A cohort study of the effect of endogenous estrogen on spine fracture risk and bone structure in elderly women and an assessment of its diagnostic usefulness R.L. Prince a,b, ⁎ , I.M. Dick a,b , J. Beilby d , S.S. Dhaliwal e , A. Devine a,b,c a School of Medicine and Pharmacology, Sir Charles Gairdner Hospital Unit, University of Western Australia, Australia b Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Australia c School of Exercise, Biomedical and Health Science, Edith Cowan University, Australia d PathWest Laboratory Medicine WA and School of Surgery and Pathology, University of Western Australia, Australia e School of Public Health, Curtin University of Technology, Australia Received 23 October 2006; revised 9 March 2007; accepted 23 March 2007 Available online 31 March 2007 Abstract The decline in endogenous estrogen concentration after menopause is associated with accelerated bone loss. However, effects in older women remain controversial and the usefulness of estrogen status as a predictor of spine fracture has not been assessed. Therefore, we undertook a prospective cohort study of 1350 women mean age 75 years in order to study the role of endogenous estrogen concentration on the risk of morphometric X-ray absorptiometry (MXA)-defined vertebral deformity and atraumatic clinical spine fracture and the association of endogenous estrogen with bone structure. At 5 years 70 patients (5.2%) had sustained ≥ 1 incident spine fracture. The fracture group had significantly lower concentrations of baseline free estradiol index (FEI) median (IQ range) (0.38 (0.22–0.60) vs. 0.49 (0.29–0.84) pmol/nmol, p = 0.009). The patients in the lowest tertile of FEI (FEI < 0.35) had twice the risk of sustaining a clinical vertebral fracture compared to those subjects in the highest tertile (FEI >0.68) (HR 2.18: 95% CI 1.11–4.28). A low FEI was associated with an increased risk of a vertebral deformity over the 5-year study (OR 1.77: 95% CI 1.02–3.07) for the lowest compared to highest tertile. A low baseline FEI was associated with lower baseline QUS heel bone structure and DXA hip bone structure at 12 months and with deterioration in QUS heel bone structure 5 years later. The effect size of the FEI in predicting spine fracture was similar to the effect size for DXA BMD and heel QUS, probably because of the beneficial effect of the FEI on bone structure. The data suggest that the estrogen effect on reducing spine fracture is at least in part due to an effect on bone structure and its measurement does not significantly improve fracture prediction. © 2007 Published by Elsevier Inc. Keywords: Estrogen; Vertebral fracture; Postmenopausal women; Bone mineral density Introduction It is generally accepted that the decline in circulating estrogen concentration after the menopause is associated with a rapid loss of bone mass, with a consequent rise in fracture risk [1]. In addition to these effects of declining estrogen around the menopause on bone loss and fracture risk, there is also evidence that low circulating concentrations of estrogen in women in their sixth and seventh decade are associated with lower bone mass and subsequent higher fracture risk [2–5] although not all investigators have supported these findings [6]. One study specifically examining vertebral fractures concluded that the association of endogenous estradiol and serum hormone binding globulin (SHBG) with spine fracture is independent of the association of hip BMD with spine fracture [7]. This would suggest that the measurement of Bone 41 (2007) 33 – 38 www.elsevier.com/locate/bone ⁎ Corresponding author. Department of Endocrinology and Diabetes, 1st Floor C Block, Sir Charles Gairdner Hospital, Nedlands, WA 6009, Australia. Fax: +61 8 9346 2587. E-mail address: rlprince@cyllene.uwa.edu.au (R.L. Prince). 8756-3282/$ - see front matter © 2007 Published by Elsevier Inc. doi:10.1016/j.bone.2007.03.014