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Elevated serum phosphate promotes parathyroid hormone (PTH) release, leading to bone resorption and decreased bone formation. Objective: This study investigated the influence of chronically elevated phosphorus intake on bone structure in rats with normal renal function, focusing on the Receptor Activator of Nuclear factor Kappa-B (RANK)\/RANK ligand (RANKL)\/osteoprotegerin (OPG) pathway and its related components, leucine rich repeat containing G protein-coupled receptor 4 (LGR4), and R-spondins (RSPOs). Methods: Rats were fed a high-phosphorus diet, followed by assessment of the bone microstructure and of the expression of key signalling molecules. Results: Elevated phosphorus intake induced significant bone deterioration, particularly in the trabecular bone compartment, associated with alterations in the RANK\/RANKL\/OPG pathway and in the LGR4 and RSPO1 and RSPO4 signalling components in bone. Moreover, we also observed changes in RANKL, RSPO1 and RSPO4 serum levels in the rats that had received a high-phosphorus diet. Conclusions: These findings highlight the detrimental impact of excessive dietary phosphorus on skeletal health, even without renal impairment, and suggest that components of this pathway, particularly RSPO1 and RSPO4, could serve as potential biomarkers of bone deterioration. The widespread consumption of phosphorus-rich processed foods underscores the importance of nutritional education to mitigate these skeletal risks in industrialized populations.<\/jats:p>","DOI":"10.3390\/nu17122049","type":"journal-article","created":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T03:05:27Z","timestamp":1750388727000},"page":"2049","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["High Dietary Phosphorus Impairs Bone Microarchitecture and Induces Alterations in the LGR4\u2013R-Spondins Axis in Rats with Normal Renal Function"],"prefix":"10.3390","volume":"17","author":[{"given":"Sara","family":"Fern\u00e1ndez-Villabrille","sequence":"first","affiliation":[{"name":"Metabolismo \u00d3seo, Vascular y Enfermedades Inflamatorias Cr\u00f3nicas, Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain"},{"name":"Redes de Investigaci\u00f3n Cooperativa Orientadas a Resultados en Salud, RICORS2040-Renal, 33011 Oviedo, Spain"},{"name":"Unidad de Metabolismo \u00d3seo, Unidad de Gesti\u00f3n Cl\u00ednica de Medicina Interna, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6155-811X","authenticated-orcid":false,"given":"Francisco","family":"Baena-Huerta","sequence":"additional","affiliation":[{"name":"Metabolismo \u00d3seo, Vascular y Enfermedades Inflamatorias Cr\u00f3nicas, Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain"},{"name":"Redes de Investigaci\u00f3n Cooperativa Orientadas a Resultados en Salud, RICORS2040-Renal, 33011 Oviedo, Spain"},{"name":"Unidad de Metabolismo \u00d3seo, Unidad de Gesti\u00f3n Cl\u00ednica de Medicina Interna, Hospital Universitario Central de Asturias, 33011 Oviedo, 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