强直性脊柱炎异位骨化机制研究进展

强直性脊柱炎是一种发病机制不明的慢性炎性脊柱关节病,主要侵犯骶髂关节、脊柱关节等,严重者可发生脊柱、关节的畸形和强直。临床表现为炎性腰背痛,夜间及休息后加重,活动后减轻。该病发病率男性高于女性,且男性主要表现为中轴关节改变,而女性大多首发于外周关节。目前生物制剂肿瘤坏死因子抑制剂通过控制炎症,从而改善病情发展,被认为是最前沿的药物,但其在阻断新骨形成方面尚未经循证医学证实有效。本文着眼于新骨形成角度,从基因及细胞因子层面探讨强直性脊柱炎的病因。目前相关研究发现LRP5、ANTXR2、PTGER4、ANKH等基因的异常表达激活骨形成信号通路,在多种细胞因子及相关蛋白(如Noggin蛋白、DKK、转化生长因子-β、骨形态发生蛋白、碳酸酐酶1等)直接或间接作用下将骨形成信号传至靶细胞表面,进而传入细胞核,改变靶细胞正常生理代谢过程,导致过度骨形成,造成异位骨化。近年的临床影像学病例分析也提示了骨赘形成的分布特点,进而推断机械应力是促进其形成的外部因素。本文对强直性脊柱炎异位骨化方面进行了文献综述,以期待能进一步加深对本病的认识,为临床治疗研究提供新的思路。     

异位骨化发病机制的研究进展

目的总结异位骨化(heterotopic ossification,HO)发病机制的研究进展。方法查阅近年有关HO危险因素及发病机制的文献,并综合分析。结果 HO发病机制尚未明确,但对HO相关的细胞外因子、信号通路、转录因子等有了更深入了解,如BMP、Smad信号通路、核心结合因子α1/成骨特异性转录因子2等可能参与了HO的形成,而一些相关的微小RNA也有可能参与HO形成。结论通过对HO发病机制进一步研究,为有效防治HO奠定基础。     

异位骨化预防与治疗的研究进展

异位骨化是指在非骨骼组织(包括肌肉,肌腱或其他软组织)中出现病理性骨组织形成。其发病机制尚不完全清楚,主要是由骨骼肌肉创伤、骨关节术后或者神经系统损伤所导致,临床表现以关节肿胀、疼痛、活动障碍为主,多发生于髋、膝和肘关节周围。目前对异位骨化预防主要包括药物、放疗、分子生物学机制干预和中医药相关手段。其中药物及放疗是预防异位骨化较为肯定有效的方法。而通过分子生物学机制干预预防异位骨化成为近年来新的研究方向和关注热点,且基本处于实验研究阶段。而关于异位骨化的治疗主要包括药物、物理治疗及手术等多种方法,其中手术是被公认的最有效的治疗手段,但关于手术时间和术式的选择尚存在一定争议和分歧。     

Carpal tunnel syndrome due to heterotopic ossification

We report a rare case of carpal tunnel syndrome due to heterotopic ossification in the carpal tunnel in a 34-year-old woman without antecedents of neurological injury, musculoskeletal trauma, or metabolic disorder. To our knowledge, this is the first reported case. Incomplete excision of heterotopic ossification resulted in partial relief of symptoms.     

自发性髋关节周围异位骨化1例

患者,男,46岁,发现右髋关节活动受限1周左右入院。入院前曾有在2年间因脑出血2次开颅手术病史,神志不清,偶有癫痫发作。第2次开颅术后曾有约2个月卧床经历。1周前家属发现患者右髋关节活动受限,而就诊于我院。查：右髋关节强直于30°位屈曲畸形,内收、外展等均为0°,双下肢肌肉萎缩,因2次开颅手术,患者查体合作欠佳,故肌力感觉不能很好检查。X线：右髋关节周围及右股骨中上段前外侧软组织可见不均匀密度增高影,边缘清晰（图1）。CT：右侧髋关节周围可见不规则骨性密度影,边界清,无明显骨质破坏（图2）。     

The use of eidronate disodium in the prevention of heterotopic ossification in burn patients

Heterotopic ossification (HO) is a well-known complication of moderate and severe burn injuries. The development and progression of HO in burn patients are poorly understood phenomena at this time. Numerous measures aimed at preventing or minimizing HO have been described, but no definitive prophylactic modality has been found. Biphosphonate compounds are known to inhibit calcification, but previous studies are equivocal regarding their effectiveness in preventing HO in burn patients. We retrospectively reviewed the effect of etidronate disodium (EDHP), a bisphosphonate, on the development of HO in severely burned patients. We found that not only was EDHP ineffective in preventing HO, the group of patients treated with EDHP demonstrated an increased incidence of HO over that seen in a comparison group. This was true after controlling for age, sex, and %TBSA burned. Based on the results of this study, the routine use of etidronate disodium to prevent HO in burn patients cannot be recommended.     

Rofecoxib inhibits heterotopic ossification after total hip arthroplasty

INTRODUCTION: Nonsteroidal anti-inflammatory drugs (NSAIDs) prevent heterotopic ossification but gastrointestinal complaints are frequently. Selective cyclooxygenase-2 (COX-2) inhibiting NSAID produce less gastrointestinal side effects. PATIENTS AND METHODS: A prospective two-stage study design for phase 2 clinical trials with 42 patients was used to determine if rofecoxib (a COX-2 inhibitor) 50 mg oral for 7 days prevents heterotopic ossification. A cemented primary THA was inserted for osteoarthroses. After 6 months heterotopic bone formation was assessed on AP radiographs using the Brooker classification. RESULTS: No heterotopic ossification was found in 81% of the patients, 19% of the patients had Brooker grade 1 ossification. CONCLUSION: Using a two-stage study design for phase 2 clinical trials, a 7-day treatment of a COX-2 inhibitor (rofecoxib) prevents effectively the formation of heterotopic ossification after cemented primary total hip arthroplasty.     

全膝关节置换术后严重异位骨化与关节僵硬

[目的]探讨全膝关节置换术后严重异位骨化与关节僵硬的关系。[方法]对420例接受全膝关节置换术的患者随访,其中9例出现了Ⅲ级异位骨化,分别测量并记录该9例患者术后2周、12个月的疼痛评分和膝关节活动度,拍摄X线片,测量异位骨的大小。随机抽取9例无异位骨化的关节置换术后患者作为对照组,并测量疼痛评分及活动度。分别将异位骨化组和对照组的结果进行对比。[结果]关节置换术后Ⅲ级异位骨化的发病率为2.1%,X线片显示异位骨>5 cm,侵及股四头肌,引起关节疼痛。异位骨化组术后2周疼痛评分平均25.6分,关节最大伸直角度平均1.1°,最大屈曲角度119.1°,与对照组比较差异均无统计学意义(P>0.05)。异位骨化组术后12个月疼痛评分平均15.56分,低于术后2周(P<0.01),与对照组术后12个月(25分)比较有显著差异(P<0.01)。关节活动度:伸直6.1°,屈曲91.7°与术后2周和对照组术后12个月比较均有显著差异(P<0.01)。[结论]全膝关节置换术后Ⅲ级异位骨化可以导致关节疼痛和活动度受限,是术后关节僵硬的原因之一,严重影响置换术后临床效果。     

Appropriate excision time of heterotopic ossification in elbow caused by trauma

Objective

The aim of this study was to investigate the optimal timing for the resection of heterotopic ossification (HO) of the elbow.

Effects of indomethacin on demineralized bone-induced heterotopic ossification in the rat

Indomethacin inhibits bone formation when treatment is initiated before the implantation of demineralized bone matrix (DBM). For the inhibition of bone induction to occur, indomethacin treatment had to be initiated 6 h or more before implantation of DBM. Initiating the drug treatment at or after the time of DBM implantation had no effects on the amounts of new bone formed. The inhibition by indomethacin is dose related over a range between 0.04 and 4 mg/kg body weight. Recovered day-1 DBM implants, transplanted into indomethacin pre- and posttreated syngeneic rats, formed bone at the same rate as controls did. However, recovered day-1 DBM implants lyophilized before transplantation showed decreased bone formation but significant dystrophic calcification as judged by a lower alkaline phosphatase activity and an elevated calcium content.     

Management of pelvic heterotopic ossification post-myocutaneous flap reconstruction of a sacral pressure ulcer

Heterotopic ossification (HO) is a process whereby lamellar bone forms in the soft tissues surrounding a joint. The most common type of HO is traumatic myositis ossificans, which develops following traumatic injuries, burns or arthroplasty. A variety of other forms of HO also exist, such as those associated with central nervous system injury and systemic forms that can manifest at other joints simultaneously. Clinically, patients can present with decreased range of motion, pressure ulcers, nerve compression, swelling, pain or asymptomatically. Symptomatic patients are most commonly treated with surgical debridement of the affected heterotopic deposits.Spinal dysraphism (SD) is a term describing a wide range of congenital malformations of the neural tube, ranging from spina bifida occulta to the more severe form, myelomeningocele. The cause of SD is multifactorial and has been associated with chromosomal disorders, teratogenic exposure and folate deficiency. Many patients with SD experience neuropathy below the affected neurological level, making them particularly susceptible to pressure ulcers. If these ulcers are severe and do not respond to conservative therapy, they often require surgical debridement and flap reconstruction – a clinical scenario that rarely results in HO.The present article describes a case involving a patient with pelvic HO following myocutaneous flap reconstruction of a pressure ulcer. The patient was successfully treated with oral bisphosphonate and aggressive physiotherapy.     

Risk factors for heterotopic ossification in total hip arthroplasty

This study prospectively evaluated 928 patients with 1318 primary total hip replacements for heterotopic ossification (HO). The mean clinical and radiological follow-up was 2.5 years (range 1.5–3.6 years). HO was noted in 44.6% of all total hips replaced. It was graded as mild (Brooker 1) in 29.2%, moderate (Brooker 2) in 10.5%, and severe (Brooker 3 and 4) in 4.2%. The following factors showed a significantly increased risk of HO: hypertrophic osteoarthritis, HO after contralateral total hip replacement, trochanteric osteotomy, lateral or anterolateral approach, previous hip surgery, subtrochanteric femoral osteotomy, and male gender (p < 0.05 in chi-square analysis of independence and multivariable analysis). Patients with rheumatoid arthritis showed less HO. A combination of any of these factors resulted in a significant increase in the risk of developing HO. Received: 7 November 2000     

Immunohistochemical characterization of the small proteoglycans decorin and proteoglycan-100 in heterotopic ossification

Heterotopic ossification is a metabolically active process which shares several properties of orthotopic bone formation and, therefore, represents an excellent model for studying bone matrix components. Immunohistochemical methods were used to investigate the distribution pattern of the small proteoglycans decorin and proteoglycan-100 during different stages of heterotopic ossification of pressure sores of paraplegic patients. Decorin and proteoglycan-100 exhibited a substantially divergent distribution pattern. Decorin was detectable in the perivascular matrix of granulation tissue as well as in the stroma of heterotopic ossification. The ossification zone was stained most strongly. In contrast, proteoglycan-100 was predominantly detectable in fibroblasts and preosteoblasts in early areas of osteogenesis. In more mature forms of heterotopic ossification immunostaining was markedly reduced in osteoblasts and osteocytes and even absent in so-called bone-lining cells. However, at least some osteoclasts were strongly positive.These results suggest indicate that decorin and proteoglycan-100 are important components during the formal pathogenesis of heterotopic ossification. The expression of the small proteoglycans, especially of proteoglycan-100, correlates with different phases during heterotopic ossification, showing a maximum for proteoglycan-100 in matrix-forming cells in early phases of bone formation, but in osteoclasts in mature bone.     

Gluteus minimus necrotic muscle debridement diminishes heterotopic ossification after acetabular fracture fixation

OBJECTIVE: The aetiology and pathogenesis of heterotopic ossification (HO) are still obscure. We evaluated the impact of necrotic gluteus minimus muscle (GMM) debridement on the formation of HO after operative treatment of posterior wall (PW) and associated transverse-posterior wall acetabular fracture (Tr/PW) fixations utilizing a Kocher-Langenbeck surgical exposure. METHODS: Thirty-one consecutive patients with displaced PW or associated Tr/PW acetabular fracture-dislocations were operatively treated by a single surgeon using a Kocher-Langenbeck surgical exposure. Strict soft tissue technique was observed and self-retaining retractors were not used. Necrotic GMM was debrided in an attempt to diminish ectopic bone formation. RESULTS: Twenty-nine patients were available for post-operative clinical and radiographic evaluations. HO occurred in 12 patients. Significant HO (Brooker class III or IV) was noted in only three patients (10%). There were no complications associated with debridement of necrotic GMM. CONCLUSIONS: Necrotic GMM resection diminishes HO formation comparably to other reported series in which non-steroidal anti-inflammatory medications were used. Resection of the necrotic GMM from the zone of injury has proved to be an efficient and safe method of preventing significant HO in patients after operative fixation of PW and associated Tr/PW acetabular fractures treated through a Kocher-Langenbeck approach.     

脊髓损伤后髋关节周围异位骨化的危险因素分析

目的：探讨脊髓损伤后髋关节周围发生异位骨化的危险因素。方法：将1023例外伤性脊髓损伤患者根据X线检查和CT检查分为异位骨化组（A组，121例）和无异位骨化组（B组）。比较两组患者的年龄、性别、脊髓损伤情况、脊髓损伤到瘫痪肢体开始功能训练的时间、血清钙浓度、痉挛及压疮发生情况，分析与异位骨化相关的危险因素。结果：异位骨化发生率为11．8％。A组与B组患者的年龄、性别、脊髓损伤至瘫痪肢体开始功能训练的时间、血清钙浓度及压疮发生率经统计学比较无显著性差异（P〉0．05）。A组患者中完全性瘫痪者及痉挛性瘫痪者比例较高，与B组比较差异非常显著（P〈0．01）。A组患者脊髓损伤主要位于颈段及中胸段，与B组比较有非常显著性差异（P〈0．01）。A组患者脊髓损伤主要为ASIA A级和B级，与B组比较有非常显著性差异（P〈0．01）。痉挛性瘫痪改良Ashworth Ⅱ级以上者异位骨化发生率较高，统计学比较差异非常显著（P〈0．01）。结论：完全性脊髓损伤及痉挛性瘫痪是脊髓损伤后异位骨化发生的主要危险因素。脊髓损伤神经功能分级为ASIA A级和B级者、颈段或中胸段脊髓损伤者及痉挛性瘫痪改良Ashworth Ⅱ级以上者易发生异位骨化。     

Prevalence of heterotopic ossification after cervical total disc arthroplasty: a meta-analysis

Background  

Heterotopic ossification (HO) is a well-known complication after total hip and knee arthroplasty. But limited studies have focused on prevalence of HO following cervical total disc arthroplasty (CTDA) and the published data show controversial results.     

注射性臀部异位骨化症4例报告

目的:探讨注射性臀肌骨化症的发病机制与治疗。方法:自2006年4月至2011年5月采用手术方法治了疗4例注射性臀部异位骨化症患者,均为老年女性,年龄67～76岁,平均71岁;均为双侧患病,表现为双侧臀部疼痛,可用手触及结节状物,质硬;X线、CT、病理检查均符合异位骨化症表现。其中2例采用全部切除骨化组织加局部挛缩粘连软组织松解,另2例采用部分切除加局部软组织松解。结果:术后所有患者伤口愈合良好,无并发症发生。所有患者均获随访,时间2～64个月,平均26个月。患者切除部位可触及肿块及疼痛均消失。结论:注射性臀部异位骨化症是注射苯甲醇等药物后发生在成年人的药物性反应,部分或全部切除痛性肿块、松解局部臀肌筋膜等软组织是治疗该病的关键。     

Association between alendronate,serum alkaline phosphatase level,and heterotopic ossification in individuals with spinal cord injury

Context/objective

Only sparse evidence exists regarding the effectiveness of oral alendronate (ALN) in the prevention of heterotopic ossification (HO) in patients with spinal cord injury (SCI). The objective of this study is to investigate the protective effect of oral ALN intake on the appearance of HO in patients with SCI.

Study design

Retrospective database review.

Setting

A Spinal Cord Unit at a Rehabilitation Hospital.

Participants

Two hundred and ninety-nine patients with SCI during acute inpatient rehabilitation.

Interventions

Administration of oral ALN.

Outcome measures

The incidence of HO during rehabilitation was compared between patients with SCI receiving oral ALN (n = 125) and patients with SCI not receiving oral ALN (n = 174). The association between HO and/or ALN intake with HO risk factors and biochemical markers of bone metabolism were also explored.

Results

HO developed in 19 male patients (6.35%), however there was no significant difference in the incidence of HO in patients receiving oral ALN or not. The mean odds ratio of not developing versus developing HO given ALN exposure was 0.8. Significant correlation was found between abnormal serum alkaline phosphatase (ALP) levels and HO appearance (P < 0.001) as well as normal serum ALP and ALN intake (P < 0.05).

Conclusion

Even though there was no direct prevention of HO in patients with SCI by oral ALN intake, abnormal serum ALP was found more frequently in patients with HO development and without oral ALN intake. This evidence could suggest that ALN may play a role in preventing HO, especially in patients with acute SCI with increasing levels of serum ALP.