| BackgroundEpilepsy is a neurological common disease.lt has been recognized that people with epilepsy are susceptible to bone diseases related to seizure-or medication-related trauma, reduced physical activity, or combined neurological deficit, and antiepileptic drugs(AEDs). Among these diseases, AED-associated osteopenia can affect bone metabolism chronically and exacerbate the decrease in bone mineralization, which leads to osteoporotic fractures at an earlier age. However, the different effects of individual AEDs are still undetermined. AEDs such as phenytoin (DPH) and carbamazepine(CBZ) are generally thought to decrease bone mineralization, but effects of non-enzyme-inducing drugs such as valproic acid (VPA) are still controversial. VPA was not associated with decreased bone mineral density(BMD) in early studies, but has been reported to affect bone metabolism in recent studies. Newer AEDs such as oxcarbazepine (OXC), topiramate (TPM) and lamotrigine (LTG) do not show osteopenic effects, but have been the subject of few studies. Moreover, detailed alterations of bone metabolism are not completely understood yet, although reduced vitamin D concentration and interference in osteoblastic function have been claimed as possible mechanisms. On the whole, at present the traditional AEDs on bone mineral density and bone metabolism already has more domestic and foreign research, and proposed a more mature conclusion. At home and abroad, few studies have reported about new antiepileptic drugs on bone mineral density and bone metabolism. Some of them have only a few articles reported and the conclusions are inconsistent.ObjectTo explore the effects of long-term application of these antiepileptic drug monotherapy on bone mineral density and bone metabolism and if possible to explore the mechanism,we selected the AEDs commonly used in China such as the traditional AEDs magnesium valproate sustained-release tablets and the newer AEDs OXC, TPM and LTG, as far as possible to exclude confounding factors. So that we can provide a theoretical basis for clinical prevention.Materials and methodsThe patients who take one of the four AEDs (VPA, OXC, TPM, LTG) for more than six months were selected as research objects, namely the treatment group and the patients who have never taken a kind of AEDs were selected as controls, named control group. The BMD of lumbar spine 2-4 vertebrae, femoral neck, trochanter and Wards triangle BMD of the treatment group and control group patients were detected, while both groups were the serum calcium, phosphorus, alkaline phosphatase and parathyroid hormone. After that, the results of each patient from each treatment group was compared with the values from control group patients to determine the effects of AEDs on bone mineral density and bone metabolism.ResultsAfter screening,88 patients were enrolled, including 71 in treatment group,17 in control group. Compared with the control group, the serum calcium, phosphorus of VPA group were lower than the control group, but the difference was not statistically significant (P>0.05); serum alkaline phosphatase have no difference compared with the control group (P>0.05); serum thyroid Hormone was higher than the control group, and have statistical significant difference (P<0.05). The levels of serum calcium, phosphorus of OXC group were lower than the control group, but the difference was not statistically significant (P>0.05); serum alkaline phosphatase was significantly higher, statistically significant (P<0.01); serum parathyroid hormone significantly higher, was statistically significant (P<0.01). The levels of serum calcium, phosphorus, alkaline phosphatase and parathyroid hormone of TPM group and LTG group compared with the control group showed no significant difference (P> 0.05). Osteoporosis in VPA group was 4 (22.2%), bone loss in 4 cases (22.2%); OXC group osteoporosis 3 (16.7%), bone loss 4 (22.2%); TPM group osteoporosis 2 (11.8%), bone loss 3(17.6%); LTG group osteoporosis 1 (5.9%), bone loss 3 (17.6%) and control group osteoporosis 2 (11.8%) bone loss 3(17.6%). Detection of the treatment group and control group bone mineral density in patients with T values, VPA Group lumbar spine bone mineral density T values were lower than the control group, with statistical significance (P<0.01); femoral neck, trochanter and Wards triangle BMD T values were lower than the control group, with statistical significance (P<0.05). The T values of bone mineral density of lumbar vertebrae and femoral neck and trochanter and Wards triangle in OXC group is lower than the control group, and the difference was statistically significant (P<0.05). The T values of bone mineral density of lumbar spine and femoral neck, trochanter, Wards triangle T compared in TPM group or LTG group are lower with the control group, but the difference was not statistically significant (P>0.05). Analysis the relevance of the time taking antiepileptic drugs and serum biochemical markers of bone metabolism, the results show that the time of taking AEDs and the concentrations ofserum calcium, phosphorus, alkaline phosphatase and parathyroid hormone had no correlation in VPA group (correlation coefficient r=0.182,0.278,0.312 and 0.253, P>0.05), and the time of taking AEDs and the concentrations ofserum calcium, phosphorus, alkaline phosphatase and parathyroid hormone in OXC group had no correlation (correlation coefficients were 1.062,0.937,0.851,1.326, P>0.05). Analysis the time of taking AEDs and bone mineral density, we found that in VPA group the time of taking AEDs and 2-4 lumbar vertebrae, femoral neck, trochanter and Wards triangle BMD was negatively correlated (correlation coefficient r=-0.262,-0.201,-0.275,-0.196, P <0.05), and the time of taking AEDs with the T values of lumbar vertebrae 2-4 bone mineral density was a negative correlation (r=-0.105, P<0.05), and the time of taking AEDs with the Z scores of lumbar vertebrae 2-4 bone mineral density was a negative correlation(r=-0.216, P<0.05). In OXC group, the time of taking AEDs and bone mineral density of lumbar vertebrae 2-4 was negatively correlated (correlation coefficient r=-0.236, P<0.05), and the time of taking AEDs with the T values of lumbar vertebrae 2-4 bone mineral density was a negative correlation (r=-1.305, P <0.05), and the time of taking AEDs with the Z values of lumbar vertebrae 2-4 bone mineral density was a negative correlation (r=-1.026, P<0.05), and there was no correlation between bone mineral density in femoral neck and trochanter and Wards triangle (correlation coefficient r were -0.186,0.362, and 0.269, P>0.05), and T values (correlation coefficient r=-0.124,-1.025 and 0.415, P>0.05), and the Z values (correlation coefficient r=-0.109,-1.520 and -0.17, P>0.05).ConclusionThe effects of long-term application of different AEDs on bone mineral density and bone metabolism, different AEDs have different results.The tradition AEDs such as VPA has negativity effects on bone mineral density and bone metabolism. BMD will become lower and lower, with the VPA application time. VPA is not a cytochrome P450 enzyme inducer. It may be that VPA enhanced the activity of osteoclasts, leading to the imbalance of bone formation and resorption that make bone loss. VPA has some impact on liver function. With the time of VPA treatment, serum 1,25(OH)D3 concentration decreased, and calcium and phosphorus absorption decreased and interfere with bone metabolism, and bone mineral density decreased, at last leading to decreased bone mineral density. The new AEDs OXC has effects on bone mineral density and bone metabolism, which may be lead to decreased bone mineral density. The mechanism may be OXC has a weak liver enzyme inducer role in long-term application of large doses. It can increase liver enzymes to speed up the catabolism of vitamin D, resulting in decreased activity of vitamin D and interfering calcium and phosphorus metabolism, causing secondary hyperparathyroidism, leading to bone metabolism disorder, bone density decreased. OXC may also inhibit osteoblasts proliferation directly, interference with bone formation to bone metabolism disorder, and bone density decreased. New AEDs TPM and LTG have no effects on bone mineral density and bone metabolism. |
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