Basal Parathyroid Hormone Research Articles

Intraoperative parathyroid hormone measurement pitfalls: parathyroid hormone spikes with carboxyl-terminal parathyroid hormone fragments in primary hyperparathyroidism—a case report

BackgroundIntraoperative parathyroid hormone (IOPTH) monitoring is a critical surgical adjunct for determining the extent of surgery for primary hyperparathyroidism (PHPT), with reported false-positive and false-negative rates of up to 10%. Surgeons must understand the parathyroid hormone (PTH) dynamics and select the appropriate IOPTH protocol and interpretation criteria for curative surgery.Case presentationWe present the case of a 64-year-old woman with a large cystic parathyroid tumor and PHPT who experienced a significant delay in IOPTH decrease but was cured without additional surgery. The patient’s basal intact PTH was 96.2 pg/mL, which decreased to 93.3 pg/mL at 25 min and 72.4 pg/mL at 55 min after removal of the parathyroid tumor. In an attempt to elucidate its pathophysiology, 1–84 PTH levels were measured in stored serum. These results can also be attributed to the relatively low basal PTH levels, intact PTH spike, and high ratio of large carboxyl-terminal PTH fragments present. The patient had normal intact PTH and calcium levels at the 9-month postoperative visit.ConclusionsAs detailed reports on these phenomena are scarce, we discuss the causes of false-negative IOPTH results in terms of PTH production, secretion, metabolism, and differences in measurement methods to avoid unnecessary surgery.

#3579 AN INITIAL LOW-DOSE ETELCALCETIDE APPROACH IS EFFECTIVE AND COST-SAVING IN HEMODIALYSIS PATIENTS WITH MODERATE SECONDARY HYPERPARATHYROIDISM

Abstract Background and Aims Etelcalcetide (ETC) is an intravenous calcimimetic approved for the management of secondary hyperparathyroidism (sHPT) in hemodialysis (HD) patients, with benefits in terms of reduction of FGF23 levels and prevention of progression of left ventricular hypertrophy. The label recommendation is a starting dose of 5 mg after HD, to be titrated every 4 weeks according to parathyroid hormone (PTH) and calcium levels. However, it remains unclear what dosage is best to start with and, thus, how this treatment can be implemented in a real-life setting. The aim of this study was to assess the efficacy and cost-effectiveness of ETC started at lower doses than those suggested by the manufacturer in patients with moderate sHPT. Methods This is a retrospective observational study comparing two different initial ETC dosing strategies, a “Low-dose approach” (LD, ETC starting dose<10 mg/week) and a “Classic approach” (CL, ETC starting dose≥10 mg/week), in terms of effects on CKD-MBD related biomarkers and costs during the first year of prescription. The study was conducted on HD patients with basal PTH between 500 and 1500 ng/l, treated with ETC for at least 3 months between 2018 and 2022 at ASST Spedali Civili di Brescia. Monthly monitoring of serum calcium, phosphorus and PTH was performed in both groups for dose adjustment. Results Overall, 53 patients were identified, 24 in the LD and 29 in the CL group. Both groups showed similar baseline characteristics (Table 1). Median follow-up was 52 weeks, during which 4 patients (one in the LD and three in the CL group) discontinued ETC (Table 1). At the end of follow-up, 92% of patients in the LD and 90% in the CL group achieved a decrease in PTH ≥30% compared to baseline, with median PTH levels of 282 (207 - 332) and 294 (151 – 382) ng/l, respectively (p = 0.825). Other CKD-MBD biochemical parameters were comparable between the two groups at all timepoints (Figure 1). The median of average ETC weekly doses per patient was 7.6 (6.2 – 10.2) mg in the LD and 10.6 (9.7 – 15) mg in the CL group (p<0.001). During follow-up, the median ETC dose remained stable in the LD group, while partially decreasing in the CL group (Figure 1). Use of paricalcitol was comparable in both groups. At cost analysis, the median of average ETC weekly costs per patient was €36.6 (29.6 – 50.0) in the LD and €50.5 (46.4 – 71.7) in the CL group (p<0.001). This translates into an average yearly cost per patient of €1909 and €2635 using the LD and CL approach, respectively, with a saving of €726 per patient-year in favour of the LD strategy. Conclusion In this retrospective study in HD patients with moderate sHPT, we showed that starting ETC at a lower dose than the one suggested by the manufacturer is as effective as the classic approach in terms of control of CKD-MBD parameters, with a significant reduction in treatment costs. Future prospective studies will be needed to validate the results in bigger cohorts, test whether these benefits can extend beyond the first year of treatment and assess the effects on FGF23 levels and other relevant clinical outcomes.

The value of intraoperative parathyroid hormone monitoring in patients with primary hyperparathyroidism and varying baseline parathyroid hormone levels.

When applying intraoperative parathyroid hormone monitoring (IOPTH) to patients with primary hyperparathyroidism (PHPT), there are established criteria predicting biochemical cure in patients with basal parathyroid hormone (PTH) levels in the medium range (100-400 pg/ml); however, there is a challenge concerning patients with low (less than 100 pg/ml) or high (more than 400 pg/ml) basal PTH levels. The aim of this study was to investigate the value of the 'Vienna criterion' applied during IOPTH in patients with PHPT and various basal PTH concentrations. Consecutive patients between 1999-2009 with a biochemical diagnosis of PHPT who underwent surgical parathyroidectomy were included. Based on preoperative PTH levels they were divided into three groups: group 1 (low) (<100 pg/ml), group 2 (medium) (100-400 pg/ml) and group 3 (high) (>400 pg/ml) basal PTH. PTH was measured at the start of the operation, when the gland was excised and then at 5, 10 and 15 min after. Calcium and PTH levels were measured at 7 days and 12 months postoperatively. Sensitivity, specificity, positive and negative predictive value, as well as accuracy of IOPTH were calculated for the different groups postoperatively. 675 patients with PHPT were analysed. Sensitivity and specificity were 83.7 per cent and 66.7 per cent in group 1 (n = 187), 90.7 per cent and 69.2 per cent in group 2 (n = 433), and 94.4 per cent and 100 per cent in group 3 (n = 55) to predict cure. Preoperative creatinine (p = 0.002) showed significant statistical difference between the groups but was not related to intraoperative PTH decline. At 12 months follow-up normocalcaemia was documented in 98.9 per cent in group 1, 99.0 per cent group 2, and 98.0 per cent of group 3 patients. Normocalcaemia was predicted intraoperatively by applying the 'Vienna criterion' in 98 to 100 per cent and was confirmed after 12 months follow-up in up to 99.0 per cent of patients. Low specificity and a high false-negative rate in patients with low basal PTH show that other criteria might be better suited for this group.

Longitudinal Bone Loss Occurs at the Radius in CKD

IntroductionChronic kidney disease (CKD) exposes to an increased incidence of fragility fractures. International guidelines recommend performing bone mineral density (BMD) if the results will impact treatment decisions. It remains unknown where bone loss occurs and what would preclude the longitudinal loss in patients with CKD. Here, we aimed to investigate factors influencing BMD and to analyze the longitudinal BMD changes.MethodsIn the NephroTest cohort, we measured BMD at the femoral neck, total hip, lumbar spine, and proximal radius, together with circulating biomarkers and standardized measured glomerular filtration rate (mGFR) by 51Cr-EDTA in a subset of patients with CKD stage 1 to 5 followed during 4.3 ± 2.0 years. A linear mixed model explored the longitudinal bone loss and the relationship of associated factors with BMD changes. A total of 858 patients (mean age 58.9 ± 15.2 years) had at least 1 and 477 had at least 2 BMD measures.ResultsAt baseline, cross-sectional analysis showed a significantly lower BMD at femoral neck and total hip and a significant higher serum parathyroid hormone (PTH) along with CKD stages. Baseline age, gender, tobacco, low body mass index (BMI), and high PTH levels were significantly associated with low BMD. Longitudinal analysis during the mean 4.3 years revealed a significant bone loss at the radius only. BMD changes at the femoral neck were associated with BMI, but not CKD stages or basal PTH levels.ConclusionsCKD is associated with low BMD and high PTH in the cross-sectional analysis. Longitudinal bone loss occurred at the proximal radius after 4.3 years.

Effects of Pamidronate and Calcitriol on the Set Point of the Parathyroid Gland in Postmenopausal Hemodialysis Patients with Secondary Hyperparathyroidism

Background/Aims: Secondary hyperparathyroidism may worsen after the administration of pamidronate in postmenopausal hemodialysis (HD) patients. The aim of this study was to evaluate the short-term effect of coadministration of calcitriol and pamidronate on dynamic parathyroid hormone (PTH) secretion. Methods: Fifteen postmenopausal women undergoing regular HD with serum intact PTH levels of >200 pg/ml were enrolled. The PTH-ionized calcium (iCa) curve was evaluated by the response to hypo- and hypercalcemia induced with 1 and 4 mEq/l of dialysate calcium, respectively. Parameters were compared after pamidronate was administered and after coadministration of pamidronate and calcitriol. Changes in serum levels of maximal serum PTH (PTH_max), basal PTH (PTH_base) and minimal PTH (PTH_min) were evaluated. Results: Pamidronate therapy resulted in a decrease in predialysis basal plasma iCa (p < 0.05) and an increase in PTH_max (p < 0.01), PTH_base (p < 0.01) and PTH_min (p < 0.01). The change in serum iCa and PTH was reversed after the coadministration of calcitriol and pamidronate. Conclusion: Our study demonstrated that pamidronate therapy is associated with a reduced plasma iCa and increased PTH secretion. These adverse effects may be reversed by calcitriol. These findings suggest that in considering pamidronate treatment in postmenopausal patients with osteoporosis receiving HD, it might be safer to add calcitriol to prevent the increased PTH secretion.

Efecto de cinacalcet sobre la hormona paratiroidea en el hiperparatiroidismo hipercalcémico del trasplantado renal

Background and objectivesCinacalcet reduces parathyroid hormone (PTH) levels in uremic hyperparathyroidism (HPT), and in renal transplantation it is useful in the management of HPT with hypercalcemia. Our main aim is to evaluate if cinacalcet administered once daily, reduces and maintains reduced PTH levels for 24hours in renal transplant recipients with HPT and hypercalcemia. Patients and methodWe studied PTH levels and other bone biomarkers in two groups of renal transplant recipients: one with HPT and hypercalcemia (Group 1), another without alteration of mineral metabolism (Group 2), and a third group of healthy volunteers (Group 3): 35 subjets. Group 1 received a single dose of 60mg of cinacalcet at 9 am. In all the groups we withdrew blood samples at 8, 10, 11, 12, 13, 19hours (day 1) and 9 am the following day (day 2), determining levels of PTH and bone biomarkers. ResultsIn Group 1, basal PTH levels decreased shortly after dispensing cinacalcet (basal PTH level 237 [86.7] versus 10 hour level 113 [54.7] p<0.05), objectifying a progressive increase to a similar level to baseline after 24hours of the administration (day 2 9h PTH level 241 [117.4] ns). In Group 2, comparisons among PTH mean levels were not different at any time. In Group 3, the mean baseline PTH level was higher than that observed at 10h (47 [22.7] versus 28 [11.2] p<0.05) and other comparisons were not significant. Beta-ctx was higher at baseline in the three groups in comparison with levels at 11, 12, 13 and 19 hour, and similar to that at 10 am on day 1 and 9 am on day 2. With respect to other bone biomarkers, no differences were observed. ConclusionCinacalcet administered once daily reduces PTH in renal transplant recipients with HPT and hypercalcemia, without holding it for 24hours.

The peptidyl-prolyl isomerase Pin1 determines parathyroid hormone mRNA levels and stability in rat models of secondary hyperparathyroidism

Secondary hyperparathyroidism is a major complication of chronic kidney disease (CKD). In experimental models of secondary hyperparathyroidism induced by hypocalcemia or CKD, parathyroid hormone (PTH) mRNA levels increase due to increased PTH mRNA stability. K-homology splicing regulator protein (KSRP) decreases the stability of PTH mRNA upon binding a cis-acting element in the PTH mRNA 3' UTR region. As the peptidyl-prolyl isomerase (PPIase) Pin1 has recently been shown to regulate the turnover of multiple cytokine mRNAs, we investigated the role of Pin1 in regulating PTH mRNA stability in rat parathyroids and transfected cells. The data generated were consistent with Pin1 being a PTH mRNA destabilizing protein. Initial analysis indicated that Pin1 activity was decreased in parathyroid protein extracts from both hypocalcemic and CKD rats and that pharmacologic inhibition of Pin1 increased PTH mRNA levels posttranscriptionally in rat parathyroid and in transfected cells. Pin1 mediated its effects via interaction with KSRP, which led to KSRP dephosphorylation and activation. In the rat parathyroid, Pin1 inhibition decreased KSRP-PTH mRNA interactions, increasing PTH mRNA levels. Furthermore, Pin1-/- mice displayed increased serum PTH and PTH mRNA levels, suggesting that Pin1 determines basal PTH expression in vivo. These results demonstrate that Pin1 is a key mediator of PTH mRNA stability and indicate a role for Pin1 in the pathogenesis of secondary hyperparathyroidism in individuals with CKD.

Deletion of the vitamin D receptor specifically in the parathyroid demonstrates a limited role for the receptor in parathyroid physiology

1,25(OH)2D3 decreases parathyroid hormone (PTH) gene transcription through the vitamin D receptor (VDR). Total body VDR(-/-) mice have high PTH levels, hypocalcemia, hypophosphatemia, and bone malformations. To investigate PTH regulation by the VDR specifically in the parathyroid, we generated parathyroid-specific VDR knockout mice (PT-VDR(-/-)). In both strains, there was a decrease in parathyroid calcium receptor (CaR) levels. The number of proliferating parathyroid cells was increased in the VDR(-/-) mice but not in the PT-VDR(-/-) mice. Serum PTH levels were moderately but significantly increased in the PT-VDR(-/-) mice with normal serum calcium levels. The sensitivity of the parathyroid glands of the PT-VDR(-/-) mice to calcium was intact as measured by serum PTH levels after changes in serum calcium. This indicates that the reduced CaR in the PT-VDR(-/-) mice enables a physiologic response to serum calcium. Serum C-terminal collagen crosslinks, a marker of bone resorption, were increased in the PT-VDR(-/-) mice with no change in the bone formation marker, serum osteocalcin, consistent with a resorptive effect due to the increased serum PTH levels in the PT-VDR(-/-) mice. Therefore, deletion of the VDR specifically in the parathyroid decreases parathyroid CaR expression and only moderately increases basal PTH levels, suggesting that the VDR has a limited role in parathyroid physiology.

Dynamics of Parathyroid Hormone Secretion in Health and Secondary Hyperparathyroidism

This review examines the dynamics of parathyroid hormone secretion in health and in various causes of secondary hyperparathyroidism. Although most studies of parathyroid hormone and calcium have focused on the modification of parathyroid hormone secretion by serum calcium, the relationship between parathyroid hormone and serum calcium is bifunctional because parathyroid hormone also modifies serum calcium. In normal animals and humans, factors such as phosphorus and vitamin D modify the basal parathyroid hormone level and the maximal parathyroid hormone response to hypocalcemia. Certain medications, such as lithium and estrogen, in normal individuals and sustained changes in the serum calcium concentration in hemodialysis patients change the set point of calcium, which reflects the serum calcium concentration at which parathyroid hormone secretion responds. Hypocalcemia increases the basal/maximal parathyroid hormone ratio, a measure of the relative degree of parathyroid hormone stimulation. The phenomenon of hysteresis, defined as a different parathyroid hormone value for the same serum calcium concentration during the induction of and recovery from hypo- and hypercalcemia, is discussed because it provides important insights into factors that affect parathyroid hormone secretion. In three causes of secondary hyperparathyroidism--chronic kidney disease, vitamin D deficiency, and aging--factors that affect the dynamics of parathyroid hormone secretion are evaluated in detail. During recovery from vitamin D deficiency, the maximal parathyroid hormone remains elevated while the basal parathyroid hormone value rapidly becomes normal because of a shift in the set point of calcium. Much remains to be learned about the dynamics of parathyroid hormone secretion in health and secondary hyperparathyroidism.

Evaluation of a standardized short-time calcium suppression test in healthy subjects: interest for the diagnosis of primary hyperparathyroidism

The diagnosis of primary hyperparathyroidism (PHP) can be difficult in patients with normal plasma calcium or parathyroid hormone (PTH) levels. We perfected a standardized short-time i.v. calcium loading test in healthy controls (HC) and compared the results with those of patients with PHP. Sixteen HC received 0.33 mmol/kg calcium gluconate intravenously for 3 h. Plasma calcium and serum PTH levels (assayed with immunoluminescent sandwich methods) were measured before, at the end of the infusion and 3 h later. Results were compared with those of 16 PHP patients. In HC, basal total plasma calcium (mean +/- s.e.m.) was 2.33 +/- 0.02 mmol/l. At the end of calcium loading, calcemia reached 3.21 +/- 0.05 mmol/l and decreased to 2.94 +/- 0.08 mmol/l 3 h later. In PHP patients, basal plasma calcium was 2.54 +/- 0.03 mmol/l and reached similar values as in HC during the testing. Basal serum PTH levels were 32.5 +/- 3.3 ng/l in HC and 86.9 +/- 6.3 ng/l in PHP. At the end of calcium loading, they dropped to 8.8 +/- 0.6 ng/l (HC) and to 31.4 +/- 4.2 ng/l (PHP). Three hours later, they were 11.6 +/- 0.8 and 39.8 +/- 4.0 ng/l respectively. There was a cut-off in serum PTH values between the two groups at the end of calcium loading and 3 h later. The standardized short-time PTH suppression test appears reliable to differentiate healthy subjects from PHP whose serum PTH levels remain >14 and >23 ng/ml respectively at the end of loading and 3 h later. This well-tolerated and easily performed test could be used for the diagnosis of PHP in patients suspected for the disease despite the normality of some basal biological markers.

Endothelin-1 regulates parathyroid hormone expression of human parathyroid cells

Parathyroid cells synthesize and release endothelin-1 (ET-1). ET-1 displays an in vitro inhibitory effect on basal parathyroid hormone (PTH) secretion and also counteracts PTH hypersecretion stimulated by low calcium. Such effects are further demonstrated in vivo, independent of the changes in calcitonin. We propose that ET-1 may regulate the pathogenesis of uremic hyperparathyroidism. However, this was not directly demonstrated in human parathyroid glands. Hyperplastic parathyroid glands are obtained from the surgical operation for uremic hyperparathyroidism. Cells are isolated by enzyme digestion and treated with ET-1, and are assessed for PTH mRNA expression. PTH in the plasma and the medium is measured by a newly developed method to detect the whole PTH (1-84). Uremic patients with severe secondary hyperparathyroidism and ultrasonography-proved hypertrophy of parathyroid glands received elective surgical approaches under general anesthesia. The resected glands were immediately taken to the laboratory for fresh isolation. Following ET-1 treatment, PTH mRNA expression is evaluated by RT-PCR method. ET-1 is detected with radioimmunoassay kit and PTH is measured by a new commercially available Duo PTH kit. ET-1 exhibited a dose-dependent inhibitory effect (from 10(-12) - 10(-7) M) on PTH mRNA expression of parathyroid cells, either in the basal or in the low-calcium-stimulated states. Release of PTH into the medium is also gradually inhibited by the increase in ET-1 concentrations. Our results demonstrate that ET-1 attenuates PTH mRNA expression in freshly isolated human parathyroid cells, and PTH release is also decreased. This result is consistent with our previously reported in vitro and in vivo experiments.

Inter-method variability in PTH measurement: Implication for the care of CKD patients

The National Kidney Foundation/Kidney-Dialysis Outcome Quality Initiative guidelines recommend to maintain the serum intact parathyroid hormone (PTH) concentration between 150 and 300 ng/l in chronic kidney disease (CKD) stage 5 patients. As these limits were derived from studies that used the Allegro intact PTH assay, we aimed to evaluate whether they were applicable to other PTH assays. We compared the PTH concentrations measured with 15 commercial immunoassays in 47 serum pools from dialysis patients, using the Allegro intact PTH assay as the reference. We also evaluated the recovery of graded amounts of synthetic 1-84 and 7-84 PTH added separately to a serum pool. Although the assays were highly correlated, the concentrations differed from one assay to another. The median bias between the tested assays and the Allegro intact PTH assay ranged from -44.9 to 123.0%. When the PTH concentrations were 150 or 300 ng/l with the Allegro intact PTH assay, they ranged with other assays from 83 to 323 ng/l and from 160 to 638 ng/l, respectively. The tested assays recognized 7-84 PTH with various cross-reactivities, whereas a given amount of 1-84 PTH was recovered differently by these assays. We found important inter-method variability in PTH results owing to both antibody specificity and standardization reasons. The unacceptable consequence is that opposite therapeutic attitudes may be reached in a single patient depending on the PTH assay used. We propose to use assay-specific decision limits for CKD patients, or to apply a correcting factor to the PTH results obtained with a given assay.

Intact parathyroid hormone in primary hyperparathyroidism

In 49 patients with primary hyperparathyroidism, intact parathyroid hormone (PTH) was measured with a recently developed immunoradiometric assay, and midregional PTH fragments (sequence 44-68) were measured with an established radioimmunoassay technique. In 47 normal subjects, the concentration of intact PTH ranged from 2.0 to 6.8 pmol/l, and in 49 patients with primary hyperparathyroidism it ranged from 6.4 to 80.0 pmol/l. In contrast, midregional PTH fragments were normal in seven of 49 patients with primary hyperparathyroidism. In five healthy controls and in 12 patients with surgically confirmed primary hyperparathyroidism and serum calcium levels below 3.0 mmol/l, a rapid calcium loading test was performed. In healthy controls, intact PTH was in the low normal to subnormal range within 2.5-5.0 min, and had recovered within 15 min of calcium infusion. In patients with primary hyperparathyroidism, the calcium infusion also led to a 30-50 per cent decrease in intact PTH levels within 5.0-7.5 min after injection, with a slow recovery after 10-15 min. In six of the patients with only slightly elevated basal intact PTH, a suppression to the normal range was observed. In 24 patients (16 patients with a solitary adenoma and eight patients with four-gland hyperplasia) the intact PTH levels were followed intraoperatively during parathyroidectomy, revealing a significantly different rate of decline for single adenomas compared with hyperplasia during the first 15 min after removal of the primary enlarged gland. Intact PTH values remained constantly elevated in one patient with primary hyperparathyroidism and an unsuccessful neck exploration. These results confirm that (a) the measurement of intact PTH in patients with primary hyperparathyroidism is superior to the measurement of midregional fragments; (b) PTH secretion in primary hyperparathyroidism is not totally autonomous; and (c) intraoperative monitoring of intact PTH values could be used to monitor the success of surgery.

Structural organization and biological relevance of oscillatory parathyroid hormone secretion

Parathyroid gland secretory activity exhibits seasonal and circadian fluctuations, which are in synchrony with changes in serum calcium, phosphate, and bone turnover. In addition, an ultradian rhythm exists, which comprises seven pulses per hour, accounts for 30% of basal parathyroid hormone (PTH) release, and is highly sensitive to changes in ionized calcium. Acute hypocalcemia induces a selective, severalfold increase in pulse frequency and amplitude, whereas hypercalcemia suppresses the pulsatile secretion component, as does prolonged calcitriol therapy. Chronic renal failure is associated with a GFR dependent decrease in metabolic PTH clearance accounting for a two- to threefold increase in plasma PTH concentrations, a consistent increase of PTH burst mass and frequency, and a markedly reduced capacity to counteract changes in ionized calcium by modulation of pulsatile PTH release. Continuous PTH excess destroys bone, whereas intermittent administration of pharmacological doses of PTH improves bone morphology and strength in experimental and clinical settings. The molecular mechanisms of the exposure pattern dependent, contrasting biological effects of PTH may involve differential regulation of osteoblastic G protein signaling feedback circuits. In this context, calcimimetic and calcilytic agents are promising new therapeutic tools allowing for tight control of plasma PTH and restoration of circadian PTH rhythmicity.

Failure to normalize parathyroid hormone during treatment of vitamin D deficiency in Asian patients

Vitamin D deficiency and osteomalacia remain commonplace within the Asian community in Bradford. The treatment of vitamin D deficiency and osteomalacia is cheap and effective, but there are few data on long-term outcomes. Studies have suggested that a minority of patients fail to normalize parathyroid hormone (PTH) levels during therapy with vitamin D. This study aimed to determine what proportion of Asian patients with vitamin D deficiency and secondary hyperparathyroidism normalize PTH levels following therapy with oral vitamin D and to examine reasons for failure to normalize PTH. This study examined the impact of an oral regimen of vitamin D 800 i.u. (20 micrograms) and calcium 1000 mg daily, on PTH levels within an endocrinology outpatient clinic. patients 51 (4M:47F) Asian patients, median age 39 years (range 16-77 years) with vitamin D deficiency (25-hydroxyvitamin D < 25 nmol/l) and secondary hyperparathyroidism (PTH > 5.7 pmol/l). All patients had at least one follow-up measurement of PTH and calcium during treatment. A subgroup of patients gave consent for examination of GP-prescribing records to indirectly asses adherence to therapy. PTH normalized in only 28/51 (55%) patients (group N) and failed to normalize in 23/51 (45%) patients (group F). Baseline patient characteristics including: age, basal serum 25-hydroxyvitamin D (25OHD), basal serum PTH, basal serum calcium and post treatment serum calcium, were similar in groups N and F. Mild hypercalcaemia occurred in only two (3.9%) patients. The proportion of prescriptions collected by patients in group N was 75 (17-100)% and in group F was 17 (0-100)%, P < 0.0001. This study has demonstrated that long-term oral treatment with vitamin D and calcium, fails to normalize PTH in a significant proportion of patients with vitamin D deficiency and osteomalacia. This is most likely related to lack of adherence to long-term treatment. Improved ways of treating this condition need to be explored.

Parathyroid gland function in the uremic rabbit

Rabbits with renal failure have been reported to be hypercalcemic and to have decreased parathyroid hormone (PTH) concentrations. Thus, it would seem that uremic rabbits are resistant to secondary hyperparathyroidism (HPT). The work reported here was designed to investigate parathyroid gland function in uremic rabbits and the effect of diets with different calcium (Ca) and phosphorus (P) content. The relationship between PTH and ionized calcium (Ca 2+), parathyroid gland size and parathyroid cell cycle were studied in three groups of rabbits: Group I, rabbits with normal renal function on a standard diet (Ca=1.2%, P=0.6%); Group II, partially nephrectomized rabbits on a standard diet; and Group III, partially nephrectomized rabbits on a low Ca (0.6%)–high P (1.2%) diet. Group I rabbits had baseline Ca 2+=1.71±0.05 mmol/l and PTH=26.9±3.2 pg/ml. During hypo- and hypercalcemic stimulation PTH reached maximal values (PTH max) of 94.4±5.5 pg/ml and minimal concentrations (PTH min) of 3.2±0.2 pg/ml. Rabbits from Group II were hypercalcemic (baseline Ca 2+=2.03±0.06 mmol/l) and had very low PTH levels (1.7±0.5 pg/ml); however, they reached a PTH max that was similar to Group I, 92±8.7 pg/ml. Group III rabbits were hypocalcemic (baseline Ca 2+=1.22±0.08 mmol/l) and had very high basal PTH levels (739±155 pg/ml). Their PTH max and PTH min were 801±169.4 pg/ml and 102.2±22.2 pg/ml, respectively. Both parathyroid gland size and parathyroid cell proliferation were increased in Group III. In conclusion, our results show that the Ca and P content of the diet markedly influence PTH secretion in the uremic rabbit and that when placed on a low Ca–high P diet uremic rabbits develop secondary HPT.

Acute effect of pamidronate on PTH secretion in postmenopausal hemodialysis patients with secondary hyperparathyroidism

Background: The purpose of this study is to evaluate the acute effect of pamidronate on plasma ionized calcium (iCa) level reduction and dynamic parathyroid hormone (PTH) secretion in postmenopausal hemodialysis-dependent women with secondary hyperparathyroidism. Methods: Twelve postmenopausal women undergoing regular hemodialysis with serum intact PTH levels greater than 200 pg/mL (200 ng/L) were included in this study. Pamidronate was administered intravenously as a single dose of 15 mg in the last hour of hemodialysis. PTH responses to hypocalcemia and hypercalcemia induced with 1 mEq/L (0.5 mmol/L) and 4 mEq/L (2 mmol/L) of dialysate calcium, respectively, were evaluated before and 1 week after pamidronate therapy. Results: Pamidronate therapy resulted in a decrease in predialysis basal plasma iCa (iCabase; P < 0.05) levels and an increase in maximal serum PTH (PTHmax; P < 0.001), basal PTH (PTHbase; P < 0.001), and minimal PTH levels (P < 0.001). The set point of serum calcium and the slope of the PTH-calcium curve were not altered by pamidronate therapy. An inverse correlation was present between iCabase and the PTHbase-PTHmax ratio before (r = −0.66; P < 0.05) and after (r = −0.84; P < 0.001) pamidronate therapy. Conclusion: Our study shows that pamidronate therapy is associated with reduced plasma iCa levels and increased PTH secretion, resulting in aggravated secondary hyperparathyroidism. These findings suggest that secondary hyperparathyroidism may worsen after the administration of pamidronate, at least in the short term, in postmenopausal hemodialysis patients.

Autoregulation in the parathyroid glands by PTH/PTHrP receptor ligands in normal and uremic rats

The secretion of parathyroid hormone (PTH) from the parathyroid glands might be regulated by autocrine/paracrine factors. We have previously shown that N-terminal parathyroid hormone-related protein (PTHrP) enhanced the secretory PTH response to low calcium in vivo and in vitro in rat parathyroid glands. N-terminal PTHrP fragments are equipotent to N-terminal PTH as ligands for the PTH/PTHrP receptor that is demonstrated in parathyroid tissue. This supports the possibility that the parathyroid cells respond to PTH/PTHrP receptor ligands and as such are target for an autoregulatory action of PTH and PTHrP. Our aim was to search for the PTH/PTHrP receptor in rat parathyroid glands and to examine the effects of PTHrP 1-40 on PTH secretion in in vivo models of secondary hyperparathyroidism (HPT) in uremic rats. PTH secretion was examined during ethyleneglycol tetraacetic acid (EGTA)-induced hypocalcemia both with and without PTHrP. Five groups, each of six normal rats, received a bolus of increasing doses of 0.1, 1.0, 10, and 100 microg of PTHrP 1-40, or vehicle only. Chronic renal failure (CRF) was induced by 5/6 nephrectomy. One group of 12 CRF rats received a standard diet, while another CRF group of 18 rats received a high phosphorus diet to induce more severe HPT. After 8 weeks of uremia, the rats were infused with EGTA and PTHrP 1-40 or vehicle. The presence of the PTH/PTHrP receptor in the rat parathyroid glands was examined by reverse transcription-polymerase chain reaction (RT-PCR) technique. PTH was measured by a rat PTH assay that does not cross-react with PTHrP. In a dose-related manner, PTHrP enhanced the PTH response to hypocalcemia in normal rats. A similar rate of decrease of plasma Ca++ was induced by EGTA in all experimental groups. In CRF rats, plasma creatinine (0.99 +/- 0.10 mmol/L vs. 0.33 +/- 0.01 mmol/L, P < 0.001) and plasma PTH (226 +/- 32 pg/mL vs. 69 +/- 16 pg/mL, P < 0.001) levels were significantly increased. The CRF rats on high phosphorus diet had significant hypocalcemia (Ca++, 1.04 +/- 0.02 mmol/L vs. 1.28 +/- 0.03 mmol/L, P < 0.001), hyperphosphatemia (3.48 +/- 0.3 mmol/L vs. 2.25 +/- 0.1 mmol/L, P < 0.001) and severe secondary HPT, PTH (984 +/- 52 pg/mL vs. 226 +/- 32 pg/mL, P < 0.001) compared to CRF rats on a standard phosphorus diet. The maximal PTH response to hypocalcemia was enhanced in CRF rats (maximum PTH 382 +/- 58 pg/mL vs. 196 +/- 29 pg/mL in normal rats, P < 0.01) and further enhanced by PTHrP 1-40 to 826 +/- 184 pg/mL (P < 0.01). The secretory capacity of the parathyroid glands in response to low Ca++ was severely diminished in uremia. In CRF rats given a high phosphorus diet, the basal PTH levels were at the upper part of the calcium/PTH curve, and the induction of more marked hypocalcemia did not stimulate PTH secretion further (maximum PTH 1475 +/- 208 pg/mL vs. basal 1097 +/- 69 pg/mL, NS). PTHrP, however, further enhanced the maximal PTH levels significantly (maximum PTH 3142 +/- 296 pg/mL, P < 0.01). The presence of the PTH/PTHrP receptor in the rat parathyroid glands was confirmed by RT-PCR technique. PTHrP enhanced significantly, in a dose-related manner, the low Ca++-stimulated PTH secretion in normal rats. The PTH/PTHrP receptor is present in rat parathyroid glands. The impaired secretory capacity of the parathyroid glands in uremic rats is significantly enhanced by PTHrP. An autocrine/paracrine role in the parathyroid glands of the PTH/PTHrP receptor targeting peptides, PTHrP and PTH, is suggested. Thus, it is hypothesized that PTH during hypocalcemia might have a positive auto-feedback regulatory role on its own secretion.

Pathogenesis of refractory secondary hyperparathyroidism

Calcitriol is currently used to reduce parathyroid hormone (PTH) levels in uremic patients. However, a significant number of patients fail to respond to calcitriol therapy. The data suggest that a poor response to calcitriol can be anticipated in patients with severe hyperparathyroidism (with a high basal PTH levels) and uncontrolled serum phosphate. The abnormal parathyroid response to calcitriol in uremic patients with severe parathyroid hyperplasia may be attributed, to a large extent, to the development of nodular hyperplasia as a result of clonal transformation from a diffuse polyclonal hyperplasia. The factors involved in the development of polyclonal parathyroid hyperplasia, at earlier stages of secondary hyperparathyroidism, appear to be the same factors that stimulate PTH secretion and synthesis: hypocalcemia, hyperphosphatemia and low serum calcitriol levels. Studies performed in vitro using parathyroid tissue from uremic patients who required parathyroidectomy demonstrate that in nodular hyperplasia there is an abnormal response to calcium and calcitriol, which suggests that there are factors intrinsic to the hyperplastic cell (such as decrease in calcium sensor receptors and vitamin D receptors) responsible for an abnormal regulation of parathyroid function. Accumulation of phosphate is a key factor in the pathogenesis of secondary hyperparathyroidism and a poor response to calcitriol treatment is associated with the failure to control the serum phosphorus. High phosphate stimulates PTH secretion as demonstrated by in vivo and in vitro studies. In addition, animal studies strongly suggest that phosphate increases parathyroid cell proliferation. There are growth-related genes potentially involved in uremic hyperparathyroidism; however, changes in the expression of these genes may be the consequence rather than the cause of parathyroid hyperplasia.

Effect of calcitriol treatment and withdrawal on hyperparathyroidism in haemodialysis patients with hypocalcaemia

Calcitriol is used to treat secondary hyperparathyroidism in dialysis patients. For similarly elevated parathyroid hormone (PTH) levels, the PTH response to calcitriol treatment is believed to be better in hypocalcaemic dialysis patients than in dialysis patients with higher serum calcium values. Furthermore, few studies have evaluated the rapidity of the rebound in serum PTH values after prolonged treatment with calcitriol. Our goal was to evaluate (i) the PTH response to calcitriol treatment in hypocalcaemic haemodialysis patients, (ii) the rapidity of rebound in PTH after calcitriol treatment was stopped, and (iii) whether the effect of calcitriol treatment on PTH levels could be separated from those produced by changes in serum calcium and phosphate values. Eight haemodialysis patients (29+/-3 years) with hypocalcaemia and hyperparathyroidism were treated thrice weekly with 2 microg of intravenous calcitriol and were dialysed with a 3.5 mEq/l calcium dialysate. Parathyroid function (PTH-calcium curve) was determined before and after 30 weeks of calcitriol treatment and 15 weeks after calcitriol treatment was stopped. Pretreatment PTH and ionized calcium values were 907+/-127 pg/ml and 3.89+/-0.12 mg/dl (normal, 4.52+/-0.07 mg/dl). During calcitriol treatment, one patient did not respond, but basal (predialysis) PTH values in the other seven patients decreased from 846+/-129 to 72+/-12 pg/ml, P<0.001 and in all seven patients, the decrease exceeded 85%. During the 15 weeks after calcitriol treatment was stopped, a slow rebound in basal PTH values in the seven patients was observed, 72+/-12 to 375+/-44 pg/ml. Covariance analysis was used to evaluate the three tests of parathyroid function (0, 30, and 45 weeks), and showed that calcitriol treatment was associated with reductions in maximal PTH values while reductions in basal PTH were affected by ionized calcium and serum phosphate. The basal/maximal PTH ratio and the set point of calcium were associated with changes in ionized calcium. In haemodialysis patients with hypocalcaemia, (i) moderate to severe hyperparathyroidism responded well to treatment with calcitriol, (ii) reductions in maximal PTH were calcitriol dependent while reductions in basal PTH were affected by the ionized calcium and serum phosphate concentrations, (iii) changes in the basal/maximal PTH ratio and the set point of calcium were calcium dependent, and (iv) the delayed rebound in basal PTH levels after withdrawal of calcitriol treatment may have been due to the long duration of treatment and the marked PTH suppression during treatment.