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 subcutaneou s injections of recombinan t human parathyroi d hormone (PTH)(1-34) for 2 years at doses of 0, 5, 30, or 75 l g/kg. Treatment caused substantial increases in bone mass consistent with the known pharmacologi c effects of once-daily administration. As determined by quantitative computed tomography (QCT) and histomorphometr y, bone mass was markedly increased. Substantial new bone formation resulted in a large decrease in marrow space accompanie d 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-l g/kg treatment groups, respectively. Focal osteoblast hyperplasia, osteoma, and osteoblastoma were much less frequent. Although the speci c 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 pharmacologi c 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.

Safety of osteoanabolic therapy: A decade of experience

“…(2) This study reported a 26% incidence of osteosarcoma in 360 Fisher 344 rats that received teriparatide at doses of 5, 30, or 75 mg/kg/day, beginning at 6 to 8 weeks of age. (2) The occurrence of osteosarcoma was dose-dependent, with the first histopathological and clinical detection occurring after 13 and 17 months, respectively. (2) Other bone neoplasms, including osteomas, osteoblastomas, and focal osteoblast hyperplasia, were found.…”

“…The effects on rats was doseand duration-dependent, with rats being treated for approximately 80% of their lifetime and at doses three to 58 times the currently approved human dose. (2) Similar toxicity was seen for PTH (3) Given the clear-cut efficacy data when the results of the abbreviated clinical trial results for teriparatide were analyzed, the FDA and equivalent other agencies in Europe and elsewhere granted approval of teriparatide with the stipulations that it should be used for no longer than 2 years. In the United States, the drug carries a ''black box warning'' and contraindicates its use in patients with existing risk factors for osteosarcoma, including Paget's disease of bone, prior skeletal radiation, and children with open epiphyses.…”

“…(2) The occurrence of osteosarcoma was dose-dependent, with the first histopathological and clinical detection occurring after 13 and 17 months, respectively. (2) Other bone neoplasms, including osteomas, osteoblastomas, and focal osteoblast hyperplasia, were found. It was noted that the duration of exposure to rats, up to 2 years, represented most of their lifespan.…”

“…(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 …”