Osteoporosis drug reduces women's risk of mild cognitive impairment

A drug prescribed for the prevention of osteoporosis reduced women's risk of mild cognitive impairment by 33 percent in a worldwide clinical trial led by researchers at San Francisco VA Medical Center (SFVAMC).

The drug, raloxifene, modulates the activity of the hormone estrogen. The finding was published in the April 2005 issue of the American Journal of Psychiatry.

Mild cognitive impairment (MCI) affects more than one-third of women and one-fifth of men aged 65 and older. It reduces short-term memory and is associated with a significantly increased risk of Alzheimer's disease.

"No other intervention has been proven to reduce the risk of mild cognitive impairment," says Kristine Yaffe, MD, the principal investigator of the trial. Yaffe is UCSF associate professor of psychiatry, neurology and epidemiology and chief of geriatric psychiatry at SFVAMC.

Raloxifene is one of the most broadly prescribed drugs for the treatment of osteoporosis (it is also used to treat breast cancer). It is manufactured by Eli Lilly, which sponsored the trial, called the Multiple Outcomes of Raloxifene Evaluation (MORE).

In the MORE trial, which took place at 180 clinical sites in 25 countries, 7,705 postmenopausal women with osteoporosis were randomly assigned to take a daily dose of either 120 milligrams of raloxifene, 60 milligrams of raloxifene, or a placebo for three years. Participants at 161 sites -- 7,023 women -- were measured for cognitive impairment at the beginning of the study and every year thereafter; cognitively impaired women were kept in the study.

Over the course of the trial, 1,637 women dropped out. At the end of the study, the remaining 5,386 were evaluated for dementia. In those women, the 120 milligram dose conferred a 33 percent lower risk of developing mild cognitive impairment when compared with the 60 milligram dose and with placebo. The 60 milligram dose offered no apparent prevention of cognitive impairment. While researchers also observed a reduced risk of developing Alzheimer's disease, that reduction was of borderline statistical significance.

Like all drugs in its class, known as selective estrogen receptor modulators, raloxifene acts like an estrogen in some tissues and as an antiestrogen in others. The authors were unable from this study to determine the mechanism of action responsible for their finding, and whether the effect was due to the drug acting like an estrogen or an antiestrogen in the brain. However, they wrote, given that other studies have shown that estrogen reduces the risk of Alzheimer's disease and cognitive impairment, it is most likely that raloxifene has an estrogen-like effect on the central nervous system. According to Yaffe, it is probable that because the preventive effect involves estrogen, a female hormone, the results of the study do not apply to men; however, the study has no data to support this.

People with MCI tend to retain critical thinking and reasoning skills, but experience significant short-term memory loss. For example, they may experience trouble remembering the names of people they meet or the flow of a conversation, or have an increased tendency to misplace things. Researchers said MCI is associated with a significantly higher-than-normal risk of developing Alzheimer's disease and other forms of dementia: about 1 percent per year for unimpaired people versus 10 to 15 percent for those with MCI. For this reason, says Yaffe, it is important that additional studies should be conducted on the potential of raloxifene and other selective estrogen receptor modulators to prevent cognitive impairment, particularly in women at high risk.

The MORE trial's primary objective was to determine the appropriate dose of raloxifene needed to prevent bone fractures and maintain mineral bone density. A secondary objective was to evaluate the drug's effectiveness in preventing cognitive impairment. The 5,386 women who were screened for dementia completed the 15-item Geriatric Depression scale and six cognitive tests at the beginning of the trial and once a year during the trial. Their scores at the end were compared to their baseline scores, and women suspected of cognitive impairment or the more-serious cognitive problem of dementia were evaluated by clinical experts and referred for further treatment. Those with dementia were also given brain scans with computerized tomography or magnetic resonance imaging to aid in their diagnosis and treatment.

In future research, Yaffe plans to look at other selective estrogen receptor modulators and their effect on cognition, and to investigate whether raloxifene may reduce cognitive impairment among women at high risk.