AbstractAlthough immune checkpoint inhibitors (ICIs) are associated with different immune‐related adverse events (irAEs), the potential effect on the skeleton is poorly defined albeit biologically plausible and assessable through pharmacovigilance. We described a case series of patients experiencing skeletal fractures while on ICIs at the National Cancer Institute of Milan. To better characterize the clinical features of skeletal irAEs reported with ICIs, we queried the FDA Adverse Event Reporting System (FAERS) and performed disproportionality analysis by means of reporting odds ratios (RORs), deemed significant by a lower limit of the 95% confidence interval (LL95% CI) > 1. Bone AEs emerging as significant were scrutinized in terms of demographic and clinical data, including concomitant irAEs or drugs affecting bone resorption or causing bone damage. Four patients with skeletal events while on ICIs were included in our case series, of which three exhibited vertebral fractures. In FAERS, 650 patients with bone and joint injuries and treated with ICIs were retrieved, accounting for 822 drug‐event pairs. Statistically significant ROR was found for eight, two and one bone AEs respectively with PD‐1, PD‐L1 and CTLA‐4 inhibitors, being pathological fracture (N = 46; ROR = 3.17; LL95%CI = 2.37), spinal compression fracture (42; 2.51; 1.91), and femoral neck fracture (26; 2.38; 1.62) the most common. Concomitant irAEs or drugs affecting bone metabolism were poorly reported. The increased reporting of serious vertebral fractures in patients without concomitant irAEs and no apparent preexisting risk factors could suggest a possible cause‐effect relationship and calls for close clinical monitoring and implementation of dedicated guidelines.