Antiepileptic Drugs and Bones

Virtual Special Editions are collections of targeted papers curated by a Guest Editor. Here Drs Dimitris Pitetzis & Maria P. Yavropoulou from Aristotle University of Thessaloniki talk about ‘Antiepileptic drugs and bones’.

Antiepileptic drugs have long been associated with bone loss and increased fracture risk, but the underlying pathophysiological mechanisms remain largely unknown and may differ among the different classes of anti-epileptic drugs.

In our recent review article published in Seizure [1], we focused on the molecular mechanisms through which a widely used anti-epileptic drug valproic acid (VPA) affects bone cells. Preclinical and clinical studies have demonstrated controversial results regarding the effect of VPA on bone metabolism. At the cellular level VPA exerts directly effects on bone cells through a decrease in the proliferation of the bone-forming cells, osteoblasts, changes in collagen synthesis and an induction of vitamin D catabolism. Indirectly VPA negatively affects bone metabolism through its action on other endocrine glands.

In an previous review by Svalheim et al [2], in the same journal the authors comment on data that show how liver enzyme inducing antiepileptics drugs such as valproic acid interfere with the reproductive endocrine system and thyroid function in both sexes causing hypogonadism and hypothyroidism and thus indirectly increasing skeletal fragility.

In addition two clinical studies by Nicholas et al [3] and Bindu Menon et al [4] have investigated the effect of anti-epileptic drugs on fracture risk and calcium metabolism. In the cohort study by Nicholas et al [3], anti-epileptic drugs have been reported to increase significantly the fracture risk at all sites only in females while hip fracture risk is increased at both males and females. In addition in the longitudinal study by Menon et al [4] most of the patients under treatment with anti-epileptic drugs had either vitamin D deficiency or insufficiency irrespective of the type of the drug.

Data in vitro and in vivo, however, are scarce. Nissen-Meyer et al [5] provided evidence from in vivo studies that valproic acid and phenytoin reduce bone mass and strength, while valproic acid also increases bone turnover, and low-dose levetiracetam reduces bone strength and formation without affecting bone mass. Less is known about the effect of newer anti-epileptic drugs on bone metabolism.

Greater understanding of the mechanisms involved in the negative effect of antiepileptic drugs in bone is warranted in order to treat properly patients with epilepsy and seizures that are per se at increased risk of fractures due to the increased risk of falls. Our goal should not only be the elimination of seizures, but also to ensure the quality of life. Calcium and vitamin D supplementation should be considered during any kind of antiepileptic treatment especially in postmenopausal women and older men.

  1. Pitetzis, D.A., Spilioti, M.G., Yovos, J.G., Yavropoulou, M.P., The effect of VPA on bone: From clinical studies to cell cultures-The molecular mechanisms revisited. Seizure, 2017. 48: p. 36-43.
  2. Svalheim, S., Sveberg, L., Mochol, M., Tauboll, E., Interactions between antiepileptic drugs and hormones. Seizure, 2015. 28: p. 12-7.
  3. Nicholas, J.M., Ridsdale, L., Richardson, M.P., Grieve, A.P., Gulliford, M.C., 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. 22(1): p. 37-42.
  4. Menon, B., Harinarayan, C.V., The effect of anti epileptic drug therapy on serum 25-hydroxyvitamin D and parameters of calcium and bone metabolism--a longitudinal study. Seizure, 2010. 19(3): p. 153-8.
  5. Nissen-Meyer, L.S., Svalheim, S., Tauboll, E., Gjerstad, L., Reinholt, F.P., Jemtland, R., How can antiepileptic drugs affect bone mass, structure and metabolism? Lessons from animal studies. Seizure, 2008. 17(2): p. 187-91.