title: Skeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone (1-34) for 2 years and relevance to human safety.
abstract: Fischer 344 rats (60/sex/group) were given daily subcutaneous injections of recombinant human parathyroid hormone (PTH)(1-34) for 2 years at doses of 0, 5, 30, or 75 microg/kg. Treatment caused substantial increases in bone mass consistent with the known pharmacologic effects of once-daily administration. As determined by quantitative computed tomography (QCT) and histomorphometry, bone mass was markedly increased. Substantial new bone formation resulted in a large decrease in marrow space accompanied by altered bone architecture. Bone proliferative lesions were observed in all PTH( 1-34)-treated groups. Osteosarcoma occurred in 3, 21, and 31 male rats and in 4, 12, and 23 female rats in the 5-, 30-, and 75-microg/kg treatment groups, respectively. Focal osteoblast hyperplasia, osteoma, and osteoblastoma were much less frequent. Although the specific cellular or molecular mechanisms responsible for the rat bone tumors have not been fully elucidated, the data suggest that these lesions resulted from the long duration of treatment and the exaggerated pharmacologic response of the rat skeleton to daily treatment with PTH(1-34). Important differences between the rat study and clinical use in adult humans suggest that the increased incidence of bone neoplasia in rats treated for 2 years is likely not predictive of an increased risk of bone cancer in skeletally mature adult humans being given PTH(1-34) for a limited period of time in the treatment of osteoporosis.
authors.affiliation: Lilly Research Laboratories, Greenfield, Indiana 46140, USA.
authors.forename: John L
authors.initials: JL
authors.lastname: Vahle
authors.forename: Masahiko
authors.initials: M
authors.lastname: Sato
authors.forename: Gerald G
authors.initials: GG
authors.lastname: Long
authors.forename: Jamie K
authors.initials: JK
authors.lastname: Young
authors.forename: Paul C
authors.initials: PC
authors.lastname: Francis
authors.forename: Jeffery A
authors.initials: JA
authors.lastname: Engelhardt
authors.forename: Michael S
authors.initials: MS
authors.lastname: Westmore
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Linda
authors.forename: James B
authors.initials: JB
authors.lastname: Nold
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects*; D001859:Bone Neoplasms / Q000139:chemically induced* / Q000473:pathology*; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D006965:Hyperplasia / Q000139:chemically induced; D007279:Injections, Subcutaneous; D008297:Male; D018215:Osteoblastoma / Q000139:chemically induced / Q000473:pathology; D010016:Osteoma / Q000139:chemically induced / Q000473:pathology; D012516:Osteosarcoma / Q000139:chemically induced / Q000473:pathology; D010281:Parathyroid Hormone / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D013997:Time Factors
chemical_list: D010281:Parathyroid Hormone; D010446:Peptide Fragments; D011994:Recombinant Proteins