|
CATIE News - Concerns about calcium supplements
22 Sep 2011 - Calcium is an important mineral used for building bones and is needed by muscles, nerves and many
other tissues to help them function properly. Generally, bones reach their largest and thickest size in early adulthood. After this, they
slowly become thinner. In women, bone thinning accelerates around the age of menopause; sometimes as much as 2% of bone mass is lost
each year for up to 14 years after the onset of menopause.
Adults require between 1,000 and 1,200 mg of calcium each day. If the body does not get enough calcium from food, a calcium
deficit occurs and the body is forced to remove calcium from bones so that other tissues can use it. If this calcium deficit continues
over a period of years, bones gradually become thinner (osteopenia), and in some cases they become severely thin (osteoporosis).
Having osteoporosis makes bones fragile and prone to breaking when falls or accidents occur.
Not everyone can achieve the daily requirement of calcium, so supplementation with this mineral is sometimes necessary. Since
vitamin D deficiency is common, supplemental vitamin D may also be necessary, as this enhances the absorption of calcium and phosphorus
(another mineral), which is also necessary for bone health.
In 2008 a team of researchers in New Zealand suggested that the use of calcium supplements might increase the risk of heart
attacks in healthy older women (average age: 74 years). They made this claim based on the results of a randomized clinical trial that
was primarily designed to assess the impact of calcium supplementation on bone mineral density and subsequent fractures in 1,471 women
who had already undergone menopause.
Although the trial was designed to assess changes in bone mineral density and fractures, the New Zealand team later decided
to re-assess the trial's data to see if calcium supplementation was associated with an increased risk for heart attacks. Doing such a
reanalysis-taking data from a trial designed for one purpose and then using this data for another purpose-is fraught with risk because
conclusions derived such an analysis can be skewed due to many factors. Therefore, interpretations reached from such re-analyses are
very limited in their robustness and can never be definitive.
Nonetheless, the conclusions arrived at by the New Zealand team have caused some doctors, researchers, bone societies and agencies
as well as members of the public to question the safety of calcium supplementation. Since the New Zealand team's conclusions are not
definitive, heated debate and confusion has erupted over its findings.
Bone thinning appears to be a problem in some people who have HIV infection and in those who are exposed to certain anti-HIV
drugs-so calcium supplementation may be necessary. Therefore, it is worth critically examining the methods used by the New Zealand team
to help readers understand the perceived strength of its claims and what further courses of action are necessary.
Initial reanalysis
In 2008 the New Zealand team, led by professor Ian Reid, used data from a five-year randomized controlled trial of calcium
supplementation (taken at a dose of 1 gram per day) designed to assess changes in bone density and fracture. The team reanalyzed the
data, looking specifically for cardiovascular events and outcomes such as these:
- death
- sudden death
- heart attack
- chest pain
- stroke
- mini-stroke
The participants were 1,471 healthy women who had undergone menopause.
Based on reports of heart attacks (and other events) by patients, there was a statistically significant increased link between
the use of calcium and subsequent heart attacks.
Flaws in the re-analysis
A critical reading of the re-analysis by an Australian research team with a solid understanding of statistics, nutrition and
cardiology has found flaws undermining the claims made by the New Zealand researchers, as indeed have leading researchers in several
other countries. The Australian team notes that after verifying the patient reports by examining hospital records and noticing
additional reports of heart attack unreported by patients but captured in hospital databases and further statistical analysis,
neither heart attacks nor any of the events listed above were statistically significantly linked to calcium intake.
Another attempt with some odd findings
In 2010 the New Zealand team conducted a review of 11,000 publications, examined 190 of them and then selected 28 research papers
that reported on 15 studies with 8,151 men and women. They used the data from these 15 studies to conduct a meta-analysis. This type of
analysis combines related studies and is a statistical tool used to assess the strength of a relationship-in this case, between calcium
and cardiovascular outcomes; a meta-analysis is not an actual study.
In its meta-analysis, the research team found that only participants whose calcium from the diet exceeded 805 mg per day and who
took supplemental calcium were at heightened risk of a heart attack.
What was odd about the meta-analysis findings was that the risk of a heart attack did not increase when very high rates of calcium
supplementation were used (compared to lower doses of calcium). Furthermore, there were no statistically significant effects of calcium
supplementation on outcomes such as stroke, sudden death and other events suggestive of cardiovascular complications.
Moreover, there are other issues with the methods used by the New Zealand team that render its conclusions problematic. To delve
deeply into the details of these problems is beyond the scope of our report, so we will cover key points that have been raised by
scientists who have investigated and critically analysed the New Zealand team's work.
An issue of design
None of the clinical trials used in the meta-analysis were primarily designed to assess cardiovascular events-heart attack, stroke
and so on. This is an important point. Therefore, these trials cannot be reasonably used to extract firm conclusions about the effect of
calcium on heart attacks and related events.
Imbalances
Although all of the studies used for the meta-analysis were randomized, by itself randomization does not eliminate factors or
personal characteristics of participants (such as obesity, smoking and so on) that could lead to biased interpretation of results.
Randomization is merely a tool that helps to reduce the likelihood of imbalances in how such factors are distributed among a
study's volunteers.
For example, randomizing volunteers before a trial begins into two groups where one will receive calcium supplementation and the
other will receive placebo should result in people having risk factors for heart attacks being roughly evenly distributed or balanced
between the two groups.
However, in the case of the New Zealand data, a critical review by researchers not involved with the study found that the study
groups (calcium vs. placebo) were imbalanced. Specifically, the reviewers found that people who were given calcium tended to have risk
factors for cardiovascular disease compared to people who did not receive calcium. This imbalance or difference in the distribution
of cardiovascular risk factors was statistically significant. These imbalances were not adequately adjusted for by the New Zealand
researchers when they tried to interpret the data. Therefore, the possibility arises that the team's conclusions were
inadvertently biased. That is, the connection apparently found between calcium supplementation and heart attacks is a false one.
Quality
The many methods of confirming an outcome, such as a heart attack, in the New Zealand team's studies is another source of problems.
The researchers relied a great deal on patients reporting if they did or did not have a heart attack or were hospitalized. This use of
self-reported data generally does not produce high-quality conclusions. Indeed, other studies have found that relying on self-reports
of heart attack is not reliable. An example of this unreliability is that in the 2008 reanalysis, 45 heart attacks were reported by
patients but medical evidence for only 31 heart attacks could be found. There are additional problems (mostly statistical) related
to the self-reporting of heart attacks that we will not detail.
Calcium as a possible cause of heart attacks
Another issue with the New Zealanders' work is that they claim that taking calcium supplements in the studies they re-analyzed
likely led to a large and unnatural increase in the concentration of calcium in the blood. This large and unnatural increase somehow
predisposes some people to develop a heart attack. There is currently no evidence to support such a claim.
Most of the studies re-analysed by the New Zealand team used a formulation called calcium carbonate in doses of between 600 and
1,200 mg per day. At these doses, calcium carbonate has not been shown to damage cells in people.
Increasingly, calcium is taken with vitamin D, as this vitamin helps the body absorb calcium. A subsequent review by the New
Zealand team of people who took vitamin D with or without supplementary calcium found that vitamin D might reduce cardiovascular
outcomes and that calcium had minimal and non-significant effects on outcomes such as heart attack.
Timing
A strange finding from the New Zealand reanalysis is that if calcium were somehow linked to heart problems, such problems tend
to occur within the first year of supplementation but not afterward. This does not make biological sense and therefore weakens the case
for calcium causing harm.
A look at the real world
In many high-income countries there has been an increase in the use of calcium supplementation in the past 20 years. However,
a review of heart attack data collected in one high-income country, Australia, suggests that the rising use of calcium supplements has
not been linked to rising rates of heart attacks in the average person. Instead, what the review found was that heart attack rates
have been falling.
Taken together, a critical examination of several important problems associated with the New Zealand reanalysis suggests that
the team's conclusions are hardly robust. Yet, despite its questionable methods, it may be plausible that the New Zealand team could have
found a signal of harm that needs investigation. Until well-designed clinical trials can resolve this issue, approaches that balance the
need for calcium against the remote plausibility of its cardiovascular risk may be needed to help guide decisions by doctors and their
patients. Canada's leading bone health organization, Osteoporosis Canada has taken such an approach, which we explain below.
What to do?
The New Zealand data have underscored an issue that nutritionists and dieticians have been repeating for several years: It is best
to get your nutrients from food rather than supplements. In food, nutrients are available in forms that the body can easily digest and is used
to. However, not everyone can obtain their daily requirement of calcium from food.
Osteoporosis Canada has a commonsense approach as well as a
handy guide to helping people easily assess the amount of calcium in common foods.
Osteoporosis Canada has stated that in spite of the New Zealand data people should not stop taking calcium supplements. However,
the organization prefers that people obtain their daily calcium intake from food "whenever possible." This organization discourages the
use of "high doses of calcium supplements (1,000 mg/day)" by people, particularly post-menopausal women, who do not need extra calcium
or who need just a modest amount of calcium. Osteoporosis Canada also says that people who are not able to meet their calcium needs
from food may use "low-dose supplements" containing either calcium carbonate or calcium citrate. Perhaps most importantly of all,
Osteoporosis Canada encourages people to discuss their need for calcium supplements with their physicians. This is particularly
excellent advice as each person's cardiovascular risk is different.
These approaches by Osteoporosis Canada are entirely reasonable and reduce the risk of possible harm that might arise from
excessive calcium supplementation while still helping people get the calcium they need to keep bones healthy. Hopefully, a large
funding agency such as the American National Institutes of Health (NIH) will conduct a well-designed clinical trial to provide
clear and firm conclusions about calcium supplementation and cardiovascular health.
A final word
To build and maintain healthy bones the body requires several nutrients and exercise. In the case of a chronic inflammatory
condition such as HIV, relying just on calcium and vitamin D intake for optimal bone health-particularly in people who have been
diagnosed with osteopenia or osteoporosis-is not optimal. In cases of osteopenia and osteoporosis, prescription medicines are
available to increase bone density and reduce the risk of fractures.
For further information about nutrients for bone health see CATIE's A Practical Guide to Nutrition for People Living with HIV .
-Sean R. Hosein
REFERENCES:
- Meier C, Kränzlin M. Calcium supplementation, osteoporosis and cardiovascular disease. Swiss Medical Weekly . 2011 Aug 31;141:w13260.
- Lewis JR, Calver J, Zhu K, et al. Calcium supplementation and the risks of atherosclerotic vascular disease in older women: results of a 5-year RCT and a 4.5-year follow-up. Journal of Bone and Mineral Research . 2011 Jan;26(1):35-41.
- Wilson C. Calcium supplements and osteoporosis: the heart of the matter. Nature reviews. Endocrinology . 2011 May 31;7(7):373.
- Abrahamsen B, Sahota O. Do calcium plus vitamin D supplements increase cardiovascular risk? BMJ . 2011 Apr 19;342:d2080.
- Burckhardt P. Potential negative cardiovascular effects of calcium supplements. Osteoporosis International . 2011 Jun;22(6):1645-7.
- Nordin BE, Lewis JR, Daly RM, et al. The calcium scare-what would Austin Bradford Hill have thought? Osteoporosis International . 2011 Jun 2. [Epub ahead of print].
- Aspray TJ, Francis RM. Calcium and vitamin D supplementation and cardiovascular disease: quo vadis? Maturitas. 2011 Aug;69(4):285-6.
- Reid IR, Mason B, Horne A, et al. Randomized controlled trial of calcium in healthy older women. American Journal of Medicine . 2006 Sep;119(9):777-85.
- Bolland MJ, Barber PA, Doughty RN, et al. Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial. BMJ . 2008 Feb 2;336(7638):262-6.
- Biggs WS. Calcium supplementation: Data were misrepresented. BMJ . 2008 Feb 23;336(7641):404.
- Lappe JM, Heaney RP. Calcium supplementation: results may not be generalisable. BMJ . 2008 Feb 23;336(7641):403.
- Bolland MJ, Grey A, Avenell A, et al. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women's Health Initiative limited access dataset and meta-analysis. BMJ . 2011 Apr 19;342:d2040.
- Prince RL, Zhu K, Lewis JR. Evidence of harm is unconvincing. BMJ . 2011 Jun 7;342:d3541.
- Bolland MJ, Grey A, Reid IR. Calcium supplements and cardiovascular risk. Journal of Bone and Mineral Research . 2011 Apr;26(4):899.
- Lewis JR, Calver J, Zhu, et al. Reply to "Calcium supplements and cardiovascular risk." Journal of Bone Mineral Research . 2011;26(4):900-901.
- Heiss G, Hsia J, Pettinger M, et al. Calcium and heart attacks. No evidence for increased risk. BMJ. 2010 Sep 15;341:c4995.
- Cleland JG, Witte K, Steel S. Calcium supplements in people with osteoporosis. BMJ . 2010 Jul 29;341:c3856.
- Bolland MJ, Avenell A, Baron JA, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ . 2010 Jul 29;341:c3691.
- Tang BM, Nordin BE. Calcium supplementation does not increase mortality. Medical Journal of Australia. 2008 May 5;188(9):547.
- Bolland MJ, Grey AB, Reid IR. Re: Calcium supplementation does not increase mortality. Medical Journal of Australia . 2008 Jul 7;189(1):55.
- Hsia J, Heiss G, Ren H, et al. Calcium/vitamin D supplementation and cardiovascular events. Circulation . 2007 Feb 20;115(7):846-54.
- Osteoporosis Canada. Calcium intake statement . April 2011.
- Osteoporosis Canada. Calcium is good - are calcium supplements bad? May 2011.
- Holick MF. Vitamin D deficiency. New England Journal of Medicine . 2007 Jul 19;357(3):266-81.
- Holick MF, Binkley NC, Hike A, et al. Evaluation, treatment and prevention of vitamin D deficiency: an Endocrine Society Clinical Practice Guideline. Journal of Clinical Endocrinology and Metabolism . 2011 Jul;96(7):1911-30.
- Wang TK, Bolland MJ, van Pelt NC, et al. Relationships between vascular calcification, calcium metabolism, bone density, and fractures. Journal of Bone and Mineral Research. 2010 Dec;25(12):2777-85.
- Sutter JR, McDowell H, Brown WE. Solubility study of calcium hydrogen phosphate. Ion-pair formation. Inorganic Chemistry . 1971;10(8):1638-43.
CATIE-News is written by Sean Hosein, with the collaboration of other members of the
Canadian AIDS Treatment Information Exchange, in Toronto.
From Canadian AIDS Treatment Information Exchange (CATIE). For more information visit CATIE's Information
Network at http://www.catie.ca
Source: CATIE: CANADIAN AIDS TREATMENT INFORMATION EXCHANGE
|
