{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T14:13:06Z","timestamp":1771337586361,"version":"3.50.1"},"reference-count":21,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T00:00:00Z","timestamp":1771286400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Objective: Bone-modifying agents (BMA) are central to the prevention of skeletal-related events (SREs) in patients with cancer bone metastases, yet evidence guiding agent selection in very old patients remains limited. This study aimed to compare the effectiveness and safety of Denosumab versus bisphosphonates in patients aged \u226575 years with solid tumour-related bone metastases using a target trial emulation framework. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network to emulate a hypothetical randomised trial. Patients aged \u226575 years with solid tumour-related bone metastases initiating Denosumab or bisphosphonates were included. After 1:1 propensity score matching (PSM), 10,662 patients were analysed in each treatment group. The primary outcome was time to first SRE. Secondary outcomes included individual SRE components, all-cause mortality, and safety events. Results: Among 21,324 matched patients (mean age, 75.6 years), bisphosphonate use was associated with a higher risk of SREs compared with Denosumab (hazard ratio [HR], 1.15; 95% CI, 1.06\u20131.25). The excess risk was driven by pathological fractures (HR, 1.28; 95% CI, 1.10\u20131.49), whereas other SRE components did not differ significantly. All-cause mortality was higher among bisphosphonate users (HR, 1.41; 95% CI, 1.33\u20131.49, p &lt; 0.001). Hypocalcaemia occurred more frequently with Denosumab (5.7% vs. 2.4%), while risks of acute kidney injury and end-stage renal disease (ESRD) were similar. Findings were consistent across sensitivity and subgroup analyses. Conclusions: In patients aged \u226575 years with solid tumour-related bone metastases, Denosumab was associated with lower risks of skeletal-related events\u2014particularly pathological fractures\u2014and reduced all-cause mortality compared with bisphosphonates. These results extend randomised trial evidence to a clinically vulnerable population and support Denosumab as a preferred BMA in older adults.<\/jats:p>","DOI":"10.3390\/life16020346","type":"journal-article","created":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T13:15:35Z","timestamp":1771334135000},"page":"346","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comparative Effectiveness and Safety of Denosumab Versus Bisphosphonates in Elderly Patients with Cancer Bone Metastases: A Target Trial Emulation Study"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1674-1703","authenticated-orcid":false,"given":"Che-Wei","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Orthopaedics, Cathay General Hospital, Taipei 10630, Taiwan"},{"name":"School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 242062, Taiwan"},{"name":"School of Medicine, National Tsing Hua University, Hsinchu 300044, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8014-6311","authenticated-orcid":false,"given":"Shun-Neng","family":"Hsu","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical University, Taipei 114202, Taiwan"},{"name":"Department of Internal Medicine, School of Medicine, College of Medicine, National Defense Medical University, Taipei 11258, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0021-7676","authenticated-orcid":false,"given":"Shao-Hsuan","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Chang Gung University, Taoyuan 333323, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8937-6105","authenticated-orcid":false,"given":"Wei-Cheng","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Universe Eye Center, Taipei 115, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chun-Liang","family":"Hsu","sequence":"additional","affiliation":[{"name":"Orthopaedic Department, Tri-Service General Hospital, National Defense Medical University, Taipei 114202, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hsin-Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Family Medicine, Chi Mei Medical Center, Tainan 710, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0280-6417","authenticated-orcid":false,"given":"Po-Huang","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical University, Taipei 114202, Taiwan"},{"name":"Department of Oncology, Tri-Service General Hospital, National Defense Medical University, Taipei 114202, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6061-5168","authenticated-orcid":false,"given":"Cho-Hao","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical University, Taipei 114202, Taiwan"},{"name":"Department of Oncology, Tri-Service General Hospital, National Defense Medical University, Taipei 114202, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1053\/ctrv.2000.0210","article-title":"Metastatic bone disease: Clinical features, pathophysiology and treatment strategies","volume":"27","author":"Coleman","year":"2001","journal-title":"Cancer Treat. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Hernandez, R.K., Wade, S.W., Reich, A., Pirolli, M., Liede, A., and Lyman, G.H. (2018). Incidence of bone metastases in patients with solid tumors: Analysis of oncology electronic medical records in the United States. BMC Cancer, 18.","DOI":"10.1186\/s12885-017-3922-0"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1860","DOI":"10.1002\/cncr.22991","article-title":"Pathologic fractures correlate with reduced survival in patients with malignant bone disease","volume":"110","author":"Saad","year":"2007","journal-title":"Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1007\/s10549-011-1475-5","article-title":"Survival in breast cancer patients with bone metastases and skeletal-related events: A population-based cohort study in Denmark (1999\u20132007)","volume":"129","author":"Yong","year":"2011","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1200\/JCO.2010.32.5209","article-title":"American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer","volume":"29","author":"Temin","year":"2011","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_6","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. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_7","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_8","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1200\/JCO.2010.31.3304","article-title":"Randomized, double-blind study of Denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma","volume":"29","author":"Henry","year":"2011","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1038\/ki.2008.356","article-title":"Bisphosphonate nephrotoxicity","volume":"74","author":"Perazella","year":"2008","journal-title":"Kidney Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1002\/jbmr.1613","article-title":"A single-dose study of Denosumab in patients with various degrees of renal impairment","volume":"27","author":"Block","year":"2012","journal-title":"J. Bone Miner. Res. Off. J. Am. Soc. Bone Miner. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1093\/aje\/kwv254","article-title":"Using Big Data to Emulate a Target Trial When a Randomized Trial Is Not Available","volume":"183","author":"Robins","year":"2016","journal-title":"Am. J. Epidemiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.jclinepi.2016.04.014","article-title":"Specifying a target trial prevents immortal time bias and other self-inflicted injuries in observational analyses","volume":"79","author":"Sauer","year":"2016","journal-title":"J. Clin. Epidemiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3083","DOI":"10.1002\/sim.3697","article-title":"Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples","volume":"28","author":"Austin","year":"2009","journal-title":"Stat. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"268","DOI":"10.7326\/M16-2607","article-title":"Sensitivity Analysis in Observational Research: Introducing the E-Value","volume":"167","author":"VanderWeele","year":"2017","journal-title":"Ann. Intern. Med."},{"key":"ref_15","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_16","doi-asserted-by":"crossref","first-page":"e003173","DOI":"10.1136\/bmjresp-2025-003173","article-title":"Denosumab usage is associated with better overall survival of patients with lung cancer and bone metastases: A retrospective cohort study","volume":"12","author":"Yu","year":"2025","journal-title":"BMJ Open Respir. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.2215\/CJN.0000000000000260","article-title":"Treating Osteoporosis with Denosumab in Patients on Hemodialysis: The Good, the Bad, and the Ugly","volume":"18","author":"Nickolas","year":"2023","journal-title":"Clin. J. Am. Soc. Nephrol. CJASN"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1056\/NEJMoa0809493","article-title":"Denosumab for prevention of fractures in postmenopausal women with osteoporosis","volume":"361","author":"Cummings","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1812","DOI":"10.1016\/j.ejca.2015.05.016","article-title":"Hypocalcaemia in patients with metastatic bone disease treated with Denosumab","volume":"51","author":"Body","year":"2015","journal-title":"Eur. J. Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Hong, S., Youk, T., Lee, S.J., Kim, K.M., and Vajdic, C.M. (2020). Bone metastasis and skeletal-related events in patients with solid cancer: A Korean nationwide health insurance database study. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0234927"},{"key":"ref_21","unstructured":"TriNetX (2026, January 24). TriNetX Global Collaborative Network. Available online: https:\/\/trinetx.com."}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/16\/2\/346\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T13:22:53Z","timestamp":1771334573000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/16\/2\/346"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,17]]},"references-count":21,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["life16020346"],"URL":"https:\/\/doi.org\/10.3390\/life16020346","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,17]]}}}