Limited-duration anabolic therapy in postmenopausal osteoporosis

绝经后骨质疏松症的限期合成代谢治疗

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要三分之一的女性和五分之一的男性在一生中都会经历骨质疏松性骨折。每年有超过 300,000 名 65 岁以上的人因髋部骨折住院，这些骨折与 1- 目前的骨质疏松症治疗可降低高危患者的椎骨骨折风险。但它们降低非椎骨骨折和髋部骨折风险的能力特别有限。最近批准的骨质疏松症药物 romosozumab 具有独特的作用机制，因为它既然而，刺激新骨形成并抑制骨吸收的时间不同。其对新骨形成的刺激作用是短暂的，仅持续1-3个月，而其对骨形成的抑制作用最近，romosozumab 被证明可以降低脊柱和非脊柱的风险。骨折超过了最近FDA批准的最广泛使用的骨质疏松药物阿仑膦酸钠。然而，romosozumab 伴随着一个“黑匣子”警告，因为研究报告了显着的主要不良心脏事件的风险增加，包括中风、心肌梗塞和心血管疾病由于 romosozumab 仅短暂刺激骨形成，因此我们认为该时间要短得多。 romosozumab 的疗程，然后是一种有效但选择性抑制骨吸收的药物，将有与 romosozumab 标准 12 个月疗程相似的疗效。显着更具成本效益，更容易被患者接受（romosozumab 每次注射 2 次）月），并且可能会降低 romosozumab 介导的主要不良心脏事件的风险。根据提案，我们将通过一项为期 12 个月的开放标签原理验证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 romosozumab 治疗 3 个月，然后接受抗骨吸收药物，狄诺塞麦，为期 9 个月或标准 12 个月治疗该研究的主要终点是双能 X 射线吸收测定法的变化。 0-12 个月的髋部总骨矿物质密度，其他部位的骨矿物质密度的生化变化。骨代谢标志物、高分辨率 QCT 衍生的骨密度骨密度、小梁骨微结构、桡骨和胫骨的皮质骨结构，以及估计的通过有限元分析评估的骨强度将被评估为关键的次要或探索性终点。拟议研究的成功完成将定义一种更安全、更便宜、更合理的方法。使用一种有前途的新型骨质疏松药物的方法这样做，这项研究有潜力。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和严重骨质疏松症的患者既定的疾病。