Interactions Between Adrenal and Parathyroid Hormones in Human Health

肾上腺激素和甲状旁腺激素在人类健康中的相互作用

基本信息

批准号：
9144401
负责人：
Anand Vaidya
金额：
$ 48.93万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9144401
关键词：
Adrenal hormone preparation Aging Aldosterone Amiloride Angiotensinogen Angiotensins Blinded Bone Density Bone Resorption Calcium Cardiovascular Diseases Chronic Clinical Clinical Trials Cohort Studies Combined Modality Therapy Complement Data Development Disease Disease of parathyroid glands Diuretics Double-Blind Method Elderly Endocrine Epidemic Fracture Future Health Heart Diseases Hip region structure Homeostasis Human Hyperparathyroidism Individual Interruption Intervention Intervention Studies Life Expectancy Longitudinal Studies Mediating Mediator of activation protein Medical Methods Mineralocorticoid Receptor Nurses&apos Health Study Observational Study Osteopenia Osteoporosis Outcome PTH gene Parathyroid gland Participant Pathway interactions Patients Peptidyl-Dipeptidase A Pharmaceutical Preparations Placebo Control Placebos Potassium Prevalence Prevention Prospective Studies Public Health Publishing Randomized Renin Renin-Angiotensin-Aldosterone System Research Design Risk Risk Factors Role Serum Sodium Testing Therapeutic Tissues Vascular Diseases Woman bone turnover cardiovascular disorder risk cardiovascular health cardiovascular risk factor cinacalcet effective therapy eplerenone improved inhibitor/antagonist innovation insight mortality novel prevent prospective public health relevance response skeletal skeletal disorder spine bone structure wrist fracture

项目摘要

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

描述（由适用提供）：确定可减轻和/或治疗甲状旁腺和骨骼疾病的新的可修改生物学靶标可以大大改善公共卫生。甲状旁腺激素（PTH）物理调节钙稳态；然而，在连续超过的情况下，PTH降低了骨矿物质密度并增加了骨折的风险。原发性甲状旁腺功能亢进症（P-HPTH）是一种过度PTH的状态，在高级时代的患病率迅速上升，但对P-HPTH的病理生理理解却很差，医疗治疗有限。我们产生了新的证据，表明肾素 - 血管紧张素 - 醛固酮系统（RAAS）和PTH之间存在内分泌关系。醛固酮（Aldo）和矿物皮质激素受体（MR）是RAAS的关键介质。观察性研究表明，高的ALDO水平与发生骨质疏松症和脆弱性骨折的可能性更高，而使用MR拮抗剂可以阻止Aldo阻断Aldo。我们发表的初步数据表明，刺激RAA会增加PTH水平，并且对RAAS的药物抑制降低了PTH。为了扩大我们的强烈初步结果，该提案将检验两个假设：1）MR拮抗作用，以阻止Aldo的效果，是降低P-HPTH中PTH的一种机制；从而成为P-HPTH的新型医疗； 2）慢性RAAS抑制剂的使用降低了与甲状旁腺过度活跃性（入射P-HPTH）和流行性骨骼疾病相关的入射临床结果的风险，这些骨骼疾病可能会随着PTH的降低（低骨密度和脆弱性骨折）而改善。我们的创新研究目的包括一项临床试验，以检验假设1 AD进行大量纵向前瞻性研究，以检验假设2。 AIM 1涉及一项双盲和安慰剂对照的干预研究，其中60名患有P-HPTH的受试者将被随机分配以接收eplerenone（MR拮抗剂），氨基酯（一种不直接阻止MR）或安慰剂4周。预计与安慰剂和淀粉样纤维相比，eplerenone疗法将降低P-HPTH的PTH，血清钙和骨转换的标志物。随后，除了盲目的研究药物外，所有受试者都将用cinacalcet（一种降低PTH的钙化）治疗2周，以确定与eplerenone+cinacalcet组合治疗相比，与安慰剂+固定剂治疗相比，eplerenone+cinacalcet组合疗法是否会产生附加性或协同作用。 AIM 1的结果将证明MR拮抗作用，单独或与Cinacalcet结合使用，作为P-HPTH的一种潜在的新型药物疗法。 AIM 2将评估来自护士健康研究的> 140,000名参与者，然后评估长期使用RAAS抑制剂是否会降低发生P-HPTH，骨质疏松症或骨质疏松症以及脆弱性骨折的风险（手腕，髋关节，臀部，椎骨）。这项大型前瞻性研究的结果将在AIM 1中完成机械结果，并将突出显示