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Principles of Bone Biology Fourth Edition Volume 1 Edited by John P. Bilezikian Division of Endocrinology, Department of Medicine College of Physicians and Surgeons Columbia University, New York, NY, United States T. John Martin St. Vincent’s Institute of Medical Research; Department of Medicine at St. Vincent’s Hospital The University of Melbourne Melbourne, Australia Thomas L. Clemens Department of Orthopaedic Surgery Johns Hopkins University School of Medicine; Baltimore Veterans Administration Medical Center Baltimore, MD, United States Clifford J. Rosen Maine Medical Center Research Institute Scarborugh, ME, United States Principles of Bone Biology Fourth Edition Volume 2 Edited by John P. Bilezikian Division of Endocrinology, Department of Medicine College of Physicians and Surgeons Columbia University, New York, NY, United States T. John Martin St. Vincent’s Institute of Medical Research; Department of Medicine at St. Vincent’s Hospital The University of Melbourne Melbourne, Australia Thomas L. Clemens Department of Orthopaedic Surgery Johns Hopkins University School of Medicine; Baltimore Veterans Administration Medical Center Baltimore, MD, United States Clifford J. Rosen Maine Medical Center Research Institute Scarborugh, ME, United States Academic PressisanimprintofElsevier 125London Wall,LondonEC2Y5AS,UnitedKingdom 525BStreet,Suite1650,SanDiego,CA92101,UnitedStates 50HampshireStreet,5thFloor,Cambridge,MA02139,UnitedStates TheBoulevard,Langford Lane,Kidlington,OxfordOX5 1GB,UnitedKingdom Copyright©2020ElsevierInc.Allrightsreserved. Nopart ofthispublicationmay bereproduced ortransmitted inanyform orbyanymeans, electronicor mechanical,including photocopying, recording,oranyinformation storageandretrieval system,withoutpermission inwritingfromthepublisher. Details onhowtoseek permission, furtherinformation aboutthePublisher’spermissions policiesandourarrangements with organizations suchastheCopyrightClearanceCenterandtheCopyrightLicensing Agency,canbefoundatourwebsite: www.elsevier.com/permissions. Thisbookandtheindividual contributionscontainedinitareprotected undercopyrightbythePublisher (otherthanasmay benotedherein). Notices Knowledgeandbestpracticeinthisfieldareconstantlychanging. As newresearchandexperiencebroadenourunderstanding, changesinresearch methods,professional practices,ormedical treatmentmay becomenecessary. Practitionersandresearchers mustalwaysrelyontheir ownexperience andknowledgeinevaluatingandusingany information,methods,compounds,orexperiments describedherein. Inusingsuchinformation ormethodsthey shouldbe mindfuloftheirown safetyandthesafetyofothers,including partiesforwhom theyhaveaprofessional responsibility. Tothefullestextentofthelaw,neither thePublishernortheauthors,contributors, oreditors, assumeany liabilityforany injuryand/ordamagetopersonsorpropertyasamatterofproductsliability,negligence orotherwise,or fromanyuseor operation ofanymethods,products, instructions,or ideascontainedinthematerialherein. LibraryofCongressCataloging-in-Publication Data Acatalogrecord forthisbook isavailablefromtheLibrary ofCongress BritishLibraryCataloguing-in-Publication Data Acataloguerecord forthisbook isavailablefromtheBritishLibrary SETISBN:978-0-12-814841-9 Volume1ISBN:978-0-12-819932-9 Volume2ISBN:978-0-12-819933-6 Forinformation onallAcademic Presspublications visitourwebsite at https://www.elsevier.com/books-and-journals Publisher:StacyMasucci AcquisitionEditor: TariBroderick EditorialProjectManager:Megan Ashdown ProductionProjectManager:PoulouseJoseph Coverdesigner: GregHarris TypesetbyTNQTechnologies Dedication of Fourth Edition to Lawrence G. Raisz Bytheendofthe1970s,whentheboneresearchcommunityfeltthatitwasreadyforitsownscientificsociety,LarryRaisz was one of the leaders of the group that founded the American Society for Bone and Mineral Research (ASBMR). The ASBMR had its first annual conference in 1979, with Larry serving as its second president. As the first editor of the Journal of Bone and Mineral Research, for a decade, Larry set the highest scientific standards for quality and integrity. That standard remains untarnished today. Larry’s knowledge of the facts in our field was prodigious. His expertise and experience in basic elements of bone biology were exceptional. He had great understanding and wisdom in interpretation of the clinical implications of basic bonebiology.Buthealwayswantedtoknowmore.AtASBMRandotherannualmeetings,itwasalwaysLarrywhorose to the microphone after a presentation to ask, not only the first question, but typically the best one! Remarkably, Larry could translatebasic bonebiologytotheclinical arena. Few inourfieldthen ornow could so smoothlyintegrate clinical aspectsofmetabolicbonediseaseswiththeburgeoningknowledgeofunderlyingpathophysiologicalmechanisms.Adding to these talents was a collegiality and an exuberant enthusiasm that pervaded all venues of Larry Raisz’s world. As osteoporosis became more widely recognized to be a medical scourge, then and now, Larry quickly grasped the need to speak about the burden of the disease and contributed to the international dialogue, raising awareness among us all. This awareness was a major factor in the recognition among countries that we are dealing with a disease that needs greater understanding at all levels. And, indeed, at all levels, Larry contributed so much. These qualities made Larry Raisz a wonderfully effective coeditor of the first three editions of Principles of Bone Biology.Muchmorethanthat,though,hewasapleasuretoworkwithasacolleagueandfriend,exceptionallyefficientand withunfailinghumorandoptimismwhenfacedwithanyadversity.Larrywouldsharethehighsandlowswithyou,butthe lows were rare and short lived. WerememberhimconstantlyanddedicatetoLawrenceG.Raisz,MD,thisfourtheditionofwhathecalled“BigGray.” John P. Bilezikian T. John Martin Thomas L. Clemens Clifford J. Rosen List of Contributors DavidAbrahamCentreforRheumatologyandConnective George Bou-Gharios Institute of Ageing and Chronic Tissue Diseases, University College London, London, Disease, University of Liverpool, Liverpool, United United Kingdom Kingdom Maria Almeida Division of Endocrinology and Metabo- Roger Bouillon Laboratory of Clinical and Experimental lism, Center for Osteoporosis and Metabolic Bone Endocrinology, Department of Chronic Diseases, Diseases, University ofArkansas forMedicalSciences, Metabolism and Aging, KU Leuven, Belgium Little Rock, AR, United States; The Central Arkansas Mary L. Bouxsein Center for Advanced Orthopaedic Veterans Healthcare System, Little Rock, AR, United Studies, Beth Israel Deaconess Medical Center, Bos- States ton, MA, United States; Department of Orthopaedic Elena Ambrogini Center for Osteoporosis and Metabolic Surgery, Harvard Medical School, Boston, MA, Uni- Bone Diseases, University of Arkansas for Medical ted States; Endocrine Unit, Department of Medicine, Sciences Division of Endocrinology and Metabolism, Massachusetts General Hospital, Boston, MA, United Little Rock, AR, United States; Central Arkansas Vet- States erans Healthcare System, Little Rock, AR, United Brendan F. Boyce Department of Pathology and Labo- States ratory Medicine, University of Rochester School of Andrew Arnold Center for Molecular Oncology and Medicine and Dentistry, Rochester, NY, United States Division of Endocrinology and Metabolism, University Steven Boyd McCaig Institute for Bone and Joint Health, of Connecticut School of Medicine, Farmington, CT, The University of Calgary, Calgary, AB, Canada United States Maria Luisa Brandi Department of Experimental and Bence Bakos 1st Department of Medicine, Semmelweis Clinical Biomedical Sciences, University of Florence, University Medical School, Budapest, Hungary Florence, Italy Clemens Bergwitz Departments of Pediatrics and Internal DavidB. Burr DepartmentofAnatomyandCell Biology, Medicine, Yale University School of Medicine, New Indiana Center for Musculoskeletal Health, Indiana Haven, CT, United States University School of Medicine, Indianapolis, IN, Uni- Daniel D. Bikle VA Medical Center and University of ted States California San Francisco, San Francisco, California, Laura M. Calvi Department of Medicine and Wilmot United States CancerCenter,UniversityofRochesterMedicalCenter, JohnP.BilezikianDivisionofEndocrinology,Department Rochester, NY, United States of Medicine, College of Physicians and Surgeons, Ernesto Canalis Departments of Orthopaedic Surgery and Columbia University, New York, NY, United States Medicine, and the UConn Musculoskeletal Institute, Neil Binkley University of Wisconsin School of Medicine UConn Health, Farmington, CT, United States and Public Health, Madison, Wisconsin, United States XuCaoDepartmentofOrthopedicSurgery,JohnsHopkins Alessandro Bisello Department of Pharmacology and UniversitySchoolofMedicine,Baltimore,MD,United Chemical Biology, Laboratory for GPCR Biology, States University of Pittsburgh School of Medicine, Pitts- Geert Carmeliet Laboratory of Clinical and Experimental burgh, PA, United States Endocrinology, Department of Chronic Diseases, L.F.BonewaldIndianaCenterforMusculoskeletalHealth, Metabolism and Ageing, KU Leuven, Leuven, Bel- Departments of Anatomy and Cell Biology and Ortho- gium; Prometheus, Division of Skeletal Tissue Engi- paedic Surgery, Indiana University, Indianapolis, IN, neering, KU Leuven, Leuven, Belgium USA xiii xiv List of Contributors Thomas O. Carpenter Departments of Pediatrics and Benoit de Crombrugghe The University of Texas M.D. InternalMedicine,YaleUniversitySchoolofMedicine, Anderson Cancer Center, Houston, TX, United States New Haven, CT, United States Hector F. DeLuca Department of Biochemistry, Uni- Wenhan Chang Endocrine Research Unit, Department of versity of WisconsineMadison, Madison, Wisconsin, Veterans Affairs Medical Center, Department of Med- United States icine, University of California, San Francisco, CA, David W. Dempster Regional Bone Center, Helen Hayes United States Hospital, West Haverstraw, NY, United States; Shek Man Chim Regeneron Pharmaceuticals, Inc. Tarry- Department of Pathology and Cell Biology, College of town, NY, United States Physicians and Surgeons, Columbia University, New Shilpa Choudhary Department of Medicine and Muscu- York, NY, United States loskeletal Institute, UConn Health, Farmington, CT, Matthew T. Drake Department of Endocrinology and United States Kogod Center of Aging, Mayo Clinic College of Sylvia Christakos Department of Microbiology, Bio- Medicine, Rochester, MN, United States chemistryandMolecularGenetics,Rutgers,NewJersey Patricia Ducy Department of Pathology & Cell Biology, Medical School, Newark, NJ, United States Columbia University, College of Physicians & Sur- Yong-Hee Patricia Chun Department of Periodontics, geons, New York, NY, United States University of Texas Health Science Center at San FrankH.EbetinoDepartmentofChemistry,Universityof Antonio, San Antonio, TX, United States Rochester, Rochester, NY, United States; Mellanby Cristiana Cipriani Department of Internal Medicine and Centre for Bone Research, Medical School, University of Sheffield, United Kingdom Medical Disciplines, Sapienza University of Rome, Italy Klaus Engelke Department of Medicine, FAU University Roberto Civitelli Washington University in St. Louis, Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; Bioclinica, Hamburg, Germany DepartmentofMedicine,DivisionofBoneandMineral Diseases, St. Louis, MO, United States Reinhold G. Erben Department of Biomedical Research, Thomas L. Clemens Department of Orthopaedic Surgery, University of Veterinary Medicine Vienna, Vienna, Austria Johns Hopkins University School of Medicine, Balti- more, MD, United States; Baltimore Veterans Admin- David R. Eyre Department of Orthopaedics and Sports istration Medical Center, Baltimore, MD,UnitedStates Medicine, University of Washington, Seattle, WA, Michael T. Collins Skeletal Disorders and Mineral United States Homeostasis Section, National Institute of Dental and Charles R. Farber Center for Public Health Genomics, Craniofacial Research, National Institutes of Health, Departments of Public Health Sciences and Bio- Bethesda, MD, United States chemistry and Molecular Genetics, University of Caterina Conte Vita-Salute San Raffaele University, Virginia School of Medicine, Charlottesville, VA, United States Milan, Italy; Division of Immunology, Transplantation andInfectiousDiseases,IRCCSSanRaffaeleScientific MarinaFeigensonDepartmentofDevelopmentalBiology, Institute, Milan, Italy Harvard School of Dental Medicine, Boston, MA, Mark S. Cooper The University of Sydney, ANZAC United States Research Institute and Department of Endocrinology & Mathieu Ferron Institut de Recherches Cliniques de Metabolism,ConcordHospital,Sydney,NSW,Australia Montréal, Montréal, QC, Canada Jillian Cornish Department of Medicine, University of Pablo Florenzano Endocrine Department, School of Auckland, Auckland, New Zealand Medicine, Pontificia Universidad Católica de Chile, Serge Cremers Department of Pathology & Cell Biology Santiago, Chile and Department of Medicine, Vagelos College of Francesca Fontana Washington University in St. Louis, Physicians and Surgeons, Columbia University Irving DepartmentofMedicine,DivisionofBoneandMineral Medical Center, United States Diseases, St. Louis, MO, United States Bess Dawson-Hughes Jean Mayer USDA Human Nutri- Brian L. Foster Biosciences Division at College of Den- tion Research Center on Aging at Tufts University, tistry at Ohio State University, Columbus, OH, United Boston, Massachusetts, United States States List of Contributors xv Peter A. Friedman Department of Pharmacology and FadilM.HannanDepartmentofMusculoskeletalBiology, Chemical Biology, Laboratory for GPCR Biology, Institute of Ageing and Chronic Disease, Faculty of University of Pittsburgh School of Medicine, Pitts- Health & Life Sciences, University of Liverpool, Liv- burgh, PA, United States erpool, United Kingdom; Academic Endocrine Unit, Seiji Fukumoto Fujii Memorial Institute of Medical Sci- Radcliffe Department of Medicine, University of Oxford,OxfordCentreforDiabetes,Endocrinologyand ences, Institute of Advanced Medical Sciences, Metabolism (OCDEM), Churchill Hospital, Oxford, Tokushima University, Tokushima, Japan United Kingdom LauraW. Gamer DepartmentofDevelopmentalBiology, StephenE.HarrisDepartmentofPeriodontics,University Harvard School of Dental Medicine, Boston, MA, of Texas Health Science Center at San Antonio, San United States Antonio, TX, United States Thomas J. Gardella Endocrine Unit, Department of Iris R.HartleyInterinstitute Endocrine TrainingProgram, Medicine and Pediatric Nephrology, MassGeneral Eunice Kennedy Shriver National Institute of Child Hospital for Children, Massachusetts General Hospital Health and Human Development, National Institutes of and Harvard Medical School, Boston, MA, United Health, Bethesda, MD, United States States Patrick Garnero INSERM Research Unit 1033-Lyos, Christine Hartmann Institute of Musculoskeletal Medi- cine, Department of Bone and Skeletal Research, Lyon, France MedicalFacultyoftheUniversityofMünster,Münster, Harry K. Genant Departments of Radiology and Medi- Germany cine, University of California, San Francisco, CA, Robert P. Heaney Creighton University, Omaha, NE, United States United States FrancescaGiustiDepartmentofExperimentalandClinical Geoffrey N. Hendy Metabolic Disorders and Complica- Biomedical Sciences, University of Florence, Florence, tions, McGill University Health Center Research Insti- Italy tute, and Departments of Medicine, Physiology and Andy Göbel Department of Medicine III, Technische Uni- Human Genetics, McGill University, Montreal, QC, versität Dresden, Dresden, Germany; German Cancer Canada Consortium (DKTK), Partner site Dresden and German Matthew J. Hilton Department of Orthopaedic Surgery, Cancer Research Center (DKFZ), Heidelberg, Germany DepartmentofCellBiology,DukeUniversitySchoolof David Goltzman Calcium Research Laboratories and Medicine, Durham, NC, United States DepartmentofMedicine,McGillUniversityandMcGill Lorenz C. Hofbauer Center for Regenerative Therapies University Health Centre, Montreal, QC, Canada Dresden, Center for Healthy Aging and Division of Jeffrey P. Gorski Department of Oral and Craniofacial Endocrinology, Diabetes, and Bone Diseases, Depart- Sciences, School of Dentistry, and Center for Excel- ment of Medicine III, Technische Universität Dresden, lence in Mineralized and Dental Tissues, University of Dresden, Germany MissourieKansasCity,KansasCity,MO,UnitedStates Gill Holdsworth Bone Therapeutic Area, UCB Pharma, James Griffith Department of Imaging and Interventional Slough, United Kingdom Radiology, The Chinese University of Hong Kong, Yi-Hsiang Hsu Department of Medicine, Beth Israel Hong Kong, China Deaconess Medical Center and Harvard Medical R. Graham G Russell Mellanby Centre for Bone School, Harvard School of Public Health, Hinda and Research, Medical School, University of Sheffield, Arthur Marcus Institute for Aging Research, Hebrew UnitedKingdom;NuffieldDepartmentofOrthopaedics, SeniorLife, Boston, MA, United States Rheumatology and Musculoskeletal Sciences, The DavidM.HudsonDepartmentofOrthopaedicsandSports Oxford University Institute of Musculoskeletal Scien- ces,The BotnarResearch Centre, NuffieldOrthopaedic Medicine, University of Washington, Seattle, WA, United States Centre, Oxford, United Kingdom Kurt D. Hankenson Department of Orthopaedic Surgery, Marja Hurley Department of Medicine, University of Connecticut School of Medicine, UConn Health, University of Michigan Medical School, Ann Arbor, Farmington, CT, United States MI, United States xvi List of Contributors Karl L. Insogna Departments of Pediatrics and Internal Yasuhiro Kobayashi Institute for Oral Science, Matsu- Medicine, Yale University School of Medicine, New moto Dental University, Nagano, Japan Haven, CT, United States Martin Konrad Department of General Pediatrics, Uni- Robert L. Jilka Center for Osteoporosis and Metabolic versityChildren’sHospitalMünster,Münster,Germany Bone Diseases, University of Arkansas for Medical Paul J. Kostenuik Phylon Pharma Services, Newbury Sciences Division of Endocrinology and Metabolism, Park, CA, United States; School of Dentistry, Uni- Little Rock, AR, United States; Central Arkansas Vet- versity of Michigan, Ann Arbor, MI, United States eransHealthcareSystem,LittleRock,AR,UnitedStates Christopher S. Kovacs Faculty of Medicine, Memorial Mark L. Johnson Department of Oral and Craniofacial University of Newfoundland, St. John’s, NL, Canada Sciences, UMKC School of Dentistry, Kansas City, Richard Kremer Calcium Research Laboratories and MO, United States DepartmentofMedicine,McGillUniversityandMcGill RachelleW.JohnsonVanderbiltCenterforBoneBiology, University Health Centre, Montreal, QC, Canada Department of Medicine, Division of Clinical Pharma- Venkatesh Krishnan Lilly Research Laboratories, Eli cology, Nashville, TN, United States Lilly&Company,LillyCorporateCenter,Indianapolis, Glenville Jones Department of Biomedical and Molecular United States Science, Queen’s University, Kingston, ON, Canada Henry M. Kronenberg Endocrine Unit, Massachusetts Stefan Judex Department of Biomedical Engineering, General Hospital, Harvard Medical School, Boston, BioengineeringBuilding,StateUniversityofNewYork MA, United States at Stony Brook, Stony Brook, NY, United States Peter A. Lakatos 1st Department of Medicine, Semmel- HaraldJüppnerEndocrineUnit,DepartmentofMedicine weis University Medical School, Budapest, Hungary and Pediatric Nephrology, MassGeneral Hospital for Uri A. Liberman Department of Physiology and Phar- Children, Massachusetts General Hospital and Harvard macology, Sackler Faculty of Medicine, Tel Aviv Medical School, Boston, MA, United States University, Tel-Aviv, Israel Ivo Kalajzic Department of Reconstructive Sciences, Joseph A. Lorenzo The Departments of Medicine and UConn Health, Farmington, CT, United States Orthopaedics, UConn Health, Farmington, CT, United Gérard Karsenty Department of Genetics and Develop- States ment,ColumbiaUniversityMedicalCenter,NewYork, Conor C. Lynch Department of Tumor Biology, Moffitt NY, United States Cancer Center, Tampa, FL, United States Hua Zhu Ke Angitia Biopharmaceuticals Limited, Karen M. Lyons Department of Orthopaedic Surgery/ Guangzhou, China Orthopaedic Hospital, University of California, Los Sundeep Khosla Department of Medicine, Division of Angeles, CA, United States; Department of Molecular, Endocrinology, Mayo Clinic College of Medicine, Cell, & Developmental Biology, University of Cal- Rochester, MN, United States; The Robert and Arlene ifornia, Los Angeles, CA, United States KogodCenteronAging,Rochester,MN,UnitedStates Y.LindaMaBiotechnologyandAutoimmunityResearch, Douglas P. Kiel Department of Medicine, Beth Israel Eli Lilly and Company, Indianapolis, IN, United States Deaconess Medical Center and Harvard Medical Christa Maes Laboratory of Skeletal Cell Biology and School, Harvard School of Public Health, Hinda and Physiology(SCEBP),SkeletalBiologyandEngineering Arthur Marcus Institute for Aging Research, Hebrew Research Center (SBE), KU Leuven, Leuven, Belgium SeniorLife, Boston, MA, United States J. Klein-Nulend Department of Oral Cell Biology, Michael Mannstadt Endocrine Unit, Massachusetts Gen- eral Hospital, Harvard Medical School, Boston, MA, Academic Centre for Dentistry Amsterdam (ACTA), United States University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Amster- Stavros Manolagas Division of Endocrinology and dam, The Netherlands Metabolism, Center for Osteoporosis and Metabolic Frank C. Ko Center for Advanced Orthopaedic Studies, Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, AR, United States; The Central Beth Israel Deaconess Medical Center, Boston, MA, ArkansasVeteransHealthcareSystem,LittleRock,AR, United States United States List of Contributors xvii RobertMarcusStanfordUniversity,Stanford,CA,United Nicola Napoli Unit of Endocrinology and Diabetes, Uni- States versity Campus Bio-Medico, Rome, Italy; Division of DavidE.MaridasDepartmentofDevelopmentalBiology, Bone and Mineral Diseases, Washington University in St Louis, St Louis, MO, United States Harvard School of Dental Medicine, Boston, MA, United States TallyNaveh-ManyMinervaCenterforCalciumandBone Pierre J. Marie UMR-1132 Inserm (Institut nationalde la Metabolism,NephrologyServices,HadassahUniversity Hospital, Hebrew University School of Medicine, Jer- SantéetdelaRechercheMédicale)andUniversityParis usalem, Israel Diderot, Sorbonne Paris Cité, Paris, France Francesca Marini Department of Experimental and Clin- Edward F. Nemeth MetisMedica, Toronto, ON, Canada ical Biomedical Sciences, University of Florence, ThomasL.Nickolas DivisionofNephrology,Department Florence, Italy of Medicine, Columbia University Medical Center, Jasna Markovac California Institute of Technology, New York, NY, United States Pasadena, CA, United States Michael S. Ominsky Radius Health Inc., Waltham, MA, T. John Martin St. Vincent’s Institute of Medical United States Research, Melbourne, Australia; Department of Noriaki Ono Department of Orthodontics and Pediatric Medicine at St. Vincent’s Hospital, The University of Dentistry, University of Michigan School of Dentistry, Melbourne, Melbourne, Australia Ann Arbor, MI, United States BryaG.MatthewsDepartmentofMolecularMedicineand David M. Ornitz Department of Developmental Biology, Pathology, University of Auckland, Auckland, New Washington University School of Medicine, St. Louis, Zealand MO, United States Antonio Maurizi Department of Biotechnological and Nicola C. Partridge Department of Basic Science and Applied Clinical Sciences, University of L’Aquila, Craniofacial Biology, New York University College of L’Aquila, Italy Dentistry, New York, NY, United States SasanMirfakhraeeTheUniversityofTexasSouthwestern VihitabenS.PatelDepartmentofBiomedicalEngineering, Medical Center, Department of Internal Medicine, BioengineeringBuilding,StateUniversityofNewYork Endocrine Division, Dallas, TX, United Sates at Stony Brook, Stony Brook, NY, United States SharonM.MoeDivisionofNephrology,IndianaUniversity J.WesleyPikeDepartmentofBiochemistry,Universityof School of Medicine, Rodebush Veterans Administration WisconsineMadison, Madison, WI, United States Medical Center, Indianapolis, IN, United States Carol Pilbeam Department of Medicine and Muscu- David G. Monroe Department of Medicine, Division of loskeletal Institute, UConn Health, Farmington, CT, Endocrinology, Mayo Clinic College of Medicine, United States Rochester, MN, United States; The Robert and Arlene Lori Plum Department of Biochemistry, University of KogodCenteronAging,Rochester,MN,UnitedStates WisconsineMadison,Madison,Wisconsin,UnitedStates Carolina A. Moreira Bone Unitof Endocrine Division of John T. Potts, Jr. Endocrine Unit, Department of Federal University of Parana, Laboratory PRO, Section Medicine and Pediatric Nephrology, MassGeneral of Bone Histomorphometry, Pro Renal Foundation, Hospital for Children, Massachusetts General Hospital Curitiba, Parana, Brazil and Harvard Medical School, Boston, MA, United Ralph Müller Institute for Biomechanics, ETH Zurich, States Zurich, Switzerland J. Edward Puzas Department of Orthopaedics and Reha- David S. Musson Department of Medicine, University of bilitation, University of Rochester School of Medicine Auckland, Auckland, New Zealand and Dentistry, Rochester, NY, United States Teruyo Nakatani Department of Basic Science and Cra- Tilman D. Rachner Department of Medicine III, Techni- niofacial Biology, New York University College of sche Universität Dresden, Dresden, Germany; German Dentistry, New York, NY, United States Cancer Consortium (DKTK), Partner site Dresden and Dorit Naot Department of Medicine, University of Auck- German Cancer Research Center (DKFZ), Heidelberg, Germany; Center for Healthy Aging and Division of land, Auckland, New Zealand