The effect of long-term valproate (VPA) treatment on bone mineral density (BMD) in adult epileptic patients is not clearly known, although several studies have been done in children. In adult epileptic patients (n = 50; 24 men, 26 women) treated with VPA, the bone mineral density at lumbar level (L1-L4) and neck, trochanter, and intertrochanter regions of left femur was studied by dual energy X-ray absorptiometry (DXA) at the beginning of the study and after 6 months, with the specific aim to evaluate the effect of long-term valproate monoteraphy on bone mineral density. Routine biochemical parameters were also evaluated. Sixty healthy control subjects were evaluated. Control subjects were similar to patient group with respect to age, race (all White), geographic area, and socioeconomic status. Lumbar and femural BMD values were significantly lower in patient group than control group (0.814 +/- 0.157 g/cm(2) versus 0.894 +/- 0.102 g/cm(2), P = 0.003) and (0.824 +/- 0.144 g/cm(2) versus 0.906 +/- 0.104 g/cm(2), P = 0.001), respectively. Osteopenia were detected in 13 of 60 control subjects (22%) and the others had no osteoporosis. In epileptic group, osteoporosis and osteopenia were detected in 8 subjects (16%), and in 26 subjects (52%), respectively. In epileptic group 16 subjects were normal (32%) at the lumbar regions, and 7 had osteoporosis (14%), 28 had osteopenia (56%), and 15 were normal (30%) at the femoral region. In the second measurements of the patients on valproate treatment, after 6 months, all of the DXA BMD values had worsened compared with the first measurements (P = 0.001 for lumbar BMD values and P = 0.004 for femural BMD values). In the patient group, a significant inverse correlation was observed between duration of valproate therapy and all DXA BMD values in the first and second measurements. Parathyroid hormone, alkaline phosphatase, and phosphor levels of patients were significantly higher than those of control group (52 +/- 11 pg/ml versus 46 +/- 13 pg/ml, P = 0.013), (113 +/- 32 U/l versus 95 +/- 36 U/l, P = 0.006), and (4.50 +/- 0.5 mg/dl versus 4.0 +/- 0.7 mg/dl, P = 0.0001), respectively. However, all of the parameters were within the normal reference ranges. It has been concluded that long-term (more than one year) valproate treatment induces a decrease in bone mineral density in epileptic adults. However, the multivariate analysis did show no association between BMD changes and parathyroid hormone, alkaline phosphatase or phosphorus levels.