Associations of RANKL/RANK/OPG pathway genetic variants and prosthodontic factors with severe residual ridge resorption

Severe residual ridge resorption (RRR) compromises prosthodontic success in edentulous patients, yet the underlying genetic mechanisms driving this alveolar bone loss remain undefined. Although genetic variants within the receptor activator of nuclear factor-κB ligand (RANKL)/receptor activator of nuclear factor-κB (RANK)/osteoprotegerin (OPG) axis drive osteoclast-mediated bone pathology, their specific role in RRR is largely uncharacterized. This study investigated the independent effects of targeted genetic variants within this pathway - RANKL (rs9533156), RANK (rs1805034), and OPG (rs2073618) - alongside clinical factors on severe RRR susceptibility. A cross-sectional sample of 226 healthy Vietnamese edentulous adults (95 severe RRR; 131 non-severe) was evaluated. Alveolar resorption, denture retention/stability, and occlusal factors were assessed using standardized clinical criteria. Following salivary DNA extraction, the variants were genotyped via Sanger sequencing. Multivariable regression revealed that not wearing dentures was associated with lower odds of severe RRR (aOR = 0.14; p = 0.027), whereas inappropriate occlusion was associated with higher odds (aOR = 3.28; p = 0.008). Genetically, a sex-specific interaction was observed for the RANKL rs9533156 polymorphism (p_interaction = 0.008, Wald test). Among individuals carrying the wild-type TT genotype, women were substantially more likely to have severe RRR than men (aOR = 6.65; p = 0.009). However, men carrying the minor C allele (TC/CC) exhibited a 5.22-fold increase in the odds of severe RRR relative to their TT counterparts (aOR = 5.22; p = 0.022), whereas no significant association was observed among women. For the OPG rs2073618 variant, an initial association was observed for the homozygous CC genotype in univariable models, while multivariable analysis assessing carriers of at least one C allele yielded a non-significant adjusted association (aOR = 0.50, p = 0.055). The RANK rs1805034 variant showed no statistical relationship with RRR risk. In conclusion, the RANKL rs9533156 polymorphism may represent a potential sex-specific marker of advanced mandibular bone loss. Larger-scale, independent investigations are required to confirm these exploratory associations before the genetic variants identified here could be considered for personalized RRR risk assessment.