title: Effects of denosumab, alendronate, or denosumab following alendronate on bone turnover, calcium homeostasis, bone mass and bone strength in ovariectomized cynomolgus monkeys.
abstract: Postmenopausal osteoporosis is a chronic disease wherein increased bone remodeling reduces bone mass and bone strength. Antiresorptive agents including bisphosphonates are commonly used to mitigate bone loss and fracture risk. Osteoclast inhibition via denosumab (DMAb), a RANKL inhibitor, is a newer approach for reducing fracture risk in patients at increased risk for fracture. The safety of transitioning from bisphosphonate therapy (alendronate; ALN) to DMAb was examined in mature ovariectomized (OVX) cynomolgus monkeys (cynos). One day after OVX, cynos (7-10/group) were treated with vehicle (VEH, s.c.), ALN (50 μg/kg, i.v., twice monthly) or DMAb (25 mg/kg/month, s.c.) for 12 months. Other animals received VEH or ALN for 6 months and then transitioned to 6 months of DMAb. DMAb caused significantly greater reductions in serum CTx than ALN, and transition from ALN to DMAb caused further reductions relative to continued ALN. DMAb and ALN decreased serum calcium (Ca), and transition from ALN to DMAb resulted in a lesser decline in Ca relative to DMAb or to VEH-DMAb transition. Bone histomorphometry indicated significantly reduced trabecular and cortical remodeling with DMAb or ALN. Compared with ALN, DMAb caused greater reductions in osteoclast surface, eroded surface, cortical porosity and fluorochrome labeling, and transition from ALN to DMAb reduced these parameters relative to continued ALN. Bone mineral density increased in all active treatment groups relative to VEH controls. Destructive biomechanical testing revealed significantly greater vertebral strength in all three groups receiving DMAb, including those receiving DMAb after ALN, relative to VEH controls. Bone mass and strength remained highly correlated in all groups at all tested skeletal sites, consistent with normal bone quality. These data indicate that cynos transitioned from ALN to DMAb exhibited reduced bone resorption and cortical porosity, and increased BMD and bone strength, without deleterious effects on Ca homeostasis or bone quality.
authors.affiliation: Metabolic Disorders Research, Amgen Inc., Thousand Oaks, CA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kostenuik
authors.forename: Susan Y
authors.initials: SY
authors.lastname: Smith
authors.forename: Rana
authors.initials: R
authors.lastname: Samadfam
authors.forename: Jacquelin
authors.initials: J
authors.lastname: Jolette
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.forename: Michael S
authors.initials: MS
authors.lastname: Ominsky
mesh_terms: D015502:Absorptiometry, Photon; D019386:Alendronate / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D050071:Bone Density Conservation Agents / Q000009:adverse effects / Q000494:pharmacology*; D001842:Bone and Bones / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D000069448:Denosumab / Q000009:adverse effects / Q000494:pharmacology*; D005260:Female; D006706:Homeostasis / Q000187:drug effects*; D008252:Macaca fascicularis; D010052:Ovariectomy
chemical_list: D050071:Bone Density Conservation Agents; D000069448:Denosumab; D002118:Calcium; D019386:Alendronate
keywords: ALENDRONATE; BONE STRENGTH; CALCIUM HOMEOSTASIS; DENOSUMAB; OSTEOPOROSIS