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

原理和目的：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（SCI）、多发性硬化和肌萎缩侧索硬化。骨丢失后， SCI是特别迅速和严重的。患有神经系统疾病的人的骨骼变薄， 在福尔斯跌倒后或甚至由于轻微撞击而造成的创伤中骨折的风险增加。这种断裂导致 住院、费用和生活质量下降。大约46%的SCI患者可能有骨折， 他们的一生，风险大大增加。尽管这一问题十分紧迫，但迄今为止， 与固定相关的骨损失形式（例如，SCI）对FDA批准的药物无效， 骨质疏松症测试此适应症。本申请旨在解决这一关键的治疗需求。 全身低强度振动（LIV）作为一种潜在的减缓 或预防骨质疏松症。例如，LIV减少了绝经后妇女和患有 脑瘫LIV是否能改善SCI患者的骨量尚不清楚，尽管有一例报告 这表明了一些有益的效果。我们最近进行了试点研究，以评估LIV对 使用中重度SCI的大鼠模型进行骨丢失。LIV在SCI后28天开始，并持续 35天LIV诱导了骨形成的血液标志物和培养的人骨形成细胞的基因表达的有利变化。 成骨细胞我们的试验结果首次确立了LIV对骨骼的潜在益处， SCI模型，并首次在严重的神经系统疾病或障碍的模型。然而，LIV没有 增加骨密度。最近的一项研究表明，全身振动（WBV）部分 在运动完全性（严重）SCI大鼠的早期阶段减轻骨退化。我们最初的工作 和现有的知识提供了坚实的支持，进一步研究使用LIV作为一个方便的 SCI相关骨丢失的治疗选择。该应用程序的前提是LIV将更 如果长期给药有效，并且当与减少净骨丢失的药物组合时， 特别是一种药物，减少骨质疏松（抗RANKL抗体）和一个，促进建设 新骨（雄激素）作为新的治疗方法，以阻止SCI后骨丢失。 目的1：在大鼠中度挫伤SCI模型中，我们将测试LIV的延长过程是否会 在保存骨方面提供更显著的效果。我们还将研究LIV 可能刺激骨形成并减少骨吸收，这与骨细胞的调节有关。在 此外，我们将评价抗RANKL抗体和/或雄激素联合给药时， 与LIV联合，增强LIV对SCI后病灶下骨丢失的影响 目标2.在大鼠严重SCI模型中，我们将评估延长LIV疗程是否会保护 在非负重条件下严重SCI后亚急性骨丢失;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的组合进一步增强。 意义和影响：研究结果可用于减缓或逆转SCI后的骨丢失。是 目前还不确定这种益处是否会延迟严重骨丢失的发生，或者骨丢失是否会导致骨丢失。 损失可以被完全阻断。在这两种情况下，可以设想使用拟议的干预措施， 在神经修复治疗可用之前保留骨头此外，拟议的干预措施认为， 承诺增加有资格接受负重康复策略的个人数量，例如 ReWalk、eLegs或其他用于步态训练和功能独立的模式。相关知识 分子机制将以更基本的方式适用，通过提供对基本的见解， 机械再加载和雄激素作用的机制。最后，调查结果可以通过提供 为未来相关基础科学研究提供见解，或指导未来药物的开发。

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.