title: Low hepatic cytochrome P450 3A activity is a risk for corticosteroid-induced osteonecrosis.
abstract: BACKGROUND
  Osteonecrosis of the femoral head (ONFH) is one of the major side effects of corticosteroid therapy. Because corticosteroids are metabolized by hepatic cytochrome P450 (CYP) 3A, a low endogenous activity of this enzyme may contribute to the pathogenesis of ONFH. The purpose of this study was to examine the possible association of hepatic CYP3A activity and the susceptibility to ONFH in patients treated with corticosteroids.
  
  
  METHODS
  In this prospective controlled study we measured the clearance of intravenous midazolam (0.25 mg/kg) to estimate hepatic CYP3A activity in patients with steroid-induced ONFH (n = 26), patients with alcohol-related ONFH (n = 29), and non-ONFH control patients (n = 75) undergoing orthopedic surgery. Midazolam clearance was compared between the groups, and the relationship between the level of hepatic CYP3A activity and the prevalence of ONFH was evaluated by multivariate analysis.
  
  
  RESULTS
  Midazolam clearance in patients with steroid-induced ONFH was significantly lower than that in control patients and patients with alcohol-related ONFH (7.7 +/- 1.8 mL x kg(-1) x min(-1) versus 11.4 +/- 3.5 mL x kg(-1) x min(-1) and 10.5 +/- 2.8 mL x kg(-1) x min(-1), respectively; P < .001). Patients with low midazolam clearance (<9.5 mL x kg(-1) x min(-1)) had a 9-fold greater risk for steroid-induced ONFH (adjusted odds ratio, 9.08 [95% confidence interval, 2.79-29.6]; P < .001). Midazolam clearance did not show a significant correlation with the prevalence of alcohol-related ONFH.
  
  
  CONCLUSIONS
  Low hepatic CYP3A activity may significantly contribute to the risk for steroid-induced ONFH.
authors.affiliation: Department of Orthopedic Surgery, Graduate School of Medicine, Osaka City University, Osaka, Japan. kaneshiro@tk2.so-net.ne.jp
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Kaneshiro
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Oda
authors.forename: Kentaro
authors.initials: K
authors.lastname: Iwakiri
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Masada
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Iwaki
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hirota
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kondo
authors.forename: Kunio
authors.initials: K
authors.lastname: Takaoka
mesh_terms: D000305:Adrenal Cortex Hormones / Q000008:administration & dosage / Q000009:adverse effects*; D000328:Adult; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D005260:Female; D005270:Femur Head / Q000473:pathology*; D006801:Humans; D008099:Liver / Q000201:enzymology*; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics; D008875:Middle Aged; D015999:Multivariate Analysis; D019637:Orthopedic Procedures; D010020:Osteonecrosis / Q000139:chemically induced* / Q000201:enzymology*; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D000305:Adrenal Cortex Hormones; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam