What is risk of incident osteoporosis following incident adult-onset epilepsy and antiseizure medication use?

A recent study published in JAMA Neurology suggests that epilepsy is independently associated with a clinically meaningful increase in the risk for osteoporosis, as are both enzyme inducing and non- enzyme inducing antiseizure medications.

Active epilepsy affects almost 50 million people worldwide, with age-standardized disability-adjusted life-years of 182.6 per 100 000 population. Although seizures account for a substantial proportion of this burden, epilepsy-associated comorbidities also exert significant influence. Osteoporosis is of particular interest given its association with high rates of fractures, morbidity, and mortality.

Recent studies have found both enzyme-inducing ASMs (eiASMs) and non-eiASMs to be associated with increased risks of fractures. Certain ASMs, especially carbamazepine, are associated with enhanced vitamin D metabolism and accelerated bone turnover, but studies have often yielded conflicting results regarding the effects of ASMs, even for eiASMs, such as carbamazepine, on bone density.

Josephson et al conducted an open cohort study to study this problem, where they quantified the hazard of osteoporosis following incident epilepsy and ASM exposure in the general population. They also sought to determine whether the hazard related to eiASMs is elevated compared with non-eiASMs in people with incident adult-onset epilepsy and late-onset epilepsy.

Their study showed a clear association between incident adult-onset epilepsy and incident osteoporosis, independent of medications, common risk factors, fragility fractures, and falls. Their findings also showed clear associations between both eiASM and non-eiASM use and incident osteoporosis, independent of incident epilepsy. This risk continued to increase over the 15 years following an epilepsy diagnosis. Finally, the hazard associated with late-onset epilepsy was comparable to that of adult-onset epilepsy, indicating that the risk does not appear to be further elevated in an older population.

The prevailing theory has been that eiASMs convey a higher risk than non-eiASMs due to interactions with the cytochrome P450 system, which could accelerate metabolism of vitamin D, leading to compensatory increases of parathyroid hormone. Parathyroid hormone releases active vitamin D metabolites in an attempt to replenish stores, but the undesirable consequence is increased bone turnover. However, prior studies have reported conflicting results on the outcomes of ASMs. Some indicate that strong inducers, like carbamazepine, decrease bone density and bone turnover,26 while others have reported no association. “Consistent with our results, prior literature has highlighted that even non-eiASM use, such as valproate and levetiracetam, is associated with low bone mass density, with effect sizes comparable to or even greater than eiASMs”, state the authors.

Their study findings also highlight the importance of risk mitigation in all people with epilepsy. However, a recent large randomized controlled trial revealed that daily supplementation with 2000 IU of vitamin D did not reduce the risk of bone loss over 2 years or fractures over 5 years compared with placebo, even when calcium was concomitantly administered.Thus, although vitamin D deficiency and lower serum calcium were more common in people with epilepsy , controlling for supplementation may have had a minimal effect on their conclusions.

“There may still be benefit in patients with low baseline free 25-hydroxyvitamin D levels, meaning that efforts to study routine supplementation in all people with epilepsy are paramount given their risks of vitamin D deficiency. The outcomes of supplemental calcium on fracture risk have been varied, and caution should be taken when recommending daily doses of 1000 to 1500 mg. Algorithms for routine screening through laboratory work and bone mass densitometry should be validated and deployed for all people with epilepsy, given that early detection could improve outcomes.,” they conclude.

Reference

Independent Associations of Incident Epilepsy and Enzyme-Inducing and Non–Enzyme-Inducing Antiseizure Medications With the Development of Osteoporosis, Colin B. Josephson, MD, MSc; Arturo Gonzalez-Izquierdo, PhD; Spiros Denaxas, PhD; et al JAMA Neurol. Published online June 12, 2023. doi:10.1001/jamaneurol.2023.1580