title: One year of abaloparatide, a selective peptide activator of the PTH1 receptor, increased bone mass and strength in ovariectomized rats.
abstract: Abaloparatide is a novel 34 amino acid peptide selected to be a potent and selective activator of the parathyroid hormone receptor 1 (PTHR1) signaling pathway. The effects of 12months of abaloparatide treatment on bone mass, bone strength and bone quality was assessed in osteopenic ovariectomized (OVX) rats. SD rats were subjected to OVX or sham surgery at 6months of age and left untreated for 3months to allow OVX-induced bone loss. Eighteen OVX rats were sacrificed after this bone depletion period, and the remaining OVX rats received daily s.c. injections of vehicle (n=18) or abaloparatide at 1, 5 or 25μg/kg/d (n=18/dose level) for 12months. Sham controls (n=18) received vehicle daily. Bone changes were assessed by DXA and pQCT after 0, 3, 6 or 12months of treatment, and destructive biomechanical testing was conducted at month 12 to assess bone strength and bone quality. Abaloparatide dose-dependently increased bone mass at the lumbar spine and at the proximal and diaphyseal regions of the tibia and femur. pQCT revealed that increased cortical bone volume at the tibia was a result of periosteal expansion and endocortical bone apposition. Abaloparatide dose-dependently increased structural strength of L4-L5 vertebral bodies, the femur diaphysis, and the femur neck. Increments in peak load for lumbar spine and the femur diaphysis of abaloparatide-treated rats persisted even after adjusting for treatment-related increments in BMC, and estimated material properties were maintained or increased at the femur diaphysis with abaloparatide. The abaloparatide groups also exhibited significant and positive correlations between bone mass and bone strength at these sites. These data indicate that gains in cortical and trabecular bone mass with abaloparatide are accompanied by and correlated with improvements in bone strength, resulting in maintenance or improvement in bone quality. Thus, this study demonstrated that long-term daily administration of abaloparatide to osteopenic OVX rats led to dose-dependent improvements in bone mass, geometry and strength.
authors.affiliation: Charles River Laboratories, Montreal, Canada.
authors.forename: Aurore
authors.initials: A
authors.lastname: Varela
authors.affiliation: Charles River Laboratories, Montreal, Canada.
authors.forename: Luc
authors.initials: L
authors.lastname: Chouinard
authors.affiliation: Charles River Laboratories, Montreal, Canada.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Lesage
authors.affiliation: Petit Institute for Bioengineering, Bioscience and Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Guldberg
authors.affiliation: Charles River Laboratories, Montreal, Canada.
authors.forename: Susan Y
authors.initials: SY
authors.lastname: Smith
authors.affiliation: University of Michigan, Ann Arbor, MI, USA; Phylon Pharma Services, Newbury Park, CA, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kostenuik
authors.affiliation: Radius Health, Waltham, MA, USA. Electronic address: ghattersley@radiuspharm.com.
authors.forename: Gary
authors.initials: G
authors.lastname: Hattersley
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology*; D003720:Densitometry; D005260:Female; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D044162:Parathyroid Hormone-Related Protein / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000378:metabolism*; D014057:Tomography, X-Ray Computed
chemical_list: D044162:Parathyroid Hormone-Related Protein; D044168:Receptor, Parathyroid Hormone, Type 1; C000596789:abaloparatide
keywords: Abaloparatide; Anabolic agents; Bone strength; Osteoporosis; PTH1 receptor