Abstract: Introduction: The biological mechanisms associated with an inadequate response to treatment with bis-phosphonates are not well known. This study investigates the association between circulating levels ofsclerostin and estradiol with an inadequate clinical outcome to bisphosphonate therapy in women withpostmenopausal osteoporosis. Methods: This case-control study is based on 120 Spanish women with postmenopausal osteoporosisbeing treated with oral bisphosphonates. Patients were classified as adequate responders (ARs, n = 66,mean age 68.2 ± 8 years) without incident fractures during 5 years of treatment, or inadequate responders(IRs, n = 54, mean age 67 ± 9 years), with incident fractures between 1 and 5 years of treatment. Bonemineral density (DXA), structural analysis of the proximal femur and structural/fractal analysis of thedistal radius were assessed. Sclerostin concentrations were measured by ELISA and 17 -estradiol levelsby radioimmunoassay based on ultrasensitive methods. Results: In the ARs group, sclerostin serum levels were significantly lower (p = 0.02) and estradiol concen-trations significantly higher (p = 0.023) than in the IRs group. A logistic regression analysis was performed,including as independent variables in the original model femoral fracture load, 25 hydroxyvitamin D,previus history of fragility fracture, sclerostin and estradiol. Only previous history of fragility fracture(OR 14.04, 95% CI 2.38?82.79, p = 0.004) and sclerostin levels (OR 1.11, 95% CI 1.02?1.20, p = 0.011), bothadjusted by estradiol levels remained associated with IRs. Also, sclerostin concentrations were associatedwith the index of resistance to compression (IRC) in the fractal analysis of the distal radius, a parameteron bone microstructure. Conclusions: Sclerostin and estradiol levels are associated with the response to bisphosphonate therapyin women with postmenopausal osteoporosis.

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