Calcium and Cardiovascular Risk: The Devil is in the Details

Michaëlsson K, Melhus H, Lemming EW, Wolk A, Byberg L. Long term calcium intake and rates of all cause and cardiovascular mortality: community based prospective longitudinal cohort study. BMJ. 2013;346.

 

Prospective longitudinal cohort study

 

61,433 postmenopausal, Swedish women (born between 1914 and 1948), established as a population-based cohort between 1987 and 1990. Of these, 38,984 participated in a second dietary questionnaire in 1997.

 

Using Swedish cause of death registry data, researchers assessed time to death from all causes, cause-specific cardiovascular disease, ischemic heart disease, and stroke.

 

Based on baseline questionnaire data at the time of study enrollment (1987–1990) participants consuming >1,400 mg/day of calcium from dietary sources had higher rates of all-cause mortality (HR: 1.40; 95% CI: 1.17–1.67), cardiovascular disease mortality (HR: 1.49; 95% CI: 1.09–2.02), and ischemic heart disease mortality (HR: 2.14, 95% CI: 1.48–3.09) when compared to dietary consumption of 600–1,000 mg/day. Among the 6% of participant women using calcium supplements (500 mg/tablet calcium is used as prescription in Sweden), those who were also consuming >1,400 mg/d in their diet had a hazard ratio of 2.57 (95% CI: 1.19–5.55) for all-cause mortality compared to those consuming 600–1,000mg/day. There was also a trend for an increase in all-cause mortality in those consuming less than 600 mg/day of calcium (HR: 1.38; 95% CI: 1.27–1.51). All statistics are derived from the baseline information on diet and supplement use from 1987 to 1990. In 1997, 1/4 of women queried were taking calcium supplements. In this latter survey, there was no association with death from cardiovascular disease or ischemic heart disease with dietary or supplemental calcium at any level of intake.

 

This is the second of 2 studies published in February 2013 suggesting high calcium intake is associated with greater risk of cardiovascular mortality and/or all-cause mortality.¹ These epidemiological studies come on the heels of a 2011 meta-analysis of 11 studies of women taking calcium (>500mg), without vitamin D or magnesium, that suggested there was a 30% increase in myocardial infarctions.² The aim of the following commentary is to assess the current studies, shed light on possible reasons for the observed correlations, and determine what advice we should give our patients now, since clinicians are in a position that necessitates such advice despite the inconclusiveness of the evidence.

 

The current study found that women with the highest dietary intakes (>1,400 mg/day) had greater all-cause mortality, as well as mortality from cardiovascular disease and ischemic heart disease (but not stroke). Of those taking a calcium supplement, only those already consuming >1,400 mg/day in their diet and taking a calcium supplement had an increased risk of all-cause mortality. Therefore, this study suggests that dietary intakes over 1,400 mg/day with or without calcium supplementation is associated with increased risk of all-cause mortality. This is an extremely high dietary intake. Even in Sweden, where dairy intake is high, only 2% of the study population was consuming >1,400 mg/day of calcium through diet.

 

In comparison, US dietary intakes are considerably lower. A recent analysis of the National Health and Nutrition Examination Survey (NHANES) done by the CDC showed that only 32% of Americans achieve the RDA for calcium through diet.³ (Table I) In addition, the combined average intake through diet, supplements, water, and antacids rarely exceeds the Tolerable Upper Limits for any age group, in either gender in the United States. Of particular interest is that the majority of age groups in both genders only achieve recommended daily allowances when a calcium supplement is used. This analysis is corroborated by other studies that have found that many Americans do not ingest the recommended daily allowance for their age group/gender.^4,5 Therefore, extrapolation of data from the highest intake quartile of the Swedish population is likely relevant for a very limited number of US residents.

 

That said, data extracted from the NHANES showed that 17% of women in the >71 year old group were achieving the RDA for calcium through supplementation alone.³ Due to this higher supplementation intake, this age group did have 4% of participants exceeding the Tolerable Upper Limit for total calcium consumption. Clinicians should be aware of this and counsel patients on a more judicious total calcium intake that ensures adequacy of calcium without excess.

 

It should be noted that Michealsson and colleagues report a similar hazard ratio for death from cardiovascular events in the lowest quartile of calcium intake (<600mg/day) as they do for the highest intake. This led to a U-shaped curve, where the least amount of associated risk was in those consuming 600–1,000mg/day of calcium in their diet. Calcium supplementation in those consuming less than 1,400 mg/d through diet was not associated with greater risk, even when the total intake was in excess of 1,400mg/day. For Americans, 600 mg/d is a low intake given the average consumption found in NHANES, but it may be relevant for select populations, such as those avoiding dairy and certain ethnicities.⁶

 

 

Many media outlets ran headlines in March, such as Medscape’s “Trash the Calcium, Save the Patient!” This overreaction was due to Michaelsson’s publication combined with findings of a study published in JAMA Internal Medicine.¹ It was based on data from the National Institutes of Health (NIH)-American Association of Retired Persons (AARP) Diet and Health Study cohort. The participants included 388.229 men and women aged 50 to 71 years who were queried at enrollment in 1995–1996. Calcium supplements included multivitamin/mineral blends, as well as individual supplements. Fifty-one percent of men and 72% of women were taking some form of calcium at enrollment. The study found that “in men, supplemental calcium intake (1,000 mg/d vs. 0 mg/d) was associated with an elevated risk of CVD death (RR: 1.20; 95% CI: 1.05–1.36), more specifically with heart disease death (RR: 1.19; 95% CI: 1.03–1.37) but not significantly with cerebrovascular disease death (RR: 1.14; 95% CI: 0.81–1.61).” In women, there was no association between calcium supplementation and death from cardiovascular disease or cerebrovascular disease.

 

The NIH-AARP Diet and Health Study was originally designed to track supplement use and cancer risk⁷ and has given a plethora of data on that topic over the years. However, it was not designed to assess other diseases in relation to diet and supplement usage. One question not controlled for is the reason 51% of men were taking calcium supplements, considering the fact that osteoporosis is a lesser concern for men than women.

 

 

Of course, nutritional supplement usage is usually self-directed. In addition to the perceived prevention of osteoporosis, calcium is often taken for digestive disturbances. The use of antacids, such as the popular pink tabs of calcium carbonate, may account for the high intake of supplemental calcium in men. The presence of gastric upset or reflux is the most common reason such over-the-counter calcium supplementation would be used. If this is the case, then the study may be reporting a calcium association when in fact the association is with gastroesophageal reflux, a demonstrated risk factor for cardiovascular disease.⁸ Indeed, even the Michaelsson study assumes women were taking calcium for bone health. Given that calcium is a prescription in Sweden, it would not be unusual for practitioners to prescribe calcium carbonate for symptomatic relief of occasional gastric disturbance.

 

It is important to note that the conclusions of the NIH-AARP Diet and Health cohort diverged from Michaelsson’s study. First, unlike the Swedish study there was no association with dietary calcium and death from cardiovascular disease in either gender, even at the highest intakes. Second, there was no association of CVD mortality and calcium supplementation at all in the 72% of women consuming calcium in supplemental form. This finding corroborates the Swedish cohort, where the only women who had increased all-cause mortality were those consuming more than 1,400 mg/day of calcium and taking a supplement.

 

A stunningly curious omission across many studies of calcium intake is the lack of information on magnesium intake. The study reviewed here by Michaelsson and colleagues, while it did track vitamin D and potassium, did not account for magnesium intake. High calcium intake may exacerbate underlying magnesium deficiency through competitive uptake in the gut, as well as increased magnesium excretion in the kidneys. It can be assumed that many of those taking calcium over 50 years of age are doing so for perceived benefit for “bone health.” Unfortunately, magnesium deficiency can also be a causal factor in low bone mineral density.9 Thus, there can be a bias whereby those most likely to self-prescribe calcium for bone health are also those who may have a magnesium deficiency to begin with.

 

There are many physiological reasons that magnesium deficiency may underlie cardiovascular disease and ensuing CVD mortality. Magnesium deficiency is linked to high C-reactive protein, as well as metabolic syndrome.¹⁰ Even in young adults, magnesium intake is inversely correlated to insulin resistance and systemic inflammation.¹¹ Lastly, a 2013 publication showed a statistically significant relationship between lower magnesium intake and death from coronary heart disease in the Nurses’ Health Study Cohort.¹²

 

Calcium intake in excess of the Upper Limits set by the Institute of Medicine may be associated with CVD mortality and/or all cause mortality. Nearly all of the studies suggesting this have been done on calcium alone, without consideration for vitamin D and/or magnesium intake.² It is unclear whether any associated CVD risk is mitigated by simultaneously high magnesium intake, since it has been assessed in only 1 publication. However, in the 1 prospective observational cohort that that did track magnesium intake (men only), calcium intakes in excess of 2,000 mg daily were not associated with death from CVD or all-cause mortality when magnesium intake was also high.¹³ There is ample reason to assume that magnesium has a role in the outcome based on the prevalence of magnesium deficiency in the general population and the physiological role of both minerals.

 

The saying is “the devil is in the details.” Our understanding of calcium’s role in cardiovascular disease still needs clarification. It appears from the study under review in this commentary that the highest and the lowest intakes should be avoided. Total intake of calcium in the range of 600–1,400 appears not only safe, but advisable. Most urgent is an accounting of magnesium intake as well as calcium in ongoing studies.