AdvAnces in GeRd · gastroesophageal reflux disease went out to 3 years in order to specifically...
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Gastroenterology & Hepatology Volume 7, Issue 12 December 2011 831 GERD ADVANCES IN GERD Section Editor: Joel E. Richter, MD Current Developments in the Management of Acid-Related GI Disorders Examining the Potential Relationship Between Proton Pump Inhibitor Use and the Risk of Bone Fracture David C. Metz, MD Professor of Medicine Associate Chief for Clinical Affairs Division of Gastroenterology Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania G&H Proton pump inhibitors have generally been known for their overall efficacy, safety, and widespread use for treating gastroesophageal reflux disease. How was the possible link to an increased risk of bone fracture first discovered? DCM Over the past decades, proton pump inhibitors (PPIs) have been shown to be the therapy of choice for gastroesophageal reflux disease due to their proven supe- riority over other medical therapies, such as H 2 -receptor antagonists. PPIs have also shown superiority over H 2 -receptor antagonists for the other 2 major indications for long-term acid suppression: hypersecretory states and prophylaxis for nonsteroidal anti-inflammatory drug (NSAID) gastropathy. However, PPIs should not neces- sarily be considered first-line therapy for other gastroin- testinal complaints, and at times, PPIs are overprescribed for dyspepsia and other nonspecific foregut complaints. e possibility that PPI use may be associated with an increase in the risk of bone fracture was first reported in 2006 by 2 independent groups. Vestergaard and associates showed a positive association between PPIs and bone fracture risk without a dose or duration effect, whereas the study conducted by my colleagues and I, which analyzed the United Kingdom General Practice Research Database, identified both a dose and duration effect. (All epidemiologic analyses are limited by the potential for confounding; if a dose and/or duration effect can be shown in an analysis, it lends credence to the validity of the association.) Before conducting our study, my colleagues and I had hypothesized that bone fracture would be less frequent in patients who were exposed to PPIs. However, as has been widely cited since our study was published (and in agreement with the study by Vestergaard and colleagues), our results showed the exact opposite. We subsequently performed another analysis in patients with a naturally occurring cause for hypochlorhydria (pernicious anemia) and found a similar relationship, suggesting that our finding was accurate and potentially directly mediated by acid suppression. G&H How did you explain this unexpected relationship? DCM After our study and many subsequent studies by other researchers, a working hypothesis to explain the rela- tionship between PPI exposure and fractures has emerged. We believe that suppression of gastric acid secretion may impair effective calcium absorption and, therefore, pre- dispose patients to possible fractures due to osteopenia. Our supplementary study mentioned above supports this hypothesis, and other studies in humans have demon- strated that gastric pH affects calcium absorption. How- ever, epidemiologic (ie, population database) studies do not lend themselves to interventions in which only some PPI patients receive calcium replacements in a double- blind, randomized fashion; thus, it is not possible for these types of studies to definitively prove the hypothesis. In addition, the available epidemiologic databases do not provide information on dietary and/or over-the-counter supplements, so it is not possible to stratify results based on the calcium intake of these patients. Finally, surrogate marker trials, such as the epidemiologic bone density trial by Targownik and associates, have failed to identify reduced bone density in patients who were exposed to long-term PPI therapy compared to patients who were not exposed to PPIs. In short, it is still unknown whether the risk of bone fracture can be mitigated by providing excess oral calcium to improve calcium absorption.
Transcript of AdvAnces in GeRd · gastroesophageal reflux disease went out to 3 years in order to specifically...
Gastroenterology & Hepatology Volume 7, Issue 12 December 2011 831
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AdvAnces in GeRd
section editor: Joel e. Richter, Md
C u r r e n t D e v e l o p m e n t s i n t h e M a n a g e m e n t o f A c i d - R e l a t e d G I D i s o r d e r s
Examining the Potential Relationship Between Proton Pump Inhibitor Use and the Risk of Bone Fracture
David C. Metz, MDProfessor of MedicineAssociate Chief for Clinical AffairsDivision of GastroenterologyPerelman School of MedicineUniversity of PennsylvaniaPhiladelphia, Pennsylvania
G&H Proton pump inhibitors have generally been known for their overall efficacy, safety, and widespread use for treating gastroesophageal reflux disease. How was the possible link to an increased risk of bone fracture first discovered?
DCM Over the past decades, proton pump inhibitors(PPIs)havebeenshowntobe the therapyofchoice forgastroesophagealrefluxdiseaseduetotheirprovensupe-riorityoverothermedicaltherapies,suchasH2-receptorantagonists. PPIs have also shown superiority overH2-receptorantagonistsfortheother2majorindicationsforlong-termacidsuppression:hypersecretorystatesandprophylaxis for nonsteroidal anti-inflammatory drug(NSAID)gastropathy.However,PPIs shouldnotneces-sarilybeconsideredfirst-linetherapyforothergastroin-testinalcomplaints,andattimes,PPIsareoverprescribedfordyspepsiaandothernonspecificforegutcomplaints.
ThepossibilitythatPPIusemaybeassociatedwithanincreaseintheriskofbonefracturewasfirstreportedin 2006 by 2 independent groups. Vestergaard andassociates showed a positive association between PPIsandbonefractureriskwithoutadoseordurationeffect,whereas the study conducted by my colleagues and I,which analyzed the United Kingdom General PracticeResearchDatabase,identifiedbothadoseanddurationeffect. (All epidemiologic analyses are limited by the
potential for confounding; if a dose and/or durationeffectcanbeshowninananalysis, it lendscredence tothe validity of the association.) Before conducting ourstudy,mycolleaguesandIhadhypothesized thatbonefracture would be less frequent in patients who wereexposedtoPPIs.However,ashasbeenwidelycitedsinceour study was published (and in agreement with thestudybyVestergaardandcolleagues),ourresultsshowedtheexactopposite.Wesubsequentlyperformedanotheranalysis inpatientswithanaturallyoccurringcauseforhypochlorhydria(perniciousanemia)andfoundasimilarrelationship,suggestingthatourfindingwasaccurateandpotentiallydirectlymediatedbyacidsuppression.
G&H How did you explain this unexpected relationship?
DCM Afterourstudyandmanysubsequentstudiesbyotherresearchers,aworkinghypothesistoexplaintherela-tionshipbetweenPPIexposureandfractureshasemerged.Webelievethatsuppressionofgastricacidsecretionmayimpair effective calcium absorption and, therefore, pre-disposepatients topossible fracturesdue toosteopenia.Oursupplementarystudymentionedabovesupportsthishypothesis, and other studies in humans have demon-stratedthatgastricpHaffectscalciumabsorption.How-ever, epidemiologic (ie, populationdatabase) studies donotlendthemselvestointerventionsinwhichonlysomePPI patients receive calcium replacements in a double-blind, randomized fashion; thus, it is not possible forthesetypesofstudiestodefinitivelyprovethehypothesis.Inaddition,theavailableepidemiologicdatabasesdonotprovide informationondietary and/orover-the-countersupplements,soitisnotpossibletostratifyresultsbasedonthecalciumintakeofthesepatients.Finally,surrogatemarker trials, such as the epidemiologic bone densitytrialbyTargownikandassociates,havefailedtoidentifyreduced bone density in patients who were exposed tolong-term PPI therapy compared to patients who werenotexposedtoPPIs.Inshort,itisstillunknownwhetherthe riskofbone fracture canbemitigatedbyprovidingexcessoralcalciumtoimprovecalciumabsorption.
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G&H Can we conclude that PPI use increases the risk of bone fracture? What is the current understanding of this relationship?
DCM As originally suggested by our epidemiologicstudy—aswellasbyanumberofotherstudiesand,morerecently, a large meta-analysis—it appears that there is asmallincreasedlikelihoodofdevelopingabonefractureinapatienttakinglong-termPPIs.Inaddition,thereislikelyadoseresponse,suchthatthehigherthedose(orthelongerthedurationoftherapy),themorelikelyitwillbethatapatientwilldevelopabonefracture.Thus,theassociationappearstobesmallbutreal,anditispotentiallyrelevantinelderlyindividuals,manyofwhomarealreadyatriskforosteopeniaandfractures,whichhaveamajorimpactonqualityoflifeandaredrainsonhealthcareresources.Consequently,whenconsideringacid-suppressivetherapy,myusualapproachistofirstdeterminewhetherthepatienttrulyhasanindicationforaPPIand,ifso,tousethelowesteffectivemaintenancedose,whichdependsontheindication.
G&H What are the main indications for long-term PPI use?
DCMThere are3main indications for long-termPPIuse.Thefirst indicationisrefluxdisease.Intheabsenceof documented erosive disease or Barrett esophagus, Ifavortheuseofon-demandPPItherapy.IfrefluxpatientshaveBarrettesophagus,documentederosiveesophagitis,orsignificantsymptomsdespiteon-demandtherapy,theyshouldbeplacedonaonce-dailydoseofPPItherapy.Isupporttheuseoftwice-dailyPPIsonlyrarelyinpatientswithreflux(eg,whenpatientshavedocumentedsubopti-malcontrolwhileonaonce-dailyPPIandhavefindingsfrom an impedance pH test that support higher-dosetherapy). The old adage “if once-daily therapy is good,thentwice-dailytherapyisbetter”probablydoesnotholdtruewhenitcomestolong-termPPIuse.
The second indication for long-term maintenancePPItherapyisnonsteroidalgastropathy.Withallofthisrecent interest surrounding the potential risks of PPIs,theremaybemanypatientswhoarenottakingPPIsbutshouldbe.Nonsteroidalgastropathy is a significantdis-ease.AccordingtoanoldpaperbySinghandcolleagues,approximately 80% of 1,920 patients on NSAIDs whopresented with life-threatening upper gastrointestinalbleedingdidsowithoutanypreemptivesymptoms,dem-onstratingthatitisimportanttopreventriskratherthanwait to treat symptoms when they develop, as the firstsymptomcanbelife-threatening.Studieshaveshownthattherisksofnonsteroidalgastropathyincreasewithahis-toryofpriorpepticulceration(bleedingornonbleeding),concomitant therapywithanticoagulation, concomitanttherapy with steroids, increasing age, and taking more
thanoneNSAIDsimultaneously;ifsuchpatientsareeverplacedonNSAIDs,theyshouldalsobeplacedonaonce-dailyPPI.Inthesesettings,aonce-dailyPPIreducesthelikelihood of a life-threatening event by approximately50%.Therefore,PPIsshouldbecontinuedlongterminthese patients despite potential side effects, including aslightlyincreasedriskofbonefracture.
Thethirdindicationforlong-termmaintenancePPItherapyisahypersecretorystate.Althoughthisconditionis rare, it can be life-threatening, and suppressing highlevelsofacidoutputcansavethelivesofthesepatients.Inthesepatientsspecifically,Isupporttheuseoftwice-dailyPPImaintenancetherapy,andIalsotrytotitratethePPIdosetoacidoutputlevelsifpossible.
G&H Despite the potential risk of bone fracture, do you support the use of PPIs in all patients with any of these indications?
DCM Ibelievethatdenyingtherapytopatientswiththese3indicationsexposesthepatientstosignificantrisk.RatherthanfocusingtoomuchontherisksassociatedwithPPIs,weshouldbebalancedandusethesedrugsappropriatelyin the individualswhoneed themandavoid thesedrugsin individualswhodonotneed them.Clearly, therehasbeensomePPIoveruseinpatientswhodonothaveclassicrefluxdiseaseorhypersecretory statesorwhodonotuseNSAIDs.InsuchpatientswhoaretakingPPIs,physiciansshouldreevaluatewhetherthedrugsaretrulyindicatedandshouldconsiderslowlyweaningthesepatientsoffofPPIstopreventpossiblereboundgastricacidhypersecretionandtopotentiallylimitlong-termsideeffects.
G&H What is considered long-term PPI use, and are there any alternatives?
DCMTherapylastingmorethan8weeksisusuallyconsid-eredtobelong-termtreatment,butinreality,wearetalkingabout years of treatment. Most studies of reflux patientswithdocumentedhealingof erosiveesophagitishave fol-lowedpatientsfor6months;afewmaintenancetrialsthatwereusedtoobtainapprovalforlong-termPPItherapyforgastroesophagealrefluxdiseasewentoutto3yearsinordertospecificallyassessforadverseevents.AclinicalstudybyKlinkenberg-Knolfollowedpatientsforaslongas11years.Long-termusesignifieschronicuse.Refluxdiseasecannotbecuredbyacidsuppression,whichmerelytreatstheeffectsof acid. The underlying pathophysiology of reflux is nothypersecretion;rather,itisthetranslocationofappropriateamountsofacidfromthestomachtotheesophagus,whichisaninhospitablelocation.
Therefore, it could be argued that instead of long-term PPI use, it might be appropriate to perform asurgicalfundoplicationingastroesophagealrefluxdisease
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patientstoavoidtheuseoflong-termPPIsandeliminatetheassociatedrisks.However,fundoplicationitselfpoten-tially involves additional morbidity (at reasonably highlevelseveninthebesthands)andmortality(albeitatverylow levels),aswellas theriskofbreakdownand lossofefficacy over time.Many gastroenterologists havedocu-mentedcasesinwhichapatientunderwentafundoplica-tionthatwassuccessfulformanyyears,butthepatient’ssymptomseventuallybegantorecurasthefundoplicationbrokedown.SeveralcostanalyseshaveexaminedthecostsoffundoplicationversusPPImaintenance.Thecrossoverpoint appears to be approximately 10 years (ie, if thefundoplicationlastsmorethan10years,itmightbemorecost-effective tooperateon thepatient).However, evenwiththemostexperiencedsurgeon,afundoplicationhaspotentialrisksandmorbidity.
G&H Should all patients who are taking PPIs also take calcium supplementation or undergo screening for osteoporosis?
DCM Inmyopinion,anypersonwho ispotentiallyatriskforosteoporosis(eg,anyelderlypersonorpostmeno-pausalwoman)shouldundergobone-densitystudiesandscreening for osteoporosis, whether or not he or she istakingPPIs.Idonotbelievethatspecialinterventions—suchasundergoingadual-emissionX-rayabsorptiometry(DXA)scanatanearlierage—shouldnecessarilybeper-formedmerelybecauseofPPIuse.However,thegeneralguidelinesforosteoporosisscreeningshouldbefollowed.
That being said, I recommend that individuals onlong-termPPItherapymakesurethattheyhaveagoodcalciumintake(althoughIrecommendthatallpatientshaveagoodcalciumintake,whetherornottheyaretak-ing PPIs). No studies have compared PPI users takingcalcium supplementation with PPI users who are nottakingcalciumsupplementation;therefore, it isunclearwhether calcium impacts apatient’s outcome.Withoutanyfirmdatatosupporttheuseofcalciumsupplementa-tion,Idonotthinkthatitisincumbentonustomakeanyspecificrecommendations.
G&H Has the potential risk of increased fractures caused concern in patients taking PPIs?
DCM Absolutely. Unfortunately, when a prominentjournalpublishesapaperthatdisseminatesinformationtothelaypress,patientsreadthelaypressarticlesanddecidetotakeactionontheirown,suchasunilaterallystopping PPI use because they are worried that theywill develop fractures. After my study was publishedin2006,manyofmyownpatientscametomyoffice,tellingme that theyhad read inanewspaper that thedrug I had prescribed for them was bad, so they had
stoppedusingit,butnowtheywereexperiencingsevereheartburn,andwhatwasIgoingtodoaboutit?Patientsmaybeinformed,buttheydonotnecessarilytakeintoaccountthewholepicture.Doctorsshouldhaveabal-anced discussion with their patients regarding all ofthe risks and all of thebenefitsof anydrug that theyprescribebeforethestartoftreatment.
G&H What studies should be conducted to better understand the association between PPIs and the risk of bone fracture?
DCM Iwouldliketoseefurtherstudyonthemecha-nismofpossibleosteopeniainthesepatients.Interest-ingly, a large Canadian study that recently looked atDXA scans did not find an increased risk of fractureaccording to bone density measurements; this findingcontradicts an earlier finding by the same group ofresearchers that showed an increased risk of fracturewithPPIs.This recentfinding raises thepossibility ofothermechanismsforfracture,suchasparathyroidhor-mone dysfunction, or perhaps the finding shows thatmeasurement of bone density is imprecise and othersurrogates,suchasclinicalchemistrymeasuresofboneturnover,shouldbeemployedinstead.
TobetterunderstandthemagnitudeofthepotentialriskbetweenbonefractureandPPIuse,adouble-blind,randomizedstudyshouldbeconductedtocomparetreat-ment with and without calcium supplementation andwithandwithoutPPIexposure.Althoughtheriskofbonefracture may be increased with PPI use, its magnitudemay be minor and may be overcome with appropriatecalciumintake.Toobtainaninitial lookintothis issue,animal studies should be conducted, as this study can-not be performed easily in humans and should not beperformedinratsbecauseoftheirdifferentphysiology.Alargermammalwouldbenecessary.
Suggested Reading
VestergaardP,RejnmarkL,MosekildeL.Protonpumpinhibitors,histamineH2receptorantagonists,andotherantacidmedicationsandtheriskoffracture.Calcif Tissue Int.2006;79:76-83.
EomC-S,ParkSM,MyungS-K,YunMJ,AhnJ-S.Useofacidsuppressivemedicationandriskoffracture:ameta-analysisofobservationalstudies. Ann Fam Med.2011;9:257-267.
MerrimanNA,PuttME,MetzDC,YangYX.Hipfractureriskinpatientswithadiagnosisofperniciousanemia.Gastroenterology.2010;138:1330-1337.
SinghG,RameyDR,MorfeldD, ShiH,HatoumHT,Fries JF.Gastrointesti-nal tract complications of nonsteroidal anti-inflammatory drug treatment inrheumatoidarthritis.Aprospectiveobservationalcohortstudy.Arch Intern Med.1996;156:1530-1536.
TargownikLE, LixLM, MetgeCJ, PriorHJ, LeungS, LeslieWD.Useofprotonpumpinhibitorsandriskofosteoporosis-relatedfractures. CMAJ. 2008;179:319-326.
Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitortherapyandriskofhipfracture.JAMA. 2006;296:2947-2953.
TargownikLE, LixLM, LeungS, LeslieWD.Proton-pumpinhibitoruseisnotassociatedwithosteoporosisoraccelerated bonemineraldensityloss.Gastroenterol-ogy. 2010;138:896-904.
