Skeletal and mineral metabolic effects of risedronate in a rat model of high-turnover renal osteodystrophy

• Published in: Journal of bone and mineral metabolism 2020-07, Vol.38 (4), p.501-510
• Main Authors: Ishida, Hiroaki, Komaba, Hirotaka, Hamano, Naoto, Yamato, Hideyuki, Sawada, Kaichiro, Wada, Takehiko, Nakamura, Michio, Fukagawa, Masafumi
• Format: Article
• Language: English
• Subjects: Animals; Biomechanical Phenomena; Bisphosphonates; Blood Urea Nitrogen; Bone and Bones - drug effects; Bone and Bones - pathology; Bone and Bones - physiopathology; Bone diseases; Bone loss; Bone remodeling; Bone Remodeling - drug effects; Bone strength; Bone turnover; Calcium - blood; Cancellous bone; Chronic Kidney Disease-Mineral and Bone Disorder - blood; Chronic Kidney Disease-Mineral and Bone Disorder - drug therapy; Chronic Kidney Disease-Mineral and Bone Disorder - physiopathology; Cortical bone; Creatinine - blood; Disease Models, Animal; Fibroblast Growth Factor-23; Fibrosis; Gene Expression Regulation - drug effects; Humans; Hyperphosphatemia; Kidney diseases; Male; Mechanical properties; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Minerals - metabolism; Nephrectomy; Original Article; Orthopedics; Osteodystrophy; Peptide Fragments - blood; Phosphorus - blood; Procollagen - blood; Rats, Sprague-Dawley; Renal osteodystrophy; Risedronic acid; Risedronic Acid - pharmacology; Risedronic Acid - therapeutic use; Rodents; Vitamin D
• ISSN: 0914-8779; 1435-5604
• DOI: 10.1007/s00774-020-01095-0

Introduction High-turnover bone disease is a major consequence of SHPT and may explain the high risk for fracture in patients with advanced chronic kidney disease (CKD). Bisphosphonates suppress bone turnover and improve bone strength, but their effects have not been fully characterized in advanced CKD with severe SHPT. Bisphosphonates also increase 1,25-dihydroxyvitamin D levels in normal and uremic rats, but the underlying mechanism remains to be determined. Materials and methods We investigated the skeletal and mineral metabolic effects of RIS, a pyridinyl bisphosphonate, in rats with severe SHPT induced by 5/6 nephrectomy plus a high phosphate diet. Results Nephrectomized rats developed severe SHPT, along with hyperphosphatemia, low 1,25-dihydroxyvitamin D, and markedly increased FGF23. Moreover, these rats exhibited characteristic features of high-turnover renal osteodystrophy, including increased indices of trabecular bone turnover, decreased cortical bone thickness, inferior cortical biomechanical properties, and a prominent increase in peritrabecular fibrosis. RIS treatment increased bone volume and partially attenuated trabecular bone remodeling, cortical bone loss, and mechanical properties, whereas it produced a marked improvement in peritrabecular fibrosis along with a corresponding decrease in osteogenic gene markers. RIS treatment also suppressed the elevation of FGF23, which was associated with increased 1,25-dihydroxyvitamin D. Conclusions In a rat model of severe SHPT, treatment with RIS partially attenuated histological manifestations of high-turnover bone disease. RIS treatment also suppressed the elevation of FGF23, which may explain the increased 1,25-dihydroxyvitamin D production during the treatment.