Osteosarcoma in Sprague-Dawley rats after long-term treatment with teriparatide (human parathyroid hormone (1-34))
Atsushi WatanabeShigeki YoneyamaMikio NakajimaNorihiro SatoRyoko Takao-KawabataYukihiro IsogaiAki Sakurai-TanikawaKazuhiro HiguchiAkihito ShimoiHideyuki YamatoyaKenji YoshidaTerutomo Kohira
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Abstract:
Teriparatide, a therapeutic agent for osteoporosis, has been reported to increase the incidences of bone neoplasms such as osteosarcoma when administered subcutaneously to Fischer 344 (F344) rats for a long term, but its non-carcinogenic dose level following 2-year daily administration has not been established. Here we report detailed studies on the carcinogenicity of teriparatide following long-term administration. When teriparatide was administered subcutaneously to male and female Sprague-Dawley (SD) rats daily for 2 years, the incidence of osteosarcoma was increased at 13.6 µg/kg/day. The non-carcinogenic dose level was 4.5 µg/kg/day for both males and females. The development of osteosarcoma in SD rats depends on the dose level of, and treatment duration with, teriparatide. Responses of the bones to teriparatide were similar between F344 and SD rats in many aspects. These results suggested that the carcinogenic potential of teriparatide in SD rats is essentially the same as in F344 rats.Keywords:
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Osteoporosis is considered a challenge affecting women more than men, and the outcomes of the condition are not well-known. The prevalance of osteoporosis-linked fractures is less in men, but osteoporosis leads to higher rate of mortality and morbidity in men. In more than half of the patients with osteoporosis, the disorder arises from a secondary result. Among the most frequent reasons of secondary osteoporosis in men are over-consumption of alcohol, hypogonodism and overuse of glucocorticoids. In post-menauposal women, osteoporosis is described as bone mineral density lower than -2.5 standard deviation of peak bone density of young adult reference population. The same criterion is also used for men; however, peak bone density is higher in men, compared to women, and the fact that the same diagnostic reference values for women are used may cause healthcare providers to ignore the diagnosis of osteoporosis in men. The number of drugs to be used in the treatment of osteoporotic men is too limited. Osteoclastic activity is inhibited by antiresorptive treatment (biphosphonates, calcium, vitamin D); thus, bone turnover decreases, bone mineral density increases, and risk of vertebral and/or peripheric fractures diminishes. Antiresorptive treatment may cease the loss of bones, but is effective neither in the formation of new bones nor in the amelioration of microstructure. Anabolic treatment, however, is based on the stimulation of bone formation. Teriparatide (parathyroid hormon 1-34) is
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Osteoporotic fractures are common resulting in increased morbidity and mortality.Exercise can help prevent osteoporosis.It can also benefit patients with osteoporosis, but the exercises must be tailored to the patient.Most Australians should be able to obtain adequate calcium in their diet and vitamin D from the sun.Supplements may be needed in some patients and they are recommended for use with other drugs for osteoporosis.Bisphosphonates, and in some patients denosumab, are first-line drugs for osteoporosis.Raloxifene and strontium ranelate can be considered in patients who cannot take bisphosphonates or denosumab.Teriparatide is reserved for patients with severe osteoporosis and the use of strontium ranelate is declining because of cardiovascular safety concerns.to higher peak bone mass in adulthood. 7,8Impact exercises are also beneficial for middle-aged and older adults for increasing or preventing age-related bone loss.Although the gains in bone mass are promising, there is insufficient evidence to suggest exercise might reduce fractures.The frequency and severity of falls may be reduced by exercises that maintain muscle strength, muscle mass, flexibility, mobility, balance and ease of movement.For people with established osteoporosis, any exercise that promotes these characteristics is recommended.The Box lists exercises according to their 'osteogenic' profile and more detailed information is available at www.osteoporosis.org.au/exercise.9][10][11] Any recommendation for exercise must be tailored to the individual.For example, in patients who have already sustained osteoporotic fractures, moderateto high-impact activities may be unsuitable.
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Despite the availability of safe and effective anti-osteoporosis treatments, osteoporosis continues to be undertreated. The increase in fragility fractures, which is the main clinical consequence of osteoporosis, is a major problem for healthcare systems of countries. A broad range of drugs including antiresorptive and anabolic agents are used in the pharmacological treatment of osteoporosis. Fracture risk assessment in drug selection is of utmost importance in terms of guiding treatment. The recommended thresholds for osteoporosis treatment decision making are based on major osteoporotic and hip fracture probabilities from the Fracture Risk Assessment Tool (FRAX®). Currently, antiresorptive agents are usually the first choice to increase bone mineral density (BMD) and reduce the fracture risk. Bisphosphonates and antiresorptive drugs such as denosumab, a nuclear factor kappa-B ligand (RANKL) inhibitor, are the most widely used drugs in the treatment of osteoporosis. Bisphosphonates alone are unlikely to provide long-term protection against fracture and restore BMD in patients with severe osteoporosis and high fracture risk. In such patients, treatment with an anabolic agent such as teriparatide, abaloparatide, or romosozumab should be ideally initiated to achieve maximal gain in bone mass and preserve the microarchitecture. Ideally, an antiresorptive drug should be continued to maintain gain in bone mass.
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Teriparatide, a treatment formula of parathyroid hormone (PTH) , is a powerful anabolic agent on bone, improving its mass, geometry and microarchitecture. It can decrease the occurrence of fracture in the subjects with increased fracture risks. Teriparatide can provide good protection against fracture using as monotherapy, and possibly as combination with an antiresorptive agent such as zoledronate. Teriparatide should be considered in patients with osteoporosis who sustained the reduction of BMD or fracture on established bisphosphonates or SERMs. Treatment period of teriparatide is 1.5-2 years and consecutive use of antiresorptive agents is greatly recommended to secure long-term protection against fracture after teriparatide treatment.
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Osteoporosis is a skeletal disorder characterized by decreased bone strength, leading to increased fracture risk. In this article, we discuss the use of parathyroid hormone analogs (teriparatide and abaloparatide) in the treatment of osteoporosis. Parathyroid hormone analogs are potent osteoanabolics developed to treat osteoporosis. We discuss important topics pertinent to clinical care to provide clinicians with helpful information in their daily practice when prescribing parathyroid hormone analogs for osteoporosis treatment. We also discuss the potential side effects and strategies to mitigate these side effects.
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As the population ages, the burden of osteoporosis in men is expected to rise. Implementation of preventive measures such as falls prevention strategies, exercise and adequate calcium and vitamin D intake is recommended. However, when the diagnosis of osteoporosis is made, effective treatments need to be initiated to prevent fractures. As opposed to postmenopausal women, reduced bone formation is the predominant mechanism of age-related bone loss in men, making anabolic agents a logical treatment option for men with osteoporosis. Teriparatide is the only anabolic agent currently approved for treatment of osteoporosis in men. This paper summarizes the mechanism of action of teriparatide, as well as its tolerability and safety. Furthermore, the evidence supporting the efficacy of teriparatide treatment in men with osteoporosis is reviewed and its current role in the management of osteoporosis in men is discussed.
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