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In particular, estrogen helps prevent excessive bone resorption by its impact on bone remodeling. When estrogen levels decrease, bone resorption increases, often resulting in weakened bones and osteoporosis in post-menopausal women. Experimental studies have also shown that estrogen regulates the renin-angiotensin system (RAS), a hormone system involved in many physiological processes, including blood pressure regulation. Additionally, the RAS has an interconnected relationship with calcium regulatory and bone remodeling systems. Given these dynamic interplays, we developed a physiology-based mathematical model that simulates the interactions of estrogen, key RAS components, calcium regulation, and bone remodeling to investigate how perturbations in one system affect the others. This represents the first known model to include the direct impacts of estrogen on the RAS and to couple the RAS with calcium homeostasis and bone remodelling systems in humans. Through model simulations and sensitivity analysis, we investigated how declining estrogen levels affect the RAS and bone mineral density. Furthermore, we quantified how RAS inhibitors, specifically angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB), may increase bone density during post-menopausal estrogen decline. Our simulation results suggest that ARB treatment may be more effective at improving bone mineral density during postmenopausal estrogen decline, and that this trend remains consistent regardless of the age of RAS inhibitor initiation.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1013101","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T17:35:37Z","timestamp":1790098537000},"page":"e1013101","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["A physiology-based mathematical model of the renin-angiotensin system, bone remodeling, and calcium homeostasis: Effects of estrogen and renin-angiotensin system inhibitors"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4215-8004","authenticated-orcid":true,"given":"Melissa M.","family":"Stadt","sequence":"first","affiliation":[{"name":"University of Waterloo","place":["Waterloo, Ontario, Canada"],"department":["Department of Applied Mathematics"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3387-5884","authenticated-orcid":true,"given":"Victoria A.","family":"Ralph","sequence":"additional","affiliation":[{"name":"University of Waterloo","place":["Waterloo, Ontario, Canada"],"department":["Department of Applied Mathematics"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1753-4063","authenticated-orcid":true,"given":"Anita T.","family":"Layton","sequence":"additional","affiliation":[{"name":"University of Waterloo","place":["Waterloo, Ontario, Canada"],"department":["Department of Applied Mathematics"]},{"name":"University of Waterloo","place":["Waterloo, Ontario, Canada"],"department":["Cheriton School of Computer Science, Department of Biology, School of Pharmacology"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,9,22]]},"reference":[{"key":"pcbi.1013101.ref001","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/B978-0-12-416015-6.00004-6","article-title":"Bone Modeling and Remodeling","volume-title":"Basic and Applied Bone Biology","author":"MR Allen","year":"2014"},{"key":"pcbi.1013101.ref002","doi-asserted-by":"crossref","first-page":"1368555","DOI":"10.3389\/fsysb.2024.1368555","article-title":"A review of mathematical modeling of bone remodeling from a systems biology perspective","volume":"4","author":"CV Cook","year":"2024","journal-title":"Front Syst Biol"},{"issue":"9","key":"pcbi.1013101.ref003","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1002\/jbmr.5650070902","article-title":"Perspective: How Many Women Have Osteoporosis?","volume":"7","author":"LJI Melton","year":"1992","journal-title":"Journal of Bone and Mineral 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