Cognitive Decline

Abstract & Commentary

Calcium Plus Vitamin D Supplementation and Cognitive Decline in Women

By Melissa Quick, DO, and David Kiefer, MD, Dr. Quick is PGY-2 Family Medicine Resident, Beth Israel Medical Center, New York, NY. Dr. Quick reports no financial realtionships relevant to this field of study.

Synopsis: Calcium and vitamin D supplementation do not confer any statistically significant benefit compared to placebo in preventing cognitive decline in women aged 65 years and older.

Source: Rossom RC, et al. Calcium and vitamin D supplementation and cognitive impairment in the Women’s Health Initiative. Am Geriatrics Soc 2012;60:2197-2205.

To assess the effects of vitamin D and calcium supplementation on cognitive outcomes in elderly women, researchers performed a post hoc analysis of women who participated in two studies: the Women’s Health Initiative Calcium and Vitamin D Trial (WHICaD) and the WHI Memory Study (WHIMS). Each study — including the author’s post hoc analysis being reviewed — is addressed in turn.

The WHICaD was a randomized, double-blind, placebo-controlled clinical trial designed to evaluate the role of calcium and vitamin D on the incidence of hip fractures and colorectal cancer in postmenopausal women. In the WHICaD, 36,282 postmenopausal women between the ages of 50 and 79 were randomized into two groups: group 1 took 1000 mg of calcium carbonate and 400 international units (IU) of vitamin D3 and group 2 took a placebo.1

The WHIMS was also a randomized, double-blind, placebo-controlled clinical trial in which 4532 cognitively intact, postmenopausal women were divided into two groups: group 1 took daily estrogen plus progesterone and group 2 took a placebo. The objective was to evaluate the effects of supplemental hormones on the incidence of dementia and mild cognitive impairment.2

The authors of the post hoc analysis assessed women who participated in both the WHICaD and WHIMS studies. The aim was to assess whether the supplements administered to women in the WHICaD study (calcium and vitamin D) had a similar effect on their cognitive outcomes as the cognitive benefits from hormone treatment in the WHIMS study. From the combined assessment of these studies, 4143 women aged 65 and older (mean age = 71) without dementia at baseline were randomly assigned either a combined pill containing 1000 mg of calcium carbonate and 400 IU of vitamin D3 (n = 2043) or placebo (n = 2109) and assessed over a mean of 7.8 years for cognitive changes at annual clinical visits. Adherence was assessed annually through structured interviews and weighing the remaining pills.

To measure cognitive change, the authors of the study relied on the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) test to classify the women into three categories: “probable dementia,” “mild cognitive impairment (MCI),” or “cognitively normal.” The study also assessed global cognitive function using the Modified Mini-Mental State Examination (3MSE). A central panel of experts at Wake Forest School of Medicine presided over outcome classifications to assure that outcomes were not due to psychiatric or medical conditions other than dementia.

The study found no significant reduction in the incidence of cognitive impairment (probable dementia or MCI) in the treatment group compared with the placebo group. Specifically, the results indicated that 4.8% of treatment participants (62.2/10,000 person-years) and 5.1% of placebo participants (65.9/10,000 person-years) developed cognitive impairment during the mean follow-up of 7.8 years (hazard ratio, 0.96; 95% confidence interval, 0.72-1.24; P = 0.68). Global cognitive function was highly preserved and statistically indistinguishable across the two groups with 3MSE scores ranging from 95.3 to 96.7. In short, the finding of this study was that calcium and vitamin D supplementation is no more effective than placebo in reducing the incidence of cognitive impairment in women.

Commentary

Cognitive impairment — an umbrella term used to encompass Alzheimer’s disease, vascular dementia, Lewy Body dementia and many other conditions that develop when brain cells malfunction or die — is an increasing public health concern. In the United States, Alzheimer’s disease affects one in eight people aged 65 and older (13% of the population) and nearly half of people 85 and older (45% of the population), and is the sixth-leading cause of death.3 Unfortunately, there are few treatments to slow or stop dementia. Nevertheless, scientists around the world are continuously developing studies to test new treatments — including supplements like calcium and vitamin D — that may alter the course of the disease. Indeed, this study is the first randomized, controlled trial to be published on the effect of calcium and vitamin D on cognitive outcome.

The authors point out that calcium is often taken with vitamin D to improve absorption rates and is commonly prescribed to elderly, postmenopausal women, a population highly susceptible to osteoporosis and hip fractures.4 Though the doses of calcium and vitamin D in this study were selected initially to analyze bone health, no less valuable was the study’s inquiry into the secondary effects of these supplements on cognitive decline in women. Given the disproportionate incidence of Alzheimer’s disease in women — almost two-thirds of Americans with Alzheimer’s are women5 — studies such as this are highly valuable. Furthermore, vitamin D deficiency remains a major public health concern, especially among the elderly.

Of note, the vitamin D dose used in this study was selected in the early 1990s. At that time, the recommended daily intake of calcium and vitamin D to prevent osteoporosis was 800-1200 mg of calcium and 400 IU of vitamin D.6 Current guidelines suggest the same daily dose for calcium (1200 mg for women > 50), but the recommended daily dose for vitamin D has doubled to 800 IU.7,8 Indeed, a 2005 meta-analysis of randomized, controlled studies found that vitamin D levels between 700-800 IU were most effective in preventing fracture.9 Thus, the dosing schedule used in this study was likely too low to have any meaningful impact on the vitamin D levels of participants.

Vitamin D levels are most often measured by clinicians via serum 25-hydroxyvitamin D [25(OH) D]. Vitamin D levels are generally considered “deficient” with a serum concentration of 25(OH) D < 30 nmol/L; “inadequate” with levels between 30-50 nmol/L; “adequate” if between 50-75 nmol/L; and “concerning” if > 125 nmol/L.10,11 Although some debate exists regarding the precise parameters to define deficiency, it is well established that low 25(OH)D levels are commonly found among community-dwelling elderly, irrespective of latitude, and an almost universal finding among institutionalized elderly.12 In addition, some studies support hypovitamin D’s connection with cognitive impairment.13 A gap in the article being reviewed here is that the researchers did not stratify the research participants by serum 25(OH)D.

We know that nutrition is crucial to maintaining good health, and that deficiencies in certain nutrients can degrade health. Recent research reveals that vitamin D, classically viewed as a regulator of calcium and bone metabolism, is also an important agent in the reduction of cellular inflammation and modulation of cell growth and immune function, and works as a neuroprotective agent that may protect against cognitive decline.14,15 Vitamin D receptors have been identified in the human cortex and hippocampus, and their absence has been linked to various types of dementia.16

If vitamin D has so many potential benefits to slow or prevent cognitive decline, why did this study fail to show a significant difference between placebo and treatment groups? We will explore three elements of this study that may have contributed to the equivocal findings.

First, participants from both groups were encouraged to continue taking their own calcium and vitamin D supplements throughout the study. Thus, a woman in the placebo group could have been taking her own supplemental vitamin D and calcium (up to 1000 mg/day of calcium and up to 600 IU/day of vitamin D) equaling or even exceeding the doses administered to the treatment group (1000 mg of calcium and 400 IU of vitamin D). The study data show that more women took their own calcium and vitamin D supplements within the placebo group than in the treatment group (calcium: 56.7% vs 52.2%, P = 0.003; vitamin D: 49.6% vs 45.7%, P = 0.01).

Second, serum vitamin D levels — a measure that enables researchers to assess adherence and determine whether the supplements are in fact improving baseline serum levels — were not checked on all participants. Of course, diet and capacity to absorb calcium and vitamin D vary from one person to the next, and lifestyle differences alter exposure to sunlight (an enormous factor in increasing serum vitamin D levels). These specifics were not overtly addressed in the study. Furthermore, while 25(OH) D levels were measured in a small subsample of each group at the outset of the study (to prove that the women were similar at baseline), the lack of consecutive measurements raises doubt as to whether vitamin D levels in fact changed at all in participants during the course of the study. Ultimately, without confirmation from serum analysis, it is impossible to assess whether supplementation effectively raises vitamin D levels to an “adequate” range.

Finally, one last potential confounding factor contributing to the study’s equivocal results is the possibility that the supplements themselves interacted to cancel each other’s effect. Essentially, research seems to suggest that vitamin D may be beneficial for preventing cognitive decline, and calcium supplementation might contribute to cognitive decline.17,18

Overall, studies on vitamin D levels and cognitive function seem promising. Research demonstrates an association between low levels of 25(OH)D and increased risk of cognitive impairment in older adults.19 Furthermore, some studies demonstrate an inverse relationship between vitamin D levels and cognitive function.20 Thus, increasing the level of vitamin D in our bodies via supplementation could lead to higher levels of 25(OH)D and could prevent cognitive decline.

Calcium is also important for the normal functioning of our brains. Although the majority of our body’s calcium supply resides in our bones and teeth, calcium is also needed to support neuronal functioning.21 Unlike vitamin D, however, higher levels of serum calcium are associated with a quickened rate of cognitive decline and a poorer baseline global cognitive function in the elderly.22 Additionally, as the authors concede, high levels of intraneuronal calcium can lead to cellular dysfunction and brain cell death. Accordingly, supplementation with calcium may actually increase the rate of cognitive decline.

Therefore, we can postulate two relationships between calcium and vitamin D as they relate exclusively to cognitive functioning: 1) increases in calcium might contribute to cognitive decline; and 2) increases in vitamin D might prevent cognitive decline. As noted above, however, the possibility exists that we are negating the effects of these supplements on cognitive decline by administering them together.

Thus, as clinicians, should we recommend these supplements to prevent the development of cognitive decline? In 2011, the Committee to Review Dietary Reference Intakes for Vitamin D and Calcium published a comprehensive review of more than 1000 studies and reports exploring the range of health outcomes, including neuropsychological functioning. This comprehensive review found that the only reliable health effects from calcium and vitamin D are the promotion and maintenance of bone growth.23 Despite this consensus and the equivocal results of this particular study, research like this is crucial to the eventual discovery of a treatment that will prevent or delay Alzheimer’s and cognitive decline.

Further clinical studies hopefully will guide us closer to slowing or stopping the progression of cognitive decline. Until then, although the results of this study do not indicate calcium and vitamin D to prevent cognitive decline, they also do no additional harm. Given the established use of these supplements for other health benefits, calcium and vitamin D overall are useful nutritional supplements for the postmenopausal population.

References

1. Jackson RD, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006;354:669-683.

2. Shumaker SA, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women — The Women’s Health Initiative Memory Study: A randomized controlled trial. JAMA 2003;289:2651-2662.

3. Alzheimer’s Association. 2012 Alzheimer’s Disease Facts and Figures. Alzheim Dementia Volume 8, Issue 2.

4. Chapuy MC, et al. Vitamin D3 and calcium to prevent hip fractures in elderly women. N Engl J Med 1992;327:1637-1642.

5. Alzheimer’s Association, 2012 Alzheimer’s Disease Facts and Figures. Alzheim Dementia Volume 8, Issue 2.

6. Jackson, RD, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006;354:669-683.

7. Dietary Supplement Fact Sheet: Vitamin D. Office of Dietary Supplements: National Institutes of Health. Available at: http://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/Accessed Jan. 21, 2013.

8. Dietary Supplement Fact Sheet: Calcium. Office of Dietary Supplements: National Institutes of Health. Available at: http://ods.od.nih.gov/factsheets/Calcium-HealthProfessional/Accessed Jan. 21, 2013.

9. Bischoff-Ferrari HA, et al. Fracture prevention with vitamin D supplementation: A meta-analysis of randomized controlled trials. JAMA 2005;293:2257-2264

10. Dietary Supplement Fact Sheet: Vitamin D. Office of Dietary Supplements: National Institutes of Health. Available at: http://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/Accessed Jan. 21, 2013.

11. “Vitamin D.” Second National Report on Biochemical Indicators of Diet and Nutrition in the U.S. Population. CDC 2012;172-192.

12. Leif M. Vitamin D and the elderly. Clin Endocrin 2005:62:265-281.

13. Llewellyn DJ, et al. Seruym 25-hydroxyvitamin D concentration and cognitive impairment. J Geriatr Psychiatry Neurol 2009;22: 188-195.

14. Grant WB. Does vitamin D reduce the risk of dementia? J Alzheimers Dis 2009;17:151-159.

15. Dietary Supplement Fact Sheet: Vitamin D. Office of Dietary Supplements: National Institutes of Health. Available at: http://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/Accessed Jan. 21, 2013.

16. Kalueff AV, Tuohimaa P Nuerosteroid hormone vitamin D and its utility in clinical nutrition. Curr Opin Clin Nutr Metab Care 2007;10:12-19.

17. Annweiler C, et al. Vitamin D and cognitive performance in adults: A systematic review. Eur J Neurol 2009;16:1083-1089.

18. Llewellyn DJ, et al. Vitamin D and cognitive impairment in the elderly U.S. population. J Gerontol A Biol Sci Med Sci 2011;66A: 59-65.

19. Annweiler C, et al. Vitamin D and cognitive performance in adults: A systematic review. Eur J Neurol 2009;16:1083-1089.

20. Llewellyn DJ, et al. Vitamin D and cognitive impairment in the elderly U.S. population. J Gerontol A Biol Sci Med Sci 2011;66A: 59-65.

21. Dietary Supplement Fact Sheet: Calcium. Office of Dietary Supplements: National Institutes of Health. Available at: http://ods.od.nih.gov/factsheets/Calcium-HealthProfessional/Accessed Jan. 21, 2013.

22. Schram, MT, et al. Serum calcium and cognitive function in old age. J Am Geriatr Soc 2007;55:1786-1792.

23. Institute of Medicine. 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press.