Limited-duration anabolic therapy in postmenopausal osteoporosis

绝经后骨质疏松症的限期合成代谢治疗

• 批准号: 10490840
• 负责人: BENJAMIN Z LEDER
• 金额: $ 17.93万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10490840
• 关键词: Affect; Aftercare; Alendronate; American; Anabolic Agents; Biochemical Markers; Bone Density; Bone Resorption; Bone Resorption Inhibition; Cardiac; Cardiovascular system; Cessation of life; Chronic Disease; Clinical; Clinical Trials; Disease; Dual-Energy X-Ray Absorptiometry; Event; Finite Element Analysis; Fracture; High Risk Woman; Hip Fractures; Hip region structure; Incidence; Injections; Mediating; Modeling; Monoclonal Antibodies; Myocardial Infarction; Neck; Oral; Osteocytes; Osteogenesis; Osteoporosis; Osteoporotic; Patients; Pattern; Persons; Pharmaceutical Preparations; Physicians' Offices; Population; Postmenopausal Osteoporosis; Postmenopause; Property; Public Health; Radial; Randomized Controlled Clinical Trials; Recording of previous events; Regimen; Reporting; Resolution; Risk; Risk Factors; Serum; Site; Spinal Fractures; Stroke; Subcutaneous Injections; TRANCE protein; Testing; Time; Treatment Protocols; Vertebral column; Woman; X-Ray Computed Tomography; base; bone; bone metabolism; bone strength; bone turnover; cortical bone; cost; cost effective; experience; falls; follow-up; fracture risk; fragility fracture; high risk; hip bone; human old age (65+); inhibiting antibody; inhibitor; men; mortality; open label; osteoporosis with pathological fracture; phase 3 study; primary endpoint; radius bone structure; secondary endpoint; skeletal; substantia spongiosa; tibia; treatment duration

PROJECT SUMMARY One in three women and one in five men will experience an osteoporotic fracture during their lifetime. Each year over 300,000 people over the age of 65 are hospitalized for hip fractures which are associated with a 1- year mortality rate of 20-30%. Current osteoporosis therapies reduce vertebral fracture risk in high-risk patients but their ability to reduce the risk of non-vertebral fractures and hip fractures, specifically, is modest. The most recently approved osteoporosis medication, romosozumab, has a unique mechanism of action in that it both stimulates new bone formation and inhibits bone resorption. The timing of these actions, however, differs in that its stimulation of new bone formation is transient, lasting only 1-3 months, whereas its inhibition of bone resorption is sustained. Recently, romosozumab was shown to reduce the risk of both spine and non-spine fractures more than the most widely used osteoporosis medication, alendronate. The recent FDA approval of romosozumab, however, was accompanied by a “black box” warning as studies reported a significant increased risk of major adverse cardiac events including stroke, myocardial infarction, and cardiovascular death. Because romosozumab only transiently stimulates bone formation, we hypothesize that a much shorter course of romosozumab, followed by a drug that potently but selectively inhibits bone resorption, would have similar efficacy to the standard 12-month course of romosozumab. This shorter course of romosozumab would be significantly more cost effective, more acceptable to patients (romosozumab is given as 2 injections every month) and would likely reduce the romosozumab-mediated risk of major adverse cardiac events. In this proposal, we will test our hypothesis via a single open-label proof-of-principle 12-month clinical trial in which postmenopausal women at a high risk of fracture will receive either romosozumab for 3 months followed by the antiresorptive medication, denosumab, for the 9 months or the standard 12-months treatment with romosozumab. The primary endpoint of the study is the changes in dual-energy X-ray absorptiometry-derived total hip bone mineral density from months 0-12. Changes in bone mineral density at other sites, biochemical markers of bone metabolism, high-resolution QCT-derived compartmental volumetric bone mineral density, trabecular bone microarchitecture, and cortical bone structure of the radius and tibia, as well as estimated bone strength assessed by finite element analysis will be assessed as key secondary or exploratory endpoints. The successful completion of the proposed study will define a safer, less expensive, and more rational approach to the use of a promising new osteoporosis medication. In so doing, this study has the potential to fundamentally change the way osteoporosis is treated, especially for those patients with severe and established disease.

项目摘要 三分之一的女人和五分之一的男性在一生中会经历骨质疏松性骨折。每个 超过30万人65岁以上的人因髋部骨折住院 年死亡率为20-30％。当前的骨质疏松疗法降低了高危患者的椎骨骨折风险 但是，他们降低非椎骨骨折和髋部骨折的风险的能力是适度的。最多 最近批准的骨质疏松药物Romosozumab具有独特的作用机理，因为 刺激新的骨形成并抑制骨骼分辨率。但是，这些行动的时机在 它的刺激新骨形成是短暂的，仅持续1-3个月，而骨骼的抑制作用 解析是持续的。最近，romosozumab被证明降低了脊柱和非脊柱的风险 骨折比最广泛使用的骨质疏松症药物，阿仑膦酸盐。最近的FDA批准 然而，romosozumab伴随着“黑匣子”警告，因为研究报告了重要的 增加了重大不良心脏事件的风险，包括中风，心肌梗塞和心血管 死亡。因为romosozumab仅暂时刺激骨形成，所以我们假设一个短得多的 romosozumab的过程，然后是一种潜在但有选择地抑制骨骼的药物，将有 类似于romosozumab的标准12个月课程类似的效率。 romosozumab的较短课程将 要有更大的成本效益，更容易被患者接受（romosozumab作为2次注射 一个月），可能会降低romosozumab介导的重大不良心脏事件的风险。在这个 提案，我们将通过单个开放标签的原则证明12个月临床试验来检验我们的假设，其中 骨折风险高的绝经后妇女将接受三个月的romosozumab，然后是 抗吸收性药物，denosumab，在9个月内或标准的12个月治疗 Romosozumab。该研究的主要终点是双能X射线绝对二肽的变化 从0-12个月开始的总髋骨矿物质密度。其他位点骨矿物质密度的变化，生化 骨代谢的标记，高分辨率QCT衍生的隔室容量骨矿物质密度， 小梁骨微体系结构以及半径和胫骨的皮质骨结构，以及估计 通过有限元分析评估的骨骼强度将被评估为关键的次要或探索性终点。 拟议的研究的成功完成将定义一个更安全，更便宜，更理性的 使用承诺的新骨质疏松药物的方法。这样，这项研究有可能 从根本上改变了骨质疏松症的治疗方式，特别是对于那些严重和 已建立的疾病。