Epilepsy Drug Carbamazepine Tied to Falling Vitamin D and Calcium Levels

Adults with epilepsy who took carbamazepine for at least a year showed measurable drops in vitamin D, calcium, and sodium, according to a retrospective pre–post study of 226 patients conducted at King Abdulaziz Medical City in Jeddah, Saudi Arabia. Serum vitamin D fell from a mean of 45 ± 23.25 nmol/L before treatment to 36.6 ± 15.68 nmol/L after treatment, a difference with a 95% confidence interval of −14.47 to −2.37 and a P-value of 0.007. Serum calcium declined from a mean of 2.3 mmol/L to 2.2 mmol/L with a P-value below 0.001, and sodium also decreased significantly with a P-value of 0.019. Alkaline phosphatase, by contrast, showed no significant change over the course of therapy.

The study, published in Acta Epileptologica, screened 2,087 medical records and enrolled adults aged 18 to 60 with epilepsy diagnosed under International League Against Epilepsy criteria who had received carbamazepine for a minimum of one year. Each patient needed at least one documented pre-treatment and one post-treatment measurement of at least one of the four biochemical markers. Pre-treatment values were defined as those obtained within three months before carbamazepine initiation, while post-treatment values had to come at least 12 months after starting the drug. Because laboratory testing varied with routine clinical care, the available sample size differed by parameter, and the analyses used separate subgroups for vitamin D, calcium, sodium, and alkaline phosphatase.

Carbamazepine is a tricyclic antiseizure medication used primarily to manage focal seizures. It works by altering voltage-gated sodium channels, inhibiting excitatory signaling and decreasing synaptic transmission. It is metabolized in the liver and is a potent inducer of cytochrome P450 enzymes, which creates numerous drug–drug and drug–food interactions. Common side effects include dizziness, nausea, vomiting, and drowsiness, while more serious effects can include central nervous system depression, nephrotoxicity, hepatotoxicity, and hyponatremia. The enzyme-inducing property is central to the bone-health concern: cytochrome P450 induction may accelerate the metabolism of vitamin D, potentially altering bone metabolism over years of treatment.

The proposed mechanism centers on vitamin D dysregulation. Cytochrome P450-inducing antiseizure medications may alter the activity of enzymes that metabolize vitamin D, decreasing levels of 1,25-dihydroxycholecalciferol, the active form of the vitamin. This may trigger secondary hyperparathyroidism, driving increased bone resorption and loss of bone mass. Reduced active vitamin D also lowers calcium absorption from the gut, and the resulting drop in calcium elevates circulating parathyroid hormone, further increasing calcium mobilization from bone. The authors note, however, that this mechanism does not explain all observed skeletal effects of antiseizure medications, since valproic acid, an enzyme inhibitor, has also been linked to reduced bone mineral density, and genetic variation in vitamin D receptor genes has been implicated in some studies.

The cohort averaged 38 years of age, included 116 women (51.33%) and 110 men (48.67%), and had a mean carbamazepine duration of approximately 50.8 months at a mean total daily dose of 648 ± 299.43 mg. Dyslipidemia was the most frequent comorbidity, present in 32 patients (14.16%), followed by hypertension in 19 patients (8.41%). Data were extracted from the hospital’s electronic medical record system by five trained data collectors using a standardized form, capturing age, sex, body mass index, therapy duration and dose, comorbidities, and concomitant antiseizure medications.

Exploratory multiple linear regression examined factors associated with the change in vitamin D and calcium levels. The vitamin D model was statistically significant overall, with the included variables accounting for 55.6% of the variability in the change. Older age contributed positively, with an unstandardized coefficient of 0.867 (P = 0.01), while dyslipidemia was associated with vitamin D levels 23.45 nmol/L lower (P = 0.018). Among concomitant medications, topiramate (P = 0.001) and phenytoin (P = 0.001) were significantly associated with reduced vitamin D levels, whereas lamotrigine correlated positively (P = 0.019). No significant predictors emerged for changes in calcium. The authors caution that these regression analyses were exploratory because of the limited sample sizes for some parameters, and that only small numbers of patients took the combination regimens involved.

The regional context matters for interpreting the findings. A meta-analysis of 20,787 healthy adults in Saudi Arabia found vitamin D deficiency in 63.5%, and a report covering 13 studies with 24,399 participants estimated deficiency, defined as levels below 50 nmol/L, at roughly 81% across age groups. Epilepsy affects around 200,000 people in Saudi Arabia, and the World Health Organization estimates more than 50 million cases globally. Prior research cited by the authors suggests that patients with epilepsy on long-term antiseizure medications face a fracture risk two to six times that of the general population, and that prolonged carbamazepine treatment has been associated with altered bone metabolism, reduced bone mineral density, and increased fractures. The authors state this is the first study in Saudi Arabia to evaluate long-term carbamazepine effects on these specific biochemical markers.

The authors themselves urge restraint in translating the numbers to the clinic. Most post-treatment values remained within clinical reference ranges, even though the reductions were statistically significant, and the clinical impact is likely greatest for patients who were already deficient at baseline. Vitamin D supplements were not an exclusion criterion, and because documentation of supplement use was incomplete in the electronic record, the observed effect of carbamazepine on vitamin D may actually underestimate the true effect. Hyponatremia, meanwhile, has been reported as a risk factor for falls and fractures, potentially through mild cognitive impairment affecting gait and through direct stimulation of bone resorption via osteoclast activation and elevated arginine vasopressin. The sodium reduction seen here is consistent with carbamazepine’s antidiuretic effect on the kidney’s collecting ducts, which increases water reabsorption and dilutes serum sodium.

Several limitations frame the conclusions. The study measured biomarkers only, without bone mineral density scans, fracture records, or other bone turnover markers such as osteocalcin and parathyroid hormone, so the findings reflect associations with bone-related markers rather than definitive changes in bone health. Carbamazepine doses were adjusted for seizure control in some patients, which could have influenced dose–response relationships. Convenience sampling from available records, subgrouping by laboratory data availability, and the retrospective design all introduce potential selection bias and limit causal inference, as do unmeasured factors such as pregnancy status, menopausal status, and sun exposure. Residual confounding from concomitant antiseizure medications and comorbidities may also have influenced the observed changes despite the within-patient pre–post design, which the authors note reduces interindividual variability and control group bias.

The authors conclude that long-term carbamazepine use in adults is associated with biochemical abnormalities, specifically decreases in serum vitamin D, calcium, and sodium, and recommend routine measurement of these levels as part of epilepsy care to enable early intervention and supplementation when indicated, alongside bone-preserving lifestyle measures such as regular physical activity and a balanced diet. They call for prospective research measuring parathyroid hormone, osteocalcin, bone mineral density, and fracture rates in patients receiving antiseizure treatment, and for analyses stratifying patients by baseline vitamin D status to clarify which patients face the greatest clinical risk.

Subject of Research: Long-term effects of carbamazepine on bone-related biochemical markers in adults with epilepsy

Article Title: Long-term effects of carbamazepine on bone-related biochemical markers in patients with epilepsy

Article References: Hakami, A. Y., Althagafi, A. A., Alkhayat, A. S., Alturkistani, B. A., Mawar, H. E., Ibrahim, I. H., Abualhamail, H., & Ahmed, M. E. (2026). Long-term effects of carbamazepine on bone-related biochemical markers in patients with epilepsy. Acta Epileptologica, 8(1), Article 22. https://doi.org/10.1186/s42494-026-00262-6

Image Credits: AI Generated

DOI: 10.1186/s42494-026-00262-6

Keywords: carbamazepine, epilepsy, vitamin D, calcium, hyponatremia, bone health, antiseizure medications, cytochrome P450, biochemical markers, Saudi Arabia, observational study, drug safety