Hyponatremia-Induced Osteoporosis and Fragility

低钠血症引起的骨质疏松症和脆性

• 批准号: 9921277
• 负责人: JULIANNA BARSONY
• 金额: $ 37.22万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9921277
• 关键词: Address; Age; Age-Years; American; Anabolic Agents; Animal Model; Animals; Applications Grants; Awareness; Blood; Bone Diseases; Bone Matrix; Bone Resorption; Cell Culture Techniques; Cells; Chronic; Clinical; Clinical Research; Communities; Coupled; Data; Defect; Economic Burden; Elderly; Equilibrium; Evaluation; Event; Extracellular Fluid; Female; Fracture; Funding; Gait; Goals; Gonadal Hormones; Health; Healthcare; Human; Hyponatremia; Impairment; In Vitro; Inappropriate ADH Syndrome; Incidence; Intervention; Laboratories; Lead; Mediating; Modeling; Molecular; Molecular Target; Monomeric GTP-Binding Proteins; Morbidity - disease rate; Mus; Myocardium; Odds Ratio; Organ; Osteoblasts; Osteoclasts; Osteogenesis; Osteopenia; Osteoporosis; Pathology; Pathway interactions; Patients; Population; Prevalence; Primary Cell Cultures; Property; Publishing; Rattus; Reporting; Resistance; Risk; Risk Factors; Role; Signal Transduction; Signal Transduction Pathway; Skeletal Muscle; Sodium; Sodium-Calcium Exchanger; Surgeon; TNFSF11 gene; Testing; Testis; Therapeutic; Time; United States National Institutes of Health; World Health Organization; age related; aged; base; bone; bone fragility; bone health; bone loss; bone quality; brain dysfunction; cell type; cost; epidemiology study; extracellular; fall risk; falls; fragility fracture; hormone deficiency; improved; in vivo; male; monocyte; mortality; novel; older patient; osteoclastogenesis; osteoporosis with pathological fracture; prevent; receptor; response; senescence; sensor

PROJECT SUMMARY/ABSTRACT Osteoporosis, and resulting osteoporotic fractures, are major health problems in the world. Age and gonadal hormone deficiency are well known to be major risk factors for osteoporosis, but other causes of osteoporosis are increasingly recognized as contributing to accelerated bone loss and increased fracture incidence. Consequently, recognition of novel factors leading to osteoporosis is important from both a preventative and a therapeutic perspective. In considering other potential causes of bone loss, clinical cases of unexplained osteoporosis in patients with chronic hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) prompted us to examine this as another potential cause of accelerated bone loss. Using an animal model of SIADH developed in this laboratory, we have shown that chronic hyponatremia causes severe resorptive bone loss in young and old rats, both male and female. Our in vivo studies have indicated a direct effect of low extracellular sodium levels to stimulate osteoclastogenesis and activate osteoclast-mediated bone resorption. Additional studies in hyponatremic animals have documented damage to other organs, including testis, heart and skeletal muscle that resemble age-related senescent changes in these organs. In view of the very high reported prevalence of hyponatremia in geriatric patients (7-35%) coupled with an association between gait instability and falls with even asymptomatic hyponatremia, any additional hyponatremia-related increased risk of accelerated osteoporosis in this vulnerable aged and frail population would be of much concern. The importance of hyponatremia for bone health has now been corroborated by multiple retrospective clinical studies that have shown a significant association between even mild hyponatremia and increased bone fractures, and our epidemiological studies of 2.9 million patients that indicate odds ratios for both osteoporosis and fragility fractures of 11.2-12.1 in patients with chronic sustained hyponatremia. The proposed studies will address the cellular and molecular mechanisms by which hyponatremia increases bone fragility, the reversibility of hyponatremia-induced bone loss and gait instability, and the best treatments to prevent and/or reverse hyponatremia-induced bone and brain dysfunction using interventions specifically targeted to cellular mechanisms that we have already discovered during previous NIH funding of this project.

项目摘要/摘要 骨质疏松症和由此导致的骨质疏松性骨折是世界上的主要健康问题。年龄和性腺 众所周知，激素缺乏是骨质疏松症的主要危险因素，但其他导致骨质疏松症的原因 越来越多地被认为是加速骨质流失和增加骨折发生率的原因。 因此，从预防和预防两个方面认识导致骨质疏松症的新因素都是重要的。 治疗的角度。在考虑骨丢失的其他潜在原因时，临床病例未解释 抗利尿激素不当综合征所致慢性低钠血症患者的骨质疏松 分泌物(SIADH)促使我们将其作为加速骨质流失的另一个潜在原因进行研究。使用 本实验室建立的SIADH动物模型表明，慢性低钠血症可引起严重的 年轻和老年大鼠的骨吸收丢失，无论是雄性还是雌性。我们的体内研究表明， 低钠离子刺激破骨细胞生成及激活破骨细胞介导骨的作用 再吸收。对低钠血症动物的其他研究也证明了对其他器官的损害，包括 睾丸、心脏和骨骼肌类似于这些器官中与年龄相关的衰老变化。鉴于 老年患者中报告的低钠血症患病率很高(7-35%)，同时还有一个 在步态不稳定和跌倒之间，甚至有无症状的低钠血症，任何额外的低钠血症相关 在这个脆弱、年老和虚弱的人群中，加速骨质疏松的风险将会增加很多。 担忧。低钠血症对骨骼健康的重要性现在已被多项回顾所证实。 临床研究表明，即使是轻微的低钠血症也与骨量增加有显著关联 骨折，以及我们对290万名患者的流行病学研究，显示了骨质疏松和骨质疏松症的优势比 慢性持续性低钠血症患者脆性骨折11.2~12.1。拟议的研究将 解决低钠血症增加骨脆性的细胞和分子机制， 低钠血症引起的骨丢失和步态不稳定的可逆性，以及预防和/或最佳治疗 使用针对细胞的干预措施逆转低钠血症所致的骨和脑功能障碍 我们在NIH为该项目提供资金时已经发现的机制。