RANK/RANKL/OPG Axis Expression and Response to Anti-RANKL Therapy in Gnathic Giant Cell Lesions: A Systematic Review and Meta-Analysis

Background/Objectives: Understanding the biological role of the receptor activator of nuclear factor-κB ligand (RANK), its ligand (RANKL), and the decoy receptor osteoprotegerin (OPG) is vital for clarifying the pathogenesis of gnathic giant cell-containing lesions and directing targeted clinical treatments. Methods: Following PRISMA 2020 guidelines and a registered PROSPERO protocol [CRD420261461026], we searched PubMed, Scopus, and Web of Science databases for human tissue-level or clinical denosumab studies (2003–2026). Quality was appraised using adapted NOS and JBI checklists. A fixed-effect inverse-variance meta-analysis pooled continuous RANK parameters between aggressive and non-aggressive CGCG subtypes. Results: Eleven primary tissue-marker studies (259 specimens; two previously considered studies were excluded as unpublished, non peer-reviewed sources) and 10 non-overlapping clinical cohorts/case reports (58 patients total: 55 from 7 multi-patient cohorts + 3 single-case reports [Hameed, O’Connell, Kawamura]). Mononuclear stromal cells represent the pathogenetic driver, secreting RANKL to recruit RANK-expressing mature giant cells. Meta-analysis (k = 2 studies) showed that raw membrane RANK-positive cell percentages did not differ significantly between aggressive and non-aggressive phenotypes (pooled Hedges’ g = 0.25, 95% CI −0.29–0.80, p = 0.36), while non-aggressive lesions showed a borderline, non-significant trend toward higher staining intensity-distribution (SID) scores (g = 0.55, 95% CI −0.00–1.11, p = 0.0506). Because this 95% CI crosses zero, and only two studies (k = 2) were pooled, this represents a non-significant trend rather than a statistically confirmed difference between aggressive and non-aggressive CGCG; both pooled estimates are, therefore, hypothesis-generating only. In clinical cohorts, denosumab achieved objective clinical and radiological tumor responses in all reported cases, enabling downstaging from disfiguring resection to conservative curettage. However, post-cessation recurrence was frequent, ranging from 37% in adults to 100% in pediatric cohorts, with pediatric patients at risk of rebound hypercalcemia. Conclusions: The RANK/RANKL/OPG axis, driven by RANKL-secreting mononuclear stromal cells, underlies osteolytic activity in gnathic giant cell lesions. Denosumab is an effective neoadjuvant bridge to jaw-preserving surgery but is not curative; a RANKL-independent, OPG-resistant SOFAT pathway has been hypothesized as one possible contributor to treatment failure, although this proposal is derived from a single external study and requires independent validation before any clinical inference is drawn. Close post-treatment metabolic and radiographic surveillance is warranted in pediatric patients. Prospective studies are needed to define optimal weaning protocols.