Medical Technology

Widely Used Antiepileptic Tied to Lower Vitamin D Levels

The widely used antiseizure medication (ASM) carbamazepine is associated decreased 25-hydroxyvitamin D (25OHD) levels, new data show.

Results of a large meta-analysis have shown those taking carbamazepine had significantly lower 25OHD levels compared with controls — those treated with a non-enzyme-inducing ASM or healthy individuals not taking an ASM — with a weighted mean difference of 4.00 ng/mL.

“I would recommend that the vitamin D levels of patients of all ages taking carbamazepine be monitored at least every 2 years, which is the same time I typically recommend for bone density monitoring,” study investigator Carla LoPinto-Khoury, MD, associate professor of neurology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, told Medscape Medical News.

“In fact, I recheck vitamin D every year in these patients if they have particular risk factors, such as not going outdoors or having certain nutritional problems, and recommend supplementation, if necessary,” said LoPinto-Khoury.

The study was published in the December issue of Epilepsy Research.

Widespread Use

Carbamazepine is widely used for epilepsy and psychiatric conditions such as bipolar disorder. It is also on the World Health Organization’s list of essential drugs. Because it is “very inexpensive,” it is often used in countries where more costly ASMs are unavailable, LoPinto-Khoury noted.

One of the potential long-term side effects of carbamazepine is vitamin D deficiency caused by induction of cytochrome P450 enzymes that metabolize 25OHD, the physiologically active form, into inactive metabolites. In turn, vitamin D deficiency “has the potential to produce several chronic adverse health effects,” including osteoporosis and subsequent fractures.

“We’ve known for some time that antiseizure medications, in particular phenobarbital and phenytoin, are associated with lower vitamin D levels, which can lead to bone loss. This major finding has been around since the 1970s,” LoPinto-Khoury said. “We wanted to see whether the same concern was the case with carbamazepine, especially given its widespread use.”

LoPinto-Khoury and colleagues conducted a literature search for papers related to carbamazepine and vitamin D. Of 103 titles published between 1984 and 2015, they selected 12 studies for inclusion in the analysis, encompassing 331 patients treated with carbamazepine, with a duration of therapy of 1 to 10 years, and 328 controls.

Beyond Bone Loss

Most studies included male and female patients, with 24% to 63% of participants being female; however, two studies included only female patients and one study included only male patients. In addition, although most (n = 9) studies were in adults, three focused on children. The studies were conducted at a range of geographic latitudes.

The raw mean difference in 25OHD levels between carbamazepine and control groups was 4.00 ng/mL (95% CI, -7.00 to -0.98), “indicating that, on average, carbamazepine-treated groups demonstrated 25OHD levels 4.00 ng/mL lower than control groups,” the authors summarize. The Z-value for the null hypothesis test was 2.60 (P = .009).

The authors caution that, “given the dispersion of effects…this mean effect size applies to this particular mix of studies, and thus may be different for another mix of populations.”

When they measured heterogeneity, they found a Q-value of 77.86 with 11 degrees of freedom (P < .001), “indicating that the true effect size is not identical in these studies,” they comment.

However, the I 2 statistic was 86%, “which tells us that 86% of the variance in observed effects reflects variance in true effects rather than sampling error,” they add. Further analysis of the variance of true effects showed a T 2 of 23.24 (95% prediction interval, -15.27 to 7.27), with an SD of true effects (T) of 4.82.

The researchers analyzed several potential demographic and clinical moderator variables, including vitamin D supplementation and type of control group (ie, healthy non-epilepsy controls and epilepsy controls taking non-enzyme-inducing ASMs).

They found that in studies where a proportion of the sample was taking vitamin D supplements, the mean difference between those taking carbamazepine and controls was -0.96 (-6.51 to 4.60; Z = -0.31; P = .76). On the other hand, in studies that excluded 25OHD supplementation, the mean effect was -1.88 (-4.06 to 0.29; Z = -1.69; P = .09).

There were 10 studies that used a healthy control comparison group and two that used an epilepsy patient comparison group not taking carbamazepine (mean difference, -4.85 [95% CI, -8.03 to -1.68] and -0.24 [95% CI, -6.09 to 6.43], respectively).

There were no significant effects of age, duration of carbamazepine treatment, or geographic latitude on observed 25OHD levels.

Analyses for potential bias revealed that “the present results are unlikely to be the result of random sampling error” and “publication bias did not likely account for our findings,” the authors report.

“Our meta-analysis was done parsing out for moderator variables, so we were able to find that age and gender were not particularly associated with differences in vitamin D [between carbamazepine-treated patients and controls], nor was geographic latitude, which is a marker for the amount of sunshine,” said LoPinto-Khoury.

She noted that vitamin D deficiency could have an adverse impact not only by increasing osteopenia risk but also by affecting other body systems.

“It is a hot topic lately that vitamin D can affect vascular risk factors like cholesterol and that it can affect the immune system, which — especially now, during the pandemic — is concerning.”

As previously reported by Medscape Medical News, a recent study had experts calling for the retirement of enzyme-inducing ASMs because they found they were significantly associated with an increase in cardiovascular disease.

Monitoring Is Critical

Commenting on the findings for Medscape Medical News, Kimford Meador, MD, professor, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, California, described the study as “well-conducted.”

“[It] is important, as it highlights this potential adverse effect of carbamazepine, and likely similar effects of other enzyme-inducing antiseizure medications. The implications are beyond epilepsy, given that such medications are used for other indications,” said Meador, who was not involved with the study.

LoPinto-Khoury said that when she monitors patients taking carbamazepine, she checks basic metabolic liver function and blood counts regularly and checks vitamin D levels routinely.

“If they are deficient or insufficient, I supplement with vitamin D,” she said. She also considers the possibility of switching the patient to a “non-inducing ASM, such as lamotrigine,” she said.

No source of funding was given for the study. The authors have disclosed no relevant financial relationships. Meador has received research support from the National Institutes of Health, Eisai, and Medtronic. The Epilepsy Study Consortium pays his university for his research consultant time related to Eisai, GW Pharmaceuticals, NeuroPace, Novartis, Supernus, Upsher-Smith Laboratories, UCB Pharma, and Vivus Pharmaceuticals. Meador is on the editorial boards of several journals.

Epilepsy Res. 2021;178:106829. Abstract

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