Elsevier

Bone

Volume 46, Issue 1, January 2010, Pages 64-71
Bone

Treatment with a soluble receptor for activin improves bone mass and structure in the axial and appendicular skeleton of female cynomolgus macaques (Macaca fascicularis)

https://doi.org/10.1016/j.bone.2009.09.018Get rights and content

Abstract

A recent study suggests that activin inhibits bone matrix mineralization, whereas treatment of mice with a soluble form of the activin type IIA receptor markedly increases bone mass and strength. To further extend these observations, we determined the skeletal effects of inhibiting activin signaling through the ActRIIA receptor in a large animal model with a hormonal profile and bone metabolism similar to humans. Ten female cynomolgus monkeys (Macaca fascicularis) were divided into two weight-matched groups and treated biweekly, for 3 months, with either a subcutaneous injection 10 mg/kg of a soluble form of the ActRIIA receptor fused with the Fc portion of human IgG1 (ACE-011) or vehicle (VEH). Bone mineral density (BMD), micro-architecture, compressive mechanical properties, and ash fraction were assessed at the end of the treatment period. BMD was significantly higher in ACE-011 treated individuals compared to VEH: + 13% (p = 0.003) in the 5th lumbar vertebral body and + 15% (p = 0.05) in the distal femur. In addition, trabecular volumetric bone density at the distal femur was 72% (p = 0.0004) higher than the VEH-treated group. Monkeys treated with ACE-011 also had a significantly higher L5 vertebral body trabecular bone volume (p = 0.002) and compressive mechanical properties. Ash fraction of L4 trabecular bone cores did not differ between groups. These results demonstrate that treatment with a soluble form of ActRIIA (ACE-011) enhances bone mass and bone strength in cynomolgus monkeys, and provide strong rationale for exploring the use of ACE-011 to prevent and/or treat skeletal fragility.

Introduction

Two classes of drug therapies, anti-resorptives and anabolics, are used in the clinical setting to combat osteoporosis-related bone loss and consequent elevated fracture risk. Anti-resorptives effectively block the actions of osteoclasts and thereby prevent the worsening of fracture risk due to continued bone loss, but they are unable to stimulate new bone formation. Parathyroid hormone (PTH) is the only FDA-approved anabolic treatment for osteoporosis. Parathyroid hormone treatment (with either teripartide, 1–34, or the full peptide, 1–84) stimulates bone formation but also increases bone resorption. The anabolic effects of PTH are prominent in the cancellous bone compartments but more limited at cortical bone sites [1]. Thus, PTH is a potent anabolic drug but given the requirement for daily subcutaneous injections, there is a need to find a drug with a more convenient dosing regimen that preferably maintains or depresses bone resorption while increasing bone formation.

Activin A, a member of the transforming growth factor beta (TGF-β) superfamily, has been reported to have differing roles in bone metabolism and repair. The roles of activin have been characterized as inhibiting osteoblast differentiation [2], inhibiting bone mineralization [3], promoting osteoclastogenesis [4], [5], [6], regulating modeling and formation of the bony palate and long bones [7], [8], [9], and promoting fracture healing [10], [11]. As a member of the TGF-β superfamily, which includes the bone morphogenetic proteins, it is not surprising that activin A influences bone metabolism, but its exact role(s) remain to be determined. In vitro studies suggest that activin inhibits bone matrix mineralization, whereas follistatin, a soluble protein that sequesters activin A, promotes matrix mineralization [3]. In vivo treatment with a soluble form of the activin A type II receptor (ActRIIA) to sequester activin and block the signaling pathway corroborates this negative effect of activin A on bone formation [12]. Intermittent treatment of mice with a soluble murine ActRIIA fusion protein significantly increases trabecular and cortical bone volume, strength, and bone formation rate with no concomitant stimulation of bone resorption [12].

The recent work demonstrating a bone anabolic effect due to activin A inhibition strongly suggests that further investigation of this signaling pathway may lead to the development of a novel anabolic therapy for bone fragility. The goal of this study was to further characterize the efficacy of the ActRIIA fusion protein to promote bone formation in nonhuman primates. The cynomolgus macaque primate model is a logical next step because it is larger in body mass, shares many similarities with humans in the female hormonal profile, and also has intracortical remodeling [13]. Based on prior in vivo results with the soluble ActRIIA binding protein, we predict that treatment will result in increased bone density, as well as improved trabecular micro-architecture and bone strength. Here we report the effects of short-term treatment (7 doses over 3 months) with the human ActRIIA fusion protein ACE-011 on cancellous and cortical bone of the axial and appendicular skeleton in cynomolgus monkeys.

Section snippets

Pharmacokinetics of ACE-011 in cynomolgus monkeys

All of the protocols described below were approved by the Institutional Animal Care and Use Committee. Nine male cynomolgus monkeys (Macaca fascicularis) were divided into three groups and dosed by a single subcutaneous (SC) injection of ACE-011 at 1.0, 10.0 and 30.0 mg/kg. Blood was collected from the femoral vein prior to dosing and at 0.25, 0.5, 1, 4, 8, 24, 48, 96, 168, 252, 336, 504 and 672 h following SC administration of ACE-011. For plasma analyses, blood was collected in tubes

Pharmacokinetics

A single SC dose administration of ACE-011 at 1.0, 10.0, or 30.0 mg/kg to male cynomolgus monkeys was well tolerated and displayed a linear pharmacokinetic profile (Fig. 3a) with mean area under the plasma concentration curve from zero to 672 h (AUC0–672hr) values of 2275; 13,583; and 31,128 μg h/mL, respectively (Table 1). The ACE-011 profile was biphasic, characterized by a rapid absorption phase and a slow elimination phase, as expected for extravascular administration (Fig. 3b). The maximum

Discussion

This study assessed the skeletal effects of activin inhibition in a large animal model via a soluble ActRIIA fusion protein (ACE-011) that sequesters activin A. We hypothesized that treatment with ACE-011 would increase bone mass and strengthen the mechanical properties of bone. The cynomolgus monkey (Macaca fascicularis) model was chosen based on its size, the similarity in its monthly hormonal profile to humans, and the fact that nonhuman primates, like humans, remodel cortical bone [13], [21]

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