Pathogenesis, prevention and treatment of transplant-associated osteoporosis

Abstract

A reduction in bone mass is observed in a high percentage of patients following organ or marrow transplantation, with the prevalence of osteopenia or osteoporosis reported to be as high as 80%. Between 4 and 65% of transplant recipients will experience an osteoporosis-related fracture and the likelihood of such a serious outcome is dependent on pre-existing disease and immunosuppressive therapy. End-stage pulmonary disease is commonly associated with a reduction in BMD; chronic liver disease with osteomalacia and osteoporosis; and renal patients are often recognised to have osteodystrophy, osteopaenia or osteoporosis at the time of transplantation. Post-transplant glucocorticoid therapy plays a major role in the further reduction in bone mass observed in these patients. Glucocorticoids have several effects deleterious to the skeleton, transiently increasing bone resorption then subsequently inhibiting both osteoclast and osteoblast activity. They also interfere with calcium, vitamin D and PTH metabolism. The additional role of other immunosuppressant treatments in bone loss is less clear but there is some evidence to suggest that cyclosporin A (CsA) and tacrolimus (FK506) result in high bone turnover osteopenia. CsA can also result in hypogonadism when used in high doses and hypomagnesaemia which can contribute to a reduction in bone mass. Comparative studies in renal transplant patients have suggested that CsA monotherapy has less of an effect on BMD than combination therapy with glucocorticoids. Newer immunosuppressants such as rapamycin are believed to have minimal effects on bone metabolism compared to CsA or FK506. Although some variability exists in the studies reporting bone related outcomes following transplant, current evidence suggests that the cumulative dose of glucocorticoid, male gender, increasing age and development of an early menopause as a result of treatment are the factors associated with severe bone disease. Since the greatest loss of bone is observed in the first 3-6 months following transplant, coincident with glucocorticoid therapy, strategies to prevent bone loss should be directed at the peri-operative period. Reduction in the use of glucocorticoids by using steroid-sparing combination therapy has been effective and in cardiac transplant patients the use of vitamin D or its analogues in combination with calcium has also proved beneficial. Early reports of the use of intravenous pamidronate are encouraging with improved BMD and significant reductions in fractures reported.