Novel Pharmacological and Non-pharmacological Interventions for Bone Loss in SCI

理论基础和目的：制动相关的骨丢失发生在许多神经系统疾病中，包括 中风、脊髓损伤、多发性硬化症和肌萎缩侧索硬化症。术后的骨质流失 脊髓损伤尤其迅速和严重。患有神经疾病的人的骨骼变薄，将他们 摔倒后骨折的风险增加，甚至是由于轻微撞击而造成的创伤。这种骨折会导致 住院、费用和生活质量下降。约46%的脊髓损伤患者可能在 他们的一生，大大增加了风险。尽管这一问题性质紧迫，但迄今为止，最严重的 与制动相关的骨丢失形式(如脊髓损伤)对FDA批准的治疗药物一直难以奏效。 骨质疏松症针对这一指征进行了测试。这一应用程序旨在解决这一治疗的关键需求。 全身低强度振动(LIV)作为一种潜在的减缓振动的手段正受到极大的关注 或预防骨质疏松症。例如，LIV减少了绝经后妇女和患有骨质疏松症的儿童的骨丢失 脑性瘫痪。LIV是否能改善脊髓损伤患者的骨量尚不清楚，尽管有一例报道 暗示了一些有益的效果。我们最近进行了初步研究，以评估LIV对 使用中度严重脊髓损伤大鼠模型的骨丢失。LIV在脊髓损伤后28天启动，并持续 35天。LiV诱导的骨形成血液标志物和基因表达的有利变化 骨形成细胞。我们的试验结果首次确定了LIV在骨骼上的潜在好处 脊髓损伤模型，并首次在严重神经疾病或障碍的模型中。然而，丽芙并没有 增加骨密度。最近的一项研究表明，全身振动(WBV) 减轻运动完全性(严重)脊髓损伤大鼠早期的骨骼退化。我们最初的工作 而目前的知识为进一步研究LIV作为一种便利工具的使用提供了坚实的支持 脊髓损伤相关骨丢失的治疗选择。这一应用的前提是，LIV将比 如果长期服用，并与减少净骨丢失的药物联合使用，效果显著， 具体地说，一种是减少骨质疏松症的药物(抗RANKL抗体)，另一种是促进骨形成的药物 新骨(雄激素)作为阻止脊髓损伤后骨丢失的新疗法。 目的1：在中度挫伤的大鼠脊髓损伤模型中，我们将测试延长病程的LIV是否会 在保存骨骼方面提供了更明显的效果。我们还将研究LIVE的机制 可能刺激骨形成，减少骨吸收，这与骨细胞的调节有关。在……里面 此外，我们将评估联合应用抗RANKL抗体和/或雄激素 应用LIV增强LIV对脊髓损伤后皮下骨丢失的影响 目的2.在严重脊髓损伤的大鼠模型中，我们将评估延长LIV疗程是否具有保护作用 在非负重条件下，严重脊髓损伤后的亚急性骨丢失；以及这种作用是否可以 通过应用抗RANKL抗体和/或雄激素与LIV联合应用，进一步加强了这种作用。 意义和影响：研究结果可能应用于减缓或逆转脊髓损伤后的骨丢失。它是 目前还不确定这一益处是否将延缓严重骨丢失的发生，或者相反，骨 损失是可以完全阻止的。在任何一种情况下，人们都可以设想使用拟议的干预措施至少 备用骨骼，直到神经修复治疗变得可用。此外，拟议的干预措施持有 承诺增加符合负重康复战略的人数，例如 ReWalk、eLegs或其他用于步态训练和功能独立的方式。关于以下方面的知识 分子机制将以更基本的方式应用，通过提供对基本 机械性再负荷和雄激素作用的机制。最后，调查结果可能适用于通过提供 对未来相关基础科学研究的洞察，或指导未来药学的发展。

Rationale and Objectives: Immobilization-related bone loss occurs in many neurological conditions including stroke, spinal cord injury (SCI), multiple sclerosis, and amyotrophic lateral sclerosis. The bone loss after an SCI is particularly rapid and severe. The thinning bones of individuals with neurological conditions place them at increased risk for fractures after falls or even from trauma due to minor impacts. Such fractures result in hospitalization, cost, and decreased quality of life. About 46 % of individuals with SCI may have a fracture over their lifetime, a substantially elevated risk. Despite the pressing nature of this problem, to date, the most severe forms of immobilization-related bone loss (e.g., SCI) have been refractory to the FDA-approved medications for osteoporosis tested for this indication. This application aims to address this critical need for therapy. Whole body low intensity vibration (LIV) is receiving a great deal of attention as a potential means to slow or prevent osteoporosis. For example, LIV reduced bone loss in postmenopausal women and children with cerebral palsy. Whether LIV improves bone mass in patients with SCI is not known, although one case report suggests some beneficial effect. We have recently conducted pilot studies to evaluate the effects of LIV on bone loss using a rat model of moderately severe SCI. LIV was initiated at 28 days after SCI and continued for 35 days. LIV induced favorable changes in blood markers of bone formation and gene expression of cultured bone-forming cells. Our pilot results establish for the first time the potential benefits of LIV on the skeleton in an SCI model, and for the first time in a model of severe neurologic disease or disorder. However, LIV did not increase bone mineral density. A recent study demonstrated that whole-body vibration (WBV) partially attenuated bone deterioration during the early stage in rats with motor-complete (severe) SCI. Our initial work and current knowledge have provided solid support for further study of the use of LIV as a convenient therapeutic option for SCI-related bone loss. The premise that underlies this application is that LIV will be more effective if administrated for a prolonged time, and when combined with medicines that reduce net bone loss, specifically one medicine that reduces bone thinning (anti-RANKL antibody) and one that promotes building new bone (androgens) as novel treatments to block bone loss after SCI. Objective 1: In rat models of moderate contusion SCI, we will test whether a prolonged course of LIV will provide be a more pronounced effect in preserving bone. We will also study the mechanisms by which LIV might stimulate bone formation and reduce bone resorption that is involved in the regulation of osteocytes. In addition,,we will evaluate whether an anti-RANKL antibody and/or androgen, when administered in conjunction with LIV, enhance the effects of LIV on sublesional bone loss after SCI Objective 2. In rat models of severe SCI, we will evaluate whether a prolonged course of LIV will protect against bone loss subacutely after severe SCI in non-weight bearing conditions; and whether such effects can be further augmented by the application of anti-RANKL antibody and/or androgen in combination with LIV. Significance and Impact: Results of the research may be applied to slow or reverse bone loss after SCI. It is uncertain as yet whether this benefit will be to delay the onset of severe bone loss, or instead whether bone loss can be blocked completely. In either case, one can envision use of proposed interventions to at least spare bone until neuroreparative treatments become available. In addition, the proposed interventions hold the promise of increasing the number of individuals eligible for weight bearing rehabilitation strategies, such as ReWalk, eLegs, or other modalities for gait training and functional independence. Knowledge regarding molecular mechanisms will be applicable in a more fundamental way, by providing insights into basic mechanisms of mechanic reloading and androgen actions. Lastly, findings may be applicable by providing insight for future related basic science studies, or directing the development of future pharmaceuticals.