Decreased bone mass and increased bone turnover with valproate therapy in adults with epilepsy

Neurology. 2001 Aug 14;57(3):445-9. doi: 10.1212/wnl.57.3.445.


Background: Bone loss and hypovitaminosis D are reported in patients taking antiepileptic drugs, but little is known about changes in bone and calcium metabolism from valproic acid (VPA).

Objective: To assess the relationship of VPA to bone mass and calcium metabolism in 40 adults with epilepsy on long-term VPA monotherapy, 40 age- and sex-matched epileptic patients taking phenytoin (PHT), and 40 healthy control subjects. Bone mineral density (BMD) of the second metacarpal was determined as T- and Z-scores.

Results: BMD reduction from control values was 14% (12% in men, 16% in women) with VPA and 13% (12% in men, 15% in women) with PHT. Among patients on VPA, nine (23%) had T-scores below -2.5 SD, suggesting osteoporosis; 15 (37%) had T-scores between -1 and -2.5 SD, suggesting osteopenia. Serum concentrations of calcium were significantly higher with VPA than in PHT or control groups. Serum concentrations of bone Gla protein (a bone formation marker) and pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen (ICTP; a bone resorption marker) associated with either drug significantly exceeded control values. Z-scores for BMD in the VPA group correlated negatively with calcium and ICTP. High ICTP correlated positively with ionized calcium, implying that increased bone resorption caused the latter.

Conclusion: Long-term VPA monotherapy can increase bone resorption, leading to decreased BMD.

Publication types

  • Retracted Publication

MeSH terms

  • Adult
  • Anticonvulsants / therapeutic use*
  • Bone Density / drug effects*
  • Bone Density / physiology*
  • Bone and Bones / drug effects*
  • Bone and Bones / physiopathology*
  • Epilepsy / drug therapy*
  • Epilepsy / physiopathology*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Valproic Acid / therapeutic use*


  • Anticonvulsants
  • Valproic Acid