Performance of FRAX in Women with Breast Cancer Initiating Aromatase Inhibitor Therapy: A Registry-Based Cohort Study

Abstract

FRAX was developed to predict 10‐year probability of major osteoporotic fracture (MOF) and hip fracture in the general population. Aromatase inhibitors (AI) used in breast cancer induce loss in bone mineral density (BMD) and are reported to increase fracture risk. AI exposure is not a direct input to FRAX but is captured under “secondary osteoporosis”. To inform use of FRAX in women treated with AI, we used a population‐based registry for the Province of Manitoba, Canada, to identify women aged ≥40 years initiating AI for breast cancer with at least 12 months’ AI exposure (n = 1775), women with breast cancer not receiving AI (n = 1016), and women from the general population (n = 34,205). Among AI users, fracture probability estimated without BMD (AI use coded as secondary osteoporosis) significantly overestimated risk (10‐year observed/predicted ratio 0.56, 95% confidence interval [CI] 0.45–0.68; 10‐year hip fracture observed/predicted ratio 0.33, 95% CI 0.18–0.49). However, when BMD was included in the fracture probability, there was no significant difference between observed and predicted fracture risk. In Cox proportional hazards models, FRAX stratified risk of MOF, hip, and any fracture equally well in all subgroups (p‐interaction >0.1). When adjusted for FRAX score without BMD, with AI use coded as secondary osteoporosis, AI users were at significantly lower risk for MOF (hazard ratio [HR] = 0.78, 95% CI 0.64–0.95), hip fracture (HR = 0.46, 95% CI 0.29–0.73) and any fracture (HR = 0.75, 95% CI 0.63–0.89). AI use was no longer significantly associated with fractures when AI use was not entered as secondary osteoporosis in FRAX without BMD or when BMD was included in the FRAX calculation. In conclusion, FRAX scores stratify fracture risk equally well in women receiving AI therapy as in non‐users, but including secondary osteoporosis as a risk factor for AI users overestimates fracture risk. Our results call this practice into question. © 2019 American Society for Bone and Mineral Research.

Performance of FRAX in Predicting Fractures in US Postmenopausal Women with Varied Race and Genetic Profiles

“…Moreover, inconsistent findings regarding the performance of FRAX without BMD was reported in several other studies. Leslie et al observed that the fracture probability estimated without BMD overestimate risk among the general population [36], which is consistent with findings from the present study. Other studies have reported underestimation of fracture risk by FRAX [12,37,38], but their methodologies have lately been found to be problematic because they either compared incidence with probabilities or failed to take the competing mortality risk into account [39].…”

Osteoporosis: A Long-Term and Late-Effect of Breast Cancer Treatments

“…In the registry study, the designation of “secondary osteoporosis” as a risk factor for AI-induced bone loss overestimates fracture risks [ 67 ]. In multivariate analysis, women with breast cancer initiating AI-therapy had higher body mass index, higher BMD, lower osteoporosis prevalence, and fewer prior fractures than women not starting AIs or the healthy population [ 68 ]. The implications being AIs do not cause as many fractures as previously thought.…”

Evaluation of Pentosidine as Bone Quality Marker in Postmenopausal Breast Cancer Patients Receiving Aromatase Inhibitors

“…The Fracture Risk Assessment Tool (FRAX) is used to estimate the risk of osteoporotic fracture using femoral neck BMD and clinical risk factors, which include age, prior nontraumatic fracture, glucocorticoid use, low body mass index, family history of osteoporosis, smoking, and excess alcohol intake, which are also associated with incidence of fracture. However, FRAX is not designed to estimate the risk of AI-related fracture, and the estimated fracture risk by FRAX tends to be lower than that of the actual fracture incidence in breast cancer patients receiving AI [19]. Thus, the evaluation of other risk factors is warranted to determine appropriate administration of BMA to prevent AI-related fracture in postmenopausal breast cancer patients.…”