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.

In six unloaded cadaver knees we used MRI to determine the shapes of the articular surfaces and their relative movements. These were confirmed by dissection.

Medially, the femoral condyle in sagittal section is composed of the arcs of two circles and that of the tibia of two angled flats. The anterior facets articulate in extension. At about 20° the femur ‘rocks’ to articulate through the posterior facets. The medial femoral condyle does not move anteroposteriorly with flexion to 110°.

Laterally, the femoral condyle is composed entirely, or almost entirely, of a single circular facet similar in radius and arc to the posterior medial facet. The tibia is roughly flat. The femur tends to roll backwards with flexion.

The combination during flexion of no antero-posterior movement medially (i.e., sliding) and backward rolling (combined with sliding) laterally equates to internal rotation of the tibia around a medial axis with flexion. About 5° of this rotation may be obligatory from 0° to 10° flexion; thereafter little rotation occurs to at least 45°. Total rotation at 110° is about 20°, most if not all of which can be suppressed by applying external rotation to the tibia at 90°.

In 13 unloaded living knees we confirmed the findings previously obtained in the unloaded cadaver knee during flexion and external rotation/internal rotation using MRI. In seven loaded living knees with the subjects squatting, the relative tibiofemoral movements were similar to those in the unloaded knee except that the medial femoral condyle tended to move about 4 mm forwards with flexion. Four of the seven loaded knees were studied during flexion in external and internal rotation. As predicted, flexion (squatting) with the tibia in external rotation suppressed the internal rotation of the tibia which had been observed during unloaded flexion.