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: 10782306
• 负责人: BENJAMIN Z LEDER
• 金额: $ 8万
• 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/10782306
• 关键词: Affect; Alendronate; American; Biochemical Markers; Bone Density; Bone Formation Stimulation; Bone Resorption Inhibition; Cardiac; Cardiovascular system; Cessation of life; Chronic Disease; Clinical Trials; Disease; Dual-Energy X-Ray Absorptiometry; Event; Finite Element Analysis; Fracture; Hip Fractures; Hospitalization; Injections; Mediating; Myocardial Infarction; Osteogenesis; Osteoporosis; Patients; Persons; Pharmaceutical Preparations; Postmenopausal Osteoporosis; Postmenopause; Public Health; Reporting; Resolution; Risk; Risk Reduction; Site; Spinal Fractures; Stroke; Testing; Vertebral column; Woman; bone metabolism; bone strength; cortical bone; cost; cost effective; experience; fracture risk; fragility fracture; high risk; hip bone; human old age (65+); men; mortality; open label; osteoporosis with pathological fracture; primary endpoint; radius bone structure; substantia spongiosa; tibia

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 三分之一的女性和五分之一的男性在其一生中会经历过脊椎骨折。每个 每年有超过30万65岁以上的人因髋部骨折住院，这些骨折与1- 年死亡率为20- 30%。当前的骨质疏松症疗法可降低高危患者的椎骨骨折风险 但它们降低非脊椎骨折和髋部骨折风险的能力，特别是，是适度的。最 最近批准的骨质疏松症药物，romosozumab，有一个独特的作用机制，它既 刺激新骨形成并抑制骨吸收。然而，这些行动的时机不同， 它对新骨形成的刺激是短暂的，仅持续1-3个月，而它对骨形成的抑制作用是暂时的， 再吸收是持续的。最近，romosozumab被证明可以降低脊柱和非脊柱的风险。 比最广泛使用的骨质疏松症药物阿仑膦酸钠更有效。最近FDA批准 然而，romosozumab伴随着“黑匣子”警告，因为研究报告显示， 主要不良心脏事件（包括卒中、心肌梗死和心血管疾病）的风险增加 死亡因为romosozumab只能短暂刺激骨形成，我们假设短得多的 一个疗程的romosozumab，然后是一种有效但选择性地抑制骨吸收的药物， 与标准12个月疗程的romosozumab疗效相似。这种较短的romosozumab疗程将 显著地更具成本效益，更容易被患者接受（romosozumab以每次2次注射的形式给予， 月），并可能降低罗索珠单抗介导的主要不良心脏事件的风险。在这 根据这项提议，我们将通过一项为期12个月的开放标签原则验证临床试验来检验我们的假设， 处于骨折高风险的绝经后妇女将接受罗莫索珠单抗3个月， 抗骨吸收药物狄诺塞单抗治疗9个月或标准12个月， romosozumab。该研究的主要终点是双能X线吸收测定法衍生的 0-12个月的总髋骨矿物质密度。其他部位骨密度变化，生化 骨代谢标志物，高分辨率QCT衍生的房室体积骨密度， 桡骨和胫骨的骨小梁微结构和皮质骨结构，以及估计的 通过有限元分析评估的骨强度将作为关键次要或探索性终点进行评估。 成功完成拟议的研究将确定一个更安全，更便宜，更合理的 使用一种有前途的新的骨质疏松症药物的方法。这样做，这项研究有可能 从根本上改变骨质疏松症的治疗方式，特别是对于那些患有严重骨质疏松症的患者， 建立疾病。