# Immune Checkpoint Inhibitors and Bone Health: Mechanisms, Clinical Implications, and Emerging Perspectives on Bone Fragility

## TL;DR

This paper reviews how immune checkpoint inhibitors affect bone health, highlighting a gap between preclinical and clinical findings on bone loss and fracture risk.

## Contribution

The paper systematically addresses the understudied skeletal effects of ICIs in patients without bone metastases.

## Key findings

- Preclinical models show ICIs cause bone loss and increased osteoclast activity.
- Clinical data reveal an elevated risk of fragility fractures despite stable or improved bone mineral density.
- Current tools are insufficient to fully assess the skeletal impact of ICI therapy.

## Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, but their effects on the skeletal system, independent of the influence of bone metastases, are not fully understood. This critical review specifically summarizes the current evidence on the systemic skeletal effects of ICIs in patients without bone metastases, focusing on changes in bone turnover markers (BTMs), bone mineral density (BMD), and fracture risk, thereby addressing a significant gap in the literature. It also explores potential mechanisms, such as immune-mediated disruption of bone remodeling and alterations in bone quality.

Preclinical in vivo models consistently report that blocking the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) or cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) pathways leads to bone loss and increased osteoclast activity. However, clinical findings are paradoxical; while one study using opportunistic quantitative computed tomography (QCT) reported preserved or even improved BMD in patients on ICI therapy, large cohort studies and pharmacovigilance analyses have revealed a consistently elevated risk of fragility fractures. Current assessment tools have limitations in capturing the true skeletal burden of ICI therapy.

A significant discrepancy exists between preclinical data suggesting bone loss and clinical data showing both stable BMD and increased fracture risk. Addressing these knowledge gaps through prospective, high-resolution studies is critical for improving survivorship care. A clearer understanding is essential for developing strategies to prevent skeletal complications in the growing population of patients receiving immunotherapy.