Pharmacology of Risperidone Effects on Bone Remodeling and Energy Metabolism

描述(申请人提供)：第二代抗精神病药物(SGAs)被广泛用于治疗成人和儿童的精神障碍，是全球最畅销的10种药物之一。SGAs的药理很复杂：它们有效地拮抗多种G蛋白偶联受体(GPCRs)，包括多巴胺、5-羟色胺、α-肾上腺素能和组胺受体。SGAS的副作用包括在急性和慢性使用者中肥胖和2型糖尿病的发生率增加。最近的证据表明，SGAs还与增加骨折风险和降低骨密度有关；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，在这项建议中，我们假设骨骼在骨积累高峰期也很脆弱。因此，这项建议的总体目标是使用最广泛的处方SGA利培酮(RIS)来阐明SGA导致骨丢失的细胞/药理学机制。我们新的中心假设是，RIS治疗与显著的骨丢失有关，这种副作用通过多种机制发生：1)通过直接与骨细胞相互作用和解偶联骨重建；(2)通过高催乳素血症导致性腺功能低下]和3)通过调节交感神经系统对骨的输出。该项目的目标是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)检测RIS体内治疗对骨骼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/或性腺功能减退所介导；以及4)确定RIS对骨骼的有害影响是否可以通过机制导向的联合治疗得到改善。为了实现这些目标，我们将采用药理学方法，通过体外成骨细胞和破骨细胞培养，以及通过建立RIS诱导性骨丢失的小鼠模型，探索RIS、非催乳素SGAs、奥氮平和氯氮平的特定受体结合效应的功能后果。我们还将探索阻滞剂或双膦酸盐联合治疗是否可以改变RIS对骨骼和能量代谢的不利影响。最后，我们战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。这些研究既创新又合作，充分利用了我们跨学科研究团队的互补优势(药理学、药物新陈代谢、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为有关SGA处方和患者监测做法的公共卫生政策提供信息，并可能有助于为开出联合疗法的策略提供信息，以便将脆弱患者群体的副作用降至最低。

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.