The Calcimimetic Cinacalcet Normalizes Serum Calcium in Subjects with Primary Hyperparathyroidism

Abstract Calcimimetics increase the sensitivity of the calcium-sensing receptor (CaR) to circulating serum calcium, reducing the secretion of PTH and the serum calcium concentration. We evaluated the calcimimetic cinacalcet, a novel therapy for the management of primary hyperparathyroidism. In this randomized, double-blind, dose-finding study, patients (n = 22) with primary hyperparathyroidism were given cinacalcet (30, 40, or 50 mg) or placebo twice daily for 15 d and observed for an additional 7 d. Serum calcium, plasma PTH, and 24-h and fasting urine calcium were measured. Baseline mean serum calcium was 10.6 mg/dl for the combined cinacalcet-treated patients (normal range, 8.4–10.3 mg/dl), compared with 10.4 mg/dl for the placebo group. Mean PTH at baseline was 102 pg/ml (normal range, 10–65 pg/ml) for the combined cinacalcet-treated patients, compared with 100 pg/ml in the placebo group. Serum calcium normalized after the second dose on d 1 and remained normal through d 15 in all cinacalcet dose groups. Maximum decreases in PTH of over 50% occurred 2–4 h after dosing in all cinacalcet-treated groups. The fasting and 24-h urine calcium to creatinine ratios were similar in the cinacalcet and placebo groups. This study demonstrates that cinacalcet safely normalized serum calcium and lowered PTH concentrations without increasing urinary calcium excretion in the study subjects, indicating the potential benefit of cinacalcet as a medical treatment for primary hyperparathyroidism.

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Urinary calcium indices in primary hyperparathyroidism (PHPT) and familial hypocalciuric hypercalcaemia (FHH): which test performs best?

Postgraduate Medical Journal ◽

10.1136/postgradmedj-2020-137718 ◽

2020 ◽

pp. postgradmedj-2020-137718

Author(s):

Muhammad Fahad Arshad ◽

James McAllister ◽

Azhar Merchant ◽

Edmund Rab ◽

Jacqueline Cook ◽

...

Keyword(s):

Primary Hyperparathyroidism ◽

International Workshop ◽

Significant Proportion ◽

Urinary Calcium ◽

Calcium Excretion ◽

Clearance Ratio ◽

Urine Calcium ◽

Genetic Studies ◽

Urine Calcium Excretion ◽

Control Study

AimPrimary hyperparathyroidism (PHPT) is much more common than familial hypocalciuric hypercalcaemia (FHH), but there is considerable overlap in biochemical features. Urine calcium indices help with the differential diagnosis, but their reliability in making this distinction is not clear. The aim of this study was to compare urinary calcium values in patients with PHPT and FHH.MethodsThis was a case–control study of patients with PHPT who had successful surgery and genetically proven FHH between 2011 and 2016. Due to low FHH numbers, patients from neighbouring hospitals and outside study period (2017–2019) were allowed to improve power. Data on demographics and urinary calcium were obtained from electronic records and compared between the two groups.ResultsDuring the study period, 250 patients underwent successful PHPT surgery, while in the FHH arm, 19 genetically proven cases were included. The median (IQR) 24-hour urine calcium excretion (UCE) in the PHPT group was 8.3 (5.6–11.2) mmol/24 hours compared with 3.2 (2.1–6.1) mmol/24 hour in the FHH group (p<0.001). Median (IQR) calcium to creatinine clearance ratio (CCCR) in the PHPT and FHH groups was 0.020 (0.013–0.026) and 0.01 (0.002–0.02), respectively (p=0.001). The sensitivity of urinary tests for PHPT was 96% for UCE (cut-off ≥2.5 mmol/24 hour) and 47% for CCCR (cut-off >0.02). The specificity of the urinary tests for FHH was 29.4% for UCE (cut-off <2.5 mmol/24 hour) and 93% for CCCR (cut-off <0.02).Conclusions24-hour UCE is more sensitive in diagnosing PHPT; however, it is less specific in ruling out FHH as compared with CCCR, when the cut-offs suggested by the International guidelines from the fourth international workshop are used. A significant proportion of patients with PHPT would have also required genetic studies if the guidelines were followed.

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Vitamin D Repletion in Patients with Primary Hyperparathyroidism and Coexistent Vitamin D Insufficiency

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2004-1772 ◽

2005 ◽

Vol 90 (4) ◽

pp. 2122-2126 ◽

Cited By ~ 153

Author(s):

Andrew Grey ◽

Jenny Lucas ◽

Anne Horne ◽

Greg Gamble ◽

James S. Davidson ◽

...

Keyword(s):

Vitamin D ◽

Primary Hyperparathyroidism ◽

Serum Calcium ◽

Serum Alkaline Phosphatase ◽

Vitamin D Insufficiency ◽

Urinary Calcium ◽

Urinary Calcium Excretion ◽

Total Serum ◽

Calcium Excretion ◽

Intact Pth

Abstract Vitamin D insufficiency is common in patients with primary hyperparathyroidism (PHPT) and may be associated with more severe and progressive disease. Uncertainty exists, however, as to whether repletion of vitamin D should be undertaken in patients with PHPT. Here we report the effects of vitamin D repletion on biochemical outcomes over 1 yr in a group of 21 patients with mild PHPT [serum calcium <12 mg/dl (3 mmol/liter)] and coexistent vitamin D insufficiency [serum 25 hydroxyvitamin D [25(OH)D] <20 μg/liter (50 nmol/liter)]. In response to vitamin D repletion to a serum 25(OH)D level greater than 20 μg/liter (50 nmol/liter), mean levels of serum calcium and phosphate did not change, and serum calcium did not exceed 12 mg/dl (3 mmol/liter) in any patient. Levels of intact PTH fell by 24% at 6 months (P < 0.01) and 26% at 12 months (P < 0.01). There was an inverse relationship between the change in serum 25(OH)D and that in intact PTH (r = −0.43, P = 0.056). At 12 months, total serum alkaline phosphatase was significantly lower, and urine N-telopeptides tended to be lower than baseline values (P = 0.02 and 0.13, respectively). In two patients, 24-h urinary calcium excretion rose to exceed 400 mg/d, but the group mean 24-h urinary calcium excretion did not change. These preliminary data suggest that vitamin D repletion in patients with PHPT does not exacerbate hypercalcemia and may decrease levels of PTH and bone turnover. Some patients with PHPT may experience an increase in urinary calcium excretion after vitamin D repletion.

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Inhibition of calbindin D28K expression by cyclosporin A in rat kidney: the possible pathogenesis of cyclosporin A-induced hypercalciuria.

Journal of the American Society of Nephrology ◽

10.1681/asn.v981416 ◽

1998 ◽

Vol 9 (8) ◽

pp. 1416-1426

Author(s):

C W Yang ◽

J Kim ◽

Y H Kim ◽

J H Cha ◽

S Y Mim ◽

...

Keyword(s):

Cyclosporin A ◽

Serum Calcium ◽

Protein Level ◽

Rat Kidney ◽

Urinary Calcium ◽

Calcium Handling ◽

Calcium Excretion ◽

Urine Calcium ◽

Calbindin D28k ◽

Urine Calcium Excretion

A recent study by Steiner et al. (Biochem Pharmacol 51: 253-258, 1996) demonstrated a decreased calbindin D28K expression in the kidneys of cyclosporin A (CsA)-treated rats. To evaluate the association of renal calcium handling with calbindin D28K expression in CsA-treated rats, two separate experiments (vehicle [VH] versus CsA groups, 1,25-dihydroxyvitamin D3 [VitD] versus VitD + CsA groups) were done simultaneously. CsA (25 mg/kg per d, subcutaneously) and VitD (0.5 microg/kg per d, subcutaneously) were given for 7 d. The CsA group showed decreased serum calcium, increased urine calcium excretion, and decreased calbindin D28K protein level and immunoreactivity compared with the VH group. The VitD + CsA treatment decreased serum calcium, increased urine calcium excretion, and decreased calbindin D28K protein level and immunoreactivity compared with the VitD alone. CsA treatment did not affect the serum parathyroid hormone and VitD levels. This study demonstrates an association of calbindin D28K expression with the urinary calcium excretion in CsA-treated rats, and suggests that decreased calbindin D28K expression may play a role in renal calcium wasting.

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Successful Parathyroidectomy May Not Resolve Hypercalciuria in Patients With Primary Hyperparathyroidism

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.459 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A226-A226

Author(s):

Neriy Izkhakov ◽

Heranmaye Prasad ◽

Nicholas John Vernetti ◽

Samer Nakhle

Keyword(s):

Primary Hyperparathyroidism ◽

Serum Calcium ◽

Clinical Case ◽

Case Series ◽

Urinary Calcium ◽

Long Term Effects ◽

Normal Range ◽

History Of ◽

Average Serum

Abstract Background: Hypercalciuria, with twenty-four-hour urinary calcium of >400 mg/day, is one of the indications for parathyroidectomy in patients with primary hyperparathyroidism. We report five cases where hypercalciuria is not resolved following a successful parathyroidectomy (normalization of serum calcium) in such patients. Here resolution of hypercalciuria is defined as twenty-four-hour urinary calcium of less than 200 mg/day. Clinical Case: This is a case series of five patients who remained hypercalciuric at 6 to 19 months after successful parathyroidectomy. Pre-parathyroidectomy, average PTH was 95 pg/dL (Min 69 pg/dL, Max 120 pg/dL), average serum calcium was 11.0 mg/dL (min 10.3 mg/dL, max 12.0 mg/dL), and average twenty-four-hour urinary calcium was 455 mg/day (min 386 mg/day, max 551 mg/day). Calcium levels were corrected to normal range post-parathyroidectomy and remained in normal range. However, hypercalciuria did not resolve. Post-parathyroidectomy, average PTH was 44 pg/dL (min 25 pg/dL, max 69 pg/dL), average serum calcium was 9.6 mg/dL (min 9.3 mg/dL, max 9.8 mg/dL), and average twenty-four-hour urinary calcium was 284 mg/day (min 201 mg/day, max 376 mg/day). Two patients who had history of nephrolithiasis prior to parathyroidectomy continued to develop nephrolithiasis at six and sixteen months after successful parathyroidectomy. Conclusions: This case series showed that hypercalciuria may not resolve following a successful parathyroidectomy in patients with primary hyperparathyroidism and elevated twenty-four-hour urinary calcium at 6 to 19 months after surgery. Further observations to evaluate long term effects of parathyroidectomy on hypercalciuria is needed.

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High Rate of Occult Urolithiasis in Normocalcemic Primary Hyperparathyroidism

Kidney & Blood Pressure Research ◽

10.1159/000502578 ◽

2019 ◽

Vol 44 (5) ◽

pp. 1189-1195 ◽

Cited By ~ 2

Author(s):

Alyne Layane Pereira Lemos ◽

Sergio Ricardo de Lima Andrade ◽

Lívia Laeny Henrique Pontes ◽

Patricia Moura Cravo Teixeira ◽

Elba Bandeira ◽

...

Keyword(s):

Primary Hyperparathyroidism ◽

Serum Calcium ◽

Kidney Stones ◽

Urinary Calcium ◽

Normal Serum ◽

Urinary Calcium Excretion ◽

High Rate ◽

Calcium Excretion ◽

History Of ◽

Serum Pth

Introduction: Normocalcemic primary hyperparathyroidism (NPHPT) is characterized by elevations in serum parathyroid hormone levels in the presence of normal serum calcium concentrations after exclusion of secondary hyperparathyroidism. We have previously demonstrated no differences in the prevalence of clinically active urolithiasis between NPHPT and hypercalcemic asymptomatic PHPT, and that it is significantly higher in postmenopausal osteoporotic women with NPHPT in comparison to women with normal serum PTH and calcium concentrations. Few studies have addressed the occurrence of silent or occult kidney stones in asymptomatic hypercalcemic PHPT, but no data are available for NPHPT. Objective: To determine the presence of occult urolithiasis in NPHPT patients using routine abdominal ultrasonography. Methods and Results: We studied 35 patients with NPHPT (mean age 63.2 ± 10.7 years, 96% women; serum PTH 116.5 ± 39.2 pg/mL, 25OHD 38.5 ± 6.82 ng/mL, total calcium 9.1 ± 0.56 mg/dL; albumin 4.02 ± 0.37 g/dL; BUN 34.35 ±10.23 mg/dL; p = 3.51 ± 0.60 mg/dL; estimated glomerular filtration rate 88.44 ± 32.45 mL/min/1.73 m2, and 24-h urinary calcium excretion 140.6 ± 94.3 mg/24 h). The criteria for the diagnosis of NPHPT were as follows: serum PTH above the reference range (11–65 pg/mL), normal albumin-corrected serum calcium concentrations, normal 24-h urinary calcium excretion, serum 25OHD above 30 ng/mL, estimated GFR (MDRD) above 60 mL/min/1.73 m2 (with the exclusion of medications such as thiazide diuretics, lithium, bisphosphonates, and denosumab), a history of clinical symptoms of urolithiasis, and a family history of kidney stones. Thirty-five patients were evaluated and 25 of them met the inclusion criteria. Five patients presented nephrolithiasis corresponding to 20% of the study population. There were no statistically significant differences in any of the clinical or laboratory variables studied between patients with or without urolithiasis, although mean serum PTH levels were higher in patients with stones (180.06 ± 126.48 vs. 100.72 ± 25.28 pg/mL, p = 0.1). The size of the stones ranged from 0.6 to 0.9 cm and all of the stones were located in the renal pelvis. Conclusion: We found a high prevalence of occult kidney stones in NPHPT patients, similar to what is observed in clinically manifested urolithiasis, in hypercalcemic PHPT.

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A Randomized, Cross-Over Trial of Once-Daily Versus Twice-Daily Parathyroid Hormone 1–34 in Treatment of Hypoparathyroidism

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.83.10.5185 ◽

1998 ◽

Vol 83 (10) ◽

pp. 3480-3486 ◽

Cited By ~ 3

Author(s):

Karen K. Winer ◽

Jack A. Yanovski ◽

Babak Sarani ◽

Gordon B. Cutler Jr.

Keyword(s):

Serum Calcium ◽

Significant Rise ◽

Calcium Excretion ◽

Daily Regimen ◽

Normal Range ◽

Physiological Control ◽

Urine Calcium ◽

Once Daily ◽

Markers Of Bone Formation ◽

Serum And Urine

Once-daily sc injection of PTH 1–34 can normalize mean serum and urine calcium levels in patients with hypoparathyroidism; however, once-daily PTH has diminishing effects on serum calcium after 12 h, such that serum calcium levels fall below the normal range in some patients. Once-daily PTH also causes a marked increase in bone turnover, with persistent increases in markers of bone formation and resorption. To test the hypothesis that a twice-daily PTH regimen can produce more physiological control than a once-daily regimen, we performed a randomized cross-over trial, lasting 28 weeks, in 17 adult subjects with hypoparathyroidism. Each 14-week study arm was divided into a 2-week inpatient dose-adjustment phase and a 12-week outpatient phase. The PTH dose (given sc once daily at 0900 h or twice daily with one dose at 0900 h and the other at 2100 h) was adjusted to maintain both serum and urine calcium within, or close to, the normal range. During the second half of the day (12–24 h), twice-daily PTH increased serum calcium and magnesium levels more effectively than once-daily PTH. In patients with calcium receptor mutations (CaR), once-daily PTH normalized urine calcium, provided that serum calcium was maintained at levels below normal range. However, twice-daily PTH treatment produced higher mean serum calcium in patients with CaR with no significant rise in urine calcium excretion, and with no significant differences in either serum or urine calcium levels between CaR and patients with acquired or idiopathic hypoparathyroidism. Thus, treatment with twice-daily PTH is the better regimen for patients with CaR to overcome their tendency to hypercalciuria while producing near-normal levels of serum calcium. The total daily PTH dose was markedly reduced with the twice-daily regimen (twice daily 46 ± 52 vs. once daily 97 ± 60 μg/day, P < 0.001). We conclude that a twice-daily PTH regimen provides effective treatment of hypoparathyroidism and reduces the variation in serum calcium levels at a lower total daily PTH dose.

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Urinary 3',5'-cyclic adenosine monophosphate in relation to serum and urinary calcium in acromegaly and primary hyperparathyroidism

Acta Endocrinologica ◽

10.1530/acta.0.0940468 ◽

1980 ◽

Vol 94 (4) ◽

pp. 468-474 ◽

Cited By ~ 1

Author(s):

Johan Halse

Keyword(s):

Primary Hyperparathyroidism ◽

Serum Calcium ◽

Negative Correlation ◽

Calcium Metabolism ◽

Active Form ◽

Negative Relationship ◽

Adenosine Monophosphate ◽

Urinary Calcium ◽

Calcium Excretion ◽

Positive Correlation

Abstract. A comparison of the interrelations between serum and urinary calcium values and the urinary excretion of cAMP in acromegaly (No. of subjects: 26), patients with primary hyperparathyroidism (n = 18) and control subjects (n = 42) is presented. The cAMP excretion was greatest in primary hyperparathyroidism, but acromegalics also exhibited higher values for this parameter than controls. A positive correlation was found between serum calcium values and cAMP in primary hyperparathyroidism, while acromegalics showed no correlation between these parameters. In controls there was a negative correlation between serum calcium and cAMP. Serum calcium levels corrected for variations in total protein concentrations were elevated both in acromegaly and primary hyperparathyroidism, mostly in the latter. Acromegalics and patients with primary hyperparathyroidism exhibited an increase in 24 h calcium excretion. While there was a negative relationship between urinary calcium excretion and cAMP in acromegaly, a positive correlation between these parameters was found in primary hyperparathyroidism. Controls showed a negative correlation between urinary calcium values and cAMP. It is concluded that the role of the parathyroids in the regulation of calcium metabolism in acromegaly is different from that of both normal controls and primary hyperparathyroidism. It is postulated that an active form of Vitamin D plays a major role in the regulation of calcium metabolism in acromegaly.

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Primary hyperparathyroidism: diagnosis and management in the older individual

Acta Endocrinologica ◽

10.1530/eje.0.1510297 ◽

2004 ◽

pp. 297-304 ◽

Cited By ~ 17

Author(s):

S Boonen ◽

D Vanderschueren ◽

W Pelemans ◽

R Bouillon

Keyword(s):

Bone Density ◽

Primary Hyperparathyroidism ◽

Elderly Patients ◽

Serum Calcium ◽

Urinary Calcium ◽

Calcium Excretion ◽

Older Individuals ◽

Mineral Density ◽

Medical Problems ◽

Asymptomatic Patients

As more and more cases of primary hyperparathyroidism are being detected by screening for serum calcium concentration, the majority of patients are older individuals who are asymptomatic or have symptoms which are difficult to ascribe to hyperparathyroidism. Long-term follow-up has provided evidence that most asymptomatic patients who do not undergo parathyroidectomy will not develop symptomatic complications. Some asymptomatic patients, however, have progression of disease over time. These observations and the lack of reliable predictors of the rate of progression in most patients reinforce the need for careful monitoring in elderly individuals who do not undergo surgery. Biannual measurements of serum calcium concentrations and annual measurements of urinary calcium excretion and bone mineral density should be performed in all patients who are managed conservatively. In elderly patients with symptomatic or complicated primary hyperparathyroidism, parathyroidectomy results in biochemical cure and increased bone density, both at the lumbar spine and the femoral neck, and should be considered. Criteria for surgery include significant hypercalcemia (>1 mg/dl above the upper limit of normal), marked hypercalciuria (>400 mg per day), low bone density, unexplained renal insufficiency and an episode of acute primary hyperparathyroidism. Consideration of parathyroidectomy should also be given to elderly patients with primary hyperparathyroidism who are vitamin D deficient. Radionuclide scanning has become the initial non-invasive study of choice when parathyroid gland localization is necessary before parathyroidectomy; this is generally for fragile patients and reoperative cases. In a subset of older individuals, surgery may not be an option because of coexisting medical problems even though surgical indications are present.

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Primary Hyperparathyroidism in Homozygous Sickle Cell Patients: A Hemolysis-Mediated Hypocalciuric Hypercalcemia Phenotype?

Journal of Clinical Medicine ◽

10.3390/jcm10215179 ◽

2021 ◽

Vol 10 (21) ◽

pp. 5179

Author(s):

Edmat Akhtar Khan ◽

Lynda Cheddani ◽

Camille Saint-Jacques ◽

Rosa Vargas-Poussou ◽

Vincent Frochot ◽

...

Keyword(s):

Primary Hyperparathyroidism ◽

Sickle Cell ◽

Fractional Excretion ◽

Urinary Calcium ◽

High Rate ◽

Calcium Handling ◽

Control Group ◽

Calcium Excretion ◽

Calcium Reabsorption ◽

Chronic Hemolysis

Primary hyperparathyroidism (pHPT) has been reported to have a higher prevalence in sickle cell disease (SCD) patients, including a high rate of recurrence following surgery. However, most patients are asymptomatic at the time of diagnosis, with surprisingly infrequent hypercalciuria, raising the issue of renal calcium handling in SCD patients. We conducted a retrospective study including (1) 64 hypercalcemic pHPT non-SCD patients; (2) 177 SCD patients, divided into two groups of 12 hypercalcemic pHPT and 165 non-pHPT; (3) eight patients with a diagnosis of familial hypocalciuric hypercalcemia (FHH). Demographic and biological parameters at the time of diagnosis were collected and compared between the different groups. Determinants of fasting fractional excretion of calcium (FeCa2+) were also analyzed in non-pHPT SCD patients. Compared to non-SCD pHPT patients, our data show a similar ionized calcium and PTH concentration, with a lower plasmatic calcitriol concentration and a lower daily urinary calcium excretion in pHPT SCD patients (p < 0.0001 in both cases). Fasting FeCa2+ is also surprisingly low in pHPT SCD patients, and thus inadequate to be considered hypercalcemia, recalling the FHH phenotype. FeCa2+ is also low in the non-pHPT SCD control group, and negatively associated with PTH and hemolytic biomarkers such as LDH and low hemoglobin. Our data suggest that the pHPT biochemical phenotype in SCD patients resembles the FHH phenotype, and the fasting FeCa2+ association with chronic hemolysis biomarkers strengthens the view of a potential pharmacological link between hemolytic by-products and calcium reabsorption, potentially through a decreased calcium-sensing receptor (CaSR) activity.

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