{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T09:01:50Z","timestamp":1776934910546,"version":"3.51.2"},"reference-count":37,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T00:00:00Z","timestamp":1775952000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Skeletal-related events (SREs), including pathological fractures, spinal cord compression, radiotherapy to bone, and bone surgery, substantially worsen quality of life in breast cancer with bone metastases. Denosumab, a monoclonal antibody targeting RANKL, mechanistically differs from bisphosphonates and is not renally cleared, offering potential clinical advantages. In practice, an increasing number of patients transition from bisphosphonates to denosumab. However, the comparative effectiveness of sequential therapy versus initial denosumab remains unclear. Methods: We retrospectively analyzed 165 patients with breast cancer and radiologically confirmed bone metastases treated between 1 January 2019 and 30 April 2024 at a tertiary center in China. Patients were categorized into an initial denosumab group (n = 67) or a sequential bisphosphonate-to-denosumab group (n = 98). The primary endpoint was time to first on-treatment SRE; the 12-month first on-treatment SRE rate was also reported as a descriptive summary measure. Secondary endpoints included cumulative SRE incidence and safety. Kaplan\u2013Meier and log-rank tests compared SRE-free survival; Cox regression explored prognostic factors. Results: The median age at bone-metastasis diagnosis was 54.7 years. Median time from diagnosis to bone-targeted agents (BTAs) initiation was 0.9 months in both groups; median follow-up was longer in the sequential group (22.5 vs. 11.3 months). At diagnosis, 46 of 165 patients (27.9%) presented with synchronous SREs, more frequent in the initial denosumab group (37.3% vs. 21.4%; p = 0.040). During follow-up, 31 patients (18.8%) developed SREs: 25 of 98 (25.5%) in the sequential group versus 6 of 67 (9.0%) in the initial denosumab group (p = 0.008). After BTA initiation, on-treatment SREs occurred in 28 of 165 patients (17.0%): 25 of 98 (25.5%) in the sequential group versus 3 of 67 (4.7%) in the initial denosumab group (p &lt; 0.001). The 12-month first on-treatment SRE rate was 15.7% (95% CI 8.1\u201322.7) for sequential therapy and 5.9% (0\u201312.3) for initial denosumab. In Cox analysis, second-line systemic therapy increased SRE risk (HR = 2.651, p = 0.021). Safety outcomes were generally manageable and consistent with known class effects, with no clear exposure-adjusted safety advantage of one strategy over another. Conclusions: Initial denosumab was associated with fewer and delayed SREs compared with sequential bisphosphonate-to-denosumab therapy, supporting early denosumab initiation as a potentially preferable BTA strategy. Prospective studies are warranted to confirm these findings.<\/jats:p>","DOI":"10.3390\/cancers18081222","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T07:29:29Z","timestamp":1776065369000},"page":"1222","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Initial Denosumab Versus Sequential Bisphosphonate-to-Denosumab for Prevention of Skeletal-Related Events in Breast Cancer with Bone Metastases: A Retrospective, Single-Center Study"],"prefix":"10.3390","volume":"18","author":[{"given":"Yannan","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wanjing","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yizhao","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuanyuan","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,12]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"20175","DOI":"10.1038\/s41598-021-99726-7","article-title":"Breast cancer patients with isolated bone metastases and oligometastatic bone disease show different survival outcomes","volume":"11","author":"Zengel","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Anwar, E., Amjad, A., Zubairi, A.J., Ali, M.M., and Zeeshan, S. (2025). De Novo bone metastasis in breast cancer: Tumor biology and survival outcomes in a retrospective study from Pakistan. BMC Cancer, 25.","DOI":"10.1186\/s12885-025-14187-9"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1016\/j.annonc.2020.07.019","article-title":"Bone health in cancer: ESMO Clinical Practice Guidelines","volume":"31","author":"Coleman","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/s41413-020-00105-1","article-title":"Molecular mechanisms and clinical management of cancer bone metastasis","volume":"8","author":"Wang","year":"2020","journal-title":"Bone Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e2300396","DOI":"10.1200\/GO.23.00396","article-title":"Cost-Effectiveness Analysis of Denosumab in the Prevention of Skeletal-Related Events Among Patients With Breast Cancer With Bone Metastasis in India","volume":"10","author":"Wadhwa","year":"2024","journal-title":"JCO Glob. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1785","DOI":"10.1056\/NEJM199612123352401","article-title":"Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. Protocol 19 Aredia Breast Cancer Study Group","volume":"335","author":"Hortobagyi","year":"1996","journal-title":"N. Engl. J. Med."},{"key":"ref_8","first-page":"7047","article-title":"One changing and challenging scenario: The treatment of cancer patients with bone metastases by bisphosphonates and denosumab, the cost-benefit evaluation of different options, and the risk of medication-related osteonecrosis of the jaw (MRONJ)","volume":"30","author":"Fusco","year":"2022","journal-title":"Support. Care Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1016\/S1470-2045(12)70470-9","article-title":"NICE guidance on denosumab for prevention of skeletal-related events in adults with bone metastases from solid tumours","volume":"13","author":"Jilani","year":"2012","journal-title":"Lancet Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.2147\/CLEP.S175063","article-title":"Use of bone-modifying agents among breast cancer patients with bone metastasis: Evidence from oncology practices in the US","volume":"10","author":"McGrath","year":"2018","journal-title":"Clin. Epidemiol."},{"key":"ref_11","first-page":"1","article-title":"Bone-targeted agent treatment patterns and the impact of bone metastases on patients with advanced breast cancer in real-world practice in six European countries","volume":"11","author":"Body","year":"2018","journal-title":"J. Bone Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"100423","DOI":"10.1016\/j.jbo.2022.100423","article-title":"Risk factors associated with skeletal-related events following discontinuation of denosumab treatment among patients with bone metastases from solid tumors: A real-world machine learning approach","volume":"34","author":"Jacobson","year":"2022","journal-title":"J. Bone Oncol."},{"key":"ref_13","first-page":"3859","article-title":"Optimizing antiresorptive treatment in patients with bone metastases: Time to initiation, switching strategies, and treatment duration","volume":"27","author":"Mjelstad","year":"2019","journal-title":"Support. Care Cancer"},{"key":"ref_14","first-page":"1845","article-title":"Longitudinal patterns of bone-targeted agent use among patients with solid tumors and bone metastases in the United States","volume":"25","author":"Qian","year":"2017","journal-title":"Support. Care Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"136","DOI":"10.4103\/ijc.IJC_16_20","article-title":"Denosumab in breast cancer patients receiving aromatase inhibitors: A single-center observational study of effectiveness in adjuvant setting","volume":"58","author":"Irelli","year":"2021","journal-title":"Indian J. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5132","DOI":"10.1200\/JCO.2010.29.7101","article-title":"Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: A randomized, double-blind study","volume":"28","author":"Stopeck","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/S0140-6736(10)62344-6","article-title":"Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: A randomised, double-blind study","volume":"377","author":"Fizazi","year":"2011","journal-title":"Lancet"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3082","DOI":"10.1016\/j.ejca.2012.08.002","article-title":"Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: A combined analysis of 3 pivotal, randomised, phase 3 trials","volume":"48","author":"Lipton","year":"2012","journal-title":"Eur. J. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1080\/03007995.2018.1558849","article-title":"Bone-targeted agent treatment patterns and the impact of bone metastases on patients with advanced breast cancer in the United States","volume":"35","author":"Henry","year":"2019","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"116243","DOI":"10.1016\/j.bone.2021.116243","article-title":"Initiation of bone-targeted agents in patients with bone metastases and breast or castrate-resistant prostate cancer actively treated in routine clinical practice in Europe","volume":"154","author":"Lewis","year":"2022","journal-title":"Bone"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1097\/COC.0000000000001075","article-title":"Treatment Patterns of Bone-targeting Agents Among Solid Tumor Patients With Bone Metastases: An Analysis of Electronic Health Record Data in the United States From 2014 to 2018","volume":"47","author":"Nicholson","year":"2024","journal-title":"Am. J. Clin. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1007\/s40259-022-00528-8","article-title":"Comparative Treatment Persistence with Bone-Targeting Agents Among Asian Patients with Bone Metastases from Solid Tumors: A Multinational Retrospective Cohort Study","volume":"36","author":"Shen","year":"2022","journal-title":"BioDrugs"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Wajda, B.G., Ferrie, L.E., Abbott, A.G., Elmi Assadzadeh, G., Monument, M.J., and Kendal, J.K. (2025). Denosumab vs. Zoledronic Acid for Metastatic Bone Disease: A Comprehensive Systematic Review and Meta-Analysis of Randomized Controlled Trials. Cancers, 17.","DOI":"10.3390\/cancers17030388"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Oner, I., Anik, H., Kurt Inci, B., Kubilay Tolunay, P., Ates, O., Yalcintas Arslan, U., and Karacin, C. (2025). A Comparison of the Efficacy and Safety of Denosumab and Zoledronic Acid in Patients with Bone Metastatic Breast Cancer Receiving CDK4\/6 Inhibitor Therapy. Medicina, 61.","DOI":"10.3390\/medicina61020360"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1186\/s13018-021-02554-8","article-title":"Comparison of denosumab and zoledronic acid for the treatment of solid tumors and multiple myeloma with bone metastasis: A systematic review and meta-analysis based on randomized controlled trials","volume":"16","author":"Jiang","year":"2021","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1007\/s10549-025-07852-x","article-title":"Cardiovascular adverse events associated with denosumab versus zoledronic acid in patients with breast cancer: A propensity score overlap weighted analysis","volume":"215","author":"Iwai","year":"2025","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"83","DOI":"10.7180\/kmj.24.121","article-title":"Bone-modifying agents for bone metastasis in patients with breast cancer","volume":"39","author":"Park","year":"2024","journal-title":"Kosin Med. J."},{"key":"ref_28","first-page":"1029","article-title":"Denosumab versus bisphosphonates in patients with advanced cancers-related bone metastasis: Systematic review and meta-analysis of randomized controlled trials","volume":"26","author":"Menshawy","year":"2018","journal-title":"Support. Care Cancer"},{"key":"ref_29","first-page":"e12541","article-title":"Meta-analysis comparing denosumab and zoledronic acid for treatment of bone metastases in patients with advanced solid tumours","volume":"26","author":"Zheng","year":"2017","journal-title":"Eur. J. Cancer Care"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e069214","DOI":"10.1136\/bmjopen-2022-069214","article-title":"Assessment of bone-targeting agents use in patients with bone metastasis from breast, lung or prostate cancer using structured and unstructured electronic health records from a regional UK-based hospital","volume":"13","author":"Seesaghur","year":"2023","journal-title":"BMJ Open"},{"key":"ref_31","first-page":"5223","article-title":"Real-world use of denosumab and bisphosphonates in patients with solid tumours and bone metastases in Germany","volume":"28","author":"Diel","year":"2020","journal-title":"Support. Care Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e13166","DOI":"10.1200\/JCO.2025.43.16_suppl.e13166","article-title":"Denosumab monotherapy versus bisphosphonate switching in breast cancer bone metastases: A real-world cohort study on skeletal events and safety","volume":"43","author":"Jiang","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Oyucu Orhan, S., Orhan, B., Esenbuga, S., Sali, S., Caner, B., Ocak, B., Sahin, A.B., Deligonul, A., Evrensel, T., and Cubukcu, E. (2025). Managing Bone Metastases with Denosumab: Real-World Data and Critical Monitoring Points in Breast, Lung, and Prostate Cancers. Medicina, 61.","DOI":"10.3390\/medicina61091637"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e515","DOI":"10.1016\/j.clbc.2023.08.008","article-title":"Bone-Targeted Therapy Regimen and Skeletal-Related Events in Patients Surviving Longer Than 2 Years With Metastatic Breast Cancer and Bone Metastasis","volume":"23","author":"Jayan","year":"2023","journal-title":"Clin. Breast Cancer"},{"key":"ref_35","first-page":"172","article-title":"The effect of denosumab vs. zoledronic acid in preventing skeletal-related events, including pain-related bone metastasis: A systematic review","volume":"33","author":"Widyadharma","year":"2024","journal-title":"Adv. Psychiatry Neurol.\/Post\u0119py Psychiatrii i Neurologii"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"8403","DOI":"10.1038\/s41598-023-35308-z","article-title":"Long-term use of denosumab and its association with skeletal-related events and osteonecrosis of the jaw","volume":"13","author":"Fu","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"219","DOI":"10.24920\/004368","article-title":"Cost-Effectiveness of Denosumab for Treating Bone Metastases from Solid Tumors: A Systematic Review (2017\u20132023)","volume":"40","author":"Wang","year":"2025","journal-title":"Chin. Med. Sci. J."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/8\/1222\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T08:31:06Z","timestamp":1776933066000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/8\/1222"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,12]]},"references-count":37,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["cancers18081222"],"URL":"https:\/\/doi.org\/10.3390\/cancers18081222","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,12]]}}}