UTILIZATION OF CYCLOSPORINE-H TO ELUCIDATE THE POSSIBLE MECHANISMS OFCYCLOSPORINE-A-INDUCED OSTEOPENIA IN THE RAT

The immunosuppressive agent cyclosporine A (CsA) produces in vivo in t he rat marked osteopenia and elevation of serum bone gla protein (BGP) that reflects the high bone turnover and increased circulating levels of 1,25-dihydroxyvitamin D [1,25(OH)(2)D]. Cyclosporine H (CsH), a D- N-MeVal(11) analog of CsA, is not immunosuppressive, and in contrast t o CsA, it neither binds to cyclophilin nor alters cytokine activity. T his distinction between CsH and CsA provides a means of elucidating wh ether CsA exerts an effect on bone and 1,25(OH)(2)D via immune-mediate d mechanisms. We therefore studied three groups of male Sprague-Dawley rats (300 to 350 g body weight [BW]) randomly divided to receive eith er cyclosporine vehicle, CsA, or CsH 15 mg/kg BW by daily gavage for 2 8 days. Blood samples were assayed for ionized calcium (Ca2+), serum B GP, serum parathyroid hormone (PTH), and 1,25(OH)(2)D by specific radi oimmunoassay on days 0, 14, and 28. Histomorphometric evaluations were performed on the right tibia after tetracycline and calcein labeling and killing of the rats at the end of 28 days of treatment. In CsA-tre ated rats, serum BGP levels were significantly increased (155.2 +/- 30 .7 ng/mL v 107.3 +/- 16.8 and 111.5 +/- 13.1 at day 28, P < .05) compa red with control and CsH groups, respectively. Similarly, 1,25(OH)(2)D was significantly increased in CsA-treated rats versus control and Cs H groups (134.9 +/- 35.3 pg/mL v 70.2 +/- 16.6 and 69.8 +/- 20.6 [P < .05], respectively). PTH and CA(2+) were unchanged. Histomorphometrica lly, the CsA-treated group showed a significant loss in bone volume ([ BV]P < .05) and an increase in the indices of bone remodeling compared with the control group. The CsH group showed no significant alteratio n in indices of bone remodeling compared with the control group. These results indicate that the accelerated bone remodeling with osteopenia and the increased production of 1,25(OH)(2)D is probably mediated by immune mechanisms. Copyright (C) 1994 by W.B. Saunders Company