LOW-DOSE PHENYTOIN IS AN OSTEOGENIC AGENT IN THE RAT

Long-term use of phenytoin for the treatment of epilepsy has been asso ciated with increased thickness of craniofacial bones. The aim of the present study was to evaluate the possibility that low doses of phenyt oin are osteogenic in vivo by measuring the effects of phenytoin admin istration on serum and bone histomorphometric parameters of bone forma tion in two rat experiments. In the first experiment, four groups of a dult male Sprague-Dawley rats received daily I.P. injections of 0, 5, 50, or 150 mg/kg/day of phenytoin, respectively, for 47 days. Serum al kaline phosphatase (ALP) and osteocalcin were increased by 5 and 50 mg /kg/day phenytoin. The increases in osteocalcin and ALP occurred by da y 7 and day 21, respectively. The tibial diaphyseal mineral apposition rate (MAR) at sacrifice (day 48) was significantly increased in rats receiving 5 mg/kg/day phenytoin. At a dose of 150 mg/kg/day, the incre ase in serum ALP, osteocalcin and MAR was reversed. No significant dif ferences in serum calcium, phosphorus, or 1,25(OH)(2)D-3 levels were s een. In a second experiment, three groups of rats received daily I.P. injection of lower doses of phenytoin (i.e., 0, 1, or 5 mg/kg/day, res pectively) for 42 days. Phenytoin also did not affect the growth rate or serum calcium, phosphorus, and 25(OH)D-3 levels. Daily injection of 5 mg/kg/day phenytoin significantly increased several measures of bon e formation, i.e., serum ALP and osteocalcin, bone ALP, periosteal MAR , and trabecular bone volume. However, rats receiving lower doses of p henytoin (i.e., 1 mg/kg/day) did not show significant increases in the serum bone formation parameters. In contrast, metaphyseal osteoblast surface, osteoblast number, osteoid thickness, surface, and volume wer e all significantly increased in rats treated in 1 mg/kg/day but not w ith 5 mg/kg/day phenytoin, suggesting that the tibial diaphysis and me taphysis bone formation parameters might have different dose-dependent responses to phenytoin treatment. Administration of the test doses of phenytoin did not significantly affect the histomorphometric bone res orption parameters. In conclusion, these findings represent the first in vivo evidence that phenytoin at low doses (i.e., between 1 and 5 mg /kg/day) is an osteogenic agent in the rat.