Vitamin D Supplementation
to Prevent Cancer:
a Review of Medical Literature

Copyright 2021 by Ronald B. Standler
No copyright claimed for quotations.
No copyright claimed for works of the U.S. Government.

Introduction

On 18 February 2021 and 7-12 April 2021, I searched PubMed for articles in the medical literature on Vitamin D supplements to decrease the risk of cancers. Because there are more than 6000 articles, I concentrated on articles with a scholarly review of the medical literature since 1 January 2014.

There is an emerging consensus that the current minimum daily requirement of Vitamin D3 — only 800 International Units/day — is too low. Some of the articles cited below suggest a total intake of Vitamin D3 of 3000 or 4000 Units/day may reduce the risk of various cancers (e.g., colorectal, breast, prostate) by between 30% and 50%.

There is some evidence that higher levels of Vitamin D both decrease the risk of initial cancerous tumors and decrease the risk of recurrence of cancer (i.e., metastases). Other studies show that higher levels of Vitamin D may reduce the risk of death from cancer.

Before beginning Vitamin D supplementation, a physician should order a Vitamin D 25-Hydroxy blood test to determine a baseline level and to estimate the dose of Vitamin D3 supplementation.

While higher doses of Vitamin D3 are associated with lower risk of some cancers, there are two reasons to avoid very high doses of Vitamin D:
  1. There is obvious concern about toxicity of any lipid-soluble vitamin, like Vitamin D. The 13th edition of Goodman and Gilman's Pharmacological Basis of Therapeutics (p. 895) says at least 50,000 Units/day of Vitamin D "may result in poisoning". Blood serum concentrations of Vitamin D 25-Hydroxy greater than 50 ng/ml can cause hypercalciuria or hypercalcemia.

  2. The lipid-soluble vitamins have long half-lives in the body. Vitamin D3 has a 19 day half-life, which means that the patient can be sick for months if there is an overdose of Vitamin D.

While there are good reasons to believe that Vitamin D can prevent some cancers, some randomized clinical trials have concluded Vitamin D does not prevent cancer.

PubMed Search Queries

PubMed search queries:
  1. ((colon cancer[Text Word]) AND (Vitamin D[Text Word])) AND (Review[Title/Abstract])
  2. ((Review[Publication Type]) AND (Vitamin D[Title/Abstract])) AND (colorectal cancer[Title/Abstract])
  3. ((Vitamin D[Title/Abstract]) AND (cancer[Title/Abstract])) AND (3000[Title/Abstract]
  4. ((Vitamin D[Title/Abstract]) AND (cancer[Title/Abstract])) AND (4000[Title/Abstract]
  5. ((Clinical Trial[Publication Type]) AND (Vitamin D[Title/Abstract])) AND (Cancer[Title/Abstract])
  6. ((Randomized Controlled Trial[Publication Type]) AND (Vitamin D[Title/Abstract])) AND (Cancer[Title/Abstract])
  7. (((Vitamin D[Title/Abstract]) AND ((Cedric Garland[Author])) OR (Edward Gorham[Author])) OR (William B. Grant[Author]))
The following authors have written many papers on Vitamin D and cancer:

PubMed Search Results

The following text contains the PubMed URL for the article, bibliographic information, and the abstract of the article. The articles are in chronological order by date of publication in a printed journal, with the oldest first. The text was obtained by a cut-and-paste from PubMed, except for the title of the journal, which I typed. I have added my comments in green text after the abstract.
PubMed URL

J. Steroid Biochemistry and Molecular Biology, 2005 Oct;97(1-2): pp. 179-94.
doi: 10.1016/j.jsbmb.2005.06.018. Epub 2005 Oct 19.

Vitamin D and prevention of colorectal cancer

Edward D Gorham 1, Cedric F Garland, Frank C Garland, William B Grant, Sharif B Mohr, Martin Lipkin, Harold L Newmark, Edward Giovannucci, Melissa Wei, Michael F Holick

Abstract

Background: Inadequate photosynthesis or oral intake of Vitamin D are associated with high incidence rates of colorectal cancer, but the dose-response relationship has not been adequately studied.

Methods: Dose-response gradients from observational studies of Vitamin D intake and serum 25-hydroxyvitamin D were plotted as trend lines. The point on each linear trend line corresponding to an odds ratio of 0.50 provided the prediagnostic Vitamin D intake or 25-hydroxyvitamin D concentration associated with 50% lower risk compared to <100IU/day Vitamin D or <13ng/ml serum 25-hydroxyvitamin D. Medians of these values were determined.

Results: Overall, individuals with ≥1000IU/day oral Vitamin D (p<0.0001) or ≥33ng/ml (82nmol/l) serum 25-hydroxyvitamin D (p<0.01) had 50% lower incidence of colorectal cancer compared to reference values.

Conclusions: Intake of 1000IU/day of Vitamin D, half the safe upper intake established by the National Academy of Sciences, was associated with 50% lower risk. Serum 25-hydroxyvitamin D of 33ng/ml, which is known to be safe, also was associated with 50% lower risk. Prompt public health action is needed to increase intake of Vitamin D(3) to 1000IU/day, and to raise 25-hydroxyvitamin D by encouraging a modest duration of sunlight exposure.

Standler's comment: this one of the rare articles that mentions doses of Vitamin D3 in International Units.
PubMed URL

American Journal of Public Health, 2006 Feb; 96(2): pp. 252-61.
doi: 10.2105/AJPH.2004.045260.Epub 2005 Dec 27.

The role of vitamin D in cancer prevention

Cedric F Garland 1, Frank C Garland, Edward D Gorham, Martin Lipkin, Harold Newmark, Sharif B Mohr, Michael F Holick

Abstract

Vitamin D status differs by latitude and race, with residents of the northeastern United States and individuals with more skin pigmentation being at increased risk of deficiency. A PubMed database search yielded 63 observational studies of vitamin D status in relation to cancer risk, including 30 of colon, 13 of breast, 26 of prostate, and 7 of ovarian cancer, and several that assessed the association of vitamin D receptor genotype with cancer risk. The majority of studies found a protective relationship between sufficient vitamin D status and lower risk of cancer. The evidence suggests that efforts to improve vitamin D status, for example by vitamin D supplementation, could reduce cancer incidence and mortality at low cost, with few or no adverse effects.
PubMed URL

J. Steroid Biochemistry and Molecular Biology, 2007 Mar;103(3-5): pp. 708-11.
doi: 10.1016/j.jsbmb.2006.12.007.

Vitamin D and prevention of breast cancer: pooled analysis

Cedric F Garland 1, Edward D Gorham, Sharif B Mohr, William B Grant, Edward L Giovannucci, Martin Lipkin, Harold Newmark, Michael F Holick, Frank C Garland

Abstract

Background: Inadequate photosynthesis or oral intake of Vitamin D are associated with high incidence and mortality rates of breast cancer in ecological and observational studies, but the dose-response relationship in individuals has not been adequately studied.

Methods: A literature search for all studies that reported risk by of breast cancer by quantiles of 25(OH)D identified two studies with 1760 individuals. Data were pooled to assess the dose-response association between serum 25(OH)D and risk of breast cancer.

Results: The medians of the pooled quintiles of serum 25(OH)D were 6, 18, 29, 37 and 48 ng/ml. Pooled odds ratios for breast cancer from lowest to highest quintile, were 1.00, 0.90, 0.70, 0.70 and 0.50 (p trend<0.001). According to the pooled analysis, individuals with serum 25(OH)D of approximately 52 ng/ml had 50% lower risk of breast cancer than those with serum <13 ng/ml. This serum level corresponds to intake of 4000 IU/day. This exceeds the National Academy of Sciences upper limit of 2000 IU/day. A 25(OH)D level of 52 ng/ml could be maintained by intake of 2000 IU/day and, when appropriate, about 12 min/day in the sun, equivalent to oral intake of 3000 IU of Vitamin D(3).

Conclusions: Intake of 2000 IU/day of Vitamin D(3), and, when possible, very moderate exposure to sunlight, could raise serum 25(OH)D to 52 ng/ml, a level associated with reduction by 50% in incidence of breast cancer, according to observational studies.

Standler's comment: this one of the rare articles that mentions doses of Vitamin D3 in International Units.
PubMed URL

American J. Preventive Medicine, 2007 Mar; 32(3): pp. 210-6.
doi: 10.1016/j.amepre.2006.11.004.

Optimal vitamin D status for colorectal cancer prevention: a quantitative meta analysis

Edward D Gorham 1, Cedric F Garland, Frank C Garland, William B Grant, Sharif B Mohr, Martin Lipkin, Harold L Newmark, Edward Giovannucci, Melissa Wei, Michael F Holick

Abstract

Background: Previous studies, such as the Women's Health Initiative, have shown that a low dose of vitamin D did not protect against colorectal cancer, yet a meta-analysis indicates that a higher dose may reduce its incidence.

Methods: Five studies of serum 25(OH)D in association with colorectal cancer risk were identified using PubMed. The results of all five serum studies were combined using standard methods for pooled analysis. The pooled results were divided into quintiles with median 25(OH)D values of 6, 16, 22, 27, and 37 ng/mL. Odds ratios were calculated by quintile of the pooled data using Peto's Assumption-Free Method, with the lowest quintile of 25(OH)D as the reference group. A dose-response curve was plotted based on the odds for each quintile of the pooled data. Data were abstracted and analyzed in 2006.

Results: Odds ratios for the combined serum 25(OH)D studies, from lowest to highest quintile, were 1.00, 0.82, 0.66, 0.59, and 0.46 (p(trend)<0.0001) for colorectal cancer. According to the DerSimonian-Laird test for homogeneity of pooled data, the studies were homogeneous (chi2=1.09, df=4, p=0.90. The pooled odds ratio for the highest quintile versus the lowest was 0.49 (p<0.0001, 95% confidence interval, 0.35-0.68). A 50% lower risk of colorectal cancer was associated with a serum 25(OH)D level ≥33 ng/mL, compared to ≤12 ng/mL.

Conclusions: The evidence to date suggests that daily intake of 1000-2000 IU/day of vitamin D(3) could reduce the incidence of colorectal with minimal risk.

Standler's comment: this one of the rare articles that mentions doses of Vitamin D3 in International Units.
PubMed URL

Annals of Epidemiology, 2009 Feb;19(2):79-83.
doi: 10.1016/j.annepidem.2008.10.003.

A brief history of vitamin d and cancer prevention

Sharif B Mohr

Abstract

Purpose: To review the history of vitamin D and its use in cancer prevention.

Methods: The literature on published studies of vitamin D and its role in human health was reviewed and summarized.

Results: The modern history of vitamin D began in the mid-1800s, when it was noticed that city children were more likely to have rickets than rural children. Half a century later, Palm reported that children raised in sunny climates virtually never developed rickets. McCollum isolated vitamin D, and Windaus its precursors, receiving the Nobel Prize. Other scientists later observed that people with skin cancer had lower prevalence of nonskin cancers, and that lower overall mortality rates from all internal cancers combined existed in sunnier areas. These observations went largely unnoticed, and the field stagnated until 1970, when maps were created of cancer mortality rates. Through study of these maps, Cedric and Frank Garland of Johns Hopkins University reported a strong latitudinal gradient for colon cancer mortality rates in 1980, and hypothesized that higher levels of vitamin D compounds in the serum of people in the south were responsible, and that calcium intake also would reduce incidence. Edward Gorham and colleagues carried out cohort and nested studies, including the first study that found an association of a serum vitamin D compound with reduced cancer risk. William B. Grant then carried out numerous ecologic studies that extended the vitamin D-cancer theory to other cancers.

Conclusions: The history of the role of vitamin D in human health is rich and much of that history is yet to be written not only by scientists, but by policy makers with the vision and leadership necessary to bridge the gap between research and policy.
PubMed URL

Current Urology Reports, 2009 May;10(3):165-71.
doi: 10.1007/s11934-009-0029-4.

Chemoprevention of prostate cancer: what can be recommended to patients?

Janet L Colli, Christopher L Amling

Abstract

Prostate cancer is third to lung and colon cancer as the cause of cancer-related deaths in American men. It is estimated that there will have been more than 28,000 deaths and 186,000 new cases in 2008 that will impose a significant burden on national health care costs. Chemoprevention aims to reduce both incidence and mortality through the use of agents to prevent, reverse, or delay the carcinogenic process. This study provides clinicians with information on some chemoprevention agents that have been considered to reduce prostate cancer risks, including The evidence to support prostate cancer risk reduction benefits for each chemoprevention agent based on a review of the literature is provided.
PubMed URL

Annals of Epidemiology, 2009 Jul;19(7):468-83.
doi: 10.1016/j.annepidem.2009.03.021.

Vitamin D for cancer prevention: global perspective

Cedric F Garland, Edward D Gorham, Sharif B Mohr, Frank C Garland

Abstract

Purpose: Higher serum levels of the main circulating form of vitamin D, 25-hydroxyvitamin D (25(OH)D), are associated with substantially lower incidence rates of colon, breast, ovarian, renal, pancreatic, aggressive prostate and other cancers.

Methods: Epidemiological findings combined with newly discovered mechanisms suggest a new model of cancer etiology that accounts for these actions of 25(OH)D and calcium. Its seven phases are disjunction, initiation, natural selection, overgrowth, metastasis, involution, and transition (abbreviated DINOMIT). Vitamin D metabolites prevent disjunction of cells and are beneficial in other phases.

Results/conclusions: It is projected that raising the minimum year-around serum 25(OH)D level to 40 to 60 ng/mL (100-150 nmol/L) would prevent approximately 58,000 new cases of breast cancer and 49,000 new cases of colorectal cancer each year, and three fourths of deaths from these diseases in the United States and Canada, based on observational studies combined with a randomized trial. Such intakes also are expected to reduce case-fatality rates of patients who have breast, colorectal, or prostate cancer by half. There are no unreasonable risks from intake of 2000 IU per day of vitamin D(3), or from a population serum 25(OH)D level of 40 to 60 ng/mL. The time has arrived for nationally coordinated action to substantially increase intake of vitamin D and calcium.
PubMed URL

J. Clinical Endocrinology & Metabolism, 2012 Jul; 97(7): pp. 2315-24.
doi: 10.1210/jc.2012-1451. Epub 2012 Apr 16.

Vitamin D3 supplementation at 4000 international units per day for one year results in a decrease of positive cores at repeat biopsy in subjects with low-risk prostate cancer under active surveillance

David T Marshall 1, Stephen J Savage, Elizabeth Garrett-Mayer, Thomas E Keane, Bruce W Hollis, Ronald L Horst, Linda H Ambrose, Mark S Kindy, Sebastiano Gattoni-Celli

Abstract

Context: We wanted to investigate vitamin D in low-risk prostate cancer.

Objectives: The objective of the study was to determine whether vitamin D(3) supplementation at 4000 IU/d for 1 yr is safe and would result in a decrease in serum levels of prostate-specific antigen (PSA) or in the rate of progression.

Design: In this open-label clinical trial (Investigational New Drug 77,839), subjects were followed up until repeat biopsy.

Setting: All subjects were enrolled through the Medical University of South Carolina and the Ralph H. Johnson Veterans Affairs Medical Center, both in Charleston, SC.

Patients and other participants: All subjects had a diagnosis of low-risk prostate cancer. Fifty-two subjects were enrolled in the study, 48 completed 1 yr of supplementation, and 44 could be analyzed for both safety and efficacy objectives.

Intervention: The intervention included vitamin D(3) soft gels (4000 IU).

Main outcome measures: Adverse events were monitored throughout the study. PSA serum levels were measured at entry and every 2 months for 1 yr. Biopsy procedures were performed before enrollment (for eligibility) and after 1 yr of supplementation.

Results: No adverse events associated with vitamin D(3) supplementation were observed. No significant changes in PSA levels were observed. However, 24 of 44 subjects (55%) showed a decrease in the number of positive cores or decrease in Gleason score; five subjects (11%) showed no change; 15 subjects (34%) showed an increase in the number of positive cores or Gleason score.

Conclusion: Patients with low-risk prostate cancer under active surveillance may benefit from vitamin D(3) supplementation at 4000 IU/d.

Standler's comment: this one of the rare articles that mentions doses of Vitamin D3 in International Units.
PubMed URL

Nutrients, 2013 Sep 30;5(10):3993-4021.
doi: 10.3390/nu5103993.

Molecular link between vitamin D and cancer prevention

Meis Moukayed, William B Grant

Abstract

The metabolite of vitamin D, 1α,25-dihydroxyvitamin D₃ (also known as calcitriol), is a biologically active molecule required to maintain the physiological functions of several target tissues in the human body from conception to adulthood. Its molecular mode of action ranges from immediate nongenomic responses to longer term mechanisms that exert persistent genomic effects. The genomic mechanisms of vitamin D action rely on cross talk between 1α,25-dihydroxyvitamin D₃ signaling pathways and that of other growth factors or hormones that collectively regulate cell proliferation, differentiation and cell survival. In vitro and in vivo studies demonstrate a role for vitamin D (calcitriol) in modulating cellular growth and development. Vitamin D (calcitriol) acts as an antiproliferative agent in many tissues and significantly slows malignant cellular growth. Moreover, epidemiological studies have suggested that ultraviolet-B exposure can help reduce cancer risk and prevalence, indicating a potential role for vitamin D as a feasible agent to prevent cancer incidence and recurrence. With the preventive potential of this biologically active agent, we suggest that countries where cancer is on the rise — yet where sunlight and, hence, vitamin D may be easily acquired — adopt awareness, education and implementation strategies to increase supplementation with vitamin D in all age groups as a preventive measure to reduce cancer risk and prevalence.
PubMed URL

American Journal of Public Health, 2014 Sep;104(9):1783-7.
doi: 10.2105/AJPH.2013.301368. Epub 2013 Oct 17.

25-Hydroxyvitamin D in the range of 20 to 100 ng/mL and incidence of kidney stones

Stacie Nguyen, Leo Baggerly, Christine French, Robert P Heaney, Edward D Gorham, Cedric F Garland

Abstract

Objectives: Increasing 25-hydroxyvitamin D serum levels can prevent a wide range of diseases. There is a concern about increasing kidney stone risk with vitamin D supplementation. We used GrassrootsHealth data to examine the relationship between vitamin D status and kidney stone incidence.

Methods: The study included 2012 participants followed prospectively for a median of 19 months. Thirteen individuals self-reported kidney stones during the study period. Multivariate logistic regression was applied to assess the association between vitamin D status and kidney stones.

Results: We found no statistically significant association between serum 25-hydroxyvitamin D and kidney stones (P = .42). Body mass index was significantly associated with kidney stone risk (odds ratio = 3.5; 95% confidence interval = 1.1, 11.3).

Conclusions: We concluded that a serum 25-hydroxyvitamin D level of 20 to 100 nanograms per milliliter has no significant association with kidney stone incidence.
PubMed URL

World Journal of Gastrointestinal Oncology, 2014 Nov 15;6(11):430-7.
doi: 10.4251/wjgo.v6.i11.430.

Vitamin D and colon cancer

Lidija Klampfer

Abstract

Calcitriol, 1α, 25-dihydroxyvitamin D3 (1,25 (OH)2D3), the most active form of vitamin D, is a pleotropic hormone with a wide range of biological activities. Due to its ability to regulate calcium and phosphate metabolism, 1,25D3 plays a major role in bone health. In addition, 1,25D3 binds to the vitamin D receptor and thereby regulates the expression of a number of genes which control growth, differentiation and survival of cancer cells. In agreement, the levels of vitamin D3 appear to be an essential determinant for the development and progression of colon cancer and supplementation with vitamin D3 is effective in suppressing intestinal tumorigenesis in animal models. Vitamin D3 has been estimated to lower the incidence of colorectal cancer by 50%, which is consistent with the inverse correlation between dietary vitamin D3 intake or sunlight exposure and human colorectal cancer. Several studies confirmed that increasing vitamin D3 lowers colon cancer incidence, reduces polyp recurrence, and that sufficient levels of vitamin D3 are associated with better overall survival of colon cancer patients. Vitamin D regulates the homeostasis of intestinal epithelium by modulating the oncogenic Wnt signaling pathway and by inhibiting tumor-promoting inflammation. Both activities contribute to the ability of 1,25D3 to prevent the development and progression of colon cancer.

Standler's comment: this article discusses the biochemical basis for Vitamin D killing cancer cells.
PubMed URL

J. Steroid Biochemistry and Molecular Biology. 2015 Apr;148:239-44.
doi: 10.1016/j.jsbmb.2014.12.010. Epub 2014 Dec 19.

Could vitamin D sufficiency improve the survival of colorectal cancer patients?

Sharif B Mohr, Edward D Gorham, June Kim, Heather Hofflich, Raphael E Cuomo,  Cedric F Garland

Abstract

Purpose: To determine whether a higher serum 25-hydroxyvitamin D [25(OH)D] concentration at diagnosis is associated with longer survival of colorectal cancer patients.

Methods: A meta-analysis was performed of studies of the relationship between 25(OH)D and mortality of patients with colorectal cancer. A random-effects model was used to calculate a pooled hazards ratio. Homogeneity was evaluated through a DerSimonian-Laird test.

Results: Higher serum concentrations of 25(OH)D were associated with lower mortality in patients with colorectal cancer. Patients in the highest quintile of 25(OH)D had 37% lower mortality from colorectal cancer compared to those in the lowest quintile of 25(OH)D (pooled odds ratio=0.63, p<0.0001). Dose-response curves showed lower hazard ratios for mortality with higher serum 25(OH)D through at least 40ng/ml. There were no exceptions.

Conclusions: Higher serum 25(OH)D was associated with lower mortality of patients with colorectal cancer. These results suggest that colorectal cancer patients with deficient levels of serum 25(OH)D should have their levels restored to a normal range (30-80ng/ml). This could be done with regular testing of serum 25(OH)D to be confident that an adequate serum level is being maintained. Additional studies would be worthwhile to evaluate confounding or the possibility of reverse causation.
PubMed URL

International J. Cancer, 2015 May 15;136(10):2388-401.
doi: 10.1002/ijc.29277.Epub 2014 Nov 11.

Dietary supplement use and colorectal cancer risk: a systematic review and meta-analyses of prospective cohort studies

Renate C Heine-Bröring, Renate M Winkels, Jacoba M S Renkema, Lea Kragt, Anne-Claire B van Orten-Luiten, Ettje F Tigchelaar, Doris S M Chan, Teresa Norat, Ellen Kampman

Abstract

Use of dietary supplements is rising in countries where colorectal cancer is prevalent. We conducted a systematic literature review and meta-analyses of prospective cohort studies on dietary supplement use and colorectal cancer risk. We identified relevant studies in Medline, Embase and Cochrane up to January 2013. Original and peer-reviewed papers on dietary supplement use and colorectal cancer, colon cancer, or rectal cancer incidence were included. "Use-no use"(U-NU), "highest-lowest"(H-L) and "dose-response"(DR) meta-analyses were performed. Random-effects models were used to estimate summary estimates. In total, 24 papers were included in the meta-analyses. We observed inverse associations for colorectal cancer risk and multivitamin (U-NU: RR = 0.92; 95% CI: 0.87,0.97) and calcium supplements (U-NU: RR = 0.86; 95% CI: 0.79,0.95; H-L: RR = 0.80; 95% CI: 0.70,0.92; DR: for an increase of 100 mg/day, RR = 0.96; 95% CI: 0.94,0.99). Inconsistent associations were found for colon cancer risk and supplemental vitamin A and vitamin C, and for colorectal cancer risk and supplemental vitamin D, vitamin E, garlic and folic acid. Meta-analyses of observational studies suggest a beneficial role for multivitamins and calcium supplements on colorectal cancer risk, while the association with other supplements and colorectal cancer risk is inconsistent. Residual confounding of lifestyle factors might be present. Before recommendations can be made, an extensive assessment of dietary supplement use and a better understanding of underlying mechanisms is needed.
PubMed URL

J. Cancer, 2016 Jan 5;7(3):232-40.
doi: 10.7150/jca.13403. eCollection 2016.

Vitamin D and Colorectal, Breast, and Prostate Cancers: A Review of the Epidemiological Evidence

Elizabeth T Jacobs, Lindsay N Kohler, Andrew G Kunihiro, Peter W Jurutka

Abstract

Over the past two decades, the question of whether vitamin D has a role in cancer incidence, progression, and mortality has been studied in detail. Colorectal, breast, and prostate cancers have been a particular area of focus; together, these three malignancies account for approximately 35% of cancer cases and 20% of cancer deaths in the United States, and as such are a major public health concern. Herein, we review and synthesize the epidemiological research regarding vitamin D, as measured by the biomarker 25-hydroxycholecalciferol [25(OH)D], and the incidence, progression, and mortality of these cancers. Overall, the results of observational studies of the relationship between 25(OH)D and colorectal cancer have revealed a consistent inverse association for incidence and mortality; while for breast cancer, results have generally demonstrated a relationship between higher 25(OH)D and lower risk for progression and mortality. In contrast, randomized, double-blind clinical trials conducted to date have generally failed to support these findings. For prostate cancer, there is no convincing evidence of an association between 25(OH)D and incidence, and inconsistent data for progression and mortality, though results of one open label clinical trial suggest that supplementation with 4000 IU/d of vitamin D3 may inhibit progression of the disease. Nonetheless, until the results of additional ongoing randomized, double-blind clinical trials are reported, it will be difficult to ascertain if vitamin D itself is related to a reduction in risk for some cancer endpoints, or whether high concentrations of the vitamin D biomarker 25(OH)D may instead serve as a marker for an overall beneficial risk factor profile.
PubMed URL

British J. of Nutrition, 2016 May;115(9):1643-60.
doi: 10.1017/S0007114516000696.

Vitamin D and colorectal cancer: molecular, epidemiological and clinical evidence

Ruoxu Dou, Kimmie Ng, Edward L Giovannucci, JoAnn E Manson, Zhi Rong Qian,  Shuji Ogino

Abstract

In many cells throughout the body, vitamin D is converted into its active form calcitriol and binds to the vitamin D receptor (VDR), which functions as a transcription factor to regulate various biological processes including cellular differentiation and immune response. Vitamin D-metabolising enzymes (including CYP24A1 and CYP27B1) and VDR play major roles in exerting and regulating the effects of vitamin D. Preclinical and epidemiological studies have provided evidence for anti-cancer effects of vitamin D (particularly against colorectal cancer), although clinical trials have yet to prove its benefit. In addition, molecular pathological epidemiology research can provide insights into the interaction of vitamin D with tumour molecular and immunity status. Other future research directions include genome-wide research on VDR transcriptional targets, gene-environment interaction analyses and clinical trials on vitamin D efficacy in colorectal cancer patients. In this study, we review the literature on vitamin D and colorectal cancer from both mechanistic and population studies and discuss the links and controversies within and between the two parts of evidence.
PubMed URL

British Medical Journal, 2016 Dec 5;355:i6188.
doi: 10.1136/bmj.i6188.

Chemoprevention of colorectal cancer in individuals with previous colorectal neoplasia: systematic review and network meta-analysis

Parambir S Dulai, Siddharth Singh, Evelyn Marquez, Rohan Khera, Larry J Prokop,  Paul J Limburg, Samir Gupta, Mohammad Hassan Murad

Abstract

Objective: To assess the comparative efficacy and safety of candidate agents (low and high dose aspirin, non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs), calcium, vitamin D, folic acid, alone or in combination) for prevention of advanced metachronous neoplasia (that is, occurring at different times after resection of initial neoplasia) in individuals with previous colorectal neoplasia, through a systematic review and network meta-analysis.

Data sources: Medline, Embase, Web of Science, from inception to 15 October 2015; clinical trial registries.

Study selection: Randomized controlled trials in adults with previous colorectal neoplasia, treated with candidate chemoprevention agents, and compared with placebo or another candidate agent. Primary efficacy outcome was risk of advanced metachronous neoplasia; safety outcome was serious adverse events.

Data extraction: Two investigators identified studies and abstracted data. A Bayesian network meta-analysis was performed and relative ranking of agents was assessed with surface under the cumulative ranking (SUCRA) probabilities (ranging from 1, indicating that the treatment has a high likelihood to be best, to 0, indicating the treatment has a high likelihood to be worst). Quality of evidence was appraised with GRADE criteria.

Results: 15 randomized controlled trials (12 234 patients) comparing 10 different strategies were included. Compared with placebo, non-aspirin NSAIDs were ranked best for preventing advanced metachronous neoplasia (odds ratio 0.37, 95% credible interval 0.24 to 0.53; SUCRA=0.98; high quality evidence), followed by low-dose aspirin (0.71, 0.41 to 1.23; SUCRA=0.67; low quality evidence). Low dose aspirin, however, was ranked the safest among chemoprevention agents (0.78, 0.43 to 1.38; SUCRA=0.84), whereas non-aspirin NSAIDs (1.23, 0.95 to 1.64; SUCRA=0.26) were ranked low for safety. High dose aspirin was comparable with low dose aspirin in efficacy (1.12, 0.59 to 2.10; SUCRA=0.58) but had an inferior safety profile (SUCRA=0.51). Efficacy of agents for reducing metachronous colorectal cancer could not be estimated.

Conclusions: Among individuals with previous colorectal neoplasia, non-aspirin NSAIDs are the most effective agents for the prevention of advanced metachronous neoplasia, whereas low dose aspirin has the most favorable risk:benefit profile.
PubMed URL

Anticancer Research, 2018 Feb;38(2):1121-1136.
doi: 10.21873/anticanres.12331.

A Review of the Evidence Supporting the Vitamin D-Cancer Prevention Hypothesis in 2017

William B Grant

Abstract

The vitamin D-cancer prevention hypothesis has been evaluated through several types of studies, including geographical ecological studies related to indices of solar ultraviolet-B (UVB) dose (the primary source of vitamin D for most people), observational studies related to UVB exposure or serum 25-hydroxyvitamin D [25(OH)D] concentrations, laboratory studies of mechanisms, and clinical trials. Each approach has strengths and limitations. Ecological studies indirectly measure vitamin D production and incorporate the assumption that vitamin D mediates the effect of UVB exposure. Findings from observational studies with long follow-up times are affected by changing 25(OH)D concentrations over time. Most clinical trials have been poorly designed and conducted, based largely on guidelines for pharmaceutical drugs rather than on nutrients. However, three clinical trials do support the hypothesis. In general, the totality of the evidence, as evaluated using Hill's criteria for causality in a biological system, supports the vitamin D-cancer prevention hypothesis.

Text says:   "Clinical trials designed to show that vitamin D reduces cancer risk have largely been based on the pharmaceutical drug model: that the trial is the only source of the agent; and that there is a linear dose-response relationship. Unfortunately, that study model is not appropriate for vitamin D because vitamin D does not satisfy the two basic assumptions of drug trials: people obtain vitamin D from UVB exposure, diet, and supplements, and that the dose–response relationship is not linear."
PubMed URL

J. Nutrients, 2018 Jul 13;10(7):896.
doi: 10.3390/nu10070896.

Association between Blood 25-Hydroxyvitamin D Levels and Survival in Colorectal Cancer Patients: An Updated Systematic Review and Meta-Analysis

Haifa Maalmi, Viola Walter, Lina Jansen, Daniel Boakye, Ben Schöttker,  Michael Hoffmeister, Hermann Brenner

Abstract

Previous meta-analyses have shown an improved survival with higher blood 25-hydroxyvitamin D (25(OH)D) concentrations in patients with colorectal cancer (CRC). However, a number of much larger studies have been published since then. We provide an updated meta-analysis to synthesize current evidence. PubMed and Web of Science databases were systematically searched for eligible studies. The dose-response relationships and pooled hazard ratios for overall and CRC-specific survival comparing the highest versus the lowest categories of blood 25(OH)D concentrations were assessed. Subgroup analyses based on study geographic location, year of publication, sample size, length of follow-up time and stage were conducted to explore potential sources of heterogeneity. Overall, 11 original studies with a total of 7718 CRC patients were included. The dose-response meta-analysis showed an improvement in survival outcomes with increasing blood 25(OH)D concentrations. Pooled hazard ratios (95% confidence intervals) comparing highest versus lowest categories were 0.68 (0.55⁻0.85) and 0.67 (0.57⁻0.78) for overall and CRC-specific survival, respectively. Associations were more prominent among studies conducted in Europe, with larger sample sizes, and including stage I⁻IV patients. This updated meta-analysis reveals robust evidence of an association between higher blood 25(OH)D concentrations and better survival in CRC patients. The potential for enhancing prognosis of CRC patients by vitamin D supplementation should be explored by randomized trials.
PubMed URL

New England J. Medicine, 2019 Jan 3;380(1):33-44.
doi: 10.1056/NEJMoa1809944. Epub 2018 Nov 10.

Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease

JoAnn E Manson, Nancy R Cook, I-Min Lee, William Christen, Shari S Bassuk, Samia Mora, Heike Gibson, David Gordon, Trisha Copeland, Denise D'Agostino, Georgina Friedenberg, Claire Ridge, Vadim Bubes, Edward L Giovannucci, Walter C Willett, Julie E Buring, VITAL Research Group

Abstract

Background: It is unclear whether supplementation with vitamin D reduces the risk of cancer or cardiovascular disease, and data from randomized trials are limited.

Methods: We conducted a nationwide, randomized, placebo-controlled trial, with a two-by-two factorial design, of vitamin D3 (cholecalciferol) at a dose of 2000 IU per day and marine n-3 (also called omega-3) fatty acids at a dose of 1 g per day for the prevention of cancer and cardiovascular disease among men 50 years of age or older and women 55 years of age or older in the United States. Primary end points were invasive cancer of any type and major cardiovascular events (a composite of myocardial infarction, stroke, or death from cardiovascular causes). Secondary end points included site-specific cancers, death from cancer, and additional cardiovascular events. This article reports the results of the comparison of vitamin D with placebo.

Results: A total of 25,871 participants, including 5106 black participants, underwent randomization. Supplementation with vitamin D was not associated with a lower risk of either of the primary end points. During a median follow-up of 5.3 years, cancer was diagnosed in 1617 participants (793 in the vitamin D group and 824 in the placebo group; hazard ratio, 0.96; 95% confidence interval [CI], 0.88 to 1.06; P=0.47). A major cardiovascular event occurred in 805 participants (396 in the vitamin D group and 409 in the placebo group; hazard ratio, 0.97; 95% CI, 0.85 to 1.12; P=0.69). In the analyses of secondary end points, the hazard ratios were as follows: for death from cancer (341 deaths), 0.83 (95% CI, 0.67 to 1.02); for breast cancer, 1.02 (95% CI, 0.79 to 1.31); for prostate cancer, 0.88 (95% CI, 0.72 to 1.07); for colorectal cancer, 1.09 (95% CI, 0.73 to 1.62); for the expanded composite end point of major cardiovascular events plus coronary revascularization, 0.96 (95% CI, 0.86 to 1.08); for myocardial infarction, 0.96 (95% CI, 0.78 to 1.19); for stroke, 0.95 (95% CI, 0.76 to 1.20); and for death from cardiovascular causes, 1.11 (95% CI, 0.88 to 1.40). In the analysis of death from any cause (978 deaths), the hazard ratio was 0.99 (95% CI, 0.87 to 1.12). No excess risks of hypercalcemia or other adverse events were identified.

Conclusions: Supplementation with vitamin D did not result in a lower incidence of invasive cancer or cardiovascular events than placebo.

(Funded by the National Institutes of Health and others; VITAL ClinicalTrials.gov number, NCT01169259.).

Standler's comment: The conclusion of this article is disappointing. However, the authors did not measure serum magnesium levels. Magnesium has been shown to influence Vitamin D levels. See PubMed URL.

One year later, three authors of this NEJM study published an updated analysis, which concluded Vitamin D supplementation "showed a promising signal for reduction in total cancer mortality (HR = 0.83 [0.67-1.02]), especially in analyses that accounted for latency by excluding the first year (HR = 0.79 [0.63-0.99]) or first 2 years (HR = 0.75 [0.59-0.96]) of follow-up." See below.

PubMed URL

Annals of Oncology, 2019 May 1;30(5):733-743.
doi: 10.1093/annonc/mdz059.

Vitamin D supplementation and total cancer incidence and mortality: a meta-analysis of randomized controlled trials

N Keum, D H Lee, D C Greenwood, J E Manson, E Giovannucci

Abstract

Background: Previous meta-analyses of randomized controlled trials (RCTs) of vitamin D supplementation and total cancer incidence and mortality found inconsistent results, and most included trials administered generally low doses of vitamin D (≤1100 IU/day). We updated the meta-analysis by incorporating recent RCTs that have tested higher doses of vitamin D supplements.

Materials and methods: PubMed and Embase were searched from the inception to November 2018. Summary relative risks (RRs) and 95% confidence intervals (CIs) were estimated using a random-effects model.

Results: For total cancer incidence, 10 trials were included [6537 cases; 3-10 years of follow-up; 54-135 nmol/l of attained levels of circulating 25(OH) vitamin D [25(OH)D] in the intervention group]. The summary RR was 0.98 (95% CI, 0.93-1.03; P = 0.42; I2 = 0%). The results remained null across subgroups tested, including even when attained 25(OH)D levels exceeded 100 nmol/l (RR, 0.95; 95% CI, 0.83-1.09; P = 0.48; I2 = 26%). For total cancer mortality, five trials were included [1591 deaths; 3-10 years of follow-up; 54-135 nmol/l of attained levels of circulating 25(OH)D in the intervention group]. The summary RR was 0.87 (95% CI, 0.79-0.96; P = 0.005; I2 = 0%), which was largely attributable to interventions with daily dosing (as opposed to infrequent bolus dosing). No statistically significant heterogeneity was observed by attained levels of circulating 25(OH)D (Pheterogeneity = 0.83), with RR being 0.88 (95% CI, 0.78-0.98; P = 0.02; I2 = 0%) for ≤100 nmol/l and 0.85 (95% CI, 0.70-1.03; P = 0.11; I2 = 0%) for >100 nmol/l.

Conclusions: In an updated meta-analysis of RCTs, vitamin D supplementation significantly reduced total cancer mortality but did not reduce total cancer incidence.
PubMed URL

J. Gastrointestinal Cancer, 2019 Dec;50(4):769-779.
doi: 10.1007/s12029-018-0147-7.

Vitamin D Levels in Patients with Colorectal Cancer Before and After Treatment Initiation

Marissa B Savoie, Alan Paciorek, Li Zhang, Erin L Van Blarigan, Nilli Sommovilla,  Donald Abrams, Chloe E Atreya, Emily K Bergsland, Hueylan Chern,  Robin K Kelley, Andrew Ko, Angela Laffan, Ankit Sarin, Madhulika G Varma,  Alan P Venook, Katherine Van Loon

Abstract

Purpose: We aimed to described 25-hydroxyvitamin D [25(OH)D] levels in newly diagnosed colorectal cancer (CRC) patients and to re-evaluate levels after chemotherapy.

Methods: Permanent residents of the San Francisco Bay Area with a new CRC diagnosis of any stage were recruited prior to any non-surgical therapy. Serum 25(OH)D levels were measured at time of diagnosis and 6-month follow-up. Supplement use was not restricted. The primary endpoint was the frequency of vitamin D deficiency in patients with newly diagnosed CRC of all stages. The Kruskal-Wallis and Spearman correlation tests were used to evaluate associations of patient characteristics with 25(OH)D levels.

Results: Median 25(OH)D level at baseline was 27.0 ng/mL (range 7.2, 59.0); 65% of patients had insufficient levels (25(OH)D < 30 ng/mL) (n = 94). Race, disease stage, multivitamin use, vitamin D supplementation, and county of residence were associated with baseline 25(OH)D levels (P < 0.05). The median change in 25(OH)D from baseline to 6 months was - 0.7 ng/mL [- 19.4, 51.7] for patients treated with chemotherapy (n = 58) and 1.6 ng/mL [- 6.4, 33.2] for patients who did not receive chemotherapy (n = 19) (P = 0.26). For patients who received vitamin D supplementation during chemotherapy, the median 25(OH)D change was 8.3 ng/mL [- 7.6, 51.7] versus - 1.6 [- 19.4, 24.3] for chemotherapy patients who did not take vitamin D supplements (P = 0.02).

Conclusion: Among patients with a new diagnosis of CRC, most patients were found to have 25(OH)D levels consistent with either deficiency or insufficiency. In the subset of patients who received chemotherapy and took a vitamin D supplement, serum 25(OH)D levels increased, suggesting that vitamin D repletion is a feasible intervention during chemotherapy.
PubMed URL

Anticancer Research, 2020 Jan;40(1):491-499.
doi: 10.21873/anticanres.13977.

Review of Recent Advances in Understanding the Role of Vitamin D in Reducing Cancer Risk: Breast, Colorectal, Prostate, and Overall Cancer

William B Grant

Abstract

This article is a narrative review of recent epidemiological findings regarding ultraviolet-B (UVB) dose or exposure, serum 25-hydroxyvitamin D [25(OH)D] concentrations, vitamin D supplementation, and genetic variations in 25(OH)D concentration for incidence, survival, and mortality rates of overall and breast, colorectal, and prostate cancer. According to ecological studies, solar UVB doses are inversely correlated with incidence/mortality rates for about 20 cancer types. Observational studies support a role of higher 25(OH)D concentrations in reducing risk of breast and colorectal cancer incidence and mortality rates but, for prostate cancer, in increasing incidence rates while reducing mortality rates. Mendelian randomization studies offer little support for vitamin D in reducing cancer risk. Their primary limitation is that they only investigate small variations in genetically predicted 25(OH)D concentration near the population mean value. The secondary analyses from the VITAL clinical trial indicated significant reductions from 2000 IU/d of vitamin D3supplementation in all-cancer incidence and mortality rates for selected subgroups. Thus, Hill's criteria for causality in a biological system are now largely satisfied for supporting the claim that vitamin D reduces the risk of cancer incidence and death.
PubMed URL

J. Steroid Biochemistry and Molecular Biology, 2020 Apr;198:105522.
doi: 10.1016/j.jsbmb.2019.105522. Epub 2019 Nov 13.

Principal results of the VITamin D and OmegA-3 TriaL (VITAL) and updated meta-analyses of relevant vitamin D trials

JoAnn E Manson, Shari S Bassuk, Julie E Buring, VITAL Research Group

Abstract

Whether supplemental vitamin D reduces risk of cancer or cardiovascular disease (CVD) is relatively unexplored in randomized trial settings. The VITamin D and OmegA-3 TriaL (VITAL) was a nationwide, randomized, placebo-controlled, 2×2 factorial trial of daily vitamin D3 (2000 IU) and marine omega-3 fatty acids (1 g) in the primary prevention of cancer and CVD among 25,871 U.S. men aged ≥50 and women aged ≥55, including 5106 African Americans. Median treatment duration was 5.3 years. Vitamin D did not significantly reduce the primary endpoint of total invasive cancer incidence (hazard ratio [HR] = 0.96 [95% confidence interval 0.88-1.06]) but showed a promising signal for reduction in total cancer mortality (HR = 0.83 [0.67-1.02]), especially in analyses that accounted for latency by excluding the first year (HR = 0.79 [0.63-0.99]) or first 2 years (HR = 0.75 [0.59-0.96]) of follow-up. Vitamin D did not significantly reduce the co-primary endpoint of major CVD events (HR = 0.97 [0.85-1.12]), other cardiovascular endpoints, or all-cause mortality (HR = 0.99 [0.87-1.12]). Updated meta-analyses that include VITAL and other recent vitamin D trials indicate a significant reduction in cancer mortality but not in cancer incidence or CVD endpoints. Additional research is needed to determine which individuals may be most likely to derive a net benefit from vitamin D supplementation.

Standler's comment: Later analysis confirmed Vitamin D decreased mortality, but only for patients with normal weight, see below.

See original article, above.
PubMed URL

Cureus, 2020 Sep 30;12(9):e10734.
doi: 10.7759/cureus.10734.

Role of Vitamin D in Colorectal Cancer: A Holistic Approach and Review of the Clinical Utility

Moiz Javed, Aldanah Althwanay, Farah Ahsan, Federico Oliveri, Harshit K Goud,  Zainab Mehkari, Lubna Mohammed, Ian H Rutkofsky

Abstract

Vitamin D is well known for its effects on the homeostasis of calcium and phosphorus. Lately, considerable research has brought the extra-skeletal role of vitamin D under the spotlight, including its anti-cancer activity. Colorectal cancer (CRC) is the most extensively studied neoplasia that has been observed to be affected by vitamin D; the list includes breast, prostate, and ovarian cancer. This review aims to shine a light on the influence of vitamin D over CRC and to further understand its ability to be used as a potential economical treatment for CRC patients. For this review, PubMed was used as the main database for the literature search. Studies on the role of vitamin D on CRC within 10 years and all of the study types were included. Post the extensive research over PubMed, it was noted that vitamin D, through its effect on multiple pathways, especially Wnt/beta-catenin, apoptosis, and inflammation, hinders the progression of CRC carcinogenesis. High levels of this steroid hormone can delay the progression and may provide a cost-effective way of treating CRC patients. Further research and additional human trials are still due to bring about more knowledge on this topic. In conclusion, high serum levels of vitamin D are associated with a lower risk of incidence and progression of CRC.
PubMed URL

British J. of Cancer, 2020 Nov;123(11):1705-1712.
doi: 10.1038/s41416-020-01060-8. Epub 2020 Sep 15.

The effect of vitamin D supplementation on survival in patients with colorectal cancer: systematic review and meta-analysis of randomised controlled trials

Peter G Vaughan-Shaw, Louis F Buijs, James P Blackmur, Evi Theodoratou,  Lina Zgaga, Farhat V N Din, Susan M Farrington, Malcolm G Dunlop

Abstract

Background: Low circulating vitamin D levels are associated with poor colorectal cancer (CRC) survival. We assess whether vitamin D supplementation improves CRC survival outcomes.

Methods: PubMed and Web of Science were searched. Randomised controlled trial (RCTs) of vitamin D supplementation reporting CRC mortality were included. RCTs with high risk of bias were excluded from analysis. Random-effects meta-analysis models calculated estimates of survival benefit with supplementation. The review is registered on PROSPERO, registration number: CRD42020173397.

Results: Seven RCTs (n = 957 CRC cases) were identified: three trials included patients with CRC at outset, and four population trials reported survival in incident cases. Two RCTs were excluded from meta-analysis (high risk of bias; no hazard ratio (HR)). While trials varied in inclusion criteria, intervention dose and outcomes, meta-analysis found a 30% reduction in adverse CRC outcomes with supplementation (n = 815, HR = 0.70; 95% confidence interval (CI): 0.48-0.93). A beneficial effect was seen in trials of CRC patients (progression-free survival, HR = 0.65; 95% CI: 0.36-0.94), with suggestive effect in incident CRC cases from population trials (CRC-specific survival, HR = 0.76; 95% CI: 0.39-1.13). No heterogeneity or publication bias was noted.

Conclusions: Meta-analysis demonstrates a clinically meaningful benefit of vitamin D supplementation on CRC survival outcomes. Further well-designed, adequately powered RCTs are needed to fully evaluate benefit of supplementation in augmenting 'real-life' follow-up and adjuvant chemotherapy regimens, as well as determining optimal dosing.
PubMed URL

J. of the American Medical Association Network Open, 2020 Nov 2;3(11):e2025850.
doi: 10.1001/jamanetworkopen.2020.25850.

Effect of Vitamin D3 Supplements on Development of Advanced Cancer: A Secondary Analysis of the VITAL Randomized Clinical Trial

Paulette D Chandler, Wendy Y Chen, Oluremi N Ajala, Aditi Hazra, Nancy Cook, Vadim Bubes, I-Min Lee, Edward L Giovannucci, Walter Willett, Julie E Buring, JoAnn E Manson, VITAL Research Group

Abstract

Importance: Epidemiologic and trial data suggest that vitamin D supplementation may reduce metastatic cancer and cancer mortality, reflecting shared biological pathways.

Objective: To follow up on the possible reduction in cancer death in the Vitamin D and Omega-3 Trial (VITAL) with an evaluation of whether vitamin D reduces the incidence of advanced (metastatic or fatal) cancer and an examination possible effect modification by body mass index.

Design, setting, and participants: VITAL is a randomized, double-blind, placebo-controlled, 2×2 factorial clinical trial of vitamin D3 (cholecalciferol, 2000 IU/d) and marine omega-3 fatty acids (1 g/d). This multicenter clinical trial was conducted in the United States; participants included men aged 50 years or older and women aged 55 years or older who were free of cancer and cardiovascular disease at baseline. Randomization took place from November 2011 through March 2014, and study medication ended on December 31, 2017. Data for this secondary analysis were analyzed from November 1, 2011, to December 31, 2017.

Interventions: Vitamin D3 (cholecalciferol, 2000 IU/d) and marine omega-3 fatty acids (1 g/d) supplements.

Main outcomes and measures: For the present analysis, the primary outcome was a composite incidence of metastatic and fatal invasive total cancer, because the main VITAL study showed a possible reduction in fatal cancer with vitamin D supplementation and effect modification by body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) for total cancer incidence reduction for individuals with normal BMI, but not for individuals with overweight or obesity. Secondary analyses included examination of BMI (<25, 25 to < 30, and ≥30) as effect modifiers of the observed associations.

Results: Among 25,871 randomized VITAL participants (51% female; mean [SD] age, 67.1 [7.1] years), 1617 were diagnosed with invasive cancer over a median intervention period of 5.3 years (range, 3.8-6.1 years). As previously reported, no significant differences for cancer incidence by treatment arm were observed. However, a significant reduction in advanced cancers (metastatic or fatal) was found for those randomized to vitamin D compared with placebo (226 of 12,927 assigned to vitamin D [1.7%] and 274 of 12,944 assigned to placebo [2.1%]; HR, 0.83 [95% CI, 0.69-0.99]; P = .04). When stratified by BMI, there was a significant reduction for the vitamin D arm in incident metastatic or fatal cancer among those with normal BMI (BMI<25: HR, 0.62 [95% CI, 0.45-0.86]) but not among those with overweight or obesity (BMI 25-<30: HR, 0.89 [95% CI, 0.68-1.17]; BMI≥30: HR, 1.05 [95% CI, 0.74-1.49]) (P = .03 for interaction by BMI).

Conclusions and relevance: In this randomized clinical trial, supplementation with vitamin D reduced the incidence of advanced (metastatic or fatal) cancer in the overall cohort, with the strongest risk reduction seen in individuals with normal weight.

Standler's comment: It is well known that obesity is a risk factor for cancer.

This document is at   http://www.rbs0.com/VitD.htm
created 9 April 2021, modified 13 April 2021

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