Menopausal women with risks for osteoporosis or fracture now have several new therapies. These new options include nasal spray calcitonin (called Miacalcin) approved to treat osteoporosis in the U.S.A. and Canada, risedronate (called Actonel) which will soon be available for osteoporosis prevention, and raloxifene (brand name Evista) which is approved in Canada for prevention of osteoporosis, and in the U.S.A. for both treatment and prevention. Raloxifene became available in 1998 in the U.S.A. and in 1999 in Canada.

My purpose here is to put the benefits and risks of raloxifene into both a scientific and a practical perspective . My point of view is created by a complex interaction of my nearly menopausal status, my family history of both osteoporosis and breast cancer, my work as a physician who specializes in the treatment of people with osteoporosis and my work as a scientist on the actions of progesterone and on women's hormone-related quality of life.

Raloxifene is a non-hormonal medication designed to act like estrogen in some parts of the body and to antagonize estrogen's actions in other parts. Raloxifene decreased spinal fracture rates by 30% compared with placebo over three years in a study of 6,828 menopausal women with low initial bone density or previous spine fracture (1). Raloxifene also decreased the rates at which women got breast cancer over three years by about 65% in menopausal women with low bone density and probably lower than average risk for breast cancer (2). In the near future, raloxifene will also likely be indicated in Canada for treatment of osteoporosis in menopausal women and for the prevention of breast cancer in menopausal women at increased breast cancer risk. Depending on the results of trials currently in progress, it may also be used to prevent heart attacks and as breast cancer adjuvant therapy (to prevent breast cancer recurrence or the development of a second new breast cancer). Therefore, at first glance, raloxifene sounds like the answer to menopausal women's prayers. Is it?

What led to the creation of raloxifene?

Before answering that question, let's think about why raloxifene was created. Raloxifene was designed to be one-stop shopping, menopausal "hormone replacement therapy " (sometimes called "HRT" (. I put "HRT" into quotation marks because I can barely make myself write it. The word "replacement" means that menopausal estrogen levels require fixing before a woman could become normal. That is just plain wrong! Consequently, although it is unfortunately standard language, when I hear someone say "HRT" I experience a wave of anger and disgust. I feel the same way when someone calls me a girl! Both are profound "put downs" for women.

You ask, "But you're a doctor and you know some women have awful night sweats or a miserable time. How do you help those women if you reject 'HRT'?" I do treat them, but, what I recommend or prescribe isn't "replacement " of something deficient, it's specific therapy for a specific problem. A better term is "ovarian hormone therapy "(OHT for short). I believe that sound reasons for taking OHT include sleep-disturbing night sweats, early menopause (before age 40, or surgical menopause in a menstruating woman) and low bone density or fractures in a menopausal woman (3). Those of us lucky enough to have none of those should rejoice in our menopause!

Raloxifene was designed to do all the good things estrogen does. It was crafted to correct "estrogen deficiency" and the "problems" this is assumed to cause including osteoporosis, heart attacks, Alzheimer's disease, dementia and all the other horrible things we fear about aging. I believe that menopause is an inevitable and normal (but not always a pleasant) part of our life cycle as women. After 30-35 years of cyclic, high ovarian hormone production I believe that we need a break. High estrogen levels cause all cells to proliferate (grow), require the body to store energy and demand attention from every organ system in the body. Progesterone interacts with all the cells that estrogen does and slows the growth rate of cells. It is unique in increasing the rate of breathing, raising the core temperature and therefore increasing the metabolic rate as well as stimulating the growth of osteoblast cells that build bone. It seems to me that these demands created by high levels of ovarian hormones are necessary and appropriate during reproductive adulthood but are not needed and may even be detrimental as we age.

Yes, we do lose bone, and we start losing it during the perimenopause when we are still having periods and our estrogen levels are higher than average (4). All of the evidence says to me that women who have built dense, strong bones in childhood and the teen years, and who keep their bones strong until perimenopause can lose the usual amount of bone density during the menopausal transition and not be at increased risk for osteoporosis. That means that preventing bone loss at menopause is important only if the bone density is already low.

What about heart disease? Don't we know it increases after menopause and becomes a leading killer of women?

My 20 year old son's response to that question was,"The doctors probably couldn't figure out why elderly women died so they just wrote that their hearts failed!" Yes, heart disease does increase in older women. But why blame menopause or the normal decrease in estrogen levels when there is no increase in heart disease rate either at menopause (5) or related to hormone levels? Heart disease increases gradually after age 35 in all of us and more rapidly if we have genetic or lifestyle risks. The good news is that we have lots of things we can do to prevent heart disease. These include making sure we don't have, or are getting treatment for, high blood pressure, abnormal lipid levels or diabetes. We can also exercise regularly, avoid becoming overweight (6), and not use cigarettes. There are no good scientific grounds to believe that estrogen therapy would prevent heart attacks unless the randomized, controlled trial which is now in progress as the "Women's Health Initiative" in the U.S.A. eventually shows it. A randomized, double blind placebo-controlled study was recently published showing no OHT-related prevention of more heart attacks in women with existing heart disease (7). That study, called HERS for short, involved 2763 women aged 65-80 with coronary heart disease who were randomized to conjugated equine estrogen (CEE, Premarin 0.625 mg) and medroxyprogesterone acetate (MPA, Provera 2.5 mg) daily or identical placebos (containing no active medicine) for four years. The main study outcomes were death from heart disease, or new heart attack. This study showed no difference in either outcome with OHT when compared to the placebo group (7). The HERS results confirmed early randomized placebo controlled trials of high dose CEE treatment in men with heart disease by showing, not only no heart disease prevention, but also increased death and serious diseases related to abnormal blood clotting (8,9).

Back to the creation of raloxifene

It was made not only to do the good stuff we believe estrogen does (prevent bone loss, prevent heart attacks) but also to not do any of the bad things. Creation of a compound that acts against estrogen acknowledges that it is linked to abnormal vaginal bleeding and endometrial cancer and to breast cancer. What is interesting is that progesterone's natural job is to counterbalance the proliferation (or cancer-promoting) effects of estrogen. Maybe we don't need a designer "HRT" to do that?

Old epidemiological studies in two different groups of women indicate that women who had chronically non-ovulatory cycles (meaning that little or no progesterone was produced) and whose estrogen levels were normal or high were at increased risk for breast cancer (10,11). We also know that progesterone applied as a cream to the breast in a random, double blind study decreased the breast cell proliferation caused by normal or high levels of estrogen (12). Perhaps, changing the focus from "estrogen deficiency" at menopause to "progesterone deficiency" before menopause would be helpful!

Human studies using raloxifene

I consider raloxifene to be important because it prevents both osteoporotic fracture and breast cancer. That raises the question, "Why shouldn't all menopausal women take raloxifene?" Every medication has unwanted adverse effects as well as real personal and dollar costs. Therefore, before we can adequately consider who should take raloxifene we must review its side effects and cost.

All of the published studies currently providing new information about Raloxifene were designed, performed and paid for by the company that is marketing it. Therefore, it is wise to be skeptical. Raloxifene is a prime product of a very large multinational profit making pharmaceutical company. What we now know about Raloxifene's side effects is far less than will eventually be known after it has been used for five or ten years by community women who are less selected and more variable than women who have taken part in the published studies.