Murnaghan Mark, Li Gang, Marsh David R
SpR in Department of Trauma and Orthopaedic Surgery, Queen's University Belfast, Musgrave Park Hospital, 20 Stockman's Lane, Belfast BT9 7JB, Northern Ireland, United Kingdom.
J Bone Joint Surg Am. 2006 Nov;88 Suppl 3:140-7. doi: 10.2106/JBJS.F.00454.
Approximately 5% to 10% of fractures may result in delayed union or nonunion. The results of research done over the past three decades have shown that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) has an inhibitory effect on fracture repair, but the exact mechanism of action remains to be elucidated. Cancer research has identified that NSAIDs impede cell proliferation by inhibiting angiogenesis. It is proposed that a similar mechanism occurs in the induction of NSAID-induced nonunions. This hypothesis was investigated in a randomized placebo-controlled trial of the NSAID rofecoxib with use of a murine femoral fracture model.
Two hundred and forty mice were randomized to receive either the nonsteroidal anti-inflammatory drug rofecoxib (5 mg/kg orally) in a 0.5% methylcellulose solution (the NSAID group) or the 0.5% methylcellulose solution only (the control group). Two hundred and thirty-five of the 240 mice underwent surgery to induce an open transverse middiaphyseal femoral fracture, which was then treated with use of a custom-made external fixator. Five additional animals underwent sham surgery with no fracture induced. Outcomes measures included radiographic assessment, histologic analysis, biomechanical testing, and use of laser Doppler flowmetry to assess blood flow across the fracture gap.
Radiography revealed similar healing patterns in both groups; however, at the later stages (day 32), the NSAID group had poorer healing. Histological analysis demonstrated that the control animals healed quicker (at days 24 and 32) and had more callus and less fibrous tissue (at days 8 and 32) than the NSAID animals did. Biomechanical testing found that the control animals were stronger at day 32. Both groups exhibited a similar pattern of blood flow; however, the NSAID group exhibited a lower median flow from day 4 onward (significant at days 4, 16, and 24). Positive correlations were demonstrated between both histological and radiographic assessments of healing and increasing blood flow. NSAID-treated animals exhibited lower blood flow and poorer healing by all parameters. Regression analysis, however, demonstrated that the negative effect of NSAIDs on fracture repair is independent of its inhibitory action on blood flow.
Following the development of a novel method of analyzing functional vascularity across a fracture gap, we have demonstrated that the cyclooxygenase-2 (COX-2) inhibitor rofecoxib has a significant negative effect on blood flow across the fracture gap as well as an inhibiting effect on fracture repair.
COX-2 inhibitors are marketed as having low side-effect profiles. We propose that these drugs should be used with caution in all patients following osseous trauma and, in particular, after injuries that may already predispose a fracture to a delayed union due to osseous, vascular, or patient-related factors.
约5%至10%的骨折可能导致延迟愈合或不愈合。过去三十年的研究结果表明，使用非甾体抗炎药（NSAIDs）对骨折修复有抑制作用，但其确切作用机制仍有待阐明。癌症研究已证实，NSAIDs通过抑制血管生成来阻碍细胞增殖。有人提出，在NSAIDs诱导的不愈合过程中可能发生类似机制。本研究采用小鼠股骨骨折模型，通过随机安慰剂对照试验对NSAIDs罗非昔布进行了这一假说的研究。
240只小鼠随机分为两组，一组接受溶于0.5%甲基纤维素溶液中的非甾体抗炎药罗非昔布（5mg/kg口服）（NSAIDs组），另一组仅接受0.5%甲基纤维素溶液（对照组）。240只小鼠中有235只接受手术以造成开放性股骨干中段横行骨折，随后使用定制的外固定器进行治疗。另外5只动物接受假手术，未造成骨折。观察指标包括影像学评估、组织学分析、生物力学测试以及使用激光多普勒血流仪评估骨折间隙的血流情况。
影像学检查显示两组愈合模式相似；然而，在后期（第32天），NSAIDs组愈合较差。组织学分析表明，与NSAIDs组动物相比，对照组动物愈合更快（在第24天和第32天），骨痂更多，纤维组织更少（在第8天和第32天）。生物力学测试发现，对照组动物在第32天时更强壮。两组血流模式相似；然而，NSAIDs组从第4天起血流中位数较低（在第4天、第16天和第24天差异显著）。愈合的组织学和影像学评估与血流增加之间呈正相关。NSAIDs治疗的动物在所有参数上均表现出较低的血流和较差的愈合。然而，回归分析表明，NSAIDs对骨折修复的负面影响与其对血流的抑制作用无关。
在开发出一种分析骨折间隙功能血管的新方法后，我们证明环氧合酶-2（COX-2）抑制剂罗非昔布对骨折间隙的血流有显著负面影响，同时对骨折修复有抑制作用。
COX-2抑制剂在市场上宣传其副作用较小。我们建议，在所有骨创伤患者中，尤其是在因骨、血管或患者相关因素可能已使骨折易发生延迟愈合的损伤后，应谨慎使用这些药物。
