Hiroaki Ishida1, Hirotaka Komaba2,3,4, Naoto Hamano5, Hideyuki Yamato5, Kaichiro Sawada5, Takehiko Wada5, Michio Nakamura1, Masafumi Fukagawa5. 1. Department of Transplant Surgery, Tokai University School of Medicine, Isehara, Japan. 2. Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, 143 Shimo-Kasuya, Isehara, 259-1193, Japan. hkomaba@tokai-u.jp. 3. Interactive Translational Research Center for Kidney Diseases, Tokai University School of Medicine, Isehara, Japan. hkomaba@tokai-u.jp. 4. The Institute of Medical Sciences, Tokai University, Isehara, Japan. hkomaba@tokai-u.jp. 5. Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, 143 Shimo-Kasuya, Isehara, 259-1193, Japan.
Abstract
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.
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.
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