Rapamycin: A bone sparing immunosuppressant?

Abstract

Immunosuppressant therapy is associated with osteoporosis both clinically, 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 recently discovered immunosuppressant, rapamycin, resulted in no change of cancellous bone volume. A longer study over 28 days has now been carried 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 mg/kg, FK506 5 mg/kg, and rapamycin 2.5 mg/kg, respectively. CsA‐ and FK506‐treated rats, but not those treated with rapamycin, demonstrated high turnover osteoporosis with raised serum 1,25(OH)₂D (p < 0.05) and 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 the FK506‐treated group compared with the control animals. The CsA‐ and the rapamycin‐treated groups failed to gain weight and developed severe hyperglycemia (>20 mmol/l, p < 0.001) by day 14 but which largely resolved by day 28. Unlike the groups treated with CsA and FK506, rapamycin‐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 established immunosuppressants in not reducing bone volume in the short term. However, the increased remodeling may pose a problem with long‐term use, and the decrease in longitudinal bone growth would make the drug unsuitable for growing individuals.