Monthly high-dose cholecalciferol supplementation in prostate cancer patients (ProsD trial): A nested analysis of vitamin D metabolites, metabolic ratios, and biochemical safety

Background The effects of intermittent, high-dose cholecalciferol supplementation on circulating vitamin D metabolites and related biomarkers remain unclear. The ProsD randomised controlled trial evaluated the effects of monthly oral supplementation with 50,000 IU cholecalciferol in males with prostate cancer and assessed longitudinal changes in vitamin D metabolite responses. Objective To characterise vitamin D metabolites and ratios after a monthly dose of 50,000 IU cholecalciferol supplementation and to assess the effects on biochemical markers. Methods ProsD recruited and randomised 123 men with prostate cancer; 118 participants (placebo n = 40; vitamin D n = 78) provided blood samples at baseline, and from remaining participants at 0, 6, 12, and 24 months, at follow-up visits. Plasma vitamin D metabolites—25(OH)D 3 , 1,25(OH) 2 D 3 , 24,25(OH) 2 D 3 , and 3-epi-25(OH)D 3 —and vitamin D metabolite ratios (VMRs) were quantified. Longitudinal changes and between-group differences were evaluated using age-adjusted generalised estimating equations with estimated marginal means. Routine biochemical markers were also assessed. Results Compared with placebo, monthly cholecalciferol supplementation increased peak between-group difference at 24 months for 25(OH)D 3 (+30.10 nmol/L; p < 0.01), 1,25(OH) 2 D 3 (+12.44 pmol/L; p = 0.11), 24,25(OH) 2 D 3 (+3.95 nmol/L; p < 0.01), and 3-epi-25(OH)D 3 (+5.94 nmol/L; p < 0.01). The 25(OH)D 3 :24,25(OH) 2 D 3 VMR increased in the placebo group but remained constant in the intervention group, and between-group analysis showed consistently lower ratios in the vitamin D group. All routine biomarkers remained within normal ranges throughout follow-up. Conclusions Monthly oral supplementation of 50,000 IU cholecalciferol in men with prostate cancer produced sustained increases across multiple vitamin D metabolites over 24 months, accompanied by adaptive shifts in metabolite ratios consistent with regulated catabolic activation, with no clinically meaningful abnormalities in biochemical markers. Trial registration Australian New Zealand Clinical Trials Registry (ACTRN12616001707459), Date: 13 December 2016.