Interactions Between Adrenal and Parathyroid Hormones in Human Health

描述（由申请人提供）：识别新的可修饰生物靶点以减轻和/或治疗甲状旁腺和骨骼疾病可以大大改善公共卫生。甲状旁腺激素（PTH）在生理上调节钙稳态;然而，在持续过量时，PTH会降低骨矿物质密度并增加骨折的风险。原发性甲状旁腺功能亢进症（P-HPTH）是一种在老年人中发病率迅速上升的PTH过量状态，但由于药物治疗有限，对P-HPTH的病理生理学认识不足。我们已经产生了新的证据表明，肾素-血管紧张素-醛固酮系统（RAAS）和PTH之间的内分泌关系。醛固酮（ALDO）和盐皮质激素受体（MR）是RAAS的重要介质。观察性研究表明，高ALDO水平与发生骨质疏松症和脆性骨折的可能性较高相关，而使用MR拮抗剂阻断ALDO可能对骨折有保护作用。我们已发表的和初步的数据表明，刺激RAAS增加PTH水平和药理学抑制RAAS降低PTH。为了扩展我们强有力的初步结果，本建议将检验两个假设：1）MR拮抗作用，阻断ALDO的作用，是降低P-HPTH中PTH的机制，从而作为P-HPTH的新药物治疗; 2）长期使用RAAS抑制剂降低了发生与甲状旁腺过度活动相关的偶发临床结果的风险（偶发P-HPTH）和可能随PTH降低而改善的流行性骨骼疾病（低骨密度和脆性骨折）。我们的创新研究目标包括一项临床试验来检验假设#1和一项大型纵向前瞻性研究来检验假设#2。目的1涉及一项双盲和安慰剂对照干预研究，其中60名P-HPTH受试者将随机接受依普利酮（一种MR拮抗剂）、阿米洛利（一种不直接阻断MR的保钾利尿剂）或安慰剂治疗4周。与安慰剂和阿米洛利相比，预期依普利酮治疗将降低P-HPTH中的PTH、血清钙和骨转换标志物。随后，所有受试者将在其设盲研究药物之外再接受西那卡塞（一种降低PTH的拟钙剂）治疗2周，以确定与安慰剂+西那卡塞治疗相比，依普利酮+西那卡塞联合治疗是否产生累加或协同效应。目的1的结果将证明MR拮抗作用，单独或与西那卡塞联合，作为一种潜在的新型药物治疗P-HPTH。目标2将评估来自护士健康研究的超过140，000名参与者，随访超过25年，以评估长期使用RAAS抑制剂是否降低发生P-HPTH事件，骨质减少或骨质疏松症和脆性骨折（手腕，臀部，椎骨）的风险。这项大型前瞻性研究的结果将补充目标1中的机制发现，并将强调

DESCRIPTION (provided by applicant): Identification of new modifiable biologic targets to mitigate and/or treat parathyroid and skeletal disorders could substantially improve public health. Parathyroid hormone (PTH) physiologically regulates calcium homeostasis; however, in continuous excess, PTH lowers bone mineral density and increases risk for fracture. Primary hyperparathyroidism (P-HPTH) is one such state of excess PTH with a rapidly rising prevalence in advanced age, yet the pathophysiologic understanding of P-HPTH is poor with limited medical treatments. We have generated novel evidence indicating an endocrine relationship between the renin-angiotensin- aldosterone system (RAAS) and PTH. Aldosterone (ALDO) and the mineralocorticoid receptor (MR) are the crucial mediators of the RAAS. Observational studies have suggested that high ALDO levels associate with a higher likelihood of developing osteoporosis and fragility fracture, whereas the use of MR antagonists to block ALDO may be protective of fracture. Our published and preliminary data demonstrate that stimulation of the RAAS increases PTH levels and that pharmacologic inhibition of the RAAS decreases PTH. To expand our strong preliminary results, this proposal will test two hypotheses: 1) MR antagonism, to block the effect of ALDO, is a mechanism to decrease PTH in P-HPTH; thereby serving as a novel medical treatment for P-HPTH; 2) Chronic RAAS inhibitor use decreases the risk of developing incident clinical outcomes associated with parathyroid over-activity (incident P-HPTH) and epidemic skeletal diseases that may improve with PTH lowering (low bone density and fragility fracture). Our innovative study aims include a clinical trial to test hypothesis #1 ad a large longitudinal prospective study to test hypothesis #2. Aim 1 involves a double-blinded and placebo-controlled intervention study where 60 subjects with P-HPTH will be randomized to receive eplerenone (an MR antagonist), amiloride (a potassium-sparing diuretic that does not directly block the MR), or placebo for 4 weeks. It is anticipated that eplerenone therapy will lower PTH, serum calcium, and markers of bone turnover in P-HPTH, when compared to placebo and amiloride. Subsequently, all subjects will be treated with cinacalcet (a calcimimetic that lowers PTH) for 2 more weeks, in addition to their blinded study medication, to determine whether eplerenone+cinacalcet combination therapy results in additive or synergistic effects when compared to placebo+cinacalcet therapy. The results of Aim 1 will demonstrate MR antagonism, alone or in combination with cinacalcet, as a potential novel medical therapy for P-HPTH. Aim 2 will evaluate >140,000 participants from the Nurses' Health Studies followed for more than 25 years, to assess whether chronic use of RAAS inhibitors decreases the risk of developing incident P-HPTH, osteopenia or osteoporosis, and fragility fractures (wrist, hip, vertebral). The results of this large prospective study will complement the mechanistic findings in Aim 1, and will highlight the