Calcium Supplements and CV Events: New Data, More Debate

[Guest guest]

A new, expanded analysis of the cardiovascular risks associated with calcium

supplements [1] suggests that a previously reported 30% risk of MI linked to

calcium supplements alone [2] extends to people who are also taking vitamin

D.

Calcium and vitamin D are taken in combination, as supplements, by millions

of people in the hopes of reducing the risk of fractures, but this strategy

should be reconsidered in the face of evidence pointing to a roughly 20%

increased risk of both MI and stroke in people taking both calcium and

vitamin D, according to *Dr Mark Bolland* (University of Auckland, New

Zealand) and colleagues.

Their new study is published online April 19, 2011 in *BMJ*.

*WHI Study Showed No CV Risk With Calcium, Vitamin D*

A previous meta-analysis by Bolland and colleagues looked only at trials of

patients taking calcium alone compared with placebo, or of people taking

calcium and vitamin D, compared with people taking vitamin D alone. That

paper, as reported by *heartwire * last year, generated a huge amount of

controversy, in part because it was at odds with a Women's Health

Initiative<http://www.clinicaltrials.gov/ct2/show/NCT00000611?term=Women%27s+Hea\

lth+Initiative & rank=5>

* *(WHI) study that showed no adverse cardiovascular effects in women

randomized to this combination of supplements, as compared with those

randomized to placebo.

But as Bolland et al note, women already taking calcium and vitamin D by

personal choice at the start of the WHI study were not told to stop if they

were randomized to placebo, such that 54% of subjects were already taking

their own calcium supplements and 47% were taking vitamin D at the time of

randomization.

In an interview with *heartwire *, *Dr Ian Reid* (University of Auckland),

senior author on the new *BMJ *study, explained that this " unusual " aspect

of the WHI study prompted him and his colleagues to request patient-level

data on baseline supplement use from the *National Institutes of Health*,

which sponsored the WHI, leading to the current analysis.

As they report today in *BMJ*, among the almost 17 000 women *not *taking

personal supplements at the time of randomization, being randomized to new

supplement use was associated with a statistically significant increase in

risk of " clinical MI " (hazard ratio 1.22; p=0.05) and clinical MI and stroke

(hazard ratio 1.16; p=0.05). Among women already taking supplements at

baseline, no such spike in events was seen.

*WHI Added to Meta-Analysis*

Bolland, Reid, and colleagues then added these data from the WHI, as well as

data on concomitant calcium and vitamin-D supplementation from two other

studies they'd excluded in their earlier analysis, to their 12 000-patient

meta-analysis from last year looking at calcium use only, bringing the

sample size up to almost 30 000. All the data, they note, was from

randomized controlled trials.

With the addition of these new numbers, use of calcium or calcium plus

vitamin D significantly increased both the risk of MI and the composite of

MI and stroke in both an analysis of patient-level data and trial-level

data. Risk of stroke was significantly increased in the patient-level data.

*CV Risks of Calcium or Calcium Plus Vitamin D Supplementation*

*End point* *Hazard ratio* *95% CI* *p* *Patient-level data (24 869

patients)* *MI* 1.26 1.07–1.47 0.005 *Stroke* 1.19 1.02–1.39 0.03 *MI

or stroke* 1.17 1.05–1.31 0.005 *Trial-level data (28 072 patients)*

*MI* 1.24 1.07–1.45 0.004 *Stroke* 1.15 1.00–1.32 0.06 *MI or stroke* 1.15

1.03–1.27 0.009

" It seems that the WHI in their first analysis missed this effect because

their sample was so heavily contaminated with people already

self-administering calcium, " Reid told *heartwire *. Moreover, " it is

actually taking a supplement that matters, not how much of it you take, that

causes this increase in heart risk. "

That makes sense, he says, since even small levels of supplemental calcium

create " abrupt " increases in blood calcium levels within hours. This speaks

to one criticism levied at the group's earlier work--namely, that the

cardiovascular events seemed to be occurring too swiftly to be related to

calcified plaques. In fact, Reid told *heartwire *, he and his colleagues

believe that the stroke events may be due to a longer-term process of

calcium accruing in the vessel walls, but that the MI spikes likely reflect

a more acute response to blood calcium levels, including changes in platelet

function, blood coaguability, or endothelial cell activity.

" It's interesting in this new database, which is now two and a half times

bigger than the last one, that we see exactly the same time course for

clinical events, and that makes us think this is real, " Reid said. " What we

find is quite an early effect on heart attack, whereas for stroke, it's

much, much slower and doesn't appear until after year one. "

Vitamin D is enjoying a wave of popularity as a CVD-prevention strategy, an

effect clearly not seen in this analysis. " This doesn't rule out that

possibility [that vitamin D may be protective], but what we're saying here

is that the calcium effect seems to be dominant when you give the two

together, " Reid said.

*Numbers Needed to Harm*

The authors acknowledge that the cardiovascular effects of calcium

supplementation are somewhat " modest " --ranging from 25% to 30% for MI and

15% to 20% for stroke. But given the widespread use of calcium supplements

for the treatment or prevention of osteoporosis, their findings " justify a

reassessment " of the use of supplemental calcium, they say. According to

their calculations, 1000 people taking calcium with or without vitamin D

would cause six additional MIs or strokes (a number needed to harm of 178)

yet prevent only three fractures (a number needed to treat of 302).

Reid believes the findings should prompt physicians and doctors to discuss

the risks and other options for osteoporosis management/prevention. " But

speaking in general, we believe that patients should be encouraged to get

their calcium from their diet, because there isn't any suggestion that

dietary calcium carries these same risks, and not rely on supplements as a

source of calcium. Also, people who have a high risk of fracture should be

looking at taking medications that can safely reduce fracture risk and not

using supplements, which have only a fairly small effect on fracture risk

and appear not to be as safe as other interventions. "

In an accompanying editorial [3], *Dr Bo Abrahamsen* (Gentofte Hospital,

Copenhagen, Denmark) and *Dr Opinder Sahota* (Nottingham University

Hospitals, UK) concede that the evidence linking calcium supplements to CV

risk is strengthened by the new data but point to other studies showing that

use of calcium and vitamin D on top of bisphosphonates for osteoporosis have

in the past been " reassuring " on CV safety.

But as to the CV safety of supplements alone, " because of limitations in the

cardiovascular adjudication or study design of the underlying trials, it is

not possible to provide reassurance that calcium supplements given with

vitamin D do not cause adverse cardiovascular events or to link them with

certainty to increased cardiovascular risk, " write Abrahamsen and Sahota.

" Clearly further studies are needed, and the debate remains ongoing. "

*Dr Bart e* (Mayo Clinic, Rochester, MN), an endocrinologist,

commenting on the results for *heartwire *, agreed that Bolland et al's

latest paper is unlikely to be the " final " word. But he also speculated that

another randomized controlled trial addressing this specific question was

unlikely to take place.

" This does raise the level of concern several notches, " he admitted. " I'm

not sure it's going to change clinical practice in all settings, but it's

going to make us a lot more cautious about recommending standard doses of

calcium and vitamin-D supplementation. "

e says he himself always starts by recommending increased dietary

calcium for patients with osteoporosis and recommends supplements only to

patients who can't get their dietary calcium up. He expects he will be even

more wary about recommending supplements, especially at high levels, but

said, " I don't think I'm personally at the point where I would say patients

should stop taking *all* dietary supplemental calcium based on these

papers. "

www.medscape.com

--

Ortiz, MS, RD

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