In summary, 13 differentially methylated genes, including PLEKHA2, PLEKHB1, PNPLA7, SCD, MGST3, TSNAX, PRKCZ, GNA11, COL4A1, SOX6, ACE, SYK and TGFB3, and 5 related signaling pathways (calcium, cGMP‐PKG, endocytosis, Rap1 and AMPK) were identified in postmenopausal women with osteoporosis in this study. The gene discussed is PLEKHB1; the disease is osteoporosis.