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; 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：确保老化的退伍军人保持活跃和流动性，肌肉骨骼少 尽可能疼痛，预防骨质疏松症和促进及时骨再生的新方法 骨折之后是必要的。这项合作研究汇集了一群VA调查人员 具有潜水员的观点，见解，模型和技术，以协同攻击主要的临床问题 这导致退伍军人的发病率高和死亡率，这是骨折。每个人的总体研究策略 综合项目是使用疾病的临床前模型，该模型可以削弱骨骼或延迟骨骼修复，以 研究利用或增强甲状旁腺骑马（PTH）促进骨形成的能力的新颖方法， 并以统一，严格的方式评估对骨骼的疾病和治疗作用。已经诊断不清 并且处理不足的骨质疏松症可能会增加VA医院正在治疗的脆弱性骨折数量 没有新颖的工具用于早期检测和新颖的治疗策略，这些策略避免了罕见但毁灭性的 抑制骨质流失的当前疗法的副作用。解决这种未满足的临床需求，总体目的是 确定改善退伍军人骨骼健康的治疗策略，并增强 PTH信号传导。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，以增加骨骼分辨率，抑制骨形成或 阻碍软骨向骨骼过渡到骨折的愈伤组织中，以改善临床管理 骨质疏松症在于了解这些健康问题如何损害骨骼健康。 项目研究策略：预防断裂的传统临床护理标准是筛选 在疾病的后期，骨质疏松症是在骨裸露骨骼后的骨折之后，骨折是迫在眉睫的 诉诸抗疏松性药物疗法。但是，这种疗法在再生损失时效率低下 骨骼和骨质质量是负载强度的重要方面，通常仍然不足。那，临床 护理标准经常不足，许多患者最终继续保持骨折，而不论 治疗。复杂问题，抗抑郁（尤其是双膦酸盐）具有显着的即时 以及罕见但严重的长期副作用，使依从性差，拒绝开始治疗。 鉴于与晚期药物干预相关的一系列问题，该项目将调查“ 时间，通过检查是否使用抗代谢药物，合成代谢药物和非 - 药理营养补充剂，以防止疾病病因初期发生骨质流失， 在骨骼已经被剥去后，比晚期治疗更有效地预防骨骼骨折，并且 再生更加困难。我们将研究与骨折事件增加有关的两个疾病，并 不成比例地影响退伍军人。 1。绝经后骨质疏松症，妇女的原型骨病和 鉴于女性的VA医疗保健系统中的一个不断升级的问题是人口最快的人口。 2。由用于治疗HIV的抗逆转录病毒疗法（ART）引起的免疫重建骨质流失（IRBL） 感染。我们将在小鼠模型中进行测试，这是一个假设，即短期干预以保留骨骼质量 该疾病的早期病程优于传统的护理标准方法 干预措施，直到骨骼被严重剥去，然后才介入药物方法 固有的效率在恢复失去的骨骼方面效率低下，充其量是延迟而不是预防骨折。我们将 利用我们的VA协作合作伙伴来协同扩大我们研究的深度和范围，并允许 我们要进行广泛的最新骨表型来评估骨骼结构，质量和断裂 两模型系统中的电阻。我们的研究是否应该显示出早期治疗的重要优势，这 将支持人类未来的研究，以改变预防断裂的护理标准。