Introduction

Osteonecrosis of the femoral head (ONFH) is one of the most serious complications associated with corticosteroid therapy. In patients with ONFH, collapse of the femoral head often occurs and causes severe hip pain and impaired hip joint function. Despite the widely spread use of corticosteroids for treating various diseases and a known association between prevalence of ONFH and daily dose of corticosteroids, the pathomechanism for the development of ONFH has not been identified. Since hepatic cytochrome P4503A (CYP3A) is a predominant enzyme responsible for metabolizing corticosteroids and its activities varies more than 10-fold, low hepatic CYP3A activity leads to a remarkable increase of corticosteroid levels and its effect. We have previously reported that hepatic CYP3A levels are significantly lower in patients with corticosteroid-induced ONFH than that in control patients and patients with alcohol-related ONFH and that hepatic CYP3A activity inversely correlated with the incidence of osteonecrosis and extent of the necrotic area caused by the same dose of corticosteroids in a rabbit model, suggesting possible prevention of the corticosteroid-induced osteonecrosis by adjusting corticosteroid dose based on the level of individual hepatic CYP3A activity prior to corticosteroid therapy. To examine hepatic CYP3A activity, measuring clearance of administrated midazolam (MDZ) is a reliable method, as shown by the significant correlations between the clearance of midazolam and hepatic CYP3A levels measured by biopsy and the clearance of other CYP3A-specific substrates. However, the method is invasive and time consuming for measuring clearance of administrated MDZ, needing multiple blood samplings over half a day for each subject. The aim of this study was to develop the simple, safe and noninvasive methods for measuring the level of hepatic CYP3A activity, which is applicable to prevent the occurrence of corticosteroid-induced osteonecrosis prior to corticosteroid therapy.

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.

Introduction: Based on epidemiological results, steroid (glucocorticoid) hormone is accepted as a major causative agent of osteonecrosis, though its pathomechanism is not elucidated. However, not all patients who receive high doses of steroid develop osteonecrosis. This fact suggests risk factor(s) for steroid-induced osteonecrosis. In order to identify such risk factors, the association of CYP3A6 (a major enzyme metabolizing glucocorticoid in rabbit) level with the incidence and extent of osteonecrosis in a rabbit model was determined.

Materials and Methods: In this rabbit model, the CYP3A6 level was modulated by an inhibitory (Itraconazole, 150mg p.o. twice a day for 3 weeks) or inducing agent (rifampicin, 100mg/kg i.p. in first 3 days). Three weeks after modulation of CYP3A6, steroid-induced osteonecrosis was generated by i.m. injection of methyl-prednisolone (20mg/kg BW). Three weeks later, the animals were sacrificed and bilateral femurs were excised and examined histologically for bone and marrow necrosis.

Results: In control animals without modulation of CYP3A6, focal and/or extensive necrosis was noted in 5 of 7 animals. In Itraconazole-treated animals, all of 5 animals revealed extensive necrosis in femoral bone marrow. In rifampicin- treated animals, incidence of necrosis was similar to that of controls but necrotic foci were significantly smaller than those in controls.

Discussion: These experimental results indicated that low level of steroid-metabolizing enzyme CYP3A6 (CYP3A4 in humans) at the time of steroid treatment might be a risk factor for extension of steroid-induced bone necrosis, and that induction of CYP3A6 might prevent steroid-induced bone necrosis.