Lesser reduction in bone mineral density by the immunosuppressant, FK506, compared with cyclosporine in rats.
BACKGROUND
Posttransplantation osteopenia leading to osteoporosis induced commonly by treatment with immunosuppressants including cyclosporine (CsA) is a severe complication and results in lowering the quality of life in patients receiving organ transplantation. FK506 is a newly developed immunosuppressant and is currently being used for the prevention of rejection after organ transplantation. In this study, to investigate whether FK506 as well as CsA would cause osteopenia or not, we evaluated the effect of FK506 on bone mineral density and several parameters relevant to bone metabolism in comparison with that of CsA using normal rats.


METHODS
Ten-week-old male Sprague-Dawley rats were treated with FK506 (vehicle, 1 mg/kg, and 3.2 mg/kg) or CsA (vehicle, 10 mg/kg, and 32 mg/kg) by daily oral gavage for 28 days. Bone mineral density of the femur, plasma insulin-like growth factor I (IGF-I), and urinary deoxypyridinoline were determined by peripheral quantitative computerized tomography, radioimmunoassay, and enzyme-linked immunosorbent assay, respectively.


RESULTS
The reduction in bone mineral density of the femur was observed in both FK506- and CsA-treated rats. The reduction in CsA-treated rats, however, was statistically significant and strikingly severe, whereas that in FK506-treated rats was much less severe than CsA. Plasma IGF-I levels were significantly elevated in FK506-treated rats but not in CsAtreated rats. Urinary deoxypyridinoline levels were unchanged in FK506-treated rats but elevated in CsA-treated rats.


CONCLUSIONS
Compared with CsA, FK506 does not appear to induce severe osteopenia by high-turnover bone metabolism in the rat by mediating via IGF-I induction in part. The results suggest that FK506 may exert favorable effects on bone metabolism in patients with organ transplantation compared with CsA. To assess this idea, further clinical investigations focused on bone metabolism will be required.
Inoue
T
T
Department of Metabolic Diseases, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Kawamura
I
I
Matsuo
M
M
Aketa
M
M
Mabuchi
M
M
Seki
J
J
Goto
T
T
D000596:Amino Acids / Q000652:urine; D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood; D001663:Bilirubin / Q000097:blood; D015415:Biomarkers / Q000652:urine; D001835:Body Weight; D015519:Bone Density / Q000187:drug effects*; D016572:Cyclosporine / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D016559:Tacrolimus / Q000494:pharmacology*
D000596:Amino Acids; D001647:Bile Acids and Salts; D015415:Biomarkers; D007166:Immunosuppressive Agents; D007334:Insulin-Like Growth Factor I; D016572:Cyclosporine; C036020:deoxypyridinoline; D001663:Bilirubin; D016559:Tacrolimus