What is the current status of chondroitin sulfate and glucosamine for the treatment of knee osteoarthritis?

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Pleasecitethisarticleinpressas:HenrotinY,etal.Whatisthecurrentstatusofchondroitinsulfateandglucosamineforthetreatment ofkneeosteoarthritis?Maturitas(2014),http://dx.doi.org/10.1016/j.maturitas.2014.04.015

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MAT-6159; No.ofPages4

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ContentslistsavailableatScienceDirect

Maturitas

j ourna l h o me pa g e :w w w . e l s e v i e r . c o m / l o c a t e / m a t u r i t a s

Review

What

is

the

current

status

of

chondroitin

sulfate

and

glucosamine

for

the

treatment

of

knee

osteoarthritis?

Yves

Henrotin

a,∗

_,

_Marc

_Marty

b

_,

_Ali

_Mobasheri

c,d,e

a_Bone_and_Cartilage_Research_Unit,_Arthropôle_Liège,_University_of_Liège,_Institute_of_Pathology,_CHU_Sart-Tilman,₄₀₀₀_Liège,_Belgium b_Rheumatology_Department,_Teaching_Hospital_H_Mondor,_Creteil,_France

c_School_of_Veterinary_Medicine,_Faculty_of_Health_and_Medical_Sciences,_University_of_Surrey,_Duke_of_Kent_Building,_Guildford,_Surrey_GU2_7XH,

UnitedKingdom

d_Arthritis_Research_UK_Centre_for_Sport,_Exercise_and_{Osteoarthritis,}_Arthritis_Research_UK_Pain_Centre,_Medical_Research_Council_and_Arthritis_Research_UK

CentreforMusculoskeletalAgeingResearch,UniversityofNottingham,Queen’sMedicalCentre,Nottingham,NG72UH,UnitedKingdom

e_Center_of_Excellence_in_Genomic_Medicine_Research_(CEGMR),_King_Fahd_Medical_Research_Center_(KFMRC),_King_AbdulAziz_University,_Jeddah,_21589,

KingdomofSaudiArabia

a

r

t

i

c

l

e

i

n

f

o

Articlehistory: Received8April2014 Accepted12April2014 Availableonlinexxx Keywords: Chondroitin Glucosamine Osteoarthritis Cartilage

a

b

s

t

r

a

c

t

Chondroitinsulfateandglucosaminesulfateexertbeneficialeffectsonthemetabolismofinvitromodels ofcellsderivedfromsynovialjoints:chondrocytes,synoviocytesandcellsfromsubchondralbone,allof whichareinvolvedinosteoarthritis(OA).TheyincreasetypeIIcollagenandproteoglycansynthesisin humanarticularchondrocytesandareabletoreducetheproductionofsomepro-inflammatory media-torsandproteases,toreducethecellulardeathprocess,andimprovetheanabolic/catabolicbalanceofthe extracellularcartilagematrix(ECM).Clinicaltrialshavereportedabeneficialeffectofchondroitinsulfate andglucosaminesulfateonpainandfunction.Thestructure-modifyingeffectsofthesecompoundshave beenreportedandanalyzedinrecentmeta-analyses.TheresultsforkneeOAdemonstrateasmallbut sig-nificantreductionintherateofjointspacenarrowing.Chondroitinsulfateandglucosaminesulphateare recommendedbyseveralguidelinesfrominternationalsocietiesforthemanagementofkneeandhipOA, whileothersdonotrecommendtheseproductsorrecommendonlyundercondition.Thiscomprehensive reviewclarifiestheroleofthesecompoundsinthetherapeuticarsenalforpatientswithkneeOA.

Contents

1. Introduction... 00

2. Methods ... 00

2.1. CSandGlcNinclinicaltrials... 00

2.1.1. Glucosamine(GlcN)... 00

2.1.2. Chondroitinsulfate(CS)... 00

2.1.3. GlcNandCSincombination... 00

2.2. GlNcandCSinguidelines... 00

3. Discussionandconclusions... 00

Contributors... 00

Competinginterest... 00

Funding... 00

Provenanceandpeerreview... 00

References... 00

∗ Correspondingauthorat:BoneandCartilageResearchUnit(BCRU),UniversityofLiège,CHUSart-Tilman,InstituteofPathology,Level+5,Sart-Tilman,4000Liège,Belgium. Tel.:+3243662516.

E-mailaddress:yhenrotin@ulg.ac.be(Y.Henrotin).

http://dx.doi.org/10.1016/j.maturitas.2014.04.015

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1. Introduction

Osteoarthritis(OA),oneofthemostdisablingarthritic condi-tions,isnowclearlydeﬁnedasadiseaseofthewholeorgan;namely, thesynovialjoint[1].Itisacknowledgedthatcartilageisnotthe soletissueaffectedbyOA,butthatthesubchondralboneandthe synovialmembrane(SM)undergometabolicandstructural modi-ﬁcationsasthediseaseprogresses[2].

ThecomplexityofOApathogenesisisamatteroffactandits managementrepresentsachallengeforthescientificcommunity. Recently,differentOAphenotypeshavebeendescribedincluding obesity-relatedOA,mechanical-inducedOAandaging-relatedOA. ThissuggeststhatOAtreatmentcouldbestratifiedandtailoredto therelevantphenotype[3].Akeychallengewillbetoidentify phen-otypesforparticulartreatments.Untilnow,themanagementofOA hasconsistsmostlyofsymptommanagement,i.e.reductionofpain andimprovementofjointfunction,whichreliesonthe combina-tionofnon-pharmacologicandpharmacologicapproachesashas beenproposedbythemainpublishedguidelines[4–10].Although important,thecontrolofsymptomsisnottheonlygoalthatneeds tobeachievedinOApatients.IndeedtheidealtreatmentforOA shouldpreservethejointstructures,keepinginmindthe improve-mentinthequalityoflifeofpatients[11]andexhibitagoodsafety profile.Itisparamounttotakeintoaccountthesideeffectdueto thechronicuseofOAtherapies,suchasNSAIDs[12].

Glycosaminoglycanssuchaschondroitinsulfate(CS)and glu-cosamine (GlcN) are two natural compounds considered as Symptomatic Slow Acting Drugs for Osteoarthritis (SYSADOA). Moreover,someofthesecompoundswerealsodemonstratedto possessdisease-modifying(DMOAD)potentialbasedonthe mea-surementofjointspacenarrowingonradiographs.Nevertheless, theuseoftheseproductsaswellastherelevanceoftheirclinical efﬁcacyareconstantlyunderdebatesincetheycouldbesold“over thecounter”asdietarysupplementsinNorthAmericawhereasthey areregistereddrugsinEurope.Thisnarrativereviewwillprovidean updateonthepotentialmechanismsofactionofCSandGSandthe resultsofclinicaltrialswillbefurtherdocumentedanddiscussed.

2. Methods

TheliteraturesearchwasperformedusingthePubMed/Medline databasesbetweenJanuary2009andJanuary2014.Searcheswere performed in PubMed using the search terms “glucosamine”, “chondroitinsulphate”,“pharmaceutical-grade”,“osteoarthritis”, “randomizedclinicaltrials”,“humans”.TheMEDLINEdatabasewas searchedforallrandomizedcontrolledtrials,meta-analyses(MAs), systematicreviews,andreviewarticlesofchondroitinsulfateand glucosaminesulphateinOA.

OnlyarticlespublishedinEnglishwereincludedandclinical studiesincludingkneeOApatientswereconsidered.Studiesonthe therapeuticeffectsofinjectablesubstanceswereexcluded. 2.1. CSandGlcNinclinicaltrials

InthefollowingsectionswereviewtheevidenceforCSandGlcN inpublishedclinicaltrials.

2.1.1. Glucosamine(GlcN)

TheDMOADeffectofGlcNwasanalyzedinrecentMAs[13,14]. Wandeletal.reportednorelevantclinicaleffectbasedonaneffect size(ES) onjoint pain of −0.17 (−0.28 to−0.05) and onjoint spacewidth(JSW)of−0.16(−0.25to0.00)[13].However,thisMA showednumerouslimitationsandtheinterpretationofthedata washazardouswithregardstothedata[15].Severalexpertgroups intheﬁeldofOAhavequestionedthevalidityoftheconclusions. PitfallsofthisMAwereaddressedinpartinthereportfromthe

BritishMedical Journal post-publicationreview meeting, which statesthatthedataofthestudydidnotdirectlysupportthestrong negativeconclusionofthestudy(GrovesT.ReportfromBMJpost publicationreview meeting. Availableat: http://www.bmj.com/ content/341/bmj.c4675.full%20./reply#bmjel247719 [accessed 19.06.11]).

TheotherMA,includingonlytwotrials[14],reportedasmallto moderateprotectiveeffectofGlcN-SontheminimumJSNafter3 yearsinkneeOA.Thiswasinaccordancewiththedataofarecent trialindicatingthatGlcN-Spreventedtotalkneereplacement(TKR) [16].Incontrast,noeffectwasobservedinhipOAwithGlcN-S[17]. ItisnoteworthythattheGlucosamine/chondroitinArthritisTrial (GAIT)study,thelargestrandomizedcontrolledtrial(RCT),didnot reportanysigniﬁcanteffectforGlcN-HClinkneeOApatients[18]. ThequestionoftheimportanceofGlcNformulationwasaddressed intheMAbyWuetal.[19].TheconcludedthatGlcN-Hwas inef-fectiveforpainreductioninpatientswithkneeOA.GlcNN-Smay havefunction-modifyingeffectsinpatientswithkneeOAwhen administeredformorethan6months.However,itshowedno pain-reductionbeneﬁtsafter6monthsoftherapy.

Finally, it is also important to consider the analysis of the RCTsprovidedbytheOsteoarthritisResearchSocietyInternational (OARSI)initsrecommendationstointerpretboththesymptomatic andstructure-modifyingeffectofGlcN.Itanalyzed19RCTs(16of themwithGlcN-Sand3withGlcN-HCl)[8].ItreportedanESfor painof0.46(0.23–0.69),traducingamoderatesymptomaticeffect evenifitdecreasedsincethelastanalysis(0.61(0.28–0.95)[6]). However,itrevealedastrictdifferencebetweenGlcN-S(ESforpain 0.58(0.30–0.87))andGlcN-HCl(−0.02(−0.15to0.11)).Inaddition, ESofGlcN-Sforpaintendedtodecreasewhenconsideringonlyhigh qualityclinicaltrials(0.29(0.003–0.57)).ItalsoreportedanESon thereductionofjointspacenarrowing(JSN)of0.24(0.04–0.43)for GlcN-SonkneeOAbutnoeffectonhipOA.

2.1.2. Chondroitinsulfate(CS)

AswithGlcN, CShasalsobeenevaluatedindifferentclinical trialstodocumentbothitssymptomaticpotentialandits structure-modifyingeffect.ThesymptomaticefficacyofCSinkneeOAhas beenproven [16].In addition,a highlypurified CS formulation (800mg/day) produced symptomatic effectin hand OA [20]. A recentstudy[21]demonstratedasimilarefficacyofCSon symp-toms(painonVASandLIforfunction)whenadministeredasa singledailydoseof1200mgorthreetimesadayat400mg.The authorsconcludedatanefficientandsafeintervention. Interest-ingly, CSproduced a significantreductionin jointswelling and effusionduringtheGAITstudy[18].

AsignificantDMOADeffectforCShasbeenreportedinRCTs. ItwasshowntoproduceareductionofJSN[22],asignificant dif-ferenceinmeanandminimalJSW[23]andasignificantdifference injointspacesurfaceandmeanJSW[24].TheMAbyHochberg etal.[25]anditsupdateincludingstudiesof2-yearduration[26] demonstratedamodestbutsignificanteffectofCS(800mg/kg)on therateofdeclineoftheminimumJSW.TheMAbyLeeetal. con-cludedatadelayofdiseaseprogressionbyCS[14].Arecentclinical trial,notyetincludedinMAsreportedasymptomaticeffectofCS (800mg/day)combinedwithareductionofthecartilagevolume loss,bonemarrowlesionsandsynovitisinkneeOApatients[27].

TheanalysisprovidedintheOARSIguidelines[8]determined anESof0.75(0.50–0.99)onpainandof0.26(0.16–0.36)forJSN butmentionedtheindustrybiasthatcouldexistandthe hetero-geneityoftheresults.Ifallstudiesareconsidered,theESonpainof CS(0.75(0.50–1.01))washigherthanthosereportedforGS(0.58 (0.30–0.87))andespeciallyforNSAIDS(0.29(0.22–0.39)).Thislast considerationisimportantsinceweknowthesevereadverseeffect inducedbythelong-termuseofNSAIDSinOApatients.Clearly,the

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Y.Henrotinetal./Maturitasxxx(2014)xxx–xxx 3 risks/beneﬁtsbalanceseemstobeinfavor ofCS.Thisshouldbe

consideredatthetimeoftherapeuticdecisioninthedailypractice. 2.1.3. GlcNandCSincombination

Whileadministeredalone,neitherGlcN-HnorCSproducedany clinicaleffectduringtheGAITstudy.However,thecombination (GlcN-HCl500mg–CS400mg;threetimesaday)wasshowntobe efficientforpainreliefandfunctionimprovementinOApatients withmoderatetoseverekneepain[18].Thisfindingsuggeststhata combinationofGlcNandCScouldbemoreefficientthanCSorGlcN administratedalone.Recently,theeffectsofGlcN/CScombination onprogressionofstructuralchangesinkneeOAwasevidencedin asampleoftheNationalInstitutesofHealthOsteoarthritis Initia-tive(OAI)longitudinalcohort.Inparticipantstakingacombination ofGlcNandCS,thelossofcartilagevolumeover24monthswas reducedinsomesubregionswhentheassessmentwasmadewith quantitativemagnetic resonance imaging (qMRI),arguing for a disease-modifyingeffectofGlNcandCScombined [28].Finally, adoublerandomizedplacebo-controlledclinicaltrialwith2-year follow-upof605patientswithkneeOA,demonstratedthatafter adjustingforfactorsassociatedwithstructuraldiseaseprogression (gender,bodymassindex,baselinestructuraldiseaseseverityand Heberden’snodes),dietarysupplementcombinationofGlcNand CSresultedinastatisticallysignificantreductionofjointspace nar-rowingcomparedtoplacebowhileCSorGlcNalonewerewithout effect[29].

2.2. GlNcandCSinguidelines

The EuropeanLeague Against Rheumatism(EULAR) and the 2010OARSIguidelinesforthetreatmentofsymptomatickneeOA recommendCSandGS[5–8].Incontrast,theUK’sNational Insti-tuteforHealthandCareExcellence(NICE)hasrecommendedthat theseproductsshouldnotbeused,mainlyforeconomicalreasons, whiletheAmericanCollegeofRheumatology(ACR)recommended GSandCSundercertainconditions[4].Recently,OARSIhasreleased newguidelinesbasedonpreviousOAguidelines,anupdateofthe 2010OARSIsystematicreviewandaconsensusof13expertsfrom relevantmedical disciplinesusingtheRAND/UCLA Appropriate-nessmethodand Delphivotingprocessfor consensus[30].The experts’voteresultedinanuncertainappropriatenessforCSand GS despitea good qualityof evidence, a verylow risk score, a moderatetohigheffectsize(upto0.75forCS)andahighbeneﬁt score.

3. Discussionandconclusions

There is significant evidence in the published literature as reviewedheretosupportthepromisingDMOADpotenciesofboth GlcNand CS.SomeMAs haveevidencedthesebeneficial effects andthesecompoundsarecurrentlyrecommendedbyEULAR.In contrast,these productswere not recommended bythe recent OARSI2014,ACR2013andNICE2013guidelines.InmostEuropean countries,thesedrugsareprescribedwhereasinUS,theyare deliv-eredover-the-counterandtheyarenotofpharmaceuticalgrade. In2008,OARSI publishedevidenceand expertconsensus-based recommendationsforthemanagementofhipandknee osteoarthri-tis(OA)TreatmentwithGlcN-Sand/orCSwasrecommendedfor kneeOA withthe provisothat it shouldbe discontinuedif no responseisapparentwithin6months,althoughbothmayhave long-termstructure-modifyingeffectsasshowninprevious clini-caltrials[31,32]andconfirmedinlaterstudy[22].In2010,Zhang etal.[8]publishedanupdateoftheevidenceavailablefor thera-piesusedinthetreatmentofhipandkneeOA.Thehighestlevel ofevidence(Ia) wasavailablefor CS,GlcN-S whileglucosamine

hydrochloride(GlcN-H)receivedalowerlevel(Ib).Theeffectsize (ES; 95% CI),which measuresthe strength of efficacy compar-ing toplacebo was0.58 (0.30, 0.87) for GlcN-Sand 0.75 (0.50, 1.01)forCS.TheseESwereconsideredasmoderateandtheywere smallerinmore recentand higher qualitytrials,but theywere stillclinicallyrelevantandatleastcomparabletothoseofNSAIDs and superior toacetaminophen (paracetamol). Recently, OARSI has released new guidelines based on previous OA guidelines, anupdateofthe2010OARSIsystematicreviewandaconsensus of13expertsfromrelevantmedicaldisciplines[30].Treatments wererecommendedasappropriate,uncertain,ornotappropriate foreachsubphenotype.Appropriatepharmacologicaltreatments forspecificclinicalsubphenotypesincludedacetaminophen (para-cetamol),capsaicin,duloxetin,oralNSAIDs(COX-2selectiveand non-selective)andtopicalNSAIDs.Treatmentsofuncertain appro-priatenessforspecificsubphenotypesincludedAvocado/Soybean unsaponifiables,CS,GlcN,diacerein,opioidsandrosehip.Only rise-dronatewasconsideredasinappropriate.Theexperts’voteresulted inanuncertainappropriatenessforGlcNandCSdespiteagood quality of evidence, a very low risk score, a moderate to high effectsize(upto0.75forCS)and ahighrisk/benefitscore.Oral NSAIDs,wellknowntopossiblyinduceadverseeventsespecially inolderpatientsandinpatientswithdigestive,cardiovascular,or renalcomorbidities,wereappropriateforindividualswithout co-morbiditiesdespiteahighriskscoreandabenefitscoreinthesame orderofmagnitudeofSYSADOAs.Therefore,whythisreluctance forGlcNandCS?Severalhypothesescanbeformulated:(1) non-EuropeanexpertswerenotfamiliarwithprescriptionSYSADOA andwerefacedwithproductssoldover-the-counterwith heteroge-neousandnon-pharmaceuticalgradequality;(2)favorableresults fromclinicaltrialsoftheprescriptionproductshavebeenmixed andconfusedwiththoseobtainedinpoorerqualitystudiesand/or performedwithover-the-counterlowerqualityproducts,causing highstudyheterogeneity;(3)theremaybeagapbetweenresults fromclinicaltrials performedonasubset ofwell-characterized OApatientsandtheeffectsobservedbypractitionersonageneral populationinthereallife;(4)alackofconfidenceoftheexperts forindustrysponsoredclinicaltrials(althoughthisshouldapply toalldrugs,sincetheyarealldevelopedbytheindustry). There-fore,theterm“uncertain”associatedtoGlcNandCSmustbewell explainedtopractitioners.TheOARSIexpertsthemselvesdidnot considertheterm“uncertain”asanegativerecommendationwhich couldprecludetheuseofGlcNandCS.Rather,itrequiresarolefor physician–patientinteractionindeterminingwhethersuch treat-mentsmayhavemeritinthecontextoftheirrisk-benefitprofile andtheindividualcharacteristics,co-morbiditiesandpreference oftheindividualpatient.Inthiscontext,CSandGSwhichshow afavorablerisk/benefitratioshouldbeconsideredespeciallyfor thetreatmentof olderOA patientswithco-morbiditieslimiting thelong-termand/orrecurrentadministrationofdrugslikeoral NSAIDs and paracetamol,that wereconsideredappropriate but havealowerrisks/benefitsratio.RecentMAs[33]andclinicaltrials [22,34–37]havesuggestedthatGlcN-S,GlcN-HandCSmay con-tributetoreducetheintakeofNSAIDSorparacetamol.Exclusion ofGlcNandCSfromthetherapeuticarsenalofOApatients car-riestherisk toincreaseiatrogenic damagesdue totheoveruse of NSAIDs and analgesics that in some countries are delivered over-the-counterwithoutmedicalcontrol.Itistheresponsibility of practitionerstotreat OApatientsbyintegrating withintheir individuallevelanalysis,therisksandbenefitsforeachtreatment, theindividual’sco-morbidities,theefficacyofthetherapy (con-tinuousassessmentofthesymptoms)andthepatient’spersonal preference.

Therefore, the used of CS and GS is an individual patient/physician informed decision by scientiﬁc, medical and economicalevidence.

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4 Y.Henrotinetal./Maturitasxxx(2014)xxx–xxx Mostoftheauthorsoftheliteraturecitedrecommendtheuse

ofpharmaceuticalgradeproductsratherthanfoodsupplements. Theyinsistontheimportanceoftheformulation andqualityof GlcN[38,39]andCS[40,41].Inthesamewayofthinking,onemay considertheuseofGlcNandCSasacombinationtherapy. More-over,muchevidencehasbeengatheredherethatdocumentthe potentialthatbothcompoundscouldexertonjointtissuesduring OA.Onemaythereforeforeseeadditionalbeneﬁtsifnotmerelya synergisticpotency.

Contributors

YHhaswrittenthepaper.MMandAMhaverevieweditand checkedtheliterature.

Competinginterest

None.

Funding

None.

Provenanceandpeerreview

Commissionedfollowinga presentation byYvesHenrotin at the2ndWorldCongressonControversies,Debates&Consensus inBone,Muscle&JointDiseases,November21–24,2013,Brussels, Belgium;andexternallypeerreviewed.

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