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Skeletal Changes in Rats Given Daily Subcutaneous Injections of Recombinant Human Parathyroid Hormone (1-34) for 2 Years and Relevance to Human Safety

Lilly Research Laboratories, Greenfield, Indiana

Masahiko Sato

Lilly Research Laboratories, Greenfield, Indiana

Gerald G. Long

Lilly Research Laboratories, Greenfield, Indiana

Jamie K. Young

Lilly Research Laboratories, Greenfield, Indiana

Paul C. Francis

Lilly Research Laboratories, Greenfield, Indiana

Jeffery A. Engelhardt

Lilly Research Laboratories, Greenfield, Indiana

Michael S. Westmore

Lilly Research Laboratories, Greenfield, Indiana

Yanfei Linda Ma

Lilly Research Laboratories, Greenfield, Indiana

James B. Nold

Pathology Associates —A Charles River Company, Durham, North Carolina

Fischer 344 rats (60/sex/group) were given daily subcutaneou s injections of recombinant human parathyroi d hormone (PTH)(1-34) for 2 years at doses of 0, 5, 30, or 75 µg/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- µg/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.

Key Words: Osteosarcoma • F344 rat • osteoma • osteoblastoma • carcinogenicity • QCT • bone mass • PTH.

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Toxicologic Pathology, Vol. 30, No. 3, 312-321 (2002)
DOI: 10.1080/01926230252929882


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This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Vahle, J. L. Articles by Nold, J. B. Search for Related Content PubMed PubMed Citation Articles by Vahle, J. L. Articles by Nold, J. B. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Bone Cancer Hazardous Substances DB PARATHYROID HORMONE Social Bookmarking                         What's this?