Equine Surgery || Osteochondrosis

CHAPTER88 OsteOchOndrOsis 1239

thetermosteochondritis dissecanswascoinedbyKönigin1887and used to describe loose or semiloose bodies in joints ofyoungpersonsthatcouldhavethreecauses:veryseveretrauma,lesser trauma and necrosis, or minimal trauma acting on anunderlyinglesion.1Althoughthenameandconcepthaveledto

substantialconfusionfromtheonset,thiscategorizationisstillvalidtoday.2

Osteochondrosis (Oc) is the last of König’s categoriesdescribed in the equine veterinary literature, and it is themostdifficulttounderstand.Ocrepresentsadisturbanceofthe

CHAPTER

88 Osteochondrosis

P. René van Weeren

1240 SECTIONXII MUscULOsKeLetALsYsteM

process of endochondral ossification without a clearly under-stoodetiology.thisdisturbancecaneventuallyleadtothefor-mationofsemilooseorevencompletelyloosefragmentswithinajoint.

THEPROCESSOFENDOCHONDRALOSSIFICATIONinallmammals,theprimordialskeletonislaiddownfirstasacartilaginous structure that, during the entire period of earlydevelopmentoftheanimal,iscoupledinaprocessofsimulta-neousgrowthandtransformationintobone.itisimportanttonotethatunlikematurearticularcartilage,thesefetalcartilagi-nousstructuresarewellvascularizedbyvesselsrunningthroughcartilagecanals.Ossificationoftheprimarycentersofossifica-tioninthediaphysesofthelongbonesstartsearlyinfetallife,andatthetimeofbirth,allthediaphysesarebonystructures.thisdoesnotoccur inmanysecondarycentersofossificationlocated in the epiphyses of the long bones and in other sitessuchasapophysesandcuboidalbonesincomplexjoints,whichremainpartlycartilaginousatthetimeofbirth.

Afterbirth,longitudinalgrowthoflongbonesresultsfromthegrowth plates or physes where, from a germinal layer of cells(restingcells),chondrocytesproliferateandlaydownascaffoldof extracellular matrix. these cells initially hypertrophy andlaterundergoapoptosis.thescaffoldisusedfortheappositionofprimarybonebyosteoblastsoriginatingfromthemetaphysis(Figure88-1).thisprimaryspongiosathenundergoescontinu-ousremodelingundertheinfluenceofbiomechanicalloadingaccordingtoWolff’slawduringtheentiregrowthperiodofthefoal.thisremodelingcontinuesintheadultwhenbiomechani-calloadingchanges,forinstance,whentheskeletonisexposedtoathleticchallenges.3theentireprocessofcartilageremodel-ing,followedbycalcificationofcartilage,depositionofprimary

bone,andsuccessiveremodelingintobonytrabeculae,isknownasendochondral ossification.4

the increase indiameterof the longboneduringgrowth istheproductof adifferent,but simultaneous and coordinatedprocess,whichisbyappositionalgrowthfromtheperiosteum.thisprocessresultsintheformationofcompactcorticalbone,characterizedbythehaversiancanals.

intheepiphysesofthelongbonesagrowthprocesssimilarto that of the physis takes place, but it is not as completelydevelopedas inthediaphysesatbirth.this leadstolargedif-ferencesbetween joints in the timeswhenossificationoccurs.in some joints at birth, there is a complete ring of cartilagearound the ossification center, connecting articular cartilagewith the growth plate. Ossification of this cartilage ring takesplacefirstattheborderofthephysisandattheperimeteroftheepiphysis. the thick cartilagemass at the articular sideof theepiphysisfunctionsasatypeofgrowthplatewherethesimul-taneousprocessesofgrowth,remodeling,andossificationtakeplacethatfinallyresultinaconsiderablythinnerlayerofarticu-lar cartilage in the mature animal. it is at this level that thecharacteristiclesionsofequineOcdevelop.

PATHOPHYSIOLOGYthereislittlecontroversyaboutthegrosspathogeneticmecha-nismofOc.disturbancesoftheprocessofendochondralossi-fication result in irregularities in thickness of the epiphysealcartilage.thesecreateareasoffocalweakness,whichareexac-erbatedbecausethecartilagecanalsregresswithincreasingageandhavedisappearedinthehorsebytheageof7months.5thisaffectsthenutritionofthedeeperlayersoftheretainedcartilageplugs that cannotbe sufficientlynourishedbydiffusion fromthearticularsurface,possiblyleadingtonecrosis.Biomechani-calinfluences,mainlyshearingforces,thenleadtotheforma-tion of fissures and produce cartilage flaps, or detachment ofcartilage or fragments of cartilage and subchondral bone. insome locations where biomechanical forces are mainly com-pressive,infoldingofcartilageintheseweakenedareascanleadto the formationof subchondralbonecystsasanothermani-festationofOc.6

Many caveats concerning this seemingly straightforwardmechanismhavebeenmade.inanextensivereviewofpatho-genesisandpossibleetiologicfactorsofOc,theviewthatdefec-tiveossificationliesatthebaseofalllesionscommonlyqualifiedasOcinthehorsehasbeenquestionedbasedonclinicalandpathologicobservations.4Oneofthemajorargumentswastheobservation that after injury, bone and cartilage can manifestonly a very limited reparative response. this makes it verydifficult, if not impossible, to judge the stage of the process(recently originated or already in some phase of repair) andmoresotheoriginofthelesion(delayedossificationortrauma,forexample).7thingsbecomeevenmoredifficultifonerealizesthatOcisgenerallyassumedtobeamultifactorialdiseaseinwhichtheproblemisnottosingleoutaspecificcausativefactorbuttodeterminetowhatextent,andinwhichorder,avarietyoffactorsplayarole.theseconsiderationsarediscussedinmoredetaillater,under“etiologicFactors.”

Alongsimilarlines,comparisonsbetweenspeciesshouldbedealtwithcautiously.inthelate1970s,in-depthstudiesonthephenomenonofOcinamultitudeofspecies(includinghorses,poultry,dogs,andcattle,butwiththeemphasisonswine)con-cludedthatbecauseofthestrikingsimilaritiesinmanifestation

Figure 88-1. The relationship of the cartilage zones of the growth cartilage of a physis. (Redrawn from Watkins JW, Auer JA: Learning Systems 6:S227, 1984.)

Metaphysis

Primaryspongiosa

Calcifyingcartilage bone

Growtharea

Hypertrophiccartilage bone

Proliferativecartilage bone

Restingcartilage bone

Epiphysis


Figure 88-2. Radiograph showing a typical osteochondritic lesion of the dorsal aspect of the distal intermediate ridge of the tibia (arrow). (Courtesy Dr. AJM van den Belt, University of Utrecht, Netherlands.)

across the species, including humans, Oc should have acommonpathogenesisandetiology,thelatterbeingprincipallygrowthratethatitselfwasdeterminedbynutritionandheredi-taryfactors.8eversince,thisparadigmofa“seeminglyunifiedhypothesis”4hashoveredoverOcresearch,andtheeasewithwhich conclusions for the horse have been drawn based onresearch in entirely different species has been remarkable insomeinstances.itisquestionableifthissimpleexplanationofthepathophysiologyofOc is justifiable,givenmanyfindingsfrommorerecentresearchthatarediscussedlater.

DIAGNOSIS:CLINICALANDRADIOGRAPHICSIGNSthetypicalOcpatientisayearlingthatispresentedwitheffu-sion of the tarsocrural or femoropatellar joint that has beennotedrecentlybytheowner.thehorseusuallyisnotlame,andradiographicexaminationshowsafragmentatthecranialendof the distal intermediate ridge of the tibia (Figure 88-2) orirregularities at the lateral trochlear ridge of the distal femur(Figure 88-3). however, as with any typical presentation of adisease,manyvariationsonthisthemearepossible.Ocincervi-calfacetjointshasbeenrelatedtocervicalstenoticmyelopathy,beingacauseofwobblersyndromeinyounghorses.however,therelationshipdoesnotseemtobestraightforward,althoughcommonpathogeneticpathwaysmayexist.9

the age at which Oc becomes clinically manifest varies,althoughinthegreatmajorityofcases,Ocpatientsarejuvenileanimals.inseverecasesofOc,whicharemorecommoninthefemoropatellar(FP)jointthaninthetarsus,signscanbeseenin foalsasyoungas6months.Occanalsomanifest itselfat

Figure88-3. A, Radiographic view showing osteochondritic lesions on the lateral trochlear ridge of the distal femur (arrows). B, Postmortem view of an osteochondritic lesion of the lateral trochlear ridge of the distal femur (arrows).

A B


Figure88-4. Typical osteochondrotic lesion of the distal intermediate ridge of the tibia in a cadaveric specimen (arrow). a, Synovial groove.

a

shownthatPOFhadasignificantlinearrelationshipwithgradesofwearlines,cartilageulceration,anddorsalimpactinjuriesinacohortofthoroughbredracehorses,andhencecouldbeclassi-fiedasamanifestationoftraumaticoverloadarthrosis.24intheshoulderjoint,Ociscommonlylocatedontheglenoidandthehumeralhead.25

Lesionsareoftenencounteredbilaterally in thetcandFPjoints and quadrilaterally in the McP/MtP joints.26 Bilateralpresence,oftenwithunilateralclinicalmanifestationonly,canoccur in the tc and FP joints in more than 50% of clinicalcases.6 therefore, in horses with unilateral clinical signs it isadvisabletoradiographthecontralateraljoint.incontrast,con-comitantoccurrenceinotherjointsorjointpairsismuchlesscommon. ina studyof225horseswithtcOc, lesionswerefound in other joints in only eight cases.26 therefore, jointsotherthanthecontralateralonedonotneedtoberadiographed,exceptwhenclinicalsignsexist.

Jointeffusionisbyfar themostcommonclinicalsign,butlamenesscanoccur,especiallywhenlargeradiographiclesionsexist.LamenessisseenmoreinFPOcthanintcOcandmostlikely when a loose or semiloose fragment is observed radio-graphically, thus when the osteochondritis dissecans (Ocd)form is present. Other, less severe radiographic signs includeirregularitiesinthearticularcontourofthesubchondralboneandsometimesonlyaflatteningofthiscontour.

MinorradiographicaberrationscanbereliablyclassifiedasOc by an experienced radiologist. in one study, there was acorrelationof0.87(P<0.001)betweenradiographicclassifica-tionofOcofthedistalintermediateridgeofthetibiaona0to4scale27andhistology.12

nevertheless,thelesion’sseverityasdeterminedradiographi-callydoesnotalwayscorrespondwitharthroscopicornecropsyfindings.inmanycases,cartilagelesionsaremoreseverethanradiographic appearance suggests, or cartilaginous lesions arepresentwithoutchangesinthesubchondralboneandhencedonotshowuponradiographs(Figures88-4and88-5).severityoflesionscanbeassessedmoreaccuratelywithmoresophisti-catedimagingmodalitiessuchasmagneticresonanceimaging(Mri). however, economic and physical constraints severelylimitthewideclinicaluseofthiskindofequipment,especiallyintheFPjoint.

theagetheanimalsareputintotrainingandthejointsbecomechallenged by athletic activity. the age at which this occursvaries with the branch of equestrian industry. For example,Warmbloodhorsescommonlyarepresentedatabout3yearsofageorolder,whereasracingthoroughbredsandstandardbredsmanifestsignsmuchearlierwhentheyentertraining.

radiography is thegoldstandard fordiagnosingOcbut isnot capable of detecting very subtle lesions. For this reason,other approaches using a variety of markers (see later) havebeen tried with varying success. An interesting developmentis the use of infrared absorption spectral characterization ofsynovialfluidusingFouriertransforminfrared(Ftir)spectros-copy that was able to discriminate between samples fromOc-affectedandnormalanimalswith50%specificityand73%sensitivity.10

DistributionofLesionsOc is most commonly diagnosed in tarsal, FP, andmetacarpophalangeal/metatarsophalangeal(McP/MtP)joints,butithasbeendescribedinalmosteverydiarthrodialjoint.inanexperimentalstudy,43WarmbloodfoalswereselectedoutofpairingOc-positivesiresandpartiallyOc-positivemarestoproduceoffspringwithahighprevalenceofOc.twenty-fourfoals were sacrificed at 5 months, all joints were inspected atnecropsy,andmacroscopic lesionswereconfirmedbymicros-copy.11 Lesions were most numerous in the tarsocrural (tc)joint (averageof two lesionsper animal), followedby theFPand the cervical intervertebral (facet) joints (one lesion peranimal),theMtPjoint(0.6),theMcPandcarpaljoints(0.4),humeroradialjoint(0.2),andscapulohumeraljoint(0.04).12

AlthoughtheprevalenceofOcinthisstudywasartificiallyhigh,therelativedistributionisinagreementwithclinicalexpe-rience in theWarmblood.Breeddifferencesoccur toacertainextent with regard to lesion distribution and relative clinicalimportance.OcintheFPjointiscommonintheracingthor-oughbred,13butinWarmbloodsandstandardbreds,tcOcisseenmoreoften.14-18

AhallmarkofOcisthatlesionsalmostalwaysoccuratcertainpredilectionsiteswithinajoint.inthetcjoint,themostcommonsiteisthecranialendofthedistalintermediateridgeofthetibia(seeFigure88-2),followedbythedistalendofthelateraltroch-leaofthetalusandthemedialmalleolusofthetibia.19intheFPjoint,themostcommonpredilectionsiteisthelateraltrochlearridgeofthefemur.Lesscommonsitesarethemedialtrochlearridgeofthefemur,thetrochleargroove,andthedistalendofthepatella.6 subchondral cysts that occur in the medial femoralcondyleareamanifestationofOcaswellandarediscussedinchapter89.thepredilectionsiteintheMcP/MtPjointsisthedorsalendofthesagittalridgeofthemetacarpusandmetatarsus.notallosteochondralfragmentsareosteochondroticinorigin.Opinions on the nature of the fragments seen at the dorsalmarginoftheproximalphalanxdiffer,andthepalmarorplantarosteochondralfragments(POFs)thatwereoriginallyreportedasbeingpartoftheOccomplex20arenowconsideredtraumaticinorigin.21,22 inahistological studyonosteochondral fragmentsthatwereharvestedfrommature(averageage6years)horsesitwasshownthateveninlong-presentintra-articularfragments,histologymaygiveanindicationabouttheoriginaletiologywithmoreindicationsofosteoarthritis(higherMankinscore)infrag-mentsthatwerenotofosteochondroticnature.23recently,itwas


Overall, ithasbeenestimated that innorthwesterneuropealone, 20,000 to 25,000 foals are born annually that willdevelop some degree of Oc.11 Oc lesions are only rarelyencounteredinponies.37Further,inasurveyof80feralhorses,extremely low incidencesof2.5%were found in thetc jointand0%intheFPjoint.38BecauseOcisarelativelynewdisease(seenextsection),theseobservationsstronglyimplicatebreed-ingpoliciesandpossiblymanagementaspectsaskeyfactorsinthisdisease.

Ocisadebilitatingdiseaseonlyinexceptionalcases,wherelesionsaresoextensivethatnorepairispossible.nevertheless,theailmenthasastrongimpactontheeconomicsoftheequineindustry,andtoacertainextentonanimalwelfare,becausetensof thousands of animals are operated upon each year. Apartfromthedirecteconomic loss, there isanevenlarger indirectcost of the disease, because many studbooks do not approvehorseswith(majororminor,dependingonstudbookpolicy)evidenceofOc.ithasbeenestimatedthat thestrictbreedingpolicy the royal dutch Warmblood studbook (KWPn) hasadheredtountil recentlyprecluded30%ofallpotentialmalebreeding stock from participating in the selection proceduresforbecominganapprovedsire.Apartfromdirectfinanciallossfor the breeders, this also eliminates a large part of the genepool.A last,butnot insignificant, economic impactofOc isthelossinvalueofanimalsshowingradiographicevidenceofOc,regardlessoftheirathleticcapacities.

EVOLVINGCONCEPTSthe first description of what is retrospectively judged to havebeenOcappearedin1947whenfragmentsintheFPjointsofArdenner horses were noted.39 Although in the followingdecades some reports described intra-articular fragments thatmighthavebeenosteochondrotic,40therealhistoryofOcdoesnotstartbeforetheclassicpublicationbyBirkelandandhaak-enstadin1968.41theseauthorsdescribedaseriesofsevencasesofOcofthedistalridgeofthetibia,buttheydidnotusethetermosteochondrosis.intheearly1970sgraduallymorepublica-tions appeared,42,43 and in the mid-1970s a comprehensivestudyonOcinamultitudeofspecieswaspublished.8,44-47

Ocwasoriginallyseenasalargelystaticcondition,butthisconceptgraduallychangedafterareportappearedonchangesintheradiographicappearanceofFPOcafterrepeatedexami-nations.48 Other researchers recognized, after sequentiallyradiographinganumberoffoals,thatOclesionsofthedistalfemurcouldprogressuntiltheageof9months.49inthesameyear,anothergrouppublishedastudyinwhichtheyfollowedacohortof77horsesradiographicallyandfoundthatnomajornewOclesionswereidentifiedafter8monthsofageinthetcjoint.interestingly,theauthorsnotedaregressionofanumberofminorlesionsbeforetheageof8months,whichhadbeendetectedbetweenages1and3months.16

AgroupofresearchersradiographedthetcandFPjointsof43foalsonamonthlybasisfromtheageof1monthuntilage5months andof19of themuntil age11months. the studyshowed thatnotonlyminor lesionsbutalso radiographicallyvisiblelargerfragmentsceasedtoexist.theagesatwhichlesionsoriginated and the ages at which they became undetectablevariedforeachjoint.inthetcjoint,lesionsatthedistalinter-mediateridgeofthetibiaandatthedistalaspectofthelateraltrochlear ridgeof the talus thatwereseenwithin thefirst few

BreedPredilectionOciscommoninmanybreedsofhorses.inswedishstandard-breds,an incidenceof10.5%was found in the tarsal joints,17whichwascomparabletothe12%foundbyotherauthors15butlessthanthe26%foundearlierbyyetotherresearchers,28alsoinstandardbreds.Onegroupfoundanincidenceof35%intheFPandMcP/MtPjointsofstandardbredsinacanadianpopu-lation.29therearefewerstudiesinthoroughbreds,buttheinci-denceinthatbreedisreportedlyrelativelyhighaswell.25,30,31ina studyusing repositoryfilms takenatayearling sale innewZealand, relatively lowfiguresof4%Oc in thetc joint and3%intheFP jointwere found,but thesefigureshave limitedvaluebecausethepopulationattheyearlingsalewasstronglypreselected.32

intheWarmbloodhorse,earlyswedishdatamentionedanincidence of 15%.28 More recent figures in the dutch Warm-bloodpopulationarehigher(25%inthetcjointand15%intheFPjoint).27inalargestudyof1180horsesinFrance(mainlyselleFrançaisandAnglo-Arabs,aminorityofthoroughbreds),anincidenceof13.3%wasreportedinthetcjoint.18Alarge-scale field study in Germany in several Warmblood breedsyieldedfiguresof19.5%fortheMcP/MtPjoints,11.1%forthetcjoint,and7.2%fortheFPjoint.33thissupportsthefindingsthat Warmbloods are at higher risk to develop Oc thanthoroughbreds.34

statisticsontheprevalenceofOcmustbeconsideredwithutmostcaution,given thatOcmayoccur inalmostanydiar-throdial joint, but above all because the disease is highlydynamicwithmanylesionsdisappearingbeforematurity(seelater).Additionally,figuresareheavilyaffectedbythenumberof jointsexaminedandby theageatwhichexaminationsarecarried out. Further, any form of preselection by breeders(which is common) will affect prevalence figures. and theeffects of these factors may be dramatic. in a study on 811yearlings that had not been preselected, a staggering 67.5%prevalencewasreported,whencombiningresultsfromtc,FP,McP,andMtPjointsindutchWarmbloods.35Whenmeasuredconventionally at the age of 3 years, the mean figure for thisbreed is approximately 30%. A similarly high prevalence fortcandMcP/MtPOc(61.7%)wasfoundinapopulationofsouth German coldbloods that contained many younganimals.36

Figure 88-5. Example of an osteochondrotic lesion of the humeral condyle showing the formation of a large cartilage flap but relatively little damage to the subchondral bone.


pattern was confirmed.52 in that study, very little change inradiographic appearance was noted from 12 to 24 months.Furtherconfirmationofthesepatternsresultedfromtwoaddi-tional studies. in one study, groups of horses were used toevaluate the relationship between liver copper content andOc,53andintheotherstudytheinfluenceofnutritiononOcwasexaminedintheFrenchsaddlebred.54thelatterstudyalsofeaturedsequentialradiographicexaminations.

AlltheseobservationshaveledtotheconclusionthatOcisbynomeansastaticcondition,butincontrastisanextremelydynamic one in which lesions appear and apparently healduring the first months of life.55 the acknowledgment of thedynamiccharacterofOchasledtoaprofoundchangeintheconceptofthisdisease.

itiswellknownthattheextracellularmatrixofthearticularcartilagegoesthroughaphaseofrapidremodelinginthefetalandneonatalanimal.inabenchmarkstudyontheearlydevel-opmentofarticularcartilage,theresearchgroupfromQuébecinvestigated very early changes in epiphyseal growth cartilageandarticularcartilage(andtherelationshipbetweenthe two)infetuses(6to11monthsgestationlength)andneonates(0to8 days) using histological techniques. they showed that thedemarcationofarticularcartilagefromthemuchmorevolumi-nousgrowthcartilageoccursby6to8monthsofgestationandis followed by subsequent skeletal maturation. importantly,theyalsoshowedareasinthegrowthcartilage,notablybetweenthe proliferative and hypertrophic zones near the ossificationfront where a dramatic change in collagen fiber organizationoccurred.theseareaswereinterpretedasregionsthatwerebio-mechanicallyverysusceptibletoinducedtrauma.50

it is in the juvenile period of ongoing endochondral ossi-ficationandrapidchangesingrowththatthetopographichet-erogeneity in biochemical composition that is necessary towithstandthelocallydifferentbiomechanicalchallengesdevel-ops through the process of functional adaptation.56,57 in thisprocess,thecollagennetworkofthearticularcartilageismoldedunder biomechanical influences that induce both composi-tionalandarchitecturalchanges58 inaprocessnotunlikethatinbone.3however,whereasboneretainsitscapacitytoremodelthroughoutthelifeofthehorse,cartilagemetabolismdecreasesquicklyintheearlyjuvenileperiod,andturnovertimesareverylonginmaturehorses.59,60

thelatterfactprecludesanysubstantialremodelingorrepairandmakestheformationofthecollagennetworkintheearlyjuvenile phase a once-in-a-lifetime process that can have veryimportantconsequencesfordiseasepreventioninfuturelife.61the sharp drop in collagen metabolism in the early juvenileperioddetermineswhenthewindowforrepairoflesionscloses.somelesions,eitherbecausetheyoriginatetoolateoraretoolarge,donothaveenoughtimeforrepair.thesearethelesionsthat might eventually become clinically manifest. this meansthat in Oc, a clear distinction should be made between thepathogenesistriggeredbyanumberofetiologicfactors,whichcanbe supposed tobe specific forOcon theonehand,andtheprobablylargelyunspecificrepairprocessontheother.62,63Aflowchart for theputativemechanismofOcbasedonthisconceptispresentedinFigure88-7.

thecurrentconcept is thatOc isahighlydynamicdistur-bance of endochondral ossification that is intricately linkedwiththerapidlychangingmetabolicstatusofarticularcartilageinthejuvenileanimal.thisconcepthasledtosomehypothesesand statements regarding the origin and implications of the

months of life had become undetectable before the age of 5months. thereafter no major changes occurred and existinglesionsremainedvisible. intheFP jointwheretheepiphysealmaturation is known to be late compared to other joints,50,51lesionsoriginatedlaterandpeakedatapproximately6monthsbeforedeclininginnumberuntilabout8months,afterwhichthelesionsremainedstable(Figure88-6).27

inafollow-upstudyinanothergroupofWarmbloodfoalsthat were tracked for 24 months, this general joint-specific

Figure88-6. A, Schematic diagram of the early development of osteo-chondral lesions at the distal intermediate ridge of the tibia. At 1 month of age, several lesions can be identified that will heal (thick line pointing down). Only a few lesions originate after the age of 1 month (thin line pointing up) and, after the age of 5 months, the situation remains stable. B, Schematic diagram of the early development of osteochondral lesions at the distal aspect of the lateral trochlear ridge of the talus. The same general pattern as in A is seen, but healing potential is better. C, Schematic diagram of the early development of osteochondral lesions of the lateral femoral trochlear ridge. The pattern is distinctly different from that of the tarsus. Lesions develop only after the age of 3 months, peak at about 6 months, and have resolved at the age of 8 months, although some lesions will remain. (From Dik KJ, Enzerink EE, van Weeren PR: Radiographic development of osteochondral abnormalities, in the hock and stifle of Dutch Warmblood foals, from age 1 to 11 months.Equine Vet J Suppl 31:9, 1999 with permission from Equine Veterinary Journal Ltd.)

Distal intermediate ridge of the tibia

Abnormal

Normal

Age (months)

1 5 11

Distal aspect lateral trochlear talus

Abnormal

Normal

Age (months)

1 5 11

Midregion lateral ridge femoral trochlea

Abnormal

Normal

Age (months)

1 3 4 6 8 11

C

B

A


influences are strongly correlated with other etiologic factorssuch as exercise and genetics (through the determination ofconformationoftheanimal).however,apartfromdirectblunttraumathatwillcauseanosteochondralfracture,biomechani-calforcesareconsideredanecessaryadditivefactorratherthanasolecauseofOc.

FailureofVascularizationOne report described the existence of cartilage canals in theepiphyseal cartilage long ago.67 the author stated that “theprimaryfunctionofcartilagecanalsis…thenutritionofcarti-lagetoolargetobesuppliedbydiffusionofnutrimentsthroughtheir substance. … their presence retards rather than hastenstheendofossification.”theauthoralsodescribedtheprocessofobliterationofthesecanals,calledchondrification,whichpre-cedesossification.

in the pig, extensive studies have been performed on thevascularizationofjuvenilecartilage,thephysiologicprocessofregressionofcartilagecanals,anddisturbancesthereofaspos-sible causes for Oc. in this species, areas of chondronecrosisrelatedtoobliteratedcartilagecanalscanbefound,andtheyaremuch larger in commercialpigbreeds than inminiaturepigsfrom wild hog ancestry.68 Artificial devascularization createsislands of cartilage without vascular supply, and these coulddevelop into Oc-like lesions.69 these observations led to thehypothesis thatpremature interruptionof thevascular supplyof the growth cartilage of the articular–epiphyseal complexwouldleadtonecroticareasinthecartilagelayer.thesewouldlaterbecomeengulfedintheossificationfrontandresultinthetypicalirregularitiesandcartilageislandsseeninOc.70

Laterin-depthstudiesinthissameareaappliedamoresubtleandnaturalwayofinterruptingvascularization,bytransectingonlyalimitednumberofcartilagecanals,leadingtothedevel-opment of Oc-like lesions.71 no relationship between theoverallregressionpatternofcartilagecanalsandOcwasshown.thisledtotheconclusionthatOcisnottheresultofageneralfailure in endochondral ossification, and hence cannot becausedbyasystemic factorsuchasgrowthrate,but is incitedbylocalbiomechanicalfactors.72thisfindingled,togetherwithadditionalobservations,tothehypothesisthatOcwascausedbylocalbiomechanicaldamagetocartilagecanals,especiallytothe anastomosing branches that run through the ossification

disorder thatwere expressedat thethird internationalWork-shoponequineOsteochondrosis thatwasheldinstockholmin2008.theseassumptionsandconclusions include that (1)“Oc defined as irregularities in endochondral ossification isinherenttotheequinespecies;modernmanagementandbreed-ingpolicieshavecausedthesharpriseinincidence,”(2)“dif-ferences in collagen metabolism and/or gene expressionbetweenOccartilageandnormalcartilagemayinmanycasesreflect thesecondary repairprocess,”and(3)“theremaybeagenetic correlation between susceptibility for Oc anddesired traits such as mature height, conformation andperformance.”64

ETIOLOGICFACTORSOc is a complex disease and multifactorial in origin. Biome-chanicalinfluences,exercise,failureofvascularization,nutritionimbalances,andgeneticinfluenceshaveallbeenincriminatedas potential etiologic factors and are probably interrelated.supportforeachetiologicfactorispresentednext.

BiomechanicalInfluencesBiomechanicalloadingplaysaroleinthepathogenesisofOc.this assertion is supported by the consistency of predilectionsites within specific joints. it is probable that the dramaticchangesinbiomechanicalloadingthattakeplaceafterbirthareanimportanttriggerforinitiatinglesions.inapathologicstudyoftheFPandtcjointsof9fetusesand10foalsaged0to35days,anOclesionwasdetectedinonlyone3-day-oldfoalandnonewerefoundinanyofthefetuses.46Althoughonegroupofresearchersfoundmanytinyareasofchondronecrosisinall21fetuses they studied, which they saw as a feature of normaldevelopment,theywerenotabletofindspecificchangesinthecollagen matrix compatible with early Oc in any of them.50OtherattemptstofindOclesionsinfetuseshavealsofailed.65,66thereforebiomechanicalloadingmostlikelyplaysaroleinallproposedmechanismsforOc.

Biomechanical loading can exert an influence late in theprocess of Oc development, where it causes the formationandlooseningofcartilageflapsafterfaultyendochondralossi-fication, or early where it prematurely disrupts the vascularsupplytoneonatalcartilage(seenextsection).Biomechanical

Figure 88-7. Flow chart outlining the supposed pathway along which clinical lesions eventually could become manifest in equine osteochondrosis.

Endochondral ossification is a processin which the delicate vascularization inthe horse easily leads to irregularities

based on chondronecrosisGenetic susceptibility and

environmental factors determine thesize and severity of the irregularities

The natural decline in metabolicactivity makes repair progressively

difficult. The moment when “thewindow closes” is not identical for all

joints (the stifle lags behind)

Once a lesion forms, a repair processwill ensue immediately, facilitated bythe high natural metabolic activity of

juvenile articular cartilage

Lesions that are not repaired maydevelop into clinically important

articular defects


fromperichondralarteriestosubchondralsourcesthatarecon-nected to the original cartilage canals through newly formedanastomosesthatcrosstheossificationfront(Figure88-8).theauthorsfound12lesionsinthesesevenfoals,alllocatedwherevesselscrossedtheossificationfronttosupplycartilagecanals.76inasimilarstudyfocusingonthedistalfemur,anotherpredilec-tionsiteofOc,theycouldfindinprinciplesimilarchangesinvascularization,but the regressionofbloodvesselswasmuchlessextensiveatthisearlyagethaninthetarsus,andnolesionscouldbefound.77thismayhavetodowiththefactthattheFPjointlagsbehindinitsdevelopment50,51andshowsthepeakofOclesiondevelopmentlaterthaninmostotherjoints.27intheMcP/MtPjoint,againthepatternofchangesinvascularizationwassimilar; in thiscaseone(“latens”) lesionwas found.78Ofnote,microcomputedtomographyoftheearlylesionsshowedthat the secondary repairprocess followsalmost immediatelyaftertheformationofthelesion.79

Asaresultofrecentstudies,therenowremainslittledoubtthat,asinthepig,failureofvascularizationthroughocclusionof cartilage canals (and not retention of these, as suggestedearlier80)playsacrucialroleintheearlypathogenesisofOcinthehorse.76-79Many featuresof equineOc, suchas the joint-specificwindowsintime(relatedtojoint-specificpatternsintheprogressoftheossificationfrontandsubsequentvascularrear-rangements), and the frequent bilateral occurrence can beexplainedinthisway.however,itshouldberealizedthatthese

frontfromthebonemarrow.73Basedontheirextensiveworkinpigs,someresearcherssuggestedthatadisturbanceofthebloodsupply through cartilage canals to predilected areas of thegrowthcartilage,withensuingformationofnecroticareas,wasapivotalelementintheearlypathogenesisofOc.theauthorsproposeda refinementof theexistingnomenclatureby intro-ducingthetermsosteochondrosis latensforfocalareasofnecrosisthatarenotclinicallymanifest,andosteochondrosis manifestaforwhere the necrotic area had developed into a delay in endo-chondralossification.the termosteochondrosis dissecanswouldberetainedincasesofcleftformation.74

inthehorse,cartilagecanalsarepresentintheearlyjuvenileperiod as well, and it could be assumed that a similar earlypathogenesis seen in the pig would occur in the young foal.Muchworkinthisareahasbeendone.inthefirstcross-sectionalstudyinrandomsourcefoals(rangingfrom191daysgestationto153daysold),itwasshownthatlesionsresemblingthoseinpigs(i.e.,characterizedbychondrocytenecrosisandapparentlycausedbycartilagecanalfailure)werepresentin9outof100animals.75interestingly,inallbutthetwoyoungestindividuals(aged12and18days)anongoingrepairprocesswasalsonoted.A highly interesting follow-up experimental study into thedevelopmentofthevascularizationofthetarsusofsevenveryyoungfoals(0to7daysold)followed,showinginanelegantwayhowtheadvancingossificationfront inducesachange inthearterialsupplyofthecartilagecanalsinthegrowthcartilage

Figure88-8. Images of three-dimensional volume-rendered models of micro-CT scans of a tissue block from the cranial part of the distal intermedi-ate ridge of the tibia of a 3-week-old Standardbred foal. The block contained a permanent barium angiogram, and only the gray-scale segments representing barium and bone are shown. The block measured approximately 2 cm in all dimensions. A, A vessel originating from the perichondrial plexus on the cranial aspect of the distal tibia courses into the subchondral bone toward the cranial apex of the distal intermediate ridge (black arrow). Distal and caudal to this, toward the distal articular surface of the intermediate ridge, vessels emerge into the growth cartilage directly from sub-chondral bone (white arrow). B, In this model of the same tissue block, the gray-scale segment for bone has been rendered less opaque/more translucent than in model A. The vessels emerging from bone into growth cartilage (white arrow) are branches of the vessel entering bone on the cranial aspect of the intermediate ridge (black arrow). The model illustrates how the midsection of cartilage canal vessels is incorporated into the advancing ossification front during growth. This process, and in particular the requirement for vessels to traverse junctions between tissues of different qualities such as bone and cartilage, is believed to render vessels particularly vulnerable to failure. (Courtesy Dr. K. Olstad, Norwegian School of Veterinary Science.)

BA


the epidemiologic studies on dietary mineral and traceelementlevelsandtheoccurrenceofdevelopmentalorthopedicdiseaseinOhioandKentuckyseemedtogivefurtherevidencefor a key role of copper.90 the original national researchcouncil (nrc) recommendation91 of 10ppm copper in drymatter,whichwasbasedonastudywithalimitednumberofhorses,92 was challenged, and supplementation studies werestarted. these yielded positive results to some extent,93-95 buttheycertainlywerenotconclusiveenoughtopinpointcopperdeficiencyasasolecauseofOc.96higherdietarycopperlevelsof20 to25ppm95or50ppm97were recommended,but theywere later questioned following studies revealing that copperlevelsof4.3to8.6ppminpastureweresufficientforahealthydevelopmentofboneandcartilage.98theevidencetosupportcopper supplementation to pregnant mares is equivocal.Althoughonestudyshowedanincreaseoflivercopperconcen-tration in newborn foals after prenatal supplementation ofmaresduring latepregnancy99andnoteda(minor)reductionin articular cartilage lesions at age 5 months,98 another studyconductedinthesamecountry(newZealand)failedtodem-onstratebotheffects.100 inbothstudies lesionswereminimal,however,andnoclinicalOcwasseen.thismeansthat,ifanyeffecton the initiationof lesionsexists, thiswillbeminor. itdoesnotmean,however,thatcoppersupplementationofpreg-nantmaresornewbornfoals,whichmayalsoraiselivercoppercontent,101mayhavenoclinicalbenefits,becauseanotherstudyshowed that there was a relationship between neonatal livercopper concentration and the resolution of lesions, but therewas no correlation with the initial occurrence.53 it was con-cludedfromthatstudythatcopperhadapositiveeffectontherepairofOclesionsbutnotontheirpathogenesis.thisconceptcouldexplainmanyofthesomewhatcontradictoryandincon-clusive earlier findings. therefore copper retains a clinicallyimportantrole,becauseitistheoutcomeofboththepathoge-neticprocessandtheensuingrepairprocessthatdeterminestheeventual and clinically important lesions. Although the pro-posedmechanismoftheeffectofcoppervialysyloxidasehasbeenchallenged,102thereisstillmechanisticevidenceforaroleofcopper,becausein vitroresearchyieldedadditionalinforma-tionontheroleofcopperthatappearedtohaveachondropro-tectiveeffectthroughreductionoftheactivityoftheproteinasescathepsinBandcathepsind.103

highcalciumlevelsdidnotinfluencetheincidenceofOcinfoals,buthighlevels(fourtimesthenrcrecommendation)ofphosphorusresultedinsignificantlymorelesions.104themech-anismwas supposed tobe the inductionof secondaryhyper-parathyroidism, which would lead to increased osteoporosisandsubsequentweakeningofthesubchondralbone.thestudyisinterestingbecausefoalswerestudiedintheperiodfrom2.5to6.5monthsofage,which isnowknowntobeaperiod inwhichthedynamicprocessofOcisveryactive.

dietaryenergy levelshavebeenimplicatedinthepathogenesisofOcfordecades.105thiswasmostly,butnotsolely,inrelationtoahighgrowthrate.intheearlyscandinavianstudies,itwasstatedthatOcprimarilyoccurredinlarge-framed,fast-growinganimals,betheybroilers,bulls,dogs,swine,orhorses.8,48Later,theliteratureturnedmoreambivalentonthesubjectofgrowthrate.severalauthorsfoundnorelationtogrowthrate,14,106,107butothers reported a larger prevalence in horses taller at thewithers15,34 or in horses having a higher average daily weightgain.108 sometimes this was only true for a limited period ofdevelopment.109 in a study where a normal level of nutrition

vasculareventspresentanearlymechanismandnottheetiol-ogy, as stillother factors (likebiomechanical loadingor evenperhapsinferiorqualityofthecartilageextracellularmatrix)arenecessarytocausethelesionduringtheperiodofvulnerability.these factors will determine in the end why a given horsedevelopsOcandanotherdoesnot.

Exerciseexercise is known to be the steering factor in the process offunctionaladaptationduringwhichthebiochemicalcomposi-tionoftheextracellularmatrixofarticularcartilagetakesonatopographically heterogeneous character.57,81,82 this processtakesplaceprincipallyinthefirstyearoflife,withemphasisonthefirstfewmonths.Giventheimportantroleofexerciseinthejuvenileperiod forcartilagedevelopment, itmaybehypothe-sized that this factorwouldbeof importance in thedevelop-ment of Oc lesions too, because these originate in the sameperiodthatarticularcartilagecompositionismolded.

Preliminaryresearchinwhichcontrolledexercisewasgiventofoalsfrom3to24monthsofageusingahigh-speedhorsewalkeryieldedpromisingresults.Ocincidencewas6%inthehigh-exercise group and 20% in the low-exercise group, butresults were flawed because of a concurrently running nutri-tional study employing different energy levels that were notconsistentlyapplied.83,84Astudyfocusingontheeffectofexer-cisealone,givenfrom10daysuntil5monthsofage,didnotyieldconclusiveresults,althoughtherewasatendencytowardadecreaseinseverityofOclesionsintheexercisedgroups.12

inalargefieldstudy,oneresearcherfoundfewerOclesionsonthedistalsagittalridgeofthemetacarpusandmetatarsusintheMcPandMtPjointsoffoalsthatgotmoreexerciseduringthe first months of life. there was, however, no effect on theincidence of Oc in the tc joint.85 Another large field studyconductedinnormandy(France)revealedanincreasedriskofOcinfoalswithirregularaccesstopasture,aswellasinanimalskeptinverylargeplots.theseresultsunderlinethesomewhatambivalentcharacterof theeffectofexercise.34exercisemighthence be a factor codetermining the final appearance of Oclesions, but it does not seem to be of primary pathogeneticimportance.

Nutrition,HormonalFactors,andGrowthRateFromthestartofresearchintoequineOc,muchefforthasbeendedicated to nutritional factors. the studies can be roughlydivided into researchonmineralsand traceelements,mainlycopperandzinc,toalesserextentcalciumandphosphorus,andon dietary energy level. the latter factor is closely related togrowthrate,afactorheavilyincriminatedinOcpathogenesisinalargenumberofspecies.however,growthrateisdeterminednotonlybyenergyintakebutalsobygeneticpredisposition.

interestintraceelementswasraisedbyareportontherela-tionshipbetweenlowcopperlevelsinserumandceruloplasminconcentrations (a copper-transporting protein present in theblood)andOc.86studiesfollowedontheeffectofdeliberatelyfeeding low-copper diets87 and the possible role of zinc ininducing a relative copper deficiency.88 the mechanism wasthoughttoactviatheenzymelysyloxidase,acopper-dependentenzyme that is essential for the formation of collagen cross-links.Zincandcadmiumcanantagonizecopperbydisplacingitfromthesulfhydrylbindingsitesonmetallothionein.89


lowerincidenceinferalhorses.37,38thissuggestsaconsiderablegeneticinfluence.FurtherevidencecomesfromstudiesshowinglargedifferencesinincidenceofOcbetweenprogenygroupsofdifferentstallions.15,47,121

thereisnodoubtthatOcisapolygenictraitandthatthemethodofinheritanceiscomplex.122someestimatesonherita-bilityhavebeenmade,buttheydifferedwidely.Forthetcjoint,heritabilitiesof0.24,1230.26,15and0.52124havebeenreported.Alargeprogenystudyinthenetherlandssucceededinestablish-ingreliableheritabilitiesfornaviculardiseaseandbonespavin,butitdidnotgiveunequivocalresultswithrespecttotcOc,whichfinallywasestimatedtobeapproximately0.25.125

heritabilitiesof0.25andhigherarehighenoughtowarrantselectionprograms,which indeedhavebeen implementedbymany studbooks. however, progress has been disappointing.theroyaldutchWarmbloodstudbook(KWPn)startedreject-inganycandidatesirewitheventheslightestradiographicsignof tc Oc in 1984 and any sign of FP Oc in 1992, but nosubstantial decrease in incidence had been realized by mid-2010.thisisincontrasttotheconditionsofnaviculardiseaseand bone spavin, where a similar selection policy has beenfollowed.thenumberofpotential stallions rejected for thesedisorders at selection events has fallen dramatically over thepastdecades.126

therearevariousexplanationsforthis.Ocisclassicallyseenasanall-or-nonetraitwithanunderlyingcontinuousscale.122thegeneticbackgroundmay,howeverbemuchmorecompli-cated than originally supposed. First, there is mounting evi-dencethatdifferentgenesareinvolvedindifferentjoints.thistranslatestodifferentheritabilitiesfordifferentjoints.inastudywhereOcwasscoredona5-pointcategoricalscalein811year-lings, the h2* at animal level was estimated at 0.23, whichconcurswellwiththeotherstudiesmentionedearlier.however,thefiguresper jointstronglyvaried,beinghigh(0.36)for thetcjoint,intermediate(0.11)fortheMcP/MtPjoints,andverylow (0.06), for the FP joint.127 heritabilities are largely breeddependent. A study on south German coldbloods revealedheritabilitiesof0.16fortheMcP/MtPjoints,whichiscompa-rable to the figure found by another group, but of not morethan0.04forthetcjoint.128Asecondpointcomplicatingthegenetic approach of Oc is its dynamic nature. this featureallows many animals to be radiographically free of lesions atage3or4yearswhen theyenter the stallion selectionproce-dures,yettheywillhavehadevidenceofthediseaseasafoal.hence, these foalsaregeneticallypredisposed toOcandwillpassthis traiton.realizationof thecomplexityof thegeneticbackgroundofOchasledtoadaptationsinselectionpoliciesincertainstudbooks.theKWPnnowusesamoredifferentiatedapproach in which lesions are classified and stallions withminor lesions stillmaypass.Approval is temporary,however,becausedatafromoffspringarenowincludedintheselectionprocedureandareusedtocalculatebreedingvalues.ifaprovi-sionallyapprovedsireproducesahighprevalenceofOcinitsoffspring,itmaystillbeeliminated.

recently, studies have been undertaken to identify Oc-related genes through modern molecular genetic techniques.thepreviouslymentionedstudyonsouthGermancoldbloodsinvolvedmappingofquantitative trait loci(QtL)forOcand

wascomparedwithanincreaseof120%to150%inallcom-ponents of the diet, a fast growth rate was associated with ahigher amount of Oc lesions, regardless of whether the fastgrowthratewasdeterminedbyahighernutritionallevelorbygeneticpredisposition.54

Althoughthedataontheeffectofgrowthrateareconflictingandtheconceptofahighgrowthrateputtingpressureontheprocessofendochondralossificationandthusleadingtoirregu-laritiesmightbetoosimplistic,thereissubstantialevidenceforothermechanisms.excessive levelsof energy, especiallywhenfedintheformofeasilydigestiblecarbohydrates,110,111resultinastrongpostprandialhyperinsulinemia.Insulinanditsderiva-tives insulin-like growth factor-1 (iGF-1) and iGF-ii have adirecteffectontheprocessofendochondralossification,actingasmitogensforchondrocytesandstimulatingchondrocytesur-vivalorsuppressingapoptosis.112Manyoftoday’shorsesarefedexcessively and have low activity levels, which may, as inhumans,leadtoobesityandinsulinresistance.thelattercondi-tionhasbeenrelatedtomanypathologicalconditions,includ-inglaminitisandOc.113

insulinalsostimulatesarapidremovalfromthecirculationof the thyroid hormonest3andt4,114whichare involvedin thefinalstagesofchondrocytedifferentiationandinthemetaphy-seal invasion of growth cartilage by blood vessels.115 in fact,Oc-positivefoalshaveasignificantlyloweriGF-1activitythanOc-negativefoals.116inthisway,highcarbohydratelevelswouldinduceatransientrelativehypothyroidismandhencearetarda-tionofthematurationofgrowthcartilage.hypothyroidisminhorses has been known to produce skeletal lesions, althoughtheyarenotequivalenttothoseseeninOc.117

interestingly,theeffectofcarbohydratesonthyroidhormonelevelscanbedemonstrated inweanlings,but it isnotpresentin yearlings.118 it has been possible to induce cartilaginouslesions by administering diets with high levels of digestibleenergy.104,119Furthermore,horseswithOchavebeenshowntohave higher postprandial glucose and insulin responses tofeedinghigh-grainratiosthandidnormalhorses.120

AnotherindicationoftheimportanceofcarbohydratelevelsinthefeedcomesfromastudyinKentuckyontheinfluenceofthe season on the occurrence of Oc. early foals appeared tohaveasignificantlyhigherincidenceofOcinthetcjoints,butlatefoalshadahigherincidenceintheFPjoints.thisseeminglycontradictory effect of the season could be explained by thedifferent windows of vulnerability of these joints, whichappearedtocoincidewiththespringandautumnpeaksinthehigh-energyvalueofthegrass.31

thereishardlyanydoubtthatthepathogeneticmechanismoutlinedhereplaysacertainroleinthedevelopmentofequineOc. however, it is unlikely that it is the sole mechanism,becausemanylesionsprovokedbytheadministrationofhigh-carbohydratedietsweresimilar,buttheywerenotalwaysiden-tical to those seen in clinicalOc.Besides,many lesionswereseen in the growth plate,107 and in contrast to other species,clinical Oc is rarely, if ever, seen in the growth plate in thehorse.

Geneticsinmanyspecies,theincidenceofOcvariesconsiderablywithbreed. in wild boars, the disease seems to be nonexistent,whereas it is common in many commercial pig breeds.70 inhorses, lesions are rarely found in ponies and have a much

*h2 is thebroad-senseheritabilityandreflectsallpossiblegeneticcontributionstoapopulation’sphenotypicvariance.


natural processes involved. chondrocytes from animals olderthan5monthsdidnotundergohypertrophy,andchondrocytesfromneonates(7days)showedintermediatebehavior.138thisresearchoncemorestressestheimportanceofagewhenstudy-ingOc.FailuretoundergohypertrophyasmaincauseforOcwas discarded in a study in which Oc was induced in 3- to6-month-old foalsbyahigh-energydietand that investigatedtheexpressionofhypertrophy-relatedgenes,suchascollageni,ii, and X; matrix metalloproteinase (MMP)-13; and the tran-scriptionfactorrunx2.thehigherexpressionofcollagenXandMMP-13 (themainmatrixmetalloproteinase involved in col-lagen degradation) indicated that failure of chondrocytes toundergohypertrophyisnotthecauseofOc,ashadbeensug-gestedearlier.139Anotherstudyfoundchangesinproteoglycancompositionofosteochondroticfragments,buttheycouldnottellwhetherthiswasprimaryorsecondary.140thisisaconstantproblem, because data from clinical cases and fragments col-lected at surgery are not representative of the initial phase ofthedisease.7

studieshavefocusedonnormalandabnormal(dyschondro-plastic)cartilage,ontheexpressionofvariouscollagen typesthatare represented in the extracellular cartilage matrix (collagentypes ii, Vi, and X), and on the expression of growth factors(tGF-β, iGF-1, iGF-2) that are known to play a role in thedevelopment and maturation of cartilage.112,141-145 thereappeared to be distinct differences in expression patternsbetweennormalandabnormaltissues,withnotablyhighlevelsof activity around the chondrocyte clusters or chondrones inearly cases of Oc. this increase in activity is in line with thehigher levelofchondrocytemetabolismdemonstratedbyoneresearchgroup146andcouldbetheprimarycause,butitismorelikelyasecondaryeventrepresentinganattemptatrepair.147theborderline between the Oc lesion itself and repair tissue isvague,probablybecausetheonsetofrepairisalmostimmedi-atelyafterformationofalesionandbecauseeventsaretakingplaceinjuvenilecartilagethatstillhasconsiderableregenerativecapacity.inastudywhereOctissuewascomparedwithtissuefromhealingsurgicallycreatedosteochondroticfragments,nodiscriminationcouldbemadebetweenthetwotypesoftissue.Bothresembledananabolic,reparativeprocesswhencomparedto age-matched controls. however, immunohistochemically,theOctissuebedstainedpositiveforchondroitinsulfateandcollagentypeii,whichthefracturebeddidnot.51

Littleworkhasbeendoneonthesubchondral boneunderlyingthecartilagedefects.Onegroupshowedchangesinbonemor-phogenicenzymesandinmembranelipidcompositionofthecellularcomponentsofthesubchondralbone.148thereareclearindicationsthatthebonecomponentisinvolvedinlesionfor-mation in Oc too, as there is a strong correlation betweenserumosteocalcinlevelsasearlyasat2weeksofagewithradio-graphicallyscoredOcat5.5and11monthsandpostmortemscores at 11 months (i.e., when lesions had become virtuallyimmutable).149 Osteocalcin might therefore be a potentialmarker for thesusceptibilityof individualanimals todevelopOc.therelationshipbetweenOcandosteocalcinmayindicateveryearlyeventsindeed,becauseinanotherstudywhereserumfromfoalsaged1to49dayswasused,nosuchcorrelationwasfound.150

LevelsofMMPswerefoundtobeelevatedincopper-deficienthorses with clinical Oc lesions,95 and there is increasing evi-dencethatchangesincollagenmetabolismplayanimportantroleinthemolecularmechanismofOc.thecambridgegroup

POF in the McP/MtP and Oc in the tc joints. QtL withchromosome-wide significance on was found on 10 chromo-somes.129 the researchers later expanded the data from theirwhole-genomescanfurtherandfoundanassociationofasinglenucleotide polymorphism (snP) located in the acyloxyacylhydrolase (AOAh) gene on chromosome 4 with Oc in theMcP/MtPjoint130andofothersnPslocatedintheXin-actin-binding repeat containing 2 (XirP2) gene with Oc in bothMcP/MtPandtcjointsonchromosome18.131Asimilargenome-wide approach in hanoverian horses identified QtLs withchromosome-widesignificanceonchromosomes2,3,4,5,15,16, 19, and 21.132 Further investigations identified a relevantQtL on chromosome 5, indicating collagen type XXiV as apotential functionalcandidategene.133A later study, inwhichmarkerdensityonchromosome18wasincreasedbasedontheearlierobservationsbythesamegroupinsouthGermancold-bloods,131 showed a new QtL on this chromosome that wasassociated with Oc and located very close to the parathyroidhormone 2 receptor gene, qualifying the latter, which hadearlier been implicated in familial early-onset osteoarthritis(OA) in humans,134 as an interesting positional candidategene.135

Anotherapproachwastakenbyagroup,whocomparedgeneexpression profiles of leukocytes from horses affected by Ocandnormalcontrols,andidentifieddysregulationofanumberofpathways,amongothersWnt,*indianhedgehog(ihh),andtransforminggrowthfactor-β(tGF-β)signaling,inOc-affectedanimals.136theproblemwiththisapproach,aswiththeearlierdescribedgenome-widescans,isthatmaterialfromhorseswithestablished Oc is used so that no distinction can be madebetween primary and secondary processes. this applies to amuchlesserextenttoworkperformedontheveryyoungfoalsfromtheexperimentalstudy76onvascularchangesinthegrowthcartilagealludedtoearlier,wherethetousler-likekinase2gene(tLK2)andanunknowngenewerefoundtobeupregulatedinfoalspredisposedtoOc.136

itisclearfromthepreviousdiscussionthatthegeneticback-groundofOciscomplexandnotveryeasytounravel.thismayhavetodowiththefactthatmostgeneticstudiestrytolinkthefinalphenotype,andthustheendproductofvariousprocessesthat have most probably different genetic backgrounds, tocertaingenes. it ishighlyunlikely that in thenear futureOccanbeselectedagainstusingasimplegenetictestthatdetectsoneortwoculpritgenes.

MOLECULARMECHANISMStheneedforamorefundamentalapproachtounderstandingandpreventingOcisobvious,137andinrecentyearsalargepartofresearchonequineOchasfocusedonthemolecularmecha-nisms involved. Both chondrocyte behavior and compositionof theextracellularmatrixhavebeen targetsof study.A studyfoundthatchondrocytesthatwerefreshlyharvestedfromfetalgrowth cartilage underwent hypertrophy and subsequentlyapoptosiswhenculturedineitherthecommonlyusedfetalcalfserumorhorseseruminasituationthatstronglyresembledthe

*theWnt(pronounced“wint”)signalingpathwayisanimportantpathway in intracellular signaling. the name comes from “wing-less”(referring toaDrosophilamutantwhereall thesebasicpath-wayshavebeendiscovered).


inflammation,whichseemstobereactiveinnatureandisnotaprimaryfactor.

Parathyroidhormonerelatedprotein(PthrP)andihhhavea role in controlling cartilagedifferentiationandhypertrophyinthegrowthplate.170thisinfluenceismediatedbybone mor-phogenetic proteinsassignalingpeptides.thisledtothehypoth-esisthatthesemoleculeswouldhaveasimilarroleincartilagedifferentiationintheequinearticular–epiphysealcomplexandcould be implicated in the pathogenesis of Oc. there wasindeedasignificantincreaseofPthrPandmrnAexpressioninchondrocytesfromOc-affectedcartilageandatrendinihh.171expression of bone morphogenetic proteins 6 and 2 was notchanged.172 Also, expression of transcription factors Gli1 andGli3wasnot increased,suggestingeitheradifferent transcrip-tion factor in osteochondrotic tissue, a dysfunction in localreceptoractivation,orelevationsinihhinhibitors.itshouldbenoted that these investigations were performed on samplesfromhorsesaged6to18months,whichmakestheiroutcomelikely to be representative for early repair rather than for thepathogenesisoflesions.173thesameappliestotheobservationthat serum iGF-1 levels were higher in a large group ofOc-affected horses aged 15 months to 10 years compared tocontrols.174

TREATMENTNonsurgicalManagementtreatmentofsmallOclesionsmightnotalwaysbenecessary.single small, radiographically obvious Oc lesions in the tcjointwithouteffusiondidnotinfluenceperformanceinracingstandardbreds,incontrasttojointswheretherewassignificanteffusion.123thereisanegativeeffectonperformance,however,ifthelesionsaremoresevere.175trotterswithOclesionsinthetcjointhadasignificantlylowernumberofstartsandsome-whatlowerearningscomparedtocontrols.176

nonsurgical treatment consistsprincipallyof rest and con-trolledexercise.systemicnsAidsandintra-articularmedication(corticosteroids to enhance resolution of joint effusion andcertaindisease-modifyingosteoarthriticdrugssuchashyaluro-nan,chondroitinsulfate,orpentosansulfate)mayormaynotbeadministered,buttheyhavenotbeenreportedtobeofgreatvalueinOc.177Giventhenatureofthediseasedescribedearlier,nonsurgicalmanagementcanonlybeexpectedtobesuccessfulineitherveryyounganimals,wherethereisstillgoodcapacityforregeneration,orinverymildcases.

AlargestudyonthenaturalhistoryofFPOcinthreecropsof thoroughbred foals showed improvement and repair ofseveral lesions, which was compatible with the age of theanimalsstudied.13Onegroupdescribedafavorableoutcomeofnonsurgical treatmentoftcOcinagroupofstandardbreds,half of which were treated nonsurgically and half surgically.the authors mentioned, however, that these results werebiased, because the more severe cases tended to be treatedsurgically.178

Onestudyconcludedthatnonsurgical treatmentoftcOc(consistingofsimpleboxrestoralessintensetrainingprogramwith a low-energy diet) was a good option in Warmbloods(80%successrate),butnotinstandardbreds(25%).itshouldbenotedthat inWarmbloodhorses,especiallythosedestinedfordressage,resolutionofjointeffusionisoftenatherapeuticgoal in itself. this aspect was not classified as such in thisstudy.179

performedin-depthstudiesonthedistributionofcathepsinsB,d,andLinnormalandabnormalcartilage.theyfoundphysi-ologicdifferencesindistribution151-153aswellasastrongincreaseincathepsinBactivityinchondrocyteclonalclustersinOc.154the latter finding was confirmed in a study on the effect ofcoppersupplementation.155

Another study revealedan increase inactivityofgelatinases(MMP-2andMMP-9)inosteochondroticcartilage.156however,expression of membrane-type matrix metalloproteinase-3(Mt3-MMP)isnotsignificantlyalteredinosteochondroticcar-tilage.157 the increased collagen turnover in osteochondroticcartilage is reflected by an increase in collagen split productsthat can be detected in the synovial fluid. An increase in thec-propeptideofcollagentypeiiwasdetectedinsynovialfluidfromOchorses,butadecreasewasfoundfortheepitope846ofaggrecan,demonstratingdifferentalterationsinaggrecanandcollagenturnoverinOc.158thisfindingwasconfirmedinalaterex vivo studywherenoevidencewas found foran increase inproteoglycanmetabolism,butan increase in the levelsof thecol2-3/4 short epitope indicated increased collagen breakdown.159thedifferentsignatureofosteochondroticcartilagewithrespectto proteoglycan and collagen metabolism was further under-lined by a study on expression patterns and chondrogenicpotential of osteochondrotic cartilage (from mature animals)versusnormalcartilage(fromage-matchedcontrols)whereOccartilageshowedincreasedexpressionofcollagentypesi,ii,iii,and X; MMP-13; AdAMts-4; and tiMP-1; and decreasedexpressionoftiMP-2andtiMP-3.Furthermore,pelletculturesproduced from Oc tissues contained significantly less glycos-aminoglycans(GAGs).160In vivoincreasedcollagendegradationhasalsobeenshown.161

OnegroupwasabletopredictthepresenceofOcbasedonthedetectionofcollagen markers inserum.162inlinewiththis,awell-controlledexperimentalstudyrevealedthattheratioofthemarkersforcollagenanabolismandcatabolism(cPii/ciic)at20weekshadstrongpositivecorrelationstoOc,asdiagnosedradiographicallyat5.5months.149Additionalevidence for thecrucialroleofcollagenwasprovidedbystudiesdemonstratinga significant increase in the levelsofMMP-1(butnotgeneralMMPactivityor specificactivityofMMP-3),and in the levelsofthecollagendegradationproducthydroxyprolineinsynovialfluidfromhorseswithOccomparedtoOc-freeanimals.163-165Additionally, differences in posttranslational modifications ofcollagentypeiihavebeendemonstratedinsamplesfromearlylesions.166 serum levels of the collagen degradation markercoll2-1 were lower in Oc-affected horses, and levels of thenitratedformcoll2-1nO2werehigher.thesefindingspointtosomedegreeat an inflammatory stateandat the retentionofcartilage, rather than at accelerated breakdown.167 Also theinflammatory marker myeloperoxidase (MPO) was higher inserumfromhorsessufferingfromOc,comparedtoage-matchedcontrols.168however,thesubjectsofbothstudieswere(young)mature animals in which only secondary processes could beexpected to occur. in a study on synovial fluid markersinanothergroupofmaturehorses,anindicationfortheexis-tenceoflow-gradeinflammationwasalsofoundintheelevatedleukotriene B4 (LtB4) level, which was putatively associatedwith the occurrence of joint distention.169 Overall, there nowseems to be conclusive evidence that changes in collagenmetabolism play a crucial role in the molecular mechanismof Oc. the question of whether this is a secondary or aprimary event remains unanswered. there is also low-grade


intheMcPandMtPjoints,thereissomeconfusionabouttheextenttowhichradiographicallydetectablelesionsarepartoftheOccomplex.Fragmentsofthedorsalaspectofthedistalmetacarpusandmetatarsusarecommonlyacceptedtobeosteo-chondrotic,andinthese,57%successhasbeenreportedaftersurgery.thisfigureisnegativelybiasedbecause18%ofthecaseswereclassifiedasunsuccessfulforotherreasonsthatmadethehorseunsuitableforuse.188Amorerecentsourcementions90%return to athletic activity if the lesion is located in the moreproximalpartofthesagittalridgebutanunspecifiedlowerrateforlesionsinweight-bearingareas.189

Prognosis for arthroscopic removal of osteochondral frag-mentsofthedorsalarticularmarginoftheproximalphalanx,ofwhichtheosteochondroticnatureisstillcontentious,isgivenasnearly100%.188

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SurgicalManagementsurgical management is the treatment of choice in mostcases.180,181 clinical experience has taught that arthroscopicsurgery presents definite advantages over arthrotomy.182 soft-tissue trauma is less, the convalescent period is considerablyshorter, and functional and cosmetic recovery are better. Anadditional advantage is that a more comprehensive examina-tionofthejointispossible.6Adirectcomparisonofarthroscopictreatmentandtreatmentbyarthrotomydemonstratedthathos-pitalizationtimewasalmostfivetimesshorterafterarthroscopythanafterarthrotomy.evenmoreimportantly,horsesreturnedsignificantlymoreoftentotheirintendeduse.182

ArthroscopicsurgeryiswidelyusedintheFP,tc,McP,andMtP joints to treat Oc. in some other joints where Oc isencountered less often but can present a serious clinicalproblem, such as the scapulohumeral joint, an arthroscopicapproachisfeasibleaswell,butthetechniqueisconsiderablymore difficult.25,183 the surgical techniques applied are dis-cussedinmoredetailinchapter13andintherelevantchaptersdiscussingtherespectivejoints.

PROGNOSISthe prognosis after surgical intervention varies among jointsanddependsontheamountandextentofthelesion.itfurtherdepends on the definition of “favorable outcome.” in mostracingthoroughbredsandstandardbreds,afavorableoutcomemeansasoundhorsethatcancompeteatitsmaximalathleticcapacity. in many show horses, the cosmetic appearance isimportantaswell.ingeneral,prognosisforareturntoathleticactivityisfairtogoodforthemajorityofjointsinvolved.

FortheFPjoint,a64%successratewasreported,184butthisfigure might be too pessimistic because the study includedmanyhorsesoperatedonatayoungagebeforetheirfirstper-formance.thereforeitincludedanumberofhorsesthatwouldneverhaveraceddespitetheOclesionsbecauseattritionratesinthoroughbredtrainingarehighandmanyyounghorseswillneverrace.Jockeyclubrecordsindicatethatonlyabout60%ofall thoroughbreds intended for racing ever reach the startinggateintheUnitedstates.

in another study, 19 of 25 arthroscopically treated horses(76%)wereabletoperformtheir intendeduse.182racingper-formanceinthoroughbredstreatedforFPOcwasnotdifferentfrom that in unaffected siblings, but fewer horses raced as2-year-olds and earnings were less, both at 2 and 3 years ofage.185Also,2-year-oldthoroughbredsandstandardbredsthatwereoperatedonforOcinthetcjointwerelesslikelytorace,comparedtounaffectedsiblingsat2yearsofage,butfindingswerenotdifferentbetweengroupsat3yearsofage.186thedif-ferences might be mainly the result of the delay in trainingcausedbythesurgery.

Onegroup reported success ratesof73%and83% for thetc joint in racehorsesandnon-racehorses, respectively.syno-vial effusion resolved in89%of racehorsesand74%ofnon-racehorses.19Oftheotherjoints,prognosisisleastfavorableintheshoulderjoint,with46%successreported.25inonestudyafavorableoutcomeofonly15%wasfoundinracehorsessuffer-ing from shoulder Oc, regardless of whether treatment wassurgical or nonsurgical,187 emphasizing the poor prognosis ofshoulder Oc in animals that have to perform strenuousexercise.


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Equine Surgery || Osteochondrosis