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Effect of Raloxifene on Prevention of Dementia and Cognitive Impairment in Older Women: The Multiple Outcomes of Raloxifene Evaluation (MORE) Randomized Trial

Background: No therapeutic options have proven effective for the prevention of mild cognitive impairment and dementia in postmenopausal women exist, despite this group being at a very high risk of developing cognitive disorders. Declining estrogen levels following menopause has been proposed to be associated with an increased risk of developing cognitive impairment and dementia.

Objective: The purpose of this study is to determine whether raloxifene will affect the risk of mild cognitive impairment, dementia, or Alzheimer’s disease in postmenopausal women with osteoporosis.

Methods: This was a prospective, parallel, randomized, placebo-controlled study. Exclusion of subject analysis was used to evaluate results. Intent to treat analysis was examined, and the results were determined that there was no statistically significant differences between the two methods of analysis. Details of the study design such as inclusion and exclusion criteria were previously published and not discussed in this article. The participants were between 35 and 80 years old (mean age 66.3 years). Participants were randomly selected to receive raloxifene 60mg daily (1792 patients), raloxifene 120mg daily (1828 patients), or placebo (1766 patients). All patients also received 500mg of calcium supplementation and 400-600 IU of vitamin D daily. The three treatment groups were shown to have comparable baseline characteristics, with no observed statistical differences. Six cognitive tests were administered at baseline and annually throughout the duration of the trail: Short Blessed Test (at two sites, the Buschke Selective Reminding Test was used instead), Trail Making test A &B, Word List memory test, Word List recall test, and Word List fluency test. At the end of three years, those scoring in the worst 10% on the Short Blessed Test or Buschke Selective Reminding Test, along with those that showed manifestations of cognitive impairment were further evaluated. A qualified, blinded clinician then assessed the patient by conducting a patient interview, patient medication history, performing a physical and neurological examination, and administering the Mini-Mental State Examination (MMSE), 30-item Geriatric Depression Scale, Clinical Dementia Rating Scale, and the Hachinski Ischemic Score. Each patient receiving with dementia based on the clinical judgement of the clinician or a MMSE score less than 24 was given either a brain scan, and lab tests (B12, folate, TSH, and fluorescent treponemal antibody). All clinical data collected previously collected was recorded on standardized forms and given to two blinded dementia assessing committee members (the committee was made up of four expert physicians) judged cognitive status of these patients as normal cognitive functioning, mild cognitive impairment, Alzheimer’s Disease, vascular dementia, or other type of dementia. Log linear regression models were used to calculate relative risk and 95% confidence intervals. The primary endpoints for this study were the occurrence rate of mild cognitive impairment, dementia of any type, and Alzheimer’s disease. Relative risks were calculated for both treatment groups relative to the placebo group for each of these primary endpoints. Confidence intervals and corresponding P-values were calculated was well. The secondary endpoints were occurrence of vascular dementia and the risk of developing any cognitive impairment (mild cognitive impairment and dementia combined).

Results: The percent of participants developing mild cognitive impairment was 4.2% in the raloxifene 60mg group [RR 1.18 (95% CI 0.85-1.64, P=0.32)], 2.5% in the raloxifene 120mg group (RR 0.67 (95%CI 0.46 – 0.98 P=0.04)], versus 3.6% in the placebo group. The percent of participants developing Alzheimer’s disease in the raloxifene 60mg/day group was 0.7% [RR 0.82 (95% % CI 0.39-1.71, P=0.60)],0.4% for the raloxifene 120mg/day group [RR 0.52 (95% CI 0.22-1.21, P=0.12)] and 0.9% for the placebo group. The percent of participants developing any type of dementia for the raloxifene 60mg/day group was 1.0% [RR 0.90 (95% CI 0.47-1.74, P=0.76)], 1.0% for the raloxifene 120mg/day group [RR 0.91 (95% CI 0.47-1.76, P=0.78)], and the for the placebo group 1.0%. The percent of participants in the raloxifene 60mg/day group developing any type of cognitive impairment was 5.2% [RR 1.12 (95% CI 0.84-1.49, P=0.45), 3.4% for the raloxifene 120mg/day group [RR 0.73 (95% CI 0.53-1.01, P=0.054)], versus 4.7% for placebo.

Strengths: This was a well designed prospective, randomized controlled study. The clinical evaluators of the participants were appropriately blinded. All tests to evaluate occurrence of dementia were thorough and complete. This assessment of the results of the evaluation was limited to a group of four physicians who were deemed experts in this field. Tests for homogeneity of baseline characteristics were appropriate and thorough.

Weaknesses: The enrollment of subjects was not discussed in this article. The population studied contained largely white postmenopausal women with osteoporosis, and, therefore, the data can only be extrapolated to those groups. The drug manufacturer partially funded the research, which may introduce bias into the study. Power was assessed retrospectively, and not considered prior to conducting the trial. More participants would be needed to generate sufficient power to more appropriately draw clinically relevant conclusions. Since incidence of cognitive impairment increases with age, participants in future trials should all be clustered around advanced age groups.

Conclusions: Little is understood about the mechanism of estrogen or estrogen agonists or antagonists in preventing cognitive impairment or dementia. The use of a mixed agonist/antagonist warrants a trial such as this, but one would have to conduct such a trial utilizing a greater number of participants, and perhaps over a longer period of time to obtain statistically significant, as well as clinically results. This study does demonstrate a possible efficacy in raloxifene 120mg/day in reducing mild cognitive impairment in the studied population. This study lacks the ability to support a recommendation of raloxifene in preventative therapy for cognitive impairment or dementia, but perhaps paves the way toward future trials.

Yaffe K, Krueger K, Cummings S, Blackwell T, et. al. Effect of raloxifene on prevention of dementia and cognitive impairment in older women: the multiple outcomes of raloxifene evaluation (MORE) randomized trial. Am J Psychiatry 2005;162:683-690.

Derek L. Grimm, Pharm.D. Candidate