Elsevier

Bone

Volume 48, Issue 2, 1 February 2011, Pages 197-201
Bone

Sclerostin antibody increases bone mass by stimulating bone formation and inhibiting bone resorption in a hindlimb-immobilization rat model

https://doi.org/10.1016/j.bone.2010.09.009Get rights and content

Abstract

Sclerostin monoclonal antibody (Scl-Ab) has been shown to increase bone mass and bone strength by stimulating bone formation in an ovariectomy-induced bone loss rat model. The purpose of this study was to determine the effects of Scl-Ab in a rat immobilization/disuse model in which there was both a decrease in bone formation and an increase in bone resorption. Ten-month-old female Sprague Dawley rats were divided into normal weight-bearing (normal-loaded, NL) and right hindlimb-immobilization (under-loaded, UL) groups. Both NL and UL rats were treated with vehicle or Scl-Ab at 5 or 25 mg/kg, twice per week for 4 weeks. Trabecular and cortical bone histomorphometric analyses were performed on the proximal tibial metaphysis (PTM) and tibial shaft (TS). Compared to NL controls, UL rats had reduced body and muscle weights, increased bone marrow fat cells in the PTM, increased trabecular bone resorption and periosteal mineral apposition rate (MAR) as well as decreased trabecular MAR and bone formation rate (BFR/BS). In NL bones, treatment with Scl-Ab significantly increased bone formation and decreased bone resorption, resulting in increased trabecular and cortical bone mass. In UL trabecular bone, treatment with Scl-Ab at 5 or 25 mg/kg induced significant and dose-dependent increases in trabecular bone volume and thickness, mineralized surfaces (MS/BS), MAR and BFR/BS, and a significant decrease in eroded surface (Er.S/BS) compared with UL controls. In UL cortical bone, Scl-Ab treatment induced significant increases in cortical width, periosteal and endocortical MS/BS, MAR and BFR/BS, and significant decreases in endocortical Er.S/BS compared with UL controls. Taken together, these findings suggest that antibody-mediated blockade of sclerostin represents a promising new therapeutic approach for the anabolic treatment of immobilization-induced osteopenia.

Research Highlights

► Immobilization decreased bone formation and increased bone resorption in rats. ►Sclerostin inhibition increased trabecular, endocortical and periosteal bone formation in immobilized tibia. ► The effect of Scl-Ab on trabecular bone in immobilized tibia appears to be less dramatic than that in normal-loaded tibia.

Introduction

Sclerostin deficiency in humans, together with data from sclerostin-knockout mice, suggests that sclerostin inhibition might be an attractive approach for the development of a novel bone anabolic agent [1], [2], [3], [4]. Studies have demonstrated that inhibition of sclerostin by a sclerostin monoclonal antibody (Scl-Ab) stimulated bone formation, and increased bone mass and bone strength in the ovariectomy-induced bone loss rat [5] and gonad-intact female monkey models [6]. Dose-dependent increases in biochemical markers of bone formation and decreases in a bone resorption marker were observed following a single subcutaneous injection of Scl-Ab in healthy post-menopausal women [7]. However, it has yet to be demonstrated whether Scl-Ab can build bone in the setting of the immobilized/disuse-induced osteopenia that occurs in paraplegic conditions, space flight and prolonged bed rest. It has been reported that increases in loading of bone were associated with decreased sclerostin expression [8] and bone loss did not occur after unloading in mice lacking sclerostin [4]. In the current study, we employed the modified Swedish adult rat right hindlimb-immobilization model [9], [10], [11], [12] to test the effects of Scl-Ab on the under-loaded (UL) bone. A group of normal-loaded rats were also treated with Scl-Ab as a reference for the effects of Scl-Ab on normal-loaded bone in these adult female rats.

Section snippets

Materials and methods

The Institutional Animal Care and Use Committee at the University of Utah approved all animal procedures in this study.

Results

At the end of the study, body weights in UL rats were 15% less than those of NL rats regardless of treatment. Both doses of the Scl-Ab had no effect on body weight (data not shown).

Muscle weights in UL rats were significantly lower as compared with basal controls and NL controls. Specifically, the right soleus, gastrocnemius and quadriceps muscles weighed 44%, 59% and 56% less, respectively, relative to beginning controls. Treatment with 5 or 25 mg/kg Scl-Ab had no effect on muscle weight in

Discussion

We studied antibody-mediated sclerostin inhibition in adult female rats with or without right hindlimb-immobilization. Scl-Ab treatment significantly induced increases in trabecular and cortical bone under both normal-loaded and under-loaded conditions. The increased bone mass with Scl-Ab treatment was due to increased bone formation and decreased bone resorption on both trabecular and endocortical bone surfaces, as well as increased bone formation on periosteal surfaces. Furthermore,

Conflict of interest

Tian and Jee have no conflict of interest. Li, Paszty and Ke have corporate appointments with Amgen, Inc.

Acknowledgments

The authors acknowledge the support of Rebecca B. Setterberg and Min Chen for their excellent technical assistance. The funding for this study was supported by Amgen Inc. and UCB. The authors thank all members of the Amgen and UCB (Slough, United Kingdom) sclerostin team for their support of this study.

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