Treatment with a soluble receptor for activin improves bone mass and structure in the axial and appendicular skeleton of female cynomolgus macaques (Macaca fascicularis).
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 IgG(1) (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.
Fajardo
Roberto José
RJ
Orthopaedic Biomechanics Laboratory, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. fajardor@uthscsa.edu
Manoharan
Rajaram K
RK
Pearsall
R Scott
RS
Davies
Monique V
MV
Marvell
Tod
T
Monnell
Travis E
TE
Ucran
Jeffrey A
JA
Pearsall
Amelia E
AE
Khanzode
Deepali
D
Kumar
Ravindra
R
Underwood
Kathryn W
KW
Roberts
Benjamin
B
Seehra
Jasbir
J
Bouxsein
Mary L
ML
D030301:Activin Receptors, Type II / Q000494:pharmacology*; D000818:Animals; D015519:Bone Density / Q000187:drug effects*; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism*; D005260:Female; D006801:Humans; D008252:Macaca fascicularis / Q000378:metabolism*
D050071:Bone Density Conservation Agents; D030301:Activin Receptors, Type II; C425585:activin receptor type II-A