ST LOUIS, Missouri—High-dose glucocorticoid (GC) treatment nearly always causes bone loss, which existing treatments are powerless to prevent. New research published in The Journal of Clinical Investigation by Hyun-Ju Kim, MD, and colleagues in the laboratory of Steven L. Teitelbaum, MD, at Washington University School of Medicine, suggests that this might be because current treatments are aiming at the wrong target.1 The new study shows that disruption of the larger skeleton follows disruption of a much smaller one—the cytoskeleton of the bone-resorbing osteoclast.

"Bone remodeling is initiated by the osteoclast, whose activity is coupled to that of the osteoblast. Hence, as bone resorption falls, so does bone formation." Steven L. Teitelbaum, MD
Bone mass is the result of bone formation minus bone resorption. According to Dr. Teitelbaum, GCs disrupt the osteoclast's ability to form actin rings in response to macrophage colony stimulating factor (M-CSF). This prevents the cell from doing its job of bone resorption. "It is actually disruption of the cytoskeleton of the osteoclast that prevents it from resorbing bone. The reason bone formation falls is because bone remodeling is arrested. Bone remodeling is initiated by the osteoclast, whose activity is coupled to that of the osteoblast. Hence, as bone resorption falls, so does bone formation. There is also a direct suppressive effect of glucocorticoids on osteoblasts. The suppressed remodeling probably contributes to the structurally inferior bone, which complicates prolonged glucocorticoid therapy," Dr. Teitelbaum told CIAOMed.

The researchers reached these conclusions by comparing the effects of GCs on osteoclasts and their precursor cells from healthy mice with its effects on the same cells derived from mice with disruption of the GC receptor. In healthy mice, dexamethasone prolonged the longevity of osteoclasts but suppressed their bone-degrading capacity. No such effects were observed in mice lacking the GC receptor. Because earlier studies had shown that bone degradation by osteoclasts stimulates new bone formation by osteoblasts, this study fills in a significant piece of the puzzle by showing that the GC-induced delay in osteoclast apoptosis dampens osteoblast activity and retards new bone formation.

Because the problem is not too much bone resorption, but too little, the reason for the imperfect result of antiresorptive treatments now becomes clear.

"Bisphosphonates appear to be most effective in the early stages of glucocorticoid therapy, during which time bone loss is most aggressive. This is probably because bone resorption remains active due to persistence of bone-resorbing cytokines. As resorption falls with prolonged glucocorticoid treatment, bisphosphonates may be detrimental because they also suppress remodeling. In fact, evidence is evolving that their long-term use may be complicated by [the production of] structurally compromised bone, leading to fracture," Dr. Teitelbaum said.

Another surprise was that the effects of tumor necrosis factor (TNF) and RANK ligand (RANKL) override the glucocorticoid effect on the osteoclast. "This may account for the rapid bone loss appearing early in corticosteroid therapy," Dr. Teitelbaum said.

This study raises new questions that have implications for preventing or treating GC-induced osteoporosis. "What is the mechanism by which glucocorticoids suppress the osteoclast cytoskeleton?" Dr. Teitelbaum asked. "How does the glucocorticoid-treated osteoclast suppress the osteoblast? What is the mechanism by which TNF and RANK ligand override the glucocorticoid effect on the osteoclast?"

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Reference
1. Kim H-J, Zhao H, Kitaura H, Bhattacharyya S, Brewer JA, et al. Glucocorticoids suppress bone formation via the osteoclast. J Clin Invest . 2006 July 27 {Epub ahead of print] doi:10.1172/JCI28084. Available at http://www.jci.org.