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Although various cellular and molecular changes have been reported, the mechanisms underlying disuse osteoporosis remain incompletely understood. Using the spiral wire immobilization (SWI) model, we observed that hindlimb immobilization in mice caused trabecular bone loss within 14\u00a0days after SWI initiation. Time\u2010course analysis revealed that trabecular bone loss progressed rapidly shortly after SWI initiation, with little progression at later time points. During the early phase of bone loss, enhancement of bone resorption was sustained following transient suppression of bone formation. Administration of an antibody against receptor activator of nuclear factor\u2010\u03baB ligand (RANKL), which inhibits osteoclastogenesis, alleviated bone loss, suggesting that osteoclast\u2010mediated bone resorption contributes substantially to bone loss during hindlimb immobilization. Transcriptomic analysis of the osteocyte\u2010enriched bone cell fraction revealed SWI\u2010enhanced expression of bone development\u2010related genes, whereas expression of the\n                      <jats:italic>Tnfsf11<\/jats:italic>\n                      gene encoding RANKL remained unchanged. However, single\u2010cell RNA sequencing of bone marrow cells from RANKL fate\u2010mapping mice demonstrated that SWI increased RANKL expression specifically in adipogenic C\u2010X\u2010C motif chemokine ligand 12\u2010abundant reticular (adipo\u2010CAR) cells, but not in osteoblasts or osteocytes. These findings clarify the contribution of osteoclastic bone resorption and identify adipo\u2010CAR cells as a novel RANKL source. This study offers new insights into the pathogenesis of disuse osteoporosis and informs the development of therapeutic and preventive strategies for physical inactivity\u2010associated bone loss.\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp70307-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Prolonged physical inactivity can lead to disuse osteoporosis, yet the cellular and molecular mechanisms remain poorly understood.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>To elucidate its pathogenesis, we utilized a spiral wire immobilization (SWI) mouse model to investigate bone loss at cellular and molecular levels.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Rapid bone loss driven by sustained enhancement of osteoclastic bone resorption was effectively suppressed by early anti\u2010receptor activator of nuclear factor\u2010\u03baB ligand (RANKL) antibody treatment targeting osteoclast activity.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>SWI induced RANKL expression specifically in adipogenic C\u2010X\u2010C motif chemokine ligand 12\u2010abundant reticular (adipo\u2010CAR) cells, identifying them as a previously unrecognized cellular source of osteoclastogenic signalling.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>This study provides molecular insight into the pathogenesis of disuse osteoporosis and underscores the importance of early intervention targeting osteoclast activation, thereby informing new therapeutic strategies.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1113\/jp289268","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T05:11:41Z","timestamp":1767589901000},"page":"1235-1254","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A novel stromal cell source of RANKL during sustained osteoclast activation in 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