Effects of acid on bone

Abstract

The homeostatic regulation of a stable systemic pH is of critical importance for mammalian survival. During metabolic acidosis (a reduction in systemic pH caused by a primary decrease in serum bicarbonate concentration), as seen in clinical disorders such as the later stages of chronic kidney disease, renal tubular acidosis, or chronic diarrhea, bone buffers the accumulated acid; however, this homeostatic function of the skeleton occurs at the expense of the bone mineral content and leads to decreased bone quality. During short-term studies to model acute metabolic acidosis, there is initial physiochemical bone mineral dissolution, releasing carbonate and phosphate proton buffers into the extracellular fluid. In addition, there is net proton influx into the mineral with release of bone sodium and potassium. During long-term studies to model chronic metabolic acidosis, there is also inhibition of osteoblast activity, resulting in reduced bone formation, and an increase in osteoclast activity, resulting in increased bone resorption and release of calcium and anionic proton buffers. These physicochemical and cell-mediated bone responses to metabolic acidosis, in addition to an acidosis-induced increased urine calcium excretion, without a corresponding increase in intestinal calcium absorption, induce a net loss of body calcium that is almost certainly derived from the mineral stores of bone.

Keywords: bone; calcium; mineral metabolism.

Figure 1 |. Response of bone to metabolic acidosis.

Acidosis has both short-term (<24 hours; blue) and long-term (>24 hours; red) effects on bone. Short-term responses are primarily physicochemical exchanges of protons (H⁺) with sodium (Na⁺) and potassium (K⁺) as well as Ca release; long-term responses are cell mediated and result, in addition, to the release of H⁺ buffers carbonates (CO₃²⁻) and phosphates (PO₄^3–). Osteoblast activity is regulated, leading to decreased bone formation and increased signaling that activates osteoclastic bone resorption. Collagen, alkaline phosphatase (AP), osteopontin (OP), and matrix Gla protein (MGP) are decreased, whereas prostaglandin E₂ (PGE₂), receptor activator of nuclear factor-κB ligand (RANKL), and fibroblast growth factor 23 (FGF23) are stimulated. Osteoclasts also respond directly to H⁺ in addition to the osteoblast-mediated activation through the receptor activator of nuclear factor-κB (RANK), leading to an increase in β-glucuronidase (β-Glu).

Figure 2 |. Cellular response to metabolic acidosis.

Protons (H⁺) interact with a specific receptor, ovarian cancer G-protein coupled receptor 1 (OGR1), in both the osteoblast and the osteoclast. This receptor is coupled to phospholipase C (PLC), and its activation leads to inositol trisphosphate (IP₃)–mediated release of intracellular calcium (Ca²⁺), which can alter specific gene transcription in the osteoblast. The transcription factor early growth response 1 (Egr1), matrix Gla protein (MGP), and osteopontin (OP) are decreased in response to metabolic acidosis, whereas cyclooxygenase 2 (COX2) is increased, catalyzing increased prostaglandin E₂ (PGE₂) production from arachidonic acid (AA). PGE₂ then stimulates production of receptor activator of nuclear factor-κB ligand (RANKL) as well as fibroblast growth factor 23 (FGF23) by paracrine activation of the EP4 prostaglandin receptor. RANKL is secreted and binds to its receptor, receptor activator of nuclear factor-κB (RANK), on the osteoclast, leading to increased bone resorption. Release of the lysosomal enzyme, β-glucuronidase is indicative of osteoclast activation. The specific intracellular signaling initiated by OGR1 in the osteoclast is less well understood, but both pathways are necessary for the full response to metabolic acidosis.

Figure 3 |. Contribution of metabolic acidosis to chronic kidney disease (CKD)–mineral and bone disorder.

As kidney function declines, renal acid excretion becomes quantitatively less than endogenous acid production, leading to chronic metabolic acidosis. Metabolic acidosis is among the factors that lead to a reduction in levels of serum 1,25-dihydroxyvitamin D₃ (calcitriol) and an increase in levels of parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23). Metabolic acidosis also accelerates the progression of CKD. The osseous response to metabolic acidosis results in the release of calcium (Ca²⁺) and the proton (H⁺) buffers carbonates (CO₃²⁻) and phosphates (PO₄³⁻), which help restore the systemic pH toward normal. There is also exchange of H⁺ for sodium (Na⁺) and potassium (K⁺), which again help mitigate the severity of the acidosis. The loss of bone mineral leads to bone fragility, which will increase the rate of bone fracture.