title: Treatment with a potent cathepsin K inhibitor preserves cortical and trabecular bone mass in ovariectomized monkeys.
abstract: The cysteine protease cathepsin K is involved in osteoclast-mediated bone resorption. We evaluated the effect of daily oral dosing of an inhibitor of human cathepsin K (SB-462795 [relacatib]) for 9 months on bone turnover, mass, and architecture in estrogen-deficient cynomolgus monkeys. Ovariectomized animals were treated orally with relacatib at 1, 3, or 10 mg/kg/day, or oral vehicle plus alendronate at 0.05 mg/kg by IV injection once every 2 weeks. The control groups, ovariectomized and sham-ovariectomized animals, received vehicle (all groups n = 20 animals). Samples for biomarker analysis were collected at various times, bone mass changes were evaluated at 6 and 9 months of treatment, and histomorphometric analysis was performed at 9 months. Relacatib significantly reduced urinary N-telopeptide excretion within 1 week of treatment at all dose levels, an effect that was maintained at the highest dose level. At some time points bone formation markers were elevated at the lowest dose of relacatib. Animals treated with relacatib had dose-dependent preservation of areal bone mineral density reaching statistical significance in distal femur. In femur neck there was significant preservation of total volumetric BMD (vBMD) by relacatib. By histomorphometry, relacatib reduced indices of bone resorption and formation at cancellous sites as did alendronate. In cortical bone, osteonal bone formation rate was reduced by alendronate but preserved at low and medium doses of relacatib. Thus, relacatib preserved cortical and cancellous bone mass in ovariectomized monkeys.
authors.affiliation: Department of Musculoskeletal Diseases, GlaxoSmithKline Pharmaceuticals, Collegeville, PA 19426, USA.
authors.forename: G B
authors.initials: GB
authors.lastname: Stroup
authors.forename: S
authors.initials: S
authors.lastname: Kumar
authors.forename: C P
authors.initials: CP
authors.lastname: Jerome
mesh_terms: D019386:Alendronate / Q000494:pharmacology; D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D015519:Bone Density / Q000187:drug effects*; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D001862:Bone Resorption / Q000378:metabolism; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism*; D056657:Cathepsin K / Q000037:antagonists & inhibitors*; D024042:Collagen Type I / Q000097:blood / Q000652:urine; D004305:Dose-Response Relationship, Drug; D005260:Female; D008252:Macaca fascicularis; D023421:Models, Animal; D010012:Osteogenesis / Q000187:drug effects; D010052:Ovariectomy; D010455:Peptides / Q000097:blood / Q000652:urine; D013450:Sulfones / Q000494:pharmacology*
chemical_list: D001381:Azepines; D050071:Bone Density Conservation Agents; D024042:Collagen Type I; D010455:Peptides; D013450:Sulfones; C052929:collagen type I trimeric cross-linked peptide; C509706:relacatib; D056657:Cathepsin K; D019386:Alendronate