Summary of Findings
- More than 60 epidemiology studies conducted over the last 20 years have shown that Vitamin D deficiency is associated with increased rates of cancer. (8)
- A placebo controlled study has confirmed these findings. In the study, vitamin D supplements reduced the incidence of cancer by as much as 77% compared to patients who were given placebo (sugar pill).(29)
- The incidence of cancer is reduced by 17% and the death rate from cancer by 29% for every 10ng/ml increase in the blood level of vitamin D. The effect is particularly strong for cancers of the gastrointestinal tract where the reduction in death rate was 45% for the same increase in plasma levels of vitamin D. (30)
- Two clinical trials have demonstrated that the higher the blood level of vitamin D, the greater the degree of protection against developing cancer. (29) (30)
- A prospective study in Finland showed that women with the highest levels of vitamin D had an 84% reduction in their risk of developing lung cancer (34)
- Those living at lower latitudes and being exposed to more sun light, and thus, they had higher vitamin D levels reduced the risk of developing lung cancer by 45% in men and 65% in women.(33)
- The incidence of colon cancer is 4-6 times higher in northern regions compared to countries near the equator.(35)
- The risk of colon cancer was reduced five fold if vitamin D levels were between 33-41ng/ml.(37)
- There was a 72% reduction in the incidence of colorectal cancer between groups of patients with the highest and lowest levels (<20ng/ml vis >32ng/ml) of vitamin D.(40)
- Women living in Southern areas had an almost 60% reduction in their risk of developing breast cancer compared to those living in Northern areas. (44)
- Comparing women with the lowest and highest levels of vitamin D, there was a almost a 70% reduction of the risk of developing breast cancer in those with the highest levels. (43)
- Men with low levels of vitamin D(below 16ng/ml) were three times more likely to develop prostate cancer and six times more likely to develop aggressive invasive cancer than men with higher levels.(50)
- Two studies have suggested that the incidence of prostate cancer is reduced as much as 50% in men who were born in areas of high sun exposure which implies that high levels of Vitamin D in early life confers a long lasting anti-cancer effect. (138, 139)
- Two large long-term studies have shown that adults who have a higher dietary intake of vitamin D (300-400IU) have almost half the risk of developing pancreatic cancer than those with less than 150IU vitamin D in their diet. (54)
Worldwide Reaction to these Data
- The Canadian Cancer Society now recommends that all Canadians take vitamin D supplements to reduce their risk of cancer.
- The US Vitamin D Council recommends that everyone take at least 2000IU/day in the summer and 5000IU/day in the winter.
- A major healthcare provider in the US (Aurora Healthcare) has suggested that all Wisconsin residents take vitamin D and has started a program to educate its physicians about the dangers of vitamin D deficiency.
- The Chief Medical Officer of Scotland has proposed a program to encourage the use of vitamin D supplements throughout the country.
The Potential of Vitamin D in Cancer Prevention
The first hint of a correlation between vitamin D and cancer arose in the 1930’S when it was observed that those living in areas with higher exposure to sunlight had a lower incidence of cancer.
Explaining the link between cancer and sunlight proved difficult. At the time, vitamin D had only just been discovered (1921) and its mode of production, by the skin in response to ultraviolet (UV) light had yet to discovered.
It was not until 1974 that anyone seriously considered that vitamin D might account for the differences in cancer rates. Initially, two epidemiologists (the Garland brothers) at the University of California in San Diego discovered that being exposed to sunlight reduced the risk of colon cancer. Later they were able to show that exposure to sunlight and the incidence of breast cancer were also strongly related.
Then another researcher, Schwartz discovered that the same was true of prostate cancer.
The Garland brothers then published data supporting the role of vitamin D as as an explanation of the correlation between cancer rates and sun exposure.
By 2008 there were over 63 epidemiological studies in the world literature showing the correlation between low vitamin D levels and the development of cancer.
The incidence of over sixteen different types of cancer, which includes all the most common killers has shown some correlation with low levels of vitamin D.
Out of the 63 epidemiology studies mentioned above, 30 studied colon cancer, 26 prostate cancer, 13 breast cancer and 7 ovarian cancer. The majority of these studies showed a correlation between low level of vitamin D and an increased incidence of cancer. (8)
Studies previously conducted in animals had predicted this effect. There are multiple animal and cell-based studies that have demonstrated the anti-cancer effect of vitamin D.
While all these data amounts to a very strong signal that vitamin D levels play an important role in preventing cancer, the scientific community remained skeptical as no one had conducted a prospective double blind placebo trial to confirm these findings. The double bind placebo controlled trial is considered the gold standard in clinical trial design. In such studies patients are placed on either the active compound or placebo (sugar pill) and followed to monitor the effects.
Eventually, such a study was done with Vitamin D by Dr. Joan Lappe at Creighton University in Omaha, Nebraska. (29)
In her study she treated women over the age of 55 with either 1100IU of vitamin D and calcium or calcium alone or placebo. She followed the patients for four years and monitored the incidence of cancer. The results were very convincing
Over the four year treatment period, the group receiving vitamin D and calcium developed 60% fewer cases of cancer than occurred in the placebo group.
Dr. Lappe then reanalyzed the data looking at the incidence of cancer occurring during years 2-4 of the trial. This was done because it was highly likely that the cases of cancer that occurred during the first year of the study were already present when the patients entered the trial but were too early to be detected.
In this analysis Dr. Lappe found that the vitamin D treated group demonstrated a 77% reduction in the incidence of cancer compared to the placebo group.
In addition, Dr. Lappe explored the relationship between blood levels of vitamin D and the incidence of cancer. This analysis showed that every 25 nmol/L (10ng/ml) increase in vitamin D levels resulted in a 35% reduction in the risk of developing cancer. This finding matched almost exactly the results of a study published a year earlier by Giovannucci. (30)
Interestingly, the dose used in this study is relatively low, only 1100 IU and begs the question whether an even more impressive result could have been achieved with higher doses. In addition, the mean baseline levels of vitamin D in this patient population were higher than one might expect (28.7ng/ml). The mean level of vitamin D in the treated group rose to 38.4ng/ml. This suggests two issues: first, the response might have been even more dramatic if the baseline levels had been lower, as it usually is in northern areas. Second, there is a blood level somewhere between these two relatively close levels where the cancer preventative effects of vitamin D really takes effect. Deficiency is usually defined as a level <20ng/ml and a high percentage of the population fall below this level (see section on Vitamin D Deficiency). The fact is that 1100IU of vitamin D many not be sufficient to reach cancer protective levels in many who are more severely deficient.
Additional studies have recently been reported which support these important findings. Renal transplant patients have high rates of cancer compared to the general population. This effect is assumed to be due to immunosuppressants these patients are given to prevent rejection of the kidney.
In a study conducted in France, physicians monitored vitamin D levels prior to renal transplantation and then followed the patients to determine cancer rates in those with deficient, insufficient and adequate levels. At least 85% of the patients had deficient or insufficient levels of vitamin D. The incidence of cancer during the follow up period was 13.7% in the deficient group, 7% in the insufficient and only 3.7% in the group with normal vitamin D levels.
These numbers show an excellent dose response, ie the higher the level of vitamin D the lower the incidence of cancer. Such a dose response is a strong indicator of cause and effect which is so often missing in epidemiology studies. (31) In Germany, 3299 patients admitted to hospital for coronary angiography had their vitamin D levels measured and were then followed for almost eight years. During the follow-up period, there were 95 deaths due to cancer. Those with the highest levels of vitamin D had a 55% reduction in the risk of death from cancer compared to the group with the lowest levels. In this study levels above 30ng/ml were considered to be high and only 10% of the patient population had levels this high. Only one of the 95 patients who died from cancer was in the group with the highest vitamin D levels. (32) The studies above showed a reduction in the overall incidence of cancer. Other studies that have explored the risk of individual types of cancers are discussed below. In addition, there have been a few studies that have examined the effect of vitamin D levels on the outcome in patients once cancer has developed. These studies are discussed in the section Cancer Patients.
The vitamin D council in the USA now recommended that doses of 2000IU in the summer and 5000IU in the winter are needed to keep vitamin D at optimal levels. This is especially for populations living high above the equator.
The Canadian Oncology Society now recommends that all Canadians take vitamin D supplements to reduce the risk of cancer.
However, the Canadians are not the only people suffering from Vitamin D deficiency. Such deficiency is widespread. Almost anyone who does not live in a sunny environment and expose themselves to the sun on a regular basis is likely to have less than optimal levels. See the section on ‘Vitamin D deficiency’.
Recently a major health care provider in the US, Aurora Healthcare, has recommended that all Wisconsin residents take vitamin D and has started a program to educate its physicians about the dangers of vitamin D deficiency.
The Chief Medical Officer of Scotland has stated also that the government of Scotland should initiate a program to ensure all citizens increase their intake of vitamin D. This northern region of the UK sees little of the sun and has some of the worst rates of cardiovascular disease and cancer in the world.
Lung Cancer Prevention
Recently, Professor Garland of the University of California, San Diego published an analysis of the relationship between latitude, ultraviolet (UV) exposure and the incidence of lung cancer. (Latitude and UV exposure, both determine the quantity of vitamin D produced) Data on the incidence of lung cancer was gathered from 111 countries.(33)
This analysis showed that the higher the latitude the higher the incidence of lung cancer in both men and women. Living at lower latitudes and,thus being exposed to more sun light resulted in a reduction in the risk of developing lung cancer by 45% for men and 65% in women. The lower degree of protection seen in men is believed to be due to their increased rate of smoking compared to women.
Calculating the degree of ultraviolet exposure at various latitudes, the relationship with lung cancer was inversely associated with the amount of UV exposure --the higher the exposure to UV the lower the incidence of lung cancer. The correlation with UV exposure at different latitudes was highly statistically significant in men (P=0.003) and even more so in women (P=0.0002).
Even the amount of cloud cover correlated with the incidence of lung cancer. The more cloud cover (thus less UV) the higher the rate of lung cancer.
Professor Garland has also published similar results for breast cancer, renal cancer and endometrial cancer.
In another study in Finland, nearly 7000 subjects had their vitamin D levels checked and then followed for up to 24 years to monitor the incidence of lung cancer. Females with the highest levels of vitamin D showed a 84% reduction in the risk of developing lung cancer. The incidence of lung cancer in men was not seen to depend on vitamin D status although if the younger males and females were examined as a group they also showed a 66% reduction in the risk of developing lung cancer. As in the Garland study, older men did not show any protective effect from higher levels of vitamin D, and it is postulated that this is due to their much higher incidence of heavy smoking. (34)
Colon Cancer Prevention
The link between vitamin D levels and colon cancer is perhaps the strongest of all the types of cancer. The connection was first noted in 1980 in a study by Garland et al who noted that deaths from colon cancer were much rarer in sunny parts of the country. (35) The incidence of colon cancer was 4-6 times higher in northern areas compared to countries near the equator. Several epidemiology studies were then conducted that also showed a correlation between dietary intake of vitamin D and the incidence of colorectal cancer. (36) The higher the intake of vitamin D, the lower the incidence of cancer, usually around a 50% reduction. Because dietary intake of vitamin D is only a small contributor to total body vitamin D, these results suggested that colorectal cancer may be very sensitive to vitamin D levels. (Dietary intake is rarely more than 600 IU per day whereas the body can make as much as 20,000 IU in a few minutes in strong sunshine). Finally studies were done where the blood level of vitamin D was actually measured, and it was shown that the higher the level the less the chance of developing colon cancer. The correlation was extremely strong. The risk of colon cancer was reduced five fold if vitamin D levels were between 33-41ng/ml.(37) A similar relationship was found in a another study conducted in Finland. Vitamin D levels were sorted into four quartiles and a 63% reduction in the risk of colorectal cancer was demonstrated between the highest and lowest quartiles. Interestingly, the four quartiles showed a very convincing dose response curve which is strong evidence for a cause and effect relationship. The study also demonstrated that the Finns were very vitamin D deficient with the average level being only 13ng/ml.(38)
A prospective epidemiology study was published in November 2007 by Dr. Freedman of NCI. In this study participants had their baseline vitamin D levels measured and were followed for up to twelve years, and the overall incidence of cancer noted. Over 16000 patients were monitored in this study. It concluded that deaths due to cancer during the followup period were unrelated to baseline vitamin D levels.
This study was widely reported in the media under such headlines as "Maybe vitamin D Isn't the Answer After All" However, despite the negative conclusion and media reporting, the numbers in the publication revealed a different story. Looking at individual types of cancer there was a 72% reduction in the incidence of colorectal cancer between the groups of patients with the highest and lowest levels (<20ng/ml vis >32ng/ml) of vitamin D. This difference was highly statistically significant. In addition, there was also a 72% reduction in the incidence of breast cancer, which because of small numbers was not statistically significant but still a very interesting signal of activity.
The fact that a single estimation of the vitamin D level can predict the incidence of any form of cancer twelve years in the future is remarkable and might suggest that the cancer in question is extremely sensitive to vitamin D. (40) Finally in another study conducted at Harvard School of Public Health, 179 colorectal cancer patients were matched with control subjects and their vitamin D levels compared. Again those with the highest versus the lowest levels of vitamin D demonstrated a 50% reduction in the risk of colorectal cancer. (41)
Breast Cancer Prevention
The role of vitamin D in preventing breast cancer has been extensively studied and the results encouraging.
During the 1980's and 90's several epidemiological studies showed that women living in sunny areas of the US had much lower rates of breast cancer than those living in less sunny areas. Overall these studies showed the risk of developing breast cancer was three to five times lower in sunny areas of the country. Later studies compared the incidence of breast cancer in women with high or low dietary intake of vitamin D. Theses studies generally showed a small protective effect of high dietary intake. However, it is known that dietary intake accounts of only a small fraction of our total vitamin D levels as the vast majority (over 90%) is made in the skin following exposure to UV radiation.
Possibly the largest study looking at high and low dietary intake was published in 2007. This study estimated calcium and vitamin D intake in over 10,000 premenopausal and over 20,000 post menopausal women who where followed for ten years. There was approximately a 40% reduction in the risk of developing breast cancer in premenopausal women who had the highest calcium and vitamin D intake. No effect was seen in postmenopausal women. (42) In 2008 another large epidemiological study was published where breast cancer rates in 107 countries were studied in relationship to both modeled and measured vitamin D levels. It was demonstrated that those living in Southern areas had almost a 60% reduction in their risk of developing breast cancer compared to those living in Northern areas. (44) Finally in 2008, a study was published where actual blood levels of vitamin D were measured in post-menopausal breast cancer patients and compared to levels in a control population without breast cancer. Between the groups of patients with the lowest and highest levels of vitamin D there was a almost a 70% reduction in the risk of developing breast cancer. A strong trend was also seen across the various levels of vitamin D showing that the lower the level the greater the risk of developing breast cancer. The authors concluded that the data strongly suggest a protective effect for post-menopausal women with higher vitamin D levels. (43) In the following year the same group repeated their work in a pre-menopausal population of breast cancer patients again comparing their vitamin D levels to matched controls. Once again comparing the groups with the lowest and highest levels of vitamin D there was almost a 60% reduction in the risk of breast cancer. There was also a good trend seen across the various levels showing that the lower the level of vitamin d the greater the risk. (45)
Interestingly, in both of these studies the cut off for being classified as having a high level of vitamin D was >24ng/ml. This is still far short of what is now considered to be an optimal level. Optimal levels of vitamin D are thought to be in the range of 50-70ngs/ml. One can only speculate on how much greater the protective effects would be of such levels.
In late 2008 a study was published in the Journal of the National Cancer Institute claiming that vitamin D and calcium had no effect on the risk of developing breast cancer. This was a large placebo controlled study and conducted in many of the best centers in the USA. The negative results received much media coverage with NCI putting out press releases.
However, a closer look at the study was very enlightening. The dose of vitamin D used was only 400IU. This is little more than a placebo in terms of raising blood levels. Current opinion is that doses of between 2000 and 5000IU per day are needed.
In addition to using such a low dose, both the treatment and placebo groups were allowed to take up to 600IU of vitamin D in over the counter multivitamin preparations. This was later increased to allow both groups to take up to 1000 IU. Such a design makes no scientific sense. To allow patients to take up to two and half times as much of the very substance under test would effectively eliminate any chance of showing an effect of the 400 IU dose, even if it had any chance of showing anything in the first place (46)..
Prostate Cancer Prevention
A connection between prostate cancer and vitamin D levels was first proposed in 1990 by Schwartz et al. His paper pointed out that all the major risk factors for prostate cancer: age, darked skin and northern latitudes are assoicated with a reduced production of vitamin D. Mortality from prostate cancer was inversely correlated with ultraviolet radiation. (47) Men in the US have ten times the risk of developing prostate cancer than Japanese men. This has also been linked to vitamin D consumption as Japanese men have a higher intake due to their high intake of fatty fish which is a good source of vitamin D. The correlation between prostate cancer deaths and exposure to sunlight was again explored and a significant negative correlation was demonstrated. (48) Several studies were then published showing no correlation between vitamin D and the risk of prostate cancer.(49) However, in 2000 another study was published in which young mens level of calcidiol (vitamin D precursor) was measured and the men followed for the development of prostate cancer. This showed than men with low levels (below 16ng/ml) were three times more likely to develop prostate cancer and six times more likely to develop agressive invasive cancer than men with higher levels. (50) By this time there was a great deal of lab and animal data to support the use of calcidiol in prostate cancer and in 2003 and extensive review of these data was published and concluded that "adequate vitamin D should be maintained, not only for bone health in men and women but because it might decrease the risk of prostate cancer and prevent metastatic disease should it develop." (51) Researchers in Norway then published work showing that men diagnosed with prostate cancer during seasons with more sunlight had a significantly better prognosis that those diagnosed with the condition at other times of the year. (52) Then in 2004 results of a trial in which 15 men with advanced prostate cancer were treated with 2000 IU of vitamin D3. Impressivily,14 of the 15 men showed a reducing in, or prevention of further rises in PSA showing that vitamin D could play a role in prosate cancer (53)
Preventing Pancreatic Cancer
Two large long-term studies have shown that adults who have a higher dietary intake of vitamin D (300-400 IU) have almost half the risk of developing pancreatic cancer than those with less than 150 IU vitmain D in their diet.
The researchers followed 120,000 subjects in the Health Professionals Follow-Up study and the Nurses Health Study. Between the two studies there were 365 cases of pancreatic cancer.
Interestingly, even subjects who consumed only 150-299 IU daily had a 22% reduction in their risk of developing the condition. This graduated response suggests a dose respone which is a very good indicator of a true cause and effect relationship.(54) In 2008 another study was published suggesting that sun exposure may be associated with higher death rates in pancreatic cancer patients. However, no blood levels were measured in this study and the results would appear to contradict those seen in many other studies. No other study has suggested that high vitamin D levels are detrimental.(55)
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