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1.  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
2.  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
3.  An iPTH based protocol for the prevention and treatment of symptomatic hypocalcemia after thyroidectomy 
The Journal of surgical research  2013;186(1):10.1016/j.jss.2013.09.026.
Symptomatic hypocalcemia after thyroidectomy is a barrier to same day surgery, and the cause of ER visits. A standard protocol of calcium and vitamin D supplementation, dependent on intact parathyroid hormone (iPTH) levels, can address this issue. How effective is it? When does it fail?
We performed a retrospective review of the prospective Thyroid Database from January 2006 to December 2010. 620 patients underwent completion (CT) or total thyroidectomy (TT), and followed our post-operative protocol of calcium carbonate administration for iPTH levels ≥10pg/ml and calcium carbonate and 0.25μg calcitriol BID for iPTH <10pg/ml. Calcium and iPTH values, pathology and medication, were compared to evaluate protocol efficacy. A p value <0.05 was considered statistically significant.
Using the protocol, sixty-one (10.2%) patients were chemically hypocalcemic but never developed symptoms and twenty-four (3.9%) patients developed breakthrough symptomatic hypocalcemia. The symptomatic (SX) and asymptomatic (ASX) groups were similar with regard to gender, cancer diagnosis, and pre-operative calcium and iPTH. The symptomatic group was significantly younger (39.6 ± 2.8 vs. 49 ± 0.6 years, p=0.01), with lower post-operative iPTH levels. 33% (n=8) of SX patients had an iPTH ≤5 pg/ml vs. only 6% (n=37) of ASX patients. While the majority of patients with a PTH <5 pg/ml were asymptomatic, 62.5% (n=5) of SX patients with iPTH levels ≤5 pg/ml, required an increased in calcitriol dose to achieve both biochemical correction and symptom relief.
Prophylactic calcium and vitamin D supplementation based on post-operative iPTH levels can minimize symptomatic hypocalcemia after thyroidectomy. An iPTH ≤ 5pg/ml may warrant higher initial doses of calcitriol in order to prevent symptoms.
PMCID: PMC3871885  PMID: 24144426
intact parathyroid hormone; symptomatic; hypocalcemia; protocol
4.  Etiology of Hyperparathyroidism and Bone Disease during Chronic Hemodialysis. III. EVALUATION OF PARATHYROID SUPPRESSIBILITY 
Journal of Clinical Investigation  1973;52(1):173-180.
Parathyroid function was assessed by calcium infusions (4-8 h) in 16 patients with chronic renal insufficiency being treated by long-term hemodialysis. The concentrations of two immunoreactive species of parathyroid hormone in plasma (iPTH-9, mol wt 9500; iPTH-7, mol wt 7000) were estimated by radioimmunoassays utilizing two relatively specific antisera. Control values of the smaller species, iPTH-7, were uniformly high, whereas values of iPTH-9 were normal in 12 of 19 studies. Response of iPTH-7 to calcium infusions was variable, with significant decreases occurring only five times in 27 infusions. Concentrations of iPTH-9, however, decreased during every calcium infusion. In contrast to these acute responses, five of six patients studied during periods of dialysis against both low (< 6 mg/100 ml) and high (7-8 mg/100 ml) calcium concentrations in the dialyzate showed a decrease in values of iPTH-7 during the period of dialysis against the higher calcium concentration. It is concluded that plasma concentrations of iPTH-9 reflect primarily the moment-to-moment secretory status of the parathyroid glands, while concentrations of iPTH-7 reflect more closely chronic parathyroid functional status. It is further concluded that the failure of iPTH-7 to decrease during induced hypercalcemia should not be equated with autonomy of parathyroid gland function.
PMCID: PMC302239  PMID: 4734166
5.  Inhibition of parathyroid hormone secretion and parathyroid hormone-independent diminution of tubular calcium reabsorption by WR-2721, a unique hypocalcemic agent. 
Journal of Clinical Investigation  1985;76(5):1851-1856.
Hypocalcemia has been observed in patients receiving WR-2721 [S-,2-(3-aminopropylamino)-, ethylphosphorothioic acid]. WR-2721 is a compound that, after being dephosphorylated, provides protection of normal tissues against radio- and chemotherapy. The hypocalcemic response was accompanied by a decrease in the plasma level of parathyroid hormone (PTH) and by hypomagnesemia. Our present studies in rats on the mechanism of the hypocalcemic effect of WR-2721 indicate that: (a) The phosphorylated and dephosphorylated form of WR-2721 induced an equal dose-dependent decrement in plasma calcium. (b) In intact rats a maximal hypocalcemic dose of WR-2721 reduced urinary cyclic AMP excretion from 70.5 +/- 6.3 to 38.2 +/- 3.1 pmol/ml glomerular filtration rate (GFR), a level comparable to that observed (35.9 +/- 5.2 pmol/ml GFR) in thyroparathyroidectomized (TPTX) rats. (c) WR-2721 given to TPTX rats did not significantly interfere with the calcemic effect of bovine PTH 1-34 infused at 2.5 IU/h. Likewise, the drug did not impair the PTH actions on the renal Ca and inorganic phosphate (Pi) handling, and on the urine cyclic AMP excretion. (d) In TPTX rats made normocalcemic by low Pi diet, the hypocalcemic effect of WR-2721 was only about 25% of that observed in intact animals. However, it was associated with increased urine Ca per milliliter GFR, indicating a PTH-independent inhibitory effect on tubular Ca reabsorption. (e) In WR-2721-treated intact rats, prevention of hypomagnesemia by infusing magnesium chloride did not reduce hypocalcemia. In conclusion, the hypocalcemic effect of WR-2721 is not dependent upon the presence of a phosphate group in the molecule and is not causally related to hypomagnesemia. WR-2721 appears to be a unique hypocalcemic pharmacologic agent with strong inhibitory activity on PTH secretion and additional PTH-independent action on renal Ca reabsorption.
PMCID: PMC424224  PMID: 2997292
6.  Clinical and laboratory characteristics of neonatal hypocalcemia 
To describe the clinical characteristics of full-term neonates with hypocalcemia and to suggest factors associated with neonatal hypocalcemia
The medical records of full-term neonates with hypocalcemia were reviewed. Hypocalcemia was defined as an ionized calcium (iCa) concentration of <4 mg/dL. Parathyroid hormone (PTH) insufficiency was defined as a serum PTH level of <60 pg/mL or a serum phosphorus level higher than the serum calcium level in the presence of hypocalcemia.
Fifty-three neonates were enrolled. The median age at diagnosis of hypocalcemia was 3 days. In all the neonates, formula feeding predominance was observed. Thirty-eight neonates (69.8%) were compatible with PTH insufficiency. The number of formula-fed neonates was significantly higher than that of breast-fed patients among neonates with PTH insufficiency (P=0.017). Intact PTH was negatively correlated with serum phosphorus levels. Twelve out of 14 neonates (85.7%) had 25-hydroxy vitamin D (25OHD) levels <20 ng/mL and 9 neonates (64.3%) had 25OHD levels <10 ng/mL. Twenty-one neonates had hypocalcemic tetany. The serum calcium and iCa concentrations of neonates with tetany were 4.2-8.3 mg/dL and 1.85-3.88 mg/dL, respectively. Three neonates showed symptomatic hypocalcemia with calcium levels over 7.5 mg/dL. Among the 16 neonates who underwent electroencephalography (EEG), 12 had abnormalities, which normalized after 1-2 months.
Formula milk feeding, PTH insufficiency and low serum vitamin D concentration are associated with the development of neonatal hypocalcemia. Symptoms such as tetany and QT interval prolongation can develop in relatively mild hypocalcemia. Moreover, transient neonatal hypocalcemia can cause transient EEG abnormalities.
PMCID: PMC4504995  PMID: 26191512
Hypocalcemia; Newborn infant; Parathyroid hormone; Tetany
7.  Serum Intact Parathyroid Hormone Level After Total Thyroidectomy or Total Thyroidectomy Plus Lymph Node Dissection for Thyroid Nodules: Report From 296 Surgical Cases 
Transient hypocalcemia is one of the postoperative complications of thyroidectomy for thyroid nodules, and intraoperative and postoperative intact parathyroid hormone (iPTH) assays are used to predict postoperative hypocalcemia.
The current study was conducted to evaluate a single serum iPTH measurement on postoperative day 1 (POD 1) as a means to predict hypocalcemia occurrence after total thyroidectomy (TT).
Patients and Methods
The subjects consisted of 36 patients who underwent TT and 260 patients who underwent TT plus lymph node (LN) dissection for thyroid nodules treatment. The TT performance procedure to prevent postoperative hypoparathyroidism combines parathyroid gland preservation in situ with autotransplantation of resected or devascularized parathyroid glands. The patients’ serum iPTH level was measured on POD 1, and their serum calcium level was measured on POD 1 and on POD 3 while they were still inpatients. The serum iPTH level was subequently measured at each outpatient clinic visit until it recovered to the normal range.
Hypoparathyroidism after TT and TT plus LN dissection was ultimately diagnosed in a total of 229 patients, and in 69 of them hypocalcemia was diagnosed on POD 1. All of the 69 patients diagnosed with hypocalcemia received calcium and vitamin D supplementation therapy. The serum iPTH level of 67 of 229 patients was within normal range on POD 1, and four of them developed hypocalcemia on POD 1. Permanent hypoparathyroidism developed in 37 of 296 patients after undergoing TT or TT plus LN dissection for thyroid nodules in the hospital.
A single serum iPTH measurement on POD 1 is useful to determine whether or not to start calcium and vitamin D supplementation in order to maintain normocalcemia after surgery.
PMCID: PMC3693643  PMID: 23843829
Hypoparathyroidism; Hypocalcemia; Thyroidectomy, Thyroid Nodule; Parathyroid
8.  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
9.  Human Parathyroid Hormone Is Secreted Primarily into the Bloodstream After Rat Parotid Gland Gene Transfer 
Human Gene Therapy  2010;22(1):84-92.
Hypoparathyroidism is a hormone deficiency syndrome that leads to low blood calcium levels and for which current replacement therapy is inadequate. Gene transfer to salivary glands leads to safe and abundant secretion of therapeutic protein into either saliva or the bloodstream. We previously reported the successful transduction of rat submandibular glands with an adenoviral vector encoding human parathyroid hormone (Ad.hPTH), but unfortunately most of the hPTH was secreted into saliva. Because submandibular and parotid glands are morphologically and functionally different, we hypothesized that hPTH sorting might be different in parotid glands. After 2 days, the pattern of hPTH secretion from transduced parotid glands of intact rats was reversed from that of transduced submandibular glands, that is, most transgenic hPTH was detected in serum (5 × 1010 viral particles per gland; the saliva-to-serum ratio of total hPTH secreted was 0.04). Vector copies were localized to the targeted parotid glands, with none detected in liver or spleen. Ad.hPTH next was administered to parotid glands of parathyroidectomized rats. Two days after delivery no hPTH was detectable in saliva, but high levels were found in serum, leading to normalization of serum calcium and a significant increase in the urinary phosphorus-to-creatinine ratio. This study demonstrates for the first time differential sorting of transgenic hPTH between submandibular and parotid glands, suggesting that hPTH may be a valuable model protein for understanding the molecular basis of transgenic secretory protein sorting in these exocrine glands. We also show the clinical potential of salivary gland hPTH gene therapy for patients with hypoparathyroidism.
Physiologically sufficient levels of calcium in the blood are important for a range of vital functions and hypocalcemia can lead to seizures, tetany, or heart failure. Parathyroid hormone (PTH) is central to maintaining adequate blood calcium concentration. In this study, Adriaansen et al. demonstrate that delivery of an adenoviral vector encoding human PTH to the parotid gland of hypocalcemic rats leads to a normalization of serum calcium levels.
PMCID: PMC3025188  PMID: 20977345
10.  Effectiveness of an i-PTH Measurement in Predicting Post Thyroidectomy Hypocalcemia: Prospective Controlled Study 
Yonsei Medical Journal  2013;54(3):637-642.
Hypocalcemia is the most common complication after total thyroidectomy. The purpose of this study was to determine whether measurement of intact parathyroid hormone (i-PTH) level in thyroidectomy patients could predict hypocalcemia.
Materials and Methods
We performed a prospective study of patients undergoing total thyroidectomy. Serum concentration of i-PTH, total calcium (Ca), ionized calcium (Ca2+), phosphate (P), magnesium (Mg), and albumin were measured preoperatively and at 0 hour, 6 hours, 12 hours, 24 hours, 48 hours, and 72 hours postoperatively.
108 patients were recruited to the study. A total of 50 patients (46%) experienced hypocalcemia. The serum i-PTH concentration was linearly related to the time of measurement, while concentrations of P, Mg, albumin, Ca, and Ca2+ were not. We compared odds ratios, and found that the concentration of i-PTH at 6 hours post operation was the most closely related to the occurrence of hypocalcemic symptom. On ROC analysis using i-PTH level at 6 hours, an i-PTH level of 10.6 mg/dL was found to maximize both sensitivity and specificity at the same time point.
We found that i-PTH was a predictor of hypocalcemia, and that the earliest predictor of hypocalcemic symptoms was an i-PTH concentration lower than 10.6 mg/dL obtained 6 hours after total thyroidectomy.
PMCID: PMC3635650  PMID: 23549808
Thyroidectomy; hypocalcemia; parathyroid hormone; surgery
11.  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
12.  Correlation of vitamin D, bone mineral density and parathyroid hormone levels in adults with low bone density 
Indian Journal of Orthopaedics  2013;47(4):402-407.
Bone mineral densiy (BMD) is known to be affected by serum 25-hydroxyvitamin D (25(OH) D) levels, intact parathyroid hormone (iPTH) levels. Indian data pertinent to above observation is scant. Our study aimed to investigate the relationships between serum 25-hydroxyvitamin D (25(OH) D) levels, intact parathyroid hormone (iPTH) levels and bone mineral density (BMD) in a cohort of Indian patients.
Materials and Methods:
Adults with or without fragility fractures with low BMD at the hip or lumbar spine were evaluated clinically along with laboratory investigations. T-scores of the hip and spine were derived from BMD-DEXA (dual-energy X-ray absorptiometry). Multivariate regression models were used to investigate the relationships between serum 25(OH) D, iPTH and BMD.
Total of 102 patients (male:female = 38:64) with a mean age of 62.5 ± 6.4 years were included in the study. Forty-four patients had osteopenia. Osteoporosis was present in 58 patients. The mean values for serum 25(OH) D and iPTH levels were 21.3 ± 0.5 ng/ml and 53.1 ± 22.3 pg/ml, respectively. In 84.3% of patients, serum 25(OH) D levels were below 30 ng/ml (Normal = 30-74 ng/ml), confirming vitamin D deficiency. There was no association between 25(OH) D levels and BMD at the hip or lumbar spine (P = 0.473 and 0.353, respectively). Both at the hip and lumbar spine; iPTH levels, male gender, body mass index (BMI) and age were found to be significant predictors of BMD. Patients with higher BMI had significantly lower BMD and T-score. At levels <30 ng/ml, 25(OH) D was negatively associated with iPTH (P = 0.041).
Among our cohort of patients with low BMD, no direct relationship between serum 25(OH) D levels and BMD was observed. However, a negative correlation between iPTH and 25(OH) D at serum 25(OH) D concentrations <30 ng/ml. Serum iPTH levels showed a significant negative association with BMD at the hip and lumbar spine. Our findings underscore the critical role of parathyroid hormone in bone metabolism and health.
PMCID: PMC3745696  PMID: 23960286
Bone mineral density; osteoporosis; parathyroid hormone; vitamin D
13.  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
14.  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
15.  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
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
17.  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
18.  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
19.  The high prevalence of chronic kidney disease-mineral bone disorders: A hospital-based cross-sectional study 
Indian Journal of Nephrology  2012;22(4):285-291.
Mineral bone disorder (MBD) is an important complication of chronic kidney disease (CKD). However, there are limited data on the pattern of MBD in Indian CKD population. The aim of this study was to describe spectrum of MBD in patients with CKD in our center. This was a hospital-based cross-sectional observational study. Patients with stage 4 and 5 CKD were included in this study. Those receiving calcium supplement, vitamin D or its analogues, and calcimimetic were excluded. Serum/plasma levels of creatinine, albumin, calcium, phosphate, total alkaline phosphatase (TAP), intact parathormone (iPTH), and 25-OH vitaminD (25-vitD) were measured. Radiological survey of bones was carried out in all cases, and echocardiography done in selected patients. Statistical analysis was done using Sigmaplot 10.0 software. A total of 150 patients (114 males, 36 females) were included in this study. Mean age was 45.67±16.96 years. CKD stage 4 and 5D were found in 26% (n=39) and 74% (n=111) of study population, respectively. The most common underlying native kidney diseases in patients of CKD 4 and 5D were diabetic nephropathy (41.03%) and CGN (41.44%), respectively. Median (first quartile, third quartile) values for serum levels of corrected calcium (cCa), phosphate, cCaXPO4 product, TAP, plasma iPTH, and 25-vitD in stage 4 CKD were 8.36 (7.79, 8.91) mg/dL, 4.9 (3.92, 6.4) mg/dL, 41.11 (34.01, 53.81) mg2/dL2, 97 (76.5, 184.25) IU/L, 231 (124.5, 430.75) pg/mL, and 12 (6.98, 23.55) ng/mL, respectively; and in stage 5D CKD were 8.36 (7.66, 8.95) mg/dL, 5.7 (4.23, 6.95) mg/dL, 46.5 (37.16, 54.47) mg2/dL2, 180 (114.5, 276.25) IU/L, 288 (169.75, 625.0) pg/mL, and 18.4 (10.0, 26.4) ng/mL, respectively. Prevalence of hypocalcemia (56.41% vs. 54.95%), hyperphosphatemia (64.10% vs. 70.27%), and hyperparathyroidism (84.62% vs. 88.29%) was not different between patients with CKD 4 and 5D. However, iPTH level outside the target range and increased TAP level were significantly (P<0.001) more common in CKD stage 5D. Multiple logistic regression analysis for hyperparathyroidism revealed significant inverse correlation with cCa in CKD 5D. There were no significant differences in vitamin D status and prevalence of valvular calcification between CKD stage 4 and 5D. X-ray revealed renal osteodystrophy in 8 (5.33%) patients, while it was normal in 118 (78.67%) patients. Secondary hyperparathyroidism, hyperphosphatemia, hypocalcemia, increased TAP, and 25-OH vitamin D deficiency and insufficiency were quite common in CKD 4 and 5 patients. The commonest type of MBD in CKD 4 and 5D was secondary hyperparathyroidism.
PMCID: PMC3495351  PMID: 23162273
Chronic kidney disease; hyperparathyroidism; hyperphosphatemia; hypocalcemia; mineral bone disorder
20.  Association between long-term efficacy of cinacalcet and parathyroid gland volume in haemodialysis patients with secondary hyperparathyroidism 
NDT Plus  2008;1(Suppl 3):iii49-iii53.
Purpose. Secondary hyperparathyroidism with nodular hyperplasia is resistant to medical therapies. Cinacalcet is an effective treatment for severe secondary hyperparathyroidism. This multicentre retrospective study was designed to determine the long-term efficacy of cinacalcet in patients with nodular hyperplasia, the advanced type of parathyroid hyperplasia.
Subjects and methods. The study subjects were 20 haemodialysis patients with secondary hyperparathyroidism. Patients with ultrasonographically confirmed large parathyroid glands (volume >0.5 cm3) were considered to have nodular hyperplasia (n = 8). Cinacalcet was started at the dose of 25 mg/day and titrated up to 100 mg/day to achieve the target intact-parathyroid hormone (iPTH) level of <250 pg/ml. Serum iPTH, corrected calcium, serum phosphorus, calcium × phosphorus product were measured and compared over the 48-week period of treatment with cinacalcet in all 20 patients and over 120 weeks in 6 of the patients (2 with nodular hyperplasia and 4 with non-nodular hyperplasia). We also examined the achievement rate of K/DOQI guideline treatment targets. The dosages of vitamin D preparation, sevelamer hydrochloride and calcium- containing phosphate binder were adjusted for the above target values.
Results. iPTH levels were significantly lower at 48 weeks in both groups. However, corrected calcium levels, serum phosphorus levels and calcium phosphorus products were within the target values in the non-nodular hyperplasia group (n = 12), while the target value could not be achieved in the nodular hyperplasia group. In the long-term follow-up group, the levels of iPTH, corrected calcium, serum phosphorus and calcium × phosphorus products were significantly higher in nodular hyperplasia than in non-nodular hyperplasia.
Conclusion. Our study suggests that cinacalcet lacks long-term efficacy in nodular hyperplasia, especially for controlling serum calcium and phosphorus levels.
PMCID: PMC4421134  PMID: 25983974
cinacalcet; haemodialysis; nodular hyperplasia; secondary hyperparathyroidism; ultrasonography
21.  Early Predictors of Hypocalcemia After Total Thyroidectomy 
Postoperative hypocalcemia is common after total thyroidectomy, and perioperative monitoring of serum calcium levels is arguably the primary reason for overnight hospitalization. Confidently predicting which patients will not develop significant hypocalcemia may allow for a safe earlier discharge.
To examine associations of patient characteristics with hypocalcemia, duration of hospitalization, and postoperative intact parathyroid hormone (IPTH) level after total thyroidectomy.
Retrospective study of consecutive patients who underwent total thyroidectomy by a single high-volume surgeon between February 1, 2010, and November 30, 2012. Postoperative serum 25-hydroxyvitamin D (vitamin D), calcium, and IPTH levels were tested within 6 to 8 hours after surgery. Mild hypocalcemia was defined as any postoperative serum calcium level of less than 8.4 to 8.0 mg/dL. Significant hypocalcemia was defined as any postoperative serum calcium level of less than 8.0 mg/dL or the development of hypocalcemia-related symptoms.
Total thyroidectomy.
Associations of patient demographic and clinical characteristics and laboratory values with postoperative mild and significant hypocalcemia were examined using univariate analysis, and independent predictors of hypocalcemia, duration of hospitalization, and IPTH level were determined using multivariate analysis.
Overall, 304 total thyroidectomies were performed. Mild and significant hypocalcemia occurred in 68 (22.4%) and 91 (29.9%) patients, respectively, of which the majority were female (P = .003). The development of significant hypocalcemia was associated with postoperative IPTH level (P < .001). On multivariate analysis, males had a decreased risk of developing mild (odds ratio, 0.37 [95% CI, 0.16–0.85]) and significant (odds ratio, 0.57 [95% CI, 0.09–0.78]) hypocalcemia. Every 10-pg/mL increase in postoperative IPTH level predicted a 43% decreased risk of significant hypocalcemia (P < .001) and an 18% decreased risk of hospitalization beyond 24 hours (P = .03). Presence of malignant neoplasm carried a 27% risk of mild hypocalcemia (P = .02). There was a progressively increasing risk of lower IPTH levels for each parathyroid gland inadvertently resected or autotransplanted. Male sex and African American race were independently predictive of higher IPTH levels.
Low postoperative IPTH level, female sex, and presence of malignant neoplasm are all significant, independent predictors of hypocalcemia after total thyroidectomy. Clinicians should consider these variables when deciding how to best manage or prevent postoperative hypocalcemia.
PMCID: PMC4316663  PMID: 25321339
22.  Temporal Relationship between Vitamin D Status and Parathyroid Hormone in the United States 
PLoS ONE  2015;10(3):e0118108.
Interpretation of parathyroid hormone (iPTH) requires knowledge of vitamin D status that is influenced by season.
Characterize the temporal relationship between 25-hydroxyvitamin D3 levels [25(OH)D3] and intact iPTH for several seasons, by gender and latitude in the U.S. and relate 25-hydrovitamin D2 [25(OH)D2] levels with PTH levels and total 25(OH)D levels.
We retrospectively determined population weekly-mean concentrations of unpaired [25(OH)D2 and 25(OH)D3] and iPTH using 3.8 million laboratory results of adults. The 25(OH)D3 and iPTH distributions were normalized and the means fit with a sinusoidal function for both gender and latitudes: North >40, Central 32–40 and South <32 degrees. We analyzed PTH and total 25(OH)D separately in samples with detectable 25(OH)D2 (≥4 ng/mL).
Seasonal variation was observed for all genders and latitudes. 25(OH)D3 peaks occurred in September and troughs in March. iPTH levels showed an inverted pattern of peaks and troughs relative to 25(OH)D3, with a delay of 4 weeks. Vitamin D deficiency and insufficiency was common (33% <20 ng/mL; 60% <30 ng/mL) as was elevated iPTH levels (33%>65 pg/mL). The percentage of patients deficient in 25(OH)D3 seasonally varied from 21% to 48% and the percentage with elevated iPTH reciprocally varied from 28% to 38%. Patients with detectable 25(OH)D2 had higher PTH levels and 57% of the samples with a total 25(OH)D > 50 ng/mL had detectable 25(OH)D2.
25(OH)D3 and iPTH levels vary in a sinusoidal pattern throughout the year, even in vitamin D2 treated patients; 25(OH)D3, being higher in the summer and lower in the winter months, with iPTH showing the reverse pattern. A large percentage of the tested population showed vitamin D deficiency and secondary hyperparathyroidism. These observations held across three latitudinal regions, both genders, multiple-years, and in the presence or absence of detectable 25(OH)D2, and thus are applicable for patient care.
PMCID: PMC4349787  PMID: 25738588
23.  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
24.  R990G Polymorphism of Calcium Sensing Receptor Gene Is Associated with High Parathyroid Hormone Levels in Subjects with Vitamin D Deficiency: A Cross-Sectional Study 
BioMed Research International  2015;2015:407159.
Single nucleotide polymorphisms (SNPs), R990G and A986S of the calcium sensing receptor (CaSR) gene, are shown to influence response of parathyroid hormone (PTH) in subjects with optimal vitamin D levels. This cross-sectional study was conducted in subjects with vitamin D deficiency (VDD) to observe associations between CaSR polymorphisms, plasma iPTH, and serum calcium levels. Adult females (n = 140) with known VDD, intact parathyroid hormone (iPTH), and calcium levels were recruited for genotype analysis. The frequencies of the 986 alleles GG, GT, and TT were 68%, 25%, and 7%, respectively, whereas the frequencies of the 990 alleles AA, AG, and GG were 80%, 8.9%, and 11.1%, respectively. The subjects with GG genotype of R990G polymorphism had higher iPTH levels (148.65 versus 91.47 and 86.1 pg/mL for GG versus AA, AG, resp., P = 0.008) and lower calcium levels (8.4 versus 9.04 and 9.07 mg/dL for GG versus AA, AG, resp., P = 0.002). No such association of A986S polymorphism with plasma iPTH or serum calcium levels was observed in the present study. Patients with VDD bearing the GG genotype of R990G SNPs are prone to have higher iPTH levels and lower calcium.
PMCID: PMC4324806  PMID: 25695075
25.  The five most commonly used intact parathyroid hormone assays are useful for screening but not for diagnosing bone turnover abnormalities in CKD-5 patients 
Clinical nephrology  2009;72(1):5-14.
Assessment of bone turnover for management of renal osteodystrophy is part of routine care in chronic kidney disease Stage 5 (CKD-5) patients. Measurement of intact parathyroid hormone (iPTH) is the most commonly used surrogate marker for bone turnover in these patients. The current study was conducted to evaluate the predictive value of the five most commonly used iPTH assays for bone turnover.
In a cross-sectional study, 84 CKD-5 patients underwent bone biopsy and blood drawings for determination of iPTH and total serum alkaline phosphatase (AP).
Histologically, patients presented with a broad range of bone turnover abnormalities as determined by activation frequency and bone formation rate/bone surface. Results of the five iPTH assays in each patient correlated but were significantly different. There were also significant differences between iPTH measurements at the same bone turnover level. Using Kidney Disease Outcome Quality Initiative recommended iPTH ranges, all assays showed comparably poor diagnostic performance. At 80% specificity, cut-off values of the 5 iPTH assays for low bone turnover varied from 165 to 550 pg/ml and for high bone turnover from 404 to 1,003 pg/ml. Sensitivities at these cutoffs remained below acceptable standards. Addition of AP measurements to iPTH did not improve diagnostic accuracy.
Precise assessment of bone turnover will require utilization of established and novel bone markers reflecting effects of bone turnover rather than measuring only iPTH or other effectors.
PMCID: PMC4501021  PMID: 19640382
renal osteodystrophy; bone turnover; parathyroid hormone; PTH assays; alkaline phosphatase; end-stage renal disease; K/DOQI

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