The interaction of anabolic and antiresorptive agents in osteoporosis therapy

描述(申请人提供)：骨质疏松症是一种常见的疾病，会导致严重的发病率和死亡率。骨质疏松症的广泛流行每年导致200万人骨折，仅在美国就估计造成170亿美元的损失。目前的药物不能完全恢复已确定的骨质疏松症患者的骨骼完整性，也不足以与我们老龄化人口中骨折发生率预期的上升相匹配。因此，继续努力开发创新的、循证的骨质疏松症治疗策略是至关重要的。这项建议的科学重点是优化抗吸收和合成代谢骨质疏松症的联合治疗。与双膦酸类药物(hPTH1-34或TPTD)联合应用的结果令人失望的是，最近有报道称，与核因子-kB受体激活剂(RANKL)结合的单抗DMAB和TPTD联合使用比单独使用任何一种药物都能更好地增加骨密度。这项建议的一个具体目的是通过评估同一队列中骨骼结构、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背后的机制。具体地说，将使用胫骨远端和桡骨远端的高分辨率外围定量计算机断层扫描来比较TPTD和DMAB联合治疗与单独使用两种药物对皮质和骨小梁体积骨密度、皮质厚度和孔隙率、骨小梁微结构和估计骨强度(通过微观有限元分析)的影响。这项建议的另一个目的是扩展上述研究的最新发现，即与单独给予DMAB相比，DMAB和TPTD联合使用可以有效且同等地抑制骨吸收。具体地说，这项拟议的研究将检验这样的假设，即DMAB，而不是阿伦磷酸钠，将完全抑制增加剂量的TPTD对小鼠的急性促吸收作用。 绝经后骨质疏松症女性。如果得到证实，这将表明高剂量的TPTD(40-MCG)，当与DMAB联合使用时，可能比DMAB和标准剂量的TPTD(20-MCG)更能显著改善骨骼完整性。40名60岁以上的绝经后骨质疏松症妇女将参加一项短期、开放标签的随机对照试验。受试者将被随机接受为期8周的DMAB或阿伦磷酸钠治疗。受试者还将在8周的抗吸收治疗之前和之后接受一次TPTD 40-MCG注射。每种抗吸收药物抑制TPTD诱导的骨吸收的相对能力将在注射TPTD前和注射后4小时、基线和抗吸收治疗8周后通过骨吸收生化标记物的测定来评估。这项研究将为破骨细胞抑制和成骨细胞刺激的联合作用提供更好的机制理解，并有助于设计创新的临床试验，旨在改善骨折高危女性和男性的骨骼完整性。

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.