Background Bone formation on previously quiescent surfaces occurs through a process known as bone modeling, which differs from the resorption-coupled formation that occurs during bone remodeling. The robust anabolic effects of sclerostin antibody (Scl-Ab) on trabecular surfaces were previously demonstrated to occur almost entirely via modeling in both OVX rats1 and adolescent non-human primates.2
Objectives In the current analysis, we quantified the effects of Scl-Ab on modeling- and remodeling-based bone formation on the femur endocortical surface in male cynomolgus monkeys.
Methods Adolescent (4-5-year-old) monkeys were treated biweekly with subcutaneous vehicle (Veh) or 30 mg/kg Scl-Ab for 10 weeks. Tetracycline (25 mg/kg) was injected on days 14 and 24, and calcein (8 mg/kg) was injected on days 56 and 66. Histomorphometry was performed on cross-sections of the left femur diaphysis.
Results Calcein-based mineralizing surface (MS/BS) was increased from 14% in Veh to 88% in the Scl-Ab group (p<0.001). Bone forming surfaces were characterized as either modeling (MBF) or remodeling (RBF) surfaces based on the morphology of the underlying cement lines. The Scl-Ab-mediated increases in bone forming surface were almost entirely modeling-based, with an increase in MBF from 7% of the total bone surface in Veh to 77% in the Scl-Ab group (p<0.001). No significant change was observed in RBF between the Veh and Scl-Ab groups (10% vs 15%, p=0.20), and no eroded surface was observed in any Scl-Ab-treated animal (vs 6% in Veh, p<0.01). The period of bone formation on surfaces was extended in the Scl-Ab group, with 62% of calcein-labeled surfaces having both underlying tetracycline labels (active from day 14) as compared to only 4% in Veh (p<0.001). Scl-Ab also increased osteoblast activity as reflected in mineral apposition rate (MAR) by 48% on modeling surfaces (1.18 vs 0.80 μm/day, p<0.05), while remodeling MAR was not significantly changed.
Conclusions These results demonstrate that Scl-Ab markedly increased modeling-based bone formation and reduced bone resorption in cortical bone, similar to the findings in trabecular bone. These contrasting effects on bone formation and resorption illustrate the unique tissue-level mechanism of Scl-Ab, which was consistent across both trabecular and cortical sites. Based on these results in non-human primates, the therapeutic profile of Scl-Ab provides a rapid and efficient process by which bone mass can be increased.
Li et al. J Bone Min Res. 2007;22(S1):S36.
Ominsky et al. J Bone Min Res. 2010;25(S1):S53.
Disclosure of Interest M. Ominsky Shareholder of: Amgen Inc., Employee of: Amgen Inc., Q.-T. Niu Shareholder of: Amgen Inc., Employee of: Amgen Inc., H. Z. Ke Shareholder of: Amgen Inc., Employee of: Amgen Inc.