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。这两种不同的改善骨强度的途径表明，联合治疗可以显着降低骨折风险超过ALN或RAL单药治疗。本提案的目的是通过结合ALN和RAL对BMD（来自ALN）和材料特性（来自RAL）的积极作用，确定ALN和RAL的组合是否会对骨结构力学特性产生比单独使用任何一种药物更大的积极作用。该项目的第二个目标是确定当与RAL联合给药时，是否可以使用较低剂量的ALN，以达到至少与较高剂量的ALN单独给药相同的BMD和骨强度。通过降低ALN剂量来证明增强骨强度的功效可以通过减少口服BP治疗伴随的负面副作用来提高安全性。第三个目标是确定与RAL的联合治疗作为与非双膦酸盐抗再吸收剂如地舒单抗（FDA批准的最新抗重塑剂）的联合治疗是否有效。人抗体Denosumab不能给予动物，但在临床前研究中显示了其他抑制RANK-L途径的机制，如使用骨保护素融合化合物（OPG-Fc），以模拟Denosumab的骨骼效应。具体而言，本项目中的实验将检验以下假设：1）ALN和RAL在当前临床剂量下的组合将比每种药物单独使用更能改善骨的机械性质，2）与RAL的临床剂量组合使用的较低剂量的ALN将对骨强度产生至少与当前治疗剂量的ALN单药治疗相当的作用，和3）OPG-Fc和RAL的联合使用将比单独使用每种药物更能改善骨骼的机械性能。我们将使用传统的结果测量（离体骨密度，组织学，力学）以及一种新的体内评估工具（BioDent）来测试这些假设，以纵向跟踪动物骨材料特性的变化。本提案中生成的数据将具有高度可转换性，因为我们的分析将建立体内评估的力学性能变化与仅能在切除骨上进行的更传统测量之间的关系。此外，由于这些研究中的所有药物都已被FDA批准用于治疗骨质疏松症，因此联合治疗可以迅速转化为临床。

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. These two distinct pathways for improving bone strength suggest that combination treatment could significantly reduce fracture risk more than either ALN or RAL monotherapy. The goal of this proposal is to determine if the combination of ALN and RAL will have a greater positive effect on bone structural mechanical properties compared to either agent alone by combining their positive effects on BMD (from ALN) and material properties (from RAL). A second goal of this project is to determine if a lower dose of ALN can be used when given in combination with RAL, to achieve at least equivalent BMD and bone strength as ALN alone at higher doses. Demonstrating efficacy for enhancing bone strength with a reduced dose of ALN could improve safety by reducing negative side effects that accompany treatment with oral BPs. The third goal is to determine if combination treatment with RAL is effective as a combination therapy with non-bisphosphonate anti- resorptives such as Denosumab, the newest FDA-approved anti-remodeling agent. The human antibody denosumab cannot be given to animals, yet other mechanisms of inhibiting the RANK-L pathway such as by using osteoprotogerin fusion compound (OPG-Fc) have been shown in pre-clinical studies to mimic the skeletal effects of denosumab. Specifically, the experiments in this project will test the hypotheses that 1) the combination of ALN and RAL at current clinical doses will improve bone's mechanical properties more than each drug alone, 2) lower doses of ALN used in combination with the clinical dose of RAL will produce at least equivalent effects on bone strength as mono-therapy with ALN at the current therapeutic dose, and 3) The combination of a OPG-Fc and RAL will improve bone's mechanical properties more than each drug alone. We will test these hypotheses using both traditional outcome measures (ex vivo bone density, histology, mechanics) as well as a novel in vivo assessment tool (BioDent) to longitudinally track changes in bone material properties in animals. The data generated in this proposal will be highly translatable as our analyses will establish the relationship between changes in mechanical properties assessed in vivo to more traditional measures that can only be only made on excised bone. Additionally, as all drugs in these studies are already FDA approved for treatment of osteoporosis, combination treatment could be rapidly translated to the clinic.