Dosing time-dependent variation of bone resorption by cyclosporin A in rats' femurs

The dosing time-dependent difference of bone resorption by cyclosporin A was determined in normal rats. Rats were kept in rooms with a 12-h light/dark cycle. Cyclosporin A (3 mg/kg, once a day) or vehicle was given at either 2 h after light on (2 HALO) or 8 HALO, 14 HALO, 20 HALO for 24 weeks. Serum and 4-h urine samples were obtained before and at 12 and 24 weeks after the treatment. Body weight, creatinine clearance, serum parathyroid hormone, the trough level of cyclosporin A in whole blood and urinary excretion of Ca and P were not changed by the drug at every any dosing time. Serum Ca and P concentrations by the vehicle treatment differed with the dosing time. Furthermore, increases of these two parameters by the drug varied with dosing time; most prominently at the 2 HALO dosing, and were not seen at the 8 and 14 HALO dosings. Degree of bone resorption of the femur determined by dual-energy X-ray absorption, also varied with dosing time, most prominently at 2 HALO and less prominently at 14 HALO. Increase of urine deoxypyridinoline excretion, a marker of osteoclast activity, by the drug was highest at 2 HALO and lowest at 14 HALO, however parathyroid hormone and osteocalcin concentrations after cyclosporin A treatment did not vary with dosing time. Reduction of urinary nitric oxide (NO) was most prominent at 2 HALO and negligible at 14 HALO. We concluded that cyclosporin A-induced bone resorption and serum Ca and P increases were varied with dosing time. Sensitivity of osteoclasts by the drug was the major mechanisms of the phenomenon, while differences in pharmacokinetics, the parathyroid gland, osteoblasts and renal handling of Ca and P did not contribute to the phenomenon.