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Abstract
Background Sclerostin antibody (Scl-Ab) increases bone formation, bone mass, and bone strength in rodents and cynomolgus monkeys (cynos) in studies of up to 10 weeks duration.
Objectives To investigate the effects of 6 months of Scl-Ab treatment on cynos bone formation.
Methods Adolescent (age 3-5 years) cynos were treated for 6 months with weekly subcutaneous injections of vehicle, 3, 10, or 100 mg/kg Scl-Ab (n=4/sex/group).
Results The bone formation marker serum osteocalcin peaked within the first 3 months of Scl-Ab treatment and returned toward baseline levels at month 6, at which time the L2 vertebra bone formation rate per bone surface (BFR/BS) was similar across all treatment groups. At the tibia diaphysis, endocortical BFR/BS remained dose-dependently elevated. Despite the normalization of cancellous BFR/BS at month 6, Scl-Ab dose-dependently increased DXA bone mineral density (BMD) by 15-30% at the lumbar spine compared with vehicle (Table). By ex vivo microCT, Scl-Ab resulted in dose-dependent increases in BMD at L3 vertebral bodies and L6 cancellous cores, bone area, cortical thickness (Ct.Th), trabecular bone volume (BV/TV), and trabecular thickness (Tb.Th) (Table). Improvements in bone microarchitecture resulted in increased yield load for all dose levels at both L3 (+33-92%) and L6 (+83-142%) compared with vehicle. Stiffness and energy to failure also increased dose-dependently after Scl-Ab treatment at both sites. Strength properties were normalized to BV/TV to approximate material properties, and no group differences were found in yield strength, modulus, or toughness. Positive correlations between BMD and yield load were observed across all groups for both vertebral specimens, further supporting the maintenance of material properties. No group differences were found in the ratio of ash to dry weight in vertebral samples, reflecting normal matrix mineralization during Scl-Ab treatment. Data reported here are from male cynos; similar results were observed in females.
Conclusions Six months of Scl-Ab treatment in cynos markedly increased vertebral BMD, trabecular microarchitecture, and bone strength, with maintenance of bone material properties. These data also highlight the unique mode of action of Scl-Ab, which temporally increases cancellous bone formation, resulting in a rapid increase in bone volume of normal quality that is maintained after indices of trabecular bone formation return to baseline.
Disclosure of Interest M. Ominsky Shareholder of: Amgen Inc., Employee of: Amgen Inc., R. Samadfam Employee of: Charles River Laboratories, J. Jolette Employee of: Charles River Laboratories, S. Smith Employee of: Charles River Laboratories, H. Z. Ke Shareholder of: Amgen Inc., Employee of: Amgen Inc., R. Boyce Shareholder of: Amgen Inc., Employee of: Amgen Inc.