New Data Dispute Calcium Cardiovascular Risk in Both Sexes.


Two new studies contribute further to the debate over the cardiovascular risk associated with supplementary or dietary calcium, each decidedly coming down on the side of no significant risk — to men or women.

“[Based on these findings], clinicians should continue to evaluate calcium intake, encourage adequate dietary intake, and if necessary, use supplements to reach but not exceed recommended intakes,” Douglas C. Bauer, MD, from the University of California, San Francisco, the lead author of the first study, toldMedscape Medical News.

Results of both studies were reported at the recent American Society for Bone and Mineral Research (ASBMR) 2013 Annual Meeting.

Dr. Bauer’s observational trial is one of few contemporary studies to evaluate the level of risk among men, who are often poorly represented in calcium studies, he noted. The results showed no association between calcium dietary intake or supplementation and total or cardiovascular mortality. The second study was an updated meta-analysis of calcium supplementation among women and similarly demonstrated no increased risk for ischemic heart disease (with adjudicated outcomes) or total mortality in elderly women. It did draw some criticism for potential bias and contamination, however.

Nevertheless, says Robert Marcus, MD, a retired Stanford University bone specialist, the 2 studies are “powerful. The one involving men had very elegant, accurate reports of death and validated diagnosis of myocardial infarction, and the [study involving women] was also excellent work,” he commented.

“This field has been the subject of an enormous amount of controversy, ambiguity, and confusion for the past several years, and I think the most important thing is to help us come up with what is true,” he said. The quality of data to suggest an adverse effect of calcium is “very poor,” and there is now compelling evidence that there is little to substantiate this, he noted. But despite these reassuring new findings, public anxiety over a potential risk with calcium is unlikely to go away, he believes.

In recommendations issued in 2010, the ASBMR said that most adults 19 years of age and older require about 600 to 800 IUs of vitamin D daily and 1000 to 1200 mg of calcium daily through food and with supplements, if needed.

Contemporary Data on Calcium Intake in Men

The use of calcium supplements, predominantly with vitamin D, is an important therapy for the prevention of osteoporosis and its clinical consequences. But concerns about the cardiovascular safety of calcium have emerged periodically; in 2 alarming meta-analyses published in 2010 and 2011 by Dr. Mark Bolland and colleagues, for example, there was a 27% increase in MI among individuals allocated to calcium supplements in the first study and a 24% increased risk in the second.

More recently, a 40% increase in total mortality and up to a 50% increase in cardiovascular mortality was seenamong women from a Swedish mammography cohort with a calcium intake exceeding 1400 mg per day. In that study, the effect on mortality appeared to be especially strong if a high dietary intake of calcium was combined with calcium supplements.

In their new study, Dr. Bauer and his colleagues set out to assess rates of dietary calcium intake, use of supplements, and mortality in a prospective cohort of 5967 men over the age of 65 years in the Osteoporotic Fractures in Men (MrOS) study.

The participants completed extensive surveys at baseline on their dietary calcium intake, and supplementation was verified by a review of pill bottles by trained staff.

Mean dietary calcium intake was 1142 ± 590 mg/day, with more than half — 65% — of participants reporting use of calcium supplements.

Over the 10-year follow-up, among 2022 men who died, 687 deaths were caused by cardiovascular disease. The highest mortality for CVD was seen in the quartile with the lowest intake from calcium supplementation.

And in models that adjusted for age, energy intake, and calcium use, men in the lowest quartile of total calcium intake (less than 621 mg per day) had higher total mortality compared with those in the highest quartile (more than 1565 mg of calcium per day).

Adjustment for additional confounding factors showed no association between calcium dietary intake and total or cardiovascular mortality (P for trend .51 and .79, respectfully). Likewise, there was no association between calcium supplementation and total or cardiovascular mortality.

The authors also conducted an additional analysis of calcium intake and adjudicated cardiovascular disease events in a subcohort of the study, MrOS Sleep, involving 3120 patients who took part in a 7-year follow-up, and again there was no higher risk for cardiovascular events associated with calcium intake.

The study did have is limitations, Dr. Bauer acknowledged, including the observational design, calcium intake being assessed with a food frequency questionnaire, and cause of death not being formally adjudicated. Nevertheless, the findings are important in demonstrating the level of risk among men in a contemporary setting, he pointed out.

“Contrary to the Swedish study of women, we found no evidence that calcium supplementation is harmful to men, even among those with the highest dietary calcium intake,” he concluded, recommending that future studies should include adjudicated outcomes.

Study in Men as Expected, but Female Research Questioned

In the second study reported at the ASBMR meeting, Joshua Lewis, MD, PhD, from the University of Western Australia, Perth, and colleagues reported a meta-analysis of 19 randomized controlled trials involving women over the age of 50 years who had received calcium supplementation for more than a year.

Importantly, the analysis included reports of adjudicated cardiovascular outcomes, which the researchers note is important because gastrointestinal events can be misreported as cardiac ones. They also assessed all-cause mortality.

Among 59,844 participants in the studies, there were 4646 deaths, and the relative risk for death among those randomized to calcium supplements was 0.96 (P = .18).

The relative risk for 3334 ischemic heart disease events among 46,843 participants was 1.02 (P = .053), and the risk for 1097 MI events among 49,048 participants was 1.09 (P =.21).

“The data from this meta-analysis does not support the concept that calcium supplementation with or without vitamin D increases the risk of ischemic heart disease or total mortality in elderly women,” concluded Dr. Lewis.

But bone specialist Ian Reid, MD, from the University of Auckland, New Zealand, who was a coauthor on some of the Bolland studies, said this analysis essentially repeats previous ones, but with the inclusion of 20,000 patients from the Women’s Health Initiative (WHI), many of whom continued to take their own calcium tablets, regardless of whether they were randomized to calcium or placebo.

These “contaminated” WHI data have the potential to mask the effect of calcium, he told Medscape Medical News. In addition, in a study from Denmark also included in the meta-analysis, subjects were not properly blinded to treatment assignment and the calcium and control groups were not comparable at baseline for cardiovascular risk, which introduced “major potential bias,” he added.

Regarding the results from the study in men by Dr. Bauer and colleagues, Dr. Reid said they were not surprising to him. “Generally, people who take calcium supplements have more health-conscious behaviors than those who do not and so have a lower baseline risk of heart disease” that can “obscure small adverse effects of drugs such as calcium,” he observed.

An effect has to be “very substantial” before it can be picked up in an observational study, because of the many confounders that can obscure such an effect, he concluded.

Source: Medscape.com

Researchers assess multiple vitamin D doses in healthy breast-fed infants.


Researchers in Canada suggest that vitamin D supplementation of 1,600 IU per day increased plasma 25-hydroxyvitamin D concentrations to at least 75 nmol/L among 97.5% of infants aged 3 months. However, this dosage also increased concentrations associated with hypocalcemia, according to data.

The literature has established that vitamin D supplementation for infants is required to support healthy bone mineral accretion. However, conflicting recommendations for this patient population have led to further research.

“We have generated strong support using evidence-based dose response studies that the 400 IU dosage is quite satisfactory and that this is recommended now by the Institute of Medicine, Health Canada, Canadian Pediatric Society and the American Academy of Pediatrics,” researcher Hope Weiler, RD, PhD, of the School of Dietetics and Human Nutrition at McGill University in Quebec, said during a media telebriefing. “We also know that the higher dose recommended by the Canadian Pediatrics Society was well received by our infants and did generate a nice response in 25-hydroxyvitamin D, and the upper limits of 1,000 IU and 1,200 IU would be suitable as safety markers across the first year of life.”

According to data from a double blind, randomized study published in JAMA, Weiler and colleagues investigated the efficacy of various dosages of vitamin D supplements in supporting plasma 25-(OH)D concentrations in healthy, breast-fed infants (n=132) aged 1 month. The patients were randomly assigned to oral cholecalciferol (vitamin D3) supplements of 400 IU per day (n=39), 800 IU per day (n=39), 1,200 IU per day (n=38) or 1,600 IU per day (n=16), and they were followed for 11 months.

According to 3-month data, 55% (95% CI, 38-72) of infants in the 400-IU group demonstrated a 25-(OH)D concentration of at least 75 nmol/L vs. 81% (95% CI, 65-91) in the 800-IU group, 92% (95% CI, 77-98) in the 1,200-IU group and 100% in the 1,600-IU group. Due to elevations in 25-(OH)D concentrations, the 1,600 IU dosage was discontinued, researchers wrote. Moreover, the concentration did not continue in 97.5% of the infants at age 12 months in any of the groups.

Further data indicate that all dosages established 25-(OH)D concentrations of at least 50 nmol/L among 97% (95% CI, 94-100) of the infants at 3 months. This continued in 98% (95% CI, 94-100) at 12 months, the researchers wrote.

“Future studies should be larger and, hopefully, be able to detect early, as well as [determine], long-term benefits to bone. We may also consider other health benefits such as the immune system. Our future studies should consider other populations,” Weiler said. “We should also consider those at higher risk for deficiency, whether it’s due to geographic location where a mother’s exposure to sunshine is limited or the infant is born with vitamin D deficiency.”

In an accompanying editorial, Steven A. Abrams, MD, of the department of pediatrics at the US Department of Agriculture/Agricultural Research Service Children’s Nutrition Research Center at Baylor College of Medicine and Texas Children’s Hospital in Houston, said the study did not answer the question of what the target should be for plasma 25-(OH)D concentrations.

“Of importance, higher vitamin D dosages in this study did not lead to improved bone outcomes as reflected by DXA results for bone mineral content,” Abrams wrote.

He suggested that higher vitamin D intake and target plasma 25-(OH)D concentrations should be tested in clinical trials with markedly defined outcomes and precise safety monitoring.

 

Weiler H. JAMA. Theme Issue on Child Health: New research on the optimal dosing and possible adverse effects of different levels of vitamin D supplementation, important for bone health, for infants. Presented at: the JAMA Network 2013 Media Briefing; April 30, 2013; New York.

Disclosure: Abrams reports payment for lectures’/speakers’ bureaus from Mead-Johnson Nutrition and Abbott Nutrition and grants to his institution from Mead-Johnson Nutrition. Gallo reports travel support from CIHR Human Development Child and Youth Health and the American Society for Bone and Mineral Research. Sharma reports consulting fees for analyses prepared for Rodd and Weiler. Jones reports being cofounder and scientific advisory board member for Cytochroma Inc., and for receiving payment for speakers’ bureaus from Genzyme/Sanofi.

 

 

PERSPECTIVE

 

  • I  think it’s a helpful study in terms of the fact that they had different groups of newborn children treated with vitamin D with 400 IU being the recommended dose up to 12 months according to the Institute of Medicine and Endocrine Society guidelines. It was a well-designed study and relevant because vitamin D is a very hot topic right now due to the deficiencies in children and adults.

I agree with the editorial. This group of patients was a mostly white group with relatively high socioeconomic status. In the group that was administered 400 IU per day, researchers found that those infants reached 25(OH)D level of at least 20 ng/mL. That is a big debate. The IOM thinks 25(OH)D levels of 20 ng/mL are adequate for most, and I think a lot of endocrinologists and the Endocrine Society says most people need a level of 30 ng/mL.

This study shows that infants who were administered up to 400 IU per day reached a level of at least 20 ng/mL by 3 months. The whole group did not attain the level of 30 ng/mL, which again is what some endocrinologists think is an optimal level. To achieve a level of 30 ng/mL, perhaps 400 IU is not enough per day for some infants (especially those with darker skin pigmentation or at higher risk for deficiencies).

In addition to looking at the levels or how much vitamin D is needed to achieve a level of 20 ng/mL or 30 ng/mL, they also looked at the bone mineral content but found no significant difference in the groups. I think the editorial comment summed up this point. In treating infants with higher doses of vitamin D corresponding to higher serum levels above 30 ng/mL; does that confer other benefits? There are many early studies now looking at the relationship between vitamin D and asthma, food allergies, incidence of type 1 diabetes and autoimmune disease.

The important point Abrams raises is that we need more long-term studies to see if there is a skeletal benefit in terms of having a higher vitamin D level which would correspond to having a higher dose of vitamin D administered.

  • Dominique Noё Long, MD
  • Instructor of pediatric endocrinology
    The Johns Hopkins Children’s Center
    Baltimore, Md.

PERSPECTIVE

 

  • The strengths and usefulness of the study are the quantification of serum 25-OH vitamin D levels with various doses of vitamin D supplementation. The currently recommended dose of vitamin D, 400 IU daily, was chosen because historically this dose has proven to prevent rickets, which as pediatric endocrinologists, is our main objective. Therefore this study helps provide information in the ongoing debate regarding the optimal serum level of 25(OH) D. Interestingly, all doses of cholecalciferol increased serum levels of 25(OH) D to >50 nmol/L. Higher doses of cholecalciferol correlated with higher levels of 25(OH) D, however no group sustained >97.5% of infants to vitamin D levels >75 nmol/L. No one truly knows the ideal serum level of vitamin D, but this study suggests that >50 nmol/L was sufficient in this patient population. This study also provides information on the safety of higher doses of vitamin D supplementation. It may be harder to extrapolate in the darker-skin pigmented population who may need more vs. the white population. It’s just another piece to the puzzle of the debate on vitamin D.
  • Janet Crane, MD
  • Clinical research fellow in pediatric endocrinology
    The Johns Hopkins Children’s Center
    Baltimore, Md.