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

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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.

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Acknowledgements

This work was supported in part by a Grant from EA Pharma Co., Ltd. We thank Ms. Chigusa Ishioka for her excellent technical assistance. We are also grateful to Ms. Sachie Tanaka and Mr. Shuho Hori, the Support Center for Medical Research and Education, Tokai University.

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Authors and Affiliations

  1. Department of Transplant Surgery, Tokai University School of Medicine, Isehara, Japan

    Hiroaki Ishida & Michio Nakamura

  2. Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, 143 Shimo-Kasuya, Isehara, 259-1193, Japan

    Hirotaka Komaba, Naoto Hamano, Hideyuki Yamato, Kaichiro Sawada, Takehiko Wada & Masafumi Fukagawa

  3. Interactive Translational Research Center for Kidney Diseases, Tokai University School of Medicine, Isehara, Japan

    Hirotaka Komaba

  4. The Institute of Medical Sciences, Tokai University, Isehara, Japan

    Hirotaka Komaba

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  1. Hiroaki Ishida
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  2. Hirotaka Komaba
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  3. Naoto Hamano
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  4. Hideyuki Yamato
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  5. Kaichiro Sawada
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  8. Masafumi Fukagawa
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Correspondence to Hirotaka Komaba.

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Conflict of interest

Dr. Komaba has received honoraria, consulting fees, and/or grant support from Bayer Yakuhin, Chugai Pharmaceutical, Japan Tobacco, Kyowa Kirin, Novartis, and Ono Pharmaceutical. Dr. Wada has received honoraria, consulting fees, and/or grant support from Chugai Pharmaceutical, Daiichi Sankyo, Kyowa Kirin, and Otsuka Pharmaceutical. Dr. Nakamura received grant support from Astellas Pharma and Novartis. Dr. Fukagawa has received honoraria, consulting fees, and/or grant support from Astellas Pharma, Bayer Yakuhin, EA Pharma Co., Ltd., Kissei Pharmaceutical, Kyowa Kirin, Ono Pharmaceutical, and Torii Pharmaceutical. The remaining authors declare no competing interests.

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All experiments were approved by the Institutional Review Board of Tokai University School of Medicine.

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Ishida, H., Komaba, H., Hamano, N. et al. Skeletal and mineral metabolic effects of risedronate in a rat model of high-turnover renal osteodystrophy. J Bone Miner Metab 38, 501–510 (2020). https://doi.org/10.1007/s00774-020-01095-0

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