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Given the impaired renal function in these patients, common antiresorptive agents, including bisphosphonates, must be used with caution or even contraindicated. Therefore, an alternative therapy without renal burden to combat renal osteodystrophy is urgently needed. Here, we report that clinically relevant aerobic exercise significantly prevents high-turnover renal osteodystrophy in CKD mice and patients with CKD without compromising renal function. Mechanistically, 4-week aerobic exercise in CKD mice increased expression of skeletal muscle PPAR\u03b3 coactivator-1\u03b1 (PGC-1\u03b1) and circulating irisin. Both exercise and irisin administration significantly activated osteoblasts, but not osteoclasts, via integrin \u03b1v\u03b25, thereby conferring bone quality benefits. Removal of irisin-influenced thermogenic adipose tissues or genetic ablation of uncoupling protein 1 did not alter the irisin-conferred antiosteodystrophy effect. Importantly, in a pilot clinical study, 12-week aerobic exercise in patients with high-grade CKD significantly increased circulating irisin and prevented osteodystrophy progression, without detectable renal burden. The combination of irisin and current antiresorptive agents effectively rescued renal osteodystrophy in mice. Our work provides mechanistic insights into the role of exercise and irisin in renal osteodystrophy, and it highlights a clinically relevant, low-cost, kidney-friendly therapy for patients with this devastating disease.<\/jats:p>","DOI":"10.1172\/jci.insight.184468","type":"journal-article","created":{"date-parts":[[2025,1,30]],"date-time":"2025-01-30T12:00:29Z","timestamp":1738238429000},"source":"Crossref","is-referenced-by-count":12,"title":["Aerobic exercise prevents renal osteodystrophy via irisin-activated osteoblasts"],"prefix":"10.1172","volume":"10","author":[{"given":"Meng","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China."},{"name":"Department of Nephrology, Longyan First Affiliated Hospital of Fujian Medical University, Longyan, 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