Long-term anticonvulsant therapy leads to low bone mineral density - evidence for direct drug effects of phenytoin and carbamazepine on human osteoblast-like cells

Anticonvulsant therapy causes changes in calcium and bone metabolism and ma y lead to decreased bone mass with the risk of osteoporotic fractures. The two widely used antiepileptic drugs phenytoin and carbamazepine are recogni zed to have direct effects on bone cells. The aim of our study was to measu re the influence of long-term treatment with antiepileptic drugs on bone mi neral density (BMD) and to look on direct effects of carbamazepine and phen ytoin on human osteoblast-like cells. BMD was measured by dual-energy X-ray absorptiometry. Markers of bone forma tion and bone resorption were determined in serum and urine. Data of 59 pat ients were compared to 55 age and sex matched controls. Direct effects of p henytoin and carbamazepine on human osteoblast-like cells were investigated in experimental studies. BMD in the lumbar spine region (L2 through L4) was significantly lower in t he patient group as compared to controls (p < 0.0004). At femoral sites BMD was lower in patients, but this difference did not reach statistical signi ficance. The decrease in BMD at both sites was dependent on the duration of therapy. Excretion of pyridinoline crosslinks was markedly increased in th e patients. 25-hydroxy-vitamin D3 and 1,25-dihydroxy-vitamin D3 were signif icantly decreased in patients. Proliferation rate of human osteoblast-like cells was increased by phenytoin in low doses. Both, phenytoin and carbamaz epine inhibited cell growth at concentrations equivalent to therapeutic dos es for the treatment of epileptic diseases. Our clinical and experimental data indicate that long-term treatment with a nticonvulsant drugs leads to a lower BMD. The experimentally observed decre ase in bone cell proliferation might be clinically associated with impaired new bone formation. Beside alterations in calcium and vitamin D homeostasi s leading to osteomalazia, direct effects of anticonvulsant drugs on bone c ells may contribute to the damaging effects on the skeletal system.