We have recently demonstrated that the effect of E2 on cortical bone mass requires AF-2 but not AF-1 in ERα.1 The dissimilar roles of AF-1 and AF-2 for the loading response, requiring AF-1 but not AF-2, and E2 response, requiring AF-2 but not AF-1, in cortical bone, demonstrate that the signaling pathways for these ERα-mediated mechanisms differ. The gene discussed is ESR1; the disease is atrial fibrillation.