Study of the Association Between Serum Vitamin D Levels and Prostate Cancer

MILITARY MEDICINE, 182, 5/6:e1769, 2017 Study of the Association Between Serum Vitamin D Levels and Prostate Cancer Marcus Stanaland, PharmD, MSCR, MBA; Michael R. Jiroutek, DrPH, MS; Melissa A. Holland, PharmD, MSCR ABSTRACT Introduction: Vitamin D has been suggested as a marker for prostate cancer risk, but prior study results are conflicting. This study evaluated the association of prostate cancer diagnosis with vitamin D levels as well as with each of the following variables of interest: age, race group, military service, smoking status, and alcohol use. Methods: A total of 11,547 adult males aged 18 or older who participated in the National Health and Nutrition Examination Survey for years 2001 2010 were included in this retrospective, cross-sectional, observational study. National Health and Nutrition Examination Survey is an annual, nationally representative sample of noninstitutionalized civilian adult and child residents of the United States. Active duty military are excluded from the survey. Subjects were excluded if they answered don t know or refused to vitamin D or prostate cancer survey questions. χ 2 analyses were performed to analyze associations between diagnosis of prostate cancer and variables of interest. The military service variable was developed on the basis of the response to survey question Did you ever serve in the Armed Forces of the United States? A multivariable logistic regression model included all the variables of interest that were available in the database. All analyses were appropriately weighted for extrapolation to average annual population-based estimates for the years included in the study. Results: Two percent had a diagnosis of prostate cancer, whereas 72% had less than 75 nmol/l of vitamin D. Unadjusted χ 2 test results suggested those with a vitamin D level of <75 nmol/l, <65 years of age and consuming at least one alcoholic drink per day were significantly less likely to be diagnosed with prostate cancer although smokers and those with military service were significantly more likely to be diagnosed with prostate cancer. However, after adjusting for covariates included in the multivariable logistic regression model, only the following covariates remained significant: men <65 years old were less likely to be diagnosed with prostate cancer (odds ratio [OR] = 0.07, 95% confidence interval [CI] = 0.04 0.12), although those with military service and non-hispanic blacks were more likely to be diagnosed with prostate cancer (OR = 1.66, 95% CI = 1.09 2.53 and OR 1.73, 95% CI 1.28 2.33, respectively). No other factors in the model, including vitamin D level, retained significance. Conclusion: Among the documented risk factors for prostate cancer from the available data, age, military service, and race group were significantly associated with prostate cancer diagnosis. Further study on a larger cohort with prostate cancer is needed to better assess for associations. INTRODUCTION Vitamin D deficiency is common and low serum levels have been associated with various skeletal and nonskeletal effects. Recently, more interest has been placed on the nonskeletal effects. The consequences are not fully understood, but vitamin D deficiency has been linked to muscle disorders, altered immunity, diabetes mellitus, and increased risk of cancer. 1 An issue many practitioners face is difficulty evaluating serum vitamin D levels as a result of inconsistencies in population reference ranges. Variations exist because of different ethnic backgrounds and geographical locations. Furthermore, seasonal variations can also affect the ability to establish optimal serum levels. Most populations will have higher levels in the summer months when temperature and sunlight exposure are increased compared to colder months. The optimal level of 25-hydroxyvitamin D is controversial, ranging from 62.5 nmol/l (25 ng/ml) to Campbell University College of Pharmacy & Health Sciences, 180 Main Street, PO Box 1090, Buies Creek, NC 27506. The authors have no disclosures concerning possible financial or personal relationships with commercial entities that may have a direct or indirect interest in the subject matter of this manuscript. doi: 10.7205/MILMED-D-16-00331 200 nmol/l (80 ng/ml); however, research suggests that insufficiency begins at <75 nmol/l (30 ng/ml). 1 Epidemiology studies 2 5 have illustrated that vitamin D levels below 75 nmol/l (30 ng/ml) may be associated with prostate cancer risk. Prostate cancer is the most common cancer in men, and among all race groups and men of Hispanic origin, it is one of the leading causes of death. 6 Black men appear to have the highest risk of prostate cancer, followed by Hispanics, Asian/Pacific Islanders, and Native Americans. In 2012, a total of 177,489 men were diagnosed with prostate cancer in the United States, and 27,244 men died from the disease. 6 The exact epidemiology of prostate cancer is unclear. However, identified risk factors include: age, family history, and race. Studies 2 report vitamin D as a marker for risk, but results are conflicting. The link between vitamin D levels and prostate cancer involves vitamin D receptors, which are present in both cancerous and noncancerous prostate cells. 7,8 vitamin D receptors are responsible for the antiproliferative action of 1,25 dihydroxyvitamin D3. 2,7 These receptors are involved with induction of apoptosis, cell-line differentiation, prevention of tumor cell invasiveness, inhibition of telomerase expression, and suppression of tumor-induced angiogenesis. 7 e1769

There is much debate regarding the true benefits of achieving adequate vitamin D levels through both supplementation and sunlight intake. Although not fully understood, vitamin D deficiency may increase the risk of chronic disease such as cancer. 1 Prostate cancer risk begins around the age of 40, and nearly 75% of men above age 80 will show signs of latent disease. This age group is commonly known to have insufficient vitamin D levels. To reduce risk of disease, this age group must establish preventative measures. Research suggests that incidence of prostate cancer can be reduced through improved diet and nutrient supplements. Specifically, less high calorie foods, less calcium, and increased vitamin D (or increased sun exposure) have all been linked to prostate cancer prevention. 9 This study evaluated prostate cancer and vitamin D levels as well as other less commonly studied predictors of prostate cancer such as alcohol intake and military service. This study is one of few, if any, which has utilized the National Health and Nutrition Examination Survey (NHANES), a large, nationally representative U.S. database, to evaluate the relationship between prostate cancer and vitamin D levels. METHODS This retrospective, cross-sectional, observational study analyzed data from NHANES years 2001 2010. NHANES is an annual, nationally representative sample of noninstitutionalized civilian adults and child residents of the United States. Active duty military are excluded from the survey. NHANES is a unique combination of interviews and physical examinations that is conducted by the Centers for Disease Control and Prevention, National Center for Health Statistics. 10 Five NHANES data releases covering 10 years, 2001 2010, (the most recent vitamin D data available at the time of the analysis) were included in this study. Males 18 years of age or older who participated in the NHANES years studied (2001 2010) and responded to the survey question Have you ever been told by a doctor or other health profession that you had cancer or malignancy of any kind? (MCQ220) were included in the final analysis dataset, although subjects who answered either MCQ220 or MCQ230A-D ( What kind of cancer? ) as don t know or refused, or subjects missing vitamin D data (LBDVIDMS, LBXVIDMS) were excluded. Across all 10 years included in this study, a total of 11,547 raw records met the inclusion/exclusion criteria. 10 The dependent variable of interest was prostate cancer diagnosis, where the denominator is the number of cases meeting the inclusion/exclusion criteria. A prostate cancer diagnosis was defined by a prostate response to any of the survey questions MCQ230A-D. 10 Rao-Scott χ 2 tests of association were used to analyze whether any association exists between prostate cancer diagnosis and vitamin D level (<75 nmol/l, 75 nmol/l) as well as prostate cancer diagnosis and each of the following variables: age, race group, military service, smoking status, and alcohol use. The military service variable was developed on the basis of the response to survey question Did you ever serve in the Armed Forces of the United States? (DMQMILIT). 10 These variables were grouped for analysis as shown in Table I. p Values, odds ratios (ORs), and corresponding 95% confidence intervals (CIs) were reported. Additionally, a multivariable logistic regression model was constructed to evaluate the predictive value of all the independent variables of interest simultaneously on diagnosis of prostate cancer. ORs and corresponding 95% CIs for each level of each variable included in the model (in comparison to each variable s reference group) were reported. All analyses were generated using SAS software, version 9.3 (SAS Institute Inc., Cary, North Carolina). The SURVEYFREQ and SURVEYLOGISTIC procedures were utilized. Because of the manner in which this survey is designed, proper statistical analysis allows for the generation of national annual estimates of those meeting the study inclusion and exclusion criteria developed on the basis of the study sample. All of the presented results are developed on basis of the national annual estimate numbers extrapolated from the study sample, following best practices as recommended by the National Center for Health Statistics. As this was a retrospective, hypothesis generating-type study, no adjustments for multiple comparisons were made. p values <0.05 were considered statistically significant. TABLE I. Demographic and Clinical Characteristics of Men 18 in the NHANES survey, 2001 2010 (N = 11,547) a Characteristic b No. (%) of Subjects c Age (Years) Mean ± Standard Error 45.9 ± 0.27 <65 75,629,316 (85) 65 13,557,586 (15) Race Non-Hispanic Black 8,672,357 (12) Non-Hispanic White 64,078,651 (88) Smoking Status Smoker 49,252,884 (55) Nonsmoker 39,934,017 (45) Alcohol Use (Drinks/Day) 1 64,360,561 (82) 0 13,766,218 (18) Military Service Yes 21,974,081 (25) No 67,186,037 (75) Vitamin D (nmol/l) Mean ±SE 63.5 ± 0.58 <75 64,112,986 (72) 75 25,073,915 (28) Prostate Cancer Yes 1,576,668 (2) No 87,583,451 (98) a Unweighted, raw sample size meeting inclusion/exclusion criteria from NHANES database, 2001 2010. b Reference groups are listed last for each variable. c Analyses appropriately weighted and clustered to reflect average annualized national estimates for those meeting the inclusion/ exclusion criteria. e1770

RESULTS A total raw sample size of 52,195 participated in NHANES from 2001 to 2010, 11,547 of which met the inclusion/ exclusion criteria. The complex survey design was accounted for in all of the following results in order to extrapolate the results developed on the basis of the study sample to average annual national estimates. A majority of the subjects were age <65 (85%), and in the non-hispanic white race group (88%). Furthermore, smokers and nonmilitary service men represented the majority of subjects, 55% and 75%, respectively. The majority of subjects consumed at least one alcoholic drink per day (82%). The mean (± SE) serum vitamin D level was 63.5 nmol/l ± 0.58. This information is summarized in Table I. The individual tests of association (Table II) suggested a significant association between all but one of the factors of interest studied (race group) and prostate cancer diagnosis. The percentage of subjects with prostate cancer with vitamin D levels <75 nmol/l (1.6%) was significantly less than subjects with vitamin D levels 75 nmol/l (2.2%) (0.74; 95% CI = 0.58 0.93, p = 0.0103). In addition, the following variables were statistically significantly associated with prostate cancer diagnosis: age (OR = 0.05; 95% CI = 0.03 0.07, p < 0.0001), military service (OR = 5.76; 95% CI = 4.41 7.52, p < 0.0001), smoking status (OR = 1.31; 95% CI = 1.03 1.68, p = 0.0256), and alcohol use (OR = 0.47; 95% CI = 0.35 0.61, p < 0.0001). In the weighted multivariable logistic regression model (Table III), after adjusting for covariates of interest, age and military service retained significance although race group gained statistical significance as a predictor of prostate cancer diagnosis. Adjusted for the covariates included in the model, men aged <65 years old were 93% less likely to be diagnosed with prostate cancer compared to men aged 65 or older (adjusted OR = 0.07; 95% CI = 0.04 0.12). Men with a military service were 66% more likely to be diagnosed with prostate cancer compared to men with no such history (adjusted OR = 1.66; 95% CI = 1.09 2.53), although non-hispanic black men were 73% more likely to be diagnosed with prostate cancer compared to non-hispanic white men (adjusted OR = 1.73; 95% CI = 1.28 2.33). Vitamin D level, smoking status, and alcohol use lost significance after adjusting for covariates of interest in the model. DISCUSSION The results of this study were similar to results from previous epidemiology studies, 2 4,11 14 unable to conclusively determine an association between serum vitamin D and risk of prostate cancer. Although nonsignificant, this study showed a trend toward men with vitamin D levels <75nmol/L as less likely to be diagnosed with prostate cancer. It is worth noting that NHANES lacked data regarding hormonal therapy often used in the treatment of prostate cancer. Calcium and vitamin D supplementation in patients undergoing androgen depravation therapy is recommended in order to preserve bone mineral density, 15 and this could be confounding the lack of association found. For example, The Prostate Cancer Research Institute supports dietary supplementation with 1,200 to 1,500 mg of calcium and 2,000 IU of vitamin D, for patients with prostate cancer. Similar recommendations have been made by the Bone and Cancer Foundation. It is important to note this potential confounding factor that was unable to be controlled for in this analysis. It may explain higher serum vitamin D levels observed in cases TABLE II. Individual χ 2 Results for Predictors of Prostate Cancer for Men 18 in the NHANES, 2001 2010 a Variable Prostate Cancer N (%) b OR (95% CI) P Value Vitamin D (nmol/l) 0.0103 <75 1,031,147 (1.6) 0.74 (0.58 0.93) 75 545,520 (2.2) Reference Age <0.0001 <65 342,416 (0.5) 0.05 (0.03 0.07) 65 1,234,252 (9.1) Reference Race 0.2080 Non-Hispanic Black 198,591 (2.3) 1.16 (0.92 1.47) Non-Hispanic White 1,269,263 (2.0) Reference Smoking Status 0.0256 Smoker 973,339 (2.0) 1.31 (1.03 1.68) Nonsmoker 603,329 (1.5) Reference Alcohol Use (Drinks/Day) <0.0001 1 966,417 (1.5) 0.47 (0.35 0.61) 0 436,069 (3.2) Reference Military Service <0.0001 Yes 1,016,145 (4.6) 5.76 (4.41 7.52) No 560,523 (0.8) Reference a Analyses appropriately weighted and clustered to reflect average annualized national estimates for those meeting the inclusion/exclusion criteria. b Percent in each stratum of variable. Only the number (percent) for those with prostate cancer are presented from which the number and percent of those with no prostate cancer can be determined. e1771

TABLE III. Multivariable Logistic Regression Model of Prostate Cancer for Men 18 in the NHANES, 2001 2010 a Adjusted OR (95% Wald Variable b Confidence Limits) Vitamin D (<75 nmol/l vs. 75 nmol/l) 0.81 (0.64, 1.04) Age (<65 vs. 65) 0.07 (0.04, 0.12) Military Service (Yes vs. No) 1.66 (1.09, 2.53) Smoking Status 0.90 (0.65, 1.24) (Smoker vs. Nonsmoker) Alcohol Use 0.92 (0.68, 1.26) ( 1 vs. 0 Drinks/Day) Race (Non-Hispanic Black vs. 1.73 (1.28, 2.33) Non-Hispanic White) a Analyses appropriately weighted and clustered to reflect average annualized national estimates for those meeting the inclusion/exclusion criteria. b The reference group is listed last in each row. of prostate cancer, as well as a lack of association between serum vitamin D levels and diagnosis of prostate cancer. 15 Nomura et al 11 studied a cohort of Japanese-American men in Hawaii between 1967 and 1970 to assess the relationship between serum vitamin D levels and prostate cancer risk using 136 blood specimens with confirmed cases of disease. The results suggested a lack of evidence for the association. 11 A study by Ahn et al 12 investigated the same association using participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial where 749 patients with an incidence of prostate cancer, diagnosed within 8 years of a blood draw, were matched with controls. The results showed no overall statistical significance between prostate cancer risk and season-standardized serum vitamin D levels. However, serum levels greater than the lowest vitamin D quartile (12.8 to 42.5 nmol/l) were associated with an increased risk of aggressive prostate cancer. 12 A similar study, by Platz et al 13 examined serum vitamin D divided into quartiles for patients with a risk of prostate cancer. The OR for the lowest quartile compared to the highest quartile was not statistically significant. 13 Ahonen et al 3 conducted a nested case control study within a cohort of men who were participating in the Helsinki Heart Study. Results showed lower levels of vitamin D were associated with an increased risk of prostate cancer and associated with age at diagnosis. Li et al 4 found an increased risk of aggressive prostate cancer in men with low levels of vitamin D and 1,25 dihydroxyvitamin D3. However, Tuohimaa et al 2 discovered conflicting findings in a nested case control study of Nordic men participating in the Helskinki Heart Study in Finland and the Northern Sweden Health and Disease Cohort. Both low and high concentrations of 25-hydroxyvitamin D were associated with risk of prostate cancer. Authors attributed this to the use of the normal average concentration group as the referent. 2 To date, most studies have been performed in areas of higher latitude where naturally occurring vitamin D levels are suboptimal, such as Finland and Sweden. In these areas of the world, there appears to be an association between vitamin D status and incidence of prostate cancer. 9 Another consideration is the pharmacokinetics of serum vitamin D. Serum vitamin D has a short half-life in the blood, therefore most studies evaluating the relationship between vitamin D and prostate cancer should be evaluated with caution measured levels may not accurately reflect risk of disease. 9 It is worth noting the mean (±SE) vitamin D level of 63.5 nmol/l ± 0.58, which suggests insufficiency for the entire study population. This is consistent with prior NHANES studies which also found a higher prevalence of vitamin D deficiencies. Forest and Stuhldreher found vitamin D deficiency (<50 nmol/l) in 41.6% of the 2005 2006 NHANES population. 16 Yetley found over 70% of 2000 2004 NHANES population to be vitamin D deficient (<80 nmol/l). 17 The overall mean vitamin D level has decreased over the years per NHANES data, from 75 to 60nmol/Lbetween1998and2004and60to50nmol/L between 2004 and 2006. 17 19 Contributing factors to this decrease include less milk intake, increased body mass index, and the use of sun protection. 18 A study by Dennis et al 20 evaluated U.S. military personnel and risk of prostate cancer with regard to sexually transmitted infections. The authors reasoning behind the study involved increased prostate-specific antigen screening among military men. As a result of increased emphasis on screening in this population, prostate cancer is less likely to go undiagnosed. 20 The Prostate Prevention Trial, which started in 1993, showed high rates of prostate cancer among U.S. military personnel. 21 Consistent results were found in this study even after adjusting for the other factors of interest for which data were available. One hypothesis regarding this finding involves men who served in the Vietnam War and were exposed to the carcinogenic herbicide known as Agent Orange. The exact number of veterans exposed to the herbicide is unknown; however, over 3 million U.S. military personnel served in the war and are now of sufficiently advanced age where prostate cancer would be expected to manifest. 22 Vitamin D deficiency in veterans has also been found to be associated with decreased survival in veterans with prostate cancer. 23 The results of this study did not find an association with alcohol intake and prostate cancer after adjusting for factors of interest. However, because of the small number of participants with prostate cancer in the database, a suboptimally informative grouping of alcohol intake was required (0 vs. 1 drinks/day) to allow the variable to be included in the analysis at all. There are very few studies evaluating the association of alcohol intake and prostate cancer. Prior studies have hypothesized that alcohol may affect testosterone levels in the body. Alcohol use is known to decrease the plasma concentration, production rate, and metabolic clearance of testosterone. 24 Gordon et al 24 studied this association in 1976 and found men who consumed alcohol during the 4-week study period had significantly different testosterone levels compared to those who did not, which was e1772

caused by decreased hepatic clearance and the plasma binding capacity of the androgen. 24 This study confirmed the widely known results that a highly significant association remains evident between age and the diagnosis of prostate cancer, even after adjusting for covariates of interest. Currently, the incidence of prostate cancer is approximately 1 in 55 for men aged 40 to 60 years of age. The incidence rate is 1 in 7 for men aged 60 to 80 years. It has been hypothesized that prostate cancer risk is higher in older populations because there was most likely less emphasis on screening at an earlier age. 9 However, screening was not able to be assessed in this study because of limitations in the data collected in NHANES. In addition to age and military service, the multivariable analysis revealed that race group was a predictor of prostate cancer diagnosis. This result is consistent with previous findings of a 70% higher incidence rate of prostate cancer in older African-American men, compared to white men. 25 Ross et al 25 studied the association by evaluating the role of androgens in the pathogenesis of prostate cancer adenocarcinomas. The study reported that mean testosterone levels were 15% higher in African-American males compared to white males and the amount of bioavailable, or unbound testosterone, was 13% higher. 25 The authors concluded that differences in the hypothalamic-pituitarytesticular feedback system between the two groups may explain the discrepancy in circulating hormone levels which in turn may have explained the difference in prostate cancer incidence rate. 25 A study by Brawn et al 26 found that, among those with prostate carcinoma, 26% of white males and 52% of black males presented with late stage, or stage D disease, which led to an overall poorer survival rate in the black race group. Collectively, the authors involved with these two studies observed that African-American men present with prostate adenocarcinomas at an earlier age, with a higher initial diagnosis stage, and with a higher tumor grade, thus higher mortality rates compared to white males. 27 Unfortunately, this study was unable to evaluate tumor burden and disease stage as a result of limitations in the survey data collected for NHANES. Among the variables investigated, the significant univariate findings for vitamin D, smoking status and alcohol use disappeared in the multivariable model after adjusting for the covariates of interest. The inconsistent results in the literature across studies and populations in regard to these variables and their association with prostate cancer are reflected in their loss of significance in the model. In spite of any relationship between the factors considered, the model demonstrated only the robustness of the association between age group, military service, and race group with prostate cancer diagnosis. This study is the first to evaluate serum vitamin D levels and the diagnosis of prostate cancer using NHANES. No NHANES studies were found investigating military service or alcohol intake as predictors of prostate cancer. However, the study is not without limitations. Because of the crosssectional design, only associative relationships, not causality, can be determined. Larger longitudinal studies would aid in determining causality. Despite including five surveys of NHANES data covering ten years time (the only years with vitamin D level data available), the extrapolated national estimates are developed on the basis of a total of 347 cases of prostate cancer. These extrapolations, although remaining valid and informative, can be expected to be more variable than extrapolations drawn on the basis of larger numbers of subjects, yielding wider CIs, and so on. Lastly, as noted previously in the discussion, NHANES lacked data regarding hormonal therapy for prostate cancer, of which calcium and vitamin D supplementation is recommended. 15 This study did have several strengths. This is one of very few studies performed on the basis of national surveys of the U.S. population examining the association of prostate cancer and vitamin D levels. In addition, this study utilized sample weights to account for the complex survey design, allowing for extrapolation to average annualized national estimates for those meeting the study inclusion/exclusion criteria. Furthermore, very few studies have been published examining the relationship between covariates such as alcohol use and military service with prostate cancer. CONCLUSION There does not appear to be a significant association between serum vitamin D levels and diagnosis of prostate cancer in the data analyzed after adjusting for factors of interest. However, non-hispanic black men and/or men who have served in the military may be at an increased likelihood of being diagnosed with prostate cancer, although men aged <65 years old remain significantly less likely to be diagnosed with prostate cancer. All the variables included in this analysis, as well as those mentioned for which there was no data available, merit further evaluation to more definitively establish an association with prostate cancer diagnosis. REFERENCES 1. Kennel K, Drake M, Hurley D: Vitamin D deficiency in adults: when to test and how to treat. Mayo Clin Proc 2010; 85(8):752 58. 2. 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