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.

总体研究战略：确保老年退伍军人在尽可能少的肌肉骨骼下保持活跃和活动 尽可能疼痛，预防骨质疏松症和促进及时骨再生的新方法 骨折后是必要的。这项合作研究汇集了一组退伍军人管理局的调查人员 以不同的视角、见解、模型和技术，协同解决重大临床问题 这会导致退伍军人的高发病率和死亡率，导致骨折。每个项目的总体研究策略 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，要么推迟骨骼修复，以 探索利用或增强甲状旁腺激素(PTH)促进骨形成的新方法， 并对骨骼疾病和治疗效果进行统一、严格的评估。已经被低估了 如果治疗不当，骨质疏松症可能会增加退伍军人医院治疗的脆性骨折的数量 没有新的早期发现工具和新的治疗策略来规避罕见但毁灭性的 目前抑制骨质流失的治疗方法的副作用。解决这一未得到满足的临床需求，总体目标是 确定治疗策略以改善退伍军人的骨健康，并增强退伍军人的骨合成代谢 PTH信令。这项合作将解决这个最重要的假设：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，从而改善临床治疗 骨质疏松的关键在于了解这些健康问题是如何损害骨骼健康的。 项目研究策略：预防骨折的传统临床护理标准，是筛查 骨质疏松症在疾病病程的晚期，在骨质被剥离和骨折迫在眉睫之后，在 求助于抗骨质疏松症药物疗法。然而，这样的疗法在再生丢失方面效率低下。 骨骼和骨骼质量是承重强度的一个重要方面，但往往仍然不足。因此，临床上 护理标准往往是不够的，许多患者最终会继续骨折，无论 接受治疗的机会。使问题雪上加霜的是，抗吸收药(尤其是双膦酸盐)有显著的立竿见影的效果， 以及罕见但严重的长期副作用，导致依从性差，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，该项目将调查 时间，节省9“，通过检查早期预防是否使用抗分解代谢药物，合成代谢药物和非 药理营养补充剂，以防止在疾病病因早期发生骨丢失， 在预防骨折方面比晚期治疗更有效，因为骨已经剥离和 再生则更加困难。我们将研究与骨折发病率增加相关的两种疾病 不成比例地影响退伍军人。1.绝经后骨质疏松症--妇女的典型骨病 鉴于女性是增长最快的人群，退伍军人医疗保健系统中不断升级的问题。 2.用于治疗HIV的抗逆转录病毒疗法(ART)引起的免疫重建骨丢失(IRBL) 感染。我们将在小鼠模型中测试这一假说，即短期干预以保护骨量在 疾病的早期病程，优于传统的扣留标准的护理方法 干预直到骨骼被严重剥离，然后再用药理学方法进行干预 这在修复丢失的骨骼方面天生效率低下，充其量只能延缓而不是防止骨折。我们会 利用我们的退伍军人管理局协作合作伙伴协同扩展我们研究的深度和范围，并允许 美国将进行广泛的最先进的骨骼表型鉴定，以评估骨骼结构、质量和骨折 双模型系统中的阻力。如果我们的研究揭示了早期治疗的显著优势，这一点 将支持未来在人类身上进行的研究，以改变预防骨折的护理标准。