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，发病率和死亡率高。骨质疏松症的广泛流行导致每年约200万例骨折，仅在美国就造成约170亿美元的损失。目前的药物不能完全恢复骨质疏松症患者的骨骼完整性，也不足以应对老龄化人口中骨折发生率的预期上升。因此，继续努力开发创新的、基于证据的骨质疏松症治疗策略至关重要。本建议的科学重点是优化联合抗吸收和合成代谢骨质疏松症治疗。与双膦酸盐与特立帕肽（hPTH1-34或TPTD）联合治疗的令人失望的结果相反，denosumab (DMAB)，一种结合核因子- kb配体受体激活剂（RANKL）的单克隆抗体，与TPTD联合治疗比单独用药更能增加骨密度。该建议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潜在机制。具体而言，将使用胫骨远端和桡骨远端高分辨率外围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、皮质厚度和孔隙度、小梁微结构和估计骨强度（通过微有限元分析）的影响。本提案的另一个目的是扩展上述研究的最新发现，即DMAB和TPTD联合使用比单独使用DMAB更有效且同样地抑制骨吸收。具体来说，本研究将验证DMAB，而不是阿仑膦酸钠，将完全抑制增加剂量的TPTD的急性促吸收作用

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.