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

Francesco Pantano; Flavia Tramontana; Michele Iuliani; Giulia Leanza; Sonia Simonetti; Alessandra Piccoli; Annalisa Paviglianiti; Alessio Cortellini; Gian Paolo Spinelli; Umile Giuseppe Longo; Rocky Strollo; Bruno Vincenzi; Giuseppe Tonini; Nicola Napoli; Daniele Santini

doi:10.1016/j.jbo.2022.100459

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

J Bone Oncol. 2022 Oct 28:37:100459. doi: 10.1016/j.jbo.2022.100459. eCollection 2022 Dec.

Authors

Francesco Pantano¹, Flavia Tramontana², Michele Iuliani¹, Giulia Leanza², Sonia Simonetti¹, Alessandra Piccoli², Annalisa Paviglianiti^{2

3

4}, Alessio Cortellini¹, Gian Paolo Spinelli⁵, Umile Giuseppe Longo⁶, Rocky Strollo⁷, Bruno Vincenzi¹, Giuseppe Tonini¹, Nicola Napoli², Daniele Santini^{1

5}

Affiliations

¹ Medical Oncology Department, Campus Bio-Medico University of Rome, Rome, Italy.
² Department of Medicine, Unit of Endocrinology and Diabetes, Università Campus Bio-Medico di Roma, Rome, Italy.
³ Hematology Department, Institut Català d'Oncologia Hospitalet, Barcelona, Spain.
⁴ Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain.
⁵ UOC Oncologia Universitaria, Sapienza University of Rome- Polo Pontino, Italy.
⁶ Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University of Rome, Rome, Italy.
⁷ Dipartimento di Scienze e Tecnologie per l'Uomo e l'Ambiente, Università Campus Bio-Medico di Roma, Rome, Italy.

Abstract

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 association 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 prospective studies, it would identify a new class of skeletal-related irAEs.

Keywords: APRIL, a proliferation-inducing ligand; Bone health; CT-scan, Computed Tomography Scan; CTX-I, type I collagen C-Terminal telopeptide; ECOG, Eastern Cooperative Oncology Group; ELISA, Enzyme-Linked Immunosorbent Assay; ICIs, Immune Checkpoint Inhibitors; IFN-γ, Interferon-γ; IL-6, Interleukin-6; Immune checkpoint inhibitors (ICIs); N-terminal propeptide of type I procollagen (PINP); NSCLC, Non-Small Cell Lung Cancer; OPG, Osteoprotegerin; OS, Overall Survival; PD-L1, Programmed cell Death Ligand 1; PINP, N-terminal Propeptide of type I Procollagen; RANKL, nuclear factor kappa-B ligand; RCC, Renal Cell Carcinoma; RECIST, Response Evaluation Criteria in Solid Tumors; T0, Time 0; T1, Time 1; TNF-α, Tumor Necrosis Factor-α; TTF, Time to Treatment Failure; Th17, T helper 17; Type I Collagen C-Terminal Telopeptide (CTX-I); irAEs, Immune-Related Adverse Events.