Management of Postmenopausal Osteoporosis

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? Our comprehensive searchFurtherManagementofPostmenopausalOsteoporosisPanagiotaAndreopoulou1andRichardS.Bockman1,2DepartmentofMedicine,EndocrineService,HospitalforSpecialSurgery,NewYork,NY,

10021;email:andreopouloup@hss.edu

21

Annu. Rev. Med. 2015.66:329-342. Downloaded from http://wendang.chazidian.com Access provided by Lanzhou University on 02/04/15. For personal use only.

WeillCornellMedicalCollege,NewYork,NY,10065;email:bockmanr@hss.eduAnnu.Rev.Med.2015.66:329–42FirstpublishedonlineasaReviewinAdvanceonOctober29,http://wendang.chazidian.com

Thisarticle’sdoi:

10.1146/annurev-med-070313-022841

c2015byAnnualReviews.Copyright??

AllrightsreservedKeywordsbonemicroarchitecture,fracturerisk,combinationtherapyAbstractAhallmarkofmenopause,whichfollowsthedeclineintheovarianpro-ductionofestrogen,istheaggressiveandpersistentlossofbonemineralandstructuralelementsleadingtolossofbonestrengthandincreasedfrac-turerisk.Thisreviewfocusesonnewermethodsofdiagnosingosteoporosis

andassessingfracturerisk,aswellasonnovelmanagementstrategiesforpreventionandtreatment.Fracture-riskpredictionhasbeensigni?cantlyenhancedbythedevelopmentofmethodssuchasthetrabecularbonescore,whichhelpsassessbonemicroarchitectureandaddsvaluetostandardbonedensitometry,andtheFractureRiskAssessmentTool(FRAX)algorithmtechniques.Thetreatmentofosteoporosis,whichhasthegoalsoffracturepreventionandriskreduction,ismovingbeyondtraditionalmonotherapieswithantiresorptivesandanabolicagentsintonewcombinationregimens.

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INTRODUCTIONGeneticallydeterminedlowbonemassalongwiththelossofboneassociatedwithestrogende-?ciencyprobablyaccountforthemajorityofpatientswithpostmenopausalosteoporosis.Never-theless,allpostmenopausalpatientswithosteoporosisshouldbeevaluatedforsecondarycausesofboneloss,suchaslong-term(morethanthreemonths)administrationofsystemicglucocorticoids,includinghighdosesofinhaledsteroidsandendogenoushypercortisolism;rheumatoidarthri-tis;chronicliverdisease;alcoholism;untreatedhypogonadismfollowingbilateraloophorectomy;anorexianervosaorothersevereeatingdisorders;administrationofchemotherapyoraromataseinhibitors;hypopituitarism;prolongedimmobilityassociatedwithspinalcordinjury,Parkinson’sdisease,stroke,musculardystrophyorankylosingspondylitis;immunosuppressioninorgantrans-plantationpatients;diabetesmellitustype1ortype2;untreatedhyperthyroidismandoverre-placementinhypothyroidism;in?ammatoryboweldisease;andchronicobstructivepulmonarydisease.However,thisreviewfocusesonnewerissuesinpostmenopausalosteoporosisthatarenotattributabletosecondaryconditions.IDENTIFYINGPATIENTSATRISKBonemineraldensity(BMD)isanassessmentofthemineralcontentinkeyskeletalregions.TheWorldHealthOrganization(WHO)hasde?nedosteoporosisusingaBMDscorederivedfromdual-energyX-rayabsorptiometry(DXA),thatis,2.5(T-score)standarddeviationsbelowthemeanforhealthyyoungadultsatthespine,femoralneckortotalhip(1).T-scoresbetween?1.0and?2.5areconsistentwithlowbonemass,andthoseabove?1.0areconsiderednormal.Acon-sensusreportbytheUSNationalInstitutesofHealthemphasizedthestructuralbasisbyde?ningosteoporosisas“askeletaldisordercharacterizedbycompromisedbonestrengthpredisposingtoincreasedriskoffracture”(2).Hence,surrogatemeasurementsofbonestrengthhaveprovenextremelyhelpfulinbetterassessingfracturerisk.DualX-RayAbsorptiometryCentralDXAisusedformeasurementofBMDofthespineandhip.Ithasprovenutilityforthediagnosisofosteoporosis,assessmentoffracturerisk,andmonitoringofresponsetotreatment.Thismethodiswidelyavailablewithreadilyinterpretableresults(3,4).TheriskoffractureexponentiallyincreasesasBMDdecreasesatthespine,hip,forearm,humerus,andpelvis(3).NearlyallrandomizedclinicaltrialshaveutilizedBMDchangesasasurrogateendpointforassessingtheef?cacyofagentsusedforosteoporosispreventionandtreatment(5).Additionally,

DXAmayincludeanassessmentoflowerthoracicandlumbar(T4–L4)vertebralfracture(6).ArealBMDmeasurements,however,areaffectedbybonesizeandshape,softtissuecom-position,severedegenerativediscdisease,vertebralfractures,priorspinalsurgery,bilateralhipreplacement,andobesity.Mostimportantly,itisnotpossibletodifferentiatebetweenundermin-eralizedbone(osteomalacia)andosteoporosis.

PeripheralDXAmeasurementsoftheBMDoftheforearm,heelorhandcorrelatelesswellwithcentralDXAmeasurements(7),andtheyhavelittleutilityasserialmeasurementstoassesstreatmentef?cacy.

FractureRiskAssessmentTool

TheWHO’sFractureRiskAssessmentTool(FRAX)isafractureriskpredictionmodelthatutilizesthefemoralneckBMDasmeasuredbyDXAandincorporatesclinicalriskfactorsforboneloss330Andreopoulou·BockmanAnnu. Rev. Med. 2015.66:329-342. Downloaded from http://wendang.chazidian.com

inordertobetterestimatethe10-yearprobabilityofhipandothermajorosteoporoticfractures(spine,humerus,forearm).Theclinicalriskfactorsincludethecountryorgeographicregionandthepatient’sethnicorigin,age,sex,weight,height,priorfragilityfracture,parentalhistoryofhipfracture,currentsmoking,excessalcoholintake,long-termuseoforalglucocorticoids,rheumatoidarthritis,andsecondaryosteoporosis(8).TheFRAXalgorithmwasbasedondataderivedfrompopulationcohortsinEurope,NorthAmerica,Asia,andAustralia(9–11).FRAXisbecomingpartofstandardDXAreportsandmaybeaccessedonlineathttps://www.shef.ac.uk/FRAX/.FRAXmodelsareavailablefor52countries,andthereareadditionalethnic-speci?cmodelsfortheUnitedStates,becausefractureprobabilityvariessigni?cantlyamongdifferentregionsandethnicgroups(12).

IntheUnitedStates,theNationalOsteoporosisFoundationrecommendstreatmentofpa-tientswithaFRAX-calculated10-yearfractureprobabilityof>3%forhipfractureand>20%formajorosteoporoticfracture.FRAX,however,hasnotbeenevaluatedinpatientswhohavealreadyreceivedtreatment(13).Itisimpossibletoincorporateeverypossibleclinicalscenario.

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nintotheFRAXalgorithm,suchasthenumberorsitesofpriorfractures,thedoseandduration

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eofglucocorticoids,oruseoftobaccoandalcohol.Currently,onlythefemoralneckBMDcanbe

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aenteredintotheFRAXalgorithmdespitethefrequentdiscordancebetweenBMDofthehipandn

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sspine,althoughcorrectivecalculationshavebeenproposed(14).Finally,DXAandFRAXdonot

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ptakeintoaccountinformationonthemicrostructuralintegrityofbone.

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1AssessmentsofBoneMicroarchitecture

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2AlthoughdiagnosisandtreatmentdecisionsoftenrelyonDXAmeasurements(4),whenoneclosely

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oreviewsfractureincidence,themajorityoflow-traumafracturesoccurinindividualswithlowor

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inormalbonedensitymeasurements(15).Therefore,assessmentofothermajordeterminantsof

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evbonestrength—suchastrabecularstructure,corticalthickness,focaldefects,materialproperties,

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Uandgeometry,aswellaspersonalclinicalandfamilyhistoryandpropensityforfalls—mustbe

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oconsideredforamorecompleteriskassessment.

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aExtensiveprogresshasbeenmadeinassessingmicrostructureandbonestrengthutilizinghigh-

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yresolutionperipheralquantitativecomputedtomography(QCT)(16),advancedCTimaging(17),

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dandhigh-?eldmagneticresonanceimaging(MRI)(18).DetailedplainCTanalysesofthefemoral

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vneck,forexample,haverevealedfocalsitesofcorticalthinningwithamuchhigherfrequency

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pinpatientswithpriorhipfractures(16,19).Utilizationofgeometricpropertiesderivedfrom

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eDXA(20)coupledwithcomputationalmodeling(21)provideincreasedunderstandingoffracture

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Asusceptibility.Unfortunately,theuseofthesemethodsislimitedtocenterswithwell-established

expertiseintheparticulartechnique.

TrabecularBoneScore

NewlydevelopedadvancesinDXAmethodshavegreatlyexpandedtheirfunctionality(22).Newsoftware(TBSiNsight??R,MedimapsGroup,Plan-les-Ouates,Switzerland)enablesestimationoftrabecularbonetexture,whichcanbecorrelatedtobonemicroarchitecture(23).Arelationshipbetween3Dbonecharacteristics,mechanicalparameters,andthetrabecularbonescore(TBS)hasbeenestablished(23,24).

ManystudieshavedemonstratedthatTBSpredictscurrentandfuturefragilityfracturesinosteoporosisbeyondthosepredictedbyBMDandclinicalriskfactorsandhasvalueinmonitoringresponsetotreatment(25).TBSmayhaveadditionalvalueinsecondaryosteoporosiswhenabnor-maltrabecularmicroarchitecturemayhelpexplaintheparadoxofincreasedfracturesatahigherBMDinspeci?cdiseasesorconditions(e.g.,diabetes,rheumatoidarthritis,glucocorticoid-induced

http://wendang.chazidian.com?ManagementofPostmenopausalOsteoporosis331Annu. Rev. Med. 2015.66:329-342. Downloaded from http://wendang.chazidian.com

Table1Proposedtrabecularbonescore(TBS)rangesforpostmenopausalwomen(28)TBS

<1.2

1.2–1.35

>1.35MicroarchitectureDegraded=higherriskoffracturePartiallydegraded=mediumriskoffractureNormal=lowerriskoffracture

Annu. Rev. Med. 2015.66:329-342. Downloaded from http://wendang.chazidian.com Access provided by Lanzhou University on 02/04/15. For personal use only.osteoporosis).TheprecisionerrorforTBSisequivalenttoarealBMD(26,27).Onewayofin-terpretingTBSwouldbetoprovideclinicallyrelevantranges(28)(Table1).BecauseTBSdataaregeneratedautomaticallyintheregularDXAscanofthelumbarspine,hugedatabasesareavailableforanalysis(25).Asummaryof?ndingsfromclinicalstudiesisgiveninTable2(26,27,29–36).DegenerativediscdiseaseandperiarticularspinaldiseasehavelittleeffectonTBS,incontrasttotheirimpactonbonedensitymeasurements(37).BMDhasshownapositivecorrelationwithbodymassindex(BMI)(38).Bycontrast,TBShasshownanegativebutmildcorrelationwithBMI.BothBMDandTBSpredictfractureriskbutareconsistentlyfoundtobeindependentpredictors(38),andbothshowastrongpositiveassociationwithmanyriskfactorsthatcanpredictosteoporoticfracturerisk.Furthermore,TBSsigni?cantlyenhancestheabilityofFRAXtoclassifyfracturerisk(9,39).TheWHOisconsideringpossibleinclusionofTBSintheFRAXcalculation.TherearelimitstoTBS.OlderdensitometerscanimpairthequalityofthevariogramandmaynotbecompatiblewithTBSsoftware.Theeffectofabdominalsofttissueinattenuatingphotonabsorptionhasnotbeenfullyelucidated,andBMIhasnotprovenhelpfulincorrectingforartifactsduetobodytypeorcomposition.Appropriatephantommeasurementstoenableinter-andintrascancalibrationhavebeenusedbythemanufacturerwheninstallingthesoftware.ThecurrentTBSalgorithmisusedonlyinwomen;however,aninternationalprospectivemeta-analysisisunderwaythatshouldprovideriskthresholdsforbothsexesandfordifferentethnicities.Nevertheless,theeasyavailabilityoftoolstoassessbonemicroarchitecturehasenormouspotentialtoidentifyskeletaldeteriorationandfragilityasthesetoolsareintegratedintophysicians’work?owwithoutconsumingextratime.INTERVENTIONALSTRATEGIESAstrategicapproachtopostmenopausalosteoporosiswouldembraceearlydetectionandstagedinterventions.Bonemassislargelygeneticallydetermined.Morethanone-thirdofwomenreach

Table2Clinicalstudiesusingthetrabecularbonescore(TBS)Goal

Fractureriskassessment

FractureriskassessmentStudytypeRetrospectiveProspectiveOutcomeLowTBSassociatedwith?2×greaterriskinwomenandmen1SDdeclineinTBSassociatedwith35%increaseinfracturerisk

afteradjustmentforspineBMDandclinicalriskfactors

TBSbetterpredictorthanBMD

LowerTBSinpatientswithfractures

ChangeinTBS<BMD

TBSandBMDchangesnotcorrelated

NocorrelationbetweenchangesinTBSandBMD,bothslightly

increasedReferences29–3326,27,34Treatmentresponse:antiresorptivesTreatmentresponse:teriparatideProspectiveProspective3536

Abbreviations:BMD,bonemineraldensity;SD,standarddeviation.

332Andreopoulou·Bockman

menopausewithlowbonedensity,whichisfrequentlyworsenedbyyearsofinadequatecalciumand/orvitaminDintake.Thiscanleadtoregionsofundermineralizedboneandlossofstruc-turalelements,resultinginincreasedskeletalfragilitythatisoftenundetectedbybonedensitymeasurementsalone.

Therefore,astartingpointforproperriskassessmentincludesadetailedmedical,activity,andnutritionalhistory.BonedensitymeasurementbyDXAprovidesanexcellentsurrogatemeasureoffracturerisk.Inaddition,anappreciationofthegeometryofthebonesfromtheDXAprintoutscanbeinformative.Anarrowfemoralneckorradialshaftresultinginalowmomentofinertiacanbeapredictoroflowbonestrength.AssessingtrabecularbonestructurebycalculatingTBSmayprovideinsightsintothestructuralintegrity.

Startingearlytopreventosteoporosismeansensuringadequatecalcium,vitaminD,andex-erciseduringtheformativeyearstobuildbonemasstoitsgeneticallyprogrammedideallevel.De?cienciesincalciumandvitaminDintakeduringtheperimenopausalyearscanacceleratetherateofboneloss,ascandietshighinphosphateoracidcontent.Therefore,initiatingand.

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nmaintainingahealthyboneprogramasearlyaspossibleisonestartingpoint.

o

e

s

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aCalciumn

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eBoneisalivinganddynamictissue,whichallowsforcontinuedgrowthandremodelingthroughout

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rlife.Thousandsofmilligramsofcalciumpassivelydiffuseintoandoutofbonedailyandare

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5bioactivelymovedintoandoutofthebonematrixduringcell-mediatedboneremodeling.As

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/4muchas10,000mgofcalciumare?lteredbythekidneysdaily,andmorethan98%ofthatis

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2reabsorbed.Minorincrementsintherenal?lteredloadoveraprolongedperiodoftimecanlead

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otochronicde?citsincalciumbalance.Inadequatedietarycalciumcanresultinacompensatory

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ilossofcalciumfrombone—anegativespending—thatcanhavedetrimentalconsequencesfor

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evskeletalintegrity.Duringnormalbonehomeostasis,thereareobligatorylossesofcalciumbythe

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Ukidneys,gastrointestinaltract,andskin;replenishmentviadietaryintakeisnecessarytomaintain

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oapositivecalciumbalance.Beyondcalciumhomeostasis,severalstudiessuggestadditionalbone

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abene?tsfromcalciumsupplementation.

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yEvidencethatcalciumsupplementationreducesfractureincidencewouldbethemostconvinc-

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dingproofofskeletalbene?t.Posthocanalyseshaveshownapositiveeffectofcalciumsupple-

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vmentationonfracturesincompliantpatients;however,intent-to-treatanalyseshavenotshownan

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peffect.Inameta-analysisof17trialswith52,625participants,therewasa12%riskreduction.In

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ethesubgroupthathadcalciumsupplementationalone,ananalysisofonly6,517participants,the

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Areductioninfractureriskwasevengreater(24%)whencompliancewashigh(greaterthan80%)

andwhencalciumsupplementationwasequaltoorgreaterthan1,200mgperday(40).

Recently,controversyhasragedovertheincidenceofmyocardialinfarctioninpatientsre-ceivingcalciumsupplements.Randomizedcontrolledtrialsandmeta-analyseshavenotresolvedthecontroversy(41–43),andthedisagreementpersists(44).In2013,astudyinpatientswithosteoporosiswhowerefollowedfor10yearsreportedthatcalciumsupplements,upto1,000mgperday,alongwithincreaseddietaryintakeofcalciummaybeassociatedwithareducedriskofmortalityinwomen(45).

VitaminD

Basedondatafromrandomizedplacebo-controlledclinicaltrialsevaluatingfallsandfractures,theUSInstituteofMedicinerecentlyrecommendedthatacirculatinglevelof25-hydroxyvitaminD(25OHD)at20ng/mlissuf?cientfor97.5%ofthepopulation,althoughupto50ng/mLissafe

(46).Adultsupto70yearsoldneed600IUvitaminDdailytomeetthegoalof20ng25OHD,

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