title: Adverse effects of valproate on bone: defining a model to investigate the pathophysiology.
abstract: OBJECTIVE
  Bone disease and fractures are common with chronic antiepileptic drug (AED) therapy, but the underlying mechanisms are poorly understood. This study aimed to characterize adverse bone effects of valproate and to identify mouse strains either resistant or sensitive to these effects.
  
  
  METHODS
  Seven mouse strains (n = 40/strain; 10/diet) were screened for the effect of chronic (8 weeks) valproate treatment (0, 2, 4, and 6 g/kg food) on total bone mineral content (BMC, by dual energy x-ray absorptiometry). In a confirmatory study the effect of valproate (0 or 4 g/kg food) over 16 weeks was assessed in five of the mouse strains (n = 60/strain; 30/diet) identified in the screening phase as either sensitive or resistant. Ex vivo volumetric bone measures and structural changes were assessed using peripheral quantitative computed tomography (pQCT) and histomorphometry.
  
  
  RESULTS
  Chronic valproate treatment reproducibly affected bone in C3H/HeJ mice, with a 9.1% (p < 0.01) reduction in total BMC and a 10.7% (p < 0.01) reduction in trabecular volumetric density, indicating a sensitive strain to AED-induced bone loss. Histomorphometry was consistent, revealing reductions in trabecular volume (19.6%, p < 0.05) and number (14.3%, p < 0.04), and a 19.9% (p < 0.05) increase in trabecular separation. In contrast the A/J mice were reproducibly resistant to the bone effects.
  
  
  CONCLUSIONS
  Mouse strains sensitive and resistant to the adverse bone effects of chronic valproate treatment were identified. The strain-specific effects suggest a role of genetic factors in the pathogenesis of AED-induced bone disease. This novel model provides a new, powerful tool to investigate the pathophysiology and therapy of AED-associated bone disease.
authors.affiliation: Department of Medicine, Bone Mineral Service and Neurology, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Senn
authors.forename: Susan
authors.initials: S
authors.lastname: Kantor
authors.forename: Ingrid J
authors.initials: IJ
authors.lastname: Poulton
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Morris
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Sims
authors.forename: Terence J
authors.initials: TJ
authors.lastname: O'Brien
authors.forename: John D
authors.initials: JD
authors.lastname: Wark
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects* / Q000502:physiology; D001847:Bone Diseases / Q000139:chemically induced* / Q000235:genetics / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D051379:Mice; D008806:Mice, Inbred AKR; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D013045:Species Specificity; D013977:Tibia / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D014635:Valproic Acid / Q000009:adverse effects*
chemical_list: D014635:Valproic Acid