ERAAs for menopause treatment: Welcome the ‘designer estrogens’
ABSTRACT
Estrogen receptor agonist-antagonists (ERAAs) selectively inhibit or stimulate estrogen-like action in targeted tissues. This review summarizes how ERAAs can be used in combination with an estrogen or alone to treat menopausal symptoms (vasomotor symptoms, genitourinary syndrome of menopause), breast cancer or the risk of breast cancer, osteopenia, osteoporosis, and other female midlife concerns.
KEY POINTS
- Tamoxifen is approved to prevent and treat breast cancer. It may also have beneficial effects on bone and on cardiovascular risk factors, but these are not approved uses.
- Raloxifene, a second-generation ERAA, was initially approved for preventing and treating osteoporosis and later received approval to reduce the risk of invasive estrogen receptor-positive breast cancer in postmenopausal women.
- Ospemifene is approved for treatment of genitourinary syndrome of menopause.
- The combination of conjugated estrogen and bazedoxifene is approved for treating moderate to severe vasomotor symptoms associated with menopause and also for preventing postmenopausal osteoporosis in women with an intact uterus.
RALOXIFENE: FOR OSTEOPOROSIS AND FOR CANCER PREVENTION
Raloxifene, a second-generation ERAA, was first approved for preventing and treating osteoporosis and later for reducing the risk of invasive estrogen receptor-positive breast cancer in postmenopausal women.
Trials of raloxifene for osteoporosis
The MORE trial (Multiple Outcomes of Raloxifene)18 was a large multicenter randomized double-blind study. Raloxifene recipients showed a significant increase in bone mineral density in the lumbar spine and femoral neck at year 3 (P < .001) compared with those receiving placebo. Even after only 1 year of treatment, raloxifene significantly reduced the risk of new fractures, despite only modest gains in bone mineral density. After 3 years of treatment, new clinical vertebral fractures had occurred in 3.5% of the placebo group compared with 2.1% of the group receiving raloxifene 60 mg.19 Relative risk reductions were similar in women who had already had a clinical vertebral fracture at baseline, whose absolute risk is higher. However, no significant effect was seen on the incidence of hip or nonvertebral fractures.
The CORE trial (Continuing Outcomes Relevant to Raloxifene)20 extended the treatment of the women enrolled in the MORE trial another 4 years and found that the benefit of raloxifene with regard to bone mineral density persisted with continued use.
Trials of raloxifene for breast cancer prevention
The MORE trial,21 in postmenopausal women with osteoporosis included breast cancer as a secondary end point, and raloxifene was shown to decrease the incidence of invasive breast cancer. At a median of 40 months, invasive breast cancer had arisen in 13 (0.25%) of the 5,129 women assigned to raloxifene and 27 (1.0%) of the 2,576 women assigned to placebo. The authors calculated that 126 women would need to be treated to prevent 1 case of breast cancer.
The CORE trial,22 as noted, extended the treatment of the women enrolled in the MORE trial another 4 years. The risk of any invasive breast cancer in postmenopausal women with osteoporosis was significantly reduced by 59% after 8 years, and the risk of estrogen receptor-positive invasive breast cancer was reduced by 66%.
There is evidence that raloxifene’s effect on breast cancer risk persists after discontinuation of use.23
Does raloxifene reduce mortality?
Grady et al24 studied the effect of raloxifene on all-cause mortality in a pooled analysis of mortality data from the MORE, CORE, and Raloxifene Use for the Heart (RUTH)25 trials. In older postmenopausal women, the rate of all-cause mortality was 8.65% in those taking placebo compared with 7.88% in those taking raloxifene 60 mg daily—10% lower. The mechanism behind the lower mortality rate is unclear, and Grady et al recommend that the finding be interpreted with caution.
Trials of raloxifene for heart protection
The RUTH trial25 was a 5.6-year study undertaken to study the effects of raloxifene on coronary outcomes and invasive breast cancer in postmenopausal women. Results were mixed. Active treatment:
- Did not significantly affect the risk of coronary artery disease compared with placebo
- Significantly decreased the risk of invasive breast cancer
- Significantly decreased the risk of clinical vertebral fractures
- Increased the risk of fatal stroke (59 vs 39 events, hazard ratio 1.49, 95% CI 1.00–2.24) and venous thromboembolism (103 vs 71 events, hazard ratio 1.44, 95% CI 1.06–1.95).
The STAR trial (Study of Tamoxifen and Raloxifene)26,27 compared raloxifene and tamoxifen in postmenopausal women at increased risk of breast cancer. Women were randomized to receive either tamoxifen 20 mg or raloxifene 60 mg for 5 years. Results:
- No difference in the number of new cases of invasive breast cancer between the groups
- Fewer cases of noninvasive breast cancer in the tamoxifen group, but the difference was not statistically significant
- Fewer cases of uterine cancer in the raloxifene group, annual incidence rates 0.125% vs 0.199%, absolute risk reduction 0.74%, NNT 1,351, relative risk with raloxifene 0.62, 95% CI 0.30–0.50
- Fewer thromboembolic events with raloxifene
- Fewer cataracts with raloxifene.
Adverse effects of raloxifene
Raloxifene increases the risk of venous thromboembolism and stroke in women at high risk of coronary artery disease.19
Ideal candidates for raloxifene
Postmenopausal women with osteopenia or osteoporosis and a higher risk of breast cancer who have minimal to no vasomotor symptoms or genitourinary syndrome of menopause are good candidates for raloxifene. Raloxifene is also a good choice for women who have genitourinary syndrome of menopause treated with local vaginal estrogen. Raloxifene has no effect on vasomotor symptoms or genitourinary syndrome of menopause.
