Benefits and risks of adjuvant treatment with zoledronic acid in stage II/III breast cancer. 10 years follow-up of the AZURE randomized clinical trial (BIG 01/04)

Coleman, Robert E.; Collinson, Michelle; Gregory, Walter M.; Marshall, Helen; Bell, Richard H.; Dodwell, David; Keane, Maccon M.; Gil, Miguel; Barrett-Lee, Peter; Ritchie, Diana; Bowman, A.; Liversedge, Victoria; Boer, Richard H. De; Passos‐Coelho, José Luís; O’Reilly, Seamus; Bertelli, G.; Joffe, Johnathan; Brown, Janet; Wilson, Caroline; Tercero, Juan-Carlos; Jean-Mairet, J; Gomis, Roger R.; Cameron, David

doi:10.1016/j.jbo.2018.09.008

Cited by 72 publications

(58 citation statements)

References 28 publications

(44 reference statements)

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“…(27) However, some observational studies of oral bisphosphonate use and cancer are negative. (30) However, breast cancer incidence was not reduced in randomized trials of alendronate or zoledronate in osteoporotic women. A meta-analysis of trials giving bisphosphonates to women with early breast cancer found no benefit in premenopausal women but, among 11,767 postmenopausal women, bisphosphonates significantly reduced recurrence (relative risk 0.86; 95% CI, 0.78 to 0.94), distant recurrence (0.82; 95% CI, 0.74 to 0.92), bone recurrence (0.72; 95% CI, 0.60 to 0.86), and breast cancer mortality (0.82; 95% CI, 0.73 to 0.93).…”

Section: Discussionmentioning

confidence: 99%

“…(5) Follow-up to 10 years in the adjuvant zoledronic acid to reduce recurrence (AZURE) trial showed that benefits were sustained. (30) However, breast cancer incidence was not reduced in randomized trials of alendronate or zoledronate in osteoporotic women. (31) The present findings are the first trial evidence of reduced cancer risk with zoledronate in women not selected for having a history of breast cancer.…”

Section: Discussionmentioning

confidence: 99%

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Effects of Zoledronate on Cancer, Cardiac Events, and Mortality in Osteopenic Older Women

Reid

Horne

Mihov

et al. 2019

Journal of Bone and Mineral Research

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We recently showed that zoledronate prevented fractures in older women with osteopenia (hip T-scores between −1.0 and −2.5). In addition to fewer fractures, this study also suggested that women randomized to zoledronate had fewer vascular events, a lower incidence of cancer, and a trend to lower mortality. The present analysis provides a more detailed presentation of the adverse event data from that study, a 6-year, double-blind trial of 2000 women aged >65 years recruited using electoral rolls. They were randomly assigned to receive four infusions of either zoledronate 5 mg or normal saline at 18-month intervals. Supplements of vitamin D, but not calcium, were provided. There were 1017 serious adverse events in 443 participants in the placebo group, and 820 events in 400 participants in those randomized to zoledronate (relative risk = 0.90; 95% CI, 0.81 to 1.00). These events included fractures resulting in hospital admission. Myocardial infarction occurred in 39 women (43 events) in the placebo group and in 24 women (25 events) in the zoledronate group (hazard ratio 0.60 [95% CI, 0.36 to 1.00]; rate ratio 0.58 [95% CI, 0.35 to 0.94]). For a prespecified composite cardiovascular endpoint (sudden death, myocardial infarction, coronary artery revascularization, or stroke) 69 women had 98 events in the placebo group, and 53 women had 71 events in the zoledronate group (hazard ratio 0.76 [95% CI, 0.53 to 1.08]; rate ratio 0.72 [95% CI, 0.53 to 0.98]). Total cancers were significantly reduced with zoledronate (hazard ratio 0.67 [95% CI, 0.51 to 0.89]; rate ratio 0.68 [95% CI, 0.52 to 0.89]), and this was significant for both breast cancers and for non-breast cancers. Eleven women had recurrent or second breast cancers during the study, all in the placebo group. The hazard ratio for death was 0.65 (95% CI, 0.40 to 1.06; p = 0.08), and 0.51 (95% CI, 0.30 to 0.87) in those without incident fragility fracture. These apparent beneficial effects justify further appropriately powered trials of zoledronate with these nonskeletal conditions as primary endpoints.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effects of Zoledronate on Cancer, Cardiac Events, and Mortality in Osteopenic Older Women

Reid

Horne

Mihov

et al. 2019

Journal of Bone and Mineral Research

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“…In addition, bisphosphonates decrease the risk of bone metastases and breast cancer death among postmenopausal women (1,6,7). On the contrary, in young premenopausal women bisphosphonates may be associated with an increase in relapse risk and a worse overall survival [34]. Since bisphosphonates are not without risk in young women, exercise could provide a safe and natural means to preserve bone mass in premenopausal women with early breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Five-year follow-up results of aerobic and impact training on bone mineral density in early breast cancer patients

et al. 2020

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A 12-month exercise program reversibly prevented hip bone loss in premenopausal women with early breast cancer. The bone-protective effect was maintained for 2 years after the end of the program but was lost thereafter. Purpose Breast cancer survivors are at an increased risk for osteoporosis and fracture. This 5-year follow-up of a randomized impact exercise intervention trial evaluated the maintenance of training effects on bone among breast cancer patients. Methods Five hundred seventy-three early breast cancer patients aged 35-68 years and treated with adjuvant therapy were allocated into a 12-month exercise program or a control group. Four hundred forty-four patients (77%) were included in the 5year analysis. The exercise intervention comprised weekly supervised step aerobics, circuit exercises, and home training. Areal bone mineral density (aBMD) was measured by dual-energy X-ray absorptiometry. Physical activity was estimated in metabolic equivalent (MET) hours per week and physical performance assessed by 2-km walking and figure-8 running tests. Results In premenopausal patients, the 12-month exercise program maintained femoral neck (FN) and total hip (TH) aBMD for 3 years, but the protective effect was lost thereafter. The mean FN aBMD change in the exercise and control groups was − 0.2% and − 1.5% 1 year, − 1.1% and − 2.1% 3 years and − 3.3% versus − 2.4% 5 years after the beginning of the intervention, respectively. Lumbar spine (LS) bone loss was not prevented in premenopausal women and no training effects on aBMD were seen in postmenopausal women. The main confounding element of the study was the unexpected rise in physical activity among patients in the control group. The physical performance improved among premenopausal women in the exercise group compared with the controls. Conclusion The 12-month exercise program prevented FN and TH bone loss in premenopausal breast cancer patients for 3 years. The bone-protective effect was reversible and lost thereafter.

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“…The former showed a significant DFS advantage in premenopausal ER-positive BC patients receiving adjuvant hormone treatment (including ovarian suppression) plus six-monthly zoledronate (88.4% versus 85% of control arm, p < 0.05) [62]. The latter, by applying a more intensive zoledronate schedule to a wider patient cohort, described no benefit in the overall population but a significant advantage in terms of invasive DFS and occurrence of BM as first relapse (HR 0.76, 95%CI 0.63-0.92, p = 0.005) in women receiving the BP who were postmenopausal at the time of randomization [63,64].…”

Section: Adjuvant Bpsmentioning

confidence: 99%

Role of Bone Targeting Agents in the Prevention of Bone Metastases from Breast Cancer

D’Oronzo

Silvestris

Paradiso

et al. 2020

IJMS

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Breast cancer (BC) is the most common malignancy in women worldwide and leads, in more than 70% of patients with advanced disease, to skeleton colonization and formation of bone metastases (BM). This condition implies a severe disability and deterioration of the quality of life, with consequent additional social costs. In recent decades, several studies explored the role of agents acting within the bone microenvironment to counteract BM development, and several bone-targeting agents (BTAs) have been introduced in the clinical practice to manage bone lesions and reduce the risk of skeletal complications. However, long-term exposure to these agents is not free from potential toxicities and needs careful monitoring. In this context, the potential capability to prevent BM onset in selected BC patients, through the early administration of BTAs, has been explored by several researchers, with the belief that “prevention is better than cure” and that, ultimately, metastatic BC is an incurable condition. Here, we revised the mechanisms of BM development in BC as well as the strategies for selecting high-risk patients suitable for early BTA treatment.

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Benefits and risks of adjuvant treatment with zoledronic acid in stage II/III breast cancer. 10 years follow-up of the AZURE randomized clinical trial (BIG 01/04)

Cited by 72 publications

References 28 publications

Effects of Zoledronate on Cancer, Cardiac Events, and Mortality in Osteopenic Older Women

Effects of Zoledronate on Cancer, Cardiac Events, and Mortality in Osteopenic Older Women

Five-year follow-up results of aerobic and impact training on bone mineral density in early breast cancer patients

Role of Bone Targeting Agents in the Prevention of Bone Metastases from Breast Cancer

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