title: Exposure to CYP3A4-inducing and CYP3A4-non-inducing antiepileptic agents and the risk of fractures.
abstract: OBJECTIVE
  To evaluate whether exposure to Cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)-inducing antiepileptics increases fracture risk compared to CYP3A4-non-inducing antiepileptics.
  
  
  METHODS
  We performed a retrospective cohort study of initiators of antiepileptic agents using a UK medical record database (The Health Improvement Network) from 1995 to 2007. We considered an antiepileptic user an initiator if he or she had not received a prescription for an antiepileptic agent within the first year after entry in the database. Proportional hazards regression was used to calculate hazard ratios for fracture during long-term (≥ 6 months) exposure to CYP3A4 inducing versus CYP3A4 non-inducing antiepileptics.
  
  
  RESULTS
  We identified 4077 initiators of CYP3A4-inducing antiepileptics and 6433 initiators of CYP3A4-non-inducing antiepileptics with at least 6 months of antiepileptic exposure. During 6006 person-years exposed to CYP3A4-inducing antiepileptics, 118 fractures were identified for an incidence rate of 1.96 (95% confidence interval (CI): 1.63-2.35) fractures per 100 person-years. During 7184 person-years exposed to CYP3A4-non-inducing antiepileptics, 127 fractures were identified, for an incidence rate of 1.77 (95% CI: 1.47-2.10) fractures per 100 person-years. The adjusted hazard ratio for CYP3A4-inducing antiepileptic versus CYP3A4-non-inducing antiepileptic was 1.21 (95% CI: 0.93-1.56). No duration-response relationship was evident.
  
  
  CONCLUSIONS
  Our results do not support the hypothesis that CYP3A4 induction by antiepileptic agents increases the fracture risk. Further research will be needed to evaluate whether mechanisms other than CYP3A4 induction might explain some of the elevated risk of fractures associated with long-term use of antiepileptic agents.
authors.affiliation: Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104‐6021, USA.
authors.forename: Hedi
authors.initials: H
authors.lastname: Schelleman
authors.forename: John R
authors.initials: JR
authors.lastname: Pollard
authors.forename: Craig
authors.initials: C
authors.lastname: Newcomb
authors.forename: Clyde E
authors.initials: CE
authors.lastname: Markowitz
authors.forename: Warren B
authors.initials: WB
authors.lastname: Bilker
authors.forename: Mary B
authors.initials: MB
authors.lastname: Leonard
authors.forename: Sean
authors.initials: S
authors.lastname: Hennessy
mesh_terms: D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis*; D016208:Databases, Factual; D057286:Electronic Health Records / Q000706:statistics & numerical data; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D050723:Fractures, Bone / Q000453:epidemiology / Q000209:etiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012306:Risk; D013997:Time Factors; D006113:United Kingdom
chemical_list: D000927:Anticonvulsants; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human