The oxidative metabolism of estradiol conditions postmenopausal bone density and bone loss

Because lifelong exposure to estrogen is a strong determinant of bone mass, we asked whether metabolic conversion of estrogen to either inactive or ac tive metabolites would reflect postmenopausal bone mineral density (BMD) an d rate of bone loss. Biochemical markers of inactive estrogen metabolites, urinary 2-hydroxyestrogen (20HE(1)) and 2-methoxyestrogen (2MeOE(1)), and a ctive metabolites, urinary 16 alpha -hydroxyestrone (16 alpha UOHE1), estra diol (E-2), and estriol (E-3), were determined in 71 untreated, healthy pos tmenopausal women (age, 47-59 years) followed prospectively for 1 year. Uri nary 2MeOE(1) was correlated negatively with baseline vertebral (anteropost erior [AP] projection, r = -0.23 and p < 0.05; lateral view, r = -0.27 and p < 0.05) and proximal femur bone density measured by dual-energy X-ray abs orptiometry (DXA; total, r = -0.38 and p < 0.01; neck, r = -0.28 and p = 0. 02; trochanter, r = -0.44 and p < 0.01). BMDs of women in the lowest quarti le of urinary 2MeOE(1) (<15 ng/g) were significantly higher than those in t he highest quartile at all skeletal sites (p < 0.05). Likewise, women in th e lowest quartile of urinary 20HE(1)/16 alpha OHE1 ratio (<1.6) did not exp erience bone loss after 1 year, in contrast to women in the higher quartile s. We propose that the rate of inactivation of estrogens through 2-hydroxyl ation may contribute to postmenopausal osteoporosis.