Genetic Relationship Between Estradiol Concentrations and Bone Mineral Density

osteoporotic bone
osteoporotic bone
Investigators sought to determine whether a relationship exists between estradiol level and bone mineral density.

Results of a genome-wide association study identified a significant association between estradiol levels and bone mineral density (BMD) among both men and women. These findings were published in the Journal of Clinical Endocrinology and Metabolism.

Researchers from Uppsala University in Sweden sourced data from the United Kingdom biobank. Individuals (n=438,417; n=49,994) were recruited between 2006 and 2010 and were genotyped via 2 different arrays. Participants were measured for estradiol, and BMD was assessed by ultrasound of the calcaneus.

A total of 135,200 men had estradiol below the detection limit (175 pmol/L) and 13,499 were above, 117,158 postmenopausal women were below and 10,090 were above, and 10,807 premenopausal women were below and 27,672 were above the limit. All 3 groups differed significantly for BMI on the basis of estradiol levels (all P <.05). For women, age, smoking status, hysterectomy status, hormone replacement therapy, contraceptive use, and age at menarche differed significantly on the basis of estradiol levels (all P <.05). Among the postmenopausal cohort, age at menopause and number of live births differed as well (both P <.05).

A total of 15 loci were significantly associated with estradiol (P <5´10-8), of which 13 were only significant among men, 1 was significant among both genders, and 1 was significant among only women.

Some of the identified loci had previously been associated with estradiol metabolism, the adrenal gland, androgen receptor, testosterone catabolism, and sex hormones.

For the locus that was common among men and women, the effect was largest among postmenopausal women (odds ratio [OR], 0.703; 95% CI, 0.642-0.770), followed by men (OR, 0.811; 95% CI, 0.758-0.868) and premenopausal women (OR, 0.907; 95% CI, 0.837-0.984).

Among the 96,432 men and 112,611 women who had available BMD information, a Mendelian randomization analysis calculated T-scores of -0.085 among men and -0.58 among women.

High estradiol was found to have a causal effect on BMD among men (b, 0.10; P =1.57´10-11) and women (b, 0.03; P =7.48´10-6). For every 1 standardized-unit increase in estradiol, there was a 0.38 (95% CI, 0.30-0.46) and 0.53 (95% CI, 0.31-0.74) increase in standard units of BMD among men and women, respectively.

This study may have included some reverse causation, in which the outcome was affected by the exposure.

These data indicated there was a causal relationship between estradiol concentrations and BMD among men and women.


Schmitz D, Ek WE, Berggren E, Höglund J, Karlsson T, Johansson Å. Genome-wide association study of estradiol levels, and the causal effect of estradiol on bone mineral density. J Clin Endocrinol Metab. Published July 13,2021. doi:10.1210/clinem/dgab507