Human Interventions to Characterize Novel Relationships Between the Renin–Angiotensin–Aldosterone System and Parathyroid Hormone

Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based). The quote only partly states this claim.

Spironolactone therapy over 6 weeks modestly lowered PTH when compared to placebo (P<0.05).

“However, analyses comparing the change in these parameters induced by each intervention revealed a decrease in serum calcium and increase in PTH in the placebo group (possibly mediated by chronic and persistent vitamin D deficiency) that was significantly blunted by spironolactone treatment (Table 2, ANOVA P-value).”

May combine two claims.

Within each treatment arm, neither placebo nor spironolactone therapy significantly altered PTH, serum calcium, 25(OH)D, or markers of bone formation and resorption over 6 weeks.

“When comparing the pre- versus post-intervention effect of each treatment arm, neither placebo nor spironolactone therapy significantly altered the levels of PTH, serum calcium, 25(OH)D, or markers of bone formation and resorption over 6 weeks (Table 2).”

May combine two claims.

Both ACE inhibition and vitamin D3 therapy independently enhanced the PTH response to angiotensin II infusion.

“The role of AngII as the mediator of these effects was further supported by the fact that the regulation of PTH was influenced by interventions known to sensitize tissue-responsiveness to AngII4,33: both ACE inhibition and vitamin D3 therapy independently enhanced the PTH-response to AngII infusion.”

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mRNA levels of AT1R and MR were expressed in normal parathyroid tissue and increased 3-4-fold in adenomatous tissue.

“To further confirm AT1R and MR expression in parathyroid tissue, we quantified mRNA levels and observed expression in normal parathyroid tissue and a 3–4-fold increase in expression within adenomatous tissue (Supplementary Figure S1).”

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Infusion of angiotensin II at 1 ng/kg/min in a vitamin D deficient state acutely increased serum aldosterone by 148% and PTH by 10.3% from baseline.

“Infusion of AngII (1 ng/kg/min) in a vitamin D deficient state resulted in an expected rise in serum aldosterone (+148%) (as previously described)4, but also a +10.3% increase in PTH from baseline (Figure 1a).”

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A single dose of captopril acutely decreased serum aldosterone by 12% and PTH by 9.7% below basal levels in the vitamin D deficient state.

“A single dose of captopril lowered serum aldosterone levels (−12%) and also acutely lowered PTH below basal levels (−9.7%), and thereafter, a second infusion of AngII following captopril administration resulted in an enhanced stimulation of PTH (+16.0% from baseline) (Figure 1a).”

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Infusion of angiotensin II at 3 ng/kg/min induced larger increments in aldosterone (+241%) and a more robust PTH response (+36% from baseline) than the lower dose, independent of acute changes in serum calcium or 1,25-dihydroxyvitamin D.

“In comparison with Study 1, the infusion of 3 ng/kg/min of AngII resulted in greater increments in aldosterone (+241%) and a more robust PTH-response (+36% from baseline), which were independent of any acute changes in serum calcium or 1,25-dihydroxyvitamin D (1,25[OH]2D) concentrations (Figure 1c).”

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Aldosterone infusion (0.7 μg/kg/hr) robustly raised serum aldosterone (+892%) without modifying PTH when compared to vehicle.

“The infusion of aldosterone resulted in a robust increase in serum aldosterone concentration (+892%) that was substantially higher than that induced by AngII infusions in Studies 1 and 2, as well as non-significant trends of increased blood pressure and decreased potassium. However, PTH was not modified by the infusion of aldosterone when compared to vehicle (Supplementary Table S1).”

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The effect of chronic spironolactone therapy was evident within the treatment group via increments in aldosterone concentrations and decrements in blood pressure.

“The effect of chronic spironolactone therapy was evident within the treatment group via increments in aldosterone concentrations and decrements in blood pressure (Table 2).”

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The PTH response to angiotensin II was further enhanced in the same subjects following vitamin D3 therapy, which also marginalized the influence of captopril on subsequent angiotensin II infusions.

“The PTH-response to AngII was further enhanced in the same subjects following vitamin D3 therapy, which also marginalized the influence of captopril on subsequent AngII infusions (presumptively due to maximal suppression of the endogenous tissue-RAAS with vitamin D3 therapy)4.”

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The results demonstrate that raising circulating angiotensin II and aldosterone acutely stimulates PTH in a dose-dependent manner, while lowering endogenous angiotensin II and aldosterone acutely with an ACE inhibitor lowers PTH.

“Our results demonstrate that raising circulating AngII and aldosterone acutely stimulates PTH in a dose-dependent manner, while lowering endogenous AngII and aldosterone acutely with an ACE inhibitor lowers PTH (Supplementary Table S2: columns a+b - (see http://hyper.ahajournals.org).”

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The study has demonstrated new pleiotropic relationships between RAAS components and PTH that may have important implications for the treatment of PTH-mediated disorders.

“Despite the notable limitations of our methods (the use of 4 small and separate study populations of obese individuals, post hoc analyses, and the absence of data on ionized and urinary calcium that could help uncover underlying mechanisms), we have nonetheless demonstrated new pleiotropic relationships between RAAS components and PTH that may have important implications for the treatment of PTH-”

Probably not a substantial claim: may not pass S3 (load-bearing).

In Study 4, the 27 subjects with available blood and urine were selected for analyses prior to un-blinding of their intervention status or knowledge of their intervention outcomes.

“These 27 subjects were selected for our analyses prior to un-blinding of their intervention status or knowledge of their intervention outcomes.”

Classified as probably not a substantial claim. May combine two claims.

Aldosterone action through the mineralocorticoid receptor may impact PTH over the long-term by influencing PTH synthesis directly at the parathyroid gland and/or indirectly via renal regulation of calcium handling.

“Since we, along with Maniero et al10, have identified the presence of MR in normal and abnormal parathyroid tissue, we speculate that aldosterone action through the MR may impact PTH over the long-term by influencing PTH synthesis directly at the parathyroid gland and/or indirectly via renal regulation of calcium handling.”

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The identification of AT1R in normal and adenomatous human parathyroid tissue is a novel finding that further supports an acute and direct effect of angiotensin II on PTH.

“Our identification of AT1R in normal and adenomatous human parathyroid tissue is a novel finding that further supports an acute and direct effect of AngII on PTH; we speculate that given the acuity of the findings, AngII may regulate the secretion of pre-formed PTH.”

May combine two claims.

The blunted sensitivity to angiotensin II could be corrected by lowering the tissue-RAAS with an ACE inhibitor or vitamin D3 therapy.

“We previously showed that vitamin D deficiency blunts tissue-responsiveness to exogenous AngII by inducing a state of high tissue-RAAS activity4,6,31; this blunted sensitivity to AngII could be corrected by lowering the tissue-RAAS with an ACE inhibitor or vitamin D3 therapy4,33.”

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The sample sizes were small but were more than sufficient to detect robust changes in PTH in Studies 1 and 2 and expected changes in serum aldosterone levels and blood pressure due to aldosterone infusion and spironolactone.

“The sample sizes were small but were more than sufficient to detect robust changes in PTH (Studies 1 and 2) and expected changes in serum aldosterone levels and blood pressure due to aldosterone infusion (Study 3) and spironolactone (Study 4).”

Classified as probably not a substantial claim.

Prior research has shown that chronic aldosterone excess results in hypercalciuria and hypocalcemia.

“Although we did not have urine calcium measurements in this study, prior research has shown that chronic aldosterone excess results in hypercalciuria and hypocalcemia16,38,39.”

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The subjects in all four studies were overweight or obese, as previously reported, but had comparable 25-hydroxyvitamin D concentrations.

“The subjects in all four studies were overweight or obese, as previously reported4, but had comparable 25-hydroxyvitamin D (25[OH]D) concentrations (Table 1).”

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When integrated with Study 1, an incremental relationship between the RAAS and PTH was observed, modulated by angiotensin II dose, ACE inhibition, and vitamin D status.

“When integrated with the findings from Study 1 (Figure 1a–c), an incremental relationship between the RAAS and PTH was observed, which was modulated by AngII dose, as well as by ACE inhibition and vitamin D status (both of which sensitize the tissue responsiveness to AngII infusion)4,6,31–33.”

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Angiotensin II appears to be an acute modulator of PTH, potentially through direct stimulation of PTH release via the AT1R at the parathyroid gland.

“AngII appears be an acute modulator of PTH, potentially through direct stimulation of PTH release via the AT1R at the parathyroid gland.”

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The acute modulation of PTH by the RAAS appears to be mediated by angiotensin II, whereas the long-term influence of the RAAS on PTH may involve aldosterone.

“We observed novel pleiotropic relationships between RAAS components and the regulation of PTH in individuals without PA: the acute modulation of PTH by the RAAS appears to be mediated by AngII, whereas the long-term influence of the RAAS on PTH may involve aldosterone.”

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In Study 4, chronic mineralocorticoid receptor antagonism may have modestly lowered PTH and raised serum calcium.

“In our Study 4, chronic MR antagonism may have modestly lowered PTH and raised serum calcium.”

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Overall, the findings suggest pleiotropic effects of RAAS components on PTH that may vary with time of exposure.

“Overall, our findings suggest pleiotropic effects of RAAS components on PTH that may vary with time of exposure.”

Probably not a substantial claim: may not pass S2 (checkable).

Identifying whether PTH is regulated by angiotensin II, aldosterone, or both could have implications for pharmacologic therapies.

“Identifying whether PTH is regulated by AngII, or aldosterone, or both, could have implications for pharmacologic therapies.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The observed effect of spironolactone on PTH may have reflected a mild progressive secondary hyperparathyroidism in the placebo group due to chronic vitamin D deficiency that was blunted by spironolactone.

“This phenomenon may have reflected a mild progressive secondary hyperparathyroidism in the placebo group due to chronic vitamin D deficiency that was blunted by spironolactone.”

May combine two claims.

Although the studies were performed in separate populations, these populations were similar across demographic variables and, though obese, were otherwise largely healthy.

“Although the studies were performed in separate populations, as necessitated by the complex protocols performed in Clinical Research Centers, these populations were similar across demographic variables and though obese, were otherwise largely healthy.”

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

The reestablishment of the PTH-RAAS equilibrium may be most evident in physiologic states where both calcium- and sodium-regulatory hormones can modulate their activity appropriately.

“The reestablishment of the PTH-RAAS equilibrium may be most evident in physiologic states where both calcium- and sodium-regulatory hormones can modulate their activity appropriately.”

May combine two claims.

In endocrine systems, the absolute circulating level of any hormone may not be sufficient to evaluate biologic and clinical outcomes; the setting of a new homeostatic equilibrium may not be detected by circulating levels alone.

“Although we used PTH levels as our outcome, it is important to realize that in endocrine systems, where feedback mechanisms are complex, the absolute circulating level of any hormone may not be sufficient to evaluate biologic and clinical outcomes; the setting of a new homeostatic equilibrium may not be detected by circulating levels alone.”

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

All variables presented were normally distributed and were not transformed in any way.

“All variables presented were normally distributed and were not transformed in any way.”

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Despite an acute 10-fold increase in serum aldosterone concentrations in Study 3, PTH remained unchanged, implicating angiotensin II as the primary stimulus for PTH in the acute setting.

“However, despite an acute 10-fold increase in serum aldosterone concentrations in Study 3, PTH remained unchanged (Table S2: column d), implicating AngII as the primary stimulus for PTH in the acute setting.”