DIFFERENT EFFECTS OF CYCLOSPORINE-A ON BONE REMODELING IN YOUNG AND ADULT-RATS

Reported effects of cyclosporin A (Sandimmun(R), CsA) on bone have bee n 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 tur nover to CsA treatment at different stages of skeletal development, co mparative experiments were conducted in young growing female rats and in adults. Fifty-six young animals (study A) and 40 adults (study B) r eceived orally either the carrier substance or 5, 15, and 30 mg/kg CsA for 30 days. The following parameters were measured: (a) total skelet al mineral content by dual energy X-ray absorptiometry (DEXA) on days 1 and 30; (b) tibial trabecular volume at day 30; (c) serum osteocalci n at 5-day intervals; (d) urinary deoxypyridinoline (Dpd) excretion (d ays 1, 15, and 30); and (e) plasma levels of CsA. Results can be summa rized 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 ind uced a significant decrease (-15%, p < 0.01). This parameter was not s ignificantly modified in adult animals (study B) subjected to the same doses. The administration of 5 mg/kg CsA did not alter tibial trabecu lar volume in young rats, but 15 and 30 mg/kg significantly lowered th is parameter (-16.3%, p < 0.02, and -42%, p < 0.001, respectively). In adult rats, tibial trabecular volume remained unchanged with the exce ption of the group receiving 30 mg/kg which exhibited significantly lo wer values (-28%, p < 0.001). These results indicate higher sensitivit y of cancellous appendicular bone to CsA in comparison with total skel etal mineral measurements. In general, serum osteocalcin and urinary D pd varied in accordance with bone remodeling rates, although a tendenc y to return to normal was observed in the latter on day 30. No clear e xplanation 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 le vels of CsA were in agreement with standard pharmacokinetic data for t he administered doses. In conclusion, the administration of 5 mg/kg Cs A to normal female rats did not modify bone remodeling, whereas 15 mg/ kg produced tibial but not generalized osteopenia, and 30 mg/kg result ed in global toxic demineralization. The attenuated reaction to the sa me doses of CsA observed in the adult animal strongly suggests reduced sensitivity of the skeleton to this substance after completion of som atic growth, and renders untenable the extrapolation of findings from one bone segment to the entire skeleton. These results should be viewe d in the context of the therapeutic dose use CsA which in rats produce s 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 osteop enia, which is of limited clinical relevance.