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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服務(wù)機(jī)構(gòu)身體健康檢查隊列(2002年至2019年)的數(shù)據(jù)進(jìn)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(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，ONFH風(fēng)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(yù)后。由于股骨頭壞死的發(fā)生和預(yù)后是一個復(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(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，許多患者往往在年輕時接受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].韓國國民健康保險服務(wù)(NationalHealthInsuranceService,NHIS)是一項覆蓋韓國約97%公民的國民保險服務(wù)，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(wù)-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(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(fēng)險之間的關(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(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(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(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，ONFH的風(fēng)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(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)時間，如在3個月內(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)險增加有關(guān)，當(dāng)潑尼松龍累積使用1800毫克(180cDDDs)或更多時，ONFH發(fā)展的風(fēng)險迅速增加。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ONFH風(fēng)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(fēng)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(fēng)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(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(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(shè)皮質(zhì)類固醇治療時間越長也與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的危險因素。此外，還證實了低于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(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(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，ONFH的風(fēng)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(yù)后沒有影響。由于ONFH的發(fā)展和預(yù)后是一個復(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，導(dǎo)致早期終末期關(guān)節(jié)炎和THA。這讓這些年輕人經(jīng)歷了一個經(jīng)常需要多次revisions的過程，有時還會出現(xiàn)嚴(yán)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(yù)測哪些患者股骨頭塌陷的風(fēng)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(fēng)險的因素（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。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(guān)[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(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，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.即使在日本的一個創(chuàng)新中心，針對非創(chuàng)傷性O(shè)NFH成功實施截骨術(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，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，股骨頭塌陷被認(rèn)為是進(jìn)行性的；這個增量可能太小而無關(guān)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(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用于實時三維指導(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(shù)創(chuàng)新的地理位置，我期待著它出現(xiàn)時的閱讀。
韋標(biāo)方教授把學(xué)科帶入“國家隊”韋標(biāo)方教授作為股骨頭專科創(chuàng)始人，用了20年時間，把學(xué)科打造成國家級中西醫(yī)協(xié)同旗艦科室。也就是說，用了20年時間，把學(xué)科帶入“國家隊”。在大骨科，本無股骨頭?？萍?xì)分。中國股骨頭壞死患者人群很多病程時間長，以中青年居多。在醫(yī)療2.0時代，如何去關(guān)注這個特殊群體、關(guān)愛這批人？如何讓每一個股骨頭壞死患者受益最大化？有一個人以他獨到的眼光，把它視為一種大情懷、大事業(yè)去做，把它單獨拎出來，倍加深究和考量，也把它視作自身醫(yī)療團(tuán)隊去實現(xiàn)完美逆襲的一個突破口和大機(jī)會。于是，中西醫(yī)結(jié)合治療股骨頭?？茟?yīng)運而生，走向了春天般聚光燈下的舞臺中央。?一組數(shù)據(jù)比對，令人嘆為觀止！一個美國骨科中心，每年的診療股骨頭壞死患者有800-1000人；國內(nèi)較大的骨科醫(yī)院每年診療股骨頭壞死患者也不超過15000人；而在山東省臨沂市人民醫(yī)院股骨頭科，每年診療的股骨頭壞死患者有22000人，妥妥的遙遙領(lǐng)先，而且是以一個蓬勃上揚的豎線生長姿態(tài)，生生地把那幾家排名靠前的醫(yī)院甩開了幾條大街。以一句好理解的話可以概括為：許多需要治療股骨頭壞死的病人，大部分都去了臨沂，臨沂市人民醫(yī)院股骨頭科也成了股骨頭壞死患者最大的集散地。好多人在想，醫(yī)院好專業(yè)那么多，怎么會想到去開辟一個股骨頭?？颇?？好醫(yī)生那么多，這又是怎樣的一個牛人？在那么多好醫(yī)院中，這家是怎么做到全國遙遙領(lǐng)先的呢？他是病人眼里的好醫(yī)生，在中西醫(yī)結(jié)合治療股骨頭壞死領(lǐng)域，始終倡導(dǎo)中西醫(yī)結(jié)合“階梯化”治療，讓患者更受益；他是團(tuán)隊的主心骨，所推行的中西醫(yī)結(jié)合“階梯化”成長路徑，讓每個成員都找準(zhǔn)了自己的成長臺階；他是股骨頭科的創(chuàng)始人，科室從無到有、從弱到強(qiáng)，作為學(xué)科帶頭人，他一直將團(tuán)隊帶到國家級平臺。他就是臨沂市人民醫(yī)院股骨頭科韋標(biāo)方教授。中西醫(yī)結(jié)合“階梯化”治療病人有著14億人口基數(shù)的中國，醫(yī)療向來都是一個紛紛擾擾的話題，說正話反話的都很多，繞不開的焦點不外乎：我們需要更好的醫(yī)療環(huán)境，我們需要更好的醫(yī)生。什么是好醫(yī)生？不同處境、不同場景的每個人心中都有自己的一桿秤。但幾乎可以肯定，一個不懂家庭、情感和悲喜的人，很難成為一名好醫(yī)生。試想，一個人生病，無論輕癥還是重癥，對于患者來講，事關(guān)身體，絕無小事。在這種情境下，醫(yī)生如果做不到換位思考，就很難理解病人和家屬的情形，很可能做出錯誤的選擇，從而加深病人的傷痛。談及這些，對于股骨頭壞死的治療，韋標(biāo)方毫不回避他的定海神針——中西醫(yī)結(jié)合“階梯化”治療觀：股骨頭壞死是世界級骨科難題，單純的中醫(yī)或西醫(yī)都不能幫你解決問題，需要中西醫(yī)結(jié)合階梯化治療，根據(jù)疾病不同階段、不同表現(xiàn)、患者個體化差異，采取不同的治療方案。在病情較輕的初期，可通過簡單的中藥內(nèi)服、中藥外敷配合功能鍛煉，達(dá)到股骨頭壞死的有效控制。如果病情進(jìn)一步發(fā)展，則用保髖手術(shù)聯(lián)合中藥治療。而在股骨頭壞死后期，則需要全髖關(guān)節(jié)置換配合中藥治療?！拔业墓晒穷^壞死治好啦，不用換關(guān)節(jié)了?！比照帐袞|港區(qū)的包女士高興地說。包女士骨頭壞死屬于早期，韋主任用了一段時間的中藥治療，最終，包女士沒再換關(guān)節(jié)。中醫(yī)中藥治療股骨頭壞死可讓大部分早期患者不用手術(shù)，基本恢復(fù)到正常生活的狀態(tài)，韋標(biāo)方教授團(tuán)隊歷經(jīng)數(shù)十年，形成了一套成熟的股骨頭壞死診療方案。?12月底，年關(guān)將近，新年的日歷即將翻開。臨沂剛下過一場瑞雪，在臨沂市人民醫(yī)院的股骨頭科病房，筆者親身感受到了韋標(biāo)方團(tuán)隊的骨干們與來自天南地北患者們之間溝通的熱度。學(xué)科帶頭人韋標(biāo)方教授也在其中，忙得不亦樂乎，不是電話接個不停，就是走廊上被病人家屬“攔截”，親眼目睹了這位“最美醫(yī)生”與患者之間的“零距離”。一個病人還開了韋主任一句玩笑：“韋主任這么年輕，比電視上還要帥！”值得一提的是，線上做科普，線下做醫(yī)治，也是韋標(biāo)方的神來一筆。他通過各種傳播方式貼近病友，宣傳中西醫(yī)結(jié)合階梯化治療股骨頭壞死，僅單個社交平臺就擁有近萬粉絲，很多外地患者，就是通過他的科普，慕名前來?，F(xiàn)在飛機(jī)、高鐵很方便，除了本省的病人、外省的患者多了起來。中西醫(yī)結(jié)合“階梯化”培育團(tuán)隊既然選擇了醫(yī)生這個職業(yè)，就要有一個成為“神醫(yī)”的理想，去成為“華佗再生”、“扁鵲再世”這樣的一個人。永遠(yuǎn)以謙卑的心態(tài)，向?qū)I(yè)大醫(yī)級的最強(qiáng)者學(xué)習(xí)，帶著團(tuán)隊向著有光的地方行進(jìn)，也讓自己成為一個有光的人。韋標(biāo)方教授在科室推行的中西醫(yī)結(jié)合“階梯化”團(tuán)隊成長計劃，在管理上，首先得到了院領(lǐng)導(dǎo)的充分肯定；在專業(yè)上，在國際上得到了歐洲關(guān)節(jié)中心ThorstenGehrke教授的支持；在國內(nèi)得到了人工關(guān)節(jié)之父呂厚山教授、林劍浩教授團(tuán)隊的支持；在中西醫(yī)結(jié)合階梯化治療股骨頭壞死方面得到了全國著名股骨頭壞死診療專家、廣州中醫(yī)藥大學(xué)附屬醫(yī)院何偉教授的鼎力支持。特別值得一提的是，不論是保髖課程的普及，還是技術(shù)方向的提升等，何偉教授都給予了無私的奉獻(xiàn)和傳授。在專業(yè)上，韋標(biāo)方主任從不吝嗇自己的學(xué)究、門道和成果，毫無保留地不斷向外分享經(jīng)驗、輸出技術(shù)，讓更多的同行認(rèn)可中西醫(yī)結(jié)合理念，讓更多患者受益。自身的醫(yī)學(xué)成就，如果能最大限度地轉(zhuǎn)化為治療價值、團(tuán)隊價值、社會價值，這是他最想看到的。韋標(biāo)方從醫(yī)40年，帶領(lǐng)團(tuán)隊診療患者10余萬例，用20年的時間把科室打造成國家級的診療團(tuán)隊。獲評“山東好醫(yī)生”、“山東省五一勞動獎?wù)隆钡葮s譽稱號，同時獲批“山東省韋標(biāo)方教授創(chuàng)新工作室”?！笆姑鈽s，做一名永遠(yuǎn)在路上的傳承者”。這句話很好地詮釋了韋標(biāo)方教授教書育人的初心。?中西醫(yī)結(jié)合“階梯化”發(fā)展學(xué)科“我將竭盡全力，在學(xué)科建設(shè)、人才培養(yǎng)等方面，為全市、乃至全省股骨頭壞死事業(yè)發(fā)展做好支撐，打造一支高水平的學(xué)科醫(yī)療人才隊伍?！表f標(biāo)方主任說。?在韋主任及團(tuán)隊的努力下，股骨頭科也一步步成長起來，把臨沂經(jīng)驗變?yōu)樯綎|標(biāo)準(zhǔn)，并帶領(lǐng)科室走向國家級中西醫(yī)結(jié)合旗艦學(xué)科的平臺。很多年前，臨沂的股骨頭壞死治療幾乎是一個空白，“股骨頭壞死是不死的癌癥”“股骨頭壞死很快就會癱瘓”，許多患者聽信這些傳言，到處求“偏方”，同時由于基層醫(yī)院缺乏經(jīng)驗豐富的?？漆t(yī)生，患者往往得不到有效治療，喪失勞動能力。在此背景下，韋標(biāo)方教授前往全國各地交流學(xué)習(xí)，不斷補(bǔ)強(qiáng)。憑借36年的臨床經(jīng)驗，韋標(biāo)方教授團(tuán)隊總結(jié)出中西醫(yī)結(jié)合治療股骨頭壞死的成熟方案：能不手術(shù)的就不手術(shù)，能“保髖”的不換髖，需要換髖的不再勉強(qiáng)“保髖”。?“韋標(biāo)方教授及團(tuán)隊在中西醫(yī)結(jié)合治療股骨頭壞死領(lǐng)域是做出了貢獻(xiàn)的。”許多同行這樣評價韋主任。多家媒體采訪也表示，自從韋標(biāo)方教授在魯南地區(qū)創(chuàng)建了股骨頭科，成為了千萬百姓的福音，越來越多的股骨頭壞死患者的健康得到了保障。韋主任卻自嘲地說：“臨沂市人民醫(yī)院之前沒有股骨頭科也正常運轉(zhuǎn)，但有了股骨頭科，廣大患者受益了，感覺自己及團(tuán)隊在中西醫(yī)結(jié)合治療股骨頭壞死方面做出了貢獻(xiàn)，得到了認(rèn)可?！背酥?，韋標(biāo)方教授還身兼國家中西醫(yī)結(jié)合旗艦學(xué)科學(xué)術(shù)帶頭人、國際骨壞死循環(huán)研究會(ARCO)中國區(qū)資深常務(wù)委員等10余個大醫(yī)級頭銜。他很喜歡社會和病人給予他的“最美醫(yī)生”以及“好大夫”的稱謂，他感覺很親切、很踏實，也很有斗志和希望感。韋標(biāo)方教授帶領(lǐng)團(tuán)隊走向國家級學(xué)科平臺向?qū)W科帶頭人韋標(biāo)方教授及團(tuán)隊致敬，我們需要千千萬萬韋標(biāo)方式的“最美醫(yī)生”，好大夫。一定要說一句感謝的話作為本次的結(jié)尾：感謝學(xué)科帶頭人韋標(biāo)方教授，祝愿他帶領(lǐng)的骨科團(tuán)隊，在這份春天般的事業(yè)上，沿著中西醫(yī)結(jié)合“階梯化”的道路，一步一個腳印的走得更高，走得更遠(yuǎn)；也祝愿天下所有被股骨頭壞死困擾的患者，在韋標(biāo)方教授及團(tuán)隊中西醫(yī)結(jié)合“階梯化”醫(yī)療的臺階上，早日康復(fù)，奔向?qū)儆谧约旱脑娕c遠(yuǎn)方！?