Romosozumab to Improve Bone Mineral Density and Architecture in Chronic SCI

慢性脊髓损伤(SCI)患者骨量显著减少，骨骼丢失。 建筑的完整性，这使他们容易受到低冲击的骨折。目前，还没有实际的治疗方法。 以逆转慢性脊髓损伤患者的严重骨丢失。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将是 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。 生活质量将大大提高，因为有能力更安全地参与日常活动 生活和融入社区。尽管骨骼活动低于损伤水平 慢性脊髓损伤患者，因吸收超过形成而发生净骨丢失，两者有差异 在那些患有脊髓损伤的人中，这一比例高于在健康人群中观察到的比例。因此，它 预计对慢性脊髓损伤患者增加骨转换是有价值的，目的是 促进骨形成超过骨吸收。在一项临床前研究中，应用了一种抗硬化素 大鼠脊髓全横断后12周抗体、骨密度(BMD)几乎完全恢复 在股骨远端干骺端修复，骨结构和机械强度得到改善；相比之下， 完全脊柱横断后，赋形剂治疗的动物股骨远端干骺端明显减少。 BMD和骨骼结构和机械强度的恶化。何时用于治疗绝经后 骨质疏松，罗莫佐单抗，一种人类抗硬化素的单抗，对增加骨质疏松症更有效 骨密度(BMD)和减少骨折比任何其他抗吸收或骨合成代谢药物，以及 这种影响在慢性脊髓损伤患者的附件骨骼上也很明显。 最严重的骨质流失和最频繁的骨折。由于缺乏可供选择的临床方案， 治疗慢性瘫痪患者的骨质疏松症，研究人员建议测试一个 硬化素的拮抗剂，这是一种有效的骨合成代谢药，已被证明有效治疗女性 绝经后骨质疏松症，改善骨量，减少脆性骨折。 39名患有慢性完全性脊髓损伤的男性和女性受试者(&gt；3损伤后，美国脊柱 伤害协会损害评定量表A和B)年龄在18岁至50岁之间，在 股骨远端处的股骨远端≥为0.7g/cm~2但≤为1.0g/cm~2将被招募用于参与随机的， 双盲、安慰剂对照、平行分组临床试验。拟议研究的成果衡量标准如下 外周定量CT和双能X线测定骨密度(BMD) 骨吸收(DXA)和骨吸收和骨形成的生化标志物。具体目标1：恢复 外周定量测量股骨远端基础骨密度的5%≥ 罗莫佐单抗治疗12个月的计算机断层扫描(PQCT)(主要目标)。特定目标 2：维持或进一步增加基线后24个月股骨远端vBMD的增加 双重药物治疗的测量(罗莫佐单抗12个月，地诺舒单抗12个月) (主要具体目标)。具体目标3：证明骨骼生物标记物的变化幅度 罗莫佐单抗治疗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(次级目标)。探索性目标：pQCT中的其他变量 胫骨近端vBMD、股骨远端和胫骨近端骨小梁密度(TBMD)、胫骨皮质骨密度(38%) 胫骨长度)、胫骨远端的微结构以及股骨远端、近端的面积骨密度的变化。 取胫骨、DXA全髋关节。骨吸收生物标志物的额外时间点 将获得与BMD变化相关的形成。如果成功，这一方法将改变 关爱慢性脊髓损伤患者，提高直立康复活动能力。

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.