Immune Checkpoint Inhibitors and Fracture Risk: A Systematic Literature Review and Pooled and Meta-Analysis of Randomized Controlled Trials.

Abstract

Immune checkpoint inhibitors (ICIs) are indicated for numerous malignancies, but may have off-target effects called immune-related adverse events (irAEs). Fractures are not considered irAEs, but ICIs may promote osteoclast activation, leading to fractures. This study aimed to evaluate fracture risk associated with ICI therapy using data from randomized controlled trials (RCTs). We conducted a systematic literature review of phase II and III ICI RCTs in individuals with solid malignancies that reported fractures in PubMed and Embase from inception to September 25, 2024. Supplementary materials were reviewed for all eligible studies to ascertain fracture outcomes. Fractures were categorized as any fracture, osteoporotic, and pathologic. Pooled analysis, random-effects meta-analysis, and multivariate meta-regression were conducted to determine the overall risk of fracture in ICI users compared to non-ICI users. Two subgroup analyses were performed: (1) studies without an active comparator, and (2) studies without an active comparator and ≥ 6 months of ICI treatment. A total of 35 RCTs met the inclusion criteria (n = 23,404 patients). There were 91 fractures in ICI groups (66 osteoporotic and 5 pathologic), compared with 70 fractures in the controls (49 osteoporotic and 5 pathologic). Pooled analysis showed no significant association between ICI therapy and risk of any fracture (OR: 1.10, 95% CI: 0.80-1.50, p = 0.54), osteoporotic fracture (1.14, 95% CI: 0.78-1.64, p = 0.48), or pathologic fracture (OR: 0.84, 95% CI: 0.26-2.73, p = 0.79). Meta-analysis similarly showed no statistically significant differences. Meta-regression did not identify any variables associated with increased fracture risk. Statistical heterogeneity was non-significant (I2 = 0.0%). There was no statistically significant difference in reported fractures between ICI and non-ICI treatment groups. However, few studies reported fracture outcomes and observation periods for these studies were short. Longer-term comprehensive fracture-adverse-event reporting in ICI RCTs is needed to evaluate fracture risk in ICI users.