EFFECT OF SUPPRESSED BONE TURNOVER ON SKELETAL FRAGILITY

骨转换受到抑制对骨骼脆弱性的影响

• 批准号: 6200960
• 负责人: David B Burr
• 金额: $ 24.16万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6200960
• 关键词: acid phosphatase; aging; alkaline phosphatase; biomarker; bone density; bone fracture; bone metabolism; calcification inhibitor; chemoprevention; diphosphonate; dogs; dosage; drug administration rate /duration; drug adverse effect; drug screening /evaluation; etidronate; histopathology; nonhuman therapy evaluation; normal ossification; osteocalcin; osteoporosis; pathologic bone resorption; physiologic bone resorption; radiography; skeletal pharmacology

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.

关于抑制的机械效应已经提出了问题 骨转换对骨强度的影响。这些讨论影响了FDA 关于骨质疏松症治疗药物指南的决定。 这项工作的目标是确定（a）是否有重大的 骨转换减少将增加骨脆性;（B）骨 可以在强度受损之前抑制重塑;以及（c） 抑制骨转换是否会通过允许 微损伤累积。两种不同的双膦酸盐（依替膦酸盐和 利塞膦酸盐）将用于抑制骨转换。犬（n= 12只/组） 将每天接受低剂量安慰剂治疗7或12个月 依替膦酸盐或大剂量依替膦酸盐。将对不同的组进行治疗， 低剂量或高剂量利塞膦酸盐治疗12个月， 转换而不抑制矿化。狗将被双重标记 在处死前使用荧光染料，并拍摄X光片 在7到12个月之间检测自发性骨折。生化 将从采集的血清中测量骨形成和再吸收的标志物 基线、3个月、6个月、9个月和12个月。主要结果将是力量 肋骨、股骨干、椎体和 从力学测试测量的脊椎棘突，和刚度 通过扫描声学显微镜测量。微损伤累积，静态 动态组织形态学参数和生化标志物， 次要结局指标。方差分析将是主要的 组间主要和次要指标平均值差异的统计学方法 次要结果变量。这个实验将检验一个假设， 长期抑制正常骨转换会降低骨强度， 强度的下降是由 骨基质微损伤。