High-dose Vitamin D Supplementation for ADT-induced Side Effects

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DESCRIPTION (provided by applicant): 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 5- to 10-fold greater loss of bone mineral density (BMD), a 7-fold increase in bone fractures, and a significant increase in sarcopenia (muscle mass atrophy) compared to age-matched prostate cancer patients not on ADT and men without cancer. The loss of BMD and muscle mass is associated with a high prevalence of physical deficits such as falls, reduced muscular strength, and decreased balance. Despite the high prevalence of ADT-related side effects, treatment options are limited. Bisphosphonate therapy is an effective treatment for ADT-induced bone loss, but is not indicated for the prevention of bone loss. Vitamin D protects against BMD loss and fractures, but its effects are strongly dose-dependent. Current IOM recommended supplementation (600 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, as evidenced by increased BMD with serum 25-OH vitamin D levels e32 ng/mL. In addition, RCT interventions of 400-500 IU/day of vitamin D failed to prevent ADT-induced bone loss. High-dose 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. Vitamin D has also been shown to increase muscular strength, reduce falls, and improve balance. Preliminary data from our group in 190 cancer patients demonstrates high-dose vitamin D supplementation (e50,000 IU/week) for 6 months in prostate cancer patients receiving treatment (e.g., ADT, chemotherapy) is safe and well-tolerated. Other preliminary data from our group also show high-dose vitamin D supplementation (50,000 IU/week) in cancer patients significantly increases 25-OH vitamin D levels while low-dose vitamin supplementation (7,000 IU/week) does not. Based on biological plausibility and our preliminary data, we propose to conduct a two-arm randomized controlled trial in which 76 prostate cancer patients 65 years old and older on ADT will be randomized to receive 1) 50,000 IU/week vitamin D or 2) a matching placebo. All participants will receive a daily multivitamin (600 IU vitamin D) and a 1,000 mg/day calcium supplement to ensure a minimum of 100% RDA. The primary aim will evaluate the effect of high-dose vitamin D supplementation on BMD, while the secondary aims will evaluate the effect of high-dose vitamin D supplementation on muscle mass, falls, muscle strength, and physical performance. The study proposed herein is designed to provide critical preliminary information and data to inform an anticipated R01 proposal. This study would represent one of first clinical trials to examine the effect of high-dose vitamin D supplementation on ADT-related side effects in older prostate cancer patients. If successful, the benefit of a reduced burden from ADT in older prostate cancer patients as a result of this study could be considerable.