胫骨中下段骨折不愈合原因的研究进展

常文利 张英泽 陈伟

. 综述 Review .

胫骨中下段骨折不愈合原因的研究进展

常文利 张英泽 陈伟

胫骨骨折；骨折，不愈合；延迟愈合；综述

成人胫骨干骨折占全部成人胫腓骨骨折的 24.75%[1]。临床中胫骨干骨折不愈合的发生率为 5%，开放性胫骨骨折延迟愈合的发生率为 6.80%，其中胫骨中段 1 / 3 延迟愈合的发生率高达 92.40%，给临床治疗带来很多困难[2-7]。明确胫骨中下段的解剖及临床特质有助于全面认识胫骨中下段骨折，对其发生率、危险因素、相应的治疗措施的认识有助于对骨折进行评估并判断预后，以指导临床。通过检索现有文献，将胫骨延迟愈合或不愈合的原因和相关治疗措施综述如下。

一、胫骨中下段骨折特有的损伤机制

随着经济、交通运输业、建筑业的蓬勃发展，高能致伤的胫骨骨折发生率也日渐增长。胫腓骨作为人体重要的负重骨，其遭受直接暴力打击、压轧的机会也相对较多，再加上胫骨前内侧紧邻皮下，软组织覆盖少，因此开放性骨折较多见，且常为大创面污染伤口，软组织锉灭，骨折粉碎严重。间接暴力如高处坠落、旋转、滑倒等所致的骨折，骨折线多呈斜形或螺旋形[6-7]，虽然组织损伤较轻，但骨折多移位且尖端极易穿破皮肤形成开放伤。

二、不愈合的解剖学基础

血供差是骨折延迟愈合和不愈合的主要原因[8-10]。胫骨干的血供由滋养动脉系统、骨膜血管系统和骨骺干骺端血管系统组成[11]。其中任一血管损伤，骨折延迟愈合和不愈合率可达 3 倍以上[12]。胫骨滋养动脉作为三大血管之一，其主要源自胫后动脉，通过胫后肌群的近端，于比目鱼肌线下胫骨中段 1 / 3 后外侧面的滋养孔进入骨皮质[11,13]。发生在滋养孔周围的胫骨干骨折易导致滋养动脉损伤，骨质的血供大为减少，从而影响骨折的愈合。此外，软组织覆盖不足也会引起不愈合[14]。小腿肌肉中仅趾长伸肌、胫骨后肌、趾长屈肌、拇长屈肌部分起自胫骨远端 1 / 2，无一直接止于胫骨中下 1 / 3 的肌肉。胫骨下段多只由肌腱及皮肤所包裹，一旦发生骨折直接破坏其骨膜结构，血液供应不足加之贫瘠的血管床，直接导致胫骨中下段骨折延迟愈合或不愈合。

三、相关危险因素

患者的年龄、吸烟史、既往病史、合并用药及手术等危险因素都会影响骨折的愈合。与年龄相关的信号分子和间充质细胞功能的变化可能会延缓骨折愈合[15]。研究表明，尼古丁通过下调纤维母细胞生长因子、血管内皮生长因子和骨形态形成蛋白影响骨折早期的血管重建，从而不利于骨折愈合[16]。Hernigou 等[17]对 1999 年 1 月至 2010年 12 月收治的股骨干、胫骨干、肱骨干骨折的患者进行多变量分析发现，无论是闭合性还是开放性骨折，吸烟与不愈合均有密切关系并且由单一变量分析得出烟草是骨折愈合的危险因素。

内分泌代谢性疾病也是阻碍骨形成的重要因素，如糖尿病、甲状腺疾病、甲状旁腺病、佝偻病、骨软化症、维生素 D 缺乏、雌激素缺乏、库欣病、佩吉特病和吸收不良综合征等。维生素 D 利于肠钙吸收，在维持钙稳态和骨骼的完整性方面发挥核心作用，因此，维生素 D 缺乏在难以解释的胫骨骨折不愈合患者中很普遍，特别是在维生素 D 极其缺乏的地区，这可能是导致不愈合的重要原因之一[18-20]。血管异常也同样会导致骨折不愈合。Dickson等[21]对 1981～1991 年旧金山医院的 114 例胫骨开放性骨折患者进行研究发现：患有动脉阻塞的胫骨开放性骨折的患者更容易发展为延迟愈合或不愈合。动脉不正常的患者骨折延迟愈合或不愈合的几率是动脉正常患者的 3 倍。

骨折愈合受到某些常见药物的影响，如糖皮质激素、钙通道阻滞剂、非选择性非甾体抗炎药、选择性 Cox-2 抑制剂等。非选择性非甾体抗炎药对骨折愈合过程有抑制作用。非选择性非甾体类抗炎药物可降低血钙以及羟基脯氨酸水平，同时还可抑制成骨细胞的形成作用，从而导致骨折不愈合率增加[22]。选择性 Cox-2 抑制可能对骨愈合的炎性反应产生损害。具体来说，选择性 Cox-2 抑制剂可以抑制骨髓间充质细胞向成骨细胞的分化，从而影响骨折愈合[23]。

手术方式的选择同样会影响胫骨骨折的愈合。髓内钉会直接或间接造成骨折不愈合或延迟愈合。扩髓会造成更多的骨内膜血管损伤和骨皮质坏死，从而出现骨折的不愈合。即使不扩髓，髓内钉也会因为锁定不稳而出现延迟愈合[24]。与髓内钉相比，应用开放复位内固定术后骨折的不愈合率显著增高[25]。Jensen 等[26]采用 Eggers 或 Lane 钢板内固定治疗胫骨干骨折，开放性胫骨骨折常规钢板固定的不愈合率为 8%，闭合性胫骨骨折常规钢板固定的不愈合率高达 24%。当然，清创术时间、软组织的处理、皮肤暴露时间也同样会影响骨折愈合[14]。

四、手术治疗方案对比

基于对胫骨骨折不愈合原因的探讨，现将几种常见的手术治疗方式作如下对比，以供参考。微创钢板接骨术( minimally invasive plate osteosynthesis，MIPO )、髓内钉和外固定架是骨科常用的固定技术。MIPO 对胫骨血运及周围软组织破坏较少、对位和愈合较好、感染率低，优于开放性接骨板固定术[27-28]。其中经皮 MIPO 手术时间短、血液损失少、不易感染、不愈合率低，但仍会导致骨折畸形愈合[29]。胫骨骨折不愈合还可通过髓内钉治疗，获得早期功能恢复[30]。Ohtsuka 等[31]应用抗生素浸泡过的丙烯酸水泥钉治疗胫骨开放骨折，结果表明该技术除控制感染外，其稳固作用还可促进骨折的愈合。近年来，随着髓内钉在长骨干骨折的广泛应用，髓内钉的治疗弊端也逐渐显现，同样会造成骨折不愈合或延迟愈合。扩髓会造成更多的骨内膜血管损伤和骨皮质坏死，从而出现骨折的不愈合。即使不扩髓，髓内钉也会因为锁定失败而出现延迟愈合[24]。早在 1991 年 Mohsen 等[32]就已采用单独外固定架治疗胫骨干骨折延迟愈合，患者无需住院即可获得成功治愈。Ilizarov 环外固定架[33]不仅可治疗胫骨骨折不愈合，还可治疗复杂性胫骨开放性骨折。单边外固定架在治疗下肢骨折不愈合方面，能同时纠正成角和长度，是一种有效的手术方式[34]。外固定技术可获得骨折端的稳定，但太坚强的外固定也同样会延迟愈合过程[35]。

无论何种治疗方法均应尽可能减少对胫骨骨膜、周围组织及骨折周围血管的破坏，加速骨痂形成，促进骨折愈合[36-37]。Kadas 等[38]通过应用单一疗法和联合疗法分别对352 例和 270 例患者进行对比研究得出，联合疗法在治疗胫骨开放性骨折过程中，显示出了更大的优势。联合疗法具有并发症少、愈合不良率低和截骨率低等特点。因此，临床医生在选择具体手术方式的时候，需综合考虑，以实现骨折的尽快愈合。比如，外固定结合部分开放复位内固定术不会出现局部软组织炎症，具有适应范围广、软组织并发症少、功能恢复好的特点[39]。

除上述主要的固定技术之外，还有一些技术也可治疗胫骨骨折不愈合。自体髂骨尤其适用于伴有骨缺损的感染性胫骨骨折不愈合，通过建立胫腓骨骨联合，达到骨折愈合的目的[40-41]。一些理疗技术可在骨折不愈合中扮演着重要角色，文献报道脉冲式电磁场作为一种非侵入性的治疗方法，在胫骨血液供应良好的条件下疗效确切，可利用脉冲式电磁场产生微弱的电流来促进骨折愈合[42-43]。

综上所述，胫骨中下段特殊的解剖特点和特有的损伤机制是影响胫骨骨折愈合的重要因素。除此之外，年龄、吸烟、既往病史、合并用药、骨折类型、手术方式等因素均可引起胫骨中下段骨折不愈合。上述各影响因素并非独立存在而是相互影响，最终导致骨折不愈合。对其发生率、危险因素、治疗措施的认识有助于全面认识胫骨骨折并判断预后，以指导临床。

[1] Zhang YZ. Tibial diaphyseal fracture (Segment 42). Clinical epidemiology of orthopaedic trauma[M]. 2nd edition. New York: Thieme. 2016: 257.

[2] Csongradi JJ, Maloney WJ. Ununited lower limb fractures[J]. West J Med, 1989, 150(6):675-680.

[3] 丁凌志, 夏宁晓. 加压交锁髓内钉固定加植骨治疗胫骨骨不连的临床研究[J]. 中国骨伤, 2012, 25(4):331-334.

[4] 张朝春, 张发惠, 张志宏, 等. 胫骨中下段后路手术的解剖学基础及临床应用[J]. 中国骨与关节损伤杂志, 2003, 18(9): 141-142.

[5] Rommens P, Schmit-Neuerburg KP. Ten years of experiences with the operative management of tibial shaft fractures[J]. J Trauma, 1987, 27(8):917-927.

[6] Marsh D. Concepts of fracture union, delayed union, and nonunion[J]. Clin Orthop Relat Res, 1998, (355 Suppl):S22-30.

[7] Heppenstall RB, Brighton CT, Esterhai JL Jr, et al. Prognostic factors in nonunion of the tibia: an evaluation of 185 cases treated with constant direct current[J]. J Trauma, 1984, 24(9): 790-795.

[8] Babhulkar S, Pande K, Babhulkar S. Nonunion of the diaphysis of long bones[J]. Clin Orthop Relat Res, 2005, (431):50-56.

[9] Matuszewski PE, Mehta S. Fracture consolidation in a tibial nonunion after revascularization: a case report[J]. J Orthop Trauma, 2011, 25(2):e15-20.

[10] Lu C, Xing Z, Yu YY, et al. Recombinant human bone morphogenetic protein-7 enhances fracture healing in an ischemic environment[J]. J Orthop Res, 2010, 28(5):687-696.

[11] 李汉云, 钟世镇. 胫骨血液供应的实验和解剖学研究[J]. 第一军医大学学报, 1986, 6(2):138-140.

[12] Dickson KF, Katzman S, Paiement G. The importance of the blood supply in the healing of tibial fractures[J]. Contemp Orthop, 1995, 30(6):489-493.

[13] 裴丽霞. 胫骨血供的临床解剖研究[J]. 现代预防医学, 2008, 35(9):1741-1744.

[14] Yokoyama K, Itoman M, Uchino M, et al. Immediate versus delayed intramedullary nailing for open fractures of the tibial shaft: A multivariate analysis of factors affecting deep infection and fracture healing[J]. Indian J Orthop, 2008, 42(4):410-419.

[15] Hobby B, Lee MA. Managing atrophic nonunion in the geriatric population: incidence, distribution, and causes[J]. Orthop Clin North Am, 2013, 44(2):251-256.

[16] Sloan A, Hussain I, Maqsood M, et al. The effects of smoking on fracture healing[J]. Surgeon, 2010, 8(2):111-116.

[17] Hernigou J, Schuind F. Smoking as a predictor of negative outcome in diaphyseal fracture healing[J]. Int Orthop, 2013, 37(5):883-887.

[18] Brinker MR, O’Connor DP, Monla YT, et al. Metabolic and endocrine abnormalities in patients with nonunions[J]. J Orthop Trauma, 2007, 21(8):557-570.

[19] Pourfeizi1 HH, Tabrizi1 A, Elmi1 A, et al. Prevalence of vitamin d deficiency and secondary hyperparathyroidism in nonunion of traumatic fractures[J]. Acta Med Iran, 2013, 51(10):705-710.

[20] Cashman KD. Calcium and vitamin D. Dietary supplements and health: novartis foundation symposium[M]. Wiley Online Library. 2007: 282:123-142.

[21] Dickson K, Katzman S, Delgado E, et al. Delayed Unions and Nonunions of Open Tibial Fractures. Correlation with arteriography results[J]. Clin Orthop Relat Res, 1994, (302): 189-193.

[22] Busti AJ, Hooper JS, Amaya CJ, et al. Effects of perioperative antiinflammatory and immunomodulating therapy on surgical wound healing[J]. Pharmacotherapy, 2005, 25(11):1566-1591.

[23] Zhang X, Schwarz EM, Young DA, et al. Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair[J]. J Clin Invest, 2002, 109(11):1405-1415.

[24] Oh CW, Bae SY, Jung DY, et al. Treatment of open tibial shaft fractures using tightly fitted interlocking nailing[J]. Int Orthop, 2006, 30(5):333-337.

[25] Avilucea FR, Sathiyakumar V, Greenberg SE, et al. Open distal tibial shaft fractures: a retrospective comparison of medial plate versus nail fixation[J]. Eur J Trauma Emerg Surg, 2016, 42(1):101-106.

[26] Jensen JS, Hansen FW, Johansen J. Tibial shaft fractures. A comparison of conservative treatment and internal fixation with conventional plates or AO compression plates[J]. Acta Orthop Scand, 1977, 48(2):204-212.

[27] Newman SD, Mauffrey CP, Krikler S. Distal metadiaphyseal tibial fractures[J]. Injury, 2011, 42(10):975-984.

[28] Borrelli J, Prickett W, Song E, et al. Extraosseous blood supply of the tibia and the effects of different plating techniques: A human cadaveric study[J]. J Orthop Trauma, 2002, 16(10): 691-695.

[29] Zhang QX, Gao FQ, Sun W, et al. Minimally invasive percutaneous plate osteosynthesis versus open reduction and internal fixation for distal tibial fractures in adults: a metaanalysis[J]. Zhongguo Gu Shang, 2015, 28(8):757-762.

[30] Alho A, Ekeland A, Stromsoe K, et al. Nonunion of tibial shaft fractures treated with locked intramedullary nailing without bone grafting[J]. J Trauma, 1993, 34(1):62-67.

[31] Ohtsuka H, Yokoyama K, Higashi K, et al. Use of antibioticimpregnated bone cement nail to treat septic nonunion after open tibial fracture[J]. J Orthop Trauma, 2002, 52(2):364-366.

[32] Mohsen AM, Foss MV. Day case treatment of delayed union of fracture of the shaft of the tibia with an external fixator[J]. Injury, 1991, 22(1):51-53.

[33] Hasankhani E, Payvandi MT, Birjandinejad A. The ilizarov ring external fixator in complex open fractures of the tibia[J]. Eur J Trauma Emerg Surg, 2006, 32(1):63-68.

[34] Harshwal RK, Sankhala SS, Jalan D. Management of nonunion of lower-extremity long bones using mono-lateral external fixator--report of 37 cases[J]. Injury, 2014, 45(3):560-567.

[35] 鲁迪, 巴克利, 莫兰. 复位、入路及固定技术. 骨折治疗的AO 原则. 2 版[M]. 上海: 上海科学技术出版社. 2010: 229.

[36] 姚国仕, 李冀, 张丽. 胫骨骨折的手术治疗进展[J]. 华北煤炭医学院学报, 2011, 13(2):185-187.

[37] Jack MC, Newman MI, Barnavon Y. Islanded posterior tibial artery perforator flap for lower limb reconstruction: review of lower leg anatomy[J]. Plast Reconstr Surg, 2011, 127(2): 1014-1015.

[38] Kadas I, Magyari Z, Vendegh Z, et al. Changing the treatment to reduce complication rate in open tibial fractures[J]. Int Orthop, 2009, 33(6):1725-1731.

[39] Li Y, Jiang X, Guo Q, et al. Treatment of distal tibial shaft fractures by three different surgical methods: a randomized, prospective study[J]. Int Orthop, 2014, 38(6):1261-1267.

[40] Borrelli J Jr, Leduc S, Gregush R, et al. Tricortical bone grafts for treatment of malaligned tibias and fibulas[J]. Clin Orthop Relat Res, 2009, 467(4):1056-1063.

[41] Gulan G, Jotanović Z, Jurdana, et al. Treatment of infected tibial nonunion with bone defect using central bone grafting technique[J]. Coll Antropol, 2012, 36(2):617-621.

[42] Assiotis A, Sachinis NP, Chalidis BE. Pulsed electromagnetic fields for the treatment of tibial delayed unions and nonunions. A prospective clinical study and review of the literature[J]. J Orthop Surg Res, 2012, 7:24.

[43] Ito H, Shirai Y. The efficacy of ununited tibial fracture treatment using pulsing electromagnetic fields[J]. J Nippon Med Sch, 2001, 68(2):149-153.

Research progress on the reasons of the middle and distal tibial fracture nonunion

CHANG Wen-li, ZHANG Ying-ze, CHEN Wei. Department of Orthopedic Surgery, the third Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050051, China

The incidence of tibial shaft fracture accounts for 24.75% in all adults with tibiofibular fracture. The delayed union rate of open tibial fracture was 6.80%, and that for the middle third tibial fracture 92.40%. Special anatomical features of the middle and distal tibial fracture and the injury mechanism are important factors, affecting the tibial fracture healing. The blood supply of the tibial shaft is composed of three vascular systems: nutrient artery system, periosteum vascular system, and metaphyseal vascular system. If any of these blood supplies was destroyed, the rate of tibial fracture delayed union and nonunion can reach more than 3 times. Soft tissue defect with arterial damage is a risky factor for delayed union. Besides, age, smoking, previous history of fracture, drug combination, fracture types, and operation approaches also can result in the middle and distal tibial fracture nonunion. Endocrine metabolic disease is also an important factor to hinder the bone formation, such as diabetes, thyroid disease, vitamin D deficiency, and lack of estrogen. Clinical doses of nonselective NSAIDs can reduce calcium levels and hydroxyproline levels, subsequently increase the rate of nonunion. Cox-2-selective inhibitors can inhibit mesenchymal cell differentiation into osteoblasts. All the above-mentioned factors eventually lead to tibial fracture nonunion. This article reviews causes of the tibial delayed union and nonunion and their related treatment measures with the aim to improve the outcomes of clinical treatment.

Tibial fracture; Fracture, ununited; Delayed union; Review

CHEN Wei, Email: surgeonchenwei@126.com

10.3969/j.issn.2095-252X.2017.09.015

R683.4

050051 石家庄，河北医科大学第三医院创伤急救中心

陈伟，Email: surgeonchenwei@126.com

2016-10-08 )

( 本文编辑：李慧文 王永刚 )