Sunday, July 22, 2018

Vitamin D has no effect on prostate cancer, heart disease, or bone mineral density*


Observational studies have reported conflicting effects of Vitamin D on prostate cancer - some reported no association (as in this study), some reported a positive association (as in this study), and some reported an inverse association (as in this study). We now have three large randomized clinical trials (Level 1a evidence) that show that large doses of Vitamin D have no effect on cancer incidence or deaths. This trumps all previous observational and epidemiological studies.

Manson et al.  reported the results of the VITAL randomized clinical trial (RCT) on 25,871 (including 5,000 African-Americans) men over 50 and women over 55 who were given either:
  1. Vitamin D3 at 2,000 IU per day and marine omega-3 fatty acids (1000 mg/day containing 840 mg EPA and DHA)
  2. Vitamin D3 placebo and fish oil placebo
  3. Fish oil and Vitamin D3 placebo
  4. Vitamin D3 and fish oil placebo
Blood samples were taken and questionnaires were administered to assure compliance. The group assignment was double-blind. Participants agreed to keep vitamin D from all other sources (like sunlight, milk, multi-vitamins, etc.) to under 800 IU per day.

After a year, serum 25-hydroxyVitamin D increased from 30 ng/ml to 42 ng/ml among those supplementing Vitamin D and didn't change in the placebo groups.

After 5.3 years of follow-up, there was:
  • No difference in incidence any kind of cancer (including prostate, breast and colorectal cancers) between Vitamin D3 and Placebo.
  • No difference in deaths from any kind of cancer
  • Low BMI  (<25) may potentiate the effect of Vitamin D on cancer.
  • No difference in any kind of cardiovascular disease, including myocardial infarction, stroke or death from myocardial causes or of interventions like PCI or coronary bypass.
  • There was no synergism with omega-3 fatty acids.
  • There were no statistically significant differences in any subgroup.

Manson et al. also did a separate analysis of omega-3 fatty acids. After 5.3 years of follow-up, there was:
  • No difference in incidence any kind of cancer (including prostate, breast and colorectal cancers) between omega-3 and Placebo.
  • No difference in deaths from any kind of cancer.
  • There was no synergism with Vitamin D.
  • Those with low fish consumption (<1.5 servings per week) may gain some cardiovascular benefit from omega-3 supplementation.
  • No difference in cardiovascular disease overall, stroke or death or of interventions like PCI or coronary bypass.
  • There was significant improvement in the rate of myocardial infarctions and total coronary heart disease among those taking omega-3s.
  • African-Americans, especially those with multiple CV risk factors, taking omega-3s had lower incidence of myocardial infarctions.
  • Myocardial infarctions (MI) were also better for those taking omega-3s among younger people (<67), men, smokers, diabetics, people with hypertension, people taking cholesterol medications, no parental history of MI, 3 or more risk factors, baseline aspirin use, and baseline statin use.
(update 11/18/20) Chandler et al. reported on an updated analysis of the VITAL RCT. They looked at whether Vitamin D supplementation affected the risk of developing metastatic or fatal cancer among people who were cancer-free at baseline. With a median intervention period of 5.3 years, there was almost no chance of finding metastatic or fatal prostate cancer in men who were prostate cancer-free at baseline (In the ProtecT trial, 10-year prostate cancer survival among men initially diagnosed with localized prostate cancer was 99%, and metastasis-free survival was 96%.) Because the metastasis-free and cause-specific survival with prostate cancer are so long when starting from a "no cancer" diagnosis, the authors looked for the effect on other cancers, excluding prostate cancer. They found:
  • there were no significant differences due to Vitamin D on the incidence of any cancer
  • there were no significant differences due to Vitamin D on the metastatic spread across all cancers
  • there were no significant differences due to Vitamin D on all-cancer mortality
  • Adding together metastases and fatalities due to all cancers, the difference (2.1% vs 1.7%) was statistically significant, especially after the first two years
  • The reduction was only statistically significant among those with a normal body-mass index (<25)
  • For prostate cancer patients, there were only 6 such cases among those who got Vitamin D and 14 such cases among those who got the placebo - not significantly different. Presumably, they were missed at diagnosis or had a rare virulent type of PCa.
(Update 3/16/2021) in an ancillary analysis of the VITAL trial data, Albert et al. reported that neither Vitamin D nor Omega-3 supplementation had any effect on the incidence of atrial fibrillation.

(update 2/19/2022) Neale et al. reported the results of the D-Health RCT. This was a randomized double-blind prospective trial among 21,315 Australians aged 60 or over.
  • 10,662 were given Vitamin D; 10,653 were given a placebo
  • Vitamin D3 was given as 60,000 IU/month for 5 years
  • A random sample of both groups was checked for compliance via a blood test for serum 25-hydroxyVitamin D; it was 115 nmol/L in the treatment group vs 77 nmol/L in the placebo group.

After 5 years of follow-up:
  • There was no statistically significant difference in the number of deaths (5% in each group)
  • There was no statistically significant difference in cardiovascular disease mortality
  • There was no statistically significant difference in cancer mortality
  • There was no statistically significant difference in all other causes of mortality
  • Excluding those who died during the first 2 years of follow-up, cancer mortality was 24% higher among those taking Vitamin D

Scragg et al. in a post-hoc analysis of the ViDA trial reported on 5,110 50-84 year-old people seen in community practice in NZ between 2011 and 2012. The study was originally set up to investigate cardiovascular benefit to Vitamin D supplementation (it found none), but they also asked about incidence of cancer and tracked deaths from cancer.
  • 2558 were given Vitamin D; 2552 were given a placebo
  • Vitamin D3 was initially given as one 200,000 IU pill, followed by 100,000 IU monthly pills
  • Serum 25-hydroxyVitamin D was 26.5 ng/ml (seasonally adjusted) at baseline
  • Serum 25-hydroxyVitamin D consistently increased by 20 ng/ml among a sample of treated patients
  • Compliance was excellent
  • There was no difference in the percent who took calcium or Vitamin D supplements or in sun exposure
After a median of 3.3 years of follow-up, there were:
  • 375 new cancer cases; 60 died of new cancers. 
  • 24% had a pre-existing cancer diagnosis; 29 died
  • no significant difference between the Vitamin D cohort and the placebo cohort in the number of new cancers or cancer deaths.
  • 6% had a pre-existing prostate cancer diagnosis; 7 died
  • 64 new cases of prostate cancer (1 died)
  • no significant difference between the Vitamin D cohort and the placebo cohort in the number of new prostate cancers or in prostate cancer deaths.
One can argue that a consistent daily Vitamin D3 intake might have had an effect, or that it takes more than 3 years for an effect (whether beneficial or increased risk) to be observed. There is, at present, only observational studies for either assertion. Sample size prevents consideration of the hypothesis that Vitamin D may prevent early growth of prostate cancer but may accelerate metastases (as in this mouse study).

Jiang et al. report the results of a Mendelian randomization study of the causal connection between serum Vitamin D levels and prostate cancer. They identified 6 genetic mutations associated with low serum levels and looked for them in 79,148 men who were diagnosed with prostate cancer. They found no greater incidence of those genetic mutations in men with prostate cancer or advanced prostate cancer. Nor was there any association in women with breast cancer. The genetic mutations were also not statistically different in 73,699 people who did not have breast or prostate cancer. This proves there is no causal connection between low Vitamin D and prostate cancer.

No Effect or Negative Effect on Bone Mineral Density*

Some men on hormone therapy take Vitamin D and calcium for the purpose of maintaining bone mineral density (BMD). 

(update 7/27/22) An update of the VITAL randomized clinical trial reported no difference in fractures among people supplementing Vitamin D vs. people not supplementing it. There were no differences by age, sex, race, BMI, baseline use of calcium or Vitamin D supplements, or serum Vitamin D levels.

Reid et al. reported that Vitamin D supplementation had no effect on bone mineral density. They further noted that lower doses had more effect than higher doses, probably because Vitamin D has been found to pull calcium out of bones at high doses. However, Datta and Schwartz reported that at 200-500 IU/day Vitamin D and 400 mg-1,000 mg calcium supplementation had no effect on men's bone mineral density. Calcium supplementation has been associated with increased risk of prostate cancer (see this link or this link). Trajanoska et al. found that mutations in the genes responsible for regulating serum Vitamin D levels had no effect on fracture risk, nor did the genes regulating the tolerance for dairy (which is correlated with calcium intake). They also question the routine use of Vitamin D and calcium supplements in men who are taking Xgeva or a bisphosphonate like Zometa to preserve bone mineral density. (Estrogen patches may also prevent loss of bone mineral density.) They wrote:

Studies seeking to show whether these supplements do increase the efficacy of osteoporotic treatment or decrease adverse events (that is, hypocalcaemia) are lacking. In either case, screening for vitamin D deficiency and seeking its correction should be warranted before the initiation of anti-resorptive treatment [e.g., Zometa or Xgeva].  Moreover, in a recent mendelian randomisation study investigating the role of vitamin D in maintaining bone mineral density, increased levels of vitamin D had no effect on bone mineral density measured by [DEXA scan]. However, increased 25-hydroxy-vitamin D was associated with a slight reduction in heel bone mineral density estimated by ultrasonography. These results are consistent with our mendelian randomisation findings of no causal effect of vitamin D levels on fracture.
(Update 9/2/2019) Burt et al. published the results of a randomized clinical trial (RCT) of three different doses of Vitamin D on the bone mineral density of 311 men with 3 years of follow up. The experiment was set up as follows:

  • 1/3 received 400 IU/day; 1/3 received 4000 IU/day; 1/3 received 10,000 IU/day
  • none had osteoporosis at baseline
  • all had baseline serum Vitamin D between 30-125 nmol/L (12-50 ng/ml)
  • those whose total intake of calcium (dietary+supplements) was < 1200 mg/day received calcium supplements
  • baseline serum calcium was 8.4-10.2 mg/dl
  • 53% were men
  • average age was 62 (range:55-70)

After 3 years on their vitamin D regimen:
  • Serum Vitamin D was 77 nmol/L, 132 nmol/L, and 144 nmol/L in those taking 400 IU/day, 4000 IU/day, and 10,000 IU/day, respectively
  • BMD in the radius bone of the arm decreased in all groups in a dose-dependent manner:
    • -1.2% in the 400 IU/day group
    • -2.4% in the 4,000 IU/day group
    • -3.5% in the 10,000 IU/day group
  • Hypercalcemia (too much calcium in the blood) and hypercalciuria (too much calcium in the urine) increased with increased Vitamin D dose
  • Kidney/liver dysfunction, falls, fractures and cancer did not vary with dose.

In a Medpage interview, the authors point out that this is plausible because of two effects of Vitamin D:
  • It increased bone resorption (more than bone formation), as measured by an increase in CTx.
  • It increased parathyroid hormone, either directly or by increasing calcium absorption from the gut

The study did not include people taking bisphosphonates, Zometa or Xgeva.

Also, the dose-dependent effect (higher doses were more damaging than lower doses) increases the plausibility of this being a real effect.

(update 3/23/24) *Peppone et al. found in a small randomized trial that ultra-high doses of Vitamin D (50,000 IU/wk!) could lessen the deleterious effect on BMD of  ADT in men who recently (last 6 months) started ADT and had low-end baseline serum Vitamin D (<27 ng/ml). Even so, they still lost BMD after 24 weeks of ADT but at about ⅓ the rate of those who only took much smaller amounts of Vitamin D. There were no differences in toxicity at 24 weeks. Of course, these men started with a deficiency, only took ADT for a short time, and they weren't followed long enough for the megadoses of Vitamin D to rob their bones of BMD.

 It’s worth noting that Vitamin D, unlike other vitamins, is a steroid. Steroids tend to interact and to have wide-ranging effects in humans. Overwhelming our steroid-control systems with massive doses of any one steroid is bound to have unintended consequences.

Possible increase in testosterone 

It should be remembered that Vitamin D is a steroidal hormone (like testosterone, estrogen, progesterone, and cortisol) and there are receptors for it on virtually all cells, healthy and cancerous. It has far-ranging effects. It also is part of the human biochemical factory that inter-converts many different kinds of steroids. In fact, Anic et al. showed there was a positive association between serum Vitamin D level and the amount of serum testosterone - not an effect that a man who is taking androgen deprivation wants.

Given that Vitamin D has no effect on incidence of cancer or cancer mortality, that it has no cardiovascular benefit, and no effect on bone mineral density, there is no reason to take supplemental Vitamin D unless serum levels are too low (below 20 ng/ml). 


  1. Every anti-vitamin person has said mega doses are a waste of money and yet every study I've seen is based on giving the study participants mega does of vitamins. I've taken what would be considered mega doses of D but it was 10,000IU not 200,000 IU. Researchers don't seem to understand that too much is as bad as too little.

    1. Vitamin D is stored in the liver and fat until needed. See the update above - they looked at 2,000 IU/day - still, no effect.

  2. Sorry I don't speak your language. Must say I' m very sick. You seem to be very good informed. And I am confused by all te comments on the Vital study. The next link says the following: 'For people taking vitamin D who developed cancer, the death rate from cancer was 25 per cent lower, possibly because the vitamin may affect the biology of the tumour so it’s less likely to spread and become metastatic,” said lead author Dr. JoAnn Manson, chief of the division of preventive medicine at Brigham and Women’s Hospital in Boston.'
    Please let me know your opinion.

    1. I'm not sure what you're quoting. What they wrote was: "The intervention also did NOT lead to a lower incidence of total deaths from cancer or a lower incidence of breast, prostate, or colorectal cancer than placebo."

  3. Thank you for answering; here is the quote. Must say I don't understand it very well because it is not conform with the fact that the death rates were the same.
    'For people taking vitamin D who developed cancer, the death rate from cancer was 25 per cent lower, possibly because the vitamin “may affect the biology of the tumour so it’s less likely to spread and become metastatic,” said lead author Dr. JoAnn Manson, chief of the division of preventive medicine at Brigham and Women’s Hospital in Boston.' I know the study did not go about this and it's only an additional quote but 25 percent is quite a lot I think.

    1. What they are focussing on is a secondary analysis the authors did where they excluded the first two years of follow up. I suppose that their hypothesis is either that (1) it takes more than two years for the supplemental Vitamin D to take effect, or that (2) Vitamin D only has an effect on the less virulent cancers, or that (3) those who died of a cancer within 2 years probably had undiagnosed cancer before entering the trial. There was no significant effect when the entire treatment group of 793 people who were diagnosed with any kind of cancer were included, but there was a significant effect when they excluded the 303 people diagnosed with any kind of cancer in the first two years. So, excluding the first two years, 23% of those taking Vitamin D died of their cancer between 2 years and 5.3 years median follow up. This compares to a death rate of 29% among those not taking the supplement - a 25% decrease. Prostate cancer was diagnosed in about a quarter of the people in the study, but they do not say how many of the men in the study died of prostate cancer within the 5.3 years - presumably, very few. So I doubt there was any effect on prostate cancer deaths specifically in this relatively short follow up.

    2. Thank you very much for answering

  4. Sorry I notice now that I gave you the same post as before. Am I so wrong than? I's clearly written in the text. But my Englsh is not so good ... must admit that.
    Hope you understand. I really don't understand what dr Manson meant with her quote.
    Indead "The intervention did not lead to a lower incidence of total deaths from cancer or a lower incidence of breast, prostate, or colorectal cancer than placebo." But why she says that there were fewer deaths with people who already developped cancer. To me she contradicts herself somehow.

  5. Dear sir
    I know studies are contradicting each other all the time.
    I'm glad people like you exist. They are good informed and have the capability of changing their opinion.
    I read in the study you mention that vitamin D may be working against androgen deprivation (just the conclusion)' ... suggest a possible mechanism through which vitamin D may be related to increased prostate cancer risk ...' Suggest/possible/may be ... These are really a pile up of uncertainties. My theory could also be true: men with high testosterone are more likely to develop prostate cancer. Let us assume that this is proven. But men with high testosterone are in my opinion people who are more exposed to sunlight because they are more muscular/sportive/outdoor people ... and so have higher vitamine D levels. By the way: Here is a link to a site which is somewhat too optimistic in my opinion but why not ... One of the points is: 'The study’s authors theorized that since vitamin D has a similar structure to androgen, it might amplify the therapeutic effects of lowering androgen levels and improve the survival chances of men with prostate cancer.' See following site (where you can find the quote). One thing seems to be sure: nobody is sure. Also by the way I wrote an e mail to professor JManson and to my surprise she answered almost immediately (I thank her for that). Of course I did expected her answer, namely that I had to talk with my oncoloog. But it was what she did not say that took my attention. I think that if her study results would have pointed to a sowewhat doubtful conclusion about prostate cancer she would have written it. Instead she said that taking 2000 iu has minimal side effects.

  6. Yes sir I'm here again. Last time I write you. Promise. But I think nature has developped over hundreds of thousands of years her own mechanism to protect the strongest people. No doubt people with high testosterone levels are -in general- stronger, more popular, confident ... you name it. (Of course, again there will be studies who say the contrary but so be it). So maybe nature protected those strong people by giving them vitamin D which on its turn protected them (pitty, just a litlle bit) against cancer. As I said and as you will agree: people with high testosterone levels will see more sunlight (because of more than one reason) and more sunlght means more vitamin D ... Just a thought :-)

  7. Bart-

    I use terms like "suggest/possible/may be" (and "association") when studies do NOT come up to the standards set for the highest level of evidence. The two studies two I wrote about in this article, VITAL and VIDA, attain the highest level of evidence (Level 1a) for which I use more definitive terms like "proved, shown, and caused." Conclusions drawn from observational studies are provisional; those drawn from large, well-done randomized, clinical trials (like these) are definitive. However, even conclusions drawn from Level 2 or 3 observational studies are better than hypotheses that you or random sites on the Internet come up with.

    You wrote: "men with high testosterone are more likely to develop prostate cancer." This has been studied. Actually, the opposite seems to be true. Men who have had low level of testosterone ("hypogonadal") are more likely to be diagnosed with prostate cancer and higher grade prostate cancer. For example:

    It had been hypothesized in some early epidemiological studies (low level of evidence) that sunlight had a protective effect because of Vitamin D. Studies suggest that the mechanism for the beneficial effects of sunlight may be something other than Vitamin D, especially that it directly enhances the immune response, resets circadian rhythm, and the degrades folic acid:

  8. The quality of these studies is quite convincing. Does this data suggest that the benefit of checking vitamin D and repleting when deficient is of little value?

    Each of us has a unique set of variables which may not be consistent with the study population. I dealt with hypogonadism and was placed on TRT, prior to PCa diagnosis. Vit D was 6 ng/ml, PTH was elevated as serum calcium. Vit D repletion was associated with normalized PTH and calcium for a short period until a parathyroid tumor was identified and removed. I have not found quality evidence that would suggest an association between Vit D, PTH and PCa. These studies address one of those questions.

  9. Excellent review of the literature about Vit-D. However, there are a few important points from the paper by Burt et al. that should be mentioned. The cohort of men was healthy men with normal levels of Vit-D. The study excluded men with osteoporosis or low levels of Vit-D (i.e., less than 12 ng/ml), and the authors speculate that a positive BMD response to supplemental Vit-D may have been more likely in this cohort of men with low Vit-D. The study also reported that high-dose Vit-D supplementation did not decrease the hip BMD and did not decrease the bone strength.

    1. It was a random sample of men with normal Vitamin D. It shows why men with normal Vitamin D should NOT supplement.