Article Text

PDF
OP0042 Increased modeling-based bone formation and decreased bone resorption on endocortical surfaces in male cynomolgus monkeys treated with sclerostin antibody
  1. M.S. Ominsky,
  2. Q.-T. Niu,
  3. H.Z. Ke
  1. Amgen Inc., Thousand Oaks, United States

Abstract

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.

  1. Li et al. J Bone Min Res. 2007;22(S1):S36.

  2. 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.

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.