RANKL and OPG Polymorphisms Are Associated with Aromatase Inhibitor-Related Musculoskeletal Adverse Events in Chinese Han Breast Cancer Patients

BACKGROUND: Breast cancer patients treated with aromatase inhibitors (AIs) may experience musculoskeletal adverse events (MS-AEs). Several studies have confirmed that the RANKL/RANK/OPG signaling pathway plays a dominant role in bone health. Therefore, this study aimed to analyze the relationship between the serum levels of RANKL, OPG and their SNPs (single nucleotide polymorphisms) with AI-related MS-AEs. METHODOLOGY AND PRINCIPAL FINDINGS: Patients with early stage, hormone-sensitive breast cancer who were receiving AI therapy were enrolled. We included 208 cases with AI-related MS-AEs and 212 without (controls). The levels of estradiol, bone-turnover markers, multiple inflammatory cytokines, RANKL,OPG and lumbar spine BMD were measured, and questionnaires were completed. We analyzed 29 SNPs of RANKL, RANK and OPG using Sequenom MassARRAY assays and PCR-based TaqMan assays. The levels of bone-turnover markers and RANKL and the ratio of RANKL/OPG were higher in patients with AI-related MS-AEs than controls (all p < 0.05). A genetic assay showed that the RANKL SNP rs7984870 and OPG SNP rs2073618 were associated with AI-related MS-AEs. In patients with AI-related MS-AEs, rs7984870 CC and rs2073618 CC were risk genotypes. Carriers of the rs7984870 CC genotype were more likely to have a higher RANKL level and RANKL/OPG ratio than carriers of the GG genotype, and carriers of the rs2073618 CC genotype were more likely to have a lower OPG level and a higher RANKL/OPG ratio than carriers of the GG genotype (all p < 0.05). Moreover, risk genotypes were associated with higher levels of serum CTX and PINP and a lower lumbar spine BMD (all p < 0.05). CONCLUSIONS AND SIGNIFICANCE: In conclusion, the RANKL and OPG risk genotypes synergize to negatively impact bone health and predispose breast cancer patients to AI-related MS-AEs.