{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T12:01:44Z","timestamp":1790596904030,"version":"4.1.0"},"reference-count":109,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"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. Immunol."],"abstract":"<jats:p>Osteoporosis has long been understood, and treated, as an imbalance between osteoblastic bone formation and osteoclastic resorption. Yet many patients continue to lose bone, pointing to upstream regulators of the remodeling unit that remain poorly defined. Macrophages are developmentally continuous with osteoclasts and functionally coupled to bone-forming cells, and are now recognized as central immune regulators of skeletal homeostasis. What sets their polarization state, however, has been comparatively neglected in bone. This review adopts metabolic\u2013polarization coupling as a unifying framework for macrophage function in osteoporosis. We argue that the metabolic program a macrophage selects acts as an upstream regulator that biases its phenotype and, in turn, the balance of bone resorption and formation, and we examine how this switch is reinforced epigenetically, amplified by comorbidity, and rendered therapeutically actionable. Aerobic glycolysis via the HIF-1\u03b1 axis, versus oxidative phosphorylation and fatty-acid oxidation, sets M1 versus M2 phenotype and thereby the balance of resorption and osteogenic\u2013vascular support. Lactate-derived post-translational modifications, notably histone lactylation, make this metabolic state durable at the epigenetic level, while metabolic comorbidities, including ageing, diabetes and obesity, amplify the axis to accelerate bone loss. We emphasize at the outset that direct intra-osseous evidence for this axis remains scarce: the skeletal phenotypes conferred by macrophage-specific deletion of HIF-1\u03b1 or CPT1A are unreported, histone lactylation has yet to be quantified in bone-resident macrophages, and much of the mechanistic support stems from non-skeletal tissues, inflammatory bone-loss, or periodontal models rather than from primary postmenopausal or age-related osteoporosis. Accordingly, throughout this review we explicitly distinguish evidence established within bone from evidence merely extrapolated to bone. Repositioning macrophage metabolism from a passive correlate to an upstream causal node yields an emerging regulatory axis yields a testable sequence, metabolic node to polarization to remodeling imbalance to bone loss, that identifies metabolic enzymes such as HIF-1\u03b1 and CPT1A as candidate druggable targets and polarization and lactylation signatures as candidate readouts for stratification. This perspective reframes osteoporosis therapy from suppressing mature osteoclasts toward reprogramming macrophage metabolism itself.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1953599","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T11:36:55Z","timestamp":1790595415000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Macrophage immunometabolism in osteoporosis: an emerging regulatory axis linking metabolic\u2013polarization coupling to therapeutic targets"],"prefix":"10.3389","volume":"17","author":[{"given":"Lian","family":"Weng","sequence":"first","affiliation":[{"name":"The Second Department of Orthopedics, Luzhou Longmatan District People's Hospital","place":["Luzhou, Sichuan, China"]},{"name":"Department of Orthopedics, Affiliated Hospital of Southwest Medical University","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianli","family":"Yuan","sequence":"additional","affiliation":[{"name":"The Second Department of Orthopedics, Luzhou Longmatan District People's Hospital","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taizhou","family":"Mo","sequence":"additional","affiliation":[{"name":"The Second Department of Orthopedics, Luzhou Longmatan District People's Hospital","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taiming","family":"Yuan","sequence":"additional","affiliation":[{"name":"The Second Department of Orthopedics, Luzhou Longmatan District People's Hospital","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongwei","family":"Xiong","sequence":"additional","affiliation":[{"name":"The Second Department of Orthopedics, Luzhou Longmatan District People's Hospital","place":["Luzhou, Sichuan, China"]},{"name":"Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liao","family":"Ding","sequence":"additional","affiliation":[{"name":"The Second Department of Orthopedics, Luzhou Longmatan District People's Hospital","place":["Luzhou, Sichuan, China"]},{"name":"Department of Orthopedics, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1177\/0192623313512428","article-title":"Osteoporosis-bone remodeling and animal models","volume":"42","author":"Bonucci","year":"2014","journal-title":"Toxicol 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