Enhancing bone strength using combination drug therapy

描述（由申请人提供）：用于治疗骨质疏松症的药物通过不同的机制显著降低骨折风险，最终增强结构或材料的生物力学性能。双膦酸盐如阿仑膦酸盐（ALN）几乎完全通过促进骨体积和密度的增加来增加骨结构强度，但以损害材料性能为代价。雷洛昔芬（Raloxifene， RAL）对骨量的影响最小，但能显著改善材料性能，从而提高整体骨强度。本BIRT修订的目的是验证RAL药物治疗增强骨骼水化的假设，这些变化与增强的生物力学性能相关。已知骨骼水合作用对骨骼力学性能有影响，我们实验室产生的初步数据显示，ral处理增强了骨骼结合水。利用纵向体内超短回波时间（UTE）磁共振成像（MRI）扫描，我们旨在确定ALN， RAL及其组合如何影响骨骼水化（结合水和自由水）。为了实现这一目标，我们与医学物理/成像专家建立了新的合作关系，他们有使用UTE-MRI的经验。具体而言，本BIRT的实验将验证以下假设：1)与其他治疗组相比，RAL单一治疗或RAL和ALN联合治疗会增加UTE-MRI测量的骨总水化和结合水分数；2)UTE-MRI测量的总水化和结合水分数增加会增加骨折所需的能量，并与骨韧性的改善呈正相关。在这个项目中产生的数据将提供药物如何调节体内骨骼水合作用的第一个证据，以及这与骨骼的生物力学特性之间的关系。由于UTE-MRI可以用于人类，这些数据有可能为骨折风险评估的非侵入性方法开辟一个新的重点领域。

DESCRIPTION (provided by applicant): Pharmaceutical agents used to treat osteoporosis significantly reduce fracture risk via different mechanisms that ultimately enhance either structural or material biomechanical properties. Bisphosphonates such as Alendronate (ALN) increase structural bone strength almost entirely by promoting increased bone volume and density, but at the expense of impaired material properties. Raloxifene (RAL) minimally affects bone mass yet significantly improves material properties leading to an enhancement in overall bone strength. The goal of this BIRT revision is to test the hypothesis that pharmacological treatment with RAL enhances skeletal hydration and these changes correlate with enhanced biomechanical properties. Skeletal hydration has known effects on bone mechanical properties and preliminary data generated in our laboratory show enhanced skeletal bound water with RAL-treatment. Using longitudinal in vivo ultrashort echo time (UTE) magnetic resonance imaging (MRI) scans we aim to determine how ALN, RAL, and their combination affect skeletal hydration (bound and free water). To achieve this goal we have established a new collaboration with experts in medical physics/imaging who have experience with UTE-MRI. Specifically, the experiments in this BIRT will test the hypotheses that 1) Monotherapy with RAL, or combination treatment with RAL and ALN, will increase the total hydration and the bound water fraction in bone as measured by UTE-MRI compared to other treatment groups and 2) Increased total hydration and bound water fraction as measured by UTE-MRI will increase the energy required to fracture the bone, and will be positively correlated to improvements in bone toughness. The data generated in this project will provide the first evidence of how pharmacological agents modulate skeletal hydration in vivo and how this relates to the biomechanical properties of the bone. As UTE-MRI can be utilized in humans, these data have the potential to launch a new focus area for non- invasive methods of fracture risk assessment.