Cyclosporin A does not affect the absolute rate of cortical bone resorption at the organ level in the growing rat

Abstract

The weanling rat, an animal model of rapid bone turnover, was used to evaluate the effects of various doses of cyclosporin A (CsA) on various bones during different time periods. Sprague-Dawley male rats were extensively prelabeled with ³H-tetracycline during 1–3 weeks of age. At 4 weeks of age, four groups of rats were given daily subcutaneous injections: vehicle or CsA—low dose (10 mg/kg), intermediary dose (20 mg/kg), or high dose (30 mg/kg) for 7, 14, or 28 days. Three different whole bones—the femur (low turnover), scapula (moderate turnover), and lumbar-6 vertebra (high turnover) were harvested intact at 4, 5, 6, and 8 weeks of age. The whole bones were assayed weekly for total dry defatted weight, calcium mass (formation), and loss of ³H-tetracycline (bone resorption) following treatment with CsA. Serum CsA levels, calcium creatinine, and alkaline phosphatase were measured weekly. Significant decreases in serum calcium and alkaline phosphatase were observed at 1 and 2 weeks, and were normalized by 4 weeks of treatment. No significant changes in serum creatinine were noted. For all three doses of CsA, no effect was observed on the absolute rate of cortical bone resorption of three different, whole bones over three time periods. Body weight and bone formation in treated animals was significantly smaller in a dose- and time-related fashion compared with control animals at sacrifice. However, compared with the initial control animals, body weights and bone masses of the final treated animals were much larger, suggesting that the smaller bone masses were due to insufficient growth and slow gain in bone mass. Our isotopic data demonstrate that CsA has no effect on the basal rate of bone resorption and decreases rate of bone formation, as observed globally at the whole bone level. Bone measurements at the organ level may lead to different interpretations from those observed at the tissue level.