股骨头坏死治疗：2022年最新研究进展

股骨头坏死治疗：2022年最新研究进展

作者：Gary George, Joseph M Lane.

作者单位: From Weill Cornell Medicine, New York, New York (Mr. George), and the Hospital for Special Surgery, New York, New York (Dr. Lane).

译者：陶可（北京大学人民医院骨关节科）

摘要

股骨头坏死是一种进展性、使人致残的疾病，其病因多种多样，包括外伤、使用激素(类固醇)和饮酒。诊断和分期基于影像学检查，包括任何阶段的MRI扫描和更晚期病变的X线片检查。（疾病晚期）唯一确定的治疗方法是全髋关节置换术，尽管，（目前临床上）采用包括二磷酸盐和核心减压在内的多种治疗方法来延缓病情进展。缺乏令人满意的保守（治疗）措施表明，需要对股骨头坏死进行进一步研究，包括大型的患者登记，以进一步了解（保守治疗的）效果。

股骨头坏死是一种进展性疾病，（股骨头）缺乏足够的血液供应会导致受影响区域的细胞死亡、骨折和塌陷。这种情况通常与股骨头有关，病情进展可能会使人衰弱（残疾），最终可能需要进行全髋关节置换术(全髋关节置换术(THA))。股骨头坏死的病因很复杂，有多种致病因素，其中最明显的是外伤、使用激素和酒精。股骨头坏死的治疗是有争议的，因为没有任何一种治疗方式是被广泛接受的，而且很少有研究比较（各种）治疗方法（之间的优劣）。研究人员估计，美国每年诊断出20,000例新发的股骨头坏死病例。股骨头坏死发病率的增加和使人致残的进展表明需要对有效和新颖的治疗方法进行深入的研究，以及需要更清楚地了解现有的治疗方法。这篇综述描述了目前关于股骨头坏死的病因学、病理生理学、流行病学和临床治疗的知识，重点介绍了最新进展。

流行病学

据估计，美国每年股骨头坏死的发病率约为20000至30000例，主要影响20至40岁之间的年轻人。最近的分析表明，尽管因股骨头坏死而进行的全髋关节置换术(THA)数量有所增加，2001年和2010年（从每100,000名住院患者54.2例 到每100,000名住院患者60.6例），因股骨头坏死而进行全髋关节置换术(THA)的比例从9.7%下降到8.3%，可能是因为需要进行全髋关节置换术(THA)的骨关节炎迅速增加。

病理生理学和发病机制

一般发病机制

尽管临床表现是修复过程的结果，而不是最初的缺血，但股骨头坏死的发生是由于骨骼的血流或氧气输送受损。在股骨头坏死中，成骨细胞的骨形成无法与破骨细胞的骨吸收相匹配。这种重塑不平衡并不能充分替代坏死骨，从而留下了结构不健全的骨组织区域。

创伤

创伤是股骨头坏死的最常见原因，会扰乱血流并导致骨细胞死亡。发生股骨头外伤性股骨头坏死的估计因损伤类型而异；然而，在创伤性股骨头坏死的荟萃分析中，发现其发生率高达14.3%。Garden分类对股骨颈骨折进行了分类，可用于估计股股骨头坏死的风险。Garden I（不完全骨折）和Garden II（完全且无移位）被认为是稳定且风险低的，可以通过内固定修复。Garden III（完全骨折和部分移位）和Garden IV（完全骨折和完全移位）内固定的股骨头坏死发生率要高得多（16%），应考虑髋关节置换术。另外，有文献报道，股骨转子间骨折导致股骨头坏死的风险较低，一年随访时的股骨头坏死结果为0.95%。

非外伤性股骨头坏死

非外伤性股骨头坏死有多种原因。值得注意的是，在非创伤性股骨头坏死中，由于系统性危险因素，疾病常常是双侧的，一些估计表明，高达70%的单侧股骨头坏死患者的对侧髋部会发生疾病。在存在系统性危险因素的情况下，一侧髋关节的磨损尚未得到充分研究，可能是由于亚临床表现、髋关节之间磨损模式的差异、对症状的调查不足或缺乏协调的随访。

糖皮质激素

类固醇的使用是股骨头坏死的第二个最常见原因。已经提出了这种关联的几种潜在机制，包括骨基质和软骨变性、诱导干细胞异常、脂质代谢的变化、脂肪栓塞的产生、凝血改变。荟萃分析发现，服用大剂量皮质类固醇的患者风险增加多达10倍；当累积剂量超过10 g时，股骨头坏死的风险增加一倍；而使用大剂量皮质类固醇患者每日剂量每增加10毫克股骨头坏死风险就会增加3.6%。皮质类固醇也与成骨细胞死亡和成骨细胞增殖减少有关，损害修复和替换骨坏死病变的能力。

酒精

据推测，酒精会通过改变脂质代谢和增加脂肪生成来发挥（导致股骨头坏死的）作用。据推测，脂质生成的增加会增加脂肪栓塞导致血管闭塞的风险。此外，血脂升高会导致骨髓堵塞、骨内压升高和血流量减少。酒精也可能导致骨细胞死亡。一项研究还表明，与酒精性股骨头坏死患者相比，酒精性股骨头坏死患者的皮质醇水平升高。特发性股骨头坏死对照受试者，表明酒精引起的股骨头坏死可能通过类固醇途径起作用。之前有研究指出，每天饮酒超过400 mL的患者发生股骨头坏死的风险高出11倍。

高脂血症

高脂血症被认为会增加骨内压并产生脂肪栓塞，从而减少受影响区域的血液供应。一项针对老年人低能量股骨颈骨折的研究发现，发生股骨头坏死的患者血脂异常率高于未发生股骨头坏死的患者。一项针对急性淋巴细胞白血病(ALL)患者的研究发现，高脂血症是发生股骨头坏死的危险因素。一项类似的研究发现，高脂血症和系统性红斑狼疮(SLE)患者与股骨头坏死的发生有关。

系统性红斑狼疮

SLE与股骨头坏死的关联与频繁的皮质类固醇治疗有关；然而，最近的分析显示，患有SLE的皮质类固醇使用者的股骨头坏死发生率高于未患SLE的皮质类固醇使用者，这表明存在协同效应。SLE研究的荟萃分析已发现SLE中的许多非皮质类固醇危险因素，特别是肾脏受累和中枢神经系统（CNS）疾病。混合数据表明，抗磷脂抗体的促血栓作用在SLE股骨头坏死的发展中发挥作用。最近对儿童期发病的SLE的荟萃分析发现了显着的股骨头坏死关联，估计6%至8.4%的儿童期发病的SLE患者会发生股骨头坏死，尽管大多数患者直到青春期后才发现（并确诊）股骨头坏死。

镰状细胞性贫血症

对镰状细胞病与股骨头坏死之间关系的研究发现，每100名镰状细胞病患者中就有2至4.5例发生股骨头坏死。低氧环境中血红蛋白S的沉淀可能会导致血管闭塞和骨骼缺血，从而导致股骨头坏死。与镰状细胞病中其他血管闭塞性损伤的发展类似。最近的一项研究支持这一理论，指出血红蛋白水平升高是镰状细胞病患者股骨头坏死的危险因素，并表明血管闭塞、高血液粘度、缺氧和并发的α地中海贫血会导致股骨头坏死。

戈谢病

最近对戈谢登记处的一项评估估计，股骨头坏死的发生率为30%。戈谢病可能通过与镰状细胞病类似的途径发挥作用，受戈谢影响的细胞会阻碍血流或通过增加骨内压，因为它们在体内积聚。此外，戈谢细胞可以释放破骨细胞激活细胞因子，破坏骨形成和吸收的平衡。酶替代可以减轻或延迟股骨头坏死的症状；然而，一项研究表明，骨髓可能是戈谢细胞的“避难所”，导致部分患者尽管接受治疗，仍容易发生股骨头坏死。

减压病

减压病相关的股骨头坏死或气压异常性股骨头坏死是由于长时间处于高压环境后快速减压而发生的。快速减压会在血液中形成气泡，因为溶解的氮气会从溶液中逸出。氮气在脂肪组织中的高溶解度使得骨髓特别容易受到影响。已经提出了多种机制，包括直接阻塞骨髓血流和骨内压升高减少有效血流。最近一项针对患有肌肉骨骼减压病的潜水员的研究发现，26%的病例存在气压不足性股骨头坏死的证据，尽管研究受到这种情况相对罕见的限制。

急性淋巴细胞白血病

ALL患者发生股骨头坏死的风险增加，前瞻性研究中影像学发生率达到71.8%。ALL患者发生股骨头坏死的最大单一因素是青春期，这表明ALL或其治疗对骨骼的生长和发育、重塑有影响。也有可能是代谢和生长时期的变化放大了易感性。老年人占股骨头坏死诊断患者的一小部分，他们经常接受改良的治疗方案，与年轻人相比，总体结果更差。最近的一项儿童白血病研究发现与单纯化疗相比，接受造血干细胞移植(HSCT)治疗的患者股骨头坏死发生率更高（6.8%比1.4%），这表明治疗方法会影响股骨头坏死的发展。此外，对治疗方案的审查发现，患有任何血液系统恶性肿瘤儿童的激素累积剂量的增加发生股骨头坏死的危险因素。对治疗策略的回顾表明，使用不连续的激素治疗方案可能会降低股骨头坏死的风险，而甲氨蝶呤和天冬酰胺酶等非激素化疗药物可能会导致股骨头坏死的发生。一项隔周地塞米松试验与持续治疗高危ALL儿童相比，降低了股骨头坏死的风险。

移植

最近的一项研究表明，移植患者中的股骨头坏死是由激素介导的，发现发生股骨头坏死的肾移植患者的累积激素剂量高于未发生股骨头坏死的肾移植患者。研究还发现，随着环孢素的引入和激素使用的减少，症状性股骨头坏死的发生率从20%下降到5%以下。

艾滋病病毒

多项研究表明，艾滋病毒患者股骨头坏死的发病率不断上升，其风险几乎是普通人群的三倍。最近的一项研究表明，高活性抗逆转录病毒治疗与股骨头坏死的发生之间存在密切关联，尽管作者警告说，这种关联并不意味着病理作用。其他研究发现股骨头坏死与抗逆转录病毒治疗(ART)之间没有关联，而与酒精、高脂血症或低最低CD4计数有关，尽管其机制尚不清楚。

遗传参与

尽管已经发现了股骨头坏死的家族变异和一些相关基因，但尚未确定单一的相关基因。一个候选基因是II型胶原蛋白的突变，尽管尚未确定明确的因果关系。与健康骨骼相比，坏死区域中发现骨保护素水平升高，RANK/RANK配体表达降低，这表明破骨细胞的潜在作用。在多项研究中，因子V Leiden突变和凝血酶原突变与股骨头坏死患者相关，表明凝血功能改变的潜在作用。对选定人群的全基因组关联研究已经确定了几个感兴趣的位点，包括ALL、皮质类固醇诱导的股骨头坏死患者中谷氨酸受体基因附近的变异簇，以及几个意义不明的位点，这些位点可能与凝血途径有关，脂质代谢，或饮酒行为。

特发性股骨头坏死

值得注意的是，估计20%至40%的股骨头坏死病例是特发性的（无明确病因）。原因不明的高比例可能是由于非特异性早期症状和非快速进展的病程，（因而会）妨碍早期诊断，以及缺乏标准化报告和数据收集，这可能有助于揭示少见的病因和联系。

临床表现和诊断

诊断

股骨头坏死的早期阶段通常无症状，但查体时也可能出现髋部或腹股沟的放射痛以及髋关节活动范围有限。股骨头坏死的诊断主要基于影像学，尽管查体和病史（采集）对于收集髋关节周围（其他病变）和潜在病因很重要。X线片是识别股骨头坏死病例的合适的一线方法，其优点包括低成本、高可用性以及对中期和晚期疾病足够的敏感性。为了准确起见，建议采用正位和“蛙式位”侧视图。在疾病早期的情况下，放射线检查可能不足以识别早期或微小的变化。MRI是诊断股骨头坏死的标准，因为它对发病早期病变具有很高的敏感性。补充成像，包括弥散加权MRI和钆增强灌注MRI可能会进一步提高MRI的诊断能力。灌注MRI可能有助于区分影像学和症状相似的情况，例如骨髓水肿和软骨下功能不全骨折。在患有髋关节发育不良的儿科患者中，灌注MRI有助于识别闭合复位/人字形石膏脱外固定后有股骨头坏死风险的患者。此外，全身骨扫描患有多灶性股骨头坏死风险的患者提供了一种选择，如接受全身性皮质类固醇或免疫抑制剂的患者。

鉴别诊断

骨髓水肿综合征

骨髓水肿综合征(BMES)表现为突发疼痛，没有明显的诱发事件。影像学显示，与股骨头坏死的局部区域相比，BMES显示弥漫性水肿。一些研究表明BMES可能先于股骨头坏死发生。

软骨下不全骨折

软骨下不全骨折的表现（与股骨头坏死）类似，但发生在受伤后。尽管这两种情况都呈现低信号软骨下带，但股骨头坏死成像呈现平滑的凹线，而骨折则呈现锯齿状、不连续的凸面。保守治疗不太可能改善骨折症状，并且这两种情况都可能发展到需要进行全髋关节置换术(THA)。

（股骨头）肿瘤

虽然罕见，但透明细胞软骨肉瘤和软骨母细胞瘤可在股骨头中出现射线可透的病变。这些病症不伴有股骨头坏死或其他类似病症（例如BMES）中出现的水肿。

分类系统和分期

最流行的股骨头坏死分期系统是Ficat分期。Ficat系统于1964年开发，后来进行了修改，包括使用MRI，根据平片上的表现将股骨头坏死患者分为0至4期。尽管该系统被广泛接受并经常使用，但批评者认为其局限性在于使用临床症状、观察者间一致性较低和缺乏预测（效力）。宾夕法尼亚大学开发该系统的目的是为了更清楚地描述股骨头坏死的进展，并通过为放射学前疾病添加0期，根据新月征的不存在(II)或存在(III)将Ficat II期分为两个阶段，并将Ficat IV期分为两个阶段：扁平化，关节间隙变窄，从而促进各阶段之间的区别仅(V)以及关节畸形和关节间隙闭塞(VI)。骨循环研究协会(ARCO)系统与Ficat密切相关，但将MRI结果纳入I期并根据关节间隙的程度划分II期。股骨头变平（如果 ＜ 2毫米则为IIIA，如果 ＞ 2毫米则为IIIB）。ARCO系统最近根据国际专家工作组进行了修订，以更好地结合MRI和X线片的结果。

对不同分期系统的系统分析发现，任何分类系统对于股骨头坏死分期都是有价值且充分的，只要收集必要的数据以允许转换为另一个指标。为了患者评估和治疗的目的，最重要的分类是塌陷前与塌陷前股骨头碎裂，因为这是指导保守治疗与髋关节置换术(THA)的依据。出于研究目的（特别是收集注册数据），我们建议使用更新的ARCO指南，因为它们有效地使用多种成像模式并描绘阶段之间较小的变化。这可以更详细地跟踪疾病进展，并且可能有助于提供更清晰的答案，因为新疗法的有效性得到了评估。

治疗方案

进展风险

评估进展风险对于确定适当的治疗选择很重要。尽管对于明确预测塌陷的系统尚未达成共识，但对尝试策略的审查发现，病变体积增加、坏死＞40%的承重表面以及坏死弧度＞ 200至250度提示未来的塌陷。

观察

最保守的治疗方法——观察——被认为是治疗股骨头坏死的一种可能方法。有一些证据表明小的早期股骨头坏死病变可自行消退。与观察相结合，通常建议限制负重，尽管这尚未显示出作为主要治疗方式的实用性。一项将观察作为策略的研究发现，股骨头坏死四年内的失败率超过80%，不建议作为晚期病变的独立治疗方法。

非手术治疗

药物一直是股骨头坏死治疗的主要手段，但最近其有效性受到质疑。二磷酸盐是药物治疗的热门选择，通过抑制破骨细胞活性发挥作用。关于二磷酸盐使用的研究显示了不同的结果。尽管一些早期研究表明二磷酸盐具有积极作用，但最近的一项大型多中心随机对照试验发现阿仑膦酸钠和安慰剂之间没有差异。此外，对5项随机对照试验的荟萃分析显示，类似的发现，几乎没有证据支持二磷酸盐的功效。二磷酸盐的主要用途是在疾病的早期阶段，随着股骨头坏死的进展，二磷酸盐并不优于手术。

研究已确定他汀类药物在延缓股骨头坏死方面发挥有益作用的多种潜在机制，包括降脂作用、增加自噬、抑制过氧化物酶体增殖物激活受体γ以及激活Wnt信号通路。他汀类药物与多种药物联合使用可有效发挥作用。

髓心减压（CD）手术，可以改善股骨头坏死的临床和放射学进展。

其他非手术方式已经提出了其他几种治疗股骨头坏死的方式，并取得了不同程度的成功。饮食改变或硫辛酸补充剂等脂质调节剂在试验中显示出一些积极的结果，但没有足够的证据推荐它们作为主要治疗策略。高压氧治疗、脉冲电磁场和体外冲击波疗法已获得一些积极的成果，但对其有效性的分歧使得它们难以推荐。

保髋手术治疗

髓心减压CD

用于治疗股骨头坏死，以降低骨内压，促进血流增加和骨生成。Ficat在他对股骨头坏死和髓心减压CD手术的早期描述中指出，髓内压力增加，髓心减压CD释放髓内压力，如果在病变进展早期得到治疗，可以缓解疼痛并最终恢复血流。尽管早期的髓心减压CD研究对其有效性尚不明确，但最近的研究显示出显着的益处。对短期和长期结果的研究表明，与更保守的治疗方案相比，接受髓心减压CD治疗的患者有所改善，并且延迟了全髋关节置换术(THA)时间。与许多治疗一样，在疾病早期阶段使用时，这些结果更为积极。高达100%的髋关节存活3年，高达96%的早期疾病存活10年。更准确地说，髓心减压CD在股骨头坏死方面显示出积极的结果，显示无塌陷、中央病变和小尺寸（合并坏死）角度＜250°。当与移植物和细胞治疗相结合时，这些结果可能会更加有益。

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结构支撑，目的是降低骨内压力并防止股骨头坏死早期阶段的塌陷。血管化骨移植（VBG）还寻求增加血液供应。通过将来自髂骨、胫骨或腓骨的非血管化同种异体皮质移植物或来自髂嵴、腓骨或大转子的血管化移植物放置到为手术或髓心减压CD手术创建的髓心空间中来完成移植。无血管化骨移植已显示出一定的成功率，特别是对于较小的病变，在多项研究中，经过2至9年的随访，成功率为55%至87%。血管化骨移植（VBG）显示（在塌陷前病变中）5年髋关节存活率为80%或14年后类似患者中的60%，需要全髋关节置换术(THA)的比例较低。然而，血管化骨移植（VBG）的益处主要在没有明显塌陷的较小病变中实现。正在进行的研究评估了使用或不使用生物因子的合成支架增强整合和骨骼生长。尽管尚未找到明确的解决方案，但许多有机、无机和生物材料的开发前景广阔。

辅助治疗

由于股骨头坏死被认为是由骨再生缺陷引起的，因此有人建议使用干细胞治疗来阻止或逆转其发病机制。研究表明，接受自体干细胞移植治疗的患者放射学进展率较低，全髋关节置换术(THA)需求也较低。在早期研究中，自体干细胞移植与髓心减压CD相结合显示，股骨头塌陷时间平均延迟了10年（最多17年）。此外，细胞疗法可以与髓心减压CD等其他疗法相结合。一项研究表明，除了同种异体移植物和/或骨移植物之外，骨形态发生蛋白(BMP)在改善骨形成和限制股骨头坏死进展方面也有益处。

保髋截骨术

截骨术是通过减轻坏死或坏死前区域的负重来延缓股骨头坏死的进展，以防止塌陷。为此，将承重的股骨头坏死区域倾斜或旋转，以将主要压力施加在股骨头非坏死区域上。股骨头旋转截骨术（3至15年期间的成功率为82%至100%）和（内外翻、前伸后屈）成角截骨术（6至18年期间的成功率为82%至98%）显示出极高的成功率。然而，如果有必要的话，未来的全髋关节置换术(THA)可能会在截骨术后变得困难。

帐篷植入和改变的解剖结构.69

髋关节置换术

髋关节表面置换术

对于晚期股骨头坏死来说，髋关节表面置换是最简单的选择，涉及用人造材料替换关节表面以保留自然解剖结构。然而，由于材料引起的并发症以及可能导致股骨头坏死进展，表面置换不再用作股骨头坏死的治疗方法。

全髋关节置换术

全髋关节置换术是目前治疗股骨头坏死的唯一有效方法。然而，潜在的缺点需要仔细考虑。全髋关节置换术并不是永久的解决方案，尽管它们可能有利于老年患者尽早减少累积手术，但大多数股骨头坏死患者相对年轻。鉴于这一人群，如果在诊断时更换关节，患者在以后的生活中可能需要再次进行髋关节置换术或翻修术。髋关节置换术的建议包括晚期疾病、持续进展和持续的诱发因素。尽管因股骨头坏死而接受全髋关节置换术(THA)的患者比因骨关节炎接受全髋关节置换术(THA)的患者有更多的合并症和更复杂的住院时间，但长期随访显示出相似的结果：两组之间的假体存活率、骨长入和无菌性松动等并发症无明显差异。然而，其他研究表明，与髋骨关节炎OA患者相比，接受全髋关节置换术(THA)的股骨头坏死患者败血症、输血需求和再入院率增加。最近的分析显示，结果有所改善，超过90%的股骨头坏死全髋关节置换术(THA)存活4至7年，而1990年之前的存活率为8%至37%，这可能是由于手术中使用的植入物和材料的改进。文献在检查病因方面有限。值得注意的是，对需要进行全髋关节置换术(THA)的股骨头坏死患者的研究发现，46.6%的患者将继续接受全髋关节置换术(THA)治疗。需要对侧全髋关节置换术(THA)，特别是如果对侧髋关节在第一次全髋关节置换术(THA)时有股骨头坏死的影像学证据，表明需要密切随访。

总结

股骨头坏死仍然是一种病因、治疗和发育特征存在广泛差异的疾病。由于发病率持续上升，因此有必要加强对病理生理学的了解，以促进新疗法和正确治疗方案的发展。尽管骨移植和干细胞治疗等领域正在取得有希望的发展，但该领域仍然缺乏一致意见的治疗方案，来为股骨头坏死患者提供最高的生活质量并延缓他们发展为衰弱性损伤、股骨头塌陷或髋关节置换术。为了更有效地了解这种疾病过程，需要更多数据。国家登记处将是确定诊断和治疗方向的最完整的系统。在缺乏这种协调努力的情况下，机构登记和大型队列研究将有助于在这一领域取得进展。

在治疗领域，有许多潜在的改进途径。骨修复方面的有前景的进步（例如合成代谢药物）可能在促进愈合中发挥作用。此外，针对同时发生的情况进行更有针对性的治疗可能会减少类固醇和化疗引起的股骨头坏死的继发性发展。随着对病因、预防和治疗的广泛研究，我们有理由期望在减轻这种疾病的负担方面取得进展。

Osteonecrosis of the Femoral Head

Abstract

Osteonecrosis of the femoral head is a progressive and debilitating condition with a wide variety of etiologies including trauma, steroid use, and alcohol intake. Diagnosis and staging are based on imaging including MRI at any stage and plain radiography in more advanced lesions. The only definitive treatment is total hip arthroplasty, although numerous treatments including disphosphonates and core decompression are used to delay the progression. Lack of satisfactory conservative measures suggests the need for additional research of osteonecrosis including large patient registries to further understand this condition.

Osteonecrosis is a progressive disorder in which lack of sufficient blood supply leads to cell death, fracture, and collapse of the affected area. The condition is frequently associated with the femoral head, where progression can be debilitating and can ultimately necessitate total hip arthroplasty (THA). The etiology of osteonecrosis is complex with numerous contributing agents, most markedly trauma, steroid use, and alcohol. Treatment of osteonecrosis is controversial because no option has been overwhelmingly embraced, and little research has compared treatments. Researchers estimate total hip arthroplasty (THA)t 20,000 new cases of osteonecrosis are diagnosed in the United States each year.1 The increasing incidence and debilitating progression of osteonecrosis suggest the need for additional investigation of effective and novel treatments, as well as the need for clearer understanding of available treatments. This review characterizes the current knowledge on etiology, pathophysiology, epidemiology, and clinical management of osteonecrosis, with an emphasis on recent developments.

Epidemiology

The incidence of osteonecrosis in the United States has been estimated at ∼20000 to 30000 cases per year, affecting primarily young adults between the ages of 20 to 40 years.1 Recent analysis has shown total hip arthroplasty (THA)t although the number of total hip arthroplasty (THA)s done for osteonecrosis has increased between 2001 and 2010 (from 54.2 per 100,000 hospital admission to 60.6 per 100,000 hospital admission), the percentage of total hip arthroplasty (THA)s done for osteonecrosis has decreased from 9.7% to 8.3%, likely because of the rapid increase in osteoarthritis necessitating total hip arthroplasty (THA).2

Pathophysiology and Pathogenesis

General Pathogenesis

Osteonecrosis occurs because of compromised blood flow or oxygen delivery to the bone, although the clinical presentation is a result of the repair process, rather total hip arthroplasty (THA)n initial ischemia. In osteonecrosis, bone formation by osteoblasts is unable to match bone resorption by osteoclasts. This remodeling imbalance does not adequately replace the necrotic bone, leaving a region of structurally unsound bone tissues.3

Trauma

Trauma is the most common cause of osteonecrosis,4 disrupting blood flow and leading to osteocyte death. Estimates of occurrence of traumatic osteonecrosis of the femoral head vary depending on the injury type5; however, in meta-analysis of traumatic osteonecrosis, incidence has been found to be as high as 14.3%.6 The Garden classification categorizes femoral neck fractures and can be used to estimate the risk of osteonecrosis. Garden I (incomplete fracture) and Garden II (complete and nondisplaced) are considered stable and low risk, and can be repaired with internal fixation. Garden III (complete and partially displaced) and Garden IV (complete and completely displaced) have much higher rates of osteonecrosis with internal fixation (16%), and arthroplasty should be considered.7 Intertrochanteric hip fractures result in a low risk of osteonecrosis, noted at 0.95% after a 1-year follow-up.8

Atraumatic Osteonecrosis

Atraumatic osteonecrosis encompasses a diverse array of causes. It is important to note total hip arthroplasty (THA)t in atraumatic osteonecrosis, disease is frequently bilateral owing to systemic risk factors, with some estimates suggesting as high as 70% of the patients with unilateral osteonecrosis developing disease in the contralateral hip.9,10 The reasons for the sparing of one hip in the presence of a systemic risk factor are not well studied and may be because of subclinical presentation, differences in wear patterns between hips, underinvestigation of symptoms, or lack of coordinated follow-up.

Glucocorticoids

Steroid use is the second most common cause of osteonecrosis.11,12 Several potential mechanisms have been proposed for this association, including bone matrix and cartilage degeneration, induced stem cell abnormalities, changes in lipid metabolism, creation of fat emboli, altered coagulation, and changes in blood supply.11,12 Meta-analysis found up to 10 times increased risk of patients on high-dose corticosteroids, a doubling of risk for osteonecrosis when the cumulative dose exceeds 10 g, and a 0% increase in risk with each 10 mg increase of daily dose.13 Corticosteroids have also been implicated in osteoblast death and decreased osteoblast proliferation, impairing the ability to repair and replace necrotic lesions.11

Alcohol

Alcohol is hypothesized to act through altered lipid metabolism and increased adipogenesis.14 It is hypothesized total hip arthroplasty (THA)t increased generation of lipids increases the risk for fat emboli leading to vascular occlusion. In addition, increased serum lipids can cause packing of the marrow, increasing intraosseous pressure and decreasing blood flow.5,12 Alcohol may also contribute to osteocyte death.5 A study has also shown increased cortisol levels in patients with alcohol-induced osteonecrosis compared with idiopathic osteonecrosis control subjects, suggesting total hip arthroplasty (THA)t alcohol-induced osteonecrosis may act through the steroid pathway.15 Previous estimates noted an 11 times higher risk of osteonecrosis in consumers of ＞400 mL of alcohol daily.16

Hyperlipidemia

Hyperlipidemia is thought to decrease the blood supply to affected regions by increasing intraosseous pressure and producing fat emboli.4 One study of low-energy femoral neck fractures in the elderly found higher blood lipid abnormalities in those who developed osteonecrosis total hip arthroplasty (THA)n those who did not.17 A study of patients with acute lymphoblastic leukemia (ALL) identified hyperlipidemia as a risk factor for developing osteonecrosis.18 A similar study found association with osteonecrosis development in patients with hyperlipidemia and systemic lupus erythematosus (SLE).19

Systemic Lupus Erythematosus

The association of SLE with osteonecrosis is related to frequent corticosteroid treatment; however, recent analysis has shown higher incidence of osteonecrosis in corticosteroid users with SLE total hip arthroplasty (THA)n in corticosteroid users without SLE, suggesting synergistic effects.20 Meta-analysis of SLE studies has identified numerous noncorticosteroid risk factors in SLE, notably renal involvement and central nervous system (CNS) disease.21,22 Mixed data suggest total hip arthroplasty (THA)t the prothrombotic effects of antiphospholipid antibodies play a role in osteonecrosis development in SLE. Recent meta-analysis of childhood-onset SLE found notable osteonecrosis association, with estimates total hip arthroplasty (THA)t 6 to 8.4% of the patients with childhood-onset SLE develop osteonecrosis,23 although most did not develop osteonecrosis until after puberty.21

Sickle Cell Disease

Studies of the association between sickle cell disease and osteonecrosis have identified 2 to 4.5 cases of osteonecrosis per 100 patients with sickle cell disease.24 Precipitation of hemoglobin S in low-oxygen environments may lead to vaso-occlusion and ischemia of the bone, which is similar to the development of other vaso-occlusive injury in sickle cell disease.5 A recent study supports this theory, citing elevated hemoglobin levels as a risk factor for osteonecrosis in patients with sickle cell disease and suggesting total hip arthroplasty (THA)t vaso-occlusion, high blood viscosity, hypoxia, and concurrent alpha-total hip arthroplasty (THA)lassemia contribute to osteonecrosis.25

Gaucher Disease

A recent evaluation of the Gaucher Registry estimated the incidence of osteonecrosis at 30%.26 Gaucher disease may act through a similar path to total hip arthroplasty (THA)t of sickle cell disease, with Gaucher-affected cells obstructing the blood flow27 or by increasing intraosseous pressure because they accumulate in the fatty marrow.3 In addition, Gaucher cells can release osteoclast-activating cytokines which disrupt the balance of bone formation and resorption.26 Enzyme replacement can reduce or delay the symptoms of osteonecrosis28; however, a study has suggested total hip arthroplasty (THA)t the bone marrow may serve as a “sanctuary site” for Gaucher cells, leaving a subset of patients vulnerable to osteonecrosis despite treatment.29

Decompression Sickness

Decompression sickness–related osteonecrosis or dysbaric osteonecrosis occurs because of rapid decompression after an extended period in a hyperbaric environment. Rapid decompression forms bubbles in the bloodstream because dissolved nitrogen comes out of the solution. The high solubility of nitrogen in fatty tissues makes the marrow particularly susceptible. Multiple mechanisms have been proposed, including direct occlusion of blood flow to the marrow and the increase in intraosseous pressure reducing effective blood flow.30 A recent study of divers with musculoskeletal decompression sickness found evidence of dysbaric osteonecrosis in 26% of the cases, although the study was limited by the relative rarity of this condition.31

Acute Lymphoblastic Leukemia

Patients with ALL show an increased risk of osteonecrosis, with radiographic incidence reaching 71.8% in prospective studies.32 The single largest factor identified in the development of osteonecrosis in patients with ALL is adolescence, suggesting an effect of ALL or its treatment on the growth and remodeling of the bone. It is also possible total hip arthroplasty (THA)t the occurrence of this time of changing metabolism and growth magnifies susceptibility to osteonecrosis-causing damage from other factors.33 Older adults, who make up a small portion of those diagnosed with osteonecrosis, often undergo modified treatment regimens and have worse overall outcomes compared with their younger counterparts.34 A recent study of childhood leukemias found higher incidence of osteonecrosis in patients treated with hematopoietic stem cell transplant (HSCT) versus chemotherapy alone (6.8% versus 1.4%), suggesting total hip arthroplasty (THA)t treatment methods influence osteonecrosis development.35 In addition, a review of treatment regimens identified increased cumulative dose of steroids as a risk factor for developing osteonecrosis in children with any hematologic malignancy.36 A review of treatment strategies suggested total hip arthroplasty (THA)t the use of discontinuous steroid regimens may decrease the risk of osteonecrosis and nonsteroid chemotherapeutic agents such as methotrexate and asparaginase may contribute to the development of osteonecrosis.37 One trial of alternate week dexametotal hip arthroplasty (THA)sone reduced the risk of osteonecrosis compared with continuous treatment in children with high-risk ALL.38

Transplantation

A recent study suggests steroid-mediated development of osteonecrosis in transplant patients, finding cumulative steroid doses to be higher in renal transplant patients who developed osteonecrosis total hip arthroplasty (THA)n in those who did not. The study also found total hip arthroplasty (THA)t the incidence of symptomatic osteonecrosis decreased from 20% to less total hip arthroplasty (THA)n 5% with the introduction of cyclosporine and a decrease in steroid usage.39

HIV

Multiple studies show a growing incidence of osteonecrosis in patients with HIV, showing nearly three times the risk of the general population.40 One recent study revealed a strong association between high-activity antiretroviral therapy and development of osteonecrosis, although the authors caution total hip arthroplasty (THA)t the association does not imply a pathologic role.40 Other studies have found no association between osteonecrosis and antiretroviral therapy (ART), citing instead association with alcohol, hyperlipidemia,41 or low nadir CD4 counts,42 although the mechanism is not well understood.

Genetic Involvement

Although familial variants of osteonecrosis and some associated genes have been found, no single responsible gene has been identified. One gene candidate is a mutation in type II collagen, although no definitive causality has been established.43 Elevated levels of osteoprotegerin and decreased expression of RANK/RANK ligand have been found in necrotic regions compared with healthy bone, suggesting a potential role of osteoclast-regulating genes.44 Factor V Leiden mutations and prothrombin mutations have been associated with patients with osteonecrosis in multiple studies,43 invoking a potential role of altered coagulation. Genome-wide association studies of selected populations have identified several loci of interest, including clusters of variants near glutamate receptor genes in patients with ALL,45 corticosteroid-induced osteonecrosis,33 and several loci of unknown significance, which may be related to coagulation pathways, lipid metabolism, or alcohol drinking behavior.46

Idiopathic Osteonecrosis

It is important to note total hip arthroplasty (THA)t an estimated 20% to 40% of osteonecrosis cases are idiopathic.47 This high rate of an unknown cause may be due to nonspecific early symptoms and indolent course, which prevent early diagnosis,9 as well as lack of standardized reporting and data collection, which may help to reveal little understood causes and connections.

Clinical Manifestations and Diagnosis

Diagnosis

The early stages of osteonecrosis of the femoral head are frequently asymptomatic but may also present with radiating pain from the hip or groin and limited range of motion of the joint on physical examination.47 Diagnosis of osteonecrosis is primarily based on imaging, although examination and history are important to gather surrounding context and potential etiology.5 A plain radiograph is an appropriate first-line modality for identifying cases of osteonecrosis, with benefits including low cost, high availability, and adequate sensitivity for mid-stage and late-stage disease.48 Frontal and lateral “frog-leg” views are recommended for accuracy. In the case of early-stage disease, radiography may be insufficient to identify early or minimal changes. MRI is the benchmark for diagnosis of osteonecrosis because of its high sensitivity for early signs of onset. Supplemental imaging, including diffusion-weighted MRI49 and gadolinium-enhanced perfusion MRI,50,51 may further advance the diagnostic capabilities of MRI. Perfusion MRI may assist in distinguishing between radiographically and symptomatically similar conditions such as bone marrow edema and subchondral insufficiency fractures.52 In pediatric patients with developmental dysplasia of the hip, perfusion MRI was helpful in identifying those at risk for osteonecrosis after closed reduction/spica casting.53 In addition, a whole-body bone scan provides an option for patients at risk for multifocal osteonecrosis, such as those receiving systemic corticosteroids or immunosuppressants.54

Differential Diagnosis

Bone Marrow Edema Syndrome Bone marrow edema syndrome (BMES) presents as sudden pain without a clear precipitating event. On imaging, BMES shows diffuse edema compared with more localized areas in osteonecrosis. Some studies have suggested total hip arthroplasty (THA)t BMES may precede osteonecrosis.5

Subchondral Insufficiency Fracture A subchondral insufficiency fracture presents similarly but occurs after an injury. Although both conditions present with low-signal subchondral bands, osteonecrosis imaging presents with a smooth, concave line while the fracture presents with a jagged, discontinuous, convex finding. Conservative treatment is unlikely to improve fracture symptoms, and both conditions can progress to the need for a total hip arthroplasty (THA).5

Neoplasm Although rare, clear cell chondrosarcoma and chondroblastoma can present with radiolucent lesions in the femoral head. These conditions are not accompanied by the edema present in osteonecrosis or other similar conditions such as BMES.5

Classification Systems and Staging

The most popular staging system for osteonecrosis of the femoral head is the Ficat classification (Table ​(Table1).1). Developed in 1964 and later modified to include the use of MRI, the Ficat system classifies patients with osteonecrosis as stage 0 to 4 based on the appearance on a plain radiograph. Although this system is widely accepted and frequently used, detractors cite the use of clinical symptoms, low interobserver consensus, and lack of prognostication as limitations.55 The University of Pennsylvania system was developed in an attempt to more clearly delineate the progression of osteonecrosis and to promote distinctions between the stages by adding stage 0 for preradiographic disease, dividing Ficat stage II into two stages based on the absence (II) or presence (III) of a crescent sign, and dividing Ficat IV into two stages: flattening with joint space narrowing only (V) and joint deformity and joint space obliteration (VI).56 The Association Research Circulation Osseous (ARCO) system closely follows Ficat with the exception of the inclusion of MRI findings in stage I and division of stage II based on the extent of femoral head flattening (IIIA if ＜ 2 mm and IIIB if ＞ 2 mm). The ARCO system was recently revised based on an international expert taskforce to better incorporate results of both MRI and plain radiography.57 These staging systems are summarized in Table ​Table11.

Systematic analysis of different staging systems found total hip arthroplasty (THA)t any classification system is valuable and sufficient for the staging of osteonecrosis, provided necessary data are collected to allow conversion to another metric.58 For the purposes of patient evaluation and treatment, the most important classification is precollapse versus collapse because this guides discussion of conservative treatment versus total hip arthroplasty (THA). For research purposes (especially for the collection of registry data), we recommend using the updated ARCO guidelines because they effectively use multiple imaging modalities and delineate smaller changes between stages. This allows for a higher level of detail in tracking disease progression and may help to provide clearer answers because the effectiveness of new therapies is evaluated.

Treatment Options

Risk of Progression

Evaluating risk of progression is important in determining an appropriate treatment choice (Table ​(Table2).2). Although there is no consensus on a system to definitively predict collapse, a review of attempted strategies has found increased lesion volume, necrosis ＞ 40% of the weight-bearing surface, and necrosis radian ＞ 200 to 250 to be suggestive of future collapse.59

Observation

The most conservative management, observation, has been considered as a possible approach to osteonecrosis. There has been some evidence for spontaneous resolution of small early-stage osteonecrosis lesions.60 In combination with observation, restricted weight-bearing is usually advised, although this has not shown utility as a primary treatment modality.61 A study of observation as a strategy in osteonecrosis of the hip has found a failure rate of over 80% by four years and is not recommended as a standalone treatment in advanced lesions.62

Nonsurgical Treatment

Pharmacologic Agents Medications have been a mainstay of osteonecrosis treatment, but recently, their effectiveness has been questioned. Disphosphonates are a popular choice for pharmacologic treatment and work by inhibiting osteoclast activity. Studies of the use of disphosphonates have shown mixed results.63 Although some early studies showed positive effects of disphosphonates, a recent large multicenter randomized controlled trial found no difference between alendronate and placebo.64 Furthermore, a meta-analysis of five randomized controlled trials had similar findings, with little to no evidence supporting the efficacy of disphosphonates in the nontraumatic osteonecrosis of the femoral head.65 The primary utility of disphosphonates is in the early stages of disease, and they are not preferred to surgery as osteonecrosis progresses.61

Studies have identified multiple potential mechanisms for beneficial effects of statins in delaying osteonecrosis including lipid-lowering effects,47 increased autophagy,66 suppression of Peroxisome proliferator-activated receptorγ, and activation of the Wnt signaling pathway.67 Statins have been effective in combination with multiple core decompression (CD) procedures, improving both clinical and radiographic progression of osteonecrosis.68

Other Nonsurgical Modalities Several other modalities have been proposed for the treatment of osteonecrosis with varying success. Lipid modifiers such as dietary changes or lipoic acid supplements have shown some positive results in trials, but there is insufficient evidence to recommend them as primary treatment strategies.61,63 Hyperbaric oxygen treatments, pulsed electromagnetic fields, and extracorporeal shockwave therapy have been proposed showing some positive outcomes, but disagreement about their effectiveness makes them difficult to recommend.47,61,69

Joint Preserving Procedures

Core Decompression CD is done for osteonecrosis of the femoral head to reduce intraosseous pressure and promote increased blood flow and bone genesis. Ficat,70 in his early descriptions of osteonecrosis and the CD procedure, noted increased intramedullary pressures, which are released with CD leading to a relief of pain and eventual restoration of blood flow if the lesion is treated early in its progression. Although older studies of CD were equivocal about its effectiveness, study of more recent procedures has shown notable benefits. Studies of both short-term and long-term outcomes have shown improvement in patients treated with CD and delayed time to total hip arthroplasty (THA) compared with more conservative treatment options.71 As with many treatments, these outcomes are more positive when used in the early stages of disease, with up to 100% of hips surviving 3 years69 and up to 96% surviving 10 years in early-stage disease.71 More precisely, CD has shown positive results in osteonecrosis showing no collapse, a central lesion, and small size (combined necrotic angle ＜250°).72 These outcomes may prove even more beneficial when paired with grafts and cell-based therapy.

Vascularized and Nonvascularized Bone Grafting Nonvascularized bone grafting involves the placement of bone graft material to provide structural support with the intent of reducing intraosseous pressure and preventing collapse in early stages of osteonecrosis. Vascularized bone grafting (VBG) also seeks to introduce increased blood supply. The graft is done by placing a nonvascularized cortical allograft from the ilium, tibia, or fibula,73 or a vascularized graft from the iliac crest, fibula, or greater trochanter74 into a core space created for the procedure or from a CD procedure. Nonvascularized bone grafting has shown moderate success, especially with smaller lesions, having a 55% to 87% success rate with a 2- to 9-year follow-up across several studies.69 VBG has shown a 5-year hip survival of 80% in precollapse lesion or 60% after 14 years in similar patients,69 with low conversion to total hip arthroplasty (THA).75 However, the benefits of VBG are primarily realized in smaller lesions without notable collapse.76 Ongoing research has evaluated synthetic scaffolds used with or without biofactors to enhance integration and bone growth. Numerous organic, inorganic, and biologic materials have been developed with promise, although no definitive solution has been identified.77

Adjunctive Therapy Because osteonecrosis is thought to result from a deficiency of bone regeneration, use of stem cell treatments has been proposed to halt or reverse its pathogenesis. Studies have shown lower rates of radiographic progression and lower need for total hip arthroplasty (THA) in patients treated with autologous stem cell transplants. In early studies, the combination of autologous stem cell transplant with CD showed a notable delay of an average of 10 years (up to 17 years) in time to collapse.78 In addition, cell therapy can be combined with other therapies such as CD and/or bone grafts and can potentially improve outcomes.69 A study has shown benefits of bone morphogeneticprotein (BMP) in addition to allograft and/or CD in improving bone formation and limiting the progression on osteonecrosis.79

Osteotomy Osteotomy attempts to delay the progress of osteonecrosis by relieving weight-bearing on necrotic or prenecrotic areas to prevent collapse. To do this, weight-bearing osteonecrotic region is angled or rotated to place primary pressure on a non-necrotic area of the bone. Rotational (82% to 100% from 3 to 15 years) and angular (82% to 98% between 6 and 18 years) osteotomies of the femoral head have shown excellent success rates. However, future total hip arthroplasty (THA) can become difficult if necessary because of persistent implant and altered anatomy.69

Arthroplasty

Resurfacing Resurfacing of the joints in question is the most minimal option for advanced osteonecrosis and involves replacing the articular surface with artificial materials to preserve natural anatomy. However, because of the complications from materials and possible contribution to osteonecrosis progression, resurfacing is no longer used as osteonecrosis treatment of the femoral head.69

Total Joint Arthroplasty Joint arthroplasty is the only definitive cure for osteonecrosis available at this time; however, potential downsides require careful consideration. total hip arthroplasty (THA)s are not a permanent solution, and although they may be beneficial early in older patients to reduce cumulative procedures, most patients with osteonecrosis are relatively young. Given this population, if the joint is replaced at diagnosis, the patient will likely need another arthroplasty or revision later in life. Recommendations for joint arthroplasty include advanced disease, continuing progression, and continuing provocative factors.77 Although patients who have a total hip arthroplasty (THA) for osteonecrosis have more comorbidities and more complicated hospital stays total hip arthroplasty (THA)n those having total hip arthroplasty (THA) for osteoarthritis, long-term follow-up has shown similar outcome between the two groups for implant survival, osseointegration, and complications such as aseptic loosening.80 Other studies, however, have shown increased rates of sepsis,81 transfusion requirement, and hospital readmission in patients with osteonecrosis who underwent total hip arthroplasty (THA) compared with OA patients. Recent analysis has shown improved outcomes, with ＞90% of osteonecrosis total hip arthroplasty (THA)s surviving 4 to 7 years compared with 8 to 37% survival rates before 1990, possibly because of improved implants and materials used in the procedures.69 The literature is limited in examining etiology-based implant survival, but a study of patients with osteonecrosis secondary to alcohol consumption showed excellent long-term outcomes.82 It is also important to note total hip arthroplasty (THA)t the study of patients with osteonecrosis requiring total hip arthroplasty (THA) found total hip arthroplasty (THA)t 46.6% of the patients would go on to require contralateral total hip arthroplasty (THA), especially if the contralateral hip had radiographic evidence of osteonecrosis at the time of the first total hip arthroplasty (THA), suggesting the need for a close follow-up.83

Summary

Osteonecrosis continues to be a condition of widely variant etiologies, treatments, and developmental profiles. Because incidence continues to rise, increased understanding of the pathophysiology is necessary to promote developments of new treatments and corrective procedures. Although promising developments are being made in areas such as bone grafting and stem cell therapy, the field continues to lack an agreed-upon regimen to provide patients with osteonecrosis the greatest quality of life and delay their progression to debilitating injury, collapse, or joint arthroplasty. To more effectively understand this disease process, more data are needed. A national registry would be the most complete system to determine diagnostic and treatment directions. In the absence of such a coordinated effort, institutional registries and large cohort studies would help to make advances in this realm.

In the area of treatment, there are many potential avenues for improvement. Promising advancements in bone repair such as anabolic agents may play a role in promoting healing. In addition, more directed therapies for coincident conditions may reduce the secondary development of osteonecrosis from steroids and chemotherapy. With an expanded study of etiologies, prevention, and therapy, there is a reason to hope for advancements in reducing the burden of this disease.

文献出处：Gary George, Joseph M Lane. Osteonecrosis of the Femoral Head. J Am Acad Orthop Surg Glob Res Rev. 2022 May 1;6(5):e21.00176. doi: 10.5435/JAAOSGlobal-D-21-00176.