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: 7046953
• 负责人: R. BRUCE MARTIN
• 金额: $ 19.58万
• 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/7046953
• 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糖尿病。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内替换的骨量低于去除的骨量。双膦酸盐通过减少BMU激活和每个BMU去除的骨量来帮助纠正这个问题，而不会改变骨替代量。然而，印第安纳州大学的大卫伯尔教授的研究表明，用双膦酸盐治疗1年会干扰损伤的清除，达到微损伤累积和抗骨折能力开始下降的程度。这项工作目前正在伯尔教授的实验室进行一系列为期3年的实验。我们自己的实验室有着专注于骨结构、抗疲劳性和重塑之间关系的研究历史。包括在这项工作中，这些关系的计算机模拟，最近，bisphosphonate的影响。这些模型预测了在1年犬研究中观察到的损伤累积，但它们也预测，如果如当前数据所示，药物导致正BMU水平骨平衡，则随后将逆转损伤累积。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，包括微损伤增加，但随后由正BMU水平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2个具体目标来测试这一假设：1。调整我们的计算模型，以适应双膦酸盐治疗犬骨骼的骨小梁和皮质区域的重塑，并使用1-3年阿仑膦酸钠研究的数据，以确定微损伤积累是否随着治疗的进展而减缓。2.通过对照组和阿仑膦酸钠治疗组犬的骨中BMU重塑分析微损伤清除，以确定骨“转向”损伤是否增强损伤清除。