New Developments in the Pathogenesis and Treatment of Steroid‐Induced Osteoporosis

THE ADVERSE EFFECTS OF HYPERCORTISOLISM on bone were recognized more than half a century ago, but today, the iatrogenic form of the disease has become far more common than Cushing’s syndrome and glucocorticoid excess is the third leading cause of osteoporosis following loss of sex steroids and old age. It is estimated that as many as 50% of patients requiring glucocorticoids for the control of pulmonary, rheumatologic, autoimmune, hematopoietic, gastrointestinal disease, or to prevent transplant rejection will ultimately suffer fractures. The underlying cause of the fractures in glucocorticoid-induced osteoporosis, as in other forms of osteoporosis, is loss of bone. With glucocorticoid treatment, the loss of bone is biphasic with a rapid initial phase of approximately 12% during the first few months, followed by a slower phase of about 2–5% annually. Both cortical and cancellous bone are lost, but the adverse effects of steroids have a predilection for the axial skeleton. Hence, spontaneous fractures of the vertebrae or ribs are often presenting manifestations of the disorder. Besides these fractures, a frequent accompaniment of longterm glucocorticoid therapy is osteonecrosis—otherwise known as aseptic or avascular necrosis—which causes collapse of the femoral head in as many as 25% of patients. Because of the heterogeneity of the underlying conditions—some of which (e.g., rheumatoid arthritis, lymphoma, myeloma, Crohn’s disease) independently contribute to skeletal deterioration—wide variations of dose and duration of treatment and lack of a faithful animal model, progress toward the elucidation of the mechanism(s) responsible for the adverse impact of glucocorticoids on the skeleton has been slow. As a result, the management of this condition has remained largely empirical. Recent advances in bone biology, in general, and elucidation of key mechanisms in glucocorticoid-induced osteoporosis, in particular, provide for the first time a convincing explanation of the pathogenesis of the disease and raise hope that more rational therapy may be forthcoming. The purpose of this editorial is to highlight these new developments and to point out their pharmacotherapeutic implications. To appreciate them better, however, one must first understand some basic principles of bone homeostasis.