title: Comparing the incidence of bone tumors in rats chronically exposed to the selective PTH type 1 receptor agonist abaloparatide or PTH(1-34).
abstract: Prolonged treatment with human parathyroid hormone (hPTH) in rats results in development of bone tumors, though this finding has not been supported by clinical experience. The PTH type 1 receptor agonist abaloparatide, selected for its bone anabolic activity, is under clinical development to treat postmenopausal women with osteoporosis. To determine the carcinogenic potential of abaloparatide, Fischer (F344) rats were administered SC daily abaloparatide at doses of 0, 10, 25, and 50 μg/kg or 30 μg/kg hPTH(1-34) as a positive control for up to 2 years. Robust increases in bone density were achieved at all abaloparatide doses and with hPTH(1-34). Comprehensive histopathological analysis reflected a comparable continuum of proliferative changes in bone, mostly osteosarcoma, in both abaloparatide and hPTH(1-34) treated rats. Comparing the effects of abaloparatide and hPTH(1-34) at the 25 and 30 μg/kg respective doses, representing similar exposure multiples to the human therapeutic doses, revealed similar osteosarcoma-associated mortality, tumor incidence, age at first occurrence, and metastatic potential. There were no increases in the incidence of non-bone tumors with abaloparatide compared to vehicle. Thus, near life-long treatment with abaloparatide in rats resulted in dose and time dependent formation of osteosarcomas, with a comparable response to hPTH(1-34) at similar exposure.
authors.affiliation: Charles River Laboratories, Preclinical Services, Montreal, 22022 Transcanadienne, Senneville, Quebec H9X 3R3, Canada.
authors.forename: Jacquelin
authors.initials: J
authors.lastname: Jolette
authors.affiliation: Charles River Laboratories, Preclinical Services, Montreal, 22022 Transcanadienne, Senneville, Quebec H9X 3R3, Canada.
authors.forename: Bassem
authors.initials: B
authors.lastname: Attalla
authors.affiliation: Charles River Laboratories, Preclinical Services, Montreal, 22022 Transcanadienne, Senneville, Quebec H9X 3R3, Canada.
authors.forename: Aurore
authors.initials: A
authors.lastname: Varela
authors.affiliation: Experimental Pathology Laboratories Inc., Sterling, VA 20166, USA.
authors.forename: Gerald G
authors.initials: GG
authors.lastname: Long
authors.affiliation: Charles River Laboratories, Preclinical Services, Montreal, 22022 Transcanadienne, Senneville, Quebec H9X 3R3, Canada.
authors.forename: Nacera
authors.initials: N
authors.lastname: Mellal
authors.affiliation: Charles River Laboratories, Preclinical Services, Montreal, 22022 Transcanadienne, Senneville, Quebec H9X 3R3, Canada.
authors.forename: Sabile
authors.initials: S
authors.lastname: Trimm
authors.affiliation: Charles River Laboratories, Preclinical Services, Montreal, 22022 Transcanadienne, Senneville, Quebec H9X 3R3, Canada.
authors.forename: Susan Y
authors.initials: SY
authors.lastname: Smith
authors.affiliation: Radius Health, Inc., 950 Winter Street, Waltham, MA 02451, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Ominsky
authors.affiliation: Radius Health, Inc., 950 Winter Street, Waltham, MA 02451, USA. Electronic address: ghattersley@radiuspharm.com.
authors.forename: Gary
authors.initials: G
authors.lastname: Hattersley
mesh_terms: D000818:Animals; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000633:toxicity*; D001859:Bone Neoplasms / Q000139:chemically induced* / Q000453:epidemiology; D005260:Female; D006801:Humans; D015994:Incidence; D012516:Osteosarcoma / Q000139:chemically induced* / Q000453:epidemiology; D010281:Parathyroid Hormone / Q000008:administration & dosage / Q000633:toxicity*; D044162:Parathyroid Hormone-Related Protein / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D050071:Bone Density Conservation Agents; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; C000596789:abaloparatide
keywords: Abaloparatide; Bone mineral content; Carcinogenicity; F344 rat; Osteoblastoma; Osteosarcoma; PTH1R