Vitamin D and Calcium Fail to Reduce Risk for Adenomas

Roxanne Nelson, RN, BSN

October 14, 2015

Supplementing with vitamin D and calcium does not appear to reduce the risk of developing colorectal adenomas, according to a new study published this week in the New England Journal of Medicine.

In a population of 2259 individuals who had previously been diagnosed with adenomas, taking supplements containing daily doses of 1000 IU of vitamin D3, 1200 mg of calcium, or both did not significantly reduce the risk for recurrent colorectal adenomas over a period of 3 to 5 years.

The authors found that 42.8% of patients developed one or more adenomas after taking vitamin D, compared with 42.7% of those not taking it.

Of patients taking calcium, 45.3% developed adenomas, compared with 47.6% of patients who did not take calcium. And for those patients receiving both supplements, 45.7% developed one or more adenomas, compared with 48.2% of those taking neither.

The results were surprising and also a disappointment, commented lead author John Baron, MD, professor of medicine at the University of North Carolina School of Medicine, Chapel Hill.

Previous observational studies have suggested supplementation with calcium and vitamin D was associated with a lower risk for adenomas, and studies have also suggested that higher serum levels of vitamin D may be beneficial in colorectal cancer.

"We were really surprised that calcium supplementation had no effect," Dr Baron told Medscape Medical News. "There have been randomized trials that have shown a benefit, and in fact, our group conducted a study which showed a lower risk of recurrent adenomas."

In that study (N Engl J Med. 1999;340:101-107), the adjusted risk ratio for any recurrence of adenoma with calcium as compared with placebo was 0.85 (95% confidence interval [CI], 0.74 - 0.98; P = .03). "We used the same calcium product, the same dose, and patients were from many of the same clinical centers," he said. "But calcium isn't so much on people's minds and in the popular press as vitamin D."

Vitamin D has been a subject of great interest and has been extensively investigated for its protective benefits against a range of diseases, including colorectal cancer, he noted.

Previous Studies Suggest Benefit

In their article, Dr Baron and his coauthors point out that a number of studies have shown vitamin D to be antineoplastic, particularly in the colorectum. In vitro studies have demonstrated that vitamin D and its analogues can inhibit proliferation, induce differentiation, inhibit angiogenesis, and promote apoptosis in epithelial tissues.

However, they also noted that trials of vitamin D supplementation have not shown it to decrease the incidence of colorectal cancer, although they point out that these studies were limited by factors such as low vitamin D doses, small numbers of events, and relatively short follow-up periods for cancer end points. These trials were also not designed with colorectal cancer as the primary end point.

High calcium intake, on the other hand, has been associated with lower risk for colorectal neoplasia and with inhibition of carcinogenesis in experimental models. In addition, results from epidemiologic studies have suggested a lower risk for both colorectal cancer and adenomas, and trials of calcium supplementation for adenoma prevention have demonstrated a reduced risk.

Additionally, calcium and vitamin D could have a synergistic chemopreventive effect against colorectal neoplasia, the authors argued, and they set out to investigate this also. Their main hypothesis was that supplementing with both calcium and vitamin D would lower the risk of developing an adenoma and that both agents together would reduce that risk even further than calcium used alone.

No Significant Differences From Supplementing

Patients from 11 academic centers who had a history of at least one colorectal adenoma that was removed within 120 days before enrollment in the trial were randomly assigned to receive daily vitamin D3 (1000 IU), calcium as carbonate (1200 mg), both, or neither. Women could elect to receive calcium plus random assignment to vitamin D or placebo.

Overall, supplementation, alone or combined, did not have a significant effect on the risk for adenoma.

The adjusted risk ratio for developing any adenoma in the cohort receiving vitamin D, in comparison with patients who did not take vitamin D, was 0.99 (95% CI, 0.89 - 1.09). The adjusted risk ratio for participants taking calcium vs those not taking calcium was 0.95 (95% CI, 0.85 - 1.06).

For the group that used both supplements in comparison with those taking calcium alone, the adjusted risk ratio was 1.01 (95% CI, 0.88 - 1.15). The adjusted risk ratio among patients taking vitamin D plus calcium compared with those using neither one was 0.93 (95% CI, 0.80 - 1.08).

The authors also conducted a subgroup analysis according to baseline 25-hydroxyvitamin D [25(OH)D] level, and those findings were similar among participants with baseline 25(OH)D levels lower than the study median of 23.2 ng/mL and those with levels higher than the study median.

Of note was that body mass index (BMI) score appeared to modify the effects of calcium on adenoma risk (P = .02). The lower the BMI, the greater the person's response to calcium supplementation. There was also a suggestion that supplementing with either vitamin D or calcium conferred lower risks among individuals who were followed and treated for a longer period, although the differences were not significant.

Points to Ponder

There are a number of possible reasons why the results of this trial were negative, according to two experts.

"One possible reason is that there is truly no impact of vitamin D supplementation on adenoma development," said Kimmie Ng, MD, an assistant professor of medicine at Harvard Medical School and director of clinical research, Center for Gastrointestinal Oncology, at the Dana-Farber Cancer Institute, Boston. "However, this does not exclude the possibility that vitamin D may still have chemopreventive potential against colorectal cancer, which is a more clinically meaningful end point."

Dr Ng pointed out that the study authors themselves note that observational studies have shown a weaker link between serum vitamin D levels and adenomas, as compared with serum vitamin D levels and cancer (both risk for colorectal cancer and survival of patients with established colorectal cancer).

"Therefore, it could be that vitamin D has more of an antineoplastic role against invasive cancer than lesions at the diminutive polyp stage," she told Medscape Medical News. "The ongoing VItamins And Lifestyle (VITAL) chemoprevention trial has colorectal cancer as a primary end point and will be able to provide more information about the link between vitamin D and cancer."

Another possible reason for the negative results is that the dose of vitamin D was not high enough. "The median level was only 23 ng/mL in the study population, with a mean increase of only 7 ng/mL during the treatment period," said Dr Ng, suggesting that for many patients, vitamin D levels were not increased to the optimal range.

These negative results are further complicated by the fact that many of the participants had a high BMI, and it is well known that overweight and obese individuals require higher doses of vitamin D to achieve sufficient levels, she noted. "Indeed, in subgroup analyses, it seems that vitamin D and calcium had a greater impact among leaner individuals than heavier individuals, though the interaction was significant only for calcium."

"It would be interesting to see if the subjects who did manage to achieve higher levels of 25(OH)D had a lower risk of adenoma, but this analysis was either not done or not reported in the publication," Dr Ng added.

Finally, another possible reason for the negative results is that the duration of supplementation may not have been long enough, given the fact that preventive benefits of many chemoprevention agents often require regular use for 10 years or longer. "Supporting this are the subgroup analyses that suggest that subjects who underwent a longer treatment period seemed to have a greater benefit from vitamin D and calcium," she said.

Other Possibilities

Another expert pointed to other possibilities that could account for the lack of response.

"A difference from previous studies may be in part due to a chance variation and/or differences in populations," commented Shuji Ogino, MD, PhD, a professor of pathology at Harvard Medical School, Boston, and professor, Department of Epidemiology, Harvard T. H. Chan School of Public Health. "This study included a selected group of participants with a history of adenomas."

Another reason might be a difference in outcome measures ― in this study, recurrent adenoma. Of note, not all adenomas become fully malignant cancers.

Dr Ogino and colleagues published an article this year that showed a link between vitamin D and the immune response to cancer in a large human population (Gut. 2015;64:260-271). He pointed out that in his own study, "we looked into etiologic heterogeneity by means of the molecular pathological epidemiology [MPE] approach."

"By this new MPE approach, we have shown that vitamin D is unlikely to be equally preventive against all tumor types," he added.

Dr Baron agrees that the vitamin D dose may not have been high enough to have reached optimal levels in the study group, and a longer follow-up period may be necessary, especially given the trend seen in subgroup analyses.

But why the results were so different for calcium supplementation is a matter of speculation. "The US population has evolved in the years since the previous study," he said, "and that may explain some differences between the two trials."

"People are heavier than they were, with higher BMI, and that effect showed up in the current study," he noted. "There are fewer smokers and some differences in racial composition, although I don't think that made too much of a difference."

Hopefully, they will have some answers in the near future. "We are starting to comb through the statistics of both studies and analyze the difference in findings, and we will know more in about 6 months' time," Dr Baron said.

The study was supported by a grant from the National Institutes of Health and the National Cancer Institute. Dr Baron received grant support from the National Institutes of Health and nonfinancial support from Lederle/Pfizer while the study was being conducted. He also holds a patent related to the chemopreventive use of calcium. Several coauthors have disclosed relationships with industry.

N Engl J Med. 2015;373:1519-1530.

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