Osteosarcoma in Sprague-Dawley rats after long-term treatment with teriparatide (human parathyroid hormone (1-34))

Watanabe, Atsushi; Yoneyama, Shigeki; Nakajima, Mikio; Sato, Norihiro; Takao-Kawabata, Ryoko; Isogai, Yukihiro; Sakurai-Tanikawa, Aki; Higuchi, Kazuhiro; Shimoi, Akihito; Yamatoya, Hideyuki; Yoshida, Kenji; Kohira, Takahiro

doi:10.2131/jts.37.617

Cited by 76 publications

(58 citation statements)

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“…The authors reported data from five individual studies testing the effect of different teriparatide doses and treatment regimens and substantially confirmed the results in Fisher 344 rats. (61) A significant increase in the incidence of osteosarcoma was found in the highest-dose group, compared to controls. (61) Hence, as for the Fisher 344 studies, a dose-and duration-dependent development of bone tumors was observed.…”

Section: Osteosarcomamentioning

confidence: 89%

Section: Osteosarcomamentioning

confidence: 99%

“…(3) Data on other rat strains A 2001 guidance document from the FDA on the development of PTH for the prevention and treatment of osteoporosis reported preclinical data on the rare occurrence of osteosarcoma in two strains of rat and one strain of mice treated with PTH and related peptides from weaning to 18 months of age, whereas no bone malignancy was observed in the control animals. (60) A recent study by Watanabe and colleagues (61) investigated the 2-year carcinogenicity of teriparatide in male and female SpragueDawley rats. The authors reported data from five individual studies testing the effect of different teriparatide doses and treatment regimens and substantially confirmed the results in Fisher 344 rats.…”

Section: Osteosarcomamentioning

confidence: 99%

“…(61) Hence, as for the Fisher 344 studies, a dose-and duration-dependent development of bone tumors was observed. (61) No influence of age at initiation of treatment was found. (61) The study also established the noncarcinogenic and the carcinogenic dose level of teriparatide as 4.5 mg/kg/d and 13.6 mg/kg/d, respectively.…”

mentioning

confidence: 97%

“…(61) The study also established the noncarcinogenic and the carcinogenic dose level of teriparatide as 4.5 mg/kg/d and 13.6 mg/kg/d, respectively. (61) The area under the receiver operating characteristic curve (AUC) values of teriparatide per week at these doses were 3.9-to 11.6-fold and 17.8-to 37.1-fold; the corresponding AUC values in humans receiving the weekly injection would be the dose of 56.5 mg. (61) Studies in humans and nonhuman primatesThe osteoanabolic effect of PTH has also been extensively studied in cynomolgus macaque monkeys. Osteosarcoma has not developed in this non-human primate with exposure range of 1 to 25 mg/kg/d of teriparatide or PTH(1-84) for up to 18 months of treatment and 36 months of observation.…”

mentioning

confidence: 99%

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Safety of osteoanabolic therapy: A decade of experience

Capriani

Irani

Bilezikian

2012

Journal of Bone and Mineral Research

130

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IntroductionO steoporosis is a prevalent disease that affects more than 10 million Americans. The lifetime risk of an osteoporosisrelated fracture is 50% for Caucasian women and 25% for men. Hip fractures carry a 10% to 20% increase in mortality rate within the first year after fracture. (1) The burden of the hip and other fractures can result in chronic pain, disability and other indices of reduced quality of life.Amidst these sobering statistics is the welcome advent over the past two decades of effective pharmacological therapies that reduce fracture risk. The therapies approved for the management of osteoporosis include bisphosphonates, raloxifene (a selective estrogen-receptor modulator), calcitonin, denosumab, strontium ranelate, and parathyroid hormone and PTH(1-84)]. The fulllength PTH molecule and its foreshortened amino-terminal fragment (teriparatide) are currently the only osteoanabolic agents approved for use. PTH(1-84) is not available in the United States. In November, 2002, teriparatide was approved by the U.S. Food and Drug Administration (FDA) for the treatment of postmenopausal osteoporosis and, later, in men. The approval came with restrictions in duration of therapy (18-24 months) and was limited to individuals with advanced osteoporosis at high risk for fracture. Reasons for these limitations relate, at least in part, to the unexpected occurrence of osteosarcoma and other bone neoplasms in Fischer 344 rat toxicity studies. In fact, the pivotal phase 3 trial of teriparatide was suspended when these rat toxicity data became available. 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(1-84) (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.Teriparatide has now been used in the United States for 10 years. With a decade of experience, it is timely to review the efficacy and safety profile of this medication. PTH(1-84) will also be reviewed. This perspective will be limited to PTH formulations that are available for the treatment of osteoporosis; we will not be discussing other anabolic agents that are currently being studied but are not yet approved, such as the sclerostin antibody (http://clinicaltrials.gov/ct2/results?term ¼ sclerostin þ anti-þ antibody). PTH mechanisms of actionTeriparatide is an amino-terminal fragment of PTH that is biologically identical to the amino-terminal fragment of human PTH. This fragment contains all the classical bio...

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Section: Osteosarcomamentioning

confidence: 89%

Section: Osteosarcomamentioning

confidence: 99%

Section: Osteosarcomamentioning

confidence: 99%

mentioning

confidence: 97%

mentioning

confidence: 99%

See 3 more Smart Citations

Safety of osteoanabolic therapy: A decade of experience

Capriani

Irani

Bilezikian

2012

Journal of Bone and Mineral Research

130

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Single‐dose local administration of teriparatide with a octacalcium phosphate collagen composite enhances bone regeneration in a rodent critical‐sized calvarial defect

et al. 2017

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Octacalcium phosphate and collagen composite (OCP/Col) achieves stable bone regeneration without cell transplantation in preclinical studies. Recently, a sponsor‐initiated clinical trial was conducted to commercialize the material. The present study investigated bone regeneration by OCP/Col with the single local administration of teriparatide (parathyroid hormone 1‐34; TPTD). OCP/Col was prepared by mixing sieved granules of OCP and atelocollagen for medical use and a disk was molded. After the creation of a rodent critical‐sized calvarial defect, OCP/Col or OCP/Col with dripped TPTD solution (1.0 or 0.1 µg; OCP/Col/TPTDd1.0 or OCP/Col/TPTDd0.1) was implanted into the defect. Six defects in each group were fixed 12 weeks after implantation. Radiographic examinations indicated that radiopaque figures in defects treated with OCP/Col with TPTD (OCP/Col/TPTDd) occupied a wider range than those treated with OCP/Col. Histological results demonstrated that most of the defect in OCP/Col/TPTDd was filled with newly formed bone. A histomorphometrical examination indicated that the percentage of newly formed bone was significantly higher in the defects of OCP/Col/TPTDd 1.0 (53.6 ± 4.3%) and OCP/Col/TPTDd 0.1 (52.2 ± 7.4%) than in those of OCP/Col (40.1 ± 8.4%), whereas no significant differences were observed between OCP/Col/TPTDd1.0 and OCP/Col/TPTDd0.1. These results suggest that OCP/Col with the single local administration of TPTD enhances bone regeneration in a rodent calvarial critical‐sized bone defect. © 2017 The Authors Journal of Biomedical Materials Research Part B: Applied Biomaterials Published by Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1851–1857, 2018.

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Osteoprotection Through the Deletion of the Transcription Factor Rorβ in Mice

Farr

Weivoda

Nicks

et al. 2017

Journal of Bone and Mineral Research

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There is a clinical need to identify new molecular targets for the treatment of osteoporosis, particularly those that simultaneously inhibit bone resorption while stimulating bone formation. We have previously shown in overexpression studies that retinoic acid receptor-related orphan receptor β (Rorβ) suppresses in vitro osteoblast differentiation. In addition, the expression of Rorβ is markedly increased in bone marrow-derived mesenchymal stromal cells with aging in both mice and humans. Here we establish a critical role for Rorβ in regulating bone metabolism using a combination of in vitro and in vivo studies. We used Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 gene editing to demonstrate that loss of Rorβ in osteoblasts enhances Wnt signaling, specifically through increased recruitment of β-catenin to T-cell factor/lymphoid enhancer factor (Tcf/Lef) DNA binding sites in the promoters of the Wnt target genes Tcf7 and Opg. This resulted in increased osteogenic gene expression and suppressed osteoclast formation through increased osteoprotegerin (OPG) secretion in Rorβ-deficient cells. Consistent with our in vitro data, genetic deletion of Rorβ in both female and male mice resulted in preserved bone mass and microarchitecture with advancing age due to increased bone formation with a concomitant decrease in resorption. The improved skeletal phenotype in the Rorβ mice was also associated with increased bone protein levels of TCF7 and OPG. These data demonstrate that loss of Rorβ has beneficial skeletal effects by increasing bone formation and decreasing bone resorption, at least in part through β-catenin-dependent activation of the Wnt pathway. Thus, inhibition of Rorβ represents a novel approach to potentially prevent or reverse osteoporosis. © 2017 American Society for Bone and Mineral Research.

show abstract

Osteosarcoma in Sprague-Dawley rats after long-term treatment with teriparatide (human parathyroid hormone (1-34))

Cited by 76 publications

References 15 publications

Safety of osteoanabolic therapy: A decade of experience

Safety of osteoanabolic therapy: A decade of experience

Single‐dose local administration of teriparatide with a octacalcium phosphate collagen composite enhances bone regeneration in a rodent critical‐sized calvarial defect

Osteoprotection Through the Deletion of the Transcription Factor Rorβ in Mice

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