Why Does Inflammation Result in Resorptive Bone Loss? What the Study of Burns Teaches Us

Abstract

Burn injury serves as an example of a condition with a robust systemic inflammatory response. The elevation of circulating interleukins (IL)-1β and -6 in children and adolescents with severe burn injury upregulates the parathyroid calcium-sensing receptor (CaSR), resulting in hypocalcemic hypoparathyroidism accompanied by urinary calcium wasting. This effect protects the body from the hypercalcemia that results from bone resorption, liberating calcium into the circulation. Extracellular calcium can exacerbate and prolong the inflammatory response by stimulating mononuclear cell chemokine production as well as the NLRP3 inflammasome of the innate immune system, resulting in increased IL-1 production by monocytes and macrophages. Interestingly, the CaSR upregulation in response to inflammatory cytokines disappears with age, potentially trapping calcium from bone resorption in the circulation, allowing it to contribute to increased inflammation and possibly increased calcium deposition in small arteries, such as the coronaries, as conditions with increased chronic inflammation, such as spinal cord injury, osteoarthritis, and rheumatoid arthritis have an incidence of cardiovascular disease and coronary artery calcium deposition significantly higher than the unaffected age-matched population.