LACK OF CHANGE OF CANCELLOUS BONE VOLUME WITH SHORT-TERM USE OF THE NEW IMMUNOSUPPRESSANT RAPAMYCIN IN RATS

Immunosuppressants have adverse effects on bone mineral metabolism in animal and human studies, with corticosteroids producing low-turnover osteopenia, and cyclosporin-A (CsA) producing high-turnover osteopenia . Rapamycin (RAPA) is a new immunosuppressant reported to be at least 10 times more potent than CsA, and acts via a different pathway to CsA and the other new immunosuppressant FK506. This study investigated th e effects of RAPA on bone mineral metabolism in the rat. Forty-two, 10 -week-old, male Sprague Dawley rats were divided into three groups, an d treated according to the following protocol: group A (control) recei ved RAPA vehicle by daily gavage for 14 days (n = 12); group B (high d ose RAPA) received RAPA 2.5 mg/kg/day by daily gavage for 14 days (n = 15); group C (low dose RAPA) received RAPA 1.25 mg/kg/day by daily ga vage for 14 days (n = 15). Rats were weighed and bled on days 0, 7, an d 14 for measurement of blood ionized calcium, bone Gla protein (BGP), parathyroid hormone (PTH), and 1,25(OH)2D. Tibial bone histomorphomet ry was determined on day 14 after double-calcein labeling. Weight gain was similar in the two groups treated with RAPA compared with control animals. High-dose RAPA (group B) transiently depressed serum BGP lev els on day 7, with elevated blood ionized calcium levels on day 7, and lowered 1,25(OH)2D levels on day 14. Serum PTH levels were unchanged. Low-dose RAPA (group C) did not affect calciotropic hormones. Histomo rphometric analyses of tibial metaphyses revealed that parameters of b one formation and resorption were not significantly different in the g roups treated with RAPA (group B and C) compared with control animals (group A). Trabecular bone volume (BV/TV) in group B (high-dose RAPA) (15.39 +/- 1.01%) and C (low-dose RAPA) (15.38 +/- 0.57%) was not sign ificantly altered compared with group A (control) (16.42 +/- 0.86%). S hort-term treatment with RAPA, unlike CsA, does not result in excess r esorption and loss of bone volume. The depressed serum 1,25(OH)2D leve ls seen with high-dose RAPA therapy may adversely effect bone mineral metabolism in the long term.