The Epidemiology of Vitamin D and Cancer Risk

The relation between vitamin D status and cancer risk has been investigated in a number of epidemiologic studies, while data from interventional studies remain scarce. The approaches to estimate vitamin D status have been varied, and include direct measures of circulating 25(OH)vitamin D (25(OH)D) levels, surrogates, or determinants of 25(OH)D, including region of residence, intake, and sun exposure estimates. In terms of cancer sites, the body of evidence is the most extensive for colorectal cancer, for which support comes from studies of 25(OH)D, vitamin D intake, multiple predictors of 25(OH)D, and region of residence in a sunny climate. The evidence for breast cancer is also intriguing, but prospective studies of 25(OH)D are sparse and somewhat conflicting. In one case–control study, retrospectively reported sun exposure during ages 10–19 was most strongly associated with reduced risk of breast cancer. For prostate cancer, the data on circulating 25(OH)D have been equivocal, suggesting no association or a weak inverse association, but studies tend to support a benefit of sun exposure on prostate cancer risk. It is plausible that for prostate cancer, exposure to vitamin D level much longer before the time of diagnosis is the most relevant. Most of the epidemiologic studies to date have examined vitamin D status in relation to risk of cancer, but emerging evidence suggests that vitamin D may be an important factor for cancer progression and mortality, independently of any effects on incidence. Further study is needed to establish the precise role of vitamin D on carcinogenesis, especially in terms of when in the lifespan and on what stages of carcinogenesis vitamin D is relevant, the precise intakes and levels required, the magnitude of the association, and which cancer sites are most affected.     

Plasma Vitamin D Levels,Menopause, and Risk of Breast Cancer: Dose-Response Meta-Analysis of Prospective Studies

Previous evidence suggests that higher circulating 25-hydroxyvitamin D (25[OH]D) levels are variably associated with lower breast cancer risk; however, prospective studies and clinical trials have been inconsistent, particularly between older and younger women of differing menopausal status. We conducted a quantitative nonlinear dose-response meta-analysis of prospective studies evaluating the association between circulating 25(OH)D and breast cancer risk, stratified by menopause. A systematic search of MEDLINE and EMBASE included studies published through May 2011. We reviewed references from retrieved articles and contacted relevant investigators for additional data from prospective studies on circulating 25(OH)D levels and incident breast cancers. Prospective studies of circulating vitamin D and breast cancer risk were reviewed, and no language restrictions were imposed. Information on study population, menopausal status, 25(OH)D levels, and relative risk (RR) estimates were extracted using a standardized protocol.A total of 9 prospective studies were included, comprising 5206 cases and 6450 controls. Data were pooled using dose-response random-effects meta-regression models. Identifying nonlinear effects, spline models were optimized for thresholds. The relationship between circulating 25(OH)D and breast cancer risk differed by menopausal status (p = 0.05 for effect modification). While no association was found in premenopausal women, dose-response modeling revealed a nonlinear inverse association among postmenopausal women. Notably, a flat association was observed in the lowest range of 25(OH)D levels <27 ng/mL (RR = 1.01 per 5 ng/mL; 95% confidence interval [CI], 0.98–1.04). In contrast, postmenopausal breast cancer risk decreased with 25(OH)D levels 27-<35 ng/mL (p = 0.02 for nonlinear risk change), where a 5 ng/mL increase in 25(OH)D was associated with a 12% lower risk of breast cancer (RR = 0.88 per 5 ng/mL; 95% CI, 0.79–0.97), with suggestive flattening at higher doses >35 ng/mL. The significant inverse association did not appear to vary across strata of invasive/in-situ cases, body mass index adjustment, region, postmenopausal hormone use, or assay method.In summary, this dose-response meta-analysis of prospective studies of plasma 25(OH)D suggested a breast cancer risk differential by menopause, whereby a step-wise inverse association was observed beyond a threshold of 27 ng/mL, but with flattening of effects above 35 ng/mL, in postmenopausal women. These findings help resolve prior inconsistent findings and may carry important clinical and public health implications.     

Interactions Between Vitamin D and Calcium Intake,Vitamin D Receptor Genetic Polymorphisms,and Colorectal Cancer Risk

Digestive Diseases and Sciences - Vitamin D has anticarcinogenic properties and acts through vitamin D receptor (VDR) to carry out its functions. This study explored the independent and combined...     

Vitamin D for Cancer Prevention and Survival

Higher levels of the principal circulating form of vitamin D, 25-hydroxyvitamin D (25(OH)D), are associated with substantially lower incidence and death rates from colon, breast, and ovarian cancer, with a linear dose–response gradient. The accumulated evidence from observational studies and a randomized trial reveal that population serum levels of 25(OH)D in the range of 40 to 50 ng/ml will markedly reduce incidence and mortality rates of several cancers including those of the breast, colon, and ovary. There is an immediate clinical need for cancer care providers worldwide to assure that a serum 25(OH)D level >40 ng/ml is achieved as soon as feasible after diagnosis of patients with breast and colon cancer, unless specifically contraindicated by pre-existing hypercalcemia. This serum target could be revisited after further rigorous studies are performed, but the evidence that has accumulated during the past 29 years is sufficiently strong now to adopt the above dosages and serum targets for professional and public health action. Such prompt action is likely to cut mortality from these cancers by half within approximately 5 years. Research on a wider range of cancer types with higher serum 25(OH)D levels (≥50 ng/ml or 125 nmol/l) is needed. In the meantime, vitamin D₃ intake by everyone in the continental US and Canada aged 1 year and older should not be less than 2000 IU/day of vitamin D₃, and 1000 IU/day for infants. The views expressed in this report are those of the authors and do not represent an official position of the Department of the Navy, Department of Defense, or the US Government.     

Vitamin D and Cardiovascular Risk

Vitamin D deficiency is a common condition that has well-documented effects on musculoskeletal health. A growing body of literature has related vitamin D deficiency to other chronic disorders, including cardiovascular disease. Several plausible biological mechanisms have been postulated to explain this association, including the effect of poor vitamin D status on intermediate risk factors (eg, hypertension and diabetes), neurohormonal activation, inflammation, and cardiac remodeling. These mechanisms have been explored in experimental and animal studies, as well as several small interventional studies. The results of the controlled trials have not been conclusive to date. In this review, we summarize the existing studies investigating the effects of vitamin D on cardiovascular health, and propose that additional well-designed, prospective, randomized controlled trials are necessary to delineate the appropriate role of vitamin D supplementation in reducing the burden of cardiovascular disease.     

维生素D状态与心血管危险

已知维生素D最重要的功能是维持人体钙离子代谢的平衡。近些年来的研究发现维生素D受体广泛存在于人体的多种组织细胞中,因此维生素D是否还具有其他重要的生物学功能成为研究热点,其中维生素D缺乏与心血管风险的关系颇为引人注目。一些研究提示维生素D缺乏可能增加心血管风险,包括高血压、心力衰竭和缺血性心脏病等。但其致病机制和影响程度尚不十分明确。现综述了目前有关维生素D状态与心血管危险间关系的假设机制,并探讨为验证有关假设已进行的一些重要研究。     

Association of Vitamin D Receptor Cdx-2 Polymorphism With Cancer Risk: A Meta-Analysis

Vitamin D receptor (VDR) Cdx-2 polymorphism (rs11568820) has been indicated to be associated to cancer susceptibility. However, published studies reported mixed results. This meta-analysis was conducted to get a more accurate estimation of the association between Cdx-2 polymorphism and cancer risk.We identified 25 independent studies with a total of 34,018 subjects published prior to March 2015. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the susceptibility to cancer. Separate analyses were conducted on features of the population such as ethnicity, source of controls, and cancer types.Meta-analysis results showed that Cdx-2 polymorphism significantly increased cancer risk in the homozygous model in overall analysis. According to the further stratified analysis, significant association was found between Cdx-2 variant and cancer risk in American-Africans in the homozygous, recessive, and dominant comparison models. However, no significant associations were found in Caucasians and Asians. When stratified by different cancer types, significant association was observed between Cdx-2 variant and an increased risk of colorectal cancer in the homozygous, recessive, and dominant models. In addition, ovarian cancer susceptibility increased based on the homozygous and dominant comparison models.Our study indicated that VDR Cdx-2 polymorphism was associated with an increased cancer risk, particularly in American-Africans, colorectal, and ovarian cancers. However, other factors may impact on the association. Further multicenter studies are needed to confirm the effects of Cdx-2 polymorphism on cancer susceptibility.     

Strategies for Managing Breast Cancer Risk After the Menopause

Postmenopausal women in Western societies are conscious of breast cancer as a potential cause of death and ill health, which they wish to avoid with the advice of their doctors. Yet many factors that predispose women to the development of cancer will have been laid down before the menopause, in their genetic makeup or during their adolescent years. Even in middle age it is important to take account of the intrinsic level of risk, and to give women advice tailored to their own individual risk level. This results from their family history, previous diseases such as benign breast disease, and previous treatment for breast cancer or Hodgkin's disease. For those at the highest level of risk, strategies will include regular screening, prophylactic mastectomy, and the use of chemoprevention agents, such as tamoxifen. These women should avoid hormone replacement therapy (HRT) and control their menopausal symptoms and osteoporosis through the use of other agents now available - venlafaxine for menopausal symptoms and bisphosphonates for osteoporosis. Raloxifene is an agent under trial that may be valuable for breast cancer control as well as for osteoporosis. Women at standard population risk will require less robust preventive strategies, which will include screening and lifestyle modification. Their decisions regarding HRT should now be modified by recent evidence of associated risks. Recent studies show that tibolone causes less mammographic density and has a lower relative risk of breast cancer than combined estrogen/progestogen preparations. There is limited evidence that controlling obesity, participating in exercise and adopting a diet low in fats and high in fruit and vegetables will alter risk at this age. These precautions will, however, reduce the risk of other diseases common in this age group, such as hypertension, heart disease, stroke, and type 2 diabetes mellitus. Alcohol, even in small amounts, is a risk factor for breast cancer. Given the cardioprotective effect of moderate alcohol intake, advice on alcohol must reflect the individual relative risk of cardiovascular disease and breast cancer. Personal risk assessment is relevant for all women. Screening and a healthy lifestyle are worthwhile approaches for all, with the more aggressive approaches such as chemoprevention and prophylactic surgery reserved for those who have substantially elevated levels of risk. Once the menopause has passed, screening is probably the most effective evidence-based tool for breast cancer control by early diagnosis.     

Vitamin D Receptor Gene Polymorphisms and the Risk of Colorectal Cancer in a Chinese Population

Objective The purpose was to investigate single nucleotide polymorphism of the vitamin D recepter gene and its possible relationship with colorectal cancer (CRC) in a Chinese population. Methods The vitamin D receptor (VDR) genotypes were determined by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) using endonuclease BsmI and FokI, and direct sequencing in 400 Chinese people, comprised of 200 CRC patients and 200 controls from the same area in China. Results The distribution of alleles (F/f) and genotypes (FF/Ff/ff) of the FokI had no significant difference between CRC patients and normal controls (P > 0.05), while that of the B allele and the BB genotype of the BsmI in CRC patients was significantly lower compared with the control group (0.1625 versus 0.740, P < 0.05, OR = 0.068, 95% CI: 0.048–0.096 and 0.060 versus 0.590, P < 0.05, OR = 0.015, 95% CI: 0.007–0.032). Conclusion The BB genotype of the VDR BsmI variant was significantly associated with a decreased risk of CRC in a Chinese population, while the VDR FokI polymorphism was not significantly associated with it.     

Serum Vitamin D Concentrations and Unexplained Elevation in ALT Among US Adults

Background  

Low serum levels of vitamin D are associated with metabolic syndrome. Participants in NHANES III with unexplained elevation in ALT levels have high prevalence of metabolic syndrome. We hypothesized that the serum concentrations of vitamin D were inversely associated with unexplained elevation in ALT.     

Radiation Therapy and Cardiovascular Disease Risk in Breast Cancer

The cardiovascular disease risk among the breast cancer population is becoming increasingly important as the population of long-term survivors continues to rise. Radiation therapy decreases local reoccurrence and improves overall survival. These benefits however are not met without challenges including the potential for an increased risk of developing cardiovascular disease. Early clinical trials demonstrate that cardiovascular mortality is increased following radiation therapy compared to those treated without radiation therapy. Cardiovascular disease morbidity is also associated with radiation therapy for women with breast cancer. Among those who are irradiated, potential risk factors including age, surgery type, left-sided disease, dose, and previous cardiovascular disease may increase the risk of developing fatal cardiovascular disease. Newer clinical trials are showing promising results, with a decline in cardiovascular disease risk among those treated with radiation therapy; however, longer-term follow up is needed to confirm these findings.     

Risk of Breast Cancer in Men With Liver Cirrhosis

Objective : Liver cirrhosis is associated with increased levels of estrogens, which may be causally related to breast cancer. Because background estrogen levels are lower in men than in women, an estrogen-mediated link between liver cirrhosis and breast cancer would be easier to detect in men. Methods : Men hospitalized with liver cirrhosis in Denmark from January 1, 1977, to December 31, 1989, were followed up, through record linkage, until the end of December 1993 for the possible occurrence of breast cancer. Results : A total of 11,642 men with liver cirrhosis were identified and were followed for a mean period of 4.3 yr, for a total of 49,687 person-years. Three cases of male breast cancer were observed whereas 0.75 was expected, for a standardized incidence ratio of 4.0 (95% confidence interval, 0.8–11.7). Conclusions : Cirrhosis, possibly via high levels of endogenous estrogens, increases the risk of breast cancer in men.     

Serum Concentrations of 25-Hydroxyvitamin D and Vitamin D-binding Protein in Elderly People

ABSTRACT Serum concentrations of 25-hydroxyvitamin D (25-OH-D) and vitamin D-binding protein (DBP) were measured in institutionalized and non-institutionalized elderly people. The institutionalized subjects were found to have low serum 25-OH-D in confirmation of other studies, but their serum DBP levels were similar to those found in non-institutionalized elderly subjects. Serum DBP concentrations were slightly higher in elderly females than in males, while no age dependence was found for DBP. Elderly people with protein-energy malnutrition who lived in their own homes had slightly reduced serum DBP and 25-OH-D levels. Elderly subjects with infections or other diseases causing acute inflammation, as indicated by an elevated serum haptoglobin and C-reactive protein, had normal levels of DBP.     

Antihypertensive Combination Therapy: Optimizing Blood Pressure Control and Cardiovascular Risk Reduction

Treating hypertension reduces the rates of myocardial infarction, stroke, and renal disease; however, clinical trial experience suggests that monotherapy is not likely to be successful for achieving goal blood pressure (BP) levels in many hypertensive patients. In multiple recent clinical trials including various subsets of hypertensive patients, the achievement of BP goal has typically required the combination of 2 or more medications, particularly in patients with BP levels >160/100 mm Hg. When initiating combination therapy for hypertension, careful consideration must be given to the choice of medication. Clinical trial evidence has shown the efficacy of various combinations of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, and diuretics in reducing BP and cardiovascular risk. Ongoing trials should provide additional guidance on the optimal choice of combination regimens in specific clinical settings.     

Vitamin D as a Novel Nontraditional Risk Factor for Mortality in Hemodialysis Patients

We examined the prevalence of vitamin D deficiency in hemodialysis patients and tested the hypothesis that decreased levels of 25‐hydroxyvitamin D (25D) are associated with an increased risk for early all‐cause mortality. One hundred and two patients, 57 (56%) men and 45 (44%) women, mean age 60.5 ± 13.1 years, were included in our study. Serum calcium and phosphorus levels were measured by routine laboratory methods. Parathyroid hormone (PTH) was measured by immunoassay and 25D by enzyme immunoassay. Patients were divided into two groups depending on the serum concentration of 25D: below or above 50 nmol/L. Survival rates were analyzed using the Kaplan–Meier survival curves. The Cox regression model was used to define potential variables effecting all‐cause mortality. The mean level of 25D in all patients was 58 ± 35.6 nmol/L, 52% of patients had 25D levels >50 nmol/L and 48% had levels of 10.5–50 nmol/L. Compared with men, women were more likely to be 25D deficient (67% vs. 37%; P = 0.005). Patients were observed from the date of laboratory measurement until their death or to a maximum of 730 days. Kaplan–Meier survival analysis showed that mortality in patients was significantly higher in the group with 25D levels ≤50 nmol/L (P < 0.033). With Cox multivariable regression modeling, the PTH level (P < 0.029) turned out to be the only predictor of mortality in our patients. Using the definitions recommended in the National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines, we found that our hemodialysis patients on average have vitamin D insufficiency. Our results indicate that patients with 25D levels ≤50 nmol/L are associated with higher all‐cause early mortality.     

Vitamin D and Sunlight: Strategies for Cancer Prevention and Other Health Benefits

Vitamin D deficiency is a worldwide health problem. The major source of vitamin D for most humans is sensible sun exposure. Factors that influence cutaneous vitamin D production include sunscreen use, skin pigmentation, time of day, season of the year, latitude, and aging. Serum 25-hydroxyvitamin D [25(OH)D] is the measure for vitamin D status. A total of 100 IU of vitamin D raises blood level of 25(OH)D by 1 ng/ml. Thus, children and adults who do not receive adequate vitamin D from sun exposure need at least 1000 IU/d vitamin D. Lack of sun exposure and vitamin D deficiency have been linked to many serious chronic diseases, including autoimmune diseases, infectious diseases, cardiovascular disease, and deadly cancers. It is estimated that there is a 30 to 50% reduction in risk for developing colorectal, breast, and prostate cancer by either increasing vitamin D intake to least 1000 IU/d vitamin D or increasing sun exposure to raise blood levels of 25(OH)D >30 ng/ml. Most tissues in the body have a vitamin D receptor. The active form of vitamin D, 1,25-dihydroxyvitamin D, is made in many different tissues, including colon, prostate, and breast. It is believed that the local production of 1,25(OH)₂D may be responsible for the anticancer benefit of vitamin D. Recent studies suggested that women who are vitamin D deficient have a 253% increased risk for developing colorectal cancer, and women who ingested 1500 mg/d calcium and 1100 IU/d vitamin D₃ for 4 yr reduced risk for developing cancer by >60%.Vitamin D is likely to be one of the oldest hormones. It has existed for at least 750 million years, when phytoplankton synthesized it in response to sunlight (1). Throughout evolution, vitamin D played a critical role in the evolution of vertebrates as they left their high-calcium ocean environment for the calcium-deficient terra firma. Nocturnal rodents and other rodent-like species that lived underground needed little, if any, vitamin D to survive. It has been speculated that when the asteroid hit the earth 65 million yr ago, one of the survival characteristics for nocturnal mammals was that they did not require sunlight-mediated vitamin D synthesis to survive, unlike the dinosaurs. Dinosaurs likely depended on the sun to satisfy their vitamin D requirement to utilize dietary calcium efficiently for the maintenance of their massive skeletons (1). Thus, the lack of sunlight-mediated vitamin D synthesis after the asteroid impact may have been related to the demise of the dinosaurs.The industrialization of Europe and the United States in the 17th through the 19th centuries gave birth to the devastating bone-deforming and growth-retarding disease rickets. Although Sniadecki in 1822 suggested that children who were living in the industrialized cities in Poland were at a higher risk for rickets than children who were living in rural areas as a result of lack of sun exposure, it would take 100 yr before it was reported that exposure to ultraviolet radiation from a mercury arc lamp or sun exposure prevented and cured rickets (2,3).