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激素使用對股骨頭骨壞死發(fā)生和進(jìn)展的影響:一項(xiàng)全國性巢式病例對照研究（2024）激素使用對股骨頭骨壞死發(fā)生和進(jìn)展的影響:一項(xiàng)全國性巢式病例對照研究（2024）EffectofCorticosteroidUseontheOccurrenceandProgressionofOsteonecrosisoftheFemoralHead:ANationwideNestedCase-ControlStudy?KwonHM,HanM,LeeTS,JungI,SongJJ,YangHM,LeeJ,LeeSH,LeeYH,ParkKK.EffectofCorticosteroidUseontheOccurrenceandProgressionofOsteonecrosisoftheFemoralHead:ANationwideNestedCase-ControlStudy[J].JArthroplasty,2024轉(zhuǎn)載文章的原鏈接1：https://pubmed.ncbi.nlm.nih.gov/38830431/轉(zhuǎn)載文章的原鏈接2：https://www-clinicalkey-com-443.vpnm.ccmu.edu.cn/#!/content/journal/1-s2.0-S0883540324004595?AbstractBackgroundAlthoughitisverywellknownthatcorticosteroidscauseosteonecrosisofthefemoralhead(ONFH),itisunclearastowhichpatientsdevelopONFH.Additionally,therearenostudiesontheassociationbetweencorticosteroiduseandfemoralheadcollapseinONFHpatients.WeaimedtoinvestigatetheassociationbetweencorticosteroiduseandtheriskofONFHamongthegeneralpopulationandwhatfactorsaffectONFHoccurrence.Additionally,weaimedtodemonstratewhichfactorsaffectfemoralheadcollapseandtotalhiparthroplasty(THA)afterONFHoccurrence.雖然眾所周知，皮質(zhì)類固醇會導(dǎo)致股骨頭骨壞死(ONFH)，但目前尚不清楚哪些患者會發(fā)生ONFH。此外，沒有關(guān)于皮質(zhì)類固醇使用與ONFH患者股骨頭塌陷之間關(guān)系的研究。我們的目的是調(diào)查普通人群中皮質(zhì)類固醇使用與ONFH風(fēng)險(xiǎn)之間的關(guān)系，以及影響ONFH發(fā)生的因素。此外，我們旨在證明哪些因素影響ONFH發(fā)生后股骨頭塌陷和全髖關(guān)節(jié)置換術(shù)(THA)。?MethodsAnationwide,nestedcase-controlstudywasconductedwithdatafromtheNationalHealthInsuranceServicePhysicalHealthExaminationCohort(2002to2019)intheRepublicofKorea.WedefinedONFH(N=3,500)usingdiagnosisandtreatmentcodes.PatientswhohadONFHwerematched1:5toformacontrolgroupbasedonthevariablesofbirthyear,sex,andfollow-upduration.Additionally,inpatientswhohaveONFH,welookedforriskfactorsforprogressiontoTHA.使用韓國國民健康保險(xiǎn)服務(wù)機(jī)構(gòu)身體健康檢查隊(duì)列(2002年至2019年)的數(shù)據(jù)進(jìn)行了一項(xiàng)全國性的巢式病例對照研究。我們使用診斷和治療代碼定義ONFH(N=3,500)。根據(jù)出生年份、性別、隨訪時(shí)間等變量對ONFH患者進(jìn)行1:5匹配，形成對照組。此外，在患有ONFH的患者中，我們尋找進(jìn)展為THA的危險(xiǎn)因素。?ResultsComparedwiththecontrolgroup,ONFHpatientshadalowhouseholdincomeandhadmorediabetes,hypertension,dyslipidemia,andheavyalcoholuse(drinkingmorethan3to7drinksperweek).Systemiccorticosteroiduse(≥1,800mg)wassignificantlyassociatedwithanincreasedriskofONFHincidence.However,lipidprofiles,corticosteroidprescription,andcumulativedosesofcorticosteroiddidnotaffecttheprogressiontoTHA.與對照組相比，ONFH患者家庭收入較低，糖尿病、高血壓、血脂異常和重度飲酒(每周飲酒超過3至7天)的發(fā)生率更高。全身使用皮質(zhì)類固醇(≥1800mg)與ONFH發(fā)生率增加顯著相關(guān)。然而，脂質(zhì)譜、皮質(zhì)類固醇處方和皮質(zhì)類固醇累積劑量對進(jìn)展到THA沒有影響。?ConclusionsTheONFHriskincreasedrapidlywhencumulativeprednisoloneusewas≥1,800mg.However,oralorhigh-doseintravenouscorticosteroiduseandcumulativedosedidnotaffecttheprognosisofONFH.SincetheoccurrenceandprognosisofONFHarecomplexandmultifactorialprocesses,furtherstudyisneeded.當(dāng)累積使用潑尼松龍≥1800mg時(shí)，ONFH風(fēng)險(xiǎn)迅速增加。然而，口服或大劑量靜脈注射皮質(zhì)類固醇和累積劑量不影響股骨頭壞死的預(yù)后。由于股骨頭壞死的發(fā)生和預(yù)后是一個(gè)復(fù)雜的多因素過程，需要進(jìn)一步研究。?Osteonecrosisofthefemoralhead(ONFH)maycauseseverehippain,andcanultimatelyleadtocollapseofthefemoralheadandsubsequentrapiddestructionofthehipjointinrelativelyyoungpatients[1-3].Intractablepaincausedbyfemoralheadcollapseeventuallyleadstototalhiparthroplasty(THA)atayoungage[4,5].Althoughtrauma,theuseofcorticosteroid,andexcessivealcoholintakearewell-knownriskfactorsforONFH,theetiologyofONFHremainsmultifactorial,andnoconsensusexistsonthecommonpathophysiology[6-9].Impairedperfusionofbloodtobone,abnormalcellularreparativeprocesses,andgeneticpointmutationsarepresumedtoaffectONFHoccurrence,butithasnotyetbeenclarified[10-12].股骨頭壞死(Osteonecrosisoffemoralhead,ONFH)可引起嚴(yán)重的髖關(guān)節(jié)疼痛，在相對年輕的患者中，最終可導(dǎo)致股骨頭塌陷并隨后迅速破壞髖關(guān)節(jié)[1-3]。股骨頭塌陷引起的頑固性疼痛最終導(dǎo)致在年輕時(shí)進(jìn)行全髖關(guān)節(jié)置換術(shù)(THA)[4,5]。雖然創(chuàng)傷、皮質(zhì)類固醇的使用和過量飲酒是眾所周知的ONFH的危險(xiǎn)因素，但ONFH的病因仍然是多因素的，對共同的病理生理尚未達(dá)成共識[6-9]。據(jù)推測，骨血流灌注受損、細(xì)胞修復(fù)過程異常以及基因點(diǎn)突變可能影響ONFH的發(fā)生，但尚未明確[10-12]。AlthoughitisverywellknownthatcorticosteroidscauseONFH,itisunclearastowhichpatientsdevelopONFH.Thereareseveralstudiesreportingthathigh-dosecorticosteroiduseof2grams(g)ormorewithin3monthsisassociatedwithONFHdevelopment[8,13-15].However,thesewerestudieswitharelativelysmallnumberofpatients,andthereareheterogeneitiesinpatientdemographicsandepidemiologicvariabilities.OnceONFHoccurs,theprognosisisknowntobepoor,andtherearestudiesstatingthatfemoralheadcollapseprogressesfromabout24.6to42.8%withnaturalevolutionwithin2years[16,17].Inparticular,whenfemoralheadcollapseoccurs,manypatientsoftenreceiveTHAatayoungage,sopredictingtheprognosisforfemoralheadcollapseisasimportantaspredictingtheoccurrenceofONFH.SeveralstudieshavedemonstratedthatfemoralheadcollapseinONFHpatientsisassociatedwithsize,volume,locationofnecroticlesions,andanatomicalparameters[1,2,18,19].However,therearenostudiesontheassociationbetweencorticosteroiduseandfemoralheadcollapseinONFHpatients.雖然眾所周知，皮質(zhì)類固醇會引起ONFH，但尚不清楚哪些患者會發(fā)生ONFH。有幾項(xiàng)研究報(bào)道，在3個(gè)月內(nèi)使用2克或更多的高劑量皮質(zhì)類固醇與ONFH的發(fā)生有關(guān)[8,13-15]。然而，這些研究的患者數(shù)量相對較少，并且在患者人口統(tǒng)計(jì)學(xué)和流行病學(xué)變異方面存在異質(zhì)性。一旦發(fā)生ONFH，預(yù)后很差，有研究表明股骨頭塌陷在2年內(nèi)自然演化，從24.6%發(fā)展到42.8%[16,17]。特別是股骨頭塌陷發(fā)生時(shí)，許多患者往往在年輕時(shí)接受THA，因此預(yù)測股骨頭塌陷的預(yù)后與預(yù)測ONFH的發(fā)生同樣重要。多項(xiàng)研究表明，ONFH患者股骨頭塌陷與壞死灶的大小、體積、位置和解剖學(xué)參數(shù)有關(guān)[1,2,18,19]。然而，目前還沒有關(guān)于ONFH患者使用皮質(zhì)類固醇與股骨頭塌陷之間關(guān)系的研究。TheNationalHealthInsuranceService(NHIS)ofSouthKoreaisanationalinsurancecoverageservicethatcoversabout97%ofcitizensinSouthKorea,includingdemographicdataandaclaimdatabaseincludingdiagnosesandprescriptions[20].Additionally,theNHISoffershealthscreeningexaminationsforinsuredKoreansaged40yearsorolder,includingbasicbloodtests,smoking,drinking,andphysicalactivitiesusingself-reportedquestionnaires.BecausetheNationalHealthInsuranceService–NationalSampleCohort(NHIS-NSC)isahighlyrepresentativepopulation-basedcohortoftheentireKoreanpopulation,itcanbeusedasapopulation-based,nationwidestudyforepidemiologicresearchonvariousdiseases[20-22].韓國國民健康保險(xiǎn)服務(wù)(NationalHealthInsuranceService,NHIS)是一項(xiàng)覆蓋韓國約97%公民的國民保險(xiǎn)服務(wù)，包括人口統(tǒng)計(jì)數(shù)據(jù)和包括診斷和處方在內(nèi)的索賠數(shù)據(jù)庫[20]。此外，國民健康保險(xiǎn)制度還為40歲或40歲以上的參保韓國人提供健康檢查，包括基本的血液檢查、吸煙、飲酒和使用自我報(bào)告問卷的體育活動。由于國民健康保險(xiǎn)服務(wù)-國民樣本隊(duì)列(NationalHealthInsuranceService-NationalSampleCohort,NHIS-NSC)是韓國人口中極具代表性的基于人群的隊(duì)列，因此可以作為一項(xiàng)基于人群的全國性研究，用于各種疾病的流行病學(xué)研究[20-22]。Therefore,inthepresentstudy,weaimedtoinvestigatetheassociationbetweencorticosteroiduseandtheriskofONFHdevelopmentamongthewholegeneralpopulationandwhatfactorsaffectONFHdevelopmentusinganationwidelargesamplefromlongitudinalnestedcase-controldatainalong-termcohortstudy.Inaddition,weaimedtodemonstratewhichfactorsaffectTHAafterthedevelopmentofONFH.因此，在本研究中，我們旨在通過一項(xiàng)長期隊(duì)列研究，在全國范圍內(nèi)采用縱向嵌套病例對照數(shù)據(jù)的大樣本，調(diào)查皮質(zhì)類固醇使用與整個(gè)普通人群中ONFH發(fā)生風(fēng)險(xiǎn)之間的關(guān)系，以及影響ONFH發(fā)生的因素。此外，我們旨在證明哪些因素會影響ONFH發(fā)展后的THA。?MaterialsandMethodsStudyPopulationWeuseda2002to2019datasetfromtheNHISPhysicalHealthExaminationCohort(NHIS-NSC)2.0databaseintheRepublicofKorea[23].TheNHIS-NSC2.0databasewascomprisedofatotalof1,137,861participantswhowerestratifiedandrandomlysampledsuchthattheage,sex,region,healthinsurancetype,andhouseholdincomesofthesamplesremainedproportionaltothoseofthe2006Koreanpopulationof50million.Weexcluded223,474participantswhowerealreadyprescribedintravenous(IV)ororalcorticosteroidstoreducethebiasintheanalysisoftheeffectoftheprescribedcorticosteroiddoseonONFH.Fromtheremainingcohort,weexcluded241participantswhowerealreadydiagnosedwithONFHin2002toobtainthenewdevelopmentofONFH(washoutperiod).Therefore,theindexdatewasthedatethatthepatientwasdiagnosedwithONFH.Weincluded914,146participantsinthefinalanalysis.Theinformationinthedatasetincludedallinpatientandoutpatientmedicalclaimsdata,includingprescriptiondruguse,diagnosticandtreatmentcodes,primaryandsecondarydiagnosticcodes,andhealthexaminationdata.AlltheindividualsincludedintheNHIS-NSCwerefolloweduntil2019,unlesstherewasadeathordisqualificationforNationalHealthInsurance,suchasemigration.TheprotocolofthisstudywasapprovedbytheInstitutionalReviewBoardofourinstitution(4-2022-0304)andtheNHIS(NHIS-2022-2-232).我們使用了2002年至2019年的數(shù)據(jù)集，這些數(shù)據(jù)集來自韓國NHIS身體健康檢查隊(duì)列(NHIS-nsc)2.0數(shù)據(jù)庫[23]。國民健康保險(xiǎn)制度-國家安全保障制度2.0數(shù)據(jù)庫共包括1137861名參與者，這些參與者的年齡、性別、地區(qū)、健康保險(xiǎn)類型和家庭收入與2006年韓國5000萬人口的比例保持一致，并進(jìn)行了分層和隨機(jī)抽樣。我們排除了223,474名已經(jīng)靜脈注射或口服皮質(zhì)類固醇的參與者，以減少處方皮質(zhì)類固醇劑量對ONFH影響分析的偏倚。從剩余隊(duì)列中，我們排除了241名在2002年已經(jīng)診斷為ONFH的參與者，以獲得ONFH的新進(jìn)展(洗脫期)。因此，索引日期為患者被診斷為ONFH的日期。我們在最終分析中納入了914146名參與者。數(shù)據(jù)集中的信息包括所有住院和門診醫(yī)療索賠數(shù)據(jù)，包括處方藥使用、診斷和治療代碼、初級和二級診斷代碼以及健康檢查數(shù)據(jù)。納入國家健康保險(xiǎn)制度-國家安全保障制度的所有個(gè)人都被跟蹤到2019年，除非死亡或喪失參加國家健康保險(xiǎn)的資格，例如移民。本研究的方案經(jīng)我院機(jī)構(gòu)審查委員會(4-2022-0304)和NHIS(NHIS-2022-2-232)批準(zhǔn)。?CaseandControlSelectionWeusedtheInternationalStatisticalClassificationofDiseasesandRelatedHealthProblems,10thRevision(ICD-10)toidentifycasepatients.WedefinedONFH(N=3,500)usingthediagnosticcodeandtreatmentcodeICD-10codesforosteonecrosisofthefemur(SupplementaryTable1).Toavoidlengthbias,anestedcase-controlanalysiswasdesignedtoinvestigatetheeffectoftheprescribedcorticosteroiddoseonONFH.PatientswhohadONFHwerematched1:5toformacontrolgroupbasedonthevariablesofbirthyear,sex,andfollow-upduration.Identicalexclusioncriteriawereappliedtothecontrolgroup(N=12).Finally,casepatients(N=3,488)andcontrolpatients(N=17,440)werematchedbasedonsexandageattheindexdateandcompared(Figure1).我們使用國際疾病和相關(guān)健康問題統(tǒng)計(jì)分類第十次修訂版(ICD-10)來確定病例患者。我們使用股骨骨壞死的診斷代碼和治療代碼ICD-10來定義ONFH(N=3,500)(補(bǔ)充表1)。為避免長度偏倚，設(shè)計(jì)了巢式病例對照分析，以調(diào)查處方皮質(zhì)類固醇劑量對ONFH的影響。根據(jù)出生年份、性別、隨訪時(shí)間等變量對ONFH患者進(jìn)行1:5匹配，形成對照組。對照組(N=12)采用相同的排除標(biāo)準(zhǔn)。最后，根據(jù)索引日期的性別和年齡對病例患者(N=3,488)和對照患者(N=17,440)進(jìn)行匹配和比較(圖1)。??Fig.1Studyflow:selectionofparticipantsofcasesandmatchedcontrolsONFH,osteonecrosisoffemoralhead.??DefinitionofParametersFromthehealthexaminations,participantswereclassifiedinto4groupsbasedonthebodymassindex(BMI)accordingtotheWorldHealthOrganizationWesternPacificRegionguidelineandtheKoreanpracticalguidelineasfollows:low(<18.5),normal(18.5to23),overweight(23to25),andobese(>25).UnderlyingcomorbiditiesweredefinedbyatleastoneadmissionoroutpatienttreatmentupontheprimaryorfirstsecondarydiagnosisusingtheICD-10codeforthepastyear(hypertension:I10-I15,diabetesmellitus:E10-E14,dyslipidemia:E78).Thefrequencyofdrinkingalcoholwascategorizedas“non-alcoholuse”(drinkinglessthan1drinkperweek),“mildalcoholuse”(drinking1to2drinksperweek),or“heavyalcoholuse”(drinkingmorethan3to7drinksperweek).Smokingstatuswascategorizedasnonsmoker,pastsmoker,orcurrentsmoker.Afterovernightfasting,bloodsampleswereobtained,andserumhigh-densitylipoproteincholesterol,low-densitylipoprotein(LDL)cholesterol,andtriglyceride(TG)resultscouldbeobtained.根據(jù)健康檢查結(jié)果，根據(jù)世界衛(wèi)生組織西太平洋地區(qū)指南和韓國實(shí)踐指南，將參與者的身體質(zhì)量指數(shù)(BMI)分為4組:低(<18.5)、正常(18.5~23)、超重(23~25)和肥胖(>25)。潛在的合并癥是在過去一年中使用ICD-10代碼進(jìn)行原發(fā)性或首次繼發(fā)性診斷時(shí)至少進(jìn)行一次住院或門診治療(高血壓:I10-I15，糖尿病:E10-E14，血脂異常:E78)。飲酒頻率分為“不飲酒”(每周飲酒少于1杯)、“輕度飲酒”(每周飲酒1至2杯)或“重度飲酒”(每周飲酒超過3至7杯)。吸煙狀況分為不吸煙者、過去吸煙者和現(xiàn)在吸煙者。禁食過夜后采集血樣，得到血清高密度脂蛋白膽固醇、低密度脂蛋白膽固醇和甘油三酯(TG)結(jié)果。?SystemicCorticosteroidPrescriptionWedefinedsystemiccorticosteroidprescriptionsasoralcorticosteroidprescriptionsandIVcorticosteroidprescription.Systemiccorticosteroidusewasdefinedastheprescriptionofmedicationcodesduringadmissionsandoutpatientvisitsfrom2003totheindexdate(Table1).Bothgroupshadidenticalobservationperiods.Allcorticosteroidformulationswereconvertedintoadailydosebasedonprednisoneequivalentdoses[24](1mgprednisolone=4mghydrocortisone=0.8mgmethylprednisolone=0.8mgtriamcinolone=0.16mgbetamethasone=1.2mgdeflazacort),andwecalculatedcumulativedosesofexposureforcorticosteroidswiththesumofthedosesforalltheprescribeddays,whichwasexpressedasthecumulativedefineddailydose(cDDD)accordingtotheWorldHealthOrganizationdefinition.我們將系統(tǒng)性糖皮質(zhì)激素處方定義為口服糖皮質(zhì)激素處方和靜脈糖皮質(zhì)激素處方。系統(tǒng)性糖皮質(zhì)激素使用定義為從2003年到基線日期（見表1）的住院和門診就診期間的藥物代碼處方。兩組觀察期相同。將所有糖皮質(zhì)激素制劑轉(zhuǎn)換為基于潑尼松等效劑量（1毫克潑尼松龍等于4毫克氫化可的松等于0.8毫克甲基潑尼松龍等于0.8毫克曲安奈德等于0.16毫克倍他米松等于1.2毫克德夫氯喹）的每日劑量，并根據(jù)世界衛(wèi)生組織的定義計(jì)算糖皮質(zhì)激素的累積暴露劑量（累積定義每日劑量，cDDD），即將所有處方天數(shù)的劑量相加。?Table1PrescriptionDrugCodesandDosageofSystemicCorticosteroidBasedontheHealthInsuranceClaimsPaymentCodingSystem.Drug???????Code??????CorticosteroidandDosageOralcorticosteroids116401ATB???betamethasone0.5mg116501ATB???betamethasonesodiumphosphate0.5mg296900ATB???betamethasone0.25mg140801ATB???deflazacort6mg140802ATB???deflazacort30mg141901ATB???dexamethasone0.5mg141903ATB???dexamethasone0.75mg141904ATB???dexamethasone4mg170901ATB???hydrocortisone10mg170905ATB???hydrocortisone20mg170906ATB???hydrocortisone5mg193301ATB???methylprednisolone16mg193302ATB???methylprednisolone4mg193303ATB???methylprednisolone8mg193304ATB???methylprednisolone2mg193305ATB???methylprednisolone1mg217001ATB???prednisolone5mg243201ATB???triamcinolone1mg243202ATB???triamcinolone2mg243203ATB???triamcinolone4mgHigh-doseIVcorticosteroids?171201BIJ???????hydrocortisonesodiumsuccinate100mg171202BIJ?????hydrocortisonesodiumsuccinate250mg171203BIJ?????hydrocortisonesodiumsuccinate40mg193601BIJ?????methylprednisolonesodiumsuccinate125mg193602BIJ?????methylprednisolonesodiumsuccinate250mg193603BIJ?????methylprednisolonesodiumsuccinate40mgmethylprednisolonesodiumsuccinate500mg193604BIJ?????methylprednisolonesodiumsuccinate1000mg193605BIJ?????prednisolonesodiumsuccinate1000mg217301BIJ?????prednisolonesodiumsuccinate250mg217302BIJ???????SubgroupAnalysisATHAafteranONFHdiagnosiswasusedasasurrogateforfemoralheadcollapse.Therefore,wedividedallcasesinto2groups:agroupthatreceivedTHAandanothergroupthatdidnotreceiveTHAusingtreatmentcodes(N0711.N7020).Amongatotalof3,430patients,weexcluded70patientswhohadaTHAtreatmentcodepriortodiagnosis,1,175patientswhoreceivedTHAduringtheobservationperiod,and2,255patientswhodidnot.Wecomparedthe2groupsandanalyzedthemusingtheCoxproportionalhazardsmodel,whichfactorsaffectdiseaseprogressionleadingtoTHA(Figure2).診斷為ONFH后進(jìn)行THA作為股骨頭塌陷的替代。因此，我們使用治療代碼(N0711)將所有病例分為兩組:接受THA治療的組和未接受THA治療的組。N7020)。在總共3430例患者中，我們排除了70例在診斷前有THA治療代碼的患者，1175例在觀察期間接受THA治療的患者和2255例未接受THA治療的患者。我們對兩組患者進(jìn)行比較，并使用Cox比例風(fēng)險(xiǎn)模型進(jìn)行分析，分析影響THA病情進(jìn)展的因素(圖2)。??Fig.2Studyflow:comparisonofpatientswhoreceivedanddidnotreceivetotalhiparthroplastyafterdiagnosisONFH,osteonecrosisoffemoralhead;THA,totalhiparthroplasty.??DataAnalysisChi-squaredtestsforcategoricalvariableswereperformedtocomparethebaselinecharacteristicsbetweencaseandcontrolpatients.AconditionallogisticregressionanalysiswasperformedtoevaluatetheassociationbetweensystemiccorticosteroiduseandtheriskofONFH.Forsubgroupanalysis,weusedCoxproportionalhazardmodelstoestimateadjustedhazardratios(aHRs)and95%confidenceintervals(CIs).APvalue<.05wasconsideredsignificant.AllstatisticalanalyseswereperformedusingSASEnterpriseGuideversion7.1(SASInstitute,Cary,NorthCarolina).?ResultsDemographicDataforONFHCasesandMatchedControlsTable2showsthebaselinecharacteristicsofcasesandmatchedcontrols.The2groupshadevendistributionsinthematchingvariables,includingsexandbirthyear.Subjectswerepredominantlymen(61.1%),andthemostcommonagegroupwasthoseborninthe1950s(age63to72asof2022).Comparedwiththecontrolgroup,ONFHcasepatientshadlowhouseholdincomeandhadmorediabetes,hypertension,dyslipidemia,andheavyalcoholuse(drinkingmorethan3to7drinksperweek).Inaddition,thecasepatientshadnormalserumLDLlevels(<100mg/dL),butconversely,thereweremanycasesofhypertriglyceridemiawithserumTGlevelsof200mg/dLormore.??Table2BaselineCharacteristicofOsteonecrosisofFemoralHeadCasesandMatchedControls.totalN=20,928(%)?????CasesN=3,488(%)ControlsN=17,440(%)?????PSex????????????????????????Men12,792(61.1)?2,132(61.1)???10,660(61.1)?Women???8,136(38.9)???1,356(38.9)???6,780(38.9)???????Birthyear??????????????????????????????<1930????852(4.1)142(4.1)710(4.1)1930to1939?3,024(14.4)???504(14.4)??????2,520(14.4)?????1940to1949?4,074(19.5)???679(19.5)??????3,395(19.5)?????1950to1959?5,112(24.4)???852(24.4)??????4,260(24.4)?????1960to1969?3,786(18.1)???631(18.1)??????3,155(18.1)?????1970to1979?2,184(10.4)???364(10.4)??????1,820(10.4)?????1980to1989?1,080(5.2)?????180(5.2)900(5.2)1990to1999?558(2.7)93(2.7)??465(2.7)2000to2009?210(1.0)35(1.0)??175(1.0)2010to2019?48(0.2)??8(0.2)????40(0.2)??Age(atindexdate)55.2±16.9????55.2±16.9???????55.2±16.9????Householdincome????????????????????????Low4,535(21.7)???896(25.7)??????3,639(20.9)???????<.001Middle???6,500(31.0)???1,090(31.2)???5,410(31.0)???????High???????9,893(26.5)???1,502(43.1)???8,391(48.1)???????Comorbidities????????????????????????Hypertension?6,631(31.7)???1,301(37.3)???5,330(30.6)?????<.001Diabetesmellitus???4,567(21.8)???908(26.0)???????3,659(21.0)???<.001Dyslipidemia??5,555(26.5)???1,120(32.1)???4,435(25.4)?????<.001Frequencyofdrinkingalcohol??????????????????????????????<1d/wk??10,044(48.0)?1,613(46.2)???8,431(48.3)???????<.0011to2d/wk?????3,987(19.1)???560(16.1)??????3,427(19.7)?????3to7d/wk?????2,794(13.3)???621(17.8)??????2,173(12.5)?????Missing??4,103(19.6)???694(19.9)??????3,409(19.5)???????Smokingstatus?????????????????????????????Non-smoker???9,455(45.2)???1,539(44.1)???7,916(45.4)?????.199Ex-smoker?????2,865(13.7)???462(13.3)??????2,403(13.8)?????Currentsmoker??????4,488(21.4)???790(22.6)???????3,698(21.2)???Missing??4,120(19.7)???697(20.0)??????3,423(19.6)???????BMI,kg/m2??24.0±3.3??????23.9±3.4??????24.0±3.3??.547<18·5?????608(2.9)113(3.2)495(2.8).09018·5to22·9???6,126(29.3)???1,029(29.5)???5,097(29.2)?????23·0to24·9???4,239(20.3)???651(18.7)??????3,588(20.6)?????≥25·0?6,113(29.2)???1,049(30.1)???5,064(29.0)???????Missing??3,842(25.1)???646(18.5)??????3,196(18.3)???????HDL,mg/dL??54.2±20.5????55.2±22.7????54.0±20.0.015<40?2,113(10.1)???339(9.7)1,774(10.2%).03340to59??8,856(42.3)???1,411(40.5)???7,445(42.7%)??≥60???????4,700(22.5)???830(23.8)????3870(22.2%)???????Missing??5,259(25.1)???908(26.0)??????4,351(24.9%)??LDL,mg/dL???114.8±77.2??110.6±56.9??115.7±80.6<.001<100??????5,627(26.9)???1,045(30.0)???4,582(26.3)???????<.001100to159?????8,493(40.6)???1,297(37.2)???7,196(41.3)?????≥160?????1,528(7.3)?????234(6.7)1,294(7.4)?????Missing??5,280(25.2)???912(26.1)??????4,368(25.0)???????TG,mg/dL?????144.5±108.7154.8±125.0142.5±105.1??????<.001<150??????10,395(49.7)?1,651(47.3)???8,744(50.1)???????<.001150to199?????2,447(11.7)???390(11.2)??????2,057(11.8)?????≥200?????2,829(13.5)???540(15.5)??????2,289(13.1)???????Missing??5,257(25.1)???907(26.0)??????4,350(24.9)???????BMI,bodymassindex;HDL,highdensitylipoprotein;LDL,lowdensitylipoprotein;TG,triglyceride.??Table3showsthecomparisonofprescribedsystemiccorticosteroidsincasepatientsandcontrolpatients.Bothgroupshadidenticalobservationperiods(meanobservationperiodwas8.26years).Systemiccorticosteroidwasprescribedatleastoncemoreinthecasegroupthaninthecontrolgroup(71.8versus62.9%,P<.001).EvenwhenoralcorticosteroidsandIVcorticosteroidswerecompared,respectively,thenumberofcasesprescribedcorticosteroidsatleastoncewashigherinthepatientswhohadONFH(oralcorticosteroids:71.2versus62.4%,P<.001/IVcorticosteroids:10.7versus4.9%,P<.001).??Table3DifferenceinCorticosteroidUseBetweenCasesandMatchedControlsFrom2003UntilDiagnosis.TotalN=20,928(%)?????CasesN=3,488(%)ControlsN=17,440(%)?????PCorticosteroid(oralorhigh-doseIV)???????????????????????????Neveruse???????7,453(35.6)???983(28.2)??????6,470(37.1)?????<.001Everuse?13,475(64.4)?2,505(71.8)?10,970(62.9)???????Oralcorticosteroid????????????????????????Neveruse???????7,562(36.1)???1,004(18.8)???6,558(37.6)?????<.001Everuse?13,366(63.9)?2,484(71.2)?10,882(62.4)???????Neveruse???????7,562(36.1)???1,004(18.8)???6,558(37.6)?????<.001<180cDDDs??12,667(60.5)?2,192(62.8)???10,475(60.1)?????180to364cDDDs?397(1.9)146(4.2)251(1.4)365to729cDDDs?179(0.9)84(2.4)??95(0.5)??≥730cDDDs123(0.6)62(1.8)??61(0.4)??High-doseIVcorticosteroid??????????????????????????Neveruse???????19,703(94.2)?3,116(89.3)???16,587(95.1)?????<.001Everuse?1,225(5.8)?????372(10.7)??????853(4.9)Neveruse???????19,703(94.2)?3,116(89.3)???16,587(95.1)?????<.001<180cDDDs??988(4.7)266(7.6)722(4.1)180to364cDDDs?120(0.6)46(1.3)??74(0.4)??365to729cDDDs?77(0.4)??40(1.2)??37(0.2)??≥730cDDDs40(0.2)??20(0.6)??20(0.1)??cDDDs,cumulativedefineddailydoses(prednisolone10mg);IV,intravenous.??CumulativeCorticosteroidDoseandONFHDevelopmentConditionallogisticregressionanalysiswasperformedtoanalyzetheeffectofthecumulativedoseofsystemiccorticosteroidsfor1yearbeforediagnosisontheincidenceofONFH(Table4).SystemiccorticosteroidusewassignificantlyassociatedwithanincreasedriskofONFHincidencecomparedtothatofnonusers.Specifically,higherdosesoforalcorticosteroidwereassociatedwithincreasedriskofONFH(oddsratiosof1.61(95%CI1.47to1.78,P<.001),4.39(95%CI3.47to5.56,P<.001),6.42(95%CI4.65to8.87,P<.001),and5.44(95%CI3.65to8.13,P<.001)forpatientswhohavecorticosteroiduseof<180,180to365,365to720,and>720cDDDs(valuesconvertedtodailyprednisolone10mg),respectively.TheriskofONFHincreasedrapidlywhenthecDDDwas180ormore,thatis,whencumulativeprednisoloneusewas1,800mgormore.Inaddition,atrendtowardriskincreasewithcumulativedosesofIVcorticosteroidusewasshownwithadjustedoddsratio(AOR)of1.63(95%CI1.39to1.90,P<.001),2.34(95%CI1.57to3.49,P<.001),3.77(95%CI2.33to6.10,P<.001),and2.76(95%CI1.41to5.39,P=.003)forpatientswhohavecorticosteroiduseof<180,180to365,365to720,and>720cDDDs(valuesconvertedtodailyprednisolone10mg),respectively.??Table4AdjustedRiskofOsteonecrosisofFemoralHeadOccurrence.ConditionalLogisticRegressionAnalysisforONFHDevelopmentCrudeOR??????95%CI???P?????AdjustedOR??95%CI???????PHouseholdincome????????????????????????????????????????Low1.381.26to1.52???<.001?????1.381.25to1.51???????<.001Middle???1.131.03to1.23???.0071.131.03to1.23???????.008High???????1.00ref.?????????1.00ref.??Comorbidities???????????????????????????????????????Hypertension?1.471.35to1.60???<.001?????1.21???????1.06to1.37???.004Diabetesmellitus???1.381.26to1.51???<.001???????1.070.95to1.20???.289Dyslipidemia??1.471.35to1.60???<.001?????1.18???????1.04to1.34???.012Frequencyofdrinkingalcohol?????????????????????????????????????????????<1d/wk??1.00ref.?????????1.00ref.??1to2d/wk?????0.870.78to0.97???.0150.900.80to1.01.0713to7d/wk?????1.541.38to1.73???<.001?????1.54???????1.36to1.74???<.001Missing??1.080.97to1.20???.1801.120.59to2.14???????.731Smokingstatus?????????????????????????????????????????????Non–smoker??1.00ref.?????????1.00ref.??Ex–smoker?????1.010.89to1.15???.8670.930.82to1.07.314Currentsmoker??????1.131.01to1.26???.0321.01???????0.90to1.14???.855Missing??1.060.95to1.18???.2791.030.55to1.94???????.923BMI,kg/m2?????????????????????????????????????????<18·5?????1.130.91to1.41???.2621.150.92to1.44???????.23218·5to22·9???1.00ref.?????????1.00ref.??23·0to24·9???0.900.81to0.99???.0490.900.80to1.01.062≥25·0?1.020.93to1.13???.6280.990.89to1.09???????.784Missing??1.000.90to1.13???.9450.800.55to1.17???????.254HDL,mg/dL?????????????????????????????????????????<40?1.010.88to1.15???.9250.950.83to1.09???????.44740to59??1.00ref.?????????1.00ref.??≥60???????1.131.03to1.25???.0091.100.99to1.21???????.069Missing??1.121.01to1.23???.0312.910.14to60.46???????.490LDL,mg/dL??????????????????????????????????????????<100??????1.00ref.?????????1.00ref.??100to159?????0.790.72to0.86???<.001?????0.86???????0.78to0.94???.001≥160?????0.790.67to0.92???.0030.84071to0.98???????.031Missing??0.930.83to1.03???.1520.840.28to2.56???????.762TG,mg/dL????????????????????????????????????????????<150??????1.00ref.?????????1.00ref.??150to199?????1.010.89to1.14???.9170.990.88to1.13.970≥200?????1.261.13to1.40???<.001?????1.171.04to1.32.009Missing??1.121.01to1.23???.0250.460.03to7.70???????.585Medication????????????????????????????????????????????Steroid(oralorhigh–doseIV)?????????????????????????????????????????????Neveruse???????1.00ref.?????????1.00ref.??Everuse?1.751.59to1.92???<.001?????1.771.60to1.94<.001POsteroid?????????????????????????????????????????????Neveruse???????1.00ref.?????????1.00ref.??Everuse?1.731.57to1.90???<.001?????1.681.53to1.85<.001Neveruse???????1.00ref.?????????1.00ref.??<180cDDDs??1.631.49to1.79???<.001?????1.61???????1.47to1.78???<.001180to364cDDDs?4.983.96to6.25???<.001???????4.393.47to5.56???<.001365to729cDDDs?7.515.50to10.27?<.001???????6.424.65to8.87???<.001≥730cDDDs8.966.16to13.02?<.001?????5.44???????3.65to8.13???<.001High–doseIVsteroid????????????????????????????????????????????Neveruse???????1.00ref.?????????1.00ref.??Everuse?2.422.12to2.76???<.001?????2.201.92to2.51<.001Neveruse???????1.00ref.?????????1·00?????ref.??<180cDDDs??2.041.76to2.38???<.001?????1.63???????1.39to1.90???<.001180to364cDDDs?3.402.35to4.92???<.001???????2.341.57to3.49???<.001365to729cDDDs?5.863.74to9.18???<.001???????3.772.33to6.10???<.001≥730cDDDs5.232.81to9.73???<.001?????2.76???????1.41to5.39???.003BMI,bodymassindex;cDDDs,cumulativedefineddailydoses(prednisolone10mg);CI,confidenceinterval;HDL,highdensitylipoprotein;IV,intravenous;LDL,lowdensitylipoprotein;ONFH,osteonecrosisoffemoralhead;OR,oddsratio;PO,peroral;TG,triglyceride.??RiskFactorsforTHAinPatientswhoHaveONFHFortheONFHcasepatients,asubgroupanalysiswasperformedon1,175patientsintheTHAgroupand2,255patientsinthenon-THAgroupduringtheobservationperiod.Thefollow-updurationoftheTHAgroup(1,175patients)was1.03±2.25years,andthefollow-updurationofthenon-THAgroup(2,255patients)was7.93±5.15years.Table5showsthebaselinecharacteristicsofTHAcasesandnon-THAcases.IntheTHAgroup,therewasagreaterproportionofmen(63.9versus60.0%,P=.028),higherBMI(24.1versus23.8,P=.027),heavyalcoholuseofthosewhoconsumedalcoholmorethan3to7daysaweek(22.9versus15.2%,P<.001),currentsmokers(26.4versus20.8%,P<.001),andhigherTG(162.3mg/dLversus150.0,P≤.001).However,whentheeffectondiseaseprogressionwasanalyzedusingCoxproportionalhazardsmodelforsurvivalanalysisafterONFHdiagnosis,heavyalcoholuseandlongercorticosteroidusesweretheriskfactorsaffectingdiseaseprogression,anddiabeteswasafactorthatslowedprogression.Moreover,otherlipidprofilesaswellascorticosteroidsusedandcumulativedosesofcorticosteroidsdidnotaffecttheincidenceofTHA(Table6).Inaddition,whenthesurvivalanalysiswasperformedafterthediagnosisofONFHbydividingthepatientgroupintomalesandfemales,heavyalcoholuseinvolvingthosewhoconsumedalcoholmorethan3to7daysaweekincreasedtheriskofdiseaseprogressionafterONFHdiagnosisinmalesonly(aHR:1.38,95%CI1.16to1.65,P<.001),andaBMIof25orhigherinfemalesonlyincreasedtheriskofincidenceofTHAafterONFHdiagnosis(aHR:1.52,95%CI1.18to1.96,P<.001).??Table5Comparisonofthe2GroupsAccordingtoWhetherorNotTotalHipArthroplastywasPerformedDuringtheFollow-UpPeriodAfterOsteonecrosisofFemoralHeadDiagnosis.TotalN=3,430(%)??????THAafterDiagnosisN=1,175(%)?????NoTHAafterDiagnosisN=2,255(%)???????PSex????????????????????????Men2,104(61.3)???751(63.9)??????10,660(61.1)???????.028Women???1,326(38.7)???424(36.1)??????6,780(38.9)???????Birthyear??????????????????????????????<1930????141(4.1)16(1.4)??125(5.5)<.0011930to1939?492(14.3)??????153(13.0)??????339(15.0)?????1940to1949?665(19.4)??????246(20.9)??????419(18.6)?????1950to1959?837(24.4)??????344(29.3)??????493(21.9)?????1960to1969?621(18.1)??????229(19.5)??????392(17.4)?????1970to1979?359(10.5)??????118(10.0)??????241(10.4)?????1980to1989?180(5.3)56(4.8)??124(5.2)1990to1999?92(2.7)??13(1.1)??79(3.5)??2000to2009?35(1.0)??0(0.0)????35(1.6)??2010to2019?8(0.2)????0(0.0)????8(0.3)????Age(atindexdate)55.1±17.0????56.41±13.8???????54.6±18.4????.007Householdincome????????????????????????Low880(25.7)??????283(24.1)??????597(26.5)???????.008Middle???1,077(31.4)???409(34.8)??????668(29.6)???????High???????1,473(42.9)???483(41.1)??????990(43.9)???????Comorbidities????????????????????????Hypertension?1,269(37.0)???445(37.9)??????824(36.5)?????.466Diabetesmellitus???888(25.9)??????285(24.3)???????603(26.7)??????.125Dyslipidemia??1,095(31.9)???383(32.6)??????712(31.6)?????.568Frequencyofdrinkingalcohol??????????????????????????????<1d/wk??1,581(46.1)???504(42.9)??????1,077(47.8)???????<.0011to2d/wk?????549(16.0)??????207(17.6)??????342(15.2)?????3to7d/wk?????613(17.9)??????269(22.9)??????344(15.2)?????Missing??687(20.0)??????195(16.6)??????492(21.8)???????Smokingstatus?????????????????????????????Nonsmoker????1,507(43.9)???491(41.8)??????1,016(45.1)?????.199Ex-smoker?????454(13.2)??????180(15.3)??????274(12.2)?????Currentsmoker??????780(22.7)??????310(26.4)???????470(20.8)??????Missing??689(20.1)??????194(16.5)??????495(21.9)???????BMI,kg/m2???23.9±3.4??????24.1±3.4??????23.8±3.3??.027<18·5?????112(3.3)37(3.2)??75(3.3)??<.00118·5-22·9??????1,014(29.3)???355(30.2)??????659(29.2)?????23·0-24·9??????640(18.7)??????218(18.5)??????422(18.7)?????≥25·0?1,024(29.8)???388(33.0)??????636(28.2)???????Missing??640(18.7)??????177(15.1)??????463(20.5)???????HDL,mg/dL??55.3±22.9????55.7±16.0????55.1±26.1.015<40?331(9.6)110(9.4)221(9.8).03340-59?????1,379(40.2)???494(42.0)??????885(39.2)???????≥60???????822(24.0%)??322(27.4%)??500(22.2%)???????Missing??898(26.2%)??248(21.2%)??649(28.8%)???????LDL,mg/dL???110.6±57.1??111.4±80.9??110.1±37.0.668<100??????1,023(29.8%)378(32.2%)??645(28.6%)???????<.001100-159?1,277(37.2%)464(39.5%)??813(36.1%)???????≥160?????229(6.7%)????81(6.9%)??????148(6.5%)???????Missing??901(26.3%)??252(21.4%)??649(28.8%)???????TG,mg/dL?????154.5±125.1162.3±141.3150.0±114.5??????.024<150??????1,626(47.4%)576(19.0%)??1,050(46.6%)??<.001150-199?378(11.0%)???140(11.9%)???238(10.5%)???????≥200?????530(15.5%)??211(18.0%)???319(14.2%)???????Missing??896(26.1)??????248(21.1)??????648(28.7)???????Systemiccorticosteroid(Oralorhigh-doseIV)???????????????????????????Neveruse???????2,090(60.9)???710(60.4)??????1,380(61.2)?????.687Everuse?1,340(39.1)???465(39.6)??????875(38.8)???????Oralcorticosteroid????????????????????????Neveruse???????2,119(61.8)???718(61.1)??????1,401(62.1)?????.584Everuse?1,311(38.2)???457(38.9)??????854(37.9)???????.690Neveruse???????2,119(61.8)???718(61.1)??????1,401(62.1)?????<180cDDDs??1,240(36.1)???434(36.9)??????806(35.7)?????180-364cDDDs????47(1.4)??15(1.3)??32(1.4)??365-729cDDDs????21(0.6)??8(0.7)????13(0.6)??≥730cDDDs3(0.1)????0(0.0)????3(0.1)????High-doseIVcorticosteroid??????????????????????????Neveruse???????3,322(96.9)???1,142(97.2)???2,180(96.7)?????.471Everuse?108(3.1)33(2.8)??75(3.3)??.858Neveruse???????3,322(96.9)???1,142(97.2)???2,180(96.7)?????<180cDDDs??84(2.4)??26(2.2)??58(2.5)??180-364cDDDs????9(0.3)????2(0.2)????7(0.3)????365-729cDDDs????10(0.3)??4(0.3)????6(0.3)????≥730cDDDs5(0.1)????1(0.1)????4(0.2)????BMI,bodymassindex;cDDDs,cumulativedefineddailydoses(prednisolone10mg);CI,confidenceinterval;HDL,highdensitylipoprotein;IV,intravenous;LDL,lowdensitylipoprotein;ONFH,osteonecrosisoffemoralhead;OR,oddsratio;TG,triglyceride;THA,totalhiparthroplasty.??Table6AdjustedRiskofTotalHipArthroplastyofOsteonecrosisofFemoralHeadPatients.ConditionalLogisticRegressionAnalysisforONFHDevelopmentCrudeOR??????95%CI???P?????AdjustedOR??95%CI???????PSex????????????????????????????????????????Men1.00ref.?????????1.00ref.??Women???0.890.79to1.01???.0601.030.88to1.20???????.731Age?1.011.00to1.01???<.001?????1.011.01to1.02???????<.001Householdincome????????????????????????????????????????Low1.000.86to1.16???.9891.020.88to1.19???????.786Middle???1.201.05to1.37???.0081.211.06to1.38???????.006High???????1.00ref.?????????1.00ref.??Comorbidities???????????????????????????????????????Hypertension?1.120.99to1.26???.0581.100.91to1.32.340Diabetesmellitus???0.950.83to1.09???.4460.80???????0.68to0.96???.013Dyslipidemia??1.090.97to1.23???.1570.980.81to1.19.842Frequencyofdrinkingalcohol?????????????????????????????????????????????<1d/wk??1.00ref.?????????1.00ref.??1to2d/wk?????1.231.05to1.45???.0111.231.02to1.47.0263to7d/wk?????1.501.30to1.74???<.001?????1.38???????1.16to1.65???<.001Missing??0.900.76to1.06???.2043.120.80to12.23???????.103Smokingstatus?????????????????????????????????????????????Nonsmoker????1.00ref.?????????1.00ref.??Ex-smoker?????1.311.11to1.56???.0020.251.03to1.52.027Currentsmoker??????1.261.09to1.45???.0021.17???????0.98to1.41???.085Missing??0.860.73to1.02???.0850.400.10to1.64???????.203BMI,kg/m2?????????????????????????????????????????<18·5?????0.940.67to1.31???.6980.890.63to1.25???????.51018·5to22·9???1.00ref.?????????1.00ref.??23·0to24·9???0.940.80to1.12???.4940.950.80to1.12.519≥25·0?1.090.95to1.26???.2321.110.96to1.29???????.176Missing??0.770.65to0.93???.0051.040.61to1.77???????.880HDL,mg/dL?????????????????????????????????????????<40?0.930.76to1.15???.5170.910.74to1.12???????.37640to59??1.00ref.?????????1.00ref.??≥60???????1.130.98to1.30???.0941.161.01to1.34???????.043Missing??0.770.66to0.90???<.001?????0.320.03to3.11.325LDL,mg/dL??????????????????????????????????????????<100??????1.00ref.?????????1.00ref.??100to159?????0.970.84to1.11???.6140.990.86to1.13.844≥160?????0.930.73to1.18???.5610.960.75to1.23???????.728Missing??0.740.63to0.87???<.001?????5.091.59to16.28??????.006TG,mg/dL????????????????????????????????????????????<150??????1.00ref.?????????1.00ref.??150to199?????1.070.89to1.29???.4471.050.87to1.27.583≥200?????1.191.02to1.39???.0301.110.94to1.31???????.231Missing??0.780.67to0.91???.0010.490.07to3.60???????.485Medication????????????????????????????????????????????Steroid(oralorhigh–doseIV)?????????????????????????????????????????????Neveruse???????1.00ref.?????????1.00ref.??Everuse?1.090.97to1.22???.1721.070.95to1.21???????.268POsteroid?????????????????????????????????????????????Neveruse???????1.00ref.?????????1.00ref.??Everuse?1.090.97to1.23???.1341.070.95to1.21???????.268Neveruse???????1.00ref.?????????1.00ref.??<180cDDDs??1.090.97to1.23???.1421.080.95to1.21.247180to364cDDDs?1.100.66to1.83???.7161.22???????0.73to2.06???.449365to729cDDDs?1.280.64to2.58???.4821.62???????0.79to3.36???.191≥730cDDDs<0.001???<0.001to999.944<0.001???????<0.001to999.943High–doseIVsteroid????????????????????????????????????????????Neveruse???????1.00ref.?????????1.00ref.??Everuse?0.910.64to1.29???.5920.900.63to1.28???????.552Neveruse???????1.00ref.?????????1.00ref.??<180cDDDs??0.950.64to1.39???.7760.870.59to1.30.504180to364cDDDs?0.600.15to2.41???.4740.71???????0.17to2.87???.626365to729cDDDs?1.200.45to3.20???.7191.35???????0.50to3.64???.554≥730cDDDs0.480.07to3.38???.4580.540.07to4.01.545Steroiduseduration?????????????????????????????????????????????Neveruse???????1.00ref.?????????1.00ref.??<3mobeforediagnosis?1.601.45-1.76<.001???????1.621.47-1.78<.0013-6mobeforediagnosis3.863.22-4.63<.001???????3.913.25-4.70<.0016-12mobeforediagnosis??????5.284.16-6.71<.001???????5.234.10-6.67<.001>12mobeforediagnosis7.575.98-9.59<.001???????7.405.82-9.42<.001?查看原圖BMI,bodymassindex;cDDDs,cumulativedefineddailydoses(prednisolone10mg);CI,confidenceinterval;HDL,highdensitylipoprotein;IV,intravenous;LDL,lowdensitylipoprotein;ONFH,osteonecrosisoffemoralhead;OR,oddsratio;PO,peroral;TG,triglyceride;THA,totalhiparthroplasty.??DiscussionWeevaluated3,488ONFHcasesand17,440controlcaseswithmatchingvariablesincludingage,sex,andthetimeofthefollow-upata1:5ratiofromtheNHIS-NSC,includingthefollow-updatafrom2002to2019of1,137,861participantsinanationwidelongitudinalnestedcase-controlstudy.Wedemonstratedthatalowhouseholdincome,diabetes,hypertension,dyslipidemia,heavyalcoholicswhoconsumedalcoholmorethan3daysaweek,andserumTGlevelsof200mg/dLormorewereassociatedwiththedevelopmentofONFH.Inaddition,systemiccorticosteroidusewassignificantlyassociatedwithanincreasedriskofONFHincidencecomparedtothatofnonusers.Specifically,theriskofONFHincreasedrapidlywhenthecDDDswere180ormorecumulativedosesofcorticosteroiduse.WeanalyzedthefactorsaffectingtheprogressionofthediseasebycomparingpatientswhounderwentTHAwiththosewhodidnotundergoTHAduringthefollow-upperiodafterONFHdiagnosis.Men,whohadahigherBMI,heavyalcoholicswhoconsumedalcoholmorethan3daysaweek,currentsmokers,andserumTGlevelsof200mg/dLormorewereassociatedwithTHAafterONFHdiagnosis.However,afteradjustingforcompoundfactors,heavyalcoholicsweretheonlyfactoraffectingtheincidenceofTHAafterONFHdiagnosis,anditmaybeusedtocounselONFHpatients.Otherlipidprofiles,corticosteroidsused,andcumulativedosesofcorticosteroidsdidnotaffecttheincidenceofTHA.我們評估了3488例ONFH病例和17440例對照病例，匹配變量包括年齡、性別和隨訪時(shí)間，比例為1:5，來自NHIS-NSC，包括2002年至2019年全國縱向巢式病例對照研究中1137861名參與者的隨訪數(shù)據(jù)。研究表明，家庭收入低、糖尿病、高血壓、血脂異常、每周飲酒超過3天的重度酗酒者以及血清TG水平≥200mg/dL與ONFH的發(fā)生有關(guān)。此外，與不使用皮質(zhì)類固醇的患者相比，全身性使用皮質(zhì)類固醇與ONFH發(fā)生率增加顯著相關(guān)。特別是，當(dāng)皮質(zhì)類固醇的累積使用劑量達(dá)到180或更高時(shí)，ONFH的風(fēng)險(xiǎn)迅速增加。我們通過比較ONFH診斷后隨訪期間接受THA和未接受THA的患者來分析影響疾病進(jìn)展的因素。BMI較高的男性、每周飲酒超過3天的重度酗酒者、當(dāng)前吸煙者、血清TG水平≥200mg/dL的男性在ONFH診斷后與THA相關(guān)。然而，在調(diào)整復(fù)合因素后，重度酗酒者是ONFH診斷后唯一影響THA發(fā)生率的因素，可用于指導(dǎo)ONFH患者。其他脂質(zhì)特征、使用的皮質(zhì)類固醇和皮質(zhì)類固醇的累積劑量對THA的發(fā)生率沒有影響。TherelationshipbetweencorticosteroiduseandONFHdevelopmenthasbeenrevealedinseveralstudies[8,25,26],andtherearealsosomestudiesthathavesuggestedspecificdosesanddurationsofcorticosteroiduse,suchastheassociationwiththedevelopmentofdiseasewhenusingmorethan2gwithin3months[27]orthemeancorticosteroiduseofpatientswhohaveONFHdevelopmentof3,314mg[28].Inthecurrentlargecohortstudyofthegeneralpopulation,weanalyzedvariousfactorsthatcanaffectthedevelopmentofONFH.Asinpreviousstudies,thecaseofcorticosteroiduseatleastonceandadditionalcumulativecorticosteroiddosewereassociatedwiththeincreasedriskofONFHdevelopment,andwhencumulativeprednisoloneusewas1,800mg(180cDDDs)ormore,theriskofONFHdevelopmentincreasedrapidly.Surely,thedevelopmentofONFHrelatedtocorticosteroiduseisthoughttobecausedbyacombinationofnotonlycorticosteroidusebutalsoseveralfactorssuchascomorbidities,alcohol,smoking,andgeneticfactors.Sincecorticosteroidtreatmentisoftenessentialformanydiseases,itisnecessarytobeawareofthecumulativedoseatwhichtheriskofONFHincreasesrapidlywhencontinuouscorticosteroidtreatmentisrequired.?一些研究已經(jīng)揭示了皮質(zhì)類固醇的使用與ONFH發(fā)展之間的關(guān)系[8,25,26]，也有一些研究提出了皮質(zhì)類固醇使用的特定劑量和持續(xù)時(shí)間，如在3個(gè)月內(nèi)使用超過2g與疾病發(fā)展的關(guān)系[27]，或ONFH發(fā)展患者的平均皮質(zhì)類固醇使用量為3,314mg[28]。在目前針對普通人群的大型隊(duì)列研究中，我們分析了影響ONFH發(fā)展的各種因素。與之前的研究一樣，至少使用一次皮質(zhì)類固醇和額外的皮質(zhì)類固醇累積劑量與ONFH發(fā)展的風(fēng)險(xiǎn)增加有關(guān)，當(dāng)潑尼松龍累積使用1800毫克(180cDDDs)或更多時(shí)，ONFH發(fā)展的風(fēng)險(xiǎn)迅速增加。當(dāng)然，與皮質(zhì)類固醇使用相關(guān)的ONFH的發(fā)展被認(rèn)為不僅是由皮質(zhì)類固醇使用引起的，還包括合并癥、酒精、吸煙和遺傳因素等多種因素。由于皮質(zhì)類固醇治療通常對許多疾病至關(guān)重要，因此有必要了解在需要持續(xù)皮質(zhì)類固醇治療時(shí)ONFH風(fēng)險(xiǎn)迅速增加的累積劑量。Tothebestofourknowledge,nostudyhascomparedtheincidenceofONFHwithhigh-doseIVandoralcorticosteroidsatthesamecumulativedose.Inthepresentstudy,bothoralcorticosteroidandhigh-doseIVcorticosteroidsincreasedtheriskofdevelopingONFH,andwhencomparingtheoralandhigh-doseIVatthesamecumulativedose,oralcorticosteroidhadahigherrisk;totheAORsoforalcorticosteroidwere1.61(<180cDDDs),4.39(180to365cDDDs),6.42(365to720cDDDs),and5.44(>720cDDDs).TheAORsofhigh-doseIVcorticosteroidwere1.63(<180cDDDs),2.34(180to365cDDDs),3.77(365to720cDDDs),and2.76(>720cDDDs),respectively.Ingeneral,sincetheprednisolonepotencyoforalcorticosteroidsismuchlowerthanthatofhigh-doseIV,thedurationoforalcorticosteroidusewouldhavebeenlongerifthesamecumulativedosewasused.Montetal.reportedthatONFHoccurrencewasassociatedwithmeandailycorticosteroiddose,cumulativedose,andtreatmentduration[8].Ofcourse,ONFHoccurrenceswouldbeaffectedbygeneticsusceptibilityandexposuretovariousriskfactors,butinourstudy,weconfirmedthatmoreONFHoccurredinoralcorticosteroidswitharelativelysmalldailydoseatthesamecumulativedosecomparedtohigh-doseIVcorticosteroid,soitisassumedthatthelongertreatmentperiodofcorticosteroidisalsoassociatedwithdevelopingONFH.據(jù)我們所知，沒有研究比較相同累積劑量的高劑量靜脈注射和口服皮質(zhì)類固醇對ONFH的發(fā)生率。在本研究中，口服皮質(zhì)類固醇和高劑量靜脈注射皮質(zhì)類固醇都增加了發(fā)生ONFH的風(fēng)險(xiǎn)，并且在相同累積劑量下，口服皮質(zhì)類固醇與高劑量靜脈注射皮質(zhì)類固醇相比，風(fēng)險(xiǎn)更高;口服皮質(zhì)類固醇的AORs分別為1.61(<180cDDDs)、4.39(180~365cDDDs)、6.42(365~720cDDDs)和5.44(>720cDDDs)。高劑量靜脈注射皮質(zhì)類固醇的AORs分別為1.63(<180cDDDs)、2.34(180~365cDDDs)、3.77(365~720cDDDs)和2.76(>720cDDDs)。一般來說，由于口服皮質(zhì)類固醇的強(qiáng)的松龍效力遠(yuǎn)低于高劑量靜脈注射，如果使用相同的累積劑量，口服皮質(zhì)類固醇的使用時(shí)間會更長。Mont等人報(bào)道ONFH的發(fā)生與皮質(zhì)類固醇的平均每日劑量、累積劑量和治療時(shí)間有關(guān)[8]。當(dāng)然，ONFH的發(fā)生會受到遺傳易感性和暴露于各種危險(xiǎn)因素的影響，但在我們的研究中，我們證實(shí)在相同累積劑量下，相對于高劑量靜脈注射皮質(zhì)類固醇，日劑量相對較小的口服皮質(zhì)類固醇更易發(fā)生ONFH，因此我們假設(shè)皮質(zhì)類固醇治療時(shí)間越長也與ONFH的發(fā)生有關(guān)。ItiswellknownthatahigherTGlevel,orLDLcholesterol,isanimportantriskfactorforischemicheartdiseaseandstrokebyinhibitingbloodflow,andONFHispresumedtoberelatedtoinhibitionofbloodflowtothefemoralheadinasimilarmechanism[29].Similartopreviousstudies[7,30],higherTGwasariskfactorforONFHinourstudy.Inaddition,itwasconfirmedthatLDLatlessthan100mg/dLhasaprotectiveeffectontheoccurrenceofONFH.眾所周知，較高的TG或LDL膽固醇水平通過抑制血流是缺血性心臟病和中風(fēng)的重要危險(xiǎn)因素，而ONFH被認(rèn)為與股骨頭血流的抑制有類似的機(jī)制[29]。與以往的研究相似[7,30]，在我們的研究中，高TG是ONFH的危險(xiǎn)因素。此外，還證實(shí)了低于100mg/dL的LDL對ONFH的發(fā)生有保護(hù)作用。SinceONFHoccurspredominantlyinyoungerpatientsandpreservationofthenativejointasmuchaspossibleistheprincipleoftreatment,thediseaseprogressionandprognosisareasimportantastheoccurrenceofthedisease.WeoftenseecasesofbilateralONFHdevelopmentwhereonesidehasfemoralcollapseandtheothersideremainsasymptomaticwithoutfemoralheadcollapse.Alternatively,somecaseswereasymptomaticwithoutfemoralheadcollapse,butreceivedTHA.ItisknownthattheprognosisafterONFHdevelopmentisinfluencedbyvariousfactors,anduntilnow,therehavebeenstudiesshowingthatradiologicfactorssuchasthesizeorlocationofnecrosisoracetabularanatomicalfactorshaveaneffect[1,19,31].Montetal.reportedthattheprevalenceoffemoralheadcollapsewas38%(106of282hips)inameta-analysisandvariedfrom17to73%dependingontheriskfactor[16].Inourstudy,34.3%ofpatientsunderwentTHA,anaverageof1.03±2.25yearsafterdiagnosis,similartothepreviousstudy.Althoughradiologicassessmentcouldnotbeperformed,casesthatmayhaveseengreaterphysicalloads,suchasmen,whohadahigherBMI,excessivedrinking,smoking,andahigherserumTGlevelover200mg/dL,wereassociatedwithdiseaseprogression.Inparticular,thefactorsthatincreasedtheriskofdiseaseprogressionweredifferentinmenandwomen.Wefoundthatcorticosteroidsprescribedornotandcumulativedosesofcorticosteroidswereunlikelytoaffectdiseaseprogression.由于ONFH主要發(fā)生在年輕患者中，治療原則是盡可能保留原有關(guān)節(jié)，因此疾病的進(jìn)展和預(yù)后與疾病的發(fā)生同樣重要。我們經(jīng)?？吹诫p側(cè)ONFH發(fā)展的病例，其中一側(cè)有股骨頭塌陷，另一側(cè)無股骨頭塌陷癥狀。另外，一些病例無股骨頭塌陷癥狀，但接受了THA。眾所周知，ONFH發(fā)生后的預(yù)后受多種因素影響，迄今已有研究表明，壞死的大小或位置等放射學(xué)因素或髖臼解剖因素對ONFH的預(yù)后有影響[1,19,31]。Mont等人在一項(xiàng)薈萃分析中報(bào)道，股骨頭塌陷的患病率為38%(282髖中的106髖)，根據(jù)危險(xiǎn)因素的不同，患病率從17%到73%不等[16]。在我們的研究中，34.3%的患者接受了THA，平均診斷后1.03±2.25年，與之前的研究相似。雖然無法進(jìn)行放射學(xué)評估，但可能出現(xiàn)較大身體負(fù)荷的病例，如男性，BMI較高，過度飲酒，吸煙，血清TG水平高于200mg/dL，與疾病進(jìn)展相關(guān)。特別是，增加疾病進(jìn)展風(fēng)險(xiǎn)的因素在男性和女性中是不同的。我們發(fā)現(xiàn)，開具或不開具皮質(zhì)類固醇以及皮質(zhì)類固醇的累積劑量不太可能影響疾病進(jìn)展。Ourstudyhasseveralpotentiallimitationsthatshouldbeaddressedinfurtherstudies.TheONFHwasassessedbyanoperationaldefinitionusingadiagnosiscode,notbyaradiologicevaluationsuchasanx-rayorMRI.However,theincidenceofONFHinthisstudywassimilartothatinapreviousAsiangeneralpopulationstudythatdefineditusinghipjointx-raysand/orMRI[32].BecauseanaccurateselectionofONFHpatientsmaynothavebeenmade,anestedcase-controlanalysisfromapopulation-basedcohortwasperformedtoincreasetheaccuracyoftheanalysis.Additionally,usingtheNHIS-NSCdatabase,prescriptionrecordsforcorticosteroidscouldbeaccessed.However,theactualintakeofcorticosteroidsinsubjectsmightbedifferentfromtheprescriptionrecords.Fortunately,severalstudieshaveshownagoodcorrelationbetweenprescriptionsandrealexposuretodrugs[33,34].Also,wecouldnotobtaininformationabouttraumaticONFH,whichmayhaveinfluencedtheresultsofthecurrentstudy.Inaddition,wecouldnotassessotherinterventionsthatcouldaffectdyslipidemia,microvascularbloodflow,andosteogenesis,suchastheuseoflipid-loweringmedication,aspirin,antiplatelets,andanticoagulantmedication.Thisshouldbeevaluatedinfuturestudies.Furthermore,ananalysisofmultiplecomorbiditiessuchasrheumaticdisease,sicklecelldisease,humanimmunodeficiencyvirus,organtransplantation,andsoonthatcouldaffecttheoccurrenceandprognosisofONFHwasnotperformed.Inparticular,sincetheprognosisofONFHisdifferentforeachdisease,subgroupanalysisaccordingtocomorbidityisabsolutelynecessaryforfuturestudies.Additionally,weanalyzedtheassociationbetweencumulativedoseofcorticosteroidanddiseaseprogressionafterONFHdiagnosisusingcDDD,andweconfirmedthatcumulativedoseofcorticosteroiddidnotaffectdiseaseprogression.However,sincethenumberofpatientswhohave180cDDDormorewassmall,additionalanalysiswithalargernumberofpatientsmaybeneededtoobtainmoreaccurateresults.我們的研究有幾個(gè)潛在的局限性，應(yīng)該在進(jìn)一步的研究中加以解決。ONFH通過使用診斷代碼的操作定義進(jìn)行評估，而不是通過x射線或MRI等放射學(xué)評估。然而，本研究中ONFH的發(fā)生率與先前的亞洲普通人群研究相似，該研究使用髖關(guān)節(jié)X光片和/或MRI來定義ONFH[32]。由于可能沒有對ONFH患者進(jìn)行準(zhǔn)確的選擇，因此進(jìn)行了基于人群的隊(duì)列嵌套病例對照分析，以提高分析的準(zhǔn)確性。此外，使用NHIS-NSC數(shù)據(jù)庫，可以訪問皮質(zhì)類固醇的處方記錄。然而，受試者的實(shí)際皮質(zhì)類固醇攝入量可能與處方記錄不同。幸運(yùn)的是，有幾項(xiàng)研究表明，處方與實(shí)際接觸藥物之間存在良好的相關(guān)性[33,34]。此外，我們無法獲得有關(guān)創(chuàng)傷性O(shè)NFH的信息，這可能影響了當(dāng)前研究的結(jié)果。此外，我們無法評估其他可能影響血脂異常、微血管血流和成骨的干預(yù)措施，如使用降脂藥物、阿司匹林、抗血小板和抗凝藥物。這應(yīng)該在未來的研究中進(jìn)行評估。此外，對風(fēng)濕病、鐮狀細(xì)胞病、人類免疫缺陷病毒、器官移植等可能影響ONFH發(fā)生和預(yù)后的多重合并癥未進(jìn)行分析。特別是，由于每種疾病的預(yù)后不同，因此根據(jù)合并癥進(jìn)行亞組分析對于未來的研究是絕對必要的。此外，我們分析了使用cDDD診斷ONFH后皮質(zhì)類固醇累積劑量與疾病進(jìn)展之間的關(guān)系，我們證實(shí)皮質(zhì)類固醇累積劑量不影響疾病進(jìn)展。然而，由于cDDD≥180的患者數(shù)量較少，因此可能需要對更多患者進(jìn)行額外分析，以獲得更準(zhǔn)確的結(jié)果。?ConclusionLowhouseholdincome,diabetes,hypertension,dyslipidemia,heavyalcoholicswhoconsumedalcoholmorethan3daysaweek,serumTGlevelsof200mg/dLormore,andoralorhigh-doseIVcorticosteroiduseareassociatedwithONFHdevelopment.Specifically,theriskofONFHincreasedrapidlywhencumulativeprednisoloneusewas1,800mgormore.However,oralorhigh-doseIVcorticosteroiduseandcumulativedosedidnotaffecttheprognosisofONFH.SincethedevelopmentandprognosisofONFHarecomplexandmultifactorialprocesses,furtherstudyisneeded.低收入家庭、糖尿病、高血壓、血脂異常、每周飲酒超過3天的重度酗酒者、血清TG水平≥200mg/dL、口服或高劑量靜脈注射皮質(zhì)類固醇與ONFH的發(fā)生有關(guān)。具體來說，當(dāng)累積使用強(qiáng)的松龍超過1800毫克時(shí)，ONFH的風(fēng)險(xiǎn)迅速增加。然而，口服或高劑量靜脈注射皮質(zhì)類固醇和累積劑量對ONFH的預(yù)后沒有影響。由于ONFH的發(fā)展和預(yù)后是一個(gè)復(fù)雜的多因素過程，需要進(jìn)一步研究。
CORR深刻見解?:股骨頭壞死患者股骨頭塌陷和髖臼覆蓋之間是否存在關(guān)聯(lián)?（2023）CORR深刻見解?:股骨頭壞死患者股骨頭塌陷和髖臼覆蓋之間是否存在關(guān)聯(lián)?（2023）CORRInsights?:IsThereanAssociationBetweenFemoralHeadCollapseand?AcetabularCoverageinPatientsWithOsteonecrosis??PrasadK.CORRInsights?:IsThereanAssociationBetweenFemoralHeadCollapseand?AcetabularCoverageinPatientsWithOsteonecrosis?[J].ClinOrthopRelatRes,2023,481(1):60-62.?轉(zhuǎn)載文章的原鏈接1：https://pubmed.ncbi.nlm.nih.gov/36441115/?轉(zhuǎn)載文章的原鏈接2：https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9750567/?WhereAreWeNow?我們現(xiàn)在在哪里?Nontraumaticosteonecrosisofthefemoralhead(ONFH)isadevastatingdiseasethatdisproportionatelyaffectsyoungpatientsandcarriesarealriskoffemoralheadcollapse,resultinginprematureend-stagearthritisandTHA.Thisputstheseyoungpeopleonacoursethatoftenincludesmultiplerevisionsandsometimesseverecomplications.ClassificationsystemsofONFHbasedonsize,extent,volume,andlocationscanhelpsurgeonsanticipatewhichpatientsareatthegreatestriskoffemoralheadcollapse[1,10-12].However,thesesystemsdonotperfectlycapturethemanyfactorsthatcanmodifythisrisk(whetherthesebehost-relatedfactorsorinterventions),andovertime,clinician-scientistsareuncoveringnewriskfactorsthatarenotincludedintheoldclassificationsystems.Suchfactorsmayincludepelvicincidenceandacetabularcoverage,whichcanresultingreatercontactstressesonthefemoralheadandmayinfluencetheriskofprogressioninpatientswithONFH.非創(chuàng)傷性股骨頭壞死（ONFH）是一種破壞性疾病，主要影響年輕患者，并具有股骨頭塌陷的real風(fēng)險(xiǎn)，導(dǎo)致早期終末期關(guān)節(jié)炎和THA。這讓這些年輕人經(jīng)歷了一個(gè)經(jīng)常需要多次revisions的過程，有時(shí)還會出現(xiàn)嚴(yán)重的并發(fā)癥?；贠NFH的大小、范圍、體積和位置的分類系統(tǒng)可以幫助外科醫(yī)生預(yù)測哪些患者股骨頭塌陷的風(fēng)險(xiǎn)最大[1,10-12]。然而，這些系統(tǒng)并不能完美地捕捉到許多可以改變這種風(fēng)險(xiǎn)的因素（無論這些因素是與宿主相關(guān)的因素還是干預(yù)措施），隨著時(shí)間的推移，臨床科學(xué)家正在發(fā)現(xiàn)舊分類系統(tǒng)中未包括的新風(fēng)險(xiǎn)因素。這些因素可能包括骨盆入射角和髖臼覆蓋范圍，這可能導(dǎo)致股骨頭上更大的接觸應(yīng)力，并可能影響ONFH患者進(jìn)展的風(fēng)險(xiǎn)。Patientswithhighpelvicincidence,conceptualizedasthesumofpelvictiltandsacralslopeanddefinedastheanglebetweenalineperpendiculartothemidpointofthesacralplateauandalinefromthispointtothecenterofthefemoralhead,reportedlyhaveinadequateanteriorcoverageofthefemoralhead,whichmaybeassociatedwithacceleratedfemoralheadcollapseinpatientswithONFH[6].However,anotherstudydiffered,withnoassociationfoundbetweenpelvicincidenceandacetabularcoverage[3].InthecurrentstudyinClinicalOrthopaedicsandRelatedResearch?,therewerenodifferencesinpelvicincidencebetweenthecollapseandnoncollapsegroupswithin1yearafterpresentation[4].Basedonthis,theassociationbetweenpelvicincidenceandfemoralheadcollapseinpatientswithONFHremainsuncertain.6.KwonHM,YangI-H,ParkKK,etal.Highpelvicincidenceisassociatedwithdiseaseprogressioninnontraumaticosteonecrosisofthefemoralhead.ClinOrthopRelatRes.2020;478:1870-1876.3.IwasaM,AndoW,UemuraK,HamadaH,TakaoM,SuganoN.Pelvicincidenceisnotassociatedwiththedevelopmentofhiposteoarthritis.BoneJointJ.2021;103-B:1656-1661.4.IwasaM,AndoW,UemuraK,HamadaH,TakaoM,SuganoN.Isthereanassociationbetweenfemoralheadcollapseandacetabularcoverageinpatientswithosteonecrosis?ClinOrthopRelatRes.2023;481:51-59.高骨盆入射角的患者，被定義為骨盆傾斜和骶骨傾斜的總和，并被定義為垂直于骶骨平臺中點(diǎn)的線與從該點(diǎn)到股骨頭中心的線之間的夾角，據(jù)報(bào)道，股骨頭前部覆蓋不足，這可能與ONFH患者股骨頭加速塌陷有關(guān)[6]。然而，另一項(xiàng)研究卻有所不同，沒有發(fā)現(xiàn)骨盆發(fā)病率與髖臼覆蓋率之間的關(guān)聯(lián)[3]。在臨床骨科及相關(guān)研究?中，塌陷組和非塌陷組在發(fā)病后1年內(nèi)盆腔發(fā)病率沒有差異[4]?；诖?，ONFH患者盆腔發(fā)生率與股骨頭塌陷之間的關(guān)系仍不確定。Inaddition,thecurrentstudyfoundtherewasaslightlysmallerlateralcenter-edgeangleof28°inthecoronalplanewithahigheroddsofcollapseinpatientswithseveregradesofONFH,buttherewasadifferentialeffectsizeofjust4°betweenthecollapseandnoncollapsegroupsandnodifferencesinfouradditionalangularparametersinthesagittalandaxialplanesoftridemensionalacetabularcoverage[4,8].Thus,thecontributiontoandclinicalsignificanceofthelateralcenter-edgeangleandacetabularcoverageregardingcollapseinpatientswithONFHisquestionable.Thus,factorsotherthanacetabularcoveragemaybepredominant,particularlybecause35patientswithONFH(35%),allwithsymptomsinitially,experiencedrapidlyprogressivecollapsewithin1year(potentiallyrisingto71%in24months[6]).Ontheotherhand,anassociationbetweensurgicaltreatmentoutcomesandlateralcenter-edgeangleinpatientswithONFHhasbeendocumented;asmallerangleentailsasubstantialriskofcollapseandhipsurvivalleadingtoTHAafterfreevascularizedfibulargraftingforONFH[9],whichdiffersfromthenaturalhistorythecurrentstudy[4]investigated.此外，目前的研究發(fā)現(xiàn)，嚴(yán)重程度的ONFH患者的冠狀面外側(cè)中心邊緣角略小，為28°，塌陷的幾率更高，但塌陷組和非塌陷組之間的差異效應(yīng)大小僅為4°，并且在髖臼三維覆蓋的矢狀面和軸向面四個(gè)額外的角度參數(shù)沒有差異[4,8]。因此，外側(cè)中心邊緣角和髖臼覆蓋范圍對ONFH患者塌陷的貢獻(xiàn)和臨床意義值得懷疑。因此，髖臼覆蓋范圍以外的因素可能占主導(dǎo)地位，特別是35例ONFH患者(35%)，最初都有癥狀，在1年內(nèi)經(jīng)歷了快速進(jìn)行性塌陷（24個(gè)月內(nèi)可能上升到71%[6]）。另一方面，ONFH患者的手術(shù)治療結(jié)果與外側(cè)中心邊緣角之間的關(guān)聯(lián)已被記錄；較小的角度會帶來很大的塌陷和髖關(guān)節(jié)存活風(fēng)險(xiǎn)，從而導(dǎo)致ONFH游離帶血管腓骨移植術(shù)后的THA[9]，這與當(dāng)前研究[4]所調(diào)查的自然病史不同。ThekeymessageofthisstudyinCORR?[4]isthatmorethanone-thirdofpatientswithsymptomaticONFHoninitialpresentationexperiencedacceleratedcollapseofthefemoralheadwithin1year,andthatacetabularcoveragewasnotasstronganassociatedfactorinthenaturalhistoryofONFHasonemighthaveexpectedittobe.Basedonthesefindings,surgeonsshouldfocusonsymptomaticONFHandmonitorsusceptiblevascularityandearlycollapsecloselywithin2yearsafterpresentationforappropriatejoint-preservinginterventions,withconservationandpromotionofvascularity.CORR?[4]這項(xiàng)研究的關(guān)鍵信息是，超過三分之一的首發(fā)癥狀性O(shè)NFH患者在1年內(nèi)股骨頭加速塌陷，并且髖臼覆蓋在ONFH自然病史中的相關(guān)因素并不像人們預(yù)期的那樣強(qiáng)?；谶@些發(fā)現(xiàn)，外科醫(yī)生應(yīng)關(guān)注有癥狀的ONFH，并在就診后2年內(nèi)密切監(jiān)測易感血管和早期塌陷，以采取適當(dāng)?shù)谋ｊP(guān)節(jié)干預(yù)措施，保護(hù)和促進(jìn)血管。?WhereDoWeNeedtoGo?我們需要去哪里?Althoughthevascularenvironmentandmechanicalenvironmentarenotalwaysentirelyindependentofoneanother,IbelievenontraumaticONFHpredominantlyreflectsdeteriorationofthevascularityofthefemoralhead,whetherasaprimaryphenomenon,asecondaryone,orboth.盡管血管環(huán)境和機(jī)械環(huán)境并不總是完全獨(dú)立的，但我認(rèn)為非創(chuàng)傷性O(shè)NFH主要反映了股骨頭血管的惡化，無論是作為原發(fā)性現(xiàn)象，繼發(fā)性現(xiàn)象，還是兩者兼而有之。EveninaninnovativecenterinJapangearedtosuccessfullyperformosteotomiesfornontraumaticONFH,only9%ofpatientsyoungerthan30yearswereselectedforfemoralosteotomiesbasedonstringentcriteria,whilethosewhoweresignificantlysymptomatic(83%)underwentTHAwithinadecade[4].Ideally,anomaliesofthevascularsupply(includingvariationsinmicrocirculatorypatternsandcollateralcirculationintheheadofthefemur)andmechanicalvariantsandvariationsofhipmorphologymeritapreciseinvestigationbeforesurgicalplanningwhenjoint-preservingproceduressuchasosteotomiesareconsidered,inordertopreservethefemoralhead’sbloodsupply.4.IwasaM,AndoW,UemuraK,HamadaH,TakaoM,SuganoN.Isthereanassociationbetweenfemoralheadcollapseandacetabularcoverageinpatientswithosteonecrosis?ClinOrthopRelatRes.2023;481:51-59.即使在日本的一個(gè)創(chuàng)新中心，針對非創(chuàng)傷性O(shè)NFH成功實(shí)施截骨術(shù)，根據(jù)嚴(yán)格的標(biāo)準(zhǔn)，30歲以下的患者中只有9%被選中進(jìn)行股骨截骨術(shù)，而那些有明顯癥狀的患者（83%）在十年內(nèi)接受了THA[4]。理想情況下，血管供應(yīng)的異常（包括股骨頭微循環(huán)模式和側(cè)支循環(huán)的變化）、機(jī)械變異和髖關(guān)節(jié)形態(tài)的變化值得在手術(shù)計(jì)劃之前進(jìn)行精確的調(diào)查，當(dāng)考慮進(jìn)行關(guān)節(jié)保護(hù)手術(shù)（如截骨）時(shí)，為了保持股骨頭的血液供應(yīng)。Futurestudiesshouldalsoassessthedegreeandrateofcollapse.Inthecurrentstudy[4],femoralheadcollapsewasdeemedprogressivewhentheamountofcollapseincreasedby>1mmcomparedwithpreviousradiographs;thisincrementmightbetoosmalltomatter.AnotherstudyreportedthatinasmallproportionofpatientswithJapaneseInvestigationCommitteeTypeBandcollapseoflessthan2mm,thecollapsemaystopandpatientsmaybecomeasymptomaticforanindeterminateperiod[8].Rapidlyprogressiveandstaticcollapsedemandsclosemonitoringbasedonprecisecriteria.8.NishiiT,SuganoN,OhzonoK,SakaiT,SatoY,YoshikawaH.Signi?canceoflesionsizeandlocationinthepredictionofcollapseofosteonecrosisofthefemoralhead:anewthree-dimensionalquan-ti?cationusingmagneticresonanceimaging.JOrthopRes.2002;20:130-136.未來的研究還應(yīng)評估坍塌的程度和速度。在目前的研究中[4]，當(dāng)股骨頭塌陷的數(shù)量比之前的X線片增加>1mm時(shí)，股骨頭塌陷被認(rèn)為是進(jìn)行性的；這個(gè)增量可能太小而無關(guān)緊要。另一項(xiàng)研究報(bào)道，在一小部分日本調(diào)查委員會B型塌陷小于2mm的患者中，塌陷可能停止，患者可能在不確定的時(shí)間內(nèi)無癥狀[8]?？焖贊u進(jìn)和靜態(tài)坍塌需要基于精確標(biāo)準(zhǔn)的密切監(jiān)測。Otherfundamentalquestionsrelatetojointpreservationthroughnonoperativeoptionsincludingmedicationssuchastransientbisphosphonatesforprecollapselesionsorpotentiallyforsmall,mediallesions;directsurgicaloptionsrelatedtopreservationofandimprovementinvascularityincludingcoredecompression,adjunctivebonegrafting,andvascularizedbonegrafting;selectiveredirectionalosteotomiestoreducemechanicalstressesandfacilitatevascularimprovement;andtheadditionofnoveladjunctivetherapiesincludingstemcelltherapiesinisolationorincombination.其他基本問題涉及到通過非手術(shù)選擇來保護(hù)關(guān)節(jié)，包括藥物治療，如用于塌陷前病變或潛在的小的、內(nèi)側(cè)病變的短暫性雙膦酸鹽；與保存和改善血管性相關(guān)的直接手術(shù)選擇包括髓芯減壓、輔助植骨和帶血管的植骨；選擇性定向截骨術(shù)減少機(jī)械應(yīng)力，促進(jìn)血管改善;以及新的輔助療法的加入，包括分離或聯(lián)合的干細(xì)胞療法。FuturestudiesmustevaluatepatientswithsymptomaticprecollapselesionscausedbynontraumaticONFHtoidentifyanomaliesofthevascularsupplyandvariationsinmicrocirculatorypatternsandcollateralcirculation.Thiswillhelpguidesurgicalplanningtopreserve,promote,andrestorethatvascularsupply.Whetherthatmightbethroughprecisesurgicaltargetingofcoredecompressionorvascularizedbonegraftingisyettobedetermined.未來的研究必須評估非創(chuàng)傷性O(shè)NFH引起的癥狀性塌陷前病變患者，以確定血管供應(yīng)異常、微循環(huán)模式和側(cè)枝循環(huán)的變化。這將有助于指導(dǎo)手術(shù)計(jì)劃，以保護(hù)、促進(jìn)和恢復(fù)血管供應(yīng)。這是否可能是通過精確的手術(shù)靶向髓芯減壓或血管化骨移植尚未確定。?HowDoWeGetThere?我們?nèi)绾蔚竭_(dá)那里?Theannualincidenceofnew-onsetONFHwasreportedtobe1.91per100,000personsinJapan[2],whichmakesaccumulatingpatientsdifficultforsingle-centerstudies,especiallyforasubgroupanalysis.Obviously,studieswithmorepatientsareneededinthefutureforcomprehensiveanalyses.Multicenterstudieswithsuperiorstatisticalpowerincludingsubgroupsarelikelytocontributemore-robustdataandconclusionswithwiderimplicationsforprecisetimingofadvancingmodalitiesofinvestigationsanddifferentialmanagementoptionsofONFH.據(jù)報(bào)道，日本新發(fā)ONFH的年發(fā)病率為每10萬人1.91例[2]，這使得單中心研究難以積累患者，尤其是亞組分析。顯然，未來需要更多患者的研究來進(jìn)行全面分析。包括亞組在內(nèi)的具有卓越統(tǒng)計(jì)能力的多中心研究可能會提供更可靠的數(shù)據(jù)和結(jié)論，對ONFH的先進(jìn)調(diào)查模式的精確時(shí)間和不同的管理選擇具有更廣泛的意義。Nationalandmultinationalstudiesandlarge-databasestudiesthatevaluateregionalandethnicvariations,guidedbytheAssociationofResearchCirculationosseousstagingsystemofosteonecrosisofthefemoralheadandJapaneseInvestigationCommittee,aredesirablebutaresubjecttologisticandresourceimplications.在研究循環(huán)協(xié)會股骨頭壞死骨分期系統(tǒng)和日本調(diào)查委員會的指導(dǎo)下，評估地區(qū)和種族差異的國家和多國研究和大型數(shù)據(jù)庫研究是可取的，但受后勤和資源影響。Contrast-enhancedMRarteriographydeservesmoreattention.Itcanbeusedtoevaluatehipswithprecollapsetodeterminevascularcompromiseandmayhelpusanticipatewhichhipsareatthegreatestriskofcollapse.Prognosticstudiesusingthistechniqueseemplausible,giventheconstraintsofsmallpatientnumbersandhowoftencollapseoccursinpatientswiththisdiagnosis.Dependingonthefindings,thisimagingtoolmayproveclinicallyusefulinthiscontext.增強(qiáng)磁共振動脈造影值得更多關(guān)注。它可以用來評估髖關(guān)節(jié)塌陷前的血管損傷，并幫助我們預(yù)測哪些髖關(guān)節(jié)塌陷的風(fēng)險(xiǎn)最大?？紤]到患者數(shù)量少的限制以及這種診斷的患者發(fā)生崩潰的頻率，使用這種技術(shù)進(jìn)行預(yù)后研究似乎是合理的。根據(jù)結(jié)果，這種成像工具可能在臨床上證明是有用的。MRIuseinreal-timethree-dimensionalguidanceforcoredecompressionistechnicallyfeasible,safe,andaccurate[5].EvolutionofMRI-guided(withMR-compatibleinstrumentation)[5,7]robot-assistedsurgicalapproachesmaybethenextfrontierinjointpreservationinpatientswithONFH.Evaluatingit,though,wouldprobablyrequirethecooperationofseverallike-mindedcentersthattreatalargenumberofpatientswiththiscondition.GivenitsrelativefrequencyinsomeregionsofAsia(comparedwithEuropeortheUnitedStates),Isuspectmoreofthisresearchwillcomefromthosegeographiclocationswithworldwidetechnologicalinnovation,andIlookforwardtoreadingitwhenitappears.5.KerimaaP,VaananenM,OjalaR,etal.MRI-guidanceinpercutaneouscoredecompressionofosteonecrosisofthefemoralhead.EurRadiol.2016;26:1180-1185.7.MontMA,SalemHS,PiuzziNS,GoodmanSB,JonesLC.Nontraumaticosteonecrosisofthefemoralhead:wheredowestandtoday?:A5-yearupdate.JBoneJointSurgAm.2020;102:1084-1099.MRI用于實(shí)時(shí)三維指導(dǎo)髓芯減壓在技術(shù)上是可行的、安全的、準(zhǔn)確的[5]。MRI引導(dǎo)（與MRI兼容的儀器）[5,7]機(jī)器人輔助手術(shù)入路的發(fā)展可能是ONFH患者關(guān)節(jié)保護(hù)的下一個(gè)前沿。然而，評估它可能需要幾個(gè)志同道合的中心的合作，這些中心治療了大量患有這種疾病的患者?？紤]到它在亞洲某些地區(qū)的相對頻率（與歐洲或美國相比），我猜想更多的這類研究將來自那些具有全球技術(shù)創(chuàng)新的地理位置，我期待著它出現(xiàn)時(shí)的閱讀。
喜報(bào)！韋標(biāo)方教授團(tuán)隊(duì)榮獲國家級中醫(yī)藥項(xiàng)目！近日，從國家中醫(yī)藥管理局官方網(wǎng)站獲悉，韋標(biāo)方教授團(tuán)隊(duì)榮獲國家級中醫(yī)藥項(xiàng)目1項(xiàng)。股骨頭壞死是骨科難治疾病之一。中西醫(yī)結(jié)合治療骨科疾病是當(dāng)前學(xué)術(shù)熱點(diǎn)方向。臨沂市人民醫(yī)院韋標(biāo)方教授團(tuán)隊(duì)歷經(jīng)30余年臨床實(shí)踐，在取得了眾多科研成績的基礎(chǔ)上，再次獲得國家級中醫(yī)藥項(xiàng)目，標(biāo)志著團(tuán)隊(duì)在中西醫(yī)結(jié)合治療股骨頭壞死領(lǐng)域再上新臺階！?韋標(biāo)方教授帶領(lǐng)團(tuán)隊(duì)刻苦攻關(guān)，采用中西醫(yī)結(jié)合方法破解股骨頭壞死醫(yī)療難題，形成了一套成熟的診療方案。堅(jiān)持個(gè)性化分期治療原則，對股骨頭壞死早、中、晚期患者采用階梯治療，診療各類患者20余萬例，深受全國各地患者好評。學(xué)科從無到有，經(jīng)過20余年的努力，成功邁入“國家隊(duì)”——國家級中西醫(yī)協(xié)同旗艦科室。相信團(tuán)隊(duì)會在此基礎(chǔ)上更加努力，更好地服務(wù)于患者。?項(xiàng)目負(fù)責(zé)人簡介韋標(biāo)方，臨沂市人民醫(yī)院骨科主任醫(yī)師，二級教授，博士生導(dǎo)師，博士后導(dǎo)師。國家級中西醫(yī)協(xié)同旗艦科室學(xué)術(shù)帶頭人，享受政府特殊津貼專家，山東省中醫(yī)藥臨床重點(diǎn)?？茖W(xué)術(shù)帶頭人。作者簡介于浩，廣州中醫(yī)藥大學(xué)博士研究生，師從韋標(biāo)方教授，研究方向：中西醫(yī)結(jié)合治療股骨頭壞死。