Table Of ContentPrimer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism
Ninth Edition
An Official Publication of the American Society for Bone and Mineral Research
Primer on the Metabolic Bone
Diseases and Disorders of
Mineral Metabolism
Ninth Edition
Editor-in-Chief
John P. Bilezikian, MD, PhD (hon)
Senior Associate Editors
Roger Bouillon, MD, PhD, FRCP
Thomas Clemens, PhD
Juliet Compston, OBE, MD, FRCP, FRCPE, FRCPath, FMedSci
Associate Editors
Douglas C. Bauer, MD
Peter R. Ebeling, AO, MBBS, MD, FRACP
Klaus Engelke, PhD
David Goltzman, MD
Theresa Guise, MD
Suzanne M. Jan de Beur, MD
Harald Jüppner, MD
Karen Lyons, PhD
Laurie McCauley, DDS, MS, PhD
Michael R. McClung, MD, FACP, FACE
Paul D. Miller, MD, FACP
Socrates E. Papapoulos, MD, PhD
G. David Roodman, MD, PhD
Clifford J. Rosen, MD
Ego Seeman, BSc, MBBS, FRACP, MD, AM
Rajesh V. Thakker, MD, ScD, FRCP, FRCPath, FMedSci, FRS
Michael P. Whyte, MD
Mone Zaidi, MD, PhD, FRCP
This edition first published 2019 © 2019 by American Society for Bone and Mineral Research
Edition History
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
Eighth Edition published by American Society for Bone and Mineral Research © 2013 American Society for Bone and Mineral Research
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The right of John P. Bilezikian to be identified as the author of the editorial material in this work has been asserted in accordance with law.
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Library of Congress Cataloging-in-Publication Data
Names: Bilezikian, John P., editor.
Title: Primer on the metabolic bone diseases and disorders of mineral metabolism.
Description: Ninth edition / editor-in-Chief, John P. Bilezikian, MD, PhD (hon) ; senior associate editors,
Roger Bouillon, MD, PhD, FRCP, Tom Clemens, PhD, Juliet Compston, MD, FRCP, FRCPath, FMedSci ;
associate editors, Doug Bauer, MD [and nine others]. | Hoboken, NJ : Wiley-Blackwell, 2019. |
Includes bibliographical references and index. |
Identifiers: LCCN 2018038448 (print) | LCCN 2018038631 (ebook) | ISBN 9781119266570 (Adobe PDF) |
ISBN 9781119266587 (ePub) | ISBN 9781119266563 (paperback)
Subjects: LCSH: Bones–Metabolism–Disorders. | Mineral metabolism–Disorders. | Bones–Diseases. |
Minerals–Metabolism. | BISAC: SCIENCE / Life Sciences / Cytology.
Classification: LCC RC931.M45 (ebook) | LCC RC931.M45 P75 2019 (print) | DDC 616.7/16–dc23
LC record available at https://lccn.loc.gov/2018038448
Cover images: (Top row left to right) © Wiley; © Paul Gunning/Science Source; By kind permission of Alan Boyde;
Courtesy of Kevin Mackenzie, Microscopy Facility University of Aberdeen; © GenScript USA Inc.; © Designua/Shutterstock;
Reproduced with permission from Juliet Compston, M.D.; (Bottom row left to right) Courtesy of Prof. Ego Seeman; © designua/123RF;
© SCOTT CAMAZINE/science source; © ZEPHYR/science source; (Floor) © DonNichols/Getty Images; (Frames) © iStock.com/JackF
Cover design by Wiley
Set in 9.5/11pt TrumpMediaeval by SPi Global, Pondicherry, India
10 9 8 7 6 5 4 3 2 1
Contents
Contributors xi 9 Recent Developments in Understanding the Role
Preface to the Ninth Edition of the Primer: of Wnt Signaling in Skeletal Development
John P. Bilezikian xxiv and Disease 68
About ASBMR xxv Zhendong A. Zhong, Nicole J. Ethen,
and Bart O. Williams
President’s Preface: Michael J. Econs xxvi
About the Companion Website xxvii
10 Mechanotransduction in Bone Formation
and Maintenance 75
Section I: Molecular and Cellular Determinants Whitney A. Bullock, Lilian I. Plotkin, Alexander
of Bone Structure and Function 1 G. Robling, and Fredrick M. Pavalko
Section Editor: Karen Lyons
11 The Composition of Bone 84
1 Early Skeletal Morphogenesis in Embryonic Adele L. Boskey and Pamela G. Robey
Development 3
Yingzi Yang
12 Assessment of Bone Mass, Structure, and Quality
in Rodents 93
2 Endochondral Ossification 12 Jeffry S. Nyman and Deepak Vashishth
Courtney M. Karner and Matthew J. Hilton
13 Skeletal Healing: Cellular and Molecular
3 Local and Circulating Osteoprogenitor Determinants 101
Cells and Lineages 20 Alayna E. Loiselle and Michael J. Zuscik
Naomi Dirckx and Christa Maes
14 Biomechanics of Fracture Healing 108
4 Osteoblasts: Function, Development, Elise F. Morgan, Amira I. Hussein,
and Regulation 31 and Thomas A. Einhorn
Elizabeth W. Bradley, Jennifer J. Westendorf, Andre
J. van Wijnen, and Amel Dudakovic
Section II: Skeletal Physiology 115
Section Editor: Ego Seeman
5 Osteocytes 38
Lynda F. Bonewald
15 Human Fetal and Neonatal Bone
Development 117
6 Osteoclast Biology and Bone Resorption 46 Tao Yang, Monica Grover, Kyu Sang Joeng,
Hiroshi Takayanagi and Brendan Lee
7 Signal Transduction Cascades Controlling 16 Skeletal Growth: a Major Determinant of Bone’s
Osteoblast Differentiation 54 Structural Diversity in Women and Men 123
David J.J. de Gorter, Gonzalo Sánchez‐Duffhues, Ego Seeman
and Peter ten Dijke
17 Racial Differences in the Acquisition
8 The TGF‐β Superfamily in Bone Formation and Age‐related Loss of Bone Strength 131
and Maintenance 60 Shane A. Norris, Marcella D. Walker, Kate Ward,
Ce Shi and Yuji Mishina Lisa K. Micklesfield, and John M. Pettifor
v
vi Contents
18 Calcium, Vitamin D, and Other Nutrients During Section IV: Investigation of Metabolic Bone
Growth 135 Diseases 241
Tania Winzenberg and Graeme Jones Section Editors: Douglas C. Bauer
and Klaus Engelke
19 Mechanical Loading and the Developing
Skeleton 141 31 Techniques of Bone Mass Measurement
Mark R. Forwood in Children with Risk Factors
for Osteoporosis 243
Nicola J. Crabtree and Leanne M. Ward
20 Pregnancy and Lactation 147
Christopher S. Kovacs and Henry M.
Kronenberg 32 Standard Techniques of Bone Mass Measurement
in Adults 252
21 Menopause and Age‐related Bone Loss 155 E. Michael Lewiecki, Paul D. Miller,
Carlos M. Isales and Ego Seeman and Nelson B. Watts
33 Advanced Techniques of Bone Mass Measurements
Section III: Mineral Homeostasis 163
and Strength in Adults 260
Section Editors: David Goltzman
Kyle K. Nishiyama, Enrico Dall’Ara,
and Harald Jüppner
and Klaus Engelke
22 Regulation of Calcium Homeostasis 165
34 Magnetic Resonance Imaging of Bone 272
Line Vautour and David Goltzman
Sharmila Majumdar
23 Magnesium Homeostasis 173
35 Trabecular Bone Score 277
Aliya Aziz Khan, Asiya Sbayi, and Karl Peter
Barbara C. Silva and William D. Leslie
Schlingmann
24 Fetal Calcium Metabolism 179 36 Reference Point Indentation 287
Christopher S. Kovacs Adolfo Diez‐Perez and Joshua N. Farr
25 FGF23 and the Regulation of Phosphorus 37 Biochemical Markers of Bone Turnover
Metabolism 187 in Osteoporosis 293
Kenneth E. White and Michael J. Econs Pawel Szulc, Douglas C. Bauer,
and Richard Eastell
26 Gonadal Steroids 194
Stavros C. Manolagas and Maria Schuller 38 Scintigraphy and PET in Metabolic
Almeida Bone Disease 302
Lorenzo Nardo, Paola A. Erba,
and Benjamin L. Franc
27 Parathyroid Hormone 205
Thomas J. Gardella, Robert A. Nissenson, and
Harald Jüppner 39 Bone Histomorphometry in Clinical
Practice 310
28 Parathyroid Hormone‐Related Protein 212 Robert R. Recker and Carolina
John J. Wysolmerski and T. John Martin Aguiar Moreira
29 Calcium‐Sensing Receptor 221 40 Diagnosis and Classification of Vertebral
Geoffrey N. Hendy Fracture 319
James F. Griffith and Harry K. Genant
30 Vitamin D: Production, Metabolism, Action,
and Clinical Requirements 230 41 FRAX: Assessment of Fracture Risk 331
Daniel D. Bikle, John S. Adams, and Sylvia John A. Kanis, Eugene V. McCloskey,
Christakos Nicholas C. Harvey, and William D. Leslie
Contents vii
Section V: Genetics of Bone 341 53 Juvenile Osteoporosis 419
Section Editor: Rajesh V. Thakker Francis H. Glorieux and Craig Munns
42 Introduction to Genetics 343 54 Transplantation Osteoporosis 424
Paul J. Newey, Michael P. Whyte, and Peter R. Ebeling
Rajesh V. Thakker
55 Premenopausal Osteoporosis 436
43 Animal Models: Genetic Manipulation 351
Adi Cohen and Elizabeth Shane
Karen Lyons
56 Osteoporosis in Men 443
44 Animal Models: Allelic Determinants for Bone
Eric S. Orwoll and Robert A. Adler
Mineral Density 359
J. H. Duncan Bassett, Graham R. Williams, and
Robert D. Blank 57 Bone Stress Injuries 450
Stuart J. Warden and David B. Burr
45 Transcriptional Profiling for Genetic
Assessment 367
58 Inflammation‐Induced Bone Loss in the
Aimy Sebastian and Gabriela G. Loots
Rheumatic Diseases 459
Ellen M. Gravallese and Steven R. Goldring
46 Approaches to Genetic Testing 373
Christina Jacobsen, Yiping Shen, and
59 Glucocorticoid‐Induced Osteoporosis 467
Ingrid A. Holm
Kenneth Saag and Robert A. Adler
47 Human Genome‐Wide Association Studies 378
Douglas P. Kiel, Emma L. Duncan, and Fernando 60 Human Immunodeficiency Virus and Bone 474
Michael T. Yin and Todd T. Brown
Rivadeneira
48 Translational Genetics of Osteoporosis: From 61 Effects on the Skeleton from Medications Used
Population Association to Individualized to Treat Nonskeletal Disorders 482
Nelson B. Watts
Assessment 385
Bich Tran, Jacqueline R. Center, and
Tuan V. Nguyen 62 Diabetes and Fracture Risk 487
Serge Ferrari, Nicola Napoli,
and Ann Schwartz
Section VI: Osteoporosis 393
Section Editors: Paul D. Miller, Socrates E. Papapoulos,
and Michael R. McClung 63 Obesity and Skeletal Health 492
Juliet Compston
49 Osteoporosis: An Overview 395
Michael R. McClung, Paul D. Miller, and Socrates 64 Sarcopenia and Osteoporosis 498
E. Papapoulos Gustavo Duque and Neil Binkley
50 The Epidemiology of Osteoporotic Fractures 398 65 Management of Osteoporosis in Patients
Nicholas C. Harvey, Elizabeth M. Curtis, Elaine M. with Chronic Kidney Disease 505
Dennison, and Cyrus Cooper Paul D. Miller
51 Fracture Liaison Service 405 66 Other Secondary Causes of Osteoporosis 510
Piet Geusens, John A. Eisman, Andrea Singer, and Neveen A. T. Hamdy and Natasha M.
Joop van den Bergh Appelman‐Dijkstra
52 Sex Steroids and the Pathogenesis 67 Exercise for Osteoporotic Fracture Prevention
of Osteoporosis 412 and Management 517
Matthew T. Drake and Sundeep Khosla Robin M. Daly and Lora Giangregorio
viii Contents
68 Prevention of Falls 526 82 Primary Hyperparathyroidism 619
Heike A. Bischoff‐Ferrari Shonni J. Silverberg, Francisco Bandeira, Jianmin
Liu, Claudio Marcocci, and Marcella D. Walker
69 Nutritional Support for Osteoporosis 534
Connie M. Weaver, Bess Dawson‐Hughes, 83 Familial States of Primary
Rene Rizzoli, and Robert P. Heaney Hyperparathyroidism 629
Andrew Arnold, Sunita K. Agarwal,
and Rajesh V. Thakker
70 Estrogens, Selective Estrogen Receptor Modulators,
and Tissue‐Selective Estrogen Complex 541
Tobias J. de Villiers 84 Non‐Parathyroid Hypercalcemia 639
Mara J. Horwitz
71 Bisphosphonates for Postmenopausal
Osteoporosis 545 85 Hypocalcemia: Definition, Etiology, Pathogenesis,
Andrea Giusti and Socrates E. Papapoulos Diagnosis, and Management 646
Anne L. Schafer and Dolores M. Shoback
72 Denosumab 553
Aline Granja Costa, E. Michael Lewiecki, 86 Hypoparathyroidism 654
and John P. Bilezikian Tamara Vokes, Mishaela R. Rubin, Karen K. Winer,
Michael Mannstadt, Natalie E. Cusano, Harald
Jüppner, and John P. Bilezikian
73 Parathyroid Hormone and Abaloparatide Treatment
for Osteoporosis 559
Felicia Cosman and Susan L. Greenspan 87 Pseudohypoparathyroidism 661
Agnès Linglart, Michael A. Levine, and Harald
Jüppner
74 Combination Anabolic and Antiresorptive Therapy
for Osteoporosis 567
Joy N. Tsai and Benjamin Z. Leder 88 Disorders of Phosphate Homeostasis 674
Mary D. Ruppe and Suzanne M. Jan de Beur
75 Strontium Ranelate and Calcitonin 573
Leonardo Bandeira and E. Michael Lewiecki 89 Rickets and Osteomalacia 684
Michaël R. Laurent, Nathalie Bravenboer,
Natasja M. Van Schoor, Roger Bouillon, John M.
76 Adverse Effects of Drugs for Osteoporosis 579
Pettifor, and Paul Lips
Bo Abrahamsen and Daniel Prieto‐Alhambra
90 Pathophysiology and Treatment of Chronic Kidney
77 Orthopedic Principles of Fracture
Disease–Mineral and Bone Disorder 695
Management 588
Mark R. Hanudel, Sharon M. Moe,
Manoj Ramachandran and David G. Little
and Isidro B. Salusky
78 Adherence to Osteoporosis Therapies 593
91 Disorders of Mineral Metabolism in Childhood 705
Stuart L. Silverman and Deborah T. Gold
Thomas O. Carpenter and Nina S. Ma
79 Cost‐Effectiveness of Osteoporosis Treatment 597
92 Paget Disease of Bone 713
Anna N.A. Tosteson
Julia F. Charles, Ethel S. Siris, and G. David
Roodman
80 Future Therapies 603
Michael R. McClung
93 Epidemiology, Diagnosis, Evaluation,
and Treatment of Nephrolithiasis 721
Section VII: Metabolic Bone Diseases 611 Murray J. Favus and David A. Bushinsky
Section Editors: Suzanne M. Jan de Beur
and Peter R. Ebeling 94 Immobilization and Burns: Other Conditions
Associated with Osteoporosis 730
81 Approach to Parathyroid Disorders 613 William A. Bauman, Christopher Cardozo, and
John P. Bilezikian Gordon L. Klein
