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激素使用對股骨頭骨壞死發(fā)生和進展的影響:一項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)生和進展的影響:一項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，沒有關于皮質(zhì)類固醇使用與ONFH患者股骨頭塌陷之間關系的研究。我們的目的是調(diào)查普通人群中皮質(zhì)類固醇使用與ONFH風險之間的關系，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節(jié)置換術(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服務機構(gòu)身體健康檢查隊列(2002年至2019年)的數(shù)據(jù)進行了一項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、隨訪時間等變量對ONFH患者進行1:5匹配，形成對照組。此外，在患有ONFH的患者中，我們尋找進展為THA的危險因素。?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。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展到THA沒有影響。?ConclusionsTheONFHriskincreasedrapidlywhencumulativeprednisoloneusewas≥1,800mg.However,oralorhigh-doseintravenouscorticosteroiduseandcumulativedosedidnotaffecttheprognosisofONFH.SincetheoccurrenceandprognosisofONFHarecomplexandmultifactorialprocesses,furtherstudyisneeded.當累積使用潑尼松龍≥1800mg時，ONFH風險迅速增加。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后。由于股骨頭壞死的發(fā)生和預后是一個復雜的多因素過程，需要進一步研究。?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)可引起嚴重的髖關節(jié)疼痛，在相對年輕的患者中，最終可導致股骨頭塌陷并隨后迅速破壞髖關節(jié)[1-3]。股骨頭塌陷引起的頑固性疼痛最終導致在年輕時進行全髖關節(jié)置換術(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成共識[6-9]。據(jù)推測，骨血流灌注受損、細胞修復過程異常以及基因點突變可能影響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。有幾項研究報道，在3個月內(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[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)計學和流行病學變異方面存在異質(zhì)性。一旦發(fā)生ONFH，預后很差，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，許多患者往往在年輕時接受THA，因此預測股骨頭塌陷的預后與預測ONFH的發(fā)生同樣重要。多項研究表明，ONFH患者股骨頭塌陷與壞死灶的大小、體積、位置和解剖學參數(shù)有關[1,2,18,19]。然而，目前還沒有關于ONFH患者使用皮質(zhì)類固醇與股骨頭塌陷之間關系的研究。TheNationalHealthInsuranceService(NHIS)ofSouthKoreaisanationalinsurancecoverageservicethatcoversabout97%ofcitizensinSouthKorea,includingdemographicdataandaclaimdatabaseincludingdiagnosesandprescriptions[20].Additionally,theNHISoffershealthscreeningexaminationsforinsuredKoreansaged40yearsorolder,includingbasicbloodtests,smoking,drinking,andphysicalactivitiesusingself-reportedquestionnaires.BecausetheNationalHealthInsuranceService–NationalSampleCohort(NHIS-NSC)isahighlyrepresentativepopulation-basedcohortoftheentireKoreanpopulation,itcanbeusedasapopulation-based,nationwidestudyforepidemiologicresearchonvariousdiseases[20-22].韓國國民健康保險服務(NationalHealthInsuranceService,NHIS)是一項覆蓋韓國約97%公民的國民保險服務，包括人口統(tǒng)計數(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、飲酒和使用自我報告問卷的體育活動。由于國民健康保險服務-國民樣本隊列(NationalHealthInsuranceService-NationalSampleCohort,NHIS-NSC)是韓國人口中極具代表性的基于人群的隊列，因此可以作為一項基于人群的全國性研究，用于各種疾病的流行病學研究[20-22]。Therefore,inthepresentstudy,weaimedtoinvestigatetheassociationbetweencorticosteroiduseandtheriskofONFHdevelopmentamongthewholegeneralpopulationandwhatfactorsaffectONFHdevelopmentusinganationwidelargesamplefromlongitudinalnestedcase-controldatainalong-termcohortstudy.Inaddition,weaimedtodemonstratewhichfactorsaffectTHAafterthedevelopmentofONFH.因此，在本研究中，我們旨在通過一項長期隊列研究，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)類固醇使用與整個普通人群中ONFH發(fā)生風險之間的關系，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身體健康檢查隊列(NHIS-nsc)2.0數(shù)據(jù)庫[23]。國民健康保險制度-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，并進行了分層和隨機抽樣。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)。納入國家健康保險制度-國家安全保障制度的所有個人都被跟蹤到2019年，除非死亡或喪失參加國家健康保險的資格，例如移民。本研究的方案經(jīng)我院機構(gòu)審查委員會(4-2022-0304)和NHIS(NHIS-2022-2-232)批準。?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健康問題統(tǒng)計分類第十次修訂版(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)(補充表1)。為避免長度偏倚，設計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、隨訪時間等變量對ONFH患者進行1:5匹配，形成對照組。對照組(N=12)采用相同的排除標準。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代碼進行原發(fā)性或首次繼發(fā)性診斷時至少進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。我們對兩組患者進行比較，并使用Cox比例風險模型進行分析，分析影響THA病情進展的因素(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。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。特別是，當皮質(zhì)類固醇的累積使用劑量達到180或更高時，ONFH的風險迅速增加。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、當前吸煙者、血清TG水平≥200mg/dL的男性在ONFH診斷后與THA相關。然而，在調(diào)整復合因素后，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)時間，如在3個月內(nèi)使用超過2g與疾病發(fā)展的關系[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)展的風險增加有關，當潑尼松龍累積使用1800毫克(180cDDDs)或更多時，ONFH發(fā)展的風險迅速增加。當然，與皮質(zhì)類固醇使用相關的ONFH的發(fā)展被認為不僅是由皮質(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重要，因此有必要了解在需要持續(xù)皮質(zhì)類固醇治療時ONFH風險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的風險，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，風險更高;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)類固醇的強的松龍效力遠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)類固醇的使用時間會更長。Mont等人報道ONFH的發(fā)生與皮質(zhì)類固醇的平均每日劑量、累積劑量和治療時間有關[8]。當然，ONFH的發(fā)生會受到遺傳易感性和暴露于各種危險因素的影響，但在我們的研究中，我們證實在相同累積劑量下，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，因此我們假設皮質(zhì)類固醇治療時間越長也與ONFH的發(fā)生有關。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的重要危險因素，而ONFH被認為與股骨頭血流的抑制有類似的機制[29]。與以往的研究相似[7,30]，在我們的研究中，高TG是ONFH的危險因素。此外，還證實了低于100mg/dL的LDL對ONFH的發(fā)生有保護作用。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節(jié)，因此疾病的進展和預后與疾病的發(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因素或髖臼解剖因素對ONFH的預后有影響[1,19,31]。Mont等人在一項薈萃分析中報道，股骨頭塌陷的患病率為38%(282髖中的106髖)，根據(jù)危險因素的不同，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。雖然無法進行放射學評估，但可能出現(xiàn)較大身體負荷的病例，如男性，BMI較高，過度飲酒，吸煙，血清TG水平高于200mg/dL，與疾病進展相關。特別是，增加疾病進展風險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.我們的研究有幾個潛在的局限性，應該在進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行評估，而不是通過x射線或MRI等放射學評估。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，該研究使用髖關節(jié)X光片和/或MRI來定義ONFH[32]。由于可能沒有對ONFH患者進行準確的選擇，因此進行了基于人群的隊列嵌套病例對照分析，以提高分析的準確性。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，受試者的實際皮質(zhì)類固醇攝入量可能與處方記錄不同。幸運的是，有幾項研究表明，處方與實際接觸藥物之間存在良好的相關性[33,34]。此外，我們無法獲得有關創(chuàng)傷性ONFH的信息，這可能影響了當前研究的結(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措施，如使用降脂藥物、阿司匹林、抗血小板和抗凝藥物。這應該在未來的研究中進行評估。此外，對風濕病、鐮狀細胞病、人類免疫缺陷病毒、器官移植等可能影響ONFH發(fā)生和預后的多重合并癥未進行分析。特別是，由于每種疾病的預后不同，因此根據(jù)合并癥進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展之間的關系，我們證實皮質(zhì)類固醇累積劑量不影響疾病進展。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行額外分析，以獲得更準確的結(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。具體來說，當累積使用強的松龍超過1800毫克時，ONFH的風險迅速增加。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的預后沒有影響。由于ONFH的發(fā)展和預后是一個復雜的多因素過程，需要進一步研究。
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風險，導致早期終末期關節(jié)炎和THA。這讓這些年輕人經(jīng)歷了一個經(jīng)常需要多次revisions的過程，有時還會出現(xiàn)嚴重的并發(fā)癥。基于ONFH的大小、范圍、體積和位置的分類系統(tǒng)可以幫助外科醫(yī)生預測哪些患者股骨頭塌陷的風險最大[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險的因素（無論這些因素是與宿主相關的因素還是干預措施），隨著時間的推移，臨床科學家正在發(fā)現(xiàn)舊分類系統(tǒng)中未包括的新風險因素。這些因素可能包括骨盆入射角和髖臼覆蓋范圍，這可能導致股骨頭上更大的接觸應力，并可能影響ONFH患者進展的風險。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的線與從該點到股骨頭中心的線之間的夾角，據(jù)報道，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[6]。然而，另一項研究卻有所不同，沒有發(fā)現(xiàn)骨盆發(fā)病率與髖臼覆蓋率之間的關聯(lián)[3]。在臨床骨科及相關研究?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]。基于此，ONFH患者盆腔發(fā)生率與股骨頭塌陷之間的關系仍不確定。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大小僅為4°，并且在髖臼三維覆蓋的矢狀面和軸向面四個額外的角度參數(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)歷了快速進行性塌陷（24個月內(nèi)可能上升到71%[6]）。另一方面，ONFH患者的手術治療結(jié)果與外側(cè)中心邊緣角之間的關聯(lián)已被記錄；較小的角度會帶來很大的塌陷和髖關節(jié)存活風險，從而導致ONFH游離帶血管腓骨移植術后的THA[9]，這與當前研究[4]所調(diào)查的自然病史不同。ThekeymessageofthisstudyinCORR?[4]isthatmorethanone-thirdofpatientswithsymptomaticONFHoninitialpresentationexperiencedacceleratedcollapseofthefemoralheadwithin1year,andthatacetabularcoveragewasnotasstronganassociatedfactorinthenaturalhistoryofONFHasonemighthaveexpectedittobe.Basedonthesefindings,surgeonsshouldfocusonsymptomaticONFHandmonitorsusceptiblevascularityandearlycollapsecloselywithin2yearsafterpresentationforappropriatejoint-preservinginterventions,withconservationandpromotionofvascularity.CORR?[4]這項研究的關鍵信息是，超過三分之一的首發(fā)癥狀性ONFH患者在1年內(nèi)股骨頭加速塌陷，并且髖臼覆蓋在ONFH自然病史中的相關因素并不像人們預期的那樣強?；谶@些發(fā)現(xiàn)，外科醫(yī)生應關注有癥狀的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?shù)谋ｊP節(jié)干預措施，保護和促進血管。?WhereDoWeNeedtoGo?我們需要去哪里?Althoughthevascularenvironmentandmechanicalenvironmentarenotalwaysentirelyindependentofoneanother,IbelievenontraumaticONFHpredominantlyreflectsdeteriorationofthevascularityofthefemoralhead,whetherasaprimaryphenomenon,asecondaryone,orboth.盡管血管環(huán)境和機械環(huán)境并不總是完全獨立的，但我認為非創(chuàng)傷性ONFH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.即使在日本的一個創(chuàng)新中心，針對非創(chuàng)傷性ONFH成功實施截骨術，根據(jù)嚴格的標準，30歲以下的患者中只有9%被選中進行股骨截骨術，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）、機械變異和髖關節(jié)形態(tài)的變化值得在手術計劃之前進行精確的調(diào)查，當考慮進行關節(jié)保護手術（如截骨）時，為了保持股骨頭的血液供應。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.未來的研究還應評估坍塌的程度和速度。在目前的研究中[4]，當股骨頭塌陷的數(shù)量比之前的X線片增加>1mm時，股骨頭塌陷被認為是進行性的；這個增量可能太小而無關緊要。另一項研究報道，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間內(nèi)無癥狀[8]?？焖贊u進和靜態(tài)坍塌需要基于精確標準的密切監(jiān)測。Otherfundamentalquestionsrelatetojointpreservationthroughnonoperativeoptionsincludingmedicationssuchastransientbisphosphonatesforprecollapselesionsorpotentiallyforsmall,mediallesions;directsurgicaloptionsrelatedtopreservationofandimprovementinvascularityincludingcoredecompression,adjunctivebonegrafting,andvascularizedbonegrafting;selectiveredirectionalosteotomiestoreducemechanicalstressesandfacilitatevascularimprovement;andtheadditionofnoveladjunctivetherapiesincludingstemcelltherapiesinisolationorincombination.其他基本問題涉及到通過非手術選擇來保護關節(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的直接手術選擇包括髓芯減壓、輔助植骨和帶血管的植骨；選擇性定向截骨術減少機械應力，促進血管改善;以及新的輔助療法的加入，包括分離或聯(lián)合的干細胞療法。FuturestudiesmustevaluatepatientswithsymptomaticprecollapselesionscausedbynontraumaticONFHtoidentifyanomaliesofthevascularsupplyandvariationsinmicrocirculatorypatternsandcollateralcirculation.Thiswillhelpguidesurgicalplanningtopreserve,promote,andrestorethatvascularsupply.Whetherthatmightbethroughprecisesurgicaltargetingofcoredecompressionorvascularizedbonegraftingisyettobedetermined.未來的研究必須評估非創(chuàng)傷性ONFH引起的癥狀性塌陷前病變患者，以確定血管供應異常、微循環(huán)模式和側(cè)枝循環(huán)的變化。這將有助于指導手術計劃，以保護、促進和恢復血管供應。這是否可能是通過精確的手術靶向髓芯減壓或血管化骨移植尚未確定。?HowDoWeGetThere?我們?nèi)绾蔚竭_那里?Theannualincidenceofnew-onsetONFHwasreportedtobe1.91per100,000personsinJapan[2],whichmakesaccumulatingpatientsdifficultforsingle-centerstudies,especiallyforasubgroupanalysis.Obviously,studieswithmorepatientsareneededinthefutureforcomprehensiveanalyses.Multicenterstudieswithsuperiorstatisticalpowerincludingsubgroupsarelikelytocontributemore-robustdataandconclusionswithwiderimplicationsforprecisetimingofadvancingmodalitiesofinvestigationsanddifferentialmanagementoptionsofONFH.據(jù)報道，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行全面分析。包括亞組在內(nèi)的具有卓越統(tǒng)計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的先進調(diào)查模式的精確時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.增強磁共振動脈造影值得更多關注。它可以用來評估髖關節(jié)塌陷前的血管損傷，并幫助我們預測哪些髖關節(jié)塌陷的風險最大?？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，使用這種技術進行預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用于實時三維指導髓芯減壓在技術上是可行的、安全的、準確的[5]。MRI引導（與MRI兼容的儀器）[5,7]機器人輔助手術入路的發(fā)展可能是ONFH患者關節(jié)保護的下一個前沿。然而，評估它可能需要幾個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創(chuàng)新的地理位置，我期待著它出現(xiàn)時的閱讀。