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ONO-5334, a cathepsin K inhibitor, improves bone strength by preferentially increasing cortical bone mass in ovariectomized rats

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Abstract

This study compared the effects of ONO-5334, a cathepsin K inhibitor, with those of alendronate on bone mass and strength in ovariectomized rats. Ovariectomy resulted in significant elevation in urinary deoxypyridinoline and plasma C-terminal cross-linking telopeptide of type I collagen (CTX) 8 weeks after surgery. Peripheral quantitative computed tomography analysis showed that total, trabecular, and cortical bone mineral content (BMC) decreased in the proximal tibia, which was paralleled with a significant decline in bone strength. Treatment with ONO-5334 (0.12, 0.6, 3 or 15 mg/kg) once daily for 8 weeks dose-dependently restored the decrease in total BMC and bone mineral density (BMD) in the proximal tibia and suppressed urinary deoxypyridinoline and plasma CTX levels. Alendronate (1 mg/kg, once daily) also fully restored these bone mass parameters. Separate analysis of trabecular and cortical bones, however, showed that ONO-5334 only partially restored trabecular BMD and BMC at 15 mg/kg, whereas alendronate fully restored these parameters. On the other hand, ONO-5334 increased both cortical BMD and BMC with an effect more potent than that of alendronate. Bone geometric analysis indicated that ONO-5334 at 15 mg/kg decreased endosteal circumference without affecting periosteal circumference, resulting in marked increase in cortical thickness. Interestingly, the effects of ONO-5334 on bone strength parameters were more prominent than those of alendronate, although the two test compounds had a similar effect on total BMC. Taken together, our results indicate that ONO-5334 has pharmacological characteristics different from those of alendronate and may offer a unique therapy for patients with osteoporosis.

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Acknowledgments

We thank Yoko Kishida for technical support in animal care and assessments. We also thank Akiko Kunishige, Satoshi Nishikawa, Yasuaki Hashimoto, Masafumi Sugitani, and Katsuya Kishikawa (Ono Pharmaceutical Co., Ltd.) for their helpful comments and discussions on this manuscript.

Conflict of interest

All authors have no conflicts of interest.

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Authors and Affiliations

  1. Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai Shimamoto-cho Mishima-gun, Osaka, 618-8585, Japan

    Yasuo Ochi, Hiroyuki Yamada, Hiroshi Mori, Naoki Kawada, Ryoji Kayasuga, Yasutomo Nakanishi, Makoto Tanaka, Akira Imagawa, Kazuyuki Ohmoto & Kazuhito Kawabata

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  1. Yasuo Ochi
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  2. Hiroyuki Yamada
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  3. Hiroshi Mori
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  4. Naoki Kawada
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  5. Ryoji Kayasuga
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  6. Yasutomo Nakanishi
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  7. Makoto Tanaka
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  8. Akira Imagawa
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  9. Kazuyuki Ohmoto
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  10. Kazuhito Kawabata
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Correspondence to Hiroshi Mori.

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Ochi, Y., Yamada, H., Mori, H. et al. ONO-5334, a cathepsin K inhibitor, improves bone strength by preferentially increasing cortical bone mass in ovariectomized rats. J Bone Miner Metab 32, 645–652 (2014). https://doi.org/10.1007/s00774-013-0542-x

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  • DOI: https://doi.org/10.1007/s00774-013-0542-x

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