17 July, 2017: 

Several guidelines have been reported for bone-directed treatment in women with early breast cancer for averting fractures, particularly during aromatase inhibitor (AI) therapy. A systematic literature review identified both several fracture-related risk factors as well as recent advances in the management of aromatase inhibitor-associated bone loss (AIBL). Although the FRAX algorithm includes fracture risk factors in addition to bone mineral density (BMD), it does not seem to adequately address the effects of AIBL. Several antiresorptive agents can prevent and treat AIBL. However, concerns regarding compliance and long-term safety remain. Overall, the evidence for fracture prevention is strongest for denosumab 60 mg s.c. every 6 months. Additionally, recent studies as well as an individual patient data meta-analysis of all available randomized trial data support additional anticancer benefits from adjuvant bisphosphonate treatment in postmenopausal women, with a 34% relative risk reduction in bone metastasis and 17% relative risk decrease in breast cancer mortality that needs to be taken into account when advising on management of AIBL.

A Joint Position Statement of the International Osteoporosis Foundation, the Cancer and Bone Society, the European Calcified Tissue Society, the International Expert Group for AIBL, the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases, the International Society for Geriatric Oncology and the International Menopause Society recently provided a treatment algorithm [1]. In all patients initiating AI treatment, fracture risk should be assessed and recommendation with regard to exercise and calcium/vitamin D supplementation given. Bone-directed therapy should be given to all patients with a T-score <−2.0 or with a T-score of < –1.5 SD with one additional risk factor, or with two or more risk factors (without BMD) for the duration of AI treatment. Patients with a T-score > −1.5 SD and no risk factors should be managed based on BMD loss during the first year and the local guidelines for postmenopausal osteoporosis. Compliance should be regularly assessed as well as BMD on treatment after 12–24 months. Furthermore, because of the decreased incidence of bone recurrence and breast cancer-specific mortality, adjuvant bisphosphonates are recommended for all postmenopausal women at significant risk of disease recurrence.

Comment

The use of adjuvant endocrine therapy in women with hormone-sensitive breast cancer is divided, usually by menopausal status, between the selective estrogen receptor modulator tamoxifen and the newer class of drugs known as aromatase inhibitors. The latter are indicated in postmenopausal women only. A Cochrane systematic review [2] found that disease-free survival and overall survival were improved with AI monotherapy compared to tamoxifen. Sequenced therapy with AI to tamoxifen (or vice versa) improved disease-free survival compared to tamoxifen but not overall survival. Fractures were more frequently associated with AI use. Thromboembolic disease and endometrial cancer were more frequently associated with tamoxifen use. AIs have largely replaced tamoxifen in adjuvant treatment of postmenopausal hormone receptor-positive breast cancers.

Compared to the general population, breast cancer patients have an increased risk of fracture [3] (RR 1.25, 95% CI 1.23–1.28). Women taking AIs are also at increased risk of fracture compared to those taking tamoxifen (RR 1.48, 95% CI 0.98–2.22). Bone loss due to AI therapy is two- to four-fold higher than seen at normal menopause, thus explaining the increased fracture risk. Randomized, controlled trials including an AI for 5 years reported an increased absolute fracture risk of about 10%, but this may be an underestimate due to the strict inclusion and exclusion criteria imposed, meaning that more than one in ten women may sustain a fracture during AI therapy [1]. Because of the increased risk of fracture with AI use, Hadji and colleagues felt a new updated algorithm, incorporating some risk factors not previously used in online calculators such as FRAX, should be devised. FRAX is not designed to estimate fracture risk in women with breast cancer and may underestimate prospective fracture risk in view of the fact that ongoing AI therapy will continue to cause increased fracture risk for as long as active treatment continues. The new algorithm is based on the pre-treatment T-score plus additional risk factors including age > 65, smoking, body mass index < 20 kg/m², family history of hip fracture and oral glucocorticoid use for > 6 months. An examination of clinical trials of the effects of various interventions to prevent fracture risk in women receiving AI therapy after hormone-dependent breast cancer found the strongest evidence of fracture prevention for denosumab, with further supportive evidence for bisphosphonate therapy when used according to the above algorithm.

There is also growing evidence that adjuvant therapy with bisphosphonates will reduce recurrences in bone and prolong survival in postmenopausal women [4]. A recent consensus statement [5] has also recommended the use of adjuvant bisphosphonate therapy in women with breast cancer at moderate or significant risk of disease recurrence. This joint position statement supported by international and regional societies gives new clear guidance for the management of bone health and recurrent disease risk in postmenopausal women with hormone-positive breast cancer

Rod Baber

Clinical Professor of Obstetrics and Gynaecology, The University of Sydney, Australia

References

1. Hadji P, Aapro MS, Body JJ, et al. Management of AIBL in postmenopausal women with hormone sensitive breast cancer. Joint Position Statement of IOF, CABS, ECTS, IEG, ESCEO, IMS and SIOG. J Bone Oncol 2017;7:1-12
   http://www.ncbi.nlm.nih.gov/pubmed/28413771
2. Ryden L, Heibert Arnlind M, Vitols S, Hoistad M, Ahlgren J. Aromatase inhibitors alone or sequentially combined with tamoxifen in postmenopausal early breast cancer compared with tamoxifen or placebo. Breast 2016;26:106-14
   http://www.ncbi.nlm.nih.gov/pubmed/27017249
3. Colzani E, Clements M, Johansson AL, et al. Risk of hospitalization and death due to bone fracture after breast cancer; a registry based cohort. Br J Cancer 2016;115:1400-7
   http://www.ncbi.nlm.nih.gov/pubmed/27701383
4. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet 2016;386:1353-61
   http://www.ncbi.nlm.nih.gov/pubmed/26211824
5. Hadji P, Coleman RE, Wilson C, et al. Adjuvant bisphosphonates in early breast cancer: consensus guidance for clinical practice from a European Panel. Ann Oncol 2016;27:379-90
   http://www.ncbi.nlm.nih.gov/pubmed/26681681