Trabecular bone loss after administration of the second-generation antipsychotic risperidone is independent of weight gain

Abstract

Second generation antipsychotics (SGAs) have been linked to metabolic and bone disorders in clinical studies, but the mechanisms of these side effects remain unclear. Additionally, no studies have examined whether SGAs cause bone loss in mice. Using in vivo and in vitro modeling we examined the effects of risperidone, the most commonly prescribed SGA, on bone in C57BL6/J (B6) mice. Mice were treated with risperidone orally by food supplementation at a dose of 1.25 mg/kg daily for 5 and 8 weeks, starting at 3.5 weeks of age. Risperidone reduced trabecular BV/TV, trabecular number and percent cortical area. Trabecular histomorphometry demonstrated increased resorption parameters, with no change in osteoblast number or function. Risperidone also altered adipose tissue distribution such that white adipose tissue mass was reduced and liver had significantly higher lipid infiltration. Next, in order to tightly control risperidone exposure, we administered risperidone by chronic subcutaneous infusion with osmotic minipumps (0.5 mg/kg daily for 4 weeks) in 7 week old female B6 mice. Similar trabecular and cortical bone differences were observed compared to the orally treated groups (reduced trabecular BV/TV, and connectivity density, and reduced percent cortical area) with no change in body mass, percent body fat, glucose tolerance or insulin sensitivity. Unlike in orally treated mice, risperidone infusion reduced bone formation parameters (serum P1NP, MAR and BFR/BV). Resorption parameters were elevated, but this increase did not reach statistical significance. To determine if risperidone could directly affect bone cells, primary bone marrow cells were cultured with osteoclast or osteoblast differentiation media. Risperidone was added to culture medium in clinically relevant doses of 0, 2.5 or 25 ng/ml. The number of osteoclasts was significantly increased by addition in vitro of risperidone while osteoblast differentiation was not altered. These studies indicate that risperidone treatment can have negative skeletal consequences by direct activation of osteoclast activity and by indirect non-cell autonomous mechanisms. Our findings further support the tenet that the negative side effects of SGAs on bone mass should be considered when weighing potential risks and benefits, especially in children and adolescents who have not yet reached peak bone mass.

Propranolol Attenuates Risperidone-Induced Trabecular Bone Loss in Female Mice

“…Because of the strong relationship between the regulation of bone and energy metabolism (17)(18)(19)(20)(21)(22)(23)(24)(25)49), we developed a model to study the effects of RIS treatment on bone in mice. Consistent with the clinical presentation, we found low trabecular bone volume fraction after administration of RIS, due to both increased resorption and reduced bone formation (26). However, the bone loss in mice occurred in the absence of overt metabolic dysfunction (as evidenced by no changes in body mass, fat mass, blood glucose, insulin tolerance, and glucose tolerance) (26).…”

Bone Remodeling and Energy Metabolism: New Perspectives

“…While the stereotype of androgenic and gynecoid patterns of obesity drew attention to visceral and subcutaneous fat as unhealthy and healthy adipose tissue, it is clear that white fat accumulation in other sites may also have adverse effects (89). For instance, intra muscular fat impairs muscle performance, and is directly involved in myocyte insulin resistance (90)(91)(92).…”

Bone mineral density in male adolescents with autism spectrum disorders and disruptive behavior disorder with or without antipsychotic treatment

“…First, hyperprolactinemia might directly affect bone turnover by stimulating bone resorption relative to bone formation (13,14). Second, prolonged hyperprolactinemia may cause hypogonadotropic hypogonadism (15), resulting in suppression of GNRH secretion in the hypothalamus and diminished secretion of LH and FSH by the pituitary gland, resulting in a diminished secretion of sex hormones and ultimately in changes in bone metabolism.…”