Bone Health Implications of Antiepileptic Drug Therapy

Antiepileptic drugs (AEDs) have transformed epilepsy management by reducing seizure burden and improving quality of life. However, a growing body of evidence indicates that long-term therapy, particularly with enzyme-inducing agents, can compromise skeletal integrity. These drugs accelerate the metabolism of vitamin D and calcium through induction of cytochrome P450 enzymes, leading to reduced bone mineral density (BMD), altered bone remodelling markers and increased fracture risk. Both paediatric and adult populations exhibit this pattern, with children facing potential disruptions to growth velocity and adults at heightened risk of osteoporosis. The mechanisms involve an imbalance between osteoclast-driven bone resorption and osteoblast-mediated formation, modulated by factors such as receptor activator of nuclear factor-kappa B ligand (RANKL) and its decoy receptor osteoprotegerin (OPG). Recognition of these adverse effects has prompted calls for routine bone health monitoring, vitamin D supplementation and consideration of newer AEDs with more favourable skeletal profiles. A multidisciplinary approach, incorporating endocrinology, neurology and primary care, is essential to mitigate long-term complications and guide individualised treatment strategies.

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Bone Health Implications of Antiepileptic Drug Therapy publication trend

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Technical terms

Bone mineral density (BMD): A measure of the amount of mineral in bone tissue per unit volume, used as an indicator of skeletal strength and fracture susceptibility.

Enzyme-inducing antiepileptic drugs: A class of AEDs that increases the activity of hepatic cytochrome P450 enzymes, accelerating the breakdown of endogenous hormones and vitamins.

Osteoprotegerin (OPG): A glycoprotein acting as a decoy receptor for RANKL, inhibiting osteoclast formation and reducing bone resorption.

Receptor activator of nuclear factor-kappa B ligand (RANKL): A cytokine that binds to its receptor RANK on osteoclast precursors, promoting their differentiation, activation and subsequent bone resorption.

References

1. Causal Relationships Between Epilepsy, Anti‐Epileptic Drugs, and Serum Vitamin D and Vitamin D Binding Protein: A Bidirectional and Drug Target Mendelian Randomization Study. CNS Neuroscience & Therapeutics (2024).
2. Bone Status in Patients with Epilepsy: Relationship to Markers of Bone Remodeling. Frontiers in Neurology (2014).
3. Potential effects of valproate and oxcarbazepine on growth velocity and bone metabolism in epileptic children- a medical center experience. BMC Pediatrics (2016).
4. Bone Mineral Density Loss in People With Epilepsy Taking Valproate as a Monotherapy: A Systematic Review and Meta-Analysis. Frontiers in Neurology (2019).
5. Impaired bone health as a co-morbidity of epilepsy. Best Practice & Research Clinical Rheumatology (2022).