The designer estrogen drug raloxifene has been prescribed to millions of
postmenopausal women for osteoporosis, but its effects on the aging brain are
unclear. A new study led by a University of California, San Francisco
researcher shows that although raloxifene does not affect the cognitive
performance of most women, it may help prevent decline among women older than
70 and women whose cognitive performance is declining regardless of age.
Raloxifene helped these groups of women to sustain better scores on tests of
attention and verbal memory, according to Kristine Yaffe, MD, chief of
geriatric psychiatry at San Francisco Veterans Affairs Medical Center, and UCSF
assistant professor of psychiatry, neurology and epidemiology.
Over the last several years researchers had learned that raloxifene can work
very much like estrogen on some systems in the body, but have opposite or
anti-estrogen effects on others, Yaffe said. For example, raloxifene, like
estrogen, can strengthen bones and reduce the risk of fractures in
post-menopausal women. But while estrogen suppresses the hot flashes
experienced by women at menopause, raloxifene does not decrease hot flashes and
may occasionally induce them in some women.
While estrogen’s effect on the brain still is unclear, some studies have
suggested that it can help prevent the decline in cognitive function
experienced by many older women. To assess whether raloxifene might have a
similar effect, Yaffe and her colleagues analyzed the cognitive data gathered
during the clinical trial called Multiple Outcomes of Raloxifene Evaluation
(MORE), which showed the drug has beneficial effects on bone and can help
reduce the risk of breast cancer.
“In general, raloxifene didn’t help cognitive function, and it didn’t hurt
either. And that’s reassuring for women given the previous concerns that is
might be acting as an anti-estrogen, causing harm to the brain,” Yaffe said.
In the trial, published in the April 19 issue of the New England Journal of
Medicine, 7,705 post-menopausal women from hospitals and clinics in 25
countries were given daily doses of either raloxifene or a placebo for three
years. All of the women were tested every year with six tests that measured
various cognitive abilities, such as memory, attention, language, orientation,
and visual-spatial skills.
Yaffe and her colleagues were interested in whether, for example, the scores of
women taking placebo might decline more sharply than scores of women taking
For most women in the study, their scores declined little if at all, and
raloxifene did not affect this decline significantly. “This indicates that
raloxifene doesn’t have much of an effect on healthy younger women after
menopause,” Yaffe said
However, she said, the study also suggested that raloxifene did make a
difference for women older than 70, and the subgroup of women whose scores were
declining substantially. Their scores declined less than the placebo group on
two of the tests, which measured attention and verbal memory, suggesting that
raloxifene might offer some protection against cognitive decline for these
Although these results aren’t proof of a benefit, Yaffe said, they fit with
some of the research on estrogen therapy for post-menopausal women, showing
that it gives a small boost on tests of memory and attention. Also, she noted,
“typically the first things affected in the early stages of Alzheimer’s disease
are verbal memory and attention.”
The true test of whether raloxifene or estrogen protects against Alzheimer’s
disease or other types of dementia will be to track the women in the clinical
trials for many more years to see whether one group is more likely to develop
dementia. Yaffe and her colleagues are planning to do just that.
Co-authors on the study included Deborah Grady, MD, MPH, a physician in general
internal medicine at SFVAMC and a UCSF professor of epidemiology and
biostatistics; four researchers from Lilly Research Laboratories, Eli Lilly and
Company: Kathryn Krueger, MD, senior clinical research physician, Somnath
Sarkar, PhD, research scientist, David Cox, PhD, associate medical consultant,
and Thomas Nickelsen, MD, lead clinical research physician; and Elizabeth
Barrett-Connor, MD, professor of family and preventive medicine at University
of California, San Diego.
The study was funded by Eli Lilly and company, which manufactures and sells