Raloxifene in women: medical indications

Raloxifene is a drug created specifically for postmenopausal women. It protects the vertebrae from fractures and reduces the risk of estrogen-receptor-positive breast cancer, but it has serious contraindications. The editorial team explains who it is intended for, who it is not, and how it looks against other treatment options.

How raloxifene works in the female body

Raloxifene belongs to the selective estrogen receptor modulators (SERMs). It binds to the same receptors as the body's own estradiol, but the result depends on the tissue: in bone it acts like estrogen, while in the breast and endometrium it acts as an antagonist or neutrally.

After menopause, estrogen levels fall sharply, and bone tissue begins to break down faster than it is rebuilt. Raloxifene partly compensates for this loss specifically in bone, suppressing osteoclast activity and slowing resorption. The bone density of the spine and hip increases moderately.

At the same time, raloxifene does not stimulate the endometrium, so it does not increase the risk of uterine cancer, as estrogen-only therapy might. In the breast, it blocks the proliferative action of estrogens, which explains the reduced incidence of hormone-dependent tumors.

It is important to understand the limitations too: raloxifene does not relieve menopausal symptoms. On the contrary, hot flashes are one of its common side effects. So for a woman with pronounced vasomotor symptoms, it does not replace menopausal hormone therapy.

Indication: osteoporosis

According to the FDA label, raloxifene is indicated for the treatment and prevention of osteoporosis in postmenopausal women. The dose stated in the official label is 60 mg once a day; with insufficient dietary intake, adding calcium and vitamin D is recommended.

The evidence base is the MORE study (Ettinger et al., 1999), in which more than 7,000 women with osteoporosis received raloxifene or placebo over three years. In the raloxifene group there were noticeably fewer new vertebral fractures, while for hip fractures and other non-vertebral fractures no significant reduction was found.

Therefore, in modern guidelines raloxifene is regarded primarily as an option for women whose main risk is related to the spine and whose hip fracture risk is not dominant. For women with a high risk of hip fracture, bisphosphonates or denosumab are more often chosen.

An additional advantage for some patients may be a reduction in LDL levels. However, the RUTH study showed that this does not translate into a reduction in cardiovascular events, so there are no grounds for prescribing raloxifene "for the heart."

Indication: reducing breast cancer risk

Since 2007, the FDA has approved raloxifene for reducing the risk of invasive breast cancer in two groups: postmenopausal women with osteoporosis and postmenopausal women at high risk of such cancer. This indication appeared thanks to data from MORE, CORE, and RUTH.

In the STAR study (Vogel et al., 2006), raloxifene was compared with tamoxifen in women at increased risk. Both drugs reduced the risk of invasive cancer to a similar degree in the primary analysis, but in the raloxifene group there were fewer cases of endometrial cancer, thromboembolic complications, and cataracts. A long-term update showed that raloxifene is somewhat inferior to tamoxifen in effectiveness but remains safer for the uterus.

It is fundamentally important: raloxifene is not intended for treating already diagnosed breast cancer and does not reduce the risk of estrogen-receptor-negative tumors. It is a means of prevention in postmenopausal women, not a tumor therapy.

Recommendations from the USPSTF and oncology societies on drug-based prevention of breast cancer emphasize that the decision must be individual: the benefit outweighs the risks only when the baseline cancer risk is high enough and the thrombosis risk is low.

Contraindications and risks

The FDA label contains a boxed warning about an increased risk of venous thromboembolism (deep vein thrombosis, pulmonary embolism) and death from stroke. In the RUTH study, which enrolled women with coronary heart disease or high risk, the rate of fatal strokes in the raloxifene group was higher than in the placebo group.

Common side effects include hot flashes, leg muscle cramps, peripheral edema, and flu-like symptoms. They are usually not dangerous, but they can reduce quality of life and adherence to treatment.

The doctor also takes interactions into account. Cholestyramine reduces the absorption of raloxifene, so they are not combined. With simultaneous use of warfarin, a decrease in prothrombin time is possible, which requires INR monitoring.

Raloxifene is not used in women of reproductive age. The drug can harm the fetus, and there are no data on benefit in young women.

Its place among other treatment options

The choice of a drug for bone depends on the risk profile. Bisphosphonates (alendronate, risedronate, zoledronic acid) and denosumab reduce the risk of both vertebral and hip fractures. Anabolic agents — teriparatide, abaloparatide, romosozumab — are usually reserved for very high risk.

• Raloxifene may be appropriate:younger postmenopause, risk of vertebral fractures, increased risk of breast cancer, low risk of thrombosis.
• Another choice is better:high risk of hip fracture, a history of thrombosis, pronounced hot flashes.
• Hormone therapy:is considered when the main problem is menopausal symptoms, taking its own risks into account.

The Endocrine Society clinical guidelines for treating osteoporosis in postmenopausal women regard raloxifene as an option for select patients, in particular those with a low risk of thrombosis and a high risk of breast cancer, rather than as a first-line drug for everyone.

Any osteoporosis therapy is supplemented by basic measures: adequate calcium and vitamin D, strength and impact loading, fall prevention, giving up smoking, and limiting alcohol.

Editorial conclusions

Raloxifene has two clear official indications for postmenopausal women: the treatment and prevention of osteoporosis, and the reduction of the risk of invasive breast cancer.

The strongest effect has been proven for vertebral fractures and ER-positive cancer; for the hip and the heart, no benefit was found.

The main risks are thrombosis and fatal stroke, so careful patient selection is mandatory.

We also recommend reading our materials on the history of raloxifene's creation, on the tests used during therapy, and on its effect on the liver.

References

1. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA. 1999;282(7):637–645.
2. Cummings SR, Eckert S, Krueger KA, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. JAMA. 1999;281(23):2189–2197.
3. Barrett-Connor E, Mosca L, Collins P, et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med. 2006;355(2):125–137.
4. Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP STAR P-2 trial. JAMA. 2006;295(23):2727–2741.
5. Eastell R, Rosen CJ, Black DM, et al. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2019;104(5):1595–1622.
6. US Preventive Services Task Force. Medication use to reduce risk of breast cancer: US Preventive Services Task Force recommendation statement. JAMA. 2019;322(9):857–867.
7. U.S. Food and Drug Administration. EVISTA (raloxifene hydrochloride) tablets: prescribing information. Eli Lilly and Company.