Molecular effects of calcineurin inhibitors

This chapter reviews the cellular and molecular mechanisms that have recently been discovered regarding the bone loss associated with calcineurin inhibitors. Calcineurin inhibitors are widely used in the management of auto-immune disorders and have revolutionized organ transplantation. A direct causative role for calcineurin inhibitors has been difficult to demonstrate in clinical studies as a result of the concomitant use of glucocorticoids. The rapid and severe bone loss that occurs after organ transplant is likely to be attributable not only to glucocorticoids, but also to calcineurin inhibitors, CsA and FK506. These agents block T-cell proliferation by inhibiting the Ca⁺⁺++-calmodulin-sensitive phosphatase calcineurin. These drugs have been shown to cause high-turnover bone loss in both human and animal studies. Animal studies have demonstrated acute increases in bone remodeling, consisting of both osteoclast activation and, in some circumstances, increases in osteoblastic bone formation. There is limited but persuasive evidence that T cells may mediate the action of both CsA and FK506, but again, this needs further confirmation.