ESR2 and osteoporosis: 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