Changes in bone turnover markers in patients without bone metastases receiving immune checkpoint inhibitors: An exploratory analysis

Immune checkpoint inhibitors (ICIs) has revolutionized the treatment of different advanced solid tumors, but most patients develop severe immune-related adverse events (irAEs). Although a bi-directional crosstalk between bone and immune systems is widely described, the effect of ICIs on the skeleton is poorly investigated. Here, we analyze the changes in plasma levels of type I collagen C-terminal telopeptide (CTX-I) and N-terminal propeptide of type I procollagen (PINP), reference makers of bone turnover, in patients treated with ICIs and their associ-ation with clinical outcome.A series of 44 patients affected by advanced non-small cell lung cancer or renal cell carcinoma, without bone metastases, and treated with ICIs as monotherapy were enrolled. CTX-I and PINP plasma levels were assessed at baseline and after 3 months of ICIs treatment by ELISA kits.A significant increase of CTX-I with a concomitant decreasing trend towards the reduction of PINP was observed after 3 months of treatment. Intriguingly, CTX-I increase was associated with poor prognosis in terms of treatment response and survival. These data suggest a direct relationship between ICIs treatment, increased osteoclast activity and potential fracture risk.Overall, this study reveals that ICIs may act as triggers for skeletal events, and if confirmed in larger pro-spective studies, it would identify a new class of skeletal-related irAEs.