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: 9291753
• 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 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9291753
• 关键词: Address; Amyotrophic Lateral Sclerosis; Androgens; Animal Model; Antibodies; Architecture; Attention; Attenuated; Automobile Driving; Basic Science; Biological Preservation; Blood; Bone Density; Bone Resorption; Caring; Case Study; Cells; Cerebral Palsy; Child; Clinical; Clinical Trials; Collaborations; Data; Deterioration; Development; Eligibility Determination; FDA approved; Fracture; Future; Gene Expression; Genes; Goals; Hospitalization; 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; 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; Stem cells; 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; clinical care; cost; dalton; experimental study; falls; fracture risk; gait rehabilitation; improved; inhibitor/antagonist; innovation; insight; mRNA Expression; nervous system disorder; novel; osteoblast differentiation; osteoclastogenesis; prevent; receptor; rehabilitation strategy; 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：与固定相关的骨质流失发生在许多神经系统条件下 中风，脊髓损伤（SCI），多发性硬化症和肌萎缩性侧面硬化症。骨质流失 SCI特别快速且严重。具有神经系统疾病的个体的骨头变薄 由于跌倒后甚至因创伤而导致骨折的风险增加。这样的骨折导致 住院，成本和生活质量下降。大约46％的SCI患者可能会骨折 他们的一生，风险大大提高。尽管这个问题的性质紧迫，但迄今为止，最严重的 与FDA批准的药物难治的固定形式（例如，SCI）的形式 骨质疏松症测试了这种指示。该应用程序旨在满足这种对治疗的关键需求。 全身低强度振动（LIV）正在受到大量关注，这是一种慢速的手段 或预防骨质疏松症。例如，LIV减少了绝经后妇女和儿童的骨质流失 脑瘫。尽管一例病例报告 提出了一些有益的效果。我们最近进行了试点研究，以评估LIV的影响 使用中等严重的SCI大鼠模型的骨丢失。 LIV在SCI后28天开始，并继续 35天。 LIV引起的骨形成血液标记和培养的基因表达的有利变化 骨形成细胞。我们的飞行员结果首次建立了LIV在骨骼中的潜在优势 SCI模型，这是严重神经疾病或疾病模型的第一次。但是，丽芙没有 增加骨矿物质密度。最近的一项研究表明，全身振动（WBV）部分 在患有运动完全（严重）SCI的大鼠的早期阶段，骨骼恶化减弱。我们的最初工作 当前的知识为进一步研究LIV提供了坚实的支持 科学相关骨质流失的治疗选择。该申请基础的前提是Liv将更多 如果长时间管理，则有效，并且与减少净骨质流失的药物相结合， 特别是一种减少骨骼变薄的药 新骨（雄激素）作为SCI后阻止骨质流失的新疗法。 目标1：在中度挫伤SCI的大鼠模型中，我们将测试长时间的LIV过程是否会 在保存骨头方面提供更明显的效果。我们还将研究LIV的机制 可能刺激骨形成并减少骨细胞调节所涉及的骨吸收。在 此外，我们将评估抗好砂抗体和/或雄激素是否在结合中进行给药。 使用LIV，增强LIV对SCI后骨损失的影响 目标2。在严重SCI的大鼠模型中，我们将评估长时间的LIV过程是否会保护 在非体重轴承条件下严重的SCI后，反对骨质流失；以及这种影响是否可以 通过将抗好砂抗体和/或雄激素与LIV结合使用，可以进一步增强。 显着性和影响：研究结果可用于SCI后缓慢或反向骨质流失。这是 尚不确定该好处是否会延迟严重的骨质流失，还是骨 损失可以完全阻止。无论哪种情况，都可以设想使用建议的干预措施至少 备用骨头直到可用神经疗法治疗。此外，建议的干预措施持有 承诺增加有资格获得负重康复策略的个人数量，例如 步态训练和功能独立性的回升，节拍或其他方式。有关的知识 分子机制将通过提供基本的见解，以更基本的方式适用 机械重新加载和雄激素作用的机制。最后，发现可以通过提供 洞察未来相关的基础科学研究，或指导未来药物的开发。