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Comparison of the Efficacy and Renal Safety of Bisphosphonate Between Low-Dose/High-Frequency and High-Dose/Low-Frequency Regimens in a Late-Stage Chronic Kidney Disease Rat Model

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Abstract

The efficacy and renal safety of low-dose/high-frequency (LDHF) dosing and high-dose/low-frequency (HDLF) dosing of bisphosphonates (BPs) are comparable in patients with normal kidney function but might be different in patients with late-stage chronic kidney disease (CKD). This study aimed to compare the efficacy and renal safety of two different dosage regimens of a BP, alendronate (ALN), in stage 4 CKD using a rat model. Male, 10-week-old Sprague–Dawley rats were subjected to either 5/6 nephrectomy or sham surgery. The animals received subcutaneous administration of vehicle (daily) or ALN in LDHF dosage regimen (LDHF-ALN: 0.05 mg/kg/day) or HDLF dosage regimen (HDLF-ALN: 0.70 mg/kg/2 weeks). Medications commenced at 20 weeks of age and continued for 10 weeks. Micro-computed tomography, histological analysis, infrared spectroscopic imaging, and serum and urine assays were performed to examine the efficacy and renal safety of the ALN regimens. Both LDHF-ALN and HDLF-ALN increased bone mass, improved micro-structure, and enhanced mechanical properties, without causing further renal impairment in CKD rats. Histologically, however, HDLF-ALN more efficiently suppressed bone turnover, leading to more mineralized trabecular bone, than LDHF-ALN in CKD rats, whereas such differences between LDHF-ALN and HDLF-ALN were not observed in sham rats. Both LDHF-ALN and HDLF-ALN showed therapeutic effects on high bone turnover osteoporosis in CKD stage 4 rats without causing further renal impairment. However, as HDLF-ALN more efficiently suppressed bone turnover than LDHF-ALN in late-stage CKD, HDLF-ALN might be more appropriate than LDHF-ALN for fracture prevention in high bone turnover osteoporosis patients with late-stage CKD.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This work was supported by the Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research (KAKENHI); Grant-in-Aid for Young Scientists B; Grant Number JP17K16670.

Funding

This work was supported by the Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research (KAKENHI); Grant-in-Aid for Young Scientists B; Grant Number JP17K16670. Grant Number 17K16670.

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Authors and Affiliations

  1. Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15 Nishi-7, Kita-ku, Sapporo, 060-8638, Japan

    Ryo Fujita, Masahiro Ota, Dai Sato, Tomohiro Shimizu, Hideyuki Kobayashi, Norimasa Iwasaki & Masahiko Takahata

  2. Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan

    Daigo Nakazawa

  3. Graduate School of Photonics Science, Chitose Institute of Science and Technology, Chitose, Hokkaido, Japan

    Hiromi Kimura-Suda & Fumiya Nakamura

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Contributions

RF, MO, and MT designed the research; RF, MO, DS, DN, HK-S, FN, TS, and HK performed the research; RF, MO, MT, and HK-S analyzed the data; RF and MT wrote the paper; and NI contributed to the interpretation of the results.

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Correspondence to Masahiko Takahata.

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Conflict of interest

R.F., M.T., M.O., D.S., D.N., H.K-S., F.N., T.S., H.K., and N.I. declare that they have no conflicts of interest.

Ethical Approval

All animal studies were performed in accordance with protocols approved by Institutional Committee on Animal Resources.

Human and Animal Rights and Informed Consent

The Ethics Review Committee for Animal Experimentation of Hokkaido University approved the experimental protocol.

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223_2020_723_MOESM1_ESM.tif

Supplementary file1 (TIF 27659 kb) Supplemental Fig. 1　Longitudinal changes in serum level of Cre among the CKD groups. (a) Serum levels of Cre at the start of the treatment and at 10 weeks of treatment. (b) The relationship between the serum level of Cre at 20 weeks of age and at 30 weeks of age.

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Fujita, R., Ota, M., Sato, D. et al. Comparison of the Efficacy and Renal Safety of Bisphosphonate Between Low-Dose/High-Frequency and High-Dose/Low-Frequency Regimens in a Late-Stage Chronic Kidney Disease Rat Model. Calcif Tissue Int 107, 389–402 (2020). https://doi.org/10.1007/s00223-020-00723-1

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