Interactions Between Adrenal and Parathyroid Hormones in Human Health

描述(由申请人提供)：确定新的可修改的生物靶点以缓解和/或治疗甲状旁腺和骨骼疾病可以显著改善公众健康。甲状旁腺激素(PTH)在生理上调节钙稳态；然而，在持续过量的情况下，PTH降低骨密度并增加骨折的风险。原发性甲状旁腺功能亢进症(P-HPTH)是甲状旁腺功能亢进的一种状态，在高龄人群中发病率迅速上升，但由于药物治疗有限，对该病的病理生理认识较差。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)和甲状旁腺激素之间存在内分泌关系。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更高相关，而使用MR拮抗剂阻断Aldo可能对骨折具有保护作用。我们已发表的和初步的数据表明，刺激RAAS可增加PTH水平，而药物抑制RAAS可降低PTH水平。为了扩大我们强有力的初步结果，这项提议将检验两个假设：1)MR拮抗，以阻断ALDO的作用，是降低P-HPTH中PTH的一个机制；从而成为治疗P-HPTH的新药物；2)长期使用RAAS抑制剂可降低发生与甲状旁腺过度活动(事件P-HPTH)和可能随着PTH降低而改善的流行骨骼疾病(骨密度低和脆性骨折)相关的临床结果的风险。我们的创新研究目标包括一项检验假说1的临床试验和一项检验假说2的大型纵向前瞻性研究。目的1包括一项双盲和安慰剂对照干预研究，其中60名患有P-HPTH的患者将被随机分为依普利酮(MR拮抗剂)、阿米洛利(一种不直接阻断MR的省钾利尿剂)或安慰剂，为期4周。与安慰剂和阿米洛利相比，预计依普利酮治疗将降低甲状旁腺激素、血钙和P-HPTH患者的骨转换指标。随后，所有受试者在接受盲法研究药物治疗的同时，还将接受两周以上的Cinacalcet(一种降低甲状旁腺素的仿钙剂)治疗，以确定与安慰剂Cinacalcet治疗相比，依普利酮Cinacalcet联合治疗是否会产生相加或协同作用。AIM 1的结果将证明MR拮抗，单独或与Cinacalcet结合，作为治疗P-HPTH的潜在的新药物疗法。AIM 2将评估来自护士健康研究的140,000名参与者，跟踪调查超过25年，以评估长期使用RAAS抑制剂是否降低发生P-HPTH、骨量减少或骨质疏松症以及脆性骨折(手腕、髋部、脊柱)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，并将突出

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