‘Fracture incidence after 3 years of aromatase inhibitor therapy’

Abstract

We read with interest the study by Bouvard et al. [1.Bouvard B. Soulié P. Hoppé E. et al.Fracture incidence after 3 years of aromatase inhibitor therapy.Ann Oncol. 2014; 25: 843-847Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar], who conclude that aromatase inhibitors (AI) have limited impact on bone mineral density (BMD) and fracture incidence in post-menopausal women without baseline osteoporosis, whereas oral bisphosphonates in the group with baseline osteoporosis are associated with persistent fracture risk, particularly in older women. We are concerned that the skeletal risks of AI are underplayed by both the authors as well as media coverage claiming that ‘AI don't increase fracture risk’. First of all, the World Health Organization diagnosis of osteoporosis is a BMD T-score of ≤-2.5 and not <-2.5; a common mistake, sometimes reiterated by reimbursement agencies. Therefore, women with a T-score of -2.5 were misclassified in this study and probably merited treatment e.g. with a generic bisphosphonate. The average age of the overall cohort is somewhat lower than in the original cohort (63.1 versus 63.8 years). We wonder whether fracture risk may have been underestimated because participants lost to follow-up were older? The fracture rates of 5.6 and 9.8% over 3 years translate to a 10-year fracture risk of at least 18.7 and 32.7% in the respective groups (and probably more, given the exponential increase in fracture incidence with aging and the fact that AI are usually given for 5 years). US guidelines advise treatment if this risk is ≥20%; therefore, we consider the observed fracture incidences high for both groups. The lack of a control group is a major limitation of this study, but if we calculate baseline FRAX for the untreated AI group, the estimated 10-year probability of major osteoporotic fractures was only 3.1%. This suggests that AI indeed increased fracture risk, which is supported by evidence from randomized trials [2.Howell A. Cuzick J. Baum M. et al.Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer.Lancet. 2005; 365: 60-62Abstract Full Text Full Text PDF PubMed Scopus (2031) Google Scholar, 3.Coleman R.E. Banks L.M. Girgis S.I. et al.Skeletal effects of exemestane on bone-mineral density, bone biomarkers, and fracture incidence in postmenopausal women with early breast cancer participating in the Intergroup Exemestane Study (IES): a randomised controlled study.Lancet Oncol. 2012; 13: 275-284PubMed Google Scholar]. A ‘real-life’ observational study cannot controvert this. The conclusion that BMD losses were only moderate is also flawed; this is due to the poor resolution and sensitivity of dual-energy X-ray absorptiometry. BMD losses of similar magnitude were not only highly significant versus placebo in the MAP.3 trial, but also associated with much larger deterioration in true volumetric BMD and cortical thickness [4.Cheung A.M. Tile L. Cardew S. et al.Bone density and structure in healthy postmenopausal women treated with exemestane for the primary prevention of breast cancer: a nested substudy of the MAP.3 randomised controlled trial.Lancet Oncol. 2012; 13: 275-284Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar]. Finally, since bisphosphonates have been suggested to increase survival in post-menopausal breast cancer patients [5.Ben-Aharon I. Vidal L. Rizel S. et al.Bisphosphonates in the adjuvant setting of breast cancer therapy—effect on survival: a systematic review and meta-analysis.PLoS One. 2013; 8: e70044Crossref PubMed Scopus (32) Google Scholar], we believe that therapeutic nihilism about skeletal health in older women receiving AI is unjustified. MRL is a fellow of the Research Foundation Flanders (FWO) and received lecture fees from Flanders' Agricultural Marketing Board (VLAM). DV is a senior clinical investigator of the Clinical Research Funds of the University Hospitals Leuven, Belgium. PN has no conflicts of interest.