Sodium Homeostasis and Bone

Growing evidence suggests that skeletal bone, which contains 30–40% of total body sodium in humans, may play a role in body sodium homeostasis. Sodium balance is primarily regulated through the renin‐angiotensin‐aldosterone system (RAAS). Extracellular fluid (ECF) sodium concentrations ([Na + ]) reflect body sodium content but are also influenced by the osmoregulatory system, which is controlled by the posterior pituitary hormone arginine vasopressin (AVP). Consequently, changes in total body sodium content are not always accurately reflected by the ECF [Na + ], and conversely the ECF [Na + ] may not always accurately reflect total body sodium content. The most common clinical disorder of ECF [Na + ] is hyponatremia, which can lead to increased morbidity and mortality even when relatively mild. Hyponatremia has been shown to be associated with increased falls and fracture risk. Studies from our laboratory have shown that part of the increased fracture risk is likely due to adverse effects of hyponatremia on bone density and quality. The mechanisms through which this occurs are not yet completely understood, but prominently involve increased bone osteoclast formation and resorptive activity. In vitro studies using transformed rat bone marrow macrophages indicate that osteoclast formation and osteoclast activity are both stimulated by low ECF [Na + ] rather than low ECF osmolality. A potential physiological explanation for why osteoclasts are activated by low ECF [Na + ] is that bone acts as an internal sodium reservoir that can be accessed and deployed during sodium deficiency, which is detected by low ECF [Na + ]. The sodium resorbed from bone is retained by the kidney due to activation of RAAS. Mobilization of internal sodium stores would help to stabilize ECF volume and blood pressure, and in that sense would be evolutionarily protective under conditions of environmental sodium deficiency. In contrast, the low ECF [Na + ] in the syndrome of inappropriate antidiuretic hormone secretion (SIADH) is primarily due to water retention, not sodium deficiency. However, if ECF [Na + ] is the signal by which osteoclasts sense ECF and total body sodium, then this would represent a pathological “misinterpretation” of the low ECF [Na + ] as signifying deficient total body sodium. Furthermore, sodium resorbed from bone during SIADH would be excreted by the kidneys since RAAS is down‐regulated in SIADH. Consequently, there is no brake to the stimulated bone resorption, since the ECF [Na + ] would remain low no matter how much bone is resorbed. In summary, osteoclast [Na + ] sensing would be evolutionarily protective during times of sodium deficiency by augmenting ECF sodium from bone stores. However, when low ECF [Na + ] reflects water excess rather than sodium deficiency, this evolutionarily adaptive mechanism to maintain sodium homeostasis becomes maladaptive by negatively impacting bone quality and increasing fracture risk in hyponatremic patients. It therefore appears increasingly likely that sodium homeostasis is intrinsically linked to bone physiology, but further research will be needed to more accurately delineate the complex interplay between these two homeostatic systems.