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

针对 SCI 骨丢失的新型药理学和非药理学干预措施

• 批准号: 10394117
• 负责人: Weiping Qin
• 金额: --
• 依托单位: JAMES J PETERS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394117
• 关键词: Address; Amyotrophic Lateral Sclerosis; Androgens; Animal Model; Antibodies; Architecture; Attention; Attenuated; Automobile Driving; Basic Science; Blood; Bone Density; Bone Resorption; Caring; Case Study; Cells; Cerebral Palsy; Child; Clinical; Clinical Trials; Collaborations; Data; Deterioration; Development; FDA approved; Financial Hardship; Fracture; Future; Gene Expression; Genes; Goals; Hospital Costs; Immobilization; Individual; Injury; Intervention; Knowledge; Life; Ligands; Marrow; Mechanics; Mediating; Medical; Medicine; Minor; Modality; Modeling; Molecular; Morbidity - disease rate; Motor; Multiple Sclerosis; Muscular Dystrophies; Nature; Neurologic; Nuclear; Osteoblasts; Osteocalcin; Osteocytes; Osteogenesis; Osteoporosis; Osteoporosis prevention; Outcome; Paralysed; Pathological fracture; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Pilot Projects; Postmenopause; Primary Lateral Sclerosis; Quality of life; Rattus; Refractory; Regulation; Rehabilitation therapy; Research; Risk; Rodent; Serum; Skeleton; Solid; Spinal Cord Contusions; Spinal cord injury; Spinal cord injury patients; Stanolone; Stroke; Testing; Therapeutic; Thick; Thinness; Time; Trauma; United States; Veterans; WNT Signaling Pathway; Weight-Bearing state; Woman; Work; base; bone; bone loss; bone mass; bone metabolism; bone preservation; clinical care; dalton; efficacious treatment; experimental study; falls; fracture risk; functional independence; gait rehabilitation; improved; inhibitor/antagonist; innovation; insight; mRNA Expression; nervous system disorder; novel; osteoblast differentiation; osteoclastogenesis; preservation; prevent; receptor; rehabilitation strategy; stem cells; trend; vibration

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.

基本原理和目标：与制动相关的骨质流失发生在许多神经系统疾病中，包括 中风、脊髓损伤 (SCI)、多发性硬化症和肌萎缩侧索硬化症。术后骨质流失 SCI 发病特别迅速且严重。患有神经系统疾病的人骨骼变薄，使他们 跌倒后骨折的风险增加，甚至因轻微撞击而受到创伤。此类骨折会导致 住院、费用和生活质量下降。大约 46% 的 SCI 患者可能会发生骨折 在他们的一生中，风险大大增加。尽管这个问题很紧迫，但迄今为止，最严重的 FDA 批准的药物难以治疗与固定相关的骨质流失（例如 SCI） 针对此适应症进行了骨质疏松症测试。该应用程序旨在解决这一关键的治疗需求。 全身低强度振动（LIV）作为一种潜在的减慢速度的方法受到了极大的关注。 或预防骨质疏松症。例如，LIV 可以减少患有绝经后妇女和儿童的骨质流失 脑瘫。 LIV 是否可以改善 SCI 患者的骨量尚不清楚，尽管有一份病例报告 表明有一些有益的作用。我们最近进行了试点研究来评估 LIV 对 使用中度严重 SCI 大鼠模型进行骨质流失。 LIV 在 SCI 后 28 天开始并持续 35天。 LIV 诱导培养的骨形成和基因表达的血液标志物发生有利的变化 骨形成细胞。我们的试点结果首次确定了 LIV 对骨骼的潜在益处 SCI 模型，并且首次用于严重神经系统疾病或紊乱的模型。然而，LIV并没有 增加骨矿物质密度。最近的一项研究表明，全身振动（WBV）部分地 运动完全性（严重）SCI 大鼠早期阶段的骨退化减轻。我们的初步工作 和现有的知识为进一步研究LIV作为一种便捷的方法提供了坚实的支持。 SCI 相关骨质流失的治疗选择。该应用程序的前提是LIV将更加 长期服用并与减少净骨丢失的药物联合使用会有效， 特别是一种减少骨质疏松的药物（抗 RANKL 抗体）和一种促进骨骼生长的药物 新骨（雄激素）作为阻止 SCI 后骨质流失的新疗法。 目标 1：在中度挫伤 SCI 大鼠模型中，我们将测试延长 LIV 疗程是否会导致损伤。 提供更显着的保护骨骼的效果。我们还将研究LIV的机制 可能会刺激骨形成并减少参与骨细胞调节的骨吸收。在 此外，我们将评估抗 RANKL 抗体和/或雄激素联合给药时是否 与 LIV 联合使用，增强 LIV 对 SCI 后病灶下骨丢失的影响 目标 2. 在严重 SCI 大鼠模型中，我们将评估延长 LIV 疗程是否能起到保护作用 在非负重条件下防止严重 SCI 后的亚急性骨质流失；以及这种影响是否可以 通过抗 RANKL 抗体和/或雄激素与 LIV 的组合应用进一步增强。 意义和影响：研究结果可用于减缓或逆转 SCI 后的骨质流失。这是 目前还不确定这种益处是否会延缓严重骨质流失的发生，或者是否会影响骨质流失。 可以完全阻止损失。无论哪种情况，人们都可以设想使用拟议的干预措施至少 保留骨头直到神经修复治疗可用。此外，拟议的干预措施 承诺增加有资格接受负重康复策略的人数，例如 ReWalk、eLegs 或其他步态训练和功能独立性方式。有关知识 分子机制将以更根本的方式应用，通过提供对基本原理的见解 机械重新加载和雄激素作用的机制。最后，研究结果可能适用于提供 对未来相关基础科学研究的洞察，或指导未来药物的开发。