PROJECT SUMMARY Overactive bladder (OAB), the presence of urgency, frequency, and nocturia, is common with aging, as is urgency urinary incontinence (UUI). These are among the most bothersome lower urinary tract symptoms – associated with worse mental health, poor physical well-being, and increased falls, fractures, and nursing home placement. Despite treatment options, many patients do not become symptom-free and discontinue medications due to side effects or perceived inefficacy. Attention is shifting to possible prevention and early treatment strategies. Potential benefits of vitamin D may extend to several relevant organ systems, and vitamin D could act via multiple pathways to reduce lower urinary tract symptoms by improving detrusor activity and decreasing inflammation. Indeed, evidence emerging from epidemiologic studies indicate that higher vitamin D levels are associated with decreased risk for OAB and UI. In this revision application, we will leverage two large, complementary epidemiologic studies – the VITamin D and omegA-3 TriaL (VITAL, n=25,000 women and men) and the observational Nurses’ Health Studies (n>100,000 women) -- to conduct a rich exploration of vitamin D and OAB, as well as UUI. In this revision, we extend research to both OAB and UUI, increasing clinical relevance by broadening the outcomes (previously only UI) while focusing on symptoms related to detrusor contractility. We also improve innovation by targeting research in: (1) African Americans (n=2300 in NHS, n=5200 in VITAL), who disproportionately suffer from OAB and UUI, and have higher prevalence of vitamin D deficiency; and in (2) obese adults (n=34,000 in NHS, n=7200 in VITAL), who are at higher risk of OAB and UUI, and have lower bioavailability of vitamin D as it is retained in adipose tissue. Our main Aims are to: 1) assess if vitamin D3 supplementation decreases OAB and UUI in VITAL, where participants have been assigned to 2000IU/day of vitamin D or placebo for five years, and in NHS, where observational data are available on a large range of doses, from <400 IU to >800 and >1000 IU/day; and 2) to prospectively assess if higher plasma 25(OH)D levels at baseline are related to a decreased incidence and progression of UUI in the NHS. In VITAL, where an estimated 50% of participants had 25(OH)D<30ng/mL at baseline, we propose to collect data on OAB and UI symptoms at year 5 by adding new questions on urgency, frequency, nocturia and urine leakage at the close of the trial. The NHS already includes extensive UUI data, and we will newly measure baseline vitamin D levels from stored blood samples and add OAB questions in upcoming follow-up periods. The large samples of African American and of obese adults in these cohorts uniquely enable important and novel research. The expected outcomes will be to provide exciting new knowledge regarding vitamin D as a possible convenient, low-cost intervention for preventing OAB and UUI symptoms and progression among women and men, specifically targeting high-risk subgroups of African Americans and obese adults.

PROJECT NARRATIVE Overactive bladder (OAB) can occur with or without urgency urinary incontinence (UUI). OAB and UUI affects the lives of millions of men and women and is very costly. Emerging evidence from epidemiologic studies link higher vitamin D levels with lower rates of OAB and UUI. With this proposal, our goal is to understand the relationship of vitamin D supplementation compared to placebo on OAB and UUI symptoms, especially in high- risk subgroups. We will also evaluate how supplementation may improve new-onset OAB and UUI over time.