Taken together, our study demonstrated that a QKI deficiency could aggravate osteopenia, and the mechanisms mainly included QKI deficiency increasing the local RANKL/OPG ratio to activate OC differentiation stimulated by RANKL, promoting OC formation by amplifying the signaling cascade of NF-κB and MAPK pathways, and inhibiting OB formation via the inflammatory microenvironment. Here, NFKB1 is linked to Osteopenia.