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Vitamin D

March 2006

Benefits and requirements of vitamin D for optimal health: a review.

Vitamin D sufficiency is required for optimal health. The conditions with strong evidence for a protective effect of vitamin D include several bone diseases, muscle weakness, more than a dozen types of internal cancers, multiple sclerosis, and type 1 diabetes mellitus. There is also weaker evidence for several other diseases and conditions. There are good reasons that vitamin D sufficiency be maintained during all stages of life, from fetal development to old age. Adequate calcium intake is also recommended. The current vitamin D requirements in the United States are based on protection against bone diseases. These guidelines are being revised upward in light of new findings, especially for soft-tissue health. The consensus of scientific understanding appears to be that vitamin D deficiency is reached for serum 25-hydroxyvitamin D (25OHD) levels less than 20 ng/mL (50 nmol/L), insufficiency in the range from 20-32 ng/mL, and sufficiency in the range from 33-80 ng/mL, with normal in sunny countries 54-90 ng/mL, and excess greater than 100 ng/mL. Solar ultraviolet-B (UVB) irradiation is the primary source of vitamin D for most people. In general, the health benefits accruing from moderate UV irradiation, without erythema or excess tanning, greatly outweigh the health risks, with skin pigmentation (melanin) providing much of the protection. In the absence of adequate solar UVB irradiation due to season, latitude, or lifestyle, vitamin D can be obtained from fortified food, oily fish, vitamin D supplements, and artificial sources of UVB radiation.

Altern Med Rev. 2005 Jun;10(2):94-111

Vitamin D and vitamin D analogs in cancer treatment.

The secosteroid hormone 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) is a key player in the regulation of bone mineralization and calcium homeostasis. In addition, 1,25-(OH)2D3 has antiproliferative and prodifferentiation effects on various cells in vitro and in vivo. The growth-inhibitory properties of 1,25-(OH)2D3 could be harnessed in the treatment of cancer. However, its use as an anti-cancer drug is limited because of the calcemic effects of pharmacological doses. In an attempt to dissociate the antiproliferative and calcemic effects, numerous vitamin D3 analogs were developed. The mechanisms by which 1,25-(OH)2D3 and 1,25-(OH)2D3 analogs exert their growth-inhibitory effects are not clear but include effects on cell differentiation, apoptosis, cell cycle regulation, metastases, and angiogenesis. In the current review aspects involved in the tumor suppressive activity of 1,25-(OH)2D3 and 1,25-(OH)2D3 analogs will be addressed. The use of vitamin D3 compounds, alone or in combination with other drugs, in cancer treatment and the potential drawbacks will also be discussed.

Curr Drug Targets. 2002 Feb;3(1):85-94

Vitamin D and prevention of colorectal cancer.

BACKGROUND: Inadequate photosynthesis or oral intake of vitamin D are associated with high incidence rates of colorectal cancer, but the dose-response relationship has not been adequately studied.

METHODS: Dose-response gradients from observational studies of vitamin D intake and serum 25-hydroxyvitamin D were plotted as trend lines. The point on each linear trend line corresponding to an odds ratio of 0.50 provided the prediagnostic vitamin D intake or 25-hydroxyvitamin D concentration associated with 50% lower risk compared to <100IU/day vitamin D or <13ng/ml serum 25-hydroxyvitamin D. Medians of these values were determined.

RESULTS: Overall, individuals with >or=1000IU/ day oral vitamin D (p<0.0001) or >or=33ng/ml (82nmol/l) serum 25-hydroxyvitamin D (p<0.01) had 50% lower incidence of colorectal cancer compared to reference values.

CONCLUSIONS: Intake of 1000IU/ day of vitamin D, half the safe upper intake established by the National Academy of Sciences, was associated with 50% lower risk. Serum 25-hydroxyvitamin D of 33ng/ml, which is known to be safe, also was associated with 50% lower risk. Prompt public health action is needed to increase intake of vitamin D(3) to 1000IU/day, and to raise 25-hydroxyvitamin D by encouraging a modest duration of sunlight exposure.

J Steroid Biochem Mol Biol. 2005 Oct;97(1-2):179-94

The epidemiology of vitamin D and colorectal cancer: recent findings.

PURPOSE OF REVIEW: To highlight the human studies published over the past year examining the influence of vitamin D on risk of colorectal cancer.

RECENT FINDINGS: Studies over the past year have added more support to the idea that higher levels of vitamin D may decrease risk of colorectal cancer. Further, typical dietary intakes such as 200-400 IU/day may be too low to exert appreciable benefits, and protection may occur with higher levels of vitamin D associated with exposure to sunshine. Recent studies also suggest a potential benefit of vitamin D on other digestive-tract cancers, and that vitamin D status at the time of diagnosis and treatment may influence survival of cancer. However, the evidence for these latter findings is based on limited data and needs to be confirmed. Higher vitamin D levels may also be associated with a higher rate of apoptosis in colorectal mucosa.

SUMMARY: Recent studies add more support to a potential role of vitamin D on risk of colorectal cancer, but suggest that intakes higher than customary are required if solar ultraviolet-B exposure is low. More studies are required to determine the optimal levels and intakes of this vitamin to reduce cancer risk. Potential benefits of vitamin D on other digestive-tract cancers and on survival in patients with colorectal cancer have been suggested by recent studies, but require confirmation.

Curr Opin Gastroenterol. 2006 Jan;22(1):24-29

The association of calcium and vitamin D with risk of colorectal adenomas.

The Polyp Prevention Trial (PPT) was a multicenter randomized clinical trial designed to determine the effects of a high-fiber, high-fruit and vegetable, low-fat diet on the recurrence of adenomatous polyps in the large bowel. Detailed dietary intake and supplement use data were collected at baseline and at each of 4 annual study visits. Adenoma recurrence was ascertained by complete colonoscopy at baseline and after 1 and 4 y. Recurrence was found in 754 of the 1,905 trial participants. We evaluated the association between calcium and vitamin D intake and adenomatous polyp recurrence after adjusting for intervention group, age, gender, nonsteroidal anti-inflammatory drug use, total energy intake, and the interaction of gender and intervention group. Vitamin D models were also adjusted for the location of the clinic site. Dietary variables were adjusted for total energy intake via the residual method. There were no overall significant associations between adenoma recurrence and dietary calcium intake [odds ratio (OR) for the 5th compared with the lowest quintile = 0.91; 95% CI = 0.67-1.23; P-trend = 0.68], total calcium intake (OR = 0.86; 95% CI = 0.62-1.18; P-trend = 0.20), or dietary vitamin D intake (OR = 0.93; 95% CI = 0.69-1.25; P-trend = 0.43) averaged over follow-up. Total vitamin D intake was weakly inversely associated with adenoma recurrence (OR = 0.84; 95% CI = 0.62-1.13; P-trend = 0.03). Supplemental calcium and vitamin D use during follow-up also were inversely associated with adenoma recurrence (OR for any compared with no use = 0.82; 95% CI = 0.68-0.99; and OR = 0.82; 95% CI = 0.68-0.99; for calcium and vitamin D, respectively). Slightly stronger associations were noted for the prevention of multiple recurrences. Our analyses did not suggest a significant effect modification between total calcium and total vitamin D intake (P = 0.14) on risk for adenoma recurrence. This trial cohort provides some evidence that calcium and vitamin D may be inversely associated with adenoma recurrence.

J Nutr. 2005 Feb;135(2):252-9

Clinical trials involving vitamin D analogs in prostate cancer.

Vitamin D shows significant potential as a therapy for prostate cancer. However, its use in clinical trials has been hampered by its induction of hypercalcemia at serum concentrations required to suppress cancer cell proliferation. This has spurred the development of less calcemic analogs of vitamin D. In this article, we review the clinical trials and consider the future directions of the use of vitamin D and its analogs in the treatment or chemoprevention of prostate cancer. First, we summarize the epidemiological evidence leading to the hypothesis that vitamin D has anticancer activity. We then review the clinical trials using vitamin D analogs that involve patients with prostate cancer and conclude with a brief overview of our planned study with vitamin D5, [1alpha(OH)D5], which will begin shortly. Data for this review were identified by searches of PubMed, the Cochrane Library, Biosis, and references from relevant articles, using the search terms “vitamin D,” “prostate cancer,” “chemoprevention” and “vitamin D analog.” Abstracts from recent international meetings were also reviewed but were only included when they were the only known reference to the clinical trial or the research mentioned.

Cancer J. 2005 Sep-Oct;11(5):362-73

Sun exposure, vitamin D receptor gene polymorphisms, and risk of advanced prostate cancer.

Substantial experimental evidence indicates that the hormonal form of vitamin D promotes the differentiation and inhibits the proliferation, invasiveness, and metastasis of human prostatic cancer cells. Results from epidemiologic studies of vitamin D status and/or vitamin D receptor (VDR) polymorphisms and prostate cancer risk have been mixed. We conducted a population-based, case-control study of advanced prostate cancer among men ages 40 to 79 years from the San Francisco Bay area. Interview data on lifetime sun exposure and other risk factors were collected for 905 non-Hispanic White men (450 cases and 455 controls). Using a reflectometer, we measured constitutive skin pigmentation on the upper underarm (a sun-protected site) and facultative pigmentation on the forehead (a sun-exposed site) and calculated a sun exposure index from these measurements. Biospecimens were collected for 426 cases and 440 controls. Genotyping was done for VDR polymorphisms in the 5’ regulatory region (Cdx-2), exon 2 (FokI), and the 3’ region (TaqI and BglI). Reduced risk of advanced prostate cancer was associated with high sun exposure determined by reflectometry [odds ratio (OR), 0.51; 95% confidence interval (95% CI), 0.33-0.80] and high occupational outdoor activity (OR, 0.73; 95% CI, 0.48-1.11). Significant risk reductions with the high-activity alleles FokI FF or Ff, TaqI tt, and BglI BB genotypes and a nonsignificant reduction with Cdx-2 AG or AA genotype were observed in the presence of high sun exposure, with ORs ranging from 0.46 to 0.67. Our findings support the hypothesis that sun exposure and VDR polymorphisms together play important roles in the etiology of prostate cancer.

Cancer Res. 2005 Jun 15;65(12):5470-9

Pilot study: potential role of vitamin D (Cholecalciferol) in patients with PSA relapse after definitive therapy.

When local treatments for prostate cancer have failed, and prostate-specific antigen (PSA) rises in the absence of symptoms, there is little consensus as to the best management strategy. Calcitriol has been shown to prolong the doubling time of PSA in this context, but near-toxic doses are required. We investigated the effect of the nutrient vitamin D (cholecalciferol), a biochemical precursor of calcitriol, on PSA levels and the rate of rise of PSA in these patients. Fifteen patients were given 2,000 IU (50 microg) of cholecalciferol daily and monitored prospectively every 2-3 mo. In 9 patients, PSA levels decreased or remained unchanged after the commencement of cholecalciferol. This was sustained for as long as 21 mo. Also, there was a statisticallysignificant decrease in the rate of PSA rise after administration of cholecalciferol (P = 0.005) compared with that before cholecalciferol. The median PSA doubling time increased from 14.3 mo prior to commencing cholecalciferol to 25 mo after commencing cholecalciferol. Fourteen of 15 patients had a prolongation of PSA doubling time after commencing cholecalciferol. There were no side effects reported by any patient. Further study is needed to confirm this finding and to explore the potential therapeutic benefit of nutrient vitamin D in prostate cancer.

Nutr Cancer. 2005;51(1):32-6

Prenatal and perinatal correlates of adult mammographic breast density.

BACKGROUND: Adult mammographic percent density is one of the strongest known risk factors for breast cancer. In utero exposure to high levels of endogenous estrogens (or other pregnancy hormones) has been hypothesized to increase breast cancer risk in later life. We examined the hypothesisthat those factors associated with higher levels of estrogen during pregnancy or shortly after birth are associated with higher mammographic breast density in adulthood.

METHODS: We analyzed data on 1,893 women from 360 families in the Minnesota Breast Cancer Family Study who had screening mammograms, risk factor data, over age 40, and no history of breast cancer. Prenatal and perinatal risk factor data were ascertained using a mailed questionnaire. Mammographic percent density and dense area were estimated from the mediolateral oblique view using Cumulus, a computerassisted thresholding program. Linear mixed effects models incorporating familial correlation were used to assess the association of risk factors with percent density, adjusting for age, weight, and other breast cancer risk factors, all at time of mammography.

RESULTS: The mean age at mammography was 60.4 years (range, 40-91 years), and 76% were postmenopausal. Among postmenopausal women, there was a positive association of birthweight with percent density (P trend <0.01), with an adjusted mean percent density of 17.1% for <2.95 kg versus 21.0% for > or = 3.75 kg. There were suggestive positive associations with gestational age (mean percent density of 16.7% for preterm birth, 20.2% for term birth, and 23.0% for late birth; P trend = 0.07), maternal eclampsia/ preeclampsia (mean percent density of 19.9% for no and 14.6% for yes; P = 0.16), and being breast-fed as an infant (mean percent density of 18.2% for never and 20.0% for ever; P = 0.08). There was no association of percent density with maternal age, birth order, maternal use of alcohol or cigarettes, or neonatal jaundice. Except for being breast-fed, these associations showed similar but attenuated trends among premenopausal women, although none were statistically significant. The results for dense area paralleled the percent density results. The associations of gestational age and being breast-fed as an infant with percent density attenuated when included in the same model as birthweight.

CONCLUSIONS: Birthweight was positively associated with mammographic breast density and dense area among postmenopausal women and more weakly among premenopausal women, suggesting that it may be a marker of this early life exposure. These results offer some support to the hypothesis that pregnancy estrogens or other pregnancy changes may play a role in breast cancer etiology, and suggest that these factors may act in part through long-term effects on breast density.

Cancer Epidemiol Biomarkers Prev. 2005 Jun;14(6):1502-8

Vitamin D is associated with improved survival in early-stage non-small cell lung cancer patients.

Vitamin D may inhibit the development and progression of a wide spectrum of cancers. We investigated the associations of surgery season and vitamin D intake with recurrence-free survival (RFS) and overall survival in 456 early-stage non-small cell lung cancer patients. The data were analyzed using logrank test and Cox proportional hazards models. The median (range) follow-up time was 71 (0.1-140) months, with 161 recurrence and 231 deaths. Patients who had surgery in summer had a better RFS than those who had surgery in winter (adjusted hazard ratio, 0.75; 95% confidence interval, 0.56-1.01), with 5-year RFS rates of 53% (45-61%) and 40% (32-49%), respectively (P = 0.10, log-rank test). Similar association between surgery season and RFS was found among the 321 patients with dietary information (P = 0.33, log-rank test). There was no statistically significant association between vitamin D intake and RFS. Because both season and vitamin D intake are important predictors for vitamin D levels, we investigated the joint effects of surgery season and vitamin D intake. Patients who had surgery during summer with the highest vitamin D intake had better RFS (adjusted hazard ratio, 0.33; 95% confidence interval, 0.15-0.74) than patients who had surgery during winter with the lowest vitamin D intake, with the 5-year RFS rates of 56% (34-78%) and 23% (4-42%), respectively. Similar associations of surgery season and vitamin D intake with overall survival were also observed. In conclusion, the joint effects of surgery season and recent vitamin D intake seem to be associated with the survival of early-stage non-small cell lung cancer patients.

Cancer Epidemiol Biomarkers Prev. 2005 Oct;14(10):2303-9