Gene-Hormone Therapy Interaction and Fracture Risk in Postmenopausal Women

J Clin Endocrinol Metab. 2017 Jun 1;102(6):1908-1916. doi: 10.1210/jc.2016-2936.


Context: Evidence supports a protective effect of menopausal hormone therapy (HT) on bone. However, whether genetic susceptibility modifies the association of HT and fracture risk is not sufficiently explored.

Objective: The objective was to test an interaction between genetic susceptibility and HT on fracture risk.

Design: We constructed two weighted genetic risk scores (GRSs) based on 16 fracture-associated variants (Fx-GRSs) and 50 bone mineral density variants (BMD-GRSs). We used Cox regression to estimate the main effects of GRSs and their interactions with HT on fracture risk. We estimated the relative excess risk due to interaction (RERI) as a measure of additive interaction. We also used the case-only approach to test for a multiplicative interaction.

Setting: Forty US clinical centers.

Participants: A total of 9922 genotyped white postmenopausal women (age, 50 to 79) from the Women's Health Initiative HT randomized trials.

Main outcome measures: Adjudicated fracture incidence.

Results: Both GRSs were associated with fracture risk per 1-unit increment in GRS (hazard ratio, 1.04 [95% confidence interval, 1.02 to 1.06] for Fx-GRS and hazard ratio, 1.03 [95% confidence interval,1.02-1.04] for BMD-GRS). We found no evidence for multiplicative interaction for either of the GRS. However, we observed a substantial additive interaction, where the highest quartile of both GRSs and randomization to placebo have excess fracture risk: Fx-GRS P for RERI = 0.047, BMD-GRS P for RERI = 0.046.

Conclusions: These results suggest that HT reduces fracture risk in postmenopausal women, especially in those at highest genetic risk of fracture and low BMD.

MeSH terms

  • Aged
  • Bone Density / genetics*
  • Contraceptive Agents, Female
  • Estrogen Replacement Therapy / statistics & numerical data*
  • Estrogens / therapeutic use
  • Estrogens, Conjugated (USP) / therapeutic use
  • Female
  • Fractures, Bone / epidemiology
  • Fractures, Bone / genetics*
  • Gene-Environment Interaction
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Incidence
  • Medroxyprogesterone Acetate / therapeutic use
  • Middle Aged
  • Proportional Hazards Models
  • United States
  • White People / genetics


  • Contraceptive Agents, Female
  • Estrogens
  • Estrogens, Conjugated (USP)
  • Medroxyprogesterone Acetate