Fracture Risk in Women with Breast Cancer
An expert analysis of recent studies looking at the impact that breast cancer treatments may have on bone health, and the recommended managed to reduce risk of fracture.
July 2021
Volume 7, Issue 1

Adjuvant Denosumab Reduces Bone Fracture Risk in Postmenopausal Women With Breast Cancer

Lancet. 2015;386(9992):433-443

Introduction: The study was designed to investigate the effects of the anti-RANK ligand antibody densosmab on fracture risk, bone health, and safety outcomes in postmenopausal women undergoing adjuvant endocrine therapy with aromatase inhibitors for the treatment of breast cancer.

Methods: This multicenter, prospective, double-blind trial—known as ABCSG-18—involved 3,420 women with nonmetastatic hormone receptor-positive breast cancer who were receiving aromatase inhibitors. The patients were randomized to denosumab 60 mg (n=1,711) or placebo (n=1,709) subcutaneously every 6 months until a prespecified number of 247 first clinical fractures was reached.

Results: The time from randomization to first clinical fracture (primary outcome) was significantly longer in the denosumab group (hazard ratio, 0.50; P<0.0001). Women in the denosumab group had a lower number of fractures in all patient subgroups, including those with a normal bone mineral density (BMD) at baseline (T-score ≥–1; n=1,872; HR, 0.44; P<0.0001) or in those with decreased BMD at baseline (T-score <–1; n=1,548; HR, 0.57; P=0.002).

The fracture rate at 36 months was 5.0% of the denosumab group and 9.6% in the placebo group. At 84 months, these rates were 11.5% and 26.2%, respectively.

At 36 months, the denosumab group showed a relative increase in BMD at the lumbar spine (10%), total hip (7.9%), and femoral neck (6.5%) compared with the placebo group (P<0.0001 for all comparisons).

Both groups reported a high rate of adverse events (79%-80%) and serious adverse events (30% in each group). Arthralgia and other aromatase-inhibitor related symptoms were the most common adverse events in both groups, with no additional toxicity associated with denosumab. No cases of osteonecrosis of the jaw were reported. One death was believed to be denosumab related; the authors did not provide information on the nature of this death.

Conclusion: Adjuvant treatment with denosumab 60 mg significantly reduces the risk for fractures and improves bone mineral density in postmenopausal women with breast cancer receiving aromatase inhibitors. For patients with modest risk of disease recurrence, denosumab should be added to clinical practice to prevent the most serious side effects of aromatase inhibitor therapy, the authors concluded.


Dr. Azeez Farooki is an academic endocrinologist practicing in New York City. His expertise includes general endocrinology with a sub-focus in osteoporosis / metabolic bone diseases.

This well-designed study carefully captured fragility fractures in postmenopausal breast cancer patients across a wide age range initiating adjuvant aromatase inhibitors. The results: (1) demonstrate that the increase in fracture risk related to these drugs may have been underestimated from earlier studies that didn't focus on fragility fractures, and (2) show that denosumab reduces the risk of fractures in this patient population.

What is surprising to me is that the fracture reduction demonstrated was independent of age and baseline T score (above or below minus 1.0), implying that aromatase inhibitors increase fracture risk independent of bone mineral density (BMD). Analogously, this type of increase in fracture risk can occur at relatively "good" BMD in patients initiating corticosteroids. However, at this point I am not ready to treat all women initiating aromatase inhibitors with denosumab.

First, the patient population studied was higher risk due to ethnicity (Swedish and Austrian) than other ethnicities. Second, analysis from the FREEDOM trial of denosumab in postmenopausal osteoporosis revealed that nonvertebral fracture efficacy was present at T scores below minus 2.5,1 which is stark contrast to the study by Gnant, et al. Finally, data on whether denosumab can prevent bone recurrence is pending and will weigh heavily in the decision on where to use denosumab.

1. Min YK. Update on Denosumab Treatment in Postmenopausal Women with Osteoporosis. Endocrinol Metab (Seoul). 2015 Mar;30(1):19-26.

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