{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T05:02:17Z","timestamp":1790226137656,"version":"4.1.0"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"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>The kidney-bone axis constitutes a conserved bidirectional endocrine network that orchestrates skeletal remodeling and systemic mineral homeostasis. Its dysregulation underlies chronic kidney disease-mineral and bone disorder (CKD-MBD), renal osteodystrophy, secondary hyperparathyroidism, and associated vascular calcification, markedly elevating fracture and cardiovascular mortality risks. This review offers a unique cross-cultural and chronological synthesis of the kidney-bone relationship, bridging ancient medical insights with modern molecular endocrinology. Horizontally, we systematically compare the \u201ckidney governing bones\u201d doctrine in Traditional Chinese Medicine (TCM), ancient Greek humoral theory, and Ayurvedic Asthi Dhatu concept, revealing their shared holistic visceral-skeletal paradigm as the primitive prototype of contemporary multi-organ crosstalk, while highlighting distinct interpretive and therapeutic frameworks. Vertically, modern research is delineated into three developmental stages: (1) clinical-pathological observation of renal osteodystrophy and vitamin D-PTH disturbances (19th\u2013early 20th century); (2) core molecular endocrine discoveries centered on the FGF23-Klotho, vitamin D, and OPG\/RANKL\/PTH signaling axes; and (3) expansion to novel multi-organ networks involving gut microbiota-derived uremic toxins, exosomes, and O-GlcNAc modification. We further summarize the multi-target mechanisms of kidney-tonifying TCM formulas (e.g., Zuogui Pill, Gushudan) and Western interventions, critically analyze translational bottlenecks\u2014including biomarker limitations, stratified therapy challenges, and insufficient high-level clinical evidence\u2014and propose integrated Chinese-Western strategies, multi-omics precision biomarkers, and cross-cultural theoretical fusion to advance personalized management of CKD-MBD and related metabolic bone diseases.<\/jats:p>","DOI":"10.3389\/fendo.2026.1835818","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T04:35:04Z","timestamp":1790224504000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The cross-cultural and chronological evolution of the kidney-bone relationship: from ancient medical insights to modern molecular endocrinology"],"prefix":"10.3389","volume":"17","author":[{"given":"Jinke","family":"Sun","sequence":"first","affiliation":[{"name":"Shandong Wendeng Osteopathic Hospital","place":["Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaoling","family":"Yuan","sequence":"additional","affiliation":[{"name":"Shandong Wendeng Osteopathic Hospital","place":["Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Yu","sequence":"additional","affiliation":[{"name":"Shandong Wendeng Osteopathic Hospital","place":["Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiqi","family":"Wei","sequence":"additional","affiliation":[{"name":"Shandong Wendeng Osteopathic Hospital","place":["Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongping","family":"Qiao","sequence":"additional","affiliation":[{"name":"Shandong Wendeng Osteopathic Hospital","place":["Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1007\/s11684-014-0362-y","article-title":"Mechanisms of \"kidney governing bones\" theory in traditional Chinese medicine","volume":"8","author":"Ju","year":"2014","journal-title":"Front Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.108102","article-title":"Multifocal uremic tumoral calcinosis from prolonged hyperparathyroidism in ADPKD","volume":"18","author":"Harris","year":"2026","journal-title":"Cureus"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3390\/biom16040513","article-title":"High-Intensity Interval and Aerobic Training Alleviate Cardiac Pathology, Apoptosis, and Atrial Fibrillation in Rats with Chronic Kidney Disease: The Roles of FGF23 and Klotho","volume":"16","author":"Rokhsati","year":"2026","journal-title":"Biomolecules"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/1685052","article-title":"Biological Deciphering of the \"Kidney Governing Bones\" Theory in Traditional Chinese Medicine","volume":"2022","author":"Zhu","year":"2022","journal-title":"Evid Based Complement Alternat Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/7044775","article-title":"Integrated RNA-Seq Analysis Uncovers the Potential Mechanism of the \"Kidney Governing Bones\" Theory of TCM","volume":"2022","author":"Yang","year":"2022","journal-title":"Evid Based Complement Alternat Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/1116923","article-title":"Data Mining and Network Pharmacology Analysis of Kidney-Tonifying Herbs on the Treatment of Renal Osteodystrophy Based on the Theory of \"Kidney Governing Bones\" in Traditional Chinese Medicine","volume":"2022","author":"Tong","year":"2022","journal-title":"Evid Based Complement Alternat Med"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2026.05.009","article-title":"Gut-derived uremic toxin indoxyl sulfate and aryl hydrocarbon receptor in renal osteodystrophy","volume":"248","author":"Russell","year":"2026","journal-title":"Biochimie"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202302704R","article-title":"Comparative effects of calcitriol and calcimimetic on bone health in renal insufficiency","volume":"38","author":"D\u00edaz-Tocados","year":"2024","journal-title":"FASEB J"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1093\/ageing\/afae096","article-title":"Alterations in regulators of the renal-bone axis, inflammation and iron status in older people with early renal impairment and the effect of vitamin D supplementation","volume":"53","author":"Christodoulou","year":"2024","journal-title":"Age Ageing"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1113\/EP092401","article-title":"Molecular pathophysiology of chronic kidney disease-mineral and bone disorder: Focus on the fibroblast growth factor 23-Klotho axis and bone turnover dynamics","author":"Waitupu","year":"2025","journal-title":"Exp Physiol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1007\/s00223-026-01537-3","article-title":"Circulating \u03b1-Klotho and Multidimensional Aging and Frailty Outcomes: A Systematic Review and Meta-Analysis from the European Renal Association CKD-MBD Working Group","volume":"117","author":"Guldan","year":"2026","journal-title":"Calcif Tissue Int"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1007\/s00467-024-06395-5","article-title":"The role of fibroblast growth factor 23 in phosphate balance","volume":"39","author":"Wilson","year":"2024","journal-title":"Pediatr Nephrol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2026.1854704","article-title":"The role of gut dysbiosis in endocrine and metabolic derangements of chronic kidney disease: mechanisms, controversies, and future perspectives","volume":"17","author":"Ouyang","year":"2026","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrep.2026.102635","article-title":"O-GlcNAcylation: A bridge for regulating the function of the \"heart-kidney-bone axis","volume":"46","author":"Wang","year":"2026","journal-title":"Biochem Biophys Rep"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2026.1764206","article-title":"Heterogeneous regulation of fibroblast growth factor 23 in acute kidney injury, chronic kidney disease, and polycystic kidney disease: mechanisms, diagnostic utility, and clinical implications","volume":"13","author":"Hu","year":"2026","journal-title":"Front Mol Biosci"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2026.1762302","article-title":"Research on vitamin D metabolic regulation in the pathogenesis of related diseases","volume":"17","author":"Ji","year":"2026","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1093\/joneph\/aajag035","article-title":"Effects of gliflozins on bone health of patients with chronic kidney disease: a systematic review","author":"Cassani de Oliveira","year":"2026","journal-title":"J Nephrol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1053\/j.ajkd.2026.02.642","article-title":"Risks of Hypocalcemia and Other Bone Mineral Disorders for Denosumab Versus Zoledronate Across the Spectrum of Kidney Function: A Target Trial Emulation","volume":"88","author":"Xiao","year":"2026","journal-title":"Am J Kidney Dis"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2026.1685724","article-title":"Molecular mechanisms of polysaccharide components of kidney-tonifying traditional Chinese medicine in regulating osteoporosis","volume":"17","author":"Zheng","year":"2026","journal-title":"Front Pharmacol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchromb.2025.124540","article-title":"Integration of UHPLC-MS and mass spectrometry imaging techniques revealed the protective mechanism of Gushudan in postmenopausal osteoporosis rats via branched-chain amino acid metabolism based on the 'kidney-bone' axis","volume":"1256","author":"Ren","year":"2025","journal-title":"J Chromatogr B"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2026.121026","article-title":"High-throughput UHPLC-MS\/MS method for 15 protein-bound uremic toxins in human serum","volume":"589","author":"Wu","year":"2026","journal-title":"Clin Chim Acta"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2025.119455","article-title":"Zuogui Pills alleviate iron overload-induced osteoporosis by attenuating ROS-mediated osteoblast apoptosis via the PI3K-AKT pathway and mitigating mitochondrial damage","volume":"344","author":"Lin","year":"2025","journal-title":"J Ethnopharmacol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"115919","DOI":"10.1016\/j.jpba.2022.114843","article-title":"Combined 1H NMR fecal metabolomics and 16S rRNA gene sequencing to reveal the protective effects of Gushudan on kidney-yang-deficiency-syndrome rats via gut-kidney axis","volume":"217","author":"Tong","year":"2024","journal-title":"J Pharm BioMed Anal"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2025.117544","article-title":"Bone histomorphometry for the diagnosis of renal osteodystrophy - a European consensus statement","volume":"199","author":"Lafage-Proust","year":"2025","journal-title":"Bone"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.ekir.2026.103800","article-title":"Markers of Mineral Metabolism in Children With CKD Stages 2 to 5D","volume":"11","author":"Tschirner","year":"2026","journal-title":"Kidney Int Rep"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26093967","article-title":"In Vitro Study of Vitamin D Effects on Immune, Endothelial, and Vascular Smooth Muscle Cells in Chronic Kidney Disease","volume":"26","author":"Kamboj","year":"2025","journal-title":"Int J Mol Sci"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1210\/jendso\/bvag014","article-title":"Parathyroid histology in normocalcemic and hypercalcemic primary hyperparathyroidism with hypercalciuric renal stones","volume":"10","author":"Blanchard","year":"2026","journal-title":"J Endocr Soc"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1093\/jbmr\/zjag081","article-title":"Intratrabecular tunneling remodeling \u2013 a previously overlooked mode of remodeling hyperactivated by PTH","author":"Thomsen","year":"2026","journal-title":"J Bone Miner Res"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1172\/jci163627","article-title":"Title incomplete in source","volume":"133","author":"Yoon","year":"2023","journal-title":"J Clin Invest"},{"key":"B30","doi-asserted-by":"crossref","first-page":"106734","DOI":"10.1016\/j.jsbmb.2025.106734","article-title":"Kidney deletions of Cyp27b1 fail to reduce serum 1,25(OH)2D3","volume":"250","author":"Lee","year":"2025","journal-title":"J Steroid Biochem Mol Biol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.95419","article-title":"Renal Sarcoidosis With Increased 1,25(OH)2D3 Production via CYP27B1-Expressing Epithelioid Granuloma: A Case Report and Review","volume":"17","author":"Harada","year":"2025","journal-title":"Cureus"},{"key":"B32","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1007\/s12013-024-01244-6","article-title":"N1F(Improved-Nephropathy 1 Formula) Ameliorates Renal Interstitial Fibrosis via Inhibiting Extracellular Matrix Deposition and Regulating the FGF23\/P38MAPK\/Wnt Pathway","volume":"82","author":"Yu","year":"2024","journal-title":"Cell Biochem Biophys"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.nefroe.2021.11.014","article-title":"Hyporesponsiveness or resistance to the action of parathyroid hormone in chronic kidney disease","volume":"41","author":"Bover","year":"2021","journal-title":"Nefrologia (Engl Ed)"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3390\/ijms27115094","article-title":"Pre-parathyroidectomy PTH as an integrated biomarker of glandular remodeling and skeletal turnover in secondary hyperparathyroidism","volume":"27","author":"Liao","year":"2026","journal-title":"Int J Mol Sci"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1097\/MNH.0000000000001190","article-title":"New regulators of parathyroid hormone synthesis and secretion","volume":"35","author":"Naveh-Many","year":"2026","journal-title":"Curr Opin Nephrol Hypertens"},{"key":"B36","article-title":"Macrophage Activation in Lupus Nephritis: An Unknown Cause of Severe Hypercalcemia","volume":"108","author":"Crespo Trevino","year":"2025","journal-title":"R I Med J (2013)"},{"key":"B37","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1186\/s12882-026-05004-x","article-title":"Parallel metabolomic and transcriptomic profiling reveals the cytotoxic mechanism of protein-bound uremic toxin p-cresol sulfate via disruption of glutathione and glycerophospholipid metabolism in MC3T3-E1 osteoblasts","volume":"27","author":"Wu","year":"2026","journal-title":"BMC Nephrol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1002\/2211-5463.13745","article-title":"A PAI-1 antagonist ameliorates hypophosphatemia in the Hyp vitamin D-resistant rickets model mouse","volume":"14","author":"Qian","year":"2024","journal-title":"FEBS Open Bio"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00250.2021","article-title":"Fibroblast growth factor 23 leads to endolysosomal routing of the renal phosphate cotransporters NaPi-IIa and NaPi-IIc in vivo","volume":"321","author":"K\u00fcng","year":"2021","journal-title":"Am J Physiol Renal Physiol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1002\/jbt.70877","article-title":"Patulin Affects the Hydroxylation of Vitamin D by Downregulating 25-hydroxylase (CYP2R1) and 25-hydroxyvitamin D 1-alpha-hydroxylase (CYP27B1) Expression and Interfering Their Substrate Binding Sites","volume":"40","author":"Lu","year":"2026","journal-title":"J Biochem Mol Toxicol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.nefro.2025.501337","article-title":"The multiple functions of insulin-like growth factor 1 in kidney disease","volume":"45","author":"D\u00edaz Tocados","year":"2025","journal-title":"Nefrologia (Engl Ed)"},{"key":"B42","doi-asserted-by":"publisher","first-page":"106331","DOI":"10.1016\/j.jsbmb.2023.106252","article-title":"Genomic mechanisms controlling renal vitamin D metabolism","volume":"232","author":"Meyer","year":"2023","journal-title":"J Steroid Biochem Mol Biol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1080\/0886022x.2025.2575434","article-title":"Gut microbiota-derived TMAO drives the kidney-bone-vascular axis in chronic kidney disease complications","volume":"47","author":"Lei","year":"2025","journal-title":"Ren Fail"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/4370263","article-title":"From \"Kidneys Govern Bones\" to Chronic Kidney Disease, Diabetes Mellitus, and Metabolic Bone Disorder: A Crosstalk between Traditional Chinese Medicine and Modern Science","volume":"2016","author":"Wang","year":"2016","journal-title":"Evid Based Complement Alternat Med"},{"key":"B45","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1186\/s13287-026-05073-7","article-title":"Exosomes in bone health and disease: cellular crosstalk, systemic signaling, and AI-driven advances in regenerative therapy","volume":"17","author":"Liu","year":"2026","journal-title":"Stem Cell Res Ther"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1093\/joneph\/aajaf008","article-title":"New insights into the management of secondary hyperparathyroidism in non-dialysis dependent chronic kidney disease: extended release calcifediol","volume":"39","author":"Arampatzis","year":"2026","journal-title":"J Nephrol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1097\/MED.0000000000000961","article-title":"Secondary hyperparathyroidism in chronic kidney disease: update on pathophysiology and new treatment targets","volume":"33","author":"Derai","year":"2026","journal-title":"Curr Opin Endocrinol Diabetes Obes"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2024.1446609","article-title":"Corrigendum: Fucoidan ameliorates renal injury-related calcium-phosphorus metabolic disorder and bone abnormality in the CKD-MBD model rats by targeting FGF23-Klotho signaling axis","volume":"15","author":"Liu","year":"2024","journal-title":"Front Pharmacol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2026.158427","article-title":"AI-driven discovery of synergistic combinations from Psoralea corylifolia fruit for treating osteoporosis","volume":"159","author":"Liu","year":"2026","journal-title":"Phytomedicine"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1210\/jcemcr\/luad120","article-title":"Recurrent Soft Tissue Infections Associated With Burosumab Therapy in X-Linked Hypophosphatemic Rickets","volume":"1","author":"Yoon","year":"2023","journal-title":"JCEM Case Rep"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1080\/0886022X.2025.2593710","article-title":"Advances in noninvasive diagnosis of renal osteodystrophy","volume":"47","author":"Yang","year":"2025","journal-title":"Ren Fail"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1177\/15578100261458418","article-title":"Exploring the ROS-Related Therapeutic Mechanism of Bushen Huoxue Decoction in Postmenopausal Osteoporosis through Transcriptomics and Network Pharmacology","volume":"30","author":"Yin","year":"2026","journal-title":"OMICS"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.3390\/nu16050605","article-title":"Novel Biomarkers of Bone Metabolism","volume":"16","author":"Fern\u00e1ndez-Villabrille","year":"2024","journal-title":"Nutrients"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.3390\/ijms27072992","article-title":"Osteocalcin Beyond Bone: Molecular Mechanisms, Endocrine Networks, and Translational Perspectives Across Metabolism, Neurobiology, and Chronic Disease","volume":"27","author":"Derwich","year":"2026","journal-title":"Int J Mol Sci"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2026.1802845","article-title":"Gut microbiota in chronic kidney disease-mineral and bone disorder","volume":"17","author":"Wang","year":"2026","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2025.102776","article-title":"Crosstalk between kidney and bones: New perspective for modulating osteoporosis","volume":"109","author":"Duan","year":"2025","journal-title":"Ageing Res Rev"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/j.jot.2026.101119","article-title":"Deciphering inter-organ communication: The multi-organ-bone axis in osteoporosis","volume":"58","author":"Wen","year":"2026","journal-title":"J Orthop Translat"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1007\/s40618-026-02877-5","article-title":"Supplementation with the probiotic Bifidobacterium lactis BB-12 improves the efficacy of alendronate sodium\/vitamin D3 therapy on skeletal health in stage 3 CKD","volume":"49","author":"Zhao","year":"2026","journal-title":"J Endocrinol Invest"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1093\/ckj\/sfac230","article-title":"Management of fracture risk in CKD-traditional and novel approaches","volume":"16","author":"Haarhaus","year":"2022","journal-title":"Clin Kidney J"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1835818\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T04:35:16Z","timestamp":1790224516000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1835818\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,24]]},"references-count":59,"alternative-id":["10.3389\/fendo.2026.1835818"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2026.1835818","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,24]]},"article-number":"1835818"}}