Better Health: Smart Health Commentary Better Health (TM): smart health commentary

Article Comments

Calcium Supplements: Good For Your Bones But Bad For Your Heart?

Calcium is good for us, right? Milk products are great sources of calcium, and we’re told to emphasize milk products in our diets. Don’t (or can’t) eat enough dairy? Calcium supplements are very popular, especially among women seeking to minimize their risk of osteoporosis. Osteoporosis prevention and treatment guidelines recommend calcium and vitamin D as an important measure in preserving bone density and reducing the risk of fractures. For those who don’t like dairy products, even products like orange juice and Vitamin Water are fortified with calcium. The general perception seemed to be that calcium consumption was a good thing – the more, the better. Until recently.

In a pattern similar to that I described with folic acid, there’s new safety signals from trials with calcium supplements that are raising concerns. Two studies published in the past two years suggest that calcium supplements are associated with a significantly increased risk of heart attacks. Could the risks of calcium supplements outweigh any benefits they offer?

Why Calcium? Osteoporosis

Osteoporosis is a progressive bone condition of reduced bone mass and deterioration of bone tissue, and a correlating increase in fracture risk. 80% of those diagnosed are women. Hips and spines are the most common fracture locations, but they can appear in any bone, and osteoporosis makes fractures more likely. In postmenopausal women over the age of 50, the lifetime risk of a vertebral fracture is about one in three, and one in five for a hip fracture. Because they are so common, hip and vertebral fractures cause considerable aggregate and individual morbidity and mortality. So prevention and treatment are major health issues.

The initial strategy to preventing and managing osteoporosis is ensuring adequate calcium and vitamin D dietary intake, as both influence bone density. Calcium intake influences overall calcium balance: adequate vitamin D and calcium ensure calcium balance is positive. This occurs at about 1000mg per day in premenopausal women, and 1500mg per day in postmenopausal women not taking estrogen. The North American Menopause Society’s (NAMS) 2006 osteoporosis guidelines recommends [PDF] adequate calcium and vitamin D for all postmenopausal women, regardless of osteoporosis risk factors. The guidelines note that requirements increase with age owing to reduced absorption, and recommending adequate intake (preferably via diet) as the preferred sources. The 2010 Canadian guidelines [PDF] are similar, recommending 1200mg of calcium (diet and supplements) and vitamin D for all individuals over the age of 50. The Institute of Medicine recently updated its calcium and vitamin D guidelines (pdf) as well. It concluded with the caution that the consumption of levels beyond those recommended have not been shown to offer additional health benefits, and may in fact be linked to other health problems.

The effectiveness of calcium and vitamin D for the prevention and treatment of osteoporosis has been studied in both observational and prospective clinical trials. Wile there are data to demonstrate that calcium and vitamin D can prevent bone loss, the data on fracture prevention are much less convincing, with some trials showing no effect. Beyond density effects, calcium is also associated with generally positive effects on muscle strength, balance, and the risk of falls. So for most men and women with (or at risk of) osteoporosis, calcium and vitamin D are standard treatments. Given dietary intake in those at greater risk of osteoporosis may be below recommended levels, supplements are often used to meet recommended amounts.

The Safety Signals

Prior studies of calcium supplements have pointed to a possible relationship between calcium supplementation and cardiovascular events. Bolland et al specifically examined the relationship of calcium with the risk of heart attacks and cardiovascular events in a 2010 BMJ meta-analysis. It included all RCTs of calcium supplements (≥500 mg/day), with a study size of 100 or more participants, an average age over 40, and a duration of more than one year. Trials that included vitamin D as an intervention were excluded. 15 trials were identified: some with patient-level data, and some with trial level data. Analyses of both sets of data identified a significant increase in heart attacks in those randomized to calcium supplements. The trial-level analysis show a hazard ratio (pdf) of 1.27 with a 95% confidence interval of 1.01 to 1.59 (p=0.038). The patient level analysis revealed a similar hazard ratio for myocardial infarction of 1.31 (95% confidence interval 1.02 to 1.67, p=0.035). Overall, the analysis suggests that calcium supplements increase the relative risk of myocardial infarction by about 30%. Reassuringly, there were no statistically significant increases in the risk of stroke, death, or the composite endpoint of MI+stroke+death in either analysis. Based on the patient-level data, the authors estimated that treating 69 people with calcium for five years will cause one additional heart attack. The authors suggested that in light of calcium’s unimpressive efficacy against fractures, that calcium’s role in osteoporosis prevention and treatment should be reevaluated.

Time to stop the calcium? As noted above, the data to support the use of calcium supplements alone to prevent fractures are, on balance, unimpressive. And there are possible models for how calcium could be causing these harms: vascular calcification is a potential (though not proven) consequence that might be more likely in the elderly patients. However, given calcification can take years, and harms appear shortly after dosing starts, it could be a due to effects on carotid plaque thickness, leading to aortic calcificiation, and subsequent cardiovascular events. (Reid describes potential mechanisms for these harms in a2010 paper in Clinical Endocrinology.)

What happened after this paper was released? There were criticisms of the endpoints, and the fact the composite endpoint was not significant. Concerns were also raised that the trials included were not designed with cardiovascular endpoints – a valid criticism. And many pointed to the fact the studies excluded vitamin D, contrary to treatment guidelines and common use. Now the same group has done a new analysis, incorporating vitamin D. Bolland and associates followed up their calcium-only therapy with a study of calcium + vitamin D. They used the Women’s Health Initiative (WHI) dataset to answer the vitamin D question, added in some other studies, and redid their meta-analysis.

The WHI was a massive 15-year trial of over 161,000 women that sought to answer a number of questions about women’s health. The most well known components were the hormone therapy trials which changed our understanding of the risks and benefits of hormone treatments. The calcium and vitamin D study was a component of the WHI which randomized 36,282 postmenopausal women aged 50-79 into two groups. One group received 1,000 mg of calcium carbonate and 400 UI of vitamin D once daily, the other, placebos. Interesting in the design was that 54% of women were already taking calcium, and 47% were already taking vitamin D, and they were allowed to continue with their therapy, even after randomization. This meant that actual calcium and vitamin D doses women consumed varied from zero to substantially more than the intervention dose. The clinical question the study sought to answer was to understand the effects on fracture risk and the prevention of colorectal cancer — and the results were disappointing: no effects on colorectal cancer, and insignificant effects on fractures (though in a subgroup analysis of compliant patients, significant reductions in hip fractures were noted.)

Bolland sought to analyze the WHI data for cardiovascular effects, and then add these data into the previous meta-analysis. In the over 16,000 women not taking their own calcium and vitamin D, there was a significant increase (hazard ratio 1.22) in myocardial infarction noted in the group randomized to calcium and vitamin D (p=0.04, 95% CI 1.00 to 1.50). Similarly, significant effects were also noted in other composite endpoints. In contrast, women taking their own calcium and vitamin D didn’t show any changes in their cardiovascular risk when randomized to calcium and vitamin D. In addition, no relationship was found between calcium dose and risk of cardiovascular events.

The authors then pooled their own WHI analysis with two other studies of calcium and vitamin D where trial-level data for cardiovascular events were available: In total, over 20,000 participants could be studied. In this pooled analysis, calcium and vitamin D were associated with a significant increases in myocardial infarction (relative risk 1.21), stroke (RR 1.20) and a composite endpoint of both (RR 1.16).

Finally the authors combined the trial level data from their calcium-only meta-analysis with their trial level calcium plus vitamin D data:, resulting in a pool of over 28,000 patients across nine trials. In this analysis, there was risk increase of 1.24 (95% confidence interval 1.07-1.45, P=0.004) for myocardial infarction and 1.15 for the combined endpoint (1.03-1.27, P=0.009).

Difficult to interpret? Yep. The lack of effect of “personal” use of calcium on endpoints, and the lack of dose response, means this isn’t case closed for the clinical question. But the persistent and significant correlation between randomization to calcium, with or without vitamin D, and myocardial infarction, does concern me. There are a number of additional criticisms outlined in the editorial that accompanied the Bolland WHI analysis, and the keen reader is referred there for more.

Evaluation

Is it possible that calcium supplements can be causing harms that could outweigh their benefits? Yes, but the evidence isn’t clear enough to give an definitive answer. These data need to be factored into individual evaluations of diet as well as risk factors for cardiovascular disease and osteoporosis. I’d like to see these findings validated by other groups, as both meta-analyses came from the same group of researchers. The meta-analysis can be a very useful tool, but it’s not without its own limitations, as is often pointed out by the contributors to this blog. Interestingly, a 2010 meta-analysis, from a different group of authors, and using a different methodology, has come to a different evaluation of calcium. So the question remains an open one. More data may help refine our estimates of number needed to treat, and number needed to harm, to inform treatment decisions. And it should help guide advice for younger, premenopausal women, as well as men. So until more data emerges, my tentative recommendations to consumers are as follows:

  • Calcium supplementation has been associated with increased risks of cardiovascular events like heart attacks. Until there is more evidence to confirm or refute this association, it’s prudent to be cautious when taking calcium supplements.
  • No harms have been shown from calcium consumption via dietary sources. Efforts should be made to first meet dietary requirements through food products, before considering supplements.
  • Routine supplementation, in the absence of a dietary deficiency, is not necessary or advisable.
  • Calcium supplements may still be advisable for those with low dietary intakes, or those at risk of or being treated for osteoporosis. The risk-benefit assessment for calcium supplements needs to consider risk factors for both osteoporosis and for cardiovascular disease.
  • Vitamin D supplements are advisable for most people, and are recommended for the prevention and treatment of osteoporosis. The suggested doses of calcium and vitamin D may vary based on diet, medical conditions, and other considerations. Sources for target doses could include the IOM or recent osteoporosis guidelines (Canada) (USA).

Conclusion

The emerging safety data on calcium may yet become another cautionary tale about the unexpected and undesirable outcomes of targeted supplements. Until more evidence emerges, the safety of calcium supplements will continue to be questioned and debated. But that’s science-based practice: Data can be conflicting, messy, and difficult to interpret. There is always the possibility of unintended consequences when we make therapeutic decisions, and only by rigorously evaluating what we’re doing can we continue to improve the way we prevent and treat disease.

References
Bolland MJ, Avenell A, Baron JA, Grey A, MacLennan GS, Gamble GD, & Reid IR (2010). Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ (Clinical research ed.), 341 PMID: 20671013

Bolland, M., Grey, A., Avenell, A., Gamble, G., & Reid, I. (2011). 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, 342 (apr19 1) DOI: 10.1136/bmj.d2040

*This blog post was originally published at Science-Based Medicine*


You may also like these posts

Read comments »


Comments are closed.

Return to article »

Latest Interviews

How To Make Inpatient Medical Practice Fun Again: Try Locum Tenens Work

It s no secret that most physicians are unhappy with the way things are going in healthcare. Surveys report high levels of job dissatisfaction burn out and even suicide. In fact some believe that up to a third of the US physician work force is planning to leave the profession…

Read more »

Caring For Winter Olympians In Sochi: An Interview With Team USA’s Chief Medical Officer Dr. Gloria Beim

I am a huge fan of the winter Olympics partly because I grew up in Canada where most kids can ski and skate before they can run and partly because I used to participate in Downhill ski racing. Now that I m a rehab physician with a reconstructed knee I…

Read more »

See all interviews »

Latest Cartoon

Richmond, VA – In an effort to simplify inpatient medical billing, one area hospitalist group has determined that “altered mental status” (ICD-9 780.97) is the most efficient code for use in any patient work up.

“When you enter a hospital, you’re bound to have some kind of mental status change,” said Dr. Fishbinder, co-partner of Area Hospitalists, PLLC. “Whether it’s confusion about where your room is located in relationship to the visitor’s parking structure, frustration with being woken up every hour or two to check your vital signs, or just plain old fatigue from being sick, you are not thinking as clearly as before you were admitted. And that’s all the justification we need to order anything from drug and toxin screens, to blood cultures, brain MRIs, tagged red blood cell nuclear scans, or cardiac Holter monitoring. There really is no limit to what we can pursue with our tests.”

Common causes of mental status changes in the elderly include medicine-induced cognitive side effects, disorientation due to disruption in daily routines, age-related memory impairment, and urinary tract infections.

“The urinalysis is not a very exciting medical test,” stated Dr. Fishbinder. “It doesn’t matter that it’s cheap, fast, and most likely to provide an explanation for strange behavior in hospitalized patients. It’s really not as elegant as the testing involved in a chronic anemia or metabolic encephalopathy work up. I keep it in my back pocket in case all other tests are negative, including brain MRIs and PET scans.”

Nursing staff at Richmond Medical Hospital report that efforts to inform hospitalists about foul smelling urine have generally fallen on deaf ears. “I have tried to tell the hospitalists about cloudy or bloody urine that I see in patients who are undergoing extensive work ups for mental status changes,” reports nurse Sandy Anderson. “But they insist that ‘all urine smells bad’ and it’s really more of a red herring.”

Another nurse reports that delay in diagnosing urinary tract infections (while patients are scheduled for brain MRIs, nuclear scans, and biopsies) can lead to worsening symptoms which accelerate and expand testing. “Some of my patients are transferred to the ICU during the altered mental status work up,” states nurse Anita Misra. “The doctors seem to be very excited about the additional technology available to them in the intensive care setting. Between the central line placement, arterial blood gasses, and vast array of IV fluid and medication options, urosepsis is really an excellent entré into a whole new level of care.”

“As far as medicine-induced mental status changes are concerned,” added Dr. Fishbinder, “We’ve never seen a single case in the past 10 years. Today’s patients are incredibly resilient and can tolerate mixes of opioids, anti-depressants, anti-histamines, and benzodiazepines without any difficulty. We know this because most patients have been prescribed these cocktails and have been taking them for years.”

Patient family members have expressed gratitude for Dr. Fishbinder’s diagnostic process, and report that they are very pleased that he is doing everything in his power to “get to the bottom” of why their loved one isn’t as sharp as they used to be.

“I thought my mom was acting strange ever since she started taking stronger pain medicine for her arthritis,” says Nelly Hurtong, the daughter of one of Dr. Fishbinder’s inpatients. “But now I see that there are deeper reasons for her ‘altered mental status’ thanks to the brain MRI that showed some mild generalized atrophy.”

Hospital administrators praise Dr. Fishbinder as one of their top physicians. “He will do whatever it takes to figure out the true cause of patients’ cognitive impairments.” Says CEO, Daniel Griffiths. “And not only is that good medicine, it is great for our Press Ganey scores and our bottom line.”

As for the nursing staff, Griffiths offered a less glowing review. “It’s unfortunate that our nurses seem preoccupied with urine testing and medication reconciliation. I think it might be time for us to mandate further training to help them appreciate more of the medical nuances inherent in quality patient care.”

Dr. Fishbinder is in the process of creating a half-day seminar on ‘altered mental status in the inpatient setting,’ offering CME credits to physicians who enroll. Richmond Medical Hospital intends to sponsor Dr. Fishbinder’s course, and franchise it to other hospitals in the state, and ultimately nationally.

***

Click here for a musical take on over-testing.

See all cartoons »

Latest Book Reviews

The Spirit Of The Place: Samuel Shem’s New Book May Depress You

When I was in medical school I read Samuel Shem s House Of God as a right of passage. At the time I found it to be a cynical yet eerily accurate portrayal of the underbelly of academic medicine. I gained comfort from its gallows humor and it made me…

Read more »

Eat To Save Your Life: Another Half-True Diet Book

I am hesitant to review diet books because they are so often a tangled mess of fact and fiction. Teasing out their truth from falsehood is about as exhausting as delousing a long-haired elementary school student. However after being approached by the authors’ PR agency with the promise of a…

Read more »

Unaccountable: A Book About The Underbelly Of Hospital Care

I met Dr. Marty Makary over lunch at Founding Farmers restaurant in DC about three years ago. We had an animated conversation about hospital safety the potential contribution of checklists to reducing medical errors and his upcoming book about the need for more transparency in the healthcare system. Marty was…

Read more »

See all book reviews »