In osteoporosis, a gene-environment interaction was observed between <i>CYP19A1</i> SNVs (rs700518, rs1062033, rs4775936, rs767199), <i>IL1β</i> rs16944, and 10-year probability of major fracture (CVC = 10/10).<h4>Conclusion</h4>Our findings suggest that <i>RANK</i> and <i>ESR1</i> variants are independently and interactively associated with osteoporosis and fracture risk, and that gene-gene and gene-environment interactions play a critical role in disease susceptibility among Mexican women. Here, ESR1 is linked to osteoporosis.