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1.  Immunoreactive Forms of Circulating Parathyroid Hormone in Primary and Ectopic Hyperparathyroidism 
Journal of Clinical Investigation  1974;54(1):175-181.
The immunoreactive forms of parathyroid hormone (iPTH) in the plasma of six patients with primary, adenomatous hyperparathyroidism and six patients with ectopic hyperparathyroidism due to non-parathyroid cancer were compared by using gel filtration on columns of Bio-Gel P-150 and radioimmunoassay of iPTH in eluted fractions after concentration. We found much less (p<0.001) small (mol wt<9,500) COOH-terminal fragments of iPTH in plasma samples from ectopic hyperparathyroid patients (0.52±0.13 ng eq/ml) than in samples from primary hyperparathyroid patients (3.70±1.15 ng eq/ml). The quantity of iPTH eluting with or before native bovine PTH [1-84] was the same in both syndromes (ectopic hyperparathyroidism, 0.82±0.22 ng eq/ml; primary hyperparathyroidism, 0.73±0.09 ng eq/ml), and these values correlated positively with plasma calcium concentration (ectopic hyperparathyroidism, r=0.908; primary hyperparathyroidism, r=0.919). In both syndromes, plasma samples had an iPTH component that eluted well before PTH [1-84] (mol wt 9,500), but this component was present in much larger quantities in three patients with ectopic hyperparathyroidism. We conclude that (a) the decreased quantity of biologically inactive COOH-terminal fragments of iPTH circulating in ectopic hyperparathyroidism accounts for the previously reported relatively lower total serum iPTH values in this syndrome as compared with primary hyperparathyroidism (Riggs et al. 1971. J. Clin. Invest. 50: 2079); (b) there appears to be sufficient iPTH with presumed biologic activity to account for the hypercalcemia in both syndromes; (c) a large PTH component, not previously recognized in plasma, is present in both ectopic and primary hyperparathyroidism and may exist as the predominant immunoreactive form of the hormone in some patients with ectopic hyperparathyroidism.
PMCID: PMC301537  PMID: 4834887
2.  Acute Parathyroid Hormone Response to Epinephrine In Vivo 
Journal of Clinical Investigation  1973;52(10):2434-2440.
The acute effects of epinephrine, norepinephrine, and isoproterenol on the plasma immunoreactive parathyroid hormone (iPTH) response were studied in 13 550-600 kg cows. Catecholamines were infused for 7.0 min. During epinephrine infusions at 0.08 μmol/min iPTH increased from 0.48±0.12 (mean±SE, ng/ml) to 1.09±0.18 ng/ml (P < 0.02). Small increases in plasma free fatty acids and glucose could be detected with 0.08 μmol/min epinephrine; the iPTH response to epinephrine was as sensitive as the free fatty acid and glucose responses and possibly of physiological importance. Plasma calcium (total and ionized) and magnesium did not change.
The responses were more pronounced at 0.8 μmol/min epinephrine with a mean iPTH increase from 0.49±0.16 ng/ml to 1.74±0.35 ng/ml (P < 0.01). Small decreases in plasma calcium occurred at 0.8 μmol/min epinephrine, but the plasma magnesium remained unchanged. However, when the plasma calcium was lowered with ethylene glycol bis(β-aminoethyl ether)-N, N′-tetraacetic acid (EGTA), a much more pronounced lowering of the plasma calcium was required to produce comparable increases of the plasma iPTH concentrations than when epinephrine was infused. It appears that epinephrine has a direct effect on the release of iPTH from the parathyroid glands.
Simultaneous infusions of calcium and epinephrine suppressed the stimulation by epinephrine. This points towards a common mechanism of the regulation of parathyroid hormone secretion caused by decreases in the extracellular calcium concentration and/or alterations in the distribution of calcium within parathyroid cells following the administration of epinephrine.
The iPTH response to epinephrine was suppressed in the presence of propranolol. Isoproterenol was less active in raising iPTH than epinephrine, and norepinephrine was the least active. The stimulation by isoproterenol and the suppression by propranolol suggest beta adrenergic receptor sites within the parathyroid glands.
PMCID: PMC302502  PMID: 4729041
3.  Effect of dietary phosphorus on circulating concentrations of 1,25-dihydroxyvitamin D and immunoreactive parathyroid hormone in children with moderate renal insufficiency. 
Journal of Clinical Investigation  1984;73(6):1580-1589.
The hyperparathyroidism characteristic of patients with moderate renal insufficiency could be caused by decreases in the plasma concentration of ionized calcium (Ca++) evoked by: (a) recurring increases in the plasma concentration of inorganic phosphorus that may be detectable only in the post-prandial period; (b) a reversible, phosphorus-mediated suppression of renal 25-hydroxyvitamin D-1 alpha-hydroxylase that decreases the plasma concentration of 1,25-dihydroxyvitamin D (1,25-(OH)2D) enough to decrease both gut absorption and bone resorption of Ca++; (c) both of these. In a group of eight children with moderate renal insufficiency, mean glomerular filtration rate (GFR) 45 +/- 4 (SE) ml/min per 1.73 M2, ages 6-17 yr, we tested these hypotheses by determining the effect of short term (5 d) restriction and supplementation of dietary intake of phosphorus on the plasma concentration of 1,25-(OH)2D, the serum concentrations of immunoreactive parathyroid hormone (iPTH) and phosphorus, and the fractional renal excretion of phosphorus ( FEPi ). When dietary phosphorus was normal, 1.2 g/d, the serum concentrations of phosphorus throughout the day were not greater than those of normal control children, and the serum concentrations of carboxyl-terminal iPTH (C-iPTH) were greater, 59 +/- 9 vs. 17 +/- 3 mu leq/ml, and unchanging; the serum concentration of intact-iPTH was also greater, 198 +/- 14 vs. 119 +/- 8 pg/ml. The plasma concentration of 1,25-(OH)2D was lower than that of age-matched controls, 27 +/- 3 vs. 36 +/- 2 pg/ml (P less than 0.01). When dietary phosphorus was restricted to 0.35 g/d, the plasma concentration of 1,25-(OH)2D increased by 60% to a mean value not different from that of normal controls, while serum concentrations of C-iPTH and intact-iPTH decreased by 25%, the latter concentration to a mean value not different from that of controls. FEPi decreased from 31 to 9%. When dietary phosphorus was supplemented to 2.4 g/d, the plasma concentration of 1,25-(OH)2D decreased 32%, while those of C-iPTH and intact-iPTH increased by 131 and 45%, respectively; FEPi increased from 27 to 53%. Plasma concentrations of 25-hydroxyvitamin D remained normal and unchanged, and GFR did not change when dietary phosphorus was manipulated. The data demonstrate that in children with moderate renal insufficiency: (a) A normal dietary intake of phosphorus in attended by a decreased circulating concentration of 1,25-(OH)2D and an increased concentration of iPTH, but not by recurring increases in the serum concentration of phosphorus at any time of the day; (b) Dietary phosphorus is, however, a major determinant of the circulating concentrations of both 1,25-(OH)2D and iPTH, which vary inversely and directly, respectively, with dietary intake of phosphorus, and increase and decrease, respectively, to normal values when phosphorus is restricted for 5 d; (c) Restriction and supplementation of dietary phosphorus induces changes in the serum concentration of iPTH that correlate strongly but inversely with those induced in the plasma concentration of 1,25-(OH)2D (r = -0.88, P < 0.001); and (d) The physiologic responsiveness of the renal tubule to changes in dietary phosphorus is to a substantial extent intact. The data provide support for the second hypothesis stated.
PMCID: PMC437069  PMID: 6547151
4.  Reversal of Secondary Hyperparathyroidism by Cimetidine in Chronically Uremic Dogs 
Journal of Clinical Investigation  1981;67(6):1753-1760.
Chronic cimetidine therapy has been shown to suppress circulating concentrations of immunoreactive parathyroid hormone (iPTH) in hemodialysis patients. To evaluate the long-term metabolic effects of cimetidine treatment, we studied seven chronically uremic dogs for 20 wk. The dogs were studied under metabolic conditions before, during, and after cimetidine therapy. iPTH fell progressively in the five treated dogs from 536±70 μleq/ml (mean±SE) (nl < 100 μleq/ml) before treatment to 291±25 μleq/ml at 12 wk (P < 0.001) and 157±32 μleq/ml at 20 wk (P < 0.001). The control dogs showed no consistent change in iPTH. The fall in iPTH was not associated with a change in serum ionized calcium. However, serum phosphorus decreased from 5.7±0.9 mg/dl to 3.4±0.2 mg/dl by the 20th wk (P < 0.05). By contrast, the serum concentration of 1,25-dihydroxycholecalciferol increased in all treated dogs from 33.4±4.3 pg/ml to 51.8±2.4 pg/ml during treatment (P < 0.01). Calcium balance was negative in all seven dogs before cimetidine (−347±84 mg/72 h) and remained so in the control dogs; it became positive in the five treated dogs after 12 wk (1,141±409 mg/72 h) (P < 0.05). Phosphorus balance, 24-h fractional phosphate excretion, and creatinine clearance remained unchanged. Pooled samples of serum obtained during the control and 20th wk of therapy were fractionated by gel filtration and the eluates assayed for immunoreactivity. The decrease in iPTH was associated with a decrease in all the immunoreactive species, indicating suppression of parathyroid gland secretion.
These observations indicate that cimetidine suppressed circulating concentration of biologically active parathyroid hormone. A probable net decrease in the loss of phosphorus from bone to blood ensued, resulting in a fall in serum phosphorus. This may have stimulated synthesis of 1,25-dihydroxycholecalciferol and led to a positive calcium balance, thereby maintaining the serum ionized calcium concentration. The maintenance of phosphate balance, despite suppression of iPTH by cimetidine, indicates that factors other than hyperparathyroidism relate to phosphate homeostasis in chronically uremic dogs.
PMCID: PMC370753  PMID: 7240419
Journal of Clinical Investigation  1974;54(2):287-296.
Serum immunoreactive parathyroid hormone (iPTH) and plasma total calcium, ionized calcium, magnesium, and phosphorus levels were determined during the first 9 days of life in 137 normal term infants, 55 “sick” infants, and 43 hypocalcemic (Ca <7.5 mg/100 ml; Ca++<4.0 mg/100 ml) infants.
In the cord blood, elevated levels of plasma Ca++ and Ca were observed, while levels of serum iPTH were either undetectable or low. In normal newborns during the first 48 h of life there was a decrease in plasma Ca and Ca++, while the serum iPTH level in most samples remained undetectable or low; after 48 h there were parallel increases in plasma Ca and Ca++ and serum iPTH levels. Plasma Mg and P levels increased progressively after birth in normal infants.
In the sick infants, plasma Ca, Ca++ and P levels were significantly lower than in the normal newborns, while no significant differences were found in the plasma Mg levels. The general pattern of serum iPTH levels in the sick infants was similar to that observed in the normal group, though there was a tendency for the increase in serum iPTH to occur earlier and for the iPTH levels to be higher in the sick infants.
In the hypocalcemic infants, plasma Mg levels were consistently lower than in the normal infants after 24 h of age, while no significant differences were found in the plasma P levels. Hyperphosphatemia was uncommon and did not appear to be a contributing factor in the pathogenesis of hypocalcemia in most infants. Most of the hypocalcemic infants, including those older than 48 h, had inappropriately low serum iPTH levels.
Evidence obtained from these studies indicates that parathyroid secretion is normally low in the early new born period and impaired parathyroid function, characterized by undetectable or low serum iPTH, is present in most infants with neonatal hypocalcemia. Additional unknown factors appear to contribute to the lowering of plasma Ca in the neonatal period. The net effect of unknown plasma hypocalcemic factor(s) on the one hand and parathyroid activity on the other may account for differences in plasma Ca levels observed between normal, sick, and hypocalcemic infants. Depressed plasma Mg is frequently present in hypocalcemic infants. To what degree the hypomagnesemia reflects parathyroid insufficiency or the converse, to what degree parathyroid insufficiency and hypocalcemia are secondary to hypomagnesemia, is uncertain.
PMCID: PMC301556  PMID: 4858778
6.  Efficacy and safety of oral doxercalciferol in the management of secondary hyperparathyroidism in chronic kidney disease stage 4 
Indian Journal of Nephrology  2013;23(4):271-275.
This study was carried out to evaluate the efficacy and safety of doxercalciferol as therapy for secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) stage 4 in a prospective clinical trial. A total of 35 CKD-4 patients who had a baseline parathyroid hormone (iPTH) >150 pg/mL and had not received any vitamin D analog in the preceding 8 weeks were followed up at intervals of 6 weeks for 18 weeks on oral therapy with doxercalciferol. The starting dose was 1.5 μg/day, and the dose was increased in steps of 1 μg/day if iPTH did not decrease by at least 30% on the subsequent visit. Doxercalciferol was stopped temporarily if low iPTH (<70 pg/mL), hypercalcemia (>10.7 mg/dL), or severe hyperphosphatemia (>8.0 mg/dL) occurred, and was restarted at a lower dose on reversal of these abnormalities. Calcium acetate was the only phosphate binder used. Mean iPTH decreased by 35.4 ± 4.4% from 381.7 ± 31.3 pg/mL to 237.9 ± 25.7 pg/mL (P < 0.001). The proportion of patients who achieved 30% and 50% suppression of iPTH levels was 83% and 72%, respectively. Mean serum calcium, phosphorus, and calcium-phosphorus product values did not differ significantly from the baseline values. Four, two, and nine patients developed hypercalcemia, severe hyperphosphatemia, and high CaxP (>55), respectively. Almost all patients recovered to an acceptable level within 2 weeks of stopping doxercalciferol and adjusting the phosphate binder dose. In all, 21 patients required temporary stoppage of therapy. Most of them were restarted on therapy at a reduced dose during the study. It can, therefore, be concluded that doxercalciferol is effective in controlling SHPT in CKD-4 patients with an acceptable risk of hyperphosphatemia and hypercalcemia.
PMCID: PMC3741971  PMID: 23960343
Chronic kidney disease; doxercalciferol; parathyroid hormone; pre-dialysis; secondary hyperparathyroidism; vitamin D
7.  Correlates of parathyroid hormone concentration in hemodialysis patients 
Nephrology Dialysis Transplantation  2013;28(6):1516-1525.
The implications of chemical hyperparathyroidism on bone and mineral metabolism measures in maintenance hemodialysis (MHD) are not well known. We hypothesized that a higher serum intact parathyroid hormone (iPTH) level is associated with the higher likelihood of hyperphosphatemia, hyperphosphatasemia [high serum alkaline phosphatase (ALP) levels] and hypercalcemia.
Over an 8-year period (July 2001–June 2009), we identified 106 760 MHD patients with iPTH and calcium (Ca), phosphorous (P) and ALP data from a large dialysis clinic. Logistic regression models were examined to assess the association between serum iPTH increments and the likelihood of hyperphosphatemia (P ≥5.5 mg/dL), hypercalcemia (Ca ≥10.2 mg/dL) and hyperphosphatasemia (ALP ≥120 U/L).
Patients were 61 ± 16 years old and included 45% women, 59% diabetics and 33% Blacks. Compared with an iPTH level of 100 to <200 pg/mL, patients with an iPTH level of 600–700, 700 to <800 and ≥800 pg/mL had 122% (OR: 2.22, 95% CI: 2.04–2.41), 153% (OR: 2.53, 95% CI: 2.29–2.80) and 243% (OR: 3.43, 95% CI: 3.22–3.66) higher risk of hyperphosphatemia, respectively, and had 109% (OR: 2.09, 95% CI: 1.93–2.26), 130% (OR: 2.30, 95% CI: 2.10–2.52) and 376% (OR: 4.76, 95% CI: 4.50–5.04) higher risk of hyperphosphatasemia, respectively. Compared with an iPTH level of 100 to <200 pg/mL, both the low iPTH (<100 pg/mL, OR: 2.45, 95% CI: 2.27–2.64) and the high iPTH (≥800 pg/mL: OR: 2.13, 95% CI: 1.95–2.33) levels were associated with hypercalcemia.
Higher levels of iPTH are incremental correlates of hyperphosphatemia and hyperphosphatasemia, whereas both very low and high PTH levels are linked to hypercalcemia. If these associations are causal, correction of hyperparathyroidism may have overarching implications on bone and mineral disorders in MHD patients.
PMCID: PMC3685307  PMID: 23348879
hemodialysis; serum alkaline phosphatase; serum calcium; serum intact parathyroid hormone; serum phosphorous
8.  Immunoheterogeneity of Parathyroid Hormone in Venous Effluent Serum from Hyperfunctioning Parathyroid Glands 
Journal of Clinical Investigation  1977;60(6):1367-1375.
The immunoreactive parathyroid hormone (iPTH) in the plasma of hyperparathyroid man consists largely of carboxyl (COOH)-terminal fragments of the hormone. Although these fragments have been thought to arise principally or solely from peripheral metabolism of intact human PTH {hPTH(1-84)} secreted from the parathyroid gland, there is disagreement about the source of iPTH fragments in vivo.
To reexamine this question, we fractionated peripheral and thyroid or parathyroid venous effluent sera from four patients with primary hyperparathyroidism using a high-resolution gel filtration system (Bio-Gel P-150 columns run by reverse flow). The column effluents were analyzed using two PTH radioimmunoassays, one directed toward the amino(NH2)-terminal region of the molecule, the other toward the COOH-terminal region.
In all four thyroid or parathyroid venous effluent sera studied, iPTH was 9-180 times higher than in peripheral serum from the same patient; after fractionation, hPTH(1-84) accounted for only a portion of the total iPTH (35-55% with the assay directed toward the COOH-terminal region of hPTH, >90% with the NH2-terminal directed assay.) The remaining iPTH eluted from Bio-Gel P-150 after hPTH(1-84) as NH2-or COOH-terminal hPTH fragments. These results suggest that parathyroid tumors secrete large quantities of hPTH fragments. Based on estimates of their molar concentrations in serum, tumor-secreted COOH-terminal hPTH fragments could account for most of these peptides in peripheral serum if their survival times were, as estimated by several other workers, 5-10 times that of hPTH(1-84).
We conclude that, in contrast to published information, secretory products of hyperfunctioning parathyroid tissue are probably a major source of serum PTH immunoheterogeneity.
PMCID: PMC372494  PMID: 915003
9.  Impact of mineral and bone disorder on healthcare resource use and associated costs in the European Fresenius medical care dialysis population: a retrospective cohort study 
BMC Nephrology  2012;13:140.
Secondary hyperparathyroidism (SHPT) is associated with mortality in patients with chronic kidney disease (CKD), but the economic consequences of SHPT have not been adequately studied in the European population. We assessed the relationship between SHPT parameters (intact parathyroid hormone [iPTH], calcium, and phosphate) and hospitalisations, medication use, and associated costs among CKD patients in Europe.
The analysis of this retrospective cohort study used records of randomly selected patients who underwent haemodialysis between January 1, 2005 and December 31, 2006 at participating European Fresenius Medical Care facilities in 10 countries. Patients had ≥ 1 iPTH value recorded, and ≥ 1 month of follow-up after a 3-month baseline period during which SHPT parameters were assessed. Time at risk was post-baseline until death, successful renal transplantation, loss to follow-up, or the end of follow-up. Outcomes included cost per patient-month, rates of hospitalisations (cardiovascular disease [CVD], fractures, and parathyroidectomy [PTX]), and use of SHPT-, diabetes-, and CVD-related medications. National costs were applied to hospitalisations and medication use. Generalised linear models compared costs across strata of iPTH, total calcium, and phosphate, adjusting for baseline covariates.
There were 6369 patients included in the analysis. Mean ± SD person-time at risk was 13.1 ± 6.4 months. Patients with iPTH > 600 pg/mL had a higher hospitalisation rate than those with lower iPTH. Hospitalisation rates varied little across calcium and phosphate levels. SHPT-related medication use varied with iPTH, calcium, and phosphate. After adjusting for demographic and clinical variables, patients with baseline iPTH > 600 pg/mL had 41% (95% CI: 25%, 59%) higher monthly total healthcare costs compared with those with iPTH in the K/DOQI target range (150–300 pg/mL). Patients with baseline phosphate and total calcium levels above target ranges (1.13–1.78 mmol/L and 2.10–2.37 mmol/L, respectively) had 38% (95% CI: 27%, 50%) and 8% (95% CI: 0%, 17%) higher adjusted monthly costs, respectively. Adjusted costs were 25% (95% CI: 18%, 32%) lower among patients with baseline phosphate levels below the target range. Results were consistent in sensitivity analyses.
These data suggest that elevated SHPT parameters increase the economic burden of CKD in Europe.
PMCID: PMC3504570  PMID: 23106934
10.  Acute metabolic acidosis enhances circulating parathyroid hormone, which contributes to the renal response against acidosis in the rat. 
Journal of Clinical Investigation  1990;86(2):430-443.
Acute PTH administration enhances final urine acidification in the rat. HCl was infused during 3 h in rats to determine the parathyroid and renal responses to acute metabolic acidosis. Serum immunoreactive PTH (iPTH) concentration significantly increased and nephrogenous adenosine 3H,5H-cyclic monophosphate tended to increase during HCl loading in intact and adrenalectomized (ADX) rats despite significant increments in plasma ionized calcium. Strong linear relationships existed between serum iPTH concentration and arterial bicarbonate or proton concentration (P less than 0.0001). Serum iPth concentration and NcAMP remained stable in intact time-control rats and decreased in CaCl2-infused, nonacidotic animals. Urinary acidification was markedly reduced in parathyroidectomized (PTX) as compared with intact rats during both basal and acidosis states; human PTH-(1-34) infusion in PTX rats restored in a dose-dependent manner the ability of the kidney to acidify the urine and excrete net acid. Acidosis-induced increase in urinary net acid excretion was observed in intact, PTX, and ADX, but not in ADX-thyroparathyroidectomized rats. We conclude that (a) acute metabolic acidosis enhances circulating PTH activity, and (b) PTH markedly contributes to the renal response against acute metabolic acidosis by enhancing urinary acidification.
PMCID: PMC296745  PMID: 2166755
11.  The Relationship Between Technetium-99m-Methoxyisobutyl Isonitrile Parathyroid Scintigraphy and Hormonal and Biochemical Markers in Suspicion of Primary Hyperparathyroidism 
Objective: Technetium-99m-methoxyisobutyl isonitrile (Tc-99m MIBI) has been widely used to evaluate hyperfunctioning autonomous parathyroid glands in patients with elevated intact parathyroid hormone (iPTH) and/or calcium (Ca) level. The aim of this study was to evaluate the relationship between Tc-99m MIBI parathyroid scintigraphy and hormonal and biochemical markers in suspicion of primary hyperparathyroidism (PHPT).
Material and Methods: Dual-phase Tc-99m MIBI parathyroid scintigraphy and total serum iPTH, Ca, phosphorus (P) and albumin measurements were performed in 60 patients (52 females, 8 males; mean age, 59.38±12.51 years; range, 34 to 86 years) with suspicion of PHPT.
Results: The iPTH median level was 160.3 pg/mL (47.8 to 782.6). Thirty-five of the patients had surgical resection of hyperfunctioning parathyroid glands. Of the 35 patients, parathyroid gland pathology was detected in 30 patients using scintigraphic examination. Tc-99m MIBI parathyroid scintigraphy was negative in 30 patients. The iPTH, Ca and P levels were significantly different between in the Tc-99m MIBI positive group and the negative group, respectively: For iPTH, 202.1 (47.8-782.6) pg/mL versus 111.6 (80.1-373) pg/mL; p<0.001. For Ca, 11.7±1.15 mg/dL versus 10.3±1.05 mg/dL; p<0.001 and for P levels, 2.46±0.62 mg/dL versus 3.40±0.70 mg/dL; p<0.001). There was no significant difference in serum albumin levels between the MIBI positive and MIBI negative groups (4.25±0.27 g/dL versus 4.25±0.41 g/dL; p>0.05). Tc-99m MIBI parathyroid scintigraphy showed good correlation with iPTH level and histopathological diagnosis. Sensitivity and specificity was found 83.3% and 76.7%, respectively at the level of iPTH>147.7pg/mL.
Conclusion: Tc-99m MIBI parathyroid scintigraphy is most likely to produce identification and localization of a parathyroid adenoma when both iPTH and Ca are elevated as well as decreased P levels.
Conflict of interest:None declared.
PMCID: PMC3629790  PMID: 23610725
Technetium-99m sestamibi; primary hyperparathyroidism; parathyroid hormone; calcium; phosphorus
12.  A randomized, double-blind, placebo-controlled trial of calcium acetate on serum phosphorus concentrations in patients with advanced non-dialysis-dependent chronic kidney disease 
BMC Nephrology  2011;12:9.
Hyperphosphatemia in patients with chronic kidney disease (CKD) contributes to secondary hyperparathyroidism, soft tissue calcification, and increased mortality risk. This trial was conducted to examine the efficacy and safety of calcium acetate in controlling serum phosphorus in pre-dialysis patients with CKD.
In this randomized, double-blind, placebo-controlled trial, 110 nondialyzed patients from 34 sites with estimated GFR < 30 mL/min/1.73 m2 and serum phosphorus > 4.5 mg/dL were randomized to calcium acetate or placebo for 12 weeks. The dose of study drugs was titrated to achieve target serum phosphorus of 2.7-4.5 mg/dL. Serum phosphorus, calcium, iPTH, bicarbonate and serum albumin were measured at baseline and every 2 weeks for the 12 week study period. The primary efficacy endpoint was serum phosphorus at 12 weeks. Secondary endpoints were to measure serum calcium and intact parathyroid hormone (iPTH) levels.
At 12 weeks, serum phosphorus concentration was significantly lower in the calcium acetate group compared to the placebo group (4.4 ± 1.2 mg/dL vs. 5.1 ± 1.4 mg/dL; p = 0.04). The albumin-adjusted serum calcium concentration was significantly higher (9.5 ± 0.8 vs. 8.8 ± 0.8; p < 0.001) and iPTH was significantly lower in the calcium acetate group compared to placebo (150 ± 157 vs. 351 ± 292 pg/mL respectively; p < 0.001). At 12 weeks, the proportions of subjects who had hypocalcemia were 5.4% and 19.5% for the calcium acetate and the placebo groups, respectively, while the proportions of those with hypercalcemia were 13.5% and 0%, respectively. Adverse events did not differ between the treatment groups.
In CKD patients not yet on dialysis, calcium acetate was effective in reducing serum phosphorus and iPTH over a 12 week period.
Trial Registration NCT00211978.
PMCID: PMC3055808  PMID: 21324193
13.  Immunologic differentiation of primary hyperparathyroidism from hyperparathyroidism due to nonparathyroid cancer 
Journal of Clinical Investigation  1971;50(10):2079-2083.
Serum immunoreactive parathyroid hormone (IPTH) was measured by radioimmunoassay in 54 patients with primary hyperparathyroidism and in 18 consecutive patients with ectopic hyperparathyroidism due to nonparathyroid cancer without apparent skeletal metastasis. Although serum calcium concentration was higher in the group with ectopic hyperparathyroidism, serum IPTH was lower (rank sum test, P < 0.001) and was undetectable in eight. A second anti-PTH antiserum also differentiated between IPTH in the two groups, although IPTH was undetectable in only 1 of 14 sera. When IPTH values in serial dilutions were plotted, slopes for the two patients with ectopic hyperparathyroidism who had relatively high IPTH were less (P < 0.001) than slopes for standard hyperparathyroid sera. By using differences in either IPTH rank or slope of the dilutional curve of sera, primary hyperparathyroidism could be excluded as a cause of the hypercalcemia in 16 of the 18 patients with ectopic hyperparathyroidism. The data are interpreted as indicating that PTH-like material in the serum of these patients with ectopic hyperparathyroidism is immunologically different from the PTH in the serum of patients with primary hyperparathyroidism.
PMCID: PMC292141  PMID: 4330004
14.  Evidence for Skeletal Resistance to Parathyroid Hormone in Magnesium Deficiency 
Journal of Clinical Investigation  1979;64(5):1238-1244.
Hypocalcemia during magnesium (Mg) depletion has been well described, but the precise mechanism(s) responsible for its occurrence is not yet fully understood. The hypocalcemia has been ascribed to decreased parathyroid hormone (PTH) secretion as well as skeletal resistance to PTH. Whereas the former is well established, controversy exists as to whether or not Mg depletion results in skeletal resistance to PTH. These studies examine the skeletal response to PTH in normal dogs and dogs fed a Mg-free diet for 4-6 mo. Isolated tibia from normal (serum Mg 1.83±0.1 mg/100 ml) and experimental dogs (serum Mg 1.34±0.15 mg/100 ml) were perfused with Krebs-Henseleit buffer during a constant infusion of 3 ng/ml of synthetic bovine PTH 1-34 (syn b-PTH 1-34). The arteriovenous (A-V) difference for immunoreactive PTH (iPTH) across seven normal bones was 37.5±3%. In contrast, the A-V difference for iPTH was markedly depressed to 10.1±1% across seven bones from Mg-depleted dogs. These findings correlated well with a biological effect (cyclic AMP [cAMP] production) of syn b-PTH 1-34 on bone. In control bones, cAMP production rose from a basal level of 5.8±0.2 to 17.5±0.7 pmol/min after syn b-PTH 1-34 infusion. In experimental bones, basal cAMP production was significantly lower than in controls, 4.5±0.1 pmol/min, and increased to only 7.1±0.4 pmol/min after syn b-PTH 1-34 infusion. Even when PTH concentrations were increased to 20 ng/ml, cAMP production by experimental bones was lower than in control bones perfused with 3 ng/ml. Histological examination of bones from Mg-deficient dogs showed a picture compatible with skeletal inactivity. These studies demonstrate decreased uptake of iPTH and diminished cAMP production by bone, which indicates skeletal resistance to PTH in chronic Mg deficiency.
PMCID: PMC371269  PMID: 227929
15.  Response of bone metabolism related hormones to a single session of strenuous exercise in active elderly subjects 
Objective: To evaluate the effect of strenuous exercise on bone metabolism and related hormones in elderly subjects.
Methods: Twenty one active elderly subjects (11 men and 10 women; mean age 73.3 years) showing a mean theoretical Vo2max of 151.4% participated. Concentrations of plasma ionised calcium (iCa), serum intact parathyroid hormone (iPTH), 25-hydroxyvitamin D (25(OH)D), and 1.25-dihydroxy-vitamin D3 (1.25(OH)2D3), as well as the bone biochemical markers type I collagen C-telopeptide for bone resorption and osteocalcin and bone alkaline phosphatase for bone formation, were analysed before and after a maximal incremental exercise test.
Results: At basal level, iPTH was positively correlated with age (r = 0.56, p<0.01) and negatively correlated with 25(OH)D (r = –0.50; p<0.01) and 1.25(OH)2D3 (r = –0.47; p<0.05). Moreover, 25(OH)D and 1.25(OH)2D3 levels were negatively correlated with age (r = –0.50, p<0.01 and r = –0.53, p<0.01, respectively). After exercise, iCa and 25(OH)D decreased (p<0.001 and p = 0.01, respectively) while iPTH increased (p<0.001). The levels of 1.25(OH)2D3, bone biochemical markers, haematocrit, and haemoglobin were unchanged. The variations in iCa and 25(OH)D were not related to age and/or sex. The iPTH variation was directly related to basal iPTH levels (p<0.01) and indirectly related to age.
Conclusions: In active elderly subjects, strenuous exercise disturbed calcium homeostasis and bone related hormones without immediate measurable effect on bone turnover. Although an increase in iPTH could have an anabolic action on bone tissue, our findings from our short term study did not allow us to conclude that such action occurred.
PMCID: PMC1725278  PMID: 16046330
16.  Etiology of hyperparathyroidism and bone disease during chronic hemodialysis 
Journal of Clinical Investigation  1971;50(3):599-605.
Plasma concentration of immunoreactive parathyroid hormone (IPTH) was measured in 18 patients who had been on a hemodialysis program for longer than 6 months. A negative correlation was found between the predialysis plasma concentration of IPTH and the mean concentration of calcium in the dialysate previously used: plasma concentrations of IPTH were higher in patients dialyzed against a calcium concentration between 4.9 and 5.6 mg/100 ml than in patients dialyzed against a calcium concentration of 6.0 mg/100 ml or more. Plasma concentrations of IPTH also were higher in patients with bone disease than in patients without bone disease. Furthermore, a positive correlation was found between predialysis plasma concentrations of IPTH and calcium, and between mean predialysis concentration of IPTH and phosphate. To obviate the possibility that individual differences in susceptibility could have accounted for the observed effects of plasma phosphate and of dialysate calcium, a 2 × 2 factorial study was conducted in seven of these patients to examine the independent effects of perturbation of each of these factors. It was observed that plasma concentration of IPTH was lowest with the combination of high dialysate calcium and low plasma phosphate, highest with the combination of low dialysate calcium and high plasma phosphate, and intermediate with the two other combinations. It is concluded that both dialysate calcium and plasma phosphate are important determinants of parathyroid function in these patients.
PMCID: PMC291968  PMID: 5545122
17.  Hypertension and hyperparathyroidism are associated with left ventricular hypertrophy in patients on hemodialysis 
Indian Journal of Nephrology  2009;19(4):153-157.
Conflicting data for association between left ventricular hypertrophy (LVH) and secondary hyperparathyroidism has been reported previously among dialysis patients. The present study was conducted to evaluate the association of hyperparathyroidism and hypertension with LVH. Charts of 130 patients on hemodialysis for at least six months were reviewed. All were subjected to M-mode echocardiography. Left ventricular mass (LVM) was calculated by Devereux's formula. LVM Index (LVMI) was calculated by dividing LVM by body surface area. Sera were analyzed for intact parathyroid hormone (iPTH). iPTH of > 32 pmol/l and a mean blood pressure (MAP) of > 107 mmHg were considered high. Patients were stratified into groups according to their MAP and iPTH. A total of (47.7%) patients were males and 68 (52.3%) were females. Their median age was 57 years. The median duration on dialysis was 26 months. Forty eight (36.9%) patients had high BP and 54 (41.5%) had high iPTH. Both high BP and high iPTH were present in 38 (29.2%) patients. Analysis of the relationship between LVM, LVMI, MAP and iPTH showed that LVM and LVMI were significantly (P < 0.001) higher in patients with concomitant high BP and high iPTH. LVMI was significantly higher in patients with high iPTH alone. Concomitant high iPTH and high MAP increase the risk of LVH in hemodialysis patients. High iPTH alone might contribute in escalating LVH. Adequate control of hypertension and hyperparathyroidism might reduce the risk of developing LVH.
PMCID: PMC2875705  PMID: 20535251
Hemodialysis; hypertension; hyperparathyroidism; left ventricular hypertrophy
18.  The pattern of the descent of PTH measured by intraoperative monitoring of intact-PTH in surgery for renal hyperparathyroidism 
The Indian Journal of Surgery  2008;70(2):62-67.
In the setting of total parathyroidectomy and autotransplantation surgery (TPTxAS) treatment for secondary hyperparathyroidism (SHPT) we evaluated whether intraoperative parathyroid hormone (iPTH) monitoring is an useful tool as a reference for total parathyroid removal.
Prospective open single value measurement efficacy study of one intraoperative (i.o.) diagnostic monitoring method (iPTH) on a cohort of surgical patients.
All patients (n = 35) undergoing TP and SCTx at the Department of Surgery, Donostia Hospital from January 2002 to December 2006.
Main outcome measures
Serum levels of iPTH during surgery and prediction time of the of descent of PTH levels (measured in the clinic, at admission day and intra-operatively during induction of anesthesia, and every 5 and 10 minutes after removal of adenoma and 24 hours thereafter) were analyzed.
iPTH levels dropped clearly at ten minutes in all 35 patients and were non-measurable at 24 hours. iPTH decreased from pathological (1302.24 + 424.9 pg/ml) to half (50%) the values at the third intra-operative determination — minute 10 − (614.8 ± 196.62) and was undetectable at 24 hours.
Intra-operative measurement of iPTH is useful in the prediction of complete removal of all parathyroid tissue prior to autotransplantation thus avoiding persistence because of incomplete surgery.
PMCID: PMC3452396  PMID: 23133023
Total parathyroidectomy; Autotransplantation surgery; Secondary hyperthyroidism; Parathyroid hormone
Journal of Clinical Investigation  1974;54(6):1382-1394.
Antibodies to a urea-trichloroacetic acid extract [hPTH-(TCA)] of human parathyroid tumors and to the synthetic NH2-terminal fragments of human parathyroid hormone hPTH-(1-12) and -(1-34) were developed in goats to characterize immunochemically various PTH preparations and to estimate immunoreactive PTH (iPTH) in human sera. They were quantitated on the basis of their capacity to bind [131I]-hPTH-(1-12), [131I]hPTH-(1-34) or [131I]bovine PTH (bPTH-(1-84)). The quality of the antibodies was assessed by reference to inhibition of their interaction with labeled peptides by synthetic hPTH comprising 34 NH2-terminal amino acid residues or fragments thereof [hPTH-(1-12), -(13-34), -(18-34), -(25-34), -(18-24)] or by the Sephadex G-100-purified full-length peptide hPTH-(1-84) [hPTH-(1-84)G-100]. The synthetic peptides used in this work correspond in their structure to the NH2-terminal amino acid sequence 1-34, as elucidated by Brewer and collaborators (1972. Proc. Natl. Acad. Sci. U. S. A.69: 3583-3588). Inhibition studies were also carried out with bPTH-(1-34) and bPTH-(1-84). Anti-hPTH-(TCA) exhibited specificities directed to determinants in the COOH-terminal and NH2-terminal part of hPTH-(1-84) and exhibited cross-reactivity with bPTH-(1-84). Anti-hPTH-(1-34), on the other hand, showed immunological specificities mainly directed to antigenic determinants located in the COOH-terminal half of hPTH-(1-34). In addition, some reactivity with the NH2-terminal hPTH-(1-12) and with the extractive full-length peptides of human and bovine origin was observed. Antibodies to hPTH-(1-12) cross-reacted with hPTH-(1-34) and -(1-84)G-100.
iPTH was radioimmunologically determined in human sera by the following systems: (a) [131I]bPTH-(1-84), anti-hPTH-(TCA) and hPTH-(1-84)G-100 as standard; (b) [131I]hPTH-(1-34), anti-hPTH-(1-34) and hPTH-(1-34) as standard. With system (a), COOH-terminal fragments of hPTH-(1-84) having a molecular weight of approximately 7,000 were detected, and there was an almost total discrimination of serum iPTH levels in normal and in hyperparathyroid subjects. With system (b), on the other hand, several molecular species of iPTH were detected, including a component larger than hPTH-(1-84) and others similar to hPTH-(1-84) and to a fragment co-eluting with the NH2-terminal fragment hPTH-(1-34). When serum iPTH was assayed in system (b), there was a large overlap of iPTH levels in control subjects and in patients with primary hyperparathyroidism.
PMCID: PMC301693  PMID: 4474187
20.  Serum calcitonin-lowering effect of magnesium in patients with medullary carcinoma of the thyroid. 
Journal of Clinical Investigation  1975;56(6):1615-1621.
The effect of magnesium chloride or magnesium sulfate infusion on circulating levels of immunoreactive calcitonin (iCT) was evaluated on nine occasions in three patients with metastatic medullary carcinoma of the thyroid. One patient was normocalcemic and had normal circulating levels of immunoreactive parathyroid hormone (iPTH), one patient was hypocalcemic and had surgical hypoparathyroidism, and one patient had mild to moderate hypercalcemia associated with bone metastases. The basal serum iPTH levels were undetectable in the latter two patients. In every instance magnesium administration produced a rapid and striking fall in circulating iCT and usually a detectable fall in serum calcium. During the hypermagnesemic state, serum iPTH fell from normal to undetectable in the patient with normal parathyroid function, while serum iPTH levels remained undetectable in the hypoparathyroid patient and in the patient with hypercalcemia associated with bone metastases. The results of these studies indicate that: (a) contrary to what has been reported in normal experimental animals, magnesium administration lowers circulating iCT in human subjects with thyroid medullary carcinoma and (b) the calcium-lowering effect produced by magnesium in patients with medullary carcinoma may, in part at least, be due to a redistribution of body calcium that is not mediated by the actions of either parathyroid hormone or clacitonin.
PMCID: PMC333141  PMID: 1202087
21.  Effects of paricalcitol on calcium and phosphate metabolism and markers of bone health in patients with diabetic nephropathy: results of the VITAL study 
Nephrology Dialysis Transplantation  2013;28(9):2260-2268.
Chronic kidney disease (CKD) is associated with elevations in serum phosphate, calcium–phosphorus product and bone-specific alkaline phosphatase (BAP), with attendant risks of cardiovascular and bone disorders. Active vitamin D can suppress parathyroid hormone (PTH), but may raise serum calcium and phosphate concentrations. Paricalcitol, a selective vitamin D activator, suppressed PTH in CKD patients (stages 3 and 4) with secondary hyperparathyroidism (SHPT) with minimal changes in calcium and phosphate metabolism.
The VITAL study enrolled patients with CKD stages 2–4. We examined the effect and relationship of paricalcitol to calcium and phosphate metabolism and bone markers in a post hoc analysis of VITAL. The study comprised patients with diabetic nephropathy enrolled in a double-blind, placebo-controlled, randomized trial of paricalcitol (1 or 2 μg/day). Urinary and serum calcium and phosphate, serum BAP, and intact PTH (iPTH) concentrations were measured throughout the study.
Baseline demographics and calcium, phosphate, PTH (49% with iPTH <70 pg/mL), and BAP concentrations were similar between groups. A transient, modest yet significant increase in phosphate was observed for paricalcitol 2 μg/day (+0.29 mg/dL; P < 0.001). Dose-dependent increases in serum and urinary calcium were observed; however, there were few cases of hypercalcemia: one in the 1-μg/day group (1.1%) and three in the 2-μg/day group (3.2%). Significant reductions in BAP were observed that persisted for 60 days after paricalcitol discontinuation (P < 0.001 for combined paricalcitol groups versus placebo). Paricalcitol dose-dependent reductions in iPTH were observed. Paricalcitol in CKD patients (±SHPT) was associated with modest increases in calcium and phosphate.
Paricalcitol reduces BAP levels, which may be beneficial for reducing vascular calcification.
Trial registration
Trial is registered with, number NCT00421733.
PMCID: PMC3769981  PMID: 23787544
bone-specific alkaline phosphatase; calcitriol; hypercalcemia; hyperphosphatemia; paricalcitol; vitamin D receptor activation
22.  Intact PTH Combined With the PTH Ratio for Diagnosis of Bone Turnover in Dialysis Patients: A Diagnostic Test Study 
Determination of parathyroid hormone (PTH) is the most commonly used surrogate marker for bone turnover in stage 5 chronic kidney disease patients on dialysis (CKD-5D patients). The objective of the current study was to evaluate the predictive value of various PTH measurements for identifying low or high bone turnover rate.
Study design
Diagnostic test study.
Settings & Participants
141 CKD-5D patients from 15 US hemodialysis centers.
Index Tests
Intact PTH, PTH 1–84, and PTH ratio (ratio of level of PTH 1–84 to level of large carboxy-terminal PTH fragments).
Reference Test or Outcome
Bone turnover determined by bone histomorphometry
Other Measurements
Demographic and treatment related factors, serum calcium and phosphorus.
Histologically, patients presented with a broad range of bone turnover abnormalities. In White patients (n=70), the iPTH cut-off of >420 pg/ml resulted in classifying 84% of the patients correctly as high turnover. A PTH ratio <1.0 when added to an intact PTH <420 pg/ml increased the positive predictive value for low bone turnover from 74% to 90% in these patients. In Black patients (n=71), adding a PTH ratio <1.2 to an intact PTH <340pg/ml increased the positive predictive value for low bone turnover from 48% to 90%. Adding a PTH ratio >1.6 to an intact PTH between 340 and 790 pg/ml increased the positive predictive value for high bone turnover from 56% to 71%.
Since the research protocol called for carefully controlled blood specimen handling, drawing of blood and routine specimen handling might be less stringent in clinical practice. By limiting study participation to Black and White CKD-5D patients, we cannot comment on the roles of intact PTH, PTH 1–84 and the PTH ratio in other racial/ethnic groups.
In Black CKD-5D patients, addition of the PTH ratio to intact PTH measurements is helpful for diagnosing low and high bone turnover. In White CKD-5D patients, it aids in the diagnosis of low bone turnover.
PMCID: PMC2882243  PMID: 20347512
23.  High-intensity focussed ultrasound (HIFU) treatment in uraemic secondary hyperparathyroidism 
The recently developed non-invasive high-intensity focussed ultrasound (HIFU) technique for the destruction of parathyroid adenomas could also be of interest for the treatment of secondary hyperparathyroidism (SHP) in patients with chronic kidney disease (CKD). We conducted a pilot study using this method.
Five chronic haemodialysis patients with severe SHP underwent one to three HIFU treatments, respectively. They had at least one or two enlarged parathyroid glands, which were accessible to this technique.
In Patients 1-I and 5-V, serum intact parathyroid hormone (iPTH) could be successfully reduced in the long run. In Patient 3-N, serum iPTH decreased dramatically down to the normal range but increased again subsequently. In Patients 2-E and 4-D, transient reductions in serum iPTH were also obtained but HIFU failed to correct SHP during follow-up. Serum total calcium and phosphorus decreased in four among the five patients, either transiently or permanently. Serum total alkaline phosphatases were reduced in four of five patients. Side effects included local oedema, transient impairment of vocal cord mobility and bitonal voice.
HIFU treatment may be of help in controlling SHP in selected patients with CKD. Further experience is clearly needed.
PMCID: PMC3276310  PMID: 22015443
chronic kidney disease; high-intensity focussed ultrasound; parathyroid ablation; secondary hyperparathyroidism
24.  Do current screening recommendations allow for early detection of lithium-induced hyperparathyroidism in patients with bipolar disorder? 
Current screening recommendations for early detection of lithium-associated hyperparathyroidism propose an exclusive measurement of serum albumin-adjusted calcium (Aac) concentration as a single first step. However, longitudinal data in patients with recurrent affective disorders suggest that increases in serum intact parathyroid hormone (iPTH) levels in lithium-treated patients may not necessarily be accompanied by a parallel increase in the concentration of Aac. If true, patients with an isolated increase in iPTH concentration above the reference range might be missed following current screening recommendations. Therefore, this study set out to examine key parameters of calcium metabolism, including iPTH and 25-hydroxycholecalciferol concentrations in patients with bipolar disorder that was or was not managed with lithium.
Sixty patients with bipolar disorder according to DSM-IV were enrolled, 30 of whom had received long-term lithium treatment (lithium group), whereas the other 30 patients were on psychopharmacological treatment not including lithium (non-lithium group) at the time of the study. Owing to exclusion criteria (e.g., lithium < 6 months, laboratory results indicative of secondary hyperparathyroidism), 23 bipolar patients composed the final lithium group, whereas 28 patients remained in the non-lithium group for statistical analyses.
Patients in the lithium group showed a significantly higher concentration of iPTH compared to the non-lithium group (p < 0.05). Similarly, Aac concentrations were significantly increased in the lithium group compared to the non-lithium group (p < 0.05). However, in a multivariate linear regression model, group affiliation only predicted iPTH concentration (p < 0.05). In line with this, none of the four patients in the lithium group with an iPTH concentration above the reference range had an Aac concentration above the reference range.
This study suggests that the biochemical characteristics between primary hyperparathyroidism and lithium-induced hyperparathyroidism differ substantially with regard to regulation of calcium homeostasis. As such, current screening practice does not reliably detect iPTH concentrations above the reference range. Therefore, further research is needed to elucidate the consequences of an isolated iPTH concentration above the reference range in order to develop the most appropriate screening tools for hyperparathyroidism in lithium-treated patients with bipolar disorder.
PMCID: PMC4230432  PMID: 25505674
Bipolar disorder; Lithium; Hyperparathyroidism; Calcium
25.  Parathyroid-Specific Deletion of Klotho Unravels a Novel Calcineurin-Dependent FGF23 Signaling Pathway That Regulates PTH Secretion 
PLoS Genetics  2013;9(12):e1003975.
Klotho acts as a co-receptor for and dictates tissue specificity of circulating FGF23. FGF23 inhibits PTH secretion, and reduced Klotho abundance is considered a pathogenic factor in renal secondary hyperparathyroidism. To dissect the role of parathyroid gland resident Klotho in health and disease, we generated mice with a parathyroid-specific Klotho deletion (PTH-KL−/−). PTH-KL−/− mice had a normal gross phenotype and survival; normal serum PTH and calcium; unaltered expression of the PTH gene in parathyroid tissue; and preserved PTH response and sensitivity to acute changes in serum calcium. Their PTH response to intravenous FGF23 delivery or renal failure did not differ compared to their wild-type littermates despite disrupted FGF23-induced activation of the MAPK/ERK pathway. Importantly, calcineurin-NFAT signaling, defined by increased MCIP1 level and nuclear localization of NFATC2, was constitutively activated in PTH-KL−/− mice. Treatment with the calcineurin-inhibitor cyclosporine A abolished FGF23-mediated PTH suppression in PTH-KL−/− mice whereas wild-type mice remained responsive. Similar results were observed in thyro-parathyroid explants ex vivo. Collectively, we present genetic and functional evidence for a novel, Klotho-independent, calcineurin-mediated FGF23 signaling pathway in parathyroid glands that mediates suppression of PTH. The presence of Klotho-independent FGF23 effects in a Klotho-expressing target organ represents a paradigm shift in the conceptualization of FGF23 endocrine action.
Author Summary
Inorganic calcium is a critical element for a diverse range of cellular processes ranging from cell signaling to energy metabolism, and its extracellular concentration is controlled by parathyroid hormone (PTH). Klotho is expressed in parathyroid chief cells and reported to facilitate PTH secretion during hypocalcemia and mediate FGF23 suppression of PTH synthesis and secretion. To dissect the role of parathyroid Klotho in health and disease, we generated parathyroid-specific Klotho knockout mice. The mutant mice had normal serum levels of PTH and calcium. Further, their parathyroid sensitivity to acute fluctuations in serum calcium and response to FGF23 treatment were preserved, and mutant mice developed secondary hyperparathyroidism of similar magnitude as wild-type mice when challenged with renal failure. A previously unknown parathyroid FGF23 signaling pathway involving calcineurin was constitutively activated in the mutant mice, and blocking this pathway abolished FGF23-induced suppression of PTH secretion. Our data challenges the concepts of Klotho as a mandatory factor for the acute hypocalcemic PTH response and decreased Klotho abundance as a pathogenic factor in secondary hyperparathyroidism. Finally, the presence of Klotho-independent FGF23 effects in a Klotho-expressing target organ represents a paradigm shift in the conceptualization of FGF23 endocrine action.
PMCID: PMC3861040  PMID: 24348262

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