Hyponatremia Is Linked to Bone Loss, Osteoporosis, Fragility and Bone Fractures

Chronic hyponatremia may not cause overt symptoms, and therefore frequently remains untreated. More recently, growing evidence indicate that this condition is not benign, and can lead to unsteady gait, deterioration of bone mass and strength, increased fragility, and increased all-cause mortality. We provided the first evidence for hyponatremia-induced osteoporosis based on markedly reduced bone mineral density and bone structural changes in hyponatremic rats, which is an experimental model of the syndrome of inappropriate antidiuresis (SIAD). These animal data were supported by results of the analysis of the National Health and Nutrition Examination Survey III dataset showing a 2.5-fold increased OR of osteoporosis in participants with serum sodium concentration [Na+] below 135 mmol/L. A subsequent cross-sectional study from Michigan analyzed data from 25,000 patients and found a strong association between the odds of osteoporosis by bone density and hyponatremia. This study pointed out that age-dependent decline in bone density may mask hyponatremia-induced bone loss. Multiple independent retrospective studies, epidemiological studies, and prospective clinical studies have since confirmed and extended our findings, reporting evidence for increased bone fractures and increased mortality in patients with hyponatremia. Cell culture studies have elucidated some of the adaptive mechanisms by which low extracellular fluid [Na+] increases osteoclast formation and bone resorbing activity, thereby liberating stored sodium from the bone matrix. Studies on older SIAD rats indicated that the damage may not be restricted to bone alone, but may involve other organs, including the heart, testis, kidney, and the brain. Finally, compelling open questions and future research directions about the effect of hyponatremia on bone are outlined.