Repositório Institucional UFC: Treatment of postmenopausal osteoporosis: a literature-based algorithm for use in the public health care system

ww w . r e u m a t o l o g i a . c o m . b r

REVISTA

BRASILEIRA

DE

REUMATOLOGIA

Review

article

Treatment

of

postmenopausal

osteoporosis:

a

literature-based

algorithm

for

use

in

the

public

health

care

system

Ellen

Luz

Pereira

Caires

_,

_Mailze

_Campos

_Bezerra

_,

Ana

Flávia

Torquato

de

Araújo

Junqueira

_,

_Sheila

_Márcia

_de

_Araújo

_Fontenele

_,

Silvana

Cristina

de

Albuquerque

Andrade

_,

_Catarina

_Brasil

_d’Alva

a_{UniversidadeFederaldoCeará(UFC),FaculdadedeMedicina,Servic¸odeEndocrinologiaeDiabetes,Fortaleza,CE,Brazil} b_{UniversidadeFederaldoCeará(UFC),FaculdadedeMedicina,Servic¸odeReumatologia,Fortaleza,CE,Brazil}

c_{UniversidadeFederaldoCeará(UFC),FaculdadedeMedicina,NúcleodeAtendimentoMultidisciplinaràsDoenc¸asOsteometabólicas,}

Fortaleza,CE,Brazil

d_{UniversidadeFederaldoCeará(UFC),FaculdadedeMedicina,Servic¸odeNefrologiaeTransplanteRenal,Fortaleza,CE,Brazil}

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received3July2016 Accepted5December2016 Availableonline15February2017

Keywords:

Osteoporosistreatment Bisphosphonates Publichealthcare

a

b

s

t

r

a

c

t

Bisphosphonatesareconsideredfirst-lineagentsinthetreatmentofpostmenopausal osteo-porosisbased on extensive experience ofuse, safety, and proven efficacy in reducing vertebral,non-vertebralandfemurfractures.However,post-marketingreportsbasedon thetreatmentofmillionsofpatients/yearoverlengthyperiodsoftimehaverevealedthe occurrenceofinitiallyunexpectedadverseeffects,suchasosteonecrosisofthejawand atypicalfemoralfracture,leadingtotherestrictionoftreatmentdurationwith bisphospho-natesbyglobalregulatoryagencies.However,despitetheassociationbetweentheseeffects andbisphosphonates,thisriskshouldbeanalyzedinthecontextofosteoporosistreatment, alongsidethebenefitofpreventingosteoporoticfracturesandtheirclinicalconsequences. Therefore,weconsideritplausibletodiscusstherestrictiontotheuseofbisphosphonates, possibleindicationsforprolongedtreatmentandalternativetherapiesfollowingthe suspen-sionofthisdrugclassforpatientswithpersistenthighriskoffractureafterinitialtreatment, especiallyconsideringtheproblemsofpublichealthfundinginBrazilandtheshortageof drugsprovidedbythegovernment.Thus,tostandardizethetreatmentofosteoporosisinthe publichealthcaresystem,weaimtodevelopaproposalforascientifically-based pharmaco-logicaltreatmentforpostmenopausalosteoporosis,establishingcriteriaforindicationand allowingtherationaluseofeachpharmacologicalagent.Wediscussthedurationofthe ini-tialbisphosphonatetreatment,thetherapeuticoptionsforrefractorypatientsandpotential indicationsofotherclassesofdrugsasfirst-choicetreatmentinthesphereofpublichealth, inwhichassessingriskandcosteffectivenessisapriority.

©2017ElsevierEditoraLtda.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

∗ _{Correspondingauthor.}

E-mails:cbdalva@terra.com.br,majaco@terra.com.br(C.B.d’Alva). http://dx.doi.org/10.1016/j.rbre.2017.01.001

Tratamento

da

osteoporose

pós-menopáusica:

um

algoritmo

baseado

na

literatura

para

uso

no

sistema

público

de

saúde

Palavras-chave:

Tratamentodaosteoporose Bisfosfonatos

Saúdepública

r

e

s

u

m

o

Combasenavastaexperiênciadeuso,seguranc¸aeeficáciacomprovadanareduc¸ãode fraturasvertebrais,nãovertebraisefemorais,osbisfosfonatossãoconsideradosagentes deprimeiralinhanotratamentodaosteoporosepós-menopáusica.Noentanto,osrelatos pós-vendabaseadosnotratamentodemilhõesdepacientes/anoduranteperíodos prolon-gadosdetemporevelaramaocorrênciadeefeitosadversosinicialmenteinesperados,como osteonecrosedamandíbulaefraturaatípicadofêmur.Issolevouasagênciasreguladoras globaisarestringiremadurac¸ãodotratamentocombisfosfonatos.Noentanto,apesarda associac¸ãoentreessesefeitoseosbisfosfonatos,esseriscodeveseranalisadonocontexto dotratamentodaosteoporose,paralelamenteaobenefícionaprevenc¸ãodefraturas osteo-poróticasesuasconsequênciasclínicas.Portanto,considera-seplausíveldiscutirarestric¸ão aousodosbisfosfonatos,possíveisindicac¸õesparaotratamentoprolongado eterapias opcionaisapósasuspensãodessaclassedefármacoparapacientescomaltorisco persis-tentedefraturaapósotratamentoinicial,especialmenteseconsiderarmososproblemas financeirosdesaúdepúblicanoBrasileaescassezdefármacosfornecidospelogoverno. Assim,parapadronizarotratamentodaosteoporosenosistemapúblicodesaúde pretende--sedesenvolverumapropostadetratamentofarmacológicocientificamentefundamentada paraaosteoporosepós-menopáusica,estabelecercritériosdeindicac¸ãoepermitirouso racionaldecadaagentefarmacológico.Discutem-seadurac¸ãodotratamentoinicialcom bisfosfonatos,asopc¸õesterapêuticasparapacientesrefratáriosepotenciaisindicac¸õesde outrasclassesdemedicamentoscomotratamentodeprimeiralinhanaesferadasaúde pública,emqueaavaliac¸ãodoriscoecusto-efetividadeéumaprioridade.

©2017ElsevierEditoraLtda.Este ´eumartigoOpenAccesssobumalicenc¸aCC BY-NC-ND(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Osteoporosisischaracterizedbylossofbonemassand dete-riorationoftissuemicroarchitecture,leadingtobonefragility andincreasedriskoffractures,theclinicalconsequencesof whicharedeformities,chronicpain,disabilityanddeath.1_It isacommondiseasewithincreasingprevalenceamongmen andwomen duetoincreasedlifeexpectancy andanaging population.

Bisphosphonatesrepresentthe first-line therapy forthe preventionofosteoporoticfractures.2 _{These drugsare} syn-thetic analogs of inorganic pyrophosphate obtained by replacingtheoxygenatomwithacarbon(P-C-P),makingthem resistant tobiologicaldegradation,and byadding twoside chains(R1and R2),responsible forskeletalbindingaffinity andpower,respectively.Thischemicalstructurehasthe prop-ertyofforming compoundswithdivalent cations,showing greataviditywithhydroxyapatitecrystals ofbonesurfaces, particularlyofactiveremodelingsites.In theacid environ-mentofresorption,bisphosphonates arereleasedfrom the boneandabsorbedbytheosteoclast,causingtheinhibition ofthe enzyme farnesyl pyrophosphate synthase, which is importantfortheintegrityofitscytoskeletonandcell func-tion.Thisleadstoalossinresorptivefunctionandpotential osteoclastapoptosis. Considering that boneformation and resorptionare coupledprocesses, reducedresorptionis fol-lowed by a decrease in bone formation, thus achieving a

new stateof decreasedbone remodeling afterstarting the treatment.3

Thefirst drug ofthisclass wassynthesized inthe 19th century,butitsclinicalrelevancewasonlyrecognizedinthe late1960s,whenbisphosphonatesstartedbeingusedinthe treatmentofvariousbonemetabolicdiseases.4_However,the widespreaduseofbisphosphonatesinosteoporosistherapy occurredafter1993,whenWorldHealthOrganization(WHO) established the diagnosis ofosteoporosis bythe technique ofbone densitometryby dual-energy X-rayabsorptiometry (DEXA).5

Effectiveness

of

bisphosphonates

in

the

prevention

of

osteoporotic

fractures

55–81years,neckT-score≤−2.1,2.9-year follow-up),which showedareductionof47%,55%and51%intheriskof radio-graphic vertebral fractures, clinical vertebral fractures and femurfractures,respectively,inthisgroupofpostmenopausal womenwithpreviousvertebralfractures.7

Thesecond bisphosphonateapproved forthetreatment of osteoporosis in the US was risedronate, in 2000. The use of risedronate (VERT study, n=2458 women, age <85 years, 2 prior vertebral fractures or 1 prior vertebral frac-tureplusspineT-score≤−2.0, 3-yearfollow-up) resultedin 41%and39%reductionsinvertebralandnon-vertebral frac-tures,respectively.9_{Then,a40%reductionofhipfracturerisk} wasshownbyMcLunget al.inalargestudy thatincluded 5445womenaged70–79,withneckT-score≤−4.0orneckT -score≤−3.0plus1riskfactorforhipfracture,inatwo-year follow-up.10

Ibandronate,approvedin2005forthetreatmentof osteo-porosis,reducedtheriskofvertebralfractureby62%(BONE study,n=2946women,age55–80years,T-score≤−2.0inat leastonevertebrapluspriorvertebralfracture,3-year follow-up). In this study, there was no reduction in the risk of non-vertebralfractures,exceptforaposthocanalysisofthe subgroupofwomen withneck T-score<−3.0.11 In order to estimatethe effectonnon-vertebralfractures,afew meta-analyzes of randomized studies that evaluated individual patientdatawerepublishedsuggestingabeneficialeffectof higherdosesofibandronate(correspondingto150mg/month orallyor 12mg/yeari.v.).12,13 _{However,thereisno evidence} from placebo-controlled studies showinga reduced risk of non-vertebralfracturewiththeuseofibandronate.

Zoledronicacid,abisphosphonatewithgreater antiresorp-tivepotency,wasapprovedforthetreatmentofosteoporosis in2007.Anannualinfusionofzoledronicacidfor3 consec-utiveyears(HORIZONPFT,n=7765women,age65–89years, neck T-score≤−2.5 or neck T-score≤−1.5 plus 1 vertebral fracture,3-yearfollow-up)waseffectiveinreducingby70%, 41%and25%theriskofvertebral,femurandnon-vertebral fractures,respectively.14

Safety

of

bisphosphonates

in

osteoporosis

treatment

Given that osteoporosis is a chronic disease, along with thegoodsafetyprofileofbisphosphonatesdemonstratedby placebo-controlled studies, osteoporosis treatment should, conceptually,beextendedthroughoutthepatient’swholelife. However,post-marketingreportsbasedonthetreatmentof millionsofpatients/yearoveralengthyperiodoftimerevealed theoccurrenceofinitiallyunexpectedadverseeffectsof bis-phosphonatetreatmentsuchasosteonecrosisofthejaw(ONJ) andatypicalfemoralfracture.15–17

ONJ is characterized by exposure ofbone tissue in the maxillofacialregionwithouthealingafter8weeks.18_Evidence suggeststheexistenceofacausalrelationshipbetweenthe useofbisphosphonatesandONJ,withadose-responseeffect duetothegreater incidenceofthis complicationincancer patientsreceivinghighcumulativedosesofbisphosphonates. Theprevalencewasestimatedat0.4%amongcancerpatients and0.001%inpatientswithosteoporosisinasurveyofcases

observed byCanadianmaxillofacial surgeons.19 _A random-ized, double-blind, placebo-controlled study involving 2046 patientswithbreastcancerobservedtheoccurrenceofONJ in2.0%and 1.4%ofthose treatedwithhighdosesof deno-sumaborzoledronicacid,respectively(p=0.39),revealingthat thiseffectisnotspecifictobisphosphonates,buttotreatment withpotentantiresorptives.20_{Therefore,ONJisveryrareinthe} treatmentofosteoporosisanddiscontinuationof antiresorp-tivetherapyinosteoporoticpatientspriortodentalprocedures possiblydoesnothaveanyimpactinreducingthisrisk.

However,recently,the TaskForce onONJ recommended tostopantiresorptivetherapy,ifitispossibletodoso with-out adverseconsequencesforbonehealth,inpatientswho requireextensiveinvasiveoralsurgeryaswellasthosewith multipleriskfactorsforONJ,althoughthereislittleevidence tosupportthisrecommendationasbisphosphonatesremain in bone foryears.21 _{Therefore, clinical judgmentis always} essential.

Afurthercomplicationobservedfollowingthemarketing ofbisphosphonateswasatypicalfemoralfracturedefinedas noncomminutedtransverseorshortobliquefractures,which occurinthesubtrochantericregionafterminimaltrauma.22 Despitetheinconclusivestudiesonbonephysicalproperties inbisphosphonatesusers,itisbelievedthatsuchfracturesare theresultofexcessiveandprolongedsuppressionof remod-eling,causinglossofbonequalityandmechanicalfunction, whichleadstotheaccumulationofmicrofracturesand skele-tal fragility.The resultis the development ofinsufficiency fractures atthe maximum mechanical overloadpoint rep-resentedbythesubtrochantericordiaphyseal regionofthe femur.Hencethetermatypicalfracture,sinceitinvolvesthe strongest regionofthe femur, unlikeosteoporotic fracture, whichcommonlyoccursinthefemoralneck.23

Afterreviewing12,777femurfracturescasesthatoccurred in Sweden in 2008,Schilcher et al.24 _{identified 59 atypical} fractures,78%ofwhichoccurred inbisphosphonatesusers. Despitethisassociation,theabsoluteriskofatypicalfracture relatedtotheuseofbisphosphonatesislow(50cases/100,000 patients-year). Dell et al.25 _{analyzed approximately 15,000} subtrochantericfracturesinCaliforniabetween2007and2009, identifying 102 atypical fractures, 97 of which in patients usingbisphosphonatesforanaverageof5.5years.However, when analyzingthe useofbisphosphonates overtime, the absoluteriskwas2cases/100,000patients-yearin2yearsof treatment and 78 cases/100,000 patients-year in8 yearsof treatment.

Warnings

from

drug

regulatory

agencies

worldwide

Impact

of

the

regulatory

restriction

on

duration

of

bisphosphonates

use

in

the

Brazilian

public

health

system:

a

critical

analysis

Despite the association demonstrated between atypical femoralfracturesand bisphosphonates, thisriskshould be analyzedinthecontextofosteoporosistreatment,alongside thebenefitofpreventingosteoporoticfractures.Itisestimated thatforeach100typicalfemoralfracturespreventedby bis-phosphonates,1atypicalfractureoccurs.29_{Forpatientswith} severeosteoporosisandhighriskoffracture,3300osteoporotic fractures are prevented per 100,000 patients-year treated, whileforpatientswithmoderaterisk,1700osteoporotic frac-tures are prevented per 100,000 patients-year treated with bisphosphonates.22_{Therefore,theeffectivenessofthisclass} ofdrugsinthepreventionofosteoporoticfracturesinpatients withmoderatetohighriskosteoporosisoutweighstheriskof atypicalfractures(Fig.1).30

In Brazil, where the constitution guarantees universal accesstohealthcare,onlyraloxifeneandalendronateare reg-ularlyavailableinourpublichealthsystem.Inordertoobtain drugssuchaszoledronicacidandteriparatide,patientsturn tothecourts,obligingthegovernmenttoprovidethe medica-tions,whichdisruptsitsbudgetandimpairshealthpolicies. Thus,itisreasonabletoquestiontherestrictionontheuseof bisphosphonates,especiallywhenweconsiderpublichealth fundingproblemsinBrazilandthescarcityofdrugssupplied bythegovernment.

Therefore, given the potential severity of osteoporosis, theabsolutelowriskofatypicalfracture andtherestricted drug supply by our public health system, it is reason-able to propose long-term bisphosphonates treatment for women with osteoporosis and moderate to high risk of fracture.

Withtheobjectiveofstandardizingthetreatmentof osteo-porosis in Brazilian public health care system, as well as reducing the phenomenon of judicialization of health, we proposetodevelopascientifically-basedprotocolforthe treat-ment ofpostmenopausalosteoporosis, establishingcriteria forindicationandallowingtherationaluseofeach pharma-cologicalagent.

3100 1600

650 78 2

3500 3000 2500 2000 1500 1000 500 0 Major osteoporotic fracture in

high-risk women Major osteoporotic fracture

in low-risk women

Major osteoporotic fracture in moderate-risk women Atypical femoral fracture

(8 yr bisphosphonate) Atypical femoral fracture

(2 yr bisphosphonate)

Incidence per 100 000 person-years Events

Fig.1–Riskofosteoporoticfracturesandatypicalfemoral fractures.

AdaptedfromBrownetal.30

Efficacy

of

prolonged

treatment

with

bisphosphonates

Itisworthexaminingwhetherprolongeduseof bisphospho-nates offers benefits, sincethese drugs accumulate in the skeleton and continue to bereleased for months to years afterthetreatmentissuspended,resultinginaresidual anti-fractureeffect.31_{Belowaredescribedsomeextensionstudies} oftreatmentwithbisphosphonates.

TheextensionoftheFITstudy(FractureInterventionalTrial Long-term Extension,FLEX), inwhich, followingthe first 5 yearswithalendronate,patientsinthetreatedgroupwere ran-domizedinto5moreyearsofalendronateorplacebo,showed nodifferenceintheriskofnon-vertebralfractureand mor-phometricvertebralfracturesbetweenthegroups.However, it demonstratedareducedriskofclinicallyapparent verte-bralfractures(RR:0.45;95%CI0.24–0.85)inpatientscontinuing treatmentfor10 years.32 _{Itisnoteworthythat, intheFLEX} study, many women had osteopenia only, and those with a femurneck T-score<−3.5 were excluded, indicating that partofthemalreadypresentedlowriskandhadnoneedto prolongtreatment.Moreover,asubsequentanalysisofFLEX datashowedthatmaintenanceofalendronatefor10yearsin the subgroupofwomenwithafemoralneckT-score≤−2.5 decreasedby50%theriskofnon-vertebralfractures(RR:0.50, CI95%0.26–0.96).33_{Theseresultsindicatethatsomewomen,} especiallythosewithhighriskoffracture,canbenefitfrom themaintenanceoftreatmentwithalendronatefor10years. Inotherwords,theeffectivenessoftheprolongedtreatment dependsonthefracturerisk,whichcanbeevaluated,among otheraspects,byBoneMineralDensity(BMD).

To investigate the long-term effects of zoledronic acid, patientswho hadbeen treatedfor3yearsintheHORIZON studywererandomizedinto3moreyearsofzoledronicacid or placebo. This study showed a reduction in the risk of morphometricvertebralfractures(OR:0.51;p=0.035)with con-tinuedtreatment.Thisfindingledtotheconclusionthatmany patientscansafelydiscontinuethemedicationaftertheinitial 3yearsoftreatment,whilesomeofthemmaybenefitfromthe maintenanceofzoledronicacidforanother3years.34

Wecanconcludethatsuspensionofthebisphosphonate after3(zoledronicacid)to5years(alendronate) isjustified for patients who, at the end of this period, present low risk of fracture. However, those who persist with femoral

T-score≤−2.5 after the initial course of treatment should havethis treatmentcontinued forup to6(zoledronic acid) to10 years(alendronate).Moreover,despitethe absenceof evidence-based recommendations, it is likely that women who persistwithmoderate tohighrisk offractures dueto factorsindependentoffemoralT-scoremayalsobenefitfrom treatmentmaintenance.

Transition

studies:

what

to

do

in

the

case

of

women

who

persist

with

high

risk

of

fracture

following

10

years

of

treatment

with

bisphosphonates?

bisphosphonates, becoming candidates for treatment with otheranti-osteoporoticdrugs.However,bisphosphonatesare potentsuppressorsofboneremodelingandhavehighaffinity andretentiontimeinthebone,inhibitingturnoverforyears aftertheirsuspension.Therefore,theimpactoftheswitchto otherdrugsmustbecarefullyanalyzed.35,36

Giventhegreaterpotencyofthezoledronicacid,McLung et al.37 _{studied the effect ofa single dose of this drug in} menopausalwomenpreviouslytreatedwithalendronatefor anaveragetimeof4years(n=225,age46–79years,spineor neckT-score≤−2.0).BMDremainedessentiallystableafter12 monthsofalendronateorzoledronicacid,withnodifference betweenthegroups.

Denosumab,thefirstbiologicaldrugapprovedforthe treat-mentofosteoporosis,isamonoclonalantibodythatbindsto receptoractivatorofnuclearfactorkappa␤ligand(RANKL), a cytokine secreted bythe osteoblast considered essential forthe differentiation, activity and survival ofosteoclasts, potentlyreducing boneresorptionand therisk ofvertebral (68%),non-vertebral(20%)andfemur(40%)fracture.38,39

Two studies investigated the effects of denosumab in patients previously treated with bisphosphonates.40,41 Kendleretal.,40_{analyzingpatientstreatedwithalendronate} foranaverageof36months(n=504,age≥55years,−4.0≤_T -score≥−2.0), observed that the transition to denosumab resulted in a significantly greater increase of BMD in the totalfemurandlumbarspineafter12monthscomparedto themaintenanceofalendronate (1.9%vs.1.0%totalfemur,

p<0.0001;3.0%vs.1.8%lumbarspine,p<0.0001).

In patients using alendronate irregularly for a median of 20 months (n=870, age≥55 years), there was a signifi-cantlygreaterincreaseinBMDatallbonesitesfollowingthe transitiontodenosumabcomparedwiththetransitionto rise-dronate(totalfemur2.0%vs.0.5%,neck1.4%vs.0%;spine3.4% vs.1.1%,p<0.0001atallsites).41

Denosumabandbisphosphonatesarebothantiresorptive drugs,buthavedifferentmechanismsofaction.Theydecrease osteoclast activity and survival, but RANKL inhibition by denosumabalsopreventsthedifferentiationofthesecells.42 Furthermore,itispossiblethatboneformationina resorption-independentprocess,known as bone-modeling, persistsat a lesser extentin adultskeletons and is preserved during denosumabtreatment, as it was recentlydemonstrated in cynomolgusmonkeys treatedwithdenosumab.43 _Detection ofendocorticalandperiostealsurfacefluorochromelabeling reflectedcontinuedboneformationatspecificsites,outside thetrabecularcompartment, providingpreclinical evidence forapotentialmechanismthatcouldcontributetotheeffects ofdenosumabinBMDandfracturerisk.43_Thedifferent mech-anismofactionmayberesponsibleforthefurtherincreasein bonemasscausedbydenosumabinpreviousbisphosphonate users.40

However, when BMD was analyzed according to the lengthofprioralendronate use, agreater increase inBMD withdenosumabwasobservedingroupswithshorter alen-dronatetreatmentduration,whichcanbeexplainedbythe filling of the bone remodeling units during the previous antiresorptivetreatment.40_{Thishypothesiscanalsoexplain} the greater BMD gain with teriparatide in treatment-naïve patients.40

Inthiscontext,itisworthnotingthattheseauthorsstudied theeffectofdenosumabinwomenreceivingbisphosphonates foramaximumperiodof4years,while,inourproposal,we intendtojustifytheuseofotherdrugsafter10yearsof bis-phosphonates,whichwesuggestasatherapeuticstrategyfor ourpublichealthreality.Giventhelackoftransitionalstudies aftersuchalongtherapeuticcoursewithbisphosphonates,it isourassumptionthattheswitchtoanotherantiresorptive drugmightnotofferanyadditionalbenefitinthisparticular circumstance.

Unlike the antiresorptive drugs discussed above, teri-paratide, the 1-34 N-terminal fragment of parathyroid hormone (PTH),isananabolic agent(inducerofosteoblast boneformation)whoseintermittentadministrationresultsin theincreaseinthenumberandactivityofosteoblasts, caus-ing rapidbonemassincreaseand improvedtrabecularand corticalarchitecture.44 _{Itistheonlyclassofanabolicdrugs} currentlyusedinthetreatmentofosteoporosis.Itcausesa significantreductionintheriskofvertebral(RR:0.35;CI95% 0.22–0.55)andnon-vertebral(RR:0.47;CI95%0.25–0.88) frac-tures in menopausal women withprior vertebral fractures (n=1637),althoughreductionoffemurfracturehasnotbeen demonstratedsofar.45,46

An importantquestion is whether the prior antiresorp-tivetreatmentmodifiestheanabolicresponsetoteriparatide. Thebenefitsofteriparatideinpatientspreviouslyexposedto antiresorptivedrugsoverlongperiodsoftimeweretestedby someauthors.47–52

Ettinger et al.47 _{studied theeffect of18 monthsof} teri-paratide in women previously treated with raloxifene or alendronateforaperiodof18–36months(EUROFORSstudy,

n=59,age60–87years,T-score≤−2.0).Bothgroupsshowed astatisticallysignificant increaseinboneturnovermarkers (BTM)(P1NP,boneFAandosteocalcin)asearlyastheendof the firstmonthofteriparatide,withatendency forfurther increaseinthegrouppreviouslytreatedwithraloxifene.BMD increaseoccurredearlierinraloxifeneusers,butbytheend oftreatmentBMDincreaseinthelumbarspinewasobserved inbothgroups,again of10.2% forprevioususers of ralox-ifeneandof4.1%forprevioususersofalendronate(p<0.001). However, BMDincreaseintotal femurwas significantonly in previoususers ofraloxifene(0.5% inprevious raloxifene usersand–1.8%inpreviousalendronateusers,p=0.002).The authorsconcludedthatteriparatidestimulatesboneturnover inwomenpreviouslytreatedwithraloxifeneoralendronate for18–36months,althoughpreviousexposuretoalendronate slowsskeletalresponsetoteriparatide.Thisdelayedeffecton BMDandmorelimitedresponseafterprioruseof bisphos-phonatesisprobablyduetotheabsenceoftargetcellsforthe anabolic effectofteriparatide.Afterfewyearsoftreatment withapotentantiresorptive,theextremelylowboneturnover reducestheavailabilityofpre-osteoblasts,osteoblastsand lin-ingcellstobeconvertedintoosteoblasts.35,48

followingitssuspension,comparedtotheinitial6monthsof thistreatment).

In addition, clinical studies examining bone mass by histomorphometry, high-resolution peripheral quantitative computed tomography (HR-pQCT) and finiteelement anal-ysis in HR-pQCT showed that the suppressive effect of bisphosphonatesmaybeoffsetbycontinuedtreatmentwith teriparatide.50–52

Inshort,thesestudiesshoweffectiveanabolicresponseto teriparatideafterprevioustreatmentwithbisphosphonates foranaverageperiodof36months.Again,thereisnoevidence oftheuseofteriparatidefollowingmoreprolongedtreatment withbisphosphonates,asweproposeinourtherapeutic strat-egy.Theremaybegreaterdelayandmorelimitedresponseof BTMandBMD,andclinicaltrialsareneededtoevaluatethis therapeuticscenario.However,giventheavailableevidence, weconsideritacceptabletousedrugswithanaboliceffectin previoususersofantiresorptivesoveraprolongedtimespan that,aftersuchtreatment,persistwithsevereosteoporosis andhighriskoffracture.

Protocol

for

pharmacological

treatment

of

postmenopausal

osteoporosis

in

the

public

health

care

system

Alendronateasfirst-linetreatment

Due to the extensive experience of use, safety and anti-fracture efficacy, bisphosphonates are the mainstay of osteoporosistreatmentandshouldgenerallybeusedasdrugs offirst choice (Fig. 2). Considering the availability of alen-dronateintheBrazilianpublichealthservice,mostpatients with an indication of pharmacological treatment should

receivealendronate,aprioriforaperiodoffiveyears, accord-ingtothepresentedevidence.

Duringtreatment,norandomizedstudyassessedthevalue ofserialbonedensitometryontheriskoffracture,butthistest canbeusefulifusedcorrectly.53_{Therefore,treatment} moni-toringbysequentialBMDassessmentisindicated,withbone massstabilityandabsenceofnewfracturesinmajorbonesites asindicatorsoftherapeuticsuccess.54_Inaddition, demonstra-tionofacross-linktelopeptideoftype1collagen(CTx)decline of25%frombaselinelevelsafter3–6monthsoftreatmentcan beusedasearlyevidenceofinhibitionofboneresorptionand goodtherapeuticresponse.53,54

Following the first 5 years oftreatment, stopping alen-dronate therapy is suitable for most patients and a drug holidayshouldbeconsideredwithreassessmentoffracture risk after 2 or 3 years. However, women with a femoral

T-score≤−2.5shouldhavethistreatmentcontinued, consid-eringtheevidenceofbenefitinthissubgroupofwomenby FLEX study.33 _{Another important consideration is whether} thepatienthadexperiencedpreviousosteoporoticfractures, especiallyinmajorbonesites.Sincesuchfracturesincrease substantiallyfuturefracturerisk,thesepatientsshouldalso havebisphosphonatetreatmentcontinued.Itisworth consid-eringthatthebenefitoutweighstheriskofatypicalfemoral fracturesinthesegroupsofindividuals,aswellasthegreat impactofanosteoporoticfractureonmortality,qualityoflife andcoststothehealthsystem.55_{Duringthisprolonged} treat-mentperiod,drugsuspensionshouldbedeterminedbythe periodicassessmentoftheindividualriskoffragilityfractures. After10yearsusingalendronate,theriskofosteoporotic fracture should be reassessed. In view of the absence of evidence for fracture reduction and safety beyond such a long-termtherapy,maintenanceofbisphosphonatemaynot beappropriate.Then,inlower-riskpatients,adrugholiday

CTx above meana

Oral bisphosphonate for 5 years

CTx below meana

IV bisphosphonate Denosumab Teriparatide

Drug holiday

Continue bisphosphonate for 10 yr

After 10 yr:

Stop bisphosphonate and reassess risk

Drug holiday

Teriparatide

After 5 years: reassess risk

BMD stability or gain BMD loss or new major fracture

Teriparatide Denosumab

- T ≤ −3.5

- T ≤ −2.5 with previous fracture

IV bisphosphonate

Femoral T ≤ –2.5 Previous fragility fractures Low fracture risk:

Low fracture risk

- Age ≥ 65 plus - T ≤ − 4.0 or ≥ 2 pre-existing vertebral fractures

- GFR < 30 mL/min after excluding renal osteodystrophy - Severe esophageous disease

- Pre-existing fracture

Raloxifene

- Isolated spinal osteoporosis and recent menopause

High fracture risk: - T ≤ −3.5

- T ≤ −2.5 with previous fracture

a CTx above or below mean for premenopausal range.

shouldbeconsideredandalendronatediscontinued.However, for the non-negligible percentage of women with persis-tent high risk of fragility fractures, stopping osteoporosis treatmentisnotadvisable.Theoptionsaretocontinue treat-ment with alendronate or switch to another anti-fracture medication.Atthispoint, weproposeadrugwithanabolic mechanismofactionforthesehigh-riskpatientswith persist-ingsevereosteoporosis,althoughtherehavenotbeenstudies evaluatingefficacy ofsuchan approach.Theonlyanabolic drugavailableintheBrazilianmarketisteriparatide,approved forthetreatmentlengthof24months.Becauseofitshighcost and limitedevidence aftersuchaprolonged antiresorptive treatment,wesuggestselectingforitsuseonlythesubgroup ofwomenwithsevereosteoporosisandhigherrisk.

ThedefinitionofsevereosteoporosisbyWHOincludes pre-existingfragilityfractures inthepresenceofT-score≤−2.5. Theriskofanewvertebral fracture isfivetimeshigher in patientswithpriorvertebralfractures.56_Moreover, consider-ingBMDasanimportantdeterminantoffracturerisk,high riskcanalsobearbitrarilydefinedasT≤−3.5score,evenin theabsenceoffractures.46

Patientsrefractorytotreatmentwithalendronate

Somepatientsareconsideredrefractorytothetreatmentwith alendronate,whichmustbeverifiedbyadeclineinBMDin atleasttwoserialBMDmeasurementsoroccurrenceofnew fragilityfracturesinmainbonesites.54_{Insuchcases,reviewof} complianceandasearchforoccultsecondarycausesof osteo-porosisaremandatory.Ifadherencecannotbeimprovedand secondaryosteoporosisisexcluded,switchingtoan alterna-tivetherapyisindicated.54

Mostclinicalpracticeguidelines havenotrecommended themeasurementofBTMinthemanagementofosteoporosis largely because they demonstrate high degrees of pre-analyticalandanalyticalvariability.57_{However,theyprovide} asurrogatemeasureoftherateofboneturnoverand there isgrowingevidencethattheyarepotentiallyusefulin deter-miningfractureriskandresponsetotherapy.57 _Thereisno reference tosupport their measurementto assess fracture riskafterlong-termbisphosphonate,butthisisnotthecase. Consideringthewiderangeofqualityofavailable bisphospho-nateformulationsaswellasthepooradherencetotreatment, serum CTx levels may help to identify patients with high boneturnover,inwhom bisphosphonateisnotexertingits effects.Therefore, duringbisphosphonatetreatment,aCTx drop lower than 25% from baseline or, in the absence of pre-treatment values, a CTx above the mean of the pre-menopausalreferenceinterval areindicativeofactivebone reabsorption.54,58_{Therefore,inthiscaseoftreatmentfailure} alongwithCTxexceedingthelower halfofpremenopausal range,thetransitiontootheranti-resorptivedrugs,zoledronic acidordenosumab,wouldbeindicatedduetofullabsorption andgreateranti-resorptiveeffect.

For patients who failto alendronatedespite adequately suppressedCTx,webelievethat zoledronic acidmight not offerbenefitbasedonitsabsenceofsuperiorityonBMDin womenwithpostmenopausalosteoporosispreviouslytreated with alendronate, although this effect was demonstrated regardless of CTx.37 _{Therefore, in patients with treatment}

failure along with adequately suppressed CTx, we infer that denosumab and teriparatide may represent the most appropriateagents.Onceagain,becauseofthehighcostof teriparatide, the most severe subgroup of women with T -score≤−3.5orT-score≤−2.5withprevious fractureswould alsohaveanindicationforteriparatide.46

AlthoughitisimpracticaltoobtainCTxlevelsroutinelyin thepublichealthsystem,weconsideritsmeasurement specif-icallyincasesoftreatmentfailuremayhelpclinicianinthe decisionofalternativetherapy.

Useofotherdrugsasfirstchoice

Finally,indicationofotherdrugsasfirst-linetreatmentshould alsobeconsideredinsomeclinicalsettings.

Zoledronicacid,owingtoitsgreatefficacyinreducing ver-tebral,non-vertebralandfemoralfractures,aswellasforits ease ofadministration and guaranteed absorption, can be the drug ofchoicein allscenarios wherebisphosphonates areindicated.However,duetoitsunavailabilityinthe pub-lic healthsystem, wecan arbitrarilyreserveit forpatients withcontraindicationfororalbisphosphonates,patientswith moresevereesophagealdiseaseorthosewithpriorfractures forhavingahigherriskofnewfractures.Itisestimatedthat adherence totreatmentwithoralbisphosphonatesislower than40%in1year.59

Denosumab is the only drug indicated for the treat-ment of osteoporosisin patientswith creatinine clearance <30mL/min.However,thecharacterizationofosteoporosisin patients with chronickidney disease is complex,requiring theexclusionofrenalosteodystrophythroughlaboratorytests andoftenbonehistomorphometry.

Raloxifene,aselectiveestrogenreceptormodulatorwith antiresorptivemechanismofaction,discretelyincreasesBMD andreducesby30%theriskofvertebralfractures,notacting onnon-vertebralandfemurfractures.60_{Duetoitslower} effi-cacyinreducingfractures,wesuggestitsuseinwomenwith isolatedspinalosteoporosis,inperimenopausalage.

Finally,giventhefastimprovementinbonemassand archi-tecture seeninresponsetoteriparatide,this drugcouldbe indicated asfirst-line therapy inindividuals atparticularly high-riskforfractures,whichincludesthesamemoresevere subgroupofwomenwithT-score≤−3.5orT-score≤−2.5with pre-existingfractures.

highcost,wearbitrarilyrelocateitsuseasinitialtherapyinthe groupofwomenwithverylowBMDwithoutpreviousfractures tothosewithT-score≤−4.0.

Conclusion

Inconclusion, alendronateisan appropriatefirst-linedrug to be used for a period of five years, with recommended extensionforpatientswithpersistentfemoralT-score≤−2.5 andforthosewithpreviousfragilityfractures.After10years of bisphosphonate treatment, there have not been clini-calstudies evaluatingdifferent approaches.Atthis time, a drugwithanabolicmechanismofactionmaybeappropriate forthe high-riskpatientswithpersistentsevere osteoporo-sis.Furthermore,drugsasdenosumab,zoledronicacid and teriparatideareoptionsincasesofrefractorinesstooral bis-phosphonatesaswellasfirst-linetherapyinspecificclinical settings.

Itisimportanttomentionthatcurrently,inviewofthe limitedevidence,wedonothaveanswerstomanyofour clin-icalquestions,butwetake advantageofthe best scientific knowledgeavailabletoproposecriteriafortherationaluseof pharmacologicaltreatmentofpostmenopausalosteoporosis inthesphereofpublichealth.

Conflicts

of

interest

Theauthorsdeclarenoconflictofinterest.

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