A significant gene-gene interaction between <i>ESR1</i> (rs2228480) and <i>RANK</i> (rs3018362) increased osteoporosis risk (OR = 2.1 [1.4-3.2], CVC = 10/10), and a gene-gene model involving <i>ESR1</i>, <i>IL6R</i>, <i>IL1β</i>, and <i>RANKL</i> was identified for hip fracture (CVC = 8/10). Here, IL1B is linked to osteoporosis.