Mechanisms of glucocorticoid induced osteoporosis

Glucocorticoid-induced osteoporosis is the most common cause of secondary osteoporosis, and the degree of bone loss is related to the dose of glucocorticoids and the duration of the exposure. However, prolonged exposure to modest doses of glucocorticoids increases the risk of fractures and there is differential individual sensitivity to these steroids. Following treatment with glucocorticoids, there is an initial rapid loss of bone probably due to increased bone resorption and then a slower progressive loss probably secondary to decreased bone remodeling. Glucocorticoids decrease gastrointestinal calcium absorption and enhance bone resorption by increasing osteoclastogenesis since they stimulate the expression of receptor activator of NF-κB ligand and colony stimulating factor-1, and decrease the levels of osteoprotegerin, a soluble decoy receptor for receptor activator of NF-κB ligand. Glucocorticoids may prolong the life of mature osteoclasts under selected conditions. Eventually, glucocorticoids decrease bone remodeling by depleting the population of osteoblasts. This occurs by a decrease in osteoblastogenesis, and an increase in the apoptosis of mature osteoblasts and osteocytes. Glucocorticoids delay the maturation of immature stromal cells toward osteoblasts and inhibit the function of mature osteoblasts. Instead, glucocorticoids enhance adipogenesis, and this probably occurs at the expense of osteoblastic differentiation. The effect is secondary to the induction of CAAT enhancer binding protein beta and CAAT enhancer binding protein delta, and of peroxisome proliferator-activated receptor gamma, which inhibits osteoblastic differentiation. These effects suggest that glucocorticoids play a role in the trade of osteoblasts and adipocytes. This is confirmed further by the fact that Notch is induced by glucocorticoids and Notch inhibits osteoblastogenesis and enhances adipogenesis. Clinically, the early effects of glucocorticoids on bone resorption can be reversed by the administration of bisphosphonates, whereas the inhibitory effects on bone formation might be reversed by parathyroid hormone. In conclusion, glucocorticoids have profound effects on skeletal cells that lead to the development of osteoporosis.