Contributors.........................................................................................................v
Preface ...........................................................................................................xxvii
John P. Bilezikian
Section I. Molecular and Cellular
Determinants of Bone Structure
and Function.........................................................1
Section Editors: Karen M. Lyons and Christa Maes
1. Early Skeletal Morphogenesis in Embryonic
Development..................................................................................2
Przemko Tylzanowski
2. Endochondral Ossification.........................................................9
Ernestina Schipani, Elena Sabini, and
Karen M. Lyons
3. Skeletal Stem/Progenitor Cells.............................................15
Christa Maes and Pamela G. Robey
4. Osteoblasts: Function, Development, and
Regulation.................................................................................... 22
Samantha R. Weaver, Haydee M. Torres, and
Jennifer J. Westendorf
5. Osteocytes..................................................................................28
Matthew Prideaux, Lynda F. Bonewald, and
Sarah L. Dallas
6. Osteoclast Biology and Bone Resorption...........................34
Lena Batoon, Megan M. Weivoda, and
Michelle McDonald
7. The TGF-β Superfamily in Bone Formation and
Maintenance................................................................................ 41
Ce Shi and Yuji Mishina
8. Wnt Signaling In Skeletal Development
and Disease.................................................................................48
Zhendong Zhong, Nicole Ethen, and Bart O. Williams
9. Mechanotransduction in Bone Formation
and Maintenance........................................................................54
Whitney A. Bullock, Connor Cunningham, and
Alexander G. Robling
10. Composition of Bone................................................................62
Joseph M. Wallace and Tamara Alliston
11. Assessment of Bone Mass, Structure, and Quality
in Rodents....................................................................................68
Jeffry S. Nyman and Chelsea Heveran
12. Skeletal Healing.......................................................................... 74
Gilbert Smolyak, Chao Xie, and Alayna E. Loiselle
13. Biomechanics of Fracture Healing........................................78
Elise F. Morgan and Amira I. Hussein
14. Omics in Bone Biology..............................................................83
Matthew B. Greenblatt and Seoyeon Bok
Section II. Skeletal Physiology......................89
Section Editor: Ego Seeman
15. Human Fetal and Neonatal Bone Development.................90
Ronit Marom, I-Wen Song, Monika Weisz-Hubshman,
and Brendan Lee
16. Skeletal Growth: A Major Determinant of Bone’s
Structural Diversity in Women and Men.................................95
Ego Seaman
17. Racial Differences in the Acquisition and
Age-Related Loss of Bone Strength...................................102
Shane Norris, Marcella D. Walker, Kate A. Ward,
Nicole C. Wright, Lisa Micklesfield, and John M. Pettifor
18. Calcium, Vitamin D, and Other Nutrients During
Growth.........................................................................................106
Tania Winzenberg, Lieke E.J.M. Scheepers, and
Graeme Jones
19. Mechanical Loading and the Developing Skeleton........112
Mark R. Forwood
20. Pregnancy and Lactation.......................................................118
Sarah A. Hartery and Christopher S. Kovacs
21. Menopause-Related and Age-Related Bone Loss..........126
Carlos M. Isales and Ego Seeman
Section III. Mineral Homeostasis.................133
Section Editors: David Goltzman and John J. Wysolmerski
22. Regulation of Calcium Homeostasis..................................134
David Goltzman
23. Magnesium Homeostasis......................................................140
Aliya A. Khan, Salma H. Hussein, and
Karl Peter Schlingmann
24. Fetal Calcium and Phosphate Metabolism.......................145
Sarah A. Hartery and Christopher S. Kovacs
25. FGF23 and the Regulation of Phosphorus
Metabolism.................................................................................152
Kenneth E. White and Michael J. Econs
26. Gonadal Steroids. ....................................................................159
Stavros C. Manolagas and Maria Schuller Almeida
27. Parathyroid Hormone.............................................................170
Thomas J. Gardella, Robert A. Nissenson,
John T. Potts Jr, and Harald Jüppner
28. Parathyroid Hormone–Related Protein.............................177
Diana Athonvarangkul and John J. Wysolmerski
29. Calcium-Sensing Receptor: Biochemistry,
Physiology, and Signal Transduction.................................185
Dolores M. Shoback
30. Vitamin D: Production, Metabolism, Action, and
Clinical Requirements.............................................................193
Daniel D. Bikle and Sylvia Christakos
xxix

31. Bone Health in Gender Diverse Patients...........................203
Micol S. Rothman, Charlotte Verroken, Janet Y. Lee,
and Chantal M. Wiepjes
32. Clinical Aspects of Vitamin D: Controversial Issues,
Including the Concept of a Threshold Nutrient...............210
Roger Bouillon, Luigi di Filippo, Leen Antonio, and
Andrea Giustina
Section IV. Investigation of Metabolic
Bone Diseases...................................................217
Section Editors: Klaus Engelke, Richard Eastell, and
Barbara C. Silva
33. Techniques of Bone Mass Measurement in Children
with Risk Factors for Osteoporosis....................................218
Nicola J. Crabtree and Leanne M. Ward
34. Standard Techniques of Bone Mass
Measurement in Adults..........................................................228
E. Michael Lewiecki, John J. Carey,
and Marian Schini
35. Advanced Techniques of Bone Mass
Measurements and Strength in Adults..............................233
Enrico Dall’Ara, Xiaoguang Cheng,
and Klaus Engelke
36. Assessment of Bone Structure............................................241
Andrew J. Burghardt, Steven K. Boyd, and
Sharmila Majumdar
37. Trabecular Bone Score...........................................................250
Barbara C. Silva and William D. Leslie
38. Reference Point Indentation.................................................260
Xavier Nogues, Joshua N. Farr, and
Adolfo Diez-Perez
39. Biochemical Markers of Bone Turnover in
Osteoporosis. ...........................................................................266
Pawel Szulc, Albert Shieh, and Richard Eastell
40. Molecular Imaging of Metabolic Bone Disease...............273
Gary J.R. Cook
41. Bone Histomorphometry in Clinical Practice and
Research.....................................................................................278
Carolina Aguiar Moreira, Mathew R. Allen, Corinne E.
Metzger, Thomas L. Nickolas, and David W. Dempster
42. Diagnosis and Classification of Vertebral Fracture.......285
James F. Griffith and Wang Yi-Xiang
43. FRAX: Assessment of Fracture Risk...................................296
John A. Kanis, Helena Johansson, Nicholas C. Harvey,
Mattias Lorentzon, Enwu Liu, Liesbeth Vandenput,
William D. Leslie, Marian Schini, and Eugene V. McCloskey
44. Opportunistic CT for Clinical Skeletal Status
Assessment...............................................................................306
Neil Binkley and Paul A. Anderson
45. Dual-Energy X-Ray Absorptiometry (Dxa)–Beyond
Bone Mineral Density (BMD).................................................311
Diane Krueger, Namki Hong, and Gary Slater
46. Bone Mineral Density as a Surrogate Biomarker for
Fracture Risk Reduction.........................................................318
Austin R. Thompson, Mary L. Bouxsein, Richard Eastell,
and Dennis M. Black
Section V. Genetics of Bone..........................323
Section Editors: Rajesh V. Thakker and
Fernando Rivadeneira
47. Introduction to Genetics........................................................324
Paul J Newey, Fadil M. Hannan, Michael P. Whyte, and
Rajesh V. Thakker
48. Animal Models: Genetic Manipulation................................335
Noriaki Ono, Karen M. Lyons, David Karasik, and
Chrissy Hammond
49. Animal Models: Allelic Determinants for BMD.................345
Ryan C. Chai and Robert D. Blank
50. Human Genome-Wide Association Studies.....................351
Carolina Medina-Gomez, John P. Kemp, Douglas P. Kiel,
and Fernando Rivadeneira
51. Whole Genome- and Exome-Sequencing Studies.........358
Alice Costantini and Outi Mäkitie
52. Big Data Analysis and Machine Learning in
Human Genetics.......................................................................363
J. Brent Richards
53. Epigenomics and Multi-Omics in Bone Research...........367
Cheryl L. Ackert-Bicknell, Alvaro del Real,
Charles R. Farber, and Jose A. Riancho
54. Polygenic Risk Scores and Mendelian Randomization...372
Monika Frysz and Jonathan H. Tobias
55. Translational Genetics of Osteoporosis: From
Population Association to Individualized
Assessment................................................................................377
Tuan V. Nguyen
Section VI. Osteoporosis I (Epidemiology
and Etiologies)..................................................381
Section Editors: Peter R. Ebeling, Manju Chandran, and
Bente L. Langdahl
56. Osteoporosis: An Overview..................................................382
Manju Chandran
57. The Epidemiology of Osteoporotic Fractures.................388
William D. Leslie, Elizabeth M. Curtis, Elaine M. Dennison,
Cyrus Cooper, and Nicholas C. Harvey
58. Fracture Liaison Services......................................................394
Paul J. Mitchell, Hidenori Arai, Ding-Cheng (Derrick) Chan,
M. Kassim Javaid, Douglas P. Kiel, Joon Kiong Lee, Jay
Magaziner, and Andrea Singer
59. Sex Steroids and the Pathogenesis of Osteoporosis.....400
Sundeep Khosla, Elaine Yu, and Matthew T. Drake
60. Transplantation Osteoporosis.............................................406
Peter R. Ebeling
61. Premenopausal Osteoporosis. ............................................416
Adi Cohen and Elizabeth Shane
62. Osteoporosis in Men...............................................................423
Robert A. Adler and Eric S. Orwoll
63. Inflammation-Induced Bone Loss in the
Rheumatic Diseases................................................................428
Ulrike Steffen, George Schett, and Ellen M. Gravallese

64. Glucocorticoid-Induced Osteoporosis..............................434
Kenneth G. Saag and Robert A. Adler
65. Human Immunodeficiency Virus and Bone.......................440
Michael T. Yin, Ryan D. Ross, and Todd T. Brown
66. Effects on the Skeleton From Medications Used to
Treat Nonskeletal Disorders.................................................446
Hans Peter Dimai and Barbara Obermayer Pietsch
67. Diabetes and Fracture Risk...................................................453
Ann V. Schwartz, Nicola Napoli, Tatiane Vilaca, and
Serge L. Ferrari
68. Obesity and Bariatric Surgery..............................................460
Juliet Compston and Anne L. Schafer
69. Sarcopenia and Osteoporosis.............................................467
Marc Sim and Gustavo Duque
70. Management of Osteoporosis in Chronic Kidney
Disease. ......................................................................................475
Hanne Skou Jørgensen, Pieter Evenepoel, and
Thomas Nickolas
71. Other Secondary Causes of Osteoporosis......................482
Núria Guañabens and Frances Milat
72. Infiltrative Marrow Disorders and Osteoporosis............488
Liping Xiao, Phillip Wong, Matthew T. Drake, and
Marja Marie Hurley
73. The Effect of COVID-19 on Bone.........................................494
Amy Creecy, Luigi di Filippo, Melissa A. Kacena, and
Andrea Giustina
SECTION VII. Osteoporosis II
(Therapeutics)................................................... 499
Section Editors: Michael R. McClung,
Ghada El-Hajj Fuleihan, and E. Michael Lewiecki
74. Overview of Strategies for Managing Osteoporosis
in Postmenopausal Women..................................................500
Michael R. McClung, Ghada El-Hajj Fuleihan, and
E. Michael Lewiecki
75. Exercise for Osteoporotic Fracture Prevention
and Management.....................................................................505
Lora M. Giangregorio and Robin M. Daly
76. Prevention of Falls...................................................................511
Heike A. Bischoff-Ferrari and Maud Wieczorek
77. Nutritional Support of Bone Health in Older Adults.......517
Bess Dawson-Hughes and Rene Rizzoli
78. Estrogens, Selective Estrogen Receptor Modulators,
and Tissue-Selective Estrogen Complex..........................523
JoAnn V. Pinkerton
79. Bisphosphonates for Postmenopausal
Osteoporosis. ...........................................................................529
Polyzois Makras and Socrates E. Papapoulos
80. Denosumab................................................................................535
Bente L Langdahl, Elena Tsourdi, and Serge L. Ferrari
81. Teriparatide and Abaloparatide Treatment
for Osteoporosis......................................................................540
Felicia Cosman
82. Anti-Sclerostin Therapy for Osteoporosis.......................546
Michael R. McClung and Yumie Rhee
83. Considerations for Osteoporosis Management in
Medically Complex Older Patients......................................553
Joshua D. Niznik, Sarah D. Berry, and Douglas P. Kiel
84. Combination Anabolic and Antiresorptive Therapy
for Osteoporosis......................................................................560
Joy N. Tsai and Benjamin Z. Leder
Section VIII. Metabolic Bone Diseases.........567
Section Editors: Claudio Marcocci, Jianmin Liu, and
Maria Belen Zanchetta
85. Approach to Parathyroid Disorders...................................568
John P. Bilezikian and Marcella D. Walker
86. Primary Hyperparathyroidism..............................................573
John P. Bilezikian, Shonni J. Silverberg, and
Marcella D. Walker
87. Familial States of Primary Hyperparathyroidism............583
Andrew Arnold and Filomena Cetani
88. Nonparathyroid Hypercalcemia...........................................591
Tariq Chukir and Azeez Farooki
89. Hypocalcemia: Definition, Etiology, Pathogenesis,
Diagnosis, and Management................................................597
Anne L. Schafer and Kelly L. Wentworth
90. Hypoparathyroidism: Diagnosis, Evaluation
and Management.....................................................................604
Aliya A. Khan, Dalal S. Ali, and Lars Rejnmark
91. Pseudohypoparathyroidism.................................................615
Emily L. Germain-Lee and Michael A. Levine
92. Disorders of Phosphate Homeostasis...............................629
Erik A. Imel and Suzanne M. Jan de Beur
93. Rickets and Osteomalacia.....................................................637
Michaël R. Laurent, Nathalie Bravenboer, Natasja M. Van
Schoor, Roger Bouillon, John M. Pettifor, and Paul Lips
94. Pathophysiology and Treatment of Chronic Kidney
Disease-Mineral and Bone Disorder...................................647
Wei Chen, Aline Martin, and Thomas Nickolas
95. Disorders of Mineral Metabolism in Childhood...............655
Thomas O. Carpenter, Julio Soto Barros, and Nina S. Ma
96. Paget Disease of Bone...........................................................663
Julia F. Charles, Laëtitia Michou, and Ethel S. Siris
97. Epidemiology, Diagnosis, Evaluation, and
Treatment of Nephrolithiasis................................................670
Francisco Rodolfo Spivacow, Elisa Elena del Valle, and
Armando Luis Negri
98. Immobilization and Burns: Other Conditions
Associated With Osteoporosis............................................676
Christopher M. Cirnigliaro, Christopher P. Cardozo, and
Gordon L. Klein
Section IX. Metabolic Bone Issues
in Orthopedics..................................................681
Section Editors: Susan Bukata and Laura L. Tosi
99. Introduction: What Every Specialist in Metabolic
Bone Diseases Should Know About Orthopedics..........682
Naoko Onizuka and Julie A. Switzer

100. What Every Orthopedic Surgeon Should Know
About Metabolic Bone Disease............................................685
Steven M. Rivero and Kenneth A. Egol
101. Perioperative Bone Health Optimization for
Orthopedic Patients................................................................700
Aamir Kadri, Neil Binkley, and Paul A. Anderson
102. Corrective Orthopedic Surgery for Individuals
With Rare Bone Disease and Skeletal
Deformities................................................................................705
Laura L. Tosi
103. Postfracture Rehabilitation of Osteoporosis:
Management and Braces.......................................................711
Mehrsheed Sinaki, Jad G. Sfeir, Michael Pfeifer, and
Mahmood Gharib
104. Stress and Insufficiency Fractures and the
Treatment of Nonunions........................................................723
Ting Cong, Dan Carai Maia Viola, Heather Berman,
William Friedman, Jeri W. Nieves, and Joseph M. Lane
105. Fractures in Children: How to Differentiate
Between Metabolic and Genetic Bone Disorders
and Abuse..................................................................................730
Ellen Fung, Laura K. Bachrach, Aenor Sawyer, and
M. Zulf Mughal
106. Kyphoplasty and Vertebroplasty........................................735
Anthony Tadros, Brandon Key, and Sean Tutton
107. Bone Stress Injuries................................................................741
Stuart J. Warden, Aurelia Nattiv, and David B. Burr
108. The Biomechanics of Gait Disturbances...........................747
Dennis E. Anderson and Seyed Javad Mousavi
109. AFF (Surgical Aspects, Prophylactic Nailing of the
Contralateral Side)...................................................................752
Joseph M. Lane, David Burr, Witchaporn Witayakom, and
Peter Prescott
Section X. Cancer and Bone..........................761
Section Editors: Matthew T. Drake and Evan Keller
110. Clinical and Preclinical Imaging in Osseous
Metastatic Disease..................................................................762
Rajshekhar Chakraborty, Siyang Leng, and
Suzanne Lentzsch
111. Myeloma Bone Disease and Other Hematological
Malignancies. ............................................................................770
Claire M. Edwards and Rebecca Silbermann
112. Osteosarcoma..........................................................................777
Nino Rainusso, Yi-Ting Chen, Lisa L. Wang, Brendan Lee,
and Yangjin Bae
113. Skeletal Complications of Breast and Prostate
Cancer and Their Therapies..................................................782
Catherine Van Poznak and Pamela Taxel
114. Bone Cancer and Pain.............................................................787
Andrew F. Ormseth and Denis R. Clohisy
115. Radiation Therapy–Induced Osteoporosis.......................793
Laura E. Wright
116. Skeletal Complications of Childhood Cancer..................797
Nadine G. Haddad and Linda A. DiMeglio
117. Medical Prevention and Treatment of Bone
Metastases. ...............................................................................802
Steven L. Wood and Janet E. Brown
118. Radiotherapy of Skeletal Metastases................................810
Adrian Wai Chan, Oliver Sartor, Elizabeth Chuk,
Edward Chow, Øyvind S. Bruland, and Srinivas Raman
119. Concepts and Surgical Treatment of Metastatic
Bone Disease.............................................................................818
Cara A. Cipriano, Steven Zhang, and Ling Qin
120. Osteocytes and Bone Malignancies...................................824
Teresita Bellido and Jesus Delgado-Calle
Section XI. Pediatric and Adult Rare
Bone Diseases...................................................831
Section Editors: Michael P. Whyte and Michael T. Collins
121. Sclerosing Bone Disorders...................................................832
Michael P. Whyte
122. Fibrous Dysplasia/McCune-Albright Syndrome.............844
Alison M. Boyce, Michael T. Collins, and Mara Riminucci
123. The Osteochondrodysplasias..............................................851
Fabiana Csukasi, Carlos R. Ferreira, and Deborah Krakow
124. Hyperphosphatemic Tumoral Calcinosis..........................856
Rache l. Gafni, Iris R. Hartley, and Kelly L. Roszko
125. Fibrodysplasia Ossificans Progressiva and
Progressive Osseous Heteroplasia....................................862
Matthew A. Brown and Eileen M. Shore
126. Osteogenesis Imperfecta......................................................867
Joan C. Marini and Antonella Forlino
127. Skeletal Manifestations of Marfan Syndrome and
Marfan-Related Disorders.....................................................873
Gary S. Gottesman, Catherine F. Gooch, and
Michael P. Whyte
128. Hypophosphatasia and Other Enzyme Deficiencies
Affecting the Skeleton...........................................................880
Michael P. Whyte
129. Ischemic and Infiltrative Disorders of Bone.....................885
Michael P. Whyte
Section XII. Oral and Maxillofacial
Biology and Pathology...................................893
Section Editors: Laurie McCauley and Erin Ealba Bumann
130. Craniofacial Morphogenesis.................................................894
Erin Ealba Bumann and Vesa Kaartinen
131. Development and Structure of Teeth and
Periodontium.............................................................................899
Olivier Duverger and Brian L. Foster
132. Genetic Craniofacial Disorders Affecting the
Dentition.....................................................................................908
Tian Liang, Audrey Rakian, and Yong-Hee Patricia Chun
133. Genetic Disorders Affecting Craniofacial Bones............913
Konstantinia Almpani, Priyam Jani, Olivier Duverger,
and Janice S. Lee

134. Pathology of the Hard Tissues of the Jaws......................921
Paul C. Edwards and Nasser Said-Al-Naief
135. Medication Related Osteonecrosis of the Jaw...............928
Sotirios Tetradis, Laurie McCauley, and Tara Aghaloo
136. Alveolar Bone Homeostasis in Health and
Disease. ......................................................................................933
Jessica D. Hathaway-Schrader and Chad M. Novince
137. Oral Manifestations of Metabolic Bone Diseases...........938
Mohamed G. Hassan, Erica L. Scheller, and
Roberto Civitelli
138. Dental Implants and Osseous Healing in the
Oral Cavity.................................................................................943
Takashi Matsuura and Junro Yamashita
Section XIII. Integrative Physiology
of the Skeleton................................................949
Section Editors: Clifford J. Rosen, Stavroula Kousteni,
and Martina Rauner
139. Integrative Physiology of the Skeleton.............................950
Gerard Karsenty
140. The Hematopoietic Niche and Bone...................................955
Benjamin Frisch, Rossella Labella, Brian J. Chernack,
Laura M. Calvi, and Stavroula Kousteni
141. Adipocytes and Bone..............................................................965
Xiao Zhang, and Erica L. Scheller
142. The Vasculature and Bone....................................................973
Zhangfan Ding, Joan Mane Pujol, Saravana K. Ramasamy,
and Anjali P. Kusumbe
143. Immune Cells Relevant to Bone...........................................977
Roberto Pacifici
144. Metabolic Regulation of Skeletal Cell Function
During Endochondral Ossification......................................988
Steve Stegen and Geert Carmeliet
145. Bioenergetics of Bone............................................................995
Elizabeth Rendina-Ruedy, and Ryan C. Riddle
146. Central Neuronal Control of Bone Remodeling............1002
Patricia Ducy
147. Peripheral Neuronal Control of Bone Remodeling
and Repair...............................................................................1007
Katherine J. Motyl and Ryan E. Tomlinson
148. Pituitary Hormones in Regulating Skeletal
Homeostasis. ......................................................................... 1014
Se-Min Kim, Judith Gimenez-Roig, Victoria Laurencin,
Daria Lizneva, Funda Korkmaz, Farhath Sultana,
Anisa Gumerova, Vitaly Ryu, Peng Liu, Terry Davies,
Harry C. Blair, Clifford J. Rosen, Tony Yuen, and
Mone Zaidi
149. Neuropsychiatric Disorders and the Skeleton.............1025
Madhusmita Misra, Marcella D. Walker, and
Pouneh Fazeli
150. Systemic Iron Homeostasis and Bone
Metabolism............................................................................. 1031
Sandro Altamura, Martina U. Muckenthaler,
Maja Vujic Spasic, Andrea U. Steinbicker,
Ulrike Baschant, and Martina Rauner
Index .............................................................................................................1039