Incident Epilepsy and Antiseizure Medications Independently Associated With Osteoporosis Risk in Adults

Colin B. Josephson, MD, MSc, FRCPC

Using a large-scale cohort of electronic health records, recently published findings identified robust and clinically meaningful independent associations between incident epilepsy and both epilepsy/enzyme-inducing antiseizure medication (eiASM) use with incident osteoporosis. These data highlight the need for enhanced vigilance and consideration of prophylaxis for all patients with epilepsy.

Among a cohort of 6275 individuals with adult-onset epilepsy, their condition was independently associated with a 41% faster time to incident osteoporosis (time ratio [TR], 0.59; 95% CI, 0.52-0.67; P <.001) after controlling for osteoporosis risk factors. Both eiASMs (TR, 0.91; 95% CI, 0.87-0.95; P <.001) and non-eiASMs (TR, 0.77; 95% CI, 0.76-0.78; P <.001) were also associated with statistically significant increased risks independent of epilepsy, accounting for 9% and 23% faster times to incident osteoporosis, respectively.

"People with epilepsy are more likely to be deficient in vitamin D, and those who are deficient may still benefit from routine supplementation,” lead investigator Colin B. Josephson, MD, MSc, FRCPC, associate professor of neurology, University of Calgary, and colleagues, wrote.¹ "Randomized controlled trials studying this approach universally in epilepsy are expediently required, as are evidence-based algorithms for routine osteoporosis screening irrespective of ASM type."

The trial, conducted from 1998 to 2019, included individuals with adult-onset epilepsy and a control cohort of 8,089,166 controls who were free of osteoporosis. The median duration of ASM exposure was 8.9 years (IQR, 4.8-14.8). Cox proportional hazards or accelerated failure time models where appropriate were used to determine incident osteoporosis, with covariates that included age, sex, socioeconomic status, cancer, 1 or more years of corticosteroid use, body mass index, bariatric surgery, eating disorders, hyperthyroidism, inflammatory bowel disease, rheumatoid arthritis, smoking status, falls, fragility fractures, and osteoporosis screening tests.

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Prior research has shown that even non-eiASM use, such as valproate and levetiracetam, is associated with low bone mass density, with effect sizes comparable or even greater than eiASMs. In the present study, the association between non-eiASM use and osteoporosis remained consistent when valproic acid was excluded from this group (TR, 0.77; 95% CI, 0.76-0.78; P <.001). In a sensitivity analysis that excluded BMI because of 30% missing values, estimates for the associations with osteoporosis remained consistent (epilepsy: TR, 0.54 [95% CI, 0.48-0.62]; eiASM: TR, 0.90 [95% CI, 0.86-0.94]; non-eiASM: TR, 0.76 [95% CI, 0.74-0.77]; all P <.001).

A subcohort of controls (n = 193,225) matched 5:1 to patients exposed to 4 consecutive eiASMs (n = 38,645) was generated through propensity score matching on measures that could estimate prescription behavior. After the model failed the proportional hazards assumption (global test, P <.001), an accelerated failure time model that incorporated interaction term between age and cancer was used. Results showed that when used as a time-varying covariate, incident epilepsy was associated with incident osteoporosis (TR, 0.72; 95% CI, 0.47-0.97; P = .011), as were non-eiASMs (TR, 0.80; 95% CI, 0.74-0.86; P <.001) and eiASMs (TR, 0.89; 95% CI, 0.84-0.94; P <.001).

In a subgroup of 1048 individuals with late-onset epilepsy and 10,095 controls, the survival model for late-onset epilepsy failed proportional hazards assumptions (global P <.001). Using an accelerated failure time model incorporating an age-by-cancer interaction term, findings showed that late-onset epilepsy was associated with an elevated risk of incident osteoporosis (TR, 0.81; 95% CI, 0.72-0.90; P <.001), as were non-eiASMs (TR, 0.90; 95% CI, 0.83-0.97; P = .007); however, there was no statistically significant association with eiASMs (TR, 0.95; 95% CI, 0.81-1.11; P = .56). investigators noted that the lack of association may have been because only 3% (n = 298) of the cohort in this analysis were exposed to eiASMs compared with 15% (n = 1696) who were exposed to non-eiASMs, and 82% (n = 9149) who lacked exposure to any ASMs.

REFERENCE
1. Josephson CB, Gonzalez-Izquierdo A, Denaxas S, et al. Independent associations of incident epilepsy and enzyme-inducing and non-enzyme-inducing antiseizure medications with the development of osteoporosis. JAMA Neurol. Published online June 12, 2023. doi:10.1001/jamaneurol.2023.1580