Influence of the UGT2B17 Gene on the Relationship Between Exemestane and Bone Mineral Density in Postmenopausal Women

Abstract

Background: In the Mammary Prevention.3 (MAP.3) randomized placebo-controlled trial of exemestane, postmenopausal women experienced a loss in bone mineral density (BMD). UGT2B17 facilitates excretion of androgens and exemestane. For Caucasian postmenopausal women, this gene deletion is hypothesized to have 1) a protective effect on BMD and 2) worsened BMD in exemestane users.

Objective: The study objectives include studying the relationship between UGT2B17 genotype and 1) total hip and lumbar spine BMD at baseline with effect modification by previous bone medication or HRT use and 2) a meaningful decline total hip and lumbar spine BMD after two-years with effect modification by exemestane.

Methods: The BMD of all MAP.3 participants was assessed at study entry, and two-year follow-up BMD was obtained from two bone sub-studies, MAP.3 Bone Strength Substudy and MAP.3 Bone Substudy. The relative risk was calculated from multivariate modified Poisson regression models to assess the association between the UGT2B17 genotype and BMD with interaction by previous bone medication or HRT use and two-year change in BMD with interaction by exemestane.

Results: Amongst women who never used bone medications or HRT, the UGT2B17 deletion polymorphism had a borderline significant association with lumbar spine BMD at baseline (RR=0.72, 95% CI: 0.51-1.00), but the relationship was null with the total hip. There were no statistically significant associations between the UGT2B17 gene deletion and change in the total hip and lumbar spine BMD two years from baseline (RR = 1.17, 95% CI: 0.64-2.12 and RR = 0.98, 95% CI: 0.58-1.64 respectively), nor was there a significant interaction with treatment (pinteraction = 0.57 and pinteraction = 0.18 respectively).

Conclusions: While the UGT2B17 deletion polymorphism was associated with a borderline protective effect in lumbar spine BMD amongst postmenopausal women who never used bone medications or HRT, it was not significantly associated with two-year change in BMD. There was no evidence of a statistical interaction by treatment between UGT2B17 genotype and two-year change in BMD. Future goals of research pertaining to the UGT2B17 gene deletion should focus on its effect on endogenous estrogen availability in relation to BMD.