EFFECT OF SUPPRESSED BONE TURNOVER ON SKELETAL FRAGILITY

人们对压制的机械效应提出了质疑 骨骼的周转率取决于骨骼强度。这些讨论影响了FDA 关于治疗骨质疏松症药物指南的决定。 这项工作的目标是确定(A)是否存在显著的 骨骼周转减少会增加骨骼的脆弱性；。(B)多少骨骼 可以在强度受损之前抑制重塑；以及，(C) 抑制骨转换是否会降低骨强度 微小的损伤累积起来。两种不同的双膦酸盐(依替磷酸二钠和乙二磷酸 利塞膦酸盐)将被用来抑制骨转换。狗(n=L2/组) 将在7或12个月内每天服用低剂量的安慰剂 依替膦酸盐，或高剂量的依屈膦酸盐。不同的群体将接受治疗 服用低剂量或高剂量利塞膦酸酯12个月，这会抑制骨骼 在不抑制矿化的情况下周转。狗将被贴上双重标签 在献祭前使用荧光染料，并将拍摄X光片 在7到12个月之间检测自发性骨折。生化 骨形成和骨吸收的标记物将从采集的血清中测量 在基线、3、6、9和12个月时。主要结果将是力量 肋骨、股骨干、椎体和 从力学测试中测量的椎体棘突和硬度 通过扫描声学显微镜测量。微损伤累积，静态 以及动态组织形态计量学参数和生化标记物 次要结果衡量标准。方差分析将是主要的 小学生与小学生平均成绩组间差异的统计方法 次要结果变量。这项实验将检验这一假设 长期抑制正常的骨转换会降低骨骼强度， 强度的降低是由于堆积的 骨基质中的微损伤。

Questions have been raised regarding the mechanical effects of suppressing bone turnover on bone strength. These discussions have influenced FDA decisions about guidelines for drugs for the treatment of osteoporosis. The goals of this work are to determine (a) whether a significant reduction in bone turnover will increase bone fragility; (b)how much bone remodeling can be suppressed before strength is compromised; and, (c) whether suppression of bone turnover will reduce bone strength by allowing microdamage to accumulate. Two different bisphosphonates (etidronate and risedronate) will be used to suppress bone turnover. Dogs (n= l2/group) will be treated daily for 7 or 12 months with placebo, low-dose etidronate, or high-dose etidronate. Separate groups will be treated for 12 months with low- or high-dose risedronate, which suppresses bone turnover without inhibiting mineralization. Dogs will be double labeled with fluorochromes prior to sacrifice, and radiographs will be taken between 7 and 12 months to detect spontaneous fractures. Biochemical markers of bone formation and resorption will be measured from serum taken at baseline, 3, 6, 9, and 12 months. The primary outcomes will be strength and elastic modulus of ribs, femoral diaphysis, vertebral bodies and vertebral spinous processes measured from mechanical tests, and stiffness measured by scanning acoustic microscopy. Microdamage accumulation, static and dynamic histomorphometric parameters, and biochemical markers will be secondary outcome measures. Analysis of variance will be the primary statistical method for between-group differences in means of primary and secondary outcome variables. This experiment will test the hypothesis that prolonged suppression of normal bone turnover reduces bone strength, and that the reduction in strength is caused by the accumulation of microdamage in bone matrix.