CALCIUM SUPPLEMENTATION INCREASE RISK OF COLORECTAL POLYPS

Researchers thought calcium supplementation might reduce development of precancerous colorectal polyps. It didn't.

Calcium supplementation alone more than doubled the risk for serrated sessile adenomas or polyps (SSA/Ps), and when combined with vitamin D, it almost quadrupled the risk, according to the results of a large randomized chemoprevention trial published online today in Gut.

Earlier research had suggested that people with high dietary calcium intake are at lower risk for polyps, including the serrated type. "So it stands to reason that calcium supplementation could have beneficial effects in terms of preventing colon cancer or polyps," lead author Seth D. Crockett, MD, from the University of North Carolina's Division of Gastroenterology and Hepatology in Chapel Hill, told Medscape Medical News.

"But, in contrast, we found evidence that calcium supplementation appeared to be associated with a risk of precancerous serrated polyps." He noted, however, that neither dietary calcium nor vitamin D supplements alone appear to increase risk.

Between 2005 and 2008, Crockett and colleagues enrolled 2259 participants, 45 to 75 years of age, from 11 US academic centers in the US Vitamin D/Calcium Polyp Prevention Study. All patients had had at least one adenoma removed during a baseline colonoscopy and were randomly assigned to four main treatment groups: 1200 mg/day of elemental calcium carbonate plus placebo (n = 419), 1000 IU/day of vitamin D³ plus placebo (n = 420), calcium plus vitamin D (n = 421), or placebo (n = 415). Women unwilling to discontinue calcium supplements were randomly assigned to a calcium-plus-placebo (n = 295) group or a calcium-plus-vitamin D group (n = 289).

After 3 or 5 years of supplementation (treatment phase), patients underwent a colonoscopy and were assessed again 3 to 5 years after stopping supplementation (observation phase).

During the treatment phase, researchers diagnosed serrated polyps in 565 (27.5%) of 2058 evaluable participants. There were 1111 serrated polyps, including 955 hyperplastic polyps and 132 SSA/Ps.

In the observation phase, investigators diagnosed serrated polyps among 329 (29.7%) of 1108 participants who underwent a colonoscopy. There were 607 serrated polyps, including 498 hyperplastic polyps and 79 SSA/Ps.

When analyzed by type of supplementation, the authors found no statistically significant differences in risk for serrated polyps, hyperplastic polyps, or SSA/Ps during the treatment phase.

However, risk differences were apparent during the observation phase for SSA/Ps, but not for serrated polyps or hyperplastic polyps. Specifically, the adjusted risk ratio (aRR) for SSA/Ps among patients randomly assigned to calcium alone was 2.65 (95% confidence interval [CI], 1.43 - 4.91) vs placebo, and for those taking combined calcium and vitamin D, it was 3.81 (95% CI, 1.25 - 11.64).

The risks were greatest for women and current smokers. Although nonsmokers had a calcium-associated aRR for any serrated polyp of 1.04 (95% CI, 0.87 - 1.24), current smokers had an aRR of 2.16 (95% CI, 1.32 - 3.51; P interaction = .02). In women, calcium was associated with a higher risk for serrated polyps overall (aRR, 2.62; 95% CI, 1.39 - 4.95; P for trend = .004), and specifically of hyperplastic polyps (aRR, 2.50; 95% CI, 1.22 - 5.13; P for trend = .004).

Crockett and associates conclude that although risks should be always weighed against benefits, patients with a history of premalignant sessile polyps, particularly women and smokers, might consider avoiding these supplements.

Supplements had no effect on the development of conventional adenomas, which is consistent with earlier data reported from the same trial.

These new findings are cause for concern, as serrated polyps are precursors to 20% to 30% of sporadic cases of colorectal cancer and need to be targeted along with conventional adenomas, the authors note. "Further studies are recommended to confirm these results, which may have important implications for [colorectal cancer] screening and prevention," they write.

In the meantime, should supplement users take any action in light of these results? "It's important to put these findings in perspective and not to cause alarm as calcium and vitamin D supplements are taken by lots of people and have many beneficial effects," Crockett said. "The possible association we found does not necessarily negate the other benefits."

However, for people such as smokers and those with a history of serrated polyps, the findings could alter the balance of risks and benefits of calcium supplementation. "And people need to keep their regular screening and colonoscopies up to date," he adds.

This study was funded by a grant from the National Institutes of Health, National Cancer Institute. Lead author Crockett was supported in part by a grant from the National Institutes of Health. The authors have disclosed no competing interests related to this article, but several reported ties to industry outside this work.

Gut. Published online March 1, 2018.