The Case for Bone-Directed Adjuvant Therapy in Postmenopausal Early Breast Cancer


“A duration of endocrine therapy beyond 5 years has gained traction in the treatment of endocrine receptor (ER)-positive early-stage breast cancer. Long-term use of aromatase inhibitors (AIs), however, may increase the risk of bone loss and bone fracture. Data suggest that the use of bone-targeted agents can substantially reduce the risk of osteoporotic complications associated with AI use, and even reduce the risk of bone recurrence in postmenopausal women with early-stage breast cancer.”

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Denosumab Reduces Clinical Fracture Risk in Postmenopausal Women Receiving Aromatase Inhibitors

“In a phase III trial (ABCSG-18) reported in The Lancet, Gnant et al found that adjuvant denosumab (Xgeva) reduced the risk of clinical fracture in women with breast cancer receiving aromatase inhibitor therapy.

“In the double-blind study, 3,420 women from Austria and Sweden with early hormone receptor–positive breast cancer receiving aromatase inhibitors were randomized between December 2006 and July 2013 to receive subcutaneous denosumab 60 mg (n = 1,711) or placebo (n = 1,709) every 6 months.

“The primary endpoint was time to first clinical fracture on intention-to-treat analysis. Patients were treated until the prespecified number of 247 first clinical fractures was reached.

“Patients had a median age of 64 years. At baseline, 55% had normal total lumbar spine bone mineral density (T score ≥ –1.0), and the remainder had T scores lower than –1.0. Overall, 16% of patients started aromatase inhibitor therapy at the time of randomization, with the remainder having been on treatment for a median of 1 month prior to randomization. In total, 25% of patients had also received (neo)adjuvant chemotherapy.”

Amgen Presents Phase 3 Data At ASCO Showing Prolia Significantly Reduced Bone Fractures In Breast Cancer Patients Receiving Aromatase Inhibitors

“Amgen AMGN 0.49% today announced results from a randomized, double-blind, placebo-controlled, multicenter Phase 3 study evaluating the treatment effect of adjuvant Prolia® (denosumab), 60 mg once every six months, therapy in postmenopausal women with early hormone receptor positive (HR+) breast cancer receiving aromatase inhibitor therapy. The trial met its primary endpoint of time from randomization to first clinical fracture (HR=0.5, 95 percent CI 0.39-0.65, p<0.0001). The observed 50 percent reduction in fractures between the Prolia and placebo arms, 92 versus 176, respectively, was similar in patients with normal bone health at baseline (n=1,872, HR=0.44, p<0.0001) and in patients who started the trial with early signs of bone loss (n=1,548, HR=0.57, p=0.0021). The data will be presented at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago today at 9:12 a.m. CT (abstract no. 504). In addition to the presentation, the paper was published online by The Lancet.

“This is the first Prolia trial to enroll patients independent of baseline bone mineral density (BMD) and with the majority in the normal BMD range. The study, which enrolled a total of 3,425 patients, was conducted by the Austrian Breast and Colorectal Cancer Study Group (ABCSG).

” ‘Fracture is a common side effect of aromatase inhibitors, which are an important first-line therapy for postmenopausal women with non-metastatic breast cancer,’ said principal investigator Michael Gnant, professor of surgery at Medical University of Vienna. ‘These encouraging data demonstrate the potential benefit of initiating Prolia simultaneously with aromatase inhibitor therapy, regardless of the patient’s baseline BMD, to decrease the risk of fracture.’ “

Risedronate Reduces Anastrozole-Related Bone Loss in Osteopenic/Osteoporotic Postmenopausal Women

The gist: Postmenopausal women who take the drug anastrazole to prevent breast cancer often suffer from bone loss. Now, a clinical trial with volunteer patients has shown that a drug called risedronate might reduce anastrozole-associated bone loss.

“In a substudy of the IBIS-II trial reported in The Lancet Oncology, Sestak et al found that risedronate treatment reduced anastrozole-related bone loss over 3 years in postmenopausal women at increased risk for breast cancer…

“The study involved assessment of bone mineral density changes among a subgroup of women in the IBIS-II trial. Patients were stratified according to T score: stratum I = ≥−1.0; stratum II (osteopenic) = ≥ −2.5 and < −1.0; and stratum III (osteoporotic) = < −2.5 and > −4.0. All patients were randomly assigned to anastrozole 1 mg/d or placebo, those in stratum II were randomly assigned to risedronate 35 mg/week vs placebo, and all patients in stratum III received risedronate…

“The investigators concluded: ‘Risedronate counterbalances the effect of anastrozole-induced bone loss in osteopenic and osteoporotic women and might be offered in combination with anastrozole treatment to provide an improved risk–benefit profile.’ ”

Breast Ca: The Price of a 'Cure'

“The majority of women with newly diagnosed invasive breast cancer will experience ‘personal cures.’ This means they will live out their lives without recurrent breast cancer. There are certain consequences of treatment that women should be aware of, however, and among them is bone loss that may lead to greater risks of subsequent osteoporosis.

“Osteoporosis is a major worldwide health problem, and the resultant hip and spine fractures cause significant morbidity, mortality, and healthcare expenditures. The estimated 1-year mortality after a hip fracture is 25%.

“One can think about osteoporosis as an equation. On one side is the bone mass you start with that peaks around age 35. The other side of the equation is the bone loss that occurs normally over time. The bone mass you start with versus the extent of bone you lose over a lifetime determines whether osteoporosis will develop and the risk of fractures.

“Having a mother who had an osteoporotic fracture is the strongest risk factor for osteoporosis, implying that the genes you are born with play a large role is this disease. Indeed, the genetics of osteoporosis is complicated and not fully understood. Lifestyle factors such as smoking or drinking alcohol, the use of chronic steroids, and certain diseases such as rheumatoid arthritis all increase the risk of osteoporosis, but do so to a lesser extent than genetics.”