LOW FUNCTIONAL LEVEL OF A HEPATIC CYTOCHROME P450 (CYP3A4) IS A POTENTIAL MAJOR RISK FACTOR FOR CORTICOSTEROID-INDUCED OSTEONECROSIS OF THE FEMORAL HEAD (ONFH)

Abstract

Introduction: Osteonecrosis of the femoral head (ONFH) has a close association with corticosteroid therapy. As corticosteroids are accepted to be metabolized mainly by CYP3A4 in the liver, low constitutive levels of the enzyme might lead to an excessive response to corticosteroids and lead to adverse events including bone necrosis. This clinical study was designed to elucidate this hypothesis and to present potential modalities to avoid corticosteroid-associated ONFH by tailoring the steroid dose according to individual metabolic capacities of corticosteroid.

Materials and Methods: Twenty-two steroid-associated ONFH patients, 27 alcohol-related ONFH patients, and 65 general population controls were enrolled in this study. To estimate functional level of hepatic CYP3A4 level, a midazolam (MDZ) clearance test was carried out in respective subjects. The results from the tests were compared between those groups.

Results: The distribution profile of the MDZ clearance in steroid-associated ONFH patients were shifted to the left, indicating lower hepatic CYP3A4 activity in those patients when compared with the general population. By using an unconditional logistic regression model, patients with low (< 9.7) MDZ clearance due to low hepatic CYP3A4 activity were at 9.5 times greater risk for corticosteroid-induced ONFH compared with those with high (9.7+) MDZ clearance (OR 9.5 [95% CI 2.79–32.2], p< 0.001). The hepatic CYP3A4 activity was not associated with prevalence of alcohol-associated ONFH.

Discussion: A significantly low constitutive hepatic CYP3A4 function in corticosteroid-associated ONFH patients was found. The corticosteroid-associated ONFH might result from excessive responsiveness to corticosteroids in those patients due to prolonged exposure of bone to high levels of corticosteroids because of low functional level of the steroid metabolizing enzymes. The steroid-associated ONFH might be avoided by tailoring the corticosteroid dose in accordance with the functional level of hepatic CYP3A4.