03.05.18
A new randomized trial published online in the British Medical Journal Gut found evidence that calcium supplementation and the combination of calcium and vitamin D may increase the risk of serrated polyps during later follow-up—specifically sessile serrated adenomas or polyps (SSA/Ps), which are important colorectal cancer precursors—among patients with a history of colorectal polyps.
The increased risk appeared to be a late effect (6-10 years after supplementation began), according to the study. Authors said further research is recommended to confirm these results, which may have important implications for screening and prevention. And these possible risks must be weighed against the benefits of calcium and vitamin D supplementation.
Study Design
For this study, participants with one or more adenoma at baseline were randomized to receive 1,200 mg/day of elemental calcium, 1,000 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 generalized linear models.
SPs were diagnosed in 565 of 2,058 (27.5%) participants during the treatment phase and 329/1,108 (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, researchers 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).
Surprising Results
Researchers said they were surprised by the findings. In addition, they found evidence women and current smokers had higher risks of SPs when exposed to supplemental calcium. They did not observe an association between vitamin D alone and the risk of SSA/Ps.
The authors noted that other researchers have previously reported inverse associations between dietary calcium intake and hyperplastic polyps (HPs), the most prevalent SP subtype. They cited a case-control study of 560 patients with HPs, where Davenport et al reported the highest quartile of calcium intake was associated with lower risk of HPs (>1217 mg/day vs ≤595.8 mg/day: OR 0.66, 95% CI 0.44 to 0.99, P for trend 0.03).
Similarly, another smaller case-control study of 81 patients with HPs by Martínez et al reported an inverse association between dietary calcium intake and HPs (≥1094 mg/day vs ≤558 mg/day: OR 0.41, 95% CI 0.19 to 0.90, P for trend 0.05).
In contrast, the recent study found a null association between treatment with calcium supplements and HPs. Researchers did evaluate the association with dietary calcium as well (as in the previous observational studies) and also did not find any statistically significant associations with risk of HPs in either the treatment or observational phase. “Taken together, our results would suggest that only calcium supplementation, not dietary calcium intake, is associated with SPs overall and SSA/Ps specifically. However, it should be noted that our study design evaluated risk of incident SSA/Ps in contrast to observational studies, which generally evaluate associations between dietary factors and prevalent polyps.”
Uncertain Mechanisms
The possible mechanisms by which calcium could influence serrated neoplasia aren’t clear, researchers said. “Our findings of the relatively long latency period would suggest that calcium (with or without vitamin D) likely influences early events in the serrated neoplasia pathway rather than late effects such as progression to dysplasia or cancer. Calcium is involved in myriad cellular functions, but most of its proposed mechanisms and actions are antineoplastic. Serrated pathway lesions have been associated with Annexin A10. Annexins are a family of calcium-regulated phospholipid binding proteins that have varied cellular functions. The specific function of Annexin A10 is uncertain, but it has been shown to be highly expressed in both SSA/Ps and serrated adenocarcinomas. Therefore, it is possible that calcium supplementation could influence Annexin A10 expression and thereby alter progression through the serrated pathway. Calcium is also involved with Mucin 5AC production,another marker of the serrated pathway.”
Calcium and vitamin D supplements are taken by roughly 40% of the US population, which equates to over 100 million persons. Women represent the majority of those taking calcium supplements in the general population. It is interesting therefore that SSA/Ps are at least as common if not more common in women than men, in contrast to conventional adenomas, which are more common in men.
Andrea Wong, PhD, vice president, scientific & regulatory affairs, Council for Responsible Nutrition (CRN) said the association was surprised by the results of this new study as previous research has indicated calcium supplementation may have a protective effect against colorectal polyps. “Even the study’s authors acknowledge they do not understand the mechanism by which the calcium supplements seemingly had the opposite effect of what was hypothesized. Given these opposing outcomes in the research to date, this is clearly a case where additional research is needed to discern whether this study’s outcome was an anomaly.”
“Until further research is conducted, we caution the medical community and consumers against haphazardly dismissing or downplaying the value of calcium supplementation,” she continued, “particularly in people most likely to develop osteoporosis or bone loss. This particular study focused on a very specific population—patients with a history of colorectal polyps—and therefore, the study’s results are not applicable to the general population. We recommend consumers with a history of colorectal polyps talk with their doctors about whether calcium supplementation is appropriate.”
Calcium Facts
CRN also noted a few facts about calcium:
During childhood and adolescence, a proper intake of calcium plus vitamin D helps build optimum bone mass. Throughout adulthood, calcium will slow the rate of bone loss that naturally occurs with aging. Because of the natural loss of calcium that occurs with age, getting enough of this essential nutrient is especially important for the older populations, who are at risk for falls and fractures.
Substantial research has demonstrated supplementing with calcium and vitamin D to be effective in maintaining or increasing bone density, preventing osteoporosis, and potentially in protecting health in other ways as well. Calcium also helps blood clot, nerves send messages, muscles contract, and other body functions.
The 2015 Dietary Guidelines for Americans identified calcium as a “nutrient of public health concern” because getting insufficient amounts of calcium has been linked in the scientific literature to adverse health outcomes.
They human body cannot produce calcium on its own, and when people don’t get enough, calcium is taken from the bones. Individuals who do not achieve adequate intake levels of calcium through their diets can rest assured that supplemental calcium is safe and effective for ensuring optimal bone health.
26% of supplement users take dietary supplements, according to the 2017 CRN Consumer Survey on Dietary Supplements.
The increased risk appeared to be a late effect (6-10 years after supplementation began), according to the study. Authors said further research is recommended to confirm these results, which may have important implications for screening and prevention. And these possible risks must be weighed against the benefits of calcium and vitamin D supplementation.
Study Design
For this study, participants with one or more adenoma at baseline were randomized to receive 1,200 mg/day of elemental calcium, 1,000 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 generalized linear models.
SPs were diagnosed in 565 of 2,058 (27.5%) participants during the treatment phase and 329/1,108 (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, researchers 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).
Surprising Results
Researchers said they were surprised by the findings. In addition, they found evidence women and current smokers had higher risks of SPs when exposed to supplemental calcium. They did not observe an association between vitamin D alone and the risk of SSA/Ps.
The authors noted that other researchers have previously reported inverse associations between dietary calcium intake and hyperplastic polyps (HPs), the most prevalent SP subtype. They cited a case-control study of 560 patients with HPs, where Davenport et al reported the highest quartile of calcium intake was associated with lower risk of HPs (>1217 mg/day vs ≤595.8 mg/day: OR 0.66, 95% CI 0.44 to 0.99, P for trend 0.03).
Similarly, another smaller case-control study of 81 patients with HPs by Martínez et al reported an inverse association between dietary calcium intake and HPs (≥1094 mg/day vs ≤558 mg/day: OR 0.41, 95% CI 0.19 to 0.90, P for trend 0.05).
In contrast, the recent study found a null association between treatment with calcium supplements and HPs. Researchers did evaluate the association with dietary calcium as well (as in the previous observational studies) and also did not find any statistically significant associations with risk of HPs in either the treatment or observational phase. “Taken together, our results would suggest that only calcium supplementation, not dietary calcium intake, is associated with SPs overall and SSA/Ps specifically. However, it should be noted that our study design evaluated risk of incident SSA/Ps in contrast to observational studies, which generally evaluate associations between dietary factors and prevalent polyps.”
Uncertain Mechanisms
The possible mechanisms by which calcium could influence serrated neoplasia aren’t clear, researchers said. “Our findings of the relatively long latency period would suggest that calcium (with or without vitamin D) likely influences early events in the serrated neoplasia pathway rather than late effects such as progression to dysplasia or cancer. Calcium is involved in myriad cellular functions, but most of its proposed mechanisms and actions are antineoplastic. Serrated pathway lesions have been associated with Annexin A10. Annexins are a family of calcium-regulated phospholipid binding proteins that have varied cellular functions. The specific function of Annexin A10 is uncertain, but it has been shown to be highly expressed in both SSA/Ps and serrated adenocarcinomas. Therefore, it is possible that calcium supplementation could influence Annexin A10 expression and thereby alter progression through the serrated pathway. Calcium is also involved with Mucin 5AC production,another marker of the serrated pathway.”
Calcium and vitamin D supplements are taken by roughly 40% of the US population, which equates to over 100 million persons. Women represent the majority of those taking calcium supplements in the general population. It is interesting therefore that SSA/Ps are at least as common if not more common in women than men, in contrast to conventional adenomas, which are more common in men.
Andrea Wong, PhD, vice president, scientific & regulatory affairs, Council for Responsible Nutrition (CRN) said the association was surprised by the results of this new study as previous research has indicated calcium supplementation may have a protective effect against colorectal polyps. “Even the study’s authors acknowledge they do not understand the mechanism by which the calcium supplements seemingly had the opposite effect of what was hypothesized. Given these opposing outcomes in the research to date, this is clearly a case where additional research is needed to discern whether this study’s outcome was an anomaly.”
“Until further research is conducted, we caution the medical community and consumers against haphazardly dismissing or downplaying the value of calcium supplementation,” she continued, “particularly in people most likely to develop osteoporosis or bone loss. This particular study focused on a very specific population—patients with a history of colorectal polyps—and therefore, the study’s results are not applicable to the general population. We recommend consumers with a history of colorectal polyps talk with their doctors about whether calcium supplementation is appropriate.”
Calcium Facts
CRN also noted a few facts about calcium:
During childhood and adolescence, a proper intake of calcium plus vitamin D helps build optimum bone mass. Throughout adulthood, calcium will slow the rate of bone loss that naturally occurs with aging. Because of the natural loss of calcium that occurs with age, getting enough of this essential nutrient is especially important for the older populations, who are at risk for falls and fractures.
Substantial research has demonstrated supplementing with calcium and vitamin D to be effective in maintaining or increasing bone density, preventing osteoporosis, and potentially in protecting health in other ways as well. Calcium also helps blood clot, nerves send messages, muscles contract, and other body functions.
The 2015 Dietary Guidelines for Americans identified calcium as a “nutrient of public health concern” because getting insufficient amounts of calcium has been linked in the scientific literature to adverse health outcomes.
They human body cannot produce calcium on its own, and when people don’t get enough, calcium is taken from the bones. Individuals who do not achieve adequate intake levels of calcium through their diets can rest assured that supplemental calcium is safe and effective for ensuring optimal bone health.
26% of supplement users take dietary supplements, according to the 2017 CRN Consumer Survey on Dietary Supplements.
