PTH(1-34) Treatment Increases Bisphosphonate Turnover in Fracture Repair in Rats
PTH(1-34) Treatment Increases Bisphosphonate Turnover in Fracture Repair in Rats
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DOI：
10.1002/jbmr.2424
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发表时间：
2015-06-01
影响因子：
6.2
通讯作者：
Little, David G.
中科院分区：
文献类型：
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作者：
Murphy, Ciara M.;Schindeler, Aaron;Little, David G.
双膦酸盐（BP）是一种对骨具有高亲和力的抗骨吸收药物。尽管在治疗骨质疏松症和代谢性骨疾病方面取得了成功，但长期使用 BP 与微损伤和非典型股骨骨折 (AFF) 的修复减少有关。后者预后较差，尽管特立帕肽 (PTH(1-34)) 等合成代谢干预措施已被建议作为治疗选择，但支持其疗效的证据基础有限。由于 PTH(1-34) 具有增加骨转换的作用，因此我们假设它可能能够增加骨骼中转换的血压，从而可能改善骨愈合。为了测试这一点，我们使用了荧光 Alexa647 标记的帕米膦酸 (Pam) 和放射性标记的 C-14-ZA（唑来膦酸）的混合物。这些可追踪的 BP 被注射到 Wistar 大鼠的正常生长和闭合骨折修复模型中。大鼠用生理盐水或25g/kg/d PTH(1-34)联合治疗，并通过X射线、显微CT、放射自显影和荧光共聚焦显微镜检查对血压释放和骨愈合的影响。与 PTH(1-34) 增加的血压再动员一致，与对照组相比，治疗动物的长骨和骨折愈伤组织中的荧光显着降低。这通过 C-14-ZA 放射自显影进一步证实。在这种急性BP治疗模型中，骨折肢体中的愈伤组织骨体积（BV）显着增加，尽管我们注意到PTH（1-34）使愈伤组织结合的BP显着降低，但这些不足以改变这种BV。然而，在再吸收破骨细胞中注意到细胞内血压增加，这证实了原则上 PTH(1-34) 增加了骨转换以及血压转换。 (c) 2015 年美国骨与矿物质研究学会。
Bisphosphonates (BP) are antiresorptive drugs with a high affinity for bone. Despite the therapeutic success in treating osteoporosis and metabolic bone diseases, chronic BP usage has been associated with reduced repair of microdamage and atypical femoral fracture (AFF). The latter has a poor prognosis, and although anabolic interventions such as teriparatide (PTH(1-34)) have been suggested as treatment options, there is a limited evidence base in support of their efficacy. Because PTH(1-34) acts to increase bone turnover, we hypothesized that it may be able to increase BP in turnover in the skeleton, which, in turn, may improve bone healing. To test this, we employed a mixture of fluorescent Alexa647-labelled pamidronate (Pam) and radiolabeled C-14-ZA (zoledronic acid). These traceable BPs were dosed to Wistar rats in models of normal growth and closed fracture repair. Rats were cotreated with saline or 25g/kg/d PTH(1-34), and the effects on BP liberation and bone healing were examined by X-ray, micro-CT, autoradiography, and fluorescent confocal microscopy. Consistent with increased BP remobilization with PTH(1-34), there was a significant decrease in fluorescence in both the long bones and in the fracture callus in treated animals compared with controls. This was further confirmed by autoradiography for C-14-ZA. In this model of acute BP treatment, callus bone volume (BV) was significantly increased in fractured limbs, and although we noted significant decreases in callus-bound BP with PTH(1-34), these were not sufficient to alter this BV. However, increased intracellular BP was noted in resorbing osteoclasts, confirming that, in principle, PTH(1-34) increases bone turnover as well as BP turnover. (c) 2015 American Society for Bone and Mineral Research.