growing field of ancient viromics has also examined viruses in coprolites. Viruses or phages (viruses that infect bacteria) are an important component of the larger microbiome picture, particularly because they may regulate many bacteria. They are thought to outnumber bacteria by at least 10 or 100 to 1 (Chibani-Chennoufi et al., 2004).

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In the first study of an ancient virome, a 14th-century coprolite from Belgium was found to include systemic pathogens, intestinal parasites, and a number of bacteriophages (Appelt et al., 2014a,b). Such analyses can also be performed in other animals. For example, frozen Caribou coprolites dating from 700 to 3230 BP tested positive for a number of plant- and insect-infecting viruses (Ng et al., 2014). Another study confirmed the presence of ancient bacteriophages in the intestinal tract of 11th-century pre-Columbian Andean mummies, showing that they are preserved during the mummification process (Santiago-Rodriguez et al., 2016a).

investigated metabolites (Velsko et al., 2017). Velsko et al. (2017) found that certain biological molecules (monounsaturated and long-chain fatty acids) are more prone to preservation compared to others (carbohydrates, dipeptides, free amino acids, and free nucleotides). Recent reviews of research using dental calculus highlight the variety of research questions that have been addressed and potential directions for future studies (Huynh et al., 2016b; Warinner, 2016; Warinner et al., 2015; Weyrich et al., 2015).

The Oral Microbiome

FUTURE PROSPECTS FOR ANCIENT PATHOGEN RESEARCH

The oral cavity is home to a diverse ecosystem of microscopic organisms, and this is often reflected in the dental calculus. The use of dental calculus as a source of DNA from ancient or degraded contexts is relatively new, but both host DNA and DNA from microbes found in the mouth can be recovered (Adler et al., 2013; Black et al., 2011; Huynh et al., 2016a; Ozga et al., 2016; Preus et al., 2011; Santiago-Rodriguez et al., 2017; Warinner et al., 2014b; Weyrich et al., 2017). Dental calculus (sometimes called tartar) is a hardened dental plaque that contains minerals, bacterial cells, and food particles (Warinner et al., 2015). It is commonly found today in people who do not have regular dental care, and it is fairly ubiquitous across the archeological record (Warinner et al., 2015) even being found in Miocene apes (Hershkovitz et al., 1997). DNA sequences extracted from European dental calculus have shed light on the effects of the shift from hunter-gatherers to farming on the microbiome (Adler et al., 2013), changes in commensal and pathogen diversity including the absence of antibiotic resistance genes in medieval Germany (Warinner et al., 2014b), and the assessment of methanogen diversity and decreased Methanobrevibacter oralis in 14th 19th-century France compared to modern populations (Huynh et al., 2016a). Dental calculus from pre-Columbian Puerto Rico also showed distinct differences compared to modern calculus, which may be reflective of shifts away from the horticulturalist lifestyle and diet found in the past (SantiagoRodriguez et al., 2017). In addition, dental calculus has provided considerable information about diet from DNA sequence data and from phytoliths, starches, and proteins embedded in the calculus (Cristiani et al., 2016; Hardy et al., 2009; Henry and Pipemo, 2008; Power et al., 2015; Radini et al., 2016; Santiago-Rodriguez et al., 2017; Warinner et al., 2014a; Wesolowski et al., 2010). Such studies are important since dietary changes over time have had major implications for host health. Interestingly, a recent study of calculus from modern and historic (200 BP) samples has also

Ancient DNA research has resulted in many surprises over the past 30 years, including findings that Denisovans admixed with some groups of modern humans, that plague affected people as early as the Late Neolithic and Bronze Ages, and that seals brought tuberculosis to South America. Predicting what will be discovered next is difficult, but a number of major challenges, as well as stimulating questions, remain. Some of the big questions include how did major demographic and subsistence changes (such as during the Neolithic transition) change human pathogens and the microbiome? Did agriculture and pastoralism foster zoonotic jumps (and did the distributions of pathogens in domesticated animals change)? Additional questions relate to the impact of contact between populations: What new pathogens did modern humans leaving Africa encounter? How did immune alleles that introgressed from archaic humans into modern humans assist in adaptation to these new environments? What was the pace and extent of the “Columbian Exchange”? What is the origin of syphilis? What is the role of major trade routes (such as the Silk Road) in spreading pathogens? Finally, there are questions related to the biology of pathogens or their hosts: What are the circumstances and adaptations that allow a zoonosis to become a successful human pathogen? How did selective pressures on the human immune system shift through time? How is the disease course influenced by coinfections, and are certain pathogens more likely to cooccur? What characterizes pathogens thought to have coexisted with humans for millennia (i.e., “heirloom” pathogens) versus pathogens thought to have jumped into humans recently (i.e., “souvenir” pathogens) (Armelagos et al., 2005; Sprent, 1962) or is this just the same process with the difference being time? Why do some pathogens cause skeletal lesions in some hosts but not in others? To answer these questions and to better understand health and disease in the past, insights from genetic data (both ancient and modern) will need to be combined with other data from paleopathology, osteology, and

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bioarcheology as well as archeology, history, and microbiology. For example, such data could be incorporated into host pathogen models of evolution to predict the consequences of introducing a pathogen into a system in which it does not currently exist (McCallum et al., 2001). While we cannot extract the reproductive ratio and many of the other parameters often used in epidemiological analyses directly from the archeological record, we can adapt models to investigate how population movements, novel technologies, and anthropogenic activities (such as human encroachment upon wildlife habitats) may have enhanced the risk of pathogen transmission among humans. In tandem, we can examine how changes in the pathogen might have facilitated transmission and spread. The latter is possible through functional studies in modern pathogens and through the use of genetic engineering to recreate a pathogen in vitro under highly controlled conditions as was the case with the 1918 influenza virus. Not surprisingly, the recreation of the 1918 flu virus was not without controversy (von Bubnoff, 2005). Significant challenges also remain for ancient pathogen DNA research. Searching for pathogen DNA is very much like searching for a needle in a haystack, though improvements in laboratory methods and bioinformatic techniques have made this search much easier. Despite this, the search is relatively expensive since many samples must be deeply screened in order for pathogen DNA detection, and additional resources are needed to recover a sufficient amount for evolutionary analyses. At present, samples from many environments are not amenable to ancient DNA analyses, and in many cases, they may never be. This leads to a series of methodological questions related to these challenges: Which tissues (and during which stages of infection) are most likely to yield pathogen DNA? Will methodological improvements allow the accurate characterization of RNA viruses? How do we identify pathogens that are extinct and distinguish them from benign environmental bacteria? What is the character and distribution of environmental microbes around the world (and how does this impact preservation in the archeological record)? Even if most of these challenges are surmounted, ancient DNA data do not always produce answers, as in the case of HBV. In addition, our understanding of the microbial world is poor, with limited representation in DNA databases. Thus, there is a critical need to categorize microbes from many environments. Analyses of ancient pathogens (paleopathogenomics?) are a new and increasingly productive area of research that provide insights into the evolutionary histories of the many microbes that humans harbor. This can include identifying the cause of known epidemics or pandemics and refining case studies of specific individuals. More importantly, it enables us to see the evolutionary steps that a pathogen or an ecosystem (if we think of the

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microbiome) has taken and investigate how it changes over geographic space and time. Reconstruction of ancient pathogens (in vivo or in silico) can be used to assess why some strains of a virus or bacteria might be more virulent than others. Laboratory and analytic methods have made great strides since ancient DNA research began in the 1980s, allowing for glimpses into aspects of past population history long thought inaccessible. Methodological improvements now allow for the successful recovery of DNA from many environments that are generally not conducive to DNA preservation and from much older contexts. New materials, such as coprolites and calculus, provide a means of analyzing ancient microbiome profiles as well as host DNA. Finally, there is also the possibility of incorporating ancient protein and epigenetic data into ancient disease research. In particular, proteins can be useful for indicating stress levels, immune function, signs of starvation or obesity, and other physiological information in the host (Jones et al., 2016; Sawafuji et al., 2017), while epigenetic data can provide information about gene expression in the target tissue, and these can also be related to disease. Such data can be important for understanding chronic noncommunicable disease progression and host susceptibility to disease in general. In sum, ancient DNA research opens up new possibilities for assessing health and disease in the past and will likely offer many new surprises and insights in the years to come.

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Wesolowski, V., de Souza, S.M.F.M., Reinhard, K.J., Ceccantini, G., 2010. Evaluating microfossil content of dental calculus from Brazilian sambaquis. J. Archaeol. Sci. 37 (6), 1326 1338. Weyrich, L.S., Dobney, K., Cooper, A., 2015. Ancient DNA analysis of dental calculus. J. Hum. Evol. 79, 119 124. Weyrich, L.S., Duchene, S., Soubrier, J., Arriola, L., Llamas, B., Breen, J., et al., 2017. Reconstructing Neandertal behavior diet, and disease using ancient DNA from dental calculus. Nature 544, 357 361. Willerslev, E., Hansen, A.J., Poinar, H.N., 2004. Isolation of nucleic acids and cultures from fossil ice and permafrost. Trends Ecol. Evol. 19 (3), 141 147. Woese, C.R., Fox, G.E., 1977. Phylogenetic structure of the prokaryotic domain: the primary kingdoms. Proc. Natl. Acad. Sci. U.S.A. 74 (11), 5088 5090. Worobey, M., Gemmel, M., Teuwen, D.E., Haselkorn, T., Kunstman, K., Bunce, M., et al., 2008. Direct evidence of extensive diversity of HIV-1 in Kinshasa by 1960. Nature 455 (7213), 661 664. Xiao, Y.L., Kash, J.C., Beres, S.B., Sheng, Z.M., Musser, J.M., Taubenberger, J.K., 2013. High-throughput RNA sequencing of a formalin-fixed, paraffin-embedded autopsy lung tissue sample from the 1918 influenza pandemic. J. Pathol. 229 (4), 535 545. Yang, D.Y., Eng, B., Waye, J.S., Dudar, J.C., Saunders, S.R., 1998. Improved DNA extraction from ancient bones using silica-based spin columns. Am. J. Phys. Anthropol. 105 (4), 539 543. Yatsunenko, T., Rey, F.E., Manary, M.J., Trehan, I., Dominguez-Bello, M.G., Contreras, M., et al., 2012. Human gut microbiome viewed across age and geography. Nature 486 (7402), 222 227. Ziesemer, K.A., Mann, A.E., Sankaranarayanan, K., Schroeder, H., Ozga, A.T., Brandt, B.W., et al., 2015. Intrinsic challenges in ancient microbiome reconstruction using 16S rRNA gene amplification. Sci. Rep. 5, 16498. Zink, A., Haas, C.J., Reischl, U., Szeimies, U., Nerlich, A.G., 2001. Molecular analysis of skeletal tuberculosis in an ancient Egyptian population. J. Med. Microbiol. 50 (4), 355 366. Zink, A.R., Reischl, U., Wolf, H., Nerlich, A.G., 2002. Molecular analysis of ancient microbial infections. FEMS Microbiol. Lett. 213 (2), 141 147. Zink, A.R., Sola, C., Reischl, U., Grabner, W., Rastogi, N., Wolf, H., et al., 2003. Characterization of Mycobacterium tuberculosis complex DNAs from Egyptian mummies by spoligotyping. J. Clin. Microbiol. 41 (1), 359 367.

Chapter 9

Trauma Rebecca Redfern1 and Charlotte A. Roberts2 1

Centre for Human Bioarchaeology, Museum of London, London, United Kingdom, 2Department of Archaeology, Durham University, Durham, United

Kingdom

INTRODUCTION Most connective tissues have remarkable potential for repair in the event of injury. Fortunately, bone is such a tissue, because damage to bone requiring significant repair is one of the most common pathological conditions that humans confront. In archeological human remains, evidence of trauma such as fracture callus is one of the most prevalent conditions encountered. In most cases the diagnosis of trauma in skeletons is easily made. There are, however, manifestations of trauma that can confuse the paleopathologist, and there are other pathological processes that can produce lesions that resemble fracture callus or other trauma. Furthermore, skeletal evidence of trauma occurring in subadults may be completely invisible because of modeling and remodeling of the bone associated with normal growth. This means that estimates of trauma prevalence based on archeological skeletal samples will almost certainly underestimate the actual prevalence in the living population represented by the sample. It is also important for the paleopathologist to be aware that trauma occurring around the time of death (perimortem trauma) can easily be confused with postmortem taphonomic processes, such as damage caused by weathering or water erosion. Even if this distinction can be made, the cause of perimortem trauma can be very challenging to identify. The controversy over the interpretation of perimortem fracturing of bone as possible evidence of cannibalism (White, 1991: 394 406; Turner, 1993; Darling, 1998) is an example of the problems encountered in establishing the cause of perimortem fractures. Paleoanthropologists are also caught in controversies over the identification of perimortem trauma, e.g., Mirazo´n Lahr et al. (2016) versus Stojanowski et al. (2016). In the most general sense, trauma affects the skeleton in four ways: (1) a partial or complete break in a bone, (2) an abnormal displacement or dislocation of a joint, (3) a disruption in nerve and/or blood supply, and (4) an

artificially induced abnormal shape or contour of bone. The causes of skeletal trauma include accidental and intentional injury, cosmetic or therapeutic practices that affect bone, and pathological conditions that can increase the vulnerability of bone to biomechanical stress. There are other traumatic conditions that occasionally can be inferred from the circumstances of burial, such as death from complications of pregnancy. It is important to remember that trauma most commonly represents extrinsic influences that can result from many factors. Clearly the prevalence and location of trauma in the skeleton are influenced by many factors, such as the social and economic, but also the landscapes our ancestors negotiated (Angel, 1974a; Lovejoy and Heiple, 1981; Roberts and Manchester, 1995: 73 79; Jurmain and Bellifemine, 1997; Roberts, 2000; Eshed et al., 2010). Hunter-Gatherers (and Fishers) undoubtedly had a different pattern of trauma compared to sedentary farmers. Fracture patterns in women generally differ from men, and children differ from adults. Of course, there are physiological factors to be considered as well, such as osteoporosis and other morbid conditions, which greatly increase the vulnerability of the skeleton to trauma. The various types of trauma that affect the skeleton include (1) fracture, (2) dislocation, (3) post-traumatic deformity, and (4) miscellaneous traumatic conditions, including those that do not affect the skeleton directly, but can be inferred by their position or association of other bones from the individual. Additional definitions of the different types of trauma that may be observed in human remains have been published by Aufderheide and Rodriquez-Martin (1998), with the work of Wedel and Galloway (2014) providing detailed descriptions and definitions of each form of blunt-force injury that can cause a partial or incomplete break in a human bone. To facilitate data-sharing and comparability with clinical datasets, the International Classification of Diseases published by the World Health Organization can also be used when recording trauma

Ortner’s Identification of Pathological Conditions in Human Skeletal Remains. DOI: https://doi.org/10.1016/B978-0-12-809738-0.00009-0 © 2019 Elsevier Inc. All rights reserved.

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(Judd and Redfern, 2012). This hierarchical system emphasizes the use of multiple coding and includes secondary changes related to and complicating trauma. It also separates obstetric and birth trauma, fracture complications, stress-induced, and pathological fractures into different categories (World Health Organization, 2010). In general, however, we find that Lovell’s (1997) assertion that one system may not suit all investigations compelling. Changes to the body that are considered to have a traumatic origin are summarized in Table 9.1. In this chapter, we will review the various types of trauma that affect the skeleton and provide a brief summary regarding the diagnosis of each of these types. We will also discuss the importance of recognizing societal level patterns of trauma in the past (e.g., Martin and Harrod, 2015; Murphy and Klaus, 2016), as well as review data collection standards specific to trauma studies.

TRAUMA Pathology In this discussion, the term “trauma” is used in its broadest sense to mean any event that results in partial or complete discontinuity of a bone (Hamblen et al., 2007). Examples include sword or axe wounds, injuries to bone from spears or arrows, or surgical procedures such as trephination, as well as the more conventional discontinuities of bone caused by accidental or intentional fractures. There are multiple ways of describing fracture that relate to the severity, type of stress causing the fracture, and conditions that increase the likelihood of fracture. If the break does not pass through the entire bone, it is known as an incomplete fracture (also called an infraction); if the break passes entirely through the bone, it is called a complete fracture (Table 9.2).

TABLE 9.1 Summary of Injury, Poisoning, and Certain Other Consequences of External Causes: Headings Only (http://apps.who.int/classifications/icd10/browse/2016/en#/S00-S09) Body Location/Type

Injury Types

Excludes

Head

Superficial injury

Fracture: pathological, with osteoporosis, stress

Neck

Open wound

Thorax

Fracture: closed

Abdomen, lower back, lumbar spine, and pelvis

Fracture: open

Shoulder and upper arm

Malunion of fracture

Elbow and forearm

Nonunion of fracture

Wrist and hand

Dislocation, sprain, and strain

Hip and thigh

Injuries to nerves and spinal cord

Ankle and foot

Injury to blood vessels

Multiple body regions

Injury to muscle, fascia, and tendon

Unspecified part of trunk, limb, or body region

Crushing injury

Effects of a foreign body entering through a natural orifice

Traumatic amputation

Burns and corrosions

Injury to internal organs

Frostbite

Other and unspecified injuries

Poisoning by drugs, medicaments, and biological substances Toxic effects of substances chiefly nonmedicinal as to source Other and unspecified effects of external causes Certain early complications of trauma Complications of surgical and medical care Sequelae of injuries, of poisoning, and of other consequences of external causes

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TABLE 9.2 Injury Mechanism and Fracture Type Injury Mechanism

Fracture Type

Direct

Penetrating: partial or complete penetration of the bone cortex

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2016; Toman et al., 2016). Today, there is a move away from making such associations, particularly because of changes in technology (meaning that a specific type of fracture could be associated with many different repetitive activities) and the potential for error in delivering patient care through the use of eponymous names for fractures (Lee et al., 2004).

Comminuted: broken in more than two pieces Transverse: force is applied in a line perpendicular to the long axis of the bone Crush Depression: crush to one side of a bone Compression: crushing to both sides Pressure: force applied to growing bone Indirect trauma

Spiral: rotational and longitudinal stress on the long axis Oblique: rotational and angular stress on long axis Torus/greenstick: bending of the bone due to longitudinal compression Impacted: bone ends are forced together Burst: vertebral fracture type due to vertical compression Comminuted: a T- or Y-shaped fracture Avulsion: caused by tension at the attachment site of a ligament or tendon attachment

Stress

Caused by repetitive force, typically perpendicular to the long axis

Pathological

A fracture caused by an underlying disease state (e.g., Paget’s disease, osteomalacia, or osteoporosis)

Classification of Fractures A study of trauma is also reliant on an understanding of the different forces at play and their effect on the bones (loading), as these forces are responsible for producing an injury (see Westcott, 2013). Force can be defined as a mechanical disturbance, which produces fractures by one or more of the following types of force: (1) tension (sometimes known as avulsion), (2) compression, (3) torsion or twisting, (4) flexion or bending, and (5) shearing (Wedel and Galloway, 2014). Fig. 9.1 illustrates the different directions of force for these types of stress. A dynamic fracture is the most common traumatic condition in archeological skeletal remains. It also forms the bulk of cases in modem orthopedic practice. Each type of dynamic stress produces a different type of fracture. However, many fractures are the result of more than one type of stress. Although it is not always possible to identify the type of stress from the resulting fracture once a callus has developed and the fracture has healed, attention to this aspect of fracture may provide significant insights

Source: After Lovell (1997).

Fractures most often result from abnormal stress applied to one or more bones. This stress can be dynamic, meaning sudden high stress, or it can be static in which the stress is low initially, but gradually increases until the break occurs (Resnick et al., 2002). If a bone is exposed to excessive but intermittent stress over a fairly long time (several weeks), a fatigue or stress fracture may develop (e.g., Martin-France´s et al., 2013). The historical clinical literature has identified a relationship between specific occupations or other repetitive activities and some fracture types, e.g., the “clay shoveler’s fracture” of the spinous process of the seventh cervical vertebra and/or the first thoracic vertebra due to a flexion force. This was first described in people shoveling heavy “sticky” soils in the 1930s (Knu¨sel et al., 1996; Posthuma de Boer et al.,

FIGURE 9.1 Types of stress in bone that can result in fracture: (A) tension, (B) compression, (C) twisting, (D) bending, and (E) shearing.

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regarding common traumatic related stress in archeological skeletal remains. For this reason, we provide a brief review of the relationships between a specific type of stress and the resulting fracture. The reader should consult reference works on skeletal radiology or fractures for a more detailed discussion (e.g., Christensen et al., 2018; Wedel and Galloway, 2014; Paton, 1992: 3 6; Harkess et al., 1996: 4 19; Hipp and Hayes, 1998: 101 108). Tension fractures are generally associated with tendinous attachments to bone. The tubercle or process to which the tendon is attached breaks off as a result of excessive tension from the tendon (Fig. 9.2). Joint dislocation is often associated with this type of fracture (Viciano et al., 2015). Compression fractures occur due to sudden excessive impaction, and result in a variety of fracture patterns (Kimmerle and Baraybar, 2008). For example, bone can split in the same axis as the direction of the force. Compression fractures are most easily recognized in the spine, where most fractures of the vertebral body are the result of compression (Figs. 9.3 9.5). Many of the fractures of joint surfaces are also the result of compression. Injuries to the skull tend to be caused by blows involving compressive forces that produce different patterns of fracture (Schinz et al., 1951 1952: 1600 1609; Berryman and Haun, 1996; Guyomarc’h et al., 2010). Some compressive forces may result in fractures that

radiate from the compressed site. Other injuries result in circular fractures in which there is a depression of bone tissue caused by the trauma (Fig. 9.6). If these heal, they tend to leave a circular depression in the cranial vault. These lesions can be confused with dermoid cysts, which also leave circular depressions in the skull vault (Ko¨hler and Zimmer, 1968: 201). It may not be possible to distinguish between these two diagnostic options in archeological human remains. However, one criterion that should be evaluated is whether or not the inner table has been affected. Depressed fractures often but not always affect the inner table; dermoid cysts are less likely to do this.

FIGURE 9.2 Transverse, partially healed fracture of the patella (arrow). This fracture is attributed to trauma to the patella, resulting from a fall on the knee from a great height. The morphology of the fracture is also compatible with fracture resulting from sudden tension of the quadriceps tendon and the ligamentum patellae. (WM S33 A1.)

FIGURE 9.3 Multiple compression fractures of the thoracic (T) vertebrae. T6 (upper arrow) was fractured about 1 year before death. Callus is evident on the anterior portion of the vertebral body. T10 and T12 (lower arrows) were fractured in a fall occurring shortly before death. No callus is evident. (68-year-old male. IPAZ 929/54.)

FIGURE 9.4 Healed fracture of the 12th thoracic vertebra (second vertebra from top). (A) Anterior view. The vertebral body has collapsed because of compression; however, the spinous process has separated from tension produced during the compression of the anterior portion of the body; the fracture resulted in angular deformity. Healed fracture of the 12th thoracic vertebra (second vertebra from top). (B) Lateral view. (24-year-old male, FPAM 5085.)

FIGURE 9.5 Healed compressed fracture of the 12th thoracic vertebra (third vertebra from top). Both femora show marked, periosteal, bone hypertrophy over the trochanters, suggestive of myositis ossificans or a reaction to decubital ulcers secondary to the interruption of the spinal cord. A bone fragment had been pushed into the spinal cord adjacent to the fracture. (PMUG 4697a.)

In torsion fractures, force is directed in a spiral or twisting direction, such as when one end of a limb is fixed and the other rotates. Today, this type of fracture is frequently associated with downhill skiing accidents, in which the lower leg is rigidly fixed and the body twists during a fall. Because the stress occurs in a spiral direction, the fracture line also spirals. Torsion fractures can be confused with compression fractures in long bones, the former following a natural spiral cleavage plane in the bone. Torsion fractures always involve abnormal rotation of the bone. Bending fractures are the most common type of bone fracture and are often complicated by other types of stress. Abnormal stress can result when the bone is bent during a fall or in response to a blow, as in the case of the forearm when it is raised to protect the face and takes the force of a blow. In either case, the maximum stress often occurs at a discrete spot in the bone and may result in a simple transverse separation. In some cases of bending stress the transverse fracture occurs on the tensile side of the bone and an oblique fracture occurs on the compressive side. This produces a triangular wedge of bone (Fig. 9.7) known as a butterfly fragment (Hipp and Hayes, 1998: 103). Studies have shown that assessment of butterfly fractures in long bones can contribute to the determination of the mechanism and direction of injury in blunt-force trauma (e.g., Reber and Simmons, 2015). In a young person, bending fractures may produce an incomplete transverse break in a long bone associated with longitudinal splitting. This condition is known as a “green stick fracture” (Jones, 1994) (Fig. 9.8). Most often, because alignment is normally excellent, these fractures will heal with little residual evidence of a break.

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FIGURE 9.6 Depressed fracture of the skull vault. (A) Some broken fragments are still attached to the skull, which is indicative of fracture occurring at or near the time of death. (B) Internal view. (Calvarium from a 19-year-old male, FPAM 2022.)

FIGURE 9.7 Schematic representation of bending fracture and the triangular fragment that may occur in such fractures.

However, in some cases the split in the bone may not be completely reduced, leaving a noticeable defect (Fig. 9.9). Shearing fractures result when opposite forces are applied to bone in slightly different planes. The opposing forces need not both be dynamic. The bone may be supported by a static force in one axis with dynamic force applied in the opposite direction (Fig. 9.10). One example of shearing trauma is a Colles’ fracture of the distal radius. This is a fracture resulting from a fall forward, in which the individual reacts by extending the arms to minimize the impact. In this case, the dynamic force is the falling, and the static force is the ground or floor. The result is a fracture in which the distal end of the radius is sheared off and displaced backward. Schinz et al. (1951 1952: 276) note that in a Colles’ fracture, the shearing stress rapidly changes to bending stress, and it may be impossible to distinguish the effects of the two types of stress in the resulting fracture. Bone fractures vary not only in terms of the type of stress but also with respect to its severity, which is related to the extent of the fracture. A simple fracture is one in which there is only one separation of the bone. This contrasts with a more severe fracture with many broken fragments, which is called a comminuted fracture. In either of these types of fractures, the traumatic event may result in

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217

FIGURE 9.8 Schematic representation of bending fracture, which produces a greenstick separation of part of a bone. Both transverse and longitudinal breakage may occur.

the broken bone being exposed through the skin. This used to be called a compound fracture but open fracture is the preferred term today (Harkess et al., 1996: 4)—interestingly, clinical data show that they have a different epidemiology compared to closed fractures (Redfern, 2017: 109). An opening or defect in the protective skin and overlying soft tissue can greatly complicate healing, because of the likelihood of infection. Whereas fractures caused by a sudden overwhelming stress are the most frequent of traumatic problems, other types of fractures occur in which different patterns of stress or underlying pathological conditions are contributory factors. In living populations, unusual and continued stress over a period of weeks may result in a fatigue fracture. However, in fatigue fractures the stress applied to bone does not immediately result in fracture. In all cases, such fractures are associated with the onset of

FIGURE 9.9 Incomplete reduction of a probable greenstick fracture of the clavicle. (Adult from an archeological site in Lisht, Upper Egypt, dated to the 12th Dynasty, NMNH 256427.)

intense physical activity of a type not engaged in previously. Fatigue fractures are often seen in military recruits during their initial training period (Schinz et al., 1951 1952: 285; Harkess et al., 1996: 9) but are also increasingly seen in athletes (Bruckner et al., 1999: 21). In fatigue fracture of the tibia, the predilected site is the proximal part of the medial metaphysis, particularly in the region of active cutback, where cancellous bone support is poor. Such fractures are often incomplete,

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FIGURE 9.11 Stress fracture of the neural arch of L5 (spondylolysis) in an adult male skeleton from the Early Bronze Age site of Bab edhDhra’, Jordan. (NMNH uncataloged, from tomb A 100E.)

FIGURE 9.10 Depressed fracture of the skull of sufficient force to produce a shear between the large fragment and the rest of the skull. (Calvarium of an adult male, WM S19.4.)

involving only a portion of the cross-sectional plane of a bone. They are also associated with unosteonized circumferential lamellar bone (Johnson, 1964: 607). The physical activity triggers an attempt by the bone to increase its mechanical strength by osteon remodeling. However, the first step in osteonization is the formation of resorption spaces, which initially weakens the bone. Normally resorption space formation would be accomplished without a serious reduction in the mechanical integrity of the bone. Abnormal physical activity, however, greatly accelerates bone resorption and, if continued, results in fracture and callus formation. Part of the problem of increased osteon remodeling is the fact that osteonal refill of a resorption space occurs at about onetenth the speed of resorption. Stress fractures tend to be incomplete and, unless they proceed to complete fractures, alignment will be excellent, with the likelihood that remodeling will eliminate most if not all the evidence of the fracture. This means that fracture prevalence in archeological skeletons is likely to be underrepresented. In the discussion of paleopathological evidence of fracture, we will present evidence where this diagnosis seems likely. Thus, a stress fracture is a condition about which researchers should be aware. As the stress involved is quite different from that in direct blows, there is a danger that the presence of such fractures could contribute misleading data in frequency tables of fractures caused by violent mechanicisms in various parts of the skeleton.

Stress fractures of the spine are well known in the paleopathological literature largely through the very careful research of Stewart (1931, 1956) and Merbs (1983). Another example is the fracture through the pars interarticularis of (usually) the 5th lumbar vertebra (spondylolysis), which is classified as a type of stress fracture (Fig. 9.11). This is believed to be associated with a congenitally weakened area of the bone (e.g., see Yurube et al., 2017), which becomes stressed through particular movements such as bending and lifting. A complication of spondylolysis is spondylolisthesis, occurring when the affected vertebral body slides anteriorly over the underlying vertebra (Merbs, 1996). Spondylolysis has been noted in many skeletal populations in both the Old and New Worlds (e.g., Fibiger and Knu¨sel, 2005; Lessa, 2011; Merbs, 1996; Weiss, 2009). Stewart (1931) has reported on the frequency of this condition among Inuit skeletal remains and found an unusually high frequency (27.4%) in this group, which he associated with hunting. Within the Inuit populations, he found that skeletons from the northern part of Alaska had a greater frequency than those from the southern part. Lester and Shapiro (1968), in a study of another Inuit skeletal sample, also found a high prevalence (40%) of spondylolysis and that the frequency of the defect increased with age. In pre-Colonial coastal sites in southern Brazil, throwing harpoons and rowing were suggested to be the most likely physical activities associated with spondylolysis in males, while carrying weights, such as plant resources and mollusks, were associated with spondylolysis in females (Lessa, 2011). However, the combination of a genetic and environmental etiology for this condition makes assigning specific activities challenging. Ortner (2003) notes two examples out of 92 burials in the Early Bronze I (3150 3000 BC) shaft tombs excavated at Bab edh-Dhra’, Jordan in 1977. Both examples are associated with adult males. One of these individuals

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was buried in the east chamber of tomb A100 (Fig. 9.11). The age at death of the skeleton was in excess of 50 years old. The arch defect is on the fifth lumbar vertebra. The arch is completely free of the vertebra, with the break occurring at the pars interarticularis. The broken edges of the bone exhibit considerable remodeling, indicating that the break was long-standing. The anterior surface of the vertebral body has considerable periosteal reactive bone, perhaps the result of periosteal reaction due to anterior slippage of the vertebra. The inferior edge of the vertebral body has slight osteophytes, as do the corresponding areas of the first sacral vertebra. The second and third thoracic vertebrae of this skeleton are fused. Fusion occurred at the spinous processes, diarthrodial joints, and the lateral portions of the vertebral bodies. The disk space is preserved and the cause of the fusion is not apparent. The problems in differential diagnosis are highlighted in a burial from the medieval hospital site of St. James and St. Mary Magdalene in Chichester, England. In this burial, a long-standing fracture is apparent in the third thoracic vertebra (Fig. 9.12). The fracture occurs in an oblique line passing between the posterior part of the spinous process and the articular facets on the right side. This could be an example of stress fracture but the location is very atypical for this type of fracture, and a more likely diagnosis is accidental trauma, caused perhaps by a fall on the back. The capacity of bone to resist stress depends on maintaining its quantity, quality, and normal architecture. There are pathological conditions that can adversely affect one or more of these features, creating a situation in which bone is unable to withstand a moderate force that normally would be tolerated easily. When fracture occurs in such situations, it is called a pathological fracture, meaning that some underlying pathological process has weakened the bone to the point that it cannot resist relatively normal biomechanical stress. Many diseases can produce abnormal bone loss and result in pathological fractures (Fig. 9.13). Collins (1966: 52) lists some of these, which include congenital, metabolic, and infectious diseases, as well as neoplasms. For example, leprosy and the tertiary stage of venereal syphilis can lead to problems with balance, subsequent falls, and potential fractures (e.g., see, respectively, Clarke, 2002; Judd and Roberts, 1998; Resnick and Niwayama, 2002a; Zuckerman et al., 2017), and rheumatoid arthritis may be associated with osteopenia and osteoporosis, the latter potentially leading to fractures in the spine, hip, and wrist bones (Resnick and Niwayama, 2002b). Collins (1966) also reports that pathological fractures caused by different diseases are associated with rather specific age categories. To this list should be added aging, which is generally associated with gradual bone loss that can contribute to a pathological fracture (Schinz et al., 1951 1952: 256).

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FIGURE 9.12 Healed fracture of the 12th thoracic vertebra (second vertebra from top) (a) Anterior view. The vertebral body has collapsed because of compression; however, the spinous process has separated from tension produced during the compression of the anterior portion of the body; the fracture resulted in angular deformity.

Previous studies have shown that the location of fractures in the skeleton varies with the age and sex of the individual (e.g., Buhr and Cooke, 1959; Ogden et al., 1996: 22; Kimmerle and Baraybar, 2008; Wedel and Galloway, 2014). Furthermore, there are differences in the frequencies of fracture in various locations in the skeleton, which may be associated with socio-cultural and environmental differences (Hamilton, 1853; Schinz et al., 1951 1952: 249; DeSouza, 1973; Iqbal, 1974). These different conditions create different fracture hazards and risks. The potential fracture risk for someone negotiating an icy sidewalk is quite different from that of a person living in the tropics.

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shown in recent literature (Westaway et al., 2016). These advances have produced methods that enable different weapon types to be identified in the absence of them being embedded in the bone, which have been successfully applied to archeological human remains, even very ancient ones (Milner, 2005; Scott Murphy et al., 2014). Blunt-force injuries are those created by the impact of a blunt object or by the impact of the body against a blunt surface (Wedel and Galloway, 2014). These injuries may produce: G G

A linear fracture represented by a single fracture line; Comminuted fractures represented by multiple extended fracture lines (Komar and Buikstra, 2008).

These injuries may be the result of a single event or may be caused by multiple traumatic events. Assessment of blunt-force trauma must include examination of the location of the fracture(s), fracture patterning, the impression at the impact site (if possible), and the sequence of impacts. Due to the viscoelastic nature of bone, blunt-force trauma results in the bone failing first under tension, with fractures progressing towards the side of the compression (Wedel and Galloway, 2014). An incomplete, or “greenstick” fracture, as mentioned above, can be the result of bone withstanding these forces without breaking. Sharp-force injuries are those created by an implement or an instrument such as a weapon, with at least one sharp edge, which produces a lesion that has: G G G G

FIGURE 9.13 Pathological fractures of the left femur. Unhealed fractures are seen in the neck of the femur and the proximal metaphysis. The fracture of the upper diaphysis has healed but with angulation. (Adult female with carcinoma of the breast, WM HS78.1.)

Similarly, the fracture risk for the ancient hunter-gathererfishers are likely to be different from that of the ancient urban dweller. Differences in fracture patterns have considerable significance for paleopathology, in part because of these cultural variations and the inferences that can be made regarding the hazards encountered by different groups (Redfern, 2017: 64, 69 70, 108).

Fracture Mechanisms The study of fracture mechanisms in paleopathology has benefited significantly from adopting methods and techniques employed in forensic anthropology. The importance of (digital) microscopy in facilitating the identification of injuries, particularly perimortem injury, has also been

One elliptical or straight fracture outline; A well-defined “clean” edge or sharp fracture margin; A smooth surface with a polished appearance, and The margin opposite the cut is irregular, often showing flaking and a roughened appearance (Boylston, 2006; Knu¨sel, 2005).

Although forensic anthropological studies have shown that determining the direction of a blow is not without problems (Kimmerle and Baraybar, 2008), the angle of a cut can suggest blow directionality (Boylston, 2006). Chopping injuries can result in both blunt and incised marks in the bone and may produce multiple fragments (Komar and Buikstra, 2008). Often, because these injuries are sustained in combat, with individuals able to move about on foot, mounted, or in a vehicle, e.g., in a chariot (e.g., Shackley, 1986), they may sustain a “glancing blow” that removes a portion of bone, leaving behind a smooth, often “glossy”, lesion (Knu¨sel, 2005). If the person does not die, then usually the removed fragment may be within a flap of soft tissue, particularly in the case of cranial injuries, and thus it may reattach itself during healing (Knu¨sel, 2005). Penetrating injuries can also be caused by projectiles, which often had bladed edges in the past (e.g.,

Trauma Chapter | 9

stone-tipped versus wooden arrows, but experimental research has found that there is little advantage in depth of penetration between these two - see Waguespack et al. (2009). These projectiles usually produce small depressions or can penetrate through a bone, especially the cranium, and create apertures that mimic the shape of the projectile (Forsom and Smith, 2017; Knu¨sel, 2005; Smith et al., 2007). The inner surface of the injury will be bevelled, but if the person survives then this will be remodeled (Knu¨sel, 2005; Fibiger et al., 2013). Often, these injuries are very difficult to identify, particularly without microscopy, and care must be taken to differentiate changes caused by these weapons from those produced by taphonomic action, such as the use of metal probes or the tips of trowels during excavation (Dale Spencer, 2012). However, projectiles may be found still embedded in bone or in the soil surrounding a skeleton, and a few rare examples show evidence for remodeling, indicating that the person survived (Ferna´ndez-Crespo, 2017; Lieverse et al., 2014, 2017; Ryan and Milner, 2006; Tur et al., 2016).

Fracture Healing Fundamental to the diagnosis and reporting of skeletal trauma is the assessment of the timing of the injury in relation to death, which is tied directly to evidence for healing in the bone. Antemortem trauma may be defined as an injury occurring prior to the time of death, whereas perimortem trauma may be defined as one occurring around the time of death (Sauer, 1998). Only by noting evidence for fracture healing may antemortem and perimortem trauma be distinguished in dry bone. If a healing response is observed in the bone, the injury is categorized as antemortem. If there is no indication of healing, then perimortem injury must be distinguished from postmortem damage (see Galloway and Zephro, 2005). Criteria used to distinguish between peri- and postmortem fractures in bone include the staining/color of the fracture, the location of the injury, the morphology of the fracture pattern(s), the angle and margin of the fracture, as well as various contextual clues such as taphonomic conditions and evidence for carnivore activity (Fleming-Farrell et al., 2013; Galloway et al., 2014, for detailed discussion). In assessing trauma to the skeleton, then, the location of the injury and the conditions associated with the fracture event itself are significant (Galloway, 1999; Claes et al., 2012). Fractures of the skull heal more slowly than fractures of the long bones (Schinz et al., 1951 1952: 1603). Fractures heal more rapidly in children, and the length of time needed for healing increases as one ages (Burt and Fleming, 2008). Accidental injuries, fatigue/ stress fractures, and fractures caused by underlying pathological conditions will also vary in the healing process.

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The state of healing often may be assessed using radiographs, wherein the presence of overlap, apposition, and angulation of the fracture fragments can be assessed (Grauer and Roberts, 1996; Roberts, 1991). In the following review of fracture healing, the major emphasis is on the biology of traumatic fracture repair. It is convenient to divide the fracture healing process into stages associated with the major vascular and tissue components associated with fracture repair. Schinz et al. (1951 1952: 377) define a process that includes six stages: (1) hematoma formation, (2) organization of the hematoma, (3) formation of fibrous callus, (4) formation of primary bony callus, (5) transformation of primary callus to secondary bony callus, and (6) remodeling of callus. Paton (1992: 11) combines steps 3 and 4 but the general process is essentially the same. Resnick et al. (2002) divide the healing process into the inflammatory, reparative, and remodeling phases; the longest in time is the latter phase (70%) and the shortest is the reparative phase (10%)—these phases overlap during the course of the fracture healing. Regardless of the phase system employed, several events occur with the fracture of a bone. Blood vessels are ruptured both in the cortex (in Haversian canals) and in the periosteum and marrow. Blood vessels in overlying muscle may also be torn. With the rupture of the blood vessels, blood flows into the fracture region, forming a hematoma, which coagulates. Though earlier studies suggested that the hematoma interferes with healing (e.g., Schell et al., 2017; Schenk, 1973), recent research actually indicates that the hematoma likely provides essential periosteal cell proliferation during fracture healing (Ozaki et al., 2000; Kolar et al., 2010). The broken ends of the blood vessels contract and the open ends are sealed by clotted blood. However, the traumatic event stimulates an inflammatory reaction in which intact blood vessels and the undamaged portions of broken vessels dilate and release a plasma exudate, which adds to the fluid at the fracture site (Collins, 1966: 44; Schell et al., 2017 and Garcia 2003; Claes et al., 2012). The periosteum will usually be broken during fracture, although this is not inevitable, particularly in young individuals. The stress that breaks the periosteum also tends to strip it from the surface of the bone for a few millimeters adjacent to the fracture site. This appears to activate the bone-forming potential of the osteogenic layer in the periosteum and initiates the formation of callus (Schinz et al., 1951 1952: 378). Breakage of the blood vessels at the fracture site also results in the death of tissue and cells within the tissue, including the osteocytes, supplied by such vessels and any bone fragments resulting from the breakage. This bone will ultimately have to be replaced. In classic fracture healing, the formation of a blood clot is followed by the second step in fracture repair, in which the blood clot is permeated by fibrous connective

222 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

(granulation) tissue (Paton, 1992: 11). Collins (1966: 50) notes that the hematoma, if not extensive, can assist in initial union by providing a matrix for the advance of granulation tissue. However, granulation tissue can penetrate the hematoma only to a limited depth; thus, an extensive hematoma between the broken ends of the bone seems to delay the healing process. The fibrous callus that unites the ends of the fragments is derived from the granulation tissue. This fibrous union of the broken ends is the third stage of fracture healing. Although the fibrous callus is unmineralized, it provides the matrix for the formation of fiber bone and the primary bony callus, which is the fourth stage in fracture healing (Marshall and Einhorn, 2011). As discussed in Chapter 4, woven or fiber bone is associated with rapid bone formation. Under normal conditions it occurs only during the growth phase. Fiber bone is a temporary tissue, replaced by lamellar bone, which has much greater mechanical strength. Collins (1966: 47) notes that primary callus formation in human bone generally begins about 1 week after fracture. Initially, primary callus consists of coarse, fibrillar trabeculae within the fibrous callus. Primary callus is associated with different areas of the fracture site and three basic types have been defined for conceptual purposes (Schinz et al., 1951 1952: 378; Schenk, 1998: 55 59). The intermediate or sealing callus joins the broken ends of the bone. The endosteal callus unites the opened marrow spaces, forming a plug between the two ends, whereas the periosteal or bridging callus arches over the fracture site. The bridging callus provides the externally visible evidence of a healed fracture in an archeological bone. One other component of primary callus is the occasional occurrence of cartilage in the region of the callus. Collins (1966: 48) expresses the opinion that cartilage is incidental to the overall process of fracture healing. In support of this conclusion, he cites the work of Ham (1930) who suggested that cartilage formation is associated with poor vascular supply. Aegerter and Kirkpatrick (1975: 237) challenge this concept but offer no alternative. Schenk (1998: 55 56) discusses the presence of mineralized fibrocartilage in fracture consolidation as a normal part of the repair process (see also, Marshall and Einhorn, 2011). It is important to remember that bone formation requires an adequate blood supply. Intense vascular proliferation begins with the formation of granulation tissue and is associated with callus formation. The blood vessels enabling the formation of callus also create conditions in which resorption of bone fragments and remodeling of the bone ends at the fracture site can occur. The fifth stage in fracture healing involves conversion of the fiber bone callus to lamellar bone. This includes the apposition of lamellar bone to existing fiber bone surfaces, the removal of fiber bone by osteoclasts, and

FIGURE 9.14 Compensatory remodeling in an angulated healed fracture of the right femur. Arrows indicate the thickness of the new cortical bone added to the concave side of the angulated femur shaft. On the opposite side some of the cortical bone of the broken ends has been removed. (Adult, IPAZ 192/60.)

internal osteon remodeling. The result is a much stronger union of the broken ends. This, in turn, means that less bone is needed for optimal biomechanical strength. In the final, sixth stage of fracture healing, the callus is reduced to a minimum (Fig. 9.14). If the orientation of the broken ends is good, the callus may no longer be apparent. If angulation has occurred there is compensatory remodeling (Fig. 9.15).

Trauma Chapter | 9

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FIGURE 9.15 Healed fracture with angulation in an adult right femur. (A) Anterior view. (B) Posterior view, arrow indicates callus. (IPAZ 1780/62.)

The time for fracture healing varies based on several variables, including (1) the bone involved, (2) the severity of the fracture, (3) the apposition of the ends, (4) the stability of the fractured ends, (5) the nutritional status of the individual, and (6) the age of the individual. Collins (1966: 52) indicates that in a typical bone under ideal conditions the primary callus takes about 6 weeks to develop. The secondary callus becomes significant after this time, but bony union and return to adequate function are too variable to predict. Paton (1992: 11) also emphasizes the variability in the time for a fracture to repair. His general guidelines indicate that cortical bone in adults heals in about 3 months, cancellous bone takes about 6 weeks, and fractures in children repair about twice as quickly as those in adults. Barbian and Sledzik (2008) used microscopy to study skull injuries in an American Civil War (1861 1865 AD) skeletal collection. They found that the earliest response to cranial fracture was 5 days after injury, and by week 6 all of the 127 crania/fragments of crania had either an

osteoclastic or osteoblastic response. De Boer and colleagues (2015) have further contributed to this discussion by producing radiological and histomorphological criteria that represent different stages in the healing process. There have also been studies of the criteria used to identify perimortem versus antemortem and postmortem fractures (Cappella et al., 2014a; Wieberg and Wescott, 2008), and studies focusing on fractures in subadults and their healing rates (Malone et al., 2011). However, it should be remembered that healing rates can vary even for the same type of fracture in the same bone (Resnick et al., 2002), which indicates the many different factors operating for an individual as a fracture heals. Cruess and Dumont (1975: 97), rather than assigning a specific timetable, indicate the approximate percentage of the total healing time spent in the three major phases of fracture healing. These phases include the inflammatory phase (10%), the reparative phase (40%), and the remodeling phase (70%). Because these phases overlap somewhat, the total exceeds 100%. In any case, the time

224 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

Bony Sequelae of Trauma

FIGURE 9.16 Fracture with nonunion and extensive callus formation on the proximal side of the fracture, and sealing off of the medullary space on the distal side of the fracture. (Left and right femur of a juvenile orangutan, NMNH VZ 293165.)

period associated with reduced biomechanical function is at least a matter of weeks even in an ideal situation. The significance of this period of reduced activity is difficult to assess. Schultz (1939: 578) reports that the percentage of fracture cases for free-ranging nonhuman primates varies between 12 and 34. Primates killed in the wild present numerous examples of well-healed fractures (Duckworth, 1912; Schultz, 1939), indicating that a fracture need not be a serious threat to life. Indeed, nonunion of a femoral fracture in a free-ranging orangutan shows evidence of lengthy post-trauma survival (Fig. 9.16). In human populations, the threat is likely to be even less, but greatly dependent on the environment and economy of the group. For an adult in a small social unit heavily dependent on hunting, such an injury could be very serious indeed for the hunters and those who depend on their productivity.

The complications of fracture include: (1) infection, (2) tissue necrosis and loss of innervation, (3) inadequate healing of the fracture, (4) bone deformity, (5) traumatic related arthritis, (6) joint fusion, and (7) traumatic myositis ossificans. This aspect of trauma analysis can be very challenging, as it is often not possible to determine whether the fracture came before or after an infection or osteoarthritic condition. Neither should we forget that even simple fractures can result in injury to the softtissues, such as the lungs being punctured by rib fractures, as well as in more complex fractures, such as those to the pelvic girdle, which can injure the gastrointestinal tract. The following discussion provides a brief review of each of these conditions. Infection is a serious complication of fracture and can occur whenever infectious agents infiltrate the fracture site. This can happen if the soft tissue in the fracture area is penetrated by one or both of the broken ends of the bone. It can also occur if the agent producing the fracture also penetrates the skin, as would be the case with a spear, arrow, bullet, or other projectile. Infection is also possible if bone penetrates any portion of the digestive tract, or any body -cavity where infectious organisms exist. Bo¨hler (1935: 65) indicates that open (compound) fractures with direct injury to the skin (crushing or penetrating wounds) have a much greater risk of infection than those due to indirect injury (as when a broken bone penetrates the skin). Two major infectious conditions pose a serious threat to life. The first of the conditions is gas gangrene arising in necrotic tissue due to the action of organisms, such as Clostridium, which do not require oxygen to survive (anaerobic). The other major threat to life is pus-forming (suppurative) organisms, which can spread from the fracture site andproduce general infection of the blood (septicemia) and ultimately death. Bo¨hler (1935: 64) reports statistics for 1887 (preantibiotic period), in which the estimated mortality from open fractures in German hospitals was 40%. These 19th century reported data indicate that open fractures (open-comminuted and open only) occur in about 19% of all fracture cases. Another complication of local infection at the fracture site is disruption of the blood supply to bone, leading to death of the tissue (necrosis). At the boundaries of the dead tissue, osteoclasts may isolate the dead bone through osteoclastic resorption. Such an isolated segment of dead bone is known as a sequestrum. Often, if the blood supply to the bone itself is cut off, the periosteum remains intact and produces a new sheath of bone called the involucrum around the necrotic tissue. A more detailed review of infection in bone is presented in Chapter 10 on infectious diseases. With respect to fracture, the significant point is that infection, certainly in preantibiotic times, is a serious

Trauma Chapter | 9

complication, having a significant risk of mortality. However, in archeological skeletons, it will require very careful and observant excavation techniques to distinguish an unhealed fracture resulting in or associated with death from that of postmortem damage from soil movement, overriding pressure from animals or vehicles, or careless excavation (White, 1991: 358 360; Ubelaker and Adams, 1995). Although the rupture of some blood vessels is an inevitable result of all fractures, damage to major blood vessels and nerves is not inevitable because of the flexible and relatively tough nature of these structures. Risks of damage to major blood vessels and nerves is greatest in crushing injuries that result in fracture. However, even in simple fractures, the displacement of the bone ends can compress or twist blood vessels or nerves (Bo¨hler, 1935: 73) and lead to ischemia and loss of nerve stimulation. Loss of blood supply will lead to delayed fracture healing and, if uncorrected, can result in bone necrosis. Loss of nerve supply is serious, but does not appear to be as dangerous. However, if sensory nerve supply is lost to the fracture site, the lack of pain may result in continued use of the broken bone and prevent healing, or in the case of a fracture in an articular surface, lead to a neuropathic or Charcot joint, in which there will be exuberant bony response to unrelieved trauma to the joint (Fig. 9.17). For example, the radial nerve may be damaged in association with a humeral fracture, and wrist drop and lack of normal function of the hand can develop (Resnick and Goergen, 2002). In some cases, the distribution of dynamic force immediately after trauma may not break the bone but will disrupt the blood supply, lead to ischemia, and may result in tissue necrosis. Three such examples may be seen in the medical Hunterian Collection in London (Figs. 9.18 9.20). All three are attributed to a blow on the head. If the blood supply in the immediate region of the blow is disrupted, the tissue becomes ischemic or necrotic, and there is an inflammatory response adjacent to the affected bone. Traumatic interruption of the blood supply in a growing bone can produce abnormal shortening of a long bone. The epiphyseal plate in such bones is particularly vulnerable to trauma, because of the relative weakness of calcified cartilage. Trauma to the ends of growing bone not only can break the cortex, but can also shear the epiphysis (Schinz et al., 1951 1952: 422). In both cases, the blood supply is disrupted and growth is retarded. Such injuries to the epiphysis may also result in premature fusion of the growth plate. The result of any of these complications is a shortened bone. If only one of the two bones of the forearm or lower leg is involved, and becomes shortened and/or rotated, then abnormal angulation of the hand or foot may develop. If both the radius and ulna, or the tibia and fibula are affected, the entire forearm or lower leg will be shortened. Similarly, fracture

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FIGURE 9.17 Charcot joint resulting from fracture of the left femoral neck. (A) Anterior view of the innominate bone and the femur; note the large mass of bone over the acetabulum creating a new joint, which comes in contact with the greater trochanter. (B) Infero-lateral view. (ANM 2243.)

at the growth zone of other long bones can lead to reduced length in a bone. Fracture healing also brings increased vascular flow to a bone. In situations where the epiphyseal plate has not been adversely affected, this inflammatory stimulus may cause an abnormal increase in growth of the affected long bone (Ogden et al., 1996: 22). Serious disruption of nerves in other parts of the body may be associated with fracture of the vertebral column, depending on the vertebrae involved, because either the spinal cord or the spinal nerves can be affected. Bo¨hler (1935: 109 145) reviews these fractures and their complications. The most serious complication occurs when the spinal cord is completely severed. The permanent paralysis below the level of the injury, which inevitably results, affects various parts of the body, depending on where the break occurs. Comminuted fragments can put pressure on the spinal cord or spinal nerves, producing paralysis, which probably

226 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 9.18 Central bone necrosis surrounded by a zone of hypervascularity (arrows) following a blow to the head. (Portion of the left frontal bone, HM P626.)

FIGURE 9.20 Small area of bone necrosis surrounded by a zone of hypervascularity and bone resorption (arrows) following a blow to the head. The traumatic nature of the lesion is demonstrated by the partially healed bone fragment occurring internally. (Portion of the frontal bone, HM P628.)

FIGURE 9.19 Large area of bone necrosis (arrows) surrounded by a zone of hypervascularity following a blow to the head. (Frontal bone, HM P627.)

will not heal spontaneously. Because surgical procedures were generally not accessible to people in the past, evidence of a partially occluded neural canal above the second lumbar vertebra would be suggestive of paralysis. Evidence of this should be sought in the limbs likely to have been affected (e.g., Fig. 9.5). In general, paralysis prevents effective use of the paralyzed limb, and will result in

subnormal bone development in children and bone atrophy in adults. A less serious result of spinal fracture is a blood clot or callus producing pressure on the spinal cord or nerve root. The blood clot will disappear in time if the individual rests, and the callus may be partially remodeled after the break heals. Dysfunction in the form of paralysis in such cases may be temporary. In some fractures, the healing process is delayed or incomplete (Paton, 1992: 27). The reasons for delayed or nonunion of fracture are not fully understood, but inadequate immobilization of the fracture during the healing phase is a major factor. Regrettably, the terminology used to describe inadequate fracture healing can be confusing. In one type of inadequate fracture healing, the fibrocartilage connection between the broken bone pieces does not mineralize and go on to compact bone remodeling of the callus. Another possible outcome of inadequate fracture healing is the formation of a joint at the fracture site, complete with a synovial capsule. In the earlier European clinical literature (e.g., Schinz et al., 1951 1952: 425 430), the terminology

Trauma Chapter | 9

applied to the first of these complications was pseudarthrosis. The second condition, where a new joint is formed, was termed nearthrosis. Resnick et al. (2002: 2575) accept a different term whereby nonunion with a fibrocartilage connection between the broken ends occurs but lacks mineralization is called nonunion. The situation where a new joint is formed is termed pseudarthrosis. Despite the confusing use of terminology, the process described in the clinical literature is clear. The break is followed by a failure to restore reasonably full biomechanical function to the fracture site. There may be differences in the skeletal manifestations associated with these two types of nonunion, and these should be kept in mind when one encounters this type of abnormality in archeological human remains. Fibrocartilagenous connection can be associated with considerable callus formation. However, it can also be linked to a tapered remodeling of the fractured bone ends. The latter should certainly be distinguishable from the bony changes associated with the formation of a synovial joint, and this distinction should be noted when encountered in human remains. Schinz et al. (1951 1952: 379) indicate that nonunion is the result of repeated disruption of the callus formation, which results in increased hyaline cartilage formation instead of the mineralizable osteoid normally expected in the callus. This may be a response to reduced blood supply caused by trauma to developing vessels during movement of the broken ends (Schinz et al., 1951 1952: 427). Another possibility is the interposition of other tissue (e.g., muscle) between the broken ends. Inadequate immobilization of the fracture remains the prime suspect for nonunion of fractures in the more recent literature (e.g., Resnick et al., 2002: 2575), but other complicating factors are recognized as well, including adequacy of innervation and vascular supply. In pseudarthrosis resulting from fracture, the ends of the broken bone are joined by connective tissue and, indeed, extensive callus may form. However, this tissue does not mineralize properly due to a lack of osteoid, and the union remains flexible. With time, the broken ends of the bone will be sealed off by new bone formation and will be connected by flexible fibrocartilage. With continued movement, hyaline cartilage may develop near the middle of the fibrocartilage mass and a cleft created, forming a true joint. Ultimately, a joint capsule may surround the joint space, thus approximating the anatomy of a normal joint. In either case, the result is severely diminished functionality of a limb. However, in the case of the forearm or lower leg, if nonunion involves only one of the two bones, extensive hyperplasia of the other bone may occur to partially compensate for the reduced function of the unhealed fracture in the other (Schinz et al., 1951 1952: 428). Problems in biomechanical function can also be caused by misalignment of the broken ends. Two factors contribute

227

to this. The trauma resulting in fracture may produce misalignment. At least equally significant, however, is the fact that the sensory stimuli triggered by the fracture produce a virtually instantaneous and powerful contraction of the muscles in the fracture area. Subsequent movement of the limb will repeat this stimulus if pain results (Bo¨hler, 1935: 58 59). Reactive muscle contraction exacerbates the poor alignment of the broken components of the bone, and the likelihood of misalignment during healing is high. In modern clinical practice, initial management of fracture involves minimizing muscle contraction and careful realignment of the broken ends so that the bone approximates, as near as possible, its original shape. However, misalignment can occur in modern cases of fracture where realignment is poor (Fig. 9.15). The effects of poor alignment vary with the bone involved and the severity of the fracture. Rarely, if ever, does it produce a direct threat to life. However, it can lead to premature and severe degeneration of a joint, because of the abnormal biomechanical loading on the joint brought about by misalignment. In the long bones, this can result in reduced locomotion and manipulative ability. Misalignment of a vertebral fracture can result in abnormal angulation of the spine and abnormal biomechanical loading on the adjacent vertebrae. Fracture can, directly or indirectly, produce premature osteoarthritic degeneration of joints. If a joint surface is broken, the associated cartilage and subchondral bone are disrupted. Because of the absence of a blood supply, cartilage repair depends on nutrients from the joint capsule, and any repair is a slow process. A break of the subchondral plate will usually result in permanent discontinuity of the bony joint surface. This complicates the healing processin the articular cartilage, because it results in poor contact between the gliding surfaces of the joint. This creates serious problems in dissipating the loading applied to the joint and results in premature deterioration of the articular cartilage. The fracture need not involve the joint itself to produce premature degenerative changes in the joint. A change in the axis of a long bone can shift the major focus of loading to a portion of the joint less well adapted for such stress. Similarly, abnormal shortening of a long bone after fracture (Fig. 9.21) can produce uneven locomotion, which results in unusual stress to the joint and premature degenerative change (Schinz et al., 1951 1952: 430). In trying to distinguish between premature degenerative change resulting from fracture and osteoarthritis associated with aging, the observer may find it useful to compare the joint associated with the fracture to the contralateral joint. Fracture of the joint surfaces can also result in destruction and fusion across the joint. This problem is associated with comminuted fractures of the joint where more than one joint surface is involved and callus formation

228 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 9.21 Healed diagonal fracture of the distal left femur with marked mediolateral and longitudinal displacement of the broken ends. (A) Medial view. (B) Posterior view. The displaced ends are joined by abundant callus. There has been considerable cortical remodeling of the broken ends, which have been sealed off with compact bone. (WM S32.7.)

joins two or more bones. In the limbs, this means loss of movement for the joint. In the vertebral column, such a fusion is seen in Fig. 9.5, which is a common sequela of compression fractures of one or more vertebral bodies (Bo¨hler, 1935: 142 143). In such cases, the mechanism is activation of the periosteum of the body with callus formation extending to one or more adjacent vertebrae. The effect is a rigid segment of spine, perhaps associated with angulation, but often with little overall loss of spinal movement. Fusion of fractured joints can easily be confused with fusion following infection of the joint (septic arthritis). In some cases, a distinction may not be possible; however, traumatic related fusion in joints may show evidence of one or more fracture lines). Trauma to the vertebrae does have the potential for serious complications arising from damage to the spinal cord, and the nerves extending from the cord to supply innervation to other parts of the body. The remarkable

flexibility of the spine is the result of its special anatomical structure, which includes the bony components of the diarthrodial joints of the posterior elements, the amphiarthrodial joints of the vertebral bodies, and the complex of muscles, tendons, and ligaments that provide the stability to the spine while also permitting a range of motion in virtually all axes (Paton, 1992: 41). The bony elements of the spine are subject to a variety of stresses that produce different types of traumatic manifestations, including fractures resulting from abnormal compression, flexion, and tension (Paton, 1992: 42). In addition, vertebral disks have the potential to rupture and affect the end -plates of the vertebral bodies. Disk trauma can also result in anterior rupture, which strips the periosteum away from the vertebral bodies and stimulates reactive bone formation. This manifestation of disk trauma is fairly common in human skeletal remains but can easily be confused with the features of degenerative joint disease.

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FIGURE 9.23 Major trauma to the left parietal and occipital bones probably due to an axe or sword wound, with remodeling of the edges indicating long-term survival. (Adult, probably male, FPAM 5719.)

FIGURE 9.22 Saber wounds of the left parietal bone. (A) There is a large, displaced fragment on the lateral portion; the wound healed with the fragment in the displaced position, leaving an opening in the skull; the second healed saber wound is seen superior to the large defect. Only the outer table was affected. (B) Internal view. (Adult male, ANM 2069.)

Thus far, in this review of fractures and their complications, we have made only limited reference to the skull. Fracture of the skull presents an additional potential complication similar in some aspects to fracture of the spine, but not associated with fractures in other bones. The most immediate problem in skull fracture is hematoma and edema, both of which are common results of such trauma. An unrelieved increase in pressure on the brain from hematoma or edema will force the brain tissue into the foramen magnum, disrupting the blood supply to the brain and damaging the brain stem. If the skull is fractured by a blow, the pressure buildup may be relieved through the fracture site. Obviously, if the blow is too severe, death will result from direct injury to the brain. The extent of injuries to the skull that an individual can survive is often remarkable. Fig. 9.22 shows views a skull due to a weapon called a saber, in which a piece of the left parietal bone was completely dislodged, with healing of the fragment in the displaced position. In this skull (ANM 2069), currently located in the National Museum of Anthropology, Prague, Czech Republic, the

edges of the wound are well remodeled, indicating considerable time after the injury before death occurred, probably due to an unrelated cause. In this skull, the glancing nature of the sword wound may have prevented any damage to the underlying dura and brain. Another case of severe trauma to the skull is seen in a skull (FPAM 5719) curated in the Federal PathologicAnatomy Museum in Vienna, Austria (Fig. 9.23). It shows massive fracturing of the left parietal and occipital bones with fracture lines radiating from the major fracture site. The size of the gap is suggestive of a wound from a saber or axe in which the weapon was twisted to pry the broken edges of the bone apart. The edges of the break are well remodeled, indicating longterm survival after the traumatic event. Surgical intervention in pathological conditions that affect the skull or its contents is a common practice today. Such a procedure carries with it the risk of infection and damage to the brain, as seen in injuries of the skull caused by accident or intentional violence. Fortunately drug therapy (antibiotics) are now available to us. The lines of defense for infection of the brain include the hair and skin, the cranium with its two layers of compact bone separated by the spongy diploe, and the dura, a tough layer of connective tissue that directly overlies the brain. Traumatic penetration of the dura carries a high risk of infection as a complication of the trauma itself. In view of this risk, evidence of surgical treatment of the skull (trepanation) in antiquity is a remarkable phenomenon

230 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

TABLE 9.3 Summary of the Range of Trauma That Can Be Sustained by the Teeth and Surrounding Structures Structure

Type of Trauma

Hard dental tissues and pulp

G G G

Pulp, periodontal ligament, and alveolar process

G G G

Supporting tissuesa

G G G

G

G

Gingiva, oral mucosa, or skina

G G

Enamel: infraction (crack), fracture Enamel dentin fracture Enamel dentin pulp fracture Crown root fracture Root fracture Fracture of the maxillary or mandibular alveolar socket wall and/or processa Subluxation: increased mobility without displacement Extrusive luxation: partial displacement of the tooth out its socket Lateral luxation: displaced in any direction other than axially. Typically accompanied by comminution of fracture of the labial/palatal/lingual alveolar bone Intrusive luxation: displacement of the tooth into the alveolar, usually accompanied by comminution or fracture of the alveolar socket Avulsion: the tooth is completely displaced from its socket Contusion: may be associated with an underlying fracture Laceration: a shallow or deep wound, typically produced by a sharp object. Can disrupt blood vessels, nerves, muscles, and salivary glands

a

Potentially identified by the presence of periosteal new bone formation.

Source: After Andreasen et al. (2011).

and will be discussed as part of the review of the paleopathology of surgical intervention.

Dental Trauma Dental trauma includes injuries sustained by the teeth (crown and roots) and surrounding alveolar bone (Andreasen et al., 2011). This type of injury is produced by direct force to a tooth or teeth and/or their supporting structures, which produces a fracture and/or displacement in addition to separation and/or crushing of the surrounding areas (Andreasen et al., 2011). Trauma to the mouth is a serious event, particularly in presurgical eras, as injury to this area could have resulted in permanent or transient impairment of speech and/or eating. Further, trauma to the mouth can lead to serious infection that can be transmitted to the brain (Corson et al., 2001). Dental trauma also has the potential to negatively impact a person’s social identity, as it can significantly change their appearance (Lee and Divaris, 2009). Similar to other injuries (e.g., unreduced joint dislocations), the consequences of a single trauma related injury can be experienced for many years afterwards, such as permanent tooth buds being malformed, particularly if the subadult also experienced trauma to both jaws (Andreasen et al., 2011; Koenig et al., 1994). A range of injuries can be sustained by the hard structures of the mouth, many of which require radiography to be identified unless the teeth have become loose postmortem, or the injury is identified during excavation (e.g., Lukacs and Hemphill, 1990). These are described in Table 9.3, but they can be summarized as including fractures (complete and incomplete), subluxation, and avulsion.

Identifying dental trauma is a very difficult task, as it is beset with confounding factors, and it must be acknowledged that we may be unable to securely identify some types of dental trauma, such as avulsion injuries. Perhaps the most problematic is distinguishing between antemortem and postmortem enamel infractions, which may only be possible if microscopy is used to identify evidence for the margins of the teeth showing a “rounding-off,” indicating survival for a time following the infraction. Subluxation is also complicated to identify, because periodontal disease may cause instability and create false-positive evidence for this type of trauma (Barker, 1975). Although prehistoric evidence for dentistry exists (Bernardini et al., 2012), until the 19th century AD dental restoration techniques do not appear to have included individual replacement crowns, although metals and other materials were used to fill crown fractures and chips to the teeth (see Miles et al., 2008). Therefore, if a tooth sustained a crown root fracture, leading to loss of the crown, the exposed root would become worn and therefore it would be very difficult, if not impossible, to differentiate the injury from a crown lost due to a carious lesion. Dental trauma is, of course, experienced by all age groups. Epidemiological studies, however, show clear age and sex differences across the life-span, a result likely to be biased by contemporary gender roles and childhoods, as well as the majority of published data being derived from European and North America populations (Andreasen et al., 2011). With respect to accidental mechanisms, subadults have an increased risk of sustaining craniofacial trauma because they have greater cranial-mass-to-body ratios and shorter statures, in addition to experiencing the various

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developmental milestones of childhood; the role of over/ under-jet has also been suggested as a biasing factor in sustaining an injury in this age group (Eggensperger Wymann et al., 2008; Haug and Foss, 2000). Subadults are more likely to sustain a dental injury if they have fractured their mandible, which can cause delayed dental eruption, partial resorption and impaction of a tooth or teeth (Suei et al., 2006). Most injuries are sustained to the anterior teeth by males, particularly the upper central incisors and between the ages of 2 and 5 years old. In living populations, these are due to accidents affecting the deciduous dentition during sports and play, with a peak in injuries in children learning to walk and run (Andreasen et al., 2011). The permanent dentition is more likely to be injured than the deciduous, because it is present in the mouth for more years than the deciduous dentition. The permanent dentition is easily injured during play/sports, and it can be damaged due to blows and falls during fights which occur from childhood onwards, particularly in males (Gassner et al., 2004). Today, most trauma is sustained by young men, usually from accidental falls or during sport; a minority are the result of violence (Caldas and Burgos, 2001; Holland et al., 1994). However, this may not have been the case in past societies, as socially expected male behavior and concepts of masculinity strongly determine male patterns of aggression (Redfern, 2017). Contemporary studies have shown that the majority of injuries are sustained to the anterior dentition; note that in these clinical studies, it is not clear whether the injured teeth had been subject to previous dental work, which can compromise their structural integrity (Brunner et al., 2009; Kaste et al., 1996). Most injuries reported by dental practitioners are crown fractures (Brunner et al., 2009), but self-reported datasets describe chipping as the most frequently reported injury (Locker, 2007). This suggests a bias in the clinical data, as people are more likely to seek treatment for an injury if it significantly impacts on their physical appearance and ability to masticate (Enabulele et al., 2016). In archeological contexts, care must also be taken to differentiate between intentional cultural modification and trauma to the teeth, as many past societies removed the anterior dentition for aesthetic purposes and the attainment of certain life course events, such as marriage (e.g., Durband et al., 2014; Stojanowski et al., 2014; Willman et al., 2016). This practice still occurs today (e.g., Friedling and Morris, 2007), and some communities also gougeout canine tooth buds in order to stave-off illness in small children (Dewhurst and Mason, 2001; Hassanali et al., 1995). Population-based studies of dental trauma include investigations of a variety of groups from across the globe (e.g., Alvrus, 1997; Gibbon and Grimoud, 2014; Lukacs, 1990, 2007; Merbs, 1968; Turner and Cadien, 1969), and some researchers have employed imaging techniques in order to establishing the timing of injuries (e.g., Viciano et al., 2012).

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Dental chipping also is reported and is commonly encountered in contemporary populations, as described above. Paleopathologists are, however, faced with the challenge of distinguishing between changes produced by activities/accidents related to occupation and those caused by intentional trauma. Temporal and spatial contextual information is important in identifying the mechanisms behind the chipping (e.g., Scott and Winn, 2011; Waters-Rist et al., 2010). More rare are reports of tooth dislocations. Again, distinguishing between a traumatic etiology, an accidental cause, or instability because of dental disease is incredibly complex (Clarke and Hirsch, 1991). Dental traumais also difficult to identify in cremated human remains because the process of cremation will cause the tooth crowns to fracture and fragment (Fairgrieve, 2008). However, Merbs (1967) reports the occurrence of alveolar bone fracture and antemortem loss of a premolar tooth in cremated human remains from pre-Columbian Arizona (USA).

Subluxation and Dislocation Another major category of trauma concerning the skeleton involves the disruption of the normal relationship between the bones and associated articular cartilage of a joint. Most commonly the disruption is caused by trauma. Traumatically induced dislocation (or luxation) can be defined as “complete loss of contact between two osseous surfaces that normally articulate” (Resnick et al., 2002:2631), and subluxation defines partial loss of contact. Both involve damage to the associated soft tissues of the joint. They can also occur as a result of a congenital condition (e.g., joint dysplasia) or be acquired during life, making the integrity of the surrounding musculature of the joints weaker in a variety of ways. Congenital and developmental abnormalities in joint development that increase the likelihood of dislocation are discussed in Chapter 21. The connective tissue capsule enclosing the joint may be torn by the trauma too. In addition, muscles, tendons, ligaments, nerves, and the vascular supply associated with the joint may be disrupted. If trauma exposes the underlying joint, it is described as an "open" dislocation or subluxation. If there is no exposure of the joint, the dislocation or subluxation is closed. While both dislocation and subluxation can be associated with a fracture, they often occur without fracture. They can also can occur in most joints, but some joints are more vulnerable than others. The most commonly dislocated joints are the shoulder, interphalangeal, elbow, hip, knee, and ankle joints; some joints dislocate more readily than others because of their underlying anatomy. For example, the shoulder joint is inherently less stable than the hip joint because the glenoid cavity of the scapula is very shallow compared to the deep acetabulum of the hip joint, and the shoulder has greater overall movement. While these conditions are

232 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

much rarer in the archeological record when compared to fractures, sometimes fractures can be associated with dislocations (e.g., those of the forearm; see also, Viciano et al., 2015). There are also some diseases that can lead to bone formation and destruction that can make the joint surfaces unstable, which can underlie later subluxation and dislocation. An example of this is the destruction of the margins of the metacarpophalangeal joints of the hands in rheumatoid arthritis (Resnick, 2002a). To be detected in an archeological skeleton, disruption to the joint must result in remodeling that produces a visible anatomical change in subchondral bone or bone adjacent to the joint. This means that subluxation will rarely be identified, and evidence of dislocation will be seen most often in joints where their anatomical structure makes spontaneous correction of the problem difficult. The two joints particularly prone to chronic or permanent dislocation are the shoulder and the hip, and we will focus on these to illustrate the problems associated with this type of trauma. The anatomy of the shoulder joint permits maximum movement of the arm in virtually all axes (Fig. 9.63). This degree of movement is highly useful for performing the manipulative functions of the arm and hand. However, the biological trade-off for this mobility is a relatively unstable joint. Undoubtedly, this inherent instability is the major factor in the glenohumeral joint being among the most commonly dislocated major joints in the body (Rockwood, 1975: 624; Resnick and Goergen, 2002: 2694). The bony components associated with the shoulder joint are the scapula, humerus, and clavicle. The round head of the humerus articulates with the glenoid cavity of the scapula. However, unlike the acetabulum of the hip, the glenoid cavity is little more than a slight depression in the subchondral bone, so that the humeral head rests against the glenoid joint surface but receives little support from it. The major support for the glenohumeral joint is the ligament and capsule attaching the humeral head to the scapula. Overlying these are the muscles of the rotator cuff and the deltoid, which also help to stabilize the joint. However, these supporting structures are developed to permit optimal movement, and provide little resistance to the forces of trauma that cause dislocation. Indirect force is the most common cause of glenohumeral dislocation (Rockwood, 1975: 641). The mechanism by which the force is applied involves sudden and extreme movement of the upper arm away from the body (abduction) in association with external rotation as could happen in a backward fall in which the hands are used to break the impact. The effect is to drive the humeral head into the anterior capsule. The result is anterior dislocation, the most common type of shoulder dislocation (Resnick and Goergen, 1995: 2694). An example of this type of dislocation is seen in the right scapula (Fig. 9.24) of a modem anatomical scapula that is part of the collection of the Museum

FIGURE 9.24 Secondary joint formation on the anterior right scapula following unreduced dislocation of the shoulder joint. (Adult, SDMM 1981-30-772.)

of Man in San Diego, California (SDMM 1981-30-772). The formation of a secondary joint on the anterior surface of the scapula indicates long-term contact with that surface and the likelihood that the dislocation was not reduced. Forces associated with this traumatic effect frequently produce a compression fracture as the edge of the glenoid cavity is forced into the head of the humerus (Rockwood, 1975: 642). According to Rowe (cited in Rockwood, 1975: 641), 96% of dislocations are traumatic in origin; 4% are nontraumatic. Congenital defects in the bony structure or supporting ligaments and muscles appear to play a minor role in traumatic and nontraumatic dislocations. Because of the anatomy of the glenohumeral joint, spontaneous reduction of the dislocation often will occur. Rockwood (1975: 625 627) notes that the methods for reducing shoulder dislocations go back at least to the time of Hippocrates (c. 430 BC). Thus, it seems possible that the treatment of dislocations could have existed in many archeological populations. However, it is also clear that unreduced dislocations do occur in archeological populations. In such situations, a new joint surface is created where the humeral head comes in contact with the scapula and provides clear evidence of dislocation. Whereas the anatomy of the hip permits considerable movement, its structure is influenced by its major weightbearing function. In contrast with the glenohumeral joint,

Trauma Chapter | 9

the hip is a classic ball-and-socket joint with the head of the femur deeply extended into the hip socket or acetabulum. Given this anatomical difference in contrast with the shoulder, it is not surprising that the prevalence of hip dislocations is less common than dislocations of the shoulder. Unlike the glenohumeral joint, the hip joint components are joined directly by a ligament (ligamentum teres), which also contains the vascular supply for approximately the medial third of the femoral head adjacent to the ligament. Dislocation of the femoral head thus threatens the vascular supply of part of the femoral head. In developmental hip dysplasia, the acetabulum is abnormally shallow and the femoral head is often abnormally formed, meaning that it can slip out of the socket in response to slight trauma or even during normal walking. The mechanism for traumatic hip dislocation in an otherwise normal hip varies, depending on the position of the leg and the direction of the force. Depending on these factors, dislocation of the femoral head may occur in an anterior or posterior direction, with the latter being much more common in modem orthopedic practice (Epstein, 1973: 116; Resnick and Goergen, 2002: 2752). Reduction

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of hip dislocations is more difficult than those of the shoulder. The failure to reduce the dislocation will result in the formation of a secondary articular surface on the innominate bone (Fig. 9.25). Because spontaneous reduction is less likely, identification of this type of trauma to the hip in archeological human remains should be fairly easy and should more accurately reflect the actual prevalence of dislocations in an archeological population than evidence of shoulder dislocation. We have reviewed dislocation of only two of the major joints for illustrative purposes here. The student of paleopathology interested in this subject should consult the orthopedic source materials for a more comprehensive treatment (e.g., Resnick, 2002a; Rockwood et al., 1996; Browner et al., 1998). However, these two examples of dislocation reveal several principles that are associated with all dislocations: (1) Although there may be congenital and developmental factors involved, trauma is by far the most common cause of dislocation; (2) dislocation may be associated with fracture; (3) unreduced dislocation creates a secondary joint surface; (4) the evidence for dislocation in archeological human remains reflects only a portion of the actual prevalence of this type of trauma; (5) the blood supply to the bony part of the joint may be disrupted by dislocation, resulting in tissue death (aseptic necrosis); and (6) the trauma associated with dislocation may also tear the ligaments, tendons, and muscles associated with the joint, and may be associated with injury to blood vessels and nerves.

Recording Trauma

FIGURE 9.25 Luxation of the right hip (left side of figure) with secondary joint formation in an adult male skeleton from an archeological site at Jones Point, Kodiak Island, Alaska. (A) The acetabulum is shallower than normal in both innominate bones. (B) Detailed view of porous secondary joint surface on the right innominate bone of the skeleton (A); note secondary arthritic change on the associated femoral head. (NMNH 372897.)

Over the past 20 years, several systems for recording systematic data from human remains have been devised by professional bodies (Brickley and McKinley, 2004; Buikstra and Ubelaker, 1994; Mitchell and Brickley, 2017; Rose et al., 1991); increasingly, individuals and institutions are providing these systems as free digital resources (e.g., Smithsonian National Museum of Natural History, 2016). While these systems are not specifically designed to record skeletal trauma, they do provide guidelines for collecting much of the basic data necessary for undertaking a trauma study, for example age, sex, bone segment presence, bone completeness, and taphonomic changes present (Buikstra and Ubelaker, 1994), and they allow for the necessary data to be recorded for exploring interpersonal violence in a wider social context (e.g., Geber, 2015). To a certain extent, these systems also provide a fail-safe to the clinical adage to remember that a patient has a front, back, and two sides (Sherry et al., 2008), one which also applies to paleopathology, where all the extant remains from an individual should be examined to ensure that associated or co-occurring traumas or other lesions are identified. When considering the evidence for trauma, this is most pertinent for the study of abuse and injury recidivism in past societies (Redfern,

234 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

2017). Further, work on commingled and disarticulated human remains has shown that supplementary approaches may have to be employed in order to enable robust and reliable data collection, such as accurately using specific methods for determining the minimum number of individuals present and calculating prevalence rates (Knu¨sel and Outram, 2004; Osterholtz et al., 2013). All recording protocols emphasize the need that, as a minimum, an observer must correctly identify the bone(s) present, the location of the trauma, its appearance, and evidence for complications (Lovell, 1997, 2008). Roberts’ (2006) protocol guides an observer through this process, as it provides a detailed list of the range of secondary changes that can arise (complications of trauma), and suggests ways to integrate imaging evidence (Table 9.4), thereby creating a sufficiently robust dataset to explore aspects of care and treatment by using methods such as the Index of Care (Tilley and Cameron, 2014). (Table 9.4). As noted briefly in the earlier section, central to the recording of trauma in skeletal remains, particularly when distinguishing between ante-, peri-, and postmortem fracturing, is an understanding of taphonomy (Stodder, 2008). Poor preservation and other taphonomic changes can lead to pseudo-trauma, as recently shown in an analysis of storm damage to donated bodies at the outdoor Anthropology Research Facility in Knoxville (USA) (Maijanen et al.,

TABLE 9.4 Fracture Recording Method 1. 2. 3. 4. 5. 6. 7. 8. 9.

10.

11.

12.

Age and sex of the individual Bone, side, and segment affected Fracture position (use anatomical terms, e.g., proximal) Fracture type (supported by imaging if possible) State of healing: healed, unhealed, healing (is the callus of woven, mixed, or lamellar bone?) Evidence for infection (presence of: pitting, periosteal new bone formation (periostosis), osteitis, or osteomyelitis) Evidence for underlying pathology (e.g., Paget’s disease or osteoporosis) Evidence for joint degeneration in adjacent joints Evidence for angulation of the fractured segments: ideally measure on image; macroscopically determine whether it is good (,45 degrees) or poor ( . 45 degrees) using a protractor Evidence for linear/rotational deformity (amount of deviation from the normal bone axis): ideally measure on image; macroscopically determine whether present or absent Amount of overlap/apposition: ideally measure on image; macroscopically, if bone complete, take greatest length measurement and also of the opposite side. Determine if contact between the two fracture segments was of 0% 25%, 25% 50%, 50% 75%, and 75% 100% of contact Alignment of bone (consider features noted for points 10 and 11)

Source: After Redfern (2010), Roberts (2006).

2016). Taphonomic change also impacts the survival and identification of peri- and antemortem injuries (Calce and Rogers, 2007; Cappella et al., 2014a,b; Fleming-Farrell et al., 2013; Holz et al., 2015; Karr and Outram, 2012). Studies have further highlighted the importance of the archeological context and excavation history when accounting for this factor (Dale Spencer, 2012). Taphonomic considerations can also be used to help differentiate between lesions due to ritual violence and/or funerary processes (Mollerup et al., 2016; Pe´rez, 2012). For example, excavation of a wetland area in Denmark uncovered the remains of over 380 individuals dating to the 1st century AD (Holst et al., 2018). Analysis of these remains showed that they had been exposed for up to a year before being put in the lake, and many had been manipulated—multiple ossa coxae had been threaded onto sticks and then placed in the lake (Holst et al., 2018). Taphonomic change also may directly influence skeletal and dental completeness and therefore the calculation of trauma frequency in a given sample. Judd (2002b) has explored the relationship between recording methods and trauma reporting and interpretation. She concluded that the segment count method was best for paleopathology, because it enables a researcher to establish prevalence figures that are not biased by preservation and more completely represents frequencies than techniques that require full bone completeness for recording to take place, such as that of Lovejoy and Heiple (1981). Judd’s work has also shown how the attribution of eponyms such as “parry fracture” can (unintentionally) result in false or biased datasets and may lead to the misclassification of a fracture (Judd, 2008). Methods for identifying and recording healed subadult trauma in adult remains was pioneered by Glencross and Stuart-Macadam (2000). Their study, based upon clinical knowledge, argues that subadult injuries could be identified in adult human remains by their location (e.g., intraarticular fractures) and evidence for deformity; wherever possible, radiography should be employed to identify them because often they are not visible macroscopically (Glencross and Stuart-Macadam, 2000; see also, Glencross and Stuart-Macadam, 2001; Stuart-Macadam et al., 1998). Their approach has been successfully used to compare fracture types and distributions between adult and subadult groups from the same population and, because the sex of adult skeletons can be estimated, we can explore the fracture mechanisms experienced by boys and girls during childhood. (e.g., Walker, 2012b).

Paleopathology Introduction Fractures are evident within all stages of human evolutionary development. For example, they have been documented

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in some of the Early Paleolithic skeletal remains from Choukoutien cave in China (Weidenreich, 1939: 37). Fractures have also been reported in individuals from the Middle and Upper Paleolithic (Moodie, 1922: 393; Weidenreich, 1939: 38; Roper, 1969), as well as the Mesolithic (Frayer, 1997). Angel (1974a) surveyed the prevalence of fractures from the Neolithic to Modern times in skeletal remains from the Eastern Mediterranean, and Jones (1910c: 293 340) provided a very detailed report on fractures in ancient Nubian skeletons. In the New World, Hooton (1930: 312) found a rate of 3.96% fractures of long bones or pelves in 503 pre- and post-Columbian skeletons from the Pecos site in the North American southwest. When fractures of the skull are added, the total percentage increases to 7.23%. As sociocultural factors and the subsistence base of human societies changed, the prevalence and distribution of fractures in the skeleton also appear to have changed, as demonstrated by the Western Hemisphere Health Project (Steckel and Rose, 2002). Although the human species is still subject to trauma, treatment, particularly for complications such as infection, has greatly improved. This improvement took a quantum leap forward with the identification of organisms that cause infection, and the development of ways of minimizing exposure to infectious agents through improved hygiene. The discovery of antibiotics provided an additional method for reducing the prevalence of infection as a complication of trauma. Although these developments greatly reduced morbidity and mortality associated with fractures, it is important to add that, in the treatment of fractures, earlier human societies often did a remarkably good job (e.g., Elliott-Smith, 1908: 734). Fractures and the complications arising from fractures most often provide the paleopathologist with easily interpretable lesions in archeological skeletons. However, those attempting to evaluate this type of trauma should be aware of the potential problems. First, evidence of healed fractures can be completely obliterated by skeletal modeling. For children this is particularly the case due to relatively rapid remodeling and growth. Similarly, fractures in adults may be well aligned and therefore remodeling may eliminate fracture evidence. Second, it is difficult and sometimes impossible to distinguish between fractures occurring at the time of death, and those that occur subsequent to death and burial. Jones (1908b: 736) indicates that in ancient Egyptian skeletons, fractures occurring at the time of death produced blood staining in the soil matrix adjacent to the fracture site. However, such staining is likely to survive only under conditions of minimal rainfall and the water content of a grave, so that this criterion may be of little value in most geographical areas. In fractures occurring while the periosteum and other soft tissues are still intact, small bone fragments in the fracture site may still adhere to adjacent bone (Fig. 9.26). This

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FIGURE 9.26 Adherent bone fragments at multiple fracture sites (arrows) in the left parietal bone of an adult skull. The adherent nature of the fragments is indicative of trauma occurring while the periosteum and other soft tissues are still intact. (NMNH 266571.)

condition is very helpful in distinguishing between trauma at the time of death and damage to the skeleton after interment that results from shifting soil or damage during excavation. In addition, the surfaces of bone tend to be stained by the soil constituents with a somewhat different color from bone not in direct contact with the soil. Thus, breaks occurring during excavation or in subsequent processing may have a surface coloration quite distinct from surfaces in direct contact with the soil for a long period of time. A third factor of significance to the paleopathologist is the distinction between accidental fracture, as from a fall, and fracture resulting from intentional violence, either in individual aggression or in warfare. In some reports on fractures in archeological human remains, the findings suggest that accidental trauma, rather than intentional interpersonal violence, is the most common cause of fracture (Lovejoy and Heiple, 1981; Grauer and Roberts, 1996)—but context is always key to exploring possible interpretations (e.g., de la Cova, 2012). It may not always be possible to determine which of these two options caused the fracture. Grauer and Roberts (1996) argue that intentional violence is more likely to result in transverse fractures, whereas accidental fractures will be more often the result of oblique breaks in bone (see also Wedel and Galloway, 2014). Clearly the observer should make the distinction between intentional violence and accidental trauma only when the evidence makes this possible.

Trauma Resulting From Intentional Violence Evidence of interpersonal violence is both direct, in the form of injury to the skeleton, and indirect, as reconstructed from the burial context (Martin and Frayer, 1997). It is usually inflicted without weapons and may associated with structural violence (see below), but it is difficult to define

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because there is huge cultural variation as to what is considered to be an act of violence (Herrenkohl et al., 2010). Parry fractures of the forearm, various traumas to the skull, sword wounds in bone, projectile points embedded in bone, and scalping are examples of evidence of interpersonal violence directly apparent in the skeleton. Modern clinical data suggest that there is considerable cross-cultural homogeneity in injury patterning, with the face and head being the focus, and injuries are usually inflicted by fists, feet, or blunt objects, with males being more likely than females to be victims and participants (Brink, 2009; Downing et al., 2003; Eggensperger et al., 2007). Although the majority of injuries sustained are limited to the soft tissue, there are several characteristic patterns and fractures: in the head, the zygomatic bones, orbital floors, mandible, maxillae, nasal bones, orbital rims, and ethmoid bones are the most frequently fractured elements (Shepherd et al., 1990). In the dentition, typically only crown or crown-and-dentin fractures, dento-alveolar fractures, and luxations occur, usually affecting the upper central incisors; for the rest of the body, the heads of the metacarpals and ribs can be affected (Andreasen et al., 2011). In paleopathology, injuries from interpersonal violence are a frequently encountered type of trauma, and the distinctive pattern of fractures seen have been observed in numerous populations across the world (e.g., Brickley and Smith, 2006; Buzon et al., 2005; Walker, 1997). It has also been reported in known documented collections, such as the two individuals from the Hamann-Todd collection who were known to regularly participate in boxing, and had evidence for multiple fractures to the zygoma, nasal bones, ribs, and hand bones, a fractured hyoid bone, and a high rate of antemortem tooth loss (Hershkovitz et al., 1996). Further, perimortem trauma associated with atypical burial contexts, such as evidence of careless placement and orientation of the bodies in a burial pit, or evidence of human bone being cracked open to extract the marrow, may provide indirect evidence to support interpersonal violence as the cause of fracture and, possibly death. In this section, we review these common trauma types and locations in a paleopathological context. Later in the chapter, we will expand on this discussion to consider such topics as organized violence and specific types of physical abuse that may be noted in the skeleton. The majority of sharp-force injuries observed in the archeological record are perimortem and, although they can be encountered in human remains excavated from community burial grounds (Brødholt and Holck, 2012; Hirata et al., 2004), they are frequently identified in catastrophic funerary contexts where victims of raids and people subject to homicide are buried (e.g., Walker et al., 2011). For example, the 55 crania excavated from a 14thto 15th-century AD mass grave in Japan, had evidence for

sharp-force injuries, and cut marks suggestive of trophytaking (Nagaoka et al., 2010). It should be noted that sharp instruments can also produce blunt-force injuries if the cutting edge does not penetrate the bone, particularly if people are wearing protective clothing; often comminuted fractures are the end result, but because of the force necessary to produce a sharp-force injury, blunt-force injuries can occur at the same time (Knu¨sel, 2005). Projectile points or portions of these points embedded in bone provide unmistakable evidence of interpersonal violence and resulting traumatic lesions, with peri- and antemortem evidence identified (e.g., Schutkowski et al., 1996). Examples from two archeological sites in Illinois, USA illustrate this type of trauma. The first two examples are tips of stone projectile points embedded in vertebrae (Figs. 9.27 and 9.28). A computed tomography (CT) image of another vertebra shows the position and trajectory of the arrow that must have passed through vital viscera before striking the bone (Fig. 9.28). The third example from Illinois has a point embedded in the medial surface of the ilium (Fig. 9.29) which must have torn through the intestines. There is no evidence of healing so the victim must have died at the time of the injury or shortly thereafter. Parry fractures are a frequently observed forearm fracture, and can occur when a person tries to fend off an attack (see Judd, 2008 for a full discussion). Jones (1910c: 297) notes a high prevalence of fractures of the ulna in ancient Egyptian remains in comparison with its low prevalence in modern city populations (see Judd,

FIGURE 9.27 Stone projectile point embedded in the posterior portion of the body of a 12th thoracic vertebra. (Adult male skeleton from an archeological site in Illinois, NMNH 379841.)

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FIGURE 9.29 Tip of stone projectile point embedded in the inner aspect of a right innominate bone. (Adult male skeleton from an archeological site in Illinois, NMNH 380120.)

FIGURE 9.28 (A) Broken stone projectile point embedded in the anterior portion of the body of a fifth lumbar vertebra. (Adult female skeleton from an archeological site in Illinois, NMNH 380118.) (B) CT composite reconstruction of a stone projectile point embedded in a lower thoracic vertebra. The angle of the point relative to the vertebra indicates that the projectile passed through vital organs and resulted in death shortly following the trauma. Image courtesy of Dr. Bruno Frohlich, Department of Anthropology, Smithsonian Institution, NMNH 169663.

2008). This contrasts with fractures of the humerus, which have virtually the same prevalence, suggesting that fractures of the humerus are more likely to be produced by an accidents, a result seen across time boundaries and in many cultural contexts. However, as Grauer and Roberts (1996) and Judd (2008) emphasize, not all fractures of the forearm are Parry fractures, which are defined as having a transverse fracture line and are located below the midshaft with little malalignment (Judd, 2008). There are, however, distinctive accidental fractures (such as Colles’ fracture of the distal radius), which are well known in modern clinical practice and are identifiable in archeological human remains (Fig. 9.30).

FIGURE 9.30 Healed Colles’ fracture of the distal left radius (center), shown with the unaffected left ulna (right) and compared with the normal right radius (left). (Female skeleton excavated from an Inuit burial ground in Alaska, NMNH 345315.)

One remarkable archeological site that has produced evidence for intentional violence in England, is a mass grave associated with the Battle of Towton (Boylston et al., 1997; Thorp, 1997; Fiorato et al., 2000). This battle was part of the War of the Roses, and it was fought on a single day in Yorkshire (March 29, 1461 AD). During the conflict 28,000 men were killed, and it remains the bloodiest battle ever fought on British soil. The heaviest losses were inflicted by the Yorkists on their Lancastrian enemies. Disposing of the dead would have been a monumental task and the bodies found in the mass grave, presumably Lancastrian dead, had been buried there with minimal care. Forty-three individuals were recovered during excavations and most show evidence of perimortem

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trauma, mostly to the skull. Some of the individuals show evidence of healed injuries, presumably caused by injuries received during previous battles. Cranial injuries from the Towton grave include sword wounds (Burial 6) (Fig. 9.31), poleaxe wounds (Burial 9) (Fig. 9.32), and crushing injuries from a relatively blunt weapon such as a mace or ball hammer (Burial 11) (Fig. 9.33). Burial 16 is the skeleton of an adult male with multiple perimortem injuries undoubtedly associated with his death, including a battle-axe wound of the left parietal bone (Fig. 9.34A). This individual also had a healed sword wound of the mandible, which is testament to the remarkable repair potential of bone. The trauma cut through the anterolateral portion of the left mandibular body (Fig. 9.34B and C). Most of the injury had healed, but the posterior portion of the fracture remained ununited (Fig. 9.34D). One of the Towton burials (Burial 30) demonstrates the range of lesions that can be produced by a heavy direct blow (Fig. 9.35A). An injury to the posterior aspect of the right ulna in this adult male skeleton has shattered the impact site and created a transverse fracture through the anterior portion of the bone. Another of the relatively uncommon postcranial injuries is a sword cut to the

posterior aspect of the left elbow of this person (Fig. 9.35B and C). The entry of the cut must have been from a posterior aspect and implies that the victim was lying face down with the elbow flexed at the time of the trauma. In Sudan, Jones reports a prevalence of fractures of 3% in a series of 5000 6000 ancient Nubian skeletons (1910c: 294). However, 31% of all observed fractures occurred in the bones of the forearm. Jones found that the ulna was broken more often than the radius, more frequently on the left side. This led Jones to conclude that most of these fractures were the result of an attempt to fend off a blow using the forearm (1910c: 297). In support of this conclusion, Jones cited the habit in southern Egypt and Sudan of men using a heavy staff for offense and defense, a practice that persisted from dynastic Egyptian times (see Judd in Redfern, 2017: 138 for a critique of this suggestion). Jones (1910c: 295) also reports that the prevalence of forearm fractures was about twice

FIGURE 9.32 Poleaxe or war hammer wound of the right parietal bone. Death occurred at the time of the trauma or very shortly thereafter. (Adult, male, Battle of Towton, AD 1461, Burial 9.)

FIGURE 9.31 Massive sword wound in a coronal axis. The extent of the injury combined with the circumstances of burial indicates that death was virtually instantaneous (Adult, male, Battle of Towton, AD 1461, Burial 6.)

FIGURE 9.33 Blunt-force trauma to the left parietal and temporal bones. (Adult, male, Battle of Towton, AD 1461, Burial 11.)

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FIGURE 9.34 Trauma to the skull. (A) Poleaxe or war hammer trauma to the left parietal bone. (B) Healed sword wound to the left mandible. (C) Interior detail of healed mandibular sword wound. (D) Reflected left mandibular ramus, showing the remodeling following the trauma that is apparent on the posterior aspect of the left mandibular body. (Adult, male, Battle of Towton, AD 1461, Burial 16.)

that found in early-20th-century Western urban populations. Other comparisons indicate fewer fractures of the lower leg bones in ancient Nubian remains in contrast with modern urban dwellers. Jones attributed this difference to modern footwear, which increased slipping and was not worn by the ancient Nubians (Jones, 1910c: 296). Another marked contrast with modern populations was the prevalence of hand fractures, which was about 10 times greater in early-20th-century urban populations. Injuries from machinery appeared to be a major factor in this difference (Jones, 1910c: 297). Angel’s studies (1974a: 13) of skeletal remains of various time periods from the Eastern Mediterranean found that the most common site of fracture was the forearm, which he also attributed to an effort to ward-off a blow. This suggests that intentional violence was a leading cause of fracture in the Eastern Mediterranean, as well as in ancient Nubia. In Jurmain and Bellifemine’s (1997) a study of cranial trauma in Native American archeological skeletons from California, the evidence for violent fracture was substantial. The individuals date from about 500 BC to European

contact in the 16th century AD. The authors identified skull trauma in seven of 260 adult skulls (2.7%) (Jurmain and Bellifemine, 1997; see also Walker, 1989). A later study determined that in the CA-ALA-329 population from this county, males sustained the majority of fractures, with the facial bones particularly affected (Jurmain et al., 2009). The reasons for the violence observed in human remains from this area of North America have been discussed; light stable isotope and mtDNA analyses of skeletons from a mass burial site (CA-ALA-554) suggest that many adult males with evidence for antemortem violence and/or a violent death had participated in skirmishes and raids, because population increase meant that new villages and territories were established in the region, most likely in contested territory (Eerkens et al., 2016). An example of a more extensive healed fracture is seen in an adult female skull from Cinco Cerros, Peru (NMNH 293818). The archeological age is unknown. There are two large, depressed fractures, both of which are on the right parietal bone (Fig. 9.36). One of these is located near the sagittal suture on the posterior portion Radiating from this lesion are two fracture lines, one of

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FIGURE 9.35 Multiple injuries to the extremities. (A) Posterior view of a probable Parry fracture of the right ulna shaft. (B) Sword wound of the left elbow involving both the humerus and the radius. (C) Posterior view of the trauma to the left elbow. The injury probably occurred with the victim lying prone with the left elbow flexed and extended above the back. (Adult, male, Battle of Towton, AD 1461, Burial 30.).

FIGURE 9.36 Two healed depressed fractures in the right parietal bone of an adult female skull (arrows). Note lateral fracture lines radiating from the medial depression. (Skull from Cinco Cerros, Peru, NMNH 293818.).

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FIGURE 9.37 Probable healed, glancing sword wound of the right parietal bone from a 12th Dynasty rock tomb at Lisht in Upper Egypt. Note the central area comprised of the spongy bone- the exposed diploe. Arrows indicate the porous, reactive margin of the wound. (NMNH 256414a.)

which crosses the sagittal suture, passing into the left parietal bone. The other depressed fracture is located in the central portion of the right parietal bone, superior to the squamous portion of the right temporal bone. This lesion is deeper and more extensive than the first lesion, but it does not exhibit the long, radiating fracture lines. Both lesions are completely healed, indicating long survival after the injury. A right adult parietal bone (NMNH 256414a) from the rock tombs at Lisht in Upper Egypt exhibits a circular lesion suggestive of a healed, glancing sword wound (Fig. 9.37). This burial was dated to the 12th Dynasty. The outer boundary of the lesion is pitted, perhaps indicative of an inflammatory response. The sword wound apparently removed the outer portion of the parietal bone in the region of the parietal boss, exposing the diploe in the central portion of the lesion and creating the porous appearance, which was partially filled in by subsequent remodeling. Another individual from the rock tombs at Lisht, dated between the 20th and 25th Dynasties (NMNH 256384) illustrates a lesion resulting from a sword or axe wound, which occurred at the time of death. The wound penetrated the left parietal bone near the vertex (Fig. 9.38A), and the blow removed a portion of the right parietal bone (Fig. 9.38B). No postcranial bones were associated with this adult male skull. A remarkable example of trauma was observed in the archaeological remains of an Aboriginal person whose

FIGURE 9.38 Sword or axe wound in an adult male skull from a rock tomb at Lisht in Upper Egypt dated between the 20th and 25th Dynasties. (A) The point of contact is the left parietal bone near the vertex; the blow produced a large bone fragment mainly in the parietal bone. (B) Skull with bone fragment reflected. (NMNH 256384.)

burial was excavated from a site near the Stewart River in northern Queensland (Australia). In this adult male, the injury was likely to have been caused by an oblique

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FIGURE 9.40 Extensive radiating fractures from a central impact point (arrow) in an adult female skull from Pachacamac, Peru. (NMNH 266584.)

only with the gum (Fig. 9.39). Evidence of survival and healing is clear. The weapon that caused the injury is not certain, but Aboriginal peoples did make swords out of hard wood that were known to cause major injuries when used in interpersonal conflict. An adult female skull from Pachacamac, Peru (NMNH 266584) has an extensive unhealed fracture of the left parietal bone (Fig. 9.40). The archeological age of this individual is pre-European (AD 500 1500). The focus of the trauma is the anterior portion of the left parietal bone, which exhibits a crushing injury with fracture lines radiating down the left parietal bone along the coronal suture. The perimortem fracture in the left zygomatic bone could have occurred at the time of the skull fracture. Another fracture line proceeds posterolaterally across the sagittal suture and into the right parietal bone. There is no evidence of healing, indicating that the fracture occurred at the time of death.

FIGURE 9.39 A healed sword wound that removed the left maxilla and the right mandible so that no remaining teeth were in occlusion. Healing and long-term survival are evident from the bone remodeling that has occurred. (A) Anterior view. (B) Left oblique view, showing details of the trauma and subsequent healing. (Adult male from an archeological site near the Stewart River, Queensland, Australia, SAM A 11411.)

sword cut that passed through the right mandibular body and left maxilla. The cut sheared off the entire lower right half of the dentition and all the teeth of the left upper jaw, creating a situation in which the remaining teeth occluded

Fractures Resulting From Accidental Events Making the distinction in archeological human skeletal remains between fractures caused by intentional violence and fracture caused by an accident will not always be possible. The difference observed by Grauer and Roberts (1996) between transverse and oblique fractures is helpful but not definitive. Some oblique fractures can be secondary to a victim being pushed or thrown, leading to injury. However, it is certainly plausible that many, if not most fractures of the long bones, other than Parry fractures, are the result of accidental causes. Lovejoy and Heiple (1981)

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FIGURE 9.41 Compression fracture of the second lumbar vertebral body in an adult male skeleton from the Hawikuh archeological site in New Mexico. (NMNH 308653.)

analyzed a Late Woodland (late prehistoric) Native American individuals (N . 225) from Ohio (USA) for evidence of fractures. The fracture rates varied among bones, ranging from 1.3% in the humerus to 11.5% in the clavicle. The authors attribute most of the fractures encountered to accidental causes, and conclude that fracture treatment was practiced and successful. Compression fractures of the spine tend to occur from a fall and are probably caused by accidental mechanisms. Three examples of fractures in the vertebral column serve to illustrate the essential features of these injuries in archeological human remains. When the sacrum is affected by trauma, it can result in neurological damage leading to impairment (Gibbons et al., 1990). The first example is a second lumbar vertebra of an adult male from the Hawikuh archeological site in New Mexico (USA). This is a multicomponent site dating from the late prehistoric to early historic period. The anterior portion of the second lumbar vertebral body is crushed (Fig. 9.41). There is fusion with the left lateral and central portions of the inferior border of the first lumbar vertebra, and contact between large bony projections from the inferior L2 and superior L3 vertebral bodies. The second example is a male sacrum from Lisht in Egypt dated to between the 18th and 21st Dynasties

FIGURE 9.42 Partial fracture of the third segment (arrow) of a sacrum from the rock tombs at Lisht, Upper Egypt, dated between the 18th and 21st Dynasties. (A) Posterior view. (B) Detailed view; note partial bony fill-in of fracture gap and porous reactive bone (arrow) adjacent to the fracture line. (NMNH 252874.)

(NMNH 252874). The fracture occurs in the third sacral segment, and radiates laterally from the superior portion of the spinous process (Fig. 9.42). The fracture involves only a portion of the posterior segment and was in the early stages of healing at the time of death. Evidence of early callus formation can be seen in Fig. 9.42B. The third example is from an Anglo-Saxon archeological site in Winchester, England (BMNH CG66, XXIII, layer IV). The left portion of the body in the first lumbar vertebra is wedge shaped (Fig. 9.43). There is bony bridging between the right sides of the L1 and L2 vertebral bodies and considerable rotation of the axis of L1. The fracture is well-healed, indicating survival after the trauma. Compression fracture of the sacrum can also occur. A probable example of this injury is seen in the abnormal angulation of a sacrum from the

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FIGURE 9.44 Compression fracture of the S3 vertebra. (15 year old individual from the medieval hospital of St. James and St. Mary Magdalene, Chichester, England, Burial C-31.)

FIGURE 9.43 Compressed fracture of a first lumbar vertebra in a male skeleton from the Anglo-Saxon period at Cathedral Green, Winchester, England. Anterior view of lumbar vertebrae and sacrum. Note evidence of periosteal reactive bone on the bodies of the lumbar vertebrae. (BMNH CG66, XXIII, layer IV.)

skeleton of a 15 year old individual. The skeleton was excavated from the site of the medieval hospital of St. James and St. Mary Magdalene in Chichester, England. The body of the third sacral vertebra is compressed anteriorly, creating the abnormal angulation (Fig. 9.44). Fracture in the remaining postcranial bones is common in archeological human remains, and in most cases it poses few diagnostic problems. However, healed and well-remodeled lesions of an infectious focus can resemble a remodeled fracture callus. A careful comparison with the contralateral bone will often show abnormal deviation or rotation, indicating a healed fracture, which will not be present in a bone with a lesion caused by infection. Healed fractures may be associated with a line of increased density that will be apparent on a radiograph of the lesion. Unfortunately, these lines are regularly missing in archeological human skeletal examples of fracture callus, because of long-term survival and remodeling

. A clear sclerotic line associated with a focal enlargement of a bone is almost certainly indicative of a fracture. However, absence of such a line in a focal enlargement does not preclude fracture as the cause of the lesion. Cortical remodeling of the fracture callus can obliterate evidence of a sclerotic fracture line. In some cases of fracture, particularly if the individual died within a few months following the trauma, the line may be radiolucent. An example of the latter is seen in an isolated left humerus from an Inuit cemetery from St. Lawrence Island off the coast of Alaska, USA (NMNH 364816-32). The archeological age of this bone is uncertain. The fracture is located near the midshaft with the fracture seen, externally, as a porous bony callus (Fig. 9.45A). The radiographic appearance shows a general increase in radiodensity resulting from the callus being added to the cortical bone. However, the radiolucent fracture line is apparent in Fig. 9.45B. The specialized anatomy of the elbow creates the potential for fractures that split the medial and lateral components. These are caused by a fall onto the elbow in which the wedge-shaped ulnar component of the joint is forced into the medial humeral component at the trochlear ridge (Fig. 9.46).

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FIGURE 9.45 Early stages of fracture healing and callus formation in the midshaft of an isolated left humerus from an Inuit cemetery on St. Lawrence Island, Alaska. (A) Note the porous nature of the recently formed callus. (B) Radiograph; note the radiolucent line (arrow) indicating the fracture line. (NMNH 364816-32.)

Incomplete fractures and stress fractures are also encountered in archeological human skeletal remains. The gross anatomical features of both types of fractures can be similar, and careful attention must be paid to the overall context in order to distinguish between the two types of fractures. An example of an incomplete fracture occurs in the left femoral neck of a young adult male who was about the age of 20 at the time of death (NMNH 365778). The skeleton is from a 19th-century archeological site in Umalaklet, Alaska. The fracture is almost certainly due to a fall, in which the femoral neck was partially forced into the proximal shaft of the femur, producing a fracture of the medial part of the neck while the lateral portion remained intact. A comparison of both sides reveals the abnormal angulation of the left femoral neck relative to the shaft (Fig. 9.47A). The presence of a woven bone

callus at the fracture site indicates survival to the early healing stage, but death occurred before complete union took place (Fig. 9.47B). The anteroposterior radiograph reveals the greatly increased density at the fracture site resulting from the formation of callus and the compression of a portion of the femoral neck into the cancellous bone of the proximal shaft (Fig. 9.47C). Stress fractures of the major long bones are most common during growth and development. A probable case of this type of fracture occurs in the distal right femur of a subadult excavated from the Pecos Pueblo archeological site in New Mexico (USA). This site dates from about AD 1300 to 1834. The subadult was about 9 years of age at the time of death, and the stress fracture is in the early stages of callus formation and repair. The incomplete fracture occurs on the right posterior distal metaphysis

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(Fig. 9.48A and B). The increased porosity associated with active osteoclastic resorption is apparent in a wide area adjacent to the fracture site. Callus is more readily appreciated on the lateral view (Fig. 9.48C). Stress fractures of the long bones are rarely encountered in archeological human remains (Lewis 2016); it would also be uncommon for such a fracture to be a significant cause of mortality. This means that survival with healing and complete elimination of the evidence of fracture will be the most likely outcome. It is only in the rare circumstance where the child happens to have a stress fracture and dies of other causes that these examples will come to the attention of a paleopathologist.

Fracture Treatment

FIGURE 9.46 Fracture near the midline of the distal humerus, probably caused by the wedge-shaped trochlea of the distal humerus experiencing considerable force, which split the two compartments of the joint. A deep groove is retained from the trauma. (Adult female from a site in Alaska, NMNH 345310.)

The treatment of many fractures can be accomplished on the basis of intuitive knowledge and common sense. The frequent occurrence of well-healed fractures in archeological skeletons testifies eloquently to this fact. Bo¨hler (1935: 566) lists three fundamental laws for fracture treatment. They are (1) reposition and realignment of the broken ends (reduction of the fracture), (2) temporary immobilization (fixation) of the broken bone, and (3)

FIGURE 9.47 Partial compression fracture (infraction) of the medial, left femoral neck. (A) Posterior view of the proximal femora. (B) Detail of the fracture site and callus formation in the left femoral neck. (C) Anteroposterior radiograph of the femora, showing the substantial sclerosis at the fracture site. (Adult male about 20 years of age from a historic site on Umalaklet, Alaska, NMNH 365778.)

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FIGURE 9.48 Probable stress fracture of the distal right femur. (A) Fracture site (arrow), distal posterior right femur. (B) Detail of callus formation on the distal right femur. (C) Lateral view of the left and right distal femora, showing the fracture site. (Subadult, 9 years old, Pecos Pueblo, New Mexico, dated between AD 1300 and 1834, PMH 60149 (reburied).)

maintenance of circulation and muscle tone through careful exercise of the affected limb. These principles continue to guide the treatment of fracture today. Obviously, in comminuted fractures, open fractures, or simple fractures where marked displacement has taken place, proper reduction and restoration may be difficult, if not impossible, without modem techniques, including traction and surgical intervention. However, it is also apparent in archeological human remains that badly misaligned bones do heal and, judging from the lack of disuse atrophy, provide at least limited use of the limb. Perhaps such fractures heal spontaneously, with the pain associated with movement being the immobilizing force. However, it is clear that splinting and other forms of fracture reduction and immobilization have a long history (e.g., Elliott-Smith, 1908: 734; Wells, 1974a; Hallba¨ck, 1976 1977; Knu¨sel et al., 1995; Grauer and Roberts, 1996).

As the basic concepts of fracture treatment are intuitive, it is not surprising to find that immobilization of fractured bones with a splint was practiced at least as early as the Fifth Dynasty in Egypt (Elliott-Smith, 1908). Although much later in time, there is evidence of similar sophistication in treating fracture among the Incas of Peru (Daland, 1935: 550). Wells (1974a) finds documentary evidence for both reduction and splinting in Anglo-Saxon England (c. 8th century). Indeed, it is now well known that “bonesetters” operated in Medieval Europe, often traveling around communities and treating fractures. Families also passed down their skills through the generations (Phillips and Biant, 2011). Bonesetters still operate today in many parts of the world and are familiar with treating fractured bones (e.g., see Huber and Anderson, 1996; Nwachukwu et al., 2011). Grauer and Roberts (1996) interpret the rarity of poorly aligned fractures in their study ofmedieval skeletons from the lower socioeconomic levels in York,

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FIGURE 9.49 Healed but malaligned fracture of the right humerus. (A) Posterior view. (B) Anterior view. (C) Detail of anterior callus; note remodeling of diaphyseal ends. (Adult female skeleton from Goat Cove, Texas, NMNH 372527.)

England, as monastic hospitals often provided this service as part of their charitable care of the poor. While recognizing that fracture treatment may have been fairly sophisticated in regions of ancient high civilization, it is equally apparent that many fractures even in these areas received little, if any, useful treatment (Jones, 1910c: 294). The large number of badly deformed healed fractures from many archeological skeletons testifies to this (Fig. 9.49). The fact that fractures heal spontaneously, allowing at least some continued function of the affected bone, is not surprising in view of the reports of healed

fractures in wild shot primates (Duckworth, 1912; Schultz, 1939, 1956) where, obviously, there was no treatment. In her study of great apes in the collection of the National Museum of Natural History, Washington, DC, Lovell (1990: 206 207) found that fracture was by far the most common problem encountered in the chimpanzee, gorilla, and orangutan samples. Percentages of individuals showing evidence of fracture ranged from 15% in the gorilla sample to 46% in the orangutan sample. Lovell (1990: 231) argues that these samples are, for the most part, reasonably representative of a wild population. This means

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that fracture was a common problem in the lives of many free-ranging great apes. All of these fractures would have had no special treatment other than the natural tendency to minimize use of the affected bone during the healing phase. Direct evidence regarding the methods for treating fractures in archeological populations who lack written records is scanty. However, among non-European groups living in historic times, there are records of fairly sophisticated techniques to reduce fractures (bringing about optimal realignment of the broken ends) and immobilize the broken bone until healing can take place (Elliott-Smith, 1908: 734; Daland, 1935: 550). Elliott-Smith (1908) describes an ancient Egyptian mummified 14-year-old girl having four wooden splints applied to her fractured femur and held in place with linen bandages. It is difficult to know whether this is a genuine example of fracture treatment following injury, but what it does indicate is the knowledge needed to treat a fracture. It may be that the injury was “sustained” during the mummification process and a splint applied for the afterlife. However, the blood-stained bandages in both cases suggests the fractures were compound in type and offers convincing evidence for the use of splints, pads to absorb blood in open fractures, and linen bandaging by the Fifth Dynasty (2730 2625 BC) (Elliott-Smith, 1908: 732 733). Grauer and Roberts (1996) found that most fractures in medieval skeletal remains from York, England, were from accidental causes and the alignment of the broken bones indicated that reduction and stabilization of fractures was practiced and available to the poorest people living in that region of York. In a more recent study of fractures in Iron Age and Romano-British skeletons from Dorset, England, analysis revealed that in both periods male and female fractures had healed very well, with few complications (Redfern, 2010). In both periods, highly skilled practitioners successfully treated a range of fractures and thus minimized the patient’s risk of impairment (Redfern, 2010). Recent work by Mant (2016) comparing a hospital cemetery population from London with the institution’s contemporaneous records has highlighted a large discrepancy between the trauma patterns and outcomes reported in clinical records and what may be observed in human remains. Therefore, it is imperative that more work in this area of paleopathology is undertaken, as scholars are increasingly exploring the potential for assessing care in the past (Tilley and Schrenk, 2017). Freeman (1918: 445) reports that manipulation and splinting of fractures occurs among the indigenous peoples of North America as well. Lovejoy and Heiple’s (1981) study of fracture patterns in a Late Woodland (c. AD 500 1000) skeletal sample from Ohio found that most fractures were caused by accidents and that there was good evidence for bone setting. However, while Elliott-Smith (1908: 733) notes one ancient Egyptian case where splinting did

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little to stabilize the fracture, this is not a serious indictment of the practitioner’s skill because, without radiographic examination and in the presence of considerable pain, it could be very difficult to identify the exact location of the fracture. With or without effective reduction and immobilization, most often the healing of a fracture was uneventful. Elliott-Smith (1908: 733) notes evidence of infection in only one of 100 fractures studied from ancient Egypt.

Complications of Fracture Severe pain usually accompanies any attempt to reduce a fracture. Thus, even in those time periods and places where fractures could be treated, it is not surprising to find examples of malaligned, but healed, fractures in archeological skeletons, particularly if medical care was costly and individuals may not have been able to access quality care. Jones (1910c) reports many such examples in his review of fractures in ancient Nubian skeletons. Wells (1974a) finds similar evidence in Anglo-Saxon England. Perhaps the important point to be made regarding these deformed bones is that individuals having them generally continue to live and somehow compensate for the dysfunction that results. The failure of the broken ends of a bone to form wellmineralized callus that joins the broken units has the potential to cause serious dysfunction, particularly if this occurs in a major long bone. Stewart (1974) has summarized the evidence for nonunion in archeological populations and published five examples from the ancient New World. He concludes (1974: 878) that in both Egypt and North America the forearm is the most common site of nonunion. This probably reflects the high frequency of fractures at this site (Fig. 9.50). He notes that ulnar nonunion was higher in Egypt, but nonunion of the radius was more common in New World remains. In both geographical areas the prevalence of nonunion was low. Fractures of the clavicle are relatively common and occasionally they are complicated by nonunion. This condition is apparent in the right clavicle from an adult burial (NMNH 256427) from the 12th Dynasty site at Lisht in Upper Egypt (Fig. 9.51). The extensive callus formation and remodeling of the broken ends of the bone indicate considerable time between the fracture and the death of the individual. The challenge in distinguishing between nonunion and the early stages of fracture healing are demonstrated in a rib fracture from a burial excavated from the same site (dated between the 18th and 21st Dynasties NMNH 252874). The fracture was not fused, although there is evidence of woven bone callus formation and porosity of the broken ends indicative of the early stagesof fracture healing (Fig. 9.52). The presence of woven bone and extensive porosity provide clear evidence of the short time between injury and death. These details preclude a diagnosis of nonunion.

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FIGURE 9.51 Fracture and nonunion of the right clavicle. (Adult from an archeological site in Lisht, Upper Egypt, dated to the 12th Dynasty, NMNH 256427hI.) FIGURE 9.50 Fracture and nonunion of the left ulna. (Adult from an archeological site in California, NMNH 226001.)

In Stewart’s (1974) survey, all the examples of nonunion were from the upper extremity. Although this probably approximates reality, it is important to note that nonunion does occur in the lower limb. Another relatively common site for nonunion is the neck of the femur. In most cases, there is evidence of continued use of the limb although with reduced biomechanical function. In some cases the fractured end of the femoral neck becomes embedded in the marrow space of the greater trochanter

and proximal shaft. One example (NMNH 333453) comes from an Inuit site in Golovin Bay, Alaska (Fig. 9.53A). The skeleton is that of an adult male between 20 and 25 years of age. The archeological age is uncertain but probably post-European. The fracture occurred through the neck of the left femur. The radiograph of both femora reveals considerable osteoporosis of the left femur shaft and diminished density of the ununited femoral head, particularly in the medial half of the femoral head. The latter

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FIGURE 9.53 Fracture and nonunion of the left femoral neck in an adult male skeleton from an Inuit archeological site at Golovin Bay, Alaska. (A) The fractured femoral neck has been pushed into the proximal metaphysis. (B) Detail of sclerotic reaction of the broken femoral neck and the corresponding cavity of the femoral metaphysis in the bone in (A). (NMNH 333453.) FIGURE 9.52 Fracture of the rib with woven bone callus indicative of active repair at the time of death. Although the broken ends remain ununited, active callus formation precludes a diagnosis of nonunion. (Adult male from an archeological site in Lisht, Upper Egypt, dated to between the 18th and 21st Dynasties, NMNH 252874.)

is suggestive of abnormal blood supply. There has been considerable remodeling on both sides of the fracture site (Fig. 9.53B). Another example of a femoral neck fracture comes from the site of Lisht in Egypt (NMNH 256276), which is dated to the 12th Dynasty, approximately 1990 1786 BC.

The fracture occurs in an adult female skeleton whose age at death was in excess of 50 years (Dequeker et al., 1997). All the bones of the skeleton were gracile and unusually light, suggesting that the woman had osteoporosis, a disease which increases the risk of femoral neck fracture (see Brickley and Ives, 2008; Ives et al., 2017). The fracture occurs in the femoral neck of the left proximal femur (Fig. 9.54). The femoral neck and the medial portion of the trochanter were completely remodeled away. The only fragment of the femoral head that

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remains is the delicate remnant of its outer third with the bone’s vascular supply coming from the acetabulum through branches of the obturator blood vessels. The fracture is extracapsular and long-term survival of this type of

FIGURE 9.54 Proximal, anterior, left femur with the detached femoral head reflected to show remodeled surfaces of the femoral head and the proximal, medial, femoral metaphysis. The remodeling following a femoral neck fracture and nonunion is indicative of long-term survival. This fracture is associated with severe systemic osteoporosis with even greater loss of bone mass in the left femur from disuse. (Adult female over 50 years of age at the time of death from a site in Lisht, Egypt, dated to the 12th Dynasty, NMNH 256276.)

fracture in older individuals is uncommon. Dequeker et al. (1997) conclude that the woman must have had a strong social support network to have survived as long as is suggested by the extensive remodeling associated with the fracture. Of the fractures occurring in archeological skeletons, very few show evidence of infection. In part, this observation must reflect the low prevalence of open fractures that would permit the passage of infectious organisms to the fracture site, but also that people may have died before the healing process reached a stage that can be observed in the archeological record. Hamilton’s data (1853), from a 19th-century American city population, summarized earlier in Table 9.5, indicate that 19% of the fracture examples in his sample were open. Of all the open fractures of the bones, 63% involve the tibia and fibula. Thus, the lower leg was by far the most vulnerable to open fracture in that population. Infectious complications of fractures are not limited to open fractures, nor will all open fractures become infected. Jones (1910c) cites two Old World examples of fractures complicated by infection. One is a clavicle (1910c: 306); the other an ulna (1910c: 313). He does not mention infection in fractures of the tibia or fibula. Indeed, fractures of the tibia of any kind are less common in archeological populations than in modern groups. Hooton (1930: 312) found, among the prehistoric Pecos skeletal sample from New Mexico, that the humerus and femur were the most commonly fractured long bones. He states that some fractures show a lack of union, although

TABLE 9.5 Distribution and Types of Fractures in Cases Reported by Hamilton (1853:33) Bone(s) Affected

Open (Compound) and Comminuted

Open

Simple

Total Number of Cases

Nose and face Clavicle Scapula Humerus Radius Ulna Radius and ulna Ulna Radius and ulna Femur Patella Tibia Fibula Tibia and fibula Bones of the hand Ribs Vertebral column Pelvis Total number of cases

6 0 0 2 0 0 0 0 0 3 0 0 1 13 1 0 0 0 26

6 4 0 1 2 2 2 2 2 1 0 6 4 19 2 0 0 0 49

12 37 3 36 25 20 25 20 31 67 7 13 11 40 2 4 3 1 312

24 41 3 39 27 22 27 22 33 71 7 19 16 72 5 4 3 1 387

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he does not indicate whether this is due to death occurring shortly after fracture or to nonunion. Hooton (1930) also indicates that some fractures seem to have suppurated, indicating that they were complicated by infection. Archeological examples of fractures complicated by infection tend to show marked deformation, suggesting considerable traumatic force resulting in exposure of the fracture site to infectious agents. One example of probable open fracture occurs in the skeleton of a young adult female from an archeological site near Akron, New York, USA (NMNH 326853). The archeological age is uncertain. The fracture occurs in the distal shaft of the right femur. There is considerable axial deviation, as well as some rotation. The callus is large with considerable porosity. On the posterior portion of the callus there is a large oblong cloaca measuring 15 3 25 mm (Fig. 9.55). This cloaca suggests a long-term chronic infection, which very likely drained through a sinus extending to the overlying skin surface. The tibia of the same leg was also fractured but with good alignment and no evidence of infection. A remarkable example of trauma with multiple skeletal manifestations comes from the medieval site of St. James and St. Mary Magdalene in Chichester, England. The burial (Burial 83) is that of an adult male about 30 years of age at the time of death. The primary injury was a fracture of the right proximal tibia (Fig. 9.56A). Alignment of the fracture is almost normal. The only indication of the severity of the fracture is a cloaca in the anterior aspect of the remodeled callus (Fig. 9.56B). Osteoarthritis is apparent in the joint areas of both knees, but it is much more severe in the right knee (Fig. 9.56C). The difference in osteoarthritis may be due to the slight deviation in normal alignment or perhaps a secondary effect of the trauma itself. Other evidence of trauma in this skeleton occurs in the spine where destructive lesions are apparent in the inferior end plates of the sixth, seventh, and eighth thoracic vertebral bodies (Fig. 9.56D). The severity of the herniation of the disk is most extreme in the inferior end plate of the eighth thoracic vertebral body (Fig. 9.56E). It cannot be certain that the trauma apparent in the vertebral column occurred at the same time as the fracture of the tibia, but this seems probable. If fractures occur in or near the growth plate, trauma may cause premature fusion and can result in subnormal length of the affected bone (see Verlinden and Lewis, 2015). The abnormal bone’s length will depend on the age of the individual at the time of the injury. In Fig. 9.57, we see premature fusion of the growth plate in the skeleton of a subadult about 15 years of age at the time of death. The burial (Burial 31) is from the medieval hospital of St. James and St. Mary Magdalene in Chichester, England. The fracture occurred at the distal end of the right tibia, very close to the growth plate, which was still open on the contralateral side at the time

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FIGURE 9.55 Healed compound fracture complicated by infection in the right femur of a young adult female skeleton excavated from an archeological site near Akron, New York. Note the deviated axis of the distal shaft at the fracture site. There is a large cloaca and reactive bone (arrow) probably associated with a fistula. (NMNH 326853.)

of death. Given age of the individual, not much additional growth would have occurred in the tibiae but, even so, the slight shortening of the fractured bone is apparent. In archeological populations, one occasionally finds an increased prevalence and severity of osteoarthritis associated with fracture. We have already seen an example of this in Chichester Burial 83, described previously.

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FIGURE 9.56 Trauma and secondary osteoarthritis of the knee associated with trauma to the vertebral bodies of the spine. (A) Anterior view of the right and left knees, showing the fracture site on the right proximal tibia. Compare the osteophyte development between the two knees. (B) Detail of cloaca in the fracture callus of the tibia indicating infection. Trauma and secondary osteoarthritis of the knee associated with the trauma to the vertebral bodies of the spine. (C) Severe osteoarthritis of the right knee, probably secondary to the fracture. (D) Inferior view of the T6 T8 vertebrae with lytic lesions of the vertebral body end plates that may have been associated with the trauma. (E) Inferior view of the T8 vertebra with a large lytic focus. (Adult male about 30 years of age from the medieval hospital site of St. James and St. Mary Magdalene in Chichester, England, Burial C-83.)

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FIGURE 9.57 Fracture of the distal right tibia, resulting in premature fusion of the distal growth plate. (A) Anterior view of the right and left tibia, showing the prematurely fused distal right physis and the unfused physis in the left distal tibia. (B) Detail of the distaltibiae. (Subadult about 15 years of age from the medieval site of St. James and St. Mary Magdalene in Chichester, England, Burial C-31.)

Although not specifically addressing this problem, Jones (1910c: 308, 312, 315, 317, 318, 322) cites several examples of fracture contributing to the development of osteoarthritis in ancient Egyptian remains. Morse (1969: 100, 104) cites similar conditions in archeological individuals from the midwestern United States. Making the distinction between traumatically induced osteoarthritis and osteoarthritis associated with aging depends on two factors: (1) demonstration of fracture in the affected bone and (2) lack of bilateral symmetry in the pattern and degree of arthritis (Morse, 1969: 13). Trauma to adjacent bones may also result in ankylosis. An example of this condition is found in a historic period archeological individual from South Dakota (NMNH 383010), in which the distal tibia and fibula are fused at the fracture site (Fig. 9.58). Clearly such an injury and its sequelae could have affected locomotion. However, the long-standing callus and extensive remodeling indicate long survival and mobility after trauma.

The last complicating factor in fracture healing to be discussed in this review is myositis ossificans traumatica. Johnson (1964: 610) notes that muscle tissue can provide cells that contribute to callus formation around the fracture site. As with bone, muscle trauma tends to produce hematoma. With time the hematoma is usually dissolved. Occasionally, however, the muscle tissue will respond to the trauma by producing bone directly in the muscle tissue itself, often in association with the hematoma. It can be caused by a minor injury, avulsion of the muscles, a direct blow, a fracture complication, or a dislocation (e.g., of the elbow), with most cases affecting the quadriceps (Walczak et al., 2015). This excessive formation of bone by muscle can be entirely separated from the bone (Fig. 9.59) or it can become part of existing bone tissue (Fig. 9.60). Although the new bone mass typically forms directly on the cortex of the underlying bone, it can also develop in the subcutaneous fat, tendons, or nerves (Walczak et al., 2015). In paralyzed patients, minor

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FIGURE 9.58 Bony fusion of the distal tibia and fibula following fracture. (NMNH 383010.)

trauma of the insensitive muscles may lead to metaplastic bony bridging of joints, especially in the hip. Myositis ossificans traumatica is more likely to occur in response to trauma in young individuals (Resnick and Niwayama, 2002a: 4577). It can also develop in response to beatings during torture, particularly to the upper limbs and trunk (Rodrı´quez-Martin, 2006). The sometimes-dramatic bony projections associated with myositis ossificans traumatica can be confused with primary bone tumors such as osteosarcoma and chondrosarcoma. In living patients, a history of trauma affecting the site is important in differential diagnosis. In archeological human remains, the linkage of the bony projection to a site of tendon or ligament origin/

FIGURE 9.59 Traumatic myositis ossificans (arrow) within muscle tissue overlying a healed fracture of the left femur. (40-year-old male, FPAM 4751; scale in centimeters.)

insertion provides a helpful clue in the diagnosis of myositis ossificans traumatica. Care must also be taken to differentiate this from the rare diseases of myositis ossificans progressiva and heterotopic ossificans. In the clinical literature, myositis ossificans is most often observed at the elbow joint, along the linea aspera of the femur, at the shoulder joint, and on the pelvis (Aufderheide and Rodriquez-Martin, 1998: 26). Overwhelming numbers of clinical cases are observed in

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FIGURE 9.61 Hypertrophic bone development, probably due to traumatic myositis ossificans, on the left femur of Homo erectus (Pithecanthropus) skeleton from Java. (NMNH 362452, fossil cast.)

FIGURE 9.60 Myositis ossificans of the proximal femur. (A) Anterior view. (B) Posterior view. (Adult, sex unknown, SDMM 1981-30-321.)

adults, through accidents or sports, although children can be affected usually because of a sports injury (Clapton et al., 1992; Gindele et al., 2000; Miller et al., 2006; Walczak et al., 2015). Perhaps the most famous archaeological example of this condition, is the bone excrescence on a fossil left femur from Java (Fig. 9.61) associated with the fossil species Pithecanthropus. In this bone, there is an exuberant growth on the posterior aspect of the femur extending from the insertion of the adductor muscles. Jones (1910c:

317) has also published a line drawing of a right femur from ancient Nubia with fracture of the femoral neck. There is an extensive bony spur projecting medially, which Jones (1910c) attributes to extensive callus. The extent and shape of the bony mass suggest ossification in muscle tissue rather than exuberant callus formation. However, the distinction between the two may be academic. Although the fossil Javanese and the ancient Nubian examples have the bony growth attached, the paleopathologist should be aware that ectopic bone can develop in muscle tissue and be completely unattached to any bone. Associating this manifestation of myositis ossificans traumatica will require exceptional care during excavation.

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Many paleopathological examples of myositis ossificans traumatica have been misdiagnosed as osteosarcoma or other malignant primary tumors of the bone. This is not surprising, as this condition is a troublesome diagnosis in clinical and surgical practice. Indeed, pathologists can have difficulty if the biopsy tissue only includes the more actively developing areas of the lesion. An important factor in establishing a differential diagnosis is the anatomical location of the lesion. When attached to bone, myositis ossificans traumatica usually occurs at the origin or insertion of tendons or ligaments. Tumors may arise at these sites as well, but the association is not as specific. Enthesopathies also occur at sites of tendon and ligament insertion. These will be discussed in greater detail in Chapter 22. The pathogenesis of enthesopathy differs from myositis ossificans traumatica, in that the bony projections are probably the result of repeated hard use of the muscle over a relatively long duration of time rather than from a single traumatic event. Making the distinction between the two conditions in archeological human remains may be challenging in some cases. However, enthesopathies tend to be a much less severe manifestation of abnormal mineralizing connective tissue than is the case with myositis ossificans traumatica. As a general rule, Ortner (2003) suggested that any large bony projection associated with an insertion or origin of a tendon or ligament is myositis ossificans traumatica unless there is good anatomical evidence that the lesion is cancerous. Many such examples of soft-tissue injury have been published in the paleopathological literature, including in a 26- to 35-year-old male from medieval London, whose right femur had a large elongated mass of ossified soft tissue present on its anterior aspect, corresponding to the origin for the lateral head of the quadriceps femoris (vastus intermedius) (Walker, 2012a). Injuries to this muscle are often observed in athletes, although in the past some suggested that myositis ossificans to this body area was related to occupation (Mann and Hunt, 2013). A probable example of myositis ossificans traumatica that illustrates the challenge of determining when callus formation stops and myositis ossificans traumatica begins is seen in the right femur from a skeleton (NMNH 327101) excavated from the prehistoric site of Pueblo Bonito, New Mexico. The site dates to between AD 950 and 1250. There is clear evidence of fracture with poor alignment (Fig. 9.62). However, there is a bony projection extending from the fracture that greatly exceeds the boundaries expected for callus formation. Both the morphology and the location of the projection of abnormal bone tissue are compatible with a diagnosis of myositis ossificans traumatica. The evidence of trauma in this case is unmistakable.

FIGURE 9.62 Fracture of the right femur with callus and probable myositis ossificans traumatica. (Adult male from the archeological site of Pueblo Bonito, New Mexico, dated between AD 950 and 1250, NMNH 327101.)

Dislocation (Luxation) and Subluxation In paleopathology, very few luxations and subluxations are reported (e.g., De Luca et al., 2013; Drier, 1992)

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probably because, for these conditions to be recognized, a new articulation or partial articulation needs to be present adjacent to the original joint surface. However, whether this surface can be recognized is dependent on the interval between injury and death, as illustrated in the case of a prehistoric subadult from Croatia reported by Nitkitovic and colleagues (2012). The bony changes observed to the elbow of a 7- to 8-year-old subadult suggested that they had sustained an injury that caused radial head dislocation at least 6 months before their death. Shoulder and hip dislocations have been noted most frequently in paleopathology (Figs. 9.24 and 9.25) and there is interesting evidence in the published literature. For example, in a study of 700 individuals from 4th to 13th century AD France, seven dislocated and four subluxed hip joints were identified, and differential underlying diagnoses proposed (Blondiaux and Millot, 1991). This study illustrates indeed how rare these conditions are in the archeological record. Dislocation of the shoulder and hip should come to the attention of the paleopathologist more often than other joint dislocations because of their high frequency and problems in reduction reported in the clinical literature, which make permanent dislocation more likely. In his survey of ancient Nubian skeletal remains, Jones (1910c: 341) reports that evidence of dislocation is rare, with only one hip dislocation identified in several hundred skeletons. He cites other examples but admits that the diagnoses were uncertain. One possible example described by Jones is of an abnormal forearm (case 7:6), which is probably not a dislocation but a congenital malformation. Elliot-Smith appends to Jones’ report (1910c: 342) a traumatic knee dislocation associated with a fracture. An Old World example of anterior dislocation of the right shoulder occurs in the skeletal remains from the medieval site of the hospital of St. James and St. Mary Magdalene in Chichester, England. The example is found in the right scapula of Burial C-123 (Fig. 9.63). This burial is that of an adult male about 45 years of age at the time of death. The remodeling of the glenoid cavity has created a new joint surface on the anterior edge of the glenoid margin. Eburnation apparent on the new joint surface is indicative of breakdown of the articular cartilage of the humeral head. Several reports of dislocation are found in the skeletal collections of the Smithsonian National Museum of Natural History. Most of the shoulder cases involve anterior dislocation. One example of this type of dislocation is from an adult male skeleton from Norton Bay, Alaska (NMNH 346205). The archeological age is uncertain. The left humeral head is completely displaced and articulates with the anterior surface of the left scapula (Fig. 9.64A). Continued use of the arm has resulted in the formation of a secondary joint on the scapula, accompanied by arthritic

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FIGURE 9.63 Unreduced anterior dislocation of the right shoulder with formation of a new joint in the anterior margin of the glenoid fossa. (Adult male about 45 years of age from the medieval hospital site of St. James and St. Mary Magdalene in Chichester, England, Burial C-123.)

degeneration and eburnation of the humeral head (Fig. 9.64B). Another example is from an adult male skeleton from Kodiak Island off the coast of Alaska (NMNH 363615). The archeological dating of this case is also uncertain. The joint dislocation in this skeleton also involves the left shoulder. However, the dislocation was not as severe, having created a secondary joint on the anterior portion of the glenoid fossa (Fig. 9.65). There is considerable secondary arthritic degeneration on the humeral head. Fig. 9.25 illustrates fairly typical changes associated with hip dislocation. The skeleton is also from Kodiak Island, Alaska (NMNH 372897), and its archeological age is uncertain. Fig. 9.25A shows the effects of the dislocation on the right innominate bone, comparing it with the normal left innominate. In both innominate bones, the acetabulum is somewhat shallower than normal, suggesting underlying developmental dysplasia, which would have increased the likelihood of dislocation. Fig. 9.25B provides a detailed view of the secondary joint on the innominate bone and the osteoarthritic changes on the femoral head.

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FIGURE 9.65 Anterior dislocation and secondary joint formation of the left scapula in a male skeleton from Kodiak Island, Alaska. Part of the glenoid fossa has been remodeled away and a new joint surface has been formed on the remodeled surface (arrow). There is considerable degenerative arthritis on the humeral head. (NMNH 363615.)

Mortality Patterns in the Past

FIGURE 9.64 Anterior dislocation of the left shoulder in an archeological skeleton from Norton Bay, Alaska. (A) The humeral head articulates with a new joint on the anterior surface of the scapula; there is some degeneration of the anterior glenoid fossa. (B) Secondary joint formation on the scapula; note the porous surface of the new joint surface and arthritic degeneration, including eburnation (arrow) on the humeral head. (NMNH 346205.)

Trauma, Mortality, and Violence in Past Societies In our review of trauma to the skeletal system thus far, we have discussed the features and mechanics of fractures and dislocations/luxations in bone, along with the healing process and bony sequelae resulting from such events. We have also provided an overview of the diagnosis and recording of trauma in paleopathological contexts. In the closing sections of this chapter, we will consider the application of trauma analysis to questions of mortality rates, violence, and cultural modification. These populationbased approaches allow the paleopathologist to place trauma analysis within culturally specific contexts and to use such analyses to address “big picture” questions.

Demographic studies have identified an “accident hump” in human mortality patterns, whereby individuals of both sexes in their late teens to early 30s have a higher mortality rate because of risk-taking behaviors, pregnancy, and childbirth (Courtenay, 2002). Longitudinal studies of demographic data have shown that this trend has changed over time, because puberty is beginning at a younger age compared to historical populations; this has also been attested archeologically (Lewis et al., 2016). Nevertheless, in many past societies, adolescent and young adult age-groups (usually males) were active participants in societal-scale violence, such as raiding parties and warfare, and as such are overwhelmingly represented in catastrophic funerary contexts (e.g., Bridges, 1996; Kurin et al., 2016; Loe et al., 2014). The absence of, or low numbers of children and young females in these contexts has been interpreted as evidence for their capture (Teschler-Nicola et al., 1999). When they are present, along with middle and older adults, interpretation shifts toward massacres and mass killings, where the intention of the aggressor is to annihilate their enemy (Clinton et al., 2007; Tegtmeyer and Martin, 2017; op cit. female warriors, see Murphy, 2003). The bodies of these individuals may conform to normative, clandestine, or other nonnormative funerary practices, as shown in the Neolithic example of the family members killed and buried following community traditions at Eulau, Germany (Meyer et al., 2009). All too often, these individuals show evidence for over-kill and lethal violence, such as multiple blunt and/or sharp-force weapon injuries, maiming and mutilating injuries, and embedded weaponry, such as projectiles (Erdal, ˇ 2012; Novak, 2008; Slaus et al., 2010).

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The link between dying young and risk-taking behaviors is well-established in the clinical literature, particularly for the subgroup known as “injury recidivists” (Cunningham et al., 2015; McCoy et al., 2013). Judd’s (2002a) work on injury recidivism in the past has identified many examples in young adult males from ancient Sudan, demonstrating that this clinical model could be applied successfully to past populations. However, the demographic aspects of the relationship between mortality risk and the presence of antemortem fractures in past populations were not explored until the work of Boldsen, Milner, and colleagues (Boldsen et al., 2015; Milner et al., 2015). Their work examining the relationship between cranial fractures and mortality in archeological populations from Denmark showed that individuals with multiple healed cranial fractures, usually male, died younger than their peers without multiple injuries (Boldsen et al., 2015). This pattern was subsequently tested cross-culturally, using skeletal samples from different time periods, including both antemortem and postmortem cranial injuries (Redfern et al., 2017). This broader study also found that males were more likely to sustain multiple injuries and die in young adulthood; importantly, it did not find a relationship between multiple injuries and poor health, a pattern identified in the clinical literature (Redfern et al., 2017). The cause and manner of death, terms adopted from forensic science, are not interchangeable. Cause specifically refers to the injuries or disease that resulted in a person’s death. Manner of death is divided into several categories, including natural, homicide, suicide, and unknown. In a paleopathological setting we may be able to identify both, depending on the context in which the individual is found, but typically the literature limits itself to determining the cause of death (Jime´nez-Brobeil et al., 2014; Murad and Mertz, 1985). Evidence has been found in both skeletonized remains and in preserved bodies; in all these studies the importance of interpreting the evidence within the archeological context is brought to the fore. This is most evident in Verano’s (2014) work at the Pyramid of the Moon in Pre-Columbian Peru, where he identified the remains of sacrificed prisoners who the Moche had captured during warfare. Their remains showed that they had sustained fractures typical of assault a few weeks before death, because the fractures had active woven new bone comprising the callus. Many deaths, however, had been the result of throat-slitting, with the bodies later defleshed and many limbs used for display. Preserved bodies often provide stronger evidence for homicide than skeletons; for example, an ancient Peruvian male has evidence for a broken neck, as seen by subluxation and rotation of the upper cervical vertebrae, and a hematoma of the cervical spinal canal that protruded into the skull (Sokiranski et al., 2011). The

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remains of another male from the Canary Islands (Spain) presented multiple perimortem fractures to the cranium, cervical vertebrae, ribs, and leg bones; the injuries were suggested to have been caused by extensive trauma, with the manner of death being suicide or ritual homicide (Velasco-Va´zquez et al., 2017). There are also numerous examples of sacrificial deaths reported in the paleopathological literature, with the majority of studies focusing on evidence from the Americas (Chacon and Mendoza, 2007a,b). One multidisciplinary study established that the ritualized context of the person’s death may have begun long before they were killed. This was seen in the naturally mummified body of the Llullaillaco Maiden (AD 1430 1520) found in Argentina, which revealed that she had migrated to the area only a short time before her sacrificial death. For a year beforehand, her diet had changed to one which had greater amounts of animal protein and C4 carbon plants, suggesting special treatment and care (Wilson et al., 2007). Organized Violence This is defined as violence enacted at the community or state level, and the archeological record has evidence for this scale of violence occurring from the Neolithic to the 19th century AD (Armit et al., 2007; Baustian et al., 2012; Chacon and Mendoza, 2007a,b). Recent work has demonstrated the need for multidisciplinary approaches when studying violence in past societies, as shown by the work of Arkush and Tung (2013), who explored warfare in pre-Columbian Peru from 400 BC to AD 1400. They found that periods of warfare and peace could be correlated with episodes of rapid climate change (also known as shocks) and failures in sociopolitical structures, rather than with changes such as the adoption of domesticated plants and animals, or the use of bloody and violent imagery in public art and performances. Importantly, they found that human remains and settlement patterns were the two most reliable sources of data for examining warfare (Arkush and Tung, 2013). Structural Violence The study of vulnerable people in past communities is a developing area of bioarchaeological research, which has been a particular area of study for those examining structural violence in an archeological context (e.g., de la Cova, 2012). Defining who is a vulnerable person is a value judgment, and it must also be recognized that it can be a temporary or permanent state. One definition has been proposed by Mechanic and Tanner (2007), “vulnerability results from developmental problems, personal inadequacies, disadvantaged social status, inadequacy of interpersonal networks and supports, degraded neighborhoods and environments, and the complex interactions of

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these factors over the life course.” For example, in the United Kingdom, victims may be abused by their caregiver or family member; these episodes can be infrequent or take place regularly. The range of abuse that they experience is predominantly psychological, with physical abuse only being part of the spectrum. The injuries they sustain are inflicted by hitting, slapping, pushing, kicking, and the use of restraints (Department of Health, 2000). Victims are all too-frequently neglected, a situation that could result in physical changes, as they may be denied food and have their care needs withheld (Department of Health, 2000). For bioarcheology, the Index of Care approach is invaluable in assessing the presence of this abuse, as it could potentially identify evidence for localized infection and/or ulceration and compromised nutrition (Tilley, 2015). At present, abuse of vulnerable people has only been identified in 19th- and 20th-century AD skeletal collections of known individuals from North America (de la Cova, 2012). De la Cova’s examination of individuals and associated records from the Robert J. Terry Collection (Smithsonian Institution, Washington, DC), highlighted that many of the fractures that had been assumed to be age-related or the result of accidental falls, may have actually occurred during their confinement in mental hospitals (de la Cova, 2012). However, 19th century AD primary sources show that many institutions which purported to care for vulnerable people, particularly migrants and women, frequently perpetrated acts of assault against their inmates (Esther, 1997; Wallis, 2013). In the following subsections, we will review briefly the diagnosis of trauma indicative of the abuse of several specific categories of vulnerable individuals: children, elderly adults, and intimate partners. Considerable research on this topic has been published in the context of forensic anthropology, radiology, and pathology (e.g., Love et al., 2011; Hegarty et al., 2013; Kleinmanet al., 2015; Wong et al., 2017). However, given the difficulty of diagnosing trauma in the past and the compounding issues of preservation and demographic representation in an archeological context, the translation of these studies to paleopathological contexts remains underexplored. Child Abuse There is no generally accepted definition of what constitutes child abuse, but the World Health Organization (2007, 7) recognizes that it is not limited to physical injuries: “child maltreatment refers to the physical . . . mistreatment . . . neglect and negligent treatment of children.” Forensic anthropological work has emphasized the issues of neglect and insufficient care alongside evidence for fractures. Their cases often identify children whose dental age and skeletal development are divergent, thus supporting neglect (Ross and Abel, 2011). The majority of

victims are less than 4 years old, which has been attributed to their small body size, lack of strength to defend themselves, and because for much of early childhood they are entirely reliant on their caregivers for survival (Child Welfare Information Gateway, 2016). The practice of infanticide may be included within the scope of child abuse. Evidence for infanticide is dependent on our ability to accurately age and sex infant remains (Dapling, 2010; Gowland et al., 2014; Smith and Kahila, 1992), allowing us to provide evidence for skewed sex ratios and for death occurring shortly after birth. Ideally, data collection should be supplemented by ancient DNA analysis to establish an individual’s sex (Mays and Faerman, 2001) and CT imaging may also be used to differentiate between live and stillborn infants (Booth et al., 2016). Furthermore, the context in which the remains are discovered should play a central role, because anthropological work has shown that the reasons for this practice are highly diverse and tremendously complex (Scheper-Hughes, 1987a,b, 1993). A compelling case has been published by Crist (2005) from 19th-century AD New York (USA), where two partially commingled neonatal and one fetal skeleton were recovered from a privy located within a slum district renowned for its poverty and high numbers of sex-workers. Identifying skeletal evidence for child abuse is complex; no one fracture is indicative of intentional violence (Love, 2014). The bones that are frequently affected in a clinical setting (skull, ribs, vertebrae, clavicles, long bones, hand and foot bones) are also often fractured during childhood, due to birth trauma during delivery, when infants are learning to walk, or during play (Kleinman et al., 1995, 1996). The location and type of fracture therefore play a central role in judging whether they could have been caused by intentional violence. Clinicians also emphasize the importance of: multiple fractures being observed, fractures at different stages of healing, epiphyseal separations, fractures to vertebral bodies, and complex skull fractures (Allington, 2008). Head injuries are often commonplace during infancy, particularly linear fractures, but in abused children diastatic and multiple fractures are also observed. Rib fractures are less likely to be produced by falls or other accidental mechanisms. Autopsy studies show that many victims have multiple bilateral fractures to sequential ribs, which are most likely to be located at the head, tubercle, and neck, as well as at the sternal portion and costochondral junction (Love, 2014). Other torso fractures suggestive of abuse are: scapula fractures, particularly to the acromion, Hangman’s fracture of the axis vertebra, compression deformities, and fractures to the end-plates and spinous processes of the thoracolumbar vertebrae (Allington, 2008; Cirak et al., 2004; Love, 2014). The

Trauma Chapter | 9

sternebrae may also be fractured, but these are more likely to be caused by accidental mechanisms (Ferguson et al., 2003). Although long bones are frequently fractured due to accidents, certain locations and fracture types produced by torsional or tractional forces acting on an extremity are considered to be indicative of abuse, particularly metaphyseal fractures to the proximal and distal tibia and distal femur (Johnson, 2009; Kleinman et al., 1995, 1996). Care should be taken to ensure that normal morphology and skeletal development are not confused with injuries caused by abuse, e.g., delayed fusion of an ossification center in the pubic bone (Perez-Rossello et al., 2008). In the clinical literature, other pathological conditions have been proposed to result in similar fractures or bone locations, rickets being one example (Schilling et al., 2011). Although osteogenesis imperfecta is rarely encountered in the archeological record, it can also cause spiral, transverse, and metaphyseal fractures (Dent and Paterson, 1991; Lowenstein, 2009). Child abuse has been identified ina number of archeological populations (Blondiaux et al., 2002; Cook et al., 2014; Mays, 2014), and in some cases its occurrence has been linked to wider political and social changes (Gaither, 2012; Gaither and Murphy, 2012). Identification of a partially mummified victim from Roman period Egypt by Wheeler and colleagues (2007, 2013) used multiple imaging and other scientific techniques to establish the range and type of abuse directed at this 2- to 3-yearold subadult. Micro-CT, digital radiography, and macroscopic analyses identified healing fractures and perimortem fractures to the right clavicle, humerii, ilia, right pubic bone, and two thoracolumbar vertebrae (Wheeler et al., 2013). Micro-CT scans suggested that the new bone formation present on the forearm bones, ribs, scapulae, and lower leg and foot bones had been produced by bruising (Wheeler et al., 2013). The presence of hair meant that a time-depth perspective of diet and health could be achieved, which provided evidence for the catabolic recycling of nitrogen and anabolic nutritional depletion, showing that the subadult had experienced multiple episodes of dietary insufficiencies (Wheeler et al., 2013). Elder Abuse The identification and discussion of this form of abuse in elderly people is a very recent development in the clinical literature, despite it being raised in the 1970s, as “granny battering” (Baker, 1975). It is defined by the - World Health Organization (2002, 3) as “a single, or repeated act or lack of appropriate action, occurring within any relationship where there is an expectation of trust which causes harm or distress to an older person.” This form of abuse has been identified cross-

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culturally in a variety of settings, between spouses, within families, and in care-homes, and by institutions. Elder abuse is a spectrum of violence, including neglect and physical violence (Collins and Presnell, 2007; World Health Organization and International Network for the Prevention of Elder Abuse, 2002), and it usually includes blunt-force injuries inflicted by fists or blunt objects. Evidence of restraints and physical neglect may also be present. The majority of injuries are directed to the upper extremities, maxillofacial area, dentition and neck, skull and brain, lower extremity, and torso (Murphy et al., 2013). A range of dental trauma has been identified in victims of this abuse: crown fractures of the incisors, avulsed teeth, and loosened teeth (Senn and Stimson, 2010; Wiseman, 2008). Individuals can have mixed active and healed trauma, but a differential diagnosis should include falls, which are a common cause of death and injury in elderly people due to mobility and visual impairments (Chew and Edmondson, 1996). As with other forms of abuse, physical injuries are not limited to the skeleton. The skin is particularly vulnerable because of age-related thinning and loss of elasticity (Collins and Presnell, 2007). Bruises and hematomas are common and often found on the head, neck, torso, and soles of the feet. Because people may be confined and/or restrained, they can develop decubitus ulcers (Collins and Presnell, 2007; Gibbs and Mosqueda, 2014). Evidence for such ulcers has been identified in archeological skeletons (Redfern, 2017); the “Index of Care” model provides help in identifying neglect, as it enables bioarcheologists to establish the minimum requirements for care, and to determine whether or not these were met (Tilley and Cameron, 2014). The clinical literature teaches us that we should identify the presence of comorbidities, impairment, compromised nutrition, and the physiological changes caused by senescence (Crews, 2004). These will influence the severity of an injury, and the length of healing time (Bennett and Hogan, 2008). Nevertheless, care should be taken not to automatically assume that a suite of health conditions is the result of neglect or maltreatment, as they could have been the result of poverty and other forms of structural violence (Redfern, 2017). At the time of writing, elder abuse has only recently entered the paleopathological literature, through the work of Gowland (2016, 2017a) on older females from Roman Britain. Growing numbers of individuals are being recognized as victims of this abuse, from prehistory to historic medical collections (Gowland, 2017b; Worne, 2017). Because the skeleton is a cumulative record of a person’s trauma history, care must be taken to ensure that earlier traumatic life course events are not misinterpreted as evidence of elder abuse (Redfern, 2017).

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Intimate Partner Abuse This form of abuse can be defined as, “any behavior within an intimate relationship that causes physical, psychological or sexual harm to those in the relationship” (World Health Organization, 2012). Cross-cultural studies have found that it increases during and after warfare and in periods of economic decline (Colson, 1995; Tjaden and Thoennes, 1998), with gender studies showing that it cannot be understood without examining these contributory factors (Engle Merry, 2009). Physical injuries experienced by victims of domestic violence are, of course, only one part of the spectrum (Johnson, 2008). A suite of injuries believed to be indicative of domestic violence has been identified by clinicians, primarily in Europe and North America who work in “Accident and Emergency” or “Emergency Room” settings. Because the majority of injuries are limited to the soft tissue, many victims will not seek medical help, especially if the clinicians are legally bound to notify the police, and do not want to put themselves at further risk of violence (Crandell et al., 2004; Hester, 2009). Other studies have shown that there are differences between age groups for rates of domestic violence, in addition to changes in people’s personal responsibilities, such as caring for dependents (see Redfern, 2015). Consequently, we must acknowledge that many biases impact on published data, whether in the clinical or social science literature (see Redfern, 2015). The injuries sustained by victims of domestic violence in a clinical setting are targeted at the head, face, neck, and arms, and they are more likely to present with multiple injuries (Allen et al., 2007; Kyriacou et al., 1999). Importantly, forensic and a minority of clinical reviews have challenged this model, showing that there are no clear differences in injury type and patterning between domestic violence victims and people who have been assaulted (Juarez and Hughes, 2014; Reijnders and Ceelen, 2014; Seifert et al., 2007). The literature has overwhelmingly focused on female victims in the creation of this model, but male victims injured by opposite sex perpetrators were found to have more upper limb injuries and were less likely to fracture or dislocate a bone. Such injuries were inflicted by a female, who was typically shorter and not as strong (Carmo et al., 2011). Therefore, we must also focus on the mechanism of injury, as that may be more instructive, particularly for identifying male victims. Additionally, many victims had also experienced child abuse and sustained repeated injuries, because the abuse can be perpetrated over many years (Redfern, 2015). Consequently, we must be alert to the fact that victims could be misidentified as injury recidivists (Judd, 2002a; Redfern et al., 2017). As domestic violence is a spectrum of abuse, additional health variables should be included in its

identification. Clinical studies have shown that victims can experience dietary insufficiencies and have general poor overall health (Campbell et al., 2002; Campbell, 2002; Rahman et al., 2013). Caution should be exercised in identifying victims of repeat offenders, as abused victims have higher mortality risk and poorer health (Redfern et al., 2017). Distinguishing between victims of domestic violence rather than assault in the archeological record is very difficult, because interpretation must be context-driven to understand the life course, gender, and status hierarchies present in a society at a given time and, if present, how these were governed by legislation (Redfern, 2015). For example, in the Roman period, adolescent females could be married, usually to an older man (Harlow and Laurence, 2002). If they had been a victim of domestic violence and the context was not taken into consideration, as men could beat their wives, their injuries could be described as child abuse. A tombstone from Italy dedicated to a 16-year-old wife by her parents recorded her death at the hands of her husband (Carroll, 2006). In contrast, the Siberian Iron Age burials of Scythian female warriors show evidence for craniofacial fractures caused by direct blows to the head. Because we know women were active participants in Scythian warfare and raids, it is more likely that they were combatants rather than victims of domestic violence (Murphy, 2003). Even when detailed primary source information is available, care must be taken not to attribute victimhood status to an individual without offering alternative explanations, as people are likely to have had complex personal histories where they were both aggressor and victim. For example, judicial sources from 18th-century AD London show that poor women were active participants in assaults against men and women, but they could also be victims of domestic violence at the hands of their spouses/partners and employers (Hurl-Eamon, 2001; Hurl-Eamon and Lipsett-Rivera, 2006). Nevertheless, there are several convincing cases of domestic violence identified in the archeological record (Kjellstro¨m, 2009), such as in the Pre-Columbian Native American populations studied by Shermis (1983). Shermis was one of the first scholars to use clinical models to identify domestic violence in past communities; however, an alternative interpretation for injured females in these populations is that they were captives and/or slave laborers, and the violence was perpetrated because of their social status (Martin et al., 2010). Violence Directed Toward Bodies Scalping, along with other forms of trophy-taking and cannibalism, are common forms of violence directed toward bodies (see Chacon and Dye, 2008). Certainly,

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FIGURE 9.66 Accidental scalping in a female industrial worker from the early 20th century. (A) The irregular external surface of the parietal bones is the bony response to infection and proliferation of granulation tissue during an 8-month period after the accident and before death due to septic meningitis. The arrow indicates the anterior margin of the lesion. (B) The inner table, showing the region of the sagittal suture. Note the porosity indicative of an inflammatory response in this area. (PMES 1.EB.I.(6).)

skulls and other body parts may be collected and venerated, while starvation may lead to cannibalism, the illfated Donner Party being one example (Hardesty, 1997). While most forms of trophy-taking engage with sharpforce trauma, discussed in earlier sections, we shall consider scalping here, as it is usually associated with larger-scale acts of violence. The identification of cannibalism depends largely upon taphonomic changes in bone, which are beyond the scope of this volume. Traumatic avulsion of the scalp may be the result of accident or intentional violence and determining which of these options is correct can be challenging if not impossible (Fig. 9.66). Scalping is reported in Herodotus’s 5thcentury fourth book and in the second book of the Maccabees (c. 67 37 BC), which describes the practice of scalping of living captives in ancient Palestine (Ortner, 2003). Reese (1940) reports that the Visigoths, AngloSaxons, and Franks practiced scalping, and it is noted among Native Americans in 1520 AD, just 28 years after the European discovery of the New World. Scalping appears to be more commonly reported in New rather than Old World skeletons (e.g., Bueschgen and Case, 1996; De Vore and Jacobi, 2016; Murphy et al., 2002). Scalping is certainly well documented in early Colonial times for many Native American peoples in North America. Catlin (1844: 239 240) reported that colonists would pay for the scalps of both European and Native Americans. Indeed, he notes that the knife commonly used for scalping was made in Sheffield, England and traded to the Native Americans in exchange for horses (Catlin, 1844: 236).

The scalp was frequently removed to provide evidence of having killed an enemy. Nadean (1941: 181 182) indicates that some tribal variation existed regarding the amount of scalp taken. Catlin (1844: 30 31, 238) shows that the scalp taken from “the place where the hair radiates from a point” was most important, but that the scalp from other areas would be used to decorate clothing in some communities (e.g., Blackfoot tribe). In removing the scalp, the skin would be cut around the desired area and peeled off. The initial cutting may have left marks on the skull, whether or not the victim was dead (Owsley et al., 1977). Cut marks on the skull provide the most convincing evidence of perimortem trauma associated with scalping. Indeed, identification of scalping in an archaeological context rests on the presence of cut marks to the cranium, evidence of necrosis, and if the person survived there may be evidence of healing (e.g., see Toyne, 2011) (Fig. 9.67). Catlin (1844: 239), Reese (1940: 16), and Nadean (1941: 193) report that survival after scalping did occur in some cases (e.g., see Smith, 2008), although scalping was most typically done after the victim had been killed. Reese (1940: 18 19) included in his paper a report by a physician who treated a person who had been scalped by the Cheyenne tribe in 1867. The report indicates that the scalp was removed and the periosteum covering the skull was cut and badly damaged. The outer table was exfoliated (shed), after which the wound healed. Hamperl and Laughlin (1959: 88), in commenting on this case, suggest that the destruction of the periosteum deprived the outer table of its superficial blood supply. This resulted in

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FIGURE 9.68 Anterior detail of the frontal bone demonstrating the bone reaction to scalping. At the margin (arrow) where the scalp was removed, intact vasculature permits osteoclastic removal of adjacent necrotic bone, creating a groove in the outer table (arrow). (Adult female 20 years old from the Sully Site, South Dakota, NMNH 381356.)

FIGURE 9.67 Probable example of scalping in a pre-Columbian adult female skull from the Sea Island Mound in Georgia, USA. The irregular surface of the skull vault is virtually identical to that seen in Fig. 9.65A. The anterior margin of the injury is indicated by the arrow. (NMNH 379000.)

necrosis with granulation tissue in the diploe, eventually separating the necrotic tissue from the skull. An archeological skull showing a lesion probably reflecting this same process is reported by Hamperl and Laughlin (1959). A groove around the circumference of the cranium has also been identified, defining the area incised and removed (Hamper, 1967). An unequivocal archaeological example of a New World scalping occurs in the skull of a young female (NMNH 381356) from the Sully Site in South Dakota (USA) who was about 20 years of age at the time of death. The Sully Site is dated to approximately AD 1650 and thus does not contribute to our understanding of the antiquity of the practice. But what this case does demonstrate is the association between clear evidence of cut marks on the skull and a lytic process at the margins of the cut made to remove the scalp (Fig. 9.68). Clearly there was some time, probably a few weeks, between the trauma and her death. A well-documented example of accidental scalp avulsion illustrates the gross morphological features of this trauma. The skull and mandible of a 55 year old female jute weaver curated by the Pathology Museum of the Royal College of Surgeons of Edinburgh (PMES. 1.EB.I.(6)) and dates from the early 20th century AD. The female’s hair had been caught in machinery, tearing the scalp from the parietal region, but leaving it

suspended by its frontal attachment. The scalp was replaced and sutured, but became infected, leading to extensive sloughing and proliferation of granulation tissue. The infection led to septic meningitis, and death occurred 8 months after the injury. The outer table of the her skull exhibits the irregular surface typical of the bony response to granulation tissue, as well as marginal porosity indicative of hypervascularity and inflammation. These changes are more extensive on the left parietal bone (Fig. 9.66A). On the inner table there are many small pores along the sagittal sulcus, reflecting hypervascularity in this region (Fig. 9.66B). This provides evidence for the range of changes that can occur over 8 months. Thus, relatively short-term survival after scalping might be expected to produce changes in the skull that could be identified in the paleopathological record. The clinical history of this case highlights the serious potential of infection as a complicating factor in scalping. The scalp along with the underlying periosteum provides important vascular pathways supplying the outer table of the calvarium. Scalping can disrupt this vascular supply and lead to partial necrosis of the outer table. However, revascularization can occur from the diploe, but this may not occur with sufficient speed or be evenly distributed to all the bone affected by the scalping. The result may be evidenced as areas of necrotic bone within the affected area. With long-term survival after the trauma, some of these areas of dead outer table may be sloughed off, leaving a very irregular surface.

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Traumatic Surgical Interventions Whether in response to fracture or to soft-tissue injury, surgical interventions often leave permanent marks on the skeleton. In trepanation and amputation, these marks are in the form of sharp-force trauma that can be identified by the paleopathologist. Here, we review the diagnostic criteria for the identification of these interventions in archeological samples. Amputation Evidence of amputation in the archeological record is rarely identified, although historical documents and art reveal that this operation was performed in the past (Porter, 1999; Stryla et al., 2013). Occasionally, data are synthesized in an attempt to assess the scale of interventions (e.g., Mays, 1996). The paucity of evidence for amputation in past populations might be because people in the past died before the amputation healed, typically because of infection and shock, or that the person died from hemorrhage during or after the operation (e.g., Chaloner et al., 2001). Furthermore, identification of an amputated limb in the archeological record also may be confounded by postmortem breaks of bones, as perimortem and unhealed amputated limbs might be mistaken for postmortem breaks. Consideration must also be given to the causes of amputations that go beyond the surgical, because amputation can happen accidentally or as today, may be performed as a punishment(Mavroforou et al., 2014). For example, the finding of three individuals with perimortem amputations in medieval Estremoz, Portugal, who were buried next to each other, suggested that the amputations may have been performed as a result of punishment. This also may indicate the application of “justice” in a militarily strategic region. Amputation of body parts for punishment has also been recorded in the medieval Portuguese historical record (Fernandes et al., 2017). Brothwell and Møller-Christensen (1963b) report evidence of amputation with subsequent healing of the stump in a distal right forearm from Egypt dated 2000 BC. They offer three possibilities for the cause of the mutilation: (1) injury during warfare, (2) punitive action against a criminal or captive, and (3) surgical amputation for therapeutic reasons. Although punishment for criminal behavior remains a possibility, Aldred (1964: 56) challenges the likelihood that the ancient Egyptians would have cut off the hand of a captive. He notes that to do so would have deprived the captors of a valuable spoil of war: the slave labor. He further notes that amputation of the hand was limited to the dead and dying victims of warfare, and was used as a method of counting the dead. In another report, Brothwell and MøllerChristensen (1963a) describe an amputation of the distal left forearm in a skeleton from Sicily dated to the 7th century AD. The ends of the radius and ulna have fused,

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indicating healing. They conclude that the amputation was punishment for a criminal act—a practice common in that age; however, it may have been a surgical amputation due to injury. Stewart (1950: 43) reports the existence of bones showing amputations from Peru but does not indicate which bones are involved. Some skeletal evidence for amputation is also found in hospital contexts that may indicate the surgery was done for reasons of disease (e.g., leprosy: Lee and Boylston, 2008), but most of the time the underlying reason is not known. For example, analysis of the arm bones of a man living over 5000 years ago in Israel showed that his hand had been amputated (Bloom et al., 1995), as had that of a man buried in medieval Ipswich, England (Mays, 1996). Ancient Egyptian evidencehas also been reported (Dupras et al., 2010). Four individuals dated to the First Intermediate (2181 2055 BC) and Middle Kingdom (2055 1650 BC) periods from the archeological site of Dayr al-Barsh¯a had received amputations; two of them had had both feet amputated, one through the metatarsophalangeal joints, and the other transmetatarsally, both for unknown reasons; both individuals’ amputations had healed. Foot binding or the use of prosthetic devices may have been practiced for these people post-amputation. Further examples from this site include a young adult male recovered from a shaft containing commingled and fragmentary human remains. His left ulna appears to have been amputated beneath the coronoid process—the radius was missing (Old Kingdom—2686 2181 BC), and another individual, whose arm has been amputated at the level of the distal humerus (Old Kingdom or First Intermediate period) (Dupras et al., 2010). Evidence for bilateral forefoot amputation has also been reported in a male buried in Romano-British Winchester, with punishment or surgery for trench foot suggested as possible reasons for the amputation (Stuckert and Kricun, 2011). Finally, a very rare example of amputation evidence alongside a wooden prosthesis has been found in Egypt. There were clear marks of use on the sole of the prosthetic toe indicating that the person had actually used their artificial toe prior to death. In this case, the individual was a 50- to 60-year-old female who had lived between 1550 700 BC and had been buried at Thebes-West (Nerlich et al., 2000). CT scans of both legs showed slight osteopenia, which might suggest some disuse atrophy of the legs. Additional evidence for arteriosclerosis of the aorta and “extensive calcifications and arteriosclerotic microangiopathy of small arterial vessels of the affected foot” were found (Nerlich et al., 2000), suggesting that the toe may have been lost through gangrene, necessitating the need for amputation. Finally, Binder and colleagues (2016) report an example of a wood and iron prosthesis replacing the left amputated foot of a man buried in 6th-century AD Austria.

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FIGURE 9.69 Detail of trephination in a mural by artist Alton Toby. The mural was created for an exhibition hall, which no longer exists, on physical anthropology at the National Museum of Natural History, Smithsonian Institution.

Trepanation Trepanation refers to the surgical removal of a piece of bone from the skull, with the term trephination being reserved for a hole made by a trephine tool (Clowes, 1926; Parry, 1926) (Figs. 9.69). It is more commonly encountered than amputation in archeological populations. The earliest written accounts of trepanation are found in the Hippocratic writings (460 377 BC). However, evidence of this practice goes back at least to the Neolithic period in Europe (Moodie, 1919: 484; Guiard, 1930; Parry, 1931; Hrdliˇcka, 1939; Stewart, 1958: 470; Oakley et al., 1959: 93). Like amputation, the operation continues to be carried out today (Freeman, 1918: 445; Ruffer, 1918a: 99 102; Moodie, 1919: 485; Hrdliˇcka , 1939; Oakley et al., 1959; Furnas et al., 1985; Hershkovitz et al., 1991; Mahone, 2014), though under more controlled circumstances and with effective anesthesia and postoperative care and rehabilitation, including antibiotics to treat infections. The geographical distribution of the practice in antiquity is extensive, including Australia (Webb, 1984: 88 198), Europe, the Pacific, North Africa, the Middle East, and North and South America (Stewart, 1958: 470 480; Stone and Miles, 1990; see also Arnott et al., 2003; Verano, 2016a). The proposed reasons for this practice variably include letting the spirits escape and the treatment of migraines, epilepsy, and head injuries. Occasionally, individuals display both antemortem and perimortem injuries and trepanations (e.g., Roberts and McKinley, 2003: 8 of 43 trepanned skulls had associated head injuries, and 7 of those had healed), and also evidence of infection (Zias

FIGURE 9.70 Trephination of the frontal bone with healing and long term survival. The outer margin of the remodeled bone indicated by the arrow. (Adult female from the site of Cinco Cerros, Peru, NMNH 293794.)

and Pomeranz, 1992). In the latter case, an ancient skull found in a cave near Jericho had evidence for frontal sinusitis and intracranial infection, alongside three trepanation holes (or craniotomies) in the frontal bone. In the archaeological literature, five different types of trepanations have been identified (Gross, 2003): scraping, intersecting cutting, cutting a circular groove, boring holes in a circle and cutting between the holes, and drilling with a trephine, with various instruments used depending on time and space (Figs. 9.70, 9.71, 9.72). For example, a study of pre-Contact trepanation in skeletons from 11 sites in the Cuzco region, Peru, found evidence for 109

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FIGURE 9.71 Trephination by cutting in a child about 8 years of age from Cinco Cerros, Peru. (a) There is clear evidence of association with cranial trauma. Note the long circular fracture (arrow) adjacent to the trephine and the radiating fracture line extending inferiofly and posteriorly from the circular fracture. (b) Radiating fracture line in the base of the skull (arrow) continuing the fracture line seen on the lateral aspect of the skull. There is no evidence of healing of the fracture or the trephination, indicating death during or shortly after surgery. (NMNH 293315.)

trepanation holes in 66 individuals, many of which had associated trauma. Circular cutting and scraping methods were common and a large proportion was healed, proving that the methods were highly successful (Fig. 9.70). Survival rates increased over time, perhaps suggesting care and treatment, an improvement in methods, and surgeons choosing to operate on areas of the skull that mitigated the likelihood of damage to the cerebral meninges and venous sinuses. However, when attempting to diagnose trepanations, differential diagnoses for holes in the cranium should always be considered (Verano, 2016b). These might include developmental anomalies, infection, neoplasm, and taphonomic damage (see Kaufman et al., 1997), and the possibility that holes induced by trauma may then be overlain by a trepanation used to treat the injury. A number of reviews of trepanations in different countries have revealed interesting data. In a study of ancient Anatolian evidence, 40 people from 23 sites dated over a range of 10,000 years had evidence for trepanations. Single holes were identified, mainly in male skulls. Drilled trepanations were performed until the Ottoman period, with scraping and rectangular sawing methods applied from the Early Bronze Age, and boring and cutting techniques used from the Iron Age. In more than half of the trepanations there was evidence of cranial trauma. It was concluded that techniques employed, mirrored

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FIGURE 9.72 Extensive trephination by cutting in an adult male skull from Cinco Cerros, Peru. There seems to have been some indecision on the part of the surgeon about the appropriate place to cut. There is no evidence of healing. Suggesting that the patient died during or shortly after surgery. The somewhat indecisive natute of the trephination suggests the possibility of experimentation. perhaps on a cadaver. (NMNH 293785.)

those of South America and the Mediterranean region (Erdal and Erdal, 2011). In a study from Italy, 54 individuals buried at 43 sites, dating from the 5th millennium BC to the 18th 19th centuries AD, had been trepanned. There were no special funerary treatments afforded to affected people when compared to the non-trepanned part of the populations. Again, most people affected were male and they experienced only one trepanation. The most common technique was scraping, and purported causes included trauma, disease, ritual intervention, or experimental surgery. A high percentage of the Italian trepanned skulls showed healing, and thus survival of the person beyond the time of the operation (Giuffra and Fornaciari, 2017). A review of British skeletons with evidence of trepanation found similar patterns: they dated from prehistory to the post-medieval period, the method used was mainly scraping, and a large proportion had healed at the time of death. Most people with evidence for the surgery were male, and their funerary treatment was no different to the rest of the community (Roberts and McKinley, 2003). Trepanation today is, of course, used in hospitals to treat various ailments, such as head injuries. It has also been advocated as an alternative treatment method: “making an opening in the skull favorably alters movement of blood through the brain and improves brain functions which are more important than ever before in history to adapt to an ever more rapidly changing world” (http:// www.trepan.com/).

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Sincipital T-Mutilation Skull lesions thought to be associated with cautery in the treatment of mental illness were first brought to the attention of anthropologists by Manuouvrier (1895). He used the term “T-sincipital” to describe the lesion. What appears on the skull is a depression in the shape of a T or a cross, in which the vertical portion of the T is associated with the sagittal suture, whereas the cross bar or top of the T is often associated with the lambdoidal suture. In Europe, skulls with these lesions have been found in skeletons of the Neolithic period (Manuouvrier, 1895). Zaborowski (1897) reports similar findings in central Asia. Moodie (1921) and Weiss (1955) report the sincipital-T pattern in ancient Peruvian skulls. Aufderheide and Rodriquez-Martin (1998) report a geographical distribution for this practice that includes the New World, Europe, Africa, and Central Asia. Furthermore, Campillo (1994 1995) reproduces a drawing implying a link between trephination and the sincipital-T procedure, however Stewart (1958) cautions against interpreting any large bone scar as a result of cautery. Virchow (cited in MacCurdy, 1905) suggested that a tartar-emetic ointment smeared on the scalp could produce scarring and affect the bone. However, weight is lent to the hypothesis of cautery being the cause of the lesion by Avicenna’s medieval prescription for melancholia in which the “the head is to be cauterized in the form of a cross” (MacCurdy, 1905: 23). Most often the lesion resulting from cautery did not expose the dura (MacCurdy, 1905), although at least one skull exists, in which the sincipital-T defect in part penetrated through both tables of the skull.

Trauma to the Skeleton Through Cultural Modifications Returning to Ortner’s (2003: 119) fourth category of the ways in which trauma can affect the human skeleton, the final section of the chapter considers various cultural modifications resulting in “an artificially induced abnormal shape or contour of bone.” That is, chronic, lowgrade compression over an extended period of time can modify the normal shape of bone. Such deformities are often, but not always, intentional, and should be understood in their cultural setting, as many were used to control behaviors, particularly in women (see Stone, 2012). The basic principle to be emphasized is that any longterm, deforming pressure brought to bear on a bone, or group of bones can result in permanent deformity, particularly if it occurs during the growth period. Here, we will consider the effects and cultural contexts of cranial modification, foot-binding, waist training, and dental avulsion, paying particular attention to the skeletal manifestations

FIGURE 9.73 Fronto-occipital artificial skull deformation in an adult female skull from an archeological site near Chavina, Peru. (NMNH 293691.)

of these practices, considering their ties to reflections of social identity (Chapter 3).

Cranial Modification Dingwall’s review (1931) of cranial deformation indicates that artificial modification of the skull was one of the most ubiquitous cultural practices in antiquity, being found on every continent except Australia. A more recent review (Gerszten and Gerszten, 1995) traces the history of this cultural practice back to 45,000 BC in Iraq. A comprehensive review of cranial deformation and other forms of artificial modification of the skull is beyond the scope of this book. It is important, however, that cultural deformation is not confused with a pathological processes, such as osteomalacia or craniostenosis, which can result in bones of abnormal shape. Whereas several methods of producing cranial deformation exist, most modifications of skull shape are the result of applying pressure to various areas of the skull at a young age, namely: (1) the occipital region, (2) the frontal region, (3) both frontal and occipital regions (Fig. 9.73), and (4) along a transverse axis, approximately passing through the vertex, the mastoid process region, and the region just above the insertion of the nuchal ligament on the occipital bone. This last type of pressure, utilizing circular bands, produces the circular or Aymara type of deformity (Stewart, 1941: 343) (see also Blom, 2005) and proportionately lengthens the skull (Fig. 9.74). An Old World example of cranial deformation occurs in a

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FIGURE 9.75 Left lateral view of an artificially deformed skull from the archeological site of Choga Mish, Iran, dated to the fifth millennium BC. Adult female studied through the courtesy of Dr. Helene J. Kantor, University of Chicago.

FIGURE 9.74 Circular or Aymara type of artificial skull deformation, which results from circular constricting bands wrapped around the posterior half of the skull during the early growth phase of the individual: (A) lateral view, (B) top view showing somewhat elongated aspect of the deformed skull. (Specimen from Ancon, Peru, archeological age unknown, NMNH 242844.)

fifth millennium BC adult female skull from the site of Choga Mish in Iran (Fig. 9.75). Other Old World examples have been reported from Byzantine Greece (Tritsaroli, 2011) and 5th- to 6th-century AD Hungary (Molna´r et al., 2014). The universal reason for the practice of cranial deformation is cosmetic, and is frequently associated with physical manifestations of high social status and ethnic/ cultural identity in both males and females (e.g., Mayall et al., 2017; see also Tiesler, 2014). Research by TorresRouff and colleagues on this practice in South America, has shown that it was used to create and signal identities during periods of migration and cultural change (TorresRouff and Yablonsky, 2005; Torres-Rouff, 2008, 2009; Nado et al., 2012). The complications of cranial deformation are mainly cosmetic; however, Mendonc¸a de Souza et al. (2008) suggest that it may have been the cause of death for one late Inca period mummified infant from Peru, as their crania displayed changes associated with deformation, and also severe bone necrosis in the area of occipital compression. Stewart (1948: 71) suggests that compression may disrupt the normal growth that takes place at the skull sutures and can give rise to a depression in the sagittal region. This depression creates a bi- or tri-lobed appearance in the skull and could be confused with the results of a therapeutic practice producing the sincipital-T deformation discussed in this chapter. McGibbon (1912) and Moss (1958) report minor anatomical abnormalities that are associated with cranial deformation. However, Moss (1958: 284)

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emphasizes that the magnitude of growth is not reduced. This suggests that the practice probably did not produce any serious health problems. Nevertheless, studies have shown that cranial modification will influence the results of any studies (e.g., ancestry), which rely on the use of craniofacial metrical data (see Boston et al., 2015). In modern anatomical skulls, one occasionally finds the skull vault to be asymmetrical or the occipital bone flattened. These skulls occur in cultural contexts where intentional deformation of the skull is not practiced. This raises the issue of whether some manifestations of skull deformation may be caused by natural conditions, an issue that has come to the forefront of clinical concerns in recent years in living populations. To counteract the rise in Sudden Infant Death Syndrome (SIDS) and positional asphyxia in the 1990s, national and international ‘Back to Sleep’ campaigns were launched in an effort to ensure infants were placed to sleep on their backs (Task Force on Infant Positioning and SIDs, 1996). While this campaign has had success in lowering rates of positional asphyxia (American Academy of Pediatrics Task Force on Sudden Infant Death Syndrome, 2005), in recent years practitioners have noted the rise in a related issue: positional plagiocephaly, or “flat head” (Najarian, 1999; Morrison and Chariker, 2006). Thus, this deformity noted in archeological skulls also may be the result of an infant or child lying with minimal movement on a relatively hard surface during development, e.g., being carried in a cradle-board (e.g., Tubbs et al., 2006). Such deformation raises the possibility that slight pressure occurring for a few hours per day but over a long period of time may be adequate to produce a gross deformity in a bone.

Foot Binding In relatively recent times perhaps the best known intentional deformity was the foot-binding practice of upper class Chinese women from the 10th to early 20th centuries AD (Jackson, 1997); many soft-tissue examples exist in medical collections across the world. In this practice, the feet of female children, usually between the ages of 4 and 7 years old, were bound in such a way that the metatarsals were bent downwards and forced toward the heel of the foot. This resulted in the tarsals and metatarsals being fractured multiple times in order to create a “lotus foot.” Secondary complications included necrosis of the toes, and sepsis, when sharp fragments of glass were also bound to the foot to encourage the loss of the toes and soft-tissue (Jackson, 1997; Zhang et al., 2015) (Fig. 9.72). This created abnormal angulation of the tarsal bones, and abnormal relationships among all the bones and joints of the foot (Fig. 9.76); an archaeological example from China is now attested (Berger et al., 2019). Long-term studies in elderly Chinese women have found that over

FIGURE 9.76 Lateral view of artificially deformed right foot in an adult Chinese female resulting from foot binding. The arch of the foot is greatly exaggerated with major changes occurring in the tarsals. (WM S17.1.)

the course of their life, they had reduced activity levels compared to their nonbound peers, and in old age, their bound-foot deformities increased their risk of falling, resulted in poor balance, and; some also had lower hipbone density (Cummings et al., 1997; Qin et al., 2015).

Waist Training Osteological evidence for corset-wear is predominantly found in European post-Medieval cemetery populations, becoming a popular form of dress from the 16th century and reaching a peak in the mid-19th century AD. They were worn by both men and women, with the incredibly narrow-waist versions being fashionable for women during the 1840s 1850s (Steele, 2005). In skeletal remains, work by Gibson (2015) has identified a range of changes to the torso: inferiorly and laterally directed deformation of the spinous processes in the thoracic vertebrae, and deformation of the 4th to 10th ribs (although not limited to these pairs) creating an “S”-shape and causing the sternal ends to be inferiorly directed. In many archeological skeletons, the ribs also display multiple antemortem fractures at their necks and bodies, and the ribs themselves have a “tapered” appearance (Walker, 2012a). The majority of the evidence reported in males appear to be related to a co-existing pathological condition. For example, a 19th-century AD male from England had destruction of multiple thoracic and lumbar vertebrae, lumbar vertebral kyphosis, and ankylosis caused by tuberculosis, but he also had changes to his ribs and thoracic spine suggesting that he had worn a corset to provide support and stability (Moore and Buckberry, 2016). In very rare cases, medical corsets have also been encountered at excavation. The skeleton of Samuel Lord (c.1790s 1830s AD)

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recovered from the crypt at St Bride’s Church in London, showed that he had suffered from severe kyphoscoliosis, multiple other congenital anomalies, bilateral ankylosis of the sacroiliac joints and, potentially, residual rickets (Conlogue et al., 2017). He lived into his mid-30s, and recovered along with his skeleton from his lead coffin were a number of leather and hessian straps, which appear to have been part of a bespoke corset to help him (Conlogue et al., 2017).

Dental Modification Intentional dental modification, such as chipping, avulsion, and inlay, are often traumatic processes (e.g., Tiesler et al., 2002) They may lead to infection and can cause death (Logan and Qirko, 1996). They are another example of the body being changed to reflect a social identity, e.g., warriors from the Viking Age in Scandinavia and England often had filed teeth (Arcini, 2005; Kjellstro¨m, 2014). Dental avulsion, the process in which teeth are deliberately extracted, has been practiced for a variety of reasons, such as to mark life course transitions, and it has been documented in diverse contexts in both the Old and New Worlds (see Milner and Larsen, 1991; Willman et al., 2016; Burnett and Irish, 2017). Avulsion must be differentiated from trauma, antemortem tooth loss, congenital absence, and postmortem loss (Bolhofner and Baker, 2012). Similarly, the use of labrets, a lip plug/ornament placed through a pierced or slit lower lip, may be recognized in the archeological record, because it produces atypical patterns of dental wear, and they have been excavated in situ (e.g., see Torres-Rouff, 2003; Stojanowski et al., 2015).

SUMMARY AND CONCLUSIONS The variants of trauma, both accidental and intentional, affect the skeleton in so many ways that a comprehensive review would fill the pages of a substantial book. The intention of the preceding discussion is to highlight the major categories of skeletal trauma that might be encountered in archaeological human remains. In particular, we have sought to show that diagnosis and interpretation of trauma in past people is far from straightforward. The basis of any study is high-quality and standardized data collection, which contains the necessary observations from which all resulting interpretations are derived—fortunately, much of this can be achieved macroscopically. We have also highlighted shifts in contemporary clinical practice and reporting, combined with technological and economic changes in the developing world, have meant that we must use clinical data with caution and with a critical eye (see Redfern 2017, 90 91). Over the past quarter-century, paleopathology has become more ethically situated, as we become increasingly

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aware of and sensitive to the complexities and histories of the collections of human remains from which the evidence for trauma in the past is gleaned. This nuanced perspective has resulted in significant shifts in how patterns of injuries are interpreted, but it has also led us to question the extent to which these individuals are representative of the population from which they derive (e.g., de la Cova, 2017). Relatively few people complete life without some type of skeletal trauma. The importance of this generalization for the paleopathologist is that trauma should be high on the list of diagnostic options for many of the abnormalities seen in archeological human skeletons. Trauma can shed light on the behaviors and organization of society as a whole and also the life of an individual. As violence in the past has become a subject of debate by public intellectuals, such as Steven Pinker (2011), it is exceedingly important that we represent our work responsibly, both to our colleagues and to nonspecialist audiences (Redfern and Fibiger, 2018).

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Chapter 10

Infectious Disease: Introduction, Periostosis, Periostitis, Osteomyelitis, and Septic Arthritis Charlotte A. Roberts Department of Archaeology, Durham University, Durham, United Kingdom

INTRODUCTION Infectious diseases have been a part of human society for thousands of years, particularly becoming challenges to humans at the first epidemiological transition—from the Neolithic, or c.5000 years BP (Barrett and Armelagos, 2013). Today, these diseases often are associated with poverty, as they were undoubtedly in the past (see Wilkinson and Pickett, 2010). As people became more mobile in later periods, so did their infectious diseases. Through migration, e.g., the Portuguese and Spanish influx into the Americas in the 15th century and later during 19th-century colonialism, specific scenarios enabled pathogens to travel more easily, often infecting and killing previously unexposed people (e.g., see Merbs, 1992). During the 20th century, which saw the development of antibiotics to treat infections, many infectious diseases declined or disappeared, while noncommunicable diseases, such as cancer, cardiovascular disease, diabetes, and dementia became more prevalent. By the end of the 20th century, antibiotic resistance had started to become a challenge, as had emerging and reemerging infections (Barrett and Armelagos, 2013). Today, those challenges remain with our global population. This chapter is one of three that deals with the paleopathology of infections. This is a particular field within paleopathology that is beginning to show, through molecular studies (Harkins and Stone, 2015), how exploring the origin and long evolutionary history of disease can complement the rapidly developing field of evolutionary medicine (Ness and Williams, 1994; Trevathan et al., 2008). Today, what we know about the body’s response to disease, and particularly infectious disease agents, reflects a large quantity of research accumulated over at least 150

years. The general knowledge regarding the role of disease organisms in infection was established with the research of Robert Koch in the 19th century. Koch demonstrated a link between particular types of microorganisms and specific infectious diseases (Janeway and Travers, 1994: 1 2). However, the biological mechanisms of how these organisms cause disease, how the body responds to the challenge of these organisms, and the many factors that affect both the pathogenicity of the organism and the immune response of the individual remain a major focus of biomedical research today. Since the publication of the second edition of this book, new infectious agents have been identified as human pathogens (Petersen et al., 2018). Much more is known about the mechanisms the body uses to defend itself against various pathogens. Both the biology of infectious agents and the human response to these agents have important implications for interpreting evidence of infectious disease in archeological human skeletal remains. For this reason, a summary is provided of current understanding regarding these mechanisms and their importance for research in human paleopathology. However, the reader should be aware that a comprehensive introduction to the defense of the body against infectious agents would fill the pages of a large book. Those interested in a complete review of the subject should consult a reference work on immunology (e.g., Janeway and Travers, 1994).

Humoral Versus Cellular Responses to Infectious Agents Exposure to microbes during childhood and having a healthy well-balanced diet are essential in developing and

Ortner’s Identification of Pathological Conditions in Human Skeletal Remains. DOI: https://doi.org/10.1016/B978-0-12-809738-0.00010-7 © 2019 Elsevier Inc. All rights reserved.

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maintaining a strong immune system throughout life (Gollwitzer and Marshland, 2015). While the first lines of defense for the body are physical barriers, such as the skin, it is the immune system of the body that is key to dealing with pathogenic organisms. This system includes all the biochemical, cellular, and vascular mechanisms used to defend against infectious agents. This system also participates in other biological processes that respond to trauma and disease, such as the elimination of body cells that have become cancerous. Further, there is a whole category of diseases, known as autoimmune diseases, caused by problems in the immune system when the control mechanisms fail to recognize normal body tissues and cells. There is a poorly understood link between infectious agents and the development of some autoimmune diseases, such as the erosive arthropathies (Harrison and Fleming, 2008) discussed in Chapter 20. Further, there is increased recognition of the link between poor health in early life, including infectious disease, and later adult health (Mirembe and Moffat, 2018). This connection is exemplified in the developmental origins of health and disease, originating in the Barker fetal origins/Barker hypothesis (Barker, 1992). Dental infections have also been linked to heart disease (Mattila et al., 2000), and paleopathological research is beginning to explore these links in skeletal remains through the analysis of dental calculus (Warinner et al., 2014). Two general categories of immunity have been identified, innate and adaptive (Sompayrac, 2015), and within the latter there are humoral and cellular-mediated immune responses. These two types of immunities interact in complex ways in response to a stimulus from an infectious agent. The humoral component of the immune system consists of a class of proteins known as antibodies. These proteins, known as immunoglobulins, are found in the plasma of blood. They interact with infectious agents by binding to the agent, by rendering it ineffective, or by coating the agent with a substance that is recognized by cells in the immune system that destroy the infectious organism (Janeway and Travers, 1994: 1 20, 22). Cellular or cell-mediated immunity is particularly important in the response to pathogenic agents like viruses that reproduce within normal body cells and are not recognized by humoral antibodies. The cells involved in this type of immunity are white blood cells or leukocytes. They are divided into two groups: (1) polymorphonuclear leukocytes and (2) mononuclear leukocytes. Subtypes within polymorphonuclear leukocytes are basophils, eosinophils, and neutrophils. Neutrophils and eosinophils destroy infectious agents and dead body cells. The specific function of basophils is unclear; however, the presence of histamine within the cell argues for a role in the allergic response to antigens such as pollen.

Mononuclear leukocytes are divided into monocytes and lymphocytes. Monocytes differentiate into macrophages, which eliminate infectious agents and dead or damaged body cells. Lymphocytes are subdivided into specialized cells. Some T lymphocytes destroy infected cells directly; other T-cells identify and label infected cells, enabling other white cells to eliminate the them. B-cells are another type of lymphocyte that, when exposed to an infectious agent, differentiate into plasma cells whose primary function is to synthesize antibodies specific for infectious agents.

Vascular Changes in Response to Infectious Agents The inflammatory response to infection begins as a vascular phenomenon (Burt and Fleming, 2008). The capillaries dilate and their walls begin to allow the escape of large molecular proteins and cells normally retained in the circulation. Albumins, globulins, and fibrinogen enter the tissue where fibrinogen is converted into fibrin. This is followed by active emigration of neutrophilic leukocytes, which are capable of ameboid motion and thereby can squeeze through the boundary between epithelial cells in the vascular wall. In the tissue they migrate, by chemotactic attraction, to the infectious focus. It is these leukocytes, in connection with proteins and fibrin, that make up the yellowish white pus of acute infections. Many leukocytes ingest bacteria by phagocytosis and may inactivate or destroy them; others succumb to bacterial toxins and disintegrate. The severity of the inflammatory response is proportional to the number and virulence of the infecting organisms. If the capillary leakage becomes severe, erythrocytes, which have no active mobility, may also enter the tissue in large numbers. Thus, it is customary to classify the inflammatory response by the type of exudate as serous, fibrinous, hemorrhagic, or purulent, reflecting the increasing severity of the infection. After the acute phase other cells, from the blood and from the tissue, participate in the inflammatory response. T and B lymphocytes and the differentiated B lymphocytes or plasma cells appear in increasing numbers in and around the lesion in the subacute and chronic phases of infections. Macrophages are mobilized and serve in cleaning up infected areas by means of phagocytosis of debris and of organisms. Multinucleated giant cells, thought by many to be specialized macrophages, may appear in this phase. The healing is mainly accomplished by proliferation of fibroblasts laying down collagen, which is the main constituent of scar tissue. In infections that have a component of allergic reactivity, particularly those caused by parasites, eosinophilic leukocytes may be prominent in the

Infectious Disease: Introduction, Periostosis, Periostitis, Osteomyelitis, and Septic Arthritis Chapter | 10

immediate inflammatory response. In viral infections, where the organisms propagate intracellularly and offer no opportunity for phagocytosis, the initial leukocytic response as well as the formation of pus are usually lacking. Lymphocytes, plasma cells, and macrophages dominate the picture even in the acute phase, mainly in response to the breakdown of infected tissue cells. Organisms that are difficult or impossible to control by the ordinary cellular defense mechanisms discussed previously produce the so-called granulomatous response to infection. Such organisms include the acid-fast mycobacteria of tuberculosis and leprosy, many of the fungi, and treponemal infections. In these infections, specialized monocytes, known as histiocytes, proliferate around the organisms and form nodular foci. Multinucleated giant cells phagocytose the organisms but often are not able to kill them. Thus, the center of the granuloma may undergo necrosis but harbor confined viable organisms for a long time. Lymphocytes, particularly plasma cells, border the granulomas, indicating the continued response to the infection.

The Biology of Infection In human populations of antiquity, generally about half the individuals born died before they reached sexual maturity, that is, before they transmitted their genes to the next generation. In late medieval Florence, Italy, one third of babies died in infancy (Carmichael, 1989). The major cause of this mortality was infectious disease, the single greatest threat to life. Of those living to adulthood, many died of the direct or indirect effects of infectious disease, but trauma became increasingly significant. Even among hunters and gatherers living today, infection of the digestive system results in the death of many infants and children (Froment, 2001). With the development of agriculture and its associated sedentary life, many more infectious diseases became endemic in human populations (Roberts, 2015). Civilization, with its high concentration of people in a limited area, brought with it the specter of death on a massive scale, with epidemics killing half or more of the inhabitants of a city. For the paleopathologist, one of the great sources of frustration is the fact that infectious diseases, particularly those that result in death, rarely leave behind any direct anatomical evidence of their existence in the skeletons of the individuals who die from them. There are many reasons for this lack of evidence, including people dying from acute infections before bony changes could occur, or the fact that most infections only affect the soft tissues anyway (Wood et al., 1992). This challenge can place great restrictions on the ability to investigate the biological effects of these diseases on past human populations. However, these issues increasingly are being overcome,

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as biomolecular analysis can now detect infections that only affect the soft tissues as well as those that killed a person in the acute stages (e.g., plague: Schuenemann et al., 2011). Yet some infectious conditions do affect the skeleton, and careful observation, recording, and analysis can reveal much about human adaptation in response to disease, and the coevolution of infectious diseases in humans and other animals. Recent developments in the recovery and analysis of DNA of pathogens from archeological human tissues have been highlighted in Chapter 8. These developments show great promise for the further clarification of the origin, evolution, prevalence, and history of infectious diseases in antiquity and their impact on recent human evolution. It is important to emphasize that infectious conditions affecting the skeleton tend to be subacute, chronic diseases and may not be the immediate cause of death. Furthermore, many of the chronic infectious diseases produce morphologically overlapping responses in skeletal tissue. These responses make specific diagnosis difficult, even in patients where many more of the variables of the disease state are known, and clinical practitioners have access to a wide range of diagnostic tests. There is, however, useful variation among different infectious diseases that affect the skeleton in the type of bone lesions and the distribution of these lesions within the skeleton. Therefore, while recording the presence of bone abnormalities (bone formation and destruction) forms the basis for eventual diagnosis, their distribution and characteristics are used to develop differential diagnoses (Ortner, 2008). In addition, increasingly it is considered to be important to record the nature of any new bone formation, that is whether healed or active. This information is particularly helpful in interpreting whether the causative infection was active at the time of death (e.g., see DeWitte, 2014). Inflammation in bone is a general response to one or more abnormal stimuli, including the presence of infectious agents, but other conditions, including trauma and cancer, can also invoke an inflammatory response in bone. When inflammation occurs in bone it can affect the inner or medullary surfaces of bone, the compact or cortical bone, and the soft tissue covering the outer surfaces of bone. Different terms are used to differentiate the primary sites of inflammation (Resnick and Niwayama, 1995a: 2326). Osteomyelitis is an inflammatory condition that begins in the marrow spaces of bone and primarily affects the inner (endosteal) surface. Osteitis is used to describe an inflammatory condition within compact bone. It is often associated with infection, but may be caused by other pathological conditions and needs an adjective such as “infective” or “suppurative” to restrict its meaning to infectious conditions. Periostitis/periostosis is an inflammation within the periosteum (membrane covering the

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bone) that will affect primarily its outer surface. Like osteitis, pathological conditions other than infection (where periostitis would be the word to use) can cause the bone changes visualized in the skeleton, including trauma, scurvy, rickets, hypertrophic pulmonary osteoarthropathy, leprosy, treponemal disease, scalping (see Weston, 2008, 2009, 2012), and also child abuse. Therefore, an additional modifier, that can be used would be infective or suppurative periostitis, which helps to limit the meaning of this term to infectious causes. We should also remember that new bone formation occurs in the normal growing skeleton, and therefore we must ensure new bone growth is not necessarily diagnosed as pathological in children’s bones (see Lewis, 2018: 132). These terms are useful particularly in a clinical setting, where diagnosis and treatment of bone disease can be affected by the location of the primary site of bone inflammation. Although these terms should be used to describe pathological conditions encountered in archeological skeletal remains, it is important to recognize that the primary site of an infection will not be apparent in many situations. Infection beginning in the bone marrow will often stimulate changes in compact or cortical bone and on its outer surfaces, and all other permutations may be encountered as well in archeological skeletal remains. Imaging techniques can be very helpful in establishing diagnoses of osteitis and osteomyelitis.

osteoarthropathy), a sunburst pattern where the new bone fans out from the focus (osteosarcoma), and a triangular elevation of layers of new bone (malignant tumor). To these categories one needs to add the additional variant of the quality and nature of the abnormal periosteal bone. Periostosis commonly stimulates the initial formation of woven bone (Fig. 10.1), which matures and later may become incorporated into the underlying cortex and remodeled into lamellar bone, indicating chronicity (Fig. 10.2). Woven bone always has a porous appearance and is a color distinct from the underlying cortical bone. The porous appearance is partially due to the irregular orientation and distribution of the mineralized collagen fibers, but it can also reflect the presence of increased vascularity penetrating the surface of the woven bone. In most of the infections discussed in Chapters 10 12, periosteal new bone formation is one of the significant changes seen in skeletons. First and foremost, inflammatory periostitis plays a role in infections of bone, specific

PERIOSTITIS OR PERIOSTOSIS Pathology Periostitis or periostosis? The former word is used most often in paleopathology to describe a reaction to “damage” to the periosteum and subsequent new bone formation. However, increasingly there is a developing tendency to use “periostosis” (e.g., see Klaus, 2017), because “periostitis” should only be used to refer to inflammation due to infection and it is well known that there are many causes of new bone formation beyond infection (see The Biology of Infection above). Periostosis usually represents part of, or a reaction to, pathological changes of the underlying bone. The inner layer of the periosteum retains osteoblastic capacity throughout life, even after termination of growth. It is, therefore, not surprising that the periosteum reacts to many different insults with formation of new bone. Again, it is extremely important to remember that periosteal new bone formation is not restricted to a response to an infection. Seven different morphological variants of periostosis are described, each of which may have multiple diagnostic options (Resnick and Niwayama, 1995b: 4435). These variants include a single layer of new bone (benign or malignant tumors, infection or hypertrophic

FIGURE 10.1 Woven bone on scapula.

FIGURE 10.2 Lamellar bone on a long bone.

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FIGURE 10.3 Periostosis resulting from a chronic ulcer of the lower left tibia. No data, MM 2288, access for study and photography provided through the courtesy of Paul S. Sledzik, National Museum of Health and Medicine, AFIP, Washington, DC.

and nonspecific (known and unknown specific causative organism, respectively). Obviously, transitory periosteal reaction, which neither leaves permanent bone deposition nor resorptive pitting of the underlying cortex, cannot be identified on dry bone. Unfortunately, there are no unequivocal characteristics that are limited to bone formed by infection. Generally, inflammatory periosteal bone deposited over a long period of time tends to be unevenly distributed, not involving the entire bone. The surface tends to be irregular and the thickness often variable. The marked, uneven hypervascularity visible on dry bone in the form of smaller and larger pores in the periosteal bone formed is often striking. In most cases, changes in the underlying bone will answer the question of what has caused the bone change, but a purely subperiosteal bone deposit may be difficult or impossible to classify.

Periostosis in Particular Parts of the Skeleton In areas where the periosteum is close to the skin surface, as on the anterior surface of the tibia, localized periostosis

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FIGURE 10.4 Active manifestation of periostosis related to a skin ulcer of the left tibia. Adult male, MM 2767, access for study and photography provided through the courtesy of Paul S. Sledzik, National Museum of Health and Medicine, AFIP, Washington, DC.

can be observed secondary to trauma. Such long-standing periosteal bone deposition can be completely incorporated into the cortex in the form of remodeled lamellar bone. Large chronic ulcers on the skin, especially those due to venous stasis, not uncommonly produce a reactive, local, ossifying periostosis on the tibia (Figs. 10.3 and 10.4). This may represent a plaque-like deposition of periosteal bone of considerable thickness, roughly copying the outline of the ulcer (Van der Merwe et al., 2009). Less commonly, the ulcer may stimulate a lytic response (Fig. 10.5). In later phases of the bony reaction to the ulcer, partial healing may occur and the abnormal bone surface can become relatively smooth (Fig. 10.6). Occasionally, such reactive bone deposits may bridge the gap between the tibia and fibula (see Fig. 10.6). Another example of focal bone reaction is massive reactive periosteal new bone formation (and destruction) of the mandible that used to be observed in the 19th century in people exposed to vapors of yellow and white phosphorus over long periods of time, and usually contracted by people who worked in the match-making industry (Fig. 10.7A; see Roberts et al., 2016 and Fig. 10.7B). The ribs can be affected similarly by periostosis, suggesting that a lower respiratory tract (lung) disease has

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FIGURE 10.5 Periostosis resulting from an overlying skin ulcer. Note the sharply defined margins of the lesion, which are virtually pathognomonic for an ulcer. No data, MM 3391, access for study and photography provided through the courtesy of Paul S. Sledzik, National Museum of Health and Medicine, AFIP, Washington, DC.

spread through the pleura to directly affect their visceral surfaces (Eyler et al., 1994: clinical study; Roberts et al., 1994 and Santos and Roberts, 2001: studies of skeletons from collections with documented causes of death; Lambert, 2002 and Nicklisch et al., 2012: archeological studies). A radiographic study of living people with lung diseases by Eyler et al. (1994) noted a thickening of the ribs, especially in people with tuberculosis, which suggests new bone formation. The studies of Roberts et al. and Santos and Roberts focused on documented skeletons. Both studies found a clear association with tuberculosis as a cause of death, but it was recognized that many different lung diseases could cause the bone changes (Fig. 10.8). The upper respiratory tract may also be affected (facial sinuses; Fig. 10.9) (Holgate and Frew, 2002). Inhalation of poor-quality air, whether due to particulates in the air or exhaled droplets containing infective organisms, can cause new bone formation on the sinus surfaces. Few paleopathological studies have focused on maxillary sinusitis, but those that have show an increased

FIGURE 10.6 Ossifying periostosis of a right tibia beneath a leg ulcer, synostosis of tibia and fibula. (Adult, WM S 47.1 before 1831.)

prevalence in urban contexts (Lewis et al., 1995; Merrett and Pfeiffer, 2000, Roberts, 2007; Digangi and Siranni, 2016). Even less has been written about middle ear and mastoid disease in the past, but it is undoubted that people had ear disease, including that caused by infections. For example, evidence of infection was found on ear bones in medieval skeletons with leprosy buried in a leprosy hospital cemetery in England (Bruintjes, 1990; see also Ziemann-Becker et al., 1994; Flohr et al., 2014; KrenzNiedbala and Lukasik, 2016). Mastoiditis has also been recognized (Flohr and Schultz, 2009). New bone formation on the endocranial surface of the cranium is also seen in archeological contexts (Fig. 10.10), although its etiology has been suggested to be multifactorial (e.g., see Lewis, 2004). While there have been suggestions that the reaction may be a response to meningeal infection, it is unlikely that a person in the past would have survived meningitis long enough for bone changes to occur.

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FIGURE 10.7 (A) Phosphorus necrosis of mandible with involucrum (IPAZ 1758, no date). (B) Phosphorus related destruction (necrosis) of the mandible with associated new bone formation (12 14-year-old child; 18th/19th century, Coach Lane, North Shields, Tyne and Wear, England).

FIGURE 10.8 New bone formation (outlined in white) overlying the normal and lighter color of the visceral surfaces of several ribs (archeological).

Paleopathology Although periostosis as an isolated disease process is uncommon in clinical literature and practice, undifferentiated, nonspecific periosteal lesions of long bones are among the most common abnormalities encountered in archeological skeletons. The main reason for this difference between clinical experience and paleopathology is that many periosteal reactions may be part of the expression of a specific disease process, which can be identified in a living patient, whereas in archeological skeletons the pathological characteristics necessary to make a specific

FIGURE 10.9 New bone formation in a maxillary sinus (archeological).

diagnosis are not accessible. However, it should be remembered that very subtle new bone formation is not readily visible on radiographs and thus is not part of the diagnostic repertoire of clinicians. It is important to emphasize that periostosis (as is also the case with osteomyelitis) has both a general descriptive usage and a discrete usage. Thus, periostosis can be part of a disease syndrome such as treponemal disease, but can also be a reaction to a specific disease itself. This varied usage of the term is well illustrated in Brothwell and Sandison (1967). The index to their work lists six references to periostitis/periostosis. Of these six, the term is used five times in the context of a syndrome associated

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FIGURE 10.10 New bone formation on the endocranial surface of the occipital bone (archeological).

with a specific disease, such as treponemal disease. Only once is the term applied to primary periostosis. Because we discuss secondary periostosis in the context of specific disease entities, the following discussion on the paleopathology of periostosis will focus on the primary type. However, the designation of primary periostosis in paleopathological skeletons may mean only that a more specific diagnosis is impossible and does not eliminate the possibility that the periosteal reaction is secondary to a specific disease process. Primary periostosis is most often the result of two pathological conditions, trauma and infection (Senn, 1886: 5 6). Putschar (1966: 60) notes that it is often impossible to determine which of these two conditions gave rise to a given lesion in an archeological skeleton. Whereas the periosteum will always be activated in a fracture, periosteal reactive new bone can also be stimulated by injury that does not lead to a fracture. The latter may resemble periosteal reactions stimulated by localized infectious foci. Trauma-related periostosis is the result of a sudden or chronic insult to bone. Wood-Jones (1910: 285 286) described periostosis of the skull being common in Nubian archeological skeletons. The initial lesion was characterized by hypervascularity either on or near the vertex of the skull. However, there were also small spicules of bone formed, and in the later stages the bone changes could be characterized by hypervascularity and, in extreme cases, exfoliation of portions of the skull. Wood-Jones attributed this periostosis to a chronic insult produced by women carrying water jars on their heads. This observation was supported by the fact that the lesion occurred much more often in female skulls, a finding that

should be tested with more data. Periosteal reactions of the skull are occasionally associated with trepanation; however, here the periostosis is probably due to the surgical procedure being complicated by infection. One of the most common sites of periostosis in archeological skeletons is the tibial diaphysis. There has been considerable speculation about the cause of the condition in this location, but the reasons for this localization remain obscure. It is, however, instructive to note that periosteal reaction in treponemal disease forms on bones that tend to be near the skin surface, such as the tibia and skull vault. Such bones may be somewhat cooler than bones like the femur, which are enclosed in a heavy mass of muscle and fat. It is also true that bones near the skin are more exposed to direct trauma than bones protected by overlying muscle. Perhaps both these factors are significant in the localization of periostosis. Periostosis has become an important index of health in publications of studies archeological skeletal remains. Although it is highly probable that the most common cause of periostosis is infection, we simply do not have a good basis for estimating what percentage of people identified with periostosis in an archeological skeletal sample is due to infection. This limitation, when added to others discussed in Chapter 2, needs to be given careful consideration. Despite these reservations, paleopathologists have used this pathological condition as a marker of a response to various types of “stress,” although “stress” has many definitions and is debated in more recent literature (Klaus, 2014; Reitsema and McIlvaine, 2014). Powell (1988) has used periostosis to investigate the effect of status differences on health in archeological skeletal remains. Larsen (1997: 82 93) summarizes the research of several osteologists who use the prevalence of periostosis as a variable to show the effect of various types of “stress” in archeological human populations. In both these studies a plausible case was made for the prevalence of periostosis rising in frequency as stressful conditions increased (see also Chapter 2 of Larsen 2015 devoted to this subject). The distinction between osteomyelitis and periostosis cannot always be made in dry bones. However, in periostosis there will be no cloacae, involucrum, or changes in the marrow cavity. Furthermore, pathological periosteal bone tends to be superficial to the normal cortex, at least in the early stages of the disease causing it. The superficial nature of periosteal lesions can be seen in two bones from Ossuary II at the Juhle Site near Nanjemoy, Maryland (NMNH 384380), dated to the 16th century. The secondary nature of the burials means that complete skeletons were not available for study. However, the two long bones in question, the left ulna and tibia, exhibit similar periosteal lesions and both are from an individual between 14 and 18 years of age.

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FIGURE 10.11 Periosteal reactive bone on the left ulna of an individual between 14 and 18 years of age. Some of the periosteal reactive bone was broken away postmortem, revealing the underlying cortex (arrow), which exhibits minimal changes—skeleton from an archeological site in Maryland. (NMNH 384380; scale in centimeters.)

Thus, the probability is high that the two bones came from the same individual. The periosteal reactive bone is superficial to the intact cortex (Fig. 10.11) and is porous woven bone rather than lamellar bone. There is no evidence of a cloaca or marrow involvement. Thus, a diagnosis of primary periostosis is justified. However, its cause remains elusive. In his study of pre- and post-Columbian Pecos Pueblo skeletal remains, Hooton (1930: 308 309) distinguished between periostosis and osteomyelitis. Although he did not give his criteria, Hooton diagnosed periostosis in 13 of 503 skeletons, a prevalence of 2.6%. There were four people with osteomyelitis, indicating that periosteal reactions were more common. Morse (1969: 17, 106 111) presents four prehistoric skeletons with periostosis in his monograph on paleopathology in archeological skeletons from the Midwestern United States. With the possible exception of Burial 42 from the Klunk Site in Illinois, this evidence appears to be secondary reactions to infection.

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One example of a nonspecific periosteal lesion is found in a skeleton (NMNH 308679) from the Hawikuh archeological site in New Mexico, dated archeologically to between AD 1200 and 1670. The woman was aged between 25 and 35 years of age. The preservation of the skeleton was excellent, with virtually all bones present except for some of the hand and foot bones. The skull is normal except for a slight amount of occipital flattening, dental caries, and the loss of the lower left second molar antemortem. There is a supernumerary premolar in the left mandible. The postcranial skeleton is also normal except for a bilateral, diaphyseal, cortical thickening of the tibiae (Fig. 10.12). The thickening is circumferential. The lesions of both tibiae are remarkably similar. The bone surface of both lesions is smooth except for a medial focus, where there is a slightly raised plaque adjacent to a region of longitudinal striations. The overall appearance of the lesion is one of a well-contained chronic process. There are no cloacae and no evidence of fracture. The original cortex of both tibiae has been partially remodeled near the main focus of the lesion. A somewhat greater amount of periosteal bone has developed on the lateral side, and it is on this side that the maximum cortical remodeling has taken place. The predominant lesion is periosteal and thus it is appropriately classified as periostosis. However, there is evidence of encroachment in the marrow cavity by bone reacting to the disease. This means that the focus of the lesion could have been the marrow cavity with secondary activation of the periosteum, as does occur in osteomyelitis. However, the superficial nature of the lesion and minimal medullary change make a periosteal origin somewhat more probable. A more active example of periostosis is seen in an archeological skeleton from the Canaveral Peninsula of Florida (NMNH 377457). The skeleton is an adult male approximately 30 years of age as estimated by pubic symphysis morphology. Osteoarthritic degeneration elsewhere in the skeleton is suggestive of a somewhat older age, but osteoarthritis can occur in young people, too. The presence of trade beads indicates a post-Columbian date for the site. The skull vault is normal, although the temporal portion of the temporomandibular joint exhibits considerable osteoarthritic degeneration. The mandibular portion of the joint is much less severely affected. The dentition is considerably worn, as is typical of this population, and there is evidence of at least two dental abscesses. The postcranial skeleton is incomplete. With the exception of severe osteoarthritic degeneration of the right elbow, there is no evidence of disease except for a lesion on the shaft of the right tibia (Fig. 10.13). This lesion begins at the midshaft and extends distally 10 cm. It involves both the medial and the lateral sides of the shaft and encompasses most, but not all, of the circumference. On the medial side, the lesion consists of fine porous bone with a

FIGURE 10.12 Bilateral midshaft thickening. (A) Left and right tibiae of an archeological skeleton from the site of Hawikuh, New Mexico. (B) A detailed view of the thickened midshaft of the left tibia; note the lack of any foci of active reaction. This lesion represents a healed periosteal lesion. (NMNH 308679.)

FIGURE 10.13 Right and left tibiae of a post-Columbian adult male skeleton from an archeological site in Florida. (A) Lateral view; note the presence of a porous, thickened lesion below the midshaft on the right tibia. The left tibia is normal. (B) Detailed view of the lateral aspect of the lesion on the right tibia. (C) Medial view of the right and left tibiae. The thickened area is less porous than the lateral aspect of the lesion. (NMNH 377457.)

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longitudinally striated appearance at the boundary with normal bone. Laterally the lesion has a more irregular surface but is still composed of fine porous bone. Posteriorly, there are two small isolated plaques of fine periosteal bone located distally to the main lesion. The overall appearance of the lesion suggests an active, but chronic, inflammation limited to a single bone of the skeleton. The location, morphology, and circumscribed nature of the lesion are suggestive of the bony reaction to an overlying skin ulcer. The radiograph of the two tibiae is of poor quality due to soil infiltration into the cortex and medullary cavity. There has been a slight degree of remodeling of the original cortex beneath the lesion, in which the lytic process predominates. There may have been slight encroachment into the medullary cavity by reactive bone, although the predominant disease process is periosteal. Periostosis may be unilateral or bilateral and, if bilateral, can be more severe on one side than on the other. An example of bilateral periostosis with marked differences in severity is seen in two femora of a skeleton from the Pecos Pueblo Site in New Mexico (Fig. 10.14). The

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site has an archeological date ranging between AD 1300 and 1838. The skeleton was from the collection of the Peabody Museum of Archaeology and Ethnology, Harvard University, but has been repatriated. The individual represented by the femora was a woman about 50 years of age when she died. Both femora have bone changes resulting from periostosis but the left femur had developed much more periosteal reactive bone. The crosssection of the left femur made at about one third the distance from the distal end demonstrated extensive pathological remodeling of the cortex that was composed of spongy rather than compact bone in much of the crosssectional area (Fig. 10.14B). This spongy cross-sectional appearance is a common condition found in the diaphysis of long bones affected by periostosis. Clearly, the inflammatory stimulus was much less severe in the right femur, and the resulting periosteal new bone formation has added only minimally to the normal compact bone surface. In neither bone is there any evidence of sequestration or a cloaca. There are also chronic expressions of periostosis on the humeri and on the left side of the skull. The most severely affected humerus is the right. In addition

FIGURE 10.14 Bilateral but not symmetrical periostosis of the femora. (A) Anterior view, showing enlargement of the left femur (right side) due to periosteal new bone formation on both diaphyses. (B) Reflected, cut surfaces of the distal left diaphysis. Note the enlarged and spongy character of the entire cortex that is particularly apparent on the medial side. Adult female more than 50 years of age from Pecos Pueblo, New Mexico, with permission of the Peabody Museum of Archaeology and Ethnology, Harvard University, Cambridge, Massachusetts, Catalog No. 60301; skeleton now repatriated.

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FIGURE 10.15 Right adult tibia from the Juhle Site in Maryland. This site is dated to the 16th century. (A) Medial view; note the large area of reactive bone on the medial side just distal to the midshaft (scale in centimeters). (B) Detailed view of the bony reaction to an overlying skin ulcer. Distal to this lesion is an additional periosteal reaction, which is not as well organized (arrow). (NMNH 384299.)

to the periostosis the right humerus is much longer (c. 13 mm) than the left. This size discrepancy may reflect an infectious condition during the growth phase that stimulated abnormal growth of the more severely affected humerus. An overlying skin ulcer can stimulate a localized periostitis, and the bony manifestations of this pathology are encountered in archeological human remains (see also Figs. 10.3 and 10.4). A good example of this condition is seen in the right tibia of a skeleton excavated from Ossuary II at the Juhle Site near Nanjemoy, Maryland (NMNH 384299). This site is dated to the 16th century. There is a large area of reactive thickening on the medial part of the bone just below the midshaft. This lesion measures 65 3 40 mm (Fig. 10.15A). There is a nodular thickening superior to this lesion and another area of reactive bone on the distal metaphysis (Fig. 10.15B). The sharply demarcated, thickened nature of the central lesion is characteristic of a bony response to a skin ulcer. In this case the ulcer appears to have been complicated by disseminated infection giving rise to the two other foci of periostosis. Two Old World skeletons also illustrate the presence of skin ulcers. The first of these is the left radius of an adult skeleton from the McArthur River area in Australia (Fig. 10.16). The archeological date is unknown and the skeleton is from the collections of the South Australia Museum in Adelaide, Australia. There are multiple

FIGURE 10.16 Possible evidence of a soft tissue ulcer that overlay the left radius in an Aboriginal skeleton from the McArthur River area in Australia. (No data, SAM A 11442.)

skeletal lesions in this skeleton that are probably due to some type of treponematosis. The lesion on the left radius shows one of the less common, destructive manifestations of skin ulcers. The central area of the lesion is a large cavity that has eroded much of the cortex of the radius. However, at the margin of the lytic focus, reactive bone has been formed, creating a slightly elevated rim of well-organized compact bone. This is indicative of a long-standing pathological process that may have been an additional complication of the systemic disease. The other Old World skeleton is an example of the more common, proliferative bone response to a skin ulcer. The burial is from the medieval site of the Hospital of St. James and St. Mary Magdalene in Chichester, England. The skeleton (Burial C-34) is part of the archeological human skeletal collection at the Department of Archaeological Sciences at the University of Bradford. The bone showing the response to an ulcer is the right tibia of an adult male (Fig. 10.17). The bone lesion demonstrates the well-defined margin between the pathological bone formation and the relatively normal diaphysis of the tibia. Within the bone lesion the surface is irregular and porous, which is indicative of active inflammation at the time of death.

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The result of such localized infections would be focal periosteal bone deposition around a partial cortical defect, with or without a small sequestrum, and with some sclerotic response in the vicinity. Such local infections may heal with sclerotic scarring around a depression. These scars may be effaced subsequently by remodeling, particularly when they occur in subadults.

Hematogenous Osteomyelitis

FIGURE 10.17 Reactive periostosis likely to an overlying skin ulcer. (Adult male, medieval site of the hospital of St. James and St. Mary Magdalene, Chichester, England, Burial C-34.)

OSTEOMYELITIS Pathology Osteomyelitis is most often the result of the introduction of pyogenic bacteria into bone. However, other infectious agents, including viruses, fungi, and multicelled parasites, can also infect bone marrow (Resnick and Niwayama, 1995a: 2326). The infectious agents may reach the skeleton by several different routes: (1) by direct infection through traumatic or surgical wounds, (2) by direct extension from adjacent soft-tissue infections, or (3) by the hematogenous route from a remote septic focus. The causative organism, in close to 90% of cases, is Staphylococcus aureus; the second in frequency is Streptococcus, with other infectious agents making up the remainder. Osteomyelitis secondary to wounds, open fractures, or surgery obviously can occur at any age and in any part of the skeleton. Infection initiated by trauma of some type may result in acute and chronic osteomyelitis, but it is more often limited and localized. This is also true of osteomyelitis secondary to adjacent soft-tissue infection. In such cases, infection may be limited to the periosteum and cortex and not spread through the medullary cavity.

Hematogenous osteomyelitis results when bacteria spread through the bloodstream from a distant source to the lesion. It runs a fairly typical course and shows distinct variations in frequency and appearance in different age groups (Trueta, 1959: 671 680; Putschar, 1976: 41 60). In Trueta’s (1959) study of over 200 individuals, 7% were infants, 80% children, and 13% adults. In preantibiotic days, the hematogenous osteomyelitis of childhood and adolescence made up an even greater percentage of the total. In this age group, there is a marked predominance of males over females with a ratio of at least 3:1. The sex difference in infant osteomyelitis is not marked and in adult osteomyelitis is less than in the juvenile form. In infancy and through to adolescence, hematogenous osteomyelitis greatly predilects the long bones of the extremities. In adults, the axial skeleton is more commonly affected (Resnick and Niwayama, 1995a: 2328). It is limited to one bone in 80% of cases; two or, rarely, more bones are affected in only 20% of people affected (Garre´, 1893: 276). The localization of juvenile hematogenous osteomyelitis is intimately related to the rate and time of growth of the various growth plates as well as the vascular supply associated with the various stages of growth in the long bone (Resnick and Niwayama, 1995a: 2330 2331). The infection almost always starts in the metaphysis near an actively growing plate. The distal femoral metaphysis, the proximal tibial metaphysis, the distal tibial metaphysis, and the proximal femoral metaphysis are mainly affected, in decreasing order. The femur and tibia together account for close to 80% of locations, followed by the humerus at about 10%. Other long bones of the extremities are less often affected, especially those of the hands and feet. The cancellous bones and the skull are affected least in hematogenous osteomyelitis (Wilensky, 1934: 276, 277). Acute hematogenous osteomyelitis begins with one or several purulent foci in a metaphysis, leading to lytic destruction of the newly formed spongiosa. The exudate spreads through the marrow cavity, increasing the pressure within the rigid confinement of the diaphysis and resulting in more or less extensive necrosis of the cortex by means of vascular compression. In the metaphysis, near the growth plate, the thin remodeling cortex permits

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FIGURE 10.18 Osteomyelitis of distal right femur. (A) Anterior view, showing smooth total sequestrum with involucrum above and below the living bone. (B) Posterior view, showing destruction of the metaphysis and proximal diaphysis; notice the jagged border of the sequestrum at the junction with the living bone. (About 10 years of age, WM HS 44.5 from 1841.)

easy extension of the exudate under the periosteum. The active osteogenic periosteum of the child readily strips itself from the cortex, permitting the formation of a subperiosteal abscess and depriving the diaphyseal cortex of its external blood supply. This results in circumferential lesions (Fig. 10.18) and sometimes total necrosis of the diaphysis (Fig. 10.19). The dead bone becomes the sequestrum, which can only be resorbed or remodeled if small. Large sequestra remain and maintain the infection if they are not extruded through sinuses/cloacae or removed by surgical intervention. The elevated periosteum continues to produce bone, forming a shell of hypervascular bone surrounding the sequestrum (Fig. 10.20). This enveloping reactive bone formation is called the involucrum and serves as a scaffold for ultimate repair. The metaphyseal bone usually does not undergo total necrosis because of the easy escape of the exudate through the thin, porous cortex. The separation of living bone and sequestrum takes place in this area by means of osteoclastic resorption (Fig. 10.21). The subperiosteal pus seeks escape through the involucrum and through the surrounding soft tissue to the skin surface, causing large, round cloacal openings in the involucrum (Fig. 10.21B), often exposing parts of the sequestra to view (Fig. 10.22). Sinuses between the infectious focus and the skin surface develop to provide pathways for the discharge of pus and fragments of dead bone (sequestra).

FIGURE 10.19 Osteomyelitis of right femur with total diaphyseal sequestrum, involvement of both metaphyses, and involucrum; epiphyses missing. (A) Anterior view. (B) Posterior view (About 14 years of age, FPAM 837.)

FIGURE 10.20 Chronic osteomyelitis of the tibia. Involucrum with large cloacal opening exposing cortical sequestrum. (IPAZ 1782.)

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FIGURE 10.21 Osteomyelitis of the distal right tibia. (A) Massive involucrum exposing sequestrum (arrow) in a large opening. (B) Porous involucrum with multiple cloacal openings (arrows). (HM P618)

FIGURE 10.22 Osteomyelitis of the left tibia following slight injury of 18-months duration. Notice the massive hypervascular involucrum exposing large sequestra in large cloacal openings and periostosis of the fibula. (Adolescent, WM HS44.6 from 1851.)

299

The epiphysis in the growing child is relatively protected by the growth plate and by the fact that its vascular supply does not communicate with that of the metaphysis and diaphysis. For this reason, extension into the epiphysis and the adjacent joint is uncommon in that age group. An exception is the hip and, to a lesser extent, the shoulder joint, where part of the metaphysis is located within the articular space. However, in long-standing or recurring osteomyelitis the adjacent joint may become involved at any age and terminate with bony ankylosis (Figs. 10.23 10.25). In the active phase of the disease, the growth cartilage may be partly destroyed. Epiphysiolysis (Fig. 10.26) used to occur in up to 15% of people (Garre´, 1893: 287). Pathological fractures, mostly through the area of demarcation between living and dead bone, and rarely through the involucrum, have been observed in 8% of people with the condition (Garre´, 1893: 293). The endosteal process of lytic destruction was followed by reactive sclerosis, limiting the intraosseous infection to local areas (Figs. 10.27 and 10.28). The combination of these various phenomena over a period of months, years, and, sometimes, decades results in a great variety of pictures that defy detailed description. However, the common characteristics are the presence of sequestra, porous hypervascular periosteal new bone, and

FIGURE 10.23 Chronic osteomyelitis of the left tibia with involvement of the proximal epiphysis and partial bony ankylosis of the knee in flexion. Notice cloacal openings, involucrum, and sequestrum. (12 years of age, FPAM 4948 from 1888; scale in centimeters.)

FIGURE 10.24 Chronic osteomyelitis of the right tibia with ankylosis of the ankle joint, involvement of the talus, and periostosis of the fibula. Notice massive involucrum with multiple cloacae exposing sequestra. (About 20 years of age, FPAM 358 from before 1817.)

FIGURE 10.25 Chronic osteomyelitis of the right femur with bony ankylosis of the knee and disuse osteoporosis of the tibia; two fistulae draining a large periosteal abscess were found at autopsy. (A) External view. (B) Cut surface. (58-year-old male, IPMI KM 180, autopsy 4802, annual 249 from 1898.)

FIGURE 10.26 Chronic osteomyelitis of the right tibia with slipped distal epiphysis and ankylosis of the ankle joint, resulting in deformity of the foot. (17-year-old female, PMUG 3239, autopsy 8278 from 1877.)

FIGURE 10.27 Chronic osteomyelitis of the left femur. (A) Medial, outside view, showing remodeled periosteal reactive bone and cloaca. (B) Cut surface and lateral view, showing sclerotic remodeled involucrum, central sequestrum, and multiple cloacae. (ANM 2950.)

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FIGURE 10.28 Chronic osteomyelitis and periostosis of the left femur, showing cancellous bone filling the medullary canal around residual abscess cavities. (34-year-old male, IPAZ surgical specimen 1515/36).

cloacal openings. Because dead bone is not easily attacked by osteoclasts, large sequestra may exhibit a smooth surface but with a jagged border at the line of separation (Fig. 10.29). Mortality from this disease used to be at least 20%. In many instances, the disease remained active for a long time; in others it healed temporarily only to recur years later; others healed permanently. A rare form of osteomyelitis that is known as sclerosing osteomyelitis of Garre´ (1893: 257 263) shows a less severe course, but with the formation of considerable periosteal and endosteal bone. Necrosis and sequestration are rare, as is a purulent discharge (Resnick and Niwayama, 1995a: 2327), which means that cloacae are unlikely (Fig. 10.30). In the absence of sequestra and of cloacal openings entering the medullary canal, differentiation from tertiary syphilis is difficult or impossible (Fig. 10.31). Some cases result only in the formation of a local abscess (Brodie’s abscess) (Figs. 10.32 and 10.33), usually near the growth plate in the metaphysis and surrounded by sclerotic bone. The collateral hyperemia, not uncommonly, results in excessive longitudinal growth of the affected bone if the growth plate (Fig. 10.34) is not destroyed. The epithelium of the sinus tract may undergo a

FIGURE 10.29 Sequestrum, midshaft tibia. Notice the very irregular ends of the compact bone. (Child, 8 years of age, HM P614.)

malignant transformation in some cases of chronic osteomyelitis, giving rise to epidermoid carcinoma (Fig. 10.35). The time span between the onset of osteomyelitis and the development of cancer tends to be between 20 and 30 years (Resnick and Niwayama, 1995a: 2361).

Infant Osteomyelitis This disease exhibits some differences from juvenile osteomyelitis. It used to be uncommon in the pre-antibiotic period because most infants succumbed to septicemia before osteomyelitis was established (Green and Shannon, 1936). The growth plate separating the epiphysis from the metaphysis does not become established until after infancy. Thus, the barrier provided by the growth plate to infectious agents does not exist and the ends of the long bones as well as the developing joint can be affected (Trueta, 1957: 360 366; Resnick and Niwayama, 1995a: 2331). In

302 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 10.32 Brodie’s abscess of the right distal tibia. (Adult male, PMSG 9/8.39D.) FIGURE 10.30 (A) Chronic sclerosing osteomyelitis of the left tibia, showing central lytic cavities and medullary sclerosis; marked, mostly anterior, periosteal bone deposition. Notice absence of sequestra and cloacal openings. (About 17 years of age, IPMI KM 187; scale in centimeters.). (B) Possible example of sclerosing osteomyelitis of Garre´.

FIGURE 10.31 Sclerosing osteomyelitis and periostosis of the left femur, probably nonspecific but, in the absence of sequestra and cloacae, treponematosis cannot be excluded. (A) Cut surface (KM 133c) and outside surface (KM 133c). Sclerosing osteomyelitis and periostosis of the left femur, probably nonspecific but, in the absence of sequestra and cloacae, treponematosis cannot be excluded. (B) Detail of periosteal surface. (Adult, no data, IPMI KM 133c.)

FIGURE 10.33 Brodie’s abscess of the right proximal tibia. (No data, PMES 1.EB.16.(3).)

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FIGURE 10.34 Bones of both lower legs. Chronic osteomyelitis of the right tibia with elongation and ankylosis of the ankle joint, with periostosis of the fibula. (53-year-old female, FPAM 5217, autopsy 91835 from 1892.)

infantile osteomyelitis, massive sequestration is unusual because the thin, loosely structured cortex permits escape of pus without raising the intramedullary pressure to critical levels. However, extensive development of the involucrum does occur in infant osteomyelitis and later may fuse with the underlying cortex (Resnick and Niwayama, 1995a: 2331). If the infection is somehow contained and eliminated, the potential of bone repair during infancy and early childhood is remarkable. As osteomyelitis heals, rapid remodeling removes much of the evidence of the disease, for in the rapidly enlarging bone the entire old cortex is removed as the bone grows in diameter. In one remarkable modern instance, the major portion of the tibia was completely regenerated after surgical removal of a large sequestrum in which the periosteum was preserved (Fig. 10.36).

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FIGURE 10.35 Squamous cell carcinoma of the left tibia secondary to chronic osteomyelitis. Notice the extensive destruction and pathological fracture of the tibia and periostosis of the fibula. (45-year-old male with osteomyelitis since childhood, PMES IVNa 16(4).)

Adult Osteomyelitis Adult hematogenous osteomyelitis is rare and may often represent continued or recurrent juvenile osteomyelitis. New infections also predilect the metaphyseal areas of the long bones, especially the femur and tibia. The inflammation is less acute and less extensive. Sequestra tend to be small. The firm attachment of the periosteum prevents extensive stripping, but local subperiosteal abscesses and sinuses are common. Following closure of the growth plate, communication of metaphyseal and epiphyseal blood vessels is re-stablished to some extent, which means that involvement of the epiphysis and of the adjacent joint is not unusual.

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FIGURE 10.36 Acute osteomyelitis of the left tibia. (A) Tibial diaphyseal sequestrum, extracted from the fistula. (B) Radiograph 1 year later, showing complete regeneration of the tibia. (2-month-old African child, WM S44.6, from 1963.)

Hematogenous osteomyelitis caused by infectious organisms other than Staphylococcus and Streptococcus should be briefly discussed. About 1% of patients with typhoid fever, regardless of age, develop osteomyelitis (Murphy, 1916). The main locations are the ribs, tibia, and spine. The tibial lesion often is a diaphyseal subperiosteal abscess involving the underlying cortex. The spinal lesion predilects the lumbar segment and often involves two adjacent vertebrae and the intervertebral disk between them. Today, in infants and small children, Haemophilus influenzae is a significant cause of osteomyelitis (Resnick and Niwayama, 1995a: 2327). In various hemoglobinopathies, especially sickle cell anemia, complicating Salmonella osteomyelitis is not uncommon (Hook et al., 1957: 403 407; Golding et al., 1959: 711 718). Multiple bones are affected in about two thirds of these cases. Long bones are predilected, but about 25% of the patients show involvement of the bones of the hands and feet. There are usually no major sequestra and periosteal reactive bone is sparse (Putschar, 1976: 49).

CHANGES IN SPECIFIC BONES The overall description of hematogenous osteomyelitis given previously mainly focuses on changes in the long

FIGURE 10.37 Osteomyelitis of the skull. (Adult male, 24 years of age, PMSG 9/361 H.)

bones of the extremities. A discussion of the peculiarities of osteomyelitis in different parts of the rest of the skeleton is therefore required.

Skull Primary osteomyelitis of the skull is rare (Figs. 10.37 and 10.38). However, the usual expression is extension of an empyema of the frontal sinus into the frontal bone. The structure of the diploe¨, with its interconnecting large vascular channels, permits spread of the infection through the cranial vault. Sutures may act as a temporary barrier, but extension into the parietal bone is not uncommon. The occipital bone is usually spared. Osteomyelitis of the skull base, originating from an empyema of the sphenoid sinus, is even more rare. Of more importance is traumatic osteomyelitis of the cranial vault following open wounds or blunt trauma, with or without fracture and surgical intervention. As noted briefly in Chapter 9, this occurrence is particularly pertinent to the problems of archeological trepanation and the custom of scalping. Infection, spreading from the intact scalp or through an open wound into the periosteum and bone of the cranial vault, tends to remain localized. The course of infection often is protracted,

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FIGURE 10.38 Osteomyelitis of the right parietal bone. (Adult male, 50 years of age, IPAZ 4205.)

eliciting a sclerotic response around a central, partly lytic, area around a sequestrum. The lesion usually is larger on the outer than on the inner table. Even direct infections of the opened diploe¨ tend to remain circumscribed and take a chronic course with considerable perifocal sclerosis. Infected compound fractures may become the source of spread for osteomyelitis of the cranial vault, extending along the many venous channels of the diploe¨. In some instances, avascular necrosis of fracture fragments is followed by infection in and around the dead bone. For a detailed discussion of traumatic osteomyelitis of the skull, see Adelstein and Courville (1933). Localized, often chronic, and sclerotic osteomyelitis secondary to middle ear infections occurs in the mastoid process, and the temporal and the petrous bones. Occasionally, ear infections spreading to the venous sinuses or meninges may lead to cranial osteomyelitis (Figs. 10.39 and 10.40). The jaws of infants and small children, which are crowded with dental buds, may become infected from the mucosal surface or through the bloodstream. In the course of the infection, dental follicles may be sequestrated and extruded through mucosal ulcerations. Extension of the infection into the floor of the orbits before formation of a maxillary sinus is not uncommon. After 2 years of age, the infection is much more common in the mandible (Lauche, 1939: 37). Baranoff (1934) reports that the mandible was affected in 91% of maxillae in 9% of the people studied in a Chinese series, most of which were in

FIGURE 10.39 Osteomyelitis of the posterior portion of the skull secondary to chronic left middle ear infection and streptococcal meningitis. (A) Endocranial view, showing lytic foci in sulcus transversus. (B) Ectocranial view, showing corresponding defects of the outer table. (67year-old male, PMES 1E.B.1(2a).)

the young adult age range (16 30 years). The preponderance of mandibular infections remains throughout the adult period due to extension from oral, dental, and periodontal infections. The course is usually very chronic, revealing little pus formation and no sequestrum. The condition is dominated by osteosclerotic condensation (periapical inflammatory disease due to a dental related infection), with or without thickening of the mandible (Panders and Hadders, 1970). The changes can simulate Paget’s disease;

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however, the typical mosaic pattern of Paget’s disease is not found microscopically. Other facial bones may be affected by extension of the infection to the paranasal sinuses or the facial soft tissues.

Spine

FIGURE 10.40 Osteomyelitis of the cranial vault secondary to chronic ear infection and streptococcal meningitis, showing disseminated lytic foci of the inner table along the branches of both middle meningeal arteries. (67-year-old male, PMES 1E.B.1(2).)

Vertebral osteomyelitis is uncommon, amounting to about 2% of all people with osteomyelitis (Schmorl and Junghanns, 1971: 389). It occurs more often in adults than in children (Kulowski, 1936: 343 344). In contrast to tuberculosis, only one vertebra is usually affected, as seen in 75% of affected people in one study (Donati, 1906: 1132 1133). The frequency in the spine increases distally. Lauche (1939: 39) estimates cervical, thoracic, and lumbar involvement at a ratio of 1:2:3. The first and second cervical segments are very rarely affected. As far as the location within the vertebra is concerned, in contrast to tuberculosis, the spinous process and neural arch are often involved. The infection may even be limited to the neural arch and/or spinous process: 66% (Donati, 1906: 1133); 58% (Volkmann, 1915: 485). The transverse process is rarely affected. In destructive spinal osteomyelitis, collapse of a vertebra is not uncommon. In multiple involvement of adjacent vertebrae, some of the intervertebral disks are usually better preserved than in tuberculosis, but they may show bony bridging (Junghanns, 1939: 325 326). Destruction of several adjacent vertebrae may result in angulation of the spine, which may be indistinguishable from the deformity of the spine seen in tuberculosis (gibbus). Paravertebral abscesses can occur and may elicit reactive periosteal bone formation.

Short Tubular Bones Phalanges, metacarpals, and metatarsals are uncommon sites of osteomyelitis. However, in young children hematogenous infections in these rapidly growing bones do occur and lead to rapid destruction of the thin cortex and formation of a massive expanded involucrum, resembling the spina ventosa in tuberculosis and similar changes in congenital syphilis (Fig. 10.41). Adult phalanges, especially of the toes, are more often involved in cases of peripheral vascular disease secondary to skin ulcerations. These cases resemble the features of chronic adult osteomyelitis in other bones (Fig. 10.42). A common cause of osteomyelitis of the hand is injury caused by bites and striking the teeth of another person with the fist (Resnick and Niwayama, 1995a: 2357).

Cancellous Bones FIGURE 10.41 Radiograph of hematogenous staphylococcal osteomyelitis of the first metatarsal, with a large involucrum of the diaphysis. (3-year-old male, surgical specimen MGH 7737 1970.)

These bones are rarely involved in osteomyelitis but, when they are affected, the process locates in the area with the most cancellous bone: the scapulae (Fig. 10.43), and the iliac crest of the pelvis (Fig. 10.44), the sacrum,

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FIGURE 10.42 Osteomyelitis of the basal phalanx of the right big toe with an involucrum and sequestrum along with periostosis, secondary to infected wound. (Adult, PMES 1 EB18 (100).)

FIGURE 10.44 Chronic osteomyelitis of the right ilium with right sacroiliac ankylosis and septic arthritis of the right hip, 3-years duration. (A) Anterior view showing ankylosis of the sacroiliac joint. (B) Lateral view. (17-year-old female, FPAM 5636.)

FIGURE 10.43 Osteomyelitis of the right scapula, posterior view. (Adult male, 46 years of age, PMES 1.EB.8.(101).)

and the lateral wing. Pelvic osteomyelitis may localize in the acetabular roof, secondary to septic arthritis of the hip or around a ruptured pubic symphysis in puerperal septicemia (Putschar, 1931: 91, 92). Ribs account for about 2% of osteomyelitis. The infection is usually located near the junction with the cartilage or posteriorly at the angle. There is usually no sequestration (Lauche, 1939: 39).

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PALEOPATHOLOGY OF OSTEOMYELITIS

The Skull

In historical times, before the availability of antibiotics, osteomyelitis was a common clinical condition well known to physicians of the period. This would suggest that osteomyelitis might be common in archeological skeletons, too. However, there are few references to this disease entity in the literature on paleopathology. Hooton (1930: 309) reports four individuals with osteomyelitis in a total sample of 503 pre- and post-Columbian New World Pueblo Indians (0.8%). Wood-Jones (1910: 283), in his report of disease in ancient Egyptian skeletons, states that inflammatory conditions of bones were very rare. Even in open fractures, where osteomyelitis was such a dreadful sequela in historical times, evidence for purulent infection in Egyptian skeletons was very limited. Wood-Jones (1910: 283) concluded that the ancient Egyptians had a much greater resistance to infectious diseases of bone than Europeans of his day. However, this conclusion may reflect inadequate or biased sampling of the European population, because Wood-Jones, as an anatomist, probably would have based his observation regarding the prevalence of European osteomyelitis on its frequency in dissecting room cadavers. This source does not provide a human sample comparable with an ancient Egyptian skeletal sample. Although osteomyelitis may have been a common ailment in early-20th-century medical practice, particularly in poorer, working-class people, this does not mean that the prevalence of the disease in the general population was high. This is evidenced by the League of Nations epidemiological report for 1921 (1922), which does not include osteomyelitis as a significant disease entity. Thus, in an archeological skeletal sample, the prevalence of osteomyelitis might be low but not differ significantly from a "peasant" population today or one in a developing country. Both osteitis and periostosis are descriptive terms in the paleopathological literature used to describe inflammatory conditions that could include osteomyelitis. By definition, osteomyelitis is an infection of bone involving the marrow. Although this may be a helpful concept in the differential diagnosis of osteomyelitis in archeological skeletons, it should be emphasized that clear evidence of marrow involvement may not be revealed in a bone. It is due to such problems in diagnosis that scholars, reporting on lesions in archeological skeletons that could be osteomyelitis but are not clearly so, tend to avoid identifying a lesion as osteomyelitis unless there is other evidence such as a cloaca or sequestrum to support this conclusion. Thus, many diffuse periosteal lesions possibly arising from osteomyelitis will not be attributable to this specific disease.

Wood-Jones (1910: 283) notes that dental disease accounted for almost all of the infectious conditions seen in skulls and mandibles. This conclusion is supported by the clinical studies of Wilensky (1932: 197) and Blum (1924: 802). In ancient Nubian skulls, Wood-Jones (1910: 283 284) reported bony destruction in the nasal and palatal regions of a young female who had worn and carious teeth. He attributes the destructive process to chronic rhinitis. Hooton (1930: 310) reports three crania with inflammatory lesions in which a diagnosis of osteomyelitis is possible; however, treponematosis is also a differential diagnosis. Roney (1966: 102) reports two examples of bones with osteomyelitis in a sample of 44 skeletons recovered from the pre-Columbian Pueblo Indian site at Mesa Verde, Colorado. The bones involved include the mandible, ulna, femur, and tibia. Infectious conditions of the mastoid region have been also reported in ancient Nubian skulls by Wood-Jones (1910: 284). Although a more detailed treatment of infection arising from dental disease is presented in Chapter 21, brief mention is appropriate here regarding the relationship of dental caries to systemic infection affecting bone. One possible example of this condition occurs in the skeleton of a young child in the skeletal collections of the National Museum of Natural History, Smithsonian Institution, Washington, DC (NMNH 379345). The child was buried at a site in Virginia and is dated to around AD 1550. In the left maxilla there is a periapical abscess which has destroyed bone adjacent to the root of the first deciduous upper left molar on the buccal side (Fig. 10.45A). A zone of periosteal reactive bone extends beyond the lytic focus for 1 2 cm. There is clear evidence of caries in the deciduous second molar that exposed the pulp cavity, leaving no doubt regarding the initial focus of the infectious process. The long bones of the skeleton show extensive development of periosteal reactive bone indicative of a disseminated inflammatory condition (Fig. 10.45B D). Although it could be that the infectious condition of the maxilla and the inflammatory reaction in the long bones are unrelated, it is possible that the maxillary infection was the initial focus for hematogenous dissemination of the infectious organism. Such a condition could have stimulated a general, periosteal response before the child succumbed to this or other problems. There are also increasing links being reported between dental disease (e.g., periodontal disease and caries) and systemic infections in skeletal remains (Xiaojing et al., 2000).

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FIGURE 10.45 Possible disseminated hematogenous osteomyelitis. (A) Large abscess of the first deciduous upper left molar in the skull of a child about 6 years of age; note the presence of a broad zone of reactive bone (arrow) on the maxilla peripheral to the abscess. (B) Periosteal reactive bone predominantly in the metaphyseal areas of the major long bones (scale in centimeters). Possible disseminated hematogenous osteomyelitis. (C) A central lytic focus (arrow) surrounded by periosteal reactive bone in the proximal right ulna. (D) Extensive accumulation of periosteal reactive new bone in the metaphyseal region of the posterior, distal, left humerus. (NMNH 379345.)

Postcranial Osteomyelitis The best diagnostic evidence for osteomyelitis in skeletal remains is a drainage canal in bone (cloaca) or sequestration in association with periosteal bone formation (involucrum). Lacking this, inflammatory lesions of the long bones are difficult to attribute to osteomyelitis. WoodJones (1910: 287) reports on an ancient Nubian humerus with a necrotic distal portion associated with a superficial layer of inflammatory bone. He attributed this to an infectious complication of an injury. Hooton (1930: 308) found 13 of 503 Pueblo skeletons had nonspecific periostosis, some of which could have been affected by osteomyelitis. However, he did identify four individuals that he judged to definitely have osteomyelitis (Hooton, 1930: 309). Cressman and Larsell (1945: 332) reported probable osteomyelitis in a prehistoric native skeleton from Oregon. The right arm was

fused at the elbow and the left tibia, tarsals, and metatarsals were also fused together. They attribute this condition to osteomyelitis acquired during childhood. The infection resulted in septic arthritis. Jarcho et al. (1963) published their observations on a pre-Columbian Pueblo skeleton from Arizona, where the left femoral head was fused to the innominate bone. They suggest the possibility that this condition is septic arthritis with ankylosis following infection, possibly of pneumococcal, gonococcal, staphylococcal, or streptococcal origin. There is reported evidence of osteomyelitis of the left tibia in an individual from a medieval site in the Czech ˇ ˇ ´ and Stukavec, Republic (Cerny 1993). The bones available for study were limited to the left femur, tibia, and fibula. The authors recognize the limits in estimating age and sex, but suggested that the bones were from an older adult man. The tibia exhibits two cloacae and extensive periosteal bone formation at its proximal end. The knee joint had evidence

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of extensive destruction of the cartilage and reactive new bone formation suggestive of septic arthritis secondary to the chronic infection of the tibia. In the skeletal collections of the National Museum of Natural History, Washington, DC, there are several archeological skeletons with lesions which could appropriately be attributed to osteomyelitis. One example where this diagnosis is certain is the incomplete skeleton of a juvenile from Peru (NMNH 378243). All that was recovered of this skeleton was the right and left tibiae, both of which are in an excellent state of preservation. The estimated age, based on the length of the normal right tibia, is 9 years. Unfortunately, the archeological provenience is poorly documented, but it seems likely that the skeleton is pre-Columbian. The two tibiae differ dramatically in size (Fig. 10.46). The measurements in Table 10.1 indicate the marked

increase in size of the pathological left tibia in contrast with the normal right tibia. Osteomyelitis results in hyperemia, which may stimulate excessive growth in the affected bone as long as the growth plate is not affected. This effect of the disease is clearly seen in the two tibiae of this skeleton. The excessive growth of periosteal involucrum is the result of pathological stimulation in response to necrosis of the cortex. This problem does not exist at the growth plate where excessive longitudinal growth was stimulated by general hyperemia associated with chronic inflammation. Whereas the proximal growth plate of the pathological left tibia is enlarged, the surface appears normal, although there is a postmortem break present. There is a cloaca one centimeter below the growth plate, but it does not penetrate it. The distal medial cortex of this bone has a large, FIGURE 10.46 Osteomyelitis of the left tibia compared with the normal (right) tibia of a child about 9 years of age from an archeological site near La Oroya, Peru. (A) Anterior view; note the sequestrum (arrow) and cloacae. (B) Detail of sequestrum and cloaca (arrow) in left tibia. (C) Medial view of pathological and normal tibiae. Large channel penetrates the distal growth plate (arrow). (D) Detailed view of channel penetrating the distal growth plate of the pathological tibia. (E) Posterior view of pathological and normal tibia. (F) Anteroposterior radiograph of pathological and normal tibiae; note the presence of Harris lines in the normal tibia (arrows). (G) Mediolateral radiograph of pathological and normal tibia. The cortex, which was sequestrated at the onset of the disease, is apparent (arrows) but is completely surrounded by an involucrum, which forms the externally visible cortex. (NMNH 378243; scales in centimeters.)

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FIGURE 10.46 (Countined)

TABLE 10.1 Metric Comparisons of the Right (Normal) and Left (Pathological) Tibiae in Osteomyelitis From a 9-Year-Old Child From an Archeological Site Near La Oroya, Peru (NMNH 378) Left

Right

Measurement

(mm)

(mm)

Maximum length

219

196

Maximum midshaft diameter

34

17

Mediolateral diameter of proximal growth plate

50

45

cloacal opening with a sinus penetrating the distal growth plate. There is also some postmortem damage. The cloacal sinuses penetrate into the marrow space and are lined with smooth compact bone, indicating a long-standing chronic condition. The proximal metaphysis of the left tibia contains a cloaca in the anterior cortex. There is a small bony spur on the lateral anterior cortex, which is a localized periosteal reaction. The distal metaphysis has a cloaca on the medial aspect, which is continuous with the opening in the growth plate mentioned previously. The diseased shaft contains a sequestrum, which projects through a large cloaca on the anterior shaft (Fig. 10.46B). There is a smaller

(5 mm diameter) cloaca inferior to the large cloaca. Both of these openings are part of a single channel that contains the sequestrum. There is a small lytic pit near the sequestrum and a cloaca in the posterior portion of the distal shaft. The radiographic appearance of the diseased left tibia shows a greatly thickened, but porous, involucrum. The old sequestrated shaft is still apparent, although the cortex of the metaphyses has been removed by remodeling. The diameter of the necrotic shaft is compatible with that of a 4 5-year-old child. Because sequestration would most likely have occurred shortly after the onset of the disease, this suggests that the child experienced osteomyelitis for about 5 years before death. In the lateral radiograph of the osteomyelitic tibia, there appears to be another, much smaller, sequestrum in the distal anterior cortex (Fig. 10.46G). Grossly, there is an expansion in this area but no cloaca. There are other radiographic features also suggesting sequestra, but their identification on the radiograph is less clear cut. A comparison of Harris lines also offers some insight into the disease process. In the normal (right) tibia there are four distinct lines in the distal and three in the proximal ends. The osteomyelitic tibia contains two distinct Harris lines and two much less distinct lines, all in the distal part of the tibia, which may correspond to the four distally located lines seen in the normal tibia. There is no evidence of Harris lines in the proximal end of the pathological tibia. If they existed, the disease has obliterated

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TABLE 10.2 Distance (in Millimeters) Between the Harris’ Lines for the Right (Normal) and Left (Pathological) Tibiae of NMNH 378243 (Lines 1 and 4 are Indistinct in the Left Tibiae, Making the Associated Measurement Somewhat Speculative as Emphasized by the Question Marks) Left

Right

Harris line

(mm)

(mm)

First to second

20 (?)

18

Second to third

27

21

Third to fourth

6 (?)

3

Total

53

42

TABLE 10.3 Distance (in Millimeters) Between the Distal Harris Lines and the Distal Growth Plate of the Right (Normal) and Left (Pathological) Tibiae of NMNH 378243 (Lines 1 and 4 are Indistinct in the Left Tibia, Making the Associated Measurement Somewhat Speculative as Emphasized by the Question Marks) Left

Right

Harris line

(mm)

(mm)

First to growth plate

63 (?)

50

Second to growth plate

42

32

Third to growth plate

15

10

Fourth to growth plate

8 (?)

3

the radiographic evidence. Table 10.2 shows the distances between the Harris lines in both distal tibiae. Because the distances between all Harris lines are greater in the osteomyelitic tibia, it would appear that accelerated growth has characterized all stages of the disease process. Table 10.3 shows the distances between the distal Harris lines and the growth plate. In every case, the distance is greater in the pathological tibia. If we assume that growth in the distal tibia accounts for approximately two thirds of total tibial growth, we can provide an estimate of the age of the individual when the first Harris line was formed. In the normal tibia we find that there is a distance of 50 mm from the first Harris line to the growth plate. This translates to about 75 mm of total growth for the tibia from the first arrested growth

FIGURE 10.47 Osteomyelitis of the right (on left of figures) and left tibia with cloacae and periostosis. (A) Anterior view of entire tibiae. (B) Detail of distal growth plates. (Child from an archeological site in Maryland, USA, dated to between AD 1200 and 1300, NMNH 383712.)

line. Extrapolating from Stewart (1968: 133), the tibia grows about 17 mm per year between the ages of 4 and 9 years. At this rate, it would take approximately 4 1/2 years to add 75 mm to the total length of the tibia. Because the child was about 9 years old at the time of death, this suggests that the first Harris line was formed between the ages of 4 and 5 years. Because this age is in agreement with the age estimated on the basis of the midshaft diameter of the sequestrated tibial shaft, this first Harris line may coincide with the time of onset of the osteomyelitis. Osteomyelitis that is probably linked to an open fracture was found in the skeleton of a child (NMNH 383712) who died at about 6 years of age (Fig. 10.47). The child was buried at an archeological site in Montgomery County, Maryland, that dates to between AD 1200 and

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313

FIGURE 10.48 Dactylitis of the left metacarpals. (Child 3 5 years from the medieval site of St. Gregory’s Cemetery, Canterbury, England, CAT Burial SK 1201.) Studied and photographed through the courtesy of Trevor Anderson.

1300. Both the right and left tibiae are affected although the most severe evidence of infection occurs in the left tibia. The left tibia has an abnormal deviation in its long axis that occurs in the diaphysis about one third of the distance from the proximal end. This is almost certainly due to a fracture that had completely healed by the time of death. Osteomyelitis involving both metaphyses of the left tibia strongly suggests that the fracture was open or compound, providing a pathway for infectious organisms. The left fibula was not available/preserved for study. A cloaca occurs in the distal third of the right tibial diaphysis and the associated fibula has periostosis on the lateral surface of the midshaft diaphysis. Other evidence of infection is expressed as a destructive focus of the distal left fourth metacarpal. The metacarpal lesion is large and exhibits a sclerotic response at the margins of the lesion that is indicative of some repair. The most likely pathogenesis in this case is osteomyelitis secondary to an open fracture of the left tibia. Although osteomyelitis is most severe in the left tibia, hematogenous dissemination to a few other sites in the skeleton occurred, giving rise to the other lesions. Osteomyelitis can also affect the smaller bones of the skeleton, particularly in children. An example of this occurs in the metacarpals and the proximal first phalanx of a child (Burial 1201) about 4 years of age from the medieval site of St. Gregory’s Cemetery,

Canterbury, England. The left first through fourth metacarpals and the left first phalanx were available for study, and all these bones show evidence of enlargement (dactylitis) suggestive of chronic infection (Fig. 10.48).

SEPTIC ARTHRITIS Pathology Septic arthritis is caused by bacteria entering the synovium and the joint cavity via the bloodstream by extension of infection from a bone (osteomyelitis) or soft tissue, or by direct introduction through a wound. Occasionally, any joint may be involved, but about one third of people who acquire this condition have involvement of the knee and one third the hip joint, leaving one third for all other locations. About 10% also have osteomyelitis. The causative organisms identified are staphylococci in about one third and streptococci in about 25% of affected people (Heberling, 1941). Other organisms causing septic arthritis are gonococci, pneumococci, meningococci, and various Gram-negative rods from enteric infections (Salmonella, Shigella). Gonococcal arthritis is often more multiarticular than other septic joint infections, and multiarticular involvement has been observed

314 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 10.50 Chronic osteomyelitis of the left ilium with left sacroiliac ankylosis and septic arthritis of the congenitally dislocated left hip. (Underdeveloped 24-year-old male, PMUG 3477, autopsy 9928 from 1879.)

Paleopathology FIGURE 10.49 Septic arthritis of right knee with bony ankylosis following violent trauma to the joint; anterior view. Notice reactive bone formation and hypervascularity around the joint and on the patella. (45year-old male, WM HS 84.7 from 1842.)

in over 80% of instances of gonococcal arthritis (Harkness, 1942). The acute phase of septic arthritis is limited to the synovial membrane and the articular cartilage and will not be recognizable in dry bone unless the subchondral bone has become affected and eroded. Unrelieved septic arthritis will often terminate in bony ankylosis (Fig. 10.49). The acute and final stages are very similar to tuberculous arthritis in dry bone, although there is usually less bone destruction and concomitant shortening in septic arthritis than in tuberculosis. In infants, before separation of the blood supply of the femoral head from that of the proximal metaphysis, direct extension of osteomyelitis to the hip joint is common. In such cases, destruction of the femoral head and of the growth cartilage may result in bony ankylosis between the femoral metaphysis and the acetabulum, followed by marked growth deficit of the proximal femur. The most marked destructive changes in dry bone are seen in osteoarthritis complicating chronic osteomyelitis (Figs. 10.50 and 10.51) or infected fractures (Fig. 10.52).

References to osteoarthritic change resulting from infection of one or more joints are uncommon in paleopathological literature. Wells (1962) has attributed degeneration of the left humeral head in a young, female skeleton to septic arthritis from an Early Saxon cemetery at Caister-on-Sea, England. Jarcho et al. (1963) have described a fused hip in an individual buried at a preColumbian archeological site at Wupatki Pueblo, Arizona. The authors conclude that the fusion was the sequela of infection of the hip. Brothwell (1965: Plate 7E) illustrates a pair of humeri from a medieval adult skeleton from Scarborough, England. The head of the left humerus is abnormal with a flattened, irregular joint surface. Brothwell suggested a septic condition, such as osteomyelitis, as the cause for the arthritic change. The humerus is unusually short. This could be the result of diminished growth due to infection during childhood. However, the combination of reduced length and a rather robust diaphysis also suggests the possibility of a congenital abnormality, such as achondroplasia. Moodie (1928) suggested an association between degenerative osteoarthritis and dental disease. He based this observation on degenerative changes of the right temporomandibular fossa and the presence of a dental abscess in a female skull from an archeological site at Cinco Cerros, Peru. The skull (No. 348) is part of the skeletal collection at the San Diego Museum of Man,

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315

FIGURE 10.52 Septic arthritis of the left elbow secondary to a partly healed comminuted fracture. Notice destruction of joint constituents, massive reactive bone formation, and ulno-humeral ankylosis; posterior view. (Adult, WM S 81.1 from 1851.)

FIGURES 10.51 Chronic sclerosing osteomyelitis of the left tibia with involvement of the proximal epiphysis and joint surface. (A) External view, showing periosteal hyperostosis. (B) The bisected bone shows sclerotic obliteration of the medullary cavity and a recent surgical defect in the distal metaphysis. (C) The proximal articular surface of the tibia shows multiple perforations. (ANM 2997.)

California. However, it is apparent in Moodie’s (1928) Figure 10.1 that there is a fracture through the temporomandibular fossa with some refilling of the defect, indicating healing. Thus, a more probable diagnosis would be osteoarthritis following trauma. Ingelmark et al. (1959) report a correlation between osteoarthritic change in the spine and the presence of dental infection in a cemetery population from Aebelholt Monastery in Northern Zealand, Denmark, dating from

approximately AD 1185 to 1559. The authors controlled for one variable, age, which would be a major factor in this correlation. However, this does not mean that a causal relationship between the two pathological conditions can be assumed because there may be other underlying factors with which the pathological conditions may be related. Morse (1969: Plate 11E) briefly describes an osteoarthritic right hip joint from an adult male skeleton. The acetabulum is shallow and enlarged. The head of the femur is deformed. Two isolated pieces of bone appear to be sequestra from the head of the femur. The skeleton is from the Klunk Site in Illinois and is probably preColumbian (Hopewell Culture). Morse attributes the arthritic changes to infection. Clear evidence of septic arthritis is seen in the fused left femur and tibia from an isolated surface find near Chancay, Peru (Fig. 10.53A D). There are no data on cultural association or date. The skeleton is part of the skeletal collections of the National Museum of Natural History, Washington, DC (NMNH, uncataloged). Although the bones are somewhat short, they are robust. Osteoarthritic change is limited to the knee. The radiograph indicates

316 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 10.53 Septic arthritis of the knee resulting in fusion of the left femur and tibia. (A) Medial view; note the periosteal reactive bone on the distal femur. (B) Radiograph of the mediolateral view. (C) Anterior view; note enthesophyte development. Septic arthritis of the knee resulting in fusion of the left femur and tibia. (D) Radiograph of anteroposterior view. (E) Detail of posterior knee fusion with a cloaca (arrow) superior to the lateral condyle. (Adult, surface find from Chancay, Peru, NMNH uncataloged.)

normal cortical bone thickness and density, indicating that the limb was used throughout the life of the individual (Fig. 10.53B and D). The knee has fused in the extended position with some rotation of the axis of the tibia relative to the femoral condyles. Because of this rotation, the medial condyle of the tibia projects posteriorly. There is extensive periosteal bone reaction on the distal diaphysis and metaphysis of the femur. Periosteal reactive bone on

the tibia is minimal and limited to the bone adjacent to the proximal articular surface. There is a cloaca in the posterior cortex of the distal femur just superior to the lateral condyle (Fig. 10.53E). The radiograph reveals considerable sclerosis in the distal femur. The periosteal reactive bone, sclerosis, and cloaca are indicative of infection and inflammation, making a diagnosis of septic arthritis highly probable.

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SUMMARY The basic biology of how infections affect the body, and ultimately the skeleton, has been described alongside the humoral versus cellular and vascular responses to infectious agents. The chapter has also covered the nature of periostosis and periostitis, noting that appropriate terms should be used and people in the past should not necessarily be given a label of infection when there can often be no certainty. Nonspecific responses to a range of etiologies can lead to the same bone change, which may include infection, and if infection could be the etiology, it may also be the result of a range of any one of many infectious organisms. “Nonspecific” is a phrase that perhaps should be used more in paleopathology for bone responses that lead to new bone formation and destruction, and location on the skeleton may give better clues to specific etiologies (e.g., ribs and sinuses). Osteomyelitis and septic arthritis complete this chapter. The following chapter considers infections that have specific infectious etiologies: leprosy, tuberculosis, brucellosis, and glanders, which are all classed as zoonoses.

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Klaus, H.D., 2017. Paleopathological rigor and differential diagnosis: case studies involving terminology, description, and diagnostic frameworks for scurvy in skeletal remains. Int. J. Paleopathol. 19, 96 110. Krenz-Niedbala, M., Lukasik, S., 2016. Skeletal evidence for otitis media in Mediaeval and post-Mediaeval children from Polan, Central Europe. Int. J. Osteoarchaeol. 26, 633 647. Kulowski, J., 1936. Pyogenic osteomyelitis of the spine: An analysis and discussion of 102 cases. J Bone Joint Surg 18, 343 364. Lambert, P., 2002. Rib lesions in a prehistoric Puebloan sample from Southwestern Colorado. Am. J. Phys. Anthropol. 117, 281 292. Larsen, W., 1997. Human Embryology, 2nd ed. Churchill Livingstone, New York. Larsen, C., 2015. Bioarchaeology: Interpreting Behavior from the Human Skeleton, 2nd ed. Cambridge University Press, Cambridge. Lauche A. (1939). Die Unspezifischen Entziindungen der Knochen. In: Lubarsch, O., Henke, F., Rtissle, R., (Eds.), Handbuch der Speziellen Pathologischen Anatomie und Histologie, vol. 9 (4). Springer, Berlin, pp. 1 80. League of Nations. Corrected Statistics for the Year 1921, 1922: Annual Epidemiological Report No. 6. League of Nations Health Organization, Geneva. Lewis, M.E., 2004. Endocranial lesions in non-adult skeletons: understanding their aetiology. Int. J. Osteoarchaeol. 14, 82 97. Lewis, M.E., 2018. Paleopathology of Children. Identification of Pathological Conditions in the Human Skeletal Remains of NonAdults. Academic Press, London. Lewis, M.E., Roberts, C.A., Manchester, K., 1995. A comparative study of the prevalence of maxillary sinusitis in Medieval urban and rural populations in Northern England. Am. J. Phys. Anthropol. 98 (4), 497 506. Mattila, K.J., Asikainen, S., Wilf, J., Jousimies-Somer, H., Valtonen, V., Nieminen, M., 2000. Age, dental infections and coronary heart disease. J. Dent. Res. 79, 756 760. Merbs, C., 1992. A new world of infectious disease. Yearb. Phys. Anthropol. 35, 3 42. Merrett, D., Pfeiffer, S., 2000. Maxillary sinusitis as an indicator of respiratory health in past populations. Am. J. Phys. Anthropol. 111, 301 318. Mirembe, M., Moffat, N., 2018. Developmental origins of health and disease: the relevance to developing nations. Int. Health 10, 66 70. Moodie, R., 1928. Studies in paleo-odontology, IX: Definite association of rheumatic lesions with disease of the teeth in an ancient Peruvian. Pacific Dental Gazette 36, 757 759. Morse, D. (1969). Ancient disease in the midwest, Illinois State Museum Reports of Investigations, Springfield, Illinois. Murphy, J., 1916. Bone and joint disease in relation to typhoid fever. Surgery, Gynecology and Obstetrics 23, 119 143. Nesse, R.M., Williams, G.C., 1994. Why We Get Sick. The New Science of Darwinian Medicine. Vintage Books, New York. Nicklisch, N., Maixner, F., Ganslmeier, R., Friederich, S., Dresely, V., Meller, H., et al., 2012. Rib lesions in skeletons from early Neolithic sites in central Germany: on the trail of tuberculosis at the onset of agriculture. Am. J. Phys. Anthropol. 149, 391 404. Ortner, D., 2008. Differential diagnosis of skeletal lesions in infectious disease. In: Pinhasi, R., Mays, S. (Eds.), Advances in Human Palaeopathology. Wiley, Chichester, pp. 193 214. Panders, A., Hadders, H., 1970. Chronic sclerosing inflammations of the jaw: Osteomyelitis sicca (Garrr), chronic sclerosing osteomyelitis

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Chapter 11

Bacterial Infections Charlotte A. Roberts1 and Jane E. Buikstra2 1

Department of Archaeology, Durham University, Durham, United Kingdom, 2Arizona State University, Tempe, AZ, United States

INTRODUCTION The bacterial infections tuberculosis (TB), leprosy, treponematosis, brucellosis, glanders, actinomycosis, nocardiosis, and plague form the subject matter of this chapter. While infections may be caused by viruses, fungi, parasites, and protozoa, the most common organisms causing infectious disease are bacteria. Tuberculosis and leprosy, and to a lesser extent treponemal disease (TD), are the bacterial infections most often reported in paleopathology. Plague is the only bacterial infection solely affecting soft tissue that is reported here, as it has received considerable recent biomolecular attention (see Chapter 8). Actinomycosis, glanders, and nocardiosis rarely affect the skeleton but are included to maintain continuity from Ortner (2003).

TUBERCULOSIS Introduction Tuberculosis (TB) is a chronic infectious disease caused by one of the species of the Mycobacterium tuberculosis complex (MTC) (Table 11.1). Along with leprosy, it is one of the more common mycobacterial diseases recorded in skeletal remains, although a very low percentage of people who contract the both infections develop bone changes. Mycobacterium tuberculosis, Mycobacterium africanum, and Mycobacterium canettii are the most significant organisms for humans, their principal hosts (Grange, 2014). Humans are also secondary hosts for M. bovis and M. caprae. Many animals, both wild and domestic, may contract TB and thus are a risk for transmission to humans and vice versa (Pfeiffer and Corner, 2014: Table 28.1; also see Mays, 2005 on the evidence of TB in ancient animals). Direct spread of the relevant MTC organisms occurs via droplet transmission between humans. Mycobacterium bovis is also transmitted to humans through ingestion of infected animal products, e.g., meat and milk.

Tuberculosis is a reemerging disease. In 2016, 10.4 million people fell ill with TB, and 1.7 million died; 40% of HIV-related deaths were also due to TB (human immunodeficiency virus). TB is the ninth leading cause of death worldwide and the leading cause of death from a single infectious agent (WHO, 2017a,b). Thus, the statement by Smith (1988) that tuberculosis had been “defeated” was nullified by 1993, when the World Health Organization declared a global TB emergency. Risk factors include poverty, poor living conditions and malnourishment, migration, specific occupational risks such as working with animals and their products, vitamin D deficiency, HIV, and stress. TB is treated with a suite of antibiotics, which has led to a drug resistance due to adaptation by the pathogen (Lange et al., 2018). Sanatoria were opened in the 19th and 20th centuries for care and treatment of people with TB (Bryder, 1988; Macdonald, 1997). Treatments included rest, a good diet, graded exercise, and surgery, although their efficacy continues to be debated. In the more distant past, more puzzling treatment methods are described, including “Touching for the King’s Evil” in Europe (Crawfurd, 1911), alongside herbal remedies. Historically, TB has been stigmatized and this remains a challenge for those who have TB today (Mason et al., 2016).

Pathology If a person becomes infected with TB via droplet transmission, a primary pulmonary focus forms, followed by single or multiple foci in the regional hilar lymph nodes, found on the medial aspect of each lung. The lymphatic system carries lymph, a clear fluid that contains white blood cells, including lymphocytes that attack infective organisms. Lymph nodes are part of the lymphatic system and occur in groups in specific parts of the body where lymph is drained to rid the body of toxins and other waste products (e.g., in the groin, armpits, and neck).

Ortner’s Identification of Pathological Conditions in Human Skeletal Remains. DOI: https://doi.org/10.1016/B978-0-12-809738-0.00011-9 © 2019 Elsevier Inc. All rights reserved.

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322 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

TABLE 11.1 Members of the Mycobacterium tuberculosis Complex (Grange, 2014: Table 3.1) Species

Principal Hosts

Mycobacterium tuberculosis

Humans

Mycobacterium africanum

Humans

Mycobacterium bovis

Cattle, deer, elk, bison, badger, opossum

Mycobacterium canettii

Humans

Mycobacterium caprae

Goat

Yes

Mycobacterium microti

Vole, hyrax, llama

Very rare

Mycobacterium mungi

Banded mongoose in Botswana

Very rare

Mycobacterium pinnipedii

Seal, sealion

Very rare

The initial focal lesions of TB form the primary TB complex. Typically, this is an acute systemic disease of childhood, which is commonly acquired through droplet transmission (Wainwright, 2014). The transmission of TB via contaminated animal products is much less frequent and occurs through the intestinal pathway with formation of a primary complex in the wall of the intestines and mesenteric lymph nodes. The pathogenesis of TB depends on the size of the inoculum, the virulence of the organism, and the immune resistance of the host. Therefore, a person with a compromised immune system is more susceptible to infection than an individual who is not immunocompromised. In most instances (in Western populations), the primary complex heals without leading to a progressive disease. If the primary complex fails to heal, the lung (or intestinal) lesion progresses, and tubercle bacilli may be disseminated through the bloodstream and/or lymphatic systems to other organs and tissues, including the skeleton (secondary TB; Wainwright, 2014). Secondary TB is usually a chronic disease of adults due to reactivation of dormant bacilli or reinfection. Again, the number of organisms and the immunological defence capacity of the person determine whether early hematogenous dissemination will eventually lead to fatal miliary tuberculosis, with multiple small tubercles in the tissues involved, and/or tuberculous meningitis, or to isolated organ TB, including the bones of the skeleton. Organ TB may not make its appearance until years after the early dissemination of the bacteria and it is precipitated by lowered immune system strength, poor host resistance due to malnutrition, other diseases, or possibly local trauma. Because dormant primary pulmonary foci may harbor viable organisms for many years, late hematogenous dissemination also may become the source of organ TB. Skeletal TB is, with rare exceptions, the result of limited hematogenous dissemination. Whether or not the secondary TB is the result of activation of dormant tubercle bacilli or the introduction of new TB organisms, the

Humans as Secondary Hosts?

Yes

immune system quickly recognizes the pathogens and may initiate a very aggressive immune response. This response attacks the pathogen but also can destroy normal organ tissues that are nearby, with potentially serious dysfunction of affected organs. This overly aggressive response by the host’s immune response illustrates an important dimension of disease, i.e., the adverse consequences of hyperimmunity. This problem is confronted in other pathological conditions such as rheumatoid arthritis.

Statistical Data Estimating the frequency of tuberculosis prior to the identification of M. tuberculosis by Robert Koch in 1882 is problematic because people combined different primary lung diseases into a single category known as “consumption” (Roberts and Manchester, 1995: 135; Roberts and Cox, 2003: Chapter 6). References to TB in early documentary sources are also challenging because the disease shares common signs and symptoms with other lung diseases such as pneumonia and lung cancer (see Mitchell, 2011 for a general overview). There is, however, a strong probability that TB was a significant cause of morbidity in England during the medieval period. This morbidity increased until about the middle of the 19th century when, in Europe and the United States at least, its frequency began to decline for reasons that continue to be debated (Davies et al., 1999). Although extrapolating information from TB data between the date of discovery of the organism (1882) and the introduction of antibiotic treatment (B1950) requires caution, data can provide insight on the impact of TB that may be applied to earlier periods. For example, TB mortality in Germany in 1892 was 260 per 100,000 living inhabitants. For the beginning of the 20th-century (1901) data are only available for part of Europe and the United

Bacterial Infections Chapter | 11

States, covering mortality from pulmonary TB. Within this subset, TB mortality ranges from 111 to 289 per 100,000 living inhabitants. The age and sex distribution of all tuberculosis deaths for Western Europe, the United States, and Canada for 1949 were published by the International Union Against Tuberculosis in 1964. While earlier data show a predominance of male over female TB-related deaths, with ratios of almost 2:1, more recently the morbidity difference between the sexes has disappeared (Resnick and Niwayama, 1995a: 2462). However, such figures can be deceptive. While women have a higher resistance to infectious disease per se (Nhamoyebonde and Leslie, 2014), they may be less likely to be diagnosed due to sociocultural factors that prevent or delay their access to clinics for diagnosis and treatment. However, one must appreciate that the data for 1892 and 1901 are already modified by successful surgery, and the figures for 1949 by the early availability of effective chemotherapy. Therefore, these data represent a lower prevalence than one should expect in earlier periods. Even so, in the official yearbook for 1956 West Germany reported 20,342 people affected by TB, with an incidence of 3358 (Kastert and Uehlinger, 1964). Total TB mortality in West Germany has, however, steadily declined, especially in infants and children. Among 560 people autopsied who had died from fatal hematogenous TB from 1923 through to 1932, 115 had involvement of the skeleton (21%). Of these, 58 were limited to the skeleton, whereas 21 showed tuberculous foci in other organs, 12 showed active pulmonary tuberculosis, and 24 organ and lung TB (Kastert and Uehlinger, 1964: 447). In general, skeletal tuberculosis affects only about 3% of those with pulmonary and about 30% of those with extrapulmonary TB (Kastert and Uehlinger, 1964: 444, 445). The distribution and frequency of tuberculosis in bones and joints in a large clinical series (1752 individuals) prior to 1892 was published by Alfer (1892) (Table 11.2). Of these, 91 presented with multiple tuberculous bone and joint lesions. The age distribution of the same series is shown in Table 11.3. It indicates the great preponderance of skeletal tuberculosis affecting infants and children, but the age distribution today has changed, with patients of all ages being affected (Resnick and Niwayama, 1995a: 2462). However, in low-incidence countries an older age is particularly associated with TB, i.e., those born when TB was common (Abubakar and Aldridge, 2014).

323

TABLE 11.2 Locations of Bone Lesions in Skeletal Tuberculosis Listed in Order of Decreasing Frequency Location

No. of Instances

Bones Spine

239

Tarsals and metatarsals

184

Carpals and metacarpals

109

Ribs

67

Tibia and fibula

49

Radius and ulna

48

Phalanges of fingers

38

Temporal bone

33

Phalanges of toes

31

Pelvis

27

Sternum

21

Femur

14

Humerus

10

Mandible

9

Scapula

8

Orbital margin

7

Parietal bone

5

Frontal bone

5

Maxilla

5

Sacrum

3

Zygoma

2

Patella

2

Clavicle

2

Occipital bone

1

Coccyx

1

Joints Knee

281

Hip

241

Elbow

113

Ankle

43

Shoulder

28

Wrist

20

Metacarpal phalangeal

5

Metatarsal phalangeal

4

General Pattern of Bone and Joint Tuberculosis

Sternoclavicular

4

Acromioclavicular

1

Bone TB affects 3% 5% of people with untreated TB (Jaffe, 1972). This frequency can vary across different

Source: After Alfer, 1892.

TABLE 11.3 Age Distribution of Skeletal Tuberculosis in Bones and Joints Listed in Order of Decreasing Frequency Years old* Location

0 5

5 10

10 15

15 20

20 25

25 30

30 35

35 40

40 45

45 50

50 55

55 60

60 65

65 70

70 75

75 80

Spine

89

59

32

23

9

10

3

6

3

1

4

Tarsals and metatarsals

9

20

26

38

14

10

10

7

6

8

Carpals and metacarpals

16

12

16

23

12

5

1

5

3

6

11

9

9

5

2

1

2

2

4

2

9

10

7

2

2

1

1

2

Bones

Ribs

4

9

8

5

Tibia and bula

12

5

7

x8

3

Radius and ulna

6

9

6

8

4

2

5

5

1

7

5

1

2

3

1

Phalanges of fingers

15

7

4

4

1

2

2

Temporal bone

6

4

2

3

7

5

2

1

Phalanges of toes

2

6

5

7

1

Pelvis

1

1

3

7

5

3

1

Sternum

1

Femur

2

Humerus

1

2

Scapula Orbital margin1

2

Frontal bone Maxilla Mandible

1

Parietal bone Sacrum

2

Zygoma Occipital bone Coccyx

1

1

1

1

1

1

1

3

1 3

1

2

1 2

Eˆ1

1

1 1 1

1

1

2

2

3

1 1

2

1

1 1

3

2

1

Clavicle

2

2

Eˆ1

1

Patella

1

3

1

1

1

1

2

1

1

1

1

1

1

2

3

1

1

3

1

2

2

1

1

1

1

3

2

2

2

2

1

1

1

2

1

1

1

1

1

Joints Knee

47

52

47

37

20

11

23

11

11

3

2

8

6

Hip

58

59

43

46

9

11

6

4

1

1

3

Elbow

7

14

14

21

12

9

6

5

9

8

5

2

Ankle

5

9

10

5

2

1

1

3

2

2

6

3

5

3

1

1

2

2

1

1

5

3

1

3

2

1

3

1

1

1

1

1

2

1

5

4

3

Shoulder Wrist

1

Metacarpal phalangeal joints Metatarsal phalangeal joints

1

Sternoclavicular joint

1

3

3

2 2

3 1

1

6

5

1

Acromioclavicular joint Multiple foci

19

13

Overlap in age categories is from Alfer and is not resolved here.

Source: After Alfer, 1892.

14

11

4

3

1

326 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

sources, and there may be a higher prevalence in children. For example, Roberts and Bernard (2015) and Bernard (2003) report a 12% frequency rate for children hospitalized in a sanatorium during the 1930s 1950s. Tubercle bacilli circulating in the bloodstream can enter the bones of the skeleton, particularly in areas of hematopoietic (red) marrow, which has a high circulatory and metabolic rate. Thus, the areas of cancellous bone are favored, rather than the cortex or medullary cavity. Any bone of the skeleton can potentially be affected, but some are more frequently involved than others. In adults, the metaphyses and epiphyses of long bones are especially at risk. In infants and young children, the distribution of hematopoietic marrow involves much more of the skeleton. Therefore, tuberculous foci often occur in the tubular bones of the hands and feet (metacarpals, metatarsals, and phalanges) and in ossification centers of the tarsal and carpal bones, in addition to occasional diaphyseal lesions in long bones. Lewis (2018: 156 162) usefully summarizes the clinical literature on the bones most commonly affected in children. The vertebrae, ribs, and sternum have hematopoietic marrow throughout life, and so TB of the spine is observed at all ages. In the lower spine, the specialized paravertebral venous plexus of Batson seems to provide the optimum vascular environment for the bacteria (Resnick and Niwayama, 1995a: 2464). The flat bones, particularly the cranial vault, are more commonly involved in infants and children than adults. Tuberculous arthritis is intimately linked to infectious involvement of the bones of the adjacent joints and for that reason will be discussed here. Tuberculous arthritis may begin in the synovial membrane, in the bone, or simultaneously in both. This is explained by the joint’s blood supply both to the epiphysis and joint capsule. In an advanced stage, the original focus often cannot be ascertained. The morphology of tuberculous lesions in dry bones is not specific and overlaps considerably in appearance with manifestations of other bone infections, but some bone changes are more specific than others. For example, the spine is considered a very useful part of the skeleton for TB diagnosis in an archeological skeleton (more specific evidence), while endocranial new bone formation, periostosis on the ribs, and pleural calcification are considered nonspecific (see summary in Roberts and Buikstra, 2003: 99 107). However, there are some general characteristics of diagnostic value, in addition to the age distribution of skeletal lesions. TB, in its exudative phase, permeates marrow spaces, devitalizes areas of cancellous bone and this leads to the formation of centrally located sequestra (caries). The proliferative granulomatous phase leads to local destruction and cavitation in cancellous bone (Resnick and Niwayama, 1995a). In either case very little, if any,

perifocal reactive bone formation is elicited, and often bones will show perifocal or general osteoporosis. In long bones, TB tends to remain localized, mostly in the metaphyses or epiphyses. In contrast to purulent osteomyelitis, massive sequestra, especially of cortical bone, are rare. Periosteal reactive new bone is limited or absent, except in the small tubular bones in infants and children where destruction or sequestration of the cortex and the formation of an expanded shell of periosteal reactive bone occurs as tuberculous dactylitis or spina ventosa (Resnick and Niwayama, 1995a: 2477). Similar changes affecting part of an involved long bone are also observed in the young age groups. Perforation of the cortex with formation of an extraosseous abscess, with or without pustulous perforation of the skin, is common. Traces of such an abscess can sometimes be seen in the presence of reactive periosteal bone in the vicinity of the opening and, occasionally, ossification of the abscess wall. In joints, destruction of the articular surface may be minimal if the process is limited to the synovium. Undermining and resorptive grooving of the articulating bones frequently occurs along the line of the synovial membrane or ligamentous attachments. If the process started in the bone, or involves bone extensively, destruction of the articular surface and the epiphyses often occurs, with formation of cancellous sequestra and/or cavitation. Substantial reactive new bone formation as a secondary osteoarthritis following partial destruction of the joint can occur. Skeletal TB can heal without specific therapy. Small tuberculous foci, particularly in infants and small children, may leave no trace because the area is removed during subsequent growth and remodeling. Foci destroying a growth plate will leave a growth deficit and/or deformity in the young age groups. Foci in the vicinity of a growth plate may lead to excessive growth. This is no different to the effect of osteomyelitis. Joint TB may heal with obliteration of the joint cavity, often terminating in bony ankylosis with varying degrees of bone mass loss in the constituent bones. After healing, the spongiosa undergoes remodeling along altered stress lines but never reaches the original density of cancellous bone (Kastert and Uehlinger, 1964: 467). The bone changes of TB and their understanding have benefitted in recent decades from research on documented skeletal collections such as the Robert J. Terry Collection (Smithsonian Institution, Washington DC, United States), the Hamann Todd Collection (Cleveland Museum of Natural History, Ohio, United States), and the Coimbra Identified Skeletal Collection curated at the Department of Anthropology, University of Coimbra, Portugal. Bone changes have also been the recent subject of discussion in relation to antibiotic treatment (Holloway et al., 2013a,b; Steyn et al., 2013). For example, Steyn et al. (2013)

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argues that today more skeletal TB is seen because people live longer with the infection due to long-term antibiotic use, giving more time for lesions to develop. In addition, Wilbur et al. (2008) consider the effect of diet on the expression of TB in archeological skeletons, finding that iron and protein are important for immune function and infection outcome in TB, and that diet may influence the potential for TB to disseminate from the lungs to the skeleton. General frailty, which may be related to having TB, may also lead to poorer growth of the bones of the skeleton (e.g., see Mansukoski and Sparacello, 2018). The order in which affected bones are considered within this chapter reflects how frequently they are affected, starting with the most commonly involved area, the spine.

327

FIGURE 11.1 Kyphotic spine in a person with tuberculosis. Courtesy: Peter Davies.

The Spine Vertebral TB (also named tuberculous spondylitis, or Pott’s disease, after Percival Pott who first named it in the 18th century) is, in practically all clinical and autopsy studies, the most common and most characteristic skeletal change associated with the TB. In earlier times, the disease usually began in childhood. This age distribution seems to be changing, with older individuals being affected more often today (Resnick and Niwayama, 1995a: 2464). For example, a rapid decline in incidence for those over 7 years of age was reported in a welldocumented, post-1920 series of 1490 individuals (Sorrel and Sorrel-Dejerine, 1932). The fourth, fifth, sixth, and seventh decades showed only 100, 50, 18, and 2 new people affected, respectively. Because the disease takes a very chronic course, people with active or healed lesions may be observed at any age. Destruction of the vertebral bodies is usually purely lytic, leading to cavitation. As a result of this process, vertebral collapse can occur and may be combined with a pathological fracture (Fig. 11.2) and a kyphotic deformity of the spine (Figs. 11.1 and 11.2). Small wedge-shaped remnants of the affected vertebrae often remain in contact with their end plates and are displaced anteriorly or posteriorly by the collapse. Extension of TB to adjacent vertebrae mostly occurs through the area of the nucleus pulposus of the intervertebral disc. Central spongiosa sequestra can also occur (Fig. 11.2B). The most common site for TB infection in the spine is the first lumbar vertebra, with the frequency of occurrence decreasing with distance from this vertebra (Resnick and Niwayama, 1995b: 2436). The lower spine is the primary focus in skeletal TB at all ages (see Fig. 11.3). Autopsy data on the frequency of involvement for individual vertebrae show that in about 80% of clinical and autopsy cases at least two adjacent vertebrae are involved (Fig. 11.3), whereas three or more were affected

in about 10% of the total. Multiple foci separated by intact vertebrae were also observed in about 4% of people. The part of the vertebra involved in skeletal TB is almost exclusively the vertebral body and overwhelmingly its anterior portion (Resnick and Niwayama, 1995a: 2464). Even after extensive destruction of one or several adjacent vertebral bodies, extension into the vertebral arches is uncommon, and the true intervertebral joints (apophyseal facets) and spinous processes are almost never destroyed. When the posterior elements of the vertebrae are involved, neurological compromise is a common complication (Resnick and Niwayama, 1995a: 2464; see also Travlos and Du Toit, 1990). A site in the vertebral column where posterior element involvement is more common is suboccipital TB involving the atlas and the axis. Because of the rudimentary bodies of these vertebrae, their intervertebral joints are commonly involved (Oehlecker, 1924: 242). Isolated tuberculous foci in posterior elements of vertebrae are extremely rare. Sorrel and Sorrel-Dejerine (1932: 500) observed only three cases of isolated spinous process destruction, and one with lumbar transverse process involvement, in a large sample of individuals with skeletal TB. A common complication of vertebral TB is extension to adjacent soft tissues (Resnick and Niwayama, 1995a: 2465). When this occurs, a unilateral or bilateral paravertebral (psoas) abscess develops that can be accompanied by an associated fistula. A connective tissue sack encapsulates the abscess (Fig. 11.4). The skeletal response to the presence of a paravertebral abscess is highly variable. There may be flared, shell-like bony extensions from the affected vertebra at the site where the abscess initially exits the bone (Fig. 11.5). Distinguishing between bone abnormalities resulting directly from an active tuberculous focus and the changes that are secondary reactions to the

FIGURE 11.2 Spinal TB, partly healed, involving thoracic (T) vertebrae 7 and 8 and the first lumbar (L) vertebra, with kyphotic deformity: (A) lateral view, showing fusion of vertebrae and periosteal new bone; (B) cut surface, showing vertebral body involvement at two sites (arrows), T8 and L1. Note the sequestrum in L1 (lower arrow) (52-year-old female, IPAZ autopsy S901 from 1948).

Location on Spine

Number of Vertebrae C1 C2 C3 C4 C5 C6 C7 T1 T2 T3 T4 T5 T6 T7 T8 T9 T10 T11 T12 L1 L2 L3 L4 L5 S1 S2 S3 S4 S5

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 FIGURE 11.3 Distribution of lesions in 62 autopsies of people with vertebral tuberculosis (after Kastert and Uehlinger, 1964) (C 5 cervical, T 5 thoracic, L 5 lumbar, S 5 sacralr).

FIGURE 11.4 Tuberculosis of the dorsolumbar spine with kyphosis and evidence of a large right psoas abscess (adult, PMUG, no number).

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329

FIGURE 11.5 Healed spinal TB with kyphosis (thoracic vertebrae 6 9) and a paravertebral abscess (thoracic 10 to lumbar 1): (A) lateral view; (B) cut surface (48-year-old female with pleural (visceral) and miliary tuberculosis, who died in 1936; IPAZ S 793 ).

presence of the paravertebral abscess overlying the bone can be challenging. A psoas abscess may also affect the proximal femur and the pelvic bones, leading to bone formation, destruction, or both. In Johannsson’s (1926) clinical series of 86 individuals with TB, 32 developed only an abscess, 22 had an abscess and fistula, and 2 had fistulae only. The psoas abscess extends usually downward, following the line of gravity, beneath the anterior longitudinal ligament and along the fascial plane of the psoas muscle, occasionally showing ossification of the abscess wall (Fig. 11.6). It may become an important source of contact infection for additional vertebrae, especially below the original focus. The tuberculous process erodes the cortical surface and slowly extends into the anterior portion of the vertebral bodies (Figs. 11.7 and 11.8). Such secondary extension into adjacent ribs is occasionally observed. The lower spine of a 17-year-old woman who had TB (Robert J. Terry Anatomy Collection) presented no evidence of destruction of any vertebral body. Therefore, the extensive reactive bone formation is probably a response to an overlying paravertebral abscess (Fig. 11.9A and B). There is a lytic focus in the pelvis associated with reactive

FIGURE 11.6 Ossification in the wall of a right tuberculous psoas abscess extending to the femur; secondary to spinal tuberculosis (55year-old male, FPAM 2894).

330 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 11.8 Lumbosacral TB with kyphosis and a prevertebral (sacral) abscess. Notei the almost complete destruction of the lumbar vertebral bodies alongside lytic lesions of the sacrum (the individual was about 10 years old, FPAM 1493).

FIGURE 11.7 Tuberculosis of the lumbar vertebrae. Anterior destruction of lumbar vertebrae 3 5 by an abscess anterior to the vertebrae (prevertebral); marked kyphotic angulation (20-year-old male, FPAM 3583).

periostosis on the right iliac crest (Fig. 11.9C and D) and a destructive lesion probably associated with a draining sinus on the inferior margin of the left eighth rib (Fig. 11.9E). Reactive bone formation is also seen in association with a fairly limited lytic focus (Fig. 11.10A) in the first lumbar vertebra of a 19-year-old man who also died of tuberculosis (Robert J. Terry Anatomy Collection). Reactive bone formation adjacent to the lytic focus (Fig. 11.10B) and extending superiorly onto the lower thoracic vertebrae suggests a paravertebral abscess. Evidence of pleural periostosis associated with a lytic

focus eroding the inferior margins of the fifth and sixth right ribs argues for the presence of a draining sinus from a tuberculous focus in the thoracic vertebrae (Fig. 11.10C). Collapse of one or several vertebral bodies, with vertebral arches and spinous processes remaining, leads to a sharply angular kyphosis (gibbus). This deformity was observed in about 60% of individuals with spinal TB in the preantibiotic era (Reinhart, 1932). The kyphosis is most marked in the thoracic spine (Fig. 11.5), whereas lumbar lesions may terminate with ‘telescoping’ of the defect rather than severe angulation (Girdlestone, 1965: 81:3). Healing may occur with permanent preservation of the deformity by fusion of the vertebral body remnants. Formation of new spongiosa and of cortex is rather meager, and residual cavity defects may remain. There is usually secondary bony ankylosis between the true intervertebral joints of the involved segment and often ossification of the interspinous ligaments. If a sharp kyphosis develops in childhood, increased height of the vertebrae below due to compensatory growth is often observed. In some cases, a lateral deformity (scoliosis) may occur as a consequence of lateral destruction of one or more vertebral bodies rather than the much more common anterior destruction.

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331

FIGURE 11.9 Spinal TB without vertebral collapse but with reactive bone formation on the lower vertebral bodies: (A) anterior view of the L1 S5 vertebrae showing extensive reactive new bone formation probably in response to an overlying abscess; (B) detail of L5 S1 vertebrae; (C) lytic focus on the right ilium with bone destruction; (D) reflected right sacroiliac joint showing subchondral bone destruction; (E) pleural surface of left eighth and ninth ribs with a lytic focus on the inferior margin of the eighth rib (17-year-old female, Robert J. Terry Anatomy Collection; NMNH 382085329).

A differential diagnosis for these bone changes includes osteomyelitis and healed compression fractures of the vertebral body. In osteomyelitis, the extensive destruction of several vertebral bodies leading to the sharply angulated kyphosis is uncommon. Paravertebral abscesses are also less frequently observed and, if present, may extend above the lesion as well as below because

they form rapidly. In a healed fracture with angular deformity usually only one vertebra is involved, and there is much less extensive destruction of the vertebral body. Isolated TB of the sacrum and of the coccyx is rare (David, 1924). Abscess formation is a frequent complication, and in the case of the coccyx, total sequestration is not unusual (Konschegg, 1934).

332 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 11.10 Tuberculosis with spinal and rib involvement: (A) anterior view of T11 S5 vertebrae; note the lytic focus on the vertebral body of L1; (B) detail of lytic focus with only minimal remodeling; (C) pleural surface of the right ribs 4 6 showing destructive remodeling with reactive bone formation (19-year-old male, Robert J. Terry Anatomy Collection; NMNH 382085-129).

Finally, with respect to spinal TB, caution is urged regarding lytic ‘lesions’ in vertebral centra that have been described to be related to TB (Baker, 1999). These present as circumferential apertures appearing halfway between the superior and inferior end plates. These holes may represent normal vascularization or other developmental process (Scheuer and Black, 2000: 190), although it is not possible to discount co-occurrence of normal ‘developmental’ holes or vascularization compounded by a pathological process. While some aDNA analysis of

such skeletons with these lesions has been positive for TB (e.g., Haas et al., 2000), this does not mean that the lesions can be objectively and directly linked to TB.

The Hip Tuberculosis of the hip joint is the second most frequent skeletal lesion after tuberculous spondylitis. All statistical series agree that the majority of people who contract hip TB develop it in childhood and that its onset after 25 years

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of age is rare (Johannsson, 1926: 159; Sorrel and SorrelDejerine, 1932: 309). In Sorrel and Sorrel-Dejerine’s study of 995 individuals with hip TB, the highest incidence occurred between 4 and 6 years of age, with a second smaller peak around puberty. There were only 28 people in their fourth decade, 11 in their fifth decade, and 4 who developed hip TB after 50 years of age. In most cases, the lesion starts with an osseous focus (Konschegg, 1934: 461, 462). The anatomy of the hip joint enables early access of the bacteria into the joint space, not only into the acetabulum and femoral epiphyses but also the metaphysis of the femoral neck. In the “Kastert series,” one-third of the individuals with hip TB had an origin with an extra-articular focus (Kastert and Uehlinger, 1964: 508). In addition to the usual hematogenous route, direct extension to the hip joint occurred through long-standing abscesses from vertebral or pelvic TB. However, in advanced stages of the disease, the point of origin could not be determined. In a study of 416 individuals with hip TB reported by Vacchelli (1922, cited in Kremer and Wiese, 1930: 202), the distribution of involvement was total destruction of the femoral head and acetabulum (22; 0.5%), diffuse involvement of the femoral head and acetabulum (220; 52%), diffuse synovial TB

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(52; 52%), and isolated osseous tuberculous foci (122; 2.9%). The isolated foci were distributed as follows: femoral head (60; 14.4%), femoral neck (24; 9.2%), acetabulum (30; 9.4%), and greater trochanter (8; 4.1%). The foci in the femoral head or neck may be small cavitating lesions or larger triangular foci with a spongiosa sequestrum in the center. These lesions may represent ‘territories’ of terminal arteries. Acetabular foci predilect the posterior part of the superior rim and the cartilage-free center around the origin of the round ligament (Fig. 11.11). Lesions in the neck of the femur are often adjacent to the medial inferior cortex (Girdlestone, 1965: 44, 45). Extension of primarily synovial TB into the bone occurs along the synovial attachment on the neck of the femur. The weight-bearing articular surfaces are preserved for the longest period. Ultimately, destruction may be very extensive with an upward-sloping extension of the acetabulum, leading to partial or complete dislocation of the remnant of the femoral head and/or neck (Figs. 11.12 and 11.13). If the dislocation is complete, a new acetabulum is formed on the lateral surface of the iliac wing. In contrast to the appearance of a congenital dislocation of the hip, the head of the femur is more eroded and there is no groove for the round

FIGURE 11.11 Tuberculous arthritis of the left hip, 3 months after resection of the femur; evidence of upward subluxation: (A) lateral view; periosteal build up on the ischium, probably secondary to a cold abscess—one that lacks the classic signs of inflammation and is often associated with tuberculosis of the bone; (B) medial view; hypervascularity of acetabular base (66-year-old female with chronic pulmonary tuberculosis; DPUS 7641, autopsy 880 from 1912).

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FIGURE 11.13 Destructive arthritis of the right hip with upward subluxation; probably tuberculosis. Note the severe osteoporosis of the femur and ilium and the iliac shelf secondary to subluxation (88-year-old female with pulmonary and lymph node tuberculosis who died in 1954; IPAZ autopsy 1445, museum number 5947).

FIGURE 11.12 Tuberculous arthritis of the right hip with upward subluxation, partly healed. Note the restoration of the subchondral bone plate on the partly destroyed femoral head (16-year-old male, who died of tuberculous meningitis in 1936; IPAZ S325).

ligament, which is destroyed by the infection before the dislocation occurs. The original acetabulum is not rudimentary in TB, and the new acetabulum shows evidence of infection. If there is extensive necrosis and destruction of the acetabulum, its pelvic aspect can have lytic defects (Fig. 11.14); perforation of its floor with central dislocation of the remnants of the proximal femur can also occur (Fig. 11.15). Me´nard (1900) observed 105 people with acetabular perforation in the course of 268 hip resections for TB, and Tregubow (1929) reported 12 acetabular perforations in a series of 500 radiologically studied individuals with hip TB. In people with hip TB where healing has taken place, bony ankylosis usually occurs. Growth deficits also may be observed. Differential diagnosis is mainly between tuberculous and nontuberculous septic arthritis. The septic process is rapid and bone destruction is much more limited. Dislocation upwards or centrally is not observed. Bony ankylosis as a final outcome usually reveals little, if any, bone loss of the joint constituents.

Complete destruction of the femoral head is seen only in infants with septic arthritis, which is usually accompanied by osteomyelitis of the shaft. Statistically, hip TB is much more common than septic arthritis. Tuberculosis of the greater trochanter of the femur is an uncommon but characteristic lesion. Sorrel and SorrelDejerine (1932: 70) reported 32 instances of TB of the trochanter (11 in children and 21 in adults) in 6578 individuals with skeletal TB (0.4%), and McNeur and Pritchard (1955) reported 38 affected individuals treated at the Royal National Orthopaedic Hospital (London, England) over a period of 35 years. The age distribution was 30 individuals between 10 and 40 years of age, three children below 10, and five individuals over 40 years of age. The infection may start in the trochanteric bursa or in the bone. It takes a very chronic course and has a great tendency to recur over many years. The lesion tends to remain localized to the trochanteric region, which is progressively destroyed (Fig. 11.16). The cavity often contains a sequestrum of cancellous bone (Sorrel and Sorrel-Dejerine, 1932: 70). Abscess and fistula formation are common. This actually represents the most identifiable tuberculous bone lesion of adults with the exception of spinal TB. It is relatively little known except to orthopedists, although a number of studies have been published (Meyerding and Mroz, 1933; Wassersug, 1940; Alvik, 1949; Ahern, 1958). After the acetabulum, the sacroiliac joint is the most common joint involved in pelvic TB (Fig. 11.17), usually by extension of a lumbosacral focus unilaterally or bilaterally. This is observed more often in young adults than

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FIGURE 11.14 Tuberculosis of the left hip: (A) anterior view; (B) medial view. Note the destruction of the femoral head with exposure of porotic spongiosa and perforations of the involved acetabulum (adult, IPMI KM 352).

FIGURE 11.15 Tuberculous arthritis of the right hip with complete destruction of the acetabulum and central dislocation of the remnant of the femoral head; notice the sparsity of reactive new bone: (A) lateral view; (B) medial view (male about 30 years old; IPAZ 1940, old no. 2167).

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FIGURE 11.16 Tuberculosis of the left hip with destruction of the femoral head and perforation of the acetabulum, and tuberculosis of the left ilium and of both sacroiliac joints. Notice minimal reactive new bone in all affected areas (15-year-old, FPAM 5669, who died in 1895).

FIGURE 11.18 Chronic TB of the right greater trochanter with a fistulating abscess; the hip joint was unaffected. Notice the scalloped destruction of the greater trochanter (54-year-old female with a pulmonary tuberculous focus who died in 1924; FPAM, Jubila¨umspital 857; autopsy).

FIGURE 11.17 Tuberculosis of the spine and left ilium; reactive new bone in the wall of a cold abscess in the left inguinal area. Notice the round defect in the ilium, and erosion and bony build up in the inguinal area (28-year-old male; FPAM 2488, autopsy 33582 from 1853/54).

in children. Unlike in brucellosis, isolated sacroiliac TB is very rare. In their large series, Sorrel and Sorrel-Dejerine (1932: 501) observed only two affected individuals, compared to 114 people who had secondary lumbosacral involvement. There may be considerable destruction of

the sacral wing with some reactive osteosclerosis (Kremer and Wiese, 1930: 198). Healing with bony fusion may lead to asymmetrical pelvic deformity. Isolated tuberculous foci in the ilium are rare, usually consisting of round or oval cavities with or without a central sequestrum, perforation of the cortex, or fistula (Konschegg, 1934: 409 410). However, extension of a psoas abscess into the ilium can occur (Fig. 11.18). It is thus worth noting whether there is any reactive new bone formation (or destruction) evident along the track of the psoas muscle from the spine to the lesser trochanter of the femur (i.e., on the internal surface of the ilium and over the iliopubic eminence). This may reflect a psoas abscess due to TB. TB rarely affects the pubis. However, if the pubis is involved, both sexes are affected about equally and most instances concern older children and young adults.

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The largest study is that of Fares and Pagani (1966). About half of 27 individuals with pubic TB showed other adjacent or remote tuberculous skeletal foci. There is apparently no relationship to trauma or parturition. The lesion in adults is usually close to the symphysis, which may be also involved. In these cases, both pubic bones may be affected (Kremer and Wiese, 1930: 195). The lesion is lytic and destructive, occasionally with the formation of small sequestrae. Abscess formation and fistulas are common. In children, the lesion may be medial to the hip joint because of the incomplete ossification of the pubic area. Similar lesions occur in the ischial ramus (14 ischial compared to 20 pubic lesions in Sorrel and Sorrel-Dejerine, 1932: 76). In addition, occasionally an isolated lesion can occur in the ischial tuberosity, similar to the more common lesion in the greater trochanter (Blankoff, 1927).

The Knee Tuberculosis of the knee joint occurs about as often as or even more frequently than hip TB (Fig. 11.19). Again, the majority of instances begin in infancy, childhood, and adolescence. For example, Johannsson (1926: 177) observed 50% before the age of 5 years, with about an equal distribution between the sexes. In Sorrel and SorrelDejerine’s study (1932: 247) of 558 individuals, 34 infants developed knee TB in the first year of their lives, and only 51 people developed it after age 20. Most hip TB starts as synovial tuberculosis, and it may remain in this area. However, extension of the synovial infection can occur along the capsular insertions of the femur and tibia and along the attachments of the cruciate ligaments. Linear cortical erosion and undermining destruction of the adjacent portion of the articular surface occurs. Significant amounts of localized destruction of the femoral condyles or of the tibial plateau are observed only if a primary or simultaneous hematogenous osseous focus is present, with or without sequestrum (Fig. 11.19). Such foci are more often found in the femoral condyles or in the tibial epiphysis, but rarely in the patella or fibula. Kønig (1906: 112) observed patella involvement in 50 people of 720 considered. In 33 (46%) of these, the patella was the only focus, with or without secondary extension to the knee joint. In healing, fibrous or bony ankylosis results. If bone destruction was absent or limited, differentiation from the bone changes of the end stage of rheumatoid or septic arthritis may be impossible. Both rheumatoid arthritis and TB affecting the knee are usually accompanied by osteoporosis of the involved limb. Tuberculous and septic arthritis are more often unilateral than rheumatoid arthritis. In severe instances, particularly in children, dislocation and valgus or varus deformity of the knee is observed, depending on the

FIGURE 11.19 Tuberculosis of the knee that recurred after previous surgery; notice the destruction of subarticular bone and the minimal reactive new bone formation (13-year-old female who died in 1899; DPUS 3921).

relationship of the affected area to the growth plate. Generally, adults have less destructive bone changes than infants (Sorrel and Sorrel-Dejerine, 1932: 267).

The Ankle (Distal Tibia and Fibula) and Tarsal Bones Tuberculosis of the ankle most commonly involves the tibiotalar joint (Fig. 11.20), and much less commonly the talocalcaneal joint. The lesion is most common in

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FIGURE 11.20 Tuberculous arthritis of the right ankle with extensive destruction of the distal tibial epiphysis and partial ankylosis, with remnants of the talus; histologically proven, and of 9 years duration. Initiated by crushing trauma (25-year-old male who died in 1930; PMES 2 FT 16(1)).

children. In the study of Sorrel and Sorrel-Dejerine (1932: 210), the tibiotalar joint was involved in 185 individuals, of whom 121 were below 13 years of age and only 64 were adolescents or adults. The maximum age of onset occurs at 3 years. In most cases the process seems to start with a hematogenous osseous focus. In most people, the primary bone focus is the talus, less commonly the distal tibia, and rarely the fibula. Ossification of the talus begins at birth and essentially fills the cartilage model at 2 years of age, leaving only the articular cartilage between the ossification center and the adjacent joints. This explains why isolated TB of the talus without involvement of the adjacent joints is not observed (Sorrel and Sorrel-Dejerine, 1932: 210). However, early extension into the tibiotalar joint and also, but less often, into the talocalcaneal joint is common. In tibiotalar TB of talar origin, the talus is cavitated and often ultimately destroyed. Where the tibia was the original origin, significant destruction involves the distal tibial epiphysis and sometimes the metaphysis. Healing always leads to tibiotalar bony ankylosis. In people with

advanced TB of the ankle, the talocalcaneal joint frequently becomes involved at any age. If the talus is completely destroyed, tibiocalcaneal bony ankylosis develops with an uptilted position of the calcaneus. This would not be the case in ankylosis following juvenile chronic arthritis. Because the ankle is a weight-bearing joint, limited perifocal osteosclerosis does occur. Isolated involvement of the talocalcaneal joint usually occurs due to secondary extension of a calcaneal focus. This bone change, limited to the lower ankle joint, is observed only in older children between the ages of 7 and 16 (Sorrel and Sorrel-Dejerine, 1932: 207). Healing terminates with broad bony fusion of the talus and calcaneus. After the talus, of the tarsal bones, the calcaneus is most frequently affected. Sorrel and Sorrel-Dejerine (1932: 207) observed 131 individuals with calcaneal TB but only 29 for all other tarsal bones. The explanation for the frequent and often isolated involvement of the calcaneus rests with its development. An ossification center usually appears as early as the last trimester of intrauterine life and ossification is not completed until 17 18 years of age. This makes it a highly vascular area available for tuberculous seeding in infancy and early childhood, whereas thick layers of the cartilage still separate the focus from the adjacent joint cavity (Sorrel and SorrelDejerine, 1932: 268). In early childhood, central TB of the calcaneus is fairly frequent and may heal without permanent traces because of the effect of growth and remodeling. At age 7 9 years, an apophyseal ossification center appears on the posterior portion of the calcaneus, and during later childhood tuberculous foci adjacent to the anterior surface of the posterior growth plate appear. The lesion usually shows a cavity with a central spongiosa sequestrum and often some perifocal osteosclerosis. After termination of growth in the adult, tuberculous foci of the calcaneus readily break through or around the articular cartilage into the talocalcaneal joint, and from there spread to the tibiotalar joint (Sorrel and Sorrel-Dejerine, 1932: 59 60). In Sorrel and Sorrel-Dejerine’s study, the cuboid bone was much less often involved and most of the patients were children (11 children, two adults). The ossification of the cuboid bone begins at 3 months of age and terminates at 9 10 years. Occasionally, the navicular bone was involved in older children (six children, one adult). Ossification of the navicular bone begins at 21/2 5 years and terminates between 10 and 12 years of age. The cuneiform bones are rarely involved; if destroyed, medial deflection of the foot may occur. Foci like these may remain isolated in children and may heal without joint involvement (Sorrel and Sorrel-Dejerine, 1932: 63 65). In adults, tarsal bones may be affected in extensive TB of the ankle. A differential diagnosis between TB and subacute osteomyelitis based on isolated tarsal lesions may be impossible in dry bone.

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ischemic necrosis and/or penetration of the thin cortex. The cortex may be resorbed rapidly or form a sequestrum. The elevated periosteum forms a new bony shell that accounts for the ballooned appearance of the involved bone (Fig. 11.21). These lesions often accompany other skeletal manifestations of TB. If the child does not die from TB located elsewhere, the lesion usually heals. Destruction of the growth plate in metacarpals and metatarsals and, less commonly, of phalanges, may lead to marked shortening of the digit after healing. If this is not the case, evidence of the healed lesion will disappear in remodeling. Very similar lesions are produced by osteomyelitis, congenital syphilis (CS), and sickle cell anemia. However, those foci are usually singular, and expansion of the involved bone is usually much less marked. In children, tuberculous dactylitis spares the interphalangeal joints. In adults, the phalanges may be involved, but only rarely does the lesion extend into the joint. The body of these bones is not expanded by the disease process (Girdlestone, 1965: 183).

The Shoulder

FIGURE 11.21 Tuberculous dactylitis (spina ventosa) of a first metacarpal. Notice expanded involucrum surrounding the remnant of the diseased bone; the epiphyses are spared (PMES 1 FT 12(1)). NB: This image appears may be a composite of bones from different individuals.

The Tubular Bones of the Hands and Feet The most frequent localization of skeletal TB in infancy and early childhood is the often multiple involvement of phalanges, metacarpals, and metatarsals (tuberculous dactylitis or spina ventosa). Sorrel and Sorrel-Dejerine (1932: 2) reported that, among 4660 children with skeletal TB, 649 had spina ventosa (15%), with 1 10 foci in individual patients. Bailleul (1911: 4) reported that in 274 patients there were 495 lesions of spina ventosa, of which 381 were located in the hands and 114 in the feet (80% and 39%, respectively). The age distribution in Johannsson’s (1926: 144) study was: 15% affected in the first year, 62% affected below 3 years of age, and 77% affected below 5 years. The lesion rarely occurred after 10 years of age. Of his patients, 50% showed solitary lesions. The affected sites were the fingers (108), metacarpals (68), metatarsals (32), and toes (11). In infancy and early childhood, these short tubular bones still have hematopoietic marrow throughout the shaft, and a focus will readily occupy the whole diaphysis, leading to

Tuberculosis of the shoulder is much less common than that of the hip or knee. For example, Kastert and Uehlinger (1964: 517) report only 77 cases (4.7%) among 2457 patients with skeletal TB. It may be observed at any age, but it appears in adults more often than in children. Males are more affected than females, and the right side is three times more affected than the left for both sexes (Kremer and Wiese, 1930: 291). The complicated relationship of the shoulder joint to the synovial sheath of the long biceps tendon and to the subdeltoid bursa favor extensive synovial involvement. If osseous foci are present, they are more frequently found in the head or proximal metaphysis of the humerus than in the scapula (Fig. 11.22). In children, cavities with sequestra occur in the epiphysis and metaphysis of the proximal humerus (Sorrel and Sorrel-Dejerine, 1932: 165 168). In the synovial form, extension to the humerus occurs along the capsular attachment, creating a resorption groove on the lateral aspect of the humeral head. In children, shoulder TB may heal. In adults, extensive destruction of the humeral head and of the glenoid fossa is common. Occasionally the acromion and clavicle may also be involved (Fig. 11.23). Abscess formation and fistula are less frequent than in other large joints. In a differential diagnosis, septic arthritis is the main consideration. Bone destruction in septic arthritis is usually much less extensive and the lateral grooving and undermining defect on the humeral head are not observed. The scapula is very rarely involved, except by extension of TB of the shoulder joint into the glenoid fossa or the acromion.

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In hematogenous TB of the scapula, the vertebral margin is predilected (Kremer and Wiese, 1930: 301).

The Elbow

FIGURE 11.22 Tuberculosis of the humeral head with cavitation; sequestrum removed (resection example). Note the exposed porotic hypervascular bone with little reactivity (17-year-old female; PMWH W0709).

In many studies, TB of the elbow is the most frequent joint affected of the upper extremity (50%; Kremer and Wiese, 1930: 304). Most lesions develop at between 1 and 20 years of age (Kønig, 1906: 141; Cheyne, 1911: 328). In the period between 1918 and 1928, Sorrel and Sorrel-Dejerine (1932: 121) observed TB of the elbow in 164 children and 72 adults. Osseous foci, if present, were most common in the distal humerus, secondly the proximal ulna, and least in the proximal radius. Kønig (1906: 141 142) found bony foci in 91 of 128 patients (75%), with 43 cases involving the distal humerus (mostly in the lateral condyle), 36 cases including the ulna (olecranon), and 2 cases engaging the proximal radius. In people with advanced TB, several of the adjacent bones may be involved. In very young children, a central tuberculous focus in the olecranon may be present as part of multiple skeletal foci (fingers, toes, calcaneus, zygoma). This is a cavitating lesion with a central sequestrum and reactive periostosis resembling spina ventosa. In cases like these, the joint may not be affected (Sorrel and SorrelDejerine, 1932: 121). After 6 years of age, the joint is often involved by extension of the ulnar focus through the joint cartilage. This leads to deeper excavation of the trochlear notch of the ulna, with elongation of its coronoid process. In children, the process may heal with fibrous ankylosis. In adults, destruction of the adjacent bones may be extensive, and usually the head of the radius is the least and last affected. Healing usually terminates in bony ankylosis (Fig. 11.24). Ankylosis without major bone loss may be impossible to differentiate from erosive arthropathy or septic arthritis. Periarticular osteophytosis can occur in extensive capsular involvement (Fig. 11.25).

The Wrist and Carpal Bones

FIGURE 11.23 Cavitating TB of the lateral portion of a right clavicle. Notice the scarcity of reactive bone (an adult with tuberculous arthritis of the shoulder who died prior to 1920 ;PMES 1. FT. 5 (2)).

The wrist consists of three partly separated joints: the radiocarpal joint, the intercarpal joints, and the carpometacarpal joint. Any one or all of them may be involved in TB. The following discussion is mainly based on the detailed study of Sorrel and Sorrel-Dejerine (1932: 91 120). They observed 63 instances of TB in these joints in children and 51 instances in adults. The location and manifestation of the lesions vary greatly in different age groups. In children, the carpometacarpal joint is mainly involved and the radiocarpal joint is spared. In adults, the process usually begins in the radiocarpal joint and spreads rapidly throughout the joint compartments of the wrist (Fig. 11.26). The difference in age groups is explained by the anatomy and maturation of the

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FIGURE 11.24 Tuberculosis of the right elbow with bony ankylosis between the radius, ulna, and humerus. Notice the marked involvement and enlargement of the distal humerus. The defect of the olecranon process is artificial (amputated from a child; PMES 2 FT 7(4)).

constituent bones. In children below 4 years of age, the carpus is mainly a block of cartilage with minimal focal ossification. At this stage, carpal TB is not observed. From 4 12 years of age, carpal ossification centers become larger and more numerous. At this time, localized carpometacarpal involvement is observed because adjacent bones are still protected by thick layers of unossified cartilage. The carpometacarpal joint is uncommonly involved by extension of spina ventosa of an adjacent metacarpal. In general, an active growth plate serves as a barrier to the extension of TB to the adjacent joint. Metacarpals 2 5 are devoid of a proximal growth plate. These localized joint lesions may heal, along with healing of the accompanying spina ventosa, leading to bony fusion between individual carpals and metacarpals. With increasing age, the cartilage cover diminishes and extensive joint involvement becomes the rule. In children and adults, the joint lesion may originate directly in the synovium or by contact with tuberculous tenosynovitis. Osseous destructive foci are not infrequently present in

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FIGURE 11.25 Tuberculosis of the right elbow. Notice exposure of subchondral porotic spongiosa on all the joint surfaces and partial destruction of the radial head. The periarticular new bone formation suggests extensive capsular involvement (68-years-old; IPAZ 1969, old number 253).

FIGURE 11.26 Tuberculosis of the left wrist: wet preparation with soft tissue attached, showing extensive destruction of the distal radius, ulna, carpal bones, and carpometacarpal joints of 1-year duration (56-year-old male with pulmonary tuberculosis who died in 1876; WM S82.1).

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the distal radial epiphysis and/or metaphysis of adults. The disease rapidly spreads through the entire wrist and, in contrast to the type seen in infants, the proximal row of carpal bones is more severely involved. In healing, with various degrees of bone loss, the entire carpus becomes a solid bone block, fused to the radius and often to the base of the metacarpals.

The Shaft of Long Bones Tuberculosis of the shaft of long bones is uncommon. It is almost exclusively observed in children and frequently as a manifestation of multiple skeletal foci, particularly spina ventosa. Sorrel and Sorrel-Dejerine (1932: 2, 21) observed about 100 instances in infants and children compared to 649 children with spina ventosa. The lesion consists of eccentric cavitation, usually in the metaphysis, with a small sequestrum (Fig. 11.27), and is often marked by reactive periosteal bone formation over the overlying cortex (Fig. 11.28). Thus, in children, there is considerable resemblance to the appearance of spina ventosa (Figs. 11.29 and 11.30). In adults, the lesion is extremely rare, and periosteal bone formation is meager (Fig. 11.31). Perifocal osteoporosis may be followed in long-standing cases by perifocal osteosclerosis. A certain differentiation from

FIGURE 11.27 Tuberculosis of the lateral epicondyle of the right humerus. Notice the smooth cavity with a porotic sequestrum and minimal reactive new bone in the vicinity (adult; DPUS 5989, French catalog no. 834).

FIGURE 11.28 Tuberculosis of the medial epicondyle of the right humerus. Notice the central lytic focus with moderate periosteal reactive bone. The joint is not involved (adult; DPUS 5982, French catalog no. 827).

FIGURE 11.29 Tuberculosis of the proximal left ulna with extension to the elbow joint and humerus; posterior view. Notice the bulbous expansion of the new ulnar cortex with a single cloaca, destruction of the olecranon, and erosion of the humerus (child; PMES 2. FT. 7 (6)).

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osteomyelitis and Brodie’s abscess may be impossible on dry bone. The frequency of involvement in descending order is the tibia, ulna, radius, humerus, femur, and fibula (Konschegg, 1934: 422). While TB of the shafts of long bones is uncommon, hypertrophic pulmonary osteoarthropathy (HPOA) may be caused by TB (Assis et al., 2012). Florid new bone formation on long and short tubular bones occurs in this condition and is commonly seen on the lower-limb long bones (Resnick and Niwayama, 1995c). Assis et al.’s (2012; see also Binder and Saad, 2017) study of skeletons with known cause of death curated in the Coimbra Identified Skeletal Collection, Portugal, found that the risk of developing HPOA was greater in people who had died from TB. While not pathognomonic for TB, HPOA is one of the nonspecific changes in the skeleton that could be associated with TB.

Ribs

FIGURE 11.30 Tuberculosis of the proximal radius with enlargement of a new cortex and multiple perforations (cloaca/sinuses); the epiphysis and articular surface are spared (6-year-old girl with tuberculosis of the cervical lymph nodes, who died prior to 1900; PMES 1 FT 10(2)).

Tuberculous involvement of one or several ribs is not rare. Sorrel and Sorrel-Dejerine (1932: 84 88) observed 93 instances (56 children and 37 adults.) The infection is usually hematogenous, but direct extension from paravertebral abscesses and other adjacent tuberculous foci can occur (Kremer and Wiese, 1930: 283). The hematogenous foci predilect the area near the osteocartilaginous border

FIGURE 11.31 Healed TB of the distal femur with partial ankylosis of the knee and severe osteoporosis due to disuse: (A) external view; note periosteal hyperostosis; (B) cut surface; note cavitation in the femoral metaphysis and severe osteoporosis (68-year-old male; IPAZ 6052; surgical example MB 6936 dated to 1955).

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and may involve the cartilage secondarily (Kastert and Uehlinger, 1964: 515). The process creates a lytic lesion with fusiform enlargement of the involved area and often perforations of the cortex lead to chest wall abscesses. Periosteal reactive bone formation is usually rather meager. The middle ribs are more often affected than the upper or lower ones and secondary involvement of adjacent ribs can occur (Konschegg, 1934: 407). It is rare for the clinical literature to reference new bone formation on ribs as a result of any pulmonary disease (but see Eyler et al., 1996: enlarged ribs on radiographs likely due to new bone formation); the predominant bone change for TB on ribs is described as lytic. This may be explained by the subtle new bone formation seen on dry bone not being visible on a radiograph. Research on modern (late 19th early 20th centuries) documented human skeletons of individuals known to have died from TB suggests that rib involvement (Fig. 11.32) is most likely to occur in people with TB than for any other pulmonary affliction (Kelley and Micozzi, 1984; Roberts et al., 1994; Santos and Roberts, 2001, 2006). Lung diseases inflame the pleura, and they can thus affect bone because the pleura attaches to the visceral surfaces of the ribs. This can stimulate an inflammatory reaction on the rib surface. Like many skeletal lesions stimulated by disease, there are multiple potential causes for these periosteal bone-forming lesions (e.g., pneumonia, chronic bronchitis, lung cancer, and any situation where poor air quality is present), but research suggests that the type of bone formed and the position of the reactive new bone on the rib cage can help focus on a specific diagnosis (Santos and Roberts, 2006). However, differentiation from osteomyelitis, other infectious conditions affecting the pleura, fibrous dysplasia, and

Langerhans cell histiocytosis may be very difficult on dry bone. Rib lesions such as those described here have formed the focus of several studies in paleopathology, including Lambert (2002), who considered them indicative of exposure to poor air quality in prehistoric Puebloan people from Southwestern Colorado, and Nicklish et al. (2012) who concluded that the rib lesions of people buried at early Neolithic sites in central Germany were the result of TB (based on positive DNA data). The latter study made the assumption that the lesions were caused by TB, although this cannot be proven. The pleura may be also be calcified in TB, but other lung diseases can cause this pathological change, and sometimes pleura have been found archeologically (Donoghue et al., 1998).

Sternum The sternum is much less frequently involved in TB than the ribs. Kønig (1906: 155) observed that ribs are five times more often affected compared to the sternum. The most frequent location is in the manubrium (Fig. 11.33). These lesions may extend into the sternoclavicular joint and involve the medial portion of the clavicle. The sternal lesion is mostly lytic and may perforate the anterior or posterior cortex or both. In a differential diagnosis, erosion of the manubrium by an aortic aneurysm must be considered.

The Skull The skull is a rare area to be affected in TB, except in young children. Tuberculosis involvement of the skull is separated into three areas: cranial vault, cranial base, and face.

FIGURE 11.32 Reactive periostosis of the pleural surface of the left ribs 7 and 8 from a patient who died with tuberculosis (female 18 years old, Robert J. Terry Anatomy Collection, NMNH 382085306).

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FIGURE 11.33 Tuberculosis of the sternum (posterior view), probably by direct extension from TB of the visceral layer of the pleura. Note destruction of the manubrium and body of the sternum with a moderate amount of reactive new bone (PMWH WO 706).

Cranial Vault This is the most common location of cranial TB. Sorrel and Sorrel-Dejerine (1932: 78) observed 21 individuals with vault TB (16 children and five adults). In a statistical survey (Straus, 1933), the distribution of cranial TB was as follows: frontal bone, 86; parietal bone, 86; occipital bone, 18; and temporal bone, 16. The majority of those affected were infants and children below 10 years of age. The infection is usually spread through a hematogenous route to the cranial vault. In children, the lesions are often multiple and secondary to or coexistent with other active tuberculous skeletal foci (Sorrel and Sorrel-Dejerine, 1932: 79 80). The presence of hematopoietic marrow and the growth activity in the cranium at this age determine the frequency of involvement. The most characteristic lesion is a round lytic focus of not more than 2 cm in diameter, with or without a “moth-eaten” central sequestrum, terminating in complete perforation of the inner and outer tables (Fig. 11.34; see also Hackett, 1976: 51). There is often abscess formation and a fistula with transcutaneous elimination of the sequestrum. The lesion

FIGURE 11.34 Tuberculosis of the cranial vault: (A) external view; notice little reactive new bone around the frontal bone defect and a porous sequestrum in the parietal bone lesion; (B) endocranial view; the frontal bone lesion is broader based on the inner table (adult; DPUS 4584).

frequently crosses suture lines. The margin of the typical lesion shows active resorption with minimal reactive bone formation at the margins of the lesion. However, in some cases large destructive lesions can occur with considerable marginal bony repair (Fig. 11.35).

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FIGURE 11.35 Cranial TB with a lytic lesion penetrating both tables of the skull on the left frontal bone just above the greater wing of the sphenoid bone: (A) left lateral view of the skull; (B) interior view of the skull. Note that the area of bone destruction is much larger on the interior surface (female 17 years old, Robert J. Terry Anatomy Collection; NMNH 382085-329).

FIGURE 11.36 Tuberculosis of the cranial vault secondary to tuberculous external pachymeningitis (diffuse inflammation of the dura mater): (A) ectocranial view showing small perforation of the outer table; (B) endocranial view; notice the lesions are much larger on the inside; (C) left lateral view, showing healing (12-year-old female who died in 1914 ; FPAM Jubila¨umspital 40).

Spread along the internal periosteum of the cranial vault, perifocal bone resorption, and hypervascularity are often observed. In juveniles, the lesions have to be differentiated from Langerhans cell histiocytosis and metastatic neuroblastoma. Solitary lesions of Langerhans cell histiocytosis usually do not contain a central sequestrum and do not cross suture lines. Multiple lesions of

reticulosis usually do not spare the skull base. Metastatic neuroblastoma often shows a marked osteoblastic reaction. In adults, the cranial vault lesion is almost always solitary and often much larger than in infants and children. In addition to the hematogenous route, extension from tuberculoma of the brain or dura does occur (Fig. 11.36). The process is characterized by a chronic

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FIGURE 11.37 Tuberculosis of the right parietal bone: (A) ectocranial view; notice the small perforation in the exposed diploe; (B) endocranial view, showing the larger defect on the inner table sloping to a smaller perforation on outer table (55-year-old female who died of tuberculosis in 1896; ANM 2480, autopsy 658-(16)).

progressive destruction of the cranial vault with irregular margins. Major sequestration is uncommon, in contrast to osteomyelitis, and bony reaction is very limited or absent, in contrast to tertiary acquired syphilis. The defect of the inner table is usually larger than that of the outer (Fig. 11.37), whereas in tertiary syphilis the greater defect is usually external and the inner table may be completely intact (Erdheim, 1932: 355). Metastatic cancer of the skull is another differential diagnostic option (Hackett, 1976: 50). In archeological skeletons, involvement (or not) of the two tables of the skull may have been a developing lesion at death. Thus, the end result might have been more extreme. Another lesion of the inner table may also be seen in skeletons of individuals who had TB. The lesion consists of a cluster of vascular lines on the inner table that are probably the result of hypervascularity stimulated by a tuberculosis focus in the adjacent soft tissue (Fig. 11.38). There has been some discussion and debate about the causes of these endocranial lesions (Schultz, 1999; Hershkovitz et al., 2002; Lewis, 2004) alongside endocranial destructive lesions (Kappelman et al., 2008; Roberts et al., 2009). These studies conclude that multiple etiologies should be considered in a differential diagnosis, such as normal bone growth in nonadults, scurvy, and TB meningitis.

FIGURE 11.38 Vascular lesions of the inner table of the skull, possibly resulting from reaction to an adjacent soft-tissue tuberculous lesion (female 18 years old, Robert J. Terry Anatomy Collection, NMNH 382085-306).

Cranial Base The base of the skull is rarely involved in TB. However, tuberculous otitis media is quite common in infants; in an early 20th-century report it represented 50% of middle ear infections in the first year of life and about 3% at all

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FIGURE 11.39 Cranial TB with a lesion in the right frontal bone and left middle ear: (A) lateral view, showing exposed diploe and posterior penetration of the inner table; (B) basal exterior view, showing involvement of the left middle ear, necrosis of the mastoid process, and extension to the base of the sphenoid bone (from a child about 8 years old who died in 1837; DPUS 5266, French catalog no. 779).

ages (Fraser and Stewart, 1936: 402). There is occasional destruction and sequestration of the petrous portion and mastoid process of the temporal bone by secondary extension of mucosal middle ear TB (Krause, 1899: 54) (Fig. 11.39). Occasionally, the base of the occipital bone in the vicinity of the foramen magnum may be affected in suboccipital TB of the atlas and axis (malum suboccipitale) (Fig. 11.40). Facial Bones In small children, focal TB of the inferior lateral orbital margin is not uncommon, including the maxilla, especially at the junction with the zygoma. Involvement of the zygoma itself is also seen frequently. Chronic TB of the zygomatic arch may lead to an abscess, which typically ascends the temporal squama along the temporal muscle (Fig. 11.41). In most instances, there are multiple skeletal TB foci elsewhere. These facial lesions are superficial, leading to small sequestra that are frequently eliminated by fistulae (Krause, 1899: 54 55; Kremer and Wiese, 1930: 153 155). The bony walls of the nasal cavity may be secondarily affected by extension of mucosal TB (Fig. 11.42). The facial bones also can be secondarily involved by longstanding TB of the facial skin and soft tissues (lupus vulgaris: Fig. 11.43), which often leads to destruction of the nasal bones, as in leprosy (Figs. 11.44 and 11.45).

FIGURE 11.40 Tuberculosis of the cranial base and atlas with superficial erosion of the anterior surface of the cervical vertebrae suggestive of a paravertebral abscess. This person had a sudden death by compression of the medulla (55-year-old male with chronic pulmonary tuberculosis; PMWH WO 702).

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FIGURE 11.41 Cranial TB with destruction of the left zygomatic arch and involvement of the temporal bone and mastoid process with periosteal reaction to the subtemporal abscess. Separate foci in the frontal and left parietal bones (adolescent who died in 1837; DPUS 5268, French catalog 778a).

FIGURE 11.42 Tuberculosis of the cranium with a right frontal bone and basal lesion: (A) ectocranial view, showing small sieve-like perforation of the outer table; (B) endocranial view, showing large dura-based lesion crossing the coronal suture; (C) endocranial view of destructive lesion of the sphenoid-ethmoid bone area; (D) exterior view of the skull base (10-year-old female, ANM 2439 who died in 1870).

FIGURE 11.42 Continued

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FIGURE 11.42 Continued

FIGURE 11.43 Lupus vulgaris—skin TB. Lupus vulgaris exulcerans ˜ r Rongeante: Albert. (Hebra); Synon: Lupus; Lupus exedens; DartrA Bears number: Plate III. Credit: Welcome Collection (free to use with attribution: https://wellcomecollection.org/works/yduk4vpk? query 5 lupus 1 vulgaris).

FIGURE 11.44 Craniofacial TB in lupus vulgaris, with destruction of the nose: (A) anterior view, showing porotic erosion around the nasal aperture and maxilla; extensive destruction of the mandible; (B) left lateral view, showing multiple superficial erosive lesions of the cranial vault and extensive destruction of the mandibular angle (12-year-old male with pleural TB and meningitis who died in 1888; FPAM 5001, autopsy 87916).

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(or any other animal that can be infected—see Introduction above) could have acquired the disease by breathing similar aerosols. Dissemination of the bacteria from the gastrointestinal tract to other sites within the affected person is always a possible complication of gastrointestinal TB acquired from animals. However, from Brosch et al.’s (2002: 3685) research we now know that the M. bovis species did not precede M. tuberculosis and that “M. tuberculosis and or M. canettii are most closely related to the common ancestor of the tubercle bacilli.” Nevertheless, whatever the evolutionary scenario, the transmission of a bovid or other MTC zoonotic disease to people and vice versa could have occurred at almost any time in ancient human history, and this continues to be the case today. For example, our hunter-gatherer ancestors could have eaten contaminated meat of animals and acquired the disease. When humans adopted farming, this gave the requisite conditions for both the animal and human form of TB to thrive. Higher population density promoted the spread of M. tb from human to human and closer association of humans with their animals facilitated the transmission of the MTC organisms to humans. Stable populations with many potential new hosts would have been an important factor in developing an endemic disease. FIGURE 11.45 Cranial TB in lupus vulgaris, with partial destruction of the nasal bones, conchae, nasal septum, maxilla, and palate, along with periostosis of the mandible; 10-year duration (15-year-old male who died prior to 1920; PMES 1 FT 2(1)).

It may potentially also cause underlying bone destruction (Roberts et al., 1998). In infants, the mandible occasionally also shows hematogenous foci near its angle. These lesions may be very similar to foci of Langerhans cell histiocytosis. In adults, in advanced stages of open pulmonary TB, extension of oral mucosal lesions into the alveolar process of the mandible uncommonly and, even less often, of the maxilla has been described (Zandy, 1896).

Paleopathology Tuberculosis is one of several diseases that can be transmitted between humans and animals. The prevailing hypothesis until 2002 had been that TB was first transmitted to humans by cattle or their bovid ancestors through the ingestion of meat or milk of infected animals (Brosch et al., 2002). This caused the gastrointestinal form of the disease, which is not spread from person to person. Cattle probably contracted the disease in antiquity through breathing in the organism-laden aerosol of infected cattle, which is one of the modes of transmission in cattle today (Pfeiffer and Corner, 2014). Humans in contact with cattle

Old World Evidence Finding the earliest evidence of TB continues to be a tantalizing quest in paleopathology, which extends to early work, such as that of Bartels (1907), who reported on a Neolithic skeleton found near Heidelberg, Germany. The fourth and fifth thoracic vertebrae had collapsed and fused with the somewhat abnormal sixth vertebra, creating an angulation often, but not exclusively, seen in spinal TB. Roberts (2015) and Roberts and Buikstra (2003: 129 213) provide helpful summaries on more recent research on the antiquity of TB in both the New and Old Worlds (see also special issue of Tuberculosis, 2015). Roberts (2012) discusses developments in understanding of this ancient disease, and Roberts and Brickley (in press) discuss the synergies between infectious and metabolic diseases. Pa´lfi et al. (1999) also remains a good source of information. The survey of paleopathological evidence here cannot be allencompassing, but it provides a reasonable overview both temporally and geographically. Aufderheide and Rodriguez-Martin (1998: 126) note the lack of convincing evidence of spinal lesions potentially caused by TB in any reports on Paleolithic human remains. This remains the case as this volume goes to press. There is also limited evidence, although increasing over recent years, of Pott’s disease occurring in the Neolithic period at about the time when human groups

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were beginning to live in large, settled communities. This is a strong argument for the association between infectious disease and increasing population size, dependence on agriculture, the domestication of animals, and the emergence of urbanism. However, spinal destruction

possibly attributable to Pott’s disease has been reported in skeletons from two sites in Italy dated to between 3500 and 4000 BC (Formicola et al., 1987; Canci et al., 1996), and more recently a 3500 BC skeleton with multifocal TB was reported from Liguria, Italy (Sparacello et al. 2017 FIGURE 11.46 Multifocal tuberculosis. Pollera cave skeleton 21, Liguria, Italy (Sparacello et al., 2017); (A) Lateral and superior view of the proximal left humerus; new bone formation, and destruction of the surface in contact with the growth plate and the underlying remodeled trabeculae. (B) Detail of the inferior margin of the right scapula, visceral view. (C) Inferior view of the fourth cervical vertebral body. (D) Inferior view of the ninth thoracic vertebral body. (E) Sternal ends of three ribs with lytic lesions and proliferative bone. (F) Left, the right ischium: absence of the ischio-pubic ramus; Right, anterior view of the lesion. Courtesy: Vitale Sparacello.

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FIGURE 11.46 Contiuned

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and see Fig. 11.46). Two early skeletons with TB from Hungary are also described by Ko¨hle et al. (2014) at the site of Versend-Gilencsa (late Neolithic or 6000 BC), and by Masson et al. (2016) dated to 5000 BC. Germany also claims Neolithic evidence for TB dated to 5400 4800 BC (Nicklish et al., 2012). People living in the Neolithic Yaoi period in Japan are further reported to have skeletal evidence of TB (Suzuki and Inoue, 2007: c.300 BC to AD 300), as have those living in Korea (Suzuki et al., 2008: 1st century BC). In the Middle East a skeleton was also reported by Ortner (1979) from a site in Jordan that is dated to the Early Bronze IA period (c.3100 BC), and there is evidence for a prehistoric skeleton with TB in England from the Iron Age, 300 BC (Mays and Taylor, 2003). Not surprisingly, Egyptian skeletal remains have revealed evidence of TB, too (Derry and Elliot-Smith, 1909; Elliot-Smith and Dawson, 1924; Derry, 1938). For example, Elliot-Smith and Ruffer (1910) reported probable TB in an Egyptian mummy dating from the 21st Dynasty (c.1000 BC). There was extensive destruction of the last four thoracic and first lumbar vertebrae. Inferior to the lesion on the lumbar vertebra was a swelling in the soft tissue, which Elliot-Smith and Ruffer judged to be a paravertebral abscess within the psoas muscle. Although no tubercle bacilli were found in any of the soft-tissue lesions, the morphological evidence for TB is strong. Indeed, although discounting much of the purported evidence for TB in ancient Egyptian remains, Williams (1929: 869 873) concluded that the evidence for TB in Egyptian human remains was convincing. Morse et al. (1964) and Buikstra et al. (1993) reached a similar conclusion. Since the early 20th century, there has been further work on TB in Egypt. Dabernat and Crubezy (2010) report multiple bone TB in a child from Predynastic Upper Egypt (3200 3100 BC). The macroscopic evidence for TB in human remains from the Old World is clearly convincing, and some of it is of very early in date. There has also been considerable ancient DNA analysis of remains since the early 1990s to identify TB in such remains, and this has included exploring the evolution of the MTC organisms (see Chapter 8).

New World Evidence The study of TB in the New World has a contentious history that extends across more than 100 years. A number of themes and tensions common to paleopathology as a discipline are illustrated here. These include: (1) early contributions primarily by medical doctors; (2) concern for a lack of contextual information; (3) tensions between medical doctors, whose opinions reflect their patient experience, and anthropological scholars whose inferences develop from historical and global literature reviews; and (4) the genomic revolution that began in the 1990s (see

Chapter 8). Our discussion is organized around two basic questions: (1) Was TB present in the Western Hemisphere prior to European contact? and (2) If present, what was its phylogeography—when did it enter the New World and how did it spread? Was There Pre-Columbian Tuberculosis? This discussion begins with the earliest proposed evidence of TB. In the 18th and 19th annual reports of the Peabody Museum at Harvard, Whitney (1886) described three skeletons with bone changes he attributed to TB. This was among other anomalies, injuries, and diseases that he observed in archeologically recovered bones from North American “native races”. Whitney was a clinical pathologist and anatomist, as well as the appointed curator of the Warren Anatomical Museum at the Harvard Medical School (1879 1921). The three individuals he described included an individual from a “stone-grave mound, near Nashville, Tennessee “(Whitney, 1886: 445), who presented with vertebral body destruction and kyphosis extending from C4 to T5. Attention also was called to ceramic water bottles from stone box graves with artwork identified by Whitney as kyphotic upper spines. The other two examples, also from stone box graves, involved the right knee and left ankle. Thus, Whitney established an American tradition of evaluating both diseased bones and artistic representations. In his important early 20th-century report on TB among native populations of the American West, Aleˇs Hrdliˇcka (1909) argued that TB must have been absent or perhaps rare in pre-Columbian America. He based his conclusion on the paucity of securely dated prehistoric skeletal examples, the lack of reports by the earliest settlers and elderly Native Americans, the absence of traditional remedies, the recent virulence of the disease, and the apparent absence of an immune response. While Hrdliˇcka’s conclusions were logical at the turn of the 20th century (Buikstra, 1981a), skeletal evidence continued to accumulate (see summaries in Buikstra, 1981b, 1999; Roberts and Buikstra, 2003), convincing the prominent medical historian, Erwin H. Ackerknecht (1955) that TB existed in the Americas prior to 1492. During the 1960s, however, two physicians/paleopathologists, Dan Morse (1961, 1967, 1969) and Aidan Cockburn (1963), concluded that TB was not present in pre-Columbian America. Morse’s criteria for recognizing TB in ancient populations were grounded in his clinical experience with TB and his avocational interest in archeology (Rose and Burke, 2012). Morse (1961) was rigorous in his approach to paleopathology, establishing six criteria by which TB could be recognized in skeletal remains, concluding that, in his opinion, there was no convincing pre-Columbian evidence of TB in the Americas. As Buikstra (1981a)

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concluded two decades later, the tension between medical opinion and archeological evidence was based partly upon sampling bias—archeologists, such as Ritchie (1952), selected and presented extreme pathological examples to medical specialists. Medical specialists, on the other hand, increasingly based their conclusions on patients whose treatments had attenuated the disease course. “The anthropological bias was therefore toward the extreme, whereas Morse’s clinical experience would have tended toward the other end of the continuum” (Buikstra, 1981a: 9). Cockburn’s (1963) skepticism developed from his opinion that there were not sufficiently large, settled groups in the pre-Contact Americas, that Native Americans presented classic symptoms of groups experiencing TB for the first time, and that there were no domesticated animals to serve as an intermediate host (Buikstra, 1981a). As reported by Stone and Ozga (Chapter 8), we now know that domesticated animals were not necessary for the development of TB in ancient American people. We also know that there were large settled communities across the Americas prior to Colombian contact, and we have clear evidence that the TB strain introduced by Europeans (Lineage 4) was distinctly different from the pre-Colombian strain present in South America (Lineage 6) (Bos et al., 2014). The accumulation of skeletal and desiccated softtissue evidence for ancient TB in South America (Allison et al., 1973, 1981) stimulated further excavations in the arid western Andes (Buikstra, 1995). Pioneering molecular studies associated with this region yielded PCR products compatible with TB (Salo et al., 1994; Arriaza et al., 1995). As Stone and Ozga report in Chapter 8, PCR methods are subject to limitations that are overcome largely through next-generation sequencing approaches, which have confirmed the presence of MTC ancient DNA in 1000-year-old skeletons from the Osmore River drainage in Peru´. Similar limitations apply to a number of other PCR aDNA results from North America (e.g., Rothschild et al., 2001). Phylogeography of American Tuberculosis One of the reasons that American TB largely has been ignored in histories of infectious disease is explained by the popular evolutionary narrative—human TB derived from M. bovis when pastoralists came into close contact with domesticated host animals in the Eastern Mediterranean. There is no place for an American TB in this scenario. As we now know from genomic studies, however, the human TB forms are more complex, and therefore more ancient than those affecting other species originating in Africa. This antiquity permits reconstructions of global histories, including transfer to the Americas through human migrations. While this model

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seems plausible and may still explain ancient TB in North America, the “jump” of TB back to humans from Lineage 6 pinnipeds is now supported by empirical evidence (Bos et al., 2014). Additional studies will be required to document and hypothesize spread of this form of TB throughout South America during the first millennium AD and subsequently to North America by traders from Ecuador by AD 1000 (Buikstra, 1999).

Skeletal Examples All manifestations of skeletal TB can also occur in any one of several other infectious diseases as well as other pathological processes, including cancer (Chapter 21) and trauma (Chapter 9). This similarity in expression between TB and other diseases is a reason for caution, particularly for destructive lesions of bone other than vertebrae. However, careful description of visible bone lesions and a knowledge of the effect of TB on the bones does permit reasonable inferences about the presence of TB. In the remaining paragraphs of this discussion of the paleopathology of TB, a few examples are given from both the Old and New Worlds where a diagnosis of TB is plausible, if not probable. One of the earliest examples of probable TB is from the site of Bab edh-Dhra in Jordan (Ortner and Frolich, 2008). The skeleton (burial 73) represents a young male about 18 years old at the time of death, who was excavated from a shaft tomb chamber numbered A100E (Ortner, 1979). Tombs of this type are associated mostly with the Early Bronze IA phase (c.3200 3000 BC), and the pottery from this chamber is compatible with the earlier part of this range. The pathological changes are limited to the lumbar vertebrae, which all show evidence of antemortem damage (Fig. 11.47A). However, the most severe changes are seen in L3 L5, with a major portion of the inferior body of L4 destroyed by a pathological process. Reactive bone formed as an extension of the left body of L4, and this extension contains an opening that probably included a sinus draining the infectious focus destroying the body (Fig. 11.47B). The lower thoracic vertebrae from an individual buried at an archeological site in Giza, Egypt, provides another early example of probable TB (Fig. 11.48). The site is dated to between 3000 and 2200 BC, and the skeleton is curated at the Peabody Museum of Archaeology and Ethnology, Harvard University, Massachusetts (Catalog no. 59315). The vertebral bodies of T8 T12 have been destroyed, resulting in marked kyphosis and fusion of the remaining bone tissue. Medieval evidence of possible TB from the cemetery associated with the Hospital of St James and St Mary Magdalene, Chichester, England, is dated to between

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FIGURE 11.47 L1 L5 vertebrae, with destruction of the inferior portion of the L4 vertebral body and reactive new bone formation particularly on the left lateral portion of the remaining L4 body and the body of L5: (A) anterior view; (B) detail of reactive new bone formation on L4 with a cloaca for draining pus from the infectious focus (male about 18 years old at the time of death, from shaft tomb chamber A100E; burial no. 73 from Bab edh-Dhra in Jordan.

1200 and the 17th century AD (Magilton et al., 2008). The individual highlights some of the problems in differential diagnosis. This skeleton from burial 211 represents a person about 12 14 years of age at the time of death. The lesions of interest occur primarily on the five lumbar vertebrae and the sacrum (Fig. 11.49). The predominant abnormality consists of small lytic depressions in the margins of the vertebral bodies, with considerable periosteal reactive bone formation (Fig. 11.49A and B). What appears to be a groove for a draining sinus occurs on the right superior surface of the first sacral segment (Fig. 11.49C). The posterior surface of the right lamina of the second and third lumbar vertebrae show the development of reactive, porous, periosteal bone that is indicative of an inflammatory process active at the time of death (Fig. 11.49D). Diagnosis of TB in this case is troublesome for two reasons: (1) there is no collapse of the affected vertebral bodies and (2) the involvement of the posterior elements of L2 and L3. Certainly, mycotic infection (Chapter 12) and other bacterial infectious diseases (this chapter) need to be considered seriously in a differential diagnosis. In particular, involvement of the posterior elements is very rare in TB, although it can occur. A diagnosis of TB is preferred slightly over other options because the disease was prevalent in England at that time. Although the

FIGURE 11.48 Probable evidence of spinal TB from an individual buried at a site in Giza, Egypt: right oblique view of T7 T12 vertebrae. Probable female, 14 years old; with permission of PMH, catalog no. 59315.

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FIGURE 11.49 Possible TB, staphylococcal, or mycotic infection affecting the lumbar vertebrae and sacrum: (A) L1 S4 vertebrae with cavitation and reactive new bone formation; (B) detail of periostosis of L2 L4 vertebrae; (C) cavitation of the superior right S1 vertebra; (D) posterior view of the vertebral arches of L2 L4 vertebrae; notice the periostosis particularly on the lamina of L3 (arrow). Vertebral arch involvement is possible but unusual in tuberculosis, suggesting an alternative diagnostic option of staphylococcal or mycotic infection (adolescent; UB burial no. C-211).

skeletal manifestations in this case are unusual for skeletal TB, it certainly could be a relatively uncommon expression of this disease. Ortner and Bush (1993) described a remarkable 11 13 year-old child with probable spinal TB from the site of Abingdon, Oxfordshire, England. The site is dated to about AD 1640. The primary evidence of disease occurs in the spine where the vertebral bodies of T7 L1 were partially to completely destroyed (Fig. 11.50). In all, seven vertebral bodies were affected. This is more than

typically occurs in spinal TB and highlights the need for caution in relying too heavily on the common clinical manifestations of disease in the differential diagnosis of skeletal paleopathology. Conditions in antiquity may have been quite different and this could have affected the expression of skeletal diseases. A final Old World skeleton provides evidence supporting the antiquity of TB in Asia. Burial 3 comes from the Unoki site in Japan and is dated to between the 4th and 8th centuries AD (Fig. 11.51). Photographs of this

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FIGURE 11.50 Left lateral view of T4 L3 vertebrae with severe destruction of the vertebral bodies of T7 through L1. Tuberculosis is the probable diagnosis although the number of vertebrae involved is unusual for this disease (adolescent; Abingdon in Oxfordshire, England, dated to about AD 1640).

individual were provided through the courtesy of Dr. Takao Suzuki, who described this skeleton (Suzuki, 1978, 1985). The pathological bone consists of the lower thoracic vertebrae of an adult female. The marked kyphosis is apparent in the lateral radiograph. The New World evidence of possible bone TB in archeological skeletons is presented to illustrate the antiquity and diverse morphology associated with this disease in this part of the world. The first example comes from a child’s skeleton from Pueblo Bonito, New Mexico (NMNH 327127). The archeological date for the cultural materials from this site is AD 950 1250. The right femur of this skeleton measures 265 mm (without the epiphyses), which indicates an age at death of about 8 10 years. This estimate is in good agreement with age based on dental eruption. Estimation of sex in a child’s skeleton of this age is not reliable (Scheuer and Black, 2000: 215 216, 342 343). Although some of the bones are damaged or missing, the majority are present, including some of the hands and feet. There is no grossly

FIGURE 11.51 Lateral radiograph of the lower thoracic vertebrae of burial no. 3 exhibiting probable Pott’s disease (Unoki, Japan).

observable evidence of disease in any of the bones except the vertebrae. The 1st through the 5th cervical vertebrae are missing, although the 6th and 7th are normal. The 1st through the 10th thoracic vertebrae are present and normal. The pathological process begins with the 11th thoracic vertebra (Fig. 11.52). The superior surface of the body of this vertebra is normal, as are the transverse, spinous, and articular processes. Cavitation is seen on the anterior and left portion of the vertebral body. An enlarged canal resembling a cloaca occurs in the left sector of the body. The inferior surface of the body is eroded from the central to the left side. All elements of the vertebral arch are normal. The anterior body of the 12th thoracic vertebra is destroyed, leaving a scalloped spongy surface in the remaining bone. There is no bony fusion and the spinous, transverse, and articular processes are normal. The first lumbar vertebra is the most extensively affected bone, with almost complete destruction of the body. The left pedicle is fused to the body of L2. All vertebral processes are normal; however, there is slight deformation apparent in the lamina. This suggests the possibility of

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FIGURE 11.52 Slight to pronounced destruction of the vertebral bodies of the 11th thoracic through 1st lumbar vertebrae probably due to TB: (A) destruction of the thoracic and lumbar (arrow) vertebrae has resulted in kyphosis; there has been a limited amount of healing; (B) the right lateral view of the lower vertebrae; note the large cavity (arrow) on the remnant of the body of T12 (NMNH 327127; scale in centimeters).

compensatory remodeling after the destruction of the vertebral body. The superior surface of the body of L2 is eroded and fused with the remnant of Ll. The inferior body is intact but has slight exostoses on its left side. All processes are normal. The third through the fifth lumbar vertebrae are all normal except for slight evidence of deformity on L5, which, like the deformation seen in the lamina of L1, may be a reaction to the abnormal biomechanical loading caused by kyphosis resulting from the collapse and fusion of L1 and L2. Radiographs of the vertebrae demonstrate the anterior angulation (kyphosis) of the normal axis of the spine. The collapse of the vertebrae produced an angle of about 110 degrees (170 180 degrees is normal). The radiograph also shows evidence of a bony response to the deformity in the form of reinforced trabecular bone in the affected vertebrae. Radiographs of the femur suggest two, and possibly three, Harris’ lines, indicative of acute disease or malnutrition episodes at various times before death. The skull is badly fragmented and deformed by taphonomic changes subsequent to death and burial. However, there is no evidence of disease on the skull. The erupted teeth are normal. The age of the individual and the morphology of the lesion are compatible with a diagnosis of TB, although other diseases are possible.

The second example (Fig. 11.53) is a skeleton from Illinois (NMNH 381853). While associated archeological evidence may suggest a date before AD 400, making this skeleton one of the earliest examples of TB in the New World, the association of the burial with other materials from the site is problematic and thus the date uncertain. The age at death of this male individual was about 20 24 years. Only a few of the bones of the hands and feet are present. None of these bones shows any evidence of disease. The bones of the upper extremity are normal. In the pelvis, the sacrum is missing. There are no gross lesions of the innominate bones, although the left ilium is visibly less flared than the right. In the lower extremities, the left tibia is missing, although the right is normal, as are both fibulae. Comparative measurements of the two femora are presented in Table 11.4 and suggest differences that could be due to pathological processes. The left femur is more gracile than the right. The neck and head of the left femur are more nearly in line with the long axis of the shaft than the right (Fig. 11.53B). This condition (coxa valga) is typical when partial to complete paralysis of the limb occurs during the growth phase. The abnormally large neck-shaft angle of the left femur, the reduced size of the shaft diameters, and the diminished flair of the left ilium suggest partial paralysis of the left limb, perhaps caused

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FIGURE 11.53 Probable spinal TB in an archeological skeleton from Illinois; (A) right lateral view of the vertebral column; the entire vertebral body of T8 is destroyed and the posterior remnant is fused with T9 (arrow); (B) anteroposterior radiograph of the right and left femora, the fibulae, and the right tibia; compare the left femur with the right, noticing the diminished diameter of the midshaft and the increased neck-shaft angle of the left femur; (C) detailed view of the major lytic and kyphotic focus in the vertebrae; the body of T8 is completely missing and the partially eroded body of T7 is resting on the partially destroyed body of T9 (arrow); (D) lateral radiograph of the area of angulation of the spine; osteosclerosis is apparent in the partially destroyed remains of the T9 body (arrow) and in the body of T10 (NMNH 381853).

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TABLE 11.4 Comparative Measurements of the Left and Right Femur in an Archeological Skeleton With Possible Tuberculosis From Illinois (NMNH 381853) Left

Right

Measurement

(mm)

(mm)

Maximum length

428

421

Maximum midshaft diameter

27

29

Minimum midshaft diameter

18

21

Neck-shaft angle

152

136

by the collapse of the vertebrae. In the vertebral column (Fig. 11.53A) the first cervical vertebra is missing. The remaining cervical vertebrae are normal, as are the first three thoracic vertebrae. On T4, there is a lytic lesion on the anteroinferior surface of the vertebral body, with a similar but smaller lesion on the right portion of the body. T5 T7 have a slight periosteal bony reaction on both sides of the posterior portion of the body. The inferior articular surface of the body of T7 is eroded but shows evidence of circumscription, although there is no exuberant bone formation. The body of T8 is destroyed, with the posterior remnant fused with T9 (Fig. 11.53C and D). Both inferior articular facets are fused with their corresponding facets on T9, producing an anterior angulation. The superior plate of the body of T9 is destroyed. There is some peripheral reactive bone formation, with a large bony spur on the right lateral portion of the vertebral body. In T10 the articular surface of the vertebral body is intact. There are bilateral bony spurs on the vertebral body with slight cavitation on the anterior surface. T11 and T12 are missing. The first lumbar vertebra has slight erosion of the superior articular surface of the body and lateral bony spurs, with anterior cavitation. The inferior articular surface of the vertebral body is normal. Both L2 and L3 show evidence of destructive lesions on the anterior parts of their bodies. There is a reactive spur joining L2 and L3 on the right portion of their respective bodies, with a draining sinus affecting primarily the bodies of L3, L4, and L5; the sacrum is normal. The skull and mandible were badly damaged postmortem and not available for study. The bony spurs, fusion of T8 and T9, and draining sinuses are all suggestive of a chronic condition with life prolonged well beyond the acute stage. The abnormality of the left femur suggests an onset during growth and an illness lasting at least 7 10 years. An Inuit skeleton from the Yukon River in Alaska (NMNH 345394) illustrates possible TB of the hip (Fig. 11.54). The burial is from the historic period. The estimated age on the basis of epiphyseal union and pubic

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symphysis morphology is 18 22 years. The abnormally small size of the long bones and the distorted shape of the pelvis make sex estimation difficult but the individual was most likely female. The upper extremities are normal and, although small, suggest robust muscle activity. The bones of the hands are small but appear normal. There is no evidence of disease in the vertebrae either grossly or in the radiograph. The sacrum is normal, although small. The right innominate bone is small and somewhat deformed in response to the pathological condition in the left hip. The left innominate bone is grossly deformed, but the major focus of the infection is the acetabulum. The acetabulum is very shallow, an effect created by the destruction of the acetabular rim and its articular surface with subsequent remodeling and healing. There are large, well-organized osteophytes in the posterior rim area and a pronounced cavity in the inferior rim area. A welldeveloped bony ridge on the anterosuperior margin of the acetabulum is suggestive of upward migration and subluxation of the joint. There is a large cavitation extending through the acetabulum in the fovea region. The overall gracility of the innominate bone is exemplified by the very delicate ischial ramus. The left femoral head is destroyed, with subsequent cavitation. This destruction likely took place in late childhood with diminished growth of the bone following the acute phase of the disease. The measurements of the two femora highlight the differences in growth occurring after the onset of the disease (Table 11.5). The measurements of femoral length do not include the diseased femoral heads, and thus reflect the diminished growth of the pathological left femur. Notice that the left tibia has undergone accelerated growth, perhaps in an attempt to compensate for the shortened left femur. Indeed, the total length of the femur plus the tibia for the two sides is virtually identical. This, however, would have left the left leg somewhat shorter than the right due to the destroyed femoral head and the pathological superior subluxation of the hip joint. The resulting abnormal gait undoubtedly contributed to the deformity of both innominate bones. In addition to diminished growth in length (endochondral ossification), there is reduced appositional growth (intramembranous ossification) of the shaft diameter. Although the left tibia has undergone compensatory growth in length exceeding that of the right side, its development in midshaft diameter is relatively deficient, suggesting only limited use of the limb in locomotion. The powerful development of the arms may be the result of using some type of crutch. The developmental difference between the legs is also seen in the bones of the feet. The left metatarsals have attained the same length as the right, but they have visibly narrower shafts. Curiously, there is a lytic lesion in the right talocalcaneal joint, which has affected the medial articular surface of both bones. The lesion is

362 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 11.54 Possible TB of the left hip in an archeological skeleton: (A) radiograph of the major long bones of the lower extremity, anteroposterior view; note that the bones of the left leg are more gracile; (B) anterior view of the right and left femora; the femoral head of the left femur has been destroyed, the lesser trochanter is elongated and the shaft diameter of the left femur is much smaller; (C) detailed view of the left hip joint; note that the lytic process has produced a hole (arrow) that penetrates completely through the wall of the acetabulum (NMNH 345394).

somewhat circumscribed, indicating containment of the disease process. The relationship of this lesion to the disease process in the left leg remains problematical. Bone lesions from TB in locations other than the spine are indistinguishable from septic arthritis and some other diseases that can destroy the joint. In view of the obvious problems in differential diagnosis it is, of course, appropriate to avoid dogmatic assertions. In addition to TB, osteomyelitis and septic arthritis are important entities in the differential diagnosis. In TB, it has been noted that the active phase leads to destruction and cavitation in the cancellous bone with little perifocal reactive bone. This

description certainly applies to the destructive process in the femoral head of this individual. There is no evidence of a sequestrum or involucrum as would tend to occur in osteomyelitis, nor is there fusion of the joint, which is a common sequela in both septic arthritis and TB of the hip. Furthermore, TB of the hip is second in frequency to the involvement of the spine in bone TB and is the most common destructive lesion of the hip. Dislocation and perforation of the acetabulum in the region of the fovea are also associated with hip TB. Although ankylosis is a common sequela if healing occurs, the early death of this individual would have precluded this result. Furthermore,

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TABLE 11.5 Comparative Measurements of the Left and Right Femur and Tibia in a Skeleton With Possible Tuberculosis of the Hip (NMNH 345394) Left

Right

(mm)

(mm)

Length from medial condyle to greater trochanter

332

340

Maximum midshaft diameter

20

22

Minimum midshaft diameter

15

20

Length from lateral condyle to medial malleolus

299

290

Maximum midshaft diameter

18

20

Minimum midshaft diameter

13

15

Measurement Femur

Tibia

FIGURE 11.55 Possible TB resulting in destruction of the left sacroiliac joint in a skeleton from the Pecos Pueblo site in New Mexico, dated to between AD 1300 and 1838 (with permission of PMH; catalog no. 59811, now repatriated).

subluxation is not typical in septic arthritis. Although other diseases obviously cannot be ruled out, this skeleton does provide an example of what TB of the hip could look like in an archeological skeleton. Possible TB of the sacroiliac joint was also found in the pelvis of a skeleton from the Pecos Pueblo site in New Mexico. The site is dated between AD 1300 and 1838. Until its recent repatriation and reburial, the human remains from this site were curated at the Peabody Museum of Archaeology and Ethnology, Harvard University (Catalog no. 59811). This skeleton was from an adult female about 40 years of age when she died. The pathological process affected the left sacroiliac joint with destruction of virtually the entire subchondral bone surface and there were two large lytic defects penetrating through the entire ilium (Fig. 11.55).

LEPROSY Introduction Leprosy is a chronic infectious disease caused by either Mycobacterium leprae or Mycobacterium lepromatosis, bacteria closely related to the MTC. In M. leprae infections, the development and progression of the disease is chronic and often extends over decades, especially if left untreated. It is primarily a skin, nerve, and upper respiratory tract condition, but it can affect the skeleton and various bodily organs. The earliest signs are usually skin lesions and motor nerve impairment (e.g., “clawed” hands). The disease affects the peripheral, especially sensory, nerves, leading to loss of sensory perception in affected areas such as the hands and feet. The autonomic

364 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

nerves are also affected. Due to nerve damage, muscle activity can be affected. The bacteria are transmitted via exhalation and inhalation of droplets containing the organism, similar to transmission of the MTC (Richardus et al; http://www.who.int/news-room/fact-sheets/detail/leprosy). How humans acquired the disease is unknown. An animal host may have been a factor, but environmental sources of the bacteria are seeing increased consideration for transmission. For example, the same genotype of M. leprae has been found in soil and skin samples from people with leprosy (Turankar et al., 2012). Previous work of this type in coastal Norway by Kazda et al. (1990) and Irgens (1981) suggested that sphagnum bog vegetation was a source of M. leprae. High humidity is needed for sphagnum moss (found only in the north and west areas of Norway). This research found noncultivable acid-fast bacilli in sphagnum samples where leprosy was present in the 19th-century population who lived on farms surrounded by sphagnum. Noteworthy is that in recent years a new mycobacterial species causing diffuse lepromatous leprosy (M. lepromatosis) has been identified through molecular analysis (Han et al., 2008; 2015). Termed Lucio’s Phenomenon in Mesoamerica, M. lepromatosis has been reported to affect humans in several parts of the world, and phylogenetic work has shown that M. lepromatosis is closer to leprosy’s most recent common ancestor (MRCA) than M. leprae (Singh et al., 2015), which makes it older than M. leprae. As yet, M. lepromatosis has not been identified in human remains biomolecularly, and it is not known how it may affect the skeleton. For that reason, all subsequent discussion of leprosy will focus upon M. leprae unless M. lepromatosis is specifically relevant. Following sequencing of M. leprae (Cole et al., 2001) and aDNA analysis of skeletons from a range of sites and periods, we are beginning to better understand the origin and evolution of leprosy (e.g., see Monot et al., 2005, 2009; Schuenemann et al., 2013; Donoghue et al., 2015). Modern DNA studies by Monot have shown that leprosy likely originated in the Near East or Africa around

100,000 years ago and spread east via north (Silk Road) and south routes, and much later to the Americas via colonization and the slave trade. There is a reported predominance of the disease in males over females in a ratio of 2:1 (Faget and Mayoral, 1944), but the figures belie the facts. While women have a stronger immune resistance to infectious disease, they are less likely to come forward for diagnosis for a variety of reasons (e.g., lack of money or time to travel to clinics). Adolescents and adults contract leprosy more than infants and children overall, but detection methods, as for sex-related frequency data, will affect the figures ultimately published. M. leprae is most commonly found in humans but is also known to infect some nonhuman primates and the armadillo (e.g., Truman, 2005; Meyers et al., 1985). In recent years both M. leprae and M. lepromatosis have also been identified in red squirrels in the United Kingdom and Ireland (Meredith et al., 2015). M. leprae is acid-fast and Gram-positive, and it causes a very chronic granulomatous infection (a collection of immune cells). Although transmission of bacteria from an infected human host to another host can occur easily, disease occurs in less than half of the people exposed to the pathogen. The response by the body to M. leprae is among the most variable of any infectious disease. In individuals who experience the actual disease following exposure, its manifestations range from very mild (tuberculoid or paucibacillary) through one or more intermediate stages to very severe (lepromatous or multibacillary). The reason for this variability are largely due to the immune response of the person with the disease (Ridley and Jopling, 1966; see Fig. 11.56). Skeletal involvement can occur across the spectrum, although the skeletal manifestations are more extensive and severe in lepromatous leprosy. The skeletons of people with lepromatous leprosy in the past will likely be the ones we recognize in the archeological record. Leprosy is a declining disease today. According to the World Health Organization (2017a,b), “there were 214,783 new “cases” in 2016, with 75% of them FIGURE 11.56 The Ridley and Jopling (1966) immune spectrum.

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identified in Southeast Asia. Brazil (25,218), India (135,485), and Indonesia (16,826) had the highest numbers.” While the trend is a decline, the numbers belie the continuing challenge that people with leprosy today experience. Beyond the “new cases”, there are many more “cured” people who have been stigmatized, perhaps because of impairments that are outwardly visible. They may have lost jobs as a result and thus are living in poverty, sometimes isolated from the rest of their community. In the past, there is clear evidence that a number of people with leprosy were also stigmatized (e.g., see Roberts, 2011); some were admitted to leprosy hospitals or leprosaria, but support for the latter inference is scarce in the archeological record. Increasingly, evidence is showing that people with leprosy were more accepted within their communities than believed (e.g., see Rawcliffe, 2006; Demaitre, 2007; Roberts, forthcoming). Nevertheless, stigma and related marginalization has prevailed in the historical literature for centuries, and much of this has been due to its apparent description in the Bible. As a result, even into the 19th and 20th centuries, people were taken away from their communities and placed in often remote regions such as on islands (e.g., Molokai in Hawaii - Law, 2010).

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preferred by M. leprae. It should be noted that in both living and archeological skeletons, more foot than hand bone damage is noted. A useful overview of the effect of leprosy on the skeletons of children is provided by Lewis (2018: 167 171, and Table 7.2 provides a summary of the bone changes found in archeological contexts).

Direct Effects of M. leprae

Pathology

The direct effects of the M. leprae bacteria are seen in the skull with destruction of the nasal bones, nasal septum, turbinate bones, and the hard palate (Job et al., 1966). The characteristic features frequently found in RMS include the resorption and eventual disappearance of the anterior nasal spine, rounding/remodeling of the edges and widening of the nasal aperture, resorption, recession, and remodeling of the alveolar process of the maxilla (with or without loss of the upper incisor teeth), and sometimes nasal structure collapse (Fig. 11.57). Similar nasal lesions can occur in tertiary syphilis, lupus vulgaris (TB), leishmaniasis, and cancer (see Manchester, 1983). The oral and nasal surfaces of the palatal bones may also experience inflammatory pitting and possible destruction, as well as leprogenic odontodysplasia (Danielsen, 1970). The latter is characterized by constriction and shortening of the roots of the permanent maxillary incisors, which is caused by M. leprae. There has been little archeological

Skeletal involvement is generally thought to affect about 3% 5% of people with untreated leprosy (Paterson and Rad, 1961). However, in one study of 483 people with leprosy, 306 (63%) had radiologically identified bone lesions (Esguerra-Gomez and Acosta, 1948). The facial, hand, and foot bones are affected most commonly, reflecting inhalation of the bacteria into the nasal and oral areas, along with damage to peripheral nerves. There have been three significant leprosy hospital cemetery populations studied in the last 50 or so years, two being located in England: St James and St Mary Magdalene, Chichester (Magilton et al., 2008), and St Mary Magdalene, Winchester (Roffey and Tucker, 2012). These examples have added to our knowledge not only of medieval leprosy in England, but also the bone changes associated with the infection. Such studies have complemented and extended the work of the medical doctor Vilhelm MøllerChristensen (e.g., 1953), who pioneered the study of leprosy in skeletal remains. He investigated the skeletons from the cemetery associated with a medieval Danish leprosy hospital (Naestved) and described for the first time in archeological skeletons the pathological changes that occur in the bones of people with leprosy. These included facies leprosa, later renamed rhinomaxillary syndrome, or RMS (Andersen and Manchester, 1992), and hand and foot bone changes. The changes of RMS reflect the cooler temperature of exposed mucous membranes and skin

FIGURE 11.57 Lateral view of a person with leprosy showing collapse of the nasal structures. Figure 70 in Mitsuda (1952) Atlas of leprosy. Okayama, Japan, Chot Foundation. ¯ okai ¯

366 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

evidence of leprogenic odontodysplasia found, to date (e.g., Matos and Santos, 2013), but Danielsen’s (1970) work showed that the condition was only present in individuals with marked RMS. Lepromatous osteomyelitis is also a direct feature of leprosy. However, it is an uncommon and frequently insignificant lesion, which may take decades to develop and involves only a small portion of a bone. For example, in one study only 5.6% of people with lepromatous leprosy showed specific lepromatous leprosy-related disease (Faget and Mayoral, 1944). If present, the small bones of the extremities (phalanges, metacarpals, and metatarsals) are targeted. Further, erosions of the cranial vault, underlying lepromatous leprosy scalp lesions, may be observed but are also rare.

Indirect Effects of M. leprae The indirect effects of leprosy relate to M. leprae’s impact on the sensory, motor, and autonomic nerves, with subsequent damage to soft tissues and bones. Sensory nerve involvement in leprosy leads to anesthesia and subsequent trauma and ulceration of the hands and feet (Fig. 11.58). If ulcers are left to develop, the bones are ultimately affected. In the hand, anesthesia often begins in the ulnar nerve, and therefore the terminal phalanx of the fifth finger is usually involved first (Hopkins, 1928). Resorption of the ends of the distal hand phalanges progresses proximally, and occasionally includes the metacarpals, but the resorption usually goes no further down the hand. There may, however, be carpal disintegration. The intertarsal, metatarsophalangeal, and interphalangeal joints in the foot can all be involved, and tarsal disintegration can occur. Severe osteoarthritis, and even neuropathic arthropathy similar to a Charcot’s joint can be seen in the ankles and feet of people with advanced leprosy. In addition, the existing anesthesia facilitates traumatically induced damage and secondary infections. Other conditions, such as spina bifida, may also lead to anesthesia and ulceration. Joint degeneration, with a similar

FIGURE 11.58 Ulcer of the heel in leprosy.

pathogenic mechanism, is seen in advanced rheumatoid arthritis, but in leprosy no primary arthritic changes are seen. Diabetes and even frostbite are other diagnostic options that should be considered for the metatarsal changes. The bone changes due to motor nerve degeneration potentially involve damage and even paralysis of muscles, muscle groups, ligaments, and tendons. This may lead to subluxation and dislocation of the interphalangeal joints, hyperextension of the metacarpophalangeal joints and the metatarsophalangeal joints, and hyperflexion of interphalangeal joints of the hands and feet. The latter cause “claw” hand (ulnar nerve) and “claw” foot (posterior tibial nerve) deformities. Although not pathognomonic of leprosy because other conditions could cause “claw hands” (e.g., “stroke” or cardiovascular accident), these deformities potentially lead to “grooves” on the palmar surfaces of the proximal hand phalanges and the plantar surfaces of the proximal foot phalanges (Enna et al., 1971; Andersen and Manchester, 1987). A “dropped foot” can further occur due to loss of the longitudinal and transverse arches of the foot, but this is not pathognomonic of leprosy, either. Such changes can cause strain on the ligaments that attach to the dorsal surfaces of the tarsal bones and “dorsal tarsal bars”, but again, these conditions are not pathognomonic for leprosy (Andersen and Manchester, 1988; see also Fig. 11.59). Deformities in the hands and feet, as a result of motor nerve damage, can predispose people to trauma and subsequent ulcers as a result of the synergy between motor and sensory nerve damage. Facial nerve involvement in leprosy may lead to paralysis and the inability to close the eyelids, or lagophthalmos (Fig. 11.60) and subsequent eye infection. Deformities will also affect the progression of any associated leprosy-related sepsis (septic arthritis, osteitis, osteomyelitis). Secondary bacterial invasion of the bones and joints may modify the appearance of the skeletal

FIGURE 11.59 Tarsal bars showing on a radiograph of the foot, and clawing of the toes.

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367

and is fractured (acro-osteolysis; Andersen et al., 1992). In the foot, concentric resorption starts in the proximal phalanges and distal metatarsals, with a cup and peg deformity eventually occurring at the joints, the latter being a change that may also affect the hands. This resorptive change can terminate in subluxation and dislocation. In addition to concentric atrophy there may be erosive changes in the hands and feet. The remaining fragments continue to remodel and may develop a teardrop profile. The affected metacarpals and metatarsals can eventually become pointed at their distal ends, although a complete cortex on the tapered remnants of involved bones is observed (Cooney and Crosby, 1944).

Periostosis of Limb Bones

FIGURE 11.60 Lagophthalmos of the eyes. Figure 69 in Mitsuda (1952), Atlas of leprosy. Okayama, Japan, Chot Foundation. ¯ okai ¯

lesions of leprosy in the terminal phase, and the hands or feet may be almost completely destroyed. Even secondary tuberculous arthritis is not uncommon (Beitzke, 1934a: 611). In seven of eight autopsied people with leprosy, active pulmonary TB was found (Brutzer, 1898). The specific granulomatous bone lesions, especially in the phalanges of the hands and feet, very closely resemble those observed in sarcoidosis (Paterson and Job, 1964: 432). Mutilations also occur in both diseases. Differentiation of these lesions on dry bone alone may be impossible, but sarcoidosis is a rare disease today. If it occurred at all, it was probably rare in antiquity too, which should be considered in differential diagnosis. When the autonomic nerves are affected, there is disruption of sympathetic parasympathetic nerve balance leading to loss of arteriole control and osteoclast osteoblast harmony. This can cause slow, progressive, concentric atrophy/remodeling of the diaphyses of the metacarpals, metatarsals, and proximal and mid phalanges and “knife-edge”/mediolateral remodeling of the metatarsals (Enna et al., 1971). Concentric atrophy in leprosy is a process that involves resorption = and remodeling of the cortex, resulting in a gradual loss of the diaphyseal diameter and medullary cavity in the hand and foot bones, although the cortex itself is maintained until late in the process. Concentric atrophy may continue until the diaphysis is unable to withstand biomechanical stress

Møller-Christensen (1953) frequently found subperiosteal new bone formation on the tibia and/or fibula in skeletons from medieval Denmark. This was suggested to be a likely reaction to leprous involvement of the feet. Other studies of skeletons with leprosy have also noted this bone change (e.g., Lewis et al., 1995; Roberts, 2002; Magilton et al., 2008; Roffey and Tucker, 2012), and new bone formation has also been found on the radius and ulna, perhaps reflecting involvement of the hands, as opposed to the feet (Lewis et al., 1995). While periostosis has many etiologies, its presence with bone changes that are more certain to be associated with leprosy supports its relationship with the infection. Patients with leprosy can have swollen legs due to infection of the feet, leading to chronic venous stasis (Price, 1961), which could be an explanation for lower-leg bone periosteal reaction (Jopling and McDougall, 1988). Even so, this bone change cannot be claimed to be pathognomonic. Bone reaction to overlying skin ulcers is also not pathognomonic for leprosy, but may be present in the form of circumscribed new bone formation (Boel and Ortner, 2013).

Other Bone Changes Associated With Leprosy There are a number of co-morbidities that should be considered when diagnosing leprosy. Osteopenia and osteoporosis in patients with leprosy have been recorded (Ishikawa et al., 1999), especially in men when the testes are affected. Hearing problems (Awasthi et al., 1990) and upper and lower respiratory tract involvement (Kaur et al., 1979) may also occur. In one study of ear bones in skeletons with and without leprosy, Bruintjes (1990) found over 50% had erosive lesions. Maxillary sinusitis is also associated with people who have leprosy today (Hauhnar et al., 1992), and this has been noted in archeological skeletons (Boocock et al., 1995), likely as a result of the infection entering the nasal passages and causing an inflammatory response in the upper respiratory tract. Poorer oral health has also been described in people with

368 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 11.61 Cribra orbitalia in a child with leprosy. (Child about 12 years old from the medieval (c. AD 1175 1600) hospital cemetery at Naestved, Denmark; DNM burial no. 127).

leprosy (e.g., see Reichart et al., 1976), and although dental disease has been recorded in the teeth and jaws of skeletons with leprosy, no detailed studies of the evidence have been done in comparison to nonleprous skeletons. Trauma has been explored in relation to leprosy infection utilizing a subset of individuals with and without leprosy buried in a medieval leprosy hospital cemetery at Chichester (Judd and Roberts, 1998). This study explored whether leprotic infection predisposed individuals to fractures, but no differences in fracture frequency were found between people with and without leprosy. Finally, cribra orbitalia (Fig. 11.61) was identified by MøllerChristensen (1965) as being present in 69.7% of 99 skeletons at the medieval Naestved site in Denmark. While many etiologies were proposed, e.g., eye infection due to lagophthalmos (also suggested by Ortner, 2006), it is possible that this is an adaptive response to leprosy, i.e., a high pathogen load (see Stuart-Macadam, 1992).

Diagnosis of Leprosy in Skeletal Remains Møller-Christensen and Hughes (1966) argued that a diagnosis of lepromatous leprosy was convincing only when facies leprosa (RMS) was accompanied by bilateral periostosis of the tibiae and fibulae. However, in people diagnosed with leprous bone changes today, a more varied combination of bone changes occurs. Individual immune responses undoubtedly influence the expression of leprosy in both the soft tissues and the skeleton, and thus variations in which bones would ultimately be affected are expected. When only an archeological skeleton is available for diagnosis, which may be poorly preserved, the diagnostic process becomes challenging. Lepromatous leprosy, as discussed above, is the most likely diagnosis

in an archeological context. Tuberculoid leprosy diagnostic criteria—bilateral or unilateral hand and foot bone involvement and no RMS—have been proposed, based on Portuguese leprosarium archives (Matos, 2009). Other methods for evaluating leprosy in the past have estimated the specificity and sensitivity of leprosy-related lesions and calculated leprosy frequency (Boldsen, 2001). In reaching a diagnosis of leprosy in an archeological skeleton, one needs to pay particular attention to the overall pattern of skeletal involvement. As noted, some of the skeletal changes that result from leprosy also occur in other skeletal diseases. However, if the skeleton is well preserved, a combination of lesions in different parts of the skeleton (face, hands, and feet) provide a relatively certain diagnosis of leprosy, i.e., the RMS, in combination with atrophy and truncation of the fingers and toes, would appear to be almost pathognomonic for leprosy. Where leprosy is endemic, there will almost certainly be some archeological skeletal evidence that shows a pattern that can be attributed to this disease with a high degree of certainty.

Paleopathology Leprosy is a disease in which features identified in archeological human remains have been of value in the diagnosis of living patients. While medical practitioners knew that leprosy affected the skeleton, the detailed changes identified by Møller-Christensen (1965: 603) had not been previously described. Today, the distribution of leprosy is virtually worldwide. Similarly, the evidence of leprosy (M. leprae) in the ancient Old World is very convincing, but its potential presence in pre-Columbian New World populations has yet to receive empirical support (Cochrane, 1964: 10; Aufderheide and Rodriguez-Martin, 1998: 149; Roberts: www.international textbookofleprosy.org/). There is archeological evidence of leprosy in skeletons from three continents: Africa, Asia, and Europe (see Roberts, forthcoming; also see Roberts et al., 2002). It was particularly common in Europe, as seen in evidence from Denmark, Hungary, Sweden, and the United Kingdom. In recent years, more skeletal evidence has been published, which is contributing to our understanding of leprosy’s geographical distribution and timeline (e.g., Blau and Yagodin, 2005 and Taylor et al., 2009—Central Asia; Robbins Schug et al. 2009—India; Belcastro et al., 2005, Mariotti et al., 2005, and Rubini and Zaio, 2009—Italy; Boldsen, 2005, 2008 and Boldsen and Mollerup, 2006— Denmark; Baker and Bolhofner, 2014—Cyprus; Lunt, 2013—Scotland; Likovsky´ et al., 2006—Bohemia; Suzuki et al., 2013—Japan).

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The earliest evidence of leprosy appears to be in Hungary (3700 3600 BC—Hadju et al., 2010), India (2000 BC—Robbins Schug et al., 2009), and possibly Turkey (2700 2300 BC—Angel, 1969). This predates the earliest record in historical documents from China (Lu yu (Analects) 500 BC) and India (Atharva Veda 1400 BC). However, most burials are from the late medieval period of Europe (12th 16th centuries AD). Leprosy saw a decline from the 14th century onwards, possibly resulting from the rise of the related disease, tuberculosis (Manchester, 1984; see also Stone et al., 2009 on the synergies between leprosy and tuberculosis). Note that very few skeletons have been found with both diseases (e.g., see Donoghue et al., 2005; Weiss and Møller-Christensen, 1971). In 1798, with the death of the last person with leprosy in the Shetland Islands of Scotland, the disease died out in Britain, although it continued to be a minor problem in continental Europe (Cochrane, 1964: 7). For example, leprosy was present in Norway through the 19th century (Fig. 11.62), with a few new “cases” being reported as late as the 1940s (Kazda et al., 1990). Prior to the genomic work by Monot et al. (2005, 2009), a number of scholars developed theories about how leprosy had been introduced to the Western world. Andersen (1969: 123), e.g., proposed that it came with the soldiers of Alexander the Great returning from their military campaign in India in 327 326 BC. One of the problems, however, in using historical documents for studying the history of leprosy is the vague description of diseases and imprecision in the use of terms (see also Mitchell, 2011, for a general discussion about historical record use in understanding the history of disease). As an example of the challenges in knowing what diseases are being described, MacArthur (1953: 8) quite rightly suggested that the term “leprosy” was used in the past for nonspecific skin diseases, elephantiasis, smallpox, bubonic plague, mange, etc. He further suggested that many of the people segregated into leprosy hospitals in the medieval period may have had diseases other than leprosy. This has proved true in some of the most recent work on skeletons with leprosy (e.g., Magilton et al., 2008), but at the cemetery associated with the medieval leprosy hospital in Winchester, England, a majority of skeletons had bone changes of leprosy (Roffey and Tucker, 2012), as was also seen at Naestved, Denmark (Møller-Christensen, 1953). It can be argued that the often-devastating consequences of a diagnosis of leprosy may have been a significant factor in ensuring that the diagnosis was carefully undertaken and the criteria used in diagnosis rigorously applied. Nevertheless, there is increasing evidence for people with leprosy being buried in community cemeteries (e.g., see Roberts, forthcoming; Baker and Bolhofner, 2014; Lunt, 2013). It is unclear whether this means diagnosis

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FIGURE 11.62 A restored 18th-century leprosy hospital in Bergen, Norway; the hospital was founded in the early 15th century: (A) courtyard; (B) hospital atrium with patients’ rooms and attending physicians’ offices surrounding the atrium.

was ineffective, or that people were indeed welcome in their communities. Leprosy (M. leprae) was introduced into the New World during the colonial period, and therefore archeological evidence of skeletons with leprosy should be rare and limited to the post-Contact period. MøllerChristensen and Inkster (1965: 12), for example, reference a skull found in 1866 on Vancouver Island, off the coast of Canada, which they suggest had RMS. Leprosy remains a condition rarely mentioned in New World paleopathology in the post-Contact period. Certainly, it is one of the least contagious of transmissible infectious diseases (Browne, 1970: 640). Thus, its introduction into the New World would not have had nearly the impact of other infectious diseases, such as malaria, measles, and smallpox. In the remaining pages of this section, examples of leprosy in skeletons from archeological sites in Denmark and England are described and discussed. The objective

370 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

of presenting these skeletons is to highlight the different manifestations of skeletal leprosy.

Naestved, Denmark Among the best documented archeological examples of skeletons with leprosy are those that were excavated by the late Vilhelm Møller-Christensen at Naestved, Denmark. This town was the site of a medieval hospital for people with leprosy and was part of a complex called the St. Jorgen’s Hospitals, which were built throughout Denmark (Møller-Christensen, 1953: 14 15). Most of the 200 individuals excavated show bone changes attributable to leprosy. Møller-Christensen’s experience with analyzing the skeletons from the Naestved cemetery provides significant insight regarding the bone changes to be expected from this disease (Møller-Christensen, 1961). As we have seen, the major foci for the disease are the bones of the face and the small bones of the hands and feet, although other bones may be affected. The skull lesions include rounding and enlargement of the pyriform (nasal) aperture, destruction of the anterior nasal spine, and destructive remodeling of the alveolar process of the anterior maxilla (Figs. 11.63 and 11.64). Less commonly, a lytic focus will destroy a portion of the hard palate (Fig. 11.65). As discussed above, there are a number of differential diagnostic options for these facial changes. However, Møller-Christensen (1965: 604) indicates that in leprosy, pathological changes are not found on the

FIGURE 11.64 Rhinomaxillary remodeling in a skeleton with leprosy. Note the alveolar recession and the narrowed rounded margins of the pyriform (nasal) aperture (adult female about 16 years old from the medieval cemetery associated with the hospital of St. James and St. Mary Magdalene, Chichester, England ;UB burial no. C-360).

FIGURE 11.65 Destructive focus in the hard palate of a skeleton with leprosy (adult female from the medieval (c. AD 1175 1600) cemetery associated with the hospital at Naestved, Denmark; BMNH 1962.1.1.2).

FIGURE 11.63 Rhinomaxillary remodeling in a skeleton with leprosy: Note the rounded margins of the pyriform (nasal) aperture (adult male about 45 years old from the medieval cemetery associated with the hospital of St. James and St. Mary Magdalene, Chichester, England; UB burial no. C-19).

skull vault. This contrasts with venereal syphilis (VS), where changes on the cranial vault can be present. This is certainly a helpful criterion for differentiating leprosy from VS, but should not be considered absolute because the absence of cranial vault lesions may be counterbalanced by other lesions considered consistent with VS.

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FIGURE 11.66 Destruction of the majority of each metatarsal and many of the phalanges of the left foot—with phalangeal concentric atrophy—in a skeleton with leprosy (adult from the medieval (c. AD 1175 1600) hospital cemetery at Naestved, Denmark; DNM burial no. 254). Note that some of the phalanges have been glued the incorrect way round.

The postcranial lesions are most pronounced in the extremities, particularly the hands and feet, including concentric atrophy of the shafts of the tubular bones (Fig. 11.66) and shortened phalanges (Fig. 11.67) (Møller-Christensen, 1965: 15). The bony destruction affects the subarticular and more highly vascularized bone in the epiphysis adjacent to the articular surface. This process compromises the joint, leading to collapse and a cupping deformity of the joint. Møller-Christensen also provided archeological evidence of the pressure erosion resulting from flexion contractures of the hand (Fig. 11.68), and this has been reported in more recent work on other skeletons (e.g., Magilton et al., 2008). The indentations caused by the pressure erosions occur on the proximal phalanges on their distal palmar surfaces (Fig. 11.69).

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FIGURE 11.67 Destruction of some of the metacarpophalangeal joints and truncation of some of the phalanges in the left hand of a skeleton with leprosy. Note also the presence of multiple cartilaginous exostoses on the humerus and radius (adult male from the medieval (c. AD 1175 1600) hospital cemetery at Naestved, Denmark; DNM burial no. 2).

FIGURE 11.68 Flexion contracture in the fingers (phalangeal joints) of the left hand of a skeleton with leprosy (adult from the medieval (c. AD 1175 1600) hospital site at Naestved, Denmark; DNM burial no. 407X).

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FIGURE 11.69 Proximal and middle phalanges of the left and right third fingers in a skeleton with leprosy. Note the palmar grooving of the distal proximal phalanges that is the result of flexion contracture (adult male about 40 years old from the medieval cemetery for the hospital of St. James and St. Mary Magdalene, Chichester, England; UB burial no. C-44).

Chichester, England The skeletal remains excavated from the cemetery associated with the medieval hospital of St. James and St. Mary Magdalene in Chichester, England, provide an important window on leprosy in medieval England. This is the largest leprosy hospital cemetery to be excavated to date in England. Most of the skeletal evidence for leprosy of the facial bones includes enlargement and rounding of the pyriform (nasal) aperture, where a smooth surface indicative of a very slow, chronic process is present. Clearly destruction has taken place, but evidence of active resorption is rare. However, two skeletons with active rhinomaxillary destructive remodeling are part of the skeletal sample from Chichester. The first of these skeletons (burial no. 187) with relevant bone changes is represented by the skull of an 17 20-yearold male (Ortner and Connell, 1996). The maxillary bone surrounding the pyriform (nasal) aperture is porous with fine depressions in its cortical surface (Fig. 11.70A C). Evidence of active inflammation is also seen on the nasal floor and the hard palate (Fig. 11.70D and E). The second skeleton discussed here (burial no. 354) is represented by

FIGURE 11.70 Early rhinomaxillary changes in leprosy: (A) anterior view of the rhinomaxillary area of the skull; note the presence of porosity probably resulting from inflammation in the bone surrounding the pyriform (nasal) aperture; (B) detail of porous lesion on the right maxilla; (C) porous bone surface in the left nasal passage; (D) porous bone surface of the nasal floor; (E) abnormal porosity of the oral surface of the hard palate (adult male about 18 years old from the medieval cemetery for the hospital of St. James and St. Mary Magdalene, Chichester, England; UB burial no. C-187).

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FIGURE 11.71 Early rhinomaxillary changes on the margins of the pyriform (nasal) aperture. Note the porosity and remodeling of the edge of the aperture (adult male about 27 years old from the medieval cemetery for the hospital of St. James and St. Mary Magdalene, Chichester, England; UB burial no. C-354).

FIGURE 11.72 Alveolar resorption in the maxilla of a skull with leprosy (adult male about 26 years old from the medieval cemetery for the hospital of St. James and St. Mary Magdalene, Chichester, England; UB burial no. C-350).

FIGURE 11.70 Contiuned

the skull of an adult male about 20 25 years of age at death. In this case, the erosive change is largely limited to the margins of the pyriform (nasal) aperture with minimal evidence of inflammatory bone changes on the maxillary bone surfaces away from the margins (Fig. 11.71). The alveolar process associated with the premaxilla is affected by this destructive remodeling. This, of course,

undermines the support for the upper incisor loss observed in patients with long-standing leprosy (Fig. 11.72). If the onset of leprosy occurs during dental development, the dental roots may not develop to their full size; this is a condition Møller-Christensen (1978: 123) called dens leprosus or leprogenic odontodysplasia (Fig. 11.73). As seen at Chichester, abnormalities in the lower-leg bones may be extensive. Neurological problems of the foot tend to result in destructive remodeling of the foot, particularly affecting the metatarsals and phalanges. The

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FIGURE 11.73 Radiograph of leprogenic odontodysplasia of the incisor teeth, resulting in almost complete failure of dental root development (child about 9 years of age from the medieval (c. AD 1175 1600) hospital site at Naestved, Denmark; DNM burial no. 1).

FIGURE 11.75 Severe destructive remodeling that has greatly reduced the diaphyses of the left metatarsals, leaving only the proximal metaphysis and the remnants of the former diaphysis. (Adult male from the medieval cemetery associated with the hospital of St. James and St. Mary Magdalene, Chichester, England; UB burial no. C-62).

FIGURE 11.74 Metatarsals and proximal phalanges of the right foot of a skeleton with leprosy. Notice particularly the “blade-like” remodeling of the fifth metatarsal (adult from the medieval (c. AD 1175 1600) hospital site at Naestved, Denmark; DNM burial no. Z).

expression of this pathological process can be relatively mild (Fig. 11.74), but can result in major bone loss with severe disfigurement and loss of biomechanical function (Fig. 11.75). Because of the loss of sensation, injuries to the foot may go unnoticed and untreated. Secondary infections are a common complication and they tend to become chronic. These secondary infections can stimulate periostosis that may extend from the primary site in the foot to the tibia and fibula. In contrast with other conditions, such as treponematosis, reactive new bone formation is most severe near the ankle and diminishes in severity toward the knee (Fig. 11.76).

FIGURE 11.76 Periostosis of the lower tibia and fibula that is probably the result of a chronic infection of the foot (adult male about 35 years from the medieval cemetery for the hospital of St. James and St. Mary Magdalene, Chichester, England; UB burial no. C-88).

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TREPONEMATOSIS, TREPONEMAL INFECTION, OR TREPONEMAL DISEASE (TD) Introduction Whether the treponematoses—venereal syphilis (VS), yaws, endemic syphilis (ES) (also known as bejel), and pinta—are caused by different species of treponeme or by variants of the same species is still unresolved. Until the 1990s, the bacteria causing all the “syndromes” were indistinguishable using any known histological, immunological, or molecular biological methods (Hoeprich, 1989: 1022). Research on the DNA of bacteria causing TD has identified a difference between the bacterium associated with VS and that which causes nonvenereal TD (Centurion-Lara et al., 1998). However, this difference occurred in a segment of DNA that did not code for protein (flanking region). It is therefore considered unlikely that the difference had any relationship to the clinical manifestations of the syndromes (Lukehart, 1997, personal communication). Nevertheless, this research was an important step in initially clarifying the relationship between the pathogens causing the different clinical syndromes of TD which had been (and are) used to diagnose TD in an archeological skeleton dated to the historic period in the New World (Kolman et al., 1999). The geographic distribution of the nonvenereal treponemal syndromes tends to be limited to specific climatic zones. Pinta is a skin disease found in people in the Americas, yaws is a disease usually associated with tropical indigenous populations, and bejel is found mostly among indigenous populations in drier areas of subtropical North Africa, the Near East, and temperate Asia (but it is not found in the Americas). Bejel may have also occurred in northern Europe during the 17th and 18th centuries (Hoeprich, 1989: 1032). VS has a global distribution today and a contested past. There are several interrelated bioarcheological, historical, medical, and biological issues that contribute to the diverse opinions that exist about TD. Resolution of these issues has important implications for our understanding of the evolution and history of host pathogen interactions, as well as the historical questions embedded in the arguments about where the disease originated and how it spread from one geographical area to others. These issues continue to be debated as more skeletal evidence is found and critiqued, older evidence is reexamined (e.g., see Cook, 1976; Powell and Cook, 2005; Cook and Powell, 2012; Harper et al., 2011; de Melo et al., 2010), and new developments in modern and ancient DNA analysis of TD are incorporated (e.g., Montiel et al., 2012, and see Chapter 8). Unfortunately, the limited and mostly unsuccessful work regarding DNA analysis of skeletons with

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TD has not expanded our understanding of this infection in archeological contexts. While ancient and modern genomes of both leprosy and TB have been sequenced, TD genomic data are ambiguous and of limited utility in understanding the archeological record. As Stone and Ozga suggest (Chapter 8): “Data from modern strains indicate that T. pallidum subspecies pertinue and endemicum cluster with each other and that the TMRCA [the most common recent ancestor] for T. pallidum pallidum is estimated to have evolved around AD 1611 1859, long after the first historical reports of syphilis (Arora et al. 2016). This late date may reflect the limitations in geographic strain diversity in the available data, particularly in strains from Africa, or it could reflect the success of a particular set of strains to the detriment of more virulent strains, since there is some indication of more severe disease in early reports of syphilis.” A fundamental biological question is: are the four different clinical syndromes of TD caused by one or more different bacteria (see description below of the syndromes)? If a single pathogen is responsible for all four clinical syndromes, then the clinical differences between the syndromes must be explained by other factors that can affect the expression of infectious disease (see Table 11.6). We have seen in the discussion of leprosy that a single organism has the capacity to elicit a very broad range of responses from a host. At one end of the spectrum, the person may be completely unaware of the presence of the pathogen. At the other extreme, a person may develop severe disfigurement and/or suffer premature death. In the case of leprosy, the major factor in these differences is variation in the immune response of the person infected. This

TABLE 11.6 Factors That Can Affect the Expression of Infectious Disease in the Human Host Host Factors

Pathogen Factors

Age of onset

Biology of the pathogen

Age of the host

Pathogen reaction to host’s immune response

Adequacy of the host’s diet Gender differences in immune reactivity

Size of the inoculum

Exposure of the host to pathogens

Reproductive strategy of the pathogen

Immune response of the host General health of the host Portal of entry of the pathogen Social factors (e.g., population density) Efficacy of treatment

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highlights the possibility of population-based genetic variation in the immune response, resulting in different patterns of skeletal involvement in different human groups. If, on the other hand, more than one bacterium is responsible for at least some of the clinical variation between the syndromes, pathogen differences become a more important factor in understanding the clinical syndromes. It is, of course, possible that both differences in the pathogen and in the human immune response are responsible for the different clinical manifestations of TD and subsequent bone changes. All of these options have significant implications for our understanding of the evolutionary adjustments made by the host and the bacteria. For example, one potential evolutionary strategy for the pathogen is to evolve a very flexible relationship with the host, including the ability to infect a person via multiple pathways and respond to variation in immune responses. Another potential strategy would be for the bacterium to specialize in a restricted entry portal and vigorously counter a limited range of host immune responses. The following subsections address the evolutionary history of TD, the biology of the treponemal organism, and the bioarcheological evidence of TD. It addresses the following questions: 1. Is the pathogen that causes TD highly specialized in its relationship to the human host or is it an organism that adjusts easily to different host conditions and responses? 2. Do the different syndromes of TD exhibit distinguishable differences in their skeletal manifestations? and 3. Does the bioarcheological evidence address the issues of where and when the various syndromes developed?

Pathology The following discussion of TD is limited to the three syndromes that affect the skeleton: yaws, bejel or (ES), and VS. Individuals working with desiccated soft tissues in the Americas should, however, be aware of the possibility that pinta may be the cause of skin lesions. In all the treponematoses, the infecting organisms enter the body through the skin or mucous membrane near the skin’s surface. In bejel and yaws, the infection may locate anywhere on the body surface via direct contact between an open sore of an affected person with a break in the skin of another person. The age of onset in both bejel and yaws tends to be in childhood (Resnick and Niwayama, 1995a). VS is a sporadic disease that, because of its venereal mode of transmission, can occur in any human population, primarily affecting sexually active adults and infants who receive the bacterium via the placenta or during childbirth (congenital syphilis CD). In all three treponematoses, the organisms are disseminated throughout the body and reach the skeleton via the bloodstream.

Treponemal bacteria tend to affect skeletal elements with minimal overlying soft tissue. The reasons for this are not entirely clear. Jaffe (1972: 921) hypothesizes that these bones are more commonly affected by trauma and may thus make it easier for bacteria to enter the body. Bacteria also tend to reproduce optimally at very specific temperatures (see also the relevant discussion above for leprosy). The slightly cooler temperatures of bone located close to the skin surface may be an attractive environment for the treponeme. This predilection for affecting bone closer to the skin surface creates a pattern of skeletal involvement in TD that, when combined with the typical crater-like lesions containing the stellate radiating lines, is virtually pathognomonic for skeletal treponematosis. However, not all skeletons with TD have this characteristic type and/or pattern of skeletal lesions, and it is these skeletons that provide a diagnostic challenge in archeological contexts. The absence or poor preservation of skulls weaken the diagnosis, as does the knowledge that periostosis of long bones can have many etiologies (see Chapter 10). There is ongoing debate about differences between the syndromes in their skeletal manifestations. Hackett (1976), whose seminal work on diagnostic criteria for TD is a “must read” for any paleopathologist, argued that the distribution of lesions within the skeleton of VS, bejel, and yaws are so similar that diagnostic differences for individual skeletons cannot be made with certainty. In generating his diagnostic criteria, Steinbock (1976: 86 169), on the other hand, suggested that some differences in the typical pattern of bone involvement did exist between the three syndromes. It is certainly possible that slight differences in the type and distribution of bone lesions may exist for each of the three syndromes. However, a review of the current medical literature indicates a very considerable similarity in the bone lesions. When one is confronted with one or two skeletons with TD, as often happens, differential diagnosis between the three syndromes is likely to be difficult, if not impossible.

Yaws Bone lesions are somewhat more common in yaws than either VS or bejel. Estimates of skeletal involvement in patients with the disease range between 5% and 15% (Steinbock, 1976: 142 143). In a study of 101 individuals conducted by Goldman and Smith (1943), bone lesions were found in various skeletal elements with the following frequencies: tibia (46), fibula (20; 19 associated with the tibia), femur (13), ulna (10), humerus (9), radius (7; six times alongside the ulna), spine (5), clavicle (4), hand bones (4), foot bones (4), skull (3), ribs (3), and pelvis (2). Because yaws is usually acquired in childhood, the most active lesions are seen in children and in adolescents. Many lesions are similar to those seen in congenital

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FIGURE 11.77 Dactylitis of the right hand caused by yaws: (A) view of the hand; note the swelling in the area of both the metacarpals and the phalanges; (B) radiograph of the hand; note the enlargement of some metacarpals and phalanges (male 2 years old, from the monograph on yaws by Hackett, 1976, Figs. 47 and 48; “case” 241).

syphilis. This is particularly true of the often symmetrical dactylitis of the spina ventosa type (Fig. 11.77) and periostosis (Hackett, 1957: 14 15). If the child survives into adulthood, the early bone lesions of yaws may completely heal without leaving permanent bone changes. Another finding frequently observed in yaws is “bending” or “bowing” of the tibia (boomerang leg) (Fig. 11.78), which is very similar to the saber tibia of CS and usually develops before 15 years of age (Wilson and Mathis, 1930). Jaffe (1972: 921, 937) distinguishes between true bowing and pseudo-bowing of the tibia. In the former, the long axis of the tibia is abnormally curved. Pseudo-bowing is the result of periosteal reactive bone formation on the anterior and medial surfaces of the tibia without any distortion of the long axis. True bowing tends to be associated with subadult TD and pseudo-bowing with adults. Hackett (1936: 54 56) describes disseminated radiological lucencies in the anterior cortex in the early stages of yaws followed by anterior cortical thickening and bending. In the late stages, the posterior concave cortex is thickened and the anterior cortex thinned, as in late-stage deformities in rickets. Rarely, the fibula is also deformed and occasionally the radius and ulna show similar bending (Hackett, 1936: 52 4). These changes are indistinguishable from deformities of rickets and may not be due to yaws alone. Bending of the long bones also needs to be differentiated from normal variation.

The bone changes in the late stages of yaws show destructive dactylitis of single hand phalanges. The long bones, especially the tibia and the bones of the forearm, may show periostosis and osteomyelitis with gummata (focal infective destructive lesions containing bacteria, white blood cells—mostly lymphocytes—and connective tissue) very similar to tertiary VS. Indeed, Buckley and Dias (2002) have noted that the position of the lymph nodes and lymphatic vessels is the same as the characteristic pattern of skeletal involvement in TD. In contrast to the early stages of yaws, the overlying soft tissues frequently ulcerate and thus open the way for secondary pusforming infections, pus being a fluid containing bacteria and dead white blood cells produced in infected tissue (Hackett, 1976: 16). Skull changes due to yaws include chronic lesions of the vault characterized by central destruction surrounded by reactive bone formation that creates the crater-like lesion of classic caries sicca. Hackett (1976) has provided a careful description of the development of these lesions because they also occur in VS. The lesions begin with a roughly circular cluster of holes penetrating the outer table of the skull that are linked in the living patient to gummas. Lesions of the facial bones include the formation of periosteal reactive new bone on the maxilla (goundou) and destruction of the bones of the nasal cavity with penetration of the hard palate (gangosa).

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FIGURE 11.78 Radiograph of saber tibia in yaws: notice the bowed and elongated tibia with anterior cortical osteoporosis and posterior cortical thickening (48-year-old Javanese male with yaws since childhood; studied by W.G.J. Putschar at Orthopedic Rehabilitation Center, Solo, Java, Indonesia).

FIGURE 11.79 Radiograph of osteomyelitis from yaws affecting the left elbow, showing destructive areas and periosteal reactive new bone formation particularly on the metaphysis (male 14 years old, from the monograph on yaws by Hackett, 1976, Fig. 11.1; “case” 284).

One of the clinical manifestations of yaws is swelling in the joints (Hoeprich, 1989: 1024, 1026). Less well known are the erosive arthropathies of the joint and juxtaarticular bone that also occur (Sengupta, 1985: 195). In Hackett’s remarkable study of bone lesions in patients with yaws in Uganda (1947), he included at least two individuals (#284 and #368) with destructive joint disease. Individual #284 was a young male of 14 years of age who had suffered from yaws for at least 7 years. He had a painful swelling of the left elbow for a year before being examined by Hackett. The radiograph shows considerable

periosteal new bone formation in the metaphysis, particularly of the distal humerus. Although Hackett calls attention to this abnormality, he did not describe clear evidence of joint destruction also apparent in the lateral radiograph (Fig. 11.79). Individual #368 was a girl aged 12 years who had had yaws since infancy. The first interphalangeal joint of her left hand was destroyed, resulting in the abnormal angulation of the finger distal to that joint (Fig. 11.80). In yaws, lesions can also destroy the diaphysis of the hand phalanges resulting in a shortened finger (Fig. 11.81) and reduced biomechanical function.

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FIGURE 11.80 Joint destruction of the left hand in yaws: (A) note the enlarged joints and abnormal angulation of the proximal interphalangeal joints of the second, fourth, and fifth digits; (B) radiograph of the hand showing the joint destruction of the proximal interphalangeal joints (female 12 years old, from the monograph on yaws by Hackett, 1976, Figs. 116 and 117; “case” 388).

FIGURE 11.81 Diaphyseal destruction of the middle phalanx of the right middle finger: (A) shortened middle finger; (B) radiograph of the right hand showing loss of the diaphysis of the middle third phalanx (male 18 years old, from the monograph on yaws by Hackett, 1976, Figs 114 and 115; “case” 239).

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In the clinical literature on TD, VS is regarded as the only treponemal disease that is associated with a congenital variant. However, there is also evidence of congenital yaws (Hoeprich, 1989: 1026). Almost certainly, congenital variants of both VS and yaws are related to the age of onset for the syndrome. In the early phase of TD, spirochetes in the bloodstream can lead to spirochetemia. Transplacental transmission of the organism is much more likely during this early stage (Resnick and Niwayama, 1995a: 2493). Although yaws is most often acquired in childhood, well before sexual maturity and a first pregnancy, some women will acquire the disease later in life and may have the early stage of yaws when they become pregnant and thus are likely to transmit the disease to the fetus.

Bejel (or Endemic Syphilis or Treponarid) Bejel is most commonly associated with the dry areas of the Middle East and Africa, although there is evidence that in the past it occurred in other areas, including northern Europe (Hoeprich, 1989). In a survey of 25,000 people in Bechuanaland (now Botswana), 26% showed latent and 1.4% active bejel (Murray et al., 1956: 991). In this study, the predilected skeletal locations for lesions were the tibia and ulna. Bone lesions were not seen in children less than 2 years old (Murray et al., 1956: 1000) and congenital transmission of bejel is not known to occur today (Hoeprich, 1989: 1033). In a study from Syria, the changes observed resemble those of acquired or late-stage CS. They consisted mostly of periosteal new bone formation causing a fusiform (spindle-shaped) enlargement of long bones but little, if any, medullary cavity changes. Intracortical, sharply lytic, rounded gummas are occasionally found. Reactive new bone formation on the tibia (Fig. 11.82) produces the classic saber tibia when viewed laterally. The term “saber” has been used to describe the appearance because it looks like the curved bladed weapon (Rost, 1942: 321 323; see also Fig. 11.83). Periostosis and gummas in the short bones of the hands and feet have also been observed in people from Bosnia (Grin, 1935: 482). Charcot joints are not observed in bejel, unlike in VS (Rost, 1942: 323; Murray et al., 1956: 1001). Destructive nasal lesions leading to perforation of the hard palate occur (Grin, 1935: 482; Murray et al., 1956: 1000) but are rare (Hoeprich, 1989: 1033).

FIGURE 11.82 Radiograph of a tibia and fibula of a person with bejel showing the classic saber shin (tibia) from periosteal new bone formation on the anterior and medial surfaces. Adult male, courtesy: Dr. George El-Khoury, Department of Radiology, University of Iowa Hospitals and Clinics, Iowa City, Iowa.

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FIGURE 11.83 Saber shin and skin ulceration (Figure 4 from “La syphilis he´re´ditaire tardive”) Credit: Wellcome Collection. Free to use with attribution (https://wellcomecollection.org/works/rmzedejx? query 5 syphilis).

Venereal Syphilis (VS) Syphilis transmitted through sexual contact is known as acquired or VS, terms used to distinguish this type of syphilis from that transmitted transplacentally to the developing fetus of an infected mother (CS). The latter is discussed below. In view of the mode of transmission, it is obvious that, in most cases, acquired syphilis begins after sexual maturity. Following an incubation period of several weeks following infection, the initial or primary phase of the disease occurs, followed by the secondary and tertiary stages. The primary stage begins with the appearance of the chancre (painless ulcer on the genitals) and ends with the involvement of the regional lymph nodes, to which the bacteria migrate. The secondary stage begins with dissemination of the bacteria through the bloodstream, characterized by a transitory skin rash and mucous membrane lesions. The borderline between the secondary and the tertiary stages is not as clearly defined. However, the tertiary stage is mostly characterized by progressive involvement of different organs, including the skeleton. It is in this stage that the tissue reaction may assume a distinct

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granulomatous appearance of nodular foci with a central necrosis (gumma). The characteristics of the inflammation at all stages is more chronic, with lymphocytes and plasma cells predominating. Neutrophils and leukocytes (white blood cells that fight infection) are not prominent, and there is no significant formation of pus. Hypervascularity is usually marked. In the secondary stage periostosis with reactive new bone formation is not uncommon. These changes are usually transitory and leave no characteristic permanent alterations on the bone. Estimates for the prevalence of VS in the late 19th/ early 20th centuries vary. In Europe, before about 1910, about 10% of inhabitants in cities gave positive serological reactions for VS, although this is not identical to active disease (McElligott, 1960). In a survey of 2000 individuals with VS in Norway from 1890 to 1920, Gjestland (1955) found that approximately 1% of the patients had bone lesions. The combination of these figures would result in a frequency of syphilitic bone lesions of about 1 in 1000 Europeans in the time period before effective treatment was discovered (Hackett, 1976: 114). Other estimates of the prevalence of bone lesions in patients with VS vary from less than 1.5% to as many as 20% (Resnick and Niwayama, 1995a: 2496). This variation highlights the need for caution in reconstructing the paleoepidemiology of treponematosis on the basis of the prevalence of the disease in archeological human remains. Paleopathology’s main interest centers on the bone lesions of the tertiary stage. The key reference point for understanding the skeletal manifestations of VS are the bones from documented individuals with VS in pathology collections that date to before the advent of effective treatment (approximately before 1910). Two ethically questionable studies of people with untreated VS have occurred in the United States (the Tuskegee study, between 1932 and 1972; Rockwell et al., 1964) and Norway (between 1890 and 1910; Giestland, 1955). These provided observations of the effects of VS on the human body, including the bones of the skeleton, in untreated people. Although paleopathology has focused on the skeletal manifestations of VS, treatment of skin lesions associated with VS may have altered the course of the disease. In Europe, mercury has been used in ointments and in other treatments since the medieval period, continuing into the 19th century (Quetel, 1990: 28 31, 60; Ioannou et al., 2015a,b). Skeletons of people with VS who were treated in the late 19th century show severity of skeletal involvement that far exceeds any archeological skeletal evidence. In the following pages one of these skeletons will be presented as an example that argues for the possibility that treatment using mercury might have been a factor in this uncommon manifestation of skeletal lesions. Related to mercury treatment, recent work has highlighted the effects of this substance, particularly on the dental changes of CS (Kepa et al., 2012: Poland; Ioannou et al., 2015a,b: south

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TABLE 11.7 Localization of 945 Tertiary Syphilitic Bone Lesions in Order of Decreasing Frequency Bone

No.

Tibia

248

Nose and palate

238

Skull

179

are characterized by an excessive osteosclerotic response to the infection. In many instances adjacent mucosal surfaces, as in the nasopharyngeal area, and overlying skin, as on the scalp or shin, or other soft tissue are involved and ulcerated. The most characteristic lesions are those with a gummatous destruction and perifocal osteosclerotic reaction involving the periosteum and the underlying bone (for a detailed analysis of morphological features and their relative diagnostic specificity, see Hackett, 1976). The lesions usually develop between 2 and 10 years after the infection, but may occasionally occur earlier or much later. Often, more than one bone is affected and involvement tends to be bilateral. Although any bone can be the location of a lesion, there are a few areas that are greatly predilected: the tibia, the bones surrounding the nasal cavity, and the cranial vault. These three locations combined represent about 70% of all tertiary bone lesions in VS. These are followed in decreasing frequency by bones with large amounts of cancellous bone (rich in hematopoietic marrow—ribs, sternum), and the other long bones of the extremities. A survey of frequency from the greatest series of Fournier (1906, as cited in Beitzke, 1934b: 471) is given in Table 11.7. The spine is an exception to the behavior of other cancellous bones; it is rarely affected by VS. When it is affected, the most common site are cervical vertebrae (Jaffe, 1972: 938).

Ulna

37

Ribs

35

Sternum

29

Clavicle

27

Metacarpals

21

Humerus

20

Radius

17

Femur

16

Mandible

14

Fibula

12

Spine

9

Nasal bone

9

Fingers

7

Pelvis bone

5

Metatarsals

4

Scapula

4

Ribs and sternum

3

The Skull

Tarsals

3

Toes

3

Maxilla

3

Patella

1

Carpals

1

Transient cranial periostosis is common in the earlier stages of VS, but this is not diagnostic. However, in the tertiary stage of the infection, the most common location of lesions in clinical patients is in the skull, particularly in the perinasal area and the cranial vault (see Fig. 11.84). These lesions represent the most specific diagnostic features. The main focus is on the gummatous, osteoperiostotic cranial vault lesions, the majority of which begin in the frontal bone. As the disease develops, new lesions may occur in the adjacent parietal and facial bones. Less commonly, the first lesion in the cranial vault begins in a parietal bone, while the occipital bone may be involved when a person is severely affected, but it is usually spared, even if the process extends to the lambdoid suture. The characteristic lesion of VS was classically described by Virchow (1858, 1896) as “caries sicca.” Hackett (1976: 30 49) revived this phrase, added more detail to the developmental stages of the lesion, and designated the most diagnostic feature for VS in dry bone. The lesion begins at or near the osteoperiosteal border, and is usually of the outer skull table. It elicits hypervascularity that, on inspection of the outer table of a skull, reveals itself in the form of grouped and fine vascular foramina. This initial change has the same reaction as that observed in TB and metastatic cancer. However, in the

Source: After Fournier, 1906.

Australia). We therefore need to be very careful before assuming that skeletal evidence of any disease from the preantibiotic era is typical of the natural, untreated expression of the disease. Throughout human history medical practitioners used various substances to treat their patients, and some of these treatments could easily have had adverse effects on the patients that could affect the skeletal manifestations. The tertiary bone changes of VS are the result of either chronic nongranulomatous inflammation or granulomatous (gummatous) processes. In many cases, a combination of the two is present. Both of these changes can affect a localized area of the bone or the entire bone. The inflammation may begin on the periosteum or in the bone. Ultimately, however, the periosteum and cortex, and more rarely the medullary cavity, are involved. All tertiary bone lesions

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FIGURE 11.84 Tertiary syphilis of the face. Figure 492 of Stokes (1927).

latter two, the inner skull table is predilected and ultimately shows the larger defect. In osteolytic metastatic cancer, due to its frequently rapid development, fullthickness destruction of both tables and the intervening diploic space is common, resulting in a hole with a nonreactive border that is crenelated (has notches). In TB, in addition to involvement of the inner table, reactive bone formation tends to be a late development and may not be apparent in some individuals. The syphilitic lesion leads to a focal destructive remodeling of the outer skull table and part of the diploic space by granulation tissue, but it often spares the inner table almost completely. As part of this remodeling there is a strong sclerotic response in the bone surrounding the lytic focus, forming a sclerotic base and an elevated sclerotic margin around the defect (Fig. 11.85). Microscopically, focal bone necrosis is common and may well be a major stimulant to reactive sclerosis in the process of remodeling (Axhausen, 1913). However, pus formation is not significant and large sequestra usually do not form. In the chronic course of VS, even if untreated, individual foci will heal but new foci will form in the vicinity. The healed individual caries sicca lesions leave a depressed, sclerotic, radially grooved stellate scar (Fig. 11.86). This is somewhat less obvious in confluent healed areas (Fig. 11.87). The process continues and leads to confluent pitting in a circinate (“circular and rolled up inwards”) arrangement surrounded by reactive bone, with partly smooth and partly hypervascular surfaces (Fig. 11.88). In advanced confluent (merging) caries sicca lesions, the diploe may be markedly thickened and

FIGURE 11.85 Tertiary syphilis of the cranial vault, ectocranial view. These are relatively early lesions with central destruction and peripheral reactive bone. The inner table shows only minimal diffuse reactive bone deposition (adult; ANM 2232).

sclerotic, whereas the inner table exhibits only minor reactive new bone formation (Fig. 11.89). Destruction and perforation of the full thickness of the cranial vault does occur, especially when secondary pyogenic osteomyelitis is present, but even then the changes on the inner

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FIGURE 11.86 Tertiary syphilis of the cranial vault, ectocranial view; multiple small cavitating lesions with advanced and partly complete healing; inner table unchanged (adult; ANM 2468).

FIGURE 11.87 Tertiary syphilis of the cranial vault with considerable healing (HM; P717).

FIGURE 11.88 Extensive tertiary syphilis of the cranial vault with advanced sclerotic healing (adult WM S50a.2 from 1828).

FIGURE 11.89 Confluent caries sicca lesions of the skull vault caused by tertiary syphilis: (A) skull vault; (B) radiograph showing variation in mineral density and greatly thickened bone (adult; PMS 9/1.372E).

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FIGURE 11.90 Infectious defect of the frontal bone covered by scarred soft tissue; probably tertiary syphilis with superimposed osteomyelitis; 25-year duration (58-year-old male; PMES 1E.B.1(4) from 1899).

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FIGURE 11.92 Tertiary syphilis of the nasal cavity, anterior view, showing widening of the nasal cavity, complete destruction of the nasal septum and large perforation of the hard palate (old female ANM 2423).

FIGURE 11.93 Tertiary syphilis of the nasal cavity with destruction of the hard palate and perforations of the palatal bone; exterior basal view (24-year-old male with VS (WM HR 4.1 from 1848). FIGURE 11.91 Tertiary syphilis of the cranial vault, surface view (wet preparation), showing multiple scalp ulcerations exposing the affected bone (GHPM; 3914 from 1914).

table are less pronounced (Fig. 11.90). Major sequestra are seen in skulls with VS-related bone lesions in European contexts, often showing darker discoloration of the necrotic bone. This is due to exposure of the affected bone when the scalp is ulcerated and this probably largely represents the result of secondary pyogenic (pus forming) infection (Fig. 11.91). In contrast to the sequestra in pyogenic osteomyelitis, these sequestra will have a “worm-eaten” appearance, indicating their involvement in the disease process before becoming necrotic. Hackett (1976: 57) did not find sequestra in skulls of native

Australian individuals affected by bejel or yaws. He attributes this to the presumed absence of pyogenic infections in these populations. The facial bones most often affected by tertiary VS are the nasal bones, the bony nasal septum, the hard palate, the turbinate bones, and the lateral walls of the maxillary antrum. These bones are involved secondary to soft-tissue involvement of the nasal mucous membranes in VS. The thin bones are often destroyed and this destruction can extend with perforation of the nasal septum, the hard palate, and of the medial walls of the maxillary sinuses (Figs. 11.92 11.94). The nasal cavity appears enlarged and empty in the dry skull. However, in

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FIGURE 11.94 Nasomaxillary tertiary syphilis with extensive endonasal destruction and some sclerotic healing, destruction of the palate, and involvement of the maxilla (43-year-old female; ANM 2221 from 1889).

FIGURE 11.96 Frontonasal tertiary syphilis with active destruction of the nasal bones and medial orbital walls, healed margin of enlarged nasal aperture, and completely healed lesions of the frontal bone (adult; WM HS 50a.2 from 1841; lines on the forehead are shadows from the plastic box containing the skull).

FIGURE 11.97 Destructive remodeling of the pyriform (nasal) aperture with perforation of the hard palate in a person with tertiary syphilis (female 30 years old; WM RCS S50a.3).

FIGURE 11.95 Cranionasal tertiary syphilis, mostly healed: notice scarring of the nasal and frontal bones, and preservation of the inferior nasal spine (43-year-old male ANM 2000 from 1893).

contrast to neoplastic destruction in this area, the margins of the defect are bordered by smooth sclerotic bone. In contrast to leprosy, the frontal bone is usually involved, perforation of the nasal septum and hard palate is common, the sclerotic response is marked, and the inferior nasal spine may be spared (Fig. 11.95). The zygoma, the nasal bones, and the medial aspects of the orbital walls may be affected by direct extension of the process from the frontal bone (Fig. 11.96). Destruction of the bony support of the bridge of the nose results in “syphilitic saddle nose”. Nasal lesions can also penetrate the palate

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the vertebral bodies are most commonly affected and the arches and processes are rarely involved (Jaffe, 1972: 938). The Long Bones The tibia is approximately 10 times more often the site of lesions in VS than any other long bone of the extremities. The lesions of long bones can be separated into nongummatous and gummatous osteoperiosis. The nongummatous lesions are suggestive but probably not diagnostic of treponemal infection (Fig. 11.99). It should be noted that Hackett (1976: 87 90) puts them

FIGURE 11.98 Cranionasal tertiary syphilis, external basal view, showing active destruction of the palate, and sclerotic scarring of the nasal roof with extension to the sphenoid bone (30-year-old male; FPAM 1552; autopsy 8826 from 1834).

(Fig. 11.97). The skull base is rarely involved, but extension of the nasopharyngeal process into the sphenoid bone does occur (Fig. 11.98), resulting in marked sclerosis of the area (Schinz et al., 1951, 1952: 627). The Spine Osteomyelitis consequent to VS in the spine is rare (Whitney and Baldwin, 1915), and the changes in dry bone would not be diagnostic in themselves. The outcome may be kyphosis, after destruction of adjacent vertebrae, similar to TB. In contrast to TB, a paravertebral abscess is missing, which may not be obvious on dry bone. In addition, and in contrast to Pott’s disease, the cervical vertebrae are affected three times as often as any other segment in the instance of VS infection of the spine (Beitzke, 1934b: 510; Jaffe, 1972: 938). This may suggest extension from nasopharyngeal mucosal lesions rather than being of hematogenous origin. However, like TB,

FIGURE 11.99 Tertiary syphilis affecting the left tibia complicated by a skin ulcer: note the mid diaphyseal involvement and the erosion at the ulcer base below. The medullary cavity was filled with reactive bone (27-year-old female; ANM 2914 from 1872).

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FIGURE 11.100 Tertiary syphilis affecting the distal left femur (P374) with periostosis and sclerotic plaques of new bone (HM 374).

into his “on trial” category of diagnostic lesions, and therefore continued caution should be taken if these lesions are to be attributed to treponematosis per se without any more specific bone changes. The localized form of nongummatous periostosis in VS may leave elevated, plaque-like new bone on the cortex of bones that have a major overlying layer of muscle, such as the femur (Fig. 11.100), or surface parallel lamellar type new bone of varying thickness and density on bones close to the skin surface, such as the ulna and clavicle (Figs. 11.101 and 11.102). Extensive periosteal thickening is often combined with cortical thickening, including on the endosteal surface. Diffuse nongummatous osteoperiosis tends to leave the bone thicker and heavier than would be

FIGURE 11.101 Treponemal related lesions of the right ulna (P372) with periostosis and slight pitting (HM 372).

FIGURE 11.102 Treponemal related lesions of the left clavicle (P369) with diffuse periosteal bone and focal pitting (HM 369).

expected for the age and sex of the individual. The entire surface, with the exception of the cartilage-covered articular surfaces, may be involved. The periosteal bony buildup may be thick and becomes firmly merged with

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the old cortex of the bone. The outer bone surface is rough and markedly hypervascular. In the late stages of nongummatous osteoperiosis, the medullary canal may be completely filled with sclerotic trabeculae, while the definition of the old cortex may be less obvious due to Haversian canal resorption. This means that in crosssection the bone appears uniformly, coarsely cancellous, with loss of the distinction of the cortex and medullary cavity. A differential diagnosis of Paget’s disease may be considered, but differentiation can be made microscopically by observing the absence of typical Paget’s disease mosaic patterns. Gummatous osteoperiostitis is a much more characteristic lesion for VS. In its localized form, it may

result in a tumor-like enlargement of the affected area of the bone (Axhausen, 1913). In dry bone the marked hypervascular, periosteal, bony buildup surrounds a scooped-out defect that extends into the cortex. This corresponds with the location of a destructive gumma in the soft tissues of a living person. At times, the scooped-out lesions are smaller and several are grouped together, resembling the picture of caries sicca in the cranium (Fig. 11.103), but individual gummatous defects on long bones tend to be larger than on the skull. The underlying cortex is hyperostotic and endosteal new bone formation may encroach upon the medullary canal (Fig. 11.104). In some cases, larger defects are seen in the layer of hypervascular

FIGURE 11.103 Tertiary syphilis affecting the right femur; anterior view with massive gummatous periostosis and typical snail-track pattern (55-year-old male; PMUG 3466).

FIGURE 11.104 Treponemal related lesions of the left femur with fusiform hyperostosis and medullary osteosclerosis: (A) anterior view, showing snail-track pitting, especially on the metaphysis; (B) cut section showing extensive medullary sclerosis (adult; WM S 50b.1 from 1831).

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FIGURE 11.104 Contiuned

periosteal new bone, exposing the deep cortex (Fig. 11.105) and sometimes small sequestra. These lesions must not be confused with cloacal openings (sinuses) of osteomyelitis; major sequestra are not present, and the margins of the defects are rough and thin, not smooth and sclerotic. Hackett (1976: 82, 93 97) accepts this form of osteoperiostosis as diagnostic of treponemal infection. Central gummas of the medullary cavity occur in the form of larger lytic lesions surrounded by a marked perifocal reactive sclerosis. This lesion may not be differentiated with assurance from a Brodie’s abscess (variant of subacute osteomyelitis), although the sclerosis is more marked than in the latter. Pathological fractures in bones weakened by osteoperiostosis in VS are not uncommon.

FIGURE 11.105 Tertiary syphilis affecting the cranial vault: (A) anterior view, showing quiescent external defect with sclerotic healing; (B) cranial vault showing more active destructive lesions in both parietal bones; (C) left arm bones; notice absence of sequestra and cloacae (scale in centimeters) (45-year-old female; PMUG 2647, autopsy 6262 from 1874).

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FIGURE 11.105 Contiuned

The Joints Arthritis occasionally occurs during the secondary stage of VS and affects the large joints (shoulder, elbow, knee, including Clutton’s joint in CS). This bone damage is transitory and leaves no changes visible on dry bone. However, occasionally, an epiphyseal gumma may perforate into a joint and lead to gummatous arthritis (Axhausen, 1913). The perforation predominantly occurs near the margin of the articular cartilage (Freund, 1933). Subsequent bone changes, if present, are not significantly different from other forms of arthritis, particularly osteoarthritis. Only the presence of the gummatous bone lesion may be a clue to a treponemal etiology. Indirect suspicion of VS infection may be aroused by observation of pressure erosions (aneurysms) of the sternum, ribs, or thoracic vertebrae or from findings of a Charcot joint (neuropathic arthropathy that can be related to the presence of VS). However, not all aneurysms of the thoracic aorta are due to VS and not all neuropathic arthropathies are the result of tabes dorsalis (nerve degeneration associated with the tertiary stage of VS). Two complete skeletons of patients who had VS from the Pathology Museum of the University of Strasbourg, France, illustrate skeletal manifestations that are unusual in both the severity of chronic bone destruction and in the bones that are affected. The first skeleton (# 4479) is that of a male aged 51 years whose body was accessioned to the anatomy laboratory in 1907. This means that most of this person’s life was lived in the

FIGURE 11.106 Tertiary syphilis of the skeleton: (A) posterior view of the skeleton showing involvement of virtually all bones; (B) lateral view of the skull and cervical vertebrae showing involvement of the mandible, lesions on the inferior portion of the occipital bone, and fusion of the diarthrodial joints including the occipital condyles through the sixth cervical vertebra; (C) severe involvement of the clavicles and sternum; (D) extensive destruction of the right scapula and ribs; (E) lateral view of the right femoral diaphysis, showing a penetrating defect surrounded by periosteal buildup of bone; (F) posterior midshaft of the right tibia and fibula (51-year-old male with visceral and cerebral syphilis; DPUS 4479, autopsy 697 from 1907).

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FIGURE 11.106 Contiuned

late 19th century. Ortner (2003:289) stated that “Bone involvement in the first of these skeletons (Fig. 11.106) far exceeds the involvement encountered in archeological human remains of treponematosis that I have

studied. It seems likely that this patient had a severely compromised immune response to the pathogen.” The second skeleton (# 5527) does not have an associated date but the higher catalog number suggests that it is

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FIGURE 11.107 Tertiary syphilis of the total skeleton: (A) anterior view; (B) syphilitic lesions of both arms; posterior view, showing symmetrical involvement of both humeri; (C) lesions of the bones of both legs, anterior view, showing especially marked symmetrical involvement of both tibiae (adult male; DPUS 5527 from before 1820).

from a somewhat later time period. This skeleton is more typical of VS-related skeletal lesions (Fig. 11.107), and the comparison between the two skeletons provides an insight into the skeletal involvement of syphilis at the extreme end of severity.

Congenital Syphilis (CS) CS was a common disease with a high mortality prior to the development of effective treatment for the infected mother during pregnancy. Among 4500 consecutive autopsies at Johns Hopkins Hospital, Baltimore, Maryland,

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United States, before 1933, there were 189 fatalities with CS, only two of which were older than 4 years (Smith, 1933). In CS, the treponemal infection is transmitted transplacentally from the infected mother to the fetus, most commonly during the early acute phase of the disease. The result is fetal death followed by miscarriage in the first half of pregnancy, fetal death with delivery of a premature or mature diseased stillborn fetus, or delivery of a living infected infant. If the infection is mild, it may not manifest itself for several years (syphilis congenita tarda). In severe infections, all organs and tissues of the fetus are permeated with numerous treponemal organisms. Because the immune capacity to mount an inflammatory response is not yet developed in the first half of pregnancy, such aborted fetuses show no tissue changes. Furthermore, such fetuses are unlikely to be recovered during archeological excavations and therefore are not seen in paleopathological research. In premature and full-term stillborns, as well as in actively infected newborn living infants, characteristic skeletal changes are almost always present in the form of CS-related osteochondritis, inflammation of the cartilage or bone, or both (Jaffe, 1972: 910 917). This is the result of hematogenous dissemination of the bacterium to the fetus in utero. It affects all areas of enchondral growth in the entire skeleton, but is most marked in the fastest-growing metaphyses (distal femur and proximal tibia). The lesions are symmetrical. They consist of accumulation of calcified cartilage adjacent to an area of lucency due to poor bone formation (Fig. 11.108). In radiographs of long bones, this area appears as a zone of increased density (Fig. 11.109). This may represent merely a toxic effect on enchondral (within cartilage) ossification (“passive osteochondritis” of Schneider, 1923 1924: 205) or be the result of formation of syphilitic granulation tissue in this area (“active osteochondritis” of Schneider 1923 1924: 205). Similar disturbances of enchondral growth are seen in a variety of conditions and are not diagnostic of CS (Caffey, 1939). These fetal and neonatal alterations pose a challenge for differential diagnosis in archeological human remains. In surviving infants, transverse metaphyseal pathological fractures through this weakened area of the metaphysis not uncommonly occurs (Parrot’s pseudoparalysis). Because before walking, the infant’s arms are more mechanically stressed than the legs, the distal humerus is the predilected site of such fractures. This osteochondritis heals in the infant, even if untreated. CS-related periostosis often develops during infancy, mostly following the osteochondritis. Occasionally, it has already begun in intrauterine life and is present at birth. It consists of usually symmetrical, circumferential deposition of subperiosteal bone on the shafts of long bones. The trabeculae in this bone deposit often show a radial arrangement. This change is frequently transitory but may be recognizable

FIGURE 11.108 Syphilitic osteochondritis of distal femur (wet preparation): notice the broadened and irregular area of provisional calcification at the metaepiphyseal junction (2-month-old male; WM S 51.2 from 1910).

on infant bones under conditions of ideal preservation (Fig. 11.110). Similar periosteal bone deposits may occur on the cranial vault (Fig. 11.111). Gummatous periostosis and osteomyelitis occasionally occur in CS, especially in older children who have passed through mild, unrecognized, and untreated manifestations in infancy (syphilis congenita tarda) (Wimberger, 1925: 307 370). In this age group, bone involvement is neither so frequent nor so generalized as in infants but comes

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FIGURE 11.109 Radiograph of the long bones of an infant with probable congenital syphilis with the zone of increased density near the growth plate (NMNH 249602).

FIGURE 11.111 Congenital syphilis of the cranial vault with periosteal bony build up on both frontal and parietal bones. The mother had extensive ulcerated nasofacial syphilis (1-year-old; PMWH WO 734 from 1886; the lines on the skull vault are shadows from the box containing the skull).

FIGURE 11.110 Long bone with subperiosteal new bone formation on the shaft in congenital syphilis (31/2-month-old infant; WM S 51.1 from 1880).

closer to the distribution and appearance of VS (Fig. 11.112) (Pendergrass et al., 1930). Only 32 of 462 patients (6.9%) over 13 years of age with late-stage CS showed active bone changes in Smith’s 1933 study. The

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FIGURE 11.112 Long bones of a 12-year-old child with tertiary congenital syphilis: (A) left femur; note the periosteal new bone formation and the snail-track patterns in the bone; (B) bisected left femur with cortical resorption and medullary reactive new bone; notice absence of medullary penetration and sequestrum; (C) fibula, ulna, and radius (bisected), showing similar lesions (ANM 2999, 3163, 3166, 3185).

FIGURE 11.113 Tertiary congenital syphilis affecting the radius and ulna bilaterally (all bones bisected longitudinally): notice pitting destruction and marked hyperostosis without cloacae or sequestra (about 6 years old; ANM 3386).

lesions in the long bones predilect the tibia, ulna, and radius (Fig. 11.113). Skull lesions occur but usually appear as multiple, rounded, destructive foci without the characteristic features of the caries sicca sequence (Fig. 11.114). The saddle nose in CS may be mainly the result of disturbed enchondral ossification of the base of the skull. In adolescents, the tertiary bone lesions may more closely resemble those observed in adults, and differentiation of a late stage of congenital from VS may be impossible without clinical data (Figs. 11.115 and 11.116). Occasionally, extensive involvement of the facial bones can occur in CS (Fig. 11.117). Nongummatous periostosis results in osteosclerosis (hardening of the bone with increased density) with the subperiosteal new bone deposits ultimately merging with the underlying cortex. The most characteristic lesion of this type is the so-called saber tibia of Fournier (1886: 265 269). Such tibial bowing results from abnormally stimulated growth (“true bowing”). The appearance of bowing can also be created by layered bone deposition on the anterior and medial surfaces, known as “pseudo-bowing.” In CS, excessive growth of the tibia is stimulated by the disease. The fibula experiences normal growth in length and shape. True bowing in CS is the result of the differential growth of the tibia which ends up remaining fixed by ligaments and tendons to the shorter fibula (Jaffe, 1972: 921). As previously mentioned, similar bony buildup on the anterior tibial surface occurs in nongummatous periostosis of VS (Fig. 11.118). In this case,

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FIGURE 11.114 Congenital syphilis with a destructive lesion of the right side of the frontal bone involving both tables: (A) ectocranial view. (B) endocranial view (8-month-old female; ANM 2233 from 1865).

FIGURE 11.115 Tertiary cranial syphilis (congenital?): note active and healing lesions in the frontonasal area, a widened nasal aperture, loss of the nasal septum and inferior nasal spine, and perforation of the palate (16-year-old male; ANM 2009 from 1870).

FIGURE 11.116 Anterior view of a skull with destruction of the nasal bones and involvement of the zygomas; the frontal bone lesion is partly healed. The young age raises the question of tertiary and congenital syphilis (17-year-old female; ANM 2427).

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however, the tibia is not abnormally elongated and curved, and the posterior contour remains straight. One method of distinguishing between the two types of bowing is to determine whether the interosseous line of the

FIGURE 11.117 Child with congenital syphilis showing sclerotic healing of the frontal and nasal bones: (A) anterior view of the skull; the teeth are normal; (B) lateral view of the skull showing an active frontoparietal lesion (8-year-old with a history of syphilis; OM F 133).

tibia is straight. If it is, the bowing is of the pseudo type. If the interosseous line is curved in any direction, but particularly in the anteroposterior axis, then true bowing has occurred. Syphilitic dactylitis used to be more frequently observed in congenital than in acquired syphilis. It

FIGURE 11.118 Treponemal disease affecting the right tibia showing the characteristic saber morphology: (A) lateral view, showing anterior periosteal new bone deposition; (B) lateral radiograph showing anterior cortical thickening and preservation of the medullary cavity (adult Caucasian male; Pathology Department of the University of Otago, New Zealand). Courtesy: Dr. Bruce Ragsdale, Central Coast Pathology Consultants, Inc., San Luis Obispo, California.

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recent research on these abnormalities has reviewed the literature (Hillson and Grigson, 1998). However, the combination of defective dental formation in association with systemic manifestations of skeletal disease particularly affecting the facial bones, ulna, and tibia does provide a relatively high degree of confidence in a diagnosis of CS, although yaws is possible in geographical areas where this syndrome is endemic. Although there are a variety of skeletal changes occurring in different phases of CS (see Lewis, 2018: 178 182 for an overview of the skeletal changes), the findings must be critically evaluated in relationship to the context of the skeletal observations. Individual lesions may not be distinguishable from TB or other infectious changes.

Paleopathology

FIGURE 11.118 Contiuned

concerned the fingers more often than the toes and predilects the basal phalanges. The condition often affected more than one finger and was frequently bilateral but not symmetrical. The appearance, especially in small children, may closely simulate that of spina ventosa in TB, with widening of the diameters of the phalanges and formation of a thin, bony shell. In adults there is less expansion and more reactive osteosclerosis. Hutchinson’s and Moon’s teeth, although present in a variable number of individuals with CS, have been questioned in their specificity (Kranz, 1927: 263), and more

Considerable scientific and scholarly debate about the history of TD has focused on the origin of VS, with special attention to an “epidemic” of VS in Italy following the return of Columbus’s first voyage. As also reviewed in Chapter 8, some have argued that Columbus’ crew returned from the Americas with VS (the Columbian hypothesis; Crosby, 1969). Others have proposed that the disease was present in Europe and/or Africa prior to the late 15th century (pre-Columbian hypothesis, e.g., Livingstone, 1991). A further alternative identifies a global treponemal distribution that adapted to local circumstances (the Unitarian theory; Cockburn, 1961; Hackett, 1963; Hudson, 1965, 1968). Several summaries have emphasized skeletal evidence, with support distributed across the theories (Baker and Armelagos, 1988; Dutour et al., 1994; Harper et al., 2011; Meyer, 2002; Powell and Cook, 2005). These different and conflicting opinions are based on four distinct, but not necessarily mutually exclusive, sources of information: (1) historical documents, (2) archeological human remains, (3) theories about the evolution and adaptation of pathogens and the host’s immune response, and (4) molecular evidence. We briefly discuss each of the data categories below.

Historical Documents Bru¨hl (1880) cites many primary historical sources, including early chroniclers of colonial life in the Americas, such as Oviedo and Las Casas, who supported the view that VS existed in the New World at the time of its discovery by Europeans. He also cites Diaz de Isla, the physician who treated Columbus’ men for presumed VS. Bloch (1901, 1908, 1911) provides a review of older relevant source material and concludes that all available statements indicate that VS first appeared in the Old World during the years 1493 1500. He also argues that there is

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no historical evidence to show that the disease existed in Europe before that time. Dennie (1962: 61 63) notes that VS was particularly virulent after its initial introduction from the New World and subsequently became milder. He argues that this reflects the normal progress of a newly introduced disease and thus supports the theory of a New World origin for VS. In an opposing argument, Holcomb (1941) cites early descriptive medical reports of a disease process attributed by the early writers to leprosy. However, he (1941: 151 152) indicates that many of these purported people with leprosy were clearly affected by VS, in terms of both their appearance and the venereal mode of transmission (leprosy is not transmitted in this way). He concluded that VS in a congenital and acquired form certainly prevailed in Europe long before the discovery of America (1941: 167). This conclusion is supported by a description reported by Thorndike (1942: 474) on a disease process resembling VS dated to AD 1412. Elsewhere in the Old World, Hyde (1891: 117) stated that the ancient medical literature of China, Greece, India, and Italy contained unmistakable proof that early in the world’s history genital lesions were known to occur from sexual contact. However, Crosby (1969: 219) offers an opposing opinion that there is no unequivocal description of VS in the ancient Old World medical literature. In particular, Crosby cites Wong and Wu (1936: 218), who argued that no Chinese writer had ever described a disease which could be attributed to VS.

Skeletal Remains In discussing the evidence for pre-Columbian VS in the New World, we are primarily limited to human remains. There are two fundamental requirements to explore the theories describe above: (1) an unambiguous identification of TD and (2) a convincing pre-Columbian date. The earliest reference to VS in New World skeletons is from Jones (1876: 66), who reported on archeological skeletons from Tennessee. Indeed, this early discussion appears to have been the basis for subsequent reports in which other authors concluded that VS was present in populations in the New World before Columbus (e.g., Lamb, 1898). Morgan (1894) challenges Jones’ conclusions, calling into question both the diagnosis of VS and the pre-Columbian date. Much other purported evidence of VS has been reported in New World skeletons. One of the most respected early 20th-century scholars studying these skeletons was H.U. Williams, a pathologist, who concluded on the basis of a critical review of published work and his own observations that the case for pre-Columbian syphilis was probable beyond reasonable doubt (Williams, 1932: 978). He found the evidence for Old World skeletal syphilis before 1490 to be much less convincing. Turning to

the northern regions of the New World, Holcomb (1940: 189) concluded that VS probably did not exist among the Inuit or the Aleutian Islanders until after contact with Russian sailors and traders during the 18th century. Although a comprehensive review of the recent published literature documenting the history of TD through archeological human remains is beyond the scope of this work, a brief summary is provided below. Key overviews that should be consulted for paleopathological evidence of TD are Baker and Armelagos (1988), Dutour et al. (1994), Harper et al. (2011), Meyer et al. (2002), and Powell and Cook (2005). There have been a number of relatively recent publications on skeletal evidence for the treponematoses from North America (e.g., Hutchinson and Richman, 2006; Jacobi et al., 1992; Mansilla and Pijoan, 1995; Marden and Ortner, 2011; Nystrom, 2011). Even so, the conclusions voiced by Cook and Powell (2005) in their summary chapter remain convincing: (1) that treponematosis was present and variable in pre-Columbian North America and (2) that nearly all reports of VS prior to 1500 in the New World are inconclusive. This echoes other opinions (e.g., Baker and Armelagos, 1988). For the Old World, there is less consensus. A conference summary of evidence (Dutour et al., 1994) concluded that TD was certainly in the European population before AD 1492, and that a plausible case could be made for VS being the syndrome associated with this early expression of the disease. By contrast, Harper et al. (2011) argued that there was no TD in Europe prior to 1500, based upon their evidence-based survey. Isolated examples of TD, including VS, continue to be offered (e.g., Cole and Waldron, 2011, 2012, 2015; Zuckerman et al., 2012; Mays et al., 2003 Mays and Vincent 2009; Mitchell, 2003; Steyn and Henneberg, 1995). The most convincing evidence to date, however, is that of Walker et al. (2015), who report a temporal sequence of TD evidence from the medieval burial ground of St. Mary Spital, London (United Kingdom). Their extensive research program, which investigated 5387 skeletons that spanned the period between 1220 and 1539, presents convincing evidence for TD, likely VS. The rising prevalence during the most recent period suggests to the authors that their data may reflect the late 15th-century epidemic reported in historical documents.

Theories of Disease Evolution The third source of speculation on the history of TD is based on evolutionary theoretical reconstructions. In essence, these concepts about the TDs suggest that they have evolved with humans, migrated with them throughout the world, and thus were endemic in both the Old and New Worlds long before Columbus (Hudson, 1968;

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Cockburn, 1961; Hackett, 1976). Although not phrased in evolutionary terms, the concept of TDs being endemic in both Europe and the Americas goes back to an early report by Krumbhaar (1936: 232), who stated: “Personally, I regard as most convincing the theory of the existence of syphilis in both continents as far back as prehistoric times.” Similarly, Stewart and Spoehr (1952) speculate that TD existed in the Old and New Worlds but different strains of the bacteria had developed while isolated from each other. When contact between European explorers and indigenous Americans occurred, they “traded” strains of treponemal organisms to which neither had developed any immunity. This, they suggest, is the reason for the VS epidemic in Europe after the return of Columbus and the increase in bony lesions possibly attributable to VS in post-Columbian indigenous human remains in the New World. Stewart and Spoehr’s (1952) observations on the increase in VS-type lesions in postColumbian indigenous American skeletons are significant because of Stewart’s extensive experience with New World skeletal remains. In several papers, Hudson attempted to reconstruct the evolutionary history of the treponemal organism. In one of his earlier papers (1958: 23), he suggests that the treponeme evolved from a saprophyte (a microorganism that is closely related to the treponemal organism) early in human evolutionary history through the introduction of such an organism into a break in the skin. He further speculates that this event may have taken place in Central Africa in an environment similar to the rainforests of today (Hudson, 1965: 890 891). Such an early disease would probably have been similar to yaws of today, where the organism survives on moist skin. Crucial to an understanding of Hudson’s evolutionary history of TD is the concept that the treponemal organisms represent a “biological gradient” rather than separate species. In this scheme, the various treponemal syndromes or diseases reflect adaptations by the same microorganism to varying environmental conditions. Thus, when humans moved to more temperate regions, the organism migrated to the moister regions of the body (the mouth, axillae, and crotch), creating a new disease syndrome that Hudson (1965: 891) called endemic syphilis (or bejel or treponarid). Hudson (1965: 895) argued that VS developed alongside the development of cities, with improved hygiene associated with city life. In addition, the increased use of clothing in temperate climates prevented the frequent skin contact in children necessary for the transmission of endemic syphilis. Following human migration to the New World, the development of South American TD (pinta) was, in Hudson’s reconstruction, the result of a local adaptation in which the treponeme was again introduced to environmental conditions similar to those found in Central Africa (Hudson, 1965: 892).

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Hudson recognized the inherent question in his theory, which is: why did VS not develop sooner in the evolutionary process if all TDs are the result of adaptations of a single species? In response to this question, he noted that immunity to the treponeme would be acquired during childhood as the result of exposure to non-VS, so that venereal transmission after sexual maturity was not possible until children no longer contracted the disease (Hudson, 1965: 892). One cannot help but wonder about the manner in which Columbus’s immunologically naive sailors might have reacted to American treponematosis, whether or not a strain of TD was present in the Old World at that time. Hackett (1963) took a somewhat different approach in reviewing the origin and history of TD. Although recognizing that the organisms associated with the four TDs are indistinguishable microscopically, he continued to distinguish the diseases as clinical entities (Hackett, 1963: 9). In Hackett’s evolutionary scheme, TDs began in the Afro-Asian landmass around 15,000 BC. This was the syndrome pinta, which spread throughout the world and subsequently became isolated in America. Yaws also developed in the Afro-Asian landmass through mutation of the pinta treponeme and spread throughout the Old World. ES evolved from yaws during the drying trend following the last Pleistocene glaciation. As in Hudson’s reconstruction, Hackett associates the development of VS with the emergence of cities. However, he suggests that the disease was mild until a virulent mutation towards the end of the 15th century AD gave rise to the European epidemic attributed to the return of Columbus from the New World (and documented in historical literature). Subsequent to this event, VS spread throughout the world during European colonial expansion in the 16th and 17th centuries (Hackett, 1976: 38). Like Hudson, Hackett does find a likely association between the evolution of TDs and the environment, particularly the climate. However, these two scholars differ on the evolutionary mechanism. Hudson supports the concept of a pluripotential organism; Hackett invokes multiple mutations and different organisms. Cockburn (1963: 74) noted that, through time, human populations tend to become genetically resistant to infectious pathogens. This trend, when combined with Crosby’s observation (1969: 219) that the typical evolutionary development of an infectious disease is characterized by decreasing virulence and will result in chronic disease, does seem to fit the pattern of infectious disease that is encountered in archeological human remains. It is, however, inadequate to explain all the host pathogen relationships that occur in infectious diseases, some of which (e.g., cholera, dysentery, and plague) involve a very virulent illness often with rapid and high mortality (Ewald, 1994: 1 13). Virtually all infectious diseases that

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affect the skeleton are chronic diseases in which skeletal involvement often occurs as a late manifestation of the disease. It is thus likely that the evolutionary path of these pathogens was towards less virulence, combined with increasing genetic resistance to the pathogen in the human host population. This raises the possibility that even milder forms of the disease could have developed, along with an improved host response, in which the skeleton was not affected, as is the case with pinta today. Recent, empirical evidence concerning cycles of VS is relevant to our consideration of TD epidemiology. Grassley et al. (2005) report modern cycles of VS peaking every 8 11 years due to protective immunity. Walker et al. (2015) suggest that this may explain the chronological difference in the evidence for TD noted at medieval St. Mary Spital, referenced above.

Molecular Evidence As detailed in Chapter 8, Kolman et al. (1999) used PCR and immunological approaches to identify VS in a historical period individual from Easter Island. Other researchers have been unsuccessful in identifying VS in adult remains (Barnes and Thomas, 2006; Bouwman and Brown, 2005; Von Hunnius et al., 2006). As Barnes and Thomas (2006) emphasize, such results illustrate the fact that the T. pallidum subsp. pallidum is common in individuals only during the acute, early stages of the disease, when there are no bony changes. Those with skeletal evidence of tertiary syphilis have few pathogens in their bodies. For this reason, screening young adults in the same skeletal series wherein older adults present suspected evidence of tertiary syphilis should be more productive than sampling extremely pathological individuals. Similarly, the probability of recovering ancient pathogens increases when screening neonates with dental or skeletal changes compatible with CS. Montiel et al. (2012) have reported PCR products from two 16th- to 17th-centuries infants recovered from a crypt in southwest Spain. In summary, while aDNA analyses hold promise for clarifying the phylogeography of TD, to date molecular studies have not contributed significantly to our knowledge.

Skeletal Examples Congenital Syphilis Traditionally, a congenital variant of TD was only thought to occur in VS. However, this can occur in yaws but is still not reported in bejel. The major factor in the transplacental transmission of a treponeme appears to be the timing of the early acute phase of the disease and timing of the pregnancy of the female. When both occur at about the same time, transplacental infection of the

developing fetus can occur. If this infection occurs relatively late in pregnancy, then survival of the infant is possible. Obviously, the mode of transmission is a major factor in the prevalence of congenital TD. The early stage of VS is much more likely to be associated with pregnancy than yaws. This means that the most probable diagnosis of congenital TD will be VS. However, the fact that archeological evidence of congenital TD is still very uncommon might be an argument for a nonvenereal cause in these “cases.” Two examples of probable congenital TD in New World archeological skeletons demonstrate the skeletal manifestations of this disease that include defective dental development, systemic periostosis that affects the major long bones, and at least in one individual nasofacial lesions that would have been associated with the classic saddle nose indicative of CS. The first of these two skeletons is from a 6- to 7-year-old Native American child from Virginia, United States. The sex of the child is unknown. There were no European artefacts found at the site. Both the pottery types and the presence of stone pipes suggest a date before AD 1400. Although a later date cannot be ruled out, this evidence points to the preColumbian period. Lesions on the skull are confined to the face and forehead (Fig. 11.119A). There is some postmortem damage to the skull, which complicates the picture. The lesion on the forehead is located near the midline and measures about 35 mm by 45 mm. It may extend to the left of the frontal bone, but postmortem damage precludes confirmation. The lesion itself consists of periosteal new bone formation, which shows only slight evidence of porosity (Fig. 11.119B). The most markedly abnormal bone tissue occurs around the nose. The nasal bones and the maxillary bone adjacent to the nasal bones, along with the nasal aperture, have thickened, porous, periosteal new bone on their external surfaces (Fig. 11.119D). The remaining portions of the maxilla appear to be normal. There is a slight degree of porosity of the orbital roof. There are plaques of porous, periosteal new bone on the inferior and anterior portions of the mandibular body. This is accompanied by a slight expansion in the thickness of the body on the left side. The maxillary deciduous incisors are missing on the left side. However, both right maxillary incisors have marked hypoplastic defects (Fig. 11.119C). Indeed, some of the defects were so severe that, for example, the lower portion of the right lateral incisor appears to have broken off antemortem. There is a less severe hypoplastic defect on the left deciduous maxillary canine. The enamel of the right canine has been damaged postmortem, although there is a slight trace of a defect on this tooth too. The deciduous

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FIGURE 11.119 An archeological skeleton with probable congenital syphilis: (A) anterior view of the skull; note the abnormal periosteal, reactive bone (arrows) on the frontal, nasal, and maxillary bones; (B) detailed view of the frontal bone lesion; (C) detailed view of the hypoplastic development of some of the deciduous dentition; note the hypoplastic enamel lines and the loss of a portion of the crowns of some of the defective incisors (arrows); (D) detailed view of the periosteal reactive new bone on the nasal and maxillary bones; (E) anterior view of the femora, tibiae and left fibula; note that the diaphyses of the tibiae (arrows) are much thicker than the diaphyses of the femora; (F) a detailed view of the expansive periosteal new bone on the left tibia; (G) laterosuperior view of the right fifth metatarsal; note the thickened porous nature of the periosteal reactive new bone; (H) superomedial view of the right fifth metatarsal; note the diminished amount of reactive bone on the medial aspect (arrow) (6- to 7-year-old child from an archeological site in Virginia; NMNH 379177).

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FIGURE 11.119 Continued

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and first permanent molars are normal, as is the emerging permanent left central incisor. The dentition of the mandible is less severely affected. The central incisors are hypoplastic with antemortem loss of the superior portions of their crowns. The lateral incisors have a very slight enamel defect. The remaining teeth appear to be normal, although the severe caries of both deciduous second molars suggests weakened enamel. Caries of the lower left first deciduous molar has resulted in a periapical lesion on the left side. All of the major long bones of the postcranial skeleton exhibit porous, periosteal lesions. The severity and thickness of these lesions vary and are significant in reaching a preferred diagnosis. Both scapulae are normal, as is the manubrium. Both clavicles have periosteal new bone deposits on the anterior medial aspect of their diaphyses; the metaphyses are normal. Both humeri have patchy, periosteal new bone deposits, which are limited to the diaphysis. Involvement is slight and there is no appreciable expansion of the cortex. The radii are somewhat damaged but clearly indicate a general deposition of periosteal new bone on their diaphyses, which is more severe distally. There is slight enlargement of the diaphysis, and the metaphysis is normal. A similar distribution of periosteal new bone occurs on the ulnae, but the diaphyseal enlargement is more marked. This increase in cortical thickness occurs through the apposition of periosteal bone, but this is also associated with an enlarged marrow space, although there appears to be a net increase in the thickness of the cortex. Many of the smaller bones of the hands were not recovered during excavation, although all the metacarpals were present. In general, they exhibited a low-grade, diaphyseal periostosis, which resulted in slight enlargement of their diaphyses. All bones appeared to have been affected to approximately the same degree except the fourth metacarpal, which was only slightly affected on the right and was normal on the left. The vertebrae and pelvis were normal, as were the existing fragments of ribs. There was slight periostosis on the femora, which was limited to the anterior distal diaphyses and metaphyses with involvement extending almost to the growth plate. Both tibiae were greatly enlarged, with clear evidence of active periostosis. The major foci of bone formation were the anterior proximal portions of the diaphyses (Fig. 11.119E and F). However, the entire shafts were abnormally thickened. There was also marked true bowing along the mediolateral axis. The appearance of bowing in the anteroposterior axis is due to the anterior build up of abnormal bone and not because of true bowing in this axis. The fibulae were less severely affected with a similar lesion. The major focus was the mid to

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distal portion of the shafts with the right fibula somewhat more affected than the left. Many of the smaller bones of the feet are missing. Both tali were normal, although the calcanei exhibited periostosis. The involvement was more severe on the right calcaneus. The metatarsals showed a bilateral pattern of involvement, in which the first and fifth metatarsals were most severely affected. The fifth metatarsal, in particular, exhibited a much more severe condition than that seen on the other metatarsals (Fig. 11.119G and H) and both the first and fifth metatarsals were more severely affected than any of the metacarpals. The overall pattern of bone changes in this skeleton showed that the bones that had minimal overlying or adjacent tissue were most severely affected. The bones affected include the frontal, nasal, and adjacent maxillary bones, the ulnae, tibiae, and first and fifth metatarsals. The position of the marked hypoplastic defect on the incisors indicate that it would have developed in utero because that portion of the tooth develops at about the seventh fetal month. This indicates a congenital disease and, in combination with the pattern of relatively severe lesions in the skeleton, suggests CS. Hutchinson (1909: plate 31) illustrates the upper incisor and canine teeth of a 3-year-old child with CS. The canine teeth are normal but the incisor teeth have hypoplastic defects, which resulted in part, or all, of the crown breaking off (Fig. 11.120; see also Fig. 11.121). The second example of probable congenital TD is illustrated in the skeleton of a child about 3 years of age from the Fisher site in Virginia, United States. The site is dated to about AD 925. While the site was being excavated by Howard MacCord, Don Ortner was invited to remove this burial along with an adult burial whose

FIGURE 11.120 Drawing of upper incisor and canine teeth of a 3year-old child with congenital syphilis; note that the crowns are partly to completely missing from the incisors. Redrawn from Hutchinson, 1909, Plate 31, Figure 3, facing page 460.

406 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 11.121 Child with possible CS from the Fisher site in Virginia, dated to c. AD 925: (A) anterior maxilla and mandible; note the enamel hypoplasia and malformed dental crowns as well as the deformed root (arrow) of the left, upper central incisor; (B) left lateral view of the maxilla and mandible; note the hypoplastic crowns of the first and second deciduous molars (arrows); (C) occlusal view of the upper and lower dentition; note the severe caries (arrows) resulting from the hypoplastic crowns; (D) left and right tibiae with periosteal reactive woven bone formation (arrow) (child ca. 3 years old; NMNH 385786).

skeleton had the classic pattern of pathological changes associated with TD, including “saber” tibiae. The adult skeleton will be discussed in the section on the paleopathology of adult TD. Preservation of the skeleton was less

than ideal, but the teeth were preserved and show severe developmental defects that affected the formation of the enamel and also the root formation of the left upper central incisor (Fig. 11.121A C). The long bones available

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for study exhibited a porous periostosis that was particularly pronounced on the tibiae (Fig. 11.121D). The combination of dental pathology that developed in utero, along with the evidence of systemic periostosis, provides

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plausible evidence for a diagnosis of CS. The presence of an adult skeleton with unequivocal skeletal signs of TD buried a few meters away makes this diagnosis even more likely.

FIGURE 11.122 Adult treponemal disease from the Fisher site in Virginia, dated to c. AD 925; this burial was within a few feet of the child’s skeleton seen in Fig. 11.122: (A) anterior view of the frontal bone showing classic caries sicca lesions (arrow); (B) right and left inferior clavicles with lytic foci and reactive periostosis; (C) lower ribs with lytic foci and periostosis; (D) right and left humeri, ulnae, and radii with destructive lesions of the diaphyses and periostosis; (E) radiograph of destructive lesion of the left humerus diaphysis showing sclerosis at the margins of the lesion; (F) right and left femurs, tibiae, and fibulae with classic saber shin of the tibiae and periostosis of the lower left femur; (G) radiograph of the right and left femurs, tibiae, and fibulae with classic saber shin of the tibiae; (H) left metatarsals and proximal phalanges with destructive lesions of the first metatarsal and periostosis; (I) CAD drawing of the distribution of lesions in this skeleton; triangles indicate a predominately bone-destroying process; circles indicate a predominately bone-forming process. C 5 bone destruction with well-defined margin and evidence of repair; D 5 central destruction with marginal bone formation; E 5 D-type lesion but in the repair phase; B1 5 smooth compact bone; B2 5 porous compact bone (adult c. 30 years old; NMNH 385788).

408 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 11.122 Contiuned

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409

FIGURE 11.122 Contiuned

Adult Treponemal Disease In a differential diagnosis of any infectious disease in archeological human remains, it is very helpful to have a “classic” example of the disease from a site that provides strong evidence that the disease was present in the group being studied. This is illustrated with another human burial of an adult male about 30 years of age also from the Fisher site in Virginia. The skull of this skeleton exhibited lytic lesions of the frontal bone (Fig. 11.122A) that are certainly possible for a diagnosis of TD but not necessarily pathognomonic. The pathological changes apparent on the postcranial bones provide the most convincing evidence of TD. Destructive lesions occur on the clavicles (Fig. 11.122B) and lower ribs (Fig. 11.122C). The upper extremity also has multifocal destructive lesions (Fig. 11.122D and E). However, the most diagnostic feature is the presence of bilateral saber tibiae (Fig. 11.122F and G). The bones of

the feet, particularly the left first metatarsal, have lytic lesions accompanied by periostosis that has enlarged the diaphysis (Fig. 11.122H). The overall pattern of skeletal involvement includes multifocal, often bilateral, lesions that may be lytic but in which periosteal reactive new bone formation is a major component (Fig. 11.122I). A classic example of caries sicca is seen in the skull of an adult female Native American from Arkansas. This skeleton was excavated by Clarence Moore during fieldwork conducted in 1909 and 1910. Moore (1910: 258) believed that the burial was pre-Columbian, and a date between AD 1350 and 1500 is likely. The bones that were recovered included a fragmentary skull, the right clavicle, both humeri, the left radius and proximal ulna, the distal right radius, the proximal right tibia, the shaft of the right fibula, and the right talus and calcaneus. Of these bones, the skull, left ulna, both femora, and the left tibia have obvious lesions. The right calcaneus has slight periostosis

410 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 11.123 Probable acquired treponemal disease in a Native American skeleton from Arkansas; site dated between AD 1350 and 1500: (A) right lateral view of the skull; note that the reactive bone is minimal below the area of the temporalis muscle attachment; (B) detailed view of the irregular, lumpy outer table of the right parietal bone; this is a typical bony reaction to gummatous lesions; (C) anterior view of the femora and tibiae; (D) detailed view of the medial side of the right femur near the midshaft; note the bony bridging that took place over blood vessels (white arrows) and the undercut periosteal bone (black arrow). Such lesions are typical of bony reactions in treponemal disease (adult female; NMNH 258778).

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of its superior and lateral cortex. The other bones were unaffected. The lesions of the skull (Fig. 11.123A and B) were most pronounced on the cranial vault and were much less apparent on bone underlying the temporal muscle mass. However, both temporal bones show a thickened, irregular, and slightly porous surface. The major focus for the lesions was the external table, although some of the lesions penetrated to the inner table and others seemed to originate there. However, inner table involvement was

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much less extensive. Broken sections of the frontal and parietal bones revealed a thickening of the skull, with almost complete filling in of the diploe with compact bone. The lesions of the external table were typical gummatous lesions characterized by a mixture of bone formation and destruction, creating an irregular lumpy appearance. In this case, the smoothed surfaces of the lesions indicate a long-term chronic condition. The left orbital roof was not recovered, but the right orbital roof exhibited slight periostosis, which may or may not be

FIGURE 11.124 Probable acquired treponemal disease in an adult female skull from a historic site in Alaska: (A) anterior view exhibits an active, bony reaction typical of a gummatous condition; (B) detail of lesions on the frontal bone; (C) left lateral view; (D) detailed view of the reactive new bone on the left parietal bone showing destructive foci but with some reactive bone formation (NMNH 280095).

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associated with the disease process affecting the rest of the skeleton. The proximal left ulna was the only long bone of the upper limb that exhibited abnormality. The lesion consisted of an enlarged proximal metaphyseal cortex with slight porosity. Because of the rotation of the biceps tendon and the biceps tubercle of the radius, the superior lateral portion of the metaphysis could not participate in this expansion, creating a depression in this region of the ulna. The insertion of the brachial muscle was markedly rough, with spicules occurring on the periphery of the insertion area. The joint surface itself showed slight breakdown on the coronoid portion, which may reflect an expansion of the disease process into the joint. However, the joints of the affected bones of the lower extremity were unaffected. The abnormal new bone of the left femur was restricted to the proximal shaft and metaphysis (Fig. 11.123C). The lesion did not extend to the trochanters or the femoral neck. The disease process had resulted in concentric thickening of the cortex, which was most pronounced on its posterior aspect. The surface was generally smooth with isolated regions of slight porosity. Muscle attachments in the affected area were noticeably rugose. The entire shaft of the right femur was abnormal, somewhat more so distally than proximally (Fig. 11.123C and D). The lesion consists of thickening (new bone) with isolated patches of porosity. The proximal muscle attachments appeared normal. However, there was considerable thickening of the bone with a very irregular surface in the distal region of the linea aspera. The anterior surface revealed raised plaques of new bone and bony spicules, which appear to be bridging over superficial blood vessels. There were no cloacae. The pathological lesions of the ulna and femur are very typical of conditions occurring in long bones of known examples of TD, and in Ortner’s experience are not found together in other infectious diseases. A very similar pattern of abnormal bone was seen on the left proximal tibia. The abnormal new bone had isolated foci of porosity. There were occasional, slightly raised plaques of new bone and bony bridges that would originally have lain over superficial blood vessels. The attachments of the proximal parts of the attached posterior muscles and ligaments, including the soleus, popliteus, and the tibial collateral ligament, were markedly rugose (wrinkled). The surface appearance suggests that the periosteal new bone grew around the ligament attachments but did not affect the attachment area. The radiological picture for both femora and the left tibia revealed the thickened cortex. The outline of the original cortex was still apparent but had become cancellous in focal areas of the three bones. The endosteal surfaces of the cortex did not encroach on the medullary cavity, as often

happens in osteomyelitis and occasionally in osteitis and periostosis. A now reburied skull excavated from an Inuit site on St. Lawrence Island, Alaska, demonstrates the progression of lesions from the frontal bone to the posterior portions of the skull. The mandible and postcranial bones were not recovered. Regrettably, the date for the burial is unknown, but other skeletons collected at the same time were thought to postdate Russian contact, which began during the 1740s. The skull is from a female and the maxillary teeth, except the right canine, had been lost before death. The canine tooth is badly worn which, with the loss of teeth, suggests an age at death well into adulthood. The lesions were largely confined to the skull vault, although there was a focus on the left parietal bone superior to the mastoid process, which also involved the adjacent temporal bone (Fig. 11.124). Although the most obvious lesions are confined to the outer table of the skull, the external lesions penetrated to the endocranial surface in the region of the left mastoid process (Fig. 11.124D), the right parietal bone, and the posterior sagittal suture. There is considerable fine porosity on the endocranial surface of the vault with some lytic depressions about 0.5 cm in diameter, particularly on the right parietal bone. The lesions in the frontal bone region of the outer table (Fig. 11.124B) reveal a fairly typical, coalescing, lytic-blastic response associated with the chronic healing phase of TD. In the posterior portion of the skull, the lesions are more active and predominantly lytic (Fig. 11.124C). However, there is slight reactive new bone at the margins of the more active lesions. The general picture in this case was that of a more chronic course of the disease process with considerable healing in the frontal bone region, but with lesions that become progressively destructive toward the posterior portion of the skull. This pattern of healing lesions on the frontal bone with more active lesions in the posterior portion of the skull is also seen in a skull of an adult female native Australian. The degree of tooth wear suggested an age in excess of 30 years. It dates to before 1920 and probably is much older. Currently the skull is curated in the Pathology Museum of the Royal College of Surgeons of Edinburgh. The frontal bone exhibits extensive, but mostly healed, lesions (Fig. 11.125A). However, the lesions become more destructive towards the occipital region (Fig. 11.125B and C). The most active lesions are seen in the occipital bone, and they extend up into the left parietal bone (Fig. 11.125B). The skull has been sectioned and reveals a sclerotic diploe similar to that seen in the archeological skeleton from Arkansas described earlier. Two skeletons with TD from archeological sites in England provide important insight into the skeletal manifestations of this disease and its history in England. The

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FIGURE 11.125 Probable treponemal disease in an adult native Australian: (A) anterior view of the skull; note the healed nature of the frontal bone lesions and the sclerotic diploe in the sectioned portion of the frontal bone; (B) posteriorlateral view, showing active lesions on the occipital and posterior parietal bones; (C) top view of the skull, showing the more active nature of the lesions towards its posterior portion (PMES 1GD1(116)).

first represents that of a young adult female about 22 years of age (Roberts, 1994). The skeleton was excavated from the Blackfriars site in Gloucester, which was archeologically dated to between AD 1240 and 1538, but radiocarbon dated to 1438 1635 (uncorrected for the marine component of the diet). This skeleton is of particular interest because of the extent of the bone involvement in such a young person, and it raises the possibility that this may be originally the result of CS. It is also of interest, being one of the first skeletons studied to explore the impact of mobility on the spread of infectious disease. Stable isotope analysis applied to this skeleton to explore the person’s origin showed that the person originated in

western England and moved to Gloucester after the age of 8 years (Mongomery, 2002). The frontal and facial bones exhibit healing and active lesions (Fig. 11.126A). The nasal bones were involved and the region around the nasal bones is depressed and suggestive of the “saddle nose” depression primarily associated with CS. Destruction of bone within the nasal antrum was extensive and penetrated the hard palate, leaving a major defect in that tissue (Fig. 11.126B). The bones of the pectoral girdle including the sternum, clavicles, and the spines of the scapulae have destructive lesions (Fig. 11.126C). The ribs and upper extremity bones have destructive lesions and reactive periosteal

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FIGURE 11.126 Treponemal disease, probably venereal syphilis, in a skeleton from the Blackfriars site in Gloucester, England, dated between 1240 and 1538 AD: (A) anterior view of the skull with a large, active, lytic lesion of the frontal bone and extensive destructive remodeling of bone around the nose; there is also a healed lytic lesion (arrow); (B) hard palate with a large lytic lesion with periostosis surrounding the lytic focus; (C) clavicles, sternum, and fragmentary spine of the scapulae with multifocal lytic foci and reactive bone formation; (D) left 8th and 9th ribs with lytic lesions and periostosis; (E) right and left humeri, ulnae, and radii with lesions of the diaphyses; note particularly the destructive lesion of the right radial head; (F) detail of radial head with complete destruction of the subchondral bone; (G) right and left femurs, tibiae, and fibulae with blastic lesions of the left tibia midshaft and the distal right tibia (adult female about 22 years old; Blackfriars burial no. 77).

bone formation (Fig. 11.126D and E). The subchondral bone of the right radius was completely destroyed (Fig. 11.126F). Periosteal reactive new bone formation also occurred on the lower-limb bones (Fig. 11.126G). The lesions tended to be bilateral, although not necessarily symmetrical. Other than TD of some type, there are no good diagnostic options. A plausible case can be made for a young adult expression of CS, but the use of the site could be post-Columbian. A further example of TD from England is that of a medieval skeleton from the friary site of Hull Magistrates Court, Hull, dated to 1316 1539 (Roberts et al., 2012; Boylston et al., 2001). The skeleton has been radiocarbon dated and the date corrected for the marine component of the diet to 1492 1657 (95% confidence interval) (Harper et al., 2011). The skeleton of interest is burial no. HMC 1216 and is from a male about 17 25 years of age. Skeletal involvement in this case is remarkable with virtually every lesion that can occur in treponematosis occurring

somewhere in the skeleton. Skull lesions occur mostly on the frontal and facial bones (Fig. 11.127A). Classic caries sicca lesions can be seen on the frontal bone over the nose (Fig. 11.127B). Over the left orbit an early stage in Hackett’s caries sicca sequence can be seen as a roughly circular lesion with fine holes penetrating through the cortical surface (Fig. 11.127C). The bones of the nasal antrum are missing postmortem but the destructive process affecting this area of the face can be assumed on the basis of a destructive lesion of the hard palate (Fig. 11.127D). This skeleton is one of the very few examples of TD from an archeological site that shows involvement of the vertebral column. As indicated earlier in this chapter, the most common site for such involvement is the cervical spine and this skeleton shows periosteal reactive bone formation on the upper cervical vertebrae (Fig. 11.127E). A periosteal lesion composed of proliferative porous bone occurs on the anterior surface of the right clavicle (Fig. 11.127F). Other forms of infectious osteomyelitis

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FIGURE 11.127 Treponemal disease, probably venereal syphilis, in a skeleton (burial HMC 1216) from the Hull Magistrate’s site in Hull, England, dated between 1317 and 1539 AD: (A) anterior view with caries sicca of the frontal bone; (B) detail of midline lesions of the frontal bone; (C) earlystage porous caries sicca (arrow) with a healing stage of that type of lesion just above; (D) view of the hard palate, showing a lytic focus; (E) vertebral body of C3 with periostosis; (F) right clavicle midshaft with woven reactive new bone formation; (G) left radius: diaphysis with a lytic focus and woven reactive bone surrounding the focus; (H) left femur diaphysis with chronic periosteal new bone development; (I) left fibula distal diaphysis with a lytic focus surrounded by reactive woven bone; (J) CAD drawing of the distribution of bone lesions in this case; triangles indicate a predominately bone-destroying process; circles indicate a predominately bone-forming process; D 5 central destruction with marginal formation; E 5 D-type lesion but in the repair phase; F 5 focal porous destruction; B2 5 porous compact bone; B3 5 striated compact bone.

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FIGURE 11.127 Contiuned

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rarely affect the clavicle and the presence of this lesion on this bone is a helpful criterion in a differential diagnosis. Reactive periosteal new bone formation is seen on several of the long bones. One of these lesions occurs on the distal diaphysis of the left radius (Fig. 11.127G). The central portion of the lesion is composed of woven bone and contains a central lytic focus that is not a cloaca. Note the absence of a smooth margin within the opening that would be composed of smooth, dense compact bone in a cloaca. At the margins of the lesion, particularly where it grades into the normal compact bone, the bone in the lesion is denser, indicating a slower development of the abnormal bone. Lesions in the lower-extremity bones exhibit both the reactive periostotic bone formation associated with a nongranulomatous infection (Fig. 11.127H) and lesions associated with a granulomatous focus (Fig. 11.127I) that are very similar to lesions occurring in the upper extremity bones. Differential diagnosis of this skeleton really offers no reasonable alternative to treponematosis. The lesions of the skull are classic manifestations of caries sicca and the overall type and distribution of the skeletal lesions in this case fit this diagnosis to the exclusion of any other (Fig. 11.127J). The question of whether this is VS or a nonvenereal treponematosis remains an issue that may be resolved in the future if aDNA analysis develops for this infection (see Chapter 8). Another possible Old World example of treponematosis is from a site in or near El Kurrew in Egypt that is dated to between AD 300 and 700. The skeleton provides some insight regarding the antiquity of this disease in North Africa. The skeleton is from a male about 42 years of age and is part of the collection of the Peabody Museum of Archaeology and Ethnology, Harvard University, United States (catalog no. N3913). The importance of the skeleton is complicated by the fact that there has been some commingling with bones of at least one other individual. However, the type and distribution of abnormal bone lesions is congruent and argues for the pathological bones belonging to a single skeleton. The features most indicative of treponematosis occur on the skull (Fig. 11.128A) and are limited to the frontal and parietal bones. The lesions are indicative of a granulomatous destructive condition that was probably inactive at the time of death. The skull lesions are multifocal (Fig. 11.128B) and consist of depressed foci with stellate lines radiating from the central focus of destruction. There is no evidence of significant change in the bones of the face, maxilla, the palate, or the area around the nose. The mandible is normal. On the left humerus there is a large erosive lesion in the para-articular area between the humeral head and the greater tubercle (Fig. 11.128C). This is a large depression that in its shortest axis is almost a centimeter in width and

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in its longest axis probably 12 or 13 mm in length with a depth of 3 4 mm. The lesion is well circumscribed, with dense compact bone in the destroyed area indicative of healing. Erosive joint changes do occur in treponematosis, and the presence of this condition supports the evidence apparent in the skull. The vertebrae are normal except for the sacrum, which shows evidence of chronic proliferative periostosis in the anterior midline. The femora exhibit proliferative periostosis in the distal half of their diaphyses, grading into the metaphyseal area that involves the entire circumference of the bone (Fig. 11.128D). Like the lesions seen on the skull, this lesion appears to have been inactive at the time of death. A left tibia that may be associated with this skeleton has a large lesion on its anteromedial aspect at about midshaft. The lesion is porous and could have been associated with a chronic skin ulcer overlying that area. There is no evidence of any other pathology in this tibia or in the right tibia. The type and distribution of bone lesions argue for a diagnosis of treponematosis, although other infectious conditions such as osteomyelitis should be considered. The geographical association of this individual suggests a specific diagnosis of bejel, and this instance may be one of the earliest examples of this disease. A skeleton with probable yaws from a native Australian site near Coolah dated to the post-European period provides a remarkable example of the skeletal manifestations of TD and the severity of joint lesions that can occur. The skeleton is from an adult female and is curated by the Shellshear Museum of the University of Sydney (catalog # 136). An understanding of the pathological lesions is complicated by postmortem destruction. However, most of the destructive foci have clearly sclerotic margins that are indicative of an antemortem process. In the skull, there are multiple granulomatous lesions on the frontal bone (Fig. 11.129A and B). The lesions are depressed with sclerotic margins indicative of healing. Some of the lesions have the stellate rays of classic caries sicca. The postcranial skeleton exhibits multiple lesions that include periosteal reactive bone formation, but also some of the most remarkable destructive lesions that Ortner had ever encountered. The left clavicle shows an enlargement of the shaft (Fig. 11.129C). In the right scapula the coracoid process and the subchondral bone of the glenoid cavity have been destroyed antemortem (Fig. 11.129D). This destruction corresponds with antemortem destruction of virtually the entire right humeral head (Fig. 11.129E and F). Although not as severe, the left humeral head also shows some loss of subchondral bone and juxta-articular erosive lesions (Fig. 11.129F). Both humeri exhibit extensive periosteal reactive new bone formation in the distal diaphysis and metaphysis, and the right humerus has a large lytic focus on the posterior midshaft area (Fig. 11.129E) that is surrounded by

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FIGURE 11.128 Possible treponemal disease in a skeleton dated to between 300 and 700 AD: (A) anterior view of the skull with multiple caries sicca lesions of the frontal bone; (B) detail of frontal bone lesions; (C) para-articular erosion of the proximal humerus; (D) right and left femur with periosteal lesions on the distal femora. Adult male about 42 years of age, with permission, PMH N3913.

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FIGURE 11.129 Probable yaws in a post-European skeleton from a site near Coolah, Australia: (A) anterior view of the skull showing caries sicca of the skull vault; some of the lesions may be postmortem but there is clear evidence of healed lesions (arrow); (B) detail of frontal bone lesions showing healed carries sicca; (C) right and left superior clavicles with lytic foci and periosteal new bone formation on the left; (D) destruction of subchondral bone of the glenoid cavity of the right scapula; (E) right and left humeri with large midshaft lesion of the right accompanied by extensive reactive new bone formation; (F) subchondral bone and juxtaarticular erosions of the right and left humeral heads; destructive remodeling particularly of the proximal right humerus (right image); (G) anterior view of the right tibia and fibula showing a large antemortem destructive lesion of the proximal tibia and periosteal reactive bone on the diaphyses; (H) detail of proximal lesion of the tibia demonstrating the reactive new bone formation deep in the lesion (arrow) (adult female; SM 136).

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FIGURE 11.130 Tibial lesions attributed to yaws or endemic syphilis in a skeleton from Australia dated to pre-European contact: (A) posterior view of tibiae; (B) medial view of tibial lesions. AIAC SF 19:27, in Hackett (1978); photograph courtesy: Dr. C. J. Hackett and the South Australian Museum.

dense, reactive bone formation. The bones of the forearm have multiple sites of reactive new bone formation. Most of the bones of the hands and feet are missing. There are some lytic lesions on the bone surfaces, but some of this may be the result of postmortem processes. Despite considerable postmortem destruction, there do appear to be lytic foci with reactive bone on at least two of these ribs, indicating axial involvement of bone in the disease process. The vertebrae are all missing postmortem. The left femur has a healed fracture of the diaphysis with poor alignment and much of the pathology appears to be related to trauma. The right femur is relatively normal. The right proximal, anterior tibia has a large, antemortem destructive lesion that certainly encroaches on the joint surface itself but is largely metaphyseal (Fig. 11.129G). There has been considerable remodeling and formation of compact bone at the margins of the lytic focus (Fig. 11.129H) indicating the antemortem nature of the disease process and that the disease had become chronic, at least at this site. The distal end of the tibia shows a lumpy kind of remodeling bone formation and

proliferation that have been seen in other bones in this particular skeleton. On the left fibula, there is an irregular enlargement of the diaphysis with spicules extending from some of the areas of the interosseous ligament. The right tibia and fibula are relatively normal in appearance. Hackett (1978) describes several examples of bone lesions in pre-European skeletons from Australia. He attributes these lesions to yaws or endemic syphilis because VS is not thought to have been present until European contact. The long-bone lesions of one of these skeletons are shown in Fig. 11.130. The lytic lesions in this case have the appearance of a granulomatous condition in contrast with the smoother surface of nongranulomatous periosteal reactive new bone seen in some examples of adult VS.

BRUCELLOSIS Introduction Brucellosis (undulant fever) is a bacterial infection caused by several Brucella species in which domestic animal

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hosts play an important role (zoonoses). It is endemic in Saudi Arabia, South America, Spain, Italy, and the Midwestern United States (Resnick and Niwayama, 1995a). The most common animal hosts for infection transmission to humans are cattle, sheep, goats, pigs, and dogs, but camels, buffalo, deer, antelope, elk, and caribou may also be affected. Ingestion of infected (and unpasteurized) dairy products is the most common mode of transmission. People can also contract brucellosis via droplet infection and through close contact with animals. Today, veterinary surgeons, abattoir, and meat-packing workers are those most at risk. Entry of the organism through breaks in the skin or through the mucous membranes is possible in people doing these jobs, but this can also happen if animals are being hunted, slaughtered, and consumed (https://www.cdc.gov/brucellosis/transmission/ index.html). Brucellosis is classed as one of the most common zoonotic diseases in developing countries (El-Sayed and Awad, 2018) and is now known to be transmissible from human to human as well as from animals to human. The evolutionary history of brucellosis and other zoonoses of domestic animals is closely linked to the history of animal domestication in human societies. Research in zooarcheology has added much to our understanding of the presence of animal domestication (Zeder, 2008, 2017). Generally speaking, the current evidence for the first domestication of sheep, goats, cattle, and pigs appears to be around 10,500 years ago, with dogs a little later, around 7000 8000. The earliest confirmed domesticated dog has been found in China and dated to the early Neolithic (7000 5800 BCE) (Larson et al., 2012). As skeletal involvement in brucellosis is relatively common, it seems likely that skeletal evidence of this disease could be found in human remains at any time during the past 10,000 years. To date, there has been little evidence published (but see Curate, 2006; Mays, 2007; Mutolo et al., 2011), likely in part because differentiating skeletal evidence of this disease from other diseases that can affect the skeleton is a challenging exercise and is not possible in every case.

Pathology Brucella is a genus of Gram-negative rods (bacilli) containing three species pathogenic to domestic animals and, through them, to humans: Brucella abortus, which causes miscarriage in cattle and horses; Brucella melitensis, mainly affecting goats in the Mediterranean area, transmitted to humans primarily through infected milk; and Brucella suis in domestic pigs, transmitted through infected meat. The human disease is a chronic infection of the lungs and other organs, characterized by recurring bouts of fever—undulant fever (Spink, 1956). The skeleton is frequently involved through a hematogenous route.

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However, skeletal changes are usually quite rare (Resnick and Niwayama, 1995a), although they can vary in frequency from 2% to 70%, but they are especially high in B. melitensis infections (Jaffe, 1972: 1048). Adult males are affected much more frequently than females (Glasgow, 1976). The most common skeletal lesion in adults is in the spine or the sacroiliac joint (Madkour and Sharif, 1989: 92; Rajapakse, 1995). Ganado and Craig (1958) observed 130 instances of spondylitis in 6300 patients with brucellosis. Long bones are rarely involved in brucellosis infections. Kelly et al. (1960) observed in 36 people the following localizations of lesions: spine, 17; humerus, 3; femur, 2; ilium, 1; hand, 1; foot, 1. The spinal lesions are located predominantly in the vertebral bodies, especially of the lower thoracic, lumbar, and lumbosacral areas, often involving more than one vertebra (Lowbeer, 1948, 1949; Madkour and Sharif, 1989: 92). Unlike TB, brucellosis of the spine does not result in collapse of the vertebral bodies and angular deformity (Madkour and Sharif, 1989: 114). Brucellosis can occur in children and tends to affect the major joints of the skeleton (hip and knee), but it rarely affects the spine or sacroiliac joint (Madkour and Sharif, 1989: 90; al-Eissa et al., 1990). The earliest and most common lesion of the spine occurs as a small destructive focus on the superior, anterior margin of the vertebral body. This destructive early phase is followed by sclerotic repair of the lytic focus, often resulting in bone formation extending around the margin of the lesion, creating the “parrot’s beak” feature on lateral radiographs (Mohan et al., 1990). In the later phases of the disease, further infectious involvement of the disk results in its destruction and the end plates of the vertebral bodies. Loss of joint space and ankylosis of the vertebral bodies can occur (Madkour and Sharif, 1989: 110). Lytic cavitation of vertebral bodies is rarely severe but external and radiographic observations indicate that it may penetrate the vertebral end plate and extend through the nucleus pulposus of the disk into the next vertebral body (Fig. 11.131). The cancellous bone within the focus is destroyed without formation of a significant sequestra. The cortex also may be perforated, leading to periosteal abscesses. Because the skeletal manifestations are slow in developing, there is ample time for reactive bone to form and sclerosis occurs in affected vertebrae (Mohan et al., 1990: 66). In contrast to TB, which it resembles in several ways, complete collapse of the vertebrae with kyphosis is usually not observed (Keenan and Metz, 1972; Madkour and Sharif, 1989: 111), and paravertebral abscesses are also rare (Kelly et al., 1960; Glasgow, 1976) and, when they occur, they tend to be small (Mohan et al., 1990: 66). Another common site of involvement in the skeleton is the sacroiliac joint (Rajapakse, 1995: 165).

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FIGURE 11.131 Sagittal radiograph of a patient with brucellosis showing destructive lesions of the anterior vertebral bodies with reactive bony projections (parrot’s beak). Adult male; courtesy: Dr. George Y. El-Khoury, Dept. of Radiology, University of Iowa Hospitals and Clinics, Iowa city, Iowa.

Paleopathology As the spread of brucellosis between humans is very rare (Glasgow, 1976: 283), the presence of the disease depends on the presence of domestic hosts, including cattle, horses, goats, sheep, pigs, and dogs. Clearly, if brucellosis was endemic in the past, it should be seen in archeological skeletons. However, brucellosis received little attention at the time of writing of the 2nd edition of this volume, and still remains rarely mentioned in paleopathology. Brothwell (1965b: 690, 692 693) reports bone inflammation in Early Bronze Age skeletal remains from Jericho in the Near East, which he tentatively identifies as brucellosis. However, he attributed the diseased lower lumbar vertebrae to infectious arthritis. Although the description of the Jericho skeleton is incomplete, the disease involves the two fibulae and the lumbar spine.

One fibula is irregular and has a somewhat thickened shaft; the other is also enlarged but has no evidence of active infection. Capasso (1999) reports vertebral lesions in 16 adults from the skeletal sample recovered from the Roman site of Herculaneum in Italy (AD 79). Osteolysis of the superior vertebral margins, with a sclerotic response typical of brucellosis, occurs in each of the skeletons. Supporting a diagnosis of brucellosis, he also notes the Roman use of untreated milk from sheep and goats in their diet. The argument is that brucellosis would almost certainly have been endemic in Roman society, and one should expect to find evidence of the disease in the vertebrae of Roman skeletons. One of the pathological skeletons in the National Museum of Natural History, Washington, DC, has lesions that possibly can be attributed to brucellosis. This individual is a female skeleton from Norway accessioned by the museum in 1904. The estimated age at death on the basis of epiphyseal fusion and pubic symphysis morphology is 20 25 years. The archeological date is unknown. The skull of this skeleton is normal. Unfortunately, there is some mixture of bones from other skeletons. This problem is particularly apparent with the hand and foot bones, in which at least four individuals are represented. However, there is no obvious evidence of disease in any of these bones, and therefore in all likelihood the hands and feet were not affected by disease in this case. Of the remaining bones of the upper extremity, only the left humerus is abnormal, with the head of the humerus affected. Indeed, on superficial inspection, the affected bone could easily be confused with postmortem damage due to the burial environment. However, the presence of periosteal reactive new bone peripheral to the destroyed area on the humeral head provides evidence of a pathological process. The humeral head itself has been eroded, leaving exposed somewhat cavitated spongy bone, in which there has been no osteoblastic response to the disease process. However, the picture of the lytic process is obscured by what is undoubtedly some postmortem damage to the pathological bone. The glenoid cavity of the left scapula exhibits a similar destructive pathological process obscured by postmortem damage. Here, again, there is a slight perifocal bony reaction. The left radius and ulna are normal. The radiograph of the humerus indicates much more extensive involvement than is seen macroscopically. The cortex is much thinner than in the right humerus, and the appearance of the bone resembles a fairly coarse, “net like” structure, suggesting multiple foci for the disease process. The entire left humerus is virtually affected. The cervical vertebrae are all normal, as are the first three thoracic vertebrae. An initial radiograph of the thoracic and lumbar vertebrae indicated that the fourth through the sixth thoracic vertebrae were markedly

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osteoporotic. However, comparison of the corresponding articular facets and shape of the vertebral bodies revealed that these vertebrae were from another individual. Initially, this fact was not obvious because both the size and the color of these vertebrae were appropriate. This problem serves to highlight the need to ensure that all bones associated with a pathological skeleton actually belong to a single individual, and that great care must be taken to prevent mixing bones during excavation and subsequent processing and frequent handling. The seventh and eight thoracic vertebrae are normal. However, T9 has a large lytic process that has created a cavity in the body. The inferior plate of the body is largely destroyed, and there is a hole 1 cm in diameter into the neural canal. There is no marked evidence of bony reaction to the disease process. The tenth thoracic vertebra contains a similar lesion except that the superior plate of the body is involved. Thus, the vertebral bodies adjacent to a single intervertebral disk are affected. The anterior cortex of the bodies of the tenth thoracic through to the second lumbar vertebrae have enlarged vascular foramina but are otherwise normal. There is a suggestion of a lytic cavity inside the body of L3. On the anterior cortex of the body of L4 there are four depressed lytic lesions, which are not linked. In the largest of these, there is slight scalloping, suggesting coalescence of two or more lytic foci. The fifth lumbar vertebra exhibits slightly reactive new bone on the lateral cortex of the body. In the sacrum, the anterior surface of the first and second bodies shows slight erosion and reactive bone. However, the left and right articular surfaces of the sacrum show an extensive lytic process with multiple foci (Fig. 11.132). The large cavities created by the disease process subsequently have been well circumscribed. There is a corresponding circumscribed, lytic destruction on the articular portion of the innominate bone and the adjacent bone. However, the cavities are somewhat larger than those in the sacrum. The major lesion on the left innominate bone measures 25 by 40 mm, and on the right, 20 by 30 mm. Both cavities are at least 10 mm deep. The long bones of the lower extremities are all normal with the exception of the left femur. In this bone, there is a well circumscribed lytic lesion 15 by 18 mm and approximately 5 mm deep, which is lateral to the lesser tubercle on the posterior diaphysis. Some of the edges of this lesion have been broken postmortem, suggesting that the lesion was a cyst rather than a shallow depression during life. Differential diagnosis for this individual must include, in addition to brucellosis, TB, osteomyelitis, mycotic infections, and cancer. The lesions of greatest significance are the lytic cavities found in the corresponding end plates of the ninth and tenth thoracic vertebrae. The appearance of the two cavities suggests an initial focus for the disease in the intervertebral disk. This is an unlikely focus for

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FIGURE 11.132 Brucellosis of the vertebral bodies, with multifocal cavitating abscesses with perforation of intervertebral disk. Histological section. Courtesy: Dr. L. Lowbeer, Tulsa, Oklahoma.

TB, osteomyelitis, or mycotic infections, but is typical for brucellosis (Glasgow, 1976: 286). The fact that the vertebral bodies have not collapsed argues against TB, but the person may have died before that collapse occurred. The radiological appearance of the humerus has at least a superficial resemblance to patterns seen in multiple myeloma (or in solitary multiple myeloma lesions, called a plasmacytoma), although the irregular distribution of the lytic process argues against this disease. Another example of vertebral involvement in disease highlights some of the diagnostic ambiguities confronting the paleopathologist in interpreting skeletal disease in archeological human remains. The skeleton is from an archeological site in Tysfjord, Nordland, Norway. It is that of a young male about 18 20 years of age at the time of death and is thought to be associated with the native people known for their close herding association with caribou. The vertebral bodies from the mid-thoracic through the lumbar vertebrae exhibit multifocal lytic lesions with minimal sclerosis in the margins of the lesion (Fig. 11.133A and B).

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There is no evidence of vertebral body collapse despite partial destruction of the superior end plate of the third lumbar vertebra (L3) and corresponding, though less severe, cavitation of the inferior end plate of L2 (Fig. 11.133C). The type and distribution of spinal lesions would be very atypical for TB. The vertebral body destruction seen in L2 and L3 could reflect a fairly severe manifestation of

FIGURE 11.133 Large circumscribed, lytic lesion in the sacroiliac subchondral bone surface of the right innominate bone (arrow) with multiple lytic foci on the corresponding surface of the sacrum, possibly due to brucellosis (adult female skeleton from Norway; NMNH 227474).

brucellosis. However, the multiple cavities seen on the other vertebral bodies are not typical of brucellosis but could occur in echinococcosis and fungal disease. The ambiguity arises from comparisons with modern clinical examples, which often represent relatively early phases and perhaps less severe skeletal manifestations in the expression of brucellosis that responds well to antibiotic treatment. We can only make inferences about what brucellosis would look like in a completely untreated individual where death occurred after a lengthy course of disease. Another instance in which brucellosis should be considered in differential diagnosis is from a historic archeological site in Merida, Mexico. The skeleton is from a female about 35 45 years of age at the time of death and is curated at the Peabody Museum of Archaeology and Ethnology, Harvard University. The pathological lesions are multifocal and largely destructive with minimal evidence of repair. The lesion most compatible with a diagnosis of brucellosis is a destructive focus of the right sacroiliac joint (Fig. 11.134A). The left sacroiliac joint is completely fused, and there are multiple destructive foci in the thoracic vertebrae (Fig. 11.134B and C). Other lytic foci are seen in the sternal body (Fig. 11.134D) and the left distal femur adjacent to the lateral aspect of the medial condyle (Fig. 11.134E). The complete destruction of the T5 body and the inferior body of T6 does not fit the usual clinical manifestation of brucellosis. Fungal infection, echinococcosis, and metastatic carcinoma need to be considered in differential diagnosis (Fig. 11.135). FIGURE 11.134 Multifocal lytic lesions of the T8 L3 vertebrae, possibly the result of brucellosis. (A) Anterior view of T8 L3 vertebrae. Note the multifocal lytic lesions. (B) Right three-quarter view of T10 T12 vertebral bodies, showing the lytic foci with the sclerotic margins. (C) L1 L2 vertebral body end plates reflected to show cavitation (male, about 19 years of age from an archeological site near Tysfjord, Norland, Norway; UO 1338).

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FIGURE 11.135 Multifocal lytic lesions possibly due to brucellosis. (A) Reflected right sacroiliac joint subchondral bone, showing lytic lesions; (B) Lateral view of T2-T9, showing destruction of vertebral bodies but also some less severe lytic sites; (C) Detail of lytic lesions of T6 T9; (D) Lytic focus on the body of the sternum. (E) Lytic focus on the distal left medial condyle of the femur (adult female about 42 years of age from a historic archeological site in Merida, Mexico). With permission of the Peabody Museum of Archaeology and Ethnology, Harvard University, Cambridge, Massachusetts, Catalog No. 61016.

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there have been no examples of naturally occurring glanders since the 1940s. Nevertheless, instances of it affecting humans are reported from Africa, Asia, the Middle East, and Central and South America (https://www.cdc. gov/glanders/exposure/index.html).

Pathology

FIGURE 11.136 Lumbar vertebral body of a skeleton, with possible brucellosis, from the archeological site of Bab edh-Dhra, Jordan dated to about 3100 BC (burial from tomb A108NW).

A possible example of brucellosis occurs in the spine of an adult from the site of Bab edh-Dhra in Jordan (tomb A108NW). This is a secondary burial and there is some mixture between the burials found in the tomb chamber so that the association of the affected vertebra with other bones in the tomb is problematic. The lumbar vertebra shows destruction of the anterior part of the superior body with a large osteophyte extending in an anterosuperior axis (Fig. 11.136). Other diagnostic options certainly exist for this lesion, including osteoarthritis and earlystage TB. The radiograph of this vertebra shows a large area of trabecular sclerosis adjacent to the lesion. This would be atypical of osteoarthritis but could occur in early-stage TB. However, the most probable diagnostic option is brucellosis, and this may be an early example of this disease.

GLANDERS Glanders is included in this chapter to emphasize that while it is rare today, it may have been an important infection for our ancestors and the animals with which they interacted. People who work with or are exposed to animals with the infection are most at risk, e.g., veterinary surgeons and people working with horses or processing their meat. Today, humans rarely contract the infection, with the last person with glanders in Britain being reported in 1928 (https://www.gov.uk/guidance/glanders-and-farcy#how-to-spot-glanders-and-farcy). In the United States

Glanders is an infectious disease caused by Burkholderia mallei and primarily affects horses, donkeys, and mules (e.g., see Ghori et al., 2017), but other mammals can also contract this bacterial disease (e.g., goats, dogs, and cats). It is caused by the Gram-negative bacterium Pseudomonas mallei. The disease is transmissible from animals to humans via contact with tissues or body fluids of infected animals (https://www.cdc.gov/glanders/). The nasal mucosa is frequently involved and often the portal of entry. In humans, the bacteria can also enter the body through cuts and abrasions, or through bacteria-laden droplets in the air from animals. Glanders may result in a localized infection (ulcer and lymph node involvement), or affect the respiratory tract (pneumonia, pulmonary abscesses, and pleural effusion), or the bloodstream (where if untreated, death rapidly ensues). If the infection becomes chronic, multiple abscesses develop in the muscles and skin of the arms and legs, lungs, spleen, and/or liver. Bone lesions in glanders are rare. The organism may affect the periosteum from adjacent soft-tissue abscesses and skin ulcers, and in archeological skeletons the signs of bone damage underlying soft-tissue involvement may be considered (as in lupus vulgaris—TB of the skin). While hematogenous osteomyelitis in glanders can occur, it is very rare (Beitzke, 1934c). The part of the skeleton most often affected is the skull, secondary to nasal and oral mucosal lesions. Involvement causing defects of the nasal bones, nasal septum, and the ethmoid and sphenoid bones has been observed. Destruction of the turbinate bones with perforation into the maxillary sinuses, and perforations of the hard palate may also occur. Cranial vault lesions secondary to ulcers of the scalp have also been noted. Other bone lesions in glanders are almost exclusively limited to the bones of the lower extremities, particularly the tibia. The lower-extremity lesions may present as periostosis or osteomyelitis, and occasionally with secondary infection by staphylococci which modify the picture towards the appearance of “ordinary” osteomyelitis. Joint involvement in glanders is not rare, occurring mostly by extension from adjacent soft-tissue lesions and only occasionally secondary to an epiphyseal bone focus. In 27 examples of people studied with glanders affecting the joints gathered from the literature, Beitzke (1934c)

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found the distribution as follows: knee, 16; elbow, 4; ankle, 4; toes, 2; fingers, 1; tarsus, 1. Bone lesions in glanders are not pathognomonically diagnostic in dry bone. The main reason to mention them is to point out their similarity to tertiary syphilis and to some lesions seen in leprosy.

ACTINOMYCOSIS AND NOCARDIOSIS Actinomycosis is a very rare noncontagious bacterial infection that is seen across the world today, but rarely in the West. The Actinomycetes bacteria causing this condition normally live in the body commensally (meaning that they live within the host without injury to the body). It is only when they get into the linings of the gastrointestinal tract—including the oral and nasal cavities—that they cause problems. Actinomycosis cannot be passed from human to human (https://www.nhs.uk/conditions/ Actinomycosis/). There are three presentations of the infection: cervicofacial, thoracic, and abdominal (Finch et al., 2002). Possible causes of each include poor oral hygiene and dental decay, along with oral surgery (cervicofacial), inhaling the bacteria via contaminated food and drink into previously damaged lungs (thoracic), and involvement of the cecum, situated at the start of the large intestine (abdominal). While rare today, the disease was likely a challenge for populations in the past who would have struggled to maintain oral hygiene and prevent food and drink contamination.

Pathology Gram-positive bacterial species of the genus Actinomyces have the potential to cause actinomycosis in humans (Finch et al., 2002). Some of them include Actinomyces israelii, Actinomyces bovis, Actinomyces naeslundii, Actinomyces viscosus, and Actinomyces odontolyticus (Resnick and Niwayama, 1995a). At one time, these organisms were thought to be fungi, and this association is seen in the name of the genus. However, the pathogen is indeed a bacterium and closely related to another bacterial genus Nocardia, which will also be discussed briefly at the end of this section. After a person is infected in the face, lung, or gastrointestinal tract, Actinomyces can spread hematogenously to the liver, spleen, kidneys, brain, and bones and joints. The disease can also spread from an adjacent soft-tissue focus to another area of the body, such as bone. Infection is normally a secondary complication of injury to the tissue that permits entry via the oral cavity to the internal organs and tissues. However, as the pathogens spread through tissue, they are not limited to fascial planes or vascular

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pathways. This means that they can affect almost any area of the skeleton that is in relative proximity to an infective focus (as for lupus vulgaris in TB and possibly for glanders—see above). This can create an almost random pattern of skeletal involvement, and thus the skeletal manifestations do resemble those caused by fungi. In a study including of 486 individuals with human actinomycosis, Gra¨ssner (1929, cited in Beitzke, 1934d: 540) reported 73 instances of skeletal involvement (15%). The mandible, the flat bones of the axial skeleton, and the major joints of the appendicular skeleton are mainly affected in actinomycosis (Resnick and Niwayama, 1995a). Of 60 clinical instances reported by Baracz (1902), 55 involved the head and neck, 3 were thoracic lesions, and 2 were abdominal lesions. Involvement of the mandible tends to result in the development of periosteal reactive new bone that may appear as irregular mounds of abnormal bone similar to the lumpy jaw that occurs in actinomycosis of cattle. Thoracic involvement can lead to destruction of the ribs and sternum or the pectoral girdle (Smego and Foglia, 1998). Abdominal and pelvic actinomycosis tends to be the most indolent (causes little or no pain) of the various clinical syndromes, and because of this, might be expected to affect the bones of the lower spine and pelvis. Lytic lesions and sclerosis are the key bone changes. Note that pleuritis can occur in this condition, and thus the ribs may be affected by inflammatory new bone formation (and destruction). As noted, the bones are usually affected by direct extension of the infection from adjacent soft-tissue lesions. This means that, in most instances, the bone infection starts on the periosteal surface and frequently remains limited to it. The frequency of actinomycotic lesions in the different bones in Gra¨ssner’s study (1929) was as follows: vertebrae 37%, mandible 25%, ribs 10%, maxilla 8%, extremities 5%, skull base 4%, pelvis 4%, sternum 3%, zygoma 3%, and clavicle 1%. The periosteal involvement usually leads to hypervascularity, which is noticeable on the dry bone by the increased number and size of vascular channels and foramina. In addition, there is usually a varying degree of reactive subperiosteal new bone formation of porous or solid character. There is superficial erosion of the cortex and a varying degree of destruction of the adjacent cancellous bone, with little or no endosteal sclerotic response, in contrast to bacterially induced osteomyelitis. Formation of sequestrated bone is also rare. The most characteristic lesion is that of the spine (Young, 1960), with frequencies decreasing across the segments: thoracic . lumbar . cervical . sacral (Beitzke, 1934d: 554). Because the spine is usually infected from spreading pleural, abdominal, or cervical soft-tissue

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FIGURE 11.137 Actinomycotic periostosis of the lumbosacral spine and left ilium, secondary to actinomycosis of the sigmoid colon, left ovary, and soft tissue anterior to the sacrum (21-year-old female; FPAM 5315, autopsy 93144 from 1891).

FIGURE 11.138 Actinomycosis of the cervical spine. Note the periosteal reactive new bone, including the transverse processes and superficial erosion of the vertebral bodies (53-year-old male with actinomycosis of the cervical soft tissues and both lung apices; UGPM autopsy 203 from 1907).

FIGURE 11.139 Actinomycosis of the fifth lumbar vertebra and sacrum. Notice pitted transcortical erosions based on the periosteum (46-year-old female; FPAM 5649 from 1897).

lesions in broad contact with its anterior surface, the anterior periosteum of several vertebral bodies may be involved (Fig. 11.137). The transverse processes and, in the thoracic portion, attached ribs are often affected (Fig. 11.138). The involvement of the vertebral bodies, if present, starts anteriorly and seldom extends very deep into their structure (Fig. 11.139). Vertebral collapse and kyphosis hardly ever occur. The neural arches and spinous processes are usually spared but can be affected (Resnick and Niwayama, 1995a), and the intervertebral discs are usually preserved, as well. Lumbosacral actinomycosis may spread to the pelvic bones (Fig. 11.140), but this is not pathognomonic to actinomycosis. Mandibular lesions are mostly limited to periosteal reactive new bone formation of moderate extent, with occasional destruction and focal necrosis of the underlying bone, especially of the alveolar process. Central involvement of the mandible, possibly through a dental alveolus, leading to cavitation and expansion of the bone, is very rare in humans. By contrast, mandibular involvement is the most frequent type of actinomycosis observed in bovine and equine animals infected with A. bovis, which is usually not pathogenic for humans. In actinomycosis of the maxilla the adjacent paranasal sinuses, facial bones (zygoma), and middle and inner ear may become involved. Destruction of the mastoid process and the petrous part of the temporal bone has been observed. In the small and flat bones (ribs, sternum, pelvis), the destruction may be more extensive, creating a

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FIGURE 11.140 Actinomycosis of the lumbar spine and left innominate bone, showing mainly periosteal reactive new bone deposition and hypervascularity with focal erosion of the cortex: (A) internal view; (B) external view (18-year-old male; FPAM 5686, autopsy 130155-1353 from 1909).

“worm-eaten” appearance and large cortical perforations. Actinomycosis of the long bones is, as noted, rather rare and probably mostly the result of hematogenous dissemination from a pulmonary focus. The area most frequently affected is the metaphysis. Extensive destruction of the cortex with reactive periosteal new bone formation may be observed, but large cortical sequestra, as in bacterial osteomyelitis, do not occur. Focal cavitation may closely resemble a Brodie’s abscess, but perifocal osteosclerosis is usually slight or wanting. Joint involvement may occur secondarily to lesions in adjacent bones. This is most often the case in the costovertebral joints and less commonly in intervertebral joints (Beitzke, 1934d: 563). Nocardia is also a genus of the Actinomycetes group of Gram-positive bacteria that includes four species that

can cause disease in humans (Resnick and Niwayama, 1995a: 2505). They are Nocardia asteroides, Nocardia brasiliensis, Nocardia farcinica, and Nocardia caviae. The most common pathogen for humans is N. asteroides. In contrast to Actinomyces, the organism grows aerobically and stains acid-fast. Infections occur through the pulmonary route and mostly are confined to the lung and pleural cavity (Pizzolato, 1971: 1064 1066), but infection via the gastrointestinal route or after skin trauma can occur (Resnick and Niwayama, 1995a). In rare instances, hematogenous spread to bones and joints occurs, and the tubular or flat bones are involved. The lesions predilect cancellous areas and mainly consist of lytic cavitation, often complicated by fistulae (Fig. 11.141). There is little, if any, reactive bone formed. Immunocompromised individuals are at highest risk.

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FIGURE 11.141 Radiograph of nocardia osteomyelitis of the pubis with a fistula, proven by culture (27year-old female with pulmonary cavity actinomycosis; MGH 1293348).

PLAGUE Introduction To complete this chapter on bacterial infectious diseases, plague will be mentioned briefly, even though it does not directly affect the skeleton. Plague is caused by the bacterium Yersinia pestis. It is a zoonosis that is found in small mammals (e.g., black rats; but see Hufthammer and Walloe, 2013) and their fleas (http://www.who.int/en/ news-room/fact-sheets/detail/plague). There are three types of plague: bubonic (bite from an infected flea that leads to painful and swollen lymph nodes), septicemic (the bacteria spread via the bloodstream from bites of infected fleas or from handling infected animals), and pneumonic (people can inhale droplets containing the infection, or it can develop from bubonic or septicemic plague after it spreads to the lung). Untreated pneumonic plague is always fatal, as it would have been in the past. The latter is the only type that can be transmitted from human to human, while the other two types are spread from animals to humans via insects or other vectors. People with septicemic plague can develop black skin and other tissues (fingers, toes, and nose), and these structures may eventually necrose (die). This form is contracted via inhaling infectious droplets or from untreated bubonic or septicemic plague after the bacteria has spread to the lungs (https://www.cdc.gov/plague/symptoms/index.html). The last plague epidemic in the United States was in 1925/26, but it is now confined to rural areas of the west and southwest (https://www.cdc.gov/plague/maps/index. html). On a worldwide scale, plague occurs not only in North America but also in South America (especially Peru), Africa, and Asia. African regions have dominated global distributions since the 1990s, especially those of the

Democratic Republic of Congo and Madagascar. A useful summary of the history of the plague is provided by the Centers for Disease Control and Prevention (https://www. cdc.gov/plague/history/index.html). The World Health Organization states that between 2010 and 2015, there were 3248 people affected by the plague worldwide, including 584 deaths (http://www.who.int/en/news-room/ fact-sheets/detail/plague).

Paleopathology There have been three major plague pandemics during the past two millennia: the 6th-century Justinian Plague, the 14th-century “Great” or Black Death, and “Modern” outbreaks beginning in the 19th century. Millions of people have died throughout history from this infection. This makes it important for paleopathologists to remember that although the plague does not affect the skeleton, there are other characteristics of archeological skeletons and their context that can help us to reconstruct the history of the plagues. This includes not only features of human remains that give us an insight into plague demography, but also funerary contexts. In addition, molecular methods have convincingly addressed questions about earlier plague pandemics (Bos et al., 2011; Schuenemann et al., 2011; Wagner et al., 2014; see Chapter 8). Demographic studies of skeletal populations have considered the proposition that specific age and sex groups may have been preferentially affected; much of this work has centered around the AD 1348/49 East Smithfield cemetery in London (e.g., Margerison and Knusel, 2002; DeWitte, 2009, 2015; see also Gowland and Chamberlain, 2005 on Bayesian analysis and demography). DeWitte (2009) found that sex did not strongly affect risk of death,

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and that health in general was already declining in the 13th century, which might have led to a higher mortality during the Black Death (DeWitte, 2015). Identifying plague pits is a challenge. Historical evidence for plague is crucial (e.g. see data on the London Bills of Mortality in Roberts and Cox, 2003), and in some instances grave accompaniments such as coins may be informative (Gilchrist and Sloane, 2005). The most convincing evidence, however, is the identification of the pathogen Y. pestis, which has now been recovered from remains dating to the Justinian Plague and the Black Death (Bos et al., 2011; Schuenemann et al., 2011; Wagner et al., 2014). This molecular evidence recovered from ancient dental pulp cavities illustrates the power of genomic analyses in the identification of past infectious diseases that in particular do not affect the skeleton.

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Walker, D., Powers, N., Connell, B., Redfern, R., 2015. Evidence of skeletal treponematosis from the medieval burial ground of St Mary Spital, London, and implications for the origins of the disease in Europe. Am. J. Phys. Anthropol. 156, 90 101. Wassersug, J., 1940. Tuberculosis of the greater trochanter and trochanteric bursae. Journal of Bone and Joint Surgery 22, 1075 1079. Weiss, D.L., Møller-Christensen, V., 1971. An unusual case of tuberculosis in a medieval leper. Danish Med. Bull. 18, 11 14. Whitnery, W.F., 1886. Notes on the anomalies, injuries and diseases of the bones of the native races of North America. Annu. Rep. Peabody Museum 3, 433 448. Whitney, J., Baldwin, W., 1915. Syphilis of the spine. Journal of the American Medical Association 65, 1989 1994. Wilbur, A.K., Farnbach, A.W., Knudson, K.J., Buikstra, J.E., 2008. Diet, tuberculosis and the palaeopathological record. Curr. Anthropol. 49, 963 991. Williams, H., 1929. Human paleopathology, with some original observations on symmetrical osteoporosis of the skull. Archives of Pathology 7, 839 902. Williams, H., 1932. The origin and antiquity of syphilis: The evidence from diseased bones, a review with some new material from America. Archives of Pathology 13, 779 814. 931 983. Wilson, P., Mathis, M., 1930. Epidemiology and pathology of yaws, based on study of 1423 consecutive cases in Haiti. Journal of the American Medical Association 94, 1289 1292. Wimberger H., V. Klinisch-Radiologische Diagnostik von Rachitis, 1925, Skorbut und Lues Congenita im Kindesalter, Ergebnisse der Inneren Medizin und Kinderheilkunde 28, 264-370. Wong, K., Wu, L., 1936. History of Chinese Medicine. National Quarantine Service, Shanghai. World Health Organization, 2017a. Global Tuberculosis Report. WHO, Geneva. World Health Organization, 2017b. Global leprosy update, 2016: accelerating reduction of disease burden. Wkly Epidemiol. Rec. 92, 501 520. Young, W., 1960. Actinomycosis with involvement of the vertebral column: Case report and review of the literature. Clinical Radiology 11, 175 182. ¨ ber die Tuberculose der Alveolarfortsa¨tze. Archive Zandy, C., 1896. U fu¨r Klinische Chirurgie 52, 178 189. Zeder, M., 2008. Domestication and early agriculture in the Mediterranean Basin: origins, diffusion, and impact. Proc. Natl Acad. Sci. 105, 11597 11604. Zeder, M., 2017. Out of the fertile crescent: the dispersal of domestic livestock through Europe and Africa. In: Boivin, N., Crassard, R., Petraglia, M. (Eds.), Human Dispersal and Species Movement: From Prehistory to the Present. University Press, Cambridge, pp. 261 303. Zuckerman, M.K., Harper, K.N., Armelagos, G.J., 2012. Letter to the editor: response to Cole and Waldron’s “Letter to the editor: syphilis revisited”. Am. J. Phys. Anthropol. 149, 151 153.

Chapter 12

Fungal, Viral, Multicelled Parasitic, and Protozoan Infections Anne L. Grauer1 and Charlotte A. Roberts2 1

Loyola University Chicago, Chicago, IL, United States, 2Department of Archaeology, Durham University, Durham, United Kingdom

This chapter on infectious diseases includes some of the less common conditions that have the potential to affect the human skeleton. Differentiating them from the more common infectious diseases will often be difficult, if not impossible, because the skeletal manifestations regularly coincide with those of the diseases discussed in this chapter and those previously reviewed. However, with careful evaluation of the environmental, social, and biological contexts within which a skeleton was found, determining the presence of these diseases might be possible in archaeological contexts.

FUNGAL INFECTIONS Introduction Of the over 100,000 named species of fungi, fewer than 500 are associated with human disease, and even fewer have the potential to alter human bone during the disease process (Richardson and Warnock, 2012). However, Bongomin et al. (2017) report that fungal diseases kill more than 1.5 million people each year and affect over a billion people worldwide. Systemic, or deep, mycoses, which are fungal infections that extend beyond cutaneous or subcutaneous involvement, fall into two groups: those linked directly to primary pathogens, and those that are “opportunists” (Richardson and Warnock, 2012). The first group consists of conditions caused by fungi capable of infecting an otherwise healthy host. These include diseases such as blastomycosis, paracoccidioidomycosis, coccidioidomycosis, histoplasmosis, mucormycosis, and mycetoma. The second category of fungal disease includes conditions that more commonly develop into systemic conditions only in an immunologically compromised host, which include sporotrichosis and aspergillosis. The following discussion will be limited to fungal diseases that more commonly

manifest as systemic involvement that might subsequently be encountered in archeological human remains.

Pathology Pathogenic fungi usually enter the host through the respiratory tract, leading to primary internal lesions of the lung. Occasionally, especially in systemic cases, hematogenous dissemination to the skeleton can occur. Bone involvement can also develop as a direct extension of soft-tissue lesions (most commonly subcutaneous). Since different fungi share similar bone lesion distributions in the skeleton, differential diagnosis between various mycotic diseases in dry bone will often be impossible. Adding to the complexity of differential diagnosis is the possibility that lesions can appear bilaterally, a pattern more often found with other infections. However, lesions associated with systemic mycotic disease in the human skeleton are more often randomly distributed. This randomness, along with careful assessment of the geographical origin and environmental context of the skeletal remains can assist with diagnosis since different types of mycotic disease tend to occur today in specific geographic regions, under somewhat predictable environmental and sociocultural conditions (Hospenthal, 2015). Thus, paleopathologists working in areas where mycotic disease is present today should consider the possibility that mycotic disease may be present in human remains recovered from those geographical areas, but should not assume geographical distribution of pathogens remains unchanged over time.

North American Blastomycosis North American blastomycosis is most commonly caused by Blastomyces dermatitidis or Blastomyces gilchristii. Infection in humans most commonly occurs when soil containing microfoci of mycelia (the vegetative part of a fungus) is disturbed and airborne conidia (asexually

Ortner’s Identification of Pathological Conditions in Human Skeletal Remains. DOI: https://doi.org/10.1016/B978-0-12-809738-0.00012-0 © 2019 Elsevier Inc. All rights reserved.

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reproducing spores that are produced by mycelia) are inhaled (Saccente and Woods, 2010). The incubation period ranges from 3 to 15 weeks, leading to an asymptomatic response in some individuals and to a lifethreatening condition involving the lungs and other systems in others (Witorsch and Utz, 1968: 169 171). Blastomycosis can also manifest as a skin infection after a bite from an infected animal (Benedict et al., 2012). Although immunosuppression is not directly linked with severe manifestations of the disease, the development into a systemic condition can be hastened by a compromised immune response (Benedict et al., 2012: 332). The geographical distribution of the disease today centers in North America, especially in the Mississippi and Ohio river valleys and North Carolina, but it can be found worldwide (McBride et al., 2018). Moist environments, in particular, appear to be influential factors in the growth and dispersal of the fungus (Benedict et al., 2015). Reports on living populations indicate that adult males are more commonly affected than females, but that children of both sexes developed serious manifestations of the disease (Chu et al., 2006). These patterns suggest that a biological risk factor for infection in males does not exist, but rather, sociobehavioral variables might increase the likelihood of contact with the fungi and thus susceptibility to infection (Cano et al., 2003). In cases where blastomycosis has disseminated to bone, it appears that the predilected areas are the vertebrae and ribs (often multiple), skull, tibia, and tarsus (Jain et al., 2014). In a study of 45 patients hospitalized with blastomycosis, 41 presented with osteomyelitis, and 12 with septic arthritis (Oppenheimer et al., 2007). Lesions associated with blastomycosis tend to be lytic with welldefined borders, and sclerosis at the margins is common. Periosteal reactive new bone may form at the margins of the lytic focus (Resnick and Niwayama, 1995a: 2506). Like tuberculosis, vertebral body resorption occurs, as does the formation of paravertebral abscesses. Severe vertebral body resorption will result in collapse and kyphosis (Resnick and Niwayama, 1995a: 2506). In long bones, the focus can mimic an infarct. The foci in long bones predilect subarticular, epiphyseal, and metaphyseal areas (Chick, 1971: 485 486). Importantly, blastomycosis has been called “one of the great mimickers in medicine” as clinically, lesions are often confused with cancer and tuberculosis (Saccente and Woods, 2010).

Paracoccidioidomycosis Paracoccidioidomycosis is a South American variant of blastomycosis, caused by the fungus Paracoccidioides brasiliensis. Like blastomycetes, the fungus is associated with humid environments (Matos et al., 2012). A clear demographic predilection for males has been reported in Brazil, along with a recognized association with rural populations,

smoking, and alcohol consumption (Bellissimo-Rodrigues et al., 2011). Coinfection with tuberculosis and HIV is also common (Loth et al., 2011). The skeletal manifestations of the disease are similar to blastomycosis. Lesions are round and lytic, of varying size, single or multiple, and may mimic ‘basic’ osteomyelitis (Emmons et al., 1970: 336). Monsignore et al. (2012) report that lesions most often appear without marginal sclerosis or periosteal reaction. The predilected locations are the long bones, clavicles, ribs, and vertebrae (Angulo and Pollak, 1971: 555 556).

Cryptococcosis Cryptococcosis is the result of infection by two known species of the genus Cryptococcus: Cryptococcus neoformans, which has been associated with immunocompetent and immunocompromised hosts, and Cryptococcus gattii, more recently associated with immunocompromised hosts (Chayakulkeeree and Perfect, 2015). The fungus is ubiquitous, being found in soil worldwide, and commonly enters the body through inhalation. There appears to be no age or sex predilection for the disease (Salfelder, 1971: 385 390), but approximately 5% 10% of the disseminated infections show bone involvement (Witte et al., 2000). The predilected areas are the vertebrae, pelvis, ribs, femur, and tibia, and occasionally the cranium, with nearly 25% of hosts displaying lesions on more than one bone (Corral et al., 2011). The lesions usually appear lytic and well circumscribed in radiographs (Collins, 1950) and, like other mycoses, mimic malignant neoplasm.

Coccidioidomycosis Coccidioidomycosis is the result of inhalation of spores of Coccidioides immitis or Coccidioides posadasii. The disease appears endemic to the Western hemisphere, where the fungi flourish in warm soil in arid and semiarid environments. Importantly, the lifecycle of Coccidioides spp. is reliant on changing climatic conditions, as moisture fosters fungal mycelia growth, while hot, dry seasons are essential for their desiccation and maturation into arthroconidia (fungal spores). When aerosolized (often by human intervention), the conidia can be inhaled by hosts (Talamantes et al., 2007; Tamerius and Comrie, 2011). Hence, the highest prevalence of the disease occurs in southern and central Arizona and California, northern Mexico, and Central and South America (Brown et al., 2013). Although coccidioidomycosis occurs in all age groups, modern epidemiological patterns of the disease can be misleading. Clinical literature reports the highest incidence rates occurring among older adults, but this trend might be a feature of modern seasonal or permanent relocation of retirement-age individuals to these warmer, more arid environments (Leake et al., 2000). Most cases of coccidioidomycosis are mild with full recovery of the

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patient. However, approximately 1% 5% of infected hosts develop disseminated disease (Brown et al., 2013), and about 25% of people with fatal dissemination display bone lesions (Huntington, 1971: 184). Biological risk factors for the disease include immune compromisation, diabetes, and pregnancy. Males are more often infected, potentially related to occupational dust exposure, but clinical studies reporting a higher risk of dissemination of the disease suggest that there might be a genetic or hormonal aspect to the infection (Forbus and Bestebreurtje, 1946). Modern sociocultural risk factors, irrespective of sex, include participating in recreational activities in desert environments, military training exercises and, as a warning to paleopathologists, archeological excavation (Werner et al., 1972; Poirier and Feder, 2001). Disseminated bone involvement most commonly affects the cranium and axial skeleton, with the thoracic vertebrae appearing particularly susceptible (Bisla and Taber, 1976). Bone foci may be solitary, but multiple sites with symmetrical involvement are common (Resnick and Niwayama, 1995a: 2510). Spinal lesions may be indistinguishable from tuberculosis, although in coccidioidomycosis the posterior elements are not spared and vertebral collapse with gibbus formation usually does not occur. In general, the bone lesions tend to be lytic on radiographs and may be associated with periosteal reactive new bone formation. However, marginal sclerosis is not common (Resnick and Niwayama, 1995a: 2510). Fistulas are rarely seen in this disease. The most characteristic aspect of these systemic fungal lesions is that they predilect areas of the skeleton usually spared by other infections. These areas include bony prominences such as the acromion and coracoid process of the scapula, the styloid processes of the radius and ulna, the condyles of the humerus, the ends of the clavicles, the tibial malleoli, and any tuberosity. There is also involvement of small bones of the carpus (Fig. 12.1) and the tarsus, and the patella. Marginal destructive lesions of the ribs and destructive lesions of the skull, limited to the outer table, do occur (Carter, 1934). In the carpal and tarsal lesions, adjacent joints are often implicated.

Histoplasmosis Histoplasmosis, caused by Histoplasma capsulatum, is the most common endemic mycotic infection in the United States today (Cano and Hajjeh, 2001). Like most mycoses, the fungus is usually inhaled, although the disease can be acquired through the gastrointestinal tract (Resnick and Niwayama, 1995a: 2510). Infections are usually slight and self-healing and are most common amongst people living in the Mississippi and Ohio River valleys. A few cases occur sporadically worldwide. Bone lesions are uncommon, even in people with systemic infection, but, if present, resemble those in other systemic fungal diseases (Schwartz, 1971: 95 97).

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FIGURE 12.1 Radiograph of coccidioidomycosis of the right carpal bones. Note the round lytic focus in the os triquetrum and os pisiform (arrows). Thirty-eight-year-old male from California with pulmonary lesion; MGH admission no. 1187633.

The presence of histoplasmosis in Africa, now linked to the species Histoplasma duboisii (or arguably, the duboisii variant of H. capsulatum), may cause severe systemic infections in immunocompromised hosts. However, the infection is more often asymptomatic or spontaneously self-limiting in immunocompetent hosts (Oladele et al., 2018). In its severe manifestation when disseminated to bone, multiple round lytic lesions are present in the cranial vault (Fig. 12.2A) and in the long and small bones of the extremities (Fig. 12.2B) (Cockshott and Lucas, 1964). The ribs and pelvis can also become involved (Resnick and Niwayama, 1995a: 2510). Lesions in long bones may lead to enlargement of their shafts (Edington, 1971: 131 138).

Mucormycosis (Phycomycosis and Zygomycosis) Mucormycosis (also known as zygomycosis or phycomycosis) can potentially infect any host but is more often clinically noted as affecting individuals with compromised immune systems. The infection is linked most often to fungi from several genera within the orders Mucorales: Rhizopus, Mucor, and Lichtheimia (formerly called Absidia). Infection occurs from inhalation of spores or

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FIGURE 12.2 (A) Bone lesions in Histoplasma duboisii infection: radiograph of lateral view of the skull; notice multiple round lytic lesions of the cranial vault; (B) radiograph of the right hand; notice multiple lytic lesions in the bones of the forearm and the hand, partly with sclerotic borders. Adolescent African, courtesy of Dr. Stanley Bohrer, Ibadan, Nigeria.

inoculation from compromised skin or mucosa (Ibrahim et al., 2004). In developed countries, the disease is uncommon, but is found occasionally in patients with diabetes or undergoing chemotherapy for hematological malignancies (Petrikkos et al., 2012). In developing countries, infection is associated with the presence of trauma, as well as diabetes mellitus, neonatal prematurity, and malnourishment (Prabhu and Patel, 2004; Roden et al., 2005). The clinical manifestations of mucormycosis include rapidly progressing tissue necrosis, most commonly of the sinuses and lungs, associated with high mortality (Petrikkos et al., 2012). Disseminated infection of pulmonary mucormycosis affecting the ribs has also been recorded (Fukushima et al., 1995), as has dissemination of rhinocerebral mucormycosis to the facial bones (Hosseini and Borghei, 2005). Facial manifestations may involve the nasal cavity and the paranasal sinuses and their walls. This lesion may result in perforation of the hard palate and, in dry bone, resemble lesions that are seen in treponematosis and leprosy. Because only one maxillary sinus is usually affected by mucormycosis, the perforation of the hard palate is more often unilateral (Baker, 1971: 835 860).

Mycetoma (Maduromycosis) Mycetoma is a clinicopathological entity caused by aerobic actinomycetes (higher bacteria) and true fungi of various genera (Winslow, 1971 :591; Fahal, 2011). Mycetoma caused by actinomycetes bacteria is called actinomycetoma and is most commonly found in hot/arid environments, whereas mycetoma resulting from infection by

FIGURE 12.3 Skin lesions from mycetoma in the right foot. Adult male. RCSE 07. JB. 7(2).

true fungi is known as eumycetoma or maduromycetoma and is more common in warm geographical areas with considerable rainfall (Mahgoub, 1999: 616). The high incidence of the disease in what is known as the “mycetoma belt,” which extends globally from Sudan, India, Mexico and down to Argentina (to name a few countries), may be influenced as much by climate as socioeconomic conditions (Bakshi and Mathur, 2008). Hosts are often agricultural workers with malnutrition or poor general health (Relhan et al., 2017). Infections are located predominantly in the lower extremities, most commonly in the foot (hence, the colloquial name, “Madura foot”). It is usually preceded by trauma, which allows the pathogen entry into tissues, producing long-lasting and progressive soft-tissue lesions (Maiti et al., 2002) (Fig. 12.3). The bones become

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FIGURE 12.4 Bone lesions in mycetoma of the right foot: (A) superior view of the destructive lesions of the tarsal and metatarsal bones; (B) detail view of the bone destruction of the distal tibia, talus, and calcaneus. RSCE 04. JB. 4. (3).

secondarily infected through the periosteum. In eumycotic mycetoma, the tarsal and metatarsal bones usually show multiple lytic foci and progressive osteoporosis (Fig. 12.4A and B). In actinomycotic mycetoma, both osteolytic and osteosclerotic lesions develop and progress rapidly, accompanied by greater inflammation and earlier tissue destruction and invasion of bone than eumycotic infection (Relhan et al., 2017) (Fig. 12.5A and B). The distal tibia and fibula, as well as the metatarsals, may be affected in people with advanced disease, showing multiple cortical perforations and destruction with very little reactive bone formation. If the process is arrested and there is healing, bony ankylosis of the affected joints can be expected.

Sporotrichosis Sporotrichosis mainly manifests as a skin and soft-tissue infection (colloquially referred to as “rose gardener’s disease”), caused by Sporotrichum schenckii and entering the body through skin lacerations. While the fungal infection may arise from direct contact with soil, it is also known to be transmitted by cats (Aguinaga et al., 2014). In its severe form, sporotrichosis can affect the respiratory and skeletal systems in immunocompromised hosts (Appenzeller et al., 2006). Thus, unlike the fungal infections discussed above,

systemic sporotrichosis is identified as a very rare but true opportunistic infection. Bone lesions represent the most frequent extracutaneous foci. Involvement of bone may occur by contiguity of an overlying skin lesion, or through hematogenous diffusion, which can manifest variably as small granulomas to large lytic lesions, similar to osteomyelitis (Resnick and Niwayama, 1995a: 2515; Costa et al., 2008; Aguinaga et al., 2014).

Aspergillosis Several species of Aspergillus, especially Aspergillus fumigatus, may act as opportunistic invaders in immunocompromised individuals. Aspergillosis has been reported worldwide. Epidemiological differences in dissemination and mortality rates are likely linked to the differing predominance of the underlying causes of a compromised immune system (Lin et al., 2001). Bone involvement is rare but may occur through direct extension from a lesion in the skin or hematogenous dissemination to bone, most commonly involving the ribs, sternum, or vertebrae (Resnick and Niwayama, 1995a: 2521). Destruction and necrosis of bone between affected paranasal sinuses and the orbits or the anterior cranial fossa can be observed. In vertebral

446 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 12.5 Actinomycosis of the left hand: (A) volar view; notice extensive periosteal involvement of the carpals, metacarpals, and phalanges; (B) radiograph; notice the subcortical involvement and cloacal openings on some bones. Adult Iranian male. AFIP 859604.

aspergillosis, collapse and a gibbus deformity occur, which may mimic tuberculous lesions (Pen˜a, 1971: 807 812).

Paleopathology of Fungal Infections Mycotic infection has likely impacted humans throughout our evolutionary history, eliciting both innate and adaptive immunological responses (Blanco and Garcia, 2008), and developing as “heirloom” conditions in geographical areas where habitation has been long-standing, and as “souvenir” infections in areas with more recent migration (Darling and Donoghue, 2014). Fungal species currently known to cause human disease today are widely distributed across the globe and are indigenous to many different environments. Interaction with soils through subsistence strategies and changing exposure from migration has brought humans in close and constant contact with fungi. This makes mycotic infection an outstanding portal into understanding human/environmental interactions and behavioral/social variables, both past and present. Clinical studies of human mycotic disease have increased over the past decades in response to the growing rates of disseminated infection associated with medical intervention and the rise of new pathogens. Organ transplants, cancer treatments, and the escalation of autoimmune diseases render an increasing number of hosts unable to immunologically manage otherwise common

fungal infections. The increasing presence of fungal infections today, however, should not dissuade paleopathologists from keeping mycotic infection on their list of diseases causing skeletal change during the process of differential diagnosis. Morse (1969: 45), for instance, argues that both blastomycosis and coccidioidomycosis must be considered in the differential diagnosis of destructive lesions of the spine. Similarly, Buikstra (1976) advises differentiating fungal infections from other infectious conditions by incorporating an understanding of epidemiological factors, as well as the morphology and location of the lesions in the skeleton. Hershkovitz et al. (1998) offer bone lesion characterizations associated with mycotic infections found in the Terry and Hamann-Todd skeletal collections as a means towards differential diagnosis of these diseases in archeological human remains. Similarly, Aufderheide and Rodrı´guez-Martı´n (1998) carefully review the skeletal manifestations of a number of mycoses diagnosed in clinical settings. Paleopathological reports of mycotic infection are relatively few, likely due to disseminated mycotic infections mimicking other conditions affecting bone, the destructive nature of most of the bone lesions, and the body’s ability, in most cases, to contain infection before dissemination to bone occurs. In spite of these obstacles, fungal infection has been detected in human skeletal remains. Poswall (1976), for instance, called attention to the presence of

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both coccidioidomycosis and blastomycosis in North America. She suggests that skeletal lesions from these fungal diseases may be distinguishable from other infectious diseases of bone and may be a more probable diagnosis for bone lesions seen in skeletal remains of some Native American groups. Kelley and Eisenberg (1987) argue, largely on paleoepidemiological grounds, that some skeletal pathology observed in skeletal remains from two North American archeological sites (the historic era Mobridge site from South Dakota, and the prehistoric Averbuch site from Tennessee) are more likely to be caused by blastomycosis than tuberculosis. Temple (2006) reports on a skeleton with likely coccidioidomycosis at the Los Muertos site Arizona, dated AD 1150, based on careful skeletal analysis and knowledge about the

447

endemicity of the disease in that region today. Recently, Curto and Fernandes (2016) argue for the presence of maduromycosis (Madura foot) in a skeleton from a medieval site in Portugal based on macroscopic and radiographic evaluation of skeletal elements, as well as an evaluation of climatic conditions appearing conducive to the presence of this fungus. Mycosis is also likely in a skeleton from the National Museum of Natural History, Smithsonian Institution, Washington, DC (catalog number 381074), represented by a skull and mandible from an adult female dated to the 18th century, recovered near the Ogooue´ River in Gabon, Western Africa. Anterior and left lateral views of the skull (Fig. 12.6A and B) show chronic granulomatous lesions particularly apparent on the frontal bone. These

FIGURE 12.6 Possible evidence of Histoplasmosis duboisii with possible complications from treponematosis affecting the skull in an 18th-century case from Gabon, Western Africa: (A) anterior view of the skull; notice the destructive lesions of the frontal bone that could be caused by treponematosis; (B) left lateral view of the skull; notice the round, porous lesions of the posterior parietal bone; (C) lateral radiograph of the skull. There are multiple lytic lesions affecting the diploe¨ that would very unlikely be the result of treponematosis. Adult female. NMNH 381074.

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FIGURE 12.7 Multifocal lytic lesions, some of which have a sclerotic margin, in a skeleton from Merida, Mexico, dated to AD 1920: (A) right lateral view of T2 T9 vertebrae with multifocal lytic lesions; (B) anterior view of T2 T9 vertebrae; (C) detail of lesions on T6 T9 vertebrae; (D) posterior view of the sternum with a lytic lesion on the right sternal body; this lesion shows evidence of reactive bone formation around the site and sclerosis at the margins of the lytic focus; (E) lytic lesions of the right sacroiliac joint; (F) lytic lesion of the sacrum; (G) lytic lesion in the medial condyle of the distal left femur. Female 35 45 years of age, with permission; PMH no. 61016.

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449

FIGURE 12.7 (Continued.)

lesions are strongly suggestive of treponematosis. However, a lateral radiograph (Fig. 12.6C) reveals many more lytic lesions than are apparent macroscopically. These lesions clearly involve the diploe¨, which is unusual for treponemal lesions. Since the skull is a predilected site for lytic lesions in histoplasmosis (Resnick and Niwayama, 1995a: 2515), and H. duboisii is endemic in Gabon, a plausible diagnostic option for this skeleton is treponematosis complicated by histoplasmosis. Another possible example of mycotic infection is found in a skeleton curated in the Peabody Museum of Archaeology and Ethnology, Harvard University, Massachusetts (catalog no. 61016), dated to approximately AD 1920 and from a cemetery in Merida, Mexico. The notable lytic lesions are widely distributed in the skeleton and most show some evidence of reactive bone formation (sclerosis) in/on their margins but minimal periosteal reactive new bone formation on the bone surface surrounding some of the lytic foci. The most extensive involvement is in the axial skeleton but the appendicular bones are affected as well. The most severe bone destruction appears in the thoracic vertebrae (Fig. 12.7A C). The lesions occur in all components of the vertebrae and the affected vertebrae are separated by intervening normal vertebrae. The ribs and sternum are also affected (Fig. 12.7D). Periosteal reactive new bone formation is seen in a large area surrounding the sternal defect. The sacrum and left innominate bone are fused but appear normal otherwise. There is a large lytic defect in the right sacroiliac joint that affects both the sacrum and the os coxa (Fig. 12.7E). In the right side of the sacrum, a separate lytic focus penetrates the postero-lateral surface

(Fig. 12.7F). The appendicular skeleton is less extensively involved but one destructive lesion is apparent in the medial condyle of the left distal femur (Fig. 12.7G). In this case, the skull is free of abnormalities related to conditions seen in the rest of the skeleton. The multifocal distribution of lesions makes tuberculosis unlikely. Other diagnostic options include brucellosis, echinococcosis, and cancer. However, the most probable option is mycotic infection with coccidioidomycosis being the possible specific diagnosis. The diagnosis of mycotic infection has been enhanced further in some cases by the use of multiple lines of evidence. Harrison et al. (1991) describe an archeological skeleton with destructive bone lesions from Arizona in which the authors recovered C. immitis spherules (small round structures created by spores within a host), confirming the presence of coccidioidomycosis in pre-Columbian North America. Afonso-Vargas et al. (2015) successfully isolated and identified fungal spores in 18th-century human dental calculus from the Canary Islands. Although the spores were not from a fungus pathogenic to humans, the researchers were able to determine that they were not postmortem contaminants, but rather were remnants of dietary consumption of corn. Exploring the paleogenomics of fungi has allowed researchers to propose that fungi such as C. immitis and C. posadasii, which adopt mammals as their hosts (including humans), are likely more recent evolutionary variants, while virtually all other species of the genus rely on plant hosts (Whiston and Taylor, 2014). Sharpton et al. (2009) posit that C. immitis and C. posadasii, both associated with dead animals in soil, and not with soil alone, may indicate a dietary shift

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in human groups from plant-based foraging to hunting and scavenging. Darling and Donoghue (2014) integrate these findings into a broad-scale analysis of the evolution of fungi in the New World and their impact on human populations.

VIRAL INFECTIONS Introduction Understanding the nature of viral pathogens and the host response is important in understanding the evolution and history of viral disease in the past (Enard et al., 2016). Viruses are known to infect all living organisms, including those in the bacteria and Archaea domains (Abedon and Murray, 2013), and therefore human populations have certainly been exposed to viruses throughout our evolutionary history (Van Blerkom, 2003). Since all vertebrates have the capacity to engage in innate and adaptive responses to pathogenic invasion, it is likely that these abilities have a long evolutionary history as well, predating the rise of mammals (Buchmann, 2014). The adaptive immune response is labile, as it is the product of the recombination of immunoglobulin genes, the insertion of foreign DNA fragments into certain host cell loci, and modulation by hormones and physiological stress (Danilova, 2013; Koonin and Krupovic, 2015). The result of this plasticity is the potential for coevolution of host and pathogen, with hosts selected to withstand the effects of a specific viral infection, and viruses selected for the ability to quickly alter their genetically based antigens. It has also resulted in the development of viral pathogens with preferential or exclusive hosts. Hence, if a virus is to succeed, it needs either plenty of new hosts of a specific type (humans, for instance) to infect, or the ability to alter its genetic structure in order to infect different hosts (e.g., influenza).

Pathology Viral pathogens rarely affect the human skeleton. When skeletal involvement occurs, however, it is usually through one of three mechanisms: through direct stimulus of bone cells (as in smallpox), through neurologic changes that can affect bone growth or maintenance (as in poliomyelitis), or indirectly by increasing the host’s vulnerability to other pathogens that elicit skeletal responses. Viruses, unlike the other pathogens discussed in this chapter, are unique entities composed of nucleic acid (either DNA or RNA) surrounded by a protein capsid (shell). They are technically not organisms because they rely on a host cell in order to reproduce; they kill host cells in order to survive, which renders them obligate parasites. The human immunological response to viral infection begins

with an “innate” response, which is the body’s relatively generalized and nonspecific response to foreign molecular invasion. This response includes the stimulation of lymphocytes and interferons. If this line of defense fails and the virus successfully enters, hijacks, and eventually kills a great number of cells, the host organism itself might die. However, hosts have another line of defense, the adaptive or acquired immune response, with two effective components: a cell-mediated response, which creates cytotoxic T lymphocytes that kill infected cells, and a humoral response that creates virus-specific antibodies to annihilate the pathogen itself. The end product of both of these adaptive immune responses is the production of “memory cells” capable of recognizing the pathogen and triggering a quicker immunological response should the host encounter the intruder again. The complex viral host/pathogen relationship helps explain the infrequent involvement of the human skeletal system in virally induced disease processes. Viral infections are most often acute, leaving little time for macroscopically recognizable bone change to occur before the host wins or loses the battle. The presence of viral disease also serves as an indicator of human social interaction and/or human interaction with animal hosts. Viruses using human cells as obligate hosts must have a constant supply of humans to infect (that is, a large host population) in order to remain evolutionarily viable or, conversely, must be labile enough to use multiple hosts (such as birds, pigs, and humans serving as hosts for the influenza virus) and rely upon hosts interacting with each other. Viral infections affecting the human skeleton are uncommon, and those that do affect the skeleton generally produce bone lesions that are indistinguishable from other pathological conditions of bones. However, as Resnick and Niwayama (1995a: 2522 2534) and Aufderheide and Rodrı´guez-Martı´n (1998) point out, a few viral diseases may be recognizable in the archeological record. These include variola (smallpox), rubella (German measles), Paget’s disease, poliomyelitis, and influenza.

Smallpox (Variola) Smallpox is an infection caused by the virus Orthopoxvirus variola, further recognized as having two strains: major and minor (Dumbell et al., 1961), and often referred to simply as the variola virus (VARV). An important factor of VARV, which distinguishes it from other species in its genus, is its single host: humans. The virus is transmitted from person to person through aerosols and air droplets, but has also been recorded being transmitted through contaminated cloth (WHO, 2014). The genomic similarities between VARV and other orthopoxviruses suggest that the evolutionary history of the genus is long, but the emergence of the species variola is

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more recent, perhaps within the past 3000 4000 years in Africa (Babkin and Babkina, 2015; Hughs et al., 2010). As with most host species-specific viruses, relatively large population sizes (200,000 or more) are required in order for the pathogen to remain viable in a human population (Fenner, 1996: 27), especially since smallpox appears not to be highly transmissible (Belongia and Naleway, 2003; Lane and Goldstein, 2003). However, the disease can, and has, spread from large population centers to small human groups, where it can result in high morbidity and mortality (Hopkins, 2002). There are two basic variants of smallpox virus: variola major and variola minor. Mortality from variola major ranges from 10% to virtually 100%, but tends to center around 30% (WHO, 2014). Variola minor, identified in the latter part of the 20th century, was limited to the United States and southern Africa (Fenner, 1996: 31) and was associated with a mortality rate of 1% or less (WHO, 2014). Historically, smallpox was a global disease, which remained prevalent in developing countries for decades leading up its eradication in 1980. Skeletal involvement, known as variola osteomyelitis, can initiate weeks after the onset of infection (especially in infants). As late as 1958, Cockshott and MacGregor reported a series of 2500 people with smallpox over an 18 month period in Nigeria, and Davidson and Palmer (1963) reported 400 affected people from southern Rhodesia. The skeletal involvement varied in different series from 2% to 5% (Cockshott and MacGregor, 1958: 377, 1959: 57; Middlemiss, 1962: 11 13) to about 20% (Davidson and Palmer, 1963: 687) and appeared far less common when the disease was contracted in adulthood (Davidson and Palmer, 1963). Variola osteomyelitis, in contrast to most other skeletal infections, predilects the upper extremities, especially the elbow area (Fig. 12.8) and is often symmetrical (Balaji, 2011). Resnick and Niwayama (1995a: 2529) highlight three pathogenic pathways for bone involvement in smallpox. The first is a necrotic nonsuppurative osteomyelitis, likely caused directly by smallpox. The second is suppurative arthritis, but this is due to a secondary infection. The third expression is a nonsuppurative arthritis that involves multiple sites and tends to be bilateral. Severe joint damage may occur, leading to deformity and joint fusion. With elbow involvement, the lesion usually starts in the metaphyseal area near the growth plates and spreads to the adjacent joint. There is destruction of metaphyseal bone, leading to separation of the epiphysis and, in severe cases, to pathological fracture. There is no massive sequestration, in contrast to bacterial osteomyelitis, but pronounced formation of reactive periosteal new bone attached to the cortical surface is usually present. In about 80% of the 81 patients of Davidson and Palmer (1963),

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FIGURE 12.8 Radiograph of an elbow showing osteomyelitis variola and reactive bone formation (arrows). Subadult, modern, AFIP, Courtesy of Dr. Mark Kransdorf.

the elbow was affected, and very frequently bilaterally. Often all three bones (humerus, ulna, and radius) were involved, whereas in most other infections, including tuberculosis, the radius is usually spared. Second to the elbow joints, the wrists, knees, and ankles are most often affected, but any joint may be involved. In a review of 124 published cases of variola arthritis, Cockshott and MacGregor (1958: 376) reported the following locations: elbows, 97; wrist and hands, 25; knees, 17; ankle and foot, 16. In more than half of the individuals affected, multiple anatomical areas were involved. In the carpal and tarsal bones, which are often targeted, uneven, patchy, lytic destruction is recognizable in radiographs (Fig. 12.9). Lesions in the calcaneus are common (Davidson and Palmer, 1963: 692). In fingers and toes dactylitis occurs. The ribs, spine, pelvis, and cranium are usually spared in smallpox. During the active disease, the bones may be sufficiently compromised, leading to bending deformities in weight-bearing areas. Permanent

452 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 12.9 Radiograph of osteomyelitis variola of both arms and hands: Notice the involvement of the humerus, radius, and ulna and of most of the metacarpals and phalanges. Two-year-old female Indonesian, courtesy of Dr. L. A. Tamaela, Djakarta, Indonesia.

changes are mainly deformities due to arrested growth, secondary to destruction or slipping of the growth plate (Fig. 12.9). Dactylitis may lead to short stubby digits for the same reason.

Rubella Rubella is an infection caused by the virus Rubivirus rubella. While the disease is often colloquially referred to as German measles, this is a misnomer since rubella is not genetically related to measles. Rubella is transmitted from human-to-human through direct contact with droplets and aerosols from the nose and throat. In most instances it manifests as a rash in children and adults, but has serious consequences on fetal development (often

referred to as “congenital rubella”), potentially leading to miscarriage if acquired by the mother during the first trimester of pregnancy (Annie et al., 2016). In adults, rubella infection can lead to complications, including arthritis that affects the small joints of the hands, wrists, knees, and ankles (Resnick and Niwayama, 1995a: 2522). An association between chronic joint disease and the rubella virus has further been reported (Banatvala and Brown, 2004; Bosma et al., 1998). In neonates, deafness, congenital cataracts, heart defects, central nervous system deficits, and skeletal changes occur (Banatvala and Brown, 2004). Singleton et al. (1966) report that in 81 infants with a history of maternal rubella in utero, 34 displayed skeletal involvement.

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FIGURE 12.10 Radiographic images of infant displaying classic signs of congenital rubella: (A) the distal femoral and proximal tibial metaphyses are poorly mineralized adjacent to the growth plate and display a coarse and reduced trabecular pattern; (B) periostitis along the diaphysis of the tibia and fibula. Courtesy of Drs. T. Demos and L. Lomasney, Department of Radiology, Loyola University Chicago Medical Center.

The most characteristic skeletal lesions associated with congenital rubella appear in radiographs of the long bone metaphyses of newborns (Fig. 12.10A and B). The changes affect all metaphyseal areas but are most obvious on fast-growing areas, such as the distal femoral and proximal tibial metaphyses. These changes consist of poor mineralization adjacent to the growth plate and coarsening and reduction of trabecular bone, accompanied by diaphyseal periostitis. The lesion is similar to that of congenital syphilis but, in contrast to syphilis, ossifying periostosis is not observed (Highman, 1967). There is general growth retardation, and the skull may show enlargement of the anterior fontanelle and poor mineralization. If the infant survives, the bone changes disappear at about 3 months of age without leaving residual irregularities of architecture. However, Singleton et al. (1966) report a mortality rate in infants with skeletal involvement of 32%. This disease has not been reported in archeological human skeletal remains.

Poliomyelitis Poliomyelitis is a highly contagious infectious disease spread through oral oral or oral fecal transmission of the virus Enterovirus poliovirus. In most cases, the host response is mild, consisting of minor respiratory or

gastrointestinal symptoms. In immunocompromised hosts, or in rare cases when the virus enters the central nervous system, nonparalytic aseptic meningitis can ensue, or, in fewer instances, paralytic poliomyelitis develops. Hamborsky et al. (2015) report that 72% of people with poliomyelitis are asymptomatic, while 0.5% 1.0% develop the paralytic disease, of which 79% have spinal polio, 19% have bulbospinal (brainstem and spinal), and only 2% have bulbar (brainstem) polio. Paralytic polio develops when the poliovirus infects the person and travels along nerve fibers, affecting the anterior horn motor neurons of the spinal cord and brain (Mueller et al., 2005; Munson et al., 2016). The likelihood of developing paralytic polio appears to increase with age (Gawne and Halstead, 1995) and there is clear evidence that the effects of poliomyelitis extend well past recovery from the initial viral infection—a condition referred to as postpolio syndrome (Trojan and Cashman, 2005; Ramlow et al., 1992). Spinal polio develops when motor neurons of the anterior horn cells in the spinal column are infected, as these are responsible for muscle movement of the trunk and limbs of the body. The more cranial along the vertebral column that the infection occurs, the greater the extent of trunk and limb involvement, usually resulting in irreversible paralysis (Shibuya and Murray, 2004; Yin-Murphy and Almond, 1996). In some instances, the virus will infect

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neurons enclosed by the cervical vertebrae, and at times may infect the bulbar region of the brain (Hamborsky et al., 2015). In these instances, breathing and body functions are severely impacted, requiring medical intervention in order to survive. E. poliovirus is an obligate human pathogen with no other known hosts. Its reproductive success, therefore, relies upon intense human interaction. In spite of increasing human population sizes, historical accounts of the presence of the disease are rare. It was not until 1789 that the disease was clinically described (Underwood, 1789) and relatively few affected individuals were reported until the late 19th century. By the turn of the century, however, outbreaks of “infantile paralysis” were evident, particularly in North America and Europe (Dunn, 2006). Dunn (2006) postulates that the E. poliovirus was a ubiquitous pathogen in human populations, creating an enteric infection in most infants shortly after birth, but that it was suppressed by circulating antibodies from nursing mothers. With greater measures in Europe and North America to improve personal hygiene and public sanitation, infection with E. poliovirus was delayed to later in childhood, long after the presence of passive maternal antibodies. With less immunological resistance, the pathogen was able to invade the central nervous system. Poliomyelitis became a global disease, with sporadic epidemics continuing into the 1950s until its elimination through vaccination by the 1970s.

The effects of paralytic poliomyelitis are identifiable in the skeleton but can be difficult to differentiate from other neurogenic disorders, such as cerebral palsy, “stroke”, Rasmussen’s encephalitis, and clubfoot. Skeletal changes associated with poliomyelitis are secondary effects of neuromuscular damage caused by the pathogen. Scoliosis, for instance, is a common consequence of asymmetrical trunk paralysis, found by Colonna and Saal (1941) in 30% of their 500 patients with polio, and known to be an aspect of progressive functional deterioration in polio survivors (Howard et al., 1988). The shortening of one or more limbs may also be evident and recognizable in human (and occasionally great ape) skeletons when the virus is contracted during childhood (Morbeck et al., 1991; Ring, 1957). Attempts to associate the degree of limb shortening with age at onset of the disease or severity of paralysis have not found direct or predictable correlations (Ratliff, 1959). Ratliff (1959), however, reports that in 225 patients with paralysis of one leg, 93% displayed shortening of the tibia and fibula. The other osseous changes, all residual effects of muscle impairment or paralysis and compensatory biomechanical use, include external rotation of the hip, external rotation of the tibia, knee hyperextension, excessive valgus alignment, pes cavus (creating an abnormally high medial longitudinal arch in the foot), marked foot pronation, and claw toes (Faraj, 2006) (Fig. 12.11A and B). Limb atrophy, along with asymmetrical and regional osteoporosis

FIGURE 12.11 Postparalytic deformities of the distal skeleton, showing lumbosacral scoliosis, flaring ischia from sitting, flexion contracture of both knees, and bilateral clubfoot with paralytic pes cavus deformity. (A) Overall view. (B) Dorsal view of the left foot. Twenty-four-year-old male many years after poliomyelitis; FPAM 5013, autopsy 88103 from 1880.

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FIGURE 12.12 Femora from individual with poliomyelitic paralysis of the left leg. Note the reduced diameter and minimal surface relief of the affected left femur. Nineteen-year-old male, died 15 years after onset of paralysis. IPAZ 468/39.

may also serve as diagnostic characteristics of paralytic poliomyelitis, as these have been linked with postpolio syndrome (Ratnasingam et al., 2016) (Fig. 12.12).

Paget’s Disease Paget’s disease was originally described in a report that has become a classic in the medical literature (Paget, 1877). Paget called the disease osteitis deformans in part because of the extensive and deforming changes that took place in the skeleton. The disease is a chronic bone abnormality, which may affect a single, several, or many bones, but never involves the entire skeleton. It occurs commonly in populations of European descent, especially British descent (Vallet and Ralston, 2016), with conflicting reports of its prevalence in African-American, African, and Asian populations (Altman et al., 2000). What appears undeniable, however, is that the disease predominantly affects people over the age of 40 years and is found more commonly in men (Mirra et al., 1995a;

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Van Staa et al., 2002). Schmorl (1932: 698 699) reports a prevalence of Paget’s disease in 3% of over 4600 autopsies of individuals above 40 years of age, but studies over the past decades have reported varying frequencies ranging from as low as 0.2% to 8%, depending on the population under investigation (Altman et al., 2000). Many researchers note that the frequency of the disease has been decreasing over the past decades (Barker, 1984; Cooper et al., 1999; Cundy et al., 1997; Poor et al., 2006). The bones and anatomical areas most affected by Paget’s disease include the vertebral column, femora, tibiae, os coxae, and the cranium, but other bones of the extremities are also commonly involved (Tuck et al., 2017) (Fig. 12.13). The etiology of the Paget’s disease is complex. The recognition that the disease can appear in kin groups has been noted by many (Barry, 1969; Morales-Piga et al., 1995; Sofaer et al., 1983), leading researchers to explore genetic bases for the disease. To date, a number of genetic mutations have been isolated, including, but not limited to, the SQSTM1 gene on chromosome 5 (Laurin et al., 2002), TNFRSF11A on chromosome 18 (Nakatsuka et al., 2003), and the TNFRSF11B gene on chromosome 8 (Daroszewska et al., 2004), all associated with the regulation of osteoclastic differentiation and function, and perhaps inherited as autosomal dominant mutations with incomplete penetrance (Daroszewska and Ralston, 2005; Singer, 2015). In rare cases of juvenile Paget’s disease, links to an autosomal recessive mutation of the TNFRSF11B gene (responsible for production of osteoprotegerin) appears to diminish the inhibition of osteoclastogenesis, causing rapid bone turnover, leading to skeletal deformity and fractures (Hofbauer and Schoppet, 2002; Whyte et al., 2007). However, genetic mutation does not appear to be the sole etiological factor in Paget’s disease (Rios Visconti, 2015; Vallet and Ralston, 2016). Decades of research have detected a link between Paget’s disease and viral infection. In particular, the presence of the slow virus Paramyxoviridae, common in vertebrate hosts, has been linked to Paget’s disease (Mundy, 1999: 183 186; Roodman and Windle, 2005), suggesting to some that particular genotypes may increase an individual’s vulnerability to paramyxoviral infection of osteoclasts (Friedrichs et al., 2002). Paramyxoviruses include the measles virus Morbillivirus measles morbillivirus and canine distemper Morbillivirus canine morbillivirus. While researchers such as Reddy et al. (2001) and Kurihara et al. (2011) have detected indicators of the measles virus in patients with Paget’s disease, and Mee and Sharpe (1993) and Mee et al. (1998) find indicators of the presence of the canine distemper virus in patients with Paget’s disease, several studies have been unable to replicate the results (Matthews et al., 2007, 2008; Ooi et al., 2000).

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FIGURE 12.14 Mosaic pattern in femoral cortex displaying numerous cement lines caused by Paget’s disease. Ground polished section of undecalcified bone. Polarized light, approximately 3 100 magnification. Section courtesy of the late Prof. E. Uehlinger.

FIGURE 12.13 Bone scan of a patient with Paget’s disease. Note the areas of impact (black) where the radioactive tracer detects “hot spots” of altered bone metabolism and turnover; in this case these are clearly visible in the os coxae, along the vertebral column, the tibiae, left tarsal bones, right radius, proximal humeri, sternum, and right clavicle. Courtesy of Drs. T. Demos and L. Lomasney, Department of Radiology, Loyola University Chicago Medical Center.

The disease process can be best characterized as a pathological increase in the rate of remodeling as great as 20 times compared to normal (Mundy, 1999: 181). The primary defect appears to be in the osteoclasts, which are larger than normal and may contain virus-like inclusion bodies (Fraser, 1997: 348). The disease is a local process but may spread through an entire bone, including the epiphyses, and involve the subchondral bone plate of the joint. In the skull, the process extends readily across suture lines and may involve the facial bones and mandible, resulting in severe deformity (Mirra et al., 1995a: 164). The initial change is excessive osteoclastic resorption accompanied by fibrous conversion of the bone marrow, accompanied by hypervascularity at the site of the lesion. This is followed by osteoblastic overstimulation, producing irregular and excessive amounts of poorly organized woven and lamellar bone. In the long and protracted course of the disease, osteoclastic and osteoblastic activity are both greatly accelerated, leading to excessive remodeling in affected areas, which results in the characteristic mosaic pattern in the histology. This pattern consists of greatly increased fragments of bone that may include both circumferential lamellar bone and the lamellar bone within osteon fragments (Fig. 12.14). These fragments are separated by cement lines but are smaller in size and more numerous than in normal bone. This pattern is present in trabecular and cortical bone. This mosaic pattern seen in a histological section of bone is virtually pathognomonic of Paget’s disease and is an example of the value of microscopic examination of archeological bone where a diagnosis may be established on the basis of the histology. The early lesions are predominantly lytic and osteoporotic; later, thickening of the cortex by endosteal and periosteal bone deposition, with enlargement of the bones, is

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observed. The trabecular architecture becomes accentuated and its usually smooth outline assumes irregular surface contours in radiographs. Alternating resorptive and sclerotic areas create a mottled appearance in radiographs (Fig. 12.15). Bone changes at different stages of the disease and at different locations in the skeleton present a variety of distinctive patterns (see below).

Skull The early Paget’s disease lesion of the skull is a single, or sometimes multiple, lesion of the cranial vault that is characterized by prevailing bone resorption. This results in reduction of trabeculae in the diploe¨ and marked thinning of the inner and outer tables, creating an area of markedly increased radiolucency. This abnormal area is known as “osteoporosis circumscripta” (Erdheim, 1935). The thinned tables may exhibit a porous surface. The outline of the lesion is somewhat wavy, may cross suture lines, and has a sharp interphase against adjacent uninvolved bone. Although this lesion may remain for a number of years, ultimately, characteristic blastic lesions of Paget’s disease will develop either in the skull or in other areas of the skeleton (Kasabach and Gutman, 1937: 598). The location and appearance of this lesion are distinct enough to make one suspect early cranial Paget’s disease in dry bone. Changes of fully developed Paget’s disease of the cranial vault may exhibit distinct thickening of the calvarium by both endocranial and ectocranial bone formation. Such calvaria may reach several centimeters in thickness and there may be considerable encroachment on the intracranial space (Fig. 12.16). The cross section of

FIGURE 12.15 Radiograph of lateral aspect of a tibia displaying recognizable thickening and lamination of the cortex, along with a mottled appearance. Courtesy of Drs. T. Demos and L. Lomasney, Department of Radiology, Loyola University Chicago Medical Center.

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the calvarium shows areas of laminated thickening of the tables and alternating porotic and sclerotic areas in the diploe¨, presenting the characteristic appearance of finely porous pumice-like bone (Fig. 12.17A). In the diploe¨, ball-shaped masses of sclerotic bone occur, exhibiting greatly increased radiological density (Fig. 12.17B). These masses are more common and much more dense than those seen occasionally in fibrous dysplasia. The skull base may be involved (Fig. 12.18A). Thickening takes place mostly on the endocranial surface with encroachment upon the cranial cavity. The cranial air sinuses may also be impaired by the transformation and thickening of their walls. The cortex of the petrous part of the temporal bone may be involved in Paget’s disease, but the otic capsule is usually spared due to the lack of remodeling. The facial bones are also usually spared but, if involved, subperiosteal deposition of pumice-like bone may disfigure the face and resemble leontiasis ossea

FIGURE 12.16 Paget’s disease of a calvarium, showing extreme thickening and sclerosis of the cranial vault with nodular bony masses in the diploe¨. Sixty-eight-year-old male; duration of the disease was approximately 22 years. WM HS62.1 from 1876.

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FIGURE 12.17 Paget’s disease. (A) Cranial vault, endocranial view, showing thickening, especially of the frontal bone, with nodular bony masses in the diploe¨. The bone is soft and pumice-like. (B) Close-up of frontal bone area with nodular diploe¨. Sixty-five-year-old female with polyostotic Paget’s disease. IPAZ 4566; autopsy 46 from 1940.

(Fig. 12.18B). Similarly, involvement of the jaws is uncommon, although a more common feature of Paget’s disease is the abnormal deposition of radio-dense cementum around the dental alveoli.

Long Bones The femur and the tibia are the most common major long bones to be affected. The early lesion in these bones, like that of the cranium, is purely lytic osteoclastic resorption involving the entire thickness of the cortex and showing a sharply demarcated, wedge-like radiolucency (cutting cone) border against uninvolved bone (Fig. 12.19). This lesion alone is not diagnostic in dry bone and can, even in a radiograph, be mistaken for a tumor metastasis. The later blastic phases show marked thickening and lamination of the cortex. The bones become enlarged by periosteal new bone formation. Bowing, especially of the weight-bearing bones, occurs mainly due to complete or incomplete transverse pathological fractures, which is an expression of the mechanical inferiority of the abnormal bone formed in the lesions associated with Paget’s disease (Fig. 12.20A and B). The spongiosa of the epiphyses and metaphyses shows characteristic coarsening and focal deposition of pumicelike bone (Fig. 12.21A). The cortex also undergoes a gradual conversion to pumice-like, fine porous bone (Fig. 12.21B). The medullary cavity is preserved, although it may be diminished in size. Secondary osteoarthritis over

severely affected epiphyses is common. Although any bone may be affected by Paget’s disease, the fibula and the small tubular bones of the hands and feet are usually spared, as are the tarsal and carpal bones.

Spine The axial skeleton is the most common site of bone involvement in Paget’s disease. Lesion prevalence decreases steadily from the sacrum to the cervical spine. Within the vertebrae, the body is most markedly affected. The lesions may extend into the neural arches but often spare their posterior portions, including the spinous process. The vertebral bodies show laminated thickening of the end plates and the cortex, with porotic reduction of the trabeculae in the center (Fig. 12.22). These trabeculae are reduced in number but are thickened and have uneven surfaces (Fig. 12.23). Compression fractures of severely affected vertebrae are not uncommon. Frequently, although several vertebrae show the disease, completely normal vertebrae separate them.

Flat Bones The ilium is often involved if there are lesions in the sacrum. The disease usually involves the manubrium or the body but does not cross the synchondrosis. Ribs are commonly affected and may become markedly thickened.

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FIGURE 12.19 Early Paget’s disease. Bisected tibia showing lytic transcortical lesion (dark) with wedge-shaped progressive margin. Seventy-seven-year-old female. MGH surgical specimen 4149 from 1963.

polyostotic or widespread Paget’s disease (Choquette et al., 1983; Hansen et al., 2006), but other researchers have not detected this association (Ruggieri et al., 2010). The most common sites of sarcoma resulting from Paget’s disease occur in the pelvis, the femur (Fig. 12.24), and the humerus (Mirra et al., 1995b: 179), with the vertebrae rarely involved (Mankin and Hornicek, 2005).

Paleopathology of Viral Infections Smallpox

FIGURE 12.18 Skull in advanced Paget’s disease. (A) Cranial base, showing extensive endocranial hyperostosis and sclerosis of the thickened cranial vault. (B) Frontal view, showing diffuse hyperostosis of the facial bones with porous subperiosteal bone deposition. Seventy-fiveyear-old female. FPAM, Jubila¨umspital 510, from 1917.

Paget’s Disease Sarcoma Because of the greatly increased bone turnover in Paget’s disease, malignant transformation of lesions occurs in some cases. This transformation is not common and is largely limited to people with severe and long-standing Paget’s disease (Mankin and Hornicek, 2005). The transformation to sarcoma has also been associated with

The antiquity of smallpox is difficult to estimate in part because of the acute nature of the virus and the tendency for osteomyelitis variola to mimic other diseases. However, Henderson (1999: 1095) and Fenner (1996: 27) assert that direct archeological and historical evidence suggests that smallpox extends back to Dynastic Egypt, while Aufderheide and Rodrı´guez-Martı´n (1998: 204) declare that the earliest plausible evidence for smallpox is in the early Christian era. Reports in the paleopathological literature indicate that O. variola was present in medieval Europe. Fornaciari and Marchetti (1986), for instance, report on the identification of intact smallpox particles from a 16thcentury Italian mummy, and Darton et al. (2013), document a subadult male skeleton from north-eastern France with bilateral lesions at the elbow that broadened the metaphyses and resulted in ankylosis of the joint.

FIGURE 12.20 Left femur with Paget’s disease. (A) External view showing bowing and thickening. (B) Cut surface showing cortical thickening, narrowing of the medullary canal, and irregularly coarsened cancellous bone. Sixty-four-year-old male, of 10 year’s duration. WM HS62.3.

FIGURE 12.21 Paget’s disease of the femur. (A) Longitudinal section, mediolateral plane. (B) External compact bone surface, demonstrating the porous, pumice-like bone. Modern adult, IPAZ 1313/62.

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FIGURE 12.23 Radiograph of Paget’s disease of one vertebra (lower image) with adjacent normal vertebra (upper image). Note increased density and coarsening of the spongiosa of the involved vertebra. Studied by Walter Putschar.

FIGURE 12.22 Paget’s disease of the lumbosacral spine, complicated by secondary hyperparathyroidism. Midline cut showing the characteristic coarse trabeculation of Paget’s disease and the fine pumice bone deposition along the end plate, particularly of the fifth lumbar and first sacral vertebrae, characteristic of hyperparathyroidism. Seventy-oneyear-old female. IPAZ autopsy 358 from 1960.

While smallpox perhaps originated and remained in the Old World for millennia, the colonization of the New World extended its reach across the Atlantic. The virulence and high mortality associated with the infection in Native American populations following European contact is a strong argument that smallpox was a new pathogen in the Americas. Possible skeletal evidence of smallpox in historic-period Native American skeletal remains is found in a burial (no. 33) from a Neutral Indian cemetery in southern Ontario, Canada (Jackes, 1983). The distinctive (bilateral) pathology associated with this burial is in the elbow joint, although preservation on the right side is

somewhat compromised. Much of the subchondral bone displays deformation and extensive remodeling. Another North American example of smallpox occurs in the skeleton of a child approximately 10 15 years of age, currently part of the human skeletal collection of the National Museum of Natural History, Smithsonian Institution, Washington, DC (catalog no. 377912). The skeleton was recovered from the mummy caves on Kagamil Island, Alaska, United States. Dating of this individual is problematic. There are a number of pathological lesions present on this skeleton. There is a lesion of the frontal bone suggestive of chronic infection, such as congenital syphilis. However, congenital syphilis is highly unlikely to have produced the lesions seen in the elbow region. In the elbow, bone involvement is most severe in the distal posterior humeri and consists of general destruction of the metaphyseal cortex with reactive woven bone formation that has greatly enlarged the metaphysis (Fig. 12.25A and B). Coronal CT (computed tomography) images of the affected bone indicate the extent of the

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BCE), for instance, depicts an individual with a shortened and possibly atrophied right leg (Leca, 1971). Mummified Egyptian remains of Pharaoh Siptah (1205 1187 BCE) might provide a more robust diagnosis based on a shortened and deformed left foot (Mitchell, 1900), but Galassi et al. (2017) caution against premature acceptance of the presence of polio given the difficulties with differential diagnosis. Reported evidence of poliomyelitis based on skeletal analyses is uncommon prior to the 12th century. Novak et al. (2014: 26) offer a list of skeletons with probable poliomyelitis and cerebral palsy published in the paleopathological literature. In all, 15 are listed, with 7 of them derived from sites dating after the 13th century. These findings are not surprising since historic era reports of paralytic disease appear to increase in Europe during these centuries and differentiating the effects of poliomyelitis from cerebral palsy is difficult, if not impossible. Two recent reports, one from Novak et al. (2014) and one from Schrenk et al. (2016), tackle the complexity of differential diagnosis in two skeletons from medieval sites in Croatia (Novak, 2014) and one skeleton recovered from a Bronze Age tomb in the UAE (Schrenk et al., 2016). Neither published report concludes that the pathological changes noted in the skeletons were likely associated with paralytic poliomyelitis because similarities to the effects of cerebral palsy make diagnosis of a viral infection impossible. However, Schrenk et al. (2016) assert that isotopic analysis suggests that their individual had migrated to the region some time after the age of 15, which might have increased her risk of contracting poliomyelitis. FIGURE 12.24 Osteosarcoma in Paget’s disease of the right distal femur. Eighty-year-old female. MGH surgical specimen 13584 from 1963.

cortical destruction of the metaphysis (Fig. 12.25C and D). The left radius and ulna are missing postmortem but the right proximal ulna does have a metaphyseal lesion that resembles the less severe skeletal pathology seen in the distal humerus. There has been some postmortem damage to the subchondral bone of the joint surfaces. However, there does seem to be some mild, focal destruction of the subchondral bone surface of the humeri. There are very few diagnostic options for this pathology. The condition is bilateral and therefore almost certainly the result of a systemic condition. It is limited to the distal metaphysis of both humeri, which would be very unusual in other forms of osteomyelitis. Smallpox seems a likely pathological condition stimulating this skeletal manifestation.

Poliomyelitis Poliomyelitis is identified in antiquity through a number of sources. An 18th Dynasty Egyptian stele (c.1500

Paget’s Disease The earliest reference to Paget’s disease in archeological human remains is a report by Pales (1929: 263 267), which includes a brief discussion of a femur from the Neolithic site at Lozere in France. The bone is part of the collections of the Museum of Natural History in Paris. There has been some postmortem damage to the joint surfaces, but otherwise they appear normal. There is considerable anterior curvature of the diaphysis with a marked expansion of the cortex. The radiograph indicates that the cortical bone in the diaphysis is reduced in density. The line drawings, published in Pales (1929) as figures 1 and 2, portray a gross morphology compatible with a diagnosis of Paget’s disease. No histological analysis was reported, making this diagnosis uncertain. The presence of Paget’s disease in Native American populations has been reported by a number of authors. Five purported prehistoric skeletons with Paget’s disease are described from the Illinois River Valley and published by Denninger (1933). In all cases, the long bones have a thickened cortex, and in some, the skulls were thickened. Histological support for the diagnoses, however, are again

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FIGURE 12.25 Possible smallpox related osteomyelitis of the elbow in a subadult skeleton from a historic site on Kagamil Island, Alaska: (A) anterior view of the distal humeri; the metaphyses are enlarged with large cloacae through both trochlear fossae; (B) posterior view of the distal humeri showing the reticulated woven bone enlargement of the metaphyses; (C) coronal CT image through the area of maximal enlargement of the right and left distal humerus; (D) coronal CT image through an area of enlargement a few slices proximal to that seen in (C). Child about 12 years of age. NMNH 377912.

absent. In view of the many diseases that can produce the lesions described by Denninger, including periostosis and osteomyelitis, these skeletons would need to be reevaluated before the diagnosis of Paget’s disease can be accepted. Fisher (1935) reports a skeleton with purported Paget’s disease from a prehistoric mound in Crawford County, Wisconsin. The skeleton consists of portions of both tibiae and a part of the lower jaw. Morse (1969: 57 58), in his discussion, asserts that the jaw fragment is normal, and that one of the tibiae, sent for study to the late Lent C. Johnson at the Armed Forces Institute of Pathology in Washington DC, displayed no histological evidence of Paget’s disease in the bone. These early studies reinforce the conclusion that Paget’s disease, like so many other conditions that affect bone, can be extremely difficult to diagnose. Rising to this challenge have been researchers adopting multiple diagnostic tools in their differential diagnosis in archeological bone. Bell and Jones (1991), Aaron et al. (1992), and Roches et al. (2002), to name a few, carefully integrate microscopy, including micro-CT (Wade et al., 2011), into their evaluations, providing robust diagnoses of Paget’s disease, while other studies use macroscopic and microscopic analyses to refute the original diagnosis

of the disease (Pinto and Stout, 2010). Two large-scale studies using carefully developed diagnostic criteria for the presence of Paget’s disease provide insight to its historic patterns and distribution. Rogers et al. (2002), for instance, in a macroscopic and radiographic study, examined the remains of 2770 individuals archeologically recovered from Barton-on-Humber, England, dated between AD 900 and 1850. In all, 15 skeletons with probable Paget’s disease were found, with 2.1% of the individuals over the age of 40 displaying the disease. Although the sample size with Paget’s disease is relatively small, they report that the prevalence of the disease was 1.7% prior to AD 1500 and 3.1% post-1500. The distribution of affected bones appear similar to clinical studies, and males appear more commonly affected. More recently, Mays (2010) explored the global distribution of Paget’s disease derived from evidence in archeological skeletons. Focusing on 109 reported skeletons meeting modern diagnostic criteria, 94% came from England, with the others from Western Europe. Mays concludes that even taking archeological bias into account, it appears likely that the frequency distribution is a reasonable refection of the geographical distribution in premodern times and that Paget’s disease might have originated in northwest Europe.

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MULTICELLED PARASITIC INFECTIONS Introduction There are a number of parasitic infectious conditions caused by multicelled pathogens that impact human health but rarely do they directly affect the human skeleton (Resnick and Niwayama, 1995a: 2535 2542). Hence, the discussion below is limited to echinococcal infection, the most common disease skeletally identified, to date.

Pathology Echinococcosis Echinococcosis is a zoonotic disease caused by an infestation of a helminth (tapeworm) in the genus Echinococcus at its larval stage. There are four species associated with this genus, two of which, Echinococcus granulosus and Echinococcus multilocularis, are principal causes of the disease in humans (Schantz, 1999: 1005). E. granulosus is associated with the formation of hydatid cysts, which are the common pathological feature of the disease. Hence, the disease caused by the infestation of this species is often referred to as cystic echinococcosis. E. multilocularis, on the other hand, produces small cysts (locules) which spread to many internal organs and it is associated with high mortality (Morris, 1994). The lifecycle of E. granulosus involves three developmental stages. The first involves dogs and other canids (foxes, wolves, coyotes, and jackals, for instance), which serve as definitive hosts (a host without which the parasite could not complete its lifecycle). Adult worms reside in the small intestines of the definitive host and then produce eggs (the second developmental stage) that are passed in feces. The eggs remain in the environment (the length of their viability depends upon climatic conditions) until they are ingested by sheep, pigs, horses, cattle, goats, or humans (all intermediate hosts). In the intermediate host, the eggs hatch in the small intestines and release oncospheres (the larval form of a tape worm), which penetrate the intestinal wall and travel through the circulatory system to other organs and areas of the body, including the skeleton. In the organ or tissue involved, the larvae form cysts, which stimulate formation of a fibrous capsule by the host. The inner layer of a fertile cyst forms many little tapeworm heads (scolices). If a cyst ruptures, each scolex can form a new cyst. The lifecycle of the parasite is complete when infected tissue of the intermediate host is consumed by the definitive host, allowing adult worms to develop again in the definitive hosts’ small intestines (Moro and Schantz, 2009). Hydatid cysts are usually well tolerated by the host and many patients today remain asymptomatic (Schantz, 1999: 1010). In contrast, the rare alveolar echinococcosis caused by E. multilocularis continues to invade and destroy the infected tissue,

producing extensive necrosis and giving the gross appearance of a malignant neoplasm. Cystic echinococcosis has a global distribution and is currently classified as an emerging zoonotic disease (Budke et al., 2006). It is endemic in southern South America, Canada, northern Africa, Australia and New Zealand, and central Asia (Eckert and Deplazes, 2004). Importantly, transmission is influenced by climatic and anthropogenic environmental factors, including changes in human-mediated animal population dynamics, spatial overlap of competent hosts, and weather conditions (Atkinson et al., 2013). Reported frequencies of echinococcosis range from 0 to 32 cases per 100,000 in hospitalbased studies, with the prevalence being higher in females and increasing with age (Budke et al., 2013). Cystic echinococcosis is uncommon in bone, and often remains asymptomatic until reaching advanced stages (Kalinova et al., 2005). The behavior of cystic echinococcosis in the skeleton differs from that in organs and soft tissues. Major cysts do not form in skeletal tissue but, rather, small cysts rupture and disseminate between the bone trabeculae, triggering osteoclastic resorption. There is often a foreign body giant cell reaction around ruptured cysts but no inflammatory reaction or fibrous encapsulation appears (Ivanissevich, 1934). Extensive permeation of the marrow spaces may cause local ischemic necrosis of the bone with the formation of sequestra. In contrast, in the few instances of alveolar echinococcosis involving bone, the microcyst dissemination may not be grossly recognizable but, as in other tissue, the parasite shows more aggressive growth and produces extensive necrosis and an inflammatory response (Klages, 1930: 141). The main difference between the two types is that the hydatid form resumes its macrocytic patterns when it escapes from the confines of bone into the soft tissue, whereas the alveolar form always maintains its microcytic destructive growth. The frequency of skeletal involvement in echinococcosis of the hydatid type ranges from 2% to 4% (Ivanissevich, 1934: 17; Jaffe, 1972: 1072; Papanikolaou, 2008) and predominantly affects the spine, ribs, and long bones (Pasquali, 1930: 369; Babitha et al., 2015). Vertebral lesions form in approximately 50% of all cases, followed in frequency by the pelvic bones. The segments of the spine most often affected are the mid-dorsal and sacral regions (Ivanissevich, 1934: 21). Although the initial lesions in the spine are small, they have the potential to enlarge at the expense of the surrounding trabecular bone. This enlargement of the lesion may compromise the biomechanical integrity of the vertebrae, resulting in pathological collapse that can resemble the kyphosis of tuberculosis (Schantz, 1999: 1010). The parasites most often settle in areas of cancellous bone with hematopoietic marrow. Although the most common site in the vertebrae is the body, the transverse

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parasite. This explains the absence of joint involvement. The outer contour of the involved bone may not be altered but scalloping of the endosteal cortical surface may be apparent in radiographs. Pathological fractures occur frequently in the late stage of the disease. Gangolphe (1894: 675) observed 25 individuals with long bone involvement with 14 pathological fractures (humerus, 5; femur, 5; tibia, 4). Ultimately, even long bones may be extensively destroyed if the cortex is transgressed and the parasites extend into the soft tissue. Reactive osteosclerosis and periosteal new bone formation are uncommon except in cases complicated by secondary bacterial osteomyelitis.

Paleopathology of Multicelled Parasitic Infections

FIGURE 12.26 Echinococcus granulosus cyst of the left scapula showing ballooning of the inferior angle and the lateral margin, with sparse reticulated new cortex. Adult. From Lord Joseph Lister’s collection, before 1912; WM S 54.1.

processes and posterior elements are more often involved in echinococcosis than in tuberculosis. In flat bones, the outer contour is often enlarged by slow destruction of the old cortex and formation of a new bony shell (Fig. 12.26). The progressive destruction, especially of pelvic bones (Doebbelin, 1898), may be extreme, leading to multiple large cystic cavities separated by residual bony septa (Fig. 12.27). The large cavities do not contain large parasitic cysts but numerous small cysts and tube-like membranes. Destruction of the floor of the acetabulum with central dislocation of the head of the femur has been observed (Raˇciˇc, 1935). In radiographs, the polycystic transformation and great reduction of bony density are apparent. In the differential diagnosis of dry bone, fibrous dysplasia has to be excluded. In this latter condition, the destruction of the bony structure between the fibrous foci is much less pronounced. The cystic form of hyperparathyroidism can offer a similar picture but would not be limited to one area. The rest of the skeleton would show other evidence of hyperparathyroidism. The distinguishing feature of echinococcosis is that the bony involvement tends to be limited to a single bone, two or more adjacent bones, or a limited region of the skeleton (Resnick and Niwayama, 1995a: 2539). In the long bones, the parasitic small cysts starting in the cancellous bone of the metaphysis may ultimately occupy the entire marrow cavity. Articular or epiphyseal cartilage forms a barrier, which is not penetrated by the

The paleopathology of echinococcosis, especially as it affects skeletal remains, offers tremendous insight into human subsistence and environmental interaction. With canids, especially dogs, serving as definitive hosts for E. granulosus, it is likely humans became inadvertent intermediate hosts commensurate with or shortly after the domestication of dogs. This is because the animals stayed close to human habitation sites and contaminated living spaces with feces, initiating the fecal oral transmission of the eggs. As humans domesticated other animals, especially sheep, these animals became convenient and plentiful intermediate hosts. Importantly, humans do not acquire the parasite directly through contact or consumption of domesticates; rather, it is the practice of feeding dogs the meat, organs, and viscera from intermediate hosts that maintains the parasite’s lifecycle. For humans, dogs appear to be the critical link in acquiring the parasite. The present and recent past geographic distribution of the disease is closely tied to the use of dogs in cattle and sheep herding. Paleopathological evidence of echinococcosis may occur in the skeleton but can be also inferred from the recovery of mineralized outer shells of hydatid cysts. For instance, one of the earliest examples of echinococcosis comes from the recovery of a hydatid cyst from an 8000year-old mortuary site in Siberia (Waters-Rist et al., 2014). This early Neolithic site yielded a large multichambered calcified cyst measuring 3.48 3 3.12 cm, which was carefully evaluated using macroscopic, CT imaging, biochemical, and stable carbon and nitrogen isotope analyses. Through differential diagnosis, the authors conclude that the morphology and biochemistry of the cyst, alongside isotope ratios, are consistent with a hydatid cyst and infection by E. granulosus. Two other cysts found in a contemporaneous mortuary site in the same region suggest that these early Neolithic groups of hunter-fisher-gatherers had a close association with canids, likely domesticated dogs, which were domesticated earlier in this region.

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FIGURE 12.27 Echinococcus granulosus cysts of the left pelvis with secondary infection and destruction of the acetabulum, 18-year duration: (A) lateral view; (B) medial view. Adult male. GHPM 4196.

Another potential example of early echinococcosis appears in Anderson (1968: 996, 1028), who provides a brief description of a fragmentary skeleton from Nubia (site 117, burial 17) that is tentatively dated by stone tool association (Qadan industry) to between 13,000 and 5000 BC (Wendorf, 1968: 990). Anderson notes a “Swisscheese-like” destructive process of the T12 L2 vertebrae that he associates with early spinal tuberculosis. There is no mention of vertebral body collapse, kyphosis, or involvement of the vertebral arches. Circular destructive lesions of the vertebral body without collapse could be an early manifestation of tuberculosis but are more suggestive of brucellosis or echinococcosis. Evidence of hydatid cysts in more recent populations appears in a number of reports. Wells and Dallas (1976) found a probable example of a hydatid cyst in the thoracic cavity of a skeleton excavated from Orton Longueville in England, a late 1st or early 2nd century AD site associated with a Belgic and early Romano-British farmstead. In the left side of the thoracic cavity, the excavators found a mineralized shell, ellipsoid in shape, measuring 47 3 35 mm. Remarkably, a calcified hydatid cyst, measuring 10.5 3 9.5 mm, was recovered from a 3rd-century urn associated with the Royal Tomb II containing comingled cremains at the Great Tumulus of Aegae in Greece. Common Macedonian artefacts and frescos depicting dogs, along with a known pastoral economy, suggest that humans and dogs were in close contact with

one another (Antikas and Wynn-Antikas, 2016). A close association between livestock and humans in 12th 13thcentury Spain may also have been responsible for echinococcosis in an adult female (Calleja et al., 2017). Further, Kristja´nsdo´ttir and Collins (2011) report on eight individuals excavated from a medieval site in Iceland dated from AD 1493 to 1554 with preserved calcified cysts in the abdomen and thorax. Each individual was over the age of 50 and two appeared to suffer from treponemal infection. The authors surmise that the close burial association of these individuals might indicate that the disease was a recognized condition eliciting distinct treatment upon death. There are New World examples of echinococcosis as well. Similar cyst-like structures are associated with an adult female skeleton from Jones Point, Kodiak Island, Alaska, United States (NMNH 374623, now repatriated). The skeleton is associated with what Hrdliˇcka called the intermediate, pre-Koniag period, which would have been before Russian contact. The skeleton is incomplete and fragmentary, but the skull and postcranial bones exhibit no external evidence of disease. Radiographs of the major long bones, vertebrae, and innominate bones do not reveal any cystic changes, with the exception of a partial cystlike structure in the cancellous bone of the right iliac crest. The postmortem damage to this bone makes confirmation of the antemortem nature of this lesion impossible. There are, however, three fragmentary, ovoid structures

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associated with the skeleton but not attached to any bones (Fig. 12.27). These fragmentary structures appear to represent three different mineralized cysts. The external surfaces of the cysts are irregular, with calcified spurs and holes in their surfaces, indicating that the external shell of the cyst was not completely mineralized. Internally, there is no evidence of bony divisions. The close association between the Alaskan Inuit and sled dogs provides an opportunistic environment for E. granulosus to thrive (Castrodale, 2003). Echinococcosis is prevalent in Alaska today, with over 101 reported cases occurring between 1950 and 1966, likely due to wolves and dogs serving as definitive hosts, and moose, caribou, and reindeer (and voles, in the case of E. multilocularis) contributing to the parasite’s lifecycle as intermediate hosts (Walsh, 1983: 50; Wilson et al., 1968).

PROTOZOAN INFECTIONS Pathology Leishmaniasis Leishmaniasis is a zoonotic disease caused by more than 20 different species of the protozoa in the genus Leishmania. Transmission occurs from primary hosts (many mammal species) to humans through an insect vector, usually by the bite of a female sandfly infected by the protozoa. In the Old World, however, anthroponotic protozoan species thrive with humans as their primary host (Desjeux, 2001). There are three major clinical syndromes of leishmaniasis (Pearson et al., 1999) characterized by whether they affect the skin, mucous membranes, or viscera. Cutaneous leishmaniasis is the most common syndrome producing ulcerative skin lesions. Leishmaniases caused by dermotropic species of protozoa are endemic in 82 countries with an incidence of approximately 1.5 million cases each year (Oliveira et al., 2011). Mucocutaneous leishmaniasis, the least common form of the disease, affects the mucosal tissues, especially of the palate and nasal septum, the oropharynx, and the larynx, as ulcerative and granulomatous lesions that can, if left untreated, lead to permanent facial disfigurement accompanied by skeletal involvement (Berman, 1997; Goto and Lindoso, 2012; Sabbaga Amato et al., 2007) (Fig. 12.28). Multiple species of Leishmania are linked with the presence of mucosal lesions (Diniz et al., 2011; Vexenat et al., 1996), with over 90% of the cases occurring in South America and Ethiopia (WHO, 2018a). Machado-Coelho et al. (2005) report that males appear to develop mucosal lesions more frequently than females, that the lesions appear more commonly in individuals over the age of 22, are associated four times more often in malnourished hosts, and four times more often in individuals who have had the disease for over 4 months.

FIGURE 12.28 Nasal lesions in a patient with leishmaniasis. Adult male, courtesy of Dr. G.P., Lombardi, Lima, Peru.

Lastly, visceral leishmaniasis, also known as kala-azar, affects abdominal organs and causes enlargement of the liver and spleen; it is fatal in over 95% of untreated cases (WHO, 2018a). Risk factors leading to all manifestations of the disease following exposure to the protozoa remain under investigation, but appear closely associated with regional ecological factors bringing hosts, vectors, and humans together, malnutrition, an immunocompromised host, and population density where sanitation is inadequate (Desjeux, 2001; Lainson, 1983; Oryan and Akbari, 2016).

Malaria Malaria is a disease caused by protozoa in the genus Plasmodium. Although there are hundreds of known species within the genus affecting reptiles and mammals, there are only five which successfully infect humans: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium knowlesi. Of the five species, P. falciparum is the most virulent, multiplying rapidly in the human host and leading to severe blood loss and possible death. Along with P. vivax, these two species are the most commonly identified malarial protozoans in patients today (Nadjm and Behrens, 2012), contributing to approximately 216 million cases of malaria in 2016 and 445,000 deaths, mostly in Africa (WHO, 2017). Children under 5 and pregnant women are at particular risk of dying from the infection (WHO, 2018b).

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Malaria is not a zoonotic disease. Rather, it is transmitted from human to human via vectors, specifically species of mosquitoes (females) in the genus Anopheles. This transmission route is important to the understanding of human disease (past and present) for two reasons: it indicates that the pathogens have successfully adapted to humans as the sole host due to the size and density of human populations living in natural or created environmental conditions that allow mosquitoes to thrive; and that the pathogen has adapted equally to specific mosquito vectors whose lifecycles facilitate the transmission of the protozoa. The geographic distribution of malaria centers on subSaharan Africa, southeast Asia, the eastern Mediterranean, and the western Pacific (WHO, 2018b); these are areas where ambient temperatures and moisture are conducive to the lifecycle of the local or regional species of mosquito, and where human populations are dense enough to support mosquitoes requiring human blood meals. The human body plays an integral part in the Plasmodium lifecycle. A human host becomes infected when a mosquito injects immature Plasmodium cells called sporozoites into the circulatory system as she takes a blood meal. The sporozoites travel to and multiply in the host’s liver cells, asexually reproducing and rapidly becoming cells called merozoites. These pathogenic organisms eventually cause the liver cells to burst, which again releases more of the pathogenic cells into the circulatory system of the host where they invade red blood cells. Within red blood cells, some merozoites will develop into female and male gametocytes. If a female mosquito inadvertently ingests gametocytes into her gut during a blood meal, the gametocytes begin to sexually reproduce and mature into sporozoites, which can then be introduced to a new human host. The clinical signs of malarial infection in a human host occur as the pathogen invades and destroys human red blood cells. In previously uninfected hosts, the severity of signs and symptoms is predicated partly on the amount of red blood cell destruction, with fever and damage to organs leading to death. In most instances, however, the human host survives, entering a chronic phase of the disease, which manifests as low-level infection, chronic hemolytic anemia, and an enlarged liver and spleen (Anstey et al., 2012) (see Chapter 14 for discussion of hematopoietic disorders). Skeletal indicators of malaria are reliant primarily on recognizing the secondary effects of reduced hemoglobin levels. A number of processes appear responsible for the disruption (Menendez et al., 2000). First, parasitized red blood cells are destroyed by the pathogen and both parasitized and nonparasitized red blood cells are removed by the body’s cell-mediated and humoral immune responses. Erythropoiesis also appears to be altered or inhibited by the presence of hemozoin-laden bone marrow macrophages (Douglas et al., 2012; Skorokhod et al., 2010).

The skeletal response to these conditions vary but have been argued to include diploic thickening of the cranium caused by marrow hypertrophy (Walker et al., 2009), cribra orbitalia and porotic hyperostosis (Gowland and Western, 2012), and localized extramedullary hematopoiesis creating tumor-like masses, associated with cortical thinning and coarse trabeculation (Dunnick, 2000; Al-Abassi and Murad, 2005). Detecting the presence of malaria through the presence of skeletal pathology alone is problematic since malnutrition, which itself may cause anemia, is a critical factor contributing to malaria-related anemia (Ehrhardt et al., 2006), and the presence of genetic anemias such as thalassemia and sickle-cell anemia are likely evolutionary ramifications of natural selection linked to the presence of malaria (see Chapter 14).

Paleopathology of Protozoan Infections Leishmaniasis Given the modern geographical distribution of highly endemic leishmaniasis in South America, it is not surprising to find the preponderance of reported paleopathological evidence of this disease coming from Chile and Peru. The earliest indications of the disease in South America are inferred from careful evaluation including differential diagnosis of 2nd- to 8th-century Moche ceramic sculptures from Peru (Urteaga-Ballon, 1991; Wells, 1964). Altamirano et al. (2005) report later evidence of the disease on five crania displaying naso-palatine destruction from an Inca population in Makat-Tampu, while Martinson et al. (2003) describe likely evidence from the Chiribaya culture dating approximately from AD 1000 to 1350, and Allison et al. (1982) report on a skeleton from Arica, Chile, dated to the 10th century. However, the greatest number of reported skeletons in the archeological record comes from San Pedro de Atacama, Chile, where Marsteller et al. (2011), evaluating multiple lines of evidence, found skeletal remains from six females displaying resorption of the nasal and frontal bones and in the maxilla-zygomatic region. In four of these cases a diagnosis was confirmed through molecular analysis. Much to the authors’ credit, a tremendous amount of contextual information was integrated into their analysis, supporting their hypothesis that migration was common between arid areas (like San Pedro de Atacama) and lowland rainforests, and that people with the disease were not stigmatized.

Malaria Although the history of malaria in human populations appears long, there has been little direct skeletal evidence for the disease to evaluate its frequency in the past. Angel (1966, 1978) argued that the presence of porotic hyperostosis in skeletal populations from areas with endemic

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malaria in living populations could be used to estimate the presence of the disease in antiquity. He postulated that malaria was present in 7th 2nd millennia BC eastern Mediterranean populations, especially in marshy environments. Aufderheide and Rodrı´guez-Martı´n (1998: 228 238), however, in their well-researched and thorough evaluation of malaria’s pathophysiology, epidemiology, and history of the disease, suggest that the body’s relatively generalized response to the disease, along with the confounding presence of malnutrition and immunological impairment, make it difficult, if not impossible, to detect and isolate malaria in the archeological record. This has encouraged researchers to try to isolate its presence through the implementation of multiple lines of evidence. Biomolecular markers, for instance, have been used to obtain direct evidence for the presence of the pathogen itself (see Chapter 8, Ancient DNA in the Study of Ancient Disease for further discussion). Taylor et al. (1997), Nerlich et al. (2008), Sallares and Gomzi (2001), Hawass et al. (2010), and Lalremrutata et al. (2013), for instance, report success in isolating genetic markers associated with P. falciparum, while Miller et al. (1994), Massa et al. (2000), and Fornaciari et al. (2010) report success in isolating proteins linked with the human immunological response to anemia. In spite of these published “victories,” issues with the reliability of the results due to high rates of false-positive and false-negative results, and the effects of degradation and contamination have elicited calls for caution when interpreting data and formulating conclusions (Setzer, 2014). This has led to efforts in synthesizing lines of evidence as a means of reducing error and creating stronger associations between the modes of detection. Massa et al. (2000), for instance, in their analysis of approximately 30 individuals from predynastic Egypt dated to 3200 BC, used a biomolecular test for the presence of the PfHRP-2 protein to immunologically detect P. falciparum alongside morphological analyses for cribra orbitalia and porotic hyperostosis. They report that 92% of the individuals examined tested positive for both indicators, suggesting that malaria was the cause of anemia in this ancient population. However, it is important to remind ourselves that finding a correlation between biomolecular indicators of P. falciparum and the presence of morphological change does not unequivocally mean that P. falciparum caused the lesions, or that finding the lesions can serve as a proxy indicator for the presence of malaria. As a means to incorporate other lines of evidence, Gowland and Western (2012) synthesize spatial analysis not only with instances of cribra orbitalia in Anglo-Saxon skeletal populations in England, but also with environmental and spatial epidemiological data suggesting conditions conducive for the mosquito Anopheles atroparvus to survive, and historical reports of the disease and its

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vector. They conclude that while estimating the presence and distribution of disease in the past is challenging, incorporating multiple means of detection of malaria’s presence during this time period can provide robust results. Smith-Guzma´n (2015a) reported on the presence of five skeletal lesions (cribra orbitalia, porotic hyperostosis, periosteal reaction, linear enamel hypoplasia, and periodontal disease) in 27 individuals whose noted cause of death included malaria or anemia. She concludes that the lesions appear associated with general systemic inflammation and hemolytic anemia, but cautions that the presence of these lesions without relevant archeological or geographical contextual information and in the absence of corroborating biomolecular evidence, has limited diagnostic power. Assuming that cribra orbitalia is a reasonable indicator of the presence of malaria, Smith-Guzma´n (2015b) examined the skeletal remains of 4760 individuals from 29 archeological sites along the Nile Valley ranging in date from 4400 BCE to 1500 CE and between the upper Nubia and the Nile delta. The author concludes that cribra orbitalia was not correlated with age at death, thus suggesting that infectious disease (malaria), rather than weaning stress or parasitic load, affected the population for millennia. While there is clearly great promise in associating skeletal lesions with the presence of malaria, caution is warranted when direct correlations between lesion presence and a single etiological factor are proposed. For instance, in some respects, arguments for the presence of malaria can be tautologous: malaria is known to be present in an area today, malaria causes anemia, anemia can cause skeletal lesions, and therefore skeletal lesions found in skeletons from archeological sites in these areas are caused by malaria. To the credit of almost all researchers, the complex etiology of anemia along with contested pathophysiological ramifications to skeletal tissue of various anemias is not ignored. It is at times, however, minimized. Similarly, differentiating the skeletal ramifications of genetically based hemolytic anemia with infectioninduced anemia, such as malaria-related anemia, may be impossible since there is little clinical evidence for skeletal change in individuals with chronic malaria. Further, linking the presence of malaria with skeletal indicators of thalassemia or sickle-cell anemia does not imply that malaria was present in that individual or population. Rather, it indicates that there may be an evolutionary history of malaria in the region leading to natural selection of particular genotypes, i.e., people have adapted to malaria. Lastly, large-scale analyses of skeletal remains displaying indicators of anemia, while potentially contributing greatly to our understanding of epidemiological trends, can also mask the presence and effects of age-specific or regionally experienced malnutrition, or coinfection with other pathogens which elicit similar skeletal responses.

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SARCOIDOSIS Introduction Sarcoidosis is a granulomatous disease of unknown etiology commonly affecting lymph nodes, lungs, and skin. Bones are involved in approximately 5% of patients (Ito et al., 2005; Resnick and Niwayama, 1995b: 4334). The presence of infections caused by Mycobacteria, Propionibacterium acne, and Coccidioides, along with a genetic predisposition and/or failure of the innate immune system, have been arguably offered as causes of the disease (Kuberski and Yourison, 2017; Mateyo and Tomeer, 2017; Sweiss et al., 2011; Verleden et al., 2001). Although the disease appears globally, differential reporting renders frequency patterns difficult to assess, but there appears to be a marked predilection for individuals of African descent (Rybicki et al., 1997). Ungprasert et al. (2016) report an incidence rate based on data from Olmstead County, Minnesota, United States, from 1946 to 2013, including Mayo Clinic data, of approximately 10 per 100,000 patients per year.

Pathology The bone lesions associated with sarcoidosis often occur in the fingers and toes, and less often in metacarpals and metatarsals. The second and third phalanges are most frequently involved (Fig. 12.29). Within the phalanges, the lesions predilect the distal epiphysis but do not break through into the interphalangeal joints. The granulomas cause purely lytic, round, or slightly lobulated defects in the spongiosa, varying from 1 mm to 1 cm in size or more. If the granuloma is located in the diaphysis, the cortex is markedly thinned and the shaft may be slightly widened, with loss of the dumbbell shape of the bone. There is usually no significant perifocal sclerosis and no sequestra formation. Perforations of the thin diaphyseal cortex by the granulomas are not uncommon and they create round defects. There is usually only minimal or no reactive periosteal bone formation. Occasionally, phalanges, especially distal, may be completely destroyed. Destruction of the nasal bones occurs secondarily to granulomas of the skin of the bridge of the nose (Holt and Owens, 1949). Bone lesions may be unilateral or bilateral. If bilateral, the lesions tend not to be symmetrical (Resnick and Niwayama, 1995b: 4337). Lytic lesions have been described in other bones, such as the skull, pelvis, long tubular bones, especially in the meta-epiphyseal spongiosa, and the vertebrae. The vertebral lesions are located in the vertebral bodies and usually spare the intervertebral discs and the pedicles (Fig. 12.30). Vertebral collapse may occur and tuberculosis must be ruled out in a differential diagnosis. Lesions usually involve multiple, sometimes widely separated, vertebrae, and they may show sclerotic rimming.

FIGURE 12.29 Radiograph of the hand of a patient with sarcoidosis. Notice the scalloped lesions (arrows) of the second and third middle phalanges. Courtesy of Dr. David Sartoris, M.D., CSD Medical Center Thornton Hospital, La Jolla, California.

In a differential diagnosis, the hand and foot lesions must be differentiated from leprosy, tuberculous dactylitis, and osteochondromatosis (Ollier’s disease). The greatest similarity exists between the bone lesions of sarcoidosis and those of lepromatous leprosy (Paterson and Job, 1964: 432). Both show the same predilection of the phalanges of fingers and toes, the lytic characteristics of the lesions, and an absence of reactive new bone formation. A differentiation of individual lesions may be impossible on dry bone alone. The cranial lesion may be more characteristic, because sarcoidosis mainly affects the nasal bones but not particularly the inferior nasal

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REFERENCES

FIGURE 12.30 Sarcoidosis of the vertebrae. Note the circular lytic lesions which spare the intervertebral discs caused by noncaseating granulomas. Courtesy of Drs. T. Demos and L. Lomasney, Department of Radiology, Loyola University Chicago Medical Center.

spine and maxilla and would not necessarily simultaneously affect the phalanges. Vertebral lesions must be differentiated from those of tuberculosis and osteomyelitis, which usually do not spare the intervertebral space and, therefore, often involve two adjacent vertebrae. The sarcoid lesions must also be distinguished from metastatic lytic neoplastic lesions which, by contrast, usually involve the pedicles and spinous processes multifocally. Sarcoidosis has not been reported definitively in the archeological record, but has been included in differential diagnoses leading to the diagnosis of other conditions in skeletal remains (Bauduer et al., 2014; Gonza´lez-Reimers et al., 2015; Lefort and Bennike, 2007; Kjellstrom, 2010).

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Yin-Murphy, M., Almond, J.W., 1996. Picornaviruses: the enteroviruses: polioviruses. In: Baron, S. (Ed.), Baron’s Medical Microbiology, fourth ed. University of Texas Medical Branch at Galveston, Galveston, TX. Available from: https://www.ncbi.nlm.nih.gov/ books/NBK7687/.

Chapter 13

Parasitology Karl Reinhard and Morgana Camacho Pathoecology Laboratory, School of Natural Resources, University of Nebraska - Lincoln, United States

When the landmark text Identification of Pathological Conditions in Human Skeletal Remains (Ortner, 2003) was published, the field of archeoparasitology was in its infancy. With advancements in research, archeoparasitology has since been established as an active subfield of paleopathology, offering diagnoses of all types of parasites: lice, fleas, tapeworms, flukes, roundworms, thorny-headed worms, and protozoa. Now, when properly applied, investigations can reveal past human parasite associations and reveal species that are not documented in the modern world. Paleopathology benefits from the cooperation of clinicians and academic researchers. Within paleopathology, archeoparasitology also profits from this cooperation, but with the added assistance of epidemiological paradigms that come from the broader field of parasitology. When populations are examined for parasite evidence, and parasitological data are quantified, then the resulting data can be compared to predictable patterns found in host parasite systems. This interplay is important, particularly when discoveries from archeology challenge epidemiological patterns. In studies of ancient infection, archeological data may be inconsistent with 20th/21stcentury clinical experience, but consistent with parasitological expectations. In such cases, reconstruction of lifestyle through archeology reveals the behaviors that resulted in unusual infection patterns. By applying pathoecological knowledge of parasite lifecycles in the cultural context of human parasite interactions, we gain an understanding of extinct infection patterns. The field has much to show about the continuity of parasitism from ancient to modern times, as well as how human behavior plays into the development of emergent disease and/or alters the state of longstanding infection patterns. In this chapter, we present four examples of current research in archeoparasitology to illustrate the nexus of parasitological theory and practice with paleopathology and archeology. These examples include the examination of human interactions with two helminth

species, a protozoa species, and an ectoparasite species. In two cases, parasitism has relevance to osteological diagnosis and interpretation. In the other cases, diagnosis is based on analysis of mummified human remains. Following these examples, we present cemetery investigations of parasitology from Russia and Korea in a discussion of the global distribution of parasites.

BRINGING ORTNER FORWARD IN TIME AND APPLICATION: ECHINOCOCCUS GRANULOSUS Hydatid cyst diagnosis was introduced by Ortner (2003) in an earlier edition of this volume, as hydatid cysts may be found in direct association with skeletons (Fig. 13.1) (see also Chapter 12, Fungal, Viral, Multicelled Parasitic, and Protozoan Infections). Hydatid cyst disease in humans

FIGURE 13.1 Hydatid cyst.

Ortner’s Identification of Pathological Conditions in Human Skeletal Remains. DOI: https://doi.org/10.1016/B978-0-12-809738-0.00013-2 © 2019 Elsevier Inc. All rights reserved.

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results from the ingestion of Echinococcus granulosus eggs. Once formed, the cysts are composed of several layers. Modified host cells form a dense fibrous outer layer that protects the cyst. The middle layer is acellular and permits the passage of nutrients to the inner germinal layer from which larval tapeworms generate to accumulate within the cyst. Calcification results from a host tissue reaction that walls off the cyst (Waters-Rist et al., 2014). The cysts most commonly form in the lungs and liver, but other tissues can be affected. Normally, the cysts are asymptomatic for months or years while they slowly grow to reach 15 20 cm in diameter after a decade. Calcification of the cysts produces durable structures that survive decomposition. Therefore, they can be found in an inhumation context. Kristja´nsdo´ttir and Collins (2011) suggest that densely calcified inactive cysts are resilient evidence of infection when found in a cemetery context. Today, paleopathologists are cognizant of the possibility of identifying calcified cysts in recovery and analysis. The central question in this endeavor and for training purposes should be, what does a cyst look like? Secondary issues include questions of which tests should be used to verify that the cyst had a tapeworm origin, how to sample the cyst for diagnostic tests, and who should be consulted to run the tests? Archeological calcified cysts appear as partial or whole spherical thin-walled structures of varying sizes. Various specimens have been published by these authors and more examples are cited in their literature reviews (Calleja et al., 2017; Kristja´nsdo´ttir and Collins, 2011; Waters-Rist et al., 2014). Single cysts are most common. However, Weiss and Moller-Christensen (1971) illustrated a case with 72 identifiable cysts and more cyst fragments in the abdomen of a medieval Danish skeleton. This study presents an early example of differential diagnosis in which ovarian cysts, kidney disease, and taphonomic processes were considered. Histological sections were consistent with premortem calcification of hydatid cysts. Since Weiss and Moller-Christensen’s work, radiology and 3D imaging of archeological cysts has become available as summarized below from Siberia (Waters-Rist et al., 2014). Theoretically, sediment from encountered cysts could be processed for the recovery of hooklets from the larval tapeworms, called scolices or protoscolices. Therefore, sediment from the cyst area and interior should be saved and compared to a parasite with tapeworm scolex morphology. Theoretically, molecular biology could be employed in such an endeavor. However, as summarized below, differential diagnosis can be assisted by epidemiology, chemical analysis, and radiology. At the time of Ortner’s (2003) writing, the differential diagnosis of E. granulosus based on cysts was far from

firm. Today, a number of laboratory methods can be used to support the diagnosis of hydatid cysts. The earliest documented cyst thus far, dating to 8000 years ago, was found in an individual from Lake Baikal, Siberia (WatersRist et al., 2014). Radiography, stable isotope analysis, and high-resolution computed tomography scanning confirmed that chemically and morphologically the sample was consistent with a hydatid cyst. Additional analytical approaches were explored in the analysis of a medieval-period cyst recovered from an individual excavated from the Santo Domingo de Silos churchyard cemetery, Madrid, Spain (Calleja et al., 2017). This specimen was examined with scanning electron microscopy in conjunction with energy dispersive X-ray spectroscopy. The morphology was consistent with that of a hydatid cyst. The elemental profile indicated a biogenic origin with some minerals moving into the cyst matrix from the surrounding soil. In these cases, diagnosis extended beyond clinical examination to detailed chemical analysis, revealing aspects of postburial taphonomic changes. Analyses of burial populations can reveal the geographic/temporal loci of infection and the cultural behaviors associated with disease. For example, two reviews of archeological hydatid cysts demonstrate a preponderance of hydatid cysts in areas where the medieval economy was based partly on sheep herding (Kristja´nsdo´ttir and Collins, 2011; Power, 2010). Regionally, Ireland, Denmark, and Iceland provided unequivocal evidence of hydatid cyst disease. Temporally, most cysts have been found in medieval contexts. Parasitologist Yevgeny Pavlovsky’s (1966) nidus concept addresses the ways in which hydatid disease can become established within a population. This concept suggests that parasite infection is dependent on the overlap of the parasite and hosts in a geographical space that favors transmission, the nidus. From the archeoparasitological perspective, this space can be as finite as a room enclosing rats infested with plague-infected fleas and susceptible human hosts. For E. granulosus, the nidus can be a farmyard where canine definitive hosts consume carcass remnants of an intermediate host sheep. Eggs passed by the dogs contaminate the products growing in the yard and are then ingested by humans. This provokes the development of hydatid cysts. This domestic nidus becomes established when eggs are introduced from outside of the domestic scene. Wild carnivores and ungulates are the usual hosts of E. granulosus (Waters-Rist et al., 2014). However, it appears that the parasite was introduced to Iceland by domestic dogs (Beard, 1973). Hydatidosis was a widespread endemic health problem in Iceland that became the focus of a strict control campaign by the late 1800s (Kristja´nsdo´ttir and Collins, 2011; Beard 1973) and was eradicated by 1950 (Beard 1973). Evidence of the

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severity of the problem was recovered from an AD 1493 1554 monastic hospital cemetery. A total of 160 graves were excavated, and calcified cysts were found in 8 (5%). In a clinical context, only 20% 30% of hydatid cysts calcify. Extrapolating the observed archeological percentage by this clinically derived value, the actual percentage of the population infected could have been as high as 20% 30%. Burials containing individuals affected by hydatid cysts were associated together in the cemetery. Ja´nsdo´ttir and Collins (2010) interpret this association as evidence that medieval monks recognized hydatid cyst disease as a distinct syndrome. This investigation suggests that careful excavation of a large skeletal series provides understanding as to how a sustained domestic E. granulosus cycle involving dogs and sheep resulted in wide human infection (Kristja´nsdo´ttir and Collins, 2011). Archeoparasitological data also can provide valuable evidence to researchers documenting the spread of parasites related to global climate change. E. granulosus is one organism that will likely spread as the climate changes (Atkinson et al., 2013). It has been proposed that the range of this parasite will be changed by interdependent anthropogenic and environmental variables. Two parasitological approaches to tracing the spread of parasites have emerged. The first approach is called D-A-MA, for documentation assessment monitoring action (Brooks et al., 2014). The D-A-M-A protocol seeks to establish a practical ability to understand, anticipate, and react to the outcomes of accelerating environmental change on parasite distribution expansion. In their 2013 publication, Atkinson and colleagues specifically target Echinococcus species for surveillance and control. Paleopathology can make a contribution to the documentation component of D-A-M-A by documenting the distribution of parasite species deep into the past. As demonstrated by the literature cited earlier, the distribution of E. granulosus has been shown for several parts of the world. It was apparently present in areas of the world where it is perceived as emergent today, e.g., in North Dakota (Williams, 1985). Further, it was common in areas where it is absent today, most notably Iceland. These differences signal that the environment was conducive for transmission in the past and could be so in the future. In their 2015 publication, Hoberg and Brooks also emphasized the interplay between climate change and an increasing risk of emerging infectious diseases (EIDs). Hoberg and Brooks (2015) note that for the last 15,000 years, the risk of EIDs was spread geographically by agriculture, animal domestication, and urbanization. These practices altered human parasite interactions and established EID patterns. However, during the past 50 years, explosive human population growth, rapid global travel, and accelerating climate change act in combination

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to make the problem of EID more acute. EID expression has become much more widespread, and most of the parasites found in the archeological record would fall into today’s EID category. As host populations shift, parasite ranges have expanded rapidly, putting parasites and humans in close proximity. Throughout prehistory, and in various parts of the world, parasites switched hosts from animal species to humans. The concept of host switching includes movement of human populations into the range of a parasite that cycles with nonhuman hosts. Humans then become a new colonization opportunity for parasites. Parasitology, applied in a paleopathological setting, has addressed this phenomenon. The expansion of human and dog populations into the Lake Baikal region 8000 years ago overlapped with the sylvatic cycle of E. granulosus. This was truly a case of EID in ancient times. In some cases, there is simultaneous change in human range expansion with the loss of the ancestral host. Among animal herders, the life cycle became domestic between dogs, livestock, and humans. Once domesticated, the cycle persists as humans move onward to a new environment where the parasites did not exist. For example, once the domestic E. granulosus cycle became established, the infection spread to Iceland and became a chronic domestic infection that affected a large percentage of the human population. Therefore, archeoparasitological data can be seen as foundational for emerging parasitological paradigms and protocols.

ARCHEOLOGICAL DATA VIOLATING CLINICAL PREDICTIONS SIGNAL FRUITFUL AREAS OF INVESTIGATION: THE CASE OF ENTEROBIUS VERMICULARIS Overdispersion refers to the phenomenon characterized by the majority of parasites existing in a small proportion of a host population. Generally, the majority of hosts have few to no parasites, while a small number of hosts carry a great number of parasites. In paleopathology, this concept has been reviewed (Camacho et al., 2018) and demonstrated for ancient parasites (Morrow and Reinhard, 2018). Overdispersion has been described as being axiomatic among parasites of a variety of vertebrate and invertebrate hosts because it is a predictable, recurring ecological pattern. Given the universality of overdispersion among parasites, we should be able to define it in archeological samples. If overdispersion can be demonstrated in archeological data, then we can feel confident that the data reflect the reality of human parasite interaction at that time and place. In some regions and time periods, the archeological prevalence of parasites exceeds any clinically recorded

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FIGURE 13.2 Well-preserved pinworm eggs from Aztec Ruins, New Mexico, from trash deposits dating between 1140 and 1230 CE.

examples. These examples truly provide new insights into the diversity of parasite human interactions. This phenomenon is illustrated by Enterobius vermicularis (pinworm) data from the desert states of Mexico and the United States. Clinically, only 5% 10% of feces from pinworm-infected individuals are positive for eggs. However, pinworm egg positivity is over 20% for coprolites from the desert states of the United States and

Mexico (Fig. 13.2). It is noteworthy that this pattern emerged with the earliest agriculture in Utah around AD 50 180, and persisted into late prehistory, around AD 1250 (Reinhard et al., 2016). Thus, the evidence shows that extreme infection of agricultural peoples persisted for over 1200 years. These results have long perplexed researchers, who concluded that the data would be more acceptable if they fit known parasite host dispersion patterns. Overdispersion characterizes host parasite associations such that it has become axiomatic that about 70% of the parasites occur in about 10% of the hosts (Fig. 13.3). Morrow and Reinhard (2018) tested whether or not the data from 100 coprolites from an archeological site in Durango, Mexico, fit the overdispersion paradigm from parasitology. These researchers demonstrated that overdispersion was evident in pinworm egg abundance in coprolites. Of 100 coprolites, 34 were positive for pinworm. The concentrations of eggs in positive samples ranged from 372 to 2985 eggs/g with an average of 373. Overdispersion was demonstrated with 9% of the samples containing 70% of the eggs. Therefore, although the prevalence was inconsistent with any clinical picture, the distribution of eggs was consistent with parasite epidemiology and the data set is demonstrably reliable. The incongruity between pinworm clinical experience and archeological data suggested that focusing on the high pinworm infection in this region and time would be a productive line of inquiry. The high prevalence of pinworm infection among individuals dwelling in desert agricultural villages was likely the result of lifestyle. By the end of the 20th century, air contamination of food, drink, and even inhalation of pinworm eggs were recognized as infection modes. Statistically, pinworm prevalence was highest in villages built within rock shelters and that reinforced the hypothesis that air FIGURE 13.3 Overdispersion of pinworm eggs from Ancestral Pueblo sites.

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contamination resulted in very high prevalences (Hugot et al., 1999). The establishment of ventilated airflow within early pithouses and later kivas could have accentuated airborne infection (Reinhard, 2008). In addition, Reinhard and Pucu de Araujo (2014) note that pinworm has multiple infection modes, through interpersonal physical contact, as well as retroinfection when eggs hatch on the perianal folds and the larvae reenter the host. In our most recent analysis of Chaco great house infection, we have found prevalence levels approaching 60% (Fig. 13.3). Crowding in great houses, communal living, and even child-rearing patterns using cradleboards could have exacerbated infection. Chisholm (2017) notes that for Navajo cradleboards, fecal and urine retention could have caused fungal and bacterial infection. From a clinical perspective, the archeological pinworm data were an impossibility. However, paleoepidemiological analysis showed that the data were consistent with parasitological expectations, demonstrating a unique pinworm epidemiology, unknown in the annals of modern medicine. Pathoecological consideration of ancient lifestyles explains why this extreme infection occurred.

CHAGAS DISEASE, MUMMIES, AND MOLECULAR BIOLOGY: ADJUSTING CLINICAL PERSPECTIVES Until parasitology became a fully developed paleopathological field, the conventional wisdom was that most major human-specific helminth parasites were excluded from the New World by a Beringian cold filter (Manter, 1967). Hookworms were believed to have been introduced with the slave trade (Coelho and McGuire, 2006). A variety of quaint conventional wisdoms defined perceptions of parasite risk in the prehistoric New World as reviewed by Desowitz (1980, 1987). Molecular biology has an important role in reforming our perspectives on parasite human interactions and evolution, as illustrated by the history of archeological investigations of Trypanosoma cruzi. The origin of domestic Chagas disease has been the subject of considerable thought. T. cruzi is the blood protozoan that causes Chagas disease. Until 1997, it was thought that T. cruzi switched hosts first in the Andes. In the original sylvatic cycle, the protozoa infected rodents and marsupials and were transmitted between mammalian hosts by kissing bugs of the reduviid family. In a classic case of host switching, as permanent villages developed with domestic dogs and guinea pigs, the nidus for infection shifted to human habitations. House walls sheltered the reduviids, which were active nocturnally, to infect humans, dogs, and guinea pigs. It was also thought that, in prehistory, T. cruzi infection spread as a

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domiciled cycle to other parts of the South and Central Americas. Thus, it was a surprise when, at the turn of the 21st century, evidence of infection predating animal domestication was discovered, as reviewed by Reinhard and Araujo (2015). The first refutation of the postagricultural origin of human infection came with the molecular analysis of 283 mummies dating from 9000 to 450 years ago (Aufderheide et al., 2004). A prevalence rate for infection of about 40% was documented for all time periods and cultures. Thus, infection was established in the earliest periods and did not vary widely later in prehistory. Humans were just one of many mammalian species infected with T. cruzi. However, the strains of T. cruzi did vary through time. Subsequent research focused on identifying the different T. cruzi strains. Six strains, evidenced by molecular discrete typing units (DTUs), were recovered from the mummies; TcBat, TcI, TcII, TcIV, TcV, and TcVI (Guhl and Aufderheide, 2010). TcBat, a strain associated with bat reservoirs, was found in one mummy. TcI is a very common DTU, widely found today across Central America to northern South America. Pathologically, it is associated with chronic cardiomyopathy and meningoencephalitis. TcII is found in Brazil, Argentina, and Chile. There, it is mostly associated with the domestic cycle of chronic forms of cardiac and digestive Chagas disease. TcIV is mostly related to sylvatic cycles in South America. TcV and TcVI have domestic cycles in southern and central South America. Chronologically, TcI was found in mummies from Chinchorro (7050 1500 BC), San Lorenzo (1500 700 BP), and colonial times. TcII was isolated in mummies from San Lorenzo (1500 700 BP), Chiribaya (1050 1250), Alto Ramirez (1000 BC AD 400), and colonial times. TcIV was isolated in mummies from Chinchorro and TcV was isolated in mummies from San Lorenzo, Cabuza (AD 400 1050) and Alto Ramirez contexts. TcVI was isolated from the site of Camerones (AD 1350). Later research indicates that T. cruzi evolved from TcBat (Guhl et al., 2014). In the modern world, the components of host switching have been defined by the Stockholm paradigm: change in climate results in ecological perturbation that drives change of faunal assembly and structure (Hoberg and Brooks, 2015). This cycle promotes diversified interaction of hosts with novel parasites, resulting in parasite shifts to novel hosts from phylogenetically unrelated existing hosts. Host colonization by parasites is explained by this perspective via the concept of ecological fitting. Ecological fitting explains the circumstance when a parasite phenotypic flexibility provides an opportunity for rapid host switching. Therefore, the parasite has traits that “fit” a new host. Although the paradigm focuses on host shift in changing climate, some of its components can be applied

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to understanding host shifts in prehistory. Indeed, the molecular data from prehistoric South America fit the Stockholm paradigm of parasite switching. T. cruzi colonized human hosts very early in prehistory as generalist DTUs (TcBAT and TC IV). Interestingly, domestic cycles evolved that may exhibit some specificity to humans. TcII emerged as a human infection as early as 3000 years ago, with TcV and TcVI emerging by 1600 years ago. This shows that macroevolutionary and microevolutionary plasticity existed in the sylvatic strains such that when human occupation overlapped the sylvatic nidi of endemic transmission, T. cruzi became an ancient emergent disease. Genotypic divergence resulted in the expansion of domestic cycles across south and central America. The continuing expansion of T. cruzi as a modern emergent infection is an expansion due to human-induced climate change (Cizauskas et al., 2017). In this example, we can see how parasitology and paleopathology define a continuum of emergent and reemergent infections from the remote past up to today.

LICE REFLECT SOCIAL ORGANIZATION, INTERACTION, AND PRIVATION The first test of prehistoric parasite overdispersion was done by Reinhard and Buikstra (2003) with lice quantified on the large series of mummies. Ectoparasites from mummies present a unique opportunity for quantification that can reveal the epidemiology of parasitism. Lice adults cement eggs to the hair shafts of people in life, and the eggs and nits (hatched eggs) remain on the shafts after death. On mummies, nits and eggs on hair shafts are a permanent record of infestation at the time of host death and for a few weeks before death (Arriaza et al., 2013a; Reinhard and Buikstra, 2003). Once quantified, the derived data can be used to estimate louse burden per individual (Arriaza et al., 2012). When the archeological and biological data from the mummies relating to status, sex, age, and other factors become available, the details of infestation risk by demographics emerge. The epidemiological data can be used to compare ancient patterns and modern patterns. They also can be to compare between ancient archeological cultures. Reinhard and Buikstra (2003) were able to quantify infestation on an individual basis by calculating the maximum number of eggs and nits cemented to hair shafts on the scalps of the 146 Chiribaya mummies from three sites in the Moquegua Valley of Peru, which date to the Middle Horizon and Late Intermediate period between AD 900 and 1250. One site, Yaral, was a herding community located inland and at a higher elevation. The second site was Chiribaya Alta, an administrative center located close to the coast and overlooking arable land and farming

communities. The third site, Algodonal, was an immigrant community of small-scale farmers. The distribution of nits and eggs among Chiribaya hosts from these sites reflects the negative binomial, which is the mathematical basis for overdispersion. This finding supports the statistical value of parasitological data when large numbers of human remains can be evaluated. Archeological comparison of Algodonal with other Chiribaya communities shows that this site represented a group of economically poor immigrants that formed a distinct and relatively destitute subpopulation. There was significant variation between the sites in the percentage of mummies infested; 18% for Yaral, 71% for Algodonal, and 36% for Chiribaya Alta. The intensity of infestation is the mean number of eggs per cm2 for infested people. This value showed some variation between the sites. The infection intensity for El Yaral was 9 nits/eggs per cm2. Chiribaya Alta infection intensity was 4.9 nits/eggs per cm2. In contrast, the intensity was much higher at Algodonal with 25.6 eggs/cm2. Demographic differences were intriguing. Adult females were more commonly infested than children at Chiribaya Alta. Children are more often infested than women at Yaral. At both sites, men had a significantly higher infestation and prevalence than women. These demographic data are inconsistent with the modern clinical experience in which children are most infested, followed by women, with men being least infested. Reinhard and Buikstra (2003) explained the unexpected higher male prevalence as a result of elaborate hairstyles that covered the scalp in braids and the use of hats. The fact that children were least often infested is evidence that children were not associated in similar social settings as modern children and also reflects more intense grooming that was focused on the children. These researchers hypothesized that combs found in mummy bundles were used for grooming, which was confirmed by a study of combs recovered with mummy bundles in Chile in which lice, nits, and eggs were trapped in 56% of the combs studied (Arriaza et al., 2014). A long-term analysis of lice from mummies has been initiated by Arriaza and his colleagues at the Instituto de Alta Investigacio´n, Universidad de Tarapaca´, Arica, Chile. In the first demographic paper by this team, 63 Chinchorro culture mummies dating from 5000 to 3000 years ago were analyzed (Arriaza et al., 2013a,b). Like Reinhard and Buikstra (2003), the Chilean team examined six 2 cm 3 2 cm areas on each mummy’s head for louse nits/eggs which were quantified. Interestingly, more Chinchorro people (79%) were infested than Chiribaya people. However, the intensity of infection was lower, with an average of 2.1 eggs/cm2 per infested individual. Chinchorro males and females did not exhibit statistically difference prevalence levels;

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76.9% of males and 88% of females were infested. The intensity of infestation did not differ statistically between males (2.2 eggs/cm2) and females (2.3 eggs/cm2). The prevalence of children less than 15 years of age was less (71%) than adults (83%). The intensity of infestation was significantly higher in adults (2.4 eggs/cm2) than children (1.2 eggs/cm2). Although some significant demographic differences between Chinchorro subgroups were found, the differences were not as striking as those within the Chiribaya comparisons. The high prevalence of Chinchorro infestation reflects a high level of sociality. The low intensities indicate an egalitarian system for grooming. In contrast, the Chiribaya expression of louse infestation reflects social complexity that resulted in the sequestering of high levels of transmission and low grooming in the immigrant community of Algodonal. Also, social distance and culture-based hairstyles and head wear resulted in Chiribaya men having very high infestation prevalence and intensity. The archeological louse studies are, in general, inconsistent with the modern clinical picture. The egalitarian nature of Chinchorro hunter-gatherers, characterized by highly social habits, resulted in high prevalence with low intensity. In contrast, the cultural complexity of the Chiribaya resulted in geographical distance between subsistence specialists, sequestration of immigrants from established societies, social distance between men and women, and cultural distance between elites and commoners. All of these factors came into play in defining the variable expression of louse infestation associated with complex societies.

Medicines and Dietary Analysis The health impact of Chagas disease can be found in archeological examples. Dietary analysis, both isotopic and microfossil, reveals the impact of gastrointestinal involvement on survivorship. In the case of megacolon from the Lower Pecos Canyonlands, dietary analysis reveals a final period of tormented existence for a Chagas disease victim (Verostick et al., 2018). The Skiles Mummy, a male who died about 1200 years ago at around 35 45 years old, was discovered by ranchers in the 1930s interred in a small rockshelter of the Rio Grande Canyon. He was “mummified” due to the casts of desiccated stomach and intestinal contents, which held the axial skeleton together. Ligaments, muscle, and cartilage maintained the appendicular skeleton integrity. The colon was distended with a mass of partly digested food consisting of grasshoppers and agave leaves (Fig. 13.4). Of the colon segments that could be weighed, 1170 g of feces were present. A large fragment had been removed for analysis in the 1980s, so the total was larger. The total

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FIGURE 13.4 Scanning electron micrograph of agave phytoliths within the Skiles Mummy fecal mass. Image by Julia Russ, Microscopy CoreResearch Facility, Center for Biotechnology, E117 Beadle Center, University of Nebraska-Lincoln.

volume of the preserved large intestine was 3710 cm3. This ancient pathology was compared to a clinical case of constipation in which the sufferer’s last year of life was documented. Immobility and the pain related to distention were extreme. The period of symptomatic pathology experienced by the Skiles Mummy in life was unknown for many years. However, application of stable isotopic analysis to the 17 cm of the mummy’s hair revealed that peristalsis and digestion ended 4 5 months before death. Prehistoric peoples in the Americas had wellestablished methods to adapt to parasitic infestations and infections. Delousing combs were used among Andean people to reduce louse infestations. Internal parasite infections were controlled largely with plants. Riley (1993) first reviewed the evidence of wormseed (Chenopodium ambrosioides) used to control infection in North America. By virtue of the worm poison ascaridole, which is present in wormseed, it appears that prehistoric cultures adapted to infection by innovated medicinal treatments. Artemisia tridentata, wormweed, was associated with a prehistoric, thorny-headed worm infection (Fugassa et al., 2011). The archeological record of parasites in the cerrado and caatinga ecological zones of Brazil provide interesting evidence of anthelmintics via pollen analysis. The prehistoric parasites found in the area include whipworm and hookworm. The biodiversity in the region offers a wide variety of medicinal plants. Two studies have focused on recovering evidence of medicinal plants (Teixeira-Santos et al., 2015). One focused on coprolites dating to 7000 8500 years from the site of Boqueira˜o da Pedra Furada, in Piauı´. Species of three genera, Anacardium, Borreria, and Terminalia, were identified as anthelmintics from archeological deposits from the

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state of Piauı´ (Chaves and Reinhard, 2006). Pollen quantification and ethnobotanical research formed the basis of medicinal interpretation. Analysis of intestinal contents from partly mummified burials provided further evidence of vermifuges. The site studied was Furna do Estrago, Pernambuco (Teixeira-Santos et al., 2015). Pollen from the genera Sida, Syagrus, and Pisonia were found in burials positive for parasites. Ethnobotanical data, pollen quantification, and pollination ecology indicate that these plants were used as vermifuges. Pollen of the species Stryphnodendron barbatiman was also found at this site in quantities demonstrating intentional ingestion of plant products. This species was found in a parasite-positive burial. Importantly, these papers present guidelines for the rigorous interpretation of pollen data from archeological contexts to ensure that medicinal interpretation is warranted from the data. The Furna do Estrago analysis is especially important for paleopathologists working with physical human remains. Discoveries of parasites and medicinal plants in burial contexts make it possible to correlate pathology evident in the burials with symptoms of parasite infections. The cultural response to the symptoms is evident in the botanical evidence of vermifugic plants or plants used to treat the symptoms of intestinal dysfunction. A different method of purging parasites may be evidenced by macroscopic vegetation remains in coprolites. The swallowing of whole leaves to eliminate parasites by primates is well-defined behavior (McLennan et al., 2017). These are “bristly leaves,” so called because of the large numbers of trichomes on the leaf surfaces. The bristles are trichomes that have been observed to trap parasitic worms, which results in the defecation of parasites (Huffman et al., 1996). This is a mechanical method of removal of parasites from the intestinal tract. It is logical that mechanical elimination of parasites via eating bristly leaves would persist in Homo sapiens populations. As noted earlier, pinworms reached very high prevalence among archeological sites in the American southwest and northern Mexico. We are analyzing diet and parasitism from three great house latrines. One latrine from Aztec Ruin, New Mexico, revealed a prevalence of 60% positivity of coprolites for pinworms. Analysis of these samples revealed bristly leaf remains of Phaseolus vulgaris (Fig. 13.5). Another well-known botanical remedy for parasitic infection, squash seeds, was also found in the coprolites. Cucurbita pepo has demonstrated values as an anthelmintic both from seed extracts and consumption of whole seeds. This site is unique among Ancestral Pueblo coprolite analysis in exhibiting a high reliance on bean leaves and squash seeds. The association of large numbers of pinworm eggs with two anthelmintic species suggests that Puebloans adjusted to pinworm infection with application of mechanical abrasives.

FIGURE 13.5 Bean leaf trichromes from coprolites positive for parasite eggs. On average, 55,000 trichomes were documented per gram of coprolite. Image by Julia Russ, Microscopy Core Research Facility, Center for Biotechnology, E117 Beadle Center, University of NebraskaLincoln.

CEMETERY STUDIES: KOREA AND CENTRAL RUSSIA AD 1500 1800 Some perceptions of the global distribution of parasites were biased by early studies that sampled only specific geographic regions. Such was the case of European studies that were dominated by whipworm (Trichuris trichiura) and mawworm (Ascaris lumbricoides). Since Pike’s (1967) documentation of these parasites in medieval deposits, every analysis of latrines, mummies, coprolites, and skeletal deposits produced evidence of one or both of these parasites (Leles et al., 2010). The preponderance of whipworm and mawworm led to a presumption that these parasites would dominate discoveries worldwide. However, the special health challenges presented by fecal contamination of villages and cities was a problem for western and central Europe. Leles and her colleagues (2010) demonstrated that the New World actually had a low prevalence of whipworm and mawworm. The rarity of fecalborne parasitism contrasted sharply with the existing data from Europe. The recovery of parasite-positive burial soils from cemetery excavations in Russia helped further demonstrate this new perspective by showing that certain parasite eggs preserve better in certain regional cemetery contexts (Slepchenko and Ivanov, 2015a,b, 2016, 2017). Among humans and domesticated dogs in central and eastern Russia, e.g., zoonotic parasites were the major parasitic challenge. These parasites included flukes and tapeworms, but the feces-transmitted roundworm parasites, so common in western and central Europe, were absent from central Russia eastward. The cultures in Slepchenko’s study area were largely herders, hunters,

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and fishers with a transitory lifestyle. This lifestyle was ill-suited to fecal contamination and transmission. In Korea, mummies and urban sediment samples are the source of parasite information. Especially in late prehistory, whipworm and mawworm were common parasites of the Joseon Dynasty elites (Seo et al., 2014, 2017). From well-preserved mummies, 88% had one or both of these parasites. Thus, fecalborne parasitism was a challenge. However, EID parasites were also an issue, as represented in 63% of mummies infected with flukes derived from crustaceans, fish, and shellfish. Therefore, in Korea sanitation and subsistence systems promoted parasite infections, even among the ruling elite.

CONCLUSION Relatively few parasites provoke pathology that can be directly observed osteologically. However, parasites exist in all human populations worldwide, and it can be said definitively that they existed in all previous human societies. Paleopathologically, they must have had an influence on community disease and cultural vitality. Russian and Korean studies show that evidence of infection can be recovered from skeleton and mummy contexts. Therefore, efforts must begin at the excavation stage to recover samples that might be positive for parasite remains. In the cases presented earlier, we illustrate various aspects of human parasite interaction. With E. granulosus, the most ancient case has an origin with a wild, sylvatic cycle into which humans and dogs intruded with resulting infections. In the case of medieval Iceland, people introduced a domestic cycle onto the island. Previously, E. granulosus was absent there. Thus, the full range of infection is represented by the E. granulosus human paleopathological record, from occasional infection among hunter-gatherers to a more chronic, common infection among sheep herders. The history of pinworm research in the desert states of Mexico and the United States is an on-going examination of how cultural developments created a crowd health problem. Architectural plans, ventilation, communal living, and child-rearing practices all exacerbated the infection. Dietary analysis shows that anthelmintic plants were used in association with high infection levels (Reinhard et al., 1985). Therefore, prehistoric treatments were improvised to control the problem. Osteologically, the evidence at this point suggests that parasitism did contribute to high levels of Puebloan porotic hyperostosis. T. cruzi and its molecular history reveal a case of ancient reemergent infection and disease, as the parasite colonized humans from endemic types adapted to animals. Over the course of a few thousand years, we see that several strains became established with domestic associations

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of humans, dogs, and guinea pigs in dwellings that promoted the proliferation of the kissing bug vectors. Pathologically, in mummies evidence of megacolon and megaesophagus signals the health threats of infection. Louse infestation, evidenced in mummies, has an especially nuanced and rich archeological record. A remarkable epidemiological contrast is evident between more egalitarian peoples and complex societies. Social stratification and division resulted in disparities of infestation between elites and deprived, men and women, and economies. In summary, since the first publication of Identification of Pathological Conditions in Human Skeletal Remains, archeoparasitology has emerged as an informative companion to paleopathology. As diagnosis continues, especially diagnoses associated with specific interred individuals, parasitism may help explain osseous changes such as porotic hyperostosis and delayed growth. This will be especially true as newer diagnostic procedures, such as molecular biology and enzyme-linked immunosorbent assay, become standardized and established as more confident diagnostic tools.

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Chapter 14

Circulatory, Reticuloendothelial, and Hematopoietic Disorders Anne L. Grauer Loyola University Chicago, Chicago, IL, United States

CIRCULATORY DISORDERS This chapter reviews a wide array of diseases linked loosely by the structure, function, and constituents of the circulatory and immune systems. As with many diseases, but especially with those classified as vascular (see Ragsdale and Lehmer, 2012), the causes of disruption vary appreciably, extending from genetic to infectious etiologies. Hence, while a wide range of conditions are included within this chapter, some, such as osteochondritis dissecans or hypertrophic osteoarthropathy (HOA), could comfortably fit within other disease categories. Furthermore, because of the circulatory link between most of the disorders in this chapter, determining the exact etiology of a particular lesion is often difficult, if not impossible. In paleopathological contexts, rigorous differential diagnosis must be employed, as careful attention to the location and anatomical details of the pathological bone and nearby tissue will be crucial in formulating a diagnosis. The following discussion is intended to highlight the diversity of circulatory, reticuloendothelial, and hematopoietic disorders, and call attention to some of their most common manifestations, or manifestations more likely to be encountered in human archeological remains.

Blood Supply of Bones The human skeletal system is heavily reliant on the circulatory system to supply oxygen, nutrients, minerals, and regulatory factors to cells, and to eliminate carbon dioxide, acid, and other metabolic waste products (Marenzana and Arnett, 2013). Experiments on animals suggest that between 5% and 15% of cardiac output is received directly by bone tissue, varying by animal, bone type, and method of detection (Ray et al., 1967; Gross et al., 1979). In spite of these variances, the vascularization of bone is

relatively consistent (Ramasamy, 2017), and adequate blood supply is an indispensable basis of bone growth and maintenance (Brooks and Revell, 1998: 3). Clinical studies of the arterial anatomy of bones have begun to identify patterns of vascularization that may lead to a higher risk for circulatory disturbance and eventually necrosis (Johnson et al., 2004). Most circulatory disturbances in archeological skeletal remains appear on long bones. For these bones, there are four separate arterial inlets: a nutrient artery of the diaphysis, periosteal arteries, metaphyseal arteries, and arteries for the epiphysis. In the diaphysis, one or more nutrient arteries enter the cortex through a grossly visible nutrient canal and divide into ascending and descending branches in the medullary cavity, supplying blood to the cortex and marrow. Periosteal arteries, themselves reliant on surrounding tissues, supply blood to the periosteum and shallowly penetrate the cortex. In the metaphysis, several smaller nutrient vessels enter through the cortex around the circumference of the bone, supplying blood to the metaphyseal cortex and marrow. Epiphyses have several small arteries, which branch from a vessel that also supplies the joint capsule and the synovium. During the growing period, the growth plate completely isolates the vascular supply of the metaphysis and the epiphysis. This structure explains why many diseases that occur during growth and development do not cross the growth plate (physis). After closure of the growth plate, some connections between the two systems are established, but the circulation, to a large extent, remains separate. The intraosseous arteries, which are enclosed in rigid compartments shielded from external pressure, are usually thin walled. This is particularly true of the arterioles. The diaphyseal cortex is, in part, supplied by ramifications of the nutrient vessels and partially by the periosteal vessels. The relative contribution of each of these two systems

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varies in different portions of the same bone. The epiphyseal vessels, which form a system of arcades beneath the articular cartilage, contribute to the nutrition of the cartilage during the growing period, before formation of a more or less solid subchondral bony plate. Cortical bone also has vascular supply through the Haversian and Volkmann canals, which connect Haversian canals and also enter directly from the periosteum. Cancellous bone trabeculae are usually avascular and depend on the vasculature of the marrow spaces for nutrition. The sinusoidal veins of the marrow are numerous, thin walled, and in hematopoietic marrow, wide. They collect into a large, thin-walled vein running lengthwise in the medullary canal. The venous return in part follows the nutrient artery, but also exits through multiple, circumferentially located venous outlets in the metaphyseal area. The epiphyseal venous return drains into that of the adjacent joint capsule. In smaller and cancellous bone, the blood supply is less complicated, except for bones that have growth plates, which always lead to separate epiphyseal and apophyseal vascular territories, at least during the growing period. The vertebral bodies show a radiant arrangement of larger veins, which converge medially and pass through two foramina close to the midline of the posterior surface of the vertebral body. These segmental veins join the longitudinal vertebral plexus in the spinal canal, which is significant in the predilection of spinal elements in infection and malignancy. The diploe¨ of the cranial vault likewise shows large interconnecting venous channels, which drain through the parietal and mastoid emissary foramina, but also have some connection with the large intracranial venous sinuses through small openings in the inner table.

Osteonecrosis Osteonecrosis (osteo 5 bone, necrosis 5 death) is a general and widely used term referring to the irreversible death of bone cells due to reduction or loss of blood supply, leading to the destruction of bone architecture. While synonyms such as avascular, aseptic, or ischemic necrosis can lead to confusion, current usage of the term avascular necrosis (AVN) tends to refer more specifically to lesions affecting the epiphyses and subchondral bone, while bone infarct is used when the metaphysis or diaphysis is affected (Fotiadou and Karantanas, 2013). Loss of blood supply, regardless of anatomical area, reduces (hypoxia) or eliminates (anoxia) tissue and cellular access to oxygen. The length of survival of bone cells following reduced oxygenation varies relative to the severity of the circulatory deficiency, but complete loss of oxygen results in bone cell death after about 12 48 hours (Sweet and Madewell, 1995: 3447).

The etiology and pathogenesis of osteonecrosis is complex and varied. For instance, osteonecrosis can be the result of trauma (Bachiller et al., 2002; Kain and Tornetta, 2015; Keating, 2015), but has also been associated with hemoglobinopathies such as sickle cell disease (Hernigou and Daltro, 2014), alcoholism (Jacobs, 1992; Takatori et al., 1993), infections such as osteomyelitis, and a long list of other conditions (Assouline-Dayan et al., 2002). Table 14.1 offers conditions that are clinically associated with osteonecrosis and are relevant to paleopathology. The clinical recognition of idiopathic osteonecrosis suggests that impairment of blood supply need not be due to a single disruption event, but rather may be associated with a repeated interruption of revascularization (Takashi and Yoshikatsu, 1992).

TABLE 14.1 Conditions Associated With the Onset of Osteonecrosis Relevant to Paleopathology Congenital Congenital hip dislocation Hereditary dysostosis Legg Calve´ Perthes disease Environmental/behavioral Alcoholism Obesity Hematological Sickle cell disease Thalassemias Hemophilia Infectious Osteomyelitis Meningococcemia Septic arthritis Septic emboli Inflammatory Pancreatitis Idiopathic Metabolic/endocrinological Chronic renal failure Cushing disease Gaucher disease Gout Hyperparathyroidism Rheumatological Rheumatoid arthritis Ankylosing spondylitis Systemic lupus erythematosus Traumatic Fracture/dislocation Burns Frostbite Keinbo¨ck disease Ko¨hler disease

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In spite of our growing knowledge of bone vascularity and microstructure, the pathogenesis of osteonecrosis remains unclear (Ma et al., 2017). In part, this is due to the multifactorial etiology of reduced flow to bone tissue. Pathogenic contributors to osteonecrosis include arteriopathy and intramedullary hemorrhage, fat embolism, intravascular coagulation, intraosseous hypertension, and fat-cell hypertrophy (Abraham and Malkani, 2004). Current research tends to focus on the association between necrosis and modern treatments, such as surgical intervention and the use of corticosteroids and bisphosphonates. However, it appears that irrespective of the etiology of osteonecrosis, hypoxia activates mature osteoclasts and inhibits the function of mature osteoblasts (Arnett, 2010), and that apoptosis of osteoblasts and osteocytes is a key constituent of the pathogenic pathway to osteonecrosis (Kaushik et al., 2012). Skeletal morphology and biomechanics factors are also correlated with the presence of the condition, as microcracks and fatigue fractures develop alongside bone remodeling, compromising bone integrity (McFarland and Frost, 1961; Yang et al., 2002). Trauma, or fracture-induced osteonecrosis may provide the most straightforward pathogenic process, as direct interruption of blood flow due to arterial damage or hemorrhage directly compromises the oxygenation of bone tissue. In infarction, larger areas of fatty bone marrow and the intervening bone trabeculae undergo necrosis, presumably due to interruption of blood circulation. The lesion is most frequently observed in the long bones of the extremities. The areas involved are principally the diaphyseal and metaphyseal marrow of the femur, tibia, and humerus. An infarction in the medullary space of a long bone undergoes mineralization at the interface between living and dead marrow. The living fat tissue at the margins of the infarct forms a mineralized margin surrounding it (Milgram, 1990: 963). Newly formed bone margins are radiographically visible as a circumscribed lesion, often up to 10 cm in length, showing a radiodense shell around the whole lesion and between its individual components (Fig. 14.1). There is little or no change in the overlying cortex. It is unknown whether mineral deposits of this type can be preserved and macroscopically identified in archeological material. Further complicating recognition and diagnosis in human archeological remains is the infiltration of soil particles into the marrow cavities of interred bones, creating areas of radiodensity that may mimic marrow infarction radiographically. Trauma-induced avascular (ischemic) necrosis of the epiphyses commonly affects the head of the femur, humerus, and talus. Importantly, however, the presence of traumatic injury and its subsequent blood flow interruption does not invariably lead to osteonecrosis (Hertel et al., 2004). Ma et al. (2017) point out that clinically,

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FIGURE 14.1 Histological preparation demonstrating a bone infarct in the distal femur. Note the central lesion surrounded by a darker-staining margin (arrow) where mineralization has occurred at the boundary with living tissue. Adult; courtesy of Dr. Bruce Ragsdale, M.D., Central Coast Pathology Associates, San Luis Obispo, California.

1 3 years can pass before postsurgical symptoms of trauma-induced osteonecrosis develop in patients, calling into question the singular role that blood flow disturbance plays in the pathogenesis of the condition.

Paleopathology Given the multifactorial causes and diverse etiology of osteonecrosis, it is not surprising that its presence is noted in the paleopathological record. With or without clear knowledge of the etiology, osteonecrosis may have occurred as early as the Mesozoic in marine reptiles (Surmik et al., 2017) and has been reported in a Late Cretaceous dinosaur (Anne´ et al., 2016). Its presence in humans reaches deep into antiquity, associated with a wide range of etiologies. The mummified remains of Tutankhamun (KV62), dating from 1333 to 1324 BC, display necrosis of the left second and third metatarsals,

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which has been associated with Ko¨hler disease and perhaps malaria (Hawass et al., 2010). A male skeleton from 1st- to 3rd-century Kazakhstan displays ankylosed carpals suggestive of traumatic AVN (Schwarz and Gresky, 2016). In North America, skeletal remains recovered from a prehistoric Late Mississippian site (AD 1540 1650) present multiple joints affected by AVN, the etiology of which remains unknown (Johnston et al., 2015). Careful consideration of the clinical literature provides important insight into the recognition and interpretation of osteonecrosis in the paleopathological record: 1. It is clear from the clinical literature that osteonecrosis develops from both extraosseous and intraosseous abnormalities (Assouline-Dayan et al., 2002; Seamon et al., 2012). 2. Paleopathological comparisons to modern studies must be made cautiously. Clinically reported frequency rates are influenced by modern surgical procedures and pharmacological intervention (Kaushik et al., 2012), type of imaging techniques employed (Steinberg and Steinberg, 2004), and the patient sample (Mont et al., 2010). 3. Sole reliance on macroscopic evaluation can compromise paleopathological diagnosis. Initial stages of the disease process are first recognizable histologically and radiographically, with macroscopically recognizable cystic and/or sclerotic changes occurring later in the disease process (Steinberg et al., 1989). 4. Predicting the behavioral effects (pain, change of gait, etc.) of osteonecrosis on the individual warrants caution. Radiographic signs of necrotic fibrovascular change, including porosis, sclerosis, or cysts (which might be macroscopically recognizable), can be clinically asymptomatic (Marcus et al., 1973; Enneking, 1997), and at times are unexpectedly identified contralateral to the area presenting pain (Mont et al., 2010). 5. For all conditions linked with circulatory disturbance, clinically derived epidemiological data must be evaluated carefully (Mays, 2017). Clinical samples, like all samples, are skewed; being based on selected patient records. For necrotic conditions, with its multifactorial etiologies, isolating an environmental cause (such as socioeconomic) from genetic, developmental, or infectious causes can be impossible.

Necrosis of the Femoral Head Necrosis of the femoral head is differentiated frequently as traumatic or nontraumatic in origin (Assouline-Dayan et al., 2002). In cases of traumatic untreated subcapital or transcervical fracture of the neck of the femur, the progression to aseptic necrosis of part or all of the femoral head can be expected (Fig. 14.2). Fielding (1980), in a

FIGURE 14.2 Aseptic necrosis of the femoral head. (A) Proximal right femur, anterior view, showing collapse and cavitation of the femoral head with a sequestrum of necrotic bone (arrow). (B) Radiograph showing reactive osteosclerosis on the border of living and dead bone. Sixtynine-year-old male with bilateral aseptic necrosis of the femoral head for several years; USPHS surgical specimen 2427, 1975; courtesy of Dr. Bruce Ragsdale, M.D., Central Coast Pathology Associates, San Luis Obispo, California.

review of the efficacy of the telescoping Pugh nail in mitigating the onset of necrosis, reported that prior to 1935, 78% of patients with femoral head fractures developed necrosis in spite of the use of manipulation and spica casts. As osteopenic or osteoporotic femoral bone is vulnerable to fracture, adult women of advanced age are particularly susceptible to femoral head necrosis (Fondi and Franchi, 2007). The femoral head is vulnerable to necrosis due to the arrangement of the blood supply. The medial and lateral femoral circumflex arteries, which rest inferiorly, branch into multiple ascending cervical arteries supplying the inferior aspect of the head. The foveal artery within the ligamentum teres vascularizes the femoral head superiorly. In cases where femoral head fracture is survived for a considerable period of time, inactivity osteoporosis is characteristically present in the surviving part of the

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femoral head and neck, whereas the necrotic portion maintains the trabecular pattern present at the time of fracture if no revascularization and new bone deposition has occurred. The necrotic portion appears dense in radiographs due to inactivity atrophy and osteoporosis in the adjacent surviving bone, the deposition of calcium into the necrotic tissue of the fatty marrow, the compression of dead bone trabeculae into a smaller area during collapse, and the deposition of new bone on dead bone in the process of repair. Traumatic AVN of the femoral head is also associated with hip dislocation. This is especially true in cases of posterior dislocation (Kain and Tornetta, 2015). In these instances, the ligamentum teres is often torn, compromising the blood supply to the medial third of the femoral head. The femoral head may become necrotic and demarcated as a sequestrum surrounded by a sclerotic rim on its base, resembling a focus of osteochondritis dissecans. Atraumatic osteonecrosis is a perplexing condition affecting any joint, but most commonly found in the hip (Johnson et al., 2014). Its presence was rarely reported prior to 1960, but has increased appreciably, associated with the growing use of corticosteroid and bisphosphonate treatment and the clinical recognition of alcoholism (Mont et al., 2010). Unlike necrosis associated with trauma, atraumatic necrosis of the femoral head is more commonly found in younger male patients between the ages of 30 50 years old (Patrascu et al., 2017; Liu et al., 2017). The necrotic bone usually appears asymptomatically in the weight-bearing area of the femoral head, beneath the articular cartilage. Joint shape plays a considerable role in the distribution of lesions. Divergent forces of concave surfaces (such as the acetabulum) lead to increased thickness of subchondral bone, and convergent forces of convex surfaces (such as the head of the femur) lead to collapse of the necrotic region due to subchondral fatigue (Simkin, 1980; Abraham and Malkani, 2004). The macroscopic and gross radiologic appearances of atraumatic necrosis are similar regardless of the etiology, known or unknown. Sickle cell anemia, Gaucher’s disease, and systemic lupus erythematosus, a disease of the connective tissue of the body, for instance, appear as unilateral or bilateral necrosis of the femoral head (Mont et al., 2010).

Paleopathology Reports of femoral head necrosis are infrequent in the paleopathological literature. This may be, in part, due to taphonomic complications, which compromise our ability to recognize the condition in skeletal remains. However, an example of a possible case is seen in a proximal fragment of a left femur (Fig. 14.3) excavated in a Native American site in Arkansas (NMNH 255142). The

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archeological age is uncertain. Most of the superior portion of the femoral head was destroyed antemortem, creating two large confluent depressions. The smallest of these is superior, lateral, and continuous with the femoral neck. The largest depression involves about one-half the area of the femoral head. There has been considerable bony reaction in the depressions, in which the exposed trabeculae have become greatly thickened, indicating a long-standing condition. On the anteroinferior margin of the articular surface there is a bony projection about 1 cm that extends inferiorly. There is noticeable periosteal bone deposition on the femoral neck that is suggestive of a low-grade inflammatory condition. This raises the possibility of a septic condition that contributed to the necrosis of the femoral head. However, periosteal reaction to an aseptic inflammation arising from trauma is also possible.

Legg Calve´ Perthes Disease and Slipped Femoral Capital Epiphysis Legg Calve´ Perthes disease is an idiopathic condition characterized by aseptic necrosis of the femoral head, resulting from disruption of blood supply to the epiphysis. While the etiology remains unknown, delayed bone age in children 4 9 years old, might lead to reduced size of the ossific secondary growth center in comparison to the cartilaginous component of the epiphysis, rendering traversing blood vessels more vulnerable to mechanical compression and damage (Little and Kim, 2011). Boys are diagnosed 5 times more often than girls, with equatorial countries exhibiting the highest incidence of the disease (Chaudhry et al., 2014). A socioeconomic correlation, with “underprivileged” populations displaying higher frequency rates, suggests a strong environmental component to this condition, rather than a genetic predisposition (Hall et al., 1983) In the course of the disease, the relative radiodensity of the necrotic epiphysis increases when contrasted with focal radiolucency of the area of the femoral neck that borders the growth plate. Later, the head flattens due to a combination of compression fracture and lack of endochondral growth. The basal bulge of the flattened head leads to subperiosteal and endochondral bone formation as well as thickening of the femoral neck. The end result, after revascularization, is a mushroom-shaped femoral head with a flared margin but with no significant shift in the center of the femoral head relative to the axis of the femoral neck. Early severe degenerative arthritis modifies the appearance and can make differentiation from the end stage of slipped capital femoral epiphysis difficult or impossible. In the acute stage, differentiation from tuberculous coxitis and from aseptic necrosis in Gaucher’s disease may be uncertain in dry bone.

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FIGURE 14.3 Necrosis of the femoral head of a left femur fragment. (A) Anterior view. (B) Radiograph of anteroposterior view. Note the radiodense sclerosis inferior to the necrotic defect. (C) Anterosuperior view of reactive bone. (D) Detailed view of reactive bone that shows the thickened trabeculae. (NMNH 255142.)

Slipped femoral capital epiphysis has a different pathogenesis than Legg Calve´ Perthes disease, although trauma is a common contributing factor. The condition presents as a stress fracture between the metaphyseal side of the growth plate and the neck of the femur. This allows medial posterior and downward displacement of the head of the femur and, not uncommonly, leads to some degree of aseptic necrosis in the epiphyseal bone. Because the growth plate remains with the epiphysis, the bone of the epiphysis is minimally altered, except in cases with extensive aseptic necrosis. The proximal end of the femoral neck, however, shows irregularities due to the fracture as well as subsequent abrasion and resorption. In dry bone, because the joint capsule and the cartilage are missing, the appearance of the proximal surface of the femoral neck is the main clue. With healing, the head, united with the neck in the slipped position, shows some dislocation of the center of the head toward the axis of the neck. In contrast, in Legg Calve´ Perthes disease, the neck is always short and thick, reflecting both attrition in the fracture area and loss of endochondral growth for varying

lengths of time. Occasionally, upward dislocation of the femur is observed to stimulate a new “acetabulum” on the lateral aspect of the ilium, while the head is held in the anatomical acetabulum by the ligamentum teres (Schinz et al., 1951 1952(1): 450 454). Similar to Legg Calve´ Perthes disease, in slipped capital femoral epiphysis early and severe degenerative arthritis complicates diagnosis. Slipped capital femoral epiphysis most commonly occurs in adolescents between the ages of 9 and 16 years old and is significantly more common in boys than in girls (Lehmann et al., 2006). The condition frequently (B20% 35%) occurs bilaterally (Loder, 1996; Loder et al., 1993). While there might be evidence of an underlying genetic factor, given that African-American and Hispanic children in the United States have been reported to suffer from the condition more frequently than those of European descent (Lehmann et al., 2006), a large international multicenter study found children of European decent with the highest rate of occurrence (Loder, 1996). The message here is that prevalence rates within and

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between populations, for virtually all pathological conditions, are contingent upon statistical sampling and the parameters of the study. Regardless of ancestry, it appears that trauma, the adolescent growth spurt, and obesity are contributing factors to the development of the condition (Murray and Wilson, 2007).

Paleopathology A right femur recovered from the Valley of Chicama in Peru provides a possible example of Legg Calve´ Perthes disease. This case is from a miscellaneous group of femora all accessioned as NMNH 265331 at the National Museum of Natural History, Washington, DC. Both the age of the individual and the antiquity of the bone are unknown. The diaphysis, distal metaphysis, and subchondral bone are normal. Part of the femoral head was damaged postmortem, although enough remains to indicate the nature of the pathology. There is a large circumscribed porous lesion covering more than half of the remaining joint surface of the femoral head (Fig. 14.4). This porosity has completely obliterated the depression for the ligamentum teres. There is a depressed groove at the boundary with normal bone. The margins of the joint surface are characterized by exuberant bony overgrowth that creates a mushroom-like appearance. This overgrowth extends well over the femoral neck. There are some bony outgrowths on the superior portion of the neck, but otherwise the neck appears normal.

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The radiographs show considerable thickening of the trabeculae under the porous lesion. This is indicated by a radiodense zone on the medial aspect of the femoral head. There are small radiolucent areas in the lateral head region and in the femoral neck. There has been considerable reduction in the mediolateral diameter of the head. Added to the marked overgrowth at the joint margins, this observation creates the false impression that the head was forced into the femoral neck. However, the normal length of the neck and the overgrowth of the joint margins make it clear that the pathological process involves collapse of the superior medial portions of the femoral head, followed by bony overgrowth on the articular margins. A possible case of bilateral Legg Calve´ Perthes disease is seen in the skeleton of an adult male from the site of the medieval hospital of St. James and St. Mary Magdalene, Chichester, England (Fig. 14.5). The skeleton is incomplete, but there is no evidence of significant osteoarthritis on any of the other bones that are present, including most of the bones of the lower extremity. The femoral neck appears to be shorter than normal, which is a feature that favors a diagnosis of slipped capital femoral epiphysis. However, both femoral heads seem to be in the correct anatomical position, which favors a diagnosis of Legg Calve´ Perthes disease. This case illustrates the diagnostic problems that can be encountered in differential diagnosis of disease in archeological human remains. Helpful criteria for differentiating Legg Calve´ Perthes disease and slipped capital femoral

FIGURE 14.4 Legg Calve´ Perthes disease in a right femur. (A) Posterior view. Notice extensive development of periarticular lipping. (B) Radiograph of anteroposterior view. Note the relatively normal length of the femoral neck. (C) Medial view of the femoral head. Note the enlargement in diameter and extensive porous degeneration. (Chicama, Peru; NMNH 265331.)

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FIGURE 14.5 Bilateral Legg Calve´ Perthes disease in a skeleton from the site of the medieval hospital of St. James and St. Mary Magdalene, Chichester, England. (A) Anterior view of the right and left proximal femur. (B) Anterior view of the pelvis. Note the extensive marginal bone formation of the right and left acetabulum. (C) Detail of the right acetabulum showing subchondral bone remodeling in response to the destruction of articular cartilage and marginal bone formation. (Adult male; UB C-13.)

epiphysis can be seen in a right femur from the miscellaneous femora from Chicama, Peru (NMNH 265331). The maximum length of this femur is 370 mm, although this value is misleading due to the inferior displacement of the femoral head. The diaphysis, distal metaphysis, and the joint surface are normal except for a moderate degree of mid-diaphyseal, anteroposterior flattening, which is due in part to the abnormal gait induced by the defective femoral head. The femoral head is displaced inferiorly (Fig. 14.6) so that the superior margin is about 15 mm lower than the greater trochanter. There is no evidence of porosity. Indeed, the joint surface is smooth and intact. The depression for the ligamentum teres is well defined, unlike that of the head in Legg Calve´ Perthes disease. Its position relative to the joint surface is much nearer the inferior, posterior margin of the joint surface than normal. The ligament attachment was maintained after the epiphysis slipped. Growth continued in the epiphysis, but occurred predominantly on the anterior and superior aspects. Ultimately, the head reunited with the neck. The femoral neck is abnormally short and thick due to the loss of growth plate activity when the epiphysis slipped. The radiograph shows an even, well-organized, trabecular

structure. It is possible to identify the growth plate of the femoral head in the film and determine that the mediolateral diameter of the head is relatively normal. In marked contrast with Legg Calve´ Perthes disease, the femoral neck is almost nonexistent on the superior aspect and greatly shortened inferiorly. Another example of slipped epiphysis is seen in a left femur of a specimen from the Historical Museum in Chur, Switzerland (HMCS GR 1582). The specimen is from the archeological site at Bonaduz in Canton Grisons, Switzerland. The epiphysis has slipped inferiorly and the femoral neck is shortened (Fig. 14.7).

OTHER DISORDERS ASSOCIATED WITH OSTEONECROSIS The following two diseases illustrate the variation in pathogenesis that is associated with a deficiency of vascular supply. Trauma seems to be a common link, but the sequence of events that lead to the diseases and the relationship between trauma and vascular insufficiency remain uncertain.

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FIGURE 14.6 Slipped capital femoral epiphysis in a right femur. (A) Anterior view displays inferior displacement of the capital epiphysis. (B) Radiograph of the anteroposterior view demonstrating the shortened femoral neck. (Adult male, NMNH 265331.)

FIGURE 14.7 Slipped capital femoral epiphysis in a left femur. (A) Anterior view. Note that the superior articular surface is below the level of the greater trochanter. (B) Posterior view. (HMCS GR 1582.)

Ko¨hler’s Disease of the Tarsal Navicular The navicular bone is in a key position in the vault of the foot. Disruption of the blood supply to the ossification center may be impaired in the growing child, leading to aseptic necrosis. This is usually expressed as flattening of the bony center, reduced size, and increased density in radiographs. Flattening may be due to compression of the

necrotic bone and/or an effect of arrested endochondral ossification in the necrotic area (Fig. 14.8). Skeletal repair can occur secondary to revascularization. The disease is uncommon, usually presents unilaterally, and occurs more often in males than in females. The onset of the disease is often noted between 4 and 5 years of age, first detected by a noticeable limp (Khoury et al., 2007; Shastri et al., 2012).

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FIGURE 14.9 Radiograph of Kienbo¨ck’s disease of the carpal lunate bone showing areas of alternating density and lucency. Courtesy of Drs. T. Demos and L. Lomasney, Department of Radiology, Loyola University Chicago Medical Center.

FIGURE 14.8 Radiograph of Ko¨hler disease of the left pedal navicular showing flattening, reduction in size, and increased density associated with necrosis. Courtesy of Drs. T. Demos and L. Lomasney, Department of Radiology, Loyola University Chicago Medical Center.

Freiberg’s Disease of a Metatarsal Head The gross manifestation of this disease is an irregular depression in the subchondral bone of the distal second metatarsal, although other metatarsal heads can be affected. The metatarsal is somewhat shortened, the head is broadened transversely, and the distal portion of the metaphysis and diaphysis is abnormally enlarged due to the necrotic collapse of the cartilage and subchondral bone (Ko¨hler, 1923). The margins of the lesion tend to be sclerotic. Lesions are often unilateral rather than bilateral. Associated with the condition is a corresponding enlargement of the articular surface of the associated basal phalanx. Although the second metatarsal is usually the longest and bears the burden of pressure against the ground, perhaps leading to trauma, impaired vascularization and systemic disorders are also etiological factors (Carmont et al., 2009; Stanley et al., 1990). Importantly, other diseases, including erosive arthropathies, may produce similar bone abnormalities, but localization to the

second metatarsal, the presence of sclerotic margins, and bone remodeling, known to occur in Freiberg’s disease, can be cautiously used to eliminate diagnostic alternatives. The carpal lunate is the center of the proximal carpal chain, and thus tends to bear the brunt of mechanical impact transmitted to the radius. Repeated trauma results in disrupted vascular supply, subsequent necrosis, and fragmentation of the lunate. Radiologically, areas of increased density and lucency alternate, and in dry bone areas may actually be fragmented after the disappearance of interposed fibrous and cartilaginous tissue (Fig. 14.9).

OTHER DISEASES ASSOCIATED WITH TRAUMA AND VASCULAR DEFICIENCY Osteochondritis Dissecans Osteochondritis dissecans involves fragmentation of cartilage and, possibly, the underlying subchondral bone (Resnick et al., 1995: 2611), although subchondral bone may not participate in the abnormality in some cases. The prevailing consensus is that trauma is a major etiologic factor, although other factors including a defect in the development of the subchondral bone, depending on the joint affected, appear etiologically important (Schenck and Goodnight, 1996; Waldron, 2009). Classic osteochondritis dissecans is associated with true separation of a

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small sequestrum, typically triangular in profile view, consisting of articular cartilage and necrotic subchondral compact and cancellous bone. The onset of disease often occurs in adolescents and young adults, and appears more commonly in the lateral portion of the articular surface of the medial femoral condyle, and more commonly in males than in females (Kessler et al., 2013). Familial occurrence has been observed (Stougaard, 1964). In the course of the disease, the necrotic fragment may pass into the joint cavity and become a loose osteocartilaginous body, which often enlarges due to continuing growth of the surviving cartilage. The cartilage may calcify, but the bone fragment remains dead and unaltered in size and shape. The subchondral osseous defect of the condyle may close over with a thin layer of bone, but always remains a depression on the bony articular surface.

Paleopathology A number of cases of osteochondritis dissecans have been reported in archeological populations. Wells (1962, 1974) and Aufderheide and Rodriguez-Martin (1998: 81 82) provide a brief review of cases. A classic case of osteochondritis dissecans, however, is found in the skeleton of an adolescent from the medieval site of St. George’s Church (burial no. 81), Canterbury, England. This burial is curated at the Canterbury Archaeological Trust. The lesion occurs on the medial condyle of the right femur and includes both the subchondral bone fragment and the depression in the condylar surface that remained when the fragment was created (Fig. 14.10). Although the shape of the fragment corresponds generally to the defect on the condyle, it is larger, which indicates continued growth after its avulsion. More recent cases of the lesion in the archeological record are reported in an analysis of 140 skeletons from The Netherlands, dated to the early to mid-19th century, where 12.9% of the adults displayed pedal osteochondritis dissecans potentially associated with repetitive trauma caused by footwear (Vikatou et al., 2017).

Osgood Schlatter Disease The tibial tubercle is the site of the insertion of the patellar tendon. It develops from one or more apophyseal ossification centers that, during the growth period, are separated from the proximal tibial metaphysis by a cartilage plate. There is considerable variation in this process, but the powerful pull of the quadriceps may lead to partial avulsion of the tendon insertion accompanied by fragmentation of the apophyseal center (Gholve et al., 2007). The avulsed fragment may eventually fuse with the epiphysis and/or tibial metaphysis. However, the fragment may remain free and result in an abnormal flattened or

FIGURE 14.10 Osteochondritis dissecans in the distal right femur in a burial from the medieval site of St. George’s Church, Canterbury, England. (A) Inferior view with bone fragment in place. (B) Inferior view with bone fragment reflected. Note that the bone fragment diameter is greater than the diameter of the residual defect in the subchondral bone. This indicates possible continuing growth of the fragment and/or healing with partial closure of the defect in the subchondral bone. (14years-old; CAT burial no. 81.)

depressed surface of the anterior, proximal tibial metaphysis. The etiology of the disease includes mechanical, growth, and/or traumatic factors (Demirag et al., 2004).

Paleopathology A possible case of Osgood Schlatter disease is found in the miscellaneous long bones from Chicama, Peru (NMNH 265330-661). This specimen is a right tibia (Fig. 14.11) from a small adult. The archeological age is unknown. The diaphysis, distal metaphysis, and distal joint surface are normal. In the region superior to the tibial tubercle there is a flattened surface. Inferior to this abnormal surface is a large irregular spur that projects toward the knee joint and is a partially ossified patellar tendon that probably reflects the trauma associated with the abnormal flattened surface. Both medial and lateral to the spur are zones of periosteal reactive bone. These are

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FIGURE 14.11 Possible Osgood Schlatter disease of the tibial tubercle in a right tibia. (A) Anterolateral view displays the bony spur. Note the defect (arrow) inferior to the joint surface possibly the result of a crushing injury. (B) Radiograph of the mediolateral view of the proximal tibia. (NMNH 265330-661.)

well healed, indicating that the condition was not active at the time of death. The proximal joint surface of the tibia is abnormal. The bony surface for the attachments of the cruciate ligaments is poorly defined. The lateral and medial joint surfaces are poorly delimited. The medial joint surface extends posteriorly, creating an irregular surface. There is a sharply defined narrow depression 11 mm long, by 3 mm wide, and 4 mm deep on the anterior lateral edge of the lateral joint surface. Grossly, this defect appears to have resulted from a crushing injury to this portion of the joint. Reactive bony spurs in the region of the tibial tubercle and reactive bone deposition are compatible with Osgood Schlatter disease. DiGangi et al. (2010) have rigorously discussed the presence of extensive cartilaginous dysplasia in an individual from Mississippian period Tennessee. Here, avulsion of both the left and right tibial tuberosities is recognized as indicators of Osgood Schlatter disease.

cartilaginous and osseous endplates and its correlation with the adolescent growth spurt. Radiographic and skeletal signatures include narrowing of intervertebral disk space, endplate irregularity, kyphosis greater than 45 degrees of three or more vertebrae angled greater than 5 degrees, lengthening of the vertebral body, and the presence of Schmorl’s nodes (Fig. 14.12) (Ali et al., 2000). Histological studies note the disorganized endochondral ossification of the endplates (Lowe and Line, 2007). The etiology of the disease remains controversial (Palazzo et al., 2014). While Scheuermann believed that AVN led to endplate disruption and growth disturbance, recent research does not corroborate this assertion (Ippolito and Ponseti, 1981). The presence of a genetic link or predisposition has been noted (Damborg et al., 2011), but mechanical stress, both repetitive and acute, are consistently recognized as essential etiological factors (Palazzo et al., 2014).

Scheuermann’s Disease

Paleopathology

Scheuermann’s disease is a perplexing condition. Unlike many vascular disruptions affecting long and sesamoid bones, this condition impacts the growth plates and secondary ossification centers (annular epiphyses) of thoracic and lumbar vertebrae, often leading to kyphosis (Scheuermann, 1920, 1921). The disease is classified as a form of juvenile osteochondrosis due to alterations to the

A few cases of Scheuermann’s disease appear in the paleopathological literature. Early occurrences have been reported by Cook et al. (1983) on a Pliocene Australopithecine skeleton from Hadar, known colloquially as “Lucy” (AL-288), by Wells (1961) on a case from 1600 BCE Bronze Age England, by Anderson and Carter (1994) reporting on a case from Iron Age England, and

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the classic expression is a dense, “lumpy” surface (Fig. 14.13B and C). The new bone is usually thickest mid-diaphysis, tapering toward the metaphysis (Fig. 14.13A) and spares the epiphyses and tendon insertions. The new bone is first fibrous and later is remodeled into lamellar bone. The new bone may be separated from the original cortex by a thin, fibrous layer, and when fully developed, several millimeters thick at mid-diaphysis. In the late stages, the underlying cortex shows resorption, widening of the Haversian canals, and at times, endosteal resorption leading to widening of the medullary cavity (Fig. 14.13C). A considerable number of conditions lead secondarily to HOA (Yap et al., 2017). Pulmonary conditions, such as cancer of the lungs and pleura, cystic fibrosis, injury, and parenchyma, as well as compromised lung circulation stemming from cyanotic heart disease, have a recognized association with the presence of HOA. Nonpulmonary associations include gastrointestinal cancers, infections such as tuberculosis and irritable bowel disease, and cirrhosis of the liver. In children, bacterial and congenital heart diseases, along with chronic lung diseases, more commonly lead to HOA (Yap et al., 2017).

FIGURE 14.12 Scheuermann’s disease recognizable in a radiograph of thoracic vertebrae displaying narrowed and lengthened anterior bodies, and substantial endplate disruption appearing as undulating, interrupted endplate borders. Courtesy of Drs. T. Demos and L. Lomasney, Department of Radiology, Loyola University Chicago Medical Center.

most recently by Viciano et al. (2017) on a case from 3rd- to 4th-century Spain. The paucity of reported incidence is more likely due to the difficulty of diagnosing the condition in skeletal remains, rather than it being a reflection of the frequency of the disease in past populations. Vertebral bodies are often recovered with substantial taphonomic damage, which would be exacerbated, no doubt, by the effects of Scheuermann’s disease.

Hypertrophic (Pulmonary) Osteoarthropathy Hypertrophic (pulmonary) osteoarthropathy (HOA) is an uncommon secondary condition characterized by skin and periosteal proliferation. Clinically, three features are diagnostically key: periostosis of long bones, digital clubbing, and synovial effusion (Pineda and Martin-Lavin, 2013). For paleopathologists, the presence of periostosis serves as the only persistent indicator, as the other two manifest in soft tissues. In skeletal HOA, symmetrical diaphyseal periostitis appears commonly in the tibiae, fibulae, radii, and ulnae, and less commonly in other major long bones or tubular bones of the hands and feet (Fig. 14.13). The morphology of the periosteal bone formation varies, but

Paleopathology Given the osteoblastic nature of HOA, it is likely that bony remnants of the condition will be recovered from archeological populations. However, differential diagnosis of HOA is challenging. Periosteal reaction is one of the most common pathological conditions encountered in the archeological record and several pathological conditions cause these lesions. Careful attention to the type and distribution pattern of periosteal lesions is thus critical. In leprosy, for example, the lesions of the tibia and fibula usually are limited to the distal diaphysis, metaphysis, and epiphysis in contrast with the mid-diaphyseal distribution in HOA. The fact that HOA is a secondary condition further complicates attempts to diagnose the primary disease. Yap et al. (2017) and Flohr et al. (2018) warn against prematurely associating HOA with a pulmonary disorder. HOA is reported in prehistoric and historic archeological populations across a broad geographic range, and even in faunal remains (Lawler et al., 2015). Its etiology is frequently associated with pulmonary tuberculosis (Mays and Taylor, 2002; Masson et al., 2013), perhaps due to the rare skeletal involvement of other disorders. However, Assis et al. (2011) report from their sample of 125 identified individuals from the Coimbra skeletal collection that HOA was 3.41 times more common in individuals with recorded tuberculosis, suggesting a true association between the primary disease and the secondary condition.

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FIGURE 14.13 Hypertrophic osteoarthropathy. (A) Anterior view of the right tibia and fibula. (B) Detail of diaphyseal pathological bone formation demonstrating the “candle wax” morphology. (C) Cross-section of the fibula, enlarged to show periosteal bone deposition and cortical bone resorption. (D) Right radius and ulna displaying diffuse periosteal hyperostosis with pronounced vascular grooving. (E) Right foot, dorsal view. Note periosteal hyperostosis of metatarsals and phalanges. (58-year-old female with large, solitary metastasis of breast cancer in lung; IPAZ 6649, autopsy 1259, 1961.)

Aneurysmal Erosion An aneurysm is the abnormal dilation of a blood vessel caused by hereditary and acquired conditions. It commonly occurs in the aorta, brain, posterior knee joint, intestine, and spleen. The aorta, in particular, appears vulnerable to this abnormality, with rupture of the aorta, whether thoracic or abdominal, being fatal. Blood vessels, regardless of location in the body, produce pulsating

pressure on closely adjacent bones, leading to normal and abnormal vascular grooves on bony surfaces. An extreme case in point is the long-term effect of a large saccular dilatation of an artery (aneurysm) to bone. For instance, the ascending portion of the aortic artery is located immediately behind the manubrium of the sternum. Aneurysms in this area can cause defects of varying depths on the posterior surface of the manubrium. Complete round perforation of the manubrium can occur. Posteriorly, the

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FIGURE 14.14 Erosion of vertebral bodies by aortic aneurysm, probably arteriosclerotic. Note the multiple deep scalloping defects that partly show a thin layer of reactive bone. (A) Lateral view. (B) Anterior view. Note the resistance to erosion of the areas adjacent to disks. (FPAM, Jubila¨umspital 593.)

descending aorta is closely attached to the left side of the vertebral column. Aneurysms of this portion of the artery may erode impact several vertebral bodies with an emphasis on the left lateral portion of the vertebral body. Because cartilage does not resorb as readily as bone in response to pulsating pressure, deeply scalloped resorption defects occur on several adjacent vertebral bodies, while the endplates adjacent to the intervertebral disks are better preserved (Fig. 14.14). The predilection for the left side of the mid-thoracic vertebral bodies is clearly apparent in another modern case from the skeleton of a 68year-old male (Fig. 14.15). The left-sided focus and the marginal sclerosis in this condition provide some help in differential diagnosis from the many other diseases that can result in destructive lesions of the vertebrae. Although not creating as dramatic a bony response, internal mammary arteries are closely attached to the posterior surface of the ribs near the osteochondral junction. In congenital extreme narrowing of the aorta below the left subclavian artery (coarctation), the internal mammary arteries show marked compensatory dilatation. In this condition, deep pressure grooves are produced on the ribs near the osteochondral junctions. Aneurysms have been linked to heritable and/or spontaneous genetic mutations, such as those responsible for Marfan and Loeys Dietz syndromes (Gelb, 2006; Loeys et al., 2007). More commonly, they are associated with acquired conditions. Abdominal aortic aneurysms, for instance, are clinically associated with the presence of atherosclerosis, as older males display the condition more frequently than females (Norman and Powell, 2007). However, a recent epidemiological study, finding little association between individuals with atherosclerosis and abdominal aortic aneurysm, calls this etiology into

FIGURE 14.15 Scalloping defects Erosion of the central thoracic vertebral bodies on the left side by an aortic aneurysm. Note the reactive bone formation at the costovertebral joint margins. (65-year-old male; IPAZ 1006/56.)

question (Blanchard et al., 2000). Thoracic aortic aneurysms have been clinically associated with syphilis (Kunz, 1980; Jackman and Radolf, 1989).

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Paleopathology Convincing evidence of the presence of aortic aneurysm is well established in the paleopathological literature (Aufderheide and Rodriguez-Martin, 1998: 81) based carefully on the presence of relatively smooth-walled erosive lesions with minimal reactive bone located in anatomical areas in close proximity to arteries. Rigorous differential diagnosis is crucial in the evaluation of aneurysms, as cysts and diseases producing a lytic bony response must be considered. Ascribing a cause for this secondary condition is even more difficult. Taphonomic processes and incomplete recovery of skeletal material can greatly impede diagnosis. In spite of these obstacles, the antiquity of aneurysm has been associated with the presence of syphilis by Walker (1983) and Kelley (1979). More recently, a pre-Columbian skeleton dated to 210 BC, has been reported to display lesions associated with aneurysm and syphilis, offering implications for the origins of syphilis in the New World (Castro et al., 2016).

RETICULOENDOTHELIAL DISORDERS The reticuloendothelial system consists of the various cells of the body that primarily function to remove dead or abnormal cells, tissues, and foreign substances. Not surprisingly, the cells are highly phagocytic, and abnormalities either in the cells or in the biological mechanisms for controlling the cells result in disease. Reticuloendothelial diseases affect the human skeleton largely through abnormalities of the histiocytes, a type of macrophage. There are two general pathologic mechanisms involved in reticuloendothelial diseases. In one of these there is an abnormal accumulation of lipids within the histiocyte. The other mechanism involves a loss of control over the proliferation of histiocytes. Both can result in skeletal manifestations, although the primary pathology is in other tissues. There are very few reports of reticuloendothelial diseases in the paleopathological literature, in part because these diseases are uncommon, but also because some of the changes that occur in the skeleton resemble other diseases, making differential diagnosis challenging.

Lipid Storage Diseases Gaucher’s Disease Gaucher’s disease is the most common of the lipid storage diseases. It is, however, a relatively uncommon familial abnormality linked to multiple known autosomal recessive mutations that affect lipid metabolism. The presence of the mutations is associated with a deficiency of the enzyme glucocerebrosidase (Hruska et al., 2008). In this disorder, cerebrosides are accumulated in histiocytes (macrophages) of the reticuloendothelial system,

especially in the spleen, liver, lymph nodes, and bone marrow (Charrow et al., 2000). The disease is classified into three types: type 1, which is a chronic and nonneuronopathic form affecting all organs except the brain in adulthood (most frequently in Jews of Ashkenazi descent) (Grabowski, 1997); type 2, which is a fatal neuronopathic form affecting infants; and type 3, a chronic/subacute neuronopathic form affecting juveniles and young adults. Types 1 and 3 affect the skeletal system. Bone changes associated with the disease are due to the accumulation of cerebroside-laden histiocytes, called Gaucher cells, in bone marrow. The accumulation may be diffuse or in the form of nodular aggregates. The deposition, although widespread throughout the skeleton, does not involve all bones equally. Diffuse infiltration in hematopoietically active bones (vertebrae, sternum, ribs, pelvis, and cranial vault) is most common, but bone infarcts, AVN, lytic lesions, and fractures due to osteopenia or osteoporosis in other skeletal elements have also been associated with the disease (Mikosch and Hughes, 2010). The presence of Gaucher cells leads to a widening of marrow spaces and reduction of the number and diameter of bone trabeculae, giving a coarse, spongy appearance in radiographs and in dry bone. Focal concentrations of abnormal histiocytes may also result in cortical scalloping and thinning, with the periosteal surface remaining smooth. The long bones, most commonly the distal diaphysis and metaphysis of the femur, may become the seat of nodular and diffuse infiltration with Gaucher cells, resulting in a modeling defect and an abnormally enlarged bone diameter. Instead of the usual concave flare, the bone shows a straight contour or even a slightly bulging outline, giving rise to the descriptive term Erlenmeyer flask deformity (Fig. 14.16). This deformity can be due, in part, to inhibited modeling during the growth period or actual enlargement of the thin metaphyseal cortex in adult life. The nodular infiltration may also lead to complete trabecular resorption in the affected area, giving a lytic appearance in radiographs and a cystic defect in dry bone. Wenstrup et al. (2002) report that skeletal involvement appears as three processes: irreversible focal bone changes such as osteonecrosis and osteosclerosis, local bone change such as cortical thinning and long bone deformity, which appear adjacent to areas greatly affected by marrow involvement, and generalized osteopenia.

Niemann Pick Disease Niemann Pick disease is a rare, congenital, familial disorder of phospholipid metabolism that leads to progressive storage of phospholipids (mainly sphingomyelin) in the reticuloendothelial cells of the liver, spleen, lymph nodes, and bone marrow. Inheritance patterns suggest that multiple mutations are associated with the disease, all

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FIGURE 14.16 Radiograph of a juvenile distal femora displaying Gaucher’s disease with modeling during growth. Note the enlarged metaphyses. Courtesy of Dr. Morrie E. Kricun, M.D., Department of Radiology, University of Pennsylvania Medical Center, Philadelphia, PA.

believed to be autosomal recessive (Simonaro et al., 2002). Three main types of Niemann Pick disease have been identified (A, B, and C), which vary in clinical manifestations, age of onset, and mutated gene. Type A appears more frequently in individuals of Ashkenazi Jewish decent, while type B is more common in individuals of Turkish, Arabic, and North African decent (Simonaro et al., 2002). Bone changes, including a reduction of the number and the size of trabeculae, cortical thinning of long bones, and the Erlenmeyer flask, appear in some long bones, rendering differential diagnosis from Gaucher’s disease difficult. However, the enlargement of the long bone metaphysis seems less severe than in Gaucher’s disease (Crocker and Farber, 1958: 82). Osteonecrosis is not associated with Niemann Pick disease. This means that collapse of the subchondral bone in long bone epiphyses does not occur. This, along with the absence of focal lytic lesions (Gildenhorn and Amromin, 1961), provides helpful distinctions in differential diagnosis. The generally poor health of affected infants may manifest itself in delayed appearance of secondary ossification centers. Superimposed deficiency in vitamins D and C may add features of rickets and scurvy to the picture.

Other Lipidoses Essential familial hypercholesteremia is a disorder of cholesterol metabolism linked to a genetic mutation. The condition is characterized by elevated blood cholesterol levels and often leads to tumor-like deposits of cholesterol in subcutaneous and periarticular connective tissues or

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tendons (xanthoma tuberosum). Observed erosive bone changes are believed to have an intraosseous origin (Bjersand, 1979). Lipid (cholesterol) granulomatosis (Erdheim Chester disease) is a rare disorder characterized by massive cholesterol deposition in the bone marrow and occasionally in other organs, but sparing the spleen. The condition remains asymptomatic into adult life. The reason for mentioning it here is that distinct bone changes have been demonstrated radiologically and anatomically (Dion et al., 2006). The most marked lesions were found symmetrically in the long bones of the forearms and lower legs. The changes consist of spotty and diffuse osteosclerosis, most pronounced in the metaphyseal area, but often involving the epiphysis. The diaphyseal cortex may be thickened, but shows widened Haversian canals. The changes extend into the bones of the hands and feet, most markedly so in the talus and calcaneus. The femur and humerus are less affected and the skull is normal. The sclerosis observed is due to both trabecular thickening and ossification of medullary cholesterol granulomas.

Langerhans Cell Histiocytosis (Histiocytosis X) Langerhans cell histiocytosis (LCH) was originally described as histiocytosis X (Lichtenstein, 1953). Recognition of the diagnostic significance of the abnormal histiocytes known as Langerhans cells has led to the more recent terminology for this disease. Langerhans cells are histiocytes that contain abnormal cytoplasmic granules. As macrophages, histiocytes are normally responsible for the removal of abnormal and dead cells. Recent studies using cell-specific gene expression profiling suggest that LCH arises from bone marrow-derived immature myeloid dendritic cells, rather than from epidermal Langerhans cells (Harmon and Brown, 2015). There are a number of classification systems used to categorize LCH. For paleopathological evaluation, however, the recognition of three clinical manifestations is germane: Letterer Siwe disease (disseminated multifocal multisystem LCH), Hand Schu¨ller Christian disease (multifocal unisystem LCH), and eosinophilic granuloma (unifocal LCH). Satter and High (2008) report a widely varying incidence of unifocal bone involvement in clinical reports ranging from 28% to 83% of patient cases, and multifocal involvement in 19% 28% of patients. Children display an overall higher incidence of bone involvement than adults. The common link between the three conditions is proliferation of histiocytes in various tissues and organs. Although bone lesions are similar in all three conditions, their distribution may vary. Bone lesions generally present as a central, purely lytic, lesion with or without sclerotic margins or reactive bone formation. The small

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lesions are round or oval and may coalesce, creating an undulating or “geographic” border (Fig. 14.17). In Letterer Siwe disease, multiple skull lesions are usually present, involving the cranial vault and base, especially the sphenoid. In some cases, facial bones are involved. In eosinophilic granuloma, the most common lesion is a solitary, purely lytic, round or oval defect in an area of the cranial vault, showing a beveled edge and, occasionally, a central sequestrum. In Hand Schu¨ller Christian disease, large, multiple, confluent cranial defects are often seen (Fig. 14.18). The lesions of the cranial vault, even after destruction of both tables, are usually devoid of periosteal reactive bone, although in some cases marginal sclerosis of a lytic focus may occur. In eosinophilic granuloma, destructive focal involvement of the mandible is not uncommon: the teeth become elevated, creating the appearance of “floating” teeth in radiographs. Lesions of the vertebral bodies, especially in small children, often lead to collapse, creating the appearance of flattened vertebral bodies (vertebra plana). The involvement of long bones is also primarily subcortical, mostly metaphyseal, less commonly mid-diaphyseal, and rarely epiphyseal. If the overlying cortex is destroyed, subperiosteal reactive bone formation does occur. Rib lesions may circumferentially erode the old cortex and expand the diameter, eliciting some sclerotic response in the new cortex. Pathological fractures can occur in long bones and ribs.

abnormalities seen in the Paleolithic Cro-Magnon Skeleton No. 1 to LCH, although he recognizes the challenges in differential diagnosis. Strouhal (1976 1977) describes Hand Schu¨ller Christian disease in two individuals (a young adult and an adolescent) from the Nagaed-Der cemetery dated to the 5th 6th Dynasties of the Old Kingdom in Upper Egypt, and Campillo (1977) describes three possible cases of eosinophilic granuloma from archeological sites in Spain. Lastly, Barnes and Ortner (1997) describe destructive lesions on an adolescent skeleton from a medieval cemetery in Corinth, Greece, with destructive lesions limited to the skull, possibly due to the incomplete preservation of the skeleton (Fig. 14.19).

HEMATOPOIETIC DISORDERS Anemias The term anemia describes pathological symptoms linked to a variety of abnormalities of red blood cells, which affect the circulatory system’s ability to exchange oxygen. The condition can be clinically linked to excessive red blood cell destruction caused by malaria (Ha˚kan, 2003), or to excessive red blood cell loss due to parasitic or bacterial infection, injury, menstruation, or childbirth. It can

Paleopathology In spite of the rarity of LCH, there are a few cases reported in the archeological record. Thillaud (1981 1982) attributes the largely destructive

FIGURE 14.17 Radiograph of humoral lesion associated with Langerhans cell histiocytosis. Note the coalescing oval lytic lesions with undulating borders, the absence of sclerotic margins, and in this case, reactive periosteal bone formation. Courtesy of Drs. T. Demos and L. Lomasney, Department of Radiology, Loyola University Chicago Medical Center.

FIGURE 14.18 Langerhans cell histiocytosis: cranial vault with multiple penetrating defects that show geographic contours and little reactive bone. Multiple destructive lesions were found in many bones. (31/2 years known duration; IPAZ autopsy 1328, 1955.)

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FIGURE 14.19 Probable multifocal eosinophilic granuloma in an adolescent skeleton from a medieval cemetery in Corinth, Greece. (A) Top view of the right and left parietal bones with multifocal lytic lesions. (B) Scalloped edges of a large lytic lesion in the occipital bone. (C) Sclerotic margins of the occipital lesion. Adolescent ca. 13 years; courtesy Dr. C. K. Williams II and the American School of Classical Studies in Athens.

also be caused by insufficient or abnormal red blood cell production caused by poor dietary intake or absorption of iron and essential vitamins (e.g., A, B12, folic acid), increased need for nutrients due to growth or disease (such as diarrheal diseases), infectious disease, and hereditary (genetic) hemolytic disorders (Camaschella, 2015). Importantly, parsing a single cause is often impossible, as a suite of conditions, leading to compromised health, are often concomitantly found in human populations (Verhagen et al., 2013) (Fig. 14.20).

Thalassemia Thalassemia is a pathological condition linked to deficient synthesis of hemoglobin due to alterations in genes creating alpha and beta globin protein chains; both needed for the production of a healthy hemoglobin molecule. Four genes on homologous chromosome 16 are responsible for the production of alpha globin, while two genes on homologous chromosome 11 contribute to the production of beta globin. The two main categories of thalassemia are based on whether the abnormality results from deficient synthesis of the alpha or the beta hemoglobin chain. In alpha thalassemia, if one of the four genes contains one or more of the 100 known allelic variants (often deletions) (Piel and Weatherall, 2014), the carrier is usually asymptomatic. However, if two or three of the four genes contain deletions (manifestations of three genetic mutations is known as HbH disease), the individual displays mild to

moderate microcytic red blood cells and hemolytic anemia (Galanello, 2011). If all four alpha globin genes are affected, the result is a fatal condition known as hemoglobin Bart’s hydrops fetalis. In beta thalassemia, an inherited mutation of one gene on chromosome 11, responsible for the production of beta globin, may result in a condition referred to as thalassemia minor, which is asymptomatic, or thalassemia intermedia, with a range of clinical symptoms. When two genes on the homologous loci carry one of the 200 known mutations at this locus, the resulting condition is classified as thalassemia major (Cao and Galanello, 2010). Predicting the systemic, let alone the skeletal effects of many of the globin mutations is difficult, as wide genotypic variation leads to even greater variation in phenotypic responses (Taher et al., 2006), and environmental factors impact the presence of symptoms (Weatherall, 2001). Both alpha and beta thalassemia have wide geographic distributions, likely associated with genetic selection by the presence of malaria. Both alpha and beta thalassemia appear in elevated frequency in tropical and subtropical regions such as Southeast Asia, the Mediterranean area, the Indian subcontinent, the Middle East, and Africa, with alpha thalassemia extending more widely into southeast Asia and continental Africa (Piel and Weatherall, 2014). A detailed discussion of the geographic, ethnic, and genetic problems of this disease complex has been offered by Rucknagel (1966). Although helpful in understanding the genetic factors that contribute to the disease, the

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Hereditary

Thalassemia

Compromised hemoglobin molecules

Infection

Sickle cell anemia

Microbial and parasitic

Compromised RBC formation

Hemolysis

Inflammation

↓ Eurethropoeisis

Diet

Vitamin deficiency A,K,B12

Blood loss

Phagocytosis

Iron deficiency

Blunted villi

↓ Micronutrient absorption

Anemia FIGURE 14.20 Multiple pathways of clinically recognized anemia. Numerous etiological factors contribute to the complexity of diagnosis and the unlikelihood of attributing a single cause of anemia in archeological populations. Although variables contributing to anemia are represented here as unidirectional, the interrelationship between the variables is far more complex. Adapted from Foote et al. (2013).

skeletal manifestations of all types of thalassemia are the same, so differentiating between them in archeological human remains on the basis of anatomical features is impossible. Skeletal changes have been associated with HbH and intermediate thalassemia. Bone lesions are entirely due to compensatory hyperplasia of bone marrow leading to expansion of the marrow cavity (Helmi et al., 2017). In keeping with the general distribution of hematopoietic marrow, the entire skeleton of the child is usually affected, more or less uniformly, whereas in the adult, characteristic bone changes remain only in areas of permanent hematopoietic activity. Baldini et al. (2014) report that bone disease was observed in 76% of their sample, osteoporosis in 49%, and osteopenia in 51%. The most severe changes associated with thalassemia are in the skull. In children, the diploe¨ of the cranial vault enlarges, leading to marked thickening of the cranial vault, usually beginning in the upper portion of the frontal bone (Fig. 14.21A C). The trabeculae of the diploe¨ are reduced in number and accompanied by thickening, and later radial rearrangement of the remaining trabeculae. The external table is progressively impacted and subsequently completely destroyed. This is accompanied by honeycombed compartments of subperiosteal new bone that harbor hyperplastic marrow. The destruction of the inner table comes much later and is always much more limited than that of the outer table. In radiographs of severe cases, the honeycombed compartments create the appearance of “hair-on-end” rays perpendicular to the normal bone surface (Fig. 14.22). The external dimensions of the facial bones, especially the maxilla and

zygoma, are enlarged, and show thin cortices and loose spongiosa producing prominent cheek bones, referred to as chipmunk facies. Development of maxillary and sphenoid sinuses, as well as the mastoid cells, is inhibited and delayed (Caffey, 1957, 1972[1]: 89). Ethmoid sinuses are better developed because there is little marrow in these bones. The involvement of the maxilla and, to a lesser extent, of the mandible leads to disorderly eruption of the teeth and malocclusion of the jaws. In general, the reduction of the total mass of trabecular and cortical bone throughout the skeleton leads to arrangement of the remaining trabeculae along stress lines to give maximum mechanical stability with minimum encroachment on marrow space. This is most pronounced in ribs, where the cortex can be completely missing and the trabeculae show diagonal arrangement with occasional buttressing trabeculae approximately perpendicular to the main trabeculae (Fig. 14.21D and E). Linear reinforcement occurs on the concave surface in response to respiratory bending stresses. The diameter of the ribs is enlarged. Similar enlargement and alteration of the trabecular pattern are seen in flat bones (pelvis and scapulae), and show a fan-like pattern in radiographs. In addition to porosis, the vertebrae show decreased height, increased width, and cupping of the endplates. Actual compression fractures occur, especially in the lower thoracic and lumbar vertebrae. In children, metacarpals, metatarsals, and phalanges show enlargement with diagonally crossing trabeculae and reticulated thin cortices. Long bones of the extremities show marked widening of the medullary cavity accompanied by thinning of the cortex, most pronounced in the femur. In the metaphyseal

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FIGURE 14.21 Thalassemia major involving multiple bones in a child. (A) External view of the frontoparietal segment of the cranial vault. (B) Endocranial view. (C) Cross-section that shows widening of the diploic spaces and honeycombed buildup of subperiosteal bone replacing the outer and inner tables. (D) Longitudinal cut (left) of the proximal tibia that shows widening of the epiphyseal and metaphyseal marrow spaces and of the medullary cavity, marked thinning of the cortex, and lines of arrested growth. External view (right) of the distal radius that shows lace-like reduction of the metaphyseal cortex. (E) Rib plural surface that shows extreme lacy cancellization of the cortex. (8-year-old Thai studied by Dr. W. J. G. Putschar, M.D. in 1962, Department of Pathology, Medical School, Chiengmai, Thailand.)

area, the cortex may become reticulated and have markedly enlarged vascular foramina, containing hyperplastic marrow. There is often inhibited remodeling of the distal femoral metaphysis, leading to a widened contour that does not have the usual concave flair and closely resembles the Erlenmeyer flask deformity seen in Gaucher’s disease. Multiple “lines of arrested growth” are frequently present and indicate growth initiation after a period of inhibited growth due to severe illness. Delayed

epiphyseal closure is also observed in this disease. In some cases, premature and irregular fusion of the growth plate occurs, especially of the proximal humerus, leading to an abnormal medial angulation of the humeral head. In the series published by Currarino and Erlandson (1964), 12 of 79 thalassemia patients showed premature fusion of growth plates beginning after 10 years of age that produced shortening and deformity. Of these, nine involved the proximal humerus (three bilateral) and three involved

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FIGURE 14.22 Thalassemia major involving the cranium of a child. Note the extensive hair-on-end ectocranial surface created by subperiosteal new bone. Courtesy of Drs. T. Demos and L. Lomasney, Department of Radiology, Loyola University Chicago Medical Center.

the distal femur (one bilateral). Generalized growth stunting in children has also been noted (Foote et al., 2013). In adults, the tubular bones of the hands and feet resume normal contours and may develop some osteosclerosis subsequent to the replacement of erythropoietic marrow by fatty marrow (Caffey, 1972 [2]: 1284). The widening and reticulation of the ribs remains mostly in the posterior portions and, rarely, may lead to a tumorlike expansion of erythropoietic marrow covered by a thin, enlarged, cortical shell that projects into the thoracic cavity. Changes in the vertebrae and, to a lesser extent, in the cranium remain. Pathological fractures, especially of the femur, occur in adults more frequently than in children. In the differential diagnosis of dry skeletal elements, other hemoglobinopathies, congenital spherocytic anemia, and iron-deficiency anemia (IDA) must be considered. The cranial changes of thalassemia occasionally resemble those in sickle cell anemia, but the extensive lesions of the rest of the skeleton do not. Cyanotic congenital heart disease (Ascenzi and Marinozzi, 1958) and, rarely, polycythemia (Dykstra and Halbertsma, 1940) can mimic the skull changes in thalassemia. In congenital hemolytic anemia and IDA the bone changes are less severe and do not affect the facial bones.

Sickle Cell Anemia and Its Genetic Variants Sickle cell anemia is a genetic anemia that occurs when the autosomal recessive gene (hemoglobin S) is present in the homozygous condition (HbSS). Individuals with one

sickle cell gene and the normal hemoglobin A gene (SA) have the sickle cell trait. The abnormality in the hemoglobin occurs on the seventh codon of the beta chain and involves the substitution of the amino acid valine for glutamic acid. In spite of the disease being associated with a single gene Mendelian disorder (homozygosity for HBB glu6val), the noted phenotypic variations are great, suggesting that environmental and epigenetic factors are critical to symptomology (Steinberg, 2009). The gene for hemoglobin S is predominantly found in people of African descent, with instances in Mediterranean populations (southern Italy, Greece, and Armenia). Gene frequencies exhibit a strong geographical link with areas of high malaria endemicity (Piel et al., 2010). There are three other genetic variants associated with sickle cell disease. Hemoglobin SC disease is the second most common type of sickle cell disease. It is a heterozygous form of the disease, where HbS is inherited from one parent and the variant HbC gene from the other. Individuals with HbSC have similar but less severe symptoms than individuals with HbSS. Hemoglobin SB 1 (beta) thalassemia is another variant, which affects beta globin gene production. If this gene is inherited with the HbS gene, the size of the red blood cell is reduced due to reduced production of beta protein. Symptoms are not as severe. Sickle beta-zero thalassemia is the third type of sickle cell disease, displaying symptoms similar, but at times more severe than HbSS anemia. Individuals with this disease have a particularly poorer prognosis. Individuals with homozygous SS develop hypoxemic stress when tissue oxygen needs exceed availability, usually met through exchanges between red blood cells and body tissues. In this hypoxemic state, the erythrocytes will assume a sickle shape due to crystallization of the abnormal hemoglobin within the cell. The abnormal red blood cells have a shorter lifespan and are less effective in transferring oxygen, creating an increased demand for red cell production to compensate for increased cell turnover and decreased oxygen exchange. Additionally, during hypoxemic crises, the misshapen red blood cells conglutinate and cause vascular obstructions, leading to areas of ischemic necrosis and infarction. Although the genetic abnormality is present at birth, clinical manifestation is prevented before 6 months of age due to the protective effect of the high concentration of fetal hemoglobin F. The mortality rate of infants and children with sickle cell anemia is high. In persons with sickle cell trait (SA), only extreme hypoxemic stress can produce hemolysis and infarctions. Persons with the genetic combination of sickle cell trait and persistent fetal hemoglobin (SF) are usually free of anemia. Sickle cell disease manifests in the skeleton in three different ways: (1) changes secondary to increased demand of space for hematopoietic marrow; (2) sequelae

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of vascular obstruction of smaller and larger blood vessels; (3) secondary infections superimposed on ischemic areas. Although a variety of bone changes have been described in sickle cell anemia, it should be emphasized that, as a rule, they are not common, obvious, or specific. A careful and detailed study of bone changes in this disease was published by Diggs et al. (1937) in a series of their own cases. Their series comprised 39 patients of African descent who had active severe sickle cell anemia and ranged in age from 1 to 51 years old. The data included eight autopsies at which special attention was paid to bone changes. The frequency and degree of bone involvement increased with age beginning in children past 5 years of age. The bones most likely to reveal alterations were the skull, vertebrae, tibia, and fibula; the cranial changes appear the earliest. Diggs et al. found that the majority of patients showed no alteration in bone size, shape, and density in radiographs. There is general agreement among all observers that bone changes are not related to the severity of the disease. The first and most conspicuous changes are observed in the skull. The diploe¨ may be enlarged and there may be diminished definition of the outer table in radiographs. The radiation density is diminished, sometimes with coarsened trabeculation arranged perpendicular to the inner table. Complete destruction of the outer table with hair-on-end orientation of bony septa is uncommon: it was present in only 1 of 39 cases cited by Diggs et al. (1937). They also found diploic enlargement to be bilateral, symmetrical, and usually limited to the parietal bones, less often involving the frontal and occipital bones. The maximal enlargement occurs in the vertex, tapering to normal toward the temporal area. Cranial changes are most often observed in older children and in young adults. Occasionally osteoporosis may lead to small focal lytic lesions that resemble myeloma. The facial bones showed normal appearance in radiographs. Sarjeant (1974: 166) stated that the zygoma may be enlarged and the orbital roof thickened, but the frontal sinuses develop normally, although the other sinuses may be delayed and hypoplastic. The finding of enlarged orbital roof plates also has been identified in radiographs of clinical patients with various anemias (Stuart-Macadam, 1987a). In the mandible, reduction and coarsening of trabeculae is observed, accompanied by prominence of the lamina dura of the alveoli and thinning of the cortex. The vertebrae show rarefaction of the spongiosa in the vertebral bodies, at times leading to collapse (Emodi and Okoye, 2001). In adults, depression of the central portion of the endplate results in the fish vertebra appearance also seen in postmenopausal osteoporosis. A virtually pathognomonic radiographic change in the vertebral bodies is squared-off indentations (Resnick, 1995: 2110), often referred to as “H”-shaped vertebrae (Williams et al.,

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2004). The scapula, sternum, pelvic bones, and ribs (flat bones) may show increased lucency and coarsening of the trabeculation. In long bones, the most marked changes occur in the tibia and fibula. Hematopoietic marrow may occupy Haversian resorption spaces in the cortex, especially near the medullary canal. In adults with advanced disease, endosteal reactive lamellar bone and occasional bony plugging of segments of the marrow cavity can occur. In these cases, neither the medullary cavity nor the diameter of the shaft is widened. On the contrary, the cortex is thickened and the medullary cavity actually narrowed. Diggs et al. (1937) found 11 cases out of 39, mostly adults, with marked changes to long bones. The hyperplastic marrow also may produce multifocal spotty radiolucency in the metaphyseal areas. The medullary cavities of metacarpals may be widened and vascular foramina may be enlarged. Dactylitis of the fingers and toes is also seen in radiographs of children (Resnick, 1995: 2110; Kim and Miller, 2002), at times with extensive infarction of the marrow, medullary trabeculae and inner layer of the cortical bone, and subperiosteal new bone formation (Weinberg and Currarino, 1972). The changes produced by sickling and blocking of blood vessels are essentially ischemic infarctions, which may be large and located in the medullary cavity, small and spotty in the metaphysis, or involve portions of shaft cortex due to blockage of Haversian vessels. Generally, the large medullary infarcts are indistinguishable from those produced by other causes. As in those other causes, the infarcts also tend to collect calcium salts around the necrotic focus, which is readily visible in radiographs. The metaphyseal foci may appear as focal increased densities that alternate with spotty lucencies of hyperplastic marrow. In fact, some of the bony plugging of the medullary cavity, as described by Diggs et al. (1937), may well represent healed infarctions. The cortical infarcts may reveal a lytic intracortical separation in radiographs. Infarctions of the cortex of short tubular bones of the hands and feet are not uncommon in infants and small children. These may elicit moderate periosteal reactive bone formation, and spotty densities and lucencies in the course of repair. Of special significance is the occurrence of aseptic necrosis in the head of the femur in sickle cell anemia and its genetic variants. It resembles Legg Calve´ Perthes disease, but with two differences: the lesion occurs several years later and it lacks metaphyseal changes adjacent to the growth plate. If the necrotic focus is small, hugging the base of the articular cartilage, it may simulate an unusually large osteochondritis dissecans or Legg Calve´ Perthes disease. Secondary infections are not uncommonly superimposed on ischemic necrotic foci, which permit colonization of bacteria

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occurred in infancy or early childhood may show the most marked changes (Moseley, 1963: 10 11).

Iron-Deficiency Anemia IDA, or acquired anemia, is the most common type of anemia found globally. It is associated with the presence of microcytic and hypochromic RBC, along with depressed levels of total body iron (Camaschella, 2015). Bone changes in IDA tend to be clinically mild. Changes in the skull vault resemble those described for other anemias, i.e., radiographically recognizable enlargement of the diploe¨ with vertical orientation of the trabeculae. Aksoy et al. (1966) report that generalized granular osteoporosis of the skull and long bones might also appear in some patients. IDA has received the greatest attention as a diagnostic option for porous hypertrophic lesions of the skull in the paleopathological record. However, the tendency for this anemia to produce only limited skeletal involvement has raised questions about the legitimacy of the diagnosis. Importantly, a wide range of conditions invoke an anemic response by the body, rendering the isolation of the cause of hypertrophic lesions extremely difficult (Table 14.2).

Erythroblastosis Fetalis

FIGURE 14.23 Radiograph of the right humerus in sickle cell anemia with Salmonella osteomyelitis. Nigerian case; courtesy of Dr. Stanley Bohrer, Ibadan, Nigeria.

circulating in the bloodstream in only small numbers. In these infections, intestinal pathogens, especially strains of Salmonella, make up an unusually large percentage (Fig. 14.23). As in ordinary types of osteomyelitis, the metaphyses of growing long bones are predilected. In contrast to purulent osteomyelitis, there is often destruction of the growth plate, which may lead to abnormal angulation of the hip joint. Pathological fracture through the osteoporotic bone also occurs.

In some infants with erythroblastosis fetalis, which is usually based on Rh incompatibility between an Rh-negative sensitized mother and an Rh-positive fetus, bone changes have been described. These changes consist of alternating band-like areas of increased and decreased radiodensity, especially in the metaphysis of the most rapidly growing bones (distal femur and proximal tibia). Such changes were present in 20 of 110 cases (Brenner and Allen, 1963), but are not specific. They reflect disturbances of late fetal endochondral ossification with delayed resorption of calcified cartilage cores in primary trabeculae (Follis et al., 1942). The condition may be confused with congenital syphilis and scurvy. However, the absence of periostitis in patients with erythroblastosis fetalis provides a useful skeletal feature in differential diagnosis (Resnick, 1995: 2139).

Paleopathology of Anemia Hereditary Spherocytosis (Congenital Hemolytic Anemia) Hereditary spherocytosis is a genetically determined hemolytic disorder characterized by the globular shape of the erythrocytes. It is the most common inherited anemia in individuals of European decent (Perrotta, 2008). The disease manifests itself at various ages. Bone changes are uncommon and slight, usually limited to the cranial diploe¨, and rarely affect long bones. Cases where onset

The presence of anemia in the archeological record is complex and controversial. Porous and hypertrophic lesions (porotic hyperostosis (PH)) of the skull are frequently recorded by paleopathologists (Jatautis et al., 2011). However, despite evidence that infection, cancer, and metabolic disease can produce porous and hypertrophic lesions in bone, PH is consistently attributed to anemia, to the extent that the presence of the lesion in bone has been treated synonymously with the presence of

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TABLE 14.2 Causes of Iron Deficiency and IronDeficiency Anemia Environmental Insufficient dietary intake Dietary restrictions or predilection (grain intensive, vegetarian, vegan, etc.) Genetic Iron-refractory iron-deficiency anemia Pathologic Decreased absorption Atrophic gastritis Celiac sprue Helicobacter pylori infection Inflammatory bowel diseases Parasitic infestation Chronic blood loss Gastrointestinal tract Benign and malignant tumors Diverticulitis Erosive gastritis Esophagitis Hookworm infestation Peptic ulcer Genitourinary system Intravascular hemolysis Heavy mensis or menorrhagia Systemic bleeding Chronic schistosomiasis Hemorrhagic telangiectasia Physiologic Increased demand for iron Infancy Rapid growth (adolescence) Menstruation Pregnancy Source: After Camaschella (2015).

anemia, especially IDA (Stodder, 2006). This is unacceptable. Without careful analysis of cranial and postcranial remains and rigorous differential diagnosis, researchers must avoid simplistically assuming that porous lesions of the skull, even when hypotrophic, are caused by anemia. In general, inferences made about the presence of anemia in paleopathological specimens are based on the presence of porous, periosteal bone lesions on the skull vault, primarily affecting the outer table of the frontal and parietal bones, and the orbital roof (Fig. 14.24A and B). Several descriptive terms have been used for this condition, including cribra crania, symmetrical osteoporosis, and spongy hyperostosis. However, the term PH, which was introduced by Angel (1966), has become the term used by most researchers to describe this condition in human archeological skeletal remains, with cribra orbitalia (CO) being used to describe lesions of the orbital roof.

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Given the tendencies by many researchers to assume that PH and CO are manifestations of the same condition that simply occur in different anatomical locations, and to assume that the presence of the lesions are indicative of anemia, it is imperative that two questions are explored. First, what is the relationship between PH and CO? A variety of hypotheses for the relationship between the calvarial and orbital lesions have been proposed. StuartMacadam (1987a,b) offered clinical radiographic data, alongside macroscopic data to support a link between orbital and calvarial lesions. The radiographs used in the study included documented cases of genetic and acquired anemia. More recently, Rivera and Lahr (2017) have explored the relationship between orbital and calvarial lesions, and conclude that cribrotic lesions can be associated with PH under conditions invoking compensatory bone marrow expansion due to increased hematopoiesis, such as genetically based anemias and IDA. However, in CO cases where bone marrow expansion of the orbit is absent, the lesions are more likely related to anemias producing localized diploic atrophy or hypoplasia, such as anemia of chronic disease. The second question to evaluate is whether all lesions recorded as CO and PH are etiologically linked with anemia. Many early researchers were careful in their description of lesions classified as CO or PH, and most descriptions included hyperostotic ectocranial porosity accompanied by diploic thickening (hence the early term hyperostosis spongiosa). I would argue, however, that terminology and concomitant diagnosis changed inadvertently with the widespread adoption of Buikstra and Ubelaker’s (1994) Standards for Data Collection From Human Skeletal Remains. Here, under the purely descriptive pathological term “porotic hyperostosis” were codes for varying skeletal manifestations including pinpoint porosity, coalescing foramina, and diploic thickening. This led to an unfortunate trend towards researchers conflating description with diagnosis. The presence of pinpoint porosity, since categorized by Buikstra and Ubelaker as a descriptive form of PH, became treated as an indicator of anemia, most commonly, IDA. However, the clinical and much of the early paleopathological literature was clear: only in instances where hyperporotic changes were evident, triggering compensatory bone marrow expansion, was anemia invoked as the cause. Tiny pinpoint lesions of the calvarium and orbits were not diagnostic. A number of recent studies draw attention to the need for careful lesion description, analysis, and differential diagnosis. Wapler et al. (2004), for instance, identify multiple alternative etiologies for CO, such as localized inflammation and the presence of rickets, based on histological evidence. Walker et al. (2009) argue that IDA is an unlikely contributor to the diploic thickening of PH, as

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FIGURE 14.24 Child with severe porotic hyperostosis with marrow hyperplasia. (A) Orbital roof with cribra orbitalia. (B) Broken section through the left orbital lesion that shows enlargement of the marrow space. (C) Anterior view. (D) Porous hypertrophic lesions of the skull vault. (E) Lateral view of the skull. (F) Radiograph of the skull, lateral view. (1- to 2-year-old child from pre-Columbian site of Pueblo Bonito, New Mexico; NMNH 327074.)

the disease suppresses rather than triggers marrow and red blood cell formation. Megaloblastic and hemolytic anemia, linked to B12 and B9 deficiency, is a more likely etiology. Although Oxenham and Cavill (2010) take issue with Walker et al.’s assessment, they emphasize that differential diagnosis is critical in all analyses of lesions, while Gowland and Western (2012) and Smith-Guzma´n (2015) emphasize the role that malaria can play in the development of anemia. One distinction that might assist differential diagnosis is the geographical distributions of genetic anemias. Sickle cell anemia and thalassemia have been associated with the geographical distribution of malaria, while acquired anemia is a response to several variables, including nutrition and debilitating diseases, and thus occurs in any human population irrespective of the presence of malaria. Carefully evaluating the archeological context from which the individuals are recovered

thus becomes an essential component of differential diagnosis. DNA analyses might also prove beneficial, as Filon et al. (1995) successfully identified the beta thalassemia mutation in an archeological specimen displaying marked PH. Faerman et al. (2000) positively identified the homozygous mutation of adenine to thymine at codon 6 of chromosome 11, associated directly with sickle cell anemia, in a skeleton with clinically diagnosed sickle cell disease, highlighting the promise of genetic analyses accompanied by stringent controls and differential diagnosis. Interpreting the presence of PH and CO in the paleopathological record is also confounding. By far the most common diagnosis associated with the presence of these lesions is that of IDA. In 1965, Moseley added acquired anemia to the list of possible morbid conditions that produce PH. On the basis of his clinical experience as a

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radiologist, he proposed to differentiate thalassemia major from other genetic and acquired anemias because of involvement of the face and long bones. He expressed the opinion (1965: 141) that PH seen in skulls from Peru and Yucatan was due to IDA. This diagnosis was also applied to a Bronze Age (1650 1550 BC) skull of a 6-year-old child from Wales that had PH, as described by Cule and Evans (1968). Sir Arthur Keith, however, who also saw the skull, attributed the lesions to rickets (Wheeler, 1923: 21). El-Najjar (1976) and El-Najjar et al. (1975, 1976) offered hallmark studies on the presence of PH in archeological samples from the southwestern United States. Here the authors found an association between presumed dietary factors (maize consumption) and the frequency of skeletons displaying PH. They concluded that acquired anemia due to inadequate iron absorption caused by a maize-intensive diet was the most likely causative factor for PH. A few years later, however, Mensforth et al. (1978:38) reported a more complex association between evidence of infectious disease and the occurrence of PH in prehistoric skeletons from Ohio. They suggest that illness and nutritional stress were important factors stimulating IDA. Today it is clear that enthusiasm for the hypothesis that the human diet plays a predominant role in provoking IDA may be warranted in some contexts, but can only be concluded after thorough evaluation of both the skeletal lesions and the archeological context. A number of unresolved issues exacerbate the complexity surrounding the determination of causes and interpretation of PH and CO in the archeological record: 1. There are no known associations between the severity of lesions found within skeletal remains and the severity of the condition in vivo. Greater skeletal involvement does not necessarily correlate with greater severity during the life of the individual, since other variables such as the age of the individual and the presence of other conditions/diseases influences the body’s response. 2. The duration of the condition cannot be determined by the types or extent of the skeletal lesions due to the changing plasticity of the human skeletal system throughout childhood and adolescence, and changes to the hematopoietic processes of the human body. 3. Interpreting the presence of active (unremodeled) and “healed” (remodeled) lesions is complicated by unknown associations between these lesion types and clinical measures of anemia. 4. The interrelationship between variables associated with IDA is complex, with a cascade effect obscuring primary causes of the disease. For instance, the presence of infection (affecting nutrient absorption or leading to malaise or culturally defined behavioral

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responses) can alter dietary consumption (reduced volume or selection for particular food types) leading to IDA. Alternatively, dietary consumption (choice or availability of food) can lead to infection (e.g., pathogenic contamination), which can lead to IDA. Importantly, the role of human agency, choice, and cultural constructs impacts the variables contributing to IDA. A further development is the hypothesis that a reduction in available iron within the body may be part of the arsenal of the immune system in response to exposure to infectious agents, as pathogen proliferation is compromised by low iron/oxygen levels (Stuart-Macadam, 1992; Weinberg, 1984). In this scenario evidence of PH is a reflection of the infectious disease load of a skeletal sample rather than a specific indication of anemia. Known as the optimal iron hypothesis, Wander et al. (2009) have suggested that serum iron levels are mediated, in part, by external ecological demands. Moderate iron deficiency might therefore be prophylactic in environments of high pathogenic loads. Recent tests of this hypothesis, however, call for care in adopting this premise. Hadley and DeCaro (2015) found in their study of 1164 Tanzanian children that those with IDA had very similar levels of elevated C-reactive protein (a marker of infection) to those without clinical manifestations of IDA. Further research is needed in order to determine whether reduced iron levels is, in fact, protective or produced as an adaptive response by the body once infection is present.

THALASSEMIA AND SICKLE CELL ANEMIA The presence and antiquity of thalassemia have been reported by a number of researchers, primarily using macroscopic and radiographic analysis. Zaino (1964: 403) proposed that PH, which he reported in pre-Columbian skulls from Peru, is due to thalassemia, while Jarcho et al. (1965) reported a case of PH from a Pueblo Indian site in the American Southwest. The problem with inferring the presence of thalassemia in the New World before the arrival of Europeans is that there is no evidence of this genetic expression of anemia in post-Columbian Native American populations. The case for archeological evidence of thalassemia in the Old World is much more convincing. Angel (1964, 1966) proposed that PH found in ancient Greek skulls was evidence for the presence of thalassemia in antiquity. He made this argument largely on the basis of skeletal lesions. However, he combined these data with a reconstruction of the ecology in ancient Greece, in which the conditions would have favored the presence of anopheline mosquitoes as carriers of malaria. Because the evidence for the genetic variant in modern ethnic groups is

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unquestioned, this inference is certainly plausible. At issue here, however, is that both thalassemia and malaria can result in anemia, with thalassemia compromising the production of hemoglobin, and Plasmodium falciparum, a protozoan parasite transmitted by the female Anopheles mosquito, provoking excessive removal of nonparasitized erythrocytes and immune destruction of parasitized red cells. Hence, using the presence of PH without rigorous evaluation of other skeletal modifications and archeological context cannot directly lead to conclusions regarding either the presence of thalassemia or malaria within an individual or population. A number of studies have sought to tackle these obstacles. Lagia et al. (2007), for instance, provide a macroscopic and radiographic evaluation of an individual with clinically diagnosed thalassemia as a means to improve our ability to differentially diagnose the disease. Likewise, a careful evaluation utilizing multiple diagnostic criteria in an archeological context has been offered by Lewis (2012), who evaluated 364 juvenile skeletons from Roman-era Britain, finding skeletal lesions on two individuals more consistent with thalassemia than acquired anemia. The successful isolation of the beta globin mutation itself in bone, rather than its secondary effects on the human skeleton, further improves our ability to assess thalassemia in antiquity (see Filon et al., 1995 and Vigano´ et al., 2017). In spite of the fact that millions of people carry the sickle cell gene today, there are few reports of the disease in the archeological record. This is likely due to the shared primary and secondary changes macroscopically and radiographically evident in the human skeleton associated with genetic and acquired anemias. Means toward differential diagnosis are offered by Hershkovitz et al. (1997:220), but highlight the fact that key differences between the anemias are subtle (e.g., statistically affecting an anatomical area more or less frequently, rather than present/absent), and that there are few diagnostically unique manifestations of sickle cell anemia. According to the authors, of the 62 anatomical characteristics offered for differential diagnosis between thalassemia, sickle cell anemia, and primary and secondary iron deficiency, only diffuse calcification of the skull, increased radiolucency and coarsened trabeculae of the mandible, patchy sclerosis of the pelvis, enlarged basivertebral foraminae, vertebral sclerosis (dense bands), retarded bone age and delayed closure of growth plate, growth deformity of the proximal femoral epiphyses after the age of 10, bone infarcts and osteonecrosis, osteomyelitis, bone elongation (pseudo Marfan syndrome), and structural abnormality of the teeth, serve as distinguishing features for sickle cell anemia. While these appear to be substantial in number, the types of skeletal changes associated with sickle cell anemia overlap with other conditions/diseases (e.g., necrosis and osteomyelitis) and/or appear in areas of the

body vulnerable to taphonomic destruction (e.g., vertebral bodies and epiphyseal ends of tubular bones).

IRON-DEFICIENCY ANEMIA Two examples from the National Museum of Natural History, Washington, DC, provide useful insight into the expression of PH caused by marrow hyperplasia in archeological populations. Both cases are from the American Southwest (NMNH 327074 and 327107) and are skeletons of young children from the Pueblo Bonito Ruin, Chaco Canyon, New Mexico. This site is associated with the precontact Pueblo III cultural period and is dated between AD 919 and 1130 (Seltzer, 1944: 25). During this period, skulls show marked cultural modification characterized by occipital flattening. The dental age of the first specimen (NMNH 327074) is about 11/2 years (Fig. 14.24C F). The lesions in this specimen are primarily porous, but some labyrinth-like lesions are present as well. The affected area involves the frontal bone including the orbital roofs, but predominantly involves the outer table of the parietal bones; the inner table is not affected. The skeleton is characterized by severe occipital flattening and the lesion encroaches only slightly on the deformed part of the skull. The facial bones and mandible are not markedly affected, although the region surrounding the zygomaticofacial foramen on the zygomatic bone suggests an inflammatory reaction. The lateral X-ray film shows the perpendicular striations found in many examples of PH. A postmortem break through the lesion in the right parietal reveals an intact inner table, greatly enlarged diploe¨, and the virtual elimination of the outer table. Radiographic evaluation of the extant long bones including major portions of both femora, right tibia, both humeri, and ulnae, reveals relatively enlarged marrow cavities and greatly diminished thickness of the cortices in all long bones. The second case (NMNH 327107) has a dental age of about 2 years. The state of preservation is not as good. Like the previous example, the most severely affected region is the external table of the parietals (Fig. 14.25A and B). The lesion does not cross the sagittal suture. The left frontal bone is also affected and the disease process is continuous across the coronal suture. Only portions of the right orbit are present. They reveal no evidence of PH. The left temporal bone is abnormal: it has an irregular surface that is thickened and slightly porous. Like the first skeleton, the long bones are affected by the disease process. An X-ray film of the complete right femur and the partially complete tibiae, left femur, and humerus reveals a generalized enlargement of the medullary cavity and much thinner cortex than normal. Comparison of the abnormal femur with normal femora (Fig. 14.25C) of similar size from the same population reveals a cortical

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FIGURE 14.25 Bone marrow reactions in a skeleton with porotic hyperostosis. (A) Porous labyrinth-like lesions of the skull vault. (B) Broken sections of the parietal that demonstrate hyperplasia of the diploe¨. (C) Radiograph of the femur of a skeleton with anemia (center) compared with the femora of two children from the same site who did not have skeletal evidence of anemia. Note the enlarged marrow space and thinned cortex. (2-year-old child from the pre-Columbian site of Pueblo Bonito, New Mexico; NMNH 327107.)

thickness of less than 1 mm for the abnormal specimen, whereas the normal femora are between 2 and 3 mm. Two features distinguish this case from the preceding one. First, the lesion does occur in the region of deformation. This may be related to the fact that the occipital deformation is not as severe. Second, unlike the preceding example, there appears to be slight deposition of reactive bone on the inner table. The abnormal bone is concentrated in the region of the anterior fontanel and reactive tissue is apparent at its sutural borders. There is a solitary lesion on the left parietal boss. A lateral radiograph of the skull reveals vertical striations in the area where PH is most pronounced. Also apparent in the film is the absence of the outer cortex in the porous area. The lesion itself is slightly different from the first specimen in that it is more variable in appearance. Beginning on either side of the sagittal suture, the parietal lesion has a narrow zone of finely porous bone. This quickly merges with bone that is labyrinthian in gross appearance. Continuing in a lateral direction the lesion is characterized by a circular porosity that becomes finer and less pronounced in the area below the temporal muscle. Here the bone takes on the lumpy quality seen in the left temporal bone. Certainly, a diagnosis of some type of anemia is a strong probability in the two cases described. However, determining the specific type of anemia is more problematic. Moseley (1963: 6, 1966: 128) reported that the long bones are not affected in IDA. This conclusion is not supported by Lanzkowsky (1968: 24), who found widened medullary spaces and thinned cortices in the postcranial bones, particularly the metacarpals and phalanges. This

difference of opinion highlights the need for additional research on the manifestations of the anemias that can affect the skeleton. The research reported by Hershkovitz et al. (1997) on skeletal pathology associated with thalassemia, sickle cell anemia, and acquired anemia is a helpful step in clarifying these differences, but much remains to be known about the overlap between these anemias, particularly in cases where the skeletal manifestations are less severe. It will also be important to pursue additional research on various biochemical and epidemiological variables that have the potential to aid in differential diagnosis. If some types of PH are caused by acquired anemia, in which a deficiency of iron is a factor, the formation of tissues dependent in some way on iron might be altered as well. Von Endt and Ortner (1982) hypothesized that bone collagen might reflect iron deficiency because it is an important cofactor in the hydroxylation of two amino acids, lysine and proline, in the synthesis of hydroxylysine and hydroxyproline, which are important constituents of bone collagen. More specifically, bone tissue from skeletons with PH due to IDA should show relatively reduced amounts of hydroxylysine and hydroxyproline compared to normal controls. Von Endt and Ortner evaluated this possibility using one of the specimens described previously (NMNH 327107). They compared the amino acid residues of bone protein from the skeleton of this child with presumed anemia with a similar skeleton from the same site that did not have PH. A bone protein sample from a modern child who died from accidental causes was used as an additional control. The hydroxylysine and

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hydroxyproline residues of the archeological and modern skeletal samples that did not have PH were virtually identical. In the bone of the child who had PH there was 5% less hydroxyproline and 25% less hydroxylysine. The authors argued that these reduced concentrations support a diagnosis of IDA in the skeleton with PH. There is the further problem of differentiation between PH from anemia and similar lesions seen in cancer, infectious diseases, and metabolic diseases. Briefly, porous lesions of the skull in infectious diseases are usually periosteal. They do not involve expansion of marrow space. The lesion typically is superficial to normal bone. In early stages of the periosteal lesion the outer cortex remains intact. However, in later stages the outer table may undergo remodeling and a section through that part of the skull may resemble the PH of anemia. The bony reactions that occur in scurvy (Ortner and Ericksen, 1997; Ortner et al., 1999, 2001) could be confused easily with those of anemia or infectious disease. Hypertrophic lesions are less common in scurvy, but they do occur. However, this hypertrophy does not involve marrow hyperplasia. The porous bone associated with rickets occurs in the skull and postcranial skeleton (Ortner and Mays, 1998). The porosity of the skull is much finer and could not be confused with PH associated with anemia. However, keep in mind that anemia resulting from dietary deficiency can also be associated with other deficiencies including those that result in scurvy and rickets.

Leukemia In general, detecting and diagnosing the presence of neoplastic disease in human skeletal remains is especially difficult. In part, this is due to the overlapping and relatively narrow skeletal responses created by different types of cancer (Marquez et al., 2017; Ragsdale et al., 2017). It is exacerbated by taphonomic factors, which might compromise or destroy remnants of the body’s lytic responses over time. Regardless, leukemias are cancers of the myeloid and lymphoid hematopoietic cells of the bone marrow, which might be detected in the archeological record. Both myeloid and lymphoid cancers occur in acute and chronic forms in children and adults, with tumor cells extensively replacing normal bone marrow throughout the skeleton. Although adult and chronic forms of leukemia can affect the skeleton, the changes are nonspecific and often difficult to immediately diagnose (Riccio et al., 2013). Skeletal manifestations include generalized loss of bone mass and diffuse, small osteolytic lesions, joint compression, vertebral collapse, pathological fractures, and periosteal reaction (Sinigaglia et al., 2008). Since the major changes that affect the skeleton occur in acute leukemia of childhood, that will be the focus of the following discussion.

Bone changes in acute leukemia of childhood occur in 50% 70% of cases (Resnick and Haghighi, 1995: 2248). In growing bones of children, the replacement of the normal marrow cells by tumor cells and their subsequent proliferation results in recognizable alterations to the bone structure. The most frequent lesion is a narrow radiolucent line on the metaphyseal side of the growth plate. This change is not specific and resembles, to some extent, the lucent metaphyseal zone in scurvy. Another alteration seen in acute childhood leukemias involves the cortical surface of the metaphyses. Normally, in these areas, osteoclastic resorption of the modeling process creates a rough and somewhat grooved or porous cortical surface. In acute leukemia, these areas of the periosteum may be colonized by tumor cells that emanate through the vascular foramina. This leads to widening of the vascular foramina and exaggerated grooving and porosity of the metaphyseal cortical surface. This may be the most characteristic bone lesion of acute leukemia. Occasionally, widespread nonspecific subperiosteal bone deposits are observed over thinned cortices of long bones and ribs (Fig. 14.26). In spite of the rarity of leukemia, careful differential diagnosis has been used to detect its presence in the past. Most recently, Klaus (2016) attributes relatively diffuse abnormal porous loci and periosteal reaction on the clavicle and ribs of a child associated with the Lambayeque Valley Complex of the north coast of Peru, dated AD 1533-1620, to acute leukemia.

Myeloma Myeloma is a highly malignant disorder of plasma cells that usually arises in hematopoietic bone marrow. The disease is the most common primary malignancy of bone: it has an incidence of between 2 and 4 cases per 100,000 (Mulligan, 2000: 127). It may begin as a single site, at which stage it is known as solitary plasmacytoma. However, virtually all cases move on quickly to multiple myeloma (Mulligan, 2000). Skeletal involvement is common (noted in 80% 90% of modern cases) and often affects many, if not most, areas of the skeleton (Kuehl and Bergsagel, 2002). The lesions are sharply defined holes typically 5 mm to 2 cm in diameter and often penetrate both tables in the skull. They often have scalloped margins. Endosteal scalloping of the cortex is an important radiographic feature in the long bones (Mulligan, 2000: 127). The malignant plasma cells inhibit local osteoblastic activity at the site of the lytic focus, so sclerotic margins do not occur in most cases. This feature, along with the extensive involvement of the skeleton, is helpful in differential diagnosis with metastatic carcinoma. Even the mandible may be involved and this is very uncommon in metastatic carcinoma (Mulligan, 2000: 128).

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FIGURE 14.27 Multiple myeloma. Endocranial view of the cranial vault that shows multiple lytic lesions destroying the internal table. (65-year-old male; MGH autopsy 33606.)

FIGURE 14.26 Acute leukemia in a child. Note the considerable amount of periosteal new bone growth along the diaphysis of the femur and the faint radiolucent line along the metaphysis. Courtesy of Drs. T. Demos and L. Lomasney, Department of Radiology, Loyola University Chicago Medical Center.

The initial lesion usually arises in the axial skeleton because that part of the skeleton contains hematopoietic marrow. In the long bones, lesions can occur in the proximal metaphyses, especially of the femur and the humerus. Single tumor cells disseminate through the blood and colonize mostly in the areas of hematopoietic marrow. In the cranial vault and portions of the long bones of the extremities, reactivated hematopoietic marrow appears, secondary to massive marrow involvement in the trunk. The small bones of the extremities are usually spared. A typical location for the primary lesion is the proximal metaphysis of the femur and humerus. The initial lesion may remain localized and solitary for months or years (solitary plasmacytoma), but dissemination to other parts of the skeleton almost always occurs. The solitary lesion is slow

FIGURE 14.28 Multiple myeloma. Bisected spine and ribs with severe osteoporosis, compression fractures, and kyphosis. Notice the disseminated small lytic lesions in the ribs and spinous processes. (77-year-old female; IPAZ autopsy 1703, 1954.)

growing, creating an osteolytic defect and ultimately eroding the cortex. The lesion can include formation of an expanded bony shell with ridge-like internal reinforcements. These appear as a “soap bubble” pattern in

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radiographs. Pathological fractures through the lesion are a complicating factor and callus formation is normal. The lesion usually does not extend into the head of the humerus or femur. This distinguishes it from giant cell tumor and chondroblastoma. In dry bone, the solitary lesion cannot be differentiated with certainty from unicameral bone cysts, chondromyxoid fibroma, or nonossifying fibroma, except for the fact that these would usually occur in a younger age group. Differentiation of the lesion from solitary lytic metastasis of renal or thyroid carcinoma may be impossible. The most frequently observed and most characteristic manifestation of myeloma is the disseminated form (multiple myeloma). The lesions start within bone marrow and in long bones tend to destroy the endosteal surface of the cortex, producing the scalloped appearance in radiographs. In most affected bones (vertebrae, ribs, sternum, clavicles, scapulae, pelvis, calvarium, and long bones) the individual lesions create punched out, purely lytic defects without reactive bony margins (Fig. 14.27). Most lesions are round and small, but individual large lesions, particularly the primary lesion, do occur and small lesions can become confluent, often showing scalloped margins. In vertebral bodies this confluence of individual lesions is particularly common. The spinous processes are often involved. Destruction of the vertebral spongiosa often

leads to collapse of multiple vertebrae, frequently with deep cupping of the endplates due to pressure from the intervertebral disks (Fig. 14.28). Wedge-shaped vertebrae, kyphosis, and scoliosis are common. The ribs also frequently show multiple transverse fractures and a coarsely reticulated irregular pattern of the few remaining trabeculae. Differential diagnosis between multiple myeloma and osteolytic metastatic cancer, particularly of the breast, is difficult (Marques et al., 2013). The male prevalence in myeloma and the female predominance in breast cancer are helpful considerations, along with the more extensive involvement of the skeleton in multiple myeloma. Furthermore, in metastatic carcinoma, even if it is predominately lytic, some of the lesions usually show an osteoblastic response in association with at least some of the lesions. Multiple myeloma frequently involves the glenoid fossa of the scapula and the lateral portion of the clavicle, and disseminates into the radius and the ulna, a condition that is uncommon in metastatic carcinoma (Schinz et al., 1951 1952: 951). The presence of a larger, older lesion also helps in the differentiation from metastatic carcinoma. Rarely, multiple myeloma may leave the bone structure unchanged or produce only a pattern of diffuse osteoporosis without distinct lytic lesions. These changes are nonspecific, making differential diagnosis even more troublesome. FIGURE 14.29 Multiple lytic lesions of the skull and postcranial skeleton. (A) Left lateral view of the skull and mandible. (B) Lateral radiograph of the skull that shows multiple lytic lesions of relatively uniform size. (C) Posterior view of the left scapula that shows lytic lesions and porous bone hypertrophy (arrow) adjacent to the lytic focus. (Adult female from Indian Knoll, Kentucky; NMNH 2990064.)

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Paleopathology It is not surprising that the identification of myeloma in paleopathological specimens is particularly complicated given the similarity between bone lesions of myeloma and some types of metastatic carcinoma, and taphonomic effects over time. In spite of these obstacles, a number of researchers have cautiously suggested the presence of multiple myeloma in the archeological record (see, for example, Ritchie and Warren, 1932; Williams et al., 1941; Brooks and Melbye, 1967; Morse et al., 1974; Wells, 1964; Strouhal, 1991; and most recently Abegg and Desideri, 2017), with a number of the earlier cases being called into question by Ortner (2003). Three paleopathological specimens from the National Museum of Natural History, Washington, DC, provide further insight into the problems of differentiating

523

between multiple myeloma and osteolytic metastatic carcinoma. The first of these is a female skeleton (NMNH 290064) from the Indian Knoll site in Kentucky. Most of the artifacts from this site are dated in the Late Archaic period (c.3000 1000 BC); however, some components date to the Late Woodland period (c. AD 800 1700). Thus, the archeological age of this specimen remains obscure. The age of the individual cannot be determined, but certainly is adult. The disease process consists of multifocal, mostly lytic lesions distributed in the skull, mandible, axial skeleton, and the proximal left femur (the right femur is missing). The bones of the hands and feet are unaffected except for a slight, superficial osteoporosis of the superior surface of the calcanei. The gross lesions vary in size from barely detectable to about 15 mm in diameter. Most of the cranial lesions (Fig. 14.29A) FIGURE 14.30 Multiple scalloped lesions of the skull in a probable case of multiple myeloma. (A) Left lateral view of the skull that shows lytic lesions of varying size. (B) Lateral radiograph of the skull that shows multiple lytic lesions of relatively uniform size. (C) Mid-sagittal coronal computed tomography (CT) scan that demonstrates lack of sclerosis in the margins of the lesions. (D) Mid-frontal coronal CT scan that shows lack of marginal sclerosis in lytic lesions. (E) Scanning electron microscope photomicrograph of the surface in a lytic lesion of the skull. Virtually the entire surface consists of Howship’s lacunae, indicating active bone destruction at the time of death. There is no evidence of osteoblastic repair in any field. (Adult female from Caudivilla, Peru; NMNH 242559.)

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penetrate both tables and have no clear pattern with regard to which table is most extensively affected. The lytic process is more extensive in the diploe¨, suggesting that the marrow was the focal point for the disease process. The roentgen films of the skull and long bones reveal additional lytic foci that are not visible from the outside (Fig. 14.29B). The scapulae are present and both show multiple lytic foci (Fig. 14.29C). The glenoid fossa is normal, although there are lytic foci in adjacent tissue. However, unlike lesions elsewhere in the skeleton, there is a slight osteoblastic response adjacent to several of the lytic foci. With this exception, there is no osteoblastic reaction to any of the other lytic lesions in the skeleton. This suggests a rather acute disease process. Steinbock (1976: 381 384) reported on this case and concluded that “the size, location, and appearance of the destructive lesions in this Archaic Indian are highly indicative of multiple myeloma rather than metastatic carcinoma.” While conceding that multiple myeloma is a strong possibility based on some aspects of the gross and roentgen film morphology of the lesions, there is other evidence supportive of a diagnosis of metastatic carcinoma. The peripheral bone reaction on the scapulae is more characteristic of metastatic carcinoma, as is the age and sex of the skeleton. However, the presence of a lytic lesion on the mandible is more typical of multiple myeloma. Another possible case of multiple myeloma is a female skull from Peru (NMNH 242559). This specimen is fully adult. The archeological age is unknown. The external gross aspect of the entire skull, except the face, reveals several scalloped, lytic lesions (Fig. 14.30A) that vary in size from pinholes to 15 mm in diameter. There is no evidence of bony circumscription either by inspection or on roentgen films (Fig. 14.30B). This is confirmed in coronal computed tomography slices (Fig. 14.30C and D). Scanning electron microscopy of one of the lesions shows virtually all surfaces covered with Howship’s lacunae and no evidence of osteoblastic repair on any surface (Fig. 14.30E). The size and morphology of the lytic lesions as well as the absence of any evidence of repair make a strong case for multiple myeloma, although metastatic carcinoma remains a possibility. The third case from the National Museum of Natural History, Washington, DC, is also a female skull from Peru (NMNH 242578). Age at death is unknown, but like the two previous cases, clearly adult. The archeological age is unknown. Unlike the lesions in the preceding two cases, the external appearance of these lesions is much less obvious. The lytic lesions that do penetrate the surface are small holes, typically 1 2 mm in diameter. On the internal table, the lesions are somewhat more pronounced. All bones of the skull are affected, but the facial bones and occipital bone show much less involvement. The greater wings of the sphenoid and the body of the

FIGURE 14.31 Lateral radiograph that shows multiple lytic lesions of the skull. Note the lack of sharply defined boundaries of the lytic foci. (Adult female from Peru, NMNH 242578.)

sphenoid are markedly affected; much of the latter is totally destroyed. In the radiograph (Fig. 14.31), it is apparent that the major focus of the lytic process is the diploe¨. There is no evidence of any osteoblastic reaction in any of the lesions. In the radiograph, a typical lesion consists of a lytic focus that ranges in diameter up to 2 cm. Many of the lesions coalesce. The overall picture presented by this case is not typical of either multiple myeloma or metastatic carcinoma. However, Schinz et al. (1951 1952: 947, 949) briefly described a case of atypical multiple myeloma in which “rather numerous individual foci are distinctly delimited, and a moth-eaten, finely mottled kind of osteolysis develops. . ..” This description and their published roentgen film views closely match the appearance of the Peruvian skull. However, Schinz et al. cautioned that the case they described is not easily distinguishable from metastatic carcinoma. Provisionally, however, it is might be useful to consider this skull as an example of atypical multiple myeloma.

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Chapter 15

Metabolic Disease Megan B. Brickley1 and Simon Mays2 1

Department of Anthropology, McMaster University, Hamilton, ON, Canada, 2Historic England, Portsmouth, United Kingdom

INTRODUCTION Metabolic bone diseases are conditions that cause an alteration in normal bone formation, resorption, or mineralization, or a combination of these; in most conditions these alterations are systemic. Metabolic bone disease may arise due to nutritional problems, hormonal imbalance, or other causes. In this section we consider disease associated with vitamin C deficiency (scurvy) and vitamin D deficiency (rickets and osteomalacia), osteoporosis (which normally arises from age-related hormonal changes), together with certain other conditions arising from imbalances in bone metabolism. The classical approach to diagnosis of disease in paleopathology is essentially to use lesions in a reference group or groups to help us interpret lesions in a target individual or population. The target group is archeological remains showing pathological lesions. The reference group comprises individuals showing skeletal lesions and with independent evidence concerning which disease was present. Reference materials comprise specimens from medical pathology museums; radiographic and other imaging studies of living individuals also contribute. Whilst having clear strengths, using lesions observed in a reference population to interpret alterations in a target group or individual also has limitations. Ideally, we would wish a reference group to be representative of the full range of skeletal expression of the disease of interest. Medical pathology museum specimens collected prior to the mid-20th century predate the advent of effective drug and other treatments which radically altered the natural history of many diseases, an advantage when acting as reference material for archeological target groups. However, pathology museum collections were assembled for a variety of didactic and other purposes, none of which were concerned with facilitating paleopathological diagnosis. Accessioning and deaccessioning policies were often rather idiosyncratic, and heavily dependent upon the interests of individual curators (Arnold, 1999). There was

often a tendency toward collection of the spectacular or unusual (Alberti, 2011; Stephens, 2011). This bias in the reference group may mean that the manifestations of disease may differ from those likely to be encountered in an archeological target group. In addition, specimens gathered for medical pathology museum collections may have come from individuals who suffered from multiple conditions, some of which may have affected the skeleton and only one of which was diagnosed by physicians. These considerations should always be borne in mind when using reference material in paleopathology, but are especially to the fore in metabolic bone disease. For example, most pathology museum specimens showing vitamin C and vitamin D deficiency show much more severe bony alteration than will usually be encountered in archeological material (Brickley and Ives, 2008: 118; Mays, 2008a). It has long been recognized (e.g., Barlow, 1883) that, especially in infants, deficiencies of vitamin C and vitamin D may often coexist, and some medical museum specimens diagnosed with rickets also appear to show lesions due to scurvy (Brickley and Ives, 2008: 11). Recent paleopathological work directed at identification of vitamin C and vitamin D deficiencies has emphasized an alternative approach, involving careful reading of primary clinical sources coupled with a close understanding of the pathophysiology of the bony alterations, as a means of augmenting and refining our diagnostic criteria (Ortner, 2011; Crandall and Klaus, 2014). We therefore use not only documented cases, but also archeological material to illustrate pathology typical of these diseases. For another major condition discussed in this section, osteoporosis, we are forced to step away from the reference/target population, lesion-based approach. Osteoporosis is a condition, often age-related, that involves a decline in bone mass and in microstructural integrity of bone. Osteoporosis is identified in skeletal remains by direct measures of bone mass or microstructural integrity; in our discussion we emphasize the strengths and weaknesses of applying various methods to assess these parameters in ancient remains.

Ortner’s Identification of Pathological Conditions in Human Skeletal Remains. DOI: https://doi.org/10.1016/B978-0-12-809738-0.00015-6 © 2019 Elsevier Inc. All rights reserved.

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532 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

VITAMIN C DEFICIENCY Scurvy is a disease caused by inadequate vitamin C. Unlike most other animals, humans are unable to synthesize their own vitamin C, so are reliant on dietary intake. Fresh fruit and vegetables are rich in vitamin C, and smaller amounts are available in meat, fish, and dairy products. Vitamin C content of foods is diminished by heating (Igwemmar et al., 2013) and, unless air is excluded, by prolonged storage (Montan˜o et al., 2006). Vitamin C deficiency principally reflects faulty diet, food preparation, or storage.

SUBADULT SCURVY Neonatal levels of vitamin C are related to maternal levels, and vitamin C is present in breast milk (Agarwal et al., 2015). Scurvy is rarely observed before age 4 months (unless the mother is deficient in the vitamin) and is most frequent in later infancy and early childhood, although it can occur at any age (Gulko et al., 2015). Prolonged deficiency is necessary to produce scurvy, perhaps for a matter of months, although research in humans on this point relates to adult rather than subadult cases (e.g., Hodges et al., 1971). Historical sources mainly discuss adult scurvy. The first good description of subadult scurvy dates from 17thcentury England (Still, 1935). It only began to be noted as a widespread problem in the 1870s when the wealthy began to feed their infants on bread and milk sterilized by heating, which destroyed the vitamin C (Carpenter, 1986: 158 172). In 1914, Hess demonstrated that scurvy could be cured by including raw milk, or fresh fruit and vegetables, in the diet, and as the benefits of these dietary components became more widely known, the frequency of the disease fell (Carpenter, 1986: 172). Vitamin C is a critical modulator of the production of collagen, the main structural protein of bone and other connective tissue. In bone, the effects of vitamin C are complex and incompletely understood, but as well as promoting collagen matrix formation, it also (inter alia) promotes osteoblastic differentiation and proliferation in osteogenic cells (Aghajanian et al., 2015). Deficient vitamin C results in reduced bone formation, with consequent rarification of trabecular bone and cortical thinning. Although the metabolic effects of scurvy are systemic, in the growing skeleton, alterations are most pronounced at rapidly growing long-bone ends, particularly the distal femur, and at the sternal rib ends. These alterations, most of which are best visualized using radiographic or other medical imaging techniques, are described below. There may be a transverse band of decreased density, visible as a radiolucent line (termed a scurvy line or Tru¨mmerfeld zone) adjacent to the metaphyseal end of a

long bone. There may also be osteopenia of the trabecular bone of the epiphysis. Mineralization in the provisional zone of calcification at the growth plate margin is maintained and is visible as a thin, more radiodense line at the metaphyseal surface immediately beneath the growth plate. This is known as the white line of Fra¨nkel. Similarly, the radiolucent epiphyseal spongiosa tends to be surrounded by a thin, more radiodense line termed Wimberger’s ring (Noordin et al., 2012; Agarwal et al., 2015). The poorly mineralized growing end of the bone may yield to mechanical forces, resulting in microfracture of the spongiosa beneath the growth plate. This may be evident as irregularity or concavity (“cupping”) of the growing end of the bone (Duggan et al., 2007). Repair of microfractures may lead to bony spur formation at metaphyseal margins (Pelkan’s spurs) (McCann, 1962; Tamura et al., 2000). Some of these alterations are shown diagrammatically in Fig. 15.1, and radiographically in Fig. 15.2. The most frequent of the bony alterations associated with the direct effects of vitamin C deficiency is generalized osteopenia (Weinstein et al., 2001), which is too nonspecific to aid diagnosis. The other changes are less frequent and may not form at all, even in advanced disease (Tamura et al., 2000; Weinstein et al., 2001; Akikusa et al., 2003). Most of the above alterations are removed by remodeling following restoration of adequate vitamin C, but metaphyseal deformity may persist in severe cases (Sprague, 1976). In buried bone, care is

FIGURE 15.1 Radiographic alterations that may be observed in subadult scurvy (Brickley and Ives 2008, Fig. 4.7).

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FIGURE 15.2 Anteroposterior radiograph of the left knee in a modern case of scurvy. In addition to generalized osteopenia, there are radiolucent “scurvy” lines running transversely in the metaphyseal bone beneath the growth plate, and irregularity of the metaphyseal end of the femur due to microfracturing. Illustration courtesy of Michael Weinstein and the American Academy of Pediatrics. Pediatrics (2001), 108: E55.

needed in evaluating radiographic changes. Soil erosion of bone ends or superficial soil infiltration may potentially remove or mimic the Fra¨nkel and Wimberger signs. Collagen is the major structural protein in blood vessel walls, so deficiency of vitamin C leads to hemorrhage. When hemorrhage occurs close to bone it may potentially cause osteological lesions. Outside the circulatory system, blood elicits an inflammatory response (Klaus, 2017). Inflammation, or mechanical pressure on the periosteum from localized bleeding, may provoke an osteoblastic response (Weston, 2012), resulting in new bone deposition upon the existing cortex. The vascular component of the inflammatory response to hemorrhage results in proliferation of capillaries in the affected area. This may result in localized porosity of cortex to provide pathways for the vessels through bone (Ortner et al., 1999). These pores are characteristically ,1 mm diameter and fully penetrate the outer cortex (Brown and Ortner, 2011). In addition, deposits of new bone may show small branching channels indicating capillary proliferation, and such “branched lysis” may also be seen on the normal cortical surface (Mays, 2008b; Brown and Ortner, 2011). Although lesions may take the form of subperiosteal new bone formation and/or porosity of existing cortex, the latter is more frequent (Ortner et al., 2001; Krenz-Niedbała, 2016). In some instances, both types of alteration may occur, with new bone formation upon cortex which itself shows porosis. A range of terminology has been used to

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describe such lesions (Brickley et al., 2016: 93; Klaus, 2017: 6), but in this chapter the term mixed lesion is used. The cranium is a frequent site of hemorrhagic lesions in subadult scurvy, but lesions may also be seen postcranially. The most typical sites for changes are itemized in Table 15.1, and illustrated in Figs. 15.3 15.7. Perhaps the most consistent cranial location for osteological hemorrhagic lesions in scurvy is the external surface of the greater wing of the sphenoid bone (Ortner and Ericksen, 1997). Here, major blood vessels lie between the temporalis muscle (one of the major muscles involved in mastication) and the bone. Minor traumata due to contraction of the muscle would potentially cause bleeding that might elicit an osteological response. Lesions at locations 2 6 in Table 15.1 may also be associated with minor traumata associated with mastication (Ortner et al., 1999). Lesions on the orbital walls may be elicited by eye movement, and cranial vault lesions by minor scalp trauma. Foramina, such as the foramen rotundum of the sphenoid bone and the infraorbital foramen of the maxilla, convey nerves and blood vessels, so bleeding at these structures might potentially be responsible for localization of hemorrhagic alterations in these locations. Although some vitamin C is required for new bone formation, animal studies (Bourne, 1942, 1943; Murray and Kodicek, 1949a,b) suggest that only very small amounts of the vitamin (2% 5% of the dose required to maintain vitamin C saturation) are needed to enable an osteoblastic response. Other than in starvation, total absence of vitamin C from the diet is rare. Therefore, proliferative lesions are expected not only in the recovery phase but also in active disease, and this has been confirmed radiographically in humans (Joffe, 1961). In the identification of hemorrhagic lesions in subadult scurvy, care is needed to distinguish abnormal porosity from normal skeletal morphology. It is only once an infant reaches about 1 year of age that the fiber bone that formed the fetal skeleton is fully replaced by lamellar bone. Therefore, bones of infants are often rather porous. Even in older individuals, bone at some locations, including the alveoli, the inferior surface of the hard palate and long bone metaphyses, retains a porous appearance. In such cases, as well as detailed morphological examination, comparison with elements from remains of individuals of similar age at death may help resolve whether or not porosity is abnormal. In addition, care is needed to distinguish hemorrhagic lesions in the orbit and cranial vault from lesions due to rickets or anemia. It should be remembered that these conditions frequently cooccur (Weinstein et al., 2001; Lewis et al., 2006). In any event, none of the alterations listed in Table 15.1 is diagnostic in isolation, but, in combination, they are strongly suggestive of scurvy.

534 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

TABLE 15.1 Typical Sites for Hemorrhagic Lesions in Infantile Scurvy Lesion Location

Comments

Cranial 1. Sphenoid, external surface, greater wing

Generally bilateral and symmetric

2. Zygomatic bone, medial surface/posteromedial surface of maxillary zygomatic process 3. Posterior surface of maxilla 4. Coronoid process of mandible, medial surface 5. Inferior surface, palatine processes of maxillae 6. Maxillary and/or mandibular alveolar bone 7. Orbital walls

Superior wall most often affected Alterations may show left/right asymmetry

8. Cranial vault

Ectocranial surface more often affected than endocranial

9. Infraorbital foramen of maxilla 10. Foramen rotundum of sphenoid bone Postcranial 1. Long bones

Especially metaphyses

2. Scapulae, supra- and infraspinous fossae 3. Ilia Sources: Ortner and Ericksen (1997); Ortner et al. (1999, 2001); Brown and Ortner (2011); Geber and Murphy (2012); Klaus (2017).

FIGURE 15.3 Left side of the cranium of a child aged about 2 years. There is an area of abnormal porosity focused on the greater wing of the sphenoid bone. (Archeological individual, Pachacamac, Peru.)

Paleopathology Starting in the 1980s, some paleopathological cases of subadult scurvy were reported, diagnosed on the basis of the microscopic appearance of subperiosteal new bone deposits (e.g., Schultz, 1989; Schultz et al., 1998).

FIGURE 15.4 Posterior part of right maxilla of a 9 10-year-old child showing abnormal porosity (arrowed). (Archeological individual, Kilkenny, Ireland.) (Geber and Murphy, 2012, Fig. 15.2B.)

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FIGURE 15.5 Medial surface, right hemimandible from a child aged about 18 months. There is an area of abnormal porosity at the base of the coronoid process (indicated by arrows). (Archeological individual, Alikianos, Greece.) (Bourbou, 2014, Fig. 15.4.)

FIGURE 15.7 Endocranial surface of left sphenoid of a 3-year-old child showing new bone formation around the foramen rotundum. (Archeological individual, Kilkenny, Ireland.) This figure was kindly supplied by Dr. Jonny Geber.

FIGURE 15.6 Cranial vault of an infant with scurvy showing new bone formation on frontal and parietal bones. (WM RCSE S56.4.)

However, the value of this diagnostic approach has been questioned, so that until they are reviewed using more recent diagnostic criteria, their status remains uncertain (Mays, 2014). Little use has been made of radiographic diagnostic criteria for identifying scurvy in paleopathology, perhaps because the fragile metaphyseal ends and epiphyses are often missing or poorly preserved in archeological material. Since Ortner’s work in the late 1990s,

the dominant approach has been to use his macroscopic criteria (augmented by later authors—see Table 15.1) to identify the disease. On this basis, cases have been identified from early populations in North America (Ortner et al., 2001), South America (Klaus, 2014), Europe (Mays, 2014), Asia (Ortner and Ericksen, 1997; Halcrow et al., 2014), Africa (Pitre et al., 2016), and Oceania (Buckley et al., 2014). In most large collections that have been examined, few cases have been found. Reviewing the European evidence, Mays (2014) concluded from this relative rarity, that in a temperate environment, seasonal fluctuations in vitamin C availability, and yearon-year variations in crop yields must not normally have been enough to induce serious vitamin C deficiency in subadults. Occasional findings of groups with high prevalences ( . 20%) of subadults showing lesions suggestive of scurvy were associated with famine or other historic events that disrupted normal food supply (Mays, 2014). A Bronze Age round barrow at Barrow Clump (Mays, 2008b) provides an early case of scurvy from England. The remains date from 2200 to 1970 BC and are of a child aged about 2 years. The postcrania survive poorly, precluding radiographic or other study of the metaphyses for signs of scurvy, but the skull was in good condition and shows a constellation of hemorrhagic

536 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

lesions. These are summarized in Table 15.2 and illustrated in Figs. 15.8 15.11. Some alterations were slight, and needed to be carefully evaluated against nonpathological skeletons from the same site to ascertain that they lay beyond the range of normal morphological variation (Figs. 15.8 and 15.10). Taken as a whole, the cranial lesions are as expected in vitamin C deficiency, and the array of alterations cannot credibly support another diagnosis.

Turning to postcranial lesions, scapular alterations are illustrated by another European case, from medieval Serbia (Brown and Ortner, 2011). This individual (aged about two years at death) showed porosis/new bone formation at most of the cranial locations listed in Table 15.1. There were also porotic alterations in the infraspinatus and supraspinatus fossae of the scapulae (Fig. 15.12). These sites underlie the major muscles of the rotator cuff; minor traumata due to arm movements may

TABLE 15.2 Lesions in Burial 6010 From Barrow Clump, England Feature

Type of Alteration Present

Sphenoid, external surface, greater wing

P

Zygomatic bone, medial surface/posteromedial surface of maxillary zygomatic process

P

Posterior surface of maxilla

P

Coronoid process of mandible, medial surface

P

Inferior surfaces of palatine processes of maxillae

P

Alveolar bone Orbital walls

NB, P

Cranial vault

Ectocranial: P; endocranial NB, P, BrL

Infraorbital foramen of maxilla Foramen rotundum of sphenoid

N

, no observation possible; BrL, branched lysis; N, no pathological change; NB, new bone formation; P, porosity.

FIGURE 15.8 Barrow Clump, burial 6010. (A) Greater wing of sphenoid bone, showing porosity. (B) A normal bone from a child of similar age for comparison. Although the normal bone shows some pores they are fewer and larger than in the Barrow Clump individual and tend to enter the cortex at oblique angles. Although the alterations in the Barrow Clump sphenoid are less severe than in Fig. 15.3, comparison with a reference bone indicates that the porosis is clearly abnormal.

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FIGURE 15.9 Barrow Clump, burial 6010. Right orbital roof showing new bone formation. FIGURE 15.11 Barrow Clump, burial 6010. Endocranial surface of the right parietal bone showing multiple contiguous bony channels (“branched lysis”). Areas of most intense channeling link with channels whose morphology indicates they conveyed blood vessels, supporting the notion that “branched lysis” alterations reflect proliferation of capillaries on the bone surface.

FIGURE 15.10 Barrow Clump burial 6010. (A) Inferior surface of the hard palate of the right maxilla showing porosis. (B) Normal bone from a child of similar age at death for comparison. Although the inferior surface of the hard palate is normally somewhat porotic, the Barrow Clump bone is outside of the normal range of morphology.

have elicited the lesions. A New World Case, from the 16th to 17th-centuries AD Shannon site, Virginia, shows abnormal porosity of the metaphyses of several long bones (Fig. 15.13). Clinical cases of scurvy often show bleeding around the joints (Fain, 2005), and the lesions in this 12month-old child, who also showed cranial signs of scurvy, are probably in response to periarticular hemorrhage.

ADULT SCURVY In adults, scurvy tends to occur in individuals that have restricted access to food. Food sources can become restricted for various reasons including practicalities of long sea voyages, problems of provisioning armies, prisons, and other institutions, lack of familiarity with available foods for those that move, and disruption of food

supplies caused by conflict and natural disasters (see Hess, 1920; Carpenter, 1986). Once growth has ceased, changes in the skeleton due to the presence of scurvy will be limited and subtle. Pathological lesions that develop secondary to hemorrhage will be the primary change found in adult skeletal remains (Brickley et al., 2016). If the condition persists for any time, reduced bone formation will lead to the development of osteopenia, but this type of change is nondiagnostic and poses problems for interpretation in paleopathology (Ortner, 2012). The first reports of possible cases of scurvy in paleopathology were in adults (e.g., Wells, 1967; Saul, 1972). Recognition of the limitations of paleopathology led to extensive research on subadults where pathological changes develop more rapidly, but recently further work on possible cases of scurvy in adult skeletal material has been undertaken. Although some of the pathological changes found in the subadult skeletal remains also develop in adults, these lesions occur less frequently and their expression is less clear (Mays, 2014). Skeletal changes associated with scurvy include porosity at sites of blood vessels in the cranial bones and periosteal new bone formation (PNBF) on the cranial and long bones. Mixed lesions occasionally also develop in the cranial bones.

Paleopathology Possible cases of changes in adult skeletons linked to scurvy have been proposed in individuals buried at an Arctic whaling station at Spitsbergen (Maat, 1982; Maat and Uyttershaut, 1984), inmates who died in a workhouse

538 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 15.12 Zidine, Serbia, burial LZIDS 18, left scapula. (A) Posterior view, showing porosity in infraspinous fossa. (B) Superior view showing porosity in supraspinous fossa. (Brown and Ortner, 2011, Fig. 15.8.)

FIGURE 15.13 Shannon site, NMNH 382489. (A) Anterior view proximal humeri. (B) Anterior view, distal femora. Each bone shows abnormal metaphyseal porosity.

during the Great Irish Famine (Geber and Murphy, 2012), early European colonists in North America (Crist and Sorg, 2014), prisoners in an early North American colonial settlement (Brickley et al., 2016), individuals voyaging from Europe to the Americas buried on La Isabela, in what is now the Dominican Republic (Tiesler et al., 2014), and workers from a South African mining community (Van der Merwe et al., 2010). In all cases careful evaluation of contextual information was key to using the skeletal changes identified to suggest cases of scurvy. There have been two investigations at archeological sites with good contextual information for the presence of scurvy in which no pathological changes that would allow cases of scurvy to be suggested were identified (Brickley et al., 2006; Cook, 2012). It is likely that many cases of scurvy in past communities will not produce clear pathological changes, and without good contextual information the lack of specificity in the pathological lesions produced may make it difficult to suggest scurvy as a likely diagnosis. In light of the nature of pathological lesions, investigations of attritional cemeteries are unlikely to produce many clear cases of scurvy (Brickley et al., 2016). Comparisons between evidence of pathological conditions in adult and subadult individuals have the potential to provide more nuanced information on social and cultural factors operating in past societies (Mays, 2014). In the case of scurvy, differences in the speed and frequency of development of recognizable skeletal lesions between adults and subadults are sufficiently large that comparisons using currently available techniques are unlikely to produce useful results. Recognition of the earliest cases of scurvy in adult skeletal material relied heavily on PNBF, particularly in the postcranial skeleton (e.g., Saul, 1972). Work by Geber and Murphy (2012) on skeletal remains of both adult and subadult individuals known to have died during the Great

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FIGURE 15.14 Porosity of the greater wing of the sphenoid bone in an adult male (estimated age of death of ./ 5 46 years) from the Kilkenny Union workhouse intramural mass burial ground, Ireland. This figure was kindly supplied by Dr. Jonny Geber.

Irish Famine, during which scurvy was known to have been a serious problem, identified some of the characteristic changes in adults (see Table 15.1). Amongst the changes found in adults were porotic lesions of the greater wing of the sphenoid bone (Fig. 15.14). The pathological changes are not as marked as some reported in subadults, but as in other reported cases in adults and subadults the porosity extends onto the temporal bone. Active areas of porosity with small deposits of sub-PNBF were present at a number of cranial areas including the infraorbital foramina (Fig. 15.15). In Fig. 15.15, slight porosity can also be seen along the alveolar process. Pathological changes to the gums are commonly mentioned in both contemporary and past texts covering scurvy in adults (Fain, 2005). In adults, dental eruption can be excluded as a cause for such change, but extensive dental pathology present in many past communities makes it hard to be certain that porosity observed is linked to scurvy (Brickley et al., 2016). The medial surface of the mandibular rami, in the region above the mandibular foramen, is another area in which porosity, hypertrophy, and slight areas of new bone formation have been reported in the skeletal remains of individuals suggested to have had scurvy. The very slight deposits of new bone formation in this region in an individual with other clear changes suggesting the presence of scurvy illustrate the very slight nature of some of the pathological changes formed in cases of scurvy in adults (Fig. 15.16).

FIGURE 15.15 Slight deposits of subperiosteal new bone formation around the infraorbital foramen in an adult female (estimated age at death 26 35 years). Slight porosity is also present in the area of the alveolar process marked. The individual pictured was excavated from the Kilkenny Union workhouse intramural mass burial ground, Ireland. This figure was kindly supplied by Dr. Jonny Geber.

FIGURE 15.16 The medial surface of the mandibular ramus foramen in an adult male (estimated age at death 26 35 years). The individual pictured was excavated from the Kilkenny Union workhouse intramural mass burial ground, Ireland. This figure was kindly supplied by Dr. Jonny Geber.

540 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

VITAMIN D DEFICIENCY Vitamin D is essential for calcium and phosphorus metabolism. In the absence of adequate levels of the vitamin, there is reduced absorption of these minerals from the gut. The resultant serum hypocalcemia stimulates the release of parathyroid hormone. This has the effect of mobilizing calcium stores from the skeleton, and there is increased loss of phosphorus in the urine (Holick, 2006, 2007). The effect of vitamin D deficiency is therefore poor mineralization of bone formed during growth and remodeling. Most foods naturally contain little vitamin D, but it is synthesized in the body via the action of ultraviolet light upon the skin. This produces a chemical precursor, 7dehydrocholesterol, which then undergoes successive hydroxylation in the liver and kidney to produce 1,25 dihydroxyvitamin D, which is the most physiologically active form (Henry and Norman, 1992). In subadults the term rickets is commonly used to refer to diseases caused by lack of availability of vitamin D, in adults it is termed osteomalacia.

RICKETS Rickets may be produced by a variety of conditions that affect vitamin D metabolism, including various disorders

of the gut, liver, and kidney (Resnick and Niwayama, 1988: 2089 2126). Most of these conditions are rare and/ or would not have been survivable for prolonged periods in the absence of modern medical care. Historically, the most important cause of vitamin D deficiency was inadequate acquisition of the vitamin. Given the importance of ultraviolet light in its synthesis, exposure of the skin to sunlight is crucial. Although there is less solar ultraviolet at higher latitudes, cultural factors that limit the exposure of skin to sunlight are of prime importance in determining the frequency of the disease in populations. The adoption of indoor lifestyles, the use of enveloping clothing, or living in an urban industrial environment where tall, closely spaced buildings and atmospheric pollution combine to limit sunlight reaching ground level are key variables (Brickley et al., 2014). Historical sources are a rich body of evidence concerning rickets in the past. The first convincing descriptions come from 1st-century AD Rome (Jackson, 1988: 38). The first clinical treatises come from mid-17thcentury England (O’Riordan, 2006), and it was then that it seems first to have become a regular problem. The prevalence of the disease increased sharply with industrialization, so that by the early 20th century, it affected up to 90% of children of the poor in some cities in northern Europe (Steinbock, 1993). By the mid-20th century it had

TABLE 15.3 Some Macroscopic Abnormalities That May Occur in Rickets Feature

Active/Healed

1. Cranial vault porosity

A

2. Orbital roof porosity

A

3. Cranial vault thickening

H

4. Deformed mandibular ramus 5. Rib bending deformity 6. Costochondral rib flaring 7. Costochondral rib porosity

A

8. Ilium concavity 9. Bending deformity—upper-limb long bones 10. Bending deformity—lower-limb long bones 11. Long-bone metaphyseal flaring/cupping of ends 12. Long-bone general thickening

H

13. Long-bone cortical (especially metaphyseal) porosity

A

14. Superior flattening femoral metaphysis 15. Coxa vara 16. Porosis/roughening on bone underlying growth plates

A

A, presence denotes disease active at time of death; feature generally removed by remodeling in healed cases. H, presence denotes healed/healing disease. Remaining features may be seen in both active and healed cases.

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become rare once more, as a result of treatment and prophylaxis using vitamin D-rich cod liver oil (Loomis, 1970). Rickets rarely appears before 4 months of age unless the mother was herself vitamin D-deficient (Maiyegun et al., 2002), and cases rarely develop after 4 years. Bone changes may be divided into those that arise directly due to metabolic disturbance, which leads to inadequate mineralization of bone deposited during growth, and biomechanical deformation of the weakened, poorly mineralized bone. The former are seen most readily at bone surfaces undergoing rapid endochondral or appositional growth. The latter are usually most pronounced in weight-bearing elements. Some of the bony changes most useful in identification of rickets are listed in Table 15.3 and are described below. Defective mineralization of bone deposited beneath the growth plate leads to subchondral porosis and irregularity. Where severe, this may be visible in radiographs of living patients (Fig. 15.17) as “fraying” of bone ends (Thacher et al., 2000; Pettifor, 2003). Changes are most often seen at the diaphysial ends of long bones (Fig. 15.18), but in archeological material care is needed to distinguish this from postdepositional erosion. Deficient mineralization of bone deposited in appositional growth leads to porosity of external cortical surfaces. In vivo, the pores and other defects on growing surfaces are filled with osteoid. Cortical porosity may occur at most subperiosteal surfaces but is often most evident on the external cranial vault (Fig. 15.19), orbital roofs (Fig. 15.20), and in metaphyseal parts of long bones; at the latter locations care is needed to distinguish pathology from the normal slight porosity seen there. When adequate vitamin D is restored, the pores are filled in with bone and obliterated, so the presence of porosity denotes disease active at death (Table 15.3). Because much osteoid may accumulate, ossification on recovery often results in thickening of bones. In the cranium this thickening is often greatest at the frontal and parietal bosses (Fig. 15.21). Flaring of long-bone metaphyses (Fig. 15.22) and sternal rib ends (Fig. 15.23) may occur, and seems to reflect both increased width of the growth plate and biomechanical deformation of the weakened bone. Mechanical forces may also result in concavity (cupping) of diaphyseal ends; the distal ends of the tibia and forearm bones and the sternal rib ends are favored sites (Figs. 15.17 and 15.23). Bending deformity (or less often, pathological fracture) is most often seen in the long bones, but sometimes in other elements, particularly the ribs and mandibular condyles. Among the long bones, deformity tends to be greatest in the lower limb, unless disease was active when the infant was still crawling

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FIGURE 15.17 Rickets in a 5-year-old child. There is widening, cupping, and fraying of the distal ends of radius and ulna. Courtesy of the University of Virginia.

when upper limbs may be more affected. In the femur, diaphyseal bending most often takes the form of accentuation of the normal anterior curvature, and the area of sharpest angulation is often in the subtrochanteric area. There may also be flattening of the superior surface of the proximal metaphysis and/or coxa vara (Fig. 15.22). Tibiae and fibulae most often show medial and/or anterior bowing; in the tibia there may be localized medial tilting of the distal end, and the fibula shaft is often flattened. Sometimes new bone is deposited on the concave side of bending deformities, thickening the cortex on that side. Upon recovery, bone deformity may be progressively removed by growth and modeling, but in some cases it may remain into adult life. The frequency with which residual deformity remains depends upon the severity and timing of childhood disease, but Hess (1930) suggests 10% 25% of cases of rickets may retain noticeable deformity.

542 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 15.18 Sequence to show increasing severity of porosity and roughening of diaphyseal bone underlying the epiphyseal growth plate in active rickets. (A) Proximal end of a tibia of a 9-month-old infant showing normal morphology. (B) Distal radius, 18 24-month-old child showing slight roughening, giving a “velvety” texture (the exposed trabecular bone toward the bottom in the photograph is a postdepositional artifact). (C) Distal end of a femur from a 3-month-old infant showing more marked roughening. (D) Distal end of a tibia from a 3-year-old child showing marked porosis. There is also concavity (“cupping”) of the bone end. (E) Distal end of a radius from a 6 12-month-old infant showing extreme roughening and porosis. (Archeological bones, (A), (C), (E) from Wharram Percy, UK; (B), (D) from St Martin’s Birmingham, UK.)

FIGURE 15.19 Ectocranial surface of a cranial vault fragment from an infant aged 6 8 months showing severe porotic alterations. (Archeological individual, Wharram Percy, UK.)

Radiographic signs of active rickets include diffuse osteopenia, coarsening and thinning of the trabecular structure, and loss of corticomedullary distinction (Thacher et al., 2000; Pettifor, 2003; Mays et al., 2006). Upon microscopic study, evidence of defective mineralization should be visible, and indications of hyperparathyroidism

FIGURE 15.20 Left orbital roof from an infant aged about 8 months, showing marked porosis. (Archeological individual, Wharram Percy, UK.)

(qv) are present (Goodman et al., 1994; Adams, 1997; Mays et al., 2007). These alterations are gradually removed as the child recovers. Some of the more subtle alterations seen in dry bone would not be visible on clinical imaging, but the

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FIGURE 15.21 Cranium of a 7-month-old infant with rickets, showing porotic bone deposition focussed on the frontal and parietal bosses (PMUG 2465, autopsy 6115, 1874).

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FIGURE 15.23 Sternal rib-ends. The top three bones from a child aged about 8 months showing signs of rickets, displaying porosity of cortex and “cupping” of their ends. The lower bone is a normal example for comparison. (Archeological bones from Wharram Percy, UK.)

mechanical deformities, and the more severe grades of porotic change seen at growing surfaces, appear to be the dry bone manifestation of alterations that have been documented radiographically in living patients (e.g., Thacher et al., 2000; Pettifor, 2003). In combination, the alterations described above represent compelling evidence of childhood vitamin D deficiency.

Paleopathology

FIGURE 15.22 Femur from a 2 3-year-old child showing signs of rickets (left), together with a normal comparative bone (right). The diseased bone shows marked flaring and cortical porosis of the distal metaphysis, and, at the proximal end, coxa vara and superior flattening of the metaphysis. (Archeological individual, St Martins, Birmingham, UK.)

Sporadic paleopathological cases of rickets have been noted from around the world (Littleton, 1998; Angel et al., 1987; Pfeiffer and Crowder, 2004), but most come from Europe. A few European cases date back to the prehistoric or Roman periods (Bennike, 1985: 213 214; Blondiaux et al., 2002), but frequencies in populations increase (up to c. 34% in some cases) in post-medieval urban industrialized groups (e.g., Clevis and ConstandseWestermann, 1992; Brickley et al., 2006; Henderson et al., 2013; Ellis, 2014). Clusters of cases occurring earlier than this, or in post-medieval rural groups, have occasionally been reported, with factors such as swaddling of infants (Veselka et al., 2015), sickly infants being confined indoors (Ortner and Mays, 1998), or cultural avoidance of exposure of skin to sunlight (Littleton, 1998) being invoked as explanations. There are 21 cases of rickets among 164 subadults from 19th-century St Martin’s churchyard, Birmingham,

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FIGURE 15.24 St Martin’s Birmingham, UK, burial HB772. Distal ends of radius and ulna, showing flaring and cortical porosis.

FIGURE 15.25 St Martin’s Birmingham, UK, radius burial HB772 (at left) with a normal radius for comparison (right).

England. Among these is burial HB772, a child of about 3 years. The distal metaphyses of all long bones, save the humeri, showed flaring and abnormal porosity of cortex (Fig. 15.24), as did some sternal rib ends. There was roughening of the bone underlying the endochondral growth plate at the distal ends of the tibiae (Fig. 15.18D), radii, and ulnae. Radiographically, there was osteopenia, loss of normal corticomedullary distinction and coarsening and thinning of cancellous bone structure (Fig. 15.25). Scanning electron microscopy of a section taken from the distal radial metaphysis showed poor levels of

FIGURE 15.26 St Martin’s Birmingham, UK, burial HB772. Scanning electron micrograph, trabecular bone. Some areas of newly formed bone (A) are darker, indicating poor mineralization. Defective cement lines (open arrows) are also evident. The long arrows indicate areas of erosion of trabecular bone within trabecular elements.

mineralization of more recently formed bone and defective cement lines (Fig. 15.26). Taken together, these alterations are consistent with rickets; the porotic alterations, and the radiographic and microscopic changes suggest disease active at time of death. There are also indications of hyperparathyroidism. Radiographically, linear radiolucencies were evident within cortical bone, giving it a longitudinally striated appearance (Fig. 15.25). Microscopically, there is erosion of trabecular bone from within trabecular elements (Fig. 15.26). These alterations are consistent with the skeletal effects of hyperparathyroidism, which is expected secondary to vitamin D deficiency. Two medieval subadult cases from medieval Wharram Percy illustrate biomechanical deformities characteristic of rickets. Burial V57 is an infant aged 6 12 months. The skeleton is rather incomplete but shows abnormal porosity of cortex, and of bone underlying the growth plates on long-bone diaphyses, indicative of active vitamin D deficiency. The only intact long bone is the left radius, which shows marked angulation of the distal end (Fig. 15.27). Consistent with the age of the individual, this suggests active vitamin D deficiency, whilst the infant was still crawling. Lower-limb bone deformity is evidence on an older infant (burial SA070, approximately 18 months). This child shows predominantly healed lesions (thickened ribs, long bones), but there is some porosity of the cranial bones suggesting that disease recrudesced shortly before death. The arm bones show little deformity, but there is abnormal angulation of the mandibular condyles (Fig. 15.28) and abnormal curvature of ribs and femora (Fig. 15.29). The latter show marked localized anterior angulation in the subtrochanteric area. The tibiae are rather damaged and difficult to assess for

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FIGURE 15.29 Wharram Percy, UK, burial SA070. There is abnormal anterior curvature of the femur shaft, most pronounced in the subtrochanteric area (arrowed).

FIGURE 15.27 Wharram Percy, UK, burial V57. Left radius showing abnormal angulation toward its distal end.

FIGURE 15.30 A femur from a 19th-century adult from St Martin’s Birmingham, UK (disarticulated bone D3). The bending deformity suggests that this person suffered from rickets as a child.

FIGURE 15.28 Wharram Percy, UK, burial SA070. Posterior view of the right mandibular ramus; there is abnormal angulation of the mandibular condyle (arrowed). On the left is a normal individual for comparison.

diaphyseal bowing, but the deformation of the femora suggests active disease after the child had begun walking, which normally occurs at about 12 months (Størvold et al., 2013). Similar femoral deformity, persisting into adult life, is illustrated by another case from St Martin’s, Birmingham (Fig. 15.30).

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OSTEOMALACIA Pathological changes to the skeleton in cases of osteomalacia are reliant on bone turnover and so require a longerstanding deficiency to manifest, and in most cases will be far less marked than skeletal changes in subadults. In investigations where deficiency has been considered in both adults and subadults, cases of skeletal pathology are much higher in subadults who are undergoing bone growth and development (Mays et al., 2006; Brickley et al., 2007). The development of osteomalacia due to an underlying pathological condition is possible in adults from past communities, but would be relatively rare. In many cases muscle weakness and bone pain would have been the main symptom of osteomalacia, with some individuals having limited mobility (Stapleton, 1925). The severe bony deformity and extensive pathological fractures that have been collected in European pathology museums (Brickley et al., 2005) would only have occurred in the most extreme cases. Descriptions of osteomalacia in historical sources are limited (see brief review in Maxwell, 1947), but due to the desperate consequences, deformity to the pelvis (Fig. 15.31) causing complications of childbirth has received quite a bit of attention. Severe pelvic deformities have been reported from a number of regions including Europe, India, and China (Hess, 1930: 317 20). In both adults and subadults the failure of newly formed bone matrix to mineralize can lead to the

development of osteopenia, and in adults profound bone loss has been reported in those with vitamin D deficiency (Reid and Bolland, 2014). Bone loss is, however, a nonspecific skeletal change linked to advancing age and a variety of pathological conditions that can cooccur, so is of limited value in suggesting the diagnosis of a specific condition in paleopathology (Ortner, 2012). Skeletal changes include deformation due to the accumulation of osteoid (Jaffe, 1972; Mankin, 1974) and pathological fractures at sites of osteoid accumulation (Mankin, 1974; Albright et al., 1946; Hodkinson, 1971; Lips et al., 2013). Common sites for changes are listed in Table 15.4. The most marked changes occur in bones with a high remodeling rate due to considerable trabecular bone content. Buildup of osteoid can eventually result in bones literally folding; affected vertebral bodies can resemble a crumpled tin can. Both deformity and fractures commonly occur in the thorax, with ribs, sterna, and vertebrae often affected. The systemic nature of the condition, however, means long bones can also develop pathological changes, with those of the leg more frequently affected than arm bones (Hess, 1930; Jaffe, 1972). The weight of the body or simple daily activities can be sufficient to produce these changes (Figs. 15.32 and 15.33). Pseudofractures are a key feature of osteomalacia, occurring due to a build-up of osteoid. Clinically pseudofractures appear on radiographs as zones of high radiolucency (Steinbach et al., 1954; Mankin, 1974; Pitt, 1988: 2096). Frequently, fractures develop at these sites FIGURE 15.31 Active osteomalacia. Pelvis and lumbar spine that show maximal malacic deformity of the cardboardlike bones and delayed fusion of the growth plates. This individual, an 18-year-old male (DPUS 7664c and 7664d, 1896), displayed changes across the skeleton with bending deformities of most bones.

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TABLE 15.4 Typical Sites for Bone Deformation and Pseudofractures in Osteomalacia Lesion Location

Comments

Postcranial 1. Ribs

Deformation can be hard to identify in fragmented bone Pseudofractures, often multiple. Particularly common where corsets were worn, but also noted in noncorsetwearing communities

2. Scapulae

Deformation of blade, exaggerated posterior curvature Pseudofractures noted at spinous process and lateral boarder

3. Iliac crest

Deformation Pseudofractures

4. Pubic bone

Deformation

5. Spine

Compression fractures of vertebral body

Pseudofractures

Pseudofractures noted on transverse processes 6. Long bones

Deformation From macroscopic assessment it can be difficult to establish when the deformity occurred. Deformity more common in cases of rickets Pseudofractures Any bone can be affected, but more commonly noted locations include the femoral neck

7. Sternum

Deformation

8. Sacrum

Deformation

Cranial 1.

Extensive porosity and “cardboard-like” texture reported in pathology museum collections. Not observed in archeological bone to date

2.

Invagination of foramen magnum. Not observed in archeological bone to date

Sources: Brickley et al. (2005), Brickley and Ives (2008), Ives and Brickley (2014).

and, observed on dry bone, slight raised areas of spiculated bone will often be present at the margins and in fractured ends as a result of often long-standing impaired attempts at repair. Unless very extensive it is unlikely pseudofractures (Stapleton, 1925) or deformity would have been noticed by affected individuals. Maxwell (1930) states that the extent to which bending deformity and fracture are present in cases of osteomalacia is very variable. It is likely that expression and distribution of these features will depend on the length and severity of deficiency experienced coupled with habitual activities undertaken. In considering activities all things from the wearing of a corset to lifting and carrying heavy objects and the customary mode of sitting or standing should be considered.

Analysis of evidence for systematic mineralization defects in dentin (defects have been termed interglobular dentin) offers the potential to identify individuals who experienced past deficiency. Interglobular dentin (Fig. 15.34) is formed when some of the calcospherites, groups of crystals that compose dentin, fail to fuse, resulting in hypomineralized (poorly mineralized) areas that have a marbled appearance when thin sections are viewed microscopically using polarized light (D’Ortenzio et al., 2016).

Paleopathology Vitamin D deficiency can occur at any stage of life, and it is likely that individuals who are affected once will

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FIGURE 15.32 Osteomalacia skeleton with severe pelvic and thoracic deformity. Notable rib deformities are present from the weight of the arms. Other features present are angulated protruding sacrum and the folded iliac wings. (Adult female; died after seventh pregnancy; PMES 1 QAM(1).)

have a high probability of being affected multiple times (Brickley et al., 2014). This adds a certain level of complexity to examination of pathological features, but consideration of this point increases the potential contributions paleopathological investigations can make regarding the experiences of individuals in past communities. The number of paleopathological investigations undertaken to date is relatively small (Brickley et al., 2005,

2007; Mensforth, 2002; Schamall et al., 2003a,b). The skeletal changes associated with osteomalacia are easily overlooked and it is likely that many cases have not been spotted because the observers were not specifically looking for the condition. A large-scale study of pathological changes found in archeological skeletons undertaken using UK sites (c. AD 1700 1855) revealed examples of pathological fractures in many areas of the skeleton (Ives and Brickley, 2014). Ribs, which have been noted to be

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FIGURE 15.33 Severe osteomalacia with angular kinking of sacrum through a segment (arrow) from sitting. (43-year-old female; FPAM 5676.)

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frequently affected by deformity and fractures (Jaffe, 1972; Pettifor and Daniels, 1997), were the bones most often affected. The prevalence of rib fractures in the study by Ives and Brickley (2014) was probably influenced by corset wearing amongst females, but individuals with numerous fractured ribs and multiple fractures in a single rib have been reported by clinicians working with noncorset-wearing communities (Jaffe, 1972). Deformity can be viewed by macroscopic examination of bone in paleopathology, as can many pseudofractures. Features of pseudofractures such as disorganized and poorly formed bone callus (spiculated bone) produced by individuals with vitamin D deficiency are discussed by Brickley and Ives (2008, pp. 118 119). Recent work in the Roman site (1st 2nd century AD) of Velia, Italy, identified a case of osteomalacia in an older adult female (VEL94). Pathological fractures were identified across the thoracic skeleton, scapulae, ilium (Fig. 15.35), ribs (Fig. 15.36), and a lumbar vertebra. A clear pseudofracture was present in the left scapula (Fig. 15.37). On the right scapula an area of spiculated new bone formation was located on the spinous process, a classic site at which pseudofractures have been recorded in other archeological skeletons (Ives

FIGURE 15.34 Histological image of interglobular dentin observed in a thin section of a first maxillary molar from an adult with past deficiency. The circle marks an area of extensive mineralization defects (grade 3 interglobular severity, D’Ortenzio et al., 2016) from St. Matthew, Quebec City, Canada (AD 1771 1860). This figure was kindly supplied by Dr. Lori D’Ortenzio and Bonnie Kahlon.

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FIGURE 15.35 (M3) Pseudofracture on left ilium, immediately lateral to the superior portion of the sacroiliac joint. There is a slight raised area of spiculated new bone formation around the margins of the fracture (V94, Velia Italy).

FIGURE 15.36 (M4) Pseudofracture of a right rib. (A) The two sides of the pseudofracture. (B) End-on view of the left side of the rib fracture with clear build-up of spiculated bone that will have formed as the body attempted to heal the fracture (V94, Velia, Italy).

FIGURE 15.37 Pseudofracture of the left scapula located immediately inferior to the spinous process. A raised area of poorly formed fracture callus (outlined with white oval) with a small curvilinear fracture line running across part of the area is present (V94, Velia, Italy).

and Brickley, 2014). Radiological examination would have helped determine whether a pseudofracture was present on the right scapula, but was not possible in this case. The location of the lesions was not symmetrical between the left and right sides. A probable pseudofracture, that was not quite as clear as the others, was present at the inferior articular process of a lumbar vertebra (Fig. 15.38); if this was the only fracture present there is a strong possibility it would have been overlooked. Careful examination of the margins revealed spiculated bone, and in light of the other fractures present in this individual and previously reported cases of fractures in the transverse processes of vertebrae (Ives and Brickley, 2014) the fracture is taken as a pseudofracture.

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CO-OCCURRENCE OF RICKETS AND SCURVY

FIGURE 15.38 Location of the probable pseudofracture marked with an arrow on the right inferior articular process of a lumbar vertebra (V94, Velia, Italy).

Situations that leave individuals open to poor health often facilitate the development of multiple pathological conditions. The term co-occurrence is used where multiple conditions occur simultaneously; it may also be possible to suggest the occurrence of multiple conditions at different stages of the life of an individual. Rickets and scurvy, which were frequently noted to cooccur in past clinical work, have now been identified from a number of archeological sites (see review in Schattmann et al., 2016). Features of both conditions as set out in Tables 15.1 and 15.3 need to be present to suggest a case of cooccurrence. A number of the lesions that can develop in rickets and scurvy are similar; in archeological bone it may be impossible to determine the cause of these lesions. Interaction of the two conditions, order of initiation, and severity will all influence lesion appearance. Consideration of disease stage is an important aspect of evaluation of c-ooccurrence. In scurvy there will be impaired osteoid formation, thus limiting the development of bone deformity in rickets. Rickets will be far more visible if it occurs first and bone deformity due to an accumulation of osteoid has time to develop. In contrast, hemorrhage, a key feature of scurvy, will not be disrupted by the presence of rickets (see Fig. 15.39); these issues

FIGURE 15.39 Individuals from Saint-Ame´ collegiate church in Douai, France (AD1500 and AD 1776). (A) Cranial changes in co-occurrence case, porosity on the sphenoid greater wing, S56. (B) Ribs showing pathological features of rickets and scurvy co-occurrence. Clear porosity and flaring of the sternal ends, S264. Comparison of long bone deformity in the left humerus. (C) Cases of co-occurrence of rickets and scurvy. Left hand bone, S221 has no bending and slight abnormal curvature is present in S208 (right). (D) More marked deformity in case of just rickets (non-comorbid case, S835).

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are discussed more fully by Schattmann et al. (2016). Those authors found use of macroscopic, radiological assessment of rickets and scurvy, and histological assessment of rickets facilitated identification and interpretation of pathological lesions observed.

OSTEOPOROSIS When there is sustained alteration of the normal balance between bone formation and bone resorption in favor of the latter there is loss of bone mass (osteoporosis). Osteoporosis may occur secondary to some diseases or to injury or immobility, and may be either localized or systemic. In addition, systemic loss of bone mass is an accompaniment of the aging process in the adult. Localized reduction of biomechanical forces, such as may occur to a limb that is injured or paralyzed leads to localized osteoporosis in the affected area (Fig. 15.40). Systemic loss of bone mass may occur in those with spinal cord injury or in individuals who are bed-ridden (Sieva¨nen, 2010). Some diseases lead to localized loss of

bone mass. In rheumatoid arthritis, activation of osteoclasts near joints affected by the disease leads to localized osteoporosis (Sommer et al., 2005). Conditions that interfere with collagen formation (e.g., vitamin C deficiency), or that prevent adequate absorption of calcium from the gut (e.g., vitamin D deficiency or inflammatory bowel disease) may lead to systemic loss of bone mass, as may a variety of other types of conditions (Mirza and Canalis, 2015). However, in paleopathology, most attention has focused upon the progressive, systemic loss of bone mass that occurs with advancing age. This reflects the importance of age-related osteoporosis in modern populations. Osteoporosis weakens the skeleton and leads to a propensity to fracture, often consequent upon only minor trauma, so that it presents a major health threat to the elderly today. Bone mass is built up during the growth period, and peaks in early adult life, but from middle age onward, bone resorption generally outstrips bone formation so that there is progressive loss of skeletal mass. In osteoporosis, bone resorption occurs from the endosteal envelope

FIGURE 15.40 Anteroposterior radiograph of long bones from the lower limbs of a male adult burial (6th century AD, Austria). This individual had suffered an amputation of the left foot. The left leg bones (to the right in the radiographs) show thinned cortical bone and rarified spongiosa, consistent with osteoporosis due to reduced weight bearing on the affected leg. (Fig. 15.12 from Binder et al., 2016.)

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FIGURE 15.41 Anteroposterior radiographs of three second metacarpals from (from left to right) young adult, middle aged, and elderly females excavated from St Bride’s Lower Churchyard, London, UK (post-medieval), to illustrate progressive thinning of cortical bone with age. (Brickley and Ives, 2008, Fig. 6.2.)

(Parfitt, 2003; Szulc and Seeman, 2009). There is rarification of trabecular bone. The normal slow apposition of cortical bone continues subperiosteally (Lazenby, 1990), but this is not enough to compensate for loss at the endosteal surface so that there is progressive thinning of cortical bone. There is also increased intracortical porosity. Because of its greater metabolic activity, there is earlier and greater loss of trabecular bone (Riggs and Melton, 1986) and losses here lead to alterations in bone microstructure, an aspect of “bone quality” that, in addition to bone mass, influences resistance to fracture (Grynpas, 2003). Perforations occur in the trabecular structure, interrupting its continuity, so that mechanical strength is compromised to a greater extent than simple loss of mass would predict. Some age-related changes in cortical thickness and trabecular bone microarchitecture are illustrated in Figs. 15.41 and 15.42. The amount of bone mass retained into old age is dependent both on peak bone mass attained in early adulthood and on the amount lost during the aging process. A multiplicity of environmental, lifestyle, and genetic factors influence these parameters, but sex hormones play a pivotal role (Carnevale et al., 2010; Clarke and Khosla, 2010). In females, there is a phase of rapid bone loss following menopause, with a slower rate of loss thereafter. Males also lose bone with age, but because they lack the early phase of accelerated loss seen in women, and because they normally attain higher peak

bone mass, osteoporosis is less severe in men (Khosla and Riggs, 2005). Osteoporosis is clinically silent until fracture occurs. Fractures may affect any skeletal element, but sites rich in trabecular bone are most vulnerable. Characteristic fracture sites are the hip, wrist, and spine. Hip fracture (Brunner and Eshillian-Oates, 2003) occurs in the proximal femur, most often in the region of the neck (Figs. 15.43 and 15.44). Due to the nature of the blood supply at the proximal femur, fracture union is often problematic and hip fractures may lead to significant disability and increased risk of mortality (Brunner and Eshillian-Oates, 2003). Osteoporotic fracture due to a fall on an outstretched hand may lead to fracture of the distal radial metaphysis, with dorsal angulation of the distal fragment—Colles’ fracture (de Brujn, 1987). Vertebral compression fractures, which may result in forward angulation of the spine or in biconcave “cod-fish” deformity of the vertebrae, may occur during normal activities such as lifting. They mainly occur in the lumbar spine and in thoracic segments below T3 (Griffith et al., 2013).

Methods in the Study of Osteoporosis in Paleopathology Paleopathological studies of hip fracture (e.g., Curate et al., 2011; Ives et al., 2017), Colles’ fracture (e.g., Mays, 2006a), and vertebral compression fracture (e.g.,

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FIGURE 15.43 Basic fracture types in the region of the femoral neck.

FIGURE 15.42 Vertical section of fourth lumbar vertebral bodies from female adults from medieval Wharram Percy: (A) aged 18 30 years, (B) aged 30 50 years, (C) aged 50 1 years, to demonstrate age changes in trabecular bone structure. (A) Three-zonal arrangement of cancellous bone, characteristic of a young adult. Superior and inferior zones of dense cancellous bone surround a central band of more open trabecular structure. (B) Thinning of trabecular structure, especially by loss/thinning of horizontal trabeculae, is evident. (C) Further rarification of cancellous bone is apparent. Some very long, slender trabeculae are evident, and the loss of many horizontally orientated trabecular elements means that the course of some vertically orientated struts can be traced through most of the height of the vertebral body.

FIGURE 15.44 Right femur from an elderly adult male from medieval St Mary Spital, London. There is a healed fracture of the femoral neck, with inferior displacement of the head. Comparison with Fig. 15.43 identifies this as a subcapital fracture. (Walker, 2012, Fig. 208.)

Curate et al., 2016) have been undertaken. However, fractures at these locations may occur due to trauma in individuals showing no reduction in bone mass, so the presence of these types of fracture is insufficient to diagnose osteoporosis. The dominant approach to studying osteoporosis in past populations has been to identify patterns of loss of bone mass or bone quality in skeletal collections.

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FIGURE 15.45 Dual-energy X-ray absorptiometry (DXA) scan of the proximal femur of a 58-year-old woman from the Coimbra identified skeletal collection (early 20th century, Portugal). The rectangular box drawn across the femur neck defines the area scanned for bone mineral density (BMD) measurement at the neck. The smaller box within this defines Ward’s triangle, an area of low bone density where the greatest age-related loss of BMD generally occurs. The scanner calculates BMD at these and other sites in the proximal femur and tabulates the results. (Curate, 2014, Fig. 6.)

Measurement of Bone Quantity In clinical practice, and in biomedical research, the “gold standard” for assessment of bone status in osteoporosis is measurement of bone mineral density (BMD) using dualenergy X-ray absorptiometry (DXA). This uses an X-ray source that emits beams at two different energy levels. This allows attenuation specifically due to bone to be isolated and used to calculate BMD. Scanned sites are generally those that are most vulnerable to fracture: the hip (Fig. 15.45), spine, and wrist. This produces a measurement of areal density (i.e., g.cm2) rather than a true (volumetric) density (Lees et al., 1998), so results are not fully normalized for bone size. Because archeological bones lack marrow and soft tissue, absolute BMD, measured using DXA, is not directly comparable with data from living subjects. Therefore peak BMD cannot be compared between skeletal and living populations. However, provided significant diagenetic alteration in BMD can be excluded, patterns of age-related loss of BMD can be compared between living and ancient populations. The World Health Organization defines osteoporosis as a BMD, measured using DXA, .2.5 standard deviations below the young adult mean for individuals of the same sex; a value of between 1.0 and 2.5 standard deviations below the mean is termed osteopenia (WHO, 1994).

However, these are arbitrary diagnostic thresholds imposed upon what is a continuous process of BMD loss. Rather than using BMD to classify individuals as osteoporotic or not, most paleopathological work has taken a more exploratory approach, investigating age patterning in BMD. Radiographic or other imaging, microscopy, and chemical analyses can be used to check for diagenetic alterations that might alter BMD readings in ancient bones (Mays, 2008a,b). Cortical bone may be quantified by taking measurements of cortical thickness from radiographs—a method termed radiogrammetry. In clinical practice, measurement is normally taken at the metacarpals. The method predicts bone density and fracture risk at the hip, spine, and wrist, and is a rapid, low-cost way of screening patients for osteoporosis (Ka¨lvesten et al., 2016). Clinicians use an automated method which involves measurements at metacarpals 2 4. This has not been applied to archeological material, due in part to the requirement for three intact metacarpals limiting sample size in the fragmentary and incomplete remains typical of the archeological record. Paleopathologists typically use an older method in which measurements are taken at the second metacarpal alone, either with calipers from hard-copy radiographs (Ives and Brickley, 2004), or digitally using image analysis. Results

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FIGURE 15.46 Schematic diagram of a second metacarpal showing the method for measuring total bone width (T) and medullary width (M) from anteroposterior radiographs. Measurements are taken at the midshaft, and cortical index is calculated as 100 3 (T M)/T.

are usually expressed in terms of cortical index, a measure of thickness of cortical bone standardized by bone width (Fig. 15.46). In dry bone studies, the metacarpal can be positioned for radiography in an orientation that closely mimics that used in radiographic work on living subjects. This means that, provided that bones showing soil erosion or other damage are excluded, results on skeletal remains are closely comparable with older clinical and biomedical studies, which used second metacarpal radiogrammetric measurements. Unlike BMD, both peak cortical bone thickness and patterns of loss can be directly compared between living and skeletal populations.

Measurement of Bone Quality Bone quality comprises various structural parameters of bone that affect fragility, including bone microarchitecture, mineralization, and material properties (Grynpas, 2003). An aspect of bone quality that can be fairly readily assessed in paleopathology is microarchitecture. Bones may be physically sectioned, and microstructural features captured photographically or microscopically (Agarwal et al., 2004). High-resolution computed tomography provides an alternative, noninvasive method of capturing three-dimensional images of trabecular structure (Macho et al., 2005), and potentially facilitates comparisons between archeological skeletal remains and modern data gathered on living individuals. In trabecular bone, various microstructural parameters may be measured using image analysis, including trabecular number, thickness, and connectivity (Agarwal et al., 2004). Aspects of cortical microarchitecture, such as intracortical porosity, may also be quantified (Agnew and Stout, 2012).

Paleopathology As long ago as the 18th century, physicians began to note that bones in elderly people were more vulnerable to fracture (Brickley, 2002), but prior to the advent of

radiography in the last decade of the 19th century it was impossible to evaluate bone mass in living patients. Therefore, to investigate osteoporosis in the past we are reliant on paleopathological studies. These have focused on investigating patterns of bone loss with age in the past and on assessing the health impact of the disease through study of osteoporotic fracture. Because the study of osteoporosis in the past is based on measuring bone status in individuals of different ages, rather than identification of lesions, its study has demanded a population-based approach rather than one focused on case studies of isolated skeletons. A key avenue of investigation has been the extent to which patterns of age-related loss of bone in the past resemble or differ from that seen today (reviews in Mays, 2008a; Curate, 2014). One skeletal collection in which osteoporosis has been extensively studied is that from medieval Wharram Percy, England (summarized in Mays, 2007). Among the variety of techniques that have been used to assess bone status in this group is DXA of the femoral neck. Studies were done to assess whether readings might be affected by soil ingress or by postdepositional chemical alteration of bone. Femora were radiographed and any that showed soil intrusion were excluded from study. Microscopic analysis showed little evidence for minor soil ingress that might have escaped detection on radiography; chemical and microscopic analyses suggested no great changes to bulk mineral content or composition (TurnerWalker and Syversen, 2002; Mays, 2003). This seemed to support the validity of using DXA to assess osteoporosis in this population. The results for the Wharram Percy women, together with some modern comparative data, are shown in Fig. 15.47. Recalling that absolute BMD measured using DXA cannot be directly compared between living subjects and dry bone studies, comparisons were restricted to agerelated patterning. Given the shortcomings in currently available methods of estimating age from skeletal remains, individuals were assigned to the broad age at death classes. It seems likely that menopause generally began in the late 40s in the past, as it does today (Pavelka and Fedigan, 1991). Comparing BMD in 30 49 and 50 1 age groups suggests a similar postmenopausal loss to today. A problem with this comparison is that if the age composition of the 50 1 age group differed between the Wharram Percy group and the modern reference sample then this could prejudice comparisons. In an attempt to deal with this problem, the age composition of the 50 1 group at Wharram Percy was modeled using medieval demographic data from historical sources. This suggested that if anything the women in the 50 1 group at Wharram Percy were likely to have been younger than those in the same group in the modern reference population used for the comparative data in Fig. 15.47. This

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FIGURE 15.47 Bone mineral density at the femoral neck in women from Wharram Percy, UK (N 5 54), compared with results from a living reference population (Lunar Corporation, 1993). Although absolute BMD figures from dry bones cannot be directly compared with reference data from living populations, valid comparisons of age-related patterns can be made.

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suggests that postmenopausal bone loss in the Wharram Percy women was likely no less than in modern subjects, although it leaves open the possibility that it was greater. Unlike the modern population, the medieval women showed evidence of significant reduction on BMD in the 30 49 age group compared with the 18 29 group. This suggests significant premenopausal loss of BMD. Reasons for this are unclear but one factor may be losses of BMD due to prolonged lactation combined with poor nutrition, and/or hormonal changes consequent upon poor energy balance due to high levels of physical activity coupled with inadequate nutrition (Mays, 2010). Some vertebral compression fractures were identified in the Wharram Percy women (Fig. 15.48). Despite the age-related loss of BMD demonstrated at the hip, no hip fractures were found. One reason might be that too few women survived into the advanced old age groups at which hip fractures typically tend to occur. However, additional studies of the Wharram Percy bones suggested other possible explanations. Study of trabecular bone quality (Agarwal et al., 2004) suggested trabecular microstructural integrity was conserved into old age, perhaps helping to offset the effects of loss of BMD on bone strength. In addition, the relative length of the femur neck was less at Wharram Percy than in a modern reference group (Chumley et al., 2004). Shorter femoral necks tend to be less vulnerable to fracture (Cummings et al., 1994). Successful study of BMD in trabecular bone-rich locations in the skeleton demands well-preserved remains. At

FIGURE 15.48 Healed compression fractures of the bodies of the twelfth thoracic and first lumbar vertebrae from an elderly female from Wharram Percy, UK. This individual had a femur neck BMD approximately four standard deviations below the female young adult mean.

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FIGURE 15.49 Metacarpal cortical index in women from Ancaster, UK (N 5 39). Data from women from Wharram Percy, UK (N 5 67) and a modern female reference population (Virtama and Helela¨, 1969) are also included.

another British cemetery site, Ancaster (3rd 4th century AD), many of the femora and vertebrae were damaged or showed soil ingress, precluding use of DXA. Instead, radiogrammetry of the second metacarpal was used (Mays, 2006b). Plain-film radiographs were taken, and total width and medullary width were measured using calipers, and cortical index calculated (Fig. 15.46). The results are shown in Fig. 15.49. Mean peak cortical index, taken as the value in women in the 18 29-year group, was less than the modern group. This was also a finding for Wharram Percy (Fig. 15.49) and appears to be a general pattern in past populations (Mays, 2008a). Reasons for this are unclear, but one factor may be poorer nutrition in the growth period—this is known to lead to deficient apposition of cortical bone (Himes et al., 1975). At both Ancaster and Wharram Percy, there was evidence for premenopausal loss of bone. Comparison of cortical index in 30 49 and 50 1 age groups suggested postmenopausal bone loss was greater at Ancaster than in modern women (Fig. 15.49), a pattern that demographic modeling using Roman written sources suggested was unlikely to be due to discrepancies in the age composition of the 50 1 age group. A total of six Ancaster females showed eight osteoporotic fractures—one hip, four Colles’ fractures (Mays, 2006a) (Fig. 15.50), and three vertebral compression fractures. Unlike other fractures, these injuries were only seen

FIGURE 15.50 Medial view of radii from an elderly female burial from Ancaster, UK. The right radius shows a Colles’ fracture (arrowed) through its distal metaphysis. The fracture is firmly healed and shows the dorsal angulation of the distal fragment (“dinner fork deformity”) characteristic of this fracture type.

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in the 50 1 age group. The frequency of these types of fractures was greater than at Wharram Percy, presumably reflecting the lower cortical index in the Ancaster women. Why the Ancaster females should have suffered osteoporosis more severely than their modern or medieval counterparts was unclear.

Conclusion G

G

G

G

G

The study of osteoporosis in the past demands a population-based rather than case study-based approach. Ideally, several different methods of assessing bone status (quantity, quality) should be brought to bear so that a fuller picture of age-related patterns in the group under study can be obtained. Study of fractures should be integrated within this approach. Attention should be paid to possible diagenetic effects on DXA BMD studies. Attention should be paid to the potential effects of imprecision in currently available age estimation techniques for adults when interpreting results.

FLUOROSIS Fluoride is essential for normal development and maintenance of bones and teeth (Perumal et al., 2013) and is added to drinking water in many areas of the world to increase the ability of dental enamel to resist caries (WHO, 2011). Naturally high fluoride concentrations in water are found in many regions of the world, but have been noted to be unusually high in some areas (e.g., areas of the United States, with the highest levels recorded in Idaho, parts of India, China, South America, and Iran). Many foodstuffs, particularly those derived from vegetation, also contain at least traces of fluoride (DenBesten and Li, 2011). Exposure to fluoride can also occur though inhalation of fluoride dust from burning fluoride-rich coal, although in homes where such coal is used most fluoride is probably ingested from foods contaminated during cooking and drying (Qin et al., 2009). Levels of fluoride added to water for therapeutic purposes usually result in water with between 0.5 and 1 part per million (ppm) (DenBesten and Li, 2011; units converted using unit conversion.org). Fluoride of ,2 ppm can cause dental fluorosis with mottled enamel development (Shomar et al., 2004) and levels of .3 ppm can lead to the development of skeletal fluorosis (Jha et al., 2013). Research has demonstrated that the type of exposure (chronic exposure to low levels vs acute exposure to high levels), type of intake (ingested vs inhaled), age when exposure occurs (which will affect type and speed of tissue formation), nutrition (e.g., availability of calcium and

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magnesium), renal function, and possibly genetic factors all play a role in the pathological consequences of exposure to high levels of fluoride (DenBesten and Li, 2011). Dental fluorosis will reflect exposure to fluoride during enamel development and in most cases the permanent dentition, which forms during childhood, is affected (Jarvis et al., 2013). Disrupted mineralization of enamel is the primary pathological change associated with raised fluoride intake. Changes include subsurface porosity, hyper- and hypomineralized areas, and marked pitting (hypoplastic defects) in severe cases. Dentin formation can also be affected, but these changes are less well understood (DenBesten and Li, 2011). The system of classifying and recording dental fluorosis developed by Dean (1942), the dental fluorosis index, which allows enamel changes to be recorded for each tooth is still considered the “gold standard” for clinical recording (DenBesten and Li, 2011). Skeletal fluorosis develops in cases of prolonged exposure to high levels of fluoride (Perumal et al., 2013). In adults, levels of skeletal fluorosis have been noted to increase with age (Shruthi et al., 2016), but skeletal fluorosis can also occur in subadults, most often following rapid bone growth in adolescence (Jarvis et al., 2013). Skeletal changes include an increase in density (osteosclerosis) and ossification of skeletal attachment sites of ligaments and tendons (Gupta et al., 2016). Bone formed is of poor quality and pathological fractures can occur. There is considerable subperiosteal and endosteal bony accretion, often accompanied by increased resorption in the old cortex on long bones (Fig. 15.51) (see Aggarwal, 1973). Skeletal fluorosis in subadults can result in deformity of weight-bearing bones (Jarvis et al., 2013).

Paleopathology Fluorosis has not been widely studied and this is probably a reflection of relative levels of paleopathological research undertaken in areas of the world where fluoride in the water supply has been present at toxic levels. The earliest cases of fluorosis were reported from the site of Mehrgarh in Baluchistan (Lukacs et al., 1985). Dental pathology associated with fluorosis was found in nine skeletons from two levels dating between 7000 and 4000 BC. The abnormalities are limited to staining and pitting of the enamel of adult teeth and no lesions were found in the bones. Both dental and severe skeletal fluorosis were present in the skeleton of an adult male (aged 45 1 ) from a site in Bahrain dated to about 2100 BC (Frohlich et al., 1987 1988). Brown staining and pitting were present on the enamel, lesions characteristic of skeletal fluorosis were present in the spine, and fusion of ligaments that connect the vertebrae can be seen in Figs. 15.52 and 15.53.

560 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 15.51 Severe fluorosis. Radiograph of a cross-section of a femur that shows massive subperiosteal bone deposition and some intracortical resorption. (Adult Asian Indian male. Courtesy of Dr. Niranjan Das Aggarwal, Rajendra Hospital and Medical College, Patiala, India.)

FIGURE 15.53 Skeletal evidence of fluorosis in a burial from an archeological site in Bahrain dated to about 2100 BC (shown in Fig. 15.52). (A) T9 T12 vertebrae fused into a single block of bone. The fused vertebrae were broken postmortem. (B) Mineralized connective tissue partially filling the neural canal, and there is partial mineralization of the intervertebral disk on the inferior vertebral body. FIGURE 15.52 Skeletal evidence of fluorosis in a burial from an archeological site in Bahrain dated to about 2100 BC. Right lateral view of the completely fused spine.

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Bone formation in the neurological canal (Fig. 15.53) could have been associated with some neurological problems. Bone also formed in the interosseous ligaments of the forearm (Fig. 15.54). Littleton and colleagues also identified individuals with both dental (Fig. 15.55) and skeletal changes indicative of fluorosis from historic Bahrain (Littleton and Frolich, 1989; Littleton, 1999). More recently, cases of fluorosis have been recognized from a number of geographical contexts with individuals with both skeletal and dental evidence for fluorosis reported from the Ray Site (Middle Woodland, 50 BC to AD 400) in west-central Illinois (n 5 8/117) (Nelson et al., 2016).

HYPEROSTOSIS FRONTALIS INTERNA

FIGURE 15.54 Skeletal evidence of fluorosis in a burial from an archeological site in Bahrain dated to about 2100 BC. Mineralization of the interosseous ligament between the radius and ulna on both sides.

FIGURE 15.55 Mottled and pitted enamel on the labial surfaces of the maxillary central incisors of an adult diagnosed with fluorosis from an early Dilmun period tomb Bahrain c.2200 1800 BC. The irregular nonchronological pitting near the crown with staining is characteristic of fluorosis teeth beyond the whitening seen with modern fluoridated water supplies. Picture courtesy of Dr. Judith Littleton.

Hyperostosis frontalis interna (HFI) is a condition in which the endocranial surface, principally on the frontal bone, displays marked thickening through deposits of bone. Only the cranial bones are involved. Hershkovitz and coworkers (1999) report that the condition was first described by Morgagni in 1769, and it is frequently observed during modern autopsies (Bracanovic et al., 2016). There is a strong relationship between age and sex and the presence of HFI. Females are more likely to have the condition than males, and both prevalence and severity have been noted to increase with age, with the highest levels seen in postmenopausal women (Bracanovic et al., 2016). Links with sex and age are sufficiently strong that HFI has been investigated as a way of establishing probable sex and age at death in forensic examinations (May et al., 2011). No significant differences in occurrence linked to ancestry have been reported (Hershkovitz et al., 1999; May et al., 2011). The most common location of the lesion is the frontal bone, but cases that involve the temporal, parietal, and very rarely, the sphenoid bones have been noted (Nguyen et al., 2015). The thickening occurs as a result of expansion of the diploe¨, with increased porosity noted in the endocranial bone (Bracanovic et al., 2016). Although various symptoms have been reported as a consequence of HFI (Bracanovic et al., 2016), HFI does not usually cause significant clinical disease and is often an incidental finding (She and Szakacs, 2004). HFI was originally thought to be a feature of one of the syndromes that affect multiple organs, but is now known to occur independently (Raikos et al., 2011). Hormonal factors are now believed to be the most likely cause with strong consideration of the possible role of the sex hormones; at present there are insufficient data to make firm statements on the pathogenesis (Bracanovic et al., 2016). There has been some discussion of the possibility that there has been a rise in prevalence of HFI, potentially linked to changes in parity, breastfeeding, and increases

562 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

known individuals, the study by Western and Bekvalac (2016) study recorded HFI to clinical standards to investigate the effects of industrialization, age, and parity on the condition. Age was found to be the primary factor in the development of HFI, but at 15.9% the prevalence was lower than that reported for more recent and current groups. This research provides a good overview of considerations pertinent to paleopathological work and current ideas on the condition (Western and Bekvalac, 2016).

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FIGURE 15.56 Case of HFI from Wharram Percy, UK (AD 950 1850). Bilateral nodular bony growth is present on the frontal bone of V61, a female aged 35 45.

in consumption of dietary phytoestrogens (Hershkovitz et al., 1999; Bracanovic et al., 2016).

Paleopathology Archeological cranial material is frequently broken, allowing direct examination of the endocranial surface (Fig. 15.56), but any systematic study would need to assess this surface in complete crania. Consideration would need to be given to the difficulty of identifying less severe cases with radiological assessment (Hershkovitz et al., 1999). There are a number of other conditions that can result in cranial hypertrophies, and less severe cases of HFI will be more difficult to confidently identify; as with all conditions, a differential diagnosis should be undertaken (see Hershkovitz et al., 1999; May et al., 2011; She and Szakacs, 2004). Multiple cases of HFI have been reported from Pueblo Bonito (AD 860 1150), Chaco Canyon, New Mexico (12/37 observable frontal bones). The frequency and age/ sex distribution found at this site is comparable with that reported for current groups (Mulhern et al., 2006). Although the general age/sex pattern seen in recent groups was found in the investigation by Hajdu et al. (2009), the prevalence in this evaluation of 803 individuals from nine archeological sites in Hungary, ranging in date from the Middle Bronze Age (15 14th century BC) to the 17th century AD, was lower at 20/803 individuals. Using skeletal remains of women living in London, UK from the 17th 19th centuries, some of whom were

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Cook, D.C., 2012. Pretos novos: in search for signs of adult scurvy in the slave trade to Brazil, 1769-1830. Am. J. Phys. Anthropol. 147 (Suppl. 54), 119. Crandall, J.J., Klaus, H.D., 2014. Advancements, challenges and prospects in the palaeopathology of scurvy: current perspectives on vitamin C deficiency in human skeletal remains. Int. J. Palaeopathol. 5, 1 8. Crist, T.A., Sorg, M.H., 2014. Adult scurvy in New France: Samuel de Champlain’s “Mal de la terre” at Saint Croix Island, 1604-1605. Int. J. Palaeopathol. 5, 95 105. Cummings, S.R., Cauley, J.A., Palermo, L., Ross, P.D., Wasnich, R.D., Black, D., et al., 1994. Racial differences in hip axis lengths might explain racial differences in rates of hip fracture. Osteoporos. Int. 4, 226 229. Curate, F., 2014. Osteoporosis and palaeopathology: a review. J. Anthropol. Sci. 92, 119 146. Curate, F., Assis, S., Lopes, C., Silva, A.M., 2011. Hip fractures in the Portuguese archaeological record. Anthropol. Sci. 119, 87 93. Curate, F., Silva, T.F., Cunha, E., 2016. Vertebral compression fractures: towards a standard scoring methodology in palaeopathology. Int. J. Osteoarchaeol. 26, 366 372. Dean, H.T., 1942. The investigation of physiological effects by the epidemiological method. In: Moulton, F.R. (Ed.), Fluoride and Dental Health. American Association for Advancement of Science, Washington, DC, pp. 23 31. DenBesten, P., Li, W., 2011. Chronic fluoride toxicity: dental fluorosis. Monogr. Oral Sci. 22, 81 96. D’Ortenzio, L., Ribot, I., Raguin, E., Schattmann, A., Bertrand, B., Kahlon, B., et al., 2016. The rachitic tooth: a histological examination. J. Archaeol. Sci. 74, 152 163. Duggan, C.P., Westra, S.J., Rosenberg, A.E., 2007. Case 23-2007: a 9-year-old boy with bone pain, rash and gingival hypertrophy. New Engl. J. Med. 357, 392 400. Ellis, M.A.B., 2014. A disciplined childhood in 19th century New York City: social bioarchaeology of the subadults of the Spring Street Presbytarian church. In: Thompson, J.L., Alfonso-Durruty, M.P., Crandall, J.J. (Eds.), Tracing Childhood. Bioarchaeological Investigations of Early Lives in Antiquity. University Press of Florida, Gainesville, FL, pp. 139 155. Fain, O., 2005. Musculoskeletal manifestations of scurvy. Joint Bone Spine 72, 124 128. Frohlich, B., Ortner, D., Al-Khalifa, H., 1987 1988. Human disease in the ancient Middle East. Dilmun 14, 61 73. Geber, J., Murphy, E., 2012. Scurvy in the Great Irish Famine: evidence of vitamin C deficiency from a mid-19th century skeletal population. Am. J. Phys. Anthropol. 148, 512 524. Goodman, W.G., Ramirez, J.A., Belin, T.R., Chon, Y., Gales, B., Segre, S.V., et al., 1994. Development of adynamic bone in patients with secondary hyperparathyroidism after intermittent calcitriol therapy. Kidney Int. 46, 1160 1166. Griffith, J.F., Adams, J.E., Genant, H.K., 2013. Diagnosis and classification of vertebral fracture. In: Rosen, C.J. (Ed.), Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, eighth ed. American Society for Bone & Mineral Research/WileyBlackwell, Chichester, pp. 317 335. Grynpas, M.D., 2003. The role of bone quality on bone loss and fragility. In: Agarwal, S.C., Stout, S.D. (Eds.), Bone Loss and Osteoporosis: An Anthropological Perspective. Kluwer/Plenum, New York, pp. 33 44.

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Gulko, E., Collins, L.K., Murphy, R.C., Thornhill, B.A., Taragin, B.H., 2015. MRI findings in pediatric patients with scurvy. Skeletal Radiol. 44, 291 297. Gupta, N., Gupta, N., Chhabra, P., 2016. Image diagnosis: dental and skeletal fluorosis. Perm. J. 20 (1), e105 6. Available from: https:// doi.org/10.7812/TPP/15-048. Hajdu, T., Fothi, E., Bernert, Z., Molnar, E., Lovasz, G., Kovari, I., et al., 2009. Appearance of hyperostosis frontalis interna in some osteoarchaeological series from Hungary. HOMO 60, 185 205. Halcrow, S.E., Harris, N.J., Beavan, N., Buckley, H.R., 2014. First bioarchaeological evidence of probable scurvy in southeast Asia: multifactorial etiologies of vitamin C deficiency in a tropical environment. Int. J. Paleopathol. 5, 63 71. Henderson, M., Miles, A., Walker, D., Connell, B., Wroe-Brown, R., 2013. ‘He Being Dead yet Speaketh’. Excavations at Three Post-Mediaeval Burial Grounds in Tower Hamlets, East London, 2004-10. Museum of London Archaeology Monograph 64. Museum of London Archaeology, London. Henry, H.L., Norman, A.W., 1992. Metabolism of vitamin D. In: Coe, F. L., Flavus, M.J. (Eds.), Disorders of Bone and Mineral Metabolism. Raven Press, New York, pp. 149 162. Hershkovitz, I., Greenwald, C., Rothschild, B.M., Latimer, B., Dutour, O., Jellema, L.M., et al., 1999. Hyperostosis frontalis interna: an anthropological perspective. Am. J. Phys. Anthropol. 109, 303 325. Hess, A.F., 1920. Scurvy Past and Present. JB Lippincott Company, Philadelphia, PA. Hess, A.F., 1930. Rickets. Including Osteomalacia and Tetany. Kimpton, London. Himes, J.H., Matorell, R., Habicht, J.-P., Yarbrough, C., Malina, R.M., Klein, R.E., 1975. Patterns of cortical bone growth in moderately malnourished preschool children. Hum. Biol. 47, 337 350. Hodges, R.E., Hood, J., Canham, J.E., Sauberlich, H.E., Baker, E.M., 1971. Clinical manifestations of ascorbic acid deficiency in man. Am. J. Clin. Nutr. 24, 432 443. Hodkinson, H.M., 1971. Fracture of the femur as a presentation of osteomalacia. Gerontol. Clin. 13, 189 191. Holick, M.F., 2006. Resurrection of vitamin D deficiency and rickets. J. Clin. Invest. 116, 2062 2072. Holick, M.F., 2007. Vitamin D deficiency. New Engl. J. Med. 357, 266 281. Igwemmar, N.C., Kolawole, S.A., Imran, I.A., 2013. Effect of heating on vitamin C content of some selected vegetables. Int. J. Sci. Technol. Res. 2, 209 212. Ives, R., Brickley, M.B., 2004. A procedural guide to radiogrammetry in archaeology. Int. J. Osteoarchaeol. 14, 7 17. Ives, R., Brickley, M., 2014. New findings in the identification of adult vitamin D deficiency osteomalacia: results from a large-scale study. Int. J. Palaeopathol. 7, 45 56. Ives, R., Mant, M., de la Cova, C., Brickley, M., 2017. A large-scale palaeopathological study of hip-fractures from Post-Mediaeval urban England. Int. J. Osteoarchaeol. 27, 261 275. in press. Jackson, R., 1988. Doctors and Diseases in the Roman Empire. British Museum Press, London. Jaffe, H.L., 1972. Metabolic, Degenerative, and Inflammatory Diseases of Bones and Joints. Lea & Febiger, Philadelphia, PA. Jarvis, H.G., Heslop, P., Kisima, J., Gray, W.K., Ndossi, G., Maguire, A., et al., 2013. Prevalence and aetiology of juvenile skeletal fluorosis in the south-west of the Hai district, Tanzania a community-

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Metabolic Disease Chapter | 15

Macho, G.A., Abel, R.L., Schutkowski, H., 2005. Age changes in bone microstructure: do they occur uniformly? Int. J. Osteoarchaeol. 15, 421 430. Maiyegun, S.O., Malek, A.H., Devarajan, L.V., Dahniya, M.H., 2002. Severe congenital rickets secondary to maternal hypovitaminosis D: a case report. Ann. Trop. Paediatr. 22, 191 195. Mankin, H., 1974. Rickets, osteomalacia and renal osteodystrophy. Part I. J. Bone Joint Surg. Am. 56, 101 128. Maxwell, J.P., 1930. Further studies on osteomalacia. Proc. R. Soc. Med. 23, 639 652. Maxwell, J.P., 1947. Osteomalacia. [Summary.]. Proc. R. Soc. Med. 40, 738 740. May, H., Peled, N., Dar, G., Cohen, H., Abbas, J., Medlej, B., et al., 2011. Hyperostosis frontalis interna: criteria for sexing and aging a skeleton. Int. J. Legal Med. 125, 669 673. Mays, S., 2003. Bone strontium: calcium ratios and duration of breastfeeding in a Mediaeval skeletal population. J. Archaeol. Sci. 30, 731 741. Mays, S.A., 2006a. A palaeopathological study of Colles’ fracture. Int. J. Osteoarchaeol. 16, 415 428. Mays, S.A., 2006b. Age-related cortical bone loss in women from a 3rd4th century AD population from England. Am. J. Phys. Anthropol. 129, 518 528. Mays, S., 2007. The human remains. In: Mays, S., Harding, C., Heighway, C. (Eds.), The Churchyard. Wharram: A Study of Settlement in the Yorkshire Wolds. York University Press, York, pp. 77 192. 337 397. Mays, S., 2008a. Metabolic bone disease. In: Pinhasi, R., Mays, S. (Eds.), Advances in Human Palaeopathology. Wiley, Chichester, pp. 215 251. Mays, S., 2008b. A likely case of scurvy from early Bronze Age Britain. Int. J. Osteoarchaeol. 18, 178 187. Mays, S., 2010. The effects of infant feeding practices on infant and maternal health in a Mediaeval community. Childhood Past 3, 63 78. Mays, S., 2014. The palaeopathology of scurvy in Europe. Int. J. Paleopathol. 5, 55 62. Mays, S., Brickley, M., Ives, R., 2006. Skeletal manifestations of rickets in infants and young children in an historic population from England. Am. J. Phys. Anthropol. 129, 362 374. Mays, S., Brickley, M., Ives, R., 2007. Skeletal evidence of hyperparathyroidism in a 19th century child with rickets. Int. J. Osteoarchaeol. 17, 73 81. McCann, P., 1962. The incidence and value of radiological signs in scurvy. Br. J. Radiol. 35, 683 686. Mensforth, R., 2002. Vitamin D deficiency mortality: impaired immune response in infants and elevated cancer risk in adults. Am. J. Phys. Anthropol. 34, 112. Mirza, F., Canalis, E., 2015. Secondary osteoporosis: pathophysiology and management. Euro J. Endocrinol. 173, R131 R151. Montan˜o, A., Casado, F.J., Rejano, L., Sa´nchez, A.H., de Castro, A., 2006. Degradation kinetics of the antioxidant additive ascorbic acid in packed table olives during storage at different temperatures. J. Agric. Food Chem. 54, 2206 2210. Mulhern, D.M., Wilczak, C.A., Dudar, C., 2006. Unusual finding at Pueblo Bonito: multiple cases of hyperostosis frontalis interna. Am. J. Phys. Anthropol. 130, 480 484. Murray, P.D.F., Kodicek, E., 1949a. Bones, muscles and vitamin C. II. Partial deficiencies of vitamin C and mid-diaphyseal thickenings of the tibia and fibula in guinea-pigs. J. Anat. 83, 205 223.

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Murray, P.D.F., Kodicek, E., 1949b. Bones, muscles and vitamin C. III. Repair of the effects of total deprivation of vitamin C at the proximal ends of the tibia and fibula in guinea-pigs. J. Anat. 83, 285 295. Nelson, E.A., Halling, C.L., Buikstra, J.E., 2016. Investigating fluoride toxicity in a Middle Woodland population from west-central Illinois: a discussion of methods for evaluating the influence of environment and diet in paleopathological analyses. J. Archaeol. Sci. 5, 664 671. Nguyen, A.H., Moore, M., Hunter III, W., 2015. Hyperostosis of the frontal, temporal, and sphenoid bones: case report and review of the literature. Int. J. Anat. Res. 3, 817 820. Noordin, S., Baloch, N., Salat, M.S., Memon, A.R., Ahmad, T., 2012. Skeletal manifestations of scurvy: a case report from Dubai. Case Rep. Orthop. 2012, 624628. O’Riordan, J., 2006. Rickets in the 17th century. J. Bone Miner. Res. 21, 1506 1510. Ortner, D.J., 2011. Human skeletal palaeopathology. Int. J. Palaeopathol. 1, 4 11. Ortner, D.J., 2012. Differential diagnosis and issues in disease classification. In: Grauer, A.L. (Ed.), Companion to Paleopathology. Academic Press, New York, pp. 250 267. Ortner, D.J., Ericksen, M.F., 1997. Bone changes in the human skull probably resulting from scurvy in infancy and childhood. Int. J. Osteoarchaeol. 7, 212 220. Ortner, D.J., Mays, S., 1998. Dry-bone manifestations of rickets in infancy and early childhood. Int. J. Osteoarchaeol. 8, 45 55. Ortner, D.J., Kimmerle, E.H., Diez, M., 1999. Probable evidence of scurvy in subadults from archaeological sites in Peru. Am. J. Phys. Anthropol. 108, 321 331. Ortner, D.J., Kimmerle, E.H., Diez, M., 2001. Evidence of probable scurvy in subadults from archaeological sites in North America. Am. J. Phys. Anthropol. 114, 343 351. Parfitt, A.M., 2003. New concepts of bone remodelling: a unified spatial and temporal model with physiologic and pathophysiologic implications. In: Agarwal, S.C., Stout, S.D. (Eds.), Bone Loss and Osteoporosis: An Anthropological Perspective. Kluwer/Plenum, New York, pp. 3 17. Pavelka, M.S.M., Fedigan, L.M., 1991. Menopause: a comparative life history perspective. Yearb. Phys. Anthropol. 34, 13 38. Perumal, E., Paul, V., Govindarajan, V., Panneerselvam, L., 2013. A brief review of experimental fluorosis. Toxicol. Lett. 223, 236 251. Pettifor, J.M., 2003. Nutritional rickets. In: Glorieux, F., Pettifor, J., Ju¨ppner, H. (Eds.), Pediatric Bone: Biology and Diseases. Academic Press, New York, pp. 541 565. Pettifor, J.M., Daniels, E.D., 1997. Vitamin D deficiency and nutritional rickets in children. In: Feldman, D., Glorieux, F., Pike, J. (Eds.), Vitamin D. Academic Press, San Diego, CA, pp. 663 679. Pfeiffer, S., Crowder, T., 2004. An ill child among mid-holocene foragers of southern Africa. Am. J. Phys. Anthropol. 123, 23 29. Pitre, M.C., Stark, R.J., Gatto, M.C., 2016. First probable case of scurvy in ancient Egypt at Nag el-Qarmila, Aswan. Int. J. Paleopathol. 13, 11 19. Pitt, M., 1988. Rickets and osteomalacia. In: second ed. Resnick, D., Niwayama, G. (Eds.), Diagnosis of Bone and Joint Disorders, vol. 8. W.B. Saunders, Philadelphia, PA, pp. 2086 2119. Qin, X., Wang, S., Yu, M., Zhang, L., Li, X., Zuo, Z., et al., 2009. Child skeletal fluorosis from indoor burning of coal in Southwestern China. J. Environ. Public Health 2009, 969764. Available from: https://doi.org/10.1155/2009/969764.

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Raikos, A., Paraskevas, G.K., Yusuf, F., Kordali, P., Meditskouc, S., Al-Haj, A., et al., 2011. Etiopathogenesis of hyperostosis frontalis interna: a mystery still. Ann. Anat. 193, 453 458. Reid, I.R., Bolland, M.J., 2014. Skeletal and nonskeletal effects of vitamin D: is vitamin D a tonic for bone and other tissues? Osteoporos. Int. 25, 2347 2357. Resnick, D., Niwayama, G., 1988. Diagnosis of Bone and Joint Disorders, second ed. WB Saunders, London. Riggs, B.L., Melton, L.J., 1986. Involutional osteoporosis. New Engl. J. Med. 314, 1676 1686. Saul, F., 1972. Human skeletal remains of Altar de Sacrificios. Pap. Peabody Mus. Am. A 63, 1 123. Schamall, D., Teschler-Nicola, M., Kainberger, F., Tangl, S., Brandsta¨tter, F., Patzak, B., et al., 2003a. Changes in trabecular bone structure in rickets and osteomalacia: the potential of a medico-historical collection. Int. J. Osteoarchaeol. 13, 283 288. Schamall, D., Kneissel, M., Wiltschke-Schrotta, K., Teschler-Nicola, M., 2003b. Bone structure and mineralization in a late antique skeleton with osteomalacia. Am. J. Phys. Anthropol. 120, 184. Schattmann, A., Bertrand, B., Vatteoni, S., Brickley, M., 2016. Approaches to co-occurrence: scurvy and rickets in infants and young children of 16th 18th century Douai, France. Int. J. Palaeopathol. 12, 63 75. Schultz, M., 1989. Causes and frequency of diseases during early childhood in Bronze Age populations. In: Capasso, L. (Ed.), Proceedings of the Paleopathology Association 7th European Meeting, (Lyon, 1988). Marino Sofinelli, Chieti, pp. 175 179. Schultz, M., Schmidt-Schultz, T.H., Kreutz, K., 1998. Ergebnisse der pala¨opathologischen Untersuchung an den fru¨hbronzezeitlichen Kinderskeletten von Jelˇsovce (Slowakishe Republik). In: Ha¨nsel, B. (Ed.), Mensch und Umwelt in der Bronzezeit Europas. OetkerVoges, Kiel, pp. 77 90. She, R., Szakacs, J., 2004. Hyperostosis frontalis interna: case report and review of literature. Ann. Clin. Lab. Sci. 34, 206 208. Shomar, B., Mu¨ller, G., Yahya, A., Askar, S., Sansur, R., 2004. Fluorides in groundwater, soil and infused black tea and the occurrence of dental fluorosis among school children of the Gaza Strip. J. Water Health 2, 23 25. Shruthi, M.N., Santhuram, A.N., Arun, A.N., Kishore Kumar, B.N., 2016. A comparative study of skeletal fluorosis among adults in two study areas of Bangarpet taluk, Kolar. Indian J. Public Health 60, 203 209. Sieva¨nen, H., 2010. Immobilisation and bone structure in humans. Arch. Biochem. Biophys. 503, 146 152. Sommer, O.J., Kladosek, A., Weiler, V., Czembirek, H., Broek, M., Stiskal, M., 2005. Rheumatoid arthritis: a practical guide to state-ofthe-art imaging, image interpretation, and clinical implications. RadioGraphics 25, 381 398. Sprague, P.L., 1976. Epiphyseo-metaphyseal cupping following infantile scurvy. Pediatr. Radiol. 4, 122 123. Stapleton, G., 1925. Late rickets and osteomalacia in Deli. An analysis of seventy-three cases. Lancet 205, 1119 1123. Steinbach, H., Kolb, F., Gilfillan, R., 1954. A mechanism of the production of pseudofractures in osteomalacia (Milkman’s syndrome). Radiology 62, 388 395. Steinbock, R.T., 1993. Rickets and osteomalacia. In: Kiple, K.F. (Ed.), The Cambridge World History of Disease. Cambridge University Press, Cambridge, pp. 978 980.

Stephens, E., 2011. Anatomy as Spectacle. Public Exhibitions of the Body from 1700 to the Present. Liverpool University Press, Liverpool. Still, G.F., 1935. Infantile scurvy: its history. Arch. Dis. Child. 10, 211 218. Størvold, G.V., Aarethun, K., Bratberg, G.H., 2013. Age for onset of walking and prewalking strategies. Early Hum. Dev. 89, 655 659. Szulc, P., Seeman, E., 2009. Thinking inside and outside the envelopes of bone. Osteoporos. Int. 20, 1281 1288. Tamura, Y., Zic, J.A., Cooper, W.O., Stein, S.M., Hummell, D.S., 2000. Scurvy presenting as painful gait with bruising in a young boy. Arch. Pediatr. Adolesc. Med. 154, 732 735. Thacher, T.D., Fischer, P.R., Pettifor, J.M., Lawson, J.O., Manaster, B.J., Reading, J.C., 2000. Radiographic scoring method for the assessment of the severity of nutritional rickets. J. Trop. Pediatr. 46, 132 139. Tiesler, V., Coppa, A., Zabala, P., Cucina, A., 2014. Scurvy-related morbidity and death among Christopher Columbus’ crew at La Isabela, the first European Town in the New World (1494 1498): an assessment of the skeletal and historical information. Int. J. Osteoarchaeol. 26, 191 202. Turner-Walker, G., Syversen, U., 2002. Quantifying histological changes in archaeological bones using BSE-SEM image analysis. Archaeometry 44, 461 468. Unit conversion.org. ,http://www.unitconversion.org/concentrationsolution/milligrams-per-liter-to-parts-per-million-ppm-conversion. html. (accessed November 2016). Van der Merwe, A.E., Steyn, M., Maat, G.J.R., 2010. Adult scurvy in skeletal remains of late 19th century mineworkers in Kimberly, South Africa. Int. J. Osteoarchaeol. 20, 307 316. Veselka, B., Hoogland, M.L.P., Waters-Rist, A.L., 2015. Rural rickets: vitamin D deficiency in a post-Mediaeval farming community from the Netherlands. Int. J. Osteoarchaeol. 25, 665 675. Virtama, P., Helela¨, T., 1969. Radiographic measurements of cortical bone. Acta Radiol. Suppl. 293, 1 268. Walker, D., 2012. Disease in London, 1st-19th centuries. An Illustrated Guide to Diagnosis. Museum of London Archaeology Monograph 56. Museum of London Archaeology, London. Weinstein, M., Babyn, P., Zlotkin, S., 2001. An orange a day keeps the doctor away: scurvy in the year 2000. Pediatrics 108, e55. Wells, C., 1967. Weaver, tailor or shoemaker? An osteological detective story. Med. Biol. Illus. 17, 39 47. Western, A.G., Bekvalac, J.J., 2016. Hyperostosis frontalis interna in female historic skeletal populations: age, sex hormones and the impact of industrialization. Am. J. Phys. Anthropol. Available from: https://doi.org/10.1002/ajpa.23133. Weston, D.A., 2012. Nonspecific infection in paleopathology: interpreting periosteal reactions. In: Grauer, A.L. (Ed.), A Companion to Palaeopathology. Wiley-Blackwell, Chichester, pp. 492 512. WHO, 1994. Assessment of Fracture Risk and Its Application to Screening for Postmenopausal Osteoporosis. Report of a WHO Study Group. WHO Technical Report Series 843. WHO, Geneva. WHO, 2011. Guidelines for Drinking-Water Quality, fourth ed. WHO Press, Geneva.

Chapter 16

Endocrine Disturbances Mary Lewis University of Reading, Reading, United Kingdom

INTRODUCTION The endocrine system comprises several glands that synthesize and secrete hormones into the circulatory system. These hormones control a variety of metabolic processes throughout the body. The secretions of some of these glands affect the growth and maintenance of skeletal tissue. Abnormal secretions, either too little or too much, can affect the shape, size, and biomechanical strength of bone. Although there is considerable overlap in the skeletal manifestations, it is possible to diagnose some endocrine problems on the basis of the abnormalities apparent in archeological human skeletal remains. The endocrine glands associated with skeletal pathology include: (1) the pituitary, (2) the thyroid, (3) the parathyroid, (4) the adrenals (cortex), (4) the ovaries, and (6) the testes. Normal skeletal growth and maturation is mainly controlled by an intricate interrelationship between the pituitary and thyroid glands. The pituitary mainly controls growth, while the thyroid controls maturation of bone (Urist, 2012). The parathyroid glands play a crucial role in the maintenance of calcium and phosphate concentrations in serum. Parathyroid hormone stimulates the action of osteoclasts, which release calcium and phosphate into the bloodstream. Excessive amounts of the hormone secreted by the adrenal glands (adrenocortical glucocorticoid steroids) increase the activity of osteoclasts while depressing osteoblasts, resulting in osteoporosis (Canalis et al., 2007). Inadequate secretions by the ovaries or testes can result in deficient growth.

PITUITARY DISTURBANCES Pathology The pituitary gland and hypothalamus govern the endocrine system. The pituitary gland is located in the pituitary fossa or sella turcica, a hollow in the sphenoid bone at the base of the brain. The anterior lobe is connected to

the hypothalamus via blood vessels, while the posterior lobe is connected by the pituitary stalk. A normal pituitary gland is around 14 mm across, but it increases in size during pregnancy and decreases with age (Hinson et al., 2010). The anterior lobe of the pituitary derives from Rathke’s pouch and produces somatotrophic (growth) hormone, which affects skeletal growth and stimulates the production of insulin-like growth factor (IGF-1) by the liver. In addition to thyroxine produced by the thyroid, the growth hormone is responsible for linear growth via the actions of IGF-1. In the absence of the growth hormone there is a failure of linear growth. Oversecretion of the growth hormone either as an intrinsic abnormality (hyperplasia) or the result of a tumor (most commonly a benign adenoma) of the anterior pituitary produces excessive skeletal growth, besides affecting other tissues and organs not discussed here. Depending on the age of onset in the individual affected by hyperpituitarism, either pituitary gigantism (growth plates open) or acromegaly (growth plates closed) will result.

Pituitary Gigantism This is a very rare condition in which the continued excessive production of somatotrophic hormone, during the growing period and beyond, leads to much larger than normal proportions of the skeleton. This is caused by overstimulation of endochondral and intramembranous growth. Fifty per cent of cases result from genetic mutations on the aryl hydrocarbon receptor-interacting protein or AIP gene (Rostomyan et al., 2015). While predominantly a male condition, recently a new form of X-linked acrogigantism (X-LAG) has been discovered and is caused by chromosome duplication. Such sporadic cases may occur in females, with the mutation passed from mother to son (Trivellin et al., 2014). In pituitary gigantism, total body height reaches giant proportions involving the thickness, length, and diameter of all bones. If the underlying cause was a tumor, the sella turcica is usually

Ortner’s Identification of Pathological Conditions in Human Skeletal Remains. DOI: https://doi.org/10.1016/B978-0-12-809738-0.00016-8 © 2019 Elsevier Inc. All rights reserved.

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markedly enlarged, with thinning or destruction of the anterior and posterior clinoid processes and, occasionally, with perforation of the bony floor of the sella. The latter results in an open communication between the sella and the sphenoidal sinus, which would be apparent in a dry skull. However, it is possible to have pituitary hyperplasia with a sella turcica that is normal in size and shape. Continued hyperpituitarism beyond the growing period leads to superposition of acromegalic features onto the giant skeleton (Fig. 16.1). An important characteristic of pituitary gigantism is that the abnormal growth is proportional; that is, the growth in width increases proportionately with the growth in length. The severity of gigantism is related to the age of onset. If it begins in childhood, abnormal growth is likely to be great and in X-LAG acrogigantism abnormal changes will be apparent earlier in a female than male. Onset of the condition toward the end of the growth period will have much less impact (Resnick and Krandsdorf, 2005: 589).

the remaining cartilage and the periosteum can respond to stimulation by the growth hormone, and this restricts the location and amount of abnormal growth that can occur. However, acromegalic features may be superimposed on to preexisting pituitary gigantism.

Acromegaly This condition is much more common than pituitary gigantism and is usually the result of secretory tumor (adenoma) of the pituitary occurring in an adult (Figs. 16.2 and 16.3) (Resnick and Krandsdorf, 2005: 589). Oversecretion of somatotropin results in increased production of IGF-1, causing enlargement of the bone and soft tissues (Cordero and Barkan, 2008). The onset of symptoms is slow and clinically there is gradual coarsening of the facial features with increased growth of the lips, tongue, nose, and skin above the eyes, enlargement of the heart and cardiovascular system, high blood pressure, sweating, and impaired glucose tolerance (Hinson et al., 2010). After closure of the epiphyseal plates, only

(A)

FIGURE 16.2 Radiograph of modern acromegalic skull. Note the greatly elongated mandibular body and condyle. The sella turcica is enlarged (arrow), and the posterior clinoids are longer than normal (Institute of Pathological Anatomy, University of Zurich, Switzerland, case no. 1904).

(B)

FIGURE 16.1 Pituitary giant with acromegaly. (A) Lateral view of the pituitary giant skull compared with a normal skull. Note the greatly elongated mandibular condyle. (B) Bones of the right hand and foot of the pituitary giant compared with normal. The skeleton belonged to a 49-year-old Japanese male sumo wrestler exhibiting giant stature and massive periosteal, especially cranial, bone apposition. University Museum (catalog no. M2726), University of Tokyo, Japan. Photographs courtesy of Dr. Toshiro Kamiya and Dr. Hisao Baba.

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FIGURE 16.3 Acromegaly. (A) Lumbar vertebrae, showing marked subperiosteal apposition. (B) Right hand, showing extreme arrowhead tufting of terminal phalanges, and periosteal hyperostosis. (C) Skull base, showing enlarged frontal sinuses, an enlarged sella turcica (arrow) with resorption of anterior and posterior clinoid processes in a 39-year-old male with pituitary adenoma (FPAM, Jubila¨umspital 610).

The reinitiated growth mainly affects the cartilage of the mandibular condyle (Fig. 16.2). Because the cartilage of the mandibular condyle is a growth cartilage, marked elongation of the mandible occurs primarily because of elongation of the ramus, and this leads to pronounced prognathism and dental malocclusion. There is marked periosteal bony build-up on the chin, adding to the distortion of the mandible. Marginal build-up of bone on the alveolar process of the mandible and of the maxilla leads to separation between the teeth. The rib cartilages, the synchondrosis of sternum and pubis, and to some extent, the articular cartilages and intervertebral discs are also affected (Fig. 16.3A). The ribs show marked elongation, increasing the diameters of the thorax. The periosteal build-up is slow and consists of lamellar bone, intimately fused to the old cortex. The tufts of the terminal phalanges are characteristically enlarged, with an arrowhead appearance (Fig. 16.3B). Changes in articular cartilage are not directly visible on dry bone, but the complicating osteoarthritis is. The spine may show marked periosteal build-up with anteroposterior and lateral enlargement of the vertebral bodies, complicated by osteoarthritic lipping (Erdheim, 1931: 203 210). There is often kyphosis, mainly secondary to muscular weakness. Periosteal bone deposition is most marked at terminal points of bones (Fig. 16.3B) and at normal prominences and insertions of tendons and ligaments such as trochanters and the linea aspera. There is exaggeration of the

supraorbital ridges and of the posterior occipital protuberance. The facial bones are enlarged, as are the paranasal sinuses. The cranial vault is thickened. Enlargement of the sella turcica occurs in 80% 90% of clinical cases as a result of the pressure erosion of an intrasellar tumor (Fig. 16.3C) (Resnick, 1988).

Hypopituitarism Hypopituitarism only affects the skeleton significantly if the functioning pituitary is destroyed during the growing period. This is most often due to a tumor which develops from the embryonic cells of Rathke’s pouch (or craniopharyngioma) within or above the sella in a child. Trauma or infection may also destroy the pituitary gland, and in 10% of cases the cause is genetic (Resnick and Kransdorf, 2005: 595). There are many causes of stunted growth in children, and hypopituitarism is relatively rare, causing increased body fat and loss of muscle tone. Hypopituitarism in the adult produces no demonstrable skeletal changes beyond nondescript osteoporosis.

Pituitary Dwarfism Deficiency of the somatotrophic hormone in early life leads to pronounced inhibition of growth, resulting in dwarfism of infantile proportions (Priesel, 1920). The proportionality seen in pituitary gigantism is also apparent in

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pituitary dwarfism, with reduced growth in the length and width of the bones. The synergism between the pituitary and thyroid is demonstrated by the concomitant hypothyroidism secondary to the deficiency of thyrotropic hormone. Therefore, not only is growth stunted, but the development of secondary ossification centers may be delayed and the epiphyseal and apophyseal growth plates tend to remain open well into adult life (Erdheim, 1916: 338 344, 356), although they may ultimately close in older adults (Priesel, 1920: 252). The cranial sutures also tend to remain open well into adulthood. The sella turcica may show enlargement if the tumor was intrasellar or may have an aperture in the floor as a remnant of a persistent craniopharyngeal canal. The skeleton is gracile in dimensions, the cortices are thin, and the spongiosa is porotic and sparse. Although growth plates may remain open, the metaphyseal surface is usually closed by a thin layer of bone, indicating arrested growth.

PALEOPATHOLOGY Gigantism Pituitary gigantism is rare in modern human populations, but references to this condition in the paleopathological literature are increasing. A convincing case has been reported from an archeological cemetery in Poland dated between the end of the 11th and the beginning of the 14th centuries (Gladykowska-Rzeczycka et al., 1998). The authors consider the skeleton to be that of an adult female between 25 and 30 years of age when she died. The stature was estimated to be 215.5 cm, which is almost one and one-half times the average height of the other female skeletons from the same site. Both the size and the anatomical features of the skull suggest abnormal pituitary hormone stimulation of growth beginning in childhood, with some features of acromegaly indicative of continuing abnormal pituitary hormone secretions after cessation of growth. Another possible case of gigantism and acromegaly was presented by Mulhern (2005) in a 20- to 30-yearold male from 5th Dynasty Giza, Egypt. The stature was estimated to be 192 cm in comparison to an average of 168 cm for Egyptian male skeletons. This was associated with wedging of the lumbar spine and a fractured femoral head that may have resulted from joint weakness during prolonged and excessive growth. Thinned parietal bones were considered indicative of osteopenia due to additional hypogonadism, and it was suggested that the individual may have been a eunuch. Minozzi and colleagues (2015) argued for gigantism as a diagnosis in a well-preserved 20- to 30-year-old male from Fidenae, Italy. This individual displayed an enlarged pituitary area for the sella turcica of at least 16 mm, in addition to a large mandible with prominent chin, delayed epiphyseal fusion, and a stature

estimated to be 21% above the average for the population. One of the most well-preserved cases of gigantism and acromegaly comes from postmedieval Tasmasor, Turkey in Anatolia (M-218). This individual was estimated to be 189 cm tall, and while shorter than other cases, he was taller in comparison to the average Tasmasor male stature of 164 cm. The sella turcica was enlarged with lytic destruction suggesting a tumor as the main cause of the ¨ zdemir et al., 2017). A case of X-LAG acrocondition (O gigantism in a 19th century male from Reutlingen, Germany, was confirmed by aDNA analysis. The male started to grow abnormally from the age of 14 years and was 8 ft 6 in. (2.6 m) when he died in 1872 (Beckers et al., 2017).

Acromegaly Brothwell (1981) describes an ancient Egyptian skull in which the face is unusually long. The photograph of the skull shows an enlarged mandible and an apparent overgrowth leading to prognathism and malocclusion. All of the abnormal anatomical features support a diagnosis of acromegaly. Morse (1978) provides a brief summary of features associated with acromegaly accompanied by a lateral photograph and radiograph of the skull and mandible of a Late Woodland (c. AD 900) burial from Dickson Mound in Illinois. He describes the long bones as elongated and thickened and the lower jaw as lengthened. The radiographic appearance and description of the long bones support a diagnosis of acromegaly. Rhine (1985) describes a possible case of acromegaly from a preColumbian archeological site in New Mexico. The skeleton is from an adult male who was about 30 40 years of age when he died. The stature is normal, indicating that the onset of the disease occurred after growth had ceased. The tufting of the terminal phalanges, along with several other features of acromegaly, argues for this diagnosis. Although less conclusive, a poorly preserved young adult male from the Jewish necropolis of “Ronda Sur” in Lucena, Spain (8 12th centuries) was suggested to be suffering from acromegaly based on an enlarged and thickened mandible, and increased cortical thickness of the long bones, ribs, and spine (Viciano et al., 2015). Charlier and Tsigonaki (2011) diagnosed acromegaly in a 7th century individual from Greece, which they argued resulted from a macroadenoma based on the appearance of the space for the sella turcica. More complete descriptions are provided by Hoˇsovski (1991) for a 30-year-old male from medieval Bosnia and Herzegovina (AD 1300 1400), and Bartelink et al. (2014) who provide the oldest evidence for acromegaly in a 30- to 40-year-old male from Blossom Mound California, dating to the Windmill Culture (4350 2980 BC).

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The almost complete skeleton from the Midwestern United States (NMNH 227508) provides another possible example of acromegaly in which the skeletal manifestations are less severe. This skeleton has an interesting history and was accessioned into the Museum’s collection as a “historic period Sioux Giant” that featured in a 19th century Wild West show. Reevaluation of the skeleton revealed that it was that of an adult white male (Ousley et al., 2000). The listed cultural association may have been a marketing gimmick to attract additional customers to the show. The skeleton is remarkable because of the unusually large size of both skull and postcranial bones. The maximum length of the skull is 201 mm, the maximum breadth, 144 mm. The cranial capacity is estimated to be 1865 cm3, which is well within the normal human range but about 400 cm3 greater than average. The gross morphology of the skull is rugged (Fig. 16.4A and B) with pronounced and unusually high markings (near the (A)

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sagittal suture) for the origin of the temporalis muscle. The mandible has slightly overgrown the development of the maxilla and has prominent bony projections on the anteroinferior border of the chin, with an increased angle between the ramus and mandibular body. The radiograph (Fig. 16.4C) shows a large but not abnormal pituitary fossa; thus the presence of a pituitary tumor as the cause is doubtful, making this more likely to have been abnormal growth stimulated by pituitary hyperplasia. The long bones are long and heavy. The right femur is damaged postmortem, but the estimated length is 545 mm. Stature estimates based on this length are 189.75 cm (c. 75 in.). This suggests greater pituitary function during growth but with major morphological changes, such as in the skull, occurring after the normal growth period had ended. The skeleton appears to be an adult male with estimated age, based on the morphology of the fragmentary pubic symphysis, about 35 45 years (C)

(B)

FIGURE 16.4 Possible acromegaly. (A) Comparative facial views of normal (left) and possible acromegalic (right) skulls. (B) Left lateral view; note the projection of the chin in the skull on the right. (C) Radiograph of lateral view of possible acromegalic skull (normal skull, NMNH 243703; possible acromegalic skull, NMNH 227508).

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of age. The ends of the ribs show evidence of secondary growth, as would be expected in acromegaly. The bones of the hands and feet are large but of normal proportions, although the phalanges, particularly the terminal phalanges, show evidence of secondary growth and remodeling on the distal ends (tufting). The abnormal features of this skeleton are compatible with a diagnosis of acromegaly, but the disease process does not appear to be as severe as it is in the individuals shown in Figs. 16.2 and 16.3.

Pituitary Dwarfism References to pituitary dwarfism continue to be uncommon in the paleopathological literature. One possible case in a female has been reported from a Roman cemetery in Gloucester, England (Roberts, 1987). The long bones are proportionally short and gracile. The estimate of stature is about 131 cm, with the typical stature of a female during this period being about 153 cm. A further case has been reported in an individual from Bronze Age Tuva, Russia (Aristova et al., 2006). This well-preserved individual is considered to be 45 1 years, with skeletal dimensions of those expected in a modern 7-year-old. They have an estimated stature of 124 131 cm, delayed maturation of the long bones, pelvis, and sternum, and lytic lesions on the left acetabulum suggesting inflammation of the hip. Histological examination reveals vascular canals that are sparse, and secondary osteons are absent. The report of a Native American skeleton of a child estimated to be about 3 years of age highlights the importance of evaluating both the skull and postcranial skeleton in arriving at a diagnosis of abnormally small skulls and/or skeletons (Richards, 1985). The burial is from an archeological site in California, United States, that is dated between AD 1100 and 1700. The skull is abnormally small, with disproportionate development of the cranial vault relative to the bones of the face. Unlike the skull, the postcranial bones are only slightly smaller than normal. Richards (1985) argues for a diagnosis of microcephaly, and this seems probable, given the relatively normal development of the postcranial skeleton. However, if one only had the skull to analyze, differentiating this case from pituitary dwarfism would be more challenging. A probable case of pituitary dwarfism is in the collections of the National Museum of Natural History, Washington, DC, United States (NMNH 314306). This remarkable case is from the Hawikuh site in New Mexico, which includes late precontact and early historical components. The skeleton is fragile and damaged but includes most of the bones. The features of dental and skeletal maturation used in estimating age are affected by a deficiency of pituitary hormone. Therefore, the age of

the skeleton cannot be determined with certainty. However, the second permanent molars have erupted. There is no evidence of a third molar in the left mandibular fragment; however, this absence might be due to agenesis rather than young age. All the teeth that are present are normal in size, which has created severe crowding in the small jaws. In the postcranial skeleton most epiphyses are unfused. The primary elements of the innominate have fused but the ischiopubic ramus is unfused. The distal epiphysis of the humerus has fused. These features, added to the dental eruption, clearly indicate an age in excess of 12 years in a normal individual. Because of the delayed development and fusion of epiphyses in pituitary dwarfism, a minimum age in the 20s would seem more likely. The skull is somewhat deformed postmortem but is obviously much smaller than normal (Fig. 16.5A and B). The maximum length is 145 mm; the maximum width is 108 mm. Typical skull measurements for a 12-year-old child from the same site would be a maximum length of 160 mm and a maximum width of 127 mm. The relative proportions of the skull are normal although more typical of a child than a 20-year-old. Unfortunately, the base of the skull has been damaged and lost, making observations of the pituitary fossa impossible. The postcranial long bones are very slender and shorter than normal (Fig. 16.5C and D). Stewart (1968: 133) indicates that the approximate femoral length (without epiphyses) of a 12-year-old is 310 mm. The femoral length of the dwarf is about 280 mm or 90% of the expected length of a 12-year-old. If, as seems likely, the dwarf was fully grown, the expected femur length would be about 370 mm and thus would have been only threefourths as tall as normal. The torsion angle of the left femur is unusually large and probably would be associated with an abnormal gait during life. The vertebrae are small but of normal proportions, although the bodies of thoracic vertebrae T5 T11 show a slight eccentric development to the right, which might be associated with a slight scoliosis. The sacrum and innominates are small but of fairly normal proportions, although the anteroposterior dimension of the pelvis is longer than would be expected. The pubic symphysis is poorly formed, lacking the normal features of the symphyseal face and the ridge formation. The bones of the hands and feet are of normal shape, although they are very small. The overall appearance of the skeleton conveys the impression of proportional, diminished growth and development. The features of the face, particularly the large but depressed nasal aperture, are features that are associated with less than normal growth at the basioccipital and sphenoidal synchondroses and that occur in hypothyroidism and achondroplasia. The general morphology of the skull and long bones, however, would rule out

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FIGURE 16.5 Pituitary dwarf from an archeological site in the American Southwest. (A) Comparative facial views of normal (left) and dwarf (right) skulls: normal skeleton also from an archeological site in the American Southwest and with comparable dental and epiphyseal development and closure. (B) Right lateral view of skulls; note the prognathism of the dwarf skull. (C) Comparative anterior views of the right normal and abnormal femur and tibia. (D) Radiograph of the same long bones (normal bones, NMNH 308611; pituitary dwarf, NMNH 314306).

either of these possibilities. In general there has been diminished growth and delayed fusion of epiphyses, both of which are compatible with a diagnosis of pituitary dwarfism. Another specimen in the collection of the National Museum of Natural History, United States, is of interest in the context of pituitary dwarfism. The specimen consists of only the skull from Chilca, Peru (NMNH

379510). The archeological date is unknown. The skull was initially donated by Wells (1942). He reports that the skull was microcephalic, with a cranial capacity of 485 cm3. He concludes that the skull does not resemble congenital hypothyroidism as described in the clinical literature. Hrdliˇcka (1943) added additional data and observations in a subsequent report. Hrdliˇcka (1943:77) concluded that except for its small size, “the skull is

574 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

unquestionably a ‘normal’ specimen, that is, it shows nothing of any pathological nature.” The profile of the Peruvian skull reveals diminished development of the frontal region of the skull (Fig. 16.6). A measure of this feature is the length of the arc from nasion to bregma. On the Peruvian skull this arc is 76 mm. This arc on the New Mexico pituitary dwarf is 100 mm. To the extent that diminished frontal bone development is indicative of brain abnormality, this Peruvian individual would appear to have suffered from congenital hypothyroidism (cretinism), usually as the result of maternal iodine deficiency (see later) rather than pituitary dwarfism or microcephaly.

OTHER ENDOCRINE DISTURBANCES Introduction Together, the pituitary and hypothalamus control several endocrine systems including the hypothalamic pituitary thyroid axis, the hypothalamic pituitary gonadal axis, and the hypothalamic pituitary adrenal axis. Excessive or inadequate secretions from these glands have serious consequences for the person affected. There are also feedback secretions between the glands that are important as well, so that a deficiency in the secretions of one gland will affect the secretions of another. This means that abnormal skeletal changes from the malfunction of any one of these glands may also be affected by inadequate secretions from another gland. The specifics of the skeletal changes will be influenced by many factors, including the severity of the hormone deficiency and the age of onset of the deficiency.

PATHOLOGY Hypothyroidism Thyroxine and triiodothyronine are the two main hormones secreted by the thyroid (Resnick and Kransdorf, 2005: 597). The pituitary gland secretes thyrotropic hormone, which stimulates the formation of thyroxine by the thyroid. Thyroxine stimulates the metabolism and has local effects on skeletal maturation, as well as feeding back to the pituitary to stimulate further secretion of somatotrophic hormone. Most individuals with hypothyroidism show no skeletal evidence of the disease, with the main skeletal alterations seen only in severe thyroxine deficiency. Females are more affected than males with a ratio of 2:1 (Andersen, 1975). Severe deficiencies occur as the result of a congenital absence of the thyroid (sporadic hypothyroidism) but cancer can also depress the activity of the thyroid. Normal functioning of the thyroid depends on the amount of iodine in the diet as the hormones it produces contain three or four iodine atoms (Hinson et al., 2010). A dietary deficiency of iodine causes endemic hypothyroidism, which is associated with physical and mental retardation. However, the skeletal abnormalities that are caused by the two variants will be indistinguishable in the skeleton. Endemic hypothyroidism is mainly observed in mountainous areas of the world where iodine may be deficient in water and soil. In these areas, prevalence of the condition may be as high as 8% (Ortner and Hotz, 2005). The most noticeable clinical manifestation is goiter, or a large swelling in the neck caused by an enlargement of the thyroid gland that is located just below the larynx. One of these endemic areas is the alpine region of Switzerland, and much of what we know about

FIGURE 16.6 Possible hypothyroid dwarf (left) compared with pituitary dwarf skull (right), right lateral view. Note the different contour of the frontal bones (hypothyroidism, NMNH 379510; pituitary dwarf, NMNH 314306).

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the skeletal manifestations of endemic hypothyroidism is based on cases studied in that country by Uehlinger (Schinz et al., 1952: 1184 1195). One of these cases demonstrates many of the characteristic features of this pathological condition (Fig. 16.7), including secondary growth of the mandibular condyle (Fig. 16.7A), the abnormal length of the long bones, and inadequate development of the ribs (Fig. 16.7B), and secondary osteoarthritis from inadequate development of the epiphyses (Fig. 16.7C and D). Complete absence of the thyroid gland creates the most severe expression of dwarfing because of a complete absence of thyroxine. This is accompanied by great delay in formation of secondary ossification centers and permanently open epiphyseal plates, resulting in a great discrepancy between radiological and chronological bone age. In endemic cases there exists a gradient of deficiency leading to a subnormal stature (de Quervain and Wegelin, 1936: 35 41). Growth in length (endochondral ossification) is more severely affected than growth in width

(A)

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(intramembranous ossification) of long bones (Schinz et al., 1952). In affected individuals, the epiphyseal plates ultimately close, although later than normal, the last to close is the spheno-occipital growth plate. Inadequate growth at the basi-occipital and spheno-occipital growth plates results in a brachycephalic shape of the skull. The cranial sutures also remain open longer than normal. Continued growth at the mandibular condyle may ultimately result in abnormal prognathism (Fig. 16.7A). The marginal ossification centers of the scapula and the ilium may form only incompletely and remain open (Looser, 1929). Ortner and Hotz’s (2005) examination of 12 documented cases of hypothyroidism from Switzerland demonstrated that while basion nasion length was normal, individuals with the condition commonly showed reduced frontal bone height, broader interorbital space, and prognatism relating to the characteristic short, broad face. In the postcranium, most epiphyses show multifocal irregular ossification centers, which later fuse (Wilkins,

(B)

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FIGURE 16.7 Hypothyroid dwarf. (A) Left lateral view of the skull and mandible, demonstrating midfacial depression indicative of deficient growth of the cranial base. (B) Pectoral girdle and thoracic cage. Note the shortened humeri and deficient development of the ribs. (C) Pelvis and hips. Note the reactive bone formation associated with severe osteoarthritis of the femoral head. (D) Detail of right femoral head and acetabulum (80-year-old male, IPAZ 85 4059).

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archeological human remains may not be possible. However, Resnick and Kransdorf (2005: 597) suggest radiographic features such as cystic lesions in the frontal bone and other long bones that mimic multiple myeloma, and the more unusual expression of osteoporosis in the pelvis, cervical vertebrae, and hand and foot bones may aid in diagnosis.

Cushing’s Disease

FIGURE 16.8 Dysplastic femoral head with multiple ossification centers and short, plump neck, markedly delayed epiphyseal closure in a 37year-old female suffering from hypothyroidism with nodular goiter; body length 114 cm (FPAM, Jubila¨umspital 869).

1941) (Fig. 16.8). The development of the ossification center of the head of the femur is not only delayed but often abnormal. The lack of bony support of the femoral head leads to deformation of the cartilage model, secondary to static and dynamic stresses. The end result is a misshapen, flattened head with a mushroom-like deformity (not unlike the end stage of Perthes’ disease), with poor conformity with the shape of the acetabulum. However, in contrast to Perthes’ disease, there is no aseptic necrosis. This misshapen “cretin hip” leads to early and severe osteoarthritis (de Quervain and Wegelin, 1936) (Fig. 16.7D). Although less common, similar changes may occur on the humeral head (Ortner and Hotz, 2005).

Hyperthyroidism Excessive amounts of thyroxine (thyrotoxicosis) released by the thyroid are observed in toxic nodular goiter and Grave’s disease, but it may also occur as the result of a hormone-secreting pituitary adenoma (Hinson et al., 2010). Clinically, a sufferer will experience several physical symptoms including weight loss, increased appetite, irritability, hand tremors, and more seriously, tachycardia. Skeletal changes in this condition may be absent, or limited to increased bone resorption that causes osteoporosis. Occasionally, these changes mimic those in mild hyperparathyroidism and result in stress fractures (Askanazy and Rutishauser, 1933; Uehlinger, 1957). If hyperthyroidism occurs during the growth period, accelerated maturation of skeletal development may occur, including premature closure of epiphyses and sutures (Resnick and Kransdorf, 2005: 597). The skeletal abnormalities of hyperthyroidism resemble those found in several other diseases, and differential diagnosis in

Of the different hormones produced by the adrenal cortex under stimulation of pituitary adrenocorticotrophic hormone, only adrenocortical glucocorticoid steroid has the potential to affect the skeleton. The disease associated with excessive secretions of this steroid is Cushing’s disease, which may be caused by any of the following: hyperplasia, adenoma, carcinoma of the adrenal cortex, or less commonly, adenoma of the basophilic pituitary cells. The condition may be observed at any age. The excessive secretion of adrenocortical glucocorticoid steroid leads to suppression of protein synthesis, including production of collagen. The ensuing osteoblastic suppression and scarcity of bone matrix production result in severe osteoporosis. In addition, the skin becomes thinned and prone to bruising while wound healing is impaired and the individual is prone to infection due to a suppressed immune system (Hinson et al., 2010). Osteoclastic resorption is normal, but depressed bone formation causes severe osteoporosis that is most marked in bones rich in trabeculae, where normal turnover is relatively rapid. The vertebral column and ribs are most severely affected. The vertebral bodies show marked cortical thinning and severe reduction in the number and size of the trabeculae (Fig. 16.9). The end-plates bulge inward

FIGURE 16.9 Cushing’s disease in a 51-year-old female, showing vertebra with extreme osteoporosis after 10 years of cortisone therapy (MGH autopsy 20884).

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because of the pressure exerted by the resilient intervertebral discs, creating the biconcave and codfish vertebrae seen in several other conditions as well. The vertebral bodies lose height and compression fractures are common. Anterior wedging with kyphotic deformity occurs in the vertebral column. The ribs become severely osteoporotic and may exhibit multiple pathological fractures (Sissons, 1956). The long tubular bones also show trabecular osteoporosis and endosteal cortical resorption, but the changes are less obvious and the outer cortical surface appears normal. Although this osteoporosis is not specific, severe changes of this kind and severity, particularly in a child or young individual, are very suggestive of Cushing’s disease.

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Hypoparathyroidism The parathyroid hormone is produced and secreted by the parathyroid glands and has a primary effect on the kidneys and bone, which regulate calcium homeostasis (Rolighed et al., 2013). The parathyroid hormone acts on the skeleton by stimulation of osteoclastic resorption, liberating calcium from the bone matrix. Inadequate production of parathyroid due to an inherited condition, congenital absence, or acquired impairment of the parathyroids, results in hypoparathyroidism. In this rare condition, suppression of osteoclastic remodeling can lead to a degree of nondiagnostic osteosclerosis as a result of the continued osteoblastic endosteal and periosteal bone formation (Fig. 16.10).

Hypogonadism Hypogonadism arises from a failure of testicular or ovary function (primary hypogonadism), pituitary failure (secondary hypogonadism), or hypothalamic failure (tertiary hypogonadism). Estrogen and testosterone both stimulate linear (endochondral) growth and skeletal maturation. In both sexes subnormal production of gonadal hormones will delay the appearance of secondary ossification centers and postpone the closure of epiphyses and sutures. Subperiosteal (intramembranous) bone formation is also inhibited, resulting in a gracile skeleton with thin cortices. Because the period of endochondral growth is markedly lengthened, the normal skeletal proportions are altered because of the disproportionate length of the upper and lower extremities (eunuchoid stature) and elongation of the mandible, producing abnormal prognathism. Because castration of the male was practiced in various cultures, it is worth mentioning that in the early castrate (eunuch) the abovementioned changes are present to a most marked degree, resulting in a tall, longlegged, gracile skeleton. The earlier the procedure occurs the more epiphyses will be affected, and the greater the stature of the individual (Eng et al., 2010). Cessation of production of gonadal hormones in the adult, by either involution (menopause) or pathologic destruction of the gonads may, in the long term, result in axial osteoporosis in either sex (Nowakowski, 1959).

Hypergonadism Excessive amounts of gonadal hormones produced by various neoplasms or other abnormalities will result in precocious puberty in affected children. Endochondral growth is stimulated and the epiphyseal plates close prematurely, resulting in a short but stocky skeleton (Wilkins, 1950: 230; Prader and Maassen, 1953: 148).

FIGURE 16.10 Hypoparathyroidism. Frontally bisected proximal right tibia showing marked cortical thickening, some periosteal hyperostosis, and enlarged trabecular bone. The femur showed the same features. The individual is a 62-year-old female with hypothyroidism and postsurgical hypoparathyroidism of 10 years’ duration (IPAZ 6168, autopsy 1265 from 1955).

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Albright’s Hereditary Osteodystrophy Albright’s hereditary osteodystrophy (AHO) is a genetic disorder resulting from molecular defects at the GNAS locus. There are five variants (Levine, 1998: 510). Two variants do not result in significant physical abnormalities. Three variants do develop the characteristic physical changes of AHO that consist of a round face, short neck, short stature, stocky physique, shortened metacarpals (brachydactyly), and mental retardation. The two variants of AHO do result in abnormal physical changes: pseudohypothyroidism (type 1a), where the mutation is inherited from the mother, and pseudopseudohypothyroidism, where the mutation is passed through the paternal line. The primary physiological problem in pseudohypothyroidism is the inability of bone and the kidney to respond to parathyroid hormone. In pseudopseudohypothyroidism the physical changes are essentially the same, but there is no abnormality in the response of bone and the kidneys to parathyroid hormone, and the reasons for the physical changes are not yet known. In the skeleton, abnormalities of the two variants are indistinguishable (Resnick and Kransdorf, 2005: 575), and differentiating between them in archeological human remains based on anatomical evidence will not be possible. However, there may be potential to isolate the gene mutation causing AHO through aDNA analysis.

Hyperparathyroidism Hypersecretion of parathyroid hormone leads frequently to marked skeletal changes, mainly osteoporosis and increased fracture risk. It occurs as a primary condition or secondary to renal impairment (Rolighed et al., 2013).

Primary Hyperparathyroidism (Osteitis Fibrosa Cystica Generalisata) This condition, first described by Recklinghausen (1891), is the result of hypersecretion by either a parathyroid adenoma of one or more glands, or by diffuse hyperplasia of all parathyroids. It normally affects people between 50 and 60 years of age but can occur in infancy and at any age. Women are more commonly affected than men at a ratio of 3:1 (Silverberg and Bilezikian, 2001). The continued overstimulation of osteoclastic resorption results in osteoporosis, and the continued loss of the liberated calcium through the kidneys causes a negative calcium balance. Early changes are demonstrable only microscopically. They consist of osteoclastic intratrabecular resorption (Fig. 16.11) accompanied by fibrous conversion of the bone marrow (“dissecting bone atrophy”). Only advanced cases will show significant radiologic and gross skeletal

FIGURE 16.11 Hyperparathyroidism. Vertebral spongiosa showing centrotrabecular resorption (dissecting atrophy) (70-year-old female, IPAZ autopsy 1204 from 1970; courtesy Prof. E. Uehlinger).

changes. As a direct effect of continued bone resorption that exceeds bone formation, general osteoporosis develops. This loss of bone mass may be radiologically and grossly demonstrable, particularly on the cortical surface of phalanges, forming scalloped depressions. Similarly, the normally present thin layer of lamellar bone (lamina dura) lining the dental alveoli undergoes resorption, which is visible in radiographs and by direct inspection of the macerated or archeological jaws. The osteoporosis of the spine may lead to biconcave deformity of the vertebral bodies. Cranial osteoporosis tends to diminish the distinction of the outer and inner table. There is transformation of the diploe¨ into fine trabecular, poorly mineralized, cancellous bone (salt and pepper skull). The major gross abnormalities observed are the result of continued and repeated minor trauma acting upon the vulnerable skeleton. These changes consist of cyst formation and proliferation of fibrous marrow (“brown tumors”) secondary to hemorrhage and microfractures (Jaffe, 1940). These lesions appear on dry bone as cystic, lytic defects with one or several cavities separated by bony septa and ridges (Fig. 16.12). They may enlarge the affected area of the bone remarkably and lead to pathological fractures and deformities. These lesions can appear in any bone but appear more often in the mandible, the long and short tubular bones of the extremities, and the pelvis. A classic feature is also tapering of the distal third of the clavicle and the individual may develop gout (Silverberg and Bilezikian, 2001). In extreme cases the skeleton may become more pliable and deformed than in osteomalacia or fibrous dysplasia.

Secondary Hyperparathyroidism In a variety of chronic renal diseases, parathyroid hyperplasia occurs as a response to disturbance of the

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FIGURE 16.13 Secondary hyperparathyroidism. X-ray of skull showing “cotton-wool” appearance of cranial vault (62-year-old female, IPAZ surgical specimen 12807154).

FIGURE 16.12 Hyperparathyroidism (osteitis fibrosa cystica) in a bisected femur.

metabolism of calcium and phosphorous. The majority of these cases concern children and will show, in addition to rickets-like changes (Chapter 15) and stunted growth, features of hyperparathyroidism. In adults, of course, alterations to growth no longer can occur, and, therefore, the picture of renal osteopathy is a combination of hyperparathyroidism and osteomalacia. In rare instances of longlasting renal impairment in adults, all features of primary hyperparathyroidism, including skull changes (Fig. 16.13), cysts, and brown tumors, can be observed (Jaffe, 1972: 326).

PALEOPATHOLOGY Hypothyroidism A Native American skeleton from the American Southwest has skeletal abnormalities that are best explained as the result of sporadic hypothyroidism in which some but not all thyroid function was absent (Fig. 16.14). The skeleton is that of an adult female from an archeological site dated between AD 1250 and 1700 that is currently curated in the National Museum of

Natural History, United States (NMNH 271813). There is evidence of diminished endochondral growth throughout the skeleton, but not all bones are affected to the same degree. The skull base is shorter relative to the overall size of the skull, resulting in a slightly depressed midfacial profile (Fig. 16.14A). The clavicles, ribs, and sternum are shorter than normal (Fig. 16.14B). The pedicles of the vertebral arches are shorter than normal, making the vertebral foramen compressed in the anteroposterior axis (Fig. 16.14C). The major bones of the upper extremities show disproportionate growth, with abnormally short humeri and an abnormal angular deviation of the distal joint axis, but the radii and ulnae are normal in length, although they are affected by the humeral deviation (Fig. 16.14D). The pelvis has the shape of a female pelvis but is about two-thirds the size of a normal female pelvis (Fig. 16.14E). The femora are disproportionately shorter than normal, with abnormal formation of the femoral head and a short femoral neck (Fig. 16.14F and G). Differential diagnosis in this case would include several options, including the dysplasias and other endocrine problems. The fact that the affected individual reached adulthood indicates that some thyroid hormone was present. The fact that endochondral ossification was affected implies that the abnormality began during the growth period. The disproportional growth is not easily explained by hypothyroidism. A thyroid deficiency should affect all the bones more or less equally. The disproportional sizes of the long bones suggest that different bones may have different thresholds for being adversely affected by inadequate thyroid hormone secretions, perhaps related to the age of onset (Ortner and Hotz, 2005).

580 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

(A)

(B)

(C)

FIGURE 16.14 Probable hypothyroidism. (A) Left lateral view of the skull showing inadequate growth in the midfacial area. (B) Clavicles, ribs, and sternum with subnormal development, particularly of the sternal body. Probable hypothyroidism. (C) Superior view of C7, T1, and T2 vertebrae, showing diminished growth of the pedicles, resulting in a narrow anteroposterior dimension of the vertebral foramen. (D) Right and left humerus, ulna, and radius, demonstrating abnormal growth, particularly of the humeri. (E) Pelvis (right side of figure) compared with a normal female, anatomical pelvis showing diminished growth. (F) Anteroposterior radiograph of proximal femora showing abnormal development of the femoral head and shortened femoral neck (NMNH 271813, an adult female from an archeological site in the American Southwest, AD 1250 1700). (G) Right and left femur, tibia, and fibula with abnormal length and shape, particularly of the femur. The femoral neck is shorter than normal.

Albright’s Hereditary Osteodystrophy AHO is a rare disease today, with only two examples so far reported in an archeological context (Ward, 1996). The first case is the skeleton of an adult male who was about 35 40 years of age at the time of death. In addition to the evidence of AHO there are unmistakable signs of leprosy in the skeleton. The skeleton is from the site of

the medieval cemetery associated with the hospital of St. James and St. Mary Magdalene in Chichester, England (burial 58). The skull is very round in shape, and the individual is clearly much more brachycephalic (Fig. 16.15A) than other skulls in the Chichester sample. The sternum is unusually narrow in the mediolateral axis. The humeri are slightly shorter than normal, and the bicipital groove is very deep. The

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(D)

(E)

(F)

(G)

FIGURE 16.14 (Continued).

forearm is certainly shorter than normal (Fig. 16.15B). The radius measures only about 200 mm in length. The feature that is virtually pathognomonic for AHO is the disproportionately shortened fourth and fifth metacarpals (Fig. 16.15C).

In the lower extremity the pelvis is normal, as is the femur, although the muscle markings are very well marked and robust. There is some evidence on the right femur of abnormal curvature, with both a rotation and a lateral deviation of the distal end of the femur. This is

582 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

(A)

(B)

(C)

L

R

FIGURE 16.15 Probable Albright’s hereditary osteodystrophy. (A) Left lateral view of the skull, showing diminished endochondral growth of the cranial base. (B) Sternum, humeri, ulnae, and radii with subnormal length growth of the forearm. (C) Right and left second through fifth metacarpals. Note the disproportionate shortening of the fourth and fifth metacarpals (Chichester 58, University of Bradford).

slightly the case on the left side, although the lateral deviation of the distal end is not as severe. The tibias and fibulae are abnormally short. The overall pattern of disproportional development of the long bones is similar to that seen in the case of possible hypothyroidism from the American Southwest. However, the pelvis was not affected, and the abnormalities of the metacarpals make a diagnosis of AHO probable. A second probable case from the Anasazi site of Kin Tiel, Arizona, has been proposed (Dudar and Ortner, 2004) and is curated in the National Museum of Natural History (NMNH 350241). This young adult female has cranial thickening, bowing and deflection of the joints of the radius, tibia, and fibula and bilateral shortening of the fourth and fifth metacarpals and distal thumb phalanx. The authors suggest Turner’s syndrome as a possible differential diagnosis, but the average stature and finger shortening make AHO a more likely explanation.

Hyperparathyroidism Three possible cases of secondary hyperparathyroidism have been identified from an archeological context and show the necessity for histological analysis in determining a diagnosis. The first is a 2- to 3-year-old (Burial HB772) from 19th century Birmingham in England, where histology revealed linear radiolucencies within the trabecular bone (dissecting osteitis), giving the cortical bone a longitudinal striated appearance on the radiograph (Mays et al., 2007). The second case is of a 13- to 15-year-old (WCO58) from Wharram Percy, Yorkshire (AD 960 1700), where active widespread subperiosteal new bone, cortical porosity, and a mass of poorly organized spicules occupy the medullary cavity. The absence of rickets and presence of subperiosteal new bone formation led Mays and Turner-Walker (2008) to suggest renal osteodystrophy as a primary cause of the condition.

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Finally, a possible case is suggested by changes identified in a poorly preserved adult female (CN3) from the same site, believed to have been buried in AD 1420 1640 (Mays et al., 2001). The suggested diagnosis rests on the presence of “tunneling” resorption of the cortical bone, while the volume of cancellous bone is maintained. The loss of corticomedullary distinctiveness, subperiosteal resorption of the foot phalanges, and subchondral resorption of the appendicular and axial skeleton, all are seen on the radiograph. However, there is an absence of brown tumors in the parts of the skeleton that survive.

REFERENCES Andersen, H., 1975. Hypothyroidism. In: Gardner, L. (Ed.), Endocrine and Genetic Diseases of Childhood and Adolescence. WB Saunders, Philadelphia, PA, pp. 234 238. Aristova, E., Chikisheva, T., Seidman, A., Mashak, A., Khoroshevskaya, Y., 2006. Pituitary dwarfism in an early Bronze Age individual from Tuva. Archaeol. Ethnol. Anthropol. Eurasia 27 (1), 139 147. Askanazy, M., Rutishauser, E., 1933. Die Knochen der BasedowKranken. Virchows Archiv fu¨r pathologische Anatomie und Physiologie und fu¨r klinische Medizin 291 (3), 653 681. Bartelink, E.J., Willits, N.A., Chelotti, K.L., 2014. A probable case of acromegaly from the Windmiller Culture of prehistoric Central California. Int. J. Paleopathol. 4, 37 46. Beckers, A., Fernandes, D., Fina, F., Novak, M., Abati, A., Rostomyan, L., et al., 2017. Paleogenetic study of ancient DNA suggestive of X-linked acrogigantism. Endocr. Relat. Cancer 24 (2), L17 L20. Brothwell, D., 1981. Digging up Bones. Cornell University Press, New York. Canalis, E., Mazziotti, G., Giustina, A., Bilezikian, J., 2007. Glucocorticoid-induced osteoporosis: pathophysiology and therapy. Osteoporos. Int. 18 (10), 1319 1328. Charlier, P., Tsigonaki, C., 2011. A case of acromegaly (Greece, 7th century AD). Eur. J. Endocrinol. 165 (5), 819 821. Cordero, R.A., Barkan, A., 2008. Current diagnosis of acromegaly. Rev. Endocr. Metab. Disord. 9 (1), 13 19. De Quervain, F., Wegelin, C., 1936. On Endemic Cretinism. Springer, Berlin. Dudar, J.C., Ortner, D., 2004. A possible rare case of Albright Hereditary Osteodystrophy from the Anasazi site of Kintiel, Arizona. In: Poster presented at the European Palaeopathology Association Meeting, University of Durham. Eng, J.T., Zhang, Q., Zhu, H., 2010. Skeletal effects of castration on two eunuchs of Ming China. Anthropol. Sci. 118 (2), 107 116. Erdheim, J., 1916. Nanosomia pituitaria. Beitr. Path. Anat 62, 302. ¨ ber Wirbelsa¨ulenvera¨nderungen bei Akromegalie. Erdheim, J., 1931. U Virchows Archiv fu¨r pathologische Anatomie und Physiologie und fu¨r klinische Medizin 281 (1), 197 296. Gladykowska-Rzeczycka, J., Smiszkiewicz-Skwarska, A., Sokol, A., 1998. A giant from Ostrow Lednicki (XII-XIII c), dist. Lednogora, Poland. Mankind Quarterly 39 (2), 147 172. Hinson, J.P., Raven, P., Chew, S., 2010. The Endocrine System. Churchill Livingstone, London.

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Hoˇsovski, E., 1991. A case of acromegaly in the Middle Ages. Anthropol. Anzeiger. 49 (3), 273 279. Hrdliˇcka, A., 1943. Skull of a midget from Peru. Am. J. Phys. Anthropol. 1 (1), 77 82. Jaffe, H.L., 1940. Hyperparathyroidism. Bull. N.Y. Acad. Med. 16 (5), 291 311. Jaffe, H., 1972. Metabolic, Degenerative, and Inflammatory Diseases of Bones and Joints. Lea & Febiger, Philadelphia. Levine, M., 1998. Hypoparathyroidism and pseudohypoparathyroisism. In: Avioli, L.V., Krane, S.M. (Eds.), Metabolic Bone Disease. Academic Press, San Diego, pp. 501 529. Looser, E., 1929. Die Kretinenhufte. Schweiz. med. Wschr 10, 1258. Mays, S., Turner-Walker, G., 2008. A possible case of renal osteodystrophy in a skeleton from medieval Wharram Percy, England. Int. J. Osteoarchaeol. 18 (3), 307 316. Mays, S., Rogers, J., Watt, I., 2001. A possible case of hyperparathyroidism in a burial of 15 17th century AD date from Wharram Percy, England. Int. J. Osteoarchaeol. 11 (5), 329 335. Mays, S., Brickley, M., Ives, R., 2007. Skeletal evidence for hyperparathyroidism in a 19th century child with rickets. Int. J. Osteoarchaeol. 17 (1), 73 81. Minozzi, S., Pantano, W., Catalano, P., Gennaro, F., Fornaciari, G., 2015. “The Roman Giant”: overgrowth syndrome in skeletal remains from the Imperial Age. Int. J. Osteoarchaeol. 25, 574 584. Morse, D., 1978. Ancient Disease in the Midwest. Springfield, Illinois State Museum. Mulhern, D., 2005. A probable case of gigantism in a fifth dynasty skeleton from the western cemetery at Giza, Egypt. Int. J. Osteoarchaeol. 15 (4), 261 275. Nowakowski, H., 1959. Der Hypogonadismus im Knaben-und Mannesalter. In: Heilmeyer, L., Schoen, R., De Rudder, B., Prader, A. (Eds.), Ergebnisse der inneren Medizin und Kinderheilkunde. Springer, Berlin, pp. 219 301. Ortner, D., Hotz, G., 2005. Skeletal manifestations of hypothyroidism from Switzerland. Am. J. Phys. Anthropol. 127 (1), 1 6. Ousley, S., Owlsey, D., Mulhern D., Lost and found in the museum: repatriation, ancestry, ethnicity and history. Poster presented at the 68th Annual Meeting of the American Association of Physical Anthropologists, April 12-15, San Antonio, TX, 2000. ¨ zdemir, K., Erdal, O ¨ .D., Erdal, Y.S., 2017. A case of pituitary giganO tism and acromegaly in Anatolia (Tasmasor, Erzurum, Turkey). Int. J. Osteoarchaeol. 27 (5), 725 744. Prader, A., Maassen, A., 1953. Effect of androgen hormones on skeleton; bone and teeth development, calcium phosphorus and phosphatases in blood in congenital adrenogenital syndrome. Helv Paediatr Acta 8 (2), 136. Priesel, A., 1920. Hypophysaere Zwergwuchs: Ein Beitrag zur Kenntnis des hypophysaeren Zwergwuchses. Beitr. Pathol. Anat. Allg. Pathol. 67, 220 274. Recklinghausen, F., 1891. Die fibrose oder deformierende Ostitis, die Osteomalacic und die osteoplastische Carcinose, in ihren gegenseitigen Beziehungen. Rudolf Virchow Festschriften 1 89. Resnick, D., 1988. Disorders of other endocrine glands and pregnancy. Diagnosis of Bone and Joint Disorders. WB Saunders, Philadelphia, pp. 2286 2317. Resnick, D., Kransdorf, M., 2005. Bone and Joint Imaging, third ed. Elsevier Saunders, Philadelphia.

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Rhine, S., 1985. A possible case of acromegaly from New Mexico. Health and Disease in the Prehistoric Southwest 210 219. Richards, G., 1985. Analysis of a microcephalic child from the later period (ca. 1100-17AD) of Central California. Am. J. Phys. Anthropol. 68, 343 357. Roberts, C., 1987. Case Report No. 9. Paleopathology Newsletter 57, 14 15. Rolighed, L., Rejnmark, L., Christiansen, P., 2013. Bone involvement in primary hyperparathyroidism and changes after parathyroidectomy. Eur. Endocrinol. 9 (2), 181 184. Rostomyan, L., Daly, A.F., Petrossians, P., Nachev, E., Lila, A.R., et al., 2015. Clinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients. Endocr. Relat. Cancer 22 (5), 745 757. Schinz, H., Baensch, W., Friedl, E., Uehllnger, E., Lehrbuch der Rontgendiagnostik, G. Thieme, Stuttgart, 1952. Silverberg, S., Bilezikian, J., 2001. Clinical Presentation of Primary Hyperparathyroidism in the United States, 2001, Academic Press, New York, pp. 349 360. Sissons, H., 1956. The osteoporosis of Cushing’s syndrome. J. Bone Joint Surgery. Brit. 38 (1), 418 433. Stewart, T.D., 1968. Identification by the skeletal structures. In: Camps, F. (Ed.), Gradwohl’s Legal Medicine. Williams and Wilkins, Baltimore, pp. 123 154.

Trivellin, G., Daly, A.F., Faucz, F.R., Yuan, B., Rostomyan, L., et al., 2014. Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. N. Engl. J. Med. 371 (25), 2363 2374. Uehlinger, E., 1957. Thyreogene Osteodystrophie bei inkretorisch aktivem, metastasierendem, kleinfollikula¨rem Schilddru¨senadenom. Schweiz, med. Wschr 87, 683. Urist, M.R., 2012. Growth hormone and skeletal tissue metabolism. Biochem. Physiol. Bone 2, 155 194. Viciano, J., De Luca, S., Lo´pez-La´zaro, S., Botella, D., Die´guezRamı´rez, J.P., 2015. A probable case of gigantism/acromegaly in skeletal remains from the Jewish necropolis of “Ronda Sur” ´ (Lucena, Cordoba, Spain; VIII XII centuries CE). Anthropol. Anz. 72 (1), 67 87. Ward, S., 1996. A consideration of mental retardation in pre-Modern England: Historical and anthropological perspectives with a case study. MSc Dissertation, University of Bradford, England. Wells, J.R., 1942. A diminutive skull from Peru. Am. J. Phys. Anthropol. 29 (3), 425 427. Wilkins, L., 1941. Epiphysial dysgenesis associated with hypothyroidism. Amer. J. Dis. Child. 61, 13 34. Wilkins, L., 1950. Hypothyroidism in Children. In: Soskin, S. (Ed.), Progress in Clinical Endocrinology. Butterworth-Heinemann, Illinois, pp. 51 60.

Chapter 17

Congenital and Neuromechanical Abnormalities of the Skeleton Mary Lewis University of Reading, Reading, United Kingdom

INTRODUCTION Congenital abnormalities and neuromechanical changes are influenced by the intimate feedback mechanisms that exist among nerves, muscles, and bone, meaning that a defect in one or more of these tissues can have an impact on the others. Abnormal conditions resulting from such defects are most pronounced when they occur during development. However, significant changes to the skeleton can result from abnormalities that occur in the adult and may mimic those that are congenital. The possible combinations of skeletal defects that can result from various permutations of these abnormal conditions is substantial. This chapter will concentrate on providing a brief review of the more common abnormalities the paleopathologist might encounter. The diseases described here have much in common with those that will be discussed in the following chapter on skeletal dysplasias (Chapter 18). Most of the diseases discussed in this chapter and all of the diseases reviewed in Chapter 18 are congenital, although some may not be fully expressed until later in development. Some congenital abnormalities affect all or most of the skeleton. Typically they are the result of a problem in embryological development and are associated with defects in the formation of other organs that are incompatible with prolonged postfetal life. One example of this is incomplete twinning (Fig. 17.1). Less serious malformations of the skeleton are often due to failure of closure of fetal clefts or suppression of a portion of the skeletogenic mesenchyme. Many of these are compatible with life and maturity. In most diseases there is a strong probability that a genetic defect is associated with the pathogenesis. However, it is important to recognize that disruption in

the nervous or vascular supply of a part of the body from a variety of causes, including infection, can produce abnormal size and/or shape of a skeletal element that may be very similar to a congenital problem affecting development. Also, there are several diseases or their variants for which there is no known cause. Congenital conditions will be reviewed by primary anatomical region, beginning with those that affect the skull.

SKULL Pathology Anencephaly During embryonic development the central nervous system begins as a flat plate that becomes the neural tube by fusing along the median line, first in the cervical region, then progressing both caudally and cranially (Charon, 2004). The extremities of the neural tube (neuropores) then close. Disturbances to this fusion result in defects of the cranium and spine. The most frequent fatal malformation of the skull, making up 25% of all cases, is anencephaly. It results from severe malformation of the embryonic neural tube, resulting in cranial vault aplasia causing the cerebral parenchyma to float in amniotic fluid, it deteriorates to become a mass of amorphous brain tissue, that is exposed to the environment at birth (Charon, 2004) (Fig. 17.2). This condition is often combined with partial or complete failure of closure of the neural canal (craniorachischisis). The skull base shows marked deformities of its constituent bones. The skull vault is absent or deficient and the orbits may be rudimentary. A deficiency in folic acid is strongly associated with its etiology (Kalter, 2003), but anencephaly is generally

Ortner’s Identification of Pathological Conditions in Human Skeletal Remains. DOI: https://doi.org/10.1016/B978-0-12-809738-0.00017-X © 2019 Elsevier Inc. All rights reserved.

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586 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 17.1 Dicephalic infant with partial duplication of the spine. (Newborn, FPAM 1576.)

FIGURE 17.2 Anencephalic infant, lateral view. (Newborn, IPAZ 2224.)

more often associated with mothers of low socioeconomic status (Aufderheide and Rodriguez-Martı´n, 1998). Anencephalic skulls show great variability in their morphology, but flattened frontal bones and an unusual appearance of the sphenoid body and wings may signal the presence of this condition in perinatal skulls (Dudar, 2010).

Cleft Lip and/or Palate Defects in the embryological development of the maxilla and premaxilla may result in a cleft lip and/or palate and nonodontogenic cysts (Gregg et al., 1983). There is great variety in the severity of cleft palate, which can be unilateral or bilateral, and range in severity from a minor cleft, to a “U”-shaped deformity of the whole hard palate. The most severe defects prohibit sucking in infants and may result in death shortly after birth (Fig. 17.3). Complete clefts of the maxilla and lip occur in around 1 in 700 births (Waldron, 2009) (Fig. 17.3). Cysts can occur in several locations in the maxilla, premaxilla, and mandible, and care is needed to distinguish this abnormality from the defects caused by dental abscesses (Gregg et al., 1983).

FIGURE 17.3 Cleft lip and palate in an adult skull. (WM RCS A1.2.)

Congenital Herniations These result from failure in the fusion of the anterior neuropore, allowing the meninges (meningocele) or meninges and cephalic mass (meningoencephalocele) to protrude through an aperture in the skull (Aufderheide and Rodriguez-Martı´n, 1998). This aperture is usually located on the sagittal plane of the occipital (75%), frontal (15%),

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or parietal bones (10%); however lesions may also be evident on the roof of the orbit, nasal bones, or sella turcica (Aufderheide and Rodriguez-Martı´n, 1998; Barnes, 1994) (Fig. 17.4). Given the large size of the defect, infants born with meningoencephalocele will die, but individuals can survive with a meningocele until adulthood. (A)

(B)

FIGURE 17.4 Anterior midline encephalocele in a 5-year-old. (A) Anterior view; notice flattened protruding nasal bones above defect. (B) Endocranial view; notice smooth-edged defect of ethmoid area. (PMUG 3824, autopsy 17395 from AD 1890.)

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Premature Suture Closure Craniosynostosis refers to premature suture fusion causing craniostenosis, or an abnormal cranial shape (Cohen, 2005). Premature closure of one or several cranial sutures results in various characteristic skull deformities. The severity of the deformity will depend on when the fusion of the sutures occurs, and how many sutures are affected. The most severe deformities are caused by suture fusion during embryological development or a complete failure of a suture to form (sutural agenesis) (Fig. 17.5A). Subsequent increasing pressure caused by the growing brain may lead to separation of any open sutures (Fig. 17.5B), and deep cerebral impressions on the inner table may be evident in some cases (Fig. 17.6). Craniosynostosis may occur in isolation (primary) or may be secondary to another condition (Jabs, 1998). Conditions that may lead to craniosynostosis include hyperthyroidism, vitamin D deficiency, Hurler’s syndrome, genetic anemia (Khanna et al., 2011), head-binding, and birth trauma (Aufderheide and Rodriguez-Martı´n, 1998). The etiology of premature suture fusion is complex and it has been associated with over 169 monogenetic disorders and 90 syndromes, although only one-third of cases have a clear etiology (Jabs, 1998; Oostra et al., 2005). Changes in the morphology of the cranium are due to cessation of growth at the affected site with compensatory growth at the patent sutures (Duncan and Stojanowski, 2008). This compensatory growth is particularly evident at sutures that are parallel to affected side (Jane et al., 2000).

Hydrocephalus Resulting in an enlarged cranium, hydrocephalus is caused by abnormal production of cerebrospinal fluid, defective absorption of the fluid, or more commonly, a blockage in the circulation of the cerebral ventricular system (Johanson et al., 2008; Murphy, 1996). A build-up of fluid or “water-on-the-brain” causes increasing pressure on the brain, resulting in headaches and a loss of balance (Fig. 17.7). If left untreated, hydrocephalus may cause blindness, deafness, and paralysis, with 50% of suffers dying before the age of 5 years (Murphy, 1996). Today, 25% of cases of hydrocephalus are sporadic, but it is also related to prenatal trauma or anoxia, tumors, and infections such as mumps and measles (Laurence and Coates, 1962). The age of onset and the severity of fluid build-up can vary extensively, and because of this the amount of cranial enlargement is also variable. The major factor in the diagnosis of this condition in skeletal remains is a significant enlargement of the cranial vault relative to the size of the face, although addition features such as asymmetry of vault, thinning of cranial bones, cerebral imprinting, interdigitation of sutures, and extra wormian bones may also aid in diagnosis (Richards and Anton, 1991).

588 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

(A)

FIGURE 17.6 Premature synostosis of the sagittal and midportion of the coronal suture in a 2-year-old male, showing pressure atrophy with deep cerebral impressions and midline perforations of the cranial vault; endocranial view. (FPAM 2118 from AD 1844.)

(B)

FIGURE 17.5 Premature synostosis of sagittal suture in a 9-week-old infant with midline bony ridge and lateral defects along suture lines, secondary to intracranial pressure. (A) Top view. (B) Lateral view of skull. (FPAM 3576 from AD 1877.)

FIGURE 17.7 A severe case of hydrocephalus with thinned cranial bones and lacunae Anterior view of the skull. (Infant, IPAZ 883.)

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Paleopathology Cleft Lip and Cleft Palate These abnormalities are uncommon in reports of archeological skeletons, but this does not mean that cleft lip and palate were rare in antiquity. Tretsven (1965: 229) found the prevalence of cleft abnormalities among living Native Americans in Montana to be higher than that of nonNative Americans. He further notes (p. 236) that the language of many Native American groups includes descriptive terms for cleft abnormalities. Mortality of infants with severe cleft lip and palate would have been high in antiquity. In open clefting, the defect inhibits effective nursing, which may have resulted in their early death, and infants with grossly observable deformities may have been killed. However, there are several examples of mild cleft palate and/or lip in nonadults that would have allowed for survival into adulthood (Lewis, 2017). Berndorfer (1962) has described a female about 25 30 years of age excavated in south Hungary and dated to the 15th century. The only abnormality of the skull is a poorly developed premaxilla and a small defect of the inferior aspect of the right pyriform aperture. The anterior alveolar region of the maxilla has a slight indentation suggestive of a cleft lip. The incisors are missing antemortem and the sockets for the roots are not present. Berndorfer rules out gingival atrophy following antemortem loss of the incisors, because the remaining teeth are normal. He does not consider cultural artificial extraction of the teeth as a possible cause of the slight defect in the alveolar bone. However, the abnormality of the pyriform aperture and subnormal development of the premaxilla would support a diagnosis of slight cleft lip. Brooks and Hohenthal (1963) report the presence of cleft abnormalities in three indigenous skulls from two archeological cemeteries in California. Two of the skulls are from the Newark Site on the southeastern shore of San Francisco Bay. The skulls come from the Late Middle Horizon level dated by carbon-14 to 2340 BP (Museum of Anthropology, University of California, Berkeley, Skulls 8474 and 9859). The third cranium (Skull 22,117) is from a site in Sacramento County in California and is dated between 2000 and 4000 BP. Skull 8474 is from a male about 30 40 years of age. Both the maxilla and the palate have cleft defects. The upper right incisors were missing antemortem. The mandible is reported to be normal. Skull 9859 is also male, with an estimated age of between 22 and 25 years. The nasal bones are abnormal, but the picture is obscured by postmortem damage. Both the maxilla and the palate have cleft-type defects. The extensive nature of the facial abnormality added to the general porosity of the bones of the forehead and face are atypical of cleft palate and lip. The authors suggest the possibility of injury, although

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they conclude that cleft abnormality is the best interpretation of the defect. Skull 22,117 is that of a female between 25 and 28 years of age. The skull has a marked unilateral loss of bone of the alveolar portion of the right maxilla. There are also extensive inferior bony projections on the maxilla near the suture with the zygomatic bone. The authors conclude that this is a case of unilateral harelip. On this individual there is also evidence of porosity, which may be indicative of a reactive response to injury and/or infection. Derry (1938) reports two examples of agenesis of the premaxillary region of the maxilla. The first example is a cranium from a 25th Dynasty Egyptian site on the east bank of the Nile. The individual is female, past middle age, and normal except for the absence of the premaxilla. The hard palate is reduced in size and the maxillary incisors are absent antemortem. The provenience of the second individual is unknown. The cranium appears to be from an adult female. As in the first example the premaxilla is absent. The mandibles associated with the crania project beyond the anterior border of the maxilla (mandibular prognathism), supporting the observation of subnormal development of the maxilla. Gregg et al. (1983) reviewed the evidence of clefting and cysts in archeological Native American remains from two regions of the United States and reported on six cases of these defects. Old World examples of cleft lip and palate include a medieval adult (c. late 11th or 12th century) from St. Gregory’s Priory, Canterbury, England (Anderson, 1994). In the Nubian pathology collection of the Natural History Museum, London, England, there is a complete cranium of an adult female that exhibits cleft palate (BMNH 210 72/291). Most of the teeth have been lost postmortem, but judging from the intact dental alveoli the teeth were normal. The cleft defect is bilateral and involves only the central and posterior portions of the palate (Fig. 17.8).

FIGURE 17.8 Severe cleft palate of the central and posterior area. (Nubian skull, BMNH 210 72/291.)

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An example of both cleft lip and cleft palate is seen in an individual from the Wellcome Museum of Pathology, Royal College of Surgeons in London, England (Fig. 17.9). The individual (WM A1.3) is an indigenous South Pacific islander. The right side of the alveolar arch (A)

is relatively normal, although there is a complete cleft through the left portion of the anterior maxilla, which is continuous with the cleft of the left hard palate. The maxillary defect is continuous with the pyriform aperture. Two cases from the National Museum of Natural History collections at the Smithsonian Institution, Washington, DC, provide additional evidence for the presence of cleft abnormalities in New World indigenous populations. The first of these is a complete cranium of a young adult female about 18 20 years of age from southwestern Colorado (NMNH 316482). The date of the skull is unknown. The skull exhibits some occipital flattening, which is unrelated to the abnormality of the maxilla. Both maxillary central incisors and the right lateral incisor are absent antemortem. The sockets are absent and the alveolar bone is thin. Dental alveoli are present for the remaining teeth, although the socket for the upper right canine is poorly formed with the anterior portion missing. There is a small cleft in the central portion of the intermaxillary suture (Fig. 17.10A). The nasal bones are depressed about (A)

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FIGURE 17.9 Cleft lip and palate in an indigenous South Pacific islander. (A) Facial view. (B) View of palate. (WM A1.3.)

FIGURE 17.10 Cleft palate and possible cleft lip in a young adult, female skull from an archeological site in Colorado. (A) Facial view. (B) View of palate. (NMNH 316482.)

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15 mm below the nasion, as if the result of a healed blow in childhood. The palate is cleft primarily to the right of the midline with slight abnormality to the left (Fig. 17.10B). Both the palatine process of the maxilla and the palatine bone are involved, although the defect is less severe in the posterior portion of the palate. The mandible is normal. The second is in an 8- to 10-year-old from the Nasca region in Peru (NMNH 293252). The archeological age is not known. Only the anterior portion of the skull is present, including the frontal, sphenoid, zygomatic, nasal, and palatine bones and the maxilla. The cleft defect is primarily on the left side (Fig. 17.11) and involves the alveolar and palatine process of the maxilla, as well as the palatine bone

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and the internal bones of the nasal cavity. The cleft of the alveolus and palate are continuous with each other and with the nasal cavity. There has been a lateral deviation of the intermaxillary suture toward the right side of the face. More subtle cases of maxillary clefts that involve the anterior aspect of the maxilla indicating cleft lip have been identified with two cases, an adult and a child, showing accompanying dental anomalies. Tur et al. (2017) present a bilateral cleft lip and alveolus in an 18- to 23-year-old male from the Altai Region in Russia (1883 1665 BC) with accompanying aplasia of the frontal sinuses, smaller than average premolars, maleruption of the second maxillary premolar, and subsequent retention of the second deciduous molar. The second case is of a 10- to 12-year-

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FIGURE 17.11 Cleft lip and palate in an 8- to 10-year-old from the Nasca region in Peru (right) compared with a normal cranium (left) of about the same age from an archeological site in Kentucky. (A) Facial view. (B) View of palate. (NMNH 293252, right; NMNH 243198, left.)

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FIGURE 17.12 Differential diagnosis for cleft palate. An oval midline cyst in an individual from an archeological site in Kentucky. (NMNH 243208.)

old with severe anterior dental overcrowding, dental maleruption, and an enlarged supernumerary central incisor, or macrodont, on the left side (Lewis, 2013). A case described as an example of cleft palate in the first edition of this book (Ortner and Putschar, 1981: 350) is from an archeological site in Kentucky (NMNH 243208). Gregg et al. (1983: 301) argue, correctly, that this defect is more likely to have been caused by a midline cyst. The archeological age is unknown. The alveolar portion of the left maxilla may have been affected as is suggested by the antemortem loss of the central and lateral incisors. The vomer and conchae are also missing. However, the major defect is a large, oval opening in the palate (Fig. 17.12). It is the oval shape and the central location of this defect that supports a diagnosis of cyst rather than cleft palate. The examples described here serve to document the presence of cleft lip and palate as well as nonodontogenic cysts in the New World and cleft lip and palate in the Old World archeological populations. They also serve to illustrate the point that other conditions, such as trauma and infection, need to be considered in the differential diagnosis.

Congenital Herniation Stewart (1975) has called attention to the misinterpretation of congenital herniations (dysraphism) of the cranium. The defects in the bone produced by such herniations have been attributed to the practice of trephination (Powell, 1965; Sublett and Wray, 1970). Both examples published by Stewart (1975) exhibit herniation very close to the bregma. They have a sharply defined anterior border, but a more gradual slope to the depression posteriorly. An excellent example of this abnormality occurs in the cranium of a 6- to 8-year-old from an

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FIGURE 17.13 Congenital herniation of the cranial vault in a 6- to 8-yearold from an archeological site in Ancon, Peru. (A) Facial view. (B) Top view; note the porous, reactive bone surrounding the herniation. (FM 40208.)

archeological site in Ancon, Peru, curated at the Field Museum of Natural History, Chicago, Illinois (FM 40208). The site is thought to date between AD 1000 and 1200. The large abnormality is located on the frontal bone anterior to the bregma (Fig. 17.13). The main focus of the defect extends through both tables of the frontal bone. The margin is most sharply defined on the posterior edge with a gradual elongated depression extending anteriorly about midway toward the nasion. Lateral to the defect are two areas of porous reactive bone. The defect itself is well circumscribed, exhibiting smooth compact bone throughout. The nature of the soft tissue lesion, of course, is not known. Stewart (1975: 437) notes that the prognosis in a living patient depends on the type of herniated tissue and the amount of herniation. The prognosis for survival to adulthood would be poor in a case where the herniation

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was as extensive as evidenced by the size of the defect in the Ancon child and this abnormality may have led to their premature death.

Hydrocephalus At least 30 possible cases of hydrocephalus have been reported in the archeological record dating from 10,000 BC to AD 1670 (Murphy, 1996). Derry (1913) provides a detailed report on an abnormally large skull and postcranial bones from the Roman period in Egypt. The bones are those of a fully adult male. Derry reports that the cranial capacity is at least 2900 cm3, which exceeds the normal range of cranial capacity by several hundred cubic centimeters. The lateral drawing of the skull exhibits relatively normal proportions for the face, so that the skull abnormality is limited to the brain case. The postcranial bones exhibit abnormalities that Derry attributes to partial paralysis of the left side. Grimm and Plathner (1952) describe a hydrocephalic skull from central Europe dated to the Stone Age, while Armelagos (1969) reports the presence of a hydrocephalic child from Nubia dated between AD 350 and 550. Richards and Anton (1991) provide a thorough review of the archeological evidence of hydrocephalus along with a detailed a description of a 10-year-old from California dated between 2500 BC and AD 500. The child exhibits the “setting-sun” sign of the orbits, where the eyes are pushed downwards due to the posterioinferior inclination of the orbital plates and shallow orbital frontal junction. Evidence for femoral atrophy indicates the child also suffered from right-sided paraplegia.

Biparietal Fenestra Broca (1875) first described a congenital defect of the cranial vault in which there are unusually large perforations of the parietal bones. These normally occur bilaterally as often equally sized slits or oval perforations in the vault, near or including the parietal foramina. While parietal fenestra and enlarged parietal foramen are used to describe the defect, clinicians argue that fenestrae are a separate condition and may occur adjacent to normal parietal foramen (Kaufman et al., 1997). Barnes (2012a: 392) attributes these defects to hereditary mutations of either MSX2 or ALX4 genes causing failure in the ossification of the parietal membrane where Santorini’s emissary vessels pass through the vault. These defects have beveled edges and may get smaller with age. They may also be associated with other craniofacial defects, metopism, or craniostenosis (Kaufman et al., 1997). Although the majority of cases are asymptomatic, individuals may experience violent headaches and vomiting if mild pressure is applied to the area (Dura˜o et al., 2016). An example of this condition is seen in an individual from California (NMNH 276981). The adult male exhibits bilateral perforations of the parietals

FIGURE 17.14 Biparietal perforations in an adult from an archeological site in California. (NMNH 276981.)

exceeding 1 cm in diameter (Fig. 17.14). The perforations are located on the posterior portion of both parietals near the sagittal suture. Verano (2016) warns that parietal fenestra should be distinguished from trepanations and senile parietal thinning leading to perforation.

Premature Fusion of Sutures Changes to the normal shape of the cranium due to premature suture fusion depend on which sutures are involved, and the age at which the fusion occurred. For example, fusion of the sagittal suture in early childhood produces an elongated cranium with a prominent forehead, while fusion of the coronal suture results in a shorter cranium but prominent development of the frontal region with a very high forehead. Craniosynostosis after the age of 6 years tends to show less severe changes as the majority of cranial growth is complete. Several reports of craniostenosis in archeological skeletons have been published (e.g., Davis, 1865; Bolk, 1915; Eiseley and Asling, 1944; Hohenthal and Brooks, 1960; Comas, 1965; Bennett, 1967; Stewart, 1972; Barnes, 1994: 152 157; Duncan and Stojanowski, 2008). Morphological changes to the cranium are varied and are often described using terms such as scaphocephaly, brachycephaly, oxycephaly, etc. However, this terminology is complex and is often applied differently, making comparative research difficult. Hence, emphasis should be placed on describing the sutures affected and subsequent changes in shape (Barnes, 1994). Of the many examples of craniostenosis in the collections of the National Museum of Natural History,

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Washington, DC, three illustrate the relevant features associated with this abnormality. A child’s cranium (NMNH 258504) from the 20th to 25th Dynasty site of Karga in Egypt illustrates premature closure of the sagittal suture (Fig. 17.15). This child was 3 4 years of age at the time of death. Except for the anterior 2 cm, the entire sagittal suture was fused. All other sutures, which are normally open at 3 4 years of age, are open. Even at this

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early age, the cranium is slightly elongated with a slight axial deviation of the skull, suggestive of excessive growth on the right side of the vault. The lack of severe elongation indicates that the fusion was not present at the time of birth but probably occurred a few months before death. Had the child lived longer there may have been additional abnormal elongation. However, maximum brain volume is achieved by about 7 years of age so further elongation would have been minimal. Premature fusion of the coronal suture is seen in a female Inuit skull from Wales, Alaska (NMNH 333470). The skull is from an individual about 25 30 years of age at the time of death. Endocranially the coronal, sagittal, and lambdoid sutures are fused. Ectocranially both the sagittal and the lambdoid have begun to fuse. Except for 2 cm on either side of the midline, the coronal suture is completely fused ectocranially with obliteration of the sutural lines (Fig. 17.16). The sphenoparietal suture is also fused and obliterated. In profile, the skull vault exhibits a saddle-like depression just posterior to the bregma. Otherwise, the shape of the skull is normal, indicating that the premature fusion of the coronal and sphenoparietal suture occurred after significant growth of the brain and skull had ceased. Another example of craniostenosis in an adult illustrates the morphological features that occur when premature fusion occurs early in childhood or infancy. The male individual is from Cinco Cerros, Peru (NMNH 293841). The archeological date is not known with certainty but is thought to be pre-Columbian. The cranium is long and very narrow (markedly dolichocephalic), with the elongation primarily in the posterior portion (Fig. 17.17). The sagittal suture is completely fused both endo- and ectocranially. The coronal and lambdoid sutures are completely fused endocranially and partially fused ectocranially.

SPINE Pathology Barnes (1994, 2012b) provides an excellent review of the congenital abnormalities that affect the spine and the factors that influence their expression. There is substantial variation in the type and severity of many of these abnormalities and the following discussion is intended to provide a summary of some of the more common conditions.

Spina Bifida

FIGURE 17.15 Premature fusion of the sagittal suture in a 3- to 4year-old from the 20th to 25th Dynasty site of Karga in Egypt. (A) Left lateral view; note the somewhat abnormal length of the cranium. (B) Top view, showing the fused sagittal suture. (NMNH 258504.)

A failure in the development of the neural canal may be associated with incomplete development of the elements of the neural arch of one or more vertebrae, or spina bifida. The etiology of the condition includes chromosome abnormalities, single gene disorders, and teratogenic exposures (e.g., folic acid deficiency), but in most cases

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FIGURE 17.16 Premature fusion of the coronal and sphenoparietal suture in a young adult from Wales, Alaska. (A) Left lateral view, showing complete fusion of the sphenoparietal suture and the slight saddle depression near the bregma. (B) Top view. (NMNH 333470.)

the cause is unknown (Mitchell et al., 2004). In a living patient incomplete development of the elements of the neural arch may be accompanied by a protrusion of spinal cord and nerves through the defective spinal canal

FIGURE 17.17 Early premature fusion of the sagittal suture in an adult male (NMNH 293841) from the Cinco Cerros region of Peru. (A) Facial view, showing the keel-like vault of the cranium. (B) Top view. (C) Left lateral view. (NMNH 293841.)

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FIGURE 17.18 Spina bifida cystica in an 8-year-old female (RCSE100.BD.8a) with abnormal development of the pelvis and severe scoliosis. (A) Anterior view. (B) Posterior view; note failure of vertebral arch development particularly apparent in the upper lumbar vertebrae (arrow).

(meningomyelocele) and is known as spina bifida cystica. This is commonly associated with defects in the spinal cord and nerves that cause other serious complications, including paraplegia. Spina bifida cystica is also associated with kyphoscoliosis and underdevelopment of the pelvis (Fig. 17.18). Less severe failures of vertebral arch development occur with little or no clinical significance and are known as spina bifida occulta, present in around 5% 10% of the population (Fig. 17.19). In this variant, there is incomplete fusion of posterior neural arches, mainly in the sacral and/or lumbar segments (Barnes, 1994). In living patients some vertebral arch defects will be covered over by connective tissue, fat, and skin with no disability. In archeological material, spina bifida occulta is often overrecorded and several adjacent neural arches need to be open before a diagnosis is made, as the first, fourth, and/or fifth sacral neural arches commonly may remain open in nonspina bifida cases (Roberts and Manchester, 2007). In general, the more skeletal elements that are involved the more severe the problem was likely to have been.

Congenital Kyphosis and Lordosis Other abnormalities of the spine include lateral or dorsal hemivertebrae, causing abnormal curvature of the spine (congenital scoliosis and kyphosis). Kyphosis is the pathological increase in the normal anterior concave curvature of the thoracic spine that results in the abnormal forward bending of the spine (Fig. 17.20). This is in contrast to the less common lordosis, which is an abnormal curvature of the posterior spine that results in a saddle-back deformity (Ozonoff, 2005).

Scoliosis Scoliosis is the term used for lateral deviations of the spinal column from the midsagittal plane (S-shaped curvature). The factors leading to this deformity are varied and usually not obvious. An exception to this is scoliosis due to congenital maldevelopment of one or several spinal segments such as lateral hemivertebra, or other early developmental defects in vertebral formation and segmentation

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FIGURE 17.19 Spina bifida of the sacrum. (Young adult female, FPAM 2381.)

(e.g., wedge vertebrae, unilateral block vertebrae, neural arch fusion). However, the bone changes, which develop secondary to the deformity, are all essentially the same no matter the underlying cause. Scoliosis, with or without a significant kyphotic component (kyphoscoliosis), often starts in childhood and progresses throughout the growing age and early adult life. This factor is of importance because the bone changes are, to a large extent, the result of altered growth and modeling under abnormally directed static and dynamic stresses (Ozonoff, 2005). The deformity usually shows a double curvature, which permits the position of the head close to the midsagittal plane despite the lateral deviation of the spinal column. These deviations are not purely lateral but

FIGURE 17.20 Supernumerary wedge vertebra (arrow) between first and second lumbar with secondary scoliosis and right sacralization of fifth lumbar vertebra. (A) Anterior view. (B) Lateral view. (60-year-old male, FPAM autopsy 61729.)

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FIGURE 17.21 Severe thoracic and lumbar kyphoscoliosis. Notice the structural torsion of the vertebrae, the fusion on the concavity, and the new joint formations between compressed ribs. (VM, no number.)

include a considerable element of rotation toward the convexity (Fig. 17.21). This, as well as abnormal pull of tendons and ligaments, accounts for the bone changes by means of modified growth and modeling. Because, in the dry skeleton, the continuity of the vertebral column is not maintained, alterations of individual vertebrae are important for the recognition of the deformity. The transverse processes of the thoracic vertebrae are deflected backward on the convex and forward on the concave side. The transverse processes of the lumbar spine are short and plump on the convex side and long, slender, and pointed on the concave side. The spinous processes usually are deflected toward the concavity in the lumbar spine. The vertebral bodies show lateral wedging at the apex of the curvature in addition to rotation and torsion. The latter is reflected in a diagonal pattern of the vertebral cortex, secondary to the altered course of the fibers of the anterior spinal ligament. The bodies also may exhibit an eccentric shape rather than the normal oval morphology. The spongiosa architecture of the laterally wedged vertebrae usually shows sclerotic reinforcement on the overburdened concave side and a reduction in the number and size of trabeculae on the relatively unburdened convex side. The areas of the neural arch and of the diarthrodial

intervertebral joints show the least amount of deformation. In long-standing severe scoliosis, additional bone changes may occur secondary to degenerative processes in the eccentrically stressed intervertebral disks. These changes are most marked laterally on the concave side of the wedged vertebrae. Bony fusion across the narrowed intervertebral space occurs in the apex of the curvature. The overexpansion of the disk on the convex side may lead to bony replacement of the disk itself. Ossification of various spinal ligaments and, occasionally, ankylosis across the diarthrodial joints can occur, especially on the concave side of the apex of the curvature. The ribs, which are firmly attached to the spine by two joints and to the sternum through the rib cartilage, must adapt their shape and curvature to the spinal deformity. Generally, they are spread on the convexity and pressed together on the concavity of the spinal deformity. These changes include alterations in the size and location of the costovertebral articular facets and in the angulation of the neck of the ribs. Length, width, and curvature are altered by modified growth and modeling. If the curvature is extreme, ankylosis of costovertebral joints and formation of new, joint-like, irregular areas between ribs in direct contact can occur (Fig. 17.21). In order to describe the severity and angle of the deformity in clinical cases, the Cobb method is employed. The Cobb angle (Cobb, 1948) may be applied to dry bone by articulating the bones and selecting the most affected vertebrae above and below the apex of the curve. The angle between intersecting lines drawn from the top of the top vertebra and the bottom of the bottom vertebra is the Cobb angle. A special type of kyphoscoliosis can occur in neurofibromatosis (Chapter 17). In this disease, the maximal scoliotic deformity more frequently involves the cervical spine. The tumors of spinal nerves in this condition lead to smooth widening of interspinal foramina in the affected area. This feature would permit recognition of such a scoliosis as due to neurofibromatosis in the dry skeleton.

Sacralization and Lumbarization Changes in the morphology of the fifth lumbar or first sacral vertebrae are caused by “border shifting” are commonly reported spinal defects. Sacralization refers to partial or complete fusion of L5 to the sacrum, with the lumbar vertebra often developing rudimentary sacral alae (or enlarged transverse processes) resulting in six sacral segments. Lumbarization, where S1 fails to fuse to the sacrum, is less common. This border shifting may be bilateral or unilateral, with unilateral changes predisposing to scoliosis. Determining which form of transitional vertebra has occurred can be difficult if the whole sacrum

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is not preserved (Roberts and Manchester, 2007) or, in younger individuals, if the sacrum is still unfused.

Klippel Feil Syndrome Clinically, this syndrome is recognized as a triad of changes: a short neck, low posterior hairline, and limited movement of the neck. The etiology of the condition is not clear and it may be hereditary or occur sporadically. The primary skeletal feature is vertebral segmental failure between the third to eighth week of embryogenesis resulting in block vertebrae, usually of the upper spine. In 30% of cases there may also be facial asymmetry, occipitalization, scoliosis, cleft or high arch palate, unilateral or bilateral elevation of the scapula, supernumerary digits, upper-limb hypoplasia, malformation of the occipital bone, and spina bifida (Aufderheide and Rodriguez-Martı´n, 1998; Davidson et al., 2008). The condition is divided into three types: type I involves several cervical and thoracic vertebrae confined in one osseous block that usually signals major additional defects (Barnes, 1994). Type II involves two or three vertebral segments only, usually C2 and C3 or C5 and C6, but less commonly T2 and T5. Hemivertebrae and occipitalization may also be present (Pany and Teschler-Nicola, 2007). Type 3 Klippel Feil involves block cervical vertebrae with additional thoracic and lumbar segmental errors (Barnes, 1994). Congenital fusion of the vertebrae can be identified as being wide and flat with concavity of the anterior and posterior cortex resulting in a “wasp-waist” appearance (Guille and Sherk, 2002). In addition to fusion of the vertebral body, the lamina, pedicle, and spinous process should also be fused. The intervertebral disk space will be narrowed, but in cases of trauma or arthritis there may be early osteophyte formation (Gunderson et al., 1967).

Spondylolysis Another defect of the spine involves separation of a major portion of the neural arch (spondylolysis) from one or more vertebrae. The defect separates the main part of the vertebra from the inferior facets and may permit the vertebral body to slide forward (spondylolisthesis). Stewart (1931) has reported on the frequency of this condition among Inuit remains and found an unusually high frequency (27.4%) in this human group. He found that individuals from the northern part of Alaska had a greater frequency than those from the southern part. Because the condition was thought to be congenital, Stewart attributed the differences to inbreeding of an isolated group for the northern skeletal sample or perhaps differences in origins for the two groups. Stewart (1956) later found an agerelated association in which the incidence of spondylolysis increased with age and concluded that stress rather

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than genetics was the significant factor in the expression of separate neural arches. He did not rule out a genetic substrate but expressed the opinion that any genetic predisposition was related to erect posture rather than any specific genetic defect of the bone.

Postparalytic Deformities of the Spine Neuromuscular paralysis occurring in childhood and adolescence can affect the skeleton in various ways. Paralysis of different muscle groups can unbalance the spinal column and cause postparalytic scoliosis. The examination of such a spine will not reveal the pathogenesis of the deformity. Because the growth and surface modeling of a bone are influenced by muscle pull and weight bearing, the lack of either or both will alter its size and shape.

Paleopathology Spinal deformities in the literature on paleopathology are attracting greater attention from researchers but reports are still rare. Vertebrae are often not as well preserved as many other parts of the skeleton, which limits research. Another problem is that kyphosis and scoliosis are most easily observed in an articulated spine and thus would tend to be overlooked in disarticulated archeological contexts unless the defects were noticed during excavation. (For some examples of kyphosis induced by infectious destruction of vertebral bodies, see Chapters 9 12.) Barclay-Smith (1911) provided a detailed report of multiple anomalies in the vertebral column of a young female skeleton from excavations at Sakkara in Egypt. The site probably dates to a period between 600 and 500 BC. In this case there are eight cervical vertebrae. The first or atlas vertebra is fused to the base of the skull; the second or axis vertebra and the third cervical are fused together. The neural arch of C7 is divided through the spinous process and an extra cervical vertebra (C8) has an associated cervical rib on the right side. Damage to the left side precludes evaluation of the presence of a cervical rib on that side. The thoracic vertebrae are normal except for the diarthrodial joints between T11 and T12. The left joint has the morphology of a lumbar vertebra, whereas the right is a typical thoracic joint. The lumbar vertebrae exhibit a slight lateral curvature. The neural arches of L3 L5 are divided at the lateral portion of the right lamina. L5 has an additional division of the spine, creating a separate arch segment. The sacrum also has a separate neural arch segment, including a portion of the left lamina of the first sacral vertebra (S1). Barclay-Smith (1911: 170) suggests that the multiple anomalies were the result

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FIGURE 17.22 Malformation of the third, fourth, and fifth thoracic vertebrae from the prehistoric site of Puye, New Mexico. (NMNH 262939.) FIGURE 17.23 Scoliosis of T12 L5 vertebrae, anterior view. (Adult female, postmedieval, St. George’s Chapel, Canterbury, England.)

of early training and activity as a contortionist. A developmental malformation is more likely. Another case of vertebral malformation is seen in a young adult female skeleton from the pre-Columbian site of Puye in New Mexico (NMNH 262939). The skeleton is well preserved and normal except for the abnormal segmentation and fusion of the third through the fifth thoracic vertebrae. The spines, the diarthrodial joints, and the vertebral bodies of these vertebrae are fused (Fig. 17.22). The left segment of T4 is fused to T3. Likewise, the left segment of T5 is fused to the right segment of T4. The right segment of T5 is also fused to T4, but the line of the early division between T5 and T4 is still apparent. Because there are no extra ossification centers and an abnormal segment is on each side, there is no scoliosis.

Scoliosis Brothwell (1961: 327 328) reviewed five published and unpublished cases of scoliosis in British skeletons. One of these is from the Beaker period (c. 2000 BC). Brothwell attributes the scoliosis in this individual to congenital

problems in which additional centers of ossification developed as hemivertebrae. The anterior view shows the lateral deviation that resulted from this abnormal development. A more recent case of scoliosis is seen in the spine of a postmedieval burial from Canterbury, England (Fig. 17.23). The deformity occurs in an adult female and is particularly severe in the lower spine. Barnes (1994) identified several cases of scoliosis in archeological human remains. Scoliosis has also been identified in two New World sites. The first of these is from a late prehistoric Iroquoian village in Canada (Pfeiffer et al., 1985). The case is from an adult skeleton and affects the thoracic vertebrae and has the additional complication of anterior fusion of T8 T11 vertebral bodies. Another case is reported in the mummy of a 6-year-old from northern Chile (Gerszten et al., 2001). The burial is dated to around 1000 BC. An interesting case of scoliosis comes from the archeological site of Hawikuh located near the modern village of Zuni in New Mexico. The site includes pre-Columbian and historic components. During the early historic period

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the site was used as a base of operations for the Spanish explorer Francisco Vasquez de Coronado, and a Franciscan mission was established there in 1630 (Smith et al., 1966: 1). The site, including the cemetery, was excavated between 1917 and 1923. Skeletal material from both the pre- and postcontact periods was recovered from the cemetery. The individual in question (NMNH 314297) is from the historic period. The skull is morphologically different from the Indian Christian burials and is thought to have been the remains of one of the priests massacred during the Pueblo Revolt of 1680. The estimated age of the individual is between 25 and 35 years. The sex is clearly male. There is no evidence of deformity on the skull, although there is considerable antemortem tooth loss, including all incisors. The upper extremities have a slight lateral deviation of the distal humeri and considerable bowing of both radii and ulnae. The major abnormality is seen in the vertebrae, which exhibits an S-shaped scoliosis (Fig. 17.24A). The ribs (Fig. 17.24B) and manubrium are also abnormal, reflecting the conditions in the vertebrae. The cervical vertebrae and first two thoracic vertebrae are normal. The first lateral deviation to the right begins at T3 and continues to T8, where the lateral deviation begins to be oriented toward the left, continuing until L2, when the lateral orientation shifts back toward the right. The sacrum shows minimal evidence of abnormality and the pelvis appears normal. The major long bones of the lower limbs have a slight lateral bowing of the distal tibiae and fibulae. The combination of scoliosis and slight deformity of the limbs suggests the possibility of rickets in early childhood as the cause of scoliosis. This case also highlights the importance of carefully comparing the right and left ribs for evidence of scoliosis. Perhaps the most famous example of scoliosis was identified in the recovered remains of King Richard III of England. Notoriously “hunchbacked,” Richard’s deformities were shown to have been less severe than expected. There was a right-sided curve of the thoracic vertebrae with an apex at T8 9. The lack of any developmental abnormities of the individual vertebrae led Appleby and colleagues (2014) to conclude that the condition developed around 10 years of age and was an example of adolescent-onset idiopathic scoliosis.

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Spina Bifida Varying degrees of spina bifida are a commonly mentioned abnormality in reports of archeological contexts. Virtually all of these reports are of cases from the less severe end in the range of expression of vertebral arch defects (spina bifida occulta). Ferembach (1963) reports an unusually high frequency of this abnormality in the sacra of a skeletal sample from a cave at Taforalt in northeastern Morocco.

FIGURE 17.24 Scoliosis. (A) Spinal column, exhibiting an S-shaped lateral curve. (B) Second and tenth ribs, showing asymmetrical development in response to scoliosis. (Adult male, NMNH 314297.)

The site is dated to 10,500 12,070 BP. Ferembach calls attention to the problem of deciding what constitutes an abnormal condition in sacra, as many sacra have some

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FIGURE 17.25 Sacral spina bifida occulta in a young adult skeleton from the Early Bronze Age site of Bab edh-Dhra’, Jordan. (NMNH uncataloged, from Tomb A100E.)

evidence of incomplete development of a neural arch. Ortner excavated an unambiguous example of sacral spina bifida occulta from the Early Bronze Age site of Bab edhDhra’ in Jordan. The individual is dated between 3150 and 3000 BC and is a young male (Tomb A100E). In life he had probably suffered from tuberculosis, which resulted in destruction of the fourth lumbar vertebral body. This infectious condition is unrelated to the spina bifida occulta of the sacrum. The neural arch of the first sacral segment is divided at the midline of the spine (Fig. 17.25). The arches of segments 2 5 never formed, leaving the canal exposed.

Klippel Feil Syndrome Jarcho (1965) has reviewed a vertebral abnormality, first described by MacCurdy (1923), that is a probable example of Klippel Feil syndrome. The individual is from Poricarcancha, Peru, and apparently is an adult male. The sixth and seventh cervical and first thoracic vertebrae are fused. There are two hemivertebrae on the right side, the first between T3 and T4, the second between T4 and T5. These wedge vertebrae have resulted in a sharply angled scoliosis with T4 at the apex of the angle. On the right side of the thoracic vertebrae there are 13 rib facets with the extra rib on the hemivertebra between the third and fourth vertebrae. On the left side there are the normal 12 facets. The first four ribs are fused near their proximal ends. Another possible New World case of Klippel Feil syndrome occurs in the cervical vertebrae of an adult

FIGURE 17.26 Fusion of C4 and C5 and C6 and C7 vertebrae, possible Klippel Feil syndrome in an adult female spine. (Pastolik, Alaska, NMNH 332549.)

female from an archeological site in Alaska (Fig. 17.26). Vertebrae 4 5 and 6 7 are fused with significantly reduced heights of the C4 and C6 vertebral bodies.

Spondylolysis In their study of a skeletal Inuit sample, Lester and Shapiro (1968) found a high incidence (40%) of spondylolysis and that the frequency of the defect increased with age. In a careful review of the literature combined with his own extensive research, Merbs (1996) has argued convincingly that the most common cause, by far, is stress fracture. Spondylolysis is not limited to the New World, although comparative data are not available for Old World groups. There are two examples in the 92 burials from the Early Bronze I (3150 3000 BC) shaft tombs excavated at Bab edh-Dhra’, Jordan. Both examples are from adult males. One of these is from the east chamber

Congenital and Neuromechanical Abnormalities of the Skeleton Chapter | 17

603

FIGURE 17.27 Separate neural arch of the fifth lumbar vertebrae in an adult male skeleton from the Early Bronze Age site of Bab edh-Dhra’, Jordan. (NMNH uncataloged, from Tomb A100E.)

of Tomb A100 (Fig. 17.27). The age of the skeleton is in excess of 50 years. The arch defect is on the fifth lumbar vertebra. The arch is completely free of the vertebra, with the break occurring at the pars interarticularis. The broken edges of the bone exhibit considerable remodeling, indicating that the break was long-standing. The anterior surface of the vertebral body has considerable periosteal reactive bone, perhaps the result of periosteal activation due to anterior slippage of the vertebrae. The inferior edge of the vertebral body has slight arthritic lipping as do the corresponding areas of the first sacral vertebra. The second and third thoracic vertebrae of this skeleton are fused. Fusion occurred at the spines, diarthrodial joints, and the lateral portions of the vertebral bodies. The disk space is preserved and the cause of the fusion is not apparent.

RIBS AND STERNUM Pathology and Paleopathology Rudimentary unilateral or bilateral supernumerary cervical ribs attached to the seventh cervical vertebra are not uncommon. A supernumerary thoracic rib is often attached to a lateral supernumerary hemivertebra. Segmental disarrangement may result in a forked rib with one cartilage. This abnormal rib is usually broader than normal. The sternum may be affected by many congenital conditions that will alter the size and shape of the bone. One defect is the failure of embryological centers of ossification to fuse into a single bone. This defect usually leaves a central hole in the body of the sternum that can look very much like a healed penetrating wound (Fig. 17.28).

FIGURE 17.28 Sternal body with a developmental defect creating an abnormal hole in the lower portion. (Male c. 45 years of age, Pecos Pueblo, New Mexico (AD 1300 1838), Peabody Museum of Archaeology and Ethnology, Cambridge, Massachusetts, Catalog No. 60274.)

PELVIS Pathology Failure of proper development of the anterior abdominal wall may leave the urinary bladder open (exstrophy of bladder). In this situation, which is compatible with adult life, the pubic symphysis is absent and, although the pubic and ischial rami are properly fused, there is a gap of several centimeters between the two halves of the pelvis anteriorly (cleft pelvis) (Fig. 17.29). Failure of development of the massa lateralis of the first sacral vertebra results in marked pelvic asymmetry (Fig. 17.30). A hypoplastic shallow acetabulum on one or both sides leads to congenital superior dislocation of the femur.

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ligament. There is often a large marginal exostosis present, which points downward. The acetabulum is small, flat, and triangular, indicating that it never articulated with nor supported a mature femoral head.

Paleopathology

FIGURE 17.29 Cleft pelvis in a 20-year-old male with exstrophy of the bladder and sacrum with six segments. (FPAM 3545, AD 1877.)

FIGURE 17.30 Asymmetrical pelvis due to absence of right massa lateralis of the first sacral vertebra in a 30- to 40-year-old male. (FPAM 4071.)

This is compatible with adult life and will result in the formation of a bony reaction on the lateral cortex of the ilium, creating a new acetabulum. Subsequent degenerative arthritis in this abnormal “joint” may reveal eburnation of the bony surface. The femoral head is flattened and shows a vertical groove for the flattened round

In addition to the formation of a secondary acetabulum, some abnormalities of the hip may result in chronic slippage of the femoral head within the shallow acetabulum, with no permanent dislocation and no formation of a new joint. It will not always be possible to distinguish between dislocation induced by trauma and congenital dislocation, although Mitchell and Redfern (2008) provide a series of features that may be evident in congenital dislocation where a false joint (pseudoarthrosis) is formed. The true acetabulum will be triangular or oval, smaller than normal, with the base angled toward the obturator foramen and the apex situated posterior-superiorly. The false acetabulum may vary in its expression from a plaque of bone or shallow depression, to a fine layer of bone on the cortex. In some cases the acetabulum may be rounded, but not as deep as normal. In addition, there may be a greater sciatic notch angle, shorter and broader ilium, flattened femoral head, thinner femoral shaft, a change in the position of the trochanter, and asymmetric facets of the spine indicating secondary scoliosis (Mitchell and Redfern, 2008). Baudouin (1906) found that the incidence of congenital dislocation in prehistoric European skeletal samples was rare. Moodie (1923) reported an example of hip dislocation in an ancient Peruvian skeleton in which a new joint was formed. Pales (1930) published a photograph and a radiograph of a pathological femur from the Neolithic period, which he attributed to congenital dislocation. However, the morphology is more compatible with slipped epiphysis. Morse (1969: 33, 92) includes a brief description of congenital hip dislocation in an individual (Burial 10) from the Morse Site in Illinois. The abnormal bones include the left innominate and both femora. The acetabulum is abnormally shallow and distorted and the femoral heads irregular and small. An adult male skeleton from Tomb A100E at the Early Bronze Age cemetery of Bab edh-Dhra’ in Jordan has an abnormally shallow acetabulum of the right hip. This is the same skeleton that had a separate neural arch. The acetabulum is also much larger in diameter than the corresponding acetabulum of the left innominate (Fig. 17.31A). There is a moderate amount of arthritic lipping on the margin of the abnormal acetabulum, but there is no secondary joint. The clearest evidence of dislocation is seen on the head of the right femur (Fig. 17.31B). The

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FIGURE 17.31 Chronic subluxation of the right hip, perhaps of congenital origin, in an individual from the early Bronze Age site of Bab edh-Dhra’, Jordan. (A) Comparative views of the right (left portion of photograph) and left acetabulae, showing the shallow and enlarged diameter of the right. (B) Bony components of the right hip; note the grooves from pressure erosion on the femoral head. (NMNH uncataloged, from Tomb A100E.)

head itself is enlarged with two obvious defects on the inferior surface. The most anterior of these defects is a shallow curved depression about 1 cm wide by 2 cm long. The margins are sharply defined and the base of the lesion is porous but well remodeled. The posterior defect is a narrow deep groove beginning with the pit for the ligamentum teres and continuing posteriorly through the boundary of the joint surface. The curvature of the anterior defect corresponds to the curvature of the anterior margin of the acetabulum. There is little doubt that chronic and abnormal abrasion of the femoral head during repeated episodes of partial, anterosuperior subluxation produced this defect. The posterior defect is due to abnormal pressure on the joint surface by the ligamentum teres,

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FIGURE 17.32 Bilateral congenital hip dislocation with secondary joint formation in an adult female from Ft. Ancient, Proctorville, Ohio, AD 1200 1400. (NMNH 368989.) (A) Lateral view of the right and left innominate. (B) Detail of secondary joint in the right innominate.

perhaps during dislocation. Another possibility is that part of an abnormally elongated ligamentum teres might have lain across the joint surface when the head was in the normal anatomical position. In view of the lack of a secondary joint and any evidence of fracture, congenital dislocation would appear to be the most appropriate diagnosis. A bilateral case of inadequate development of the acetabulum associated with hip dislocation occurs in the innominates of a Native American adult female from an archeological site in Ohio (NMNH 368989), dated between AD 1200 and 1400 (Fig. 17.32). Another example of hip dislocation with secondary joint formation is seen in an adult female from the ancient Pueblo site of Kwasteyerkiva in New Mexico (NMNH 271828). The case consists of the right innominate and femur, although

606 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

only the innominate was available for study. The most noticeable feature is the presence of a large secondary joint projecting well above the acetabular rim (Fig. 17.33). The articular surface is rough, with many pores penetrating the surface. Considerable remodeling has taken place in the acetabulum. The original surface is very coarse and is almost completely covered over by a concave layer of bone, which may have been a temporary shallow joint before the femur slipped again and stimulated the formation of the final joint. The acetabulum appears to be abnormally shallow, which would support a diagnosis of congenital hip malformation, leading to dislocation and secondary development of another joint. Because of postmortem damage, trauma cannot be ruled out.

EXTREMITIES Pathology

developmental condition in which the extremities have less than the normal number of rays in the hands or feet, creating the appearance of a seal-like flipper (Fig. 17.34). As far as individual simple long-bone defects are concerned, the radius and the tibia (Fig. 17.35) are more often missing than the ulna or the fibula. Congenital bony ankylosis between the proximal radius and ulna (Fig. 17.36) and between the distal tibia and fibula are typical anomalies preventing, in the former, pronation of the forearm but not affecting the function of the ankle significantly in the latter. There are many, frequently hereditary and familial, syndromes concerning the number, length, and position of digits of fingers and toes (e.g., polydactyly, brachydactyly, clinodactyly). The number may be more or less than normal (Fig. 17.37). Single rays may be fused through their entire length or only distally, causing various forms of syndactyly. Clubfoot deformity (pes equinovarus), which is often bilateral, can also occur on a congenital basis with or without malformation of the spine (Fig. 17.38).

Complete failure of development of one or several limb buds results in amelia (Schinz et al., 1952: 797); abnormal shortening is called micromelia. Phocomelia refers to a

FIGURE 17.33 Hip dislocation with secondary joint formation in the right innominate of an adult female from an ancient Pueblo site in New Mexico. Note the bony remodeling in the original acetabulum and the porosity of the new joint. (NMNH 271828.)

FIGURE 17.34 Lower skeleton of a 49-year-old male with phocomelia. (IPAZ 2029/69.)

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FIGURE 17.36 Proximal congenital radioulnar synostosis. The radial head is hypoplastic. (Adult, WM S8.1.)

FIGURE 17.35 Congenital absence of left tibia with hypertrophic fibula and equinovarus deformity of foot in a 18-year-old female. (WM S16.2 from AD 1892.)

Postparalytic Deformities of the Appendicular Skeleton Paralysis of an extremity results in smooth and slender shafts because of a reduction in periosteal bone formation (Fig. 17.39). The lack of muscle pull and weight bearing is most pronounced when it affects the hip joint. The paralyzed hip develops a much steeper angle of the femoral neck, which is slender and elongated (paralytic coxa valga) (Fig. 17.40). The most common postparalytic foot deformity is a clubfoot (pes equinovalgus), which may be combined with an exaggerated plantar arch and uptilted calcaneus (pes cavus) (Fig. 17.41).

FIGURE 17.37 Polydactyly of right hand and right foot. The supernumerary finger extends from the fifth metacarpal and has only two phalanges; the supernumerary toe articulates with the fifth metatarsal and has three phalanges. (FPAM 2866b.)

608 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

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FIGURE 17.38 Congenital clubfoot deformity, bilateral (maximal pes equinovarus) in a 16-year-old. (A) Dorsal view. (B) Plantar view. (FPAM 152.6 and 147.6.)

Paleopathology The identification of congenital absence of one or more limbs in archeological contexts is difficult due to the many postmortem conditions that affect the recovery of skeletons. A case has been reported by Hawkes and Wells (1976) in which such a diagnosis appears appropriate. The individual was excavated from Hampshire, England, from a site probably dated to the late 6th or early 7th century. The skeleton

(Burial 38) is that of a man about 28 30 years of age. The preservation was good and the excavation was carefully done. The entire left extremity, scapula, and clavicle were missing at the time of excavation. The authors conclude that this absence of the limb is a congenital condition. They point to the presence of other abnormalities and compensatory development of other bones in support of the conclusion that the abnormality was a long-standing antemortem condition.

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FIGURE 17.39 Femora in a 19-year-old male (IPAZ 468/39) with poliomyelitic paralysis of the left leg. He died 15 years after onset of paralysis. Notice the small diameter and minimal surface relief of the affected left femur.

Congenital fusion of the proximal radius and ulna has been noted in archeological contexts. Morse (1969: 33) reports two cases of this abnormality from the Crable Site in Illinois. Both cases involve the left arm. Vyhna´nek et al. (1965: 2190) report the presence of congenital radioulnar synostosis in ancient Slavic skeletal material. The congenital nature of radioulnar synostosis is demonstrated in two individuals from archeological sites in North America. The first of these (NMNH 384347) is the fused right radius and ulna from the skeleton of a near-term fetus or young infant (Fig. 17.42). The child was recovered from Ossuary II, Juhle Site in Nanjemoy, Maryland. No European trade goods were found, although the date is Late Woodland and thus could be post-Columbian. Even at such a young age,

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FIGURE 17.40 Postparalytic deformity of the proximal right femur in a 14-year-old female, 9 years after acute poliomyelitis, showing extreme coxa valga, flattened, elongated lesser trochanter, slender femoral shaft, and small femoral head. (IPAZ 4337, autopsy 1372 from 1938.)

the radioulnar fusion is well established. The second example of radioulnar synostosis is from an adolescent from the Mobridge Site in South Dakota (NMNH 382993). This site contained trade goods and is thought to date to around AD 1750. The right ulna and radius are fused in a slightly pronated position (Fig. 17.43). The fusion has taken place in the radial tuberosity and the supinator fossa of the ulna. The radial head is not involved. There is no evidence of trauma, and the young age of the child, as well as the nature of the fusion, make congenital radioulnar synostosis the appropriate diagnosis. Deformities attributed to clubfoot have been described in the literature on paleopathology. Pales (1930: 36 38) reviews some of the earlier reports on this condition. His discussion highlights the problems in

610 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

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FIGURE 17.41 Postparalytic deformities in a 24-year-old male, many years after poliomyelitis, showing lumbosacral scoliosis, flaring ischia from sitting, flexion contracture of both knees, bilateral clubfoot with paralytic pes cavus deformity. (A) Overall view. (B) Dorsal view of left foot. (FPAM 5013, autopsy 88103 from 1880.)

distinguishing between congenital clubfoot and postparalytic deformities, such as those produced by poliomyelitis. Brothwell (1967: 424) has reviewed one reported case of clubfoot in a 12th Dynasty Egyptian mummy and finds the evidence inadequate to support this diagnosis. Brothwell (1967: 425 428) describes a fragmentary Neolithic skeleton from Gloucestershire, England, with foot deformities attributable to clubfoot. Johnson and

FIGURE 17.42 Synostosis of the proximal right radius and ulna in a near-term fetus or young infant from the late prehistoric Juhle Site at Nanjemoy, Maryland. (NMNH 384347.)

Kerley (1974) found evidence of clubfoot deformity in four skeletons from the pre-European site at Mokapu in Hawaii. They also note the problem in distinguishing between congenital and postparalytic deformities. Johnson and Kerley make the useful conceptual distinction between malformation, which could be associated with congenital abnormalities, and deformation, which would be more likely in postparalytic changes. The youngest reported case is of a 15- to 20-year-old male from Roman-British Gloucester (Roberts et al., 2004). This individual had marked atrophy of the left femur and tibia, with a bowed fibula due to abnormal mechanical loading. The calcaneus had a pseudo-facet for the talus, and the talus has reduced facets with a narrower head when compared to the right. When articulated, medial deviation of the talus was evident. There was buttressing on the lateral aspect of the left femur, and shortening of the left os coxae, perhaps due to abnormal weight bearing through the sacroiliac joint. The additional presence of an atrophied left arm meant that poliomyelitis was considered the underlying cause (Roberts et al., 2004). A bilateral case of congenital clubfoot occurs in the

Congenital and Neuromechanical Abnormalities of the Skeleton Chapter | 17

FIGURE 17.43 Synostosis of the proximal right radius and ulna in an adolescent skeleton from the historic period, Mobridge Site in South Dakota. (NMNH 382993.)

skeleton of a male (Burial 847) estimated to be between 35 and 40 years of age and excavated from the medieval site of St. Gregory’s Priory, Canterbury, England (Fig. 17.44). The relationship between the tarsal bones and the tibia and fibula indicates that a severe flexion was present during life.

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FIGURE 17.44 Case of bilateral congenital clubfoot in an adult male. Right lateral view of the articulated bones of the lower leg and foot. Note the abnormal development of the talus and calcaneus, as well as the abnormal flexion of the foot relative to the lower leg. The enlargement of the tibia is the result of a healed fracture. (St. Gregory’s Priory, Canterbury, England, Burial 847.)

this condition to poliomyelitis. Elliot-Smith (1912) noted the existence of a deformity of the left foot in the 19th Dynasty Egyptian mummy of Pharaoh Siptah. Initially he attributed the deformity to poliomyelitis, but in a subsequent publication (Elliot-Smith and Dawson, 1924: 100, 157) he refers to this case as an example of clubfoot.

Postparalytic Deformities Wells (1964a: 92) reports the presence of a left humerus and radius that are shorter and lighter than the right humerus and radius in a Neolithic skeleton from Sussex, England. He notes a similar deformity in a Bronze Age individual from Norfolk, England. Both of these cases are probable examples of postparalytic deformity. Mitchell (1900) has described a predynastic Egyptian skeleton in which the left femur is shorter than the right. He attributes

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Armelagos, G.J., 1969. Disease in ancient Nubia. Science. 163 (3864), 255 259. Aufderheide, A.C., Rodriguez-Martı´n, C., 1998. The Cambridge Encyclopedia of Human Paleopathology. Cambridge University Press, Cambridge. Barclay-Smith, E., 1911. Multiple anomaly in a vertebral column. J. Anat. Physiol. 25 (2), 144. Barnes, E., 1994. Developmental Defects of the Axial Skeleton in Palaeopathology. University of Colorado Press, Niwot, CO. Barnes, E., 2012a. Developmental Disorders in the Skeleton. In: Grauer, A. (Ed.), A Companion to Paleopathology. Wiley Blackwell, Chichester, pp. 380 400. Barnes, E., 2012b. Atlas of Developmental Field Anomalies of the Human Skeleton: A Paleopathology Perspective. John Wiley & Sons, New Jersey. Baudouin, M., 1906. La pre´histoire de la luxation conge´nital de la hanche. Homme Pre´histoireique 7, 129 139. Bennett, K., 1967. Craniostenosis: a review of the etiology and a report of new cases. Am. J. Phys. Anthrop 27, 1 10. Broca, P., 1875. Sur les trous parie´taux et sur la perforation conge´nitale double et syme´trique des parie´taux. Bull. Me´moires Soc. d’Anthropologie Paris 10 (1), 326 336. Berndorfer, A., 1962. A 500-year-old skull with cleft lip. Brit. J. Plastic Surg 15, 123 128. Bolk, L., 1915. On the premature obliteration of sutures in the human skull. Am. J. Anat. 17 (4), 495 523. Brooks, S.T., Hohenthal, W.D., 1963. Archaeological defective palate crania from California. Am. J. Phys. Anthrop. 21 (1), 25 32. Brothwell, D., 1961. The palaeopathology of early British man: an essay on the problems of diagnosis and analysis. J. Royal Anthropol. Institute 91, 318 343. Brothwell, D., 1967. Major congenital anomalies of the skeleton: evidence from earlier populations. In: Brothwell, D., Sandison, A. (Eds.), Diseases in Antiquity: A Survey of Diseases, Injuries and Surgery of Early Populations. Charles C. Thomas, Springfield, pp. 423 443. Charon, P., 2004. Contribution to osteo-archaeological knowledge of anencephaly. J. Paleopathol. 16 (1), 5 13. Cobb, R.J., 1948. Outline for the study of scoliosis, American Academy of Orthopaedic Surgeons Instructional Course Lectures, 5. J W Edwards, Ann Arbor, MI, pp. 261 275. Cohen, M., 2005. Perspectives on craniosynostosis. Am. J. Med Gene. 136A, 313 326. Comas, J., 1965. Craˆnes Mexicains scaphoce´phales. L’Anthropologie 69, 273 112. Davidson, J., Cleary, A., Bruce, C., 2008. Disorders of bones, joints and connective tissues. In: McIntosh, N., Helms, P., Smyth, R., Logan, S. (Eds.), Forfar & Arneil’s Textbook of Pediatrics. Elsevier, Edinburgh, pp. 1385 1447. Davis, J.B., 1865. On synostotic crania among Aboriginal race of man. Dutch Soc. Sci Haarlem 22, 1 39. Derry, D.E., 1913. A case of hydrocephalus in an Egyptian of the Roman Period. J. Anato. Physiol. 67, 436 458. Derry, D.E., 1938. Two skulls with absence of the premaxilla. J. Anat. 72 (2), 295. Dudar, J., 2010. Qualitative and quantitative diagnosis of lethal cranial neural tube defects from the fetal and neonatal human skeleton, with a case study involving taphonomically altered remains. J. Forensic Sci. 55 (4), 877 883.

Duncan, W., Stojanowski, C., 2008. A case of squamosal craniosynostosis from 16th century Southeastern United States. Int. J. Osteoarchaeol. 18, 407 420. Dura˜o, C., Carpinteiro, D., Pedrosa, F., et al., 2016. Enlarged parietal foramina: a rare forensic autopsy finding. Int. J. Legal Med. 130, 855. Eiseley, L., Asling, C., 1944. An extreme case of scaphocephaly from a mound burial near Troy, Kansas. Trans. Kansas Acad. Sci 47 (2), 241 255. Ferembach, D., 1963. Frequency of spina bifida occulta in prehistoric human skeletons. Nature 199 (4888), 100. Gerszten, P., Gerszten, E., Allison, M., 2001. Diseases of the spine in South American mummies. Neurosurg 48 (1), 208 213. Gregg, J.B., Allison, M., Clifford, S., Gerszten, E., Klippel, W., 1983. Ancient inborn facial clefts and nonodontogenic fissural cysts. Plains Anthropologist. 28 (102), 293 304. ¨ ber einen jungsteinzeitlichen hydroGrimm, H., Plathner, C.H., 1952. U cephalus von Seeburg in mansfelder seekreis und sein gebiet. Deutche Zahnaerzteblatt, Mund, und Kieferheilkinde 15, 1 7. Guille, J., Sherk, H., 2002. Congenital osseous anomalies of the upper and lower cervical spine in children. J. Bone Joint Surg. 84-A (2), 277 288. Gunderson, C., Greenspan, R., Glaser, G., Lubs, H., 1967. The Klippel Feil syndrome, genetic and clinical re-evaluation of cervical fusion. Medicine 46 (6), 491 512. Hawkes, S.C., Wells, C., 1976. Absence of the left upper limb and pectoral girdle in a unique Anglo-Saxon burial. Bull. New York Acad. Med. 52 (10), 1229. Hodge, F., Smith, W., Woodbury, R., Woodbury, N., 1966. The excavation of Hawikuh by Frederick Webb Hodge: report of the Hendricks-Hodge expedition, 1917 1923. Heye Foundation, Museum of the American Indian. Hohenthal, W.D., Brooks, S.T., 1960. An archaeological scaphocephaly from California. Am. J. Phys. Anthrop 18 (1), 59 67. Jabs, E., 1998. Towards understanding the pathogenesis of craniosynostosis through clinical and molecular correlates. Clin. Genet. 53, 79 86. Jane, J., Lin, K., Jane, J.S., 2000. Sagittal synostosis. Neurosurg. Focus 9 (3), 1 6. Jarcho, S., 1965. Human paleopathology. The development and present condition in the United States. Arch. Path 79, 425 427. Johanson, C., Duncan III, J., Klinge, P., Brinker, T., Stopa, E., Silverberg, G., 2008. Multiplicity of cerebrospinal fluid functions: new challenges in health and disease. Cerebrospinal Fluid Res. 5 (10), 1 32. Johnson, L., Kerley, E., 1974. Appendix B: Report on pathological specimens from Mokapu. In: Snow, C. (Ed.), Early Hawaiians: an initial study of skeletal remains from Makapu, Oahu. University of Kentucky Press, Lexington, pp. 149 158. Kalter, H., 2003. Teratology in the 20th century. Environmental causes of congenital malformations in humans and how they were established. Neurotoxicol. Teratol. 5546, 131 283. Kaufman, M., Whitaker, D., McTavish, J., 1997. Differential diagnosis of holes in the calvarium: application of modern clinical data to palaeopathology. J. Archaeol. Sci. 24 (3), 193 218. Khanna, P., Thapa, M., Prasad, S., 2011. Pictorial essay: the many faces of craniosynostosis. Ind. J. Radiol. Imag. 21 (1), 49 56. Laurence, K., Coates, S., 1962. The natural history of hydrocephalus. Detailed analysis of 182 unoperated cases. Arch. Dis. Child. 37, 345 362.

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Lester, C.W., Shapiro, H.L., 1968. Vertebral arch defects in the lumbar vertebrae of pre-historic American Eskimos. A study of skeletons in the American Museum of Natural History, chiefly from Point Hope, Alaska. Am. J. Phys. Anthrop 28 (1), 43 47. Lewis, M., 2013. Children of the Golden Minster: St Oswald’s Priory and the impact of industrialisation on child health. J. Anthropol. Available from: https://doi.org/10.1155/2013/959472 Article ID 959472. Lewis, M., 2017. Paleopathology of Children. Academic Press, New York. MacCurdy, G., 1923. Human skeletal remains from the highlands of Peru. Am. J. Phys. Anthrop 6 (3), 217 352. Merbs, C.F., 1996. Spondylolysis and spondylolisthesis: a cost of being an erect biped or a clever adaptation? Am. J. Phys. Anthrop 101 (23), 201 228. Mitchell, J.K., 1900. Study of a mummy affected with anterior poliomyelitis. Trans. Ass. Am. Physic 15, 134 136. Mitchell, L.E., Adzick, N.S., Melchionne, J., Pasquariello, P.S., Sutton, L.N., Whitehead, A.S., 2004. Spina bifida. Lancet 364 (9448), 1885 1895. Mitchell, P., Redfern, R., 2008. Diagnostic criteria for developmental dislocation of the hip in human skeletal remains. Int. J. Osteoarch 18, 61 71. Morse, D., Winters, H., Watson, P., Parmalee, P., Yarnell, R., Guilday, J., 1969. Ancient Disease in the Midwest. Illinois State Museum, Illinois. Moodie, R.L., 1923. Paleopathology. An introduction to the study of ancient evidence of disease. University of Illinois, Urbana. Murphy, E.M., 1996. A possible case of hydrocephalus in a medieval child from Doonbought Fort, Co. Antrim, Northern Ireland. Int. J. Osteoarchaeol. 6, 435 442. Oostra, R.-J., van der Wolk, S., Maas, M., Hennekam, R., 2005. Malformations of the axial skeleton in the Museum Vrolik II: craniostenosis and suture related conditions. Am. J. Med. Genet. 136A, 327 342. Ortner, D.J., Putschar, W., 1981. Identification of Pathological Conditions in Human Skeletal Remains. Smithsonian Institution Press, Washington. Ozonoff, M., 2005. Spinal deformities and curvatures. In: Resnick, D., Kransdorf, M. (Eds.), Bone and Joint Imaging, third ed. Elsevier Saunders, Philadelphia, PA, pp. 1326 1334. Pales, L., 1930. Pale´opathologie et Pathologie Comparative. Masson et Cie, Paris. Pany, D., Teschler-Nicola, M., 2007. Klippel Feil syndrome in an early Hungarian period juvenile skeleton from Austria. Int. J. Osteoarchaeol. 17 (4), 403 415.

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Pfeiffer, S., Katzenberg, M.A., Kelley, M.A., 1985. Congenital abnormalities in a prehistoric Iroquoian village: the Uxbridge ossuary. Canadian Rev. Phys. Anthropol 4, 83 92. Powell, B., 1965. Spruce swamp: a partially drowned coastal midden in Connecticut. Am. Antiquity 30 (4), 460 469. Richards, G., Anton, S., 1991. Craniofacial configuration and postcranial development of a hydrocephalic child (ca. 2500 B.C. 500 A.D.): with a review of cases and comment on diagnostic criteria. Am. J. Phys. Anthropol. 85, 185 200. Roberts, C., Knusel, C., Race, L., 2004. A foot deformity from a Romano-British cemetery at Gloucester, England, and the current evidence for Talipes in palaeopathology. Int. J. Osteoarchaeol. 14, 389 403. Roberts, C.A., Manchester, K., 2007. third ed. Cornell University Press, Cornell. Schinz, H., Baensch, W., Friedl, E., Uehlinger, E., 1952. Roengten Diagnostics. Grune and Stratton, New York. Smith, G.E., 1912. The Royal Mummies. Catalogue de Imprimerie de l’Institut Franc¸ais d’Arche´ologie Orientale. Smith, G.E., Dawson, W., 1924. Egyptian Mummies. Allen & Unwin, London. Stewart, T.D., 1931. Incidence of separate neural arch in the lumbar vertebrae of Eskimos. Am. J. Phys. Anthrop. 16 (1), 51 62. Stewart, T.D., 1956. Examination of the possibility that certain skeletal characters predispose to defects in the lumbar neural arches. Clin. Orthop. Rel. Res. 8, 44 60. Stewart, T.D., 1972. Racial differences in manifestation of scaphocephaly. Am. J. Phys. Anthrop. 37 (3), 451. Stewart, T.D., 1975. Cranial dysraphism mistaken for trephination. Am. J. Phys. Anthrop. 42 (3), 435 437. Sublett, A., Wray, C., 1970. Some examples of accidental and deliberate human skeletal modification in the Northeast. Bull. J. New York State Arch. Ass 50, 14 26. Tretsven, V.E., 1965. Impressions concerning clefts in Montana Indians of the past. Cleft Palate J 36, 229 236. Tur, S., Svyatko, S., Nechvaloda, A., 2017. Cleft lip case in a middle Bronze Age young man from Altai, Russia. Int. J. Osteoarchaeol. 27, 276 287. Verano, J.W., 2016. Differential diagnosis: trepanation. Int. J. Paleopathol. 14, 1 9. Vyhna´nek, L., Hana´kova´, H., Stloukal, M., Kola´r, J., 1965. Angeborene synostosen im altslawischen knochenmaterial. Zentralblat fu¨r Chirurgie 90, 2188 2191. Waldron, T., 2009. Cambridge University Press, Cambridge.

Chapter 18

Skeletal Dysplasias and Related Conditions Mary Lewis University of Reading, Reading, United Kingdom

INTRODUCTION The number of conditions within the skeletal dysplasia family is large and ever increasing, with a myriad of complex terminology used to describe them. They are generally congenital, developmental, or genetic in origin. While hereditary dysplasias are becoming understood in terms of their chromosomal characteristics, for many the exact etiology is still being elucidated (McAlister and Herman, 2005; Rimoin et al., 2007). Dysplasias are characterized by an abnormal shape or size of the skeleton, an increase or decrease in the number of skeletal elements, and/or an abnormal bone texture due to disrupted endochondral or intramembranous bone formation (Waldron, 2009). Many are grouped in accordance with the clinical and radiographic features that they share. Skeletal dysplasias are divided into three main subgroups: osteodysplasias, chondrodysplasias, and dysostoses. Osteodysplasias are associated with primary abnormalities in bone, leading to abnormal bone mineralization or density (e.g., osteogenesis imperfecta, osteopetrosis). Chondrodysplasias are caused by genetic abnormalities affecting cartilage formation, leading to short stature (e.g., achondroplasia). Dysostoses are malformations of individual or groups of bones (Rimoin et al., 2007). Limb dysplasias are classified as (1) micromelic (shortening of whole limb), (2) rhizomelic (shortening of the proximal limb—humerus, femur), (3) mesomelic (shortening of middle limb segments—radius ulna, tibia fibula), or (4) acromelic (shortening of the distal segment—hand and feet). Despite these categories, the genetic distinction between them is often blurred. While there are over 370 forms of skeletal dysplasia, they are considered rare with an incidence of 3.22 per 10,000 births (Stoll et al., 1989). There is a much smaller number of manifestations that may be encountered in

archeological human skeletal remains. It is possible to understand, through a limited number of examples, the underlying principles of abnormal bone development so that one can recognize the presence of these conditions in archeological skeletons even in situations where a more specific diagnosis may be challenging or impossible. The most common forms of skeletal dysplasia are achondroplasia and osteogenesis imperfecta (Stoll et al., 1989), with achondroplasia also the most often identified in the archeological record. Most of the various types of chondrodysplasia are rare and terminate fatally in infancy or early childhood. These may be present in perinatal skeletal remains but will require very careful observation by the paleopathologist for the abnormality to be detected. Some cartilage dysplasias permit longer-term survival but fail to show diagnostic features in the macerated skeleton that would permit classification beyond the term “dysplasia.” For the paleopathologist, dysplasias may be categorized according to the site of abnormal bone deformation. Endochondral disorders (chondrodysplasias) lead to changes to the axial skeleton, long and flat bones, and intramembranous ossification disorders (osteodysplasias) cause deformities of the skull, face, nose, and diaphyses of the long bones (Boulet et al., 2016). This chapter discusses the most common conditions identified in the archeological record according to this categorization, although it is important to note that each type of defective bone development may exhibit slight manifestations of another type. Mucopolysaccharidosis (MPS, strictly a metabolic disorder) can produce skeletal abnormalities that can be confused with achondroplasia and so it is included here. The abnormalities of intramembranous bone formation and resorption more often develop specific skeletal manifestations, often permitting a more precise diagnosis in archeological remains.

Ortner’s Identification of Pathological Conditions in Human Skeletal Remains. DOI: https://doi.org/10.1016/B978-0-12-809738-0.00018-1 © 2019 Elsevier Inc. All rights reserved.

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DEFECTS IN ENDOCHONDRAL BONE FORMATION Achondroplasia Pathology Achondroplasia is a familial or sporadic congenital disorder of cartilage growth, which means that it can be transmitted by parents who have one or more of the genes that cause the disease, or it can occur spontaneously as a mutation in the child of parents who do not have the defective genes. It is an autosomal dominant condition that results from a defect in fibroblast growth factor receptor (FGFR) 3 gene located on chromosome 4p (Waldron, 2009). The modern incidence is 1 per 15,000 40,000 births. This condition is the cause of the most common form of dwarfism. As the name suggests, the basic defect is a severe inhibition of cartilage proliferation, thereby limiting the endochondral growth in all areas of the body. The endochondral ossification of a limited amount of proliferated cartilage proceeds normally as does intramembranous bone formation. Achondroplasia is linked to another form of dwarfism, hypochondroplasia, which in its mildest form is indistinguishable from the latter, although it tends to spare the skull and face (Scott, 1976). There is also a severe manifestation of achondroplasia, thanatophoric dysplasia, that usually results in death in utero or shortly after birth. However, the most common expression of achondroplasia is compatible with a relatively normal life span. Adult achondroplastic dwarfs usually reach a height of 130 cm or less. These individuals are of normal intelligence, but daily life may be hindered by an inability to fully extend the elbows and knees, lumbar lordosis, and short fingers. A narrow pelvis can cause obstetric difficulties that in the past, probably resulted in the death of mother and child (Mørch, 1941). Achondroplasia is a disproportionate dwarfism (Fig. 18.1). This is due to the fact that the bones with the fastest growth and the least number of growth plates are most severely shortened. Thus, the trunk, although shortened, is least affected because of the many growth plates in the spine. The extremities are much more severely shortened and, in the extremities, the fast-growing long bones, which have only two growth plates, are most markedly affected. The femur is more shortened than any other bone, followed by the humerus, the bones of the lower legs, and forearms. The fingers and toes with more growth plates relative to their total length are less affected. The body disproportions in the achondroplastic newborn are about the same as in the adult. The discrepancy between longitudinal growth, controlled by cartilage proliferation, and intramembranous growth results in changes in the shape of the bones (Fig. 18.2). The diameter of the diaphyses and the cortical thickness are close to

FIGURE 18.1 Achondroplastic dwarf. Notice the short and thick bones and the rudimentary development of humeral and femoral heads. (Skeleton of adult female, who died in childbirth; PMUG 2668, autopsy 15050.)

normal. The epiphyses and metaphyses are usually disproportionately wide relative to the length of the bones (Fig. 18.3). The degree of penetration varies from case to case and milder forms are observed. For details, the reader is referred to the monograph of Mørch (1941), who studied more than 100 achondroplastic individuals. The skull typically is brachycephalic, but large and bulbous. This is due to the discrepancy between growth of the short skull base, much of which is formed by

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endochondral bone development, particularly at the intersphenoidal and spheno-occipital synchondroses, and the normal-sized cranial vault, which is intramembranous in its development. The more normally large cranial vault over the short skull base exhibits an increased curvature, which is responsible for the bulging forehead. On the other hand, the shortness of the skull base is responsible for the markedly depressed bridge of the nose and midfacial area. Mørch (1941: 118) found this typical skull deformity in 80% of his cases. However, the characteristic shortness of all four limbs was present in all cases. All patients also showed increased lumbar lordosis and approximately one half revealed the typical “trident” hand, in which the fingers tend to be of more equal length than normal, with tapering terminal phalanges.

Thanatophoric Dwarfism FIGURE 18.2 Achondroplasia, showing narrow pelvis with flaring iliac wings and thick, short femora with accentuated muscular insertion. (Adult, probably female, FPAM 5680.)

Thanatophoric dwarfism is a rare inherited disease caused by mutations in the gene responsible for the growth factor receptors in the fibroblasts and, hence, affects the structural integrity of the tissues (Spranger et al., 2002). This is the lethal form of achondroplasia that usually results in death in utero due to a severely restricted triangular thorax (Lewis, 2018). The severest form, type 1, is characterized by extreme rhizomelia, bowed and shortened long bones with flared metaphyses, a “telephone-receiver” appearance to the femur, a narrow thorax, a short cranial base, and short flattened vertebrae (platyspondyly) (Fig. 18.4). In some cases there may be radio-ulnar synostosis. In the less severe form, or type 2, the long bones are short but straight and individuals have a cloverleaf skull (Resnick and Kransdorf, 2005).

Paleopathology

FIGURE 18.3 Hyperplastic achondroplasia of right femur. Notice the short and thick diaphysis and the enlarged flaring metaphyses. (Newborn, WM S59.3 from 1880.)

Achondroplastic dwarfs have attracted special attention in human societies for centuries. Early Egyptian art shows an achondroplastic dwarf in a family context complete with wife and children (Wells, 1964: 42). Because there is no mental deficiency associated with this dysplasia, people with the condition often achieved prominence in various social roles. In the court of Philip IV of Spain, dwarfs, probably of the achondroplastic type, were court jesters and attendants of the royal children. Diego Vela´zquez’s painting titled Las Meninas (AD 1656) in the Prado Museum, Madrid, Spain, shows the child Margarita, heiress to the Spanish throne, being attended by maids of honor and what is probably an achondroplastic dwarf. This is one of several paintings of dwarfs by Vela´zquez. Brothwell (1967: 433) described two achondroplastic skeletons from the Fourth Dynasty Egyptian tomb of King Mersekha. The first consists of long bones only. The

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(A)

(B)

second individual (BMNH AF.11.4/427) includes the skull, the left humerus, the right femur, and both tibiae. The cranial vault is of normal size (Fig. 18.5A C). However, the cranial base is shortened, as evidenced by the very short basioccipital (Fig. 18.5D). The shortened cranial base contributes to the appearance of a depression in the middle third of the face. The nasal bones and the frontal processes of the maxilla are broad, and the short face is accentuated by the prognathism of the alveolar portion of the maxilla. All adult teeth have erupted, but have little wear, suggesting that the individual was a young adult. The long bones are very short (Fig. 18.5D) with the femur about 235 mm in maximum length. The epiphyses and apophyses are all fused, indicating adulthood. The tibiae have slight medial bowing of the distal half. The humerus is robust, with the abnormal joint morphology associated with achondroplasia. The diaphyses of all the long bones have near normal diameters, indicating virtually normal periosteal bone formation. Slon et al. (2013) provide a detailed description of achondroplasia in a 35 50-year-old male from 5 8th-century Rehovot-in-the-Negev, Israel. In Europe, examples of

FIGURE 18.4 Thanatophoric dwarf. (A) Anterior view; note the disproportionately large cranial vault relative to the bones of the face. (B) Left lateral view; note the length of the upper extremity relative to the spine. (Skeleton of an infant, probably a neonate, ANM 3398.)

achondroplasia have been reported from France (Susanne, 1970), Poland (Gladykowska-Rzeczycka, 1980), and Hungary (Farkas et al., 2001), with individuals buried in a similar manner to the rest of the population. Sables (2010) presented suspected chondrodysplasia in an 18 24-monthold from early medieval (AD 540 1020) Wales, UK. The skeletal changes included shortened and broad long bones, flared metaphyseal distal ends, shortened humeral and femoral necks, reduction of the femoral trochanters, the beginnings of coxa vara, and extreme lateral bowing of the distal tibiae. Waters-Rist and Hoogland (2013) examined the skeletal remains of a known Dutch family from 19thcentury Middenbeemster. The adult female, indentified as 66-year-old Sara Note, has an estimated stature of 130 cm. There was frontal and parietal bossing, the foramen magnum was oval rather than circular in shape, the long bones were shortened with the proximal segments most affected, and the vertebrae had reduced neural canals. It is argued Sara was suffering from hypochondrodysplasia (Fig. 18.6A and B) as the trident hands characteristic of achondroplasia are absent. Her 10-year-old daughter and 21-year-old son showed more subtle signs of macrocephaly and mesomelia,

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FIGURE 18.5 Achondroplastic skeleton from the Fourth Dynasty Egyptian tomb of King Mersekha. (A) Facial view. (B) Left lateral view; note the depression in the region of the nose. (C) Cranial base; note the abnormal shape of the foramen magnum and the short basioccipital. (D) Long bones (left humerus, right femur, and both tibiae); notice the short length but relatively normal diameter of the shafts and epiphyses. (BMNH AF. 11.4/427.)

respectively, that might have been overlooked but for the skeletal changes in their mother. It is likely the skeletal changes in these cases provide evidence for varied expressions of hypochondrodysplasia.

A potential case of thanatophoric dwarfism has also been identified in a 38-week perinate from the cemetery of St Hilda’s Church (AD 1813 1815), Newcastle-uponTyne. The vertebral bodies are abnormally flattened, the

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(A)

(B)

FIGURE 18.6 Adult female from 19th-century Middenbeemster with hypochondroplasia (a milder expression of achondroplasia) identified as 66year-old Sara Note. (A) Shortened limbs are evident with the upper segments of the limbs most severely affected (rhizomelia). The femora and tibiae are bowed mediolaterally causing genu varum. (B) The left humerus (on the right) is shown in comparison to an unaffected female from the same site. Additional features included frontal bossing, a depressed nasal bridge, oval foramen magnum, and spinal stenosis. Changes to the hands characteristic of achondroplasia were absent. From Waters-Rist, A., Hoogland, M., 2013. Osteological evidence of short-limbed dwarfism in a nineteenth century Dutch family: achondroplasia or hypochondroplasia. Int. J. Paleopathol. 3 (4), 248.

ribs are wide and flared at the sternal end. The upper limb bones are straight but short and abnormally broad, the metaphyseal ends of all of the long bones are flat, angled, and sharp. The short, broad tibiae and fibulae are bowed. In the pelvis, the ilia are short and broad and the acetabulum has a sharp angular appearance and is orientated

anteriorly. The severity of the lesions and flattening of the vertebral bodies may indicate thanatophoric dwarfism type 1, but the lack of a skull means the presence of a cloverleaf skull cannot be assessed (Lewis, 2018). In the New World, Hoffman (1976) described an achondroplastic skeleton from Sacramento County,

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California (AD 1500 1800) and another North American case has been reported from a Middle Woodland site dating between 50 BC and AD 250 (Osterholtz et al., 2001). Snow (1943) argues for achondroplasia in two indigenous New World skeletons recovered during excavations of an Indian village site in precontact Moundville, Alabama. The first of the skeletons was an adult female with a stature estimated to be about 125 cm. The posterior portion of the skull was not recovered. The forehead is prominent. The region around the nose is depressed, and the maxilla and mandible are prognathous. All the adult teeth had been lost antemortem. The postcranial bones exhibit the classic features of achondroplasia. The vertebral column, because of the multiple growth centers, is less affected than the long bones. The bones of all limbs are short but robust. The second skeleton is a male excavated five years later but from the same area of the mound (Fig. 18.7A). The reported stature is about 150 cm, but this estimate is probably too large. The skull (Fig. 18.7B) is virtually complete and exhibits abnormal features similar to the female. The cranium is large, but the cranial base is short, creating a midfacial depression. The long bones are short but robust. The humeral and femoral heads are abnormally displaced distally. In the femora, the greater trochanter is at the same level as the femoral head. The morphological features of both skeletons are compatible with a diagnosis of achondroplasia. An isolated skull from Ossuary IV at the Ferguson Farm, Accokeek, Maryland, is probably another New World example of achondroplasia. The site is Late Woodland with no evidence of European trade goods associated with the ossuary. This suggests a precontact date for the site. The skull vault is of normal size. The face is fragmentary, although there is little doubt that the midfacial region was depressed (Fig. 18.8A). The base of the cranium exhibits a smaller than normal foramen magnum and an abnormally short basioccipital (Fig. 18.8B). The subnormal size of the foramen magnum is a feature associated with achondroplasia (McAlister and Herman, 2005). A case of chondrodysplasia from Belle Glade, a Late Prehistoric site in Florida, demonstrates the major abnormal features of the long bones (Putschar and Ortner, 1982). There is no skull associated with the long bones. The length of the bones suggests a subadult age with death probably occurring in childhood. The distal femora show both the disproportionate widening of the metaphysis (Fig. 18.9A) and the abnormal angulation of the growth plate (Fig. 18.9B).

MULTIPLE EPIPHYSEAL DYSPLASIAS These are hereditary disorders resulting in severe dwarfism or short stature. They are traditionally divided into

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two types: spondyloepiphyseal dysplasia, which affects the spine causing platyspondyly and beaking; and multiple epiphyseal dysplasia (MED) that rarely involves the spine. Genetic mutations affect three loci responsible for cartilage formation, particularly of the epiphyseal chondrocytes. Both types show short limbs, irregular epiphyseal formation, delayed ossification of the epiphyses, and premature osteoarthritis (Goldman, 2005). The condition affects both sexes equally and skeletal involvement is bilateral and symmetrical. The most frequent sites of involvement are the hips, knees, shoulders, ankles, and wrists. The epiphyses are late to appear and often form multiple ossification centers giving them an irregular and fragmented or “mulberry” appearance (Goldman, 2005: 1297). Slipped femoral epiphyses and coxa vara deformities are common, with flattened femoral heads and femoral condyles. Fusion of carpal bones is frequent and the phalanges are stubbed. In spondyloepiphyseal dysplasia Scheuermann disease-like changes are most prominent in the mid-thoracic vertebrae (Goldman, 2005).

Paleopathology Four cases of MED have been identified in the literature. Arcini and Fro¨lund (1996) described a male and female from medieval Uppsala, Sweden. Both adults were buried close together, in the same way, with similar grave goods. The male was a mature individual with short long bones, flattening of the thoracic vertebrae, bilateral femoral coxa vara, flattening and fragmentation of the femoral heads, and severe secondary osteoarthritis. The elbows, ankles, and knees were also arthritic. The female, although less well preserved, had similar findings but also appeared to have a slipped proximal epiphysis of the first metacarpal. Both had a stature under 130 cm. While the spinal changes suggested spondyloepiphyseal dysplasia for the male, a lack of spine in the female prevented a more specific diagnosis. Kozieradzka-Ogunmakin (2011) argued for MED in a 25-year-old male from Saqqara, Egypt (2868 2181 BC). The individual demonstrated mild scoliosis of the thoracic spine, there was rhizomelia, flattening of the humeral heads, bilateral genu varus of the proximal tibiae, and severe osteoarthritis of the glenoid cavities and rib facets. Kozma’s (2008) reexamination of another dwarf from Egypt (4400 4000 BC) led to the conclusion that this individual also suffered from MED.

ACROMESOMELIA Acromesomelic dysplasia is a rare autosomal recessive disorder characterized by disproportionate dwarfism, with short hands and feet (acromelia) and shortening of the upper arms in comparison to the lower limbs. Adults are usually 106 120 cm in height (Borrelli et al., 1983). The

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FIGURE 18.7 Achondroplastic male skeleton from a pre-Columbian archeological site at Moundville, Alabama. (A) Front view of skeleton. (B) Left lateral view of skull. Photograph from Snow (1943), figures 4 and 6; courtesy of Dr. Joseph Vogel and the Natural History Museum, University of Alabama.

face has normal proportions but frontal and parietal bossing may be present. The clavicles will appear normal. The radius becomes markedly bowed with varying degrees of severity, and is susceptible to subluxation and

dislocation, limiting pronation and supination of the elbow. There may be thoracic kyphosis and flaring of the costal margins of the ribs (Langer et al., 1977). This condition may be difficult to distinguish from the other

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FIGURE 18.8 Achondroplastic skull from Ossuary IV, Accokeek, Maryland. (A) Left lateral view; note the concave profile of the face. (B) Base of skull; note the abnormal foramen magnum and short basioccipital. (Skull of an adult of unknown sex from a Late Woodland site in Accokeek, Maryland, NMNH 379527.)

mesomelic dysplasias (e.g., Le´ri Weill dyschondrosteosis, Langer’s mesomelic dysplasia) (Lewis, 2018).

LE´RI WEILL DYSCHONDROSTEOSIS This common condition causes mesomelia short stature that is accompanied by Madelung’s deformity of the forearm (McAlister and Herman, 2005). Dyschondrosteosis is an autosomal dominant condition, expressed more severely and frequently in females, and appearing in late childhood (Waldron, 2000). Individuals with the condition have deletions and mutations of the short stature homobox containing the gene SHOX, with homozygous mutations resulting in the more severe Langer’s mesomelic dysplasia (Waldron, 2000). Madelung’s deformity involves a shortened radius that is bowed dorsally and laterally, causing the shortened ulna to become subluxated, or to dislocate dorsally at the wrist, with a widened interosseous space. The carpus fits within the resulting V-shaped deformity with the lunate at the apex and may have a wedged appearance (Langer, 1965). In some cases there may be corresponding changes to the lower limb with tibia varum and a long fibula distorting the shape of the ankle. Just as in acromesomelia, the hands and feet may also be shortened (McAlister and Herman, 2005). Madelung’s deformity was considered pathognomonic of dyschondrosteosis by Langer (1965), although unilateral manifestations of the deformity may result from

trauma during development of the wrist, or in juvenile idiopathic arthritis. Bilateral Madelung’s deformity is characteristic of a congenital manifestation, although the severity of expression may differ (Zebala et al., 2007). Radial deformities are usually caused by an underdeveloped distal radial epiphysis and tethering (premature fusion) of the medial aspect of the metaphysis. Individuals with the deformity suffer a range of limited wrist movements most commonly loss of extension of the wrists and ulnar deviation (Titelbaum et al., 2015).

Paleopathology The earliest skeletal evidence for mesomelic dwarfism reported thus far is from a Late Upper Paleolithic site in Italy dating to about 10,000 BP (Frayer et al., 1988). The skeleton was male, about 17 years of age when he died. Abnormal shortening of the major long bones provides clear evidence of a defect in endochondral ossification that is particularly severe in the left and right radius and ulna. Because of the severity in the shortening of the forearm, the authors attribute the chondrodysplasia to acromesomelic dwarfism. There have been numerous cases of Madelung’s deformity associated with Le´ri Weill dyschondrosteosis reported in the literature. Waldron (2000) identified a possible case of dyschondrosteosis in a 20 25-year-old male from Romano-British Gloucester on the basis of shortening of the humerus and Madelung’s deformity of the right

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FIGURE 18.9 Long bones of an achondroplastic child. (A) General anterior view; note that the length of the bones is disproportionate relative to the diameter. (B) Detailed view of the right and left distal femur and proximal tibia; notice the disproportionate width of the bone ends and the abnormal angulation of the subchondral bone, particularly in the distal femora.

forearm. Preservation was too poor to assess the left side. Clear cases of bilateral Madelung’s deformity have been identified in a mature female from early medieval Gene`ve (Kauffman et al., 1979), a young female from 3rd 2nd century BC Mallorca (Campillo and Malgosa, 1991), a mature male from Bronze Age Sardinia (Canci et al., 2002), early medieval England (Cummings and Rega, 2008), and a 12-year-old from Late Neolithic Switzerland (Milella et al., 2015). Titelbaum et al. (2015) discovered two cases of bilateral Madelung’s deformity in an adult male and female from a series of disarticulated remains discovered in a single tomb in Ancash, Peru (AD 1250). That the individuals may have been related suggests that

the tomb was being used by the same family group (Fig. 18.10).

MUCOPOLYSACCHARIDOSIS Pathology Mucopolysaccharides (or glycosaminoglycans) are long chains of sugar molecules that are found throughout the body, often in mucus and in fluid around the joints. Mucopolysaccharidosis (MPS) describes a disorder in the metabolism of this enzyme resulting in its abnormal build-up in connective tissues and other organs, causing

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(A)

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(B)

(A)

(B)

FIGURE 18.10 Right radius and ulna showing shortening, a widened interosseous space and dorsal displacement of the distal radius in a possible female (A) and possible male (B) from Chullpa 26, Ancash Peru. These changes are characteristic of Madelung’s deformity, with a bilateral expression suggestive of Le´ri Weill dyschondrosteosis. The female expression is more severe. From Titelbaum, A., Ibarra, B., Naji, S., 2015. Madelung’s deformity and possible Le´ri-Weill dyschondrosteosis: two cases from a Late Intermediate period tomb, Ancash, Peru. Int. J. Paleopathol. 9, 12.

defects in the skeletal and central nervous system, eyes, liver, skin, teeth, and respiratory system. Mucolipidoses are a group of genetic disorders that affect the body’s

ability to carry out the normal turnover of various materials within cells, causing a build-up of both glycosaminoglycans and lipids in the body. Because

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mucopolysaccharides form a large part of the cartilage matrix, cartilage proliferation and hence, skeletal growth and development are variously affected in these conditions. Both mucopolysaccharidoses and mucolipidoses occur in a variety of clinical manifestations with overlapping abnormal skeletal features (McAlister and Herman, 2005) and may be indistinguishable in archeological human skeletal remains. The mucopolysaccharidoses are inherited mostly as an autosomal recessive disorder and often affect several members of one family. There are at least eight types of mucopolysaccharidoses with other conditions showing similar radiographic deformities that are designated dysostosis multiplex (McAlister and Herman, 2005: 1318). The three best types that are best characterized by their skeletal manifestations will be discussed here: Hurler’s syndrome (gargoylism), Hunter’s syndrome, and Morquio Brailsford’s syndrome. Hurler’s syndrome (MPS I) is transmitted as an autosomal recessive trait affecting children of either sex. The time and degree of its manifestations vary. Often it becomes apparent in infancy, and few individuals live beyond 10 years of age, with death as the result of heart failure or respiratory complications (McAlister and Herman, 2005). Skeletal changes have even been observed in the newborn (Caffey, 1951). The abnormality involves many tissues and organs of the body and individuals have distinctive faces (gargoylism), mental retardation, deafness, and corneal opacities (McAlister and Herman, 2005). In typical cases, the affected growth cartilages lead to markedly stunted growth. Also, the development of secondary ossification centers is delayed and morphologically abnormal (Jaffe, 1972: 545). Skeletal abnormalities include macrocephaly, craniostenosis (Fig. 18.11), widening of the costochondral end of

FIGURE 18.11 Radiograph of the lateral skull in a male child with Hurler’s syndrome. Note the greatly enlarged and elongated cranial vault relative to the size of the face. (Children’s Hospital, Washington, DC, case 904-042.)

the ribs, and abnormal shape of the vertebral bodies and shortened long bones (McAlister and Herman, 2005: 4229). The cranial bones are thick and dense. The skull base in the area of the sella is elongated; the mandibular condyles are flattened or even concave (Aegerter and Kirkpatrick, 1968: 138 152). The scapulae are often broad and thick, as are the ribs, with the exception of their misshapen necks and their narrow osteocartilaginous junctions. The spine shows a characteristic ossification defect at the dorsolumbar junction. This may affect the twelfth thoracic, but usually involves the first and often, to a lesser degree, the second lumbar vertebral body. The cartilage model of any involved vertebra is ossified only in the posterior and inferior portions, giving the impression of a beak-like inferior projection on the lateral view of the radiograph and this will be apparent in dry bone. This lack of anterior ossification at the dorsolumbar junction leads to a sharply angulated kyphosis at this level. The hand shows marked widening of the metaphyses of the metacarpals and phalanges adjacent to the growth plate, with tapered narrowing on the other end. Thus, the enlarged metacarpals taper proximally, the phalanges distally. The first metacarpal behaves like a phalanx. The distal phalanges are hypoplastic. The changes are less marked in the corresponding bones of the feet. Early in the disease, the long bones show periosteal bone deposition followed by increased endosteal cortical resorption, leading to widening of the marrow space and cortical thinning (Caffey, 1951). The humeri often show varus deformities of the head. Other deformities are coxa valga with plump femoral necks, shallow acetabulae, and genu valgum due to lateral tilting of the maldeveloped distal femoral epiphysis (Jaffe, 1972: 542 552). Hunter’s syndrome (MPS II) has a sex-linked inheritance so that only males are affected. In the severe forms of this syndrome the skeletal changes are practically identical with those of Hurler’s syndrome with death by the second decade of life. In the mild form of the disease, the only skeletal manifestation may be osteoarthritis of the hip (McAlister and Herman, 2005). Morquio’s syndrome (MPS IV) is transmitted as an autosomal recessive trait. Both sexes are involved equally and there are usually multiple siblings affected in one family. The syndrome is not apparent at birth, but begins to manifest itself in early childhood. Individuals with the condition may have corneal clouding and deafness, but intelligence is usually normal. The outstanding bone change is the flattening of all vertebrae with widening of the transverse and anteroposterior diameter. There is anterior wedging, especially at the dorsolumbar junction, leading to severe kyphosis. Subsequent to this deformity, the ribs show an altered configuration and the thorax is enlarged in its anteroposterior diameter. The sternum is angulated at the junction of the manubrium and corpus and protrudes

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forward. Severe dwarfism is typical. There is disproportionate shortening of the neck and trunk due to general flattening of the vertebral bodies (platyspondylia). The skull is normal and, therefore, too large relative to the body. Enamel hypoplasia of the primary and secondary dentition is common (McAlister and Herman, 2005), but whereas the deciduous teeth appear otherwise normal, the permanent teeth are abnormal in shape and position (Aegerter and Kirkpatrick, 1968: 141). Secondary ossification centers are delayed and show abnormal configuration. The long bones are usually severely shortened and often show flaring of the metaphyses with lipping at the junction with the epiphysis. Similar spike-like projections occur on tarsal bones (Jaffe, 1972: 220). Hip deformities are common, consisting of large deep acetabulae with irregular contour and delayed ossification of the femoral head (Jaffe, 1972: 219).

DEFECTS IN INTRAMEMBRANOUS BONE FORMATION Osteogenesis Imperfecta Pathology Osteogenesis imperfecta is a general term applied to a cluster of pathological conditions that are associated with fragile bones. This condition is uncommon with an incidence of 1 in 20,000 50,000 live births, although it is likely that mild forms go undetected (Waldron, 2009). Osteogenesis imperfecta has been reported in all populations with an equal sex distribution. Current clinical practice has identified five major variants of osteogenesis imperfecta but this classification is likely to change as research into this disease continues (Basal and Steiner, 2009). Osteogenesis imperfecta is caused by an inborn deficiency of mesenchymal cells that results in defective formation of type I collagen. Abnormal bone can be the result of a deficiency in the amount of type I collagen formed, or an abnormality in the chemical composition of the collagen (Basal and Steiner, 2009). Any tissue that normally contains a significant concentration of type I collagen will be affected. Ninety percent of bone protein (osteoid) is composed of type I collagen so the effect of osteogenesis imperfecta is particularly severe in bone. Because the dentine of teeth is virtually identical to bone, both the crown and the roots of teeth may be defective (dentinogenesis imperfecta). The expression of osteogenesis imperfecta is highly variable and in many cases involves organs in addition to the skeleton. In some variants the generalized problems of connective tissue are so severe that death occurs at birth or in childhood (Cope and Dupras, 2011; Glorieux et al., 2002). Thin cranial bones with lacunae are common and in the most severe

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cases the skull may be represented only by a membranous bag at birth (Caffey, 1945).

Type I (A and B) Osteogenesis Imperfecta This is the most common and least severe variant of osteogenesis imperfecta. Some cases are associated with dentinogenesis imperfecta (type IB), but other cases have relatively normal teeth (type IA). In type IB osteogenesis imperfecta the teeth of the first and second dentition show deficient and discolored dentin, whereas the ectodermal enamel is normally formed. However, inadequate support of the enamel leads to chipping and early dental loss. In this type of osteogenesis imperfecta, inadequate amounts of collagen are formed although the chemical composition is normal (Basal and Steiner, 2009). The continued deficiency of bone formation results in frequent fractures, particularly of the long bones. These fractures heal but often result in abnormal angulation and deformity, especially of the weight-bearing bones of the lower extremities and the pelvis (Fig. 18.12). Any bone except the skull may be deformed. In some cases callus formation is excessive and can be mistaken for an osteosarcoma. The tendency to develop new fractures usually diminishes in adult age. In type I osteogenesis imperfecta, endochondral growth is normal, but periosteal bone formation is very limited. This results in bones of normal length but subnormal character of the shafts. The cortex is very thin and the cancellous bone sparse. The inhibited osteoblastic activity is also reflected in the delay of cortical remodeling. This can be demonstrated microscopically in undecalcified ground sections, revealing the persistence of surface parallel lamellar bone and scarce osteonization.

Type II Osteogenesis Imperfecta Type II (A and C) are lethal forms resulting from new genetic mutations (autosomal dominant) which manifest in uterine life, with bones fracturing while the child is still in the womb, and during childbirth. Osteoblastic inhibition results in great reduction of both endochondral and intramembranous bone formation. The condition is often fatal at birth or in early childhood. The newborn reveals markedly shortened extremities because of the numerous transverse fractures of the long bones. The trunk is also shortened because of compression fractures of the vertebral bodies. Numerous transverse rib fractures exhibit multiple knobby enlargements associated with fracture callus. Thin cranial bones with lacunae are common and in the most severe cases the vault may be represented only by a membranous bag at birth (Caffey, 1978). If the condition is survived for a longer time, multiple ossification centers may form, giving rise to wormian bones. The bones show an extremely thin cortex and very sparse and thin cancellous trabeculae. Recognition of type II

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FIGURE 18.12 Osteogenesis imperfecta; note the widespread evidence of multiple fractures and subsequent deformity. (Skeleton of a female 32 years of age at the time of death, IPAZ S901/46.)

osteogenesis in archeological skeletal remains would depend on ideal conditions of preservation. However, because the condition affects the entire skeleton, it could be surmised even from single bones.

Types III and IV Osteogenesis Imperfecta These variants of osteogenesis imperfecta are uncommon and distinguishing them in archeological human remains is likely to be difficult as clinical diagnosis tends to rely on careful biochemical analysis. Skeletal deformity in type III is severe and deformity with dramatic dwarfing occurs if the individual survives beyond infancy. Type IV is the most variable of the manifestations of osteogenesis

imperfecta (Goldman, 1995: 4112). However, survival into adulthood is fairly common.

Paleopathology Wells (1965) describes a burial from an Anglo-Saxon cemetery at Burgh Castle in Suffolk, England, dated about the 7th century. The abnormality occurs in the left femur and consists of a 90-degree angulation of the proximal diaphysis. Wells estimates the age to be at least 18 years. The femur appears to have been fractured twice at the point of the angulation. Wells states that possible causes are rickets, fibrous dysplasia, and osteogenesis imperfecta. He rejects rickets, because the disease was at that point

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unknown in other Anglo-Saxon burials, and fibrous dysplasia for unstated reasons, concluding that osteogenesis imperfecta is most likely. As type I osteogenesis imperfecta is the most common variant and is associated with survival to adulthood, this is the most probable diagnosis, if osteogenesis imperfecta is the cause. A more certain archeological example of osteogenesis imperfecta is described by Gray (1970). The skeletal

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specimen is that of a young child (Registry No. 41603) around 2 years of age from the cemetery of Beni Hassan on the east bank of the Nile at a site known as Speos Artemidos in Egypt. This site is dated to the 21st Dynasty (ca. 1000 BC). The bones are friable and extremely light. The skull has an enlarged vault with vertically elongated eye orbits and multiple wormian bones (Fig. 18.13A). The long bones are deformed (Fig. 18.13B). The bones of

FIGURE 18.13 Osteogenesis imperfecta (type IIb) in a child about 2 years of age at the time of death. (A) Anterior view of the skull; note the open fontanelle and the elongated orbits. (B) Skull and postcranial bones; note the evidence of multiple fractures and deformity of the long bones. Child on display in the Roxie Walker Galleries of Egyptian Funerary Archaeology, photograph courtesy of the British Museum.

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the lower extremities show well-marked anterolateral bowing. The cortex is thin and the spongiosa poorly developed. The age of the child suggests this was not the lethal form (type II), but the deformities may be the result of type IIb osteogenesis imperfecta, where children may live for several years (Lewis, 2018). Also in Egypt, Cope and Dupras (2011) identified osteogenesis imperfecta in a perinate from the Roman cemetery of Kellis 2, Dakhleh Oasis. The child had distinctive bowing of the long bones with possible perimortem fractures of the femur and tibia.

uniformly in a row, or erupt haphazardly within the maxilla and mandible, and may be misshapen (Roberts et al., 2013). There may also be delayed shedding of the primary dentition, delayed or incomplete eruption of the secondary dentition (Fig. 18.14A), and formation of dentigerous cysts. Because this disturbance does not interfere with survival, the adult skeleton may demonstrate changes that are fairly diagnostic of this anomaly.

CLEIDOCRANIAL DYSPLASIA

Pathology

Pathology

Osteopetrosis is a rare genetic disorder with an incidence of 1 in 300,000 births (Tolar et al., 2004). It is characterized by varying degrees of inadequate osteoclastic activity. The result of this defect is that calcified cartilage of the primary spongiosa is not removed during modeling and the metaphysis is not cut back to form the diaphysis as growth in length of the long bones occurs. The latter defect results in the greatly enlarged ends of long bones associated with this disease. The failure to remove the primary spongiosa means that the marrow space normally occupied by hematopoietic tissue is filled with bone, causing anemia. The loss of bone plasticity due to an absent medullary cavity results in widespread secondary fractures (Filho et al., 2005). Radiographically, thick bands of radiolucent and radioopaque bone are evident. Foramina fail to enlarge properly during the growth process (Dent et al., 1965) causing additional neurological problems. In severe manifestations of osteopetrosis, the result is death in utero or at birth. The variability in the clinical manifestations of osteopetrosis is attributed to at least four distinct types, each caused by a different genetic defect (McAlister and Herman, 2005). Type 1, infantile, or malignant osteopetrosis is the most severe form and is usually fatal in utero. Even in this early developmental stage, the characteristic features of osteopetrosis are apparent in the skeleton and particularly in the increased density apparent in radiographs of all bones, including the skull (McAlister and Herman, 2005). Type 2, childhood osteopetrosis, is an autosomal recessive type where multiple pathological fractures result in short stature and severe mental retardation. Anemia, osteomyelitis, and blindness due to pressure on the optic nerve are also characteristic. Sufferers usually die before the age of 20 years (Lorı´a-Corte´s et al., 1977). Type 3, or benign osteopetrosis, is usually asymptomatic and only visible on radiograph, but fractures and osteomyelitis of the mandible are common in later adulthood (Fig. 18.15). The inferior architecture of the bones is present, and pathological fractures in adults are common. The delayed remodeling of the diaphyseal cortex microscopically shows small osteons separated by

Cleidocranial dysostosis is a congenital autosomal dominant disorder characterized by skeletal and dental dysplasia causing numerous skeletal and dental anomalies. The majority of cases arise from mutations of the runt-related transformation factor 2 gene (RUNX2) responsible for differentiation of the osteoblasts and osteoclasts (Hassan et al., 2016). The condition is usually familial but sporadic cases occur. The most marked changes concern the dentition, cranial vault, clavicles, and in some cases the pubic bone (Fig. 18.14). The cranium is brachycephalic with increased transverse diameter and accentuated frontal and parietal bosses (Fig. 18.14A). The fontanels are large and persist long beyond the normal time for closure. The sutures are widely separated and remain open much longer than normal. The space between the sutures may develop separate centers of ossification, creating numerous wormian bones (Fig. 18.14B). The cranial base may be slightly shortened and the basal growth plates fail to fuse. The facial bones may be small and the mandible may not be fused at the chin. While features vary, the most common defect in cleidocranial dysostosis is the complete absence of the lateral part of the clavicles (Rubin, 1964) causing narrow sloping shoulders in life. Another common defect is the failure of bone development of the middle shaft of the clavicle. This portion of the clavicle begins embryonic development as a fibrous model unlike the cartilage model associated with the long bones. Failure to develop this part of the clavicle results in a congenital pseudoarthrosis. Similarly, the pubic bone may not develop normally, leaving it shorter than normal (Fig. 18.14C) and resulting in a gap between the pubic bones. In the rest of the skeleton, late and rudimentary ossification of the femoral head and neck may result in severe coxa vara deformity. The pelvic bones may show delayed or incomplete fusion of ischium and pubis (Hassan et al., 2016). Supernumerary teeth may result from hyperactivity of the fetal dental germs and/or incomplete resorption of tooth buds during formation, leading to dental crowding and malalignment. The extra teeth may be arranged

OSTEOPETROSIS

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FIGURE 18.14 Cleidocranial dysplasia in a 25-year-old male who died in 1909 (FPAM 5701). (A) Frontal view, showing enlarged frontal bone with wide open anterior fontanel and rudimentary clavicles; the maxilla is hypoplastic and the mandible prognathic. (B) Posterior view, showing numerous wormian bones. (C) Anterior view of the pelvis showing malalignment of the shortened pubic bones, and coxa vara of the femora.

residual periosteal and endochondral bone (Laubmann, 1935). Type 4, intermediate osteopetrosis, can occur in adults and children and covers a whole spectrum of symptoms, from the most severe, to being asymptomatic (Dent et al., 1965; Filho et al., 2005). Other sclerosing bone dysplasias such as pyknodysostosis (Ortner, 2003: 498), Pyle’s disease, diaphyseal sclerosis, and melorheostosis should be considered as differential diagnoses.

Malignant Osteopetrosis This condition begins in fetal life. The basic defect is severe inhibition of osteoclastic activity without suppression of osteoblastic activity. This leads to preservation of primary trabeculae of endochondral growth containing cores of calcified cartilage. Continued deposition of bone on such trabeculae results in a poorly organized mass of bone and calcified cartilage that occupies the space

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FIGURE 18.15 Generalized osteosclerosis, probably osteopetrosis, in a 45-year-old male with fractures and progressive anemia (WM S66.2 and S66.3 AD 1932). (A) Massive ivorylike osteosclerosis with occlusion of medullary cavity of distal right humerus. (B) Lower thoracic vertebrae with sclerotic obliteration of cancellous pattern. The age of the individual suggests type 3 or 4 of the condition.

needed for hematopoietic marrow, causing anemia and increased risk of infection. This usually results in death in infancy or early childhood. This condition first becomes noticeable on the metaphyseal side of the fast-growing plates, such as the distal femur and proximal tibia; however, ultimately all bones show abnormal density. Because there is some fluctuation in the degree of osteoclastic suppression, parallel banding of denser and more lucent areas occurs in the metaphyses. Corresponding to this are concentric layers of alternating degrees of density in ossification centers (Fig. 18.16A and B). Ultimately, the whole medullary space is filled with the abnormal bone containing calcified cartilage (Fig. 18.16C). On the long bones, the physiological modeling of the metaphysis is inhibited, resulting in marked widening of this area instead of the usual concave contour. In spite of the excessive amount of bone present, its quality is inferior and a stress-oriented trajectorial trabecular system is not developed. Therefore, pathological, usually transverse, fractures commonly occur (Fig. 18.16A).

The cranium shows thickening of the base and of the vault. In cases with severe anemia, there may be expansion of the medullary space beneath the outer periosteum, giving a striated pattern in radiographs (Schinz et al., 1951). The suppressed osteoclastic activity prevents the normal endocranial resorption and the necessary widening of the foramina for the passage of the various cranial nerves. The facial bones also become dense. The normally cancellous bones (vertebrae, ribs, sternum, pelvis) show marble-like density in radiographs without distinct trabecular pattern; the bones are heavy.

METAPHYSEAL DYSPLASIA (PYLE’S DISEASE) Pathology This is a rare familial hereditary disorder characterized by delayed modeling of metaphyseal cortical bone. It normally develops in later childhood causing mild joint pain

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FIGURE 18.16 Osteopetrosis. (A) Right and left femora with pathological fracture to the left bone; notice the complete bony filling of the medullary canal and the lack of metaphyseal remodeling. (B) Radiograph of vertebral bodies; notice the great density and concentric arrangement of bone. (C) Radiograph of femur; notice the great density of the secondary ossification centers and the alternating bands of density and lucency in the unremodeled metaphyses (15-month-old male, MGH autopsy 34143).

and muscle weakness (Gupta et al., 2008). Osteoclastic dysfunction disrupts bone remodeling resulting in flared metaphyses or Erlenmeyer-flask deformity (Fig. 18.17). Pyle’s disease most commonly affects the distal femur, tibia, and fibula, but there may also be flattening of the vertebrae and expanded ilia, clavicles, and ribs (Lewis, 2018). On radiographic images, the affected bones show cortical thinning associated with atrophy, a reduced medullary cavity, and the trabeculae have a cloudy appearance. Pyle’s disease is also associated with scoliosis, knock-knees, dental malocclusion, secondary fractures, and thickening of the craniofacial (Gupta et al., 2008). Differential diagnoses should include osteopetrosis, osteomyelitis, and flask deformity in Gaucher’s disease.

Paleopathology Urteaga and Moseley (1967) provide an excellent example of metaphyseal dysplasia in a partial skeleton from a Mochica period (AD 200 800) burial from Peru. Unfortunately, except for the right humerus, the upper portion of the skeleton was destroyed by grave diggers. This humerus has an enlarged metaphysis, which extends toward the midshaft. The shaft itself is bowed laterally. The major abnormality is seen adjacent to both knees. In this region, there is a pronounced failure of remodeling

during the growth phase, which has created the classic Erlenmeyer-flask deformity of the metaphyses associated with metaphyseal dysplasia. Both tibiae are deformed with lateral S-shaped bowing. A longitudinal section through one femur and tibia reveals extensive cancellous bone development in the abnormal areas adjacent to the knee. The failure of cortical and cancellous bone modeling in the metaphyseal areas leaves no doubt about the diagnosis of metaphyseal dysplasia. GladykowskaRzeczycka (1995) presented two possible child cases from Poland, one based on a single humerus, and the other in a 16 18-year-old with hypertrophy of the distal tibiae.

PROGRESSIVE DIAPHYSEAL DYSPLASIA (CAMURATI ENGELMANN’S DISEASE) Pathology This hereditary disorder, caused by mutations in the TGFbeta-1 gene (Boulet et al., 2016), is characterized by bilateral periosteal and endosteal bone deposition on the diaphyses of tubular bones, sparing the metaphyses and epiphyses (McAlister and Herman, 2005). The cortical thickening is most marked at the midshaft and tapers toward both metaphyses. The diaphysis may increase to

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FIGURE 18.17 Clinical case of metaphyseal dysplasia in a 4-year-old male (IPAZ S796/47). (A) Anterior view of the right femur; note the abnormal shape, particularly of the distal femur. (B) Longitudinal section through the right femur; note the virtual absence of marrow space.

twice its normal size. This results in columnar or even fusiform shape of the long bones. The cancellous bones and the skull are not involved. The disease usually manifests itself in childhood, but mild cases may not be discovered until adult age. The disease may eventually regress, with individuals appearing taller than their peers (Boulet et al., 2016). Osteomyelitis is a differential diagnosis. Multiple diaphyseal sclerosis (Ribbing disease) is a similar condition that affects the lower limbs either unilaterally or bilaterally and shows similar features (Boulet et al., 2016).

Palaeopathology Giuffra et al. (2016) presented a possible case of Camurati Engelmann’s disease in a mature male excavated from a plague cemetery in 16th-century Italy. The individual displayed bilateral diaphyseal thickening of the upper and lower limbs and dense cranial bones.

MELORHEOSTOSIS (LERI’S DISEASE) Pathology Melorheostosis is a rare nonhereditary disorder causing abnormal endochondral and intramembranous ossification. It may involve a single bone (monostotic form) or multiple bones (polystotic form), usually occurs in the second decade of life, and affects males and females equally (Boulet et al., 2016). It is associated with muscular and tendonous complications that can lead to significant deformity, and there may also be blood and lymph vessel abnormalities. It is thought the defect develops in the embryo when sclerotomes migrate to the limb buds (Boulet et al., 2016). The skeletal changes consist of deposition of dense compact bone on the periosteal and endosteal surface that resembles melted wax flowing down a candle, hence the Greek name (melos: limb; rhein: to flow; ostos: bone) (Fig. 18.18). Usually a continuous group of bones is involved, representing a ray of the

Skeletal Dysplasias and Related Conditions Chapter | 18

635

FIGURE 18.18 Melorheostosis. (A) Left leg, lateral view, showing nodular and plaque-like periosteal hyperostosis. (B) Detail of lesion on the left distal femur. This individual was a 24-year-old male (IPAZ MB 6672 from AD 1964).

extremity; for instance, humerus, radius, radial carpal, thumb, and index finger. The lower limbs are more commonly involved and lesions tend to spare the skull and facial bones. Unlike progressive diaphyseal dysplasia, the epiphyses are normally involved (Kotwal and Clarke, 2017).

OSTEOPOIKILOSIS Pathology Osteopoikilosis is a rare asymptomatic hereditary osteosclerotic dysplasia, which affects both sexes and all age groups. The incidence is reported at 1 in 50,000. Although it develops in childhood, it is rare in children before 3 years of age (Benli et al., 1992). It may be

associated with skin lesions or other clinical problems but these are not specific. Diagnosis relies on the presence of characteristic radiographic features of multiple areas of sclerotic bone in several bones of the body (Spranger et al., 2002). The individual dense foci are one to several millimeters in diameter, round or oblong, and, in some areas, confluent. Histologically, the foci are condensations of compact lamellar bone, situated within the trabecular bone (Benli et al., 1992). The lesions tend to be symmetrical and they are most commonly found in the epiphyses and metaphyses of the long bones, the carpal and tarsal bones, and the small tubular bones of the hands and feet. With the exception of the sacrum and areas adjacent to the glenoid fossa and the acetabulum, the bones of the trunk and skull are normally spared. This lesion is so

636 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

characteristic that it should be readily identifiable in radiographs of dry bone provided that postmortem sand infiltration, which could mimic the picture, can be excluded. The condition may also mimic the mosaic pattern of Paget’s disease or a metastatic cancer.

OSTEOPATHIA STRIATA Pathology This rare anomaly is similar to osteopoikilosis and likewise is not visible by external inspection of the bones. The lesion consists of parallel, streak-like condensations of cancellous bone, involving the epiphyses and metaphyses of the long bones. The skeletal distribution is similar to that in osteopoikilosis and mixtures of both anomalies have been observed. The condition has also been linked to osteopetrosis, cleft palate, and mental retardation (Bloor, 1954).

Paleopathology Western and Bekvalac (2015) identified osteopathia striata in the distal femur of a 14-year-old from Worcester Royal Infirmary in England. The femur showed fine horizontal striae with vertical radiolucent bands running up the shaft (Lewis, 2018).

REFERENCES Aegerter, E., Kirkpatrick, J.A., 1968. Orthopedic Diseases. Saunders, Philadelphia. Arcini, C., Fro¨lund, P., 1996. Two dwarves from Sweden: a unique case. Int. J. Osteoarchaeol. 6 (2), 155 166. Basal, D., Steiner, R., 2009. Osteogenesis imperfecta: recent findings shed new light on this once well-understood condition. Genet. Med. 11 (6), 375 385. Benli, I., Akalin, S., Boysan, E., Mumcu, E., Kis, M., Turkoglu, D., 1992. Epidemiological, clinical and radiological aspects of osteopoikilosis. Bone Joint J. 74 (4), 504 506. Bloor, D., 1954. A case of osteopathia striata. J. Bone Joint Surg. Br. 36 (2), 261 265. Borrelli, P., Fasanelli, S., Marini, R., 1983. Acromesomelic dwarfism in a child with an interesting family history. Periatr. Radiol. 13, 165 168. Boulet, C., Madani, H., Lenchik, L., Vanhoenacker, F., Amalnath, D.S., De Mey, J., et al., 2016. Sclerosing bone dysplasias: genetic, clinical and radiology update of hereditary and non-hereditary disorders. Br. J. Radiol. 89 (1062), 20150349. Brothwell, D., 1967. 1. Major congenital anomalies of the skeleton: evidence from earlier populations. In: Brothwell, D., Sandison, A. (Eds.), Diseases in Antiquity: A Survey of Diseases, Injuries and Surgery of Early Populations. Springfield: Charles C. Thomas, pp. 423 443. Caffey, J., 1945. Pediatric X-Ray Diagnosis. Year Book Medical Publishers, Inc, Chicago, IL.

Caffey, J., 1951. Gargoylism (Hunter-Hurler disease, dysostosis multiplex, lipochondrodystrophy); prenatal and neonatal bone lesions and their early postnatal evolution. Bull. Hosp. Jt. Dis. 12 (2), 38 49. Caffey, J., 1978. Pediatric X-Ray Diagnosis. Year Book Medical Publishers, Inc, Chicago. Campillo, D., Malgosa, A., 1991. Braquimelia en un esqueleto procedente de la necropolis Tayaotica de ‘S’Illot de Porros’ (Mallorca). In: Actas IX Congreso Nacional de la Historia de la Medicina, 1179 1188. Canci, A., Marini, E., Mulliri, G., Usai, E., Vacca, L., Floris, G., et al., 2002. A case of Madelung’s deformity in a skeleton from Nuragic Sardinia. Int. J. Osteoarchaeol. 12 (3), 173 177. Cope, D., Dupras, T., 2011. Osteogenesis imperfecta in the archaeological record: an example from the Dakhleh Oasis, Egypt. Int. J. Paleopathol. 1, 188 199. Cummings, C., Rega, E., 2008. A case of dyschondrosteosis in an Anglo-Saxon skeleton. Int. J. Osteoarchaeol. 18 (4), 431 437. Dent, C., Smeillie, J., Watson, L., 1965. Studies in osteopetrosis. Arch. Dis. Child. 40 (7), 7 15. Farkas, G., Nagy, E., Ko´sa, F., 2001. Skeleton of a dwarf from excavations. Acta Biol. Szeged. 45 (1 4), 79 82. Filho, A., de Castro Domingos, A., de Freitas, D., Whaites, E., 2005. Osteopetrosis a review and report of two cases. Oral Dis. 11, 46 49. Frayer, D., Macchiarelli, R., Mussi, M., 1988. A case of chondrodystrophic dwarfism in the Italian Late Upper Paleolithic. Am. J. Phys. Anthropol. 75, 549 565. Giuffra, V., Montella, A., Bianucci, R., Milanese, M., Tognotti, E., Caramella, D., et al., 2016. Sclerosing bone dysplasia from 16th century Sardinia (Italy): a possible case of Camurati Engelmann Disease. Int. J. Osteoarchaeol. 26 (5), 830 841. Gladykowska-Rzeczycka, J., 1980. Remains of achondroplastic dwarf from Legnica of XI XIIth century. Ossa 7, 71 74. Gladykowska-Rzeczycka, J., 1995. Morbus Pyle (dysplasia metaphysealis congenita) from medieval cemeteries in Poland. J. Paleopathol. 7 (1), 57 62. Glorieux, F., Ward, L., Rauch, F., Lalic, L., Roughley, P., Travers, R., 2002. Osteogenesis imperfecta Type VI: a form of brittle bone disease with a mineralisation defect. J. Bone Miner. Res. 17 (1), 30 38. Goldman, A., 1995. Heritable diseases of connective tissue. In: Resnick, D. (Ed.), Diagnosis of Bone and Joint Disorders. Saunders, Philadelphia, pp. 4095 4162. Goldman, A., 2005. Heritable diseases of connective tissue, epiphyseal dysplasias and related conditions. In: Resnick, D., Kransdorf, M. (Eds.), Bone and Joint Imaging. Elsevier Saunders, Philidelphia, PA, pp. 1279 1298. Gray, P., 1970. A case of osteogenesis imperfecta, associated with dentinogenesis imperfecta, dating from antiquity. Clin. Radiol. 21 (1), 106 108. Gupta, N., Kabra, M., Das, C., Gupta, A., 2008. Pyle metaphyseal dysplasia. Indian Pediatr. 45, 323 325. Hassan, N.M.M., Dhillon, A., Huang, B., 2016. Cleidocranial dysplasia: clinical overview and genetic considerations. Pediatr. Dent. J. 26 (2), 45 50. Hoffman, M., 1976. An achondroplastic dwarf from Augustine site (CaSac-127). Contributions of the University of California, Archaeological Research Facility. 30, 65 119. Jaffe, H., 1972. Metabolic, Degenerative, and Inflammatory Diseases of Bones and Joints. Lea & Febiger, Philadelphia.

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Kauffman, H., Lagier, R., Baud, C., 1979. Un cas denanisme par dyschondrosteose au Vie siecle a Geneve. In: Acts de XIIIe Colloque de Anthropologie et Medecine (Caen), 204 211. Kotwal, A., Clarke, B.L., 2017. Melorheostosis: a rare sclerosing bone dysplasia. Curr. Osteoporos. Rep. 15, 1 8. Kozieradzka-Ogunmakin, I., 2011. Multiple epiphyseal dysplasia in an Old Kingdom Egyptian skeleton: a case report. Int. J. Paleopathol. 1 (3 4), 200 206. Kozma, C., 2008. Skeletal dysplasia in ancient Egypt. Am. J. Med. Genet. A. 146A (23), 3104 3112. Langer, L., 1965. Dyschondrosteosis, a hereditable bone dysplasia with characteristic roentgenographic features. Am. J. Roentgenol. 95 (1), 178 188. Langer, L.O., Beals, R.K., Solomon, I.L., Bard, P.A., Bard, L.A., Rissman, E.M., et al., 1977. Acromesomelic dwarfism: manifestations in childhood. Am. J. Med. Genet. 1, 87 100. ¨ ber die Knochenstruktur bei marmorknochenkLaubmann, W., 1935. U rankheit. Virchows Archiv fu¨r pathologische Anatomie und Physiologie und fu¨r klinische Medizin 296 (2), 343 357. Lewis, M., 2018. Paleopathology of Children. Academic Press, New York. Lorı´a-Corte´s, R., Quesada-Calvo, E., Cordero-Chaverri, C., 1977. Osteopetrosis in children: a report of 26 cases. J. Pediatr. 91 (1), 43 47. McAlister, W., Herman, T., 2005. Osteochondroplasias, dysostoses, chromosomal aberrations, mucopolysaccharidoses, and mucolipidoses. In: Resnick, D., Kransdorf, M. (Eds.), Bone and Joint Imaging. Elsevier Saunders, Philadelphia, PA, pp. 1298 1325. Milella, M., Zollikofer, C., Ponce de Leo´n, M., 2015. A Neolithic case of mesomelic dysplasia from Northern Switzerland. Int. J. Osteoarchaeol. 25 (6), 981 987. Mørch, E., 1941. Chondrodystrophic Dwarfs in Denmark. Munksgaard, Denmark. Ortner, D., 2003. Identification of Pathological Conditions in Human Skeletal Remains. Academic Press, New York. Osterholtz, A., Burgess, S., Buikstra, J.E., 2001. Achondroplasia in the Middle Woodland period, Elizabeth Site, IL. Am. J. Phys. Anthropol. Suppl. 115. Putschar, W.G., Ortner, D.J., 1982. Paleopathology of skeletal malformations and dysplasias. Verhandlungen der Deutschen Gesellschaft fur Pathologie 66, 147. Resnick, D., Kransdorf, M., 2005. Bone and Joint Imaging., third ed. Elsevier Saunders, Philadelphia, PA. Rimoin, D.L., Cohn, D., Krakow, D., Wilcox, W., Lachman, R.S., Alanay, Y., 2007. The skeletal dysplasias. Ann. N. Y. Acad. Sci. 1117 (1), 302 309. Roberts, T., Stephen, L., Beighton, P., 2013. Cleidocranial dysplasia: a review of the dental, historical, and practical implications with an overview of the South African experience. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 115 (1), 46 55.

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Rubin, P., 1964. On organizing a dynamic classification of bone dysplasias. Arthritis & Rheum. 7 (6), 693 708. Sables, A., 2010. Rare example of an early medieval dwarf infant from Brownslade, Wales. Int. J. Osteoarchaeol. 20 (1), 47 53. Schinz, H., Baensch, W., Friedl, E., Uehlmger, E., 1951. Roentgen Diagnostics, Vol. I. Saunders, Philadelphia. Scott, C., 1976. Achondroplastic and hypochondroplastic dwarfism. Clin. Orthop. Relat. Res. 114, 18 30. Slon, V., Nagar, Y., Kuperman, T., Heshkovitz, I., 2013. A case of dwarfism from the Byzantine city of Rehovot-in-the-Negev, Israel. Int. J. Osteoarchaeol. 23 (5), 573 589. Snow C.E., 1943. Two prehistoric Indian dwarf skeletons from Moundville. Alabama Museum of Natural History Paper 21, 1 90. Spranger, J., Brill, P., Poznanski, A., 2002. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. Oxford University Press, Oxford. Stoll, C., Dott, B., Roth, M.-P., Alembik, Y., 1989. Birth prevalence rates of skeletal dysplasias. Clin. Genet. 35, 88 92. Susanne, C., 1970. L’achondroplase de la population d’aˆge Franc de Coxyde (Belgique). Institut Royal des Sciences Naturelles de Belgique. Titelbaum, A., Ibarra, B., Naji, S., 2015. Madelung’s deformity and possible Le´ri-Weill dyschondrosteosis: two cases from a Late Intermediate period tomb, Ancash, Peru. Int. J. Paleopathol. 9, 8 14. Tolar, J., Teitelbaum, S., Orchard, P., 2004. Osteopetrosis. N. Engl. J. Med. 351, 2839 2849. Urteaga, O., Moseley, J.E., 1967. Craniometaphyseal dysplasia (Pyle’s disease) in an ancient skeleton from the Mochica culture of Peru. Am. J. Roentgenol. 99 (3), 712 716. Waldron, H., 2000. A case of dyschondrosteosis from Roman Britain. J. Med. Genet. 37 (10), 27. Waldron, T., 2009. Palaeopathology. Cambridge University Press, Cambridge. Waters-Rist, A., Hoogland, M., 2013. Osteological evidence of shortlimbed dwarfism in a nineteenth century Dutch family: achondroplasia or hypochondroplasia. Int. J. Paleopathol. 3 (4), 243 256. Wells, C., 1964. Bones, Bodies and Disease. Thames and Hudson, London. Wells, C., 1965. Osteogenesis imperfecta from an Anglo-Saxon burial ground at Burgh Castle, Suffolk. Medical History 9 (1), 88 89. Western, A., Bekvalac, J., 2015. Digital radiography and historical contextualisation of the 19th century modified human skeletal remains from the Worcester Royal Infirmary, England. Int. J. Paleopathol. 10, 58 73. Zebala, L.P., Manske, P.R., Goldfarb, C.A., 2007. Madelung’s deformity: a spectrum of presentation. J. Hand Surg 32 (9), 1393 1401.

Chapter 19

Tumors of Bone Carina Marques1,2 1

Research Centre for Anthropology and Health (CIAS), Department of Life Sciences, University of Coimbra, Coimbra, Portugal,

2

Department of Anthropology, William Paterson University, Wayne, NJ, United States

INTRODUCTION In recent decades, our understanding of oncological disorders has increased considerably due to knowledge gained from diverse fields of biomedical research. Some of these advances are addressed in this chapter. The term “tumor” serves to accommodate a broad category of bone disorders, including benign and malignant neoplasms, as well as nonneoplastic (e.g., developmental abnormalities) and undefined conditions (Miller, 2008). The latter are included as they are essential to the discussion and differential diagnosis of neoplastic bone diseases. The terms tumor and neoplasm are commonly used interchangeably in the current biomedical literature (Coleman and Rubinas, 2009; Kumar et al., 2015). However, some scholars have been advocating the strict use of the term neoplasm when a neoplastic nature is well established. These researchers criticize the interchangeability between these terms, since tumor is a term that is too broad and includes any mass or swelling of variable etiology (Zaydfudim et al., 2013). A neoplasm is an abnormal cellular proliferation in a tissue or organ where the abnormal cells no longer obey the strict normal regulatory pathways of cell proliferation, differentiation, or survival, reaching a new behavioral and/or functional status. Oncogenesis is triggered by multiple and cumulative genetic/epigenetic changes (tumor suppressor genes, proto-oncogenes, and DNA repair genes are key targets) acquired in a multistep manner by the cells over a lengthy period of time (Coleman and Rubinas, 2009; Weinberg, 2014; Samuels et al., 2015). It also should be noted that a single massive genetically disruptive event—chromothripsis—has been proposed recently as a potential mechanism as well (Samuels et al., 2015). As with all types of neoplasms, development and progression of bone neoplasms are dependent not only on the set of genetic/epigenetic traits acquired by the cells, but also on the fundamental crosstalk that is established

between the neoplastic cells and the surrounding bone microenvironment, ultimately leading to skeletal lesions. Neoplastic cells in the bone microenvironment disrupt the balance between bone resorption and bone formation to create a beneficial environment for their growth and survival (Broadhead et al., 2011; Cle´zardin, 2011; Fournier et al., 2014; Weinberg, 2014; Redini and Heymann, 2015; Makhoul et al., 2016). If the neoplasm remains localized without invading adjacent tissues and does not spread to distant organs, it is termed benign. These cellular growths usually consist of well-differentiated cells and generally have low proliferation rates. By definition, malignant neoplasms (cancer) have local infiltrative and invasive properties and have the capacity to reach other parts of the body (metastases) through the hematogenous and/or lymphatic circulation, or, less commonly, by direct extension. Malignant neoplasms have a wide spectrum of cell differentiation, ranging from well-differentiated to undifferentiated (anaplastic). These neoplasms tend toward rapid growth with higher rates of cell proliferation, but can display considerable variability (Coleman and Rubinas, 2009; Kumar et al., 2015). From a classificatory point of view, an intermediate, locally aggressive, or rarely metastasizing category is assigned to those neoplasms that do not neatly fall within the benign/malignant dichotomy (Fletcher et al., 2013). Malignant neoplasms generally are categorized into broad subgroups depending on the tissue in which they originate. Carcinomas, the most common malignant neoplasms, arise in epithelial tissue. Sarcomas develop in connective tissues (bone, muscle, fibrous, cartilaginous, vascular, or adipose tissues). Other distinct groups include neoplasms of the lymphoid and hematopoietic tissue, neuroglial neoplasms (that develop in nerves and supporting tissues), germ cell neoplasms, and melanomas (Oien et al., 2007; Weinberg, 2014; Kumar et al., 2015).

Ortner’s Identification of Pathological Conditions in Human Skeletal Remains. DOI: https://doi.org/10.1016/B978-0-12-809738-0.00019-3 © 2019 Elsevier Inc. All rights reserved.

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640 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

Primary bone neoplasms are the result of uncontrolled proliferation of any of the skeletal tissues (osteoid, cartilaginous, fibrous, or adipose tissues, and other bone marrow elements). Pathologic classification of primary bone neoplasms generally is based on the cell type and/or their products (matrix) (Klein, 2007; Czerniak, 2016). The World Health Organization (WHO) recognizes more than 50 different types of primary bone tumors (Fletcher et al., 2013). Primary bone neoplasms are rare when compared to the array of neoplasms of other tissues of the body (Hauben and Hogendoorn, 2015; Czerniak, 2016). Benign bone neoplasms are significantly more common than primary malignant neoplasms. Osteochondromas, enchondromas, giant cell tumor (GCT) of bone, osteoid osteomas, chondroblastomas, and osteoblastomas are the most common today. For the malignant counterparts, hematopoietic intraosseous neoplasms, osteosarcomas, chondrosarcomas, Ewing sarcoma, and chordomas are among the most frequent. Other primary bone malignancies are exceedingly rare (Grimer et al., 2013; Hauben and Hogendoorn, 2015; O’Donnell et al., 2015). Generally, primary malignant neoplasms of bone have a bimodal age distribution, peaking in young, actively growing individuals, followed by a second peak in individuals older than 60 years of age (Grimer et al., 2013; Hauben and Hogendoorn, 2015). Factors contributing to these patterns will be addressed later in this chapter. Metastatic bone disease occurs mostly after the fourth decade of life, or, to a much lesser degree, during the first decade commonly due to neuroblastomas, retinoblastomas, rhabdomyosarcomas, and other extraskeletal neoplasms (Hernandez et al., 2012; Grimer et al., 2013; Greenspan and Borys, 2016). Metastatic bone disease is much more common than primary malignant bone neoplasms (Grimer et al., 2013; Fournier et al., 2014; O’Donnell et al., 2015; Greenspan and Borys, 2016; Reith, 2016), and for this reason it is likely they will be encountered in archeological human skeletal remains more frequently. Primary neoplasms of bone and metastatic bone disease produce signs and symptoms of variable severity and can impact morbidity and mortality significantly. Intractable pain, localized swelling, gait abnormalities, neurological dysfunction due to associated neural damage, pathological fractures, and, in some instances, systemic alterations such as hypercalcemia, fever, weight loss, or fatigue are often experienced by patients (Grimer et al., 2013; Hauben and Hogendoorn, 2015; O’Donnell et al., 2015). The following review considers various types of bone lesions produced by neoplasms and neoplastic-like conditions, in accordance with the updated World Health Organization (WHO) classification of bone tumors

(Fletcher et al., 2013). Hematopoietic and lymphoid tissue neoplasms are discussed in Chapter 14. Additionally, there are many helpful reference works, both clinical and radiological, on bone neoplasms, and the reader may consult these for a more comprehensive review of such conditions (e.g., Bullough, 2010; Unni and Inwards, 2010; Fletcher et al., 2013; Czerniak, 2016; Greenspan and Borys, 2016).

Principles of Diagnosis The clinical identification and diagnosis of neoplastic lesions in bone often depends upon careful histology of soft-tissue components and the clinical, radiologic, and molecular datasets available to the modern oncologist (Czerniak, 2016). This information typically will not be available to those engaged in differential diagnosis of neoplasms in archeological human remains. Thus, diagnosis of specific neoplasm types will not always be possible. Furthermore, this nosologic group encompasses a wide array of distinct entities, often presenting similar changes in bone morphology and anatomical distribution. This is also the case with metastatic bone lesions, which often have very similar skeletal manifestations regardless of the primary site of the neoplasm (Greenspan and Borys, 2016). For these reasons, it is best to exert caution in identifying specific neoplasm types—or the primary organ causing bone metastases—in dry bone, and to establish broad disease categories (Ragsdale and Lehmer, 2012; Marques et al., 2013). However, careful analysis of the variables available may offer the paleopathologist helpful clues. For example, radiology can be employed relatively easily in the diagnosis of neoplastic lesions in dry bone. A significant proportion of these processes arise in, or affect, the intramedullary space and may or may not progress to the external cortical surface. Thus, radiologic techniques are an indispensable diagnostic modality. The analytic approach for the diagnosis of bone neoplasms and their distinction from other disease categories must include: (1) description and identification of the size and number of lesions (single or multiple, bilateral or symmetric); (2) location of the lesion in the skeleton and in the bone (i.e., epiphysis, metaphysis, diaphysis, central, eccentric, cortical, periosteal); and (3) morphological features of the lesion (Table 19.1; Miller, 2008; Costelloe and Madewell, 2016; Greenspan and Borys, 2016). In some circumstances, the age of the individual also may be helpful (Miller, 2008), though this variable is of more limited value in paleopathology (Ragsdale and Lehmer, 2012). That is, paleopathologists observe lesions at the time of death, which are often untreated, rather than at age of onset or age at diagnosis, as in clinical settings. During direct and radiographic examination of the morphology of dry bone lesions, three fundamental

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641

TABLE 19.1 Summary of radiographic and paleopathological features of neoplastic (nonhematological) and tumor-like lesions of bone reviewed in this chapter

Common Location—Skeleton

Common Location—Bone

Main Radiographic and Paleopathological Features

Long bones, feet, ilium, vertebrae, ribs

Epiphysis

Small OL defect with well-demarcated and sclerotic margin. Possible PR

Osteochondroma

Long bones, tubular bones of the hands and feet, pelvic bones

Metaphysis

Sessile or pedunculated bony outgrowths. Continuous with the host bone

Enchondroma

Tubular bones of the hands and feet, long bones

Metaphysis/diaphysis

Small round or oval radiolucent defect. Lobulated contour. Endosteal scalloping and matrix mineralization common

Long bones, tubular bones of the hands and feet

Metadiaphyseal

Long bones lower extremity, ilium

Metaphysis/diaphysis

Epithelioid hemangioma

Variable

Intramedullary

Well-demarcated OL lesion

Giant cell tumor of bone (GCT)

Long bones, pelvic bones, vertebrae

Epiphysis/metaphysis (eccentric)

OL lesion with well-defined margins and without sclerosis. Sometimes internal septa. Cortical “shell”

Hemangioma/vascular lesions

Craniofacial bones, vertebrae

Diploe, inner and outer tables; vertebral body

OL defect with coarsened trabeculae (honeycomb, corduroy, polka-dot appearances)

Osteoblastoma

Vertebrae, sacrum, craniofacial bones

Intracortical

Similar to osteoid osteoma but larger

Osteoid osteoma

Long bones (femur, tibia), hands, feet, vertebrae

Diaphysis/metaphysis

Round or oval radiolucent nidus with surrounding sclerosis

Adamantinoma

Tibia, fibula

Diaphysis

Bone metastasis

Pelvic and thoracic bones, craniofacial and long bones

Variable

Pelvic bones, long bones, ribs

Metaphysis

Chordoma

Sacrococcygeal, sphenooccipital region, vertebrae

Midline

OL lesion with ill-defined or well-defined margins. Cortical destruction possible

Ewing’s sarcoma

Long bones, pelvic bones, vertebrae

Metaphyseal diaphyseal

OL lesion with frequent moth-eaten/ permeative margins. Cortical destruction. PR frequent

Benign or Intermediate Chondroblastoma Chondroma

Periosteal chondroma

Chondromyxoid fibroma

Intramedullary

Bone surface

Intramedullary (eccentric)

Intracortical

Cup-shaped depression of the outer cortex with cortical lip. May show mineralization of the matrix Round or oval radiolucent lesion with welldemarcated and lobulated margins

Malignant OL or mixed lesions

Intracortical

Chondrosarcoma

Osteosarcoma (conventional, periosteal, telangiectatic)

Long bones

Intramedullary, rarely cortical

Intramedullary/ juxtacorticala

Intramedullary Metaphysis/diaphysis Variable

a

OL, OB, mixed lesions. Variable type of margins

OL lesion with ill-defined margins. Chondroid or amorphous calcifications, cortical scalloping/disruption. PR possible

OL, OB, mixed. Variable type of margins. Cortical destruction or thickening.a PR with aggressive features. Osteoid matrix

(Continued )

642 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

TABLE 19.1 (Continued)

Common Location—Skeleton

Common Location—Bone

Main Radiographic and Paleopathological Features

Metaphysis

OL defect, multilocular, with soap bubble appearance. Widening of the bone contour with thin cortex at outer edge

Undefined or Nonneoplastic Nature Aneurysmal bone cyst

Long bones, vertebrae

Intramedullarycortical (eccentric) BPO and subungual exostosis

Tubular bones of the hands and feet

Bone surface

Bony outgrowth

Epidermoid/dermoid cysts

Calvarium, tubular bones of the hands and feet

Diploe or intramedullary (central)

Well-delimited radiolucent lesion

Fibrous dysplasia

Femur, tibia, craniofacial bones, ribs, pelvic bones

Diaphysis/metaphysis

Variable: radiolucent with sclerotic margins to radiopaque. Ground-glass appearance common. Endosteal scalloping and alteration of the bone contour may occur

Tibia, fibula

Diaphysis

Osteofibrous dysplasia

Intramedullary (central)

Intracortical

OL defects with well-demarcated, sclerotic and multilocular margins. Alteration of the bone contour

Osteoma

Craniofacial bones

Outer table or paranasal sinus

Radiodense/sclerotic

Nonossifying fibroma/FCD

Long bones (femur, tibia)

Metaphysis/diaphysis

OL defect with well-demarcated and lobulated margins

Simple bone cyst

Long bones (humerus, femur)

Intracortical (eccentric) Metaphysis Intramedullary (central)

Oblong radiolucent defect. Sclerotic margin and possible alteration of the bone contour. Inner partial trabeculation may occur

a

Depends on the type; FCD, fibrous cortical defect; BPO, bizarre parosteal osteochondromatous proliferation; OB, osteoblastic; OL, osteolytic; PR, proliferative periosteal reaction.

Source: Compiled from Miller (2008), Motamedi and Seeger (2011), Rajiah et al. (2011), and Costelloe and Madewell (2016).

parameters must be evaluated: (1) pattern and margin of the bone destruction; (2) characterization of the new bone formation and matrix mineralization; and (3) type of periosteal new bone formation (Miller, 2008; Costelloe and Madewell, 2016; Greenspan and Borys, 2016; Ragsdale et al., 2018). For the pattern and margin of the bone destruction, the classification system implemented for radiographic evaluation described, for example, in Miller (2008), Costelloe and Madewell (2016), and Ragsdale et al. (2018) also may be adapted to the visual inspection of dry bone, as suggested by Ragsdale and Lehmer (2012). The radiographic grading system proposed by Lodwick (1964) and modified by Madewell et al. (1981) for scoring the margins and zone of transition (interface between the normal bone and lesion) in osteolytic lesions, also may be useful in paleopathological diagnosis (Fig. 19.1). These margin changes are distinguished into geographic (type I), referring to a focal osteolytic lesion with a welldefined, recognizable delineated border and a narrow zone of transition (Fig. 19.1). In most cases, this margin

is indicative of a slow-growing, nonaggressive condition, particularly when it exhibits a sclerotic rim (type IA). However, geographic margins also can be seen in malignant neoplasms, particularly in lesions with sharp margins and nonsclerotic rim (type IB) or with ill-defined margins (type IC) (e.g., chondrosarcoma, osteosarcoma, metastatic bone disease, multiple myeloma, osteomyelitis). Motheaten (type II) and permeative or permeated (type III) margins appear as diffuse and confluent areas of bone loss, with multiple small areas of osteolytic activity interposed with normal bone and a wide zone of transition (Fig. 19.1). Since the combination of these two lesion margins (type II and type III) is common, and their distinction difficult, Caracciolo et al. (2016: 153) suggest to “group them together among the most aggressive patterns of bone destruction by classifying them as grade IIIB.” These margins typically are characteristic of aggressive lesions (e.g., bone metastases, Ewing sarcoma, osteosarcoma, lymphoma, leukemia) but are not exclusively neoplastic (Miller, 2008; Caracciolo et al., 2016; Costelloe

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FIGURE 19.1 Schematic representation of osteolytic bone lesion margins classification. Based on Lodwick (1964) and Madewell et al. (1981). Type I: geographic (IA, sclerotic; IB, nonsclerotic; IC, ill-defined); type II: moth-eaten; and type III: permeative/permeated. Caracciolo et al. (2016) score types II and II combined (revised type III). Reproduced with permission from Elsevier, Figure 2.5 in Costelloe and Madewell (2016).

and Madewell, 2016). Infectious diseases can show these types of margins and mimic neoplasms. For example, “osteomyelitis has a spectrum of imaging appearances from predominantly sclerotic to purely lytic, including permeative osteolysis. Thus, osteomyelitis continues to be ‘the great mimicker’ and should always be considered” within the differential diagnosis (Caracciolo et al., 2016: 156). When the above-mentioned lesions affect or extend to the external cortical surface of bone, they can be recognized by visual inspection (Fig. 19.2). In primary or secondary bone neoplasms, the osteolysis is due mainly to the osteoclastogenesis or osteoclast activation stimulated by the neoplastic cells and by cells in the microenvironment, which may also include inflammatory cells associated with the immune response (Fournier et al., 2014; Inagaki et al., 2016). In bone neoplastic lesions, new bone formation may also occur due to the activity of the neoplastic osteoblasts themselves (e.g., osteosarcomas), or due to osteoblast stimulation mediated by secreted products from the neoplastic cells (e.g., osteoblastic metastasis). Bone radiographically visible within a tumor may also have been formed through other processes (e.g., cellular metaplasia,

replacement of cartilage, reactive bone) (see Ragsdale et al., 2018). For diagnostic purposes, it is important to evaluate the radiographic pattern and density of the mineralization of the tumor matrix. The term “matrix” connotes the type of tissue produced by the neoplastic cells (e.g., osteoid, chondroid, fibrous, myxoid) (Miller, 2008), and its mineralization results from deposition of calcium hydroxyapatite in the organic background produced by the neoplasm (Ragsdale et al., 2018). Mineralized tumor osteoid (Fig. 19.3A) can present a spectrum of radiodensity, from dense, homogeneous, ivory-like appearances, to amorphous, “fluffy,” or “cloud-like” appearances; as in bone islands, osteoid osteomas, osteoblastomas, and osteosarcomas (Ragsdale et al., 2018). If cartilaginous matrix accepts minerals at all, they can have a radiographic “stippled,” punctate, or flocculent pattern (Fig. 19.3B). Curvilinear “arc-and-ring” radiographic patterns are also common in cartilaginous neoplasms. These changes are often seen in enchondromas, chondroblastomas, or chondrosarcomas. Fibrous or fibro-osseous matrix generally has hazy, ground-glass densities due to scattered spots of mineral deposition (Costelloe and Madewell, 2016; Greenspan and Borys, 2016; Ragsdale et al., 2018). Some

(A)

(B)

(C)

(D)

FIGURE 19.2 Examples of osteolytic lesions margin as observed in dry bone. (A) Geographic (type IA): thickened and sclerotic margin (distal radius, adult, Sk. no. 583, LLAC- MUHNAC, Portugal). (B) Geographic (type IB): sharply demarcated margin without sclerosis (ilium, adult, Sk. no. 323, CISC, Portugal). (C) Geographic (type IC): osteolytic foci surrounded by smaller areas of bone destruction. Wide zone of transition. The illdefined margin of the geographic lesion is confirmed by radiograph (60 kV, 56 mAs) (distal femur, nonadult, Sk. no. 146, LLAC- MUHNAC, Portugal). (D) Moth-eaten (type II): lesion composed by scattered and multiple confluent small areas of osteolysis. Wide zone of transition. Features observed in dry bone and corresponding radiograph (60 kV, 56 mAs) (ilium, adult, Sk. no. 340, LLAC- MUHNAC, Portugal). (E) Possible example of permeative (type III) margin in the lateral cortex of a proximal humerus showing very small osteolytic spots. (C) X-ray courtesy Dr. C. Prates, IMI-S. A. (D) X-ray courtesy Dr. C. Prates, IMI-S.A. (E) Reproduced with permission from Elsevier, Figure 8 in Ragsdale et al. (2018).

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(E)

FIGURE 19.2 (Continued)

neoplasms can produce more than one type of matrix. Diagnoses of neoplasms with unmineralized matrix must be based on location, margin features, and the character of any periosteal reaction, as with nonmatrix-producing tumors. Of course, mineralized matrix may be lost in dry bone or altered by taphonomic processes. The presence of periosteal bone formation can also be informative, even if proliferative periosteal responses are not a hallmark of any particular type of neoplasm and are common in many conditions (Greenspan and Borys, 2016). Irregular, multilamellated, interrupted (e.g., Codman angle), spiculated (e.g., parallel/“hair-on-end” and radiant/“sunburst”), or combined reactions are most often seen in aggressive conditions, including malignant neoplasms (for further details see Miller, 2008; Costelloe and Madewell, 2016; Greenspan and Borys, 2016; Ragsdale et al., 2018). For the evaluation of these three fundamental parameters it is important to include a radiologic analysis. A systematic radiographic evaluation of bones with changes to the external surface is essential for diagnosis (Fig. 19.4), as a neoplastic intramedullary lesion may be discovered, and the differential diagnosis is also more reliable.

The anatomic location of the lesion in the skeleton and in the individual bone is particularly relevant for diagnostic purposes, since some bone neoplasms show a predilection for certain locations (Table 19.1). The following review describes the most characteristic and classic patterns for each condition, but it must be noted that variability, exceptions, and overlapping of features are common. In this chapter, differential diagnosis is performed to distinguish primarily between neoplastic and neoplastic-like conditions. However, the first approach to diagnosis of bone neoplasms requires a detailed and careful differential diagnosis to exclude other broad categories such as infectious, vascular, congenital, metabolic, and trauma (Unni and Inwards, 2010).

Paleopathology There are several factors that influence the prevalence of bone neoplasms that are critical for paleopathology. Demographic, biological, environmental, and sociocultural factors are known to play significant roles in both the type and prevalence of neoplasmss (for details see DeVita et al., 2015). As Greaves (2008: 278) notes,

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FIGURE 19.3 Radiographic examples of matrix mineralization. (A) Radiograph with “cloud-like” mineralization of tumor osteoid in a clinical patient with conventional high-grade osteosarcoma of the distal femur. (B) Chondroid matrix mineralization, visible in the radiograph (a) and axial CT (b), in a 57-year-old female patient with enchondroma of the distal femur. (A) Reproduced with permission from Elsevier, Figure 1A and B in Rajiah et al. (2011). (B) Reproduced with permission from Elsevier, Figure 6 in Motamedi and Seeger (2011).

“cancer risk is underpinned by intrinsic fallibility, increasing in expression age and greatly exacerbated by some aspects of human activity.” The environmental context and activity patterns in many modern populations are very different from those observed for the past. However,

it is also true that carcinogens (endogenous and exogenous) have a long history of impacting human groups (e.g., hormonal changes, metabolic products, dietary natural carcinogens, sunlight, ionizing radiation, asbestos and toxic metals in the natural environment, microtoxins,

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FIGURE 19.4 Visual inspection of distal right femur shows only a slight alteration to the bone contour (arrow), however radiographs reveal a lobulated eccentric lesion with geographic sclerotic margins (type IA) characteristic of nonossifying fibroma. This condition would go unnoticed in the absence of radiographic evaluation. (Young adult male, Islamic period, necropolis of Quinta da Boavista, Loule´, Portugal.)

infectious agents, indoor pollution from biomass fuels, manmade carcinogens), even if both the number and the concentration of some of these agents have changed recently. Thus, we cannot ignore the potential impact of these carcinogens in the past. Ancient populations were exposed to high inflammatory environments, not only through the exposure to pathogens, but also to multiple inflammatory agents as a consequence of human activities (e.g., exposure to dust and pollen, domestic smoke inhalation) (Finch, 2010). The roles of infections as carcinogenic vectors and of chronic inflammation in oncogenesis have been widely demonstrated (Weinberg, 2014). As such, infection-related cancers (e.g., gastric, uterine, liver cancers) may be expected more frequently in the paleopathological record. Carcinomas of the lungs, primarily associated with smoking, air pollution, or occupational hazards, are common in modern groups. Metastases to the skeleton from this type of cancer may have been minimal in past populations, but exposure to indoor air pollution from biomass fuels is a significant health burden in lowincome countries today (Fullerton et al., 2008), and it could also have contributed to the development of lung cancers in the past. Skin cancers are currently a common cause of mortality worldwide (Coleman and Rubinas, 2009). Exposure to sunlight and other risk factors associated with the development of these conditions may also have been

relevant in earlier human groups (Osborne and Hames, 2014). Overall, it is expected that chronological shifts of the most frequent types of neoplasms occurred through time in human societies (Marques et al., 2018). Paleopathology has an important role in identifying these shifts. However, modern medical and epidemiological data on oncological disorders are based on relatively recent populations, thus establishing parallels between ancient and modern realities must be made cautiously. Demographic factors must also be considered when examining the antiquity of oncological diseases. Because primary bone neoplasms often arise during the growth period, their frequency in ancient skeletons might be expected to be closer to that of modern human populations. Further, childhood malignancies that show metastatic potential (e.g., leukemia, lymphoma, neuroblastoma, retinoblastoma, rhabdomyosarcoma) should also be encountered more often in the paleopathological record. Most bone metastatic disease is associated with older ages, and their prevalence in archeological human skeletons is likely to be moderate because of demographic profiles. Longer life spans increase exposure to carcinogens, allow time for the acquisition of genetic/ epigenetic mutations, and reduce immune competence and the efficacy of DNA repair mechanisms (Coleman and Rubinas, 2009; Kumar et al., 2015). However,

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recently it has been argued that while it is clear that human life expectancy at birth significantly increased in the 20th century, the notion that human longevity has increased drastically through time is a much more contentious idea (Chamberlain, 2006; Gurven and Kaplan, 2007; Finch, 2010; Osborne and Hames, 2014). The traditional view that malignant neoplasms were remarkably rare in the past is thus being challenged (Marques et al., 2018). Limitations in bone preservation, sample sizes, difficulties in paleopathological diagnosis, and nonsystematic use of radiological techniques are some of the factors that preclude a reliable assessment of cancer landscape in the past and thus contribute to the underreporting of cases in the paleopathological literature (Brothwell, 2012; Zuckerman et al., 2016; Marques et al., 2018). A growing corpus of publications on ancient malignant neoplasms has developed in recent years (Strouhal and Nˇemeˇckova´, 2009; Hunt, 2013). This research argues that malignant neoplasms affected human populations at least during the last six millennia (Strouhal and Nˇemeˇckova´, 2009) and possibly in premodern hominins as well (Odes et al., 2016). Regrettably, few population-based approaches have been employed. Fortunately, this is a scenario that is likely to change in the near future.

PRIMARY BENIGN TUMORS Pathology The following review does not include all benign neoplasms and neoplastic-like conditions of bone listed in the WHO classification of bone tumors (Fletcher et al., 2013). Rather, emphasis is placed on the most common conditions, although some rare disorders were included due to their peculiar skeletal presentation or importance for differential diagnoses.

Osteogenic Tumors Osteoma An osteoma is an osteogenic tumor composed by wellorganized mature bone. This benign bone-forming condition is of unknown etiology and its dysplastic or neoplastic origin is not yet well-established (Czerniak, 2016). Three histological patterns of osteomas are distinguished: compact or ivory osteoma composed by dense and mature lamellar bone without Haversian canals; cancellous or mature osteoma in which the morphology resembles normal bone with trabecular bone; and a mixed type that captures the ivory and mature histology. Osteomas are usually a fortuitous finding in clinical settings; therefore, prevalence is difficult to ascertain (Baumhoer and Bras, 2013). The age distribution is quite

FIGURE 19.5 Osteoma of frontal sinus. (A) Cut surface view from below. Notice the ivory-like masses bulging and penetrating the sinus wall externally and endocranially. (B) Frontal view, showing multiple perforations through outer table. (Adult, HM P809 from before 1799.)

variable, with a peak incidence between 30 and 50 years of age. No sex differences have been reported (Baumhoer and Bras, 2013). Osteomas occur almost exclusively in the craniofacial skeleton, seldom in the long bones. The mineral density of the lesion facilitates preservation in archeological material. Approximately 75% of cases of osteomas clinically diagnosed result from bony proliferation in the frontal or other paranasal sinuses or orbits (Fig. 19.5) (Greenspan and Borys, 2016). These tumors occasionally become very large, disfiguring the facial bone contours and projecting into the orbit and/or the nasal cavity. Mucocele, sinusitis, nasal discharge, headache, facial pain, or loss of vision are some of the symptoms associated with these osteomas (Greenspan and Borys, 2016). Occasionally, a sizeable nodular projection into the anterior cranial fossa with compression of the frontal lobe of the brain occurs. Osteomas of the cranial vault and mandible (“button osteoma” or “ivory exostosis”) consist of dense mature lamellar bone (Fig. 19.6) and are less common clinically.

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FIGURE 19.6 Osteoma of frontal bone (“button osteoma”). (58-year-old, female, CISC, Portugal.)

They are usually located on the outer table and consist of smooth, compact bone typically not more than 2 4 cm in maximal diameter. Sometimes they show marginal undercutting at the junction with the outer table. Usually the lesion is single, but multiple lesions can occur, often in association with Gardner syndrome (Czerniak, 2016). The most frequent locations for these osteomas are the parietal and frontal bones, and they are easily identifiable in archeological remains. In the Hamann-Todd collection, 37.6% of the 585 skeletons analyzed by Eshed et al. (2002) shown cranial vault osteomas. No sex differences were noted, though an age-related increment was found to be significant (Eshed et al., 2002). Eshed et al. (2002) proposed a differentiation of “button lesion” and osteomas based on distinct histological features on dry bones. Osteomas of the paranasal sinuses or orbit are less commonly reported in archeological contexts (Premuˇzi´c et al., 2013), and clinically they correspond to radiopaque and well-defined lesions, which are often lobulated and relatively homogeneous. The base of these osteomas can be broad or pedunculated. Another lesion commonly found in archeological samples is an overgrowth of cortical bone in the lateral portion of the bony auditory canal. These lesions vary in size from a small outgrowth to a large growth that virtually fills the entire auditory canal. Some are true osteomas, generally unilateral and solitary, showing a pedunculated protrusion with a narrow neck in the tympanosquamous suture lateral to the isthmus. These osteomas are difficult

to distinguish from, and often confused with, exostoses of the external auditory canal. The latter are most often multiple, bilateral, with a smooth bordered and broad base (Eshed et al., 2002; Baik et al., 2011; Carbone and Nelson, 2012). These are distinct clinical entities; however, the parameters to distinguish auditory canal osteomas and exostoses of the auditory canal have been a source of debate in clinical settings (Baik et al., 2011; Carbone and Nelson, 2012). Auditory canal lesions are well documented in archeological material and are discussed in greater detail below. Osteoid Osteoma An osteoid osteoma is a benign, osteoid-forming neoplasm. Osteoid osteomas represent 10% 12% of all benign bone tumors. Diverse chromosomal abnormalities (more frequently chromosomal alterations of 22q and 17q) have been associated with these lesions (Bocklage et al., 2014; Czerniak, 2016). Histologically, they consist of small vascularized fibrous connective tissues in which differentiated osteoblasts produce osteoid or immature woven bone (Klein, 2007; Nielsen and Rosenberg, 2010; Greenspan and Borys, 2016). They occur in a wide age range, but most cases are diagnosed in adolescents and young adults, particularly in males (2:1 to 3:1 ratio). The location of these lesions is often on a long bone, most frequently in the femur, tibia, and humerus (combined account for 50% of the cases). Lesions may also be found

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in the hands and feet (20%) or vertebrae (10% 15%) (Czerniak, 2016). Flat bones seem to be unaffected. In long bones, a location near the end of the diaphysis is more common, either in the cortex or affecting also the spongiosa of a bone. Radiologically, the lesion appearance is quite diagnostic, presenting as a small (1.5 2 cm) round or oval, well-demarcated radiolucent focus (nidus), with or without central calcifications, and surrounded by an accentuated area of sclerosis, which is out of

proportion to the size of the central lesion. This reactive buildup of dense bone may appear as an external or internal cortical thickening of several centimeters in axial length, reaching its maximum over the small lesion (Fig. 19.7) (Nielsen and Rosenberg, 2010; Czerniak, 2016). Liu et al. (2011: 170) note that CT images of osteoid osteomas typically show a “characteristic vascular groove”. That is, a low-density and curvilinear groove radiating through the thickened sclerotic surrounding

FIGURE 19.7 Osteoid osteoma. (A) Gross specimen of osteoid osteoma in a clinical patient. Notice the small ovoid red (gray in print version) central lesion (nidus) surrounded by dense reactive bone that alters the bone contour. (B) Radiograph of osteoid osteoma of femur. Notice the osteolytic corticomedullary lesion with a central nidus of decreased density and pronounced cortical hyperostosis. (Adult, AFIP 116267.) (A) Reproduced with permission from Elsevier, Figure 14.10 in Nielsen and Rosenberg (2010).

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bone from the periosteal surface of the cortex down to the nidus. This feature may be helpful for diagnosis. The density of the reactive bone should preserve the appearance of the lesion in dry bone, though the unmineralized osteoid portion would not be preserved. A widened long bone contour suggests the need for a radiographic analysis in order to detect this lesion. Differentiation from a small intracortical abscess may not be possible. Osteoblastoma Osteoblastomas are relatively rare neoplasms, accounting for less than 1% of all primary bone tumors (Bocklage et al., 2014; Czerniak, 2016). In the series of bone tumors recorded by the Mayo Clinic prior to 2003, these conditions accounted for 3.5% of all benign neoplasms (Unni and Inwards, 2010). The histological pattern resembles that of osteoid osteoma; however, osteoblastomas are much larger. Thus, the distinction between osteoid osteomas and osteoblastomas is based on size (osteoblastomas nidus are larger than 1.5 2 cm, whereas osteoid osteomas are smaller) as well as on its atypical location, including the spine (preferentially vertebral arches), sacrum, or craniofacial bones (Klein, 2007; Czerniak, 2016). Although the radiographic diagnosis of osteoblastomas is relatively straightforward, confusion with malignant neoplasms is possible. In their 1994 study of 306 osteoblastomas, Lucas et al. (1994) note that 39% of the cases showed cortical widening and destruction, features that would make differentiation of osteoblastomas from malignant bone neoplasms difficult.

Chondrogenic Tumors Chondroma A chondroma is a benign neoplasm with a chondroid matrix. It usually arises within the bone (enchondroma) or, less often, beneath the periosteum as a periosteal/juxtacortical chondroma. Enchondromas are one of the most common primary bone neoplasms, representing nearly 10% 25% of all benign bone neoplasms (Unni and Inwards, 2010; Czerniak, 2016). Enchondromas appear to arise from deregulation in the differentiation and proliferation of the growth plate chondrocytes (Bove´e et al., 2010; Singer et al., 2015). Thus, enchondromas develop during periods of growth. Several chromosomal abnormalities (e.g., chromosomes 6, 12, and 24) and mutations in IDH1/2 genes have been associated with the development of these neoplasms (Douis and Saifuddin, 2012; Singer et al., 2015). Enchondromas are diagnosed across a wide age distribution, yet are more frequently detected between the second and fourth decades of life. There is no sex predilection. They typically occur in the diaphysis or metaphysis (less often in the epiphysis) of tubular bones,

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especially the small tubular bones of the hand (40% 65% of the cases); 25% of cases involve other long bones (Douis and Saifuddin, 2012). The localization of these enchondromas in the Mayo Clinic files prior to 2003, arranged in order of decreasing frequency, is as follows: hand, femur, humerus, tibia, feet, fibula, scapula, innominate, radius, ulna, vertebrae, sternum, carpals, sacrum, patella, and tarsals (Unni and Inwards, 2010). Enchondromas do not occur in bones developing through intramembranous ossification. The cranial base and facial bones are usually unaffected. In long bones, they are centrally (sometimes eccentrically) located in the marrow space. These cartilaginous masses have an oval shape and lobulated margins that may be surrounded by a thin rim of bone. This feature gives a lobulated contour to the radiolucent lesion visible in radiographs (Fig. 19.8A). Mineralization of the cartilage can have a wide spectrum of radiodensity in radiographs (Fig. 19.8B), often presenting as stippled or flocculent densities that may or may not be preserved in dry bone. An arc and ring pattern is also seen on X-ray. Large enchondromas may scallop the inner cortex of long bones, with associated cortical thinning and a variable degree of alteration of the outer bone contour. Cortical perforation and periosteal reactions are rare, indicating a possible malignant transformation. In the small bones of the hands and feet, the outer contour is often distorted and widened, which may be the only feature visible to the naked eye on dry bone. In these bones, the location is mostly diaphyseal. The diagnosis is relatively straightforward when showing the typical matrix mineralization. However, an unmineralized enchondroma must be considered in the differential diagnosis of any intramedullary radiolucent lesion. Periosteal chondromas are rare (less than 1% 2% of all chondromas) (Czerniak, 2016). They are usually located adjacent to the metadiaphyseal areas, particularly in the proximal humerus, femur, or small tubular bones of the hands and feet. They cause a small (1 7 cm) cupshaped depression of the underlying outer cortex with an elevated cortical lip surrounding the defect (“crater-like” or “saucerization” appearance) (Fig. 19.9). Periosteal chondromas typically remain separated from the interior of the bone by a distinct sclerotic border, which allow the differential diagnosis with osteochondromas. The central portion of the tumor may show mineralization. Enchondroma protuberans is an extremely rare form of chondroma. It arises in the intramedullary space and extends through the cortex as an exophytic growth (Douis and Saifuddin, 2012). Multiple enchondromas (enchondromatosis), in which multiple and often numerous enchondromas are present in the metaphysis and diaphysis of long bones, are exceedingly rare (Douis and Saifuddin, 2012). They occur predominantly in association with two nonhereditary

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these lesions assume an elongated, streak-like, radiolucent appearance along the long axis of bone, radiologically termed a “fluted-column sign” in long bones or “fanshaped grooves” in the pelvis. The presence of large cartilage masses results in diminished growth, bowing deformities due to uneven growth, and widening of the metaphysis of involved bones due to delayed and incomplete modeling.

FIGURE 19.8 (A) Radiograph of enchondroma of proximal phalanx of fourth digit (clinical patient). Notice the widening of the bone contour and well-defined (geographic) intramedullary lesion, with lobulated contour, cortical thinning, and endosteal scalloping. Minor calcification observed (arrow). (B) Radiographic and gross features of intramedullary enchondroma of proximal humerus (clinical patient). Notice the lobules of hyaline cartilage in the gross specimen and heavy calcified matrix visible in the radiograph. The external bone surface remains unaltered; hence such a case would not be identified in archeological skeletons without a radiographic examination. (A) Reproduced with permission from Elsevier, Figure 17.17 in Bullough (2010). (B) Reproduced with permission from Elsevier, Figure 6.10 in Czerniak (2016).

developmental disorders, Ollier disease and Maffucci syndrome (enchondromas coexisting with soft-tissue hemangiomas). Five other rare forms of enchondromatosis are clinically known (Czerniak, 2016). In the small bones, these cartilage neoplasms exhibit deformities bordered by a thin cortical shell. In the process of growth, some of

Osteochondroma Osteochondromas (osteocartilaginous exostosis) are the most common benign bone neoplasms, comprising approximately 20% 50% of benign bone neoplasms and 1% 2% of individuals undergoing radiographic evaluation (Murphey et al., 2000; Unni and Inwards, 2010). Osteochondromas have been considered developmental in origin; however, recent studies have consistently shown cytogenetic abnormalities in these conditions, namely mutations in the exostosin gene family (EXT), supporting the idea of a neoplastic origin (Bove´e et al., 2010; Singer et al., 2015). Osteochondromas result from an abnormal proliferation and differentiation of chondrocytes, which grow away from the normal growth plate. Abnormal diffusion of Indian hedgehog ligands is associated with the loss of polar organization of the cells and consequent growth in the wrong location (Douis and Saifuddin, 2012; Cuellar and Reddi, 2013). The lesion is characterized by a cartilage-capped bony outgrowth (the cartilage portion is not retained in dry bone), located on the outer bone surface and originating in the metaphysis. The cartilage cap (disorganized growth plate-like cartilage) undergoes endochondral ossification, mimicking the endochondral growth of the normal growth plate. The exostosis enlarges due to the growth of the basal layer of the cartilage cap. Characteristically, there is never a cortex separating the medullary spaces of the lesion from those of the host bone. The lesion’s initiation is limited to the growth period of the skeleton, stopping when the nearby plate terminates its growth (Murphey et al., 2000; Bove´e et al., 2010). Males are affected roughly twice as often as females (1.8:1 ratio), with an incidence peak between the ages of 10 and 30 years. The lesion may occur in any bone that develops by endochondral ossification, but the cranial base and the facial bones are rarely involved. The lesions most commonly occur near the growth plate on the metaphyseal surface of long bones: distal femur (30%), proximal and distal tibia (15% 20%), proximal humerus (10% 20%), and proximal femur, followed by the small bones of hand and feet (10%), ilium (5%), and scapula (4%) (Murphey et al., 2000; Bove´e et al., 2010; Douis and Saifuddin, 2012). The final shape of the lesion is greatly modified by mechanical stresses (muscle pull and tendon insertions) in the affected area. Osteochondromas

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FIGURE 19.9 Radiographic (A and B) and gross (C) features of a periosteal chondroma of humerus (clinical case). Notice the concave cortical destruction without perforation (“saucerization”) and periosteal bone buttressing. Reproduced with permission from Elsevier, Figure 6.21 in Czerniak (2016).

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FIGURE 19.10 Radiographic and dry bone features of pedunculated and sessile osteochondromas. (A) Large pedunculated osteochondroma of proximal tibia (thin arrow). (B) Multiple sessile osteochondromas of distal femur (thick arrows) with irregularity of the surface reflecting the area under the cartilage cap in vivo. (C) Radiograph of the femoral lesions, showing continuity between the osteochondroma and host bone on the right side of the image. The apparent cortical lines on the left side are due to structures superimposition. (Adult, male, 16th 19th centuries, Convento de Nossa Senhora da Anunciada, Setu´bal, Portugal.) Image courtesy Dr. N. Antunes-Ferreira.

can be broad-based and rather bulky without pedunculation (sessile osteochondromas), or they produce an elongated and slender pedicle with bulbous tip (pedunculated osteochondromas) pointing away from the joint (Fig. 19.10). In dry bone and in radiographs, the tumor shows easily recognized diagnostic characteristics. If transected or observed in radiographs, the continuity of the cancellous marrow spaces of the lesion and of the involved bone are readily apparent, as is the reflection of the cortex onto the lesion. The inner structure consists of more or less regular cancellous bony trabeculae that may in some cases be mingled with areas of calcified cartilage. Fractures of slender, elongated exostoses are not uncommon. The flaring remodeling of the metaphysis is often inhibited on the side of the bone bearing the osteochondroma. Deformity, bowing, or synostosis between paired bones may also occur. Osteochondromas of the pelvis may appear as cauliflower-like masses projecting outward or toward the pelvic canal (Fig. 19.11). Hereditary multiple osteochondromas (formerly known as hereditary multiple exostoses or diaphyseal aclasis) is a hereditary autosomal dominant condition

associated with germline mutations in the EXT gene family (Singer et al., 2015). The global incidence of multiple osteochondromas is approximately 1:50,000. It usually manifests itself in several siblings and several generations of one family. There is a marked male predominance (2:1 ratio). Basically, the individual lesion is identical with that of an osteochondroma. Locational specificity favors the knees, ankles, and shoulders, often symmetrically (Fig. 19.12). The number of lesions may vary from a few to several hundred with variability in size. If numerous lesions are present in a metaphyseal area, remodeling of the metaphysis is lacking, leaving a broad metaphysis without flare (Fig. 19.12). Growth is retarded and, at times, irregular, leading to shortening and axial deviation of the affected bone. If the distal ulnar metaphysis involvement is severe, the ulna is shortened and the radius, due to its intimate attachment to the ulna, is abnormally curved, giving the appearance of a Madelung deformity of the forearm. In a moderate number of cases (1% 3%) among the older age groups, malignant transformation to chondrosarcoma may occur in one or more of the lesions (Greenspan and Borys, 2016).

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FIGURE 19.11 Massive osteochondroma of left ilium. (59year-old, female, IPAZ autopsy 1776 from 1962.)

FIGURE 19.12 Multiple osteochondromas. (A) Right femur; notice lack of metaphyseal remodeling in area of exostosis. (B) Left tibia and fibula with multiple exostoses. (54-year-old, male, IPAZ S.1201 from 1965.)

Chondroblastoma This fairly rare neoplasm (less than 1% of all bone neoplasms) is classified as an intermediate category, since it rarely metastasizes (Fletcher et al., 2013). It is a neoplasm characterized by proliferation of immature cartilage cells (chondroblast-like cells), thus regarded as a cartilageproducing lesion (Czerniak, 2016). Structural alterations in chromosomes 5, 8, and 17 have been frequently reported (Greenspan and Borys, 2016). This neoplasm typically involves the epiphysis of long bones in skeletally immature individuals. This feature is helpful for identification in dry bone. However, after closure of the adjacent growth plate, the lesion may extend into the adjacent metaphysis. Most cases are diagnosed in the second decade of life, with a preponderance of males over females (1.4:1 to 2:1) (Unni and Inwards, 2010). Epiphyses of long bones (Fig. 19.13A) are affected in 75% 80% of the cases (Douis and Saifuddin, 2012), particularly the proximal tibia, distal femur, proximal humerus, and proximal femur. In the humerus and femur, common locations are the separate apophysis for the greater tubercle and the greater trochanter (Unni and Inwards, 2010). Occurrences in the feet, acetabular area, ilium, scapula, spine, and ribs are also common, particularly in older individuals. This is one of the rare neoplasms to occur in the patella, calcaneus, or talus (Czerniak, 2016). The radiographic presentation is of a relatively small (1 6 cm) round or oval osteolytic lesion with sharply demarcated (geographic) and thin sclerotic margins with lobulated contour (Fig. 19.13B). It can be centrally or eccentrically located. In 30% of cases there is matrix mineralization (Douis and Saifuddin, 2012). Imaging studies have demonstrated a frequent (60% of cases) presence of periosteal reaction (thick solid or layered) located adjacent or at some distance from the lesion (Shinmura et al., 2004; Douis and Saifuddin, 2012). Neoplasm-induced inflammatory reaction has been

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suggested as the explanatory mechanism for the periosteal new bone formation (Shinmura et al., 2004). Chondroblastomas and clear-cell chondrosarcomas have similar locations and both develop in young individuals. The latter is an extremely rare condition and may present malignant features. GCT of bone, intraosseous ganglions, enchondromas, chondromyxoid fibromas, simple bone cysts, or aneurysmal bone cysts (ABC) are challenging for differential diagnoses in skeletally mature individuals, especially when they extend into the epiphyses. Bizarre Parosteal Osteochondromatous Proliferation and Subungual Exostosis Although both conditions are quite rare in the clinical practice, their specific location and presentation allow for fairly reliable recognition in paleopathology. Bizarre parosteal osteochondromatous proliferation (Nora’s lesion) is characterized by periosteal new bone formation and cartilage proliferation on the surface of the bone, particularly in the long bones of the hands and feet (Unni and Inwards, 2010; Czerniak, 2016). A protruding bony mass that might be pedunculated in a mushroom shape often is seen on the surface of the bone. Subungual exostosis (Dupuytren exostosis) is a neoplastic lesion characterized by subperiosteal development of a bony protuberance with a cartilaginous cap located in the distal phalanges of hands and feet, near the nail bed. In both conditions, absence of marrow and cortical continuity between the host bone and the lesion aids in distinguishing from osteochondromas (Sciot and Mandahl, 2013). Fracture callus and myositis ossificans must also be considered in the differential diagnosis. Chondromyxoid Fibroma

FIGURE 19.13 (A) Radiograph of chondroblastoma of proximal left humeral epiphysis. Notice the eccentric radiolucency with a thin bony shell and slight sclerotic reaction (adolescent). (B) Radiograph of chondroblastoma of greater trochanter of the femur (clinical case). Osteolytic lesion with well circumscribed margins and matrix mineralization. (A) Image courtesy Dr. S. Werthammer, Huntington, West Virginia, 1952. (B) Reproduced with permission from Elsevier, Figure 15.8 in Horvai (2010).

A chondromyxoid fibroma is a rare cartilaginous neoplasm, accounting for less than 1% of all benign bone neoplasms and less than 0.5% of all bone tumors (Unni and Inwards, 2010). It is classified within the intermediate (locally aggressive) category (Fletcher et al., 2013). Histologically, a chondromyxoid fibroma consists of lobules with an admixture of spindle-shaped, stellate cells and chondrocyte-like cells. The matrix is fibrous at the periphery and myxoid and chondroid at the center. It occurs mostly in adolescents and young adults, primarily in males (1.3 to 1.5:1), with a second peak around the fifth to seventh decades (Unni and Inwards, 2010; Cappelle et al., 2016). These lesions most commonly develop in short or long bone metaphyses or diaphyses, mainly of the lower extremity and ilium, but they may occur in any bone or location (Unni and Inwards, 2010).

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They usually have an intramedullary location, yet cortical or subperiosteal locations have been described (Douis and Saifuddin, 2012). The radiographic features of a chondromyxoid fibroma involve an oval or round geographic radiolucent lesion, eccentrically or centrally located, with sclerotic margins and lobulated contour. Occasionally, ridges within the lesion are observed. Widening of the bone contour may be observed and cortical destruction is noted in approximately one third of cases (Douis and Saifuddin, 2012; Cappelle et al., 2016). In dry bone, differential diagnosis from other lesions producing solitary areas of bone rarefaction is difficult. It must be considered in the differential diagnosis of GCT of bone and chondroblastomas for epiphyseal locations; ABC, chondrosarcomas, nonossifying fibroma (NOF), and enchondromas for other locations (Cappelle et al., 2016).

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2011). The lesion begins close to the growth plate, but migrates away during growth. The most common presentation is as a single lesion; however, multiple metaphyseal foci may occasionally be seen, particularly in association with other conditions (e.g., neurofibromatosis, Jaffe Campanacci syndrome). Radiographic images show an oval radiolucent and well-demarcated cortical lesion with a rim of sclerotic bone. As the lesion enlarges, it involves the medullary cavity and becomes eccentric, often presenting with distinct lobulated borders. The inner aspect of the lesion can be uniloculated or multiloculated (Fig. 19.14). A moderate widening of the bone contour if often visible, without a prominent periosteal reaction. Although this is the most common presentation, the lesions in NOF range from an oval osteolytic focus with a

Fibrogenic, Fibrohistiocytic, and FibroOsseous Lesions Desmoplastic Fibroma Desmoplastic fibroma of bone is an extremely rare neoplasm (0.1% of all bone tumors) included in the category of fibroblastic tumors. It is composed by welldifferentiated fibroblasts with collagen matrix production (Greenspan and Borys, 2016). It consists of an intramedullary osteolytic lesion, without sclerotic margins, that rarely contains mineralized matrix. Since it does not present specific features it is difficult to diagnose in archeological human remains. Nonossifying Fibroma and Benign Fibrous Histiocytoma The NOF and fibrous cortical defect or metaphyseal fibrous defect are histologically the same. Fibrous cortical defect is the term used to describe lesions smaller than 3 cm and restricted to the cortex, while NOFs are larger and may also involve the intramedullary space. These fibrous bone lesions are very common, estimated to be present in 30% 40% of children and adolescents (Bła˙z et al., 2011; Nielsen and Kyriakos, 2013). They are most likely a developmental abnormality rather than a true neoplasm. Genetic abnormalities have not been consistently reported, and a frequent spontaneous resolution seems to support this argument (Klein, 2007; Bocklage et al., 2014). NOFs consist of benign proliferation of fibrous tissue, which are characterized by fibroblast-like cells mixed with multinucleated osteoclast-like giant cells and histiocytes (Nielsen and Kyriakos, 2013). NOFs typically develop in skeletally immature individuals between the ages of 5 and 20 years, with a male predominance. The origin of these lesions is in the metaphyseal cortex of the long bones, particularly in the distal femur and proximal and distal tibia (Bła˙z et al.,

FIGURE 19.14 Radiograph of nonossifying fibroma of distal right tibia. Notice the eccentric lobulated lesion with slightly bulging cortex and pronounced deep sclerotic margin. (Adolescent, MGH surgical specimen 14645 from 1969.)

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neoplasm or if it is related to NOFs but with atypical anatomical location (flat bones, vertebrae, or epiphysis of long bones) in older individuals (Klein, 2007; Czerniak, 2016). Fibrous Dysplasia

FIGURE 19.15 Different stages of lesion morphology of nonossifying fibroma (clinical cases). (A) Oval osteolytic lesion with sclerotic margin. (B) Oval osteolytic lesion with lobulated contour and sclerotic margins (most common). (C) Pronounced sclerotic lesion. (D) Totally sclerotic lesion. Reproduced with permission from the Polish Journal of Radiology, Figure 1 in Bła˙z et al. (2011).

thin sclerotic rim, to partly or entirely sclerotic lesions in healing stages (Fig. 19.15) (Bła˙z et al., 2011). Only in a thin long bone, like the fibula, may the tumor ultimately transect the entire diameter. Even then, the cortex distant from the primary site is less involved. Because large portions of cancellous bone and cortex are progressively destroyed, pathological, diagonal, fractures commonly occur, especially in weight-bearing bones. The lesion may reach up to 10 cm in length. When located on juvenile tibia, NOF may be difficult to differentiate from osteofibrous dysplasia (OFD), yet fibrous dysplasia, simple bone cyst, or ABC are also part of the differential diagnoses. Benign fibrous histiocytomas have histological patterns identical to NOFs. It is not yet established if benign fibrous histiocytoma represents a distinct benign

Fibrous dysplasia is a benign fibro-osseous lesion of nonneoplastic origin; hence it is included in the tumors of undefined neoplastic nature in the WHO classification (Fletcher et al., 2013). This condition is often associated with mutations in the GNAS gene that encodes the signaltransducing G-proteins (Siegal et al., 2013). Fibrous dysplasia results from defects in osteoblastic differentiation and maturation leading to a localized inability to form mature lamellar bone. The bone lesion consists of islands of fibrous tissue and woven bone that develop in the marrow space (Klein, 2007; Siegal et al., 2013; Czerniak, 2016). From this location the fibrous lesions enlarge, often at the expense of cortical bone, which will gradually be replaced by the fibrous tissue. Depending on the amount of bone and the degree of mineralization, the lesion may appear in radiographs as purely osteolytic with well-defined sclerotic geographic margins, it may have a diffuse, ground-glass appearance, or it may be a dense area. The bone contour is generally widened. It may ultimately involve most parts of a bone, sparing some portions and practically always sparing the epiphysis. It may occur as a single lesion in one bone (monostotic form) or it may involve several bones with multiple foci (polyostotic form), the latter is less common (Klein, 2007). It is often limited to one limb or one side of the body (monomelic) or show widespread skeletal manifestations, usually not symmetrical (polymelic). Craniofacial bones, ribs, proximal femora, and tibiae are the most common sites of involvement in the monostotic form, while widespread lesions that can also frequently affect the pelvic bones and limbs are common in the polyostotic form (Figs. 19.16 and 19.17). In the proximal femur, a common presentation is designated as shepherd’s-crook deformity when the dysplastic focus weakens the subtrochanteric area, resulting in lateral bowing (Fig. 19.16). In small bones, a thin shell of newly formed periosteal bone surrounds the lesion at all times. This results in a cyst-like lesion confined by a ridged, thin, bony shell, particularly in small and flat bones, such as ribs and pelvis. In the polyostotic form, the lesions in the cranial vault and face are asymmetrical and often unilateral (Fig. 19.18). Rounded masses of woven bone can be found in the diploe¨, similar to those seen more frequently in advanced Paget’s disease. Lesions of the skull base tend to be sclerotic and inhibit pneumatization of the paranasal sinuses. The combination of abnormal growth and pathological fractures may lead to severe deformity

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FIGURE 19.16 Polyostotic fibrous dysplasia, showing “shepherd’s crook” deformity of both proximal femora and deforming involvement of many bones. (A) Anterior view. (B) Posterior view. (40-year-old, female, DPUS 4016, French catalog 323a from before 1891.)

(Fig. 19.18). Fracture, pain, swelling, skeletal deformity, leg asymmetry, or nerve impingement can be present in an otherwise asymptomatic monostotic form. The polyostotic form might produce more severe skeletal deformities. Severe craniofacial lesions (facial cherubism), deafness, and visual and vocal anomalies, can occur in the triad of polyostotic fibrous dysplasia, endocrinopathies, and cafe´-au-lait skin pigmentation ascribed to McCune Albright syndrome (Fig. 19.18). The recognition of fibrous dysplasia in dry bone would depend on at least partial preservation of the fine or coarse woven bone trabeculae (Fig. 19.17). Admittedly, preservation in an archeological context will

be variable and depend on the acidity of the soil as well as moisture. Almost certainly, abnormal bone in fibrous dysplasia cases will not survive in the burial environment as well as normal bone. Differentiation from other lesions, especially Paget’s disease, GCT, unicameral cysts, enchondromas, NOF, and Langerhans cell histiocytosis may be impossible. Osteofibrous Dysplasia OFD is a rare benign fibro-osseous lesion (formerly known as ossifying fibroma of long bones or Kempson Campanacci disease), accounting for less than

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However, this idea remains controversial (Bethapudi et al., 2014; Czerniak, 2016; Scholfield et al., 2017).

Osteoclastic Giant Cell-Rich Tumors Giant Cell Tumor of Bone

FIGURE 19.17 Polyostotic fibrous dysplasia of bisected distal tibia, showing finely porous abnormal bone replacing cortex and spongiosa. (40-year-old, Chinese male; studied by Putschar in 1960 at Department of Pathology, National University, Taipei, Taiwan.)

1% of all primary bone tumors (Greenspan and Borys, 2016). Histologically, OFD consists of a mixture of fibrous connective tissue with spicules of woven bone and osteoblastic rimming (Bethapudi et al., 2014; Czerniak, 2016). Its nonneoplastic nature justifies its inclusion in the group of tumors of undefined neoplastic nature in the WHO classification (Fletcher et al., 2013). OFDs develop during infancy and childhood, usually in the proximal or middle diaphysis of the tibia and distal diaphysis of the fibula (Klein, 2007), presenting as a radiolucent lesion with well-demarcated, sclerotic and multiloculated margins. It arises in the cortex, but can extend into the medullary cavity and also cause cortical widening, with anterior bowing of the tibia (Fig. 19.19). Multifocal confluent lesions along the longitudinal axis of the bone may be seen, as well as involvement of both tibia and fibula. The OFD, OFD-like adamantinoma, and malignant adamantinoma may represent the same group of fibroosseous bone tumors, sharing histology, anatomical location, and radiological features, with OFDs at the beginning of the spectrum and adamantinomas at the end.

GCT of bone is a primary bone neoplasm of intermediate category, locally aggressive but rarely metastasizing (Fletcher et al., 2013). It is relatively common, representing 5% 10% of all primary bone neoplasms and 20% of benign bone neoplasms (Unni and Inwards, 2010). It is characterized by a proliferation of ovoid mononuclear stromal cells mixed with osteoclast-like multinucleated giant cells. Only a subset of the mononuclear stromal cells, derived from mesenchymal stem cells most likely of osteoblast lineage, seems to represent the neoplastic component (Flanagan et al., 2015). These neoplasms do not produce extracellular matrix. A frequent driver mutation in histone 3.3 variants exclusively in H3F3A genes leading to G34W alterations, have been frequently reported in GCT (Flanagan et al., 2015). In a very small number of cases (,1%) GCT can undergo malignant transformation, or even more rarely, malignancy arises as a de novo phenomenon (Flanagan et al., 2015). GCT is a neoplasm developing in adulthood, mostly between ages 20 and 40 years. Contrary to most other bone neoplasms, it characteristically arises in the epi/ metaphyseal area of bone after epiphyseal closure. This characteristic allows its identification with a reasonable degree of confidence in dry bones in after skeletal maturity. Females are more commonly affected than males (2:1). It is found most often in long bones (60% 85% of cases) (Flanagan et al., 2015), the preferential areas are the distal femur, proximal tibia (knee involved in 40% 50% of patients), distal radius, and proximal humerus, pelvic bones, and vertebral bodies (Unni and Inwards, 2010). Small bones of the extremities are affected in approximately 5% of the cases (Flanagan et al., 2015). The lesion is an eccentric and well-defined (geographic) osteolytic foci, without sclerotic margins. It usually destroys the original cortex, allowing the formation of a thin periosteal cortical shell, which may have small perforations and reinforcing ridges on the inner surface (Fig. 19.20). This accounts for the radiological “soap bubble” appearance. The lesion often excavates the epiphysis and closely approaches the articular surface, without penetrating into the joint. Pathological fractures through advanced lesions, especially in weight-bearing bones, are not uncommon. The normal consistency and appearance of the rest of the bone and of other bones of the same skeleton should permit differentiation from brown tumors in severe hyperparathyroidism. Clear cell chondrosarcoma has an epiphyseal location and differential diagnosis is difficult, although this condition is relatively rare.

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Intraosseous ganglion shares a similar location, however contrary to GCT it has sclerotic margins.

Vascular Tumors Hemangioma and Vascular Malformations The classificatory scheme of the osseous vascular anomalies remains under debate (Bruder et al., 2009; Kadlub et al., 2015; Van Ijzendoorn and Bove´e, 2017). According to the International Society for the Study of Vascular Anomalies, vascular anomalies comprise developmental vascular malformations and neoplasms. Bruder et al. (2009) argue that localized osseous venous malformations clinically termed hemangiomas of bone may, in most cases, correspond to vascular malformations and are therefore not a true neoplastic condition. While the former

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are alterations in vascular morphogenesis, true hemangiomas are benign neoplasms of endothelial cells (Bruder et al., 2009; Kadlub et al., 2015). The latter are histologically characterized by “numerous smaller or larger bloodfilled spaces, lined by flat endothelium” (Van Ijzendoorn and Bove´e, 2017: 623). Although osseous hemangiomas are considered by Bruder et al. (2009) to be very rare in any part of the skeleton (less than 1% of all primary tumors of bone), contrary to the common vascular malformations; Van Ijzendoorn and Bove´e (2017) argue that in large clinical series, these neoplasms can be found in c.10% of autopsies. A compilation of clinically reported hemangiomas prior to 2000 showed a mean age of 32 years and a slight preponderance in females (Van Ijzendoorn and Bove´e, 2017). The cranium (52%), vertebrae (18%), long bones (18%), and flat bones (9%) are the typical bones FIGURE 19.18 Polyostotic fibrous dysplasia with precocious puberty and skin pigmentations (Albright’s disease). (A) Skull, showing left-sided involvement and deformity. (B) Skull base, showing massive frontal involvement, somewhat resembling Paget’s disease. (C) Vertebrae and ribs, showing multiple pathological fractures. (D) Pectoral girdle and upper extremity, showing abnormal development of the sternum and healed pathological fracture of the left humerus. (E) Both lower extremities with multiple deformities and fractures. (16-year-old, female, 161 bones were affected, FPAM 5807, autopsy 331 from 1949, St. Po¨lten, Austria.)

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FIGURE 19.18 (Continued) FIGURE 19.19 Radiograph of osteofibrous dysplasia of tibia (clinical case). (A) Anterior view showing bilateral involvement. (B) Lateral view. Note the areas of osteolytic activity and sclerosis, with marked anterior bowing. Reproduced with permission from Elsevier, Figure 17.25 in Czerniak (2016).

involved, often with an intramedullary (45%) location; however, periosteal (33%) and intracortical (12%) lesions are possible (Van Ijzendoorn and Bove´e, 2017). Of 149 hemangiomas observed at the Mayo Clinic, 55 cases were

located in the skull and 37 in the vertebrae, with other locations being far rarer (Unni and Inwards, 2010). These vascular lesions do not alter the contour of the vertebral body, and therefore they might be easily missed on

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FIGURE 19.20 Giant cell tumor of distal femur. (A) Outside view, showing enlarged cortical shell with small perforations. (B) Cut surface, showing osteolytic center and ridged cortical shell. (HM P837.)

FIGURE 19.21 Clinical patient with vertebral hemangioma. (A) Notice the characteristic “polka-dot” sign on axial CT. (B) Vertical trabeculae reduced in number and increased in diameter, giving the aspect of vertical striation (“corduroy” sign) in the sagittal CT. (82-year-old, female.) Image courtesy Dr. C. Oliveira.

archeological remains. Characteristically, the lesions show an area of osteolysis with vertical trabeculae coarsening, producing thick vertical striations in radiographs, termed “corduroy” or “honeycomb.” Axial CT images

produce a “polka-dot” pattern, which is rather characteristic (Fig. 19.21) (Bruder et al., 2009; Greenspan and Borys, 2016). Cranially, these lesions show a sharply defined geographic osteolysis, often with a significant

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FIGURE 19.22 Clinical patient with hemangioma of skull. (A) Radiograph of frontal bone with osteolytic lesion showing trabeculations of the bone. (B) Corresponding CT scan with bulging of the lesion. (C) Corresponding bisected bone with honeycomb appearance. (D) Microscopic features. Reproduced with permission from Elsevier, Figure 2 in Van Ijzendoorn and Bove´e (2017).

protrusion of bone contour and a characteristic radial arrangement of coarse diploic trabeculae around large vascular channels (“sunburst,” “honeycomb,” or “spokewheel” effect); however, the spicules tend to be thinner than those observed in malignant neoplasm (Figs. 19.22 19.24; Miller, 2008; Greenspan and Borys, 2016; Van Ijzendoorn and Bove´e, 2017). These lesions may affect the inner and outer tables. Smaller lesions present lytic rarefaction with or without a honeycomb appearance. In dry bones, the condition may be difficult to distinguish from cranial metastases or Langerhans cell histiocytosis, since hemangiomas may also produce multiloculated osteolytic and sometimes sclerotic lesions, which are not sufficiently characteristic for identification in dry bone.

They are characterized by vascular proliferation with well-formed vessels lined by cells that have an endothelial phenotype and epithelioid morphology (Rosenberg and Bove´e, 2013; Czerniak, 2016). The age interval can span from 10 to 75 years (Van Ijzendoorn and Bove´e, 2017). These are uncommon conditions, occurring in many anatomical locations, and are characterized by a well-defined intramedullary osteolytic lesion, sometimes with a radiographic “honeycomb” pattern. There is minimal marginal osteosclerosis or widening of the bone contour. Due to the nonspecific characteristics of this lesion and in the absence of histopathological analysis, its identification in dry bones is difficult.

Meningioma Epithelioid Hemangioma Epithelioid hemangiomas are true vascular neoplasms, classified within the intermediate/locally aggressive category of the WHO classification (Fletcher et al., 2013).

Meningiomas are thought to arise from the arachnoidal (meningothelial, arachnoid cap) cells in the arachnoid villi (Albayrak and Black, 2010). Meningiomas represent approximately 30% of primary brain neoplasms

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FIGURE 19.23 Hemangioma of cranial vault. Transverse cut, showing radiant bone trabeculae between distended marrow spaces, protruding bluntly outward and sharply inward. (35-year-old, female, IPAZ surgical specimen 16132 from 1966.)

(Albayrak and Black, 2010). Most cases are benign, but malignant meningiomas can also occur. In very rare instances, meningiomas can arise as primary tumors of the extradural compartment, including the skull. This rare condition is termed primary intraosseous meningioma (Lang et al., 2000). More common is the extension of a meningioma into an adjacent bone, which occurs in approximately 20% 44% of cases (Erzen, 2010). Meningiomas are known to produce osteolytic lesions, clinically detected in 22% of cases, but osteoblastic lesions are more common (78% of the cases) (Erzen, 2010). Osteolytic lesions show delimited or irregular margins with no specific diagnostic features. Osteosclerotic lesions lead to increased density of the cortical or cortical and medullary areas, altering the bone contour. These osteosclerotic lesions may be also associated with simultaneous bone destruction (Erzen, 2010). Cranial vault meningiomas may elicit a massive reactive bony response, forming radiating spicules that may project outward from the destroyed outer table (Fig. 19.25). Such findings may be indistinguishable from hemangiomas or osteosarcomas in dry bone, but a destructive defect of the inner table without internal spiculated reactions favors the diagnosis of meningioma. Meningiomas invading the cranial base tend to be more osteosclerotic. Unusually large arachnoid granulation may occasionally create deep, smooth-walled defects in the cranial vault, which are usually lined by a thin internal table. Meningiomas that cause bone destruction may resemble metastatic bone disease. Although aggressive meningiomas may not be malignant, the damage they cause may result in complications that affect biomechanical stability, particularly if the cranial base is involved. Other conditions such as Langerhans cell histiocytosis, fibrous dysplasia, dermoid cysts, and ABC must be considered in the differential diagnosis (Erzen, 2010).

FIGURE 19.24 Hemangioma of frontal bone. (A) Wet specimen, endocranial view, showing spongy bone with large vascular channels. (B) Radiograph, showing the typical “spoke-wheel” effect of cranial hemangioma. (47-year-old, female, 2 years’ duration, PMSG 9/1.741a, surgical specimen 2369 from 1955.)

Cystic Lesions A cyst is a lesion characterized by a fluid-filled cavity enclosed by a lining typically composed of connective tissue. There are several types of cysts that occur in bone, each of which tends to be found in characteristic locations. Simple Bone Cysts Simple bone cysts (unicameral bone cyst, solitary bone cyst) are of unknown etiology, and are most likely developmental or reactive defects, not neoplastic in nature. This lesion is included in the WHO category of tumors of

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FIGURE 19.25 Meningioma of cranial vault of 6 years’ duration. (A) External view; notice the massive bone formation outward. (B) Cut surface; notice the radiant arrangement of the new bone, sclerosis of diploe¨, destruction of both tables, and only slight endocranial buildup. (20-yearold, male, WM N9.2 from 1884.)

undefined neoplastic nature (Fletcher et al., 2013). When fully developed, simple bone cysts consist of a round or oval fluid-filled cystic cavity, which is lined by a thin membranous wall of fibrous tissue. With a male to female ratio of approximately 2:1 to 3:1, this is a relatively common finding for individuals younger than 20 years of age, but such lesions may be carried into adult age. Simple bone cysts are most common in long bones; however, in older individuals they can occur in the ilium, talus, and calcaneus (Mascard et al., 2015). Typically, such cysts start in the metaphysis close to the growth plate (Fig. 19.26) and are located within the medullary cavity central to the bone’s axis and sparing the epiphysis. In the course of longitudinal growth, the cyst tends to migrate toward the diaphysis by interposition of newly formed bone between the cyst and the growth plate. Radiographs of simple bone cysts will show a round or oval geographic radiolucent lesion with sclerotic margins. The cortex may be thinned, scalloped, and ultimately replaced by a newly formed shell of cortical bone, which may occasionally show reinforcing ridges on the inner surface. The lesion is most often unilocular, but in some a prominent inner trabeculation (multilocular) may occur. Pathological fractures through the thin wall are common. There are several conditions that must be considered in the differential diagnosis. ABC, NOF, enchondroma,

FIGURE 19.26 Unicameral bone cyst of proximal left humerus; bisected wet preparation. Notice the thin new cortex and the contact of the cyst with the growth plate. (7-year-old, male, WM S61a.44 from 1905.)

fibrous dysplasia, and GCT of bone, are some of the most relevant; however, in typical cases the location is helpful. Aneurysmal Bone Cyst Primary ABC is a relatively rare lesion, accounting for nearly 2.5% 6% of all primary bone tumors (Czerniak, 2016). WHO classifies the ABC as an intermediate (locally aggressive) lesion, included in the category of undefined neoplastic nature (Fletcher et al., 2013). Recent research has shown recurrent cytogenetic abnormalities (translocation of the USP6/TRE17 oncogene), demonstrating that at least some ABC might be true neoplasms (Bocklage et al., 2014; Mascard et al., 2015). ABC is characterized by numerous blood-filled cystic cavities separated by vascular fibrous tissue septa. The wall contains fibroblasts, myofibroblasts, histiocytes, and multinucleated giant cells, with focal calcified osteoid (Flanagan et al., 2015; Czerniak, 2016). Secondary ABC occurs in association with other conditions (e.g., chondroblastoma, fibrous dysplasia, GCT, osteosarcoma).

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FIGURE 19.27 Aneurysmal bone cyst of left distal femoral metaphysis. (A) Showing a big cystic mass with thin reticulated bony shell. (B) Radiograph of specimen, showing the slight mineralization of the shell and some sclerosis at the deep border. (12-year-old, male, PMES 1 TF 14 (2) from before 1842.)

Primary ABC develops in a wide age range, with predilection for the first two decades of life (75% 90% of the cases) and equal distribution in both sexes or a slight female predilection (Mascard et al., 2015). The lesion can originate in any bone; however, it is commonly found in the long bones and spine, less commonly in the pelvis, craniofacial bones, and bones of hands and feet. In long bones, the location of the primary ABC is usually the metaphysis, and it seldom occurs in the diaphysis or epiphysis. Primary ABC is eccentric in location relative to the axis of the involved bone. It shows a distinct widening of the bone contour, consisting of a thin newly formed shell over the eroded cortex, which accounts for its name (Fig. 19.27). Usually there is no breakthrough of the bony shell, and the contralateral cortex of the involved bone is usually spared. ABCs are usually multilocular, with numerous rounded protuberances, as seen on radiographs (“soap bubble” appearance). In the spine, it usually affects the transverse processes and neural arches. If the lesion is large, defects on adjacent vertebrae can occur. ABCs may be difficult to differentiate from multiple conditions that alter the bone contour, including chondroblastomas, simple bone cysts, GCT of bone, osteosarcomas, NOF, and fibrous dysplasia.

Intraosseous Epidermal Cyst and Dermoid Cyst Intraosseous epidermal (epidermoid) bone cysts are fairly rare. One of the possible mechanisms for the development of these lesions may be ectodermal tissue that becomes trapped during the closing neural tube in the course of

embryonic development (developmental epidermal cysts). The cyst is lined by squamous epithelium and filled with keratin (Arana et al., 1996). Developmental epidermal cysts occur most frequently in the bones of the calvarium, notably in the parietal (35%), frontal (27%), and occipital (19%) bones, and orbit (16%) (Arana et al., 1996). They are usually solitary and small, confined to the diploe¨ and appearing as a small round or anteroposteriorly elongated radiolucent area in radiographs. Occasionally such cysts can become rather large, 10 cm or more in diameter. In these cases, the overlying tables bulge, and may be destroyed. Epidermal cysts may also develop in association with a crushing trauma (epidermal inclusion cyst), particularly in the phalanges, and may displace some squamous epithelium into the fractured bone. This displaced epithelium continues to grow, forming a cystic space in the bone that fills with keratin material. In dry bone this would present as a well-delimited central osteolytic lesion, usually not more than 1 cm in diameter, with or without evidence of a healed fracture. It would be difficult or impossible to distinguish the lesion from the much more common enchondroma. Rare clinical cases of trauma-induced epidermal cysts were reported in other locations, such as the spine or cranium (Park et al., 2003; Kalfas et al., 2012). Developmental and inclusion epidermal cyst presentation is rather nonspecific, and its diagnosis is difficult in dry bones. Small round inclusion cysts may not be distinguishable from the more common vascular lesions, enchondroma, aneurysmal bone cyst, simple bone cyst, Langerhans cell histiocytosis, and any other conditions inducing solitary osteolytic lesions (Arana et al., 1996).

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Paleopathology Osteogenic Tumors

FIGURE 19.28 Cranial defect from dermoid cyst. Notice the smooth destruction of the left frontal bone and supraorbital ridge with inward sloping, slightly sclerotic edges. (61-year-old, male, DPUS 7878 from 1905.)

Dermoid cysts are distinguished from epidermal cysts because they also contain elements of dermal structures, including hair follicles, and sebaceous and sweat glands. They are most frequent along the midline and often in the orbit (Fig. 19.28) or sacrum (Czerniak, 2016). It is noteworthy that the presence of skin appendages can also occur in mature teratomas (sometimes confused with dermoid cysts), which are germ cell neoplasms, but these contain elements of the three embryonic layers: ectoderm, mesoderm, and endoderm. For this reason, teratomas may contain many different types of tissues (e.g., fatty tissue, brain, gastrointestinal tissue, glands, cartilage, bone, teeth). Although teratomas are relatively rare, they are encountered not only in the pediatric population, which is affected mostly by sacrococcygeal, cervical, intracranial, retroperitoneal, or craniofacial teratomas (Isaacs, 2013; Paradis and Koltai, 2015), but in adults as well, often having a gonadal location. Mature teratomas may be of particular interest to paleopathology due to the ability to recognize their osseous and dental components. A few very interesting cases of ovarian (Armentano et al., 2012; Klaus and Ericksen, 2013; Wasterlain et al., 2017) and mediastinal (Charlier et al., 2009) teratomas have been paleopathologically identified so far.

Osteoma Of the primary benign bone-forming tumors known in modem medical practice, only a few have been identified in paleopathology. Osteomas, however, are an exception, being fairly common in archeological contexts. Small “button” osteomas occur primarily on the outer table of the skull vault. Typically, this osteoma is no larger than 4 cm in diameter. It is generally solitary, dense, with little relief, but a slight degree of undercutting at the boundary with normal bone. Some of these lesions have been identified in specimens with considerable time depth. For example, Curnoe and Brink (2010) reported a small (4.4 3 3.9 mm) ivory osteoma in the frontal bone of the Middle Pleistocene (c. 259,000 6 35,000 years) Florisbad cranium (Free State, South Africa). Similar lesions were identified by Pe´rez and Colleagues (1997) in skeletal remains from the Middle Pleistocene site of Sima de los Huesos, Spain. Large osteomas also have been reported, e.g., on a skull excavated near Lima, Peru (NMNH 242462). This tumor measures 2 cm in diameter and almost 4 mm above the plane of normal bone at the center of the lesion (Fig. 19.29; Ortner, 2003). Walker (2012), Moghaddam et al. (2013), and Shin et al. (2015) also have reported osteomas with large dimensions. Less commonly reported in archeological settings are osteomas of the paranasal sinus. Be´raud et al. (1961) describe an osteoma of the ethmofrontal region in a skull of an individual 22 25 years of age at death, from France (cemetery of St. Hermentaire, 11th century) that encroaches on the endocranium (Ortner, 2003). Bourry et al. (1990), Hagedorn et al (2002), Ru¨hli et al. (2004), Campillo (2005), and Riccomi et al. (2018a) reported frontal sinus osteomas in archeological material from France, Egypt, Switzerland, Spain, and Italy, respectively. Premuˇzi´c et al. (2013) noted a large (12.7 mm in diameter) and rounded growth located in the right frontal sinus of a middle-aged female from the medieval site of Vranicanijeva poljana, Croatia. The lesion is composed of dense and homogeneous bone with a smooth surface (Fig. 19.30). Another common type of lesion seen in archeological specimens is a small bony growth that may partially to completely occlude the external auditory meatus (Ortner, 2003). As previously mentioned these must be differentiated from osteomas. Hrdliˇcka (1935) observed that males are far more likely to present with such auditory exostoses than females, and that the prevalence of these lesions increased with the age of the individual. These early findings were corroborated subsequently in several studies ¨ zbek, 2012). Pe´rez et al. (1997) describe one very (see O early case in the paleontological record from the Middle Pleistocene site of Sima de los Huesos, Spain. Chronic

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FIGURE 19.29 Large osteoma of the right parietal in an adult skull from a site near Lima, Peru (NMNH 242462).

FIGURE 19.30 Large frontal sinus osteoma. Notice the dense and homogeneous mass in the radiograph (35 to 50-year-old, female, 16th century, Vranicanijeva poljana, Zagreb, Croatia). Reproduced with permission from Elsevier, Figures 4 and 5 in Premuˇzic´ et al. (2013).

irritation due to exposure to cold aquatic environments or temperature extremes, trauma, inflammation, chronic infection, developmental disorders, or genetic alterations are cited as possible causative factors of auditory exostoses in the clinical and paleopathological literature (Ortner, 2003; Crowe et al., 2010; Baik et al., 2011; ¨ zbek, 2012). High frequenCarbone and Nelson, 2012; O cies of auditory exostoses in association with activities related to diving in cold water have long been hypothe¨ zbek, 2012). Differences in the sized (for a review see O prevalence of external auditory exostoses in two Neolithic sites from Anatolia (17.5% in C¸ayo¨nu¨1 and 3.6% in A¸sıklı Hu¨yu¨k) were also attributed to differences in exposure to aquatic environments between the two groups, an inference supported by local archeologi¨ zbek, 2012). cal findings (O There are numerous examples of auditory exostoses in the collections of the National Museum of Natural History (Ortner, 2003). Only two will be described here. The first of these is an adolescent skull from Chicama,

Peru (NMNH 264344), illustrating what appears to be the incipient stage of this condition (Fig. 19.31). All secondary teeth have erupted. The basioccipital synchondrosis is not fused, indicating an age of around 18 years at the time of death. The sex is thought to be female. Both auditory canals exhibit narrowing; the right auditory meatus has a slight, hypertrophic ridge that may represent the early stage of development. The second skull is from an adult male, recovered in present-day Illinois (NMNH 243180). Like the previous specimen, the auditory canals are abnormally narrow. In addition, there are large bilateral bony excrescences (Fig. 19.32). Both arise from the posterior portion of the canal (Ortner, 2003). Osteoid Osteoma and Osteoblastoma Osteoid osteoma was the diagnostic proposal made by Randolph-Quinney et al. (2016) for the osseous changes detected in the right lamina of the sixth thoracic

670 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 19.31 Bony protuberance of left external auditory meatus of an adolescent skull from Chicama, Peru (NMNH 264344).

FIGURE 19.32 Large bony protuberance of left external auditory meatus of an adult male from an archeological site in Illinois (NMNH 243180).

vertebra in a juvenile male Australopithecus sediba, Malapa Hominin 1 (MH1). The skeleton was recovered from the Malapa site, South Africa, and has a chronology of approximately 1.977 6 0.002 million years. GladykowskaRzeczycka (1997) reported two osteoid osteomas in Polish medieval cemeteries. Farkas et al. (2007) describes one case of osteoid osteoma in a 15 16-year-old skeleton (grave number 1336) from the medieval site of Ba´tmonostor-Pusztafalu, Hungary. This case is very convincing since the radiographs of the midshaft of the left tibia reveal a characteristic cortical radiolucent nidus surrounded by an area of sclerotic bone extending to the medullary cavity. The bone external surface shows thickening and a rough surface. One of the rare cases of osteoblastoma was proposed by Riccomi et al. (2018b) in the skeletal remains of a male of 25 35 years excavated from the cemetery of S. PietroPava, Siena, Italy (10th 12th centuries AD). An oval bone formation was observed in the right frontal sinus (Fig. 19.33). The conebeam CT image provides a clear

recognition of a central radiolucent nidus surrounded by an ovoid area of radiodensity (11 3 4.8 mm) (Riccomi et al., 2018b). Despite the rarity of osteoblastoma development in the paranasal sinuses, the lesion presentation has some features compatible with osteoblastoma/ osteoid osteoma.

Chondrogenic Tumors Chondroma A few examples of enchondromas have been proposed (e.g., Armelagos, 1969; Carter and Anderson, 1996; Ciranni et al., 2006; Baxarias, 2007; Charlier et al., 2012; Polo-Cerda´ and Flores, 2009), including multiple enchondromas as those observed in the left hand of an adult male skeleton from the medieval cemetery of Auricarro, Italy (Ciranni et al., 2006). This individual exhibits a well-defined alteration of the bone contour (shell-like), with smooth surface, of considerable size (3 cm) on the palmar surface of the proximal phalanx of the second

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FIGURE 19.33 Macroscopic view of right frontal sinus with a possible osteoblastoma (25 35-year-old, male, 10th 12th centuries, cemetery of S. Pietro-Pava, Siena, Italy). Image courtesy Prof. G. Fornaciari.

FIGURE 19.34 Enchondromas on left hand (second metacarpal, first and second phalanges). (A) Macroscopic view of the multiple enchondromas (arrows) showing widening of the bone contour, and severe bulging on the phalanges. (B) Corresponding radiograph showing heavily mineralized matrix, widening of the bone contour, and endosteal scalloping. (40 45-year-old, male, 11th 14th centuries, Auricarro, Italy.) Image courtesy Prof. G. Fornaciari.

digit. A smaller ovoid neoformation (1.5 3 1.0 cm) in the intermediate phalanx, and enlargement of the diaphysis of the second metacarpal bone was also noticeable. The radiographic images show several typical aspects of hand

enchondromas, namely the formation of a new cortical “shell,” lobulated margins of the lesion, tenuous scalloping of the inner cortex and irregular (punctate, flocculent) densities (Fig. 19.34). An enchondroma is the most likely

672 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

etiological possibility to a femoral lesion (7 cm) detected in a skeleton exhumed from the Carolingian (AD 770 1020) necropolis of Sant Pere, Terrassa, Spain (McGlynn et al., 2018). The most interesting feature of this case is the radiological observation of stippled and “arc and rings” radiodensities observable on CT scan and located in the medullary cavity of the right femur (Fig. 19.35). The right tibia from a Peruvian skeleton described by Phillips and Verano (2011) provides a good example of a lesion producing cortical “saucerization” (12 3 3 cm), with osteolytic destruction (scalloping) of the outer cortical surface without perforation and associated with a thin and incomplete bone shell of irregular contour (Fig. 19.36). The authors propose a diagnosis of a subperiosteal ganglion, but the features of the lesion are also suggestive of a large periosteal chondroma, a condition that is rarely reported in the paleopathological literature. Osteochondroma As in clinical settings, both osteochondromas and multiple osteochondromas syndrome are moderately common findings in paleopathology. Murphy and McKenzie (2010) tabulated at least 16 cases of multiple osteochondromas syndrome published in the paleopathological literature. Henderson et al. (2013) identified at least seven cases of osteochondromas in three postmedieval series from Tower Hamlets, London. Recently Antunes-Ferreira et al. (2014) added another example, in which a male skeleton exhibits 46 osteochondromas, sessile and pedunculated, of several dimensions distributed in the metaphyseal and diaphyseal regions of the long bones, as well as in the right os coxa and one right rib (Fig. 19.10). This male skeleton was excavated from a 16th to 19th century site in Setu´bal, Portugal. Another archeological example of multiple osteochondromas is located in the Winchester Saxon skeletal pathology collections of the Natural History Museum, London. This individual (BMNH G932, CG69, TRXL 1085) includes most of the major postcranial bones. The age estimate based on femur length is around 4 years; the sex is unknown. Prominent bony projections can be seen on the distal metaphyses of the left humerus and both femora (Fig. 19.37). The left scapula and both iliac bones are affected as well. Other bones, including the ribs, vertebrae, and tarsals, are normal. Because this neoplasm is usually benign, it is unlikely to have been the cause of death. Sjøvold et al. (1974) describe a most interesting burial from a cemetery on the island of Gotland off the southeastern coast of the Swedish mainland. The burial is dated to about AD 1250 and includes the skeleton of a young female between 17 and 20 years of age and a near-term

FIGURE 19.35 Enchondroma of right distal femoral diaphysis. (A) The eccentric intramedullary mass is visible due to taphonomic cortical destruction. (B) CT images show an irregular (7 3 2.8 cm) lesion, with typical flocculent and “arc and ring” pattern, attached to the endosteal surface. (160-year-old, male, 7th 10th centuries, St. Pere de Terrassa, Spain.) Reproduced with permission from Elsevier, Figures 1 and 2 in McGlynn et al. (2018).

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FIGURE 19.36 Right tibia showing cortical “saucerization” with scalloping of the outer cortical surface without intramedullary involvement (45 55year-old, male, 13th 14th centuries, Punta Lobos, Peru). Image courtesy Prof. J. Verano.

FIGURE 19.37 Multiple osteochondromas in a child’s skeleton from a Saxon cemetery, Winchester, England. Arrows indicate the location of some of the exostoses (BMNH G932, CG69, TRXL 1085).

674 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

exostosis is continuous with the innominate (Ortner, 2003). This feature allows a fairly confident diagnosis for this condition in dry bone. A New World example is seen in a right femur of an adult from Chicama, Peru (NMNH, uncatalogued). There are no other bones associated with the skeleton and the archeological age is unknown. There is a large bony exostosis, which developed between the greater trochanter and the superior surface of the femoral neck. The remaining lesions are in the distal metaphyseal region (Fig. 19.38) and consist of multiple bony projections (Ortner, 2003). Chondroblastoma Smith and Nicosia (2017) propose a diagnosis of chondroblastoma for an osteolytic lesion that perforates the cortex and epiphyseal plate of the right calcaneus in a 14 17year-old from pre-Columbian North America site of Schroeder Mounds (AD B800 1100). The lesion is associated with periosteal reaction. This case illustrates the difficulty of distinction between diverse benign intraosseous neoplasms, intraosseous cysts, or even infection in the presence of solitary osteolytic lesions in atypical anatomical sites.

Fibrogenic, Fibrohistocytic, and Fibro-Osseous Lesions Nonossifying Fibroma

FIGURE 19.38 Probable case of multiple osteochondromas in an isolated right femur of an adult from an archeological site in Chicama, Peru. Medial view of the distal femur; arrows indicate the location of some of the exostoses (NMNH, uncataloged).

fetus. Both skeletons exhibit multiple osteochondromas. The authors suggest that exostoses protruding from the pelvis prevented the birth of the infant and led to the death of both the mother and the fetus (Ortner, 2003). A probable example of what may have been an osteochondroma appears in the right os coxa of a female recovered in a 12th Dynasty rock tomb at Lisht in Upper Egypt (NMNH 256474). The lesion, which measures 25 by 33 mm and extends 18 mm above the plane of the normal adjacent surface, occurs at the junction between the fused pubic and iliac bones. The joint surface of the acetabulum is normal; however, the tumor has extended the anterosuperior margin of the acetabulum. The radiograph of the osteochondroma reveals that the medullary space of the

Anderson (2002) estimates a prevalence of 4.7% (2/43) of NOF in children and adolescents from Norwich, and 0.2% from St. Gregory in Britain archeological sites. The presumptive low frequency of NOF in archeological material when compared with current clinical studies is likely related to a lack of systematic radiographic survey of skeletal remains. The external bone surface may remain unchanged, or it may present a subtle widening of the bone contour. A NOF in the femur of a young adult male individual from the Islamic necropolis of Loule´, southern Portugal, illustrates this point. The visual inspection revealed a slight medial alteration of the diaphysis; however, the radiographic image showed a typical presentation of NOF, with a well-delimited lesion. Lobulated margins were eccentrally located in the distal diaphysis of the femur (see Fig. 19.4). Fibrous Dysplasia Denninger (1931) provides a description of a probable case of polyostotic fibrous dysplasia in an adult male skeleton from a pre-Columbian site in Illinois. The disease affected the bones of the left side of the body. The left side of the skull was deformed, and there was the characteristic shepherd’s crook deformity of the left

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femur. The cortex of the bowed upper end of the left femur is thin. This region has multiple cyst-like lesions revealed in the roentgen film. Postmortem breakage reveals the poorly organized bone partially filling the marrow space. The right femur is not deformed but exhibits some pathological changes on the proximal end. In the region of the greater trochanter, there are perforations of the cortex with poorly organized, woven bone apparent through the perforations. Similar lesions are found on both tibiae and fibulae. The bones of the left foot show increased porosity of the cortical surface, with cortical perforations and woven bone apparent in the first and second metatarsals. Perforations and woven bone development are also seen in the bones of the pelvis, primarily on the left side. The ribs of the left side are similarly affected as is the seventh cervical vertebra and many of the thoracic vertebrae. Denninger’s description of this case leaves little doubt that this pre-Columbian Indian skeleton is an example of polyostotic fibrous dysplasia (Ortner, 2003). Wells’ (1963) report of an adult skeleton from an Anglo-Saxon site in Britain, dated to the 7th century, provides another example of probable fibrous dysplasia (Ortner, 2003). A possible case of fibrous dysplasia is seen in a young adult female skull from Egypt (NMNH 256360). The skull is from the rock tombs at Lisht, a 12th Dynasty site near Matanieh in Upper Egypt. The skull is fragmentary but includes much of the vault and face. The abnormality is limited to the frontal bone in the region of the frontal sinus. Indeed, it was a postmortem break in the skull in this region that revealed the presence of dense round nodules of bone near the frontal sinus and coarse bony spicules covering the internal bony surface of the sinus cavity (Fig. 19.39). The gross morphology of the lesions is compatible with a diagnosis of either Paget’s disease or fibrous dysplasia. The young adult age estimate would,

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however, make Paget’s disease unlikely. A ground section through one of the circular nodules of bone reveals a mixture of well-organized lamellar bone and poorly organized woven bone. There is no evidence of the characteristic mosaic pattern associated with Paget’s disease. The combination of fiber bone proliferation, the lack of mosaic pattern in the histology, and the young age of the specimen support a diagnosis of fibrous dysplasia, although a very mild expression of this disease (Ortner, 2003). Willmon et al. (2013) reported a case of fibrous dysplasia diagnosed through the presence of an enlarged left temporal bone with radiopaque and radiolucency areas, as seen on CT imaging. The cranium belongs to an adult excavated from the pre-European (14th century) site designated by Glen Williams Ossuary, near Toronto, Canada. A possible case of fibrous dysplasia causing facial deformity was also identified in the cranial bones and mandible of a 6 7-year-old recovered from the Anglo-Saxon Cemetery at Spofforth, North Yorkshire, dated from the 8th to 12th centuries AD (Craig and Craig, 2013). Monge et al. (2013) proposed the diagnosis of fibrous dysplasia to the rib lesion of a (c. 120,000 years) Neandertal from Krapina, Croatia.

Osteoclastic Giant Cell-Rich Tumors Giant Cell Tumor of Bone In a brief description of a mandibular lesion affecting the left mandibular condyle, Sawyer et al. (1988) emphasize the difficulties of differential diagnosis in archeological human skeletal remains. The case is from an archeological site in Chile dated around AD 1100 1200 and includes the skull and mandible of a woman about 25 30 years of age when she died. The lesion consists of the enlargement of the left condyle, which in the radiograph presents as bubbles surrounded by thin walls of

FIGURE 19.39 Probable fibrous dysplasia in the region of the frontal sinus. Note roughened texture and nodular fiber bone proliferation (arrows) (NMNH 256360).

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bone. The authors suggest several options in differential diagnosis but conclude that GCT or a cartilage neoplasm such as osteochondroma is the most likely cause of this lesion (Ortner, 2003).

Vascular Tumors Hemangioma and Vascular Anomalies These lesions have been sporadically reported in the paleopathological literature and are often part of the differential diagnosis of cranial vault alterations. One of the earliest cases of vascular lesion/hemangioma was detected in the Neolithic French site of Trou Perdu, Villars-le`s-Blamont (Doubs) by Aime et al. (1993). The right parietal bone of an adult male (45 70 years at death) exhibits a small round osteolytic lesion (20 mm in diameter) located on the diploe¨ and outer table that has an irregular contour with some porosity and radially oriented coarse trabeculae between distended marrow spaces, in a honeycomb appearance which is common in these conditions (Fig. 19.40).

Meningioma A considerable number of meningiomas have been described from diverse chronological and geographic archeological contexts (for an extended review see Brothwell and Brothwell, 2016). Rogers (1949) briefly describes two skulls from Egypt having lesions, which he attributes to meningiomas. The first of these is from the First Dynasty and shows a hyperostotic lesion of the right parietal involving both the inner and the outer table. The second specimen is from the 20th Dynasty and exhibits a large honeycomb lesion with a focus in the right parietal

but involving the left parietal and the frontal bone. The lesion is large and includes most of the right parietal. It is not clear whether the inner table was involved (Ortner, 2003). A medieval example of hypertrophic meningioma is from an archeological site in Rochester, England (Anderson, 1992). The skull of an adult from a site in Chavina, Peru, studied by Don Ortner at the Museum of Man in San Diego, California, provides an example of a bone-forming meningioma (catalog no. 1915-2-158). The large lesion primarily involves the left frontal and parietal bones (Fig. 19.41) with large pores in the surface reflecting the relatively rapid growth of the bone in an axis perpendicular to the outer table (Ortner, 2003). Abbot and Courville (1939) also described two meningioma cases in two skulls located in the Museum of Man, San Diego, California (Ortner, 2003). MacCurdy (1923: 264, plate 39) describes an adult male cranium from Paucarcancha, Peru, with a large tumor of the left parietal and frontal bones, which is probably the same Peruvian cranium described later by Abbot and Courville (1939). The coalescing osteophytes extend outward from the vault about 4.5 cm, with both tables of the cranium destroyed beneath the tumor. MacCurdy attributes this tumor to osteosarcoma, but a meningioma would seem more likely (Ortner, 2003). A possible example of meningioma has been reported in the skull of an adult male between 35 and 40 years of age at the time of death (Campillo and Salas-Cuesta, 1995). The case is from a historic period site in Mexico. There are two lesions associated with this case. The most prominent lesion involves the formation of porous, poorly organized bone in the left lateral frontal bone

FIGURE 19.40 Right parietal bone showing radially oriented coarse trabeculae in a honeycomb appearance, possibly caused by a vascular lesion/hemangioma (45 70-year-old, male, Neolithic period, Trou Perdu a` Villars-les-Blamont (Doubs), France). Image courtesy Dr. M. Billard.

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FIGURE 19.41 Osteoblastic meningioma of the frontal bone. (A) Anterior view of skull with lesion on the left frontal bone. (B) Left lateral view, showing encroachment of meningioma on the left parietal bone. (Adult skull from Chavina, Peru, Museum of Man, San Diego California, Catalog No. 1915-2-158.)

extending to the greater wing of the sphenoid. The lesion has also affected the lateral wall of the left orbit. The second lesion occurs in the occipital bone (Ortner, 2003). An adult male from St. Lawrence Island, Alaska (NMNH 280091), exhibits lesions that may be an example of an osteolytic meningioma. The archeological provenience is not certain but is most likely historic. The individual is likely a male at 45 65 years of age. The mandible is missing, as are all the postcranial bones. On the external table of the vault, there is a diffuse porosity, which is also seen to a more limited degree on the nasal bones and maxilla. There has been some postmortem erosion that obscures the surface texture somewhat, but the remaining surface has a pumice-like quality. In the posterior portion of the left parietal the most dramatic feature is a large osteolytic lesion, which is confluent with a smaller osteolytic lesion encroaching on the right parietal (Fig. 19.42). The larger of the two osteolytic lesions has a maximal diameter of 4 cm and a slightly scalloped but well-circumscribed appearance, with the inner table somewhat more affected than the outer. The smaller osteolytic lesion is similar in appearance but less well circumscribed, suggesting osteolytic activity at the time of death. Other smaller lesions occur primarily on the left side of the skull with only one moderately large lesion, which measures 1.5 cm in diameter, in the right temporal bone and which also involves the sphenoid. The skull is somewhat thicker than normal, measuring 1.3 cm near the edge of the major osteolytic foci. In addition to meningioma, there are several conditions that could give

FIGURE 19.42 Multiple lytic lesions of the skull possibly due to meningioma. Adult male from an archeological site on St. Lawrence Island, Alaska. (A) Posterolateral view, showing large lesion on the left parietal. (B) Detailed view of large, parietal bone lesion; note the partial bony fill-in of the exposed diploe¨ in the larger lesion. (NMNH 280091.)

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rise to the type of lesions seen in the skull. Langerhans cell histiocytosis and epidermal inclusion cyst produce lesions similar to that seen in this skull. Metastatic carcinoma and angiosarcoma are also possibilities (Ortner, 2003). Another possible example of an aggressive, destructive meningioma is seen in the cranium of an adult male from a historic site on Unalaska Island, Alaska (NMNH 378717). This lesion occurs in the base of the cranium with a primary focus in the region of the basioccipital synchondrosis. However, the osteolytic process extends laterally to include a large area of the left temporal bone, where there is a large osteoblastic lesion that involves the left greater wing of the sphenoid, the temporal bone, and the lateral surface of the left orbit. Diagnostic options include a variety of head and neck malignant neoplasms (Ortner, 2003). Weber and Czarnetzki (2002) propose a diagnosis of primary intraosseous meningioma for the hyperostosis observed in a skull from an ossuary in Vaihingen, Germany. However, the distinction from a primary meningioma and an osseous extension following a softtissue meningioma is difficult to establish. Brothwell and Brothwell (2016) recently reported an illustrative case of a meningioma in an adult male skeleton from Medieval Tarbat, Scotland. The lesion involves the inner and outer tables of the cranium. The outer table shows an abnormal formation of porotic bone (4.2 3 3.7 cm) posterior to the

coronal suture near the bregma and extending over the sagittal suture. Endocranially, the corresponding area shows a zone of bone destruction with irregular margins (2.9 3 3.2 cm) and 5 mm deep. Axial CT imaging shows an alteration of the outer contour and remodeling of the outer table as well as adjacent destruction of the inner table, features often described in clinical cases (Fig. 19.43). This case report provides an excellent illustration of the expected osseous presentation of meningiomas. It also emphasizes the importance of radiological imaging for the evaluation of lesion features and their distinction from, e.g., hemangiomas due to the absence of honeycomb or sunburst patterns.

Cystic Lesions Reports of bone cysts in the paleopathological literature are uncommon. Lagier et al. (1987) describe a possible case of a solitary bone cyst in a child from an archeological site in Switzerland dated between the fifth and seventh centuries. The lesion occurs in the proximal diaphysometaphyseal portion of the right femur. The lesion shows an osteolytic nature that has been partially filled in by poorly organized, fibrous bone (Ortner, 2003). A possible solitary bone cyst also was reported in the right radius of a 14-year-old individual from the late Neolithic site of Yermenonville, in France (Kacki et al., 2010). The lesion is ovoid with well-demarcated borders surrounded by

FIGURE 19.43 Possible skull meningioma. (A) Notice the ectocranial lesion with new bone formation and pitting. (B) Endocranial lesion. (C) CT scan shows bulging of the calvaria with new bone formation and bone destruction of the endocranial surface. (D) CT scan showing thinning of the outer table. (Adult male, Medieval, Tarbat, Scotland.) Reproduced with permission from Elsevier, Figures 2 and 3 in Brothwell and Brothwell (2016).

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FIGURE 19.44 (A) Widening of the bone contour in distal right radius (arrow). (B) Radiograph shows an oval geographic osteolytic lesion with surrounding sclerosis. (114-year-old, Neolithic period, Dolmen of Yermenonville, France.) Image courtesy Dr. S. Kacki.

sclerotic reaction (Fig. 19.44). Aside from a solitary bone cyst, osteoid osteoma and NOF are also conditions that should be included as diagnostic possibilities. A cystic cavity with well-defined borders and smooth walls was noticed in the left ilium of a 15-year-old individual exhumed from the medieval site of St. Mary Spital, London. Walker (2012) suggests a possible ganglion cyst as the most likely cause. A possible case of an epidermal cyst from an archeological site in the American Southwest dates to between the 13th and 17th centuries (NMNH 271858). The lesion occurs in the frontal bone of an adult female skull

(Fig. 19.45). The cyst has prevented development of both the diploe¨ and the inner and outer table of compact bone at the site of the lesion. The margins of the lesion are very well defined and clearly sclerotic. The radiograph shows no evidence of abnormal bone beyond the sclerotic margin of the lesion (Fig. 19.45B), which is further evidence of the benign nature of the lesion (Ortner, 2003). Despite their rarity today, there are other publications referring to epidermal cysts in the paleopathological literature, e.g., in Campillo (2005), Oxenham et al. (2005), Hublin et al. (2009), or Klaus and Byrnes (2013).

680 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

Registries from the National Cancer Institute Surveillance Epidemiology and End Result (SEER) in the United States between 1973 and 2010 indicate that osteosarcomas accounted for 35.7% of the primary malignant bone neoplasms, while chondrosarcomas represented 27.4%, Ewing sarcoma family tumors represented 13.6%, and chordomas 7.7% (Czerniak, 2016). All other types of primary bone malignancies are rare (undifferentiated highgrade pleomorphic sarcoma of bone, fibrosarcoma of bone, malignant fibrous histiocytoma, angiosarcoma, adamantinoma, epithelioid hemangioendothelioma, leiomyosarcoma, and liposarcoma of bone). The following review will be limited to the aforementioned most common four main primary malignant bone neoplasms and adamantinomas that, albeit rare, have a peculiar osseous presentation.

Osteosarcoma

FIGURE 19.45 Probable epidermal inclusion cyst. (A) Defect of the frontal bone, showing the sclerotic margin of the lesion. (B) Anteroposterior radiograph of skull, showing defect with well-defined sclerotic margin and normal bone beyond the margin. (Adult, female from Kwasteyukwa, New Mexico, dated between the 13th and 17th centuries, NMNH 271858.)

PRIMARY MALIGNANT BONE TUMORS Pathology Except for hematopoietic neoplasms (see Chapter 14), primary malignant bone neoplasms are comparatively rare in contrast to other malignant neoplasms of the body. They represent ,6% of childhood/adolescent and ,1% of adulthood malignant neoplasms (Ottaviani and Jaffe, 2009). Primary malignant bone neoplasms have an estimated annual incidence of 0.8 2 per 100,000 individuals in North America and Europe, corresponding to less than 0.2% of all malignant neoplasms (Grimer et al., 2013; Hauben and Hogendoorn, 2015; Czerniak, 2016). Osteosarcomas, chondrosarcomas, Ewing sarcomas, and chordomas are the most common in decreasing frequency.

This malignant neoplasm accounts for the great majority of bone sarcomas. Data from the SEER estimate an average annual incidence of 4 5 per million (Bocklage et al., 2014). Osteosarcomas are characterized by the proliferation of bone-forming mesenchymal stem cells or from cells at different stages of osteogenic differentiation, capable of producing osteoid matrix or immature bone (Broadhead et al., 2011; Singer et al., 2015; CletonJansen, 2015). These neoplasms show high genomic instability, with multiple and complex cytogenetic and molecular alterations identified up to now (Broadhead et al., 2011; Singer et al., 2015; Cleton-Jansen, 2015). Osteosarcomas comprise a group of diverse clinical, histological, and morphologic variants: conventional osteosarcoma (chondroblastic, fibroblastic, osteoblastic), telangiectatic osteosarcoma, small cell osteosarcoma, low-grade central osteosarcoma, periosteal and parosteal osteosarcomas, high-grade surface osteosarcoma, and secondary osteosarcoma (Fletcher et al., 2013). Conventional osteosarcoma is the predominant subtype (approximately 90% of osteosarcomas), and as such will be described here along with the parosteal and periosteal osteosarcomas due to their peculiar skeletal presentation. Conventional osteosarcomas have a bimodal age distribution, with one peak occurring between the ages of 10 20 and a lesser proportion of cases developing in individuals older than 50 years. Males are more commonly affected than females (1.3:1 to 1.6:1) (Ottaviani and Jaffe, 2009; Broadhead et al., 2011; Rosenberg et al., 2013). The development of osteosarcomas, as a group, is closely related to the areas and periods of greatest endochondral growth (a milieu rich in growth factors and increased cell turnover increases the risk for malignant transformation), whereas the second peak is related to secondary development of the disease (Ottaviani and Jaffe, 2009; Broadhead et al., 2011; Bocklage et al., 2014).

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Osteosarcomas can develop in any bone, however, the most common expressions are within the growth plates of the femur (42%), tibia (19%), and humerus (10%) (Ottaviani and Jaffe, 2009). Involvement of the pelvic bones (8%), mandible and craniofacial bones (8%) is also possible, particularly in older patients (Unni and Inwards, 2010). When located in long bones, the epiphyses are practically never the primary site (,1%) and often remain uninvolved, protected by the cartilage growth plate. If this area becomes involved, the joint surface usually remains intact. Diaphyseal involvement is also less frequent (9%), as the condition arises preferentially at or near the metaphyseal side of the growth plate (90%) (Rosenberg et al., 2013; Bocklage et al., 2014). Conventional osteosarcomas arise within the bone, with variable amounts of normal bone being destroyed, but it usually extends through the cortex into the surrounding soft tissue. The appearance of the lesions ranges from almost purely osteolytic forms, with large and ill-defined

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lesions (Fig. 19.46), to those with massive sclerosis (Fig. 19.47). A combination of both features is also common. On radiography, radiodensities with ground-glass, “cloud-like” solid, or ivory-like patterns are possible (Czerniak, 2016; Ragsdale et al., 2018). The extracortical portion of the neoplasm may elicit a variety of prominent periosteal reactions, including multiple layers (“onion skin”), Codman’s angle, or a radiant alignment, the socalled “sunburst” pattern (Figs. 19.48 19.50). Osteosarcomas metastasize most frequently to the lungs and liver, but they can also extend to other bones (Fig. 19.51). In 1952 osteosarcoma cases from the Mayo Clinic files, 42 had more than one bone affected, demonstrating the relative rarity of these occurrences (Unni and Inwards, 2010). Parosteal (originating on the outer layer of the periosteum) and periosteal osteosarcomas (arising in the inner layer of the periosteum or outer cortical surface) are two variants of surface (juxtacortical) osteosarcomas

FIGURE 19.46 (A) Gross specimen of a low-grade fibrous osteosarcoma in the distal femur (clinical patient). Notice the neoplastic mass and extensive osseous destruction including cortical perforation. The elevated periosteum is visible. (B) Dry bone osteolytic osteosarcoma of distal right femur, anterior view. Notice cortical destruction and hypervascularity. The epiphysis was spared. (13-year-old, female, CGH surgical specimen 2229 from 1957.) (A) Reproduced with permission from Elsevier, Figure 16.52 in Bullough (2010).

682 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 19.47 (A) Gross specimen showing an osteoblastic osteosarcoma in the distal femur (clinical patient). The lesion extends through the cortex and to the epiphysis. (B) Corresponding radiograph with a solid pattern of matrix mineralization. (C) Dry bone osteoblastic osteosarcoma of distal femur. Outside view, showing extraosseous portion of tumor extending to knee joint. (D) Corresponding cut surface, showing bone filling the medullary cavity. (Young adult, male, died with pulmonary metastases, HM P826 from 1786.) (A) and (B) Reproduced with permission from Elsevier, Figure 16.44 in Bullough (2010).

FIGURE 19.48 (A) Radiograph and (B) CT image of rib osteosarcoma (clinical patient). Notice the “sunburst” pattern. Osteolytic activity and extension of the lesion to the soft tissue is visible. (6-year-old, male.) Image courtesy Dr. C. Oliveira.

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(Murphey et al., 2004; Czerniak, 2016). Parosteal osteosarcomas are low-grade neoplasms (Klein, 2007; Lazar and Mertens, 2013) and the most common form of surface osteosarcomas. Their occurrence is more evenly spread

FIGURE 19.49 Osteosarcoma of left frontoparietal area. The irregular bone projecting outward is similarly projected endocranially. Specimen recovered from a grave. (Adult, ANM 2042.)

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throughout adult ages, and they are most commonly located on the distal metaphysis of the femur posteriorly (Fig. 19.52) or on the proximal tibia and humerus. This neoplasm is slow-growing and produces large, extraosseous masses of dense bone attached to the cortex in a wide base (Fig. 19.53A) (Lazar and Mertens, 2013). The mass generally has a multiloculated surface. Penetration into the marrow cavity is late or absent (Fig. 19.53B). Differentiation from myositis ossificans may be a challenging exercise in cases lacking medical history and tumor histopathology; parosteal osteosarcoma, however, tends to be denser centrally when compared to myositis ossificans. Periosteal osteosarcoma is an intermediate- to lowgrade neoplasm. It elicits prominent periosteal new bone formation. In long bones, these lesions can be diaphyseal. It shows frequent involvement of the femur and tibia (85% 95%), ulna and humerus (5% 10%), or fibula and pelvis (Murphey et al., 2004). The clavicle, ribs, cranium, and mandible are less frequent sites of involvement. Analysis of imaging records from 40 patients with periosteal osteosarcoma by Murphey et al. (2004) showed that spiculated reaction (“hair-on-end” or “sunburst”) occurred in 95% of cases, cortical erosion of the underlying cortex FIGURE 19.50 Osteoblastic osteosarcoma of distal left femur. (A) Surface. (B) Cut surface. Notice extensions of bone through the cortex into soft tissue and reactive bone at proximal tumor margin (Codman’s angle). (12-year-old, male, MGH surgical specimen 11078 from 1972.)

684 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 19.51 Metastatic osteosarcoma of ninth thoracic vertebra. (A) Lateral view, showing a dense sclerotic lesion. (B) Cut surface, showing ivory-like pattern. There was a smaller second focus in the 12th thoracic vertebra. (20-year-old, male, FPAM 3171, autopsy 56719 from 1870 1871.)

(“saucerization”) in 92%, cortical thickening in 82%, and mineralization of soft tissue in 68%. Codman’s angle was also frequently seen in Murphey and Colleagues’ (2004) study. Extension into the medullary canal was rare. This lesion may be very hard to differentiate from other malignant neoplasms or even from infections. In older ages, secondary osteosarcomas develop in association with preexisting conditions. Paget’s disease of the bone, chronic osteomyelitis, fibrous dysplasia, bone infarct, hereditary retinoblastoma, osteoblastoma, Li Fraumeni, and Rothmund Thomson syndromes are all conditions associated with the development of secondary osteosarcomas (Klein, 2007; Grimer et al., 2013). Overall, the patterns of bone formation and destruction observed in osteosarcomas can be variable. They are extremely difficult to distinguish in dry bone from osteomyelitis, aggressive forms of osteoblastoma, Ewing sarcoma family of tumors, chondrosarcoma, lymphoma, or solitary metastases.

Chondrosarcoma

FIGURE 19.52 Parosteal osteosarcoma of distal left femur. (Young adult, FPAM 2102 from before 1848.)

Chondrosarcomas are the second most common bone sarcoma (Unni and Inwards, 2010). They are cartilaginous matrix-forming neoplasms thought to develop from mesenchymal stem cells that undergo chondrogenic differentiation (Boeuf et al., 2008; Cleton-Jansen, 2015; Czerniak, 2016). A malignant transformation of a previously benign

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FIGURE 19.53 Parosteal osteosarcoma of proximal right tibial metaphysis. (A) External view, showing layer of reactive bone at junction of cortex and the neoplasm. (B) Cut surface, showing dense radiating bone. Notice slight involvement of underlying cortex. (Young adult, FPAM 3639 from 1878.)

cartilage neoplasm is also hypothesized (Bove´e et al., 2010). Frequent mutations observed in this group of neoplasms occur in the isocitrate dehydrogenase (IDH) genes, COL2A1 gene, TP53 and RB genes (Singer et al., 2015; Czerniak, 2016). The age distribution is broader than that for osteosarcoma but shows a tendency to occur in older individuals, with a slightly higher incidence in males (Bocklage et al., 2014). Chondrosarcomas may be distinguished into different histologic subtypes: conventional chondrosarcoma (grade I, II, III), dedifferentiated chondrosarcoma, mesenchymal chondrosarcoma, and clear cell chondrosarcoma. The most common (85% 90%) of these subtypes is the conventional chondrosarcoma (Rosenberg et al., 2013; Bocklage et al., 2014), as described here. Conventional chondrosarcomas are most commonly located in the pelvic bones, ribs, proximal femur, humerus, tibia, or scapula. Yet they can arise in any bone formed through enchondral ossification. The small tubular bones of the hands and feet or craniofacial bones are rarely affected (Unni and Inwards, 2010; Bocklage et al., 2014). The soft-tissue masses tend to be nodular and are associated with cancellous bone destruction and accentuated endosteal scalloping (Fig. 19.54). In radiographs, it appears as a demarcated radiolucent intramedullary lesion with poorly defined margins. Widened bone contour (bone shell) with focal cortical thinning or cortical

thickening with periosteal reaction (irregular or “onion skin”) may also occur. Cortical penetration is a predominant feature of flat bone chondrosarcomas, and it is a feature of more advanced lesions in long bones (Fig. 19.55). The more mature forms of chondrosarcoma tend to undergo matrix mineralization. Only such chondrosarcomas would show characteristic features in dry bone subject to radiological analysis, as stippled, flocculent, or “arcs and rings” densities, typically of 1 4 mm in size. Although the matrix mineralization of a chondrosarcoma tends to be more mature and orderly than that of an osteosarcoma, the differentiation between the two may be difficult in dry bone. Periosteal (juxtacortical) chondrosarcomas (Fig. 19.56) are typically located in the metaphysis of long bones. The soft-tissue mass has sharply defined borders and may show a variable degree of matrix mineralization. The underlying cortex may be thickened or show a “saucerization,” which can be identified in paleopathology. Differential diagnosis of chondrosarcomas must take into account conditions such as osteosarcomas and GCT of bone. Benign cartilage neoplasms must also be included in the differential diagnosis, but those show less aggressive features and tend to form sclerotic borders around the neoplastic focus, a milder endosteal scalloping, and a more uniform or minimal cortical thinning than the malignant forms.

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FIGURE 19.54 Intramedullary chondrosarcoma (9.5 cm) of the metadiaphysis of proximal femur (clinical patient). Notice the neoplastic cartilaginous mass of lobulated contour and endosteal scalloping. There is minimal alteration of the external bone contour. In dry bone such changes would be undiagnosed in the absence of radiographic examination. Reproduced with permission from Hindawi Publishing Corporation, Figure 2 in Kim et al. (2011).

Ewing Sarcoma of Bone Ewing sarcoma includes a family of neoplasms (classic Ewing sarcoma, peripheral neuroectodermal tumor, and Askin tumor) that are relatively common. Ewing sarcoma of bone is the third most frequent bone sarcoma, and it is the second most common bone sarcoma of childhood and adolescence (Unni and Inwards, 2010; Alava et al., 2013; Redini and Heymann, 2015). SEER data point to an average annual incidence of 1.1 per million (Bocklage et al., 2014). Ewing sarcoma is a small round-cell neoplasm, which does not produce extracellular matrix of any kind. The cell of origin is not fully determined, although mesenchymal stem cells or neural crest-derived stem cells have been hypothesized (Alava et al., 2013; Singer et al., 2015; Cleton-Jansen, 2015; Redini and Heymann, 2015). Ewing sarcoma family of tumors cell’s signature is a characteristic chromosomal translocation that fuses the EWSR1 gene (translocation of chromosomes 11 and 22) to a member of the ETS gene family (Alava et al., 2013; Singer et al., 2015; Redini and Heymann, 2015).

FIGURE 19.55 Chondrosarcoma (6.5 cm) of the metaphysis of distal femur (clinical patient). Notice the nodular neoplastic masses that extend through the cortex into the soft tissue. Reproduced with permission from Hindawi Publishing Corporation, Figure 1 in Kim et al. (2011).

It occurs most commonly in childhood and adolescence, with a peak incidence at 15 years of age, with more than 80% of the cases occurring in individuals between the ages of 8 and 20 (Klein, 2010). There is a slight male propensity (1.3 to 1.4:1 ratio) (Alava et al., 2013). Although it can arise in any bone, it favors the metaphyseal diaphyseal areas of long bones, pelvic bones, and ribs (Askin tumor), followed by the skull, vertebrae, and scapulae (Alava et al., 2013; Bocklage et al., 2014). In the Mayo Clinic files, most of the 614 cases of Ewing sarcoma were located in the femur (131 cases) and innominate (115 cases) (Unni and Inwards, 2010). Ewing sarcoma produces osteolytic destruction with ill-defined margins (moth-eaten or permeative in radiography). Because the neoplastic cells progress through intertrabecular marrow spaces and generally invade Haversian canals and Volkmann canals of the cortex, small osteolytic foci permeating the cortex are created (Klein, 2010; Czerniak, 2016). The result of this is that a large area of the bone is involved. The destruction of trabecular bone may be less marked, but resorption along Haversian canals leads to lamination of the cortex. When the neoplastic mass is confined between the periosteum and the

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FIGURE 19.56 Parosteal chondrosarcoma of distal right femur. (A) Outside view; notice the nodular character of the mineralized portion of the neoplasm. (B) Cut surface; notice the mature trabecular pattern of the bone replacing the core of the neoplasm. (31-year-old, male, 10 years’ duration, WM S.72a.2 from 1894.)

cortical surface, a concave erosion—produced by osteoclastic action—of the external cortical is formed, giving the radiographic aspect of “saucerization” (Fig. 19.57) (Klein, 2010). Often, the periosteal stimulation elicits reactive bone formation. These bone formations may be multilayered and parallel to the bone surface (“onion skin”) and Codman’s angle or, less commonly, a spiculated pattern (“hair on end” or “sunburst”) (Fig. 19.58) (Klein, 2007, 2010; Alava et al., 2013). Ewing sarcomas may metastasize to the lungs and other bones (Unni and Inwards, 2010). The presence of an osteolytic process and reactive bone makes the distinction between Ewing sarcomas and osteosarcomas or chondrosarcomas difficult in dry bone. The absence of massive destruction and long axial involvement, together with permeative intracortical resorption, would arouse suspicion that the lesion may have been an Ewing sarcoma or a primary lymphoma of bone in adults. In younger individuals, metastatic neuroblastoma and rhabdomyosarcoma must be considered (Klein, 2010). Osteomyelitis and Ewing sarcoma also share similar features in radiographs. Misdiagnosis of Ewing sarcoma as osteomyelitis has been frequently reported in the clinical literature (McCarville et al., 2015).

Chordoma Chordomas are low-grade malignant neoplasms showing notochordal cell differentiation, some deriving from vestigial notochordal remnants, but it is unclear if this is the case for all chordomas (the benign counterpart is called notochordal tumor). SEER data (1994 2008) indicate an

average annual incidence of 0.6 per million (Bocklage et al., 2014). It has a wide age distribution, with an incidence peak in middle-aged adults; males are more commonly affected than females (2:1). Chordomas develop in the axial skeleton, mainly in the sacrococcygeal, sphenooccipital regions, and vertebral bodies (Unni and Inwards, 2010). In radiography it appears as an osteolytic lobulated lesion with speckled areas of radiodensity. In the sphenooccipital region there is destruction of the clivus and sella turcica. The sacral lesion may produce an osteolytic lesion and/or an area of widening of the bone contour. As this feature is nonspecific, identification in dry bone is extremely difficult; however, it should be considered on differential diagnosis of osteolytic lesions located in the neuro-axis.

Adamantinoma Adamantinomas are malignant neoplasms of relative rarity, representing 0.1% 0.5% of all primary malignant bone neoplasms (Bethapudi et al., 2014). The majority occur in the second and third decades of life, yet the age range can be broad. Histologically, adamantinomas consist of spindle-cell, fibro-osseous, and epithelial components. These neoplasms predominantly affect the tibial diaphysis, yet have been observed in other anatomical locations. They consist of a cortical lesion with variable degrees of osteolysis and sclerosis. The osteolytic component may show a single focus or multiple circular or elongated foci interposed with reactive bone. Widening of the bone contour is often observed

688 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 19.57 Ewing sarcoma of the tibia (clinical patient). (A) Radiograph showing a concave cortical erosion (“saucerization”) of the outer surface adjacent to the poorly visible soft tissue mass. (B) Corresponding gross specimen showing the subperiosteal mass and cortical “saucerization.” Notice the small areas of permeation in the diaphysis and the periosteal reaction. Reproduced with permission from Elsevier, Figure 17.2 in Klein (2010).

FIGURE 19.58 Ewing sarcoma of the fibula. (A) Cut surface through the neoplastic bone lesion. Note the porosity of the cortex (permeative margins) and the abnormal bone filling the marrow space. (B) Radiograph of the lesion with “sunburst” pattern. (C) Detail of bone spicules (“sunburst”) in the macerated specimen. (17year-old, male, IPAZ, Catalog No. 24282/72.)

(Fig. 19.59) and is an important condition for the differential diagnosis, as adamantinomas and OFD have similar radiographic characteristics (Bethapudi et al., 2014; Czerniak, 2016; Scholfield et al., 2017).

Paleopathology Primary malignant neoplasms of bone are rare in modern oncological practice and equally rare in archeological

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FIGURE 19.59 Adamantinoma of the tibia (clinical patients). (A) Radiograph shows widening of the bone contour with bowing and multiple osteolytic areas (hollow black arrows). The bone destruction is interposed with sclerosis (42-year-old, female). (B) Radiograph shows a large osteolytic lesion in the mid-tibial shaft and fibula (solid black arrows) with cortical and medullary infiltration. Note the moth-eaten margin inferiorly (hollow black arrow) (38-yearold, male). Reproduced with permission from Elsevier, Figures 4 and 5 in Bethapudi et al. (2014).

contexts. A review of the paleopathological publications of malignant neoplasms by Strouhal and Nˇemeˇckova´ (2009) shows that bone sarcomas accounted for 21 (11.5%) cases out of 183 malignant neoplasms. These reports are mostly of osteosarcomas, chondrosarcomas, and much less frequently Ewing sarcomas. Recently, Ortner et al. (2010), Lo´pez (2011), Henderson et al. (2013), Bona et al. (2014), Arnay-de-la-Rosa et al. (2015), Odes et al. (2016), Molna´r et al. (2017), SmithGuzma´n et al. (2018), and Ruffano and Waldron (2018) added to the number of paleopathological cases on primary malignant osseous neoplasms. It is of note that the work of Bona et al. (2014) also involved the detection of tumor biomarkers (proteomics), an interesting avenue of future research (Nerlich, 2018). Ruffer and Willmore (1914) report a lesion of the pelvis from ancient Egyptian remains dated to about AD 250. The lesion affects the right innominate, particularly the ischium and inferior ilium. It appears to have started in the cancellous tissue of the pelvis and produced a slight enlargement of bone that deformed the obturator foramen and encroached on the acetabulum. The authors rule out bone metastases and infection, suggesting either primary or secondary osteosarcoma. The illustration of the lesion is of little diagnostic value, but it does not show the active irregular growth of bone usually seen in osteosarcoma. The lesion appears to be chronic rather than acute, which

would tend to rule out osteosarcoma. However, a neoplasm of some type is possible, as is infection (Ortner, 2003). Dastugue (1965) describes a tumor of the right maxilla and zygomatic bone on a skull from a site associated with the town of Caen in France dated to the Middle Ages. The tumor measures 60 mm wide by 40 mm high and encroaches on both the nasal passage and the right orbit. The surface of the tumor is very irregular with relatively large coalescing spicules. There are three inferior projections. Curiously, there is antemortem damage to the right zygomatic bone adjacent to the tumor, and Dastugue (1965) suggests the possibility of surgical intervention to explain this defect. The tumor appeared malignant to Dastugue, and he expresses the opinion that was the cause of death. The morphology of the lesion is compatible with a primary malignant neoplasm of bone. However, other possibilities, such as callus following trauma to the face, seem more probable. In view of the injury to the zygomatic bone, trauma rather than surgical intervention is more probable as an explanation of the zygomatic defect (Ortner, 2003). A mandibular tumor was found in an American Indian skeleton excavated in the state of West Virginia, dated to the mid-17th century (Kelln et al., 1967). The case is described in Ortner (2003), referring that the position of the lesion near the symphysis and the young age of the individual are compatible with a diagnosis of primary malignant neoplasm. However, the chin is

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prone to trauma and infection and bony reaction to these morbid conditions is more likely (Ortner, 2003). The three cases aforementioned illustrate the difficulty of differential diagnosis of primary malignant bone neoplasms of the craniofacial region. Another example of a craniofacial osteosarcoma, was recently described. An impressive spiculated bone formation combined with osteolytic activity (Fig. 19.60), is described by Molna´r et al. (2017) in a 40 50-year-old female from the Pusztapa´ka-Na´ndorhalom site in Central Hungary (11th 12th centuries AD). The lesion extends through the ethmoidal sinuses, left orbit, nasal cavities, frontal bone, left maxillary sinuses, and the hard palate. The medial part of the left orbital floor and medial wall of the left maxillary sinus were absent in vivo. Aside from the large area of spiculated periosteal reaction, there is also extensive bone destruction and porosity. Scanningelectron microscopic analysis showed bony spiculae and numerous Howship’s lacunae, but also, according to Molna´r et al. (2017: 585), “at least two different levels of bony tissue, apparently representing different qualities of woven bone. Small regions of lamellar bone which might represent residual autochthonous bone (i.e., remnants of the original bony wall of the nasal cavity or the conchae) were alternating with larger regions of woven bone. Strikingly and in contrast to the external macroscopic view, there were very small areas of lamellar bone which were situated close to the part of the bone sample where the bone had been cut for sampling.” Woven bone coats not only the remnants of existing bone but also areas of osteoclastic resorption. This case is quite convincing and a good demonstration of different types of osteoblastic and osteoclastic processes concomitantly developing in osteosarcomas. This cranium also shows evidence of trephination. Osteolytic and/or osteoblastic lesions of the craniofacial region suggestive of osteosarcomas were detected in other paleopathological studies (e.g., Pahl, 1986; Stroud, 1993; Strouhal, 1994; Strouhal et al., 1997; Campillo, 2005; Nerlich et al., 2006). Campillo (2005) also refers to a possible Ewing sarcoma of the skull in a 18- to 20-yearold male from the Bronze Age site of Cova Joan d’Os; however, the multiple osteolytic lesions with geographic margins observed in this skeleton make the differential diagnosis intricate. The difficulty in diagnosing osteosarcomas of the craniofacial bones is also well-illustrated with skeleton nr. 174, from the 19th to 20th centuries Coimbra Identified Skeletal Collection, Department of Life Sciences, University of Coimbra, Portugal (CISC). In the collection records, the cause of death of this 58-year-old female is indicated as osteosarcoma of the left maxilla (Fig. 19.61). The left maxilla, part of the palate, and the left zygomatic bone were absent antemortem, an inference established due to the partially remodeled borders of these areas. The palate exhibits diffuse pitting, four very small osteolytic

foci (,1.0 cm), and very discrete patches of woven bone, the latter extending to the nasal bones. An area of woven bone proliferation (4.4 3 0.8 cm) is clearly noticeable in the left mandibular ramus. CT scans did not reveal inner osteolytic foci on the mandible or of the cranial vault. The skeleton also has signs of woven bone in the visceral surface of the fourth and fifth left ribs, likely unrelated to the neoplastic condition. The absence of exuberant new bone formation or severe destructive processes would make the diagnosis of an osteosarcoma unlikely if this skeleton was recovered in bioarcheological settings, albeit identified in vivo. These lesions could easily be attributed to trauma or infectious conditions in an undocumented context. It should be noted that the latter may coexist with a neoplasm, as illustrated by skeleton nr. 657 from the 19th to 20th centuries International Exchange Collection, Department of Life Sciences, University of Coimbra, Portugal (IEC). A 17-year-old male whose recorded cause of death is described as “sarcoma of right cervical region with metastases, [and] osteitis of the maxilla” shows antemortem destructive lesions and to a lesser extent new bone formation in the skull, which was the only element present. On the left maxilla there is an osteolytic lesion (2.9 3 1.6 cm) with irregular margins and marginal porosity (Fig. 19.62A) that affects the alveolar process of the second premolar and molars (teeth are missing) and a small part of the left palatine and sphenoid bones. The destructive process is consistent with the neoplastic and metastatic process described in the cause of death. The base of the skull has widespread porosity that in some areas merge into osteolytic foci. The left zygomatic process of the temporal bone was destroyed antemortem. The left temporal and sphenoid bones have osteolytic lesions ( . 5.0 cm) with moth-eaten margins surrounded by woven bone (Fig. 19.62B) with similar lesions severely affecting the mandible (Fig. 19.62C). Superficial porosity was widespread in the outer table of frontal, parietals, and occipital bones. The postcranial skeleton was not recovered. The concomitance of a malignant primary neoplasm of the cervical region, that metastasized, with an infectious process, as described in the cause of death, makes this case quite interesting. It also illustrates the difficulties of the differential diagnosis of these conditions. Long bone osteosarcomas have also been reported in the paleopathological literature (Brothwell, 1967; Suzuki, 1987; Strouhal, 1994; Aufderheide et al., 1997; Gladykowska-Rzeczycka, 1997; Alt et al., 2002; Jo´zsa and Fo´thi, 2003; Farkas et al., 2007; Henderson et al., 2013; Bona et al., 2014; Smith-Guzma´n et al., 2018). Aufderheide et al. (1997) published a probable example of osteosarcoma occurring in the right distal humerus of a 30- to 35-year-old female burial from a site in southern Peru dated between AD 1150 and 1300. The lesion consists of radially oriented spicules of poorly organized

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FIGURE 19.60 Osteosarcoma of skull with prominent bone formation and bone destruction. (A) Bone proliferation in a “sunburst” pattern visible in the orbit. (B) Partial resorption of the posterior wall of the left maxillary sinus. (C) Scanning-electron microscopy (20 kV and 5 8 mm distance) of the orbital roof lesion. (40 50-year-old, female, 11th 12th centuries, Pusztapa´ka-Na´ndorhalom, To¨ro¨k Aure´l Collection of the Eo¨tvo¨s Lora´nd University, Hungarian Natural History Museum, Hungary.) Macroscopic images courtesy Prof. Erika Molna´r and Dr. Tama´s Hajdu and SEM image courtesy Dr. Krisztina Buczko´.

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FIGURE 19.61 Osteosarcoma of the maxilla. (A) Absence of the left maxilla and adjacent bones. (B) Palate with small osteolytic foci (white arrows) and generalized pitting. Poorly visible woven bone. (C) Mandibular ramus with a patch of woven bone. (Sk. no. 174, 58-year-old, female, death in 1926, cause of death: osteosarcoma of the left maxilla, CISC, Portugal.)

FIGURE 19.62 (A) Osteolytic lesion (2.9 3 1.6 cm) that affects the alveolar process (black arrow), the left palatine, and sphenoid bones. The base of the skull has porosity, in some areas merging into a larger osteolytic focus (white arrow). (B) Left temporal and sphenoid bones with an area of osteolysis. (C) Mandible with similar destructive process. (Sk. no. 657, 17-year-old, male, death in 1931, cause of death: sarcoma of right cervical region with metastases and osteitis of the maxilla, IEC, Portugal.)

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FIGURE 19.63 Osteosarcoma or chondrosarcoma of the proximal left humerus of a Celtic warrior (approximately 800 600 BC) found near Muensingen, Canton Bern, Switzerland. (A) Medial view; note that the articular surface is spared. (B) Lateral view. (C) Radiograph. (NHMB A95.)

woven bone. The authors include Ewing sarcoma, hemangioma, meningioma, and metastatic bone disease in their differential diagnosis, but they conclude that the best diagnostic fit is with osteosarcoma. Another example of a primary malignant neoplasm of bone is found in the skeletal collections of the National History Museum in Bern, Switzerland. The left humerus from a Celtic warrior tomb (NHMB A95) dated to approximately 800 600 BC and found near the town of Muensingen, Canton Bern, exhibits a possible lesion described in Brothwell (1967). Although damaged by postmortem erosion, the humerus is complete except for the distal epiphysis, which was lost postmortem. The lesion completely encircles the proximal humerus but is least developed on the medial aspect. The bone associated with the lesion is approximately 7 cm in maximum diameter and abnormal tissue extends slightly more than one third the length of the humerus (Fig. 19.63A and B). The bone proliferation overlies the insertion of the joint capsule but does not involve the joint surface itself. The gross morphology of the lesion consists of large coalescing bony projections, which have a coarse coral-like appearance. Although the age at death of the individual cannot be determined, the humeral head appears to be fused, indicating an age in excess of 15 years (Ortner, 2003). Radiographs of this specimen were provided courtesy of Dr.

Walter Huber, the director of the Natural History Museum in Bern at the time of Don Ortner’s visit in 1974. The films reveal an osteolytic process extending 2 3 cm into the externally normal cortex distal to the lesion (Fig. 19.63C). The location of the lesion, as well as its gross and radiographic appearance, is compatible with the diagnosis of primary osteosarcoma or chondrosarcoma (Ortner, 2003). Recently, Ruffano and Waldron (2018) argued in favor of an osteosarcoma, of the parosteal subtype, in the right humerus of an adult ( . 45 years old) female exhumed from the Anglo-Saxon cemetery at Cherry Hinton, England. A large spherical mass (5.3 3 3.8 cm), with some bosselated contour and spiculated lesions, was attached with a broad-based pedicle to the proximal diaphysis. Deposits of spiculated new bone confer an irregular surface to the diaphysis, and angulation is also present. Foci of cortical destruction are observed; the larger ones perforate the cortex and those with smaller dimensions are of superficial and coalescent nature (Fig. 19.64). Intramedullary lesions are demonstrated by radiography, which show a heavily mineralized matrix and a cleavage plane/string sign (i.e., a cleft between the base of the mass and the cortex) (Fig. 19.64). Interestingly another three bone masses were associated with the burial. The radiographic and dry bone features are illustrative of an osteosarcoma, with the cleavage plane, the

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FIGURE 19.64 Parosteal osteosarcoma of right humerus. (A) Extensive new bone formation (3) and areas of cortical perforation (1). Notice the area of exposed cortex (2). (B) Anteromedial view showing a lobulated mass with broad base (4). Cortical destruction (1) and new bone formation (3) is also noticeable. (C) Corresponding radiograph with the “string sign” (5). (145-year-old, female, Anglo-Saxon, Cherry Hinton, England.) Reproduced with permission from Elsevier, Figures 4 to 6 in Ruffano and Waldron (2018).

pedunculation, and broad base attachment, the bosselated contour and the satellite lesions are all suggestive of a parosteal osteosarcoma (Ruffano and Waldron, 2018). Smith-Guzma´n et al. (2018) report a malignant primary bone neoplasm in an individual recovered from the pre-Columbian site of Cerro Brujo (CE 1265 1380), Panama´. The mid-diaphysis of the right humerus of a 14 16-year-old individual had a localized widening of the bone contour with multiple sharp osteolytic lesions on this area (moth-eaten margins). The areas of bone destruction allow the visualization of a large intramedullary

and endosteal sclerotic mass (4.7 3 2.0 cm), characterized by highly mineralized matrix visible on the radiographs. The proposed diagnosis of osteosarcoma seems likely, even if Ewing sarcoma or chondrosarcoma (less likely due to age profile) cannot be definitively ruled out. Rib osteosarcomas with a spiculated periosteal reaction were reported recently by Lo´pez (2011), in a seventh right rib (lesion dimensions were 18 3 7 3 8 cm) in a male adult skeleton from Ca´diz, Spain, dated from the 2nd century BC, and by Ortner et al. (2010) in a skeleton from 19th-century England. The adult ( . 45 years old)

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male skeleton from England, Wolverhampton site (burial HB 39), is of interest due to the multifocal distribution of the bone-forming and osteolytic lesions. Osteolytic and osteoblastic processes are visible in the axial skeleton, clavicles, scapulae, and pelvic bones. The osteolytic foci consist of clusters of round pores that vary in size, and in some instances combined with a small amount of new bone formation. One osteolytic lesion with geographic margin was observed in the left mandibular corpus. “Sunburst” lesions were observed in the left sixth and seventh ribs, T8 T11 vertebrae, and right ala of S1. Radiological examination shows multiple areas of sclerosis and bone destruction (Ortner et al., 2010). Ortner et al. (2010) indicates that it is difficult to distinguish if the multiplicity of the lesions in this skeleton arises from multiple simultaneous or metachronous osteosarcomas (osteosarcomatosis) or if it resulted from osseous

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metastases from a primary osteosarcoma. Although osteosarcoma is most often a single lesion, it can metastasize to other organs and to bone, as illustrated above by skeleton no. 657 from the International Exchange Collection (IEC). Evidence of a possible secondary osteosarcoma in the right femur associated with Paget’s disease of bone was reported by Henderson et al. (2013) in the postmedieval site of Sheen’s Burial Ground, London. Arnay-de-la-Rosa et al. (2015) documented one of the few cartilage-forming malignant neoplasms observed in the paleopathological record. A Prehispanic young adult skeleton (1600 1800 years BP) from La Gomera, Canary Archipelago, shows a proliferative and destructive lesion (3.5 3 1.9 cm) located in the metaphyseal and epiphyseal areas of the left tibia. The lesion extends from the medullary cavity through the cortical surface (Fig. 19.65). Bone

FIGURE 19.65 Chondrosarcoma of the left tibia. (A) Tibial lesion with intramedullary and cortical changes. The pathological process also affects the tibio-talar joint. A small area of woven bone is visible in the distal portion of the lesion. (B) CT image shows the osteolytic process and bone outgrowth. (C) Radiograph shows the osteolytic lesion with sharply defined and irregular borders and intralesional areas of mineralization, characteristic of chondroid matrix mineralization. Reproduced with permission from Elsevier, Figures 2 and 3 in Arnay-de-la-Rosa et al. (2015). Radiograph courtesy Dr. E. Gonza´lez-Reimers.

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production is coarse and irregular; however, it does not present a spiculated appearance. The osteolytic lesion has an oval configuration and well-delimited margins, with a narrow zone of transition. The CT and radiographic images show an osteolytic lesion with sharply defined and lobulated borders associated with spotty areas of radiopacity (Fig. 19.65B and C). The radiographic features of this case are strong arguments towards the plausible cartilage-forming malignant neoplasm, most likely a chondrosarcoma, as proposed by the authors.

BONE METASTASES Pathology Metastatic bone disease is by far the most common cause of neoplastic malignant bone lesions, as they are more frequent than primary bone neoplasms (Czerniak, 2016). Indeed, the skeleton is one of the preferential sites for metastatic development, after the liver and lungs. The dynamic nature of the bone microenvironment, bone physical and biochemical properties (e.g., rich vascular network, the characteristics of the bone marrow sinusoids, multitude of growth factors, cytokines, chemo-attracting factors and adhesion molecules, high calcium and phosphate concentration, hypoxic environment, low pH, and other factors) make it a favorable tissue for the development of metastases (Fournier et al., 2014; Kumar et al., 2015; Roodman and Silbermann, 2015), as postulated by Stephan Paget in the seminal “seed and soil” theory in the late 19th century. Even if virtually any malignant neoplasm has the potential to metastasize to bone, some more rarely do so (e.g., neuroglial or germ cell malignant neoplasms) (Reith, 2016). Osseous metastases from carcinomas are the most common, yet nonepithelial cancers, such as hematopoietic malignancies or melanomas, often lead to bone metastatic disease. Even sarcomas may produce bone metastases, particularly in younger individuals (Oien et al., 2007; Bocklage et al., 2014; Kumar et al., 2015; Reith, 2016). Some carcinomas show a higher propensity to metastasize to bone (osteotropism), as the well-known cases of prostate and breast neoplasms, with up to 60% 80% of patients presenting skeletal metastases. Lung, thyroid, and kidney neoplasms also frequently metastasize to bone (c. 30% 65%). The frequency on clinical studies of bone metastases in melanoma shows a wide range (6% 45%). Conversely, colorectal, gastrointestinal, or gastroesophageal (,15%) neoplasms less often do so (Kumar et al., 2015; Portales et al., 2015; Reith, 2016). However, radioisotopic scan studies showed abnormal changes suggestive of metastasis in approximately 25% 45% of patients who have stomach cancer (Choi et al., 1995; Reith, 2016). Acquisition of specific genetic and phenotypic signatures attained by neoplastic cells and that are beneficial to the interaction with bone

microenvironment seems to be one of the explanatory mechanisms for the variance in osteotropism in different types of primary soft-tissue neoplasms. The role of blood flow, circulatory patterns, and vascular accessibility are also relevant factors (Fournier et al., 2014; Obenauf and Massague, 2015; Roodman and Silbermann, 2015). The overall epidemiological burden of skeletal metastases is difficult to assert, as it depends on the epidemiological profile of a population in terms of the neoplasm primary organ, as well as on the detection techniques used (Hauben and Hogendoorn, 2015). Recent results from Li et al.’s (2012) analysis of Medicare and MarketScan databases in the United States suggests that approximately 280,000 adults had metastatic bone disease in 2008. Results based on bone scintigraphy indicate that, if the most common carcinomas are considered, 70% 85% of patients will have skeletal involvement (Reith, 2016). Autopsy statistics based on two decades of cases of the Zurich Pathological Institute preceding 1948 are as follows: of over 3000 malignant tumors, 12% metastasized to the skeleton (Walther, 1948). Abrams et al.’s (1950) autopsy findings on 1000 patients with varied primary malignant neoplasms reported 27% of skeletal metastases. The autopsy findings are not very divergent from the values obtained, even if we emphasize that it depends on the most frequent types of primary neoplasms on the cohort, from human skeletal reference collections with known cause of death. Through visual inspection of skeletons from the Hamann-Todd Collection, Cleveland, USA, Rothschild and Rothschild’s (1995) tally of visually detected metastatic bone disease was 8.5%. This value was 17.6% for the pooled Luı´s Lopes (LLAC-MUHNAC) and Coimbra (CISC) reference collections, Portugal (Marques et al., 2018), and 27.4% for the W.M. Bass Donated Skeletal Collection, Tennessee, USA (Maijanen and Steadman, 2013). In past skeletal remains, without effective therapeutic approaches, and with the malignancy having taken its natural course, a high figure for skeletal metastases should be expected, particularly in slowly progressing cancers. On the other hand, reduced survival time also restrains the development of skeletal metastases. For cancers that show a fast progression, leading to a quick death, the occurrence of bone metastases would be uncommon (Mundy, 2002). However, radiological features of skeletal metastasis are generally not diagnostic (Greenspan and Borys, 2016), which means that differential diagnosis of many metastatic lesions in archeological human skeletal remains is likely to be difficult. The vast majority of metastatic lesions affect older individuals, with most cases being diagnosed in patients older than 40 50 years. However, one should not disregard the occurrence of metastatic disease at younger ages, that although less frequent, may occur due to diverse extraskeletal neoplasms (Reith, 2016). Hernandez et al.’s

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(2012) survey of 2652 children (,18 years) with cancer, from the Danish Cancer Registry, reported 1.3% of skeletal metastasis. In children, besides the osseous involvement in leukemia and lymphoma, neuroblastoma, rhabdomyosarcoma, clear cell sarcoma of the kidney, and Wilms tumor have a higher propensity to metastasize to bone (Hernandez et al., 2012; Bocklage et al., 2014; Reith, 2016). Bone metastases impact considerably on morbidity and life quality in cancer patients. Skeletal-related events include severe pain, disability, pathologic fractures, neurologic dysfunction, reduced mobility, and systemic symptoms associated with hypercalcemia, with nearly half of the patients showing one of these occurrences (Coleman and Holen, 2014; Hauben and Hogendoorn, 2015; Roodman and Silbermann, 2015).

Biology of Bone Metastases Bone metastases development entails the successful accomplishment of the multistep metastatic cascade: proliferation in the host organ; ability to invade the surrounding tissue and matrix; invasion of the blood vessels and motility; embolization and transport in the circulatory/ lymphatic system (surviving the cellular mechanisms attempting their destruction); arrest and adherence to the endothelium; extravasation and colonization at new sites (Weinberg, 2014; Obenauf and Massague, 2015; Reith, 2016). The metastatic process is initiated well before the metastatic cascade begins, as neoplastic cells modulate hematopoietic cells and release products that prepare the distant host bone to successfully receive the metastatic cells (premetastatic niche) (Reith, 2016). The current model for the pathophysiology of skeletal metastatic disease is centered on the ability of neoplastic cells to interact and modulate host osteoclast, osteoblast, and osteocyte regulatory pathways. Systemic and bone local factors secreted or stimulated by the malignant cells (e.g., parathyroid hormone-related protein, interleukins, tumor necrosis factors, metalloproteases, and others) induce osteoclastogenesis and osteoclastic activation. Thus, osteoclast-activating factors are released by the neoplastic cells themselves or by cells in the bone microenvironment in response to the presence of the neoplasm (e.g., breast cancer-mediated induction of RANKL from the stroma, or the role of immune cells in osteoclast activation in bone metastases). “For tumor cells to occupy a territory of the stromal matrix, the existing elements of the stromal matrix have to be at least partly destroyed or degraded” (Reith, 2016: 1220). During bone resorption, multiple bone-derived cytokines and growth factors (e.g., transforming growth factor β, insulin-like growth factors) and calcium are released, which further stimulate the neoplastic cell’s proliferation and survival. Simultaneously, angiogenesis, apoptosis, and immune suppression further allow the neoplastic growth. As the neoplasm grows it

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further stimulates osteoclastic activity in a complex and perpetual “vicious cycle” (Chen et al., 2010; Fournier et al., 2014; Obenauf and Massague, 2015; Mori et al., 2015; Roodman and Silbermann, 2015; Makhoul et al., 2016). In a broad depiction these are the mechanisms responsible for osteolysis in skeletal metastases. The mechanism of osteoblastic metastasis is less well understood (Reith, 2016), but it seems to result from an analogous mechanism, with the involvement of other set of factors (e.g., endothelin-1, bone morphogenetic proteins, TGF-β2, platelet-derived growth factor, insulin-like growth factor (IGF-1), fibroblast growth factor) secreted or induced by the neoplastic cells that directly or indirectly regulate diverse osteogenic signaling mechanisms at different stages of osteoblast development or osteoclast apoptosis, leading to new bone formation (Fournier et al., 2014; Obenauf and Massague, 2015; Roodman and Silbermann, 2015; Reith, 2016). New bone formation seen in metastasis may also be the result of reactive bone due to the disruption of the osteoclastic/osteoblastic homeostasis. In the 1960s and 1970s, it was postulated that bone resorption could result either from the tumor pressure or due to the direct action of the neoplastic cells in bone degradation (Mundy, 2002; Chen et al., 2010). These ideas have been revised, since several in vivo and in vitro studies have shown that “bone destruction, as well as tumor-induced bone formation, are entirely the result of tumor activation of resident bone cells and are not related at all to any direct action of the tumor cells themselves on the skeleton” (Makhoul et al., 2016: 4). Classically, metastatic lesions are categorized into predominantly osteolytic, predominantly osteoblastic, or mixed. Osteolytic or osteoblastic metastases represent “extremes of a spectrum of activity” (Makhoul et al., 2016: 4), since due to the tight coupling of osteoblastic and osteolytic activity in bone remodeling, one can expect at least some degree of increased bone formation and bone resorption in most neoplasms (Mundy, 2002; Cle´zardin, 2011; Fournier et al., 2014; Makhoul et al., 2016; Chappard et al., 2018), as well as both phenomena occurring early in the metastatic process (Chen et al., 2010). For this reason, a wide range of patterns and lesion presentations are expected to be seen in archeological skeletons with metastatic lesions. Malignant neoplasms of the lung, breast, kidney, thyroid, gastrointestinal tract, colorectum, as well as from melanoma, are often predominantly osteolytic. Predominantly osteoblastic lesions are commonly caused by prostate cancer, yet they can also result in other conditions, e.g., breast, lung, bladder, colon, neuroblastoma (Fig. 19.66), or other neuroendocrine cancers (Vassiliou et al., 2007; Coleman and Holen, 2014). Mixed lesions can be produced by diverse primary organs, but are most common in breast, ovarian, or colorectal cancers (Resnick

698 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 19.66 Osteoblastic metastases of adrenal neuroblastoma. (A) External view of frontal bone, showing radiating reactive bone spicules (“sunburst”) in supraorbital area. (B) Endocranial view, showing radiating trabeculae replacing the inner table. (C) Basal external view of sphenoid bone, showing involvement of both wings. (14-month-old, male, PMES 1VUH from before 1929.)

and Kransdorf, 2005; Greenspan and Borys, 2016). Due to the considerable variability of the presentation of metastatic bone disease, it is extremely unlikely that paleopathologists will be able to accurately infer the primary site based solely on the skeletal presentation. For example, more than 15% 40% of patients with advanced malignant breast neoplasms have osteoblastic or mixed lesions (Mundy, 2002; Vassiliou et al., 2007). As argued by Hall (2005), even if metastatic breast cancer initiates with osteolytic metastases, its relatively indolent nature means that long-term survivors show sclerotic or mixed bone lesions. Osteolytic metastases may also be present in prostate cancer (Keller and Brown, 2004), and may be dominant particularly in small cell variants or poorly differentiated prostate carcinomas (Reith, 2016). As mentioned by Chappard et al. (2018: 2) “most of the osteolytic tumors are in fact mixed and contain an osteoblastic component associated with the predominant osteolytic areas.” The degree of invasiveness and metastatic potential is highly variable, even among neoplasms of the same organ/tissue, due to the heterogeneity at molecular, histological, and genomic levels (Hoadley et al., 2018). The difficulty in identifying the primary organ through the analysis of the pattern of osseous metastases is amplified when studying archeological remains.

Diagnostic Features In adults, the bones most commonly involved in metastatic neoplasms are those of the axial skeleton and proximal areas of the appendicular skeleton, in particular metaphyses and epiphyses of the long bones. Vertebrae, pelvic bones, ribs, sternum, proximal femur, and humerus, or the skull are the most frequently affected bones, even if virtually any bone can be affected (acrometastases are distinctly uncommon). This coincides with the location of hematopoietic marrow, which is rich in sinusoidal vascular networks. Furthermore, circulatory patterns (the valveless Batson venous plexus and retrograde venous spread) can also be linked with propensity to spinal metastases. In children, metastases are most frequent in the appendicular region (Reith, 2016). In the spine, the most frequently involved are the thoracic and lumbar segments, followed by the sacral and cervical regions. Multilevel involvement is also frequent. The metastases are predominantly located in the vertebral bodies, but neural arches and spinous processes may also be affected (Kalogeropoulou et al., 2009). Compression fractures are common, secondary to osteolytic metastases. In the cranial vault, the most marked destruction is in the diploe¨, followed by the outer and inner tables. The lesion may be single or multiple, generally with lesions of

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variable size. Metastases in the long bones predilect the intertrochanteric area of the femur or proximal portion of the humerus, but diaphyseal lesions are not uncommon. Pathological fractures secondary to osteolytic deposits in long bones are common and often the presenting condition in skeletal metastasis of clinical patients. The great majority of bone metastases originate in the medullary cavity and may progress to the cortical compartment. Metastases arising in the intracortical or subperiosteal regions are less common, but have been reported in the clinical literature, mostly in the appendicular skeleton and are common in lung or renal cancers (Miric et al., 1998). They are usually osteolytic, causing scalloping or saucerization of the underlying cortex. Metastatic osteolytic lesions present variously, ranging from a destructive focus with geographic margin (with sharp or ill-defined borders) to dispersed and diffuse areas of osteoclastic resorption (moth-eaten and/or permeative margins) in the cancellous bone or extending to the cortical outer surface (Fig. 19.67). It is of note that in early progression to the outer cortex a small area of coalescent porosity may be the only change observed in dry bone (Fig. 19.68). In these circumstances a radiographic evaluation is essential to detect intramedullary changes. Typically, in skeletal radiology, aggressiveness is indicated by the morphology of a lesion’s margins. Welldefined margins of an osteolytic lesion connote a less aggressive process. The least troublesome osteolytic lesion is one with a sclerotic margin indicative of reactive repair of the edge, which is relatively rarer in bone metastases. Most troublesome and aggressive are osteolytic lesions in which the margin is poorly delineated with a fairly continuous gradient of bone density between the osteolytic focus and normal bone (wide zone of transition). New bone formation is often seen in these areas and/or in their vicinity, replacing old trabeculae or coating remaining old trabeculae. When the destructive lesion progresses through the cortex, extension to the soft tissue and periosteum may occur, leading to some degree of periosteal new bone formation (Reith, 2016). Although not frequent, a localized shell of new cortex showing a soap bubble appearance may also be visible, most commonly in kidney, thyroid, and hepatocellular carcinomas (Kalogeropoulou et al., 2009; Greenspan and Borys, 2016). Metastatic lesions can also be predominantly osteoblastic, consisting of new bone deposits replacing old trabeculae, or coating remaining old trabeculae. This results in blotchy or diffuse densities in radiographs. With disease progression, the osteoblastic lesions can be confluent and extremely sclerotic (Fig. 19.69). The outer contours of the involved bones may not be significantly altered in most cases, and thus the lesion could be only identified on incidental radiographic analysis in archeological specimens. Bones appearing heavy or showing areas of

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enlargement of the bone contour should be subject to radiographic analysis. In advanced cases, extensive osteoblastic metastases can be associated with extensive subperiosteal new bone formation (Reith, 2016). A nodular and rounded (“mossy” or “coral-like” appearance) new bone formation is observable (Figs. 19.69 and 19.70). In some circumstances, a spiculated or “sunburst” reaction may be visible, particularly in prostate or gastrointestinal carcinomas, retinoblastoma, and neuroblastoma (Fig. 19.66) (Kalogeropoulou et al., 2009). Mixed metastases, that is the presence of both osteoblastic and osteolytic changes in the bone or skeleton, can also occur (Figs. 19.71 and 19.72). Multiplicity of skeletal lesions is a hallmark of metastatic bone disease (Reith, 2016). Solitary metastases are most often caused by thoracic and abdominal organ neoplasms, including kidney, lung, breast, pancreas, thyroid, and colon (Reith, 2016). These solitary lesions occur with a predilection in the shaft of the femur or humerus, less commonly in the cranial vault. Solitary lesions mainly may mimic infectious conditions, benign or malignant primary bone neoplasm, lymphoma, among other conditions, thus are difficult to diagnose in paleopathology. Metastatic bone disease with multiple foci also poses problems in differential diagnosis in dry bone in respect to other forms of skeletal disease. The differential diagnosis with infectious diseases can be challenging. One problem is also the distinction between metastatic lesions from carcinomas and osseous changes due to hematopoietic neoplasms, particularly multiple myeloma. These two types of cancer reflect a morphological gradient in bone, making differential diagnosis impossible in some cases (Strouhal, 1991; Marques et al., 2013). The absence of associated new bone formation and a tendency towards a more regular size of the osteolytic lesions in multiple myeloma may be an aid in differentiating these conditions. For further discussion on the skeletal manifestations of multiple myeloma see Chapter 14. Langerhans cell histiocytosis in adults, brown tumors of hyperparathyroidism, Paget’s disease of bone, or multifocal presentation of primary malignant neoplasms (e.g., osteosarcoma or Ewing sarcoma) may represent diagnostic problems. The differentiation from Paget’s disease can be difficult on gross inspection or in radiographs. However, on radiographs a jigsaw or accentuated coarse trabecular markings are visible particularly in flat bones. In long bones, a sharp area of demarcation between the lesion and the normal bone (blade of grass sign) may be helpful in differentiating Paget’s disease from osseous metastases. It is also difficult to distinguish cranial bone metastases from the craniofacial involvement due to direct extension from a broad range of soft-tissue malignant neoplasms of the head and neck, particularly from squamous cell carcinomas, causing bone destruction with

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FIGURE 19.67 Predominantly osteolytic metastases throughout the skeleton. (A) Right and left innominate with multiple osteolytic lesions (geographic and moth-eaten margins). The outer cortex also shows areas of external scalloping. A thin layer of new bone formation surrounds the main osteolytic lesion and minimal new bone formation is also noticeable on the internal surface (arrow). (B) The sacrum with extensive destruction. (C) Lumbar segment with osteolytic lesions in the vertebral body. (D) Left clavicle with an osteolytic process with moth-eaten margins. The left scapula is affected mostly by osteolytic lesions with geographic margins. Notice the external cortical scalloping (arrow head). (E) Right rib with osteolytic foci. Other ribs of this individual show remodeling fractures. (F) Right femur with osteolytic lesion in the metaphysis. (Sk. no. 1423, 32-year-old, female, death in 1954, cause of death: stomach carcinoma, LLAC-MUHNAC, Portugal.)

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FIGURE 19.67 (Continued)

possible new bone formation (Carter et al., 1983; Ampil et al., 2004). For example, invasion of the skull base by nasopharyngeal carcinomas was reported as a frequent event in several clinical studies of Asian populations (Han et al., 2012) but facial bone lesions have been reported as well (Mark, 2007). Carcinoma of the ethmoid sinus may destroy the adjacent frontal bone and the orbital wall (Fig. 19.73). Carcinoma of the nasal and paranasal sinuses may destroy part of the maxilla, hard palate, zygomatic bone, frontal or ethmoid bones (Fig. 19.74), whereas the oral cavity and oropharyngeal cancers can often affect the mandible, maxilla, and hard palate (Carter et al., 1983; Ampil et al., 2004). For this reason, craniofacial lesions observed in the paleopathological context require the consideration of head and neck soft-tissue neoplasms, primary or metastatic bone neoplasms, but also nonneoplastic conditions, such as, e.g., lesions of tertiary syphilis, leprosy, lupus vulgaris, or leishmaniasis. As argued in the excellent review by Mark (2007), paleopathologists are advised to readdress the predominance of nasopharyngeal carcinoma diagnosis in detriment

of other possibilities with emphasis placed on detailed differential diagnosis. Special mention should be made of the appearance of skeletal metastasis in children/younger individuals. Rhabdomyosarcoma can often show skeletal metastases, typically with diffuse osteolytic lesions. Neuroblastoma, a malignant neoplasm of the adrenal or of the sympathetic chain in infants and children, usually occurs before 3 years of age. This neoplasm, a round-cell lesion, readily metastasizes to the bone marrow, most often metastasizing to the orbit, jaw, and metaphysis of long bones (Fig. 19.66). The lesions are typically osteolytic, nonetheless they often elicit periosteal layered bone formation of varying thickness on the long bone shafts of the actively growing childhood skeleton. In the cranial vault an osteoblastic reaction can lead to “hair-on-end” appearance (Fig. 19.66). The periosteal deposits may assist to differentiate neuroblastoma from similar skull lesions in severe anemias. Osteomyelitis or hematological malignancies should also figure in differential diagnoses of skeletal metastases (Reith, 2016).

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FIGURE 19.68 Metastatic bone disease. (A) Small area (0.5 3 0.5 cm) of coalescent porosity in the left parietal bone with coarse trabeculae (left image). The skull base shows severe changes (arrows). (B) Diaphysis of tibia with a circumscribed porosity. (C) The manubrium shows a clear osteolytic focus (2.3 3 0.8 cm). (D) Spinous process with an osteolytic lesion in a lumbar vertebra (left image). The right image shows diffuse destruction of the atlas with new bone formation. (Sk. no. 1106, 65-year-old, female, death in 1946, cause of death: breast cancer, LLAC-MUHNAC, Portugal.)

The paleopathologist is well advised to be cautious in identifying a specific primary organ of the osseous metastatic disease observed in past skeletal remains. As illustrated in Fig. 19.69, the skeleton of a 66-year-old male from Luı´s Lopes Anthropological Collection (LLACMUHNAC), Portugal, shows marked osteoblastic activity associated with more mild areas of osteoclastic activity in the axial and appendicular skeleton. Aside from the most common, “mossy” appearance, in some areas radiant spicules (“sunburst”) are also seen. This individual died of rectum neoplasm, as recorded on the cause of death,

illustrating the variability of primary neoplasms associated with predominantly osteoblastic lesions.

Paleopathology Osseous metastases are by definition malignant and they are much more common than primary malignant neoplasms of bone. Thus, even though they are associated with the older age categories, they should be more common in archeological skeletons and, indeed, the 21stcentury paleopathological record of metastatic skeletal

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FIGURE 19.69 Predominantly osteoblastic metastases. (A) Right os coxa (anterior and posterior views) with massive nodular new bone formation. The corresponding radiograph (60 kV 56 mAs) shows highly sclerotic areas. (B) Three ribs with different lesion typology; ranging from massive nodular new bone formation, radiant spicules, to diffuse porosity. (C) Sternum and manubrium with massive new bone formation. (D) Proximal humerus with an osteolytic lesion (moth-eaten margin) and coarse trabeculae. (Sk. no. 457, 66-year-old, male, death in 1929, cause of death: rectum neoplasm, LLAC-MUHNAC, Portugal.) Radiographs courtesy Dr. C. Prates, IMI-S.A.

lesions is significantly increasing. So far, there are approximately 160 published cases in the paleopathological record. In the remaining pages of this chapter a brief enumeration of some recent paleopathological literature depicting metastatic bone disease will be provided. However, before doing this, I remind the reader that

neoplasms affect the skeleton both directly and indirectly through the abnormal conditions they create, or by the effects of paraneoplastic syndromes (e.g., hypertrophic pulmonary osteoarthropathy). The most common tumor of the pituitary is an adenoma that is benign but can stimulate conditions in the skeleton that are dramatic visually

FIGURE 19.69 (Continued)

FIGURE 19.70 Massive osteoblastic metastases of prostate carcinoma of pelvis and spine. (A) Notice the diffuse nodular hyperostosis. (B) Detail of osteoblastic changes in the surface of the bone. (66-year-old, male with cancer of the prostate, IPAZ autopsy 497/46.)

FIGURE 19.71 (A) Posterior view of the sacrum with a large area of osteolysis associated with irregular deposits of new bone (arrow). Notice smaller areas of osteolytic activity (arrowhead). (B) Anterior view of the sacrum. (C) Right rib with diffuse osteolytic activity on the outer cortex (white arrows show the larger osteolytic foci) and minimal new bone formation (black arrow). (D) The corresponding radiograph (60 kV 56 mAs) shows intense and diffuse sclerosis and osteolysis. (Sk. no. 397, 87-yearold, male, death in 1943, cause of death: prostate neoplasm, LLACMUHNAC, Portugal.) Radiograph courtesy Dr. C. Prates, IMI-S.A.

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705

FIGURE 19.72 Mixed pattern of metastatic bone disease. (A) Right innominate with multiple osteolytic lesions (geographic margin) visible with the naked eye and on radiographs (60 kV 56 mAs). Smaller areas of sclerosis are also visible. (B) Proximal humerus with an osteolytic lesion with wide zone of transition (geographic IC). (C) Rib with osteoblastic (nodular) lesion and disperse osteolytic activity. A fracture line is also noticeable (arrow) (Sk. no. 1298, 67-year-old, male, death in 1936, cause of death: prostate neoplasm, LLACMUHNAC, Portugal.) Radiographs courtesy Dr. C. Prates, IMI-S.A.

and create the risk of serious complications. Pituitary neoplasms are rarely mentioned in the literature on paleopathology (Ortner, 2003). A brief description of a possible case comes from the archeological site of Abingdon Abbey, Oxfordshire, England, which is dated between AD 1200 and 1400 (Hacking, 1995). The incomplete skull of an adult male contains evidence for a pituitary tumor. Apparently, the abnormality is confined to the sella turcica, which is greatly enlarged. Another example of pituitary tumor is found in a well-preserved adult male burial from Kaskanuk, Alaska, dated between the 18th and 19th centuries (NMNH 363553). The most obvious abnormality is the presence of multiple lytic lesions in the skull (Fig. 19.75A and B). The edges of the lesions are

remodeled and smooth, indicating a benign process. Internally the clinoid processes are missing antemortem, and the normal saddle shape of the sella turcica has been remodeled into a shallow and greatly enlarged depression. The latter remodeling appears to have completely penetrated through to the base of the sphenoidal sinus and formed a new floor for what was undoubtedly a greatly enlarged pituitary gland (Fig. 19.75C and D). There is evidence of osteoporosis in other areas of the skeleton, indicative of some serious endocrine imbalances. The importance of this case is to highlight the fact that benign tumors can cause significant bone changes that can mimic a metastatic neoplasm (Ortner, 2003). Such examples require careful study to clarify the differential diagnosis (Ortner, 2003).

706 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 19.73 Probable carcinoma of the ethmoid with destruction of ethmoid bone, medial orbital wall, and adjacent frontal bone. Notice the almost complete absence of bony reactivity (elderly individual, ANM 2490).

Predominantly osteolytic lesions have been the most common expression of metastatic lesions reported in the paleopathological literature (e.g., Cybulski and Pett, 1981; Strouhal and Vyhna´nek, 1981; Gregg et al., 1982; Manchester, 1983; Waldron, 1987; Suzuki, 1989; Ortner et al., 1991; Strouhal, 1991; Ricci et al., 1994; Duhig et al., ˇ ca´kova´ et al., 2001; Campillo, 1996; Strouhal et al., 1996; Sefˇ 2005; Melikian, 2006; Nerlich et al., 2006; Ciranni and Tempestini, 2008; Luna et al., 2008; Molna´r et al., 2009; Esche et al., 2010; Enciso and Mendoza, 2013; Vargova´ et al., 2013; Binder et al., 2014; Merczi et al., 2014; Kozieradzka-Ogunmakin, 2015; Micciche` et al., 2018). One example of a metastatic process predominantly osteolytic refers to the incomplete skeleton of an adult female from a site in Huacho, Peru (NMNH 379293), dated between AD 1000 and 1450. Osteolytic lesions are distributed throughout the skull and postcranial skeleton, and there is little reactive bone formation associated with any of the lesions (Fig. 19.76). However, the margins of the lesions are well defined. Adjacent to some of the osteolytic foci but not associated with the margins are reactive spicules of bone (Fig. 19.76C). This case does appear to be a probable example of metastatic bone disease, with unknown primary site. The second example of probable osteolytic neoplasm is found in the skull of an adult female from an archeological site in Varangerfjord,

FIGURE 19.74 Carcinoma of the nasal cavity with destruction of palate and inner portion of maxilla. Notice the complete absence of reactive bone (adult, ANM 2051).

Norway, dated to the 17th century (NMNH 241876). The osteolytic lesion occurs in the right lateral portion of the skull (Fig. 19.77). In comparison to the previous case, the margins are less well defined, with fine porous holes penetrating the cortex for several millimeters from the margin at some locations, indicating a wider zone of transition (Fig. 19.77B). There is reactive bone formation on the right mandibular condyle that was probably stimulated by the nearby soft-tissue mass and does not imply that the tumor had crossed the joint. A mixed pattern of osteolytic and osteoblastic lesions can also be found in metastatic bone disease. Some archeological examples of this pattern have been described, e.g., by Nerlich et al. (2006), Schultz et al. (2007), Assis and Codinha (2010), Wasterlain et al. (2010), San Milla´n et al. (2011), Walker (2012), Lieverse et al. (2014), and Luna et al. (2015). Of note is the work of Schultz et al. (2007) where the diagnosis of prostate carcinoma of a 40 50-year-old male skeleton from southern Siberia was sustained not only on the visible osteolytic and osteoblastic lesions but also through positive biomolecular markers (prostate specific antigen-PSA). It is not uncommon that prostate cancers show both osteoblastic and osteolytic

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707

FIGURE 19.75 Skull changes resulting from pituitary tumor. (A) Lateral view of the skull, showing multiple osteolytic lesions. (B) Lateral radiograph of the skull with highly variable densities. (C) Remodeled sella turcica (arrow) resulting from greatly enlarged pituitary gland. Remodeling destroyed the original base of the sella, creating a new floor in the base of the sphenoidal sinus. (D) Detailed view of the internal table, showing the lobulation resulting from erosion of the bone. (Adult, male from a site in Kaskanuk, Alaska, dated between the 18th and 19th centuries, NMNH 363553.)

lesions (Keller and Brown, 2004). Studies show that osteoblastic lesions form at the location of bone resorption. Osteoblasts are not only involved in new bone formation but also release RANKL and other osteoclastic mediators (Chen et al., 2010). An archeological example of this condition is seen in a skeleton from Kachemak Bay, Alaska (FM SEL30 AMU3 Burial 11), which was excavated in 1974 and dated circa AD 350 by carbon-14 analysis. The skeleton was analyzed by Don Ortner courtesy of Dr. John Lobdell. Lobdell has published a description of the case in which he argues for a diagnosis of hemangioendothelioma (Lobdell, 1981). Ortner (2003) considers this a plausible option but argues for another diagnostic possibility for this skull and the incomplete portions of the postcranial female skeleton with an age in the 50-yearplus range. The disease process is multifocal with lesions on the skull, ribs, vertebrae, left humerus, both innominates, right femur, and both tibiae. The cranial lesions are circular and fairly large (Fig. 19.78A and B); the smallest is about 25 mm in diameter and the largest about 45 mm

in diameter. One lesion is on the frontal bone, two are entirely on the left parietal bone, and a third is partially on the left parietal, but crosses the sagittal suture into the right parietal. The lesions show an active osteolytic front at the boundary with normal bone. The osteolytic process resulted in the normal cortical bone being replaced by woven bone that entirely filled the osteolytic focus. The central osteoblastic activity produced bone that extends above the plane of the normal bone. The lesions in this skull are similar to those occurring in the skull of a modern case of metastasis from lung carcinoma. In this case of documented lung carcinoma, there is an osteolytic front adjacent to normal bone with woven or fiber bone formation in the central portion of the lesion. The postcranial lesion in the Alaskan specimen appears to be more variable morphologically than those of the skull, although the picture is complicated by considerable postmortem damage, including missing cervical vertebrae. The upper thoracic vertebrae are somewhat osteoporotic but are normal, except for slight degenerative-arthritic changes. However, T10 and T12 both have osteolytic lesions of the laminae.

708 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 19.76 Osteolytic lesions from metastatic cancer. (A) Anterior view of the skull, showing large osteolytic focus probably resulting from the coalescence of two or three osteolytic lesions. (B) Left lateral view of the skull with other osteolytic lesions. (C) Detail of frontal lesion. Note the fine spicules arising from the surface of the inner table. (D) Right and left innominate with multiple osteolytic foci. (Adult, female from a site in Huacho, Peru, dated between AD 1000 and 1450, NMNH 379293.)

Similar destructive lesions occur on the laminae of the first two lumbar vertebrae. The few rib fragments show active osteolytic involvement. Both ossa coxae present large osteolytic areas near the acetabulum, where the bone is entirely destroyed. Both of these lesions appear to have been active at the time of death. The left femur appears to be normal, although the distal end is missing postmortem. Only the diaphysis of the right femur is preserved, and it shows multiple lesions, all of which combine osteolytic and osteoblastic processes (Fig. 19.78C). The proximal ends of both tibiae have large, purely osteolytic defects in the metaphyseal cortex (Fig. 19.78D). Both lesions are oblong, the left measuring about 40 by 20 mm on the radiograph. Postmortem damage has

destroyed part of the lesion on the right tibia. The remaining bone suggests an osteolytic lesion that is even larger than the one seen on the left. The morphological similarity of the skull lesions to those seen in known metastatic lesions suggests the presence of a metastatic process. The lesions of the long bones would be compatible with this diagnosis (Ortner, 2003). Osteoblastic metastatic lesions are less frequently reported by paleopathologists. This may also be related to the fact that proliferative lesions have been traditionally associated with conditions other than neoplasia in paleopathological studies. The most common osteoblastic carcinoma is prostate cancer, although bone proliferation can occur in other types of neoplasms, as aforementioned.

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709

FIGURE 19.77 Skull lesion from osteolytic metastatic cancer. (A) Anterior view of the skull with large osteolytic focus involving the right side of the skull. (B) Right lateral detailed view of the lytic lesion. Note the porosity of the bone adjacent to the margin, which is indicative of a more aggressive destructive process. (Adult, female from a 17th century site in Varangerfjord, Norway, NMNH 241876.)

Reports of predominant osteoblastic lesions have been noticed on the paleopathological record (e.g., Anderson et al., 1992; Wakely et al., 1995; Mays et al., 1996; Waldron, 1997; Nerlich et al., 2006; Farkas et al., 2007; Prates et al., 2011; Merczi et al., 2014; Miles and Bekvalac, 2014).

FIGURE 19.78 Mixed (osteoblastic and osteolytic) lesions of the skeleton due to metastatic bone disease. (A) Left lateral view of a skull, showing two large porous lesions on the parietal bone. (B) Detailed view of inferior left parietal bone lesion. (C) Osteoblastic and osteolytic lesions of the diaphysis of the right femur. (D) Osteolytic lesion of the proximal tibia. (Adult, female from an archeological site dated about AD 350 located near Kachemak Bay, Alaska, FM SEL30 AMU3 Burial 11, IPAZ autopsy 1850/67.)

710 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 19.79 (A) Osteoblastic lesion of the right innominate due to metastatic bone disease. (Adult, male skeleton from a cemetery near Dubendorf, Switzerland, dated between the 11th and 15th centuries). (B) Osteoblastic lesion due to metastatic bone disease of the right rib from lower chest region. (AIUZ 7757.)

A skeleton from the cemetery near Dubendorf, Canton Zurich, Switzerland, dated between the 11th and 15th centuries, exhibits diffuse, poorly organized bone formation. The specimen is an adult male probably in excess of 50 years of age at the time of death. Excavated in 1974, the remains were observed in the Anthropological Institute of the University of Zurich, Switzerland (AIUZ 7757). The right os coxa contains a lesion largely limited to the periosteal surfaces of the ilium (Fig. 19.79A), which consists of extensive fine porous, osteoblastic changes. There is no obvious destruction of underlying bone or evidence of abscesses or cloacae. There is a similar bony reaction on the fight anterior proximal femur. Two ribs also show periosteal lesions (Fig. 19.79B). The disseminated nature of the disease and the morphology of the lesions are compatible with metastatic neoplasm, possibly with origin in the prostate. A possible New World example of osteoblastic metastases is found in the skeleton of an adult male from a site in Canaveral, Florida (NMNH 377434), dated between AD 1500 and 1600. The skeleton is fragmentary and incomplete. Therefore, one cannot be confident about the distribution of lesions, but they seem to be limited to the right os coxa (Fig. 19.80). Both the medial and the lateral surfaces exhibit multilobed hypertrophic and porous lesions that could be caused

FIGURE 19.80 Osteoblastic lesions of the right innominate due to metastatic bone disease. (A) Right innominate, medial view. (B) Right innominate, lateral view. (Adult, male from an archeological site in Canaveral, Florida, dated between AD 1500 and 1600, NMNH 377434.)

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by several diseases, including a localized infection. However, the location and nature of the lesion argue for metastatic bone disease.

ABBREVIATIONS Carina Marques AFIP AIUZ ANM BMNH CGH CISC

DPUS FM FPAM HM IEC

IPAZ LLACMUHNAC MGH NHMB NMNH PMES WM

Armed Forces Institute of Pathology, Washington, DC, United States Anthropological Institute, University of Zurich, Zurich, Switzerland National Museum of Anthropology, Prague, Czech Republic British Museum, The Natural History Museum, London, England Department of Pathology, Charleston General Hospital, Charleston, West Virginia, United States Coimbra Identified Skeletal Collection, Departamento de Cieˆncias da Vida, Universidade de Coimbra, Portugal Department of Pathology, University of Strasbourg, Strasbourg, France Field Museum of Natural History, Chicago, Illinois Federal Pathologic-Anatomy Museum, Vienna, Austria Hunterian Museum, The Royal College of Surgeons of England, London, England International Exchange Collection, Departamento de Cieˆncias da Vida, Universidade de Coimbra, Coimbra, Portugal Institute of Pathological Anatomy, University of Zurich, Zurich, Switzerland Luı´s Lopes Anthropological Collection, Museu Nacional de Histo´ria Natural e da Cieˆncia, Lisbon, Portugal Department of Pathology, Massachusetts General Hospital Boston, Massachusetts, United States Natural History Museum, Bern, Switzerland National Museum of Natural History, Smithsonian Institution, Washington, DC, United States Pathology Museum, The Royal College of Surgeons of Edinburgh, Edinburgh, Scotland Wellcome Museum, The Royal College of Surgeons of England, London, England

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Chapter 20

Joint Disease Tony Waldron University College London, London, United Kingdom

Joint disease is the most common condition seen in human remains. In a skeletal assemblage from a typical urban cemetery, joint disease usually will account for about a third of all the pathological lesions seen. Without some interest in the disease, therefore, budding paleopathologists will have a less than rewarding time. This chapter reviews the skeletal manifestations of joint disease, with particular attention paid to those conditions that may be distinguished in the paleopathological record. It is customary to separate joint disease into two broad groups, those in which the production of bone is predominant, and those in which loss of bone is the defining characteristic. The first group contains only a single member—osteoarthritis (OA)—whereas there are several in the second group; these are generally referred to as the erosive arthropathies. There is also a rather special subcategory of the erosive arthropathies, these are the socalled crystal arthropathies, which will be dealt with separately.

OSTEOARTHRITIS OA is by far the most common joint disease today, with a prevalence in Western countries, based on radiographic evidence, of more than 50% in people over 60 years of age (Cooper, 1998; Solomon, 2001). The prevalence in autopsy samples is even higher, and virtually all people over 65 years of age have at least some evidence of OA in the articular cartilage (Solomon, 2001). The clinical definition of OA is based in part on factors such as joint pain and diminished joint space. These factors are among the earliest signs of OA and, lacking any associated bone changes, will not be apparent in archeological human skeletal remains. This means that the relationship between OA as defined and understood by the clinician and what is apparent to the paleopathologist is likely to be inexact at best. Other pathological features, such as subchondral bone eburnation, sclerosis, and development of osteophytes can be seen in archeological skeletal remains, but

these features reflect the later stages of OA or its more severe manifestations. Another feature that is not well known to the clinician but which is encountered in archeological human skeletal remains is porosity of the subchondral bone in osteoarthritic joints. This feature can occur in association with eburnation, but it also is seen without any evidence of eburnation. Hough (2001: 2173) notes that newly formed cartilage strands penetrate through gaps in eburnated subchondral bone, which, presumably, would appear as porosity in archeological joint surfaces. OA is a disease of great antiquity and was almost certainly a trial to any of our hominin ancestors who lived to any great age—relatively speaking, that is. Thus, despite the challenges of accurate diagnosis of OA and the problems inherent in obtaining reliable data on the prevalence of this condition in archeological skeletal samples, the importance of OA makes it a dimension of paleopathology that deserves careful analysis and interpretation. As a disease of synovial joints, it may affect any animal possessing such structures. The pathology in both humans and animals is the same, and although this chapter is confined to human pathology, it can be taken as read, that the general remarks apply equally to animals.

A Note on Nomenclature Those who study old medical texts or papers—i.e., those written a century or two ago, rather than those that might have appeared in the medical press in the last decade or two—may be puzzled by the appearance of diseases that seem to have no modern counterpart. Until the 19th century, all joint diseases were subsumed under the general rubric of gout, and the trend since then has been to split them into ever more categories—of which more when considering the erosives. Since the suffix “itis” in clinical parlance refers to an inflammatory process, and since inflammation is not usually a major feature in OA, some authors prefer to use the more neutral term, osteoarthrosis

Ortner’s Identification of Pathological Conditions in Human Skeletal Remains. DOI: https://doi.org/10.1016/B978-0-12-809738-0.00020-X © 2019 Elsevier Inc. All rights reserved.

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for the disease; this usage has never really caught on— certainly not among clinicians in Europe—and so will not be used here. Clinicians in the past have used many other names for OA, however, including arthritis deformans, senile arthrosis, morbus coxae senilis, spondylitis deformans, chronic rheumatic arthritis, hypertrophic arthritis, and most perplexingly of all, it has even been called, rheumatoid arthritis (RA). Confusion over names is not unique to joint disease, and obsolete terms are likely to turn up in any old medical writing, as are eponymous terms which are nowadays generally frowned upon; instead the modern trend is to use acronyms as much as possible.

Pathophysiology of Osteoarthritis OA is a disease of synovial joints, and the lesions begin in the articular cartilage. As the disease progresses, all the structures of the joint are involved (Mobasher and Batt, 2016). There are three major components of skeletal involvement in the pathology of OA (Mobasher and Batt, (A)

(B)

2016): breakdown of articular cartilage, which may result in bone-on-bone contact and abnormal abrasion of the subchondral bone (Galasso et al., 2012), reactive bone formation (sclerosis) both in the subchondral compact bone (eburnation) and in the trabeculae (Fig. 20.1) underlying the affected subchondral compact bone and possibly associated with cyst formation (Yang et al., 2013), and new growth of cartilage and bone at the joint margins (osteophytes) (Fig. 20.2). Although inflammation does occur in some destructive manifestations of OA (Cooper, 1998: 2.3; Dieppe and Lim, 1998: 3.12; Solomon, 2001: 1414), it is relatively uncommon. In most cases OA is slowly progressive, and demonstrable bone changes are preceded by alterations to the articular cartilage. In the early stages, fissures, both vertical and horizontal, can be seen in the cartilage, a change that is referred to as fibrillation. In subsequent stages, the cartilage thins, giving rise to the radiological sign of joint space narrowing. These changes are brought about by the action of matrix metalloproteinases released from damaged tissue (Galasso et al., 2012; Yang et al., 2013), but, FIGURE 20.1 Subchondral bone in a section through the capitulum.(A) Normal joint surface and subchondral trabeculae. (B) Sclerosis of trabeculae underlying porous degenerative change of the capitular joint surface (NMNH, unidentified humeri from the Huntington Collection).

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(A)

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(B)

FIGURE 20.2 Marginal osteophyte development on the right distal humerus. (A) Osteophyte developing on the medial margin of the trochlea. Note also the development of erosive enthesopathy on the medial condyle. (B) Osteophytes on the lateral margin of the capitulum (NMNH 333454, 35-year-old male from Golovnin Bay, Alaska).

in addition, proinflammatory cytokines, including IL-1 and TNF-α, are found in the joint (Fernandes et al., 2002). The inflammatory component of OA is variable, but in some cases the concentration of proinflammatory cytokines within the joint may be similar to that found in RA (Westacott and Sharif, 1996), which is interesting considering that synovial fluid from patients with OA is sometimes used as the control in research into the inflammatory components of rheumatoid joints. As the disease progresses, the subchondral bone thickens, and the tide mark may duplicate itself, a sign that is pathognomonic of OA, but, of course, not one that can be seen on the bare bones. All the changes that follow can be taken as an attempt by the joint to repair itself and, in a very few cases, reversion to normal has been reported, but only in small joints such as the proximal or distal interphalangeal joints (Bijlsma et al., 2011). Subsequent changes include the production of marginal osteophytes, new bone on the joint surface (secondary to increased vascularity of the subchondral bone), pitting on the joint surface, and alteration of the joint contour (Fig. 20.3). Occasionally, some of the pits on the joint surface may communicate with underlying bone cysts, but this can only be demonstrated radiologically and is not helpful

diagnostically. If the articular cartilage is completely worn away, and bone comes into contact with bone, then continued movement of the joint will produce eburnation on the joint surface; this is a glassy shine on the congruent surfaces on the two opposing sides of the joint. Eburnation, which can be seen on the joint surface, is pathognomonic of OA and is the most useful sign by which to diagnose it in the skeleton. In some cases, scoring or grooving may be found on the joint surface, with the grooves always orientated in the direction of movement of the joint, vertically in the knee joint, horizontally on the odontoid peg, for example. This scoring is presumably caused by detritus such as calcified cartilage, fragments of osteophyte, or crystals within the joint becoming trapped between the articulating joint surfaces.

Types of Osteoarthritis OA is usually said to be either primary or secondary. Primary OA is said to be idiopathic or cryptogenic, both terms indicating that the underlying cause is not known. It is the most common type and tends to occur in later life, perhaps as a result of multiple factors, including biomechanical stress, trauma, etc. Secondary OA, as its name

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implies, occurs earlier in life and is secondary to some other condition, most often trauma, but there are several other diseases or conditions that predispose to the production of secondary OA, including Paget’s disease, RA, congenital dislocation of the hips (CDH), and Perthes’ disease (a more comprehensive list is shown in Table 20.1). The necessary concomitant of trauma in inducing OA in a joint is a fracture that alters the normal anatomy of the bone; fractures extending into a joint will almost certainly lead to the supervention of OA. In the past, treatment was available for fractured limbs, as clear from (A)

(B)

the skeletal record, but there would have been little that could be done for a fracture that involved a joint. Whatever the event, if it resulted in the mechanics of the joint being permanently altered, then OA would have been virtually inevitable, supposing the individual lived sufficiently long after the event. If a fractured bone is found in a skeleton, both proximal and distal joints should be examined for the presence of OA; this will at least show that several years had elapsed between sustaining the fracture and death. OA also may be described as hypertrophic or atrophic (or minimal change). In the hypertrophic type, there is FIGURE 20.3 Osteoarthritis of elbow and wrist. (A) Anterior view of the distal humerus; note the porosity of the capitular surface and the bone hypertrophy of the capitular and trochlear fossae. (B) Osteophyte development adjacent to the trochlear joint surface. (C) Hypertrophic bone filling in the olecranon fossa. (D) Osteoarthritis of the distal joints of the radius and ulna (adult male Eskimo skeleton from Golovnin Bay, Alaska, United States, NMNH 279209).

Joint Disease Chapter | 20

(C)

(D)

FIGURE 20.3 (Contiuned)

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Age – sex–genetic factors – activity – weight – ethnicity

TABLE 20.1 Some Causes of Secondary Osteoarthritis Acromegaly Alkaptonuria Blount’s disease Chondrocalcinosis Congenital dislocation of the hips

Interactions

Costochondritis Ehlers Danlos syndrome Gout

Trauma Other conditions

Hemochromatosis Joint infections

Joint failure

Kashin Beck disease Lyme disease

FIGURE 20.4 A model of the precipitants of osteoarthritis. Precipitants in the top box represent primary OA; those in the side box, secondary OA.

Marfan’s syndrome Ochronosis Osteoporosis Paget’s disease Perthes’ disease Pseudogout Rheumatoid arthritis Sickle cell disease Slipped capital femoral epiphysis Trauma Wilson’s disease

There is a particular kind of multifocal OA, known as generalized OA, which is commonly referred to but about which there is little agreement as to definition—there are at least 15 different definitions in use. All agree that there should be multifocal OA of the hands (including the thumb base), and OA of at least one large joint, such as the hip, knee, or elbow (Nelson et al., 2014). Finally, there is a type of OA that affects either the PIPs or the DIPs of the hand, producing swellings that are referred to as nodes; Heberden’s nodes when the DIPs are involved, Bouchard’s nodes, when it is the PIPs. This is the socalled nodal OA. There is a strong genetic component to nodal OA, it tends to run in families, and is more common in women than in men.

Precipitants of Osteoarthritis considerable production of new bone, particularly of marginal osteophyte. This is particularly likely to occur in larger rather than smaller joints and if the individual has a concurrent bone-forming condition such as diffuse idiopathic skeletal hyperostosis (DISH) (see section on DISH below). Conversely, minimal change is more likely to characterize small-joint OA, although there is a form of hip OA in which very little new bone is produced and some forms of OA of the knee produce little in the way of new bone. The erosive component of OA is extremely variable, but usually not great, although there is a true erosive form of OA which will be dealt with later. OA also may be unifocal or multifocal, i.e., affect only a single joint (or set of joints such as the proximal interphalangeal joints (PIPs) or distal interphalangeal joints (DIPs)), or several. There is some evidence that the condition has tended to become more often multifocal than unifocal in the modern period (Waldron, 1993).

There are a number of intrinsic factors that are associated with the development of OA (Fig. 20.4). By far the most important of these is movement; movement is a sine qua non for the development of OA and joints that do not move do not develop primary OA. The next most important precipitant is age; there is a positive correlation between the prevalence of OA and increasing age (Losser, 2010), so that by the seventh or eighth decade, there can be scarcely anyone who has not got at least one joint affected. Sex is important, although less so than age in this context. Thus, OA tends to be slightly more common in females than in males, and some forms in particular, are more prevalent in women (Felson et al., 2000). There are also genetic factors at play; identical twin and family aggregation studies have shown that genetics can explain a great deal of variance in some forms of OA. This is about 70% for OA of the spine, 65% for OA of the hands, 60% for OA of the hip, and 40% for OA of the

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knee (Yucesoy et al., 2015). Obesity is well known to predispose to OA, and this is especially true for OA of the hands and knees, but rather less so for OA of the hip (Biddal et al., 2014), suggesting that it is not simply stress on the joint that is responsible for its development. There are also ethnic differences in the expression of OA. Thus, OA of the knee seems to be more common in AfricanAmericans than in US Caucasians, and in Chinese women than Caucasian women, whereas the converse is true for OA of the hand and hip (Allen, 2010). The model of the production of OA in Fig. 20.4 shows that these various factors may interact to produce what is generally referred to as joint failure, with the production of the morphological appearances that are together called OA. Secondary OA is produced by different mechanisms that do not directly involve the primary precipitants.

Paleopathological Diagnosis As noted above, clinically, OA is diagnosed by the combination of joint swelling and pain; radiologically, by the presence of joint space narrowing, sclerosis (eburnation), and marginal osteophyte, while to the pathologist, an osteoarthritic joint will exhibit some or all of the morphological features referred to above. Paleopathologists are denied the opportunity to converse with their patients, nor can they demonstrate joint space narrowing. They have, then, to rely on morphological features when making their diagnosis. Here, we suggest an operational definition for OA that states that the condition can be diagnosed in the skeleton by the presence of eburnation alone, since this is a pathognomonic sign. If eburnation is not present, then it may be diagnosed if two or more of the following are present: marginal osteophyte, new bone on the joint surface, pitting on the joint surface, or alteration in the joint contour. It is a matter of no clinical importance whether paleopathologists get their diagnoses wrong, but it is important that they agree on some common criteria if there is to be any valid comparison between studies. In the past, diagnosis has not always been subject to strict (not to mention, valid) criteria—there have been several occasions when the presence of marginal osteophytes has been sufficient for a diagnosis to be made, even though this is a normal concomitant of aging and by no means confined to OA. In practice, if eburnation were used as the sole criterion for the diagnosis, estimates of the prevalence would not be greatly affected and then conformity would reign.

The Distribution of Osteoarthritis in the Skeleton From rheumatology textbooks, it would seem that the joints most commonly affected by OA are the hip, knee,

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or thumb base, because these are the joints that hurt when they are arthritic, and so are the ones about which patients complain most. In the skeleton, however, the joints most affected are the acromioclavicular joint (ACJ), the facet joints of the spine, and the joints of the hand, especially the PIPs, DIPs, and the thumb base. OA of the hip and the knee is relatively uncommon and it is probable that the pattern of involvement has changed since the medieval period. Thus, in the premedieval period, OA of the hip was more common than OA of the knee, whereas the converse is true in the postmedieval period (Waldron, 1995). The reasons for this are not clearly understood, but may have something to do with improvements in nutrition and consequent increase in body mass.

Particular Features of Osteoarthritis in Different Joints The ACJ: The ACJ is part of the shoulder joint complex and is one of a number of joints which contain intraarticular structures, in this case, a fibrocartilaginous disk which frequently disappears sometime during adulthood. OA of the ACJ is common in clinical practice, resulting in shoulder pain and some limitation of movement (Mall et al., 2013). It is also very common in the skeleton, although it is unusual to find eburnation on the ACJ, and so the diagnosis has to rely on the presence of two or more of the minor criteria referred to above. The vertebral facet joints: These joints are also commonly affected by OA which may cause neck pain (Gellhorn et al., 2013) (Fig. 20.5). The pattern of involvement in the skeleton is similar to that noted nowadays; i.e., the distribution shows two prominent humps, one in the cervical region, and one in the lumbar region, both tending to center on the central vertebrae in the region (Waldron, 1991). There may be a smaller hump in the upper thoracic region; the lower thoracic vertebrae are infrequently affected. OA of the facet joints is frequently found in association with intervertebral disk disease (IVD), but this is not invariably the case. It is also common to find OA on the odontoid peg of C2, sometimes associated with horizontal grooving on the articular surface. Clinically this may present as suboccipital pain (Zapletal et al., 1996). The shoulder joint: The true shoulder joint—the glenohumeral joint—is the least often affected of all the large joints but, when it is, it is usually painful and causes some degree of limitation of movement (Kerr et al., 1985). In the skeleton, eburnation will be found on the axial pole and there will be concomitant changes within the glenoid. There is a form of OA of the shoulder which progresses exceedingly rapidly, due to the presence of oxalate crystals within the joint, and which is known as

726 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

(A)

FIGURE 20.5 Osteoarthritis of vertebrae. (A) Diarthrodial joint eburnation and porosity of the third and fourth cervical vertebrae. (B) Porous degeneration of the diarthrodial joint between the tenth and eleventh thoracic vertebrae. (adult female Eskimo skeleton from an archeological site in the Hooper Bay area of Alaska, United States, NMNH 339115).

(B)

Milwaukee shoulder (Santiago et al., 2014). The head of the humerus is worn down but without the production of much new bone; Waldron has only seen one possible case in the skeleton.

In the event that there is a tear in the rotator cuff, the head of the humerus may be elevated by the action of deltoid and come to rest beneath the acromion. Continued movement of the shoulder may result in the so-called

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impingement syndrome (Cone et al., 1984), and then eburnation may be found on the superior pole of the head of the humerus and on the undersurface of the acromion, with or without the production of new bone; this sign is pathognomonic of impingement and is not uncommon. The elbow joint: The elbow is a compound joint, with three compartments, the radiohumeral, ulnohumeral, and proximal radioulnar joints. OA of the elbow is rarely seen in the skeleton but when it is, the radiohumeral joint is invariably the only one of the three affected; disease of the ulnohumeral joint is extremely uncommon, as is OA of the proximal radioulnar joint unless injury to the joint has occurred. This is unlike the case in clinical practice where all compartments have been found to be involved in the condition. It is often bilateral, and often found in association with OA at other sites, particularly the hands (Doherty and Preston, 1989). This may suggest that the expression of OA at this joint has undergone change in recent times. The wrist and carpal joints: The wrist joint is formed between the distal radius and the proximal articulations of the scaphoid and lunate; the distal ulna is separated from the carpus by a triangular fibrocartilaginous pad and does not enter into the joint. It is infrequently affected by OA. Similarly, the joints between the individual carpal bones are seldom affected by OA but may be secondary to trauma, or avascular necrosis, as in Kienbo˝ ck’s disease of the scaphoid, for example. There is also a wellrecognized form of scapho-trapezium-trapezoid involvement that may be present when all the other joints are normal (Weiss and Rodney, 2007). The joints of the hand: The joints of the hand are frequently affected by OA, but those on the radial side of the hand are more often affected than those on the ulnar side. It has been suggested that this is because the joints affected have undergone rapid evolutionary change (relatively speaking), are, therefore, underdesigned, and thus subject to increased loading compared with those that are not affected (Hutton, 1987). The PIPs and DIPs are often involved as is the thumb base, i.e., the joint between the first metacarpal and the trapezium; OA of these joints is more common in women than in men (Wilder et al., 2006). OA of the first metacarpophalangeal joint is also a common finding; OA of the second and third metacarpophalangeal joints (MCPs) may also be seen but less commonly, whereas OA of the fourth and fifth MCPs is distinctly rare (Waldron, 1993). The sternoclavicular (SCJ) joint: The SCJ is divided into two by the interarticular disk. The upper part of the disk has a fibrous attachment to the superior part of the sternal end of the clavicle, only the inferior part forms the synovial joint. Eburnation of this joint may occasionally be seen in the skeleton; OA of the SCJ is relatively common in clinical practice, especially in those over 50

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(Lawrence et al., 2017). Changes on the upper part of the proximal clavicle will be due to disk disease and must not be confused with the minor criteria of OA. Familiarity with the anatomy of the attachment of the disk is therefore essential. The costovertebral (CV) and costotransverse (CT) joints: There are 12 pairs of CV joints and 10 pairs of CT joints through which the ribs articulate with the thoracic vertebrae. The first, tenth, eleventh, and twelfth CV joints are single, but the others are divided into an upper and a lower joint by the interarticular ligament that runs from the head of the rib to insert into the IVD. In total, therefore, there is a total of 40 CV and 20 CT joints. The pattern of involvement seems to be constant, regardless of time or place, with the first, eleventh, and twelfth being those most commonly affected (Waldron and Willoughby, 2016). They are seldom mentioned in the paleopathological literature, presumably because they are not routinely examined. The hip joint: There is a school of thought that OA of the hip joint is always secondary. And, indeed, there are many conditions that may predispose it, including Paget’s disease, CDH, Perthes’ disease, slipped capital epiphysis, anteversion or retroversion of the femoral neck, coxa vara, and acetabular dysplasia. More recently, femoroacetabular impingement has been suggested as a cause, especially in elite athletes (Ganz et al., 2008). When CDH is untreated—as it would have been in the past—the femoral heads may come into contact with the external surfaces of the iliac blades. The individual is able to walk after a fashion, but the continued movement of femur on ilium will produce a false joint surrounded by a collar of new bone and often with eburnation at its base. It is an easy condition to recognize. With OA of the hip (Fig. 20.6), eburnation is found most commonly on the superior pole of the femoral head, but may sometimes be seen on the axial pole. The amount of new bone formed in hip OA is extremely variable; there may be virtually none, while at the other extreme, there may sometimes be a collar of new bone around the acetabulum, so extensive that it completely surrounds the femoral neck, holding the femur in place. It is not uncommon to see new bone around the head of the femur and the acetabulum that actually prevents full movement of the hip. Following a fracture of the neck of the femur, the head may undergo avascular necrosis. The stump of the neck may remain in the acetabulum and as the individual continues to walk—albeit it with some difficulty, presumably—the movement of the stump will provoke the production of new bone, both within the acetabulum and on the stump, and occasionally, eburnation may be present. The knee joint: The knee joint has three compartments, the medial and lateral plateaus, and the patella-femoral joint. Any of the three may be affected by OA, but the

728 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 20.6 Severe osteoarthritis of the left hip. Note the abnormal contour of the femoral head (HMCS GR 1248).

patella-femoral is more often affected than the others. New bone is generally rather exuberant and the joint surfaces are relatively often grooved. OA of the medial and lateral plateaus is generally not florid and may be represented merely by a small area of eburnation. Medial compartment OA is painful and there is some suggestion that OA of this compartment has increased in frequency in the last 200 years or so. The ankle joint: Although the ankle joint is subject to the highest pressure of any joint in the body, it is rarely affected by OA unless it has suffered trauma or is

secondary to some other pathological process (Valderrabano et al., 2009). The reasons for this are by no means clear although a number of suggestions have been made, including the thickness of the articular cartilage compared with other joints, and differences in metabolism between it and other joints (Salzman et al., 2005). Rarely, the joint may become arthritic secondary to Paget’s disease of the tibia (or tibiae). The joints of the foot: Again, unless subject to trauma, almost none of the joints of the foot in the skeleton is usually affected by OA, the sole exception being the first

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metatarsophalangeal joint, which is often diseased, although there is usually little proliferation of new bone. By contrast, several other joints of the foot are found to be arthritic in clinical practice (Menz et al., 2009). The other joints affected tend to be in very elderly patients, which might explain the discrepancy between ancient and modern feet. The temporomandibular (TMJ) joint: The TMJ is divided into an upper and a lower portion by the presence of the fibrocartilaginous interarticular disk. It is often subject to disease but unless the disk is actually worn through—something that does not happen very often— there is no eburnation to be seen, and so the diagnosis of OA has to rely on finding the minor criteria to satisfy the operational definition (Rando and Waldron, 2012). It is another joint that has received relatively little attention in the paleopathological literature.

Effects of Osteoarthritis During Life It is understandable that paleopathologists would like to explain how the conditions that they see in the skeleton may have affected the individuals during life, but with conditions such as OA this practice can produce false interpretations. It is clear that if a large osteophyte is preventing the femur from moving freely in the acetabulum, this would have affected the individual’s mobility during life, but did he or she feel much pain? The answer is that we are unlikely to know and we will not be helped by the appearances of the joint since there is little relationship between the morphological appearances of a joint and the pain it causes (Link, 2009). There is evidence that joint pain is related to the speed of radiological progression of the disease (Riddle and Jiranek, 2015), but this is not a matter that the paleopathologist can examine. However, we know clinically that OA of large joints, such as the knee and the hip, and of the thumb base is often painful no matter what the appearances of the joint are, and so it is reasonable to suppose that this was also the case in the past. Just how painful, however, is a matter on which it is best not to pontificate.

Osteoarthritis and Occupation As movement is essential for a joint to develop OA, some paleopathologists have supposed that occupations that involved heavy and/or repetitive movements might be particularly likely to induce OA in their participants. As such, there have been many attempts to predict the occupation of a particular individual (or individuals) from the pattern of OA in their skeletons, an exercise that has been proven futile for several reasons, some of which we will discuss here.

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There have been many epidemiological studies of OA in different occupational groups, and a proportion of these have found that some occupations do indeed have an excess of some types of OA (Aluoch and Wao, 2009). Perhaps the most interesting of these findings is that farmers have a risk of developing OA of the hip that is between 2 and 10 times greater than that of the general population (Thelin et al., 2004). This correlation has been found in a number of countries, irrespective of the type of farming being undertaken and the machinery used. Can one say, then, that a skeleton with OA of the hip is that of a farmer? That is, can one argue from the wrong end, so to speak? The answer is clearly, no, since OA of the hip is not confined to farmers, and it is certain that of all those with the disease, more individuals will be nonfarmers than farmers. Another very cogent reason for the inability to deduce occupation from the pattern of OA is that no pattern is unique to any one occupation, so that any conjecture that this is a corn grinder from the Neolithic, or a steersman from the Swedish navy, can only be a guess, and a bad guess at that. Consider the following thought experiment: You attend a rheumatology clinic and are shown the X-rays of the patients waiting to be seen. From these you are asked to determine the patients’ occupations. You may not talk to the patients or see their notes. In how many cases are you likely to get the correct answer? I would suggest that the answer would be close to zero, and yet this is exactly what some have tried to do from archeological human skeletal remains.

OTHER CONDITIONS WITH PROLIFERATION OR EBURNATION There are a number of other conditions that may produce new bone or eburnation (or both), but which are not truly osteoarthritic in nature. These include rotator cuff disease, IVD disease, Baastrup’s disease, spondylolysis, scoliosis, and DISH. Rotator cuff disease: The rotator cuff is formed from the joint tendons of the subscapularis, supraspinatus, infraspinatus, and teres minor, and the cuff helps to stabilize the otherwise unstable shoulder joint. The tendons of the rotator cuff frequently become inflamed for a variety of extrinsic and intrinsic reasons (Tytherleigh-Strong et al., 2001), and this produces changes in their insertion on the greater and lesser tuberosities of the humerus. These changes include the proliferation of new bone (enthesophytes) and pitting on the surface of the insertion. There are often accompanying changes in the ACJ and the acromion. Rotator cuff disease is a common cause of shoulder pain and limitation of movement at the joint (Bunker, 2002), and the pattern of involvement in the past seems identical with that noted in current clinical practice.

730 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

In some cases, a tear may develop in the rotator cuff, usually in the supraspinatus tendon. The cause of the tear is not well understood, but seems to be related to some extent to the morphology of the acromion (Balke et al., 2013). One consequence of the tear is that the head of the humerus impinges on the undersurface of the acromion. Following impingement, eburnation may be seen on the superior pole of the head of the humerus and on the undersurface of the acromion, which makes diagnosis straightforward. IVD disease: The IVD is subject to degeneration as the result of progressive structural failure (Adams and Houghley, 2006), although variations in the COL9A2 gene have also been implicated (Annunen et al., 1999). The degeneration, which is highly age-dependent, produces a series of changes in the adjacent vertebrae—the disks, of course, do not survive. The earliest changes seen in IVD disease may be a series of pits around the rim of the vertebrae, which represent inflammation in the Sharpey’s fibers that hold the disk down to the vertebral end plates. As the disease progresses, there is progressive pitting and new bone formation on the end plates, and the development of marginal osteophytes, which have a characteristic “frilly” appearance. IVD disease in the skeleton is extremely common, especially in the cervical region, less common in the lumbar region, and rarely seen in the thoracic. It is often seen in association with OA of the facet joints, but this is by no means always the case. Baastrup’s disease: In Baastrup’s disease (“kissing spine disease”), a pseudarthrosis is formed between the spinous processes of two or more lumbar vertebrae, usually in the context of degenerative disease of the spine (Phillipp et al., 2016). The approximated spinous processes (usually between L4 and L5) become hypertrophic, and with continued movement may become eburnated. The eburnated area generally enlarges slightly and becomes somewhat elliptical in shape. Baastrup’s disease is a common cause of back pain, but is a condition that is not often considered by paleopathologists (Kacki et al., 2011). Spondylolysis: Spondylolysis is most often the result of a stress fracture of the pars interarticularis, although there are five classifications in total: hypoplastic, isthmic, degenerative, traumatic, and pathological (Syrmou et al., 2010). The condition is more common in males than in females, and in adults is usually asymptomatic (Ko and Lee, 2011). The great majority of cases occur at L5, followed by L4. If the fracture is bilateral, which is the norm, then the lamina of the vertebra becomes separated from the vertebral body. It may then become displaced and rub against the lamina below, with the production of eburnation on both. The condition is common, with a prevalence of up to 5% noted in clinical settings (Waldron, 1991) and diagnosis is straightforward,

although those new to paleopathology may be a little perplexed if the detached lamina is not recovered. In some instances, the body of a spondylitic vertebra may slip forward on the sacrum (or the vertebra below if the lesion is higher than L5), a condition known as spondylolisthesis; this is particularly the case if the affected vertebra is hypoplastic (Niggemann et al., 2012). The degree of slippage on the caudal vertebra is accorded five grades: I, slippage up to 25%; II, up to 50%; III, up to 75%; IV, up to 100%; and V, completely separate. Spondylolisthesis may be difficult to recognize in the skeleton, although in long-standing cases the cranial and caudal vertebrae may show some complementary sloping when fitted together. Scoliosis: Scoliosis is a lateral curvature of the spine. It most often presents in adolescence and is more common in girls than in boys. The majority of cases are idiopathic, but biochemical, neuromuscular, hormonal, and genetic factors have all been suggested as being of etiological significance (Veldhuizen et al., 2000; Latalski et al., 2017). The curvature of the spine varies in degree, and clinically is defined by the Cobb angle, i.e., the angle made between the top-most and bottom-most vertebrae in the curve (Weiss et al., 2006). In severe cases, the vertebrae on the concave side of the curve are collapsed and the ribs may be tightly packed together. Examination of the facet joints and of the CT and CV joints on the concave side may reveal the presence of eburnation and other changes typical of OA. Other neuropathic disorders that produce muscular spasms that may induce strain in a joint may also result in eburnation even though there is no voluntary movement. In florid cases, diagnosis of scoliosis is straightforward, but lesser degrees may present more difficulty, especially if vertebrae are missing or badly damaged to the point that it is impossible to reconstruct the spinal column. DISH: The modern diagnosis of DISH requires the presence of four contiguous fused vertebrae with extraspinal enthesophytes (Resnick et al., 1975). The spinal fusion on its own typically is referred to as Forestier’s disease, but is often the only evidence seen in a disarticulated skeleton. The characteristic feature of DISH is the production of florid ossification into the anterior longitudinal ligament, which appears only on the right side in the thoracic region, but may affect the entire spinal column. The reason for the restriction of change to the right side in the thoracic region is thought to be that the presence of the descending aorta (on the left) somehow prevents the ossification there. This explanation seems to be confirmed by that fact that in those with situs inversus and DISH, the ossification is only on the left. The disk spaces typically are normal (Fig. 20.7).

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FIGURE 20.7 Diffuse idiopathic skeletal hyperostosis (DISH) of the spine with some osteoarthritis as well. Note the major difference in the amount of hypertrophic bone formation on the left versus the right side of the thoracic vertebral bodies (male 71 years of age, modem anatomical case, IPAZ 2287/63).

DISH is associated with obesity and type 2 diabetes (which are themselves highly correlated) and with elevated serum uric acid levels (Sarzi-Puttini and Atzeni, 2004). Recently, it has been found that individuals with DISH have low circulating levels of DKK-1, a cytokine that inhibits the Wnt signaling system, thus allowing free range for the production and activity of osteoblasts (Mader et al., 2017); genetic factors may also be involved (Senold et al., 2012). DISH is much more common in skeletons recovered from high-status sites, such as

monasteries (Rogers and Waldron, 2001), but this is not to say that one can infer that a skeleton with DISH is necessarily that of a high-status individual. The condition is highly age-related and more common in men than women. It is often asymptomatic, discovered as an incidental finding at X-ray, but patients may complain of some stiffness in the back and, occasionally, pain at sites of enthuses. Fractures of the spine are rare, but may go undetected. If they are displaced, they may cause serious neurological complications (Maxie`res, 2013), such as

732 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

spinal cord compression (Takagi et al., 2017). DISH in the cervical region may be an unusual cause of dysphagia (Krishnarasa et al., 2011). DISH may be the most straightforward condition in the skeleton which one can diagnose confidently, though paleopathological cases may not conform exactly to the clinical criteria. Thus, fewer than four contiguous fused vertebrae may be present—in a spine damaged postmortem, for example. And where four or more vertebrae are present, they may not be completely fused; probably because the condition was not fully developed. Individuals with DISH may have fused joints if ligaments such as the sacroiliac are involved, and ossified soft tissues may sometimes be recovered. These individuals are also likely to produce heterotopic bone, and if they develop OA, they produce masses of new bone.

THE EROSIVE ARTHROPATHIES The erosive arthropathies comprise two groups, RA, and the so-called sero-negative arthropathies, of which only the four most common will be considered here. There is also another condition that may be said to bridge the gap between the two great classes of joint disease—erosive osteoarthritis (EOA). The so-called crystal arthropathies will be considered separately, as they have a number of features that separate them from the others in this group.

Rheumatoid Arthritis RA is a chronic inflammatory disease, the cause of which is presently unclear, although the consensus seems to be that it is multifactorial (Alamanos and Drosos, 2005). Genetic factors are clearly important, and there is a strong association between the risk of developing RA and the presence of several alleles of the HLA DRB1 gene (Flugger and Svejgaard, 2000). RA has a clinical prevalence of between 0.5% and 1%, affects women more frequently than men, and has a peak age of onset in the thirties. The first clinical description of the disease was given in 1800 by Augustin Jacob Landre´-Beauvais (1772 1840), who called it a new form of gout—goutte asthe´nique primitive. His description formed his MD thesis and was based on the case histories of nine elderly women in the Salpe´trie`re hospital in Paris. Cases have been described in the paleopathological literature that predate Landre´-Beauvais’ description (Waldron et al., 1994; Dieppe et al., 2006), so it seems likely that something happened in the late 17th century to change the character of the disease, causing it to become clinically more severe. RA is now becoming both less prevalent and less severe, at least in Western countries, suggesting that its character is changing once more, but this time in the direction of becoming less virulent.

Pathophysiology: The synovial membrane is infiltrated with inflammatory cells and swells to form a pannus that gradually spreads across the joint surface, causing considerable destruction in its wake. A number of inflammatory cells can be found within the joint, including fibroblasts, macrophages, T-cells, and neutrophils. The joint also contains a number of proinflammatory cytokines including TNF-alpha, IL-1, and IL-8, which stimulate the action of osteoclasts, together with reactive oxygen radicals, superoxides, and nitric oxide (McInnes and Schett, 2007). The disease, which is usually painful, normally begins in the small joints of the hands or the feet and is characterized by the presence of symmetrically arranged erosions at the margins of the joints; the MCP and MTP joints tend to be preferentially affected. As the joint progresses, the MCP joints may sublux and the fingers become displaced to the ulnar side of the hand. This socalled ulnar deviation has a complex etiology, but involves, in part, destruction of the tissues of the MCP joints and the unopposed pull of the finger extensors (Bielefeld and Neumann, 2005). Ulnar deviation is not found solely in RA, however, but other causes are less common (Zuber et al., 1996). Any joint may become involved in RA (Fig. 20.8), and there are also systemic effects, including, cardiovascular disease (Sattar et al., 2003). Clinically, these extraarticular effects are more common in men than women (Cojocaru et al., 2010), but in all patients there is some shortening of life expectancy (Charles et al., 2001). There is almost no new bone formation in RA and ankylosis is rare. The cortex around an affected joint is frequently thinned, both from disuse, but also from the stimulation of osteoclasts by IL-6. The sacroiliac joint is always spared in RA, and there is never any spinal fusion.

FIGURE 20.8 Rheumatoid arthritis of the hip with cartilaginous ankylosis. Notice minimal separation between the acetabulum and femur and severe osteoporosis, especially of the unburdened portion of the femoral head (73-year-old male, MGH autopsy 34283).

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A number of patients may suffer from subluxation of the atlantoaxial joint, in some cases leading to myelopathy; other patients may suffer atraumatic fractures of the odontoid peg (Lewandrowski et al., 2006). The characteristics of an erosion: In order to recognize an erosive arthropathy in the skeleton, it is important to be clear about the characteristics of an erosion and to be able to differentiate it from other defects in bone such as vascular foramina, small cortical defects, taphonomic changes, or postmortem damage. A true erosion is characterized by: 1. 2. 3. 4. 5.

Cortical destruction; Undercut margins; Exposed trabeculae; Sharp or scalloped ridges; and A scooped floor.

Under the electron microscope, it may be possible to see osteoclast footprints, and on X-ray the erosion may have a sclerotic margin. Any hole in the bone that has an intact cortex cannot be an erosion. Damage to bone, either while in the ground or during excavation, may damage the cortex and expose trabeculae, but it is extremely unlikely that such damage would produce undercut edges or a scooped floor. Clinical course: Classically, there are said to be three types of RA: progressive, intermittent, and malignant. In the progressive type, which affects the majority of patients, the disease inevitably worsens, although the severity of the disease may fluctuate from time to time; about a fifth of patients have intermittent disease in which periods of activity are interspersed with remissions which may be long-lasting; the minority of patients with malignant RA suffer most from extra-articular symptoms, which are often fatal (Scott and Steer, 2007). During the progression of the disease the hands may become very deformed, and it is difficult to see how early physicians could have overlooked the signs in the hands, supposing they were affected to the same extent in pretreatment days. Rheumatoid factor (RF): Until the 1950s, all the erosive arthropathies that did not conform to the typical appearance of RA were considered to be atypical variants (Copeman, 1948). It was then discovered that the majority of patients with typical RA had a protein in their blood which was usually absent from patients with the atypical forms. This protein, which came to be known as RF, was later shown to be an IgM (or IgA0) directed against IgG. After this, the atypical forms of the disease began to be referred to as sero-negative, although this description did not enter into general usage until some years later and the term did not enter the rheumatology texts until about the early 1960s. Citrullinated proteins: RF has a low specificity and is not entirely satisfactory for diagnosing RA, even though

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clinically it is used as a diagnostic indicator. Antibodies directed against citrullinated peptides (CPs), which are thought to be produced in the synovium by the citrullination of arginine, are much more specific for RA, may have a pathogenic role in the production of the disease, and can be detected much earlier in the course of the disease than RF (Yamada et al., 2005). Paleopathological diagnosis: The diagnosis of RA depends very much on having an intact skeleton; it is imperative that either the hands or the feet (and preferably both) are present and well preserved. The criteria for the diagnosis would include: symmetrical erosions in the small joints of the hands or the feet, sparing of the sacroiliac joint, and no spinal fusion. In instances when the skeleton is incomplete, or where one is dealing with disarticulated material, it is unlikely that a positive diagnosis of RA could be made with any confidence, no matter how suggestive the erosions around a joint might be. It is, of course, perfectly possible to make a diagnosis of possible or probable RA, but the element of doubt always should be explicit. As an adjunct to diagnosis, it may be possible to extract RF or CP antibodies from bone thought to show RA. We failed in one attempt to detect RF probably because the method used was not sensitive enough to pick up what were most likely to be low levels in the bone (Antoine and Waldron, unpublished data). As with other tests for biomarkers in the skeleton, a positive result may help to confirm a diagnosis but a negative one cannot be used to rule out a diagnosis for the simple reason that the particular gene or protein may not have survived (if it was ever there in the first place).

THE SERO-NEGATIVE ARTHROPATHIES There are four major members of the group of seronegative arthropathies: ankylosing spondylitis (AS), psoriatic arthropathy, reactive arthropathy (ReA, formerly known as Reiter’s syndrome), and enteropathic arthropathy. Some other conditions also are considered part of the spectrum, including some forms of juvenile arthritis, acute uveitis, Bec¸het’s disease, and Whipple’s disease; there is also an undifferentiated form. The clinical prevalence of all forms of sero-negative arthropathy is ca. 3% (Stolwijk et al., 2012). The sero-negative arthropathies share a number of features in common, aside from lacking RF. The sacroiliac joint is always affected in some way, and there is also some degree of spinal fusion. Because of the spinal fusion, these diseases often are referred to as spondyloarthropathies (Kettering et al., 1996). There is also a strong association with the HLA-B27 antigen, the strength of which varies from disease to disease (Table 20.2). The strongest association is with AS, but the presence of the

734 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

TABLE 20.2 The Frequency of HLA-B27 in Patients With Sero-Negative Arthropathies Disease

Proportion of Positive Patients

Ankylosing spondylitis

. 90

Reactive arthropathy

70 90

Psoriatic arthropathy

60 70

Enteropathic arthropathy

50 60

Undifferentiated

50

antigen is not a sufficient cause for the disease, however, since although a great many patients with the disease are antigen-positive, only a small proportion of those with the antigen (1% 2%) are affected by it (Reveille, 1998).

Ankylosing Spondylitis AS is an inflammatory condition that clinically affects men considerably more often than women, and has a peak age of onset between the ages of puberty and the early thirties (Sieper et al., 2002). AS is more common in Caucasians than others, and over 90% of Caucasians with the disease are positive for HLA-B27, compared with only about 50% of African-Americans. The prevalence varies pari passu with the prevalence of HLA-B27 in the population, so that the prevalence is low in countries such as Japan where the prevalence of HLA-B27 is also low (Otsuka et al., 2015). Clinical course: The first manifestation of the disease is often stiffness in the back in the early morning. As it progresses, the spine becomes increasingly stiff and painful, with varying degrees of kyphosis and, in the days before the advent of disease-modifying medication, the individual might become completely stooped. There may be pain in other joints, pain at sites of enthuses, especially those around the calcaneus, and there may be pain in the costochondral junctions. The course is variable, but the outcome is usually worse in those in whom the onset occurs at an early age, and there is an increased mortality compared with the general population (Exarchou et al., 2016). Skeletal manifestations: AS has a predilection for the axial skeleton (Fig. 20.9). The sacroiliac joints are affected bilaterally and symmetrically and eventually become fused, and erosions may be seen within them on X-ray. Within the spine, the earliest sign, sclerosis at the attachment of the annulus fibrosis to the anterior corner of the end plate, may be seen radiologically. There may also be erosions at this site. The vertebrae may appear to

be squared as the normal concavity is filled with periosteal new bone. This is best seen in the lumbar region of the spine. The most characteristic feature of AS, however, is the development of syndesmophytes on the sides and anterior surface of the vertebral bodies, which are the result of heterotopic ossification of the annulus. The syndesmophytes, which may acquire considerable size, bridge the IVD and fuse the vertebrae eventually to produce a smooth, undulating contour (Fig. 20.10). The squared-off appearance of the vertebrae and the bulging syndesmophytes produce an appearance somewhat like that of a bamboo cane, and this is the epithet conferred upon it by radiologists—bamboo spine. There are no skip lesions in the fused spine, that is to say, there are no normal areas of spine interspersed between the fused areas. There may be ossification of the supraspinous ligament. The CV and CT joints may be affected, in which case, the ribs will be fused to the thoracic vertebrae (Østergaard and Lambert, 2012). Extraspinal erosions are uncommon, although there may often be a large erosion on the anterolateral aspect of the humeral head, which may sometimes be confused with a Hill Sachs lesion (Babini et al., 1992). Enthesophytes may also be found, and when they do occur it is most often around the calcaneus. Paleopathological diagnosis: A full-blown case of AS in the skeleton is a spectacular sight. If the spine, pelvis, and ribs are completely fused, then they may be lifted up en bloc. The appearances of the syndesmophytes are characteristic, although they are sometimes confused with the flowing, melted candle-wax appearance of the osteophytes in DISH, in which pelvic fusion may also occur, but due to ossification of the sacropelvic ligaments, not fusion of the sacroiliac joint. The combination of sacroiliac fusion, spinal fusion with no skip lesions, and syndesmophytes should be sufficient to render the diagnosis certain.

Reactive Arthropathy The first description of the occurrence of arthritis with urethritis and uveitis is generally attributed to Hans Reiter (1881 1969), who reported the triad in a German army officer in 1916. This form of arthritis came to be known as Reiter’s syndrome, although it was reported in the same year in the French medical press by Noe¨l Fiessinger (1881 1946) and Edgar Leroy (1883 1965), and in France their names were attached to the syndrome rather than Reiter’s (Wu and Schwartz, 2008). Because of Reiter’s reprehensible behavior during the Second World War (Halioua, 2009), his name eventually was removed from the syndrome, and it is now referred to as ReA. Clinical course: The disease is triggered by a urethral or gastrointestinal infection. One of the most common causes is a genital infection with Chlamydia trachomatis,

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735

FIGURE 20.9 L2 L5 vertebrae and left innominate of a case of ankylosing spondylitis. (A) Anterior view, showing smooth ankylosis of left sacroiliac joint and fusion of vertebral bodies. (B) Sagittal section, showing ankylosis of the joints, ossification of interspinal ligaments and the anulus fibrosus, and severe osteoporosis of vertebral bodies (67-year-old male, IPAZ autopsy 572 from 1963).

but in the past it frequently followed gonorrheal infections. Gastrointestinal infections with Salmonella, Shigella, Campylobacter, and Yersinia species are also frequent precipitants. Symptoms usually develop within 1 4 weeks following the infections, and patients present with inflammation of large joints, usually fewer than five in total, but most often affecting the sacroiliac and knee joints, plus uveitis and urethritis. Men are affected more commonly than women, and the peak age of onset is between 20 and 40 years of age. The predominant complaint is of pain in the affected joint or joints, and often, pain in the heel as the result of plantar fasciitis. The disease generally is self-limiting and remits within a few weeks or months, but up to a third of patients enter a chronic phase with sacroiliitis and other skeletal manifestations. Life expectancy is not shortened (Selmi and Gershwin, 2014). Skeletal effects: Sacroiliac involvement may be unilateral or bilateral, but is generally asymmetrical. The spine

is not affected to the same extent as in some of the other sero-negative disorders, but paravertebral bridges may cause spinal fusion, particularly around the thoracolumbar junction; skip lesions are always present. The cervical spine is affected much less frequently than in other spondyloarthropathies, but rarely atlantoaxial rotatory subluxation is found. Asymmetrical erosive changes are found in the small joints, and those of the feet tend to be more frequently involved than those of the hand. Erosion of the metatarsophalangeal (MTP) joints and of the metatarsal heads is relatively common, and erosions may be found on the posterior surface of the calcaneus; there may be valgus deformities of the toes. Enthesophytes are common, especially around the heel, and a calcaneal spur at the site of the insertion of the plantar fascia is a frequent observation. Fluffy periosteal new bone also may be found on the calcaneus, on the shafts of the metatarsals and phalanges, and on the tibia and fibula (Martel, 1979). In a few cases, there may be

736 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

subluxation of the MTP joints with fibular deviation of the phalanges; this is known as Lanois deformity. Paleopathological diagnosis: It is not easy to make a diagnosis of ReA in the skeleton, as the changes are often not very florid. However, diagnostic criteria include asymmetrical sacroiliitis, spinal fusion with skip lesions, erosions particularly affecting the small joints of the feet, calcaneal spur, and periosteal new bone on the lower leg and foot bones.

Psoriatic Arthropathy Clinically, up to 30% of patients with psoriasis may develop an arthropathy, usually 10 20 years after the onset of the skin disease, so that the age of onset is usually later than in many of the other sero-negative joint diseases, from 30 to 50 years (Gladman et al., 2005). Men and women are affected equally. In the great majority of cases, the arthritis develops in those who have psoriatic

FIGURE 20.10 Paleopathological case of ankylosing spondylitis. (A) Anterior view of spine. (B) Anteroposterior radiograph of fused vertebrae and ribs. Paleopathological case of ankylosing spondylitis. (C) Posterior view of spine. (D) Detail of diarthrodial joint fusion of thoracic vertebrae and ribs. (E) Anterior view of pelvis; note the ankylosis and osteophyte development of the sacroiliac joint. Paleopathological case of ankylosing spondylitis. (F) Right lateral view of spine; note the smooth, remodeled surface of the thoracic vertebrae and the more pronounced syndesmophyte development of the lumbar vertebral bodies. (G) Detail of thoracic remodeling. Paleopathological case of ankylosing spondylitis. (H) Lateral radiograph of the fused spine and ribs (adult male skeleton from Kuskokwim River, Alaska, United States, NMNH 351296).

Joint Disease Chapter | 20

FIGURE 20.10 (Contiuned)

737

738 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 20.10 (Contiuned)

Joint Disease Chapter | 20

739

1. Oligoarthritis. This is the most common type and is characterized by the asymmetric involvement of three or fewer joints. The arthritis is usually mild. 2. Polyarticular. In this variety, five or more joints are affected symmetrically, and in the past it was probably disabling in the majority of cases. This type can mimic the changes in RA. 3. Arthritis mutilans. This is a very destructive and disabling form of the disease, occurring in about 5% of those affected. It is in this form that the most florid changes are seen in the DIPs, PIPs, and MCP joints. There may be resorption of the distal ends of the proximal phalanges, with widening of the proximal ends of the distal phalanges, giving the so-called cup and pencil sign. In advanced cases, the changes are similar to those seen in severe RA. 4. Spondyloarthropathy. This is characterized by asymmetrical sacroiliac involvement, and spinal fusion with skip lesions. The cervical spine is more often involved in PsA than in the other sero-negative arthropathies. 5. Predominant involvement of the DIPs. Another uncommon form of PsA, this is characterized by involvement of the DIPs in both the hands and the feet.

FIGURE 20.10 (Contiuned)

changes in their nails. There is the usual association with HLA-B27. Clinical course: Patients generally experience joint pain in the hands and wrists, sometimes with swelling of the fingers. They may also have neck, lower back, and sacroiliac pain, as well as pain in the feet and ankles. They will, in addition, have the clinical features of psoriasis, with thickening and reddening of the skin, especially over the elbows and knees, and in the scalp. Skeletal effects: The skeletal changes in PsA may be classified into five more-or-less distinct types (Richlin et al., 2017), although, in practice, different types may coexist:

Paleopathological diagnosis: The diagnosis of PsA in the skeleton is not easy. The usual hallmarks of an erosive arthropathy are likely to be present, including some degree of sacroiliac and spinal fusion with skip lesions (Fig. 20.11). Enthesopathy is common, and other joint changes usually are confined more to the distal joints of the hands (although in the only case Waldron has seen in a skeleton, it was the feet that were affected, not the hands). The best chance of making a correct diagnosis is if the individual had arthritis mutilans (Zias and Mitchell, 1996), although there may be other causes of acroosteolysis even if few are likely to be seen in the skeleton (Table 20.3). Arthritis mutilans can closely resemble advanced RA, but in RA there is no sacroiliac or spinal involvement, which should help differentiate the two conditions.

Enteropathic Arthropathy Between 20% and 40% of patients with inflammatory bowel diseases, such as Crohn’s disease or ulcerative colitis, develop some form of arthropathy (Peluso et al., 2015). The axial skeleton and peripheral joints are affected. Clinically, the sacroiliitis and the spinal fusion are the same as in AS, and about 50% of patients are HLA-B27-positive (Colombo et al., 2009). The peripheral arthropathy has been classified into two types; type 1, the pauciarticular type (which is self-limited) and type 2, the polyarticular type which is much longer lasting. A type 3,

740 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 20.11 Possible case of psoriatic arthritis. (A) Right ilium with erosion of the subchondral bone of the sacroiliac joint; note the enthesial ossification posterior to the joint. (B) Anterior view of ankylosis of T10 L3 vertebrae. (C) Left lateral view of T10 L3 vertebrae; note fusion of diarthrodial joints, Possible case of psoriatic arthritis. (D) Superior view of the end plate of the S1 vertebral body; note the evidence of ossification involving the cartilage disk. (E) Lateral radiograph of T7 L3 vertebrae; note the less than normal density, the reduction of disk space and the reduced size of some vertebral bodies. (F) Anterior view of ankylosis between the skull base and the first three cervical vertebrae; note the abnormal axis of the vertebrae in relation to the skull base. (G) Posterior view of the skull base and C1 C3 vertebrae. (H) Reflected proximal, left tibio-fibular joint with marginal erosion of the subchondral bone surfaces. Possible case of psoriatic arthritis. (I) Anterior, proximal tibias with enthesopathy particular evident on the left. (J) Anterior, distal tibias with inflammatory remodeling (arrows) underlying the tendon of the tibialis anterior, suggestive of enthesopathy (adult male skeleton, 45 years or more, from an archeological site in New Mexico, United States, dated between AD 1275 and 1350, NMNH 239208).,

Joint Disease Chapter | 20

FIGURE 20.11 (Contiuned)

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742 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 20.11 (Contiuned)

Joint Disease Chapter | 20

TABLE 20.3 Some Causes of Acroosteolysis

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often the case that no more is seen on the radiograph than by careful examination of the bare bones.

P—psoriatic arthropathy, pyknodysostosis I—injury (e.g., burns, frostbite) N—neuropathy (e.g., diabetes, leprosy) C—collagen vascular diseases (e.g., Raynaud’s disease, scleroderma) H—hyperparathyroidism F—familial (e.g., Hajdu Cheney syndrome) O—other (e.g., progeria, exposure to vinyl chloride monomer)

has also been suggested, in which there is both axial and peripheral involvement (Smale et al., 2001). There is no possibility that this type could be distinguished from other forms of erosive arthropathy in the skeleton.

Some General Comments on the SeroNegative Arthropathies It is best to remember that textbook cases occur only in textbooks, and this is particularly the case when considering the sero-negative arthropathies in the skeleton. In clinical practice, patients can be followed over weeks or months to see how their disease develops, and it may be that a definitive diagnosis is arrived at only after a substantial period of observation. In paleopathology, the “patient” is seen only once, and it is by no means clear what stage of the disease he or she had entered at the time of their death. And moreover, there is often the problem that the skeleton is poorly preserved and elements vital for the diagnosis are missing. Of the sero-negatives that are likely to be seen in the skeleton, AS is the only one in which a diagnosis may be made with some confidence. Trying to squeeze other signs into a neat diagnostic box is so likely to prove disappointing that one must question the wisdom of trying to do so. And it must also be borne in mind that one may be dealing with the undifferentiated form of the disease in which the signs do not fit neatly into any of the diagnostic boxes. True erosions often are seen in the skeleton, single or numerous, but accompanied by none of the other signs of the erosive arthropathies such as sacroiliitis or spinal fusion, hence a definitive classification is not possible. Under those circumstances, all that can be done is to report their presence and location and swiftly move on to the next skeleton. Radiography may be helpful but only with the help of a skeletal radiologist, and even then it is

Erosive Osteoarthritis EOA is in some ways a bridge between the two major classes of joint disease, and is the form in which there is a much greater degree of inflammation. EOA was first described in 1966 and is now recognized as a distinct entity, although some authors feel that it is no more than a particularly severe form of hand OA. Clinical course: Erosive OA affects the DIPs and PIPs in about 10% of those with OA of the hands; it is much more common in women than men (Kwok et al., 2011). EOA is characterized by pain, often of acute onset, and much more impairment of function than in nodal OA (Wittock et al., 2012). Erosive changes may also be found in the thumb base and on the facet joints of the spine, and on this account some authorities consider that the time has come to redefine the condition (Punzi et al., 2015). Skeletal effects: There will, of course, be the usual changes associated with OA, but in addition, asymmetric erosions are seen in the center of the DIPs or PIPs. The loss of cortical bone gives rise to two characteristic appearances on X-ray, the gull-wing sign on proximal joint surfaces and the sawtooth sign on distal ones (Ulusoy et al., 2011). The gull-wing sign is the result of two erosions with sclerotic margins describing a rounded M-shape, reminiscent of a child’s depiction of gulls flying. The sawtooth sign results from a series of adjacent erosions simulating the jagged appearance of the cutting edge of a saw. Erosive OA is the only form in which ankyloses is at all common, and this may occur in up to 15% of all patients. Paleopathological diagnosis: The diagnosis of EOA in the skeleton is—mercifully—not difficult since it relies upon the usual features of OA in the hands, in the presence of central erosions. Additionally, some of the small joints of the hand may be fused and X-rays may show the gull-wing or sawtooth changes (Rogers et al., 1991). Radiography should not be necessary to make the diagnosis, however, and neither should sex be used as a diagnostic criterion.

THE CRYSTAL ARTHROPATHIES Four types of crystal are associated with specific types of arthropathy: monosodium urate (uric acid), calcium pyrophosphate, calcium phosphate (hydroxyapatite), and oxalate. The arthropathies that they produce differ somewhat in their epidemiology and their effects, and only one— gout—is likely to be recognized in the skeleton.

744 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

Gout Gout may be primary or secondary, acute or chronic. The primary form is the result of a defect in purine metabolism so that uric acid accumulates in the blood. When the level saturates the extracellular fluid, urate crystals may precipitate in soft tissues, including those within or around joints. Within the joint the urate crystals are phagocytosed by synovial lining cells, stimulating an inflammatory response (Martinon et al., 2006). In addition, the crystals activate caspase-1, which then stimulates monocytes and macrophages to produce the proinflammatory cytokines, IL-1β (Pope and Tschopp, 2007). Clinically, in the majority of cases the accumulation of urate results from failure of excretion, overproduction is a minor component. Genetic factors are also involved and the disease does tend to run in families. Primary gout is very much more common in men than women, in whom the disease rarely occurs before the menopause. It has a peak incidence between 30 and 50 years of age, and a prevalence of between 1% and 2% (Mikuls et al., 2005). The disease is more common in those who are overweight and who consume a great deal of alcohol. It is a disease of great antiquity, written about in detail by 16th and 17th century physicians, some of whom gave their accounts based on personal experience. Gout seems to have become particularly common in the 18th century, probably as the result of exposure to lead in food and drink, which inhibits the secretion of urate by the renal tubules. Secondary gout results from renal failure, treatment with some forms of drug, particularly diuretics, and myeloproliferative disorders, such as leukemia. Clinical course: Clinically, gout can be divided into acute and chronic phases. The acute phase presents with sudden onset of pain, redness, and swelling in a joint, typically the first MTP joint. The pain is intense, but selflimiting. A variable proportion of patients go on to develop chronic gout, which is characterized by the presence of gouty tophi—painless swellings in soft tissues composed of urate crystals. Tophi within or around a joint result in an asymmetrical polyarthropathy which affects the first MTP joint in the great majority of cases (Nakayama et al., 1984), but may also involve other peripheral joints, including the feet, hands, wrists, and elbows. The resultant erosions are sharply defined, with sclerotic margins, and sometimes an overhanging margin, the so-called Martel hook. The erosions may be unifocal or multifocal, often cross joint margins, and enthesophytes may be present especially around the calcaneus (Watt and Middlemiss, 1975) (Fig. 20.12). Paleopathological diagnosis: The diagnosis of gout in the skeleton may present some difficulties and is most likely to be made when the first MTP joint is involved. Here, a sharply defined erosion that spans the joint

FIGURE 20.12 Probable case of gout in the right and left medial first metatarsals (30-year-old male from a medieval site in Barton-on-Humber in East Yorkshire, England; burial no. 1870).

margins should be sufficiently suggestive to permit a firm diagnosis. The presence of a sclerotic margin and a Martel hook would be important confirmatory signs. Recovery of urate crystals is sometimes possible from mummified tissue (Ordi et al., 2006), but not from the skeleton. The pressure defects around the first MTP joint seen in cases of bunions (hallux valgus) are often a trap for the unwary, but since these do not have the characteristics of a true erosion, the difference should be obvious and it may sometimes be possible to demonstrate the valgus defect when MTP1 and its proximal phalanx are united. Pseudogout and other crystal arthropathies: Calcium pyrophosphate dihydrate (CPPD) crystals may be deposited in fibrocartilaginous tissues, resulting in chondrocalcinosis. Pseudogout (or CPPD disease) follows from the shedding of crystals from articular cartilage into the joint cavity and the precipitation of an inflammatory response (Ellis and Koduri, 2009). Pyrophosphate crystals often are noted in the synovial fluid in cases of OA, and the changes seen in the joint most resemble those of OA, although they are often much more florid than in OA and the distribution tends to differ from OA (Table 20.4). The most important etiological factor in pseudogout is age and the prevalence increases markedly with age (Jones and Quilty, 2013). The presence of hydroxyapatite crystals within a joint is associated with a severe, destructive form of arthropathy, mainly affecting the shoulder, in particular the supraspinatus tendon (Watt, 1983); Milwaukee shoulder, a rapidly developing form of OA, is one rare outcome.

Joint Disease Chapter | 20

TABLE 20.4 Distribution of Joint Changes in the Crystal Arthropathies Disease/Type of Crystal

Joints Typically Affected, in Order of Frequency

Gout/monosodium urate

First MTP Feet Hands Wrists Elbows

Pseudogout/calcium pyrophosphate

Shoulder Elbow Carpus

Hydroxyapatite disease/ calcium phosphate

Shoulder

Oxalate crystal disease/ calcium oxalate

PIPs MCPs Elbows Knees Ankles

Whether the presence of the hydroxyapatite crystals is the cause or the consequence of OA is not clear. Oxalate crystal disease may be the result of a rare autosomal recessive genetic disorder (primary disease) or from the increased uptake of oxalate from the gut (secondary disease). Oxalate crystals within a joint provoke an inflammatory response and a symmetrical, polyarticular arthropathy typically affecting joints of the hands, feet, elbows, knees, and ankles, while crystals within the ligamentum flavum may give rise to spinal stenosis (Lorenz et al., 2013). It is extremely unlikely that these types of crystal arthropathy could be distinguished from each other in the skeleton, or from other, much more common, types of arthropathy.

SEPTIC ARTHROPATHY Clinically, septic arthritis is an uncommon condition with an incidence of about 2 10 per 100,000 (Goldenberg, 1998). This condition results from the introduction of infectious agents into the joint cavity, usually as the result of hematogenous spread from a distant source of infection or, occasionally, by direct introduction following trauma. The most common infectious agents are Staphylococcus aureus (which gives rise to a pyogenic arthropathy), followed by streptococci and Gram-negative bacteria; in newborns and children under the age of 5, the most common infectious agent is Haemophilus influenzae (Weston et al., 1999). In the past, the most common cause would have been tuberculosis (see Chapter 10). The disease is

745

usually unifocal, the knee being most often affected in adults, and the hip in young children (Gupta et al., 2001). Precipitating factors include age, RA, diabetes, and, more rarely, gout (Yu et al., 2003). Within the joint, the bacteria elicit an inflammatory response with the release of cytokines and proteases that rapidly lead to the destruction of articular cartilage and subchondral bone. Despite modern treatments, there is a substantial mortality (10% 15%), and in up to half of all patients, there is complete loss of function of the affected joint. There seems little reason to doubt that the incidence of septic arthritis would have been greater in the past and that the outcomes would have been worse before the advent of any effective surgical or antibiotic treatments. It is probable that many of those affected would have died from septicemia, and that those fortunate enough to have survived would have been left with considerably damaged joints. There are no features of septic arthropathy that are unique to the condition, and the diagnosis has perforce to be one of exclusion. If there is no better explanation for a joint that is ankylosed, or that shows evidence of great destruction, then it seems reasonable to consider bacterial infection as an option. Extracting bacterial DNA from putative cases would be a considerable bonus, but to date does not seem to have been achieved, at least from bone. It has been extracted from a calcified abscess found in a late Byzantine skeleton from Troy (Devault et al., 2017), so the possibility remains the skeleton too may yield similar evidence in the future.

REFERENCES Adams, M.A., Houghley, P.J., 2006. What is intervertebral disc degeneration, and what causes it? Spine 31, 2151 2161. Alamanos, Y., Drosos, A.A., 2005. Epidemiology of adult rheumatoid arthritis. Autoimmun. Rev. 4, 130 136. Allen, K.D., 2010. Racial and ethnic disparities in osteoarthritis phenotypes. Curr. Opin. Rheumatol. 22, 528 532. Aluoch, M.A., Wao, H.O., 2009. Risk factors for occupational osteoarthritis. A literature review. AAOHN J. 57, 283 290. Annunen, S., Paassilta, P., Lohiniva, J., et al., 1999. An allege of COL9A2 associated with intervertebral disc disease. Science 285, 409 412. Babini, J.C., Gusis, S.E., Babini, S.M., Maldonado-Cocco, J.A., 1992. Superolateral erosions of the humeral head in chronic inflammatory arthropathies. Skeletal Radiol. 21, 515 517. Balke, M., Schmidt, C., Dedy, N., et al., 2013. Correlation of acromial morphology with impingement syndrome and rotator cuff tears. Acta Orthop. 84, 178 183. Biddal, H., Leeds, A.R., Christensen, R., 2014. Osteoarthritis, obesity and weight loss: evidence, hypotheses and horizons—a scoping review. Obes. Rev. 15, 578 586. Bielefeld, T., Neumann, D.A., 2005. The unstable metacarpophalangeal joint in rheumatoid arthritis: anatomy, pathomechanics, and physical rehabilitation considerations. J. Orthop. Sports Phys. Ther. 35, 502 520.

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Hutton, C.W., 1987. Generalised osteoarthritis: an evolutionary problem? Lancet 2, 1463 1465. Jones, R.A., Quilty, B., 2013. The crystal arthropathies. InnovAiT 6, 681 687. Kacki, S., Villotte, S., Knu¨ssel, C.J., 2011. Baastrup’s sign (kissing spines): a neglected condition in paleopathology. Int. J. Paleopathol. 1, 104 110. Kerr, R., Resnick, D., Pineda, C., Haghighi, P., 1985. Osteoarthritis of the glenohumeral joint: a radiologic-pathologic study. Am. J. Roentgenol. 144, 967 972. Kettering, J.M., Towers, J.D., Rubin, D.A., 1996. The seronegative spondyloarthropathies. Semin. Roentgenol. 31, 220 228. Ko, S.-B., Lee, S.-W., 2011. Prevalence of spondylolysis and its relationship with low back pain in selected population. Clin. Orthop. Surg. 3, 34 38. Krishnarasa, B., Vivekanandarajah, A., Ripoli, L., et al., 2011. Diffuse idiopathic skeletal hyperostosis (DISH)—a rare etiology of dysphagia. Clin. Med. Insights Arthritis Musculoskelet. Disord. 4, 71 75. Available from: https://doi.org/10.4137/CMAMD.S6949. Kwok, W.Y., Kloppenburg, M., Rosendaal, F.R., et al., 2011. Erosive hand osteoarthritis: its prevalence and clinical impact in the general population and symptomatic hand osteoarthritis. Ann. Rheum. Dis. Available from: https://doi.org/10.1136/ard.2010.143016. Latalski, M., Danielewicz-Bromberek, A., Fatyga, M., et al., 2017. Current insights into the aetiology of adolescent idiopathic scoliosis. Arch. Orthop. Trauma Surg. Available from: https://doi.org/10.1007/ s00402-017-2756-1. Lawrence, C.R., East, B., Rashid, A., Tytherleigh-Strong, G.M., 2017. The prevalence of osteoarthritis of the sternoclavicular joint on computed tomography. J. Shoulder Elbow Surg. 26, e18 e22. Lewandrowski, K.-U., Park, P.,P., Baron, J.M., Curtin, S.I., 2006. Atraumatic odontoid fracture in patients with rheumatic arthritis. Spine J. 6, 529 533. Link, T.M., 2009. Correlations between joint morphology and pain and between magnetic resonance imaging, histology, and microcomputed tomography. J. Bone Joint Surg. Am. 91 (Suppl. 1), 30 32. Lorenz, E.C., Michet, C.J., Milliner, D.S., Lieske, J.C., 2013. Update on oxalate crystal disease. Curr. Rheumatol. Rep. 15, 340 355. Losser, R.F., 2010. Age-related changes in the musculoskeletal system and the development of osteoarthritis. Clin. Geriatr. Med. 26, 371 386. Mader, R., Verlaan, J.-J., Eshed, I., Jacome, B.-A., et al., 2017. Diffuse idiopathic skeleton hyperostosis (DISH): where are we now and where to go next. RMD Open 3, e000472. Available from: https:// doi.org/10.1136/rmdopen-2017-000472. Mall, N.A., Foley, E., Chalmers, P.N., et al., 2013. Degenerative joint disease of the acromioclavicular joint. A review. Am. J. Sports Med. 41, 2684 2692. Martel, W., 1979. Radiological manifestations of Reiter’s syndrome. Ann. Rheum. Dis. 38 (Suppl.), 12 23. Martinon, F., Pe´trilli, V., Mayor, A., et al., 2006. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237 241. Maxie`res, B., 2013. Diffuse idiopathic skeletal hyperostosis (Forestier Rotes Querol disease): what’s new? Joint Bone Spine 80, 466 470.

Joint Disease Chapter | 20

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Chapter 21

The Dentition: Development, Disturbances, Disease, Diet, and Chemistry Rebecca Kinaston1, Anna Willis2, Justyna J. Miszkiewicz3, Monica Tromp1,4 and Marc F. Oxenham3 1

Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand, 2College of Arts, Society & Education, James

Cook University, Townsville, QLD, Australia, 3School of Archaeology & Anthropology, Australian National University, Canberra, ACT, Australia, 4

Department of Archaeology, Max Planck Institute for the Science of Human History, Jena, Germany

INTRODUCTION This chapter is concerned primarily with the dentition, with brief discussions of associated structures such as supporting alveolar bone, where relevant. Dental development, including the dentin and enamel, is reviewed in the first section. This is followed by a discussion of disturbances in the dentin and enamel in the second section. The third section looks at the identification of oral disease, including caries, alveolar lesions, antemortem tooth loss (AMTL), and periodontal disease. This is followed by the fourth section, which focuses on interpreting oral health, particularly in the context of sex differences and major demographic transitions. The fifth explores dental chemistry in terms of paleodietary reconstruction, breastfeeding and weaning, stress and disease, and finally mobility and migration. The final section discusses dental calculus in the context of microparticle and then chemical analyses of calculus. Ancient DNA (aDNA) and protein analyses of dental calculus are also reviewed.

DENTAL DEVELOPMENT Due to their high mineralization content, teeth preserve very well in the archeological record. Unlike bone, dental tissues are not considered predominantly “dynamic,” i.e., tissues that continuously remodel or adapt to external and internal stimuli. However, they follow a timed and sensitive process of tissue development and formation, and thus serve as a long-lasting record of growth and potential physiological disruption a once-living individual would have experienced. Enamel and dentin are frequently

studied in paleopathology (Beaumont et al., 2013b; Goodman and Rose, 1990; Reid and Dean, 2000, 2006; Sandberg et al., 2014), and are the focus of the first section of this chapter.

Dentin Dentin, along with enamel, forms “true” teeth in all vertebrates (Hall, 2015). It lies directly underneath enamel, and is primarily composed of B70% inorganic material, B20% organic, and B10% water (Nanci, 2012). Dentin formation is executed by odontoblast cells, which combine sialoprotein and phosphoprotein to secrete, synthesize, and mineralize dentin (Gopinathan et al., 2013). Odontoblasts are also mechanosensitive and immunedefensive cells, which means that dentin has reparative capabilities (Couve et al., 2013; Goldberg et al., 2011), and they originate in neural crest cells (Gopinathan et al., 2013). As the tooth crown forms, they lay down dentin as the first mineralized tissue, which next induces the production of enamel (Nanci, 2012). However, the differentiation of odontoblasts requires precursor enamel cells, meaning that there is a “reciprocal induction” between enamel and dentin (Guatelli-Steinberg and Huffman, 2011: 98). This begins in the cusp and extends down the forming tooth. The resorption of root dentin is undertaken by odontoclasts (Sasaki, 2003). Dentin is initially deposited in the form of predentin (primarily composed of glycosaminoglycans and type I collagen), and secondly mineralized by hydroxyapatite. Key genes involved in dentin development, and determining dentin mineralization, are Runx2, Msx2, COL1A1/COL1A2, SIBLINGs, and

Ortner’s Identification of Pathological Conditions in Human Skeletal Remains. DOI: https://doi.org/10.1016/B978-0-12-809738-0.00021-1 © 2019 Elsevier Inc. All rights reserved.

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DSPP (Gopinathan et al., 2013; Hart and Hart, 2007; Rajpar et al., 2002). Dentinogenesis is a tightly controlled process of dentin development and formation. The differentiation of odontoblasts commences during the crown formation phase in developing teeth (2nd trimester in utero in deciduous incisors), and once mature they occupy the pulp cavity to begin the secretion of unmineralized predentin (Nanci, 2012). The predentin zone is approximately 10 40 μm (Hart and Hart, 2007). Type I collagen secreted by odontoblasts is deposited into this zone and collagen fibril structuring begins. This phase is accompanied by a release of ions and proteins which induce the formation of apatite. As odontoblasts secrete the organic matter, they elongate and leave extended odontoblast processes behind. Once mineralized, the matrix becomes mantle dentin, which measures approximately B150 μm (Hart and Hart, 2007). Based on the formation stage, dentin can be categorized into primary, secondary, and tertiary (Guatelli-Steinberg and Huffman, 2011). Primary dentin is associated with a smaller amount of deposited collagen, which is also more tightly organized into fibrils, and is laid down during crown and root formation. Secondary dentin takes longer to form, occurs once root formation is completed, and is not unfirmly distributed across the tooth. Tertiary, or reparative, dentin forms in response to disturbances that may include caries or other abnormal stimuli (Hart and Hart, 2007). The structure of dentin is hierarchical in its organization (Kinney et al., 2003). The inorganic crystals are nanocrystalline apatite, needle- and plate-like shaped, approximately 5 nm thick. The type I collagen fibrils range between 50 and 100 nm in diameter. Their orientation is random, but perpendicular to the direction of dentin formation. The mineral component within the collagen is both intra- and extrafibrillar (inside and outside of the fibrils) (Kinney et al., 2003). The microstructural appearance of dentin is fiber or tubular like, shaped in cylindrical units. These extend from the dentin enamel junction (DEJ) to the root pulp. Each tubule is B3 μm thick near the pulp, and B0.06 μm thick near the DEJ (Linde and Goldberg, 1993). These dentin tubules essentially indicate paths created by odontoblasts, and these are also where the odontoblast processes, along with liquid matter and proteins, are found (Guatelli-Steinberg and Huffman, 2011). Dentin can be inter- or intratubular (formed outside or inside the tubules), and its curvature ranges from S-shaped to straight in the crown and the root, respectively (Nanci, 2012). This dentin architecture equips it with a range of tissue strength and fracturing properties depending on the level of mineralization. The elasticity (Young’s modulus) of dentin has been suggested to range between 20 and 25 GPa, and it withstands (beyond

mastication stress) an approximate 30 MPa of load before it fatigues (Kinney et al., 2003). Dentin growth is incremental (Dean, 2000). In histological thin sections, viewed using light microscopy, dentin microstructure can be subdivided into short- and long-period incremental lines, both of which are thought to represent a biological growth rhythm of an organism (Dean and Scandrett, 1996). The short-period lines form daily, and are known as von Ebner’s lines; whereas the long-period lines take up to several days to form, and are known as Andersen lines (Dean, 2000). von Ebner’s lines are approximately 2 5 μm, whereas Andersen lines are spaced 15 30 μm apart (Dean et al., 1993). The periodicity of Andersen lines corresponds to the increments in enamel, ranging between 6 and 12 days (Dean, 1987; Dean et al., 1993). Dentin incremental structure, and its underlying daily or longer rhythm of growth, has served as a tool for reconstructing dental growth and life history in several animals (e.g., Erickson, 1996a,b), but its implications for paleopathology remain less studied than enamel in human tissue (Dean, 2000). For example, the use of dentin increments in human tooth development research has identified long-term administration of tetracycline antibiotics in one case study (Dean et al., 1993), and differences in short-duration nutritional abnormalities from stable isotope data retained within dentin increments (Beaumont et al., 2013b; van der Sluis et al., 2016). Dentin microscopic lines can also be used to reconstruct age-at-death from teeth with incomplete roots but formed crowns, by combining crown formation rate (calculated from enamel) and estimated root extension growth rate (Dean and Vesey, 2008; Macchiarelli et al., 2006). Finally, in paleopathological contexts, dentin examination is routinely undertaken in dental wear age-at-death estimation methods, and dentin lesions associated with caries or other oral bacteria (see “Identifying Dental Wear and Oral Disease” section). It is becoming clear that microstructural investigation of dentin structure has the potential to assist with the reconstruction of tooth growth (Guatelli-Steinberg and Huffman, 2011), though as Hillson (2005) notes, its daily increments are not always clearly identifiable in sections.

Enamel Enamel envelopes the underlying dentin and is the most outer layer of dental crowns. It is the most highly mineralized and avascular tissue in all vertebrates (Hall, 2015). When compared to dentin and bone, which derive from mesenchyme, enamel is the only extracellular skeletal tissue with an epithelial origin (Soukup et al., 2008). Its extracellular matter does not contain collagen, rather it is composed of enamelin and amelogenin proteins

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(Doi et al., 1984). Enamel is almost completely mineralized, with approximately 96% inorganic (hydroxyapatite) and 4% organic and liquid components. It is formed by ameloblast cells which originate in ectodermal epithelia (Miletich and Sharpe, 2003). Key proteins involved in the formation of enamel are amelogenin, enamelin, ameloblastin, tuftelin, matrix metalloprotein-20, and serine proteinase (Brookes et al., 1995; Guo et al., 2015; Hall, 2015). Amelogenin is the most abundant, while enamelin is the largest and the least abundant (Al-Hashimi et al., 2009; Brookes et al., 1995). The process of enamel development and formation is known as amelogenesis, which begins by a deposition of the organic matter to be later mineralized by hydroxyapatite (Bronckers, 2017). Amelogenesis commences in the second trimester in utero, when deciduous incisors begin calcification (Kraus and Jordan, 1965; Nanci, 2012). Enamel in all deciduous teeth undergoes calcification in utero, with only the first permanent molar forming before or around the time of birth (Lunt and Law, 1974; Mahoney, 2011). As enamel matures over the prenatal, child, and teenage years of life, its structure retains normal growth and disruption information (Hillson, 2005). Unlike dentin, enamel is acellular and does not continue to form once tooth crown growth is completed. It begins development during crown tip formation, when ameloblast differentiation, preceded by odontogenesis (as earlier), initiates secretion of enamel proteins (Nanci, 2012). As the organic matrix is produced, cell differentiation continues along the DEJ until mature ameloblasts are able to move away in the direction of the future enamel surface (Simmer and Fincham, 1995; Simmer and Hu, 2001). At the same time, dentin undergoes mineralization, and ameloblasts join with mantle dentin collagen fibrils (Hu et al., 2007). Unlike bone or dentin (osteoid and predentin, respectively), there is no “preenamel” matter formed, but the secreted enamel simply occupies a mineralization zone. As this zone recedes, ameloblasts develop Tomes’ processes, which are secretory protrusions involved in the lengthening of enamel crystals (Franklin et al., 1991). Enamel matrix is deposited on the surface of dentin, enlarges and grows until the initial, aprismatic enamel layer is formed (Hu et al., 2007). This is the secretory stage of formation, where enamel produced is approximately 30% mineralized (Guatelli-Steinberg and Huffman, 2011). Tomes’ processes shape the organization of enamel crystals into rod and inter-rod structures (Habelitz et al., 2001). The rods, or prisms, are aligned perpendicular from the DEJ to tooth surface, and are composed of carbonated hydroxyapatite, enamelin-coated crystals which are positioned along the rod axis (Jeng et al., 2011). They measure approximately 4 5 μm in thickness (Huang et al., 2010). The inter-rod enamel are the spaces between rods, which are protein-rich and

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approximately B1 μm thick (Huang et al., 2010). The hierarchical organization of enamel, and the composite orientation of enamel apatite crystals, give enamel anisotropic mechanical properties which determine dental stress dissipation and fracturing properties (Habelitz et al., 2001). The elasticity of a single enamel rod has been noted to range between B87.5 and 72.7 GPa on the Young’s modulus scale, whereas its approximate hardness ranges from B3.9 to 3.3 GPa (Habelitz et al., 2001; Huang et al., 2010). At the histological level, similarly to dentin, enamel presents with a series of incremental lines that reflect its rhythmic and timed deposition (Reid and Ferrell, 2006). Just like in dentin, enamel increments can be divided into daily markings (short-period cross-striations), and longerperiod lines known as Retzius lines or striae of Retzius (Dean, 2000). The daily cross-striations are spaced every 4 μm and lie in between the thicker and darker Retzius lines. These striae of Retzius manifest as perikymata on the outer tooth surface, seen as a series of horizontal lines or bands. Unless worn, they can be observed on the lateral surfaces of outer enamel, but they remain “buried” in cuspal enamel (Guatelli-Steinberg and Huffman, 2011: 94). Retzius lines form when enamel matrix secretion slows down systemically, which happens at regular increments in all forming teeth (Dean, 1987). It is therefore possible to calculate Retzius periodicity by counting the number of daily markings between adjacent Retzius lines, which seems to average between 6 and 12 days in humans (Reid and Dean, 2006). This incremental premise of enamel formation has been used to create standards for reconstructing dental formation times in human and nonhuman primate teeth (Reid and Dean, 2000, 2006; Reid and Guatelli-Steinberg, 2017; Smith et al., 2007, 2010), whereby perikymata, Retzius periodicity, and crown height can be combined to estimate crown formation times. In paleopathology, these standards of enamel increments have mainly been applied when determining the timing of enamel disturbances. Enamel markings and their periodicity have been studied over the past two centuries, revealing their value in dental growth research (Boyde, 1963; Dean and Scandrett, 1996; Retzius, 1837). Several studies utilizing larger and smaller bodied animal teeth (e.g., mammoths, monkeys) identified a link between body size and Retzius periodicity (e.g., Fukuhara, 1959; Koch and Fisher, 1986), and a circadian nature of cross-striation periodicity (e.g., Hogg et al., 2015; Massler and Schour, 1946), indicating that a centralized biorhythm may be coordinating the deposition of skeletal tissues (see Antoine et al., 2009; Bromage et al., 2009, 2012). Its nature remains enigmatic for humans, as it seems to vary intraspecifically (Mahoney et al., 2016). As our understanding of skeletal biorhythms unfolds, it will no doubt have vast implications for the study of ancient human remains.

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Another type of darker striae seen histologically is the neonatal line which forms at the time of birth, and indicates an intersection between pre- and postnatal enamel (Weber and Eisenmann, 1971). Identifying its presence from dental thin sections has allowed paleopathologists to study prenatal or childhood mortality, morbidity, and development (e.g., Kurek et al., 2016; Miszkiewicz and ˙ ˛dzi´nska et al., 2015). By locating the Mahoney, 2017; Za neonatal line, and counting daily markings, the incremental structure of enamel can also help paleopathologists estimate a child’s age-at-death from dental crown remains that had not completed formation before death (Boyde, 1963, 1990; Mahoney, 2011; Smith et al., 2006).

DISTURBANCES IN DENTAL DEVELOPMENT Abnormal Quality of Teeth: Disturbance of Dentin Development Pathology Disturbances in dentin development can be inherited or acquired. The former can be broadly categorized into dentinogenesis imperfecta (DI) and dentin dysplasias (DD) (Hart and Hart, 2007; Shields et al., 1973). These are usually inherited via autosomal dominant pathways, and have been documented in a variety of different syndromes, including: osteogenesis imperfecta, rickets, and other conditions associated with abnormal calcium deposition (see Chapters 16 and 19; Hart and Hart, 2007). In DI, human teeth (both deciduous and permanent) exhibit these abnormalities usually in the form of tooth discoloration (e.g., different shades of brown), weak and fracture-susceptible enamel, and bulging tooth crowns with abnormally small roots and pulp cavities. At the histological level, dentin tubules appear irregular and are absent in some areas. This condition causes enamel to shatter easily and accrue wear at a faster rate. DI can be subdivided into types I, II, and III (Hart and Hart, 2007). Type I DI is due to a mutation in the COL1A1/COL1A2 gene (Pollitt et al., 2006), and is associated with osteogenesis imperfecta. Thus, individuals with an unusually high rate of dental wear for their age ought to also be examined for postcranial trauma, joint abnormalities, and stature. Type II DI is associated with a lack of other, nondental lesions and/or symptoms. Type III DI (gene DSPP) presents with crown discoloration and enlarged pulp chambers, and pitting in enamel. DD are not associated with tooth discoloration, but are diagnosed mainly by obliterations in the pulp cavity caused by defective dentin. This type of defect is subdivided into types I and II (Brenneise and Conway, 1999; Kalk et al., 1998). In type I DD permanent and deciduous

dental crowns exhibit no abnormalities, but roots are shortened and mobile, which leads to premature breakdown. In type II DD, only the deciduous teeth show features of type II DI, and are additionally associated with pulp stones. No root changes, as seen in type I DD, are observed. Disturbances to dentin growth that are acquired usually include some form of abnormal stimuli, such as attrition or carious lesions. Unlike enamel, dentin is cellular and thus responds to these stimuli by producing tertiary dentin, which is also known as “reparative” (Hart and Hart, 2007; Klinge, 2001). Tertiary dentin appears irregularly structured and is usually found in locations where external irritation would have occurred (Ricucci et al., 2017). Tertiary dentin has been observed in older and slower-developing carious lesions, but absent in rapidly developing ones (Bjørndal, 2001). It has been reported in primary teeth from individuals with vitamin D-resistant rickets (Hillmann and Geurtsen, 1996), or those suffering from dental injuries (Robertson, 1997). At the histological level, disturbances to the incremental growth of dentin can be deduced from the presence of accentuated markings known as Owen’s lines or contour lines of Owen (Dean, 2000). These are not incremental because they occur irregularly and are thought to form in response to illness or environmental upsets (Dean et al., 1993). Their etiology remains unclear, but it is most likely that they accentuate following a disruption to calcium metabolism, and thus simply present as thickened or darkened lines, similar to the neonatal line in enamel (Schour and Hoffman, 1939). They also seem to correspond to accentuated lines in enamel, both of which meet at the DEJ, though not in the exact same location given that dentin precedes enamel formation (Guatelli-Steinberg and Huffman, 2011).

Paleopathology Owen’s lines indicating disturbances to the incremental growth of dentin have been previously reported in dentin from modern humans with conditions such as cleidocranial dysostosis (Fukuhara, 1959), but remain rarely reported in paleopathology. The few studies examining these lines in archeological samples have linked their occurrence to disturbances in enamel to gain a more comprehensive understanding, encompassing more than one type of dental tissue, of systemic health disruptions (see discussion of enamel hypoplasia (EH) below). For example, Witzel et al. (2008) matched Owen’s lines to disturbances captured by enamel in tooth sections representing humans from an early medieval site (5 7th centuries AD) in Barbing, Germany. Out of a total of seven teeth analyzed microscopically, one canine specimen exhibited an Owen’s contour line in association with its enamel

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equivalent. This specimen demonstrated, health disturbance at the dentinogenesis stage, which would not have been otherwise inferred from macroscopic analyses of the teeth alone. Future studies may, therefore, benefit from investigating dentin at the microstructural level (Dean, 2017), as inherent skeletal pathology may lead to defective dentin, which in turn may underlie one’s susceptibility to accumulating caries or rate of dental wear.

Abnormal Quality of Teeth: Disturbance of Enamel Development Pathology Disturbances to the process of amelogenesis, and more specifically enamel secretion by ameloblasts, lead to a variety of defects in the final quality (mineral) or quantity of enamel, including thinning, hypoplastic changes, and hypermineralization (Hu et al., 2007). These can be inherited, usually as a result of abnormal proteins involved in mineral metabolism (e.g., abnormalities associated with parathyroid gland function). In this case, if abnormal enamel only originates in the dentition, the defects are known as amelogenesis imperfecta (Witkop, 1988). However, defective enamel can also develop due to other systemic conditions associated with altered skeletal mineralization pathways. Amelogenesis imperfecta manifests in three different ways (Hu et al., 2007). It can be associated with an abnormally thin (hypoplastic) layer of enamel (in extreme cases there may be hardly any enamel present on the tooth). Enamel may become hypomineralized (lack of, or poor, mineralization), where its thickness is unaffected but extreme softness increases the rate of wear and calculus accumulation. Enamel can also undergo hypomaturation, which manifests by way of discolored (brown to yellow) crowns with dentin-like tissue density. Acquired enamel defects form when severe enough physiological/systemic or environmental disturbance disrupts the highly sensitive and incremental enamel development. This results in localized areas of hypoplastic enamel, which manifest macroscopically on the outer tooth surface as “depressed” perikymata. They are categorized broadly as EH, a “marker” of childhood physiological health disruption. The literature suggests a variety of factors underlying the formation of EH, including systemic (e.g., malnutrition, illness, weaning), or localized (e.g., trauma) stimuli, exposure to toxins and radiation, environmental upsets, as well as epigenetic effects (such as DNA methylation) (Boldsen, 2007; Geber, 2014; Sarnat and Schour, 1941; Seow, 2014). Therefore, EH is considered a nonspecific dental lesion. The macroscopic expression of EH can take many forms, such as grooves, irregular pits, or furrows (Hillson,

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2005). At the histological level, enamel development disruption is recorded in the form of accentuated lines, sometimes referred to as Wilson bands (FitzGerald and Saunders, 2005). These are similar in appearance to Retzius lines, except they are darker and thicker (Goodman and Rose, 1990; Witzel et al., 2008). By studying these accentuated markings, it is possible to reconstruct the age at which a stressful event would have taken place (by referring to standards for tooth formation times, e.g., Reid and Dean, 2000), which may not be otherwise possible if, for example, the outer tooth surface presents with invisible perikymata (Cares Henriquez and Oxenham, 2017; Hassett, 2012). Studies have shown a link between the accentuated markings and their macroscopic expression (e.g., Witzel et al., 2008), though a microscopic approach linking enamel and dentin disturbances is argued to offer a fuller picture of stress affecting dental development. EH may not form on all the teeth that are developing during the period of systemic stress. Furrow, or linear enamel hypoplasia (LEH), presents as horizontal bands of depression that run along the outer tooth surface. It has been observed that the anterior teeth (incisors and canines) display a higher prevalence of LEH than posterior teeth and this is thought to be a result of the strong genetic control over the formation of the latter (Goodman and Armelagos, 1985). Canines take the longest period of time to form and are therefore potentially more susceptible to periods of stress than other teeth (Lewis, 2007). The presence of hypoplastic defects in the deciduous dentition can point to periods of stress during the third trimester in utero until about the age of 1 year (Goodman et al., 1987). Hypoplastic defects located on the deciduous dentition have also been observed as areas susceptible to caries development after birth (Cook and Buikstra, 1979; Hillson, 2008). The defective mineralization of the crown enamel as a result of these developmental defects is thought to predispose this area to the formation of circular caries (Larsen, 1997). A circular carious lesion is identified as a transverse carious band on the labial and/or buccal surface of the deciduous teeth (Cook and Buikstra, 1979; Cook, 1979). The presence of circular caries has been linked with stress during the prenatal and perinatal period, including diarrheal disease (Sweeney et al., 1971).

Palaeopathology Amelogenesis imperfecta is difficult to identify in archeological samples, but it can be considered as part of a differential diagnosis. EH assessments are routinely incorporated into paleopathological research (Armelagos et al., 2009; Guatelli-Steinberg and Lukacs, 1999; Hillson and

754 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

Bond, 1997; Miszkiewicz, 2015; Ogden et al., 2007; Oxenham and Matsumura, 2008). Enamel hypoplastic defects are favored in paleopathology as indicating nonspecific “stress” in ancient populations (the definition of which is not agreed upon, see Reitsema and McIlvaine, 2014). However, LEH is most commonly observed and thus reported, and has been investigated in a plethora of studies in paleopathology (see Bocaege and Hillson, 2016; Ritzman et al., 2008). One example of nonlinear EH types, and its relationship to ancient human stress, is localized primary canine hypoplasia (LPCH). Out of 24 subadults from a Neolithic site of Man Bac in Vietnam (B4000 3500 BP), 41.7% were observed to display LPCH (McDonnell and Oxenham, 2014). Appearing as a rounded and localized depression on the labial deciduous canine surface, the defects can be linked to a series of nonspecific etiologies, including damage from object “mouthing” and nutritional upsets arising from vitamin A and D deficiencies. These can be extended to several interpretations and inferences about the potential stress experienced by mother and infants in this sample (Goodman and Rose, 1990). Given the relatively high prevalence of these defects, McDonnell and Oxenham (2014) suggest the presence of depressed maternal health at this site, which would agree with its transitionary stage into an agricultural subsistence economy. Alternatively (or complementarily), this could also be evidence for early childhood exploratory behaviors in ancient Man Bac. Linear enamel hypoplastic defects have been routinely documented in paleopathology, spanning many different time periods and geographical locations (e.g., Boldsen, 2007; Larsen, 1997; Miszkiewicz, 2015; Starling and Stock, 2007; Tomczyk et al., 2007). A series of ancient health and disease contexts have been studied using LEH data, including childhood disease and malnutrition (Goodman and Armelagos, 1988; Tomczyk et al., 2007), weaning (Blakey et al., 1994), socioeconomic stratification of ancient societies (Miszkiewicz, 2015; Nakayama, 2016), and mortality (Boldsen, 2007) to list a few. Tomczyk et al. (2007) found increased hypoplasia records on human teeth from archeological sites in the middle Euphrates representing humans who would have experienced food scarcity associated with historical periods of warfare, political violence, and economic crisis (late Bronze, early Neo-Assyrian, Roman, and Byzantine). Starling and Stock (2007) showed a gradual decrease in hypoplasia occurrence along with the development of the state in pastoralists from Nubia and Egypt. Miszkiewicz (2015) compared low- and highsocial status groups of late medieval humans in England, reporting lower age-at-death and higher LEH in the former group. This indicated poor childhood

health in children from lower-class backgrounds. Shorter longevity (i.e., lower age-at-death estimates) has been further associated with increased frequencies of LEH records in samples from medieval Denmark (Boldsen, 2007; Palubeckait˙e et al., 2002), Croatia ˇ (Slaus et al., 2002), and Lithuania (Palubeckait˙e et al., 2002). Weaning of children has also been previously discussed as potentially reflected in the age of LEH formation, particularly when estimated to have occurred between 2 and 4 years old (Blakey et al., 1994; Lanphear, 1990; Miszkiewicz, 2015). However, complementary lines of weaning age evidence are needed for these inferences to be convincing, given the variation in enamel formation times between populations (Reid and Dean, 2006), and the definition and practice of weaning in different cultures (Griffiths et al., 2007). Studying isotopic signatures linked to breast milk feeding from the increments in enamel may be a more reliable approach (King et al., 2017). Accentuated lines in enamel histological sections have not received as much attention in paleopathology as macroscopic evidence of LEH. However, in a study by Rose et al. (1978), Wilson bands studied at the microscopic level of enamel corresponded to increased mortality and abnormal skeletal lesions in samples from the Mississippian and Woodland archeological sites in the American Midwest representative of the maize agricultural transition. Traditionally, studies of LEH utilize the “field method,” whereby the outer tooth surface is visually examined, palpated, or viewed under small magnification for obviously depressed perikymata (see Brickley and McKinley, 2004; Hassett, 2012; Hillson, 2005). Formation times of the LEH can then be estimated from charts of tooth formation having divided the whole intact dental crown into age-associated sections. Reid and Dean’s (2000,2006) standards are particularly robust as they are based on enamel histological increments that account for appositional enamel (King et al., 2002). In recent years, studies have highlighted that a sole macroscopic approach does not account for all depressed perikymata, and thus potentially underestimates the frequency of LEH (e.g., Cares Henriquez and Oxenham, 2017; Hassett, 2014). Fig. 21.1 provides an example of an adult male individual from an archeological site in Fort Concho, Texas, United States (NMNH 243490), with evidence of multiple hypoplastic transverse lines on the canines. The upper incisors are missing and the lower incisors have been damaged postmortem. Figs. 21.2 and 21.3 are further examples of severe hypoplastic defects on the maxillary and mandibular dentition from a medieval individual from St. Gregory’s Priory collection at the University of Kent, Canterbury, UK (specimen NGA 88 SK 410).

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FIGURE 21.1 Multiple hypoplastic transverse defects of the canine teeth (adult male from Fort Concho, Texas, United States, NMNH 243490).

FIGURE 21.2 Anterior view of the left and right maxillary central incisor, right lateral incisor, and the right canine in a medieval individual (specimen NGA 88 SK 410) from St. Gregory’s Priory collection at the University of Kent (Canterbury, United Kingdom) displaying severe hypoplastic defects.

Abnormal Quality of Teeth: The Effects of Disease Pathology Infectious diseases, and metabolic and endocrine disorders experienced by an individual during the time of tooth development may cause malformation of the teeth (Kreshover, 1960; Nissanka-Jayasuriya et al., 2016; Pessoa and Galva˜o, 2011; Suckling et al., 1983; Sweeney et al., 1969). EH development is associated with environmental and physiological perturbations during tooth formation, and therefore any type of infection or disorder that may result in a period of systemic stress can act to disrupt odontogenesis and amelogenesis (Goodman, 1991, 1998). Important to note is the synergistic relationship

FIGURE 21.3 Lateral anterior view of mandibular dentition in a medieval individual from St. Gregory’s Priory collection (specimen NGA 88 SK 1222) at the University of Kent (Canterbury, United Kingdom) displaying less severe hypoplasia on the right canine and premolar. The perikymata depressions are shallower compared to NGA 88 SK 410 (see Fig. 21.2).

between undernutrition and infectious disease (Goodman and Rose, 1991), which is one reason why EH is considered evidence for nonspecific stress (Lewis and Roberts, 1997). Ortner (2003: 596) provides a few examples of individuals with likely or known diseases who had hypoplastic defects, which may have formed as a result of these conditions: a 6-year-old individual with suspected vitamin D deficiency (rickets) (Fig. 21.4) and two individuals (a 3- to 6-year-old child and a 17-year-old boy) with likely and confirmed tuberculosis, respectively (Figs. 21.5 and 21.6). Since the mid-19th century, it has been known that congenital syphilis (Treponema pallidum) interrupts tooth and enamel formation causing specific dental changes (reviewed in Ioannou et al., 2018). Methods to standardize these dental changes in the permanent dentition have led Hillson et al. (1998) to suggest four pathognomonic criteria to record: (1) Moon’s molars (an abnormally close

756 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 21.4 Dental hypoplasia associated with possible rickets. (A) Occlusal view of maxillary dentition; note defective crowns of second deciduous molars and right first permanent molar. (B) Occlusal view of mandibular dentition. The crowns of both first permanent molars are defective (child about 6 years of age, FPAM 2694 from before 1858).

cusp position of the upper and lower first molars); (2) Hutchinson’s incisors (a short, ill-formed incisal edge of the upper incisors and, less frequently, notching affecting the incisal edge of the lower incisors); (3) Fournier’s or Mulberry molars (expressed by a first molar that is smaller than the second molar and an irregular, poorly formed and pitted occlusal surface of the crown (Fig. 21.7); and (4) canines with a hypoplastic defect circling the tip of the crown (for a complete description see NissankaJayasuriya et al., 2016). Some paleopathological studies have observed variations to these common dental changes associated with congenital syphilis (Ioannou et al., 2015, 2018; Nystrom, 2011). Some of these variations were attributed to the widespread treatment of the disease with mercury, which also causes hypoplastic defects, albeit ones that are substantially different from those caused by congenital syphilis (Ioannou et al., 2015, 2018).

FIGURE 21.5 Dental hypoplasia associated with a case of possible tuberculosis. Hypoplastic lines or spots and possible circular caries are visible in the crowns of all the deciduous teeth (child between 3 and 6 years of age, ANM 2028 from before 1895).

disease was the cause of the disturbance in growth. There is, however, a growing body of bioarcheological literature around the dental changes specific to congenital syphilis. Historic (Nystrom, 2011) and prehistoric (Mayes et al., 2009) evidence for the specific dental changes discussed earlier has been observed in American skeletal assemblages. The positive identification of congenital syphilis from dental changes in pre-15th-century populations in Europe has been used to argue for the presence of the disease in the Old World before contact with the Americas (Gaul et al., 2015; Ioannou et al., 2018), adding to the debate over the origins of this disease (Harper et al., 2011; Meyer et al., 2002). Pathognomonic dental changes have also been used to diagnose congenital syphilis in post-15thcentury European skeletal populations (Lauc et al., 2015).

Abnormal Quantity of Teeth and Dental Crowding

Paleopathology

Pathology

As discussed, EH is a nonspecific indicator of stress and therefore it is not possible to determine if a specific

Developmental defects may result in an abnormal quantity of teeth in the permanent and, less commonly, primary

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FIGURE 21.6 Dental hypoplasia associated with a probable case of tuberculosis. Note multiple hypoplastic lines in the teeth (17-year-old male, FPAM 2016, autopsy 16648 from 1842).

dentitions. Supernumerary teeth (hyperdontia) are defined as teeth that are in excess of the typical 20 deciduous or 32 permanent teeth, but may be accompanied by a deficit in other teeth (Rajab and Hamdan, 2002). This deficit is because the teeth adjacent to the supernumerary teeth may fail to erupt, be malformed (e.g., dilaceration), displaced or affected by root resorption. Ectopic eruption and displacement of supernumerary and original teeth, especially the maxillary canines, is not uncommon in the alveolar region (normotopic) and may occur outside the alveolar region (heterotopic) (Nelson, 2016; Rajab and Hamdan, 2002; Scheiner and Sampson, 1997). Between 0.1% and 3% of populations with European ancestry are affected by supernumerary teeth (Rajab and Hamdan, 2002) and the prevalence is higher ( . 3%) in populations with Asian ancestry (So, 1990). Males are affected approximately twice as frequently as females, but this ratio varies depending on the study population (Scheiner and Sampson, 1997). In the permanent dentition, single supernumerary teeth are most commonly observed (76% 86% of cases), double supernumerary teeth (12% 23% of cases) occur less frequently, multiple supernumerary teeth are rare (,1% of cases), and the

FIGURE 21.7 Dental hypoplasia associated with probable syphilis. (A) Anterior view; note defect of incisal edges of incisors. (B) Occlusal view of mandibular molars. The first molar is smaller than the second and has an abnormal pitted occlusal surface, typical of congenital syphilis (female about 30 years of age, NMNH 219398, dissecting room specimen from before 1903).

condition may occur unilaterally or bilaterally (So, 1990). The anterior maxilla, followed by the mandibular premolar region, are commonly affected by single and double supernumerary teeth, but they may occur elsewhere in the dental arch (Scheiner and Sampson, 1997). The classification of supernumerary teeth is based on form (conical types, tuberculate types, odontome, and supplementary teeth of similar form to a normal tooth) and position in the dental arcade (including mesiodens, paramolars, distomolars, and parapremolars) (Rajab and Hamdan, 2002). The etiology of supernumerary teeth is not clearly understood, but it is thought there is a genetic component to their development (Rajab and Hamdan, 2002). Multiple supernumerary teeth have been associated with certain conditions including Gardiner’s syndrome, cleidocranial dysostosis, growth hormone insensitivity syndrome, and cleft lip and palate (Borges et al., 2013; Scheiner and Sampson, 1997).

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Teeth may fail to develop, leading to fewer teeth in the dental arcade (tooth agenesis or hypodontia), which is the most common developmental dental anomaly, occurring in between 3% and 11% of individuals depending on population (reviewed by Larmour et al., 2005). The permanent teeth most likely affected by agenesis are third molars, maxillary lateral incisors, mandibular second premolars, mandibular incisors, and maxillary first premolars. Agenesis has also been observed in the deciduous dentition, especially the maxillary and mandibular lateral incisors and may lead to the absence of the subjacent tooth (Larmour et al., 2005). Hypodontia is a multifactorial condition that involves both genetic and environmental factors and is associated with systemic syndromes and other dental anomalies such as microdontia, the impaction of permanent canines, and the transposition of the maxillary first canine and premolar (Larmour et al., 2005; Matalova et al., 2008; Nieminen, 2009). Very rarely, an individual will be affected by both hyperdontia and hypodontia (Anthonappa et al., 2008). Without radiological examination, it is difficult to determine hypodontia from the failure of a tooth to erupt. Tooth eruption is a complex and highly regulated biological process that is not fully understood (Anthonappa et al., 2008; Liversidge, 2006; Wise et al., 2002). Normal eruption times may vary as a result of genetic, sexrelated, and individual factors, and delayed eruption has clinical and paleopathological implications, especially with regard to the correct biological age estimates of children (Halcrow and Tayles, 2008; Suri et al., 2004). A number of factors may cause a tooth to fail to erupt, including the retention of the deciduous teeth (ankylosed primary tooth), a supernumerary tooth, or crowding. An obstruction in the path of an erupting tooth or, less frequently, by the abnormal orientation of the tooth germ, can cause impaction. Impaction is common in mandibular third molars and maxillary canines, but can occur in other teeth (Nelson, 2016; Regezi et al., 2016). Primary failure of eruption is a problem with the propulsive mechanism that moves a tooth (Proffit and Frazier-Bowers, 2009). A number of genetic disorders, including osteogenesis imperfecta, can delay eruption or cause failure to erupt and some individuals may have a genetic predisposition to the condition (Borges et al., 2013; Proffit and FrazierBowers, 2009; Wise et al., 2002). Dental crowding is one of the most common dental anomalies found in modern populations. It is regularly observed in permanent and mixed dentitions, but may also occur within the deciduous dentition (Tsai, 2003). Reasons for dental crowding include the presence of supernumerary teeth, the retention of deciduous teeth, and small arch size compared to tooth size. Certain conditions, such as pituitary dwarfism and growth hormone

insensitivity syndrome, may result in severe dental crowding because bone development, but not tooth formation, is severely disturbed due to the lack of growth hormone (Borges et al., 2013). A number of theories have developed to explain the prevalence of dental crowding in modern populations, including evolution, genetics, and environmental factors (see Mockers et al., 2004; Normando et al., 2012). Although there is an increase in food accumulation and plaque retention with dental crowding, there is little evidence for crowding to become a risk factor for caries development (Hafez et al., 2012).

Paleopathology Evidence for supernumerary teeth, hypodontia, and dental crowding is not uncommon in the paleopathological literature. For example, a study of a Neolithic skeletal assemblage from Poland found evidence for all three conditions, including a supernumerary tooth present in the nasal cavity of one individual (Garłowska, 2001). Supernumerary teeth have also been observed in the nasal cavity and palate (from X-ray identification) of ancient Egyptian individuals from the Dynastic and Pre-Dynastic periods (Satinoff, 1972). Fig. 21.8 is a photograph and X-ray of a heterotopic

FIGURE 21.8 Heterotopic supernumerary canine projecting through left palate. (A) View of palate. (B) Radiograph of hard palate and heterotopic canine (adult skull from Pachacamac, Peru, NMNH 267104).

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supernumerary tooth in the left palate of a prehistoric individual from Pachacamac, Peru. Fig. 21.9 illustrates a historic individual from the Virgin Islands who displays a unilateral, normotopic, supernumerary “fourth molar.” An example of bilateral tuberculate supernumerary teeth between the second and third maxillary molars of an older

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adolescent individual from the 2700-year-old site of Pain Haka, Indonesia, is presented in Fig. 21.10. Tooth agenesis or hypodontia is commonly observed in the paleopathological literature, especially of the third molar. Radiological examination is commonly used to positively identify agenesis from a tooth that failed to erupt. An example of agenesis of the lower lateral incisors of a female individual from South Dakota can be seen in Fig. 21.11. Dental crowding can occur for a number of reasons (discussed earlier). It has been reported that crowding causing malocclusions was rare in prehistory, but severe crowding has been observed in past populations (Mockers et al., 2004). Fig. 21.12 is an example of dental crowding in the maxilla of a prehistoric child from Florida. The alveolar process of this individual is too small for the erupting teeth, leading to the displacement of the incisors.

Abnormal Size of Teeth Pathology FIGURE 21.9 Supernumerary molar on the left side of the mandible (adult female skeleton from an archeological site in the Virgin Islands, NMNH 385695).

Teeth may appear larger than normal in the dentition (macrodontia). Generalized macrodontia may result from a maxilla and mandible that are relatively small compared

FIGURE 21.10 An example of bilateral tuberculate supernumerary teeth between the second and third maxillary molar of an older adolescent individual (burial 45) from the 2700-year-old site of Pain Haka, Indonesia.

760 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

FIGURE 21.13 Abnormally small maxillary lateral incisors in an adult from Chicama, Peru (NMNH 264518).

FIGURE 21.11 Dental agenesis of the mandibular lateral incisors, occlusal view (adult female from Mobridge site, South Dakota, United States, NMNH 325417).

smaller teeth (e.g., pituitary dwarfism) or from a disproportionally large maxilla and mandible relative to normal-sized teeth (Regezi et al., 2016). Localized or focal microdontia is a relatively common condition that is expressed by a smaller than normal single tooth, often with an altered shape. In descending order, the most common microdonts observed are: (1) peg-shaped maxillary lateral incisors, (2) microdont of the maxillary third molar, and (3) supernumerary teeth (discussed above) (Regezi et al., 2016). Microdontia is closely associated with hypodontia and, similar to hypodontia, is observed in higher frequencies in females compared to males (Larmour et al., 2005).

Paleopathology To researchers familiar with dental assessments of skeletal assemblages, variations in the size of teeth should be easily recognizable. Fig. 21.13 is an example of an adult individual from Chicama, Peru, who displays upper lateral incisors that are smaller than normal. FIGURE 21.12 Severe crowding of the maxillary dentition in a child’s skull, about 10 years of age. Note the displacement of the anterior teeth (specimen is from an archeological site in Canaveral, Florida, United States, NMNH 377496).

to the dentition, or absolute, from a condition such as pituitary gigantism (Regezi et al., 2016). An abnormally large tooth or a group of teeth is known as focal or localized macrodontia. For example, third molars may be affected by macrodontia, although this is relatively uncommon (Regezi et al., 2016). Microdontia is a condition where the teeth appear smaller than normal. The generalized form of the condition affects the entire dentition due to the formation of

Dental Anomalies Pathology There is considerable, normal variation in the shape of the teeth that is genetically controlled. These morphological variations of the crown and root, also known as nonmetric traits, commonly include shovel-shaped incisors, Carabelli’s cusp, supernumerary roots, and molar cusp number and are used to assess ancestry (for an in-depth review, see Scott, 2008). Developmental dental anomalies are observed in modern populations relatively frequently. Fusion and gemination of teeth are developmental conditions that lead to similar expressions in fully formed teeth in both the primary and

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permanent dentitions (Ravn, 1971; Regezi et al., 2016). Gemination occurs as a result of the development of two teeth from one tooth germ. This can cause partial cleavage, where the two crowns share a root canal, or complete cleavage (twinning), where two teeth arise from the same tooth bud (Grover and Lorton, 1985). In contrast, the joining of two developing tooth germs is known as fusion (More and Tailor, 2013). This may result in purely root fusion of the dentin and cementum, leaving two separate crowns, or the fusion of the whole root/crown length (Regezi et al., 2000). In fusion, the root canals may be separate or shared, which may lead to difficulties in differentiating between fusion, gemination, and supernumerary teeth, although radiological examination can help with interpretations (Altug-Atac and Erdem, 2007; Regezi et al., 2000). The etiology of fusion and gemination is unknown, but trauma has been suggested as a potential cause for both conditions (Regezi et al., 2016). Concrescence is a condition defined by the joining of two tooth roots by hyperplastic cementum, which may occur during, or after, eruption. Rarely, a tooth root may attach to an impacted tooth crown by the same mechanism (Sugiyama et al., 2007). Concrescence is commonly observed between the maxillary second and third molars and is thought to be a result of trauma and overcrowding (Regezi et al., 2016). Other commonly observed dental anomalies include enamel pearls, dilaceration, and, less frequently, taurodontism. Enamel pearls are a developmental defect expressed as a small round deposit of ectopic enamel on the bifurcation or trifurcation of molars or premolars, but may also be located on single-rooted premolars (Chrcanovic et al., 2010; Regezi et al., 2016). They are most commonly observed in the maxillary, followed by the mandibular, molars (Chrcanovic et al., 2010; Risnes, 1974). Enamel pearls may form on the surface of the tooth (extradental) or in the dentin proper (intradental) (Ortner, 2003). Dilaceration is an extreme angulation of the tooth root that is believed to arise from trauma during tooth development (Regezi et al., 2016). Taurodontism is recognized by the enlargement of the pupal chamber in the apical/occlusal aspect. It is caused by an enlargement of the crown or displacement of the pulpal floor and lack of constriction at the cemento enamel junction. Taurodontism is most prevalent in permanent molars, but has been observed in both primary and permanent dentitions and in any tooth and quadrant (Jafarzadeh et al., 2008). Prevalence rates vary between populations and it has been found in higher frequencies in Middle Eastern and First Nations groups. Taurodontism is associated with a number of genetic

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FIGURE 21.14 Fusion of mandibular right incisors (Native American child about 1 1/2 years of age from a historic period site in Nebraska, United States, NMNH 243355).

FIGURE 21.15 Fusion of the mandibular deciduous right lateral incisor and canine (child, about 8 years of age, from an archeological site in New Mexico, United States, NMNH 269221).

conditions, including Down syndrome, and has also been observed in Neanderthal dentitions (Jafarzadeh et al., 2008; Regezi et al., 2000).

Paleopathology Fig. 21.14 illustrates fusion between the central and lateral right incisors in a 1.5-year-old child from the historic period in Nebraska, United States (NMNH 243355). The second case is from an archeological site in New Mexico, United States (NMNH 269221), and involves the deciduous mandibular right lateral incisor and canine (Fig. 21.15) of an 8-year-old child. A radiograph indicates that the roots were fused, as well. The third case is from the permanent dentition of an adult individual from an archeological site in New Jersey, United States (NMNH 285307). Fusion has taken place between the right lateral incisor and canine, and created a very large tooth, which might, on superficial inspection, be confused with an abnormally large tooth rather than fusion of two teeth. The roots of the two teeth are also fused (Fig. 21.16).

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FIGURE 21.16 Fusion of the permanent mandibular, right lateral incisor, and canine (arrow). An X-ray film reveals that the roots are fused. This fusion should be distinguished from abnormally large teeth (macrodontia) (specimen is from an archeological site in New Jersey, United States, NMNH 285307).

An enamel pearl can be observed on the distal surface of the roots of the left second and third molars in Fig. 21.17. The growth encroached on the alveolar bone, creating a noticeable marked cavity adjacent to the second molar but only a slight depression adjacent to the third molar.

Dental Discoloration Pathology There are three main types of dental stains or discolorations: extrinsic, intrinsic, and internal (Watts and Addy, 2001). Extrinsic staining is usually a result of environmental factors such as diet and drug use. For example, coffee, tea, tobacco and betel nut (Areca catechu) commonly cause staining to tooth surfaces (Watts and Addy, 2001). It is also thought that chromogenic bacteria may stain teeth brown, black, green, and orange, and this is primarily observed in children (Regezi et al., 2016). Intrinsic stains are a result of an issue, such as hereditary conditions or metabolic disease (including rickets) and ‘systemically circulating substances’ during amelogenesis that affects the thickness or composition of the enamel (Regezi et al., 2016; Watts and Addy, 2001). In modern times, tetracycline is a major cause of intrinsic staining of both the deciduous and permanent teeth because of its ability to bind with calcium. A high fluoride intake during deciduous or permanent tooth development may result in fluorosis, frequently observed as flecking or diffuse opacious mottling that ranges from white to black/brown in color (Watts and Addy, 2001). A number of other conditions may cause intrinsic staining,

FIGURE 21.17 Enamel pearls on the distal root surface of the mandibular, left permanent second and third molars. (A) Molars, in situ; note that the enamel pearls encroach on the alveolar bone. (B) Detail of enamel pearl on the second molar (specimen from an archeological site in South Dakota, United States, NMNH 325367).

especially of the deciduous teeth, including Rh incompatibility (erythroblastosis fetalis), congenital porphyria, liver disease, biliary atresia, and neonatal hepatitis (Regezi et al., 2016). As discussed previously, amelogenesis imperfecta may manifest as an abnormally thin (hypoplastic) layer of enamel or a hypomineralized (lack of, or poor, mineralization) area of enamel, where thickness is unaffected but extreme softness increases (Hu et al., 2007). Hypomineralized enamel may be expressed as an intrinsic stain on the tooth by a chalky spot or opacity. In both hypoplasia and hypomineralization, the affected area may be more susceptible to decay, as in the case of circular

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TABLE 21.1 Abnormal Conditions Resulting in Discoloration of the Teeth, With Typical Pattern and Color Change (Based Primarily on Pindborg, 1970: 211 224) Cause of discoloration

Pattern

Color

Fluorosis

Mottled

Yellow to brown

Congenital heart disease

Diffuse

Bluish white

Erythroblastosis fetalis

Diffuse

Green to yellow, brown or gray

Neonatal hepatitis

Diffuse

Yellowish brown

Congenital defect of bile duct

Diffuse

Green (particularly the roots)

Porphyria

Striated

Pinkish brown (roots indigo)

Hemorrhage or necrosis of pulp

Diffuse

Light brown to gray

Tobacco

Diffuse

Brown

Betel

Diffuse

Dark brown (occlusal surface and roots tend not to be affected)

caries. Enamel can undergo hypomaturation, which manifests by way of discolored (brown to yellow) crowns with dentin-like tissue density (Hu et al., 2007). Dentinogenesis imperfecta (DI) also results in extreme tooth staining, beginning with blue- or brown-colored teeth that rapidly degrade and wear (Watts and Addy, 2001). Internalized discoloration is a process of external staining that affects a tooth after development in the areas of an enamel defect or exposed dentin. The stain may be incorporated in a developmental defect, such as a hypoplasia, in patches of dentin exposed by tooth wear, on tooth roots exposed by gingival recession, in or around caries, or on restorative dental material (Watts and Addy, 2001).

Paleopathology Table 21.1 lists possible conditions and their associated expression of staining (pattern and color) that may be found in archeological samples, including fluorosis, congenital heart disease, erythroblastosis fetalis, neonatal hepatitis, congenital defects of the bile duct, porphyria, hemorrhage or necrosis of the pulp, and the use of tobacco and betel nut. Because many types of staining may appear similar, careful attention needs to be paid to the color and distribution of the stain to identify whether it is extrinsic, intrinsic, internal, or, possibly, taphonomic in nature. Extrinsic staining remains on the teeth in many burial environments. A number of researchers have identified likely betel staining, caused by the leaf of Piper betle, on the teeth of prehistoric individuals from Southeast Asia and the Pacific (Douglas et al., 1997; Oxenham et al., 2002b; Pietrusewsky et al., 1997). Recently, new methods using ultra-high-performance liquid chromatography mass spectrometry have been used to positively identify nicotine in dental calculus, even when staining

was not always observed (Eerkens et al., 2018). Differentiating hypomineralization from chemical staining as a result of taphonomic effects in the burial environment can be difficult. Methods using Raman spectroscopy, Xray microcomputed tomography, X-ray fluorescence (Garot et al., 2017), inductively coupled plasma-atomic emission spectroscopy, and scanning electron microscopy-energy dispersive X-ray analysis (SEM-EDX) (Brown et al., 2014), have successfully differentiated between postmortem and antemortem staining.

IDENTIFYING DENTAL WEAR AND ORAL DISEASE Oral pathology provides an opportunity to evaluate oral health between different individuals and within and among different populations. It is imperative that interpretations are grounded in an understanding of the demography of the assemblages, and are most informative when contextualized with a multifactorial consideration of other oral pathologies due to the recognized synergistic relationship in the oral biome (Broadbent et al., 2011; Hillson, 2001; Larsen and Fiehn, 2017). Evaluating oral health in this context allows for a deeper understanding of potential sex-based differences in the prevalence and the age-progressive nature of oral disease. There are a multitude of comprehensive syntheses of oral health in bioarcheology (Hillson, 2013; Irish and Scott, 2016; Larsen, 2015; Pinhasi and Mays, 2008). As Wood et al. (1992) predicted and DeWitte and Stojanowski (2015: 418) reiterated, advances in the fields of human biology, demography, epidemiology, and genetics have significantly contributed to our knowledge, and bioarcheological interpretations should be

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grounded in clinical evidence pertaining to oral health. The following sections describe dental wear and oral pathologies from clinical followed by bioarcheological perspectives.

Dental Wear Pathology Although there is variability in the definition of dental wear in the clinical and paleopathological literature, here we follow Burnett’s (2016: 215) definition of “wear” as “the resulting loss of tooth hard tissue from any combination of attrition, abrasion and corrosion.” Mechanical stresses exerted from tooth-on-tooth contact during the mastication of food and tooth grinding (bruxism) will result in the wear of the occlusal and interproximal surfaces of the tooth crown, known as attrition (Hillson, 2008). Attrition is recognizable by distinctive matching wear facets from the continuous contact of opposing teeth (maxilla vs mandible) or adjacent teeth in the same arch. Certain wear patterns are characteristic of attrition, such as more pronounced wear on the lingual aspect of the maxillary teeth and buccal/labial surfaces of the mandibular teeth (Burnett, 2016). Approximal, or interstitial, attrition occurs in the interproximal space of two adjacent teeth from the slight movement of teeth that accompanies chewing. This wear creates the interproximal contact facets used to help identify specific teeth, but rarely if ever exposes the dentin (Ortner, 2003). The well-defined wear facets on the crown of the teeth differentiate attrition from abrasion, which is characterized by more dispersed wear across a diffuse surface or localized area of dental tissue (Burnett, 2016). Abrasion develops when the teeth come into contact with food or other foreign objects, including inclusions in food (e.g., sand and grit). Extramasticatory behavior, such as processing plants or hides for material, food preparation, pipe smoking, and some types of oral hygiene can also cause very specific patterns of abrasion (Irish and Turner, 1997; Larsen et al., 1998; Lukacs and Pastor, 1988; Milner and Larsen, 1991; Molnar, 1972; Pindborg, 1970). Dental corrosion, or erosion, is the chemical dissolution of both enamel and dentin in the absence of bacteria (d’Incau et al., 2012; Keiser et al., 2001). It can cause wear patterns similar to attrition and abrasion, such as dentin scooping. However, any surface of the tooth may be affected by corrosion, and the lingual surfaces of the anterior teeth are particularly vulnerable. Dental corrosion can result from the consumption of acidic foods or, as commonly seen in clinical settings, regurgitated stomach acids resulting from acid reflux, eating disorders, or alcoholism (Holbrook et al., 2009; Lussi and Jaeggi, 2006; Regezi et al., 2016). Although attrition and abrasion are the most common types of wear, they do

not usually occur independently of each other or corrosion (when present), and biological and behavioral variation will dictate the expression of each type of wear (Kaidonis, 2008). As tooth wear progresses, teeth will move to maintain occlusion, leading to continued eruption, mesial drift and shortening of the dental arch, lingual tipping, and remodeling of the temporomandibular joint (d’Incau et al., 2012; Kaidonis, 2008). Extreme tooth wear that results in these changes (and others, such as a reduction in overbite and overjet) may lead to an edge-to-edge bite (labiodontia) from a “normal” scissor-bite (psalidontia) (d’Incau et al., 2012). Other factors, such as ante-mortem tooth loss (AMTL) causing tooth migration and malocclusion, weak structural integrity of the apatite crystals in the enamel, and the chemical composition of food may also influence the rate and pattern of tooth wear (Molnar and Molnar, 1990; Oxenham et al., 2002a). The abnormal position of teeth can cause localized wear on the affected teeth, known as pathologic attrition. Tooth wear is a natural process that increases with advancing age and is not pathological unless the wear becomes severe enough that the pulp cavity of the tooth is exposed. When this occurs, odontoblasts in the dentin respond by forming secondary dentin to protect the pulp cavity. If tooth wear occurs faster than the rate at which secondary dentin is deposited, the pulp and associated alveolar bone will be exposed to possible infection (Ortner, 2003). Tooth wear has the potential to destroy certain morphological attributes of a tooth and introduce bias into ancestry studies that use nonmetric dental traits (see review by Burnett, 2016).

Paleopathology The severity of tooth wear, especially attrition and abrasion, is influenced by advancing age. Methods have been developed to estimate the age of adults from the patterns of tooth wear between certain teeth, especially the molars (e.g., Benfer and Edwards, 1991; Brothwell, 1981; Mays, 2002; Walker et al., 1991). Early studies of tooth wear first identified a correlation between food type and the extent of tooth wear of prehistoric individuals, linking the pattern and severity of the wear to certain diets and food preparation techniques (Molnar, 1971, 1972; Smith, 1984). Standard methods are used to identify the extent of tooth wear in a skeletal sample. Commonly used methods include those of Scott (1979), which grades the extent of wear in each molar quadrant, and Smith (1984) and Molnar (1971) who detail the destruction of crown enamel and the extent of dentin exposure for the entire dentition. The identification of severely worn teeth can potentially provide information about the etiology of other oral pathologies. A number of studies classify “severe” tooth wear as a pathological

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FIGURE 21.18 Severe attrition of the mandibular incisors and canines with exposure of secondary dentin. The pulp cavities of the left lateral incisor and left canine are exposed; both teeth have an alveolar lesion (adult male from archeological site at Puye, New Mexico, United States, NMNH 262957).

condition in itself because the exposure of the pulp cavity from wear leaves the tooth vulnerable to infection and potential exfoliation (Domett, 2001; Lukacs, 1989; Tayles, 1999). Fig. 21.18 is an example of severe attrition complicated by pulp cavity exposure and alveolar lesions in the dentition of an adult male from the pre-Columbian site at Puye, New Mexico, United States (NMNH 262957). The maxilla, the incisors, and canines are present but badly worn. The incisors have exposed secondary dentin and the canines have wear exposing the pulp cavity on the left. On the mandible, the central incisors are missing antemortem, as apparently are the third molars. The remaining incisor crowns are worn away with exposure of secondary dentin. The canine crowns are almost worn away. There is pulp exposure of the left lateral incisor and left canine, with an alveolar lesion associated with both teeth. The crown of the left first premolar has been destroyed by caries.

Caries Pathology Caries is a complex multibacterial, multifactorial disease, which is caused by a synergistic relationship between many factors (Mira et al., 2017). Although historically Streptococcus mutans and Streptococcus sobrinus have

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commonly been linked to the etiology of caries (Loesche et al., 1975; Loesche, 1986), recent advances in molecular approaches have demonstrated the composition of the polymicrobial biofilm is much more complex (Chapple et al., 2017; Gross et al., 2012; Krzy´sciak et al., 2016; Simo´n-Soro et al., 2014; Simo´nSoro and Mira, 2015; Zaura and Ten Cate, 2015). The etiology of caries currently is understood best from the perspective of the ecological plaque hypothesis (Kilian et al., 2016; Marsh et al., 2015; Marsh, 2003; Sim et al., 2016), where caries susceptibility is a complex interplay and balance between plaque ecology and the host (Sim et al., 2016). The consumption of carbohydrates reduces the pH of the plaque biofilm that creates an acidogenic enabling environment of acid-producing and acid-tolerant bacterial colonies, which leads to an increased production of demineralizing acid (Marsh et al., 2015; Zaura and Ten Cate, 2015). Many of the dynamic processes occurring in the oral biome involved in the initiation of carious lesions occur at a microscopic level, and may be mitigated by the actions of attrition, abrasion, and erosion (Heymann et al., 2013; Holmen et al., 1987; Kumar, 2011); lesions of the enamel are the final sequela. Incipient caries begins as demineralization below the surface of the tooth, only visible at a microscopic level (Botta et al., 2016; Jones and Boyde, 1987; Lautensack et al., 2013). The macroscopic manifestation of lesions begins as a small opacity, progressing through several phases, increasing in size and intensity, and eventually causing necrosis of the dentin and pulp chamber. The pathogenesis of caries is slow and dynamic, cycling through static and active phases (Fejerskov et al., 2015; Heymann et al., 2013; Pine and ten Bosch, 1996). There are three types of caries: active, acute, and chronic (Fejerskov et al., 2015; Heymann et al., 2013). Carious lesions generally follow patterns in their predilection of tooth type due to the accumulation of biofilm as a function of occlusal morphology, where the efficacies of attrition, abrasion, or erosion are reduced (Fejerskov et al., 2015; Klein and Palmer, 1941; Macek et al., 2003; Sheiham and Sabbah, 2010). In terms of sex differences, much of the clinical literature suggests a female predisposition to higher caries prevalence (Haugejorden, 1996; Jain and Kaur, 2015; Kamate et al., 2017; Silva de Araujo Figueiredo et al., 2017). Root caries can occur as a result of periodontal disease, which effectively reduces the surrounding alveolar margin, facilitating exposure of the roots (Heymann et al., 2013). Passive eruption or overeruption can also predispose the dentition to root caries (d’Incau et al., 2012; Newman, 1999; White and Pharoah, 2014). Root caries is one of the primary causes of AMTL in older adults (Heymann et al., 2013).

766 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

Paleopathology Although caries is one of the most commonly recorded pathologies in bioarcheological assemblages, the techniques used for identification, recording, and analysis have lacked consistency (Hillson, 2001). Hillson (2001) recommends recording the position and prevalence of lesions in addition to recording caries by sex and age, as the maxillary and mandibular dentition have a differential susceptibility to caries (Thylstrup and Fejerskov, 1994). Two examples demonstrate the differential positions of carious lesions. Fig. 21.19 shows interproximal caries manifesting on all of the interproximal surfaces of the maxillary incisors of an adult male from the Shannon site in Virginia, United States (NMNH 382419). Fig. 21.20 illustrates classic root caries on the mesial interproximal surface of the lower left first molar of an adult female from Puye, New Mexico, United States (NMNH262944). There is moderate alveolar resorption indicated by the distance between the cemento enamel junction and the alveolar bone, suggesting soft-tissue recession, which would have exposed the tooth root to bacteria, predisposing the individual to caries. It is also important to take into consideration patterns of tooth wear, chipping and fractures, and cultural modifications of teeth when recording carious lesions since most carious lesions are recorded when a macroscopically observable cavitation is present. It is common for lesions to be recorded as present or absent per tooth, however, caries may manifest in several different locations on one tooth, each of these with a potentially different underlying etiology, so it is important to record multiple incidences (Hillson, 2001). The complex synergistic relationship among oral pathologies is widely acknowledged (Broadbent et al., 2011; Hillson, 2001; Larsen and Fiehn, 2017). Severe tooth wear, caries, pulp exposure and alveolar lesions influence the underlying etiology of AMTL and potentially the loss of information on carious lesions. Because of the complexity within the oral environment, several methods have been developed to try to retrospectively predict the effects of multiple etiological variables (Duyar and Erdal, 2003; Erdal and Duyar, 1999; Lukacs, 1995). These methods have largely fallen out of favor in bioarcheology since the observed caries rates may not be an accurate representation of the life history of caries in an individual. These data, however, are based on observations, as opposed to transformed data, and are more easily comparable among and between assemblages. If a comprehensive recording scheme is followed, such as proposed by Hillson (2001), the interaction between these oral pathologies should be highlighted, elucidating probable causal interactions within the oral environment.

FIGURE 21.19 Interproximal caries of the maxillary incisors (adult male from a Late Woodland site in Virginia, United States, NMNH 382419).

FIGURE 21.20 Root caries of the mesial, interproximal surface of the lower left first molar. Note the evidence of moderate alveolar resorption indicated by the distance between the cemento enamel junction and the alveolar bone. The soft tissue would have receded with the bone, exposing the tooth root to the bacteria causing caries (anterolateral view of mandible) (adult female from the archeological site of Puye, New Mexico, United States, NMNH 262944).

Historically, caries has been used to evaluate one aspect of oral health among and between populations engaging in different subsistence practices during various temporal periods, in different geographic locations, and during transitions in human prehistory (Cohen and Crane-Kramer, 2007; Larsen, 2015). There are variations in patterns geographically and chronologically, both within and between subsistence economies. However, the general trends in these data indicate that huntergatherers had fewer caries than later agricultural populations, which has been broadly interpreted as poorer oral health after the transition to agricultural subsistence (Larsen, 2015). The interpretations of sex differences in caries prevalence have been interpreted using behavioral dietary

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models. However, there has been a shift to considering clinical-based literature in these interpretations and focusing on multifactorial analyses to provide more nuanced understandings. The recent increase in the use of stable isotopes in bioarcheology provides an opportunity to evaluate whether there were actual differences in diet between the sexes or within or among different populations (Bonsall and Pickard, 2015; Petersone-Gordina et al., 2018; Tomczyk et al., 2013).

Alveolar Lesions Pathology The pathogenesis of alveolar lesions is contingent on the underlying etiology and will manifest in different ways. Exposure of the dental pulp can cause inflammation within the alveolar bone in the form of a periapical granuloma. These periapical granulomas are the result of accumulated granulation and the resorption of bone, presenting as a lesion with smooth edges (Rajendran and Sivapathasundharam, 2012). Periapical cysts, also known as radicular cysts, are usually the sequela to periapical granulomas, and are the result of a bacterial infection due to necrosis of the pulp. They manifest as epithelium-lined lesions associated with accumulated fluid and resorption of bone, presenting as a larger lesion than a periapical granuloma (Rajendran and Sivapathasundharam, 2012). Both granulomas and cysts are relatively symptomless and cause little discomfort in life (Rajendran and Sivapathasundharam, 2012). The resulting lesions from periapical inflammation will have different characteristics based on the duration of the infection and whether it is pyogenic. An acute infection produces a pressurized swelling that ruptures and is usually painful and accompanied by fever. A chronic infection produces a periapical abscess with rough edges and a sinus or channel, but does not cause pain (Rajendran and Sivapathasundharam, 2012). The distinction between these lesions is not straightforward for either clinicians nor bioarcheologists; it requires microscopic examination (Eversole, 2011; Rajendran and Sivapathasundharam, 2012). In contemporary populations alveolar lesions associated with infection of the tooth pulp and the inflammation of periapical tissue has been one of the major causes of tooth extraction (Hillson, 2005). Clinical evidence suggests that females are more predisposed to oral lesions (Armitage, 2013; Jain and Kaur, 2015).

Paleopathology There has been a lack of standardized nomenclature used to define and evaluate alveolar lesions in bioarcheology

767

(Dias et al., 2007; Ogden, 2008). The term alveolar lesions is used to broadly encapsulate lesions of the alveolar bone with no intimation as to the underlying etiology or pathogenesis. Alveolar lesions are the varying manifestations of an infection of the dental pulp, which may have been caused by caries, attrition, or trauma. Fig. 21.21 is an example of an adult male individual from Puye, New Mexico (NMNH262948), who exhibits alveolar lesions associated with gross dental caries exposing the dental pulp of both first molars. Fig. 21.21A illustrates the occlusal view of the maxilla. The left central incisor is missing postmortem, the alveolar bone of the right second premolar and third molar demonstrate alveolar resorption and remodeling indicative of AMTL. Fig. 21.21B illustrates the anterior view of the maxilla demonstrating alveolar lesions associated with the first molars and the right premolar. Also, see Fig. 21.18 (referenced earlier) as an example of alveolar lesions as a consequence of pulp exposure due to severe attrition.

FIGURE 21.21 Dental caries with destructive lesions penetrating the pulp cavity of both first molars. (A) Occlusal view; left central incisor missing postmortem. Right second premolar and third molar sockets show evidence of alveolar remodeling suggestive of antemortem tooth loss. There is an alveolar lesion associated with the premolar. (B) Anterior view of maxilla, showing alveolar lesions associated with the first molars and right second premolar (adult male from archeological site near Puye, New Mexico, United States, NMNH 262948).

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The infection of dental pulp is transmitted down the root, through the apical foramen and into the periapical alveolar bone. The resulting lesion is a consequence of the temporal nature of the inflammatory response. Alveolar lesions are commonly misdiagnosed as abscesses in bioarcheology, however, it is more likely that they are periapical granulomas or cysts. There are bioarcheological guidelines for the identification and differentiation of alveolar lesions (Dias and Tayles, 1997; Dias et al., 2007; Ogden, 2008) which are summarized below; in paleopathology the specific etiology of the lesion is not as important as noting the amount of bone lost, as this has possible implications in the etiology of AMTL. Acute periapical infections that progress through inflammation and reparation, and naturally resolve, would be difficult to identify in skeletal material (Dias and Tayles, 1997). Periapical granulomas are caused by osteoclastic activity as a result of chronic infections and manifest as a well-delineated alveolar lesion with smooth walls. If the source of the infection is removed, a periapical granuloma may resolve; however, if the infection is chronic and progressive, an apical cyst may develop from the granuloma, and once a cyst is present it will not regenerate even if the source of the irritation is removed (Dias and Tayles, 1997; Dias et al., 2007; Ogden, 2008). Apical cysts are also characterized by smooth-walled lesions, however, they are larger in size and progressively expand. Discriminating between periapical granulomas and cysts diagnostically in skeletal remains is not possible. However, as periapical granulomas are small, it has been suggested anything larger than 2 3 mm in diameter at the maximum intrabony margins would likely represent an apical cyst (Dias and Tayles, 1997; Dias et al., 2007). Periapical abscesses are the result of acute infection and are characterized by an accumulation of pyogenic material in a soft-tissue cavity. As a consequence of their acute nature, there is no osteoclastic involvement and therefore no resorption of bone (Dias and Tayles, 1997). The infection within the soft tissue causes swelling until it ruptures and discharges the pyogenic material through either existing vascular canals or perforations in the bone. Once the pyogenic material is discharged and the infection has dissipated, the connective tissue regenerates, leaving no sign of the infection. These are, therefore, difficult to identify in skeletal material (Dias and Tayles, 1997). If the periapical abscess develops within a periapical granuloma or cyst, they may roughen the smoothness of the walls of the preexisting lesion; this would be observable microscopically in skeletal remains (Dias and Tayles, 1997). If the infection persists and becomes chronic in nature, osteoclastic activity will occur in the formation of sinuses or fistulae within the alveolar to discharge the pyogenic material and alleviate the swelling. Chronic abscesses can be differentiated from other alveolar lesions through the observation of

a bony sinus or interconnecting fistulae in skeletal remains (Dias and Tayles, 1997). In summary, in terms of a differential diagnosis of alveolar lesions, a periapical granuloma manifests as a small circumscribed lesion less than 3 mm with smooth walls, an apical cyst is characterized by the same features but is more than 3 mm in diameter. If the walls of the lesion are not smooth, it indicates the secondary development of an acute abscess within the granuloma or cyst. A primary chronic abscess is characterized by a small lesion with roughened walls and sharp margins with associated sinuses or fistulae (Dias and Tayles, 1997; Dias et al., 2007).

Other Miscellaneous Conditions of the Oral Cavity Pathology There are numerous other types of pathologies that may affect the maxilla and mandible and, potentially, other parts of the skeleton. Because of their intimate relationship to the teeth and bony changes in the skull, a few of the more common lesions that are found exclusively in the jaws will be discussed. The expression of a number of these pathologies may appear similar during macroscopic analysis, and radiological analyses may provide a better diagnostic tool in some instances. Regezi et al. (2000: 86 96) provide a helpful summary of jaw abnormalities for the reader interested in more comprehensive coverage of the subject.

Odontogenic Cysts: Pathology and Paleopathology Odontogenic cysts are infections that occur in or around a tooth and include radicular, or periodontal cysts (discussed earlier), dentigerous cysts, and primordial cysts (Koseoglu et al., 2004; Regezi, 2002). After radicular cysts, dentigerous cysts are the most common type of odontogenic cyst and are likely a result of developmental problems causing the proliferation of the enamel organ remnant after crown formation, from the tooth bud of permanent or supernumerary teeth (Asaumi et al., 2004; Koseoglu et al., 2004; Regezi et al., 2016). Dentigerous cysts can cause the displacement of the unerupted tooth and the resorption of the roots of adjacent teeth, and can result from trauma, developmental syndrome, or systemic disease (Freitas et al., 2006). They are more frequently observed in the mandible than the maxilla (Kasat et al., 2012). This type of cyst is common around impacted third molars and may spread along the body of the mandible or into the ramus (Freitas et al., 2006; Ortner, 2003). In the maxilla, a dentigerous cyst affecting the canine or molars may extend into the maxillary sinus or orbital floor and may, infrequently, cause ectopic eruption of the tooth into

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these areas (Buyukkurt et al., 2010; Kasat et al., 2012). In dry bone, this type of cyst would appear as a cavity that is not intimately associated with a dental root, a possible enlargement of the overlying cortex and an association with the crown of the affected tooth if it is still intact postmortem (Ortner, 2003). There is debate over the classification of odontogenic keratocysts and keratocystic odontogenic tumors, and both names have been used to describe a proliferating cyst that develops from the remnants of the dental lamina (Regezi et al., 2016; Thompson, 2014). They occur at any age but are frequently observed in individuals in their 20s and 30s and may reoccur. They may present as solitary or multiple cysts. The mandible is affected more than the maxilla (2:1), frequently in the area of the third molar where the mandibular ramus may be affected. Similar to a dentigerous cyst, odontogenic keratocysts/keratocyst tumors will appear as a cyst not intimately associated with a tooth root, which may be multilocular or unilocular and may or may not be associated with a crown of an adjacent tooth (Regezi et al., 2016).

Odontogenic Tumors: Pathology and Paleopathology There are a number of odontogenic tumors that may arise from the epithelial or mesenchymal components of the dental bud (Ortner, 2003). One type is an ameloblastoma, that originates in the odontogenic epithelium during childhood or adolescence and continues to progress later in life. It is usually a benign tumor that affects the mandible more frequently than the maxilla, commonly in the area of the third molar (Mendenhall et al., 2007). The invasive, proliferating tumor presents as a cystic mass when developed, often multiloculated, which expands the bone but maintains a thin, ridged, bony shell. Enamel is not formed by the tumor tissue, and a tooth is not included in the lesion (Ortner, 2003). The other odontogenic tumors are of mesenchymal origin such as the odontoma, a tumor composed of dental tissues that have proliferated in an irregular way. An odontoma may present as complex, with all three dental tissues (mostly dentin, but also cementum and enamel) present as “toothlets” common in the anterior maxilla—or compound, where there is no differentiation between the dental tissues, and is usually observed in the posterior maxilla or mandible (Amado et al., 2003). Abnormal development of the cementum may result in a so-called “cementoma,” an umbrella term to describe a number of tumors of the cementum that may affect one or multiple adjacent teeth, including benign cementoblastomas and gigantiform cementomas (Matsuzaka et al., 2002). Fibro-osseous lesions of the jaw may also result in bony changes, including the relatively rare, odontogenic fibroma (Regezi, 2002). This appears in

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dry bone as a smooth-walled, more or less enlarged, lytic defect without any identifiable characteristics (Ortner, 2003).

Nonodontogenic Cysts and Tumors: Pathology and Paleopathology Previously, a number of nonodontogenic cysts, including globulomaxillary cysts and median mandibular cysts, were considered fissural cysts—arising from the “entrapment” of the epithelium during the “fusion” of the midline of the mandible or the premaxilla and maxillary processes. These are now considered a part of the spectrum of odontogenic cysts and tumors (Regezi et al., 2016). Benign fibro-osseous lesions (BFOLs) of the craniofacial skeleton are a group of poorly defined conditions that are expressed as hypercellular fibroblastic stroma and may contain bone and other calcified tissue like cementum (El-Mofty, 2014; Eversole et al., 2008). BFOL are associated with fibrous dysplasia, a condition where normal-growing bone is replaced by poorly mineralized and inadequately organized immature bone. It can occur on multiple (polyostotic) or singular bones (monostotic) and, in the case of the latter, may affect the maxilla or mandible (El-Mofty, 2014). Recognition of such lesions in dry bone would depend on good preservation of fragile trabecular bone (Ortner, 2003). A variety of lytic conditions, such as eosinophilic granuloma, “brown tumor” of hyperparathyroidism (Proimos et al., 2009), giant-cell reparative granuloma (Palacios and Valvassori, 2000), or metastatic carcinoma (Hirshberg et al., 2014) can affect the jaws. In dry bone, such lesions are devoid of identifying characteristics in themselves but may be interpretable in the context of findings elsewhere in the skeleton. Carcinoma of the oral or nasal cavity, the paranasal sinuses, and even the facial skin may cause extensive destruction of a jaw or other facial bone by direct invasion. As a rule, the lesion would show a frayed margination in dry bone with little, if any, osteosclerotic reaction (Ortner, 2003).

Hyperostosis/Tori: Pathology and Paleopathology Hyperostosis is characterized by abnormal bony growths present on the longitudinal ridge of the hard palate or lingual surface of the mandible. The torus palatinus is the maxillary form of the condition and is expressed as flat, nodular, spindle-shaped, and lobular. The torus mandibularis occurs on the mandible (commonly in the canine or premolar region), either unilaterally or bilaterally, and its shape is more amorphous and not as easily classified as the torus palatinus (Fig. 21.22) (Loukas et al., 2013). Buccal and palatal exostoses are similar to tori in that they are hyperplastic bony nodules of mature trabecular

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In modern epidemiological studies, molars are lost more frequently than the anterior teeth or premolars as a result of periodontitis (Oliver and Brown, 1993). Clinical evidence demonstrates females are more predisposed to AMTL (Russell et al., 2008; Silk et al., 2008). Not surprisingly, AMTL is usually correlated with increasing age as dental pathologies and risk of trauma also increase with age.

Paleopathology

FIGURE 21.22 Lingual hyperostosis of the mandible (no data).

and cortical bone, but they are located in different areas of the mouth and are less frequently observed than tori. Buccal exostoses are found on the buccal aspect of the mandible or maxilla and commonly near the premolars and molars. Palatal exostoses are found on the maxilla near the palatal tuberosity (Jainkittivong and Langlais, 2000). The etiology of the exostoses and tori is not known, but the higher prevalence of the conditions in some populations suggests that there may be a genetic predisposition and environmental, functional, and agerelated factors have also been suggested. Both tori and exostoses are benign and asymptomatic and there does not appear to be any negative health consequences regarding these conditions (Jainkittivong and Langlais, 2000; Loukas et al., 2013).

Antemortem Tooth Loss Pathology Permanent teeth may be lost prematurely through trauma, chronic pathology, or intentional ablation. As discussed earlier, the final culmination of a range of oral pathologies is tooth loss. This may be a sequela to gross caries, root caries, pulp chamber exposure and periapical infection, severe attrition with continuous eruption, or periodontal disease. In extremely worn teeth, which have continued to erupt, the socket may be shallow and remodeled, with the root held in place only by the gingiva. This would be represented by a shallow, remodeled alveolus and tooth roots. Intentional removal of teeth, not otherwise associated with tooth extraction, is termed tooth ablation. The distinction between intentional removal and pathological tooth loss is not always possible. An examination of the pattern of AMTL in individuals is required to investigate possible ablation as intentional removal will often be symmetrical or patterned (Burnett and Irish, 2017b).

In bioarcheology, AMTL can be differentiated from postmortem tooth loss, the latter characterized by the presence of alveoli with no evidence of remodeling (Burnett and Irish, 2017a). A differential diagnosis of AMTL requires careful consideration of the alveolar bone and the adjacent dentition to differentiate between AMTL due to underlying pathology, accidental trauma, underlying genetic factors such as agenesis or impaction, or intentional culturally-induced ablation. The presence or absence of a residual space between teeth and of wear facets on adjacent teeth can inform on whether there was preexisting dentition that has subsequently been lost (Milner and Larsen, 1991). The presence of these features provides a distinction between AMTL and agenesis or impaction. After narrowing the differential diagnosis of AMTL to pathology, accidental trauma, or intentional ablation, the presence of resorption and pathological indicators of the alveolar bone and concomitant oral pathology on adjacent dentition would indicate AMTL due to pathology. An absence of these would indicate tooth loss due to accidental trauma or intentional ablation. The presence of symmetry or an observed pattern in tooth loss, without associated dental and alveolar pathology, in multiple individuals within the same community, would indicate intentional ablation (Burnett and Irish, 2017a; Domett et al., 2013; Hrdliˇcka, 1940; Merbs, 1968; Stojanowski et al., 2016). Because intentional tooth ablation is usually associated with cultural values it is more commonly observed in the anterior dentition. Generally, molars are more affected by AMTL than the anterior teeth if the cause of the tooth exfoliation is not culturally induced. This is a result of the predisposition of the molar teeth to caries formation and severe attrition (Lukacs, 2007). Most studies that observe AMTL in archeological samples are typically associated with massive caries and/or severe macrowear with the subsequent exfoliation of the tooth (Costa, 1980; Hartnady and Rose, 1991; Lukacs, 2007; Molnar et al., 1983; Whittington, 1999). Severe periodontal disease will also result in the premature loss of a tooth. However, some researchers have asserted that periodontal disease does not usually result in exfoliation in prehistoric skeletal samples (Clarke and Hirsch, 1991). There has been no

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consistent pattern observed between the loss of the maxillary or mandibular dentition (Littleton and Frohlich, 1993; Lukacs, 2007).

Periodontal Disease Pathology Periodontal disease is initiated by polymicrobial plaque biofilm or abrasive effects of calculus (see “Dental Calculus” section), which are associated with the build-up of plaque (Clerehugh et al., 2013; Darveau et al., 2012; Hajishengallis et al., 2012). The build-up of plaque then causes an inflammatory response in the periodontal tissues of the teeth (Darveau, 2010). The inflammation agitates the periodontal connective tissues, which secures the tooth in the alveolar bone, manifesting as porosity, alveolar bone loss, and the development of pocketing or recessing, both vertical and horizontal, around the roots as the bone is resorbed. Vertical defects, or infrabony pockets, are, as the name suggests, characterized by vertical bone destruction and are defined where the pocket base is apical to the alveolar crest. Horizontal defects, or suprabony pockets, cause horizontal bone loss and are identified where the pocket base is coronal to the alveolar bone (Clerehugh et al., 2013). Periodontal disease sequentially affects the surrounding dentition, gradually exposing the roots and reducing support of the dentition, culminating in AMTL. Periodontal disease is cited as the most common cause of tooth loss in contemporary populations worldwide (Darveau, 2010) and once again females are more predisposed to periodontal infection (Armitage, 2013; Borgo et al., 2014; Pirie et al., 2007; Wu et al., 2015).

Paleopathology A range of methods for identifying and recording periodontal disease in skeletonized remains has been published. One of the most frequently seen approaches is the CEJ-AC, or cemento enamel junction to alveolar crest, method (e.g., Fyfe et al., 1993; Gargiulo et al., 1961; Khudaverdyan, 2010). The issue of intersample differences in “normal” CEJ-AC distances has led to the development of sample-specific correction factors when using this approach (e.g., Delgado-Darias et al., 2006; Tsilivakos et al., 2002), although problems with differential rates of attrition and unknown rates of continuous tooth eruption (see Clarke et al., 1986) are still serious drawbacks to such approaches. Another popular method, sometimes used in conjunction with the AC-CEJ method, is the use of Kerr’s (1988) categorization of the morphological changes to the interdental septa during periodontal disease (e.g., Oztunc et al., 2006; Wasterlain et al., 2011). Fig. 21.23 is an example of periodontal disease evidenced in the reactive alveolar bone and root exposure of

FIGURE 21.23 Molar root exposure and reactive alveolar bone suggestive of periodontal disease. Note calculus on the distolingual portion of the third molar (arrow). Left medial view of mandible (adult male from Canaveral, Florida, United States, NMNH 377439).

the left molars in an adult male from Canaveral, Florida, United States (NMNH 377439). Alveolar resorption has exposed a significant amount of the roots of the molars, resulting in very little support for the teeth. Rough porosity evidenced on the alveolar bone around the molar roots is indicative of an inflammatory response of the associated soft tissues.

INTERPRETING ORAL HEALTH Sex Differences in Oral Health There are clear and generally universal patterns in oral health based on biological sex. Meta-analysis using contemporary clinical data (Haugejorden, 1996), contemporary cultural data (Lukacs, 2011a), and prehistoric bioarcheological data (Lukacs and Thompson, 2008) have identified consistent sex differences in populations across many different cultures engaging in different subsistence economies. There has been a recent shift from the traditional behavioral dietary paradigm to a model that considers the pivotal role of female biology in the interpretation of oral health in bioarcheology (Ferraro and Vieira, 2010; Fields et al., 2009; Lukacs, 2008, 2011b, 2017; Lukacs and Largaespada, 2006; Watson et al., 2010; Willis and Oxenham, 2013). Such work has outlined the extensive literature pertaining to the clinical predisposition of females to poorer oral health, demonstrating their susceptibility as a consequence of sex-specific hormones, the size of salivary glands, the chemical composition of saliva and the confounding effects of pregnancy (Armitage, 2013; Borgo et al., 2014; Costa et al., 2017; Figuero et al., 2013; Jain and Kaur, 2015; Kamate et al., 2017; Mariotti and Mawhinney, 2013; Markou et al., 2009; Pirie et al., 2007; Rio et al., 2015; Silva de Araujo Figueiredo

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et al., 2017; Wu et al., 2015). It is clear that women are more susceptible to poorer oral health than males, a factor that needs to be taken into consideration when interpreting the prevalence of oral pathology in prehistoric assemblages.

Oral Health and Demographic Transitions Lukacs and Largaespada (2006: 550) emphasize the importance of context in a biocultural interpretation of the prevalence of caries during agricultural intensification. They predict that better oral health in pre-industrial hunter-gatherer groups, relative to farming communities, is correlated with the negative biological impacts on female health, particularly in the context of higher fertility and potentially more cariogenic diets in the latter. This observation has been developed by incorporating several different lines of evidence. The first is demographic shifts observed during the Neolithic demographic transition (NDT). The NDT defines a period where there was increased fertility in Neolithic communities, largely as a function of decreased birthing intervals in response to favorable environmental stimuli such as sedentism and sustainable agricultural crops (Bocquet-Appel and Naji, 2006). The effects of the NDT have been observed in prehistoric demographic data demonstrating an increase in birth rates (Bocquet-Appel and Naji, 2006; McFadden and Oxenham, 2018). The literature suggests a stable or declining birth rate in preagricultural groups, followed by a marked increase in fertility, subsequent to the transition to agriculture, which remained stable for 500 700 years, and then a leveling off or decline in birth rates, a pattern which has been demonstrated in many areas of the world (Bocquet-Appel and Naji, 2006; McFadden et al., 2018). The second is the variation in these demographic shifts as a function of the adoption of agriculture during the NDT. The data indicate that these demographic transitions observed through increases in fertility were slower at sites where agriculture was first being developed and more obvious in peripheral areas where the knowledge of agriculture spread (Bocquet-Appel and Naji, 2006), suggesting that population growth would be higher in populations peripheral to the origins of agriculture. It has been argued that sedentism may have been more of a catalyst than dietary change in reducing the birthing interval (BocquetAppel and Naji, 2006), however, Bellwood and Oxenham (2008: 22) suggest a consideration of both as significant in a “mutually reinforcing combination.” In a discussion of caries prevalence and fertility in relation to the NDT, Lukacs (2008) suggests the expression of a sex differentiation in caries frequency between males and females will follow the same trend as rises in fertility. This thesis has been supported for ancient Southeast Asia (Willis and Oxenham, 2013). Lukacs

(2008) further suggests that in geographical regions where agriculture was first being developed, the increase in the prevalence of caries would be small and insignificant, as a reflection of the gradual impact of changes in fertility, diet, and division of labor. While in the peripheral areas, where the transition to agriculture was faster and more intense, caries would temporarily increase at a distinct rate, the effect of increasing fertility concomitant with a decline in women’s oral health. There has been some reticence in interpreting sex differences in oral health as a function of fertility due to changes observed among both sexes. It should be reiterated that oral pathologies and the oral microbiome are complex, synergistic, and multifactorial, the underlying etiology and pathogenesis of oral pathology means both sexes are prone to developing them. The NDT, or indeed any other population-wide change, would impact the oral health of both sexes (Moynihan and Petersen, 2004; Petersen, 2003; World Health Organisation, 2003). The important difference is the increased vulnerability and biological susceptibility of females. The most parsimonious explanation for the higher frequencies of oral pathologies observed in communities influenced by the NDT with major changes in subsistence and demography is the correlation between fertility and female biology. As with all bioarcheological analyses, the interpretation of changes in oral pathology is context-specific. Situating the data and developing a multidisciplinary biocultural interpretative framework within the relevant context is imperative in understanding the environmental context, the demography of the assemblage, and any differences in diet or behavior to assist with the interpretations.

DENTAL CHEMISTRY Introduction Teeth form early in life (see “Dental Development” section), and the chemical analyses of primary dentin and enamel can provide information about the diet, health, and childhood residence of a person during the time of tooth formation (Katzenberg, 2008). Isotope and trace element analyses have become a ubiquitous aspect of modern bioarcheological research because they provide a direct means to address a diverse range of research questions that incorporate human diet, nutrition, subsistence strategies, mobility patterns, and sociocultural practices in the past (see reviews by Katzenberg, 2008; Lee-Thorp, 2008; Makarewicz and Sealy, 2015; Tsutaya and Yoneda, 2015; Turner and Livengood, 2017). The information gained from isotope and trace element analyses may be incorporated readily into any biocultural approach to

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understanding past people. Because the remains of the people themselves are being analyzed, these chemical methods may provide a direct understanding of how culture may have shaped biological responses, such as adaptation, and how it may have affected behavioral and wider societal changes that may have altered human biology, such as the impact of food choice on health. Specific chemical analyses can be chosen to tailor the research questions of each bioarcheological project and should be interpreted in conjunction with any available paleoenvironmental and archeological evidence, such as faunal and paleobotanical remains. The following subsections focus on the types of chemical analyses that are currently being used to address major research themes in the field: paleodietary reconstruction; breastfeeding and weaning; stress and disease; and human mobility; and places an emphasis on current trends and recently developed state-of-the-art methods.

Paleodietary Reconstruction: Bulk Stable Isotope Analysis Background Carbon stable isotope (δ13C) values are used to identify the consumption of plants with different photosynthetic pathways (C3, C4, CAM) and food sources from marine and terrestrial ecosystems (DeNiro and Epstein, 1978; Schoeninger and DeNiro, 1984; Smith and Epstein, 1971). Nitrogen and sulfur stable isotope ratios are used to assess marine, terrestrial, and freshwater food consumption patterns and, for δ15N values, the proportion of plants versus meat in the diet (DeNiro and Epstein, 1981; Schoeninger and DeNiro, 1984). Dietary amino acids are preferentially routed to synthesize proteinaceous tissues, of which bone collagen and tooth dentin are most commonly utilized for paleodietary reconstruction (Froehle et al., 2012). Both δ15N and δ34S values are representative of dietary protein because carbohydrates and lipids do not contain these elements (Ambrose, 1993; Richards et al., 2003). The δ13C values of enamel and apatite are representative of all the dietary macronutrients (proteins, carbohydrates, and lipids) (Krueger and Sullivan, 1984; Schwarcz and Schoeninger, 1991). Carbon from all three sources may also be utilized to synthesize bone collagen, but the preferential routing of amino acids for body proteins means that δ13C values are heavily representative of dietary protein (Froehle et al., 2010; Kellner and Schoeninger, 2007). Metabolic fractionation of stable isotope values, known as diet tissue spacing, occurs during tissue synthesis and must be corrected for when interpreting the human diet (Ambrose, 1993). Bone and dentin collagen δ13C values are about 5m higher and bone apatite and enamel 9 14m higher than diet (estimated to be near the lower range for

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humans) (for a review see Kohn and Cerling, 2002). There is a stepwise increase of 3 5m for δ15N values and 0 2m for δ13C values between trophic levels (Bocherens and Drucker, 2003; Hedges and Reynard, 2007). These trophic differences are used when comparing consumer and prey stable isotope values of bone collagen. One limitation of paleodietary studies is the variability in diet tissue spacing estimates, as they are not specific to humans and small changes in the spacing values may occur as a result of dietary (e.g., protein content), environmental, metabolic, or anthropogenic factors. This may significantly alter dietary interpretations, especially with regard to δ15N values (Makarewicz and Sealy, 2015). Comprehensive baseline dietary data are essential to correctly interpret human stable isotope data and are commonly established from analyzing the bone collagen of fauna from the site under investigation (but see discussion by Makarewicz and Sealy, 2015). Modern plant and animal values also may be used after correction for the Suess effect (the decrease in atmospheric δ13C values after the Industrial Revolution), but potential environmental variation between modern and prehistoric systems should be taken into consideration (Tieszen, 1991). The analysis of local baseline data can potentially address certain environmental factors that may affect dietary isotope values, such as the canopy effect (lower δ13C values in forest environments) (van der Merwe and Medina, 1989, 1991), the sea spray effect (high δ34S values of seawater affecting coastal terrestrial resources from sea spray) (Richards et al., 2003), aridity (high environmental δ15N values) (Heaton et al., 1986; Pate and Anson, 2008; Schwarcz et al., 1999), and manuring (higher δ15N values of manured plants) (Bogaard et al., 2007; Fraser et al., 2011; Styring et al., 2014). Baseline dietary data are a fundamental resource for interpreting human stable dietary isotope values and mixing models have been developed to estimate the proportion of certain foods within the diet (reviewed by Phillips et al., 2014). The use of mixing models incorporating Bayesian modeling methods has become increasingly popular, as this approach allows for the input of multiple dietary sources with variable element concentrations while addressing diet tissue spacing variation (Erhardt and Bedrick, 2013; Gordo´n et al., 2017; Hopkins and Ferguson, 2012; Parnell et al., 2010). However, mixing models cannot account for the complexities of metabolic routing (e.g., Webb et al., 2017), and correct interpretations rely on the researcher providing the full range of isotope variation for the complex food webs of humans in the past, which may overlap considerably (Phillips et al., 2014). Thus, mixing models may be best suited as exploratory tools to provoke new lines of thinking about diet and subsistence strategies in the past (Makarewicz and Sealy, 2015).

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Bone collagen and dentin can be affected by taphonomic processes, and quality indicators have been developed (%C, %N, %S, C:N, C:S, N:S, and collagen yield) to assess diagenetic alteration (Ambrose, 1990; Nehlich and Richards, 2009; van Klinken, 1999). There are also nondestructive methods, such as Raman spectroscopy, that are used to assess if the collagen is well preserved in a sample before destruction for stable isotope analysis (King et al., 2011). Bone apatite is subject to diagenetic alteration and therefore the biogenic δ13C values of the mineral portion of bone may not be a true representative of dietary values (Lee-Thorp and Sponheimer, 2003; LeeThorp, 2008), although a number of screening processes have been applied to address this issue such as Fourier transform infrared spectroscopy (FTIR), SEM coupled with EDX, X-ray diffraction, and microscopic observations (optical, SEM, TEM) (King et al., 2011; Lee-Thorp and Sponheimer, 2003; Reiche et al., 2003; Webb et al., 2014). Enamel is more mineralized than bone, and therefore more resistant to diagenetic alteration in the burial environment (Elliot, 1994; Kohn and Cerling, 2002; LeeThorp and Sponheimer, 2003).

Paleodietary Reconstruction: Bulk Stable Isotope Analysis in Bioarcheological Research The analysis of carbon (δ13C), nitrogen (δ15N) and, more recently, sulfur (δ34S) stable isotope ratios of prehistoric human tissues is a well-established method for reconstructing the diets of past people (see reviews by Hedges et al., 2005; Katzenberg, 2008; Lee-Thorp, 2008; Makarewicz and Sealy, 2015) (see also “Dental Calculus” section). Used in conjunction with paleopathological approaches, chemical analyses can provide important information about health, nutritional status, and mortality (Huss-Ashmore et al., 1982; Reitsema, 2013; Reitsema et al., 2016). Inadequate nutrition may result in diseases such as rickets, scurvy, and iron-deficiency anemia, compromise the immune response, and cause physiological and psychological stress (see Chapter 16). The physiological response of these processes may be observable in the skeleton in the form of disrupted growth, bony lesions, and nonspecific indicators of stress such as LEH (see “Disturbances in Dental Development” section, above) and cribra orbitalia (Larsen, 2015; Roberts and Manchester, 2005). The first point of contact for any food or drink is the oral cavity. Oral health indicators such as caries, calculus, and periodontal disease have multifactorial etiologies (see Identifying Dental Wear and Oral Disease section). Combining oral health information with the results of chemical analyses may provide insight into the possible

influence of diet on the development of these conditions (Bonsall and Pickard, 2015; Kinaston et al., 2016; Tomczyk et al., 2013; Turner, 2015). Chemical analyses may also be used to identify possible cultural and social practices and their corresponding impacts on the lives of prehistoric and historic communities, leading to a more comprehensive understanding of health and wellbeing in the past (Cheung et al., 2017; Dent, 2017; Kinaston et al., 2013a; Knudson and Stojanowski, 2008; Knudson et al., 2015; Quinn and Beck, 2016; Reitsema and Vercellotti, 2012; Turner et al., 2012).

Paleodietary Reconstruction: CompoundSpecific Isotope Analysis Background Proteins are composed of 20 amino acids, 11 of which are termed “nonessential” and may be synthesized by the body through a process known as transamination and 9 are “essential” and must be obtained from the diet (Barrett, 2012). Essential amino acids are rarely transaminated (only during excretion), because they are directly absorbed from the diet, whereas nonessential amino acids may undergo multiple transamination processes during synthesis, transformation, and excretion (Jim et al., 2006; Macko et al., 1987). Nonessential amino acids can be synthesized by higher organisms and may be representative of multiple macronutrient carbon sources (lipid, protein, and carbohydrate), whereas essential amino acids must be obtained from dietary protein (Howland et al., 2003; Jim et al., 2006). The δ15N values from bulk stable isotope analysis represent the dietary values and the sum of all fractionations of amino acids within the collagen sample, but the δ15N value of each amino acid is dependent on its specific level of isotopic enrichment of 15N during biochemical processes (O’Connell, 2017).

Paleodietary Reconstruction: CompoundSpecific Isotope Analysis in Bioarcheological Research In recent years, compound-specific isotope analyses (CSIAs) of individual organic compounds in bone, such as amino acids and lipids, have been developed as a tool for paleodietary reconstruction (Corr et al., 2008; Fogel and Tuross, 2003; Jim et al., 2004; Naito et al., 2016; Webb et al., 2015). The comparison of δ15N values of “source” and “trophic” amino acids can provide information about trophic position and has been used to address aquatic food consumption in the past (e.g., Naito et al., 2010, 2013, 2016). This is because the “source” amino acids undergo only slight fractionation, whereas the “trophic” amino acids undergo an observable enrichment in

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N with each trophic step (Chikaraishi et al., 2014; O’Connell, 2017; Styring et al., 2010). Carbon stable isotope values of specific amino acids are representative of the source of carbon in the diet (mainly from primary producers within an ecosystem) because of how the body utilizes essential and nonessential amino acids (Jim et al., 2006). The comparison of δ13C values from specific essential and nonessential amino acids therefore can provide information regarding protein and whole-diet carbon sources (e.g., aquatic and terrestrial foods) and C3/C4 resources (Corr et al., 2005, 2008; Fogel and Tuross, 2003; Webb et al., 2015). It should be noted that more research is required to understand the metabolism of source carbon for nonessential amino acids (Makarewicz and Sealy, 2015). The δ13C values from CSIAs of bone lipids, including cholesterol, have been used to assess the carbon sources of all dietary macronutrients, but the method is still in its infancy (Howland et al., 2003; Jim et al., 2004; Stott et al., 1999). CSIAs typically require smaller sample sizes than bulk isotope analyses, but the necessity to separate the compounds before isotopic analysis increases the analytical time and cost. However, as there are more analyses being conducted on one sample, CSIA can potentially provide more information than bulk isotope analyses. It is beneficial to analyze all amino acids, even if they are not being used for the current research, because it allows for the potential future use of the isotope values of these compounds.

Paleodietary Reconstruction: Trace Elements Background During life, trace elements such as strontium (Sr), barium (Br), and lead (Pb) may replace calcium in the inorganic component (hydroxyapatite) of bone and enamel (see review by Burton, 2008). These trace elements enter the food chain from the biosphere through primary producers such as plants. There is a successive decrease in Sr/ Ca and Ba/Sr ratios with increasing trophic levels because of the process of biopurification (Burton et al., 1999; Elias et al., 1982). Differences in Sr/Ca and Ba/Ca ratios are observed throughout food webs and, for the latter, between different ecosystems: marine and terrestrial (see reviews by Burton and Price, 2002; Lee-Thorp and Sponheimer, 2006). However, variability of strontium and barium concentrations has also been observed within trophic levels and between related species within an ecosystem (Lee-Thorp and Sponheimer, 2006). Marine systems generally display lower Ba/Ca ratios compared with terrestrial systems (Arnay-de-la-Rosa et al., 2009; Burton and Price, 1990; Shaw et al., 2011). Lead is found in nonpolluted environments at many orders of magnitude lower than strontium and barium (Burton, 2008). Exposure to

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anthropogenic sources of lead (at levels as low as one partper-billion) can cause major health effects and neurological development problems in infants and children (Humphrey, 2016).

Paleodietary Reconstruction: Trace Elements in Bioarcheological Research Strontium and barium were the first elements used for trace element analysis for paleodietary reconstruction due to the correlation between a reduction of strontium and barium with increasing positions in the food chain (Price et al., 1985). It was assumed that the relative proportion of plants and meat in a consumer’s diet could be ascertained using these trace elements (Sr/Ca and Br/Ca) (e.g., Burton and Price, 1990; Price and Kavanagh, 1982; Sillen, 1981). However, issues with the early methods became apparent because the strontium in bone is not just a reflection of dietary strontium, but is associated with mean dietary Sr/Ca and, similarly, bone barium is associated with dietary Br/Ca (Burton, 2008). Quantitative interpretations of plant vs. meat foods from trace element analysis have been critiqued because the Sr/Ca and Ba/Sr ratios of multicomponent diets will reflect the foods with the highest mineral components, which may lead to the overestimation of certain foods, especially those with high calcium components (Burton, 2008; Burton and Price, 2002; Burton and Wright, 1995). Concentrations of Sr and Ba and Sr/Ca have been used to address questions surrounding the consumption of plant and animal products, including milk in the past (Lugli et al., 2017; Schutkowski et al., 1999). Trace element analysis, especially Sr/Ca and Ba/Ca, of teeth is gaining popularity to address breastfeeding and weaning practices and childhood diet in the past (discussed in the following section). Differences in environmental strontium and barium abundances have been found between regions with varying geologies and climates, leading some researchers to use these trace elements as a marker of human mobility (Burton et al., 2003; Cucina et al., 2011; Knudson et al., 2012). Higher concentrations of lead in teeth and variation in lead isotope values are used to assess potential lead exposure and migration (see review by Humphrey, 2016). Other trace elements, such as copper (Cu), zinc (Zn), and magnesium (Mg) have interested researchers as paleodietary markers (Arora et al., 2014; Jaouen et al., 2017; Safont et al., 1998; Schutkowski et al., 1999). However, the applications are still developing (Dolphin et al., 2005; Ezzo, 1994a, b; Jaouen et al., 2017; Martin et al., 2015) and space constraints limit the current discussion of these methods. Diagenetic alteration of bone apatite affecting biogenic trace element concentrations is a major issue and

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must be taken into account for any such study (Dudgeon et al., 2016; Fabig and Herrmann, 2002; Lee-Thorp and Sponheimer, 2003; Reynard and Balter, 2014; Sillen, 1989). There are a number of methods to assess bone diagenesis (see Bulk Stable Isotope Analysis Background section), none of which can quantify the amount of contaminated bone or the effect it may have on biogenic trace elements (Burton, 2008). As previously mentioned, enamel is extremely robust in the burial environment and therefore retains the biogenic trace element values from the time of tooth formation.

Patterns of Breastfeeding and Weaning: Background The use of stable isotope analysis to identify breastfeeding relies on the fact that a nursing infant is one trophic level (step in the food chain) higher than its mother, as it is consuming her tissue in the form of breast milk (Fogel et al., 1989). As a result, the δ15N and δ13C values of an infant’s proteinaceous tissues that were formed during the time of breastfeeding are elevated compared to its mother’s tissues by B2 4m and B1 2m, respectively (Fuller et al., 2006a; Jenkins et al., 2001). Variation from the expected δ15N values of young infants has been observed and attributed to a number of possibilities, including maternal and infant stress (see Understanding Stress and Disease From Chemical Analyses section) and gut biome metabolism (Beaumont et al., 2015; Kinaston et al., 2009; Reynard and Tuross, 2015). Oxygen stable isotopes ratios are primarily a reflection of those in drinking water. There is a stepwise enrichment in δ18O values from drinking water to breast milk and, as breast milk is the primary source of water for infants, this trophic increase is observable in the δ18O values of their forming tooth enamel (Wright and Schwarcz, 1998).

Patterns of Breastfeeding and Weaning: The Bioarcheological Research Breastfeeding and weaning practices are integral to examining child health, and are issues that are paramount to infant and child survival rates (Humphrey, 2010; Lewis, 2007). Stable isotope, and more recently trace element analysis, have been used to identify breastfeeding practices, the timing of weaning, and types of supplementary foods consumed by young individuals (see reviews by Dean, 2017; Humphrey, 2016; Jay, 2009; Mays, 2013; Smith and Tafforeau, 2008; Tsutaya and Yoneda, 2015). Traditionally, researchers have determined the average δ15N value of the adult female bone collagen in a skeletal assemblage and then compared this to infant and young child δ15N values to assess the duration of breastfeeding,

the timing of weaning, and childhood diet in past populations (e.g., Fuller et al., 2006a; Jay et al., 2008; Prowse et al., 2008; Richards et al., 2002). Recently, researchers have introduced the use of Bayesian modeling to help refine interpretations of breastfeeding and weaning by accounting for variability in a sample caused by such factors as the unknown rate of bone remodeling and modeling in children (de Armas et al., 2017; Tsutaya et al., 2016b; Tsutaya and Yoneda, 2013). Stable isotope analysis of high-resolution incremental sections of dentin and targeted areas of dentin is becoming a popular method to provide more nuanced information regarding breastfeeding, weaning, childhood diet, and stress (Beaumont et al., 2013b, 2014; Guiry et al., 2016; Henderson et al., 2014; King et al., 2017; van der Sluis et al., 2015). This method allows for the dietary reconstruction of the people who survived the vulnerable earlier life stages (i.e., the adults) and for the determination of sex and age differences in diet during childhood (Beaumont et al., 2013a; Eerkens and Bartelink, 2013; Henderson et al., 2014; Kinaston and Buckley, 2017). Oxygen, and to a lesser extent carbon, stable isotope analysis of sequential samples of tooth enamel have also been used to investigate patterns of breastfeeding and weaning in the past (Dupras and Schwarcz, 2001; Wright and Schwarcz, 1998, 1999). Time-resolution stable isotope data from intratooth sequential sampling should be interpreted carefully because of uncertainties surrounding enamel formation times (see Dental Development section) (Balasse, 2003). The use of barium, strontium, and calcium trace elements in tooth enamel has recently been developed to address breastfeeding and weaning patterns (introduced above). Mapping changes in the concentration in these elements in incremental sections of tooth enamel can identify the trophic shift of breastfeeding and differences between the mineral component of supplementary food and breast milk on a nuanced scale in humans, other primates, and hominins (Austin et al., 2013; Humphrey et al., 2008). Stable strontium isotope ratios (δ88/86Sr) and calcium stable isotope ratios (δ44/42Ca) recently have been used to address trophic shifts in diet, and are a possible method to address childhood diet and the duration of breastfeeding in the past (Knudson et al., 2010; Lewis et al., 2017; Tacail et al., 2017).

Understanding Stress and Disease From Chemical Analyses: Background Nutritional stress can lead to a negative nitrogen balance and raise δ15N values as the body catabolizes its own tissues (Fuller et al., 2005; Hobson et al., 1993; Katzenberg, 2012; Mekota et al., 2006). Other physiological changes,

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such as pregnancy, can also affect δ15N values (Fuller et al., 2004). Variations in both δ15N and δ13C values have been observed between nonpathological and pathological bone (Katzenberg and Lovell, 1999; Olsen et al., 2014).

Understanding Stress and Disease From Chemical Analyses: The Bioarcheological Research Research has shed light on the potential influence of physiological stress and diseases on bone collagen and tooth dentin stable isotope values, although the magnitude of the stable isotope changes is variable and requires further research (Reitsema, 2013). Comparisons of the δ15N values of high-resolution incremental sections of dentin from individuals who survived childhood and those who did not have found elevated values in the latter and attributed this to possible physiological stress (Beaumont et al., 2015). A number of studies have observed fetal and perinatal individuals that display elevated δ15N values compared to the adult female mean (Fuller et al., 2006b; Nitsch et al., 2011; Richards et al., 2002), and some have attributed this to possible maternal and fetal stress (Beaumont et al., 2013b; Beaumont et al., 2015; Kinaston and Buckley, 2017; Kinaston et al., 2009). The comparison of tooth δ15N and δ13C values, representative of childhood diet and physiology, and bone δ15N and δ13C values, representative of the diet/physiology nearer to the time of death (B10 years for adult femoral cortical bone; Hedges et al., 2007), can help researchers understand the dietary “life history” of an individual (Davis and Pineda-Munoz, 2016; Eriksson and Lide´n, 2013; Mays et al., 2017; Reitsema and Vercellotti, 2012; Salamon et al., 2008; Sealy et al., 1995; Tsutaya et al., 2016a; Turner et al., 2012). This is known as a life course approach (Agarwal, 2016). Comparisons of diet from specific life stages of the “survivors” and “non-survivors” can be undertaken with isotope analyses, leading to more comprehensive interpretations that address selective mortality within the context of the Osteological Paradox (DeWitte and Stojanowski, 2015; Reitsema et al., 2016; Sandberg et al., 2014).

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forms soil, releases minerals in underground aquifers and mixes with atmospheric inputs and precipitation. The strontium sources obtainable within an ecosystem constitute the bioavailable 87Sr/86Sr values that enter food webs through primary produces such as plants (Hartman and Richards, 2014; Price et al., 2002). Seawater displays a 87 Sr/86Sr ratio of 0.7092 and soils and plants in coastal areas affected by sea spray may display elevated 87Sr/86Sr ratios closer to that of seawater (Bentley et al., 2007). Strontium substitutes for calcium in apatite, and it was hypothesized that the 87Sr/86Sr of enamel was representative of the 87Sr/86Sr ratio of the diet during the time of tooth formation (with little fractionation). A recent controlled feeding experiment has confirmed this, further validating the use of 87Sr/86Sr in paleomobility studies (Lewis et al., 2017). The δ18O values of the inorganic hydroxyapatite of tooth enamel reflect the local drinking water, and are therefore representative of the δ18O values of the local precipitation and nearby rivers, streams, and springs (Luz et al., 1984). Global precipitation δ18O values are primarily influenced by prevailing weather patterns and are closely linked to both altitude and latitude (Bowen and Wilkinson, 2002; Dansgaard, 1964). There are variations in δ18O values as a result of seasonal weather patterns, but the δ18O values of tooth enamel will represent an annual average during the time of tooth mineralization, taking into account the fractionation between skeletal tissue and environmental water (Lee-Thorp, 2008). Variation can also result from other factors such as humidity, temperature, perspiration, breast milk consumption, and distance from the sea (Dupras and Schwarcz, 2001; Gat, 1996; White et al., 2000). Researchers typically develop environmental baseline data from modern plant, animal, water, and soil samples, and prehistoric fauna to determine the isotopic variation in the local and mid-range environment (Burton and Price, 2013; Evans et al., 2009, 2010; Evans and Tatham, 2004; Price et al., 2002). The adequacy of baseline data to represent the range of isotopic diversity in local biomes and the regional landscape has been questioned, and there is a move toward developing more comprehensive isoscapes that incorporate spatial, environmental, and temporal factors through predictive modeling, including GIS (Emery et al., 2017; Pellegrini et al., 2016).

Human Mobility and Migration: Background Strontium isotope ratios (87Sr/86Sr) in human tooth enamel are representative of the place of childhood residency (Lee-Thorp, 2008). The underlying geology dictates the 87Sr/86Sr of the soils, plants, and animals in the area from which a person obtained their food during the time of tooth formation (Bentley, 2006; Knudson and Price, 2006). As bedrock weathers and breaks down, it

Human Mobility and Migration: The Bioarcheological Research Strontium (87Sr/86Sr) and oxygen (δ18O) isotope analyses are commonly used to address human mobility patterns, which can provide an insight into social relationships, methods of food acquisition, and addressing boundaries

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delineated by political agendas (see reviews by Budd et al., 2004; Lee-Thorp, 2008; Price et al., 2002; Slovak and Paytan, 2011). The δ18O values and 87Sr/86Sr ratio of tooth enamel remain unchanged throughout life. If a person moves to an area with a different underlying geology and bioavailable 87Sr/86Sr or environmental δ18O values, the isotopic signatures within their enamel will be different from the “local” people in the burial population, thus identifying them as “non-local” (Bentley et al., 2004; Price et al., 2002; Wright, 2005). The use of multiple types of biogeochemical analyses can potentially help refine interpretations of geographical origins (Gregoricka et al., 2017; Kinaston et al., 2013b; Knudson and Price, 2006; Mu¨ldner et al., 2011; Turner et al., 2012). Research focusing on δ18O and δD (hydrogen stable isotope values) of organic tissue, including bone collagen and tooth dentin has begun (Kirsanow et al., 2008; Koon and Tuross, 2013; Reynard and Hedges, 2008; Topalov et al., 2013) but space constraints limit the discussion of this new research avenue. Sulfur stable isotope analysis also has been used to identify nonlocal individuals who may have moved from coastal areas and were buried in inland cemeteries. As discussed above, coastal terrestrial ecosystems, marine foods, and some freshwater organisms display high δ34S values, and the presence of an outlier in a burial population with “marine” δ34S values may be indicative of human movement from the coast (Hemer et al., 2017; Vika, 2009).

DENTAL CALCULUS Pathology: Dental Calculus Formation Dental calculus is calcified bacterial plaque that forms throughout an individual’s life on the subgingival and/or supragingival tooth surfaces (see Periodontal Disease section) underneath a layer of nonmineralized plaque (Hillson, 1996). Plaque consists of bacteria and amorphous fluids, and dental calculus forms as a result of the deposition of calcium phosphate crystals into this plaque (Lieverse, 1999). The boundary between dental calculus and enamel or dentin is strong. There is bonding and sometimes complete fusion between the calculus and tooth apatite or enamel crystals (Rohanizadeh and Legeros, 2005), and residue may remain adhering to the teeth even after cleaning. Dental calculus is mostly inorganic, consisting primarily of calcium and phosphorus, with minor components of carbonate, sodium, magnesium, silicon, iron, and fluoride, and the minerals brushite, whitlockite, octacalcium phosphate, and hydroxyapatite (Hayashizaki et al., 2008; Lieverse, 1999; White, 1997). There is also an organic component (approximately 15% 20%) to calculus, consisting of microparticles (previously called microfossils) such as

phytoliths and starch granules, as well as biomolecules such as proteins, glycoproteins, lipids, DNA, carbohydrates, and bacteria (Lieverse, 1999; Warinner et al., 2014a,b). The microparticles and biomolecules in dental calculus originate from anything that comes in contact with the mouth, including food, animal and plant fibers, lithic detritus, bacteria, parasites, protein, and DNA (Radini et al., 2017; Warinner et al., 2014b). The rate of calculus formation, its microscopic structure, and how organic components are incorporated within it, are highly variable between individuals depending on diet, genetics, the bacterial microenvironment of the mouth (including pH and salivary flow), and dental care (Hanihara et al., 1994; Lieverse, 1999; White, 1997). However, the effects of each of these components regarding the formation of dental calculus are not well understood. There is some research suggesting that relatively high alkaline conditions created by a high-protein diet may be associated with an increased calculus build-up; however, sugary or high-carbohydrate foods also have been linked to an increase in deposits (Hillson, 2005; Lieverse, 1999). Differences in the oral fluids of individuals may be more important for determining if one is more prone to calculus formation. The unpredictable variability of dental calculus formation and composition recently was shown in an empirical study of the plant foods eaten by modern Twe foragerhorticulturalists living on the Namibia Angola border (Leonard et al., 2015). Several of the plants in the Twe diet produce microparticles (both phytoliths and starch granules), but the study found that even when people were eating microparticle-producing plants, the microparticles did not necessarily appear in dental calculus. Leonard et al. (2015) were able to confirm that microparticles extracted from dental calculus are only useful for identifying the presence or absence of plant foods and plant processing in the mouth, but not the proportion they contribute to the diet. Both the modern microparticle study (Leonard et al., 2015), and to a lesser extent the stable isotope studies described below (Poulson et al., 2013; Salazar-Garcı´a et al., 2014; Scott and Poulson, 2012), have successfully shown that analysis of various components of dental calculus are a useful way to look at population-level dietary trends, but not the diet of specific individuals.

Paleopathology: Microparticle Analyses of Dental Calculus in Bioarcheology Analysis of calculus can provide information on ancient health, diet, and environment without harming the teeth (Kelley and Larsen, 1991; Klepinger et al., 1977; Lieverse, 1999). Dental calculus first gained the attention of archeologists in the 1970s, but it took over 30 years for researchers

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FIGURE 21.24 An SEM image of archeological dental calculus. Note the irregularity of the layers as well as the “enveloping” characteristics.

to realize the full potential of this calcified bacterial microfilm. The first phytolith studies were focused on modern and archeological ungulate (cattle, sheep, and horse) dental calculus (Armitage, 1975; Dobney and Brothwell, 1987; Dobney, 1994; Dobney and Brothwell, 1986, 1988) and such work introduced recording standards still used by most researchers today (Dobney and Brothwell, 1987). Microparticle analyses have been the most common bioarcheological studies of dental calculus and the majority of this research has been used to study the plant component of diets. There are a few classes of microparticles that are commonly found in dental calculus and studied regularly: biogenic silica (phytoliths and diatoms) and starch granules. A wide range of other identifiable and unidentifiable microparticles, such as pollen and spores, unsilicified plant tissues, fungal spores, bacteria, charcoal, insects, pseudoparasites, and animal hairs have also been identified. The analysis of nondietary microremains, such as fibers and fungus, has since become the focus of a few researchers (e.g., Afonso-Vargas et al., 2015; Blatt et al., 2011; Hardy et al., 2015; Radini et al., 2016), and has been thoroughly summarized by Radini et al. (2017). After death, the lamellar, rigid, and enveloping character of dental calculus provides a relatively stable and pristine environment protected from many taphonomic processes

that commonly affect cementum or dentin. Fig. 21.24 shows an SEM image of archeological dental calculus where the irregularity of the layers, as well as the “enveloping” characteristics, can be seen. Typically, bioarcheologists focus on removing and analyzing the visible supragingival calculus build-up that creates a band on or, in extreme cases, a cap over the tooth. A simple scoring method to grade calculus deposits as mild, moderate, or severe developed by Dobney and Brothwell (1987) is commonly used in bioarcheological research (Hillson, 2008). Fig. 21.25 shows “moderate” to “severe” grades of calculus build-up on multiple maxillary teeth from a prehistoric adult individual from the c.6700-year-old Con Co Ngua, Vietnam, site. There have been attempts to rinse teeth that have barely visible or invisible deposits in order to recover any microparticles that may be embedded in thin layers resulting from a new calculus deposit forming just prior to death, or from deposits that were removed either during life or after death (Boyadjian et al., 2007). However, concern has been raised about the damage the brief (5 minutes) and weak (4% HCl) acid wash had on the morphology of the teeth and microscopic features in the enamel. It was suggested acid washes should be done only after conducting a detailed microwear analysis (Boyadjian et al., 2007; Kucera et al., 2011). Other

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FIGURE 21.25 An image of calculus deposits on multiple maxillary teeth from a skeleton from the Con Co Ngua, Vietnam site (Brothwell, 1981; grades 2 3).

studies have shown this outer layer of enamel can hold dietary evidence in the form of grass, hair, and asteriform (or globular echinate) phytoliths embedded at the end of microscopic scratches on the enamel (Lalueza Fox and Perz-Perez, 1994). A detailed SEM analysis of teeth with ephemeral or no visible calculus is warranted prior to destructive acid washes. The oldest example of microparticles extracted from a hominin are from a 2-million-year-old fossil of Australopithecus sediba (Henry et al., 2012). Analyses of Neanderthal dental calculus have expanded what we know about the role of plants in their diet and health (Hardy et al., 2012; Henry et al., 2011, 2014; SalazarGarcı´a et al., 2013). Each of these studies identified several starch granules that displayed features consistent with heat damage from cooking. These data refute previous assertions that Neanderthals ate an almost exclusively protein rich diet, which was thought to have contributed to their ultimate demise (Henry et al., 2011, 2014). At sites where both Neanderthal and modern human dental calculus were examined, it appears there were no significant differences in the breadth of their plant diets (Henry et al., 2014). In addition to Neanderthals, studies of modern human European dental calculus have also given an insight into diet, showing the use of cereals, legumes, tubers, and

fungus in various populations, as well as evidence of probable cooking techniques (e.g., Blondiaux and Charlier, 2008; Hardy et al., 2009; Henry et al., 2014; Juhola et al., 2014; Lalueza Fox et al., 1996; Lazzati et al., 2015; Power et al., 2015; Warinner et al., 2014a). There have been a few studies of microparticles extracted from the Near East (Hardy, 2007; Hardy et al., 2009) and the Middle East (Cummings et al., 2016; Henry and Piperno, 2008; Walshaw, 1999) that show the importance not only of cultivated cereals, but also wild foods in the diet. Similar results are seen further east in China, where four recent dental calculus studies focus on starch granule analysis (Li et al., 2010; Tao et al., 2015; Wang et al., 2015; Zhang et al., 2017) and show the use of various cereals, underground storage organs (USOs), acorns, palm, and beans. A study of pre-Columbian Caribbean dental calculus similarly demonstrates a diverse diet throughout the region, including maize and both wild and cultivated USOs and legumes (Mickleburgh and Paga´n-Jime´nez, 2012). Central (Scott Cummings and Magennis, 1997) and South American (Piperno and Dillehay, 2008; Wesolowski et al., 2010) dental calculus studies show regional and temporal differences in plant consumption. In Oceania, dental calculus studies have addressed questions of water availability (Dudgeon and Tromp, 2012) and the importance of the sweet potato in the diet (Tromp, 2012; Tromp and Dudgeon, 2015), as well as the stability of plant resources through time (Horrocks et al., 2014; Tromp, 2016).

Paleopathology: Chemical Analyses of Dental Calculus for Bioarcheological Research The high variability of the contents of dental calculus between individuals has made bulk chemical analyses difficult to interpret (see also Dental Chemistry section), but have been attempted by a few research groups (Eerkens et al., 2014; Poulson et al., 2013; Salazar-Garcı´a et al., 2014; Scott and Poulson, 2012). For the most part, these studies seem to disregard the high variability of dental calculus between individuals and even between different teeth of the same individual, which make it extremely difficult to create quality control criteria around C:N ratios for dental calculus, as is standard practice for other stable isotope studies (e.g., DeNiro et al., 1985). Two additional methods of chemical analysis have been utilized to study the contents of dental calculus: FTIR and thermal desorption/pyrolysis gas chromatography mass spectrometry (TD/Py-GC-MS). FTIR appears to be able to distinguish between starch and material that is comprised of similar long-chain glucoses, such as cellulose, and may be used in the attempt to taxonomically identify specific starch granules (Horrocks et al., 2014).

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FTIR analysis proved to be difficult, as samples must be dry and exposed, so cannot be in a mounting medium or obscured with a cover slip. This finding suggests that to analyze potential starch granules, samples need to either be rinsed off the slide, where there is a potential to lose the specific granules you want to target, or another subsample of dental calculus can be used. However, due to the unpredictable nature of dental calculus formation, the likelihood of finding a similar granule is low. With methodological refinement, this technique could prove quite useful in future microparticle studies where starch granules are degraded. The third major method used for chemical analysis of dental calculus is TD/Py-GC-MS, which allows for the identification of both free or unbound and bound or polymeric organic components (including lipids) (Buckley et al., 2014). Like FTIR, this method targets individual components within the dental calculus. This method has been applied to dental calculus from Neanderthals (Hardy et al., 2012), an early hominin (Hardy et al., 2015), and several Sudanese individuals (Buckley et al., 2014). The analyses have shown evidence of potential smoke inhalation (Buckley et al., 2014; Hardy et al., 2012) and possibly the use of yarrow and chamomile; a finding interpreted by the authors as medicinal use of these plants (Hardy et al., 2012).

Paleopathology: aDNA and Protein Analyses of Dental Calculus for Bioarcheological Research Biomolecular techniques are rapidly developing and, recently, three major studies have demonstrated the utility of analyzing aDNA (Adler et al., 2013; Warinner et al., 2014b; Weyrich et al., 2017) and proteins (Warinner et al., 2014a) extracted from dental calculus. Oral bacteria, the major component of dental calculus, are the primary target of aDNA calculus studies. Changes in the oral microbiota have reflected the shift from agriculture to industrialization (Adler et al., 2013) and aDNA analyses also hint at the potential to identify markers of cardiovascular and respiratory disease, and dietary components (Warinner et al., 2014b; Weyrich et al., 2017). Additionally, human mitogenomes have been extracted from the dental calculus of six 700-year-old North American individuals, despite human DNA being less than 1% of the total DNA recovered from the dental calculus after enrichment (Ozga et al., 2016). Although this needs to be explored in further regions and time periods, this study opens up exciting new possibilities for aDNA and paleopathological analyses that do not destroy human remains.

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Proteomic analyses of dental calculus are also used to better understand ancient oral pathologies and diet. One major benefit of protein analysis is the identification of both pathological bacteria and human innate immune system proteins (Warinner et al., 2014b). There is also potential for species-specific dietary proteins to be recovered. For example, human dental calculus has shown areas in Europe and Eurasia where species-specific milk was consumed up to 5000 years ago, as well as an absence of milk consumption in historic Central West Africa; confirming indirect assumptions as well as previously unidentified variability in European milk consumption (Warinner et al., 2014a). This most recent methodological advancement is likely to enable identification of many more dietary markers within dental calculus (Hendy et al., 2018).

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Wright, L.E., Schwarcz, H.P., 1998. Stable carbon and oxygen isotopes in human tooth enamel: identifying breastfeeding and weaning in prehistory. Am. J. Phys. Anthropol. 106 (1), 1 18. Wright, L.E., Schwarcz, H.P., 1999. Correspondence between stable carbon, oxygen and nitrogen isotopes in human tooth enamel and dentine: infant diets at Kaminaljuyu. J. Archaeol. Sci. 26 (9), 1159 1170. Wu, M., Chen, S.-W., Jiang, S.-Y., 2015. Relationship between gingival inflammation and pregnancy. Mediat. Inflamm. 2015, 623427. Zaura, E., Ten Cate, J.M., 2015. Towards understanding oral health. Caries Res. 49, 55 61.

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Chapter 22

Mummies and Paleopathology Niels Lynnerup Department of Forensic Medicine, University of Copenhagen, Copenhagen, Denmark

Ortner (2003) entitled his landmark book: “Identification of Pathological Conditions in Human Skeletal Remains,” thus focusing on skeletal remains to the exclusion of paleopathological conditions in mummified human remains. This is understandable, given the vastly greater number of human skeletal remains found than mummies and his passion for skeletal paleopathology. However, with this new edition of his book, a chapter on mummy paleopathology is timely. Mummies may display pathological lesions of soft tissues, for example, atherosclerosis, which simply do not exist in exclusively osteological material (see Brothwell and Sanison, 1967; Cockburn et al., 1998; Aufderheide, 2003, and references therein). Furthermore, it is always worth keeping in mind that our bones are covered and connected by soft tissues, and that many pathological processes that affect bones also affect other tissues and organs of the body. A good paleopathologist, even when working almost exclusively with skeletal remains, should have a basic knowledge of what mummies have contributed, and may contribute, to paleopathology. By definition, mummies are human (or animal) remains with preservation of nonbony tissue. The word mummy is used when soft-tissue preservation is so pronounced that body parts, or even the whole body, have preserved skin and some preserved internal structures, such as muscle fasciae, ligaments, and maybe even tissue of internal organs and muscle. Soft tissues are preserved when the postmortem conditions are such that the usual tissue decomposition, including the action of bacteria and insects, is hindered. Basically, tissue dehydration overtakes tissue postmortem decay. This condition may be achieved either naturally due to environmental conditions, such as a hot or very cold, dry climate, or it may be facilitated by mortuary practices, such as removal of internal organs and drying out of body cavities. Mummification

by the former results in natural mummies, while mummification induced by active (human) intervention results in artificial mummies. In either process, the mummification and preservation of soft tissues is highly variable. Internal organs, particularly of the digestive system, often are completely decomposed, and organs may be very shrunken and difficult to identify morphologically due to desiccation. Furthermore, various funerary rites comprising embalming and evisceration may entail the complete removal of internal organs and the brain. Generally, the soft tissues most often preserved are tissues with a high content of collagen, like the dermis, muscle fasciae, and tendons (see Aufderheide, 2003, and references therein). Bone and teeth are as much a part of a mummy as the other tissues. Therefore, mineralized tissues may play just as great a role in the investigation and paleopathological diagnostics of a mummy as any skeleton being studied. However, the presence of soft tissue, especially the skin, may make it difficult to examine the internal organs and tissues. Thus, much emphasis is being placed on the development of nondestructive methods of examination for pathologies in mummies, including radiography, CT scanning with advanced three-dimensional visualizations, biochemical, and biomolecular analyses. These methods are covered in more detail in Chapter 7. It is, however, worthwhile mentioning endoscopy in this chapter. Endoscopes are flexible tubes with a light source and with lenses capable of magnification. The flexible tube may be manipulated so that the operator can look inside cavities through a small incision or orifice. They may also be outfitted with devices allowing cutting and sampling of tissue (Tapp et al., 1984). These instruments are therefore particularly suited for studying mummies, and results of their use will be addressed after the following general introduction to the mummy autopsy.

Ortner’s Identification of Pathological Conditions in Human Skeletal Remains. DOI: https://doi.org/10.1016/B978-0-12-809738-0.00022-3 © 2019 Elsevier Inc. All rights reserved.

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PALEOPATHOLOGICAL EXAMINATION OF MUMMIES In modern pathology, an autopsy is the ultimate procedure for procuring detailed pathoanatomical knowledge of diseases in a deceased individual and includes, obtaining tissue samples for microscopy and biochemical/ biomolecular analyses. Prior to the 21st century, autopsies were carried out readily on Egyptian mummies, probably due to the enormous abundance of them and doctors‘ fascination with disease in the past (Pringle, 2001). More recently, when autopsies have been carried out, for example, at the Manchester Museum project (David, 1979), the procedure is not that different from a present-day autopsy, where definitive knowledge is gained about circumstances of death and pathological changes of internal organs; more so than through external observation alone (Cockburn et al., 1975; Zimmerman and Aufderheide, 1984; Robertson, 1988). Since pathological diagnosis is often based on gross macroscopic inspection, being able to study the remains of internal organs for pathological change is important. Autopsy is also the best procedure for securing tissue samples from specific organs, such as heart, lungs, and liver, which might otherwise be difficult to locate and sample through other techniques (El-Najjar et al., 1980, 1985). Similarly, gut contents may be recovered (e.g., Helbaek, 1958; Spindler, 1994). Since most mummies are desiccated, a mummy autopsy rarely follows modern autopsy procedures employed when dealing with newly deceased individuals or with cadavers retaining their hydrated, pliable tissues (see, for example, Saukko and Knight, 2004). Obviously, this procedure may be difficult to carry out with a crouched, desiccated mummy, so mummy autopsies often are conducted by making incisions wherever it is most opportune; for example, through the side or back of the thorax and abdomen, with a varying degree of cavity opening (Aufderheide, 2003). Postmortem changes may of course also help, in that the thoracic and abdominal skin and muscles may have decayed to such a degree that the cavities are readily visible. Loss of limbs may also facilitate access to the body cavities, and sometimes the head may have come apart from the body so that throat organs may be easily inspected. Autopsy literally means “postmortem examination,” of which the opening of the body cavities is but one part; in forensic autopsies the careful examination of the surface and skin of the corpse is also a very important part of the autopsy procedures (Saukko and Knight, 2004). Consequently, while perhaps it is not possible, or desirable, to undertake a complete, invasive autopsy including opening of the body cavities, the careful examination of the mummified skin and integuments may yield much information on penetrating wounds and cuts,

tattoos, scars, and skin pathologies (such as warts) (Verbov, 1986; Lowenstein, 2004). The appearance of mummified internal organs may deviate from the appearance of unmodified organs, in that postmortem degradation, putrefaction, etc., together with changes brought about by desiccation, can alter the morphology of organs (Aufderheide, 2003). Structures with a high collagen content may still be intact (Wei, 1973). The diaphragm often is recognizable to the point where even a hernia may be diagnosed (Gerszten et al., 1986), or if the tissue is not intact, then the fibrous and muscular attachments along the abdominal wall and around the vertebral column may be visualized. Similarly, fibrous tissue such as muscle fascia, ligaments, and tendons are often also identifiable and preserved. In the thoracic cavity, inspection of the pleura, the presence of lung remains, and their morphology may provide important clues about lung diseases, such as infections and tuberculosis (Aufderheide, 2003). The heart may be shrunken almost beyond gross morphological recognition, but the fibrous portion around the atrioventricular region including the major heart valves still may be discerned (Zimmerman, 1972, 1978, 1993). For the abdominal organs, the liver is often recognizable due to its dense structure (Aufderheide, 2003), whereas the thin-walled stomach and intestines often decay completely. The abdominal cavity may contain remnants of gut contents as well as coprolites. These may contribute to dietary studies, if found and analyzed (e.g., Reyman et al., 1998; Harild et al., 2007; Spindler, 1994). Kidneys are often also difficult to recognize, as is the spleen. Remnants of the esophagus and the big vessels (vena cava and aorta) may be seen (Aufderheide, 2003). Organs of the lower abdominal region, mainly the intestines and inner genitalia, are often not discernible. Outside the body cavities, several structures of the throat (which may be very important to determine manner and cause of death, e.g., by strangulation) are often preserved (thyroid cartilage, vocal cords), as are the bulbar structures of the eyes (although the aqueous humor will have disappeared, so that the eyes present themselves as flattened structures), and the brain. Due to its high fat content, the brain may undergo adipocerous change. This may result in excellent morphological preservation showing gyri and sulci and main brain parts (hemispheres, hindbrain, medulla oblongata with the pons, etc.) (Padanov et al., 1992). The brain may, in other circumstances, liquefy postmortem such that only a hardened “rim” along the inside of the skull remains. However, the dura mater may be well preserved (Aufderheide, 2003). Finally, external genitalia may be present (although often very dependent on mummification procedures), which allows for a definite sexing of the individual (Aufderheide, 2003).

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Endoscopy

MUMMY PALEOPATHOLOGY

Endoscopy allows the direct inspection of intracavity structures and organs (Manialawi et al., 1978; Notman et al., 1986; Tapp and Wildsmith, 1986; Bonfils et al., 1986 1987; Reyman et al., 1998; Gaber et al., 2003; Gaafar et al., 1999; Hagedorn et al., 2004; Isidro et al., 2006; Beckett and Conlogue, 2009, and references therein). Endoscopes are used in a variety of clinical settings, such as gynecological and abdominal examinations and operations, as well as ear and throat examinations and operations; this means that they are produced with different diameters. This may be important depending the size of the mummy‘s orafices and openings (whether they be natural, artificial or taphonomic) where one wishes to insert the scope. The advantage of using an endoscope is that it can secure tissue and organ samples with minimal destruction (Gaber et al., 2003). It should perhaps be noted that endoscopy may be used by the osteologist to examine the inside of an intact cranium (e.g., Knu¨sel et al., 2013).

As with diagnoses of pathology in prehistoric skeletons, descriptions of pathologies in mummies provide us with a sense of time depth in the story of human diseases (Aufderheide and Rodriguez-Martin, 1998). However, when focusing specifically on mummies, the record is uneven. For some diseases, most notably parasitic diseases, much has been learned from studying mummies, while other diseases are virtually absent in the mummy record. The presence of mummified tissues does not make the usual discussions of pathological versus pseudopathological changes and perimortem versus postmortem lesions less critical to paleopathological analysis. (Lynnerup, 2007, and references therein). Furthermore, in the case of artificial or partly artificial mummies, changes to the body may have been made postmortem, including cutting into body cavities, sewing up body orifices, replacing degenerated external genitalia with resin models, fitting wigs made of human hair onto the corpse, special treatment of certain organs and cavities, as well as the use of various dehydration techniques (smoking, use of salts in cavities, applying substances to the external surfaces, etc.) (Aufderheide and Rodriguez-Martin, 1998: 12 13).

Tissue Histology Armand Ruffer was a pioneer in applying rehydration techniques on mummified tissue (Ruffer, 1921, cited in Aufderheide, 2003). His rehydration method is still used extensively, although many researchers have tried to refine Ruffer’s solution or to develop new rehydration techniques. Much work also has been done on developing staining methods (Sandison, 1955; Turner and Holtom, 1981; Allison and Gerszten, 1982; Fulcheri et al., 1985; Walker et al., 1987; Mekota and Vermehren, 2005). Histological analyses may be helpful in determining the degree of tissue conservation and in identifying cells and tissues (Williams, 1927; Yeatman, 1971; Zimmerman et al., 1971; Zimmerman, 1973; Riddle et al., 1976; Walker et al., 1987; Nerlich et al., 1993; Hess et al., 1998; Denton et al., 2003; Moissidou, 2003). Recognizable tissue microstructure has been described for mummified mammal specimens dated over 21k years ago. (Zimmerman and Tedford, 1976). Tissue microscopy may offer definitive evidence of pathological changes, such as those associated with atherosclerosis (Shattock, 1990, cited in Aufderheide, 2003); lung pathology, including anthracosis and pneumoconiosis; liver pathology, such as cirrhosis; skin conditions (Speck and Wheeland, 1984; Giacometti and Chiarelli, 1968; Chapel et al., 1981); and various neoplastic lesions. Parasitic infestation can be ascertained through tissue microscopy (e.g., Allison et al., 1999). Combining histology with immunofluorescence has been used to reveal tissue antigens (Wick et al., 1980).

Neoplasms Very few visceral tumors have been identified in mummies (Fornaciari and Giuffra, 2012). Some researchers have attributed this to the fact that life expectancy was too short to allow the development of neoplasms. However, mummies of individuals dying at an old age have been found, and several other age-related diseases, such as vascular and joint diseases, have been identified in mummies. Another possible explanation for the paucity of neoplasms noted in mummies may be that many neoplasms are linked with modern lifestyles and environmental factors, such as pollution, smoking, and dietary habits (Zimmerman, 1981; Deeley, 1983; Roberts and Manchester, 2005: 263) Thus, we would not expect neoplasms to appear with any frequency until industrial times. Finally, the lack of standardized, epidemiological studies (Nerlich et al., 2006) actually may be the key reason for an apparent absence of tumors in mummies. As skin is often the most extensively preserved soft tissue in mummies, several of the few identified neoplasms are skin tumors (see Fornaciari and Giuffra, 2012, and references therein; Sandison, 1968). The identified neoplasms include an angiokeratoma (Horne, 1986), a skin histiocytoma (Zimmerman, 1981), a squamous papilloma (Sandison, 1967), a lipoma (Allison and Gerszten, 1983, cited in Aufderheide, 2003), and a simple wart

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(Fulcheri, 1987). More recently, Panzer et al. (2017) report a case of neurofibromatosis in an Inca child mummy. Aside from skin tumors, leiomyomas (benign tumor of the uterine smooth muscle) (Strouhal, 1976; Strouhal and Jungwirth, 1977; Kramar et al., 1983), fibroadenoma of the breast (Reyman and Peck, 1998), and a neurilemmoma (Strouhal et al., 2003), have been reported. Fornaciari (1993) published a case of colorectal adenocarcinoma (in a mummy from the 14th century), which was seemingly confirmed by DNA (for a specific oncogenetic mutation) (Thillaud, 2006). In another example, DNA tests from several Hungarian 18th-century mummies indicated that one mummy was genetically predisposed to colorectal cancer, though a tumor was not found (Feldman et al., 2016). Such analyses suggest that future genetic analyses may be productive.

Infectious Diseases Tuberculosis has been diagnosed in mummified lung tissue (Salo et al., 1994), and acid-fast bacilli have been found in association with tuberculous changes (Allison et al., 1973; Zimmerman, 1979; Gerszten et al., 2001). Also, mycobacterial DNA has been recovered from mummies (Nerlich et al., 1997; Konomi et al., 2002; Zink et al., 2003; Donoghue et al., 2004; Spigelman et al., 2006; see also Chapter 8). Another disease well known by paleopathologists is syphilis, but only one mummy has been reported to present diagnostic soft-tissue lesions. This case involved a 16th-century mummy in Italy with a bandaged ulcer, wherein subsequent immunofluorescence and histology identified spirochetes (Fornaciari et al., 1989). While extensively documented in the osteological record (e.g., Møller-Christensen, 1967; Ortner, 2003), there have been no published reports on mummified remains with lepromatous changes. Aside these infectious diseases, which have been diagnosed in osseous remains, infection by Helicobacter pylori, causing gastric ulcer, has also been found in a frozen mummy (Maixner et al., 2016). Thus, a disease once thought to be caused by modern lifestyle (“stress”) now has a much deeper history than originally believed. The viral infection known as smallpox has been identified in several mummies (Field, 1986; Fornaciari and Marchetti, 1986; Perrin et al., 1994; Marennikova et al., 1990). This is due both through the identification of skin lesions, but also, in more recent publications, by microscopic and electron microscopic analyses (Horne and Kawasaki, 1984). Most recently, DNA has been recovered (Duggan et al., 2016). Finally, mycotic infections also have been identified (e.g., Horne, 1995).

Parasitic and Helminth Diseases (See Also Chapter 14) Mummies have been very important in establishing the paleoepidemiology of parasitic and helminth diseases. In a sense, mummification can take place to both the host organism (the human) and the parasite. Furthermore, mummification may lead to preservation of specific soft tissues such as hair (where lice may be found) and bodily contents (fecal matter), where larvae and eggs of parasites may be identified.

Other Diseases of Visceral Organs Vascular diseases such as arterial degenerative disease (Sandison, 1967; Magee, 1998), atheroma, and arteriosclerosis (Zimmerman et al., 1971; Zimmerman and Aufderheide, 1984; Zimmerman, 1985; Bauduer, 2005) have been identified, including, for example, ulceration of the leg (Haneveld, 1974). The HORUS group has carried out several CT-scan-based analyses of numerous mummies focusing on atherosclerosis (Thompson et al., 2013). Their comparisons to modern rates of the disease suggest that atherosclerosis is not a recent affliction (Allam et al., 2014). Infectious cardiac diseases such as myocarditis (Long, 1931; Zimmerman, 1978) and secondary pericarditis (Blackman et al., 1991) also have been found in mummified remains. Emphysema has been identified in several mummies (Shaw, 1938; Allison, 1984a,b). Pulmonary hemorrhage has also been diagnosed (Nerlich et al., 1995), as has pneumonia due to aspiration (Allison et al., 1974a,b). A pathological condition which should, and does, surface in a paleopathological setting, is the formation of calculi in the internal organs, as calculi obviously will tend to be preserved (Hoeppli, 1972). Two major foci exist for calculus formation: the gallbladder with the biliary tract, and the urinary system (e.g., Giuffra et al., 2008; Capasso et al., 2017). Reviews of these conditions have been made by Aufderheide and Rodriguez-Martin (1998) and Steinbock (1989, 1990), including other gallbladderrelated conditions, such as infections (Munizaga et al., 1978). Other miscellaneous soft-tissue pathology includes reports of hernia (Munizaga et al., 1978; Gerszten et al., 1986), appendicitis (Smith and Wood Jones, 1910, cited in Aufderheide and Rodriguez-Martin, 1998), hydronephrosis (Allison and Gerszten, 1983), and renal disease (Long, 1931). To a further degree than dry bone analysis, paleopathological studies of mummies may reveal health aspects of everyday life and work. For example, anthracosis (deposition of soot particles in the lymph nodes in the lungs) is

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indicative of air pollution, and suggests that the people of that specific culture inhaled sooty air due to living in confined spaces with open fires or use of oil lamps. The latter would be the case for mummies from Greenland (Hart Hansen, 1989) and for the Utqiagvik mummies from Alaska (Zimmerman and Aufderheide, 1984). Anthracosis has also been found in Guanche mummies from Tenerife (Brothwell et al., 1969), mummies from Hungary (Petranyi, 1996), and Egyptian mummies (Walker et al., 1987). Inhalation and deposition of other particles may be suggestive of living in very arid and dusty environments, as has been the case for mummies from Egypt (Tapp et al., 1975; Zimmerman, 1977) and mummies from Chile (Abraham et al., 1990). Inhalation of particles from sandy soils, which contain silica (silicon dioxide), may lead to a condition known as silicosis. The silica has a local toxic effect causing fibrosis of the lung tissue (Aufderheide and Rodriguez-Martin, 1998). The condition was found in Chilean mineworkers of the 16th century (Munizaga et al., 1975). Exposure to agricultural dust was hypothesized for mummies from the southwestern United States (El-Najjar et al., 1985).

Lesions, Trauma, and Cause of Death Many lesions and lethal wounds will not leave any osseous signs, or only ambiguous ones. For example, the soft tissue of the Danish bog body from Grauballe, dated to

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approximately AD 100, revealed that his his throat had been cut (Fig. 22.1). A forensic reconstruction of his execution was therefore possible (Gregersen et al., 2007). Likewise, other bog bodies have been found with nooses, blindfolds, and tied hands and feet (van der Sanden, 1996; Fisher, 1998). A noose around the neck also has been reported for a Tihuanaco child (Allison et al., 1974a,b). Accidental causes of death have been noted in frozen mummies from Utqiagvik in Alaska (Zimmerman and Aufderheide, 1984). Evidence of hanging or strangulation has been found in Mongolian mummies (Frohlich et al., 2005). Pleural effusion containing hemoglobin may indicate that death was not instantaneous. Death due to landslide (Zimmerman and Smith, 1975), and even two cases of probable fatal pneumonia after aspiration of a deciduous tooth (Allison et al., 1974a,b; El-Najjar et al., 1985), have been described. Lesions and hemorrhaging due to trauma have been noted in a study of mummified brains (Gerszten and Martı´nez, 1995). Panzer et al. (2017) suggested probable perimortem violence in their study of an Inca child mummy. Researchers discovered that Otzi, the 5000-year-old ice-mummy from the Alps, had an arrowhead embedded in his shoulder. The projectile had probably severed major arteries around the shoulder and neck (Perntera et al., 2007). Finally, the preservation of soft tissue may show how sacrificial death need not be by sharp or blunt force trauma, or even interpersonal violence, but perhaps rather by exposure or smothering, as found in a FIGURE 22.1 Three-dimensional reconstruction based on CT scanning of the Grauballe man, an approximately 2000-year-old bog body. A wide cut lesion is visible extending from ear to ear (red arrows indicate wound margins). At close inspection, the wound margins were sharp, and the throat organs, including all major vessels, had been completely transected. Loss of consciousness would have been immediate and Grauballe man died within minutes. Forensic analyses of the throat organs further revealed that his head probably had been extended maximally backwards when the cut was made, thus pointing to an execution-style procedure. No cut marks were found on the vertebrae nor mandible. If only the skeleton had been found, these circumstances around his death would not have been known.

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study of three exceptionally well-preserved Inca child mummies (Wilson et al., 2013).

CONCLUSION The paleopathological study of mummies has made important contributions to our understanding of diseases in the past. This line of research allows us to analyze pathologies otherwise not seen in dry bones, and thus complement osteological observations. The scientist studying mummies must be aware that radiography and bone histology are important methods for studying the bones inside the mummy. These approaches will add to observations of bone pathology from mummies and other skeletal studies. Conversely, the scientist mostly working with dry bones needs to remember that those bones once were covered with soft tissues, and that pathologies seen in the bones must also have affected various soft tissues.

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Chapter 23

Nonhuman Animal Paleopathology—Are We so Different? Richard Thomas School of Archaeology and Ancient History, University of Leicester, Leicester, United Kingdom

Humans are a kind of animal that (like all kinds of animal) has been and continues to be profoundly reshaped by its interactions with other kinds of animals . . .. All history is animal history, in a sense. (Benson, 2011, p. 5).

. . .it is quite certain that if we restrict our observations of the processes of disease as they occur in man, our notion of them would be as crude as if we attempted to form conclusions as to his zoological position without reference to other species of animals. (Bland Sutton, 1890, pp. 12 13)

INTRODUCTION While the study of pathology in human skeletal remains has a long and illustrious history with established and increasingly refined theoretical and methodological foundations (e.g., Buikstra and Roberts, 2012), the same cannot be said for nonhuman (animal) paleopathology. The value of studying disease and injury in the skeletal remains of animals in the past was recognized by the early 20th century (Moodie, 1923a,b; Wintemberg, 1919); however, the subsequent development of the discipline was sporadic (Thomas, 2012). As recently as 2000, zooarcheological paleopathology was characterized as “an inchoate discipline studied by a relatively small number of analysts” (O’Connor, 2000: 98). Issues that complicate the pursuit of zooarcheological paleopathology have been explored in previous reviews (e.g., Bendrey, 2014; Siegel, 1976; Shaffer and Baker, 1997; Thomas, 2012; Thomas and Mainland, 2005; Upex and Dobney, 2012; Vann and Thomas, 2006). In brief, these can be grouped into three, interrelated problem areas:

1. Complications arising from the nature of zooarcheological material: most animal bone assemblages are comprised of disarticulated and fragmentary remains, which makes it difficult to place lesions within their biological context and to undertake differential diagnoses; the low frequency of pathological bones per site. 2. Inadequate clinical foundation: the etiology and pathogenesis of many lesions observed in archeological fauna are not observed clinically because the life expectancy of domestic livestock is considerably shorter in modern industrialized farming systems than it was in the past; the skeleton is examined less systematically than soft tissues during necropsy; many of the lesions observed in the zooarcheological record are considered incidental by veterinary pathologists because they do not affect animal health (or, critically, animal productivity) significantly, and thus feature rarely in veterinary literature; an absence of clinical evidence means that separating pathology from “normal” biological variation/adaptation can be difficult and may lead to speculative interpretation. 3. Complications arising from disciplinary practices: unsystematic recording, with an emphasis on diagnosis (over description) and a tendency to focus on “interesting specimens” (usually the most florid cases of pathology) devoid of biological and environmental context has hampered attempts to chart geographic and diachronic variation in prevalence; lack of integration with other kinds of archeological evidence; unfamiliarity with veterinary nomenclature, which is itself under constant revision. Over the past 20 years, however, things have begun to change with: improved understanding of the pathogenesis and archeological significance of skeletal lesions through analysis of known-history populations (e.g., Bartosiewicz et al., 1997; Bendrey, 2007; Darton and Rodet-Belarbi, 2018;

Ortner’s Identification of Pathological Conditions in Human Skeletal Remains. DOI: https://doi.org/10.1016/B978-0-12-809738-0.00023-5 © 2019 Elsevier Inc. All rights reserved.

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Fabiˇs and Thomas, 2011; Levine et al., 2000; Niinima¨ki and Salmi, 2016; Rafuse et al., 2013; Taylor and Tuvshinjargal, 2018; Thomas and Grimm, 2011; Zimmermann et al., 2018); technological advances in imaging, biomolecular, and histological approaches (e.g., Bathurst and Barta, 2004; Bendrey et al., 2007; Martiniakova´ et al., 2008; O’Connor and O’Connor, 2005; Rothschild et al., 2001; Tourigny et al., 2016); publication of protocols to encourage systematic recording (e.g., Bartosiewicz et al., 1997; Vann and Thomas, 2006; Thomas and Worley, 2014); the development of theoretical frameworks to aid interpretation (e.g., Binois, 2013; Thomas, 2017); increased rigor in differential diagnosis (e.g., Binois, 2013; Lawler et al., 2016); systematic spatial and temporal analyses of lesion frequencies (e.g., Bartosiewicz, 2002, 2008, 2018; Fothergill, 2016, 2017; Thomas, 2008); and epidemiological modeling (e.g., Fournie´ et al., 2017). While human skeletal analysis and zooarcheology have followed different trajectories, particularly since the emergence of the New Archaeology in the 1960s, this separation is an artifice of practice and reflective of the dominance of anthropocentrism within archeology. It is telling that while humans hold their own disciplinary specialism within paleopathology, all other species are lumped together anonymously as “animal.” This disciplinary schism is less evident in the earliest publications within paleopathology. As far as Moodie (1923b: 11) was concerned, paleopathology encompassed “all evidences of disease and injury prior to the opening of recorded medical history, which begins with the writings of Hippocrates, Aristotle, Aetius, Alcemon, Democritus, Empedocles, and other early writers on biological and medical subjects.” Evidencing this wider consideration, Moodie’s (1923a) volume encompass the description of pathology in plants, crinoids, molluscs, fish, reptiles, birds, mammals, and humans. In this chapter, I will review the relationship between human paleopathology and its nonhuman animal counterpart by identifying areas of commonality and departure, before considering the benefits and challenges of closer integration. Whilst pathology can be observed in a wide range of animal tissues, my focus will center on other mammals, rather than the animal kingdom more broadly, as this is where the closest parallels and relevance reside. Before exploring these synergies and differences, however, a brief review of the kinds of archeological questions upon which nonhuman animal paleopathology can inform is necessary.

RESEARCH FOCI WITHIN NONHUMAN ANIMAL PALEOPATHOLOGY The breadth of archeological questions that can be pursued through the identification and analysis of nonhuman

animal paleopathology has been highlighted in recent publications (Bartosiewicz and Ga´l, 2013). Shifts in emphasis are identifiable through time, however, tracking developments in (zoo)archeological theory more broadly (Thomas, 2012). An important theme has been the potential of animal pathology to contribute to our understanding of the economic exploitation of animals in the past. Considerable attention has been paid to lesions that might provide direct or proxy evidence for the use of animals for traction or riding, contributing to major debates within archeology, such as the timing and nature of the Secondary Products Revolution, the origins of horse riding, and the intensification of farming (e.g., Bartosiewicz et al., 1997; Brown and Anthony, 1998; de Cupere et al., 2000; Daugnora and Thomas, 2005; Groot, 2005; Higham et al., 1981; Issakidou, 2006; Izeta and Corte´s, 2006; Johannsen, 2009; Levine et al., 2000, 2005; Taylor and Tuvshinjargal, 2018; Telldahl, 2005; Thomas, 2008). Much of this research mirrors the approach taken by human paleopathologists using musculoskeletal stress markers to infer activity patterns in individuals and communities in the past (e.g., Hawkey and Merbs, 1995), with all the attendant challenges. Animal paleopathology has also been used to inform upon a wide range of subsistence and animal management strategies in the past, including: stock-keeping (e.g., Fothergill, 2017; Thomas, 2001); captivity (e.g., Nerlich et al., 1993; Zimmermann et al., 2018); herding (e.g., Niinima¨ki and Salmi, 2016); tethering (e.g., Darton and Rodet-Belarbi, 2018; von den Driesch, 1989: 651); breeding strategies and their consequences (e.g., Fothergill et al., 2012; Gordon et al., 2015); nutritional status (e.g., Albarella, 1995; Dobney and Ervynck, 2000; Dobney et al., 2004, 2007; Teegen, 2005); hunting techniques (e.g., Letourneux and Pe´tillon, 2008; Noe-Nygaard, 1974); and feather harvesting (e.g., Fothergill, 2016; Hargrave, 1970). Currently, zooarcheology is being advanced through engagement with ideas emerging out of animal studies and informed by posthumanist discourse (e.g., Allentuck, 2015; Armstrong Oma, 2010; Johannsen, 2009; Lorimer, 2006; Overton and Hamilakis, 2013; Russell, 2012; Sykes, 2012, 2014). These approaches acknowledge the complexity of the relationships between people and animals and stress consideration of the behavior and social lives of animals, as well as the people with whom they interacted. One zooarcheological manifestation of this perspective has been a call to employ a biographical approach to encourage consideration of the complexity of the life history (not just the death history) of animals (Morris, 2011). By way of example, MacKinnon and Belanger (2006) describe a range of pathologies in a small brachycephalic dog from Roman Carthage buried alongside a 10 15-year-old human. This dog exhibited

Nonhuman Animal Paleopathology—Are We so Different? Chapter | 23

congenital hip dysplasia, and pronounced degenerative joint disease was evident in the contralateral pelvis and femur (MacKinnon and Belanger, 2006: 41). Despite the permanently dislocated hip and advanced arthritis, which may have affected the animal’s mobility, the dog survived long enough to lose most of its teeth (potentially a consequence of its diet), suggesting that it had been cared for throughout its life (MacKinnon and Belanger, 2006). Dietary stable isotope analysis indicated a diet richer in protein compared with contemporary dogs (MacKinnon, 2010). In keeping with these concerns, and paralleling the development of the bioarcheology of care within human paleopathology (e.g., Tilley, 2015; Tilley and Schrenk, 2017), zooarcheological paleopathology is being employed to examine human attitudes to animals through the identification of maltreatment (e.g., Binois et al., 2013; Teegen, 2005), therapeutic intervention (e.g., Rozzi and Froment, 2018; Udrescu and Van Neer, 2005), and care giving (Atherton et al., 2012; Bartelle et al., 2010; Bellis, 2018; Thomas, 2017; Tourigny et al., 2016; von den Driesch et al., 2005: 227). While this brief review demonstrates the strength of animal paleopathology for informing upon multiple aspects of past human animal relationships, it should be apparent that the types of questions asked of the archeological evidence are often quite different from those asked within human paleopathology, though this is not the only point of departure.

AREAS OF DEPARTURE As Bartosiewicz and Ga´l (2013: 24) have emphasized, qualitative differences in the expression of bone lesions arise because of species-specific differences in skeletal morphology, such as the presence of horns or antlers, dental specialization, and differentiation of the pentadactyl limb. Size, life expectancy, behavior, and environment are also crucial factors. Fractures,for example, have a better chance to heal and thus be recognized archeologically in smaller species and animals that live to an advanced age (Bartosiewicz and Ga´l, 2013: 24). Interspecies differences in bone tissue composition also exist: for example, Aerssens et al. (1998) report lower bone density and fracture stress values in humans compared with dogs, pigs, cattle, sheep, chickens, and rats. As a consequence of physiological differences, some lesions affecting the skeletons of humans and other primates do not seem to be paralleled in other animals and vice versa. For example, porosities in the outer table of the cranial vault (porotic hyperostosis) and orbital roof (cribra orbitalia) appear to be almost exclusive to primates (e.g., DeGusta, 2010), early hominins (e.g., Domı´nguez-Rodrigo et al., 2012), and anatomically modern humans. Indeed, these are amongst the most frequent

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lesions observed in archeological collections of human remains (Walker et al., 2009). In humans, porotic hyperostosis has been strongly (although not exclusively) linked to anemia: the diploe¨ within the cranium expand, while the tissue of the inner and outer tables thins and becomes more porous. Given that other mammals experience anemia, the absence of these lesions in nonhuman mammals remains unexplained, although one possible case has been observed in dogs (Baker and Lewis, 1975). The reverse situation is exemplified by a diverse presentation of defects in the articular surfaces of other mammal bones, especially within the phalanges of cattle (Thomas and Johannsen, 2011). While “type 2” lesions bear resemblance to osteochondrosis in humans, and there may be a shared pathophysiology, some of the other defect types do not appear to be replicated in humans (Thomas and Johannsen, 2011). It is not only at the level of individual lesions where differences arise. Some diseases observed in human paleopathology are exceptionally rare in other mammalian taxa because of fundamental differences in physiology. Scurvy, e.g., is only observed in hominins, primates, guinea pigs (Cavia spp.), and the fruit-eating bat (Pteropus medius), because of their requirement for a continuous exogenous source of vitamin C (Brickley and Ives, 2008: 41). The similarity of lesions in humans and domestic guinea pigs (Cavia porcellus) was recognized by the early 20th century, and include: loosening of the teeth, especially the incisors and mandibular molars; enlargement of ribs adjacent to the costochondral junction; generalized osteopenia; reduced mechanical strength of long bones; and new bone formation, especially around the joints (Cohen and Mendel, 1918; Kipp et al., 1996). Notably, however, no archeological case of scurvy has been reported in domesticated guinea pigs, despite zooarcheological interest in this species (e.g., LeFebvre and deFrance, 2014; Sandweiss and Wing, 1997). Similar comments could be made in relation to the treponemal diseases (e.g., syphilis, bejel, yaws, and pinta), leprosy, and rheumatoid arthritis. While these diseases have exercised considerable interest amongst human paleopathologists, they infrequently affect nonprimate species. Rare exceptions include leprosy amongst red squirrels (Sciurus vulgaris), treponematosis in lagomorphs (e.g., Meredith et al., 2014; Verin et al., 2012), and a disease resembling rheumatoid arthritis in dogs and cats (e.g., Bennett, 1987; Hanna, 2005). Perhaps unsurprisingly, no zooarcheological cases of these conditions have been reported to date. The inevitable corollary is that there are many diseases that cause skeletal lesions in other mammals that are not paralleled in humans. This chapter is not the venue in which to review all these differences (see Craig et al., 2016 for a thorough review of skeletal lesions

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affecting domestic mammals). Instead, three examples suffice to make the point: G

G

G

Specific pathogens, e.g., canine distemper virus, bovine viral diarrhea virus, feline leukemia virus, which can cause bone lesions (e.g., growth retardation lattices) and, in the case of CDV, dental defects (i.e., enamel hypoplasia), in pups, young calves, and cats, respectively (Craig et al., 2016: 104 105; Dubielzig et al., 1981); Development disorders, e.g., canine craniomandibular osteopathy: the onset of the disease is usually between 4 and 7 months and it causes proliferative bilateral new bone formation, especially in the mandibles, occipital and temporal bones, although occasionally other bones of the skull and long bones are affected; this disease is more common in selected breeds of dog: it is autosomal recessive in terriers, for example (Riser et al., 1967); Diseases of unknown cause, e.g., hypertrophic osteodystrophy/metaphyseal osteopathy in young large/ giant breed dogs, which results in metaphyseal necrosis (Craig et al., 2016: 105, 106).

Some diseases are present in both humans and other mammal populations, but the skeletal expression differs, either in frequency or in the morphology and distribution of lesions. A relevant example of this difference is provided by tuberculosis. Tuberculosis is a chronic, progressive, infectious disease primarily spread through inhaled droplet infection, although it can also be acquired intestinally through contaminated milk. A key feature of the disease is that it is capable of being transmitted within and between wildlife populations, domestic livestock, and humans (i.e., it is zoonotic). Two groups of genetically related mycobacteria are largely responsible for skeletal lesions in animals: Mycobacterium tuberculosis complex and Mycobacterium avium complex. The former can infect humans and a wide range of domestic and wild mammals occupying terrestrial and marine environments (e.g., Cooke et al., 1993; Cousins et al., 2003; CliftonHadley et al., 1993; Luke, 1958; Monies et al., 2000). While the disease has a wide host range, infection most commonly affects cattle, pigs, and carnivores, with Mycobacterium bovis forming the primary pathogen. Among domestic livestock, the spread of tuberculosis is facilitated in intensive husbandry regimes where there is regular close contact between infected humans and other animals. In free-ranging populations of cattle and wild cervids, the prevalence of individuals infected with tuberculosis is approximately 1% 5%, compared with 25% 50% in dairy cattle and farmed deer that are housed or penned in small paddocks (O’Reilly and Daborn, 1995: 4). In contrast to human paleopathology, the number of reported/potential cases of tuberculosis in zooarcheology

remains remarkably small (e.g., Bartosiewicz et al., 2018: 33 35; Bartosiewicz and Ga´l, 2013: 100 102; Bathurst and Barta, 2004; Rothschild et al., 2001; Wooding, 2010: 532). Robust clinical data regarding the appearance and frequency of skeletal lesions in nonhuman animal tuberculosis remain frustratingly poor (Lignereux and Peters, 1999; Mays, 2005; Wooding, 2010), but suggest superficial similarity with lesion formation in humans, affecting both axial and appendicular elements at loci of abundant hematopoietic marrow. However, there do appear to be species-specific predilection sites (e.g., the pelvis in pigs: Cohrs, 1967). Moreover, M. bovis infection in cats and dogs appears to be more proliferative, potentially capable of inducing hypertrophic osteopathy (e.g., Bathurst and Barta, 2004; Snider, 1971; Wooding, 2010: 66), although pulmonary neoplasia requires consideration in any differential diagnosis. In contrast, in ruminants, as in humans, bone resorption and lysis (e.g., osteomyelitis, osteoporosis, cavitation, destruction of articular surfaces) predominates (Bartosiewicz and Ga´l, 2013: 101; Wooding, 2010: 66). Rothschild et al. (2001: 306) have suggested that an undermined subchondral articular surface is “relatively specific for the diagnosis of tuberculosis” in bovids. Robust clinical evidence for this link remains to be demonstrated. The positive extraction, polymerase chain reaction amplification, and identification of M. tuberculosis complex DNA in an extinct bison (Bison cf. antiquus) metacarpal exhibiting this lesion from Natural Trap Cave, Wyoming, dated to c.17,000 BP, is tantalizing, but the possibility of environmental mycobacteria—either ancient or modern—must also be entertained. The zooarcheological infrequency of this disease may, in part, reflect the low frequency of skeletal involvement in animals infected with M. bovis: 0.5% 1% for cattle (Cohrs, 1967); 8% 9.5% for pigs (Nieberle, 1938); and 1.7% for the European badger (Meles meles) (Gallagher and Clifton-Hadley, 2000). However, it might also reflect the fragmentary nature of the zooarcheological record and the inconsistent approach to recording ribs and vertebrae, which are common sites for tuberculous lesions (Nieberle, 1938; Cohrs, 1967). Periosteal new bone formation on the visceral surface of ribs has been suggested as a potential indicator of tuberculosis in human skeletal remains (Roberts, 1999), but is rarely reported zooarcheologically, except when its presence has been sought explicitly (e.g., Thomas and Vann, 2015; Fig. 23.1). In some cases, differences between human and nonhuman animal paleopathology reflect the questions asked of our data. For example, while sharp force trauma is treated as paleopathology in human skeletal analysis (e.g., Appleby et al., 2015), in zooarcheology it falls under the remit of taphonomic analysis through the study of slaughter and butchery marks (Lyman, 1994) (Fig. 23.2). This

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813

FIGURE 23.1 Periosteal new bone formation on the visceral surface of a medium-mammal rib fragment from a Roman site in England: a likely indicator of respiratory disease. Failure to examine elements such as these for pathology, represents a missed opportunity in zooarcheology.

FIGURE 23.2 One specialist’s trauma is another specialist’s butchery: blunt and sharp force trauma in an Iron Age cattle skull from England, comprising an unhealed penetrating injury (the cause of death) and multiple cut marks on the frontal (evidence of skinning).

may begin to change, however, as more studies are undertaken in veterinary forensic pathology (e.g., Munro and Munro, 2008). There are also identifiable differences in research foci in human and zooarcheological paleopathology. For example, one can contrast the extensive attention paid to metabolic bone diseases in human paleopathology (e.g., Brickley and Ives, 2008) with the negligible attention paid in zooarcheology, despite the potential interpretative significance of osteodystrophies for informing upon the management of animals in the past. There have been

few published accounts of osteoporosis, rickets/osteomalacia, and fibrous osteodystrophy (e.g., Brothwell, 1995: 232; Leshchinskiy, 2009; Nerlich et al., 1993; Martiniakova´ et al., 2008), and a complete absence of published cases of metal poisoning and other forms of vitamin deficiency or excess. This difference is partly a taphonomic issue, since many of the conditions described above result in demineralization of bone or its replacement by soft tissues, rendering them more susceptible to postdepositional destruction. However, this issue also

814 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

may reflect the paucity of systematic attempts to determine whether bones that qualitatively feel underweight reflect diagenetic factors or pathology: there is clearly more scope for systematic radiography and histological analysis (e.g., Horwitz and Smith, 1990; Martiniakova´ et al., 2008; Smith and Horwitz, 1984), although the large size of many faunal assemblages and the limited information concerning the normal range of bone densities for different species, breeds, ages, sexes etc., make this practically difficult. Beyond biology, fundamental differences between human and nonhuman animal paleopathology exist that reflect the composition of the archeological record. Faunal assemblages typically comprise disarticulated, isolated fragments of bone that represent waste generated from food preparation (i.e., disarticulation and butchery) and consumption, which may have experienced one or more redeposition events. Only rarely are complete skeletons preserved, and where they do it is most commonly in contexts associated with human internment and/or “ritual” (e.g., Baron, 2018; Lepetz and Van Andringa, 2003; Pluskowski, 2012). Unlike human osteology, therefore, where the nature and distribution of lesions can be assessed with regularity, pathologies in animal bone assemblages are encountered more commonly as isolated examples devoid of their biological context. Differential diagnosis in paleopathology primarily relies upon careful comparison of the morphology and bodily distribution of lesions in archeological specimens with clinical studies in which skeletal changes associated with specific diseases are documented. Conducting a differential diagnosis is a process of exclusion: ruling out all diseases that could potentially lead to the formation of similar lesions before a conclusion is drawn. The emphasis on bodily distribution is important, as bone can only form or destroy, thus limiting the variability of skeletal responses to pathology and potentially resulting in equifinality at the level of the individual lesion. Consequently, in animal bone assemblages it is often impossible to achieve greater precision than a broad nosological category, which, in turn, limits the interpretative potential. This problem is exacerbated by zooarcheological recording practices. In contrast to human osteology (e.g., Buikstra and Ubelaker, 1994), there are no minimum standards by which animal bone assemblages should be recorded. While general recommendations have been made (e.g., Baker and Worley, 2014) and a degree of conformity exists, making possible the creation of synthetic datasets (e.g., Arbuckle et al., 2014; Atici et al., 2013), zooarcheologists exercise considerable discretion in what to record and how. To a certain extent this is advantageous, permitting data to be collected to address focused research questions and avoiding a “paint by numbers” approach to recording. However, problems of comparability arise, particularly where a selective approach to recording is advocated due to

time or financial constraints. Davis (1992), for example, developed a rapid recording method for animal bones from archeological sites that focuses attention on a limited suite of body parts, discounting ribs and vertebrae. While such elements are often highly fragmentary and can be difficult to identify to taxon, these bones are susceptible to lesions arising from systemic, bloodborne diseases (such as tuberculosis) because they contain a high proportion of cancellous bone. Failure to record these bones, therefore, immediately minimizes opportunities to differentially diagnose a suite of conditions (Fig. 23.1). Standardized, descriptive-led recording is essential given the low number of pathological animal bones that are recorded on archeological sites, typically less than 1% of the total number of identified specimens (NISPs; Siegel, 1976; Shaffer and Baker, 1997; Vann and Thomas, 2008). In part, this paucity reflects the high degree of reduction of animal bone assemblages, resulting from butchery, depositional, and taphonomic processes. However, this low number also reflects differences in life expectancy. Diseased wild animals are more likely to be predated or die prematurely, reducing the occurrence of chronic conditions that affect the skeleton (Bartosiewicz, 2016). Domestic livestock were less likely to die from natural causes: instead, they would have been slaughtered for meat (irrespective of their exploitation for secondary products during life) or sometimes for “ritual” purposes: given the correlation between susceptibility to pathology and age, it is no wonder that frequencies of pathology are much higher in humans than they are in livestock. Livestock exhibiting signs of illness may have also been earmarked for early slaughter and dumped/buried in locations away from the occupation sites that typically form the focus of archeological enquiry. This certainly adds complexity to the application of the “osteological paradox” (Wood et al. 1992) to animal bone assemblages because an absence of pathology in animals could reflect: G G

G

A healthy animal that was slaughtered; A diseased animal that was slaughtered before skeletal tissues became involved; A diseased animal that died before skeletal tissues became involved.

Even where lesions are identified and recorded, challenges exist for the zooarcheologist in quantifying pathology. As Bartosiewicz (2018: 187) has emphasized, in clinical epidemiology prevalence is calculated as the number of cases of a disease in the living population divided by the total number of individuals in that population. In human osteology, calculating prevalence is hampered by the fact that cemetery populations are not representative of the living population. The challenges are even greater in zooarcheology due to imprecise dating of assemblages (usually by association with material culture), unknown

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accumulation rates, uncertain depositional histories, and the questionable validity of minimum number of individuals determinations (Lyman, 2008). Conceivably, an urban animal bone assemblage could include many individuals from multiple herds raised in different environments over a period of tens or hundreds of years. Zooarcheologists attempt to overcome this issue by relying upon the proportion of pathological bones out of the total NISP as a crude proxy of prevalence (Bartosiewicz, 2018: 187). Such an approach facilitates diachronic and regional comparisons of changing frequencies and types of pathology. However, as with other zooarcheological phenomena (e.g., taxonomic diversity), a logarithmic relationship exists between the total NISP and the character being recorded (Lyman, 2008). Thus, relatively more pathological bone is likely to be encountered in larger assemblages (up to a NISP threshold that is geographically and diachronically dependent) (e.g., Bartosiewicz, 2018: 200). Consequently, equating the zooarcheological prevalence of pathology with clinical prevalence is fraught with difficulty.

AREAS OF COMMONALITY Notwithstanding the physiological, environmental, and behavioral differences between humans and other animals, a close connection exists with respect to disease histories that demands attention by both paleopathological practitioners. Following an examination of 25 unicellular microbial pathogens with the highest burdens on human health, Wolfe et al. (2007) established that more than half of the temperate diseases considered originated from domestic animals, while over half of tropical diseases came from wild (nonprimate) animal populations. Although the focus of such research has centered on pathogens transmitted from animals to humans (zoonoses), transmission occurs just as often in the other direction (reverse zoonoses) (Messenger et al., 2014), with intermediary hosts common in both pathways. Rather than being brought in from the wild, many major pathogens emerged in the Old World in the environmental conditions of domestication and urbanization, in which bacteria, viruses, protozoa, ticks, and parasites thrive, mutate, and jump hosts (Brothwell, 1991; Wolfe et al., 2007). The interconnectivity between human and animal health, pathogen behavior, and environment is exemplified by events in 14th-century Europe. Three consecutive failed crop harvests in the period 1315 17 occurred as a consequence of torrential rainfall, and constituted a major contributing factor to a human famine resulting in the death of 10% 15% of the European population (Jordan, 1996). Almost simultaneously, there were major outbreaks of

815

disease affecting animals in the first quarter of the 14th century. Sheep murrain (an unspecified infectious disease) was epidemic between 1314 and 1316, while a panzootic in cattle (probably rinderpest) was widespread between 1319 and 1322 (Jordan, 1996; Newfield, 2009). The scale of mortality was astonishing. In England and Wales, manorial accounts indicate that around 62% of cattle died of pestilence between 1319 and 1320 (Slavin, 2012), severely affecting the ability of farmers to undertake tasks requiring animal power (e.g., harvesting and transporting crops). Notably, a systematic and quantitative analysis of degenerative changes to the lower limb bones of cattle points to intensified use of the surviving cattle for traction (Thomas, 2008). It seems likely that the high mortality was, at least in part, a consequence of nutritional vulnerability amongst the cattle, as poor crop yields and spoiled hay affected the ability of farmers to adequately feed their animals (Jordan, 1996). Less than a generation later, the Black Death arrived, decimating the human population by between one third and a half (Benedictow, 2004). Clearly, the virulence of the strain of Yersinia pestis was instrumental, but preexisting nutritional stress caused by these earlier disasters may have been a predisposing factor. It is not just disease histories upon which there is shared intellectual ground between human and nonhuman animal paleopathologists. As I have argued elsewhere, “relationships between people and animals are closely entangled and bound up with the behaviors of both, human identities and conceptions of animal consciousness and/or moral considerations” (Thomas, 2017: 180). The links between animal abuse, child abuse, and domestic violence in contemporary society are well founded (e.g., Arluke et al., 1999; Lockwood and Ascione, 1997), and considerable potential exists for exploring these interrelationships in the past through the integration of human and nonhuman animal paleopathology. Beyond collective interests in the study of health, disease, and injury in the past, there are also many points of commonality in the foundational methods of human and nonhuman animal paleopathology. At the most basic level, the underlying cellular processes by which bone tissue responds to disease and injury are comparable across mammals. Consequently, the fundamental principles of describing lesions is identical. Indeed, the experience of human paleopathologists was explicitly acknowledged and drawn upon in the development of the first systematic methodology to record pathology in animal bone assemblages (Vann and Thomas, 2006; Vann, 2008). As Thomas and Worley (2014) note, systematic recording and reporting is essential because it: 1. Draws attention to pathologies that are absent, as well as those that are present;

816 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

2. Highlights the full range of lesion manifestations, not just the “spectacular” cases; 3. Requires the calculation of lesion frequency, which in turn facilitates intra- and intersite comparisons and the identification of spatial and temporal patterns. As in human paleopathology, in the absence of quantitative recording schema (e.g., Bartosiewicz et al., 1997) individual lesions must be described in detail to capture shape, size, precise anatomical location, and morphology, especially with reference to the processes of bone formation and/or destruction and remodeling. Wherever possible, precise descriptive terminology should be employed (reflecting current clinical practice in veterinary medicine) and written descriptions should be supported by annotated illustrations (photographs, radiographs, and line drawings). This approach is vital for providing a robust foundation for differential diagnosis and overcoming the shared problem of separating pathology from taphonomic processes that result in pseudopathology. While the differential diagnosis of lesions in nonhuman animal paleopathology is challenging, for the reasons enumerated above, the intellectual process through which this is achieved is the same: requiring the exclusion of all potential causes of the lesions before a conclusion is drawn. The terminology of diagnoses should follow the precedent established in clinical literature, to recognize species-specific disorders and the fact that a terminological consensus does not exist between the two branches of medicine. Once a diagnosis is achieved, there is a shared requirement to indicate the strength of confidence in that determination. Appleby et al. (2015) have recommended the use of an adapted version of the Istanbul Protocol, a system of nomenclature ratified by the UN and widely used in forensic medicine for the identification of torture, for both human and nonhuman animal paleopathology. This system permits the degree of certainty by which a diagnosis is made to be qualified using one of five categories: 1. Not consistent: the lesion could not have been caused by the condition(s) described; 2. Consistent with: the lesion could have been caused by the condition(s) described, but it is nonspecific and there are many other possible causes; 3. Highly consistent: the lesion could have been caused by the condition(s) described, and there are few other possible causes; 4. Typical of: that the lesion is usually found with this type of condition(s), but there are other possible causes; 5. Diagnostic of: the lesion could not have been caused in any way other than by the condition(s) described (i.e., it is pathognomonic).

Some of the general principles of interpretation are equally relevant between human and nonhuman animal paleopathology (after Thomas and Worley, 2014): lesion frequencies within each species will vary as a result of age, sex, body mass, activity patterns/behavior, and inherited predisposition; lesions will, in general, increase in frequency with age; lesions occurring early in life may be obscured completely through remodeling; connecting bone lesions with symptoms (and pain) is difficult given the different ways in which these are experienced by individuals; pathology can differentially affect the preservation of bones negatively (e.g., osteoporotic bone) and positively (e.g., bones with sclerotic lesions). A strength of paleopathological investigations in both humans and other animals, is its ability to contribute meaningful archeological information at different scales of analysis. The following two examples have been selected for presentation here because they showcase how zooarcheological pathology can be used to inform upon millennia-spanning environmental change and individual human animal interactions. Systematic analysis of dental pathology in dire wolves (Canis dirus) from the Rancho La Brea tar pits, Los Angeles, revealed a decrease in fracture frequency from 7% to 2% between 15,000 and 12,000 BCE (Binder et al., 2002). This change was attributed to reduced competition caused by high prey abundance and/or low carnivore density in the early Holocene, lessening the risk factors for dental fractures (e.g., lower inter- and intraspecific aggression and reduced intensity of carcass utilization). Analysis of pathology in a 19thcentury dog burial from Toronto, Canada, revealed: systemic degenerative joint diseases; severe periodontal disease; a chipped tooth and associated abscess; a chronic ear infection (Fig. 23.3); and chronic infection of the left limb, probably secondary to a penetrating injury. When placed within a biological, archeological, and historical context, Tourigny et al. (2016) constructed a biography of the individual, reflecting upon its life history and its owners’ attitudes towards dogs.

TOWARD CLOSER INTEGRATION Human and nonhuman animal paleopathology share common goals, namely to: G

G

G

Identify, record, and differentially diagnose skeletal lesions in the past; Interpret the significance of disease and injury within past populations, at different scales (individual, local, regional) within itsbiological, cultural, and environmental context; Understand the evolutionary history of diseases.

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FIGURE 23.3 Basocranial view of a dog skull from 19th-century Canada, exhibiting reactive bone formation and destruction of the left tympanic bulla and external acoustic meatus consistent with chronic osteitis (see Tourigny et al., 2016). This advanced ear infection likely caused deafness and the dog may have walked around with his head tilted to the left and exhibited behaviors such as head shaking and scratching. Such details enable the biography of the animal to be reconstructed.

While the two disciplines share common goals, and many of the underpinning approaches to recording (e.g., lesion description, analytical methods, and the process of differential diagnosis) are compatible, differences do exist in anatomy, physiology, immune response, behavior, environment, life expectancy, and disease incidence and expression, which must be acknowledged, especially in the application of clinical evidence across taxonomic boundaries. As I demonstrated in the literature review at the beginning of this chapter, zooarcheologists are beginning to make great strides in addressing the first two goals. A particularly encouraging development has been the analysis of pathology in known-history collections to address some of the gaps in clinical knowledge (e.g., Bartosiewicz et al., 1997; Bendrey, 2007; Darton and Rodet-Belarbi, 2018; Fabiˇs and Thomas, 2011; Levine et al., 2000; Niinima¨ki and Salmi, 2016; Rafuse et al., 2013; Taylor and Tuvshinjargal, 2018; Thomas and Grimm, 2011; Zimmermann et al., 2018). The fragmentary nature of the archeological record makes the third goal the most challenging, and pessimism has been expressed in our ability to make a meaningful contribution (Bartosiewicz and Ga´l, 2013). Nevertheless, understanding the evolutionary history of disease is one arena where there is enormous potential for future collaboration. The value of comparative pathology was recognized in the late 19th century (e.g., Bland Sutton, 1890) and in the very first publications concerning paleopathology (e.g., Moodie, 1923a,b), but disciplinary specialization and an anthropocentric worldview have undermined this approach. The systematic analysis of skeletal lesions in humans and

other animals is essential for this work, but it needs to be supplemented with the direct measurement of diagnostic parameters (e.g., Horwitz and Smith, 1990) and, for infectious diseases, the direct detection of causative pathogens (e.g., parasites: Søe et al., 2018; and bacteria: Bendrey et al., 2007) (Mays, 2018). Ancient DNA analysis, in particular, has enormous potential to unpick the genetics of disease resistance in humans and other host animals. Crucially, paleopathological evidence needs to be grounded within an ecological/environmental (as well as biological) context, especially for infectious disease, to generate an understanding of the interplay between pathogen, host(s), and environment (e.g., Engering et al., 2013). The epidemiological modeling approach advocated by Fournie´ et al. (2017) is particularly exciting in this respect. This approach parallels the recommendations of contemporary movements that have taken an integrated systems approach to managing health risks (e.g., “One Health,” “Eco Health,” “Planetary Health”), which “can only be tackled by interdisciplinary working across the domains of human medicine, veterinary medicine and the life sciences” (Woods et al., 2018: 14). Such research demands a collaborative approach, not least because disease definitions, which are based upon clinical signs, pathology, and response to treatment, are constantly under review, especially with the widespread application of genetic/molecular evidence. Bringing an integrated paleopathological approach to these debates has the potential to make a major contribution to our understanding of the health consequences of domestication and the progressive intensification of agricultural systems—issues that have profound relevance in contemporary society.

818 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

ACKNOWLEDGMENTS I am indebted to Jane Buikstra for inviting me to contribute to this volume and to Elizabeth Uhl for providing insightful comments on an earlier draft. Thanks to Dennis Lawler for drawing my attention to the potential case of porotic hyperostosis in dog. I am also hugely grateful to my colleagues Jo Appleby and Mara Tesorieri, and all the students who have taken the “Human and Animal Health and Disease” module, which has provided intellectual inspiration for many aspects of this chapter. The first quotation at the beginning of this chapter was reproduced in Woods et al. (2018, 1); I was alerted to the second quotation by Elizabeth Uhl. Figs. 23.1 and 23.2 were taken by Sian Holmes. Fig. 23.3 is reproduced with the kind permission of Eric Tourigny.

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Chapter 24

Postscript Jane E. Buikstra Arizona State University, Tempe, AZ, United States

Throughout the process of reworking the chapters for this edition, many authors, including myself, were concerned about maintaining an appropriate attribution to Don’s previous work. Don’s seminal explorations of paleopathology did not require rewriting just to paraphrase, and we did not want to plagiarize. The publishers, however, emphasized the problems attendant to posthumous authorship. Deciding to name this volume Ortner’s Identification of Pathological Conditions in Human Skeletal Remains signifies Don Ortner’s fundamental and enduring contributions to the field of paleopathology, much as we link Henry Gray and John C. Boileau Grant to their anatomy text and atlas, and Donald J. Resnick to multiple volumes on bone and joint disorder. It is with a sense of relief and calm that we have decided upon this title, which symbolizes both permanence and transformation. The permanence reflects not only Don’s fundamentally important contributions, but also the field of paleopathology. This discipline has developed from an avocational interest of medical professionals to an interdisciplinary subject explored by biomedical and social scientists, along with humanists. As modern practitioners, we hold active international and national meetings and publish and present research in dedicated journals and conferences. Paleopathology therefore is established as an interdisciplinary field of substance, addressing research questions about the past that are relevant to a number of issues relating to host pathogen evolution, species transfer of disease, and the ecology of health. Settling upon the name for this volume also brought this editor a sense of calm. While wanting to make this effort the best it could possibly be, knowing that it represents a moment in the history of paleopathology rather than a “last word” has eased a tension inherent in this monumental task. With time, this effort, too, will require updating—it will and must be superseded. In this volume and elsewhere, I (Buikstra et al., 2017) have argued that modern paleopathology requires practitioners who both acknowledge and integrate knowledge

from across the sciences and humanities. The vast breadth of relevant biomedical knowledge alone is daunting and well beyond that commanded by single individuals. Adding to that, the historical and archeological information, historiography, and archeological theory required in paleopathology well illustrates the need for scholarly collaboration. As practitioners, we must therefore engage in interdisciplinary research that recognizes expertise beyond one’s own. Similarly, as we argue in Chapter 3 (see also Buikstra et al., 2017; Grauer, 2012; Ortner, 2003), there is a core interdisciplinary knowledge and scholarly approach that we should foster within ourselves, within our research groups, and transmit to students. These core topics include evolutionary and social theory, basic bone biology, and knowledge of pathological processes derived from texts and clinical reports. Within this volume, we have included and updated the core knowledge of bone pathology initially presented in Ortner and Putchar (1981) and Ortner (2003). Review of basic human osteology has been removed, as this topic is the subject of many other texts. Chapters on bone biology and pathogenesis have been significantly updated. Chapters on methods, such as imaging and histology, have also been revised. Given the immensely important contributions of molecular approaches to knowledge of past diseases, we have added a chapter on ancient DNA, including sufficient information on methodology to sufficiently inform our readership about the importance of carefully evaluating earlier approaches that used PCR techniques. Dental anthropology and dietary assessments, including biomolecular approaches, also appear here, as does a specific focus upon parasitic diseases, through the lens of archeoparasitology. Finally, we have added chapters on mummy science and animal paleopathology. As illustrated here and in those publications cited in Chapter 23, mummy science is an important aspect of our overall goal of learning about the human condition in the past. And though the separation of animal disease studies from those of humans has been an archeological

Ortner’s Identification of Pathological Conditions in Human Skeletal Remains. DOI: https://doi.org/10.1016/B978-0-12-809738-0.00024-7 © 2019 Elsevier Inc. All rights reserved.

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824 Ortner’s Identification of Pathological Conditions in Human Skeletal Remains

convention for separating human from faunal remains, the evolutionary history of disease(s) so frequently links humans to other hosts that this artificial separation seems increasingly counterproductive.

THE FUTURE OF PALEOPATHOLOGY So, what further 21st century advances shimmer before us through the lens of our crystal ball? Clearly, we have only begun to tap the knowledge available through molecular approaches. Truly fulfilling such promise will require full collaborations between historians, archeologists, and molecular scientists, as moving from description to general explanatory models will require nuanced contextual interpretations along with increasingly intricate methodologies. We can describe changing patterns of disease through time simply through molecular and radiocarbon study, yet exploring the agency of humans in the spread of disease requires knowledge of specific physical and social environments. Bringing our deep time perspectives to today’s global health issues also will assume increasing significance. Knowledge of the behavior of disease in different environmental and social contexts through time should enhance the efficacy of healthcare delivery. Similarly, knowledge of the manner in which humans have inadvertently altered microbiomes should also affect 21st-century diets and our pharmacopeia. Finally, knowledge of crossspecies disease transfer, so visible in evolutionary studies, is important in animal conservation efforts.

A further underdeveloped aspect of paleopathology involves ethical behavior, not only in clinical sampling but also in our interactions with descendent communities. We should be addressing questions of interest to such groups, being respectful of wishes regarding the treatment of their ancestors. Such collaborations require effort, but these are responsible actions that also enrich knowledge. Quite clear in the advancement of our field is that our previous dilettante interest of medical men has become a specialty that requires focus and collaborative efforts. Knowledge today is advanced in many scholarly fora— ranging from classrooms to international symposia. Global information exchange is facilitated not only by electronic journals but by less formal internet interactions. Our field is thus transformed daily and knowledge will be advanced in ways we can only imagine today. Our collaborative volume here is offered as a waystation along this ladder to the future.

REFERENCES Buikstra, J.E., Cook, D.C., Bolhofner, K.L. 2017 Scientific rigor in paleopathology. In: Buikstra, J.E., (Ed.), Rigor in Paleopathology, pp. 80 87. Special issue of the International Journal of Paleopathology, 19, 80 141. Grauer, A.L., 2012. A Companion to Paleopathology. Blackwell, New Jersey. Ortner, D.J., 2003. Identification of pathological conditions in human skeletal remains. Academic Press, San Diego, CA. Ortner, D.J., Putschar, W.G.J., 1981. Identification of pathological conditions in human skeletal remains. Smithsonian Institution Press.

Index Note: Page numbers followed by “f ” and “t” refer to figures and tables, respectively.

A ABC. See Aneurysmal bone cyst (ABC) Abiotic factors, 60 61 Abnormal bone description, 62 81 differential diagnosis, 81 82 general considerations and gross appearance, 59 61 modeling description, identification, and differential diagnoses, 82 87 Abscess formation, 331 Acetabulum, 233, 604 605 Achondroplasia, 66, 616 617 Achondroplastic skeletons from Fourth Dynasty Egyptian tomb of King Mersekha, 617 618, 619f Acromegaly, 568 572 Acromesomelia, 621 623 Acromesomelic dysplasia, 621 623 Acromioclavicular joint (ACJ), 725 Acromion, 339 340 Actinomycetoma, 444 Actinomycosis, 321, 427 429, 428f, 446f Activation, resorption, and formation cycle (ARF cycle), 50 51 Active osteochondritis, 394 Active pulmonary tuberculosis, 323 Adamantinoma, 688 696, 689f paleopathology, 696 711 aDNA. See Ancient bacterial DNA (aDNA) ADO. See Albers Scho¨nberg disease osteopetrosis (ADO) Adult osteomyelitis, 303 304 Adult scurvy, 537 539 paleopathology, 537 539 medial surface of mandibular ramus foramen, 539f porosity of greater wing of sphenoid bone, 539f slight deposits of subperiosteal new bone formation, 539f Adult treponemal disease, 409 420, 409f probable acquired treponemal disease, 410f, 411f, 413f probable yaws in post-European skeleton, 419f tibial lesions attributed to yaws or endemic syphilis, 420f treponemal disease probably venereal syphilis, 414f, 416f in skeleton, 418f

Advanced glycation end products (AGEs), 140 Advanced rheumatoid arthritis, 366 Age intersectionality of, 24 26 lacunar-canalicular architecture reflects osteocyte activity altered lacunar-canalicular architecture, 114 increased vascular porosity weakens bone, 115 116 osteocyte lacunar density decreases, 112 113 percent occupied lacunae decreases, 113 microdamage as energy-dissipating mechanism increased mineralization accelerates microdamage accumulation, 110 intraskeletal variability in microdamage accumulation, 111 112 older tissue loses osteocyte sensitivity to microdamage, 110 111 Albers Scho¨nberg disease osteopetrosis (ADO), 134 Albright’s hereditary osteodystrophy (AHO), 578, 580 582 Albumins, 286 Alkaline phosphatase, 106 Alveolar lesions paleopathology, 767 768 pathology, 767 Alveolar process, 372 373 Amelogenesis, 751, 753 Amelogenesis imperfecta, 753 754, 762 763 Amelogenin, 750 751 American tuberculosis phylogeography, 355 Amino acids, 774 775 Amputation, 267 269 AMTL. See Antemortem tooth loss (AMTL) Anasazi site of Kin Tiel, Arizona, 582 Ancestral chordates, 35 Ancient bacterial DNA (aDNA), 193 analyses of dental calculus for bioarcheological research, 781 Ancient DNA, 183 191 current methods, 185 191 DNA preservation, 185 187 microbiome analyses, 190 191 NGS analyses, 188 190 sample preparation and DNA extraction, 187 188 future prospects, 200 201

history/trajectory of field, 184 185 mass graves and “invisible” pathogens, 195 198 food and waterborne outbreaks, 196 197 influenza virus, 197 smallpox, 196 Yersinia pestis, 195 196 parasites and commensals, 198 200 gut microbiome, 199 200 lice, 198 199 oral microbiome, 200 parasites in feces, 199 of pathogens, 191 195 Ancient humans, 26 29 Ancient viromics, 199 200 Andersen lines, 750 Anemia(s), 468, 508 514, 510f erythroblastosis fetalis, 514 hereditary spherocytosis, 514 IDA, 514, 515t paleopathology, 514 517 sickle cell anemia and genetic variants, 512 514 thalassemia, 509 512, 511f, 512f Anencephaly, 585 586 Aneurysm, 504 505 Aneurysmal bone cyst (ABC), 658, 667 668, 667f Aneurysmal erosion, 504 506 erosion of vertebral bodies by aortic aneurysm, 505f paleopathology, 506 Angiitic inflammation, 76 Animal paleopathology, 810 Ankle bones, 337 338, 338f joint, 728 Ankylosing spondylitis (AS), 733 734 Ankylosis, 362 363, 597 598 Anopheles, 468 Anopheles atroparvus, 469 Antemortem damage, 355 process, 417 420 Antemortem tooth loss (AMTL), 749, 764, 770 paleopathology, 770 771 pathology, 770 Antemortem trauma, 221 Anthropogenic environmental factors, 464 Anthropological bias, 354 355 Antibodies, 286

825

826 Index

Apoptosis, 64 65 Archeological cranial material, 562 Archeological specimens, 672 Archeoparasitological data, 481 ARF cycle. See Activation, resorption, and formation cycle (ARF cycle) ARO. See Autosomal recessive osteopetrosis (ARO) Arterial vessels, 37 Arthritis, 391 Articular or epiphyseal cartilage, 465 AS. See Ankylosing spondylitis (AS) Aspergillosis, 445 446 Atraumatic osteonecrosis, 495 Atrophy, 64 Attrition, 764 Autonomic nerves, 367 Autopsy, 800 Autosomal recessive osteopetrosis (ARO), 134 Avascular necrosis (AVN), 492 Axial compression, 104 Axial loading differences assessment, 123 124 Axial skeleton, 458 Axial tension, 104

B B-cells, 286 Baastrup’s disease, 730 Backscattered electron scanning electron microscopy (BSE-SEM), 136 Bacterial infections, 321. See also Fungal infections; Viral infections actinomycosis and nocardiosis, 427 429 adult treponemal disease, 409 420 Bejel, 380 bone changes associating with leprosy, 367 368 brucellosis, 420 426 Chichester, England, 372 374 diagnosis of leprosy in skeletal remains, 368 direct effects of M. leprae, 365 366 glanders, 426 427 indirect effects of M. leprae, 366 367 leprosy, 363 374 Naestved, Denmark, 370 371 paleopathology, 351 363 periostosis of limb bones, 367 plague, 430 431 skeletal examples, 355 363 TB, 321 363 treponematosis, treponemal infection, or treponemal disease, 375 420 venereal syphilis, 381 393 yaws, 376 380 Barium (Br), 775 Basic multicellular unit (BMU), 49 51, 93 remodeling and morphology, 93 94 Basic structural units (BSUs), 93 remodeling parameters calculation from, 94 96, 100t Bejel, 380, 380f Bending fractures, 215 216, 216f, 217f

Benign fibro-osseous lesions (BFOLs), 769 Benign fibrous histiocytoma, 659 660 Beta cells (β-cells), 139 BFR. See Bone formation rate (BFR) Bilateral Madelung’s deformity, 623 Bilateral paravertebral abscess, 327 329 “Bioarchaeology of Personhood” model, 27 Bioarcheological research, 776 778 aDNA and protein analyses of dental calculus for, 781 bulk stable isotope analysis in, 774 chemical analyses of dental calculus for, 780 781 compound-specific isotope analysis in, 774 775 trace elements in, 775 776 Bioarcheology, dental calculus in, 778 780 Biological gradient, 401 Biomolecular approaches, 15 16 Biparietal fenestra, 593 Bizarre parosteal osteochondromatous proliferation, 657 660 Black Death, 196 Blastomyces dermatitidi, 441 442 Blastomyces gilchristii, 441 442 Blastomycosis, 441 “Blind steering” problem, 98 99 Blood supply of bones, 491 492 Blunt-force injuries, 220, 238f BMD. See Bone mineral density (BMD) BMPs. See Bone morphogenic proteins (BMPs) BMU. See Basic multicellular unit (BMU) Body louse (Pediculus humanus humanus), 198 199 Body mass calculations, 177 Bone formation rate (BFR), 96 Bone mineral density (BMD), 106 107, 555 Bone morphogenic proteins (BMPs), 40 42 Bone remodeling, 48 51 BMU, 49 51 imbalances osteopetrosis, 134 135 PDB, 133 134 Bone volume/tissue volume (BV/TV), 121 122 Bone(s), 91 92, 211 biology, 35 blood supply, 491 492 breakage, 98 125 cancellous bones, 306 307 changes and radiography, 176 177 body mass calculations, 177 HL, 176 osteoporosis, 177 changes associating with leprosy, 367 368 cribra orbitalia in child with leprosy, 368f changes in specific, 304 307 destruction, 73 76 disorders, 640 foci, 443 functional adaptation, 99 105 lesions, 362 363, 376 377, 426 427, 470, 507 508, 510 loss in past populations, 107 108

metastases, 696 702 paleopathology, 711 pathology, 697 698 mineral homeostasis disorders, 135 136 modeling, 44 48 neoplastic lesions, 648 pattern of bone and joint tuberculosis, 323 351 age distribution of skeletal tuberculosis in bones and joints, 324t locations of bone lesions in skeletal tuberculosis, 323t quantity measurement, 555 556 short tubular bones, 306 skeletal structure, function, and cellular basis of, 35 42 bone cells, 39 40 bone tissue, 37 38 cartilaginous tissue, 38 39 evolution of vertebrate skeleton, 35 36 gross function and anatomy, 36 37 molecules and signaling pathways, 40 42 skull, 304 306, 304f, 305f spine, 306 strength at microscale lacunar-canalicular architecture reflects osteocyte activity, 112 114 microdamage as energy-dissipating mechanism, 108 112 secondary osteon size and shape as toughening mechanisms, 117 120 vascular porosity reflects resorption activity, 114 116 tumors GCTs of bone, 661 664 paleopathology, 648 670 primary benign tumors, 648 651 primary malignant bone tumors, 680 688 principles of diagnosis, 648 679 radiographic and paleopathological features, 641t Bony ankylosis, 333 334 Bony prominences, 443 Bony sequelae of trauma, 224 230, 230t central bone necrosis, 226f charcot joint resulting from traumatic fracture, 225f large area of bone necrosis, 226f small area of bone necrosis, 226f Bouchard’s nodes, 724 Breastfeeding patterns, 776 Bridging callus, 222 “Brown tumors”, 137 Brucella, 421 Brucella abortus, 421 Brucellosis, 83, 86, 193, 420 426 paleopathology, 422 426 pathology, 421 BSE-SEM. See Backscattered electron scanning electron microscopy (BSE-SEM) BSUs. See Basic structural units (BSUs) Buikstra, Jane E. history of third edition from, 6 7

Index

Bulk stable isotope analysis, 773 774 in bioarcheological research, 774 Burkholderia mallei, 426 Butterfly fragment, 215 BV/TV. See Bone volume/tissue volume (BV/TV)

C Calcium (Ca), 38, 775 Calcium pyrophosphate dihydrate (CPPD), 744 Calve-Legg-Perthe disease, 66 68 Camurati Engelmann’s disease, 633 634 Canaliculi, 40 Cancellous bone, 38, 306 307 Cancer, 640 643 metastatic bone disease, 131 132 osseous bone tumors, 132 133 Canonical pathway. See Wnt/b-catenin pathway Canopy effect, 773 Carcinomas, 643, 706f Care, 26 29 Caries paleopathology, 766 767 pathology, 765 “Caries sicca”, 382 383 Carpal bones, 340 342, 341f Carpal joints, 727 Carpal lunate, 500 Cartilage of mandibular condyle, 569 Cartilage-associated protein (CRTAP), 143 Cartilaginous tissue, 38 39 CDH. See Congenital dislocation of hips (CDH) cDNA library, 197 CEJ-AC method. See Cemento enamel junction to alveolar crest method (CEJ-AC method) Cell cell-mediated immunity, 286 injury and death, 64 65 Cellular basis of bone formation and resorption, 93 Cellular immunity, 286 Cellular processes, 99 Cellular responses to infectious agents, 285 286 Cellular swelling, 64 65 Cemento enamel junction to alveolar crest method (CEJ-AC method), 771 “Cementoma”, 769 Cementum, 53 Cemetery studies, 486 487 Central Russia, cemetery studies in, 486 487 Cervical vertebrae, 422 423 Chagas disease, 483 484 Chichester, England, 372 374 alveolar resorption in maxilla, 373f destructive remodeling, 374f early rhinomaxillary changes in leprosy, 373f on margins of pyriform, 373f metatarsals and proximal phalanges, 374f

periostosis of lower tibia and fibula, 374f radiograph of leprogenic odontodysplasia, 374f Child abuse, 262 263 Chimpanzee lice (Pthirus pubis), 198 199 Chipmunk facies, 510 Chiribaya mummies, 484 Cholera, 195 198 Chondroblastic osteosarcoma, 132 Chondroblastoma, 656 657, 656f, 674 675 Chondrocytes in perichondrium, 45 Chondrodysplasias, 615 Chondrogenic tumors. See also Osteogenic tumors bizarre parosteal osteochondromatous proliferation and subungual exostosis, 657 660 chondroblastoma, 656 657, 656f chondroma, 655 656, 672 674 chondromyxoid fibroma, 657 osteochondroma, 656, 674, 674f Chondroma, 655 656, 672 674 Chondromyxoid fibroma, 657 Chondrosarcoma, 686 687, 686f, 693f, 695f Chopping injuries, 220 Chordoma, 687 688 Chronic bone abnormality, 455 Chronic disease, 322 Chronic fungal infections, 86 Chronic infectious diseases, 287, 321 Chronic venous stasis, 367 Chronic vitamin D deficiency, 65 66 Circadian rhythm, 44 Circulatory disorders, 491 498 blood supply of bones, 491 492 Legg Calve´ Perthes Disease and Slipped Femoral Capital Epiphysis, 495 498 necrosis of femoral head, 494 495, 494f, 496f osteonecrosis, 492 494, 492t Circumferential lamellar bone, 456 CISC. See Coimbra Identified Skeletal Collection (CISC) Citrullinated peptides (CPs), 733 Clavicle, 339 340, 387 389 Cleft lip and/or palate, 586, 589 592 Cleidocranial dysostosis, 630 Cleidocranial dysplasia, 630 pathology, 630 Clinical archaeological osteoarthritis scale (COAS), 29 Clone theory, 53 Cloning, 184 CLSM. See Confocal laser scanning microscopy (CLSM) Clubfoot deformity, 606 CO. See Cribra orbitalia (CO) CO1A2. See Pro-2 chain of type 1 collagen (CO1A2) Cobb angle, 598 Coccidioides, 470 Coccidioides immitis, 442 443 Coccidioides posadasii, 442 443 Coccidioidomycosis, 86, 441 443, 443f

827

Coimbra Identified Skeletal Collection (CISC), 694 COL1A1. See Pro-1 chain of type 1 collagen (COL1A1) Collagen, 533 disorders, 143 146 pathological alteration of collagen deposition, 129 130 Colorectal adenocarcinoma, 802 Comminuted fracture, 216 217 Comminuted fragments, 225 226 Compact bone, 38 “Compassion”, 28 Complete fracture, 212 Compound fracture, 216 217 Compound-specific isotope analysis (CSIAs), 774 775 in bioarcheological research, 774 775 Compression fractures, 214, 214f, 243f, 244f, 246f, 458 of spine, 243 244 Computed radiography (CR), 171 Computed tomography (CT), 169, 236 Concentric atrophy in leprosy, 367 Concrescence, 761 Confocal laser scanning microscopy (CLSM), 92 Congenital and neuromechanical abnormalities of skeleton, 585 extremities, 606 611 pelvis, 603 606 ribs and sternum, 603 skull, 585 594 spine, 594 603 Congenital dislocation of hips (CDH), 721 722 Congenital fusion of vertebrae, 599 Congenital hemolytic anemia, 514 Congenital herniations, 586 587, 592 593 Congenital hypothyroidism, 573 574 Congenital Kyphosis, 596 Congenital rubella, 452, 453f Congenital syphilis (CS), 339, 393 399, 402 408, 461 462. See also Venereal syphilis (VS) anterior view of skull with destruction, 397f archeological skeleton with probable, 404f child with, 398f, 406f of cranial vault, 395f with destructive lesion, 397f long bone with subperiosteal new bone formation, 395f of 12-year-old child with tertiary congenital syphilis, 396f radiograph of long bones of infant, 395f syphilitic osteochondritis of distal femur, 394f tertiary, 397f congenital syphilis of radius and ulna, 396f treponemal disease of right tibia, 399f upper incisor and canine teeth, 405f Conservation mode, 48 49

828 Index

Copper (Cu), 775 Coprolites, 199 Coronoid portion, 412 Cortical bone, 491 492 histomorphometry, 107 108 Cortical drift in growth alters cross-sectional shape, 122 123 Cortical penetration, 686 687 Cortical porosity, 541 Costotransverse joints (CT joints), 727 Costovertebral joints (CV joints), 727 “Coupling”, 93 94 Coxa vara deformities, 621 CPPD. See Calcium pyrophosphate dihydrate (CPPD) CPs. See Citrullinated peptides (CPs) CR. See Computed radiography (CR) Cranial air sinuses, 457 458 Cranial base, 347 348 cranial TB with lesion in right frontal bone, 348f tuberculosis of cranial base and atlas, 348f Cranial injuries, 238 Cranial lesion, 470 471 Cranial modification, 270 272 Cranial osteoporosis, 578 Cranial vault, 345 347 cranial TB with lytic lesion penetrating both tables of skull, 346f tuberculosis, 345f, 346f of right parietal bone, 347f vascular lesions of inner table of skull, 347f Cranionasal tertiary syphilis, 386f Craniostenosis, 593 594 Craniosynostosis, 587, 593 Cranium, 533 Cribra orbitalia (CO), 22, 469, 515 in child with leprosy, 368f Cross-sectional shape analysis, 124 Crown-group vertebrates, 35 CRTAP. See Cartilage-associated protein (CRTAP) Cryptococcosis, 442 Crystal arthropathies, 719, 732, 743 745. See also Sero-negative arthropathies gout, 744 745 CS. See Congenital syphilis (CS) CSIAs. See Compound-specific isotope analysis (CSIAs) CT. See Computed tomography (CT) CT joints. See Costotransverse joints (CT joints) Cushing’s disease, 576 577, 576f Cushing’s syndrome, 143 CV joints. See Costovertebral joints (CV joints) Cyst(s), 479 480, 667, 680 696 Cystic echinococcosis, 464 Cystic lesions, 665 666 ABC, 667 668, 667f intraosseous epidermal cyst and dermoid cyst, 668 679 simple bone cysts, 666 667

D D-A-M-A approach. See Documentation assessment monitoring action approach (D-A-M-A approach) DD. See Dentin dysplasias (DD) Degree of mineralization (DMB), 129 DEJ. See Dentin enamel junction (DEJ) Dental alveoli, 590 591 Dental anthropology, 823 824 Dental avulsion, 273 Dental calculus, 200 formation, 778 paleopathology, 778 781 Dental chemistry, 772 773 human mobility and migration, 777 778 paleodietary reconstruction, 773 776 patterns of breastfeeding and weaning, 776 stress and disease from chemical analyses, 776 777 Dental corrosion, 764 Dental crowding, 756 759 Dental development, 749 752 dental agenesis of mandibular lateral incisors, occlusal view, 760f dental hypoplasia associated with case of tuberculosis, 756f, 757f associated with probable syphilis, 757f associated with rickets, 756f dentin, 749 750 disturbances in abnormal quality of teeth, 752 756 abnormal quantity of teeth and dental crowding, 756 759 abnormal size of teeth, 759 760 dental anomalies, 760 762 dental discoloration, 762 763 enamel, 750 752 Dental erosion, 764 Dental fluorosis, 559 Dental infections, 285 286 Dental modification, 273 Dental trauma, 230 231 Dental wear, 763 771 alveolar lesions, 767 768 antemortem tooth loss, 770 771 caries, 765 767 miscellaneous conditions of oral cavity hyperostosis/tori, 769 770 nonodontogenic cysts and tumors, 769 odontogenic cysts, 768 769 odontogenic tumors, 769 pathology, 768 paleopathology, 764 765 pathology, 764 periodontal disease, 771 Dentigerous cysts, 768 769 Dentin, 52 53, 55, 749 750 development disturbance, 752 753 Dentin dysplasias (DD), 752 Dentin enamel junction (DEJ), 750 Dentinogenesis, 750 Dentinogenesis imperfecta (DI), 752

Dentition, 293 295 dental calculus, 778 781 dental chemistry, 772 778 dental development, 749 752 disturbances in, 752 763 identifying dental wear and oral disease, 763 771 interpreting oral health, 771 772 Depressed fractures, 214, 216f, 218f, 239 241 Dermoid cyst, 668 679 cranial defect from, 668f Desmoplastic fibroma, 658 659 Developmental Origins of Health and Disease Hypothesis (DOHaD), 25 DEXA. See Dual-energy X-ray absorptiometry (DXA) DI. See Dentinogenesis imperfecta (DI) Diabetes mellitus, 139 141 Diaphyseal aclasis, 657 Diaphyseal cortex, 491 492 Diaphyseal periostosis, 405 Diaphysis, 36 37, 405 Dickkopf protein family [Dkk1 and 2], 40 42, 131 Dietary analysis, medicines and, 485 486 Dietary assessments, 823 824 Diet tissue spacing, 773 Differential diagnosis of abnormal bone, 81 82 Diffuse idiopathic skeletal hyperostosis (DISH), 141, 722 724, 730 Diffuse microdamage as energy-dissipating mechanism, 109 Digital radiography (DR), 171 “Digitized diseases”, 169 DIPs, 727 Direct effects of M. leprae, 365 366 Direct Sanger sequencing, 184 Disability, 26 29 Discrete typing units (DTUs), 483 Disease evolution theories, 400 402 process identification, 83 progression, 83 84 DISH. See Diffuse idiopathic skeletal hyperostosis (DISH) Disk trauma, 228 Dislocation, 231 233, 258 259 Distal tibia, 337 338, 338f Disuse mode, 48 49 DMB. See Degree of mineralization (DMB) DNA fragment analysis, 184 library preparation, 185 preservation, 185 187 tests, 802 Documentation assessment monitoring action approach (D-A-M-A approach), 481 DOHaD. See Developmental Origins of Health and Disease Hypothesis (DOHaD) Domestic livestock, 809, 814 Dorsal tarsal bars, 366 DR. See Digital radiography (DR)

Index

“Dropped foot”, 366 DTUs. See Discrete typing units (DTUs) Dual-energy X-ray absorptiometry (DXA), 106 107, 555, 555f Dunning Poorhouse Cemetery, 25 Dupuytren exostosis, 658 Dynamic fracture, 213 214 Dyschondrosteosis, 623 Dysostoses, 615 Dysplasias, 615

E Eburnation, 727 Echinococcosis tapeworms, 83, 464 465 Echinococcus granulosus, 464, 465f, 466f, 479 481 Echinococcus multilocularis, 464 Ectoderm, 43 44 EDTA. See Ethylenediaminetetraacetic acid (EDTA) Elastic cartilage, 39 Elbow, 340 joint, 727 tuberculosis of right elbow, 341f with bony ankylosis, 341f Elder abuse, 263 ELP. See Endosteal lamellar pocket (ELP) Emerging infectious diseases (EIDs), 481 Emphysema, 802 Enamel, 52, 750 752 development disturbance, 753 754 Enamel hypoplasia (EH), 752 753, 756 Enamelin, 750 751 Enchondroma(s), 652 654, 671f, 672f, 674 Enchondromatosis, 656 Endemic hypothyroidism, 574 575 Endemic syphilis, 380, 401 Endochondral bone formation. See also Intramembranous bone formation achondroplasia, 616 617 defects in, 616 621 thanatophoric dwarfism, 617 621 Endochondral disorders, 615 Endochondral ossification, 44 45 Endocrine disturbances, 574 paleopathology, 570 574, 579 583 pathology, 574 579 pituitary disturbances, 567 570 system, 567 Endoderm, 43 44 Endogenous glucocorticoid excess, 141 Endoscopy, 801 Endosteal callus, 222 Endosteal lamellar pocket (ELP), 123 Energy-dissipating mechanism diffuse microdamage as, 109 microdamage as, 108 112 Enteric dysentery, 195 198 Enterobius vermicularis, 481 483 Enteropathic arthropathy, 739 743 Enterovirus poliovirus, 453 454 Enthesopathies, 258

EOA. See Erosive osteoarthritis (EOA) Eosinophilic granuloma, 507 508, 509f Epidemiological modeling approach, 817 Epidemiologists, 14, 16 17 Epidemiology, 14 16 Epiphysis, 37, 326, 339 340, 451 452, 491, 575 576 Epithelioid hemangioma, 664 665 Erlenmeyer flask deformity, 134 135 Erosive arthropathies, 719, 732 733 RA, 732 733 Erosive osteoarthritis (EOA), 732, 743 Erythroblastosis fetalis, 514 Estrogen, 42, 106, 577 deficiency contributes to bone loss, 122 Ethylenediaminetetraacetic acid (EDTA), 187 188 Ewing’s sarcoma of bone, 687, 688f Exostosin gene family (EXT gene family), 656 Exotic neoplasms, 70 72 External compact lamellar tissue, 38 Extremities, 606 611 paleopathology, 608 611 pathology, 606 607

F Facet joints, 725 Facial bones, 348 351 cranial TB in lupus vulgaris, 351f cranial TB with destruction of left zygomatic arch, 349f craniofacial TB in lupus vulgaris, 350f lupus vulgaris, 350f tuberculosis of cranium with right frontal bone, 350f Facial skeleton, 47 48 Fatigue fractures, 217 218 Feces, parasites in, 199 Feminist theory, 22 24 Femoral head, 66 68 necrosis, 494 495, 494f, 496f Femur, 458 FGF. See Fibroblast growth factors (FGF) Fiber bone, 221 Fibrillation, 720 721 Fibrinogen, 286 Fibro-osseous lesions, 657 658, 674 Fibroblast growth factor receptor (FGFR), 616 FGFR3 gene, 66 Fibroblast growth factors (FGF), 42 Fibroblastic osteosarcoma, 132 Fibrocartilagenous connection, 227 Fibrogenic lesions desmoplastic fibroma, 658 659 fibrous dysplasia, 660 661 fibrous dysplasia, 675 676 NOF, 674 675 NOF and benign fibrous histiocytoma, 659 660 OFD, 660 661, 662f Fibrohistiocytic lesions, 657 658, 674 Fibrous callus, 221

829

Fibrous cortical defect, 658 659 Fibrous dysplasia, 660 661, 675 676 Fibrous tissue, 800 Fibula, 377 Fibula, 337 338, 338f Fissural cysts, 769 Flat bones, 36, 458 Flu virus, 195 198 Fluoride, 559 Fluorosis, 86, 559 561, 560f paleopathology, 559 561 Focal or localized macrodontia, 759 760 Food and waterborne outbreaks, 196 197 Foot binding, 272 Foramina, 533 Force, 213 214 Forkhead box O family (FOXO), 142 Fourier transform infrared spectroscopy (FTIR), 774, 780 781 Fracture, 214f, 224f, 246f bony sequelae of trauma, 224 230, 230t classification, 213 220 complications, 249 258 dental trauma, 230 231 healing, 221 224 mechanisms, 220 221 pathology, 212 233 recording method, 234t resulting from accidental events, 242 246 massive sword wound in coronal axis, 238f poleaxe or war hammer wound, 238f resulting from intentional violence, 235 242 treatment, 246 249, 250f, 251f Freiberg’s disease of metatarsal head, 500 Frequency distribution, 463 Frontal bone, 62 Frontonasal tertiary syphilis, 386f Frost’s mechanostat model, 108 Fruit-eating bat (Pteropus medius), 811 FTIR. See Fourier transform infrared spectroscopy (FTIR) Fungal infections, 441. See also Bacterial infections pathology, 441 446 aspergillosis, 445 446 coccidioidomycosis, 442 443 cryptococcosis, 442 histoplasmosis, 443 mucormycosis, 443 444 mycetoma, 444 445 North American Blastomycosis, 441 442 paracoccidioidomycosis, 442 sporotrichosis, 445 Fusion, 760 761, 761f, 762f

G Gardnerella vaginalis, 197 Gastrointestinal tract, 443 Gaucher cells, 506 Gaucher’s disease, 506, 507f GenBank, 185

830 Index

Gender intersectionality of, 24 26 theory, 22 24 Generalized OA, 724 GH. See Growth hormone (GH) Giant cell tumor (GCT), 645, 665 of bone, 661 664, 676 cystic lesions, 665 666 meningioma, 665 668, 666f vascular tumors, 661 664 Gigantism, 570 Glanders, 321, 426 427 pathology, 426 427 Globulins, 286 Gloucester, 412 413 Glucocorticoid excess, 141 143 Glycosaminoglycans. See Mucopolysaccharidosis Gnathostomes, 35 36 Gonococcal arthritis, 313 314 Gorham tout syndrome, 73 76 Gout, 744 745 Gram-positive bacterial species, 427 Granulomatous inflammation, 76 Granulomatous processes, 382 “Green stick” fracture, 215 216, 217f, 220 Ground-breaking model, 26 Growth hormone (GH), 121 Guinea pigs (Cavia porcellus), 811 Gummatous lesions, 411 412 Gummatous osteoperiostitis, 389 390 Gummatous periostosis, 394 396 Gut microbiome, 199 200

H “H”-shaped vertebrae, 513 Haemophilus influenzae, 304 Hand Schu¨ller Christian disease, 507 508 Harris lines (HL), 176 Havers Halber oscillation (HHO), 44 “Haversian canal”, 114 Haversian system, 109 110 HbH disease, 509 HBV. See Hepatitis B virus (HBV) Head injuries, 262 263 Head louse (Pediculus humanus capitis), 198 199 Healed fractures, 215f, 222f, 223f, 228f, 235, 237f, 239 241, 248f Healing, 327 329 Heberden’s nodes, 724 “Heirloom” conditions, 446 Helicobacter pylori, 186 187, 802 genome sequences, 198 Helminth diseases, 802 Hemangioma and vascular anomalies, 676 678 and vascular malformations, 664, 665f Hematogenous osteomyelitis, 297 301 Brodie’s abscess of right distal tibia, 302f of right proximal tibia, 302f chronic osteomyelitis

of left femur, 300f of left tibia, 299f and periostosis of left femur, 301f of right femur, 300f of right tibia, 300f of tibia, 298f osteomyelitis of distal right femur, 298f of distal right tibia, 299f of left tibia, 299f of right femur, 298f sclerosing osteomyelitis and periostosis of left femur, 302f sequestrum, midshaft tibia, 301f squamous cell carcinoma of left tibia, 303f Hematopoietic disorders anemias, 508 514, 510f paleopathology of anemia, 514 517 Hematopoietic malignancies, 697 Hematopoietic marrow red blood cells, 38 Hemiosteon, 93 94 Hemoglobin, 194 Hemoglobin Bart’s hydrops fetalis, 509 Hemoglobin SC disease, 512 Hemozoin-laden bone marrow macrophages, 468 Hepatitis B virus (HBV), 198 Hereditary multiple exostoses, 657 Hereditary spherocytosis, 514 Heterogeneous frailty, 17 HFI. See Hyperostosis frontalis interna (HFI) HHO. See Havers Halber oscillation (HHO) Hip, 332 337 chronic TB of right greater trochanter with fistulating abscess, 336f deformities, 626 627 destructive arthritis of right hip, 334f joint, 727 tuberculosis of left hip, 335f, 336f of spine and left ilium, 336f tuberculous arthritis of left hip, 333f of right hip, 334f, 335f Histiocytes, 287 Histiocytosis X, 507 508 Histomorphology, 93 98 bone, 92 breakage, 98 125 calculation of remodeling parameters from BSUs, 94 96 cellular basis of bone formation and resorption, 93 pathology and histomorphometry, 125 146 remodeling and morphology of BMU, 93 94 parameters application, 96 98 Histomorphometric assessment of bone strength and fragility, 98 125 bone strength at microscale lacunar-canalicular architecture reflects osteocyte activity, 112 114 microdamage as energy-dissipating mechanism, 108 112

secondary osteon size and shape as toughening mechanisms, 117 120 vascular porosity reflects resorption activity, 114 116 mechanical loading shapes, material and structural properties bone functional adaptation, 99 104 bone loss in past populations, 107 108 describing osteopenia and osteoporosis, 106 107 material properties and bone strength, 105 mechanical loading modes experienced by bone, 104 105 normal trajectory of remodeling rate over lifespan, 106 trade-offs between strength and toughness in fracture resistance, 105 106 structural properties of whole bone in crosssection, 120 125 axial loading differences assessment through relative cortical area, 123 124 cortical drift in growth alters crosssectional shape, 122 123 cross-sectional shape as metric of loading direction, 124 estrogen deficiency contributes to bone loss in elderly men, 122 parabolic index, 124 125 radial expansion of cross-section results from growth in bone length, 120 sexual dimorphism in radial expansion, 120 121 sexual dimorphism in trabecular bone loss with age, 121 122 Histomorphometry, 125 146 bone mineral homeostasis disorders diabetes mellitus, 139 141 glucocorticoid excess, 141 143 hyperparathyroidism, 137 138 hyperthyroidism, 138 139 rickets/osteomalacia, 135 136 cancer metastatic bone disease, 131 132 osseous bone tumors, 132 133 collagen disorders, 143 146 imbalances of bone remodeling osteopetrosis, 134 135 PDB, 133 134 infection, 130 remodeling processes commonly disrupted by pathology pathological alteration of collagen deposition, 129 130 pathological alteration of mineralization, 129 pathological alteration of remodeling rate over lifespan, 125 128, 126t Histoplasma capsulatum, 443 Histoplasma duboisii, 443, 444f, 447f Histoplasmosis, 441, 443 HIV. See Human immunodeficiency virus (HIV) HL. See Harris lines (HL) HMP. See Human Microbiome Project (HMP)

Index

HOA. See Hypertrophic osteoarthropathy (HOA) Hodgkin’s lymphomas, 86 Homo sapiens neandertalensis, 26 27 Hounsfield unit scale (HU scale), 171 172 HPOA. See Hypertrophic pulmonary osteoarthropathy (HPOA) Human disease, 421, 441 Human immunodeficiency virus (HIV), 183, 321 Human Microbiome Project (HMP), 190 Human mobility and migration, 777 778 Humoral responses to infectious agents, 285 286 Hunter’s syndrome, 626 627 Hurler’s syndrome, 626 Hyaline cartilage, 38 Hydatid cysts, 466, 479 480, 479f Hydatidosis, 480 481 Hydrocephalic skull, 593 Hydrocephalus, 587 588, 593 Hydrogen, 176 Hydroxyapatite (Ca10 (PO4(6 (OH)2), 37 38 crystals, 744 745 Hypercalcemia, 129, 131 132 Hypercholesteremia, 507 Hyperdontia, 756 757 Hypergonadism, 577 Hyperosteoidosis, 136 Hyperostosis frontalis interna (HFI), 561 562, 562f paleopathology, 562 Hyperostosis/tori, 769 770 Hyperparathyroidism, 137 138, 464 465, 578, 582 583 Hyperplasia, 64 Hyperthyroidism, 138 139, 576 Hypertrophic osteoarthropathy (HOA), 86, 491, 503, 504f paleopathology, 503 Hypertrophic pulmonary osteoarthropathy (HPOA), 343 Hypertrophy, 64 Hypervascularity, 381, 427 Hypodontia, 758 Hypogonadism, 577 Hypoparathyroidism, 577 Hypopituitarism, 569 Hypoplastic shallow acetabulum, 603 604 Hypothalamus, 567 Hypothyroidism, 574 576, 579

I IDA. See Iron-deficiency anemia (IDA) IDH genes. See Isocitrate dehydrogenase genes (IDH genes) IEC. See International Exchange Collection (IEC) IGF. See Insulin-like growth factors (IGF) Ihh. See Indian hedgehog (Ihh) IL-1. See Interleukin-1 (IL-1) Illinois, skeleton from, 359 Image detector, 170 171

Imaging in paleopathology medical imaging, 169 micro-CT, 178 MRI, 178 179 other bone changes and radiography, 176 177 radiographic appearance of pathologic conditions, 174 176 radiology history in paleopathology, 169 principles and terminology, 169 173, 170t taphonomic alterations, 177 178 Immune resistance, 321 322 Immunity, 286 Immunoglobulins, 286 Immunosuppression, 441 442 “IMPACT Radiological Mummy Database of mummies”, 169 Impairment, 26 29 Impingement syndrome, 726 727 Inadequate fracture healing, 226 227 Incomplete fracture, 212, 220, 245 Indian hedgehog (Ihh), 44 45 Indirect effects of M. leprae, 366 367 lagophthalmos of eyes, 367f tarsal bars showing on radiograph, 366f ulcer of heel in leprosy, 366f Indirect force, 232 Infant osteomyelitis, 301 303 acute osteomyelitis of left tibia, 304f “Infantile paralysis”, 454 Infectious arthritis, 422 Infectious cardiac diseases, 802 Infectious disease(s), 285, 802. See also Metabolic disease(s) biology of infection, 287 288 changes in specific bones, 304 307 humoral vs. cellular responses to infectious agents, 285 286 osteomyelitis, 297 304 paleopathology of osteomyelitis, 308 313 periostitis or periostosis, 288 296 septic arthritis, 313 316, 314f, 315f vascular changes in response to infectious agents, 286 287 Inflammation in bone, 287 288 Inflammatory disorders, 73 76 Influenza virus, 197 198 Infraction. See Incomplete fracture INFγ. See Interferon-γ (INFγ) Injury mechanism and fracture type, 213t poisoning, and consequences of external causes, 212t Insulin-like growth factors (IGF), 698 IGF-1, 42, 567 Intercellular matrix, 38 Interferon-γ (INFγ), 42 Interleukin-1 (IL-1), 42 Internal periosteum, 346 347 Internalized discoloration, 763 International Exchange Collection (IEC), 694 Intersectionality of sex, gender, and age, 24 26

831

Intervertebral disk disease (IVD disease), 725, 730 Intimate partner abuse, 264 Intramembranous bone formation defects in, 627 630 osteogenesis imperfecta, 627 628 Intramembranous ossification, 46 47 Intraosseous arteries, 491 492 Intraosseous epidermal cyst, 668 679 Inuit skeleton, 361 Invavita piratica. See Tongue worm (Invavita piratica) “Invisible” pathogens, 195 198 Iron-deficiency anemia (IDA), 512, 514, 515t, 518 524 leukemia, 520 myeloma, 520 524, 521f Irregular bones, 36 Isocitrate dehydrogenase genes (IDH genes), 686 IVD disease. See Intervertebral disk disease (IVD disease)

J Joint(s), 391 393 capsule, 326 diseases, 719, 801 crystal arthropathies, 743 745 erosive arthropathies, 732 733 OA, 719 729 other conditions with proliferation or eburnation, 729 732 septic arthropathy, 745 sero-negative arthropathies, 733 743 failure, 725 of foot, 728 729 of hand, 727 tertiary syphilis of skeleton, 392f of total skeleton, 393f Justinian plaque, 195 196 Juvenile chronic arthritis, 337 338

K Kala-azar. See Visceral leishmaniasis “Kastert series”, 333 Kempson Campanacci’s disease, 664 Klippel Feil syndrome, 599, 602 Knee, 337, 337f joint, 727 728 Ko¨hler’s disease of tarsal navicular, 499, 500f Korea, cemetery studies in, 486 487 Kyphoscoliosis, 598 Kyphosis, 76 78, 387, 599 Kyphotic spine in person with tuberculosis, 327f

L L5 vertebra, 84 86 Lacunae, 39 40

832 Index

Lacunar-canalicular architecture reflecting osteocyte activity, 112 114 changes with age, 112 114 osteocyte lacunar density and volume increasing with higher strain, 112 osteocytic osteolysis and pathology, 114 Lagophthalmos of eyes, 367f Lamellar bone, 456 Langerhans cell histiocytosis (LCH), 507 508, 508f paleopathology, 508 Langerhans cell histiocytosis, 346 347 Lead (Pb), 775 Legg Calve´ Perthes disease, 495 498, 497f, 498f paleopathology, 497 498 LEH. See Linear enamel hypoplasia (LEH) Leiomyomas, 802 Leishmaniasis, 467 468 Lepromatous leprosy, 368 Leprosy, 191 192, 363 374 diagnosis in skeletal remains, 368 paleopathology, 368 374 pathology, 365 368 Ridley and Jopling immune spectrum, 364f Leri’s disease. See Melorheostosis Le´Ri Weill dyschondrosteosis, 623 624 Letterer Siwe disease, 507 508 Leukemia, 86, 520 Leukocytes, 381 Lice reflecting social organization, interaction, and privation, 484 486 Life course approach, 25 Limb atrophy, 454 455 Limb dysplasias, 615 Linear enamel hypoplasia (LEH), 753 754 Lipid(s), 774 775 granulomatosis, 507 storage diseases Gaucher’s disease, 506, 507f LCH, 507 508, 508f lipidoses, 507 Niemann Pick disease, 506 507 Lipidoses, 507 Lithuanian mummy variola virus genomes, 196 LLAC. See Luis Lopes Anthropological Collection (LLAC) Localized primary canine hypoplasia (LPCH), 754 Long bones, 36, 387 390, 458 tertiary syphilis of cranial vault, 391f of distal left femur, 388f of left tibia, 387f of right femur, 389f treponemal lesions of left clavicle, 388f of left femur with fusiform hyperostosis, 390f of right ulna, 388f Lordosis, 596 Low-density lipoprotein-related protein 5 (LRP5), 40 42

Luis Lopes Anthropological Collection (LLAC), 707 708 Lumbar vertebrae, 355 356, 358 359 Lumbar vertebral body of skeleton, 426f Lumbarization, 598 599 Lung cancer, 322 Lupus vulgaris, 350f Luxation, 233f, 258 259 Lymphatic system, 321 Lymphocytes, 286 287 Lytic cavitation of vertebral bodies, 421 Lytic lesion, 343 344, 359 361

M Macrophage-colony stimulating factors (M-CSF), 42 Macrophages, 286 287 Madelung’s deformity, 623 Maduromycosis. See Mycetoma Magnesium (Mg), 775 Magnetic resonance imaging (MRI), 178 179 Malapa Hominin 1 (MH1), 672 674 Malaria, 194, 467 469 anemia, 469 Malignant neoplasms, 640 643 Malignant osteopetrosis, 631 632 Mandibular lesions, 428 429 Manubrium, 405 MapDamage, 190 191 Marble bone disease. See Osteopetrosis Marginal osteophytes, 730 Marrow space, 38 Mass graves, 195 198 Master control mechanisms, 40 42 Mastoid process, 412 Mawworm (Ascaris lumbricoides), 486 Mechanical loading modes experienced by bone, 104 105 Mechanostat model, 115 MED. See Multiple epiphyseal dysplasia (MED) Medical imaging, 169 Medical knowledge, 4 Medullary cavity, 38 Melanomas, 697 Melorheostosis, 86, 634 635 Meningioma, 665 668, 666f, 678 679 Mesenchyme, 44 Mesoderm, 43 44 Mesodermal cells, 44 Metabolic bone diseases, 531 Metabolic disease(s), 78. See also Infectious disease(s) adult scurvy, 537 539 cooccurrence of rickets and scurvy, 551 552 fluorosis, 559 561, 560f HFI, 561 562 osteomalacia, 546 550 osteoporosis, 552 559 rickets, 540 545 subadult scurvy, 532 537

vitamin C deficiency, 532 vitamin D deficiency, 540 Metaphyseal dysplasia, 632 633 Metaphysis, 339 340 Metastatic bone disease, 131 132, 697 Metastatic neuroblastoma, 346 347 Metatarsal head, Freiberg’s disease of, 500 Methanobrevibacter oralis, 200 MH1. See Malapa Hominin 1 (MH1) Microbiome analyses, 190 191 Microcomputed tomography (micro-CT), 92, 178 Microdamage, 105 106 as energy-dissipating mechanism, 108 112 changes with age, 110 111 diffuse microdamage as energy-dissipating mechanism, 109 morphology of microdamage depends on loading mode, 108 109 tends to initiating at stress-concentrating voids, 109 110 Microdontia, 760 Microfossils, 778 Micromelia, 606 Microparticle analyses of dental calculus, 778 780 Microscopic analysis of bone tissue, 91 Microscopic imaging techniques, 92 Milwaukee shoulder, 725 726, 744 745 Mineralization, pathological alteration of, 129 Mitochondrial DNA (mtDNA), 184 Mixed metastases, 701 Modeling, 93. See also Remodeling Modern clinical X-ray equipment, 171 Modern radiological imaging technique, 175 176 Molecular archeology, 183 Molecular biology, 483 484 Molecular evidence, 402 Monocytes, 286 Mononuclear leukocytes, 286 Morbillivirus canine morbillivirus, 455 Morbillivirus measles morbillivirus, 455 Morquio’s syndrome, 626 627 Mortality, 17 in past societies, 260 269 Most recent common ancestor (MRCA), 364 “Moth-eaten” central sequestrum, 345 MRCA. See Most recent common ancestor (MRCA) MRI. See Magnetic resonance imaging (MRI) MTC. See Mycobacterium tuberculosis complex (MTC) Mucocutaneous leishmaniasis, 467 Mucolipidoses, 624 626 Mucopolysaccharidosis (MPS), 615, 624 627 pathology, 624 627 Mucormycosis, 441, 443 444 Multicelled parasitic infections, 464 paleopathology of multicelled parasitic infections, 465 467 pathology echinococcosis, 464 465

Index

Multifocal irregular ossification centers, 575 576 Multifocal lytic lesions, 424f, 425f, 449f Multifocal tuberculosis, 353f Multiple diaphyseal sclerosis, 633 634 Multiple enchondromas, 656 Multiple epiphyseal dysplasia (MED), 621 Multiple myeloma, 86 Multiple osteochondromas syndrome, 673f, 674 Multiscalar studies, 31 Mummies, 483 484, 799 lesions, trauma, and cause of death, 803 804 paleopathological examination, 800 801 paleopathology, 801 804 Mutilations, 366 367 Mycetoma, 444 445, 444f, 445f Mycobacteria, 470 Mycobacterial DNA, 802 Mycobacterium avium, 812 Mycobacterium bovis, 321, 812 Mycobacterium leprae, 183, 191, 363 364 direct effects, 365 366 indirect effects, 366 367 Mycobacterium lepromatosis, 191, 363 364 Mycobacterium pinnipedii, 192 193 Mycobacterium tuberculosis, 183 Mycobacterium tuberculosis complex (MTC), 184, 321, 322t, 812 Mycosis, 447 449 Mycotic infection, 356 357, 446 Myeloma, 131, 520 524, 521f paleopathology, 523 524 Myositis ossificans traumatica, 255 256, 256f, 257f, 258

N NA. See Nomina Anatomica (NA) Naestved, Denmark, 370 371 destruction of majority of metatarsal, 371f of metacarpophalangeal joints, 371f flexion contracture, 371f proximal and middle phalanges, 372f rhinomaxillary remodeling in skeleton, 370f Nasomaxillary tertiary syphilis, 385 387, 386f National Bone Health Alliance (NBHA), 107 National Institutes of Health (NIH), 3 National Museum of Natural History (NMNH), 3, 497, 573 574, 672 Nearthrosis, 226 227 Necrosis of femoral head, 494 495, 494f, 496f paleopathology, 495 Neolithic demographic transition (NDT), 772 Neoplasms, 70 72, 640, 801 802 Neural crest, 44 Neurogenic disorders, 454 455 Neuromuscular paralysis, 599 Neutrophils, 381 Next-generation sequencing (NGS), 183, 185, 188 190, 192 NHANES III. See Third National Health and Nutrition Examination Survey (NHANES III)

Niemann Pick disease, 506 507 NISPs. See Number of identified specimens (NISPs) Nitrous oxide (NO), 114 Nocardia species, 429 Nocardiosis, 321, 427 429 pathology, 427 429 Nodal OA, 724 Nodes, 724 Nomina Anatomica (NA), 62 Non-Hodgkin’s lymphomas, 86 Nongummatous lesions, 387 389 Nongummatous osteoperiostitis, 387 389 Nonhuman animal paleopathology areas of commonality, 815 816 areas of departure, 811 815 periosteal new bone formation, 813f research foci within, 810 811 toward closer integration, 816 817 basocranial view of dog skull, 817f Nonmetric traits, 760 Nonodontogenic cysts and tumors, 769 Nonossifying fibromas (NOF), 657f, 658 660, 658f, 674 675 Nonpulmonary associations, 503 Nontuberculous septic arthritis, 333 334 Nonunion, 226 227 North American blastomycosis, 441 442 Notochordal tumor, 690 Number of identified specimens (NISPs), 814

O OA. See Osteoarthritis (OA) Occipital flattening, 590 591 Occlusal morphology, 765 Odontoblasts, 52 53 Odontogenic cysts, 768 769 Odontogenic tumors, 769 Odontoma, 769 OFD. See Osteofibrous dysplasia (OFD) OI. See Osteogenesis imperfecta (OI) OIM. See Osteogenesis imperfecta model (OIM) OPD. See Osteon population density (OPD) Operational taxonomic units (OTUs), 190 OPG. See Osteoprotegerin (OPG) Oral health indicators, 774 interpretation and demographic transitions, 772 sex differences in, 771 772 Ordinal grading system of severity of osteoarthritis, 29 Organized violence, 261 Origination frequency (Or. f), 95 96 Orthopoxvirus variola, 450 451 Ortner, Donald J. history of first edition from, 1 3 history of first second from, 3 5 objectives of the first and second editions, 5 6 Osgood Schlatter disease, 501 502, 502f paleopathology, 501 502

833

Osseous bone tumors, 132 133 Osseous metastases, 708 709 Ossifying fibroma of long bones, 664 Osteitis, 287 288 Osteitis fibrosa cystica generalisata, 578 Osteoarthritis (OA), 253, 366, 719 729 distribution in skeleton, 725 effects during life, 729 note on nomenclature, 719 720 and occupation, 729 paleopathological diagnosis, 725 particular features in different joints, 725 729 pathophysiology, 720 721 precipitants, 724 725 types, 721 724 Osteoarthritis Initiative, 29 Osteobiography in paleopathology, 29 31 Osteoblastic metastases, 698f, 699, 704f, 711 Osteoblastic prostate cancer, 131 Osteoblastoma, 651 652, 670 674 Osteoblasts, 39, 48, 93, 98 99 Osteocartilaginous exostosis, 656 Osteochondritis dissecans, 500 501, 501f paleopathology, 501 Osteochondroma, 656, 674, 674f Osteochondroprogenitor cells, 44 Osteoclastic giant-cell-rich tumors of bone, 676 Osteoclastic resorption, 576 577 Osteoclasts, 39, 41f, 42, 48, 93, 98 99 Osteocytes, 39 40, 42, 93 Osteocytic osteolysis and pathology, 114 Osteodysplasias, 615 Osteofibrous dysplasia (OFD), 658, 660 661, 662f Osteogenesis imperfecta (OI), 96, 143 146, 627 628 paleopathology, 628 630 pathology, 627 type I, 627 type II, 627 628 types III and IV, 628 Osteogenesis imperfecta model (OIM), 144 Osteogenic tumors. See also Chondrogenic tumors chondroblastoma, 674 675 chondrogenic tumors, 670 672 cysts, 680 696 fibrogenic, fibrohistiocytic, and fibroosseous lesions, 674 meningioma, 678 679 osteoblastoma, 651 652 osteoblastoma, 670 674 osteoclastic giant-cell-rich tumors, 675 676 osteoid osteoma, 650f, 651 657, 670 674 osteoma, 648f, 649f, 651, 669 670, 669f vascular tumors, 676 Osteoid osteoma, 650f, 651 657, 670 674 Osteological paradox, 16 17, 814 Osteolytic lesions, 680, 699 701, 708f Osteolytic metastases, 699, 701f Osteolytic process, 711 Osteoma, 648f, 649f, 651, 669 670, 669f

834 Index

Osteomalacia, 135 136, 546 550, 546f, 549f histological image of interglobular dentin, 549f paleopathology, 547 550 sites for bone deformation and pseudofractures, 547t skeleton with severe pelvic, 548f Osteomyelitic tibia, 311 312 Osteomyelitis, 130, 135, 287 288, 297, 331, 339, 377, 387, 394 396, 412, 462 463, 633 634, 647 648 adult, 303 304 hematogenous, 297 301 infant, 301 303 paleopathology, 308 313 postcranial, 309 313 skull, 308 pathology, 297 variola, 459 Osteon, 49 Osteon population density (OPD), 95 Osteonecrosis, 492 494, 492t disorders associated with, 498 500 Freiberg’s disease of metatarsal head, 500 Ko¨hler’s disease of tarsal navicular, 499, 500f paleopathology, 493 494 Osteopathia striata, 636 Osteopenia, 367 368 in modern populations, 106 107 Osteopetrosis, 134 135, 630 632 malignant, 631 632 pathology, 630 632 Osteopoikilosis, 635 636 Osteoporosis, 177, 367 368, 531, 552 559 anteroposterior radiograph of long bones, 552f of three second metacarpals, 553f methods in study of osteoporosis in paleopathology, 553 556 in modern populations, 106 107 paleopathology, 556 559 bone mineral density, 557f healed compression fractures, 557f metacarpal cortical index, 558f Osteoprotegerin (OPG), 42, 106 Osteosarcoma, 132, 683f, 684 685, 691f, 692f, 693f Osterix, 42 OTUs. See Operational taxonomic units (OTUs) Overdispersion, 481, 482f Owen’s lines or contour lines of Owen, 752

P Paget’s disease, 76 78, 455 457, 456f, 457f, 458f, 459f, 460f, 461f, 462 463 sarcoma, 459 Paget’s disease of bone (PDB), 133 134 Pain, 28 29 Paleoanthropologists, 123, 211 Paleodietary reconstruction, 773 776 Paleoepidemiologists, 15 16

Paleoepidemiology, 14 17 and osteological paradox, 16 17 relationship between paleopathology and, 16 Paleopathological examination of mummies, 800 801 Paleopathological lesions, 29 30 Paleopathologists, 60 61, 480 Paleopathology, 11, 13 14, 351 363, 368 374, 369f, 381 382, 399 420, 422 426, 430 431, 483 484, 648 668, 696 711, 768 770, 778 781, 823. See also Themes in paleopathology abnormal quality of teeth, 752 754, 756 abnormal quantity of teeth and dental crowding, 758 759 abnormal size of teeth, 760 adult scurvy, 537 539 alveolar lesions, 767 768 of anemia, 514 517 aneurysmal erosion, 506 antemortem tooth loss, 770 771 brucellosis of vertebral bodies, 423f caries, 766 767 dental anomalies, 761 762 dental discoloration, 763 dental wear, 764 765 endocrine disturbances, 570 574, 579 583 extremities, 608 611 fluorosis, 559 561 mottled and pitted enamel on labial surfaces, 561f skeletal evidence, 560f, 561f future, 824 HFI, 562 historical documents, 399 400 history, 11 13 HOA, 503 imaging in medical imaging, 169 micro-CT, 178 MRI, 178 179 other bone changes and radiography, 176 177 principles and terminology, 169 173, 170t radiographic appearance of pathologic conditions, 174 176 radiology history in paleopathology, 169 taphonomic alterations, 177 178 large circumscribed, lytic lesion, 424f LCH, 508 Legg Calve´ Perthes Disease, 497 498 Le´Ri Weill dyschondrosteosis, 623 624 lumbar vertebral body of skeleton, 426f MED, 621 metaphyseal dysplasia, 633 methods in study of osteoporosis in, 553 556 bone quantity measurement, 555 556 molecular evidence, 402 of multicelled parasitic infections, 465 467 multifocal lytic lesions, 424f, 425f myeloma, 523 524

necrosis of femoral head, 495 new world evidence, 354 355 phylogeography of American tuberculosis, 355 pre-Columbian tuberculosis, 354 355 old world evidence, 351 354 multifocal tuberculosis, 353f Osgood Schlatter disease, 501 502 osteobiography in, 29 31 osteochondritis dissecans, 501 osteogenesis imperfecta, 628 630 osteogenic tumors, 668 669 osteomalacia, 547 550 of osteomyelitis, 308 313 osteonecrosis, 493 494 osteopathia striata, 636 osteoporosis, 556 559 pelvis, 604 606 periodontal disease, 771 periostosis, 291 296 progressive diaphyseal dysplasia, 634 of protozoan infections leishmaniasis, 468 malaria, 468 469 relationship between paleoepidemiology and, 16 rickets, 543 545 Scheuermann’s disease, 502 503 septic arthritis, 314 316 skeletal remains, 400 skull, 589 594 spine, 599 603 subadult scurvy, 534 537 barrow clump, burial 6010, 536f, 537f lesions in burial 6010 from barrow clump, 536t thanatophoric dwarfism, 617 621 theories of disease evolution, 400 402 trauma, 234 269 complications of fracture, 249 258, 258f dislocation (luxation) and subluxation, 258 259 fracture treatment, 246 249, 250f, 251f fractures resulting from accidental events, 242 246 fractures resulting from intentional violence, 235 242 hypertrophic bone development, 257f trauma and secondary osteoarthritis of knee, 254f of viral infections Paget’s disease, 462 463 poliomyelitis, 462 smallpox, 459 462 Parabolic index, 124 125 Paracoccidioidomycosis, 441 442 Paracoccidoidomycosis, 83 84, 86 “Paradox of plenty”, 135 Paralytic poliomyelitis, 462 Paramyxoviridae, 455 Parasites in feces, 199 Parasitic diseases, 802 Parasitology, 483 484 cemetery studies, 486 487

Index

chagas disease, mummies, and molecular biology, 483 484 Echinococcus granulosus, 479 481 Enterobius vermicularis, 481 483 lice reflect social organization, interaction, and privation, 484 486 medicines and dietary analysis, 485 486 Parathyroid glands, 567 Parathyroid hormone (PTH), 42, 91, 567, 577 Parathyroid hormone-related peptide (Ppr), 44 45 Paratyphi C genomes, 197 Paraxial mesoderm, 44 Parietal bones, 38, 62 Pars interarticularis, 730 Passive osteochondritis, 394 Pathogens, ancient DNA of, 191 195 brucellosis, 193 leprosy, 191 192 malaria, 194 syphilis, 194 195 TB, 192 193 Pathologic attrition, 764 Pathological fracture, 219, 220f Pathological periosteal bone, 292 293 Pathophysiology, 64 PCR. See Polymerase chain reaction (PCR) PDB. See Paget’s disease of bone (PDB) Pecos Pueblo, examination of pathology in, 14 Pediculus humanus, 198 199 Pelvic girdle ankle and tarsal bones, 337 338 hip, 332 337 knee, 337 tubular bones of hands and feet, 339 Pelvic osteomyelitis, 306 307 Pelvis, 603 606 paleopathology, 604 606 pathology, 603 604 Penetrating injuries, 220 221 Periapical cysts, 767 Perifocal osteosclerosis, 342 343 Perifocal sclerosis, 470 “Perilacunar remodeling”, 114 Perimortem trauma, 221, 236 Periodontal disease paleopathology, 771 pathology, 771 Periodontal ligament, 53 Periosteal blood vessels, 37 Periosteal bone deposition, 569 Periosteal new bone formation (PNBF), 537 Periosteum, 37, 221 Periostitis, 288 296 Periostosis, 288 296, 377, 462 463 of limb bones, 367 paleopathology, 291 296 bilateral midshaft thickening, 294f periosteal reactive bone on left ulna, 293f possible evidence of ulcer overlying left radius, 296f reactive periostosis to overlying skin ulcer, 297f

right adult tibia from Juhle Site in Maryland, 296f right and left tibiae of post-Columbian adult male skeleton, 294f in particular parts of skeleton, 289 290, 289f pathology, 288 289 Peripheral quantitative computed tomography (pQCT), 107 108 Permanent maxillary incisors, 365 366 Peruvian skull, 574 Pes equinovarus, 606 PH. See Porotic hyperostosis (PH) Phenol chloroform extraction method, 187 188 Phocomelia, 606 Phycomycosis. See Mucormycosis Pinta, 375 PIPs, 727 Pituitary disturbances, 567 570 acromegaly, 568 569 hypopituitarism, 569 pathology, 567 pituitary dwarfism, 569 570 pituitary gigantism, 567 568 Pituitary dwarfism, 569 570, 572 574 Pituitary gland, 567 Plague, 195 198, 430 431 paleopathology, 430 431 Plain radiography, 176 Plaque, 778 Plasmodium, 467 P. falciparum, 194, 467, 517 518 Platelets, 38 PNBF. See Periosteal new bone formation (PNBF) Pneumonia, 322 “Points of no return”, 64 65 Poliomyelitis, 453 455, 462 Polymerase chain reaction (PCR), 184 Polymorphonuclear leukocytes, 286 Population at risk, 14 15 Population level, 17 Porotic hyperostosis (PH), 22, 514 515, 516f, 811 lesions, 65 Postcranial osteomyelitis, 309 313 dactylitis of left metacarpals, 313f distance between distal harris lines and distal growth plate, 312t distance between Harris’ lines for right and left tibiae, 312t of left tibia, 311f metric comparisons of right and left tibiae, 311t of right and left tibia, 312f Postcranial skeleton, 293 Postmortem destruction, 420 destructive processes, 61 examination, 800 Postparalytic deformities, 611 of appendicular skeleton, 607 of spine, 599

835

Postparalytic foot deformity, 607 Pott’s disease, 76 78 Ppr. See Parathyroid hormone-related peptide (Ppr) pQCT. See Peripheral quantitative computed tomography (pQCT) Pre-Columbian tuberculosis, 354 355 Precipitants of OA, 724 725 Predynastic Egyptian skeleton, 611 Premature fusion of coronal suture, 594 of sutures of skull, 593 594 Premature suture closure, 587 Presumed “mechanostat”, 50 Primary benign tumors pathology, 648 649 chondrogenic tumors, 652 654 fibrogenic, fibrohistiocytic, and fibroosseous lesions, 657 658 osteogenic tumors, 649 651 Primary bone neoplasms, 643 645 Primary callus, 222 Primary hyperparathyroidism, 578 Primary malignant bone tumors pathology, 680 684 adamantinoma, 688 696, 689f chondrosarcoma, 686 687, 686f chordoma, 687 688 Ewing’s sarcoma of bone, 687, 688f osteosarcoma, 683f, 684 685 Primary OA, 721 722 Primary ossification, 45 46 Primary TB complex, 321 322 Pro-1 chain of type 1 collagen (COL1A1), 143 Pro-2 chain of type 1 collagen (CO1A2), 143 Progressive diaphyseal dysplasia, 633 634 Progressive massive osteolysis. See Vanishing bone disease Propionibacterium acne, 470 Protein analyses of dental calculus for bioarcheological research, 781 Proteinase K, 187 188 Protoscolices, 480 Protozoan infections paleopathology, 468 469 pathology leishmaniasis, 467 malaria, 467 468 Proximal left ulna, 412 “Pseudo-bowing”, 396 398 Pseudofractures, 546 547, 550f, 551f Pseudogout, 744 Pseudopathology, 86 Psoas abscess, 327 329 Psoriatic arthropathy, 736 739 Pteropus medius. See Fruit-eating bat (Pteropus medius) PTH. See Parathyroid hormone (PTH) Pthirus pubis. See Chimpanzee lice (Pthirus pubis) Pubic lice (P. pubis), 198 199 Pulmonary conditions, 503 Pulmonary hemorrhage, 802 Pyrophosphate crystals, 744

836 Index

Q Quantitative insights into microbial ecology (QIIME), 190 Quantitative PCR (qPCR), 184 185

R RA. See Rheumatoid arthritis (RA) Rachitic bone, 78 Radial deformities, 623 Radicular cysts, 768 769 Radiogrammetry, 107 108 Radiographic/radiography appearance of pathologic conditions, 174 176 mummies, paleopathology, and radiography, 176 other bone changes and, 176 177 techniques, 169 Radiology history in paleopathology, 169 “Radiopaedia”, 175 176 Radioulnar synostosis, 609 Ragsdale’s seven basic disease categories, 7 8, 8t Raman microspectroscopy, 110 Raman spectroscopy, 774 RANK, 42 RANKL. See Receptor activator of nuclear factor κ ligand (RANKL) Rathke’s pouch, 567 RCA. See Relative cortical area (RCA) Reactive arthropathy (ReA), 733 736 Reactive inflammation, 76 Reactive oxygen species (ROS), 140 Receptor activator of nuclear factor κ ligand (RANKL), 42 RANKL-OPG ratio, 84 Red bone marrow, 38 Reiter’s syndrome. See Reactive arthropathy (ReA) Relative cortical area (RCA), 123 124 Remodeling, 93 of BMU, 93 94 parameters application, 96 98, 97t “Reparative” dentin. See Tertiary dentin Reproductive stress, 106 Research methodology, 3 4 “Resorption bay”, 114 Reticuloendothelial disorders, 506 508 lipid storage diseases, 506 508 Retzius lines or striae of Retzius, 751 Reverse transcriptase PCR (RT-PCR), 184 RF. See Rheumatoid factor (RF) Rhabdomyosarcoma, 802 Rheumatoid arthritis (RA), 337, 552, 719 720, 732 733. See also Osteoarthritis (OA) Rheumatoid factor (RF), 733 Rhinomaxillary remodeling in skeleton, 370f Rib(s), 326, 343 344, 598, 603 fractures, 262 263 pathology and paleopathology, 603 reactive periostosis of pleural surface, 344f Ribbing disease, 633 634 Ribbon matching, 82

Rickets, 135 136, 540 545 cooccurrence, 551 552 ectocranial surface of cranial vault fragment, 542f left orbital roof, 542f paleopathology, 543 545 sternal rib-ends, 543f “Roadmap”, 1 ROS. See Reactive oxygen species (ROS) Rotator cuff disease, 729 RT-PCR. See Reverse transcriptase PCR (RT-PCR) Rubella, 452 453 Runt-related transcription factor 2 (Runx2), 42, 44, 630

S “Saber”, 380 Sacralization, 598 599 Sacroiliac joint, 39, 363 Sacrum, 355 356, 423 “Saddle nose” depression, 413 414 Salmonella enterica, 197 Salmonella typhi, 196 197 Sarcoidosis, 366 367, 470, 470f, 471f pathology, 470 471 Sarcomas, 643 Scalping, 264 266 Scanning electron microscopy-energy dispersive X-ray analysis (SEM-EDX analysis), 763 Scheuermann’s disease, 502 503, 503f paleopathology, 502 503 SCJ. See Sternoclavicular joint (SCJ) Sclerosing osteomyelitis of Garre´, 301 Sclerostin, 40 42 Scolices, 480 Scoliosis, 454 455, 596 601, 730 Scurvy, 532 cooccurrence, 551 552 line, 532 533 Sea spray effect, 773 Second-wave feminist theory, 25 Secondary callus, 223 Secondary hyperparathyroidism, 578 579 Secondary OA, 721 722, 724t Secondary osteons, 93 94 size and shape as toughening mechanisms, 117 120 changes with age, 119 120 mechanical strain directs threedimensional secondary osteon orientation, 118 119 small, circular osteons, 117 118 SEER. See Surveillance Epidemiology and End Result (SEER) Sella, 567 568 SEM-EDX analysis. See Scanning electron microscopy-energy dispersive X-ray analysis (SEM-EDX analysis) Sensitivity, 15 Septic arthritis, 313 316, 314f, 315f, 316f, 334 paleopathology, 314 316

pathology, 313 314 chronic osteomyelitis of left ilium, 314f chronic sclerosing osteomyelitis of left tibia, 315f Septic arthropathy, 745 Septic inflammation, 76 Sequestrum, 224 225 Sero-negative arthropathies, 732 743. See also Crystal arthropathies AS, 734 enteropathic arthropathy, 739 743 EOA, 743 general comments on, 743 psoriatic arthropathy, 736 739 ReA, 734 736 Sex, intersectionality of, 24 26 Sexual dimorphism in radial expansion, 120 121 in trabecular bone loss with age, 121 122 Shaft of long bones, 342 343 healed TB of distal femur with partial ankylosis, 343f tuberculosis of lateral epicondyle of right humerus, 342f of medial epicondyle of right humerus, 342f of proximal left ulna with extension, 342f of proximal radius, 343f Sharp-force injuries, 220 Shearing fractures, 216 Shh. See Sonic Hedgehog (Shh) Shigella dysenteriae, 196 197 Short tubular bones, 306 chronic osteomyelitis of right ilium, 307f osteomyelitis of basal phalanx, 307f of right scapula, 307f radiograph of hematogenous staphylococcic osteomyelitis, 306f Shotgun metagenomics, 190 191 Shotgun sequencing, 188 189 Shoulder, 339 340 cavitating TB of lateral portion of right clavicle, 340f joint, 725 726 tuberculosis of humeral head with cavitation, 340f Sickle cell anemia, 194, 339, 515 518 and genetic variants, 512 514, 514f SIDS. See Sudden infant death syndrome (SIDS) Silica-based extraction methods, 187 188 Silicosis, 802 803 Simple bone cysts, 666 667 Sincipital T-mutilation, 270 trauma to skeleton through cultural modifications, 270 273 “Singh index”, 177 Skeletal abnormalities, 626 Skeletal dysplasias, 65 66, 615 acromesomelia, 621 623 cleidocranial dysplasia, 630

Index

defects in endochondral bone formation, 616 621 defects in intramembranous bone formation, 627 630 Le´Ri Weill dyschondrosteosis, 623 624 MED, 621 melorheostosis, 634 635 metaphyseal dysplasia, 632 633 mucopolysaccharidosis, 624 627 osteopathia striata, 636 osteopetrosis, 630 632 osteopoikilosis, 635 636 progressive diaphyseal dysplasia, 633 634 Skeletal examples, 355 363 comparative measurements of left and right femur, 361t, 363t congenital syphilis, 402 408 L1 L5 vertebrae, 356f lateral radiograph of lower thoracic vertebrae, 358f left lateral view of T4 L3 vertebrae, 358f probable evidence of spinal TB, 356f probable spinal TB in archeological skeleton from Illinois, 360f slight to pronounced destruction of vertebral bodies, 359f TB of left hip in archeological skeleton, 362f resulting in destruction of left sacroiliac, 363f staphylococcal, or mycotic infection, 357f Skeletal indicators, 468 Skeletal lesions, 453 Skeletal morphology, 493 Skeletal pathologies, 17 Skeletal remains, 400 Skeletal studies, 25 Skeletal TB, 326 Skeletogenesis bone modeling, 44 48 embryological and developmental processes, 43 44 Skeleton, 421 periostosis in parts of, 289 290, 289f active manifestation of periostosis related to skin ulcer, 289f new bone formation on occipital bone, 292f ossifying periostosis of right tibia beneath leg ulcer, 290f periostosis resulting from overlying skin ulcer, 290f trauma to skeleton through cultural modifications, 270 273 cranial modification, 270 272 dental modification, 273 foot binding, 272 waist training, 272 273 Skull, 304 306, 304f, 305f, 308, 344 351, 382 387, 447 449, 457 458, 459f, 585 594 confluent caries sicca lesions of skull vault, 384f cranionasal tertiary syphilis, 386f, 387f

destructive remodeling of pyriform, 386f disseminated hematogenous osteomyelitis, 309f extensive tertiary syphilis of cranial vault, 384f frontonasal tertiary syphilis, 386f infectious defect of frontal bone, 385f nasomaxillary tertiary syphilis with extensive endonasal destruction, 386f osteomyelitis of cranial vault secondary to chronic ear infection, 306f paleopathology, 589 594 pathology, 585 588 tertiary syphilis of cranial vault, 383f, 384f, 385f of face, 383f of nasal cavity, 385f Slipped femoral capital epiphysis, 495 498, 499f Slipped femoral epiphyses, 621 Smallpox, 195 198, 450 452, 459 462, 463f “Snap” diagnoses, 81 Social and identity theory, 21 26, 29 30 feminist and gender theory, 22 24 intersectionality of sex, gender, and age, 24 26 Social groups, 25 Social status, 21 Solitary plasmacytoma, 520 Somatotrophic hormone, 567 Sonic Hedgehog (Shh), 44 SourceTracker method, 190 191 Sox11, 44 Sox12, 44 Sox4, 44 “Spanish” flu pandemic, 197 Specificity, 15 Sphenoid bone, 62 Sphenoidal sinus, 567 568 Sphenoparietal suture, 594 Spina Bifida, 594 596, 601 602 Spina bifida cystica, 594 596 Spina bifida occulta, 594 596 Spina ventosa, 326, 342 343 Spine, 306, 327 332, 387, 458, 594 603 distribution of lesions, 328f lumbosacral TB with kyphosis, 330f ossification in the wall of right tuberculous psoas abscess, 329f paleopathology, 599 603 pathology, 594 599 spinal TB healed with kyphosis, 329f partly healed, involving thoracic vertebrae, 328f without vertebral collapse, 331f tuberculosis of dorsolumbar spine, 328f tuberculosis of lumbar vertebrae, 330f tuberculosis with spinal and rib involvement, 332f Spoligotyping, 192 Spondyloarthropathies, 733 734 Spondyloepiphyseal dysplasia, 621 Spondylolisthesis, 730

837

Spondylolysis, 218, 599, 602 603, 730 Spongiosa sequestrum, 333 Sporotrichosis, 445 Sporotrichum schenckii, 445 Sporozoites, 468 SR. See Surface rendering (SR) Stable isotope analysis, 412 413 Staphylococci, 426 427 Staphylococcus aureus, 130, 297 Staphylococcus saprophyticus, 197 Sternoclavicular joint (SCJ), 727 Sternum, 326, 344, 345f, 603 pathology and paleopathology, 603 Strain-based mathematical model, 104 Streptococcus pneumoniae, 197 Stress, 105, 212 213, 213f and disease from chemical analyses, 776 777 fractures, 218, 245 Strontium (Sr), 775 Structural violence, 26, 261 264 child abuse, 262 263 elder abuse, 263 intimate partner abuse, 264 Stryphnodendron barbatiman, 485 486 Subadult scurvy, 532 537 anteroposterior radiograph of left knee, 533f cranial vault of infant, 535f endocranial surface of left sphenoid, 535f left side of cranium of child, 534f medial surface, right hemimandible from child, 535f paleopathology, 534 537 posterior part of right maxilla, 534f radiographic alterations, 532f sites for hemorrhagic lesions in infantile scurvy, 534t Subluxation, 230 233, 258 259 Subperiosteal bone formation, 577 Subungual exostosis, 657 660 Sudden infant death syndrome (SIDS), 272 “Sunburst” formations of spiculated new bone, 70 Supernumerary teeth, 630, 756 757 Suppurative arthritis, 451 Surface rendering (SR), 178 Surveillance Epidemiology and End Result (SEER), 684 Symphysis, 336 337 Syndesmophytes, 734 Syphilis, 194 195, 381 Syphilitic dactylitis, 398 399 Syphilitic lesion, 383 385 Syphilitic osteochondritis of distal femur, 394f

T T lymphocytes, 286 T1DM. See Type 1 diabetes mellitus (T1DM) T6 vertebral body, 82 T7 vertebrae, 82 T8 vertebra, 82 TA. See Terminologica Anatomica (TA) Talocalcaneal joint, 337 338

838 Index

Taphonomic alterations, 177 178 Taphonomic complications, 495 Taphonomic considerations, 234 Taphonomic processes, 92 Targeted capture, 185 Targeted enrichment. See Targeted capture Tarsal bones, 337 338, 338f Tarsal navicular, Ko¨hler’s disease of, 499, 500f Tartar. See Dental calculus TB. See Tuberculosis (TB) TD. See Treponemal disease (TD) Temporomandibular joint (TMJ), 729 Tension fractures, 214 Terminologica Anatomica (TA), 62 Tertiary bone lesions, 382 Tertiary dentin, 752 Testosterone, 577 Tetracycline, 762 TGF-β. See Tumor-growth factor-β (TGF-β) Thalassemia, 194, 509 512, 511f, 512f, 515 518 Thalassemia minor, 509 Thanatophoric dwarfism, 617 621, 618f Themes in paleopathology, 21 ancient humans and impairment, disability, and care, 26 29 osteobiography in paleopathology, 29 31 social and identity theory, 21 26 structural violence, 26 Thermal desorption/pyrolysis gas chromatography mass spectrometry (TD/ Py-GC-MS), 780 781 Third National Health and Nutrition Examination Survey (NHANES III), 106 107 Thoracic cavity cranial base, 347 348 cranial vault, 345 347 facial bones, 348 351 ribs, 343 344 skull, 344 351 sternum, 344 Three-dimensional imaging technology, 107 108 Thyroid stimulating hormone (TSH), 138 Thyroxine, 574 Tibia, 380, 458 Tibial lesions attributed to yaws or endemic syphilis, 420f Tibial tubercle, 501 Tibiotalar joint, 337 338 Time to most recent common ancestor (TMRCA), 191 Tissue histology, 801 TMJ. See Temporomandibular joint (TMJ) TMRCA. See Time to most recent common ancestor (TMRCA) TNF-α. See Tumor necrosis factor-α (TNF-α) Tomb A100E, adult male skeleton from, 604 605 Tomes’ process, 54 Tongue worm (Invavita piratica), 198 Tooth abnormal quality

paleopathology, 752 754, 756 pathology, 752 753, 755 756 abnormal quantity paleopathology, 758 759 pathology, 756 758 abnormal size paleopathology, 760 pathology, 759 760 morphogenesis, 53 55 structure and formation, 52 55 dentin, 52 53 enamel, 52 periodontal ligament and cementum, 53 wear, 764 Torsion fractures, 215 Torus palatinus, 769 770 Toughness of bone, 105 in fracture resistance, 105 106 Toxic inflammation, 76 Trabeculae, 38 “Trabecular atrophy”, 138 Trace elements, 775 in bioarcheological research, 775 776 Traditional Sanger sequencing, 185 Transamination process, 774 Transient cranial periostosis, 382 Transiliac biopsy, 137 138 Transitory periosteal reaction, 288 289 Trauma, 367 368, 498 diseases associating with aneurysmal erosion, 504 506 hypertrophic osteoarthropathy, 503, 504f Osgood Schlatter disease, 501 502, 502f osteochondritis dissecans, 500 501, 501f Scheuermann’s disease, 502 503, 503f fracture, 212 273, 214f, 224f, 246f recording, 233 234 mortality, and violence in past societies, 260 269 paleopathology, 234 269 sincipital T-mutilation, 270 subluxation and dislocation, 231 233 Traumatic AVN of femoral head, 495 Traumatic injuries, 68 69 Traumatic surgical interventions, 267 269 Trepanation, 267 269 Trephination, 212, 268f, 269f Treponarid, 380 Treponema carateum, 194 Treponema pallidum, 194 Treponemal disease (TD), 321, 375 420 pathology, 376 399 in skeleton, 418f venereal syphilis, 414f, 416f Treponematosis, 375 420 Triiodothyronine, 574 “Trowel trauma” resemble, 61 True negative rate. See Specificity True positive rate. See Sensitivity Tru¨mmerfeld zone, 532 533 Trypanosoma cruzi, 483 TSH. See Thyroid stimulating hormone (TSH) Tubercle bacilli, 326

Tuberculosis (TB), 15, 83 84, 183, 192 193, 321, 333 334, 451 452, 802, 812 general pattern of bone and joint tuberculosis, 323 351 pathology, 321 322 spine, 327 332 statistical data, 322 323 Tuberculous arthritis, 326 Tuberculous dactylitis (spina ventosa), 339f Tuberculous spondylitis. See Vertebral TB Tuberculous tenosynovitis, 340 342 Tubular bones of hands and feet, 339 Tumor, 640 cell signature, 687 688 Tumor necrosis factor-α (TNF-α), 131 Tumor-growth factor-β (TGF-β), 42 Turner’s syndrome, 582 Type 1 diabetes mellitus (T1DM), 139 Type 2 diabetes mellitus (T2DM), 139 Type I osteogenesis imperfecta, 627 Type II osteogenesis imperfecta, 627 628 Type III osteogenesis imperfecta, 628 Type IV osteogenesis imperfecta, 628 Type-I collagen, 78

U Ulcer of heel in leprosy, 366f Ulna, 387 389 Ultraviolet light (UV light), 187 Underground storage organs (USOs), 780 Unilateral paravertebral, 327 Upper limb elbow, 340 shaft of long bones, 342 343 shoulder, 339 340 wrist and carpal bones, 340 342 Urbanism, 351 354 “Utah Paradigm”, 93

V Vanishing bone disease, 73 76 Variola, 450 452 Variola osteomyelitis, 451, 451f Variola virus (VARV), 450 451 Vascular changes in response to infectious agents, 286 287 Vascular deficiency, diseases associating with, 500 506 Vascular diseases, 801 802 Vascular porosity reflecting resorption activity, 114 116 changes with age, 115 116 regional mechanical strain, 114 115 Vascular tumors epithelioid hemangioma, 664 665 hemangioma and vascular anomalies, 676 678 hemangioma and vascular malformations, 664 Venereal syphilis (VS), 376, 381 393. See also Congenital syphilis (CS) congenital syphilis, 393 399

Index

joints, 391 393 long bones, 387 390 paleopathology, 399 420 primary and secondary stages, 381 393 skeletal examples, 402 420 skull, 382 387 spine, 387 tertiary stage, 381 Vertebrae, 326, 417, 464 465 Vertebral body resorption, 442 Vertebral column, 35 36, 356 357 Vertebral lesions, 83 84, 470 471 Vertebral osteomyelitis, 306 Vertebral TB, 327 Vertebrate skeleton, evolution of, 35 36 Vertebrates, 35 Vibrio cholerae, 196 197 Violence in past societies, 260 269 organized violence, 261 structural violence, 261 264 traumatic surgical interventions, 267 269 violence directed toward corpses, 264 266 Viral infections, 286 287, 450. See also Bacterial infections paleopathology of viral infections, 459 463 pathology, 450 459 flat bones, 458 long bones, 458 Paget’s disease, 455 457 Paget’s disease sarcoma, 459 poliomyelitis, 453 455

rubella, 452 453 skull, 457 458 smallpox, 450 452 spine, 458 Visceral leishmaniasis, 467 Visceral organ diseases, 802 803 Vitamin C deficiency, 532 Vitamin D, 135 136 deficiency, 540, 547 548 “Volkmann’s canals”, 114 115 Von Ebner’s lines, 750 VS. See Venereal syphilis (VS)

W Waist training, 272 273 “Water-on-the-brain”, 587 Weaning patterns, 776 “Wear”, 764 Whipworm (Trichuris trichiura), 486 White blood cells, 38 White line of Fra¨nkel, 532 533 Wilson bands, 753 Wnt proteins, 40 42 Wnt/b-catenin pathway, 40 42, 78 Wolff’s law, 68 Wooden digging tools, 61 World Health Organization (WHO), 106 107, 211 212, 263, 321, 555, 643 645, 666 Wormseed (Chenopodium ambrosioides), 485 “Woven bone”, 69 70, 288, 288f Wrist

839

bones, 340 342, 341f joints, 727

X X-linked acrogigantism (X-LAG), 567 568 X-linked cases osteopetrosis (XLO), 134 X-linked hypophosphatemia, 136 X-rays technique, 169

Y Yaral, 21 Yaws, 375 380 dactylitis of right hand, 377f diaphyseal destruction of middle phalanx, 379f radiograph of osteomyelitis from yaws, 378f of saber tibia in yaws, 378f Yersinia pestis, 183 184, 195 196, 815

Z Zinc (Zn), 775 Zooarcheological paleopathology, 809 Zooarcheologists, 815 Zooarcheology, 810 811 Zoonoses, 351 Zoonotic diseases, 420 421 Zygomatic arch, 348 351 Zygomycosis. See Mucormycosis