Odanacatib, effects of 16-month treatment and discontinuation of therapy on bone mass, turnover and strength in the ovariectomized rabbit model of osteopenia

Autor: Le T. Duong, Gouxin Wu, Christopher T. Winkelmann, Michael A. Gentile, Pete Szczerba, Randy Crawford, K. R. Scott
Rok vydání: 2016
Předmět:
0301 basic medicine
medicine.medical_specialty
Histology
Bone density
Physiology
Endocrinology
Diabetes and Metabolism
Ovariectomy
Osteoporosis
030209 endocrinology & metabolism
Bone resorption
Bone and Bones
Bone remodeling
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Absorptiometry
Photon
Bone Density
Internal medicine
medicine
Cortical Bone
Animals
Femur
Lumbar Vertebrae
business.industry
Biphenyl Compounds
hemic and immune systems
Organ Size
respiratory system
medicine.disease
Biomechanical Phenomena
Bone Diseases
Metabolic
Disease Models
Animal
030104 developmental biology
medicine.anatomical_structure
Endocrinology
chemistry
Withholding Treatment
Cancellous Bone
Ovariectomized rat
Regression Analysis
Cortical bone
Female
Bone Remodeling
Rabbits
business
Tomography
X-Ray Computed
Cancellous bone
Odanacatib
Biomarkers
Zdroj: Bone. 93
ISSN: 1873-2763
Popis: Odanacatib (ODN) a selective and reversible cathepsin K inhibitor, inhibits bone resorption, increases bone mass and reduces fracture risk in women with osteoporosis. A 16-month (~7-remodeling cycles) study was carried out in treatment mode to assess the effects of ODN versus ALN on bone mass, remodeling status and biomechanical properties of lumbar vertebrae (LV) and femur in ovariectomized (OVX) rabbits. This study also evaluated the impact of discontinuing ODN on these parameters. Rabbits at 7.5months post-OVX were dosed for 16-months with ODN (7.5μM·h0-24, in food) or ALN (0.2mg/kg/wk, s.c.) and compared to vehicle-treated OVX- (OVX+Veh) or Sham-operated animals. After 8months, treatment was discontinued in half of the ODN group. ODN treatment increased in vivo LV aBMD and trabecular (Tb) vBMD until reaching plateau at month 12 by 16% and 23% vs. baseline, respectively, comparable levels to that in Sham and significantly above OVX+Veh. LV BMD was also higher in ALN that plateaued around month 8 to levels below that in ODN or Sham. ODN treatment resulted in higher BMD, structure and improved biomechanical strength of LV and central femur (CF) to levels similar to Sham. ALN generally showed less robust efficacy compared to ODN. Neither ODN nor ALN influenced material properties at these bone sites following ODN or ALN treatment for 7 remodeling cycles in rabbits. ODN and ALN persistently reduced the bone resorption marker urinary helical peptide over study duration. While ALN reduced the bone formation marker BSAP, ODN treatment did not affect this marker. ODN also preserved histomorphometry-based bone formation indices in LV trabecular, CF endocortical and intracortical surfaces, at the levels of OVX+Veh. Discontinuation of ODN returned bone mass, structure and strength parameters to the comparable respective levels in OVX+Veh. Together, these data demonstrate efficacy and bone safety profile of ODN and suggests the potential long-term benefits of this agent over ALN with respect to accrued bone mass without long-term effects on bone formation.
Databáze: OpenAIRE
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