Background: Prevention of alveolar bone destruction is a clinical challenge in periodontal disease treatment. The receptor activator of nuclear factor‐kappa B ligand (RANKL) inhibitor osteoprotegerin (OPG) inhibits osteoclastogenesis and suppresses bone resorption.

Methods: To study the effects of RANKL inhibition on alveolar bone loss, an experimental ligature‐induced model of periodontitis was used. A total of 32 rats were administered human OPG‐Fc fusion protein (10 mg/kg) or vehicle by subcutaneous delivery twice weekly for 6 weeks. Negative or positive controls received no treatment or disease through vehicle delivery, respectively. Biopsies were harvested after 3 and 6 weeks, and mandibulae were evaluated by microcomputed tomography (μCT) and histology. Serum levels of human OPG‐Fc and tartrate‐resistant acid phosphatase‐‐b (TRAP‐5b) were measured throughout the study by enzyme‐linked immunosorbent assay (ELISA). Statistical analyses included analysis of variance (ANOVA) and Tukey tests.

Results: Human OPG‐Fc was detected in the sera of OPG‐Fc–treated animals by 3 days and throughout the study. Serum TRAP‐‐b was sharply decreased by OPG‐Fc treatment soon after OPG‐Fc delivery and remained low for the observation period. Significant preservation of alveolar bone volume was observed among OPG‐Fc–treated animals compared to the controls at weeks 3 and 6 (P <0.05). Descriptive histology revealed that OPG‐Fc significantly suppressed osteoclast surface area at the alveolar crest.

Conclusion: Systemic delivery of OPG‐Fc inhibits alveolar bone resorption in experimental periodontitis, suggesting that RANKL inhibition may represent an important therapeutic strategy for the prevention of progressive alveolar bone loss.