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Safety issues with osteoporosis treatments

Bo Abrahamsen

Thepatient

• 78year-oldlady,retired dentist,active.• Familyhistory ofosteoporosis (mother,youngersister).• Humerusfracture 3months ago.• Type2diabetessince 1990,good glycaemic control,microalbuminuria.Creatinine clearance 40ml/minbyC-Gformula.

Thepatient

• 78year-oldlady,retired dentist,active.• Familyhistory ofosteoporosis (mother,younger sister).• Humerusfracture 3months ago (fall).• Type2diabetessince 1990,good glycaemic control,microalbuminuria.Creatinine clearance 40ml/minbyC-Gformula.

• Other biochemistry unremarkable.25OHD80nmol/l.• T-score -3.0atL2-L4spine (osteoporosis)

-2.8atfemoralneck (osteoporosis)• Meds Metformin,losartan,calcium+vitD• 20cigarettes daily,no alcohol

FRAX assessment

UKNOGGGuidance Which drug?

Firstchoice:Weekly oralbisphosphonate(PROS:cheap,good efficacy,guidelinesinfavour,canbe taken athome.CONS:adherence can be poor,GItoleranceissues)

”Fortunately Ithink you should be able tomanagethis onatabletonce aweek.These drugshavebeenavailable foralongtimesowe havealot ofexperience withthem andtheprice isreally low.”

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Patientconcerns

• Idon’t want osteonecrosis ofthejaw,I’ve seenpictures anditisacondition that isfarworse than abonefracture.• Thisdrughasalso been linked tocanceroftheoesophagus.Thisisusually incurable.

ONJ factsheet• Clinicaldiagnosisbasedonexposedvisibleboneinoralcavityseenbyhealthprofessional,

present>8wks.

• Morethan95%ofcasesintheliteraturehaveoccurredinpatientswithmetastaticbonediseasereceivinglong-term,high-dose,i.v. BP,inwhomtheestimatedincidenceis1to12%at36monthsofexposure(annualcumulativeoncologydoseisabout10xthedoseusedforosteoporosis).

• Riskfactors:invasivedentalprocedures,dentaldisease,poorlyfittingdentalappliances,tobacco/alcoholandcorticosteroidsorchemotherapeuticdrugs.

• Prevalenceratesinosteoporosispatientsgenerallyaround0.02%thoughonestudyreportedprevalenceupto4.3%.Noassociationwithdurationofuseshown.

• Notnecessaryforpatients(exceptoncology)toundergodentalevaluationorcompletedentaltreatmentspriortoinitiationofBP.

• Seeadentistonaregularbasis,maintaingoodoralhygiene.

• Shouldtheneedtoperformaninvasivedentalprocedureariseaftertherapyisinitiated,thereisnoevidencethatdiscontinuationofBPwillimprovedentaloutcome.

• Boneturnovermarkersnon-informative.

Suresh,Pazianas,Abrahamsen:Rheumatology(Oxford)201453(1):19-31

Oesophagealcancerfactsheet

• Raredisease.Associatedwithsmokingandalcoholusewhicharealsoriskfactorsforosteoporosis.Men>Women.

• OralBPs:Meta-analysisofsevenepidemiologicalstudies(Sun,OsteoporosisInt 2013;24:27986)• PooledRRof1.23(95%CI0.79,1.92ns)forcohortstudies• PooledRRof1.24(95%CI0.98,1.57ns)forcasecontrolstudies

• Oesophagealcancerhasverypoorsurvivalyetnoexcessoesophagealcancerdeathsinalendronateusers(Abrahamsen,JBMR2012):• 12,000alendronateusersfollowedfor6years:0.11%diedofoesophagealcancer.All

causemortality32.1%.• 48,000controlsubjectsfollowedfor6years:0.15%diedofoesophagealcancer.All

causemortality34%.• (studyalsofoundalendronateusershadhalftheriskofgastriccancerandgastric

cancermortalitycomparedwithbackground).

Suresh,Pazianas,Abrahamsen:Rheumatology(Oxford)201453(1):19-31

UpperGIissueswithoralBPsingeneral

• UpperGIirritation– heartburn- isthemostcommonsideeffectwithoralBPsandreasonmostcommonlygivenbypatientsforstoppingtreatment.• Althoughnotdemonstratedinclinicaltrials,fewerGIsideeffectshavebeennotedw/weeklyormonthlyBP,comparedwithdailyBP,inpost-marketingreports.• Notethatsomepatientsmay(inappropriately)takethedrugwithasmallamountofyoghurtormilktoalleviatethis.Notthewayforwardobviously.• IneverprescribePPIstohelppatientstolerateoralBPs;changetootherdrug(oftenzol ordmab).

Importantsafetyconsiderationswhendiscussingbestmedicationforthepatient

• Renalfunction• UpperGIproblems• Dentalstatusandplannedprocedures

Importantsafetyconsiderationswhendiscussingbestmedicationforthepatient

• Renalfunction• UpperGIproblems• Dentalstatusandplannedprocedures

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Thepatient

• 78year-oldlady,retired dentist,active.• Familyhistory ofosteoporosis (mother,younger sister).• Humerusfracture 3months ago (fall).• Type2diabetessince 1990,good glycaemic control,microalbuminuria.Creatinine clearance 40ml/minbyC-Gformula.

• Other biochemistry unremarkable.25OHD80nmol/l.• T-score -3.0atL2-L4spine (osteoporosis)

-2.8atfemoralneck (osteoporosis)• Meds Metformin,losartan,calcium+vitD• 20cigarettes daily,no alcohol• Patientagrees tostartalendronate 70mgonce weekly• 3months consult withnurse,no tolerability issues

Safetyconcernswithbisphosphonates

Irrespectiveofduration• Reflux/dyspepsia(oral)• Renaltoxicity(iv>oral)• Hypocalcaemia(iv)• Uveitis• ONJ• Acutephasereaction• Musculoskeletalpain• Atrialfibrillation(?)• Livertoxicity(extremelyrare)• Probablyunsafeinpregnancy/lactation(soabsolutelyavoid!)

Longtermuseonly• Atypicalfemurfracture

Reyes,JCellBiochem.2016Jan;117(1):20-8

BBC1st ofMarch2017

Kim,JBMR2016

ONJ AF AFF

ASBMR2014definitionofAFF

• Afemurfracturelocatedalongthediaphysisfromjustdistaltothelessertrochantertojustproximaltothesupracondylarflare.

• Withatleastfourofthesefivemajorcriteriamet:• Minimalornotrauma,asinafallfromastandingheightorless• Fracturelineoriginatesatthelateralcortexandissubstantiallytransversein

itsorientation,althoughitmaybecomeobliqueasitprogressesmediallyacrossthefemur.

• Completefracturesextendthroughbothcorticesandmaybeassociatedwithamedialspike;incompletefracturesinvolveonlythelateralcortex

• Thefractureisnon-comminuted orminimallycomminuted• Localizedperiostealorendosteal thickeningofthelateralcortexispresentat

thefracturesite(“beaking”or“flaring”)

• Minororinconstantfeatures:• Generalizedincreaseincorticalthicknessofthefemoraldiaphyses• Prodromalsymptomssuchasdullorachingpaininthegroinorthigh• Bilaterality• Delayedfracturehealing

ShaneE,JBMR2014

Atypicalfemurfracture– whatshouldIdo?• DiagnosisisusuallybyconventionalX-raythoughCTorboneisotopescanoftenhelpful.ADXA scanapplicationhasbeendeveloped(15-secSEFemurExamwithhighresolutionimageoftheentirefemurwithloweffectiveradiationdoseperformedatthetimeofahipBMDscan).• Alwayscheckoppositefemurforsimilarlesion.• Treatment– surgeryforallcompleteandmostincompletefractures(oftenpersistingpain,delayedhealingorprogresstocompletefractures).Teriparatide tostimulatehealing?• PrudenttostopantiresorptivesifAFF develops.

AFF,HipFracturesandDeaths

Numberof

fracturesin

Sweden

2008-2010

Oneyear

mortalitySMR

Deathsfirst

year

Excessdeaths

firstyear

Sutroch/shaft

fractures5,342

Excluded 4,218

AFF 172 0% 0.92 None None

non-AFF 952 22% 1.82 209 136

Hipfractures 42,993 22% 3.4 9,458 7,309

Kharazmi JBMR2016,Abrahamsen&Prieto-AlhambraJBMR2016

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0

200

400

600

800

1000

1200

1400

0 1 2 3 4 5

Agead

justed

rateper100

,000

Yearoftreatment

Fractureratebyadherenceandyear522,287femalenewBPusersUSMedicare

Datafromtable2,Wangetal,Ost Int 2014.

MPR>2/3

MPR>2/3

MPR<1/3

MPR<1/3

MPR 1/3-2/3

MPR 1/3-2/3

Hipfractures(FNandIT)

Subtrochanteric andfemoralshaftfractures

“Benefit”

“Harm”

ORand95%CIforST/FSFRACTURE

ORand95%CIforHIPFRACTURE

AlendronateUserstatusa

Pastuser(≥1yearbefore) Reference ReferenceRecentuser(<1ybefore) 1.00(0.82to1.25)p=0.931 0.79(0.74to0.86)p<0.001Currentuser 0.92(0.79to1.07)p=0.273 0.70(0.65to0.77)p<0.001MPRb

<50% Reference Reference50-80% 1.04(0.84to1.27)p=0.74 0.98(0.89to1.08)p=0.65>80% 0.90(0.78to1.03)p=0.11 0.73(0.69to0.79)p<0.001Doseyearsc

<5 Reference Reference5-10 1.05(0.87to1.28)p=0.58 0.74(0.67to0.83)p<0.001≥10 0.72(0.45to1.14)p=0.16 0.74(0.55to0.97)p=0.027

Two(ST/FSandhip,respectively)nestedcase-controlanalysesinDanishalendronateuser-onlycohort,treatmentstart1996-2007(N=63,774)followedtoendof2013.Logisticregressionadjustedforcomorbidcondition,priorfracturesandcomedications.

RiskofST/FSandhipfractures

Abrahamsen,BMJ2016

Thepatientafter 2years onaln

• 80year-oldlady,retired dentist,active.Familyhistory ofosteoporosis (mother,younger sister).Type2diabetessince1990,good glycaemic control,microalbuminuria.

• Creatinine clearance now 30ml/minbyC-Gformula.• Other biochemistry unremarkable.25-OHD 96nmol/l.• T-score -2.9atL2-L4spine (osteoporosis)– no sigchange

-2.7atfemoralneck (osteoporosis)– no sigchange• Meds Metformin,losartan,alendronate,calcium+vitD• Nosideeffects,no newcomplaints,no falls orfractures• Nolongersmokes,no alcohol

Options

• Raloxifene (no)• Zoledronic acid(no)• Strontiumranelate (no)• Risedronate??• Denosumab

Safetyconcernswithdenosumab

Irrespectiveofduration• Infections• Hypocalcaemia• Cataracts?(men)• ONJ• Pain• Flatulence• Probablyunsafeinpregnancy/lactation(soavoid)

Longtermuseonly• Atypicalfemurfracture

Suresh,ClevelandClin JMed.2015Feb;82(2):105-14

Denosumabpostmarketingsafety

• Post-marketingsafetysurveillancedataforProliaÒ hadrecordedfourcasesofatypicalfemurfracturemeetingtheASBMRcasedefinition.Allpatientshadpreviouslybeenbisphosponate users.

• Therewerealso32reportsofONJandeightcasesofseveresymptomatichypocalcaemia;sevenofthelattercaseswereinpatientswithCKD.

• Fivecasesofanaphylaxiswererecorded,generallyonthedayofinjection.Therewerenofatalcasesofanaphylaxis.

• EstimatedexposurewithProliaÒ was1.2millionpatientyears.

Geller,abstractECCEO2014

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Albuminadjustedcalciumlevelof1.32mmol/L(2.1–2.6mmol/L)Phosphate0.66mmol/L(0.8–1.4)Parathyroidhormone28.0pmol/L(1.1–6.8pmol/L)

Safetyconcernswithforteo/TPD

Irrespectiveofduration• Fatigue• Headache• Bonepain• Hypercalcaemia• Probablyunsafeinpregnancy/lactation

Longtermuseonly• Osteosarcoma??(youngratmodel)• Activationofdormantbonemetastases??

Thechallengeofselectinganappropriatescale

Communicatingriskinosteoporosis

Brown,CanFam Physician2014;60:324-33.

Redflagsintheboneclinic

Osteomalacia

Renalfunction

Redflagsintheboneclinic

Pregnancy

Osteomalacia

Renalfunction

Hypoparathyroidism

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Keypoints

• Importanttoconsiderrenalfunctionwhenprescribing.Particularlycriticalwithzoledronic acidbuttrueforallosteoporosisdrugs(allarenominallycontraindicatedatcrea/clearance<30ml,alendronateandzol at<35ml.• BemindfulofahistoryofupperGIcomplaintsandchronicPPIuseifprescribingoralbisphosphonates.• VitaminDstatus,renalfunctionandintactPTH axisimportantwhenprescribingpotentparenteralanti-resorptives (dmab andzol)– otherwiseriskoflifethreateninghypocalcaemia.

Keypoints

• Cardiovascularconcerns(stroke,deepveinthrombosis)withraloxifeneandstrontiumranelatemakethesedrugslessusefulintheolderpatient.• Atypicalfemurfracturesareveryrareandsurvivalseemstobemuchbetterthanafterahipfracture.Treatmentissurgery.Easytomissincompletefractureasthighorhippainmayhaveamultitudeofcauses(sobevigilant).• ONJ isextraordinarilyrareinosteoporosispatientsbutifpossiblethenwaittillelectivedentalworkincludingimplantshasbeencompletedifalreadyplanned.Gooddentalhygienerecommended.InformpatientsdespiterarityofthisAE.