REVIEW Collagen hydrolysate for the treatment of ......REVIEW Collagen hydrolysate for the treatment of osteoarthritis and other joint disorders: a review of the literature Alfonso

REVIEW

Collagen hydrolysate for the treatment of osteoarthritis and other joint disorders a review of the literatureAlfonsoebelloaandsteffenOesserb

aUniversity of Illinois College of Medicine at Chicago Chicago IL USAbCollagen Research Institute Kiel Germany

Address for correspondenceensp AlfonsoenspEenspBelloenspMDenspMHSenspFACPenspFACRenspDABPMenspClinicalenspAssociateenspProfessorenspofenspMedicineenspUniversityenspofenspIllinoisenspCollegeenspofenspMedicineenspatenspChicagoensp1801enspWestenspTaylorenspStreetenspChicagoenspILensp60612enspUSAenspTelensp+1ensp312ensp413ensp3631enspFaxensp+1ensp312ensp355ensp3133enspemailenspabelloibjicom

Key wordsensp ArticularenspcartilageenspndashenspCollagenensphydrolysateenspndashenspNutritionalenspsupplementsenspndashenspOsteoarthritisenspndashenspProteoglycansenspndashenspTypeenspIIenspcollagen

0300-7995

doi101185030079906X148373

Allrightsreservedreproductioninwholeorpartnotpermitted

CurrentMediCAlreseArChAndOpiniOnreg

VoL 22 No 11 2006 2221ndash2232

copy2006librAphArMliMited

Paper 3580 2221

Background There is a need for an effective treatment for the millions of people in the United States with osteoarthritis (OA) a degenerative joint disease The demand for treatments both traditional and non-traditional will continue to grow as the population ages

Scope This article reviews the medical literature on the preclinical and clinical research on a unique compound collagen hydrolysate Articles were obtained through searches of the PubMed database (wwwpubmedgov) through May 2006 using several pairs of key words (collagen hydrolysate and osteoarthritis collagen hydrolysate and cartilage collagen hydrolysate and chondrocytes collagen hydrolysate and clinical trial) without date limits In addition other sources of information such as abstracts presented at scientific congresses and articles in the German medical literature not available on PubMed were reviewed and included based on the authorsrsquo judgment of their relevance to the topic of the review

Findings According to published research orally administered collagen hydrolysate has

been shown to be absorbed intestinally and to accumulate in cartilage Collagen hydrolysate ingestion stimulates a statistically significant increase in synthesis of extracellular matrix macromolecules by chondrocytes ( p lt 005 compared with untreated controls) These findings suggest mechanisms that might help patients affected by joint disorders such as OA Four open-label and three double-blind studies were identified and reviewed although many of these studies did not provide key information ndash such as the statistical significance of the findings ndash they showed collagen hydrolysate to be safe and to provide improvement in some measures of pain and function in some men and women with OA or other arthritic conditions

Conclusion A growing body of evidence provides a rationale for the use of collagen hydrolysate for patients with OA It is hoped that ongoing and future research will clarify how collagen hydrolysate provides its clinical effects and determine which populations are most appropriate for treatment with this supplement

A B S T R A C T

Introduction

Osteoarthritis(OA)affectsmillionsofpeopleintheUnitedStatesandthenumberofpeoplewithOAispredictedtoincreaseasthepopulationages1Currently

thereisnocureforOAsomanagementofthediseaseis focusedon reducingpainmaintainingmobilityandminimizingdisability In recent years severalinvestigatorshavesuggestedthatsomesubstancesmaybecapableofrepairingdamagedarticularcartilageor

2222 Collagen hydrolysate and osteoarthritis copy2006librAphArMltdndashCurrMedresOpin200622(11)

atleastdeceleratingitsprogressivedegradation2Onesuchagentthathasbeeninvestigatedisthenutritionalsupplementcollagenhydrolysate3

The purpose of this article is to review theepidemiologyandriskfactorsforOAandreviewsomeofthecurrentmanagementoptionsforthisdisorderItsummarizesclinicalresearchwithcollagenhydrolysateanddiscussestheclinicalsignificanceofthisresearchandthepotentialofthissupplementforthetreatmentofpatientswithOAArticleswereobtainedthroughsearchesofthePubMeddatabase(wwwpubmedgov)throughMay2006usingthefollowingkeywordpairswithoutdate limits collagenhydrolysateandOAcollagenhydrolysateandcartilagecollagenhydrolysateandchondrocytescollagenhydrolysateandclinicaltrialInadditionothersourcesofinformationsuchasabstractspresentedatscientificcongressesandarticlesin theGermanmedical literaturenot availableonPubMedwerereviewedandincludedbasedontheauthorsrsquojudgmentoftheirrelevancetothetopicofthisreview

osteoarthritis epidemiology and risk factors

OA is the most common form of arthritis amongtheelderlyanda leadingcauseofdisability in thispopulation4ndash6Thediseaseaccountsfor25ofvisitstoprimarycarephysicians7OAaccounts formoretroublewithclimbingstairsandwalkingthananyotherdisease8

The prevalence of arthritis and chronic jointsymptoms increases with age (Table 1)69 In onecommunity-basedsurveytheincidenceandprevalenceofOAincreased2-to10-foldfrom30to65yearsof

ageanditincreasedfurtherbeyond65years1DuetothegeneralincreaseinlifeexpectancyandtheagingofthelsquobabyboomrsquogenerationthenumberofAmericanswhoare50yearsofageandolderisexpectedtodoubleby2020aswilltheprevalenceofOAunderscoringtheneedforeffectivetreatment10

BesidesageotherriskfactorsforOAincludemajortraumaand repetitive jointuse6Obesity is also ariskfactorforOA(Table1)11TherearedatawhichsuggestthatobesityplaysanevenlargerroleinthedevelopmentofkneeOA12OtherconditionsthatmaybeinvolvedinthedevelopmentofOAaresystemicmetabolicorendocrinedisordersneurologicdiseasesanddysplasia

Pathophysiology of cartilage degenerationthestructureofarticularcartilage

Articularcartilagealsoknownashyalinecartilageisaspecializedtoughflexibletissuewithalow-frictioncoefficientandasmootharticulatingsurfacethatmakesitideallysuitableforloaddistributionandabsorbingtheshockofmovement13Itiscomprisedofchondrocytes(about2ndash10ofthevolumeofarticularcartilage)andanextracellularmatrixwhichismaintainedbythechondrocytes14Thematrixofthearticularcartilageconsistsoftwocomponentsthetissuefluidandtheframeworkofstructuralmacromoleculesthatgivethetissueitsformandstability15Sixtytoeightypercentofthematrixiswater16ndash18

Themacromolecularframeworkofarticularcartilageconsistsofcollagens(predominantlytypeIIcollagen)proteoglycansandnon-collagenousproteins1315Thesestructuralmacromoleculescontribute20ndash40ofthe

Table 1 Persons with arthritis and chronic joint symptoms in the United States9

Characteristic Number Percent (95CIdagger)

Agegroupyears 18ndash44 20610 190 (185ndash194)45ndash64 27112 421 (415ndash428)ge65 21704 588 (580ndash597)

Sex Male 28926 284 (279ndash289)Female 41008 373 (369ndash378)

Bodymassindex(BMI) BMIlt185(underweight) 1153 272 (249ndash296)BMI185ndash249(normal) 21532 266 (261ndash271)BMI250ndash299(overweight) 25011 336 (330ndash342)BMIge30(obese) 18879 446 (437ndash454)

Total 69934 330 (327ndash334)

InthousandsdaggerConfidenceinterval

copy2006librAphArMltdndashCurrMedresOpin200622(11) Collagen hydrolysate and osteoarthritis Bello and Oesser 2223

wetweightofthetissueThecollagenfibrilsareformedintheextracellularspaceandcross-linkedbycovalentbondsforminga3-dimensionalfibrillarnetworkItisthismatrixthatprovidesthecartilagewithitstensilestiffnessandstrengthTheproteoglycans(mostnotablyaggrecans)areembeddedwithinthisfibrousnetworkcombinedwithwaterAggrecanscreatetheosmoticswellingpressurethatisresponsibleforcompressibilityandelasticityofcartilagewhichiscounteractedbytheresistanceoftheintactcollagenfibrils

Collagenscontributeabout60tothedryweightofcartilagewhileproteoglycansprovide25ndash35andnon-collagenousproteinsandglycoproteinscontribute15ndash2015 The relative amounts of the majorconstituentsofarticularcartilagedeterminethemech-anicalpropertiesofthistissue15Changesintherelativeamounts of these components and in their highlystructuredordermayoccurduetodiseaseordamagealteringthemechanicalpropertiesofthecartilage

Normalcartilagefunctionresultsinaconstantshift-ingbetweenanincreaseofpressureandareductionofpressurewithinthejointAlthoughcartilageisdevoidofnervesbloodvesselsandlymphaticsthesechang-ingpressurescauseapumpingactionthatallowsthedeliveryofnutrientstothecartilagefromitssurround-ingsandtheremovalofmetabolicwasteproducts

theroleofchondrocytes

Cartilagehasanactivemetabolismcharacterizedbyaslowbutcontinuousturnoverofitscellsandextra-cellularmatrixLocatedwithinthematrixarechon-drocyteswhichsynthesizematrixmacromoleculessuchascollagenandproteoglycansandenzymesthathelpbreakdownanddisposeofagingcollagenandproteoglycans15TheyalsodeterminethehighlyorderedstructureoftheextracellularmatrixChondrocytesarebelievedtodetectchangesinthecompositionofthematrixandnewstressesuponthearticularcartilage15Ifaparticularjointbeginstoencounterunusualpressureorsustainsdamagechondrocytesrespondbyalteringorrepairingthecartilage

Chondrocytes have a central role in regulatinganabolicandcatabolicprocessescreatingabalanceof synthetic anddegradative activity that leads tocontinuousinternalremodelingandturnoverinhealthycartilage

Cartilagemetabolism

Many factors affect cartilage turnover includingnumerousbiochemicalregulatorsanadequatesupplyof the molecules necessary for the production ofcartilagecomponentsphysicalstressonthejointsandanindividualrsquoslifestyle19ndash24

TheregulatorymechanismsarecomplexandnotfullyunderstoodSeveralsubstancesarebelievedtobeinvolvedintheregulationofcartilagemetabolismincludingcytokinesgrowthfactorstypeIIcollagenandcollagen fragmentsandvitaminsandminerals(egvitaminC)192325ndash29

Physical activitycanalsohavevaryingeffectsoncartilagemetabolismForexampleimmobilizationofthejointoramarkeddecreaseinjointloadingalterschondrocyteactivitysothatdegradationexceedssynthesisoftheproteoglycancomponentofthematrix2021Anadequateamountofphysicalactivityisnecessarytopreservecartilageandoverexertionorcontinuousstresscancontributetopathologicchanges1521

deteriorationofcartilage

Thedisruptionofthestructuralintegrityofarticularcartilageitsdeteriorationanditseventuallossarearesultofanimbalancebetweenanabolicandcatabolicactivity in the cartilage tissueThemost commonoriginsofthisimbalanceincludechondrocytesenes-cenceandpathophysiologicconditionssuchasOAAsthechondrocytesrsquosensitivitytoregulatorysignalsdecreasestheirabilitytomaintainandrepaircartilagetissueisdiminished30Alongwithadecreasedrespons-ivenesstoanabolicgrowthfactorsandreductioninsyntheticactivitysmallerless-uniformaggrecanandless-functionallinkproteinsareformedTheseage-relatedchangesalterthecompositionofthematrixandleadtoaprogressiveimbalancebetweendegradationandregenerationadecreaseintypeIIcollageninthematrixandeventually cartilagedamageChangesincludefibrillationofthearticularsurface3132causingittofrayandsoftenandincreasedcollagencross-link-ing33ndash35withlossoftensilestrengthandstiffnessofthematrix

osteoarthritis disease progression and management

OAisajointdiseasecharacterizedbyprogressivedes-tructionofjointcartilageanditsassociatedstructuressuchasbonesynovialandfibrousjointcapsulesandtheperiarticularmusculature1036Therearetwodis-tinctformsofOAprimary(idiopathic)andsecondaryPrimaryOAhasnodiscernibletriggerbutmaybeassociatedwithagingandor lifestyle factors (egjobsthatinvolverepetitivetaskssuchaskneelingorsquattingorparticipationinsportssuchasfootballorsoccer)3738SecondaryOAcanbetheresultofvariouspathologicalconditionssuchasjointinjuryinfectionordevelopmentalormetabolicdisorders10


stages

The underlying pathophysiology of OA is morecomplicatedthansimplylsquowearingoutrsquoofcartilageItisnotadiseaseofanysingletissuebutadiseasethat involves the entire joint36 There are a seriesof imbalances in the synthesis anddegradationofstructuralcomponentsalongwith injuriesbroughtaboutbybiomechanicalforces13

DuringtheinitialstageofOAthereisanexcessiveproteolyticbreakdownofthecartilagematrix13AsaresultthecartilagelosesitselasticityandismoreeasilydamagedduetoinjuryoruseNexttheshapeandstructureofthejointarealteredwhichreducessmooth joint functionFibrillationanderosionsofcartilageresultinpiecesofboneorcartilagefloatingloosely in the synovial fluidcausing irritationandpainThegradualdeteriorationof cartilagecauseschangestotheunderlyingboneincludingthickeningofboneformationofcystsunderneaththecartilagethedevelopmentofbonygrowths(iespursorosteo-phytes)near theendsof thebonesat theaffectedjointsandinmanypatientschronicinflammationofthesynovialmembrane1336

symptoms

AlthoughanysynovialjointcanbeaffectedOAoccursmost frequently in thekneehiphandandspinalapophysealjoints39ndash41Lessfrequentlyaffectedarethewristelbowshoulderandanklejoints39ndash41

OncecartilagelosesitselasticityrangeofmotionislostandsufferersofOAbegintoexperiencestiffnessintheaffectedjointThepainistypicallyactivityrelatedmadeworsewithweightbearingandimprovedwithrestUltimatelythejointisaffectedleadingtojointfailure

ItisinterestingtonotethatthecorrelationbetweenthepathologicseverityofOAandsymptomsislowIthasbeenobservedthatmanypeoplewithradiographicchangesthatsuggestadvancedOAhavenosymptoms36RiskfactorsthatresultinpainanddisabilityinpatientswithOAarenotwellunderstood36

treatment

TreatmentofOAisfocusedonreducingpainmain-tainingmobilityandminimizingdisability36Non-pharmacologic(egphysicaltherapysurgery)andorpharmacologicmeasuresmaybeindicatedforpatientswithOA

Traditional modalities for treating OA includeanalgesicsandanti-inflammatoryagentslubricatingandcushioningagentsnutritionalsupplementsandsurgeryforpatientswithadvancedOAforwhomaggressive

medicalmanagementhasfailed336Acetaminophen(upto4gday)isrecommendedasfirst-linetherapyforthesystemictreatmentofsymptomaticOA42ndash45HoweverthesemodalitiesarelimitedbytoxicityintolerancelackofpatientcomplianceorvariableresponsesForexample acetaminophenhasbeenassociatedwithprolongationofthehalf-lifeofwarfarin46Non-steroidalanti-inflammatory drugs (NSAIDs) are the mostcommonlyusedpharmacologicagentsandhavelongbeenknowntoincreasetheriskforgastrointestinalsideeffectssuchaspepticulcerdiseaseby10-to30-fold47In2004NSAIDsspecificallycyclo-oxygenase(COX)-2selectiveinhibitorswerelinkedtocardiovascularevents(iemyocardialinfarctionandstroke)resultinginsomeof theseagentsbeingwithdrawnfromthemarketbecauseofsafetyconcerns48

nutritionalsupplements

Various nutr it ional supplements have beeninvestigatedforthetreatmentofpatientswithOAandjointpainTheseincludeglucosaminechondroitinsulfatemethyl-sulfonyl-methane(MSM)S-adenosylmethionine(SAMe)andcollagenhydrolysateDespitethewidespreaduseofsomeoftheseagentstherearevaryinglevelsofevidenceconcerningtheirefficacyinpatientswithOA

Glucosamine and chondroitin sulfate

ThesetwodietarysupplementsarewidelyusedbyconsumersforthemanagementofOA49Glucosamineand chondroitin sulfate are compounds that areextractedfromanimalproductstheyhavebeenusedtotreatvariousformsofOAinEuropeformorethanadecade50Researchhasshownthattheyareabsorbedfromthegastrointestinaltract5152In vitroexperimentshavedemonstratedthatadditionofglucosaminetohumanchondrocytes in tissueculture leads to theactivationofcore-proteinsynthesisthuspromotingproteoglycanproduction5354McCartyhassuggestedthatachondroprotectiveactionofglucosaminemaybeduetoenhancedsynovialproductionofhyaluronicacidwhichdown-regulatesmechanismsthatresultincartilagedegradationandpaininpatientswithOA55

Althoughthesetwosupplementsaregenerallywelltoleratedanimalstudieshaveshownthatglucosamineinterfereswithglucosetransportandinsulinsecretionleadingtohyperglycemiaand insulinresistance56ndash58Despite someconflictingdata inhumans there isspeculation that glucosamine could predispose todiabetes59Whilearandomizeddouble-blindplacebo-controlledtrialpublishedin2003foundthatpatients(N=38)with type2diabetes takingglucosaminehydrochlorideandchondroitindidnotexperiencea


significantincreaseintheirglycosylatedhemoglobin(HbA

1c)levelsafter90daysoftherapy60moreresearch

isneededtodeterminethelong-termeffectofthesesupplementsforpatientswithdiabetes

Theefficacyofglucosamineandchondroitin forpatientswithOAhasbeentestedinover20clinicaltrials(asreviewedbyMcAlindonet al50)Howeverinvestigatorswhoconductedameta-analysisof15ofthesestudiesconcludedthatwhiletrialsofglucos-amineandchondroitinusedfortreatingOAsymptomsdemonstratemoderate-to-largeeffectsstudyqualityissuesandlikelypublicationbiasmayhaveresultedin thebenefits of theseproducts being somewhatexaggerated50Theauthorsofthemeta-analysisrecom-mendedthathigh-qualityindependentstudieswereneededtodeterminetheactualefficacyandutilityofthesesupplements50

BecauseofthescientificqualityproblemsassociatedwiththeearlierglucosamineandchondroitinstudiestheGlucosaminechondroitinArthritis InterventionTrial(GAIT)wasdesignedtorigorouslyevaluatetheeffectofthesesupplementsonpainduetoOAintheknee61Thistrialwasa24-weekrandomizedmulti-centerdouble-blindplacebo-andcelecoxib-controlledtrialsponsoredbytheNationalInstitutesofHealth61PatientswithsymptomatickneeOAreceivedeither1500mgglucosaminedaily1200mgchondroitinsulfatedailybothglucosamineandchondroitinsulfatedaily200mgofcelecoxibdailyorplacebofor24weeksUpto4000mgofacetaminophendailywasallowedasrescueanalgesiaTheprimaryoutcomemeasurewasa20decreaseinkneepainfrombaselinetoWeek2461

TheGAITinvestigatorsfoundthatglucosamineandchondroitinsulfatealoneandincombinationdidnotreducepaineffectivelyinagroupofpatientswithOAofthekneeusingthe20decreaseinkneepainastheprimaryoutcome61Analysisofaprespecifiedsubgroupofpatientswithmoderate-to-severepaindemonstratedthatcombinationtherapysignificantlydecreasedkneepainrelatedtoOA(p =0002)61ItisworthnotingthatnearlyalloftheglucosaminestudiessuggestingefficacyusedglucosaminesulfatewhileGAITusedglucosaminehydrochlorideHowever a reviewofglucosaminestudiesobservedthatwhiletheoutcomesofindustrysponsoredstudiesofglucosamineforOAweremostlypositive the results of non-industry-sponsoredstudieswerenot62MoreresearchisneededtodeterminethevalueofthesesupplementsforthetreatmentofpatientswithOA63

Methyl-sulfonyl-methane

Thisisanotherdietarysupplementthatisusedforthetreatmentofjointpain64ThereislimitedresearchonthebenefitsofthissupplementOnerecentlypublished

studyinvestigateditsuseforpatientswithOAinarandomizeddouble-blindplacebo-controlled trialwith50menandwomen(40ndash76yearsofage)withOAoftheknee64Thepatientsreceived3gofMSMorplacebotwiceeachday(6gday)for12weeksTheinvestigatorsreportedthatMSMproducedsignificantlyreducedlevelsofpainasmeasuredbytheWesternOntarioandMcMasterUniversityOsteoarthritisvisualanaloguescore(WOMAC)andinphysicalfunctionimpairment(p lt005)comparedwithplacebobutnonotablechangesinWOMACstiffnessandaggregatedtotalsymptomscores64

In this studyuse ofMSMwas also reported toimprovetheperformanceofactivitiesofdailylivingwhencomparedwithplacebo(p lt005)Theinvest-igators concluded that MSM (3g BID) improvedsymptomsofpainandphysicalfunctionduringtheshortinterventionwithoutmajoradverseeventsbutthatthebenefitsandsafetyofMSMinmanagingOAandfromlong-termusecouldnotbeconfirmedfromthispilotstudyFurtherinvestigationofMSMwillbeneededtodeterminetheseissues64

S-adenosyl-L-methionine (SAMe)

AthirddietarysupplementSAMehasbeeninvest-igatedforthemanagementofpaininOAIthasbeensuggestedthatSAMemayreducepaininOAbyreduc-inginflammationincreasingproteoglycansynthesis65andorprovidingananalgesiceffect64Adouble-blindcross-over study comparedSAMe (1200mg)withcelecoxib(200mg)for16weekstoreducepainassoci-atedwithOAofthekneeSixty-oneadultsdiagnosedwiththisconditionwereenrolledand56completedthestudyTheinvestigatorsreportedthatSAMehadasloweronsetofactionbutwasaseffectiveascelecoxibinthemanagementofsymptomsofkneeOA64Theyconcludedthatlongerstudiesareneededtodeterminethelong-termefficacyandoptimaldoseofSAMeforpatientswithOA64

Collagen hydrolysate

Thisnutritional supplementhasbeen investigatedforthemanagementofpatientswithOAandothertypesofjointpainIthasbeenshowntosignificantly(p lt001)increasethebiosynthesisoftypeIIcollageninchondrocytesinexperimentswithbovinecartilagecellcultures66CollagenproductsarerecognizedassafecomponentsofpharmaceuticalsandfoodsbytheUSFoodandDrugAdministration(FDA)CenterforFoodSafetyandNutrition67

Researchershaveinvestigatedthepotentialclinicalbenefitsofcollagenhydrolysateinfouropenlabeland


threedouble-blindstudiesinvariouspatientpopula-tions includingpatientswithOA368ndash73Thissectionreviewsthepreclinicalandclinicalfindingsfromthesestudies

preclinicalstudies

Inexperimental investigations ithasbeendemon-stratedthatorallyadministeredcollagenhydrolysateisthoroughlyabsorbedbytheintestinesandcirculatedin the blood stream reaching a maximal plasmaconcentrationin6hatwhichpointlt10ofcollagenhydrolysate remains in the gastrointestinal tract74Thesestudiesalsorevealedthatcollagenhydrolysateisnotcompletelybrokendownbythedigestivesystembutthatavarietyofcollagenfragmentsincludingupto10highmolecularformcollagenfragmentsthatrangefrom1toasymp10kDareabsorbedfollowingoraladministrationof collagenhydrolysatewith someindividualvariability74 Inexperimentswith radio-labeledcollagenhydrolysateithasbeenshownthatasignificantamountofcollagenhydrolysate-derivedpeptidesreachcartilagetissuewithin12hafteradmin-istration(p lt005comparedwithcontrolanimals)74

Incellcultureexperimentsinvestigatingtheefficacyofcollagenhydrolysateonthebiosynthesisofarticularchondrocytesitwasshownthattreatmentofculturedchondrocyteswith05mgmLcollagenhydrolysateoveracultureperiodof11daysinducedastatisticallysignificantdose-dependentincreaseintypeIIcollagensynthesisofthechondrocytes(p lt001comparedwithuntreatedcontrolcells)(Figure1)66Incontrastnativecollagensandthecollagen-freehydrolysateofproteinsdidnotstimulatethesynthesisoftypeIIcollagenbychondrocytes66Thesefindingsindicateastimulatoryeffect of collagen hydrolysate on type II collagensynthesisbychondrocytesInadditiontheamountofproteoglycanshasbeenshowntosignificantlyincreaseaftercollagenhydrolysateadministration(p lt005)75Moreoverexperimentsindicatethatsupplementationofcollagenhydrolysatehadnosignificanteffectontheexpressionofproteasesinchondrocytes75Basedonthefindingsthatcollagenhydrolysateisabsorbedfromtheintestineinitshighmolecularformpreferentiallyaccumulates incartilage74 and is able to stimulatechondrocytemetabolism itmightbereasonabletousecollagenhydrolysateasanutritionalsupplementtoactivatecollagenbiosynthesis inchondrocytesinhumansespeciallyunderconditionswherecartilageisunderconsiderablestress66

Clinicalstudies

Theclinicalbenefitsofcollagenhydrolysatehavebeeninvestigatedinfouropen-labelandthreedouble-blind

studies(Table2)368ndash73In1979resultswerepublisheddemonstratingtheclinicaleffectofcollagenhydrolysateondegenerativejointdiseaseinpatientswithkneeOAwithtibialfemoralorretropatellarinvolvementorwithdegenerativediskdiseaseofspecificpartsofthespinePatientsreceived5ndash7gofcollagenhydrolysatebymouthfor1ndash6monthsTheauthorreportedresultson56patients10(24)reportedlsquoverygoodsuccessrsquo(fivepatientsindicatedcompletefreedomfrompainandfiveindicatedimprovementintheirgeneralcondition)18 (44) reported lsquonoticeable improvementrsquo (12patients reported the general situation improvedconsiderablyandsixpatientsreportedthepainhadreceded substantially) and13 (32) reported lsquonoimprovementrsquoStatisticalanalyseswerenotreportedbytheinvestigators68

Similarfindingswerereportedina1982studyinwhich60juvenilepatientsdiagnosedwithretropatellarOAreceivedcollagenhydrolysatetreatment(one7gsachetperdaybymouth)for3months69Thesachetalsoincluded24000unitsofvitaminAand120mgofthesulfur-containingaminoacidL-cysteineAnumberofparametersweremeasuredincludingtheabilitytoclimbstairssofttissueswellingretropatellarcrepitusandkneeeffusionAtbaseline58patientspresentedwithretropatellarcrepituswhichistypicalofpatellarchondropathyTheinvestigatorsreportedthataftertreatment75ofpatientsdemonstrated improve-ment45ofpatientsweresymptomfreeand30hadclearlyimprovedsymptomsaftertakingthesachetfor3months69TheremainderofthepatientscontinuedtohavepainatrestStatisticalanalyseswerenotprovidedinthisreport69

Culture time (days)

4 0 2 6 8 10 120

1

2

BM

CH

Typ

e II

colla

gen

(microg

106

chon

dro

cyte

s)

Figure 1 Time course of type II collagen biosynthesis of chondrocytes cultured in basal medium (BM) or in medium supplemented with collagen hydrolysate (CH)66 p lt 001

compared with untreated controls


Anopen-labelstudyof154patientswithOAprovidedadditionalevidenceoftheclinicaleffectofcollagenhydrolysate70PatientswithdiagnosedOAofthekneehip or lower spinewere randomized among threetreatmentgroupstherapeuticexercisestherapeuticexercisespluscollagenhydrolysatewithvitaminAandL-cysteineorcollagenhydrolysatevitaminAandL-cysteinewithouttherapeuticexerciseThecollagenhydrolysatevitaminAandL-cysteineweregivenasonesachetperdaybymouthForallthreegroupsthedurationoftreatmentwas3monthsAtbaselineandafter3monthsoftreatmentpainintensitywasmeasuredusingapainassessmentscaleInthephysicaltherapyonlygroup20hadalsquoverygoodrsquoorlsquogoodrsquoresponsewhile56of the collagenhydrolysate vitaminAL-cysteineandphysicaltherapygrouphadalsquoverygoodrsquoorlsquogoodrsquoresponseand69ofthecollagenhydrolysatevitaminAandL-cysteine(nophysicaltherapy)grouphadalsquoverygoodrsquoorlsquogoodrsquoresponseTheresultsshowed

that43ofthephysicaltherapyonlypatientswerelsquounchangedrsquowhileonly14ofthesupplementplusphysicaltherapygroupand6ofthesupplementalonegrouphadthisresultThecompleteresultsareshowninTable3Thestatisticalsignificanceofthedifferencesbetweentreatmentgroupswasnotreported70

useinotherpopulations

The reviewof themedical literature showed thatcollagenhydrolysatehasbeenstudiedinpopulationsbesidesthosediagnosedwithOAArecentobserva-tional study investigated the effects of collagenhydrolysateinathleteswhosufferedfromjointpainbutwhowerenotdiagnosedwithOAInthisstudy100participantssufferingfromhipkneeorshoulderpain resulting from intensephysical activityweretreatedwithorallyadministeredcollagenhydrolysate(10gday)for12weeks72

Table 2 Collagen hydrolysate studies

Author Subjectsn OAlocation Trialdesign Outcomesstudied

Results

Krug68 56 Tibiafemurkneeorspine

Openlabel Paingeneralcondition

10(24)reportedlsquoverygoodsuccess18(44)reportedlsquonotice-ableimprovementrsquo13(32)reportedlsquonoimprovementrsquodagger

Goumltz69 60 Knee Openlabel Patientreportedpain

45painfree30improvedsymptoms25noimprovementdagger

Oberschelp70 154 Kneehiporlowerspine

Comparative Painintensity SeeTable3dagger

Flechsenhar72 100 NotdiagnosedwithOApaininhipkneeorshoulderfromsports

Open Painonmovement

Painreduction68subjectsimproved19wereunchangedonenotdocumenteddagger

Adam71 81 Kneeorhip Double-blindcrossover

Painconsumptionofanalgesics

Reductioninpainreported81ofthosetakingcollagenhydrolysate23ofthosetakingeggalbuminA 50decreaseinanalgesics69ofthosetakingcollagenhydrolysate35ofthosetakingeggalbumindagger

Zuckley76 250 Knee(mild)Dagger Randomizeddouble-blindplacebo-controlled

Isokineticandisometriclegstrengthpainstiffnessmobilityandflexibility

Nostatisticallysignificantdiffer-encesbetweengroupsformeasuresofpainstiffnessmobilityorflexibilitystatisticallysignificant(p lt005)improvementsin36isokineticlegstrengthmeasures

Moskowitz3 389 Knee Prospectiverandomizeddouble-blindplacebo-controlled

WOMACpainscorefunctionscoreandpatientglobalassessment

Nostatisticallysignificantdiffer-encesforthetotalstudygroupGermanpatientshadastatisticallysignificantbenefitfromcollagenhydrolysateforpainreduction(p =0016)andfunctionalimprovement(p =0007)butnotpatientglobalevaluation(p =0074)

DegenerativediskdiseasedaggerStatisticalanalyseswerenotreportedDaggerAmericanCollegeofRheumatologycriteria


Athleteswhowereintheacutephaseofajointinjuryorinflammatory(joint)conditionwereexcludedalongwiththosetakinganyOAmedicationsthatarenotclassifiedaseithercorticosteroidsNSAIDsorCOX-2inhibitorsincludingglucosamineorchondroitinthosewhoexpectedtoneedachangeinexistinganalgesicoranti-inflammatorymedicationsduringthestudyorthosewhohadinterferingconcomitantdiseases

During physical examinations clinical statusmeasures as assessed by the treating physicianincludedpainatrestpainonmovementfunctionallimitationsandinflammatoryactivityTheintensityoftheseparameterswasratedonascaleof1(nopainlimitationofactivity)to10(severepainlimitationofactivity)PatientswithhiporkneeproblemsassessedtheirpainintensitywhilewalkingwhenclimbingstairswhilestandingandatnightPatientswithshoulderarthralgiaassessedpainwhenliftingorcarryingobjectsandpainduringoverheadactivities72Thesesurveysndashcompletedatbaselineduringtreatment(4ndash6weeks)andat12weeksndashprovidedthebasisforcomparison

Of the 88 patients who could be evaluatedthroughoutthestudy51presentedwithkneearthralgia(580)20withhiparthralgia(227)and17with

shoulderarthralgia(193)Figure2whichdepictsthechangeinpainonmovementrevealsthat78ofpatientsachievedpainreductionaftertakingcollagenhydrolysatefor12weeks(68subjectsimproved19wereunchangedorworsenedandonepatientwasincompletelydocumentedforpainonmovement)72

The relative roleplayedbyanalgesics andothermedications in the results is not known althoughthenumberofsubjects takinganalgesicsandothermedicationsdecreasedbytheendofthestudyAtthestartofthestudy27subjectsweretakinganalgesics47weretakingNSAIDsorCOX-2inhibitorsandonepatientwastakingcorticosteroidsAttheendofthestudy12subjectsweretakinganalgesics13patientsweretakingNSAIDsorCOX-2inhibitorsandonepatientwastakingcorticosteroids72

CollagenhydrolysateforOApain

TheeffectofcollagenhydrolysateonpainfromOAwas studied inaprospective randomizeddouble-blindplacebo-controlledclinicaltrialconductedbyAdam71Theresearchersrecruited81patientswithOAof thekneeorhipanduseda complexcross-

Table 3 Results from study of patients taking collagen hydrolysate with vitamin A and L-cysteine with or without physical therapy70

ResponseIntervention

Verygoodn()

Goodn()

Noticeablen()

Unchangedn()

Physicaltherapy 3(6) 7(14) 18(37) 21(43)CollagenhydrolysatevitaminAL-cysteineandphysicaltherapy 9(20) 16(36) 13(30) 6(14)CollagenhydrolysatevitaminAL-cysteinenophysicaltherapy 16(26) 26(43) 15(25) 4(6)

NoteThestatisticalsignificanceofthedifferencesbetweentreatmentgroupswasnotreported

Knee Hip Shoulder

16

14

12

10

8

6

4

2

0

Num

ber

of s

ubje

cts

ndash3 ndash2 ndash1 +1 +2 +3 +40

Improved (+)by score points

Worsened (ndash)by score points

Figure 2 Change from baseline in pain on movement at Week 1272


over design to compare four different nutritionalsupplementsincludingcollagenhydrolysate(10gintheformof20capsuleseach500mgbymouth)Theyfoundthat81ofpatientstakingcollagenhydrolysateachievedmeaningfulpainreductioncomparedwith23ofpatientstakingeggalbuminInaddition69ofpatientstakingcollagenhydrolysatehadage50decreaseintheconsumptionofanalgesicscomparedwith35ofpatientstakingeggalbumin71

Inhis reporton this studyAdamnotedthat thedifferenttreatmentgroupswerestatisticallycomparedusingtheLechmachertestandthattheadministrationofeggalbuminhadanlsquoinsignificantrsquoinfluenceonpatientswhilethecollagenhydrolysatetreatmentresultedinalsquosubstantialrsquoreductionofsymptoms71Whiletheauthornotedthattheresultsfromtreatmentwithallnutritionalsupplements including collagen hydrolysate werelsquosignificantlydifferentrsquofromeggalbuminthereportdoesnotdefinestatisticalsignificance71

ThebenefitsofcollagenhydrolysateforpatientswithmildsymptomsofOAwereexploredinarandomizedplacebo-controlleddouble-blindstudythatrecruited250adultsdiagnosedwithmildsymptomsofOAoftheknee(baseduponAmericanCollegeofRheumatologycriteria)Atotalof190patientscompletedthestudy(88treatmentand102placebopatients)Treatmentconsistedoforaladministrationofcollagenhydrolysate(10gday)orplacebo for14weeks Isokinetic andisometriclegstrengthwasassessedinsubjectsusingaBiodexMulti-JointSystemB2000equippedwiththeBiodexAdvantageSoftwareprogram(BiodexNY)76A6-MinuteWalkTestanda50-FootWalkTestwereused to assess functionalmobility and jointpainstiffnessandperceivedfunctionalmobilitywasassessed

usingtheWesternOntarioandMcMasterUniversitiesOsteoarthritisIndex(WOMAC)IndextheLequesneIndexandtheKneePainScale

After 14weeks of treatment there were nostatisticallysignificantdifferencesbetweenthetreat-mentgroupsformeasuresofpainstiffnessmobilityandflexibilitymeasurementsHoweverthecollagenhydrolysate-treatedgroupshowedstatisticallysignif-icantimprovementinthreeoutofsixisokineticlegstrengthmeasures(peaktorqueBWforextensionat60ordmsec-1peaktorqueBWforflexionat60ordmsec-1andtotalworkBWforextensionat60ordmsec-1)(p lt005compared with placebo for all three tests) (seeFigure3)especiallyteststhatpresentedthegreatestchallengesofstresstothejointstructure)73TheotherthreemeasurementsapproachedstatisticalsignificancetotalworkBWforextensionat60ordmsec-1(p =0054)averagepowerforextensionat60ordmsec-1(p =0051)andaveragepowerforflexionat180ordmsec-1(p =0067)The investigators stated that the findings suggestthat collagen hydrolysate may contribute to earlychangesinkneecartilage(MCarpenterMSpersonalcommunications 2006) which is consistent withanimaldata74Thefindingsalsosuggestthatobjectiveisokineticandisometrictestsmaybemoresensitivefordetectingearlyimprovementsinjointfunctionthanpainandmobilityquestionnaires(MCarpenterMSpersonal communications2006)Theynoted thatfurtherstudiesareneededtoevaluatethelong-termbenefitsoftherapywithcollagenhydrolysate73

Moskowitzandcolleaguesconductedaprospectiverandomizeddouble-blindplacebo-controlledclinicaltrial of collagen hydrolysate between 1996 and19983Thestudyincluded20sitesinthreecountries

p = 0067

p = 0051

p = 0054p = 0022

p = 0031

p = 0015

Peak torqueBW-extension

Peak torqueBW-flexion

Total workBW-extension

Total workBW-flexion

Average powerBW-extension

Cha

nge

from

bas

elin

e

Average powerBW-flexion

9

8

7

6

5

4

3

2

1

0

ndash1

ndash2

Figure 3 Effect on isokinetic leg strength in groups treated for 14 weeks with collagen hydrolysate or placebo Black bars represent collagen hydrolysate while gray bars represent placebo73


(GermanyUnitedKingdomandtheUnitedStates)thatrecruited389patientswithkneeOAPatientswererandomizedtoreceiveeither10gofcollagenhydrolysateperdayorplacebobothbymouthfor24weeksTheprimaryoutcomemeasuresweretheWOMACpainscorefunctionscoreandpatientglobalassessment

After 24weeks of treatment there were nostatisticallysignificantdifferencesforthetotalstudygroup(allsites)fordifferencesofmeanscoreforpainHowevertheinvestigatorreportedthattheGermanpatients(n=112)experiencedastatisticallysignificantbenefit fromcollagenhydrolysate in termsofpainreduction(p =0016)andfunctional improvement(p =0007)butnotpatientglobalevaluation(p =0074)(Figure4)3Thereasons for thedifferencesobservedintheefficacyofcollagenhydrolysateintheUnitedStatesandtheUnitedKingdomversusthoseinGermanyarenotknownOneexplanationmaybethatthedropoutratesintheUKandUS(37and42respectively)weremuchhigherthaninGermany(6)Otherfactorsthatmightexplainthedifferencesbetweenthethreecountriesweredifferencesinbase-lineacetaminophenintakestudyconditionsplaceboeffectandspecialisttrainingwerenotaccountedforintheoverallanalysis77

Conclusions

Thisarticleprovidedabasicdescriptionofthemech-anismsofarticularcartilagestructureanddegradationassociated with OA and described the effects ofcollagenhydrolysateinpatientsdiagnosedwithOAbasedonareviewoftheliterature

The deterioration and eventual loss of articularcartilage inpatientswithOAiscausedbythedis-ruptionofitsstructuralintegrityassociatedwithan

imbalance inanabolicandcatabolicactivity in thecartilagetissueThisresultsinamarkeddecreaseinextracellularmatrixandeventualcartilagedamageviachangesinthestructureofarticularcartilage

It was previously thought that once damagedcartilage couldnot be restoredTreatmentswerethereforetargetedtowardsymptomaticreliefwithanalgesicsandanti-inflammatoryagentsandlubricat-ing and cushioning agentsHowever researchhasprovidedevidencethatsuggestssomeformsofinter-ventionmaybeabletohelpsupportthebodyrsquosabilitytorepairdamagedcartilage

ExperimentalstudieswithcollagenhydrolysatehaveindicatedthatitaccumulatesinjointcartilagewhereitstimulatesregenerationoftypeIIcollagenthemajortypeofcollagen incartilageand increases thebio-synthesisofproteoglycansThesefindingshaveinspiredinvestigatorstoexploretheuseofcollagenhydrolysateasanagentforstimulatingtheseregenerativeeffectsinthecartilageofpatientswithdisordersassociatedwithdamagedcartilagesuchasOA

ThisreviewidentifiedsevenstudiesontheuseofcollagenhydrolysateinvariouspatientpopulationsAlthough this review included several studies thatdidnotprovidekey informationsuchasstatisticalanalysesthataregenerallyacceptedasstandardsfortheevaluationofscientificdataitdoesprovideresultswhichsuggestthatcollagenhydrolysatemayprovidesymptomaticrelieftosomepatientswithOAIt isnotknowniftheeffectsseeninthein vitrostudiesareresponsibleforthesefindingsorwhetherothereffectsareinvolvedThisquestionwillneedtobeaddressedinfutureresearch

Giventhepotentialformodifyingcartilagesuggestedbyanimalresearchandclinicalstudieswhichreportthatcollagenhydrolysatereducespainanddisabilitymorethanplaceboinsomepatientsitseemsreasonableforphysicianstoconsidertryingcollagenhydrolysate

Figure 4 Effects on WOMAC Pain Score WOMAC Physical Function Score and Patientrsquos Global Evaluation following treatment with collagen hydrolysate or placebo77

ndash40

ndash35

ndash30

ndash25

ndash20

ndash15

ndash10

ndash5

0WOMAC Pain Score

WOMAC PhysicalFunction Score

Patientrsquos GlobalEvaluation

Rel

ativ

e im

pro

vem

ent

(Wee

k 24

min

usb

asel

ine)

CH

Placebo


forthetreatmentofjointpainanddisabilityespeciallyforthoseindividualswhoare50yearsofageorolderandactivevigorouslyactiveathletes(regardlessofage)individualsengaginginrepetitivemotionsandthosewhoareoverweightsedentaryorwithafamilialhistoryofjointdisease

Acknowledgments

Declaration of interestThisreviewwasfundedbyGELITA Health Products Vernon Hills IllinoisEditorialsupportforthismanuscriptwasprovidedbyACCESSMedicalGroupChicagoIllinois

References 1 OliveriaSAFelsonDTReedJIetalIncidenceofsymptomatic

hand hip and knee osteoarthritis among patients in a healthmaintenanceorganizationArthritisRheum1995381134-41

2 BriefAAMaurerSGDiCesarePEUseofglucosamineandchondroitinsulfate inthemanagementofosteoarthritis JAmAcadOrthopSurg2001971-8

3 MoskowitzRWRoleofcollagenhydrolysateinboneandjointdiseaseSeminArthritisRheum20003087-99

4 Felson DT Epidemiology of hip and knee osteoarthritisEpidemiolRev1988101-28

5 SharmaLSongJFelsonDTetalTheroleofkneealignmentindiseaseprogressionandfunctionaldeclineinkneeosteoarthritisJAmMedAssoc2001286188-95

6 FelsonDTLawrenceRCDieppePAetalOsteoarthritisnewinsightsPart1thediseaseanditsriskfactorsAnnInternMed2000133635-46

7 Green GA Understanding NSAIDs from aspirin to COX-2ClinCornerstone2001350-60

8 Guccione AA Felson DT Anderson JJ et al The effectsof specific medical conditions on the functional limitationsof elders in the Framingham Study Am J Public Health199484351-8

9 Prevalenceofself-reportedarthritisorchronicjointsymptomsamong adults ndash United States 2001 MMWR Morb MortalWklyRep200251948-50

10 Tesche F Miosge N New aspects of the pathogenesis ofosteoarthritis the role of fibroblast-like chondrocytes in latestagesofthediseaseHistolHistopathol200520329-37

11 Felson DT Anderson JJ Naimark A et al Obesity andknee osteoarthritis The Framingham Study Ann Intern Med198810918-24

12 Coggon D Reading I Croft P et al Knee osteoarthritis andobesityIntJObesRelatMetabDisord200125622-7

13 Pearle AD Warren RF Rodeo SA Basic science of articularcartilageandosteoarthritisClinSportsMed2005241-12

14 Kuettner KE Aydelotte MB Thonar EJ Articular cartilagematrix and structure a minireview J Rheumatol Suppl19912746-8

15 Buckwalter JA Mankin HJ Articular cartilage Part I tissuedesignandchondrocyte-matrix interactions InstrCourseLect199847477-86

16 LinnFCSokoloffLMovementandcompositionofinterstitialfluidofcartilageArthritisRheum19658481-94

17 Maroudas A Schneiderman R lsquoFreersquo and lsquoexchangeablersquo orlsquotrappedrsquo and lsquonon-exchangeablersquowater in cartilage JOrthopRes19875133-8

18 Wroble R Articular cartilage injury and autologous chondro-cyte implantationwhichpatientsmightbenefitPhysSports-med20002843-9

19 LotzMBlancoFJvonKempisJetalCytokineregulationofchondrocytefunctionsJRheumatolSuppl199543104-8

20 BuckwalterJAActivityvsrest inthetreatmentofbonesofttissueandjointinjuriesIowaOrthopJ19951529-42

21 Buckwalter JA Osteoarthritis and articular cartilage usedisuse and abuse experimental studies J Rheumatol Suppl19954313-5

22 GrayMLPizzanelliAMGrodzinskyAJLeeRCMechanicaland physiochemical determinants of the chondrocyte bio-syntheticresponseJOrthopRes19886777-92

23 McAlindon TE Jacques P Zhang Y et al Do antioxidantmicronutrientsprotectagainstthedevelopmentandprogressionofkneeosteoarthritisArthritisRheum199639648-56

24 HadlerNMGillingsDBImbusHRetalHandstructureandfunction in an industrial setting Arthritis Rheum 197821210-20

25 Trippel SB Growth factor actions on articular cartilage JRheumatolSuppl199543129-32

26 Trippel SB Corvol MT Dumontier MF et al Effect ofsomatomedin-Cinsulin-like growth factor I and growthhormoneonculturedgrowthplateandarticularchondrocytesPediatrRes19892576-82

27 Lum ZP Hakala BE Mort JS Recklies AD Modulation ofthe catabolic effects of interleukin-1 beta on human articularchondrocytesbytransforminggrowthfactor-betaJCellPhysiol1996166351-9

28 InoueHKatoY IwamotoM et al Stimulationof cartilage-matrixproteoglycan synthesisbymorphologically transformedchondrocytes grown in the presence of fibroblast growthfactor and transforming growth factor-beta J Cell Physiol1989138329-37

29 Morales TI Transforming growth factor-beta and insulin-likegrowth factor-1 restore proteoglycan metabolism of bovinearticularcartilageafterdepletionbyretinoicacidArchBiochemBiophys1994315190-8

30 Martin JABuckwalter JAAging articular cartilage chondro-cyte senescence and osteoarthritis Biogerontology 20023257-64

31 KoeppHEgerWMuehlemanCetalPrevalenceofarticularcartilage degeneration in the ankle and knee joints of humanorgandonorsJOrthopSci19994407-12

32 Buckwalter JA Lappin DR The disproportionate impact ofchronic arthralgia and arthritis among women Clin OrthopRelatRes2000159-68

33 Buckwalter J Goldberg V Woo S-Y Musculoskeletal soft-tissue aging impact on mobility Rosemont (IL) AmericanAcademyofOrthopedicSurgeons1993

34 DeGroot J Verzijl N Bank RA et al Age-related decrease inproteoglycansynthesisofhumanarticularchondrocytestheroleofnonenzymaticglycationArthritisRheum1999421003-9

35 Verzijl N DeGroot J Oldehinkel E et al Age-relatedaccumulationofMaillardreactionproductsinhumanarticularcartilagecollagenBiochemJ2000350381-7

36 BrandtKDOsteoarthritisInBraunwaldEFauciASKasperDL Hauser SL Longo DL Jameson JL editors Harrisonrsquosprinciplesofinternalmedicine15thedNewYorkMcGraw-Hill2001

37 Felson DT Hannan MT Naimark A et al OccupationalphysicaldemandskneebendingandkneeosteoarthritisresultsfromtheFraminghamStudyJRheumatol1991181587-92

38 Buckwalter JA Lane NE Athletics and osteoarthritis Am JSportsMed199725873-81

39 Cushnaghan J Dieppe P Study of 500 patients with limbjointosteoarthritis IAnalysisbyage sexanddistributionofsymptomaticjointsitesAnnRheumDis1991508-13

40 DieppePOsteoarthritisclinicalandresearchperspectiveBrJRheumatol199130(Suppl1)1-4

41 Felson DT Osteoarthritis Rheum Dis Clin North Am199016499-512

42 HochbergMCAltmanRDBrandtKD et alGuidelines forthemedicalmanagementofosteoarthritisPartIIOsteoarthritisof the knee [American College of Rheumatology] ArthritisRheum1995381541-6

43 American College of Rheumatology Subcommittee onOsteoarthritis Guidelines Recommendations for the medicalmanagementofosteoarthritisofthehipandknee2000updateArthritisRheum2000431905-15


44 Towheed TE Judd MJ Hochberg MC Wells G Acet-aminophen for osteoarthritis Cochrane Database Syst Rev2003CD004257

45 TowheedTEMaxwellLJuddMGetalAcetaminophenforosteoarthritisCochraneDatabaseSystRev2006CD004257

46 Hylek EM Heiman H Skates SJ et al Acetaminophen andother risk factors forexcessivewarfarinanticoagulation JAmMedAssoc1998279657-62

47 Lazzaroni M Bianchi Porro G Gastrointestinal side-effectsof traditional non-steroidal anti-inflammatory drugs and newformulations Aliment Pharmacol Ther 200420(Suppl 2)48-58

48 Garner SE Fidan DD Frankish RR et al Rofecoxib forrheumatoid arthritis Cochrane Database Syst Rev 2005CD003685

49 AnonAnnualnutritionindustryoverviewNutritionBusinessJ2005106-7

50 McAlindon TE LaValley MP Gulin JP Felson DT Glucos-amine and chondroitin for treatment of osteoarthritis asystematic quality assessment and meta-analysis J Am MedAssoc20002831469-75

51 RoncaFPalmieriLPanicucciPRoncaGAnti-inflammatoryactivity of chondroitin sulfate Osteoarthritis Cartilage19986(SupplA)14-21

52 Setnikar I Giacchetti C Zanolo G Pharmacokinetics ofglucosamine in the dog and in man Arzneimittelforschung198636729-35

53 BassleerCHenrotinYFranchimontP In-vitroevaluationofdrugsproposedaschondroprotectiveagentsIntJTissueReact199214231-41

54 Vidal y Plana RR Bizzarri D Rovati AL Articular cartilagepharmacology I In vitro studies on glucosamine and nonsteroidal antiinflammatory drugs Pharmacol Res Commun197810557-69

55 McCartyMFEnhancedsynovialproductionofhyaluronicacidmayexplainrapidclinicalresponsetohigh-doseglucosamineinosteoarthritisMedHypotheses199850507-10

56 Balkan B Dunning BE Glucosamine inhibits glucokinase invitro and produces a glucose-specific impairment of in vivoinsulinsecretioninratsDiabetes1994431173-9

57 Patti ME Virkamaki A Landaker EJ et al Activation of thehexosamine pathway by glucosamine in vivo induces insulinresistance of early postreceptor insulin signaling events inskeletalmuscleDiabetes1999481562-71

58 ShankarRRZhuJSBaronADGlucosamine infusion inratsmimics the beta-cell dysfunction of non-insulin-dependentdiabetesmellitusMetabolism199847573-7

59 Biggee BA McAlindon T Glucosamine for osteoarthritispart II biologic and metabolic controversiesMedHealthR I200487180-1

60 ScroggieDAAlbrightAHarrisMDTheeffectofglucosamine-chondroitinsupplementationonglycosylatedhemoglobinlevels

inpatientswithtype2diabetesmellitusaplacebo-controlleddouble-blinded randomized clinical trial Arch Intern Med20031631587-90

61 CleggDORedaDJHarrisCLetalGlucosaminechondroitinsulfateandthetwoincombinationforpainfulkneeosteoarthritisNewEnglJMed2006354795-808

62 BiggeeBAMcAlindonTGlucosamineforosteoarthritispartIreviewoftheclinicalevidenceMedHealthRI200487176-9

63 McAlindon T Why are clinical trials of glucosamine no longeruniformlypositiveRheumDisClinNorthAm200329789-801

64 Kim LS Axelrod LJ Howard P et al Efficacy ofmethylsulfonylmethane (MSM) in osteoarthritis pain of theknee a pilot clinical trial Osteoarthritis Cartilage 200614286-94

65 Harmand MF Vilamitjana J Maloche E et al Effects of S-adenosylmethionineonhumanarticularchondrocytedifferenti-ationAninvitrostudyAmJMed198783(Suppl5A)48-53

66 OesserSSeifertJStimulationoftypeIIcollagenbiosynthesisand secretion in bovine chondrocytes cultured with degradedcollagenCellTissueRes2003311393-9

67 Data on file GELITA Health Products Vernon Hills Illinois2006

68 Krug E Zur unterstuumltzenden Therapie bei Osteo- undChondropathienZErfahrungsheikunde197911930-8

69 GoumltzBGutgenaumlhrterKnorpelknirschtnichtmehrAumlrztlPrax1982923130-4

70 Oberschelp U Individuelle Arthrosetherapie ist moumlglichTherapiewoche1985445094-7

71 Adam M Welche Wirkung haben Gelatinepraumlparate TherOsteoarthroseTherapiewoche1991412456-61

72 FlechsenharKAlfDErgebnisseeinerAnwendungsbeobachtungzu Kollagen-Hydrolysat CH-Alpha Orthopaedische Praxis20059486-94

73 Zukley L Angelopoulos K Carpenter M et al Collagenhydrolysate improves joint function in adults with mildsymptomsofosteoarthritisoftheknee51stAnnualAmericanCollegeofSportsMedicine2004[poster]

74 Oesser S Adam M Babel W Seifert J Oral administrationof (14)C labeledgelatinhydrolysate leads to anaccumulationof radioactivity in cartilage of mice (C57BL) J Nutr19991291891-5

75 OesserSDegradedcollagenmodulatestheinternalremodelingofcartilageextracellularmatrixArthritisRheum200552(Suppl9)S62

76 Zuckley L Angelopoulou K Carpenter MR et al Collagenhydrolysate improves joint function in adults with mildsymptomsofosteoarthritisof thekneeMedSciSportsExerc200436(Suppl)S153-S154

77 Selbmann H-K Fischer IU Moskowitz RW Collagenhydrolysate in knee osteoarthritis (OA) population specificresponsesPosteratTheCongressoftheOsteoarthritisResearchSocietyInternational(OARSI)2004

CrossReflinksareavailableintheonlinepublishedversionofthispaperhttpwwwcmrojournalcom

PaperCMRO-3580_4Accepted for publication12September2006Published Online10October2006doi101185030079906X148373


atleastdeceleratingitsprogressivedegradation2Onesuchagentthathasbeeninvestigatedisthenutritionalsupplementcollagenhydrolysate3

The purpose of this article is to review theepidemiologyandriskfactorsforOAandreviewsomeofthecurrentmanagementoptionsforthisdisorderItsummarizesclinicalresearchwithcollagenhydrolysateanddiscussestheclinicalsignificanceofthisresearchandthepotentialofthissupplementforthetreatmentofpatientswithOAArticleswereobtainedthroughsearchesofthePubMeddatabase(wwwpubmedgov)throughMay2006usingthefollowingkeywordpairswithoutdate limits collagenhydrolysateandOAcollagenhydrolysateandcartilagecollagenhydrolysateandchondrocytescollagenhydrolysateandclinicaltrialInadditionothersourcesofinformationsuchasabstractspresentedatscientificcongressesandarticlesin theGermanmedical literaturenot availableonPubMedwerereviewedandincludedbasedontheauthorsrsquojudgmentoftheirrelevancetothetopicofthisreview

osteoarthritis epidemiology and risk factors

OA is the most common form of arthritis amongtheelderlyanda leadingcauseofdisability in thispopulation4ndash6Thediseaseaccountsfor25ofvisitstoprimarycarephysicians7OAaccounts formoretroublewithclimbingstairsandwalkingthananyotherdisease8

The prevalence of arthritis and chronic jointsymptoms increases with age (Table 1)69 In onecommunity-basedsurveytheincidenceandprevalenceofOAincreased2-to10-foldfrom30to65yearsof

ageanditincreasedfurtherbeyond65years1DuetothegeneralincreaseinlifeexpectancyandtheagingofthelsquobabyboomrsquogenerationthenumberofAmericanswhoare50yearsofageandolderisexpectedtodoubleby2020aswilltheprevalenceofOAunderscoringtheneedforeffectivetreatment10

BesidesageotherriskfactorsforOAincludemajortraumaand repetitive jointuse6Obesity is also ariskfactorforOA(Table1)11TherearedatawhichsuggestthatobesityplaysanevenlargerroleinthedevelopmentofkneeOA12OtherconditionsthatmaybeinvolvedinthedevelopmentofOAaresystemicmetabolicorendocrinedisordersneurologicdiseasesanddysplasia

Pathophysiology of cartilage degenerationthestructureofarticularcartilage

Articularcartilagealsoknownashyalinecartilageisaspecializedtoughflexibletissuewithalow-frictioncoefficientandasmootharticulatingsurfacethatmakesitideallysuitableforloaddistributionandabsorbingtheshockofmovement13Itiscomprisedofchondrocytes(about2ndash10ofthevolumeofarticularcartilage)andanextracellularmatrixwhichismaintainedbythechondrocytes14Thematrixofthearticularcartilageconsistsoftwocomponentsthetissuefluidandtheframeworkofstructuralmacromoleculesthatgivethetissueitsformandstability15Sixtytoeightypercentofthematrixiswater16ndash18

Themacromolecularframeworkofarticularcartilageconsistsofcollagens(predominantlytypeIIcollagen)proteoglycansandnon-collagenousproteins1315Thesestructuralmacromoleculescontribute20ndash40ofthe

Table 1 Persons with arthritis and chronic joint symptoms in the United States9

Characteristic Number Percent (95CIdagger)

Agegroupyears 18ndash44 20610 190 (185ndash194)45ndash64 27112 421 (415ndash428)ge65 21704 588 (580ndash597)

Sex Male 28926 284 (279ndash289)Female 41008 373 (369ndash378)

Bodymassindex(BMI) BMIlt185(underweight) 1153 272 (249ndash296)BMI185ndash249(normal) 21532 266 (261ndash271)BMI250ndash299(overweight) 25011 336 (330ndash342)BMIge30(obese) 18879 446 (437ndash454)

Total 69934 330 (327ndash334)

InthousandsdaggerConfidenceinterval








Cartilagemetabolism









stages



symptoms




treatment



























preclinicalstudies



Clinicalstudies




Culture time (days)

4 0 2 6 8 10 120

1

2

BM

CH

Typ

e II

colla

gen

(microg

106

chon

dro

cyte

s)










Results









Open Painonmovement






















Verygoodn()

Goodn()

Noticeablen()

Unchangedn()



Knee Hip Shoulder

16

14

12

10

8

6

4

2

0

Num

ber

of s

ubje

cts












p = 0067

p = 0051

p = 0054p = 0022

p = 0031

p = 0015






Cha

nge

from

bas

elin

e


9

8

7

6

5

4

3

2

1

0

ndash1

ndash2





Conclusions









ndash40

ndash35

ndash30

ndash25

ndash20

ndash15

ndash10

ndash5

0WOMAC Pain Score



Rel

ativ

e im

pro

vem

ent

(Wee

k 24

min

usb

asel

ine)

CH

Placebo



Acknowledgments



























































































Cartilagemetabolism









stages



symptoms




treatment



























preclinicalstudies



Clinicalstudies




Culture time (days)

4 0 2 6 8 10 120

1

2

BM

CH

Typ

e II

colla

gen

(microg

106

chon

dro

cyte

s)










Results









Open Painonmovement






















Verygoodn()

Goodn()

Noticeablen()

Unchangedn()



Knee Hip Shoulder

16

14

12

10

8

6

4

2

0

Num

ber

of s

ubje

cts












p = 0067

p = 0051

p = 0054p = 0022

p = 0031

p = 0015






Cha

nge

from

bas

elin

e


9

8

7

6

5

4

3

2

1

0

ndash1

ndash2





Conclusions









ndash40

ndash35

ndash30

ndash25

ndash20

ndash15

ndash10

ndash5

0WOMAC Pain Score



Rel

ativ

e im

pro

vem

ent

(Wee

k 24

min

usb

asel

ine)

CH

Placebo



Acknowledgments





















































































stages



symptoms




treatment



























preclinicalstudies



Clinicalstudies




Culture time (days)

4 0 2 6 8 10 120

1

2

BM

CH

Typ

e II

colla

gen

(microg

106

chon

dro

cyte

s)










Results









Open Painonmovement






















Verygoodn()

Goodn()

Noticeablen()

Unchangedn()



Knee Hip Shoulder

16

14

12

10

8

6

4

2

0

Num

ber

of s

ubje

cts












p = 0067

p = 0051

p = 0054p = 0022

p = 0031

p = 0015






Cha

nge

from

bas

elin

e


9

8

7

6

5

4

3

2

1

0

ndash1

ndash2





Conclusions









ndash40

ndash35

ndash30

ndash25

ndash20

ndash15

ndash10

ndash5

0WOMAC Pain Score



Rel

ativ

e im

pro

vem

ent

(Wee

k 24

min

usb

asel

ine)

CH

Placebo



Acknowledgments






































































































preclinicalstudies



Clinicalstudies




Culture time (days)

4 0 2 6 8 10 120

1

2

BM

CH

Typ

e II

colla

gen

(microg

106

chon

dro

cyte

s)










Results









Open Painonmovement






















Verygoodn()

Goodn()

Noticeablen()

Unchangedn()



Knee Hip Shoulder

16

14

12

10

8

6

4

2

0

Num

ber

of s

ubje

cts












p = 0067

p = 0051

p = 0054p = 0022

p = 0031

p = 0015






Cha

nge

from

bas

elin

e


9

8

7

6

5

4

3

2

1

0

ndash1

ndash2





Conclusions









ndash40

ndash35

ndash30

ndash25

ndash20

ndash15

ndash10

ndash5

0WOMAC Pain Score



Rel

ativ

e im

pro

vem

ent

(Wee

k 24

min

usb

asel

ine)

CH

Placebo



Acknowledgments






















































































preclinicalstudies



Clinicalstudies




Culture time (days)

4 0 2 6 8 10 120

1

2

BM

CH

Typ

e II

colla

gen

(microg

106

chon

dro

cyte

s)










Results









Open Painonmovement






















Verygoodn()

Goodn()

Noticeablen()

Unchangedn()



Knee Hip Shoulder

16

14

12

10

8

6

4

2

0

Num

ber

of s

ubje

cts












p = 0067

p = 0051

p = 0054p = 0022

p = 0031

p = 0015






Cha

nge

from

bas

elin

e


9

8

7

6

5

4

3

2

1

0

ndash1

ndash2





Conclusions









ndash40

ndash35

ndash30

ndash25

ndash20

ndash15

ndash10

ndash5

0WOMAC Pain Score



Rel

ativ

e im

pro

vem

ent

(Wee

k 24

min

usb

asel

ine)

CH

Placebo



Acknowledgments



























































































Results









Open Painonmovement






















Verygoodn()

Goodn()

Noticeablen()

Unchangedn()



Knee Hip Shoulder

16

14

12

10

8

6

4

2

0

Num

ber

of s

ubje

cts












p = 0067

p = 0051

p = 0054p = 0022

p = 0031

p = 0015






Cha

nge

from

bas

elin

e


9

8

7

6

5

4

3

2

1

0

ndash1

ndash2





Conclusions









ndash40

ndash35

ndash30

ndash25

ndash20

ndash15

ndash10

ndash5

0WOMAC Pain Score



Rel

ativ

e im

pro

vem

ent

(Wee

k 24

min

usb

asel

ine)

CH

Placebo



Acknowledgments






























































































Verygoodn()

Goodn()

Noticeablen()

Unchangedn()



Knee Hip Shoulder

16

14

12

10

8

6

4

2

0

Num

ber

of s

ubje

cts












p = 0067

p = 0051

p = 0054p = 0022

p = 0031

p = 0015






Cha

nge

from

bas

elin

e


9

8

7

6

5

4

3

2

1

0

ndash1

ndash2





Conclusions









ndash40

ndash35

ndash30

ndash25

ndash20

ndash15

ndash10

ndash5

0WOMAC Pain Score



Rel

ativ

e im

pro

vem

ent

(Wee

k 24

min

usb

asel

ine)

CH

Placebo



Acknowledgments



























































































p = 0067

p = 0051

p = 0054p = 0022

p = 0031

p = 0015






Cha

nge

from

bas

elin

e


9

8

7

6

5

4

3

2

1

0

ndash1

ndash2





Conclusions









ndash40

ndash35

ndash30

ndash25

ndash20

ndash15

ndash10

ndash5

0WOMAC Pain Score



Rel

ativ

e im

pro

vem

ent

(Wee

k 24

min

usb

asel

ine)

CH

Placebo



Acknowledgments























































































Conclusions









ndash40

ndash35

ndash30

ndash25

ndash20

ndash15

ndash10

ndash5

0WOMAC Pain Score



Rel

ativ

e im

pro

vem

ent

(Wee

k 24

min

usb

asel

ine)

CH

Placebo



Acknowledgments






















































































Acknowledgments


























































































































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