Long Term Effects of Bisphosphonate Therapy on Bone

双膦酸盐治疗对骨骼的长期影响

• 批准号: 6918183
• 负责人: R. BRUCE MARTIN
• 金额: $ 23.22万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-05 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6918183
• 关键词: alendronate; animal data; computational biology; computer simulation; diphosphonate; dogs; drug adverse effect; longitudinal human study; metabolism disorder chemotherapy; osteoporosis; physiologic bone resorption; postmenopause; skeletal disorder chemotherapy; skeletal pharmacology

DESCRIPTION (provided by applicant): The proposed research concerns bisphosphonate treatment of postmenopausal and other osteoporoses. In osteoporotic individuals, bones become fragile because Basic Multicellular Unit (BMU) remodeling is increased and the amount of bone replaced within each BMU falls short of that removed. Bisphosphonates help correct this problem by reducing BMU activation and the amount of bone removed by each BMU, without altering the amount of bone replaced. However, studies by Prof. David Burr at Indiana University have shown that treatment with bisphosphonates for 1 year interferes with damage removal to the point that microdamage accumulates and fracture resistance begins to decline. This work is currently being pursued by a set of 3 year experiments in Prof. Burr's laboratory. Our own laboratory has a history of research focused on the relationships between bone structure, fatigue resistance, and remodeling. Included in this work have been computer simulations of these relationships and, recently, bisphosphonate effects. These models predict the damage accumulation seen in the 1 year canine studies, but they also predict that damage accumulation will subsequently be reversed if, as current data suggest, the drug results in a positive BMU-level bone balance. Thus, we hypothesize that while initial responses to bisphosphonate treatment are primarily due to reduced remodeling and include increased microdamage, subsequent skeletal responses arising from a positive BMU-level bone balance will erase the excess microdamage burden. We propose to test this hypothesis by pursuing 2 specific aims: 1. Adapt our computational models for remodeling in response to bisphosphonate treatment to trabecular and cortical regions of the canine skeleton and use data from a 1-3 year alendronate study to determine whether microdamage accumulation slows as treatment progresses. 2. Analyze microdamage removal by BMU remodeling in bone from control and alendronate treated dogs to determine if damage removal is enhanced by osteonal "steering" toward damage.

描述（由申请人提供）：拟议的研究涉及双膦酸盐治疗绝经后和其他骨质疏松症。在骨质疏松症患者中，骨骼变得脆弱，因为基本多细胞单位（BMU）重塑增加，每个BMU内替换的骨骼数量少于移除的骨骼数量。双膦酸盐通过减少BMU的激活和每个BMU移除的骨量来帮助纠正这个问题，而不改变替换的骨量。然而，印第安纳大学David Burr教授的研究表明，使用双膦酸盐治疗1年会干扰损伤清除，直至微损伤累积，抗骨折能力开始下降。这项工作目前正在伯尔教授的实验室进行一组为期3年的实验。我们自己的实验室一直致力于研究骨骼结构、抗疲劳性和重塑之间的关系。这项工作包括对这些关系的计算机模拟，以及最近对双膦酸盐效应的模拟。这些模型预测了1年犬类研究中观察到的损伤积累，但它们也预测，如果像目前的数据显示的那样，药物导致bmu水平的骨平衡呈阳性，那么损伤积累随后将被逆转。因此，我们假设，虽然对双膦酸盐治疗的初始反应主要是由于重塑减少和微损伤增加，但随后由bmu水平阳性骨平衡引起的骨骼反应将消除多余的微损伤负担。我们建议通过追求两个具体目标来检验这一假设：1。将我们的计算模型应用于双膦酸盐治疗后犬骨骼小梁和皮质区域的重塑，并使用来自1-3年阿仑膦酸盐研究的数据来确定微损伤的积累是否会随着治疗的进展而减缓。2. 通过分析对照组和阿仑膦酸钠治疗犬的骨中BMU重塑对微损伤的去除，以确定骨“转向”损伤是否会增强损伤的去除。