Romosozumab to Improve Bone Mineral Density and Architecture in Chronic SCI

慢性脊髓损伤（SCI）患者的骨量明显减少， 建筑的完整性，这使他们容易受到低冲击骨折。目前，还没有实用的治疗方法 逆转慢性SCI患者的严重骨丢失。在拟议的研究中， 将测试干预措施以改善骨骼健康。在损伤水平以下的骨量恢复将是 预计将降低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，融入社会。尽管在病变水平以下的骨骼活动受到抑制， 对于慢性SCI患者，由于吸收超过形成而发生净骨丢失， 在这些比率之间，SCI患者的比率高于在健全人群中观察到的比率。因此 预计对慢性SCI患者有价值，可增加骨转换， 增加骨形成超过骨吸收。在一项临床前研究中， 完全脊髓横断骨后12周，骨密度（BMD）几乎完全 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， 溶剂处理的动物在完全脊柱横断后，股骨远端干骺端明显减少 BMD和骨结构和机械强度的退化。用于治疗绝经后 对于骨质疏松症，romosozumab，一种人单克隆抗sclerostin抗体，更有效地增加 骨矿物质密度（BMD）和减少骨折比任何其他抗再吸收或骨合成代谢剂，和 这种影响在无脊椎骨骼中也很明显，无脊椎骨骼是慢性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，在治疗女性骨质疏松症中具有已证实的疗效。 绝经后骨质疏松症，改善骨量，减少脆性骨折。 39名男性和女性慢性运动完全性SCI受试者（损伤后>3，美国脊柱 损伤相关损伤量表A和B），年龄在18至50岁之间， 将招募股骨远端≥0.7 g/cm 2但≤1.0 g/cm 2的受试者参加随机， 双盲、安慰剂对照、平行组临床试验。拟议研究的成果指标是 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） 骨吸收测定法（DXA）和骨吸收和骨形成的生化标志物。具体目标1：恢复 通过外周定量测量的股骨远端≥5%的基线积分体积BMD（vBMD） 计算机断层扫描（pQCT）与12个月的romosozumab治疗（主要特异性目的）。具体目标 2：维持或进一步增加基线后24个月时股骨远端vBMD的增加 双药治疗（12个月romosozumab，随后12个月Denosumab）的测量 （主要目标）。具体目的3：证明骨生物标志物的变化幅度 在罗莫珠单抗治疗1个月时， 12和24个月（次要特定目标）。探索性目的：根据pQCT确定的其他变量， 胫骨近端vBMD、股骨远端和胫骨近端骨小梁BMD（tBMD）、胫骨皮质BMD（38% 的胫骨长度），胫骨远端的微结构，以及股骨远端，近端 通过DXA获得胫骨和全髋关节。骨吸收生物标志物的额外时间点& 将获得与BMD变化相关的骨密度。如果成功，这种方法将改变标准。 护理慢性脊髓损伤患者，并提高进行直立康复活动的能力。

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.