April 19, 2011 (Auckland, New Zealand) — 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 (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
"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 Clarke (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."
Clarke 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."
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 (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 |
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 Clarke (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."
Clarke 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."
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