Romosozumab to Improve Bone Mineral Density and Architecture in Chronic SCI

Romosozumab 可改善慢性 SCI 患者的骨矿物质密度和结构

• 批准号: 10155113
• 负责人: William A Bauman
• 金额: --
• 依托单位: JAMES J PETERS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10155113
• 关键词: Activities of Daily Living; Address; Aftercare; Age; American; Anabolic Agents; Animals; Antibodies; Architecture; Biochemical Markers; Biological Markers; Body Weight; Bone Density; Bone Resorption; Bone structure; Caring; Chronic; Clinical; Clinical Trials Cooperative Group; Collagen Type I; Communities; Control Groups; Controlled Clinical Trials; Depressed mood; Deterioration; Distal; Double-Blind Method; Dual-Energy X-Ray Absorptiometry; Dual-Photon Absorptiometries; Employment; Female; Femur; Fracture; Hip region structure; Impairment; Individual; Injury; Intervention; Lead; Length; Lesion; Lower Extremity; Manuals; Measurement; Measures; Mechanics; Metaphysis; Modality; Morbidity - disease rate; Motor; N-terminal; Osteocalcin; Osteogenesis; Osteoporosis; Outcome; Outcome Measure; Paralysed; Participant; Peripheral; Personal Satisfaction; Persons; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Placebos; Population; Postmenopausal Osteoporosis; Principal Investigator; Quality of life; Randomized; Rattus; Rehabilitation therapy; Research Personnel; Secure; Site; Skeleton; Spinal; Spinal Cord Lesions; Spinal Cord transection injury; Spinal Injuries; Spinal cord injury; Testing; Time; Training; Veterans; Walking; Weight-Bearing state; Woman; Work; X-Ray Computed Tomography; base; bone; bone health; bone loss; bone mass; bone turnover; career; clinically relevant; cortical bone; effective therapy; exoskeleton; experience; fragility fracture; functional electrical stimulation; group intervention; human monoclonal antibodies; improved; male; novel strategies; placebo group; powered exoskeleton; preclinical study; prevent; primary endpoint; recruit; rehabilitation strategy; restoration; secondary endpoint; skeletal; standard of care; substantia spongiosa; tibia; treadmill training; walking rehabilitation

Persons with chronic spinal cord injury (SCI) have markedly reduced bone mass and the loss of skeletal architectural integrity, which predisposes them to low-impact fractures. Currently, there is no practical treatment to reverse the severe bone loss in persons with chronic SCI. In the proposed study, a dual pharmacological intervention will be tested to improve bone health. Restoration of bone mass below the level of injury would be expected to reduce the morbidity associated with fractures and permit safer participation in upright activities. Quality of life would be substantially improved because of the ability to engage more securely in activities of daily living and to integrate into the community. Despite the depressed skeletal activity below the level of lesion in persons with chronic SCI, net bone loss occurs because resorption exceeds formation, with a difference between these rates in those with SCI being greater than that observed in the able-bodied population. Thus, it would be anticipated to be of value in persons with chronic SCI to increase bone turnover with the objective to increase bone formation over that of bone resorption. In a preclinical study that administered an anti-sclerostin antibody to rats 12 weeks after complete spinal cord transection bone, mineral density (BMD) was almost fully restored at the distal femoral metaphysis, with improved bone structure, and mechanical strength; in contrast, vehicle-treated animals after complete spinal transection had a marked reduction in distal femoral metaphysis BMD and a deterioration in bone structure and mechanical strength. When used to treat postmenopausal osteoporosis, romosozumab, a human monoclonal anti-sclerostin antibody, was more effective to increase bone mineral density (BMD) and to reduce fracture than any other anti-resorptive or bone-anabolic agent, and this effect was also evident for the appendicular skeleton, which is the site in individuals with chronic SCI of greatest bone loss and most frequent fracture. Because of the absence of clinical options available for the treatment of osteoporosis in individuals with chronic paralysis, the investigators have proposed to test an antagonist of sclerostin, which is a potent bone anabolic agent with proven efficacy in treating women with postmenopausal osteoporosis, to improve bone mass and reduce fragility fractures. Thirty-nine male and female subjects with chronic, motor-complete SCI (>3 post injury, American Spinal Injury Association Impairment Scale A & B) between the ages of 18 and 50 years old who have aBMD at the distal femur at the distal femur ≥0.7 g/cm2 but ≤1.0 g/cm2 will be recruited for participation in a randomized, double-blind, placebo-controlled, parallel group clinical trial. The outcome measures of the proposed study are bone mineral density (BMD) by peripheral quantitative computed tomography (pQCT) and dual energy x-ray absorptiometry (DXA), and biochemical markers of bone resorption and formation. Specific Aim 1: To restore ≥5% of baseline integral volumetric BMD (vBMD) at the distal femur measured by peripheral quantitative computed tomography (pQCT) with 12 months of romosozumab therapy (primary specific aim). Specific Aim 2: To maintain, or to further increase, the gain in the distal femur vBMD at 24 months post the baseline measurement with dual drug therapy (12 months romosozumab followed by 12 months of denosumab) (primary specific aim). Specific Aim 3: To demonstrate that the magnitude of change in biomarkers of bone formation at 1 month of romosozumab therapy are associated with the greatest change in distal femur vBMD at 12 and 24 months (secondary specific aim). Exploratory Aims: Additional variables by pQCT for changes in the proximal tibia vBMD, distal femur and proximal tibia trabecular BMD (tBMD), cortical BMD of the tibia (38% of the tibial length), microarchitecture at the distal tibia, and changes in areal BMD at the distal femur, proximal tibia, and total hip by DXA will be obtained. Additional time points for biomarkers for bone resorption & formation will be obtained and related to changes in BMD. If successful, this approach will change standard of care for persons with chronic SCI and increase the ability to perform upright rehabilitation activities.

患有慢性脊髓损伤的人（SCI）显着降低了骨骼质量和骨骼丧失 建筑完整性，使它们易于低影响裂缝。目前，没有实际治疗 扭转患有慢性SCI的人的严重骨质流失。在拟议的研究中，双重药理 干预将进行测试以改善骨骼健康。恢复骨骼以下的骨骼质量将是 有望减少与骨折相关的发病率，并允许更安全的直立活动参与。 由于能够更牢固地参与日常活动，因此生活质量将大大提高 生活并融入社区。尽管骨骼活动低于病变水平 患有慢性SCI的人，由于分辨率超过形成而发生净骨质流失，差异很大 在SCI的人之间，这些速率大于在健全的人群中观察到的速率。那，它 预计在患有慢性SCI的人中会有价值，以增加骨骼周转，目的 将骨形成与骨骼分辨率相比。在临床前研究中，抗激素 完全脊髓转导骨后12周，对大鼠的抗体，矿物质密度（BMD）几乎完全 恢复在股骨盘中，具有改善的骨结构和机械强度；相比之下， 完全脊柱转导后，经媒介物处理的动物显着减少了股骨​​远端。 BMD和骨结构和机械强度的恶化。当用来治疗绝经后 骨质疏松症，romosozumab，一种人类的单克隆抗蛋白质抗体，更有效地增加 骨矿物质密度（BMD）并减少骨折，比任何其他抗敏感性或骨动型剂，以及 这种作用也证明了阑尾骨骼，该骨骼是患有慢性SCI的个体的部位 骨质流失最大，最常见的骨折。由于没有临床选择 研究人员提出的治疗慢性瘫痪者的骨质疏松症治疗 硬化蛋白的拮抗剂，它是一种潜在的骨合成代谢剂 绝经后骨质疏松症，以改善骨骼质量并减少脆弱性骨折。 39名男性和女性受试者患有慢性运动完整SCI（受伤后> 3，美国脊柱 伤害协会损伤量表A＆B）在18至50岁之间的ABMD年龄 股骨远端≥0.7g/cm2的远端股骨将招募≤1.0g/cm2，以参与随机， 双盲，安慰剂对照，平行组临床试验。拟议研究的结果度量是 骨矿物质密度（BMD）通过外围定量计算机断层扫描（PQCT）和双能X射线 吸收（DXA）和骨骼分辨率和形成的生化标记。特定目标1：还原 ≥5％的基线积分体积BMD（VBMD），在股骨外的盘中股骨，通过外围定量测量 具有12个月的romosozumab治疗（主要特定目的）的计算机断层扫描（PQCT）。具体目标 2：为了维持或进一步增加，基线后24个月的股骨远端VBMD的增益 双重药物疗法的测量（12个月romosozumab，然后是12个月的Denosumab） （主要目的）。特定目的3：证明骨骼生物标志物的变化幅度 romosozumab治疗1个月的形成与股骨远端VBMD的最大变化有关 12和24个月（次要特定目的）。探索目的：PQCT的其他变量用于更改 胫骨近端VBMD，股骨远端和胫骨近端小梁BMD（TBMD），胫骨皮质BMD（38％ 胫骨长度），胫骨远端的微构造以及股骨远端的面积BMD的变化，近端 将获得DXA的胫骨和总髋关节。骨骼分辨率的生物标志物的其他时间点 将获得形成，并与BMD的变化有关。如果成功，这种方法将改变 照顾患有慢性SCI的人，并提高执行直立康复活动的能力。