Glucocorticoid-induced osteoporosis (GIOP) is the most common form of secondary osteoporosis, and fractures are the most frequent adverse effects of this medication. Glucocorticoids have several direct and indirect adverse effects on bone, primarily through reduction in osteoblasts and osteocyte activity, and life span. Recent advances in the pathophysiology and prevention of this complication of therapy provide hope for its amelioration in patients being treated with glucocorticoids. Several effective pharmacologic agents are now available, and guidelines for the prevention and treatment of GIOP have been published. Despite these advances, many patients still do not receive proper prevention or therapy.
Harvey Cushing first described the association between excess endogenous glucocorticoids and fractures in 1932. Within a few years after the introduction of prednisone to treat rheumatoid arthritis by Philip Hench and colleagues, the deleterious skeletal effects of exogenous glucocorticoids, including vertebral compression fractures, were reported. Glucocorticoid-induced bone loss is the most common form of secondary osteoporosis, and fractures are glucocorticoids’ most common adverse effect. Glucocorticoids are used by 0.5% to 2.5% of adults, thus glucocorticoid-induced osteoporosis (GIOP) is one of the most common iatrogenic complications in clinical practice. Whether the patient will develop osteoporosis and fractures depends not only on the daily and cumulative dose of glucocorticoids but also on several other concomitant factors, including the patient’s baseline bone mineral density (BMD), age, sex, hormonal status, underlying disease for which the patient is being treated, and perhaps individual differences in sensitivity to glucocorticoids.
Pathogenesis of glucocorticoid-induced bone loss
The most common histomorphometric finding in GIOP is a decrease in bone mass, most commonly seen in those parts of the skeleton with a high degree of cancellous bone, although cortical bone is not spared. Glucocorticoids have both direct and indirect effects on bone, and affect both bone formation and resorption. Glucocorticoid-induced osteoporosis occurs in two phases, a rapid phase of bone loss mediated through osteoclastic bone resorption and a later phase of bone loss caused by decreased bone formation.
Among the indirect effects, glucocorticoids cause a decrease in intestinal calcium absorption and an increase in the urinary excretion of calcium. Although secondary hyperparathyroidism had been thought to play a role in GIOP, elevated parathyroid hormone levels are not consistently found, and histomorphometric analysis of bone biopsies from patients with GIOP reveal decreased bone remodeling rather than the increased remodeling seen with secondary hyperparathyroidism.
Another indirect effect of glucocorticoids on bone metabolism is through inhibition of gonadotropin secretion, leading to hypogonadism. Enhanced bone resorption ensues, at least in part, because of enhanced secretion of cytokines such as interleukin-6, tumor necrosis factor α, and macrophage-colony stimulating factor (M-CSF).
A critical system involved in the coupling of bone formation and resorption is the RANK-L (receptor activator of nuclear factor-κB ligand)-RANK-OPG (osteoprotegerin) system. Under the influence of several cytokines and hormones such as tumor necrosis factor-α, parathyroid hormone, 1,25-dihydroxyvitamin D, and so forth., RANK-L is secreted by osteoblasts, then binds to and activates its receptor RANK on the surface of osteoclast precursors and induces osteoclastogenesis. OPG is a natural inhibitor of RANK-L, preventing RANK-L from binding to its osteoclast receptor.
Glucocorticoids increase the expression of RANK-L and M-CSF, and decrease OPG expression in osteoblasts and stromal cells. Glucocorticoids also increase the expression of interleukin-6, which stimulates osteoclastogenesis, and downregulate the expression of interferon-β, an inhibitor of osteoclastogenesis. These changes result in an initial increase in the number of osteoclasts capable of resorbing bone. Glucocorticoids initially also decrease the apoptosis of osteoclasts. Eventually glucocorticoids deplete the population of osteoblasts as described below, which leads to decreased RANK-L and M-CSF expression by osteoblasts with a consequent decrease in osteoclast number.
The most significant mechanism of glucocorticoid-induced bone loss is decreased bone formation. Glucocorticoid exposure leads to a decrease in the number of osteoblasts, both by decreasing the formation of osteoblasts and by increasing osteoblast apoptosis. Pluripotent bone marrow stromal cells have the ability to differentiate into several cells of the mesenchymal lineage, including either osteoblasts or adipocytes. Glucocorticoids shift the differentiation of pluripotent stromal cells away from osteoblasts toward the adipocyte lineage through regulation of nuclear factors of the CAAT enhancer-binding protein family and by induction of peroxisome proliferator activated receptor γ (PPARγ). Glucocorticoids also suppress canonical Wnt-β-catenin signaling, a key regulator of osteoblastogenesis. The bone morphogenetic protein (BMP) pathway, involved in stimulating osteoblast differentiation and bone formation, is also suppressed by glucocorticoids.
In addition to their effects on osteoblastogenesis, glucocorticoids also have effects on bone matrix (inhibition of type I collagen synthesis and increased collagenase production) and on skeletal growth factors (glucocorticoids downregulate transcription of the insulin growth factor I gene and its binding proteins).
Osteocytes are thought to participate in the detection and healing of bone microdamage. Accelerated apoptosis of osteocytes could lead to accumulation of bone microdamage, and diminished bone quality and strength independent of BMD. Increased osteocyte apoptosis has been documented in patients with GIOP.