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

J Bone Miner Metab 2014 Nov 8;32(6):645-52. Epub 2013 Dec 8.

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

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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http://dx.doi.org/10.1007/s00774-013-0542-xDOI Listing
November 2014
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References

(Supplied by CrossRef)

Y Yasuda et al.
Adv Drug Deliv Rev 2005

T Inaoka et al.
Biochem Biophys Res Commun 1995

FH Drake et al.
J Biol Chem 1996

P Garnero et al.
J Biol Chem 1998

BD Gelb et al.
Science 1996

MR Johnson et al.
Genome Res 1996

M Gowen et al.
J Bone Miner Res 1999

CY Li et al.
J Bone Miner Res 2006

B Pennypacker et al.
Bone 2009

MA Karsdal et al.
J Bone Miner Res 2007

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