Just over a year ago raloxifene(Evista^®) was approved for the prevention of osteoporosis in postmenopausal women. Raloxifene is a SERM, a Selective Estrogen Receptor Modulator, a complex drug with many actions. Is it the answer to the many worries about hormone replacement therapy (HRT)? The short answer is, "Maybe, but we are not sure." Let me review with you its specific characteristics as it fits into the HRT picture.

Target Tissue

As a SERM, raloxifene is one of a class of drugs that interacts with the estrogen receptors on various tissues of the body as either agonist or antagonist. The key tissues of estrogen interaction that we know about so far are breast, uterus, urogenital tract, blood vessels, bone, brain and colon. There are also important effects on hot flashes, cholesterol metabolism and clotting mechanisms.

Negative Effects of Estrogen

The three potential problem areas for women taking estrogen as hormone replacement are the effects on breast, uterus and clotting. The slight increase in breast cancer incidence, after more than five years of continuous estrogen use, has discouraged many women from using estrogen. Uterine hyperplasia, from unopposed estrogen with the risk of uterine cancer, has prompted the use of progesterone with estrogen in postmenopausal women with an intact uterus. Patients with a history of risk factors for venous thromboembolism should not be given estrogen. A sobering observation in the HERS (Heart Estrogen Replacement Study), on the secondary prevention of CHD in women, showed an increase in thrombotic events in the first year after estrogen was started.(1)

Positive Effects of Estrogen

In the other areas I mentioned -- hot flashes, urogenital tissue, blood vessels, bone, brain, colon and cholesterol metabolism -- estrogen can be highly beneficial. Estrogen quells hot flashes, thickens urogenital epithelium, dilates blood vessels, stabilizes and increases bone density, improves cerebral function, is associated with decreased colon neoplasia, lowers LDL and increases HDL cholesterol levels. Keep in mind that the vasomotor, urogenital, and bone effects of estrogen are backed up by strong evidence. The other beneficial effects are based on observational studies. Even the apparent effects on preventing heart disease may be due to selection bias and are still not considered definitively proven. Watch for the results of the Women's Health Initiative on this subject.

What's Raloxifene's Role?

Where does raloxifene fit into all this? As I mentioned before, raloxifene is a SERM. The best known SERM is tamoxifen, which has been used with great success in the hormonal treatment of breast cancer. Tamoxifen blocks the estrogen receptor in breast tissue and has been shown to decrease the recurrence rate of breast cancer after treatment(2) as well as prevent breast cancer in high risk women.(3)

Raloxifene is similar to tamoxifen. It is an estrogen antagonist on breast tissue. It has not been pursued in breast cancer treatment because it is not as effective as tamoxifen and some of the other SERMs.(4) Raloxifene may have a major role in breast cancer prevention and there are studies underway to test this effect (Capitol Area Raloxifene Breast Cancer Prevention Study, NCI, 1-888-624-1937, Clinical Studies Support Center).

Contrary to tamoxifen, which is agonist to endometrium and is associated with uterine hyperplasia, polyps and even cancer,(5) raloxifene does not stimulate uterine tissue.(7),(9) This could confer an advantage in preventing and treating breast cancer in women with an intact uterus.

Like estrogen, raloxifene does have agonist effects on hemostasis and is associated with an increased risk for venous thromboembolism, so similar precautions apply to at-risk women.(6),(9)

Like tamoxifen, raloxifene will not quell hot flashes and may even increase them at higher doses. It certainly would not be the drug of choice for women for whom vasomotor symptoms were the chief reason for considering HRT. On the other hand, at the standard dose of 60mg/day, the incidence in many studies, though higher than the placebo group, was not a prominent reason for stopping the drug.(4)

Raloxifene decreases LDL cholesterol but, unlike estrogen, does not increase HDL cholesterol. Currently, there is no evidence in humans demonstrating a beneficial effect on other mechanisms, like nitric oxide-mediated arterial dilatation, which could favorably influence cardiac disease.

Nothing is yet known about whether raloxifene might, as observed with estrogen, delay the onset and progression of Alzheimer disease.(4) The same is true about the lower incidence of colon polyps and cancer observed in women on estrogen.(10)

Raloxifene was approved for its effect on bone, for the prevention of osteoporosis in postmenopausal women. It decreases bone reabsorption and promotes positive calcium balance, with the net effect of increasing bone mineral density. It is less effective than either estrogen or alendronate. One question is whether raloxifene will have an adverse effect on bone density in premenopausal women? This has been observed with tamoxifen, probably because it blocks natural estrogen at the receptor site on bone.(8)

Raloxifene has also been shown to decrease the incidence of breast cancer. In the MORE (Multiple Outcomes of Raloxifene Evaluation) study, one of the endpoints was the development of breast cancer.(9) There was a significant decrease in the diagnosis of estrogen receptor-positive breast cancer in the raloxifene-treated group compared with the placebo. There was no difference in the incidence numbers of women diagnosed with estrogen receptor-negative breast cancer. This study was on postmenopausal women with osteoporosis at average risk for breast cancer. These results, on one special group of patients, lead us to many questions about the SERMs and breast cancer. I would like you to keep these questions in mind as you see the results of more studies.

Does Raloxifene Have Any Influence on de Novo Breast Cancer or ER Negative Breast Cancer?

The MORE study only lasted 40 months. Because we think breast cancer takes 8-10 years from original mutation to clinical detection, we presume that the breast cancers diagnosed in that study were already present when the study started. It is easy to see how raloxifene would have inhibited the growth of some ER positive tumors. But what about a population with no breast cancer when the study started? How effective would raloxifene be in preventing de novo tumors, ER positive or negative?

What Would the Long-Term Effect of SERMs Be on the Type of Breast Cancer?

We know that metastatic cancer can be, or become, impervious to the beneficial effects of tamoxifen, one of our main treatment modalities.(4) Will women given raloxifene for long periods be prone to developing breast cancers resistant to hormonal therapy? The MORE trial is continuing and will be looking at the effects of long-term raloxifene use.

How Effective Would Raloxifene or Tamoxifen Be in Reducing Breast Cancer in Women with Germline Genetic Risks for Breast Cancer?

Such genetic factors might not be as susceptible to the SERMs as the effect of ambient estrogen, which is thought to be the major factor in the development of somatic breast cancer. Right now, the National Surgical Breast and Bowel Project (NSABP) Part 2 is studying women at high risk for breast cancer to compare the effects of tamoxifen with raloxifene.

Let me summarize the various actions of raloxifene in a table, comparing it with estrogen and tamoxifen.

Should She or Shouldn't She?

So, where are we with our decision about using raloxifene in a given patient? Let me tell you how I approach a postmenopausal patient who needs treatment for symptoms or risk management. First, I find out HER concerns and priorities. Is she having great difficulty with hot flashes? Does she have a particular prevention priority? Then, I review all the relevant risks: breast cancer, osteoporosis, coronary heart disease, Alzheimer's and colorectal cancer. Finally, I take a close look at the Big Three:

1. Breast cancer: personal history, family history or great fear? Keep in mind that a patient who has had breast cancer and has been treated with five years of tamoxifen is not a candidate for another anti-estrogen.
2. Intact uterus and/or unacceptable bleeding problems on HRT?
3. Thromboembolic disease? This would include deep vein thrombosis, retinal vein thrombosis or pulmonary embolism.

With answers to these questions, you should be able to make a pretty rational decision about whether raloxifene would be appropriate for a given patient. You will probably find yourself putting relatively few of your patients on this drug but scanning the journals with great interest for study results on the SERMs, as we continue to search for the ideal SERM, with the exact right combination of estrogenic an anti-estrogenic properties.