Abstract
Objective:
To evaluate vitamin D supplementation for preventing or treating overactive bladder (OAB) and urinary incontinence (UI) in men.
Methods:
Ancillary study of men aged ≥55 years in the VITamin D and OmegA-3 TriaL (VITAL). Randomized treatments included: vitamin D3 (cholecalciferol), marine omega-3 fatty acids, or matching placebo. Structured UI questions measured the prevalence of OAB at year 5, and UI at years 2 and 5, along with incidence and progression of UI from years 2 to 5. Pre-specified subgroup analyses examined men with low baseline serum vitamin D [25(OH)D<20 ng/mL].
Results:
Among the 11,486 men who provided data at year 2 and 10,474 at year 5, mean age was 68 years at Year 2, with 23% racial/ethnic minorities. In primary analyses, vitamin D supplementation compared to placebo did not lower odds of OAB at year 5 (OR 0.97, 95% CI 0.87–1.08), or weekly UI at year 2 (OR 0.94, 95% CI 0.83–1.05) or year 5 (OR 0.98, 95% CI 0.88–1.09). We found interactions of baseline serum 25(OH)D level with vitamin D supplementation for OAB (p-interaction=0.001), and secondarily, for any UI at year 2 (p-interaction=0.05). Men with baseline 25(OH)D <20 ng/mL, who were assigned to vitamin D supplements, had lower odds of OAB (OR 0.51, 0.35–0.76) compared to placebo, yet higher odds of any UI (OR 1.24, 0.93–1.64).
Conclusions:
Overall, vitamin D supplementation did not improve OAB, or UI, compared to placebo. However, specific use of vitamin D in men with lower 25(OH)D levels had inconsistent findings.
Keywords: overactive bladder, urinary incontinence, men, epidemiology, longitudinal, vitamin D, lower urinary tract symptoms
INTRODUCTION:
Lower urinary tract symptoms (LUTS) of urgency, frequent urination, urinary incontinence (UI), and/or nocturia, whether experienced singularly or as a syndrome called overactive bladder (OAB), are common, distressing symptoms that impact the lives of millions of men.1–3 Epidemiological studies indicate that these symptoms affect between 12% and 18% of community-dwelling men, and increase in prevalence with age.2,3,4
Initial UI and OAB therapy in men includes noninvasive behavioral interventions and/or medications depending on patient goals and preferences. For specific OAB symptoms, such as urgency with or without UI, frequency, and nocturia, pharmacologic treatments are often initiated. Recent data suggest that pharmacologic treatments, such as anticholinergic bladder relaxant medications, are often discontinued due to adverse side effects or perceived inefficacy,4 and there is growing concern regarding the potential for unfavorable effects on cognition over time.5 Thus, there is a clear need to develop new approaches to improve prevention and early treatment for UI and OAB in men.
Vitamin D supplementation could be a simple intervention with the potential to reduce LUTS, specifically storage symptoms related to OAB. The vitamin D receptor is present in the bladder detrusor muscle and prostate,6,7 and vitamin D administration may improve smooth and skeletal muscle function and reduce prostate size.8,9 Vitamin D may be important for adequate bladder control through direct effects on improving detrusor smooth muscle function and decreasing the sensation of urgency.
Nonetheless, epidemiologic data on the association between vitamin D status and LUTS are inconsistent. Some prior observational cohort studies have reported that higher circulating serum concentrations of 25-hydroxyvitamin D (25[OH]D) are associated with lower prevalent and incident OAB and UI.10–12 A recent systematic review and meta-analysis of observational studies and clinical trials reported that vitamin D supplementation showed “promising effects” on LUTS and UI.13 The evidence supports a higher strength of the association of vitamin D with improved UI symptoms in women. Specifically in men aged 50 and older with enlarged prostates, one randomized clinical trial (n=119) of a vitamin D analog compared to placebo reduced urinary flow rates after twelve weeks.14 However, a composite measure of LUTS did not improve in the vitamin D analog treatment group compared to placebo. Very few clinical trials exist to guide recommendations about vitamin D supplementation for OAB and UI in men.
To address this gap, we conducted an ancillary study of OAB and UI, among men and women enrolled in a nationwide vitamin D and omega-3 prevention trial for cancer and cardiovascular disease, the VITamin D and omegA-3 TriaL (VITAL). Results in women did not show improvements in the prevalence, incidence, or progression of UI symptoms after 5 years of vitamin D supplementation compared to placebo.15 The primary objective of the current study was to evaluate the effects of vitamin D supplementation on OAB at trial close (year 5), including prevalent UI at year 2 and year 5, and incident UI and progression of UI from year 2 to year 5. We also included pre-specified, sub-group analyses of men with low serum vitamin D levels. We hypothesized that men assigned to vitamin D supplementation would have lower OAB and UI prevalence and decreased incidence/progression compared to men assigned to placebo, especially in those with lower serum levels of vitamin D.
METHODS:
Study Design
The VITamin D and omegA-3 TriaL (VITAL) clinical trial16 was a randomized, double-blind, placebo-controlled trial of vitamin D3 and marine omega-3 fatty acids for the primary prevention of cancer and cardiovascular disease (N=25,871).16 Nationwide recruitment and consent was conducted through a single site (Brigham and Women’s Hospital Division of Preventive Medicine, Boston, Massachusetts) and enrolled participants representing all 50 US states. Recruitment occurred primarily through mail and telephone contacts, interventions were dispensed through the mail, and most outcomes ascertained via questionnaires. Pre-randomization blood samples were collected by the parent trial for approximately two-thirds of the participants. This report focuses on data from Year 2 and Year 5 of the trial, in which measures of UI and OAB symptoms were incorporated into questionnaires. OAB symptoms were only queried on the final questionnaire at Year 5.
Study Population
The parent trial enrolled men aged 50 and older and women aged 55 and older, without clinically apparent cardiovascular disease or cancer.16 For this analysis, men (n=12,786) enrolled at baseline were eligible and men with a diagnosis of multiple sclerosis or Parkinson’s disease at baseline were excluded (n=120), leaving 12,666 men eligible. Of these, 11,486 men responded to UI questions at year 2 (Figure 1), with 5,747 men receiving vitamin D and 5,739 receiving placebo. At the final questionnaire, 5,256 men who received vitamin D and 5,218 who received placebo responded to UI and OAB questions. Thus, 11,486 men at year 2 and 10,474 men at year 5 were included in analyses.
Figure 1.
Randomization and Follow-up of the Men in VITAL for the Ancillary Study of Lower Urinary Tract Symptoms
Interventions
As per the parent trial, participants were randomly assigned to 1 of 4 treatment groups in a 2×2 factorial design: (1) vitamin D plus omega-3 fatty acids; (2) vitamin D plus placebo; (3) omega-3 fatty acids plus placebo; and (4) two placebos.16 Vitamin D3 (cholecalciferol, 2000IU) and matching placebo were provided by Pharmavite LLC. Omega-3 fatty acids (fish oil, 1gm capsules) and matching placebo were provided by Pronova BioPharma and BASF. All participants were asked to limit vitamin D intake to 800 IU from all supplemental sources combined and to avoid using fish oil supplements. Randomization occurred from November 2011 through March 2014. Assignments were computer generated in blocks and stratified by age, sex, and race. Treatment assignments were concealed to participants and investigators. The trial intervention ended on December 31, 2017, for a median of 5.3 years of follow up (range 3.8 to 6.1 years). At baseline, serum 25(OH)D concentrations were measured by liquid chromatography-tandem mass spectrometry. Serum 25(OH)D level <20 ng/mL was defined as low 25(OH)D.17
Overactive Bladder and Urinary Incontinence Outcomes
The primary pre-specified outcomes of this ancillary study were the prevalence of OAB at year 5 and at least weekly UI at year 2 and at year 5, including subgroup analyses of men with low 25(OH)D pre-randomization. OAB symptoms of urgency, frequency, and nocturia were queried at year 5 using validated, self-reported questionnaires.18 We defined OAB as urgency occurring “frequently/all of the time;” frequency as “every 2 hours/hourly;” and, nocturia as voiding “3 or more times” at night. We defined OAB, as well as OAB wet with UI occurring at least monthly and OAB dry without UI.
Ancillary structured measures of UI were added to Year 2 and Year 5, including UI frequency and type, assessed through a self-reported questionnaire using the following questions, “During the past 3 months, how often have you typically leaked urine, even a small amount?”19 Response choices were never, less than monthly, monthly, weekly, and daily. We defined ‘any UI’ as occurring at any frequency level and ‘weekly UI’ as occurring at least weekly or daily. UI type was ascertained from all men reporting UI. UI classifications were based on the participants’ reports of their dominant symptoms. Urine loss with “the urge to urinate and can’t get to the toilet fast enough” was defined as ‘urgency UI’ or UUI; UUI was a primary, pre-specified outcome. We defined ‘stress UI’ or SUI as report of leakage primarily occurring with “cough, sneeze, laugh, lift, stand up, or exercise, etc.” Men who reported symptoms that occur with “sleeping, napping, or dozing” were classified as ‘sleep/other.’ Stress and sleep/other UI were secondary outcomes.
Secondary outcomes evaluated UI incidence and UI progression from year 2 to year 5. Incident UI at year 5 was calculated as any frequency of weekly UI reported among men who did not report UI at year 2. UI progression was defined as any progression from less than weekly to at least weekly UI frequency from year 2 to year 5 among men who had UI less than weekly at year 2.
Factors Analyzed by Randomization Group
Other participant characteristics included in analyses included demographics, comorbidities including hypertension, depression and diabetes, caffeine and alcohol intake, outside vitamin D supplementation, prostate hyperplasia, diuretic medication usage, weight and height, which were ascertained by self-report.16 Race and ethnicity were self-reported. Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared.
Data Analysis
For the primary analyses and similar to the parent trial, men were analyzed according to their randomization to vitamin D supplementation or placebo, regardless of treatment with omega-3 fatty acid supplementation, or adherence (full analytic population) using the intention-to-treat principle.16 Baseline characteristics of men were compared by treatment assignment with t-tests or chi-square tests. Primary analyses compared OAB at 5-years in the treatment versus placebo groups, including any UI and weekly UI prevalence at 2-years and 5-years, using logistic regression adjusted for age and the omega-3 intervention group, and secondary analyses compared weekly UI incidence and progression from 2-years to 5-years, using logistic regression. Subgroup analysis was restricted to men with measures of serum 25(OH)D. We compared treatment outcomes between men with lower and higher 25(OH)D for potential interactions across subgroups.
RESULTS:
Participant Characteristics
Table 1 shows Year 2 characteristics in the treatment and placebo groups. The mean age was 68 years in both groups, and 13% of men were African American. Only 7% of men currently smoked cigarettes in the treatment and placebo groups, and mean BMI was identical as well (mean=28 kg/m2 in the vitamin D group and the placebo group). Approximately 15% of men in both groups had type 2 diabetes and 9% reported having prostate enlargement. Overall, all observed characteristics of the men were balanced between the two groups (Table 1).
Table 1.
Demographic, Behavioral, Lifestyle, and Medical Characteristics at Year 2 for Men Randomized to 25-Hydroxyvitamin D Supplementation and Placebo and Providing Data on Urinary Symptoms at Year 2
| Variable Categories | Vitamin D (n=5747) N(%) unless otherwise stated* |
Placebo (n=5739) N(%) unless otherwise stated* |
P value |
|---|---|---|---|
| Sociodemographic | |||
| Age (mean, SD) | 68 (7) | 68 (7) | 0.641 |
| Age Categories | 0.600 | ||
| 50–54 years |
189 (3%) | 180 (3%) | |
| 55–64 years | 1565 (27%) | 1528 (27%) | |
| 65–74 years | 3093 (54%) | 3144 (55%) | |
| ≥75 years | 900 (16%) | 887 (16%) | |
| Race/ethnicity | 0.836 | ||
| Non-Hispanic White | 4334 (77%) | 4304 (76%) | |
| African-American | 757 (13%) | 782 (14%) | |
| Hispanic (not African American) | 295 (5%) | 282 (5%) | |
| Asian/Pacific Islander | 107 (2%) | 104 (2%) | |
| American Indian/Alaska Native | 54 (1%) | 43 (1%) | |
| Other/Unknown | 111 (2%) | 115 (2%) | |
| Education Attainment (Highest Level) | 0.137 | ||
| Did not complete high school | 64 (1%) | 42 (1%) | |
| High school diploma or GED | 482 (8%) | 510 (9%) | |
| Attended or graduated from college | 2139 (37%) | 2113 (37%) | |
| Post-college | 3058 (53%) | 3070 (54%) | |
| Geographic region | 0.317 | ||
| West (Far West, Southwest, Mountain) | 1298 (23%) | 1335 (23%) | |
| Midwest | 1142 (20%) | 1182 (21%) | |
| Southeast | 1631 (28%) | 1545 (27%) | |
| Northeast | 1676 (29%) | 1676 (29%) | |
| Behavioral and life-style characteristics | |||
| Smoking | 0.718 | ||
| Current | 412 (7%) | 421 (7%) | |
| Past | 2473 (44%) | 2425 (43%) | |
| Never | 2785 (49%) | 2810 (50%) | |
| Alcohol | 0.496 | ||
| Never | 1359 (24%) | 1341 (24%) | |
| Rarely - < weekly | 289 (5%) | 305 (5%) | |
| 1–6/week | 2025 (36%) | 1934 (34%) | |
| Daily | 1996 (35%) | 2064 (37%) | |
| Caffeine intake from tea/coffee - servings per week (mean, SD) | 14 (12) | 14 (12) | 0.878 |
| Vitamin D intake | |||
| None | 3508 (61%) | 3439 (60%) | 0.221 |
| ≤800 IU/day | 2239 (39%) | 2300 (40%) | |
| Dietary vitamin D intake – servings per day (median) | 0.674 | ||
| < 1/day | 2707 (48%) | 2625 (85%) | |
| ≥ 1/day | 2953 (52%) | 3024 (54%) | |
| Health History | |||
| BMI, kg/m2 (mean, SD) | 28 (5) | 28 (5) | 0.886 |
| BMI categories | 0.908 | ||
| <25 kg/m2 | 1685 (30%) | 1680 (30%) | |
| 25–29 kg/m2 | 2610 (46%) | 2612 (46%) | |
| ≥30 kg/m2 | 1355 (24%) | 1342 (24%) | |
| Hypertension (yes) | 3172 (55%) | 3190 (56%) | 0.674 |
| Type 2 Diabetes (yes) | 918 (16%) | 856 (15%) | 0.117 |
| Lung disease (asthma, chronic bronchitis/emphysema/COPD), (yes) | 711 (12%) | 755 (13%) | 0.208 |
| Depression diagnosis (yes) | 1185 (21%) | 1151 (20%) | 0.453 |
| Prostatic Hyperplasia (yes) | 518 (9%) | 514 (9%) | 0.915 |
| Prostatitis (yes) | 408 (7%) | 448 (8%) | 0.149 |
| Diuretic Use (yes) | 795 (14%) | 788 (14%) | 0.897 |
Effect of Vitamin D on the Prevalence of OAB
OAB was reported by 35% of all men at year 5. OAB-wet was more common than OAB-dry with 30% of men reporting OAB-wet at year 5 and 6% reporting OAB-dry at year 5 (Table 2). No differences were found in the odds of weekly OAB, OAB-wet or OAB-dry at year 5 for those taking vitamin D versus placebo. However, men with low serum 25(OH)D and assigned to vitamin D supplementation had decreased odds of OAB, OAB-wet, and OAB-dry at year 5 (OAB: OR 0.51, 95% CI 0.35,0.76; OAB-wet: OR=0.66, 95% CI 0.44, 0.98; and OAB-dry: OR=0.29, 95% CI 0.12, 0.71) compared to men assigned to the placebo group. We found significant interactions between lower/higher 25(OH)D and vitamin D supplementation for OAB (pint=0.001) and OAB-dry (pint=0.003), but not OAB-wet (pint=0.07)
Table 2.
Overactive Bladder (OAB) Symptoms at Year Five*, for All Randomized Men and Men with Available Pre-Randomization 25-Hydroxyvitamin D Serum Levels
| Overall OAB Cases N (%) |
Vitamin D supplementOAB Cases N (%) |
Placebo, OAB Cases N (%) |
Odds Ratio | 95% Confidence Interval | P value | P value for Inter-action | |
|---|---|---|---|---|---|---|---|
| OAB - Wet | |||||||
| All men | 1682 (30%) | 828 (29%) | 854 (30%) | 0.97 | 0.87–1.09 | 0.61 | |
| 25(OH)D≥20 ng/mL | 967 (30%) | 477 (30%) | 490 (30%) | 0.98 | 0.84–1.13 | 0.74 | 0.07 |
| 25(OH)D<20 ng/mL | 148 (33%) | 64 (29%) | 84 (38%) | 0.66 | 0.44–0.98 | 0.04 | |
| OAB - Dry | |||||||
| All men | 325 (6%) | 160 (6%) | 165 (6%) | 0.97 | 0.78–1.22 | 0.82 | |
| 25(OH)D≥20 ng/mL | 163 (5%) | 89 (6%) | 74 (5%) | 1.22 | (0.89–1.68) | 0.211 | 0.003 |
| 25(OH)D<20 ng/mL | 28 (6%) | 7 (3%) | 21 (10%) | 0.29 | 0.12–0.71 | 0.006 | |
| OAB – Wet/Dry | |||||||
| All men | 2007 (35%) | 988 (35%) | 1019 (36%) | 0.97 | 0.87–1.08 | 0.55 | |
| 25(OH)D≥20 ng/mL | 1130 (35%) | 566 (35%) | 564 (35%) | 1.02 | 0.88–1.13 | 0.74 | 0.001 |
| 25(OH)D<20 ng/mL | 176 (40%) | 71 (32%) | 105 (48%) | 0.51 | 0.35–0.76 | 0.001 | |
Analyses of UI at Year 5 are among the 5662 men who answered OAB questions. From these men, 3228 had sufficient pre-randomization levels of vitamin D and 444 of the men with low levels of vitamin D. Of the 3228 men with higher 25(OH)D, 1607 were in the vitamin D group and 1621 in the placebo group. Of the 444 men with lower 25(OH)D, 224 were in the vitamin D group and 220 in the placebo group
All analyses adjusted for age and omega-3 fatty acid randomization group.
Effect of Vitamin D on UI among Men, Including UI Types
Overall, 31% of men reported “any” level of UI frequency at year 2 and 41% reported “any” UI at year 5. Among men with UI, 11% reported weekly or more frequent UI at year 2 and 16% at year 5. Urgency UI was the most common type of UI reported, 23% of men reported urgency UI at year 2 and 30% reported urgency UI at year 5, with lower stress and sleep/other UI (Table 3). No differences were found in the odds of weekly UI at year 2 for those taking vitamin D versus placebo (OR 0.94, 95% CI 0.83, 1.05) or by urgency, stress, or other UI types (Table 3). At year 5, the odds of having weekly UI were similar in the vitamin D supplementation compared to placebo group (OR=0.98, 95% CI 0.88, 1.09), including among men with low serum 25(OH)D prior to randomization (OR 1.25, 95% CI 0.86, 1.83), and for urgency UI and other UI types. At year 5, the odds of having stress UI were also similar in those given vitamin D supplementation compared to placebo. Paradoxically, men with baseline 25(OH)D <20 ng/mL, who were assigned to vitamin D supplements, had higher odds of any UI (OR 1.27, 95% CI 0.95–1.69). We found interactions of baseline serum 25(OH)D level with vitamin D supplementation for any UI at year 2 (pint =0.05). And, among men with low serum 25(OH)D, vitamin D supplementation increased the odds of having sleep/other UI at both year 2 (OR=2.21, 95% CI 1.22, 4.00) and year 5 (OR=2.06, 95% CI 1.17, 3.63), compared to men in the placebo group; these interactions were significant year 2 (pint=0.02) and at year 5 (pint=0.04).
Table 3.
Urinary Incontinence (UI) Outcomes at Years Two* and Five**, for All Randomized Men and Subgroups According to Pre-Randomization 25-Hydroxyvitamin D Serum Levels
| Overall UI Cases N (%) |
Vitamin D, UI Cases N (%) |
Placebo, UI Cases N (%) |
Odds Ratio | 95% Confidence Interval | P value | P value for Inter-action | |
|---|---|---|---|---|---|---|---|
| Any UI | |||||||
| Year 2 | |||||||
| All men | 3584 (31%) | 1776 (31%) | 1808 (32%) | 0.98 | 0.90–1.06 | 0.53 | |
| 25(OH)D≥20 ng/mL | 2080 (33%) | 1015 (32%) | 1065 (34%) | 0.93 | 0.84–1.04 | 0.20 | 0.05 |
| 25(OH)D<20 ng/mL | 276 (31%) | 146 (33%) | 130 (28%) | 1.27 | 0.95–1.69 | 0.11 | |
| Year 5 | |||||||
| All men | 4306 (41%) | 2161 (41%) | 2145 (41%) | 1.00 | 0.93–1.08 | 0.98 | |
| 25(OH)D≥20 ng/mL | 2503 (43%) | 1255 (43%) | 1248 (43%) | 1.01 | 0.91–1.12 | 0.86 | 0.18 |
| 25(OH)D<20 ng/mL | 345 (43%) | 178 (45%) | 167 (40%) | 1.24 | 0.93–1.64 | 0.15 | |
| Weekly UI | |||||||
| Year 2 | |||||||
| All men | 1268 (11%) | 614 (11%) | 654 (11%) | 0.94 | 0.83–1.05 | 0.27 | |
| 25(OH)D≥20 ng/mL | 732 (12%) | 352 (11%) | 380 (12%) | 0.91 | 0.77–1.06 | 0.23 | 0.18 |
| 25(OH)D<20 ng/mL | 114 (13%) | 59 (14%) | 55 (12%) | 1.23 | 0.82–1.84 | 0.33 | |
| Year 5 | |||||||
| All men | 1677 (16%) | 834 (16%) | 843 (16%) | 0.98 | 0.88–1.09 | 0.69 | |
| 25(OH)D≥20 ng/mL | 982 (17%) | 485 (17%) | 497 (17%) | 0.97 | 0.84–1.12 | 0.68 | 0.22 |
| 25(OH)D<20 ng/mL | 148 (18%) | 77 (20%) | 77 (17%) | 1.25 | 0.86–1.83 | 0.25 | |
| Urgency UI | |||||||
| Year 2 | |||||||
| All men | 2621 (23%) | 1292 (23%) | 1329 (23%) | 0.97 | 0.88–1.06 | 0.46 | |
| 25(OH)D≥20 ng/mL | 1524 (24%) | 735 (23%) | 789 (25%) | 0.91 | 0.81–1.03 | 0.13 | 0.24 |
| 25(OH)D<20 ng/mL | 211 (24%) | 104 (24%) | 107 (23%) | 1.11 | 0.81–1.53 | 0.51 | |
| Year 5 | |||||||
| All men | 3157 (30%) | 1584 (30%) | 1573 (30%) | 0.99 | 0.91–1.09 | 0.95 | |
| 25(OH)D≥20 ng/mL | 1833 (32%) | 909 (31%) | 924 (32%) | 0.98 | 0.87–1.10 | 0.74 | 0.51 |
| 25(OH)D<20 ng/mL | 267 (33%) | 130 (33%) | 137 (33%) | 1.09 | 0.8–1.48 | 0.57 | |
| Stress UI | |||||||
| Year 2 | |||||||
| All men | 202 (2%) | 98 (2%) | 104 (2%) | 0.94 | 0.71–1.24 | 0.65 | |
| 25(OH)D≥20 ng/mL | 117 (2%) | 53 (2%) | 64 (2%) | 0.81 | 0.56–1.17 | 0.26 | 0.40 |
| 25(OH)D<20 ng/mL | 11 (1%) | 6 (1%) | 5 (1%) | 1.36 | 0.41–4.51 | 0.62 | |
| Year 5 | |||||||
| All men | 258 (3%) | 125 (2%) | 133 (3%) | 0.93 | 0.72–1.19 | 0.57 | |
| 25(OH)D≥20 ng/mL | 136 (2%) | 69 (2%) | 67 (2%) | 1.02 | 0.72–1.44 | 0.92 | 0.47 |
| 25(OH)D<20 ng/mL | 14 (2%) | 8 (2%) | 6 (1%) | 1.54 | 0.53–4.51 | 0.43 | |
| Sleep/Other UI | |||||||
| Year 2 | |||||||
| All men | 736 (6%) | 373 (6%) | 363 (6%) | 1.02 | 0.88–1.19 | 0.79 | |
| 25(OH)D≥20 ng/mL | 426 (7%) | 219 (7%) | 207 (7%) | 1.03 | 0.85–1.26 | 0.74 | 0.02 |
| 25(OH)D<20 ng/mL | 53 (6%) | 35 (8%) | 18 (4%) | 2.21 | 1.22–4.00 | 0.01 | |
| Year 5 | |||||||
| All men | 829 (5%) | 423 (8%) | 406 (8%) | 1.03 | 0.89–1.20 | 0.65 | |
| 25(OH)D≥20 ng/mL | 486 (9%) | 260 (9%) | 236 (8%) | 1.10 | 0.91–1.33 | 0.35 | 0.04 |
| 25(OH)D<20 ng/mL | 60 (7%) | 38 (10%) | 22 (5%) | 2.06 | 1.17–3.63 | 0.01 | |
Analyses of UI at Year 2 are among the 11,486 men who answered UI questions, and 897 of the men with low pre-randomization levels of vitamin D.
Analyses of UI at Year 5 are among the 10,474 men who answered UI questions, and 812 of the men with low pre-randomization levels of vitamin D.
All analyses adjusted for age and omega-3 fatty acid randomization group.
Effect of Vitamin D on UI for the Incidence and Progression of UI from Year 2 to Year 5
Men randomized to vitamin D supplementation did not differ significantly in incident UI (‘any’ UI OR 1.04, 95% CI 0.93, 1.17 or weekly UI OR 0.97, 95% CI 0.79, 1.18) or progression of UI (‘any’ UI OR 0.95, 95% CI 0.82, 1.01 or weekly UI OR 0.98, 95% CI 0.84, 1.16) from year 2 to year 5, compared to men taking placebo (Table 4). Among the subgroup of men with low 25(OH)D levels, no differences were detected for UI incidence or progression of UI from year 2 to year 5 in those taking vitamin D versus placebo.
Table 4.
Outcomes for Incident UI and Progression of UI from Years 2 to 5, for All Men and Men According to Pre-Randomization 25-Hydroxyvitamin D Levels in Serum
| Overall UI Cases N (%) |
Vitamin D, UI Cases N (%) |
Placebo, UI Cases N (%) |
Odds Ratio | 95% Confidence Interval | P value | P value for inter-action | |
|---|---|---|---|---|---|---|---|
| Any UI Incidence from Year 2 to Year 5 * | |||||||
| All men | 1637 (23%) | 840 (24%) | 797 (23%) | 1.04 | 0.93–1.17 | 0.47 | |
| 25(OH)D≥20 ng/mL | 938 (24%) | 489 (25%) | 449 (24%) | 1.08 | 0.93–1.26 | 0.29 | 0.31 |
| 25(OH)D<20 ng/mL | 134 (25%) | 70 (28%) | 64 (22%) | 1.34 | 0.90–1.98 | 0.15 | |
| Any UI Progression from Year 2 to Year 5 ** | |||||||
| All men | 895 (11%) | 441 (10%) | 454 (11%) | 0.95 | 0.82–1.01 | 0.51 | |
| 25(OH)D≥20 ng/mL | 526 (11%) | 260 (11%) | 266 (11%) | 0.95 | 0.78–1.14 | 0.56 | 0.31 |
| 25(OH)D<20 ng/mL | 74 (15%) | 37 (17%) | 37 (14%) | 1.25 | 0.75–2.08 | 0.40 | |
| Weekly UI Incidence from Year 2 to Year 5 *** | |||||||
| All men | 411 (7%) | 204 (7%) | 207 (7%) | 0.97 | 0.79–1.18 | 0.75 | |
| 25(OH)D≥20 ng/mL | 242 (8%) | 122 (8%) | 120 (8%) | 1.00 | 0.77–1.30 | 1.00 | 0.67 |
| 25(OH)D<20 ng/mL | 24 (6%) | 12 (6%) | 12 (5%) | 1.20 | 0.53–2.73 | 0.67 | |
| Weekly UI Progression from Year 2 to Year 5 ** | |||||||
| All men | 703 (12%) | 351 (12%) | 352 (12%) | 0.98 | 0.84–1.16 | 0.84 | |
| 25(OH)D≥20 ng/mL | 411 (12%) | 199 (12%) | 212 (13%) | 0.91 | 0.74–1.12 | 0.37 | 0.10 |
| 25(OH)D<20 ng/mL | 65 (14%) | 35 (16%) | 30 (12%) | 1.47 | 0.85–2.54 | 0.17 | |
Analyses of Any UI incidence are among the 7018 men who did not have UI at Year 2
Analyses of UI progression are among the 6276 men who did not have incident UI, no change in UI symptoms, or improved UI symptoms at year 5
Analyses of Weekly UI incidence are among the 5792 men who did not have UI at Year 2 and who did have UI that occurred monthly or <monthly
Analyses adjusted for age and omega-3 fatty acid randomization group.
DISCUSSION:
In this randomized trial in over 11,000 men, vitamin D3 supplementation of 2,000 IU daily did not reduce OAB or prevalence of weekly UI. In secondary outcomes, vitamin D supplementation also did not influence “any” UI, or UI incidence or progression from years 2 to 5. In our subgroup analyses among men with low serum levels of 25(OH)D, we found inconsistent results of vitamin D supplementation on reducing OAB and increasing UI compared to placebo.
In further evaluation of our subgroup analyses that examined interactions of baseline serum levels of 25(OH)D with supplementation, we found that men with low pre-randomization levels of serum 25-hydroxyvitamin D had fewer OAB symptoms after 5 years with vitamin D supplementation compared to placebo. For weekly UI, there was no interaction of serum 25(OH)D levels with supplements, but unexpectedly, in secondary analyses, we found a suggestion that men with lower serum 25(OH)D levels assigned to supplements had slightly higher odds of any UI, which was largely explained by a 2-fold higher likelihood of sleep/other UI for those assigned to vitamin D supplementation compared to placebo. Our OAB finding may be partially explained by a potential effect of vitamin D supplementation on prostate and bladder function versus only bladder function. However, the effects of vitamin D supplementation on LUTS in men with lower levels of serum 25-hydroxyvitamin D deserve further inquiry.
Overall, our analyses provide evidence that vitamin D supplementation at moderate doses has no consistent benefit for treating or preventing UI in older men. Our findings may be generalizable to the larger group of older men in the United States who experience UI and OAB symptoms, since we found comparable high UI and OAB prevalence, including weekly UI and UI subtypes, relative to other large, nationwide studies of similarly-aged men.2,3,20
Unlike other ancillary studies from this randomized trial, we did not find any improvement in UI or OAB symptoms according to weight status in men, as defined by BMI (supplemental table). In a recent publication among women with UI, we found that women with a healthy weight on vitamin D supplementation compared to placebo had a reduced odds of UI progression (OR 0.78; 95% CI 0.63–0.95; P=.01).15 Other studies found that among participants in the VITAL clinical trial with a healthy weight status had some benefit of vitamin D supplementation for reducing autoimmune disease and advanced cancer.21,22
This ancillary clinical trial analysis has several strengths, including the large sample size, high retention rate, sizable number of African Americans, and follow-up for 5 years. Further, the ability to examine subgroups of men according to lower levels of serum 25(OH)D pre-randomization were strengths. Information on dietary intake of vitamin D was available and intake was distributed equally across treatment groups. We assessed OAB symptoms with a self-reported questionnaire and our definition of OAB required the presence of urgency, frequency and nocturia.1 There were limitations as well. We did not have baseline UI or OAB data, and thus could not formally consider UI incidence or progression throughout the full study period and could only assess OAB at year 5. However, consistent rates of OAB and UI between the two randomization groups at year 2 and year 5 indicates that OAB and UI may have been evenly distributed at baseline as well. Thus, any differences in UI at year 2 and year 5 would likely represent true differences in development and/or progression between the study groups. We only assessed OAB and UI symptoms through self-reported questionnaires and did not include any in-person examinations.
In conclusion, our study provides novel high-quality evidence that 2000IU of vitamin D supplementation does not broadly treat or prevent UI in older men. Our findings also indicate that long-term vitamin D supplements reduced the potential for OAB in men with low serum 25-hydroxy vitamin D levels, although inconsistent findings included possible increases in UI in this subgroup.
Supplementary Material
SUMMARY.
In this ancillary analysis of the Vitamin D and Omega-3 Trial, a randomized trial including 11,486 older men, daily vitamin D3 supplementation did not reduce overactive bladder or urinary incontinence prevalence, incidence, or progression relative to placebo over two to five years.
In the planned subgroup analysis of men with low pre-randomization serum 25-hydroxyvitamin D levels, we found inconsistent findings with reduced overactive bladder at year 5 and increased urinary incontinence when associated with sleep or other reasons.
Our subgroup findings were paradoxical for the use of vitamin D supplementation in older men with low serum 25-hydroxyvitamin D.
ACKNOWLEDGEMENTS AND COI:
The study team would like to acknowledge the support of Ashley Gilmore, MSW, on this project. Pharmavite LLC of Northridge, California (vitamin D) and Pronova BioPharma of Norway and BASF (Omacor fish oil) donated the study agents, matching placebos, and packaging in the form of calendar packs. Quest Diagnostics (San Juan Capistrano, CA) measured the serum 25(OH) levels at no cost to the study.
Funding:
This ancillary study was supported by the National Institute of Diabetes and Digestive, and Kidney Diseases/National Institutes of Health (R01DK115473). The primary study was supported by grants (U01 CA138962 and R01 CA138962) from the National Cancer Institute, the National Heart, Lung, and Blood Institute, the Office of Dietary Supplements (ODS), the National Institute of Neurological Disorders and Stroke, and the National Center for Complementary and Integrative Health (NCCIH). Current support for VITAL is from NCCIH and ODS (R01AT011729). Co-Authors report funding from and Department of Veterans Affairs. Dr. Huang reports funding from the National Institute on Aging (K24AG068601). Dr. Tangpricha receives support from National Center for Advancing Translational Sciences of the National Institutes of Health, Award Number UL1TR002378.
KEY:
- LUTS
lower urinary tract symptoms
- UI
urinary incontinence
- UUI
urgency urinary incontinence
- SUI
stress urinary incontinence
- OAB
overactive bladder
- 25(OH)D
serum 25-hydroxyvitamin D
- vitamin D3
cholecalciferol
- OR
odds ratio
- CI
confidence interval
- VITAL
VITamin D and omegA-3 TriaL
- p-int
p value for interaction
Footnotes
Ethical Compliance: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Trial registration: ClinicalTrials.gov number NCT01169259
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