9/30/2015 Overviewofthemanagementofosteoporosisinpostmenopausalwomen

OfficialreprintfromUpToDate
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Overviewofthemanagementofosteoporosisinpostmenopausalwomen

Authors SectionEditors DeputyEditor

HaroldNRosen,MD CliffordJRosen,MD JeanEMulder,MD
MarcKDrezner,MD KennethESchmader,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Aug2015.|Thistopiclastupdated:Apr17,2015.
INTRODUCTIONThetreatmentofosteoporosisconsistsoflifestylemeasuresandpharmacologictherapy[1].
Anoverviewoftheapproachtotherapyofosteoporosisinpostmenopausalwomenwillbepresentedhere.The
diagnosisandevaluationofosteoporosisinpostmenopausalwomen,preventionofosteoporosis,andthe
managementofosteoporosisinmenandpremenopausalwomenarediscussedseparately.(See"Clinical
manifestations,diagnosis,andevaluationofosteoporosisinpostmenopausalwomen"and"Preventionof
osteoporosis"and"Treatmentofosteoporosisinmen"and"Evaluationandtreatmentofpremenopausal
osteoporosis".)

LIFESTYLEMEASURESAllpostmenopausalwomenwithosteoporosisshouldreceiveadequatecalciumand
vitaminD.Otherimportantlifestylemeasuresincludeexercise,smokingcessation,counselingonfallprevention,
andavoidanceofheavyalcoholuse.Inaddition,affectedpatientsshouldavoid,ifpossible,drugsthatincrease
boneloss,suchasglucocorticoids.(See"Falls:Preventionincommunitydwellingolderpersons"and
"Pathogenesis,clinicalfeatures,andevaluationofglucocorticoidinducedosteoporosis"and"Preventionand
treatmentofglucocorticoidinducedosteoporosis"and"Drugsthataffectbonemetabolism".)

Calcium/vitaminDAnoptimaldietfortreatment(orprevention)ofosteoporosisincludesanadequateintakeof
calories(toavoidmalnutrition),calcium,andvitaminD.

Postmenopausalwomenshouldtakeadequatesupplementalelementalcalcium(generally500to1000mg/day),in
divideddoses,atmealtime,suchthattheirtotalcalciumintake(dietplussupplements)approximates1200mg/day
[2].Womenwhoaregettingadequatecalciumfromdietaryintakealonedonotneedtotakecalciumsupplements.
Thereisconsiderablecontroversyaroundtheeffectsofcalciumsupplementsontheriskofcardiovascular
disease.Thisisdiscussedindetailseparately.(See"CalciumandvitaminDsupplementationinosteoporosis",
sectionon'Sideeffects'.)

Womenshouldalsoingestatotalof800internationalunitsofvitaminDdaily.Higherdosesarerequiredifthey
havemalabsorptionorrapidmetabolismofvitaminDduetoconcomitantanticonvulsantdrugtherapy.

DataontheefficacyofcalciumandvitaminDreplacementforosteoporosisarediscussedindetailelsewhere.

DietWhenceliacdiseaseisamajorcontributortoosteopenia,aglutenfreedietmayresultinimprovementin
bonemineraldensity(BMD)[3].(See"Managementofceliacdiseaseinadults".)

Dataontheimpactofproteinintakeonbonedensityareconflicting.Whilesomestudiessuggestthathigher
proteinintakemaybeassociatedwithalowerriskofhipfractures[4]andboneloss[58],otherssuggestthathigh
proteinintakemayincreaseboneresorptionandcalciumexcretion[9].Thus,giventheconflictingdata,wedonot
recommendmodifyingproteinintakeasastrategyforpreventingboneloss.

ExerciseWomenwithosteoporosis(orseekingtopreventit)shouldexercise(prudently)foratleast30minutes
threetimesperweek.Inprospectivecohortstudies,exercisewasassociatedwithareducedriskofhipfracturein
olderwomen[10,11].Inametaanalysisof10trials,exercisereducedtheoccurrenceofoverallfracturesinolder
adults(4.8versus10.9percentinthecontrolgroup,relativerisk[RR]0.49,95%CI0.310.76)[12].Thereduction
invertebralfractureswasnotstatisticallysignificant(threetrials,18versus30percent,RR0.56,95%CI0.31.04)
[12].Thismayberelatedtothesmallnumberofpatientsincludedinthevertebralfracturetrials.
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ExercisealsohasbeneficialeffectsonBMDinpremenopausalandpostmenopausalwomen[13,14].Ameta
analysisof43randomizedtrials(4320participants)ofexerciseandBMDinpostmenopausalwomenshoweda
significantpositiveeffectofexerciseonBMDatthelumbarspine(LSmeandifference0.85,95%CI0.621.07)
andtrochanter(meandifference1.03,95%CI0.561.49)comparedwithcontrols[14].Avarietyofexercisetypes,
includingresistancetraining,jogging,jumping,andwalking,waseffective.Themosteffectivetypeofexercisefor
BMDofthefemoralneckwasnonweightbearinghighforceexercise(eg,progressiveresistancestrength
training),whereasacombinedprogram(mixtureofmorethanoneexercisetype)wasmosteffectiveforLSBMD
[14].Themetaanalysiswaslimitedbylosstofollowupandthepoorqualityofallocationconcealmentand
blinding.

Overall,thebeneficialeffectofexerciseonbonedensityissmall.However,thesechangesreflectarealBMD
measurements.Itisstilluncertainhowlongtermexerciseaffectsothermeasuresofbonearchitecture.Therefore,
ifexercisedoesreducetheriskoffracture,itmayrelatetochangesinparametersotherthanarealbonemassor
toincreasedmuscularstrengthanddecreasedriskoffalls[10,15].(See"Falls:Preventionincommunitydwelling
olderpersons",sectionon'Exercise'.)

IntensityofexerciseThereisnoconvincingevidencethathighintensityexercise,suchasrunning,isof
greaterbenefitthanlowerintensityexercise,suchaswalking.Becauseenjoymentoftheregimenisimportant(the
benefitsofexercisearequicklylostafterthewomanstopsexercising[16]),werecommendthatwomenpicka
regularweightbearingexerciseregimenthattheyenjoytofacilitatelongtermcompliance.Excessiveexercisein
premenopausalwomenmayleadtoweightlossandamenorrhea,therebycausingosteoporosis.(See"Amenorrhea
andinfertilityassociatedwithexercise".)

CessationofsmokingWestronglyrecommendsmokingcessationtoallwomenconcernedwiththeirskeletal
healthbecausesmokingcigarettesacceleratesboneloss.Onestudy,asanexample,evaluatedfemaletwinswho
werediscordantforsmoking[17].Smokingonepackperdaythroughoutadultlifewasassociatedwitha5to10
percentreductioninbonedensity.Smokingmayalsonegatethebeneficialeffectofestrogentherapyin
postmenopausalwomen[18,19].Thismaybemediatedinpartbyaccelerationofthemetabolismofestrogen,
therebyloweringserumestrogenconcentrations.

OtherThereisagrowinginterestinothernonpharmacologictherapiesforosteoporosis.Inanimalmodels,
mechanicalstimulationfromvibrationproducedanaboliceffectsoncancellousandcorticalbone[20,21].Although
wholebodyvibrationplatformshavebeenproposedasanonpharmacologictherapyforpostmenopausal
osteoporosis,theavailabledatafromrandomizedtrialsshowminimaltonoimprovementinBMDwiththeuseof
wholebodyvibrationplatformscomparedwithshamvibration,walking,ornotreatment[2224].Inmosttrials,data
wereevaluatedperprotocol,ratherthanintentiontotreat.Noneofthetrialsevaluatedfractureoutcomes.In
addition,thesafetyofvibrationtherapyinolderpatientshasnotbeencarefullyexamined.Thus,thereare
insufficientdatatorecommendthistherapyinpostmenopausalwomen.

PHARMACOLOGICTHERAPY

CandidatesfortherapyTheabovemeasuresshouldbeadopteduniversallytoreducebonelossin
postmenopausalwomen.Patientswiththehighestriskoffracturearetheonesmostlikelytobenefitfromdrug
therapy.Fractureriskisdeterminedbyacombinationofbonemineraldensity(BMD)andclinicalriskfactors.
Particularattentionshouldbepaidtotreatingwomenwitharecentfracture,includinghipfracture,becausethey
areathighriskforasecondfracture.(See"Medicalconsultationforpatientswithhipfracture".)

WelargelyagreewiththeNationalOsteoporosisFoundation(NOF)recommendationsasoutlinedbelow[25].We
recommendpharmacologictherapyforpostmenopausalwomenwithahistoryofhiporvertebralfractureorwith
osteoporosisbaseduponBMDmeasurement(Tscore2.5).Forthetreatmentofhighriskpostmenopausal
womenwithTscoresbetween1.0and2.5,wealsosuggestpharmacologictherapy.Wecalculatefracturerisk
usingtheWorldHealthOrganization(WHO)FractureRiskAssessmentTool(FRAX)(FRAXwebsite).Although
theUnitedStatesadaptedWHOfracturepredictionalgorithmandNOFrecommendationsprovidegeneralclinical
guidance,osteoporosistreatmentshouldremainindividualizedthroughshareddecisionmakingbetweenpatient
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andclinician.

FractureriskassessmentIn2008,aWHOtaskforceintroducedaFractureRiskAssessmentTool
(FRAX),whichestimatesthe10yearprobabilityofhipfractureormajorosteoporoticfracturescombined(hip,
spine,shoulder,orwrist)foranuntreatedpatientusingfemoralneckBMDandeasilyobtainableclinicalrisk
factorsforfracture(table1).ThetechnicalaspectsofFRAXarereviewedindetailseparately.(See"Osteoporotic
fractureriskassessment",sectionon'Fractureriskassessmenttool'.)

TheNOFreleasedrevisedosteoporosistreatmentandpreventionguidelinesbaseduponFRAXinconjunctionwith
anupdatedUnitedStatesspecificeconomicanalysis(table2)[25].Therevisedguidelinesaresimilartoprevious
treatmentrecommendations.

TheNOFrecommendstreatmentofpostmenopausalwomen(andmen50years)withahistoryofhiporvertebral
fractureorwithosteoporosisbaseduponBMDmeasurement(Tscore2.5).Theserecommendationsarewidely
accepted,andclinicaltrialdatasupporttheuseofbisphosphonatestopreventfractureinsuchindividuals.(See
"Theuseofbisphosphonatesinpostmenopausalwomenwithosteoporosis"and"Treatmentofosteoporosisin
men",sectionon'Bisphosphonates'.)

Theguidelinesalsoprovidespecifictreatmentrecommendationsforpostmenopausalwomenwithosteopeniaon
BMD(Tscorebetween1.0and2.5).Intheseindividuals,themodelsuggeststhattreatmentiscosteffective
whenthe10yearprobabilityofhipfracturereaches3percentorthe10yearprobabilityofmajorosteoporotic
fracturescombinedis20percent(table2).ThesecriteriawerechosenonthebasisofaUnitedStatesspecific
economicanalysis,andtheyhavenotbeenassessedinclinicaltrials.

The10yearprobabilityofhipandmajorosteoporoticfracturecanbecalculatedforindividualpatientsusingthe
FRAXwebsite(clickonCalculationToolandselectcountry).TheFRAXalgorithmusesfemoralneckBMD
(g/cm2)forcalculationoffractureprobability.BMDfromnonhipsiteshasnotbeenvalidatedandis,therefore,not
recommendedforuse.

Interventionthresholdshavebeenestimatedforothercountriesbaseduponassessmentofabsolutefracturerisk
andcountryspecificanalyses.The2010OsteoporosisCanadaguidelinesrecommendpharmacologictherapyto
patientsathighabsoluterisk(>20percentprobabilityformajorosteoporoticfractureover10years)andto
individualsoverage50yearswhohaveafragilityfracture[26].Forthoseatmoderaterisk(10to20percent),the
decisiontotreatshouldbebaseduponthepresenceofadditionalriskfactorsnotconsideredintherisk
assessmentsystemanduponindividualpreference.

IntheUnitedKingdom,pharmacologictreatmentwascosteffectiveatallageswhenthe10yearprobabilityof
majorosteoporoticfractureexceeded7percent[27].TheUnitedKingdomNationalOsteoporosisGuidelineGroup
(NOGG)recommendsanagedependentinterventionthreshold,whichrangesfrom7.5to30percentforages50to
80years[28].ForcliniciansintheUnitedKingdom,interventionthresholdsmaybeaccesseddirectlyfromthe
FRAXwebsite(clickonCalculationTool,selectUnitedKingdom,andthenclickonViewNOGGGuidanceafter
enteringpatientspecificinformation).

LimitationsWelargelyagreewiththeNOFrecommendations.However,thebenefitoftreatmentbased
uponabsolutefracturerisk,ratherthanBMDcriteriaalone,hasnotbeenassessedinclinicaltrials.

Theemphasisonabsolutefractureriskwillincreasetheproportionofolderwomenwhoarecandidatesfortherapy.
Asanexample,inastudyusingdatafromtheStudyofOsteoporoticFracture(SOF),aprospectivecohortof
communitydwellingCaucasianwomen65yearsofage,applicationoftherevisedNOFtreatmentguidelines
resultedinrecommendationsforpharmacologictherapyfor72percentofwomenover65yearsofageand93
percentofwomenover75years[29].Applyingbonedensitycriteriaalone(BMDlowerthan2.5atlumbarspine
[LS]orfemoralneck)resultedinatreatmentrecommendationfor50percentofwomeninbothagegroups.

Thus,manymoreolderwomenwillbecandidatesforpharmacologictherapyusingthenewguidelines.Whether
theselectionofpatientsbaseduponclinicalriskfactorsandBMD,ratherthanonBMDalone,improvesbenefitin
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olderpatientshasnotyetbeenestablished.

Inaddition,theNOFeconomicanalysisestimateddrugcostsbaseduponuseofgenericbisphosphonates.The
useofmoreexpensivedrugsincreasesthe10yearfractureprobabilityatwhichinterventioniscosteffective.NOF
guidelinesshouldnotbeappliedtoindividualslivingindifferentcountriesastheNOFguidelinesarebasedupona
UnitedStatesspecificeconomicanalysis.Interventionthresholdshavebeenestimatedforothercountries,and
countryspecificguidelinesareavailableorareindevelopment.(See'Fractureriskassessment'aboveand
"Osteoporoticfractureriskassessment",sectionon'Clinicalapplicationoffractureriskassessment'.)

ChoiceofdrugIntheabsenceofhighqualityheadtoheaddrugcomparisontrialstodeterminetherelative
efficacyoftheindividualdrugs,choiceoftherapyshouldbebaseduponefficacy,safety,cost,convenience,and
otherpatientrelatedfactors[30,31].Formostpostmenopausalwomenwithosteoporosis,wesuggestoral
bisphosphonatesasfirstlinetherapy.Wepreferoralbisphosphonatesasinitialtherapybecauseoftheirefficacy,
favorablecost,andtheavailabilityoflongtermsafetydata.Intheabsenceofrandomizedtrialdatathat
ibandronatereduceshipfracturerisk,wesuggestalendronateorrisedronateasourchoiceofbisphosphonate.
Becauseoralalendronateisavailableasagenericandisveryinexpensive,manyinsurersintheUnitedStates
requirepriorapprovalforinitialtherapywithanybisphosphonateotherthanoralalendronate.

Intravenous(IV)zoledronicacid,whichhasbeendemonstratedtoreducevertebralandhipfractures,isavailablein
manycountriesforthetreatmentofpostmenopausalosteoporosis.Itisagoodalternativeforindividualswith
gastrointestinalintolerancetooralbisphosphonates.IVibandronateisalsoavailablehowever,thereisasyetno
directfracturepreventiondataforIVibandronate.(See"Theuseofbisphosphonatesinpostmenopausalwomen
withosteoporosis".)

Thereisnoconsensusontheoptimaluseofdenosumab.Althoughwepreferoralbisphosphonatesasinitial
therapy,denosumabcouldbeusedasinitialtherapyincertainpatientsathighriskforfracture,suchasolder
patientswhohavedifficultywiththedosingrequirementsoforalbisphosphonates.Inaddition,denosumabmay
havearoleinpatientswhoareintolerantoforunresponsivetoothertherapiesandinthosewithimpairedrenal
function.(See"Denosumabforosteoporosis".)

Sincetheantiresorptiveeffectsofraloxifenearelessthanthoseofbisphosphonates,wereservetheuseofthis
drugforpatientswhocannottolerateanybisphosphonatesorforwomenwithosteoporosisandincreasedriskof
invasivebreastcancer.(See"Selectiveestrogenreceptormodulatorsforpreventionandtreatmentof
osteoporosis"and"Selectiveestrogenreceptormodulatorsandaromataseinhibitorsforbreastcancerprevention",
sectionon'Raloxifene'.)

Parathyroidhormone(PTH)isananabolicagent.Incontrasttoantiresorptiveagents,PTHstimulatesbone
formationandactivatesboneremodeling.PTH134(teriparatide)reducestheriskofvertebralandnonvertebral
fractures.Givenitscost,subcutaneousrouteofadministration,longtermsafetyconcerns,andavailabilityofother
agents,PTHisgenerallynotusedasafirstlinedrugfortreatmentorpreventionofosteoporosis.Itistypically
usedinpostmenopausalwomen(ormen)withsevereosteoporosisandfractureorinpatientsforwhomother
osteoporosistherapiesfail.(See"Parathyroidhormonetherapyforosteoporosis".)

Becausestrontiumranelateisaweakantiresorptiveagentandtherearemoreeffectiveosteoporosisagentsinthe
UnitedStatesandmostcountries,wedonotusestrontiumranelateinpostmenopausalwomenwithosteoporosis.
(See'Strontiumranelate'below.)

EfficacyAsystematicreviewoftrialspublishedbetween2005and2014confirmedthefractureprevention
efficacyofmultipleagentscomparedwithplacebo[31].Bisphosphonates(alendronate,risedronate,zoledronic
acid,ibandronate),denosumab,raloxifene,andteriparatidereducetheriskofvertebralfractures.Alendronate,
risedronate,zoledronicacid,teriparatide,anddenosumabreducetheriskofnonvertebralfractures.Strontium
ranelate(availableoutsideofNorthAmerica)hasbeenshowntoreducevertebralfractureand,toalesserextent,
nonvertebralfracture.Thesedrugsarereviewedbrieflybelowandinmoredetailelsewhere.

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BisphosphonatesAlendronate,risedronate,andibandronateareeffectiveforboththepreventionand
treatmentofosteoporosis.Zoledronicacid,administeredIVonceyearly,isalsoeffectiveforthetreatmentof
osteoporosis.Thesedrugsincreasebonemassandreducetheincidenceoffractures.Generalprinciplesof
bisphosphonateadministration,adverseeffects,durationofuse,anddrugholidaysarediscussedindetail
elsewhere.(See"Theuseofbisphosphonatesinpostmenopausalwomenwithosteoporosis".)

SelectiveestrogenreceptormodulatorsTherearenonskeletalconsiderationswithselectiveestrogen
receptormodulatorsthatmayplayanimportantroleintheselectionofpostmenopausalwomenfortherapy,
includingpotentialbeneficialeffectsonbreastcancerriskreduction,butanincreaseinthromboemboliceventsand
possiblyhotflashes,andnoapparenteffectonheartdiseaseortheendometrium.Raloxifeneinhibitsbone
resorptionandreducestheriskofvertebralfracture,andisourSERMofchoicebecauseithaseightyearsafety
andefficacydataandalsoreducestheriskofbreastcancer.Raloxifeneisusuallychosenforosteoporosiswhen
thereisanindependentneedforbreastcancerprophylaxis.

Tamoxifenisanotherselectiveestrogenreceptormodulatorusedprimarilyforthepreventionandmanagementof
breastcancer.Itisnottypicallyusedforosteoporosis,butpostmenopausalwomenwhoarereceivingtreatment
withtamoxifenforbreastcancerareprobablyreceivingeffectiveboneprotection.

Bazedoxifene,anotherselectiveestrogenreceptormodulator,isavailableinEuropeandJapanforthetreatmentof
postmenopausalosteoporosisinwomenatincreasedriskforfracture.Althoughithassimilarefficacyasraloxifene
inpreventingandtreatingpostmenopausalosteoporosis,therearefewlongtermsafetydata,andithasnotbeen
adequatelystudiedforbreastcancerprevention.ItisnotavailableasastandalonedrugintheUnitedStates
however,itisavailableincombinationwithconjugatedestrogenforpreventionofosteoporosis[32].Theselective
estrogenreceptormodulatorsarediscussedinmoredetailelsewhere.(See"Selectiveestrogenreceptor
modulatorsforpreventionandtreatmentofosteoporosis"and"Selectiveestrogenreceptormodulatorsand
aromataseinhibitorsforbreastcancerprevention".)

ParathyroidhormonePTHseemsanunlikelycandidateforthetreatmentofosteoporosisbecauseofits
welldescribeddeleteriouseffectonbone[33].However,intermittentadministrationofrecombinanthumanPTH
(bothfulllength184oraminoterminalfragment134)stimulatesboneformationmorethanresorptionandis
effectiveforfracturereductioninwomenwithosteoporosis.Thistopicisreviewedindetailelsewhere.(See
"Parathyroidhormonetherapyforosteoporosis".)

DenosumabRANKL(receptoractivatorofnuclearfactorkappaBligand)isessentialforthefunctionof
boneresorbingosteoclastsRANKLacceleratesosteoclastogenesiswhenitbindstoitsreceptor,RANK,butis
blockedbyosteoprotegerin,whichisproducedbyosteoblasts.Denosumabisahumanizedmonoclonalantibody
againstRANKLthatreducesosteoclastogenesis.Inseveraltrials,ithasbeenshowntoimproveBMDandreduce
theincidenceofnewvertebral,hip,andnonvertebralfracturesinpostmenopausalwomen.Thistopicisreviewedin
detailelsewhere.(See"Denosumabforosteoporosis".)

StrontiumranelateStrontiumranelate,anorallyactivedrugconsistingoftwoatomsofstablestrontium
andanorganicmoiety(ranelicacid),isavailableforuseinEuropeforthetreatmentofosteoporosis.Inanimal
studies,strontiumappearstoinhibitboneresorptionandincreaseorhaveaneutraleffectonboneformation[34
37].Itsmechanismofactioninhumansislesscertain.Baseduponchangesinmarkersofboneformationand
resorptioninpostmenopausalwomenwithosteoporosis,itappearstohaveamodestantiresorptiveeffect,with
littleeffectonboneformation[38].

FracturereductionItshouldbenotedthatasubstantialproportionoftheincreaseinBMDduring
strontiumtherapyisduetothephysicaleffectofstrontiumaccumulationinbonetissue[39].Themagnitudeof
changeinBMDafterstrontiumtherapyisnotindicativeofgreaterfractureriskreduction,andtherefore,
improvementinBMDcannotbeusedasasurrogatemarkeroffracturereduction.

Inametaanalysisoffourtrialsevaluatingfractureriskdirectly,strontiumranelatewaseffectiveinreducingthe
riskofvertebralfracturesand,toalesserextent,nonvertebralfractures[40].

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Twoofthelargertrialsinthemetaanalysisaredescribedbelow:

Inathreeyeartrial,1649postmenopausalwomenwithosteoporosisandatleastonevertebralfracturewere
randomlyassignedtoreceivestrontiumranelate(2g/day)orplacebo[41].Theriskofnewvertebralfractures
wasdecreasedsignificantlyby41percentduringthethreeyearstudyperiod(21versus33percentrelative
risk[RR]=0.59,95%CI0.480.73numberneededtotreattopreventonefracture=9).

Inalargertrialof5091postmenopausalwomenwithosteoporosisrandomlyassignedtoreceivestrontium(2
g/day)orplaceboforfiveyears,theriskofnonvertebralfracturewasdecreasedinthestrontiumgroup
comparedwithplacebo(incidence19versus21percent,RR0.85,95%CI0.730.99)[42,43].Inaposthoc
analysisofahighriskgroup(age74yearsandTscore<2.4atbaseline),theRRofhipfracturewas
decreasedby43percent(incidence7versus10percent,RR0.57,96%CI0.330.97).Whenthe
investigatorspooledtheseresultswiththeirpreviouslypublishedtrial[41],theycalculatedthattheeffectof
strontiumwasindependentofbaselineBMD,age,smoking,ornumberofvertebralfractures[44].

Therearefewstudiesevaluatingthelongtermefficacyandsafetyofstrontium.Inanopenlabelextensionstudy
oftwoofthetrialsdescribedabove[41,42],237postmenopausalwomenreceivedstrontiumforanadditionalfive
years[45].Thecumulativeincidenceofnewfracturesinyears6to10wassimilartothatinyears0to5(20.6
versus18.5percent,respectively).Overthe10yearperiodofcontinuousstrontiumtreatment,lumbarspine(LS)
BMDincreasedannually,whereasBMDofthefemoralneckandtotalhipincreasedsignificantlyuntilyear7and
thenremainedstablethereafter.Inpatientswhohadreceivedstrontiumfor10years,theannualincidenceof
venousthromboembolism(VTE)was0.4percent.Therewerenocasesofdrugrelatedhypersensitivityskin
reactions.Thus,forthissmallsubsetofpatients,10yearsofstrontiumtherapywaseffectiveandsafe.

SafetyInthemetaanalysisoffourtrialsdescribedabove,significantlymorepatientsinthestrontium
thancontrolgrouphaddiarrhea(6.5versus4.7percent),VTE(2.2versus1.5percent),andpulmonaryembolism
(0.8versus0.4percent)[40].

Duringpostmarketingsurveillance,useofstrontiumwasassociatedwithahigherriskofsevereskinreactions
(DrugReactionwithEosinophiliaandSystemicSymptoms[DRESS],StevensJohnsonSyndrome,andtoxic
epidermalnecrolysis),thromboembolicdisease,andmyocardialinfarction[4648].In2014,theEuropean
MedicinesAgencyrecommendedrestrictionintheuseofstrontiumbaseduponananalysisofpooleddata
showinganincreasedriskofmyocardialinfarctionwithuseofstrontiumranelateandotherseriousrisks(severe
skinreactions,thromboembolicdisease)previouslyidentified[49,50].Strontiumshouldonlybeusedinmobile
postmenopausalwomenathighriskoffractureandwithsevereosteoporosis,withnohistoryofcardiovascular
diseaseorVTE,whocannotbetreatedwithothermedicinesforosteoporosis.Inaddition,itshouldbe
discontinuedifhypertension,angina,oraskinreactiondevelops,andtreatmentshouldnotberestarted.These
restrictionsarebaseduponthefollowingfindings:

InastudyfromFrance,199strontiumassociatedseveresideeffectswereidentified,ofwhichapproximately
25percentweresevereskinreactionsand50percentwerevenousthromboembolicevents[47].

InananalysisofpatientsprescribedstrontiumbygeneralpractitionersinEngland,thecrudeincidencerateof
VTEwithinthefirst12monthswas6.24casesper100patientyearsexposed,higherthanthebackground
incidencerateintheUnitedKingdompopulationbutsimilartotherateinolderpopulationsreceiving
treatmentforpostmenopausalosteoporosis[48].Theriskofthromboembolicdiseaseappearstobehigherin
patientswithahistoryofVTEorwhoareimmobilized(temporarilyorpermanently).

Inapooledanalysisoftrialsdesignedtoassesstheefficacyofstrontium(7500postmenopausalwomenwith
osteoporosis),theriskofmyocardialinfarctionwasincreasedinpatientsrandomlyassignedtostrontium
comparedwithplacebo(1.7versus1.1percentRR1.6,95%CI1.072.38)[51].

Insubsequentobservationalstudies(UnitedKingdomClinicalPracticeResearchDatalinkandanationwide
Danishstudy),theriskofmyocardialinfarctionwithuseofstrontiumranelatewasnotincreased[52,53].

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Estrogen/progestintherapyEstrogenprogestintherapyisnolongerafirstlineapproachforthetreatment
ofosteoporosisinpostmenopausalwomenbecauseofincreasedriskofbreastcancer,stroke,VTE,andperhaps
coronarydisease(althoughtheriskbenefitprofileintheunopposedestrogentrialwasdifferent)[54].(See
"Menopausalhormonetherapy:Benefitsandrisks".)

Possibleindicationsforestrogenprogestininpostmenopausalwomenincludepersistentmenopausalsymptoms
andwomenwithanindicationforantiresorptivetherapywhocannottoleratetheotherdrugs.IntheWomen's
HealthInitiative,bothcombinedestrogenprogestinandunopposedestrogentreatmentreducedhipandvertebral
fracturerisk(figure1).Theuseofestrogenforosteoporosisisreviewedindetailelsewhere.(See
"Postmenopausalhormonetherapyinthepreventionandtreatmentofosteoporosis".)

CalcitoninAlesspopularchoicefortreatmentofosteoporosisisnasalcalcitonin.Wepreferotherdrugsto
calcitoninbecauseofitsrelativelymodesteffectonBMDandweakantifractureefficacycomparedwith
bisphosphonatesandPTH[55].Thereisconcernisaboutthelongtermuseofcalcitoninforosteoporosisandan
increaseincancerrates.Thisisreviewedseparately.(See"Calcitonininthepreventionandtreatmentof
osteoporosis",sectionon'Concernsabouttheuseofcalcitonin'.)

CombinationtherapyWesuggestnotusingcombinationtherapy,astheadditionalBMDbenefitsaresmall
andthereisnoprovenadditionalfracturebenefit.

Althoughbothbisphosphonatesandestrogeninhibitboneresorption,theymayactthroughdifferentmechanisms.
Severalstudiessuggestthatconjugatedestrogens(0.625mg/day)andalendronate(10mg/day)areequally
effectiveinimprovingBMDandthatthecombinationisslightlymoreeffectivethaneitheralone.(See
"Postmenopausalhormonetherapyinthepreventionandtreatmentofosteoporosis".)

Estrogenpluscalcitonin[56],estrogenandandrogen[57],estrogenplusetidronate[58],andalendronateand
raloxifene[59]alsoappeartoactsynergisticallyonbonedensity.However,fracturedataareunavailableforthese
combinations.Inaddition,theindicationsforusingestrogenhavebeenlimitedsincetheresultsoftheWomen's
HealthInitiativewerepublished.(See"Menopausalhormonetherapy:Benefitsandrisks"and"Theuseof
bisphosphonatesinpostmenopausalwomenwithosteoporosis",sectionon'Combinationtherapy'.)

SeveraltrialshavereportedthatPTHplusalendronate(eitherstartedconcurrentlyorpriortoPTH)resultedinno
additionalbenefitforspineorhipBMDcomparedwithPTHalone,andtheadditionofalendronatemayeven
attenuatetheincreaseinBMDwithPTH.Thus,wedonotrecommendconcurrentPTHbisphosphonatetherapy.
CombinationtherapyandbisphosphonatetherapyaftercompletingacourseofPTHarediscussedseparately.
(See"Parathyroidhormonetherapyforosteoporosis",sectionon'PTHplusbisphosphonates'and"Parathyroid
hormonetherapyforosteoporosis",sectionon'AfterPTH'.)

Sometrialshavereportedthatraloxifene(eithertakenconcurrentlyorpriortoPTH)doesnotsuppresstheBMD
responsetoPTHasmuchasalendronate.PatientspreviouslytreatedwithraloxifenehaveagoodBMDresponse
toPTH,buttheoptimalmanagement(continueversusdiscontinueraloxifene)isunclear.(See"Parathyroid
hormonetherapyforosteoporosis",sectionon'Combinationtherapy'.)

OthertherapiesAdditionaltherapiesforpostmenopausalosteoporosisareeitherunderinvestigationorareused
insomecountries.Wedonotroutinelyuseanyofthesetherapies.

CalcitriolTheresultsofclinicaltrialsofcalcitriolinpostmenopausalosteoporosishavebeenmixed.(See
"CalciumandvitaminDsupplementationinosteoporosis".)

However,calcitriolhasbeenreportedtobeeffectiveinpreventingglucocorticoidinducedandposttransplant
relatedboneloss.(See"Preventionandtreatmentofglucocorticoidinducedosteoporosis",sectionon'Active
vitaminDmetabolites'and"Osteoporosisaftersolidorganorstemcelltransplantation",sectionon
'Calcitriol'.)

Patientstreatedwithcalcitriolshouldbegivenalowcalciumdietandmonitoredforhypercalcemia,

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hypercalciuria,andrenalinsufficiency.Thesepotentialproblemsplusthelackofprovenconsistentbenefit
haveappropriatelylimitedtheuseofcalcitriol.

VitaminKExogenousvitaminKisrequiredforthecarboxylationofosteocalcin,whichinturnallows
osteocalcintobindtohydroxyapatitemineral.AvitaminK2preparation(menatetrenone)iswidelyusedfor
thetreatmentofosteoporosisinJapan.

ObservationaldatasuggestthatlowvitaminKconsumptionorimpairedvitaminKstatusmaybeassociated
withanincreasedriskoffractureinoldermenandwomen[60,61].(See"VitaminKandthesynthesisand
functionofgammacarboxyglutamicacid".)

ClinicaltrialdatasuggestthatvitaminKsupplementationmayreducebonelossandfracturerisk[62].This
wasbestillustratedinametaanalysisof13trialsoforalvitaminK(phytonadioneandmenaquinone)
supplementationforbonelossandfractureprevention[63].BothsupplementsincreasedBMD.Seventrials
reportedfracturedataallwereinJapanesepatients(primarilypostmenopausalwomenwithosteoporosis)
andusedmenaquinone.Significantreductionswereseenforvertebral,hip,andallnonvertebralfractures
(oddsratio[OR]0.40,0.23,and0.19,respectively,with95%CIof0.250.65,0.120.47,and0.110.35,
respectively).

ThisreportshouldbeinterpretedwithsomecautionasfracturedataareavailableonlyinJapanesewomen,
whomayhavesignificantdietarydifferencesfromotherpopulations.Inaddition,themagnitudeofthe
fractureriskreductionsseemsunlikely,asitwasfargreaterthanwhatisseenforotherproventherapies,
suchasbisphosphonates.Furthermore,insubsequentrandomizedtrialsinhealthy,older,predominantly
CaucasianmenandwomenreceivingcalciumandvitaminDsupplements,vitaminK(200,500,or1000
microgramsphylloquinonedailyor45mgmenatetrenonedaily)didnothaveanyeffectonBMD[6466].
Basedupontheavailabledata,we,therefore,donotrecommendroutinevitaminKsupplementationforthe
maintenanceofskeletalhealthorthepreventionoffracturesinhighriskindividuals.

TiboloneTibolone,asyntheticsteroidwhosemetaboliteshaveestrogenic,androgenic,andprogestagenic
properties[67],isusedforosteoporosismanagementinsomecountries(butisnotavailableintheUnited
States).TiboloneimprovesBMDinolderpostmenopausalwomenwithestablishedosteoporosisand
preventsbonelossinearlypostmenopausalwomenwithoutosteoporosis[6871].

Tibolonealsoreducesvertebralfracturerisk.TheLongTermInterventiononFractureswithTibolone(LIFT)
trial,atrialdesignedtoexaminetheeffectoftiboloneonvertebralfractureinpostmenopausalwomen,
reportedareductionintheabsoluteriskofvertebralandnonvertebralfracture(8.6and6.9per1000person
years,respectively,relativehazardsof0.55,95%CI0.410.74and0.74,95%CI0.580.93,respectively)
[72].However,thistrialwasdiscontinuedearlyduetoanexcessriskofstroke.

Othereffectsoftibolonearediscussedseparately.(See"Preparationsformenopausalhormonetherapy",
sectionon'Tibolone'.)

Folate/vitaminB12CombinationfolateandvitaminB12therapymaylowerfractureriskinolderpatients
withresidualhemiplegiaafteranischemicstroke[73].Thisapproachhasbeenstudiedin625olderJapanese
womenandmenrandomlyassignedtodailyfolate(5mg)andvitaminB12(1500mcgorally)orplacebo.
Baselinelevelsofhomocysteineweremodestlyelevated(approximately2.7mg/L[20micromol/L])inboth
groups(referencerange1to1.9mg/L[7.7to14.3micromol/L]),whileB12andfolatelevelswereslightlylow.

Supplementationreducedthenumberofhipfracturescomparedwithplacebo(10versus43per1000patient
years,respectively).TheadjustedRR,absoluteriskreduction,andnumberneededtotreatforhipfractures
fortreatmentversusplacebowere0.20(95%CI0.080.5),7.1percent(95%CI3.610.8),and14(95%CI9
28),respectively.

WhethertheriskreductionisduetotheloweringofserumhomocysteineoranincreaseinB12isnotknown.
Inaddition,itisnotknownwhetherthistherapeuticapproachwillbeeffectiveinpatientswithnormal
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baselinehomocysteine,serumB12,andfolateconcentrationsorinotherpopulations.

ApredefinedsecondaryanalysisoftheHeartOutcomesPreventionEvaluation(HOPE)2trialsuggeststhat
thisapproachisnoteffectiveinindividualsselectedonthebasisofcardiovasculardisease(ratherthan
fracturerisk)[74].Inthistrial,adultsathighriskforcardiovasculardiseasewererandomlyassignedto
treatmentwithdailyfolicacid(2.5mg),vitaminB12(1mg),andvitaminB6(50mg)orplacebo.Mean
baselinehomocysteineconcentrationwasnormal(1.55mg/L[11.5micromol/L]inbothgroups).Vitamin
supplementationdidnotreducetheincidenceofvertebralornonvertebralfracturescomparedwithplacebo.
TheHOPE2trialisreviewedindetailelsewhere.(See"Overviewofhomocysteine",sectionon
'Cardiovasculardisease'.)

Althoughtheevidenceislimited,wedonotrecommendsupplementalfolicacidorvitaminB12forthe
treatmentofosteoporosisorprimarypreventionoffracture.

AndrogensBecausemenhavehigherbonedensitythanwomen,ithasbeensuggestedthattreatment
withandrogensmightbenefitwomenwithosteoporosis.However,theeffectoftreatmentwithandrogenplus
estrogenonBMDdoesnotappearsuperiortotheeffectofestrogenalone,andandrogenhasunwelcome
virilizingeffects[75].

Furthermore,thepresumedbeneficialeffectsoftestosteroneonboneinmenmaybemediatedbyits
conversiontoestrogen,asevidencedbythemarkedimprovementinlowbonemassfollowingestrogen
therapyinmenwitharomatasedeficiency,whichimpairstheconversionofandrogentoestrogen[76,77].

Wedonotrecommendandrogentherapyforosteoporosismanagementinwomen.Althoughtestosterone
replacementmayimprovebonedensityinwomenwithhypopituitarism,dataarelimited,andthereareno
approvedtestosteronepreparationsavailableforuse.(See"Epidemiologyandetiologyofosteoporosisin
men",sectionon'Estrogen'and"Overviewofandrogendeficiencyandtherapyinwomen",sectionon'Other
possiblebenefits'.)

IsoflavonesIsoflavones(atypeofphytoestrogen)aremicronutrientsubstancesthathaveproperties
similartoestrogen.Twotypesofisoflavones,genisteinanddaidzein,arefoundinsoybeans,chickpeas,and
lentilsandarethoughttobethemostpotentphytoestrogens(see"Preparationsformenopausalhormone
therapy",sectionon'Phytoestrogens').Ipriflavoneisasyntheticisoflavonederivativeandiswidelyavailable
asanoverthecounterproductinmanycountries.

Somestudieshavereportedthatphytoestrogenshaveabeneficialeffectonmarkersofboneresorption,
BMD,andfractureriskinanimalmodels[78]andinpostmenopausalwomen[79,80],whileothershavenot
[8183].Thedifferencesmaybedue,inpart,tothecompositionoftheisoflavonesstudied.Asexamples:

Inatwoyearrandomizedtrialof389postmenopausalwomenwithTscoresof1.0orlower,genistein
(54mgdaily)improvedfemoralneckandLSBMDcomparedwithplacebo(betweengroupdifferences
of0.06and0.10g/cm2,respectively,95%CIs0.050.07and0.080.12)[84].

Inatrialof474postmenopausalwomenwithlowbonedensitywhowererandomlyassignedtoreceive
ipriflavone(200mgthreetimesdaily)orplacebo(pluscalcium500mg/dayinbothgroups)forthree
years,therewerenodifferencesinBMDorvertebralfractureratesbetweenthetwogroups[85].
Lymphocytopeniaoccurredin13percentofthewomentakingipriflavone,theclinicalimportanceof
whichisnotknown.

Therearenorandomizedtrialsthatassesstheeffectofisoflavonesonfractureasaprimaryoutcome.Based
uponavailabledata,wedonotrecommendisoflavonesupplementsasastrategytopreventortreat
osteoporosis.

Othereffectsofisoflavonesarereviewedelsewhere.(See"Preparationsformenopausalhormonetherapy",
sectionon'Phytoestrogens'.)

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FluorideThereishistoricalinterestinfluorideasananabolicagentforthetreatmentofpostmenopausal
osteoporosis.AlthoughfluorideincreasesBMDsubstantially,clinicaltrialsoffluoridehavenotconsistently
demonstratedfracturereduction[8690].Whilesomestudiesdemonstratedadecreaseintheincidenceof
newvertebralfracture[87,88,90],othersreportednochange[89]orevenanincreaseinnonvertebral
fractures[86,91].Fluorideimpairsbonemineralization,evenwhenthedoseisaslowas20mgdaily[91].
Giventheavailabilityofothertherapies,includingPTH(anabolicagent),wedonotrecommendfluoridefor
thetreatmentofpatientswithosteoporosis.(See"Parathyroidhormonetherapyforosteoporosis".)

EmergingtherapiesThereareseveralnoveltherapiesunderinvestigationforthetreatmentofosteoporosis.
Theyareinvariousstagesofdevelopment.Asexamples:

SclerostininhibitorsSclerostinisproducedbyosteocytesandinhibitsboneformation.Sclerostinknockout
micehaveincreasedboneformationandhighbonemass[92].Itfollows,therefore,thatinhibitionof
sclerostinshouldenhanceosteoblastfunctionandimprovebonemass.InanimalmodelsandinaphaseI
trialinhealthyadults,administrationofasclerostinmonoclonalantibodydoesincreasebonemass[9395].

Similarly,inaphase2trialinpostmenopausalwomen,alldosesofamonoclonalantisclerostinantibody
(romosozumab)increasedbonedensityattheLS,totalhip,andfemoralneck[96].Inthisoneyeartrial,419
postmenopausalwomenwithlowbonemass(Tscorebetween2.0and3.5attheLS,totalhip,orfemoral
neck)wererandomlyassignedtosubcutaneousromosozumab(variabledosingoncemonthlyoronceevery
threemonths),anactivecomparator(oralalendronate,70mgweekly,orsubcutaneousteriparatide,20mcg
daily),orplaceboinjections(monthlyoreverythreemonths).Thegreatestincreaseinbonedensitywasseen
inthegroupreceivingromosozumab210mgmonthly(11.3percentcomparedwith4.1and7.1percentinthe
alendronateandteriparatidegroups,respectively).Whendosedeverythreemonths(140or210mg),the
increaseinLSbonedensitywithromosozumabwassimilartothatseenwithalendronate(5.5and4.1
percent,respectively)andsignificantlylowerthanthatachievedwithteriparatide(5.5and7.1percent,
respectively).Therewasatransientincreaseinboneformationmarkersandamoresustaineddecreasein
boneresorptionmarkers,apatternthathasnotbeenseenamongavailableosteoporosistherapies.There
wasanincreasedfrequencyofinjectionsitereactionsintheromosozumabgroup.Ongoingtrialsshould
providemoreinformationaboutantifractureefficacyandsafety.

IntegrinantagonistsIntegrinsmediatetheadhesionofosteoclaststothebonesurface,animportantinitial
stepforboneresorption[97].

CathepsinKinhibitorsCathepsinKisaproteaseexpressedinosteoclaststhatplaysaroleinosteoclast
mediatedboneresorption[98,99].CathepsinKdegradesorganicbonematrix,primarilytype1collagen.
CathepsinKinhibitors(eg,Odanacatib)inhibitmatrixdissolution,decreaseboneresorption,andimprove
BMDinpostmenopausalwomen[100104].

MONITORINGTHERESPONSETOTHERAPYMonitoringtheresponsetotherapyisimportantforidentifying
patientswhomayrequireachangeintherapy(uptoonesixthofwomentakingalendronatecontinuetolosebone)
[105].Whilethereareanumberofapproachestomonitoringtherapy,thereisnoconsensusontheoptimal
approach[106108].

OurapproachOurapproachissimilartotheInternationalSocietyforClinicalDensitometry(ISCD)guidelines
(see'Guidelines'below).Forpatientsstartingontherapy,wesuggestafollowupdualenergyxrayabsorptiometry
(DXA)ofhipandspineaftertwoyears,andifbonemineraldensity(BMD)isstableorimproved,lessfrequent
monitoringthereafter.(See'Bonemineraldensity'below.)

Monitoringwithmarkersofboneturnoverisanadditionaloptionforpatientswhohaveconditionsthatmight
interferewithdrugabsorptionorefficacy,suchassmallbowelresectionsorothertypesofmalabsorption,orfor
patientswhoarereluctanttotakeantiosteoporosismedicationsregularly.Insuchpatients,wetypicallymeasure
fastingurinaryNtelopeptide(NTX)orserumcarboxyterminalcollagencrosslinks(CTX)beforeandthreetosix
monthsafterstartingbisphosphonateorotherantiresorptivetherapy.Adecreaseofgreaterthan50or30percentin

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urinaryNTXexcretionorserumCTX,respectively,providesevidenceofcomplianceanddrugefficacy.Thepatient
canbereassuredthatthenextBMDmeasurementwilllikelybestableorimproved.Incontrast,adecreasein
markersoflessthan30percentmaynotnecessarilyindicatetreatmentfailure.However,whenthisoccurs,we
questionthepatientaboutpossiblenoncomplianceorpoorabsorption(oftenrelatedtoaninsufficienttimeinterval
betweendrugintakeandfoodingestion).(See"Useofbiochemicalmarkersofboneturnoverinosteoporosis",
sectionon'Osteoporosistherapy'.)

Thisapproach(withmarkersofboneresorption)isonlyusefulwithantiresorptivetherapy,notwithrecombinant
parathyroidhormone(PTH)(markerswouldincrease).TheapproachtomonitoringpatientsonrecombinantPTH
therapyisdiscussedseparately.(See"Parathyroidhormonetherapyforosteoporosis",sectionon'Monitoring'.)

BonemineraldensitySome[109112],butnotall[113],studiessuggestthatchangesinBMDduring
therapycorrelatewithreductioninfracturerisk.Inonestudy,thegreatestfracturereductionoccurredinthosewho
gainedBMD,althoughthosewithstableBMDstillhadfewerfracturesthanthosewholostBMD[109].Ameta
analysisof12clinicaltrialsconcludedthatimprovementinspineBMDaccountsforapredictablebutsmallpartof
thereductioninfracturerisk[114].

SerialBMDmeasurementsareoftenperformedtoassesstheclinicalresponsetotherapy.BMDthatisstableor
improvingisevidenceforatreatmentresponse.InorderforachangeinBMDtobeconsideredsignificant,it
shouldbegreaterthanthe"leastsignificantchange"(LSC)forthedensitometerinquestion.(See"Overviewof
dualenergyxrayabsorptiometry",sectionon'Precisionassessment'.)

ThefindingofaBMDdecreasegreaterthantheLSCinatreatedpatientshouldtriggeradditionalevaluationfor
contributingfactors,whichmayincludepooradherencetotherapy,inadequategastrointestinalabsorption,
inadequateintakeofcalciumandvitaminD,orthedevelopmentofadiseaseordisorderwithadverseskeletal
effects[115,116].CalciumandvitaminDsupplementationshouldbeverified,andsomeevaluationforsecondary
causesofbonelossshouldbeperformed.(See"Clinicalmanifestations,diagnosis,andevaluationofosteoporosis
inpostmenopausalwomen",sectionon'Evaluation'.)

Ifthepatientisotherwisewellandtakingthedrugandsupplementscorrectly,thecorrectactioniscontroversial.
SomecliniciansbelievethatthedecreaseinBMDtrulyreflectsatreatmentfailureandwouldconsidermodification
oftheprimarytreatmentfortheosteoporosis.OthersbelievethatthedeclineinBMDdoesnotnecessarilyimply
inadequatetherapy,butcouldbeascribedtomeasurementerror[117].TheywouldrepeatBMDoneyearlater,
takingactiononlyifthedeclineisreaffirmed.WhenthedeclineinBMDis>5percent,weusuallyswitchfroman
oralbisphosphonatetoanintravenous(IV)bisphosphonate(typicallyzoledronicacid).Theissuessurroundingthis
decisionandthealternativetreatmentoptionsarereviewedinmoredetailelsewhere.(See"Theuseof
bisphosphonatesinpostmenopausalwomenwithosteoporosis",sectionon'Responsetotherapy'.)

GuidelinesThereareseveralpublishedguidelinesformonitoringtheresponsetoosteoporosistherapyall
recommendfollowupBMD(DXA)testing.However,thereisnoconsensusontheoptimalfrequencyofmonitoring
andpreferredsitetomonitor.Theuseofbiochemicalmarkersofboneturnoverformonitoringresponsetotherapy
hasnotbeenaddressedincurrentguidelines,andtherearenoprospectivetrialstodefinethemostoptimal
approachforincorporatingmarkersintomonitoringstrategies[118].(See"Bonephysiologyandbiochemical
markersofboneturnover"and"Useofbiochemicalmarkersofboneturnoverinosteoporosis".)

ISCDTheISCDrecommendsfollowupBMDtesting(DXAspineandhip)whentheexpectedchangein
BMDequalsorexceedstheleastsignificantchange(LSC),whichistypicallyonetotwoyearsafterinitiation
orchangeoftherapy,withlongerintervalsoncetherapeuticeffectisestablished.Inconditionsassociated
withrapidboneloss,suchasglucocorticoidtherapy,testingmorefrequentlyisappropriate[119].

NOFTheNationalOsteoporosisFoundationrecommendsrepeatBMDassessments(DXAspineorhip)
onetotwoyearsafterinitiatingtherapyandtheneverytwoyearsthereafter,withmorefrequenttestingin
certainclinicalsituations[25].

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AACETheAmericanAssociationofClinicalEndocrinologists(AACE)recommendsrepeatDXAofthe
lumbarspine(LS)andtotalhipeveryonetotwoyearsuntilstabilityisachieved,andeverytwoyearsorat
lessfrequentintervalsthereafter[120].

NAMSTheNorthAmericanMenopauseSociety(NAMS)recommendsrepeatDXAonetotwoyearsafter
initiatingtherapy,andlessfrequentlythereafterifBMDisstable[121].

OtherAmoreconservativeapproachtomonitoringtakesthepositionthatmonitoringforefficacyof
antiresorptivetherapyisunnecessary,asonlyaminorityofpatientscontinuetoloseboneontherapy[122].
Thisapproachisusedinfrequentlybycliniciansbutmaybeapplicabletopatientsfromremoteareaswithout
accesstomedicalfacilities.

MEDICALINTERVENTIONAFTERFRACTUREIntheUnitedStatesandEurope,themajorityofpatients
whohavehadfragilityfractures(orareatriskforfracture)donotsubsequentlyreceiveosteoporosistherapy[123
125],despitedatademonstratingabeneficialeffectinreducingtheriskofasecondfracture.

Theratesoftestingandtreatmentforosteoporosisinpatientswithfragilityfracturesmaybeimprovedbyrelatively
simpleinterventions[126129].Asanexample,inarandomized,controlledtrialof272patientsoverage50years
withanydistalforearmfracture,faxedreminderstoclinicians(includingtreatmentguidelines)andpatienteducation
resultedinathreefoldincreaseintherateofosteoporosistestingandtreatmentwhencomparedwithacontrol
groupreceivingstandardcare[126].However,inanotherrandomizedtrial,interventiontoimproveosteoporosis
treatmentafterfracturewasnotsuccessful[130].Inaddition,evenwhentheinterventionsarereportedtobe
effective,overalllongtermtreatmentratesforosteoporosisremainlow.

Therearefewtrialsevaluatingtheinitiationofbisphosphonatesintheimmediatepostfractureperiod.Inmost
patients,arecentfractureshouldnotprecludeuseofbisphosphonates,whichcanbeinitiatedwithinfourtosix
weekspostfractureaslongasthepatientisabletosituprightforatleast30minutes(oralbisphosphonates).This
topicisreviewedelsewhere.(See"Theuseofbisphosphonatesinpostmenopausalwomenwithosteoporosis",
sectionon'Useimmediatelyafterfracture'.)

INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,TheBasicsand
BeyondtheBasics.TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6thgrade
readinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.These
articlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.Beyond
theBasicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewritten
atthe10thto12thgradereadinglevelandarebestforpatientswhowantindepthinformationandarecomfortable
withsomemedicaljargon.

Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthese
topicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon
patientinfoandthekeyword(s)ofinterest.)

Basicstopics(see"Patientinformation:Osteoporosis(TheBasics)"and"Patientinformation:Calciumand
vitaminDforbonehealth(TheBasics)"and"Patientinformation:Medicinesforosteoporosis(TheBasics)")

BeyondtheBasicstopics(see"Patientinformation:Osteoporosispreventionandtreatment(Beyondthe
Basics)"and"Patientinformation:CalciumandvitaminDforbonehealth(BeyondtheBasics)")

SUMMARYANDRECOMMENDATIONS

Lifestylemeasures

WesuggestadequatecalciumandvitaminDforallpostmenopausalwomenwithosteoporosis(Grade2B).
(See'Lifestylemeasures'above.)

Ingeneral,wesuggest1200mgofelementalcalciumdaily,totaldietplussupplement,and800international

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unitsofvitaminDdaily.SomepatientsrequireadditionalvitaminDsupplementation.(See"Calciumand
vitaminDsupplementationinosteoporosis".)

Importantadditionallifestylemeasuresincludeexercise,smokingcessation,counselingonfallprevention,
andavoidanceofheavyalcoholuseforallpostmenopausalwomenwithosteoporosis.

RecommendationsforcalciumandvitaminDsupplementationaswellasotherlifestylemeasuresfor
postmenopausalwomenwithoutosteoporosisarefoundelsewhere.(See"Preventionofosteoporosis",sectionon
'Summaryandrecommendations'.)

Pharmacologictherapy

Inadditiontononpharmacologictherapy,werecommendthatpostmenopausalwomenwithestablished
osteoporosis(Tscore2.5)orfragilityfracture(hiporvertebral)betreatedwithapharmacologicagent
(Grade1A).(See'Pharmacologictherapy'above.)

ForthetreatmentofhighriskpostmenopausalwomenwithTscoresbetween1.0and2.5,wealsosuggest
pharmacologictherapy(Grade2B).Areasonablecutpointthatmaybecosteffectiveinsomesettingsisa
10yearprobabilityofhipfractureorcombinedmajorosteoporoticfractureof3.0or20percent,
respectively.(See'Candidatesfortherapy'above.)

Forthetreatmentofosteoporosisinpostmenopausalwomen,wesuggestbisphosphonatesasfirstline
therapy(Grade2B).(See'Bisphosphonates'aboveand"Theuseofbisphosphonatesinpostmenopausal
womenwithosteoporosis".)

Wepreferoralbisphosphonatesasinitialtherapybecauseoftheirefficacy,favorablecost,andthe
availabilityoflongtermsafetydata.(See'Choiceofdrug'above.)

Formostpostmenopausalwomenwithosteoporosis,wesuggestalendronateorrisedronateoveroral
ibandronate(Grade2B).(See'Choiceofdrug'above.)Oralibandronatemaybemoreconvenientforpatients,
butareductioninhipfractureriskhasnotbeenestablishedinrandomizedtrials.

Wesuggestanintravenous(IV)bisphosphonateformulationforpatientswhocannottolerateoral
bisphosphonates,whohavedifficultywithdosingrequirements,includinganinabilitytosituprightfor30to
60minutes,orwhohaverelativecontraindicationstobisphosphonates(achalasia,sclerodermaesophagus,
esophagealstrictures)(Grade2B).ZoledronicacidistheonlyIVbisphosphonatethathasdemonstrated
efficacyforfracturepreventionandis,therefore,ouragentofchoice.(See"Theuseofbisphosphonatesin
postmenopausalwomenwithosteoporosis".)

Denosumabisanalternativeoptionforpatientswhocannottolerateoralbisphosphonatesorwhohave
difficultywiththedosingrequirementsandhaveimpairedrenalfunction.(See"Denosumabfor
osteoporosis".)

Wesuggestraloxifeneforpostmenopausalwomenwithosteoporosis(lowbonemineraldensity[BMD][T
score<2.5]andnofragilityfractures)whocannottolerateorarenotcandidatesforanybisphosphonates
(Grade2B)(see"Selectiveestrogenreceptormodulatorsforpreventionandtreatmentofosteoporosis").
Recommendationsregardingraloxifeneforthepreventionofosteoporosisarediscussedseparately.(See
"Preventionofosteoporosis",sectionon'Selectiveestrogenreceptormodulators(SERMs)'.)

Denosumabisalsoanoptionforsuchpatientswhoareintolerantoforunresponsivetoanybisphosphonates.
(See"Denosumabforosteoporosis".)

Becausestrontiumranelateisaweakantiresorptiveagentandtherearemoreeffectiveosteoporosisagents
intheUnitedStatesandmostcountries,wedonotusestrontiumranelateinpostmenopausalwomenwith
osteoporosis.(See'Strontiumranelate'above.)

Wesuggestparathyroidhormone(PTH)therapyforpostmenopausalwomenwithsevereosteoporosis(low
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BMD[Tscore<2.5]andatleastonefragilityfracture)whoareunabletotolerateanyoftheavailable
bisphosphonates(Grade2B).(See"Parathyroidhormonetherapyforosteoporosis".)

Inpostmenopausalwomenwithsevereosteoporosis(lowBMD[Tscore<2.5]andatleastonefragility
fracture)whocontinuetofractureafteroneyearofbisphosphonatetherapy,wesuggestdiscontinuingthe
bisphosphonateandswitchingtohumanrecombinantPTHtherapy(Grade2B).(See"Theuseof
bisphosphonatesinpostmenopausalwomenwithosteoporosis",sectionon'Responsetotherapy'and
"Parathyroidhormonetherapyforosteoporosis".)

OthercandidatesforPTHarepostmenopausalwomenwithosteoporosiswhoareunabletotolerate
bisphosphonates,orwhohaverelativecontraindicationstobisphosphonates(achalasia,scleroderma
esophagus,esophagealstrictures),inadditiontorelativecontraindicationstoselectiveestrogenreceptor
modulators(SERMs)(thrombosis,hotflashes),orforwhomotherosteoporosistherapiesfail(fracturewith
lossofBMDinspiteofcompliancewiththerapy).(See'Parathyroidhormone'aboveand"Parathyroid
hormonetherapyforosteoporosis".)

MonitoringThereisnoconsensusontheoptimalstrategyformonitoringpatientsontherapy.However,weuse
thefollowingapproach:

Forpatientsstartingontherapy,weobtainafollowupdualenergyxrayabsorptiometry(DXA)ofthehipand
spineaftertwoyears,andifBMDisstableorimproved,lessfrequentmonitoringthereafter.(See'Our
approach'above.)

Forpatientswithconditionsthatmightinterferewithdrugabsorptionorefficacyorforpatientswhoare
reluctanttotakeantiosteoporosismedicationsregularly,wetypicallymeasurefastingurinaryNtelopeptide
(NTX)orserumcarboxyterminalcollagencrosslinks(CTX)beforeandthreetosixmonthsafterstarting
bisphosphonatesorotherantiresorptivetherapy.Ifthemarkerhasnotdecreasedby50(NTX)or30(CTX)
percent,noncomplianceorpoorabsorption,oftenrelatedtoaninsufficienttimeintervalbetweendrugintake
andfoodingestion,shouldbeconsidered.

Thisapproach(withmarkersofboneresorption)isonlyusefulwithantiresorptivetherapy,notwith
recombinantPTH(markerswouldincrease).(See"Parathyroidhormonetherapyforosteoporosis",sectionon
'Monitoring'.)

UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.

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managementafterafracture:arandomized,controlledtrial.JAmGeriatrSoc200654:450.
128. SolomonDH,PolinskiJM,StedmanM,etal.Improvingcareofpatientsatriskforosteoporosis:a
randomizedcontrolledtrial.JGenInternMed200722:362.
129. MajumdarSR,BeaupreLA,HarleyCH,etal.Useofacasemanagertoimproveosteoporosistreatment
afterhipfracture:resultsofarandomizedcontrolledtrial.ArchInternMed2007167:2110.
130. BliucD,EismanJA,CenterJR.Arandomizedstudyoftwodifferentinformationbasedinterventionsonthe
managementofosteoporosisinminimalandmoderatetraumafractures.OsteoporosInt200617:1309.

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GRAPHICS

Clinicalriskfactorsforfracture

Advancingage

Previousfracture

Glucocorticoidtherapy

Parentalhistoryofhipfracture

Lowbodyweight

Currentcigarettesmoking

Excessivealcoholconsumption

Rheumatoidarthritis

Secondaryosteoporosis(eg,hypogonadismorprematuremenopause,malabsorption,chronicliver
disease,inflammatoryboweldisease)

Datafrom:KanisJA,BorgstromF,DeLaetC,etal.Assessmentoffracturerisk.OsteoporosInt2005
16:581.

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Guidelinesforpharmacologicinterventioninpostmenopausal
womenandmen50yearsofage

Historyofhiporvertebralfracture.

Tscore2.5(DXA)atthefemoralneckorspine,afterappropriateevaluationtoexclude
secondarycauses.

Tscorebetween1and2.5atthefemoralneckorspine,anda10yearprobabilityofhipfracture
3percentora10yearprobabilityofanymajorosteoporosisrelatedfracture20percentbased
upontheUSadaptedWHOalgorithm.

References:
1. CosmanF,deBeurSJ,LeBoffMS,etal.Clinician'sguidetopreventionandtreatmentof
osteoporosis.OsteoporosInt201425:2359.
2. WattsNB,AdlerRA,BilezikianJP,etal.Osteoporosisinmen:anEndocrineSocietyclinicalpractice
guideline.JClinEndocrinolMetab201297:1802.

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Estrogenprogestintherapyreduceshipfracture

IntheWomen'sHealthInitiative,combinedestrogenprogestin
replacementtherapywasassociatedwithsignificantreductioninhip
fracture(fivefewerhipfracturesper10,000personyears,HR0.7,
unadjusted95%CI0.41.0).

Datafrom:RossouwJE,AndersonGL,PrenticeRL,etal.Risksandbenefitsof
estrogenandprogestininhealthypostmenopausalwomen:principalresults
fromtheWomen'sHealthInitiativerandomizedcontrolledtrial.JAMA2002
288:321.

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Disclosures
Disclosures:HaroldNRosen,MDNothingtodisclose.MarcKDrezner,MDNothingtodisclose.
CliffordJRosen,MDNothingtodisclose.KennethESchmader,MDGrant/Research/ClinicalTrial
Support:Merck[Herpeszoster(Zostervaccine)].JeanEMulder,MDNothingtodisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseare
addressedbyvettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobe
providedtosupportthecontent.Appropriatelyreferencedcontentisrequiredofallauthorsandmust
conformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy

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