title: Six Weeks of Daily Abaloparatide Treatment Increased Vertebral and Femoral Bone Mineral Density, Microarchitecture and Strength in Ovariectomized Osteopenic Rats.
abstract: Abaloparatide is a novel, potent and selective activator of parathyroid hormone receptor 1 (PTHR1) under clinical development for the treatment of osteoporosis. We assessed the effect of 6 weeks of abaloparatide on bone mass, microarchitecture, quality and strength in ovariectomized (OVX) rats. After 8 weeks of post-surgical bone depletion (baseline), OVX rats (n = 20-21/group) received daily subcutaneous vehicle (OVX-Veh) or abaloparatide at 5 or 20 µg/kg. Sham-operated control rats (n = 24) received vehicle. Areal bone mineral density (aBMD) of the lumbar spine (L4), total femur and femur diaphysis was measured at baseline and after 6 weeks of treatment. Femur and vertebral bone architecture and mechanical properties were assessed at the end of the treatment phase. At baseline, OVX-Veh rats exhibited significantly lower aBMD relative to Sham controls. Treatment of OVX rats with abaloparatide at 5 or 20 µg/kg/day increased aBMD dose-dependently in the lumbar spine, total femur and femur diaphysis to levels exceeding OVX-Veh or Sham controls. The abaloparatide 5 and 20 µg/kg groups had improved trabecular microarchitecture relative to OVX vehicle, with trabecular BV/TV exceeding OVX-Veh control values by 57 and 78 % (respectively) at the lumbar spine, and by 145 and 270 % at the distal femur. Femur diaphyseal cortical volume and thickness were significantly greater in the abaloparatide 20 µg/kg group relative to OVX vehicle or Sham controls. Bone strength parameters of the femur diaphysis, femur neck and L4 vertebra were significantly improved in the OVX-ABL groups relative to OVX-Veh controls. Bone mass-strength relationships and estimated intrinsic strength properties suggested maintained or improved bone quality with abaloparatide. These data demonstrate skeletal restoration via abaloparatide treatment of osteopenic OVX rats, in association with improved trabecular microarchitecture, cortical geometry and bone strength at sites that have clinical relevance in patients with osteoporosis.
authors.affiliation: Radius Health, 950 Winter Street, Waltham, MA, 02451, USA.
authors.forename: Hila
authors.initials: H
authors.lastname: Bahar
authors.affiliation: Radius Health, 950 Winter Street, Waltham, MA, 02451, USA.
authors.forename: Kyla
authors.initials: K
authors.lastname: Gallacher
authors.affiliation: Radius Health, 950 Winter Street, Waltham, MA, 02451, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Downall
authors.affiliation: Radius Health, 950 Winter Street, Waltham, MA, 02451, USA.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Nelson
authors.affiliation: Radius Health, 950 Winter Street, Waltham, MA, 02451, USA.
authors.forename: Maysoun
authors.initials: M
authors.lastname: Shomali
authors.affiliation: Radius Health, 950 Winter Street, Waltham, MA, 02451, USA. ghattersley@radiuspharm.com.
authors.forename: Gary
authors.initials: G
authors.lastname: Hattersley
mesh_terms: D015502:Absorptiometry, Photon; D000818:Animals; D015519:Bone Density / Q000187:drug effects*; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001851:Bone Diseases, Metabolic / Q000517:prevention & control*; D005260:Female; D005269:Femur / Q000187:drug effects; D008159:Lumbar Vertebrae / Q000187:drug effects; D010052:Ovariectomy; D044162:Parathyroid Hormone-Related Protein / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055114:X-Ray Microtomography
chemical_list: D050071:Bone Density Conservation Agents; D044162:Parathyroid Hormone-Related Protein; C000596789:abaloparatide
keywords: Abaloparatide; Anabolic treatment; Bone strength; Osteoporosis; PTH; PTHR1; PTHrP