title: Decreased bone remodeling and porosity are associated with improved bone strength in ovariectomized cynomolgus monkeys treated with denosumab, a fully human RANKL antibody.
abstract: This study examined the effects of denosumab, an anti-RANKL antibody that inhibits bone resorption, on bone histomorphometry in adult ovariectomized cynomolgus monkeys (OVX cynos). A month after surgery, OVX cynos were treated with subcutaneous vehicle (OVX-Veh) or denosumab (25 or 50mg/kg/month) for 16months (n=14-20/group). Sham controls were treated with vehicle (Sham-Veh; n=17). Areal and volumetric BMD, urine NTx, and serum osteocalcin were measured at baseline and months 3, 6, 12, and 16. Double fluorochrome labels were injected prior to iliac and rib biopsies at month 6 and month 12, and prior to sacrifice at month 16. Histomorphometry was performed on these biopsies, the tibial diaphysis, the L2 vertebra, and the proximal femur. Strength of humeral cortical beams, femur diaphysis, femur neck, and trabecular cores of L5-L6 vertebrae was determined by destructive biomechanical testing. There was no evidence of woven bone, osteomalacia, or other bone histopathologic changes with OVX or with denosumab. OVX-Veh animals exhibited significantly greater bone remodeling at all skeletal sites relative to Sham-Veh controls. Both doses of denosumab markedly inhibited bone remodeling at all sites, including significant reductions in trabecular eroded surfaces (48-86% lower than OVX-Veh controls), cortical porosity (28-72% lower), and dynamic parameters of bone formation (81-100% lower). Decreased fluorochrome labeling with denosumab was related to reductions in cortical porosity and trabecular eroded surfaces, and regression analyses suggested that these reductions contributed to denosumab-related increments in BMD and bone strength. Denosumab-treated animals with the lowest levels of fluorescent labeling exhibited the greatest structural bone strength values at each site. Intracortical remodeling had no relationship with material properties including ultimate strength, elastic modulus or toughness (r(2)=0.00-0.01). These data suggest that remodeling inhibition with denosumab improved structural strength without altering material properties under these experimental conditions. Greater structural strength in the denosumab-treated animals can be primarily explained by the combined effects of increased trabecular and cortical bone mass, and reductions in trabecular eroded surfaces and cortical porosity.
authors: Metabolic Disorders, Amgen Inc., 1 Amgen Center Drive, Thousand Oaks, CA 91320, USA. paulk@amgen.com
authors: Paul J
authors: PJ
authors: Kostenuik
authors: Susan Y
authors: SY
authors: Smith
authors: Jacquelin
authors: J
authors: Jolette
authors: Joseph
authors: J
authors: Schroeder
authors: Ian
authors: I
authors: Pyrah
authors: Michael S
authors: MS
authors: Ominsky
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000652:urine; D061067:Antibodies, Monoclonal, Humanized; D015519:Bone Density / Q000187:drug effects; D016723:Bone Remodeling / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects*; D000069448:Denosumab; D005260:Female; D006801:Humans; D008252:Macaca fascicularis; D010052:Ovariectomy; D053245:RANK Ligand / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000652:urine
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053245:RANK Ligand; D000069448:Denosumab