For postmenopausal women, the decision on whether to take hormone replacement therapy has become a bit more complicated with the advent of a "designer estrogen."
The new medication, raloxifene hydrochloride, was approved in December (under the brand name Evista) specifically for the prevention of osteoporosis. But its possible benefits go beyond the bones--and enhance the health of postmenopausal women in other ways. And that has created a fair bit of excitement--as well as concern.
Raloxifene is among a class of medications called Selective Estrogen Receptor Modulators (SERMs), which are chemicals designed to mimic estrogen when it's beneficial and block estrogen in tissues when it can do harm. Tamoxifen, a drug that has been used since the 1970s in breast cancer treatment, is the best-known SERM. But with the approval of raloxifene, which should be available in pharmacies, enthusiasm for SERMs has skyrocketed--as well as the debate.
Many researchers believe that SERMs carry the benefits of estrogen--such as increasing bone density and reducing some factors that cause heart disease--while avoiding estrogen's risks. Estrogen replacement therapy is known to increase the risk of uterine cancer and may slightly increase the chance of developing breast cancer.
However, others are not convinced that SERMs, such as raloxifene, are a true alternative to estrogen replacement therapy.
"People may be overly exuberant in a premature sort of way," says Dr. Gail Greendale, an associate professor of medicine at UCLA.
"There clearly is a market to try to find a drug that will do all the good things estrogen does but none of the bad. And on one set of assumptions, raloxifene does look good. But we have to be critical," says Trudy Bush, an epidemiologist at the University of Baltimore School of Medicine.
But there is no understating the need for treatments that counteract the rapid health declines most women experience postmenopausally.
Each option--estrogen therapy and raloxifene--appears to have benefits, drawbacks and unknowns. But much less is known about raloxifene at this point.
"Is this a drug that I should be rushing up to my doctor and say, 'Give me this drug'? Doctors do not know," says Dr. Debra R. Judelson, a Beverly Hills internist and immediate past president of the American Medical Women's Assn. "The drug has not percolated through the medical literature enough for physicians to have some confidence level and to know when to offer it."
The medication was approved by the Food and Drug Administration based on two years of study showing that it increased bone density in postmenopausal women. But studies have also shown that raloxifene decreased total cholesterol and low-density cholesterol (the so-called bad kind). Moreover, officials at Eli Lilly & Co. of Indianapolis, which makes Evista, say that the drug appears to have no effect on the breast and may even decrease the risk of breast cancer.
That comment, made at an FDA advisory committee hearing last year, created a stir because the outstanding question surrounding estrogen therapy is that it may increase breast cancer risk.
"That is the area that has raised the greatest interest and the greatest number of questions based on our data to date," says Dr. Will Dere, director of medical research at Lilly.
According to Dere, there are several indications that raloxifene may be safe for women with breast cancer or who are at high risk for the disease.
Animal studies have demonstrated that the drug blocks the harmful effects of estrogen on breast tissue. And, in a small study of women with advanced breast cancer, high doses of raloxifene appeared to halt the disease.
Moreover, two years of studies on healthy women taking raloxifene showed that this group had a 62% decrease in newly diagnosed cases of breast cancer compared with a similar group not taking the medication.
"The data through two years of evaluation should be viewed as enticing but preliminary," Dere says. "It's promising. It's something we need to continue to monitor."
Others agree that there isn't enough data on raloxifene to know what it does or doesn't do.
"It looks like raloxifene halts bone loss and does a little something for lipids--not as much as estrogen, but something. It appears to leave the uterus alone," Greendale says. "The key organ we don't know about yet is the breast. There is a great hope that raloxifene will be breast-sparing and will be a drug that is very useful for women who have had breast cancer or have a high risk."
But doctors need to see published data on raloxifene's effect on the breast, Greendale said. "We really need to know what this breast evidence is. That is the thing that raloxifene will hinge on."
Another question that doctors are eager to see answered concerns the effects of raloxifene on preventing fractures. So far, the drug has only been shown to increase bone density.
"Bone density doesn't always equate to a lower fracture risk," Bush says. "It's hard to say whether it's putting down good bone. If the fracture data on raloxifene look good, we may continue to see enthusiasm for it."
According to Dere, the fracture data on Raloxifene should be released later this year.
Whether raloxifene offers women some protection against heart disease in the postmenopausal years (when heart disease rates in women soar and even surpass that of men) will take longer to answer. Lilly will launch a large, five-year study later this year to assess whether raloxifene reduces the incidence of heart attack and cardiovascular mortality.
"The reason we are very optimistic about this, and why we are starting this lengthy and expensive study, is that the preclinical data on lipid metabolism and blood vessels is very promising," Dere says. "We would not undertake this if we did not think we had a good chance of success."
With so many questions remaining, however, Bush suggests the FDA's decision to put raloxifene on a "fast track" for approval may have been hasty.
"My concern is that any drug to be used in healthy women has to be safer than a drug used in women with a life-threatening disease," she says. "And, with long-term use, we have to show long-term safety. For osteoporosis prevention, we are talking about long-term use."
Women who seek protection against osteoporosis have other choices, including estrogen replacement therapy, Fosamax and calcitonin, she adds.
"I can understand putting a drug on the fast track if there isn't anything else. But that isn't the case here. You have some other drugs, hormonal and nonhormonal," she says.
For many women, the decision to use raloxifene may hinge on how it ultimately compares with estrogen replacement therapy.
Besides alleviating many of the symptoms of menopause, such as vaginal dryness and hot flashes, estrogen has been shown to build bone and prevent fractures, and has many positive effects on the blood that may reduce the risk of cardiovascular disease.
"There are dozens of observational studies in estrogen users that show anywhere from a 50% to 60% reduction in cardiovascular events in users compared to non-users," Greendale says. "People pretty much feel the weight of that evidence is huge. An enormous number of [cardiovascular factors] are affected by estrogen. The only thing we can say confidently about raloxifene is, it did have a beneficial lipid effect. But we can't extrapolate beyond that."
Estrogen therapy has also shown promise in improving skin tone and halting signs of dementia. On the downside, estrogen clearly increases the risk of uterine cancer, although that risk is offset when estrogen is used in combination with progesterone. Finally, there is the unanswered question of whether estrogen increases the risk of breast cancer.
"We have been using hormone replacement therapy for 50 years. We have a lot of experience with it. And I still can't tell you if it increases the risk of breast cancer," Bush says. "That should be reassuring. It should have popped out by now, clearly and consistently."
Nevertheless, the breast cancer risk is one many women simply do not want to take. Other women dislike estrogen therapy because it can cause vaginal bleeding and breast swelling and tenderness. Raloxifene does not cause these symptoms, but, unlike estrogen, it doesn't alleviate hot flashes and may even make them worse.
Despite the many benefits of estrogen therapy, studies show as little as one-fifth of postmenopausal women take estrogen, and even fewer stay on the therapy long enough to accrue certain benefits.
"If women took hormone replacement therapy, that would be easy. But they fear breast cancer or they have unacceptable side effects from HRT," Judelson says.
"Women need options. They are not finding enough options and are turning to a lot of different [alternative] therapies. Raloxifene holds promise for the prevention of osteoporosis. It holds promise for assuaging women regarding a higher risk of breast cancer. But we need to continue post-marketing studies."