Boyce R W, Paddock C L, Gleason J R, Sletsema W K, Eriksen E F
Procter & Gamble Pharmaceuticals, Norwich, New York, USA.
J Bone Miner Res. 1995 Feb;10(2):211-21. doi: 10.1002/jbmr.5650100207.
To investigate the dose-dependent effects of risedronate on cancellous bone remodeling, adult female beagle dogs were treated with either placebo, 0.1, 0.5, or 2.5 mg/kg/day of risedronate orally in an intermittent cyclic regimen (7 days on 21 days off), repeated three times. Iliac cancellous bone samples were subjected to histomorphometric analysis and three-dimensional (3-D) kinetic reconstruction of the remodeling site was performed. In the 0.1 mg/kg dose group, resorption and activation indices were no different from the placebo group. However, wall thickness was increased resulting in a positive bone balance at the level of the remodeling unit. In the 0.5 and 2.5 mg/kg dose groups, a dose-dependent reduction in activation frequency and tissue level bone formation was observed. Resorption rates were also significantly decreased, 60% and 80% for the 0.5- and 2.5-mg/kg groups, respectively. An approximate 25% reduction in final erosion depth was noted in both these groups. Analyses of the growth curves of the bone packet confirmed that the kinetics of the growth of a completed packet were different in the 0.5- and 2.5-mg/kg dose groups compared with placebo. These changes were associated with a significant increase in the final wall thickness in both groups indicating no net impairment of osteoblast function. These increases in wall thickness in combination with the reductions in final erosion depth in the 0.5 and 2.5 mg/kg groups resulted in a significant dose-dependent positive bone balance. This pharmacological profile suggests that risedronate may be of therapeutic utility in the treatment of metabolic bone diseases where reductions in activation frequency and resorptive cell activity at the level of the remodeling unit are a therapeutic goal.
为研究利塞膦酸盐对松质骨重塑的剂量依赖性效应，成年雌性比格犬采用间歇循环给药方案（服药7天，停药21天），分别口服安慰剂、0.1、0.5或2.5mg/kg/天的利塞膦酸盐，重复3次。取髂骨松质骨样本进行组织形态计量学分析，并对重塑部位进行三维（3-D）动力学重建。在0.1mg/kg剂量组，吸收和激活指数与安慰剂组无差异。然而，壁厚度增加，导致重塑单位水平的骨平衡为正。在0.5和2.5mg/kg剂量组，观察到激活频率和组织水平骨形成呈剂量依赖性降低。吸收速率也显著降低，0.5mg/kg和2.5mg/kg组分别降低60%和80%。这两组的最终侵蚀深度均降低了约25%。对骨包生长曲线的分析证实，与安慰剂相比，0.5mg/kg和2.5mg/kg剂量组完成骨包生长的动力学不同。这些变化与两组最终壁厚度的显著增加相关，表明成骨细胞功能无净损害。0.5和2.5mg/kg组壁厚度的增加与最终侵蚀深度的降低相结合，导致显著的剂量依赖性正骨平衡。这种药理学特征表明，利塞膦酸盐在治疗代谢性骨病方面可能具有治疗作用，在这些疾病中，降低重塑单位水平的激活频率和吸收细胞活性是治疗目标。
