Does low estradiol after menopause increase bone resorption and does LRP5 rs3736228 reduce Wnt-mediated bone formation resilience?

Endocrine drivers of bone resorption

• Hormonal threshold: Postmenopausal depletion of endogenous estradiol below a critical threshold of 5 to 10 pg/mL removes key inhibitory brakes on osteoclastogenesis.
• Resorption biomarkers: This hormonal drop increases the systemic RANKL/OPG ratio, stimulating osteoclast survival and resulting in a two-fold elevation of bone resorption markers, specifically serum C-terminal telopeptide of type I collagen (CTX) and urinary N-telopeptide of type I collagen (NTX).

Molecular and genetic mechanisms

• LRP5 rs3736228 variant: This polymorphism causes an alanine-to-valine substitution (Ala1330Val) in the second $\beta$-propeller ligand-binding domain of the LRP5 co-receptor, acting as a hypomorphic, partial loss-of-function mutation.
• Blunted Wnt signaling: In vitro cellular stimulation by Wnt3a reveals that the rs3736228 variant significantly reduces downstream TCF/LEF transcriptional activation and canonical Wnt/$\beta$-catenin signaling.
• Uncoupled bone remodeling: The resulting impairment dampens osteoblastogenesis and bone-forming resilience. Furthermore, this attenuated Wnt signaling shifts the OPG/RANKL ratio in osteoblasts to promote osteoclast activity, compounding bone resorption.

Bottom line

• Postmenopausal estrogen deficiency directly drives bone loss by elevating the RANKL/OPG ratio (marked by increased CTX and NTX), while the LRP5 rs3736228 variant further compromises skeletal resilience by impairing Wnt-mediated bone formation and promoting additional osteoclast-mediated resorption.