6 Most ligands can bind to both types of ERs but differ in their binding affinities7 due to the high similarity of the ERα and ERβ in their DBD and a 55% similarly in their LBD.8 In response to estrogen, ERα and ERβ function as ligand-activated transcription factors that bind the estrogen response elements (EREs) and interact with co-activator or co-repressor proteins to regulate gene transcription.9–12 Aside from causing cancer, abnormal ER signaling may also give rise to cardiovascular, metabolic, inflammatory and neurodegenerative diseases as well as osteoporosis.13 This evidence concerns the gene ESR1 and osteoporosis.