Immune checkpoint inhibitors (ICIs) play a crucial role in the armamentarium of metastatic renal cell carcinoma (mRCC), demonstrating their effect both as a single agent and in combination with anti-vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs). Nivolumab is the first ICI approved for patients with mRCC after the positive results of the Checkmate 025 trial that assessed its survival superiority over everolimus after at least a precedent line with anti-VEGF TKI (1). Nevertheless, there is a proportion of patients with renal cell carcinoma (RCC) that does not obtain a remarkable and durable benefit from immunotherapies.

Bone metastases occur approximately from 30% to 50% of RCCs and represent an established negative prognostic factor in this malignancy, associated with dismal survival and inferior response to treatments (2–5). Bone metastases in mRCC are primarily osteolytic and are correlated with an augmented risk of skeletal-related events (SREs) through a complex process resulting in decreased bone integrity. SREs are defined as pathological fracture, radiotherapy to bone, surgery to bone, spinal cord compression, and hypercalcemia (6).

Therefore, the existence of bone metastases poses a formidable challenge in the treatment of these patients, given its well-known association with a bleak prognosis. Findings from the multicentric prospective phase II GETUG-AFU-26 NIVOREN trial revealed the reduced efficacy of nivolumab treatment in mRCC patients with bone metastases when compared to those without (7).

Bone-targeting agents (BTAs), such as bisphosphonates and denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor kappa-β ligand (RANKL), are commonly administered in solid tumors with bone metastases, including mRCC, to prevent SREs (5, 7, 8). Despite their utility in decreasing the occurrence of SREs, there are few and controversial data on the impact of BTAs on the survival outcomes of patients with mRCC (9).

In recent years, increasing attention has been directed toward the interaction between the bone microenvironment and the antitumor immune responses, particularly in the context of immune checkpoint inhibition. Beyond their established role in the prevention of SREs, BTAs may influence immune regulation within the bone niche through modulation of osteoclast activity and the RANK–RANKL signaling pathway. Emerging clinical and translational evidence suggests that the activation of the RANK–RANKL axis may negatively affect the response to ICIs in mRCC, positioning RANKL as a potential biomarker for resistance to immunotherapy (10, 11).

On this basis, we hypothesized that exposure to BTAs could be associated with improved clinical outcomes in mRCC patients with bone metastases treated with nivolumab. Using a large, multicenter real-world cohort from the Meet-URO 15 study, which investigated 571 patients with mRCC who received nivolumab in the second-line (or higher) setting from October 2015 to November 2019, the present analysis was designed to explore whether the use of BTAs is associated with differences in the progression-free survival (PFS) and overall survival (OS) of these patients (12–14).

Our analysis of a real-world, multicenter cohort of mRCC patients with bone metastases treated with nivolumab suggests a favorable efficacy profile of exposure to BTAs. These patterns were consistently observed across multivariable analyses and remained evident after IPTW, suggesting that the observed differences were not solely driven by imbalances in the baseline prognostic factors. Nevertheless, given the retrospective and non-randomized nature of the study, these findings should be interpreted as hypothesis-generating rather than indicative of a causal relationship.

Bone metastases represent a well-established negative prognostic factor in mRCC, reflecting both advanced disease biology and the unique immunosuppressive features of the bone microenvironment. Clinical evidence from the GETUG-AFU-26 NIVOREN trial has shown reduced efficacy of nivolumab in patients with bone involvement, underscoring the unmet need for strategies capable of mitigating the adverse impact of skeletal disease on the immunotherapy outcomes (7). In this context, our findings suggest that modulation of the bone microenvironment through BTAs may be associated with more favorable clinical outcomes in this patient population treated with ICIs.

From a biological perspective, increasing evidence supports a complex interplay between bone remodeling, immune regulation, and tumor progression. The bone marrow niche is enriched in immunosuppressive cellular populations, including regulatory T cells and myeloid-derived suppressor cells, which may limit effective antitumor immune responses. In addition, tumor-driven osteoclast activation and bone resorption contribute to the release of immunosuppressive cytokines such as interleukin-6 and transforming growth factor beta, further reinforcing an immune-tolerant microenvironment. Through inhibition of osteoclast-mediated bone resorption, BTAs may indirectly modulate these processes, potentially influencing the immune cell composition and function within the bone niche (15–18).

Recent translational data have provided additional support for the relevance of the RANK–RANKL axis in this setting. Elevated baseline circulating RANKL levels have been associated with poorer survival and reduced response to nivolumab in patients with mRCC, suggesting that the activation of this pathway may represent a mechanism of resistance to immune checkpoint inhibition (10).

Our exploratory analyses suggest that denosumab exposure was associated with more favorable survival outcomes compared with zoledronic acid and no BTA exposure. While these observations should be interpreted with caution due to the limited sample size and potential residual confounding, they are consistent with the hypothesis that direct inhibition of RANKL may exert a more pronounced modulation of the bone–immune interface than indirect anti-resorptive mechanisms. Preclinical studies have shown that RANKL blockade alone may have limited antitumor activity, but can enhance the efficacy of ICIs when used in combination, potentially through effects on immune tolerance and tumor microenvironment (TME) remodeling. However, the exact mechanisms underlying these interactions remain incompletely understood.

The possible synergistic mechanisms between BTA, especially denosumab, and ICI remain unclear.

Few studies in mouse cancer models have explored how the inhibition of RANKL affects antitumor immunity in vivo, with limited efficacy observed in RANKL inhibition alone for controlling tumor growth in melanoma, colon carcinoma, and prostate carcinoma models. Enhanced tumor control was observed when combining RANKL inhibition with immunotherapy, possibly due to the cross-modulation of the TME and the interruption of local immunosuppressive pathways mediated by RANK-expressing immune cells in the TME. Another potential mechanism involves the interruption of thymic central tolerance (11, 19–21).

In the literature, other studies have explored possible additive effects between BTAs, in particular anti-RANKL agents, and ICIs in other tumors. The initial evidence includes two case reports of patients with aggressive melanoma treated with anti-CTLA4 and denosumab, who experienced substantial and prolonged disease control. Furthermore, a retrospective analysis of US electronic health record data in patients with melanoma and non-small cell lung cancer (NSCLC) with bone metastases demonstrated that the concurrent combination of ICI and denosumab could enhance the antitumor response and improve outcomes (22–25).

It is noteworthy that zoledronic acid, although primarily classified as a bisphosphonate, has also been shown to interfere with the RANK–RANKL pathway and to exert immunomodulatory effects, including the activation of γδ T cells. Therefore, the differences observed between denosumab and zoledronic acid in this study should not be interpreted as definitive evidence of superiority, but rather as an indication of potentially distinct biological effects that merit further investigation in prospective studies (26, 27).

Several limitations of this analysis must be acknowledged. Firstly, the retrospective design precludes control over treatment allocation and introduces the possibility of residual confounding despite multivariable adjustment and IPTW correction. Secondly, patients with longer survival or less aggressive disease may have been more likely to receive BTAs, potentially introducing survivorship bias; however, exclusion of patients initiating BTA therapy after the first radiological reassessment was implemented to mitigate immortal time bias. Thirdly, heterogeneity in the BTA type, timing, and duration, as well as in prior and subsequent systemic therapies, may have influenced the outcomes and cannot be fully accounted for in this analysis. Another important limitation of the present analysis is that the potential dose–time effect of BTAs could not be adequately assessed. Information regarding treatment duration, cumulative exposure, and adherence was heterogeneous and not uniformly available across centers, precluding a formal evaluation of whether the magnitude of the observed effect varied according to treatment intensity or duration. As a consequence, the present findings do not allow conclusions with regard to an optimal timing or duration of BTA therapy in this setting. Moreover, the safety outcomes related to BTAs, including medication-related osteonecrosis of the jaw (MRONJ), were not systematically collected in the Meet-URO 15 dataset and could therefore not be formally analyzed. Therefore, the potential clinical benefit suggested by the present findings should always be weighed against the known toxicity profile of BTAs, and careful patient selection and monitoring remain essential in routine practice. Finally, mechanistic correlates, such as circulating RANKL levels or immune profiling of the bone microenvironment, were not available and would be necessary to strengthen biological interpretations.

Despite these limitations, the present study provides real-world evidence supporting an association between BTA exposure and improved clinical outcomes in mRCC patients with bone metastases treated with nivolumab. These findings align with emerging translational data implicating the RANK–RANKL axis in the modulation of the response to immune checkpoint inhibition and support further prospective evaluation of combined strategies targeting both tumor immunity and the bone microenvironment. Ongoing clinical trials, such as KEYPAD, will be crucial to clarify the clinical relevance and mechanistic basis of these observations (28).

In conclusion, our study suggests that BTA exposure is associated with more favorable survival outcomes among patients with mRCC treated with nivolumab. The observed positive impact on the survival outcomes, even after performing an IPTW adjustment to balance the clinicopathological factors in our populations, suggests the potential role of BTAs in optimizing the effectiveness of nivolumab therapy. Additional prospective studies are necessary to validate our findings, in particular in patients eligible for immune oncology–tyrosine kinase inhibitor (IO–TKI) and IO–IO combination therapies.