Side Effects of raloxifene

Raloxifene side effects we now are sure about are thrombo-embolism (abnormal clotting of blood with/without clots moving through the circulation), hot flashes/night sweats and leg cramps. It is quite clear that Raloxifene is similar to estrogen in causing abnormal clotting in about one percent of women (significantly more than 0.3% on placebo, P = 0.002) (1). That risk may be much higher in women with a family or personal history of blood clotting, especially those who have had thrombophlebitis (inflammation of a vein caused by a blood clot obstructing flow) while taking the birth control pill or during pregnancy. Those women should not take raloxifene or oral estrogen. (Patch or gel estrogen probably has less blood-clotting effect and could possibly be used in low doses in women at moderate risk for thrombo-embolism).

The hot flash/night sweat side effect of raloxifene is noted in all human studies. Commonly women close to menopause want therapy to treat hot flashes. Most trials have excluded women from participation who experience troublesome hot flashes. None of the published studies really give a good idea about how severe these symptoms are, whether they get worse or better with longer use of raloxifene, whether they bother women a lot or a little. We do know that significantly more women randomly assigned to raloxifene than those assigned to placebo quit the studies before they were over (1).

Monitoring Women's Experiences

In the raloxifene studies, as in most published studies the methods used to assess women's hormone-related quality of life are inadequate. Studies report that they routinely "queried participants at every visit about adverse events" (2). That rather off-hand way of monitoring does not accurately assess the whole range of women's experiences, would gather only the most severe symptoms, and only indicates whether they experienced any hot flashes or not. Furthermore, hot flashes are called a "non-serious adverse event"(1). What we really want to know is whether daytime hot flashes were frequent and severe or night sweats wakened women from sleep.

We do not know whether the 10% of women reporting hot flashes on raloxifene therapy were bothered by them. We do know that more women in the raloxifene group than the placebo group withdrew because of hot flashes (P < 0.001) (2).

Raloxifene does not increase vaginal bleeding, or cause stimulation of the endometrium (uterine lining) (12), in contrast to the rare but very serious endometrial cancer caused by its cousin, tamoxifen. Tamoxifen is the drug that is currently commonly used as adjuvant therapy for breast cancer. It was initially felt to have anti-estrogen effects on the endometrium but is now known to cause endometrial cancer (14).

Raloxifene also seems to cause little or no breast tenderness or pain, in contrast to approximately 20% who experience breast pain while taking estrogen therapy (15). About 13% of women on raloxifene, compared to 11% on placebo, experienced a flu-like syndrome and about 5% experienced some fluid retention or swollen feet compared with 4% of those on placebo. A few more women treated with raloxifene also developed diabetes mellitus, but the changes in fasting blood sugar levels were not different between groups.

Therefore, besides the serious risk for blood clotting problems, and an increase in night sweats, raloxifene appears to have few side effects.

What to do before beginning raloxifene

Before starting any new medication, I believe that it is important to keep a daily record of your experiences[2]. Two weeks or a month of record keeping before and after starting a new therapy will allow you to personally assess any changes, either positive or negative that are related to the new therapy.

What does Raloxifene cost?

It is currently priced at $54.02 for 24 tablets or $2.25/day (before dispensing fees) in Canada. That cost is substantially more than any estrogen preparation, than estrogen plus progesterone or the bisphosphonates which are used to treat osteoporosis. Unless health insurance plans or extended health insurance covers this, it is likely that many non-affluent women will be unable to afford raloxifene.

Who may want to take raloxifene?

First of all, it should be taken for a good reason. Because raloxifene is not appropriate for early menopause nor for treatment of night sweats, osteoporosis risk factors are the primary reason for its use. Important risk factors for osteoporosis and fracture include a family history of osteoporosis, past abnormal menstrual cycles, being chronically underweight, having used cigarettes in the past or currently smoking, chronic low exercise and low calcium and vitamin D intakes. A bone density measurement lower than one standard deviation below peak bone density (T score lower than -1) is another important osteoporosis risk factor.

Even if you have a good reason for menopausal therapy, what you choose to take depends on many factors. The first may include whether it is made in animals (as is Premarin), is chemically made or is "natural" (meaning identical to the hormone the body made before menopause, which is true of progesterone [Prometrium], and the estradiol preparations, Estrace, Estraderm, Vivelle or Estra Gel(. Another consideration is whether you prefer to have vaginal bleeding like menstrual cycles (or would much rather not]. Also, you may gag when taking any pills, or get a rash from patches or cremes. Finally, you may or may not have much money to spend on therapy.

You may choose estrogen and progesterone therapy for prevention of fractures, for example, because it is less expensive than raloxifene or the bisphosphonates (non-hormonal family of medications that decrease bone resorption and fracture - etidronate [Didronel, Didrocal], alendronate [Fosamax], or the soon-available risedronate [Actonel]).

You may also choose ovarian hormone therapy because, besides osteoporosis risk, you need something that will treat night sweats. If you are at risk for osteoporosis and are experiencing night sweats, but you have had blood clots and therefore should not take estrogen or raloxifene, you may decide to take a bisphosphonate combined with progesterone. The bisphosphonates prevent fracture.

Progesterone treats hot flashes (16) and increases bone formation (17). You can combine any of the bisphosphonates with progesterone (medroxyprogesterone, Provera 10 mg/d, or oral micronized progesterone, Prometrium 100 mg , 3 at bedtime daily). Clinical works suggest the increase in bone density is greater with bisphosphonates plus progesterone than with bisphosphonates alone. Finally, if you have an increased risk for breast cancer as well as risks for osteoporosis, if you are several years after menopause and have minor or no hot flash symptoms, raloxifene may be the right treatment for you.

Overview

In summary, raloxifene was created to be a medication that acted like estrogen for the bones and heart and against estrogen for the uterus and breasts. It does not treat hot flashes and may make them worse and is quite costly at about $2.50/day. However, it causes minimal flow or breast tenderness symptoms. Large randomized controlled trial data show that it will both prevent spinal fractures and breast cancer (although the latter is not an approved use for it). Studies of raloxifene and heart disease are currently being conducted. The Raloxifene Use and The Heart (RUTH) trial is a large (10,000 women) randomized placebo-controlled study of heart disease prevention by raloxifene in women with existing heart disease or three risk factors (18). Although raloxifene therapy lowers total cholesterol and LDL cholesterol it has no significant effect on the good HDL cholesterol (19, 20, 21). Furthermore, a double-blind placebo-controlled study of raloxifene or high dose CEE and vascular disease in menopausal monkeys showed no vascular prevention (22).