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Although current pharmacological interventions provide therapeutic benefits, long\u2010term use is limited by side effects and comorbidities. In this study, we employed driver signaling network identification (DSNI) and drug functional networks (DFN) to identify repurposable drugs from the Library of Integrated Network\u2010Based Cellular Signatures. We constructed osteoporosis driver signaling networks (ODSN) using multi\u2010omics data and developed DFN based on drug similarity. By integrating ODSN and DFN with drug\u2010induced transcriptional responses, we screened 10,158 compounds and identified several drugs with strong targeting effects on ODSN. Mendelian randomization assessed potential causal links between cis\u2010eQTLs of drug targets and BMD using genome\u2010wide association study data. Our findings indicate four drugs, including Ruxolitinib, Alfacalcidol, and Doxercalciferol, may exert anti\u2010osteoporosis effects. Notably, Acebutolol, a \u03b2\u2010blocker for hypertension, has not previously been implicated in osteoporosis therapy. For validation, zebrafish osteoporosis models were established using Dexamethasone\u2010induced bone loss, followed by treatment with Acebutolol hydrochloride and Alfacalcidol. Both compounds demonstrated significant protective effects against osteoporosis\u2010related bone deterioration. Furthermore, a population\u2010based data set, utilizing propensity score matching and analyzed via a generalized linear model, revealed that individuals taking \u03b2\u2010blocker drugs exhibited significantly higher BMD than users of other cardiovascular medications. In summary, this study integrates multi\u2010omics approaches, experimental validation, and real\u2010world population data to propose acebutolol as a novel candidate for osteoporosis treatment. These findings warrant further mechanistic studies and clinical trials to evaluate its efficacy in osteoporosis management.<\/jats:p>","DOI":"10.1002\/cpt.3738","type":"journal-article","created":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T07:44:16Z","timestamp":1749195856000},"page":"1463-1476","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Repurposing Acebutolol for Osteoporosis Treatment: Insights From Multi\u2010Omics and Multi\u2010Modal Data Analysis"],"prefix":"10.1002","volume":"118","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8015-4103","authenticated-orcid":false,"given":"Dan\u2010Yang","family":"Liu","sequence":"first","affiliation":[{"name":"Laboratory of Molecular and Statistical Genetics College of Life Sciences, Hunan Normal University  Changsha Hunan 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