Abstract Template

Low functional level of a hepatic cytochrome P450 (CYP3A4) is a potential major risk factor for corticosteroid-induced Osteonecrosis of the Femoral Head (ONFH)

Yasunori Kaneshiro M.D.* Yutaka Oda M.D. # Kentaro Iwakiri M.D.* Toshiaki Masada M.D.* Hiroyoshi Iwaki M.D.* Yoshio Hirota M.D.† , and Kunio Takaoka M.D.*

Department of Orthopaedic Surgery*, Department of Anestheiology and Intensive care medicine#, and Department of Public health†
Graduate School of Medicine, Osaka City University, Osaka, Japan

Introduction The osteonecrosis of the femoral head (ONFH) has close association with corticosteroid therapy. As corticosteroid is accepted to be metabolized mainly by CYP3A4 in the liver, low constitutive level of the enzyme might lead to excessive response to the corticosteroid and brought about adverse events including bone necrosis. This clinical study was designed to elucidate the hypothesis and to present potential modality to avoid corticosteroid-induced ONFH by tailoring the steroid dose according to individual metabolic capacity of corticosteroid.

Patients and methods 22 steroid-induced 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, midazolam clearance test was carried out in respective subject, and the results from the test were compared between those groups.

Results The distribution profile of the MDZ clearance in steroid-induced ONFH patients were shifted to left, indicating lower hepatic CYP3A4 activity in those patients when compared with general population. By using unconditional logistic regression model, patients with low (<9.7) MDZ clearance due to low hepatic CYP3A4 activity indicated 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). Meanwhile, the hepatic CYP3A4 activity was not associated with prevalence of alcohol-associated ONFH.

Conclusion The significantly low constitutive hepatic CYP3A4 function in corticosteroid-induced ONFH patients was presented. The corticosteroid-induced ONFH might be caused from excessive responsiveness to corticosteroid in those patients due to prolonged exposure of bone to high level of corticosteroid because of low functional level of the steroid metabolizing enzyme. The steroid-induced ONFH might be avoided by tailoring the corticosteroid dose in accordance with the functional level of hepatic CYP3A4.