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Toxicologic Pathology, Vol. 34, No. 7, 929-940 (2006)
DOI: 10.1080/01926230601072301
© 2006 Society of Toxicologic Pathology

Articles

Defining a Noncarcinogenic Dose of Recombinant Human Parathyroid Hormone 1–84 in a 2-Year Study in Fischer 344 Rats

Jacquelin Jolette1, Clynn E. Wilker2, Susan Y. Smith1, Nancy Doyle1, Jerry F. Hardisty3, Anna J. Metcalfe4, Thomas B. Marriott2, John Fox2 and David S. Wells2

1 Charles River Laboratories, Senneville, Quebec H9X 3R3, Canada
2 NPS Pharmaceuticals, Inc., Salt Lake City, Utah 84108, USA
3 EPL, Inc., Research Triangle Park, North Carolina 27709, USA
4 CANTOX Health Science International, Mississauga, Ontario L5N 2X7, Canada

Correspondence: Address correspondence to: Jacquelin Jolette, Charles River Laboratories CRM, 87 Senneville Road, Senneville, QC H9X 3R3, Canada; e-mail:jacquelin.jolette{at}ca.crl.com

The carcinogenic potential of human parathyroid hormone 1–84 (PTH) was assessed by daily subcutaneous injection (0, 10, 50, 150 µg/kg/day) for 2 years in Fischer 344 rats. Histopathological analyses were conducted on the standard set of soft tissues, tissues with macroscopic abnormalities, selected bones, and bones with abnormalities identified radiographically. All PTH doses caused widespread osteosclerosis and significant, dose-dependent increases in femoral and vertebral bone mineral content and density. In the mid- and high-dose groups, proliferative changes in bone increased with dose. Osteosarcoma was the most common change, followed by focal osteoblast hyperplasia, osteoblastoma, osteoma and skeletal fibrosarcoma. The incidence of bone neoplasms was comparable in control and low-dose groups providing a noncarcinogenic dose for PTH of 10 µg/kg/day at a systemic exposure to PTH that is 4.6-fold higher than for a 100 µg dose in humans. The ability of PTH to interact with and balance the effects of both the PTH-1 receptor and the putative C-terminal PTH receptor, may lead to the lower carcinogenic potential observed with PTH than reported previously for teriparatide.

Key Words: Parathyroid hormone • osteoporosis treatment • F344 rat • carcinogenicity • osteosarcoma • neoplasm • bone

Abbreviations: PTH, parathyroid hormone 1–84 • BMC, bone mineral content • BMA, bone mineral area • BMD, bone mineral density • DS, delayed start high-dose group


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