Subchondral bone cysts in osteoarthritis: abnormal reconstruction of subchondral bone

doi:10.3969/j.issn.2095-4344.1400

Abstract

Abstract:

BACKGROUND: Osteoarthritis is one of the most common chronic diseases in orthopedics. Pathological changes in subchondral bone, characterized mainly as abnormal remodeling, manifested as subchondral bone marrow lesions and subchondral bone cysts, have been revealed their significance in the pathogenesis and progression of osteoarthritis by recent studies. Pathological changes in subchondral bone may precede which in cartilage and even aggravate it. Given the paucity of studies on subchondral bone cyst, an insight into subchondral bone cyst’s pathogenesis and clinical significance may contribute to novel diagnosis and therapy of osteoarthritis in terms of subchondral bone.

OBJECTIVE: To summarize the advances in researches on the etio-pathogenic hypothesis, pathological traits, clinical significance, clinical diagnosis and therapy of subchondral bone cysts in osteoarthritis.

METHODS: Computer-based searches of PubMed and Embase databases before January 2019 with the mesh terms of “(osteoarthritis OR osteoarthrosis OR osteoarthropathy) AND (subchondral cyst OR pseudocyst OR intraosseous cyst OR bone cyst)” were conducted by two co-first authors. Articles’ language was set as “English”. A total of 1 224 articles were retrieved after excluding the duplicate ones. 58 articles were eligible for the inclusion criteria to which 11 articles were retrieved manually in addition, thus 69 articles were included eventually.

RESULTS AND CONCLUSION: (1) Subchondral bone marrow lesions may be the “predisposed change” of subchondral bone cyst, two of which belong to the respective stage of one pathological process. (2) Subchondral bone cyst may result from the inflammatory bone absorption and subsequent reactive bone formation. (3) Subchondral bone cyst is evidently correlated with cartilage degeneration and joint pain. (4) Non-steroidal anti-inflammatory drugs, anti-absorptive drugs, subchondroplasty, and bone grafting during arthroplasty may ameliorate subchondral bone marrow lesions or subchondral bone cyst. Further large sample clinical trials are warranted.

Key words: osteoarthritis, subchondral bone, bone cyst, bone marrow lesions, pathology, genesis hypothesis, joint replacement

CLC Number:

R459.9|R684.3|R318

Lu Jinwei, Chen Xi, Ye Chenyi, He Rongxin, Tang Lan, Yu Yunxian. Subchondral bone cysts in osteoarthritis: abnormal reconstruction of subchondral bone[J]. Chinese Journal of Tissue Engineering Research, 2019, 23(32): 5209-5215.

Figures/Tables 2

2.1 软骨下骨囊肿的流行病学软骨下骨囊肿在骨性关节炎中常见，大约50%膝骨性关节炎患者有软骨下骨囊肿，在健康人中亦有13.7%出现该病变[11]，伴随骨性关节炎进展，软骨下骨囊肿可增大、新发[12]。类风湿关节炎、强直性脊柱炎、股骨头坏死亦可见软骨下骨囊肿[13-15]。 2.2 软骨下骨囊肿的临床意义在疼痛症状方面，Takegami等[16]发现髋关节软骨下骨囊肿与目测类比疼痛评分及生活质量评分显著相关，股骨头及髋臼同时出现软骨下骨囊肿有着最高的目测类比疼痛评分，股骨头及髋臼软骨下骨囊肿的最大直径与目测类比疼痛评分独立相关。Burnett等[17]研究发现，伴有重度夜间痛的膝关节骨性关节炎患者，其软骨下骨囊肿的程度与无夜间痛的患者相比更严重。在关节结构进展方面，Raynauld等[18]纳入107例症状性膝关节骨性关节炎患者，随访2年的回顾性分析表明，股骨内侧髁的软骨下骨囊肿的直径与软骨量呈显著负相关。Tanamas等[11]纳入132例症状性膝关节骨性关节炎患者的前瞻性随访研究发现，与基线仅存在软骨下骨髓病变和无病变者相比，基线软骨下骨髓病变+软骨下骨囊肿的患者的胫骨内侧平台软骨丢失明显增多、胫骨内外侧平台软骨量明显降低。McErlain等[19]通过对早期膝关节骨性关节炎患者进行有限元分析，表明软骨下骨囊肿使毗邻的软骨下骨平均应力增加约2倍，软骨下骨囊肿直径与该平均应力呈正相关。作者认为由软骨下骨囊肿所致异常的应力分布可加速骨性关节炎进程，加剧疼痛和功能障碍。Kastelein等[20]通过6年的队列研究发现，膝关节内侧间室软骨下骨囊肿是更高Kellgren-Lawrence分级的危险因素，OR=11.7。之于手术，Tanner等[21]通过对75例肩关节骨性关节炎行全肩关节置换患者5-8年的随访研究发现，术前存在中度-重度软骨下骨囊肿者与无-轻度软骨下骨囊肿者相比有着更高的手术翻修率(12.5% vs. 0)，翻修原因均为关节盂假体松动，作者认为术前通过CT评估软骨下骨囊肿的程度可帮助评估手术失败的风险。 2.3 软骨下骨囊肿的成因假说软骨下骨囊肿的成因尚无定论，目前主要分为“滑液入侵假说”和“创伤性骨坏死假说”[22-24]。 1953年Landells[25]发现软骨下骨囊肿通过裂隙与关节腔相通，因此认为其并不是原发于软骨下骨病变，而是由于关节滑液等通过裂隙进入软骨下骨，造成软骨下骨小梁的不全骨折及移位形成囊肿的壁，骨小梁的推移引起了局部骨硬化的表现，同时由于空腔的形成使得应力改变，促进囊肿壁的新骨形成，且最终由于纤维组织增生、新骨形成等原因可自发封闭连通关节腔的通道，即“滑液入侵假说”。 1955年Rhaney等[26]认为软骨下骨囊肿的形成并不是“滑液入侵假说”，而是由于没有正常的关节软骨的保护，强大外力传递至软骨下骨，通过血管损伤、缺血等环节引起骨坏死，进而在骨吸收的过程中形成含有液体的腔隙，即“创伤性骨坏死假说” 。 2006年一项纳入32例骨性关节炎患者平均随访17.52个月的回顾性临床研究表明，基于MRI检查，92% 软骨下骨囊肿起源于软骨下骨髓病变的信号区域，且软骨下骨囊肿的发展通常伴随着软骨下骨髓病变大小的改变，该研究提示软骨下骨髓病变和软骨下骨囊肿可能存在密切联系[27]。2010年一项纳入1 283例膝关节骨性关节炎高危患者(超重、肥胖、膝痛、晨僵、膝关节外伤史、膝关节手术史)的随访30个月的大规模前瞻性临床研究表明，在校正了其他混杂因素后，软骨下骨髓病变与软骨下骨囊肿显著相关，二者在时间上有先后关系，在空间上有一致性，前者是后者的预测因素，表明二者可能是同一病理过程的不同阶段，随后有学者称软骨下骨髓病变为“软骨下骨囊肿前病变”[28-29]。另一方面，由于此时毗邻的关节软骨损伤并未累及全层，即关节滑液尚无法进入软骨下骨中，因而不支持“滑液入侵假说”，加之已有观点认为软骨下骨髓病变是由外力引起的软骨下骨不全骨折或微骨折所致，并可进展为骨性关节炎，所以上述研究更倾向于“创伤性骨坏死”假说[28，30]。然而Chan等[31]认为，尽管以上2种假说能部分解释负重区域软骨下骨囊肿的成因，却并不能解释分布于非负重区域的软骨下骨囊肿，缘其研究结果：在非承重部位如胫骨髁间棘或外侧间室亦可出现软骨下骨囊肿，此时其被覆的软骨并无肉眼可见的损伤。由此产生第3种假说：非负重区域软骨下骨囊肿可能与血管老化和内皮细胞功能障碍导致缺血性事件进而继发骨量减少有关(即“缺血性骨量减少假说”)。然而这一假说较少见，尚无临床研究支持或反对。 2017年Weber等[29]总结既往的研究，认为软骨下骨囊肿在骨性关节炎中可能的演变机制为：异常的机械载荷作用于软骨并传导至软骨下骨引起软骨下骨微骨折，随后募集免疫细胞(单核、多核细胞)，激活骨生长因子，启动软骨下骨异常重建，该期间形成软骨下骨髓病变，其中未吸收者形成软骨下骨囊肿，至终末期软骨下骨硬化。整个进程中，关节软骨损伤逐渐加重，见图2。"

2.4 软骨下骨囊肿病理表现肉眼观为灰色凝胶状区域，通常多发，大小从1.0-2.5 cm不等，超过1 cm的囊肿只在股骨头可见，体积分数与年龄和性别无明显关系，通常为圆形、梨形、卵形、不规则形，可单房或多房。髋关节骨性关节炎患者的软骨下骨囊肿发生的部位通常位于髋臼或股骨头，通过斜而曲折的通道与关节腔相通，有些较大的囊肿可以延伸至股骨颈，关节面的碎骨片可经该通道进入囊肿[25]。髋臼处软骨下骨囊肿总是发生于髂前下棘以及髋臼软骨和髋臼唇的交界处(即承重最大的部位)。囊肿可以长时间保持稳定或者短时间内急速增大，患者可以无症状或表现出经典的骨性关节炎症状。当囊肿壁硬化和周围硬化骨发生骨折或囊肿腔塌陷时，往往会加剧骨性关节炎的症状。囊肿内包含寡细胞的纤维组织并在囊肿周围形成硬化骨，内含物在血液供应消失后发生黏液变性，形成影像学上透亮的区域[32]。软骨下骨囊肿的区域不仅可见活化的破骨细胞，亦可见活化的成骨细胞[33]。软骨下骨囊肿的空洞形成、扩大与破骨细胞造成的骨吸收相关，亦有文献将其称为软骨下骨吸收陷窝[34-36]。Sabokbar等[37]对大鼠骨肉瘤细胞(UMR106)和软骨下骨囊肿来源的巨噬细胞的联合培养14 d后，发现其表达抗酒石酸酸性磷酸酶、玻连蛋白受体，并形成许多骨吸收腔隙，表明巨噬细胞分化成破骨细胞。该结果提示巨噬细胞向破骨细胞的分化参与了骨性关节炎患者软骨下骨囊肿的增大。动物实验表明，在软骨下骨囊肿中，炎症因子前列腺素E2明显升高[38]，而已有研究证明高水平前列腺素E2与骨吸收相关[39]，因此可能前列腺素E2通过促进骨吸收参与软骨下骨囊肿的进程。综上所述，软骨下骨囊肿的病理生理机制可能是包括炎症因子在内的各种因素引起的骨吸收及继发的反应性成骨[40-41]，该病理过程可能较骨赘及软骨下骨髓病变更为典型地反映骨性关节炎软骨下骨的异常重建。 2.5 软骨下骨囊肿的影像学评估常规X射线片对发现软骨下骨囊肿的价值有限，Audrey等[42]纳入806例保守治疗无效的症状性膝关节骨性关节炎患者，回顾性分析发现，相比骨性关节炎的其他影像学征象(关节腔狭窄99.5%，骨赘形成98.1%，软骨下骨硬化接近90%)，软骨下骨囊肿的X射线表现只见于30.6%的患者，作者认为软骨下骨囊肿不是骨性关节炎的主要影像学特征。但其他研究表明，使用负重45°屈膝后前位膝关节摄片比普通负重前后位膝关节摄片诊断膝关节骨性关节炎更准确[43]；而此方位摄片+负重前后位膝关节摄片比单用负重前后位膝关节摄片明显提高膝骨性关节炎的软骨下骨囊肿的检出率[44]。 CT和MRI对发现软骨下骨囊肿更有帮助。现在已有研究报道在骨性关节炎早期(Kellgren-Lawrence分级≤2)的患者中，通过CT可发现软骨下骨囊肿[19]。而站立位负重CT比双足外旋10°站立固定20°-30°屈曲后前位膝关节X射线片发现软骨下骨囊肿更优，灵敏度100% vs. 10%[45]。Javaid等[46]开展的研究纳入158例X射线片无骨性关节炎征象的骨性关节炎高危患者，MRI示27%的患者在基线即存在软骨下骨囊肿。Guermazi等[47]开展的骨性关节炎研究纳入X射线片上Kellgren-Lawrence分级0级的710例患者，MRI示25%的患者存在软骨下骨囊肿。但CT和MRI的价格均比X射线片昂贵，且摄片时间更长，或许是目前临床仍主要以X射线片为骨性关节炎诊断及分级标准的原因[48]。基于Chen等[12]研究证实，软骨下骨囊肿区域骨矿物密度显著低于无软骨下骨囊肿组。Burnett等[49]曾认为经定量CT或双能X射线骨矿物密度检测软骨下松质骨低骨矿物密度可能提示软骨下骨囊肿的存在，但其在2019年的定量计算机断层扫描研究中得出了截然相反的结果：软骨下骨囊肿的大小和数量与软骨下骨矿物密度正相关[50]。因而以骨矿物密度评估软骨下骨囊肿的方法仍有待探索。 2.6 软骨下骨囊肿的治疗软骨下骨囊肿的治疗包括软骨下骨囊肿的治疗和软骨下骨囊肿前病变(即软骨下骨髓病变)的治疗。 2.6.1 软骨下骨囊肿的治疗软骨下骨囊肿的治疗指征尚无定论，Lee等[51]认为出现进展的、影响关节面结构的软骨下骨囊肿需要治疗，治疗早期的伴有大的、多发软骨下骨囊肿的骨性关节炎可延缓疾病进展。动物研究表明，降钙素可显著减少软骨下骨囊肿的数量/体积，作者归因于其抑制软骨下骨异常重建从而改善了软骨下骨小梁微结构[52]。Pelletier等[53]以前交叉韧带切除建立犬膝关节骨性关节炎模型，并予以非类固醇抗炎药治疗8周，结果表明，对照组(无治疗)骨性关节炎犬的软骨下骨空腔增多，而实验组骨性关节炎犬的软骨下骨形态类似于健康犬。而2018年基于雌性骨性关节炎大鼠的动物研究表明，使用环氧化酶2抑制剂缓释剂型单次关节腔内注射后16周，软骨下骨囊肿显著改善，但与健康组相比差异仍有显著性意义，作者认为该疗效的机制是环氧化酶2抑制剂抑制“炎症相关通路(如核因子κB)所致的破骨细胞活化及继发的骨吸收”[54]。 Lee等[51]在2015年对2例伴软骨下骨囊肿的早期髋关节骨性关节炎患者行同种异体骨植入术，术后植骨长入良好，关节功能恢复良好。而Ohishi等[55]在2016年对于晚期右膝骨性关节炎伴巨大软骨下骨囊肿的患者行限制性假体全膝关节置换+软骨下骨囊肿打压植骨则同样取得了积极效果。 Jacobs[56]早在1963年便提出位于股骨的软骨下骨囊肿可以用远端截骨术以重组关节表面和重新分散过高的力学载荷，以达到减轻疼痛，减少囊肿的大小与数量和改善关节功能的作用。但Mechlenburg等[57]对26例髋关节发育不良继发骨性关节炎患者行髋关节周围截骨术后的10年随访中，发现软骨下骨囊肿的平均直径无显著变化，造成试验结果阴性的可能原因是样本量过小，失访率较高。 Iijima等[58]对12周龄大鼠以内侧半月板脱稳定术建立膝骨性关节炎模型，后进行共4周，5次/周，30 min/次，12 m/min的慢走干预，经显微CT证实，尽管未达到显著性差异(P=0.06)，慢走已表现出抑制软骨下骨囊肿进展的趋势，提示术后慢走可能对软骨下骨囊肿产生积极效果。 Bertrand[59]对13例症状性软骨下骨囊肿患者行CT和透视引导下的磷酸钙骨水泥填充术(即软骨下骨成形术)，平均随访22个月后，12例患者疼痛显著改善，所有患者无早期与晚期并发症。与传统的植骨术式相比，骨水泥填充术效果显著，侵入性小，或许可以作为有症状软骨下骨囊肿患者的手术方式首选。 2.6.2 软骨下骨髓病变的治疗曾有观点认为大多数的软骨下骨髓病变会自行吸收，呈一过性，因此可不干预，但Carrino等[27]的研究发现未经治疗的软骨下骨髓病变(有/无症状)患者，其中57%会发生进展，但究竟何种软骨下骨髓病变患者需要干预，作者并未阐明。近年的研究表明，发生在膝关节的伴有疼痛症状的软骨下骨髓病变(持续30 d-1年)难以自行吸收，因而可能需要干预[60]。 2004年一项纳入818例绝经后症状性膝骨性关节炎妇女的临床研究表明，在使用双膦酸盐平均1.8(<1-4)年后，膝关节软骨下骨髓病变程度经MRI检测好转(已校正混杂因素)[61]。2010年Jones等[62]通过切除大鼠膝关节内侧副韧带、前交叉韧带、内侧半月板建立创伤性骨性关节炎模型，术后使用非类固醇抗炎药+双膦酸盐8周比未治疗组的软骨下骨髓病变区域的T2信号降低，且与假手术组差异无显著性意义，表明其具有改善软骨下骨髓病变的效果。2011年一项多中心、随机双盲对照临床试验纳入69例骨性关节炎患者，分别予以硫酸软骨素800 mg 1次/d(35例)和安慰剂(34例)，随访12个月时，胫骨外侧平台和股骨外侧髁的软骨下骨髓病变评分显著降低[63]。 2016年Cohen等[64]通过对66例有软骨下骨髓病变的骨性关节炎患者实行软骨下骨成形术后进行回顾性研究发现，87.8%的患者目测类比疼痛评分降低。术后随访2年患者的目测类比疼痛评分平均降低了4.5分(以2分为最小有意义变化值)。同时有60例患者接受了至少2年随访，其中42例(70%)患者未进一步行关节置换术，余30%患者延长关节置换时间平均3.1年。综上所述，软骨下骨成形术对于骨性关节炎的软骨下骨髓病变的短中期疗效确切。软骨下骨成形术在保留关节的前提下减轻了疼痛，改善了关节功能，适合年纪较轻，运动需求较高且不希望接受关节置换术的患者。 2018年Brimmo等[65]学者通过犬骨性关节炎模型证实，软骨下骨成形术后一两年关节疼痛、肿胀以及关节功能改善均优于对照组，且安全性良好。但无论是人体试验抑或动物实验，在软骨下骨成形术术后早期阶段，仍可出现轻到中度的疼痛及较对照组功能障碍加重的现象，Brimmo等[65-66]猜测这可能与填充物过度注入及填充物渗出有关。尽管如此，目前软骨下骨成形术仍是一种新兴的治疗骨性关节炎软骨下骨髓病变的富有前景的手术疗法，其对于软骨下骨髓病变的结构性进展及预防软骨下骨囊肿的疗效仍需要后续试验证明。总结软骨下骨囊肿及软骨下骨髓病变的治疗见表1。"

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