RAPAMYCIN - A BONE-SPARING IMMUNOSUPPRESSANT

Immunosuppressant therapy is associated with osteoporosis both clinica lly, post-transplantation, and experimentally. In rats, cyclosporin A (CsA) and FK506 induce a state of high turnover rapid bone loss. After 14 days of administration in immunosuppressive doses, the more recent ly discovered immunosuppressant, rapamycin, resulted in no change of c ancellous bone volume. A longer study over 28 days has now been carrie d out; contrasting the new drug with CsA and FK506. Sixty, 10-week-old Sprague-Dawley rats were randomly divided into five groups of 12 rats each. The first group served as an aging control. The remaining four groups received, by daily gavage, a combined vehicle placebo, CsA 15 m g/kg, FK506 5 mg/kg, and rapamycin 2.5 mg/kg, respectively. CsA- and F K506-treated rats, but not those treated with rapamycin, demonstrated high turnover osteoporosis with raised serum 1,25(OH)(2)D (p < 0.05) a nd elevated serum osteocalcin (p < 0.05). The trabecular bone area was decreased by 66% (p < 0.01) in the CsA group and 56% (p < 0.05) in th e FK506-treated group compared with the control animals. The CsA- and the rapamycin-treated groups failed to gain weight and developed sever e hyperglycemia (> 20 mmol/l, p < 0.001) by day 14 but which largely r esolved by day 28. Unlike the groups treated with CsA and FK506, rapam ycin-treated rats had no loss of trabecular bone volume but there was increased modeling and remodeling and a decreased longitudinal growth rate. Rapamycin may thus confer a distinct advantage over the establis hed immunosuppressants in not reducing bone volume in the short term. However, the increased remodeling may pose a problem with long-term us e, and the decrease in longitudinal bone growth would make the drug un suitable for growing individuals.