title: Levetiracetam, phenytoin, and valproate act differently on rat bone mass, structure, and metabolism.
abstract: OBJECTIVE
  Long-term treatment with antiepileptic drugs (AEDs) is associated with increased risk of fractures. Phenytoin (PHT) and valproate (VPA) have both been suggested to influence bone health, whereas levetiracetam (LEV) is scarcely studied. The present study compares the effect of these AEDs on bone mass, biomechanical strength, and bone turnover in rats.
  
  
  METHODS
  Female rats received PHT (50 mg/kg), VPA (300 mg/kg), or LEV (50 and 150 mg/kg) for 90 days. Dissected femurs were analyzed using dual energy x-ray absorptiometry (DXA), three-point cantilever bending, and histomorphological evaluation. Serum levels of biochemical bone turnover markers were monitored using immunoassay quantification.
  
  
  RESULTS
  PHT and VPA reduced bone mineral density (BMD) and content (BMC) in one or more bone compartments, whereas LEV did not. VPA induced increased bone turnover, whereas modest changes were observed for PHT. Interestingly, low-dose LEV was associated with reduced biomechanical strength of the femoral neck (mainly trabecular bone). In addition, low-dose LEV treatment resulted in significantly reduced levels of serum osteocalcin, a marker of bone formation. Histomorphological analyses indicated increased retention of cartilage remnants at the growth plate metaphysis of rats treated with low-dose LEV vs. controls.
  
  
  CONCLUSIONS
  PHT, VPA, and LEV exert differential effects on bone mass and strength, suggesting different mechanisms of action. The weakening effect of low-dose LEV on the femoral neck, despite a constant BMD, suggests a primary effect on bone quality. These findings warrant further human studies of possible adverse effects of LEV on bone development and growth, particularly in children and adolescents.
authors.affiliation: Department of Biochemistry, Institute of Basic Medical Sciences, University of Oslo, Norway.
authors.forename: Lise Sofie H
authors.initials: LS
authors.lastname: Nissen-Meyer
authors.forename: Sigrid
authors.initials: S
authors.lastname: Svalheim
authors.forename: Erik
authors.initials: E
authors.lastname: Taubøll
authors.forename: Sjur
authors.initials: S
authors.lastname: Reppe
authors.forename: Tove
authors.initials: T
authors.lastname: Lekva
authors.forename: Lene B
authors.initials: LB
authors.lastname: Solberg
authors.forename: Gunhild
authors.initials: G
authors.lastname: Melhus
authors.forename: Finn P
authors.initials: FP
authors.lastname: Reinholt
authors.forename: Leif
authors.initials: L
authors.lastname: Gjerstad
authors.forename: Rune
authors.initials: R
authors.lastname: Jemtland
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D001696:Biomechanical Phenomena; D015519:Bone Density / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism; D019245:Compressive Strength / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005272:Femur Neck / Q000187:drug effects; D000077287:Levetiracetam; D023421:Models, Animal; D010012:Osteogenesis / Q000187:drug effects; D010672:Phenytoin / Q000494:pharmacology; D010889:Piracetam / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D000927:Anticonvulsants; D015415:Biomarkers; D000077287:Levetiracetam; D014635:Valproic Acid; D010672:Phenytoin; D010889:Piracetam