In this population-based study of 2,748 women 65 and over with breast cancer in 2003, the hazard for hip fracture for users of an aromatase inhibitors compared with users of tamoxifen was 3.24 (95% CI 1.05, 9.98), with an absolute increase in hip fracture of 1.1% over 36 months. Hip fracture risk among women not taking any hormone therapy was also elevated compared to users of tamoxifen. There were no statistically significant differences between these three groups in risk of total nonvertebral fractures. Although AI users were more likely than other women to be taking a bisphosphonate, this did not alter any of these findings. Major fracture risk factors in non-cancer populations including age, low body mass index, and prior fractures were strongly associated with fractures.
This study offers support for the possibility that some of the differences in fracture risk between tamoxifen and AIs occur through a protective effect of tamoxifen. Placebo-controlled studies from the 1990s reported that tamoxifen increased BMD in postmenopausal women by 1% to 2% yearly compared with placebo-controlled studies, but evidence regarding fractures has been mixed [15
]. The NSABP Breast Cancer Prevention Study P-1 reported a substantial but not statistically significant reduction in the risk of hip (relative risk (RR) 0.55 (0.25–1.15)) and total (RR 0.81 (0.63–1.05)) fractures in its primary report on 5 years of tamoxifen chemoprevention [33
]. The effect of tamoxifen vs placebo on total fractures, however, became statistically significant with two additional years of follow-up [34
]. A smaller Danish randomized trial of tamoxifen compared with placebo among breast cancer patients reported no difference in fractures [35
]. Our study is thus consistent with existing knowledge from the largest prior tamoxifen study, but to our knowledge is the first to show that adjuvant tamoxifen is associated with a lower risk of hip fracture than no hormonal therapy.
This study also provides some of the first direct evidence of the fracture risk of aromatase inhibitors when compared with no adjuvant hormonal therapy. The findings of no difference in fractures between AI users and those who did not take hormonal therapy may at first appear contradictory to the limited bone density literature to date. Adjuvant exemestane for 2 years worsened hip BMD loss compared with placebo in one study of 147 women (2.72% vs 1.42%, p
= 0.024) [18
], and another study of 2 years of letrozole after 5 years of tamoxifen [36
] found greater spine and hip BMD reductions for letrozole users than placebo [36
]. However, no patients with normal baseline BMD in either study became osteoporotic, and no differences were demonstrated in progression from osteopenia to osteoporosis. Given the potential for a delay in bone density impacts upon fracture risk, our study may thus be consistent with these previous findings. It is also possible that a smaller AI effect was not detectable, while the tamoxifen effect of 1% to 2% yearly difference between tamoxifen and placebo could be observed. Our large study of patients at high baseline fracture risk also adds to these previous reports by showing that even in a real-world setting, BMD effects of AIs did not translate into substantial short-term increases in fracture risk compared with no hormonal treatment.
Our lack of ability to identify total nonvertebral fractures between AI and tamoxifen users is somewhat surprising given the difference we found for hip fractures by AI and tamoxifen use. Given the confidence intervals in our study, it is possible that the risk conferred by aromatase inhibitors is actually similar for total and hip fractures. If there are differences, our study cannot directly address the possible reasons. However, our patients are likely to have been more frail than those in the randomized trials. They were older, with a median age near 73, and over one third had a major comorbidity. The incidence of hip fracture in our study was three times higher than corresponding early results from ATAC and was consistent with a subgroup analysis of 295 women ≥75 from the BIG 1–98 trial, in which there were four hip fractures with letrozole and one with tamoxifen [11
]. It is also possible that women who switched from tamoxifen to AIs led us to underestimate the differences between these two groups in our total nonvertebral fracture results. However, the annualized absolute risk of total fracture in the tamoxifen group in our study was higher than in the ATAC anastrozole trial [5
], and the hazard for the comparison of AIs with tamoxifen was only slightly smaller.
Our results offer important information to supplement the clinical trials regarding the absolute risk of fracture among breast cancer patients, both treated and untreated with hormonal therapy. The study cohort’s higher risk compared with AI trial enrollees is probably conferred by age, comorbidity, and the higher number of nonwhite patients in our study [11
]. Several large trials were performed primarily in Western Europe and the USA and had few nonwhite participants. Since personal or family history of fractures were not systematically measured in the randomized trials, comparison with our cohort is difficult, although it is possible that these risk factors were more prevalent in our cohort as well. The fracture risks in the breast cancer cohort are comparable to non-cancer US estimates based on a Rochester Minnesota cohort [37
Our study has limitations, several of which are common to observational research. Subjects were not randomly assigned to therapies, and it is possible that providers took fracture risk into account in treatment decisions. Our results are consistent with the possibility that physicians used lower BMI in decisions to prescribe tamoxifen. We were able, however, to adjust for this and multiple other fracture risk factors that clinicians might consider, and this adjustment did not appreciably change our findings. Our survey study could not obtain reliable information regarding bone density test results, although we did have information about bisphosphonate use. Our study was limited by the cohort’s relatively small number of fractures and short duration, although it included more older patients than any of the large AI trials. We could not exclude from our fracture outcomes any high-trauma fractures, but we would not expect these to differ by hormonal therapy use. As discussed above, women who switched therapies may have affected our results. Given that most switched from tamoxifen to AIs, however, they are not likely to explain the higher rate of hip fractures among AI vs tamoxifen users.
Our study results should also be considered in the context of recent studies of bone loss prevention in breast cancer patients. Bisphosphonates have been shown to maintain BMD in postmenopausal patients taking AIs [38
], although none of these studies was powered to examine fractures. Enthusiasm for using bisphosphonates may be further bolstered by early results of studies showing an antitumor effect of adjuvant bisphosphonates in postmenopausal women [40
]. However, bisphosphonates can cause osteonecrosis of the jaw, a severe and potentially disfiguring condition [41
], and recent warnings of possible increased risks of atrial fibrillation [42
] and esophageal cancer [44
] might also raise concerns. Furthermore, adjustment for bisphosphonate use in our study did not substantially change our results. Perhaps this occurred because of insufficient study treatment time and/or the lack of ability to adjust for baseline bone density. It is also possible, however, that the preservation of bone density shown in trials of bisphosphonates for AI-related BMD losses does not translate into measurable fracture effects. Better understandings of the comparative bony risks of hormonal therapies are thus crucial for decision making about both hormonal and bisphosphonate treatments.
In conclusion, in a population-based cohort of older female breast cancer patients, users of aromatase inhibitors had a substantially higher risk of hip fracture, though not total nonvertebral fracture, than users of tamoxifen. Furthermore, the absolute hip fracture risk difference of just over 1% over 3 years that we identified is unlikely to outweigh the benefits of aromatase inhibitors over tamoxifen in improved breast cancer survival and reduced thromboembolism and endometrial cancer [45
]. This information, including the higher fracture risks measured among our cohort than reported in randomized trials, can, however, be useful prognostically to clinicians and patients considering bony protective treatment options. Trials of AI use beyond 5 years are currently enrolling, and continuing evaluation of AIs’ long-term effects on bone will be needed.