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，最终提高结构或材料的生物力学性能。双磷酸盐，如阿伦磷酸(ALN)，几乎完全通过促进骨体积和密度的增加来增加结构性骨强度，但以损害材料性能为代价。雷洛昔芬(Ral)对骨量影响最小，但显著改善材料特性，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，联合治疗比ALN或AL单独治疗更能显著降低骨折风险。这项建议的目的是通过结合它们对骨密度(来自ALN)和材料特性(来自RAL)的积极影响，来确定联合使用ALN和RAL是否会比单独使用任何一种制剂对骨结构力学性能产生更大的积极影响。该项目的第二个目标是确定是否可以使用较低剂量的ALN与Ral联合使用，以获得至少与较高剂量的ALN单独使用相同的骨密度和骨强度。证明了减少ALN剂量增强骨强度的有效性，可以通过减少口服BPS治疗的负面副作用来提高安全性。第三个目标是确定与RAL的联合治疗是否与非双膦酸抗吸收药(如FDA批准的最新抗重塑药物Denosumab)联合治疗有效。人类抗体Denosumab不能用于动物，但在临床前研究中已显示出其他抑制RANK-L途径的机制，如使用骨原激元融合化合物(OPG-FC)来模拟Denosumab的骨骼效应。具体地说，该项目中的实验将检验以下假设：1)在当前临床剂量下，ALN和Ral的组合将比单独使用两种药物更能改善骨骼的力学性能；2)较低剂量的ALN与临床剂量的Ral将至少产生与当前治疗剂量的ALN单独治疗相同的骨强度效果；以及3)OPG-FC和Ral的组合将比单独使用两种药物更多地改善骨骼的力学性能。我们将使用传统的结果测量方法(体外骨密度、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。这项建议中产生的数据将具有很高的可译性，因为我们的分析将建立体内评估的机械性能变化与只能在切除的骨骼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，联合治疗可能很快就会进入临床。

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.