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Abstract：
BACKGROUND: Bisphosphonates 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.
OBJECTIVE: To 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).
METHODS: We 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.
METHODS: We 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.
METHODS: Two 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.
RESULTS: Forty-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).
CONCLUSIONS: When 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.
OBJECTIVE: To 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).
METHODS: We 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.
METHODS: We 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.
METHODS: Two 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.
RESULTS: Forty-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).
CONCLUSIONS: When 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.
摘要：
背景：双膦酸盐和核因子-κB受体激活剂配体（RANKL）抑制剂是在没有骨转移的乳腺癌妇女中用作支持性治疗的骨修饰剂。这些药物旨在减少骨丢失和骨折的风险。双膦酸盐已经证明了生存的益处，特别是在绝经后的妇女。
目的：评估和比较不同骨调节剂作为支持治疗的效果，以减少无骨转移的乳腺癌女性患者的骨密度损失和骨质疏松性骨折，并使用网络荟萃分析（NMA）对治疗方案进行排序。
方法：我们通过电子搜索CENTRAL，MEDLINE和Embase直到2023年1月。我们搜索了各种试验登记处，并筛选了会议记录摘要和已确定试验的参考文献列表。
方法：我们纳入了随机对照试验，比较了不同的双膦酸盐和RANKL抑制剂对无骨转移的乳腺癌患者的治疗效果，或与无进一步治疗或安慰剂对照。
方法：两位综述作者独立提取数据，并使用GRADE评估纳入研究的偏倚风险和证据的确定性。结果是骨矿物质密度，生活质量,整体骨折，总生存期和不良事件。我们进行了NMA并生成了治疗排名。
结果：47项试验（35,163名参与者）符合我们的纳入标准；34项试验（33,793名参与者）可以在NMA（8种不同的治疗方案）中考虑。骨矿物质密度我们估计没有治疗/安慰剂的参与者的骨矿物质密度测量为总T评分为-1.34。来自NMA（9项试验；1166名参与者）的证据表明，伊班膦酸钠治疗（T评分-0.77；MD0.57，95％CI-0.05至1.19）可能会略微增加骨矿物质密度（低确定性），而唑来膦酸治疗（T评分-0.45；MD0.89，95％CI0.62至1.16）可能会略微增加骨矿物质密度。利塞膦酸盐（T评分-1.08；MD0.26，95％CI-0.32至0.84）可能与无治疗/安慰剂（确定性低）相比几乎没有差异。我们不确定阿仑膦酸盐（T评分2.36；MD3.70，95％CI-2.01至9.41）是否与无治疗/安慰剂相比（确定性非常低）增加骨密度。生活质量无法对生活质量进行定量分析，因为只有三项研究报告了这一结果。所有三项研究均显示所检查的各自干预措施之间的差异很小。总体骨折率我们估计1000名没有治疗/安慰剂的参与者中有70名患有骨折。来自NMA的证据（16项试验；19,492名参与者）表明，与未治疗/安慰剂相比，使用氯膦酸盐或伊班膦酸盐治疗（1000人中的42人；RR0.60，95％CI0.39至0.92；1000人中的40人；RR0.57，95％CI0.38至0.86）减少了骨折数量（确定性高）。Denosumab或唑来膦酸（1000人中有51例；RR0.73，95％CI0.52至1.01；1000人中有55例；RR0.79，95％CI0.56至1.11）可能略微减少骨折数量；与未治疗/安慰剂相比，利塞膦酸盐（1000人中有39例；RR0.56，95％CI0.15至2.16）可能减少骨折数量（中度确定性）。帕米膦酸盐（106/1000；RR1.52，95％CI0.75至3.06）可能会增加无治疗/安慰剂的骨折数量（中度确定性）。总体存活我们估计1000名没有治疗/安慰剂的参与者中有920名总体存活。来自NMA的证据（17项试验；30,991名参与者）表明氯膦酸盐（1000人中的924人；HR0.95，95％CI0.77至1.17），denosumab（1000人中的927人；HR0.91，95%CI0.69至1.21），伊班膦酸钠(1000人中的915例;HR1.06,95%CI0.83~1.34)和唑来膦酸(1000人中的925例;HR0.93,95%CI0.76~1.14)与未接受治疗/安慰剂相比,在总生存期方面可能几乎没有差异(确定性低).此外,我们不确定帕米膦酸盐(905/1000;HR1.20,95%CI0.81~1.78)是否比无治疗/安慰剂组降低总生存期(确定性非常低).颌骨坏死我们估计1000名没有治疗/安慰剂的参与者中有1人发展为颌骨坏死。来自NMA的证据（12项试验；23,527名参与者）表明denosumab（1000人中有25人；RR24.70，95％CI9.56至63.83），伊班膦酸钠(1000人中的6例;RR5.77,95%CI2.04~16.35)和唑来膦酸(1000人中的9例;RR9.41,95%CI3.54~24.99)与未接受治疗/安慰剂相比可能增加颌骨坏死的发生率(中度确定性).此外,clodronate(3/1000;RR2.65,95%CI0.83~8.50)与无治疗/安慰剂相比可能增加颌骨坏死的发生率(低确定性).肾功能损害我们估计1000名未接受治疗/安慰剂的参与者中有14人出现肾功能损害。来自NMA（12项试验；22,469名参与者）的证据表明，与没有治疗/安慰剂相比，伊班膦酸钠（1000人中的28人；RR1.98，95％CI1.01至3.88）可能会增加肾损害的发生率（中度确定性）。唑来膦酸（1000人中的21例；RR1.49，95％CI0.87至2.58）可能会增加肾功能损害的发生率，而氯膦酸盐（1000人中的12例；RR0.88，95％CI0.55至1.39）和狄诺单抗（1000人中的11例；RR0.80，95％CI0.54至1.19）与未治疗/安慰剂相比，可能几乎没有差异（中度确定性）。
结论：当考虑使用骨调节剂治疗早期或局部晚期乳腺癌女性的骨丢失时，必须在疗效和安全性之间取得平衡。我们的发现表明，与没有治疗或安慰剂相比，双膦酸盐（不包括阿仑膦酸盐和帕米膦酸盐）或狄诺单抗可能会导致骨矿物质密度增加和骨折率降低。我们的生存分析包括绝经前和绝经后妇女，显示总体生存率几乎没有差异。这些治疗可能导致更多的不良事件。因此,形成最佳排名的骨改性剂的总体判断是具有挑战性的。更多正面比较,特别是将denosumab与任何双膦酸盐进行比较，需要弥补差距并验证本次审查的结果。
目的：评估和比较不同骨调节剂作为支持治疗的效果，以减少无骨转移的乳腺癌女性患者的骨密度损失和骨质疏松性骨折，并使用网络荟萃分析（NMA）对治疗方案进行排序。
方法：我们通过电子搜索CENTRAL，MEDLINE和Embase直到2023年1月。我们搜索了各种试验登记处，并筛选了会议记录摘要和已确定试验的参考文献列表。
方法：我们纳入了随机对照试验，比较了不同的双膦酸盐和RANKL抑制剂对无骨转移的乳腺癌患者的治疗效果，或与无进一步治疗或安慰剂对照。
方法：两位综述作者独立提取数据，并使用GRADE评估纳入研究的偏倚风险和证据的确定性。结果是骨矿物质密度，生活质量,整体骨折，总生存期和不良事件。我们进行了NMA并生成了治疗排名。
结果：47项试验（35,163名参与者）符合我们的纳入标准；34项试验（33,793名参与者）可以在NMA（8种不同的治疗方案）中考虑。骨矿物质密度我们估计没有治疗/安慰剂的参与者的骨矿物质密度测量为总T评分为-1.34。来自NMA（9项试验；1166名参与者）的证据表明，伊班膦酸钠治疗（T评分-0.77；MD0.57，95％CI-0.05至1.19）可能会略微增加骨矿物质密度（低确定性），而唑来膦酸治疗（T评分-0.45；MD0.89，95％CI0.62至1.16）可能会略微增加骨矿物质密度。利塞膦酸盐（T评分-1.08；MD0.26，95％CI-0.32至0.84）可能与无治疗/安慰剂（确定性低）相比几乎没有差异。我们不确定阿仑膦酸盐（T评分2.36；MD3.70，95％CI-2.01至9.41）是否与无治疗/安慰剂相比（确定性非常低）增加骨密度。生活质量无法对生活质量进行定量分析，因为只有三项研究报告了这一结果。所有三项研究均显示所检查的各自干预措施之间的差异很小。总体骨折率我们估计1000名没有治疗/安慰剂的参与者中有70名患有骨折。来自NMA的证据（16项试验；19,492名参与者）表明，与未治疗/安慰剂相比，使用氯膦酸盐或伊班膦酸盐治疗（1000人中的42人；RR0.60，95％CI0.39至0.92；1000人中的40人；RR0.57，95％CI0.38至0.86）减少了骨折数量（确定性高）。Denosumab或唑来膦酸（1000人中有51例；RR0.73，95％CI0.52至1.01；1000人中有55例；RR0.79，95％CI0.56至1.11）可能略微减少骨折数量；与未治疗/安慰剂相比，利塞膦酸盐（1000人中有39例；RR0.56，95％CI0.15至2.16）可能减少骨折数量（中度确定性）。帕米膦酸盐（106/1000；RR1.52，95％CI0.75至3.06）可能会增加无治疗/安慰剂的骨折数量（中度确定性）。总体存活我们估计1000名没有治疗/安慰剂的参与者中有920名总体存活。来自NMA的证据（17项试验；30,991名参与者）表明氯膦酸盐（1000人中的924人；HR0.95，95％CI0.77至1.17），denosumab（1000人中的927人；HR0.91，95%CI0.69至1.21），伊班膦酸钠(1000人中的915例;HR1.06,95%CI0.83~1.34)和唑来膦酸(1000人中的925例;HR0.93,95%CI0.76~1.14)与未接受治疗/安慰剂相比,在总生存期方面可能几乎没有差异(确定性低).此外,我们不确定帕米膦酸盐(905/1000;HR1.20,95%CI0.81~1.78)是否比无治疗/安慰剂组降低总生存期(确定性非常低).颌骨坏死我们估计1000名没有治疗/安慰剂的参与者中有1人发展为颌骨坏死。来自NMA的证据（12项试验；23,527名参与者）表明denosumab（1000人中有25人；RR24.70，95％CI9.56至63.83），伊班膦酸钠(1000人中的6例;RR5.77,95%CI2.04~16.35)和唑来膦酸(1000人中的9例;RR9.41,95%CI3.54~24.99)与未接受治疗/安慰剂相比可能增加颌骨坏死的发生率(中度确定性).此外,clodronate(3/1000;RR2.65,95%CI0.83~8.50)与无治疗/安慰剂相比可能增加颌骨坏死的发生率(低确定性).肾功能损害我们估计1000名未接受治疗/安慰剂的参与者中有14人出现肾功能损害。来自NMA（12项试验；22,469名参与者）的证据表明，与没有治疗/安慰剂相比，伊班膦酸钠（1000人中的28人；RR1.98，95％CI1.01至3.88）可能会增加肾损害的发生率（中度确定性）。唑来膦酸（1000人中的21例；RR1.49，95％CI0.87至2.58）可能会增加肾功能损害的发生率，而氯膦酸盐（1000人中的12例；RR0.88，95％CI0.55至1.39）和狄诺单抗（1000人中的11例；RR0.80，95％CI0.54至1.19）与未治疗/安慰剂相比，可能几乎没有差异（中度确定性）。
结论：当考虑使用骨调节剂治疗早期或局部晚期乳腺癌女性的骨丢失时，必须在疗效和安全性之间取得平衡。我们的发现表明，与没有治疗或安慰剂相比，双膦酸盐（不包括阿仑膦酸盐和帕米膦酸盐）或狄诺单抗可能会导致骨矿物质密度增加和骨折率降低。我们的生存分析包括绝经前和绝经后妇女，显示总体生存率几乎没有差异。这些治疗可能导致更多的不良事件。因此,形成最佳排名的骨改性剂的总体判断是具有挑战性的。更多正面比较,特别是将denosumab与任何双膦酸盐进行比较，需要弥补差距并验证本次审查的结果。
