title: Reproductive toxicity of denosumab in cynomolgus monkeys.
abstract: Denosumab is a monoclonal antibody that inhibits bone resorption by targeting RANKL, an essential mediator of osteoclast formation, function, and survival. Reproductive toxicity of denosumab was assessed in cynomolgus monkeys in an embryofetal development study (dosing GD20-50) and a pre-postnatal toxicity study (dosing GD20-parturition). In the embryofetal toxicity study, denosumab did not elicit maternal toxicity, fetal harm or teratogenicity. In the pre-postnatal toxicity study, there were increased stillbirths, and one maternal death due to dystocia. There was no effect on maternal mammary gland histomorphology, lactation, or fetal growth. In infants exposed in utero, there was increased postnatal mortality, decreased body weight gain, and decreased growth/development. Denosumab-related effects in infants were present in bones and lymph nodes. There was full recovery at 6 months of age from most bone-related changes observed earlier postpartum. The effects observed in mothers and infants were consistent with the pharmacological action of denosumab.
authors.affiliation: Amgen Inc., One Amgen Center Dr., Thousand Oaks, CA 91320, United States. Electronic address: jeanine.bussiere@amgen.com.
authors.forename: Jeanine L
authors.initials: JL
authors.lastname: Bussiere
authors.forename: Ian
authors.initials: I
authors.lastname: Pyrah
authors.forename: Rogely
authors.initials: R
authors.lastname: Boyce
authors.forename: Dan
authors.initials: D
authors.lastname: Branstetter
authors.forename: Mark
authors.initials: M
authors.lastname: Loomis
authors.forename: Dina
authors.initials: D
authors.lastname: Andrews-Cleavenger
authors.forename: Cynthia
authors.initials: C
authors.lastname: Farman
authors.forename: Glenn
authors.initials: G
authors.lastname: Elliott
authors.forename: Gary
authors.initials: G
authors.lastname: Chellman
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000633:toxicity*; D050071:Bone Density Conservation Agents / Q000633:toxicity*; D000069448:Denosumab; D047108:Embryonic Development / Q000187:drug effects; D005260:Female; D047109:Fetal Development / Q000187:drug effects; D006410:Hematopoiesis / Q000187:drug effects; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D008431:Maternal-Fetal Exchange; D011247:Pregnancy; D012098:Reproduction / Q000187:drug effects; D050497:Stillbirth
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D050071:Bone Density Conservation Agents; D000069448:Denosumab
keywords: Cynomolgus monkeys; Denosumab; Embryofetal toxicity; Pre-postnatal toxicity; Reproductive toxicity