Immune-Checkpoint Inhibitors Protect Bone by Promoting Osteogenesis
Immune checkpoint inhibitors (ICIs), widely employed anticancer agents, have been found to impact bone turnover, potentially conferring a protective effect on bone through the promotion of osteogenesis.
These surprising findings stem from a recent study conducted at the Karl Landsteiner University of Health Sciences (KL Krems), Austria, the results of which have been published in the Journal for Immuno Therapy for Cancer. The study was a comprehensive in vivo, in vitro and ex vivo analysis on the effects of PD1- or PD-L1 inhibitors on bone turnover. These results diverge from previous research indicating ICIs' potential contribution to skeletal morbidity, a significant concern for patients with advanced cancer.
Antitumor agents may have detrimental impact on the bone health of cancer patients, leading to skeletal morbidity. This elevates the risk of fractures and undermines quality of life. Thus, safeguarding bone health alongside enhancing outcomes are important treatment goals. While immune checkpoint inhibitors (ICIs), in particular PD1- and PD-L1 inhibitors, are considered standard of care in many cancers, their effect on bone health is still under debate with studies indicating their potential contribution to skeletal morbidity, a significant concern for patients with advanced cancer. In a comprehensive in-vivo, in-vitro and ex-vivo analysis, Dr. Sonia Vallet and her collaborators demonstrated a favorable effect of ICIs on bone turnover.
Dynamic Bone
The team performed a pilot study to monitor long-term changes in the levels of serum markers of bone resorption and formation in patients undergoing ICI treatment. The findings were striking. Dr. Vallet elucidates: "We observed a substantial but transient decline in bone resorption markers within the initial month of treatment." Dr. Vallet, scientist at the Division of Molecular Oncology and Hematology at KL Krems and physician at the Division of Internal Medicine 2 at UK Krems ( a teaching and research site of KL Krems), continues: "Importantly, the serum levels of PINP and OCN, both indicative of bone formation, increased after four months of treatment."
Dr. Vallet suggests: "ICIs may interfere with the differentiation of bone cells by disrupting cellular signaling pathways”. To investigate this hypothesis, the team examined the impact of ICIs on the differentiation of bone-resorbing cells, osteoclasts (OC), and bone-forming cells, osteoblasts (OB) in vitro. Their findings revealed compromised differentiation of precursor cells into bone-resorbing OCs, but no significant effect on osteogenesis.
Advanced Modeling Techniques
To explore the complex cellular interactions underlying bone remodeling, the team developed a dynamic 3D model consisting of bone-like scaffolds loaded with OC and OB precursor cells and cultured in a rotating bioreactor. Analysis of bone cell differentiation and proteins secreted in the supernatant yielded further insights, suggesting impaired OC maturation and increased OB differentiation following exposure to ICIs.
This study sheds unprecedented light on the impact of ICIs on bone, which may have a favorable effect by promoting osteogenesis. Follow-up investigations with a larger and more diverse patient cohort are needed to confirm the results. Nonetheless, the groundbreaking findings of this study at KL and UK Krems underscore the institution's commitment to cutting-edge scientific endeavors.
Original Publication: Favorable Impact of PD1/PD-L1 Antagonists on Bone Remodeling: An Exploratory Prospective Clinical Study and ex-vivo Validation. T. Gassner, C. Chittilappilly, T. Pirich, B. Neuditschko, K. Hackner, J. Lind, O. Aksoy, U. Graichen, S. Klee, F. Herzog, C. Wiesner, P. Errhalt, M. Pecherstorfer, K. Podar & S. Vallet. Journal of Immunotherapy of Cancer May 2024 - Vol 12 - 5. https://doi.org/10.1136/jitc-2023-008669
