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Study: Treatment to reduce bone fractures also improves breast cancer survival in postmenopausal people

Summary

A large study looked at the effects of adding the bone-protective drug denosumab (Prolia), to standard hormone therapy for the treatment of early-stage, postmenopausal, HR-positive breast cancer. The researchers found that adding denosumab to aromatase inhibitor hormonal therapy improved bone health, disease-free survival and overall survival. (Posted 2/27/23)

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Treatment to reduce bone fractures also improves breast cancer survival in postmenopausal people
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RELEVANCE

Most relevant for: People with early-stage breast cancer who are post-menopausal.
It may also be relevant for:

  • people with breast cancer
  • people newly diagnosed with cancer
  • healthy people with average cancer risk

Relevance: High

Strength of Science: High

Relevance Rating Details

What is this study about?

This study looked at the effects of adding the drug denosumab (Prolia) used to protect bone density to hormone therapy treatment for people with , breast cancer.  Denosumab improved bone strength, lengthened the time before cancer came back (disease-free survival) and improved overall survival.

Why is this study important?

The standard of care for postmenopausal women with HR-positive breast cancer is a type of hormone therapy called aromatase inhibitor (AI) therapy. Aromatase inhibitors lower levels. This can lead to bone loss, weakened bones () and possible broken bones. Common examples of AI drugs include anastrozole (Arimidex), exemestane (Aromasin) and letrozole (Femara).

Some previous research has shown that drugs that protect the bones may also keep cancer from returning. This study is important because it tested whether denosumab could improve cancer survival in postmenopausal breast cancer patients while reducing bone loss.

Study findings

Along with AI therapy, participants received treatment with denosumab or a every 6 months for 5 years. To look at bone health, researchers measured the number of people who had broken bones or altered bone density. To look at how denosumab affected cancer, researchers measured whether cancer came back (also called disease-free survival) after 5 years of follow-up and then after about 8 years of follow-up. Researchers measured any local or distant , breast cancer in the other breast, a second cancer of any kind or death from any cause.

Bone health was better in people taking denosumab.

  • Denosumab reduced bone fractures by half compared to the group.
  • The time to first fracture was twice as long in the denosumab group as compared to a .

Fewer people taking denosumab had their cancer progress.

  • In a final 2022 analysis, people taking denosumab had slightly improved cancer outcomes and better overall survival at 9 years:
    • 79% of the denosumab group were cancer-free at an average of 9 years of follow-up compared to 76% of the group.
    • 89% of the denosumab group had no bone metastases compared to 86% of the group after 9 years of follow-up.

Side effects of denosumab
Both groups, participants taking AIs and denosumab and participants taking AIs and a , had similar side effects, (1366 events: 80% for the denosumab group and 1334 events: 79% for the group) suggesting that most side effects were caused by the AI therapy rather than the use of denosumab.

Strengths and limitations

Strengths

  • The findings in this study confirm other, smaller studies.
  • This was a well-controlled study. Comparing participants in the denosumab group to a group allowed researchers to understand the effects of denosumab on AI treatment.

Limitations

  • After some time on treatment, patients were told which treatment they were on; if they were on a they could then choose to receive denosumab treatment. This complicates and weakens further analyses.
  • How denosumab improves cancer outcomes is not well understood and needs to be further studied.
  • The total benefit of adding denosumab to AI therapy is small, even though it is statistically meaningful.

What does this mean for me?

If you have been diagnosed with , breast cancer, you are receiving AI therapy and you are postmenopausal, you may benefit from taking denosumab. Denosumab may lower your risk of broken bones, improve your bone health and lower your risk of a cancer recurrence.

Reference

Gnant M, Frantal A, Pfeiler GG, et al. Long-term outcomes of denosumab in breast cancer. NEJM Evidence November 2022; 1 (12). DOI:https://doi.org/10.1056/EVIDoa2200162

Gnant M, Pfeiler G, Steger GG, et al. Denosumab in postmenopausal patients with hormone receptor-positive breast cancer (ABCSG-18): disease-free survival results from a randomised, double-blind, , phase 3 trial. The Lancet Oncology; 2019; 20: 339–51

Gnant M, Pfeiler G, Dubsky PC, et al. denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, trial. Lancet 2015; 386: 433–43.

Gnant M, Frantal A, Pfeiler GG, et al. Long-term outcomes of Denosumab in breast cancer: Fracture reduction and survival results from 3,425 patients in the randomised, double-blind, ABCSG-18 trial. Journal of Clinical Oncology; 2022; 40:16_suppl, 507-507

Minichsdorfer C, Fuereder T, Leutner M, et al. Effect of concomitant statin treatment in postmenopausal patients with hormone receptor-positive breast cancer receiving Denosumab or placebo: a post hoc analysis of ABCSG-18. ESMO Open. 2022 Apr;7(2):100426

Disclosure: FORCE receives funding from industry sponsors, including companies that manufacture cancer drugs, tests and devices. All XRAYS articles are written independently of any sponsor and are reviewed by members of our Scientific Advisory Board prior to publication to assure scientific integrity.

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posted 2/27/23

Questions To Ask Your Doctor
Questions To Ask Your Doctor

  • How do my cancer treatments affect my bone health?
  • I am on an AI; should I have a bone density test?
  • What do the results of my bone density test mean?
  • As a postmenopausal woman with HR+ breast cancer, would denosumab be a good addition to my current cancer treatment?
  • If denosumab is not a good option for me, are there other therapies or approaches that will help maintain my bone health during therapy?

Guidelines
Guidelines

The National Comprehensive Cancer Network (NCCN) brings together national expert panels that create guidelines for cancer treatment. NCCN guidelines include recommendations for bone-protecting drugs during the treatment of , breast cancer:

  • Bone-protecting drugs such as bisphosphonates or denosumab may be used to maintain or improve bone mineral density and reduce the risk of fractures in postmenopausal patients receiving aromatase inhibitor therapy. The ideal length of time for treatment with these agents is unknown. Factors to consider include bone mineral density, response to treatment and risk factors for continued bone loss or fracture.
  • Patients have reported broken bones that have occurred after denosumab is discontinued.
  • Patients should have a dental exam, and any dental care should be performed before starting these drugs.
  • Patients treated with a bisphosphonate or denosumab should take supplemental calcium and vitamin D.

Updated: 02/28/2023

Related resources
Related resources

The following organizations have resources related to breast cancer. 

Updated: 06/28/2023

IN-DEPTH REVIEW OF RESEARCH
Study background

Therapies that maintain bone health, such as bisphosphonates and denosumab, have been successful in treating cancer patients with therapy-related bone loss and fracture risk. Patients treated for cancer benefit from these therapies that reduce rates of bone fracture and later complications of bone breaks. A from the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) showed that the addition of bisphosphonates improved cancer outcomes in postmenopausal patients with hormone receptor-positive breast cancer. In this study, researchers tested the impact of denosumab on bone fractures in breast cancer patients and how it affected cancer outcomes.

Researchers of this study wanted to know

The ABCSG-18 study is an important study because it tested whether denosumab, an antibody used to help treat bone loss, could help reduce bone loss in postmenopausal women being treated with aromatase inhibitors (AI therapy). In addition, some preclinical and clinical data have shown that drugs used to treat bone loss may also have anti-cancer properties. Therefore, the leaders of the study wanted to determine whether denosumab could improve long-term outcomes for postmenopausal breast cancer patients while helping to reduce bone loss.

Populations looked at in this study

This study enrolled 3,425 participants from 58 health centers within Austria and Sweden. The participants were mostly white (99.5%); the remaining 0.5% of participants were Asian, Hispanic or Black.

Study design

This study took place between December 2006 and July 2013. About half of the participants received an aromatase inhibitor and denosumab; the other half received an aromatase inhibitor and a . The study was blinded—neither participants nor their immediate providers knew who received which treatment (only researchers managing the study design had access to that information).

Patients received 60 mg of denosumab or a every 6 months for 5 years. Every 6 months during treatment, investigators measured whether a patient's disease had progressed (their cancer grew) or metastasized. In addition, after 3 and 5 years of treatment, patient bone density was measured; if needed, restaging was then performed. After treatment ended, patients received follow-up care yearly to see whether their disease had progressed or metastasized. The final date for the analysis of follow-up information was September 30th, 2017.

The study reported findings in two waves: at approximately 5 years of follow-up and after 8 years of follow-up. In addition, another study used the same patient data to look at whether cholesterol-lowering drugs (statins) could also improve outcomes in these patients. The results from all three analyses are presented below.

Study findings

Bone health was better in people taking denosumab.

  • Denosumab reduced bone fractures by half as compared to the group.
    • At 36 months, 5% of participants in the denosumab group had a first fracture (92 fractures), and 10% of the group (176 fractures).
    • At 84 months, 11% of the denosumab group experienced first fractures compared to 26% of the group.
  • The time to first fracture was twice as long in the denosumab group as compared to a .

Fewer people taking denosumab had their cancer progress.

  • In a final analysis, people taking denosumab had improved cancer outcomes and overall survival at 9 years:
    • 79% of the denosumab group were cancer-free at an average of 9 years of follow-up compared to 76% of the group.
    • 89% of the denosumab group had no bone metastases compared to 86% of the group after 9 years of follow-up.

Side effects of denosumab
In the safety analysis, the frequency of adverse events did not differ between the denosumab group (1,366 events, 80%) and the group (1,334 events, 79%).

The main adverse events reported were joint pain (arthralgia) and AI-associated side effects.

  • 25% of participants in both the denosumab and groups reported joint pain.

The numbers of serious adverse events were also similar (521 vs 511—30% in each group). These suggest that most adverse events (side effects) are associated with AI therapy rather than the use of denosumab.

Context

The results from this study are the first of its kind, with no published papers looking at the effect of denosumab on breast cancer outcomes. When the first study results were released, 19 studies were registered for “denosumab” and “breast cancer,” mostly looking at breast cancer. Two other studies, the D-CARE study and the ENDEAVOR study, were similar to this study. The D-CARE study looked only at disease-related outcomes and found no effect of denosumab on cancer outcomes. Additional research is needed to understand the impact of denosumab on cancer outcomes.

Conclusions

Adding denosumab to AI therapy reduces bone fractures and may improve cancer outcomes in postmenopausal patients with hormone receptor ()-positive breast cancer.

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posted 2/27/23

Peer Support
Peer Support

The following organizations offer peer support services for people with, or at high risk for breast cancer:

Updated: 11/29/2022

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Article Rating Details

ASCO Daily News: Adjuvant Denosumab Improves Long-term Survival and Bone Protection in Patients With Early-Stage Breast Cancer Taking Aromatase Inhibitors
Rating:  5.0 Stars

  • This article clearly and accurately describes the study statistics.
  • This article presents studies with opposing results; it provides a more complete perspective on the state of the field.
  • Interviews from various scientists in the field who can provide a balanced perspective are included.
  • This article is well sourced.

Cancer Therapy Advisor: Denosumab Improves Long-Term Outcomes in AI-Treated Breast Cancer
Rating:  3.0 Stars

  • This article reports a fairly clear description of the study and the statistics.
  • Only references from the two published studies are included and only the study authors are interviewed.
  • This article does not present opposing studies or a perspective from the field.

Study Rating Details

Relevance: High

  • This research is directly about postmenopausal women on AI therapy with HR+ breast cancer.
  • The study population was not diverse. It consisted mostly of white women, so this research may not be broadly generalizable.
  • These findings could be used in practice immediately, though more research would be beneficial to understanding how denosumab improves cancer outcomes.

Scientific Strength: High

  • This is a well-designed randomized controlled trial that supports the questions that were asked.
  • The controls and number of participants are appropriate.
  • The statistical analysis is sound and the conclusions are justified.
  • This builds on prior research and is counter to some previous studies.

Research Timeline:  Human research

  • This was a Phase 3 clinical trial.