Serum estradiol and sex hormone-binding globulin and the risk of hip fracture in elderly women:: The EPIDOS study

It has been suggested that low serum 17 beta-estradiol (E2) and sex hormone-binding globulin (SHBG) may predict hip fracture in postmenopausal women. We have investigated the predictive value of serum E2 and SHBG concentrations and urinary deoxypyridinoline (D-Pyr) and type I collagen breakdown products (CTX) in a large prospective cohort of 7598 healthy elderly ambulatory women (EPIDOS study), aged 75 years or more. We performed a nested case control study, by matching 212 patients with incident hip fracture with 636 controls. Mean follow-up was 3.3 years (maximum, 4.9 years). Women having serum E2 below the limit of detection (3 pg/ml), that is, 2% of the population, were not at higher risk, with a relative hazard (RH) of 1.59 (95 % CI = 0.45-5.55). Women having serum E2 below 5, 6, 7, or 8 pg/ml, in the lowest quartile, or below the median had no increased risk of hip fracture. In contrast, women having serum E2 in the highest quartile (i.e., greater than or equal to 10 pg/ml) were protected, with an RH of 0.66 (0.44-0.98) that did not remain significant after adjustment for weight (RH = 0.71 [0.47-1.06]). High serum SHBG values with different cut-offs tended to be associated with an increased risk of hip fracture. Women in the highest quartile had an RH of 2.5 (1.37-4.61), compared with those in the lowest quartile, that decreased markedly after adjustment for body weight (1.61 [0.99 -2.62]). The highest quartile of the ratio E2/SHBG, which is an index of free E2, was associated with a lower hip fracture risk (RH = 0.6 [0.4-0.91]) that was no longer significant after adjustment for weight. In contrast, urinary D-Pyr and CTX, when elevated above the upper limit of premenopausal values, were predictive of hip fracture, with an RH of 2.07 (1.49-2.9) and 1.67 (1.19-2.32), respectively, even after adjustment for body weight, serum E2, and SHBG. We conclude that in healthy elderly French women over 75 years of age, serum E2 and E2/SHBG in the highest quartile are associated with a lower risk of hip fracture and that this association is explained by a higher body weight. In addition, serum levels of E2 and SHBG do not account for the increased risk of hip fracture associated with high levels of bone resorption markers.