Calcium and vitamin D supplementation and increased risk of serrated polyps: results from a randomised clinical trial

Abstract

Objective: Serrated lesions such as sessile serrated adenomas or polyps (SSA/Ps) are important colorectal cancer precursors, but aetiological factors for these lesions are largely unknown. We aimed to determine the effects of calcium and vitamin D supplementation on the incidence of serrated polyps (SPs) in general and hyperplastic polyps and SSA/Ps specifically.

Design: Participants with one or more adenoma at baseline were randomised to receive 1200 mg/day of elemental calcium, 1000 IU/day of vitamin D3, both or neither agent. Treatment continued for 3 or 5 years, when risk of polyps was determined from surveillance colonoscopy (treatment phase). Outcomes after treatment ceased were also assessed (observational phase). Adjusted risk ratios (aRRs) of SPs were determined via multivariable generalised linear models.

Results: SPs were diagnosed in 565 of 2058 (27.5%) participants during the treatment phase and 329/1108 (29.7%) during the observational phase. In total, 211 SSA/Ps were identified during follow-up. In the treatment phase, there was no effect of either calcium or vitamin D on incidence of SSA/Ps. However, during the later observational phase, we observed elevated risks of SSA/Ps associated with calcium alone and calcium+vitamin D treatment (aRR (95% CI): 2.65 (1.43 to 4.91) and 3.81 (1.25 to 11.64), respectively).

Conclusion: In a large multicentre chemoprevention study, we found evidence that calcium and vitamin D supplementation increased the risk of SSA/Ps. This appeared to be a late effect: 6-10 years after supplementation began. These possible risks must be weighed against the benefits of calcium and vitamin D supplementation. : Trial registration NUMBER: NCT00153816; Results.

Keywords: adenoma; cancer prevention; colon carcinogenesis; micronutrients.

Conflict of interest statement

Competing interests: None of the authors report conflicts of interest related to this article. Full disclosures are as follows: SDC: Research funding from Exact Sciences, ColoWrap and Boston Scientific. DJA: Scientific Advisory Board for Cancer Prevention Pharmaceuticals, Speakers Bureau for Ambry Genetics. DJR: Scientific Advisory Board for Medtronic and Consultant for Freenome. CAB: Research funding from Cancer Prevention Pharmaceuticals. JAB: Together with Dartmouth College, JAB: holds a use patent for the chemopreventive use of calcium, currently not licensed.

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2019. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Figures

FIGURE 1:

Study design and outcome measurement Footnotes: 1Women could elect to be randomized to either calcium-containing group outside of factorial randomization (2 group randomization). 2Interim colonoscopies taking place before 3 years were included in the treatment interval analysis. In the absence of an anticipated year 3 or 5 colonoscopy, any colonoscopy taking place more than 1 year after the baseline examination was accepted. 3End of Study colonoscopy is defined as the first surveillance colonoscopy that took place at least 3 years after the End of Treatment colonoscopy. For subjects who did not have a surveillance colonoscopy at least 3 years following End of Treatment, non-surveillance exams and interim colonoscopies taking place before 3 years were included in the observational phase analysis.

FIGURE 2:

Flow chart of treatment and observational phase composition