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Bone Neoplasms in F344 Rats Given Teriparatide [rhPTH(1-34)] Are Dependent on Duration of Treatment and Dose
John L. Vahle
Lilly Research Laboratories, Greenfield, Indiana, jvahle{at}lilly.com
Gerald G. Long
Lilly Research Laboratories, Greenfield, Indiana
George Sandusky
Lilly Research Laboratories, Greenfield, Indiana
Michael Westmore
Lilly Research Laboratories, Greenfield, Indiana
Yanfei Linda Ma
Lilly Research Laboratories, Greenfield, Indiana
Masahiko Sato
Lilly Research Laboratories, Greenfield, Indiana
A long-term study was conducted in female F344 rats to determine the relative importance of dose, treatment duration, and age at initiation of treatment on the incidence of teriparatide [rhPTH[1-34)]-induced bone proliferative lesions. Treatment groups consisted of different combinations of dose (0, 5, or 30 µg/kg/d), treatment duration (6, 20, or 24 months) and age at initiation of treatment (2 or 6 months of age). The primary endpoints were the incidence of bone neoplasms and effects on bone mass and structure as evaluated by quantitative computed tomography and histomorphometery. Significant increases in the incidence of bone tumors (osteoma, osteoblastoma, and osteosarcoma) occurred in rats treated with 30 µg/kg for 20 or 24 months. No neoplasms were found when the 5 µg/kg treatment was initiated at 6 months of age and continued for either 6 or 20 months (up to 70% of life span). This treatment regimen defined a "no-effect" dose for neoplasm formation that nevertheless resulted in substantial increases in bone mass. These results demonstrate that treatment duration and administered dose are the most important factors in the teriparatide-induced bone tumors in rats.
Key Words: PTH • teriparatide • rat • bone • neoplasms • osteoporosis treatment • osteosarcoma.
References
- Boorman, G. A., Eustis, S, L., Elwell, M. R., Montgomery, C. A.,Jr., and Mackenzie, W. F. (eds). (1990). Bones, joint, and synovia. In Pathology of the Fischer Rat (J. R. Leininger and M. G. I. Riley, eds.), pp. 209—226. Academic Press, San Diego, CA.
- Burr, D.B., Hirano, T., Turner, C.H., Hotchkiss, C., Brommage, R., and Hock, J.M. (2001). Intermittently administered human parathyroid hormone (1-34) treatment increases intracortical bone turnover and porosity without reducing bone strength in the humerus of ovariectomized cynomolgus monkeys. J Bone Miner Res 16, 157—65.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Dempster, D.W., Cosman, F., Kurland, E.S., Zhou, H., Nieves, J., Woelfert, L., Shane, E., Plavetic, K., Muller, R., Bilezikian, J., and Lindsay, R. (2001). Effects of daily treatment with parathyroid hormone on bone microarchitecture and turnover in patients with osteoporosis: a paired biopsy study. J Bone Miner Res 16, 1846—53.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Dorfman, H.D., and Czerniak, B. (1998). Bone Tumors. Mosby, St. Louis, MO.
- Garrahan, N.J., Mellish, R.W., and Compston, J.E. (1986). A new method for the two-dimensional analysis of bone structure in human iliac crest biopsies. J Microsc 142 (Pt 3), 341—49.
- Haseman, J.K., Hailey, J.R., and Morris, R.W. (1998). Spontaneous neoplasm incidences in Fischer 344 rats and B6C3F1 mice in two-year carcinogenicity studies: a National Toxicology Program update. Toxicol Pathol 26, 428—41.
- Hock, J.M. (2001). Anabolic actions of PTH in the skeletons of animals. J Musculoskel Neuron Interact 2, 33—47.
- Iddon, J., Bundred, N.J., Hoyland, J., Downey, S.E., Baird, P., Salter, D., McMahon, R., and Freemont, A.J. (2000). Expression of parathyroid hormone-related protein and its receptor in bone metastases from prostate cancer. J Pathol 191(2), 170—4.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Jerome, C.P. (1994). Anabolic effect of high doses of human parathyroid hormone (1-38) in mature intact female rats. J Bone Miner Res 9, 933—42.[Web of Science][Medline]
[Order article via Infotrieve]
- Jerome, C.P., Johnson, C.S., Vafai, H.T., Kaplan, K.C., Bailey, J., Capwell, B., Fraser, F., Hansen, L., Ramsay, H., Shadoan, M., Lees, C.J., Thomsen, J.S., and Mosekilde, L. (1999). Effect of treatment for 6 months with human parathyroid hormone (1-34) peptide in ovariectomized cynomolgus monkeys (Macaca fascicularis). Bone 25, 301—9.[Medline]
[Order article via Infotrieve]
- Jiang, Y., Zhao, J.J., Mitlak, B.H., Wang, O., Genant, H.K., and Eriksen, E.F. (2003). Teriparatide [recombinant human parathyroid hormone (1-34)] improves both cortical and cancellous bone structure. J Bone Miner Res 18, 1932—41.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Kimmel, D.B., Bozzato, R.P., Kronis, K.A., Coble, T., Sindrey, D., Kwong, P., and Recker, R.R. (1993). The effect of recombinant human (1-84) or synthetic human (1-34) parathyroid hormone on the skeleton of adult osteopenic ovariectomized rats. Endocrinology 132, 1577—84.[Abstract/Free Full Text]
- Kishi, T., Hagino, H., Kishimoto, H., and Nagashima, H. (1998). Bone responses at various skeletal sites to human parathyroid hormone in ovariectomized rats: effects of long-term administration, withdrawal, and readministration. Bone 22, 515—22.
- Lin, K.K., and Rahman, M.A. (1998). Overall false positive rates in tests for linear trend in tumor incidence in animal carcinogenicity studies of new drugs. J Biopharm Stat 8, 1—15.[Medline]
[Order article via Infotrieve]
- Long, P.H., Leininger, J.R., Nold, J.B., and Lieuallen, W.G. (1993). Proliferative lesions of bone, cartilage, tooth, and synovium in rats. In Guides for Toxicologic Pathology, pp. 1—18. STP/ARP/AFIP, Washington, DC.
- Mosekilde, L., Sogaard, C.H., Danielsen, C.C., and Torring, O. (1991). The anabolic effects of human parathyroid hormone (hPTH) on rat vertebral body mass are also reflected in the quality of bone, assessed by biomechanical testing: a comparison study between hPTH-(1-34) and hPTH-(1-84). Endocrinology 129, 421—8.[Abstract/Free Full Text]
- Neer, R.M., Arnaud, C.D., Zanchetta, J.R., Prince, R., Gaich, G.A., Reginster, J.Y., Hodsman, A.B., Eriksen, E.F., Ish-Shalom, S., Genant, H.K., Wang, O., and Mitlak, B.H. (2001). Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 344, 1434—41.[Abstract/Free Full Text]
- Oxlund, H., Ejersted, C., Andreassen, T.T., Torring, O., and Nilsson, M.H. (1993). Parathyroid hormone (1-34) and (1-84) stimulate cortical bone formation both from periosteum and endosteum Calcif Tissue Int 53, 394— 9.
- Parfitt, A.M., Drezner, M.K., Glorieux, F.H., Kanis, J.A., Malluche, H., Meunier, P.J., Ott, S.M., and Recker, R.R. (1987). Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res 2, 595—610.[Web of Science][Medline]
[Order article via Infotrieve]
- Rubin, M.R., Cosman, F., Lindsay, R., and Bilezikian, J.P. (2002). The anabolic effects of parathyroid hormone. Osteoporos Int 13, 267—77.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Sato, M., Vahle, J., Schmidt, A., Westmore, M., Smith, S., Rowley, E., and Ma, L.Y. (2002). Abnormal bone architecture and biomechanical properties with near-lifetime treatment of rats with PTH. Endocrinology 143, 3230—42.[Abstract/Free Full Text]
- Sato, M., Westmore, M., Clendenon, J., Smith, S., Hannum, B., Zeng, G.Q., Brommage, R., and Turner, C.H. (2000). Three-dimensional modeling of the effects of parathyroid hormone on bone distribution in lumbar vertebrae of ovariectomized cynomolgus macaques. Osteoporos Int 11, 871—80.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Sato, M., Zeng, G.Q., and Turner, C.H. (1997). Biosynthetic human parathyroid hormone (1-34) effects on bone quality in aged ovariectomized rats. Endocrinology 138, 4330—7.[Abstract/Free Full Text]
- Silva, L.B., and Van der Laan, J. W. (2000). Mechanisms of nongenotoxic carcinogenesis and assessment of the human hazard. Regul Toxicol Pharmacol 32, 135—43.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Stanislaus, D., Devanarayan, V., and Hock, J.M. (2000). In vivo comparison of activated protein-1 gene activation in response to human parathyroid hormone (hPTH)(1-34) and hPTH(1-84) in the distal femur metaphyses of young mice. Bone 27, 819—26.
- Stewart, A.F., Cain, R.L., Burr, D.B., Jacob, D., Turner, C.H., and Hock, J.M. (2000). Six-month daily administration of parathyroid hormone and parathyroid hormone-related protein peptides to adult ovariectomized rats markedly enhances bone mass and biomechanical properties: a comparison of human parathyroid hormone 1-34, parathyroid hormone-related protein 1-36, and SDZ-parathyroid hormone 893. J Bone Miner Res 15, 1517—25.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Tashjian, A.H., and Chabner, B.A. (2002). Clinical safety of recombinant human parathyroid hormone (1-34) in the treatment of osteoporosis in postmenopausal women and men [commentary]. J Bone Miner Res 17, 1151—61.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Vahle, J.L., Sato, M., Long, G.G., Young, J.K., Francis, P.C., Engelhardt, J.A., Westmore, M., Ma, L., and Nold, J.B. (2002). Skeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone (1-34) for 2 years and relevance to human safety. Toxicol Pathol 30, 312—21.[Abstract/Free Full Text]
- Whitfield, J.F. (2001). The bone growth-stimulating PTH and osteosarcoma. Medscape Women's Health eJournal 6.
- Zanchetta, J.R., Bogado, C.E., Ferretti, J.L., Wang, O., Wilson, M.G., Sato, M., Gaich, G.A., Dalsky, G.P., and Myers, S.L. (2003). Effects of teriparatide [recombinant human parathyroid hormone (1-34)] on cortical bone in postmenopausal women with osteoporosis. J Bone Miner Res 18, 539— 43.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
Toxicologic Pathology, Vol. 32, No. 4,
426-438 (2004)
DOI: 10.1080/01926230490462138
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