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Attenuation of Antiresorptive Action in Withdrawal of Minodronic Acid for Three Months After Treatment for Twelve Months in Ovariectomized Rats

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Abstract

The purpose of this study was to evaluate the effects of withdrawal of minodronic acid (MIN) for 3 months after 12 months of treatment in ovariectomized (OVX) rat. OVX rats were orally treated with MIN (6, 30, and 150 µg/kg/day) for 12 months and necropsied on the day after the last dosing or following 3 months of withdrawal. Lumbar and femoral BMD were decreased in OVX controls. MIN dose-dependently increased BMD. Withdrawal eliminated the effect of MIN on BMD loss after treatment at 6 µg/kg, but not after treatment at 30 and 150 µg/kg. In MIN-treated rats, trabecular thinning occurred during withdrawal after treatment at 6 µg/kg, but the trabecular microstructure was maintained at 30 and 150 µg/kg. In a mechanical test of the femoral diaphysis, stiffness of in OVX controls was decreased but ultimate load was similar to that in sham after withdrawal. MIN increased ultimate load and stiffness, but endosteal length decreased after withdrawal. Suppression of bone turnover by MIN based on bone turnover markers and histomorphometric indices was attenuated by withdrawal after treatment at 6 and 30 µg/kg and partially at 150 µg/kg. The MIN concentration in the humerus decreased during withdrawal, and half-life at 30 µg/kg was shorter than that at 150 µg/kg. These results show that the antiresorptive action of MIN was dose-dependently attenuated by 3-month withdrawal in a rat OVX model. An absence of BMD increase was only observed at a low dose but decreases in antiresorptive activity occurred over a wide dose range.

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Acknowledgments

We thank Soh-ichi Takashima and Norio Muto (Ina Research Inc.) for their expertise and technical support in animal care and assessment. We are also grateful to Chihiro Hasegawa for his critical review of the manuscript.

Conflict of Interest

Makoto Tanaka, Hiroshi Mori, and Kazuhito Kawabata are research scientists at Ono Pharmaceutical Co., Ltd. Minodronic acid was launched by Ono Pharmaceutical Co., Ltd. and Astellas Pharma Inc.

Human and Animal Rights and Informed Consent

This study was approved by Ina Research Inc. (Nagano, Japan) and performed in accordance with the by-rules of the company, including all ethical aspects related to animal treatment.

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Authors and Affiliations

  1. Research Promotion, Ono Pharmaceutical Co., Ltd., 3-1-1, Sakurai, Shimamoto-cho, Osaka, 618-8585, Japan

    Makoto Tanaka

  2. Discovery Research Laboratories, Ono Pharmaceutical Co., Ltd., Shimamoto-cho, Osaka, 618-8585, Japan

    Hiroshi Mori & Kazuhito Kawabata

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  1. Makoto Tanaka
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Correspondence to Makoto Tanaka.

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Tanaka, M., Mori, H. & Kawabata, K. Attenuation of Antiresorptive Action in Withdrawal of Minodronic Acid for Three Months After Treatment for Twelve Months in Ovariectomized Rats. Calcif Tissue Int 97, 402–411 (2015). https://doi.org/10.1007/s00223-015-0017-2

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