Denosumab Vs Bisphosphonates for the Treatment of Postmenopausal

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European Journal of Endocrinology -18-0056 be carefullyconsideredinanindividualbasis. sites. Inconclusion,bothBPsandDmabaresafeefficient therapeuticoptionsalthoughtheirparticularitiesshould Combination ofteriparatidewithDmaborzoledronicacid,butnotalendronate,providesincreasedBMDgains atall mainly BPs,shouldimmediatelyfollow, althoughtheoptimalsequential treatmentstrategyisyettobedefined. treatment-naïve patients,regardlessoftheconventionalfracturerisk.Incasediscontinuation,othertreatment, and increasestheriskforfractures;therefore,Dmabdiscontinuationshouldbediscouraged,especiallyinpreviously discontinuation. Incontrast,Dmabdiscontinuationfullyandrapidlyreversesitseffects onbonemarkersandBMD from whichtheyareslowlyreleasedduringboneremodeling,thereforecontinuingtoactforyearsaftertheir fractures. Dmabshouldbepreferredinpatientswithimpairedrenalfunction.BPsareembeddedthebone, although theyhavebeencorrelatedtorareadverseevents,suchasosteonecrosisofthejawandatypicalfemoral increases progressivelyforaslongDmabisadministered.BothBPsandaregenerallyconsideredsafe, In long-termadministration,BPsreachaplateauinBMDresponseafter2–3 years,especiallyatthehip,while sites, bothinnaïveandpretreatedpatients.Nosuperiorityonfractureriskreductionhasbeendocumentedso far. achieves greatersuppressionofboneturnoverandincreasesmineraldensity(BMD)atallskeletal denosumab (Dmab).Bothareantiresorptives,thustargetingtheosteoclastandinhibitingboneresorption.Dmab The mostwidelyusedmedicationsforthetreatmentofosteoporosisarecurrentlybisphosphonates(BPs)and Abstract *(A DAnastasilakis,SAPolyzosandPMakrascontributedequallytothiswork) Endocrinology andDiabetes,251HellenicAirForce&VA GeneralHospital,Athens,Greece Pharmacology, MedicalSchool,AristotleUniversityofThessaloniki,Greece,and 1 Athanasios D Anastasilakis treatment ofpostmenopausalosteoporosis Denosumab vsbisphosphonatesforthe THERAPY OFENDOCRINEDISEASE Department ofEndocrinology, 424GeneralMilitaryHospital,Thessaloniki,Greece, https://doi.org/ www.ej Review Review and expertise gestational diabetesandespecially metabolicbonediseases,whichrepresenthismain areaoffocus alongside abusyclinicalschedule. Hehaspublishedextensivelyintheareasofthyroid, metabolism, Thessaloniki, NorthernGreece whereheconductsseveralclinicallyorientedresearch projects Athanasios Anastasilakis Invited Author’s profile e-online.org 10.1530/EJE . -18-0056 1

is a consultant of Endocrinology at 424 General Military Hospital in is aconsultant of Endocrinologyat424 General Military 1 © , 2018EuropeanSociety ofEndocrinology *, Stergios A Polyzos S APolyzosandPMakras A DAnastasilakis, Printed inGreatBritain 2 , * and Polyzois Makras osteoporosis Dmab vsbisphosphonatesin Published byBioscientifica Ltd. 2 First Departmentof 3 Department of 3 , * Downloaded fromBioscientifica.com at09/26/202111:03:56PM (2018) Endocrinology European Journal of [email protected] Email to ADAnastasilakis should beaddressed Correspondence 179

179 :1 , R31–R45

R31 –R45 via freeaccess European Journal of Endocrinology www.eje-online.org suitable forclinicaluse( degradation, havearetained activity, andtherefore,are resulting intheformationof BPs,whichresistbiological P-O-P bindingofpyrophosphate isreplacedbyacarbon on calcification( effect of pyrophosphates advantage of theinhibitory search forpyrophosphateanalogs,inanattempttotake The BPsaresyntheticcompoundsdiscoveredduringthe Bisphosphonates treatment modalitiesandthedifferencesbetweenthem. of thesetwomostcommonlyusedantiosteoporotic higher cost. osteoporosis market year by year, despite its considerably Dmab hasgraduallygainedgroundoverBPsinthe and initiatedanewerainourattempttotreatthedisease. sophisticated, biological agents targeting the osteoclast ofmore of osteoclasts, has introduceda new category (RANKL), thus inhibiting theformation and activity binds thereceptoractivatorofnuclearfactor decade, denosumab(Dmab),amonoclonalantibodythat main representativeofthiscategory. Duringthelast wellforseveraldecadesasthe (BPs) havebeenserving cornerstone ofosteoporosistreatment.Bisphosphonates bone resorption rate. Antiresorptives are currentlythe osteoporosis istotargettheosteoclast,thusreducing than important. prolonged periodswithbothefficacyandsafetyismore for antiosteoporotic agents that can be administered for expected to continuously grow ( respective economic burden to the health care systems are of osteoporoticfracturesinthenextdecadesand and continuestorise,theprojectionsofwomenatrisk years women inWestern countriesiscurrentlyover80 advancing withaging( significant proportionofpostmenopausalwomenand is themostcommonformofosteoporosis,affectinga to low-energyfractures.Postmenopausalosteoporosis and attenuationofbonestrength,thereforepredisposing the osteoblasts,resultingingraduallossofbonemass osteoclasts thatexceedstherateofboneformationby a relativelyincreasedrateofboneresorptionbythe is causedbyanimbalanceinboneturnover, namely Osteoporosis isthemostcommonskeletaldisease.It Introduction Review In thisreview, wesummarizetheparticularities A commonandeffectivetreatmentstrategyin 2 ). Theoxygenatomthatprovides the 1 ). Giventhatlifeexpectancyfor 2 ). Theadditionalsidechains S APolyzosandPMakras A DAnastasilakis, 1 ). Therefore, the need κ - Β ligand Extension) study( TrialIn theFLEX(Fracture Intervention Long-term ( turnover stateremainsthroughoutthetreatmentperiod treatment with oral BPs and faster with iv ones. This lower monthsof turnover equilibriumisreachedafter3–6 Following BPs’administration,anewreducedbone Efficacy osteoclasts andinhibitionofboneresorption( leads toeitherinactivationorincreasedapoptosisofthe intracellular mevalonatepathway;thiseffecteventually be internalizedbytheactiveosteoclastsandinhibit especially withintheresorptionlacunaewheretheycould to bindhydroxyapatiteatthesurfaceofboneand effects ( in several chemical molecules with different biological of action (R2), while differences in these chains result (R1)andtheirpotencymechanism calcium crystals of the BPs, namely R1 and R2, enhance their affinity for and concomitantlyimproves patients’adherence( same pharmacodynamicsprofile withthedailytreatment dose of70 reduction ofhipfractures( the riskofnon-vertebralfractures(non-VFs)anda53% ALN 10 vertebral fractures(VFs)isreducedsignificantlywithdaily years ( continues to increase up to 10 (FN) BMDismaintained,whilelumbarspine(LS) years,femoralneck treatment iscontinuedbeyond5 BMD atbothtrabecularandcorticalskeletalsites.When at slightlydifferentlevels( adequately suppressboneremodeling,althoughprobably ibandronate (IBN)andzoledronicacid(ZOL).Theyall (N-BPs) and include alendronate (ALN), risedronate (RIS), postmenopausal osteoporosisarenitrogencontaining the notfullysuppressedboneremodeling( irrespective ofBPstreatmentandtheboneremovedby the new bone formed through the modeling process this isprobablythenewequilibriumestablishedbetween especially atthehip( plateau effect in BMDresponseafter 2–3 years oftreatment, however, aconsistentfindinginalllong-termtrialsis patients withhighbaselineboneremodelingrates; inhibition, andgreatergainsinBMDareexpectedamong of BPsisdirectlyrelatedwiththelevelboneremodeling improvement anddecreasedfracturerisk( osteoporosis Dmab vsbisphosphonatesin 3 ), andeventually leads to bone mineral density (BMD) ALN isapotentantiresorptiveagentthatincreases All currentlyapprovedBPsforthetreatmentof mg ( 2 ). ThecornerstoneofBPs’actionistheirability mg, currently used in every daypractice,hasthe mg, currentlyusedinevery 8 , 9 ) alongwithanoverall23%reductionof 4 ), the5-yearextensionof pivotal 4 , Downloaded fromBioscientifica.com at09/26/202111:03:56PM 5 Table 1 ). Apotentialexplanationfor 9 ). Thecollectiveonce-weekly ). 179 :1 7 2 ). The risk of 6 ). Thepotency ). Fig. 1 ). R32 10 via freeaccess ). European Journal of Endocrinology After treatingpostmenopausal womenwithRISforamean cumulative doseeitherina weekly ormonthlybasis( has longbeenreplacedwith theadministrationof Similarly withALN,theinconvenient dailyRISdose doses (70vs35 turnover inhibitionoreventothedifferenceinapproved a findingpossiblyattributedtothedifferenceinbone although atalessermagnitudecomparedwithALN, significant reductionintheriskofnon-VFs( within the osteoporotic range, and no VFs can exhibit a postmenopausalwomenwithaFNBMD up to10 years: patients whomaybenefitfromthecontinuationofALN hoc who stoppedALNafterthefirst5 years. Amorerecent yearscomparedtothose patients receivingALNfor10 risk of55%wasfoundsolelyfortheclinicalVFsamong TrialFracture Intervention ( RANK ligand. N-BPs, nitrogencontainingbisphosphonates;OPG,osteoprotegerin;RANK,receptoractivatorofnuclearfactor acid 1-adenosin-5 thereby impairedosteoclastfunctionandpossiblyapoptosis.Thus,boneresorptionisinhibited.Apppl,triphosphori c This leadstoimpairedintracellularproteinpregnylationandaccumulationofcytotoxicintermediateproducts,including Apppl, possibly throughendocytosis.Subsequently, N-BPsinhibittheFPPsynthase,akeyenzymeofmevalonatesignalingpathway. inhibition ofboneresorption.N-BPsactonosteoclasts,butnottheirprecursors.areinternalizedintotheosteoclas ts osteoclast precursordifferentiation, impairedosteoclastfunctionandpossiblyapoptosis.Alltheseeffects leadtothe osteoclasts, butalsoonosteoclastprecursors.Subsequently, RANKsignalingpathwayisnotactivated,resultinginimpaired decoy receptorofRANKL;DmabbindsRANKL,therebydeterringRANKLbindingonitsreceptor, RANK,onthesurfaceof A summaryofthedifferent mechanismsofactionDmabandN-BPs.DenosumabactssimilarlytoOPG,whichisthenatural Figure 1 Review analysisoftheFLEXstudyidentifiedasubgroup RIS increases significantly BMD atall skeletal sites, mg/week) betweenthetwo BPs( ʹ -yl ester3-(3-methylbut-3-enyl)ester;FPP, farnesyldiphosphate;HMG-CoA,3-hydroxy-3-methylglutaryl-CoA; 11 ), asignificantlylower S APolyzosandPMakras A DAnastasilakis, 12 ). 13 , 15 14 post ). ). the riskofnewmorphometric VFsby62%vsplacebo,but IBN (2.5 factors regardingtheresponse totreatment( areimportant suggest thatbothdoseanddosing intervals incidence ofthe7-yearRISgroup( years 6–7,similarwiththecorrespondingunchanged exhibited asignificantreductioninVFsincidenceduring previously on placebo, who received RIS for only 2 years, ( oftreatmentwhereaplaceboarmwasavailable years 4–5 risk (RR)reductionof59%forradiographicVFswithin study population( participants andprobablynotrepresentativeofthecore areavailable, however,to 7 years withasmallnumberof 20% andofhipfracturesby26%.Long-termstudiesup along withanoverallreductionoftherisknon-VFsby period of5 years, theriskofVFsisreducedby36–39%( osteoporosis Dmab vsbisphosphonatesin 18 ), whereasintheadditional2-yearextension,patients IBN isanothercommonly usedN-BP. IBNstudies mg) administeredfor3 years significantlyreduced 17 ). Inspecific,RISresultedinarelative Downloaded fromBioscientifica.com at09/26/202111:03:56PM 19 ). 179 www.eje-online.org :1 κ - Β ; RANKL, 2 ). Dailyoral R33 16 via freeaccess ), European Journal of Endocrinology www.eje-online.org AFF, atypicalfemoralfractures;BMD,bonemineraldensity;non-VFx,non-vertebralfracture;ONJ,osteonecrosisofthejaw;VFx,vertebralfracture. atrial fibrillationinaverysmallproportionofpatientsreceivingZolendronicacid. ( Cost (annual) patients withatotalhip(TH) orFNBMD VFs was found. A subsequent years, asignificantlylower riskofonlymorphometric Among the patients who received ZOL for six consecutive years( yearsorswitchtoplacebofor thenext3 3 HORIZON trialtoeithercontinuetreatmentforanother the ZOLextensiontrialrandomizedpatientsof Acid OnceYearly) study( Outcomes andReducedIncidencewithZolendronic hip fracturesby41%atthe3-yearcoreHORIZON(Health of treatmentandtheincidencenon-VFsby25% the incidenceofVFsby70%alreadyfromfirstyear sites rangingfrom5.1to6.7%,ZOLsignificantlyreduced of osteoporosis.BesidesanincreaseBMDatallskeletal as anivinfusionof5 endpoints, andtherewerenoplaceboarms( were analyzedasadverseevents(AEs)ratherthanstudy be drawnfromtheIBNextensionstudies,asfractures treatment ( IBN long-termtrialslastedupto5consecutiveyearsof and reduced the risk of non-VFsby 38% ( (3 3 months or ivevery doses administered either once monthly orally (150 in was onlyfoundamongpatientswithaFNBMD ZOL. Asignificant69%reductionintheriskofnon-VFs study, afindingthatdifferentiatesIBNfromALN,RISand no reductionofhipfractureswasfoundintheregistration Other AFF ONJ Safety–adverse effects Non-VFx VFx BMD Residual effect (1 yearafterdiscontinuation) Treatment duration Non-VFx VFx BMD Efficacy postmenopausal osteoporosis. Table 1 ↑ ), increased;( Bone markers Bone markers Review post hoc ZOL isthemostpotentN-BP, anditisadministered Schematic synopsisoftheadvantages/disadvantagesdenosumabvsbisphosphonatesfortreatment 5 analyses( ↓ , ), decreased;( 24 ). Unfortunately, solid conclusions cannot mg onceayearforthetreatment 20 − ), unchanged;(+),possibility;(*),multipleVFxinaminorityofpatientsfollowingdiscontinuationDenosumab;(**), mg) significantlyincreasedBMD ++ +* + + Return tobaseline* Return tobaseline ↓ ↑ Up to10 years ↓ ↓ ↑ ↓ ). However, highercumulative Denosumab 25 ↓ ↑ ↓ ↓ ↑ ↓ ↓ ↑ ↑ ↓ ). SimilartotheFLEXstudy, post hoc S APolyzosandPMakras A DAnastasilakis, analysis found that ≤ 17 + − + + Return tobaseline ↓ − ↓ Up to10 years ↓ ↓ ↑ ↓ 21 Alendronate − ↓ ↓ ↓ ↑ ↓ 2.5 and/or ). , 22 < , − mg) 26 23 3.0 ). ). and declinesfollowingdiscontinuation ( prolonged BPuse( 50 cases/100,000 patient-years, which is doubled with treated with BPfor osteoporosis ranges between 3.2 and BP treatment.Theabsolute riskforAFFamongpatients data regardingtheincidenceofONJaftercessation of general population( patient-years, afiguremarginallyhigherthanthatofthe osteoporosis isestimatedbetween1/10,000and1/100,000 and itsincidenceamongpatientstreatedwithBPsfor fractures (AFF). The pathogenesis of ONJ is still unclear osteonecrosis of the jaw (ONJ) and atypical femoral include tworarebutclinicallyseriousAEs,namely years ofN-BPtreatment( evenafterseveral skeleton torenewitselfispreserved of boneremodeling( have beenconcerns regarding the long-term suppression gastrointestinal irritationandnephrotoxicity, there Besides theearlyrecognitionofAEs,suchasupper Safety benefits ( withapparentmaintenance of least forthenext3 years, almost allpatientscanstopZOLaftersixinfusions,at 6 vs 9 consecutive years of ZOL treatment concluded that ( for 6 years treatment would benefit from the continuation of ZOL of an incidentmorphometricVFduringthefirst3 years osteoporosis Dmab vsbisphosphonatesin + − + + Return tobaseline ↓ ↓ Return tobaseline Up to7 years ↓ ↓ ↑ ↓ Risedronate ↓ ↓ 28 ). 27 Bisphosphonates ). Asecondextensiontrialthatcompared > + − + + Return tobaseline Return tobaseline ↓ Return tobaseline Up to5 years ↓ ↓ ↑ ↓ yas eindrto,7 years), years,medianduration,7 3 Ibandronate 29 ↓ 2 , , Downloaded fromBioscientifica.com at09/26/202111:03:56PM 29 32 30 ), althoughtheabilityof ). Uptonow, thereareno , 31 ). Thesesafetyconcerns 179 + +** + + Return tobaseline ↓ − ↓ Up to9 years ↓ ↓ ↑ ↓ Zolendronic acid ↓ ↓ ↓ ↓ ↑ ↓ :1 29 , 33 ). R34 via freeaccess European Journal of Endocrinology recent, rathersmall,cohort ofpatientsreceivingvarious 41 VF fracturerisk,followingdiscontinuation ofRIS( decrease or maintenance of BMD, although with a stable BMD decreaseaftercessation ofIBN( and frompreviouslyreporteddata( pharmacokinetics and pathophysiological point of view the discontinuationofIBNorRIS.However, froma the residualeffectsonBMDandfractureriskfollowing and inadouble-blindedplacebo-controlledmanner been specificallydesignedtoinvestigateprospectively following ZOL discontinuation ( clinical VFs,non-VFsandhipfracturesatleastfor3 years oflowerfractureriskfor preservation for theobserved The residualbenefitsofZOLinBMDprobablyaccount followingdiscontinuation ( in theLSwereobserved ZOL: anetlossofonly0.8%intheFNand1.2%gain ALN, aresidualBMDeffecthasalsobeenreportedwith in alltheextensiontrialsofALN( lack ofanincreasedrisknon-VFsormorphometricVFs stabilizes thereafter( yearsfollowingtreatment’s cessationand during 1–2 majority ofpatients,whileFNBMDdecreasesmodestly BMD evenafterthediscontinuationoftreatmentin probably thereasonformarginalfluctuationofLS betweensubjectsandmolecules. substantially vary both beneficialandadverseeffects,althoughitmay ( years elimination fromtheskeletoncanbeupto8–10 to remodeling;interestingly, thehalf-timeoftheir released whenevertheirburialsiteisagainsubjected inactive stateforalongtimeandcanpotentiallybe their initial binding, they remain in a pharmacologically In specific,astheyareembeddedinboneatthesiteof continue toactforyearsfollowingtheirdiscontinuation. medications used for chronic diseases, is that they could The majordifferenceofBPs,probablywithalltheother Residual effect considered weak( association between oral BP use and atrial fibrillation is findings werenotreplicatedinotherstudies( treatment groupandtheplacebo.Furthermore,these fibrillation did not differ significantly between the ZOL corestudy( fibrillation (1.5 vs 0.3%, significantly higher incidenceof serious AEs of atrial 36 Review ) seemsrationalatleastfor thefollowingyears.Ina ), and this slow release is definitely the reason for Regarding ALN, retention within the skeleton is Finally andregardingcardiovascularsafety, a 25 35 ), althoughtheoverallratesofatrial ). 7 ). Thisisprobablythecasefor P

0.001) was reported in the S APolyzosandPMakras A DAnastasilakis, 26 4 , 39 ). No studies have 37 39 , , , 40 40 38 , ), andaslight ). Similarlyto 41 ), amodest 34 39 ). The , 26 40 ). , recombinant OPGorRANKmolecules( is considerablylongerthanthatofpreviouslytested results insuppressionofboneresorption( other metabolic bone diseases ( the RANKL/OPGratioisassociatedwithosteoporosisand is thenaturalantagonistofRANKL( RANKL thatbindsit,thusintercepting RANKactivation, ( survival which promotestheirdifferentiation,functionand RANK, onthesurfaceofosteoclastsandtheirprecursors, ( binds andinhibitsRANKLwithhighspecificityaffinity Dmab isafullyhumanmonoclonalIgG2antibodythat Denosumab increase oftheriskclinicalfractures( BPs asfirst-linetreatment,drugholidaysresultedin was found.BMDincreased progressively, reachingan 20% andhipfracturesby40% comparedwithplacebo treatment, areducedRRfor VFsby68%,non-VFs months of efficacy atallskeletalsites tested.At36 6 Months) trial ( Every REduction EvaluationofDenosumabinOsteoporosis suppression, thephase3pivotalFREEDOM(Fracture increase atallsitesandboneturnovermarkers(BTM) proved theefficacyofDmabinhumanstermsBMD the persistencetotreatment( position for long or impaired memory, and it increases with polypharmacy, inabilitytoremaininan upright renders theagentappealing,especiallyforolderpatients Thisintermittent wayofadministration 6 months. every approved doseof60 ( months hormone (PTH),especiallyduringthefirst1–2 calcium levels,causinganincreaseofserumparathyroid bone remodeling results in transient reduction of serum antiresorptive agentforexampletheBPs,decreaseof following injection ( months formation markers decrease by 55–75% at 2–3 andthengraduallybegintorise,whilebone 6 months, month and remaining suppressed for the subsequent 1 ( reduced rapidly(withinthefirst12 Following Dmabinjection,boneresorptionmarkersare Efficacy osteoporosis Dmab vsbisphosphonatesin 43 47 > 80% frombaseline),reachinganadiratabout ). RANKLisessentialfortheactivationofitsreceptor, , Following thephase1( 50 ). Basedonitspharmacokinetics,Dmabatthe 44 ). Osteoprotegerin(OPG),asolublereceptorof mg isadministeredsubcutaneously 47 , Downloaded fromBioscientifica.com at09/26/202111:03:56PM 49 52 47 ). As with any other potent 51 ) proved its anti-fracture ) and2( 45 ). ). Dmab administration Fig. 1 179 h) andprofoundly 49 47 www.eje-online.org 42 :1 ) studies,which , ). ). Imbalanceof 48 ). 46 ), which R35 via freeaccess European Journal of Endocrinology www.eje-online.org ones, while13positivelyadjudicated casesofONJwere diaphyseal femoralfractures wereadjudicatedasatypical extension, twooutofthe ninesubtrochantericor ONJ), dataarealsoreassuring. BytheendofFREEDOM (hypocalcemia, AFF, impairedfracturehealingand long term. increased incidenceofsuchAEsneithershorttermnor ( tract infections,etc.)( malignancies, cellulitis,eczema,pancreatitis,urinary tissue specificity(increasedriskofseriousinfections, suggestsanacceptablesafety profile. surveillance clinical trialsandthemorethan7 years ofpost-marketing yearsofcontinuousadministrationDmabin to 10 In general,theinformationaccumulatedfromup Safety of Dmabinpatientstransitioningfromotheragents. date, therearenodataregardingtheanti-fracture efficacy despite thesimilarreductionofBTM( patients treatedwithDmab,althoughstillsignificant, Dmab weremoremodestcomparedtotreatment-naïve agents, mostcommonlyBPs,theincreasesinBMDwith studies evaluatingpatientspreviouslytreatedwithother months( have beenoff-treatmentforatleast12 trial weretreatmentnaïveandthosewhonotshould continuous BMDincreasewithDmabtreatment( remodeling hasbeenproposedtoberesponsibleforthis removal throughanalmostcompletelysuppressedbone the modeling-basedboneaccrualandminimal a plateau.Afavoringboneformationimbalancebetween as long as the treatment is continued without reaching one-third radius, suggesting a gradual increase of BMD for 21.7% at the LS, 9.2% at TH, 9.0% at FN and 2.7% at the the cumulative BMD increase from baseline reached of Dmab, placebo cohort. At the completion of 10 years yearsandlowerthanthatinavirtuallong-term first 3 intheactivetreatmentgroupduring to ratesobserved remained consistentlylowthroughoutthestudy, similar in increased fragility. In theopposite, fracture rates Prolonged reductionofboneremodelingdidnotresult of thepatients(33.6%)completedextensionstudy. ( receiving Dmab for up to 10 years compared toplacebo. overall increaseof9.2%attheLSand6.0%TH 53 Review ) and everyday clinicalpractice( ) andeveryday Regarding AEsrelatedtoboneremodelingsuppression Despite theinitialconcernsrelatedtosuboptimal The majorityofpatientsparticipatingintheFREEDOM The FREEDOMtrialwasextendedtofollowpatients 57 ) datafromboththeclinicaltrials S APolyzosandPMakras A DAnastasilakis, 58 53 30 ) donotsuggestan ). About one-third , 54 , 55 , 56 6 ). Upto 52 , 53 ). In ). effect onfracture risk reductionisnotassociated withthe filtration rate(GFR)aslow15 a broad range of subjects with estimated glomerular impaired renalfunction.Furthermore,itiseffectiveacross medications isthatitrelativelysafeinpatientswith which occurredthefirstdayofDmabdose( five reportsofmedicallyconfirmedanaphylaxis,most patients hadchronickidneydisease.Finally, therewere responded tocalcium/vitaminD,whilesevenoutofeight daysofDmabadministrationand occurred within30 symptomatic hypocalcemiawereincluded;mostevents and olderage.Inthesamereport,eightcasesofsevere and/or BPuse,chemotherapy, invasivedentalprocedures included atleastoneofthefollowing:priorglucocorticoid adjudicated cases of ONJ were reported ( all amongpatientswithprevioususeofBPs,and32 data,fouradjudicatedcasesofAFFs, safety surveillance also reported( FREEDOM study or its extension, despite the very short FREEDOM studyoritsextension, despitethevery ( have beenreportedinabout 10%ofthetreatedpatients range atthetimeofdiscontinuation ( and BMD valueswithinthe osteopenic orevennormal at ‘lowrisk’intermsofabsencepreviousfractures VFs inasubsetofpatients,eveniftheyareconsidered with increasedfragilitymanifestedasmultipleclinical efficacy, Dmabdiscontinuationseemsto be associated treatment ( of BMD decreasemay be linked to the duration of Dmab another yearofDmabre-institution( of Dmabtreatmentmaybecompletelyrestoredinjust period of just 1 year, the BMD gains achieved after 4 years 63 off-treatment( original baselinevaluesafter1–2 years last dose. BMD gains are also lost and BMD values reach afterthe again baselinelevelsapproximately30 months andremainelevateduntilreaching baseline at3 months BTMriseabove a reboundofboneturnoverisobserved; its effectsonBTMandBMD.Infact,upondiscontinuation, Dmab discontinuationseemstofullyandrapidlyreverse Residual effect treated withDmab. of serumCaiswarrantedinpatientswithrenalfailure on dialysis( of hypocalcemiainpatientswithsevererenaldeficiencyor level ofrenalfunction;however, thereisanelevatedrisk osteoporosis Dmab vsbisphosphonatesin 64 , , 64 An advantageofDmaboverotherantiosteoporotic Regarding thesustainabilityofitsanti-fracture 65 , ). Inpatientswhodiscontinued Dmabduringthe 65 ). Ofinterest,althoughlostduringawashout 66 60 ). , 53 61 ). Inearlierannouncedpost-marketing ). Therefore, early and closer monitoring Downloaded fromBioscientifica.com at09/26/202111:03:56PM mL/min ( 179 63 ). Themagnitude 67 :1 58 ). Suchevents ). Risk factors 59 ), andits R36 58 62 ). via freeaccess , European Journal of Endocrinology femoral neck;IBN,ibandronate;LS, lumbar spine;NA,notavailable;RIS,risedronate;TH,totalhip;ZOL,zoledronic acid. ALN, alendronate;approx,approximately; BMD,bonemineraldensity;BTM,turnovermarkers;BPs,bisphosphonates; Dmab,denosumab;FN, † ( ( ( ( ( Study with postmenopausalosteoporosis,asderivedfromrandomized controlledtrials. Table 2 higher increases in both LS and TH BMD after 12 months which theformerachievedgreaterBTMreductionand to-head comparisonstudybetweenDmabandALNin In treatment-naïvepatients,thereisonlyonehead- Studies directly comparingDmabtoBPs treatment ( should notbestoppedwithoutconsideringalternative 74 importance of not omitting or delaying Dmab doses ( Dmab injection effect was depleted, highlighting the monthsafterthelast as suchweredescribed2–10 limitations ( cautiously interpretedasithadseveralmethodological questioned ( role ofpriorexposuretoBPs( following discontinuation ( Dmab for longer periods ( treatment beforeDmabinitiation( are prevalentVFs( ( located atthelowerthoracicandupperlumbarspine ( is theupregulationofosteoclastformationandactivity with placebo( higher amongthosewhodiscontinuedDmabcompared subjects, whiletheriskformultipleVFswassignificantly treatment periodto7.1,avaluesimilarplacebo-treated rate increasedfrom1.2per100patient-yearsduringthe thatcouldunderestimatetherisk( 2–6 months) yearse.g. off-treatment meanfollow-upperiod(0.2–0.5 At thestageofrandomization;*Statistically significantbetweengroups. 78 77 56 55 30 67 70 Review ). Givenalltheabove,ithasbecomeclearthatDmab ) ) ) ) ) ), whilefactorspredisposingpatientstoahigherrisk ). Thelocationofthefracturesistypicallyosteoporotic,

From oralBPsto From ZOLtoDmabor From ALNtoDmabor From oralBPsto From ALNtoDmabor Comparison Dmab orZOL(1 year) ZOL (1 year) RIS (1 year) Dmab orIBN(1 year) ALN (1 year) The effect ofswitchingfromBPstodenosumaborcontinuingonthesameotherBPBMDandBTMinwomen 75 73 72 ). 69 ). Itisofclinicalsignificancethatfractures ); however, the latter study should be ). Aproposedmechanismforthiseffect (duration) 67 , 69 67 ), lackofotherosteoporotic 69 321 vs322 34 vs30 435 vs 417 vs416 253 vs251 (Dmab vsBP) ) and greater hip BMD loss Number ). The suggested preventive 67 S APolyzosandPMakras A DAnastasilakis,

, 67 71 † ), administrationof ) hasbeenrecently

3.2 vs1.1* 4.5 vs4.4 3.4 vs1.1* 4.1 vs2.0* 3.0 vs1.9* (Dmab vsBP) change % LS BMD

68 1.9 vs0.6* NA 2.0 vs0.5* 2.3 vs1.1* 1.9 vs1.1* (Dmab vsBP) ), VF change % TH BMD 67 , patients previouslytreatedwithBPs( Dmab withpracticallyallcommercially availableBPsin of treatment( on corticalsitesisthat,asBPsaremainlyattached A proposedexplanationforthesuperioreffectsofDmab compared toALN,RIS,IBN(perosoriv)andZOL( months accrual bothinLSandTHat12,2436 analysis,DmabachievedgreaterBMDan exploratory minodronate) ( and decreasedBTMsmorethanoralBPs(ALN,RIS teriparatide (TPTD),DmabincreasedLS,THandFNBMD randomized studyinpatientspreviouslytreatedwith ( ( was superiortoALN( surrogate markerofeachagent’s efficacy. Inbrief,Dmab comparisons referred to BMD and BTM changesasa small numberofpatientsincludedinallthesestudies, Given theshortduration(12 months) andtherelatively and satisfaction( ALN favoredtheformerintermsoftreatmentpreference treatment, acomparisonbetweenDmabandonce-weekly end point. orasecondary Dmab andBPs,atleastasaprimary are no data comparing fracture risk reduction between in theaccessibilityofbonecortex( level comparable with Dmab, due to their difference BPs maynotinhibitcorticalboneremodelingata around 80% of total bone remodeling ( than corticalbone,astheformerskeletalsitesharbor are morelikelytobesequesteredintrabecularrather to bonesurfaceswithactiveremodeling,they

osteoporosis Dmab vsbisphosphonatesin al 2 Table 77 1.2 vs NA 1.4 vs0.0* 1.7 vs0.7* 1.4 vs0.4*(approx) FN BMDchange% , Regarding adherence,complianceandpersistenceto 78 (Dmab vsBP) ) intermsofBMDaccrualandBTMsuppression − ). Similarly, inan1-year, head-to-head,non- 0.1*

76 79 82 ). Thereareseveralstudiescomparing ). Inaccordancewithalltheabove,in ). 0.6 vs0.0* NA NA NA 0.8 vs0.1*(approx) Radius BMDchange % 30 Downloaded fromBioscientifica.com at09/26/202111:03:56PM (Dmab vsBP) ), RIS(

56 ), IBN( 179 81 30 Greater withDmab Greater withDmab Greater withDmab Greater withDmab Greater withDmab Suppression ofBTMs www.eje-online.org ). Notably, there :1 , 55 6 55 ). Therefore, , 56 ) andZOL , 77 R37 , 80 78 via freeaccess ). ). ).

European Journal of Endocrinology www.eje-online.org of Dmabtreatmentmaintained BMDatLS,THandFN experts ( BPs, eitherorallyorintravenously areproposedbymost optimal post-Dmabtreatment iscurrentlyunknown, medication regardlessofthe fracturerisk( to beimmediatelyfollowedbyanotherantiosteoporotic ( theirbenefitsafter discontinuation partly preserve retained intheskeletonforlongandtherefore,atleast toBPswhich,asalreadymentioned, are Contrary Transitioning from DmabtoBPs treatment ( between respondersandnon-responderstopreviousBP ( pretreated withBPscomparedtotreatment-naïvepatients BTMs, despitethelowerbaselinelevelsinpatients Dmab administrationresultsinsimilarlysuppressed on BPsaresummarizedin investigating theefficacyofDmabinwomenpreviously medications (e.g.glucocorticoids))( tochronicdiseasesor or inosteoporosissecondary or morenewlow-energyfracturewhileon-treatment, osteoporotic fracture, or patients who experienceone fracture risk score, or in patients with previous major (hip BMDT-score remains onBPs holiday isnotconsideredsafefollowing3–5 years Dmab isareasonablesequentialtreatmentwhendrug Transitioning from BPstoDmab focus onrandomizedcontrolledtrials(RCTs). on-treatment sequencewillbesummarized,withaspecial this section,clinicalevidenceregardingBPsandDmab is requiredorwhenalesscostlyregimendesirable.In or whenbettercomplianceandpersistencetotreatment treatment isneededwhenapatientexperiencesanAE treatment isoftenconsidered.Additionally, sequential adequately studied duration, a sequential antiosteoporotic the administeredmedicationreachesitsmaximum bias. Giventhatosteoporosisisachronicdisease,when rates, therebybeingunderpoweredandpronetoselection extensions are usuallyopen label and have high withdrawal priori partly owingtothefactthatclinicaltrialsarenot and safetyofexistingantiosteoporoticmedications, There isuncertaintyaboutthelong-termeffectiveness Sequential treatment 86 54 Review , , 87 specifically designed for their extensions, and the 84 ), Dmabdiscontinuationishighlyrecommended , 75 85 ). ALNadministeredfor1 year following1 year 84 ). BMDincreaseswithDmabweresimilar ). al 2 Table < − 2.5, orthereisstillhigh S APolyzosandPMakras A DAnastasilakis, . Itisofinterestthat 29 75 , ). Although 83 ). RCTs a

treated withBPsorDmab. be carefully considered in high-risk patients previously effect onfracturerisk,sequential useofTPTDshould on theseconsiderations,until moredataelucidatethe decrease isminorand/ortransient withDmab( LS BMD,doesnotdeclinewithBPs( among antiosteoporoticmedications( the highesthipandnon-vertebralfractureriskreduction support ofthelatter, inanetworkmeta-analysisTPTDhad will ultimatelyimprovecorticalbonestrength( periosteal boneaccretionduringTPTDtreatment,which bone dimensions ensuing from increased endosteal and or Dmabtreatmentitisduetoanincreaseincortical is translatedinhigherfractureriskwhenTPTDfollowsBP However, it remains unknown whether this BMD decline above studiesweresmallandofshortduration,therefore, or werepromptlyswitchedtoBPs( were maintainedonlyinpatientsthatcontinuedDmab ofDmabtreatment BMD increasesachievedafter4 years achieved withDmab( uptake resultinginimprovedretentionoftheboneaccrual administration ofivBPsmightincreasetheirskeletal of thegainsatTH.Authorsproposedthatdelaying retention oftheBMDgainsatLSand87% 2 months afterthedepletionofDmabeffectachieved73% on romosozumaborplacebo( year yearwithDmabafter1 in patientstreatedfor1 2.5 years ( the LS and TH achieved with Dmab during the following infusion maintained around 60% ofthe BMD gains at withDmab,asingleZOL in patientstreatedfor2.5 years loss attheLSbutnotTH( yearswithDmabpartiallypreventedbone treated for7 ( from ALN, or RIS, or Dmab to TPTD ( monthsafterswitching below baselineforatleast12 and strength( treatment, asitcouldresultinatransientlossofhipBMD might notbetheoptimalsequenceofantiosteoporotic is common in non-responders to antiresorptives, this Although theuseofPTHanalogs,forexample,TPTD Sequential treatment combination withBPsorDmab Osteoanabolic medicationsbefore, afterorin remains currentlyunknown( strategy tohandlebonelossafterDmabdiscontinuation definite conclusionscannotbedrawn.Thus,theoptimal osteoporosis Dmab vsbisphosphonatesin 82 ). AsingleinfusionofZOLinafewpatientspreviously 89 ). Somewhat better results were reported 92 ). Morespecifically, hipBMDdeclines 90 Downloaded fromBioscientifica.com at09/26/202111:03:56PM ). IntheDATA follow-upstudy, 75 88 90 ). ) whileinanotherstudy, ). ZOLinfusedaround 91 179 31 ). However, allthe 31 98 :1 , , 93 ). Incontrast, 95 , ), whilethe 94 96 , 95 ). Based 97 R38 , ). In 96 via freeaccess ). European Journal of Endocrinology not statistically significant, were observed inanother not statisticallysignificant, wereobserved ( 2.8% attheFNand2.2,2.1 and at theLS,6.3,3.2and2.0% attheTH,6.8,4.1and monotherapy, respectively, were 12.9, 8.3 and 9.5% BMD changesforthecombination,DmaborTPTD during thesecondyear( with DmaborTPTDmonotherapy, andthis continued already from the first year of treatment ( additive effectsonLS,TH,FNanddistalradiusBMD, differ fromTPTD. the combinationgroupwerelowerthanZOL,butdidnot TPTD or ZOL monotherapy ( greater andfasterBMDgainsattheLS,THFNthan contrast withALN,TPTDcombinationZOLachieved TPTD hasalreadyprovideditsanaboliceffect( is addedonongoingTPTDtreatment,possiblybecause seems tobedifferent,especiallyforhipBMD,whenALN and smaller TH gains than ALN monotherapy ( achieves smallerLSBMDgainsthanTPTDmonotherapy BMD ( treatment results in greater increases on LS, TH and FN The addition of TPTD inpatients on ongoing ALN Combination treatment with romosozumab( showedgreater BMD increases at LS, TH and FN 3 years, high-risk womenpreviouslytreatedwithBPsforatleast comparing the1-yeareffectofromosozumabvsTPTDin LS, 5.5%atTHand4.5%FN( treatment followed by 6-month ALN were 12.8% at overall BMDgainswithan18-monthabaloparatide In comparisonwiththeromosozumab-ALNsequence, the firstyearoftreatmentwithoutfurtherincreases( gains atLS,THandFNBMDwhichwereachievedduring ALN after1-yearofromosozumabmaintainedtheBMD ( 4.3%; TH:2.0%;FN:1.4%)duringyear2ofthestudy 6.6%) ( followed by1-yearofDmab(LS:17.6%;TH:8.8%;FN: treatment withtheanti-sclerostinantibodyromosozumab antiosteoporotic medicationswereachievedwith1-year to begreaterwithDmab( 99 increased atallsiteswhentreatmentwitheitherBPs( analogs (TPTD,abaloparatide)aremaintainedorfurther 102 110 Review , 100 The combinationofTPTDwithDmabprovided The greater to-date BMDgainswithasequenceof On the other hand, BMD gains achieved with PTH ). Incontrast,postmenopausalwomentreatedwith ). SimilarBMDtrendsatthe LSandTH,although 105 102 , 101 , ). Dmab further increased BMD at all sites (LS: 106 ) or Dmab ( ). However, TPTD-ALNcoadministration 94 ). 79 79 , 110 ). 96 108 ) follows. The effects seem ). Morespecifically, the S APolyzosandPMakras A DAnastasilakis, ). Clinical fractures in − 104 1.7% atdistalradius ). Finally, anRCT 109 ) compared 106 107 ). This 103 ). In 79 ). ,

Comparison ofcost-effectiveness are notapprovedinmostcountries. as endpoints. comparative studiesareneededwithBMDorfractures providing amorepotentanabolicstimulus,further dose TPTDtoacutelyincreaseboneresorptionthereby Dmab, incontrastwithALN,inhibitstheabilityofhigh- Dmab ( inwomentreatedwithALN,butnot after 8 weeks (40 strength, especiallyincorticalbone( in improvingbonemicroarchitecture andestimated and Dmabwasalsosuperiorofeithermonotherapy study( open-label administration andcontinue toactforyearsfollowing rates. BPsremainintheskeleton forlongaftertheir increase at all skeletal sites and consistently low fracture term Dmabadministration resultsinprogressiveBMD yearsofcontinuousadministration.Long- after 2–3 documented sofar. BPsreachaplateauinBMD response risk reduction with Dmab compared to BPs has been of previoustreatment.Noevidencegreaterfracture BTM andgreaterincreasesofBMDthanBPsregardless women. Dmab seems to achieve larger suppression of significantly reducetheriskoffracturesinpostmenopausal Both BPsandDmabarepotentantiresorptives Conclusions fracture prevented( costof$46,000per reduction overALNatincremental ALN orgenericZOL( therapy forpostmenopausalosteoporosiswasgeneric cost-effectiveinitial in arecentmeta-analysis,themost more cost-effectivethangenericBPs( high-risk subgroups(e.g. than brandedbutnotgenericBPs,withtheexceptionof States, Dmabwasreportedtobemorecost-effective BPs inBelgium( Dmab was reported to be more cost-effective than oral Dmab on the treatment of postmenopausal osteoporosis. limited comparativedataoncost-effectivenessofBPsvs considerably lowerthanDmabacrosstheworld.Thereare The annualcostofBPsandespecially of thegenericones is osteoporosis Dmab vsbisphosphonatesin μ It shouldbehighlightedthatcombinationtreatments In ashort-termhead-to-headRCT, asinglehigh-dose g) ofTPTDcontinuedtoaffectboneresorption 113 ). Althoughthesefindingsmayimplythat 114 117 ) andALNinJapan( 111 117 ). Downloaded fromBioscientifica.com at09/26/202111:03:56PM ). ThecombinationofTPTD > ). DmabshowedbenefitsinVF 75 years), inwhichDmabwas 75 years), 112 179 116 www.eje-online.org :1 ). 115 ). Incontrast, ). InUnited R39 via freeaccess European Journal of Endocrinology www.eje-online.org the public,commercialornot-for-profit sector. This workdidnotreceiveanyspecific grantfromanyfundingagencyin Funding Genesis, ELPEN,VIANEX. research grants from Amgen; lecture fees from Glaxo, Lilly, Pfizer, Leo, a lecturefeefromAMGEN.PolyzoisMakrashasreceivedfeesand Lilly, ELPEN,ITFHellas,Rafarm,VIANEX.StergiosAPolyzoshasreceived Athanasios DAnastasilakishasreceivedlecturefeesfromAmgen,Eli- Declaration ofinterest affect theadherencetotreatment. in thedesignoftreatmentstrategy, asitwillsignificantly patient’s preference should betaken into consideration initiate treatmentwithDmab.Inanycase,theinformed elderly subjectswithpolypharmacyitseemsbetterto lowBMD,patientswithrenalimpairment,and very treatment aftersomeyearsunderBPs.Inpatientswith or eveninsubjectsneedingcontinuationofosteoporosis of uppergastrointestinalproblems,BPtreatmentfailure reconsider. Dmabinstead is anexcellent choice in cases probably bettertostarttreatmentwithaBPfor5 years and patients with normal renal function, it is In ambulatory Suggested treatment strategy all skeletalsites. or ZOL,butnotALN,providesmorerapidBMDgainsat around theworld,coadministrationofTPTDwithDmab currently approved by the vast majority of health systems treated with osteoanabolic medications. Although not possibly improvemineralizationinpatientspreviously important to maintain or even increase bone massand considered. SequentialtreatmentwithBPsorDmabis however, theriskofseverehypocalcemiashouldbe effective inpatientswithsevererenalimpairment, of postmenopausalosteoporosis.Dmabseemssafeand lowwithbothBPsandDmabinthetreatment AFF arevery treatment isnotknownuptodate.TheratesofONJand optimal BPandthesufficientdurationofsequential treatment withBPsshouldimmediatelyfollow;the subjects. Therefore,incaseofDmabdiscontinuation, specifically this of multiple, clinical VFs among high-risk of BMDgainsandtheensuingincreasedriskfractures, patients, becauseoftherapidincreaseBTM,loss discouraged, especiallyinpreviouslytreatment-naïve without subsequenttreatmentoptioniscurrently a ‘drugholiday’.Ontheopposite,Dmabdiscontinuation their discontinuation,thusallowingtheconsiderationof Review S APolyzosandPMakras A DAnastasilakis, References Creative CommonsAttribution3.0UnportedLicense. Servier MedicalArt,supportedbyServier, whichislicensedundera Osteoclast andosteoclastprecursorin Acknowledgements

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