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 center dot kg(-1) center dot min(-1) versus 11.4 +/- 3.5 mL center dot kg(-1) center dot min(-1) and 10.5 +/- 2.8 mL center dot kg(-1) center dot min(-1), respectively; P < .001). Patients with low midazolam clearance (< 9.5 mL center dot kg(-1) center dot 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.