{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T15:36:40Z","timestamp":1792165000620,"version":"4.4.0"},"reference-count":176,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>Osteoporosis is an increasingly important global health concern, particularly in aging populations, with prevalence rising markedly after the age of 60. Age-related alterations in the bone microenvironment play a pivotal role in disrupting skeletal homeostasis. Regulators of the bone microenvironment contribute centrally to osteoporosis pathogenesis by modulating bone remodeling through multiple, intersecting mechanisms. Accumulating evidence indicates that aging is accompanied by reduced levels of protective factors, such as osteoprotegerin and bone morphogenetic proteins (BMPs), alongside increases in pro-resorptive mediators, including receptor activator of nuclear factor-\u03baB ligand (RANKL), interleukin-6 (IL-6), and tumor necrosis factor-\u03b1 (TNF-\u03b1). This shift favors osteoclastogenesis and impairs osteoblast function, ultimately accelerating bone loss and increasing the risk of fragility fractures and disability. In this review, we synthesize current evidence on bone microenvironment regulatory factors in osteoporosis, with emphasis on their roles in bone remodeling and downstream cellular signaling pathways. We further discuss emerging intervention strategies that target these regulators to preserve or restore bone health in older adults. By clarifying age-associated microenvironmental changes and the interactions among key regulatory factors, this review aims to identify promising therapeutic targets and provide a conceptual framework to support osteoporosis prevention and treatment in the context of global population aging.<\/jats:p>","DOI":"10.3389\/fendo.2026.1783422","type":"journal-article","created":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T05:23:07Z","timestamp":1772515387000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["The role and mechanisms of bone microenvironment regulators in osteoporosis: novel intervention strategies for addressing the challenges of aging"],"prefix":"10.3389","volume":"17","author":[{"given":"Hongyuan","family":"Yao","sequence":"first","affiliation":[{"name":"Traumatic Orthopedics, The Second Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutao","family":"Cui","sequence":"additional","affiliation":[{"name":"Traumatic Orthopedics, The Second Hospital of Jilin University","place":["Changchun, China"]},{"name":"Department of Orthopedics, The First Affiliated Hospital of University of Science and Technology of China","place":["Hefei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Li","sequence":"additional","affiliation":[{"name":"Traumatic Orthopedics, The Second Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shouye","family":"Sun","sequence":"additional","affiliation":[{"name":"Traumatic Orthopedics, The Second Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuangang","family":"Peng","sequence":"additional","affiliation":[{"name":"Traumatic Orthopedics, The Second Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dankai","family":"Wu","sequence":"additional","affiliation":[{"name":"Traumatic Orthopedics, The Second Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(02)08761-5","article-title":"Diagnosis of osteoporosis and assessment of fracture risk","volume":"359","author":"Kanis","year":"2002","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)32112-3","article-title":"Osteoporosis","volume":"393","author":"Compston","year":"2019","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(25)00105-5","article-title":"The global, regional, and national burden attributable to low bone mineral density, 1990-2020: an analysis of a modifiable risk factor from the Global Burden of Disease Study 2021","volume":"7","year":"2025","journal-title":"Lancet Rheumatol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"154","DOI":"10.21203\/rs.2.22372\/v1","article-title":"Economic burden of osteoporosis in the world: A systematic review","volume":"34","author":"Rashki Kemmak","year":"2020","journal-title":"Med J Islam Repub Iran"},{"key":"B5","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1007\/s11657-013-0136-1","article-title":"Osteoporosis in the European Union: medical management, epidemiology and economic burden. 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