Effects of Long‐Term Odanacatib Treatment on Bone Gene Expression in Ovariectomized Adult Rhesus Monkeys: Differentiation From Alendronate. (8th January 2016)

• Record Type: Journal Article
• Authors: Muise, Eric S; Podtelezhnikov, Alexei A; Pickarski, Maureen; Loboda, Andrey; Tan, Yejun; Hu, Guanghui; Thomspon, John R; Duong, Le T
• Is Part Of: Journal of bone and mineral research. Volume 31:Number 4(2016:Apr.)
• Page Start: 839
• Page End: 851
• Publication Date: 2016-01-08
• Subjects: OSTEOPOROSIS -- ANTIRESORPTIVES -- OSTEOCLASTS -- OSTEOBLASTS -- PRECLINICAL STUDIES; Bones -- Metabolism -- Periodicals; Mineral metabolism -- Periodicals; 612.392
• DOI: 10.1002/jbmr.2752
• Languages: English
• ISSNs: 0884-0431

Abstract

ABSTRACT: Similar efficacy of the cathepsin K inhibitor odanacatib (ODN) and the bisphosphonate alendronate (ALN) in reducing bone turnover markers and increasing bone mineral density in spine and hip were previously demonstrated in ovariectomized (OVX)‐monkeys treated for 20 months in prevention mode. Here, we profiled RNA from tibial metaphysis and diaphysis of the same study using Affymetrix microarrays, and selected 204 probe sets ( p < 0.001, three‐group ANOVA) that were differentially regulated by ODN or ALN versus vehicle. Both drugs produced strikingly different effects on known bone‐related genes and pathways at the transcriptional level. Although ALN either reduced or had neutral effects on bone resorption–related genes, ODN significantly increased the expression of osteoclast genes (eg, APC5, TNFRSF11A, CTSK, ITGB3, and CALCR), consistent with previous findings on the effects of this agent in enhancing the number of nonresorbing osteoclasts. Conversely, ALN reduced the expression of known bone formation–related genes (eg, TGFBR1, SPP1, RUNX2, and PTH1R), whereas ODN either increased or had neutral effects on their expression. These differential effects of ODN versus ALN on bone resorption and formation were highly correlative to the changes in bone turnover markers, cathepsin K (Catk) target engagement marker serum C‐terminal cross‐linked telopeptide (1‐CTP) and osteoclast marker tartrate resistant acid phosphatase isoform 5b (TRAP5b) in the same monkeys. Overall, the molecular profiling results are consistent with the known pharmacological actions of these agents on bone remodeling and clearly differentiate the molecular mechanisms of ODN from the bisphosphonates. © 2016 American Society for Bone and Mineral Research.