Osteoporosis Osteoporosis Diagnosis and Management EDITED BY Dale W. Stovall MD ChairandResidencyProgramDirector DepartmentofObstetricsandGynecology RiversideRegionalMedicalCenter NewportNews,VA; ClinicalProfessor,DepartmentofInternalMedicine UniversityofVirginiaHealthSystem Charlottesville,VA,USA Thiseditionfirstpublished2013(cid:2)C 2013byJohnWiley&Sons,Ltd Registeredoffice: JohnWiley&Sons,Ltd,TheAtrium,SouthernGate,Chichester, WestSussex,PO198SQ,UK Editorialoffices: 9600GarsingtonRoad,Oxford,OX42DQ,UK TheAtrium,SouthernGate,Chichester,WestSussex,PO198SQ,UK 111RiverStreet,Hoboken,NJ07030-5774,USA Fordetailsofourglobaleditorialoffices,forcustomerservicesandforinformationabouthowto applyforpermissiontoreusethecopyrightmaterialinthisbookpleaseseeourwebsiteat www.wiley.com/wiley-blackwell Therightoftheauthortobeidentifiedastheauthorofthisworkhasbeenassertedinaccordance withtheUKCopyright,DesignsandPatentsAct1988. 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LibraryofCongressCataloging-in-PublicationData Osteoporosis(2013) Osteoporosis:diagnosisandmanagement/editedbyDaleW.Stovall. p.;cm. Includesbibliographicalreferencesandindex. ISBN978-1-119-96891-7(hardback:alk.paper)–ISBN978-1-118-31632-0(ePDF)– ISBN978-1-118-31631-3(ePub)–ISBN978-1-118-31630-6(Mobi)–ISBN978-1-118-31629-0 I.Stovall,DaleW.,editorofcompilation. II.Title. [DNLM:1.Osteoporosis–diagnosis. 2.Osteoporosis–therapy. 3.RiskFactors.WE250] RC931.O73 616.7(cid:3)16–dc23 2013018952 AcataloguerecordforthisbookisavailablefromtheBritishLibrary. Wileyalsopublishesitsbooksinavarietyofelectronicformats.Somecontentthatappearsinprint maynotbeavailableinelectronicbooks. Coverimage:iStock,filenumber#4907160(cid:2)C Rpsycho CoverdesignbyMeadenCreative Setin9.5/13ptMeridienbyAptara(cid:2)R Inc.,NewDelhi,India 1 2013 Contents ListofContributors,vii Preface,ix 1 EpidemiologyandGeneticsofPostmenopausalOsteoporosis,1 MarkEdwards,RebeccaMoon,NickHarvey&CyrusCooper 2 OsteoporosisinMen,15 RobertA.Adler 3 MechanismsofBoneRemodeling,31 MaziarShabestari&ErikFinkEriksen 4 FractureRiskAssessment,46 RonaldC.Hamdy 5 SecondaryCausesofOsteoporosis:BoneDiseases,62 PeterR.Ebeling 6 Glucocorticoid-inducedOsteoporosis,79 StuartSilverman&SwamyVenuturupalli 7 SecondaryCausesofOsteoporosis:OtherMedications,93 DianeM.Biskobing 8 HormoneTherapyforOsteoporosis,108 PilarValenzuelaMazo&JamesA.Simon 9 Bisphosphonates,123 PaulD.Miller&NelsonB.Watts 10 Denosumab,144 MichaelA.Bolognese 11 ParathyroidHormone:AnabolicTreatmentofOsteoporosis,158 ErikFinkEriksen 12 OptimumCalciumandVitaminDforthePreventionand TreatmentofOsteoporosis,178 MichaelF.Holick v vi Contents 13 TheUseofCombinationTherapyintheTreatmentof PostmenopausalOsteoporosis,201 JulietCompston 14 EmergingTherapies,211 MichaelR.McClung&CristianoA.F.Zerbini 15 MonitoringTherapyforOsteoporosis,227 E.MichaelLewiecki 16 PersistenceandCompliancewithMedicationstoPrevent Fractures:Epidemiology,Etiology,andManagementIssues,239 JohnT.Schousboe Appendix:AClinician’sApproachtothePatient,263 RobertLindsay Index,273 List of Contributors RobertA.Adler,MD PeterR.Ebeling,MBBS,MD,FRACP Chief,EndocrinologyandMetabolism DepartmentsofMedicine(NorthWest HunterHolmesMcGuireVeteransAffairs AcademicCentre)andEndocrinology MedicalCenter; AustralianInstituteofMusculoskeletalScience ProfessorofInternalMedicine TheUniversityofMelbourne ProfessorofEpidemiologyand St.Albans,VIC,Australia CommunityHealth VirginiaCommonwealthUniversity MarkEdwards,MB,BSc,MRCP SchoolofMedicine MRCLifecourseEpidemiologyUnit Richmond,VA,USA UniversityofSouthampton UniversityHospitalSouthampton DianeM.Biskobing,MD Southampton,UK AssociateProfessorofMedicine VirginiaCommonwealthUniversity ErikFinkEriksen,MD,DMSc SchoolofMedicine DepartmentofClinicalEndocrinology Richmond,VA,USA OsloUniversityHospital Oslo,Norway MichaelA.Bolognese,MD,FACE RonaldC.Hamdy,MD,FRCP,FACP BethesdaHealthResearch Bethesda,MD,USA ProfessorofMedicine CecileCoxQuillenChairofExcellencein JulietCompston,MD,FRCPath, GeriatricMedicine FRCP,FMedSci EastTennesseeStateUniversity ProfessorofBoneMedicine JohnsonCity,TN,USA CambridgeUniversityHospitalsNHS NickHarvey,MA,MB,BChir,MRCP, FoundationTrust PhD Cambridge,UK MRCLifecourseEpidemiologyUnit UniversityofSouthampton CyrusCooper,MA,DM,FRCP,FFPH, UniversityHospitalSouthampton FMedSci Southampton,UK MRCLifecourseEpidemiologyUnit UniversityofSouthampton MichaelF.Holick,PhD,MD UniversityHospitalSouthampton DepartmentofMedicine,Sectionof Southampton; Endocrinology,Nutrition,andDiabetes ProfessorofMusculoskeletalScience VitaminD,SkinandBoneResearchLaboratory NIHRMusculoskeletalBiomedical BostonUniversityMedicalCenter ResearchUnit Boston,MA,USA UniversityofOxford Oxford,UK vii viii ListofContributors E.MichaelLewiecki,MD, MaziarShabestari,DDS,PhD FACP,FACE DepartmentofClinicalEndocrinology NewMexicoClinicalResearch& OsloUniversityHospital OsteoporosisCenter,Inc Oslo,Norway Albuquerque,NM,USA StuartSilverman,MD,FACP,FACR RobertLindsay,MD,PhD RheumatologyDivision HelenHayesHospital; Cedars-SinaiMedicalCenter CollegeofPhysiciansandSurgeons LosAngeles,CA,USA ColumbiaUniversity NewYork,NY,USA JamesA.Simon,MD,CCD,NCMP, FACOG MichaelR.McClung,MD DepartmentofObstetricsandGynecology OregonOsteoporosisCenter TheSchoolofMedicineandHealthSciences Portland,OR,USA TheGeorgeWashingtonUniversity; Women’sHealth&ResearchConsultants(cid:2)R PaulD.Miller,MD Washington,DC,USA DistinguishedClinicalProfessorofMedicine UniversityofColoradoHealthSciencesCenter; PilarValenzuelaMazo,MD,NCMP MedicalDirector DepartmentofObstetricsandGynecology ColoradoCenterforBoneResearch PontificiaUniversidadCato´licadeChile Lakewood,CO,USA SchoolofMedicine Santiago,Chile RebeccaMoon,BM,BSc,MRCPCH MRCLifecourseEpidemiologyUnit SwamyVenuturupalli,MD,FACR UniversityofSouthampton ClinicalChief-RheumatologyDivision UniversityHospitalSouthampton Cedars-SinaiMedicalCenter; Southampton,UK AssociateClinicalProfessorofMedicine UniversityofCalifornia,LosAngeles JohnT.Schousboe,MD,PhD LosAngeles,CA,USA Co-Director,ParkNicolletOsteoporosisCenter MedicalDirectorforResearch,ParkNicollet NelsonB.Watts,MD InstituteforResearchandEducation Director,MercyHealthOsteoporosisand ParkNicolletHealthServices; BoneHealthServices AdjunctAssistantProfessor Cincinnati,OH,USA DivisionofHealthPolicyandManagement SchoolofPublicHealth CristianoA.F.Zerbini,MD UniversityofMinnesota DepartmentofRheumatology Minneapolis,MN,USA HospitalHelio´polis; CentroPaulistadeInvestigac¸a˜oClinica Sa˜oPaulo,Brazil Preface Osteoporosisisahighlyprevalentdiseasethatincreasesone’sriskforfrac- ture.Thediseaseisprimarilydefinedbytheresultsofabonemineralden- sity test. However, there are many risk factors for osteoporosis and frac- ture. Determining which patients are at significant risk for fracture; and therefore, are candidates for intervention can be challenging. The devel- opment of the ten year absolute fracture risk assessment tool, FRAX, has greatlyenhancedtheclinician’sabilitytoselectpatientsfortherapy. Currently,thereisnocureforosteoporosis,andtreatmentisfocusedon reducingthepatient’sriskforfracture.Ourunderstandingofthephysiol- ogyofboneremodelingison-going.Aswelearnmoreaboutthisprocess, our ability to identify new highly effective, safe therapies will improve. Several treatment options are currently approved and available for the treatmentofpatientswithosteoporosisandlowbonemass.Theinforma- tiongainedfromnumerousrandomizedtrialshasclarifiedthebenefitsof thesetherapies,andtheirexistenceinclinicalpracticeformanyyearshas providedclinicianswithadditionalsafetyinformationregardingtheiruse. This text reviews the epidemiology of this disease, its pathophysiology, and its clinical impact in both women and men. Assessment of fracture risk,secondarycausesofosteoporosis,initiationoftherapyandfollow-up are reviewed. Medical therapies, including the administration of calcium and Vitamin D are reviewed in detail to enhance the clinician’s depth of knowledgeofthesesubjects. The primary aim of this text is to empower the primary care clinician to identify and treat patients with osteoporosis. In addition, this text will supplytheprimarycareproviderwithin-depthinformationregardingthe mechanisms of action of numerous approved medical therapies, when treatment is indicated, how to select a therapy, and how to manage the diseaseonanon-goingbasis.Finally,alookintofuturemedicaltherapies forthisdiseaseispresented. Iamgratefultotheauthorsofthistextwhohaveputtheirtime,energy, and significant skill towards comprising a work that we hope will con- tributetotheimprovementofpatientcare. DaleW.Stovall,MD NewportNews,VA,USA ix CHAPTER 1 Epidemiology and Genetics of Postmenopausal Osteoporosis MarkEdwards1,RebeccaMoon1,NickHarvey1 & CyrusCooper1,2 1UniversityofSouthampton,UniversityHospitalSouthampton,Southampton,UK 2UniversityofOxford,Oxford,UK Introduction Osteoporosis is a skeletal disease characterized by low bone mass and micro-architectural deterioration of bone tissue with a consequent increaseinbonefragilityandsusceptibilitytofracture[1].Thetermosteo- porosis literally means “porous bone” and refers to a condition in which boneisnormallymineralizedbutreducedinquantity.In1994,aworking group of the World Health Organization (WHO) provided a practical def- inition of osteoporosis as a bone mineral density (BMD) of greater than 2.5SDbelowtheyoungnormalmean[2].Earlierdefinitionshadincorpo- ratedfractureandsotoprovidecomparability,thesubsetofwomenwith osteoporosis who had also suffered one or more fragility fractures were deemedtohavesevere“established”osteoporosis. The etiology of osteoporotic fractures is complex. Low bone density is not the only risk factor for fracture and there has been a move towards making an assessment of individualized 10-year absolute fracture risk using the WHO FRAX based on multiple clinical risk factors [3]. Family history, and in particular parental hip fracture, is included in the FRAX toolreflecting the hereditary componentof the condition.There is grow- ing recognition of a complex interaction between genetic and environ- mental factors. Only a small number of specific genes contributing to osteoporosis risk have been consistently identified; however, the inves- tigation of gene-environment interactions with developmental plasticity has yielded promising results, raising the possibility of intervening dur- ing fetal development or early life to reduce individual fracture risk and the global burden of this disease. It is estimated that around 200 million womenworldwidehaveosteoporosiswithanosteoporoticfractureoccur- ringevery3seconds[4].Thisequatesto1in3womenover50yearsofage Osteoporosis:DiagnosisandManagement,FirstEdition.EditedbyDaleW.Stovall. (cid:2)C 2013JohnWiley&Sons,Ltd.Published2013byJohnWiley&Sons,Ltd. 1 2 Chapter1 sufferinganosteoporoticfracture[5,6].Fragilityfracturesmakeup0.83% oftheworldwideburdenofnoncommunicabledisease.Thisfigurerisesto 1.75% in Europe, where fragility fractures also account for more disabil- ity adjusted life years (DALYs) than many other chronic diseases [7]. At presenttheannualcostofallosteoporoticfracturesworldwideisinexcess of $17 billion and is expected to rise to $25 billion by 2025 [8]. The cost oftreatingosteoporoticfracturesisalsoincreasingintheUKandexpected torisetoover£2billionby2020[9].Thischapterwillreviewthegenetic andearlyenvironmentalfactorsassociatedwithosteoporosisanddescribe thedemographic,globalandseculartrendsinitsepidemiology. Genetics Heritability estimates in osteoporosis Peak bone mass is an important factor in determining BMD in later life. It has been suggested by twin and family studies that between 50% and 85% of the variance in BMD is determined by heritable factors [10–12], including both genetics and shared environmental exposures. These esti- matesdo,however,varydependingontheskeletalsite,withlumbarspine BMDdemonstratingagreaterheritablecomponentthanthedistalforearm BMD[10,12,13].Severalstudieshavesuggestedthatincreasingagealso influencestheextenttowhichboneoutcomesaredeterminedbyheritable factors.IthasbeenshownthattheheritablecomponentofBMDislowerin postmenopausalcomparedwithpremenopausalwomen[10,12],probably reflectingthegreaterroleofadditionallifestyle,dietaryanddisease-related factorsoccurringinpostmenopausalwomen.Similarly,theheritablecom- ponentoftherateofchangeinBMDinpostmenopausalwomenislower thanthatforpeakbonemass,whichoccursmuchearlierinlife[14]. Intermsofosteoporoticfractures,itisknownthattheriskisgreaterin thosewithaparentwhohassufferedahipfracture.Thereis,however,less evidenceforasignificantgeneticcomponenttothisassociation.Aherita- blecomponenthasalsobeenfoundinthedeterminationoffemoralneck geometry [15], markers of bone turnover [16], age at menopause [17], andmusclestrength[18],allofwhichconfersomesusceptibilitytoosteo- porotic fracture. These factors, in addition to the associations with BMD, suggestthatthereislikelytobearoleinfractureprediction;however,due to the size of the effect, it has been difficult to demonstrate in epidemio- logicalstudies. Genetic studies in osteoporosis Having determined that there is a small, but significant, genetic compo- nent to the risk of osteoporosis, different types of genetic investigations