Combination Osteoporosis Therapy and Fracture Reduction

骨质疏松症是一个巨大的公共健康问题，在美国有超过150万人骨折 美国每年。目前的治疗方法略微降低了骨折风险，但没有一种药物能够完全恢复骨骼 大多数患者的正直。因此，仍然迫切需要更有效的治疗，尤其是 对于那些患有严重疾病的人。在数据研究中，我们报告了当绝经后骨质疏松症 女性接受合成代谢剂Teriparatide和抗吸收RANKL抑制剂的治疗， Denosumab、骨密度、皮质骨微结构和估计骨强度改善 比单独使用药物或任何可用的单一药物更有效。这种药的卓越功效 联合用药似乎与Denosumab完全抑制Teriparatide的前... 吸收效应，同时仍然允许基于Terparatide诱导的基于建模的骨形成。在接下来的- 目前正在进行的UP研究(Data-HD)，我们现在证明使用更高剂量的Teriparatide 与地诺单抗联合使用可更快、更广泛地增加骨密度 数据中使用的养生法，导致骨量的改善即使长期使用也无法实现 任何一个特工。鉴于这些极其令人鼓舞的发现，现在至关重要的是，这种方法 评估其减少严重骨质疏松症患者骨折的潜力。这样的一个示范 将允许这种方案作为治疗方案提供给那些有最高风险的患者 脆性骨折。这项建议旨在完成一项双盲安慰剂对照临床试验的规划。 一项试验验证了这一假设，即在患有严重骨质疏松症的女性中，12个月的联合大剂量 Teriparatide和denosumab加上12个月的denosumab单药治疗将减少骨折 发病率大大高于目前的护理标准(口服阿仑磷酸钠治疗)。要实现 为此，我们将合作一个经验丰富的协调中心，以确定最佳的学习地点，完成 详细的协议和分析计划，编制有效的预算，构建适当的同意书， 并最终敲定一份详细而彻底的操作程序手册。我们还将准备意见书 对监管机构和完成严格的员工培训。鉴于这部小说的独特潜力 治疗方法，这项比较疗效试验的成功规划和完成具有 有可能在骨质疏松症治疗中引入一个开创性的框架，并大幅推进 治疗最严重形式的疾病的患者。

Osteoporosis is an enormous public health problem that contributes to over 1.5 million fractures in the U.S. yearly. Current therapies modestly reduce fracture risk but no agent is able to fully restore skeletal integrity in most patients. Thus, there remains an urgent need for more effective treatments, particularly for those with severe disease. In the DATA study, we reported that when postmenopausal osteoporotic women are treated with the anabolic agent, teriparatide, along with the antiresorptive RANKL inhibitor, denosumab, bone mineral density, cortical bone microarchitecture, and estimated bone strength improve more than with either drug alone or with any available single agent. The superior efficacy of this combination approach appears to be related to denosumab’s ability to fully inhibit teriparatide’s pro- resorptive effects while still allowing for teriparatide-induced modeling-based bone formation. In a follow- up study currently underway (DATA-HD), we now demonstrate that using a higher dose of teriparatide in combination with denosumab increases bone density even more quickly and extensively than the regimen used in DATA, resulting in improvements in bone mass unachievable with even long-term use of any single agent. Given these extremely encouraging findings, it is now crucial that this approach be evaluated for its potential to reduce fractures in patients with severe osteoporosis. Such a demonstration will permit this regimen to be available as a treatment option for those patients at the highest risk of fragility fracture. This proposal aims to complete the planning of a double-blind placebo-controlled clinical trial that tests the hypothesis that in women with severe osteoporosis, 12-months of combined high-dose teriparatide and denosumab followed by 12-months of denosumab monotherapy will decrease fracture incidence substantially more than the current standard of care (oral alendronate treatment). To achieve this aim, we will collaborate an experienced coordinating center to identify optimal study sites, complete the detailed protocol and analysis plan, prepare an efficient budget, construct appropriate consent forms, and finalize a detailed and thorough manual of operating procedures. We will also prepare submissions to regulatory agencies and complete rigorous staff training. Given the unique potential of this novel therapeutic approach, the successful planning and completion of this comparative-efficacy trial has the potential to introduce a groundbreaking framework in osteoporosis therapy and substantially advance the treatment of patients with the most severe form of the disease.