Vitamin D and Calcium Supplementation Decreases the Likelihood of Developing Colorectal Cancer

By Courtney Pfalzer

Introduction
Colorectal cancer is an illness that affects the colon or rectum, both of which comprise the large
intestine and digestive system. The majority of colorectal cancers are adenocarcinomas, a type of cancer
that occurs in the epithelial cells of the body and leads to the development of malignant, and in many
cases, mucinous tumors.1 The disease initially manifests itself as a series of small growths or polyps on
the inner walls that line the colon or rectum.1 If left untreated, benign polyps have the potential to become
malignant and cancerous cells from these growths can further spread to the blood and lymphatic system
eventually leading to metastasis.2 Common signs and symptoms of colorectal cancer include rectal
bleeding and bloody stool, persistent abdominal discomfort, weakness or fatigue, inexplicable weight
loss, a change in bowel habits, and a feeling that the bowel does not empty completely following a bowel
movement.3 Although the death rate of colorectal cancer has been steadily decreasing in recent years, it
continues to be the third most common form of cancer in both men and women in the United states. 1
Presently, there is no known cause of the disease. 3 However, numerous factors have been attributed to an
increased risk in the development of colorectal cancer.3 High-fat, low-fiber diets, obesity, diabetes,
sedentary lifestyle, and a family history of the illness are just a few of the contributing factors. 3 To
combat the development of the disease, cancer screenings, colonoscopies, and polypectomies are
administered as preventative treatments. In terms of primary prevention, dietary consumption and/ or
supplementation of vitamin D and calcium may also prove to be effective. Many studies have shown a
positive correlation between higher intakes of these nutrients and a reduced risk of contracting colorectal
cancer. This may be due to potential polyp inhibition by calcium as well as the influence vitamin D has on
cell differentiation, proliferation, and apoptosis. 4 The purpose of this paper is to determine whether
vitamin D and calcium supplementation lowers the overall risk of contracting colorectal cancer.

Methods of Research
Research was conducted using the PubMed search engine, Google scholar, and the UNF Thomas
G. Carpenter library database. Search terminology included: vitamin D, calcium, colorectal cancer, colon
cancer, decreased risk, lowered risk, and cancer treatment. Because the term colon cancer, is often used
interchangeably with colorectal cancer, it was also utilized as a term to broaden the search and obtain
more results. Relevant primary research articles and meta-analyses from peer-reviewed journals were
included and cited throughout the paper. Articles on successful and unsuccessful investigations were used
to ensure the references were objective in nature. These studies focused on calcium and vitamin D
together or alone in relation to a reduced risk of colorectal cancer. Pertinent information from reliable
online resources was also incorporated into the research. The cited websites were Mayoclinic.org and
Cancer.gov, both of which provided the definition, symptoms, probable causes, and treatment options of
colorectal cancer.
Main Findings
A randomized, double-blind, placebo controlled clinical trial was conducted on ninety-two men
and women with at least one pathology-confirmed colorectal adenoma. 5 The purpose of this investigation
was to examine the effects of vitamin D and calcium supplementation on markers of apoptosis in normal
colon mucosa.5 Over a period of six months, participants of the study were treated with 2.0 g/d of
calcium or 800 IU/d of vitamin D3, either alone or together. The results were then compared to a placebo
group.5 The expression and colorectal crypt distributions of Bcl-2, an apoptosis inhibitor, and Bax, an
apoptosis stimulator, in biopsies of normal-appearing rectal mucosa were detected by automated
immunohistochemistry and quantified by image analysis.5 At the studys completion, Bax expression
increased 56% in the vitamin D group and 33% in the group randomized to both vitamin D and calcium. 5
There were found to be no significant changes caused by the effects of treatment in the Bcl-2 expression. 5
The vitamin D treatment was also found to be most effective in the upper 40% of crypts. 5 Based on these

findings, it can be determined that vitamin D and calcium, either as a combination or alone, may
potentiate apoptosis in healthy colorectal epithelium. 5
In another investigation, two crossover trials were carried out with the objective of defining the
molecular pathways in the human colorectum that were altered by a western-styled diet with calcium
and/or vitamin D supplementation .6 This diet was developed by the Nutrition Department at Rockefeller
University and was comprised of 2,200 kilocalories, 40% of which was derived from fat and 20% from
protein.6 It was also relatively low in vitamin D content and supplied 400 milligrams of calcium per day. 6
Subjects were assigned to the western influenced diet for a period of 4 weeks. During this time, the diet
was supplemented with and without 2 g/d of calcium carbonate. 6 Following the second trial, a 4-week
western-styled diet supplemented with 1,25(OH)2D3 (0.5 g/d) with or without 2 g/d of calcium carbonate
was provided.6 Gene expression in biopsy specimens of the rectosigmoid colonic mucosa and serum and
urinary calcium concentrations were measured and evaluated to obtain results. 6 The western diet without
supplementation was shown to have moderately upregulated the genes that were involved in
inflammatory pathways, including interferon mediated signaling. 6 Calcium supplementation was found to
have mostly reversed these towards baseline however.6 The western-styled diet supplemented with
1,25(OH)2D3 significantly increased the upregulation of genes involved in inflammation, immune
response, the extracellular matrix, and cell adhesion. 6 From the results of this study, it was determined that
supplementation of 1,25(OH)2D3 in a western-styled diet greatly upregulates genes in immune response
and inflammatory pathways, both of which are reversed by calcium supplementation. 6 This study provides
evidence of alterations in gene expression occurring within the human colorectum in response to calcium
and 1,25(OH)2D3 treatment.6
A randomized, double-blind, placebo-controlled trial was conducted on patients with recently
diagnosed adenomas in order to determine the chemopreventive potential of calcium and vitamin D. 7
Participants in the study also had no known colorectal polyps remaining following a routine colonoscopy. 7
2,259 patients were randomly assigned to receive 1000 IU/d of vitamin D 3, 1200 mg/d of calcium

carbonate, both, or neither of the nutrients.7 Following the endoscopists recommendation, a surveillance
colonoscopy was to be performed 3 or 5 years after the baseline examinations. 7 The end point of the
investigation was adenomas diagnosed in the time frame spanning from randomization to the anticipated
follow-up colonoscopy.7 The participants who received vitamin D supplements had a mean net increase of
7.83 ng/mL in serum-hydroxyvitamin D levels which was comparable to the participants randomized to
the placebo group.7 43% of all the recruited patients had one or more adenomas diagnosed during the
follow-up period of the investigation.7 The risk ratios for recurrent adenomas were 0.99 (0.89 to 1.09) in
vitamin D versus no supplementation, 0.95 (0.85 to 1.06) in calcium versus no supplementation, and 0.93
in (0.80 to 1.08) in both nutrients versus neither nutrients. 7 Based on this evidence, it was concluded that
daily supplementation of vitamin D3 and/or calcium did not significantly reduce the risk of recurrent
colorectal adenomas over a period of 3 to 5 years. 7
A randomized, double-blind, placebo-controlled trial involving 36,282 postmenopausal women
was conducted in order to determine if calcium and vitamin D supplementation was an effective treatment
option for colorectal cancer.8 18,176 women were assigned twice daily dosages of 500 mg of calcium
carbonate and 200 IU of vitamin D3.8 The other 18,106 participants received a placebo for an average of
7.0 years.8 To obtain results, the incidence of pathologically confirmed colorectal cancer was evaluated
upon completion of the investigation.8 Following the trial, the incidence of colorectal cancer was not
found to be significantly different in women who were assigned to calcium and vitamin D 3
supplementation and those who were randomized to the placebo (168 and 154 cases; hazard ratio, 1.08;
95 percent confidence interval, 0.86 to 1.34; P=0.51) .8 Tumor characteristics, the frequency of
colorectal-cancer screening, and abdominal symptoms were all found to be similar in both groups. 8 From
these findings, it was concluded that vitamin D and calcium supplementation lasting a period of seven
years had no significant effect on the incidence of colorectal cancer in postmenopausal women. 8 In the
study, it was noted in the conclusion that the long latency period of colorectal cancer as well as the seven
year duration of the trial may have contributed to this null finding. 8

Conclusion
Presently, not enough evidence is available to determine if vitamin D and calcium
supplementation is an effective means of prevention against colorectal cancer. Although an association
between both nutrients and a decreased risk of this illness has been drawn, information on the
mechanisms of action is lacking.6 Research on the topic has also yielded rather ambiguous results. Longterm studies with daily supplementation produced outcomes displaying insignificant effects on the
recurrence of colorectal adenomas and the incidence of cancer.7,8 In contrast, shorter randomized-trials
tended to generate more effective and successful results. However, these findings mainly affirmed
calcium and vitamin Ds influence on cell apoptosis, immune response, and inflammatory pathways rather
than the direct development of colorectal cancer. While programmed cell death, the immune system, and
biological pathways do play a pivotal role in the development of cancer, results obtained solely from these
factors are not specific enough to provide a definitive answer. Until more primary research is conducted
on these nutrients in direct relation to the disease, the claim of vitamin D and calcium supplementation
being able to lower the risk of colorectal cancer remains unconfirmed due to inconclusive evidence.

Citations
1. National Cancer Institute Web site. http://www.cancer.gov/types/colorectal. Accessed April, 1 2016.
2. Bujanda L, Cosme A, Gil I, Arenas-Mirave J. Malignant colorectal polyps. World Journal of
Gastroenterology. 2010; 16 (25): 3103-3111.
3. Mayo Clinic Web site. http://www.mayoclinic.org/diseases-conditions/colon-cancer/symptomscauses/dxc-20188239. Accessed April, 1 2016.
4. Lee JE, Li H, Chan AT, et al. Circulating Levels of Vitamin D and Colon and Rectal Cancer: The
Physicians' Health Study and a Meta-analysis of Prospective Studies. Cancer Prevention Research. 2011;
4 (5): 735-743.
5. Fedirko V, Bostick RM, Flanders WD, et al. Effects of Vitamin D and Calcium Supplementation on
Markers of Apoptosis in Normal Colon Mucosa: A Randomized, Double-Blind, Placebo-Controlled
Clinical Trial. Cancer Prevention Research. 2009; 2 (3): 213-223.
6. Provita P, Pendyala S, Nelson C, Augenlicht LH, Lipkin M, Holt PR. Calcium and 1,25dihydroxyvitamin D3 modulate genes of immune and inflammatory pathways in the human colon: a
human crossover trial. American Journal of Clinical Nutrition. March, 23 2016; doi: 10.3945/
ajcn.114.105304.
7. Baron JA, Barry EL, Mott LA, et al. A Trial of Calcium and Vitamin D for the Prevention of Colorectal
Adenomas. The New England Journal of Medicine. 2015; 373: 1519-1530.
8. Wactawski-Wende J, Kotchen JM, Anderson GL, et al. Calcium plus vitamin D supplementation and
the risk of colorectal cancer. The New England Journal of Medicine. 2006; 354 (7): 684-696.