Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism

Eighth Edition

An Offi cial Publication of the American Society for Bone and Mineral Research

Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism

Eighth Edition

Editor-in-Chief

Clifford J. Rosen , MD

Senior Associate Editors Roger Bouillon , MD, PhD, FRCP Juliet E. Compston , MD, FRCP, FRCPath, FMedSci Vicki Rosen , PhD

Associate Editors Douglas C. Bauer , MD Marie Demay , MD Theresa A. Guise , MD Suzanne M. Jan de Beur , MD Richard W. Keen , MD, PhD Karen M. Lyons , PhD Laurie K. McCauley , DDS, MS, PhD Paul D. Miller , MD, FACP Socrates E. Papapoulos , MD, PhD Ego Seeman , BSc, MBBS, FRACP, MD Rajesh V. Thakker, MD, ScD, FRCP, FRCPath, FMedSci Mone Zaidi , MBBS, PhD

A John Wiley & Sons, Inc., Publication This edition fi rst published 2013 by John Wiley & Sons, Inc. © 2013 by American Society for Bone and Mineral Research First Edition published by American Society for Bone and Mineral Research © 1990 American Society for Bone and Mineral Research Second Edition published by Raven Press, Ltd. © 1993 American Society for Bone and Mineral Research Third Edition published by Lippincott-Raven Publishers © 1996 American Society for Bone and Mineral Research Fourth Edition published by Lippincott Williams & Wilkins © 1999 American Society for Bone and Mineral Research Fifth Edition published by American Society for Bone and Mineral Research © 2003 American Society for Bone and Mineral Research Sixth Edition published by American Society for Bone and Mineral Research © 2006 American Society for Bone and Mineral Research Seventh Edition published by American Society for Bone and Mineral Research © 2008 American Society for Bone and Mineral Research

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Library of Congress Cataloging-in-Publication Data

Primer on the metabolic bone diseases and disorders of mineral metabolism. – 8th ed. / editor-in-chief, Clifford J. Rosen; senior associate editors, Roger Bouillon, Juliet E. Compston, Vicki Rosen; associate editors, Douglas C. Bauer . . . [et al.]. p. ; cm. Previous editions published by American Society for Bone and Mineral Research. Includes bibliographical references and index. ISBN 978-1-118-45388-9 (softback : alk. paper) – ISBN 978-1-118-45389-6 (eMobi) – ISBN 978-1-118-45390-2 (ePDF) – ISBN 978-1-118-45391-9 (ePub) – ISBN 978-1-118-45392-6 I. Rosen, Clifford J. II. American Society for Bone and Mineral Research. [DNLM: 1. Bone Diseases, Metabolic. 2. Bone and Bones–metabolism. 3. Minerals–metabolism. WE 250] RC931.M45 616.7 '16–dc23 2013002831

A catalogue record for this book is available from the British Library.

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Cover image: Copyright Tobi Kahn, NEBILA, 1990, Acrylic on canvas over wood, 70 × 24 inches. Cover design by Nicole Teut

Set in 9.5/11 pt Trump Mediaeval by Toppan Best-set Premedia Limited

1 2013 Contents

Contributors x 10 Neuronal Regulation of Bone Remodeling 82 Primer Corporate Sponsors xxii Florent Elefteriou and Gerard Karsenty Preface to the Eighth Edition of the Primer: Clifford J. Rosen xxiii 11 Skeletal Healing 90 About ASBMR xxiv Michael J. Zuscik President’s Preface: Lynda F. Bonewald xxv About the Companion Website xxvi 12 Biomechanics of Fracture Healing 99 Elise F. Morgan and Thomas A. Einhorn

Section I: Molecular, Cellular, and Genetic 13 Human Genome-Wide Association (GWA) Determinants of Bone Structure and Formation 1 Studies 106 Section Editor Karen M. Lyons Douglas P. Kiel

1 Skeletal Morphogenesis and Embryonic 14 Circulating Osteogenic Cells 111 Development 3 Robert J. Pignolo and Moustapha Kassem Yingzi Yang

2 Signal Transduction Cascades Controlling Osteoblast Differentiation 15 Section II: Skeletal Physiology 119 David J.J. de Gorter and Peter ten Dijke Section Editor Ego Seeman

3 Osteoclast Biology and Bone Resorption 25 15 Human Fetal and Neonatal Bone F. Patrick Ross Development 121 Tao Yang, Monica Grover, Kyu Sang Joeng, and Brendan Lee 4 Osteocytes 34 Lynda F. Bonewald 16 Skeletal Growth and Peak Bone Strength 127 5 Connective Tissue Pathways That Regulate Qingju Wang and Ego Seeman Growth Factors 42 Gerhard Sengle and Lynn Y. Sakai 17 Ethnic Differences in Bone Acquisition 135 Shane A. Norris, Lisa K. Micklesfi eld, 6 The Composition of Bone 49 and John M. Pettifor Adele L. Boskey and Pamela Gehron Robey 18 Calcium and Other Nutrients 7 Assessment of Bone Mass and Microarchitecture During Growth 142 in Rodents 59 Tania Winzenberg and Graeme Jones Blaine A. Christiansen 19 Growing a Healthy Skeleton: The Importance 8 Animal Models: Genetic Manipulation 69 of Mechanical Loading 149 Karen M. Lyons Mark R. Forwood

9 Animal Models: Allelic Determinants for BMD 76 20 Pregnancy and Lactation 156 Robert D. Blank Christopher S. Kovacs and Henry M. Kronenberg

v vi Contents

21 Menopause 165 34 FRAX®: Assessment of Fracture Risk 289 Ian R. Reid John A Kanis

35 Biochemical Markers of Bone Turnover in Section III: Mineral Homeostasis 171 Osteoporosis 297 Section Editor Ego Seeman Pawel Szulc, Douglas C. Bauer, and Richard Eastell 22 Regulation of Calcium and Magnesium 173 Murray J. Favus and David Goltzman 36 Bone Biopsy and Histomorphometry in Clinical Practice 307 Robert R. Recker 23 Fetal Calcium Metabolism 180 Christopher S. Kovacs 37 Diagnosis and Classifi cation of Vertebral Fracture 317 24 Fibroblast Growth Factor-23 (FGF23) 188 James F. Griffi th, Judith E. Adams, Kenneth E. White and Michael J. Econs and Harry K. Genant

25 Gonadal Steroids 195 38 Approaches to Genetic Testing 336 Stavros C. Manolagas, Maria Almeida, Christina Jacobsen, Yiping Shen, and Robert L. Jilka and Ingrid A. Holm

26 Parathyroid Hormone 208 Robert A. Nissenson and Harald Jüppner Section V: Osteoporosis 343 Section Editors Paul D. Miller and Socrates E. Papapoulos 27 Parathyroid Hormone-Related Protein 215 John J. Wysolmerski 39 Osteoporosis Overview 345 Michael Kleerekoper 28 Ca2+-Sensing Receptor 224 Edward M. Brown 40 The Epidemiology of Osteoporotic Fractures 348 Nicholas Harvey, Elaine Dennison, 29 Vitamin D: Production, Metabolism, Mechanism and Cyrus Cooper of Action, and Clinical Requirements 235 Daniel Bikle, John S. Adams, and Sylvia Christakos 41 Overview of Pathogenesis 357 Ian R. Reid

Section IV: Investigation of Metabolic 42 Nutrition and Osteoporosis 361 Bone Diseases 249 Connie M. Weaver and Robert P. Heaney Section Editor Douglas C. Bauer 43 The Role of Sex Steroids in the Pathogenesis 30 DXA in Adults and Children 251 of Osteoporosis 367 Glen Blake, Judith E. Adams, and Nick Bishop Matthew T. Drake and Sundeep Khosla

31 Quantitative Computed Tomography in Children 44 Translational Genetics of Osteoporosis: and Adults 264 From Population Association to Individualized C.C. Glüer Prognosis 376 Bich H. Tran, Jacqueline R. Center, and Tuan V. Nguyen 32 Magnetic Resonance Imaging of Bone 277 Sharmila Majumdar 45 Prevention of Falls 389 Heike A. Bischoff-Ferrari 33 Radionuclide Scintigraphy in Metabolic Bone Disease 283 Gary J.R. Cook, Gopinath Gnanasegaran, 46 Exercise and the Prevention of Osteoporosis 396 and Ignac Fogelman Clinton T. Rubin, Janet Rubin, and Stefan Judex Contents vii

47 Calcium and Vitamin D 403 62 Osteoporosis in Men 508 Bess Dawson-Hughes Eric S. Orwoll

48 Estrogens, Estrogen Agonists/Antagonists, 63 Premenopausal Osteoporosis 514 and Calcitonin 408 Adi Cohen and Elizabeth Shane Nelson B. Watts 64 Skeletal Effects of Drugs 520 49 Bisphosphonates for Postmenopausal Juliet Compston Osteoporosis 412 Socrates E. Papapoulos 65 Orthopedic Surgical Principles of Fracture Management 527 50 Denosumab 420 Manoj Ramachandran and David G. Little Michael R. McClung 66 Abnormalities in Bone and Calcium Metabolism 51 Parathyroid Hormone Treatment After Burns 531 for Osteoporosis 428 Gordon L. Klein Felicia Cosman and Susan L. Greenspan

52 Strontium Ranelate in the Prevention Section VI: Disorders of Mineral Homeostasis 535 of Osteoporotic Fractures 437 Section Editors Marie Demay and Suzanne M. Jan de Beur René Rizzoli

67 Approach to Parathyroid Disorders 537 53 Combination Anabolic and Antiresorptive John P. Bilezikian Therapy for Osteoporosis 444 John P. Bilezikian and Natalie E. Cusano 68 Primary Hyperparathyroidism 543 Shonni J. Silverberg 54 Compliance and Persistence with Osteoporosis Medications 448 Deborah T. Gold 69 Familial Primary Hyperparathyroidism (Including MEN, FHH, and HPT-JT) 553 Andrew Arnold and Stephen J. Marx 55 Cost-Effectiveness of Osteoporosis Treatment 455 Anna N.A. Tosteson 70 Non-Parathyroid Hypercalcemia 562 Mara J. Horwitz, Steven P. Hodak, and Andrew F. Stewart 56 Future Therapies of Osteoporosis 461 Kong Wah Ng and T. John Martin 71 Hypocalcemia: Defi nition, Etiology, Pathogenesis, Diagnosis, and Management 572 57 Juvenile Osteoporosis 468 Anne L. Schafer and Dolores Shoback Nick Bishop and Francis H. Glorieux

72 Hypoparathyroidism and 58 Glucocorticoid-Induced Bone Disease 473 Pseudohypoparathyroidism 579 Robert S. Weinstein Mishaela R. Rubin and Michael A. Levine

59 Infl ammation-Induced Bone Loss 73 Pseudohypoparathyroidism 590 in the Rheumatic Diseases 482 Harald Jüppner and Murat Bastepe Steven R. Goldring

74 Disorders of Phosphate Homeostasis 601 60 Secondary Osteoporosis: Other Causes 489 Mary D. Ruppe and Suzanne M. Jan de Beur Neveen A.T. Hamdy 75 Vitamin D–Related Disorders 613 61 Transplantation Osteoporosis 495 Paul Lips, Natasja M. van Schoor, Peter R. Ebeling and Nathalie Bravenboer viii Contents

76 Vitamin D Insuffi ciency and Defi ciency 624 90 Treatment and Prevention of Bone Metastases and J. Christopher Gallagher Myeloma Bone Disease 741 Jean-Jacques Body 77 Pathophysiology of Chronic Kidney Disease Mineral Bone Disorder (CKD–MBD) 632 91 Radiotherapy of Skeletal Metastases 754 Keith A. Hruska and Michael Seifert Edward Chow, Luluel M. Khan, and Øyvind S. Bruland 78 Treatment of Chronic Kidney Disease Mineral Bone Disorder (CKD–MBD) 640 92 Concepts and Surgical Treatment of Metastatic Hala M. Alshayeb and L. Darryl Quarles Bone Disease 760 Kristy Weber and Scott L. Kominsky 79 Disorders of Mineral Metabolism in Childhood 651 Thomas O. Carpenter Section VIII: Sclerosing and Dysplastic Bone Diseases 767 Section Editor Richard W. Keen 80 Paget’s Disease of Bone 659 Ethel S. Siris and G. David Roodman 93 Sclerosing Bone Disorders 769 Michael P. Whyte

Section VII: Cancer and Bone 669 Section Editor Theresa A. Guise 94 Fibrous Dysplasia 786 Michael T. Collins, Mara Riminucci, and Paolo Bianco 81 Overview of Mechanisms in Cancer Metastases to Bone 671 Gregory A. Clines 95 Osteochondrodysplasias 794 Yasemin Alanay and David L. Rimoin

82 Clinical and Preclinical Imaging in Osseous 96 Ischemic and Infi ltrative Disorders 805 Metastatic Disease 677 Richard W. Keen Geertje van der Horst and Gabri van der Pluijm

97 Tumoral Calcinosis—Dermatomyositis 810 83 Metastatic Solid Tumors to Bone 686 Nicholas Shaw Rachelle W. Johnson and Julie A. Sterling

98 Fibrodysplasia Ossifi cans Progressiva 815 84 Hematologic Malignancies and Bone 694 Frederick S. Kaplan, Robert J. Pignolo, Rebecca Silbermann and G. David Roodman and Eileen M. Shore

85 Osteogenic Osteosarcoma 702 99 Osteogenesis Imperfecta 822 Jianning Tao, Yangjin Bae, Lisa L. Wang, Joan C. Marini and Brendan Lee

100 Skeletal Manifestations in Marfan Syndrome and 86 Skeletal Complications of Breast and Prostate Related Disorders of the Connective Tissue 830 Cancer Therapies 711 Emilio Arteaga-Solis and Francesco Ramirez Catherine Van Poznak and Pamela Taxel

101 Enzyme Defects and the Skeleton 838 87 Bone Cancer and Pain 720 Michael P. Whyte Patrick W. O’Donnell and Denis R. Clohisy

88 Radiation Therapy-Induced Osteoporosis 728 Section IX: Approach to Nephrolithiasis 843 Jeffrey S. Willey, Shane A.J. Lloyd, Section Editor Rajesh V. Thakker and Ted A. Bateman 102 Renal Tubular Physiology of Calcium 89 Skeletal Complications of Childhood Cancer 734 Excretion 845 Ingrid A. Holm Peter A. Friedman and David A. Bushinsky Contents ix

103 Epidemiology of Nephrolithiasis 856 Section XI: The Skeleton and Its Integration Murray J. Favus with Other Tissues 959 Section Editor Mone Zaidi 104 Diagnosis and Evaluation of Nephrolithiasis 860 Stephen J. Knohl and Steven J. Scheinman 115 Central Neuronal Control of Bone Remodeling 961 105 Kidney Stones in the Pediatric Patient 869 Shu Takeda and Paul Baldock Amy E. Bobrowski and Craig B. Langman 116 The Pituitary–Bone Connection 969 106 Treatment of Renal Stones 878 Mone Zaidi, Tony Yuen, Li Sun, Terry F. Davies, John R. Asplin Alberta Zallone, and Harry C. Blair

107 Genetic Basis of Renal Stones 884 117 Skeletal Muscle Effects on the Skeleton 978 Rajesh V. Thakker William J. Evans

118 Glucose Control and Integration Section X: Oral and Maxillofacial Biology by the Skeleton 986 and Pathology 893 Patricia Ducy and Gerard Karsenty Section Editor Laurie K. McCauley 119 Obesity and Skeletal Mass 993 108 Development of the Craniofacial Skeleton 895 Sue Shapses and Deeptha Sukumar Maiko Matsui and John Klingensmith 120 Neuropsychiatric Disorders 109 Development and Structure of Teeth and and the Skeleton 1002 Periodontal Tissues 904 Itai Bab and Raz Yirmiya Petros Papagerakis and Thimios Mitsiadis 121 Vascular Disease and the Skeleton 1012 110 Craniofacial Disorders Affecting the Dentition: Dwight A. Towler Genetic 914 Yong-Hee P. Chun, Paul H. Krebsbach, 122 Spinal Cord Injury: Skeletal Pathophysiology and and James P. Simmer Clinical Issues 1018 William A. Bauman and Christopher P. Cardozo 111 Pathology of the Hard Tissues of the Jaws 922 Paul C. Edwards 123 Hematopoiesis and Bone 1028 Benjamin J. Frisch and Laura M. Calvi 112 Bisphosphonate-Associated Osteonecrosis of the Jaws 929 124 Bone and Immune Cell Interactions 1036 Hani H. Mawardi, Nathaniel S. Treister, Brendan F. Boyce and Sook-Bin Woo

113 Periodontal Diseases and Oral Bone Loss 941 Index 1043 Mary G. Lee and Keith L. Kirkwood

114 Oral Manifestations of Metabolic Bone Diseases 948 Roberto Civitelli and Charles Hildebolt Contributors

John S. Adams, MD John R. Asplin, MD, FASN Departments of Orthopaedic Surgery, Medicine and Litholink Corporation Molecular Cell and Developmental Biology and Department of Medicine University of California-Los Angeles University of Chicago Pritzker School of Medicine Los Angeles, California, USA Chicago, Illinois, USA

Judith E. Adams, MD Itai Bab Department of Clinical Radiology Bone Laboratory Manchester Academic Health Science Centre The Hebrew University of Jerusalem Central Manchester University Hospitals NHS Jerusalem, Israel Foundation Trust The Royal Infi rmary Yangjin Bae Manchester, UK Departments of Molecular and Human Genetics Baylor College of Medicine Yasemin Alanay, MD, PhD Texas Children’ s Hospital Pediatric Genetics Unit Houston, Texas, USA Department of Pediatrics Acibadem University School of Medicine Paul Baldock, PhD Istanbul, Turkey Bone and Mineral Research Program Garvan Institute of Medical Research Maria Almeida St. Vincent’ s Hospital Division of Endocrinology and Metabolism Sydney, Australia Center for Osteoporosis and Metabolic Bone Diseases University of Arkansas for Medical Sciences Murat Bastepe, MD, PhD and the Central Arkansas Veterans Healthcare System Endocrine Unit Little Rock, Arkansas, USA Department of Medicine Massachusetts General Hospital Hala M. Alshayeb, MD Harvard Medical School Division of Nephrology Boston, Massachusetts, USA Department of Medicine Hashemite University Ted A. Bateman Zarqa, Jordan Departments of Biomedical Engineering and Radiation Oncology Andrew Arnold, MD University of North Carolina Center for Molecular Medicine and Division of Chapel Hill, North Carolina, USA Endocrinology and Metabolism University of Connecticut School of Medicine Douglas C. Bauer, MD Farmington, Connecticut, USA Departments of Medicine and Epidemiology and Biostatistics Emilio Arteaga-Solis, MD, PhD University of California, San Francisco Pediatrics Pulmonary Division San Francisco, California, USA Department of Pediatrics Columbia University College of Physician and Surgeons New York, New York, USA

x Contributors xi

William A. Bauman, MD Robert D. Blank, MD, PhD Department of Veterans Affairs Rehabilitation Research Division of Endocrinology and Development Service Department of Medicine National Center of Excellence for the Medical Medical College of Wisconsin Consequences of Spinal Cord Injury Milwaukee, Wisconsin, USA and Medical Service James J. Peters Veterans Affairs Medical Center Amy E. Bobrowski, MD, MSCI Bronx, New York, USA Feinberg School of Medicine Departments of Medicine and Rehabilitation Medicine Northwestern University The Mount Sinai School of Medicine Chicago, Illinois, USA New York, New York, USA Jean-Jacques Body, MD, PhD Paolo Bianco University Hospital Brugmann Dipartimento di Medicina Molecolare Université Libre de Bruxelles (U.L.B.) Internal Medicine Universita’ La Sapienza Brussels, Belgium Rome, Italy Lynda F. Bonewald, PhD Daniel Bikle, MD, PhD Department of Oral Biology Department of Medicine University of Missouri at Kansas City School of Division of Endocrinology Dentistry VA Medical Center and Kansas City, Missouri, USA University of California, San Francisco San Francisco, California, USA Adele L. Boskey, PhD Research Division John P. Bilezikian Hospital for Special Surgery Division of Endocrinology and Department of Biochemistry and Graduate Field of Department of Medicine Physiology, Biophysics, and Systems Biology College of Physicians and Surgeons Cornell University Medical and Graduate Medical Columbia University Schools New York, New York, USA New York, New York, USA

Heike A. Bischoff-Ferrari, MD, DrPH Roger Bouillon, MD, PhD, FRCP Centre on Aging and Mobility Department of Endocrinology University of Zurich, Switzerland KU Leuven Jean Mayer USDA Human Nutrition Gasthuisberg, Belgium Research Center on Aging Tufts University Brendan F. Boyce, MBChB Boston, Massachusetts, USA Department of Pathology and Laboratory Medicine and The Center for Musculoskeletal Research Nick Bishop, MB, ChB, MRCP, MD, FRCPCH University of Rochester Medical Center Academic Unit of Child Health Rochester, New York, USA Department of Human Metabolism University of Sheffi eld Nathalie Bravenboer, PhD Sheffi eld Children’ s Hospital Department of Clinical Chemistry Sheffi eld, UK VU University Medical Center Amsterdam, The Netherlands Harry C. Blair The Pittsburgh VA Medical Center Edward M. Brown, MD and Departments of Pathology and of Cell Biology Division of Endocrinology, Diabetes and Hypertension University of Pittsburgh School of Medicine Brigham and Women’ s Hospital and Harvard Medical Pittsburgh, Pennsylvania, USA School Boston, Massachusetts, USA Glen Blake, PhD Osteoporosis Research Unit Øyvind S. Bruland, MD, PhD King ’ s College London Institute of Clinical Medicine, University of Oslo Guy ’ s Campus Department of Oncology, The Norwegian Radium London, UK Hospital Oslo University Hospital Oslo, Norway xii Contributors

David A. Bushinsky, MD Yong-Hee P. Chun, DDS, MS, PhD Nephrology Division Department of Periodontics University of Rochester School of Medicine and University of Texas Health Science Center at San Dentistry Antonio Rochester, New York, USA San Antonio, Texas, USA

Laura M. Calvi, MD Roberto Civitelli, MD Endocrine Metabolism Division Division of Bone and Mineral Diseases Department of Medicine Department of Internal Medicine University of Rochester School of Medicine and Musculoskeletal Research Center Dentistry Washington University in St. Louis Rochester, New York, USA St. Louis, Missouri, USA

Christopher P. Cardozo, MD Gregory A. Clines, MD, PhD Department of Veterans Affairs Rehabilitation Research Department of Medicine and Development Service Division of Endocrinology, Diabetes, and Metabolism National Center of Excellence for the Medical University of Alabama at Birmingham Consequences of Spinal Cord Injury, and Veterans Affairs Medical Center and Medical Service Birmingham, Alabama, USA James J. Peters Veterans Affairs Medical Center Bronx, New York, USA Denis R. Clohisy Departments of Medicine and Rehabilitation Medicine Department of Orthopaedic Surgery and Masonic The Mount Sinai School of Medicine Cancer Center New York, New York, USA University of Minnesota School of Medicine Minneapolis, Minnesota, USA Thomas O. Carpenter, MD Yale University School of Medicine Adi Cohen, MD, MHSc New Haven, Connecticut, USA Division of Endocrinology Department of Medicine Jacqueline R. Center, MBBS, MS (epi), PhD, FRACP College of Physicians and Surgeons Osteoporosis and Bone Biology Columbia University Garvan Institute of Medical Research New York, New York, USA St. Vincent’s Hospital Clinical School Department of Medicine Michael T. Collins, MD University of NSW Skeletal Clinical Studies Unit Sydney, Australia Craniofacial and Skeletal Diseases Branch National Institute of Dental and Craniofacial Research Edward Chow, MBBS, MSc, PhD, FRCPC National Institutes of Health Department of Radiation Oncology Department of Health and Human Services University of Toronto Bethesda, Maryland, USA Sunnybrook Research Institute Odette Cancer Centre Juliet E. Compston, MD, FRCP, FRCPath, FMedSci Sunnybrook Health Sciences Centre Department of Medicine Toronto, Ontario, Canada University of Cambridge Cambridge, UK Sylvia Christakos, PhD Department of Biochemistry and Molecular Biology Gary J.R. Cook, MBBS, MSc, MD, FRCR, FRCP UMDNJ–New Jersey Medical School Division of Imaging Sciences and Biomedical Newark, New Jersey, USA Engineering Kings College London Blaine A. Christiansen, PhD London, UK Department of Orthopaedic Surgery University of California Cyrus Cooper, MA, DM, FRCP, FFPH, FMedSci Davis Medical Center The MRC Lifecourse Epidemiology Unit Sacramento, California, USA University of Southampton Southampton General Hospital Southampton, UK Contributors xiii

Felicia Cosman Peter R. Ebeling, MD, FRACP Columbia College of Physicians and Surgeons Australian Institute for Musculoskeletal Science Columbia University NorthWest Academic Centre Clinical Research Center The University of Melbourne Helen Hayes Hospital Western Health West Haverstraw St. Albans, Victoria, Australia New York, New York, USA Michael J. Econs, MD, FACP, FACE Natalie E. Cusano Endocrinology and Metabolism Division of Endocrinology Medicine and Medical and Molecular Genetics Department of Medicine Indiana University School of Medicine College of Physicians and Surgeons Indianapolis, Indiana, USA Columbia University New York, New York, USA Paul C. Edwards, MSc, DDS, FRCD(C) Department of Periodontics and Oral Medicine Terry F. Davies, MBBS, MD, FRCP, FACE School of Dentistry The Mount Sinai Bone Program University of Michigan Department of Medicine Ann Arbor, Michigan, USA Mount Sinai School of Medicine New York, New York, USA Thomas A. Einhorn, MD Department of Orthopaedic Surgery Bess Dawson-Hughes, MD Boston University Medical Center Jean Mayer USDA Human Nutrition Boston, Massachusetts, USA Research Center on Aging Tufts University Florent Elefteriou, PhD Boston, Massachusetts, USA Vanderbilt Center for Bone Biology Vanderbilt University Medical Center David J.J. de Gorter, PhD Nashville, Tennessee, USA Institute for Molecular Cell Biology University of Münster William J. Evans, PhD Münster, Germany Muscle Metabolism DPU GlaxoSmithKline Marie Demay, MD Research Triangle Park, North Carolina, USA Endocrine Unit Massachusetts General Hospital and Harvard Medical Murray J. Favus, MD School Section of Endocrinology, Diabetes, and Metabolism Boston, Massachusetts, USA The University of Chicago Chicago, Illinois, USA Elaine Dennison, MA, MB, BChir, MSc, PhD The MRC Lifecourse Epidemiology Unit Ignac Fogelman University of Southampton Division of Imaging Sciences and Biomedical Southampton General Hospital Engineering Southampton, UK Kings College London London, UK Matthew T. Drake, MD, PhD Department of Internal Medicine Mark R. Forwood, PhD Division of Endocrinology School of Medical Science and Griffi th Health Institute College of Medicine Griffi th University Mayo Clinic Gold Coast, Australia Rochester, Minnesota, USA Peter A. Friedman Patricia Ducy, PhD University of Pittsburgh Department of Pathology and Cell Biology Pittsburgh, Pennsylvania, USA Columbia University Medical Center New York, New York, USA Benjamin J. Frisch, PhD Wilmot Cancer Center Richard Eastell, MD, FRCP, FRCPath, FMedSci University of Rochester School of Medicine and Department of Human Metabolism Dentistry University of Sheffi eld Rochester, New York, USA Sheffi eld, UK xiv Contributors

J. Christopher Gallagher, MD, MRCP Theresa A. Guise, MD Creighton University Medical School Department of Medicine Omaha, Nebraska, USA Division of Endocrinology Indiana University School of Medicine Harry K. Genant, MD, FACR, FRCR Indianapolis, Indiana, USA Radiology, Medicine and Orthopedic Surgery University of California Neveen A.T. Hamdy San Francisco, California, USA Department of Endocrinology and Metabolic Diseases Leiden University Medical Center Francis H. Glorieux, OC, MD, PhD Leiden, The Netherlands Genetics Unit Shriners Hospital for Children–Canada and McGill Nicholas Harvey, MA, MB, BChir, MRCP, PhD University The MRC Lifecourse Epidemiology Unit Montreal, Quebec, Canada University of Southampton Southampton General Hospital C.C. Glüer Southampton, UK Sektion Biomedizinische Bildgebung Klinik für Diagnostische Radiologie Robert P. Heaney, MD Universitätsklinikum Schleswig-Holstein Creighton University Campus Kiel Omaha, Nebraska, USA Kiel, Germany Charles Hildebolt, DDS, PhD Gopinath Gnanasegaran Mallinckrodt Institute of Radiology Department of Nuclear Medicine Washington University in St. Louis Guy ’ s and St. Thomas’ NHS Foundation Trust St. Louis, Missouri, USA London, UK Steven P. Hodak, MD Deborah T. Gold, PhD Division of Endocrinology and Metabolism Departments of Psychiatry and Behavioral Sciences, The University of Pittsburgh School of Medicine Sociology, and Psychology and Neuroscience Pittsburgh, Pennsylvania, USA Duke University Medical Center Durham, North Carolina, USA Ingrid A. Holm, MD, MPH Children ’ s Hospital Boston Steven R. Goldring, MD Manton Center for Orphan Disease Research Hospital for Special Surgery Harvard Medical School Weill Medical College of Cornell University Boston, Massachusetts, USA New York, New York, USA Mara J. Horwitz, MD David Goltzman, MD Division of Endocrinology and Metabolism Departments of Medicine and Physiology The University of Pittsburgh School of Medicine McGill University Pittsburgh, Pennsylvania, USA Montreal, Canada Keith A. Hruska, MD Susan L. Greenspan, MD, FACP Division of Pediatric Nephrology Divisions of Geriatrics, Endocrinology and Metabolism Department of Pediatrics, Medicine and Cell Biology Department of Medicine Washington University University of Pittsburgh School of Medicine St. Louis, Missouri, USA Pittsburgh, Pennsylvania, USA Christina Jacobsen, MD, PhD James F. Griffi th, MB, BCh, BAO, MD, MRCP (UK), Divisions of Endocrinology and Genetics FRCR Boston Children’s Hospital Department of Imaging and Interventional Radiology Harvard Medical School The Chinese University of Hong Kong Boston, Massachusetts, USA Hong Kong, China Suzanne M. Jan de Beur, MD Monica Grover, MD Division of Endocrinology and Metabolism Department of Molecular and Human Genetics Department of Medicine Baylor College of Medicine The Johns Hopkins School of Medicine Houston, Texas, USA Baltimore, Maryland, USA Contributors xv

Robert L. Jilka, PhD Richard W. Keen, MD, PhD Division of Endocrinology and Metabolism Institute of Orthopaedics and Musculoskeletal Sciences Center for Osteoporosis and Metabolic Bone Diseases Royal National Orthopaedic Hospital University of Arkansas for Medical Sciences Brockley Hill Central Arkansas Veterans Healthcare System Stanmore Little Rock, Arkansas, USA Middlesex, UK

Rachelle W. Johnson Luluel M. Khan Department of Veterans Affairs University of Toronto Tennessee Valley Healthcare System Department of Radiation Oncology and Vanderbilt Center for Bone Biology Odette Cancer Centre and Department of Cancer Biology Sunnybrook Health Sciences Centre Vanderbilt University Toronto, Ontario, Canada Nashville, Tennessee, USA Sundeep Khosla, MD Graeme Jones, MBBS, FRACP, MD Department of Internal Medicine Menzies Research Institute Tasmania Division of Endocrinology University of Tasmania College of Medicine Hobart, Tasmania, Australia Mayo Clinic Rochester, Minnesota, USA Stefan Judex, PhD Department of Biomedical Engineering Douglas P. Kiel, MD, MPH Stony Brook University Institute for Aging Research Stony Brook, New York, USA Hebrew SeniorLife Department of Medicine Harald Jüppner, MD Harvard Medical School Endocrine Unit and Pediatric Nephrology Unit Boston, Massachusetts, USA Departments of Medicine and Pediatrics Harvard Medical School Keith L. Kirkwood, DDS, PhD Massachusetts General Hospital Department of Craniofacial Biology Boston, Massachusetts, USA The Center for Oral Health Research Medical University of South Carolina John A Kanis Charleston, South Carolina, USA WHO Collaborating Centre for Metabolic Bone Diseases Michael Kleerekoper, MBBS, FACB, FACP, MACE University of Sheffi eld Medical School Department of Medicine, Division of Endocrinology Sheffi eld, UK University of Toledo Medical College Toledo, Ohio, USA Frederick S. Kaplan, MD Departments of Orthopaedic Surgery and Medicine Gordon L. Klein, MD, MPH Center for Research in FOP and Related Disorders Department of Orthopaedic Surgery Perelman School of Medicine at The University of University of Texas Medical Branch Pennsylvania Galveston, Texas, USA Philadelphia, Pennsylvania, USA John Klingensmith, PhD Gerard Karsenty, MD, PhD Department of Cell Biology Department of Genetics and Development Duke University Medical Center Columbia University Durham, North Carolina, USA New York, New York, USA Stephen J. Knohl, MD Moustapha Kassem, MD, PhD, DSc Department of Medicine Division of Nephrology Department of Endocrinology State University of New York Upstate Medical University Hospital of Odense University Odense, Denmark Syracuse, New York, USA xvi Contributors

Scott L. Kominsky, PhD Shane A.J. Lloyd Departments of Orthopaedic Surgery and Oncology Department of Orthopaedics and Rehabilitation Johns Hopkins University School of Medicine Division of Musculoskeletal Sciences Baltimore, Maryland, USA The Pennsylvania State University College of Medicine Hershey, Pennsylvania, USA Christopher S. Kovacs, MD, FRCPC, FACP, FACE Faculty of Medicine–Endocrinology Karen M. Lyons, PhD Health Sciences Centre UCLA Orthopaedic Hospital Memorial University of Newfoundland Department of Orthopaedic Surgery St. John ’ s, Newfoundland, Canada Department of Molecular, Cell & Developmental Biology Paul H. Krebsbach, DDS, PhD University of California Department of Biologic and Materials Sciences Los Angeles, California, USA School of Dentistry The University of Michigan Sharmila Majumdar, PhD Ann Arbor, Michigan, USA Department of Radiology and Biomedical Imaging and Orthopedic Surgery UCSF Henry M. Kronenberg, MD and Department of Bioengineering UC Berkeley Endocrine Unit San Francisco, California, USA Massachusetts General Hospital and Harvard Medical School Stavros C. Manolagas, MD, PhD Boston, Massachusetts, USA Division of Endocrinology and Metabolism Center for Osteoporosis and Metabolic Bone Diseases Craig B. Langman, MD University of Arkansas for Medical Sciences Feinberg School of Medicine and the Central Arkansas Veterans Healthcare System Northwestern University Little Rock, Arkansas, USA Chicago, Illinois, USA Joan C. Marini, MD, PhD Brendan Lee, MD, PhD National Institute of Child Health and Human Howard Hughes Medical Institute Development Department of Molecular and Human Genetics Bone and Extracellular Matrix Branch Baylor College of Medicine National Institutes of Health Houston, Texas, USA Bethesda, Maryland, USA

Mary G. Lee, DMD, MSD T. John Martin, MD, DSc Department of Craniofacial Biology St. Vincent’s Institute of Medical Research and the Center for Oral Health Research University of Melbourne Department of Medicine Medical University of South Carolina Melbourne, Australia Charleston, South Carolina, USA Stephen J. Marx, MD Michael A. Levine, MD, FAAP, FACP, FACE Genetics and Endocrinology Section Division of Endocrinology and Diabetes Metabolic Diseases Branch The Children’ s Hospital of Philadelphia and National Institute of Diabetes and Digestive and Department of Pediatrics Kidney Diseases University of Pennsylvania Perelman School of National Institutes of Health Medicine Bethesda, Maryland, USA Philadelphia, Pennsylvania, USA Maiko Matsui, BSc Paul Lips, MD, PhD Department of Cell Biology Department of Internal Medicine/Endocrinology Duke University Medical Center VU University Medical Center Durham, North Carolina, USA Amsterdam, The Netherlands Hani H. Mawardi, BDS, DMSc David G. Little, MBBS, FRACS(Orth), PhD Division of Oral Medicine Paediatrics and Child Health King Abdulaziz University University of Sydney Faculty of Dentistry Orthopaedic Research and Biotechnology Jeddah, Saudi Arabia The Children’ s Hospital at Westmead Westmead, Australia Contributors xvii

Laurie K. McCauley, DDS, MS, PhD Patrick W. O’Donnell, MD, PhD University of Michigan Center for Musculoskeletal Oncology School of Dentistry Department of Orthopaedic Surgery Ann Arbor, Michigan, USA Markey Cancer Center University of Kentucky Michael R. McClung Lexington, Kentucky, USA Oregon Osteoporosis Center Portland, Oregon, USA Eric S. Orwoll Oregon Health and Science University Lisa K. Micklesfi eld, PhD Portland, Oregon, USA MRC/Wits Developmental Pathways for Health Research Unit Petros Papagerakis, DDS, MS, PhD Department of Paediatrics Department of Orthodontics and Pediatric Dentistry Faculty of Health Sciences Center for Organogenesis University of the Witwatersrand Center for Computational Medicine and Bioinformatics Johannesburg, South Africa Schools of Dentistry and Medicine University of Michigan Paul D. Miller, MD, FACP Ann Arbor, Michigan, USA University of Colorado Health Sciences Center Colorado Center for Bone Research Socrates E. Papapoulos, MD, PhD Lakewood, Colorado, USA Department of Endocrinology and Metabolic Diseases Leiden University Medical Center Thimios Mitsiadis, DDS, MS, PhD Leiden, The Netherlands Institute of Oral Biology Department of Orofacial Development & Regeneration, John M. Pettifor, MBBCh, PhD ZZM MRC/Wits Developmental Pathways for Health Department of Medicine Research Unit University of Zurich Department of Paediatrics Zurich, Switzerland Faculty of Health Sciences University of the Witwatersrand Elise F. Morgan, PhD Johannesburg, South Africa Department of Mechanical Engineering Boston University Robert J. Pignolo, MD, PhD Boston, Massachusetts, USA Center for Research in FOP and Related Disorders Department of Orthopaedic Surgery Tuan V. Nguyen The University of Pennsylvania School of Medicine Osteoporosis and Bone Biology Research Program Philadelphia, Pennsylvania, USA Garvan Institute of Medical Research Sydney, Australia L. Darryl Quarles Division of Nephrology Robert A. Nissenson, PhD Department of Medicine Endocrine Research Unit University of Tennessee Health Science Center VA Medical Center Memphis, Tennessee, USA Departments of Medicine and Physiology University of California Manoj Ramachandran, BSc, MBBS, MRCS, FRCS San Francisco, California, USA The Royal London and St. Bartholomew’s Hospitals Barts Health NHS Trust Shane A. Norris, PhD Barts and The London School of Medicine and MRC/Wits Developmental Pathways for Health Dentistry Research Unit Queen Mary Department of Paediatrics University of London Faculty of Health Sciences London, England University of the Witwatersrand Johannesburg, South Africa Francesco Ramirez, PhD Department of Pharmacology and Systems Therapeutics Mount Sinai School of Medicine New York, New York, USA xviii Contributors

Robert R. Recker, MD, MACP, FACE Clinton T. Rubin, PhD Department of Medicine Department of Biomedical Engineering Section of Endocrinology Stony Brook University Osteoporosis Research Center Stony Brook, New York, USA Creighton University Medical Center Omaha, Nebraska, USA Janet Rubin, MD Department of Medicine Ian R. Reid, MBChB, MD, FRACP University of North Carolina School of Medicine Department of Medicine Chapel Hill, North Carolina, USA University of Auckland Auckland, New Zealand Mishaela R. Rubin, MD Division of Endocrinology Mara Riminucci Department of Medicine Dipartimento di Medicina Molecolare Columbia University College of Physicians Universita’ La Sapienza New York, New York, USA Rome, Italy Mary D. Ruppe, MD David L. Rimoin, MD, PhD * Department of Medicine Medical Genetics Institute Division of Endocrinology Cedars-Sinai Medical Center The Methodist Hospital Los Angeles, California, USA Houston, Texas, USA

René Rizzoli, MD Lynn Y. Sakai Division of Bone Diseases Department of Biochemistry and Molecular Biology Department of Internal Medicine Specialties Oregon Health and Science University Geneva University Hospital and Faculty of Medicine Shriners Hospital for Children Geneva, Switzerland Portland, Oregon, USA

Pamela Gehron Robey Kyu Sang Joeng, PhD Craniofacial and Skeletal Diseases Branch Department of Molecular and Human Genetics National Institute of Dental and Craniofacial Research Baylor College of Medicine National Institutes of Health Houston, Texas, USA Department of Health and Human Services Bethesda, Maryland, USA Anne L. Schafer, MD Department of Medicine G. David Roodman University of California, San Francisco Division of Hematology/Oncology San Francisco, California, USA Indiana University School of Medicine Indianapolis, Indiana, USA Steven J. Scheinman, MD The Commonwealth Medical College Clifford J. Rosen, MD Scranton, Pennsylvania, USA Tufts University School of Medicine Maine Medical Center Research Institute Ego Seeman, BSc, MBBS, FRACP, MD Scarborough, Maine, USA Department of Endocrinology and Medicine Repatriation Campus Vicki Rosen, PhD Austin Health Department of Developmental Biology University of Melbourne Harvard School of Dental Medicine Melbourne, Australia Boston, Massachusetts, USA Michael Seifert, MD F. Patrick Ross Division of Pediatric Nephrology Department of Pathology and Immunology Department of Pediatrics Washington University School of Medicine Washington University and Southern Illinois St. Louis, Missouri, USA University St. Louis, Missouri, USA

* Deceased. Contributors xix

Gerhard Sengle Ethel S. Siris, MD Department of Biochemistry and Molecular Biology Columbia University Medical Center Oregon Health and Science University New York Presbyterian Hospital and Shriners Hospital for Children New York, New York, USA Portland, Oregon, USA Julie A. Sterling, PhD Elizabeth Shane Department of Veterans Affairs Division of Endocrinology Tennessee Valley Healthcare System Department of Medicine and Vanderbilt Center for Bone Biology College of Physicians and Surgeons Department of Medicine/Clinical Pharmacology Columbia University Vanderbilt University New York, New York, USA Nashville, Tennessee, USA

Sue Shapses, PhD Andrew F. Stewart, MD Department of Nutritional Sciences Diabetes Obesity and Metabolism Institute Rutgers University Icahn School of Medicine at Mount Sinai Newark, New Jersey, USA New York, New York, USA

Nicholas Shaw, MBChB, FRCPCH Deeptha Sukumar, PhD Department of Endocrinology Department of Nutritional Sciences Birmingham Children’ s Hospital Rutgers University Birmingham, West Midlands, UK Newark, New Jersey, USA

Yiping Shen, PhD Li Sun Boston Children’s Hospital The Mount Sinai Bone Program Harvard Medical School Department of Medicine Boston, Massachusetts, USA Mount Sinai School of Medicine Shanghai Jiaotong University School of Medicine New York, New York, USA Shanghai, China Pawel Szulc, MD, PhD Dolores Shoback, MD INSERM University of California, San Francisco Université de Lyon Endocrine Research Unit Lyon, France San Francisco VA Medical Center San Francisco, California, USA Shu Takeda, MD, PhD Section of Nephrology, Endocrinology and Metabolism Eileen M. Shore, PhD Department of Internal Medicine Departments of Orthopaedic Surgery and Genetics School of Medicine Center for Research in FOP and Related Disorders Keio University Perelman School of Medicine at the University of Tokyo, Japan Pennsylvania Philadelphia, Pennsylvania, USA Jianning Tao, PhD Departments of Molecular and Human Genetics Rebecca Silbermann, MD Baylor College of Medicine Indiana University School of Medicine Texas Children’ s Hospital Indianapolis, Indiana, USA Houston, Texas, USA

Shonni J. Silverberg, MD Pamela Taxel, MD Division of Endocrinology Division of Endocrinology and Metabolism Department of Medicine University of Connecticut Health Center College of Physicians and Surgeons Farmington, Connecticut, USA Columbia University New York, New York, USA Peter ten Dijke, PhD Department of Molecular Cell Biology James P. Simmer, DDS, PhD and Centre for Biomedical Genetics Department of Biological and Materials Sciences Leiden University Medical Centre University of Michigan School of Dentistry Leiden, The Netherlands Ann Arbor, Michigan, USA xx Contributors

Rajesh V. Thakker, MD, ScD, FRCP, FRCPath, Lisa L. Wang, MD FMedSci Texas Children’s Cancer Center Academic Endocrine Unit Baylor College of Medicine Nuffi eld Department of Clinical Medicine Houston, Texas, USA Oxford Centre for Diabetes Endocrinology and Metabolism (OCDEM) Qingju Wang Churchill Hospital Department Endocrinology and Medicine Headington, Oxford, UK Repatriation Campus Austin Health Anna N.A. Tosteson, ScD University of Melbourne Multidisciplinary Clinical Research Center in Melbourne, Australia Musculoskeletal Diseases Geisel School of Medicine at Dartmouth Nelson B. Watts, MD Lebanon, New Hampshire, USA Mercy Health Osteoporosis and Bone Health Services Cincinnati, Ohio, USA Dwight A. Towler, MD, PhD Diabetes and Obesity Research Center Connie M. Weaver, PhD Sanford-Burnham Medical Research Institute at Lake Purdue University Nona Nutrition Science Orlando, Florida, USA West Lafayette, Indiana, USA

Bich H. Tran Kristy Weber, MD Osteoporosis and Bone Biology Research Program Departments of Orthopaedic Surgery and Oncology Garvan Institute of Medical Research Johns Hopkins School of Medicine Sydney, Australia Baltimore, Maryland, USA

Nathaniel S. Treister, DMD, DMSc Robert S. Weinstein, MD Division of Oral Medicine and Dentistry Division of Endocrinology and Metabolism Brigham and Women’ s Hospital Center for Osteoporosis and Metabolic Bone Diseases Boston, Massachusetts, USA Department of Internal Medicine and the Central Arkansas Veterans Healthcare System Geertje van der Horst, PhD University of Arkansas for Medical Sciences Department of Urology Little Rock, Arkansas, USA Leiden University Medical Centre Leiden, The Netherlands Kenneth E. White, PhD Medical and Molecular Genetics Gabri van der Pluijm, PhD Indiana University School of Medicine Department of Urology Indianapolis, Indiana, USA Leiden University Medical Centre Leiden, The Netherlands Michael P. Whyte, MD Division of Bone and Mineral Diseases Catherine Van Poznak, MD Washington University School of Medicine Department of Internal Medicine Barnes-Jewish Hospital University of Michigan and Center for Metabolic Bone Disease and Molecular Ann Arbor, Michigan, USA Research Shriners Hospital for Children Natasja M. van Schoor, PhD St. Louis, Missouri, USA Department of Epidemiology and Biostatistics EMGO Institute for Health and Care Research Jeffrey S. Willey, PhD VU University Medical Center Department of Radiation Oncology Amsterdam, The Netherlands Wake Forest School of Medicine Winston-Salem, North Carolina, USA Kong Wah Ng, MBBS, MD, FRACP, FRCP Department of Endocrinology and Diabetes Tania Winzenberg, MBBS, FRACGP, MMedSc, PhD St. Vincent’ s Health Menzies Research Institute Tasmania St. Vincent’ s Institute University of Tasmania University of Melbourne Department of Medicine Hobart, Tasmania, Australia Fitzroy, Victoria, Australia Contributors xxi

Sook-Bin Woo, DMD, MMSc Tony Yuen, PhD Division of Oral Medicine and Dentistry The Mount Sinai Bone Program Brigham and Women’ s Hospital Department of Medicine Boston, Massachusetts, USA Mount Sinai School of Medicine New York, New York, USA John J. Wysolmerski Section of Endocrinology and Metabolism Mone Zaidi, MBBS, PhD Department of Internal Medicine The Mount Sinai Bone Program Yale University School of Medicine Department of Medicine New Haven, Connecticut, USA Mount Sinai School of Medicine New York, New York, USA Tao Yang, PhD Center for Skeletal Disease Research Alberta Zallone Laboratory of Skeletal Biology Department of Histology Van Andel Research Institute, University of Bari Grand Rapids, Michigan, USA Bari, Italy

Yingzi Yang Michael J. Zuscik, PhD Developmental Genetics Section Department of Orthopaedics & Rehabilitation Genetic Disease Research Branch Center for Musculoskeletal Research National Human Genome Research Institute University of Rochester Medical Center Bethesda, Maryland, USA Rochester, New York, USA

Raz Yirmiya Department of Psychology The Hebrew University of Jerusalem Jerusalem, Israel Primer Corporate Sponsors

Distribution to the ASBMR membership of the Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, Eighth Edition , is supported by unrestricted educational grants from the following companies:

Silver: Warner Chilcott

Bronze: Alexion

Partner: OsteoMetrics

xxii Preface to the Eighth Edition of the Primer

Welcome to the eighth edition of the Primer on the bone as an organ system is updated. As with previous Metabolic Bone Diseases and Disorders of Mineral editions, it is the contributing authors, who are at the Metabolism ! Loyal readers of previous editions will fi nd top in their respective fi elds, who make the Primer so the same up-to-date summaries of clinical diseases of the valuable. skeleton as well as overviews of skeletal growth, remod- And as a real treat, our cover is an artistic image of eling, and pathophysiological disorders that they have bone painted by Mr. Toby Kahn. His creation reminds seen in the past. As always, calcium, phosphorus, and us that, since the last edition, the osteocyte has emerged vitamin D are reviewed extensively and updated. New as a major regulator of skeletal remodeling as well as visitors to the Primer will fi nd a potpourri of informa- mineral homeostasis. tion that can assist readers at the bench and at the The eighth edition is dedicated to the memory of bedside. The many tables, references, fi gures, and illus- Dr. Larry Raisz, a giant in our fi eld who led and inspired trations are certain to be helpful. In fact, many fi gures all of us, and who particularly found the Primer to be the and illustrations appear in full color for the fi rst time in premier textbook of bone. this edition. Importantly, the eighth edition has expanded by one- third, adding new chapters principally related to how the skeleton interacts with other systems and tissues, including hematopoietic, muscular, metabolic, and neu- ropsychiatric. A basic, but comprehensive, overview on Clifford J. Rosen, MD

xxiii We Make the Discoveries That Keep Bones Healthy for a Lifetime

The American Society for Bone and Mineral Research (ASBMR) is home to the world’ s foremost bone and mineral researchers and clinicians. Our 4,000 members work in more than 60 countries and are experts in a diverse range of specialti es, including endocrinology, cell biology, orthopedics, rheumatology, internal medicine, physiology, epidemiology, biomechanics and more.

ASBMR ’ s mission is to promote excellence in bone and mineral research, to foster integrati on of basic and clinical science and to facilitate the translati on of that science into clinical practi ce. For more than 30 years, our Society has remained true to its innovati ve and inclusive founding principles, fostering an encouraging environment for researchers and clinicians to develop and discuss the latest fi ndings.

ASBMR ’ s work is guided by the following key strategic objecti ves:

• GENERATING AWARENESS about bone diseases and the importance of bone research by serving as the leading authority on bone health and disease for health professionals and the public

• PROMOTING CUTTING-EDGE RESEARCH by fostering multi disciplinary connecti ons among our investi ga- tors, awarding grants and advocati ng for funding for bone and mineral research

• COMMUNICATING WITH THE NATIONAL INSTITUTES OF HEALTH to both discover and infl uence the latest directi ons in basic, clinical and translati onal research

• SUPPORTING YOUNG INVESTIGATORS through conti nuing educati on, grant funding, professional net- working and mentoring opportuniti es

Learn more about ASBMR and the vast learning and networking opportuniti es it off ers by visiti ng www.asbmr.org today.

xxiv President’s Preface

The American Society for Bone and Mineral Research Along with these changes, a new companion site has is pleased and excited to present this fully revised, been developed at www.asbmrprimer.com to provide updated and expanded eighth edition of the Primer on researchers, instructors, clinicians, and students with the Metabolic Bone Diseases and Disorders of Mineral valuable supplementary materials that support and Metabolism . Dr. Clifford Rosen returns as Editor-in- expand the content of the book. Chief, overseeing even greater coverage of the fi eld to The eighth edition of our Primer maintains the strong include the addition of a completely new section on “The tradition developed by its predecessors while continuing Skeleton and Its Integration with Other Tissues.” In to evolve to serve the changing needs of the communities addition to new content, many new reader-friendly fea- it serves. We thank and commend all those involved in tures have been incorporated into the design of the book. making this new edition a reality. This eighth edition presents numerous full-color fi gures for the fi rst time, and the layout has been updated to make accessing information easier. Dr. Rosen and the editorial team have maintained the rigorous high stan- dards of scientifi c content that have long been the trade- mark feature of the book, ensuring the Primer maintains its reputation as an essential reference in the fi eld of bone Lynda F. Bonewald, PhD health. President, ASBMR

xxv About the Companion Website

This book is accompanied by a companion website: www.asbmrprimer.com

The website includes:

• Videos • Editors’ biographies • PowerPoints of all fi gures from the book for downloading • Useful website links

xxvi