Iwata Ken, Li Jiliang, Follet Helene, Phipps Roger J, Burr David B
Indiana Uníversity School of Medicine, IN 46202, USA.
Indiana Uníversity School of Medicine, IN 46202, USA.
Bone. 2006 Nov;39(5):1053-1058. doi: 10.1016/j.bone.2006.05.006. Epub 2006 Jun 27.
Recent studies demonstrate that bisphosphonates suppress bone resorption by leading to apoptosis of the osteoclast and inhibiting the differentiation to mature osteoclasts. The influence of bisphosphonates on bone formation is unknown, although it has been hypothesized that bisphosphonates inhibit osteoblast apoptosis and stimulate osteoblast proliferation and differentiation in vitro, leading to increased bone formation. The purpose of this study was to investigate the effect of bisphosphonates on bone formation. We administered risedronate at 0.05, 0.5 or 5.0 microg/kg/day or alendronate at 0.1, 1.0 or 10 microg/kg/day subcutaneously for 17 days to 6-month-old female Sprague-Dawley rats. Control rats were given a daily subcutaneous injection of saline. Following sacrifice, the femoral and tibial mid-diaphyses were harvested and mineralizing surface (MS/BS), mineral apposition rate (MAR) and bone formation rate (BFR/BS) were measured on periosteal and endocortical surfaces. In the femur, periosteal MAR was significantly lower in all treatment groups (22-29% for risedronate, 26-36% for alendronate) than in control. In the tibia, periosteal MAR and BFR of all treatment groups were significantly lower (41-50% for risedronate, 43-52% for alendronate) than in the control group. Because the periosteal surfaces of these bones are only undergoing bone formation in modeling mode, our results show that bisphosphonates suppress bone formation independently of bone resorption. Because this effect is seen on periosteal MAR rather than on periosteal MS/BS, we hypothesize that bisphosphonates affect the activity of individual osteoblasts at the cell level. This may help to explain the reason that the anabolic effects of teriparatide are blunted when administered concurrently with or following a course of bisphosphonates in humans.
近期研究表明，双膦酸盐通过诱导破骨细胞凋亡并抑制其向成熟破骨细胞的分化来抑制骨吸收。尽管有假说认为双膦酸盐在体外可抑制成骨细胞凋亡并刺激成骨细胞增殖和分化，从而导致骨形成增加，但其对骨形成的影响尚不清楚。本研究的目的是探讨双膦酸盐对骨形成的作用。我们对6月龄雌性斯普拉格-道利大鼠皮下注射0.05、0.5或5.0微克/千克/天的利塞膦酸盐，或0.1、1.0或10微克/千克/天的阿仑膦酸盐，持续17天。对照大鼠每日皮下注射生理盐水。处死后，收集股骨和胫骨的中骨干，测量骨膜和骨内膜表面的矿化表面（MS/BS）、矿化沉积率（MAR）和骨形成率（BFR/BS）。在股骨中，所有治疗组的骨膜MAR均显著低于对照组（利塞膦酸盐组为22 - 29%，阿仑膦酸盐组为26 - 36%）。在胫骨中，所有治疗组的骨膜MAR和BFR均显著低于对照组（利塞膦酸盐组为41 - 50%，阿仑膦酸盐组为43 - 52%）。由于这些骨骼的骨膜表面仅以塑形模式进行骨形成，我们的结果表明双膦酸盐独立于骨吸收抑制骨形成。由于这种效应体现在骨膜MAR而非骨膜MS/BS上，我们推测双膦酸盐在细胞水平上影响单个成骨细胞的活性。这可能有助于解释在人类中，特立帕肽与双膦酸盐同时使用或在双膦酸盐疗程之后使用时，其合成代谢作用减弱的原因。
