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Hyponatremia-Induced Osteoporosis and Fragility

低钠血症引起的骨质疏松症和脆性

基本信息

批准号：
10165435
负责人：
JULIANNA BARSONY
金额：
$ 37.22万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10165435
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

项目摘要

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.

项目总结/摘要骨质疏松症和由此导致的骨质疏松性骨折是世界上主要的健康问题。年龄和性腺众所周知，激素缺乏是骨质疏松症主要危险因素，但骨质疏松症的其他原因越来越多地被认为是加速骨丢失和增加骨折发生率的原因。因此，识别导致骨质疏松症的新因素对于预防和治疗骨质疏松症都是重要的。治疗视角在考虑骨丢失的其他潜在原因时，抗利尿激素分泌不当综合征所致慢性低钠血症患者的骨质疏松症分泌（SIADH）促使我们将其作为加速骨丢失的另一个潜在原因进行研究。使用在本实验室开发的SIADH动物模型中，我们已经表明慢性低钠血症引起严重的年轻和老年大鼠（雄性和雌性）的骨吸收丢失。我们的体内研究表明，低细胞外钠水平对刺激破骨细胞生成和活化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记录了其他器官的损伤，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。考虑到老年患者中报告的低钠血症患病率非常高（7-35%），步态不稳和福尔斯跌倒甚至无症状低钠血症之间的关系，任何额外的低钠血症相关在这个脆弱的老年和虚弱人群中，加速骨质疏松症的风险增加将是非常重要的。关心低钠血症对骨骼健康的重要性现已得到多项回顾性研究的证实。临床研究表明，即使是轻度低钠血症和骨质增加之间也存在显著相关性，骨折，以及我们对290万患者的流行病学研究表明，骨质疏松症和慢性持续性低钠血症患者的脆性骨折为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的可逆性，以及预防和/或逆转低钠血症引起的骨和脑功能障碍，使用专门针对细胞的干预措施，我们在之前NIH资助这个项目时已经发现的机制。