Calcium and Cardiovascular Risk

Background

Calcium, along with vitamin D, is important for bone health. Low calcium intake is also associated with colon cancer, kidney stones, obesity, and hypertension.¹ Recommendations for calcium intake vary depending on age, gender, menopausal status, and the guideline-promulgating organization. In general, 1000 mg to 1200 mg are recommended daily for most adults.^1-5 However, in North America, the median daily calcium intake is only 600 mg in postmenopausal women.¹ Supplements are recommended to make up the difference.¹ However, recent studies suggest that calcium supplements increase the risk of cardiovascular events, including myocardial infarction (MI).^6-10 Additional negative press comes from a recent United States Preventative Services Task Force (USPSTF) statement that there is not enough evidence to make a recommendation to use calcium supplements to prevent fractures in most adults.¹¹ This article reviews these studies and the new USPSTF recommendation, and puts them into perspective.

Studies

Signals that calcium might be associated with an increase in cardiovascular risk first became evident in large cohorts, such as the Iowa and Boston women’s health studies.⁶ This led Bolland and colleagues to look at calcium’s cardiovascular effects in a secondary analysis of a randomized controlled calcium study.⁶ Women age 55 years or older who had been postmenopausal for at least five years were eligible for inclusion in a randomized placebo-controlled trial of calcium supplementation in New Zealand. Women being treated for osteoporosis and those taking calcium supplements were excluded. Also excluded were women with vitamin D deficiency (25-hydroxyvitamin D level <10 ng/mL), bone disease, cancer, or other major disease. Women were randomized to 400 mg of calcium citrate (Citracal) before breakfast and 600 mg in the evening or identical placebo. Follow-up was provided every six months for five years. A dietary questionnaire was used to ascertain calcium intake from diet. Tablet counts were used to assess compliance. Patients or family members were asked about events (death, MI, chest pain, stroke, TIA) at each visit. Medical records, death certificates, and a national database of hospital admissions were also reviewed to obtain the most accurate data. One thousand four hundred seventy-one women were randomized. There was an increased risk of MI in the calcium group (RR 1.49, 95% CI 0.86 to 2.57). However, this was not statistically significant. Calcium-supplemented patients also had a higher risk of the composite endpoint of MI, stroke, or sudden death (RR 1.21, 95% CI 0.84 to 1.74). Again, the increased risk did not reach statistical significance. Event rates for MI in the calcium and placebo group were 11.1 per 1000 person years and 6.6 per 1000 person years, respectively (p=0.058). Event rates for the composite endpoint were 23.3 per 1000 person years and 16.3 per 1000 person years for the calcium and placebo groups, respectively (p=0.043). This study has several limitations. It was a secondary analysis of a study designed to examine the effect of calcium supplementation on fracture risk and bone mineral density (BMD). There may have been differences in cardiac risk factors between groups that influenced the results and that were not accounted for (e.g., hormone replacement). And there were slightly more current and former smokers in the calcium group. The mean age of study participants was 74 years, so the study findings are not generalizable to a younger population. The study suggests a higher risk of cardiovascular events in older women who take calcium for five years.

The objective of a subsequent meta-analysis was to determine if calcium supplements increase cardiovascular event risk.⁷ The analysis included randomized, placebo-controlled trials of supplemental calcium 500 mg daily or greater in patients over 40 years of age. For inclusion, the studies had to have enrolled 100 or more patients and had to have lasted for over one year. Studies in which vitamin D was given only to the intervention group were excluded. Studies were identified using Medline, Embase, and clinical trial registries. Studies were analyzed separately depending on whether cardiovascular outcomes data were available at the patient-level or trial-level (i.e., summary information from all patients in the trial without details on individual patients). Eleven studies were included in the trial-level analysis. Almost 12,000 patients were included, with a mean follow-up of four years. Most study participants were women. The risk of MI was higher in the calcium group (HR 1.27, CI 1.01 to 1.59, p=0.038). Among patients allocated to calcium supplementation, the risk of MI was higher in patients whose dietary calcium intake was above the median. Five studies were included in the patient-level analysis. Over 8000 patients were included, and median follow-up was 3.6 years. For the calcium group, the hazard ratio for MI was 1.31 (95% CI 1.02 to 1.67, p=0.035). For stroke, the hazard ratio was 1.2 (95% CI 0.96 to 1.5, p=0.11), and for death, it was 1.09 (95% CI 0.96 to 1.23, p=0.18). This analysis suggests that patients who take calcium 500 mg or more daily as a supplement, without supplemental vitamin D, have about a 30% increased risk of MI.⁷

More recently, a large German cohort (n=25,540) was prospectively evaluated for associations between calcium intake and MI, stroke, and cardiovascular mortality.⁸ At enrollment, which occurred between the years 1994 and 1998, the participants were between 35 and 64 years of age. Patients were excluded if they had a previous MI, stroke, or TIA. Patients whose daily caloric intake was extremely low or extremely high were also excluded. Calcium intake was evaluated at baseline using a food frequency questionnaire. Patients were also asked about intake of calcium supplements and multivitamins. Average follow-up was 11 years. Patients who took a calcium supplement, either as calcium only or as part of a multivitamin, had almost twice the MI risk of nonusers (HR 1.86, 95% CI 1.17 to 2.96; HR 2.39 95% CI 1.12 to 5.12 for calcium-only supplement). These data were adjusted for sex; age at enrollment; education; activity; BMI (body mass index); smoking; alcohol use calorie-adjusted dietary calcium intake; vitamin D intake; saturated fat, protein, and caloric intake; hyperlipidemia; diabetes; and NSAID use. Study limitations included use of a single measure at baseline, and reliance on accurate patient recall of dietary and calcium intake. Strengths included large cohort size, prospective design, and long-term follow-up.

A large U.S. cohort study (n=388,229) set out to determine if dietary and supplemental calcium is associated with cardiovascular mortality, specifically total cardiovascular disease death, heart disease death, or cerebrovascular disease death.⁹ The cohort recruited AARP (American Association of Retired Persons) members who were 50 to 71 years of age in 1995 and 1996. Patients completed a baseline questionnaire. Patients were excluded if they had cancer (except nonmelanoma skin cancer), heart disease, stroke, diabetes, or end-stage renal disease. Patients with very high caloric or dietary calcium intake were excluded. Baseline calcium intake was based on a 124-item food questionnaire developed by the National Cancer Institute. The questionnaire also asked about the intake of calcium from calcium supplements and calcium-containing antacids, and use of multivitamins. Follow-up was 12 years. Death was determined using Social Security Administration data. Cause of death was determined by searching the National Death Index Plus. Among men, calcium supplementation of more than 1000 mg per day was associated with increased risk of total cardiovascular disease death (RR 1.20, 95% CI 1.05 to 1.36) and heart disease death (RR 1.19, 95% CI 1.03 to 1.37). Calcium supplements were not associated with increased cardiovascular mortality in women. Dietary calcium intake was not associated with cardiovascular mortality in men or women.

A large Swedish cohort study (n=61,433) looked at the association between calcium intake and all-cause and cardiovascular mortality.¹⁰ The cohort was first recruited in 1987 to 1990 and included women born between 1914 and 1948. Patients responded to questionnaires covering food frequency, lifestyle, and use of calcium supplements and multivitamins. Median follow-up was 19 years. Cause of death was determined using the Swedish cause of death registry. Compared to intakes between 600 and 1000 mg per day, dietary intake above 1400 mg per day was associated with modestly increased all-cause mortality (HR 1.4, 95% CI 1.17 to 1.67), cardiovascular disease death (HR 1.49, 95% CI 1.09 to 2.02), and ischemic heart disease death (HR 2.14, 95% CI 1.48 to 3.09). Furthermore, calcium supplement users with dietary calcium intake above 1400 mg per day had a HR for all-cause mortality of 2.57 (95% CI 1.19 to 5.55). These findings suggest that recommendations for calcium supplementation should be individualized based on dietary calcium intake.

Commentary

Observational data suggest that for every 1000 older adults who take calcium as a supplement for five years, there will be 26 fewer fractures at the expense of 13 more deaths, 10 more strokes, and 14 more MIs.⁷

The mechanism by which calcium supplementation possibly increases cardiovascular risk is unknown. One possible explanation for the studies’ findings is vascular calcification.⁷ Mean baseline age in the Bolland studies was about 73 years.^6,7 In the German cohort, mean age at enrollment was about 50 years.⁸ In the AARP study, mean baseline age was about 62 years.⁹ And in the Swedish cohort, mean age at entry was about 54 years.¹⁰ These patients could have had renal insufficiency that predisposed them to higher calcium levels and vascular calcification. However, myocardial infarction risk increases soon after beginning supplementation, while vascular calcification occurs over years. It has been hypothesized that acutely, calcium supplementation adversely affects blood coagulability or flow.^7,10 Levels of fibroblast growth factor 23 and inflammatory cytokines are also increased by high levels of calcium.¹⁰ Usual dietary calcium intake has not been associated with cardiovascular events [Evidence level B; cohort studies].^8,9 This might be because calcium supplements lead to an acute spike in serum calcium levels, while calcium from foods does not.⁷

These studies don’t prove that calcium supplements increase cardiac risk. Don’t abandon supplements, but make sure that patients aren’t getting more than they need. Assess their dietary calcium intake before recommending a supplement. People typically get about 300 mg of calcium from their diet, not including dairy products.¹² Several foods can provide 300 mg or more of calcium per one cup serving. These include milk (290 mg to 315 mg) and low-fat yogurt (340 mg to 450 mg). For people who wish to avoid dairy products, choices include collard greens (300 mg to 350 mg), calcium-fortified foods (e.g., soy milk [80 mg to 300 mg], cereal [up to 1000 mg], or even fruit juice [225 mg to 300 mg]). Breakfast bars often contain 200 mg to 500 mg. Other significant sources include cheese, canned salmon or sardines with bones, beans, broccoli, cabbage, turnip greens, bok choy, figs, tofu, and almonds. Spinach may be a poor choice due to the high levels of oxalate it contains that bind and decrease absorption of calcium.¹ People with a history of calcium-containing kidney stones should avoid calcium supplements pending urinary biochemical analysis.⁵

The USPSTF now recommends against supplementing with 400 IU of vitamin D per day and up to 1000 mg of calcium per day for fracture prevention in postmenopausal women.¹¹ But this doesn’t mean supplements should be abandoned. It just means that these low doses are probably insufficient for fracture prevention in this population.¹¹ And although the USPSTF states that evidence is inconclusive regarding the ability of higher doses to prevent fractures in anyone, they are not recommending against using higher doses or using supplements for other purposes (e.g., vitamin D for fall prevention).^11,13 Their recommendations do not apply to people with established osteoporosis, vitamin D deficiency, or people in nursing homes.¹¹

Most guidelines suggest calcium and vitamin D intakes higher than those found by the USPSTF to be ineffective for preventing fractures in postmenopausal women. The Institute of Medicine and Health Canada both recommend 1000 mg of calcium per day for women up to age 50, and 1200 mg per day for women over 50.^2,4 The Institute of Medicine, the National Osteoporosis Foundation (NOF), and Health Canada recommend 1000 mg of calcium per day for men up to age 70 years, and 1200 mg per day for men over 70.^2,4,17 The North American Menopause Society follows NOF’s recommendation of 1200 mg per day for women age 50 and older.^5,17 NOF recommends that women under age 50 get 1000 mg of calcium daily.¹⁷ Canadian osteoporosis guidelines recommend 1200 mg per day for people over 50 years of age.³

If people need a calcium supplement to reach their daily goal, suggest splitting the dose (e.g., 250 mg twice daily) to minimize possible spikes in blood levels. Also, don’t forget to ensure adults get vitamin D2 (ergocalciferol) or D3 (cholecalciferol) 800 to 2000 IU daily to maintain adequate levels (i.e., above 30 ng/mL
[75 nmol/L]) and prevent fractures.^2,3,14-17

Levels of Evidence

In accordance with the trend towards Evidence-Based Medicine, we are citing the LEVEL OF EVIDENCE for the statements we publish.

Adapted from Siwek J, et al. How to write an evidence-based clinical review article. Am Fam Physician 2002;65:251-8.

Project Leader in preparation of this PL Detail-Document: Melanie Cupp, Pharm.D., BCPS

References

1. North American Menopause Society. The role of calcium in peri- and postmenopausal women: 2006 position statement of the North American Menopause Society. Menopause 2006;13:862-77.
2. IOM (Institute of Medicine). Dietary reference intakes for calcium and vitamin D. Washington, DC: The National Academies Press; 2011.
3. Papaioannou A, Morin S, Cheung AM, et al. 2010 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada: summary. CMAJ 2010;182:1864-73.
4. Health Canada. Food and nutrition. Dietary reference intakes. Reference values for elements. August 4, 2005. http://www.hc-sc.gc.ca/fn-an/nutrition/reference/table/ref_elements_tbl-eng.php. (Accessed March 19, 2013).
5. North American Menopause Society. Management of osteoporosis in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause 2010;17:25-54.
6. Bolland MJ, Barber PA, Doughty RN, et al. Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial. BMJ 2008;336:262-6.
7. Bolland MJ, Avenell A, Baron JA, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ 2010;341:c3691.
8. Li K, Kaaks R, Linseisen J, Rohrmann S. Associations of dietary calcium intake and calcium supplementation with myocardial infarction and stroke risk and overall cardiovascular mortality in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition study (EPIC-Heidelberg). Heart 2012;98:920-5.
9. Xiao Q, Murphy RA, Houston DK, et al. Dietary and supplemental calcium intake and cardiovascular disease mortality: the National Institutes of Health-AARP diet and health study. JAMA Intern Med 2013 Feb 4:1-8. doi: 10.1001/jamainternmed.2013.328 [Epub ahead of print].
10. Michaelsson K, Melhus H, Warensjo Lemming E, et al. Long term calcium intake and rates of all cause and cardiovascular mortality: community based prospective longitudinal cohort study. BMJ 2013;346:f228. doi: 10.1136/bmj.f228.
11. U.S. Preventive Services Task Force. USPSTF Bulletin. U.S. Preventive Services Task Force issues final recommendation on vitamin D and calcium supplements to prevent fractures. February 26, 2013. http://www.uspreventiveservicestaskforce.org/bulletins/vitdbulletin.pdf. (Accessed March 13, 2013).
12. Skinner ML, Simpson JA, Buchholz AC. Dietary and total calcium intakes are associated with lower percentage total body and truncal fat in young, healthy adults. J Am Coll Nutr 2011;30:484-90.
13. U.S. Preventive Services Task Force Vitamin D supplementation for prevention. February 26, 2013. http://www.uspreventiveservicestaskforce.org/uspstf12/vitamind/vitdchart.pdf. (Accessed March 15, 2013).
14. Chapman IM. Nutritional disorders in the elderly. Med Clin North Am 2006;90:887-907.
15. Bischoff-Ferrari HA, Willett WC, Wong JB, et al. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA 2005;293:2257-64.
16. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011;96:1911-30.
17. National Osteoporosis Foundation. NOF responds to the U.S. preventive Services Task Force recommendations on calcium and vitamin D. February 26, 2013. http://www.nof.org/news/903. (March 17, 2013).

Cite this document as follows: PL Detail-Document, Calcium and Cardiovascular Risk. Pharmacist’s Letter/Prescriber’s Letter. April 2013.

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