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: 10418624
• 负责人: CHRISTOPHER P CARDOZO
• 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 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10418624
• 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; Placebo Control; 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; antagonist; 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（SCI）的人骨量明显减少，骨骼丧失 建筑完整性，这使它们易于发生低冲击断裂。目前尚无实际治疗方法 逆转慢性 SCI 患者严重的骨质流失。在拟议的研究中，双重药理学 将测试干预措施以改善骨骼健康。将骨量恢复到损伤水平以下 预计将减少与骨折相关的发病率，并允许更安全地参与直立活动。 由于能够更安全地参与日常活动，生活质量将得到显着改善 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，由于吸收超过形成而发生净骨质流失，两者之间存在差异 SCI 患者的这些比率高于在健全人群中观察到的比率。因此，它 预计对慢性 SCI 患者具有增加骨转换的价值，目的是 增加骨形成超过骨吸收。在一项使用抗硬化素的临床前研究中 完全脊髓横断骨后 12 周，大鼠产生抗体，矿物质密度 (BMD) 几乎完全达到 股骨远端干骺端恢复，骨结构和机械强度得到改善；相比之下， 完全脊柱横断后，接受媒介物治疗的动物远端股骨干骺端显着减少 BMD 以及骨骼结构和机械强度的恶化。当用于治疗绝经后时 romosozumab（一种人单克隆抗硬化素抗体）可更有效地增加骨质疏松症 与任何其他抗再吸收或骨合成代谢剂相比，骨矿物质密度 (BMD) 和减少骨折的几率更高，并且 这种效应对于阑尾骨骼也很明显，这是慢性 SCI 患者的部位。 最严重的骨质流失和最常见的骨折。由于缺乏可用的临床选择 为了治疗慢性瘫痪患者的骨质疏松症，研究人员建议测试一种 硬化素拮抗剂，这是一种有效的骨合成代谢剂，已被证明对治疗女性骨痛症有效 绝经后骨质疏松症，改善骨量，减少脆性骨折。 39 名男性和女性受试者患有慢性、运动完全性 SCI（伤后 >3 年），美国脊柱 伤害协会损伤量表 A 和 B) 年龄在 18 岁至 50 岁之间且 aBMD 处于 股骨远端 ≥0.7 g/cm2 但≤1.0 g/cm2 将被招募参加随机、 双盲、安慰剂对照、平行组临床试验。拟议研究的结果指标是 通过外周定量计算机断层扫描 (pQCT) 和双能 X 射线测定骨矿物质密度 (BMD) 吸收测定法 (DXA) 以及骨吸收和形成的生化标记物。具体目标 1：恢复 通过外周定量测量股骨远端基线积分体积 BMD (vBMD) ≥ 5% 计算机断层扫描 (pQCT) 和 12 个月的 romosozumab 治疗（主要具体目标）。具体目标 2：维持或进一步增加基线后 24 个月股骨远端 vBMD 的增益 双药物治疗的测量（12 个月的 romosozumab，随后 12 个月的地诺单抗） （主要具体目标）。具体目标 3：证明骨骼生物标志物的变化幅度 romosozumab 治疗 1 个月时的形成与股骨远端 vBMD 的最大变化相关。 12 个月和 24 个月（次要具体目标）。探索性目标：pQCT 的其他变量用于改变 近端胫骨 vBMD、远端股骨和近端胫骨小梁 BMD (tBMD)、胫骨皮质 BMD（38% 胫骨长度）、胫骨远端的微结构以及股骨远端、近端区域 BMD 的变化 通过 DXA 获得胫骨、全髋关节。骨吸收生物标志物的额外时间点和 将获得形成并与 BMD 的变化相关。如果成功的话，这种方法将改变 护理慢性 SCI 患者并提高进行直立康复活动的能力。