Bone Neoplasms in F344 Rats Given Teriparatide [rhPTH(1-34)] Are Dependent on Duration of Treatment and Dose

Abstract

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 microg/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 microg/kg for 20 or 24 months. No neoplasms were found when the 5 microg/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.

Safety of osteoanabolic therapy: A decade of experience

“…Moreover, the doses employed were large multiples (threefold to 58-fold) of the human dose. (2) The second rat carcinogenicity study by Vahle and colleagues (55) confirmed that the development of bone neoplasm in rats was strongly dependent on the dose and the duration of treatment, whereas the age at initiation had only a minor effect. Consistent findings were reported in the PTH(1-84) study, which examined Fisher 344 rats given doses of 10, 50, or 150 mg/kg/d for 24 months.…”

“…(2,3,55,56) In the United States, the FDA identifies major safety concerns with a ''black box'' warning, a designation given to teriparatide with specific reference to osteosarcoma. The labeling instructions contraindicate the use of teriparatide in any situation in which the risk of osteosarcoma is increased.…”

“…When exposed to an osteoanabolic agent like PTH, the rat responds exuberantly with a profound increase in endocortical and trabecular bone mass and a significant reduction in marrow space. (2,55) Older studies from the 1930s showed that the entire marrow space can be obliterated by chronic exposure of rats to PTH. (74) The ever-growing rat skeleton, therefore, is a developing organ harboring immature and potentially tumorigenic cells that might respond to PTH with uncontrolled behavior, losing its capacity for ordered modeling or growth.…”

“…The tumorigenic effect of PTH in rats appears to be specific to bone. (2,3,55) In the clinical trials with teriparatide and PTH , no increase in nonosseous cancers was found. (20,26,29,31) However, because many tissues and solid tumors could express the PTH/PTHrP receptor, it has been suggested that patients with a history of cancers in the past 5 years avoid PTH therapy.…”

“…When exposed to an osteoanabolic agent like PTH, the rat responds exuberantly with a profound increase in endocortical and trabecular bone mass and a significant reduction in marrow space. (2,55) Older studies from the 1930s showed that the entire …”