AbstractBackgroundAndrogen deprivation therapy (ADT) inhibits prostate cancer growth. However, ADT causes loss of bone mineral density (BMD) and an increase in fracture risk; effective interventions for ADT‐induced bone loss are limited.MethodsA phase 2 randomized controlled trial investigated the feasibility, safety, and preliminary efficacy of high‐dose weekly vitamin D (HDVD, 50,000 IU/week) versus placebo for 24 weeks in patients with prostate cancer receiving ADT, with all subjects receiving 600 IU/day vitamin D and 1000 mg/day calcium. Participants were ≥60 years (mean years, 67.7), had a serum 25‐hydroxyvitamin D level <32 ng/mL, and initiated ADT within the previous 6 months. At baseline and after intervention, dual‐energy x‐ray absorptiometry was used to assess BMD, and levels of bone cell, bone formation, and resorption were measured.ResultsThe HDVD group (N = 29) lost 1.5% BMD at the total hip vs. 4.1% for the low‐dose group (N = 30; p = .03) and 1.7% BMD at the femoral neck vs. 4.4% in the low‐dose group (p = .06). Stratified analyses showed that, for those with baseline 25‐hydroxyvitamin D level <27 ng/mL, the HDVD group lost 2.3% BMD at the total hip vs 7.1% for the low‐dose group (p < .01). Those in the HDVD arm showed significant changes in parathyroid hormone (p < .01), osteoprotegerin (p < 0.01), N‐terminal telopeptide of type 1 collagen (p < 0.01) and C‐terminal telopeptide of type 1 collagen (p < 0.01). No difference in adverse events or toxicity was noted between the groups.ConclusionsHDVD supplementation significantly reduced hip and femoral neck BMD loss, especially for patients with low baseline serum 25‐hydroxyvitamin D levels, although demonstrating safety and feasibility in prostate cancer patients on ADT.