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Mechanistic investigations on the etiology of Risperdal(®) Consta(®)-induced bone changes in female Wistar Hannover rats.

Toxicology 2012 September 29
RISPERDAL(®) CONSTA(®) is a long-acting, intramuscular formulation of risperidone microspheres for the biweekly treatment of schizophrenia and other psychiatric disorders. In a 24-month carcinogenicity study male and female Wistar Hannover rats received RISPERDAL(®) CONSTA(®) by intramuscular injection at dosages of 5 or 40 mg/kg once every 2 weeks. Bone changes described as "osteodystrophy" were observed by routine microscopic examination at 40 mg/kg in the sternum of female rats after 12 months, and in the sternum and stifle joint of both male and female rats after 24 months of treatment, respectively. To investigate the etiology of these bone changes, a 12-month mechanistic study was conducted in female Wistar Hannover rats at dosages of 5, 20 and 40 mg/kg once every 2 weeks. In addition to routine parameters, this study included bone markers, hormone measurements, and peripheral quantitative computed tomography (pQCT) and dual-energy X-ray absorptiometry (DXA) bone density measurements. It revealed a treatment-related reduction in metaphyseal trabecular bone density of the femur and tibia at 20 and 40 mg/kg, which was evident in the tibia from Week 13 of treatment onwards. There was no convincing evidence for any of the modes of action known to underlie trabecular bone loss in rats including renal, nutritional, or hepatic osteodystrophy, estrogen deficiency, hyperthyroidism or glucocorticoid excess. It is hypothetized that prolonged hyperprolactinemia accompanied by an increase in parathyroid hormone-related protein (PTHrP) levels and a slight hypoestrogenic state could have caused the reduced trabecular bone density in RISPERDAL(®) CONSTA(®)-treated rats. The relevance of this finding in terms of human risk is unknown.

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