Key Points• On a typical Western diet, humans generate metabolic acids which must be excreted, through renal mechanisms, to maintain a stable physiologic systemic pH.• Any impairment of kidney function will lead to a fall in systemic pH which is termed metabolic acidosis. During metabolic acidosis, the bone buffers acid (protons) and also releases calcium, a response that has been observed both in vivo and in vitro.• In metabolic acidosis there is direct proton-mediated physicochemical release of calcium from bone.• Sodium and potassium are also released from the mineral surface in exchange for the hydrogen ions.• With metabolic acidosis of longer duration (>24 h), release of bone calcium occurs by a cellmediated stimulation of bone resorption and inhibition of bone formation.• The cell-mediated response to metabolic acidosis involves changes in specific gene expression and is primarily due to a stimulation of endogenous osteoblastic prostaglandin E 2 production, leading to production of RANKL and subsequent activation of osteoclastic bone resorption.• The initial signaling event in the osteoblast appears to be activation of a specific proton receptor, OGR1.• In addition to a net increase in bone resorption, metabolic acidosis has also recently been shown to stimulate production of osteoblastic FGF23.• Respiratory acidosis, due to an increase in the partial pressure of CO 2 , does not alter proton or calcium flux in bone.• As renal function decreases with age, kidneys cannot excrete the daily acid load and this mild metabolic acidosis can lead to a significant decrease in bone mineralization potentially contributing to osteoporosis and fracture.