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生物力学特性。双膦酸盐（如阿仑膦酸钠（ALN））几乎完全通过促进骨体积和密度增加来增加结构骨强度，但以损害材料性能为代价。雷洛昔芬（RAL）对骨量的影响最小，但可显著改善材料性能，从而增强整体骨强度。本次BIRT修订的目的是检验RAL药物治疗增强骨骼水合作用的假设，这些变化与增强的生物力学特性相关。已知骨骼水合作用对骨机械性能有影响，我们实验室生成的初步数据显示，RAL处理可增强骨骼结合水。使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合作用（结合水和游离水）。为了实现这一目标，我们与具有UTE-MRI经验的医学物理/成像专家建立了新的合作关系。具体地，该BIRT中的实验将检验以下假设：1）与其他治疗组相比，使用RAL的单药治疗或使用RAL和ALN的联合治疗将增加骨中的总水合作用和结合水分数，如通过UTE-MRI测量的，和2）增加的总水合作用和结合水分数，如通过UTE-MRI测量的，将增加骨折所需的能量，并且将与骨韧性的改善正相关。本项目中产生的数据将提供药理学试剂如何调节体内骨骼水合作用以及这与骨的生物力学性质如何相关的第一个证据。由于UTE-MRI可用于人类，因此这些数据有可能为骨折风险评估的非侵入性方法开辟新的重点领域。

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.