Bone Safety Profile of Steroidal Aromatase Inhibitor in Comparison to Nonsteroidal Aromatase Inhibitors in Postmenopausal Women with Breast Cancer: A Network Meta-Analysis

Abstract

Background and objectives: Aromatase inhibitors (AIs) provide an alternative to tamoxifen as an adjuvant therapy for postmenopausal patients with breast cancer (BC). Large trials resulted better outcomes with AIs. Adjuvant therapy with AIs reduced the risk of relapse compared with tamoxifen. Systemic therapies for BC can interfere with bone turnover, either by affecting gonadal steroid hormone production or by inhibiting peripheral aromatization into estrogen. We aimed to evaluate the safety profile of bone-related events by comparing 3 AIs with tamoxifen and a placebo.

Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were used for network meta-analyses (NMAs). Searches were performed using PubMed, Embase/Medline, Cochrane, and Ovid databases. Randomized controlled trials comparing tamoxifen and placebo or other AIs to steroidal or nonsteroidal AIs in patients with BC reporting bone-related safety events were included in NMA. NMA in a Bayesian approach was performed using R software (ver 3.2), Gemtc package.

Results: Seventeen studies reporting 4 different bone-related endpoints were included. Although there was no statistical significance, treatment with exemestane lowered the incidence of bone pain (odds ratio [OR] vs. anastrozole and letrozole: 0.63, 0.54), fracture episodes (OR vs. anastrozole and letrozole: 0.84, 0.80), and osteoporosis (OR vs. anastrozole and letrozole: 0.85, 0.73) compared with letrozole and anastrozole. Reduction in bone mineral density was lesser in exemestane than in anastrozole (mean reduction in hip: 1.05; lumbar spine: 1.25). Treatment ranking with the surface under the cumulative ranking curve showed that exemestane was found to reduce the incidence of bone-related adverse events.

Conclusion: A lower incidence of bone-related safety events was observed in patients treated with exemestane.

Keywords: Aromatase inhibitor; Bone; Exemestane; Meta-analysis; Network; Tamoxifen.

Fig. 1

Study selection flow diagram.

Fig. 2

aNetwork diagram of evidences to show the number of studies obtained as direct evidences.bComparison of adjusted funnel plot for bone-related outcomes.

Fig. 3

aForest plot depicting relative safety with respect to bone pain with tamoxifen as comparator.bForest plot depicting relative safety with respect to bone pain with placebo as comparator.cCumulative rank plot for comparison of treatments based on safety for bone pain with tamoxifen and placebo as comparator.

Fig. 4

aForest plot depicting the relative safety with respect to osteoporosis with tamoxifen as comparator.bForest plot depicting the relative safety with respect to osteoporosis with placebo as comparator.cCumulative rank plot for comparison of treatments based on safety for osteoporosis with tamoxifen and placebo as comparators.

Fig. 5

aForest plot depicting the relative safety with respect to fracture episodes as compared to tamoxifen.bForest plot depicting the relative safety with respect to fracture episodes as compared to placebo.cCumulative rank plot for comparison of treatments based on safety for fracture episodes.

Fig. 6

aForest plot depicting the reduction in BMD in the lumbar spine compared with tamoxifen.bForest plot depicting the reduction in BMD in the lumbar spine compared with placebo.cForest plot depicting the reduction in BMD in the hip compared with tamoxifen.dForest plot depicting the reduction in BMD in the hip compared with placebo.eCumulative rank plot for comparison of treatments based on BMD at hip.fCumulative rank plot for comparison of treatments based on BMD at lumbar spine.