Immunoheterogeneity of parathyroid hormone pre- and postoperatively in primary hyperparathyroidism

Zusammenfassung Bei primärem Hyperparathyreoidismus (pHPT) kann, wie man weiß, eine Freisetzung eher von intaktem PTH (i-PTH) als von Fragmenten mit end-ständigen Carboxylgruppen erfolgen. Wir untersuchten, ob die Freisetzung von PTH-Fragmenten mit terminalen Aminogruppen (N-PTH) sich ebenfalls ändert. Es wurden die Serumspiegel von i-PTH und N-PTH unter folgenden Bedingungen bestimmt: (1) bei 6 pHPT-Patienten (a) ohne Kalziumgabe, (b) nach oraler Kalziumgabe vor und unmittelbar nach Operation und (2) bei 7 gesunden Personen. Bei ersteren waren präoperativ beide Spiegel — i-PTH und N-PTH — erhöht, die i-PTH-Spiegel etwas stärker. Daher war das Verhältnis N-PTH/i-PTH im Vergleich zu gesunden Personen vermindert (p<0,05). Postoperativ war am 1. Tag das Serum-i-PTH stärker vermindert als das N-PTH, wodurch das N-PTH/i-PTH-Verhältnis gegenüber Gesunden zunahm (p<0,05); am 5. Tag normalisierte sich dieses Verhältnis. Präoperativ verbesserte sich die Supprimierung von i-PTH-Kalzium bei den Patienten, während die Supprimierung von N-PTH-Kalzium normal blieb, was seinen Ausdruck fand in einem unveränderten N-PTH/i-PTH-Verhältnis während der oralen Kalziumeinnahme. Im Gegensatz dazu vergrößerte sich das N-PTH/i-PTH-Verhältnis in normaler Weise während der Kalziumeinnahme am 5. Tag postoperativ (p<0,05). Schlußfolgerungen: (1) Bei pHPT ändert sich die zirkulierende PTH-Immunheterogenität mit einer vorzugsweisen Freisetzung von i-PTH im Vergleich zu N-PTH, und diese Veränderung normalisiert sich nach Operation. (2) Die Sekretion von i-PTH und N-PTH zeigt unterschiedliche Sensitivität gegenüber einer Inhibierung durch Kalzium.

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Immunoheterogeneity of parathyroid hormone pre- and postoperatively in primary hyperparathyroidism

In primary hyperparathyroidism (pHPT), a preferential release of intact PTH (i-PTH) versus carboxyl-terminal PTH fragments is known to occur. We studied whether the release of amino-terminal PTH fragments (N-PTH) is also changed. Serum levels of i-PTH and N-PTH were determined under basal conditions and following oral intake of calcium in six patients with pHPT before and immediately after surgery and in seven healthy subjects. In the patients, baseline levels of both i-PTH and N-PTH were increased preoperatively. The increase was larger in i-PTH compared to N-PTH. Therefore, the N/i ratio was reduced compared to healthy subjects (P<0.05). On the first postoperative day, serum i-PTH decreased to a larger extent than N-PTH, which increased the N/i ratio above that in healthy subjects (P< 0.05). On the 5th postoperative day, the N/i ratio was normalized. Preoperatively, the suppressibility of i-PTH calcium was impaired in the patients (P<0.05), whereas the suppressibility of N-PTH was normal, resulting in unchanged N/i ratio during the oral calcium load. In contrast, the N/i ratio increased normally during the calcium load at day 5 postoperatively (P<0.05). We therefore conclude that: (1) in pHPT, circulating PTH immunoheterogeneity is altered with a preferential release of intact PTH compared to N-terminal PTH fragments and this alteration is normalized after surgery, (2) the secretion of intact PTH and N-terminal PTH shows different sensitivity to inhibition by calcium.

     

Parathyroid Hormone Content Distinguishes True Normal Parathyroids from Parathyroids of Patients with Primary Hyperparathyroidism

p < 0.001) for TN parathyroid glands; however, it was not true for glands (grossly normal or otherwise) in patients with HPT. Patient groups were similar with regard to mean patient age and intracellular PTH mRNA levels. Hypercalcemic patients were similar with regard to preoperative serum calcium and PTH levels. NA parathyroids, adenomas, and hyperplasias are different from TN parathyroids with regard to their PTH content. PTH mRNA was similar across all groups. The relation between intracellular PTH mRNA and PTH was significantly absent in patients with HPT compared with TN glands. Furthermore, we have found that PTH content of normal parathyroid in patients with adenoma is similar to that of hyperplastic and adenoma tissues. These data suggest that the PTH content of parathyroid tissues may be of use in differentiating normal from abnormal parathyroids.     

5,000 Parathyroid Operations Without Frozen Section or PTH Assays: Measuring Individual Parathyroid Gland Hormone Production in Real Time

Background  Determining the physiologic activity (hormone production) of individual parathyroid glands can provide tremendous guidance during parathyroidectomy. Methods  A 6.5-year prospective study of 5,000 patients with sporadic, non-multiple endocrime neoplasia (MEN) primary hyperparathyroidism who underwent surgery without frozen section or parathyroid hormone (PTH) assays was conducted. Patients who had a frozen section were not included; the removal of parathyroid glands was determined solely by the physiologic activity of each gland as determined by contained radioactivity. All operations were within 2.25 hours of sestamibi scanning. Ex vivo measurements of parathyroid glands, thyroid nodules, lymph nodes, thymus, and fat were obtained from all patients, constituting >32,000 specimens. All patients had at least two parathyroid glands evaluated; 59% had four glands evaluated. Ratios were compared with histology and preoperative/postoperative labs. Results  Parathyroid glands occur in three distinct groups according to their hormone production, indicating the type of pathology present. Adenomas (n = 5,120) contained 57 ± 38% of background radioactivity; hyperplastic glands (n = 640) contained 16 ± 4%; and normal glands (n = 9,400) contained 4 ± 0.1% (all p < 0.00001). Fat and lymph nodes were always less than normal glands (p < 0.005). There was no overlap between different tissue types in any individual (p < 0.001). Contained radioactivity was a better predictor of cure than histology (p < 0.0001). The average operative time was 19.4 minutes with (99.9%) discharged within 5 hours. The initial cure rate was 99.23% with missed contralateral second adenomas causing all failures (subsequently cured). Conclusions  Measures of sequestered radioactivity is an extremely accurate estimate of individual parathyroid gland hormone production allowing near 100% distinction between normal, hyperplasic, and adenomatous glands as well as distinguishing parathyroids from other neck tissues (fat, lymph nodes, thyroid). This instantaneous measurement is sufficient to determine which glands should be removed and which should remain in situ, while eliminating frozen sections and PTH assays in nearly all patients undergoing parathyroid surgery. This insight allows the operation to progress very rapidly.     

Potential factors regulating serum parathyroid hormone in maintenance hemodialysis patients: 4-year retrospective study

Background. This study was carried out to evaluate potential factors affecting long-term parathyroid function in patients on maintenance hemodialysis. Methods. Biochemical parameters, including intact parathyroid hormone (i-PTH) and intact osteocalcin (i-OC) were analyzed retrospectively in 120 outpatients receiving hemodialysis, for the 4 years between 1992 and 1996. Patients were classified into the following three groups according to their serum i-PTH levels in 1996: low PTH (<100 pg/ml), normal PTH (100–450 pg/ml), and high PTH (≧450 pg/ml). Results. Among the three PTH groups, no differences were found in age, sex, duration of dialysis, and laboratory parameters, except for serum levels of alkaline phosphatase (ALP), i-PTH, and i-OC. The percentage of diabetic patients was higher in the low PTH group than in the other two PTH groups. Both serum ALP and i-PTH levels increased in the high PTH group, and serum i-PTH level decreased in the low PTH group during the 4 years. The change in serum calcium (Ca) level was negatively correlated with that in serum i-PTH level (1994–1996, r = −0.623, 1992–1996, r = −0.565; P <0.0001). A higher correlation coefficient was observed in the low PTH group than in the other PTH groups, although the difference was not significant. A weak positive correlation of the changes in serum inorganic phosphorus (IP) level (1994–1996) and i-PTH level (1994–1996) was found in the high PTH group (r = 0.379, P < 0.05). Conclusion. Serum Ca level may play a determinant role in suppressing serum i-PTH level in hemodialysis patients. Serum IP level may stimulate serum i-PTH level in patients with hyperparathyroidism, although the physiological role of serum IP is yet to be established. Received: March 23, 1999 / Accepted: September 1, 1999     

Acute Effects of 2 Hours of Moderate-Intensity Cycling on Serum Parathyroid Hormone and Calcium

Previous studies have found that serum parathyroid hormone (PTH) increases in response to relatively short (<60 minutes), intense bouts of exercise, possibly as a result of decreases in serum calcium. Whether longer, less intense exercise also stimulates an increase in PTH is not known. The effects of 2 hours of moderate-intensity cycling on serum PTH and calcium were investigated in 20 competitive male cyclists, aged 22–45 years. Serum concentrations of PTH and calcium were measured before and after exercise. Dermal calcium loss was estimated using patch collections and loss of sweat. There were increases in PTH from 40.6 ± 15.6 to 69.5 ± 25.5 pg/mL (P < 0.001) and in serum calcium from 9.3 ± 0.3 to 9.6 ± 0.5 mg/dL (mean ± standard deviation, P = 0.001) in response to exercise. Contraction of plasma volume explained the rise in calcium but not PTH. Dermal calcium loss was estimated at 138.0 ± 71.9 mg for the 2-hour exercise bout. Neither the change in serum calcium nor the dermal calcium loss was significantly related to the increase in PTH. The study demonstrated that prolonged exercise stimulates PTH secretion. The effects of such transient increases in PTH on bone metabolism are not known.     

Insulin-like Growth Factors (IGF) I and II Utilize Different Calcium Signaling Pathways in a Primary Human Parathyroid Cell Culture Model

Background In most cell types, influx of calcium (Ca²⁺) induces a growth or secretory response. The opposite occurs in parathyroid (PTH), cells where there is an inverse relationship between intracellular Ca²⁺ concentration and PTH secretion. We have examined the effects of calcium channel and metabolism modulators on insulin-like growth factors (IGFs) in a parathyroid cell culture model. Methods Cell cultures were prepared from 9 patients undergoing operation for hyperparathyroidism. Following adhesion, the cells were transferred to serum-free medium and dosed with IGF I, II ± ethyleneglycol-bis(β-aminoethyl)-N, N, N′,N′-tetraacetic acid (EGTA), nifedipine, nickel, 2-aminoethoxy-diphenylborate (2-APB), or dantrolene. Proliferation (96 hours) was assessed by measuring tritiated thymidine incorporation and PTH release (1 and 3 hours) assayed by IRMA. Results Both IGF I and II increased DNA synthesis to 162.8% ± 10.6% (SEM) and 131.1% ± 7.7%, respectively (P < 0.05). EGTA at 0.2 mmol (ionized Ca²⁺ 0.2mmol) did not affect the response to both IGFs. EGTA at 2 mmol (ionized Ca²⁺ 0 mmol) reduced the DNA synthesis of IGF I and II to 29% and 26%, respectively (P < 0.05). Nifedipine and nickel (nonspecific Ca²⁺ channel blocker) were equally potent in negating the mitogenic effects of both IGFs. 2-APB (IP₃R blocker) reduced the basal DNA synthesis to 51.3% ± 8.4% but had no effect on either IGF. Dantrolene (ryanodine receptor blocker) negated IGF II induced mitogenisis (74.2% ± 6.7%) and partially inhibited IGF I mitogenesis (123% ± 6%) (P < 0.05). The rate of PTH secretion was greater after IGF II stimulation than after IGF I stimulation. Conclusions IGFs I and II induce mitogenesis by different calcium signaling pathways. These data suggest that parathyroid cells may utilize different calcium signaling pathways to distinguish growth factors and serum calcium changes. An erratum to this article is available at .     

Resetting of parathyroid hormone secretion after vitamin D3 treatment in hypoparathyroidism and after parathyroid adenectomy in primary hyperparathyroidism

The relationship between parathyroid hormone (PTH) secretion and extracellular calcium (Ca) level is reciprocal causality. The equilibrium operating point determines basal PTH secretion rate and basal extracellular Ca level. We studied how this equilibrium was achieved in the subjects with decreased PTH secretion or decreased parathyroid glands number. Basal/maximum ratio of serum PTH, which reflects the basal secretory state of parathyroid glands, was increased in 9 hypoparathyroid patients treated with vitamin D₃ (VD₃) [7 patients with idiopathic hypopar-athyroidism (IHP), and two patients with postsurgical hypoparathyroidism] and in seven of nine parathyroid adenectomized patients. There was a negative correlation between the ratio and basal serum Ca level in the patients with IHP after VD₃ treatment (r=0.7167, P<0.05) and in the patients after parathyroid adenectomy (r=0.7760, P<0.05). The regression curves in these two groups coincided regardless of the difference in maximum PTH secretion rate, which suggested that the basal secretory state of parathyroid glands was determined by extracellular Ca level in a similar manner in these subjects. There was a sigmoidal relationship between basal/maximum ratio of serum PTH and basal serum Ca level, when the data were collected from 15 hypoparathyroid patients before or after VD₃ treatment, 9 parathyroid adenectomized patients, and 10 normal subjects (r=0.9057, P<0.001). This sigmoidal curve is thought to represent the fundamental relationship between the basal secretory state of parathyroid glands and extracellular Ca level.     

Cinacalcet HCl Suppresses <Emphasis Type="Italic">Cyclin D1</Emphasis> Oncogene-Derived Parathyroid Cell Proliferation in a Murine Model for Primary Hyperparathyroidism

Cinacalcet HCl (cinacalcet) is a calcimimetic compound, which suppresses parathyroid (PTH) hormone secretion from parathyroid glands in both primary hyperparathyroidism (PHPT) and secondary hyperparathyroidism (SHPT). We previously reported the suppressive effect of cinacalcet on PTH secretion in vivo in a PHPT model mouse, in which parathyroid-targeted overexpression of the cyclin D1 oncogene caused chronic biochemical hyperparathyroidism and parathyroid cell hyperplasia. Although cinacalcet suppressed parathyroid cell proliferation in SHPT in 5/6-nephrectomized uremic rats, its effect on PHPT has not yet been determined. In this study, the effect of cinacalcet on parathyroid cell proliferation was analyzed in PHPT mice. Cinacalcet (1 mg/g) was mixed into the rodent diet and orally administrated to 80-week-old PHPT mice for 10 days before death. 5-Bromo-2′-deoxyuridine (BrdU, 6 mg/day) was infused by an osmotic pump for 5 days before death, followed by immunostaining of the thyroid–parathyroid complex using an anti-BrdU antibody to estimate parathyroid cell proliferation. Compared to untreated PHPT mice, cinacalcet significantly suppressed both serum calcium and PTH. The proportion of BrdU-positive cells to the total cell number in the parathyroid glands increased considerably in untreated PHPT mice (9.5 ± 3.1%) compared to wild-type mice (0.7 ± 0.1%) and was significantly suppressed by cinacalcet (1.2 ± 0.2%). Cinacalcet did not affect apoptosis in the parathyroid cells of PHPT mice. These data suggest that cinacalcet suppressed both serum PTH levels and parathyroid cell proliferation in vivo in PHPT.     

Parathormone and cyclic AMP production in human cryopreserved parathyroids

To compare the in vitro response of cryopreserved parathyroid cells from patients with primary and secondary hyperparathyroidism (HPT), immunoreactive parathormone (i-PTH) and cyclic AMP (i-cAMP) were measured at low (0.5 mM) and high (3.0 mM) calcium concentrations in a cell dispersion preparation. The in vitro suppressibility of i-PTH was 23 ± 4% in the primary HPT group and 50 ± 5% in the secondary HPT group (P < 0.01). The suppressibility of i-cAMP production in patients with primary and secondary HPT was 50 ± 2 and 19 ± 6%, respectively (P < 0.01). Evaluation of i-cAMP production by β-adrenergic (isoproterenol) stimulation in both primary and secondary HPT revealed a suppressibility similar to the isoproterenol-free group. This study demonstrated, in vitro, that cryopreserved parathyroid cells from primary HPT are less suppressible by calcium than those from secondary HPT, and that an abnormal calcium-regulated adenylate cyclase-c-AMP system may be an important factor in altered PTH secretion of neoplastic parathyroid tissue.     

Increased Serum 1,25-Dihydroxyvitamin D after Growth Hormone Administration is not Parathyroid Hormone-Mediated

To assess the effects of growth hormone (GH) on serum 1,25-dihydroxyvitamin D [1,25(OH)₂D], we performed the following prospective crossover study in six healthy, young, adult, white men. During each of two admissions for 2? days to a general clinical research center, subjects were placed on a daily dietary calcium intake of 400 mg. Serum calcium, phosphorus, 1,25(OH)₂D, immunoreactive intact parathyroid hormone (PTH), insulin-like growth factor I (IGF-I), IGF binding protein 3 (IGFBP3), tubular reabsorption of phosphate (TRP), and maximum tubular reabsorption of phosphate (TMP/GFR) were measured. Recombinant human GH (rhGH, Humatrope) (25 μg/kg/day subcutaneously for 1 week) was administered prior to and during one of the admissions. Results are expressed as mean ± SEM. Whereas serum 1,25(OH)₂D (58.9 ± 7.7 versus 51.6 ± 7.4 pg/ml, P < 0.01), serum phosphorus (4.5 ± 0.1 versus 3.7 ± 0.1 mg/dl, P < 0.01), TRP (92.0 ± 0.5 versus 87.8 ± 0.7 mg/dl, P < 0.005), TMP/GFR (4.6 ± 0.1 versus 3.5 ± 0.2, P < 0.005), and urinary calcium (602 ± 49 versus 346 ± 25 mg/day, P < 0.001) increased significantly, serum PTH decreased significantly (19.9 ± 1.9 versus 26.8 ± 4.0 pg/ml, P < 0.05) and serum calcium did not change when subjects received rhGH. These findings indicate that in humans, GH affects serum 1,25(OH)₂D independently of circulating PTH and that this effect is mediated by IGF-I. We propose, therefore, that one potential mechanism by which GH stimulates increases in bone mass is via modest increases in serum 1,25(OH)₂D. Received: 2 May 1996 / Accepted: 18 October 1996     

99mTc-sestamibi Scintigraphy and Cell Cycle in Parathyroid Glands of Secondary Hyperparathyroidism

Double-phase parathyroid MIBI (^99mTc-sestamibi) was performed in 27 patients with secondary hyperparathyroidism (SPT). Focal areas of increased uptake were scored for intensity on a three-point scale. All patients underwent subtotal parathyroidectomy (SPTx), and a total of 78 glands were removed at operation. Blood was obtained from the jugular vein before and after SPTx to measure the parathyroid hormone (PTH) levels. The volume and weight of the glands were calculated. The tissue was divided, with one aliquot being used for cell cycle analysis. The nuclei were acquired by flow cytometry and analyzed using CELLEIT software. Cell viability was assessed by flow cytometry and analyzed with LYSIS II software. Positive MIBI uptake was observed in 88.8% of patients. Focal MIBI uptake of one, two, or three glands was observed in 6, 11, and 8 patients, respectively. All patients experienced an 86% decrease in PTH blood level after SPTx compared to that before excision. A correlation was found between the volume of glands and the blood levels of intact PTH (iPTH) (r= 0.5, p < 0.05). A positive correlation was observed between MIBI uptake and the iPTH levels before SPTx (p < 0.01) and between the uptake of MIBI in the parathyroid glands and the cell cycle phases; low-grade uptake correlated with the G₀ phase and higher uptake with G₂+S phase (r= 7, p < 0.01). No correlation was observed between MIBI uptake and the weight of the glands. MIBI scintigraphy accurately reflects the functional status of the hyperplastic parathyroid glands: Higher uptake grades correlated with the active growth phase. MIBI uptake does not reveal parathyroid enlargement; rather, it identifies the presence of hyperfunctioning autonomous glands. SPTx and total parathyroidectomy with autografting (TPTx+A) are the most widely accepted surgical approaches for patients with SPT. Reoperation for recurrence is necessary in 6% to 15% of cases. MIBI is now considered to be the radionuclide of reference for parathyroid gland scanning, although it is widely accepted that it produces poor results when trying to detect hyperplastic glands.     

Acute Responses of Parathyroid Hormone and 1,25 Dihydroxyvitamin D3 to Unilateral Nephrectomy in Healthy Donors

Plasma immunoreactive parathyroid hormone (iPTH), 1,25(OH)₂D3calcium and phosphate and urinary creatinine, calcium and phosphatewere measured before and following unilateral nephrectomy insix kidney donors. Unexpectedly, plasma calcium rose, from 2.27±0.02mmol/l (mean±SEM) to 2.41±0.03 mmol/l on day 7and to 2.37±0.02 mmol/l on day 30 (P<0.02). A parallelrise in iPTH occurred, from 0.61±0.16 ng/ml initially,to 1.83±0.54 ng/ml on day 7 (P<0.05) and to 1.18±0.18on day 30 (P<0.01). The ratio of maximal tubular reabsorptionof phosphate to GFR (TmP/GFR) fell by day 2 (P<0.001), remainingreduced on day 30 (P<0.05). The significance of elevated iPTH in renal insufficiency wasfurther assessed by determining the time course of the disappearanceof iPTH after parathyroidectomy in three haemodialysis subjects.Fifty per cent baseline iPTH level occurred after an averageof 104.7 min, suggesting that the assay did not predominantlyrecognize C-terminal PTH fragments. By day 2, plasma 1,25(OH)₂D3had fallen from 34.3±4.5 pg/ml to 22.8±3.8 pg/ml(P<0.001), but by day 4 had regained its pre-nephrectomyvalue. Our results suggest that hypocalcaemia may not be thesole stimulus to parathyroid hormone secretion. It is speculatedthat reduction in circulating 1,25(OH)₂D3 may be involved.     

Parathyroid Function and Histology in Patients with Parathyroid Adenoma: Correlation of Clinical and Morphologic Findings

r = 0.4; p < 0.05). However, within certain parts of the adenomas, mostly consisting of chief cells, the expression of PTH mRNA and chromogranin A mRNA was heterogeneous and the levels did not correspond to each other. A reduced suppressibility of PTH in patients with pHPT was confirmed. Although cellular levels of PTH and chromogranin A and their mRNAs were low in the oxyphilic parts of the adenomas, there was no correlation between the amount of oxyphilic cells in the adenomas and the suppressibility of PTH by calcium. There was also no association between the cellular levels of PTH mRNA or chromogranin A mRNA as studied by image analysis and “calcium sensitivity.” Our results thus demonstrate that although PTH and chromogranin A mRNA levels are in general correlated to each other there are differences in their expression within and between individual parathyroid adenomas. It therefore seems likely that the expression of PTH and chromogranin A are differentially regulated, and that PTH and chromogranin A may not always be co-secreted. This point could be of importance, as chromogranin A and its cleavage products are known to influence PTH secretion.     

Differing effects of PTH 1–34, PTH 1–84, and zoledronic acid on bone microarchitecture and estimated strength in postmenopausal women with osteoporosis: An 18‐month open‐labeled observational study using HR‐pQCT

Whereas the beneficial effects of intermittent treatment with parathyroid hormone (PTH) (intact PTH 1–84 or fragment PTH 1–34, teriparatide) on vertebral strength is well documented, treatment may not be equally effective in the peripheral skeleton. We used high‐resolution peripheral quantitative computed tomography (HR‐pQCT) to detail effects on compartmental geometry, density, and microarchitecture as well as finite element (FE) estimated integral strength at the distal radius and tibia in postmenopausal osteoporotic women treated with PTH 1–34 (20 µg sc daily, n = 18) or PTH 1–84 (100 µg sc daily, n = 20) for 18 months in an open‐label, nonrandomized study. A group of postmenopausal osteoporotic women receiving zoledronic acid (5 mg infusion once yearly, n = 33) was also included. Anabolic therapy increased cortical porosity in radius (PTH 1–34 32 ± 37%, PTH 1–84 39 ± 32%, both p < 0.001) and tibia (PTH 1–34 13 ± 27%, PTH 1–84 15 ± 22%, both p < 0.001) with corresponding declines in cortical density. With PTH 1–34, increases in cortical thickness in radius (2.0 ± 3.8%, p < 0.05) and tibia (3.8 ± 10.4%, p < 0.01) were found. Trabecular number increased in tibia with both PTH 1–34 (4.2 ± 7.1%, p < 0.05) and PTH 1–84 (5.3 ± 8.3%, p < 0.01). Zoledronic acid did not impact cortical porosity at either site but increased cortical thickness (3.0 ± 3.5%, p < 0.01), total (2.7 ± 2.5%, p < 0.001) and cortical density (1.5 ± 2.0%, p < 0.01) in tibia as well as trabecular volume fraction in radius (2.5 ± 5.1%, p < 0.05) and tibia (2.2 ± 2.2%, p < 0.01). FE estimated bone strength was preserved, but not increased, with PTH 1–34 and zoledronic acid at both sites, whereas it decreased with PTH 1–84 in radius (?2.8 ± 5.8%, p < 0.05) and tibia (–3.9 ± 4.8%, p < 0.001). Conclusively, divergent treatment‐specific effects in cortical and trabecular bone were observed with anabolic and zoledronic acid therapy. The finding of decreased estimated strength with PTH 1–84 treatment was surprising and warrants confirmation. © 2013 American Society for Bone and Mineral Research.     

Fine Needle Aspiration and Intraparathyroid Intact Parathyroid Hormone Measurement for Reoperative Parathyroid Surgery

Some authors have praised the value of fine needle aspiration (FNA) with measurement of intraparathyroid intact parathyroid hormone (iPTH) for localization of the hypersecreting gland(s) in recurrent or persistent primary hyperparathyroidism (HPT). The aim of the present study was to determinate whether FNA for iPTH assay is an effective procedure to distinguish between normal and hypersecreting parathyroid glands. We performed a prospective study of 170 patients who underwent cervicotomy. They were divided into three groups: group A, 50 patients with thyroid diseases; group B, 100 patients with primary HPT; group C, 20 patients with secondary HPT. We performed intraoperative FNA for iPTH measurement from the thyroid, and from the normal and enlarged parathyroid glands, and we compared the different intraglandular iPTH assays. In group A, the intraparathyroid iPTH level was < 1000 pg/ml in 68% of the patients. In group B, in the pathological parathyroid gland iPTH was > 1000 in 88%; conversely, in the normal adjacent parathyroid glands it was < 1000 in 79%. In group C, intraparathyroid iPTH of enlarged glands was > 1000 in 80%. Intrathyroid iPTH was < 100 pg/ml in 96% for the three groups. We conclude that FNA for intraglandular iPTH measurement is an effective tool for distinguishing between normal and pathological parathyroid glands in the setting of primary HPT (p < 0.05), and between thyroid and parathyroid glands in groups A and B. But the procedure should be carried out in conjunction with the sestamibi scan and ultrasonography before surgical reintervention.This article was presented at the International Association of Endocrine Surgeons meeting, Uppsala, Sweden, June 14-17, 2004.     

Dynamics of Parathyroid Hormone Secretion After Total Parathyroidectomy and Autotransplantation

Background  Secondary hyperparathyroidism is a common complication in uremic patients. Total parathyroidectomy combined with partial autotransplantation into brachioradialis muscle has been the preference among the options for surgical treatment. This study was designed to evaluate the reserve and ability of suppression of autotransplanted parathyroid tissue using dynamics tests. Methods  We studied, prospectively, 12 patients in recent (RP) and late (LP) postoperative of total parathyroidectomy with autotransplantation. For analysis of the secretory reserve capacity, we induced hypocalcemia by ethylenediaminetetraacetic acid (EDTA) infusion. Furthermore, for analysis of the ability for parathyroid hormone (PTH) suppression, the hypercalcemia test was used, by intravenous administration of calcium in LP. Results  In RP, there was a decrease in the average serum levels of PTH, phosphorus, and alkaline phosphatase, which ranged from 13 to 231 (87 ± 65) pg/ml, 2.3 to 6.2 (3.3 ± 1.1) mg/dl, and 77 to 504 (250 ± 135) U/L, respectively, similar to that observed in LP. The analysis of the average curve of variations in PTH during testing of the stimulus with EDTA showed lack of secretion in RP and partial response in LP. Impaired suppression ability of the graft in LP was observed in the test with intravenous calcium. Conclusions  Total parathyroidectomy followed by partial autotransplantation was effective in reducing PTH serum levels in patients with terminal kidney disease. The elevation of serum calcium during the suppression test was not able to inhibit the autograft gland secretion of PTH. The assessment of parathyroid graft function demonstrated an inability to respond to the stimulus of hypocalcemia induced by EDTA, although there was a partial recovery, in late postoperative period.     

Effects of Growth Hormone Administration on Bone Mineral Metabolism,PTH Sensitivity and PTH Secretory Rhythm in Postmenopausal Women With Established Osteoporosis

Introduction : Growth hormone (GH) replacement improves target organ sensitivity to PTH, PTH circadian rhythm, calcium and phosphate metabolism, bone turnover, and BMD in adult GH‐deficient (AGHD) patients. In postmenopausal women with established osteoporosis, GH and insulin like growth factor‐1 (IGF‐1) concentrations are low, and administration of GH has been shown to increase bone turnover and BMD, but the mechanisms remain unclear. We studied the effects of GH administration on PTH sensitivity, PTH circadian rhythm, and bone mineral metabolism in postmenopausal women with established osteoporosis. Materials and Methods : Fourteen postmenopausal women with osteoporosis were compared with 14 healthy premenopausal controls at baseline that then received GH for a period of 12 mo. Patients were hospitalized for 24 h before and 1, 3, 6, and 12 mo after GH administration and half‐hourly blood and 3‐h urine samples were collected. PTH, calcium (Ca), phosphate (PO₄), nephrogenous cyclic AMP (NcAMP), β C‐telopeptide of type 1 collagen (βCTX), procollagen type I amino‐terminal propeptide (PINP), and 1,25‐dihydroxyvitamin D [1,25(OH)₂D] were measured. Circadian rhythm analysis was performed using Chronolab 3.0 and Student's t‐test and general linear model ANOVAs for repeated measures were used where appropriate. Results : IGF‐1 concentration was significantly lower in the women with established osteoporosis compared with controls (101.5 ± 8.9 versus 140.9 ± 10.8 μg/liter; p < 0.05) and increased significantly after 1, 3, 6, and 12 mo of GH administration (p < 0.001). Twenty‐four‐hour mean PTH concentration was higher in the osteoporotic women (5.4 ± 0.1 pM) than in healthy controls (4.4 ± 0.1 pM, p < 0.001) and decreased after 1 (5.2 ± 0.1 pM, p < 0.001), 3 (5.0 ± 0.1 pM, p < 0.001), 6 (4.7 ± 0.1 pM, p < 0.001), and 12 mo (4.9 ± 0.1 pM, p < 0.05) of GH administration compared with baseline. NcAMP was significantly lower in osteoporotic women (17.2 ± 1.2 nM glomerular filtration rate [GFR]) compared with controls (21.4 ± 1.4 nM GFR, p < 0.05) and increased after 1 (24.2 ± 2.5 nM GFR, p < 0.05), 3 (27.3 ± 1.5 nM GFR, p < 0.001), and 6 mo (32.4 ± 2.5 nM GFR, p < 0.001) compared with baseline. PTH secretion was characterized by two peaks in premenopausal women and was altered in postmenopausal women with a sustained increase in PTH concentration. GH administration also restored a normal PTH secretory pattern in the osteoporotic women. The 24‐h mean adjusted serum calcium (ACa) concentration increased at 1 and 3 mo (p < 0.001) and PO₄ at 1, 3, 6, and 12 mo (p < 0.001). 1,25(OH)₂D concentration increased after 3, 6, and 12 mo of GH (p < 0.05). An increase in urine Ca excretion was observed at 3 and 6 mo (p < 0.05), and the renal threshold for maximum tubular phosphate reabsorption rate (TmPO4/GFR) increased after 1, 3, 6, and 12 mo (p < 0.05). βCTX concentration increased progressively from 0.74 ± 0.07 μg/liter at baseline to 0.83 ± 0.07 μg/liter (p < 0.05) at 1 mo and 1.07 ± 0.09 μg/liter (p < 0.01) at 3 mo, with no further increase at 6 or 12 mo. PINP concentration increased progressively from baseline (60 ± 5 μg/liter) to 6 mo (126 ± 11 μg/liter, p < 0.001), with no further increase at 12 mo. The percentage increase in PINP concentration was significantly higher than βCTX (p < 0.05). Conclusions : Our study shows that GH has a regulatory role in bone mineral metabolism. GH administration to postmenopausal osteoporotic women improves target organ sensitivity to PTH and bone mineral metabolism and alters PTH secretory pattern with greater increases in bone formation than resorption. These changes, resulting in a net positive bone balance, may partly explain the mechanism causing the increase in BMD after long‐term administration of GH in postmenopausal women with osteoporosis shown in previous studies and proposes a further component in the development of age‐related postmenopausal osteoporosis.     

Applicability of Intraoperative Parathyroid Hormone Assay During Total Thyroidectomy as a Guide for the Surgeon to Selective Parathyroid Tissue Autotransplantation

Background Intraoperative parathyroid hormone assay (IOPTH) has been suggested to have value in predicting the development of postoperative hypoparathyroidism after thyroid surgery. IOPTH has been validated in identification of patients at risk of postoperative hypocalcemia requiring early onset of calcium supplementation therapy and in improving selection of patients eligible for a safe early discharge. However, the value of IOPTH has not been assessed in a randomized study as a guide for the surgeon to parathyroid tissue autotransplantation (PA). The objective of this study was to evaluate the applicability of IOPTH in guiding the surgeon to selective parathyroid tissue autotransplantation during total thyroidectomy (TT). Methods Between January 2005 and December 2005, 340 patients qualified for total thyroidectomy (TT) who met the inclusion criteria were randomized to two equal-sized groups (n = 170): group A, in which elective PA of at least one parathyroid gland was performed in all cases without IOPTH as a guide; and group B, in which selective IOPTH-guided PA was performed, if only the iPTH plasma level was <10 ng/L at 10–20 min after TT (before skin closure). The standard technique of PA consisting of implanting the parathyroid tissue into 10–20 sternocleidomastoid muscle pockets was used in both groups. IOPTH measurements were performed by the STAT-Intraoperative-iPTH-Assay. Serum calcium was routinely monitored at 4, 12, 24, 48, and 72 hr postoperatively. The incidence and severity of hypocalcemia and related symptoms were matched with the IOPTH results. On follow-up, serum calcium and plasma iPTH values were measured at 1, 3, and 6 months postoperatively. The primary end point was the success rate in preventing permanent postoperative hypoparathyroidism. The secondary end point was the use of postoperative medication for transient hypocalcemic symptoms. Results Twenty-one group B patients (12.3%) had plasma iPTH levels <10 ng/L at 10–20 min after TT (before skin closure) and they underwent selective IOPTH-guided PA. None of the patients from both groups experienced permanent postoperative hypoparathyroidism. Transient postoperative hypocalcemia occurred in 22.3% vs. 11.2% of patients (group A vs. B, respectively; p < 0.05). The mean cumulated serum calcium values were significantly lower for group A vs. group B patients within the entire 3-month period after TT (2.12 ± 0.09 mmol/L vs. 2.27 ± 0.05 mmol/L, respectively; p < 0.001). The mean oral calcium supplementation was significantly higher for group A vs. group B patients during the 3 months after TT (2.7 ± 0.9 g/day vs. 0.9 ± 0.4 g/day, respectively; p < 0.001). Conclusions IOPTH offers valuable information during TT, correctly identifying patients at risk of postoperative hypocalcemia. Selective IOPTH-guided PA in patients with plasma iPTH levels <10 ng/L at 10–20 min after TT reduces the risk of permanent postoperative hypoparathyroidism to zero, and this approach seems to be as effective as elective PA of at least one parathyroid gland without IOPTH guidance. Moreover, selective IOPTH-guided PA significantly decreases the incidence of transient postoperative hypoparathyroidism and the need for calcium supplementation therapy compared with elective PA without IOPTH. Presented at the 42^nd World Congress of Surgery, Montreal, Canada, August 26 to 30, 2007.     

Patients with Elevated Serum Parathyroid Hormone Levels after Parathyroidectomy: Showing Signs of Decreased Peripheral Parathyroid Hormone Sensitivity

We have previously shown that patients with elevated levels of parathyroid hormone (PTH) after surgery for parathyroid adenoma have normal parathyroid and renal function but demonstrate signs of remineralization of cortical bone, decreased calcium absorption, and low levels of vitamin D. We hypothesized that decreased peripheral PTH sensitivity could also be of importance for this condition. Thirteen patients operated on for a solitary parathyroid adenoma, with a mean +/- SD preoperative serum level of calcium of 2.72 +/- 0.12 mmol/L, were investigated 6 weeks after surgery with a standardized PTH (1-34) infusion test for 6 hours. The eight patients with elevated PTH levels had less increase in serum levels of ionized calcium (0.02 +/- 0.03 mmol/L) than did the five patients with normal PTH levels (0.06 +/- 0.02 mmol/L) (p < 0.05). Patients with elevated PTH also showed less decrease in serum phosphate levels (p < 0.05) and a trend to a larger decrease in the excretion of urinary calcium (p = 0.08). The increase in 1,25-dihydroxyvitamin D(3) did not differ between the two groups of patients. Thus patients operated on for parathyroid adenoma with postoperatively elevated serum PTH levels showed decreased peripheral sensitivity to PTH.