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05月22日
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陶可主治醫(yī)師 北京大學人民醫(yī)院 骨關節(jié)科 干細胞治療股骨頭壞死：最新進展及未來研究發(fā)展趨勢作者：LeiZhao,AlanDavidKaye,AaronJKaye,AlaaAbd-Elsayed.作者單位:DepartmentofOrthopedics,ShandongProvincialHospitalAffiliatedwithShandongUniversity,Jinan,250021,China.譯者：陶可（北京大學人民醫(yī)院骨關節(jié)科）摘要綜述目的：股骨頭壞死（ONFH）是一種常見病、多發(fā)病。它是由不同病因導致的血液供應中斷引起的。股骨頭壞死（ONFH）導致股骨頭軟骨下骨變性、壞死，最終導致股骨頭塌陷。股骨頭壞死（ONFH）致殘率較高，嚴重影響患者生活質量，且常累及中青年人群。最新發(fā)現：近年來，干細胞和再生醫(yī)學的技術和理解不斷發(fā)展。許多研究報告了干細胞移植治療股骨頭壞死（ONFH）的成功結果。因此，干細胞移植有望成為治療股骨頭壞死（ONFH）的新方法。因此，在本報告中，我們評估了利用干細胞治療股骨頭壞死（ONFH）的現有技術和結果。通過計算機在線檢索2006年1月至2017年6月期間的PubMed和Cochrane圖書館數據庫，使用英文關鍵詞“治療、干細胞、股骨頭壞死”檢索相關文章。選取與股骨頭壞死（ONFH）治療相關的文獻。我們的檢索共獲得161篇文章，但只有9篇文章符合我們的納入標準并被納入我們的報告中。本綜述表明，細胞技術在治療股骨頭壞死（ONFH）方面已顯示出良好的證據。然而，這項技術還需要進一步深入研究，以更好地探索和解決更理想的方法來克服與細胞來源相關的困難。圖示：干細胞技術被廣泛用于治療股骨頭壞死（ONFH）、骨缺損、神經退行性病變等相關疾病手術治療如果股骨頭壞死(ONFH)進展迅速且非手術治療無效，則需要手術治療。外科手術主要包括兩大類：股骨頭本身重建和全髖關節(jié)置換術(THA)。保留股骨頭的手術技術包括：髓芯減壓、截骨術以及有或無血供的植骨[36]。髓芯減壓是治療早期股骨頭壞死(ONFH)的重要手術方法之一。主要是通過髓芯減壓突破硬化區(qū)，導致骨內壓降低、血液供應改善[37]。髓芯減壓更適合早期股骨頭壞死(ONFH)患者。一些臨床醫(yī)生發(fā)明了血管化和非血管化骨移植物，或設計了用其他材料（例如鉭棒）支撐的支架治療股骨頭壞死(ONFH)[38]。目前植骨治療股骨頭壞死(ONFH)的適應癥有：（1）帶血管腓骨移植；(2)帶血管蒂髂骨移植術；(3)游離腓骨移植；(4)骨瓣移植；(5)病灶清除、打壓植骨手術；(6)病灶切除、記憶合金網植入；(7)病灶切除、打壓植骨、多孔鉭釘支撐手術。各種植骨都存在問題，因此多孔鉭棒得到了廣泛的應用。與傳統(tǒng)的單一打壓植骨相比，多孔鉭棒支撐組合在I-II期股骨頭壞死(ONFH)中具有明顯優(yōu)勢。一項研究發(fā)現，股骨頭髓芯減壓聯合植骨、2mm打壓植骨加多孔鉭棒支撐等手術方法對股骨頭壞死(ONFH)患者，可延長股骨頭壽命，推遲全髖關節(jié)置換術(THA)時間[39]。截骨術的目的是去除股骨頭承重區(qū)的壞死區(qū)。截骨術包括股骨轉子旋轉的內翻或外翻截骨術等，以不改變股骨髓腔為原則[40,41]。如果股骨頭塌陷嚴重（ARCO分期、IIIC和IV），并且關節(jié)功能嚴重喪失或中度疼痛，應選擇全髖關節(jié)置換術(THA)。傳統(tǒng)治療結合干細胞治療股骨頭壞死(ONFH)干細胞MSCs來源于中胚層間充質，廣泛分布于骨髓、骨膜、肌肉、滑膜、滑液、肝臟、外周組織、臍帶血、脂肪、胎盤、胎肺、胎腎、臍帶等組織中[42,43]。從這些組織中分離提取出具有多向分化能力的間充質干細胞，細胞具有很強的自我更新和增殖能力[44]。它們在特定的誘導條件下可以分化為骨、軟骨、脂肪組織、肌肉、肌腱和血管內皮細胞，甚至可以分化為神經細胞[45]。相關研究表明干細胞MSC同種異體移植不會發(fā)生排斥反應[46]。它已廣泛應用于干細胞移植、基因治療、組織工程和其他研究工作。對于許多難治性疾病，細胞移植似乎是一種相對有效的療法。移植的自體細胞通常具有特定的功能，包括修復受損區(qū)域，避免使用傳統(tǒng)藥物對身體產生的毒性作用或副作用[47]。間充質干細胞已廣泛應用于骨缺損、軟骨缺損、組織損傷、骨關節(jié)炎、股骨頭壞死等修復。間充質干細胞也已應用于臨床實踐的其他領域[48]。干細胞治療股骨頭壞死(ONFH)是當前研究的熱點，研究表明干細胞在特定條件下可以分化為成骨細胞。成骨細胞在骨壞死修復過程中發(fā)揮著重要作用，研究表明，使用骨髓干細胞移植到壞死股骨頭中可以使股骨頭壞死(ONFH)的發(fā)生率降低至0%[49]。髓芯減壓聯合干細胞MSC移植髓芯減壓后的干細胞MSC移植可以為壞死股骨頭的修復和重建提供種子細胞[16]。Tabatabaee等的一項研究中[14]，在髓芯減壓的基礎上，對18例28髖的股骨頭壞死(ONFH)患者進行自體骨髓移植，所有患者平均隨訪2年。所有患者的西安大略大學和麥克馬斯特大學平均骨關節(jié)炎指數(WOMAC)和視覺模擬量表(VAS)評分均顯著改善。磁共振成像（MRI）顯示聯合治療組有顯著改善。研究人員認為，這項技術可用于改善股骨頭壞死區(qū)域的修復，至少在股骨頭壞死(ONFH)的早期階段是這樣。Rastogi等[13]也得出結論，髓芯減壓聯合自體骨髓干細胞植入是一種安全有效的方法。Sen等進行了一項臨床對照研究，表明在髓芯減壓后將自體骨髓單核細胞注入核心道可以為治療股骨頭壞死(ONFH)帶來更好的臨床結果和髖關節(jié)存活率[15]。Ma等[18]評價基于髓芯減壓的骨髓血沉棕黃層（BBC）植入治療股骨頭壞死的效果。作者得出結論，在治療的第二年，92%的股骨頭壞死(ONFH)患者的髖關節(jié)功能得到改善。更重要的是，治療組ARCO分期I/II期髖部無進展率為100%，對照組為66.7%[18]。Zhang等等[17]指出，髓芯減壓聯合自體骨髓間充質干細胞移植可以減輕疼痛，延緩或避免股骨頭塌陷。MRI評估發(fā)現軟骨病變面積顯著縮小，軟骨質量顯著改善。Gangji等[19]比較了核心減壓聯合含有間充質干細胞（MSCs）或自體成骨細胞（OB）的骨髓濃縮物（BMC）治療股骨頭壞死(ONFH)的效果。他們發(fā)現，除了減輕股骨頭壞死(ONFH)的疼痛之外，自體成骨細胞（OB）植入在延緩骨循環(huán)協會(ARCO)III期進展方面比干細胞BMC治療更有效。然而，其他研究人員卻得出了不同的結論。Lim等[11]進行了一項對照試驗，比較了兩組治療股骨頭壞死的臨床效果和影像學結果：一組采用多次鉆孔減壓聯合干細胞移植，另一組采用干細胞移植聯合其他髓芯減壓方法：刮除術、植骨術等。結論是兩組之間沒有統(tǒng)計學上的顯著差異。從本研究來看，對于ARCOI-II期塌陷期的股骨頭壞死(ONFH)，髓核減壓聯合干細胞MSC移植獲得了良好的手術效果，但對于塌陷后的ARCOIII-IV期患者，這種手術方式效果不佳。生物力學支持和干細胞MSC動脈輸注股骨頭壞死(ONFH)發(fā)生后，盡管進行了髖關節(jié)挽救治療，改善股骨頭內的血液供應始終是該疾病的主要治療方法之一。自體干細胞移植和血管再生技術可以在治療中發(fā)揮重要作用。Kocher等[50]證實干細胞MSCs和內皮祖細胞可以促進缺血血流恢復。Kinnaird等[51]發(fā)現，將骨源干細胞肌肉注射到大鼠缺血后肢后，骨源干細胞可以促進側支循環(huán)和肢體功能恢復。此外，與血管生成相關的細胞因子基因表達水平增加。Mao等[12]進行了一項對照試驗，其中55例89髖的股骨頭壞死(ONFH)患者接受鉭棒植入聯合間充質干細胞靶向動脈內灌注，所有患者均隨訪36個月。隨訪36個月時，聯合治療組中有3個髖關節(jié)（6.25%）被發(fā)現臨床失敗，需要進行全髖關節(jié)置換術THA；相比之下，對照組中有9個髖關節(jié)（21.95%）接受了全髖關節(jié)置換術THA。與對照組相比，聯合治療在36個月時顯著改善了Harris髖關節(jié)評分(HHS)。他們的結論是，干細胞MSC動脈輸注是治療早期股骨頭壞死(ONFH)的有效且安全的方法。與開放式股骨頭干細胞移植相比，干細胞MSC選擇性動脈輸注具有干細胞存活更好、分化更好、操作創(chuàng)傷小、不良反應少、患者依從性好等優(yōu)點。手術可達到以下效果：（1）疏通病變股骨頭，改善靜脈回流，降低骨內壓，恢復或改善股骨頭的血液供應。(2)改善或增加股骨頭壞死區(qū)及髖關節(jié)周圍組織的血液循環(huán)，為壞死股骨頭提供良好的局部血液供應。(3)干細胞MSCs可以保護局部血管內皮，促進血管內皮細胞的修復、再生和血管生成。隨著干細胞干預的進一步研究，這種方法似乎對未來的股骨頭壞死(ONFH)患者有積極作用。骨組織工程和間充質干細胞組織工程是應用細胞生物學，在體外培養(yǎng)功能相關的活細胞，復合移植體內組織缺損并完成修復和重建。干細胞MSCs具有較強的分化潛能和增殖能力，細胞在來源、分離方式、分化組織類型等方面對于修復股骨頭壞死(ONFH)骨缺損具有獨特的優(yōu)勢。因此，它是骨組織工程種子細胞最理想的選擇。干細胞MSCs制成的復合支架可用于加強股骨頭壞死區(qū)域的修復，但也可以用作細胞、基因和生長因子的生物載體。此外，間充質干細胞可以整合細胞和受體來調節(jié)細胞功能。Kang等[52]報道采用自體髂骨松質骨移植聯合間充質干細胞移植治療股骨頭壞死(ONFH)患者，隨訪32個月，臨床療效良好。Kawate等[53]采用β-磷酸三鈣作為載體承載自體骨髓干細胞BMSCs植入股骨頭壞死部位聯合血管化腓骨移植治療股骨頭壞死(ONFH)，長期隨訪發(fā)現大部分股骨頭壞死部位患者緩解至影像學觀察不同程度的局部高密度新骨形成。該疾病已得到控制，表明組織工程方法具有更好的治療股骨頭壞死(ONFH)的潛力。Yamasaki等[54]報道22例（30髖）股骨頭壞死(ONFH)患者接受單核細胞聯合磷酸鈣治療，8例（9髖）股骨頭壞死(ONFH)患者僅接受磷酸鈣治療。平均隨訪時間為29個月。治療組股骨頭壞死面積減少，僅3髖（3/30）出現股骨頭塌陷，而對照組6髖（6/8）出現嚴重股骨頭塌陷。Xiao等[55]在復合骨上用自體骨髓間充質干細胞結合重組人骨形態(tài)發(fā)生蛋白2修復了兔股骨頭壞死(ONFH)缺損，他們發(fā)現這種方法可以防止塌陷并能形成新的骨組織。骨組織工程的興起為干細胞MSCs治療股骨頭壞死(ONFH)提供了有力支持。干細胞MSC移植聯合細胞因子隨著更多研究確定股骨頭壞死(ONFH)病因和發(fā)病機制，細胞因子已成為股骨頭壞死(ONFH)治療的焦點。目前已發(fā)現多種細胞因子可促進干細胞MSCs分化為骨細胞和軟骨細胞[56]。股骨頭壞死(ONFH)基礎實驗中使用的細胞因子包括骨形態(tài)發(fā)生蛋白（BMP）、血管內皮生長因子（VEGF）、堿性成纖維細胞生長因子（BFGF）、腫瘤壞死因子（TNF）等。這些因子可以誘導干細胞MSC不可逆地分化為成骨細胞，有的可以誘導新生血管形成并參與股骨頭壞死(ONFH)的修復[57]。Reddi等[58]得出結論，骨形態(tài)發(fā)生蛋白（BMP）可以使間充質細胞首先分化為軟骨細胞，然后分化為成骨細胞。成骨細胞可用于治療股骨頭壞死，這與它們在促進新骨形成、血運重建和促進關節(jié)軟骨生長方面的作用有關。堿性成纖維細胞生長因子（BFGF）具有較強的成骨和誘導血管生成作用，與骨形態(tài)發(fā)生蛋白（BMP）聯合應用效果優(yōu)于單獨應用骨形態(tài)發(fā)生蛋白（BMP）。Jin等[59]通過堿性成纖維細胞生長因子（BFGF）和骨形態(tài)發(fā)生蛋白（BMP）作用于兔股骨頭壞死(ONFH)，觀察到壞死區(qū)域新生骨小梁的形成，由此，作者得出結論，堿性成纖維細胞生長因子（BFGF）和骨形態(tài)發(fā)生蛋白（BMP）可以顯著促進骨細胞和成纖維細胞的生長和增殖。血管生成因子促進股骨頭壞死區(qū)域相對于正常區(qū)域的血運重建。血管生成因子可以維持壞死區(qū)域的血液供應，可能作為治療股骨頭壞死(ONFH)的有效手段。血管內皮生長因子（VEGF）具有很強的促進內皮生長和血管生成的作用，其他血管生成因子通過增強血管內皮生長因子（VEGF）的表達和產生來全部或部分促進血管生成[60]。盡管許多研究證明生長和分化因子在骨壞死的治療中發(fā)揮著重要作用，但這些研究都是在體外或動物實驗中進行的，并沒有直接證據證明它們在人體中的有效用途。在這方面，較新的治療方法通常基于對病理過程的更好理解。隨著對股骨頭壞死(ONFH)過程了解的加深，各種生長和分化因子的作用將逐漸變得清晰，這種類型的治療可能會在未來出現[61]。?SurgicalTreatmentSurgicaltreatmentisindicatedifONFHprogressesrapidlyandnon-surgicaltreatmentisnoteffective.Thesurgicalproceduresincludetwomaincategories:thereconstructionofthefemoralheaditselfandTHA.Theoperationtopreservethefemoralheadincludescoredecompression,osteotomy,andbonegraftingwithorwithoutbloodsupply[36].CoredecompressionisoneoftheimportantsurgicalmethodsforthetreatmentofearlyONFH.Itismainlythroughcoredecompressiontobreakthroughthehardeningzone,leadingtoareductioninintraosseouspressureandimprovementofbloodsupply[37].Coredecompressionismoresuitableforearly-stagepatientswithONFH.Someclinicianshaveinventedvascularizedandnon-vascularizedbonegrafts,ordesignedasupportwithothermaterials,suchastantalumrods[38].Atpresent,theindicationsforbonegraftingare(1)vascularizedfibulargrafting;(2)withvascularpediclediliacbonegraft;(3)freefibulagrafting;(4)withboneflaptransplantation;(5)lesionremoval,compressionofbonegraftsurgery;(6)lesionremoval,memoryalloymeshimplantation;and(7)lesionremoval,impactionbonegraft,andporoustantalumnailsupportsurgery.Allkindsofbonegraftinghaveissues,andthus,poroustantalumrodiswidelyused.Comparedwithtraditionalsinglecompressionosteogenesis,thecombinationofporoustantalumrodsupporthasobviousadvantagesinstageI–IIONFH.Astudyfoundthatthecoredecompressionandboneimplant,2mmimpactionbonegraftingplusporoustantalumrodsupportingmethodsofoperationinONFHpatients,canprolongthelifeofthefemoralheadandpostponeTHAtime[39].Thepurposeofosteotomyistoremovethenecroticzonefromtheweight-bearingareaofthefemoralhead.Osteotomyincludesvarusorvalgusosteotomybythefemoralrotorrotationosteotomy,andsoon,withtheprincipleofnotchangingthemedullarycavityofthefemur[40,41].Ifthefemoralheadcollapseisserious(ARCO,IIICandIV),andthereisaseverelossofjointfunctionormoremoderatepain,THAshouldbechosen.?TraditionalTreatmentCombinedwithStemCellTherapyforONFHMSCsarederivedfrommesodermalmesenchymeandarewidelydistributedinthebonemarrow,bonemembrane,muscle,synovium,synovialfluid,liver,peripheraltissue,umbilicalcordblood,fat,placenta,fetallung,fetalkidney,umbilicalcord,andothertissues[42,43].MSCswithmulti-directionaldifferentiationabilityhavebeenisolatedandextractedfromthesetissues,andthecellshavestrongself-renewalandproliferationability[44].Theycandifferentiateintobone,cartilage,adiposetissue,muscle,tendon,andvascularendothelialcellsunderspecificconditionsofinductionandcanevendifferentiateintonervecells[45].RelatedstudieshaverevealedthatMSCallogeneictransplantationdoesnotundergorejection[46].Ithasbeenwidelyusedinstemcelltransplantation,genetherapy,tissueengineering,andotherresearchendeavors.Formanyrefractorydiseases,celltransplantationappearstobearelativelyeffectivetherapy.Transplantedautologouscellsusuallyhavespecificfunctions,includingrepairingdamagedregions,avoidingtoxiceffectsonthebodyorsideeffectscausedbytheuseoftraditionaldrugs[47].MSCshavebeenwidelyusedintherepairofbonedefects,cartilagedefects,tissueinjuries,osteoarthritis,andosteonecrosisofthefemoralhead.MSCshavealsobeenappliedinotherfieldsofclinicalpractice[48].StemcellsinthetreatmentofONFHarethefocusofcurrentresearch,whichhasdemonstratedthatstemcellscandifferentiateintoosteoblastsunderspecificconditions.Osteoblastsplayanimportantroleintheprocessofrepairingbonenecrosis,andstudieshaveshownthatusingbonemarrowstemcellstransplantationintoanecroticfemoralheadleadstoadecreaseintheincidencerateofONFHto0%[49].?CoreDecompressionCombinedwithMSCTransplantationMSCtransplantationaftercoredecompressioncanprovideseedcellsfortherepairandreconstructionofanecroticfemoralhead[16].InastudybyTabatabaeeetal.[14],basedoncoredecompression,autologousbonemarrowtransplantationwasperformedonONFHin18patientswith28hips,andallpatientswerefollowedupforanaverageof2years.ThemeanWesternOntarioandMcMasterUniversitiesOsteoarthritisIndex(WOMAC)andvisualanalogscale(VAS)scoresinallpatientsimprovedsignificantly.Magneticresonanceimaging(MRI)showedasignificantimprovementinthecombinationtreatmentgroup.Theresearchersbelievethatthistechniquecanbeusedtoimprovetherepairoffemoralheadnecroticarea,atleastintheearlystagesofONFH.Rastogietal.[13]alsoconcludedthatcoredecompressioncombinedwithautologousbonemarrowstemcellimplantationisasafeandeffectivemethod.Senetal.conductedaclinicalcontrolledstudy,whichshowedautologousbonemarrowmononuclearcellinstillationintothecoretractaftercoredecompressioncanresultinbetterclinicaloutcomesandhipsurvivalfortreatingONFH[15].Maetal.[18]evaluatedtheeffectofbonemarrowbuffycoat(BBC)implantationbasedoncoredecompressionfortreatmentofosteonecrosisofthefemoralhead.Authorsconcludedthatduringthesecondyearoftreatment,improvementinhipfunctionwasnoticedin92%ofpatientswithONFH.Moreimportantly,thenon-progressionrateforstageI/IIhipswas100%inthetreatmentgroupand66.7%inthecontrolgroup[18].Changetal.[17]indicatedthatthecoredecompressioncombinedwithautologousbonemarrowMSCstransplantationcanreducepainanddelayoravoidfemoralheadcollapse.AssessmentbyMRIfoundthatthecartilagelesionareawassignificantlyreducedandthecartilagequalitywasimprovedsignificantly.Gangjietal.[19]comparedcoredecompressioncombinedwithbonemarrowconcentrate(BMC)containingmesenchymalstemcells(MSCs)orautologousosteoblasticcells(OB)totreatONFH.TheyfoundthatOBcellimplantationwasmoreefficaciousthanBMCtreatmentindelayingtheprogressiontoAssociationResearchCirculationOsseous(ARCO)stageIIIinadditiontoreducingpaininONFH.However,otherresearchershavehaddifferentconclusions.Limetal.[11]conductedacontrolledtrialinwhichtheclinicaleffectsandradiologicalresultsoftwogroupsoftreatmentforosteonecrosisofthefemoralheadwerecompared:Onegrouputilizedtheuseofmultipledrillingcoredecompressioncombinedwithstemcelltransplantation,andtheothergrouputilizedtheapplicationofothercoredecompressionmethod,curettage,andbonegrafting.Theconclusionwasthattherewasnostatisticallysignificantdifferencebetweenthetwogroups.Fromthisstudy,forthecollapseoftheARCOstageI–IIperiodofONFH,coredecompressionandMSCtransplantationobtainedagoodsurgicaloutcome,butforpost-collapseoftheARCOstageIII–IVpatients,thissurgicalapproachwasineffective.?BiomechanicalSupportandMSCsArterialInfusionAfterONFHanddespitehipsalvagetreatment,improvingbloodsupplywithinthefemoralheadisalwaysoneofthemaintreatmentsofthedisease.Autologousstemcelltransplantationandvascularregenerationtechnologiescanplayanimportantroleinmanagement.Kocheretal.[50]confirmedthatMSCsandendothelialprogenitorcellscanpromoteischemicbloodflowrecovery.Kinnairdetal.[51]foundthatafterintramuscularinjectionofbone-derivedstemcellsintotheischemichindlimbsofrat,bone-derivedstemcellscouldpromotecollateralcirculationandlimbfunctionrecovery.Inaddition,thelevelofcytokinegeneexpressionassociatedwithangiogenesiswasincreased.Maoetal.[12]conductedacontrolledtrialinwhich55patientswith89hipsofONFHunderwenttantalumrodimplantationincombinationwithtargetedintra-arterialinfusionofMSCs,andallpatientswerefollowedupfor36months.At36monthsoffollow-up,threehipsinthecombinedtreatmentgroup(6.25%)werefoundtobeclinicallyfailedandrequiredTHA;incontrast,ninehips(21.95%)receivedTHAinthecontrolgroup.Comparedtothecontrolgroup,combinationtreatmentsignificantlyimprovedtheHarrishipscore(HHS)at36months.TheyconcludedthatMSCarterialinfusionisaneffectiveandsafemethodforearlyONFH.Comparedwithopenfemoralheadstemcelltransplantation,MSCselectivearterialinfusionhastheadvantagesofbetterstemcellsurvival,betterdifferentiation,lessinvasiveoperation,lessadversereaction,andgoodpatientcompliance.Theoperationmayachievethefollowingeffects:(1)Dredgethediseasedfemoralhead,improvethevenousreturn,decreasetheintraosseouspressure,andrestoreorimprovethebloodsupplyofthefemoralhead.(2)Improveorincreasethebloodcirculationofthetissuesaroundthefemoralheadnecroticregionandthehip,providingagoodlocalbloodsupplyforthenecroticfemoralhead.(3)MSCscanprotectthelocalvascularendotheliumandpromotetherepair,regeneration,andangiogenesisofvascularendothelialcells.Withadditionalresearchusingstemcellintervention,itappearsthismethodwillbepositiveforfutureONFHpatients.?BoneTissueEngineeringandMSCsTissueengineeringistheapplicationofcellbiology,functionallyrelatedlivingcells,whichculturedinvitro,compositetransplantationinvivotissuedefectandcompleterestorationandreconstruction.MSCshavestrongdifferentiationpotentialandproliferationability,andthecellshaveuniqueadvantagesforrepairingONFHbonedefectsintermsofsource,separationmode,anddifferentiatedtissuetype.Thus,itisthemostidealchoiceforbonetissueengineeringseedcells.ThecompositescaffoldsmadeofMSCscanbeusedtoreinforcetherepairofnecroticdefectsinthestructurebutcanalsobeusedasabiologicalcarrierforcells,genes,andgrowthfactors.Inaddition,MSCscanintegratecellsandreceptorstoregulatecellularfunction.Kangetal.[52]reportedusingautoiliaccancellousbonegraftcombinedwithMSCtransplantationforONFHpatientswithfollow-upfor32monthsdemonstratinggoodclinicalefficacy.Kawateetal.[53]usedbeta-tricalciumphosphateasthecarrierloadbearingautologousBMSCsimplantedintotheareaoftheheadnecrosiscombinedwithvascularizedfibulargraftingfortreatmentofONFH,andlong-termfollow-upfoundthatmostpatientswithosteonecroticsiteswererelievedtovaryingdegrees,imagingobservedlocalhighdensityofnewboneformation.ThediseasewasundercontrolandindicatedthatthetissueengineeringapproachhadabetterpotentialforthetreatmentofONFH.Yamasakietal.[54]reportedthat22cases(30hips)ofONFHpatientsweretreatedwithmononuclearcellscombinedwithcalciumphosphateandeightcases(ninehips)ofONFHpatientsweretreatedwithcalciumphosphateonly.Theaveragefollow-upwas29months.Inthetreatmentgroup,thefemoralheadnecroticareawasreduced,andonlythreehips(3/30)developedfemoralheadcollapse,whilesixhips(6/8)inthecontrolgroupdevelopedseriousfemoralheadcollapse.Xiaoetal.[55]repairedrabbitONFHdefectswithautologousbonemarrowMSCsoncompositebonecombinedwithrecombinanthumanbonemorphogeneticprotein2.Theyfoundthatthismethodpreventedthecollapseandcanformnewbonetissue.TheriseofbonetissueengineeringprovidesastrongsupportforthetreatmentofONFHbyMSCs.?MSCTransplantationCombinedCytokineWithadditionalresearchidentifyingONFHetiologyandpathogenesis,cytokineshavebecomeafocusofONFHtherapy.Atpresent,manycytokineshavebeenfoundtopromotethedifferentiationofMSCsintobonecellsandchondrocytes[56].ThecytokinesusedinbasicexperimentsinONFHincludebonemorphogeneticproteins(BMP),vascularendothelialgrowthfactor(VEGF),basicfibroblastgrowthfactor(BFGF),tumornecrosisfactor(TNF),andothers.ThesefactorscaninduceMSCsirreversiblytodifferentiateintoosteoblasts,andsomecaninduceneovascularizationandparticipateinrepairofONFH[57].Reddietal.[58]concludedthatBMPcancausemesenchymalcellstofirstdifferentiateintochondrocytesandthendifferentiateintoosteoblasts.Osteoblastsmaybeusedinthetreatmentoffemoralheadnecrosisrelatedtotheirroleinpromotingnewboneformation,revascularization,andpromotingarticularcartilagegrowth.BFGFhasastrongroleinosteogenesisandinducedangiogenesis,combinedwithBMPeffectisbetterthantheapplicationofBMPalone.Jinetal.[59]throughtheBFGFandBMProleinrabbitONFH,observedinnecroticregionsnewbonetrabeculaeandthus,authorsconcludedthatBFGFcombinedwithBMPcansignificantlypromotegrowthandproliferationofbonecellsandfibroblasts.Angiogenicfactorspromoterevascularizationoffemoralheadnecroticarearelativetothenormalregions.AngiogenicfactorscanmaintainbloodsupplytonecroticregionsandmaybeusedasaneffectivemeansoftreatmentforONFH.VEGFhasastrongroleinpromotingendothelialgrowthandangiogenesis,andotherangiogenicfactorspromotingangiogenesisinwholeorinpartbyenhancingtheexpressionandproductionofVEGF[60].Althoughmanystudieshavedemonstratedthatgrowthanddifferentiationfactorsplayasignificantroleinthetreatmentofbonenecrosis,thesestudieswereinvitroorinanimalexperiments,andthereisnodirectevidencetoprovetheireffectiveuseinhumans.Inthisregard,newermethodsoftreatmentaretypicallybasedonimprovedunderstandingofpathologyprocesses.WithimprovedunderstandingoftheONFHprocess,theeffectsofvariousgrowthanddifferentiationfactorswillgraduallybecomeclearerandthistypeoftreatmentmaybeseeninthefuture[61].StemCellTherapyforOsteonecrosisoftheFemoralHead:CurrentTrendsandComprehensiveReviewAbstractPurposeofreview:Osteonecrosisofthefemoralhead(ONFH)isacommonandfrequentlyoccurringdisease.Itiscausedbyinterruptionofbloodsupplywithdifferentetiologies.ONFHleadstodegenerationandnecrosisofthesubchondralboneofthefemoralheadandeventuallycollapseofthefemoralhead.ONFHhasahighdisabilityrate,seriouslyaffectingthequalityoflivingofpatients,andofteninvolvesmiddle-agedandyoungerpeople.Recentfindings:Inrecentyears,thetechnologyandunderstandingofstemcellsandregenerativemedicinehavebeendevelopingrapidly.NumerousstudieshavereportedsuccessfulresultsinthetreatmentofONFHbystemcelltransplantation.Thus,stemcelltransplantationisexpectedtoserveasanewmethodinthetreatmentofONFH.Inthepresentreport,therefore,weevaluatedcurrenttechniquesandoutcomesutilizingstemcellsinthetreatmentofONFH.Acomputer-basedonlinesearchofPubMedandCochraneLibrarydatabasesbetweenJanuary2006andJune2017wasperformedtosearchrelatedarticlesusingthekeywordsof"treatment,stemcell,osteonecrosisofthefemoralhead"inEnglishlanguage.LiteraturerelatedtothetreatmentofONFHwasselected.Oursearchobtainedatotalof161articles,butonly9articlesmetourinclusioncriteriaandwereincludedinourreport.ThepresentreviewrevealsthatcelltechnologyhasdemonstratedgoodevidenceinthetreatmentofONFH.However,thistechnologyneedsadditionalin-depthstudytobetterexploreandappreciatemoreidealwaystoovercomedifficultiesassociatedwithsourceofcells.文獻出處：LeiZhao,AlanDavidKaye,AaronJKaye,AlaaAbd-Elsayed.StemCellTherapyforOsteonecrosisoftheFemoralHead:CurrentTrendsandComprehensiveReview.Review,CurrPainHeadacheRep.2018May3;22(6):41.doi:10.1007/s11916-018-0700-x.2023年08月13日491
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陶可主治醫(yī)師 北京大學人民醫(yī)院 骨關節(jié)科 股骨頭壞死：再生醫(yī)學的最新研究進展與展望Regenerativemedicineforosteonecrosisofthefemoralhead:presentandfuture.作者：Gun-IlIm作者單位:ResearchInstituteforConvergenceLifeScience,DonggukUniversity,Goyang,SouthKorea.譯者：陶可（北京大學人民醫(yī)院骨關節(jié)科）骨質自我修復的顯著例外之一是股骨頭壞死（ONFH）。在股骨頭壞死（ONFH）這種疾病中，股骨頭的血液供應受阻和骨內壓力增加，隨后導致骨細胞死亡。壞死的股骨頭無法持續(xù)自我修復，因此，微骨折會累積并發(fā)展到(股骨頭)結構塌陷。尤其是年輕患者（20至40歲）股骨頭壞死（ONFH）的高發(fā)病率，造成了重大的治療負擔。雖然髖關節(jié)置換術的立竿見影的良好效果對于患者和外科醫(yī)生都有吸引力，但在較長的預期壽命中，髖關節(jié)置換術后失敗的可能性很高，因此，嘗試保留股骨頭是合理的。因此，再生醫(yī)學中的骨再生為股骨頭壞死（ONFH）的治療中找到了良好的應用前景?？紤]到股骨頭壞死（ONFH）的發(fā)病機制與細胞死亡有關，補充可以原位制造骨骼或血管系統(tǒng)的細胞是一個很有前景的概念。髓心減壓手術去除部分壞死骨以減輕疼痛并可能治愈疾病，為在手術中添加細胞療法提供了獨特的環(huán)境，同時將額外的發(fā)病率降至最低。除了基于細胞的治療外，包括生長因子、外泌體和基因治療在內的非細胞治療也可用于股骨頭壞死（ONFH）的骨再生。用于再生治療的細胞細胞療法在股骨頭壞死（ONFH）中的原型應用是在髓心減壓產生的空腔中注射骨髓抽吸濃縮物（BMAC），以期這些細胞可以恢復壞死股骨頭中的骨小梁。多個研究小組報告了令人鼓舞的結果。然而，其他研究小組發(fā)現治療患者和對照患者之間沒有顯著差異。總體而言，由于患者數量少且隨訪時間短，大多數研究的價值相當有限。一項前瞻性雙盲試驗在五年隨訪中為骨髓抽吸濃縮物（BMAC）植入的有效性提供了更高水平的證據。隨著對干細胞的了解和表征的不斷深入，促進了這些細胞替代骨髓抽吸濃縮物（BMAC）在股骨頭壞死（ONFH）再生醫(yī)學中的應用。在各種細胞類型中，源自骨髓的間充質基質/干細胞（MSC）被認為是最佳候選細胞。然而，應用離體擴增的自體骨間充質基質/干細胞（MSC）是一個比使用骨髓抽吸濃縮物（BMAC）更復雜的過程。此外，它們還受到監(jiān)管機構的控制。除少數對照研究外，大多數報告間充質干細胞應用的研究都是非對照病例系列。另一方面，干細胞治療股骨頭壞死（ONFH）的薈萃分析顯示，并發(fā)癥都很輕微，發(fā)生率并不顯著（2.8%）。雖然不同的應用方法使得直接比較各個研究變得困難，但人們越來越認識到骨髓抽吸濃縮物（BMAC）或骨髓MSC(BMSC)治療在早期（FicatI或II）股骨頭壞死（ONFH）方面具有合理的（即使不是顯著）效果。緩解癥狀并防止股骨頭塌陷的進展。雖然骨髓抽吸濃縮物（BMAC）是股骨頭壞死（ONFH）最常用的干細胞類型，但脂肪干細胞(ASC)作為再生醫(yī)學的細胞來源具有多種優(yōu)勢。脂肪干細胞(ASC)比骨髓干細胞(BMSC)更容易獲得且痛苦更少。與骨髓干細胞(BMSC)相比，它們不僅在脂肪組織中含量更高，而且具有更大的增殖潛力。脂肪干細胞(ASC)還具有促進血管生成的優(yōu)勢。與自體干細胞MSC相比，同種異體干細胞MSC具有經濟優(yōu)勢，因為同種異體細胞可以作為“現成”產品提供，盡管它們存在疾病傳播和免疫排斥的可能性。從這個意義上說，關于同種異體干細胞MSC是否適用于股骨頭壞死（ONFH）等非致命性疾病存在爭議。另一方面，考慮到來自股骨頭壞死（ONFH）患者的干細胞MSC的增殖和成骨潛力降低，來自健康供體的同種異體干細胞MSC可能對治療這些患者有效。臍帶來源的間充質干細胞可能被證明是一個很好的候選者，因為它具有高細胞產量和低免疫原性。細胞的遞送在細胞治療中，出于經濟和治療效果的考慮，以及避免因過量而可能出現的并發(fā)癥，需要確定植入細胞的最佳數量，該數量與藥物的劑量相當。骨髓抽吸濃縮物（BMAC）和基質血管部分是細胞混合物，其中含有少量干細胞。此外，每種成體干細胞預計具有不同的存活和成骨潛力。根據目前報道的研究，使用的細胞數量從10∧6到10∧9個不等，最常用的劑量是10∧8個細胞。盡管如此，每種類型的細胞的最佳數量仍有待確定。細胞通常已在髓心減壓術中使用。一些研究還表明，可以通過動脈內輸注，有效地輸送治療細胞來治療股骨頭壞死（ONFH）。然而，這些方法的普遍適用性和安全性需要進一步研究?？紤]到再生療法的高成本，只有那些表現出高成功機會的患者才可能適合這種形式的治療。塌陷后股骨頭壞死（ONFH）可能不適合干細胞治療，因為髓心減壓后植入骨髓抽吸濃縮物（BMAC）不能獲得III期股骨頭壞死（ONFH）臨床過程的任何改善。因此，只有早期（I期或II期）患者才可以考慮采用這種治療形式。此外，據報道，創(chuàng)傷后股骨頭壞死（ONFH）患者的預后優(yōu)于非創(chuàng)傷性股骨頭壞死（ONFH）患者，這表明，與局部原因相比，患有全身性原因的髖關節(jié)對再生醫(yī)學的反應較差。此外，研究發(fā)現，病灶尺寸較小的患者可能會取得更好的效果，不進行附加細胞治療的髓心減壓也是如此。因此，塌陷前期、(壞死面積)尺寸較小、可能患有外傷性股骨頭壞死（ONFH）的髖關節(jié)更適合再生治療。最近一項使用自體骨髓抽吸濃縮物（BMAC）的研究報告稱，植入后三個月，塌陷進展的平均殘留病灶體積為10%（標準差6%）。安全性是細胞療法應用中的關鍵問題之一。干細胞的關鍵特征，如自我復制、長壽命和多分化，也是癌細胞所共有的。這意味著干細胞可以發(fā)生惡性轉化，這對干細胞植入的安全性構成了關鍵障礙。免疫排斥也會限制同種異體干細胞治療股骨頭壞死（ONFH）的臨床應用。然而，目前的文獻表明，干細胞植入治療股骨頭壞死（ONFH）沒有出現嚴重的并發(fā)癥。因此可以提出應用干細胞治療股骨頭壞死（ONFH）是相對安全的。盡管如此，仍需要更長時間的隨訪結果來確保其安全性。由于體外細胞擴增過程是必要的，整個過程必須受到控制和標準化，以便細胞保留其表型和功能潛力，并避免可能的微生物污染。迄今為止，股骨頭壞死（ONFH）干細胞治療中未被注意到和未表征的一個方面是植入細胞的體內命運。盡管干細胞被植入的目的是希望它們能移植到受體區(qū)域并分化成成骨細胞，但植入的細胞是否能在該部位存活尚未得到研究。如果沒有足夠的血管供應，這些細胞就會缺氧、低血糖、缺乏營養(yǎng)和代謝廢物堆積。在股骨頭壞死（ONFH）中，受體部位的血管供應不足可能導致局部微環(huán)境不適合干細胞的生存。這些情況可能是對照研究中干細胞植入結果不令人滿意的原因。大多數植入的細胞可能會在短時間內經歷大量細胞死亡，在死亡前發(fā)揮一定程度的旁分泌作用。因此，如果要促進植入細胞的存活和植入，使這些細胞成為成骨細胞并在植入區(qū)域內再生骨，則需要采取增強措施來增強植入細胞的血管生成潛力。其他方法如基因治療和外泌體也已被探索。治療基因的基因轉移可用于增強間充質干細胞的治療效率。骨形態(tài)發(fā)生蛋白-2(BMP-2)、血管內皮生長因子(VEGF)、堿性成纖維細胞生長因子(bFGF)和血小板衍生生長因子(PDGF)是可轉移以促進間充質干細胞骨形成和血管生成特性的候選基因。由于主要使用病毒載體的基因轉移技術，使細胞治療的安全性問題進一步復雜化，基因修飾的間充質干細胞尚未應用于治療股骨頭壞死（ONFH）患者。由于基因修飾間充質干細胞的所有數據均來自動物實驗，其在患者中的有效性和安全性目前尚不清楚，有待臨床試驗評估。生長因子可以直接植入病變部位以增強成骨和血管生成。然而，生長因子的直接植入因肽療法的實際問題而變得復雜，例如半衰期極短以及全身或高劑量給藥的副作用。因此，載體材料的組合使用對于實現生長因子的控制釋放和實際應用是必要的。重組骨形態(tài)發(fā)生蛋白BMP和成纖維細胞生長因子2（FGF-2）已與各種載體聯合應用于臨床。已知干細胞MSC的治療益處主要歸因于它們分泌的因子。另外，在生長因子和細胞因子的作用下，細胞通過細胞外囊泡(EV)與鄰近或遠處的細胞進行通訊，其中包括外泌體，外泌體是直徑小于150nm的細胞外囊泡(EV)。從人類干細胞MSC中分離的外泌體通過發(fā)揮增殖和抗凋亡作用以及促進血管生成，在股骨頭壞死（ONFH）大鼠模型中顯示出預防作用。許多研究報告了積極的結果。然而，目前尚不清楚再生醫(yī)學是否可以成為股骨頭壞死（ONFH）治療的規(guī)則改變者，真正改變該疾病的自然史。雖然有必要招募足夠數量的患者進行良好對照的隨機研究，來確定治療效果，但再生治療的性質，包括成本和供體細胞特征的個體差異，使其相當難以進行。就細胞治療而言，由于從一種細胞來源觀察到的結果無法推演到另一種細胞類型，因此必須對細胞來源和類型進行精確定義。此外，區(qū)分培養(yǎng)擴增細胞和天然細胞以及自體和同種異體來源也是必要的。除了科學問題之外，監(jiān)管問題也使再生療法變得復雜。培養(yǎng)擴增細胞的植入需要大多數發(fā)達國家監(jiān)管機構的批準，這對于同種異體或轉基因細胞更為嚴格，從而增加了細胞治療的成本。然而，由于壞死骨無法再生，年輕患者不可避免地需要進行關節(jié)置換術，因此需要進一步致力于股骨頭壞死（ONFH）再生醫(yī)學的研究和進步。???Regenerativemedicineforosteonecrosisofthefemoralhead:presentandfuture.Oneofthenotableexceptionstotheparadigmofself-healingboneisosteonecrosisofthefemoralhead(ONFH).Inthisdisease,obstructionofbloodsupplyandincreasedintraosseouspressuretothefemoralheadsubsequentlycausedeathofosteocytes.Necroticbonecannotcontinuallyrepairitself,andconsequentlymicrofracturesaccumulateandprogresstostructuralcollapse.1ThehighincidenceofONFHinyoungpatients(20to40yearsold),inparticular,createsmajortreatmentdilemmas.2Whileimmediategoodresultsofarthroplastyareappealingtobothpatientsandsurgeons,thehighchancesoffailureinthelongremaininglifespanjustifyattemptstopreservethefemoralhead.Therefore,regenerativemedicineforboneregenerationfindsagoodnicheinthetreatmentofONFH.3ConsideringthatthepathogenesisofONFHisrelatedtocelldeath,replenishingcellsthatcanmakeboneorvasculatureinsituisanappealingconcept.Coredecompressionprocedure,inwhichpartofanecroticboneisremovedtoalleviatepainandpossiblycurethedisease,providesuniquecircumstancesforaddingcelltherapytotheprocedurewithminimaladditionalmorbidity.Inadditiontocell-basedtherapy,non-cellulartherapiesincludinggrowthfactor,exosome,andgenetherapymaybeemployedtoregenerateboneinONFH.?CellsusedforregenerativetreatmentTheprototypeapplicationofacelltherapyinONFHistheinjectionofbonemarrowaspirateconcentrate(BMAC)inthecavitycreatedbycoredecompression,withaviewthatthesecellsmayrestorethetrabecularboneinthenecroticfemoralhead.3-5Encouragingresultshavebeenreportedbyseveralgroups.4-8However,othergroupshavefoundnonotabledifferencebetweentreatedpatientsandcontrolpatients.9,10Overall,thevalueofmoststudiesisratherlimitedbecauseoflownumbersofpatientsandbrieffollow-upperiods.Aprospective,double-blindedtrialhasprovidedahigherlevelofevidencefortheeffectivenessofBMACimplantationatafive-yearfollow-up.11?IncreasingknowledgeandcharacterizationofstemcellshavepromotedtheuseofthesecellsinsteadofBMACinregenerativemedicineforONFH.Amongvariouscelltypes,mesenchymalstromal/stemcells(MSCs)derivedfrombonemarrowhavebeenputforwardasthetopcandidate.12However,applicationofexvivoexpandedautologousboneMSCsisamorecomplicatedprocessthanusingBMAC.Inaddition,theyarecontrolledbyregulatoryauthorities.13MoststudiesreportingtheapplicationofMSCsareuncontrolledcaseseriesexceptforafewcontrolledstudies.Ontheotherhand,ameta-analysisofstemcelltherapyinONFHhasshownthatcomplicationsareallminorwithanunremarkablerate(2.8%).14Whileheterogeneousmethodsofapplicationmakeitdifficulttodirectlycompareindividualstudies,thereisanincreasingperceptionthatBMACorbonemarrowMSC(BMSC)treatmenthasreasonable,ifnotremarkable,effectsinearlystage(FicatIorII)ONFHintermsofsymptomaticreliefandpreventingprogressionoffemoralheadcollapse.15-17WhileBMSCisthemostusedstemcelltypeinONFH,adiposestemcells(ASCs)offerseveraladvantagesasacellsourceforregenerativemedicine.ASCsaremoreeasilyandlesspainfullyobtainedthanBMSCs.18Theyarenotonlymoreabundantinfattytissues,butalsohavegreaterproliferativepotentialcomparedwithBMSCs.19ASCsadditionallyhavetheadvantageofpromotingangiogenesis.20?AllogenicMSCshaveeconomicadvantagescomparedwithautologousMSCsbecauseallogeniccellscanbemadeavailableasan‘offtheshelf’product,althoughtheycarrythechanceofdiseasetransmissionandimmunologicalrejection.16Inthissense,thereareargumentsonwhetherallogenicMSCshouldbeappropriatefornon-lethaldiseasessuchasONFH.Ontheotherhand,consideringthattheproliferativeandosteogenicpotentialofMSCsfromONFHpatientsisreduced,21-24allogenicMSCsderivedfromhealthydonorsmightbeeffectiveintreatingthosepatients.Umbilicalcord-derivedMSCsmayprovetobeagoodcandidatebecauseofhighcellyieldandlowimmunogenicity.25?DeliveryofthecellsTheoptimalnumberofimplantedcells,whichiscomparabletothedoseofadrug,needstobedeterminedincelltherapyforthereasonofeconomyandtherapeuticeffects,aswellastoavoidpossiblecomplicationsfromoverdose.BMACandstromalvascularfractionareamixtureofcells,withasmallproportionofstemcells.Also,eachkindofadultstemcellisexpectedtohavedifferentsurvivalandosteogenicpotential.Basedoncurrentreportedstudies,thenumberofusedcellsrangesfrom106to109,andthemostfrequentlyuseddoseis108cells.6-10,26Still,theoptimalnumberremainstobedeterminedforeachtypeofcell.Cellshavemostcommonlybeendeliveredatthetimeofcoredecompression.3,6-11,26Acoupleofstudieshavealsoshownthattherapeuticcellsmaybeeffectivelydeliveredviaintra-arterialinfusiontotreatONFH.27,28However,generalapplicabilityandsafetyofthesemethodsneedfurtherinvestigation.?Giventhehighcostofregenerativetherapy,onlypatientswhowillshowahighchanceofsuccessfulresultsmaybeindicatedforthisformoftreatment.Post-collapseONFHmaynotbeindicatedforstemcelltherapy,29asimplantationofBMACaftercoredecompressioncouldnotleadtoanyimprovementintheclinicalcourseofstageIIIONFH.30Thus,onlyearly-stage(stageIorII)patientsmaybeconsideredforthisformoftreatment.Also,ithasbeenreportedthatpatientswithpost-traumaticONFHhavebetteroutcomesthanpatientswithnon-traumaticONFH,suggestingthathipswithasystemiccauseofthediseasewouldshowlessfavourableresponsetoregenerativemedicinethanthosewithlocalizedcauses.6Furthermore,ithasbeenfoundthatthosewithsmallerlesionsizesmayachievebetterresults,whichisalsothecasewithcoredecompressionwithoutadditivecelltherapy.31Therefore,hipswithpre-collapse,smallersize,probablytraumaticONFHarebettercandidatesforregenerativetherapy.ArecentstudyusingautologousBMSCsreportedthatthemeanthresholdresiduallesionvolumeforprogressionofcollapsewas10%(standarddeviation6%)atthreemonthsafterimplantation.32?Safetyisoneofthecriticalconcernsintheapplicationofcelltherapy.Keyfeaturesofstemcellssuchasself-replication,longlifespan,andmultidifferentiationarealsosharedbycancercells.Thismeansthatstemcellscanundergomalignanttransformation,whichposesakeyobstacleinthesafetyofstemcellimplantation.33ImmunerejectioncanalsolimittheclinicaluseofallogenicstemcellsforONFH.However,currentliteraturesofarshowsnoseverecomplicationsinstemcellimplantationforONFH.14,34,35Therefore,itcanbeproposedthattheapplicationofstemcellsforthetreatmentofONFHisrelativelysafe.Nevertheless,longerfollow-upresultsarestillneededtoensureitssafety.Asinvitrocellexpansionprocessisnecessary,theentireprocessmustbecontrolledandstandardizedsothatcellsmayretaintheirphenotypeandfunctionalpotential,andavoidpossiblemicrobialcontamination.33?OnehithertounheededanduncharacterizedaspectofstemcelltherapyinONFHistheinvivofateofimplantedcells.Althoughstemcellsareimplantedwiththehopethattheywillengrafttotherecipientareaandundergodifferentiationintoosteogeniccells,whetherimplantedcellswillsurviveonthesitehasnotbeeninvestigatedyet.Withoutadequatevascularsupply,thesecellswillsufferfromhypoxia,hypoglycaemia,lackofnutrients,andpilingupofwasteproducts.InONFH,thescantyvascularityattherecipientsitemayrenderthelocalmicroenvironmentunfitforthesurvivalofstemcells.Thesecircumstancesmayaccountforunsatisfactoryresultsofstemcellimplantationincontrolledstudies.Mostimplantedcellsprobablygothroughmassivecelldeathwithinashortperiodoftime,exertingadegreeofparacrineeffectbeforetheydie.Thus,ifthesurvivalandengraftmentofimplantedcellsaretobepromotedsothatthesecellsbecomeosteogeniccellsandregeneratebonewithintheimplantedarea,augmentativemeasurestoenhancetheangiogenicpotentialofimplantedcellswillbenecessary.3?Othermethodssuchasgenetherapyandexosomehavebeenexplored.GenetransferoftherapeuticgenescanbeemployedtoenhancetherapeuticefficiencyofMSCs.Bonemorphogeneticprotein-2(BMP-2),vascularendothelialgrowthfactor(VEGF),basicfibroblastgrowthfactor(bFGF),andplatelet-derivedgrowthfactors(PDGFs)arecandidategenesthatcanbetransferredtopromoteosteogenicandangiogenicpropertiesofMSCs.Asgenetransfertechniqueswhichmostlyuseviralvectorsfurthercomplicatethesafetyissueofcelltherapy,gene-modifiedMSCshavenotyetbeenappliedtotreatONFHpatients.Asalldataongene-modifiedMSCsarefromanimalexperiments,theefficiencyandsafetyinpatientsarenotpresentlyknownandawaitevaluationinclinicaltrials.36-38Growthfactorsmaybedirectlyimplantedinthelesionsitetoenhanceosteogenesisandangiogenesis.However,directimplantationofgrowthfactorsiscomplicatedbypracticalproblemsofpeptidetherapy,suchasanextremelyshorthalf-lifeandsideeffectswithsystemicorhigh-doseadministration.Thecombineduseofcarriermaterialsisthusnecessarytoenablecontrolledreleaseandpracticalapplicationofgrowthfactors.RecombinantBMPsandfibroblastgrowthfactor2(FGF-2)havebeenusedforclinicalapplicationincombinationwithvariouscarriers.39-43ThetherapeuticbenefitofMSCsisknowntobemostlyattributabletofactorstheysecrete.44Inadditiontogrowthfactorsandcytokines,cellscommunicatewithneighbouringordistantcellsviaextracellularvesicles(EVs)includingexosomes,whichareEVssmallerthan150nmindiameter.45ExosomesisolatedfromhumanMSCsshowedpreventiveeffectsinaratmodelofONFHbyexertingproliferativeandantiapoptoticeffects,46andbypromotingangiogenesis.47?Numerousstudieshavereportedpositiveresults.However,itremainsunclearwhetherregenerativemedicinecanbethegame-changerinthetreatmentofONFHthatgenuinelyaltersthenaturalhistoryofthedisease.Whilewell-controlledrandomizedstudiesrecruitingadequatenumbersofpatientsarenecessarytodefinetheplaceoftreatment,thenatureofregenerativetreatment,includingthecostandindividualdifferenceindonorcellcharacteristics,makesitratherdifficulttoperform.Inthecaseofcelltherapy,becauseanoutcomeobservedfromatypeofcellsourcecannotbeprojectedtoanothertypeofcells,precisedefinitionsofcellsourcesandtypesaremandatory.Also,distinguishingbetweenculture-expandedandnativecellsisnecessaryaswellasbetweenautologousandallogenicsources.Inadditiontoscientificconcerns,regulatoryissuescomplicateregenerativetherapies.Theimplantationofculture-expandedcellsneedsapprovalfromregulatoryagenciesinmostdevelopedcountries,whichisevenmorestrictforallogenicorgeneticallymodifiedcells,addingtothecostofcelltherapy.Nevertheless,giventhatfailuretorevitalizenecroticboneinevitablyleadstojointarthroplastyinyoungpatients,furthereffortsneedtobededicatedtotheresearchandadvancementofregenerativemedicineforONFH.?文獻出處：Gun-IlIm.Regenerativemedicineforosteonecrosisofthefemoralhead:presentandfuture.BoneJointRes.2023Jan;12(1):5-8.doi:10.1302/2046-3758.121.BJR-2022-0057.R1.2023年08月06日469
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張會文副主任醫(yī)師 唐山市第二醫(yī)院 手外科 非手術治療技術①保護性負重：減輕患髖負重可有效減輕疼痛，改善功能，并可能在骨壞死修復期避免股骨頭塌陷。例如使用雙拐輔助行走，不建議長時間使用輪椅；同時應注意避免出現對抗性及撞擊性運動。對于病變位于股骨頭內側及面積較?。ǎ?5%）的股骨頭壞死可考慮此方法。一般對于接受保髖手術治療的患者，建議術后拄拐3個月，根據術后復查情況逐漸脫拐。②藥物治療：常使用抑制破骨細胞功能和促進成骨細胞功能的藥物，如磷酸鹽類藥物，以及抗凝、降脂、擴張血管、促進纖溶等藥物。藥物治療可單獨應用于治療股骨頭壞死，也可與保髖手術配合應用。③中醫(yī)藥治療：中醫(yī)藥治療強調早期診斷、病證結合、早期治療。對高危人群及早期股骨頭壞死患者，建議給予活血化瘀、補腎健骨等中藥治療，具有促進壞死修復、預防塌陷的作用；配合保髖手術使用，可提高保髖手術效果。常用藥物有仙靈骨葆、強骨膠囊等。④物理治療：包括體外震波（亦稱為沖擊波）、電磁場、高壓氧等。手術治療股骨頭壞死進展迅速，非手術治療往往效果不佳，常需要手術治療，包括保留患者自身髖關節(jié)為主的修復重建術和人工髖關節(jié)置換術兩大類。手術的主要目的是減輕疼痛，延緩股骨頭塌陷，改善并維持髖關節(jié)功能，進而延緩甚至避免髖關節(jié)置換手術。保髖手術方法:髓芯減壓術、游離骨移植術、帶或不帶血管蒂骨移植術、截骨術等。2023年07月28日455
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陶可主治醫(yī)師 北京大學人民醫(yī)院 骨關節(jié)科 股骨頭壞死：基礎知識2019年(致每一位曾經或正在遭受股骨頭壞死折磨的病患，都需要了解的科學知識)作者：MichelleJLespasio,NipunSodhi,MichaelAMont.作者單位:DepartmentofOrthopedicSurgery,BostonMedicalCenter,MA.譯者：陶可（北京大學人民醫(yī)院骨關節(jié)科）摘要在本報告中，我們對骨股骨頭壞死進行了簡明且最新的回顧，股骨頭骨壞死是一種病理性、疼痛性且常常致殘的疾病，據報道是由于受影響的骨骼區(qū)域的血液供應暫時或永久中斷造成的。我們將討論髖關節(jié)股骨頭骨壞死的流行病學（疾病分布）、發(fā)病機制（發(fā)展機制）、病因（相關危險因素、原因和疾?。?、臨床表現（報告的癥狀和查體結果）、診斷和分類以及治療方案。ConnectionsEveryactivityofthelivingorganismisconnectedwithaseparatepartofthebodywhenceitarises.Therefore,anactivityisnecessarilydamagedwhenthepartwhichproducesitisaffected.—GalenofPergamon,130AD-210AD,prominentGreekphysician,surgeon,andphilosopherintheRomanEmpire生物體的每項活動都與其產生該活動的身體的一個單獨部分相關。因此，當產生某項活動的部分受到影響時，該活動必然會受到損害?！寮用傻纳w倫，公元130年至公元210年，羅馬帝國著名的希臘內科醫(yī)生、外科醫(yī)生和哲學家Figure1Left,radiographofahealthyhipjoint.Right,radiographofahipjointwheretheosteonecrosishasprogressedtocollapseofthefemoralhead.圖1左圖是健康髖關節(jié)的X線片；右圖是髖關節(jié)股骨頭壞死已發(fā)展到塌陷階段的X線片。Figure2ProgressionofosteonecrosisusingtheFicat＆Arletclassificationsystem.Osteonecrosiscanprogressfromanormal,healthyhip(StageI)tothecollapseofthefemoralhead(StageIV).?圖2使用Ficat和Arlet分類系統(tǒng)的股骨頭骨壞死進展情況。股骨頭骨壞死可以從正常、健康的髖關節(jié)（第一階段）發(fā)展到股骨頭塌陷(并骨關節(jié)炎)（第四階段）。介紹本文的目的是介紹影響股骨頭或髖關節(jié)的骨壞死(ON)的最新情況，以及如何在成年人群中最好地治療該病。具體來說，本報告將涵蓋髖關節(jié)股骨頭壞死(ON)的流行病學、發(fā)病機制、病因、臨床表現、診斷和分類以及治療方案。股骨頭壞死(ON)，也稱為缺血性壞死、無菌性壞死或缺血性骨壞死，與許多導致成熟骨細胞死亡的疾病和危險因素有關，從而導致骨破壞（例如塌陷）或終末期髖關節(jié)骨關節(jié)炎。這種情況可能發(fā)生在身體的任何骨骼（例如上肢、膝關節(jié)、肩關節(jié)和腳踝關節(jié)），或者在不同時間發(fā)生在超過1處骨骼，但最常見的是影響髖關節(jié)。當最初在髖關節(jié)以外的區(qū)域進行診斷時，應同時對髖關節(jié)進行臨床評估以及放射線和其他影像學研究。股骨頭壞死(ON)的原因分為外傷性（與損傷相關）或非外傷性（與損傷無關）。準確診斷和分類股骨頭壞死(ON)對于幫助指導治療選擇非常重要。識別相關風險因素和患者教育對于成功治療股骨頭壞死(ON)非常重要。針對相關危險因素、藥物管理和/或手術，包括關節(jié)保留手術和全髖關節(jié)置換術(THA)，在股骨頭壞死(ON)患者的臨床管理中也發(fā)揮著重要作用。髖關節(jié)股骨頭壞死的流行病學盡管股骨頭壞死(ON)的確切患病率尚不清楚，但據估計，美國每年有20,000至30,000名新診斷患者。在美國，約10%的THA患者的診斷是股骨頭壞死(ON)。股骨頭壞死(ON)影響所有年齡段的人，但最常見于30至65歲之間的患者。診斷時的平均年齡通常小于50歲。男女比例因相關合并癥而異。例如，與酒精相關的股骨頭壞死(ON)是在男性中更常見，而與系統(tǒng)性紅斑狼瘡(SLE)相關的股骨頭壞死(ON)是在女性中更常見。每年有超過20,000人因髖關節(jié)股骨頭壞死需要住院治療。在許多病例中，雙側髖關節(jié)都受到影響。通常，股骨頭壞死(ON)會影響股骨頭及頸部(近端骨骺)。髖關節(jié)股骨頭骨壞死的發(fā)病機制/假說髖關節(jié)股骨頭壞死(ON)發(fā)生的機制仍不清楚。在大多數情況下，股骨頭壞死(ON)被認為是遺傳傾向、代謝因素和影響血液供應的局部因素（包括血管損傷、骨內壓升高和機械應力）綜合作用的結果。大多數專家都認為產生干細胞和血小板的股骨頭和骨髓缺乏血液供應，導致骨細胞（成熟骨內的細胞）和/或間充質細胞（形成軟骨、骨和脂肪的干細胞）死亡。結果是死亡組織脫礦質或被新的但較弱的骨組織吸收（小梁變?。?，隨后導致軟骨下骨折和股骨頭塌陷。其他提出的股骨頭壞死(ON)發(fā)病機制包括由過量糖皮質激素影響骨和靜脈內皮細胞的不利影響引起的血管收縮引起的變化，以及過量糖皮質激素相關的股骨頭壞死(ON)涉及循環(huán)脂質的變化，可能會在供應骨的動脈中引起微栓子。髖關節(jié)股骨頭骨壞死的病因創(chuàng)傷性和非創(chuàng)傷性因素的結合可直接導致股骨頭骨壞死。在縱向隊列研究和薈萃分析的基礎上，發(fā)現了在股骨頭壞死(ON)發(fā)展中起明確病因作用的直接危險因素。然而，相關風險因素是與股骨頭壞死(ON)最終進展(直接)相關的大部分因素。股骨頭壞死(ON)的外傷原因股骨頭壞死(ON)的創(chuàng)傷性原因包括股骨頸骨折或脫位以及骨髓成分的直接損傷（例如與放射損傷、氣壓失調或沉箱病相關）。股骨頸骨折或脫位的機制是骨外血管受損，導致髖關節(jié)受影響區(qū)域的血液供應中斷。髖關節(jié)脫位是另一種類型的創(chuàng)傷性損傷，影響約20%的創(chuàng)傷相關股骨頭壞死(ON)患者。沉箱病（例如潛水減壓）會導致氮氣氣泡的形成，從而阻塞小動脈，導致股骨頭壞死(ON)。出現癥狀的患者可能會在經歷此過程數年后出現髖關節(jié)股骨頭壞死(ON)。壓力的深度和持續(xù)時間以及暴露的次數是這種疾病進展的重要因素。股骨頭壞死(ON)的非外傷原因許多研究報告稱，長期使用皮質類固醇激素與股骨頭壞死(ON)的發(fā)生相關，可能與藥物的持續(xù)時間和總劑量直接相關。長期使用高劑量糖皮質激素治療的患者似乎處于發(fā)生股骨頭壞死(ON)的最大風險；然而，這些患者通常有多種其他危險因素。接受長期治療的患者中有9%至40%會發(fā)生糖皮質激素誘發(fā)的股骨頭壞死(ON)，而接受短期治療的患者則發(fā)生率要低得多。一項薈萃分析和系統(tǒng)評價發(fā)現，近7%的患者發(fā)生股骨頭壞死(ON)使用＜2g皮質類固醇激素。根據這項薈萃分析，接受潑尼松劑量低于15mg/d至20mg/d治療的患者發(fā)生股骨頭壞死(ON)的風險較低。一項針對98,390名患者的基于人群的研究表明接受單次短期、低劑量甲強龍逐漸減量治療的患者股骨頭壞死(ON)的發(fā)生率為0.13%，而未接受甲強龍逐漸減量治療的患者的股骨頭壞死(ON)發(fā)生率為0.08%。約31%的股骨頭壞死(ON)患者與飲酒有關。與股骨頭壞死(ON)相關的過量飲酒被認為是由于脂質形成過多和細胞內脂質沉積增加導致骨生成減少所致，導致骨細胞死亡和股骨頭壞死(ON)。高劑量皮質類固醇激素和過量飲酒共同構成了髖關節(jié)股骨頭壞死(ON)發(fā)展的最高相關直接危險因素，并且占與創(chuàng)傷無關的病例的80%以上。一項研究比較了112名患有特發(fā)性髖關節(jié)股骨頭壞死(ON)患者與168名對照者(沒有全身性皮質類固醇激素使用史)，與對照者相比，經常飲酒者的風險升高，并且與酒精存在明顯的劑量反應關系。對于當前飲酒量低于400毫升/周、400毫升/周至1000毫升/周和超過1000毫升/周的消費者來說，相對風險分別為3.3、9.8和17.9。股骨頭壞死(ON)在鐮狀細胞病患者中很常見，因為它容易導致紅細胞鐮狀化和骨髓增生。大約50%的受影響患者在35歲時出現股骨頭壞死(ON)。鐮狀細胞血紅蛋白病可直接導致血管阻塞和股骨頭壞死(ON)。據報道，3%至30%的系統(tǒng)性紅斑狼瘡SLE患者會發(fā)生股骨頭壞死(ON)，最危險的是服用糖皮質激素和常規(guī)劑量潑尼松劑量大于20mg/d的患者。據報道，高達60%的戈謝?。ㄒ环N遺傳性疾?。┗颊呋加泄晒穷^壞死(ON)，因為它能夠直接阻礙血管供應。戈謝病是一種常染色體隱性遺傳代謝疾病，其中一種脂肪（脂質）稱為葡萄糖腦苷脂不能被充分降解。通常情況下，身體會產生一種稱為葡萄糖腦苷脂酶（細胞膜的正常部分）的酶，它會分解并回收葡萄糖腦苷脂。其他不太常見但與股骨頭壞死(ON)明顯相關的患者包括抗磷脂抗體、庫欣病和系統(tǒng)性紅斑狼瘡SLE患者。急性淋巴細胞白血病、慢性粒細胞白血病和急性粒細胞淋巴瘤的發(fā)展，使患者因使用類固醇激素治療這些疾病而面臨更高的股骨頭壞死(ON)風險。胰腺炎（通常與使用皮質類固醇激素有關）、懷孕、化療、吸煙、血管炎、胸膜炎和中樞神經系統(tǒng)因素，例如導致交感神經纖維數量減少的炎癥反應（如類風濕性關節(jié)炎、克羅恩?。?、夏科足和炎癥性腸?。c股骨頭壞死(ON)相關。有一些證據表明股骨頭壞死(ON)可能具有相關風險因素的遺傳基礎。例如，當過度飲酒是相關風險因素時，男性受到的影響是女性的3倍。然而，當狼瘡或皮質類固醇激素的使用成為相關危險因素時，女性比男性更容易受到影響。系統(tǒng)性紅斑狼瘡SLE在女性中的發(fā)病率大約是男性的9倍。這種易感性增加是可能的，至少部分原因是與激素和性染色體有關的差異。血液透析、高尿酸患者的慢性腎衰竭或終末期腎病、貧血/痛風、HIV感染、高脂血癥、器官移植和血管內凝血也與股骨頭壞死(ON)的發(fā)生有關。盡管存在許多可能的關聯和聯系，但估計20%的股骨頭壞死(ON)病例被標記為特發(fā)性或病因不明。髖關節(jié)股骨頭骨壞死的臨床表現髖關節(jié)疼痛是股骨頭壞死(ON)晚期最常見的癥狀，盡管一小部分患者可能沒有癥狀。腹股溝疼痛是最常見的癥狀，其次是大腿和臀部疼痛。疼痛可能因負重或關節(jié)運動而出現。大約三分之二的股骨頭壞死(ON)患者會出現休息時疼痛，大約三分之一的患者會出現夜間疼痛。身體多個部位的疼痛很少見，表明存在多灶性過程。髖關節(jié)股骨頭壞死(ON)的體格表現通常是非特異性的，但可能會導致受影響關節(jié)的活動范圍減小、行走疼痛、Trendelenburg征和/或骨摩擦音。髖關節(jié)股骨頭骨壞死的臨床評估髖關節(jié)股骨頭壞死(ON)通常通過：1)回顧患者病史，2)獲得適當的放射學評估，3)確定病情階段，以及4)制定治療方案來解決。在評估患者是否患有股骨頭壞死(ON)，問題應針對評估疼痛史、藥物使用（尤其是皮質類固醇）、手術、懷孕、創(chuàng)傷、慢性疾?。ㄓ绕涫晴牋罴毎?、戈謝病、自身免疫性疾病和白血?。⑽鼰熀?或飲酒。當詢問受傷/疾病時，重要的是要仔細探討與髖部骨折、脫位或沉箱病相關的傷害，因為沉箱病是非創(chuàng)傷性的。髖關節(jié)股骨頭骨壞死的診斷和分類在疾病的初始階段診斷髖關節(jié)股骨頭骨壞死對于治療很重要；在初始階段，疾病可能不會進展。大多數情況下，早期股骨頭壞死(ON)患者一般沒有癥狀，是偶然發(fā)現的；不幸的是，大多數患者直到股骨頭壞死(ON)發(fā)展到后期才前來接受評估。盡管目前還沒有已知的明確治療方法可以永久阻止股骨頭壞死(ON)進展到后期，但目前有一些治療方法用于此目的，例如降脂劑、抗凝劑和雙磷酸鹽。當患者出現癥狀、影像學檢查結果一致、并且其他引起疼痛和骨異常的原因不太可能或已被排除時，就可以準確地做出股骨頭壞死(ON)的診斷。除了臨床和體檢之外，放射線照片和磁共振成像（MRI）掃描等成像技術也用于診斷。首先，進行普通放射線照相評估，然后進行MRI。據報道，MRI對于檢測早期股骨頭壞死(ON)的特異性和敏感性＜99%。MRI圖像還可以通過對異常骨占據的股骨頭區(qū)域進行數字化，定量評估病變的大小或受影響骨的受累程度。MRI變化包括T1加權圖像上界限分明且均勻的局灶性病變，具有分隔正常骨和缺血骨的單密度線，以及T2加權圖像上的第二條高強度線（特征性雙線征標志）代表血管豐富的肉芽組織。這種級別的成像細節(jié)非常有用，因為受影響骨骼病變的大小和范圍很重要，可以幫助指導治療。然而，對于終末期疾病，股骨頭壞死(ON)患者可能沒有必要使用MRI，因為此階段的治療選擇可能有限。這些發(fā)現通常使用4個階段的Ficat和Arlet系統(tǒng)進行分類，如此處和表1中所述。X線片可以在腹股溝疼痛等癥狀出現后數月內保持正常（第一階段）。最早的放射學檢查結果通常是輕微的骨密度變化，然后是硬化和囊性變（第二階段）。然后，檢查結果會從軟骨下骨塌陷（第III期）發(fā)展到特征性新月征（在股骨頭近端前外側看到軟骨下射線可透性），并隨后出現股骨頭球形度喪失（測量圓度）或股骨頭最終關節(jié)塌陷，可見髖臼空間變窄和退行性變化（第四階段）。要尋找的關鍵放射學特征包括1)階段（塌陷前與塌陷后）、2)病變大小和3)股骨頭凹陷程度。右側股骨頭壞死的X線片表現：雙線征，承重區(qū)右側髖關節(jié)股骨頭壞死X線片（上圖）及MRI表現（下圖）生成骨骼三維圖像的計算機斷層掃描具有中等敏感性，但不具有特異性，可能會給患者帶來顯著的輻射負擔。如果股骨頭已經塌陷，計算機斷層掃描可能具有一定的特異性。幸運的是，大多數臨床醫(yī)生無需計算機斷層掃描即可診斷出股骨頭骨壞死，而計算機斷層掃描通常用于區(qū)分塌陷前和塌陷后疾病。髖關節(jié)股骨頭骨壞死的鑒別診斷由于有癥狀的髖關節(jié)股骨頭壞死(ON)患者可能會出現與許多其他髖關節(jié)病變類似的癥狀，因此在最終診斷之前應充分排除這些癥狀。骨髓水腫綜合征和軟骨下骨折是也需要考慮的許多潛在診斷中的兩個。與骨壞死相關的病因創(chuàng)傷相關的危險因素股骨頸骨折脫位或骨折脫位鐮狀細胞性貧血癥血紅蛋白病沉箱?。鈮菏д{）戈謝病輻射非創(chuàng)傷相關的危險因素皮質類固醇激素飲酒系統(tǒng)性紅斑狼瘡庫欣病皮質醇分泌過多（罕見）慢性腎功能衰竭/血液透析胰腺炎妊娠高脂血癥器官移植血管內凝血血栓性靜脈炎吸煙高尿酸血癥/痛風艾滋病病毒感染其他潛在風險因素特發(fā)性原因骨髓水腫綜合征，也稱為髖部暫時性骨質減少，可能單獨發(fā)生或與損傷相關，特別是那些導致神經損傷的創(chuàng)傷。在后一種情況下，慢性疼痛和短暫性骨質減少是復雜區(qū)域疼痛綜合征（也稱為反射性交感神經營養(yǎng)不良、灼痛等術語）的特征。骨髓水腫綜合征可根據組織學和MRI與股骨頭壞死(ON)相鑒別。股骨頭軟骨下骨折通常發(fā)生在已有骨質減少的患者中，通常被認為代表不全骨折。這些骨折可能很難通過平片觀察到。早期病變有時會出現輕微的扁平化；股骨頭塌陷是進行性的。髖關節(jié)股骨頭骨壞死的臨床治療在制定針對癥狀性髖關節(jié)骨關節(jié)炎的最佳治療方法時要考慮的因素應旨在治療骨關節(jié)炎的分期和受累程度、骨受累的程度和位置、癥狀的存在（或不存在）以及患者的合并癥。治療的目標是盡可能長時間地保留天然髖關節(jié)，同時考慮患者年齡、活動能力、職業(yè)和生活方式等生活質量問題。處理髖關節(jié)股骨頭壞死(ON)的三種主要治療選擇包括1)非手術治療、2)關節(jié)保留手術和3)全髖關節(jié)置換術THA。非創(chuàng)傷性原因引起的髖關節(jié)股骨頭壞死(ON)的影響引起了特別關注。對于受影響的患者，67%的人報告沒有任何癥狀，但最終可能會出現關節(jié)塌陷。無癥狀的中等、尤其是大面積股骨頭骨壞死的自然病程是病情惡化，最終發(fā)展為終末期疾病，許多患者出現股骨頭塌陷。對于有癥狀的患者，大約80%至85%的病例會在2年內導致股骨頭塌陷。因此，早期診斷股骨頭壞死(ON)可能會提供早期治療的機會，這可以防止塌陷，并最終避免股骨頭塌陷而需要進行的全髖關節(jié)置換的手術治療。然而，大多數患者在病程晚期就診，對于那些已知或可能存在危險因素的患者，特別是使用大劑量皮質類固醇激素的患者，必須高度懷疑（存在股骨頭壞死(ON)）。同樣，對于無癥狀的股骨頭壞死(ON)患者，應考慮影響股骨頭壞死病變的大小、范圍和位置。一般來說，影響股骨頭15%以下的病變最好采用非手術治療；15%至30%之間的病變應進行手術治療；盡管進行了手術干預，但涉及超過30%股骨頭的病變仍可能進展至塌陷，并最終需要全髖關節(jié)置換術THA。髖關節(jié)股骨頭骨壞死的非手術治療選擇物理治療物理治療可以緩解和減輕一些癥狀，但通常不會阻止進行性髖關節(jié)骨性關節(jié)炎進展到后期。同樣，使用拐杖或手杖等輔助裝置限制負重可能有助于控制疼痛、虛弱和痛性步態(tài)等癥狀。如果治療的目標是防止髖關節(jié)需要全髖關節(jié)置換，那么物理治療是不合適的，并且迄今為止沒有證據表明負重限制有助于防止進行性骨關節(jié)炎疾病進展為終末期疾病。藥物非甾體類抗炎藥和對乙酰氨基酚可以暫時緩解有癥狀患者的疼痛。當其他藥物無法有效控制中度至重度疼痛時，在考慮手術選擇時，可以明智地短期使用阿片類藥物。目前正在使用但未經證實或可靠地用于治療股骨頭壞死(ON)的研究藥物選擇包括1)抗凝劑、2)雙膦酸鹽抗吸收劑、3)降膽固醇他汀類藥物和4)高壓氧。早期股骨頭壞死(ON)的手術選擇髓心減壓髓心減壓是一種微創(chuàng)手術技術，用于控制病情早期（塌陷前）的癥狀（例如Ficat和ArletI期和II期）。該手術包括在股骨頭上鉆孔以緩解壓力并為新血管創(chuàng)造通道以滋養(yǎng)受影響的區(qū)域。已發(fā)表的髓心減壓成功率差異很大，從40%到100%不等，具體取決于患者群體。髓心減壓后的成功率在最早疾病階段的患者中可見。成功進行髓心減壓手術的患者通常會在幾個月后恢復獨立行走，并且可以完全緩解疼痛。骨移植髓心減壓可以與骨移植相結合，幫助再生健康的骨骼并支撐髖關節(jié)的軟骨。骨移植物是移植到壞死或死骨區(qū)域的健康骨組織。一種標準技術使用自體移植，涉及從身體的一個部位取出骨頭并將其移動到身體的另一部位。從捐贈者或尸體上采集的骨移植物稱為同種異體移植物，通常通過骨庫獲取。骨髓抽吸濃縮物髓心減壓配合骨髓抽吸濃縮物注射是使用濃縮骨髓，將其注射到股骨頭壞死的死骨中。這項研究技術從患者的骨髓中采集干細胞并將其注射到股骨頭壞死(ON)區(qū)域。骨髓抽吸濃縮被認為可以防止疾病進一步發(fā)展并刺激新骨生長。經皮鉆孔另一種手術選擇是經皮鉆孔。在此過程中，通過股骨頸經皮鉆一個孔，到達股骨頭的受影響部位。一份對45個髖關節(jié)進行平均隨訪24個月的報告顯示，30個患有Ficat和ArletI期疾病的髖關節(jié)中有24個（80%）取得了成功的結果（定義為Harris髖關節(jié)評分＜70）。一項最近的研究比較了多個鉆探與標準髓心減壓相比，顯示經皮鉆探獲得更好的結果。晚期股骨頭壞死(ON)的手術選擇血管化骨移植血管化腓骨移植是一種更為復雜的外科手術，其中從腓骨及其血液供應中取出一段骨。然后將移植物移植到股骨頸和股骨頭上形成的孔道中，并重新連接動脈和靜脈以幫助愈合股骨頭壞死(ON)。截骨術髖關節(jié)截骨術可以將壞死骨從主要承重區(qū)域去除。盡管該手術可能會延遲THA手術，對于股骨頭輕度塌陷前或早期塌陷后的股骨頭壞死患者最有用。然而，截骨術的一個結果是使得未來可能的全髖關節(jié)置換術更具挑戰(zhàn)性，并且通常與骨不連的風險增加有關。非血管化骨移植非血管化骨移植手術有3種類型：1)活板門手術、2)燈泡技術和3)Phemister技術?；畎彘T手術一種自體松質骨和皮質骨移植術，已成功用于Ficat和ArletIII期髖關節(jié)股骨頭壞死(ON)的中小型病變患者。對23名Ficat和ArletIII期或IV期股骨頭壞死(ON)患者進行的30次（在股骨頭上制作的）活板門手術的結果顯示，根據Harris評分系統(tǒng)的判定，結果均良好或極好。燈泡技術燈泡技術使用股骨頸前部的皮質窗口?？梢允褂迷摯翱谌コ龎乃拦?，隨后可以用非血管化骨移植物填充。Wang等對110名接受燈泡手術的患者（138髖）進行了評估。在平均25個月的隨訪中，平均Harris髖關節(jié)評分從62分提高到79分。在最近的隨訪中，總共94個髖關節(jié)(68%)被認為取得了成功。ARCO分期IIa期患者中100%、IIb期患者中77%、IIc和IIIa期患者中51%出現放射學改善。Phemister技術在Phemister技術中，通過股骨頸插入環(huán)鉆以形成通向病變部位的管道。然后插入第二個環(huán)鉆以形成通往病變部位的另一條管道。然后可以將皮質支柱移植物放置在病變處。最近的一項評論報告稱，該手術的臨床成功率在36%至90%之間。全髖關節(jié)置換術（THA）一旦股骨頭發(fā)生嚴重塌陷，置換髖關節(jié)是唯一實用的手術選擇，并且可以在晚期股骨頭壞死中提供最可預測的疼痛緩解。全髖關節(jié)置換術（THA）成功地緩解了大多數患者的疼痛并恢復了功能。在全髖關節(jié)置換術（THA）中，構成髖關節(jié)的患病軟骨和骨骼被由金屬和塑料制成的人工關節(jié)假體取代。人工髖關節(jié)置換術通?？梢允褂?5年，然后就會磨損并需要修復。對于較年輕的患者，由于可能存在活動限制，全髖關節(jié)置換術（THA）可能不是最佳解決方案。此外，由于假肢有使用壽命限制（長期使用后部件會磨損），這些患者可能需要在以后的生活中進行全髖關節(jié)置換術（THA）翻修。必須仔細考慮全髖關節(jié)置換術并與生活質量問題進行權衡，但年輕患者并非絕對禁忌。關于髖關節(jié)股骨頭壞死(ON)的患者教育預防股骨頭壞死(ON)對患者進行有關危險因素、治療和管理的教育對于患者對其病情做出更明智的決定至關重要。股骨頭壞死(ON)教育過程涉及識別個人的相關疾病和與股骨頭壞死(ON)相關的危險因素。無癥狀股骨頭壞死的患者進展為有癥狀疾病和股骨頭塌陷的可能性很高。對無癥狀疾病患者的教育是預防性的，也是必要的，以確保改變危險因素和優(yōu)化護理。預防非創(chuàng)傷性股骨頭壞死(ON)需要：1)避免過量飲酒，定義為男性每周＜15杯飲酒，女性每周＜8杯飲酒，2)避免吸煙，以及3)將皮質類固醇激素減少到盡可能低的治療劑量。告知患者皮質類固醇激素的使用與股骨頭壞死(ON)潛在發(fā)展之間的相關性對于治療這種疾病至關重要。預防股骨頭壞死(ON)的進展應告知診斷為早期骨關節(jié)炎的患者采取上述預防措施，并應避免對關節(jié)施加過度壓力，遵循健康飲食，并保持適當的體重以減緩骨關節(jié)炎的進展。盡管健康飲食本身并不能直接減少患者關節(jié)的壓力，但減肥（如果超重/肥胖）會減少髖關節(jié)的軸向負荷，從而減少施加到股骨頭/頸（股骨頭和股骨頸）的壓力。結論股骨頭壞死(ON)是一種病理性的、經常引起疼痛的病癥，涉及組織壞死區(qū)域，可影響身體的任何骨關節(jié)。髖關節(jié)是最常見的股骨頭壞死(ON)部位，當最初診斷出股骨頭壞死(ON)發(fā)生在身體的其他部位時，應始終利用放射線篩查和MRI掃描進行正確評估。越早診斷股骨頭壞死，無需手術干預或采用微創(chuàng)手術技術來挽救髖關節(jié)的機會就越大。做出股骨頭壞死(ON)診斷后，將考慮病變的大小、范圍和位置以及分類階段，以制定最佳的治療計劃。在此過程中，癥狀的存在或不存在很重要。治療的目標包括嘗試盡可能長時間地保留天然髖關節(jié)，并考慮患者的生活方式和生活質量問題。迄今為止，治療股骨頭壞死(ON)的兩種主要治療選擇包括髖關節(jié)保留手術（保髖治療）和全髖關節(jié)置換術THA。對患者進行有關潛在危險因素和股骨頭壞死(ON)發(fā)展的教育，對于預防該病癥和/或潛在地預防或阻止早期疾病進展為晚期疾病至關重要。OsteonecrosisoftheHip:APrimerAbstractInthisreport,wedeliveraconciseandup-to-datereviewofosteonecrosis,apathologic,painful,andoftendisablingconditionthatisbelievedtoresultfromthetemporaryorpermanentdisruptionofbloodsupplytoanaffectedareaofbone.Wewilldiscusstheepidemiology(diseasedistribution),pathogenesis(mechanismofdevelopment),etiology(associatedriskfactors,causes,anddisorders),clinicalmanifestations(reportedsymptomsandphysicalfindings),diagnosisandclassification,andtreatmentoptionsforhiposteonecrosis.文獻出處：MichelleJLespasio,NipunSodhi,MichaelAMont.OsteonecrosisoftheHip:APrimer.ReviewPermJ.2019;23:18-100.doi:10.7812/TPP/18-100.INTRODUCTIONTheintentofthisarticleistopresentanupdateonosteonecrosis(ON)affectingthefemoralheadorhipjointandhowitcanbestbemanagedintheadultpopulation.Specifically,thisreportwillencompasstheepidemiology,pathogenesis,etiology,clinicalmanifestations,diagnosisandclassification,andtreatmentoptionsforhipON.ON,alsoreferredtoasavascularnecrosis,asepticnecrosis,orischemicbonenecrosis,isassociatedwithmanydisordersandriskfactorsthatcausematurebonecellstodie,leadingtobonedestruction(eg,collapse)orend-stagearthritisofthefemoralhead.Theconditioncanoccurinanyboneinthebody(eg,upperextremity,knees,shoulders,andankles),orinmorethan1boneatdifferenttimes,butitmostcommonlyaffectsthehipjoint.Wheninitiallydiagnosedinanareaotherthanthehip,thehipshouldsimultaneouslybeevaluatedclinicallyandwithradiographicandotherimagingstudies.ThecausesofONareclassifiedaseithertraumatic(relatedtoaninjury)oratraumatic(notrelatedtoaninjury).AccuratelydiagnosingandclassifyingONareimportantinhelpingtodirecttreatmentoptions.IdentificationofassociatedriskfactorsandpatienteducationareimportantinsuccessfulmanagementofON.Targetingassociatedriskfactors,pharmacologicmanagement,and/orsurgery,includingjointpreservingproceduresandtotalhiparthroplasty(THA),alsoplaysignificantrolesintheclinicalcareofpatientswithON.EPIDEMIOLOGYOFHIPOSTEONECROSISAlthoughtheexactprevalenceofONisunknown,theincidenceisestimatedtobebetween20,000to30,000newlydiagnosedpatientseachyearintheUS.1ONistheunderlyingdiagnosisinapproximately10%ofallTHAintheUS.2,3ONaffectspeopleofallages,althoughitismostcommonlyseeninpatientsbetweentheagesof30and65years.4Themeanageatdiagnosisistypicallyyoungerthanage50years.3Themale-to-femaleratiovariesdependingontheassociatedcomorbidities.Forexample,alcohol-associatedONismorecommoninmen,whereasONassociatedwithsystemiclupuserythematosus(SLE)ismorecommoninwomen.3Morethan20,000peopleeachyearrequirehospitaltreatmentforhipON.4Inmanyofthesecases,bothhipsareaffectedbythecondition.Mostcommonly,ONaffectstheproximalend(epiphysis)ofthefemur(hipbone).PATHOGENESISOFHIPOSTEONECROSISThemechanism(s)bywhichhipONdevelopsremainsunclear.Forthemostpart,hipONisbelievedtoresultfromthecombinedeffectsofgeneticpredisposition,metabolicfactors,andlocalfactorsaffectingbloodsupplyincludingvasculardamage,increasedintraosseouspressure,andmechanicalstresses.2,5,6Mostexpertsagreethatalackofbloodsupplytothefemoralheadandbonemarrow,whichproducesstemcellsandplatelets,causesdeathoftheosteocytes(cellswithinmaturebone)and/ormesenchymalcells(stemcellsthatformcartilage,bone,andfat).7Theresultisdemineralizationorresorptionofthedeadtissuebynewbutweakerosseoustissue(trabecularthinning),subsequentlyleadingtosubchondralfractureandcollapseofthefemoralhead.OtherproposedmechanismsforthepathogenesisofONincludevasoconstriction-inducedchangescausedbytheadverseeffectsofexcessglucocorticosteroidsaffectingboneandvenousendothelialcells8,9andexcessglucocorticoid-associatedONinvolvingalterationsincirculatinglipidsbelievedtocausemicroemboliinthearteriesthatsupplybonewithblood.10ETIOLOGYOFHIPOSTEONECROSISAcombinationoftraumaticandatraumaticfactorscandirectlycontributetotheetiologyofON(seeSidebar:EtiologicFactorsAssociatedwithOsteonecrosis).Onthebasisoflongitudinalcohortstudiesandmeta-analyses,directriskfactorshavebeendiscoveredthatplayadefinitiveetiologicroleinthedevelopmentofON.Associatedriskfactors,however,accountformostofthelinkstotheeventualdevelopmentofON.11TraumaticCausesofHipOsteonecrosisTraumaticcausesofONincludefemoralneckfracturesordislocationsaswellasdirectinjuryofboneofmarrowelements(eg,relatedtoradiationinjury,dysbarism,orCaissondisease).Themechanisminvolvedinfemoralneckfracturesordislocationsisdamagetotheextraosseousbloodvessels,whichresultsindisruptedbloodsupplytotheaffectedregionofthehip.Hipdislocationisanothertypeoftraumaticinjury,whichaffectsapproximately20%oftrauma-relatedONpatients.12Caissondisease(eg,decompressioninscubadiving)causestheformationofnitrogenbubblesthatcanoccludearterioles,leadingtoON.PatientswhodevelopsymptomscandevelophipONyearsafterexposuretothisprocess.Thedepthanddurationofpressureandnumberofexposuresareimportantfactorsintheprogressionofthisdisorder.13AtraumaticCausesofHipOsteonecrosisNumerousstudiesreportprolongeduseofcorticosteroidsassociatedwiththedevelopmentofONcanbedirectlyrelatedtodurationandtotaldosageofthemedication.14–16PatientstreatedwithprolongedhighdosesofglucocorticoidsappeartobeatthegreatestriskofdevelopingON;however,thesepatientsoftenhavemultipleotherriskfactors.Glucocorticoid-inducedONdevelopsin9%to40%ofpatientsreceivinglong-termtherapy,anddevelopsmuchlessfrequentlyinpatientsreceivingshort-termtherapy.17Onemeta-analysisandsystematicreviewidentifiedanincidenceofONinnearly7%ofpatientswhoused＜2gofcorticosteroids.18Fromthismeta-analysis,alowerriskwasseeninpatientstreatedwithdosesofprednisonelessthan15mg/dto20mg/d.18Onepopulation-basedstudyof98,390patientsshowedtheincidenceofhipONamongpatientswhohadreceivedasingleshort-term,low-dosemethylprednisolonetaperpackwas0.13%,comparedwith0.08%inpatientswhowerenotprescribedamethylprednisolonetaperpack,thusindicatinganumberneededtoharmof2041patients.19Alcoholusehasbeenassociatedwithapproximately31%ofpatientswhodevelophipON.3,20–22ExcessivealcoholconsumptionrelatedtoONofthehipisbelievedtoresultfromthedecreasedbonegenesiscausedbyexcesslipidformationandincreasedintracellularlipiddeposits,leadingtoosteocytedeathandON.23HighdosesofcorticosteroidsandexcessivealcoholusetogetherpresentthehighestassociateddirectriskfactorsforthedevelopmentofhipON24andaccountformorethan80%ofcasesnotrelatedtotrauma.3,6Onestudycompared112patientswhohadidiopathichipONandnohistoryofsystemiccorticosteroidusewith168controls.3,20Anelevatedriskforregularalcoholdrinkersandacleardose-responserelationshipwithalcoholwerenoted,comparedwithcontrols.Therelativeriskswere3.3,9.8,and17.9forcurrentconsumersoflessthan400mL/wk,400mL/wkto1000mL/wk,andmorethan1000mL/wkofalcohol,respectively.9ONiscommoninpatientswithsicklecelldiseasebecauseofitspropensitytocauseredbloodcellsicklingandbonemarrowhyperplasia.Approximately50%ofaffectedpatientsdevelopONbytheageof35years.25SicklecellhemoglobinopathycandirectlycausevascularobstructionandON.ThedevelopmentofONhasbeenreportedin3%to30%ofpatientswithSLE,andthosemostatriskarepatientswhohavetakenglucocorticoidswithregulardosesofprednisonegreaterthan20mg/d.3,26–28ONhasbeenreportedinasmanyas60%ofpatientswithGaucherdisease(ahereditarydisorder)becauseofitsabilitytodirectlyobstructvascularsupply.3,29,30Gaucherdiseaseisanautosomalrecessiveinheriteddisorderofmetabolismwhereatypeoffat(lipid)calledglucocerebrosidecannotbeadequatelydegraded.Normally,thebodymakesanenzymecalledglucocerebrosidase(anormalpartofthecellmembrane)thatbreaksdownandrecyclesglucocerebroside.31OtherlesscommonbutapparentlinkstohipONincludepatientswithantiphospholipidantibodies,Cushingdisease,29andSLE.Thedevelopmentofacutelymphoblasticleukemia,chronicmyeloidleukemia,andacutemyeloidlymphoma3,32placespatientsatincreasedriskforONrelatedtothetreatmentwithsteroidsfortheseconditions.Pancreatitis(usuallyassociatedwithuseofcorticosteroids),pregnancy,chemotherapy,smoking,vasculitis,pleuritis,andcentralnervoussystemfactorssuchasaninflammatoryresponseresultinginareductioninthenumberofsympatheticnervefibers(asseeninrheumatoidarthritis,Crohndisease,Charcotfoot,andinflammatoryboweldisease),havebeenassociatedwithON.33ThereissomeevidencethathipONmayhaveageneticbasisunderlyingassociatedriskfactors.34Forexample,menareaffectedasmuchas3timesmorethanwomenwhenexcessivealcoholuseistheassociatedriskfactor.However,whenlupusorcorticosteroidusearetheassociatedriskfactors,womenareaffectedmoreoftenthanmen.26,27,32SLEisapproximately9timesmorecommoninwomenthaninmen.35Thisincreasedsusceptibilitymaybemadepossible,atleastinpart,owingtodifferencesrelatedtohormonesandsexchromosomes.35Chronicrenalfailureorend-stagerenaldiseaseinpatientsonhemodialysis,hyperuricemia/gout,HIVinfection,hyperlipidemia,organtransplantation,andintravascularcoagulationarealsolinkedtothedevelopmentofON.31,32,36–39Despitethemanypossibleassociationsandlinks,anestimated20%ofONcasesarelabeledasidiopathicorofunknownetiology.7CLINICALMANIFESTATIONSOFHIPOSTEONECROSISHippainisthemostcommonlyreportedsymptomoflater-stageON,althoughasmallproportionofpatientsmaynothavesymptoms.Paininthegroinisthemostcommonlyreportedsymptom,followedbypainreferredintothethighandbuttock.Paincanpresentwithweightbearingorjointmotion.Painatrestoccursinapproximatelytwo-thirdsofpatientswithON,andpainatnightoccursinapproximatelyone-thirdofpatients.33Paininmultiplelocationsofthebodyisrareandsuggestsamultifocalprocess.PhysicalfindingsofhipONaregenerallynonspecificbutmayentailreducedrangeofmotionoftheaffectedjoint,painfulambulation,Trendelenburgsign,and/orcrepitus.3,40,41ClinicalAssessmentofHipOsteonecrosisONofthehipisgenerallyaddressedby1)reviewofapatient’smedicalhistory,2)obtainingappropriateradiologicevaluation,3)determiningthestageofthecondition,and4)developingaplanfortreatmentoptions.42,43WhenevaluatingapatientforON,questionsshouldbedirectedatassessingahistoryofpain,useofmedications(especiallycorticosteroids),surgery,pregnancy,trauma,chronicmedicalconditions(especiallysicklecelldisease,Gaucherdisease,autoimmunedisease,andleukemia),smoking,and/oralcoholuse.Whenaskingaboutinjuries/illnesses,itisimportanttocarefullyexploreinjuriesrelatedtohipfractures,dislocations,orscubadivingbecauseCaissondiseaseisatraumatic.DIAGNOSISANDCLASSIFICATIONOFHIPOSTEONECROSISDiagnosinghipONintheinitialstagesofthedisorderisimportantformanagement43–46;atinitialstages,thediseasemaynotprogress.Inmostcases,patientswithearly-stageONaregenerallywithoutsymptomsandareidentifiedincidentally;unfortunately,mostpatientsdonotpresentforevaluationuntiltheONhasreachedlaterstages.AlthoughthereispresentlynodefinitivetreatmentknowntopermanentlyhaltONfromprogressingtolaterstages,therearetreatmentmethods,suchaslipidloweringagents,anticoagulants,andbisphosphonates,currentlybeingusedforthispurpose.36–38AdiagnosisofONcanaccuratelybemadewhenapatientissymptomatic,imagingfindingsarecompatible,andothercausesofpainandbonyabnormalitieseitherareunlikelyorhavebeenexcluded.Beyondtheclinicalandphysicalexamination,imagingtechniquessuchasradiographsandmagneticresonanceimaging(MRI)scanningarealsousedfordiagnosis.Plainradiographicevaluationisperformedfirst,followedbyMRI.MRIhasbeenreportedtobe＜99%specificandsensitivefordetectingearlyON.47,48MRIimagescanalsoquantitativelyassessthesizeofthelesionorinvolvementoftheaffectedbonebydigitizingtheareaofthefemoralheadoccupiedbybonewithabnormaltexture.49MRIchangesincludewell-demarcatedandhomogeneousfocallesionsonT1-weightedimageswithasingle-densitylineseparatingnormalandischemicbone,aswellasasecondhigh-intensitylineonT2-weightedimages(thepathognomonicdouble-linesign)representinghypervasculargranulationtissue.3Thislevelofimagingdetailisusefulbecausethesizeandextentofthelesionoftheaffectedboneisimportantandcanhelpdirecttreatment.Forend-stagedisease,however,useofMRIinpatientswithONmaybeunnecessarybecausetreatmentoptionsatthisstagecanbelimited.Thesefindingsareoftenclassifiedusingthe4-stageFicatandArletsystem,whichisdescribedhereandinTable1.Theplainradiographcanremainnormalformonthsaftertheonsetofsymptomssuchasgroinpain(StageI).Theearliestradiographicfindingsareusuallymilddensitychanges,followedbysclerosisandcysts(StageII).Findingsthenprogresstothepathognomoniccrescentsign(subchondralradiolucencyseenintheanterolateralaspectoftheproximalfemoralhead)fromsubchondralcollapse(StageIII),andsubsequentlossofsphericity(measurementoftheroundness)orcollapseofthefemoralheadwitheventualjoint-spacenarrowinganddegenerativechangesintheacetabulumthatarevisible(StageIV).Keyradiographicfeaturestolookforinclude1)stage(precollapsevspostcollapse),2)sizeoflesion,and3)amountofheaddepression.Table1Ficat＆ArletclassificationsystemofthefemoralheadClassificationClinicalRadiographsMRIStage0Nosymptoms;preclinicalNormalNormalStage1PossiblegroinpainNormalormildosteopeniaPossibleedemaStage2Groinpainandstiffness;painwithactivityOsteopeniaand/orsubchondralcysts;diffuseporosis;precollapseofjointspaceOutlinesareaofinvolvementofthefemoralheadStage3Groinpain,stiffness,radiationofpain;painwithactivityCrescentsignand/orsubchondralcollapse(flattening)ofjointwithsecondarydegenerativechanges;lossofsphericityoffemoralheadSameasradiographsStage4Groinpainandlimp;painatrestEnd-stagediseasewithcollapse;extensivedestructionofjoint;reducedjointspaceSameasradiographsOpeninaseparatewindowMRI=magneticresonanceimagingAcomputedtomographyscanproducinga3-dimensionalpictureofthebonehasmoderatesensitivitybutisnonspecificandcanposeasignificantradiationburdentopatients.Computedtomographycanhavesomespecificityifthereisalreadyfemoralheadcollapse.Fortunately,mostcliniciansareassuredwiththeirdiagnosisofONwithoutcomputedtomographyscanning,whichisgenerallyreservedfordistinguishingprecollapseandpostcollapsedisease.DifferentialDiagnosisofHipOsteonecrosisBecausepatientswithsymptomatichipONcanpresentwithsymptomssimilartomanyotherhippathologies,theseshouldbeadequatelyruledoutbeforefinaldiagnosis.Bonemarrowedemasyndromeandsubchondralfracturesaretwoofmanypotentialdiagnosesthatneedtoalsobeconsidered.EtiologicFactorsAssociatedwithOsteonecrosisTraumatic-associatedriskfactorsFemoralneckfractureDislocationorfracture-dislocationSicklecelldiseaseHemoglobinopathiesCaissondisease(dysbarism)GaucherdiseaseRadiationAtraumatic-associatedriskfactorsCorticosteroidadministrationAlcoholuseSystemiclupuserthyematosusCushingdiseaseHypersecretionofcortisol(rare)Chronicrenalfailure/hemodialysisPancreatitisPregnancyHyperlipidemiaOrgantransplantationIntravascularcoagulationThrombophlebitisCigarettesmokingHyperuricemia/goutHIVOtherpotentialriskfactorsIdiopathiccausesBonemarrowedemasyndrome,alsoknownastransientosteopeniaofthehip,mayoccurinisolationorinassociationwithinjuries,particularlythosethatresultinneurologicdamage.Inthelattersituation,chronicpainandtransientosteopeniaarefeaturesofthecomplexregionalpainsyndrome(alsoknownasreflexsympatheticdystrophy,causalgia,andotherterms).3BonemarrowedemasyndromecanbedifferentiatedfromONonthebasisofhistologicandMRIfindings.Subchondralfractureofthefemoralheadtypicallyoccursinpatientswithpreexistingosteopeniaandisgenerallythoughttorepresentaninsufficiencyfracture.50Thesefracturesmaybedifficulttovisualizewithplainradiographs.Subtleflatteningissometimespresentwithearlylesions;collapseofthefemoralheadisprogressive.CLINICALMANAGEMENTOFHIPOSTEONECROSISFactorstoconsiderwhendevelopinganoptimalmanagementapproachforsymptomaticONofthehipshouldbeaimedattreatingthestageanddegreeofinvolvementofON,theextentandlocationofbonyinvolvement,thepresence(orabsence)ofsymptoms,andthepatient’scomorbidities.Thegoaloftherapyistopreservethebiologicalhipjointforaslongaspossiblewhilealsotakingintoconsiderationqualityoflifeissuessuchaspatientage,mobility,occupation,andlifestyle.ThreemaintherapeuticoptionsformanagementofhipONinclude1)nonoperativemanagement,2)joint-preservingprocedures,and3)THA.TheeffectsofatraumaticcausesofhipONposespecialconcerns.Forthoseaffected,67%reportnosymptomsbutmayeventuallygoontohaveacollapsedjoint.51Thenaturalhistoryofasymptomaticmedium-sized,andespeciallylarge,osteonecroticlesionsisprogressiontoworseningoftheconditionandeventuallyend-stagediseaseandcollapseofthehipinasubstantialnumberofpatients.Forthosewithsymptoms,approximately80%to85%ofcaseswillresultincollapseofthefemoralheadwithin2years.6EarlydiagnosisofONmaythereforeprovidetheopportunityforearlytreatment,whichcanpreventcollapseand,ultimately,theneedfortotaljointarthroplasty.However,mostpatientspresentlateinthecourseofthedisease,andahighindexofsuspicionisnecessaryforthosewithknownorprobableriskfactors,particularlypatientswithhigh-dosecorticosteroiduse.3SimilarlyforpatientswithasymptomatichipON,thesize,extent,andlocationofthenecroticlesionaffectingthefemoralheadshouldbeconsidered.Generally,lesionsaffectinglessthan15%ofthefemoralheadarebestmanagednonoperatively;lesionsbetween15%to30%shouldbemanagedsurgically;andlesionsinvolvingmorethan30%ofthefemoralheadarelikelytoprogresstocollapse,despitesurgicalintervention,andeventuallyrequireTHA.3,52,53NonsurgicalTreatmentOptionsinHipOsteonecrosisPhysicalTherapyPhysicaltherapymayprovidereliefandalleviatesomesymptomsbutgenerallywillnotprecludeprogressivehipONfromadvancingtolaterstages.54Similarly,restrictingweight-bearingwiththeuseofassistivedevicessuchascrutchesoracanemaybeusefultocontrolsymptomsofpain,weakness,andantalgicgait.PhysicaltherapyisnotappropriateifthegoaloftreatmentistopreventthehipfromrequiringTHA,andtodatethereisnoevidencethatweight-bearingrestrictionsarehelpfulinpreventingprogressiveONdiseasefromadvancingtoend-stagedisease.MedicationsNonsteroidalanti-inflammatorydrugsandacetaminophenmayprovidetemporaryreliefofpaininsymptomaticpatients.Opioidmedicationsmaybeusedjudiciouslyandforshortperiodsoftimewhenotheragentsareineffectivetomanagemoderate-to-severepainwhilesurgicaloptionsarebeingconsidered.InvestigationalmedicationoptionscurrentlybeingusedbutthatarenotprovenorreliablyusedtotreatONinclude1)anticoagulants,2)bisphosphonateantiresorptiveagents,3)cholesterolloweringstatins,and4)hyperbaricoxygen.SurgicalOptionsinEarly-StageHipOsteonecrosisCoreDecompressionCoredecompressionisaminimallyinvasivesurgicaltechniqueperformedtomanagesymptomsinearlystages(precollapse)ofthecondition(eg,FicatandArletStagesIandII).Theprocedureinvolvesdrillingholesintothefemoralheadtorelievepressureandcreatechannelsfornewbloodvesselstonourishtheaffectedareas.Thepublishedsuccessratesofcoredecompressionvarygreatlyfrom40%to100%,dependingonpatientpopulation.35Highersuccessratesaftercoredecompressionareseeninpatientswiththeearliestdiseasestages.Patientswithsuccessfulcoredecompressionprocedurestypicallyreturntounassistedambulationafterseveralmonthsandcanhavecompletepainrelief.55BoneGraftingCoredecompressioncanbecombinedwithbonegraftingtohelpregeneratehealthyboneandsupportcartilageatthehipjoint.Abonegraftishealthybonetissuethatistransplantedtotheareaofnecroticordeadbone.Astandardtechniqueusesanautograftthatinvolvestakingbonefromonepartofthebodyandmovingittoanotherpartofthebody.Abonegraftthatisharvestedfromadonororcadaveriscalledanallograftandistypicallyacquiredthroughabonebank.BoneMarrowAspirateConcentrationThebonemarrowaspirateconcentrationinjectionprocedurewithcoredecompressioninvolvestheuseofconcentratedbonemarrowthatisinjectedintothedeadboneofthehip.Thisinvestigationaltechniqueharvestsstemcellsfromapatient’sbonemarrowandinjectsthemintotheareaofON.9Thebonemarrowaspirateconcentrationprocedureishypothesizedtopreventfurtherprogressionofthediseaseandtostimulatenewbonegrowth.56PercutaneousDrillingAnothersurgicaloptionispercutaneousdrilling.Inthisprocedure,aholeisdrilledpercutaneouslythroughthefemoralnecktotheaffectedsiteinthefemoralhead.Onereporton45hipswithameanfollow-upof24monthsreported24(80%)of30hipswithFicatandArletStageIdiseasehadsuccessfuloutcomes(definedasHarrisHipScore＜70).57Amorerecentstudycomparingmultipledrillingvsstandardcoredecompressionshowedfavorableresultsinfavorofpercutanteousdrilling.28SurgicalOptionsinAdvanced-StageHipOsteonecrosisVascularizedBoneGraftAvascularizedfibulagraftisamoreinvolvedsurgicalprocedureinwhichasegmentofboneistakenfromthefibulawithitsbloodsupply.Thegraftisthentransplantedintoaholecreatedinthefemoralneckandhead,andthearteryandveinarereattachedtohelphealtheareaofON.55OsteotomyOsteotomyinhipONcanbeperformedtoremovenecroticboneawayfromprimaryweight-bearingareas.AlthoughthisoperationmaydelayTHAsurgery,itismostusefulinpatientswithidiopathicONwhodemonstratesmallprecollapseorearlypostcollapseofthefemoralhead.Aconsequenceofosteotomies,however,isthattheymakesubsequentTHAmorechallengingandareoftenassociatedwithanincreasedriskofnonunionofthebone.NonvascularizedBoneGraftThereare3typesofnonvascularizedbonegraftingsurgeries:1)trapdoorprocedure,2)lightbulbtechnique,and3)Phemistertechnique.ThetrapdoorprocedureisoneinwhichautogenouscancellousandcorticalbonegraftinghavebeensuccessfulinFicatandArletStageIIIhipONinpatientswithsmall-tomedium-sizedlesions.Areviewoftheresultsof30trapdooroperationsperformedon23patientswithFicatandArletStageIIIorStageIVONofthefemoralheadperformedthroughaso-calledtrapdoormadeinthefemoralheadrevealedagoodorexcellentresultasdeterminedbytheHarrisHipScoresystem.11LightbulbTechniqueThelightbulbtechniqueusesacorticalwindowintheanterioraspectofthefemoralneck.Necroticbonecanberemovedusingthiswindow,whichcanbelaterpackedwithnonvascularizedbonegraft.Wangetal55evaluated110patients(138hips)whounderwentthelightbulbprocedure.Atmeanfollow-upof25months,meanHarrisHipScoresimprovedfrom62to79points.Atotalof94hips(68%)wereconsideredtohavesuccessfuloutcomesatlatestfollow-up.Radiographicimprovementswerenotedin100%ofAssociationResearchCirculationOsseousStageIIapatients,77%instageIIbpatients,and51%instageIIcandIIIapatients.55PhemisterTechniqueInthePhemistertechnique,atrephineisinsertedthroughthefemoralnecktocreateatracttothelesion.Asecondtrephineistheninsertedtocreateanothertracttothelesionsite.Acorticalstrutgraftcanthenbeplacedinthelesion.Arecentreviewreportsthisproceduretohaveaclinicalsuccessraterangingfrom36%to90%.25TotalHipArthroplastyOncethefemoralheadhasundergonemajorcollapse,replacingthehipjointistheonlypracticaloperativeoptionandoffersthemostpredictablepainreliefinadvancedON.THAissuccessfulinrelievingpainandrestoringfunctioninthemajorityofpatients.45–47InTHA,thediseasedcartilageandboneconstitutingthehipjointisreplacedwithartificialimplantsmadeofmetalandplastic.Aprosthetichipreplacementgenerallylasts15yearsbeforeitmightwearoutandneedtoberevised.Fortheyoungeragegroup,aTHAmaybeasuboptimalsolutionbecauseofpossibleactivityrestrictions.Additionally,becauseprostheseshavelongevityrestrictions—componentswearafterlong-termuse—thesepatientswilllikelyrequirearevisionTHAlaterinlife.THAmustbecarefullyconsideredandbalancedagainstqualityoflifeissues,butitisnotabsolutelycontraindicatedforyoungerpatients.PATIENTEDUCATIONABOUTHIPOSTEONECROSISPreventionofOsteonecrosisPatienteducationaboutriskfactors,therapies,andmanagementisessentialforpatientstomakebetter-informeddecisionsabouttheircondition.TheprocessofONeducationinvolvesidentificationofanindividual’sassociateddisordersandriskfactorsrelatedtoON.PatientswithasymptomaticONmayhaveahighprevalenceofprogressiontosymptomaticdiseaseandfemoralheadcollapse.Educationforpatientswithasymptomaticdiseaseisprecautionaryandimperativetoensuremodificationofriskfactorsandoptimizationofcare.PreventingatraumaticONrequires1)avoidingexcessiveuseofalcoholdefinedas＜15drinks/wkformenand＜8drinks/wkforwomen,102)avoidingsmoking,and3)reducingcorticosteroidstothelowestpossibletherapeuticdose.InformingpatientsaboutthecorrelationbetweencorticosteroiduseandpotentialdevelopmentofONiscriticalinmanagementofthiscondition.PreventionofProgressionofOsteonecrosisPatientsdiagnosedwithearly-stageONshouldbeadvisedoftheaforementionedprecautionsandshouldavoidplacingexcessivepressureontheirjoints,followahealthydiet,andmaintainanappropriateweighttomitigateprogressionofON.Althoughahealthydietinitselfdoesnotdirectlyreducepressureonapatient’sjoints,weightloss(ifoverweight/obese)willreduceaxialloadsonthehipjoint,whichinturndecreasesthestrainappliedtothefemoralhead/neck(toboththetensionandthecompressionsides).42CONCLUSIONONisapathologicandoftenpainfulconditioninvolvingnecroticareasoftissuethatcanaffectanybonyjointinthebody.ThehipjointisthemostcommonlocationforONandshouldalwaysbeproperlyevaluated,utilizingradiographicscreeningandMRIscanning,whenONisinitiallydiagnosedinanotherbodypart.TheearlieradiagnosisofONismade,thebettertheopportunitytosavethehipjointwithoutsurgicalinterventionorwithminimallyinvasivesurgicaltechniques.AfteradiagnosisofONismade,thesize,extent,andlocationofthelesionandtheclassificationstagesareconsideredtodevelopanoptimalplanofcare.Thepresenceorabsenceofsymptomsisimportantinthisprocess.Thegoalsoftreatmentinvolveattemptingtopreservethebiologicalhipjointforaslongaspossibleandconsiderationofapatient’slifestyleandqualityoflifeissues.Todate,the2maintherapeuticoptionsformanagementofhipONincludejoint-preservingproceduresandTHA.PatienteducationaboutpotentialriskfactorsanddevelopmentofONisessentialtopreventtheconditionand/ortopotentiallypreventorhaltprogressionofearly-stagediseasetolater-stagedisease.2023年07月10日1185
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陶可主治醫(yī)師 北京大學人民醫(yī)院 骨關節(jié)科 股骨頭壞死：病因、診斷及治療方式：2019英國醫(yī)學雜志(BMJ)(醫(yī)學生及低年資住院醫(yī)師培訓之)綜述作者：JonathanNLamb,ColinHolton,PhilipO'Connor,PeterVGiannoudis作者單位:LeedsInstituteofRheumaticandMusculoskeletalMedicine,SchoolofMedicine,UniversityofLeeds,Leeds,UK.譯者：陶可（北京大學人民醫(yī)院骨關節(jié)科）股骨頭壞死你需要了解什么？?股骨頭壞死(AVNFH)的常見危險因素包括：酗酒、使用類固醇激素、化療和免疫抑制劑藥物以及鐮狀細胞性貧血。?如果患者髖部疼痛持續(xù)超過6周且X線片正常，請考慮對髖部進行核磁共振MRI掃描，并轉診至骨科（保髖治療）團隊。?早期治療可使髖關節(jié)7年后存活率提高至88%。Fig1Demonstrationofhiprotationtoelicithippainwiththepatientsitting(A)andsupine(B,C,D).圖1?演示通過患者坐位(A)和仰臥位(B、C、D)引起髖部疼痛的髖關節(jié)旋轉活動(髖關節(jié)查體之內外旋轉活動)。Fig2Typicalchangesseenonplainradiograph(top)andMRI(bottom)ofthehipinearlyandlateAVNFH.TheappearanceofearlyAVNFHisnotapparentonplainradiographbutisvisibleonMRI.圖2?早期和晚期股骨頭壞死(AVNFH)髖關節(jié)平片（上）和MRI（下）中看到的典型變化。早期股骨頭壞死(AVNFH)的在平片上表現不明顯，但在MRI上可見明顯信號的改變。Fig3ProposedpathwayformanagingAVNFHinaprimarycaresetting.圖3?在基層醫(yī)療機構中管理股骨頭壞死(AVNFH)的建議診治流程。?典型病例：一名36歲的女性向她的全科醫(yī)生報告，有左側腹股溝疼痛放射到膝蓋的病史。疼痛很嚴重，走路時更嚴重，并伴有跛行。一年后，患者再次去看全科醫(yī)生，盡管進行了鎮(zhèn)痛，但疼痛仍持續(xù)存在。髖關節(jié)和膝關節(jié)的平片顯示髖關節(jié)間隙輕微變窄，沒有其他特征，她被轉診到二級骨科診所。髖關節(jié)磁共振成像(MRI)掃描顯示股骨頭缺血性壞死(AVNFH)伴塌陷的典型特征。什么是股骨頭缺血性壞死？股骨頭壞死（AVNFH）由于微循環(huán)異常而導致軟骨下骨結構完整性喪失。潛在的發(fā)病機制尚不清楚；風險因素可能會以某種方式影響微循環(huán)，但這尚未得到研究證實。共同的終點是微循環(huán)異常和壞死。軟骨下骨隨后塌陷，導致進行性、繼發(fā)性髖關節(jié)骨關節(jié)炎。在英國，平均發(fā)病年齡為58.3歲，每10萬名患者中有2人患病。平均而言，股骨頭壞死（AVNFH）比典型骨關節(jié)炎發(fā)生得更早。它在男性中更為常見，發(fā)病率最高的是25至44歲的男性和55至75.3歲的女性。在英國，它是50.4歲以下人群全髖關節(jié)置換術的第三大常見適應癥。以下因素與股骨頭壞死（AVNFH）風險增加相關：?血液甘油三酯、總膽固醇、低密度脂蛋白膽固醇和非高密度脂蛋白膽固醇水平高；?男性；?城市居民；?股骨頭壞死（AVNFH）家族史；?大量吸煙；?濫用酒精；?超重；?凝血病；?血管病變；?艾滋病病毒；?大量接觸類固醇激素、化療和免疫抑制藥物。類固醇激素已被證明會使骨壞死（非部位特異性）的幾率增加3倍，而免疫抑制劑則增加6倍。Zhao報告稱，服用皮質類固醇激素的患者發(fā)生股骨頭壞死（AVNFH）的幾率高出35倍，患有“酗酒”狀態(tài)的患者則高出6倍。為什么股骨頭壞死（AVNFH）會漏診呢？股骨頭壞死（AVNFH）很少見?；加羞@種疾病的患者可能同時患有慢性風濕病和血液病。這可能會導致診斷的不確定性，特別是考慮到在這些情況下使用化療、免疫調節(jié)劑和類固醇激素時，這些都是股骨頭壞死（AVNFH）的危險因素。查體可以幫助識別可能引起疼痛的解剖結構，因為髖關節(jié)疼痛可能源自髖關節(jié)和非髖關節(jié)的多個部位。臨床表現可能會被錯過，因為由于時間和空間的限制，在基層醫(yī)療機構中準確確定單純由于髖關節(jié)運動時造成的腹股溝疼痛可能具有挑戰(zhàn)性(比較困難)。股骨頭壞死（AVNFH）早期階段的正常X線片可能會錯誤地讓人放心并延遲適當的轉診。如果X線片呈陰性并且患者繼續(xù)抱怨髖關節(jié)疼痛，醫(yī)生可能會診斷為非特異性髖關節(jié)疼痛（考慮到肌肉骨骼的原因）并建議患者接受物理治療。在新發(fā)病例中，18.75%只能通過MRI進行診斷，并且在普通X線片上很容易被漏診。只有MRI掃描才具有診斷意義。為什么及早確診股骨頭壞死（AVNFH）很重要？早期診斷和轉診至關重要，因為骨質破壞通常發(fā)生在發(fā)病后2年內，因此不可能進行保留髖關節(jié)的治療干預(保髖治療在股骨頭壞死發(fā)病2年內)。股骨頭壞死（AVNFH）的早期發(fā)現使多學科團隊有時間改變可能引發(fā)股骨頭壞死（AVNFH）發(fā)作的治療方法。股骨頭髓心減壓術可降低中短期內進一步手術的需要，但僅適用于疾病的最早階段。一旦患者進展為繼發(fā)性髖關節(jié)骨關節(jié)炎，關節(jié)置換通常是不可避免的。然而，考慮到股骨頭壞死（AVNFH）患者年齡較小，翻修手術和相關發(fā)病率的終生風險很大。如何診斷股骨頭壞死（AVNFH）？股骨頭壞死（AVNFH）診斷從仔細詢問病史和檢查開始，以確定髖關節(jié)疼痛的來源。最終需要MRI來診斷股骨頭壞死（AVNFH），并且還可以診斷髖關節(jié)疼痛的其他原因。仔細的詢問病史病史顯示疼痛持續(xù)超過6周，通常位于腹股溝和大腿，負重和運動時疼痛更嚴重。通常沒有外傷史。詢問危險因素，如果患者有任何“危險信號”，請進行髖關節(jié)MRI檢查。股骨頭壞死（AVNFH）通常是雙側的，雙側股骨頭壞死（AVNFH）的風險通常是在單側確診后的2年內?？?：需要轉介或進一步評估的危險信號：?髖關節(jié)X線檢查正常，髖關節(jié)疼痛超過6周；?患有髖關節(jié)疼痛和危險因素的患者，包括：o既往單側股骨頭壞死（AVNFH），o酗酒，o大量接受類固醇激素治療，o免疫治療，?化療，o鐮狀細胞病和其他凝血病，?艾滋病毒，o新近妊娠。查體腹股溝、大腿和膝關節(jié)前側疼痛的再現并伴有單獨的大腿旋轉不能診斷股骨頭壞死（AVNFH），但有助于區(qū)分髖關節(jié)疼痛與脊柱和膝關節(jié)疼痛。這可以在患者坐位或仰臥時進行（圖1）。影像學檢查早期股骨頭壞死（AVNFH）在X線片上并不明顯。如果患者持續(xù)感到疼痛，則需要進一步檢查和轉診。股骨頭壞死（AVNFH）通過髖關節(jié)MRI進行診斷，當與臨床癥狀密切相關時，還可以診斷各種可治療的髖關節(jié)疼痛（例如風濕病、肌腱疾病和骨?。▓D2）。僅當有其他原因或高度懷疑風濕病或感染時，才應考慮進行其他檢查，例如血液檢查。轉診如果患者的髖關節(jié)MRI顯示有股骨頭壞死（AVNFH）改變時，請就診于骨科醫(yī)生（圖3）。在二級醫(yī)療機構就診時，股骨頭壞死（AVNFH）診斷應與開具類固醇激素、化療和免疫治療原發(fā)病的任何治療團隊共享。藥物和手術治療取決于患者的特征和股骨頭壞死（AVNFH）的階段。使用前列環(huán)素類似物和雙膦酸鹽對塌陷前股骨頭壞死（AVNFH），可以減輕癥狀并防止關節(jié)形合度破壞，但其療效目前尚不清楚。手術治療仍存在爭議，但大多數塌陷前股骨頭壞死（AVNFH）患者均接受髓心減壓手術，并輔以或不輔以藥物治療，以減輕疼痛，并有可能在長達7年的時間里避免88%的患者進行全髖關節(jié)置換術治療。術后恢復包括12個月的非負重康復鍛煉，并在8周后逐漸恢復工作和駕駛。通常在術后12個月即可感受到完全的治療益處。專業(yè)的三級醫(yī)療機構可以提供新的治療方法，例如骨移植和截骨術，以分別促進血管再生和減輕受損髖關節(jié)表面的負荷。一旦發(fā)生塌陷，全髖關節(jié)置換術可以為患者提供快速、可靠的疼痛緩解和功能改善，但與未來有髖關節(jié)翻修的風險，特別是對于年輕患者。?AvascularnecrosisofthehipWhatyouneedtoknow?CommonriskfactorsforAVNFHarealcoholism,useofsteroids,chemotherapyandimmunosuppressantmedication,andsicklecellanaemia.?ConsiderMRIscanofthehipandreferraltoanorthopaedicteamifapatienthasapainfulhipforlongerthansixweekswithnormalradiographs.?Earlytreatmentimprovesthechancesofhipsurvivalbyupto88%atsevenyears.?A36yearoldwomanpresentstoherGPwithahistoryofleftgroinpainradiatingtotheknee.Thepainissevere,worseonwalking,andassociatedwithalimp.ThepatientrevisitstheGPayearlaterwithpersistentpaindespiteanalgesia.Plainradiographsofthehipandkneeshowslightnarrowingofthehipjointspacewithnootherfeaturesandsheisreferredtoasecondarycareorthopaedicclinic.Amagneticresonanceimaging(MRI)scanofthehipshowsclassicfeaturesofavascularnecrosisofthefemoralhead(AVNFH)withcollapse.Whatisavascularnecrosisofthefemoralhead?Osteonecrosisofthefemoralhead(AVNFH)causeslossofintegrityofsubchondralbonestructureduetoabnormalmicrocirculation.Theunderlyingpathogenesisisunclear1;riskfactorsarelikelytoaffectmicrocirculationinsomewaybutthishasnotbeenconfirmedbyresearch.Thecommonendpointisabnormalmicrocirculationandnecrosis.Subchondralbonesubsequentlycollapses,whichleadstoprogressivesecondaryarthritis.MeanageofpresentationintheUKis58.3years,withaprevalenceoftwoper100000patients.2Onaverage,AVNFHoccursearlierinlifethantypicalosteoarthritis.Itismorecommoninmenandthehighestprevalenceisinmenaged25to44andwomenaged55to75.3IntheUKitisthethirdmostcommonindicationfortotalhipreplacementinpeopleunder50.4ThefollowingfactorsareassociatedwithanincreasedriskofAVNFH35:?Highlevelsofbloodtriglycerides,totalcholesterol,lowdensitylipoproteincholesterol,andnon-highdensitylipoproteincholesterol?Malesex?Urbanresidence?FamilyhistoryofAVNFH?Heavysmoking?Alcoholabuse?Overweight?Coagulopathies?Vasculopathies?HIV?Highexposuretosteroids,chemotherapy,andimmunosuppressantmedication.Steroidshavebeenshowntoincreaseoddsofosteonecrosis(non-sitespecific)byafactorofthreeandimmunosuppressantsbyafactorofsix.ZhaoreportedthattheoddsofAVNFHwere35timesgreaterinpatientstakingcorticosteroidsandsixtimesgreaterinpatientswith“alcoholism”status.3Whyisitmissed?AVNFHisrare.Patientswiththeconditioncanhavecoexistingchronicrheumaticandhaematologicalproblems.Thismayleadtodiagnosticuncertainty,particularlygiventheuseofchemotherapy,immunomodulatoryagents,andsteroidsintheseconditions,whichareallriskfactorsforAVNFH.Aphysicalexaminationcanhelpidentifytheanatomicalstructuresthatmightbecausingthepain,sincehippaincanoriginatefrommultiplehipandnon-hipareas.Presentationsmaybemissedbecauseaccuratereproductionofgroinpainonisolatedhipmovementscanbechallengingtoelicitinaprimarycaresettingduetotimeandspaceconstraints.NormalplainradiographsintheearlystagesofAVNFHcanbefalselyreassuringanddelayappropriatereferral.Iftheplainradiographisnegativeandthepatientcontinuestocomplainofhippain,thedoctormaygiveadiagnosisofnon-specifichippain(giventhatmusculoskeletalpresentationsarecommoninprimarycare)andsendthepatientforphysiotherapy.Ofnewpresentations,18.75%arediagnosableonlywithMRIandareeasilymissedonnormalplainradiographs.3OnlytheMRIscanisdiagnostic.Whydoesitmatter?Earlydiagnosisandreferralareessentialsincebonedestructionnormallyoccurswithintwoyearsofdiseaseonset,makingjointpreservinginterventionimpossible.6EarlyidentificationofAVNFHgivesthemultidisciplinaryteamtimetochangemedicaltreatmentswhichmightbeprovokingonsetofAVNFH.Surgicaldecompressionofthefemoralheadreducestheneedforfurthersurgeryintheshorttomediumtermbutisonlysuitablefortheearlieststagesofdisease.5Oncepatientshaveprogressedtosecondaryhiparthritis,jointreplacementisusuallyinevitable.However,giventheyoungerageofpatientswithAVNFH,thelifetimeriskofrevisionsurgeryandassociatedmorbidityisgreat.HowisAVNFHdiagnosed?AVNFHdiagnosisstartswithacarefulhistoryandexaminationtodeterminethatthehipisthesourceofpain.UltimatelyanMRIisrequiredtodiagnoseAVNFHandmayalsodiagnoseothercausesofhippain.AcarefulhistoryAhistoryshowingpainlastinglongerthansixweeks,typicallylocatedinthegroinandthighandwhichisworseonweightbearingandmovementiskey.6Usuallythereisnohistoryoftrauma.AskaboutriskfactorsandreferforMRIofthehipifthepatienthasany“redflags”(box1).AVNFHisoftenbilateralandtheriskofbilateralAVNFHishighestwithintwoyearsofunilateraldiagnosis.6Box1:Redflagsrequiringreferralorfurtherassessment?Hippainformorethansixweekswithnormalhipradiograph?PatientspresentingwithhippainandriskfactorsincludingopreviousunilateralAVNFHoalcoholexcessohighexposuretosteroidtherapyoimmunologictherapyochemotherapyosicklecelldiseaseandothercoagulopathiesoHIVorecentpregnancyExaminationReproductionofpaininthegroin,thigh,andanterioraspectofkneewithisolatedthighrotationwillnotdiagnoseAVNFH,butwillhelptodifferentiatehippainfrompainoriginatingfromthespineandknee.Thiscanbeperformedwiththepatientsittingorsupine(fig1).RadiologicaltestsEarlyAVNFHisnotapparentonplainradiographs.Ifthepatientcontinuestobeinpain,furtherinvestigationandreferraliswarranted.AVNFHisdiagnosedonMRIofthehips,7whichmayalsodiagnoseabreadthoftreatablehippain(suchasrheumatologicaldisease,musculotendinousdisease,andbonydisease)whencarefullycorrelatedwithclinicalsymptoms8(fig2).Otherinvestigations,suchasbloodtests,shouldonlybeconsideredifindicatedforotherreasonsorifthereisahighsuspicionofrheumatologicaldiseaseorinfection.ReferralIfthepatienthassignsofAVNFHonMRIofthehip,refertoanorthopaedicsurgeonforconsultation(fig3).Insecondarycare,AVNFHdiagnosisshouldbesharedwithanycareteamsinvolvedintheadministrationofsteroids,chemotherapy,andimmunologictherapy.MedicalandsurgicaltreatmentdependonthepatientcharacteristicsandstageofAVNFH.Medicaltreatmentofpre-collapsediseasewithprostacyclinanaloguesandbisphosphonatesmayreducesymptomsandpreventlossofjointcongruitybuttheirefficacyisnotcurrentlywelldefined.6Surgically,treatmentremainscontroversial,butmostpatientswithpre-collapseAVNFHareofferedcoredecompressionsurgerywithorwithoutadjunctivepharmacologicaltherapytoreducepainandpotentiallypreventtheneedfortotalhipreplacementin88%ofpatientsforuptosevenyears.910Postoperativerecoveryinvolvesaperiodofnon-weightbearingfor12monthsandgradualreturntoworkanddrivingat8weeks.Fullbenefitisusuallyfeltat12monthsaftersurgery.Specialisttertiarycentresmayoffernoveltreatmentssuchasbonegraftingandosteotomiestoencouragevascularregrowthandunloaddamagedhiparticularsurface,respectively.Oncecollapsehasoccurred,totalhipreplacementcangivepatientsrapid,reliablepainreliefandimprovedfunctionbutisassociatedwiththeriskoffuturerevision,particularlyinyoungerpatients.Afulldescriptionofalltheoptionsisbeyondthescopeofthisarticleandpatientsshoulddiscussallavailableoptionswiththeirsurgeontoenableinformedshareddecisionmaking.文獻出處：JonathanNLamb,ColinHolton,PhilipO'Connor,PeterVGiannoudis.Avascularnecrosisofthehip.BMJ.2019May30;365:l2178.doi:10.1136/bmj.l2178.2023年07月09日538
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陶可主治醫(yī)師 北京大學人民醫(yī)院 骨關節(jié)科 股骨頭壞死治療：2022年最新研究進展作者：GaryGeorge,JosephMLane.作者單位:FromWeillCornellMedicine,NewYork,NewYork(Mr.George),andtheHospitalforSpecialSurgery,NewYork,NewYork(Dr.Lane).譯者：陶可（北京大學人民醫(yī)院骨關節(jié)科）摘要股骨頭壞死是一種進展性、使人致殘的疾病，其病因多種多樣，包括外傷、使用激素(類固醇)和飲酒。診斷和分期基于影像學檢查，包括任何階段的MRI掃描和更晚期病變的X線片檢查。（疾病晚期）唯一確定的治療方法是全髖關節(jié)置換術，盡管，（目前臨床上）采用包括二磷酸鹽和核心減壓在內的多種治療方法來延緩病情進展。缺乏令人滿意的保守（治療）措施表明，需要對股骨頭壞死進行進一步研究，包括大型的患者登記，以進一步了解（保守治療的）效果。股骨頭壞死是一種進展性疾病，（股骨頭）缺乏足夠的血液供應會導致受影響區(qū)域的細胞死亡、骨折和塌陷。這種情況通常與股骨頭有關，病情進展可能會使人衰弱（殘疾），最終可能需要進行全髖關節(jié)置換術(全髖關節(jié)置換術(THA))。股骨頭壞死的病因很復雜，有多種致病因素，其中最明顯的是外傷、使用激素和酒精。股骨頭壞死的治療是有爭議的，因為沒有任何一種治療方式是被廣泛接受的，而且很少有研究比較（各種）治療方法（之間的優(yōu)劣）。研究人員估計，美國每年診斷出20,000例新發(fā)的股骨頭壞死病例。股骨頭壞死發(fā)病率的增加和使人致殘的進展表明需要對有效和新穎的治療方法進行深入的研究，以及需要更清楚地了解現有的治療方法。這篇綜述描述了目前關于股骨頭壞死的病因學、病理生理學、流行病學和臨床治療的知識，重點介紹了最新進展。流行病學據估計，美國每年股骨頭壞死的發(fā)病率約為20000至30000例，主要影響20至40歲之間的年輕人。最近的分析表明，盡管因股骨頭壞死而進行的全髖關節(jié)置換術(THA)數量有所增加，2001年和2010年（從每100,000名住院患者54.2例到每100,000名住院患者60.6例），因股骨頭壞死而進行全髖關節(jié)置換術(THA)的比例從9.7%下降到8.3%，可能是因為需要進行全髖關節(jié)置換術(THA)的骨關節(jié)炎迅速增加。病理生理學和發(fā)病機制一般發(fā)病機制盡管臨床表現是修復過程的結果，而不是最初的缺血，但股骨頭壞死的發(fā)生是由于骨骼的血流或氧氣輸送受損。在股骨頭壞死中，成骨細胞的骨形成無法與破骨細胞的骨吸收相匹配。這種重塑不平衡并不能充分替代壞死骨，從而留下了結構不健全的骨組織區(qū)域。創(chuàng)傷創(chuàng)傷是股骨頭壞死的最常見原因，會擾亂血流并導致骨細胞死亡。發(fā)生股骨頭外傷性股骨頭壞死的估計因損傷類型而異；然而，在創(chuàng)傷性股骨頭壞死的薈萃分析中，發(fā)現其發(fā)生率高達14.3%。Garden分類對股骨頸骨折進行了分類，可用于估計股股骨頭壞死的風險。GardenI（不完全骨折）和GardenII（完全且無移位）被認為是穩(wěn)定且風險低的，可以通過內固定修復。GardenIII（完全骨折和部分移位）和GardenIV（完全骨折和完全移位）內固定的股骨頭壞死發(fā)生率要高得多（16%），應考慮髖關節(jié)置換術。另外，有文獻報道，股骨轉子間骨折導致股骨頭壞死的風險較低，一年隨訪時的股骨頭壞死結果為0.95%。非外傷性股骨頭壞死非外傷性股骨頭壞死有多種原因。值得注意的是，在非創(chuàng)傷性股骨頭壞死中，由于系統(tǒng)性危險因素，疾病常常是雙側的，一些估計表明，高達70%的單側股骨頭壞死患者的對側髖部會發(fā)生疾病。在存在系統(tǒng)性危險因素的情況下，一側髖關節(jié)的磨損尚未得到充分研究，可能是由于亞臨床表現、髖關節(jié)之間磨損模式的差異、對癥狀的調查不足或缺乏協調的隨訪。糖皮質激素類固醇的使用是股骨頭壞死的第二個最常見原因。已經提出了這種關聯的幾種潛在機制，包括骨基質和軟骨變性、誘導干細胞異常、脂質代謝的變化、脂肪栓塞的產生、凝血改變。薈萃分析發(fā)現，服用大劑量皮質類固醇的患者風險增加多達10倍；當累積劑量超過10g時，股骨頭壞死的風險增加一倍；而使用大劑量皮質類固醇患者每日劑量每增加10毫克股骨頭壞死風險就會增加3.6%。皮質類固醇也與成骨細胞死亡和成骨細胞增殖減少有關，損害修復和替換骨壞死病變的能力。酒精據推測，酒精會通過改變脂質代謝和增加脂肪生成來發(fā)揮（導致股骨頭壞死的）作用。據推測，脂質生成的增加會增加脂肪栓塞導致血管閉塞的風險。此外，血脂升高會導致骨髓堵塞、骨內壓升高和血流量減少。酒精也可能導致骨細胞死亡。一項研究還表明，與酒精性股骨頭壞死患者相比，酒精性股骨頭壞死患者的皮質醇水平升高。特發(fā)性股骨頭壞死對照受試者，表明酒精引起的股骨頭壞死可能通過類固醇途徑起作用。之前有研究指出，每天飲酒超過400mL的患者發(fā)生股骨頭壞死的風險高出11倍。高脂血癥高脂血癥被認為會增加骨內壓并產生脂肪栓塞，從而減少受影響區(qū)域的血液供應。一項針對老年人低能量股骨頸骨折的研究發(fā)現，發(fā)生股骨頭壞死的患者血脂異常率高于未發(fā)生股骨頭壞死的患者。一項針對急性淋巴細胞白血病(ALL)患者的研究發(fā)現，高脂血癥是發(fā)生股骨頭壞死的危險因素。一項類似的研究發(fā)現，高脂血癥和系統(tǒng)性紅斑狼瘡(SLE)患者與股骨頭壞死的發(fā)生有關。系統(tǒng)性紅斑狼瘡SLE與股骨頭壞死的關聯與頻繁的皮質類固醇治療有關；然而，最近的分析顯示，患有SLE的皮質類固醇使用者的股骨頭壞死發(fā)生率高于未患SLE的皮質類固醇使用者，這表明存在協同效應。SLE研究的薈萃分析已發(fā)現SLE中的許多非皮質類固醇危險因素，特別是腎臟受累和中樞神經系統(tǒng)（CNS）疾病?；旌蠑祿砻?，抗磷脂抗體的促血栓作用在SLE股骨頭壞死的發(fā)展中發(fā)揮作用。最近對兒童期發(fā)病的SLE的薈萃分析發(fā)現了顯著的股骨頭壞死關聯，估計6%至8.4%的兒童期發(fā)病的SLE患者會發(fā)生股骨頭壞死，盡管大多數患者直到青春期后才發(fā)現（并確診）股骨頭壞死。鐮狀細胞性貧血癥對鐮狀細胞病與股骨頭壞死之間關系的研究發(fā)現，每100名鐮狀細胞病患者中就有2至4.5例發(fā)生股骨頭壞死。低氧環(huán)境中血紅蛋白S的沉淀可能會導致血管閉塞和骨骼缺血，從而導致股骨頭壞死。與鐮狀細胞病中其他血管閉塞性損傷的發(fā)展類似。最近的一項研究支持這一理論，指出血紅蛋白水平升高是鐮狀細胞病患者股骨頭壞死的危險因素，并表明血管閉塞、高血液粘度、缺氧和并發(fā)的α地中海貧血會導致股骨頭壞死。戈謝病最近對戈謝登記處的一項評估估計，股骨頭壞死的發(fā)生率為30%。戈謝病可能通過與鐮狀細胞病類似的途徑發(fā)揮作用，受戈謝影響的細胞會阻礙血流或通過增加骨內壓，因為它們在體內積聚。此外，戈謝細胞可以釋放破骨細胞激活細胞因子，破壞骨形成和吸收的平衡。酶替代可以減輕或延遲股骨頭壞死的癥狀；然而，一項研究表明，骨髓可能是戈謝細胞的“避難所”，導致部分患者盡管接受治療，仍容易發(fā)生股骨頭壞死。減壓病減壓病相關的股骨頭壞死或氣壓異常性股骨頭壞死是由于長時間處于高壓環(huán)境后快速減壓而發(fā)生的?？焖贉p壓會在血液中形成氣泡，因為溶解的氮氣會從溶液中逸出。氮氣在脂肪組織中的高溶解度使得骨髓特別容易受到影響。已經提出了多種機制，包括直接阻塞骨髓血流和骨內壓升高減少有效血流。最近一項針對患有肌肉骨骼減壓病的潛水員的研究發(fā)現，26%的病例存在氣壓不足性股骨頭壞死的證據，盡管研究受到這種情況相對罕見的限制。急性淋巴細胞白血病ALL患者發(fā)生股骨頭壞死的風險增加，前瞻性研究中影像學發(fā)生率達到71.8%。ALL患者發(fā)生股骨頭壞死的最大單一因素是青春期，這表明ALL或其治療對骨骼的生長和發(fā)育、重塑有影響。也有可能是代謝和生長時期的變化放大了易感性。老年人占股骨頭壞死診斷患者的一小部分，他們經常接受改良的治療方案，與年輕人相比，總體結果更差。最近的一項兒童白血病研究發(fā)現與單純化療相比，接受造血干細胞移植(HSCT)治療的患者股骨頭壞死發(fā)生率更高（6.8%比1.4%），這表明治療方法會影響股骨頭壞死的發(fā)展。此外，對治療方案的審查發(fā)現，患有任何血液系統(tǒng)惡性腫瘤兒童的激素累積劑量的增加發(fā)生股骨頭壞死的危險因素。對治療策略的回顧表明，使用不連續(xù)的激素治療方案可能會降低股骨頭壞死的風險，而甲氨蝶呤和天冬酰胺酶等非激素化療藥物可能會導致股骨頭壞死的發(fā)生。一項隔周地塞米松試驗與持續(xù)治療高危ALL兒童相比，降低了股骨頭壞死的風險。移植最近的一項研究表明，移植患者中的股骨頭壞死是由激素介導的，發(fā)現發(fā)生股骨頭壞死的腎移植患者的累積激素劑量高于未發(fā)生股骨頭壞死的腎移植患者。研究還發(fā)現，隨著環(huán)孢素的引入和激素使用的減少，癥狀性股骨頭壞死的發(fā)生率從20%下降到5%以下。艾滋病病毒多項研究表明，艾滋病毒患者股骨頭壞死的發(fā)病率不斷上升，其風險幾乎是普通人群的三倍。最近的一項研究表明，高活性抗逆轉錄病毒治療與股骨頭壞死的發(fā)生之間存在密切關聯，盡管作者警告說，這種關聯并不意味著病理作用。其他研究發(fā)現股骨頭壞死與抗逆轉錄病毒治療(ART)之間沒有關聯，而與酒精、高脂血癥或低最低CD4計數有關，盡管其機制尚不清楚。遺傳參與盡管已經發(fā)現了股骨頭壞死的家族變異和一些相關基因，但尚未確定單一的相關基因。一個候選基因是II型膠原蛋白的突變，盡管尚未確定明確的因果關系。與健康骨骼相比，壞死區(qū)域中發(fā)現骨保護素水平升高，RANK/RANK配體表達降低，這表明破骨細胞的潛在作用。在多項研究中，因子VLeiden突變和凝血酶原突變與股骨頭壞死患者相關，表明凝血功能改變的潛在作用。對選定人群的全基因組關聯研究已經確定了幾個感興趣的位點，包括ALL、皮質類固醇誘導的股骨頭壞死患者中谷氨酸受體基因附近的變異簇，以及幾個意義不明的位點，這些位點可能與凝血途徑有關，脂質代謝，或飲酒行為。特發(fā)性股骨頭壞死值得注意的是，估計20%至40%的股骨頭壞死病例是特發(fā)性的（無明確病因）。原因不明的高比例可能是由于非特異性早期癥狀和非快速進展的病程，（因而會）妨礙早期診斷，以及缺乏標準化報告和數據收集，這可能有助于揭示少見的病因和聯系。臨床表現和診斷診斷股骨頭壞死的早期階段通常無癥狀，但查體時也可能出現髖部或腹股溝的放射痛以及髖關節(jié)活動范圍有限。股骨頭壞死的診斷主要基于影像學，盡管查體和病史（采集）對于收集髖關節(jié)周圍（其他病變）和潛在病因很重要。X線片是識別股骨頭壞死病例的合適的一線方法，其優(yōu)點包括低成本、高可用性以及對中期和晚期疾病足夠的敏感性。為了準確起見，建議采用正位和“蛙式位”側視圖。在疾病早期的情況下，放射線檢查可能不足以識別早期或微小的變化。MRI是診斷股骨頭壞死的標準，因為它對發(fā)病早期病變具有很高的敏感性。補充成像，包括彌散加權MRI和釓增強灌注MRI可能會進一步提高MRI的診斷能力。灌注MRI可能有助于區(qū)分影像學和癥狀相似的情況，例如骨髓水腫和軟骨下功能不全骨折。在患有髖關節(jié)發(fā)育不良的兒科患者中，灌注MRI有助于識別閉合復位/人字形石膏脫外固定后有股骨頭壞死風險的患者。此外，全身骨掃描患有多灶性股骨頭壞死風險的患者提供了一種選擇，如接受全身性皮質類固醇或免疫抑制劑的患者。鑒別診斷骨髓水腫綜合征骨髓水腫綜合征(BMES)表現為突發(fā)疼痛，沒有明顯的誘發(fā)事件。影像學顯示，與股骨頭壞死的局部區(qū)域相比，BMES顯示彌漫性水腫。一些研究表明BMES可能先于股骨頭壞死發(fā)生。軟骨下不全骨折軟骨下不全骨折的表現（與股骨頭壞死）類似，但發(fā)生在受傷后。盡管這兩種情況都呈現低信號軟骨下帶，但股骨頭壞死成像呈現平滑的凹線，而骨折則呈現鋸齒狀、不連續(xù)的凸面。保守治療不太可能改善骨折癥狀，并且這兩種情況都可能發(fā)展到需要進行全髖關節(jié)置換術(THA)。（股骨頭）腫瘤雖然罕見，但透明細胞軟骨肉瘤和軟骨母細胞瘤可在股骨頭中出現射線可透的病變。這些病癥不伴有股骨頭壞死或其他類似病癥（例如BMES）中出現的水腫。分類系統(tǒng)和分期最流行的股骨頭壞死分期系統(tǒng)是Ficat分期。Ficat系統(tǒng)于1964年開發(fā)，后來進行了修改，包括使用MRI，根據平片上的表現將股骨頭壞死患者分為0至4期。盡管該系統(tǒng)被廣泛接受并經常使用，但批評者認為其局限性在于使用臨床癥狀、觀察者間一致性較低和缺乏預測（效力）。賓夕法尼亞大學開發(fā)該系統(tǒng)的目的是為了更清楚地描述股骨頭壞死的進展，并通過為放射學前疾病添加0期，根據新月征的不存在(II)或存在(III)將FicatII期分為兩個階段，并將FicatIV期分為兩個階段：扁平化，關節(jié)間隙變窄，從而促進各階段之間的區(qū)別僅(V)以及關節(jié)畸形和關節(jié)間隙閉塞(VI)。骨循環(huán)研究協會(ARCO)系統(tǒng)與Ficat密切相關，但將MRI結果納入I期并根據關節(jié)間隙的程度劃分II期。股骨頭變平（如果＜2毫米則為IIIA，如果＞2毫米則為IIIB）。ARCO系統(tǒng)最近根據國際專家工作組進行了修訂，以更好地結合MRI和X線片的結果。對不同分期系統(tǒng)的系統(tǒng)分析發(fā)現，任何分類系統(tǒng)對于股骨頭壞死分期都是有價值且充分的，只要收集必要的數據以允許轉換為另一個指標。為了患者評估和治療的目的，最重要的分類是塌陷前與塌陷前股骨頭碎裂，因為這是指導保守治療與髖關節(jié)置換術(THA)的依據。出于研究目的（特別是收集注冊數據），我們建議使用更新的ARCO指南，因為它們有效地使用多種成像模式并描繪階段之間較小的變化。這可以更詳細地跟蹤疾病進展，并且可能有助于提供更清晰的答案，因為新療法的有效性得到了評估。治療方案進展風險評估進展風險對于確定適當的治療選擇很重要。盡管對于明確預測塌陷的系統(tǒng)尚未達成共識，但對嘗試策略的審查發(fā)現，病變體積增加、壞死＞40%的承重表面以及壞死弧度＞200至250度提示未來的塌陷。觀察最保守的治療方法——觀察——被認為是治療股骨頭壞死的一種可能方法。有一些證據表明小的早期股骨頭壞死病變可自行消退。與觀察相結合，通常建議限制負重，盡管這尚未顯示出作為主要治療方式的實用性。一項將觀察作為策略的研究發(fā)現，股骨頭壞死四年內的失敗率超過80%，不建議作為晚期病變的獨立治療方法。非手術治療藥物一直是股骨頭壞死治療的主要手段，但最近其有效性受到質疑。二磷酸鹽是藥物治療的熱門選擇，通過抑制破骨細胞活性發(fā)揮作用。關于二磷酸鹽使用的研究顯示了不同的結果。盡管一些早期研究表明二磷酸鹽具有積極作用，但最近的一項大型多中心隨機對照試驗發(fā)現阿侖膦酸鈉和安慰劑之間沒有差異。此外，對5項隨機對照試驗的薈萃分析顯示，類似的發(fā)現，幾乎沒有證據支持二磷酸鹽的功效。二磷酸鹽的主要用途是在疾病的早期階段，隨著股骨頭壞死的進展，二磷酸鹽并不優(yōu)于手術。研究已確定他汀類藥物在延緩股骨頭壞死方面發(fā)揮有益作用的多種潛在機制，包括降脂作用、增加自噬、抑制過氧化物酶體增殖物激活受體γ以及激活Wnt信號通路。他汀類藥物與多種藥物聯合使用可有效發(fā)揮作用。髓心減壓（CD）手術，可以改善股骨頭壞死的臨床和放射學進展。其他非手術方式已經提出了其他幾種治療股骨頭壞死的方式，并取得了不同程度的成功。飲食改變或硫辛酸補充劑等脂質調節(jié)劑在試驗中顯示出一些積極的結果，但沒有足夠的證據推薦它們作為主要治療策略。高壓氧治療、脈沖電磁場和體外沖擊波療法已獲得一些積極的成果，但對其有效性的分歧使得它們難以推薦。保髖手術治療髓心減壓CD用于治療股骨頭壞死，以降低骨內壓，促進血流增加和骨生成。Ficat在他對股骨頭壞死和髓心減壓CD手術的早期描述中指出，髓內壓力增加，髓心減壓CD釋放髓內壓力，如果在病變進展早期得到治療，可以緩解疼痛并最終恢復血流。盡管早期的髓心減壓CD研究對其有效性尚不明確，但最近的研究顯示出顯著的益處。對短期和長期結果的研究表明，與更保守的治療方案相比，接受髓心減壓CD治療的患者有所改善，并且延遲了全髖關節(jié)置換術(THA)時間。與許多治療一樣，在疾病早期階段使用時，這些結果更為積極。高達100%的髖關節(jié)存活3年，高達96%的早期疾病存活10年。更準確地說，髓心減壓CD在股骨頭壞死方面顯示出積極的結果，顯示無塌陷、中央病變和小尺寸（合并壞死）角度＜250°。當與移植物和細胞治療相結合時，這些結果可能會更加有益。血管化和非血管化骨移植非血管化骨移植涉及放置骨移植材料以提供結構支撐，目的是降低骨內壓力并防止股骨頭壞死早期階段的塌陷。血管化骨移植（VBG）還尋求增加血液供應。通過將來自髂骨、脛骨或腓骨的非血管化同種異體皮質移植物或來自髂嵴、腓骨或大轉子的血管化移植物放置到為手術或髓心減壓CD手術創(chuàng)建的髓心空間中來完成移植。無血管化骨移植已顯示出一定的成功率，特別是對于較小的病變，在多項研究中，經過2至9年的隨訪，成功率為55%至87%。血管化骨移植（VBG）顯示（在塌陷前病變中）5年髖關節(jié)存活率為80%或14年后類似患者中的60%，需要全髖關節(jié)置換術(THA)的比例較低。然而，血管化骨移植（VBG）的益處主要在沒有明顯塌陷的較小病變中實現。正在進行的研究評估了使用或不使用生物因子的合成支架增強整合和骨骼生長。盡管尚未找到明確的解決方案，但許多有機、無機和生物材料的開發(fā)前景廣闊。輔助治療由于股骨頭壞死被認為是由骨再生缺陷引起的，因此有人建議使用干細胞治療來阻止或逆轉其發(fā)病機制。研究表明，接受自體干細胞移植治療的患者放射學進展率較低，全髖關節(jié)置換術(THA)需求也較低。在早期研究中，自體干細胞移植與髓心減壓CD相結合顯示，股骨頭塌陷時間平均延遲了10年（最多17年）。此外，細胞療法可以與髓心減壓CD等其他療法相結合。一項研究表明，除了同種異體移植物和/或骨移植物之外，骨形態(tài)發(fā)生蛋白(BMP)在改善骨形成和限制股骨頭壞死進展方面也有益處。保髖截骨術截骨術是通過減輕壞死或壞死前區(qū)域的負重來延緩股骨頭壞死的進展，以防止塌陷。為此，將承重的股骨頭壞死區(qū)域傾斜或旋轉，以將主要壓力施加在股骨頭非壞死區(qū)域上。股骨頭旋轉截骨術（3至15年期間的成功率為82%至100%）和（內外翻、前伸后屈）成角截骨術（6至18年期間的成功率為82%至98%）顯示出極高的成功率。然而，如果有必要的話，未來的全髖關節(jié)置換術(THA)可能會在截骨術后變得困難。帳篷植入和改變的解剖結構.69髖關節(jié)置換術髖關節(jié)表面置換術對于晚期股骨頭壞死來說，髖關節(jié)表面置換是最簡單的選擇，涉及用人造材料替換關節(jié)表面以保留自然解剖結構。然而，由于材料引起的并發(fā)癥以及可能導致股骨頭壞死進展，表面置換不再用作股骨頭壞死的治療方法。全髖關節(jié)置換術全髖關節(jié)置換術是目前治療股骨頭壞死的唯一有效方法。然而，潛在的缺點需要仔細考慮。全髖關節(jié)置換術并不是永久的解決方案，盡管它們可能有利于老年患者盡早減少累積手術，但大多數股骨頭壞死患者相對年輕。鑒于這一人群，如果在診斷時更換關節(jié)，患者在以后的生活中可能需要再次進行髖關節(jié)置換術或翻修術。髖關節(jié)置換術的建議包括晚期疾病、持續(xù)進展和持續(xù)的誘發(fā)因素。盡管因股骨頭壞死而接受全髖關節(jié)置換術(THA)的患者比因骨關節(jié)炎接受全髖關節(jié)置換術(THA)的患者有更多的合并癥和更復雜的住院時間，但長期隨訪顯示出相似的結果：兩組之間的假體存活率、骨長入和無菌性松動等并發(fā)癥無明顯差異。然而，其他研究表明，與髖骨關節(jié)炎OA患者相比，接受全髖關節(jié)置換術(THA)的股骨頭壞死患者敗血癥、輸血需求和再入院率增加。最近的分析顯示，結果有所改善，超過90%的股骨頭壞死全髖關節(jié)置換術(THA)存活4至7年，而1990年之前的存活率為8%至37%，這可能是由于手術中使用的植入物和材料的改進。文獻在檢查病因方面有限。值得注意的是，對需要進行全髖關節(jié)置換術(THA)的股骨頭壞死患者的研究發(fā)現，46.6%的患者將繼續(xù)接受全髖關節(jié)置換術(THA)治療。需要對側全髖關節(jié)置換術(THA)，特別是如果對側髖關節(jié)在第一次全髖關節(jié)置換術(THA)時有股骨頭壞死的影像學證據，表明需要密切隨訪。總結股骨頭壞死仍然是一種病因、治療和發(fā)育特征存在廣泛差異的疾病。由于發(fā)病率持續(xù)上升，因此有必要加強對病理生理學的了解，以促進新療法和正確治療方案的發(fā)展。盡管骨移植和干細胞治療等領域正在取得有希望的發(fā)展，但該領域仍然缺乏一致意見的治療方案，來為股骨頭壞死患者提供最高的生活質量并延緩他們發(fā)展為衰弱性損傷、股骨頭塌陷或髖關節(jié)置換術。為了更有效地了解這種疾病過程，需要更多數據。國家登記處將是確定診斷和治療方向的最完整的系統(tǒng)。在缺乏這種協調努力的情況下，機構登記和大型隊列研究將有助于在這一領域取得進展。在治療領域，有許多潛在的改進途徑。骨修復方面的有前景的進步（例如合成代謝藥物）可能在促進愈合中發(fā)揮作用。此外，針對同時發(fā)生的情況進行更有針對性的治療可能會減少類固醇和化療引起的股骨頭壞死的繼發(fā)性發(fā)展。隨著對病因、預防和治療的廣泛研究，我們有理由期望在減輕這種疾病的負擔方面取得進展。OsteonecrosisoftheFemoralHeadAbstractOsteonecrosisofthefemoralheadisaprogressiveanddebilitatingconditionwithawidevarietyofetiologiesincludingtrauma,steroiduse,andalcoholintake.DiagnosisandstagingarebasedonimagingincludingMRIatanystageandplainradiographyinmoreadvancedlesions.Theonlydefinitivetreatmentistotalhiparthroplasty,althoughnumeroustreatmentsincludingdisphosphonatesandcoredecompressionareusedtodelaytheprogression.Lackofsatisfactoryconservativemeasuressuggeststheneedforadditionalresearchofosteonecrosisincludinglargepatientregistriestofurtherunderstandthiscondition.Osteonecrosisisaprogressivedisorderinwhichlackofsufficientbloodsupplyleadstocelldeath,fracture,andcollapseoftheaffectedarea.Theconditionisfrequentlyassociatedwiththefemoralhead,whereprogressioncanbedebilitatingandcanultimatelynecessitatetotalhiparthroplasty(THA).Theetiologyofosteonecrosisiscomplexwithnumerouscontributingagents,mostmarkedlytrauma,steroiduse,andalcohol.Treatmentofosteonecrosisiscontroversialbecausenooptionhasbeenoverwhelminglyembraced,andlittleresearchhascomparedtreatments.Researchersestimatetotalhiparthroplasty(THA)t20,000newcasesofosteonecrosisarediagnosedintheUnitedStateseachyear.1Theincreasingincidenceanddebilitatingprogressionofosteonecrosissuggesttheneedforadditionalinvestigationofeffectiveandnoveltreatments,aswellastheneedforclearerunderstandingofavailabletreatments.Thisreviewcharacterizesthecurrentknowledgeonetiology,pathophysiology,epidemiology,andclinicalmanagementofosteonecrosis,withanemphasisonrecentdevelopments.EpidemiologyTheincidenceofosteonecrosisintheUnitedStateshasbeenestimatedat～20000to30000casesperyear,affectingprimarilyyoungadultsbetweentheagesof20to40years.1Recentanalysishasshowntotalhiparthroplasty(THA)talthoughthenumberoftotalhiparthroplasty(THA)sdoneforosteonecrosishasincreasedbetween2001and2010(from54.2per100,000hospitaladmissionto60.6per100,000hospitaladmission),thepercentageoftotalhiparthroplasty(THA)sdoneforosteonecrosishasdecreasedfrom9.7%to8.3%,likelybecauseoftherapidincreaseinosteoarthritisnecessitatingtotalhiparthroplasty(THA).2PathophysiologyandPathogenesisGeneralPathogenesisOsteonecrosisoccursbecauseofcompromisedbloodfloworoxygendeliverytothebone,althoughtheclinicalpresentationisaresultoftherepairprocess,rathertotalhiparthroplasty(THA)ninitialischemia.Inosteonecrosis,boneformationbyosteoblastsisunabletomatchboneresorptionbyosteoclasts.Thisremodelingimbalancedoesnotadequatelyreplacethenecroticbone,leavingaregionofstructurallyunsoundbonetissues.3TraumaTraumaisthemostcommoncauseofosteonecrosis,4disruptingbloodflowandleadingtoosteocytedeath.Estimatesofoccurrenceoftraumaticosteonecrosisofthefemoralheadvarydependingontheinjurytype5;however,inmeta-analysisoftraumaticosteonecrosis,incidencehasbeenfoundtobeashighas14.3%.6TheGardenclassificationcategorizesfemoralneckfracturesandcanbeusedtoestimatetheriskofosteonecrosis.GardenI(incompletefracture)andGardenII(completeandnondisplaced)areconsideredstableandlowrisk,andcanberepairedwithinternalfixation.GardenIII(completeandpartiallydisplaced)andGardenIV(completeandcompletelydisplaced)havemuchhigherratesofosteonecrosiswithinternalfixation(16%),andarthroplastyshouldbeconsidered.7Intertrochanterichipfracturesresultinalowriskofosteonecrosis,notedat0.95%aftera1-yearfollow-up.8AtraumaticOsteonecrosisAtraumaticosteonecrosisencompassesadiversearrayofcauses.Itisimportanttonotetotalhiparthroplasty(THA)tinatraumaticosteonecrosis,diseaseisfrequentlybilateralowingtosystemicriskfactors,withsomeestimatessuggestingashighas70%ofthepatientswithunilateralosteonecrosisdevelopingdiseaseinthecontralateralhip.9,10Thereasonsforthesparingofonehipinthepresenceofasystemicriskfactorarenotwellstudiedandmaybebecauseofsubclinicalpresentation,differencesinwearpatternsbetweenhips,underinvestigationofsymptoms,orlackofcoordinatedfollow-up.GlucocorticoidsSteroiduseisthesecondmostcommoncauseofosteonecrosis.11,12Severalpotentialmechanismshavebeenproposedforthisassociation,includingbonematrixandcartilagedegeneration,inducedstemcellabnormalities,changesinlipidmetabolism,creationoffatemboli,alteredcoagulation,andchangesinbloodsupply.11,12Meta-analysisfoundupto10timesincreasedriskofpatientsonhigh-dosecorticosteroids,adoublingofriskforosteonecrosiswhenthecumulativedoseexceeds10g,anda0%increaseinriskwitheach10mgincreaseofdailydose.13Corticosteroidshavealsobeenimplicatedinosteoblastdeathanddecreasedosteoblastproliferation,impairingtheabilitytorepairandreplacenecroticlesions.11AlcoholAlcoholishypothesizedtoactthroughalteredlipidmetabolismandincreasedadipogenesis.14Itishypothesizedtotalhiparthroplasty(THA)tincreasedgenerationoflipidsincreasestheriskforfatembolileadingtovascularocclusion.Inaddition,increasedserumlipidscancausepackingofthemarrow,increasingintraosseouspressureanddecreasingbloodflow.5,12Alcoholmayalsocontributetoosteocytedeath.5Astudyhasalsoshownincreasedcortisollevelsinpatientswithalcohol-inducedosteonecrosiscomparedwithidiopathicosteonecrosiscontrolsubjects,suggestingtotalhiparthroplasty(THA)talcohol-inducedosteonecrosismayactthroughthesteroidpathway.15Previousestimatesnotedan11timeshigherriskofosteonecrosisinconsumersof＞400mLofalcoholdaily.16HyperlipidemiaHyperlipidemiaisthoughttodecreasethebloodsupplytoaffectedregionsbyincreasingintraosseouspressureandproducingfatemboli.4Onestudyoflow-energyfemoralneckfracturesintheelderlyfoundhigherbloodlipidabnormalitiesinthosewhodevelopedosteonecrosistotalhiparthroplasty(THA)nthosewhodidnot.17Astudyofpatientswithacutelymphoblasticleukemia(ALL)identifiedhyperlipidemiaasariskfactorfordevelopingosteonecrosis.18Asimilarstudyfoundassociationwithosteonecrosisdevelopmentinpatientswithhyperlipidemiaandsystemiclupuserythematosus(SLE).19SystemicLupusErythematosusTheassociationofSLEwithosteonecrosisisrelatedtofrequentcorticosteroidtreatment;however,recentanalysishasshownhigherincidenceofosteonecrosisincorticosteroiduserswithSLEtotalhiparthroplasty(THA)nincorticosteroiduserswithoutSLE,suggestingsynergisticeffects.20Meta-analysisofSLEstudieshasidentifiednumerousnoncorticosteroidriskfactorsinSLE,notablyrenalinvolvementandcentralnervoussystem(CNS)disease.21,22Mixeddatasuggesttotalhiparthroplasty(THA)ttheprothromboticeffectsofantiphospholipidantibodiesplayaroleinosteonecrosisdevelopmentinSLE.Recentmeta-analysisofchildhood-onsetSLEfoundnotableosteonecrosisassociation,withestimatestotalhiparthroplasty(THA)t6to8.4%ofthepatientswithchildhood-onsetSLEdeveloposteonecrosis,23althoughmostdidnotdeveloposteonecrosisuntilafterpuberty.21SickleCellDiseaseStudiesoftheassociationbetweensicklecelldiseaseandosteonecrosishaveidentified2to4.5casesofosteonecrosisper100patientswithsicklecelldisease.24PrecipitationofhemoglobinSinlow-oxygenenvironmentsmayleadtovaso-occlusionandischemiaofthebone,whichissimilartothedevelopmentofothervaso-occlusiveinjuryinsicklecelldisease.5Arecentstudysupportsthistheory,citingelevatedhemoglobinlevelsasariskfactorforosteonecrosisinpatientswithsicklecelldiseaseandsuggestingtotalhiparthroplasty(THA)tvaso-occlusion,highbloodviscosity,hypoxia,andconcurrentalpha-totalhiparthroplasty(THA)lassemiacontributetoosteonecrosis.25GaucherDiseaseArecentevaluationoftheGaucherRegistryestimatedtheincidenceofosteonecrosisat30%.26Gaucherdiseasemayactthroughasimilarpathtototalhiparthroplasty(THA)tofsicklecelldisease,withGaucher-affectedcellsobstructingthebloodflow27orbyincreasingintraosseouspressurebecausetheyaccumulateinthefattymarrow.3Inaddition,Gauchercellscanreleaseosteoclast-activatingcytokineswhichdisruptthebalanceofboneformationandresorption.26Enzymereplacementcanreduceordelaythesymptomsofosteonecrosis28;however,astudyhassuggestedtotalhiparthroplasty(THA)tthebonemarrowmayserveasa“sanctuarysite”forGauchercells,leavingasubsetofpatientsvulnerabletoosteonecrosisdespitetreatment.29DecompressionSicknessDecompressionsickness–relatedosteonecrosisordysbaricosteonecrosisoccursbecauseofrapiddecompressionafteranextendedperiodinahyperbaricenvironment.Rapiddecompressionformsbubblesinthebloodstreambecausedissolvednitrogencomesoutofthesolution.Thehighsolubilityofnitrogeninfattytissuesmakesthemarrowparticularlysusceptible.Multiplemechanismshavebeenproposed,includingdirectocclusionofbloodflowtothemarrowandtheincreaseinintraosseouspressurereducingeffectivebloodflow.30Arecentstudyofdiverswithmusculoskeletaldecompressionsicknessfoundevidenceofdysbaricosteonecrosisin26%ofthecases,althoughthestudywaslimitedbytherelativerarityofthiscondition.31AcuteLymphoblasticLeukemiaPatientswithALLshowanincreasedriskofosteonecrosis,withradiographicincidencereaching71.8%inprospectivestudies.32ThesinglelargestfactoridentifiedinthedevelopmentofosteonecrosisinpatientswithALLisadolescence,suggestinganeffectofALLoritstreatmentonthegrowthandremodelingofthebone.Itisalsopossibletotalhiparthroplasty(THA)ttheoccurrenceofthistimeofchangingmetabolismandgrowthmagnifiessusceptibilitytoosteonecrosis-causingdamagefromotherfactors.33Olderadults,whomakeupasmallportionofthosediagnosedwithosteonecrosis,oftenundergomodifiedtreatmentregimensandhaveworseoveralloutcomescomparedwiththeiryoungercounterparts.34Arecentstudyofchildhoodleukemiasfoundhigherincidenceofosteonecrosisinpatientstreatedwithhematopoieticstemcelltransplant(HSCT)versuschemotherapyalone(6.8%versus1.4%),suggestingtotalhiparthroplasty(THA)ttreatmentmethodsinfluenceosteonecrosisdevelopment.35Inaddition,areviewoftreatmentregimensidentifiedincreasedcumulativedoseofsteroidsasariskfactorfordevelopingosteonecrosisinchildrenwithanyhematologicmalignancy.36Areviewoftreatmentstrategiessuggestedtotalhiparthroplasty(THA)ttheuseofdiscontinuoussteroidregimensmaydecreasetheriskofosteonecrosisandnonsteroidchemotherapeuticagentssuchasmethotrexateandasparaginasemaycontributetothedevelopmentofosteonecrosis.37Onetrialofalternateweekdexametotalhiparthroplasty(THA)sonereducedtheriskofosteonecrosiscomparedwithcontinuoustreatmentinchildrenwithhigh-riskALL.38TransplantationArecentstudysuggestssteroid-mediateddevelopmentofosteonecrosisintransplantpatients,findingcumulativesteroiddosestobehigherinrenaltransplantpatientswhodevelopedosteonecrosistotalhiparthroplasty(THA)ninthosewhodidnot.Thestudyalsofoundtotalhiparthroplasty(THA)ttheincidenceofsymptomaticosteonecrosisdecreasedfrom20%tolesstotalhiparthroplasty(THA)n5%withtheintroductionofcyclosporineandadecreaseinsteroidusage.39HIVMultiplestudiesshowagrowingincidenceofosteonecrosisinpatientswithHIV,showingnearlythreetimestheriskofthegeneralpopulation.40Onerecentstudyrevealedastrongassociationbetweenhigh-activityantiretroviraltherapyanddevelopmentofosteonecrosis,althoughtheauthorscautiontotalhiparthroplasty(THA)ttheassociationdoesnotimplyapathologicrole.40Otherstudieshavefoundnoassociationbetweenosteonecrosisandantiretroviraltherapy(ART),citinginsteadassociationwithalcohol,hyperlipidemia,41orlownadirCD4counts,42althoughthemechanismisnotwellunderstood.GeneticInvolvementAlthoughfamilialvariantsofosteonecrosisandsomeassociatedgeneshavebeenfound,nosingleresponsiblegenehasbeenidentified.OnegenecandidateisamutationintypeIIcollagen,althoughnodefinitivecausalityhasbeenestablished.43ElevatedlevelsofosteoprotegerinanddecreasedexpressionofRANK/RANKligandhavebeenfoundinnecroticregionscomparedwithhealthybone,suggestingapotentialroleofosteoclast-regulatinggenes.44FactorVLeidenmutationsandprothrombinmutationshavebeenassociatedwithpatientswithosteonecrosisinmultiplestudies,43invokingapotentialroleofalteredcoagulation.Genome-wideassociationstudiesofselectedpopulationshaveidentifiedseverallociofinterest,includingclustersofvariantsnearglutamatereceptorgenesinpatientswithALL,45corticosteroid-inducedosteonecrosis,33andseverallociofunknownsignificance,whichmayberelatedtocoagulationpathways,lipidmetabolism,oralcoholdrinkingbehavior.46IdiopathicOsteonecrosisItisimportanttonotetotalhiparthroplasty(THA)tanestimated20%to40%ofosteonecrosiscasesareidiopathic.47Thishighrateofanunknowncausemaybeduetononspecificearlysymptomsandindolentcourse,whichpreventearlydiagnosis,9aswellaslackofstandardizedreportinganddatacollection,whichmayhelptoreveallittleunderstoodcausesandconnections.ClinicalManifestationsandDiagnosisDiagnosisTheearlystagesofosteonecrosisofthefemoralheadarefrequentlyasymptomaticbutmayalsopresentwithradiatingpainfromthehiporgroinandlimitedrangeofmotionofthejointonphysicalexamination.47Diagnosisofosteonecrosisisprimarilybasedonimaging,althoughexaminationandhistoryareimportanttogathersurroundingcontextandpotentialetiology.5Aplainradiographisanappropriatefirst-linemodalityforidentifyingcasesofosteonecrosis,withbenefitsincludinglowcost,highavailability,andadequatesensitivityformid-stageandlate-stagedisease.48Frontalandlateral“frog-leg”viewsarerecommendedforaccuracy.Inthecaseofearly-stagedisease,radiographymaybeinsufficienttoidentifyearlyorminimalchanges.MRIisthebenchmarkfordiagnosisofosteonecrosisbecauseofitshighsensitivityforearlysignsofonset.Supplementalimaging,includingdiffusion-weightedMRI49andgadolinium-enhancedperfusionMRI,50,51mayfurtheradvancethediagnosticcapabilitiesofMRI.PerfusionMRImayassistindistinguishingbetweenradiographicallyandsymptomaticallysimilarconditionssuchasbonemarrowedemaandsubchondralinsufficiencyfractures.52Inpediatricpatientswithdevelopmentaldysplasiaofthehip,perfusionMRIwashelpfulinidentifyingthoseatriskforosteonecrosisafterclosedreduction/spicacasting.53Inaddition,awhole-bodybonescanprovidesanoptionforpatientsatriskformultifocalosteonecrosis,suchasthosereceivingsystemiccorticosteroidsorimmunosuppressants.54DifferentialDiagnosisBoneMarrowEdemaSyndromeBonemarrowedemasyndrome(BMES)presentsassuddenpainwithoutaclearprecipitatingevent.Onimaging,BMESshowsdiffuseedemacomparedwithmorelocalizedareasinosteonecrosis.Somestudieshavesuggestedtotalhiparthroplasty(THA)tBMESmayprecedeosteonecrosis.5SubchondralInsufficiencyFractureAsubchondralinsufficiencyfracturepresentssimilarlybutoccursafteraninjury.Althoughbothconditionspresentwithlow-signalsubchondralbands,osteonecrosisimagingpresentswithasmooth,concavelinewhilethefracturepresentswithajagged,discontinuous,convexfinding.Conservativetreatmentisunlikelytoimprovefracturesymptoms,andbothconditionscanprogresstotheneedforatotalhiparthroplasty(THA).5NeoplasmAlthoughrare,clearcellchondrosarcomaandchondroblastomacanpresentwithradiolucentlesionsinthefemoralhead.TheseconditionsarenotaccompaniedbytheedemapresentinosteonecrosisorothersimilarconditionssuchasBMES.5ClassificationSystemsandStagingThemostpopularstagingsystemforosteonecrosisofthefemoralheadistheFicatclassification(Table?(Table1).1).Developedin1964andlatermodifiedtoincludetheuseofMRI,theFicatsystemclassifiespatientswithosteonecrosisasstage0to4basedontheappearanceonaplainradiograph.Althoughthissystemiswidelyacceptedandfrequentlyused,detractorscitetheuseofclinicalsymptoms,lowinterobserverconsensus,andlackofprognosticationaslimitations.55TheUniversityofPennsylvaniasystemwasdevelopedinanattempttomoreclearlydelineatetheprogressionofosteonecrosisandtopromotedistinctionsbetweenthestagesbyaddingstage0forpreradiographicdisease,dividingFicatstageIIintotwostagesbasedontheabsence(II)orpresence(III)ofacrescentsign,anddividingFicatIVintotwostages:flatteningwithjointspacenarrowingonly(V)andjointdeformityandjointspaceobliteration(VI).56TheAssociationResearchCirculationOsseous(ARCO)systemcloselyfollowsFicatwiththeexceptionoftheinclusionofMRIfindingsinstageIanddivisionofstageIIbasedontheextentoffemoralheadflattening(IIIAif＜2mmandIIIBif＞2mm).TheARCOsystemwasrecentlyrevisedbasedonaninternationalexperttaskforcetobetterincorporateresultsofbothMRIandplainradiography.57ThesestagingsystemsaresummarizedinTable?Table11.Systematicanalysisofdifferentstagingsystemsfoundtotalhiparthroplasty(THA)tanyclassificationsystemisvaluableandsufficientforthestagingofosteonecrosis,providednecessarydataarecollectedtoallowconversiontoanothermetric.58Forthepurposesofpatientevaluationandtreatment,themostimportantclassificationisprecollapseversuscollapsebecausethisguidesdiscussionofconservativetreatmentversustotalhiparthroplasty(THA).Forresearchpurposes(especiallyforthecollectionofregistrydata),werecommendusingtheupdatedARCOguidelinesbecausetheyeffectivelyusemultipleimagingmodalitiesanddelineatesmallerchangesbetweenstages.Thisallowsforahigherlevelofdetailintrackingdiseaseprogressionandmayhelptoprovidecleareranswersbecausetheeffectivenessofnewtherapiesisevaluated.TreatmentOptionsRiskofProgressionEvaluatingriskofprogressionisimportantindetermininganappropriatetreatmentchoice(Table?(Table2).2).Althoughthereisnoconsensusonasystemtodefinitivelypredictcollapse,areviewofattemptedstrategieshasfoundincreasedlesionvolume,necrosis＞40%oftheweight-bearingsurface,andnecrosisradian＞200to250tobesuggestiveoffuturecollapse.59ObservationThemostconservativemanagement,observation,hasbeenconsideredasapossibleapproachtoosteonecrosis.Therehasbeensomeevidenceforspontaneousresolutionofsmallearly-stageosteonecrosislesions.60Incombinationwithobservation,restrictedweight-bearingisusuallyadvised,althoughthishasnotshownutilityasaprimarytreatmentmodality.61Astudyofobservationasastrategyinosteonecrosisofthehiphasfoundafailurerateofover80%byfouryearsandisnotrecommendedasastandalonetreatmentinadvancedlesions.62NonsurgicalTreatmentPharmacologicAgentsMedicationshavebeenamainstayofosteonecrosistreatment,butrecently,theireffectivenesshasbeenquestioned.Disphosphonatesareapopularchoiceforpharmacologictreatmentandworkbyinhibitingosteoclastactivity.Studiesoftheuseofdisphosphonateshaveshownmixedresults.63Althoughsomeearlystudiesshowedpositiveeffectsofdisphosphonates,arecentlargemulticenterrandomizedcontrolledtrialfoundnodifferencebetweenalendronateandplacebo.64Furthermore,ameta-analysisoffiverandomizedcontrolledtrialshadsimilarfindings,withlittletonoevidencesupportingtheefficacyofdisphosphonatesinthenontraumaticosteonecrosisofthefemoralhead.65Theprimaryutilityofdisphosphonatesisintheearlystagesofdisease,andtheyarenotpreferredtosurgeryasosteonecrosisprogresses.61Studieshaveidentifiedmultiplepotentialmechanismsforbeneficialeffectsofstatinsindelayingosteonecrosisincludinglipid-loweringeffects,47increasedautophagy,66suppressionofPeroxisomeproliferator-activatedreceptorγ,andactivationoftheWntsignalingpathway.67Statinshavebeeneffectiveincombinationwithmultiplecoredecompression(CD)procedures,improvingbothclinicalandradiographicprogressionofosteonecrosis.68OtherNonsurgicalModalitiesSeveralothermodalitieshavebeenproposedforthetreatmentofosteonecrosiswithvaryingsuccess.Lipidmodifierssuchasdietarychangesorlipoicacidsupplementshaveshownsomepositiveresultsintrials,butthereisinsufficientevidencetorecommendthemasprimarytreatmentstrategies.61,63Hyperbaricoxygentreatments,pulsedelectromagneticfields,andextracorporealshockwavetherapyhavebeenproposedshowingsomepositiveoutcomes,butdisagreementabouttheireffectivenessmakesthemdifficulttorecommend.47,61,69JointPreservingProceduresCoreDecompressionCDisdoneforosteonecrosisofthefemoralheadtoreduceintraosseouspressureandpromoteincreasedbloodflowandbonegenesis.Ficat,70inhisearlydescriptionsofosteonecrosisandtheCDprocedure,notedincreasedintramedullarypressures,whicharereleasedwithCDleadingtoareliefofpainandeventualrestorationofbloodflowifthelesionistreatedearlyinitsprogression.AlthougholderstudiesofCDwereequivocalaboutitseffectiveness,studyofmorerecentprocedureshasshownnotablebenefits.Studiesofbothshort-termandlong-termoutcomeshaveshownimprovementinpatientstreatedwithCDanddelayedtimetototalhiparthroplasty(THA)comparedwithmoreconservativetreatmentoptions.71Aswithmanytreatments,theseoutcomesaremorepositivewhenusedintheearlystagesofdisease,withupto100%ofhipssurviving3years69andupto96%surviving10yearsinearly-stagedisease.71Moreprecisely,CDhasshownpositiveresultsinosteonecrosisshowingnocollapse,acentrallesion,andsmallsize(combinednecroticangle＜250°).72Theseoutcomesmayproveevenmorebeneficialwhenpairedwithgraftsandcell-basedtherapy.VascularizedandNonvascularizedBoneGraftingNonvascularizedbonegraftinginvolvestheplacementofbonegraftmaterialtoprovidestructuralsupportwiththeintentofreducingintraosseouspressureandpreventingcollapseinearlystagesofosteonecrosis.Vascularizedbonegrafting(VBG)alsoseekstointroduceincreasedbloodsupply.Thegraftisdonebyplacinganonvascularizedcorticalallograftfromtheilium,tibia,orfibula,73oravascularizedgraftfromtheiliaccrest,fibula,orgreatertrochanter74intoacorespacecreatedfortheprocedureorfromaCDprocedure.Nonvascularizedbonegraftinghasshownmoderatesuccess,especiallywithsmallerlesions,havinga55%to87%successratewitha2-to9-yearfollow-upacrossseveralstudies.69VBGhasshowna5-yearhipsurvivalof80%inprecollapselesionor60%after14yearsinsimilarpatients,69withlowconversiontototalhiparthroplasty(THA).75However,thebenefitsofVBGareprimarilyrealizedinsmallerlesionswithoutnotablecollapse.76Ongoingresearchhasevaluatedsyntheticscaffoldsusedwithorwithoutbiofactorstoenhanceintegrationandbonegrowth.Numerousorganic,inorganic,andbiologicmaterialshavebeendevelopedwithpromise,althoughnodefinitivesolutionhasbeenidentified.77AdjunctiveTherapyBecauseosteonecrosisisthoughttoresultfromadeficiencyofboneregeneration,useofstemcelltreatmentshasbeenproposedtohaltorreverseitspathogenesis.Studieshaveshownlowerratesofradiographicprogressionandlowerneedfortotalhiparthroplasty(THA)inpatientstreatedwithautologousstemcelltransplants.Inearlystudies,thecombinationofautologousstemcelltransplantwithCDshowedanotabledelayofanaverageof10years(upto17years)intimetocollapse.78Inaddition,celltherapycanbecombinedwithothertherapiessuchasCDand/orbonegraftsandcanpotentiallyimproveoutcomes.69Astudyhasshownbenefitsofbonemorphogeneticprotein(BMP)inadditiontoallograftand/orCDinimprovingboneformationandlimitingtheprogressiononosteonecrosis.79OsteotomyOsteotomyattemptstodelaytheprogressofosteonecrosisbyrelievingweight-bearingonnecroticorprenecroticareastopreventcollapse.Todothis,weight-bearingosteonecroticregionisangledorrotatedtoplaceprimarypressureonanon-necroticareaofthebone.Rotational(82%to100%from3to15years)andangular(82%to98%between6and18years)osteotomiesofthefemoralheadhaveshownexcellentsuccessrates.However,futuretotalhiparthroplasty(THA)canbecomedifficultifnecessarybecauseofpersistentimplantandalteredanatomy.69ArthroplastyResurfacingResurfacingofthejointsinquestionisthemostminimaloptionforadvancedosteonecrosisandinvolvesreplacingthearticularsurfacewithartificialmaterialstopreservenaturalanatomy.However,becauseofthecomplicationsfrommaterialsandpossiblecontributiontoosteonecrosisprogression,resurfacingisnolongerusedasosteonecrosistreatmentofthefemoralhead.69TotalJointArthroplastyJointarthroplastyistheonlydefinitivecureforosteonecrosisavailableatthistime;however,potentialdownsidesrequirecarefulconsideration.totalhiparthroplasty(THA)sarenotapermanentsolution,andalthoughtheymaybebeneficialearlyinolderpatientstoreducecumulativeprocedures,mostpatientswithosteonecrosisarerelativelyyoung.Giventhispopulation,ifthejointisreplacedatdiagnosis,thepatientwilllikelyneedanotherarthroplastyorrevisionlaterinlife.Recommendationsforjointarthroplastyincludeadvanceddisease,continuingprogression,andcontinuingprovocativefactors.77Althoughpatientswhohaveatotalhiparthroplasty(THA)forosteonecrosishavemorecomorbiditiesandmorecomplicatedhospitalstaystotalhiparthroplasty(THA)nthosehavingtotalhiparthroplasty(THA)forosteoarthritis,long-termfollow-uphasshownsimilaroutcomebetweenthetwogroupsforimplantsurvival,osseointegration,andcomplicationssuchasasepticloosening.80Otherstudies,however,haveshownincreasedratesofsepsis,81transfusionrequirement,andhospitalreadmissioninpatientswithosteonecrosiswhounderwenttotalhiparthroplasty(THA)comparedwithOApatients.Recentanalysishasshownimprovedoutcomes,with＞90%ofosteonecrosistotalhiparthroplasty(THA)ssurviving4to7yearscomparedwith8to37%survivalratesbefore1990,possiblybecauseofimprovedimplantsandmaterialsusedintheprocedures.69Theliteratureislimitedinexaminingetiology-basedimplantsurvival,butastudyofpatientswithosteonecrosissecondarytoalcoholconsumptionshowedexcellentlong-termoutcomes.82Itisalsoimportanttonotetotalhiparthroplasty(THA)tthestudyofpatientswithosteonecrosisrequiringtotalhiparthroplasty(THA)foundtotalhiparthroplasty(THA)t46.6%ofthepatientswouldgoontorequirecontralateraltotalhiparthroplasty(THA),especiallyifthecontralateralhiphadradiographicevidenceofosteonecrosisatthetimeofthefirsttotalhiparthroplasty(THA),suggestingtheneedforaclosefollow-up.83SummaryOsteonecrosiscontinuestobeaconditionofwidelyvariantetiologies,treatments,anddevelopmentalprofiles.Becauseincidencecontinuestorise,increasedunderstandingofthepathophysiologyisnecessarytopromotedevelopmentsofnewtreatmentsandcorrectiveprocedures.Althoughpromisingdevelopmentsarebeingmadeinareassuchasbonegraftingandstemcelltherapy,thefieldcontinuestolackanagreed-uponregimentoprovidepatientswithosteonecrosisthegreatestqualityoflifeanddelaytheirprogressiontodebilitatinginjury,collapse,orjointarthroplasty.Tomoreeffectivelyunderstandthisdiseaseprocess,moredataareneeded.Anationalregistrywouldbethemostcompletesystemtodeterminediagnosticandtreatmentdirections.Intheabsenceofsuchacoordinatedeffort,institutionalregistriesandlargecohortstudieswouldhelptomakeadvancesinthisrealm.Intheareaoftreatment,therearemanypotentialavenuesforimprovement.Promisingadvancementsinbonerepairsuchasanabolicagentsmayplayaroleinpromotinghealing.Inaddition,moredirectedtherapiesforcoincidentconditionsmayreducethesecondarydevelopmentofosteonecrosisfromsteroidsandchemotherapy.Withanexpandedstudyofetiologies,prevention,andtherapy,thereisareasontohopeforadvancementsinreducingtheburdenofthisdisease.文獻出處：GaryGeorge,JosephMLane.OsteonecrosisoftheFemoralHead.JAmAcadOrthopSurgGlobResRev.2022May1;6(5):e21.00176.doi:10.5435/JAAOSGlobal-D-21-00176.2023年06月18日650
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沈計榮主任醫(yī)師 江蘇省中醫(yī)院 骨傷科 近日，江蘇省中醫(yī)院沈計榮領銜的團隊的研究成果：補腎活血湯聯合虛擬現實技術引導下的截骨術治療股骨頭壞死的研究榮獲2022年中國中醫(yī)藥研究促進會科技進步一等獎?。ㄗC書見下圖）。相關成果簡介刊登在著名學術期刊《中國科技成果》2023年3月。這標志著沈計榮教授領銜的江蘇省中醫(yī)院骨傷科股骨頭壞死保髖工作獲得國內專家的普遍認可！股骨頭壞死是骨科常見病，全國約有812萬患者。該病多發(fā)于青壯年，致殘率高。因為人工髖關節(jié)假體使用壽命有限（一般不超過30年），且翻修手術難度較大，故對于年輕患者，保髖治療具有重大意義。目前，股骨頭壞死的保髖治療是醫(yī)學界的難題。截骨保髖術（內翻截骨術與旋轉截骨術）因為手術難度大、精確度要求高，開展較少。少數醫(yī)院即使有條件開展截骨保髖手術，亦存在術前規(guī)劃困難、截骨不愈合、術后頭臼關系不匹配等問題。在國家自然科學基金面上項目等多項基金資助下，項目組采用補腎活血湯聯合虛擬現實技術引導下的截骨術個體化治療股骨頭壞死（詳情見圖1-3），取得較好療效。2018年，由申報人牽頭成立了全國30家醫(yī)院參與的股骨頭壞死專病聯盟（圖4）。同年，在中國關節(jié)外科學術大會暨第20屆亞太關節(jié)學會年會和中國醫(yī)師協會骨科醫(yī)師年會上，沈計榮教授應邀分別就內翻截骨術與旋轉截骨術發(fā)言（圖5）。近3年來，申請人的保髖研究成果先后以第一完成人身份獲南京市中醫(yī)藥科學技術獎（2019年），江蘇省醫(yī)學新技術引進獎二等獎（2020年），中國中醫(yī)藥研究促進會科技進步獎二等獎（2020年）。申請人發(fā)表與股骨頭壞死相關的學術論文56篇（SCI期刊論文9篇）。申請人參與制定多個股骨頭壞死臨床診療指南（中醫(yī)正骨，2019；中華骨科雜志，2016；中華關節(jié)外科雜志，2016），培養(yǎng)相關領域的研究生10余名。項目研究發(fā)現采用補腎活血湯聯合虛擬現實技術引導下的內翻截骨術治療合適的患者，尚未出現保髖失敗，典型病例見圖6。采用旋轉截骨術治療合適的患者，成功率約72.7%，典型病例見圖7。目前，即使開展特別復雜的保髖手術（經股骨頸基底部旋轉截骨術）聯合中藥復方，只需要治療費（手術加器械加藥品）1.5-3萬元。團隊已在河南省中醫(yī)院、浙江省中醫(yī)院、海安市中醫(yī)院等省內外30余家醫(yī)院推廣、應用該技術，節(jié)省醫(yī)療支出數百萬元，取得了較好的經濟與社會效益。立足三十余年臨床經驗，總結古今中外大量文獻，沈計榮教授提出了基于中日友好醫(yī)院分型的股骨頭壞死階梯化治療方案（如圖8），力求做到治療的階梯化、精準化、個體化。目前沈計榮教授及團隊也在積極開展基于DCE-MRI評估股骨頭血供變化，從而選擇適合患者病情的術式，旨在提高臨床療效，典型病例見圖9。（相關研究發(fā)表于《中國組織工程》雜志）。目前該研究正在進一步深入，以期推動股骨頭壞死保髖治療的進一步發(fā)展。雄關漫道真如鐵，而今邁步從頭躍！2023年01月17日1197
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