ISSN:
1432-0827
Keywords:
Phenytoin
;
Bone formation
;
Osteocalcin
;
Alkaline phosphatase
;
Osteogenesis
;
Rat
Source:
Springer Online Journal Archives 1860-2000
Topics:
Biology
,
Medicine
,
Physics
Notes:
Abstract Long-term use of phenytoin for the treatment of epilepsy has been associated with increased thickness of craniofacial bones. The aim of the present study was to evaluate the possibility that low doses of phenytoin are osteogenic in vivo by measuring the effects of phenytoin administration on serum and bone histomorphometric parameters of bone formation in two rat experiments. In the first experiment, four groups of adult 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 alkaline phosphatase (ALP) and osteocalcin were increased by 5 and 50 mg/kg/day phenytoin. The increases in osteocalcin and ALP occurred by day 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 increase in serum ALP, osteocalcin and MAR was reversed. No significant differences in serum calcium, phosphorus, or 1,25(OH)2D3 levels were seen. 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, respectively) for 42 days. Phenytoin also did not affect the growth rate or serum calcium, phosphorus, and 25(OH)D3 levels. Daily injection of 5 mg/kg/day phenytoin significantly increased several measures of bone formation, i.e., serum ALP and osteocalcin, bone ALP, periosteal MAR, and trabecular bone volume. However, rats receiving lower doses of phenytoin (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 were all significantly increased in rats treated in 1 mg/kg/day but not with 5 mg/kg/day phenytoin, suggesting that the tibial diaphysis and metaphysis 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 resorption 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.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00298743
