Foods/Supplements-Vitamins: D - Cholecalciferol/Calcidiol/Calcitriol - U-shaped Risk

This is the first of 3 posts on vitamin D.

My sense is that many men with PCa in the U.S. are aware that vitamin D might be useful. Dr. Myers, an early adopter, has spoken of its importance, & the difficulty his patients have in raising levels. (Which implies that he tests patient levels. How many oncologists do that?)

At one point Myers dismissed most vitamin D brands & said that the patients who had success were almost all using Life Extension [LEF] products. LEF, though, had noted that many customers who were buying 5,000 IU doses & purchasing blood tests, were having difficulty raising levels. So they introduced a 7,000 IU capsule, & later, switched to softcaps containing oil for greater absorption.

All this must seem odd to those who remember the U.S. RDA as being 400 IU. (It was raised to 600 IU in 2010, with an extra 200 IU once one reaches 71.)

Vitamin D fails the definition of a vitamin: (a) the body can't make a vitamin & (b) we can get sufficient vitamins from food. Not only can the body make vitamin D, there are no natural food sources (I am discounting fortified foods, such as vit D milk) that can provide enough.

Vitamin D is actually a steroid hormone.

The traditional steroid hormone cascade starts with cholesterol. Vitamin D production begins with the cholesterol precursor: 7-dehydrocholesterol. UVB light from the sun, if of sufficient strength, acting on 7-dehydrocholesterol in the skin, produces cholecalciferol, which is often described as "vitamin D3", but is biologically inactive. Cholecalciferol is processed by the liver to produce the prohormone calcidiol [25(OH)D3]. The hormonal form, calcitriol [1α,25(OH)2D3], is produced from calcidiol, primarily by the kidneys, as needed.

The main vitamin D blood test is for calcidiol, the inactive reservoir. What should the test result be?

Most definitions of sufficiency start at 30 or 32 ng/mL, with deficiency being <20 ng/mL.

The Mayo Clinic defines severe deficiency as <10 ng/mL, mild to moderate deficiency as 10-24 ng/mL & optimal as 25-80 ng/mL.

Dr Cannell of the Vitamin D Council recommends aiming for >50 ng/mL.

Since calcidiol circulates in the blood as a reservoir, why should we care what the level is, as long as we are replacing what we use? One of the most important control mechanisms in the body is of calcium homeostasis in the blood. There are indications that tissue that can take from the reservoir & produce calcitriol (this includes the prostate) are inhibited when the reservoir is low. In addition, the body gets nervous when the supply of vitamin D is erratic, even if the stores seem high. In terms of supplements, best to take them every day.

[1] NORDIC Studies.

I think it quite audacious for Nordic countries to publish human vitamin D - PCa studies. In Trondheim, Norway today, they are enjoying 19 hours, 24 minutes & 57 seconds of daylight, but in 6 months that will have shrunk by 14 hours. The winter months have very short days & the sunlight is too weak for vitamin D production. Much of the populations of Scandinavian countries experience vitamin D deficiency during the winter. Very few people get much above 34 ng/mL at any time let alone Dr Cannell's 50 ng/mL.

And yet these studies have reported a U-shaped risk curve for PCa, with the optimum vitamin D level being quite low. The implication is that PCa risk should increase as one moves south, but statistics show otherwise. Annual PCa incidence per 100,000 lives (age standardized) [1a]:

- Norway 195

- Sweden 178

- Finland 145

- Denmark 140

- Spain 97

- Greece 35

{Some studies use different units: 1 ng/mL = 2.5 nmol/L.}

[1b] (2004 - Finland/Norway/Sweden)

"Both high and low levels of blood vitamin D are associated with a higher prostate cancer risk"

"We studied serum 25(OH)-vitamin D levels of 622 prostate cancer cases and 1,451 matched controls and found that both low (≤19 nmol/l) and high (≥80 nmol/l) 25(OH)-vitamin D serum concentrations are associated with higher prostate cancer risk. The normal average serum concentration of 25(OH)-vitamin D (40–60 nmol/l) comprises the lowest risk of prostate cancer."

Converting to ng/mL:

"... found that both low (≤7.6 ng/mL) and high (≥32 ng/mL) 25(OH)-vitamin D serum concentrations are associated with higher prostate cancer risk. The normal average serum concentration of 25(OH)-vitamin D (16–24 ng/mL) comprises the lowest risk of prostate cancer."

16-24 ng/mL is in the Mayo's range for moderate deficiency.

I like the use of "normal average". Normal in Malmö!

[1c] (2012 - Sweden)

"Nine hundred forty-three incident prostate cancer cases were identified in the Malmö Diet and Cancer Study cohort, and each was matched with one control"

"We found a weak trend toward increasing prostate cancer risk with rising vitamin D levels"

"Dividing the cohort into deciles showed a nonlinear association. Compared to decile one, the prostate cancer risk was highest in deciles seven and eight, which corresponded to vitamin D levels of 91-97 nmol/L (1.68 ...), and 98-106 nmol/L (1.80 ...)."

Translation: "corresponded to 36.4-38.8 ng/mL {68% greater risk}, and 39.2-42.4 ng/mL {80% greater risk}."

OK, so they had to divide the cohort into ten groups to get a breakdown of the guys above 32 ng/mL. But look what that must have done to the first decile range. Those men must have been seriously deficient. I would ask how come that group had lower risk?

"In the other deciles, there was no association between prostate cancer risk and vitamin D levels." So in deciles 9 & 10, i.e. above 42.4 ng/mL, there was no extra risk.

What's missing here is enough men to examine risk in the 50-75 ng/mL range.

[1d] (2011 - U.S. - Finnish men - smokers)

"The 25-hydroxy vitamin D [25(OH)D]-prostate cancer relation was examined in a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of 50- to 69-year-old Finnish men."

"Cases had nonsignificantly 3% higher serum 25(OH)D levels"

"ORs ... for increasing season-specific quintiles of 25(OH)D concentrations were 1.00 (reference), 1.29 ... 1.34 ... 1.26 ... and 1.56 ..."

"These findings seemed stronger for aggressive disease [OR ... for fifth quintile of serum 25(OH)D [1.70 ...], among men with greater physical activity [1.85 ...], higher concentrations of serum total cholesterol [2.09 ...] or α-tocopherol [2.00 ...] and higher intakes of total calcium [1.82 ...] or vitamin D [1.69 ...], or among those who had received the trial α-tocopherol supplements [1.74 ...]"

"Our findings indicate that men with higher vitamin D blood levels are at increased risk of developing prostate cancer."

"Greater caution is warranted with respect to recommendations for high-dose vitamin D supplementation and higher population target blood levels."

[1e] (2015 - Sweden) Continuation of [1c].

"We performed a nested case-control study within the Malmö Diet and Cancer Study on 943 incident prostate cancer cases. Tumor aggressiveness was defined by Gleason score, TNM stage, and serum levels of total prostate-specific antigen."

"We found no significant association when comparing aggressive to non-aggressive disease regarding vitamin D"

"There was a trend toward an increased risk in low-grade tumors, i.e., Gleason score ≤6, and a significant association regarding Gleason score 7 tumors with OR 1.70 ... in the highest quartile of vitamin D."

[1f] (2016 - Sweden) continuation of [1c] [1e]

"We examined the associations between pre-diagnostic serum levels of vitamin D (25OHD) ... and mortality among 943 participants within the Malmö Diet and Cancer Study, who were diagnosed with prostate cancer."

"We observed a trend toward a lower prostate-specific mortality with 25OHD >85 nmol/L in the unadjusted analysis." i.e >34 ng/mL.

[1g] (2016 - U.S. - Finnish men - smokers) continuation of [1d]

"We examined prediagnostic serum 25-hydroxy-vitamin D (25(OH)D) and prostate cancer survival in a cohort of 1,000 cases in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. During 23 years of follow-up, 363 men died from their disease."

"Men with higher serum 25(OH)D were less likely to die from their prostate cancer (Q5 vs. Q1" 28% risk reduction.

...

Note that in [1b] & [1c] they appeared to have looked at vitamin D levels after diagnosis. I would expect supplementation to be greater after diagnosis.

[1d] was a prospective study & the D levels were prediagnostic. Cases had 3% higher D levels. Men with familial PCa might use D supplements. Men with an elevated PSA & a negative biopsy might turn to supplements too.

A prudent study design (for PCa incidence) would exclude men who use supplements. Usage might imply knowledge of additional risk.

[1f] & [1g], both this year & both continuation studies, found survival benefit with higher D levels. Suddenly, no U-shaped risk curves.

[2] (2011 - U.K.)

The U.K. has weak winter sun too. Glasgow is north of Copenhagen & London is only 4 degrees south.

This study looked for U-shaped risk.

"We included 1,447 prostate cancer cases (153 advanced, 469 high-grade) and 1,449 healthy controls."

"There was evidence that men deficient in vitamin D had a 2-fold increased risk of advanced versus localized cancer (OR for deficient vs. adequate total 25(OH)D=2.33 ...) and high-grade versus low-grade cancer (OR for deficient vs. adequate total 25(OH)D=1.78 ...)."

"Our study provides evidence that lower 25(OH)D concentrations were associated with more aggressive cancers (advanced versus localized cancers and high- versus low-Gleason grade), but there was no evidence of an association with overall prostate cancer risk."

[3] Gary Schwartz.

Gary is something of a hero to me. He wrote the first paper (in 1990) that asked:

"Is vitamin D deficiency a risk factor for prostate cancer?" [3a]

He has his name on over fifty vitamin D papers. He published something in 2012 that made me write to him. Part of his response:

"It's kind of you to note that in 1990 (when I was a postdoc at Chapel Hill), there were in fact, NO papers on prostate cancer and vitamin D; now it seems that it would take a backhoe to plow through them. I can’t tell you how many people openly ridiculed the idea back then."

PubMed search on <prostate "vitamin d"> = 1,141 hits.

[3b] In 2014 Gary Schwartz commented on the PCPT & SELECT trials:

"In the SELECT study, plasma 25-OHD levels were associated with a linear decrease in prostate cancer risk for high-grade cancers in African American men and an apparent "U"-shaped effect in other men."

"In the PCPT study, in which detection bias was minimized, serum 25-OHD levels were associated with a linear decrease in the risk of high-grade prostate cancers."

"The "U-shaped" curve may reflect detection bias."

-Patrick

[1a] eco.iarc.fr/eucan/CancerOne...

[1b] onlinelibrary.wiley.com/doi...

[1c] ncbi.nlm.nih.gov/pubmed/227...

[1d] cebp.aacrjournals.org/conte...

[1e] ncbi.nlm.nih.gov/pubmed/265...

[1f] ncbi.nlm.nih.gov/pubmed/270...

[1g] ncbi.nlm.nih.gov/pubmed/268...

[2] ncbi.nlm.nih.gov/pubmed/220...

[3a] ncbi.nlm.nih.gov/pubmed/224...

[3b] cebp.aacrjournals.org/conte...

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  • Patrick,

    Great article on vitamin D and why it is so important for us to have our levels checked. Many who I have told to have the doc do vitd 3 test during yearly bloodwork have come back deficient, myself I have been around 50. Funny how many Drs. will not worry about older patients when they are just barely vit d 3- 30, They say that's fine, when in fact it is the lowest end of the normal curve which many experts say is to low anyway. The bearded one (Snuffy) was always big on vitamin D, I know back in the day he was into thalomide for prostate cancer, I wonder what his thoughts are on that now?

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