Mechanisms of bone loss from administration of the second-generation antipsychoti

描述(由申请人提供)：第二代抗精神病药物(SGA)通常用于儿童和青少年的严重精神障碍、注意力缺陷障碍和与自闭症相关的易怒。这些药物的副作用包括高催乳素血症、性腺功能减退和肥胖。最近的研究将SGA与人类骨密度降低和骨折风险增加联系在一起，但尚不清楚青年时期服用SGA是否会对骨骼动态平衡产生持久的有害影响。了解SGA应用引起的骨并发症的机制对于临床制定预防和治疗策略具有重要意义。与第一代抗精神病药物(FGA)不同，SGAs结合多个受体，包括多巴胺、5-羟色胺、组胺和α-肾上腺素能受体，因此可以影响多个组织和器官系统。最近来自啮齿动物和人类的证据表明，5-羟色胺在调节骨重建中发挥着重要作用，骨细胞表达可能受SGAs影响的受体(包括5-羟色胺受体)。我有初步数据显示，在服用利培酮的小鼠中，代谢发生了变化，包括脂肪重新分配到肝脏和骨髓，并伴随着骨小梁密度下降。利培酮是最常用的SGAs之一。骨的改变可能是由于骨吸收增加，而骨小梁的形成变化很小。然而，利培酮治疗后骨膜周长也减少，提示骨膜成骨细胞功能受损。我还发现，在用利培酮处理的原代骨髓培养中，破骨细胞的大小和数量增加。我假设利培酮治疗会改变全身新陈代谢和动态平衡，导致骨骼健康受损，并直接作用于成骨细胞和破骨细胞，扰乱正常的骨骼建模和重塑。因此，我提出了两个目标：(1)检测利培酮对8、12和16周龄雌性小鼠骨骼的影响，得出骨骼变化与代谢异常、动情周期和催乳素水平之间的关系；我还将治疗4周龄的小鼠4周，观察骨重塑、代谢和内分泌的变化，直到20周龄，以确定青少年利培酮治疗是否会永久性破坏骨骼和代谢的动态平衡；(2)采用体外原代骨细胞培养和共培养技术，检测利培酮对破骨细胞分化和功能、成骨细胞依赖破骨细胞募集和/或成骨细胞分化和功能的影响。这些研究的结果将确定利培酮对骨骼的影响，测试利培酮对骨骼的间接和/或直接影响是否会导致这些变化，并为未来研究其他SGAs的骨骼和代谢影响提供垫脚石。我的结果也将增加越来越多的证据，证明神经系统在调节骨骼动态平衡方面发挥着关键作用。 公共卫生相关性：第二代抗精神病药物被指定用于成人、青少年和年仅5岁的儿童，治疗与自闭症相关的严重精神障碍和易怒。利培酮是一种会导致高催乳素血症和肥胖的药物，最近被认为与患者的骨密度降低有关。这项拟议的工作将在C57BL/6小鼠身上测试利培酮对骨细胞的非偶联骨骼重塑是否是代谢和激素相关的副作用和/或直接作用的结果。

DESCRIPTION (provided by applicant): Second generation antipsychotics (SGAs) are commonly administered to children and adolescents for major psychiatric disorders, attention deficit disorder, and irritability associated with autism. Side effects from these medications include hyperprolactinemia, hypogonadism, and obesity. Recent studies have linked SGAs to reduced bone mineral density and increased fracture risk in humans, but it is unclear whether SGA administration in youth will have lasting deleterious effects on skeletal homeostasis. Understanding the mechanism of bone complications from SGA use is important for planning of prevention and treatment strategies in the clinic. Unlike first generation antipsychotics (FGAs), SGAs bind multiple receptors including dopamine, serotonin, histamine and alpha-adrenergic receptors and could therefore affect multiple tissues and organ systems. Recent evidence from rodents and humans suggest a major role for serotonin in regulation of bone remodeling, and bone cells express receptors (including serotonin receptors) that could be affected by SGAs. I have preliminary data demonstrating metabolic changes, including adipose redistribution to liver and bone marrow, accompanied by reduced trabecular bone mineral density in mice treated with risperidone, one of the most commonly prescribed SGAs. Bone changes are likely due to increased bone resorption, with little change in trabecular bone formation. However, periosteal circumference is also reduced after risperidone treatment, suggesting impaired periosteal osteoblast function. I have also found increased osteoclast size and number in primary bone marrow cultures treated with risperidone. I hypothesize that risperidone treatment alters whole-body metabolism and homeostasis in a manner that results in impaired bone health as well as acts directly on osteoblasts and osteoclasts to disrupt normal skeletal modeling and remodeling. I therefore propose two aims: (1) Examine the skeletal effects of 4-week risperidone administration in 8, 12 and 16 week old female mice and draw associations between bone changes and metabolic abnormalities, estrus cycling, and prolactin levels; I will also treat 4-week old mice for 4 weeks and observe changes in bone remodeling, metabolism and endocrine profiles until 20 weeks of age to determine if risperidone treatment in adolescents could permanently damage skeletal and metabolic homeostasis; (2) Test whether risperidone could have direct effects on osteoclast differentiation and function, osteoblast-dependent osteoclast recruitment, and/or osteoblast differentiation and function using in vitro primary bone cell culture and co-culture techniques. The results from these studies will establish the bone consequences of risperidone use, test whether indirect and/or direct effects of risperidone on bone cause these changes, and provide a stepping stone for future research on bone and metabolic effects of other SGAs. My results will also add to the increasing evidence for a key role of the nervous system in regulating skeletal homeostasis. PUBLIC HEALTH RELEVANCE: Second generation antipsychotics are indicated for use in adults, adolescents and children as young as five years old for major psychiatric disorders and irritability associated with autism. Risperidone is one such drug that causes hyperprolactinemia and obesity, and has recently been linked to reduced bone mineral density in patients. The proposed work will test whether uncoupled skeletal remodeling from risperidone is the result of metabolic and hormone-associated side effects and/or direct effects of risperidone on bone cells using C57BL/6 mice.