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1.  A Prospective Study of Plasma Vitamin D Metabolites, Vitamin D Receptor Polymorphisms, and Prostate Cancer 
PLoS Medicine  2007;4(3):e103.
Background
Vitamin D insufficiency is a common public health problem nationwide. Circulating 25-hydroxyvitamin D3 (25[OH]D), the most commonly used index of vitamin D status, is converted to the active hormone 1,25 dihydroxyvitamin D3 (1,25[OH]2D), which, operating through the vitamin D receptor (VDR), inhibits in vitro cell proliferation, induces differentiation and apoptosis, and may protect against prostate cancer. Despite intriguing results from laboratory studies, previous epidemiological studies showed inconsistent associations of circulating levels of 25(OH)D, 1,25(OH)2D, and several VDR polymorphisms with prostate cancer risk. Few studies have explored the joint association of circulating vitamin D levels with VDR polymorphisms.
Methods and Findings
During 18 y of follow-up of 14,916 men initially free of diagnosed cancer, we identified 1,066 men with incident prostate cancer (including 496 with aggressive disease, defined as stage C or D, Gleason 7–10, metastatic, and fatal prostate cancer) and 1,618 cancer-free, age- and smoking-matched control participants in the Physicians' Health Study. We examined the associations of prediagnostic plasma levels of 25(OH)D and 1,25(OH)2D, individually and jointly, with total and aggressive disease, and explored whether relations between vitamin D metabolites and prostate cancer were modified by the functional VDR FokI polymorphism, using conditional logistic regression. Among these US physicians, the median plasma 25(OH)D levels were 25 ng/ml in the blood samples collected during the winter or spring and 32 ng/ml in samples collected during the summer or fall. Nearly 13% (summer/fall) to 36% (winter/spring) of the control participants were deficient in 25(OH)D (<20 ng/ml) and 51% (summer/fall) and 77% (winter/spring) had insufficient plasma 25(OH)D levels (<32 ng/ml). Plasma levels of 1,25(OH)2D did not vary by season. 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, 95% confidence interval [CI] 1.2–3.4), although the interaction between the two vitamin D metabolites was not statistically significant (pinteraction = 0.23). We observed a significant interaction between circulating 25(OH)D levels and the VDR FokI genotype (pinteraction < 0.05). Compared with those with plasma 25(OH)D levels above the median and with the FokI FF or Ff genotype, men who had low 25(OH)D levels and the less functional FokI ff genotype had increased risks of total (OR = 1.9, 95% CI 1.1–3.3) and aggressive prostate cancer (OR = 2.5, 95% CI 1.1–5.8). Among men with plasma 25(OH)D levels above the median, the ff genotype was no longer associated with risk. Conversely, among men with the ff genotype, high plasma 25(OH)D level (above versus below the median) was related to significant 60%∼70% lower risks of total and aggressive prostate cancer.
Conclusions
Our data suggest that a large proportion of the US men had suboptimal vitamin D status (especially during the winter/spring season), and both 25(OH)D and 1,25(OH)2D may play an important role in preventing prostate cancer progression. Moreover, vitamin D status, measured by 25(OH)D in plasma, interacts with the VDR FokI polymorphism and modifies prostate cancer risk. Men with the less functional FokI ff genotype (14% in the European-descent population of this cohort) are more susceptible to this cancer in the presence of low 25(OH)D status.
Results of this study by Haojie Li and colleagues suggest that vitamin D deficiency is common among men in the US, and that vitamin D status and genetic variation in theVDR gene affect prostate cancer risk.
Editors' Summary
Background.
Prostate cancer occurs when cells in the prostate gland (part of the male reproductive system) accumulate genetic changes that allow them to grow into a disorganized mass of cells. Patients whose disease is diagnosed when these cells are still relatively normal can survive for many years, but for patients with aggressive cancers—ones containing fast-growing cells that can migrate around the body—the outlook is poor. Factors that increase prostate cancer risk include increasing age, having a family history of prostate cancer, and being African American. Also, there are hints that some environmental or dietary factors affect prostate cancer risk. One of these factors is vitamin D, of which high levels are found in seafood and dairy products, but which can also be made naturally by the body—more specifically, by sunlight-exposed skin. One reason researchers think vitamin D might protect against prostate cancer is that this cancer is more common in sun-starved northern countries (where people often have a vitamin D deficiency) than in sunny regions. Prostate cancer is also more common in African American men than in those of European descent (when exposed to the same amount of sunlight, individuals with darker skin make less vitamin D than those with lighter skin). Once in the human body, vitamin D is converted into the vitamin D metabolite 25-hydroxyvitamin D3 (25[OH]D) and then into the active hormone 1,25 dihydroxyvitamin D3 (1,25[OH]2D). This binds to vitamin D receptors (VDRs) and inhibits cell proliferation and migration.
Why Was This Study Done?
The effect of 1,25(OH)2D on cells and the observation that related chemicals slow prostate cancer growth in rodents suggest that vitamin D protects against prostate cancer. But circulating levels of vitamin D metabolites in human male populations do not always reflect how many men develop prostate cancer. This lack of correlation may partly be because different forms of the VDR gene exist. One area of variation in the VDR gene is called the FokI polymorphism. Because everyone carries two copies of the VDR gene, individuals may have a FokI FF, FokI Ff, or FokI ff genotype. The f variant (or allele) codes for a receptor that is less responsive to 1,25(OH)2D than the receptor encoded by the FokI F allele. So levels of vitamin D sufficient to prevent cancer in one person may be insufficient in someone with a different FokI genotype. In this study, the researchers have investigated how levels of 25(OH)D and 1,25(OH)2D in combination with different VDR FokI alleles are influencing prostate cancer risk.
What Did the Researchers Do and Find?
The researchers identified 1,066 men who developed prostate cancer between enrollment into the US Physicians' Health Study in 1982 and 2000, and 1,618 cancer-free men of the same ages and smoking levels as “controls.” They measured vitamin D metabolite levels in many of the blood samples taken from these men in 1982 and determined their FokI genotype. Two-thirds of the men had insufficient blood levels of vitamin D metabolites in the winter/spring; almost one-third had a vitamin D deficiency. Men whose blood levels of both metabolites were below average were twice as likely to develop aggressive prostate cancer as those in whom both levels were above average. Compared with men with high blood levels of 25(OH)D and the FokI FF or Ff genotype, men with low 25(OH)D levels and the FokI ff genotype were 2.5 times as likely to develop aggressive prostate cancer. However, men with the ff genotype were not at higher risk if they had sufficient 25(OH)D levels. Among men with the ff genotype, sufficient 25(OH)D levels might therefore protect against prostate cancer, especially against the clinically aggressive form.
What Do These Findings Mean?
These findings confirm that many US men have suboptimal levels of circulating vitamin D. This vitamin is essential for healthy bones, so irrespective of its effects on prostate cancer, vitamin D supplements might improve overall health. In addition, this large and lengthy study reveals an association between low levels of the two vitamin D metabolites and aggressive prostate cancer that is consistent with vitamin D helping to prevent the progression of prostate cancer. It also indicates that the VDR FokI genotype modifies the prostate cancer risk associated with different blood levels of vitamin D. Together, these results suggest that improving vitamin D status through increased exposure to sun and vitamin D supplements might reduce prostate cancer risk, particularly in men with the FokI ff genotype. Because the study participants were mainly of European descent, the researchers caution that these results may not apply to other ethnic groups and note that further detailed studies are needed to understand fully how vitamin D affects prostate cancer risk across the population.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040103.
MedlinePlus encyclopedia has pages on prostate cancer and on vitamin D
Information for patients and physicians is available from the US National Cancer Institute on prostate cancer and on cancer prevention
The Prostate Cancer Foundation's information on prostate cancer discusses the effects of nutrition on the disease
Patient information on prostate cancer is available from Cancer Research UK
Cancerbackup also has patient information on prostate cancer
doi:10.1371/journal.pmed.0040103
PMCID: PMC1831738  PMID: 17388667
2.  Clinical Utility of Vitamin D Testing 
Executive Summary
This report from the Medical Advisory Secretariat (MAS) was intended to evaluate the clinical utility of vitamin D testing in average risk Canadians and in those with kidney disease. As a separate analysis, this report also includes a systematic literature review of the prevalence of vitamin D deficiency in these two subgroups.
This evaluation did not set out to determine the serum vitamin D thresholds that might apply to non-bone health outcomes. For bone health outcomes, no high or moderate quality evidence could be found to support a target serum level above 50 nmol/L. Similarly, no high or moderate quality evidence could be found to support vitamin D’s effects in non-bone health outcomes, other than falls.
Vitamin D
Vitamin D is a lipid soluble vitamin that acts as a hormone. It stimulates intestinal calcium absorption and is important in maintaining adequate phosphate levels for bone mineralization, bone growth, and remodelling. It’s also believed to be involved in the regulation of cell growth proliferation and apoptosis (programmed cell death), as well as modulation of the immune system and other functions. Alone or in combination with calcium, Vitamin D has also been shown to reduce the risk of fractures in elderly men (≥ 65 years), postmenopausal women, and the risk of falls in community-dwelling seniors. However, in a comprehensive systematic review, inconsistent results were found concerning the effects of vitamin D in conditions such as cancer, all-cause mortality, and cardiovascular disease. In fact, no high or moderate quality evidence could be found concerning the effects of vitamin D in such non-bone health outcomes. Given the uncertainties surrounding the effects of vitamin D in non-bone health related outcomes, it was decided that this evaluation should focus on falls and the effects of vitamin D in bone health and exclusively within average-risk individuals and patients with kidney disease.
Synthesis of vitamin D occurs naturally in the skin through exposure to ultraviolet B (UVB) radiation from sunlight, but it can also be obtained from dietary sources including fortified foods, and supplements. Foods rich in vitamin D include fatty fish, egg yolks, fish liver oil, and some types of mushrooms. Since it is usually difficult to obtain sufficient vitamin D from non-fortified foods, either due to low content or infrequent use, most vitamin D is obtained from fortified foods, exposure to sunlight, and supplements.
Clinical Need: Condition and Target Population
Vitamin D deficiency may lead to rickets in infants and osteomalacia in adults. Factors believed to be associated with vitamin D deficiency include:
darker skin pigmentation,
winter season,
living at higher latitudes,
skin coverage,
kidney disease,
malabsorption syndromes such as Crohn’s disease, cystic fibrosis, and
genetic factors.
Patients with chronic kidney disease (CKD) are at a higher risk of vitamin D deficiency due to either renal losses or decreased synthesis of 1,25-dihydroxyvitamin D.
Health Canada currently recommends that, until the daily recommended intakes (DRI) for vitamin D are updated, Canada’s Food Guide (Eating Well with Canada’s Food Guide) should be followed with respect to vitamin D intake. Issued in 2007, the Guide recommends that Canadians consume two cups (500 ml) of fortified milk or fortified soy beverages daily in order to obtain a daily intake of 200 IU. In addition, men and women over the age of 50 should take 400 IU of vitamin D supplements daily. Additional recommendations were made for breastfed infants.
A Canadian survey evaluated the median vitamin D intake derived from diet alone (excluding supplements) among 35,000 Canadians, 10,900 of which were from Ontario. Among Ontarian males ages 9 and up, the median daily dietary vitamin D intake ranged between 196 IU and 272 IU per day. Among females, it varied from 152 IU to 196 IU per day. In boys and girls ages 1 to 3, the median daily dietary vitamin D intake was 248 IU, while among those 4 to 8 years it was 224 IU.
Vitamin D Testing
Two laboratory tests for vitamin D are available, 25-hydroxy vitamin D, referred to as 25(OH)D, and 1,25-dihydroxyvitamin D. Vitamin D status is assessed by measuring the serum 25(OH)D levels, which can be assayed using radioimmunoassays, competitive protein-binding assays (CPBA), high pressure liquid chromatography (HPLC), and liquid chromatography-tandem mass spectrometry (LC-MS/MS). These may yield different results with inter-assay variation reaching up to 25% (at lower serum levels) and intra-assay variation reaching 10%.
The optimal serum concentration of vitamin D has not been established and it may change across different stages of life. Similarly, there is currently no consensus on target serum vitamin D levels. There does, however, appear to be a consensus on the definition of vitamin D deficiency at 25(OH)D < 25 nmol/l, which is based on the risk of diseases such as rickets and osteomalacia. Higher target serum levels have also been proposed based on subclinical endpoints such as parathyroid hormone (PTH). Therefore, in this report, two conservative target serum levels have been adopted, 25 nmol/L (based on the risk of rickets and osteomalacia), and 40 to 50 nmol/L (based on vitamin D’s interaction with PTH).
Ontario Context
Volume & Cost
The volume of vitamin D tests done in Ontario has been increasing over the past 5 years with a steep increase of 169,000 tests in 2007 to more than 393,400 tests in 2008. The number of tests continues to rise with the projected number of tests for 2009 exceeding 731,000. According to the Ontario Schedule of Benefits, the billing cost of each test is $51.7 for 25(OH)D (L606, 100 LMS units, $0.517/unit) and $77.6 for 1,25-dihydroxyvitamin D (L605, 150 LMS units, $0.517/unit). Province wide, the total annual cost of vitamin D testing has increased from approximately $1.7M in 2004 to over $21.0M in 2008. The projected annual cost for 2009 is approximately $38.8M.
Evidence-Based Analysis
The objective of this report is to evaluate the clinical utility of vitamin D testing in the average risk population and in those with kidney disease. As a separate analysis, the report also sought to evaluate the prevalence of vitamin D deficiency in Canada. The specific research questions addressed were thus:
What is the clinical utility of vitamin D testing in the average risk population and in subjects with kidney disease?
What is the prevalence of vitamin D deficiency in the average risk population in Canada?
What is the prevalence of vitamin D deficiency in patients with kidney disease in Canada?
Clinical utility was defined as the ability to improve bone health outcomes with the focus on the average risk population (excluding those with osteoporosis) and patients with kidney disease.
Literature Search
A literature search was performed on July 17th, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 1998 until July 17th, 2009. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with unknown eligibility were reviewed with a second clinical epidemiologist, then a group of epidemiologists until consensus was established. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
Observational studies that evaluated the prevalence of vitamin D deficiency in Canada in the population of interest were included based on the inclusion and exclusion criteria listed below. The baseline values were used in this report in the case of interventional studies that evaluated the effect of vitamin D intake on serum levels. Studies published in grey literature were included if no studies published in the peer-reviewed literature were identified for specific outcomes or subgroups.
Considering that vitamin D status may be affected by factors such as latitude, sun exposure, food fortification, among others, the search focused on prevalence studies published in Canada. In cases where no Canadian prevalence studies were identified, the decision was made to include studies from the United States, given the similar policies in vitamin D food fortification and recommended daily intake.
Inclusion Criteria
Studies published in English
Publications that reported the prevalence of vitamin D deficiency in Canada
Studies that included subjects from the general population or with kidney disease
Studies in children or adults
Studies published between January 1998 and July 17th 2009
Exclusion Criteria
Studies that included subjects defined according to a specific disease other than kidney disease
Letters, comments, and editorials
Studies that measured the serum vitamin D levels but did not report the percentage of subjects with serum levels below a given threshold
Outcomes of Interest
Prevalence of serum vitamin D less than 25 nmol/L
Prevalence of serum vitamin D less than 40 to 50 nmol/L
Serum 25-hydroxyvitamin D was the metabolite used to assess vitamin D status. Results from adult and children studies were reported separately. Subgroup analyses according to factors that affect serum vitamin D levels (e.g., seasonal effects, skin pigmentation, and vitamin D intake) were reported if enough information was provided in the studies
Quality of Evidence
The quality of the prevalence studies was based on the method of subject recruitment and sampling, possibility of selection bias, and generalizability to the source population. The overall quality of the trials was examined according to the GRADE Working Group criteria.
Summary of Findings
Fourteen prevalence studies examining Canadian adults and children met the eligibility criteria. With the exception of one longitudinal study, the studies had a cross-sectional design. Two studies were conducted among Canadian adults with renal disease but none studied Canadian children with renal disease (though three such US studies were included). No systematic reviews or health technology assessments that evaluated the prevalence of vitamin D deficiency in Canada were identified. Two studies were published in grey literature, consisting of a Canadian survey designed to measure serum vitamin D levels and a study in infants presented as an abstract at a conference. Also included were the results of vitamin D tests performed in community laboratories in Ontario between October 2008 and September 2009 (provided by the Ontario Association of Medical Laboratories).
Different threshold levels were used in the studies, thus we reported the percentage of subjects with serum levels of between 25 and 30 nmol/L and between 37.5 and 50 nmol/L. Some studies stratified the results according to factors affecting vitamin D status and two used multivariate models to investigate the effects of these characteristics (including age, season, BMI, vitamin D intake, skin pigmentation, and season) on serum 25(OH)D levels. It’s unclear, however, if these studies were adequately powered for these subgroup analyses.
Study participants generally consisted of healthy, community-dwelling subjects and most excluded individuals with conditions or medications that alter vitamin D or bone metabolism, such as kidney or liver disease. Although the studies were conducted in different parts of Canada, fewer were performed in Northern latitudes, i.e. above 53°N, which is equivalent to the city of Edmonton.
Adults
Serum vitamin D levels of < 25 to 30 nmol/L were observed in 0% to 25.5% of the subjects included in five studies; the weighted average was 3.8% (95% CI: 3.0, 4.6). The preliminary results of the Canadian survey showed that approximately 5% of the subjects had serum levels below 29.5 nmol/L. The results of over 600,000 vitamin D tests performed in Ontarian community laboratories between October 2008 and September 2009 showed that 2.6% of adults (> 18 years) had serum levels < 25 nmol/L.
The prevalence of serum vitamin D levels below 37.5-50 nmol/L reported among studies varied widely, ranging from 8% to 73.6% with a weighted average of 22.5%. The preliminary results of the CHMS survey showed that between 10% and 25% of subjects had serum levels below 37 to 48 nmol/L. The results of the vitamin D tests performed in community laboratories showed that 10% to 25% of the individuals had serum levels between 39 and 50 nmol/L.
In an attempt to explain this inter-study variation, the study results were stratified according to factors affecting serum vitamin D levels, as summarized below. These results should be interpreted with caution as none were adjusted for other potential confounders. Adequately powered multivariate analyses would be necessary to determine the contribution of risk factors to lower serum 25(OH)D levels.
Seasonal variation
Three adult studies evaluating serum vitamin D levels in different seasons observed a trend towards a higher prevalence of serum levels < 37.5 to 50 nmol/L during the winter and spring months, specifically 21% to 39%, compared to 8% to 14% in the summer. The weighted average was 23.6% over the winter/spring months and 9.6% over summer. The difference between the seasons was not statistically significant in one study and not reported in the other two studies.
Skin Pigmentation
Four studies observed a trend toward a higher prevalence of serum vitamin D levels < 37.5 to 50 nmol/L in subjects with darker skin pigmentation compared to those with lighter skin pigmentation, with weighted averages of 46.8% among adults with darker skin colour and 15.9% among those with fairer skin.
Vitamin D intake and serum levels
Four adult studies evaluated serum vitamin D levels according to vitamin D intake and showed an overall trend toward a lower prevalence of serum levels < 37.5 to 50 nmol/L with higher levels of vitamin D intake. One study observed a dose-response relationship between higher vitamin D intake from supplements, diet (milk), and sun exposure (results not adjusted for other variables). It was observed that subjects taking 50 to 400 IU or > 400 IU of vitamin D per day had a 6% and 3% prevalence of serum vitamin D level < 40 nmol/L, respectively, versus 29% in subjects not on vitamin D supplementation. Similarly, among subjects drinking one or two glasses of milk per day, the prevalence of serum vitamin D levels < 40 nmol/L was found to be 15%, versus 6% in those who drink more than two glasses of milk per day and 21% among those who do not drink milk. On the other hand, one study observed little variation in serum vitamin D levels during winter according to milk intake, with the proportion of subjects exhibiting vitamin D levels of < 40 nmol/L being 21% among those drinking 0-2 glasses per day, 26% among those drinking > 2 glasses, and 20% among non-milk drinkers.
The overall quality of evidence for the studies conducted among adults was deemed to be low, although it was considered moderate for the subgroups of skin pigmentation and seasonal variation.
Newborn, Children and Adolescents
Five Canadian studies evaluated serum vitamin D levels in newborns, children, and adolescents. In four of these, it was found that between 0 and 36% of children exhibited deficiency across age groups with a weighted average of 6.4%. The results of over 28,000 vitamin D tests performed in children 0 to 18 years old in Ontario laboratories (Oct. 2008 to Sept. 2009) showed that 4.4% had serum levels of < 25 nmol/L.
According to two studies, 32% of infants 24 to 30 months old and 35.3% of newborns had serum vitamin D levels of < 50 nmol/L. Two studies of children 2 to 16 years old reported that 24.5% and 34% had serum vitamin D levels below 37.5 to 40 nmol/L. In both studies, older children exhibited a higher prevalence than younger children, with weighted averages 34.4% and 10.3%, respectively. The overall weighted average of the prevalence of serum vitamin D levels < 37.5 to 50 nmol/L among pediatric studies was 25.8%. The preliminary results of the Canadian survey showed that between 10% and 25% of subjects between 6 and 11 years (N= 435) had serum levels below 50 nmol/L, while for those 12 to 19 years, 25% to 50% exhibited serum vitamin D levels below 50 nmol/L.
The effects of season, skin pigmentation, and vitamin D intake were not explored in Canadian pediatric studies. A Canadian surveillance study did, however, report 104 confirmed cases1 (2.9 cases per 100,000 children) of vitamin D-deficient rickets among Canadian children age 1 to 18 between 2002 and 2004, 57 (55%) of which from Ontario. The highest incidence occurred among children living in the North, i.e., the Yukon, Northwest Territories, and Nunavut. In 92 (89%) cases, skin pigmentation was categorized as intermediate to dark, 98 (94%) had been breastfed, and 25 (24%) were offspring of immigrants to Canada. There were no cases of rickets in children receiving ≥ 400 IU VD supplementation/day.
Overall, the quality of evidence of the studies of children was considered very low.
Kidney Disease
Adults
Two studies evaluated serum vitamin D levels in Canadian adults with kidney disease. The first included 128 patients with chronic kidney disease stages 3 to 5, 38% of which had serum vitamin D levels of < 37.5 nmol/L (measured between April and July). This is higher than what was reported in Canadian studies of the general population during the summer months (i.e. between 8% and 14%). In the second, which examined 419 subjects who had received a renal transplantation (mean time since transplantation: 7.2 ± 6.4 years), the prevalence of serum vitamin D levels < 40 nmol/L was 27.3%. The authors concluded that the prevalence observed in the study population was similar to what is expected in the general population.
Children
No studies evaluating serum vitamin D levels in Canadian pediatric patients with kidney disease could be identified, although three such US studies among children with chronic kidney disease stages 1 to 5 were. The mean age varied between 10.7 and 12.5 years in two studies but was not reported in the third. Across all three studies, the prevalence of serum vitamin D levels below the range of 37.5 to 50 nmol/L varied between 21% and 39%, which is not considerably different from what was observed in studies of healthy Canadian children (24% to 35%).
Overall, the quality of evidence in adults and children with kidney disease was considered very low.
Clinical Utility of Vitamin D Testing
A high quality comprehensive systematic review published in August 2007 evaluated the association between serum vitamin D levels and different bone health outcomes in different age groups. A total of 72 studies were included. The authors observed that there was a trend towards improvement in some bone health outcomes with higher serum vitamin D levels. Nevertheless, precise thresholds for improved bone health outcomes could not be defined across age groups. Further, no new studies on the association were identified during an updated systematic review on vitamin D published in July 2009.
With regards to non-bone health outcomes, there is no high or even moderate quality evidence that supports the effectiveness of vitamin D in outcomes such as cancer, cardiovascular outcomes, and all-cause mortality. Even if there is any residual uncertainty, there is no evidence that testing vitamin D levels encourages adherence to Health Canada’s guidelines for vitamin D intake. A normal serum vitamin D threshold required to prevent non-bone health related conditions cannot be resolved until a causal effect or correlation has been demonstrated between vitamin D levels and these conditions. This is as an ongoing research issue around which there is currently too much uncertainty to base any conclusions that would support routine vitamin D testing.
For patients with chronic kidney disease (CKD), there is again no high or moderate quality evidence supporting improved outcomes through the use of calcitriol or vitamin D analogs. In the absence of such data, the authors of the guidelines for CKD patients consider it best practice to maintain serum calcium and phosphate at normal levels, while supplementation with active vitamin D should be considered if serum PTH levels are elevated. As previously stated, the authors of guidelines for CKD patients believe that there is not enough evidence to support routine vitamin D [25(OH)D] testing. According to what is stated in the guidelines, decisions regarding the commencement or discontinuation of treatment with calcitriol or vitamin D analogs should be based on serum PTH, calcium, and phosphate levels.
Limitations associated with the evidence of vitamin D testing include ambiguities in the definition of an ‘adequate threshold level’ and both inter- and intra- assay variability. The MAS considers both the lack of a consensus on the target serum vitamin D levels and assay limitations directly affect and undermine the clinical utility of testing. The evidence supporting the clinical utility of vitamin D testing is thus considered to be of very low quality.
Daily vitamin D intake, either through diet or supplementation, should follow Health Canada’s recommendations for healthy individuals of different age groups. For those with medical conditions such as renal disease, liver disease, and malabsorption syndromes, and for those taking medications that may affect vitamin D absorption/metabolism, physician guidance should be followed with respect to both vitamin D testing and supplementation.
Conclusions
Studies indicate that vitamin D, alone or in combination with calcium, may decrease the risk of fractures and falls among older adults.
There is no high or moderate quality evidence to support the effectiveness of vitamin D in other outcomes such as cancer, cardiovascular outcomes, and all-cause mortality.
Studies suggest that the prevalence of vitamin D deficiency in Canadian adults and children is relatively low (approximately 5%), and between 10% and 25% have serum levels below 40 to 50 nmol/L (based on very low to low grade evidence).
Given the limitations associated with serum vitamin D measurement, ambiguities in the definition of a ‘target serum level’, and the availability of clear guidelines on vitamin D supplementation from Health Canada, vitamin D testing is not warranted for the average risk population.
Health Canada has issued recommendations regarding the adequate daily intake of vitamin D, but current studies suggest that the mean dietary intake is below these recommendations. Accordingly, Health Canada’s guidelines and recommendations should be promoted.
Based on a moderate level of evidence, individuals with darker skin pigmentation appear to have a higher risk of low serum vitamin D levels than those with lighter skin pigmentation and therefore may need to be specially targeted with respect to optimum vitamin D intake. The cause-effect of this association is currently unclear.
Individuals with medical conditions such as renal and liver disease, osteoporosis, and malabsorption syndromes, as well as those taking medications that may affect vitamin D absorption/metabolism, should follow their physician’s guidance concerning both vitamin D testing and supplementation.
PMCID: PMC3377517  PMID: 23074397
3.  Life course sun exposure and risk of prostate cancer: population-based nested case-control study (ProtecT) and meta-analysis 
There is currently no means of primary prevention for prostate cancer. Increased exposure to ultraviolet-radiation may be protective, but the literature is inconclusive. We investigated associations of life-course exposure to sunlight with prostate cancer. The study design was a UK-wide nested case-control study, based on 1,020 PSA-detected cases and 5,044 matched population controls and a systematic review with meta-analysis. Men with olive/brown skin (OR= 1.47; 95% CI: 1.00 to 2.17), men who burnt rarely/never (OR= 1.11; 0.95 to 1.29) and men with the lowest levels of intense sun exposure in the 2 years prior to diagnosis (OR = 1.24; 1.03 to 1.50) had an increased prostate cancer risk. However, amongst men with prostate cancer, spending less time outside was associated with a reduced risk of advanced cancer (OR = 0.49; 0.27 to 0.89) and high Gleason grade (OR = 0.62; 0.43 to 0.91), and men who burnt rarely/never had a reduced risk of advanced cancer (OR = 0.71; 0.47 to 1.08). The meta-analysis provided weak evidence that men with the lowest (versus highest) sunlight exposure had an increased prostate cancer risk (4 studies, random-effects pooled relative risk = 1.13; 0.98 to 1.29) and higher advanced or fatal prostate cancer risk (6 studies, random-effects pooled relative risk = 1.14; 0.98 to 1.33). Our data and meta-analyses provide limited support for the hypothesis that increased exposure to sunlight may reduce prostate cancer risk. The findings warrant further investigation because of their implications for vitamin D chemoprevention trials.
doi:10.1002/ijc.24411
PMCID: PMC2873563  PMID: 19444909
Prostate cancer; sun exposure; pigmentation
4.  Systems biology-based analysis implicates a novel role for vitamin D metabolism in the pathogenesis of age-related macular degeneration 
Human Genomics  2011;5(6):538-568.
Vitamin D has been shown to have anti-angiogenic properties and to play a protective role in several types of cancer, including breast, prostate and cutaneous melanoma. Similarly, vitamin D levels have been shown to be protective for risk of a number of conditions, including cardiovascular disease and chronic kidney disease, as well as numerous autoimmune disorders such as multiple sclerosis, inflammatory bowel diseases and type 1 diabetes mellitus. A study performed by Parekh et al. was the first to suggest a role for vitamin D in age-related macular degeneration (AMD) and showed a correlation between reduced serum vitamin D levels and risk for early AMD. Based on this study and the protective role of vitamin D in diseases with similar pathophysiology to AMD, we examined the role of vitamin D in a family-based cohort of 481 sibling pairs. Using extremely phenotypically discordant sibling pairs, initially we evaluated the association of neovascular AMD and vitamin D/sunlight-related epidemiological factors. After controlling for established AMD risk factors, including polymorphisms of the genes encoding complement factor H (CFH) and age-related maculopathy susceptibility 2/HtrA serine peptidase (ARMS2/HTRA1), and smoking history, we found that ultraviolet irradiance was protective for the development of neovascular AMD (p = 0.001). Although evaluation of serum vitamin D levels (25-hydroxyvitamin D [25(OH)D]) was higher in unaffected individuals than in their affected siblings, this finding did not reach statistical significance.
Based on the relationship between ultraviolet irradiance and vitamin D production, we employed a candidate gene approach for evaluating common variation in key vitamin D pathway genes (the genes encoding the vitamin D receptor [VDR]; cytochrome P450, family 27, subfamily B, polypeptide 1 [CYP27B1]; cytochrome P450, family 24, subfamily A, polypeptide 1 [CYP24A1]; and CYP27A1) in this same family-based cohort. Initial findings were then validated and replicated in the extended family cohort, an unrelated case-control cohort from central Greece and a prospective nested case-control population from the Nurse's Health Study and Health Professionals Follow-Up Studies, which included patients with all subtypes of AMD for a total of 2,528 individuals. Single point variants in CYP24A1 (the gene encoding the catabolising enzyme of the vitamin D pathway) were demonstrated to influence AMD risk after controlling for smoking history, sex and age in all populations, both separately and, more importantly, in a meta-analysis. This is the first report demonstrating a genetic association between vitamin D metabolism and AMD risk. These findings were also supplemented with expression data from human donor eyes and human retinal cell lines. These data not only extend previous biological studies in the AMD field, but further emphasise common antecedents between several disorders with an inflammatory/immunogenic component such as cardiovascular disease, cancer and AMD.
doi:10.1186/1479-7364-5-6-538
PMCID: PMC3525248  PMID: 22155603
vitamin D; age-related macular degeneration
5.  Vitamin D, arterial hypertension & cerebrovascular disease 
Vitamin D is mainly derived from endogenous ultraviolet-B induced vitamin D synthesis in the skin, and the current high prevalence of vitamin D deficiency can, therefore, largely be attributed to lifestyle related low sunlight exposure. Regulation of bone and mineral metabolism is a classic vitamin D effect, but the identification of the vitamin D receptor (VDR) in almost all human cells suggests a role for vitamin D also in extra-skeletal diseases. Experimental studies demonstrated several antihypertensive and vascular protective effects of vitamin D, such as suppression of the renin angiotensin aldosterone system, beneficial modulation of classic cardiovascular risk factors, and anti-atherosclerotic properties including improvements of endothelial function. Additional neuroprotective actions of vitamin D have also been reported. In line with this, epidemiological studies have largely shown that vitamin D deficiency is an independent risk factor for arterial hypertension and strokes. Data from randomized controlled trials (RCTs) are, however, limited and less promising, with currently no confirmation that vitamin D reduces stroke incidence. Whereas some RCTs suggest that vitamin D supplementation might modestly reduce blood pressure, this has not been consistently observed in all studies. It is, therefore, premature to recommend vitamin D supplementation for the prevention and treatment of arterial hypertension and stroke. Nevertheless, the fact that patients with arterial hypertension and cerebrovascular disease are at a relatively high risk of vitamin D deficiency, and therewith associated musculoskeletal diseases can serve as a rationale for the evaluation, prevention and treatment of vitamin D deficiency in these patients.
PMCID: PMC3724247  PMID: 23703334
Arterial hypertension; blood pressure; cerebrovascular; epidemiology; stroke; vitamin D
6.  Fundamental questions to sun protection 
Dermato-endocrinology  2010;2(1):19-25.
Since exposure to sunlight is a main factor in the development of non-melanoma skin cancer and there are associations between malignant melanoma and short-term intense ultraviolet (UV) exposure, particularly burning in childhood, strict protection from UV-radiation is recommended. However, up to 90% of all requisite vitamin D has to be formed within the skin through the action of the sun—a serious problem, for a connection between vitamin D deficiency, demonstrated in epidemiological studies, and various types of cancer and other diseases has been confirmed. A UVB-triggered skin autonomous vitamin D3 synthesis pathway has recently been described, producing the active Vitamin D metabolite calcitriol. This cutaneous vitamin D3 pathway is unique. Keratinocytes and dendritic cells can convert vitamin D to calcitriol. Cutaneous T cells activated in the presence of calcitriol express the chemokine receptor CCR10 attracting them to the chemokine CCL27 that keratinocytes express selectively in the epidermis, and migrate from dermal layers of the skin to the epidermis under UV radiation. Thus, calcitriol has endocrine roles beyond its calciotropic action, including cell growth and cancer prevention. Therefore, strict sun protection procedures to prevent skin cancer may induce the risk of vitamin D deficiency. As there is evidence that the protective effect of less intense solar radiation can outweigh its mutagenic effect, better balanced approaches to sun protection should be sought.
doi:10.4161/derm.2.1.12016
PMCID: PMC3084961  PMID: 21547144
vitamin D; vitamin D synthesis (skin); immune system (skin); sun protection; ultraviolet radiation; photo therapy; cancer
7.  Cellular and Molecular effects of Vitamin D on Carcinogenesis 
Epidemiologic data suggest that the incidence and severity of many types of cancer inversely correlates with indices of vitamin D status. The vitamin D receptor (VDR) is highly expressed in epithelial cells at risk for carcinogenesis including those resident in skin, breast, prostate and colon, providing a direct molecular link by which vitamin D status impacts on carcinogenesis. Consistent with this concept, activation of VDR by its ligand 1,25-dihydroxyvitamin D (1,25D) triggers comprehensive genomic changes in epithelial cells that contribute to maintenance of the differentiated phenotype, resistance to cellular stresses and protection of the genome. Many epithelial cells also express the vitamin D metabolizing enzyme CYP27B1 which enables autocrine generation of 1,25D from the circulating vitamin D metabolite 25-hydroxyvitamin D (25D), critically linking overall vitamin D status with cellular anti-tumor actions. Furthermore, pre-clinical studies in animal models has demonstrated that dietary supplementation with vitamin D or chronic treatment with VDR agonists decreases tumor development in skin, colon, prostate and breast. Conversely, deletion of the VDR gene in mice alters the balance between proliferation and apoptosis, increases oxidative DNA damage, and enhances susceptibility to carcinogenesis in these tissues. Because VDR expression is retained in many human tumors, vitamin D status may be an important modulator of cancer progression in persons living with cancer. Collectively, these observations have reinforced the need to further define the molecular actions of the VDR and the human requirement for vitamin D in relation to cancer development and progression.
doi:10.1016/j.abb.2011.10.019
PMCID: PMC3295909  PMID: 22085499
vitamin D receptor; cancer; vitamin D; prevention; diet
8.  Why vitamin D for cancer patients? 
ecancermedicalscience  2009;3:160.
Several epidemiological, pre-clinical and clinical studies support Vitamin D as a preventive and therapeutic cancer agent.
Background
Vitamin D and cancer: calcitriol, the biologically active form of vitamin D (1,25(OH)D), exerts its effects mainly through binding to nuclear vitamin D receptor (VDR). Calcitriol has been shown to be an anti-proliferative, pro-differentiation, pro-apoptotic agent and an inhibitor of cell migration. Animal and human in vitro studies strongly indicate that vitamin D may have benefits for many forms of cancer. Inadequate levels of circulating 25-hydroxy-vitamin D (25(OH)D) are associated with an increased risk and poor prognosis of several types of cancer.
Vitamin D and melanoma: cutaneous malignant melanoma (CMM) represents a major public health issue: rates in Italy have almost doubled in the last decade and CMM is frequent among young adults. For resected stage II melanoma no standard adjuvant treatment exists and five-year overall survival is about 70%.
Cultured melanoma cells can synthesize calcitriol from 25(OH)D and express the VDR. Moreover, 1,25(OH)D has anti-proliferative and pro-differentiation effects in human melanoma cells. 1,25(OH)D has been shown to induce apoptosis in human melanoma cell lines and has an inhibitory effect on the spreading of melanoma cells in vitro.
Preliminary results on vitamin D: epidemiological data indicate that vitamin D deficiency is relatively common in Europe. In an Italian study, we found that 85% of the participants had insufficient levels of 25(OH)D. We have shown through a meta-analysis of randomized trials that vitamin D supplementation is associated with a significant reduction (7%) in total mortality in healthy subjects and an association between VDR and 25(OH)D and CMM progression has also been demonstrated. We have also reported significant associations between VDR polymorphisms and incidence of skin cancer. In early supplementation trials, the lack of effect on cancer incidence has been attributed to insufficient vitamin D supplementation, stressing the need to better study vitamin D bioavailability.
In fact, a recent IARC report highlighted the need for new randomized trials, based on results from our meta-analyses on 25(OH)D serum levels and cancer risk.
Clinical trial and biomarkers studies: in order to assess whether vitamin D supplementation could improve prognosis of CMM, an Italian multi-centre trial in stage II resected melanoma patients was planned to monitor changes in 25(OH)D. The study will address two important questions regarding the relationship between the biology of VDR and (1) vitamin D metabolism, and (2) CMM prognosis. This will involve investigating the association between VDR polymorphisms and Breslow thickness, the most important prognostic factor of CMM, and between 25(OH)D serum level, vitamin D supplementation and VDR.
We will also evaluate at baseline whether VDR polymorphisms are associated with Breslow thickness and whether we obtain significant increase in 25(OH)D serum levels during the first year of supplementation. We will quantify the percentages of patients who have desirable levels of 25(OH)D and, if they don’t, the mean time to reach that level. The findings from this study will be of great interest because vitamin D could have anti-cancer benefits for a wide spectrum of cancers.
doi:10.3332/ecancer.2009.160
PMCID: PMC3224009  PMID: 22276021
9.  Pigmentation-related phenotypes and risk of prostate cancer 
British Journal of Cancer  2013;109(3):747-750.
Background:
Solar ultraviolet radiation exposure has been inversely related to prostate cancer incidence and mortality, possibly mediated through vitamin D status. Pigmentation-related traits influence endogenous vitamin D synthesis and may alter risk of prostate cancer.
Methods:
We examined prostate cancer in relation to hair and eye colour, and skin phototype in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort. Incident cancer was diagnosed in 1982 out of 20 863 men. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from Cox proportional hazards models.
Results:
Prostate cancer risk did not differ by eye colour or skin phototype. Men with naturally red hair were significantly less likely to develop prostate cancer (HR=0.46, 95% CI 0.24–0.89) than men with light brown hair (reference).
Conclusion:
The red hair phenotype, which results from polymorphisms in the melanocortin-1-receptor (MC1R) gene, is associated with lower risk of prostate cancer. This pigmentation-related trait may influence prostate cancer development either directly, through genetic effects or regulatory mechanisms related to MC1R, another nearby gene, or other pigmentation genes, or indirectly, through associations with other exposures such as sunlight or vitamin D status.
doi:10.1038/bjc.2013.385
PMCID: PMC3738118  PMID: 23860522
prostate cancer; MC1R; vitamin D; hair colour; red hair; pigmentation traits
10.  Seasonal variation in expression of markers in the vitamin D pathway in prostate tissue 
Cancer causes & control : CCC  2012;23(8):1359-1366.
Purpose
Recent studies suggest variation in genes along the vitamin D pathway, as well as vitamin D receptor (VDR) protein levels, may be associated with prostate cancer. As serum vitamin D levels vary by season, we sought to determine whether expression of genes on the vitamin D pathway, assessed in prostate tumor tissue, do the same.
Methods
Our study incorporates mRNA expression data from 362 men in the Swedish Watchful Waiting cohort, diagnosed between 1977 and 1999, and 106 men enrolled in the US Physicians’ Health Study (PHS) diagnosed between 1983 and 2004. We also assayed for VDR protein expression among 832 men in the PHS and Health Professionals Follow-up Study cohorts. Season was characterized by date of initial tissue specimen collection categorically and by average monthly ultraviolet radiation levels. One-way analysis of variance was used to examine variation in expression levels of six genes on the vitamin D pathway – VDR, GC, CYP27A1, CYP27B1, RXRα, CYP24A1 – and VDR protein by season, adjusted for age at diagnosis and Gleason grade. Variation was also examined separately among lethal and nonlethal cases.
Results
Tumor expression levels of the six genes did not significantly vary by season of tissue collection. No consistent patterns emerged from subgroup analyses by lethal versus nonlethal cases.
Conclusions
Unlike circulating levels of 25-OH vitamin D, expression levels of genes on the vitamin D pathway and VDR protein did not vary overall by season of tissue collection. Epidemiological analyses of vitamin D gene expression may not be biased by seasonality.
doi:10.1007/s10552-012-0016-9
PMCID: PMC3589913  PMID: 22710747
Vitamin D; Vitamin D receptor; prostate cancer; gene expression; seasonality; biomarkers
11.  Vitamins E and C in the Prevention of Prostate and Total Cancer in Men: The Physicians’ Health Study II, a Randomized Controlled Trial 
Context
Many Americans take vitamins in the hopes of preventing chronic diseases such as cancer, and vitamins E and C are among the most common individual supplements. A large-scale randomized trial suggested that vitamin E may reduce risk of prostate cancer; however, few trials have been powered to address this relationship. No previous trial in men at usual risk has examined vitamin C alone in the prevention of cancer.
Objective
To evaluate whether long-term vitamin E or C supplementation decreases risk of prostate and total cancer events among men.
Design, Setting, and Participants
The Physicians’ Health Study II is a randomized, double-blind, placebo-controlled factorial trial of vitamins E and C that began in 1997 and continued until its scheduled completion on August 31, 2007. A total of 14,641 male physicians in the U.S. initially aged ≥50 years, including 1,307 men with a history of prior cancer at randomization, were enrolled.
Intervention
Individual supplements of 400 IU of vitamin E every other day and 500 mg vitamin C daily.
Main Outcome Measures
Prostate and total cancer.
Results
During a mean follow-up of 8.0 years, there were 1,008 confirmed incident cases of prostate cancer and 1,943 total cancers. Compared with placebo, vitamin E had no effect on the incidence of prostate cancer (active and placebo vitamin E groups, 9.1 and 9.5 events per 1,000 person-years; hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.85–1.09; P=0.58) or total cancer (active and placebo vitamin E groups, 17.8 and 17.3 cases per 1,000 person-years; HR, 1.04; 95% CI, 0.95–1.13; P=0.41). There was also no significant effect of vitamin C on total cancer (active and placebo vitamin C groups, 17.6 and 17.5 events per 1,000 person-years; HR, 1.01; 95% CI, 0.92–1.10; P=0.86), or prostate cancer (active and placebo vitamin C groups, 9.4 and 9.2 cases per 1,000 person-years; HR, 1.02; 95% CI, 0.90–1.15; P=0.80). Neither vitamin E nor vitamin C had a significant effect on colorectal, lung, or other site-specific cancers. Adjustment for compliance and exclusion of the first four or six years of follow-up did not alter the results. Stratification by various cancer risk factors demonstrated no significant modification of the effect of vitamin E on prostate cancer risk or either agent on total cancer risk.
Conclusions
In this large long-term trial of male physicians, neither vitamin E nor C supplementation reduced the risk of prostate or total cancer. These data provide no support for the use of these supplements for the prevention of cancer in middle-aged and older men.
Trial Registration
http://www.clinicaltrials.gov identifier: NCT00270647
doi:10.1001/jama.2008.862
PMCID: PMC2774210  PMID: 19066368
vitamin E; vitamin C; prostate cancer; total cancer; randomized clinical trial; men
12.  Vitamin D Metabolism and Action in the Prostate: Implications for Health and Disease 
Prostate cancer (PCa) is the second most common cancer in men worldwide. Epidemiological, molecular, and cellular studies have implicated vitamin D deficiency as a risk factor for the development and/or progression of PCa. Studies using cell culture systems and animal models suggest that vitamin D acts to reduce the growth of PCa through regulation of cellular proliferation and differentiation. However, although pre-clinical studies provide a strong indication for anti-cancer activity, proof of therapeutic benefits in men is still lacking. The anti-proliferative and pro-differentiating properties of vitamin D have been attributed to calcitriol [1,25(OH)2D3], the hormonally active form of vitamin D, acting through the vitamin D receptor (VDR). Metabolism of vitamin D in target tissues is mediated by two key enzymes: 1α-hydroxylase (CYP27B1), which catalyzes the synthesis of calcitriol from 25(OH)D and 24-hydroxylase (CYP24), which catalyzes the initial step in the conversion of calcitriol to less active metabolites. Many factors affect the balance of calcitriol synthesis and catabolism and several maneuvers, like combination therapy of calcitriol with other drugs, have been explored to treat PCa and reduce its risk. The current paper is an overview addressing some of the key factors that influence the biological actions of vitamin D and its metabolites in the treatment and/or prevention of PCa.
doi:10.1016/j.mce.2011.05.010
PMCID: PMC3189327  PMID: 21664249
Prostate cancer; vitamin D; calcitriol; vitamin D receptor (VDR); 1α-hydroxylase; 24-hydroxylase; combination therapy
13.  The Yin and Yang of vitamin D receptor (VDR) signaling in neoplastic progression: Operational networks and tissue-specific growth control 
Biochemical Pharmacology  2010;79(1):1-9.
Graphical abstract
Substantive evidence implicates vitamin D receptor (VDR) or its natural ligand 1α,25-(OH)2 D3 in modulation of tumor growth. However, both human and animal studies indicate tissue-specificity of effect. Epidemiological studies show both inverse and direct relationships between serum 25(OH)D levels and common solid cancers. VDR ablation affects carcinogen-induced tumorigenesis in a tissue-specific manner in model systems. Better understanding of the tissue-specificity of vitamin D-dependent molecular networks may provide insight into selective growth control by the seco-steroid, 1α,25-(OH)2 D3. This commentary considers complex factors that may influence the cell- or tissue-specificity of 1α,25-(OH)2 D3/VDR growth effects, including local synthesis, metabolism and transport of vitamin D and its metabolites, vitamin D receptor (VDR) expression and ligand-interactions, 1α,25-(OH)2 D3 genomic and non-genomic actions, Ca2+ flux, kinase activation, VDR interactions with activating and inhibitory vitamin D responsive elements (VDREs) within target gene promoters, VDR coregulator recruitment and differential effects on key downstream growth regulatory genes. We highlight some differences of VDR growth control relevant to colonic, esophageal, prostate, pancreatic and other cancers and assess the potential for development of selective prevention or treatment strategies.
doi:10.1016/j.bcp.2009.09.005
PMCID: PMC2824849  PMID: 19737544
1α,25-(OH)2 D3, one alpha, 25 dihydroxyvitamin D3; APC, adenomatous polyposis coli; CRC, colorectal cancer; DMBA, dimethylbenzanthracene; DR3-type, directly repeated arrangement of the hexameric binding sites with three spacing nucleotides; DRIP, Vitamin D receptor-interacting protein; ERK, extracellular signal-regulated kinase; GSK3β, glycogen synthase kinase beta; HDAC, histone deacetylator co-repressor complex; MAPK, mitogen-activated protein kinase; NCoR, nuclear receptor co-repressor; NHL, non-Hodgkins lymphoma; OPN, osteopontin; RAC3, receptor activated coactivators 3; ROCK, Rho-associated coiled kinase; RXR, retinoid X receptor; SRC-1, steroid receptor coactivators-1; Tcf, T cell factor; TIF2, transcriptional intermediary factor 2; TPA, 12-O-tetradecanoylphorbol-13-acetate; VDRE, vitamin D response element; VDR, vitamin D receptor; WINAC, Williams syndrome transcription factor (WSTF) including nucleosome assembly complex; 1α,25-(OH)2 D3; Vitamin D receptor; Signaling; Cancer
14.  Molecular Link between Vitamin D and Cancer Prevention 
Nutrients  2013;5(10):3993-4021.
The metabolite of vitamin D, 1α,25-dihydroxyvitamin D3 (also known as calcitriol), is a biologically active molecule required to maintain the physiological functions of several target tissues in the human body from conception to adulthood. Its molecular mode of action ranges from immediate nongenomic responses to longer term mechanisms that exert persistent genomic effects. The genomic mechanisms of vitamin D action rely on cross talk between 1α,25-dihydroxyvitamin D3 signaling pathways and that of other growth factors or hormones that collectively regulate cell proliferation, differentiation and cell survival. In vitro and in vivo studies demonstrate a role for vitamin D (calcitriol) in modulating cellular growth and development. Vitamin D (calcitriol) acts as an antiproliferative agent in many tissues and significantly slows malignant cellular growth. Moreover, epidemiological studies have suggested that ultraviolet-B exposure can help reduce cancer risk and prevalence, indicating a potential role for vitamin D as a feasible agent to prevent cancer incidence and recurrence. With the preventive potential of this biologically active agent, we suggest that countries where cancer is on the rise—yet where sunlight and, hence, vitamin D may be easily acquired—adopt awareness, education and implementation strategies to increase supplementation with vitamin D in all age groups as a preventive measure to reduce cancer risk and prevalence.
doi:10.3390/nu5103993
PMCID: PMC3820056  PMID: 24084056
vitamin D; cancer; mechanisms; ecological studies; observational studies; prevention; animal models
15.  Vitamin D in cutaneous carcinogenesis: Part I 
Skin cancer is the most common cancer in the United States. Exposure to ultraviolet radiation is a known risk factor for skin cancer but is also the principal means by which the body obtains vitamin D. Several studies have suggested that vitamin D plays a protective role in a variety of internal malignancies. With regard to skin cancer, epidemiologic and laboratory studies suggest that vitamin D and its metabolites may have a similar protective effect. These noncalcemic actions of vitamin D have called into question whether the current recommended intake of vitamin D is too low for optimal health and cancer prevention. Part I will review the role of vitamin D in the epidermis; part II will review the role of vitamin D in keratinocyte-derived tumors to help frame the discussion on the possible role of vitamin D in the prevention of skin cancer.
doi:10.1016/j.jaad.2012.05.044
PMCID: PMC3688468  PMID: 23062903
25(OH)D levels; cholecalciferol; supplements; vitamin D; ultraviolet radiation
16.  Vitamin D in cutaneous carcinogenesis Part II 
The role of vitamin D in health maintenance and disease prevention in fields ranging from bone metabolism to cancer is currently under intensive investigation. A number of epidemiologic studies have suggested that vitamin D may have a protective effect on cancer risk and cancer-associated mortality. With regard to skin cancer, epidemiologic and laboratory studies suggest that vitamin D and its metabolites may have a similar risk reducing effect. Potential mechanisms of action include inhibition of the hedgehog signaling pathway and upregulation of nucleotide excision repair enzymes. The key factor complicating the association between vitamin D and skin cancer is ultraviolet B radiation. The same spectrum of ultraviolet B radiation that catalyzes the production of vitamin D in the skin also causes DNA damage that can lead to epidermal malignancies. Part II of this continuing medical education article will summarize the literature on vitamin D and skin cancer to identify evidence-based optimal serum levels of vitamin D and to recommend ways of achieving those levels while minimizing the risk of skin cancer.
doi:10.1016/j.jaad.2012.07.022
PMCID: PMC3706259  PMID: 23062904
25(OH)D levels; basal cell carcinoma; melanoma; nonmelanoma skin cancer; vitamin D; vitamin D receptor; squamous cell carcinoma; sunlight
17.  Predictors of Serum Vitamin D Levels in African American and European American Men in Chicago 
American journal of men's health  2012;6(5):420-426.
Vitamin D deficiency is epidemiologically linked to prostate, breast, and colon cancer. When compared with European American (EA) men, African American (AA) men have increased risk of prostate cancer, but few studies evaluate vitamin D status in AA men. The authors evaluate the biological and environmental predictors of vitamin D deficiency in AA and EA men in Chicago, Illinois, a low ultraviolet radiation environment. Blood samples were collected from 492 men, aged between 40 and 79 years, from urology clinics at three hospitals in Chicago, along with demographic and medical information, body mass index, and skin melanin content using a portable narrow-band reflectometer. Vitamin D intake and ultraviolet radiation exposure were assessed using validated questionnaires. The results demonstrated that Black race, cold season of blood draw, elevated body mass index, and lack of vitamin D supplementation increase the risk of vitamin D deficiency. Supplementation is a high-impact, modifiable risk factor. Race and sunlight exposure should be taken into account for recommended daily allowances for vitamin D intake.
doi:10.1177/1557988312437240
PMCID: PMC3678722  PMID: 22398989
health inequality/disparity; health care issues; health promotion and disease prevention; nutrition; preventive medicine; public health
18.  Calcium and vitamin D in post menopausal women 
Calcium and Vitamin D are widely used therapies for Osteoporosis. Vitamin D is not a vitamin in true sense since it is produced in response to the action of sunlight on skin. Vitamin D has multiple roles in the body, not all of them well-understood. Vitamin D supplementation must be considered a form of hormone replacement therapy. Therefore it raises all the questions about efficacy, dose, and side effects. The Efficacy of use of Calcium and Vitamin D in all post menopausal women in terms of the prevention of fracture is uncertain. The Annual worldwide sales of these supplements have been several billion dollars. The variation of the results from various studies of Calcium and Vitamin D supplementation in elderly women suggest that benefit of calcium plus vitamin D on bone mineral density or the risk of fracture is small and may vary from group to group and baseline Vitamin D status. Women taking supplemental vitamin D and calcium have a statistically increased incidence of renal stones, according to evidence from the Women's Health Initiative. Studies have shown association between calcium use and increased risk for cardiovascular disease. In a recent review of evidence from 6 randomized trials evaluating the use of vitamin D and calcium to prevent fractures in postmenopausal women who are not living in a nursing home or other institution, the United States Preventive Task Force (USPTF) found no evidence of a benefit from supplementation with 400 IU or less of vitamin D3 and 1000 mg or less of calcium. Also in a report from institute of Medicine Committee, there was insufficient evidence, particularly from randomized trials, that vitamin D treatment affected the risk of non skeletal outcomes like risk of cancer, cardiovascular disease, diabetes, infections, autoimmune disease, and other extra skeletal outcomes.
doi:10.4103/2230-8210.123549
PMCID: PMC4046613  PMID: 24910823
Calcium; post menopausal women; Vitamin D
19.  Vitamin E and the Risk of Prostate Cancer: Updated Results of The Selenium and Vitamin E Cancer Prevention Trial (SELECT) 
JAMA  2011;306(14):1549-1556.
Context
The initial report of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) found no reduction in risk of prostate cancer with either selenium or vitamin E supplements but a non-statistically significant increase in prostate cancer risk with vitamin E. Longer follow-up and more prostate cancer events provide further insight into the relationship of vitamin E and prostate cancer.
Objective
To determine the long-term effect of vitamin E and selenium on risk of prostate cancer in relatively healthy men.
Design, Setting and Participants
SELECT randomized 35,533 men from 427 study sites in the United States, Canada and Puerto Rico in a double-blind manner between August 22, 2001 and June 24, 2004. Eligible men were 50 years or older (African Americans) or 55 years or older (all others) with a PSA ≤4.0 ng/mL and a digital rectal examination not suspicious for prostate cancer. Included in the analysis are 34,887 men randomly assigned to one of four treatment groups: selenium (n=8752), vitamin E (n=8737), both agents (n=8702), or placebo (n=8696). Data reflect the final data collected by the study sites on their participants through July 5, 2011.
Interventions
Oral selenium (200 μg/day from L-selenomethionine) with matched vitamin E placebo, vitamin E (400 IU/d of all rac-α-tocopheryl acetate) with matched selenium placebo, both agents, or both matched placebos for a planned follow-up of a minimum of 7 and maximum of 12 years.
Main Outcome Measures
Prostate cancer incidence.
Results
This report includes 54,464 additional person-years of follow-up since the primary report. Hazard ratios (99% confidence intervals [CI]) and numbers of prostate cancers were 1.17(99% CI 1.004-1.36, p=.008, n=620) for vitamin E, 1.09 (99% CI 0.93-1.27, p=.18, n=575) for selenium, 1.05 (99%CI 0.89-1.22, p=.46, n=555) for selenium + vitamin E vs. 1.00 (n=529) for placebo.The absolute increase in risk compared with placebo for vitamin E, selenium and the combination were 1.6, 0.9 and 0.4 cases of prostate cancer per 1,000 person-years.
Conclusions
Dietary supplementation with Vitamin E significantly increases the risk of prostate cancer among healthy men.
Trial registration
clinicaltrials.gov identifier: NCT00006392
doi:10.1001/jama.2011.1437
PMCID: PMC4169010  PMID: 21990298
20.  Vitamin D Pathway Gene Variants and Prostate Cancer Prognosis 
The Prostate  2010;70(13):1448-1460.
Background
Observational studies linking vitamin D deficiency with increased prostate cancer mortality and the pleiotropic anticancer effects of vitamin D in malignant prostate cell lines have initiated trials examining potential therapeutic benefits of vitamin D metabolites. There have been some successes but efforts have been hindered by risk of inducing hypercalcemia. A limited number of studies have investigated associations between variants in vitamin D pathway genes with aggressive forms of prostate cancer. Increased understanding of relevant germline genetic variation with disease outcome could aid in development of vitamin D-based therapies.
Methods
We undertook a comprehensive analysis of 48 tagging single nucleotide polymorphisms (tagSNPs) in genes encoding for vitamin D receptor (VDR), vitamin D activating enzyme 1-α-hydroxylase (CYP27B1), and deactivating enzyme 24-hydroxylase (CYP24A1) in a cohort of 1,294 Caucasian cases with an average of 8 years of follow-up. Disease recurrence/ progression and prostate cancer-specific mortality risks were estimated using adjusted Cox proportional hazards regression.
Results
There were 139 cases with recurrence/progression events and 57 cases who died of prostate cancer. Significantly altered risks of recurrence/progression were observed in relation to genotype for two VDR tagSNPs (rs6823 and rs2071358) and two CYP24A1 tagSNPs (rs927650 and rs2762939). Three VDR tagSNPs (rs3782905, rs7299460 and rs11168314), one CYP27B1 tagSNP (rs3782130) and five CYP24A1 tagSNPs (rs3787557, rs4809960, rs2296241, rs2585428, and rs6022999) significantly altered risks of prostate cancer death.
Conclusions
Genetic variations in vitamin D pathway genes were found to alter both risk of recurrence/progression and prostate cancer-specific mortality.
doi:10.1002/pros.21180
PMCID: PMC2927712  PMID: 20687218
Vitamin D Receptor; 1-alpha-Hydroxylase; 24-Hydroxylase; Prostatic Neoplasms; Outcomes
21.  Vitamin D and Cancer 
Vitamin D system is a complex pathway that includes precursors, active metabolites, enzymes, and receptors. This complex system actives several molecular pathways and mediates a multitude of functions. In addition to the classical role in calcium and bone homeostasis, vitamin D plays “non-calcemic” effects in host defense, inflammation, immunity, and cancer processes as recognized in vitro and in vivo studies. The aim of this review is to highlight the relationship between vitamin D and cancer, summarizing several mechanisms proposed to explain the potential protective effect of vitamin D against the development and progression of cancer. Vitamin D acts like a transcription factor that influences central mechanisms of tumorigenesis: growth, cell differentiation, and apoptosis. In addition to cellular and molecular studies, epidemiological surveys have shown that sunlight exposure and consequent increased circulating levels of vitamin D are associated with reduced reduced occurrence and a reduced mortality in different histological types of cancer. Another recent field of interest concerns polymorphisms of vitamin D receptor (VDR); in this context, preliminary data suggest that VDR polymorphisms more frequently associated with tumorigenesis are Fok1, Bsm1, Taq1, Apa1, EcoRV, Cdx2; although further studies are needed to clarify their role in the cancer. In this review, the relationship between vitamin D and cancer is discussed.
doi:10.3389/fendo.2012.00058
PMCID: PMC3355893  PMID: 22649423
Vitamin D; 25-hydroxy-vitamin D; cancer; inflammation; immunity
22.  Vitamin D: Considerations in the Continued Development as an Agent for Cancer Prevention and Therapy 
Considerable preclinical and epidemiologic data suggest that vitamin D may play a role in the pathogenesis, progression and therapy of cancer. Numerous epidemiologic studies support the hypothesis that individuals with lower serum vitamin D levels have a higher risk of a number of cancers. Measures of vitamin D level in such studies include both surrogate estimates of vitamin D level (residence in more northern latitudes, history of activity and sun exposure) as well as measured serum 25(OH) cholecalciferol levels. Perhaps the most robust of these epidemiologic studies is that of Giovannucci and colleagues who developed and validated an estimate of serum 25(OH) cholecalciferol level and reported that among more than 40,000 individuals in the Health professionals Study an increase in 25(OH) cholecalciferol level of 62.5ng/mL was associated with a reduction in the risk of head/neck, esophagus, pancreas cancers and acute leukemia by >50%. Unfortunately very limited data are available to indicate whether or not giving vitamin D supplements reduces the risk of cancer. Many preclinical studies indicate that exposing cancer cells – as well as vascular endothelial cells derived from tumors - to high concentrations of active metabolites of vitamin D halts progression through cell cycle, induces apoptosis and will slow or stop the growth of tumors in vivo. There are no data that one type of cancer is more or less susceptible to the effects of vitamin D. Vitamin D also potentiates the antitumor activity of a number of types of cytotoxic anticancer agents in in vivo preclinical models. Vitamin D analogues initiate signaling through a number of important pathways, but the pathway(s) essential to the antitumor activities of vitamin D are unclear. Clinical studies of vitamin D as an antitumor agent have been hampered by the lack of a suitable pharmaceutical preparation for clinical study. All commercially available formulations are inadequate because of the necessity to administer large numbers of caplets and the poor “bioavailability” of calcitriol (the most carefully studied analogue) at these high doses. Preclinical data suggest that very high exposures to calcitriol are necessary for the antitumor effects. Clinical data do indicate that very high doses of calcitriol (>100mcg weekly, intravenously and 0.15mcg/kg weekly orally) can be given safely. The maximum tolerated dose (MTD) of calcitriol is unclear. While a 250 patient trial in men with castration resistant prostate cancer (CRPC) comparing docetaxel (36mg/sqm weekly) +/- calcitriol 0.15mcg/kg indicated that calcitriol was very safe, may have reduced to death rate, an adequately powered (1000 patients) randomized study of weekly docetaxel + calcitriol vs q3 week docetaxel was negative. The limitations of this trial were the unequal chemotherapy arms compared in this study and the failure to use an optimal biologic dose or MTD of calcitriol. In view of the substantial preclinical and epidemiologic data supporting the potential role of vitamin D in cancer, careful studies to evaluate the impact of vitamin D replacement on the frequency of cancer and the impact of an appropriate dose and schedule of calcitriol or other active vitamin D analogue on the treatment of established cancer are indicated.
doi:10.1097/PPO.0b013e3181c51ee6
PMCID: PMC2857702  PMID: 20164683
23.  A Prospective Study of Plasma Vitamin D Metabolites, Vitamin D Receptor Gene Polymorphisms, and Risk of Hypertension in Men 
European journal of nutrition  2012;52(7):1771-1779.
Purpose
Laboratory studies have suggested that vitamin D inadequacy may be implicated in development of hypertension. Evidence from epidemiologic studies remains limited. We aim to examine the prospective associations of circulating vitamin D metabolites, vitamin D receptor (VDR) gene polymorphisms, and their interaction with risk of hypertension.
Methods
We conducted prospective analyses among 1,211 US men that were free of baseline hypertension and had baseline plasma 25hydroxy-vitamin D (25(OH)D) or 1,25dihydroxy-vitamin D (1,25(OH)2D) measured and VDR BsmI or FokI polymorphisms genotyped.
Results
During 15.3-year follow-up, 695 men developed incident hypertension. After multivariable adjustment, the hazard ratios (HRs) and 95% CIs for hypertension across increasing quartiles of circulating vitamin D metabolites were 1.00 (ref), 0.94 (0.69–1.27), 0.69 (0.50–0.96), and 0.82 (0.60–1.13) for 25(OH)D (p, trend: 0.43), and 1.00, 0.92 (0.66–1.27), 1.12 (0.82–1.54), and 1.19 (0.86–1.63) for 1,25(OH)2D (p, trend: 0.16). Compared with carriers of VDR BsmI bb, carriers of bB or BB had a HR of 1.25 (1.04–1.51) for hypertension. For VDR FokI polymorphism, compared with carriers of FF and Ff combined, carriers of ff had a HR of 1.32 (1.03–1.70). The relation between plasma 25(OH)D and risk of hypertension did not differ by VDR BsmI and FokI polymorphisms.
Conclusions
In a prospective cohort of men, we found suggestive evidence for an inverse association between plasma 25(OH)D and risk of hypertension. We also found associations between VDR BsmI and FokI polymorphisms with hypertension risk. More research is needed to further determine the role of vitamin D in hypertension prevention.
doi:10.1007/s00394-012-0480-8
PMCID: PMC3609910  PMID: 23262750
vitamin D; polymorphisms; prospective study; hypertension; men
24.  Phase II Open Label, Multi-Center Clinical Trial of Modulation of Intermediate Endpoint Biomarkers by 1α-Hydroxyvitamin D2 in Patients With Clinically Localized Prostate Cancer and High Grade Pin 
The Prostate  2013;73(9):970-978.
BACKGROUND
Prostate cancer is the most common malignancy and second leading cause of cancer related deaths in American men supporting the study of prostate cancer chemoprevention. Major risk factors for this disease have been associated with low serum levels of vitamin D. Here, we evaluate the biologic activity of a less calcemic vitamin D analog 1α-hydroxyvitamin D2 [1α-OH-D2] (Bone Care International, Inc.) in patients with prostate cancer and high grade prostatic intraepithelial neoplasia (HG PIN).
METHODS
Patients with clinically organ-confined prostate cancer and HG PIN were randomized to 1α-OH-D2 versus placebo for 28 days prior to radical prostatectomy. Intermediate endpoint biomarkers included serum vitamin D metabolites, TGFß 1/2, free/total PSA, IGF-1, IGFBP-3, bFGF, and VEGF. Tissue endpoints included histology, MIB-1 and TUNEL staining, microvessel density and factor VIII staining, androgen receptor and PSA, vitamin D receptor expression and nuclear morphometry.
RESULTS
The 1α-OH-D2 vitamin D analog was well tolerated and could be safely administered with good compliance and no evidence of hypercalcemia over 28 days. While serum vitamin D metabolite levels only slightly increased, evidence of biologic activity was observed with significant reductions in serum PTH levels. TGF-ß2 was the only biomarker significantly altered by vitamin D supplementation. Whether reduced TGF-ß2 levels in our study is an early indicator of response to vitamin D remains unclear.
CONCLUSIONS
While further investigation of vitamin D may be warranted based on preclinical studies, results of the present trial do not appear to justify evaluation of 1α-OH-D2 in larger clinical prostate cancer prevention studies.
doi:10.1002/pros.22644
PMCID: PMC3755376  PMID: 23335089
prostate cancer; vitamin D; chemoprevention
25.  Prognostic Role of Vitamin D Status and Efficacy of Vitamin D Supplementation in Cancer Patients: A Systematic Review 
The Oncologist  2011;16(9):1215-1227.
Whether or not hypovitaminosis D can influence the prognosis of cancer patients and whether or not vitamin D supplementation improves outcome were examined through a literature review. It was concluded that the currently available evidence is insufficient to recommend vitamin D supplementation in cancer patients in clinical practice.
Background.
Whether or not hypovitaminosis D can influence the prognosis of cancer patients and whether or not vitamin D (vitD) supplementation improves outcome remain controversial.
Design.
Studies evaluating the prognostic role of vitD and vitD receptor (VDR) in cancer patients and trials evaluating the efficacy of vitD administration on patient outcome were identified by a search of MEDLINE, EMBASE, ISI Web of Knowledge, and the Cochrane Library through June 2010.
Results.
Twenty-five studies were included. A negative prognostic role for low serum vitD level was observed in five cohort studies including patients with breast cancer (one study), colon cancer (two studies), prostate cancer (one study), and melanoma (one study), but not in two studies on non-small cell lung cancer and one study on breast cancer. Three of four studies showed that VDR+ tumors carry a better prognosis than VDR− tumors, whereas VDR polymorphisms were significantly associated with prognosis in five of 10 studies. A significant interaction between serum vitD level and VDR polymorphism was observed in one study. Three randomized trials involving advanced prostate cancer patients explored the prognostic role of vitD supplementation. A meta-analysis of these trials showed no effect on survival (pooled risk ratio, 1.07; 95% confidence interval, CI, 0.93–1.23), with strong heterogeneity among studies.
Conclusion.
Hypovitaminosis D seems to be associated with a worse prognosis in some cancers, but vitD supplementation failed to demonstrate a benefit in prostate cancer patients. The currently available evidence is insufficient to recommend vitD supplementation in cancer patients in clinical practice.
doi:10.1634/theoncologist.2011-0098
PMCID: PMC3228169  PMID: 21835895
Vitamin D; Vitamin D receptor; Neoplasm; Prognosis

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