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Adverse Long-term Effects on Bone Health of Antiepileptic Drugs (AEDs) – Medical Literature Review Prompted by the Heartbreaking Event in the Life of an Adult with SYNGAP1

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Dr. Marta Dahiya, MD is SRF’s Clinical Director and serves on SRF’s Board of Trustees and its Diversity, Equity, and Inclusion Board.

Editor’s Note:

This article is meant as a resource for caregivers and physicians of SYNGAP1-Related Disorders (SRD) patients. It was prompted by the heartbreaking event in the life of an adult Syngapian described here. You can also watch a YouTube video describing a similar experience from another Syngapian.

Introduction

The long-term use of antiepileptic drugs (AEDs) has been associated with adverse effects on bone health, leading to an increased risk of fractures. This synthesis aims to consolidate findings from multiple research papers to provide a comprehensive understanding of the relationship between AED use and bone health complications.

Key Insights

  • Increased Fracture Risk with AED Use:
    • AEDs are associated with a significant increase in fracture risk, with a relative risk (RR) of 1.86 for users compared to non-users 1, 2, 3, 4.
    • Both liver enzyme-inducing AEDs (LEI AEDs) and non-LEI AEDs contribute to this increased risk, though LEI AEDs have a higher risk estimate 1, 2, 3, 4.
  • Specific AEDs and Fracture Risk:
    • Specific AEDs such as phenobarbiturate (PB), topiramate (TPM), and phenytoin (PHT) are linked to a higher fracture risk, with increases of 78%, 39%, and 70%, respectively 1, 6.
    • The second-generation anti-epileptic drugs (AEDs; levetiracetam, lamotrigine) have less adverse effects on bone metabolism makers compared to first-generation AEDs (valproic acid, carbamazepine) 11.
  • Bone Mineral Density (BMD) and AEDs:
    • Long-term use of AEDs is associated with decreased bone mineral density (BMD), which contributes to the increased fracture risk 3, 4, 6, 7. 
    • Enzyme-inducing AEDs (EIAEDs) are particularly implicated in reducing BMD and increasing fracture incidence 3, 4, 6.
  • Gender Differences in Fracture Risk:
    • The risk of fractures is higher in women than in men, especially with long-term AED use 2, 9.
  • Mechanisms of Bone Health Deterioration:
    • AEDs may lead to bone health issues through mechanisms such as vitamin D catabolism and hypocalcemia, which affect bone turnover and increase fracture risk 7, 8, 10.
  • Prevention and Management:
    • Vitamin D and Calcium Supplementation: Regular monitoring of vitamin D and calcium levels, with supplementation as needed.
    • Bone Density Monitoring: Patients on long-term AED therapy, especially those with other risk factors for osteoporosis, should undergo regular bone density tests (e.g., DEXA scans).
    • Lifestyle Modifications: Encouraging weight-bearing exercises, a balanced diet rich in calcium and vitamin D, and avoiding smoking or excessive alcohol use.
    • Alternative AEDs: In some cases, switching to non-enzyme-inducing AEDs like lamotrigine or levetiracetam might help mitigate the risk to bone health.
    • Patients on long-term AED therapy should undergo bone density studies, especially if they have been on treatment for more than 2 years, are older than 40 years, or are on enzyme-inducing AEDs 12.

Conclusion

The use of antiepileptic drugs is robustly associated with an increased risk of fractures, particularly with long-term use and among women. Both enzyme-inducing and non-enzyme-inducing AEDs contribute to this risk, with specific drugs like phenobarbiturate, topiramate, and phenytoin posing higher risks. The underlying mechanisms include decreased bone mineral density and disturbances in bone metabolism. Preventive strategies, including lifestyle modifications and nutritional supplementation, are recommended to mitigate these risks.

Patients on long-term AEDs should work closely with healthcare providers to monitor and protect bone health to reduce the risk of fractures and osteoporosis.

Citations:

  1. Shen, C., Chen, F., Zhang, Y., Guo, Y., & Ding, M. (2014). Association between use of antiepileptic drugs and fracture risk: a systematic review and meta-analysis. Bone, 64, 246-53. https://doi.org/10.1016/j.bone.2014.04.018.
  2. Souverein, P., Webb, D., Weil, J., Staa, T., & Egberts, A. (2006). Use of antiepileptic drugs and risk of fractures. Neurology, 66, 1318 – 1324. https://doi.org/10.1212/01.wnl.0000210503.89488.88.
  3. Fraser, J., Burneo, J., & Fraser, L. (2015). Fracture Risk Associated with Enzyme-Inducing Antiepileptic Drugs in Patients with Epilepsy: A Systematic Review (P4.274). Neurology. https://doi.org/10.1212/wnl.84.14_supplement.p4.274.
  4. Fraser, L., Burneo, J., & Fraser, J. (2015). Enzyme-inducing antiepileptic drugs and fractures in people with epilepsy: A systematic review. Epilepsy Research, 116, 59-66. https://doi.org/10.1016/j.eplepsyres.2015.07.003.
  5. Vestergaard, P., Rejnmark, L., & Mosekilde, L. (2004). Fracture Risk Associated with Use of Antiepileptic Drugs. Epilepsia, 45. https://doi.org/10.1111/j.0013-9580.2004.18804.x.
  6. Nakken, K., & Taubøll, E. (2010). Bone loss associated with use of antiepileptic drugs. Expert Opinion on Drug Safety, 9, 561 – 571. https://doi.org/10.1517/14740331003636475.
  7. Simm, P., Seah, S., Gorelik, A., Gilbert, L., Nuguid, J., Werther, G., Mackay, M., Freeman, J., Petty, S., & Wark, J. (2017). Impaired bone and muscle development in young people treated with antiepileptic drugs. Epilepsia, 58. https://doi.org/10.1111/epi.13893.
  8. Valsamis, H., Arora, S., Labban, B., & McFarlane, S. (2006). Antiepileptic drugs and bone metabolism. Nutrition & Metabolism, 3, 36 – 36. https://doi.org/10.1186/1743-7075-3-36.
  9. Carbone, L., Johnson, K., Robbins, J., Larson, J., Curb, J., Watson, K., Gass, M., & LaCroix, A. (2009). Antiepileptic Drug Use, Falls, Fractures, and BMD in Postmenopausal Women: Findings From the Women’s Health Initiative (WHI). Journal of Bone and Mineral Research, 25, 873 – 881. https://doi.org/10.1359/jbmr.091027.
  10. Miziak, B., Chrościńska-Krawczyk, M., & Czuczwar, S. (2019). An update on the problem of osteoporosis in people with epilepsy taking antiepileptic drugs. Expert Opinion on Drug Safety, 18, 679 – 689. https://doi.org/10.1080/14740338.2019.1625887.
  11. Fu, J., Peng, L., Li, J., Tao, T., & Chen, Y. (2019). Effects of Second-Generation Antiepileptic Drugs Compared to First-Generation Antiepileptic Drugs on Bone Metabolism in Patients with Epilepsy: A Meta-Analysis. Hormone and Metabolic Research, 51, 511 – 521. https://doi.org/10.1055/a-0963-0054.
  12. Petty, S., Paton, L., Paton, L., O’Brien, T., O’Brien, T., Makovey, J., Erbas, B., Sambrook, P., Berkovic, S., Wark, J., & Wark, J. (2005). Effect of antiepileptic medication on bone mineral measures. Neurology, 65, 1358 – 1365. https://doi.org/10.1212/01.wnl.0000180910.72487.18.