Vitamin D Supplementation to Prevent Colorectal Cancer
By David Kiefer, MD. Dr. Kiefer recently completed a fellowship at the Program in Integrative Medicine, College of Medicine, University of Arizona in Tucson; he reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study.
Evidence has accumulated about the possible involvement of vitamin D in the prevention of various types of cancer. From the 1930s and 1940s, with the observation that lower cancer rates may occur with sunlight exposure and in lower latitudes, researchers have demonstrated connections between vitamin D status and ultraviolet-B (UVB) exposure and breast, colon, and ovarian cancer risk.1 This article will explore details about the use of supplemental vitamin D specifically for the prevention of colorectal cancer.
As detailed in a prior article for this publication,2 the body is able to make its own vitamin D, produced when ultraviolet light (specifically UVB) contacts the skin and converts 7-dehydroxycholesterol to cholecalciferol, also called vitamin D3.3-5 Vitamin D3 is then hydroxylated in the liver to make 25-hydroxyvitamin D (calcitriol, or 25(OH)D), which predominates in the human body;5 25(OH)D is the compound most commonly used to check a person's overall vitamin D status.4 The more potent but less prevalent (0.1% concentration of 25(OH)D) form of vitamin D, 1,25-dihydroxyvitamin D (1,25-(OH)2D), is created through further hydroxylation, primarily in the mitochondria of the renal tubules in the kidney.
Approximately 3,000-5,000 IU of cholecalciferol is necessary for normal daily metabolism;6,7 a combination of oral intake, sun exposure, and release from tissue stores accounts for this amount. The contribution from diet is usually minimal; for example, in mid-latitudes, 90-95% of circulating 25(OH)D results from UVB exposure.8 Circulating 25(OH)D levels are an accepted way to measure vitamin D status, and is either reported as nmol/L or ng/mL. Severe vitamin D deficiency and a risk for rickets occurs at levels lower than 8-10 ng/mL (20-25 nmol/L), whereas 10-16 ng/mL (25-40 nmol/L) is common in the winter among populations in northern latitudes and is still associated with physiological alterations that could affect bone health.6 Serum 25(OH)D levels below 30 ng/mL (75 nmol/L) are associated with increased cancer risk,9 whereas toxicities occur with levels of 400-1,250 nmol/L (160 to 500 ng/mL).10
Basic science research has discovered many possible mechanisms through which the different forms of vitamin D may have anticancer effects (see Table 1).9,11 Most anticancer effects have been attributed to 1,25-(OH)2D, the more active form, but some conversion from 25(OH)D may take place in tissues other than the kidney (such as the colon), so 25(OH)D itself may also possess anticancer effects.11
Research has begun to demonstrate that some of the anticancer effects of vitamin D may be mediated through vitamin D receptors, present in many cell types.1 When these receptors are bound to 1,25-(OH)2D, the cells are signaled to differentiate and stop proliferating, and are less likely to metastasize or develop new blood vessels. Furthermore, certain neoplastic mouse models show increased tumor formation with high fat, low calcium, and low vitamin D intake within what is normal for Western diets.12 It may be possible to reverse these trends by supplementing the Western diet with calcium and vitamin D, in some cases showing a return to normal gene expression whether or not the fat content of the diet was changed.
Vitamin D has many other physiological effects, such as facilitating active calcium absorption from the lumen of the intestine, important in maintaining bone density and preventing fractures, and prevention of other conditions such as diabetes and autoimmune diseases.2-4,8
Vitamin D deficiency is thought by many experts to be an epidemic in the United States.4 One demographic particularly at risk is the elderly; vitamin D deficiency occurs in the elderly because of decreased sunlight exposure, suboptimal nutrition, and skin that is less efficient in producing vitamin D.13 However, the problem may be more extensive. Data from the Women's Health Initiative (WHI) was used to examine calcium and vitamin D intake from dietary and supplement sources in 223 colorectal cancer cases among 36,976 women.14 A 131-item food questionnaire was used and estimates were conducted for vitamin D intake from multivitamins; it was unclear if extra vitamin D supplements were accounted for in the analysis. The cohort median intakes were 882 mg daily of calcium and 271 IU daily of vitamin D; of this, 705 mg and 205 IU came from food, respectively. Sunlight exposure was not accounted for in this analysis, but it does tell us that, overall, the intake of vitamin D in this demographic is below what is being recommended for overall health and cancer prevention as discussed below.
Researchers have demonstrated that vitamin D supplementation can improve serum vitamin D. For example, in one study of 553 community-dwelling women aged 65 and older, the women were given 400 IU vitamin D as part of a multivitamin and 1-2 tablets of calcium carbonate (600 mg) plus 200 IU vitamin D, for a total of 400-800 IU vitamin D daily for three months.15 This was not a placebo-controlled trial, but the supplementation regimen decreased the rate of vitamin D deficiency as measured by serum 25(OH)D.
In another study, 139 men and women aged 40-83 years filled out a food questionnaire, and vitamin D intake was estimated (average per day) while serum 25(OH)D was checked.16 Of this group, 27 took supplements with vitamin D, which when combined with diet, yielded an average daily vitamin D intake of 374 IU for men and 354 IU for women. There was a slight and significant correlation (coefficient 0.34) between vitamin D intake and serum 25(OH)D, slightly higher for users of supplements during seasons of low light.
It appears that dietary intake influences serum vitamin D more when there is low sunlight exposure. A study in 67 men having only one glass of milk a day and no supplements in Omaha, NE, during the winter were checked for 25(OH)D and given different doses of vitamin D (either no cholecalciferol, 1,000 IU, 5,000 IU, or 10,000 IU daily), leading to a direct correlation between the dose and serum vitamin D levels.7 The researchers also found that, at a minimum, 500 IU daily was necessary to keep this serum 25(OH)D constant.
A comprehensive review of the epidemiological evidence assessed the effect of serum vitamin D markers, serum vitamin D metabolites, or sunlight on the risk or mortality of several different cancers,9 including both colon cancer and adenomatous polyps (see Table 2). There are several significant associations between vitamin D and colon cancer: Colon cancer mortality rates are higher with lower sunlight, there is increased risk of colon cancer or polyps for people with serum 25(OH)D less than 30 ng/mL (75 nmol/L), and risk of colon cancer is higher in people who consume lower amounts of vitamin D.
Using data from 18 observational studies (four examining serum 25(OH)D and 14 oral vitamin D), one statistical analysis calculated that an intake of 1,000 IU of vitamin D daily or a serum concentration of 25(OH)D of at least 33 ng/mL (82 nmol/L) would lead to a 50% decrease in the risk of colon cancer.8 The level of supplementation suggested by this study is higher than most previous recommendations.
Many of the clinical trials on the effects of vitamin D supplementation are complicated by the co-administration of calcium. The physiological activities of calcium and vitamin D are closely tied, not only for bone health but also for cancer prevention, so the methodology is sound even as it makes it difficult to sort out the isolated effect of vitamin D.
One randomized, double-blind trial in 36,282 postmenopausal women compared the incidence of colorectal cancer over seven years between two groups receiving either 400 IU daily of vitamin D3 plus 1,000 mg elemental calcium (as calcium carbonate) daily or placebo.17 This trial was a continuation of the WHI, the first part of which was to examine the risks and benefits of hormone therapy and dietary changes in menopause. For those who agreed to this part of the WHI, blood initially was drawn to be used in a nested case-control study to examine the odds ratio of cancer risk related to baseline 25(OH)D, and patients received colon cancer screening as their personal physician recommended. An intention-to-treat analysis of the 322 invasive colorectal carcinomas in the study group revealed that the calcium and vitamin D group had the same cancer risk as the placebo group. Furthermore, for these cancer cases, the baseline 25(OH)D did not correlate with any increase or decrease in risk, though a statistically significant trend (P = 0.02) did display that lower baseline 25(OH)D was inversely correlated with colorectal cancer risk. Some of the problems with this study include the fact that neither study duration (seven years) nor the vitamin D dose employed may be enough to demonstrate an effect. Also, the demographic studied was generally already healthy and took supplemental calcium and vitamin D in amounts (1,151 mg and 367 IU, respectively) about twice what is average for the U.S. population; this compromises the generalizability of these results.18
Another nested case-control study in the Nurses Health Study examined the plasma 25(OH)D levels in 193 colorectal cancer cases.11 A statistically-significant inverse relationship was observed between cancer risk and serum 25(OH)D level for women older than 60 years; the odds ratio was 0.53 for the women in the group with the highest range of 25(OH)D. The decreased incidence of cancer held for the distal colon and rectum but not for the proximal colon.
Another trial combining calcium and vitamin D randomized 19 patients with adenomatous polyps in the colon or rectum to either partial resection plus placebo or partial resection and supplementation with 1,500 mg three times daily calcium carbonate plus 400 IU vitamin D3 daily for six months.19 Various pathological techniques and immunohistochemical stainings were used to estimated the presence of vitamin D receptors, the proliferation and apoptosis of the remaining cells, and the expression of certain oncogenic proteins. The treatment group showed a significant reduction in the number of cells that initially remained behind after the partial resection; there was also a decrease in the proliferation of those cells, though the amount of apoptosis did not change. This is an interesting preliminary study, though it is small and difficult to estimate whether the effect observed was due to calcium, vitamin D, or both.
Dosing and Sources of Vitamin D
The Daily Reference Intakes (DRI) for vitamin D are 200 IU for infants, children, adults through age 50 and pregnant and lactating women; adults age 50-69 years have a DRI of 400 IU, and adults age 70 and older, 600 IU.20 As alluded to in some of the research reviewed above, the dose of vitamin D necessary to achieve optimal cancer prevention will depend on a person's vitamin D status, diet, geographic location, and sunlight exposure, but anticancer daily intakes probably should be closer to 1,000 IU.
Sunlight exposure generally provides 90-95% of a person's vitamin D needs, and, even though the conversion reaction in the skin upon exposure to UVB radiation is less efficient as a person ages, it is usually sufficient.4 During the spring, summer, and fall, 5-15 minutes daily of sun exposure during the middle of the day on the arms and legs, or arms, hands, and face is usually sufficient to provide adequate vitamin D, after which people should use sunscreen, cover up, and/or move into the shade or indoors.4 In the frail elderly, it is also possible to normalize vitamin D status by facilitating time outdoors, with 15-30 minutes daily being adequate in a temperate climate.5,21
Most supplements contain either vitamin D2, made by exposing ergosterol from yeast to UVB radiation, or vitamin D3, both of which are used by the body to make 25(OH)D.4 There is some evidence that vitamin D3 in the same doses increases serum 25(OH)D more than vitamin D2.22,23 One study randomized 72 people to take either 4,000 IU per day of vitamin D2 or vitamin D3 for 14 days during the winter.24 The serum 25(OH)D was checked at baseline and post-treatment; the vitamin D3 group displayed a 1.7 times higher rise in serum 25(OH)D (P = 0.03), which translated into an extra 7 nmol/L rise in the serum value. Those individuals with lower baseline 25(OH)D showed a better response to supplemental vitamin D.
In addition to vitamin D-fortified foods such as milk and bread, a few foods naturally contain vitamin D, at a dose of approximately 400-500 IU per serving; these include oily fish (salmon, mackerel, herring) and sun-dried mushrooms.4
Vitamin D supplementation as described in the above trials is well tolerated, with adverse effect reports similar to those from the placebo groups in most cases. Some sources state that high doses of vitamin D (50 mcg, or 2,000 IU, in both children and adults) can lead to calcinosis and hypercalciuria; therefore, in people with these pre-existing conditions or other conditions where elevated calcium would be a problem, vitamin D supplementation should be avoided.6,25 Other experts have published that the safe upper limit of 2,000 IU daily is overly conservative and that true adverse effects only surface at much higher doses, such as when 10,000-50,000 IU are consumed on a daily basis for long periods of time.10 Also, some caution is advised with excessive vitamin D supplementation in people taking thiazide diuretics, as thiazides can decrease the urinary excretion of calcium.
There is convincing basic science for the anticancer effects of vitamin D, corroborating what has been observed for colon cancer risk and mortality with sunlight exposure, geographic location, vitamin D intake, and serum 25(OH)D levels. Serum 25(OH)D levels can be checked and levels below 30 ng/mL (75 nmol/L) are associated with increased cancer risk. Vitamin D3 seems to be the optimal form of supplemental vitamin D, and cancer protective doses depend on the individual, but some studies point to a vitamin D DRI level of 200-600 IU, though the optimal amount is more likely closer to 1,000 IU daily. A cancer prevention strategy utilizing vitamin D is most effective when combined with adequate intakes of calcium, except for men at risk of prostate cancer due to a possible increased risk with calcium intakes above 600 mg/d.26 Vitamin D is very well tolerated in doses lower than 2,000 IU daily, except for some individuals with pre-existing conditions involving abnormal calcium metabolism.
Given that vitamin D deficiency is a common problem, especially as people age, health care practitioners should consider checking serum hydroxyvitamin D; optimal levels to help prevent colorectal and other cancers should be above 30 ng/mL. There is good evidence that supplementation with cholecalciferol (vitamin D3) decreases colorectal cancer risk and mortality. Vitamin D3 is the preferred form, and the dose should be at least in line with the DRIs; some evidence is accumulating that higher doses, more along the lines of 1,000 IU daily are optimal, but this certainly depends on a person's vitamin D status and sunlight exposure.
The positive effects of vitamin D supplementation appear to occur with simultaneous calcium supplementation, so patients should be counseled about appropriate doses of dietary and supplemental calcium. Regarding calcium supplementation, caution is advised for men at risk of prostate cancer; moderate calcium intakes (less than 600 mg daily from supplements and food) is recommended until this issue is further clarified in the medical literature. Given the evidence accumulating for cancer risk associated with vitamin D deficiency, all people should ensure adequate vitamin D intake, whether from supplementation, enriched or high-vitamin D foods, or prudent sunlight exposure.
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