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Serum estradiol associated with fracture risk in men

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September 13, 2018

Among white men, serum estradiol exerts a “robust causal effect” on fracture risk, independent of age, BMI, smoking status and physical activity level, according to findings from a large Mendelian randomization analysis.

Claes Ohlsson

In an analysis of genome-wide association study data from men participating in the UK Biobank, the researchers also found no causal link between testosterone levels and estimated bone mineral density, a predictor of fracture risk.

“Based on the findings in the present study, one may speculate that treatments augmenting serum estradiol, such as testosterone supplementation, may reduce fracture risk in men,” Claes Ohlsson, MD, PhD, professor at the Institute of Medicine and director of the Centre for Bone and Arthritis Research at Sahlgrenska Academy, University of Gothenburg, Sweden, told Endocrine Today. “However, to avoid androgen receptor-related side effects, one might consider bone-specific selective estrogen receptor modulators to reduce fracture risk in men. In addition, our findings indicate that nonaromatizable androgens, not augmenting estradiol, will be inefficient in reducing fracture risk in men.”

Ohlsson and colleagues analyzed genome-wide association study data from 175,583 men aged 37 to 76 years participating in the UK Biobank, including estradiol- and testosterone-associated single nucleotide polymorphisms. Researchers estimated BMD using quantitative ultrasound of the heel and self-reported fractures in select participants (n = 17,650).

In Mendelian randomization analyses, researchers observed a causal effect of serum estradiol on estimated BMD and fracture risk. Each 1-standard deviation (or 9.6 pg/mL) genetically instrumented decrease in serum estradiol was associated with a 0.38-standard deviation decrease in estimated BMD and increased risk for any fracture (OR = 1.35; 95% CI, 1.18-1.55).

When stratified by fracture type, researchers observed a greater risk for nonvertebral major osteoporotic fractures (OR = 1.75; 95% CI, 1.35-2.27) and wrist fractures (OR = 2.27; 95% CI, 1.62-3.16) for each 1-standard deviation genetically instrumented decrease in serum estradiol. Results persisted after adjustments for age, BMI, estimated BMD, smoking status and physical activity.

The researchers noted that a low number of hip and spine fractures precluded separate hip and spine fracture analyses. Researchers did not observe a causal link between testosterone levels and fracture risk.

In an interview, Ohlsson said the finding of a causal effect of serum estradiol, but not testosterone, on fracture risk might also be of importance for estimating possible skeletal side effects of endocrine therapies in men with prostate cancer.

“Our findings suggest that chemical castration with [gonadotropin-releasing hormone] agonists, as well as CYP17 inhibition using abiraterone, will result in increased fracture risk in these patients, since both treatments will reduce serum testosterone as well as serum estradiol levels,” Ohlsson said. “This notion is supported by a substantially increased fracture risk in prostate cancer patients after chemical castration. In contrast, our data, showing no causal effect of testosterone on fracture risk, indicate that endocrine prostate cancer treatment with the specific androgen receptor antagonist enzalutamide (Xtandi; Astellas, Pfizer) could avoid these skeletal side effects.” – by Regina Schaffer


For more information:

Claes Ohlsson, MD, PhD, can be reached at the Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Vita Stråket 11, SE-413 45, Gothenburg, Sweden; email:

Disclosures: The Swedish Research Council, the Swedish Foundation for Strategic Research, the ALF research grant in Gothenburg, the Lundberg Foundation, Knut and Alice Wallenberg Foundation, the Torsten and Ragnar Soderberg’s Foundation and the Novo Nordisk Foundation supported this study. The authors report no relevant financial disclosures.