Long Term Effects of Bisphosphonate Therapy on Bone

描述(申请人提供)：建议的研究涉及双膦酸类药物治疗绝经后骨质疏松症和其他骨质疏松症。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内替换的骨量低于移除的骨量。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，印第安纳大学的David Burr教授的研究表明，用双膦酸类药物治疗1年会干扰损伤的去除，以至于微损伤累积，骨折抗力开始下降。这项工作目前正在伯尔教授的实验室里进行一系列为期3年的实验。我们自己的实验室有专注于骨骼结构、抗疲劳性和重塑之间关系的研究历史。这项工作中包括了对这些关系的计算机模拟，以及最近的双膦酸效应。这些模型预测了在1年的犬类研究中看到的损害积累，但他们也预测，如果正如当前数据所表明的那样，药物导致正的BMU水平的骨平衡，损害积累随后将被逆转。因此，我们假设，虽然对双膦酸盐治疗的最初反应主要是由于重塑减少和微损伤增加，但由于BMU水平正的骨平衡引起的后续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验证这一假设：1.调整我们的计算模型，以适应狗骨骼的小梁和皮质区域的重塑，并使用1-3年阿仑膦酸盐研究的数据来确定微损伤累积是否随着治疗的进展而放缓。2.分析对照组和阿伦磷酸钠处理组犬骨骼中BMU重塑对微损伤清除的影响，以确定骨性“导向”是否能促进损伤清除。

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.