Michael W. Draper

Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women.

BACKGROUND Long-term estrogen therapy can reduce the risk of osteoporotic fracture and cardiovascular disease in postmenopausal women. At present, however, these beneficial effects are not separable from undesirable stimulation of breast and endometrial tissues. METHODS We studied the effect of raloxifene, a nonsteroidal benzothiophene, on bone mineral density, serum lipid concentrations, and endometrial thickness in 601 postmenopausal women. The women were randomly assigned to receive 30, 60, or 150 mg of raloxifene or placebo daily for 24 months. RESULTS The women receiving each dose of raloxifene had significant increases from base-line values in bone mineral density of the lumbar spine, hip, and total body, whereas those receiving placebo had decreases in bone mineral density. For example, at 24 months, the mean (+/-SE) difference in the change in bone mineral density between the women receiving 60 mg of raloxifene per day and those receiving placebo was 2.4+/-0.4 percent for the lumbar spine, 2.4+/-0.4 percent for the total hip, and 2.0+/-0.4 percent for the total body (P<0.001 for all comparisons). Serum concentrations of total cholesterol and low-density lipoprotein cholesterol decreased in all the raloxifene groups, whereas serum concentrations of high-density lipoprotein cholesterol and triglycerides did not change. Endometrial thickness was similar in the raloxifene and placebo groups at all times during the study. The proportion of women receiving raloxifene who reported hot flashes or vaginal bleeding was not different from that of the women receiving placebo. CONCLUSIONS Daily therapy with raloxifene increases bone mineral density, lowers serum concentrations of total and low-density lipoprotein cholesterol, and does not stimulate the endometrium.

Prevention of osteoporosis and uterine effects in postmenopausal women taking raloxifene for 5 years.

ObjectiveRaloxifene hydrochloride (60 mg/day) is a selective estrogen receptor modulator indicated for the prevention and treatment of postmenopausal osteoporosis. Raloxifene treatment for 3 years increases bone mineral density (BMD) and, unlike tamoxifen (a triphenylethylene selective estrogen receptor modulator), does not stimulate the endometrium in healthy postmenopausal women. The effect of longer duration of treatment with raloxifene is not known. Therefore, the main objectives of these analyses are (1) to compare the effect of 5 years of treatment with raloxifene (60 mg/day) with placebo in terms of the likelihood of developing osteoporosis and (2) to evaluate the effect of 5 years of raloxifene treatment on the endometrium and incidence of vaginal bleeding. DesignThe current analyses include integrated data from two identically designed, prospective, double-blinded trials including postmenopausal women (mean age, 55 years) randomly assigned to either placebo (n = 143) or raloxifene (60 mg/day; n = 185). Osteoporosis and osteopenia were diagnosed according to World Health Organization criteria, using the manufacturers database for the lumbar spine and the National Health and Nutrition Examination Surveys 1998 reference base for the hip. Endometrial thickness was determined using transvaginal ultrasonography. Clinical diagnoses of endometrial hyperplasia or endometrial cancer were confirmed by blinded review of histopathology reports. ResultsCompared with the case of placebo, raloxifene treatment for 5 years reduced bone turnover markers (osteocalcin: −10.9%, P < 0.001; bone-specific alkaline phosphatase: −7.2%, P = 0.042; urinary C-telopeptide: −11.1%, P = 0.034) and was associated with increased BMD in the lumbar spine (2.8%; P < 0.001) and total hip BMD (2.6%; P < 0.001). Women taking raloxifene were less likely to develop osteoporosis (relative risk [RR] for raloxifene v placebo: 0.13; 95% CI: 0.00, 0.37; P = 0.001) or osteopenia (RR: 0.23; 95% CI: 0.00, 0.81; P = 0.038) at the lumbar spine and were more likely to convert to normal BMD status at the lumbar spine (RR: 4.01; 95% CI: 1.34, 11.23; P = 0.043) and total hip (RR: 3.92; 95% CI: 1.12,14.27; P = 0.011) at 5 years, compared with the case of placebo. Raloxifene also significantly reduced total cholesterol (−5.5%; P < 0.001) and low-density lipoprotein cholesterol (−8.7%; P < 0.001), compared with the case of placebo. No significant changes in high-density lipoprotein cholesterol (P = 0.257) or triglycerides (P = 0.620) were detected. Incidence of hot flashes was higher among women taking raloxifene compared with those taking placebo [raloxifene, 47 (28.8%); placebo, 21 (16.8%); P = 0.017]. Women taking placebo or raloxifene reported a similar incidence of vaginal bleeding (P = 0.999) or of mean endometrial thickness of more than 5 mm at baseline and at each visit, up to the 5-year endpoint (P ≥ 0.349). No diagnoses of endometrial hyperplasia or endometrial cancer were made in either treatment group. ConclusionsFive years of raloxifene treatment in healthy postmenopausal women preserves BMD, significantly reduces the likelihood of development of osteoporosis, and was not associated with an increased rate of vaginal bleeding, endometrial hyperplasia, or endometrial carcinoma, compared with the case of placebo.

Antiestrogenic Properties of Raloxifene

This 21-day, open-label study evaluated the effects of raloxifene and tamoxifen on estrogen-induced changes in serum levels of anterior pituitary hormones (prolactin, luteinizing hormone, and follicle-stimulating hormone), sex steroids (testosterone, estradiol), and binding globulins [thyroid binding globulin (T3 resin uptake), transcortin, sex steroid binding globulin]. Seventeen healthy male volunteers completed the study after being randomized to one of three treatments: raloxifene, tamoxifen, or placebo. Six subjects received raloxifene (200 mg daily) for 10 days, 6 subjects received tamoxifen [20 mg twice a day (b.i.d.)] for 10 days, and 5 subjects received placebo for 10 days. All subjects received ethinyl estradiol (20 micrograms b.i.d.) for 7 days starting 3 days after initiation of study drug or placebo treatment. Results of the primary analysis of this study indicate that for six of the seven analyzable parameters of estrogen action (excluding luteinizing hormone) raloxifene blunted the estrogen response; this effect was significant only for T3 resin uptake. Tamoxifen administration significantly blunted or reversed the estrogen effect in all six of these parameters. Raloxifene, an effective antiestrogen in animal models, is also antiestrogenic in humans.

Raloxifene Treatment Is Associated With Increased Serum Estradiol and Decreased Bone Remodeling in Healthy Middle‐Aged Men With Low Sex Hormone Levels

In healthy middle‐aged men, raloxifene treatment was associated with increased serum estradiol and decreased biochemical markers of bone turnover in subjects with estradiol levels below a threshold of 101.8 pM.

Raloxifene: a selective estrogen-receptor modulator for postmenopausal osteoporosis - a clinical update on efficacy and safety

Selective estrogen-receptor modulators are molecules with specific estrogen-receptor binding affinity. Each selective estrogen-receptor modulator induces a unique conformation in the ligand–receptor complex, which leads to transcriptional activation and/or inhibition. Raloxifene 60 mg/day, a benzothiophene selective estrogen-receptor modulator, is approved for the prevention and treatment of postmenopausal osteoporosis. This article provides an update on new studies and further analyses of clinical trial data for raloxifene. The Multiple Outcomes of Raloxifene Evaluation (MORE) trial of women with osteoporosis has described the efficacy of raloxifene in decreasing vertebral fracture risk over 4 years. The Continuing Outcomes Relevant to Evista© (CORE) trial, designed to assess the effects of raloxifene on breast cancer prevention, is a 4-year continuation of MORE. The skeletal and cardiovascular effects of raloxifene in the CORE study were similar to those observed in MORE. The relative risk of developing breast cancer was significantly decreased in women treated with raloxifene, compared with placebo, after 4 years in MORE and 8 years in the CORE trial. The incidence of uterine bleeding, endometrial hyperplasia and endometrial cancer was similar between raloxifene and placebo after 8 years of treatment. Raloxifene use is associated with a higher incidence of hot flashes and leg cramps, and an increased risk of venous thromboembolic events.