Preventing bone loss in patients treated for breast cancer
Submitting InstitutionUniversity of Manchester
Unit of AssessmentClinical Medicine
Summary Impact TypeHealth
Research Subject Area(s)
Medical and Health Sciences: Oncology and Carcinogenesis
Summary of the impact
Aromatase inhibitors (AIs) significantly improve survival from breast
cancer but are associated with increases in osteoporotic fractures and
bone mineral density loss. Research at the University of Manchester (UoM)
has provided key evidence that has contributed to preventing debilitating
bone demineralisation safely in breast cancer patients undergoing adjuvant
therapy with AIs. UoM findings have led to an international consensus on
guidelines recommending Dual-energy X-ray Absorptiometry (DEXA) scanning
to identify patients at risk of bone loss as well as the use of
bisphosphonates where bone loss has been identified. Further guidelines
advise against the use of HRT to treat bone loss as a result of its
association with breast cancer recurrence.
See section 3 for references 1-6. UoM researchers are given in bold.
Two large International trials, Arimidex Tamoxifen Adjuvant Combination
(ATAC) (1) and the Breast International Group (BIG) 1-98 Study (New
England Journal of Medicine, 353:2747-2757), confirmed the
superiority of non-steroidal aromatase inhibitors (AIs) used for five
years after surgery, compared with Tamoxifen, in preventing breast cancer
recurrence. The findings led to the widespread use of AIs internationally
and AIs are now the standard NICE approved treatment for breast cancer in
oestrogen receptor positive post-menopausal breast cancer cases (NICE, Early
and locally advanced breast cancer: Diagnosis and treatment, 2009).
Research on AIs, bone loss and osteoporotic fractures
Key UoM researchers:
Nigel Bundred (Senior Lecturer, 1991-1996; Reader, 1996-2001;
Anthony Howell (Senior Lecturer, 1980-1997; Professor,
Researchers at UoM led three studies (ATAC, ZO-FAST, LIBERATE) that
generated important insights around the association between AIs, bone loss
and osteoporotic fractures as well as evidence for optimal interventions
to prevent bone loss in those treated for breast cancer. Key findings:
Howell (UK lead, ATAC) and Bundred (lead author, chief
investigator, ZO-FAST) demonstrated that the complications of using AIs
were increased bone loss and subsequent osteoporotic fractures on
treatment (1, 2).
Bundred (lead author, chief investigator) led LIBERATE, the
largest international randomised controlled trial of HRT to prevent
menopausal symptoms and bone loss in breast cancer patients. Over 3000
women in 31 countries were recruited to LIBERATE. In the bone
mineralisation study within LIBERATE, 50% of post-menopausal women with
breast cancer were found to be osteopaenic or osteoporotic at diagnosis
(3, 4). HRT increased bone mineral density by 3% but also breast cancer
recurrence (3), mostly in patients with normal bone mineral density
(BMD). There was also a significant increase in breast tumour recurrence
in patients randomised to HRT, especially for patients on AIs.
- Bisphosphonates had been shown to prevent bone loss in osteoporosis. Bundred
led research to study the effect of bisphosphonates in the setting of
hormone receptor positive patients with early breast cancer commencing
adjuvant AI therapy with Letrozole. The use of intravenous
bisphosphonates prevented bone loss and increased bone density (2).
Additionally, irrespective of BMD, there was a survival advantage for
those patients who commenced bisphosphonates from the start of
treatment, at analysis 60 months later (5, 6).
References to the research
1. Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF,
Hoctin-Boes G, Houghton J, Locker GY, Tobias JS. Results of the ATAC
(Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5
years' adjuvant treatment for breast cancer. The Lancet.
2005;365(9453):60-2. DOI: 10.1016/S0140-6736(04)17666-6
2. Bundred NJ, Campbell ID, Davidson N, DeBoer RH, Eidtmann H,
Monnier A, Neven P, von Minckwitz G, Miller JC, Schenk NL, Coleman RE.
Effective inhibition of aromatase inhibitor-associated bone loss by
zoledronic acid in postmenopausal women with early breast cancer receiving
adjuvant letrozole: ZO-FAST study results. Cancer.
2008;112(5):1001-10. DOI: 10.1002/cncr.23259
3. Kenemans P, Bundred NJ, Foidart J-M, Kubista E, von Schoultz
B, Sismondi P, Vassilopoulou-Sellin R, Yip CH, Egberts J, Mol-Arts M,
Mulder R, van Os S, Beckmann MW. Safety and efficacy of tibolone in
breast-cancer patients with vasomotor symptoms: a double-blind,
randomised, non-inferiority trial. The Lancet Oncology.
2009;10(2):135-46. DOI: 10.1016/S1470-2045(08)70341-3
4. Bundred NJ, Kenemans P, Yip CH, Beckmann MW, Foidart JM,
Sismondi P, Schoultz B, Vassilopoulou-Sellin R, Galta RE, Lieshout EV,
Mol-Arts M, Planellas J, Kubista E. Tibolone increases bone mineral
density but also relapse in breast cancer survivors: LIBERATE trial bone
substudy. Breast Cancer Research. 2012;14(1):R13. DOI:
5. Eidtmann H, de Boer R, Bundred N, Llombart-Cussac A, Davidson
N, Neven P, von Minckwitz G, Miller J, Schenk N, Coleman R. Efficacy of
zoledronic acid in postmenopausal women with early breast cancer receiving
adjuvant letrozole: 36-month results of the ZO-FAST Study. Annals of
Oncology. 2010;21(11):2188-94. DOI: 10.1093/annonc/mdq217
6. Eastell R, Adams J, Clack G, Howell A, Cuzick J, Mackey J,
Beckmann MW, Coleman RE. Long-term effects of anastrozole on bone mineral
density: 7-year results from the ATAC trial. Annals of Oncology.
2011;22(4):857-62. DOI: 10.1093/annonc/mdq541
Details of the impact
See section 5 for corroborating sources S1-S6.
Non-steroidal AIs are now the standard of care for hormone
receptor-positive breast cancers in post-menopausal women, nationally and
internationally (S1). Our research established that AIs are, however,
associated with increases in osteoporotic fractures and increased bone
mineral density loss (1, 2). Almost 30,000 post-menopausal women in the UK
develop breast cancer annually, 50% of whom already have significant bone
mineral density loss before starting treatment. Prior to the research
carried out at UoM, 2.3% of those treated with AIs annually developed bone
Pathways to impact
UoM research has led to the following standards of care now adopted
- Routine assessment of BMD using a DEXA scan prior to AI therapy in
post-menopausal women with hormone receptor positive breast cancer;
- Bisphosphonate therapy for all women with a T score < -2;
- Discontinuation of HRT as a therapeutic intervention after breast
- Contraindication of HRT in breast cancer patients with menopausal
Reach and significance of the impact
The research has had a substantial influence on clinical guidelines
governing the treatment of breast cancer in the UK and internationally.
Use of DEXA scan and bisphosphonates
As a result of the research, national and international consensus
guidelines were issued which indicate the need for pre-adjuvant therapy
bone mineral density DEXA scanning to identify patients already
osteoporotic or at risk of bone loss (S1-S4). The guidelines ensure
commencement of intravenous or oral bisphosphonates where bone loss has
been identified or patients have had previous osteoporotic fractures.
The research was cited and adopted in NICE CG80, Early and locally
advanced breast cancer: Diagnosis and treatment (2009). One of the
key priorities identified in these guidelines is that: `Patients with
early invasive breast cancer should have a baseline dual energy X-ray
absorptiometry (DEXA) scan to assess bone mineral density if they are
starting adjuvant aromatase inhibitor treatment/have treatment-induced
menopause/are starting ovarian ablation/suppression therapy' (S1, p. vi).
The guidance in the NICE document on treatment with bisphosphonates cites
our research, stating: `Evidence from RCTs (Brufsky, 2006 [S5 below] and Bundred
et al., 2008 [reference 2 above]) have indicated that in women who were
receiving adjuvant letrozole, immediate treatment with zoledronate
compared to delayed may prevent loss of BMD at both lumbar spine and total
hip. There is evidence that immediate treatment with zoledronic acid
maintains the baseline osteopenia status of patients compared with delayed
treatment at 12 months [S6 below]. Furthermore, Bundred et al.
(2008) showed no evidence to suggest a difference in the occurrence of
fractures in immediate versus delayed treatment with zoledronate and that
there was no difference in breast cancer recurrence when comparing
immediate and delayed treatment with zoledronate. There are no significant
acute adverse effects with zoledronate.' (S1, p. 68)
The US guidelines (ASCO, S3; NCCN US Task Force Report on Bone Health in
Cancer Care, S4) cite our research and advise the use of DEXA scanning and
bisphosphonates in patients on aromatase inhibitor therapy after breast
The guidelines ensure that assessment of BMD using DEXA scan prior to AI
therapy is now routine for women with hormone receptor positive breast
cancer. Bisphosphonate therapy is now offered to all women with a T score
of < -2.
The addition of bisphosphonates has led to a 5-fold reduction in fracture
rate to 0.5% annually in patients being treated with AIs. This change in
practice, adapted worldwide, has significantly decreased the morbidity and
suffering associated with the use of AIs in breast cancer.
HRT use after breast cancer treatment now contraindicated
The NICE guidelines recognise that Tibolone and HRT should not be
indicated for the vasomotor symptoms of women with breast cancer and,
importantly, that HRT is a less effective treatment than bisphosphonates
for women on AIs with breast cancer (S1).
The research has contributed to the discontinuation of HRT as a
therapeutic intervention after breast cancer diagnosis. HRT is
contraindicated for breast cancer patients with menopausal symptoms or
Sources to corroborate the impact
S1.NICE/National Collaborating Centre for Cancer. Early and locally
advanced breast cancer: Diagnosis and treatment. CG80. London: NICE;
S2.Reid DM, Doughty J, Eastell R, Heys SD, Howell A, McCloskey
EV, Powles T, Selby P, Coleman RE. Guidance for the management of breast
cancer treatment-induced bone loss: A consensus position statement from a
UK Expert Group. Cancer Treatment Reviews. 2008;34, Supplement
S3.Van Poznak CH, Temin S, Yee GC, Janjan NA, Barlow WE, Biermann JS,
Bosserman LD, Geoghegan C, Hillner BE, Theriault RL, Zuckerman DS, Von
Roenn JH. American Society of Clinical Oncology Executive Summary of the
Clinical Practice Guideline Update on the Role of Bone-Modifying Agents in
Metastatic Breast Cancer. Journal of Clinical Oncology.
S4.Gralow JR, Biermann JS, Farooki A, Fornier MN, Gagel RF, Kumar RN,
Shapiro CL, Shields A, Smith MR, Srinivas S, Van Poznak CH. NCCN Task
Force Report: Bone Health in Cancer Care. Journal of the National
Comprehensive Cancer Network. 2009;7(Suppl 3):S1-32.
S5.Brufsky A, Harker WG, Beck JT, Carroll R, Tan-Chiu E, Seidler C, et
al. Zoledronic Acid Inhibits Adjuvant Letrozole-Induced Bone Loss in
Postmenopausal Women With Early Breast Cancer. Journal of Clinical
Oncology. 2007 March 1, 2007;25(7):829-36.
S6.Gnant M, Mlineritsch B, Luschin-Ebengreuth G, Kainberger F, Kässmann
H, Piswanger-Sölkner JC, Seifert M, Ploner F, Menzel C, Dubsky P, Fitzal
F, Bjelic-Radisic V, Steger G, Greil R, Marth C, Kubista E, Samonigg H,
Wohlmuth P, Mittlböck M, Jakesz R. Adjuvant endocrine therapy plus
zoledronic acid in premenopausal women with early-stage breast cancer:
5-year follow-up of the ABCSG-12 bone-mineral density substudy. The
Lancet Oncology. 2008;9(9):840-9.