Combination Osteoporosis Therapy and Fracture Reduction

骨质疏松症治疗和骨折复位联合治疗

• 批准号: 9770768
• 负责人: BENJAMIN Z LEDER
• 金额: $ 21.75万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9770768
• 关键词: Affect; Age-Years; Agonist; Alendronate; American; Anabolic Agents; Bone Density; Bone Resorption; Budgets; Caring; Clinical; Clinical Trials; Combination Medication; Combined Modality Therapy; Consent Forms; Controlled Clinical Trials; Data; Disease; Distress; Dose; Double-Blind Method; Enrollment; Follow-Up Studies; Forteo; Fracture; Grant; Hip Fractures; Hip region structure; Incidence; Manuals; Modeling; Monoclonal Antibodies; Neck; Oral; Oral cavity; Osteoclasts; Osteocytes; Osteogenesis; Osteoporosis; Osteoporotic; Patients; Pharmaceutical Preparations; Placebos; Population; Postmenopause; Procedures; Process; Protocols documentation; Public Health; Recording of previous events; Regimen; Reporting; Research Training; Resistance; Safety; Series; Serum Markers; Site; Skeleton; Source; Spinal Fractures; Subcutaneous Injections; TNFSF11 gene; TRANCE protein; Testing; Therapeutic; Training; Woman; base; bisphosphonate; bone; bone mass; bone metabolism; bone strength; comparative efficacy; cortical bone; drug development; effective therapy; efficacy trial; experience; fracture risk; fragility fracture; high risk; improved; inhibiting antibody; inhibitor/antagonist; novel; novel therapeutic intervention; osteoporosis with pathological fracture; receptor; recruit; research clinical testing; skeletal; standard of care

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.

骨质疏松症是一个巨大的公共卫生问题，导致超过150万骨折， 美国每年一次。目前的治疗方法适度降低骨折风险，但没有药物能够完全恢复骨骼 在大多数患者中，因此，仍然迫切需要更有效的治疗，特别是 对于那些患有严重疾病的人来说。在数据研究中，我们报告说，当绝经后骨质疏松症 妇女用合成代谢剂特立哌酮，沿着抗吸收RANKL抑制剂， 地舒单抗、骨矿物质密度、皮质骨微结构和估计的骨强度改善 比单独使用任何一种药物或使用任何可用的单一药物都要多。这种药物的上级功效 联合方法似乎与地舒单抗完全抑制特立帕鲁肽前体的能力有关。 再吸收作用，同时仍然允许特立帕肽诱导的基于建模的骨形成。接下来- 目前正在进行的一项研究（DATA-HD），我们现在证明使用更高剂量的特立帕肽 与地舒单抗联合治疗相比， DATA中使用的方案，导致即使长期使用 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， 评估其减少严重骨质疏松症患者骨折的潜力。此种示范 将允许这种方案作为那些风险最高的患者的治疗选择， 脆性骨折本提案旨在完成一项双盲安慰剂对照临床试验的规划， 一项检验严重骨质疏松症女性患者12个月联合高剂量 特立帕鲁肽和地舒单抗，随后进行12个月的地舒单抗单药治疗， 发病率大大高于目前的标准治疗（口服阿仑膦酸钠治疗）。实现 为此，我们将与一个经验丰富的协调中心合作，以确定最佳的研究地点， 详细的方案和分析计划，编制有效的预算，编制适当的知情同意书， 并最后确定一份详尽的业务程序手册。我们还将准备提交材料 并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计划和完成， 有可能在骨质疏松症治疗中引入突破性的框架， 治疗患有最严重疾病的患者。