Genetic Polymorphisms of Nuclear Factor-κB Family Affect the Bone Mineral Density Response to Zoledronic Acid Therapy in Postmenopausal Chinese Women

Abstract

The aim of this study was to explore the allelic association between genetic polymorphisms of the NF-κB pathway and the variance of clinical effects of zoledronic in postmenopausal Chinese women with osteoporosis. In the study, 110 Chinese postmenopausal women with osteoporosis were recruited. Every patient received zoledronic once a year. BMD was measured at baseline and after one year of treatment. The 13 tagger SNPs of five genes in the NF-κB pathway were genotyped. In the study, 101 subjects completed the one-year follow-up. The ITCTG and DTCTG haplotypes, which are constituted of rs28362491, rs3774937, rs230521, rs230510 and rs4648068 of the NF-κB1 gene, were associated with improvement in BMD at L1-4 and femoral neck (p < 0.001, p = 0.008, respectively). The CGC haplotype, which is constituted of rs7119750, rs2306365 and rs11820062 of the RELA gene, was associated with improvement in BMD at total hip (p < 0.001). After Bonferroni correction, haplotypes ITCTG and CGC still showed significant association with the % change of BMD at L1-4 and total hip. Therefore, NF-κB1 and RELA gene were significantly associated with bone response to the treatment of zoledronic in postmenopausal Chinese women with osteoporosis.

Regulation of bone homeostasis: signaling pathways and therapeutic targets

“…In the canonical pathway, upon exposure to RANKL, TNF‐α, IGF signaling, IκB kinase β (IKKβ) and IκB kinase γ (IKKγ, also known as NEMO) phosphorylate and degrade IκB kinase α (IKKα), resulting in the nuclear translocation of the NF‐κB1 (p50) and RelA (p65) complex. 139 Conversely, in the noncanonical route, cytokine stimulation leads to TNF receptor associated factor 3 (TRAF3) degradation after binding to the cytokine receptor, stabilizing NF‐κB‐inducing kinase (NIK), continuously degraded through the TRAF3 interaction. This stabilization activates IKKα, prompting the conversion of NF‐κB2 (p100) into its active RelB (p52) form and enabling RelB/p52 complexes to enter the nucleus.…”

Are secondary effects of bisphosphonates on the vascular system of bone contributing to increased risk for atypical femoral fractures in osteoporosis?

“…BP treatment is also reported to influence the properties of bone, [41] and some genetic polymorphisms have also been implicated in the bone response to BP. [49] It is also not certain presently if such findings are directly or indirectly involved in the outcomes leading to AFF risk, but a generalized effect of BP on bone quality must be entertained as potentially playing a role in the risk as it also appears to affect surgical outcomes in the treatment of patients with an AFF. [50] Based on the characteristics discussed above, it is clear that some clues are available that pertain to what may be looked for regarding possible mechanisms contributing to AFF risk.…”