Pathogenesis, clinical features, and evaluation of glucocorticoid-induced osteoporosis
- Harold N Rosen, MD
Harold N Rosen, MD
- Assistant Professor in Medicine
- Harvard Medical School
Chronic glucocorticoid excess, either endogenous (ie, Cushing's syndrome) or exogenous, can lead to osteoporosis and fractures. The pathogenesis, clinical features, and evaluation of glucocorticoid-induced osteoporosis will be reviewed here. The prevention and treatment of glucocorticoid-induced osteoporosis are presented separately. (See "Prevention and treatment of glucocorticoid-induced osteoporosis".)
Glucocorticoids increase bone resorption and reduce bone formation (algorithm 1) [1,2]. The risk of bone loss is most pronounced in the first few months of use, followed by slower but steady loss of bone with continued use . Most agents that increase bone loss, such as thyroxine or sustained elevation of parathyroid hormone (PTH), accelerate not only bone resorption but also formation, albeit to a lesser extent . Because glucocorticoids accelerate resorption while inhibiting formation, their use is associated with early rapid bone loss [4,5]. With chronic use, osteoclast mediated bone resorption slows and suppression of bone formation becomes the predominant skeletal effect [6-8]. Glucocorticoid therapy increases the risk of fracture [2,9]. Vertebral fractures, in particular, occur early after exposure, during the rapid phase of bone loss.
As in other target tissues, glucocorticoids exert their effects on gene expression via cytoplasmic glucocorticoid type 2 receptors . In adult bone, functional glucocorticoid receptors are found in pre-osteoblast/stromal cells, osteoblasts (the cells that produce bone matrix), but not in osteoclasts [11,12]. Instead, glucocorticoids stimulate osteoclast proliferation by suppressing synthesis of osteoprotegerin, an inhibitor of osteoclast differentiation from hematopoietic cells of the macrophage lineage, and by stimulating production of the receptor activator of nuclear factor kappa-B (RANK), which is required for osteoclastogenesis. High glucocorticoid levels also stimulate RANKL synthesis by pre-osteoblast/stromal cells, supporting osteoclast differentiation and net bone resorption . In addition, glucocorticoids increase bone resorption by decreasing secretion of androgens and estrogens, mediated primarily by inhibition of gonadotropin secretion [13-16]. (See "Normal skeletal development and regulation of bone formation and resorption", section on 'Osteoclasts'.)
With long-term use, the predominant effect of glucocorticoids on the skeleton is reduced bone formation. The decline in bone formation is mediated by direct inhibition of osteoblast proliferation and differentiation and by an increase in the apoptosis rates of mature osteoblasts and osteocytes [1,17-20]. This apoptosis may also explain the tendency of glucocorticoids to cause osteonecrosis . In addition, glucocorticoids alter PTH secretory dynamics (reduce tonic secretion and increase the amount released as pulses) , antagonize the anabolic action of PTH [18,23], and inhibit production of insulin-like growth factor 1 (IGF-1) [2,17,20] and testosterone [13-15]. The reduction in bone formation is associated with a decrease in the mineral apposition rate  and in serum and urine biochemical markers of bone formation [25,26]. (See "Normal skeletal development and regulation of bone formation and resorption", section on 'Osteoblasts'.)
Glucocorticoids also decrease intestinal calcium absorption, in part by opposing the action of vitamin D, and by decreasing the expression of calcium channels in the duodenum [2,27-29]. In addition, glucocorticoids increase renal calcium excretion by decreasing calcium reabsorption [26,28,30].
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