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.