Figure 2 shows the mean changes in BMD and the corresponding reduction in vertebral fractures for the therapeutic agents currently approved for the prevention and treatment of osteoporosis. Despite significant differences in BMD increases, the reductions in vertebral fracture rates are quite comparable. In the MORE trial, there was no difference in the incidence of nontraumatic fractures at sites other than the spine, possibly because of the small number of nonvertebral fractures that occurred during the study period, which yielded insufficient power to detect a difference. A subset of patients in the MORE study is being followed for a longer time to further evaluate the incidence of nonvertebral fractures.
Effects on cardiovascular health. Raloxifene’s effects on total and low-density lipoprotein (LDL) cholesterol are similar to those of estrogen, with decreases of 11% and 6%, respectively. Unlike estrogen, which increases the circulating levels of both high-density lipoprotein (HDL) cholesterol and triglycerides, raloxifene causes an insignificant increase in HDL and a slight decrease in triglyceride levels. Serum levels of lipoprotein(a) are reduced much more with ERT (16.3%) than raloxifene therapy (4.1%), whereas fibrinogen levels are reduced more with raloxifene (12.2%) than ERT (2.8%).15
The effects of raloxifene on 2 additional independent risk factors for cardiovascular disease were recently reported. Elevated levels of C-reactive protein, a circulating marker of inflammation, are associated with a significantly greater risk of myocardial infarction. Also, elevated levels of homocysteine predict a greater risk of coronary artery disease. While ERT significantly increases circulating levels of C-reactive protein (by as much as 84%), raloxifene lacks a significant effect. Like estrogen, raloxifene significantly lowers homocysteine levels by 6% to 8%.16
The changes in serum levels of the several markers of cardiovascular health are summarized for both ERT and raloxifene in Table 1. Overall, raloxifene therapy is associated with favorable changes in the serum levels of several of these markers, suggesting that the SERM may substantially reduce the risk of heart disease in postmenopausal women. However, conclusive proof would require a clinical trial with cardiovascular events as the definitive endpoints. Such an investigation is currently being carried out in the Raloxifene Use for the Heart (RUTH) trial. The results should indicate whether these favorable biochemical effects are indeed associated with a reduction in the incidence of cardiovascular disease.
Effects on the endometrium. Unlike tamoxifen and toremifene (Fareston; Schering-Plough, Kenilworth, NJ), which stimulate endometrial proliferation and increase the risk of endometrial cancer, raloxifene has no stimulatory effects on either the endometrium or the myometrium.17,18 In postmenopausal women receiving raloxifene, the incidence of vaginal bleeding is the same as in women on placebo. In the MORE trial, raloxifene did not increase the risk of endometrial cancer, endometrial hyperplasia, or uterine bleeding over a follow-up period of 40 months.20 Several other studies have evaluated the endometrial response to raloxifene—compared with placebo or ERT—for periods ranging from 12 to 24 months. These studies have consistently reported that raloxifene has no stimulatory effects on the uterus of postmenopausal women.17,18,21 Thus, it seems clear that postmenopausal patients on raloxifene need not worry about an increased risk of polyps, endometrial proliferation, hyperplasia, or cancer. Their endometrial thickness and uterine volume will not increase, nor will they experience a greater incidence of vaginal bleeding than untreated women.5,17,18,20
In postmenopausal women, the administration of raloxifene does not require the addition of a progestin or routine endometrial monitoring by biopsy or ultrasonography. Any bleeding during raloxifene therapy should therefore be promptly evaluated, since it is unlikely to be related to the SERM.
Effects on the breast. In contrast to ERT, raloxifene does not increase the frequency of breast pain or tenderness in postmenopausal women. In addition, recent data suggest that raloxifene may reduce the risk of breast cancer.
Like tamoxifen, raloxifene inhibits the growth of mammary tumors in rodents and the growth of the human MCF-7 breast cancer cell line in vitro.9,22 The latest follow-up data from the MORE trial indicate that 4 years of raloxifene therapy reduces the risk of all breast cancers by 72% compared with placebo. At the 4-year mark of the MORE trial, a total of 79 breast cancer cases occurred—4.7 cases per 1,000 patient-years in the placebo group compared with 1.3 cases per 1,000 patient-years in the raloxifene group. The protective effect was essentially restricted to ER-positive cancers. As in previous observations, women with the highest serum estrogen levels had the highest BMD and the highest incidence of breast cancer. These same women experienced the greatest reduction in breast cancer risk with raloxifene therapy.
Because raloxifene has not yet been studied directly as a prophylactic, it cannot be recommended for the prevention of breast cancer. Several other issues regarding raloxifene and breast cancer prevention also need to be addressed. For example, the efficacy rates of raloxifene in women at increased risk for breast cancer and in younger postmenopausal women are unknown. We also lack data regarding the optimal duration of raloxifene therapy for maximal, sustained protection against breast cancer.