Different effects of cyclosporin a on bone remodeling in young and adult rats

Reported effects of cyclosporin A (Sandimmun®, CsA) on bone have been both contradictory and controversial. Thus, stimulation of new bone formation as well as increased mineral and matrix resorption have been observed. To investigate the response of basal mineral and matrix turnover to CsA treatment at different stages of skeletal development, comparative experiments were conducted in young growing female rats and in adults. Fifty-six young animals (study A) and 40 adults (study B) received orally either the carrier substance or 5, 15, and 30 mg/kg CsA for 30 days. The following parameters were measured: (a) total skeletal mineral content by dual energy X-ray absorptiometry (DEXA) on days 1 and 30; (b) tibial trabecular volume at day 30; (c) serum osteocalcin at 5-day intervals; (d) urinary deoxypyridinoline (Dpd) excretion (days 1, 15, and 30); and (e) plasma levels of CsA. Results can be summarized as follows: in young rats (study A), total skeletal mineral was not modified by the 5- and 15-mg/kg doses of CsA, whereas 30 mg/kg induced a significant decrease (−15%, p< 0.01). This parameter was not significantly modified in adult animals (study B) subjected to the same doses. The administration of 5 mg/kg CsA did not alter tibial trabecular volume in young rats, but 15 and 30 mg/kg significantly lowered this parameter (−16.3%, p< 0.02, and −42%, p< 0.001, respectively). In adult rats, tibial trabecular volume remained unchanged with the exception of the group receiving 30 mg/kg which exhibited significantly lower values (−28%, p< 0.001). These results indicate higher sensitivity of cancellous appendicular bone to CsA in comparison with total skeletal mineral measurements. In general, serum osteocalcin and urinary Dpd varied in accordance with bone remodeling rates, although a tendency to return to normal was observed in the latter on day 30. No clear explanation could be given for the elevated osteocalcin observed at 15 mg/kg on day 10 in adult animals in the absence of significant changes in total and segmental mineral content and in Dpd excretion. Blood levels of CsA were in agreement with standard pharmacokinetic data for the administered doses. In conclusion, the administration of 5 mg/kg CsA to normal female rats did not modify bone remodeling, whereas 15 mg/kg produced tibial but not generalized osteopenia, and 30 mg/kg resulted in global toxic demineralization. The attenuated reaction to the same doses of CsA observed in the adult animal strongly suggests reduced sensitivity of the skeleton to this substance after completion of somatic growth, and renders untenable the extrapolation of findings from one bone segment to the entire skeleton. These results should be viewed in the context of the therapeutic dose use CsA which in rats produces complete graft protection at 7 mg/kg and inhibition of experimental arthritis at 5 to 10 mg/kg, doses which are close to those used in man. Larger doses may lead to toxic bone resorption and subsequent osteopenia, which is of limited clinical relevance