The interaction of anabolic and antiresorptive agents in osteoporosis therapy

描述（由申请人提供）：骨质疏松症是一种常见疾病，可导致显著的发病率和死亡率。骨质疏松症的广泛流行导致每年超过200万例骨折，仅在美国估计花费170亿美元。目前的药物不能完全恢复骨质疏松症患者的骨骼完整性，也不足以满足我们老龄化人群中骨折发病率的预期上升。因此，继续努力开发创新的、循证的骨质疏松症治疗策略至关重要。该建议的科学重点是抗吸收和合成代谢性骨质疏松症治疗的优化组合。与双膦酸盐与特立帕罗（hPTH 1 -34或TPTD）联合使用的令人失望的结果相反，最近报告了狄诺塞单抗（DMAB）（一种与核因子-kB配体受体激活剂（RANKL）结合的单克隆抗体）和TPTD的联合使用，其增加骨矿物质密度的作用大于任何一种药物单独使用。该提案的一个具体目的是通过评估同一队列中骨结构、微结构和强度的变化，进一步了解这种治疗组合的附加特性的机制。具体而言，将使用胫骨远端和桡骨的高分辨率外周定量计算机断层扫描来比较TPTD和DMAB联合治疗与每种单独药物对皮质和小梁体积骨密度、皮质厚度和孔隙率、小梁微结构和估计骨强度的影响（通过微观有限元分析）。该提案的另一个目的是扩展上述研究的最新发现，即与DMAB单独给药相比，DMAB和TPTD联合给药时，骨吸收受到有效且同等的抑制。具体来说，这项拟议的研究将检验DMAB而不是阿仑膦酸钠将完全抑制增加剂量的TPTD在大鼠中的急性促吸收作用的假设。 绝经后的女性。如果得到证实，这将表明较高剂量的TPTD（40 mcg）与DMAB联合使用时，可能比DMAB和标准剂量的TPTD（20 mcg）更显著地改善骨骼完整性。40名60岁以上的绝经后女性将入组一项短期、开放标签、随机对照试验。受试者将随机接受DMAB或阿仑膦酸钠治疗8周。受试者还将在8周抗吸收治疗前后接受TPTD 40 mcg单次注射。将通过在基线和抗吸收治疗8周后TPTD注射前和注射后4小时测量骨吸收的生化标志物，评价每种抗吸收药物抑制TPTD诱导的骨吸收的相对能力。这项研究将提供一个更好的机制，破骨细胞抑制和成骨细胞刺激相结合的效果的理解，并在设计创新的临床试验，旨在提高骨折的高风险的妇女和男子的骨骼完整性的设计援助。

DESCRIPTION (provided by applicant): Osteoporosis is a common disease that causes significant morbidity and mortality. The widespread prevalence of osteoporosis results in >2 million fractures yearly with an estimated cost of $17 billion in the US alone. Current agents are unable to completely restore skeletal integrity in patients with established osteoporosis and are inadequate to match the anticipated rise in fracture incidence in our aging population. Thus, continued efforts to develop innovative, evidence-based osteoporosis treatment strategies are crucial. The scientific focus of this proposal is the optimization of combination antiresorptive an anabolic osteoporosis therapies. In contrast to disappointing results from combining bisphosphonates with teriparatide (hPTH1-34 or TPTD), the combination of denosumab (DMAB), a monoclonal antibody that binds to receptor activator of nuclear factor-kB ligand (RANKL), and TPTD was recently reported to increase bone mineral density more than either drug alone. One specific aim of this proposal is to further understand the mechanisms underlying the additive properties of this therapeutic combination by assessing the changes in bone structure, microarchitecture, and strength in this same cohort. Specifically, high-resolution peripheral quantitative computed tomography of the distal tibia and radius will be used to compare the effects of combination TPTD and DMAB therapy versus each individual agent on cortical and trabecular volumetric bone density, cortical thickness and porosity, trabecular microarchitecture, and estimated bone strength (via micro finite element analysis). A further aim of this proposal is to expand on the recent novel finding from the above study that bone resorption is potently and equally suppressed when DMAB and TPTD are combined than when DMAB is given alone. Specifically, this proposed study will test the hypothesis that DMAB, but not alendronate, will fully inhibit the acute pro-resorptive effect of an increased dose of TPTD in postmenopausal osteoporotic women. If confirmed, this will suggest that higher doses of TPTD (40-mcg), when combined with DMAB, may improve skeletal integrity significantly more than DMAB and standard dose TPTD (20-mcg). Forty postmenopausal osteoporotic women aged 60+ will be enrolled in a short-term, open label randomized controlled trial. Subjects will be randomized to receive DMAB or alendronate therapy for 8 weeks. Subjects will also receive a single injection of TPTD 40-mcg both before and after the 8 weeks of antiresorptive therapy. The relative ability of each antiresorptive agent to inhibit TPTD-induced bone resorption will be evaluated by measuring biochemical markers of bone resorption prior to and 4 hours after the TPTD injection both at baseline and after 8-weeks of antiresorptive therapy. This study will provide a better mechanistic understanding of effects of combined osteoclast inhibition and osteoblast stimulation and aid in the design of innovative clinical trials designed to improve skeletal integrity in women and men at high risk for fracture.