Putting the Breaks on Low Testosterone and Fractures in Men

Low serum estradiol found to have a causal effect on bone mineral density and fracture risk in men vs low testosterone, according to a new study.

Reference: Nethander M, Vandenput L, Eriksson AL, et al. Evidence of a causal effect of estradiol on fracture risk in men. J Clin Endocrinol Metab. 2018.

Maria Nethander and colleagues in Sweden found that low serum estradiol (E2) had a causal effect on bone mineral density and fracture risk in men while low testosterone (T) did not. Click through the slides above for details on their study and take home messages for physicians.

Sex Steroids and Male Bone Health. Observational human and animal studies have shown serum E2 is more closely associated with bone mass and strength in men vs serum T, however, the absence of randomized investigations has prevented determination of causality. Authors of the study used Mendelian randomization design to determine the effect of genetically lowered E2 or T levels on eBMD and fracture risk in European men.  

The Study. A genome-wide association study and meta-analysis led to the current study that utilized MR instrument for E2 and T, to look at SNPs in 175 583 UK men. Authors used quantitative ultrasound of the heel to obtain non-invasive eBMD to predict fracture risk. Authors assessed the effects of the SNPs on eBMD and fractures, weighting the effect of each SNP by the magnitude of its effect on E2 or T levels. 

The Results:

  • No significant association was found between E2 or T SNPs and BMI, smoking status, age, or physical activity 
  • E2-decreasing alleles of both SNPs were significantly associated with decreased eBMD and an increased risk of any fracture, non-vertebral major osteoporotic fractures, and wrist fractures
  • Using MR analysis, decrease in E2 levels by 1 SD associated with 0.38 SD decrease in eBMD
  • Causal effects of E2 on eBMD was robust; remained unchanged in stratified analyses by age, BMI, smoking status, and physical activity

The Results (cont.):

  • Decrease in E2 levels by 1 SD associated with increased risk of any fracture and non-vertebral major osteoporotic fractures
  • Post-MR analysis showed causal effect of E2 on fracture risk was robust; remained significant and of similar magnitude in stratified analyses
  • No significant interaction effect on fracture risk was observed for E2-GRS and age, BMI, smoking status, or physical activity
  • Sensitivity analyses excluded possible E2-mediated effects showed no evidence of causal effect of T on eBMD
  • Further analyses failed to reveal any significant causal effect of T on fracture risk 

Take Home Points:

  • Prior belief that T is significant factor in male bone health may be flawed
  • Study model allowed for the determination of causality that wasn't previously possible
  • Results suggest E2 deficiency has causal effect on eBMD and fracture risk in men vs low T
  • Causal relationship between low eBMD, fractures, and low E2 remains when age, BMI, eBMD, smoking status, and physical activity accounted for
  • Consider these findings in men when following endocrine treatment for prostate cancer
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