Numerous epidemiologic studies have associated hyponatremia with both osteoporosis and bone fractures. Disordered bone metabolism with hyponatremia occurs primarily by direct sodium-sensing mechanisms on osteoclasts that are independent from osmolality. Additional effects may be mediated by arginine vasopressin (AVP) receptors on osteoclasts and osteoblasts. Further, even mild hyponatremia can contribute to neurological dysfunction via gait instability and increased falls, both of which compound fracture risk. Accumulating evidence therefore supports the hypothesis that sodium homeostasis is an important component of bone metabolism. Although the cellular mechanisms are yet to be fully identified, studies in rats and cultured cell demonstrated that reducing the sodium concentration ([Na+]) causes osteoporosis primarily by increasing osteoclast formation from precursors by activation of the RANK/PI3K/Akt/mTOR pathway. More recent studies have identified immediate index responses to low [Na+] (120 mmol/l) in mature osteoclasts from primary murine bone marrow macrophages and murine RAW264.7 pre-osteoclastic cells, including: 1. Increased cellular GTP-bound Rac1 GTPase, detected through specific protein interaction with the Pak1 protein-binding domain. Specificity of the GTP-bound Rac1 response was confirmed by similar assays on GTP-bound Rho with the Rhotekin binding domain and GTP Ras with the Raf1 protein binding domain. 2. Increased cellular lysosome acidity, detected by increased fluorescence emission after 5, 15, and 30 min, peaking at 45 min in response to low [Na+], whereas no change was detected in normal [Na+] samples. Correcting the low [Na+]-induced membrane hyperpolarization by adding equimolar choline chloride (20 mmol/l) did not prevent the increase in lysosomal acidification. These data indicate that mature osteoclasts rapidly respond to low [Na+] with GTPase activation, likely from a G-protein-mediated low [Na+]-sensing mechanism with subsequent triggering of acid production promoting resorption of bone matrix. Controlled clinical trials are needed to address whether reversing disorders of sodium homeostasis can improve individual patient and population-based skeletal health.