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
We are proposing two innovative studies to evaluate whether medications that inhibit the renin-angiotensin- aldosterone system (RAAS) can serve as a novel medical treatment for patients with primary hyperparathyroidism (P-HPTH), and as a method to lower the risk of developing future P-HPTH, low bone mineral density, and skeletal fracture. Our studies will involve: 1) A randomized placebo-controlled intervention of 60 participants to evaluate whether a conventional mineralocorticoid receptor antagonist, to block the effect of aldosterone, can lower parathyroid hormone as a method to treat individuals with P-HPTH; 2) A large-scale prospective study of more than 140,000 women to evaluate whether the use of RAAS inhibitors decreases the risk of developing P-HPTH, osteopenia or osteoporosis, and skeletal fragility fractures of the wrist, hip, and vertebrae. We expect our studies to produce new public health insights into the prevention and treatment of parathyroid and skeletal disorders that are highly prevalent, particularly in women and with advanced age.
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