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Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism
Eighth Edition
An Official 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 EditorsRoger Bouillon, MD, PhD, FRCPJuliet E. Compston, MD, FRCP, FRCPath, FMedSciVicki Rosen, PhD
Associate EditorsDouglas C. Bauer, MDMarie Demay, MDTheresa A. Guise, MDSuzanne M. Jan de Beur, MDRichard W. Keen, MD, PhDKaren M. Lyons, PhDLaurie K. McCauley, DDS, MS, PhDPaul D. Miller, MD, FACPSocrates E. Papapoulos, MD, PhDEgo Seeman, BSc, MBBS, FRACP, MDRajesh V. Thakker, MD, ScD, FRCP, FRCPath, FMedSciMone Zaidi, MBBS, PhD
A John Wiley & Sons, Inc., Publication
This edition first 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 ResearchThird Edition published by Lippincott-Raven Publishers © 1996 American Society for Bone and Mineral ResearchFourth Edition published by Lippincott Williams & Wilkins © 1999 American Society for Bone and Mineral ResearchFifth Edition published by American Society for Bone and Mineral Research © 2003 American Society for Bone and Mineral ResearchSixth Edition published by American Society for Bone and Mineral Research © 2006 American Society for Bone and Mineral ResearchSeventh 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.
Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.
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
v
Contents
Contributors xPrimer Corporate Sponsors xxiiPreface to the Eighth Edition of the Primer: Clifford J. Rosen xxiiiAbout ASBMR xxivPresident’s Preface: Lynda F. Bonewald xxvAbout the Companion Website xxvi
Section I: Molecular, Cellular, and Genetic Determinants of Bone Structure and Formation 1Section Editor Karen M. Lyons
1 Skeletal Morphogenesis and Embryonic Development 3Yingzi Yang
2 Signal Transduction Cascades Controlling Osteoblast Differentiation 15David J.J. de Gorter and Peter ten Dijke
3 Osteoclast Biology and Bone Resorption 25F. Patrick Ross
4 Osteocytes 34Lynda F. Bonewald
5 Connective Tissue Pathways That Regulate Growth Factors 42Gerhard Sengle and Lynn Y. Sakai
6 The Composition of Bone 49Adele L. Boskey and Pamela Gehron Robey
7 Assessment of Bone Mass and Microarchitecture in Rodents 59Blaine A. Christiansen
8 Animal Models: Genetic Manipulation 69Karen M. Lyons
9 Animal Models: Allelic Determinants for BMD 76Robert D. Blank
10 Neuronal Regulation of Bone Remodeling 82Florent Elefteriou and Gerard Karsenty
11 Skeletal Healing 90Michael J. Zuscik
12 Biomechanics of Fracture Healing 99Elise F. Morgan and Thomas A. Einhorn
13 Human Genome-Wide Association (GWA) Studies 106Douglas P. Kiel
14 Circulating Osteogenic Cells 111Robert J. Pignolo and Moustapha Kassem
Section II: Skeletal Physiology 119Section Editor Ego Seeman
15 Human Fetal and Neonatal Bone Development 121Tao Yang, Monica Grover, Kyu Sang Joeng, and Brendan Lee
16 Skeletal Growth and Peak Bone Strength 127Qingju Wang and Ego Seeman
17 Ethnic Differences in Bone Acquisition 135Shane A. Norris, Lisa K. Micklesfield, and John M. Pettifor
18 Calcium and Other Nutrients During Growth 142Tania Winzenberg and Graeme Jones
19 Growing a Healthy Skeleton: The Importance of Mechanical Loading 149Mark R. Forwood
20 Pregnancy and Lactation 156Christopher S. Kovacs and Henry M. Kronenberg
vi Contents
21 Menopause 165Ian R. Reid
Section III: Mineral Homeostasis 171Section Editor Ego Seeman
22 Regulation of Calcium and Magnesium 173Murray J. Favus and David Goltzman
23 Fetal Calcium Metabolism 180Christopher S. Kovacs
24 Fibroblast Growth Factor-23 (FGF23) 188Kenneth E. White and Michael J. Econs
25 Gonadal Steroids 195Stavros C. Manolagas, Maria Almeida, and Robert L. Jilka
26 Parathyroid Hormone 208Robert A. Nissenson and Harald Jüppner
27 Parathyroid Hormone-Related Protein 215John J. Wysolmerski
28 Ca2+-Sensing Receptor 224Edward M. Brown
29 Vitamin D: Production, Metabolism, Mechanism of Action, and Clinical Requirements 235Daniel Bikle, John S. Adams, and Sylvia Christakos
Section IV: Investigation of Metabolic Bone Diseases 249Section Editor Douglas C. Bauer
30 DXA in Adults and Children 251Glen Blake, Judith E. Adams, and Nick Bishop
31 Quantitative Computed Tomography in Children and Adults 264C.C. Glüer
32 Magnetic Resonance Imaging of Bone 277Sharmila Majumdar
33 Radionuclide Scintigraphy in Metabolic Bone Disease 283Gary J.R. Cook, Gopinath Gnanasegaran, and Ignac Fogelman
34 FRAX®: Assessment of Fracture Risk 289John A Kanis
35 Biochemical Markers of Bone Turnover in Osteoporosis 297Pawel Szulc, Douglas C. Bauer, and Richard Eastell
36 Bone Biopsy and Histomorphometry in Clinical Practice 307Robert R. Recker
37 Diagnosis and Classification of Vertebral Fracture 317James F. Griffith, Judith E. Adams, and Harry K. Genant
38 Approaches to Genetic Testing 336Christina Jacobsen, Yiping Shen, and Ingrid A. Holm
Section V: Osteoporosis 343Section Editors Paul D. Miller and Socrates E. Papapoulos
39 Osteoporosis Overview 345Michael Kleerekoper
40 The Epidemiology of Osteoporotic Fractures 348Nicholas Harvey, Elaine Dennison, and Cyrus Cooper
41 Overview of Pathogenesis 357Ian R. Reid
42 Nutrition and Osteoporosis 361Connie M. Weaver and Robert P. Heaney
43 The Role of Sex Steroids in the Pathogenesis of Osteoporosis 367Matthew T. Drake and Sundeep Khosla
44 Translational Genetics of Osteoporosis: From Population Association to Individualized Prognosis 376Bich H. Tran, Jacqueline R. Center, and Tuan V. Nguyen
45 Prevention of Falls 389Heike A. Bischoff-Ferrari
46 Exercise and the Prevention of Osteoporosis 396Clinton T. Rubin, Janet Rubin, and Stefan Judex
Contents vii
47 Calcium and Vitamin D 403Bess Dawson-Hughes
48 Estrogens, Estrogen Agonists/Antagonists, and Calcitonin 408Nelson B. Watts
49 Bisphosphonates for Postmenopausal Osteoporosis 412Socrates E. Papapoulos
50 Denosumab 420Michael R. McClung
51 Parathyroid Hormone Treatment for Osteoporosis 428Felicia Cosman and Susan L. Greenspan
52 Strontium Ranelate in the Prevention of Osteoporotic Fractures 437René Rizzoli
53 Combination Anabolic and Antiresorptive Therapy for Osteoporosis 444John P. Bilezikian and Natalie E. Cusano
54 Compliance and Persistence with Osteoporosis Medications 448Deborah T. Gold
55 Cost-Effectiveness of Osteoporosis Treatment 455Anna N.A. Tosteson
56 Future Therapies of Osteoporosis 461Kong Wah Ng and T. John Martin
57 Juvenile Osteoporosis 468Nick Bishop and Francis H. Glorieux
58 Glucocorticoid-Induced Bone Disease 473Robert S. Weinstein
59 Inflammation-Induced Bone Loss in the Rheumatic Diseases 482Steven R. Goldring
60 Secondary Osteoporosis: Other Causes 489Neveen A.T. Hamdy
61 Transplantation Osteoporosis 495Peter R. Ebeling
62 Osteoporosis in Men 508Eric S. Orwoll
63 Premenopausal Osteoporosis 514Adi Cohen and Elizabeth Shane
64 Skeletal Effects of Drugs 520Juliet Compston
65 Orthopedic Surgical Principles of Fracture Management 527Manoj Ramachandran and David G. Little
66 Abnormalities in Bone and Calcium Metabolism After Burns 531Gordon L. Klein
Section VI: Disorders of Mineral Homeostasis 535Section Editors Marie Demay and Suzanne M. Jan de Beur
67 Approach to Parathyroid Disorders 537John P. Bilezikian
68 Primary Hyperparathyroidism 543Shonni J. Silverberg
69 Familial Primary Hyperparathyroidism (Including MEN, FHH, and HPT-JT) 553Andrew Arnold and Stephen J. Marx
70 Non-Parathyroid Hypercalcemia 562Mara J. Horwitz, Steven P. Hodak, and Andrew F. Stewart
71 Hypocalcemia: Definition, Etiology, Pathogenesis, Diagnosis, and Management 572Anne L. Schafer and Dolores Shoback
72 Hypoparathyroidism and Pseudohypoparathyroidism 579Mishaela R. Rubin and Michael A. Levine
73 Pseudohypoparathyroidism 590Harald Jüppner and Murat Bastepe
74 Disorders of Phosphate Homeostasis 601Mary D. Ruppe and Suzanne M. Jan de Beur
75 Vitamin D–Related Disorders 613Paul Lips, Natasja M. van Schoor, and Nathalie Bravenboer
viii Contents
76 Vitamin D Insufficiency and Deficiency 624J. Christopher Gallagher
77 Pathophysiology of Chronic Kidney Disease Mineral Bone Disorder (CKD–MBD) 632Keith A. Hruska and Michael Seifert
78 Treatment of Chronic Kidney Disease Mineral Bone Disorder (CKD–MBD) 640Hala M. Alshayeb and L. Darryl Quarles
79 Disorders of Mineral Metabolism in Childhood 651Thomas O. Carpenter
80 Paget’s Disease of Bone 659Ethel S. Siris and G. David Roodman
Section VII: Cancer and Bone 669Section Editor Theresa A. Guise
81 Overview of Mechanisms in Cancer Metastases to Bone 671Gregory A. Clines
82 Clinical and Preclinical Imaging in Osseous Metastatic Disease 677Geertje van der Horst and Gabri van der Pluijm
83 Metastatic Solid Tumors to Bone 686Rachelle W. Johnson and Julie A. Sterling
84 Hematologic Malignancies and Bone 694Rebecca Silbermann and G. David Roodman
85 Osteogenic Osteosarcoma 702Jianning Tao, Yangjin Bae, Lisa L. Wang, and Brendan Lee
86 Skeletal Complications of Breast and Prostate Cancer Therapies 711Catherine Van Poznak and Pamela Taxel
87 Bone Cancer and Pain 720Patrick W. O’Donnell and Denis R. Clohisy
88 Radiation Therapy-Induced Osteoporosis 728Jeffrey S. Willey, Shane A.J. Lloyd, and Ted A. Bateman
89 Skeletal Complications of Childhood Cancer 734Ingrid A. Holm
90 Treatment and Prevention of Bone Metastases and Myeloma Bone Disease 741Jean-Jacques Body
91 Radiotherapy of Skeletal Metastases 754Edward Chow, Luluel M. Khan, and Øyvind S. Bruland
92 Concepts and Surgical Treatment of Metastatic Bone Disease 760Kristy Weber and Scott L. Kominsky
Section VIII: Sclerosing and Dysplastic Bone Diseases 767Section Editor Richard W. Keen
93 Sclerosing Bone Disorders 769Michael P. Whyte
94 Fibrous Dysplasia 786Michael T. Collins, Mara Riminucci, and Paolo Bianco
95 Osteochondrodysplasias 794Yasemin Alanay and David L. Rimoin
96 Ischemic and Infiltrative Disorders 805Richard W. Keen
97 Tumoral Calcinosis—Dermatomyositis 810Nicholas Shaw
98 Fibrodysplasia Ossificans Progressiva 815Frederick S. Kaplan, Robert J. Pignolo, and Eileen M. Shore
99 Osteogenesis Imperfecta 822Joan C. Marini
100 Skeletal Manifestations in Marfan Syndrome and Related Disorders of the Connective Tissue 830Emilio Arteaga-Solis and Francesco Ramirez
101 Enzyme Defects and the Skeleton 838Michael P. Whyte
Section IX: Approach to Nephrolithiasis 843Section Editor Rajesh V. Thakker
102 Renal Tubular Physiology of Calcium Excretion 845Peter A. Friedman and David A. Bushinsky
Contents ix
103 Epidemiology of Nephrolithiasis 856Murray J. Favus
104 Diagnosis and Evaluation of Nephrolithiasis 860Stephen J. Knohl and Steven J. Scheinman
105 Kidney Stones in the Pediatric Patient 869Amy E. Bobrowski and Craig B. Langman
106 Treatment of Renal Stones 878John R. Asplin
107 Genetic Basis of Renal Stones 884Rajesh V. Thakker
Section X: Oral and Maxillofacial Biology and Pathology 893Section Editor Laurie K. McCauley
108 Development of the Craniofacial Skeleton 895Maiko Matsui and John Klingensmith
109 Development and Structure of Teeth and Periodontal Tissues 904Petros Papagerakis and Thimios Mitsiadis
110 Craniofacial Disorders Affecting the Dentition: Genetic 914Yong-Hee P. Chun, Paul H. Krebsbach, and James P. Simmer
111 Pathology of the Hard Tissues of the Jaws 922Paul C. Edwards
112 Bisphosphonate-Associated Osteonecrosis of the Jaws 929Hani H. Mawardi, Nathaniel S. Treister, and Sook-Bin Woo
113 Periodontal Diseases and Oral Bone Loss 941Mary G. Lee and Keith L. Kirkwood
114 Oral Manifestations of Metabolic Bone Diseases 948Roberto Civitelli and Charles Hildebolt
Section XI: The Skeleton and Its Integration with Other Tissues 959Section Editor Mone Zaidi
115 Central Neuronal Control of Bone Remodeling 961Shu Takeda and Paul Baldock
116 The Pituitary–Bone Connection 969Mone Zaidi, Tony Yuen, Li Sun, Terry F. Davies, Alberta Zallone, and Harry C. Blair
117 Skeletal Muscle Effects on the Skeleton 978William J. Evans
118 Glucose Control and Integration by the Skeleton 986Patricia Ducy and Gerard Karsenty
119 Obesity and Skeletal Mass 993Sue Shapses and Deeptha Sukumar
120 Neuropsychiatric Disorders and the Skeleton 1002Itai Bab and Raz Yirmiya
121 Vascular Disease and the Skeleton 1012Dwight A. Towler
122 Spinal Cord Injury: Skeletal Pathophysiology and Clinical Issues 1018William A. Bauman and Christopher P. Cardozo
123 Hematopoiesis and Bone 1028Benjamin J. Frisch and Laura M. Calvi
124 Bone and Immune Cell Interactions 1036Brendan F. Boyce
Index 1043
x
John S. Adams, MDDepartments of Orthopaedic Surgery, Medicine and
Molecular Cell and Developmental BiologyUniversity of California-Los AngelesLos Angeles, California, USA
Judith E. Adams, MDDepartment of Clinical RadiologyManchester Academic Health Science CentreCentral Manchester University Hospitals NHS
Foundation TrustThe Royal InfirmaryManchester, UK
Yasemin Alanay, MD, PhDPediatric Genetics UnitDepartment of PediatricsAcibadem University School of MedicineIstanbul, Turkey
Maria AlmeidaDivision of Endocrinology and MetabolismCenter for Osteoporosis and Metabolic Bone DiseasesUniversity of Arkansas for Medical Sciencesand the Central Arkansas Veterans Healthcare SystemLittle Rock, Arkansas, USA
Hala M. Alshayeb, MD Division of Nephrology Department of MedicineHashemite University Zarqa, Jordan
Andrew Arnold, MDCenter for Molecular Medicine and Division of
Endocrinology and MetabolismUniversity of Connecticut School of MedicineFarmington, Connecticut, USA
Emilio Arteaga-Solis, MD, PhDPediatrics Pulmonary DivisionDepartment of PediatricsColumbia University College of Physician and SurgeonsNew York, New York, USA
John R. Asplin, MD, FASNLitholink Corporationand Department of MedicineUniversity of Chicago Pritzker School of MedicineChicago, Illinois, USA
Itai BabBone LaboratoryThe Hebrew University of JerusalemJerusalem, Israel
Yangjin BaeDepartments of Molecular and Human GeneticsBaylor College of MedicineTexas Children’s HospitalHouston, Texas, USA
Paul Baldock, PhDBone and Mineral Research ProgramGarvan Institute of Medical ResearchSt. Vincent’s HospitalSydney, Australia
Murat Bastepe, MD, PhDEndocrine UnitDepartment of MedicineMassachusetts General HospitalHarvard Medical SchoolBoston, Massachusetts, USA
Ted A. BatemanDepartments of Biomedical Engineering and Radiation
OncologyUniversity of North CarolinaChapel Hill, North Carolina, USA
Douglas C. Bauer, MDDepartments of Medicine and Epidemiology and
BiostatisticsUniversity of California, San FranciscoSan Francisco, California, USA
Contributors
Contributors xi
William A. Bauman, MDDepartment of Veterans Affairs Rehabilitation Research
and Development ServiceNational Center of Excellence for the Medical
Consequences of Spinal Cord Injuryand Medical ServiceJames J. Peters Veterans Affairs Medical CenterBronx, New York, USADepartments of Medicine and Rehabilitation MedicineThe Mount Sinai School of MedicineNew York, New York, USA
Paolo BiancoDipartimento di Medicina MolecolareUniversita’ La SapienzaRome, Italy
Daniel Bikle, MD, PhDDepartment of MedicineDivision of EndocrinologyVA Medical Center andUniversity of California, San FranciscoSan Francisco, California, USA
John P. BilezikianDivision of EndocrinologyDepartment of MedicineCollege of Physicians and SurgeonsColumbia UniversityNew York, New York, USA
Heike A. Bischoff-Ferrari, MD, DrPHCentre on Aging and MobilityUniversity of Zurich, SwitzerlandJean Mayer USDA Human NutritionResearch Center on AgingTufts UniversityBoston, Massachusetts, USA
Nick Bishop, MB, ChB, MRCP, MD, FRCPCHAcademic Unit of Child HealthDepartment of Human MetabolismUniversity of SheffieldSheffield Children’s HospitalSheffield, UK
Harry C. BlairThe Pittsburgh VA Medical Centerand Departments of Pathology and of Cell BiologyUniversity of Pittsburgh School of MedicinePittsburgh, Pennsylvania, USA
Glen Blake, PhDOsteoporosis Research UnitKing’s College LondonGuy’s CampusLondon, UK
Robert D. Blank, MD, PhD Division of Endocrinology Department of Medicine Medical College of Wisconsin Milwaukee, Wisconsin, USA
Amy E. Bobrowski, MD, MSCIFeinberg School of MedicineNorthwestern UniversityChicago, Illinois, USA
Jean-Jacques Body, MD, PhDUniversity Hospital BrugmannUniversité Libre de Bruxelles (U.L.B.) Internal MedicineBrussels, Belgium
Lynda F. Bonewald, PhDDepartment of Oral BiologyUniversity of Missouri at Kansas City School of
DentistryKansas City, Missouri, USA
Adele L. Boskey, PhDResearch DivisionHospital for Special Surgeryand Department of Biochemistry and Graduate Field of
Physiology, Biophysics, and Systems BiologyCornell University Medical and Graduate Medical
SchoolsNew York, New York, USA
Roger Bouillon, MD, PhD, FRCPDepartment of EndocrinologyKU LeuvenGasthuisberg, Belgium
Brendan F. Boyce, MBChBDepartment of Pathology and Laboratory Medicine andThe Center for Musculoskeletal ResearchUniversity of Rochester Medical CenterRochester, New York, USA
Nathalie Bravenboer, PhDDepartment of Clinical ChemistryVU University Medical CenterAmsterdam, The Netherlands
Edward M. Brown, MDDivision of Endocrinology, Diabetes and HypertensionBrigham and Women’s Hospital and Harvard Medical
SchoolBoston, Massachusetts, USA
Øyvind S. Bruland, MD, PhDInstitute of Clinical Medicine, University of OsloDepartment of Oncology, The Norwegian Radium
HospitalOslo University HospitalOslo, Norway
xii Contributors
David A. Bushinsky, MDNephrology DivisionUniversity of Rochester School of Medicine and
DentistryRochester, New York, USA
Laura M. Calvi, MDEndocrine Metabolism DivisionDepartment of MedicineUniversity of Rochester School of Medicine and
DentistryRochester, New York, USA
Christopher P. Cardozo, MDDepartment of Veterans Affairs Rehabilitation Research
and Development ServiceNational Center of Excellence for the Medical
Consequences of Spinal Cord Injury,and Medical ServiceJames J. Peters Veterans Affairs Medical CenterBronx, New York, USADepartments of Medicine and Rehabilitation MedicineThe Mount Sinai School of MedicineNew York, New York, USA
Thomas O. Carpenter, MDYale University School of MedicineNew Haven, Connecticut, USA
Jacqueline R. Center, MBBS, MS (epi), PhD, FRACPOsteoporosis and Bone BiologyGarvan Institute of Medical ResearchSt. Vincent’s Hospital Clinical SchoolDepartment of MedicineUniversity of NSWSydney, Australia
Edward Chow, MBBS, MSc, PhD, FRCPCDepartment of Radiation OncologyUniversity of TorontoSunnybrook Research InstituteOdette Cancer CentreSunnybrook Health Sciences CentreToronto, Ontario, Canada
Sylvia Christakos, PhDDepartment of Biochemistry and Molecular BiologyUMDNJ–New Jersey Medical SchoolNewark, New Jersey, USA
Blaine A. Christiansen, PhDDepartment of Orthopaedic SurgeryUniversity of CaliforniaDavis Medical CenterSacramento, California, USA
Yong-Hee P. Chun, DDS, MS, PhDDepartment of PeriodonticsUniversity of Texas Health Science Center at San
AntonioSan Antonio, Texas, USA
Roberto Civitelli, MDDivision of Bone and Mineral DiseasesDepartment of Internal MedicineMusculoskeletal Research CenterWashington University in St. LouisSt. Louis, Missouri, USA
Gregory A. Clines, MD, PhDDepartment of MedicineDivision of Endocrinology, Diabetes, and MetabolismUniversity of Alabama at Birminghamand Veterans Affairs Medical CenterBirmingham, Alabama, USA
Denis R. ClohisyDepartment of Orthopaedic Surgery and Masonic
Cancer CenterUniversity of Minnesota School of MedicineMinneapolis, Minnesota, USA
Adi Cohen, MD, MHScDivision of EndocrinologyDepartment of MedicineCollege of Physicians and SurgeonsColumbia UniversityNew York, New York, USA
Michael T. Collins, MDSkeletal Clinical Studies UnitCraniofacial and Skeletal Diseases BranchNational Institute of Dental and Craniofacial ResearchNational Institutes of HealthDepartment of Health and Human ServicesBethesda, Maryland, USA
Juliet E. Compston, MD, FRCP, FRCPath, FMedSciDepartment of MedicineUniversity of CambridgeCambridge, UK
Gary J.R. Cook, MBBS, MSc, MD, FRCR, FRCPDivision of Imaging Sciences and Biomedical
EngineeringKings College LondonLondon, UK
Cyrus Cooper, MA, DM, FRCP, FFPH, FMedSciThe MRC Lifecourse Epidemiology UnitUniversity of SouthamptonSouthampton General HospitalSouthampton, UK
Contributors xiii
Felicia CosmanColumbia College of Physicians and SurgeonsColumbia UniversityClinical Research CenterHelen Hayes HospitalWest HaverstrawNew York, New York, USA
Natalie E. CusanoDivision of EndocrinologyDepartment of MedicineCollege of Physicians and SurgeonsColumbia UniversityNew York, New York, USA
Terry F. Davies, MBBS, MD, FRCP, FACEThe Mount Sinai Bone ProgramDepartment of MedicineMount Sinai School of MedicineNew York, New York, USA
Bess Dawson-Hughes, MDJean Mayer USDA Human Nutrition
Research Center on AgingTufts UniversityBoston, Massachusetts, USA
David J.J. de Gorter, PhDInstitute for Molecular Cell BiologyUniversity of MünsterMünster, Germany
Marie Demay, MD Endocrine UnitMassachusetts General Hospital and Harvard Medical
School Boston, Massachusetts, USA
Elaine Dennison, MA, MB, BChir, MSc, PhDThe MRC Lifecourse Epidemiology UnitUniversity of SouthamptonSouthampton General HospitalSouthampton, UK
Matthew T. Drake, MD, PhDDepartment of Internal MedicineDivision of EndocrinologyCollege of MedicineMayo ClinicRochester, Minnesota, USA
Patricia Ducy, PhDDepartment of Pathology and Cell BiologyColumbia University Medical CenterNew York, New York, USA
Richard Eastell, MD, FRCP, FRCPath, FMedSciDepartment of Human MetabolismUniversity of SheffieldSheffield, UK
Peter R. Ebeling, MD, FRACPAustralian Institute for Musculoskeletal ScienceNorthWest Academic CentreThe University of MelbourneWestern HealthSt. Albans, Victoria, Australia
Michael J. Econs, MD, FACP, FACEEndocrinology and MetabolismMedicine and Medical and Molecular GeneticsIndiana University School of MedicineIndianapolis, Indiana, USA
Paul C. Edwards, MSc, DDS, FRCD(C)Department of Periodontics and Oral MedicineSchool of DentistryUniversity of MichiganAnn Arbor, Michigan, USA
Thomas A. Einhorn, MDDepartment of Orthopaedic SurgeryBoston University Medical CenterBoston, Massachusetts, USA
Florent Elefteriou, PhDVanderbilt Center for Bone BiologyVanderbilt University Medical CenterNashville, Tennessee, USA
William J. Evans, PhDMuscle Metabolism DPUGlaxoSmithKlineResearch Triangle Park, North Carolina, USA
Murray J. Favus, MDSection of Endocrinology, Diabetes, and MetabolismThe University of ChicagoChicago, Illinois, USA
Ignac FogelmanDivision of Imaging Sciences and Biomedical
EngineeringKings College LondonLondon, UK
Mark R. Forwood, PhDSchool of Medical Science and Griffith Health InstituteGriffith UniversityGold Coast, Australia
Peter A. FriedmanUniversity of PittsburghPittsburgh, Pennsylvania, USA
Benjamin J. Frisch, PhDWilmot Cancer CenterUniversity of Rochester School of Medicine and
DentistryRochester, New York, USA
xiv Contributors
J. Christopher Gallagher, MD, MRCPCreighton University Medical SchoolOmaha, Nebraska, USA
Harry K. Genant, MD, FACR, FRCRRadiology, Medicine and Orthopedic SurgeryUniversity of CaliforniaSan Francisco, California, USA
Francis H. Glorieux, OC, MD, PhDGenetics UnitShriners Hospital for Children–Canada and McGill
UniversityMontreal, Quebec, Canada
C.C. GlüerSektion Biomedizinische BildgebungKlinik für Diagnostische RadiologieUniversitätsklinikum Schleswig-HolsteinCampus KielKiel, Germany
Gopinath GnanasegaranDepartment of Nuclear MedicineGuy’s and St. Thomas’ NHS Foundation TrustLondon, UK
Deborah T. Gold, PhDDepartments of Psychiatry and Behavioral Sciences,
Sociology, and Psychology and NeuroscienceDuke University Medical CenterDurham, North Carolina, USA
Steven R. Goldring, MDHospital for Special SurgeryWeill Medical College of Cornell UniversityNew York, New York, USA
David Goltzman, MDDepartments of Medicine and PhysiologyMcGill UniversityMontreal, Canada
Susan L. Greenspan, MD, FACPDivisions of Geriatrics, Endocrinology and MetabolismDepartment of MedicineUniversity of Pittsburgh School of MedicinePittsburgh, Pennsylvania, USA
James F. Griffith, MB, BCh, BAO, MD, MRCP (UK), FRCR
Department of Imaging and Interventional RadiologyThe Chinese University of Hong KongHong Kong, China
Monica Grover, MDDepartment of Molecular and Human GeneticsBaylor College of MedicineHouston, Texas, USA
Theresa A. Guise, MDDepartment of MedicineDivision of EndocrinologyIndiana University School of MedicineIndianapolis, Indiana, USA
Neveen A.T. HamdyDepartment of Endocrinology and Metabolic DiseasesLeiden University Medical CenterLeiden, The Netherlands
Nicholas Harvey, MA, MB, BChir, MRCP, PhDThe MRC Lifecourse Epidemiology UnitUniversity of SouthamptonSouthampton General HospitalSouthampton, UK
Robert P. Heaney, MDCreighton University Omaha, Nebraska, USA
Charles Hildebolt, DDS, PhDMallinckrodt Institute of RadiologyWashington University in St. LouisSt. Louis, Missouri, USA
Steven P. Hodak, MDDivision of Endocrinology and MetabolismThe University of Pittsburgh School of MedicinePittsburgh, Pennsylvania, USA
Ingrid A. Holm, MD, MPHChildren’s Hospital BostonManton Center for Orphan Disease ResearchHarvard Medical SchoolBoston, Massachusetts, USA
Mara J. Horwitz, MDDivision of Endocrinology and MetabolismThe University of Pittsburgh School of MedicinePittsburgh, Pennsylvania, USA
Keith A. Hruska, MDDivision of Pediatric NephrologyDepartment of Pediatrics, Medicine and Cell BiologyWashington UniversitySt. Louis, Missouri, USA
Christina Jacobsen, MD, PhD Divisions of Endocrinology and Genetics Boston Children’s Hospital Harvard Medical School Boston, Massachusetts, USA
Suzanne M. Jan de Beur, MDDivision of Endocrinology and MetabolismDepartment of MedicineThe Johns Hopkins School of MedicineBaltimore, Maryland, USA
Contributors xv
Robert L. Jilka, PhDDivision of Endocrinology and MetabolismCenter for Osteoporosis and Metabolic Bone DiseasesUniversity of Arkansas for Medical SciencesCentral Arkansas Veterans Healthcare SystemLittle Rock, Arkansas, USA
Rachelle W. JohnsonDepartment of Veterans AffairsTennessee Valley Healthcare Systemand Vanderbilt Center for Bone Biologyand Department of Cancer BiologyVanderbilt UniversityNashville, Tennessee, USA
Graeme Jones, MBBS, FRACP, MDMenzies Research Institute TasmaniaUniversity of TasmaniaHobart, Tasmania, Australia
Stefan Judex, PhDDepartment of Biomedical EngineeringStony Brook University Stony Brook, New York, USA
Harald Jüppner, MDEndocrine Unit and Pediatric Nephrology UnitDepartments of Medicine and PediatricsHarvard Medical SchoolMassachusetts General HospitalBoston, Massachusetts, USA
John A KanisWHO Collaborating Centre for Metabolic Bone
DiseasesUniversity of Sheffield Medical SchoolSheffield, UK
Frederick S. Kaplan, MDDepartments of Orthopaedic Surgery and MedicineCenter for Research in FOP and Related DisordersPerelman School of Medicine at The University of
PennsylvaniaPhiladelphia, Pennsylvania, USA
Gerard Karsenty, MD, PhDDepartment of Genetics and DevelopmentColumbia UniversityNew York, New York, USA
Moustapha Kassem, MD, PhD, DSc Department of Endocrinology University Hospital of Odense Odense, Denmark
Richard W. Keen, MD, PhDInstitute of Orthopaedics and Musculoskeletal SciencesRoyal National Orthopaedic HospitalBrockley HillStanmoreMiddlesex, UK
Luluel M. KhanUniversity of TorontoDepartment of Radiation OncologyOdette Cancer CentreSunnybrook Health Sciences CentreToronto, Ontario, Canada
Sundeep Khosla, MDDepartment of Internal MedicineDivision of EndocrinologyCollege of MedicineMayo ClinicRochester, Minnesota, USA
Douglas P. Kiel, MD, MPHInstitute for Aging ResearchHebrew SeniorLifeDepartment of MedicineHarvard Medical SchoolBoston, Massachusetts, USA
Keith L. Kirkwood, DDS, PhDDepartment of Craniofacial BiologyThe Center for Oral Health ResearchMedical University of South CarolinaCharleston, South Carolina, USA
Michael Kleerekoper, MBBS, FACB, FACP, MACEDepartment of Medicine, Division of EndocrinologyUniversity of Toledo Medical CollegeToledo, Ohio, USA
Gordon L. Klein, MD, MPHDepartment of Orthopaedic SurgeryUniversity of Texas Medical BranchGalveston, Texas, USA
John Klingensmith, PhDDepartment of Cell BiologyDuke University Medical CenterDurham, North Carolina, USA
Stephen J. Knohl, MDDepartment of Medicine Division of NephrologyState University of New York Upstate Medical
UniversitySyracuse, New York, USA
xvi Contributors
Scott L. Kominsky, PhDDepartments of Orthopaedic Surgery and OncologyJohns Hopkins University School of MedicineBaltimore, Maryland, USA
Christopher S. Kovacs, MD, FRCPC, FACP, FACE Faculty of Medicine–Endocrinology Health Sciences CentreMemorial University of NewfoundlandSt. John’s, Newfoundland, Canada
Paul H. Krebsbach, DDS, PhDDepartment of Biologic and Materials SciencesSchool of DentistryThe University of MichiganAnn Arbor, Michigan, USA
Henry M. Kronenberg, MDEndocrine UnitMassachusetts General Hospitaland Harvard Medical SchoolBoston, Massachusetts, USA
Craig B. Langman, MDFeinberg School of MedicineNorthwestern UniversityChicago, Illinois, USA
Brendan Lee, MD, PhDHoward Hughes Medical InstituteDepartment of Molecular and Human GeneticsBaylor College of MedicineHouston, Texas, USA
Mary G. Lee, DMD, MSDDepartment of Craniofacial Biologyand the Center for Oral Health ResearchMedical University of South CarolinaCharleston, South Carolina, USA
Michael A. Levine, MD, FAAP, FACP, FACEDivision of Endocrinology and DiabetesThe Children’s Hospital of Philadelphia and
Department of PediatricsUniversity of Pennsylvania Perelman School of
MedicinePhiladelphia, Pennsylvania, USA
Paul Lips, MD, PhDDepartment of Internal Medicine/EndocrinologyVU University Medical CenterAmsterdam, The Netherlands
David G. Little, MBBS, FRACS(Orth), PhDPaediatrics and Child HealthUniversity of SydneyOrthopaedic Research and BiotechnologyThe Children’s Hospital at WestmeadWestmead, Australia
Shane A.J. LloydDepartment of Orthopaedics and RehabilitationDivision of Musculoskeletal SciencesThe Pennsylvania State University College of MedicineHershey, Pennsylvania, USA
Karen M. Lyons, PhDUCLA Orthopaedic HospitalDepartment of Orthopaedic SurgeryDepartment of Molecular, Cell & Developmental
BiologyUniversity of CaliforniaLos Angeles, California, USA
Sharmila Majumdar, PhDDepartment of Radiology and Biomedical Imagingand Orthopedic Surgery UCSFand Department of Bioengineering UC BerkeleySan Francisco, California, USA
Stavros C. Manolagas, MD, PhDDivision of Endocrinology and MetabolismCenter for Osteoporosis and Metabolic Bone DiseasesUniversity of Arkansas for Medical Sciencesand the Central Arkansas Veterans Healthcare SystemLittle Rock, Arkansas, USA
Joan C. Marini, MD, PhDNational Institute of Child Health and Human
DevelopmentBone and Extracellular Matrix BranchNational Institutes of HealthBethesda, Maryland, USA
T. John Martin, MD, DScSt. Vincent’s Institute of Medical ResearchUniversity of Melbourne Department of MedicineMelbourne, Australia
Stephen J. Marx, MDGenetics and Endocrinology SectionMetabolic Diseases BranchNational Institute of Diabetes and Digestive and
Kidney DiseasesNational Institutes of HealthBethesda, Maryland, USA
Maiko Matsui, BScDepartment of Cell BiologyDuke University Medical CenterDurham, North Carolina, USA
Hani H. Mawardi, BDS, DMScDivision of Oral MedicineKing Abdulaziz UniversityFaculty of DentistryJeddah, Saudi Arabia
Contributors xvii
Laurie K. McCauley, DDS, MS, PhD University of Michigan School of Dentistry Ann Arbor, Michigan, USA
Michael R. McClungOregon Osteoporosis CenterPortland, Oregon, USA
Lisa K. Micklesfield, PhDMRC/Wits Developmental Pathways for Health
Research UnitDepartment of PaediatricsFaculty of Health SciencesUniversity of the WitwatersrandJohannesburg, South Africa
Paul D. Miller, MD, FACPUniversity of Colorado Health Sciences Center Colorado Center for Bone Research Lakewood, Colorado, USA
Thimios Mitsiadis, DDS, MS, PhDInstitute of Oral BiologyDepartment of Orofacial Development & Regeneration,
ZZMDepartment of MedicineUniversity of ZurichZurich, Switzerland
Elise F. Morgan, PhDDepartment of Mechanical EngineeringBoston UniversityBoston, Massachusetts, USA
Tuan V. NguyenOsteoporosis and Bone Biology Research ProgramGarvan Institute of Medical ResearchSydney, Australia
Robert A. Nissenson, PhD Endocrine Research UnitVA Medical CenterDepartments of Medicine and PhysiologyUniversity of CaliforniaSan Francisco, California, USA
Shane A. Norris, PhDMRC/Wits Developmental Pathways for Health
Research UnitDepartment of PaediatricsFaculty of Health SciencesUniversity of the WitwatersrandJohannesburg, South Africa
Patrick W. O’Donnell, MD, PhD Center for Musculoskeletal Oncology Department of Orthopaedic Surgery Markey Cancer Center University of Kentucky Lexington, Kentucky, USA
Eric S. OrwollOregon Health and Science UniversityPortland, Oregon, USA
Petros Papagerakis, DDS, MS, PhDDepartment of Orthodontics and Pediatric DentistryCenter for OrganogenesisCenter for Computational Medicine and BioinformaticsSchools of Dentistry and MedicineUniversity of MichiganAnn Arbor, Michigan, USA
Socrates E. Papapoulos, MD, PhDDepartment of Endocrinology and Metabolic DiseasesLeiden University Medical CenterLeiden, The Netherlands
John M. Pettifor, MBBCh, PhDMRC/Wits Developmental Pathways for Health
Research UnitDepartment of PaediatricsFaculty of Health SciencesUniversity of the WitwatersrandJohannesburg, South Africa
Robert J. Pignolo, MD, PhDCenter for Research in FOP and Related DisordersDepartment of Orthopaedic SurgeryThe University of Pennsylvania School of MedicinePhiladelphia, Pennsylvania, USA
L. Darryl QuarlesDivision of NephrologyDepartment of MedicineUniversity of Tennessee Health Science CenterMemphis, Tennessee, USA
Manoj Ramachandran, BSc, MBBS, MRCS, FRCSThe Royal London and St. Bartholomew’s HospitalsBarts Health NHS TrustBarts and The London School of Medicine and
DentistryQueen MaryUniversity of LondonLondon, England
Francesco Ramirez, PhDDepartment of Pharmacology and Systems
TherapeuticsMount Sinai School of MedicineNew York, New York, USA
xviii Contributors
Robert R. Recker, MD, MACP, FACEDepartment of MedicineSection of EndocrinologyOsteoporosis Research CenterCreighton University Medical CenterOmaha, Nebraska, USA
Ian R. Reid, MBChB, MD, FRACPDepartment of MedicineUniversity of AucklandAuckland, New Zealand
Mara RiminucciDipartimento di Medicina MolecolareUniversita’ La SapienzaRome, Italy
David L. Rimoin, MD, PhD*Medical Genetics InstituteCedars-Sinai Medical CenterLos Angeles, California, USA
René Rizzoli, MDDivision of Bone DiseasesDepartment of Internal Medicine SpecialtiesGeneva University Hospital and Faculty of MedicineGeneva, Switzerland
Pamela Gehron RobeyCraniofacial and Skeletal Diseases BranchNational Institute of Dental and Craniofacial ResearchNational Institutes of HealthDepartment of Health and Human ServicesBethesda, Maryland, USA
G. David RoodmanDivision of Hematology/OncologyIndiana University School of MedicineIndianapolis, Indiana, USA
Clifford J. Rosen, MD Tufts University School of Medicine Maine Medical Center Research Institute Scarborough, Maine, USA
Vicki Rosen, PhDDepartment of Developmental BiologyHarvard School of Dental MedicineBoston, Massachusetts, USA
F. Patrick RossDepartment of Pathology and ImmunologyWashington University School of MedicineSt. Louis, Missouri, USA
Clinton T. Rubin, PhDDepartment of Biomedical EngineeringStony Brook UniversityStony Brook, New York, USA
Janet Rubin, MDDepartment of MedicineUniversity of North Carolina School of MedicineChapel Hill, North Carolina, USA
Mishaela R. Rubin, MDDivision of EndocrinologyDepartment of MedicineColumbia University College of PhysiciansNew York, New York, USA
Mary D. Ruppe, MDDepartment of MedicineDivision of EndocrinologyThe Methodist HospitalHouston, Texas, USA
Lynn Y. SakaiDepartment of Biochemistry and Molecular BiologyOregon Health and Science UniversityShriners Hospital for ChildrenPortland, Oregon, USA
Kyu Sang Joeng, PhDDepartment of Molecular and Human GeneticsBaylor College of MedicineHouston, Texas, USA
Anne L. Schafer, MDDepartment of MedicineUniversity of California, San FranciscoSan Francisco, California, USA
Steven J. Scheinman, MDThe Commonwealth Medical CollegeScranton, Pennsylvania, USA
Ego Seeman, BSc, MBBS, FRACP, MDDepartment of Endocrinology and MedicineRepatriation CampusAustin HealthUniversity of MelbourneMelbourne, Australia
Michael Seifert, MDDivision of Pediatric NephrologyDepartment of PediatricsWashington University and Southern Illinois
UniversitySt. Louis, Missouri, USA
*Deceased.
Contributors xix
Gerhard SengleDepartment of Biochemistry and Molecular BiologyOregon Health and Science Universityand Shriners Hospital for ChildrenPortland, Oregon, USA
Elizabeth ShaneDivision of EndocrinologyDepartment of MedicineCollege of Physicians and SurgeonsColumbia UniversityNew York, New York, USA
Sue Shapses, PhDDepartment of Nutritional SciencesRutgers UniversityNewark, New Jersey, USA
Nicholas Shaw, MBChB, FRCPCHDepartment of EndocrinologyBirmingham Children’s HospitalBirmingham, West Midlands, UK
Yiping Shen, PhD Boston Children’s Hospital Harvard Medical SchoolBoston, Massachusetts, USA Shanghai Jiaotong University School of MedicineShanghai, China
Dolores Shoback, MDUniversity of California, San FranciscoEndocrine Research UnitSan Francisco VA Medical CenterSan Francisco, California, USA
Eileen M. Shore, PhD Departments of Orthopaedic Surgery and Genetics Center for Research in FOP and Related DisordersPerelman School of Medicine at the University of
Pennsylvania Philadelphia, Pennsylvania, USA
Rebecca Silbermann, MDIndiana University School of MedicineIndianapolis, Indiana, USA
Shonni J. Silverberg, MDDivision of EndocrinologyDepartment of MedicineCollege of Physicians and Surgeons Columbia UniversityNew York, New York, USA
James P. Simmer, DDS, PhDDepartment of Biological and Materials SciencesUniversity of Michigan School of DentistryAnn Arbor, Michigan, USA
Ethel S. Siris, MDColumbia University Medical CenterNew York Presbyterian HospitalNew York, New York, USA
Julie A. Sterling, PhDDepartment of Veterans AffairsTennessee Valley Healthcare Systemand Vanderbilt Center for Bone BiologyDepartment of Medicine/Clinical PharmacologyVanderbilt UniversityNashville, Tennessee, USA
Andrew F. Stewart, MD Diabetes Obesity and Metabolism Institute Icahn School of Medicine at Mount Sinai New York, New York, USA
Deeptha Sukumar, PhDDepartment of Nutritional SciencesRutgers UniversityNewark, New Jersey, USA
Li SunThe Mount Sinai Bone ProgramDepartment of MedicineMount Sinai School of MedicineNew York, New York, USA
Pawel Szulc, MD, PhDINSERMUniversité de LyonLyon, France
Shu Takeda, MD, PhDSection of Nephrology, Endocrinology and MetabolismDepartment of Internal MedicineSchool of MedicineKeio UniversityTokyo, Japan
Jianning Tao, PhDDepartments of Molecular and Human GeneticsBaylor College of MedicineTexas Children’s HospitalHouston, Texas, USA
Pamela Taxel, MDDivision of Endocrinology and MetabolismUniversity of Connecticut Health CenterFarmington, Connecticut, USA
Peter ten Dijke, PhDDepartment of Molecular Cell Biologyand Centre for Biomedical Genetics Leiden University Medical CentreLeiden, The Netherlands
xx Contributors
Rajesh V. Thakker, MD, ScD, FRCP, FRCPath, FMedSci
Academic Endocrine UnitNuffield Department of Clinical MedicineOxford Centre for DiabetesEndocrinology and Metabolism (OCDEM)Churchill HospitalHeadington, Oxford, UK
Anna N.A. Tosteson, ScDMultidisciplinary Clinical Research Center in
Musculoskeletal DiseasesGeisel School of Medicine at DartmouthLebanon, New Hampshire, USA
Dwight A. Towler, MD, PhD Diabetes and Obesity Research Center Sanford-Burnham Medical Research Institute at Lake
Nona Orlando, Florida, USA
Bich H. TranOsteoporosis and Bone Biology Research ProgramGarvan Institute of Medical ResearchSydney, Australia
Nathaniel S. Treister, DMD, DMScDivision of Oral Medicine and DentistryBrigham and Women’s HospitalBoston, Massachusetts, USA
Geertje van der Horst, PhDDepartment of UrologyLeiden University Medical CentreLeiden, The Netherlands
Gabri van der Pluijm, PhDDepartment of UrologyLeiden University Medical CentreLeiden, The Netherlands
Catherine Van Poznak, MDDepartment of Internal MedicineUniversity of MichiganAnn Arbor, Michigan, USA
Natasja M. van Schoor, PhDDepartment of Epidemiology and BiostatisticsEMGO Institute for Health and Care ResearchVU University Medical CenterAmsterdam, The Netherlands
Kong Wah Ng, MBBS, MD, FRACP, FRCPDepartment of Endocrinology and DiabetesSt. Vincent’s HealthSt. Vincent’s InstituteUniversity of Melbourne Department of MedicineFitzroy, Victoria, Australia
Lisa L. Wang, MDTexas Children’s Cancer CenterBaylor College of MedicineHouston, Texas, USA
Qingju WangDepartment Endocrinology and MedicineRepatriation CampusAustin HealthUniversity of MelbourneMelbourne, Australia
Nelson B. Watts, MDMercy Health Osteoporosis and Bone Health ServicesCincinnati, Ohio, USA
Connie M. Weaver, PhDPurdue UniversityNutrition ScienceWest Lafayette, Indiana, USA
Kristy Weber, MDDepartments of Orthopaedic Surgery and OncologyJohns Hopkins School of MedicineBaltimore, Maryland, USA
Robert S. Weinstein, MDDivision of Endocrinology and MetabolismCenter for Osteoporosis and Metabolic Bone DiseasesDepartment of Internal Medicineand the Central Arkansas Veterans Healthcare SystemUniversity of Arkansas for Medical SciencesLittle Rock, Arkansas, USA
Kenneth E. White, PhDMedical and Molecular GeneticsIndiana University School of MedicineIndianapolis, Indiana, USA
Michael P. Whyte, MDDivision of Bone and Mineral DiseasesWashington University School of MedicineBarnes-Jewish Hospitaland Center for Metabolic Bone Disease and Molecular
ResearchShriners Hospital for ChildrenSt. Louis, Missouri, USA
Jeffrey S. Willey, PhDDepartment of Radiation OncologyWake Forest School of MedicineWinston-Salem, North Carolina, USA
Tania Winzenberg, MBBS, FRACGP, MMedSc, PhDMenzies Research Institute TasmaniaUniversity of TasmaniaHobart, Tasmania, Australia
Contributors xxi
Sook-Bin Woo, DMD, MMScDivision of Oral Medicine and DentistryBrigham and Women’s HospitalBoston, Massachusetts, USA
John J. WysolmerskiSection of Endocrinology and MetabolismDepartment of Internal MedicineYale University School of MedicineNew Haven, Connecticut, USA
Tao Yang, PhDCenter for Skeletal Disease ResearchLaboratory of Skeletal BiologyVan Andel Research Institute,Grand Rapids, Michigan, USA
Yingzi YangDevelopmental Genetics SectionGenetic Disease Research BranchNational Human Genome Research InstituteBethesda, Maryland, USA
Raz YirmiyaDepartment of PsychologyThe Hebrew University of JerusalemJerusalem, Israel
Tony Yuen, PhDThe Mount Sinai Bone ProgramDepartment of MedicineMount Sinai School of MedicineNew York, New York, USA
Mone Zaidi, MBBS, PhDThe Mount Sinai Bone ProgramDepartment of MedicineMount Sinai School of MedicineNew York, New York, USA
Alberta ZalloneDepartment of HistologyUniversity of BariBari, Italy
Michael J. Zuscik, PhDDepartment of Orthopaedics & RehabilitationCenter for Musculoskeletal ResearchUniversity of Rochester Medical CenterRochester, New York, USA
xxii
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
xxiii
Welcome to the eighth edition of the Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism! Loyal readers of previous editions will find the same up-to-date summaries of clinical diseases of the skeleton as well as overviews of skeletal growth, remod-eling, and pathophysiological disorders that they have seen in the past. As always, calcium, phosphorus, and vitamin D are reviewed extensively and updated. New visitors to the Primer will find a potpourri of informa-tion that can assist readers at the bench and at the bedside. The many tables, references, figures, and illus-trations are certain to be helpful. In fact, many figures and illustrations appear in full color for the first time in 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
Preface to the Eighth Edition of the Primer
bone as an organ system is updated. As with previous editions, it is the contributing authors, who are at the top in their respective fields, who make the Primer so valuable.
And as a real treat, our cover is an artistic image of bone painted by Mr. Toby Kahn. His creation reminds us that, since the last edition, the osteocyte has emerged as a major regulator of skeletal remodeling as well as mineral homeostasis.
The eighth edition is dedicated to the memory of Dr. Larry Raisz, a giant in our field who led and inspired all of us, and who particularly found the Primer to be the premier textbook of bone.
Clifford J. Rosen, MD
xxiv
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 specialties, 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 integration of basic and clinical science and to facilitate the translation of that science into clinical practice. For more than 30 years, our Society has remained true to its innovative and inclusive founding principles, fostering an encouraging environment for researchers and clinicians to develop and discuss the latest findings.
ASBMR’s work is guided by the following key strategic objectives:
• 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 multidisciplinary connections among our investiga-tors, awarding grants and advocating for funding for bone and mineral research
• COMMUNICATING WITH THE NATIONAL INSTITUTES OF HEALTH to both discover and influence the latest directions in basic, clinical and translational research
• SUPPORTING YOUNG INVESTIGATORS through continuing education, grant funding, professional net-working and mentoring opportunities
Learn more about ASBMR and the vast learning and networking opportunities it offers by visiting www.asbmr.org today.
We Make the DiscoveriesThat Keep Bones Healthy for a Lifetime
xxv
The American Society for Bone and Mineral Research is pleased and excited to present this fully revised, updated and expanded eighth edition of the Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Dr. Clifford Rosen returns as Editor-in-Chief, overseeing even greater coverage of the field to include the addition of a completely new section on “The Skeleton and Its Integration with Other Tissues.” In addition to new content, many new reader-friendly fea-tures have been incorporated into the design of the book.
This eighth edition presents numerous full-color figures for the first 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 scientific content that have long been the trade-mark feature of the book, ensuring the Primer maintains its reputation as an essential reference in the field of bone health.
President’s Preface
Along with these changes, a new companion site has been developed at www.asbmrprimer.com to provide researchers, instructors, clinicians, and students with valuable supplementary materials that support and expand the content of the book.
The eighth edition of our Primer maintains the strong tradition developed by its predecessors while continuing to evolve to serve the changing needs of the communities it serves. We thank and commend all those involved in making this new edition a reality.
Lynda F. Bonewald, PhDPresident, ASBMR
xxvi
This book is accompanied by a companion website:www.asbmrprimer.com
The website includes:
• Videos• Editors’ biographies• PowerPoints of all figures from the book for downloading • Useful website links
About the Companion Website
1
Section IMolecular, Cellular, and Genetic Determinants of Bone Structure
and FormationSection Editor Karen M. Lyons
Chapter 1. Skeletal Morphogenesis and Embryonic Development 3Yingzi Yang
Chapter 2. Signal Transduction Cascades Controlling Osteoblast Differentiation 15David J.J. de Gorter and Peter ten Dijke
Chapter 3. Osteoclast Biology and Bone Resorption 25F. Patrick Ross
Chapter 4. Osteocytes 34Lynda F. Bonewald
Chapter 5. Connective Tissue Pathways That Regulate Growth Factors 42Gerhard Sengle and Lynn Y. Sakai
Chapter 6. The Composition of Bone 49Adele L. Boskey and Pamela Gehron Robey
Chapter 7. Assessment of Bone Mass and Microarchitecture in Rodents 59Blaine A. Christiansen
Chapter 8. Animal Models: Genetic Manipulation 69Karen M. Lyons
Chapter 9. Animal Models: Allelic Determinants for BMD 76Robert D. Blank
Chapter 10. Neuronal Regulation of Bone Remodeling 82Florent Elefteriou and Gerard Karsenty
Chapter 11. Skeletal Healing 90Michael J. Zuscik
Chapter 12. Biomechanics of Fracture Healing 99Elise F. Morgan and Thomas A. Einhorn
Chapter 13. Human Genome-Wide Association (GWA) Studies 106Douglas P. Kiel
Chapter 14. Circulating Osteogenic Cells 111Robert J. Pignolo and Moustapha Kassem
Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, Eighth Edition. Edited by Clifford J. Rosen.© 2013 American Society for Bone and Mineral Research. Published 2013 by John Wiley & Sons, Inc.
