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Calcitriol (1,25-D) is hormonal vitamin D. It is produced by the kidneys as needed, in order to regulate calcium homeostasis in the blood. For that reason, it is not a good measure of vitamin D status. Not a lot of calcitriol is made at one time, & it has a half-life of only 6-8 hours.
A calcitriol blood test says nothing about calcitriol in the prostate. Normal epithelial cells can convert calcidiol (25-D) tp calcitriol (1,25-D). Two enzymes are used to control levels. The first (1alpha-hydroxylase = CYP27B1) makes the conversion; the second (24-hydroxylase = CYP24A1) is produced as a reaction to the presence of calcitriol, & is responsible for its clearance. (Calcitriol also down-regulates the first enzyme.) This is a classic example of autocrine hormonal control, where the hormone is created but given a limited window for activity. In PCa, the first hormone is suppressed, while the second is upregulated. If the cell picks up calcitriol that was produced by the kidneys, it will be quickly cleared.
[1] (1993 - U.S. - Duke U. / Kaiser Permanente)
Blood was colleceted 1964-71. Cases were diagnosed before 12/31/1987.
There are problems making sense of calcitriol levels in any PCa study. (Most studies look at pro-hormone calcidiol.) This study reported that calcitriol levels were 1.81 pg/mL lower in cases than controls. Lower kidney production might be due to high intake of calcium or phosphate, or perhaps due to impaired kidney function - i.e. nothing to do with PCa. But if PCa is present & local calcitriol production has been suppressed, lower circulating calcitriol levels might help the cancer become more aggressive & speed up its diagnosis.
Calcidiol levels were similar between cases & controls. (Controls were matched to cases on date of blood draw - which gets around the seasonal variation issue.)
This early study is very important in that it shows, that when pre-hormone calcidiol status is equal, much may depend on dietary factors that affect calcitriol conversion. There was a suggestion that slightly higher phosphate levels in cases might have been the problem. Phosphates are found in soft drinks, & deli meats. Phosphorus is also found in meat - excessive intake during a meal will suppress calcitriol production for a while.
More well-known is the association between calcium from dairy & supplements with PCa aggressiveness, which may be due to calcitriol suppression.
[2] (1995 - U.S. - Duke U. / Kaiser Permanente) A follow-on of [1].
Calcitriol levels (which fluctuate throughout the day) did not demonstrate a seasonal fluctuation. In contrast: "Unexpectedly, lower case levels of 1,25-D were limited largely to the summer months".
Unexpected since 25-D levels were higher. However, soft drink intake might be significantly higher in the summer, which seems to support the earlier suggestion that phosphates were responsible.
[3] (1996 - U.S.) Physicians' Health Study [PHS].
"... results do not support the hypothesis that high circulating levels of vitamin D metabolites reduce prostate cancer risk ..."
However: "For 1,25-D, men in the highest quartile had an odds ratio of 0.88 ... compared to those in the lowest quartile."
I don't know how the PHS participants were distributed across the country, but the Kaiser Permanente men were in Oakland, CA. Might not be relevant.
[4] (1998 - U.S.) Health Professionals Follow-Up Study
Stampfer, who was part of [3], was co-author of this paper. In contrast to [3], 1,25-D was implicated in PCa risk. While calcium suppresses calcitriol, fructose can boost production.
"Higher consumption of calcium was related to advanced prostate cancer [multivariate relative risk (RR), 2.97 ... for intakes ≥2000 mg/day versus <500 mg/day" ... "and metastatic prostate cancer (RR, 4.57 ...)"
"Fruit intake was inversely associated with risk of advanced prostate cancer (RR, 0.63; ... for >5 versus ≤1 serving per day), and this association was accounted for by fructose intake. Non-fruit sources of fructose similarly predicted lower risk of advanced prostate cancer."
"Our findings provide indirect evidence for a protective influence of high 1,25(OH)2D {1,25-D} levels on prostate cancer"
Note that [3] looked at incidence risk, while this study looked at advanced disease. Kidney production of calcitriol becomes essential after PCa has evolved to stifle production. One would expect a greater association with advanced PCa.
Note also, that fruit was seen to be beneficial not because of vitamin C, etc., but because of fructose - the justly maligned sugar. Pure fructose had the same effect. I use it in my coffee for that reason.
[5] (2007 - U.S.) Physicians' Health Study [PHS].
Recall that [3] was also a PHS study that found no support for calcitriol being protective.
"Men whose levels for both 25(OH)D and 1,25(OH)2D were below (versus above) the median had a significantly increased risk of aggressive prostate cancer (odds ratio [OR] = 2.1"
In this instance they looked at aggressive PCa, rather than incidence.
...
[6] 1alpha-hydroxylase (CYP27B1) enzyme (converts calcidiol to calcitriol)
Gary Schwartz was the first to suggest a vitamin D - PCa connection in 1990. In 1998 (along with Holick) he reported that prostate cells could convert 25-D to 1,25-D (calcidiol to calcitriol) [6a]:
"This report demonstrates that two of three human prostate cancer cell lines, as well as primary cultures of noncancerous prostatic cells, possess 1alpha-hydroxylase activity and can synthesize 1,25(OH)2D3 from 25-OH-D3." (1,25-D from 25-D)
In 2001, Donna Peehl reported that [6b]:
"in primary cultures of cancer cells and established cell lines, the antiproliferative action of 25(OH)D3 was significantly less pronounced than that of 1,25(OH)2D3. Our results indicate that growth inhibition by 25(OH)D3 depends on endogenous 1alpha-hydroxylase activity, and that this activity is deficient in prostate cancer cells."
"Our findings of reduced 1α-hydroxylase activity in CA-derived prostatic cells raises the possibility that this difference may endow the malignant cells with an intrinsic growth advantage because of the resultant decrease in production of local growth inhibitory 1,25(OH)2D3. In addition, local deficiency of 1,25(OH)2D3 may allow cellular de-differentiation and invasion, hallmarks of malignancy. We conclude that decreased activity of 1α-hydroxylase may represent an important mechanism in prostate CA development and/or progression."
Michael Holick may be most responsible for the surge of interest in vitamin D (not just in PCa). From 2003 [6c]:
"the results suggest that the defect in enzyme activity may result from the decreased promoter activity in prostate cancer cells."
Promoter silencing is often an epigenetic change, & is therefore potentially reversible.
[7] 24-hydroxylase (CYP24A1) enzyme (destroys calcitriol)
Donna Peehl again (2001) [7a]:
"Ketoconazole is commonly used as a second-line androgen deprivation therapy. This imidazole derivative is an inhibitor of P-450 enzymes, including those involved in steroidogenesis. Other P-450 enzymes that are inhibited by ketoconazole include 1alpha-hydroxylase and 24-hydroxylase, which metabolize vitamin D. Growth inhibition of prostate cancer cells by vitamin D depends on levels of the active metabolite, 1,25-dihydroxyvitamin D(3) (calcitriol). The enzyme 24-hydroxylase converts calcitriol to less active products. The inhibition of 24-hydroxylase by ketoconazole maintains the magnitude and duration of response to calcitriol."
"Combined ketoconazole/calcitriol therapy might therefore potentiate the antitumor activity of calcitriol. Because androgen-independent prostate cancer cells often remain responsive to growth inhibition by calcitriol, it is also possible that calcitriol would slow or prevent development of androgen-independent cancer growth. Another consideration is that ketoconazole blocks 1alpha-hydroxylase activity, which is the key enzyme that creates calcitriol in the body. Therefore, patients receiving ketoconazole therapy are likely to be deficient in vitamin D. The detrimental consequences of vitamin D deficiency in these patients would also be alleviated by the addition of calcitriol to the therapeutic regimen."
Messy, but interesting.
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BOTTOM LINE:
It is not enough to raise calcidiol (25-D) levels to a target approved by Dr Myers or some other PCa guru. We also have to manipulate kidney conversion to calcitriol (1,25-D):
a) avoid high calcium intake. No dairy. No calcium supplement above 500 mg(?)
b) minimize phosphate / phosphorus intake. No soft drinks or deli meats with phosphates. No 16 oz T-bone steaks; reasonable portions below 4 oz OK.
c) consider using fructose to boost calcitriol production. Fruit contains different sugar types in different combinations. Not all fruits are good sources for fructose. Fructose as a coffee sweetener would work. Fructose does not spike glucose levels.
-Patrick
[1] cebp.aacrjournals.org/conte...
[2] cebp.aacrjournals.org/conte...
[3] cebp.aacrjournals.org/conte...
[4] cancerres.aacrjournals.org/...
[5] journals.plos.org/plosmedic...
[6a] cebp.aacrjournals.org/conte...
[6b] cancerres.aacrjournals.org/...
Xgeva & Calcium/vitamin D
Sunlight and vitamin d
vitamin D3 or Vitamin D 
