REVIEW
CurrentstatusofresearchonosteoporosisinCOPD:asystematicreview
L.Graat-Verboom*,#,E.F.M.Wouters#,\",F.W.J.M.Smeenk*,B.E.E.M.vandenBorne*,R.Lunde+andM.A.Spruit\"ABSTRACT:Patientswithchronicobstructivepulmonarydisease(COPD)areatincreasedriskofAFFILIATIONS
osteoporosis.However,theprevalence,correlatesandeffectivenessoftreatmentofosteoporosis*DeptofRespiratoryMedicine,inCOPDpatientsremainunclear.
CatharinaHospitalEindhoven,Eindhoven,Weperformedasystematicreviewoftheliteraturetoanswerthreequestions.1)Whatisthe#DeptofRespiratoryMedicine,prevalenceofosteoporosisinCOPD?2)WhatareidentifiedcorrelatesofosteoporosisinCOPD?MaastrichtUniversityMedicalCentre,3)WhataretheeffectsoftreatmentofosteoporosisinCOPD?AcomputerisedliteraturesearchinMaastricht,\"MEDLINE/PubMedandtheCochranedatabasewascarriedout.Inaddition,referencelistswereDeptofResearch,Development&Education,CentreforIntegratedsearchedbyhandandauthorswerecontactedifnecessary.
RehabilitationofOrganfailureTheprevalenceofosteoporosisandosteopeniavaried9–69%and27–67%,respectively.(CIRO),Horn,andPrevalenceofosteoporosiswasgenerallyhigherthaninhealthysubjectsandsomeotherchronic+DeptofRespiratoryMedicine,Stlungdiseases.CorrelatesofosteoporosisinCOPDaremainlymeasuresofbodycomposition,JansGasthuis,Weert,TheNetherlands.
diseaseseverityandtheuseofcorticosteroids,althoughcausalityhasnotbeenproven.EffectsoftreatmentofosteoporosishavenotbeeninvestigatedinsamplesconsistingofCOPDpatientsonly.CORRESPONDENCELongitudinalfollow-uptoassessdeterminantsofosteoporosisinCOPDandrandomisedL.Graat-Verboom
placebo-controlledtrialsontheeffectsoftreatmentofosteoporosisinpatientswithCOPDonlyDeptofRespiratoryMedicine
MaastrichtUniversityMedicalCentrearewarranted.
P.Debyelaan256229HXMaastrichtKEYWORDS:Boneloss,bonemineraldensity,chronicobstructivepulmonarydisease,TheNetherlands
pharmacotherapy,systemiceffects
E-mail:lidwiengraat@versatel.nlReceived:C
Aug242008
hronicobstructivepulmonarydiseasedeteriorationofbonetissueleadingtoincreasedAcceptedafterrevision:(COPD)ischaracterisedbyaprogressivebonefragilityandincreasedfracturerisk[8].Dec222008
airflowlimitationthatisnotfullyrever-Knownriskfactorsforosteoporosisinthegeneralsibleandisassociatedwithanabnormalinflam-populationare,amongothers,femalesex,matoryresponseofthelungtonoxiousparticlesadvancedage,lowbodyweight,chronicglucocor-andgases[1].Thedegreeofairflowlimitationticoidtherapyandendocrinologicaldisorderssuchcanbeassessedbyspirometryandstratifiedinashyperthyroidismandprimaryhyperparathyr-accordancewiththeGlobalInitiativeforChronicoidism[8–11].InCOPD,theprevalenceofosteo-ObstructivePulmonaryDisease(GOLD)[1].porosisisassumedtobetwo-tofive-foldhigherAlthoughprimarilyapulmonarydisease,therethaninage-matchedsubjectswithoutairflowaresignificantextrapulmonaryeffectsinCOPDobstruction[3,12].Indeed,inarecentlydeveloped[2–5].Indeed,theGOLDguidelinesincorporatedscreeningtoolformalesatriskforosteoporosis,thetheseextrapulmonaryeffectsintheirdefinitionofpresenceofCOPDisoneoftheparametersCOPD[1].Examplesofextrapulmonaryeffectsincreasingthisriskalmostfourtimes[13].areincreasedarterialstiffness[3],skeletalmuscleatrophy[4],systemichypertension[6]andTheburdenofosteoporosisvarieswiththeosteoporosis[7].
incidenceoffracturerisk[8].Fracturesofthehip,vertebraeandforearmarethemostcommonOsteoporosisisasystemicskeletaldiseasecharacte-fracturesinpatientswithosteoporosis,althoughrisedbyalowbonemassand/ormicroarchitectural
fracturesofotherbodypartscanalsobetheresult
EuropeanRespiratoryJournalPrintISSN0903-1936Thisarticlehassupplementarymaterialavailablefromwww.erj.ersjournals.com
OnlineISSN1399-3003
EUROPEANRESPIRATORYJOURNALVOLUME34NUMBER1
209
cREVIEW:COPDofosteoporosis[8].Thetreatmentofosteoporosisaimsatfracturepreventionand,accordingtotheWorldHealthOrganization(WHO),shouldconsistoflifestylemodification(suchassmokingcessation,weight-bearingphysicalexerciseandadequatecalciumintake)anddrugtreatment[8].Thelattershouldconsistofbisphosphonates,calciumsupplementation(inthecaseoflowdietaryintake)andvitaminDsupplementation(inthecaseofvitaminDdeficiency).EspeciallyinCOPDpatientsitisimportanttopreventvertebralfracturessincetheymightresultinadecreasedforcedvitalcapacity[14].Inaddition,(osteoporotic)hipfracturesinCOPDpatientsposeagreaterproblemthanhipfracturesinotherwisehealthysubjectsbecauseoftheincreasedoperativeriskinCOPDpatients[15–17].
Theaimofthisarticlewastoperformasystematicreviewoftheliteratureinordertoanswerthefollowingquestions.1)WhatistheprevalenceofosteoporosisinCOPD?2)WhatareidentifiedcorrelatesofosteoporosisinCOPD?3)WhataretheeffectsoftreatmentofosteoporosisinCOPD?
METHODS
AcomputerisedliteraturesearchoftheMEDLINE/PubMedandtheCochranedatabaseswasperformed.ThetimespanwasJanuary1988toApril2008.Foreachquestiontwogroupsofkeywordswereusedtosearchforrelevantarticles.TodeterminetheprevalenceofosteoporosisinCOPDthekeywordswere:1)COPD,chronicobstructivepulmonarydisease,emphysema,chronicbronchitis;2)osteoporosis,osteo-penia,dual-energyX-rayabsorptiometry(DXA)scan,bonemineraldensity,prevalenceofosteoporosis,prevalenceofosteopenia.
ToidentifycorrelatesofosteoporosisinCOPDthekeywordswere:1)COPD,chronicobstructivepulmonarydisease,emphysema,chronicbronchitis;2)osteoporosis,osteopenia,riskfactorsforosteoporosis,determiningfactorsforosteo-porosis,screeningforosteoporosis.
Finally,todeterminetheeffectsoftreatmentofosteoporosisinCOPDthekeywordswere:1)COPD,chronicobstructivepulmonarydisease,emphysema,chronicbronchitis;2)treat-mentofosteoporosis,lifestyleinterventionsinosteoporosis,bisphosphonates,calciumsupplementation,vitaminD.Foreachofthethreesearches,keywordsfromgroup1werecombinedwiththekeywordsfromgroup2by‘‘AND’’.Withineachgroup,thekeywordswerecombinedusing‘‘OR’’.Inaddition,referencelistsoftheidentifiedarticlesweresearchedbyhandinordertofindrelevantarticlesthatweremissedintheinitialsearchstrategy.
Articleselection
Non-Englisharticleswereexcluded.Inaddition,weexcludedreviewarticles,althoughwedidsearchtheirreferencelistsbyhandforrelevantarticles.Finally,editorials,congressabstractsandcasereportswerenotincluded.
PrevalenceofosteoporosisinCOPD
OnlystudiesthatenrolledCOPDpatientsorwhereCOPDpatientscouldbeisolatedfromthestudiedsample(inthecaseofinclusionofpatientswithotherdiseasesbesidesCOPD)wereincluded.Oneoftheoutcomeshadtobetheprevalence
210
VOLUME34NUMBER1
L.GRAAT-VERBOOMETAL.
ofosteoporosisbasedonbonemineraldensity(BMD)measurements,therebyexcludingstudieswithaprevalenceofosteoporosisbasedon(osteoporotic)fractures.Moreover,adefinitionofosteoporosishadtobegivenbytheauthors.Cross-sectional,longitudinalandinterventiontrialswereincluded.Whentheprevalenceofosteoporosiswasgivenpersiteonly(e.g.hiporlumbarspine),wecontactedtheauthorsbye-mailtoaskfortheprevalenceofthecombinedsites(i.e.ifoneofthesiteswasdiagnosedasosteoporosisthenthepatientwasdefinedashavingosteoporosis).Wedeterminedtheoverallmeanprevalenceofosteoporosisin13identifiedstudies(seeonlinesupplementarymaterial).
CorrelatesofosteoporosisinCOPD
OnlystudiesinvestigatingcorrelatesofosteoporosisinCOPDpatients,orwhereCOPDpatientscouldbeisolatedfromstudiedsamples(inthecaseofinclusionofpatientswithotherdiseasesbesidesCOPD)wereincluded.Correlationand/orregressionanalysishadtobecarriedoutbysearchingforclinicaloutcomesassociatedwithosteoporosisorBMD(therebyexcludingstudieswithfracturesasprimaryend-points).Cross-sectional,longitudinalandinterventiontrialswereincluded.
TreatmentofosteoporosisinCOPD
Again,onlystudieswheretheresultsforCOPDpatientscouldbeisolatedfromothergroupsofpatientswereincluded.Inaddition,onlyrandomisedplacebo-controlledtrialsstudyingtheeffectsoflifestyleinterventions(e.g.moreweight-bearingexercise,smokingcessation)and/or‘‘osteoporosismedication’’(e.g.bisphosphonates,calciumsupplementation,vitaminD)wereincluded.
Toassessthemethodologicalqualityofidentifiedtrials,theDelphilistwasused[18].TheDelphilistisacomprehensivecriterialistforqualityassessmentofrandomisedcontrolledtrials(RCTs)forconductingsystematicreviews.Itconsistsofnineitemsallhavinga‘‘yes’’,‘‘no’’or‘‘don’tknow’’answer.Ifbiaswasunlikely,thecriterionwasratedpositive(‘‘yes’’).Incaseswhereinformationwaslackingorinsufficientand/orifbiaswaslikely,thecriterionwasratednegative(‘‘no’’or‘‘don’tknow’’,respectively).All‘‘yes’’scores(1pointper‘‘yes’’)weresummedtoproduceanoverallqualityscore.RESULTS
PrevalenceofosteoporosisinCOPD
Thesearchresultedin240articles.Ofthese42articleswerenotintheEnglishlanguage,48werereviewarticlesandsixwereeditorialsorletters.Another94articleswereexcludedbecausetheywereaboutothertopics(clearfromtheabstractsonly).Afterreadingtheremainingarticles,another36wereexcluded:12becauseCOPDpatientscouldnotbeisolatedfromothergroupsunderinvestigationand24becausetheywereaboutothertopics.Onearticlewasexcludedbecauseasubgroupofpatientsusedinapreviouspaperwasinvestigated(seeonlinesupplement).Finally,13studieswithatotalof775COPDpatientswereincluded.Intotal,thereweremoremalepatients(67%versus33%,n5759).Moreover,patientshadamean¡SDage(ifreported)of63.4¡5.2yrs(n5775),aforcedexpiratoryvolumein1s(FEV1)of46.7¡13.5%predicted(n5514),abodymassindex(BMI)of24.9¡2.3kg?m-2(n5721)anda
EUROPEANRESPIRATORYJOURNAL
L.GRAAT-VERBOOMETAL.fat-freemassindex(FFMI)of16.7¡0.9kg?m-2(n5311)(table1).
Theprevalenceofosteoporosisvariesfrom9%to69%dependingonthepatientsunderstudy,themethodusedtoassessBMDandthedefinitionusedtodefineosteoporosis(table1).Theoverallmeanprevalenceofosteoporosisforthe13identifiedstudieswas35.1%(272of775patients).Patientswithosteoporosisconsistedofahigherproportionofwomen.Inaddition,FEV1(%pred),BMIandFFMIwerelowerintheosteoporoticCOPDpatients(table2).
Univariatebinarylogisticregressionanalysisshowedthatfemaleshadanoddsratio(OR)of1.968forosteoporosis(p,0.001).AlowerFEV1,BMIandFFMIincreasedtheORofosteoporosis,whileagehadnosignificantinfluenceonosteoporosisinCOPD(seeonlinesupplementarymaterial,tableE1).
Eightstudiesdeterminedtheprevalenceofosteopenia,whichvaries27–67%,resultinginanoverallmeanprevalenceofosteopeniaof38.4%inCOPD(table1).
Fourstudiesincludedanage-matchedcontrolgroupofhealthysubjects[3,12,23,27].TheprevalenceofosteoporosisinCOPDwasincreasedcomparedwiththehealthysubjectsinthreetrials(overallmeanprevalenceofosteoporosisof31.7%inCOPDversus5.8%inhealthysubjects,p,0.001)[3,12,27].However,KARADAGetal.[23]didnotfindasignificantdifferenceinprevalenceofosteoporosisbetweenCOPDpatientsandhealthysubjects(fig.1).Nevertheless,thesignificantdifferenceintheprevalenceofosteoporosisbetweenCOPDpatientsandhealthysubjectsstillremainedafteranalysesofthefourtrialstogether:32.5versus11.4%,respectively,p,0.001.
Fourstudiesincludedacontrolgroupofpatientswithotherchroniclungdiseases[19,25,26,29].TheprevalenceofosteoporosiswashigherinpatientswithCOPDthaninpatientswith:asthma(50%versus21%,respectively)[25];idiopathicpulmonaryfibrosis(69%versus43%,respectively)[26];pul-monaryhypertension(69%versus55%,respectively)[26];amixedgroupofidiopathicpulmonaryfibrosis,pulmonaryhypertension,sarcoidosis,sclerodermaorKartagener’ssyn-drome(45%versus15%,respectively)[29];andamixedgroupofa-1antitrypsindeficiency,sarcoidosis,lymphangioleiomyoma-tosis,fibrosingalveolitisandbronchiectasis(59%versus32%,respectively)(fig.2)[19].Inaddition,theprevalenceofosteoporosiswaslowerinpatientswithCOPDthaninpatientswithcysticfibrosisintwostudies:69%versus76%,respectively[26];and45%versus75%,respectively(fig.2)[29].
CorrelatesofosteoporosisinCOPD
Intotal,207articleswerefound.Ofthese,43werenotintheEnglishlanguage,45werereviewarticlesandthreewereeditorials,commentsorletters.Inaddition,eightarticleswereexcludedbecauseCOPDcouldnotbeisolatedfromotherpatientgroups,92becausetheywerenotaboutthetopicandanotherfourbasedontheirstatisticalmethods(nocorrelationand/orregressionanalysisperformed).Twelvestudieswereincludedforthisreview.
Correlatesofosteoporosisand/or(alow)BMDinCOPDidentifiedinmainlycross-sectionalstudieswerebodycompo-sitionmeasures[12,20,22,24,25,28,30,31],measuresof
EUROPEANRESPIRATORYJOURNAL
REVIEW:COPD
diseaseseverity[20,27,31,34]andcorticosteroids[24,31](table3).Inaddition,twolongitudinalstudiesinvestigatingchangeinBMDwereidentified(table3).SCANLONetal.[33]foundinhaledcorticosteroidstobeariskfactorfordecreasingBMDatbothfemoralneckandlumbarspine.Inaddition,theyfoundanageof.56yrstobeapredictorfordecreasingBMDatthefemoralneck,while.65yrsofageandfemalesextobepredictorsfordecreasingBMDatthelumbarspine(table3).MINEOetal.[22]investigatedCOPDpatientsbeforeandafterlungvolumereductionsurgeryandfoundsignificantcorrela-tionsbetweentheincreaseinlumbarBMDandthechangesinthefollowingparameters:residualvolume(RV),diffusingcapacityofthelungforcarbonmonoxide(DL,CO),BMI,fat-freemass(FFM),bonealkalinephosphatase(bone-AF),b-crosslaps,methylprednisolone(table3).
TreatmentofosteoporosisinCOPD
Thesearchresultedin136articles,27wereexcludedbecausetheywerenotintheEnglishlanguage,34becausetheywerereviews,threewereeditorials,lettersorcommentsand69becausetheywereaboutanothertopic.NostudieswereidentifiedinvestigatingthetreatmentofosteoporosisinCOPDpatientsalone.
DISCUSSION
TheprevalenceofosteoporosisinCOPDpatientsvaries9–69%.Inaddition,theprevalenceofosteopeniavaries27–67%.TheprevalenceofosteoporosiswashigherinCOPDpatientsthaninhealthysubjects.IdentifiedcorrelatesofosteoporosisoralowBMDinCOPDpatientsarebodycompositionmeasures,diseaseseverityandtreatmentwithcorticosteroids.TreatmentofosteoporosishasnotbeeninvestigatedinrandomsamplesconsistingofonlypatientswithCOPD.
PrevalenceofosteoporosisinCOPD
VRIEZEetal.[20]foundalowprevalenceofosteoporosiscomparedwiththeotherstudies(table1).Thismay,atleastinpart,bebecausenoneoftheGOLDstageIIpatientshadosteoporosis.Incontrast,BOLTONetal.[12]foundaprevalenceofosteoporosisin20%ofGOLDstageIIpatients.ApossibleexplanationfortheseconflictingresultscouldbetheuseofquantitativeultrasoundbyVRIEZEetal.[20]insteadofDXAscan,whichisthegoldstandardtoassessosteoporosis[8].Thehighestprevalence(69%)ofosteoporosisinCOPDwasreportedbyTSCHOPPetal.[26].IntwootherstudiesconductedinCOPDpatientsconsideredforlungtransplantation,theprevalenceofosteoporosiswaslower(48%and59%)[19,29].Thisdifferenceinprevalencemaybeduetodifferencesinpatientcharacteristics.However,intheabsenceofclinicalcharacteristicsforCOPDpatientsonly,thiswashardtocheck[26].Threeotherstudies[22,25,28]foundarelativelyhighprevalenceofosteoporosisinCOPD(50%,49%and60%,respectively).However,themeanageofthesepatientswas72,70and71yrs,respectively,whereasinotherstudiesthemeanagewasf67yrs(table1).Inaddition,KATSURAandKIDA[25]definedosteoporosisaccordingtotheJapaneseguidelineswhereasmostotherstudiesusedtheWHOcriteriatodefineosteoporosis(table1).
Wefounddifferencesinsexdistribution,FEV1,BMIandFFMIafterstratificationforpresence/absenceofosteoporosis.Inaddition,inalogisticregressionanalysisweidentifiedmale
VOLUME34NUMBER1
211
c212
Subjectsn40T-scores.InterpretationaccordingtoWHO.andFNcombined38%\"TABLE1Ageyrs5219/211919.014.8BMDatLSandFNbyDXA;LS33%,FN45%;LSM/Fn%predkg?mkg?minterpretationLS48%,FN48%;LSandFNcom-bined:59%\"#-2-2Prevalenceofosteoporosisandosteopeniainpatientswithchronicobstructivepulmonarydisease(COPD)SexFEV1BMIFFMIBMDmeasurement/OsteopeniaOsteoporosisFirstauthor[ref.]Setting/patientgroupREVIEW:COPD
selectionFØRLI[19]Patientswithadvancedpulmon-arydiseaseconsideredforlungtransplantationandreferredtotheDeptofThoracicMedicine,Rikshospitalet,Oslo,NorwaySABIT[3]hipbyDXA;T-scores.InterpretationaccordingtoWHO.Notspecified,UK756542/3356.727.617.5BMDatlumbarspineandNotreported24%VRIEZE[20]RehabilitationCentreofthe1156062/5343.426.417.3CalcanealQUS;T-scores.InterpretationofT-scoresaccordingtoWHO.40.9%8.7%UniversityMedicalCentreGroningen,Groningen,theVOLUME34NUMBER1
NetherlandsJØRGENSEN[21]Respiratoryoutpatientclinicat546314/40\"32.1NANABMDLSandFN;T-scores.InterpretationaccordingtoWHO.29.6%40.7%H:SBispebjergHospitalMINEO[22]7061Malesonly1.06L22.9PatientsselectedforlungvolumeNABMDtotalbody,LSandlefthipbyDXA;T-scores.InterpretationaccordingtoWHO.35%49%reductionsurgeryBOLTON[12]816643/3844Primarycareandrespiratoryout-24.016.2BMDtotalbody,LSandhipbyDXA;T-scores.InterpretationaccordingtoWHO.LS38%,hip52%LS27%,hip20%;LSandhipcom-bined32%\"patientsbeforepulmonaryrehabilitationKARADAG[23]OutpatientclinicoftheDeptof2863Malesonly4325.0NABMDatLSandhipbyDXA;T-scores.InterpretationaccordingtoWHO.LS42%,hip:67%LS35%,hip:10%,LSandhipcom-bined:40%\"ChestDiseases,Aydin,TurkeyDUBOIS[24]Outpatientsofthepulmonary8665Malesonly6624.9NABMDatLS,totalhipandFNbyDXA;T-scores.InterpretationaccordingtoWHO.LS27%,TH31%,FN34%LS21%,TH22%,FN28%diseaseclinicoftheReinierdeGraafGroep,DelftandVoorburg,L.GRAAT-VERBOOMETAL.
EUROPEANRESPIRATORYJOURNAL
theNetherlandsL.GRAAT-VERBOOMETAL.
REVIEW:COPD
syisgnorioetrnaop%%%%\"em-r0980%lo56260aofe4untdis:OA\":X;]D22;[kcOeEnNIaddliaMneerrtterroopooopp%AAmfeee2rr4NNeatfat:sttNdOooNNFeh;tefniopsnori-at.mgdSnnoe;Nnobpi/Luuat.hg;nFtmectlotneynAndisyesgoa.ttuxfvho.XenilenosiiuttDitOne#lemnasegriapaOooh.nodmtatHyatHarO:pSeirtebeeiyrtncraWnirHtrmdofrasoir-cmeLhttW;tarngrWruatopoeTc.eaaooonyhttseboms.aOrtumproNptFrdIotitiare%donqoeettpltfg-.ysweas0trAatnlIgdnllnnn,mrtXnHaoiodgeeoo7uwDiWtanaidn.inItesda.sdnoniddett:,dsmretrrbdtDnnaa,ytito,rliMaoDNbedohueroSecSlaciridpipocLrotFrcLaotcedDiMBnSpD-remccaMDoctaneriiBDLrefMnoposDc-aBerMtnMdmpDaBncTMs-BTbBIBnae%nonibsi:I2-D1MAAAAAMVEFm?FgNNNNNBFk;:xe#d.nniwso2shI-Mm0783....\"as2mtB?2056g22222okene:rfS-tNa#f;.1d1:priIVe,+\"Er05ASS3MhohtlFp2FauFt%NNNoa;texe:dHhtnTyyi;blnysdolnsedasexn1,o6\"eFse+38msdievS/lAs//Ma7ysomNe8la6dsroapeMFbttoo:nINM:BA:1N;)es;\"gr28513d;yAy74675edlntncouidostesranpretitlstc%uaejn06145:epb217011dviDetPuraSptiOt%nCar;uolyfatyo,zdsqftierht1:cgsSo,gla,inofrs,tfnn(poinroarlteedotdoiUiuyduehiGevcioliph,hmuttsnNCdnoeQpokeotrnrmstlonSailaNnefaityt,airrMfm;uogTcooUuZuoofHootoRa.nbrgnoll;sounr,iyhlrDoenloioyiprftnnocrtkde,deycddaoititHnooigttctine,ivatfPiiehhnntctrvaliasltiieinaoitiapSaetauaaltraoinnpzatiilrTptrlesitrlritcwp,OytisyoxwneeutlCrnoaeCe,eeaurheatoaseavpalaUiluo-liatoatytftrpltGctvcsmIeeerHorthpnhvnortawoago/enrtcnZeztiiuot,rusUCealllrrfigsennaofindAdaiomtwtyenneCorpiaoUesnttesalrtatecnpOitaae,osmhfttaSfrmoiforhafnx+:iailCteMnistttponntishzeprotartnariieht;,al)eteapttlaitseRabestgolArcotdalidiSuptsntrevirhntntoreearneeeOortapoeaGaePsiPnHttUcfiuStoNtatlnUshcHmuaaiaoarxeCood-eflnMrPnetuhtePwpwr:yi1obtnVW(EroF:COoh;t]eH.ulfeaWarm;e[]]eyrh1rftto5622]:eEh[[]8Fmybt72]LuAP9;oiRP2[[I2etdlBaUOZI[apertHAsSTALSmodiIrCMATiASICRsv:FKTDNIAMborapEUROPEANRESPIRATORYJOURNAL
VOLUME34NUMBER1
213
cREVIEW:COPDTABLE2
Noosteoporosisversusosteoporosisinpatientswithchronicobstructivepulmonarydisease
Noosteoporosis
Osteoporosisp-valueAgeyrs63.4¡4.1(503)63.4¡6.7(272)0.917SexM/F%(n)77/23(336)63/37(233),0.001**FEV1%pred47.5¡12.0(369)41.1¡15.8(145),0.001**BMIkg?m
-225.5¡2.1(471)23.7¡2.3(250),0.001**FFMIkg?m-216.9¡0.7(235)
16.2¡1.1(76)
,0.001**
Dataarepresentedasmean¡SD(n),unlessotherwiseindicated.M:males;F:females;FEV1:forcedexpiratoryvolumein1s;BMI:bodymassindex;FFMI:fat-freemassindex.**:significantatp,0.01.
sex,decreasingFEV1,BMIandFFMIaspossibledeterminantsofosteoporosisinCOPD.Nevertheless,heterogeneityofthestudydesignsmakesitsomewhatdifficulttodrawstrongconclusionsfromtheseanalyses.
Onaverage,theprevalenceofosteoporosisand/oralowBMDwassignificantlyhigherinCOPDpatientsthaninhealthysubjects(fig.1).OnlyonestudydidnotfindasignificantdifferenceinprevalenceofosteoporosisinTurkishCOPDoutpatients(40%forlumbarspineandhipcombined,35%and10%forlumbarspineandhiprespectively)comparedwiththeirhealthypeers(40%atlumbarspineand15%atthehip)[23].Nevertheless,theprevalenceofosteoporosisinthehealthygroupappearstobehigherthantheprevalenceofosteoporosisinhealthysubjectsinotherstudies(0–25%)[3,12,27,35].
4030% stecj20buS100DyDyDyDyhhhhDyPtPtPtPtllllPhtOaOaOaOaeeeeOlaCHCHCHCHCeHSABIT [3]BOLTON [12]DIMAI [27]KARADAG [23]KARADAG [23]LS+hipLS+hipFALShip
FIGURE1.
Prevalenceofosteoporosisinpatientswithchronicobstructive
pulmonarydisease(COPD)versushealthysubjects.Absolutenumbersincludedinthestudies:SABIT[3]n575COPDpatients,n542healthysubjects;BOLTON[12]n581COPDpatients,n538healthysubjects;DIMAI[27]n571COPDpatients,n540healthysubjects;KARADAG[23]n528COPDpatients,n520healthysubjects.ForKARADAGetal.[23]prevalenceforlumbarspine(LS)andhiparedisplayedseparately(theauthorprovideduswiththecombinedprevalenceofosteoporosisintheCOPDpatients(40%);however,thiscombinedprevalenceinthehealthysubjectswasnotprovided).FA:forearm.
214
VOLUME34NUMBER1
L.GRAAT-VERBOOMETAL.
807060% 50stecj40buS3020100DreDamDFFTDFrPhPPCPHeOIPPChOtOOtCOhCtsACCOFORLI [19]KATSURA [25]TSCHOPP [26]
ARIS [29]LS+hipLSLP+hipLS+hip+TB
FIGURE2.
Prevalenceofosteoporosisinchronicobstructivepulmonary
disease(COPD)versusotherrespiratorydisorders.Absolutenumbersofpatientsincluded:FORLI[19]n540COPDpatients,n531other;KATSURA[25]n520COPDpatients,n524asthmapatients;TSCHOPP[26]n516COPDpatients,n524cysticfibrosis(CF)patients,n514idiopathicpulmonaryfibrosis(IPF)patients,n511pulmonaryhypertension(PHT)patients,n59other;ARIS[29]n515COPDpatients,n520CFpatients,n520other.
Indeed,theTurkishpopulationhasBMDvalues,1SDlowerthantheSwedishpopulation[36].ThedecreasedBMDintheTurkishpopulationmaypartlyexplainthelackofdifferenceinprevalenceofosteoporosisbetweenCOPDpatientsandhealthysubjects[23].
CorrelatesofosteoporosisinCOPD
Todetermineriskfactorsforosteoporosis,longitudinal(intervention)studiesarepreferred.Todate,onlytwolong-itudinalstudiesthatmettheinclusioncriteriahavebeenidentified[22,33].Theotherstudiesarecross-sectional(table2).Forthisreason,interpretationoftheresultsshouldbewithcautionascausalityofthecorrelates(table2)needstobeconfirmed.Severalstudiesfoundbodycompositionmeasures(lowBMI,lowFFMIand%ofidealbodyweight)tohaveasignificantcorrelationwithosteoporosisand/orBMD[12,20,25,28,30].Inthegeneralpopulation,lowbodyweightand/orlowBMIhavealsobeenidentifiedasriskfactorsforosteoporosisandincorporatedinguidelines[8,13].ThelinkbetweenlowbodycompositionandosteoporosisorlowBMDinCOPDcouldbeincreasedinflammation,decreasedphysicalactivityand/orothermechanismsleadingtoproteolysis[37–42].Anotherexplanationformoreosteo-porosisinpatientswithlowerbodycompositionmeasure-mentscouldbethatboneformationisdecreasedbecausethereisrelativelylowmechanicalloadingonthesebones.Indeed,astronautsloseasmuchbonemassina1-monthspaceflightaspostmenopausalfemalesin1yr[43].Inaddition,COPDpatientshavebeenshowntobephysicallyinactivecomparedwithage-matchedhealthysubjects[44].
MINEOetal.[22]havefoundasignificantcorrelationbetweenanincreaseinBMDandanincreaseinBMIandFFMafterlungvolumereductionsurgery.Morelongitudinalstudiesare
EUROPEANRESPIRATORYJOURNAL
L.GRAAT-VERBOOMETAL.
REVIEW:COPD
+),s,));e3),):2%er)f9;)2)p7.152ae3%,oorr:C:0))o)cV0F3os..5ln.988W:c)t85d,00.so0eg:)145,)B-s.5n1Iosn;neR..,,,350sl5)2gurO)))).Er5ad10095e.i.4%Zpo,viti46970Sr5oorsi.,)(rcn-;(....(;)(-r0))2744:)r5554.0ci)rr0e;()e;N:nsupalout)nsEs00d.Oo50%2S(I5ffn:rewR7cF(W::CMbDeraRR::SRR(d.,cr62;).i00LF,p);07E1nZasert2M5r7tgmceBBrrooO.rrc0er4;aetIOOOOVorEEDF)l12y4sr.%(ipoh(ns2-eLhnuidfa((((I–eSSor14o51xl%it((DD4h.t0.u)of3ccotm5xoci,rne,I,p.c2-rIV,)0e-((51eoioott?(m–2gr)IIMIIIsII)-r,ssuLospiaetnr9iDFM,)MM10mg-sISg)5ooang1lhdiiloSo7ue5,)erkVcrac.t6pp(ipnb0LDFBDL0BB55.5m5..rDr(iOLOwwO0))n.((rr2Ecbr2300(,)cnME(S(Feoaisn-lE%1:e0IIoH2F)nbhRGGooalGEl55rH1cHFgu(2m5MMcpeetirelrlOrf)SPrp.tBBlceaaredrcyp(1(r(P6.a(Iv))aIlI(IA0M-mADu1-)oeM12itusalkaarfIrrMiMVMeu1r5BRBn5rgSTBaBmen)rno(iceotBDDor(eE)PfibS(1mpsimesDrcarlaare:2ursd6,ebpOpuoe5yIidlaasu1MmmCnc-s,ilIaMBCueaeho,(dnp1ni,MC:lnPltoedemB)Vri1pamuoaAEWgo,Maby;niptilt6VuarPe(icmuanwtgMfFBo-ik,A(roIlLEosertFvti,r)Igtetn3MoH:aermcPts%o2dele9%,Aape3:rf.4,y,nsxderue63y;-s)cd/rZ-srs-dsauengammtteookCeesaagi,a.,eenupfdcAt2sgladi,laMe,c)eem4:nngooir–outluaeso,srO4bo2baglladylpmotrCC3,jIdsrAAgobxeut.ei,i1ApL(ae;tr,oetrtaasdsMaDnsNNadesDCAA,VaFNNP/0,NoZrre;otomgvu,dF1lsdca,)nL,2lLhcjxiriiTrVtid:0ooFaO)3dnyolsreEnss;xCde,asr-rpm,eA,sG,akeysaVdFaaoCo0Lmnn,T(1,tIcttn,sFle)MiRoe;Sasu6vld,e2gd1FMoefmipupoAdpos5rce,,1g-o:F,BmeIienernhoermx,tvVIe?ifl-aMewMrssloSuuEtolgosFaghBsoskabatyd3lfrondFcCsIrm,mkI2ind,(e,A:atereanIuFM:caMgviMce2SFH:gvtiFuslBgfrraForTurafsulFDycAo;e;intae;ngziomDrasusiutlsetccecu,:sMddisheetf/e,ero)eDBoDffednoerolcbhcS;4MSR:eisngyatsDalBLi-U–OutS:imnirwsiTQ2BLTMpLcEuas(nDB2S)iLHx;alede;orvnorDnZZTD2sis,o))eMr)MM13sBaDD2)DoDeevapnvpftitoolnitpBdaruMM2B,MDrMndccpioisngeaoe:;searbbN,BMopBudllslNiBB)sstrnguarlesDeetnaaeFcdnFDNBoyersmbdZnmni)MF)dtabeerPoIurlae1B3osmbsOusihrsuftfmpoOiOo1ecen-m)2MgnSbOecdulmociCDb,3aLlarn:oefAh)t-oOS:rlftCLtip(C1oTar,tslfhe)CLck;nuI:Ds1aMreeimtnaFoe;fle:Femap2:rs2iMx;vuloDtidI-Mm123F).?.7AF6.A2.AAAAAAeaovmPuptiyFFg71N(8N61NNNNNNeOorndifCg;inalrIuak1A4slaN:ylidnNFnidsasbooomoes;rr\":m2yGldsetl-dV:oi];s2ouI479008083.........pMm63..?AoD:Rer2cit[tBg565244652562222222222NbLsI:Oe;oOEorek2MGngcNcIvBatil;iha.rtorMrcndccrooohuned;ufsttr#coD:edaeuttwiuas1d44LoLase;lalanebVe4r..hith346h43.S0SS5edtbrlndntoEr5440s49.uaieFp.N5NN1t61pchoyc%o%eilvS:tcbiiNtCfonaI1:edoed:tappyrtitn;nrylehpnoioiupmtorfilnyyn56ollcn%anuukrrxn731o0895noqoeepgnlorcneF253///s;ex1:ctiS/s1315so6////sM127365e0376els3/1S:ednen;e:leiesa2416ae8llnUe;M26ma6aiiQL:htseMFMeessIhagomly;sstn;tlirouiaowooidslicertpesonstt,66682513veoaIslogr704166557676ydneedeocrtyptieAy6666oralA:orcitttsaerNcforedoirerocpny;ivpecxitfsotcemoda%ditimebetesjn85800122nlegniep38120146edeb5118442270oatnys113cbois:tuort1opslrraSfoVeterl:D:ere1cElvrVMoFaerEBcegnnioF-st;n#:.m4:C]hZy.fe;n;tiertelB:raeigToc-ita[]]mwZaCupol3r]]]3]eoy0]1\"2]2eapgr3]5]fed;Eh30323[1[42rrcodck;olt[[enkLu2[2N2[]8]F:[bncatiilmgNA724-lBaN[I[KOELIOOevsLSR2[3[Ie;lIZ[aalv0tTZSORTNOUILaeitos0AsLENEELBSoried0rTiOINMIOATAAELmCUAMidcICKmFBREJVKMOKBSDKDNIfosrcr,1IBM:oefpof+:,EUROPEANRESPIRATORYJOURNAL
VOLUME34NUMBER1
215
cREVIEW:COPDneededtoinvestigatetheinfluenceofchangeinBMIand/orFFMIonchangeinBMDinCOPD.
AhigherGOLDstageand/oralowerFEV1havebeenshowntobecorrelatedwithosteoporosisand/oralowBMD[20,31,34].Also,insubjectswithoutCOPD,significantcorrelationsbetweenFEV1andBMDhavebeenfound[45–47].TheserelationshipsbetweenlungfunctionparametersandBMDarecomplexandnotyetclear.Again,inCOPDpatients,systemicinflammationcanbeakeyfactor,asreducedlungfunctionhasbeenfoundtobeassociatedwithincreasedinflammatorymarkers,whichisariskfactorforosteoporosis[48].Astrongrelationshipbetweenserum25-hydroxyvitaminDandpul-monaryfunctionparameterswasfoundinpatientsfromthethirdNationalHealthandNutritionExaminationSurvey[49].ThiscouldbeanotherlinkbetweenlungfunctionandBMD.ItisalsopossiblethatthereisnocausalrelationshipbetweenlungfunctionandBMD.PerhapsreducedphysicalactivitybecauseofimpairedlungfunctionisthereasonforreducedBMD[50].MorelongitudinalstudiesareneededtoinvestigatethepossiblecausalitybetweenlungfunctionandBMD.OnlySCANLONetal.[33]havefoundage.56yrsandfemalesextobeindependentcorrelatesofosteoporosisinCOPD.Indeed,inthegeneralpopulationhigher,ageandfemalesexaretwoofthemostimportantriskfactorsforosteoporosis[8].InCOPDpatientstheseriskfactorsmaydisappearaftercorrectionforotherriskfactorsthataremoreimportantinCOPDandlessimportantinthegeneralpopulation.Otherexplanationscouldbelimitedsamplesize,cross-sectionaldesignofmostofthetrials,inclusionofonlymalesoronlyfemalesand/oraselectedagecategory.Morelargelong-itudinaltrialsareneededtoinvestigatetheinfluenceofahigherageand/orfemalesexonBMDinCOPDpatients.TreatmentofosteoporosisinCOPD
Thepharmacologicaltreatmentofosteoporosisshouldconsistofbisphosphonatesincombinationwithcalciumsupplemen-tation(incaseoflowdietarycalciumintake)andwithvitaminDsupplements(incaseofvitaminDdeficiency)[8].Theprotectiveeffectofbisphosphonateshasbeenfoundinmulti-plestudies[51–54].However,nostudieswerefoundinvesti-gatingthedrugtreatmenttopreventfracturesinpatientswithosteoporoticCOPDonly.Twostudies[55,56]investigatedalendronateinpatientswithasthmaorCOPD.Bothstudiestreatedthepatientsfor1yr.SMITHetal.[56]foundasignificantimprovementinT-andZ-scoresforlumbarspineBMD,butnotforBMDatthehipinthealendronategroup.LAUetal.[55]foundanincreaseinBMDinthealendronategroupandadecreaseintheplacebogroup,andthesechangesinBMDweresignificantlydifferentbetweenthetwogroups.Inthesestudies,differenteligibilitycriteriawereused(malesandfemalesversusfemalesonly,patientswithhighfractureriskversuspatientsoninhaledcorticosteroids).Inaddition,patientcharacteristicsweredifferent(67versus49yrsofage,percentageasthmaandCOPDunknownversusmajorityasthmapatients).Theresultsofthetwostudiescouldnotbepooled.ThesetwostudiesmayindicatethatalendronateimprovesBMDinCOPDpatients.
MIRZAEIetal.[57]investigatedtheeffectofrocaltrolinpatientswithaT-score,-1andcomparedthiswithcontrolpatients.
216
VOLUME34NUMBER1
L.GRAAT-VERBOOMETAL.
However,patientsandtreatingphysicianswerenotblindedfortreatment,becausethepatientswereassignedtothecontrolgroupiftheyhadcontra-indicationsforrocaltroloriftheywereunwillingtouserocaltrol.Again,nothingcanbeconcludedabouttheeffectofrocaltrolinCOPDpatientsonly.Consideringthemethodologicalqualityofthethreedescribedtrials,onlySMITHetal.[56]scoredhighontheDelphiscoringlist(8points)whereastheothertwostudies[55,57]scoredverylow(4and2points,respectively;seeonlinesupplemen-tarymaterial,tableE2).RCTsinCOPDpatientsonlyandwithalong-termfollow-upareneeded.
NostudieswerefoundthatinvestigatedtheeffectoflifestylechangesonBMDinCOPDpatients.However,inanRCT,lungtransplantationpatientswhoperformed6monthsofexerciseonalumbarextensormachinesignificantlygainedlumbarBMD,incontrasttothecontrolpatients(alsoafterlungtransplantationwithoutexercise)wholostlumbarBMD[58].AnotherRCTcomparedtheeffectofalendronateplusmechanicalloadingtoalendronatealoneandtocontrolpatients(withoutalendronateandwithoutmechanicalload-ing)inlungtransplantrecipients[59].Again,incontrolpatientsasignificantdecreaseinBMDcomparedwithbaselineBMDwasfoundafter8months(-14.1%).InpatientstreatedwithalendronatetheBMDincreased(1.4%)andinthealendronateplusmechanicalloadinggrouptheBMDincreasedevenmore(10.8%).Incontrast,ina4-yrRCTinmiddle-agedmalesregularaerobicexercisetraininghadnosignificanteffectonfemoralBMD[60].InterventionstudiesinCOPDpatientsareneededtoinvestigatethepossibleshort-andlong-termeffectsofprogressiveresistancetrainingonBMD[61].Conclusions
PrevalenceofosteoporosisandosteopeniaseemstobehighinCOPDpatients.CorrelatesofosteoporosisinCOPDarebodycompositionmeasurements,measuresofdiseaseseverityandcorticosteroids.Althoughcausalityhasnotbeenproven,basedonthecurrentresultsitseemsreasonabletoadvise(chest)physicianstoscreenforosteoporosisinCOPDpatientswithalowBMI(,21kg?m-2)and/oralowFFMI(,16kg?m-2inmalesand,15kg?m-2infemales).TheeffectsoftreatmentofosteoporosishavenotbeeninvestigatedinpatientswithCOPDonly.Furtherareaswhereresearchisneeded
TodetermineriskfactorsofosteoporosisinCOPD,moreprospectivestudiesareneeded.Moreover,randomised(placebo-)controlledtrialsontheeffectsofpulmonaryrehabilitation(includingprogressiveresistancetrainingandnutritionalmodulation[62])and/orrelevantdrugtreatmentonBMDandfractureriskreductionarewarrantedinosteoporoticpatientswithCOPD.STATEMENTOFINTEREST
StatementsofinterestforE.F.M.WoutersandF.W.J.M.Smeenkcanbefoundatwww.erj.ersjournals.com/misc/statements.dtl
ACKNOWLEDGEMENTS
WethankE.J.Martens(PhD,statisticaladvisorfortheDeptofEducationandResearch,CatharinaHospitalEindhoven,Eindhoven,theNetherlands)forherstatisticaladvice.Wethankthefollowingauthorsforprovidingadditionalinformation:L.Førli(DeptofMedicine,Rikshospitalet,UniversityofOslo,Oslo,Norway),C.E.
EUROPEANRESPIRATORYJOURNAL
L.GRAAT-VERBOOMETAL.Bolton(DeptofRespiratoryMedicine,SchoolofMedicine,CardiffUniversity,Cardiff,UK),F.Karadag(DeptofChestDiseases,AdnanMenderesUniversitySchoolofMedicine,Aydin,Turkey),E.F.Dubois(DeptofPulmonaryDiseases,ReinierdeGraafGroepDelftandVoorburg,theNetherlands),R.M.Aris(DeptofMedicine,SurgeryandTransplant,TheUniversityofNorthCarolina,atChapelHill,NC,USA),N.R.Jørgensen(DeptofClinicalBiochemistry,CopenhagenUniversityHospitalHvidovre,Hvidovre,Denmark)andD.D.Bikle(EndocrineUnit,VAMedicalCenter,SanFrancisco,CA,USA).
REFERENCES
1RabeKF,HurdS,AnzuetoA,etal.Globalstrategyforthediagnosis,management,andpreventionofchronicobstructivepulmonarydisease:GOLDexecutivesummary.AmJRespirCritCareMed2007;176:532–555.
2AgustiAG.Systemiceffectsofchronicobstructivepulmonarydisease.ProcAmThoracSoc2005;2:367–370.
3SabitR,BoltonCE,EdwardsPH,etal.Arterialstiffnessandosteoporosisinchronicobstructivepulmonarydisease.AmJRespirCritCareMed2007;175:1259–1265.
4ScholsAM,BroekhuizenR,Weling-ScheepersCA,etal.Bodycompositionandmortalityinchronicobstructivepulmonarydisease.AmJClinNutr2005;82:53–59.
5WoutersEF.Introduction:systemiceffectsinchronicobstructivepulmonarydisease.EurRespirJSuppl2003;46:1s.
6HolguinF,FolchE,ReddSC,etal.ComorbidityandmortalityinCOPD-relatedhospitalizationsintheUnitedStates,1979to2001.Chest2005;128:2005–2011.
7BiskobingDM.COPDandosteoporosis.Chest2002;121:609–620.8WHOScientificGrouponthePreventionandManagementofOsteoporosis.PreventionandManagementofOsteoporosis:reportofaWHOscientificgroup.http://whqlibdoc.who.int/trs/WHO_TRS_921.pdf.Datelastaccessed:December2,2008.
9AbeE,SunL,MechanickJ,etal.Bonelossinthyroiddisease:roleoflowTSHandhighthyroidhormone.AnnNYAcadSci2007;1116:383–391.
10CompstonJE.Riskfactorsforosteoporosis.ClinEndocrinol(Oxf)
1992;36:223–224.
11LumachiF,CamozziV,ErmaniM,etal.Bonemineraldensity
improvementaftersuccessfulparathyroidectomyinpre-andpostmenopausalwomenwithprimaryhyperparathyroidism:aprospectivestudy.AnnNYAcadSci2007;1117:357–361.
12BoltonCE,IonescuAA,ShielsKM,etal.Associatedlossoffat-free
massandbonemineraldensityinchronicobstructivepulmonarydisease.AmJRespirCritCareMed2004;170:1286–1293.
13ShepherdAJ,CassAR,CarlsonCA,etal.Developmentand
internalvalidationofthemaleosteoporosisriskestimationscore.AnnFamMed2007;5:540–546.
14LeechJA,DulbergC,KellieS,etal.Relationshipoflungfunction
toseverityofosteoporosisinwomen.AmRevRespirDis1990;141:68–71.
15BapojeSR,WhitakerJF,SchulzT,etal.Preoperativeevaluationof
thepatientwithpulmonarydisease.Chest2007;132:1637–1645.16SmetanaGW.Preoperativepulmonaryevaluation.NEnglJMed
1999;340:937–944.
17TraynerEJr,CelliBR.Postoperativepulmonarycomplications.
MedClinNorthAm2001;85:1129–1139.
18VerhagenAP,deVetHC,deBieRA,etal.TheDelphilist:acriteria
listforqualityassessmentofrandomizedclinicaltrialsforconductingsystematicreviewsdevelopedbyDelphiconsensus.JClinEpidemiol1998;51:1235–1241.
19ForliL,MellbyeOJ,HalseJ,etal.Cytokines,boneturnover
markersandweightchangeincandidatesforlungtransplantation.PulmPharmacolTher2008;21:188–195.
EUROPEANRESPIRATORYJOURNAL
REVIEW:COPD
20VriezeA,deGreefMH,WijkstraPJ,etal.Lowbonemineraldensity
inCOPDpatientsrelatedtoworselungfunction,lowweightanddecreasedfat-freemass.OsteoporosInt2007;18:1197–1202.
21JørgensenNR,SchwarzP,HolmeI,etal.Theprevalenceof
osteoporosisinpatientswithchronicobstructivepulmonarydisease:acrosssectionalstudy.RespirMed2007;101:177–185.22MineoTC,AmbrogiV,MineoD,etal.Bonemineraldensity
improvementafterlungvolumereductionsurgeryforsevereemphysema.Chest2005;127:1960–1966.
23KaradagF,CildagO,YurekliY,etal.ShouldCOPDpatientsbe
routinelyevaluatedforbonemineraldensity?JBoneMinerMetab2003;21:242–246.
24DuboisEF,RoderE,DekhuijzenPN,etal.DualenergyX-ray
absorptiometryoutcomesinmaleCOPDpatientsaftertreatmentwithdifferentglucocorticoidregimens.Chest2002;121:1456–1463.25KatsuraH,KidaK.Acomparisonofbonemineraldensityin
elderlyfemalepatientswithCOPDandbronchialasthma.Chest2002;122:1949–1955.
26TschoppO,BoehlerA,SpeichR,etal.Osteoporosisbeforelung
transplantation:associationwithlowbodymassindex,butnotwithunderlyingdisease.AmJTransplant2002;2:167–172.
27DimaiHP,DomejW,LebG,etal.Bonelossinpatientswith
untreatedchronicobstructivepulmonarydiseaseismediatedbyanincreaseinboneresorptionassociatedwithhypercapnia.JBoneMinerRes2001;16:2132–2141.
28IncalziRA,CaradonnaP,RanieriP,etal.Correlatesofosteoporo-sisinchronicobstructivepulmonarydisease.RespirMed2000;94:1079–1084.
29ArisRM,NeuringerIP,WeinerMA,etal.Severeosteoporosis
beforeandafterlungtransplantation.Chest1996;109:1176–1183.30BoltonCE,Cannings-JohnR,EdwardsPH,etal.Whatcommunity
measurementscanbeusedtopredictbonediseaseinpatientswithCOPD?RespirMed2008;102:651–657.
31KjensliA,MowinckelP,RygMS,etal.Lowbonemineraldensityis
relatedtoseverityofchronicobstructivepulmonarydisease.Bone2007;40:493–497.
32KomerikN,AkkayaA,YildizM,etal.Oralhealthinpatientson
inhaledcorticosteroidtreatment.OralDis2005;11:303–308.
33ScanlonPD,ConnettJE,WiseRA,etal.Lossofbonedensitywith
inhaledtriamcinoloneinLungHealthStudyII.AmJRespirCritCareMed2004;170:1302–1309.
34BikleDD,HalloranB,FongL,etal.Elevated1,25-dihydroxyvitamin
Dlevelsinpatientswithchronicobstructivepulmonarydiseasetreatedwithprednisone.JClinEndocrinolMetab1993;76:456–461.35SzymanskiP,MosiewiczJ,MyslinskiW,etal.Theinfluenceof
chronicobstructivepulmonarydiseaseontheoccurrencerateandintensificationofosteoporosis.AnnUnivMariaeCurieSklodowska[Med]2002;57:187–195.
36TuzunS,AkarirmakU,UludagM,etal.IsBMDsufficientto
explaindifferentfractureratesinSwedenandTurkey?JClinDensitom2007;10:285–288.
37BalasubramanianVP,VarkeyB.Chronicobstructivepulmonary
disease:effectsbeyondthelungs.CurrOpinPulmMed2006;12:106–112.
38EidAA,IonescuAA,NixonLS,etal.Inflammatoryresponseand
bodycompositioninchronicobstructivepulmonarydisease.AmJRespirCritCareMed2001;164:1414–1418.
39KardosP,KeenanJ.TacklingCOPD:amulticomponentdisease
drivenbyinflammation.MedGenMed2006;8:54.
40RothM.PathogenesisofCOPD.PartIII.InflammationinCOPD.
IntJTubercLungDis2008;12:375–380.
41WoutersEF.Localandsystemicinflammationinchronic
obstructivepulmonarydisease.ProcAmThoracSoc2005;2:26–33.42YawnBP,KaplanA.Co-morbiditiesinpeoplewithCOPD:aresult
ofmultiplediseases,ormultiplemanifestationsofsmokingandreactiveinflammation?PrimCareRespirJ2008;17:199–205.
VOLUME34NUMBER1
217
cREVIEW:COPD43CavanaghPR,LicataAA,RiceAJ.Exerciseandpharmacological
countermeasuresforbonelossduringlong-durationspaceflight.GravitSpaceBiolBull2005;18:39–58.
44VanVlietM,SpruitMA,VerledenG,etal.Hypogonadism,
quadricepsweakness,andexerciseintoleranceinchronicobstructivepulmonarydisease.AmJRespirCritCareMed2005;172:1105–1111.45ChoiJW,PaiSH.Associationbetweenrespiratoryfunctionand
osteoporosisinpre-andpostmenopausalwomen.Maturitas2004;48:253–258.
46LekamwasamS,TrivediDP,KhawKT.Anassociationbetween
respiratoryfunctionandbonemineraldensityinwomenfromthegeneralcommunity:acrosssectionalstudy.OsteoporosInt2002;13:710–715.
47LekamwasamS,TrivediDP,KhawKT.Anassociationbetween
respiratoryfunctionandhipbonemineraldensityinoldermen:across-sectionalstudy.OsteoporosInt2005;16:204–207.
48GanWQ,ManSF,SenthilselvanA,etal.Associationbetween
chronicobstructivepulmonarydiseaseandsystemicinflamma-tion:asystematicreviewandameta-analysis.Thorax2004;59:574–580.
49BlackPN,ScraggR.Relationshipbetweenserum25-hydroxyvita-mindandpulmonaryfunctioninthethirdnationalhealthandnutritionexaminationsurvey.Chest2005;128:3792–3798.
50WatzH,WaschkiB,BoehmeC,etal.Extrapulmonaryeffectsof
chronicobstructivepulmonarydiseaseonphysicalactivity:across-sectionalstudy.AmJRespirCritCareMed2008;177:743–751.51BlackDM,SchwartzAV,EnsrudKE,etal.Effectsofcontinuingor
stoppingalendronateafter5yearsoftreatment:theFractureInterventionTrialLong-termExtension(FLEX):arandomizedtrial.JAMA2006;296:2927–2938.
52BoneHG,HoskingD,DevogelaerJP,etal.Tenyears’experience
withalendronateforosteoporosisinpostmenopausalwomen.NEnglJMed2004;350:1189–1199.218
VOLUME34NUMBER1L.GRAAT-VERBOOMETAL.
53FogelmanI,RibotC,SmithR,etal.Risedronatereversesboneloss
inpostmenopausalwomenwithlowbonemass:resultsfromamultinational,double-blind,placebo-controlledtrial.BMD-MNStudyGroup.JClinEndocrinolMetab2000;85:1895–1900.
54McClungMR,GeusensP,MillerPD,etal.Effectofrisedronateon
theriskofhipfractureinelderlywomen.HipInterventionProgramStudyGroup.NEnglJMed2001;344:333–340.
55LauEM,WooJ,ChanYH,etal.Alendronateforthepreventionof
bonelossinpatientsoninhaledsteroidtherapy.Bone2001;29:506–510.
56SmithBJ,LaslettLL,PileKD,etal.Randomizedcontrolledtrialof
alendronateinairwaysdiseaseandlowbonemineraldensity.ChronRespirDis2004;1:131–137.
57MirzaeiS,ZajicekHK,KnollP,etal.Effectofrocaltrolonbone
massinpatientswithpulmonarydiseasetreatedwithcorticoster-oids.JAsthma2003;40:251–255.
58MitchellMJ,BazMA,FultonMN,etal.Resistancetraining
preventsvertebralosteoporosisinlungtransplantrecipients.Transplantation2003;76:557–562.
59BraithRW,ConnerJA,FultonMN,etal.Comparisonof
alendronatevsalendronateplusmechanicalloadingasprophy-laxisforosteoporosisinlungtransplantrecipients:apilotstudy.JHeartLungTransplant2007;26:132–137.
60HuuskonenJ,VaisanenSB,KrogerH,etal.Regularphysical
exerciseandbonemineraldensity:afour-yearcontrolledrandomizedtrialinmiddle-agedmen.TheDNASCOstudy.OsteoporosInt2001;12:349–355.
61SpruitMA,GosselinkR,TroostersT,etal.Resistanceversus
endurancetraininginpatientswithCOPDandperipheralmuscleweakness.EurRespirJ2002;19:1072–1078.
62SpruitMA,WoutersEF.Newmodalitiesofpulmonaryrehabilita-tioninpatientswithchronicobstructivepulmonarydisease.SportsMed2007;37:501–518.
EUROPEANRESPIRATORYJOURNAL
因篇幅问题不能全部显示，请点此查看更多更全内容