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J Clin Endocrinol Metab. 2018 Sep 11. doi: 10.1210/jc.2018-00934. [Epub ahead of print]

Evidence of a Causal Effect of Estradiol on Fracture Risk in Men.

Author information

Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Bioinformatics Core Facility, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.



Observational studies indicate that serum estradiol (E2) is more strongly associated with bone mineral density (BMD) than serum testosterone (T) while both E2 and T associate with fracture risk in men.


To evaluate the possible causal effect of serum E2 and T on fracture risk in men.

Design, Setting, and Participants:

A Mendelian Randomization (MR) approach was undertaken using individual-level data of genotypes, BMD as estimated by quantitative ultrasound of the heel (eBMD), fractures (n=17,650), and relevant covariates of 175,583 unrelated men of European origin from the UK Biobank. The genetic instruments for serum E2 and T were taken from the most recent large scale GWAS meta-analyses on these hormones in men.


MR analyses demonstrated a causal effect of serum E2 on eBMD and fracture risk. A 1 SD (or 9.6 pg/ml) genetically instrumented decrease in serum E2 was associated with a 0.38 SD decrease in eBMD (p-value 9.7 x 10-74) and an increased risk of any fracture (OR 1.35, 95% CI, 1.18-1.55), non-vertebral major osteoporotic fractures (OR 1.75, 95% CI, 1.35-2.27) and wrist fractures (OR 2.27, 95% CI, 1.62-3.16). These causal effects of serum E2 on fracture risk were robust in sensitivity analyses and remained unchanged in stratified analyses for age, BMI, eBMD, smoking status, and physical activity. MR analyses revealed no evidence of a causal effect of T levels on fracture risk.


Our findings provide the first evidence of a robust causal effect of serum E2, but not T, on fracture risk in men.


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