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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/文摘