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Bone health in young women with epilepsy after one year of antiepileptic drug monotherapy
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Neurology April 29, 2008
A. M. Pack, MD, M. J. Morrell, MD, A. Randall, D. J. McMahon, MSc and E. Shane, MD
From the Departments of Neurology (A.M.P., A.R.) and Medicine (D.J.M., E.S.), Columbia University, New York, NY; and Department of Neurology (M.J.M.), Stanford University, Stanford, CA.
"....phenytoin sustained significant femoral neck bone loss after 1 year but did not have bone loss at any other site..... There was a significant decline in urine NTx, a marker of bone resorption in the phenytoin group. The clinical relevance of this decrease is also not clear, particularly in view of the significant femoral neck bone loss that occurred in this group......, the most important are older age, female sex, low body weight, history of fracture after age 50 years, excess alcohol intake, cigarette smoking, family history of fracture, and glucocorticoid treatment.14 In addition, excess bone loss associated with medications such as phenytoin can also contribute to increased future fracture risk.... AEDs that induce the hepatic CYP450 enzyme system are most commonly associated with a negative impact on bone. Phenytoin is a potent CYP450 enzyme inducer. The significant femoral neck bone loss we observed in women taking phenytoin, together with a biochemical pattern suggesting that vitamin D insufficiency among some women in that group was associated with secondary hyperparathyroidism and increased bone turnover, supports the notion that the adverse effects of this drug on the skeleton may be mediated by this mechanism....."
Abstract.
Objective: Antiepileptic drugs (AEDs) may have adverse effects on bone mineral density (BMD) and metabolism. We previously reported biochemical evidence of increased bone turnover in premenopausal women with epilepsy on phenytoin monotherapy compared with those on carbamazepine, lamotrigine, and valproate. We therefore hypothesized that rates of bone loss would be higher in young women treated with phenytoin.
Methods: Ninety-three premenopausal women with epilepsy receiving a single AED (carbamazepine, lamotrigine, phenytoin, or valproate) participated. Subjects completed nutritional and physical activity questionnaires. Biochemical indices of bone and mineral metabolism and BMD of the proximal femur and lumbar spine were measured at baseline and 1 year.
Results: Participants reported high calcium intake (>1,000 mg/day) and were physically active. Significant loss (2.6%) was seen at the femoral neck in the phenytoin group. BMD remained stable in the other AED groups. Bone turnover markers and calciotropic hormones were unchanged after 1 year in all groups except for a significant decline in urine N-telopeptide in the phenytoin group. In women receiving phenytoin, lower serum 25-hydroxyvitamin D concentrations were associated with higher parathyroid hormone, bone alkaline phosphatase, and urine N-telopeptide levels, a biochemical pattern consistent with secondary hyperparathyroidism and increased remodeling.
Conclusion: In this study, young women treated with phenytoin had significant femoral neck bone loss over 1 year. In contrast, those treated with carbamazepine, lamotrigine, and valproate did not have detectable adverse effects on bone turnover or bone mineral density. These results raise concerns about the long-term effects of phenytoin monotherapy on bone in young women with epilepsy.
GLOSSARY: 1,25(OH)2D = 1,25-dihydroxyvitamin D; AED = antiepileptic drug; ANOVA = analysis of variance; BCE = bone collagen equivalent; BMD = bone mineral density; BMI = body mass index; BSAP = bone-specific alkaline phosphatase; CBZ = carbamazepine; FN = femoral neck; LS = lumbar spine; LTG = lamotrigine; NTx = cross-linked N-telopeptide of type I bone collagen; OHD = 25-hydroxyvitamin D; PHT = phenytoin; PTH = parathyroid hormone; TH = total hip; VPA = valproate.
Antiepileptic drug (AED) treatment has adverse effects on bone and mineral metabolism that may ultimately increase the risk of fracture.1 Most studies of AED effects on bone and mineral metabolism are cross-sectional. Of the few longitudinal studies, some revealed bone loss in children and adults as well as changes in indices of bone and mineral metabolism.2-5 None have evaluated the effects of individual AEDs.
We previously reported results of a cross-sectional study of bone mineral density (BMD) and indices of bone and mineral metabolism in premenopausal women with epilepsy taking one of four AEDs in monotherapy.6 We reported significant reductions in serum calcium in women treated with phenytoin, carbamazepine, and valproate compared with women treated with lamotrigine. Similarly, phenytoin was associated with significantly higher markers of bone formation, suggesting increased bone turnover. Serum concentrations of vitamin D metabolites and BMD did not differ among the groups.
Herein, we report our findings in women treated with one of four AEDs in monotherapy followed up for 1 year. Given the biochemical evidence of increased turnover at baseline in women receiving phenytoin, we hypothesized that there would be more bone loss in this group.
RESULTS
Characteristics of the study population.
Of the 93 women (aged 18-40 years) who completed the 1-year study, 41 were taking monotherapy with carbamazepine, 23 with lamotrigine, 15 with phenytoin, and 14 with valproate (table 1). Of these women, 66% were white.
The average age was 32 ± 6 years. Subjects in the lamotrigine and valproate groups were approximately 3 years younger on average than those in the carbamazepine and phenytoin groups (p = 0.03). However, this age difference is unlikely to be clinically relevant, because there is little change in gonadal hormone production or bone mass at this age.11-13 The women had long-term epilepsy, as evidenced by an average total duration of AED therapy of 9 ± 11 years. Although women taking phenytoin and carbamazepine tended to have had longer total exposure to AEDs in general and longer exposure to the study-specific AED, there were no significant differences in between group comparisons for either total duration of AED treatment or duration of time on the individual AED. The mean dose was therapeutic for all AEDs studied. Dietary intake of calcium and vitamin D, amount of exercise, age at menarche, percent ever pregnant, and number of pregnancies among those who had been pregnant did not differ among groups.
Bone mineral density.
As we reported previously,6 baseline BMD was similar among the AED groups at the lumbar spine, femoral neck, and total hip (table 2). After 1 year of AED treatment, significant loss was seen only in the group that received phenytoin (-0.023 ± 0.030 g/cm2 or 2.6%) and only at the femoral neck (figure 1).
Because women taking phenytoin and carbamazepine tended to have had longer total exposure both to AEDs and to the study-specific AED, we used multiple regression to explore associations between duration of prior AED exposure and the second-order interaction of AED type and exposure duration. We did not detect a significant influence of duration of AED use on 1-year change in BMD at any site. However, there was a trend (p = 0.09) for longer AED duration, regardless of specific AED, to be associated with lower 1-year rates of bone loss at the total hip.
Biochemical indices of bone and mineral metabolism and bone turnover.
There were no significant between-groups differences in baseline or 1-year serum concentrations of 25-OHD, 1,25(OH)2D, PTH, or markers of bone formation (table 3). In women on phenytoin, urine NTx, a marker of bone resorption, was significantly lower at 1 year than at baseline. Serum calcium was significantly higher in subjects receiving lamotrigine than in those receiving carbamazepine, phenytoin, and valproate (p = 0.04) at baseline and 1 year. Other bone turnover markers and calciotropic hormones were unchanged after 1 year on the same AED.
DISCUSSION
In this longitudinal study of premenopausal women with epilepsy on AED monotherapy, we found that those receiving phenytoin sustained significant femoral neck bone loss after 1 year but did not have bone loss at any other site. In contrast, those treated with carbamazepine, valproate, or lamotrigine did not lose bone mass at any site. Consistent with our previous findings in the cross-sectional study,6 serum calcium concentrations were higher at baseline and also after 1 year of treatment in women taking lamotrigine than in those taking phenytoin, carbamazepine, and valproate. Given the absence of other biochemical differences in the carbamazepine and lamotrigine groups, the clinical significance of the higher serum calcium levels is unclear. There were no significant differences among the groups in markers of bone formation either at baseline or after 1 year. There was a significant decline in urine NTx, a marker of bone resorption in the phenytoin group. The clinical relevance of this decrease is also not clear, particularly in view of the significant femoral neck bone loss that occurred in this group. As we reported previously, serum vitamin D metabolites and PTH concentrations did not differ among the groups. However, within the group of women receiving phenytoin, there was sufficient variation in serum 25-OHD levels to reveal a biochemical pattern consistent with secondary hyperparathyroidism (lower serum, higher serum PTH and markers of bone turnover) in those with lower serum 25-OHD levels.
Measurement of BMD is the most commonly used predictor of fracture risk in postmenopausal women and older men. However, a number of other important risk factors also contribute to increased fracture risk. Of these, the most important are older age, female sex, low body weight, history of fracture after age 50 years, excess alcohol intake, cigarette smoking, family history of fracture, and glucocorticoid treatment.14 In addition, excess bone loss associated with medications such as phenytoin can also contribute to increased future fracture risk. A study of postmenopausal women found significant bone loss at the calcaneus in women with epilepsy treated with phenytoin in comparison with women without epilepsy.15 Similarly, we found significant femoral neck bone loss in young, premenopausal women treated with phenytoin monotherapy. To put this in context, in 614 premenopausal women aged 24 to 44 years, femoral neck BMD declined by 0.3%.16 The 2.6% loss we observed in the women receiving phenytoin is more than eight times greater than that observed in this cohort of young women. If such rates of bone loss were to be sustained over time, premenopausal women receiving long-term phenytoin therapy might enter their menopausal years with lower than normal bone mass, and their vulnerability to postmenopausal fractures might be considerably increased.
AEDs that induce the hepatic CYP450 enzyme system are most commonly associated with a negative impact on bone. Phenytoin is a potent CYP450 enzyme inducer. The significant femoral neck bone loss we observed in women taking phenytoin, together with a biochemical pattern suggesting that vitamin D insufficiency among some women in that group was associated with secondary hyperparathyroidism and increased bone turnover, supports the notion that the adverse effects of this drug on the skeleton may be mediated by this mechanism.
Although both phenytoin and carbamazepine are CYP450 enzyme-inducing AEDs, there was no significant bone loss after 1 year of treatment in the carbamazepine group, nor was there any evidence of secondary hyperparathyroidism or increased bone turnover. In this regard, our results differ from those of other investigators who have reported increased markers of bone turnover in subjects after 1 and 2 years of treatment and decreased BMD in association with this AED.2,3 In contrast, other clinical studies have not found significant changes in BMD or abnormalities in mineral metabolism in patients receiving carbamazepine and thus are consistent with our results.17-19
There were no demographic differences between the phenytoin and carbamazepine groups that could account for our observation, excepting that there were fewer white women in the phenytoin group. However, the racial composition of the phenytoin group was diverse and no racial group predominated. Phenytoin has also been reported to have direct effects on bone resorption20-22 and formation,23,24 may directly impair calcium absorption,24 and may impair the response of osteoblasts to PTH.22,25 Although carbamazepine has also been shown to inhibit bone formation23 and intestinal calcium absorption,24 it is possible that the bone loss we observed may be mediated by one or more direct effects of phenytoin on some aspect of bone and mineral metabolism that are not shared by carbamazepine, rather than by an indirect effect of phenytoin on vitamin D metabolism. This observation requires confirmation and, if confirmed, further exploration.
This study has several important strengths. It is one of very few longitudinal studies evaluating the individual effects of several commonly used AEDs on BMD and markers of bone and mineral metabolism. Other longitudinal studies have evaluated either a single drug or have studied patients taking multiple AEDs. In addition, we controlled for other factors known to affect bone health.
This study also has several important limitations. We did not include a group of women without epilepsy to serve as normal controls. Thus, we may have missed subtle differences in bone and mineral metabolism. Subjects were not randomly assigned to the studied AED but were receiving the drug best able to control their seizure activity. The findings therefore may in part be explained by a selection bias influencing AED treatment for the enrolled subjects. Fifty-four women (37%) withdrew from the study before completion. The baseline outcome variables of these women did not differ when compared with those who completed the study, excepting that those who withdrew were approximately 2.5 years younger. This age difference is unlikely to be clinically important, because bone mass is generally stable at this age. Therefore, we do not believe that the number of women who withdrew influenced our results. However, the reduced and small sample sizes due to the large dropout may have limited our ability to detect small differences which may be clinically meaningful. The subjects had long-term epilepsy, and many were treated with other agents before the investigated AED. We therefore could not control for prior AED exposure. Although the longitudinal study design provides an assessment of effects of current AED treatment, 1 year of observation may not be sufficient to detect minor changes that may accumulate over time. The women studied had well-controlled epilepsy and seemed to be health conscious in that they were on relatively high intakes of calcium and vitamin D and exercised for several hours each week. This may limit generalizability of these results to other groups of women. In addition, our subjects were estrogen replete because they were premenopausal and had regular menses. Adverse effects of AED therapy may be more apparent in postmenopausal women or older men, in whom estrogen levels may be insufficient to counter the effects of these drugs on bone turnover.
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