Aromatase inhibitor-associated bone fractures: a case-cohort GWAS and functional genomics

Mol Endocrinol. 2014 Oct;28(10):1740-51. doi: 10.1210/me.2014-1147. Epub 2014 Aug 22.


Bone fractures are a major consequence of osteoporosis. There is a direct relationship between serum estrogen concentrations and osteoporosis risk. Aromatase inhibitors (AIs) greatly decrease serum estrogen levels in postmenopausal women, and increased incidence of fractures is a side effect of AI therapy. We performed a discovery case-cohort genome-wide association study (GWAS) using samples from 1071 patients, 231 cases and 840 controls, enrolled in the MA.27 breast cancer AI trial to identify genetic factors involved in AI-related fractures, followed by functional genomic validation. Association analyses identified 20 GWAS single nucleotide polymorphism (SNP) signals with P < 5E-06. After removal of signals in gene deserts and those composed entirely of imputed SNPs, we applied a functional validation "decision cascade" that resulted in validation of the CTSZ-SLMO2-ATP5E, TRAM2-TMEM14A, and MAP4K4 genes. These genes all displayed estradiol (E2)-dependent induction in human fetal osteoblasts transfected with estrogen receptor-α, and their knockdown altered the expression of known osteoporosis-related genes. These same genes also displayed SNP-dependent variation in E2 induction that paralleled the SNP-dependent induction of known osteoporosis genes, such as osteoprotegerin. In summary, our case-cohort GWAS identified SNPs in or near CTSZ-SLMO2-ATP5E, TRAM2-TMEM14A, and MAP4K4 that were associated with risk for bone fracture in estrogen receptor-positive breast cancer patients treated with AIs. These genes displayed E2-dependent induction, their knockdown altered the expression of genes related to osteoporosis, and they displayed SNP genotype-dependent variation in E2 induction. These observations may lead to the identification of novel mechanisms associated with fracture risk in postmenopausal women treated with AIs.

Trial registration: NCT00283608.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Anastrozole
  • Androstadienes / adverse effects
  • Androstadienes / pharmacology
  • Androstadienes / therapeutic use
  • Aromatase Inhibitors / adverse effects*
  • Aromatase Inhibitors / pharmacology
  • Aromatase Inhibitors / therapeutic use
  • Bone Density / drug effects
  • Female
  • Gene-Environment Interaction
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Middle Aged
  • Nitriles / adverse effects
  • Nitriles / pharmacology
  • Nitriles / therapeutic use
  • Osteoporosis / chemically induced*
  • Osteoporosis / genetics*
  • Osteoporotic Fractures / chemically induced*
  • Osteoporotic Fractures / genetics*
  • Polymorphism, Single Nucleotide
  • Triazoles / adverse effects
  • Triazoles / pharmacology
  • Triazoles / therapeutic use


  • Androstadienes
  • Aromatase Inhibitors
  • Nitriles
  • Triazoles
  • Anastrozole
  • exemestane

Associated data