Osteoporosis Treatment of a Silently Developing Disease

MarcK.Drezner,MDSeniorAssociateDeanEmeritusProfessorofMedicineEmeritusUniversityofWisconsin-Madison

Auditorium

TheForestatDukeOctober8,2018

11A

What is osteoporosis?

•  Theword“osteoporosis”isoftenusedsynonymouslywithbonefragility

•  Theincreasedskeletalfragility,prototypicofthedisorder,istheresultoflowbonemass,whichisthequantityofbonecontainedwithinthevertebrae,hipsorotherbones,aswellasdisruptionofthemicroarchitecturewithinabone.

•  Therearemultiplecausesofosteoporosisinhumans

Multiple Causes of Osteoporosis

•  GIDisorders•  CeliacDisease•  InflammatoryBowelDiseases•  GastricBypassSurgery•  AnorexiaNervosa•  ChronicLiverDiseases

•  HematologicalDiseases•  MultipleMyleoma•  SystemicMastocytosis•  BetaThalassemiaMajor

•  EndocrineDisorders•  ExcessSteroids•  Hyperthyroidism•  Hypogonadism•  Hyperparathyroidism•  DiabetesMellitus

•  KidneyDisorders•  Hypercalciuria•  RenalTubularAcidosis•  ChronicRenalDisease

•  AutoimmuneDisorders•  RheumatoidArthritis•  Lupus•  AnkylosingSpondylitis•  MultipleSclerosis

•  CommonandWell-KnownCauses•  Age•  Menopause

•  AlternativeCauses

•  Drugs•  Steroids•  ExcessThyroidHormone•  Diuretics•  Anticonvulsants

The Role of Age and Menopause in the Genesis of Osteoporosis

Youth Aging/MenopauseAge(Years)

The Mechanisms Underlying the Bone Loss Due to Age and Menopause

MechanismsofBoneLossPathogenesisofOsteoporosis

RemodelingImbalance

IncreasedRemodelingRate

PathogenesisofMenopausalBoneLoss

ImbalancedRemodeling

PathogenesisofAgeDependentBoneLoss

↑RankL→↑OsteoclastNumber/Activity

NormalSkeletalPhysiology

QuiescenceResorptionFormation

ContinuousBoneRemodeling

Balanced Imbalanced

Normal

IncreasedRemodelingRate

IncreasedRemodelingRateImbalancedRemodeling

Normal Normal

OsteoblastsOsteoclasts

NormalOsteoporosis

VertebraeFemora(Hips)

corticalbone

trabecularbone

corticalbone

trabecularbone

Microstructural Changes in Osteoporotic Bone

Unbalancedremodelingupontrabeculaecausethemtothin,perforateanddisappear

Unbalancedintracorticalremodelinguponcanalsurfacesenlargeandcoalescethecanalsandfragmentthecortex

Microstructuraldeteriorationproducesbonefragilityoutofproportiontothebonelossproducingit

The Impact of Age-Dependent and Postmenopausal Osteoporosis •  IntheUSA,approximately54millionpeople>50yearsofagehaveanincreasedriskoffracture

•  From2005to2015to2025thetotalnumberofagerelatedfragilityfracturesperyearintheUnitedStateshasincreased,orwillincrease,from2.1to2.51to3.04million,oroverall45%,solelyonthebasisofgrowthintheelderlypopulationatrisk

• Usingcurrentcriteria,theprevalenceofosteoporosisinmenover50yearsofageis16%,whilethatforwomenis30%;however,theprevalenceincreasesinmento46.3%andinwomento77.1%amongstthosegreaterthan80yearsofage

• Collectively,thesedataclearlyindicatethatthediagnosisofosteoporosisatarelativelyearlyageisofparamountimportance,asistreatmentdesignedtomanageexistentdiseaseandpreventprogressionofthediseasewithage.

• Nevertheless,treatmentofosteoporosisoverthelastseveralyearsisataperigee,crashingbecauseofpossibletherapeuticcomplicationstoonly20%ofpatientsrequiringtreatment.

Will You Develop Osteoporosis? •  Awomanof50yearsofagehasa50%chanceofhavingavertebralcompressionfractureinherlifetime,whileamanofsimilaragehasa20-25%chanceofsustainingavertebralcompressionfractureinhislifetime

•  Womenwithpre-existingvertebralfractureshaveanapproximate7Xgreaterriskforsubsequentvertebralfractures

•  Yetonly16%ofwomenwhosufferafragilityfracturereceivetreatmentduringtheensuing6months

•  Awomanof50yearsofagehasa20-25%chanceofsustainingahipfractureduringherlifetime,whileamanofsimilaragehasa10-15%chanceofsufferingahipfractureduringhislifetime.

•  Whiletherateofhipfractureincreaseswithage,theincrementinwomenandmenisparticularlystrikingafterage70years.

•  Indeed,mosthipfracturesoccurbetweentheagesof80-90years•  Occurrenceofavertebralfractureincreasestheriskofahipfractureby77%

The Diagnosis of Osteoporosis

• Osteoporosisischaracterizedbylowbonemass,microarchitecturaldisruption,andincreasedskeletalfragility

• Aclinicaldiagnosisofosteoporosismaybemadebythepresenceofafragilityfracture,particularlyatthespine,hip,wrist,humerus,rib,and/orpelvis

•  Intheabsenceofafragilityfracture,bonemineraldensity(BMD)assessmentbydualenergyabsorptiometry(DXA)isthestandardtesttodiagnoseosteoporosis

Bone Mineral Density Measurements

RISKFACTORSIncreasedriskoffallingHistoryofhipfractureinaparentSmall,thinbodyframePreviousbrokenboneasanadultCigarettesmokingInactivelifestyleIngestinginsufficientcalciumand/orvitaminD

TheNationalOsteoporosisFoundationrecommendsmeasurementofbonedensityif:

Youareawomanage65yearsorolderYouareamanage70yearsorolderYoubreakaboneafterage50yearsYouareawomanofmenopausalagewithriskfactorsYouareapostmenopausalwomanunderage65yearswithriskfactorsYouareamanage50-69yearswithriskfactors

Bone Density Measurements LumbarVertebrae1-4HIP

SHAFT

Interpretation of Bone Mineral Density Measurements

• AclinicaldiagnosisofosteoporosismaybemadewhentheT-scoreis≥2.5standarddeviationsbelowthemeaninayoungadultpopulationatanysitemeasuredbydualenergyBMD

•  LowbonedensityorosteopeniaispresentwhentheT-scorescoreis1-2.5standarddeviationsbelowthatinayoungadultpopulationatanymeasuredsite

Consequences of Decreased Bone Mineral Density • Approximately30-50%ofwomenand15-20%ofmensufferthefracturesassociatedwithosteoporosis(diagnosedbyBMD)

• However,womenandmenwithosteopeniaarenotfreeoffracturerisk

•  Indeed,mostwomenandmensustainingfragilityfractureshaveosteopeniaandmanyhaveso-called“normal”bonedensity

•  ThisapparentcognitivedissonanceresultsfromtheinabilityofBMDmeasurementstoidentifywhetherthedecreasedbonedensityisassociatedwithmicrostructuralbonedeteriorationthatseverelypredisposestofragilityfractures

• Unfortunately,thenecessaryhighresolutionimagingmethodsnecessarytoidentifysuchmicroarchitecturalchangesarenotyetwidelyavailable.

Osteopenia: Determining Risk for Fracture

• AreasonablylargepercentageofwomenandmenwithosteopeniawhoareatriskforfracturecanbeidentifiedbyapplyingaFractureRiskAssessmentTool(FRAX),whichweightstheimpactofvariousclinicalfactorsandbonedensitymeasurementsto“determine”theprobabilityofosteoporoticfractures

• Postmenopausalwomenandmen≥50yearsofagewithosteopeniashouldbeconsideredhavingosteoporosisif,usingtheFRAXtool,the10yearprobabilityofamajorosteoporoticfractureis≥20percentand/orthatforahipfractureis≥3percent

Whatarethe“EffectiveTreatments”forPostmenopausalandAge-DependentOsteoporosis?

Anti-ResorptiveTherapy;AnabolicTherapy

WhatTherapyis“Effective”fortheVariedPresentationofthisDisease

MildvsSevereBoneLoss;RecurrentFractures;SideEffectsoftheMultipleTreatmentRegimens;ObligatoryMultiple

DrugTherapy

Varied Presentation of Patient >50 Years of Age •  NormalBoneDensitywithoutaFragilityFracture•  NormalBoneDensitywithaFragilityFractureDX:Osteoporosis:Treat• MildtoModerateDecreaseinBoneDensity(1-2.5SDDecrease)withoutaFragilityFracture:PRAXNon-Diagnostic:NoTreatment:FollowSerially

• MildtoModerateDecreaseinBoneDensity(1-2.5SDDecrease)withoutaFragilityFracture:PRAXDiagnosticDX:Osteoporosis:Treat

• MildtoModerateDecreaseinBoneDensity(1-2.5SDDecrease)withaFragilityFractureDX:Osteoporosis:Treat

• Moderate+DecreaseinBoneDensity(>2.5SDDecrease)withorwithoutFragilityFracture:DXOsteoporosis:Treat

•  SevereDecreaseinBoneDensity(>>2.5SDDecreasewithSingleorMultipleFragilityFractures):DXOsteoporosis:Treat

Treatment Options

• AlthoughcalciumandvitaminDareancillarytreatmentoptionsforosteoporosis,theyarelimitedtoprovidingadequatebonemineralandactivevitaminD,todoawaywiththeeffectsofvitaminDinsufficiency/deficiencyandtoprovideadequatemineralforboneformation

•  Theseagentsdonotinfluencetheenhancedboneresorptionandremodelingimbalancethatleadtotheosteoporosisduetoagingandmenopause

Treatment Options

• NormalBoneDensitywithaFragilityFractureDX:Osteoporosis:Treat• MildtoModerateDecreaseinBoneDensity(1-2.5SDDecrease)withoutaFragilityFracture:PRAXDiagnosticDX:Osteoporosis:Treat

• MildtoModerateDecreaseinBoneDensity(1-2.5SDDecrease)withaFragilityFractureDX:Osteoporosis:Treat

PrincipleofTherapyManagetheCurrentStatusandLimitProgressionoftheBoneLossDrugClass:AntiresoprtiveAgent

Anti-Resorptive Therapy •  Bisphosphonates(e.g.alendronate[Fosamax];risedronate[Actonel];andzoledronate[Zometa])arecurrentlythefirstlinetreatmentandmostcommonanti-resorptivetherapyused

•  Dependoninhibitionofanenzymerequiredforosteoclastmediatedboneresorption•  Theresultisslowingoftheremodelingprocessandareductionoffractureriskcomparedtothatinuntreatedsubjects,inwhomrapidremodelingcontinues

•  However,microstructuraldeteriorationisnoteliminated,whichlikelyexplainswhythefractureriskreductionismodestatbest(∼50%atthevertebrae,butonly∼20-30%atnon-vertebralfracturesthatcomprise80%ofallfracturesinthecommunity)

•  Inanycase,cessationoftherapyafter3-5yearsdoesnoteliminatetheeffectsoftreatmentforavariableperiodoftime

•  Ofcourse,inlargestudiestherearesomedifferencesintheefficacyofthevariousbisphosphonatestested

•  Risedronatesuppressesboneremodelingandpossiblyfractureriskreductionmorequickly•  Zoledronateappearsmoreeffectivefollowingcessationoftherapy

•  GIsideeffectsandatypicalfemoralfracturesareamongthesideeffectstothisdrugtherapy

Anti-Resorptive Therapy • Denosumab(Prolia)isanalternativedrugtherapytosuppressboneresorptionandisanantibodyforRANK-ligand,amajorregulatorofosteoclastdevelopmentandfunction

•  Adminstered(60mg)subcutaneouslyevery6months,thetreatmentproducesalmostcompletesuppressionofboneremodelingandafter3yearsresultsina68%reductioninvertebralfractures,40%reductioninhipfracture,and20%reductioninnon-vertebralfractures.

•  ThemorecompletesuppressionofresorptionaccountsforthegreaterincreasesinBMDachievedinpostmenopausalwomentreatedwithdenosumabcomparedtobisphosphonates

• WhethertheseBMDdifferencetranslatedtodifferencesinfractureriskreductionbetweenthetwogroupsisnotknown

•  Controlledtrialshavebeenconductedforonly3years•  Despitethesepositiveoutcomes,cessationofdenosumabtreatmentcreatesareboundincreaseinboneremodelingandincreasedfracturerisk,necessitatingcommencementofbisphosphonatetherapyatsometimearoundthetimedenosumabtreatmentisdiscontinued

Anti-Resorptive Therapy •  SelectiveEstrogenReceptorModulators(SERM),suchasRaloxifene,reducetherateofboneremodelingbyonly20-30%,therebyproducingonlyamodestandtransitoryincreaseinBMD

• Mostimportantly,SERMtreatmentaccountsforonlyaverymodestvertebralfractureriskreductionandnonon-vertebralfractureriskreduction

Treatment Options

• Moderate+DecreaseinBoneDensity(>2.5SDDecrease)withorwithoutFragilityFracture:DXOsteoporosis:Treat

•  SevereDecreaseinBoneDensity(>>2.5SDDecreasewithSingleorMultipleFragilityFractures):DXOsteoporosis:Treat

PrincipleofTherapyIncreasebonedensityandmaintaintheincreaselongtermDrugClass:AnabolicAgent(followedbyAntiresorptiveAgentforMaintenance)

Anabolic Therapy for Osteoporosis •  Teriparatide(Forteo)andAbaloparatide(Tymlos)increaseboneformation

andtherebybonevolumeandstrength,resultinginadecreaseinfracturerisk.

•  Indicatedinthosepatientswithahighriskforfracture,definedasahistoryoffragilityfracture,multipleriskfactorsforfracture,aprofounddecreaseinbonedensity,and/orfailureof,orintoleranceto,otheravailabledrugtreatmentforosteoporosis

•  Useislimitedbecauseoftheunknownrelevancetohumansofrodentosteosarcomainductionbythesedrugs;treatmentislimitedto18-24monthsduringalifetime.

•  Thesedrugsuniquelyincreasetrabecularbonethicknessandimprovetrabecularmicroarchitecture

•  Furtherinformationnecessary•  WhileTeriparatideconsistentlyreducesvertebralfractureincidence,nodataareavailableregardinghipfracturesandevidencefornon-vertebralfracturereductionisinconsistent

•  DataregardingAbaloparatideeffectsonhipfracturearelikewiseabsentbutthereisadecreaseinnon-vertebralfractures

•  Treatmentwiththeseagentsrequiresfollow-upwithabisphosphonateforatleast3years

Summary •  Osteoporosisbeginsasasilentdisease•  Osteoporosisbecomesacomplexdisease,bothpathologicallyandclinically•  Thepresentationofactivediseaseisveryvariable,buttherapyisessentialtopreventprogressionofthediseasefromthatevidentatpresentation

•  Therearemultipletreatmentoptionsforosteoporosis,noneofwhichcuresthedisease,andeachofwhichseemsappropriateundervariablecircumstances,despitepossiblecomplications

•  Carefulconsiderationmustbeappliedtoascertainingthediagnosisofosteoporosis,choosingthecorrecttreatmentstrategy,andprovidingcarefulandthoroughfollow-up.

-/-SHNURRING-3

Slit3

CD31hiEMCNhiEndothelium

↑↑BoneDensity

THEFUTURE

Questions?