Volume 1, Number 4: Winter Solstice, 1999

Consider Raloxifene - BC Endocrine Research Foundation

Jerilynn C. Prior MD, FRCPC

Division of Endocrinology, University of British Columbia, Vancouver, B.C.

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.

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).

Menopausal women in general do not need treatment

We need healthy, meaningful lives. But if we have a need to prevent osteoporosis and if our risks for breast cancer are increased, it is appropriate to consider raloxifene.

Jerilynn Prior is a Professor of Endocrinology at the University of British Columbia and an internationally known expert on women’s health.

References

  1. Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant H, 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; 282:637-645.
  2. Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women. Results from the MORE randomized trial. JAMA 1999; 281:2189-2197
  3. Prior JC. Menopause. In: Gray J, Johnson G, editors. Therapeutic Choices. Ottawa, Ontario, Canada: C.K. Productions, 1995:468-477.
  4. Prior JC. Perimenopause: The complex endocrinology of the menopausal transition. Endocr.Rev. 1998; 19:397-428.
  5. Matthews KA, Meilahn E, Kuller LH, Kelsey SF, Caggiula AW, Wing RK. Menopause and risk factors for coronary heart disease. N.Engl.J.Med. 1989; 321:641-646.
  6. Manson JE, Colditz GA, Stampfer MJ, Willett WC, Rosner B, Monson RR, et al. Prospective study of obesity and risk for coronary heart disease in women. N.Engl.J.Med. 1990; 322:882-890.
  7. Hulley S, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. J.Am.Med.Assoc. 1998; 280:605-613.
  8. Coronary Drug Project Research Group. Coronary drug project: initial findings leading to modifications of its research protocol. J.Am.Med.Assoc. 1970; 214:1303-1313.
  9. Coronary Drug Project Research Group. Coronary drug project: findings leading to the discontinuation of the 2.5 mg/day estrogen group. J.Am.Med.Assoc. 1973; 226:652-657.
  10. Coulam CB, Annegers JF, Kranz JS. Chronic anovulation syndrome and associated neoplasia. Obstet.Gynecol. 1983; 61:403-407.
  11. Cowan LD, Gordis L, Tonascia JA, Jones GE. Breast cancer incidence in women with a history of progesterone deficiency. Am.J.Epidemiol. 1981; 114:209-214.
  12. Chang KJ, Lee TTY, Linares-Cruz G, Fournier S, de Lignieres B. Influence of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo. Fertil.Steril. 1995; 63:785-791.
  13. Fugere P, Scheele WH, Srikanth KR, Anglin G, Strack TR, Nauden AB, et al. Raloxifene does not stimulate the uterus in postmenopausal women as compared to continuous combined hormone replacement therapy following 24 months of treatment. Fertil Steril 1999; 72:S182-S182 Abstract.
  14. DiSaia PJ. Hormone-replacement therapy in patients with breast cancer. A reappraisal. Cancer 1993; 71:1490-1500.
  15. Prince RL, Smith M, Dirk IM, Price RI, Webb PC, Henderson NK, et al. Prevention of postmenopausal osteoporosis: a comparative study of exercise, calcium supplementation, and hormone-replacement therapy. N.Engl.J.Med. 1991; 325:1189-1195.
  16. Paterson MEL. A randomized double-blind cross-over trial into the effect of norethisterone on climacteric symptoms and biochemical profiles. Br.J.Obstet.Gynaecol. 1982; 89:464-472.
  17. Prior JC. Progesterone as a bone-trophic hormone. Endocr.Rev. 1990; 11:386-398.
  18. Barrett-Connor E, Wenger NK, Grady D, Mosca L, Collins P, Kornitzer M, et al. Hormone and nonhormone therapy for the maintenance of postmenopausal health: the need for randomized controlled trials of estrogen and raloxifene. J.Women’s Health 1998; 7:839-846.
  19. Delmas PD, Bjarnason NH, Mitlak BH, Ravoux A-C, Shah AS, Huster WJ, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. New England Journal of Medicine 1997; 337:1641-1647.
  20. Draper MW, Flowers DE, Huster WJ, Neild JA, Harper KD, Arnaud CD. A controlled trial of raloxifene (LY139481) HCL: impact on bone turnover and serum lipid profile in healthy postmenopausal women. J Bone and Mineral Research 1996; 11:835v840.
  21. Khovidhunkit W, Shoback DM. Clinical effects of raloxifene hydrochloride in women. Ann.Int.Med. 1999; 130:431-439.
  22. Khovidhunkit W, Shoback DM. Clinical effects of raloxifene hydrochloride in women. Ann.Int.Med. 1999; 130:431-439.
  23. Clarkson TB, Anthony MS, Jerome CP. Lack of effect of raloxifene on coronary artery atherosclerosis of postmenopausal monkeys. J.Clin.Endocr.Metab. 1998; 83:721-726.

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