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All,

 

On the CR email list Al recently posted a series of studies, included below [1-3], showing that higher levels of serum vitamin D were associated with increased risk of prostate cancer. But the most recent such study Al posted [4], found the opposite - increased vitamin D level was associated with a decreased risk of prostate cancer. What the authors of [4] suggest in the discussion (included below) is that there may be a U-shaped curve between serum vitamin D and prostate cancer risk, with the 'sweet spot' being in the neighborhood of 20-30 ng/ml (or equiv. 50-75 nmol/l) range.

 

The bottom line suggested by [4] appears to be that we want to have sufficient Vitamin D, but not too much, in order to avoid prostate cancer.

 

Of course, men get a lot of their vitamin D from D-fortified dairy products, which may be driving some of this apparent positive association between vitamin D level and prostate cancer, since this recent meta-analysis [5] found:

 

High intakes of dairy products, milk, low-fat milk, cheese, and total, dietary, and dairy calcium, but not supplemental or nondairy calcium, may increase total prostate cancer risk.

 

So it is possible that higher levels of vitamin D are a marker for higher intake of dairy products in the general population, which may be driving the development of prostate cancer.

 

--Dean

 

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[1] Plasma 25-hydroxyvitamin D and prostate cancer risk: the multiethnic cohort.

Park SY, Cooney RV, Wilkens LR, Murphy SP, Henderson BE, Kolonel LN.
Eur J Cancer. 2010 Mar;46(5):932-6. doi: 10.1016/j.ejca.2009.12.030. Epub 2010 Feb 8.
PMID: 20064705 Free PMC Article
file:///C:/Documents%20and%20Settings/user/My%20Documents/Downloads/nihms169878%20(1).pdf
 
Abstract
 
The purpose of this study was to examine the relationship of plasma 25-hydroxyvitamin D (25(OH)D) concentrations to prostate cancer within a large multiethnic cohort in Hawaii and California using a nested case-control design. The study included 329 incident prostate cancer cases of African American, Native Hawaiian, Japanese, Latino, and White ancestry, and 656 controls matched on age, race/ethnicity, date/time of blood collection, and fasting status. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI). No association with prostate cancer risk was found in an analysis based on quartiles of 25(OH)D. When clinically defined cutpoints were used, there was no increased risk for the lowest 25(OH)D concentration (OR for <20 vs. 30–<50 ng/ml = 1.10, 95% CI = 0.68-1.78), while there was a suggestive increased risk for higher concentrations (OR for =50 ng/ml = 1.52, 95% CI = 0.92-2.51). The findings from this prospective study of men in the Multiethnic Cohort do not support the hypothesis that vitamin D lowers the risk of prostate cancer. Further follow-up is warranted to determine whether the findings are consistent across ethnic groups.
 
Keywords: 25-hydroxyvitamin D, multiethnic cohort, nested case-control study, plasma, prostate neoplasms
 
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[2] Circulating levels of 25-hydroxyvitamin D and prostate cancer prognosis.
Holt SK, Kolb S, Fu R, Horst R, Feng Z, Stanford JL.
Cancer Epidemiol. 2013 Oct;37(5):666-70. doi: 10.1016/j.canep.2013.07.005. Epub 2013 Aug 20.
PMID: 23972671
PMC Article
 
Abstract
 
OBJECTIVES:
 
Ecological, in vitro, and in vivo studies demonstrate a link between vitamin D and prostate tumor growth and aggressiveness. The goal of this study was to investigate whether plasma concentration of vitamin D is associated with survivorship and disease progression in men diagnosed with prostate cancer.
 
MATERIALS AND METHODS:
 
We conducted a population-based cohort study of 1476 prostate cancer patients to assess disease recurrence/progression and prostate cancer-specific mortality (PCSM) risks associated with serum levels of 25(OH) vitamin D [25(OH)D].
 
RESULTS:
 
There were 325 recurrence/progression and 95 PCSM events during an average of 10.8 years of follow-up. Serum levels of 25(OH)D were not associated with risk of recurrence/progression or mortality. Clinically deficient vitamin D levels were associated with an increased risk of death from other causes.
 
CONCLUSIONS:
 
We did not find evidence that serum vitamin D levels measured after diagnosis affect prostate cancer prognosis. Lower levels of vitamin D were associated with risk of non-prostate cancer mortality.
 
KEYWORDS:
 
1,25(OH)(2)D; 1,25-dihydroxyvitamin D(3); 25(OH) vitamin D; 25(OH)D; ADT; BMI; Cohort studies; Epidemiologic studies; FFQ; HR; Humans; Male; Mortality; PCSM; PCa; PH; PSA; Prognosis; Prostatic neoplasms; Vitamin D/blood*; androgen deprivation therapy; body mass index; food frequency questionnaire; hazard ratio; proportional hazards; prostate cancer; prostate cancer-specific mortality; prostate specific antigen
 
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[3] In older men, lower plasma 25-hydroxyvitamin D is associated with reduced incidence of prostate, but not colorectal or lung cancer.
Wong YY, Hyde Z, McCaul KA, Yeap BB, Golledge J, Hankey GJ, Flicker L.
PLoS One. 2014 Jun 20;9(6):e99954. doi: 10.1371/journal.pone.0099954. eCollection 2014. Erratum in: PLoS One. 2014;9(9):e109511.
PMID: 24949795 Free PMC Article
 
Abstract
 
CONTEXT AND OBJECTIVE:
 
Prostate, colorectal and lung cancers are common in men. In this study, we aimed to determine whether vitamin D status is associated with the incidence of these cancers in older men.
 
DESIGN:
 
Prospective cohort study.
 
SETTING AND PARTICIPANTS:
 
4208 older men aged 70-88 years in Perth, Western Australia.
 
MAIN OUTCOME MEASURES:
 
Plasma 25-hydroxyvitamin D [25(OH)D] concentration was measured by immunoassay. New diagnoses of prostate, colorectal and lung cancers were determined via electronic record linkage.
 
RESULTS:
 
During a mean follow-up of 6.7±1.8 years, there were 315, 117 and 101 new diagnoses of prostate, colorectal and lung cancer. In multivariate competing risks proportional hazards models, every 10 nmol/l decrease in 25(OH)D concentration was associated with a 4% reduction in prostate cancer incidence (sub-hazard ratio [sHR] 0.96, 95% confidence interval [CI] 0.92-1.00). Every halving of 25(OH)D concentration was associated with a 21% reduction in incident prostate cancer in multivariate analysis (SHR 0.79, 95% CI 0.63-0.99). Following exclusion of prostate cancer cases diagnosed within 3 years of blood sampling, low 25(OH)D <50 nmol/l was associated with lower incident prostate cancer, and higher 25(OH)D >75 nmol/l was associated with higher incidence, when compared to the reference range 50-75 nmol/l, respectively (p = 0.027). Significant associations were also observed when 25(OH)D was modeled as a quantitative variable. No associations were observed between plasma 25(OH)D concentration with incidence of colorectal or lung cancer.
 
CONCLUSION:
 
Lower levels of vitamin D may reduce prostate cancer risk in older men. By contrast, levels of vitamin D did not predict incidence of colorectal or lung cancers. Further studies are needed to determine whether a causal relationship exists between vitamin D and prostate cancer in ageing men.
 
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[4] A prospective study of plasma 25-hydroxyvitamin D concentration and prostate cancer risk.
 
Deschasaux M, Souberbielle JC, Latino-Martel P, Sutton A, Charnaux N, Druesne-Pecollo N, Galan P, Hercberg S, Le Clerc S, Kesse-Guyot E, Ezzedine K, Touvier M.
Br J Nutr. 2016 Jan;115(2):305-14. doi: 10.1017/S0007114515004353. Epub 2015 Nov 16.
PMID: 26568368
 
Abstract
 
Mechanistic hypotheses suggest that vitamin D and the closely related parathyroid hormone (PTH) may be involved in prostate carcinogenesis. However, epidemiological evidence is lacking for PTH and inconsistent for vitamin D. Our objectives were to prospectively investigate the association between vitamin D status, vitamin D-related gene polymorphisms, PTH and prostate cancer risk. A total of 129 cases diagnosed within the Supplémentation en Vitamines et Minéraux Antioxydants cohort were included in a nested case-control study and matched to 167 controls (13 years of follow-up). 25-Hydroxyvitamin D (25(OH)D) and PTH concentrations were assessed from baseline plasma samples. Conditional logistic regression models were computed. Higher 25(OH)D concentration was associated with decreased risk of prostate cancer (ORQ4 v. Q1 0·30; 95 % CI 0·12, 0·77; P trend=0·007). PTH concentration was not associated with prostate cancer risk (P trend=0·4) neither did the studied vitamin D-related gene polymorphisms. In this prospective study, prostate cancer risk was inversely associated with 25(OH)D concentration but not with PTH concentration. These results bring a new contribution to the understanding of the relationship between vitamin D and prostate cancer, which deserves further investigation.
 
KEYWORDS:
 
1; 25(OH)2D 1; 25(OH)D 25-hydroxyvitamin D; 25-Hydroxyvitamin D; 25-dihydroxyvitamin D; 25-dihydroxyvitamin D3 24-hydroxylase; CYP24A1 1; CaSR Ca-sensing receptor; GC vitamin D-binding globulin; MAF minor allele frequency; Nested case–control studies; PTH parathyroid hormone; Parathyroid hormone; Prostate cancer risk; RXR retinoid X receptor; SNP; SU.VI.MAX Supplémentation en Vitamines et Minéraux Antioxydants; VDR vitamin D receptor; gc-globulin or group-specific component
 
Vitamin D is a prohormone synthesised in the skin from UVB exposure and absorbed from scarce dietary sources. It is first converted to 25-hydroxyvitamin D (25(OH)D) – its main circulating form – and then to 1,25-dihydroxyvitamin D (1,25(OH)2D) – its biologically active form. As 25(OH)D-to-1,25(OH)2D conversion and 1,25(OH)2D signalling can take place directly in prostate tissues(1), vitamin D is thought to play a role in the prevention of prostate cancer through pro-differentiation, pro-apoptosis, anti-proliferative and growth control activities, as suggested by experimental studies(2–4). However, so far, epidemiological evidence regarding the relationship between 25(OH)D concentration and prostate cancer risk has been inconsistent. On the basis of a dose–response meta-analysis that involved fifteen prospective studies, the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR)(5), as part of the Continuous Update Project 2014 on prostate cancer, stated that the level of proof for the association between 25(OH)D concentration and prostate cancer risk was still ‘limited-no conclusion’. Most of the studies included in this meta-analysis observed null results.
 
Besides, vitamin D is primarily involved in Ca homoeostasis: 1,25(OH)2D increases Ca concentration through enhanced intestinal Ca absorption, reabsorption of Ca from kidneys and bone resorption. Renal 25(OH)D-to-1,25(OH)2D conversion is induced by parathyroid hormone (PTH) secretion in response to low Ca concentration. 1,25(OH)2D exerts in turn a negative feedback on PTH secretion(6–8). Vitamin D and PTH are thus closely related. To our knowledge, only one prospective study has investigated the association between PTH concentration and prostate cancer risk, with null result(9).
 
Several genes involved in vitamin D metabolism, in particular signalling (vitamin D receptor (VDR) and retinoid X receptor (RXR)), transportation (vitamin D-binding protein, also known as gc-globulin or group-specific component (GC)) and degradation (1,25-dihydroxyvitamin D3 24-hydroxylase (CYP24A1)), or in Ca homoeostasis (Ca-sensing receptor (CaSR)) could also play a role in prostate cancer aetiology(2). Recent meta-analyses found null associations between VDR BsmI, FokI and Cdx2 polymorphisms and prostate cancer risk(10–12). The epidemiological literature dealing with polymorphisms of other genes (GC, CYP24A1, RXR and CaSR) in relation to prostate cancer risk is scarce(13–16).
 
Thus, our objective was to prospectively investigate the associations between prostate cancer risk and vitamin D status (25(OH)D concentration), plasma PTH concentration and polymorphisms of genes involved in vitamin D metabolism.
 
Methods
 
Subjects
 
The Supplémentation en Vitamines et Minéraux Antioxydants (SU.VI.MAX) study was initially designed as a double-blind placebo-controlled trial (Trial Registration clinicaltrials.gov Identifier: NCT00272428) with purpose to assess the influence of a daily supplementation with nutritional doses of antioxidants (single capsule of a combination of ascorbic acid (120 mg), vitamin E (30 mg), ß-carotene (6 mg), Se (100 µg) and Zn (20 mg) or placebo) on the incidence of CVD and cancers(17). A total of 13 017 participants were enrolled in 1994–1995 for an 8-year-intervention trial and followed up for health events until September 2007. Participants were advised against taking any self-prescribed supplements (vitamin D and others) during the trial.
 
...
 
Results
 
A total of 129 prostate cancer cases diagnosed within the SU.VI.MAX cohort were included in this study. Mean age at diagnosis was 63·0 years and mean baseline-to-diagnosis time was 8·3 years. Of the cases, 49·2 % had a Gleason’s score =/>7. A total of 167 controls were randomly selected and matched to the cases. Table 1 summarises the characteristics of prostate cancer cases and controls. Compared with controls, prostate cancer cases were more likely to have a lower vitamin D status at baseline and to be better educated. Severe vitamin D deficiency (<10 ng/ml) was observed for 14·0 % of cases and 13·8 % of controls, and vitamin D insufficiency (<20 ng/ml) was observed for 62·8 % of cases and 54·5 % of controls, with no statistically significant difference between cases and controls. A seasonal fluctuation of vitamin D status was observed in controls with decreasing vitamin D status from October to March (shortening days) and increasing vitamin D status in April–May (extending days). All studied SNP respected the Hardy–Weinberg’s equilibrium (P>0·05). The repartition of subjects across the different genotypes was in accordance with that observed in European reference populations (CSHL-HapMap-CEU and 1000GENOMES-phase_1_EUR) for all SNP (P>0·05).
 
25(OH)D concentration was inversely associated with prostate cancer risk (ORper 1 ng/ml 0·96; 95 % CI 0·93, 1·00; Ptrend=0·04; ORQ4 v. Q1 0·30; 95 % CI 0·12, 0·77; Ptrend=0·007; OR<20 v. =/>20 ng/ml 0·44; 95 % CI 0·23, 0·85; P=0·01, Table 2; ORper 30 nmol/l 0·64; 95 % CI 0·42, 0·97; Ptrend=0·04, data not tabulated). Using the quartile coding this inverse association was observed in particular for cases with a Gleason’s score <7 (sixty-nine cases/ninety controls, ORQ4 v. Q1 0·03; 95 % CI 0·003, 0·40; Ptrend=0·02; data not tabulated), whereas it was not significant for cases with a Gleason’s score =/>7 (sixty cases/seventy-seven controls, ORQ4 v. Q1 0·96; 95 % CI 0·23, 4·05; Ptrend=0·5; data not tabulated). However, using the continuous 25(OH)D variable or the 20 ng/ml cut-off, these associations were not significant in both Gleason’s subgroups. Exclusion of cases diagnosed during the first 5 years of follow-up provided similar results (109 cases/140 controls, ORper 1 ng/ml 0·96; 95 % CI 0·93, 1·00; Ptrend=0·04; ORQ4 v. Q1 0·33; 95 % CI 0·12, 0·86; Ptrend=0·01; OR<20 v. =/>20 ng/ml 0·45; 95 % CI 0·23, 0·89; P=0·02; data not tabulated). No interaction was observed between 25(OH)D concentration and the intervention group of the SU.VI.MAX trial (Pinteraction>0·1 for all codings).
 
Associations between 25-hydroxyvitamin D (25(OH)D) and parathyroid hormone (PTH) plasma concentrations, and prostate cancer risk, from conditional logistic regression, Supplémentation en Vitamines et Minéraux Antioxydants (SU.VI.MAX) cohort, France (1994–2007) (Odds ratios and 95 % confidence intervals)
 
Table 2
Associations between 25-hydroxyvitamin D (25(OH)D) and parathyroid hormone (PTH) plasma concentrations, and prostate cancer risk, from conditional logistic regression, Supplémentation en Vitamines et Minéraux Antioxydants (SU.VI.MAX) cohort, France (1994–2007) (Odds ratios and 95 % confidence intervals) % confidence intervals)
--------------------------------------------------
- === - ===Quartiles*===Insufficiency
- === Per 1 unit increment===Q1 Q2 Q3 Q4 <20 ng/ml =/>20 ng/ml
- === OR 95 % CI Ptrend===OR OR 95 % CI OR 95 % CI OR 95 % CI Ptrend OR OR 95 % CI P
--------------------------------------------------
25(OH)D (ng/ml)
Cases/controls 129/167 42/32 31/43 25/49 31/43 81/91 48/76
Model 1† 0·96 0·93, 1·00 0·04 1·00 0·44 0·19, 1·04 0·18 0·07, 0·49 0·30 0·12, 0·77 0·007 1·00 0·44 0·23, 0·85 0·01
Cases/controls 96/123 27/20 23/35 20/35 26/33 57/66 39/57
Model 2† 0·95 0·91, 1·00 0·06 1·00 0·35 0·12, 1·07 0·13 0·04, 0·49 0·25 0·08, 0·81 0·02 1·00 0·43 0·19, 1·00 0·05
Cases/controls 96/123 27/20 23/35 20/35 26/33 57/66 39/57
Model 3† 0·96 0·91, 1·01 0·08 1·00 0·33 0·11, 1·03 0·12 0·03, 0·46 0·28 0·08, 0·95 0·03 1·00 0·43 0·18, 1·01 0·05
--------------------------------------------------
PTH (pg/ml)
Cases/controls 129/167 31/43 34/40 34/40 30/44
Model 1† 0·97 0·94, 1·01 0·1 1·00 0·90 0·40, 2·05 0·95 0·40, 2·27 0·66 0·28, 1·55 0·4
Cases/controls 96/123 20/35 30/26 27/30 19/32
Model 2† 0·96 0·91, 1·01 0·09 1·00 1·72 0·60, 4·90 1·95 0·62, 6·18 0·77 0·25, 2·36 0·6
Cases/controls 96/123 20/35 30/26 27/30 19/32
Model 3† 0·96 0·91, 1·01 0·1 1·00 1·63 0·56, 4·77 2·25 0·67, 7·59 0·81 0·25, 2·62 0·8
--------------------------------------------------
  Q, quartiles.
  * Model 1: cut-offs for quartiles of 25(OH)D plasma concentration (ng/ml) and PTH plasma concentration (pg/ml) were, respectively, 12·9/18·2/24·7 and 20·9/26·0/30·6. Models 2 and 3 are restricted to men who provided at least three valid 24 h-dietary records (ninety-six cases/123 controls): cut-offs for quartiles of 25(OH)D plasma concentration (ng/ml) and PTH plasma concentration (pg/ml) were, respectively, 13·7/18·5/25·2 and 20·9/25·9/30·2.
  † Model 1 was adjusted for age at baseline (continuous, matching factor), intervention group of the initial SU.VI.MAX trial (antioxidants/placebo, matching factor), month of blood draw (October–November/December–January/February–March/April–May), educational level (primary/secondary/superior), physical activity (irregular/<1 h/d walking equivalent/=/>1 h/d walking equivalent), alcohol intake (g/d, continuous), smoking status (never/former/current), height (cm, continuous), BMI (kg/m², continuous, matching factor), family history of prostate cancer (yes/no) and baseline serum prostate-specific antigen concentration (<3/=/>3 ng/l). Model 2 corresponds to model 1 further adjusted for energy intake (without alcohol) (continuous, kJ/d (kcal/d)), dietary intakes of Ca intake (continuous, mg/d) and dairy products (continuous, g/d), plasma Se (continuous, µmol/l) and Alpha-tocopherol (continuous, µmol/l) concentrations.
  Model 3 corresponds to model 2 with further mutual adjustment for 25(OH)D and PTH plasma concentrations (continuous).
 
Plasma PTH concentration was not associated with prostate cancer risk (ORQ4 v. Q1 0·66; 95 % CI 0·28, 1·55; Ptrend=0·4) (Table 2). This result was similar (124 cases/157 controls) after removing participants with possibly abnormal PTH values that may suggest potential hyperparathyroidism (i.e. PTH=/>50·8 pg/ml if 25(OH)D<20 ng/ml, PTH=/>45·5 pg/ml if 20 ng/ml</=25(OH)D<30 ng/ml and PTH=/>45·3 pg/ml if 25(OH)D=/>30 ng/ml, as previously recommended(22)).
 
Dietary Ca intake was not associated with prostate cancer risk (ninety-six cases/123 controls, ORQ4 v. Q1 0·83; 95 % CI 0·20, 3·43; Ptrend=0·5, data not tabulated), nor did dietary intake of vitamin D (ninety-six cases/123 controls, ORQ4 v. Q1 1·05; 95 % CI 0·40, 2·81; Ptrend=0·7, data not tabulated).
 
All results were similar when models were further adjusted for dietary variables (although some of the results were only borderline significant due to loss of statistical power: ninety-six cases/123 controls), dietary Ca and mutual adjustments for 25(OH)D and PTH. Two-way interactions between 25(OH)D, PTH and dietary Ca intake were not statistically significant (all P>0·1, data not shown).
 
No association was observed between the ten studied vitamin D-related SNP and prostate cancer risk in the codominant (Table 3), dominant and recessive models (data not tabulated). No interaction was observed between the SNP and 25(OH)D concentration (all P>0·1, data not shown). As no association was detected between the ten SNP and prostate cancer with a P value threshold of 0·05, no association was detected after adjustment for multiple testing (Bonferroni correction) (data not shown).
 
Associations between SNP of genes involved in vitamin D metabolism and prostate cancer risk, from conditional logistic regression, Supplémentation en Vitamines et Minéraux Antioxydants (SU.VI.MAX) cohort, France (1994–2007) (Odds ratios and 95 % confidence intervals)
 
Discussion
 
In this prospective study, plasma 25(OH)D concentration was inversely associated with prostate cancer risk. No association was detected for plasma PTH concentration or the studied SNP.
 
We observed an inverse association between 25(OH)D concentration and prostate cancer risk. Recently, a high v. low meta-analysis by Xu et al.(27) (summary ORhigh v. low 1·17; 95 % CI 1·05, 1·30) and a dose–response meta-analysis by the WCRF(5) (summary RRper 30 nmol/l 1·04; 95 % CI 1·00, 1·07) suggested an increased risk. However, in a previous study by Tuohimaa et al.(28), both high and low 25(OH)D concentrations were associated with increased prostate cancer risk: increased risk was observed for 25(OH)D concentration =/>32 or <15·6 ng/ml compared with 16–23·6 ng/ml. This U-shaped association is supported by the evidence of non-linearity observed in the WCRF dose–response meta-analysis(5). In our study, the range of 25(OH)D concentrations observed (95th percentile=36·3 ng/ml) may be positioned in the left part of this U-shaped curve, which may explain why a decreased prostate cancer risk was observed for 25(OH)D=/>20 ng/ml (insufficiency) or =/>18·2 ng/ml (median) compared with 25(OH)D<20 or <12·9 ng/ml (quartile 1 (Q1)), respectively. Consistently, a recent study by Kristal et al.(29) observed a decreased prostate cancer risk associated with 25(OH)D concentrations between 23·3 and 29·2 ng/ml (3rd quintile) compared with 25(OH)D<17·7 ng/ml (1st quintile). In contrast, some studies observing an increased risk may involve 25(OH)D concentrations situated in the right part of the U-shaped curve. For example, Brandstedt et al.(9) observed an increased risk for 25(OH)D concentrations=/>34 ng/ml compared with 25(OH)D concentrations</=27·2 ng/ml, and Meyer et al.(30) observed an increased risk for 25(OH)D concentrations=/>28 ng/ml compared with 25(OH)D concentrations between 20 and 28 ng/ml. Studies observing non-significant results may involve middle-range concentrations (such as the study by Skaaby et al.(31)). However, this point remains unclear as some studies that involved high 25(OH)D concentrations observed non-significant results(32,33), and some other studies observed a significant direct association between prostate cancer risk and 25(OH)D concentrations, even at relatively low levels(34). Thus, further studies are needed that take into account the distribution of 25(OH)D concentrations in the studied population and its position in the potential U-shaped curve. In addition, it has been suggested that large seasonal fluctuations of vitamin D status may also contribute to explain the positive association between 25(OH)D concentration and prostate cancer risk in some studies(35), adding to the complexity of this relationship. In the SU.VI.MAX cohort (Touvier et al.(21) and Table 1), seasonal fluctuation of vitamin D status was moderate with the lowest 25(OH)D concentrations observed in late winter/early spring (shorter days), consistently with the existing literature in France(36) and in other countries such as the USA(37–39).
 
The potentially protective role of vitamin D in prostate carcinogenesis observed in our study is supported by mechanistic hypotheses. Indeed, prostate cells can express the 25(OH)D-to-1,25(OH)2D conversion enzyme and the vitamin D receptor(1) and vitamin D is thought to be involved in several cell regulation pathways: pro-differentiation, pro-apoptosis, anti-proliferation and cell growth(2–4).
 
In our study, when 25(OH)D was coded into quartiles, a decreased prostate cancer risk was observed for Gleason’s score <7 but not for Gleason’s score =/>7. However, when using the other codings (continuous and 20 ng/ml cut-off), the association was non-significant in both cancer subgroups. As statistical power was limited in stratified analyses, these results should be considered with caution and further explored in large prospective studies. Thus far, the results regarding potential differences according to prostate cancer stage/grade are unclear, as shown in the WCRF meta-analysis(5), where no difference was observed between advanced/high-grade or non-advanced/low-grade prostate cancers (non-significant results in both groups), or in a recent study by Kristal et al.(29), where a decreased prostate cancer risk was observed whatever the Gleason’s score.
 
The lack of association between the ten studied SNP and prostate cancer risk in our study does not seem to support the protective role of vitamin D in prostate carcinogenesis suggested by our results on plasma 25(OH)D concentration. However, in this study, statistical power was limited in the analyses of SNP, especially for the homozygote mutant genotypes. This could explain the null associations observed. Consistent with our findings, several meta-analyses(10–12) and one recent prospective study(13) found null associations between VDR BsmI, FokI and Cdx2 polymorphisms and prostate cancer risk. Another study (not included in these meta-analyses) observed an increased prostate cancer associated with VDR BsmI GG genotype among men in the first tertile of plasma 25(OH)D concentration. The epidemiological literature dealing with the other studied polymorphisms is scarce. One study(13) observed an increased prostate cancer risk associated with GC rs4588 T allele or GC rs7041 A allele. In SU.VI.MAX(21), these alleles were associated with a lower vitamin D status. Another study(15) observed a decreased lethal prostate cancer risk associated with CaSR rs1801725 among men with low plasma 25(OH)D concentration. To our knowledge, no study has investigated the other selected SNP (CYP24A1 rs4809958, RXR rs7861779 and rs12004589 and CaSR rs4678174) in relation to prostate cancer risk. Besides, other vitamin D-related SNP than the ones included in the present study may also be associated with prostate cancer risk, as observed by Mondul et al.(14), and deserve further investigation.
 
Plasma PTH concentration was not associated with the risk of prostate cancer. To our knowledge, our study was only the second to investigate this relationship, the first one having observed null results(9). In a previous study performed in the SU.VI.MAX cohort(22), we observed an inverse correlation between 25(OH)D and PTH concentrations, with a threshold value for PTH when 25(OH)D was approximately 30 ng/ml. Thus, it could be expected that PTH concentration would decrease as 25(OH)D concentration increases. Mechanistic data are unclear regarding a potential involvement of PTH in prostate carcinogenesis. Although some data have suggested a potential pro-carcinogenic role of PTH(40–42) (potential mitogenic activity in preneoplastic lesions), others support a potential protective role. Indeed, high PTH concentration may decrease growth hormone secretion, thereby decreasing circulating insulin-like growth factor-1 (IGF-1) concentration(43,44); IGF-1 being considered as a potential risk factor for prostate cancer(45,46). Thus, further investigation is needed on the association between PTH concentration and prostate cancer risk.
 
Strengths of our study pertained to its prospective design, long follow-up, simultaneous assessment of 25(OH)D and PTH plasma concentrations, vitamin D-related gene polymorphisms and dietary intakes, and the consideration of numerous confounding factors. However, limitations should be acknowledged. First, blood Ca concentration was not available in our study. Ca concentration would have provided more information regarding the association between 25(OH)D, PTH, Ca and prostate cancer risk. Dietary Ca intake was available, but intakes within normal range are poorly correlated with blood Ca concentration(47), which is under homoeostatic control. Second, only one plasma 25(OH)D and PTH measurement was available at baseline. Repeated measures could have been of interest to study their evolution across time. Third, although the number of cases was appropriate for the analyses described here, it has limited our ability to perform separate analyses in specific subgroups, in particular regarding genetic polymorphisms or prostate cancer grade. Finally, the observed inverse association between vitamin D status and prostate cancer could be partly explained by reverse causality, considering the long lasting development of this cancer. However, results were similar when excluding cases diagnosed within the first 5 years of follow-up, thus arguing against reverse causality.
 
In this prospective study, the association between vitamin D and prostate cancer risk was addressed through 25(OH)D concentration, polymorphisms of vitamin D-related genes and PTH concentration. Prostate cancer risk was inversely associated with 25(OH)D concentration but not with PTH concentration. These results, supported by mechanistic data, bring a new contribution to the understanding of the relationship between vitamin D and prostate cancer risk and deserve further exploration.
 
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[5] Am J Clin Nutr. 2015 Jan;101(1):87-117. doi: 10.3945/ajcn.113.067157. Epub 2014
Nov 19.
 
Dairy products, calcium, and prostate cancer risk: a systematic review and
meta-analysis of cohort studies.
 
Aune D(1), Navarro Rosenblatt DA(1), Chan DS(1), Vieira AR(1), Vieira R(1),
Greenwood DC(1), Vatten LJ(1), Norat T(1).
 
Author information: 
(1)From the Department of Public Health and General Practice, Faculty of
Medicine, Norwegian University of Science and Technology, Trondheim, Norway (DA
and LJV); the Department of Epidemiology and Public Health, Imperial College,
London, United, Kingdom (DA, DANR, DSMC, ARV, RV, and TN); and the Biostatistics 
Unit, Centre for Epidemiology and Biostatistics, University of Leeds, Leeds,
United Kingdom (DCG).
 
BACKGROUND: Dairy product and calcium intakes have been associated with increased
prostate cancer risk, but whether specific dairy products or calcium sources are 
associated with risk is unclear.
OBJECTIVE: In the Continuous Update Project, we conducted a meta-analysis of
prospective studies on intakes of dairy products and calcium and prostate cancer 
risk.
DESIGN: PubMed and several other databases were searched up to April 2013.
Summary RRs were estimated by using a random-effects model.
RESULTS: Thirty-two studies were included. Intakes of total dairy products
[summary RR: 1.07 (95% CI: 1.02, 1.12; n = 15) per 400 g/d], total milk [summary 
RR: 1.03 (95% CI: 1.00, 1.07; n = 14) per 200 g/d], low-fat milk [summary RR:
1.06 (95% CI: 1.01, 1.11; n = 6) per 200 g/d], cheese [summary RR: 1.09 (95% CI: 
1.02, 1.18; n = 11) per 50 g/d], and dietary calcium [summary RR: 1.05 (95% CI:
1.02, 1.09; n = 15) per 400 mg/d] were associated with increased total prostate
cancer risk. Total calcium and dairy calcium intakes, but not nondairy calcium or
supplemental calcium intakes, were also positively associated with total prostate
cancer risk. Supplemental calcium was associated with increased risk of fatal
prostate cancer.
CONCLUSIONS: High intakes of dairy products, milk, low-fat milk, cheese, and
total, dietary, and dairy calcium, but not supplemental or nondairy calcium, may 
increase total prostate cancer risk. The diverging results for types of dairy
products and sources of calcium suggest that other components of dairy rather
than fat and calcium may increase prostate cancer risk. Any additional studies
should report detailed results for subtypes of prostate cancer.
 
© 2015 American Society for Nutrition.
 
PMID: 25527754

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I saw reports that skim milk increased the risk of getting prostate cancer, but it seems the story is different for dying from the pathology.

 

 

Whole milk intake is associated with prostate cancer-specific mortality among U.S. male physicians.

Song Y, Chavarro JE, Cao Y, Qiu W, Mucci L, Sesso HD, Stampfer MJ, Giovannucci E, Pollak M, Liu S, Ma J.

J Nutr. 2013 Feb;143(2):189-96. doi: 10.3945/jn.112.168484. Epub 2012 Dec 19.

PMID: 23256145 Free PMC Article



 

Abstract

 

Previous studies have associated higher milk intake with greater prostate cancer (PCa) incidence, but little data are available concerning milk types and the relation between milk intake and risk of fatal PCa. We investigated the association between intake of dairy products and the incidence and survival of PCa during a 28-y follow-up. We conducted a cohort study in the Physicians' Health Study (n = 21,660) and a survival analysis among the incident PCa cases (n = 2806). Information on dairy product consumption was collected at baseline. PCa cases and deaths (n = 305) were confirmed during follow-up. The intake of total dairy products was associated with increased PCa incidence [hr = 1.12 (95% CI: 0.93, 1.35); >2.5 servings/d vs. ≤0.5 servings/d]. Skim/low-fat milk intake was positively associated with risk of low-grade, early stage, and screen-detected cancers, whereas whole milk intake was associated only with fatal PCa [hr = 1.49 (95% CI: 0.97, 2.28); ≥237 mL/d (1 serving/d) vs. rarely consumed]. In the survival analysis, whole milk intake remained associated with risk of progression to fatal disease after diagnosis [hr = 2.17 (95% CI: 1.34, 3.51)]. In this prospective cohort, higher intake of skim/low-fat milk was associated with a greater risk of nonaggressive PCa. Most importantly, only whole milk was consistently associated with higher incidence of fatal PCa in the entire cohort and higher PCa-specific mortality among cases. These findings add further evidence to suggest the potential role of dairy products in the development and prognosis of PCa.

 

 

Milk and dairy consumption among men with prostate cancer and risk of metastases and prostate cancer death.

Pettersson A, Kasperzyk JL, Kenfield SA, Richman EL, Chan JM, Willett WC, Stampfer MJ, Mucci LA, Giovannucci EL.

Cancer Epidemiol Biomarkers Prev. 2012 Mar;21(3):428-36. doi: 10.1158/1055-9965.EPI-11-1004. Epub 2012 Feb 7.

PMID: 22315365 Free PMC Article



 

Abstract

 

BACKGROUND:

 

Whether milk and dairy intake after a prostate cancer diagnosis is associated with a poorer prognosis is unknown. We investigated postdiagnostic milk and dairy intake in relation to risk of lethal prostate cancer (metastases and prostate cancer death) among participants in the Health Professionals Follow-Up Study.

 

METHODS:

 

The cohort consisted of 3,918 men diagnosed with apparently localized prostate cancer between 1986 and 2006, and followed to 2008. Data on milk and dairy intake were available from repeated questionnaires. We used Cox proportional hazards models to calculate HRs and 95% CIs of the association between postdiagnostic milk and dairy intake and prostate cancer outcomes.

 

RESULTS:

 

We ascertained 229 prostate cancer deaths and an additional 69 metastases during follow-up. In multivariate analysis, total milk and dairy intakes after diagnosis were not associated with a greater risk of lethal prostate cancer. Men with the highest versus lowest intake of whole milk were at an increased risk of progression (HR = 2.15, 95% CI: 1.28-3.60; P(trend) < 0.01). Men in the highest versus lowest quintile of low-fat dairy intake were at a decreased risk of progression (HR = 0.62; 95% CI: 0.40-0.95; P(trend) = 0.07).

 

CONCLUSIONS:

 

With the exception of whole milk, our results suggest that milk and dairy intake after a prostate cancer diagnosis is not associated with an increased risk of lethal prostate cancer.

 

IMPACT:

 

This is the first larger prospective study investigating the relation between postdiagnostic milk and dairy intake and risk of lethal prostate cancer.

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I forgot about the Adventist study [1] on prostate cancer risk, that we discussed a while back, which found:

 

Vegan diets showed a statistically significant protective association with prostate cancer risk (HR: 0.65; 95% CI: 0.49, 0.85).

 

In contrast, the lacto-ovo-vegetarian Adventists saw a complete lack of any prostate cancer risk reduction ((HR: 1.0; 95% CI: 0.85, 1.18).

 

More evidence that milk may not do the body good, at least when it comes to the prostate.

 

--Dean

 

--------

[1] Are strict vegetarians protected against prostate cancer?

Tantamango-Bartley Y, Knutsen SF, Knutsen R, Jacobsen BK, Fan J, Beeson WL, Sabate J, Hadley D, Jaceldo-Siegl K, Penniecook J, Herring P, Butler T, Bennett H, Fraser G.
Am J Clin Nutr. 2015 Nov 11. pii: ajcn106450. [Epub ahead of print]
PMID: 26561618
 
Abstract
 
BACKGROUND:
 
According to the American Cancer Society, prostate cancer accounts for ~27% of all incident cancer cases among men and is the second most common (noncutaneous) cancer among men. The relation between diet and prostate cancer is still unclear. Because people do not consume individual foods but rather foods in combination, the assessment of dietary patterns may offer valuable information when determining associations between diet and prostate cancer risk.
 
OBJECTIVE:
 
This study aimed to examine the association between dietary patterns (nonvegetarian, lacto-ovo-vegetarian, pesco-vegetarian, vegan, and semi-vegetarian) and prostate cancer incidence among 26,346 male participants of the Adventist Health Study-2.
 
DESIGN:
 
In this prospective cohort study, cancer cases were identified by matching to cancer registries. Cox proportional hazards regression analysis was performed to estimate HRs by using age as the time variable.
 
RESULTS:
 
In total, 1079 incident prostate cancer cases were identified. Around 8% of the study population reported adherence to the vegan diet. Vegan diets showed a statistically significant protective association with prostate cancer risk (HR: 0.65; 95% CI: 0.49, 0.85). After stratifying by race, the statistically significant association with a vegan diet remained only for the whites (HR: 0.63; 95% CI: 0.46, 0.86), but the multivariate HR for black vegans showed a similar but nonsignificant point estimate (HR: 0.69; 95% CI: 0.41, 1.18).
 
CONCLUSION:
 
Vegan diets may confer a lower risk of prostate cancer. This lower estimated risk is seen in both white and black vegan subjects, although in the latter, the CI is wider and includes the null.
 
KEYWORDS:
 
Adventist; cancer; diet; prostate; vegan

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Here is a paper [1] describing what looks like a pretty reasonable model of how cow's milk may induce prostate cancer, via several pathways, all of which result in upregulation of the mTOR signalling pathway, which is known to be suppressed by CR. From the paper:

 

... persistent consumption of
cow´s milk proteins in humans provide highly insulinotropic branched-chain amino 
acids (BCAAs) provided by milk´s fast hydrolysable whey proteins, which elevate
postprandial plasma insulin levels, and increase hepatic IGF-1 plasma
concentrations by casein-derived amino acids. BCAAs, insulin and IGF-1 are
pivotal activating signals of mTORC1. Increased cow´s milk protein-mediated
mTORC1 signaling along with constant exposure to commercial cow´s milk estrogens 
derived from pregnant cows may explain the observed association between high

dairy consumption and increased risk of PCa in Westernized societies.

 

Here is a diagram of the mechanism linking dairy to prostate cancer proposed by the authors:

 

1743-7075-9-74-5.jpg

 

 

Like everything else in human metabolism, it appears to be amazingly complicated. But this model seems to provide a good explanation for why a plant-based diets which includes dairy products but which is otherwise quite healthy does not appear to reduce prostate cancer risk in the same dramatic way that a strictly vegan diet does.

 

--Dean

 

------------

[1] Nutr Metab (Lond). 2012 Aug 14;9(1):74. doi: 10.1186/1743-7075-9-74.

 
The impact of cow's milk-mediated mTORC1-signaling in the initiation and
progression of prostate cancer.
 
Melnik BC(1), John SM, Carrera-Bastos P, Cordain L.
 
 
Prostate cancer (PCa) is dependent on androgen receptor signaling and aberrations
of the PI3K-Akt-mTORC1 pathway mediating excessive and sustained growth
signaling. The nutrient-sensitive kinase mTORC1 is upregulated in nearly 100% of 
advanced human PCas. Oncogenic mTORC1 signaling activates key subsets of mRNAs
that cooperate in distinct steps of PCa initiation and progression.
Epidemiological evidence points to increased dairy protein consumption as a major
dietary risk factor for the development of PCa. mTORC1 is a master regulator of
protein synthesis, lipid synthesis and autophagy pathways that couple nutrient
sensing to cell growth and cancer. This review provides evidence that PCa
initiation and progression are promoted by cow´s milk, but not human milk,
stimulation of mTORC1 signaling. Mammalian milk is presented as an endocrine
signaling system, which activates mTORC1, promotes cell growth and proliferation 
and suppresses autophagy. Naturally, milk-mediated mTORC1 signaling is restricted
only to the postnatal growth phase of mammals. However, persistent consumption of
cow´s milk proteins in humans provide highly insulinotropic branched-chain amino 
acids (BCAAs) provided by milk´s fast hydrolysable whey proteins, which elevate
postprandial plasma insulin levels, and increase hepatic IGF-1 plasma
concentrations by casein-derived amino acids. BCAAs, insulin and IGF-1 are
pivotal activating signals of mTORC1. Increased cow´s milk protein-mediated
mTORC1 signaling along with constant exposure to commercial cow´s milk estrogens 
derived from pregnant cows may explain the observed association between high
dairy consumption and increased risk of PCa in Westernized societies. As
well-balanced mTORC1-signaling plays an important role in appropriate prostate
morphogenesis and differentiation, exaggerated mTORC1-signaling by high cow´s
milk consumption predominantly during critical growth phases of prostate
development and differentiation may exert long-term adverse effects on prostate
health. Attenuation of mTORC1 signaling by contemporary Paleolithic diets and
restriction of dairy protein intake, especially during mTORC1-dependent phases of
prostate development and differentiation, may offer protection from the most
common dairy-promoted cancer in men of Western societies.
 
PMCID: PMC3499189
PMID: 22891897

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