Project 3: Beta blockers and their impact on fracture risk in nursing home residents taking atypical antipsychotics

项目 3：β 受体阻滞剂及其对服用非典型抗精神病药物的疗养院居民骨折风险的影响

• 批准号: 10246811
• 负责人: CHRISTINE Woods Lary
• 金额: $ 32.72万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246811
• 关键词: Address; Adrenergic beta-Antagonists; Adult; Affect; Animal Model; Animals; Antipsychotic Agents; Basic Science; Behavioral Symptoms; Biochemical Pathway; Cardiovascular system; Centers of Research Excellence; Characteristics; Clinical; Clinical Research; Clinical Sciences; Complex; Data; Data Set; Databases; Dementia; Diagnosis; Elderly; Event; Exhibits; Exposure to; Fracture; Future; Gait; Geriatric Nursing; Heart Diseases; Heart failure; Hip Fractures; Hip region structure; Human; Hypertension; Hypotension; Individual; Lead; Left; Link; Measures; Mediating; Medicare Part A; Mesenchymal; Methods; Modeling; Molecular; Mus; Myocardial Ischemia; Nursing Homes; Observational Study; Osteoporotic; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Physiology; Population; Positioning Attribute; Problem behavior; Propranolol; Recommendation; Research; Risk; Risk Reduction; Risperidone; Scoring Method; Sedation procedure; Signal Pathway; Testing; Time; Variant; Work; atypical antipsychotic; base; bone; bone loss; falls; fracture risk; insight; member; mouse model; neuroregulation; novel; novel therapeutics; osteoporosis with pathological fracture; primary outcome; protective effect; psychiatric symptom; secondary outcome; skeletal; substantia spongiosa; translational study; treatment effect

Atypical antipsychotics (AAs), which are widely prescribed to manage psychiatric and behavioral symptoms in elderly adults in nursing home settings, are associated with an increased risk of bone fracture. The mechanism by which AAs increase fracture risk is not well understood, although recent evidence suggests molecular mechanisms that result in bone loss. β-blockers (BBs), which are widely prescribed to nursing home residents to manage cardiac disease and high blood pressure, have demonstrated effects to reduce fracture risk. The size of the risk reduction has been found to be dependent on BB class, with β1 selective blockers showing the greatest protective effect in most studies. The protective effect of BBs on fracture risk is also supported by animal studies, some of which have been completed by fellow team member and project leader in this COBRE (K. Motyl, Project 4). Our primary hypothesis is that concurrent BB use in incident AA users will result in a reduction in fracture risk, and we further hypothesize that the magnitude of this effect will vary with β1 selectivity. We propose a large observational study to measure the effect of concurrent BB use on fracture risk in elderly nursing home residents initiating AAs. Our clinical study will be supported by concomitant studies (K. Motyl) addressing bone physiology in a mouse model. We will analyze data from a large, national database of nursing home resident data with linked clinical characteristics from the Minimum Data Set and diagnosis and drug data from Medicare Parts A, B, and D for the majority of U.S. long- stay residents. In our first specific aim, we will test the hypothesis that patients initiating AA (termed AA initiates) in the nursing home with concurrent exposure to BBs will have a reduced risk of fracture. Our primary outcome will be hip fracture, and major osteoporotic fractures will be a secondary outcome. We will also analyze falls as another secondary outcome that lies along the causal pathway to fracture. We will make appropriate adjustments for imbalanced patient characteristics between BB users and non-users using propensity score methods, and use a novel time-to-event method that allows for modeling time-dependent exposure to BBs to allow for precise estimates of the effect of BB use. In our second specific aim we will estimate the within-class variation in the effect of BB on fractures and falls as a function of β1-selective vs. non-selective class. At the conclusion of this study we will discover whether BB exposure mitigates fracture risk associated with AA treatment, and show how that effect varies by class of BB drug. This study will inform animal model research and provide preliminary data for BB-based mechanisms for the treatment of AA-induced fracture risk in the nursing home setting.

非典型抗精神病药（AAs），广泛用于治疗精神和行为疾病 在养老院环境中的老年人的症状，与骨风险增加有关 骨折AA增加骨折风险的机制尚不清楚，尽管最近 有证据表明导致骨质流失的分子机制。β受体阻滞剂（BB），广泛用于 规定养老院居民管理心脏病和高血压， 已证实的降低骨折风险的效果。风险降低的幅度被发现是 依赖于BB类，β1选择性阻滞剂在大多数情况下显示出最大的保护作用。 问题研究BB对骨折风险的保护作用也得到了动物研究的支持，其中一些研究 已由该COBRE中的团队成员和项目负责人完成（K。Motyl，项目4）。 我们的主要假设是，事件AA使用者同时使用BB将导致 骨折的风险，我们进一步假设，这种影响的大小将与β1选择性。 我们提出了一项大型观察性研究，以测量同时使用BB对骨折风险的影响， 老人院居民主动提出AA。我们的临床研究将由伴随的 研究（K. Motyl）在小鼠模型中解决骨生理学。我们将分析一个大的， 全国养老院居民数据数据库与最低临床特征相关 数据集以及来自医疗保险A、B和D部分的诊断和药物数据，适用于大多数美国长期 留在居民。在我们的第一个具体目标中，我们将检验以下假设： AA发起者）在疗养院同时暴露于BB将降低骨折的风险。 我们的主要结局是髋部骨折，主要的腰椎骨折是次要结局。 我们还将分析福尔斯作为另一个次要结局，它沿着骨折的因果路径。 我们将对BB用户之间不平衡的患者特征进行适当调整， 非用户使用倾向评分方法，并使用一种新的时间到事件的方法，允许 对BB的时间依赖性暴露进行建模，以精确估计BB使用的影响。在我们 第二个具体目标是，我们将估计BB对骨折和福尔斯影响的类内变化 作为β1选择性与非选择性类别的函数。在这项研究的最后，我们将发现 BB暴露是否减轻了与AA治疗相关的骨折风险，并说明其效果如何 因BB类药物而异。这项研究将为动物模型研究提供信息，并提供初步数据 在疗养院环境中治疗AA诱导骨折风险的BB机制。