Pharmacology of Risperidone Effects on Bone Remodeling and Energy Metabolism

描述（由申请人提供）：第二代抗精神病药（SGA）被广泛用于治疗成人和儿童的精神疾病，是全球十大畅销药物之一。SGA的药理学是复杂的：它们有效地拮抗多种G蛋白偶联受体（GPCR），包括多巴胺、5-羟色胺、α-肾上腺素能和组胺受体。SGAs的副作用包括急性和慢性使用者中肥胖和2型糖尿病的发病率增加。最近的证据表明，SGAs也与骨折风险增加和骨密度降低有关;然而，导致这些严重内分泌副作用的潜在分子和药理学机制尚不清楚。儿童和青少年最容易受到代谢副作用的影响，在本提案中，我们假设骨骼在骨积累高峰期也很脆弱。因此，本提案的首要目标是阐明SGA诱导骨丢失的细胞/药理学机制，使用最广泛的处方，SGA，利培酮（RIS）。我们的新中心假设是RIS治疗与显著的骨丢失相关，并且这种不良副作用通过多种机制发生：1）通过与骨细胞直接相互作用并解偶联骨重建; [2]通过高泌乳素血症诱导性腺功能减退症]和3）通过调节交感神经系统向骨的输出。本项目的目标是：1）确定SGAs是否对破骨细胞和成骨细胞生物学有直接影响; 2）检查RIS治疗对体内能量代谢网络的影响; 3）确定影响是否至少部分由交感神经系统（SNS）和/或性腺功能减退介导;和4）确定RIS对骨的有害作用是否可以通过机制导向的共同治疗来改善。为了实现这些目标，我们将采用药理学的方法来探索RIS的特异性受体结合作用的功能后果，以及泌乳素保留的SGAs奥氮平和氯氮平，使用成骨细胞和破骨细胞培养在体外，并在体内使用建立的小鼠模型RIS诱导的骨丢失。我们还将探讨阻断剂或双膦酸盐联合治疗是否可以改变RIS对骨和能量代谢的不良影响。最后，我们策略的一个重要部分涉及持续监测血浆和骨髓中的药物暴露（RIS及其活性代谢产物，9-OH RIS），以了解与RIS治疗的不良内分泌副作用相关的药代动力学/药效学关系。这些研究都是创新和协作，利用我们的跨学科研究团队的互补优势（药理学，药物代谢，内分泌学，骨生物学，糖尿病和神经科学）。这些新的机制药理学研究的结果可能有助于告知有关SGA处方和患者监测实践的公共卫生政策，并可能有助于告知处方联合治疗的策略，以最大限度地减少弱势患者人群的副作用。

DESCRIPTION (provided by applicant): Second generation anti-psychotics (SGAs) are widely prescribed to treat psychiatric disorders in adults and children and are among the 10 top selling medications world-wide. The pharmacology of SGAs is complex: they potently antagonize multiple G protein coupled receptors (GPCRs) including dopamine, serotonin, alpha- adrenergic and histamine receptors. Side effects of SGAs include increased incidence of obesity and type 2 diabetes among both acute and chronic users. Recent evidence indicates that SGAs are also associated with increased fracture risk and reduced bone mineral density; however the underlying molecular and pharmacological mechanisms leading to these severe endocrine side effects are unknown. Children and adolescents are the most susceptible to metabolic side effects, and in this proposal we hypothesize, that the skeleton is also vulnerable during the time of peak bone accrual. Thus the over-arching goal of this proposal is to elucidate the cellular/pharmacological mechanisms underlying SGA-induced bone loss, using the most widely prescribed, SGA, risperidone (RIS). Our novel central hypothesis is that RIS therapy is associated with significant bone loss, and this adverse side effect occurs via multiple mechanisms: 1) by directly interacting with bone cells and uncoupling bone remodeling; [2) via hyper-prolactinemia induced hypogonadism] and 3) by modulating the sympathetic nervous system output to bone. The goals of this project are to 1) determine whether SGAs have direct effects on osteoclast and osteoblast biology; 2) to examine the effect of RIS treatment in vivo on the skeletal-energy metabolism network, 3) determine if effects are mediated, at least in part by the sympathetic nervous system (SNS) and/or hypogonadism; and 4) to determine if detrimental effects of RIS on bone can be ameliorated with mechanism-directed co-therapy. To achieve these goals we will employ a pharmacologic approach to explore the functional consequence of specific receptor binding effects of RIS, and prolactin-sparing SGAs olanzapine and clozapine, using osteoblast and osteoclast culture in vitro, and in vivo by using established mouse models of RIS-induced bone loss. We will also explore whether ¿-blocker or bisphosphonate co-therapy can alter adverse effects of RIS on bone and energy metabolism. Finally, an important part of our strategy involves continuous monitoring of drug exposure (RIS and its active metabolite, 9-OH RIS) in plasma and bone marrow in order to gain understanding of the pharmacokinetic/pharmacodynamic relationships associated with adverse endocrine side effects of RIS therapy. These studies are both innovative and collaborative, capitalizing on the complementary strengths (pharmacology, drug metabolism, endocrinology, bone biology, diabetes, and neuroscience) of our interdisciplinary research team. Results of these novel mechanistic pharmacology studies may help inform public health policy concerning SGA prescribing and patient monitoring practices and may help inform strategies for prescribing co-therapies in order to minimize side effects in vulnerable patient populations.