Incidence of fractures in patients with solid cancers treated with immune checkpoint inhibitors: a systematic review and meta-analysis of randomised controlled trials

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Objective: Immune checkpoint inhibitors (ICIs) have revolutionised cancer treatment but can cause several immune-related adverse events. Case reports and population-based studies have reported that ICI treatment may also be associated with higher incidence of fractures, but this has not been systematically studied. The aim of the study is to examine whether treatment with ICIs increases the incidence of fractures compared with chemotherapy or placebo. Methods and analysis: Electronic databases (PubMed, Embase and Cochrane Library) were systematically searched for randomised controlled trials (RCTs), including an ICI monotherapy arm and a placebo/chemotherapy arm, published from database inception to December 2024. Only patients with solid tumours were included. The review protocol was registered in the PROSPERO database (CRD42023448831). Aggregated data were pooled for meta-analysis. The primary outcome was the incidence of clinical, non-pathological fractures in patients with solid cancer treated with ICIs compared with those treated with chemotherapy, placebo or no treatment. Risk of bias was evaluated with the Cochrane Risk of Bias V.2.0 tool. Results: A total of 30 RCTs were identified involving 19 407 patients, of whom 10 076 were ICI users and 9331 non-ICI controls. Among 121 patients with fractures, 68 were ICI users and 53 non-ICI controls. compared with controls, ICI users had a non-significant 18% higher fracture incidence (OR 1.18, 95% CI 0.82 to 1.70). In the subgroup analysis, fracture incidence was 47% higher in ICI users compared with chemotherapy users (OR 1.47, 95% CI 0.93 to 2.32, n=19 studies) but 20% lower compared with placebo users (OR 0.80, 95% CI 0.44 to 1.48, n=10 studies). Conclusion: Our analysis suggests an 18% increase in the incidence of clinical non-pathological fractures in ICI users compared with non-ICI controls, although with considerable uncertainty due to wide CIs. Given the small number of reported fractures in RCTs, continued research is warranted to monitor fracture incidence in this patient population. PROSPERO registration number: CRD42023448831.

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