Correction: Serum 25-Hydroxyvitamin D Concentrations ≥40 ng/ml Are Associated with >65% Lower Cancer Risk: Pooled Analysis of Randomized Trial and Prospective Cohort Study.

[This corrects the article DOI: 10.1371/journal.pone.0152441.].

Breast cancer risk markedly lower with serum 25-hydroxyvitamin D concentrations ≥60 vs <20 ng/ml (150 vs 50 nmol/L): Pooled analysis of two randomized trials and a prospective cohort.

BACKGROUND: While numerous epidemiologic studies have found an association between higher serum 25-hydroxyvitamin D [25(OH)D] concentrations and lower breast cancer risk, few have assessed this association for concentrations >40 ng/ml. OBJECTIVE: To investigate the relationship between 25(OH)D concentration and breast cancer risk across a broad range of 25(OH)D concentrations among women aged 55 years and older. METHODS: Analyses used pooled data from two randomized clinical trials (N = 1129, N = 2196) and a prospective cohort (N = 1713) to examine a broad range of 25(OH)D concentrations. The outcome was diagnosis of breast cancer during the observation periods (median: 4.0 years). Three analyses were conducted: 1) Incidence rates were compared according to 25(OH)D concentration from <20 to ≥60 ng/ml (<50 to ≥150 nmol/L), 2) Kaplan-Meier plots were developed and 3) multivariate Cox regression was used to examine the association between 25(OH)D and breast cancer risk using multiple 25(OH)D measurements. RESULTS: Within the pooled cohort (N = 5038), 77 women were diagnosed with breast cancer (age-adjusted incidence: 512 cases per 100,000 person-years). Results were similar for the three analyses. First, comparing incidence rates, there was an 82% lower incidence rate of breast cancer for women with 25(OH)D concentrations ≥60 vs <20 ng/ml (Rate Ratio = 0.18, P = 0.006). Second, Kaplan-Meier curves for concentrations of <20, 20-39, 40-59 and ≥60 ng/ml were significantly different (P = 0.02), with the highest proportion breast cancer-free in the ≥60 ng/ml group (99.3%) and the lowest proportion breast cancer-free in the <20 ng/ml group (96.8%). The proportion with breast cancer was 78% lower for ≥60 vs <20 ng/ml (P = 0.02). Third, multivariate Cox regression revealed that women with 25(OH)D concentrations ≥60 ng/ml had an 80% lower risk of breast cancer than women with concentrations <20 ng/ml (HR = 0.20, P = 0.03), adjusting for age, BMI, smoking status, calcium supplement intake, and study of origin. CONCLUSIONS: Higher 25(OH)D concentrations were associated with a dose-response decrease in breast cancer risk with concentrations ≥60 ng/ml being most protective.

Plasma 25-hydroxyvitamin D concentration and risk of type 2 diabetes and pre-diabetes: 12-year cohort study.

BACKGROUND: It has been reported that higher plasma 25-hydroxyvitamin D is associated with lower risk of type 2 diabetes. However the results to date have been mixed and no adequate data based on a cohort are available for the high end of the normal range, above approximately 32 ng/ml or 80 nmol/L. METHODS: We performed a cohort study of 903 adults who were known to be free of diabetes or pre-diabetes during a 1997-1999 visit to a NIH Lipid Research Centers clinic. Plasma 25(OH)D was measured at Visit 8 in 1977-1979. The mean age was 74 years. The visit also included fasting plasma glucose and oral glucose tolerance testing. Follow-up continued through 2009. RESULTS: There were 47 cases of diabetes and 337 cases of pre-diabetes. Higher 25(OH)D concentrations (> 30 ng/ml) were associated with lower hazard ratios (HR) for diabetes: 30-39 ng/ml or 75-98 nmol/L: HR = 0.31, 95% CI = 0.14-0.70; for 40-49 ng/ml or 100-122 nmol/L: HR = 0.29, CI = 0.12-0.68; for > 50 ng/ml or 125 nmol/L: HR = 0.19, CI = 0.06-0.56. All HRs are compared to < 30 ng/ml or 75 nmol/L. There was an inverse dose-response gradient between 25(OH)D concentration and risk of diabetes with a p for trend of 0.005. Each 10 ng/mL or 25 nmol/L higher 25(OH)D concentration was associated with a HR of 0.64, CI = 0.48-0.86. 25(OH)D concentrations were more weakly inversely associated with pre-diabetes risk, and the trend was not significant. CONCLUSION: Further research is needed on whether high 25(OH)D might prevent type 2 diabetes or transition of prediabetes to diabetes.

Dose-response of serum 25-hydroxyvitamin D in association with risk of colorectal cancer: A meta-analysis.

Fifteen nested case-control or cohort studies in 14 countries have examined the association between serum 25-hydroxyvitamin D [25(OH)D] and risk of colorectal cancer. A meta-analysis of these studies would provide a useful dose-response gradient curve based on pooling of the results of known studies to date. An up-to-date dose-response curve that combines the findings of these studies has not been reported, to our knowledge. This curve would help in designing interventions for future studies. A new meta-analysis would be more precise than any previous analysis due to its larger sample size. Therefore a search of PubMed and other resources was performed in May 2016 for all cohort or nested case-control observational studies that reported risk of colon or colorectal cancer by quantiles of 25(OH)D. All but two of the 15 studies found a trend toward lower risk of colorectal cancer associated with higher serum 25(OH)D. There was a linear reduction in the odds ratio (OR) with each 10ng/ml-increment in 25(OH)D concentration. The lowest quantile of the serum 25(OH)D concentration was generally<20ng/ml. The downward trend in ORs associated with higher serum 25(OH)D concentrations was statistically significant in 3 studies. The pooled OR from all studies comparing highest with lowest quantile of 25(OH)D was 0.67 (95% confidence interval [CI], 0.59-0.76), meaning there was a 33% lower risk associated with the highest compared with the lowest quantile of serum 25(OH)D. A dose-response analysis revealed that a serum 25(OH)D of 50ng/ml was associated with an OR of 0.4 (95% CI, 0.2-1.0) compared with a concentration of 5ng/ml. The formula for the linear relationship was OR=0.008x. For example, individuals with a 25(OH)D concentration of 50ng/ml had an approximately 60% lower risk of colorectal cancer than those with a concentration of 5ng/ml. Those with a 25(OH)D concentration of 30ng/ml had a 33% lower risk than those with a concentration of 5ng/ml. The inverse association between serum 25(OH)D and risk of colorectal cancer overall was strong and statistically significant. There also was a mostly linear dose response relationship between serum 25(OH)D and risk of colorectal cancer when all studies were combined. No study reported significant adverse effects, and there was no evidence of publication bias. Misclassification in some studies could have influenced the association, causing it to appear weaker than the true association.

Serum 25-Hydroxyvitamin D Concentrations ≥40 ng/ml Are Associated with >65% Lower Cancer Risk: Pooled Analysis of Randomized Trial and Prospective Cohort Study.

BACKGROUND: Higher serum 25-hydroxyvitamin D [25(OH)D] concentrations have been associated with a lower risk of multiple cancer types across a range of 25(OH)D concentrations. OBJECTIVES: To investigate whether the previously reported inverse association between 25(OH)D and cancer risk could be replicated, and if a 25(OH)D response region could be identified among women aged 55 years and older across a broad range of 25(OH)D concentrations. METHODS: Data from two cohorts representing different median 25(OH)D concentrations were pooled to afford a broader range of 25(OH)D concentrations than either cohort alone: the Lappe cohort (N = 1,169), a randomized clinical trial cohort (median 25(OH)D = 30 ng/ml) and the GrassrootsHealth cohort (N = 1,135), a prospective cohort (median 25(OH)D = 48 ng/ml). Cancer incidence over a multi-year period (median: 3.9 years) was compared according to 25(OH)D concentration. Kaplan-Meier plots were developed and the association between 25(OH)D and cancer risk was examined with multivariate Cox regression using multiple 25(OH)D measurements and spline functions. The study included all invasive cancers excluding skin cancer. RESULTS: Age-adjusted cancer incidence across the combined cohort (N = 2,304) was 840 cases per 100,000 person-years (1,020 per 100,000 person-years in the Lappe cohort and 722 per 100,000 person-years in the GrassrootsHealth cohort). Incidence was lower at higher concentrations of 25(OH)D. Women with 25(OH)D concentrations ≥40 ng/ml had a 67% lower risk of cancer than women with concentrations <20 ng/ml (HR = 0.33, 95% CI = 0.12-0.90). CONCLUSIONS: 25(OH)D concentrations ≥40 ng/ml were associated with substantial reduction in risk of all invasive cancers combined.

Cloud cover-adjusted ultraviolet B irradiance and pancreatic cancer incidence in 172 countries.

BACKGROUND: Controversy exists regarding whether vitamin D deficiency could influence the etiology of pancreatic cancer. Several cohort studies have found that high serum 25-hydroxyvitamin D [25(OH)D] concentrations are associated with low risk of pancreatic cancer, while others have not. HYPOTHESIS: Low ultraviolet B irradiance is associated with high incidence of pancreatic cancer. METHODS: Age-standardized pancreatic cancer incidence rates were obtained from GLOBOCAN in 2008. The association between cloud-adjusted UVB irradiance and age-standardized incidence rates of pancreatic cancer was analyzed using regression. RESULTS: Overall, the lower the cloud-adjusted UVB irradiance, the higher the incidence rate of pancreatic cancer. Residents of countries with low UVB irradiance had approximately 6 times the incidence rates as those in countries with high UVB irradiance (p<0.0001 for males and p<0.0001 for females). This association persisted after adjustment for traditional risk factors of pancreatic cancer (p=0.0182 for males and p=0.0029 for females). CONCLUSIONS: There was an inverse association of cloud-adjusted UVB irradiance with incidence of pancreatic cancer that persisted after adjustment. This result is consistent with an inverse association of overall vitamin D deficiency in countries with lower UVB irradiance with risk of pancreatic cancer. Further research on the role of 25(OH)D in reduction of pancreatic cancer in individuals would be desirable to expand the limited avenues available for prevention of this highly fatal disease. This article is part of a Special Issue entitled '17th Vitamin D Workshop'.

Low Cloud Cover-Adjusted Ultraviolet B Irradiance Is Associated with High Incidence Rates of Leukemia: Study of 172 Countries.

There are 52,380 cases of leukemia and 24,090 deaths from it in the US annually. Its causes are unknown and no preventive strategies have been implemented. We hypothesized that leukemia is due mainly to vitamin D deficiency, which is due mainly to low solar ultraviolet B (UVB) irradiance. To test this hypothesis, we estimated age-standardized cloud-cover-adjusted winter UVB irradiance using cloud cover data from the International Satellite Cloud Climatology Project, latitudes of population centroids, and standard astronomical calculations. Incidence rates for 172 countries, available from the International Agency for Cancer Research, were plotted according to cloud-adjusted UVB irradiance. We used multiple regression to account for national differences in elevation and average life expectancy. Leukemia incidence rates were inversely associated with cloud-adjusted UVB irradiance in males (p ≤ 0.01) and females (p ≤ 0.01) in both hemispheres. There were few departures from the trend line, which was parabolic when plotted with the equator at the center of the display, northern hemisphere countries on the right side and southern hemisphere countries on the left. The bivariate association displayed by the polynomial trend line indicated that populations at higher latitudes had at least two times the risk of leukemia compared to equatorial populations. The association persisted in males (p ≤ 0.05) and females (p ≤ 0.01) after controlling for elevation and life expectancy. Incidence rates of leukemia were inversely associated with solar UVB irradiance. It is plausible that the association is due to vitamin D deficiency. This would be consistent with laboratory studies and a previous epidemiological study. Consideration should be given to prudent use of vitamin D for prevention of leukemia.

Are low ultraviolet B and vitamin D associated with higher incidence of multiple myeloma?

BACKGROUND: The purpose of this study was to determine whether an inverse association exists between latitude, solar ultraviolet B (UVB) irradiance, and incidence rates of multiple myeloma.Methods Associations of latitude and UVB irradiance with age-standardized incidence rates of multiple myeloma were analyzed for 175 countries while controlling for sex-specific obesity prevalence, cigarette consumption, and alcohol consumption using multiple linear regression.Results Incidence rates of multiple myeloma were greater at higher latitudes (R(2) for latitude for males=0.31, p<0.0001; females R(2)=0.27, p<0.0001). In regression models for males (R(2)=0.62, p<0.0001) and females (R(2)=0.51, p<0.0001), UVB irradiance was independently inversely associated with incidence rates.Conclusions Age-adjusted incidence rates of multiple myeloma were higher in countries with lower solar UVB irradiance. Further investigation is warranted in individuals of the association of prediagnostic serum 25(OH)D with risk.

Could vitamin D sufficiency improve the survival of colorectal cancer patients?

PURPOSE: To determine whether a higher serum 25-hydroxyvitamin D [25(OH)D] concentration at diagnosis is associated with longer survival of colorectal cancer patients. METHODS: A meta-analysis was performed of studies of the relationship between 25(OH)D and mortality of patients with colorectal cancer. A random-effects model was used to calculate a pooled hazards ratio. Homogeneity was evaluated through a DerSimonian-Laird test. RESULTS: Higher serum concentrations of 25(OH)D were associated with lower mortality in patients with colorectal cancer. Patients in the highest quintile of 25(OH)D had 37% lower mortality from colorectal cancer compared to those in the lowest quintile of 25(OH)D (pooled odds ratio=0.63, p<0.0001). Dose-response curves showed lower hazard ratios for mortality with higher serum 25(OH)D through at least 40ng/ml. There were no exceptions. CONCLUSIONS: Higher serum 25(OH)D was associated with lower mortality of patients with colorectal cancer. These results suggest that colorectal cancer patients with deficient levels of serum 25(OH)D should have their levels restored to a normal range (30-80ng/ml). This could be done with regular testing of serum 25(OH)D to be confident that an adequate serum level is being maintained. Additional studies would be worthwhile to evaluate confounding or the possibility of reverse causation.

Meta-analysis of vitamin D sufficiency for improving survival of patients with breast cancer.

BACKGROUND/AIM: To determine whether higher serum 25-hydroxyvitamin D [25(OH)D] at diagnosis is associated with longer survival of patients with breast cancer. MATERIALS AND METHODS: A meta-analysis was performed of five studies of the relationship between 25(OH)D and mortality from breast cancer. A pooled hazard ratio was calculated using a random-effects model. The Der Simonian-Laird test was used to assess homogeneity. RESULTS: Higher serum concentrations of 25(OH)D were associated with lower case-fatality rates after diagnosis of breast cancer. Specifically, patients in the highest quintile of 25(OH)D had approximately half the death rate from breast cancer as those in the lowest. CONCLUSION: High serum 25(OH)D was associated with lower mortality from breast cancer. Serum 25(OH)D in all patients with breast cancer should be restored to the normal range (30-80 ng/ml), with appropriate monitoring. Clinical or field studies should be initiated to confirm that this association was not due to reverse causation.

25-Hydroxyvitamin D in the range of 20 to 100 ng/mL and incidence of kidney stones.

OBJECTIVES: Increasing 25-hydroxyvitamin D serum levels can prevent a wide range of diseases. There is a concern about increasing kidney stone risk with vitamin D supplementation. We used GrassrootsHealth data to examine the relationship between vitamin D status and kidney stone incidence. METHODS: The study included 2012 participants followed prospectively for a median of 19 months. Thirteen individuals self-reported kidney stones during the study period. Multivariate logistic regression was applied to assess the association between vitamin D status and kidney stones. RESULTS: We found no statistically significant association between serum 25-hydroxyvitamin D and kidney stones (P = .42). Body mass index was significantly associated with kidney stone risk (odds ratio = 3.5; 95% confidence interval = 1.1, 11.3). CONCLUSIONS: We concluded that a serum 25-hydroxyvitamin D level of 20 to 100 nanograms per milliliter has no significant association with kidney stone incidence.

Serum 25-hydroxyvitamin D and breast cancer in the military: a case-control study utilizing pre-diagnostic serum.

PURPOSE: The objective of this study was to ascertain whether a relationship exists between pre-diagnostic serum levels of 25-hydroxyvitamin D (25(OH)D) and risk of breast cancer in young women. METHODS: About 600 incident cases of breast cancer were matched to 600 controls as part of a nested case-control study that utilized pre-diagnostic sera. Logistic regression was used to assess the relationship between serum 25(OH)D concentration and breast cancer risk, controlling for race and age. RESULTS: According to the conditional logistic regression for all subjects, odds ratios for breast cancer by quintile of serum 25(OH)D from lowest to highest were 1.2, 1.0, 0.9, 1.1, and 1.0 (reference) (p trend = 0.72). After multivariate regression for subjects whose blood had been collected within 90 days preceding diagnosis, odds ratios for breast cancer by quintile of serum 25(OH)D from lowest to highest were 3.3, 1.9, 1.7, 2.6, and 1.0 (reference) (p trend = 0.09). CONCLUSIONS: An inverse association between serum 25(OH)D concentration and risk of breast cancer was not present in the principal analysis, although an inverse association was present in a small subgroup analysis of subjects whose blood had been collected within 90 days preceding diagnosis. Further prospective studies of 25(OH)D and breast cancer risk are needed.

What is the relationship between ultraviolet B and global incidence rates of colorectal cancer?

The purpose of this study is to examine the relationship between ultraviolet B and global incidence of colorectal cancer, while controlling for relevant covariates. Linear regression was used to assess the relationship between latitude and incidence rates of colon cancer in 173 countries. Multiple linear regression was employed to investigate the relationship between ultraviolet B dose and colorectal cancer rates while controlling for per capita intake of energy from animal sources, per capita health expenditure, pigmentation, and life expectancy. Data on all variables were available for 139 countries. Incidence of colon cancer was highest in countries distant from the equator (R(2) = 0.50, p < 0.0001). UV B dose (p < 0.0001) was independently, inversely associated with incidence rates of colorectal cancer after controlling for intake of energy from animal sources, per capita health expenditure, pigmentation, and life expectancy (R(2) for overall model = 0.76, p < 0.0001). Consistent with previous research, UVB was inversely associated with incidence of colon cancer. Further research on vitamin D and prevention of colon cancer in individuals should be conducted, including studies of higher serum 25-hydroxyvitamin D concentrations than have been studied to date.

Does the evidence for an inverse relationship between serum vitamin D status and breast cancer risk satisfy the Hill criteria?

A wide range of epidemiologic and laboratory studies combined provide compelling evidence of a protective role of vitamin D on risk of breast cancer. This review evaluates the scientific evidence for such a role in the context of the A.B. Hill criteria for causality, in order to assess the presence of a causal, inverse relationship, between vitamin D status and breast cancer risk. After evaluation of this evidence in the context of Hill's criteria, it was found that the criteria for a causal relationship were largely satisfied. Studies in human populations and the laboratory have consistently demonstrated that vitamin D plays an important role in the prevention of breast cancer. Vitamin D supplementation is an urgently needed, low cost, effective, and safe intervention strategy for breast cancer prevention that should be implemented without delay. In the meantime, randomized controlled trials of high doses of vitamin D(3) for prevention of breast cancer should be undertaken to provide the necessary evidence to guide national health policy.

Serum 25-hydroxyvitamin D and prevention of breast cancer: pooled analysis.

BACKGROUND: Low serum levels of 25-hydroxyvitamin D [25(OH)D] have been associated with a high risk of breast cancer. Since publication of the most current meta-analysis of 25(OH)D and breast cancer risk, two new nested case-control studies have emerged. MATERIALS AND METHODS: A PubMed search for all case-control studies on risk of breast cancer by 25(OH)D concentration identified 11 eligible studies. Data from all 11 studies were combined in order to calculate the pooled odds ratio of the highest vs. lowest quantile of 25(OH)D across all studies. RESULTS: The overall Peto odds ratio summarizing the estimated risk in the highest compared to the lowest quantile across all 11 studies was 0.61 (95% confidence interval 0.47, 0.80). CONCLUSION: This study supports the hypothesis that higher serum 25(OH)D levels reduce the risk of breast cancer. According to the review of observational studies, a serum 25(OH)D level of 47 ng/ml was associated with a 50% lower risk of breast cancer.

Ultraviolet B and incidence rates of leukemia worldwide.

BACKGROUND: Recent research has suggested a relationship between vitamin D deficiency and risk of leukemia. PURPOSE: Using data from the UN cancer database, GLOBOCAN, this study will determine whether a relationship exists for latitude and ultraviolet B (UVB) irradiance with incidence rates of leukemia in 175 countries. METHODS: Multiple regression was used to analyze the independent association between UVB and age-adjusted incidence rates of leukemia in 139 countries in 2002. This study controlled for dietary data on intake of energy from animal sources and per capita healthcare expenditures. The analyses were performed in 2009. RESULTS: People residing in the highest-latitude countries had the highest rates of leukemia in both men (R(2)=0.34, p<0.0001) and women (R(2)=0.24, p<0.0001). In men, UVB was independently inversely associated with leukemia incidence rates (p≤0.001), whereas animal energy consumption (p=0.02) and per capita healthcare expenditures (p≤0.0001) were independently positively associated (R(2) for model=0.61, p≤0.0001). In women, UVB adjusted for cloud cover was independently inversely associated with leukemia incidence rates (p≤0.01), whereas animal energy consumption (p≤0.05) and per capita healthcare expenditures (p=0.0002) were independently positively associated (R(2) for model=0.51, p<0.0001). CONCLUSIONS: Countries with low UVB had higher age-adjusted incidence rates of leukemia. This suggests the possibility that low serum 25-hydroxyvitamin D status, because of lower levels of UVB, somehow might predict the development of leukemia.

High serum 25-hydroxyvitamin D is associated with a low incidence of stress fractures.

Low serum 25-hydroxyvitamin D [25(OH)D] concentrations are associated with hip fractures, but the dose-response relationship of serum 25(OH)D with risk of stress fractures in young women is unknown. This nested case-control study in a cohort of female Navy recruits was designed to determine whether those with low prediagnostic serum 25(OH)D concentrations had greater risk of stress fracture. Sera were drawn in 2002-2009 from 600 women who were diagnosed subsequently with stress fracture of the tibia or fibula and 600 matched controls who did not experience a stress fracture. The 25(OH)D concentration was measured using the DiaSorin radioimmunoassay method. Controls were individually matched to cases on race (white, black, or other), length of service (±30 days), and day blood was drawn (±2 days). There was approximately half the risk of stress fracture in the top compared with the bottom quintile of serum 25(OH)D concentration (odds ratio [OR] = 0.51, 95% CI 0.34-0.76, p ≤ 0.01). The range of serum 25(OH)D in the lowest quintile was 1.5 to 19.7 (mean 13.9) ng/mL, whereas in the highest it was 39.9 to 112 (mean 49.7) ng/mL. It is concluded that there was a monotonic inverse dose-response gradient between serum 25(OH)D and risk of stress fracture. There was double the risk of stress fractures of the tibia and fibula in women with serum 25(OH)D concentrations of less than 20 ng/mL compared to those with concentrations of 40 ng/mL or greater. A target for prevention of stress fractures would be a serum 25(OH)D concentration of 40 ng/mL or greater, achievable with 4000 IU/d of vitamin D(3) supplementation.