Glucocorticoids Antagonize the action of Bisphosphonates on bone
Bone mineral density decreases dramatically during the first six months of glucocorticoid use, but treatment with bisphosphonates can help offset this bone loss. Traditionally, it has been held that the benefits of bisphosphonates are due to their ability to induce programmed cell death, via activation of caspases, in osteoclasts, the cells that break down bone. However, bisphosphonates are also known to prolong the lifespan of osteoblasts, the cells that build bone. Weinstein et al (J. Clin. Invest. 109:1041-1048, 2002) examined the interactions of glucocorticoids with bisphosphonates in vivo in mice as well as in vitro.
Methods: Mice were treated with the glucocorticoid prednisolone or placebo for 4, 10, or 27 days. The mice also received subcutaneous injections of the bisphosphonate alendronate or a saline placebo beginning 3 days before glucocorticoid treatment and then continued daily with the glucocorticoid treatment. In vitro, the effect of the two drugs alone and together on survival of osteoclasts and osteoblasts was examined.
Results: In murine osteoclast cultures, glucocorticoids prolonged the survival of osteoclasts and antagonized bisphosphonate-induced caspase activation and apoptosis. In vivo, glucocorticoid treated mice had reduced numbers of osteoclast progenitors but increased numbers of osteoclasts overall, presumably as a result of prolonged lifespan. In mice treated with both glucocorticoid and bisphosphonates, the pro-apoptotic effect of alendronate on osteoclasts was abrogated. [However, bisphosphonate treatment did antagonize the proapoptotic effect of glucocorticoids on osteoblasts.]
Summary: Glucocorticoids exert an anti-apoptotic effect on osteoclasts, and antagonize the pro-apoptotic effect of bisphosphonates, at least in the short-term. After more prolonged treatment, bisphosphonates can overcome glucocorticoid inhibition, perhaps because new osteoclasts cannot be generated due to overall reduced numbers of progenitors.
Editorial Comment: These observations are instructive in helping to identify effective treatments to prevent or abrogate glucocorticoid-induced osteoporosis. These in vitro and in vivo animal data suggest that, even if bisphosphonates are started immediately with glucocorticoids, that they are not effective in suppressing the rapid bone resorption that occurs in the first few weeks of glucocorticoid initiation. Whether this is true in humans is unclear.
