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REVIEW

Collagen hydrolysate for the treatment of osteoarthritis and other joint disorders: a review of the literatureAlfonsoe.belloaandsteffenOesserb

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

Address for correspondence: Alfonso E. Bello, MD, MHS, FACP, FACR, DABPM, Clinical Associate Professor of Medicine, University of Illinois College of Medicine at Chicago, 1801 West Taylor Street, Chicago, IL 60612, USA. Tel.: +1 312 413 3631; Fax: +1 312 355 3133; email: [email protected]

Key words: Articular cartilage – Collagen hydrolysate – Nutritional supplements – Osteoarthritis – Proteoglycans – Type II collagen

0300-7995

doi:10.1185/030079906X148373

Allrightsreserved:reproductioninwholeorpartnotpermitted

CurrentMediCAlreseArChAndOpiniOn®

VoL. 22, No. 11, 2006, 2221–2232

©2006librAphArMliMited

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 (www.pubmed.gov) 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 authors’ 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 < 0.05 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 – such as the statistical significance of the findings – 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)affectsmillionsofpeopleintheUnitedStates,andthenumberofpeoplewithOAispredictedtoincreaseasthepopulationages1.Currently,

thereisnocureforOA,somanagementofthediseaseis focusedon reducingpain,maintainingmobility,andminimizingdisability. In recent years, severalinvestigatorshavesuggestedthatsomesubstancesmaybecapableofrepairingdamagedarticularcartilageor

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2222 Collagen hydrolysate and osteoarthritis ©2006librAphArMltd–CurrMedresOpin2006;22(11)

atleastdeceleratingitsprogressivedegradation2.Onesuchagentthathasbeeninvestigatedisthenutritionalsupplementcollagenhydrolysate3.

The purpose of this article is to review theepidemiologyandriskfactorsforOAandreviewsomeofthecurrentmanagementoptionsforthisdisorder.ItsummarizesclinicalresearchwithcollagenhydrolysateanddiscussestheclinicalsignificanceofthisresearchandthepotentialofthissupplementforthetreatmentofpatientswithOA.ArticleswereobtainedthroughsearchesofthePubMeddatabase(www.pubmed.gov)throughMay2006usingthefollowingkeywordpairs,withoutdate limits: collagenhydrolysateandOA;collagenhydrolysateandcartilage;collagenhydrolysateandchondrocytes;collagenhydrolysateandclinicaltrial.Inaddition,othersourcesofinformation,suchasabstractspresentedatscientificcongressesandarticlesin theGermanmedical literaturenot availableonPubMed,werereviewedandincludedbasedontheauthors’judgmentoftheirrelevancetothetopicofthisreview.

osteoarthritis: epidemiology and risk factors

OA is the most common form of arthritis amongtheelderlyanda leadingcauseofdisability in thispopulation4–6.Thediseaseaccountsfor25%ofvisitstoprimarycarephysicians7.OAaccounts formoretroublewithclimbingstairsandwalkingthananyotherdisease8.

The prevalence of arthritis and chronic jointsymptoms increases with age (Table 1)6,9. In onecommunity-basedsurvey,theincidenceandprevalenceofOAincreased2-to10-foldfrom30to65yearsof

age,anditincreasedfurtherbeyond65years1.Duetothegeneralincreaseinlifeexpectancyandtheagingofthe‘babyboom’generation,thenumberofAmericanswhoare50yearsofageandolderisexpectedtodoubleby2020,aswilltheprevalenceofOA,underscoringtheneedforeffectivetreatment10.

Besidesage,otherriskfactorsforOAincludemajortraumaand repetitive jointuse6.Obesity is also ariskfactorforOA(Table1)11.TherearedatawhichsuggestthatobesityplaysanevenlargerroleinthedevelopmentofkneeOA12.OtherconditionsthatmaybeinvolvedinthedevelopmentofOAaresystemic,metabolic,orendocrinedisorders,neurologicdiseases,anddysplasia.

Pathophysiology of cartilage degenerationthestructureofarticularcartilage

Articularcartilage,alsoknownashyalinecartilage,isaspecialized,tough,flexibletissuewithalow-frictioncoefficientandasmootharticulatingsurfacethatmakesitideallysuitableforloaddistributionandabsorbingtheshockofmovement13.Itiscomprisedofchondrocytes(about2–10%ofthevolumeofarticularcartilage)andanextracellularmatrix,whichismaintainedbythechondrocytes14.Thematrixofthearticularcartilageconsistsoftwocomponents:thetissuefluidandtheframeworkofstructuralmacromoleculesthatgivethetissueitsformandstability15.Sixtytoeightypercentofthematrixiswater16–18.

Themacromolecularframeworkofarticularcartilageconsistsofcollagens(predominantlytypeIIcollagen),proteoglycans,andnon-collagenousproteins13,15.Thesestructuralmacromoleculescontribute20–40%ofthe

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

Characteristic Number* Percent (95%CI†)

Agegroup,years 18–44 20610 19.0 (18.5–19.4)45–64 27112 42.1 (41.5–42.8)≥65 21704 58.8 (58.0–59.7)

Sex Male 28926 28.4 (27.9–28.9)Female 41008 37.3 (36.9–37.8)

Bodymassindex(BMI) BMI<18.5(underweight) 1153 27.2 (24.9–29.6)BMI18.5–24.9(normal) 21532 26.6 (26.1–27.1)BMI25.0–29.9(overweight) 25011 33.6 (33.0–34.2)BMI≥30(obese) 18879 44.6 (43.7–45.4)

Total 69934 33.0 (32.7–33.4)

*Inthousands†Confidenceinterval

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©2006librAphArMltd–CurrMedresOpin2006;22(11) Collagen hydrolysate and osteoarthritis Bello and Oesser 2223

wetweightofthetissue.Thecollagenfibrilsareformedintheextracellularspaceandcross-linkedbycovalentbonds,forminga3-dimensionalfibrillarnetwork.Itisthismatrixthatprovidesthecartilagewithitstensilestiffnessandstrength.Theproteoglycans(mostnotably,aggrecans)areembeddedwithinthisfibrousnetwork,combinedwithwater.Aggrecanscreatetheosmoticswellingpressurethatisresponsibleforcompressibilityandelasticityofcartilage,whichiscounteractedbytheresistanceoftheintactcollagenfibrils.

Collagenscontributeabout60%tothedryweightofcartilage,whileproteoglycansprovide25–35%andnon-collagenousproteinsandglycoproteinscontribute15–20%15. The relative amounts of the majorconstituentsofarticularcartilagedeterminethemech-anicalpropertiesofthistissue15.Changesintherelativeamounts of these components and in their highlystructuredordermayoccurduetodiseaseordamage,alteringthemechanicalpropertiesofthecartilage.

Normalcartilagefunctionresultsinaconstantshift-ingbetweenanincreaseofpressureandareductionofpressurewithinthejoint.Althoughcartilageisdevoidofnerves,bloodvessels,andlymphatics,thesechang-ingpressurescauseapumpingactionthatallowsthedeliveryofnutrientstothecartilagefromitssurround-ingsandtheremovalofmetabolicwasteproducts.

theroleofchondrocytes

Cartilagehasanactivemetabolismcharacterizedbyaslowbutcontinuousturnoverofitscellsandextra-cellularmatrix.Locatedwithinthematrixarechon-drocytes,whichsynthesizematrixmacromolecules,suchascollagenandproteoglycans,andenzymesthathelpbreakdownanddisposeofagingcollagenandproteoglycans15.Theyalsodeterminethehighlyorderedstructureoftheextracellularmatrix.Chondrocytesarebelievedtodetectchangesinthecompositionofthematrixandnewstressesuponthearticularcartilage15.Ifaparticularjointbeginstoencounterunusualpressureorsustainsdamage,chondrocytesrespondbyalteringorrepairingthecartilage.

Chondrocytes have a central role in regulatinganabolicandcatabolicprocesses,creatingabalanceof synthetic anddegradative activity that leads tocontinuousinternalremodelingandturnoverinhealthycartilage.

Cartilagemetabolism

Many factors affect cartilage turnover, includingnumerousbiochemicalregulators,anadequatesupplyof the molecules necessary for the production ofcartilagecomponents,physicalstressonthejoints,andanindividual’slifestyle19–24.

Theregulatorymechanismsarecomplexandnotfullyunderstood.Severalsubstancesarebelievedtobeinvolvedintheregulationofcartilagemetabolism,includingcytokines,growthfactors,typeIIcollagenandcollagen fragments,andvitaminsandminerals(e.g.,vitaminC)19,23,25–29.

Physical activitycanalsohavevaryingeffectsoncartilagemetabolism.Forexample,immobilizationofthejointoramarkeddecreaseinjointloadingalterschondrocyteactivitysothatdegradationexceedssynthesisoftheproteoglycancomponentofthematrix20,21.Anadequateamountofphysicalactivityisnecessarytopreservecartilage,andoverexertionorcontinuousstresscancontributetopathologicchanges15,21.

deteriorationofcartilage

Thedisruptionofthestructuralintegrityofarticularcartilage,itsdeterioration,anditseventuallossarearesultofanimbalancebetweenanabolicandcatabolicactivity in the cartilage tissue.Themost commonoriginsofthisimbalanceincludechondrocytesenes-cenceandpathophysiologicconditionssuchasOA.Asthechondrocytes’sensitivitytoregulatorysignalsdecreases,theirabilitytomaintainandrepaircartilagetissueisdiminished30.Alongwithadecreasedrespons-ivenesstoanabolicgrowthfactorsandreductioninsyntheticactivity,smaller,less-uniformaggrecanandless-functionallinkproteinsareformed.Theseage-relatedchangesalterthecompositionofthematrixandleadtoaprogressiveimbalancebetweendegradationandregeneration,adecreaseintypeIIcollageninthematrixand,eventually, cartilagedamage.Changesincludefibrillationofthearticularsurface31,32,causingittofrayandsoften,andincreasedcollagencross-link-ing33–35,withlossoftensilestrengthandstiffnessofthematrix.

osteoarthritis: disease progression and management

OAisajointdiseasecharacterizedbyprogressivedes-tructionofjointcartilageanditsassociatedstructures,suchasbone,synovialandfibrousjointcapsules,andtheperiarticularmusculature10,36.Therearetwodis-tinctformsofOA:primary(idiopathic)andsecondary.PrimaryOAhasnodiscernibletrigger,butmaybeassociatedwithagingand/or lifestyle factors (e.g.,jobsthatinvolverepetitivetaskssuchaskneelingorsquattingorparticipationinsportssuchasfootballorsoccer)37,38.SecondaryOAcanbetheresultofvariouspathologicalconditions,suchasjointinjury,infection,ordevelopmentalormetabolicdisorders10.

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stages

The underlying pathophysiology of OA is morecomplicatedthansimply‘wearingout’ofcartilage.Itisnotadiseaseofanysingletissue,butadiseasethat involves the entire joint36. There are a seriesof imbalances in the synthesis anddegradationofstructuralcomponents,alongwith injuriesbroughtaboutbybiomechanicalforces13.

DuringtheinitialstageofOA,thereisanexcessiveproteolyticbreakdownofthecartilagematrix13.Asaresult,thecartilagelosesitselasticityandismoreeasilydamagedduetoinjuryoruse.Next,theshapeandstructureofthejointarealtered,whichreducessmooth joint function.Fibrillationanderosionsofcartilageresultinpiecesofboneorcartilagefloatingloosely in the synovial fluid,causing irritationandpain.Thegradualdeteriorationof cartilagecauseschangestotheunderlyingbone,includingthickeningofbone,formationofcystsunderneaththecartilage,thedevelopmentofbonygrowths(i.e.,spursorosteo-phytes)near theendsof thebonesat theaffectedjoints,and,inmanypatients,chronicinflammationofthesynovialmembrane13,36.

symptoms

Althoughanysynovialjointcanbeaffected,OAoccursmost frequently in theknee,hip,hand,andspinalapophysealjoints39–41.Lessfrequentlyaffectedarethewrist,elbow,shoulder,andanklejoints39–41.

Oncecartilagelosesitselasticity,rangeofmotionislostandsufferersofOAbegintoexperiencestiffnessintheaffectedjoint.Thepainistypicallyactivityrelated,madeworsewithweightbearing,andimprovedwithrest.Ultimately,thejointisaffected,leadingtojointfailure.

ItisinterestingtonotethatthecorrelationbetweenthepathologicseverityofOAandsymptomsislow.IthasbeenobservedthatmanypeoplewithradiographicchangesthatsuggestadvancedOAhavenosymptoms36.RiskfactorsthatresultinpainanddisabilityinpatientswithOAarenotwellunderstood36.

treatment

TreatmentofOAisfocusedonreducingpain,main-tainingmobility,andminimizingdisability36.Non-pharmacologic(e.g.,physicaltherapy,surgery)and/orpharmacologicmeasuresmaybeindicatedforpatientswithOA.

Traditional modalities for treating OA includeanalgesicsandanti-inflammatoryagents,lubricatingandcushioningagents,nutritionalsupplements,andsurgeryforpatientswithadvancedOAforwhomaggressive

medicalmanagementhasfailed3,36.Acetaminophen(upto4g/day)isrecommendedasfirst-linetherapyforthesystemictreatmentofsymptomaticOA42–45.However,thesemodalitiesarelimitedbytoxicity,intolerance,lackofpatientcompliance,orvariableresponses.Forexample, acetaminophenhasbeenassociatedwithprolongationofthehalf-lifeofwarfarin46.Non-steroidalanti-inflammatory drugs (NSAIDs) are the mostcommonlyusedpharmacologicagentsandhavelongbeenknowntoincreasetheriskforgastrointestinalsideeffectssuchaspepticulcerdiseaseby10-to30-fold47.In2004,NSAIDs,specificallycyclo-oxygenase(COX)-2selectiveinhibitors,werelinkedtocardiovascularevents(i.e.,myocardialinfarctionandstroke),resultinginsomeof theseagentsbeingwithdrawnfromthemarketbecauseofsafetyconcerns48.

nutritionalsupplements

Various nutr it ional supplements have beeninvestigatedforthetreatmentofpatientswithOAandjointpain.Theseincludeglucosamine,chondroitinsulfate,methyl-sulfonyl-methane(MSM),S-adenosylmethionine(SAMe),andcollagenhydrolysate.Despitethewidespreaduseofsomeoftheseagents,therearevaryinglevelsofevidenceconcerningtheirefficacyinpatientswithOA.

Glucosamine and chondroitin sulfate

ThesetwodietarysupplementsarewidelyusedbyconsumersforthemanagementofOA49.Glucosamineand chondroitin sulfate are compounds that areextractedfromanimalproducts;theyhavebeenusedtotreatvariousformsofOAinEuropeformorethanadecade50.Researchhasshownthattheyareabsorbedfromthegastrointestinaltract51,52.In vitroexperimentshavedemonstratedthatadditionofglucosaminetohumanchondrocytes in tissueculture leads to theactivationofcore-proteinsynthesis,thuspromotingproteoglycanproduction53,54.McCartyhassuggestedthatachondroprotectiveactionofglucosaminemaybeduetoenhancedsynovialproductionofhyaluronicacid,whichdown-regulatesmechanismsthatresultincartilagedegradationandpaininpatientswithOA55.

Althoughthesetwosupplementsaregenerallywelltolerated,animalstudieshaveshownthatglucosamineinterfereswithglucosetransportandinsulinsecretion,leadingtohyperglycemiaand insulinresistance56–58.Despite someconflictingdata inhumans, there isspeculation that glucosamine could predispose todiabetes59.Whilearandomized,double-blind,placebo-controlledtrialpublishedin2003foundthatpatients(N=38)with type2diabetes takingglucosaminehydrochlorideandchondroitindidnotexperiencea

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significantincreaseintheirglycosylatedhemoglobin(HbA

1c)levelsafter90daysoftherapy60,moreresearch

isneededtodeterminethelong-termeffectofthesesupplementsforpatientswithdiabetes.

Theefficacyofglucosamineandchondroitin forpatientswithOAhasbeentestedinover20clinicaltrials(asreviewedbyMcAlindonet al.50).However,investigatorswhoconductedameta-analysisof15ofthesestudiesconcludedthatwhiletrialsofglucos-amineandchondroitinusedfortreatingOAsymptomsdemonstratemoderate-to-largeeffects,studyqualityissuesandlikelypublicationbiasmayhaveresultedin thebenefits of theseproducts being somewhatexaggerated50.Theauthorsofthemeta-analysisrecom-mendedthathigh-quality,independentstudieswereneededtodeterminetheactualefficacyandutilityofthesesupplements50.

Becauseofthescientificqualityproblemsassociatedwiththeearlierglucosamineandchondroitinstudies,theGlucosamine/chondroitinArthritis InterventionTrial(GAIT)wasdesignedtorigorouslyevaluatetheeffectofthesesupplementsonpainduetoOAintheknee61.Thistrialwasa24-week,randomized,multi-center,double-blind,placebo-andcelecoxib-controlledtrialsponsoredbytheNationalInstitutesofHealth61.PatientswithsymptomatickneeOAreceivedeither1500mgglucosaminedaily,1200mgchondroitinsulfatedaily,bothglucosamineandchondroitinsulfatedaily,200mgofcelecoxibdaily,orplacebofor24weeks.Upto4000mgofacetaminophendailywasallowedasrescueanalgesia.Theprimaryoutcomemeasurewasa20%decreaseinkneepainfrombaselinetoWeek2461.

TheGAITinvestigatorsfoundthatglucosamineandchondroitinsulfatealoneandincombinationdidnotreducepaineffectivelyinagroupofpatientswithOAoftheknee,usingthe20%decreaseinkneepainastheprimaryoutcome61.Analysisofaprespecifiedsubgroupofpatientswithmoderate-to-severepaindemonstratedthatcombinationtherapysignificantlydecreasedkneepainrelatedtoOA(p =0.002)61.Itisworthnotingthatnearlyalloftheglucosaminestudiessuggestingefficacyusedglucosaminesulfate,whileGAITusedglucosaminehydrochloride.However, a reviewofglucosaminestudiesobservedthatwhiletheoutcomesofindustrysponsoredstudiesofglucosamineforOAweremostlypositive, the results of non-industry-sponsoredstudieswerenot62.MoreresearchisneededtodeterminethevalueofthesesupplementsforthetreatmentofpatientswithOA63.

Methyl-sulfonyl-methane

Thisisanotherdietarysupplementthatisusedforthetreatmentofjointpain64.Thereislimitedresearchonthebenefitsofthissupplement.Onerecentlypublished

studyinvestigateditsuseforpatientswithOAinarandomized,double-blind,placebo-controlled trialwith50menandwomen(40–76yearsofage)withOAoftheknee64.Thepatientsreceived3gofMSMorplacebotwiceeachday(6g/day)for12weeks.TheinvestigatorsreportedthatMSMproducedsignificantlyreducedlevelsofpainasmeasuredbytheWesternOntarioandMcMasterUniversityOsteoarthritisvisualanaloguescore(WOMAC)andinphysicalfunctionimpairment(p <0.05)comparedwithplacebo,butnonotablechangesinWOMACstiffnessandaggregatedtotalsymptomscores64.

In this study,use ofMSMwas also reported toimprovetheperformanceofactivitiesofdailylivingwhencomparedwithplacebo(p <0.05).Theinvest-igators concluded that MSM (3g BID) improvedsymptomsofpainandphysicalfunctionduringtheshortinterventionwithoutmajoradverseevents,butthatthebenefitsandsafetyofMSMinmanagingOA,andfromlong-termuse,couldnotbeconfirmedfromthispilotstudy.FurtherinvestigationofMSMwillbeneededtodeterminetheseissues64.

S-adenosyl-L-methionine (SAMe)

Athirddietarysupplement,SAMe,hasbeeninvest-igatedforthemanagementofpaininOA.IthasbeensuggestedthatSAMemayreducepaininOAbyreduc-inginflammation,increasingproteoglycansynthesis65,and/orprovidingananalgesiceffect64.Adouble-blindcross-over study comparedSAMe (1200mg)withcelecoxib(200mg)for16weekstoreducepainassoci-atedwithOAoftheknee.Sixty-oneadultsdiagnosedwiththisconditionwereenrolledand56completedthestudy.TheinvestigatorsreportedthatSAMehadasloweronsetofactionbutwasaseffectiveascelecoxibinthemanagementofsymptomsofkneeOA64.Theyconcludedthatlongerstudiesareneededtodeterminethelong-termefficacyandoptimaldoseofSAMeforpatientswithOA64.

Collagen hydrolysate

Thisnutritional supplementhasbeen investigatedforthemanagementofpatientswithOAandothertypesofjointpain.Ithasbeenshowntosignificantly(p <0.01)increasethebiosynthesisoftypeIIcollageninchondrocytesinexperimentswithbovinecartilagecellcultures66.CollagenproductsarerecognizedassafecomponentsofpharmaceuticalsandfoodsbytheUSFoodandDrugAdministration(FDA)CenterforFoodSafetyandNutrition67.

Researchershaveinvestigatedthepotentialclinicalbenefitsofcollagenhydrolysateinfouropenlabeland

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threedouble-blindstudiesinvariouspatientpopula-tions, includingpatientswithOA3,68–73.Thissectionreviewsthepreclinicalandclinicalfindingsfromthesestudies.

preclinicalstudies

Inexperimental investigations, ithasbeendemon-stratedthatorallyadministeredcollagenhydrolysateisthoroughlyabsorbedbytheintestinesandcirculatedin the blood stream, reaching a maximal plasmaconcentrationin6h,atwhichpoint<10%ofcollagenhydrolysate remains in the gastrointestinal tract74.Thesestudiesalsorevealedthatcollagenhydrolysateisnotcompletelybrokendownbythedigestivesystem,butthatavarietyofcollagenfragments,includingupto10%highmolecularformcollagenfragmentsthatrangefrom1to≈10kD,areabsorbedfollowingoraladministrationof collagenhydrolysate,with someindividualvariability74. Inexperimentswith radio-labeledcollagenhydrolysate,ithasbeenshownthatasignificantamountofcollagenhydrolysate-derivedpeptidesreachcartilagetissuewithin12hafteradmin-istration(p <0.05comparedwithcontrolanimals)74.

Incellcultureexperimentsinvestigatingtheefficacyofcollagenhydrolysateonthebiosynthesisofarticularchondrocytes,itwasshownthattreatmentofculturedchondrocyteswith0.5mg/mLcollagenhydrolysateoveracultureperiodof11daysinducedastatisticallysignificant,dose-dependentincreaseintypeIIcollagensynthesisofthechondrocytes(p <0.01comparedwithuntreatedcontrolcells)(Figure1)66.Incontrast,nativecollagensandthecollagen-freehydrolysateofproteinsdidnotstimulatethesynthesisoftypeIIcollagenbychondrocytes66.Thesefindingsindicateastimulatoryeffect of collagen hydrolysate on type II collagensynthesisbychondrocytes.Inaddition,theamountofproteoglycanshasbeenshowntosignificantlyincreaseaftercollagenhydrolysateadministration(p <0.05)75.Moreover,experimentsindicatethatsupplementationofcollagenhydrolysatehadnosignificanteffectontheexpressionofproteasesinchondrocytes75.Basedonthefindingsthatcollagenhydrolysateisabsorbedfromtheintestineinitshighmolecularform,preferentiallyaccumulates incartilage74, and is able to stimulatechondrocytemetabolism, itmightbereasonabletousecollagenhydrolysateasanutritionalsupplementtoactivatecollagenbiosynthesis inchondrocytesinhumans,especiallyunderconditionswherecartilageisunderconsiderablestress66.

Clinicalstudies

Theclinicalbenefitsofcollagenhydrolysatehavebeeninvestigatedinfouropen-labelandthreedouble-blind

studies(Table2)3,68–73.In1979,resultswerepublisheddemonstratingtheclinicaleffectofcollagenhydrolysateondegenerativejointdiseaseinpatientswithkneeOAwithtibial,femoral,orretropatellarinvolvement,orwithdegenerativediskdiseaseofspecificpartsofthespine.Patientsreceived5–7gofcollagenhydrolysatebymouthfor1–6months.Theauthorreportedresultson56patients:10(24%)reported‘verygoodsuccess’(fivepatientsindicatedcompletefreedomfrompainandfiveindicatedimprovementintheirgeneralcondition);18 (44%) reported ‘noticeable improvement’ (12patients reported the general situation improvedconsiderablyandsixpatientsreportedthepainhadreceded substantially), and13 (32%) reported ‘noimprovement’.Statisticalanalyseswerenotreportedbytheinvestigators68.

Similarfindingswerereportedina1982studyinwhich60juvenilepatientsdiagnosedwithretropatellarOAreceivedcollagenhydrolysatetreatment(one7gsachetperdaybymouth)for3months69.Thesachetalsoincluded24000unitsofvitaminAand120mgofthesulfur-containingaminoacidL-cysteine.Anumberofparametersweremeasured,includingtheabilitytoclimbstairs,softtissueswelling,retropatellarcrepitus,andkneeeffusion.Atbaseline,58patientspresentedwithretropatellarcrepitus,whichistypicalofpatellarchondropathy.Theinvestigatorsreportedthataftertreatment,75%ofpatientsdemonstrated improve-ment:45%ofpatientsweresymptomfreeand30%hadclearlyimprovedsymptomsaftertakingthesachetfor3months69.Theremainderofthepatientscontinuedtohavepainatrest.Statisticalanalyseswerenotprovidedinthisreport69.

Culture time (days)

4 0 2 6 8 10 120

1

2

BM

CH

*

*

*

Typ

e II

colla

gen

(µg/

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 < 0.01

compared with untreated controls

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Anopen-labelstudyof154patientswithOAprovidedadditionalevidenceoftheclinicaleffectofcollagenhydrolysate70.PatientswithdiagnosedOAoftheknee,hip, or lower spinewere randomized among threetreatmentgroups:therapeuticexercises,therapeuticexercisespluscollagenhydrolysatewithvitaminAandL-cysteine,orcollagenhydrolysate,vitaminA,andL-cysteinewithouttherapeuticexercise.Thecollagenhydrolysate,vitaminA,andL-cysteineweregivenasonesachetperdaybymouth.Forallthreegroups,thedurationoftreatmentwas3months.Atbaselineandafter3monthsoftreatment,painintensitywasmeasuredusingapainassessmentscale.Inthephysicaltherapyonlygroup,20%hada‘verygood’or‘good’response,while56%of the collagenhydrolysate, vitaminA,L-cysteine,andphysicaltherapygrouphada‘verygood’or‘good’response,and69%ofthecollagenhydrolysate,vitaminA,andL-cysteine(nophysicaltherapy)grouphada‘verygood’or‘good’response.Theresultsshowed

that43%ofthephysicaltherapyonlypatientswere‘unchanged’,whileonly14%ofthesupplementplusphysicaltherapygroup,and6%ofthesupplementalonegroup,hadthisresult.ThecompleteresultsareshowninTable3.Thestatisticalsignificanceofthedifferencesbetweentreatmentgroupswasnotreported70.

useinotherpopulations

The reviewof themedical literature showed thatcollagenhydrolysatehasbeenstudiedinpopulationsbesidesthosediagnosedwithOA.Arecentobserva-tional study investigated the effects of collagenhydrolysateinathleteswhosufferedfromjointpainbutwhowerenotdiagnosedwithOA.Inthisstudy,100participantssufferingfromhip,knee,orshoulderpain resulting from intensephysical activityweretreatedwithorallyadministeredcollagenhydrolysate(10g/day)for12weeks72.

Table 2. Collagen hydrolysate studies

Author Subjects,n OAlocation Trialdesign Outcomesstudied

Results

Krug68 56 Tibia,femur,knee,orspine*

Openlabel Pain,generalcondition

10(24%)reported‘verygoodsuccess;18(44%)reported‘notice-ableimprovement’;13(32%)reported‘noimprovement’†

Götz69 60 Knee Openlabel Patientreportedpain

45%painfree;30%improvedsymptoms;25%noimprovement†

Oberschelp70 154 Knee,hip,orlowerspine

Comparative Painintensity SeeTable3†

Flechsenhar72 100 NotdiagnosedwithOA;paininhip,kneeorshoulderfromsports

Open Painonmovement

Painreduction:68subjectsimproved,19wereunchanged,onenotdocumented†

Adam71 81 Kneeorhip Double-blind,crossover

Pain,consumptionofanalgesics

Reductioninpainreported:81%ofthosetakingcollagenhydrolysate,23%ofthosetakingeggalbumin;A 50%decreaseinanalgesics:69%ofthosetakingcollagenhydrolysate,35%ofthosetakingeggalbumin†

Zuckley76 250 Knee(mild)‡ Randomized,double-blind,placebo-controlled

Isokineticandisometriclegstrength;pain,stiffness,mobilityandflexibility

Nostatisticallysignificantdiffer-encesbetweengroupsformeasuresofpain,stiffness,mobility,orflexibility;statisticallysignificant(p <0.05)improvementsin3/6isokineticlegstrengthmeasures

Moskowitz3 389 Knee Prospective,randomized,double-blind,placebo-controlled

WOMACpainscore,functionscore,andpatientglobalassessment

Nostatisticallysignificantdiffer-encesforthetotalstudygroup;Germanpatientshadastatisticallysignificantbenefitfromcollagenhydrolysateforpainreduction(p =0.016)andfunctionalimprovement(p =0.007)butnotpatientglobalevaluation(p =0.074)

*Degenerativediskdisease†Statisticalanalyseswerenotreported‡AmericanCollegeofRheumatologycriteria

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Athleteswhowereintheacutephaseofajointinjuryorinflammatory(joint)conditionwereexcluded,alongwiththosetakinganyOAmedicationsthatarenotclassifiedaseithercorticosteroids,NSAIDs,orCOX-2inhibitors,includingglucosamineorchondroitin;thosewhoexpectedtoneedachangeinexistinganalgesicoranti-inflammatorymedicationsduringthestudy;orthosewhohadinterferingconcomitantdiseases.

During physical examinations, clinical statusmeasures, as assessed by the treating physician,includedpainatrest,painonmovement,functionallimitations,andinflammatoryactivity.Theintensityoftheseparameterswasratedonascaleof1(nopain,limitationofactivity)to10(severepain,limitationofactivity).Patientswithhiporkneeproblemsassessedtheirpainintensitywhilewalking,whenclimbingstairs,whilestanding,andatnight.Patientswithshoulderarthralgiaassessedpainwhenliftingorcarryingobjectsandpainduringoverheadactivities72.Thesesurveys–completedatbaseline,duringtreatment(4–6weeks)andat12weeks–providedthebasisforcomparison.

Of the 88 patients who could be evaluatedthroughoutthestudy,51presentedwithkneearthralgia(58.0%),20withhiparthralgia(22.7%),and17with

shoulderarthralgia(19.3%).Figure2,whichdepictsthechangeinpainonmovement,revealsthat78%ofpatientsachievedpainreductionaftertakingcollagenhydrolysatefor12weeks(68subjectsimproved,19wereunchangedorworsened,andonepatientwasincompletelydocumentedforpainonmovement)72.

The relative roleplayedbyanalgesics andothermedications in the results is not known, althoughthenumberofsubjects takinganalgesicsandothermedicationsdecreasedbytheendofthestudy.Atthestartofthestudy,27subjectsweretakinganalgesics,47weretakingNSAIDsorCOX-2inhibitors,andonepatientwastakingcorticosteroids.Attheendofthestudy,12subjectsweretakinganalgesics,13patientsweretakingNSAIDsorCOX-2inhibitors,andonepatientwastakingcorticosteroids72.

CollagenhydrolysateforOApain

TheeffectofcollagenhydrolysateonpainfromOAwas studied inaprospective, randomized,double-blind,placebo-controlledclinicaltrialconductedbyAdam71.Theresearchersrecruited81patientswithOAof thekneeorhipanduseda complexcross-

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

Response*Intervention

Verygood,n(%)

Good,n(%)

Noticeable,n(%)

Unchanged,n(%)

Physicaltherapy 3(6) 7(14) 18(37) 21(43)Collagenhydrolysate,vitaminA,L-cysteine,andphysicaltherapy 9(20) 16(36) 13(30) 6(14)Collagenhydrolysate,vitaminA,L-cysteine,nophysicaltherapy 16(26) 26(43) 15(25) 4(6)

*Note:Thestatisticalsignificanceofthedifferencesbetweentreatmentgroupswasnotreported

Knee Hip Shoulder

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Worsened (–)by score points

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

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over design to compare four different nutritionalsupplements,includingcollagenhydrolysate(10gintheformof20capsules,each500mg,bymouth).Theyfoundthat81%ofpatientstakingcollagenhydrolysateachievedmeaningfulpainreduction,comparedwith23%ofpatientstakingeggalbumin.Inaddition,69%ofpatientstakingcollagenhydrolysatehada≥50%decreaseintheconsumptionofanalgesics,comparedwith35%ofpatientstakingeggalbumin71.

Inhis reporton this study,Adamnotedthat thedifferenttreatmentgroupswerestatisticallycomparedusingtheLechmachertestandthattheadministrationofeggalbuminhadan‘insignificant’influenceonpatientswhilethecollagenhydrolysatetreatmentresultedina‘substantial’reductionofsymptoms71.Whiletheauthornotedthattheresultsfromtreatmentwithallnutritionalsupplements, including collagen hydrolysate, were‘significantlydifferent’fromeggalbumin,thereportdoesnotdefinestatisticalsignificance71.

ThebenefitsofcollagenhydrolysateforpatientswithmildsymptomsofOAwereexploredinarandomized,placebo-controlled,double-blindstudythatrecruited250adultsdiagnosedwithmildsymptomsofOAoftheknee(baseduponAmericanCollegeofRheumatologycriteria).Atotalof190patientscompletedthestudy(88treatmentand102placebopatients).Treatmentconsistedoforaladministrationofcollagenhydrolysate(10g/day)orplacebo for14weeks. Isokinetic andisometriclegstrengthwasassessedinsubjectsusingaBiodexMulti-JointSystemB2000equippedwiththeBiodexAdvantageSoftwareprogram(Biodex,NY)76.A6-MinuteWalkTestanda50-FootWalkTestwereused to assess functionalmobility, and jointpain,stiffness,andperceivedfunctionalmobilitywasassessed

usingtheWesternOntarioandMcMasterUniversitiesOsteoarthritisIndex(WOMAC)Index,theLequesneIndex,andtheKneePainScale.

After 14weeks of treatment, there were nostatisticallysignificantdifferencesbetweenthetreat-mentgroupsformeasuresofpain,stiffness,mobility,andflexibilitymeasurements.However,thecollagenhydrolysate-treatedgroupshowedstatisticallysignif-icantimprovementinthreeoutofsixisokineticlegstrengthmeasures(peaktorque/BWforextensionat60º/sec-1,peaktorque/BWforflexionat60º/sec-1,andtotalwork/BWforextensionat60º/sec-1)(p <0.05compared with placebo for all three tests) (seeFigure3),especiallyteststhatpresentedthegreatestchallengesofstresstothejointstructure)73.Theotherthreemeasurementsapproachedstatisticalsignificance:totalwork/BWforextensionat60º/sec-1(p =0.054),averagepowerforextensionat60º/sec-1(p =0.051),andaveragepowerforflexionat180º/sec-1(p =0.067).The investigators stated that the findings suggestthat collagen hydrolysate may contribute to earlychangesinkneecartilage(M.Carpenter,MS;personalcommunications, 2006), which is consistent withanimaldata74.Thefindingsalsosuggestthatobjectiveisokineticandisometrictestsmaybemoresensitivefordetectingearlyimprovementsinjointfunctionthanpainandmobilityquestionnaires(M.Carpenter,MS;personal communications,2006).Theynoted thatfurtherstudiesareneededtoevaluatethelong-termbenefitsoftherapywithcollagenhydrolysate73.

Moskowitzandcolleaguesconductedaprospective,randomized,double-blind,placebo-controlledclinicaltrial of collagen hydrolysate between 1996 and19983.Thestudyincluded20sitesinthreecountries

p = 0.067

p = 0.051

p = 0.054p = 0.022

p = 0.031

p = 0.015

Peak torque/BW-extension

Peak torque/BW-flexion

Total work/BW-extension

Total work/BW-flexion

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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

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(Germany,UnitedKingdom,andtheUnitedStates)thatrecruited389patientswithkneeOA.Patientswererandomizedtoreceiveeither10gofcollagenhydrolysateperdayorplacebo,bothbymouth,for24weeks.TheprimaryoutcomemeasuresweretheWOMACpainscore,functionscore,andpatientglobalassessment.

After 24weeks of treatment, there were nostatisticallysignificantdifferencesforthetotalstudygroup(allsites)fordifferencesofmeanscoreforpain.However,theinvestigatorreportedthattheGermanpatients(n=112)experiencedastatisticallysignificantbenefit fromcollagenhydrolysate in termsofpainreduction(p =0.016)andfunctional improvement(p =0.007)butnotpatientglobalevaluation(p =0.074)(Figure4)3.Thereasons for thedifferencesobservedintheefficacyofcollagenhydrolysateintheUnitedStatesandtheUnitedKingdomversusthoseinGermanyarenotknown.OneexplanationmaybethatthedropoutratesintheUKandUS(37%and42%,respectively)weremuchhigherthaninGermany(6%).Otherfactorsthatmightexplainthedifferencesbetweenthethreecountriesweredifferencesinbase-line,acetaminophenintake,studyconditions,placeboeffect,andspecialisttrainingwerenotaccountedforintheoverallanalysis77.

Conclusions

Thisarticleprovidedabasicdescriptionofthemech-anismsofarticularcartilagestructureanddegradationassociated with OA, and described the effects ofcollagenhydrolysateinpatientsdiagnosedwithOAbasedonareviewoftheliterature.

The deterioration and eventual loss of articularcartilage inpatientswithOAiscausedbythedis-ruptionofitsstructuralintegrityassociatedwithan

imbalance inanabolicandcatabolicactivity in thecartilagetissue.Thisresultsinamarkeddecreaseinextracellularmatrixandeventualcartilagedamageviachangesinthestructureofarticularcartilage.

It was previously thought that once damaged,cartilage couldnot be restored.Treatmentswere,therefore,targetedtowardsymptomaticreliefwithanalgesicsandanti-inflammatoryagents,andlubricat-ing and cushioning agents.However, researchhasprovidedevidencethatsuggestssomeformsofinter-ventionmaybeabletohelpsupportthebody’sabilitytorepairdamagedcartilage.

Experimentalstudieswithcollagenhydrolysatehaveindicatedthatitaccumulatesinjointcartilage,whereitstimulatesregenerationoftypeIIcollagen,themajortypeofcollagen incartilageand increases thebio-synthesisofproteoglycans.Thesefindingshaveinspiredinvestigatorstoexploretheuseofcollagenhydrolysateasanagentforstimulatingtheseregenerativeeffectsinthecartilageofpatientswithdisordersassociatedwithdamagedcartilage,suchasOA.

Thisreviewidentifiedsevenstudiesontheuseofcollagenhydrolysateinvariouspatientpopulations.Although this review included several studies thatdidnotprovidekey information,suchasstatisticalanalyses,thataregenerallyacceptedasstandardsfortheevaluationofscientificdata,itdoesprovideresultswhichsuggestthatcollagenhydrolysatemayprovidesymptomaticrelieftosomepatientswithOA.It isnotknowniftheeffectsseeninthein vitrostudiesareresponsibleforthesefindingsorwhetherothereffectsareinvolved.Thisquestionwillneedtobeaddressedinfutureresearch.

Giventhepotentialformodifyingcartilagesuggestedbyanimalresearch,andclinicalstudieswhichreportthatcollagenhydrolysatereducespainanddisabilitymorethanplaceboinsomepatients,itseemsreasonableforphysicianstoconsidertryingcollagenhydrolysate

Figure 4. Effects on WOMAC Pain Score, WOMAC Physical Function Score, and Patient’s Global Evaluation following treatment with collagen hydrolysate or placebo77

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forthetreatmentofjointpainanddisability,especiallyforthoseindividualswhoare50yearsofageorolderandactive,vigorouslyactiveathletes(regardlessofage),individualsengaginginrepetitivemotions,andthosewhoareoverweight,sedentary,orwithafamilialhistoryofjointdisease.

Acknowledgments

Declaration of interest:ThisreviewwasfundedbyGELITA Health Products, Vernon Hills, Illinois.EditorialsupportforthismanuscriptwasprovidedbyACCESSMedicalGroup,Chicago,Illinois.

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CrossReflinksareavailableintheonlinepublishedversionofthispaper:http://www.cmrojournal.com

PaperCMRO-3580_4,Accepted for publication:12September2006Published Online:10October2006doi:10.1185/030079906X148373

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