Nonsteroid immunosuppressive agents and bone

The immunosuppressive agents introduced to enhance the action of glucocorticoids and to prevent organ rejection had a dramatic impact on reducing the incidence of organ rejection, enhancing donor organ, and hence patient survival following transplantation. However, these agents, cyclosporine and tacrolimus, termed calcineurin inhibitors (CIs) also have side effects, including the promotion of rapid and severe bone loss in vivo experimentally as well as clinically. The mechanism at present accounting for this action is unclear, but the role of the T lymphocyte in vivo is essential for the process of bone loss. Other immune-modifying drugs, such as azathioprine, mycophenolate mofetil, and sirolimus, which are used in conjunction with glucocorticoids and the CIs have not been shown to promote bone loss experimentally. Clinically, there is no evidence for this side effect, although the optimum trials for all these agents, excluding glucocorticoids, have not been performed and may be extremely difficult to accomplish in the clinical environment. In addition to acute rapid and severe bone loss the clinical picture shows an extremely high incidence of fractures at all sites, which also may depend on the organ transplanted, preexisting bone disease, interval before transplantation, and the dose and duration of multiple immunosuppressive drug administration. The management at this stage is largely empiric but consists of attempted rapid reduction in the dose of glucocorticoids and institution of antiresorptive agents together with calcium and vitamin D or analogs. Future studies may also find an anabolic therapy such as intermittent parathyroid hormone (RhPTH) useful to treat this disease.