Denosumab-induced hypocalcemia: detection of drug-drug interactions using disproportionality analysis in VigiBase®

Denosumab-induced hypocalcemia has been reported more frequently in real-world studies than in pivotal clinical trials; this is probably due to a closer monitoring of medication regimens in trials. Here, we sought to detect signals for drug-drug interactions (DDIs) between denosumab and other hypocalcemia-inducing drugs.

We performed a disproportionality analysis of data in VigiBase® between January 1st, 2011, and February 7th, 2024. The frequency of hypocalcemia reports for all drugs known to induce hypocalcemia was compared with that for all other drugs and was quoted as the reporting odds ratio (ROR) [95% confidence interval (CI)]. Generalized linear models were used to test for additive and multiplicative DDIs with denosumab.

Of 3,076,045 reports recorded in Vigibase®, 2638 concerned hypocalcemia. The ROR [95%CI] values for co-exposures of denosumab with calcimimetics (850.5 [397.6-1819.6]), loop diuretics (251.6 [204.5-309.4]), proton pump inhibitors (164.5 [142.2-190.3]), calcitonin (462.5 [171.5-1247.1]), H2 receptor antagonists (157.2 [114.6-215.7]), aminoglycosides (134.7 [41.5-437.4]), cisplatin (464.1 [256.8-839.0]), sodium bicarbonate (510.4 [296-879.9]), and calcium channel blockers (175.3 [143.7-213.7]) were higher than the sum of the RORs for each drug taken individually. The δ coefficient of additive models of these co-exposures was significant, while that of multiplicative models was not.

We found significant signals for hypocalcemia associated with DDIs between denosumab and a range of other hypocalcemia-inducing drugs, suggesting an increased risk of hypocalcemia. With a view to providing guidance on safe prescribing, the hypotheses generated in our disproportionality analysis need to be confirmed by further studies.