Orthopaedic Research & Biotechnology Unit, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW, 2145, Australia.
Discipline of Child and Adolescent Health, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
Calcif Tissue Int. 2020 Feb;106(2):172-179. doi: 10.1007/s00223-019-00615-z. Epub 2019 Oct 1.
Clinical concerns have been raised over prior exposure to bisphosphonates impairing fracture healing. To model this, groups of male Wistar rats were assigned to saline control or treatment groups receiving 0.15 mg/kg (low dose), 0.5 mg/kg (medium dose), and 5 mg/kg (high dose) Pamidronate (PAM) twice weekly for 4 weeks. At this point, closed fractures were made using an Einhorn apparatus, and bisphosphonate dosing was continued until the experimental endpoint. Specimens were analyzed at 2 and 6 weeks (N = 8 per group per time point). Twice weekly PAM dosing was found to have no effect on early soft callus remodeling at 2 weeks post fracture. At this time point, the highest dose PAM group gave significant increases in bone volume (+ 10%, p < 0.05), bone mineral content (+ 30%, p < 0.01), and bone mineral density (+ 10%, p < 0.01). This PAM dosing regimen showed more substantive effects on hard callus at 6 weeks post fracture, with PAM treatment groups showing + 46-79% increased bone volume. Dynamic bone labeling showed reduced calcein signal in the PAM-treated calluses (38-63%, p < 0.01) and reduced MAR (32-49%, p < 0.01), suggesting a compensatory reduction in bone anabolism. These data support the concept that bisphosphonates lead to profound decreases in bone turnover in fracture repair, however, this does not affect soft callus remodeling.
临床关注已经提出了先前暴露于双膦酸盐会损害骨折愈合。为了模拟这种情况，将雄性 Wistar 大鼠分组为生理盐水对照组或治疗组，每周两次接受 0.15mg/kg（低剂量）、0.5mg/kg（中剂量）和 5mg/kg（高剂量）帕米膦酸盐（PAM）治疗 4 周。此时，使用 Einhorn 仪器制造闭合性骨折，并继续给予双膦酸盐治疗，直到实验终点。在 2 周和 6 周时（每组每个时间点 8 个样本）分析标本。每周两次的 PAM 给药在骨折后 2 周时对早期软骨痂重塑没有影响。此时，最高剂量 PAM 组的骨体积增加了显著（+10%，p<0.05）、骨矿物质含量增加了（+30%，p<0.01）和骨矿物质密度增加了（+10%，p<0.01）。这种 PAM 给药方案在骨折后 6 周时对硬骨痂有更实质性的影响，PAM 治疗组的骨体积增加了 46-79%。动态骨标记显示 PAM 处理的骨痂中的钙黄绿素信号减少（38-63%，p<0.01）和 MAR 减少（32-49%，p<0.01），提示骨合成代谢的代偿性减少。这些数据支持双膦酸盐在骨折修复中导致骨转换率显著降低的概念，然而，这不会影响软骨痂重塑。
