Phenytoin-induced bone loss and its prevention with alfacalcidol or calcitriol in growing rats

Studies were carried out to determine the effects and mechanism of action o f phenytoin on the bone metabolism in male rats. Administration of phenytoi n, 20 mg/kg/ day for 5 weeks, did not affect the growth curve. Biochemical data indicated that the serum osteocalcin, a marker of bone formation, was decreased significantly but there were no significant differences in the le vels of serum calcium, pyridinoline, 25-hydroxyvitamin D-3 (25OHD) and para thyroid hormone (PTH) in the phenytoin-treated group compared with the vehi cle-treated group. The values of bone mineral density (BMD) were decreased in all regions of bones tested (mandibular head, tibial metaphysis, tibial diaphysis, femoral metaphysis, and femoral diaphysis) in the phenytoin-trea ted group. In histomorphometric analysis, phenytoin decreased trabecular bo ne volume and trabecular thickness, and increased osteoclast numbers per ar ea of bone surface in the secondary trabecular bone of the tibia. Additiona lly, there was no significant difference in osteoid thickness. Combined adm inistration of either alfacalcidol or calcitriol with phenytoin for 5 weeks prevented the reduction of BMD induced by phenytoin. From these findings, it is unlikely that toxic effects on the growth curve caused the decreased BMD induced by phenytoin. It is also evident that repeated administration o f phenytoin may cause osteopenia which may be due to bone loss by inhibitin g bone formation and/or by accelerating bone resorption rather than osteoid accumulation. The bone loss is not rachitic because of the lack of increas e in osteoid thickness. Moreover, combined administration of alfacalcidol o r calcitriol with phenytoin showed a preventative effect against bone loss. The bone loss induced by phenytoin in this study may be a convenient model for further research into the problem of drug-induced osteopenia.