Raloxifene and estrogen reduces progression of advanced atherosclerosis — a study in ovariectomized, cholesterol-fed rabbits

The present study investigated the effect of raloxifene, a selective estrogen receptor modulator (SERM), on aortic atherosclerosis in 80 ovariectomized, cholesterol-fed rabbits with pre-induced atherosclerosis. The animals were fed an atherogenic diet containing 240 mg cholesterol/day for 15 weeks, after this period a baseline control group was sacrificed. Thereafter, oral treatment was initiated with either estradiol 4 mg/day (n=20), raloxifene (210 mg/day) or placebo (n=20). In the treatment period of 39 weeks, the dietary cholesterol content was reduced to 80 mg cholesterol/day. Postmortem evaluation showed a significantly increased uterine weight induced by estradiol treatment (10.3±1.2 g), whereas raloxifene intervention caused a decreased uterus weight (1.21±0.1 g) when compared to placebo (2.48±0.47 g). Throughout the study, serum lipids increased in all groups to levels seen in very high risk humans. After 58 weeks the cholesterol content in the aorta was 3.18±0.54 μmol/cm2 (38% reduction) in the estradiol group, 3.66±0.52 μmol/cm2 (29% reduction) in the raloxifene group and 5.12±0.60 μmol/cm2 in the placebo group. Analyses of the aortic cholesterol content corrected for time-averaged serum cholesterol revealed that both estradiol and raloxifene therapy significantly reduced the progression of atherosclerosis (P<0.01 for both) as compared to placebo.