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RMDOpen20151:e000077doi:10.1136/rmdopen2015000077

Osteoarthritis
Exte nde dre port

Associationbetweendiabetesmellitusandosteoarthritis:systematicliteraturereview
andmetaanalysis
KarineLouati 1, 2, 3,ClineVidal 1, 2,FrancisBerenbaum1, 2, 3, 4andJrmieSellam1, 2, 3, 4
+

AuthorAf f iliations

Correspondenceto
Prof essorFrancisBerenbaumf rancis.berenbaum@sat.aphp.f r

Abstract
ObjectivesToinv estigatetheprev alenceof osteoarthritis(OA)inpatientswithdiabetesmellitus(DM)andprev alenceof DMinpatientswithOAand
whetherOAandDMareassociated.
DesignAsy stematicliteraturerev iewandmetaanaly sis.Weincludedcohort,casecontrolandcrosssectionalstudiesassessingthenumberof
patientswithDMand/orOA.Themeanprev alenceof OAamongpatientswithDMandDMamongpatientswithOAwascalculated.Dataf romtrials
assessinganassociationof diabetesandOAwerepooledandresultsarepresentedasunadjustedORand95%CI.
ResultsFromthe299publications,weincluded49studiesintheanaly sis,including28crosssectionalstudies,11cohortstudiesand10casecontrol
studies.Inall,21,5and23articlesinv olv edpatientswithOAexclusiv ely ,patientswithDMandthegeneralpopulation,respectiv ely .For5788patients
withDM,themeanOAprev alencewas29.51.2%.For645089patientswithOA,theprev alenceof DMwas14.40.1%.Theriskof OAwasgreaterinthe
DMthannonDMpopulation(OR=1.46(1.08to1.96),p=0.01),aswasDMintheOAthannonOApopulation(OR=1.41(1.21to1.65),p<0.00001).Among
the12studiesreportinganORadjustedonatleastthebody massindex,5showednoassociationof DMandOAand7identif iedDMasanindependent
riskf actor.
ConclusionsThismetaanaly sishighlightsahighf requency of OAinpatientswithDMandanassociationbetweenbothdiseases,representingaf urther
steptowardstheindiv idualisationof DMrelatedOAwithinametabolicOAphenoty pe.

Keymessages
Whatisalreadyknownonthissubject?
Metabolicsy ndromeandosteoarthritishav ebeenf oundtobeassociatedinsomestudies,delineatingthemetabolicosteoarthritisphenoty pe.
Associationbetweendiabetesmellitusandosteoarthritisinepidemiologicalstudieshav egiv enconf lictingresults.
Whatdoesthisstudyadd?
Thisisthef irstmetaanaly sisshowinganassociationbetweenosteoarthritisanddiabetesmellitus.
Howmightthisimpactonclinicalpractice?
Treatingdiabetesmellitusmay beef f ectiv einpatientswithosteoarthritis.

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Prev entioninitiativ esof osteoarthritismay bespecif ically proposedtopatientswithdiabetesmellitus.

Introduction
Osteoarthritis(OA)isthemostf requentanddisablingjointdiseaseinadults.Besidesitssev erallocalisations,arecenthy pothesishassuggestedanew
classif icationf orphenoty pingOAthatincludesageing,metabolicsy ndrome(MetS)andposttraumaticev entsandgeneticrelatedOA. 1 , 2 Despitesome
sharedpathophy siologicalmechanismsamongthesephenoty pes,eachmay display specif icpathway s.
InMetSassociatedOA,themechanicalimpactof ov erweightorobesity onjointsmay easily explainkneeOA.Howev er,withinthisphenoty pe,considering
theepidemiologicalassociationof ov erweightorobesity andhandOA,somesy stemicf actorsmay participateinthepathogenicprocessf orexample,
adiposetissueproducts,oradipokines,may hav easy stemicimpactatadistanceonjoints. 35 Bey ondobesity relatedOA,MetSandOAhav ebeen
f oundtobeassociatedinsomeepidemiologicalstudies,whichsuggeststhattheothercomponentsof MetS,suchasdiabetesmellitus(DM),highblood
pressureordy slipidaemiamay togetherorindependently participateintheOApathophy siology . 6 , 7 Alongthisline,DMandhy pergly caemiaseemedtobe
associatedwithOAinsomeepidemiologicalstudies. 811 Moreov er,thelinkbetweenthetwodiseasesmay besupportedby thedeleteriousroleof glucose
excessthroughtheaccumulationof adv ancedgly cationendproducts(AGEs),oxidativ estressandpromotionof sy stemicinf lammation. 1215 This
situationiswellillustratedby spontaneouscartilagedisruptionintheratmodelof streptozotocininduceddiabetes. 1215 Howev er,otherpublicationshav e
questionedthelinkbetweenDMandOA. 16 , 17
Tof urtheraddresstheassociationof OAandDM,weperf ormedasy stematicrev iewof theliteratureandametaanaly sistoinv estigatetheprev alenceof
OAamongpatientswithDMandthatof DMamongpatientswithOAandtodeterminewhetherDMandOAareassociated.

M e thods
Systematicliteraturesearchandselectionofrelevantstudies
Weperf ormedasy stematicrev iewof theliteratureaccordingtotheCochraneguidelines(http://handbook.cochrane.org/,24February 2014,datelast
accessed).Relev antpublicationswereselectedf romthreedatabases(PubMed,EMBASEandtheCochraneLibrary )withoutany limitationontime(upto
June2013andupdatedinJanuary 2015).Wealsosearchedf orarticlesintheref erencesof selectedpublicationsandthemaincongressesof
rheumatology f orOA(AmericanCollegeof Rheumatology (ACR),EuropeanLeagueAgainstRheumatism(EULAR)andOsteoarthritisResearchSociety
International(OARSI))andcongressesof endocrinology (Endocrinesociety 'sannualmeeting,EuropeanCongressof Endocrinology ,AmericanDiabetes
AssociationandEuropeanAssociationf ortheStudy of Diabetes)f rom2012to2014.Weusedthef ollowingkey wordsf orthePubMedsearch:(diabetes
mellitus,ty pe2[MeSH]ORdiabetesmellitus,ty pe1[MeSH]ORdiabetescomplications[MeSH]ORmetabolicsy ndromeX[MeSH]OR(blood
glucose[MeSH]ORbloodglucose[AllFields]))ANDosteoarthritis[MeSH]AND(humans[MeSH]AND(English[lang]ORFrench[lang])).
Weincludedobserv ationalstudies(ie,cohort,casecontrolandcrosssectionalstudies)assessingthenumberof patientswithOAand/orDM,orthe
incidenceorprev alenceof OAinpatientswithDMorDMinpatientswithOA,oranassociationbetweenOAandDM.Weexcludedarticlesof therapeutic
studies,rev iewsandcasereportsaswellaslettersstudiesinwhichallpatientshadOAandDMorinwhichthelinkbetweenOAandDMwasnotreported
andstudieswithoutanav ailablenumberof patientswitheachdisease.Selectionof articleswasbasedontitlesandabstractsthanonthef ulltext.One
author(KL)hasmanagedthisselection.

Dataextraction
Twoauthors(KLandCV)extractedthef ollowingdata:study designandpopulation(observ ationalstudy ,quality score,def initionof DMandOAand
localisationof OA)exposuregly caemia(f astingbloodglucose(FBG)lev el,mmol/L)orgly cosy latedhaemoglobin(HbA1c%)ornumberof patientswith
DMoutcome(numberof patientswithOA)body massindex(BMI,kg/m 2)ornumberof patientswithobesity aspotentialconf oundersassociation
measure(relativ eriskorORoronly conclusiononanassociation).Thenweconv ersely consideredOAasanexposuref actorandDMasanoutcome.The
study quality wasassessedby theStrengtheningtheReportingof Observ ationalStudiesinEpidemiology (STROBE)scaleandresultsarereportedasa
percentageof 19pertinentitemsof the22totalitems. 18

Statisticalanalysis
Weperf ormedtwoanaly seswithav ailableresultsf romtrials.First,weperf ormedadescriptiv eanaly sis:f orcrosssectional,casecontrolorcohort
studies,weusedthenumberof patientswithOAorDMandtotalnumberineachpopulationtocalculatetheprev alenceof OAamongpatientswithDMand
thatof DMamongpatientswithOA.Toestimatethisprev alencef romcohortlongitudinalprospectiv estudies,weusedbaselinedata.Prev alenceis
expressedasmeanSD.Second,weperf ormedacomparativ eanaly sisusingstudiesassessinganassociationbetweendiagnosisof DMandOAincross
sectionalstudiesandcohortstudiesof thegeneralpopulationandcasecontrolstudiesof OAorDMpopulations.Wecalculatedtheoddsof hav ingOA
amongpatientswithDMandof DMamongpatientswithOAwithORsand95%CIs.ThenweusedRev manV.5.2toperf ormametaanaly siswithaf ixed
ef f ectsmodel.Arandomef f ectsmodelwasusedwithhighheterogeneity amongstudies(>50%),ev aluatedby I 2,andasensitiv ity analy siswas
perf ormedby remov ingstudieswithaberrantresultsandcombiningstudieswiththesamecharacteristics.OR>1andp0.05wasconsideredanincreased
riskof OAamongpatientswithDMand/orDMamongpatientswithOA.

Re sults
Literaturesearchandcharacteristicsofincludedtrials
Theselectionof articlesisinf igure1:f rom299publications,weincluded49intheanaly sis.Wef oundnopublicationbias(seeonlinesupplementary f igure
S1).Thearticlesrepresented28crosssectional,11cohortand10casecontrolstudies.Intotal,21,5and23inv olv edexclusiv ely patientswithOA,
exclusiv ely patientswithDMandthegeneralpopulation,respectiv ely (table1).
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Table1
Descriptionof the49studiesselectedf oranaly sis

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Figure1
Flowchartof selectionof articles.OA,osteoarthritisDM,diabetesmellitusRA,rheumatoidarthritisMetS,metabolicsy ndromeCV,cardiov ascular
ACR,AmericanCollegeof Rheumatology EULAR,TheEuropeanLeagueAgainstRheumatismOARSI,OsteoarthritisResearchSociety International.

Thecriteriaof inclusionf orthegeneralpopulationwerev ariablef orage:f rom20to86y earsf ortheIwakiHealthPromotionProject, 20 andf rom65to84
y earsf ortheILSAstudy 46 thepatientshadradiographsof hipsf orthestudy of Ty ppo, 31 ordatawereextractedf rompublicserv icedataf orthestudy
of Nav arroetal. 34 Inmostcases,OAwasdef inedby radiologicalandclinicalcriteria,usually basedontheACRcriteria.DMwasdef inedby elev ated
gly caemia,HbA1cproportionorprescriptionof DMtreatment(table2).
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Table2
Characteristicsof the49includedstudies

Only twostudiesspecif iedthenumberof patientswithty pe1andty pe2DM: 19 , 57 inthestudy of Niev esPlazaetal, 57 therewereonly 14patientswith
ty pe1DMwithasimilarrepartitionintheOAandnonOAgroups,andinthestudy of Ray etal 19 therewere11%patientswithty pe1DMwithasimilar
repartitionintheOAandnonOAgroups.ThemedianSTROBEquality scorewas69%(range3391%table2).For6studies(4casecontroland2cross
sectionalstudies),thescorewas<50%,andf or30studiesitwas>60%.Thecountry of originof thestudieswasdiv erse(22studieswithpatientsf rom
Europeand16studieswithpatientsf romNorthAmerica).Forf ourstudies,OAwassev erebecausetheoutcomewasarthroplasty .Amongthe49studies,
34assessedtheassociationbetweenOAandDM,28thef requency of DMamongpatientswithOAand24thef requency of OAamongpatientswithDM.

Characteristicsofpatients
Atotalof 1192518patientswereincludedintheanaly ses.Themeanagerangedf rom43.843.9to76.95.4y ears. 7 , 46 Themeanproportionof f emales
was78.92%(f rom9.3%to100%). 29 , 35 , 63 Thelocalisationwasthekneef or31studies(kneeonly f or13studies),thehipf or15studies(hiponly f or3
studies),handsf or12studies(handsonly f or4studies)andthespinef or5studies(seeonlinesupplementary tableS1).ThemeanFBGlev elrangedf rom
3.95(noSDav ailable)to12.176.49mmol/LandHbA1cf rom5.10.1%to7.2%(noSDav ailable). 19 , 20 , 63 , 64 Theprev alenceof obesity v ariedgreatly
f rom9.1%to73.2%,andBMIrangedf rom22.32.7to33.85.8g/cm 2. 7 , 20 , 34 , 35 , 36 MetSwasreportedinf iv estudiesusingdif f erentdef initionsin
whichhy pergly caemiawasoneof theitemsandinv olv ed5.158.6%of patients. 7 , 20 , 34 , 36 , 42 , 48

PrevalenceofOAamongpatientswithDMandDMamongpatientswithOA
For5788patientswithDM,themeanOAprev alencewas29.51.2%(meanage=61.01y ears).Thisprev alencewascalculatedby usingthe5and12studies
of patientswithDMandthegeneralpopulation,respectiv ely ,withav ailabledataonthenumberof patientswithOAintheDMpopulation(seeonline
supplementary tableS2).Inthispopulation,theprev alenceof OAcalculatedwithav ailabledataf oreachlocalisationwas17.22.0%f ortheknee, 10 , 19 , 20
, 34 , 42 , 48 12.31.3%f orthehip 31 , 48 and38.46.8%f orthehand. 36 , 50
For645089patientswithOA,theDMprev alencewas14.40.1%.Itwascalculatedby usingthe19and12studiesof patientswithOAandthegeneral
population,respectiv ely ,withav ailabledataonthenumberof patientswithDMintheOApopulation(seeonlinesupplementary tableS2).Threestudies
inv olv ingpatientswithOAwerenotincludedbecausethey assessedsemiquantitativ eorcontinuousv ariables,theKellgrenLawrence(KL)scoreand
gly caemiabutnotOAorDMdiagnosis. 56 , 60 , 63

AssociationsbetweenOAandDM
Intotal,34studiesassessedtheassociationof OAandDMand/orgly caemiaorHbA1cproportion21showedasignif icantassociationintheirconclusions
oratleastreportedOR>1inthetext, 7 , 8 , 10 , 20 , 25 , 28 , 29 , 39 , 41 , 44 , 46 , 5052 , 54 , 55 , 57 , 58 , 60 , 61 , 63 whereas12studiesdisplay edno
association. 16 , 17 , 27 , 31 , 34 , 38 , 42 , 48 , 49

RiskofOAinDM:metaanalysisandsensitivityanalyses

Forriskof OAinaDMv ersusnonDMpopulation,among32137patients,theov erallORwas1.46(1.08to1.96),withhighheterogeneity (I 2=88%f igure

2).Af terexcludingpoorquality studies(ie,STROBEscore<50%),theheterogeneity didnotchange(I 2=88%). 55 , 31 Consideringonly studieswithv alidated
criteriaf ordiabetesincludinggly caemiaorHbA1candexcludingstudieswithdeclarativ edataonly ,theORwas1.58(1.14to2.20),withsimilar
heterogeneity (I 2=89%).Consideringallstudieswiththesamedesign(ie,crosssectional,cohortorcasecontrolstudies),theORwassignif icantf oronly
casecontrolstudies(2.85(1.71to4.73)I 2=0%).

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Figure2
Forestplotf orosteoarthritisamongpatientswithandwithoutdiabetesmellitus.

AmongOAriskf actors,ageandobesity hav eastrongimpactonOAdev elopment.Consideringonly studieswithpatients50y earsold,theORwas1.32

(1.13to1.53),withoutheterogeneity ,whichsuggestedthattheassociationremainedev eninpatientsatincreasedriskof OAbecauseof theirage. 25 , 34
, 36 , 42 , 46
Amongthe12studieswithORadjustedonBMI,5showednoassociationbetweenDMandOA, 16 , 25 , 27 , 48 , 49 but7identif iedDMasanindependentrisk
f actorof OA, 8 , 10 , 29 , 44 , 46 , 51 , 57 andwereof higherquality asillustratedby themeanSTROBEscale(697.4%v s768.5%,respectiv ely ).
Interestingly ,thepositiv estudiesweretherecentones:sixof sev enwerepublishedbetween2009and2013. 8 , 10 , 44 , 46 , 51 , 57 ConsideringOA
localisations:theresultsweresignif icantf orkneeOAonly andhandOAonly (OR=1.64(1.17to2.29)with9170patients 10 , 20 , 34 , 42 , 48 , 55 and
OR=1.31(1.07to1.61)with5879patients, 25 , 36 , 50 respectiv ely )butnotf orhip(OR=0.82(0.56to1.21),with5682patients). 31 , 48

RiskofDMinOA:metaanalysisandsensitivityanalyses
Forriskof DMinanOAv ersusnonOApopulation,among1040175patients,theov erallORwas1.41(1.21to1.65),assessedby arandomef f ectsmodel
becauseof I 2=95%(f igure3).

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Figure3
ForestPlotf orDMamongpatientswithandwithoutOA(OA,osteoarthritisDM,diabetesmellitus).

Weperf ormedf oursensitiv ity analy sestostrengthentheresults.First,withtheheterogeneity explainedby twostudieswithaberrantresults,weremov ed

thesetwostudies. 54 , 59 TheORremainedsimilar:1.42(1.22to1.66),I 2=96%.Second,wef ocusedonsev ereOA(ie,the3studieswithsurgery asanOA
outcomecorrespondingto11805patients)theORwasnotsignif icant:1.32(0.52to3.36)butwithhighheterogeneity (I 2=85%). 10 , 48 , 59 Third,we
remov edthestudiesthatdidnotuseinternationally recogniseddiagnosiscriteriaf orOAsuchasACRcriteriaortheKLscoref orOAdef initiontheORwas
1.32(1.13to1.53)withoutany heterogeneity (I 2=0%)withf iv estudiesand9947patients. 20 , 25 , 42 , 50 , 58 Fourth,weconsideredOAlocalisations:f ordata
inv olv ingkneeOAonly orhipOAonly ,theresultsweresignif icantf ortheknee(OR=1.51(1.09to2.09)with5studiesand9102patients)butnotf orthehip
(OR=0.71(0.49to1.04)with3studiesand6240patients). 10 , 20 , 31 , 34 , 42 , 48 , 59 Wealsof oundasignif icantassociationf ornonweightbearinghandOA
(OR=1.31(1.07to1.61)).Therewasnostudy thatincludedonly generalisedOA.

Discussion
OAisaheterogeneousdisorderthatcanbeseparatedinanagerelated,metabolicandposttraumaticOA,representingthusthethreemainphenoty pesof
thedisease.MetabolicOAiswiderthanobesity relatedOAsinceMetSandOAareepidemiologically linked. 2 , 7 Howev er,theassociationbetweeneach
componentof theMetSandOAneedstobef urtheraddressed.Likewise,weaimedtoassesstheov eralllinkbetweenOAandDM.Weperf ormeda
sy stematicrev iewof theliteratureandmetaanaly sisof dataf rom49studiesinv olv ingalargesampleof participants(n=1192518).Theprev alenceof OA
amongpatientswithDMwas29.51.2%andthatof DMamongpatientswithOAwas14.40.1%.Moreov er,OAandDMweresignif icantly associated:the
ov erallriskof OAintheDMpopulationwas1.46(1.08to1.96)andthatof DMintheOApopulationwas1.41(1.21to1.65).
IntheDMpopulation,theriskof OAwassignif icantwithov eralldata.Allstudieshadapproximately thesameweightintheanaly sis.Sucharesultwas
conf irmedinpatientsolderthan50y ears:DMseemstobeassociatedwithOA,ev enwhenagemay hav easignif icantimpactonOA,whichsuggeststhat
thelinkwithDMdoesnotdependonage.
IntheOApopulation,theriskof DMwasalsosignif icant(OR=1.41(1.21to1.65)).Dataf romtwostudieshadanimportantweightonthisf inding:DM
prev alenceintheOAgroupwas9.7%inthestudy of Rahmanetal, 61 and9.8%intheworkof Wangetal 62 comingf romacongressabstract,andthe
def initiv epublicationf orthisabstractwillbecriticaltoconf irmtheseresults.Itcaninf luencethef inaloutcome,buttheRahmanetal 61 study wasof good
quality .Theassociationof OAandDMwasnotsignif icantwhenweconsideredonly studiesof sev ereOA(ie,timetojointreplacement),probably because
of thesmallnumberof patients. 10 , 48 , 59 Theroleof DMinprogressionof OAiscontrov ersialsinceY oshimuraetal 64 hav ef oundthatDMdef inedas
HbA1cf raction5.5%wasnotindependently associatedwithOAprogression,whereasinarecentstudy ty pe2DMwasasignif icantpredictorof joint
spacenarrowinginmaleswithsy mptomatickneeOA. 65

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Inaddition,recruitmentbiasatthetimeof jointreplacementmay explainthef indingsbecausethepresenceof comorbiditiessuchasDMmay restrictthe

indicationf orsurgery intermsof apotentialincreaseinsubsequentperioperativ eadv erseev ents.Wef oundanespecially signif icantassociationbetween
DMandOAwiththestudiesincludinghandOAonly ,whichhighlightsthemetabolicandsy stemicnatureof handOA,highlightedrecently intheNEO
cohort. 53 , 66 Moreov er,theimpactof DMonsy mptomsoronstructurallesionsmightbedif f erent.Schettetal 67 hav eshownthatsy mptomsof OA
assessedusingtheKneeinjury andOsteoarthritisOutcomeScore(KOOS)andtheWesternOntarioandMcMasterUniv ersitiesArthritisIndex(WOMAC)
weremoresev ereandultrasoundsy nov itisandef f usionof kneesmoref requentinparticipantswithty pe2DMthanthosewithoutDM.Thisinf lammatory
aspectinimagingcorroborateswiththehigherreleaseof inf lammatory mediatorsinOAcartilageexplantsf rompatientswithDMthanthosef rompatients
withoutDM. 68 Thewellcontrolof DMby antidiabetictherapiescouldalsoinf luencetheprev alenceof OA:HbA1cf raction,thatref lectsthethreelast
monthsof DMcontrol,wassignif icantly higherinwomenkneeOAf orY oshimuraetal 8 , 64 andf orInoueetal. 20 Howev er,wehadnodataaboutthe
history of theDMcontrolduringtheprev iousy earsduringwhichOAdev elopedandprogressed.Moreov er,dataaboutantidiabeticdrugswereusedonly to
identif y patientswithDM,butnotasaf actorabletoinf luenceOAoccurrenceorprogression.Theassessmentof theradiographicpatternsof DMrelated
OA(ie,erosiv eOA,dif f useidiopathicskeletalhy perostosis)wasnotpossibleduetoalackof data.Theprev alenceof OAinpatientswithDMwas
14.40.1%.Wemeasuredprev alenceof DMamongpatientswithOA,emphasisingthelinkbetweenbothdiseases.Thisprev alencecouldbecomparedwith
theprev alenceof OAinthegeneralpopulation,butitdependsontheref erencepopulation:32%of OAinIwakiHealthPromotionProject(Japan)and13%
of OAinNHANESIII(USA). 7 , 20 Welackbasicdataontheimpactof OAonDM,butthisremainstobeinv estigatedbecauseof thepossiblesy stemic
ef f ectsof OA. 69
Ourmetaanaly sishassomelimitations.Theheterogeneity washighinthef irstanaly ses,probably becauseof populationcharacteristics(v ariousOA
localisationsordef initions,v ariousDMdef initions,nostratif icationonDMsev erity ortreatment)orv ariousty pesandqualitiesof studies.Howev er,we
perf ormedsev eralsensitiv ity analy ses,whichallowedadecreaseintheheterogeneity lev el,inparticularinsubgroupswithawellrecogniseddef initionof
inclusioncriteriaof OA.Tof urtherdecreaseheterogeneity ,weeliminatedsomestudies:thosethatwereof lowquality orwithadiagnosisof OAnotbased
onACRcriteriaorKLgrading. 39 , 41 , 54 , 60 Howev er,theheterogeneity andresultsdidnotgreatly changebecauseof thelowweightof thesestudiesin
themetaanaly sis.Anotherlimitationistheimpactof conf oundingf actors,especially ageandobesity .Howev er,despiteasignif icantimpactof increasing
ageonOA,theassociationremainedpositiv ewhenweretainedstudiesincludingpatientsolderthan50y ears.Moreov er,weidentif iedsev enstudies
showinganassociationev enaf teradjustmentonBMIintheirmultiv ariatelogisticregression.Themeanscoreof quality wasbetterandmostwererecent
(resultspublishedaf ter2009).Conf oundingf actorssuchasjointinjury ,phy sicalactiv ity ,smoking,hy pertension,dy slipidaemiamighthav eaf f ectedour
f indings,butthesef actorsweretakenintoaccountineachincludedstudy . 8 , 10 InpatientswithDM,neuropathy may alsoaf f ectOAdev elopment,butwe
didnotf indthisinf ormationintheselectedstudies.
Wehav eshownanassociationof DMandOA,butcausality isnoty etclearly demonstrated.Hy pergly caemiacouldpromotejointinf lammationand
cartilagedegradationthroughoxidativ estressandinf lammatory mediatorsinductionaswellasthroughAGEs. 12 Bey ondachronicexcessof glucose,ty pe
2DMischaracterisedby increasedinsulinresistancethatmay beinv olv edinosteophy tedev elopmentandsubchondralbonesclerosis. 9 , 70 , 71 Wethus
needadditionalspecif icprospectiv estudiesf orthatpurpose.
Insummary ,thisisthef irstmetaanaly sisshowinganassociationof OAandDM,giv ingsomeadditionalcluesaboutthedelineationof themetabolicOA
phenoty pe.Largeprospectiv estudiesareneededtoaddresswhetherDMisanindependentriskf actorof OAdev elopmentorsev erity .If thisisthecase,
newprev entiv eand/orcurativ emodalitiesbasedongly caemiacontrolcouldbetestedinOA.

Acknowle dgme nts

TheauthorsthankLauraSMALES(BioMedEditing,Toronto,Canada)f oreditingthemanuscript.KL,FBandJSaresupportedby TheFoundationArthritis
NetworkProgram(ROADproject).

Footnote s
ContributorsKL,JSandFBwereinv olv edinconceptionanddesign.KLwasinv olv edinacquisitionof dataandstatisticalanaly sis.KL,CV,JS
andFBwereinv olv edinanaly sesandinterpretationof data,draf tingof themanuscript,rev isionof themanuscriptandf inalapprov al.KL,JSand
FBhadf ullaccesstoallof thedatainthestudy andtakeresponsibility f ortheintegrity of thedataandtheaccuracy of thedataanaly sis.
CompetinginterestsNone.
ProvenanceandpeerreviewNotcommissionedexternally peerrev iewed.
DatasharingstatementNoadditionaldataareav ailable.

Receiv edJanuary 26,2015.

AcceptedMarch17,2015.
Published2June2015
Publishedby theBMJPublishingGroupLimited.Forpermissiontouse(wherenotalready grantedunderalicence)pleasegoto
http://group.bmj.com/group/rightslicensing/permissions
ThisisanOpenAccessarticledistributedinaccordancewiththeCreativ eCommonsAttributionNonCommercial(CCBY NC4.0)license,whichpermits
otherstodistribute,remix,adapt,builduponthisworknoncommercially ,andlicensetheirderiv ativ eworksondif f erentterms,prov idedtheoriginalworkis
properly citedandtheuseisnoncommercial.See:http://creativ ecommons.org/licenses/by nc/4.0/

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