Incidence of malignant transformation in giant cell tumor of bone following denosumab therapy: a systematic review and meta-analysis.

Background: Denosumab has transformed the management of giant cell tumor of bone (GCTB), particularly in cases that are unresectable or surgically morbid. However, accumulating reports of malignant transformation (MT) during or after therapy have raised concern about a potential causal association. We conducted a systematic review and meta-analysis to estimate the incidence of MT in denosumab-treated GCTB and to characterize the clinical, radiological, and pathological features of affected patients. Methods: We searched PubMed/MEDLINE, Scopus, and Web of Science to October 2025 for studies reporting denosumab-treated GCTB with MT. Clinical trials, cohort studies, case series, and case reports with original patient data were eligible. Two reviewers independently performed study selection, data extraction, and risk-of-bias assessment. A random-effects meta-analysis was used to pool MT incidence. Results: Twenty-four studies were included in the qualitative analysis, and 11 (800 denosumab-treated patients) contributed to the meta-analysis. MT was reported in 18 patients. The pooled incidence of MT was 3% (95% CI 2-7%; I Conclusions: MT in denosumab-treated GCTB is rare and does not appear more frequent than historical baseline rates, but it predominantly affects a biologically and clinically high-risk subgroup. Vigilant clinical and radiological surveillance, prompt re-biopsy of atypical lesions, and referral to expert sarcoma centers are essential, and prospective registries with integrated molecular profiling are urgently needed.