Recent research: calcium supps may not be healthy?

[DR_P]

There is a growing body of epidemiological data suggesting that high levels of dietary calcium intake - and in particular high supplemental calcium - may be associated with increased cardiovascular risk and potentially with other diseases as well.

There are several issues to consider when interpreting these research findings:

It's still "just" epidemiological data.
This means, we only get a correlation between factor A (e.g. calcium intake) and factor B (mortality or CVD risk).
What these data do NOT tell us is the causality! For example: what if people suffering from osteoporosis have to take calcium supplements but also cannot move/walk as much as people without osteoporosis, due to bone pain? In that exemplary case, a lesser amount of physical activity would explain higher cardiovascular risk just as well. Who is going to decide whether it was lower physical activity levels OR calcium intake causing higher CVD risk?

Another example: What if a diet rich in calcium (which is usually dairy products) may have poorer levels of cardioprotective compounds or vitamin K-levels?

These two examples show how important it is to control for a huge amount of variables (in particular for known other CVD risk factors) in order to eliminate potential "confounding". But still then, one can control only for known variables/confounders. What if there are confounders that we don't know?

That's why findings from epidemiological studies should always be taken with a grain of salt and why such studies need to be checked for the confounding variables that they have controlled for. That's what we will do and analyze in the subsequent two posts!


On the other hand, these studies provide a basis to generate hypotheses. For example. These findings would allow us to generate the following hypothesis:

"Based on epidemiological data, we hypothesize that dietary (or supplemental dietary) calcium increases risk for cardiovascular events"

In order to test for this hypotheses, prospective, randomized controlled trials with subjects randomly assigned to several groups with and without calcium supplementation would be necessary.
If at study end, individuals in the "high calcium supplement" study arm do indeed suffer from CVD more frequently than the other group(s), then we would have a case against calcium (supplementation).

JAMA Intern Med. 2013 Apr 22;173(8):639-46. doi: 10.1001/jamainternmed.2013.3283.

Dietary and supplemental calcium intake and cardiovascular disease mortality: the National Institutes of Health-AARP diet and health study.


IMPORTANCE: Calcium intake has been promoted because of its proposed benefit on bone health, particularly among the older population. However, concerns have been raised about the potential adverse effect of high calcium intake on cardiovascular health.

OBJECTIVE: To investigate whether intake of dietary and supplemental calcium is associated with mortality from total cardiovascular disease (CVD), heart disease, and cerebrovascular diseases.

DESIGN AND SETTING: Prospective study from 1995 through 1996 in California, Florida, Louisiana, New Jersey, North Carolina, and Pennsylvania and the 2 metropolitan areas of Atlanta, Georgia, and Detroit, Michigan.

PARTICIPANTS: A total of 388 229 men and women aged 50 to 71 years from the National Institutes of Health-AARP Diet and Health Study.

MAIN OUTCOME MEASURES: Dietary and supplemental calcium intake was assessed at baseline (1995-1996). Supplemental calcium intake included calcium from multivitamins and individual calcium supplements. Cardiovascular disease deaths were ascertained using the National Death Index. Multivariate Cox proportional hazards regression models adjusted for demographic, lifestyle, and dietary variables were used to estimate relative risks (RRs) and 95% CIs.

RESULTS: During a mean of 12 years of follow-up, 7904 and 3874 CVD deaths in men and women, respectively, were identified. Supplements containing calcium were used by 51% of men and 70% of women. In men, supplemental calcium intake was associated with an elevated risk of CVD death (RR>1000 vs 0 mg/d, 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, supplemental calcium intake was not associated with CVD death (RR, 1.06; 95% CI, 0.96-1.18), heart disease death (1.05; 0.93-1.18), or cerebrovascular disease death (1.08; 0.87-1.33). Dietary calcium intake was unrelated to CVD death in either men or women.

CONCLUSIONS AND RELEVANCE: Our findings suggest that high intake of supplemental calcium is associated with an excess risk of CVD death in men but not in women. Additional studies are needed to investigate the effect of supplemental calcium use beyond bone health.

[DR_P]

Here is a comment published in JAMA Int. Med. on the above quoted study, which nicely illustrates the potential impact of Vit. K intake on calcium-mediated CVD risk - a potentially crucial confounder for which has apparently not been controlled for:

JAMA Intern Med. 2013 Oct 28;173(19):1841
Dietary and Supplemental Calcium Intake and Mortality
Elke Theuwissen, PhD1; Vladimir Badmaev, MD, PhD2; Cees Vermeer, PhD


To the Editor
In a recent report, Xiao et al1 discuss the outcome of the National Institutes of Health (NIH)–AARP Diet and Health Study, which evaluated the role of calcium intake on cardiovascular health. The outcome of the study revealed that intake of 1000 mg/d of supplemental calcium was associated with significant increase in cardiovascular mortality in men but not in women.

Arterial calcification is an actively regulated process with a key function for the vitamin K–dependent matrix Gla protein (MGP).2 Mature MGP is a powerful inhibitor of soft-tissue calcification and is abundantly expressed by vascular smooth muscle cells. The vitamin K–dependent step in MGP synthesis is the carboxylation of 5 glutamate residues into γ-carboxyglutamate (Gla), which are essential for MGP’s calcification inhibitory activity. In healthy adults, at least 20% of plasma MGP occurs in the uncarboxylated, inactive form. Conformation-specific assays have demonstrated that circulating uncarboxylated MGP has a high predictive value for cardiovascular and overall mortality.2,3 Moreover, several independent population-based studies have shown that dietary vitamin K2 intake is inversely associated with cardiovascular disease and mortality.
Calcium supplements have been widely used for the prevention and treatment of osteoporosis. However, when nutritional vitamin K intake is low, the vitamin K–dependent proteins involved in calcium homeostasis are only partly activated resulting in suboptimal control of tissue mineralization; one of the consequences thereof may be excessive mineralization of the arteries. Recent studies have demonstrated that MGP carboxylation can be improved significantly with supplemental vitamin K2 (menaquinone), thus eliminating uncarboxylated MGP, which is now recognized as an independent risk factor for cardiovascular mortality.4

Although the study by Xiao et al1 indicates that supplemental calcium may adversely affect cardiovascular health in men only, other studies indicate that supplemental calcium intake puts women at cardiovascular risk as well.5 To further underpin the crucial importance of vitamin K in the prevention of arterial calcification, we recommend that vitamin K intake or MGP carboxylation is included as potential confounder when analyzing the association between calcium intake and cardiovascular disease.

Epidemiological findings and clinical intervention studies suggest that guidelines for calcium supplements may have to be revised; the use of calcium and vitamin D supplements clearly increases the calcium load of the body and may need optimal control of calcium homeostasis.

[DR_P]

Now, let's go in detail,which variables have been controlled for in the aformentioned study:

Multivariate models were adjusted for potential confounders, including age, race/ethnicity (non-Hispanic white, non-Hispanic black, or other), educational level (less than high school, high school graduate, some college, or college graduate/postgraduate), marital status (married or not married), self-reported health status (excellent, very good, good, fair, or poor), body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) (<18.5, 18.5-<25, 25-<30, 30-<35, or ≥35), physical activity (never/rarely, ≤3 times per month, or 1, 2, 3, 4, or ≥5 times per week), smoking status (0, 1-10, 11-20, 21-30, 31-40, 41-50, 51-60, or >60 cigarettes per day), smoking dose (0, 1-10, 11-20, 21-30, 31-40, 41-50, 51-60, or >60 cigarettes per day), years since quitting smoking (never quit, ≥10, 5-9, 1-4, or <1 year), and intakes of alcohol, fruit and vegetable, red meat, whole grain, fat, and total energy (continuous).

This is quite good, and it includes levels of physical activity, which could be an extremely important confounder (due to the mutual association between osteoporosis, calcium intake, physical activity levels and CVD risk).

Due to the extremely high number of subjects included in this study (300k) and due to the solid list of confounders that have been controlled for, we may conclude that the suggestive evidence is quite strong for a link between calcium supplementation and CVD risk.
Nonetheless - you can control for only so much potential confounders, and even though the list is quite impressive, there are important variables missing (e.g. e.g. certain vitamin levels) and there may be quite a few unknown confounders we are just not aware of.

In summary, we can conclude that the suggestive evidence for a link between CVD risk and supplemental calcium is quite strong, but there is nonetheless still no proof for a direct causality.

[LegosInMyEgos]

If dietary calcium doesn't influence mortality then the leap of logic arguing vitamin D recommendations might need to be modified really doesn't make sense.

Also, regarding vitamin K.... Its cool that it can add that COOH to glutamate and then two gamma glutamates can form a coordination complex with calcium..... But that sounds like a pretty ridiculous biological mechanism of regulating calcium at broad range of calcium serum blood levels. Calcium is present at ~10 mg/dl, for this method to "buffer" calcium over a broad range, there would need to be hilarious levels of these coordination complexes floating around the blood stream after large calcium intakes.

[DR_P]

You make some good points. However, almost everything in the body - and in particular those critical matters such as electrolytes [inc. calcium] - are regulated by multiple systems. There is no denying that vit k-dependent factors are involved in certain aspects of calcium homeostatis. But that's only one of various other regulating mechanisms.

As for Vitamin D: Vit D is certainly a crucial factor involved in absorption of calcium but Vit D has also plenty of other biological effects, so its "net"-effect on human health cannot not be entirely explained by its action on calcium levels alone.

The examples that you brought up wonderfully demonstrate that biological systems such as human body are far too complex in order to be able to figure out causal relationships between individual external factors (e.g. calcium intake) and disease risk based on mere edpidemiological data. There are too many things we don't know and don't understand, and even the impressive list of confounders used in the JAMA study is probably just a small fraction of factors with relevant influence on the outcome.

If dietary calcium doesn't influence mortality then the leap of logic arguing vitamin D recommendations might need to be modified really doesn't make sense.

Also, regarding vitamin K.... Its cool that it can add that COOH to glutamate and then two gamma glutamates can form a coordination complex with calcium..... But that sounds like a pretty ridiculous biological mechanism of regulating calcium at broad range of calcium serum blood levels. Calcium is present at ~10 mg/dl, for this method to "buffer" calcium over a broad range, there would need to be hilarious levels of these coordination complexes floating around the blood stream after large calcium intakes.

[Synapsin]

Interesting thread.

[Mr.Cooper69]

If dietary calcium doesn't influence mortality then the leap of logic arguing vitamin D recommendations might need to be modified really doesn't make sense.

Also, regarding vitamin K.... Its cool that it can add that COOH to glutamate and then two gamma glutamates can form a coordination complex with calcium..... But that sounds like a pretty ridiculous biological mechanism of regulating calcium at broad range of calcium serum blood levels. Calcium is present at ~10 mg/dl, for this method to "buffer" calcium over a broad range, there would need to be hilarious levels of these coordination complexes floating around the blood stream after large calcium intakes.

The reason vitamin D has been under the spotlight for an increased RDA is due to exactly the opposite of what you're stating. The current RDA was molded around what we thought was its sole role as an aid of calcium absorption. It turns out it is a pleiotropic hormone and deficient levels may bode poorly for a number of endpoints

[VinnyPazRules]

I have hypercalcemia and the drs cant figure out why. had it at least 8 years now. They tell me dietary calcium has very little to do with calcium levels in the body but I avoid it like the plague

[DR_P]

I have hypercalcemia and the drs cant figure out why. had it at least 8 years now. They tell me dietary calcium has very little to do with calcium levels in the body but I avoid it like the plague

Have you got your parathyreoid hormone levels checked?

[nitefeatherz]

Don't just consider osteoporosis...there's also osteopenia. Also- lots of doctors recommend ANY woman take a calcium supplement to PREVENT osteoporosis.

Interesting thought though. I saw another study that said the levels of osteoporosis have decreased steadily since all these fancy "Starbucks" and such type drinks are becoming so popular. They have tons of milk in them. Get a large latte with skim milk- it is half the recommended daily calcium. LOL.

[Mr.Cooper69]

I have hypercalcemia and the drs cant figure out why. had it at least 8 years now. They tell me dietary calcium has very little to do with calcium levels in the body but I avoid it like the plague

Idiopathic cases aren't terribly infrequent, but your doctor is right. Deranged PTH-responses are typically the culprit, though heavy supplementation probably isn't a good idea

Don't just consider osteoporosis...there's also osteopenia. Also- lots of doctors recommend ANY woman take a calcium supplement to PREVENT osteoporosis.

Interesting thought though. I saw another study that said the levels of osteoporosis have decreased steadily since all these fancy "Starbucks" and such type drinks are becoming so popular. They have tons of milk in them. Get a large latte with skim milk- it is half the recommended daily calcium. LOL.

Well lucky for the women in this study, they appear to be somewhat immune to the cardiovascular risk