• Anne Adams, Tina Jakob, Alessandra Huth, Ina Monsef, Moritz Ernst, Marco Kopp, Julia Caro-Valenzuela, Achim Wöckel, and Nicole Skoetz.
• Institute of Medical Statistics and Computational Biology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
• Cochrane Db Syst Rev. 2024 Jul 9; 7 (7): CD013451CD013451.

BackgroundBisphosphonates and receptor activator of nuclear factor-kappa B ligand (RANKL)-inhibitors are amongst the bone-modifying agents used as supportive treatment in women with breast cancer who do not have bone metastases. These agents aim to reduce bone loss and the risk of fractures. Bisphosphonates have demonstrated survival benefits, particularly in postmenopausal women.ObjectivesTo assess and compare the effects of different bone-modifying agents as supportive treatment to reduce bone mineral density loss and osteoporotic fractures in women with breast cancer without bone metastases and generate a ranking of treatment options using network meta-analyses (NMAs).Search MethodsWe identified studies by electronically searching CENTRAL, MEDLINE and Embase until January 2023. We searched various trial registries and screened abstracts of conference proceedings and reference lists of identified trials.Selection CriteriaWe included randomised controlled trials comparing different bisphosphonates and RANKL-inihibitors with each other or against no further treatment or placebo for women with breast cancer without bone metastases.Data Collection And AnalysisTwo review authors independently extracted data and assessed the risk of bias of included studies and certainty of evidence using GRADE. Outcomes were bone mineral density, quality of life, overall fractures, overall survival and adverse events. We conducted NMAs and generated treatment rankings.Main ResultsForty-seven trials (35,163 participants) fulfilled our inclusion criteria; 34 trials (33,793 participants) could be considered in the NMA (8 different treatment options). Bone mineral density We estimated that the bone mineral density of participants with no treatment/placebo measured as total T-score was -1.34. Evidence from the NMA (9 trials; 1166 participants) suggests that treatment with ibandronate (T-score -0.77; MD 0.57, 95% CI -0.05 to 1.19) may slightly increase bone mineral density (low certainty) and treatment with zoledronic acid (T-score -0.45; MD 0.89, 95% CI 0.62 to 1.16) probably slightly increases bone mineral density compared to no treatment/placebo (moderate certainty). Risedronate (T-score -1.08; MD 0.26, 95% CI -0.32 to 0.84) may result in little to no difference compared to no treatment/placebo (low certainty). We are uncertain whether alendronate (T-score 2.36; MD 3.70, 95% CI -2.01 to 9.41) increases bone mineral density compared to no treatment/placebo (very low certainty). Quality of life No quantitative analyses could be performed for quality of life, as only three studies reported this outcome. All three studies showed only minimal differences between the respective interventions examined. Overall fracture rate We estimated that 70 of 1000 participants with no treatment/placebo had fractures. Evidence from the NMA (16 trials; 19,492 participants) indicates that treatment with clodronate or ibandronate (42 of 1000; RR 0.60, 95% CI 0.39 to 0.92; 40 of 1000; RR 0.57, 95% CI 0.38 to 0.86, respectively) decreases the number of fractures compared to no treatment/placebo (high certainty). Denosumab or zoledronic acid (51 of 1000; RR 0.73, 95% CI 0.52 to 1.01; 55 of 1000; RR 0.79, 95% CI 0.56 to 1.11, respectively) probably slightly decreases the number of fractures; and risedronate (39 of 1000; RR 0.56, 95% CI 0.15 to 2.16) probably decreases the number of fractures compared to no treatment/placebo (moderate certainty). Pamidronate (106 of 1000; RR 1.52, 95% CI 0.75 to 3.06) probably increases the number of fractures compared to no treatment/placebo (moderate certainty). Overall survival We estimated that 920 of 1000 participants with no treatment/placebo survived overall. Evidence from the NMA (17 trials; 30,991 participants) suggests that clodronate (924 of 1000; HR 0.95, 95% CI 0.77 to 1.17), denosumab (927 of 1000; HR 0.91, 95% CI 0.69 to 1.21), ibandronate (915 of 1000; HR 1.06, 95% CI 0.83 to 1.34) and zoledronic acid (925 of 1000; HR 0.93, 95% CI 0.76 to 1.14) may result in little to no difference regarding overall survival compared to no treatment/placebo (low certainty). Additionally, we are uncertain whether pamidronate (905 of 1000; HR 1.20, 95% CI 0.81 to 1.78) decreases overall survival compared to no treatment/placebo (very low certainty). Osteonecrosis of the jaw We estimated that 1 of 1000 participants with no treatment/placebo developed osteonecrosis of the jaw. Evidence from the NMA (12 trials; 23,527 participants) suggests that denosumab (25 of 1000; RR 24.70, 95% CI 9.56 to 63.83), ibandronate (6 of 1000; RR 5.77, 95% CI 2.04 to 16.35) and zoledronic acid (9 of 1000; RR 9.41, 95% CI 3.54 to 24.99) probably increases the occurrence of osteonecrosis of the jaw compared to no treatment/placebo (moderate certainty). Additionally, clodronate (3 of 1000; RR 2.65, 95% CI 0.83 to 8.50) may increase the occurrence of osteonecrosis of the jaw compared to no treatment/placebo (low certainty). Renal impairment We estimated that 14 of 1000 participants with no treatment/placebo developed renal impairment. Evidence from the NMA (12 trials; 22,469 participants) suggests that ibandronate (28 of 1000; RR 1.98, 95% CI 1.01 to 3.88) probably increases the occurrence of renal impairment compared to no treatment/placebo (moderate certainty). Zoledronic acid (21 of 1000; RR 1.49, 95% CI 0.87 to 2.58) probably increases the occurrence of renal impairment while clodronate (12 of 1000; RR 0.88, 95% CI 0.55 to 1.39) and denosumab (11 of 1000; RR 0.80, 95% CI 0.54 to 1.19) probably results in little to no difference regarding the occurrence of renal impairment compared to no treatment/placebo (moderate certainty).Authors' ConclusionsWhen considering bone-modifying agents for managing bone loss in women with early or locally advanced breast cancer, one has to balance between efficacy and safety. Our findings suggest that bisphosphonates (excluding alendronate and pamidronate) or denosumab compared to no treatment or placebo likely results in increased bone mineral density and reduced fracture rates. Our survival analysis that included pre and postmenopausal women showed little to no difference regarding overall survival. These treatments may lead to more adverse events. Therefore, forming an overall judgement of the best ranked bone-modifying agent is challenging. More head-to-head comparisons, especially comparing denosumab with any bisphosphonate, are needed to address gaps and validate the findings of this review.Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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