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 万例骨折 美国每年的治疗方法可适度降低骨折风险，但没有药物能够完全恢复骨骼 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 DATA 研究中，我们报道了绝经后骨质疏松症。 女性接受合成代谢药物特立帕肽以及抗吸收 RANKL 抑制剂治疗， 狄诺塞麦、骨矿物质密度、皮质骨微结构和估计骨强度均得到改善 比单独使用任何一种药物或任何可用的单一药物具有更优越的功效。 组合方法似乎与地诺塞麦完全抑制特立帕肽前体的能力有关。 吸收效应，同时仍允许特立帕肽诱导的基于模型的骨形成。 目前正在进行的研究（DATA-HD），我们现在证明，使用更高剂量的特立帕肽 与地诺塞麦联合使用比单独使用地诺塞麦更快、更主要地增加骨密度 DATA中使用的方案，导致骨量的改善即使长期使用也无法实现 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 评估了其减少严重骨质疏松症患者骨折的潜力。 将允许该方案作为那些风险最高的患者的治疗选择 该提案旨在完成双盲安慰剂对照临床的规划。 试验检验以下假设：对于患有严重骨质疏松症的女性，12 个月的联合高剂量 特立帕肽和地诺单抗联合 12 个月的地诺单抗单药治疗将减少骨折 发病率大大高于目前的护理标准（口服阿仑膦酸钠治疗）。 为了实现这一目标，我们将与经验丰富的协调中心合作，确定最佳研究地点，完成 详细的方案和分析计划，准备有效的预算，构建适当的同意书， 并最终确定一份详细而全面的操作程序手册。 鉴于这部小说的独特潜力，监管机构并完成严格的员工培训。 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突破性的框架，并大大推进 治疗患有最严重疾病的患者。