Effects of 16-month treatment with the cathepsin K inhibitor ONO-5334 on bone markers,mineral density,strength and histomorphometry in ovariectomized cynomolgus monkeys |
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| Institution: | 1. Discovery Research Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan;2. Drug Development, ONO Pharma UK Ltd., MidCity Place, 71 High Holborn, London WC1V 6EA, UK;1. Department of Medicine, Endocrine Unit, Massachusetts General Hospital, Boston, MA, United States;2. Department of Orthopedic Surgery, Beth Israel Deaconess Medical Center, Boston, MA, United States;1. Department of Biochemistry, Wake Forest School of Medicine, 1 Medical Center Blvd, Winston-Salem, NC 27157, USA;2. Center for Diabetes Research, Wake Forest School of Medicine, 1 Medical Center Blvd, Winston-Salem, NC 27157, USA;3. Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, 1 Medical Center Blvd, Winston-Salem, NC 27157, USA;4. Center for Public Health Genomics, Wake Forest School of Medicine, 1 Medical Center Blvd, Winston-Salem, NC 27157, USA;5. Department of Biostatistical Sciences, Wake Forest School of Medicine, 1 Medical Center Blvd, Winston-Salem, NC 27157, USA;6. Department of Pathology, Wake Forest School of Medicine, 1 Medical Center Blvd, Winston-Salem, NC 27157, USA;7. Division of Public Health Sciences, Wake Forest School of Medicine, 1 Medical Center Blvd, Winston-Salem, NC 27157, USA;8. Department of Internal Medicine-Section on Nephrology, Wake Forest School of Medicine, 1 Medical Center Blvd, Winston-Salem, NC 27157, USA;9. Department of Radiology, Vanderbilt University School of Medicine, 2525 West End Ave, Suite 300-B, Nashville, TN 37203, USA;10. Department of Biostatistics, University of Alabama at Birmingham, 1665 University Boulevard, Birmingham, AL 35294, USA;11. Department of Epidemiology, University of Alabama at Birmingham, 1665 University Boulevard, Birmingham, AL 35294, USA;12. Department of Medicine, University of Alabama at Birmingham, 1665 University Boulevard, Birmingham, AL, 35294, USA;1. Sibley School of Mechanical and Aerospace Engineering, Cornell University, 105 Upson Hall, Ithaca, NY 14853, USA;2. Nancy E and Peter C Meinig School of Biomedical Engineering, Cornell University, 101 Weill Hall, Ithaca, NY 14853, USA;3. College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA;4. Research Division, Hospital for Special Surgery, 541 East 71st St., New York, NY 10021, USA;1. Shriners Hospital for Children and McGill University, Montreal, Quebec, Canada;2. Department of Joint Surgery and Sports Medicine, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan;1. Department of Clinical Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Norway and Oslo University;2. Laval University, Quebec City, Canada;3. CHU de Québec (CHUL) Research Centre, Quebec City, Canada;1. Department of General Practice/Family Medicine, University of Marburg, Karl-von-Frisch-Str. 4, 35043 Marburg, Germany;2. Health Risk Institute, Spittelmarkt 12, 10117 Berlin, Germany;3. Health Analytics Germany, Elsevier, Jägerstraße 41, 10117 Berlin, Germany |
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| Abstract: | We examined the effects of ONO-5334, a cathepsin K inhibitor, on bone markers, BMD, strength and histomorphometry in ovariectomized (OVX) cynomolgus monkeys. ONO-5334 (1.2, 6 and 30 mg/kg/day, p.o.), alendronate (0.05 mg/kg/2 weeks, i.v.), or vehicle was administered to OVX monkeys (all groups N = 20) for 16 months. A concurrent Sham group (N = 20) was also treated with vehicle for 16 months. OVX significantly increased bone resorption and formation markers and decreased BMD in lumbar vertebra, femoral neck, proximal tibia and distal radius. Alendronate suppressed these parameters to a level similar to that in the Sham-operated monkeys. ONO-5334 at doses 6 and 30 mg/kg decreased bone resorption markers to a level roughly half of that in the Sham group, while keeping bone formation markers level above that in the Sham monkeys. Changes in DXA BMD confirmed that ONO-5334 at doses 6 and 30 mg/kg increased BMD to a level greater than that in the Sham group in all examined sites. In the proximal tibia, in vivo pQCT analysis showed that ONO-5334 at doses 6 and 30 mg/kg suppressed trabecular BMD loss to the sham level. However, ONO-5334 increased cortical BMD, cortical area and cortical thickness to a level greater than that in the Sham group, suggesting that ONO-5334 improves both cortical BMD and cortical geometry. Histomorphometric analysis revealed that ONO-5334 suppressed bone formation rate (BFR) at osteonal site in the midshaft femur but did not influence OVX-induced increase in BFR at either the periosteal or endocortical surfaces. Unlike alendronate, ONO-5334 increased osteoclasts surface (Oc.S/BS) and serum tartrate-resistant acid phosphatise 5b (TRAP5b) activity, highlighting the difference in the mode of action between these two drugs. Our results suggest that ONO-5334 has therapeutic potential not only in vertebral bones, but also in non-vertebral bones. |
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