Original Full length ArticleTrabecular bone loss after administration of the second-generation antipsychotic risperidone is independent of weight gain
Highlights
► Risperidone reduced trabecular and cortical bone mass in mice. ► Risperidone elevated bone resorption and suppressed bone formation. ► Risperidone induced osteoclast (but not osteoblast) differentiation in vitro. ► Weight gain did not contribute to risperidone-induced bone loss.
Introduction
Second-generation antipsychotics (SGAs) are used to treat major psychiatric disorders in part due to their lower incidence of extrapyramidal side effects compared to first-generation antipsychotics (FGAs) [1]. Risperidone is one such SGA that is currently indicated for use in adolescents (as young as 10) and adults with schizophrenia and bipolar disorders, although it is widely used for attention deficit disorders. Risperidone is also approved for use in children as young as 5 years old for treatment of irritability associated with autism. Even though SGAs are highly prescribed, they have been linked to metabolic disorders including obesity, hyperglycemia and dyslipidemia [2], [3], [4]. The mechanism of metabolic changes associated with antipsychotics is unknown, but it is clear that a single dose (intravenous or intracerebroventricular) of certain SGAs (olanzapine, clozapine, and to a lesser degree risperidone) can dramatically reduce insulin sensitivity in the liver and this effect continues after multiple doses [5]. Additionally, SGA-linked obesity and type 2 diabetes mellitus are more prevalent in children and adolescents [6], [7], [8].
The relationship among energy metabolism, insulin signaling and bone remodeling is becoming more apparent, so it is likely that drugs that alter energy metabolism will ultimately affect bone mineral density [9]. Indeed, clinical studies demonstrate reduced bone mineral density and increased fracture risk in patients treated with risperidone and other SGAs, although these studies are confounded by indication (since the underlying disorders treated with antipsychotic medication can be associated with reduced bone mineral density in some cohorts) [10], [11], [12], [13], [14], [15], [16]. Risperidone can induce hyperprolactinemia by dopamine receptor blockade and this can lead to hypothalamic hypogonadism, which has been suggested as a possible mechanism of bone loss [11], [12], [15], [17]. However, a recent study demonstrated that less than half of the patients using risperidone developed hyperprolactinemia [11]. In addition, the increase in prolactin serum levels due to risperidone treatment is often a temporary event [18]. Moreover, unlike FGAs that bind mainly dopamine (D2) receptors, SGAs bind to multiple targets, including serotonin (5-HT), histamine, and D2 receptors, and therefore can affect additional organ systems that indirectly impact skeletal remodeling.
Despite some evidence that SGAs have a deleterious effect on bone, rodent studies involving SGA administration have focused on prolactin and the major metabolic consequences including weight gain, fat redistribution and glucose intolerance. However, no studies have examined whether risperidone is capable of causing direct deleterious effects on bone, nor have any studies been reported in mice. Here, we examined the effects of risperidone on bone and adipose tissue metabolism, and found significant trabecular and cortical bone loss independent of weight gain and overt metabolic dysfunction using two methods of risperidone administration (orally in food and by subcutaneous infusion). Reduced trabecular bone mass in mice fed a diet containing risperidone was due to increased resorption, an effect that can be recapitulated by direct risperidone administration to primary bone marrow derived osteoclasts in vitro. On the other hand, chronic infusion of risperidone suppressed bone formation, and showed a trend toward increased resorption, indicating that the mode of delivery and age of mice are important variables. Despite these differences, we have clearly established a negative role for risperidone on bone metabolism through both direct and indirect mechanisms.
Section snippets
Materials and methods
The experimental protocols were approved by the Institutional Animal Care and Use Committee of the Maine Medical Center Research Institute. The animals were maintained on 12 h light/12 h dark cycles. The mice had free access to water and food.
Oral risperidone administration
Risperidone was administered to male 3.5 week old B6 mice at a dose of 1.25 mg/kg per day in the food to examine its effects on bone metabolism. Risperidone fed mice had significantly lower body weights and lower body fat compared to controls after 5 weeks of treatment (Fig. 1). After 8 weeks, the lower body fat remained statistically significant but there was no significant difference in body mass. Although there was no detectable difference in total aBMD by DXA at either time point,
Discussion
In this paper we have clearly established that risperidone has a negative impact on bone mass in mice and that this effect may be due to both direct and indirect mechanisms. Using both male and female mice, and both oral administration and subcutaneous infusion, we found that risperidone reduces both trabecular and cortical bone mass, and that this effect is likely due to imbalanced bone remodeling (Table 2). Interestingly, both modes of administration of risperidone reduced bone mass but
Acknowledgments
The authors thank Phuong Le, Victoria DeMambro, Deborah Barlow, Marilena Preda and Terry Henderson for technical assistance. This work was funded by Grant Number F32AR061932 to K.J.M from the National Institute Of Arthritis And Musculoskeletal And Skin Diseases; Grant Number 0102-09-1 to I.D.P. from CAPES, Brazil; MMCRI Intramural Award to A.E.M.; Grant Number 201650/2008-8 to F.J.A.P. from the National Council for Scientific and Technological Development (CNPq), Brazil; and ARRA Grant Number
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Cited by (0)
- 1
Authors contributed equally to the experimental design, the phenotyping and the interpretation.
- 2
Permanent address: Department of Internal Medicine, School of Medicine of Ribeirão Preto, USP, Av. Bandeirantes, 3900, 14049-900, Ribeirão Preto, SP, Brazil.
- 3
Permanent address: University of Massachusetts Medical School, Department of Psychiatry, Biotech One, 365 Plantation Street, Worcester MA 01605, USA.