For many years, investigators have been trying to pin down the tantalizing connection between vitamin D and cancer.
Epidemiological studies have found that people who live near the equator, where exposure to sunlight produces more vitamin D, have lower incidence and death rates from certain cancers.
In cancer cells in the lab and in mouse models, vitamin D has also been found to slow cancer progression. But the results of randomized clinical trials in humans haven’t yielded a clear answer. The Vitamin D and Omega-3 Trial (VITAL), which concluded in 2018, found that vitamin D did not reduce overall incidence of cancer, but hinted at a decreased risk of cancer deaths.
Now, in a secondary analysis of VITAL, a team led by investigators at Brigham and Women’s Hospital has narrowed in on the connection between taking vitamin D supplements and risk of metastatic or fatal cancer.
In a paper published in JAMA Network Open, the team reports that vitamin D was associated with an overall 17 percent risk reduction for advanced cancer. When the team looked at only participants with a normal body mass index (BMI), they found a 38 percent risk reduction, suggesting that body mass may influence the relationship between vitamin D and decreased risk of advanced cancer.
“These findings suggest that vitamin D may reduce the risk of developing advanced cancers,” said corresponding author Paulette Chandler, MD, MPH, a primary care physician and epidemiologist in the Brigham’s Division of Preventive Medicine. “Vitamin D is a supplement that’s readily available, cheap and has been used and studied for decades.
Our findings, especially the strong risk reduction seen in individuals with normal weight, provide new information about the relationship between vitamin D and advanced cancer.”
The VITAL study was a rigorous, placebo-controlled study that took place over a span of more than five years. The VITAL study population included men who were 50 or older and women 55 or older who did not have cancer when the trial began.
The study population was racially and ethnically diverse. VITAL was designed to test the independent effects of vitamin D and omega-3 supplements as well as to test for synergy between the two.
Participants were divided into four groups: vitamin D (2000 IU/day) plus omega-3s; vitamin D plus placebo; omega-3s plus placebo; and placebos for both.
Primary endpoints were major adverse cardiovascular events and incidence of cancer. VITAL did not find a statistical difference in overall cancer rates, but researchers did observe a reduction in cancer-related deaths.
In their secondary analysis, Chandler and colleagues followed up on the possible reduction in cancer deaths with an evaluation of advanced (metastatic or fatal) cancer among participants who did or did not take vitamin D supplements during the trial. They also examined the possible modifying effect of BMI.
Among the more than 25,000 participants in the VITAL study, 1,617 were diagnosed with invasive cancer over the next five years. This included a broad mix of cancers (breast, prostate, colorectal, lung and more).
Of the almost 13,000 participants who received vitamin D, 226 were diagnosed with advanced cancer compared to 274 who received the placebo. Of the 7,843 participants with a normal body mass index (BMI less than 25) taking vitamin D, only 58 were diagnosed with advanced cancer compared with 96 taking the placebo.
While the team’s findings on BMI could be due to chance, there is previous evidence that body mass may affect vitamin D action. Obesity and associated inflammation may decrease the effectiveness of vitamin D, possibly by reducing vitamin D receptor sensitivity or altering vitamin D signaling.
In addition, randomized trials of vitamin D and type 2 diabetes have found greater benefits of vitamin D in people with normal weights and no benefit among those with obesity.
Vitamin D deficiency is common among cancer patients, with one study reporting rates of vitamin D deficiency as high as 72 percent among cancer patients. There is also evidence that higher amounts of body fat are associated with increased risk for several cancers.
“Our findings, along with results from previous studies, support the ongoing evaluation of vitamin D supplementation for preventing metastatic cancer—a connection that is biologically plausible,” said Chandler. “Additional studies focusing on cancer patients and investigating the role of BMI are warranted.”
Epidemiological studies showed that vitamin D deficiency is associated with increased mortality; however, there was not enough evidence that vitamin D status is inversely associated with cancer mortality [1].
The association between cancer risk and vitamin D has been studied in many epidemiologic studies, while data from interventional studies remain insufficient [2].
Almost all studies have proven that vitamin D has a strong and beneficial effect antagonizing and blocking multiple mitogenic processes related to tumorigenesis [2]. The association between solar ultraviolet-B exposure and cancer was proven, and it was stronger for mortality than for incidence for many cancers in the USA and China [3,4].
Vitamin D is highly important for bone health and mineral metabolism, and it is quite known that vitamin D deficiency can lead to rickets, osteomalacia and many other diseases [5]. In the recent past, however, vitamin D has been studied for the prevention of many highly prevalent cancer types.
One of the most important studies was a randomized controlled trial (RCT) in 2003 that provided good evidence of the antineoplastic effect that vitamin D had in the colon, in addition to the role of vitamin D in reducing the recurrence of colorectal adenoma [6].
In a recent meta-analysis of observational studies, low 25-hydroxy vitamin D level was directly related to breast cancer, while total vitamin D and supplemental vitamin D intake had an inverse relationship with breast cancer [7].
Although The USA Preventive Services Task Force stated in 2014 that data were insufficient to confirm the effectiveness of vitamin D supplementation for cardiovascular disease or cancer prevention [8], yet, the role of vitamin D supplementation in primary prevention for cancer is promising [9]. With rapidly surfacing large randomized controlled trials (RCTs) studying this subject [10–13], we aimed to evaluate the efficacy and safety of vitamin D supplementation as a means of primary prevention of cancer.
Discussion
In this meta-analysis of 10 RCTs, vitamin D supplementation was compared to placebo. With the use of vitamin D supplementation for at least 3 years, it was found to have benefit in reducing cancer-related mortality, however, it had no effect on cancer incidence. And when conducting a subgroup analysis including the three RCTs where cancer was reported as a primary outcome, the results were also consistent with the initial analysis results.
Several retrospective studies, large RCTs and meta-analyses have evaluated the role of vitamin D in cancer primary prevention. According to the last review that studied the role of vitamin D in primary prevention of cancer, it was proven that vitamin D supplementation alone as primary prevention had no effect on cancer mortality and incidence.
And that was after including 30 RCTs that reported cancer in their outcomes and despite including those that had long-term follow-up [21].
Keum et al., in their 2014 review, which included four RCTs with a minimum of 5 years of vitamin D supplementation, proved that long-term vitamin D supplementation did have a benefit in cancer prevention, however, only limited to cancer-related mortality [22].
In 2014, a Cochrane review also concluded that there could be decreases in all-cause mortality and cancer-related mortality among vitamin D–treated people in comparison with those who never received it. However, these results could be due to random errors [23].
Keum et al. recently reanalyzed their initial meta-analysis by adding newer RCTs with longer follow-up, which proved that vitamin D supplementation significantly reduced total cancer mortality but did not reduce total cancer incidence [24].
The strengths of our meta-analysis include an extensive search of the available literature. Furthermore, we included only RCTs, which helps eliminate the likelihood of confounding bias from nonrandomized studies. However, there are several limitations in the included clinical trials.
- First, over half of the included trials were not primarily studying vitamin D with the intent of preventing cancer and rather all the results were obtained by examining other reported primary outcomes.
- Second, due to various trial designs and protocols, there were major differences in the vitamin D forms and dosing.
- Third, only a few clinical trials reported all the predetermined outcomes of our study, and some trials reported only one of the two outcomes either directly or indirectly. Fourth, the follow-up period was short in some of the trials.
- Fifth, not all trials reported the end of trial 25-hydroxy vitamin D level to examine if the blood vitamin D levels had any effect on cancer mortality or incidence.
Conclusion
With inclusion of studies, which did not primarily examine vitamin D for the purpose of preventing cancer or reducing cancer mortality our meta-analysis highlights that the use of vitamin D supplementation for primary prevention of cancer is encouraged as it does possibly decrease cancer-related mortality once cancer is diagnosed; however, it has no role or effect on cancer incidence. However, this also opens questions for the future with the need for clinical trials that can account for all the limitations of our study including vitamin D form and dosing, length of therapy and exact therapeutic vitamin D levels, to provide stronger evidence and recommendations for the future.
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More information: Chandler PD et al. “Effect of Vitamin D3 Supplements on Development of Advanced Cancer” JAMA Network Open DOI: 10.1001/jamanetworkopen.2020.25850
