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

Abstract

"The greatly compressed bodies of the vertebrae … were so soft they could easily be cut with a knife."—Harvey Cushing, 1932 THE ADVERSE EFFECTS OF HYPERCORTISOLISM on bone were recognized more than half a century ago,1 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.2 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 long-term 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.3 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. During life, the skeleton undergoes remodeling, a periodic replacement of old bone by new, which is responsible for the complete regeneration of the adult skeleton every 10 years. Remodeling is carried out by a team of juxtaposed osteoclasts (in the front) and osteoblasts (in the rear), comprising the basic multicellular unit (BMU). In cortical bone the BMUs tunnel through the tissue, while in cancellous bone they move across the trabecular surface forming a trench. In both situations the cellular components of the BMU maintain a well-orchestrated spatial and temporal relationship with each other. Osteoclasts attach to bone and subsequently remove it by acidification and proteolytic digestion. As the BMU advances, osteoclasts leave the resorption site and osteoblasts move in to cover the excavated area and begin the process of new bone formation by secreting osteoid, which is eventually mineralized. In healthy human adults, 3–4 million BMUs are initiated per year and about 1 million are operating at any moment.4 Even though millions of small packets of bone are constantly remodeled, bone mass is preserved thanks to a remarkably tight balance between the amount of bone resorbed and formed during each cycle of remodeling (Fig. 1, upper panel). Comparison of a normal cycle of bone remodeling (upper panel) with an abnormal one caused by glucocorticoid excess (lower panel); note the decreased number of osteoblasts and their premature apoptosis as well as the incomplete repair of bone in the latter. Old bone being replaced is indicated in red; newly formed bone is in light tan. Both osteoblasts and osteoclasts are derived from precursors originating in the bone marrow. The precursors of osteoblasts are multipotent mesenchymal stem cells, which also give rise to bone marrow stromal cells, chondrocytes, muscle cells, and adipocytes, while the precursors of osteoclasts are hematopoietic cells of the monocyte/macrophage lineage. The development of both osteoblasts and osteoclasts is controlled by growth factors and cytokines that are produced in the bone marrow microenvironment and is modulated by systemic hormones and probably by mechanical signals.5 Mesenchymal cell differentiation toward the osteoblast phenotype and osteoclastogenesis are inseparably linked because both are stimulated by the same factors, proceed simultaneously, and the former event is a prerequisite for the latter. It now seems quite clear that in the postnatal bone marrow, commitment of pluripotent mesenchymal precursors to the osteoblastic li