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FRAX data suggest no increased fracture risk with aromatase inhibitor use

The Fracture Risk Assessment Tool, or FRAX, overestimated the probability of a major osteoporotic or hip fracture over 10 years among women with breast cancer when calculations included use of aromatase inhibitor therapy, according to findings published in the Journal of Bone and Mineral Research.

The findings challenge assumptions that aromatase inhibitor use increases fracture risk.

William D. Leslie

“The FRAX tool, which is widely used to assess fracture risk in the general population, works equally well to assess fractures in women with breast cancer receiving aromatase inhibitor therapy,” William D. Leslie, MD, MSc, FRCPC, professor of medicine and radiology at the University of Manitoba, Winnipeg, told Endocrine Today. “It extends the use of FRAX, and our article provides guidance for not including aromatase inhibitor use as a secondary cause of osteoporosis in the calculation.”

In a registry-based, cohort study, Leslie and colleagues analyzed data from women aged 40 years or older with and without a diagnosis of breast cancer who underwent a baseline bone mineral density measurement via DXA between 2005 and 2016. The data included retrospectively calculated FRAX scores and at least 1 year of follow-up after BMD testing. Women were stratified into three groups: breast cancer with aromatase inhibitor use (n = 1,775), breast cancer without aromatase inhibitor use (n = 1,016) and no breast cancer diagnosis (controls; n = 34,205). Incident fracture history was assessed via health service records. Researchers calculated 10-year probability of a major osteoporotic fracture and hip fracture using the Canadian FRAX tool, calibrated with nationwide hip fracture and mortality data.

Mean follow-up ranged from 6.2 years for women prescribed aromatase inhibitors to 7.3 years for women with breast cancer who did not use aromatase inhibitors. During follow-up, 3,808 women died, 2,795 women experienced a major osteoporotic fracture, 864 women experienced a hip fracture and 3,736 women experienced any clinical fracture.

Compared with controls, women with breast cancer were at higher risk for death, with similar HRs for women prescribed aromatase inhibitors (HR = 1.35; 95% CI, 1.17-1.55) and those not using aromatase inhibitors (HR = 1.37; 95% CI, 1.16-1.61).

Among aromatase inhibitor users, calculations of fracture probability without BMD, with aromatase inhibitor use coded as secondary osteoporosis, overestimated 10-year predicted risk for major osteoporotic fracture when compared with observed fractures during follow-up (13% vs. 7.2%; observed/predicted ratio, 0.56; 95% CI, 0.45-0.68). This discrepancy was attenuated when secondary osteoporosis was not included in the FRAX estimates, according to researchers. When BMD was included in the fracture probability, observed and predicted fracture risks did not differ significantly. Results for 5-year fracture outcomes were similar.

In Cox proportional hazards models that did not include BMD in baseline fracture probability, aromatase inhibitor use was associated with lower risk for major osteoporotic fracture vs. controls (HR = 0.78; 95% CI, 0.64-0.95), as well as lower risk for hip fracture (HR = 0.46; 95% CI, 0.29-0.73) and any fracture (HR = 0.75; 95% CI, 0.63-0.89).

“When secondary osteoporosis was excluded or BMD was included in the estimation of baseline fracture risk, [aromatase inhibitor] use was no longer significantly associated with fracture,” the researchers wrote. “Breast cancer without [aromatase inhibitor] use was not associated with a significant increase in any fracture outcomes.”

The researchers noted that a higher baseline BMI and BMD observed in women prescribed aromatase inhibitor therapy, along with a lower incidence of prior fracture, may offset the adverse effects of aromatase inhibitor exposure.

“Our findings challenge the view that the average woman with breast cancer is at high risk for fracture at the time of initiation of [aromatase inhibitor] therapy,” the researchers wrote. “In fact, at baseline, these women appear to be at relatively lower fracture risk than the general population and women with breast cancer not initiating [aromatase inhibitor] therapy because of higher BMI, BMD, T-score and lower prevalence of a prior fracture. Fracture probability scores from FRAX stratify fracture risk equally well in women receiving [aromatase inhibitor] therapy as in nonusers, but including secondary osteoporosis as a risk factor for [aromatase inhibitor] users in the calculation leads to overestimation in predicted fracture risk. Our results call this practice into question.” – by Regina Schaffer

Disclosures: Leslie reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.

The Fracture Risk Assessment Tool, or FRAX, overestimated the probability of a major osteoporotic or hip fracture over 10 years among women with breast cancer when calculations included use of aromatase inhibitor therapy, according to findings published in the Journal of Bone and Mineral Research.

The findings challenge assumptions that aromatase inhibitor use increases fracture risk.

William D. Leslie

“The FRAX tool, which is widely used to assess fracture risk in the general population, works equally well to assess fractures in women with breast cancer receiving aromatase inhibitor therapy,” William D. Leslie, MD, MSc, FRCPC, professor of medicine and radiology at the University of Manitoba, Winnipeg, told Endocrine Today. “It extends the use of FRAX, and our article provides guidance for not including aromatase inhibitor use as a secondary cause of osteoporosis in the calculation.”

In a registry-based, cohort study, Leslie and colleagues analyzed data from women aged 40 years or older with and without a diagnosis of breast cancer who underwent a baseline bone mineral density measurement via DXA between 2005 and 2016. The data included retrospectively calculated FRAX scores and at least 1 year of follow-up after BMD testing. Women were stratified into three groups: breast cancer with aromatase inhibitor use (n = 1,775), breast cancer without aromatase inhibitor use (n = 1,016) and no breast cancer diagnosis (controls; n = 34,205). Incident fracture history was assessed via health service records. Researchers calculated 10-year probability of a major osteoporotic fracture and hip fracture using the Canadian FRAX tool, calibrated with nationwide hip fracture and mortality data.

Mean follow-up ranged from 6.2 years for women prescribed aromatase inhibitors to 7.3 years for women with breast cancer who did not use aromatase inhibitors. During follow-up, 3,808 women died, 2,795 women experienced a major osteoporotic fracture, 864 women experienced a hip fracture and 3,736 women experienced any clinical fracture.

Compared with controls, women with breast cancer were at higher risk for death, with similar HRs for women prescribed aromatase inhibitors (HR = 1.35; 95% CI, 1.17-1.55) and those not using aromatase inhibitors (HR = 1.37; 95% CI, 1.16-1.61).

Among aromatase inhibitor users, calculations of fracture probability without BMD, with aromatase inhibitor use coded as secondary osteoporosis, overestimated 10-year predicted risk for major osteoporotic fracture when compared with observed fractures during follow-up (13% vs. 7.2%; observed/predicted ratio, 0.56; 95% CI, 0.45-0.68). This discrepancy was attenuated when secondary osteoporosis was not included in the FRAX estimates, according to researchers. When BMD was included in the fracture probability, observed and predicted fracture risks did not differ significantly. Results for 5-year fracture outcomes were similar.

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In Cox proportional hazards models that did not include BMD in baseline fracture probability, aromatase inhibitor use was associated with lower risk for major osteoporotic fracture vs. controls (HR = 0.78; 95% CI, 0.64-0.95), as well as lower risk for hip fracture (HR = 0.46; 95% CI, 0.29-0.73) and any fracture (HR = 0.75; 95% CI, 0.63-0.89).

“When secondary osteoporosis was excluded or BMD was included in the estimation of baseline fracture risk, [aromatase inhibitor] use was no longer significantly associated with fracture,” the researchers wrote. “Breast cancer without [aromatase inhibitor] use was not associated with a significant increase in any fracture outcomes.”

The researchers noted that a higher baseline BMI and BMD observed in women prescribed aromatase inhibitor therapy, along with a lower incidence of prior fracture, may offset the adverse effects of aromatase inhibitor exposure.

“Our findings challenge the view that the average woman with breast cancer is at high risk for fracture at the time of initiation of [aromatase inhibitor] therapy,” the researchers wrote. “In fact, at baseline, these women appear to be at relatively lower fracture risk than the general population and women with breast cancer not initiating [aromatase inhibitor] therapy because of higher BMI, BMD, T-score and lower prevalence of a prior fracture. Fracture probability scores from FRAX stratify fracture risk equally well in women receiving [aromatase inhibitor] therapy as in nonusers, but including secondary osteoporosis as a risk factor for [aromatase inhibitor] users in the calculation leads to overestimation in predicted fracture risk. Our results call this practice into question.” – by Regina Schaffer

Disclosures: Leslie reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.

    Perspective
    Bart Clarke

    Bart Clarke

    The data are the data. This is a well-controlled study showing that aromatase inhibitor therapy may not increase fracture risk. This finding was unexpected, based on previous studies. The findings will need to replicated to verify that they are true, and not unique to the Manitoba registry.

    The study was well controlled for age, but less well controlled for BMI, femoral neck BMD, and perhaps other risk factors for fracture. Presumably, the cohorts were balanced for calcium and vitamin D intake, although I didn’t see this mentioned specifically in the paper. The authors acknowledge a number of limitations to the study that might help explain the findings. Regardless, I think we have to wait for other studies to confirm these findings.

    • Bart Clarke, MD
    • Professor of Medicine, Division of Endocrinology, Metabolism, Diabetes and Nutrition
      Mayo Clinic College of Medicine Rochester, Minnesota
      President, American Society for Bone and Mineral Research

    Disclosures: Clarke reports no relevant financial disclosures.