When I was diagnosed in 2004, the first paper warning of a U-shaped risk curve had just been published [1].
"... both low (</=19 nmol/l) and high (>/=80 nmol/l) 25(OH)-vitamin D serum concentrations are associated with higher prostate cancer risk."
i.e. < 7.6 & > 32 ng/mL (<20 is deficiency; 20-30/32 is insufficiency - old style)
"The normal average serum concentration of 25(OH)-vitamin D (40-60 nmol/l) comprises the lowest risk of prostate cancer."
i.e. 16 - 24 ng/mL. I like the use of "normal". Normal for Helsinki!
With all respect to Tuohimaa (Finland), the findings seemed to be a crazy anomaly. & isn't Finland just about the worst place to conduct a vitamin D study?
Daylight in Helsinki Dec 22: 9:24 am - 3:13 pm, 5 hours & 49 minutes. And if there is sun, it is far too low & weak to affect vitamin D levels.
Helsinki latitude: 60.17° (Anchorage, Alaska, is a bit worse 61.21°; the northernmost tip of mainland Scotland, John O'Groats is more hospitable at 58.54°.)
The study subjects actually comprised "Nordic men (Norway, Finland and Sweden) using serum banks of 200,000 samples."
In this population, deficiency is the norm for many months of the year, unless supplements are used. & this paper appeared at a time when the high dose supplements seen today in America were not available. To get above 32 ng/mL in those latitudes, one has to be serious about raising 25-D levels.
It subsequently occurred to me that men at risk of PCa due to family history, say, would be motivated, & this might explain the association. The Nordic population is actually ideal for this type of bias to show up.
In an analysis of data from the SELECT trial [2], the risk for Gleason score 8-10 (using model 3, which used quintiles - see Table 3) was:
25-D ng/mL ... relative risk
<17.67 ... 1.00 (reference)
17.67 - <23.32 ... 0.68
23.32 - <29.21 ... 0.36
29.21 - <36.34 ... 0.85
36.34 & up ... 0.78
Sort of U-shaped, but not well-behaved at the upper reaches.
As usual, there are not enough cases at the high end for us to see the risk when 25-D is above 50 ng/mL, as recommended by the Vitamin D Council. Or at ~75 ng/mL which many with PCa use as a target.
The SELECT population was American. Unlike the Nordic countries, America was quick to adopt PSA for PCa screening. Men without diagnosed PCa, but worried about climbing PSA levels might be inclined to look for supplements that might help. One would have to exclude all men who were using high doses of D because of a perceived risk of PCa, & treat them as a subgroup.
Gary Schwartz responded to the SELECT paper in 2014 [3]. In 1990, Gary had suggested a latitude/vitamin D association with PCa [4]. The hypothesis was not well-received at the time.
He contrasts SELECT with the PCPT trial (the prevention trial that used Finasteride):
"An important advantage of the PCPT study was its ability to minimize detection bias. All men had annual PSA and digital rectal examinations and the absence or presence of prostate cancer was confirmed by biopsy either during (for cases) or at the end of the trial (for all men). The key finding was that among combined treatment arms of this trial, comparing the highest with lowest quartile of serum 25-OHD, 25-OHD levels were associated with a linear decrease in the risk of Gleason 8–10 prostate cancer [OR, 0.55 ...]. There was no evidence of a preventive effect for Gleason 2–6 cancers, which were nonsignificantly increased, or of a “U”-shaped curve."
"What is the “take-home” message from these studies? First, both studies support a protective role for circulating 25-OHD on prostate cancer risk. The effect was clearer in the PCPT study, which found that 25-OHD levels were associated with a linear decrease in risk of Gleason 8–10 prostate cancer, than in the SELECT study, which found that 25-OHD was associated with a linear decrease in the risk of high-grade cancers in African Americans and an apparent “U”-shaped curve in other men. Because a “U”-shaped curve was observed in the SELECT study, which was vulnerable to detection bias, but was not observed in the PCPT study, which was largely free from this bias, the “U”-shaped curve in the SELECT study may reflect such bias. Second, both studies show that the protective effect of 25-OHD was associated more strongly with high-grade than with low-grade prostate cancers. This finding is consistent with the hypothesis that vitamin D inhibits the development of clinically relevant, but not subclinical prostate cancer ..."
In the U.S. & in other populations where PCa screening is common, Gleason 8-10 is not common. Taking cases as a whole, not broken down by Gleason, it might appear that vitamin D does little to prevent occurrence.
The recently maligned Holic, & Grant et al, mentioned this in a 2016 paper [5] on the U-shaped risk studies:
"For prostate cancer, there seems to be little effect of 25(OH)D concentration on incidence; however, there is an inverse correlation between 25(OH)D concentration and mortality rates."
Over the years, papers have appeared in support of U-Shaped risk. I never believed in it, but it continues to be an unresolved issue.
And so I was quite surprised that the new vitamin D study gave participants 2,000 IUs without regard to 25-D status. I think it was reckless. And it seems to me to be a replay of SELECT, where men at the extreme end of selenium sufficiency were included in the study.
If U-shaped risk is real, the study would reduce cases at the low end only to increase them at the high end.
I dwell on this because Tall-Allen believes that D supplementation is dangerous, & a number of members rely on his opinion.
For me, the last word on the subject of U-shaped risk was this study [6]:
"A number of observational studies have shown an inverse association between circulating 25-hydroxyvitamin D and total mortality, but a reverse J-shaped association has also been reported. In a large nested case-control study, serum-25-hydroxyvitamin D (s-25(OH)D) was positively associated with incident prostate cancer. Based on the same study population, the primary aim of the present study was to investigate the association between s-25(OH)D and total mortality."
"In men with prostate cancer (n = 2282), there was a significant inverse association between s-25(OH)D {serum 25-D} and total mortality after controlling for potential confounders (HR = 1.25 ..., s-25(OH)D <50 nmol/l {20 ng/mL} versus s-25(OH)D ≥50 nmol/l)."
"In this study population, s-25(OH)D was inversely associated with total mortality during more than two decades of follow-up, despite, as previous reported, high s-25(OH)D was associated with increased risk of prostate cancer."
It is inconceivable to me that vitamin D could, both, cause PCa & protect men with PCa from PCa death.
***
As I mentioned in a recent post, it is crazy & potentially risky for a clinical trial to test the protective effect of an agent on participants who are not deficient.
I came across a paper yesterday by Bosland, Lü, et al [7]:
They examined why SELECT failed:
"Lesson 1: The antioxidant hypothesis was tested in wrong subjects/patient populations"
Too legthy to paste here, but the lesson ends with:
"Se status in most US residents is more than adequate from a nutritional perspective. ... the hypothesis of cancer prevention by dietary Se can only be tested in populations with marginal to deficient Se intake." I had to smile.
But it is so blindingly obvious.
I would add that if one starts with a definition of adequacy, one should tailor the dose to attain that level.
Most of the men I know who are serious about vitamin D, test 25-D (calcidiol) & modify their intake accordingly.
-Patrick
[1] ncbi.nlm.nih.gov/pubmed/146...
[2] cebp.aacrjournals.org/conte...
[3] cebp.aacrjournals.org/conte...
[4] ncbi.nlm.nih.gov/pubmed/224...
[5] ncbi.nlm.nih.gov/pmc/articl...
