Enzyme-Inducing Antiepileptic Drugs and the Risk of Vitamin D Deficiency

by | Feb 6, 2026 | Articles | 0 comments

6 minutes read time

Epilepsy is a chronic neurological disorder characterised by an enduring predisposition to generate epileptic seizures. It is defined by the International League Against Epilepsy (ILAE) as [1]:

  • at least two unprovoked seizures occurring more than 24 hours apart
  • one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years
  • diagnosis of an epilepsy syndrome

Long-term pharmacological therapy with antiepileptic drugs (AEDs) remains the cornerstone of epilepsy management.

Vitamin D is a fat-soluble prohormone essential for calcium homeostasis and bone mineralisation. It is obtained through cutaneous synthesis following ultraviolet B exposure, dietary intake (e.g. oily fish, fortified foods), and supplementation. In adults, recommended daily vitamin D intake generally ranges from 400 to 1000 IU, depending on age and risk factors, with higher doses advised in individuals at risk of deficiency [2].

Studies indicate that certain AEDs, particularly enzyme-inducing agents, may adversely affect vitamin D metabolism. This increases the risk of deficiency and associated skeletal complications [3][4].

 

Enzyme-Inducing Antiepileptic Drugs (EIAEDs)

Commonly prescribed enzyme-inducing antiepileptic drugs (EIAEDs) include:

  • Phenytoin
  • Carbamazepine
  • Phenobarbital
  • Primidone

These agents are well-established treatments for focal and generalised epilepsy and are recognised as inducers of hepatic cytochrome P450 enzymes, particularly during long-term therapy. Their enzyme-inducing properties are clinically significant due to their effects on the metabolism of co-administered medicines and endogenous compounds, including vitamin D [4].

vitamin d deficiency risk with enzyme inducing aeds 1

EIAEDs induce hepatic cytochrome P450 enzymes, accelerating the metabolic degradation of vitamin D into inactive metabolites. 25‑hydroxyvitamin D is the major circulating form of vitamin D and the standard laboratory measure of vitamin D status. This increased clearance reduces circulating concentrations of 25-hydroxyvitamin D, impairing calcium absorption and secondary bone mineralisation processes [2][5].

Clinical studies show that low serum 25‑hydroxyvitamin D is common in patients with epilepsy, particularly those receiving EIAEDs [4].

 

Consequences of Vitamin D Deficiency

Vitamin D deficiency is associated with a range of skeletal complications [2], including:

  • Reduced bone mineral density
  • Osteomalacia
  • Osteoporosis
  • Increased fracture risk
  • Rickets (in paediatric populations)

A large cohort study using general practice databases demonstrated that patients with active epilepsy receiving liver enzyme-inducing AEDs had a significantly higher risk of fractures compared to patients receiving non-liver enzyme-inducing AEDs [3]. A recent meta‑analysis of cross‑sectional, retrospective and prospective studies has reinforced the association between AED exposure with lower bone mineral density and higher fracture risk, with the findings most consistent for enzyme‑inducing AEDs [6].

 

Risk Factors for Vitamin D Deficiency in Patients Receiving EIAEDs

Several factors may further increase susceptibility to vitamin D deficiency in patients treated with EIAEDs [4][7]:

  • Longer duration of antiepileptic treatment
  • Concomitant use of multiple AEDs
  • Inadequate sun exposure particularly during fall and winter months
  • Insufficient dietary and vitamin D supplementation
  • Obesity
  • Female sex
  • Darker skin pigmentation

Vitamin D deficiency in patients receiving EIAEDs results from multiple risk factors, which likely contribute to the increased prevalence of deficiency in this population [4][7].

vitamin d deficiency risk with enzyme inducing aeds 2

Evidence-based approaches to reducing vitamin D deficiency in patients receiving EIAEDs include:

  • Regular monitoring of serum 25-hydroxyvitamin D levels, particularly in long-term therapy [2][4]
  • Periodic assessment of bone mineral density, especially in high-risk populations [3]
  • Vitamin D supplementation, with studies supporting routine supplementation in patients receiving enzyme-inducing AEDs [2][5]

Clinical judgement is required to individualise supplementation strategies based on patient age, comorbidities, and baseline vitamin D status.

How Does MIMS Clinical Decision Solutions Help?

The Drug Interaction Alert module within MIMS CDS helps to alert prescribers to potential reductions in the effectiveness of vitamin D supplementation during concurrent use of enzyme-inducing antiepileptic drugs, including recommendations for monitoring and management.

The Generic Monograph module also provides AED-specific information on vitamin D deficiency risks where applicable, to support clinician awareness and decision‑making.

When used together, these modules support safer prescribing practices in patients who require chronic EIAED treatment and bring awareness to bone health complications.

Conclusion

Enzyme-inducing antiepileptic drugs play a critical role in seizure control but are associated with clinically meaningful reductions in vitamin D levels. Evidence demonstrates that long-term exposure to these agents increases the risk of vitamin D deficiency, reduces bone mineral density, and increases fracture risk, particularly in patients with additional risk factors.

Through awareness of these risks and the use of structured monitoring and supplementation strategies, prescribers can minimise preventable harm. MIMS Clinical Decision Solutions supports this process by providing timely, evidence-based insights at the point of care, enabling safer and more consistent prescribing for patients requiring chronic antiepileptic therapy.

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References

  1. Fisher RS, Acevedo C, Arzimanoglou A et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia. 2014 Apr;55(4):475-82. See more
  2. Ramasamy I. Vitamin D Metabolism and Guidelines for Vitamin D Supplementation. Clin Biochem Rev. 2020 Dec;41(3):103–126. See more
  3. Nicholas JM, Ridsdale L, Richardson MP et al. Fracture risk with use of liver enzyme inducing antiepileptic drugs in people with active epilepsy: cohort study using the general practice research database. Seizure. 2013 Jan;22(1):37–42. See more
  4. Teagarden DL, Meador KJ, Loring DW. Low vitamin D levels are common in patients with epilepsy. Epilepsy Res. 2014 Oct;108(8):1352-6. See more
  5. Offermann G, Pinto V, Kruse R. Antiepileptic drugs and vitamin D supplementation. Epilepsia. 1979 Feb;20(1):3–15. See more
  6. Buoso C, Pezzaioli LC, Gatta E et al. ANTIEPILEPTIC DRUGS AND BONE HEALTH: A COMPREHENSIVE REVIEW AND META-ANALYSIS. Acta Endocrinol (Buchar). 2024 Jul-Sep;20(3):356–372. See more
  7. Liu Y, Gong C, Li J et al. Vitamin D content and prevalence of vitamin D deficiency in patients with epilepsy: a systematic review and meta-analysis. Front Nutr. 2024 Aug 30;11:1439279. See more