Cognitive function in relation with bone mass and nutrition: cross-sectional association in postmenopausal women

It is well known that a decline in estrogen is related to bone loss and possibly a loss in cognitive function as well. It has been suggested that bone loss and cognitive decline are co-occurring conditions, likely due to their relationship with estrogen [1, 2]. Recent studies suggest estrogen replacement therapy may benefit cognitive function in postmenopausal women without memory impairment [3]. Other studies report estrogen therapy may benefit women with Alzheimer's disease (AD) [4] or those at risk for AD [5]. Conversely, studies also report estrogen deficiency is not associated with poor cognitive function [6]. These conflicting results could be due to various reasons, including the type of cognitive assessment tool, inclusion (or not) of confounders, degree of cognitive decline, age of the subjects, to name just a few.

Few studies have examined the relationship between cognitive function and bone mineral density (BMD), both as possible markers of cumulative estrogen exposure. Two studies found a positive relationship with total hip BMD [1, 2] and femoral neck BMD [1] and cognitive function in older adults presumably due to higher cumulative exposure to estrogen [1, 2]. Women with osteoporosis were found to have poorer cognitive function (presumably due to lower estrogen exposure) [2]. However, both of these studies used elderly subjects with significant cognitive impairment and/or history of osteoporotic fractures and one of them [1] did not control for physical activity, a significant predictor of both BMD [7] and cognitive function [8].

Both cognitive function and BMD also depend on various nutrients in food. Studies have found elderly people who performed better on cognitive tests had higher intakes of energy, fruits, vegetables, fiber, carbohydrate, protein, B-vitamins, vitamins A and C, calcium, phosphorous and iron [9–11], and overall better healthy diet score [12]. In general, it appears a more balanced diet that contains more vitamins and minerals is associated with better cognitive function. Substantial research in the past decade has focused on the relationship between antioxidants from diet and/or supplements and cognitive function. However, no clear consensus has been reached as to whether taking antioxidant supplements will help preserve cognitive function and prevent the development of dementia. Some studies suggest vitamin E [13, 14], vitamin C [15] and beta-carotene [15, 16] positively benefit cognitive function, while other studies have not found a relationship between vitamin E [16, 17], vitamin C [13, 14, 16–18] or beta-carotene [13, 17, 18] and cognitive function. There is also controversy as to whether particular fats in the diet are beneficial or potentially harmful to cognitive function due to their relation to the development of atherosclerosis, thrombosis, and inflammation of arterial walls [17, 19].

Due to the above inconsistencies and uncertainties in the literature we investigated cognitive function and its relationship with bone, as well as with nutrients from both diet and supplements, in healthy postmenopausal women with either no or mild cognitive impairment. Our research questions were as follows: 1) Does bone mass in various skeletal sites differ by cognitive function among postmenopausal women when controlling for confounders known to impact bone, such as age, height, weight, hours of total activity, alcohol consumption and total energy, sodium and calcium intake? 2) How do various nutrients in the diet relate to cognitive function in postmenopausal women when controlling for the above confounders?

Our results suggest subjects with lower MMSE scores had overall lower bone mass than subjects with higher MMSE scores. MANCOVA results indicated a moderate effect (η² = 0.21), or 21% of generalized variability in BMD from the whole body, all sites of hip, spine and forearm is accounted for by differences in MMSE scores after correcting for subjects' age, height, weight, total activity, alcohol consumption, and total energy, calcium and sodium intake. Unadjusted group means were lower in Group 1 (MMSE score <27.9) for all bone sites except the Ward's triangle (Table 2). However, with the ANCOVA follow-up tests to MANCOVA the group differences for individual bone sites diminished. Several of the confounders had a significant influence on various bone sites, which might have accounted for the diminished significance with ANCOVA. Additionally, stronger statistical significance may have been reached in other bone sites with more subjects in each group.

Our results based on unadjusted means, agree with Yaffe et al, who also found older women with poor cognitive function to have lower total hip BMD [2]. Zhang et al, found elderly men and women with moderate verbal memory impairment (a measure of cognitive function) to also have lower femoral neck BMD [1]. Lui at al [28] in a large prospective cohort study of over 4000 women found those with more rapid total hip bone loss were more likely to have a decline in cognitive function than those who had lower rates of bone loss. It therefore appears based on the above evidence lower levels of cognitive function are associated with lower hip BMD. The above researchers did not measure the whole body, lumbar spine or forearm to assess their relationship with cognitive function. In our study, these bone areas were significantly lower in subjects with lower MMSE scores although the statistical significance slightly diminished after the univariate follow-up tests.

We attribute the diminished difference between the groups to several factors. First, the average score on the MMSE in our subjects was 27.9, which is considered normal cognitive function [24], indicating on average our subjects were not cognitively impaired. Group 1 (MMSE score of <27.9) had only 34 subjects, and 10 of them had a score of 27, which is considered normal. Therefore out of 97 subjects only 24 had a MMSE score between 22–26 (mild cognitive impairment), and 73 were in the normal range for cognition. If there were more subjects with mild cognitive impairment, stronger significant group differences may have been reached even after the correction tests. Second, subjects in Group 1 had significantly lower weight than those in Group 2. Lower weight is associated with lower bone mass [27, 29]. In this data set weight was a stronger predictor for BMD than MMSE score, and when entered as a co-variate in MANCOVA, statistical significance was diminished in univariate follow-up tests. Third, the MMSE only measures overall cognitive function. Measuring verbal memory specifically, similarly to Zhang et al [1], may have shown a stronger positive relationship with BMD.

Regarding diet, the main finding was that total potassium intake was significantly higher in subjects with normal cognitive function compared to subjects with mild cognitive impairment. When comparing adjusted means, it appears about 300 mg of additional potassium a day may positively benefit cognitive function. MANCOVA results indicated a small effect (η² = 0.07), or about 7% of generalized variability in both potassium and carbohydrate intake was accounted for by differences in MMSE scores after correcting for subjects age, height, weight, total activity, average daily alcohol consumption and vitamins intake. Adjusted means for both potassium and carbohydrate intake were higher in Group 2 (normal cognitive function). It is possible that both carbohydrate and total potassium intake may have served as markers for a diet higher in fruits and vegetables (excellent sources of both carbohydrates and potassium). Such kind of diet may benefit cognitive function in older women. This research supports the findings of other studies, which found older people who consume more of the above foods to have better cognitive function than people who consume less [9–12]. None of the other nutrients in our study examined by MANCOVA were significant predictors of cognitive function.

Saturated fat was a significant negative predictor of MMSE score in multiple regression analysis, which agrees with the findings of Ortega et al [9]. They found elderly people with scores of 28 or higher on the MMSE to have lower intakes of saturated fat. The Rotterdam study found no significant relationship with any type of fat in the diet and risk of dementia or its subtypes in a prospective evaluation in over 5,000 elderly subjects [19]. These subjects had a normal cognition at baseline and the diet was compared with the incidence of a diagnosis of dementia after a mean follow-up of 6 years. However, the researchers did not measure cognitive function in their subjects so it is not known whether milder cases of cognitive decline such as in our study may be related negatively to saturated fat intake.

There are a few limitations to our study. Although some variables were expressed as cumulative averages collected within 2-year period, this is a cross-sectional evaluation with respect of cognitive functioning that was evaluated only once. Therefore all findings have to be taken within that context and within the limitations of cross-sectional study. Education level was not controlled for, which has been found to affect individual scores on the MMSE [24]. However, this study population did report having at least a high school education and many reported having a college education as well. None of the subjects were currently using estrogen but 14 reported past estrogen use for a short time (up to 1 year). The past-estrogen use was not controlled for, however, in our previous analyses, it did not influence BMD or MMSE scores for those individuals [20, 27]. We used two criteria for determining the cut-off levels for MMSE scores on which to stratify subjects into groups. One was the internal criterion (mean for MMSE score of 27.9) and was used for the evaluation of the relationship between BMD and cognition. Another was an external criterion distinguishing normal from cognitively impaired subjects (MMSE score of 27) and was used for the evaluation of the relationship between diet and cognition. We performed all analyses with each cut-off level, and although the results were similar, those based on above described stratification showed slightly higher significance and therefore they are reported.

Our study also has several strengths and is distinct with respect to a comprehensive approach in measuring and evaluating BMD of various skeletal sites, precise identification and inclusion of covariates and analysis of their independent effect on bone and/or cognition, as well as the comprehensive dietary and activity assessment. By using MANCOVA we were able to simultaneously evaluate all measurable skeletal sites and their relationship with MMSE scores and consequently strengthen the overall conclusion. An important issue in this context is possible interaction among age, BMD, cognitive function and dietary intake and physical activity. For example, age alone may be responsible for both the decline in BMD and cognitive function, hence the association between the two. A similar case could be made for dietary intake and physical activity. In order to overcome these effects, all our analyses were performed with taking into account the variables that might interact, be co-linear, and/or independently influence either BMD or cognition. The dietary and activity assessment was a result of a cumulative average over a 2-year period. This provides additional strength to the data and the assurance that both assessments are fairly accurate and representative of subjects' long term intake and activity, not necessarily a case in some other studies.

It appears based on the findings of this study and others, mild degrees of cognitive impairment may be associated with lower levels of BMD specifically in the hip. Lumbar spine and forearm BMD seems to be slightly lower (2–3%) in subjects with lower MMSE scores, based on adjusted means in our study, but clearly more research is needed to determine these relationships. Our findings also indicate a diet containing carbohydrate sources that are also high in potassium such as fruits and vegetables may benefit cognitive function, while saturated fat may influence it negatively. A prudent action (if practical and possible) may be the evaluation of bone status and dietary intake in older women presenting with cognitive impairment, for both potential bone loss and poor diet lacking in good sources of potassium and containing excess amounts of saturated fat.