股骨头坏死（ONFH）是骨科领域中一种常见但难治的疾病, 是由股骨头的血液供应受损引起的一种疾病。ONFH可分为两类：创伤性和非创伤性。前者主要由髋关节创伤（股骨颈骨折、关节脱位等）引起，而后者主要由应用皮质类固醇、大量饮酒和减压病引起。激素性股骨头坏死（SONFH）是指由大剂量激素引起的股骨头活性成分（骨细胞、骨髓造血细胞和脂肪细胞）死亡的病理过程。SONFH占非侵入性坏死发病率的首位。
股骨头的血供不稳定，而它是一个主要的承重关节，因此是最常见的受骨坏死影响的骨骼之一。骨坏死（ON）或股骨头的血管性坏死是一种以骨细胞和骨髓死亡为特征。骨坏死是由于软骨下受影响部分的血液供应不足引起的，有时被称为 “髋关节冠状动脉疾病”，比拟了心脏的缺血状况。
股骨头坏死（ONFH）通常影响生命中第三和第四个十年的成年人。
每年美国约有10,000至20,000个新病例被诊断。据文献报道，每年约有5%～12%的髋关节置换术用于治疗这个疾病。首先是一个股骨头受累；72%病例在两年内发生双侧受累。
被诊断为髋关节骨坏死的患者有两类：
（a）无明显病因或危险因素的患者；
（b）有明确病因的患者。
根据病因，骨坏死可以是特发性的（原发性）或继发性的。
骨坏死有多种致病因素。
使用糖皮质激素和过度饮酒与80%以上的非创伤性病例有关。
ONFH是遗传易感性、代谢因素和影响血液供应的局部因素（如血管损伤、骨内压力增加和机械应力）综合作用的结果。
ONFH是一种进展性疾病，在没有有效治疗的情况下，80%会在1到3年内进展为塌陷。
一旦出现股骨头塌陷（软骨下骨折和新月征阳性），病程就难以逆转。
在几年内，大多数患者会出现严重的骨关节炎，需要进行人工关节置换。人工关节置换的长期影响仍然难以预测。因此，寻找保持自身关节的有效治疗方法就显得尤为重要。
血管解剖结构各不相同，但大多数人都有股外侧环状动脉，它产生三或四个分支（即网状血管）；股骨后动脉，产生韧带内的血管；股内侧环状动脉的上升支，供应大转子并与股外侧环状动脉吻合。
近年随糖皮质激素在临床上的广泛应用，特别03年SARS流行期间，大量使用激素导致SONFH的发病率大幅上升。大剂量激素和长期影响与ONFH有关。而短期小剂量与骨坏死无明显相关性。SONFH的发病多发生在激素治疗后24个月内，也可能在6个月内发生。增强型MRI 和 DSA 是检测早期骨坏死的方法。SONFH的治疗仍然棘手，许多方法疗效和机理仍不明确。
SONFH有许多假说，如脂肪栓塞、骨内压增加和高凝假说。
对于早期无症状的ONFH，是否早期手术干预仍有争议。早期诊断和治疗可以减少患者的痛苦及降低社会成本。
骨坏死的病理生理
最终，股骨头坏死是通过一个共同的途径发生的。股骨头的血流减少导致骨缺血和死亡。
然而，导致这一最终途径的诱发机制是多样的。
血管闭塞可以由局部血栓、脂肪栓子、氮气泡或形状异常的红细胞引起。
渗出的血液与骨髓腔内的脂肪或细胞成分一起，可以外在地压迫动脉和静脉。股骨头内的血管可能因脉管炎、（放疗）辐照或化学毒性而直接受损。如果侧支循环充足，骨细胞可保持活力。虽然骨有相对丰富的血管供应，但分布是不均匀的，使一些区域比其他区域更脆弱。一旦达到缺血阈值，受影响的骨内的形态学变化是相似的，无论诱发疾病是什么。
在血管受损后24至72小时之前，没有明显的组织学证据表明有损伤。对骨髓的检查显示，造血细胞、内皮细胞和脂肪细胞坏死。骨细胞萎缩和死亡，随着时间的推移，越来越多的空隙变得很明显。溶酶体的释放使周围组织酸化，因为垂死的脂肪细胞释放出游离脂肪酸，与细胞外的钙皂化，形成不溶性皂质。随后脂肪骨髓含水量的增加可以通过磁共振成像（MRI）检测到，这代表了临床上最早的异常。皂化的脂肪和其他坏死区域最终会钙化，在疾病过程的后期可以通过平片检测到。
细胞死亡后，修复过程开始启动。炎症连锁反应由邻近的活体组织发起，导致细胞死亡区域的纤维血管生长。可以看到血管管穿透松质骨的髓质管和上覆皮质骨的haversian管。这些血管伴随着原始间质细胞，这些细胞分化为成骨细胞和破骨细胞。不成熟的编织骨沉积在整个死亡的小梁骨网络中。无生命力的骨小梁通过蠕动替代的过程慢慢被吸收。不幸的是，新沉积的骨不能达到股骨头该区域以前的结构完整性，导致这些区域在适当的负重负荷下出现软骨下塌陷。最终，这导致了股骨头正常光滑的软骨表面的不规则性，并发展为晚期关节炎。此外，在疾病的过程中，由于患者相对不活动，周围的活骨可能会失去质量并变得骨质疏松。
Phemister首先提出 “无菌性坏死 “可能是由骨折、骨移植、辐射和血栓形成的血管阻塞或栓塞造成的。后来被认为是一个原始的血管问题。有些人认为，股骨头坏死是由一种血管炎导致的。Chandler认为是骨外栓塞过程，提出了 “髋关节冠状动脉疾病 “的概念。在对31例特发性股骨头坏死的微血管学研究中，Atsumi发现上行网动脉的骨外中断，以及早期血管生成和未受影响的周围血管的代偿性肥大。他们还发现沿承重区的软骨下塌陷区发生的血管再通受阻。相反，Glimcher和Kenzora在150例成人股骨头坏死患者中没有发现支持血管受累的证据，而是认为这纯粹是代谢综合征导致的细胞死亡。在过去的二十年里，人们提出了许多关于非创伤性ON的发病机制的理论。骨内高血压、血管内脂肪或气体栓子、骨髓脂肪储存增加造成的血管外压迫是几种公认的理论。大多数人支持 “多重打击 “理论，各种损伤积累的组织压力达到一个临界点，启动了疾病过程。许多人同意这些理论不是相互排斥，而是相互支持的。
骨坏死与高凝血症和遗传改变的关系
Paul-Jones在1992年首次提出高凝状态，特别是血管内凝血可能是骨坏死的原因之一。遗传性血栓性疾病、纤维蛋白溶解障碍或抗磷脂抗体可导致微循环的血栓性闭塞。其他原因包括环境或获得性/原有的条件，如高脂血症、超敏反应、妊娠期血栓素释放、恶性肿瘤和炎症性肠病都可能给具有潜在遗传倾向的个体带来额外的风险，形成微血管血栓。镰状细胞病和其他血红蛋白病在促进股骨头坏死方面的作用已被充分证实，而且似乎也是通过血管内凝血的最终途径发挥作用。
Björkman等人在对63名成年股骨头坏死患者的回顾性研究中显示，在特发性骨坏死患者中，V型莱顿因子或凝血酶20210A基因的突变明显多于类固醇或酒精引起的骨坏死患者，也多于健康对照组人群。这一点得到了Zalavras及其同事的支持，他们证明在72名成年白种人患者中，有18%出现了V型莱顿因子突变，而在300名健康对照对象中只有4.6%。此外，导致血栓性疾病的蛋白C和蛋白S的缺乏与股骨头坏死有关。Jones等人研究了45名骨坏死患者的血样，其中5名患者没有已知的可能导致ON的其他预存条件。与40名年龄匹配的健康对照组相比，骨坏死患者出现促进抗凝血的基因异常的可能性要高3倍，而在那些没有预先存在的疾病的患者中，100%有促进抗凝血的基因异常。Glueck等人在分析高凝状态和ON的作用方面做了大量工作。在进入低分子量肝素（LMWH）治疗股骨头坏死试验的36名患者中，他们发现基因多态性导致血浆蛋白原激活剂抑制剂-1基因（PAI-1）活性增加，亚甲基四氢叶酸还原酶（MTHFR）发生改变，导致纤维蛋白溶解度降低，同时同型半胱氨酸和脂蛋白水平高于对照组。在同一组患者中，他们表明，依诺肝素可防止早期患者骨坏死的进展。Chang等人发现MTHFR基因的多态性增加了韩国人群中ON的风险，而Kim等人未能显示MTHFR基因位点的单核苷酸多态性（SNPs）与韩国人群中ON的发展之间存在明显的关联。
现在已经很清楚，一般来说，促进血管内凝血的遗传异常或遗传性疾病与骨坏死的发生有关。未来的研究可能会集中在如何筛查和定位与高凝血症相关的多态性，以便为这一患者群体提供更早甚至是预防性的治疗。
遗传关系
如前所述，由于凝血级联中的关键成分包括C蛋白、S蛋白、PAI-1和其他一些因素的遗传改变，由可遗传疾病和SNP等遗传异常引起的血栓性疾病在ON的病因和进展中起着重要作用。Chen等人评估了两个具有家族性常染色体显性股骨头坏死的台湾血统。他们能够将蛋白C、蛋白S和PAI-1蛋白的突变与2q13-q14、3q11.1-q11.2和7q21.3-q22染色体段分别联系起来。Pierre-Jacques等人报道了一个多灶性骨坏死患者的家族性杂合蛋白S缺乏症。许多其他的遗传关联已经被确认。Glueck等人证明，T-786C果蝇一氧化氮合成酶（dNOS）SNP导致一氧化氮的活性下降，而一氧化氮负责促进血管生成、骨形成和抑制血小板聚集。在他们的系列研究中，22%的特发性ON患者有这种SNP，而对照组中只有5%。同样，Koo等人发现，在他们的研究人群中，一氧化氮合成酶基因的多态性增加了ON的风险[47]。Hong等人在450名股骨头坏死患者和300名匹配的健康对照组的对比研究中，评估了转铁蛋白（TF）、血管内皮生长因子C（VEGFC）、甾醇调节元件结合转录蛋白-3（IGFBP3）和血管紧张素I转换酶（ACE）基因的SNP。他们发现，IGFBP3基因上的SNP R2453839S与ON的发展显著相关，ACE基因上的SNP与类固醇诱导的ON进展的机会增加有关。令人惊讶的是，他们发现kinase insert domain receptor（KDR）和neuropilin 1（NRP1）基因位点的SNPs与ON的发病率下降有关。Kim等人在韩国人口中做了大量工作，以确定SNP可能与ON发病率增加有关的基因。他们已经确定了SREBP-2基因、白细胞介素受体23基因、附件素基因家族、过氧化氢酶基因以及血管内皮生长因子基因的启动子多态性的SNPs。Dai等人的研究表明，抑制组织因子途径的基因多态性可能导致骨坏死的风险增加。除了前面讨论的基因外，多态性的维生素D受体（VDR）基因、胸苷酸合成酶基因（TYMS）和II型胶原A1（COL2A1）基因都被确认为增加股骨头坏死的风险。
并非所有接受大剂量类固醇的病人都会发生ON。
Asano等人推测，与遗传变异有关的药物代谢差异可能解释了为什么一些人发生ON而另一些人没有。他们研究了136名肾移植后的患者，发现那些表达编码运输蛋白P-糖蛋白（P-gp）的基因中的特定核苷酸多态性的患者与ON的抗性有很大关系。P-gp在药物的吸收和分布中起着重要作用。通过测量血清中他克莫司（一种免疫抑制药物，其生物利用度已知受到P-gp的影响）的通过水平，他们能够将P-gp活性的增强与对ON的抗性联系起来。P-gp活性的增加可能导致更快速的类固醇清除，随后降低血清中类固醇的浓度。此外，他们发现，表达编码P-gp的基因的C3435TT基因型的个体，其P-gp活性明显较高，ON的发病率明显较低。他们的结果表明，编码P-gp的基因的C3435TT基因型的患者对类固醇引起的ON有遗传上的抗性。He和Li表明，调节糖皮质激素摄取的P-糖蛋白基因ABCB1可能与ON的发生有关。在对长期服用糖皮质激素的患者和没有ON的患者的比较中，他们发现G2677T/A SNP与类固醇诱发的ON的发展有关。Kim等人也发现ABCB1（c3435t）基因的SNPs与类固醇诱导的ON的敏感性增加有关，并发现CBP（r3751845s）基因的伴随SNPs增加了相对敏感性。
外源性皮质类固醇与非创伤性骨坏死有关。剂量影响和产生骨坏死的确切机制仍然是未知的，目前是一个研究的主题。
自从1957年在一名类风湿性关节炎患者中首次出现病例报告以来，过量使用皮质类固醇与ON的发展之间的关系已被充分证实。随着用于治疗全身性疾病和器官移植的糖皮质激素治疗的增加，ON的发病率也随之增加。在目前接受糖皮质激素治疗的3000万美国人中，多达40%会出现某种程度的骨坏死。糖皮质激素是导致非创伤性骨坏死的最常见原因。接受类固醇治疗的病人发生骨坏死的可能性大约增加20倍。尽管皮质类固醇治疗对骨坏死的剂量影响在很大程度上仍是未知的，但最近的研究表明，皮质类固醇剂量超过25-40毫克/天是肾移植和SLE患者非创伤性ON的重要风险因素。关于类固醇诱发ON的原因，有几种假说是围绕着脂肪栓塞小血管和类固醇治疗后脂肪浸润导致骨内压升高而导致窦性血流受阻的概念。虽然潜在的疾病过程中的诱发因素混淆了这种情况，但在使用皮质类固醇的患者中，阐明导致ON的机制一直是一个激烈的研究领域。
研究显示，人类和动物在接触皮质类固醇后，脂质代谢都出现了异常。在动物研究中，诱导的高皮质醇症导致脂肪细胞肥大、高脂血症、脂肪肝和全身性脂肪栓塞。虽然经常观察到骨髓水肿和脂肪坏死，但在四足物种研究中，没有发现骨坏死或关节塌陷的区域。另一方面，用类固醇处理的鸡确实显示出ON的证据，表明双足和四足物种之间生物力学的差异可能是一个重要的促成因素。
对小鼠和人类的研究表明，以剂量和时间依赖的方式给予地塞米松，可诱导骨髓衍生干细胞分化为脂肪细胞，同时抑制成骨。用地塞米松治疗5天后，在人类股骨头的组织学标本中观察到脂肪细胞肥大。地塞米松已被证明可抑制 I型胶原蛋白和骨钙素的表达，从而抑制骨髓干细胞向成骨细胞的分化。已发现泼尼松龙治疗会降低骨密度和松质骨面积，同时导致骨小梁变窄。从皮质类固醇诱导的股骨头坏死患者中提取的间质干细胞已被证明具有较低的增殖能力，这可能解释了这些患者的骨再生能力较低。
洛伐他汀添加到细胞培养基中后，被发现可以抑制地塞米松补充剂引起的脂肪生成和脂肪特异性基因表达。此外，降脂药能抵消类固醇对成骨基因表达的抑制作用。这些发现在体外和体内都得到了证实。在一项支持性研究中，转染可追踪基因后移植到宿主小鼠体内的间质细胞显示，全身类固醇治疗后脂肪生成增加。基于这些观察，有人推测类固醇诱导的ON可能是由于骨髓脂肪过度堆积引起的骨内高压或骨髓干细胞向脂肪细胞分化的转变，导致可用于成骨细胞生产的干细胞库减少，最终导致坏死骨的修复和重塑不足。
人们在分子水平上研究了类固醇处理的间充质干细胞表现出增加脂肪生成和减少骨生成的机制。过氧化物酶体增殖体激活受体-γ（PPAR-γ）和核心结合因子a1（Cbfa1）是转录因子，被发现在多能细胞分化为成脂细胞和成骨细胞系时分别具有重要作用。地塞米松已被证明可增加PPAR-γ的mRNA表达，减少Cbfa1的mRNA表达。这些研究结果支持地塞米松促进脂肪生成而抑制成骨的观点。此外，这些研究还表明，地塞米松通过抑制血管内皮生长因子的产生而损害了血管生成。已发现来自股骨头的成骨细胞在糖皮质激素培养的24小时内表现出VEGF的下调。然而，在一个类固醇诱导的兔子骨坏死模型中，VEGF水平在甲基强的松龙治疗3天后增加到峰值水平。这些研究表明，虽然类固醇在分离的成骨细胞培养物中抑制了VEGF的表达，但在体内发生的与类固醇有关的缺血事件很可能促成了VEGF反应的上调。成骨细胞分流到脂肪细胞途径，同时抑制血管生成生长因子的产生，至少可以部分解释类固醇诱导的ON的基础。
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