Low hepatic cytochrome P450 3A activity is a risk for corticosteroid-induced osteonecrosis.
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.
Kaneshiro
Yasunori
Y
Department of Orthopedic Surgery, Graduate School of Medicine, Osaka City University, Osaka, Japan. kaneshiro@tk2.so-net.ne.jp
Oda
Yutaka
Y
Iwakiri
Kentaro
K
Masada
Toshiaki
T
Iwaki
Hiroyoshi
H
Hirota
Yoshio
Y
Kondo
Kyoko
K
Takaoka
Kunio
K
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
D000305:Adrenal Cortex Hormones; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam