辛伐他汀涂层内固定对大鼠骨质疏松骨折愈合晚期的影响

Effects of internal fixation with simvastatin coating on healing of rat osteoporotic fractures at late period

背景:降脂类药物辛伐他汀具有一定的促进骨形成作用潜能,局部应用效果更佳。先前研究对骨质疏松大鼠骨折愈合中期的观察证实辛伐他汀涂层内固定可促进骨质疏松大鼠骨折愈合,但其对骨折愈合晚期的影响未见报道。目的:观察局部应用辛伐他汀涂层内固定对骨质疏松大鼠骨折愈合晚期进程的影响。方法:将雌性SD大鼠分为单纯骨折组、骨质疏松性骨折组及辛伐他汀干预组。单纯骨折组仅暴露腹腔卵巢不予切除,其余2组采用双侧卵巢切除法建立骨质疏松模型。卵巢切除后6周,所有大鼠建立股骨中段开放性骨折模型,单纯骨折组、骨质疏松性骨折组及辛伐他汀干预组分别采用无涂层、聚乳酸涂层和辛伐他汀复合聚乳酸涂层克氏针内固定。骨折造模后12周分析骨折侧股骨骨密度,X射线摄片和苏木精-伊红染色分析骨折愈合情况,免疫组织化学分析骨形态发生蛋白2在骨折局部的表达。结果与结论:骨密度检测结果提示股骨全长及中段骨密度骨质疏松性骨折组、辛伐他汀干预组显著低于单纯骨折组,辛伐他汀干预组骨折部位骨密度显著高于骨质疏松性骨折组。X射线摄片结果提示,单纯骨折组骨折两端对位、对线良好,骨痂与骨皮质密度接近相同并相互连接,塑形基本完成;骨质疏松性骨折组愈合质量差,骨痂密度浅淡,部分标本仍见模糊的骨折线;辛伐他汀干预组骨折线消失,骨痂填满骨缺损,骨膜反应深,单纯骨折组、辛伐他汀干预组X射线评分显著高于骨质疏松性骨折组(P<0.05)。苏木精-伊红染色提示,骨质疏松性骨折组骨折愈合进程较单纯骨折组延迟,辛伐他汀干预组骨小梁较骨质疏松性骨折组更规则有序。免疫组化结果提示各组大鼠骨形态发生蛋白2的表达水平差异无显著性意义。提示辛伐他汀局部应用可有效促进骨质疏松大鼠骨折愈合。

BACKGROUND： As a lipid-lowering drug, simvastatin has been proved to be effective in promoting bone formation. Previous studies have demonstrated that locally applied simvastation accelerated fracture healing at middle phase in osteoporotic rats, while no study focuses on the influence of locally applied simvastatin on fracture healing at late period in an osteoporotic rat. OBJECTIVE： To investigate the effect of simvastatin locally applied from a bioactive polymer coating of implants on osteoporotic fracture healing at late period. METHODS： Female Sprague-Dawley rats were divided into sham group, osteoporotic fracture group and simvastatin group. In the sham group, the abdominal cavity was exposed without ovariectomy. Six weeks later,femur fracture models were established in normal or osteotoporotic Sprague-Dawley rats, and intramedullary stabilization was achieved with uncoated titanium Kirschner wires in normal rats （sham group）,with polylactic acid coated titanium Kirschner wires （osteoporotic fracture group） and with simvastatin/polylactic acid coated titanium Kirschner wires （simvastatin group）. Femurs were harvested after 12 weeks, bone mineral density was determined with dual X-ray absorptiometry, and then radiographic and histological analysis was performed for analysis of fractUre healing. Immunohistochemica# evaluation was employed for bone morphogenetic protein 2 expression. RESULTS AND CONCLUSION： The bone mineral densities of both the total fractured femur and fractured site 12 weeks after fracture in the osteoporotic fracture group and simvastatirl group were markedly decreased compared to normal fractured rats. The bone mineral density of the fractured site was significantly higher in the simvastatin group than the osteoporotic fracture group. Radiographic results demonstrated completely finished callus remodeling in the sham group; poor healing, pale callus density and blurred fracture line were seen in the osteoporotic fracture group; disappearance of fracture line, bone defects filled with callus, and deep periosteal reaction were found in the simvastatin group. X-ray scores in the sham and simvastatin groups were significantly higher than that in the osteoporotic group （P 〈 0.05）. Hematoxylin-eosin staining showed a delayed healing process in the osteoporotic group, and revealed a significantly processed callus with regular-shaped newly formed bone trabeculae in the simvastatin group. Immunohistochemical evaluation showed no significant difference in the bone morphogenetic protein 2 expression between any two groups. These findings suggest an improved fracture healing under local application of simvastatin in osteoporotic rats.