Pravastatin reduces steroid-induced osteonecrosis of the femoral head in SHRSP rats

Background and purpose

Although the definite cause of steroid-induced osteonecrosis of the femoral head (ONFH) is unknown, peripheral circulatory failure, lipid metabolism disturbance, and increased oxidative stress are considered to be possible causes. We investigated whether pravastatin as a statin treatment reduces (1) the incidence of ONFH, (2) the adipocyte area, and (3) bone marrow changes in the femoral head.

Methods

We divided up 81 thirteen-week-old spontaneously hypertensive stroke-prone (SHRSP)/Izm male rats into 4 groups: a control group (group C), a group given pravastatin (group P), a group given steroid (group S), and a group given both pravastatin and steroid (Group PS). The steroid was administered at 15 weeks of age. Pravastatin, as a statin, was administered in the drinking water for 4 weeks. The rats were killed when 17 weeks old. Osteonecrosis was diagnosed based on histopathological examination. Oxidative stress was assessed from immunostaining.

Results

The incidence of histological osteonecrosis was lower in the groups given pravastatin. The percentage of adipocyte area in the bone marrow was lower in the PS group than in the S group. Immunohistochemical staining for oxidative stress showed that staining was less in the PS group than in the S group. Pravastatin had no effect on the blood-derived biochemical findings on lipid metabolism. However, it reduced the incidence of steroid-induced ONFH in these SHRSP rats. We presume that this occurred by reducing oxidative stress and by reducing the percentage of adipocyte area in the femoral heads.

Interpretation

Our data suggest that pravastatin may be effective in reducing steroid-induced ONFH.Every year, 3,000 of the 128 million inhabitants in Japan develop osteonecrosis of the femoral head (ONFH), and the number of patients—particularly those treated with steroid therapy—has been increasing over the years (Hirota et al. 1997). The proposed pathogenesis of steroid-induced ONFH includes increased oxidative stress, lipid metabolism disturbance, and disturbances of the coagulation-fibrinolysis system due to steroid hormones (Fisher 1978, Cheras 1997, Ichiseki et al. 2004, 2006). Statins are lipid-lowering, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (Endo 1992). Some statins have been reported to enhance the antioxidant activity and local lipid kinetics by directly acting on adipocytes and blood vessels, thus reducing the severity and frequency of ONFH (Cui et al. 1997, Pritchett 2001, Ichiseki et al. 2004, 2006, Nishida et al. 2008, Yagi et al. 2008 , Kuribayashi et al. 2010).ONFH observed in spontaneously hypertensive stroke-prone (SHRSP) rats closely resembles human ONFH, not only histologically but also physiologically (Hirano et al. 1989, Wada et al. 2004, Murata et al. 2007, Suzuki et al. 2008). We have reported a 50% incidence of spontaneous osteonecrosis of the femoral head in SHRSP rats at the age of 16–18 weeks, and they develop ONFH more frequently (up to 90%) with steroid administration (Murata et al. 2007, Suzuki et al. 2008). Unlike rabbits, chickens, and other rats, SHRSP rats are an inbred, established model of ONFH.In this work, we studied the ability of pravastatin to reduce the incidence of steroid -induced osteonecrosis in SHRSP rats. We also examined whether pravastatin could reduce the number of sites of osteonecrosis development in individual rats that developed osteonecrosis. Finally, we determined whether pravastatin has any effects on disorders of lipid metabolism and lipid peroxidation after corticosteroid administration.