Aromatase inhibitors are associated with a higher fracture risk than tamoxifen: a systematic review and meta-analysis

Abstract

Background: In this paper, our aim was to systematically evaluate published evidence of bone fracture risk associated with tamoxifen and aromatase inhibitors in women aged 65 and under, and diagnosed with nonmetastatic breast cancer.

Methods: We comprehensively searched MEDLINE, EMBASE and CINAHL databases from January 1997 through May 2015, and reference lists of the selected articles to identify English-language randomized controlled trials and cohort studies of fracture risk. Two independent reviewers screened articles and assessed methodological quality using Risk of Bias assessment for randomized controlled trials and the Newcastle-Ottawa Scale for cohort studies. Fracture risk was estimated as pooled risk ratios using a random-effects model and inverse variance method.

Results: Of 1926 identified articles, 21 independent studies fulfilled our selection criteria. Similar fracture risk was observed in women treated and not treated with tamoxifen [pooled risk ratio (RR) 0.95; 95% confidence interval (CI) 0.84-1.07]. A 35% (95% CI 1.21-1.51) higher fracture risk was observed in the aromatase inhibitor group compared with the tamoxifen group. A 17% (95% CI 1.07-1.28) higher fracture risk was observed in the aromatase inhibitor group than the no aromatase inhibitor group. Compared with the tamoxifen group, aromatase inhibitor-associated fracture risk increased by 33% (pooled RR 1.33; 95% CI 1.21-1.47) during the tamoxifen/aromatase inhibitor treatment period, but did not increase (pooled RR 0.99; 95% CI 0.72-1.37) during the post-tamoxifen/aromatase inhibitor treatment period.

Conclusions: Fracture risk is significantly higher in women treated with aromatase inhibitors, especially during the treatment period. Tamoxifen is not associated with lower fracture risk while tamoxifen could potentially preserve bone mass. Better osteoporosis management programs, especially during the treatment period, are needed for this group of women.

Keywords: aromatase inhibitors; breast cancer; fracture risk; hormonal treatment; tamoxifen; women.

Figure 1.

Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) flow diagram for systematic review of the fracture risks associated with breast cancer treatments. ^aNo tamoxifen; ^bNo AIs. AIs, aromatase inhibitors; BMD, bone mineral density; RCT, randomized controlled trial; Tam, tamoxifen.

Figure 2.

Forest plot of comparison for fracture risk between women treated with tamoxifen and not treated with tamoxifen (control) by study design subgroups. The large diamond at the bottle of the table represents the pooled risk ratio of all studies. The width of the diamond represents with 95% CI. Results of study quality assessment were included. Risk of bias: (A) random sequence generation (selection bias); (B) allocation concealment (selection bias); (C) blinding of participants and personnel (performance bias); (D) blinding of outcome asessment (detection bias); (E) incomplete outcome data (attrition bias); (F) selective reporting (reporting bias); (G) other bias. Low risk of bias Unknown risk of bias High risk of bias CI, confidence interval; d.f., degrees of freedom; IV, inverse variance; RCT, randomized controlled trial; SE, standard error; Tam, tamoxifen.

Figure 3.

Forest plot of comparison for fracture risk between women treated with aromatase inhibitors and not treated with aromatase inhibitors (control) by study design subgroups. The large diamond at the bottle of the table represents the pooled risk ratio of all studies. The width of the diamond represents with 95% CI. Results of study quality assessment were included. Risk of bias: (A) random sequence generation (selection bias); (B) allocation concealment (selection bias); (C) blinding of participants and personnel (performance bias); (D) blinding of outcome asessment (detection bias); (E) incomplete outcome data (attrition bias); (F) selective reporting (reporting bias); (G) other bias. Low risk of bias Unknown risk of bias High risk of bias AI, aromatase inhibitor; CI, confidence interval; d.f., degrees of freedom; IV, inverse variance; RCT, randomized controlled trial; SE, standard error.

Figure 4.

Forest plot of comparison for fracture risk between women treated with aromatase inhibitors and treated with tamoxifen by study design subgroups. The large diamond at the bottle of the table represents the pooled risk ratio of all studies. The width of the diamond represents with 95% CI. Results of study quality assessment were included. Risk of bias: (A) random sequence generation (selection bias); (B) allocation concealment (selection bias); (C) blinding of participants and personnel (performance bias); (D) blinding of outcome asessment (detection bias); (E) incomplete outcome data (attrition bias); (F) selective reporting (reporting bias); (G) other bias. Low risk of bias Unknown risk of bias High risk of bias AI, aromatase inhibitor; CI, confidence interval; IV, inverse variance; RCT, randomized controlled trial; SE, standard error; Tam, tamoxifen.