Bone metastases remain an important clinical challenge in metastatic renal cell carcinoma (mRCC), affecting survival and quality of life and increasing the risk of skeletal-related events (SREs). However, evidence on their prognostic impact and the role of bone-targeting agents (BTAs) remains limited in patients receiving contemporary first-line systemic therapy.
A new subanalysis of the Meet-URO 33 study, published as an Article in Press in Clinical Genitourinary Cancer on August 24, 2026, examined bone metastases, SREs, and BTA use in a large real-world cohort of patients with mRCC receiving first-line treatment.
The original study was titled “Assessment of Bone Metastases, Skeletal-Related Events and Bone-Targeting Agents in Patients With Metastatic Renal Cell Carcinoma Receiving First-Line Systemic Therapy (Meet-URO 33 Study Subanalysis).”
Authors: Anna Amela Valsecchi, Sara Elena Rebuzzi, Maria Concetta Cursano, Francesco Pantano, Rossana Berardi, Davide Bimbatti, Lucia Bonomi, Giovanni Bozza, Enrico Bronte, Sebastiano Buti, Claudia Carella, Alessia Cavo, Emilia Cocorocchio, Alberto Dalla Volta, Filippo Maria Deppieri, Andrea Di Marco, Marilena Di Napoli, Martina Fanelli, Emanuela Fantinel, Arianna Dri, Roberto Filippi, Giuseppe Fornarini, Luca Galli, Annalisa Guida, Massimiliano Icardi, Francesca La Russa, Cristian Lolli, Laura Lombardo, Francesca Maines, Brigida Anna Maiorano, Cristina Masini, Carlo Messina, Cecilia Nasso, Cinzia Ortega, Francesco Pierantoni, Giuseppe Procopio, Sarah Scagliarini, Alessio Signori, Mariella Sorarù, Luca Tondulli, Elena Verzoni, Francesca Vignani, Maria Giuseppa Vitale, Silvia Zai, Paolo Andrea Zucali, Ugo De Giorgi, Daniele Santini, and Massimo Di Maio.
Study Design
This analysis was conducted within Meet-URO 33–REGAL, an Italian multicenter retrospective/prospective observational study including patients with mRCC treated with first-line systemic therapy beginning January 1, 2021. Data available through November 1, 2025, were analyzed from 52 Italian institutions. After excluding patients with missing follow-up dates or unavailable first-line treatment start dates, 1,696 patients were included.
The primary objective of the subanalysis was to assess the prognostic role of bone metastases in terms of overall survival (OS). Secondary objectives included progression-free survival (PFS), clinical characteristics of patients with bone metastases, the incidence of SREs, and the impact of BTAs on skeletal outcomes.
Bone Metastases at Diagnosis
Among the 1,696 patients, 526 (31%) had bone metastases at the time of metastatic diagnosis. Patients with bone metastases more frequently had poorer ECOG performance status and unfavorable IMDC risk. ICI–TKI combinations were used as first-line treatment in 73.0% of patients with bone metastases compared with 59.8% of those without bone metastases. ICI–ICI combinations were used in 16.5% versus 20.9%, respectively, while TKI monotherapy was used in 9.3% versus 16.6%.
Detailed information on bone metastases was available for 224 of the 526 patients. The spine was involved in 49.1%, the pelvis in 35.7%, the ribs in 31.7%, and other bone sites in 39.3%. Most patients, 90.6%, had fewer than 10 bone lesion sites. Bone lesions were predominantly osteolytic: 84.4% had exclusively osteolytic lesions, 9.4% had mixed lesions, and 6.2% had exclusively osteoblastic lesions.
Overall Survival
With a median follow-up of 21.3 months, median OS was 26.9 months in patients with bone metastases, while median OS was not estimable in patients without bone metastases. The difference was statistically significant, with an HR of 0.53(95% CI, 0.45–0.64; P < .001).
In multivariable analysis including age, sex, ECOG performance status, IMDC category, and type of first-line treatment, the presence of bone metastases remained an independent prognostic factor for OS (HR 0.81; 95% CI, 0.67–0.98; P = .03). The difference in OS according to bone metastasis status remained statistically significant across all three IMDC risk groups and across patients receiving ICI–ICI combinations, ICI–TKI combinations, and TKI monotherapy.
Among patients with bone metastases, median OS was 23.5 months with nivolumab plus ipilimumab, 29.2 months with pembrolizumab plus axitinib, and 20.4 months with nivolumab plus cabozantinib. Median OS was not reached with pembrolizumab plus lenvatinib, while it was 33.8 months with TKI monotherapy.
The authors emphasized that differences between individual treatment regimens should be interpreted cautiously because of limited subgroup sizes, the absence of formal between-treatment comparisons, and potential confounding from treatment selection. Neither the anatomical site nor the number of bone metastases was significantly associated with OS.
Progression-Free Survival
Median PFS was 14.2 months in patients with bone metastases compared with 19.4 months in those without bone metastases (HR 0.71; 95% CI, 0.61–0.82; P < .001). However, bone metastases did not retain an independent prognostic association with PFS in multivariable analysis (HR 0.89; 95% CI, 0.76–1.04; P = .15).
Among patients with bone metastases, median PFS was 6.8 months with nivolumab plus ipilimumab, 12.4 months with pembrolizumab plus axitinib, 13.4 months with nivolumab plus cabozantinib, 20.9 months with pembrolizumab plus lenvatinib, and 11.1 months with TKI monotherapy. PFS differences according to the presence of bone metastases were not statistically significant in the favorable- and intermediate-risk IMDC groups or among patients receiving TKI monotherapy.
Skeletal-Related Events
Valid SRE data were available for 493 patients with bone metastases, of whom 132 (26.8%) experienced at least one SRE. Among reported SREs, 58% involved radiotherapy to bone, 16% bone surgery, 16% pathological fractures, 8% spinal cord compression, and 2% hypercalcemia.
SREs were more frequent among patients with spinal involvement than among those without spinal metastases, at 52.0% versus 18.4%. Higher SRE rates were also observed with rib involvement, at 37.5% versus 24.4%, and with involvement of other bone sites, at 48.1% versus 20.9%. Pelvic involvement was not associated with a statistically significant difference. No significant association was identified between the number of bone metastases and SRE occurrence, although this analysis was limited by missing data and the small number of patients with 10 or more bone lesions.
Bone-Targeting Agents
BTA data were available for 499 of the 526 patients with bone metastases. 137 patients (27.4%) initiated a BTA concomitantly with first-line systemic therapy. Among these patients, 46.7% received bisphosphonates and 52.5% received denosumab. Among patients who had not experienced an SRE before systemic treatment, SREs subsequently occurred in 22.2% of patients receiving BTAs compared with 13.7% of those not receiving BTAs. The authors noted that this finding was likely influenced by selection bias because BTAs were more likely to be given to patients with more extensive or higher-risk bone disease.
Adverse events associated with BTAs included osteonecrosis of the jaw in 12 patients (8.6%), grade 1 hypocalcemia in six patients (4.4%), and renal failure in one patient (0.8%). The investigators did not analyze the association between BTA exposure and OS or PFS because the nonrandomized design and variable timing of BTA initiation would introduce a substantial risk of bias.
Limitations
The study was observational and included a retrospective component, limiting control of confounding and selection bias. Missing data were frequent, particularly for detailed characteristics of bone metastases. The impact of the extent of bone involvement on prognosis was not analyzed in detail, and systematic information on local treatments was unavailable, preventing assessment of potential synergistic effects between local and systemic therapies.
The authors also cautioned against direct comparisons of outcomes across individual first-line treatment regimens because subgroup sizes were limited and treatment selection was influenced by clinical and IMDC characteristics.
Takeaway
The Meet-URO 33 subanalysis confirms the negative prognostic role of bone metastases in mRCC, with their impact on OS observed across IMDC risk groups and different first-line treatment strategies. Among patients with available SRE data, more than one-quarter experienced an SRE, while BTA use was heterogeneous and its clinical impact could not be established from this observational analysis. The authors concluded that these findings support a multidisciplinary, risk-adapted approach to the management of bone metastases, integrating patient- and disease-specific factors.
The full article is available in Clinical Genitourinary Cancer.
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