Use of androgen deprivation therapy (ADT), which causes near-total loss of testosterone, has increased dramatically in elderly prostate cancer patients over the last decade. ADT is associated with a significant increase in bone mineral density (BMD) loss (2-5% annually) and bone fractures, combined with a significant decrease in skeletal muscle mass (2-5% annually) compared to age-matched prostate cancer patients not on ADT and men without cancer. The loss of BMD and muscle mass results in a high prevalence of falls, reduced muscular strength, and decreased balance. Despite the high incidence of ADT-related side effects, treatment options are limited. Bisphosphonate therapy is commonly used for ADT-induced bone loss, but is associated with significant side effects and poor compliance. Vitamin D protects against BMD loss and fractures, but its effects are strongly dose-dependent. Current IOM recommended supplementation (600-800 IU/day) and serum 25-OH levels (20 ng/mL) are inadequate to protect against bone loss in a high risk population such as prostate cancer patients on ADT. In addition, RCT interventions of 400-500 IU/day of vitamin D fail to prevent ADT-induced bone loss. Highdose vitamin D supplementation (e.g., 50,000 IU/week) is a promising intervention that significantly increases 25-OH vitamin D to levels shown to improve BMD in other populations. Vitamin D has also been shown to increase muscular strength, reduce falls, and improve balance. In preparation for this R01, we conducted a Phase II randomized controlled trial (RCT) investigating the feasibility, safety, and preliminary efficacy of HDVD versus placebo for 24 weeks in 59 prostate cancer patients receiving ADT (NCI R21CA185678; PI: Peppone). Compelling evidence from our pilot study showed: 1) 50,000 IU/week of vitamin D (HDVD) was safe with no increase in toxicity versus low-dose vitamin D, 2) compliance was excellent at 94%, and 3) HDVD significantly increased 25-OH vitamin D levels. Those randomized to HDVD lost 1.9% BMD at the total hip versus 3.7% loss in the placebo group (p=0.03). Stratified analyses showed the HDVD group lost 2.3% BMD at the total hip vs 7.1% for the placebo group for those with baseline vitamin D <27 ng/ml (p<0.01). Based on our preliminary data, we propose to conduct a definitive, multi-center, phase III RCT in which 366 prostate cancer patients ≥65 years old starting ADT with vitamin D <27 ng/ml will be randomized to 1) 50,000 IU/week vitamin D or 2) a matching placebo for 52 weeks. All participants will receive a daily supplementation (800 IU vitamin D/1,000 mg calcium) to ensure a minimum of 100% RDA. The primary outcomes is the change in BMD, while secondary outcomes include changes in the clinically relevant outcomes of falls, balance, quality of life and fractures. We also plan to explore the biological pathways of ADT-induced bone loss and response to HDVD using bone biomarkers. If found to be efficacious, HDVD would be a safe, low-cost, widely-available OTC treatment that could revolutionize management of ADT-induced bone loss and change clinical practice paradigms.