NIHR DC Discover

NIHR Signal Common osteoporosis drugs may prevent breast cancer spreading to bone

Published on 13 March 2018

doi: 10.3310/signal-00567

Drugs commonly prescribed to prevent bone thinning probably help prevent the spread of early breast cancer to the bones in a few women, when taken in addition to standard cancer therapies. However, the overall benefits may be small, for example preventing spread to bone or death in about one extra woman in every 100 treated for about five years. This is a complex area because many of the treatments for breast cancer are known to worsen bone thinning, but there are other bone strengthening benefits to these drugs.

This large review of 44 studies with more than 37,000 participants looked at women with either early breast cancer or advanced breast cancer with or without bone involvement.

The reviewers also concluded that for women with cancer that had already spread to the bones, bisphosphonates reduced their chance of getting a fracture or bone pain.

Denosumab worked better than bisphosphonates for these women. For women with advanced breast cancer without bone involvement, drugs to prevent bone-thinning seemed to make no difference.

The study suggests more women with breast cancer might benefit from bisphosphonates or denosumab but implies that a discussion about the likely risks and benefits of treatment would also be worthwhile.

Share your views on the research.

Why was this study needed?

Breast cancer is one of the commonest cancers in the UK, with more than 55,000 new cases each year. If breast cancer spreads, it often spreads to the bones. This is known as bone metastases. Bisphosphonates, drugs that affect bone growth, are sometimes used to try to prevent bone metastases. Bisphosphonates and a newer drug called denosumab are also used to treat people with bone metastases from breast cancer.

There are many studies of how bone-modifying drugs work for women with different types of breast cancer. This study is the fourth update of the topic by the Cochrane collaboration and includes 10 new studies.

What did this study do?

Researchers carried out a systematic review, with meta-analyses of results for women with early, advanced, and breast cancer that had spread to the bones.

They searched for all randomised controlled trials comparing drugs that affected bone growth with each other, or with a placebo.

For early or advanced breast cancer, they looked to see if drugs prevented bone metastases. They found 17 studies with 26,129 participants with early breast cancer and three studies with 330 participants with advanced breast cancer.

For cancer that had spread to the bone, they looked to see if drugs prevented fractures or bone pain. Researchers pooled the results in meta-analyses. They found 24 studies with 10,853 participants with breast cancer that had spread to the bone.

The quality of evidence for the main outcomes reviewed was moderate to high so that we can be fairly confident in the estimates of these effects. 

What did it find?

  • For women with early breast cancer, bisphosphonates lowered the chances of cancer spreading to the bone by 14% (relative risk [RR] 0.86, 95% confidence interval [CI] 0.75 to 0.99, based on 11 studies with 15,005 women). The absolute risk was 9% for women who didn’t take a bisphosphonate, compared with 7.7% for women who did take a bisphosphonate, meaning just over one person on average in every 100 would benefit.
  • For women with early breast cancer, bisphosphonates improved overall survival in studies with up to 10 years follow up by 8% (hazard ratio 0.91, 95% CI 0.83 to 0.99, based on 9 studies with 13,949 women). The absolute risk was 8% for women who didn’t take a bisphosphonate, compared with 7.3% for women who did take a bisphosphonate, meaning just under one person, on average, in every 100 would benefit.
  • For women with advanced breast cancer which had not spread to the bone, bisphosphonates did not seem to lower the chances of cancer spreading to the bone (RR 0.96, 95% CI 0.65 to 1.43, based on three studies with 330 women)
  • For women with breast cancer which had spread to the bone, bisphosphonates lowered the chances of a fracture or bone pain by 14% (RR 0.86, 95% CI 0.78 to 0.95, based on 9 studies with 2810 women).
  • For women with breast cancer that had spread to the bone, denosumab lowered the chances of a fracture or bone pain by 22% compared to a bisphosphonate (RR 0.78, 95% CI 0.72 to 0.85, based on three studies with 2,345 women). 

What does current guidance say on this issue?

NICE published an evidence summary on the use of bisphosphonates to prevent recurrence of breast cancer and improve survival in July 2017. It does not make specific recommendations for the use of bisphosphonates, but says: “Local decision makers need to take safety, efficacy, cost and patient factors into account when considering the likely place in therapy of adjuvant bisphosphonates.”

NICE’s 2012 technology appraisal of denosumab says: “Denosumab is recommended as an option for preventing skeletal-related events (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in adults with bone metastases from breast cancer … if bisphosphonates would otherwise be prescribed and the manufacturer provides denosumab with the discount agreed in the patient access scheme.”

What are the implications?

The results add further evidence to support previous conclusions about the potential role of drugs that affect bone growth in the treatment of women with breast cancer.

It updates the evidence for adding bisphosphonates to the treatment of women with early breast cancer, but absolute reductions in risk are small and will require individual discussions with women considering the frequency of side effects from these medications and with their breast cancer treatment. These were not quantified here.

Citation and Funding

O’Carrigan B, Wong MHF, Willson ML, et al. Bisphosphonates and other bone agents for breast cancer. Cochrane Database Syst Rev. 2017;(10):CD003474.

No funding information was provided for this study.

Bibliography

NICE. Denosumab for the prevention of skeletal-related events in adults with bone metastases from solid tumours. TA 265. London: National Institute for Health and Care Excellence; 2012.

NICE. Early breast cancer (preventing recurrence and improving survival): adjuvant bisphosphonates. ES 15. London: National Institute for Health and Care Excellence; 2017.

Jin A, Cobb J, Hansen U, et al. The effect of long-term bisphosphonate therapy on trabecular bone strength and microcrack density. Bone Joint Res. 2017;6(10):602-9.

Why was this study needed?

Breast cancer is one of the commonest cancers in the UK, with more than 55,000 new cases each year. If breast cancer spreads, it often spreads to the bones. This is known as bone metastases. Bisphosphonates, drugs that affect bone growth, are sometimes used to try to prevent bone metastases. Bisphosphonates and a newer drug called denosumab are also used to treat people with bone metastases from breast cancer.

There are many studies of how bone-modifying drugs work for women with different types of breast cancer. This study is the fourth update of the topic by the Cochrane collaboration and includes 10 new studies.

What did this study do?

Researchers carried out a systematic review, with meta-analyses of results for women with early, advanced, and breast cancer that had spread to the bones.

They searched for all randomised controlled trials comparing drugs that affected bone growth with each other, or with a placebo.

For early or advanced breast cancer, they looked to see if drugs prevented bone metastases. They found 17 studies with 26,129 participants with early breast cancer and three studies with 330 participants with advanced breast cancer.

For cancer that had spread to the bone, they looked to see if drugs prevented fractures or bone pain. Researchers pooled the results in meta-analyses. They found 24 studies with 10,853 participants with breast cancer that had spread to the bone.

The quality of evidence for the main outcomes reviewed was moderate to high so that we can be fairly confident in the estimates of these effects. 

What did it find?

  • For women with early breast cancer, bisphosphonates lowered the chances of cancer spreading to the bone by 14% (relative risk [RR] 0.86, 95% confidence interval [CI] 0.75 to 0.99, based on 11 studies with 15,005 women). The absolute risk was 9% for women who didn’t take a bisphosphonate, compared with 7.7% for women who did take a bisphosphonate, meaning just over one person on average in every 100 would benefit.
  • For women with early breast cancer, bisphosphonates improved overall survival in studies with up to 10 years follow up by 8% (hazard ratio 0.91, 95% CI 0.83 to 0.99, based on 9 studies with 13,949 women). The absolute risk was 8% for women who didn’t take a bisphosphonate, compared with 7.3% for women who did take a bisphosphonate, meaning just under one person, on average, in every 100 would benefit.
  • For women with advanced breast cancer which had not spread to the bone, bisphosphonates did not seem to lower the chances of cancer spreading to the bone (RR 0.96, 95% CI 0.65 to 1.43, based on three studies with 330 women)
  • For women with breast cancer which had spread to the bone, bisphosphonates lowered the chances of a fracture or bone pain by 14% (RR 0.86, 95% CI 0.78 to 0.95, based on 9 studies with 2810 women).
  • For women with breast cancer that had spread to the bone, denosumab lowered the chances of a fracture or bone pain by 22% compared to a bisphosphonate (RR 0.78, 95% CI 0.72 to 0.85, based on three studies with 2,345 women). 

What does current guidance say on this issue?

NICE published an evidence summary on the use of bisphosphonates to prevent recurrence of breast cancer and improve survival in July 2017. It does not make specific recommendations for the use of bisphosphonates, but says: “Local decision makers need to take safety, efficacy, cost and patient factors into account when considering the likely place in therapy of adjuvant bisphosphonates.”

NICE’s 2012 technology appraisal of denosumab says: “Denosumab is recommended as an option for preventing skeletal-related events (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in adults with bone metastases from breast cancer … if bisphosphonates would otherwise be prescribed and the manufacturer provides denosumab with the discount agreed in the patient access scheme.”

What are the implications?

The results add further evidence to support previous conclusions about the potential role of drugs that affect bone growth in the treatment of women with breast cancer.

It updates the evidence for adding bisphosphonates to the treatment of women with early breast cancer, but absolute reductions in risk are small and will require individual discussions with women considering the frequency of side effects from these medications and with their breast cancer treatment. These were not quantified here.

Citation and Funding

O’Carrigan B, Wong MHF, Willson ML, et al. Bisphosphonates and other bone agents for breast cancer. Cochrane Database Syst Rev. 2017;(10):CD003474.

No funding information was provided for this study.

Bibliography

NICE. Denosumab for the prevention of skeletal-related events in adults with bone metastases from solid tumours. TA 265. London: National Institute for Health and Care Excellence; 2012.

NICE. Early breast cancer (preventing recurrence and improving survival): adjuvant bisphosphonates. ES 15. London: National Institute for Health and Care Excellence; 2017.

Jin A, Cobb J, Hansen U, et al. The effect of long-term bisphosphonate therapy on trabecular bone strength and microcrack density. Bone Joint Res. 2017;6(10):602-9.

Bisphosphonates and other bone agents for breast cancer

Published on 31 October 2017

O'Carrigan, B.,Wong, M. H.,Willson, M. L.,Stockler, M. R.,Pavlakis, N.,Goodwin, A.

Cochrane Database Syst Rev Volume 10 , 2017

BACKGROUND: Bone is the most common site of metastatic disease associated with breast cancer (BC). Bisphosphonates inhibit osteoclast-mediated bone resorption, and novel targeted therapies such as denosumab inhibit other key bone metabolism pathways. We have studied these agents in both early breast cancer and advanced breast cancer settings. This is an update of the review originally published in 2002 and subsequently updated in 2005 and 2012. OBJECTIVES: To assess the effects of bisphosphonates and other bone agents in addition to anti-cancer treatment: (i) in women with early breast cancer (EBC); (ii) in women with advanced breast cancer without bone metastases (ABC); and (iii) in women with metastatic breast cancer and bone metastases (BCBM). SEARCH METHODS: In this review update, we searched Cochrane Breast Cancer's Specialised Register, CENTRAL, MEDLINE, Embase, the World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov on 19 September 2016. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing: (a) one treatment with a bisphosphonate/bone-acting agent with the same treatment without a bisphosphonate/bone-acting agent; (b) treatment with one bisphosphonate versus treatment with a different bisphosphonate; (c) treatment with a bisphosphonate versus another bone-acting agent of a different mechanism of action (e.g. denosumab); and (d) immediate treatment with a bisphosphonate/bone-acting agent versus delayed treatment of the same bisphosphonate/bone-acting agent. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data, and assessed risk of bias and quality of the evidence. The primary outcome measure was bone metastases for EBC and ABC, and a skeletal-related event (SRE) for BCBM. We derived risk ratios (RRs) for dichotomous outcomes and the meta-analyses used random-effects models. Secondary outcomes included overall survival and disease-free survival for EBC; we derived hazard ratios (HRs) for these time-to-event outcomes where possible. We collected toxicity and quality-of-life information. GRADE was used to assess the quality of evidence for the most important outcomes in each treatment setting. MAIN RESULTS: We included 44 RCTs involving 37,302 women.In women with EBC, bisphosphonates were associated with a reduced risk of bone metastases compared to placebo/no bisphosphonate (RR 0.86, 95% confidence interval (CI) 0.75 to 0.99; P = 0.03, 11 studies; 15,005 women; moderate-quality evidence with no significant heterogeneity). Bisphosphonates provided an overall survival benefit with time-to-event data (HR 0.91, 95% CI 0.83 to 0.99; P = 0.04; 9 studies; 13,949 women; high-quality evidence with evidence of heterogeneity). Subgroup analysis by menopausal status showed a survival benefit from bisphosphonates in postmenopausal women (HR 0.77, 95% CI 0.66 to 0.90; P = 0.001; 4 studies; 6048 women; high-quality evidence with no evidence of heterogeneity) but no survival benefit for premenopausal women (HR 1.03, 95% CI 0.86 to 1.22; P = 0.78; 2 studies; 3501 women; high-quality evidence with no heterogeneity). There was evidence of no effect of bisphosphonates on disease-free survival (HR 0.94, 95% 0.87 to 1.02; P = 0.13; 7 studies; 12,578 women; high-quality evidence with significant heterogeneity present) however subgroup analyses showed a disease-free survival benefit from bisphosphonates in postmenopausal women only (HR 0.82, 95% CI 0.74 to 0.91; P < 0.001; 7 studies; 8314 women; high-quality evidence with no heterogeneity). Bisphosphonates did not significantly reduce the incidence of fractures when compared to placebo/no bisphosphonates (RR 0.77, 95% CI 0.54 to 1.08, P = 0.13, 6 studies, 7602 women; moderate-quality evidence due to wide confidence intervals). We await mature overall survival and disease-free survival results for denosumab trials.In women with ABC without clinically evident bone metastases, there was no evidence of an effect of bisphosphonates on bone metastases (RR 0.96, 95% CI 0.65 to 1.43; P = 0.86; 3 studies; 330 women; moderate-quality evidence with no heterogeneity) or overall survival (RR 0.89, 95% CI 0.73 to 1.09; P = 0.28; 3 studies; 330 women; high-quality evidence with no heterogeneity) compared to placebo/no bisphosphonates however the confidence intervals were wide. One study reported a trend towards an extended period of time without a SRE with bisphosphonate compared to placebo (low-quality evidence). One study reported quality of life and there was no apparent difference in scores between bisphosphonate and placebo (moderate-quality evidence).In women with BCBM, bisphosphonates reduced the SRE risk by 14% (RR 0.86, 95% CI 0.78 to 0.95; P = 0.003; 9 studies; 2810 women; high-quality evidence with evidence of heterogeneity) compared with placebo/no bisphosphonates. This benefit persisted when administering either intravenous or oral bisphosphonates versus placebo. Bisphosphonates delayed the median time to a SRE with a median ratio of 1.43 (95% CI 1.29 to 1.58; P < 0.00001; 9 studies; 2891 women; high-quality evidence with no heterogeneity) and reduced bone pain (in 6 out of 11 studies; moderate-quality evidence) compared to placebo/no bisphosphonate. Treatment with bisphosphonates did not appear to affect overall survival (RR 1.01, 95% CI 0.91 to 1.11; P = 0.85; 7 studies; 1935 women; moderate-quality evidence with significant heterogeneity). Quality-of-life scores were slightly better with bisphosphonates than placebo at comparable time points (in three out of five studies; moderate-quality evidence) however scores decreased during the course of the studies. Denosumab reduced the risk of developing a SRE compared with bisphosphonates by 22% (RR 0.78, 0.72 to 0.85; P < 0.001; 3 studies, 2345 women). One study reported data on overall survival and observed no difference in survival between denosumab and bisphosphonate.Reported toxicities across all settings were generally mild. Osteonecrosis of the jaw was rare, occurring less than 0.5% in the adjuvant setting (high-quality evidence). AUTHORS' CONCLUSIONS: For women with EBC, bisphosphonates reduce the risk of bone metastases and provide an overall survival benefit compared to placebo or no bisphosphonates. There is preliminary evidence suggestive that bisphosphonates provide an overall survival and disease-free survival benefit in postmenopausal women only when compared to placebo or no bisphosphonate. This was not a planned subgroup for these early trials, and we await the completion of new large clinical trials assessing benefit for postmenopausal women. For women with BCBM, bisphosphonates reduce the risk of developing SREs, delay the median time to an SRE, and appear to reduce bone pain compared to placebo or no bisphosphonate.

Expert commentary

Like most UK women diagnosed in recent years, my breast cancer was “early” (in my case, stage 1). This Cochrane review does not persuade me to take bisphosphonates.

First, following successful evidence-based treatment, I already have a greater than 99% chance of being disease-free in 10 years. My chance of ever developing bone metastases is around one or two in a 1,000.

Second, this large review’s findings produced a just-significant survival benefit (confidence interval 0.83 to 0.99), a pretty tiny absolute benefit for any individual woman, even if she’s beyond stage 1 at diagnosis.

Third, the side effects of bisphosphonates are troublesome for almost everyone and lethal for an unlucky few.

Finally, I am alarmed by recent evidence that bisphosphonate treatment appears to weaken rather than strengthen bone.

Trish Greenhalgh, Professor of Primary Care Health Sciences, University of Oxford