SUN-371 Hyponatremia Correction Normalizes Bone Mineral Density and Bone Fragility in Rats

Multiple epidemiologic studies have associated chronic hyponatremia with both osteoporosis and bone fractures. Studies in experimental animals and cultured cells have demonstrated that reducing the extracellular sodium concentration ([Na(+)]) causes bone loss primarily by increasing osteoclast formation and bone resorbing activity. In osteoclastic cell cultures, reducing [Na(+)] activated biochemical and functional changes in osteoclast activity, which appear to occur by direct sodium-sensing mechanisms on osteoclasts that are independent from changes in osmolality. Whether the pathological changes in bones induced by hyponatremia can be reversed by correction of hyponatremia has not been studied. The present studies were initiated to address this question. 22-month-old F344BN F1-hybrid rats were made hyponatremic using a desmopressin continuous infusion while fed a liquid diet. After 3 months of chronic sustained hyponatremia, a cohort of the hyponatremic rats were corrected to a normal [Na(+)] by removal of the desmopressin minipumps and allowed to recover for 2 months. Both bone density measurements by DXA and biomechanical testing were performed on excised bones from normonatremic control rats (NN, [Na(+)]=145±5.6 mmol/L, n=9), chronically hyponatremic rats (HN, [Na(+)]=114±4.7 mmol/L, n =9) and hyponatremic corrected rats (HC, [Na(+)]=139±1.4 mmol/L, n =9). The results confirm that chronic hyponatremia caused significant decreases in bone mineral density (BMD, g/cm(2)) in the L4 vertebra (NN=0.166±0.003, HN=0.151±0.002, P=0.002) and femur (NN=0.229±0.004, HN=0.213±0.005, P=0.024). Bone fragility as measured by ultimate load to fracture (UL, Newtons) was also increased in the L5 vertebra (NN=369.8±51.1, HN=262.9±29.4, P=0.0001), but only slightly in the femur (NN=295.4±57.5, HN=286.0±35.4, P=0.682). Following correction of hyponatremia, both BMD and UL recovered after 2 months to levels not significantly different than the normonatremic controls: L4 BMD (NN=0.166±0.003, HC=0.167±0.002, NS); femur bone density (NN=0.229±0.004, HC=0.226±0.003, NS); UL in the L5 vertebra (NN=369.8±51.1, HC=384.1±63.5, NS). These results show that bone fragility parameters are adversely affected by chronic hyponatremia in addition to the previously reported decreases in BMD in rats. Consistent with the BMD results, the trabecular bone in the spine was more severely affected than the cortical bone in the femur. Our results show that much of the bone pathology of hyponatremia-induced osteoporosis can be reversed following correction of the hyponatremia without using specific antiresorptive therapy. Our findings therefore raise the possibility that correction of hyponatremia may be effective as a therapy for treatment of hyponatremia-induced osteoporosis in selected patients.