Increased hepatic cytochrome P4503A activity decreases the risk of developing steroid‐induced osteonecrosis in a rabbit model

Abstract

Low hepatic cytochrome P4503A (CYP3A) activities might play an important role for inducing osteonecrosis of the femoral head (ONFH) by corticosteroids. However, the relationship between hepatic CYP3A activity and steroid-induced ONFH is unknown. We have examined the relationship between hepatic CYP3A activity and the inducibility of ONFH in a rabbit model. Sixty rabbits were divided into three groups. Hepatic CYP3A inducer (phenobarbital, group P; n ¼ 15), inhibitor (itraconazole, group I; n ¼ 15), or saline (group C, n ¼ 30) was administrated for 3 weeks before intramuscular methylprednisolone. In groups P and I, hepatic CYP3A levels were measured by midazolam clearance before treatment (baseline) and before methylprednisolone injection. All animals were sacrificed 3 weeks after methylprednisolone injection and both femurs were harvested and examined histologically for osteonecrosis. Midazolam clearance was significantly increased and decreased, compared with baseline in groups P and I respectively (p < 0.0005, p < 0.002). The incidence of osteonecrosis in group P (33%) was significantly lower than in group I (100%) and group C (83%; p < 0.001 for both). The percentage necrotic area to whole bone marrow area on cross sections in group P (8.2 AE 5.9%) was significantly lower than in group I (69.8 AE 20.8%) and group C (51.5 AE 30.7%; p < 0.005 for both). Hepatic CYP3A activity inversely correlated with the incidence of osteonecrosis and extent of the necrotic area caused by the same dose of corticosteroids, suggesting possible prevention of the steroid-induced osteonecrosis by reducing steroid dose in poor corticosteroid metabolizers. ß

Dose Effects of Corticosteroids on the Development of Osteonecrosis in Rabbits

“…Recently, the activity of hepatic cytochrome P450 3A4, which metabolizes corticosteroids, has been suggested to be associated with the development of ON 18 . Masada, et al revealed the inverse relationship between hepatic cytochrome P450 3A activity and the prevalence of ON in rabbits 18 , suggesting the possibility that development of ON may be avoided by reducing corticosteroid doses in patients with low hepatic cytochrome P450 3A activity. This finding gives us hope for development of precisely calculated corticosteroid treatments.…”

Enoxaparin Prevents Steroid-Related Avascular Necrosis of the Femoral Head

“…Glucocorticoids lead to vasoconstriction. Drescher and colleagues [9, 13] were previously able to demonstrate increased vasoconstriction and coagulability following high-dose glucocorticoid application in a swine model—possibly leading to reduced blood supply and enhanced capillary occlusion causing ischemia. Glucocorticoids are known to suppress the production of vasodilators such as prostacyclin and nitric oxide [14].…”

Preventive effects of siRNA targeting PPARγ gene on steroid-induced osteonecrosis in rabbits

“…Excessive use of exogenous steroids can cause many side effects on the skeleton through either direct or indirect effects (19,20). Although a number of studies have tried to protect the femoral head against ON, the mechanisms of ONFH remain unknown and presently there are no effective treatments for the condition (21,22). Several possible hypotheses of ON have been proposed in the literature, including an increase in the size and number of fatty cells, increased intraosseous pressure, fatty degeneration of osteocytes, fatty embolisms, and extraosseous arterial occlusions due to abnormal changes in histologic features, hemodynamics, metabolism, and biochemical features within the femoral head (3,4,(23)(24)(25)(26)(27)(28).…”