RANK/RANKL/OPG Axis Expression and Response to Anti-RANKL Therapy in Gnathic Giant Cell Lesions: A Systematic Review and Meta-Analysis.
4 affiliations
- 1Oral Pathology, Oral Diagnosis Department, College of Dentistry, University of Sulaimani, Sulaimani 46001, Iraq.
- 2Department of Prosthodontics, College of Dentistry, University of Sulaimani, Sulaimani 46001, Iraq.
- 3Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21218, USA.
- 4Department of Dental Research Cell, Dr. D. Y. Patil Dental College & Hospital, Dr. D. Y. Patil Vidyapeeth, Pune 202001, India.
Abstract
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Eleven primary tissue-marker studies (259 specimens; two previously considered studies were excluded as unpublished, non peer-reviewed sources) and 10 non-overlapping clinical cohorts/case reports (58 patients total: 55 from 7 multi-patient cohorts + 3 single-case reports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.
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BibTeX
@article{mahmood2026rankranklopg,
title = {{RANK/RANKL/OPG Axis Expression and Response to Anti-RANKL Therapy in Gnathic Giant Cell Lesions: A Systematic Review and Meta-Analysis.}},
author = {Darya Khalid Mahmood and Arivan Mahmood Hama and Ahmad Shoeb Hashmi},
journal = {Diseases (Basel, Switzerland)},
year = {2026},
month = oct,
doi = {10.3390/diseases14100360},
url = {https://europepmc.org/article/MED/42929987},
note = {CC BY},
}
RIS
TY - JOUR
TI - RANK/RANKL/OPG Axis Expression and Response to Anti-RANKL Therapy in Gnathic Giant Cell Lesions: A Systematic Review and Meta-Analysis.
AU - Darya Khalid Mahmood
AU - Arivan Mahmood Hama
AU - Ahmad Shoeb Hashmi
PY - 2026
DA - 2026/10/01
JO - Diseases (Basel, Switzerland)
DO - 10.3390/diseases14100360
UR - https://europepmc.org/article/MED/42929987
AB - 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.
SN - 2079-9721
ER -