VDR agonists safety profiles in EudraVigilance 2004-2024

This study analyzed 5,369,581 reports in the EudraVigilance system, from which 17,947 reports (0.33%) involving 80,050 ADRs were linked to VDR agonists. The most-reported drugs were cho-lecalciferol (12,944 cases) and calcitriol (1355 cases). Serious ADRs were more prevalent with pa-ricalcitol, alfacalcidol, and calcitriol than with cholecalciferol (p < 0.05). Hypercalcemia was a hallmark ADR for all VDR agonists, with the highest risk linked to dihydrotachysterol (ROR = 5668; 95%CI = 3332 to 9641; p < 0.0001), alfacalcidol (ROR = 965.7; 95%CI = 843.6 to 1106; p < 0.0001), and calcitriol (ROR = 726.0; 95%CI = 634.6 to 830.5; p < 0.0001). Logistic regression highlighted dehy-dration, overdose, and concomitant administration of calcium salts as major predictors of hyper-calcemia. The co-administration of multiple VDR agonists was also found to increase hyper-calcemia risk. However, the disproportionality analysis showed that only active VDR agonists (e.g., calcitriol, alfacalcidol) were associated with severe complications like renal and urinary dis-orders and cardiac issues due to hypercalcemia. Natural precursors (cholecalciferol, ergocalciferol) were more often linked to non-calcemic ADRs such as gastrointestinal symptoms, which were more prevalent in infants and children compared to adults.