Corticosteroid-induced osteoporosis: pathogenesis and prevention

In spite of their adverse side effects, natural and synthetic glucocorticoids (GCs) occupy a unique role in several fields of medicine. They are potent regulators of bone cell growth and differentiation and the actions on the skeleton and related tissues depend on several factors including the dose, duration of the exposure, the steroid type and the species. In humans some of the effects are indirect, such as the regulation of intestinal calcium absorption and PTH secretion. Other effects are due to the cellular response that occurs within the bone microenvironment. It has been well established in in vitro studies that GCs can promote osteoblast differentiation from mesenchymal osteoprogenitors both in rat calvarial culture and in adherent marrow stromal cells. Moreover, GCs are able to enhance expression of the mature osteoblast phenotype, increasing mineralized nodules, osteocalcin secretion, and the bone morphogenetic protein-6 message level. However, the mechanisms by which GCs affect bone metabolism are still unclear. Recent studies with GCs on bone cells suggested that the production of cytokines and growth factors and the expression of their receptors may also be influenced by GCs. In fact, GCs are able to inhibit the synthesis of cytokines, such as interleukin-1 which stimulates bone remodeling by monocytes and macrophages. Moreover, osteoprotegerin, a recently cloned member of the tumor necrosis factor receptor family, is down-regulated by GCs, offering a possible interpretation for the induction of bone resorption by GCs. GC-induced inhibition of bone resorbing cytokines may contribute to explain the therapeutic actions of GCs in several diseases such as rheumatoid arthritis and myeloma. Furthermore, GCs modulate osteoclast recruitment, even if there is no clear explanation for a direct effect of GCs on osteoclastic precursors. Sustained stimulation of matrix degradation by isolated avian osteoclasts incubated with GCs has been reported, as well as cytotoxic effects on osteoclastic cells from neonatal rat long bones.