BCCMA: Foundational Research to Act Upon and Resist Conditions Unfavorable to Bone (FRACTURE CURB): A stitch in time saves nine!

BCCMA：采取行动并抵抗对骨骼不利的条件的基础研究（骨折遏制）：及时缝一针可以节省九针！

• 批准号: 10483595
• 负责人: Mervyn Neale Weitzmann
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10483595
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Aging; Anabolism; Animal Model; Anxiety; Biological Models; Bone Density; Bone Diseases; Bone Regeneration; Bone Resorption; Bone callus; Bone necrosis; Bone structure; Cartilage; Chronic; Clinical; Clinical Management; Collaborations; Diagnosis; Disease; Disease model; Dual-Energy X-Ray Absorptiometry; Early Diagnosis; Early Intervention; Early treatment; Economic Burden; Elderly; Ensure; Estrogen deficiency; Etiology; Femoral Fractures; Financial cost; Fracture; Fright; Future; Goals; HIV; HIV Infections; Health; Health Personnel; Healthcare Systems; Hip Fractures; Hospitals; Human; Incidence; Individual; Integrated Health Care Systems; Intervention; Jaw; Medical; Mental Depression; Modeling; Morbidity - disease rate; Mus; Musculoskeletal Pain; Natural regeneration; Oral; Osteogenesis; Osteoporosis; Osteoporosis prevention; Osteoporotic; Outcome Measure; PTH gene; Participant; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phenotype; Postmenopausal Osteoporosis; Postmenopause; Pre-Clinical Model; Prevention; Prevention approach; Process; Prophylactic treatment; Quality of life; Rehabilitation therapy; Rejuvenation; Reporting; Research; Research Personnel; Research Project Grants; Resistance; Resort; Resources; Signal Pathway; Skeleton; Source; Techniques; Technology; Testing; Therapeutic; Time; Veterans; Weight-Bearing state; Woman; absorption; antiretroviral therapy; bisphosphonate; bone; bone health; bone loss; bone mass; bone preservation; bone quality; bone repair; bone turnover; chronic pain; cost; dietary supplements; disability; efficacy evaluation; fracture risk; fragility fracture; high risk; hormonal signals; immune reconstitution; improved; in vitro Model; in vivo; innovation; insight; male; men; mortality; mouse model; novel; novel strategies; novel therapeutic intervention; pharmacologic; prevent; psychologic; research study; side effect; skeletal disorder; standard of care; stem; tool; treatment effect; treatment strategy

Overall Research Strategy: To ensure aging Veterans remain active and mobile with as little musculoskeletal pain as possible, new approaches to the prevention of osteoporosis and promotion of timely bone regeneration following a fracture are necessary. This collaborative research study brings together a group of VA investigators with diverse perspectives, insights, models, and techniques, to synergistically attack a major clinical problem that leads to high morbidity and mortality among Veterans, a bone fracture. The overall research strategy of each integrated project is to use pre-clinical models of a disease that either weakens bone or delays bone repair, to investigate novel ways to utilize or enhance the ability of parathyroid hormone (PTH) to promote bone formation, and to assess disease and treatment effects on bone in a unified, stringent manner. Already under-diagnosed and under-treated, osteoporosis is likely to increase the number of fragility fractures being treated at VA hospitals without novel tools for early detection and novel treatment strategies that circumvent the rare but devastating side effects of current therapies that inhibit bone loss. Addressing this unmet clinical need, the overall aims are to identify therapeutic strategies to improve bone health among Veterans and to enhance the bone anabolism of PTH signaling. The collaboration will address this overarching hypothesis: health problems disproportionately affecting Veterans activate signaling pathways that increase bone resorption, suppress bone formation, or impede the transition of cartilage to bone in a fracture callus such that improvements in the clinical management of osteoporosis lie in understanding how these health problems hurt bone health. Project Research Strategy: The traditional clinical standard of care for fracture prevention, is to screen for osteoporosis late in the course of the disease, after bone has been denuded and fracture is imminent, before resorting to anti-osteoporotic pharmacotherapies. Such therapies however, are inefficient at regenerating lost bone, and bone quality, an important aspect of load bearing strength, often remains deficient. Thus, the clinical standard of care is frequently inadequate and many patients ultimately go on to sustain a fracture, irrespective of therapy. Compounding the problem, anti-resorptives (especially bisphosphonates) have significant immediate, as well as rare, but serious long-term side-effects, making for poor compliance and refusal to initiate therapy. Given this array of issues associated with late drug intervention, this project will investigate whether “a stich in time, saves nine”, by examining if early prophylaxis using anti-catabolic drugs, anabolic drugs and a non- pharmacological nutritional supplement, to prevent bone loss from occurring early in the etiology of the disease, is more effective at preventing bone fracture than late therapy after bone has already been denuded and regeneration is more difficult. We will study two maladies associated with increased fracture incidence and that disproportionally affect Veterans. 1. Postmenopausal Osteoporosis, the archetypal bone disease of women and an escalating problem in the VA healthcare system given women are the most rapidly increasing demographic. 2. Immune reconstitution bone loss (IRBL) which is caused by antiretroviral therapy (ART) used to treat HIV infection. We will test in mouse models, the hypothesis that short-term intervention to preserve bone mass during the early course of the disease, is superior to the traditional standard of care approach of withholding interventions until the skeleton has been seriously denuded, before intervening with pharmacologic approaches that are inherently inefficient at rejuvenating lost bone, and at best delay rather than prevent fractures. We will leverage our VA collaborative partners to synergistically expand the depth and scope of our studies and allow us to perform extensive state-of-the-art bone phenotyping to assess bone structure, quality and fracture resistance in the two-model system. Should our studies reveal a significant advantage for early therapy, this would support studies future studies in humans towards a change in the standard of care for fracture prevention.

总体研究策略：确保老年退伍军人保持活跃和移动的，肌肉骨骼尽可能少 疼痛尽可能，新的方法来预防骨质疏松症和促进及时骨再生 在骨折后是必要的。这项合作研究汇集了一组VA调查人员 通过不同的视角、见解、模型和技术，协同解决重大临床问题 导致退伍军人的高发病率和死亡率，骨折。每个研究中心的总体研究战略 一个综合项目是使用一种疾病的临床前模型，这种疾病要么削弱骨骼，要么延迟骨骼修复， 研究利用或增强甲状旁腺激素（PTH）促进骨形成的能力的新方法， 并以统一、严格的方式评估疾病和治疗对骨的影响。已经诊断不足了 骨质疏松症治疗不足，可能会增加在VA医院治疗的脆性骨折的数量 如果没有新的早期检测工具和新的治疗策略， 目前抑制骨质流失疗法的副作用。为了解决这一未满足的临床需求，总体目标是 确定改善退伍军人骨骼健康的治疗策略， PTH信号传导。这项合作将解决这一总体假设：健康问题不成比例 影响退伍军人激活信号通路，增加骨吸收，抑制骨形成，或 阻碍骨折骨痂中软骨向骨的转变 了解这些健康问题如何损害骨骼健康。 项目研究策略：传统的骨折预防的临床护理标准是筛选 骨质疏松症在病程的后期，在骨骼已被剥脱和骨折即将发生之前， 求助于抗癫痫药物治疗然而，这种疗法在再生损失方面是低效的。 骨和骨质量（承重强度的一个重要方面）通常仍然不足。因此，临床 护理标准常常不足，许多患者最终继续承受骨折， 心理治疗使问题复杂化的是，抗再吸收剂（尤其是双膦酸盐）具有显著的立即， 以及罕见但严重的长期副作用，导致依从性差和拒绝开始治疗。 考虑到这一系列与晚期药物干预相关的问题，本项目将调查“一个斯蒂奇在 时间，节省九个”，通过检查是否使用抗分解代谢药物，合成代谢药物和非 药理学营养补充剂，以防止在疾病病因学早期发生骨丢失， 在预防骨折方面比骨已经剥脱后的后期治疗更有效， 再生是比较困难的。我们将研究两种与骨折发病率增加有关的疾病， 影响退伍军人。1.绝经后骨质疏松症，女性的典型骨病， 鉴于妇女是增长最快的人口，退伍军人管理局医疗保健系统的问题不断升级。 2.免疫重建骨丢失（IRBL）是由用于治疗HIV的抗逆转录病毒治疗（ART）引起的 感染我们将在小鼠模型中测试以下假设： 病程的早期，是上级于传统的标准治疗方法的保留 干预，直到骨骼已经严重裸露，然后再用药物方法干预 这在恢复失去的骨骼方面本来就效率低下，充其量只能延迟而不是预防骨折。我们将 利用我们的VA合作伙伴协同扩大我们的研究的深度和范围，并允许 我们进行了广泛的最先进的骨表型，以评估骨结构，质量和骨折 两个模型系统中的阻力。如果我们的研究揭示了早期治疗的显著优势， 将支持未来的人类研究，以改变骨折预防的护理标准。