The effect of histamine and histamine H2 receptors on secretion off parathyroid hormone (PTH) was evaluated by 1) adding histamine phosphate (with or without the histamine H2 receptor antagonist, cimetidine) to the medium in in vitro incubation studies with bovine parathyroid tissue, 2) infusing histamine into rats, and 3) infusing the histamine H1 receptor antagonist, diphenhydramine, or cimetidine into normal men and patients with primary hyperparathyroidism. In vitro, histamine (10(-5)-10(-7) M) caused a dose-related significant stimulation of immunoreactive PTH (iPTH) secretion; this was blocked by the simultaneous addition of cimetidine (10(-5) M). Intravenous infusion of histamine significantly increased serum iPTH in rats. In normal man, infusion of diphenhydramine had no effect, but cimetidine (300 or 450 mg) significantly decreased serum iPTH. However, cimetidine had no effect on serum iTh in primary hyperparathyroid patients. The in vitro observations indicate that histamine can stimulate iPTH secretion by a direct effect on the parathyroid cell and that this is probably a specific effect via histamine H2 receptors because the effect was blocked by the H2 receptor antagonist, cimetidine. The observed inhibition of basal PTH concentration by cimetidine induced histamine H2 receptor blockade (but not by H1 blockade) in normal human subjects suggests that endogenous histamine with H2 receptor activation stimulates even basal PTH secretion and may serve as a modulator of PTH secretion in normal man. Loss of this modulating effect of H2 receptors on PTH secretion is a characteristic of primary hyperparathyroidism.

OBJECTIVE

To analyze the utility of quick intraoperative parathyroid hormone (PTH) measurement in the surgical management of primary hyperparathyroidism.

BACKGROUND

The use of intraoperative PTH monitoring is well established in the surgery of primary hyperparathyroidism. However, some false-negative predictions lead to unnecessary explorations; furthermore, surgeons are becoming increasingly dependent on hormone measurement for intraoperative decisions, which raises concerns about the cost-effectiveness of the method.

METHODS

A retrospective analysis of 268 neck explorations performed for primary hyperparathyroidism using intraoperative PTH monitoring from April 2001 to February 2003 was done. We used the criterion of "biologic recovery" of hyperfunctioning tissue, defined as a more than 50% decrease in PTH level from baseline value at 5 minutes after excision to predict the outcome of successful parathyroidectomy documented by normal postoperative serum calcium level. Additionally, we also sampled PTH at 10 minutes, 30 minutes, and the morning after surgery to compare the predictive value of delayed sampling. Patients were classified according to the prediction being concordant or discordant with the outcome. The data were analyzed using a 2 x 2 table construct for each of the sampling times, therefore providing sequential sensitivity, specificity, positive and negative predictive values, and overall accuracy of the predictions.

RESULTS

Concordance or overall accuracy of prediction (true positives and negatives) was obtained in 229 cases (85.4%), and discordance or failure of prediction (false positives and negatives) was obtained in 34 cases (12.7%) at T5. On analyzing the iPTH prediction at T10, T30, and D1 among the group of 33 false negatives, we found that 28 (10.4%) patients reached the concordance at 30 minutes, while by the first day 32 patients (12.3%) had achieved concordance. Thus, there was a progressive increase in sensitivity and overall accuracy, but more importantly, in the negative predictive value reaching 88.9% on the day after surgery.

CONCLUSIONS

The method of sampling PTH intraoperatively at 5 minutes has a high positive predictive value (99.5%) but a low negative predictive value (19.5%), which can lead to unnecessary explorations and a delay in the operative procedure. The negative predictive value increases substantially at 30 minutes and is best on the day after surgery. We suggest giving up the intraoperative measurement of PTH to adopt the first day postoperative measurement of PTH as a predictor of successful parathyroidectomy.

The bone mineral content and the serum levels of immunoreactive parathyroid hormone (iPTH), and protein-corrected calcium and magnesium were measured in 13 manic depressive patients before and during treatment with lithium. Initially all four parameters were normal. During the treatment the bone mineral decreased and the serum levels of iPTH, calcium, and magnesium increased. Although altered metabolism of parathyroid hormone cannot be ruled out, these data, together with other observations, suggest that a mild 'primary' hyperparathyroidism sets in quite early after institution of lithium therapy.

BACKGROUND

Persons of Pakistani origin living in Oslo have a much higher prevalence of vitamin D deficiency and secondary hyperparathyroidism but similar bone mineral density compared with ethnic Norwegians. Our objective was to investigate whether Pakistani immigrants living in Oslo have an altered vitamin D metabolism by means of compensatory higher serum levels of 1,25-dihydroxyvitamin D (s-1,25(OH)2D) compared with ethnic Norwegians; and whether serum levels of ionized calcium (s-Ca2+) differ between Pakistanis and Norwegians.

METHODS

In a cross-sectional, population-based study venous serum samples were drawn from 94 Pakistani men and 67 Pakistani women aged 30-60 years, and 290 Norwegian men and 270 Norwegian women aged 45-60 years; in total 721 subjects.

RESULTS

Pakistanis had lower s-1,25(OH)2D compared with Norwegians (p < 0.001). Age- and gender adjusted mean (95% CI) levels were 93 (86, 99) pmol/l in Pakistanis and 123 (120, 126) pmol/l in Norwegians, p < 0.001. The difference persisted after controlling for body mass index. There was a positive relation between serum 25-hydroxyvitamin D (s-25(OH)D) and s-1,25(OH)2D in both groups. S-Ca2+ was higher in Pakistanis; age-adjusted mean (95% CI) levels were 1.28 (1.27, 1.28) mmol/l in Pakistanis and 1.26 (1.26, 1.26) mmol/l in Norwegians, p < 0.001. In both groups, s-Ca2+ was inversely correlated to serum intact parathyroid hormone levels (s-iPTH). For any s-iPTH, s-Ca2+ was higher in Pakistanis, also when controlling for age.

CONCLUSIONS

Community-dwelling Pakistanis in Oslo with low vitamin D status and secondary hyperparathyroidism have lower s-1,25(OH)2D compared with ethnic Norwegians. However, the Pakistanis have higher s-Ca2+. The cause of the higher s-Ca2+ in Pakistanis in spite of their higher iPTH remains unclear.

The effect of excessive growth hormone (GH) on parathyroid function in rats was evaluated in order to determine whether the GH-induced increase in serum calcium (Ca) may be mediated via stimulation of parathyroid hormone (PTH) secretion. Rats receiving injections of bovine GH 2 mg daily for 4 weeks showed a progressive significant increase in both serum Ca and immunoreactive PTH (iPTH) after the second week. Rats receiving daily injections of rat GH, 0.25 mg daily for 3 weeks, followed by 0.5 mg daily for 3 additional weeks, showed a significant increase in serum iPTH during administration of the higher dose, and also a significantly increased parathyroid gland weight and PTH content. The concomitant increase in serum Ca and iPTH suggest that GH stimulates the parathyroid glands to increase PTH secretion, which in turn causes an increase in serum Ca. The parathyroid response increases with the increase in dose and duration of GH stimulus. The data suggest that the hypercalcemia often observed in acromegaly may be due, at least in part, to GH-induced excessive secretory activity of the parathyroid glands.

The functional evolution of autogenous parathyroid grafts was monitored in six patients with primary parathyroid hyperplasia using a sensitive radioimmunoassay specific for the midregion of parathyroid hormone (PTH). After successful total parathyroidectomy and graft implantation in the forearm, basal immunoreactive PTH (iPTH) fell to undetectable levels for about 12 to 18 weeks, and then rose to normal. By 3 weeks after surgery, an iPTH increment appeared in venous blood from the arm bearing the graft. Graft function was demonstrated in all six cases. Graft-independent hypercalcemia occurred in two patients and appeared to inhibit PTH secretion by the graft. In one case, elevated levels of calcium and iPTH persisted after surgery but iPTH remained equal in both arms. At 5 months, a fifth hyperplastic gland was resected from the mediastinum, and the calcium level decreased to normal; the parathyroid implant was secreting iPTH vigorously 5 days later. Hypercalcemia had not prevented establishment of a viable implant. In the second case, hypercalcemia developed 80 weeks after operation, and the previously demonstrated iPTH gradient disappeared; presumably a fifth gland had become hyperplastic. In this patient, iPTH had remained in the upper portion of the normal range during the first postoperative week, probably indicating the potential for recurrence. Each of the other five patients remains normocalcemic 4 to 103 weeks after grafting.

OBJECTIVE

The aim of this study was to determine the changes in serum vitamin D distribution at an institute in India over the past 6 y and compare it with global trends.

METHODS

We conducted an audit of 25-hydroxyvitamin D (25-OHD), calcium, and plasma intact parathyroid hormone (iPTH) reporting from January 2011 to February 2016. References for review were identified through searches of PubMed, Medline, and Embase for articles published until February 2016 using keywords "hypervitaminosis D" (MeSH Terms) OR "vitamin D toxicity" (All Fields) OR "vitamin-D intoxication" (All Fields).

RESULTS

Reports of 25-OHD from 5527 patients were analyzed. Calcium and iPTH were available for 5501 (99.5%) and 1787 (32.3%) patients, respectively. Vitamin D deficiency and insufficiency were observed in 59.4 and 77.3%. Hypervitaminosis D (25-OHD >250 nmol/L) was noted in 225 (4.1%) patients, of whom 151 (2.7%) had vitamin D intoxication (25-OHD >375 nmol/L). We found that 46.22% (104 of 225) patients with hypervitaminosis D and 62.25% (94 of 151) with vitamin D intoxication had elevated calcium or suppressed iPTH. Orthopedic, pediatric, and surgery patients had the highest rates of hypervitaminosis D (7.9, 7.2, and 7% respectively; P < 0.001). An increasing trend for hypervitaminosis D was observed (1.48, 3.62, 3.90, 4.78, 6.21, and 7.82% in 2011, 2012, 2013, 2014, 2015, and 2016, respectively). A similar steady upward trend in 25-OHD has been reported in Ireland, England, Canada, and Australia. However, hypervitaminosis D reports are scant and have not increased over the years in the developed world.

CONCLUSIONS

There is a global secular trend of increases in 25-OHD over years. There is a disturbing trend of increased hypervitaminosis D at an Indian institute. Empiric, unmonitored, prolonged vitamin D supplementation, using non-recommended supraphysiological doses, especially when administered intramuscularly, should be discouraged.

To determine whether the 24-h intact PTH (iPTH) profile is influenced by the sleep-wake cycle, and whether iPTH pulses show a temporal relationship with internal sleep structure, eight normal young men were studied during 24 h under basal conditions, once with normal nighttime sleep from 2300-0700 h and once after a night of sleep deprivation followed by an 8-h period of daytime sleep from 0700-1500 h. During the 8-h nighttime sleep period, mean iPTH levels were significantly increased by +13% and mean iPTH pulse amplitudes by +31% as compared with the 8-h subsequent waking periods. During the 8 h of total sleep deprivation, mean iPTH levels were not significantly different from the corresponding period in nighttime sleep condition, but mean iPTH pulse amplitudes were significantly lower (P < 0.01). The 8-h daytime sleep period was associated with increased mean iPTH levels and mean iPTH pulse amplitudes (+15% and +57%, respectively, as compared with the corresponding period in nighttime sleep condition). The number of pulses was similar in both experimental series and was not influenced by sleep or by time of day. Analysis of coincidence between iPTH pulses, plasma ionized calcium and plasma phosphate pulses, and slow wave sleep, as well as with rapid eye movement sleep episodes, did not reveal any significant association. Cross-correlation analysis between iPTH, plasma ionized calcium, and plasma phosphate fluctuations during sleep also showed no systematic association. Seven other subjects were studied during a nighttime sleep period in which temporal relationships between iPTH and internal sleep structure were reevaluated using spectral analysis of the sleep electroencephalogram. Cross-correlation analysis between iPTH levels and delta-relative power fluctuations showed nonsignificant results, which confirms the lack of relationship with slow wave sleep. This study demonstrates that the iPTH 24-h profile is influenced by sleep processes with a weak circadian component. However, iPTH pulses are not temporally linked with sleep electroencephalographic activity nor with calcemia and phosphatemia fluctuations. This evidence raises questions about the origin of iPTH pulses.

Combinations of anabolic and anti-resorptive agents have potential to improve bone density more than either agent alone. In this study, we determine the combining effect of anti-IL17 antibody and PTH (1-34) in mitigation of ovariectomy induced bone loss. Ovariectomized BALB/c female mice were treated with anti-IL17 and iPTH monotherapies and their combination. Combination of iPTH and anti-IL17 has synergistic effect in the restoration of skeletal and immune parameters compared to mono-therapies. Immunofluorescence analysis shows decreased expression of PTHR1 in iPTH+anti-IL17 treated bone sections. Our studies show that IL-17 up regulates N-cadherin which disrupts PTHR1/LRP-6 interaction thereby inhibiting wnt signaling and promoting bone loss. Our studies advocate use of iPTH and anti-IL17 combination therapy for post-menopausal osteoporosis.

Disturbances in bone and mineral metabolism are common in chronic kidney disease (CKD) patients. Most studies have been performed in hemodialysis and there is less information on non-dialysis patients, on the coexistence of other risk factors and on the achievement of more recent and stringent guidelines. Cross sectional study of analytical mineral and bone parameters in 125 incident patients (creatinine clearance <60 ml/min) in a monographic CKD clinic. Evaluation after one year of follow-up in 69 patients. Progression of CKD was associated with significant increased levels of phosphate, calcium x phosphate and iPTH and decreased calcium and 1,25 dihydroxyvitamin D. Levels of 25-hydroxyvitamin D were unchanged, but lower than recommended. Phosphate correlated negatively with 1,25-dihydroxivitamin D and creatinine clearance, and positively with iPTH. At every stage of CKD, most patients had PTH values outside recommended limits. More than 69% CKD 3 and CKD 4 patients had higher than recommended PTH levels. Above recommended phosphate levels were present in 25% of CKD 4 and 47% of CKD 5 patients. Most of these had associated high LDL-cholesterol. Higher than recommended calcium levels were more prevalent than low calcium and there was a high prevalence (31%) of vascular calcification. One year of intervention improved the percentage of patients with controlled calcium or iPTH, but not phosphate.

CONCLUSIONS

In incident CKD patients there is a high prevalence of out-of-target mineral and bone analytical parameters. The currently authorized therapeutic arsenal for these patients may not be adequate to deal with the problem.

The coexistence of hyperparathyroidism complicating thyrotoxicosis is quite rare. We report the case of one patient who presented with thyrotoxicosis, (total thyroxine of 15.1 micrograms/dl (5-13), free thyroxine index of 18 (4-15) and triiodothyronine by RIA of 305 ng/dl (70-230) and asymptomatic hypercalcemia of 15 mg/dl (8.5-10.6), who was also initially noted to have an elevated (C-terminal) serum immunoreactive parathyroid hormone (iPTH) level of 8,800 pg/ml (50-340). With propylthiouracil and propranolol, however, this patient became normocalcemic with a decrease in iPTH values to 714 pg/ml. As the patient was tapered from medication, after being rendered euthyroid, a recurrence of hypercalcemia with rising iPTH levels occurred. PTH levels should be helpful in defining coexisting hyperparathyroidism in patients with thyrotoxicosis since in the latter iPTH is usually suppressed. Our findings support the recommendation that in patients suspected of having both hyperparathyroidism and hyperthyroidism, a diagnosis of the former can only be made with certainty after the patient has been rendered euthyroid with persistently elevated serum calcium and iPTH levels. While there are no clinical features which permit the easy identification of patients who present with dual lesions, the determination of iPTH values may be the most consistently helpful test initially, whereas other parameters such as vitamin D, serum phosphate are less reliable.

Parathyroidectomy (PTX) is an effective treatment for severe secondary hyperparathyroidism (SHPT); however, persistent SHPT may occur because of supernumerary and ectopic parathyroids. Here a diagnostic accuracy study of intraoperative and perioperative serum intact parathyroid hormone (iPTH) was performed to predict successful surgery in 501 patients, who received total PTX + autotransplantation without thymectomy. Serum iPTH values before incision (io-iPTHiPTHiPTHiPTH, D4-iPTH) were recoded. Patients whose serum iPTH was >50 pg/mL at the first postoperative week were followed up within six months. Successful PTX was defined if iPTH was <300 pg/mL, on the contrary, persistent SHPT was regarded. There were 86.4% patients underwent successful PTX, 9.8% remained as persistent SHPT and 3.8% were undetermined. Intraoperative serum iPTH demonstrated no significant differences in two subgroups with or without chronic hepatitis. Receiver operating characteristic (ROC) curves showed that >88.9% of io-iPTHiPTH >147.4 pg/mL could predict persistent SHPT (AUC 0.998, sensitivity 100%, specificity 99.5%), so that medical intervention or reoperation start timely.

In this study we evaluated the effects of high-dose corticosteroid (CS) therapy and the character of the nephrotic syndrome (NS) itself on bones in patients with normal glomerular filtration rate. We measured serum osteocalcin (OC), alkaline phosphatase (ALP), intact parathyroid hormone (iPTH), 25-hydroxyvitamin D, calcium (Ca), phosphorus (P), and magnesium (Mg) levels, and urinary Ca and protein excretion in nephrotic children during the active phase before (group Ia) and after CS treatment (group Ib). The results were compared with age-matched control subjects. A significant increase in urinary Ca excretion was observed after CS treatment. Serum ALP, OC, and iPTH levels were within normal limits at the time of study entry. However, both serum OC and ALP levels showed a significant decrease after the completion of CS treatment (OC from 13.6+/-9.2 ng/ml to 6.7+/-5.2 ng/ml and ALP from 151.8+/-60.2 U/l to 116+/-43.8 U/l). 25-Hydroxyvitamin D levels increased to 17.2+/-8.9 microg/l from 9.9+/-6.9 microg/l after CS treatment. The effects of recurrent use of CSs were assessed by dividing nephrotic patients into two subgroups: infrequent relapsers (IFR) and frequent relapsers (FR). The cumulative dose of CS was 28,125 mg/m(2) for IFR and 105,000 mg/m(2) for FR. The changes in OC, ALP, and 25-hydroxyvitamin D levels after CS treatment were significantly different between IFR and FR. We conclude that high-dose CS treatment causes a decrease in bone formation, as shown by the changes in OC and ALP levels. 25-Hydroxyvitamin D levels remained lower than control subjects after CS therapy. The higher the cumulative dose of CS used the more marked the changes in biochemical bone markers. The contribution of FR to baseline 25-hydroxyvitamin D levels needs further study.

Although about 25% of all hip fractures occur in men, little is known about the pattern of their age-related bone loss and its main determinants. The aim of this cross-sectional study was to evaluate the age-related changes of intestinal calcium absorption, bone mass, and bone turnover in normal men. In 70 normal males (age 17-91 years), we measured spinal and forearm bone density (FBD) (by DXA), fractional intestinal calcium absorption (by oral test), serum immunoreactive parathyroid hormone (PTH), dietary calcium intake (diet records), biochemical markers of bone turnover (serum alkaline phosphatase (ALP), osteocalcin, urine calcium, creatinine, and hydroxyproline), and 1,25(OH)2D3 serum levels. Vertebral bone density (VBD) showed a modest decline before age 50 and a greater decline after age 50, whereas FBD presented a significant decrease with advancing age starting at age 40, suggesting a predominant age-related cortical bone loss. Intestinal calcium absorption (47CaFA) and serum 1,25(OH)2D3 also presented an age-related decline similar to FBD. Simple correlation analysis revealed that age was significantly related to 47CaFA (r = 0.60), calcium intake (r = 0.32), VBD and FBD (r = 0.79 and 0.63, respectively), serum 1,25(OH)2D3 (r = 0.69), and serum iPTH (r = 0.72). No significant correlation was found between age and biochemical markers of bone remodeling. Partial correlation and stepwise variable selection analyses, using 47CaFA and bone mass as dependent variables, showed that in normal males, serum 1,25(OH)2D3 and dietary calcium intake were the main contributors (64%) to 47CaFA variability, whereas only age accounted for 63% of VBD and age and dietary calcium accounted for 45% of FBD variability. These results indicate that bone loss in men accelerates after age 50 years and that among other factors, intestinal calcium malabsorption and 1,25(OH)2D3 serum levels play a role.

Basal serum and urinary biochemical parameters and their response to PTH or calcium infusion were examined in 14 untreated patients with familial hypophosphatemic rickets (FHR) from 5 kindreds and 9 normal control subjects after a period of dietary equilibration. FHR subjects exhibited significantly elevated basal serum iPTH levels (FHR: 11.4 +/- 0.8, controls: 5.1 +/- 0.5 ng/ml, P less than 0.001) and urinary cAMP excretion (FHR: 7.83 +/- 0.81, controls: 3.78 +/- 0.46 nmol/mg creatinine P less than 0.001). In response to PTH infusion (6 units/kg over 4 hours) FHR subjects exhibited a mean 34% decrease in TRP and a 22-fold increase in cAMP excretion, both comparable to the control response. Calcium infusion (10 mg/kg over 1 h) rapidly suppressed serum iPTH and urinary cAMP values in FHR subjects. However, TRP remained inappropriately low for the level of serum phosphate. Basal and post-calcium infusion serum iPTH levels correlated positively with urinary cAMP in FHR subjects and controls. Pre- and post-calcium infusion iPTH levels correlated with serum calcium in FHR subjects. Mean Salivary phosphate concentration was significantly reduced in FHR subjects (FHR: 12.68 +/- 0.87, controls: 22.47 +/- 2.16 mg/100 ml, P less than 0.001). However, calculated salivary phosphate clearance rates were similar in FHR and control subjects. PTH or calcium infusion did not significantly alter salivary phosphate concentration or clearance rates in either patients or controls. We concluded that untreated FHR patients exhibit a state of mild secondary hyperparathyroidism and an at least normal renal phosphaturic response to PTH. In addition, there is no evidence for increased salivary phosphate excretion in FHR.

BACKGROUND

The overall effect of pamidronate on bone mass density (BMD) in the early renal transplant period varies considerably among studies. The effects of pamidronate on graft function have not been determined.

METHODS

A comprehensive search was conducted in PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL) and Embase independently by two authors. Randomized controlled trials of pamidronate evaluating bone loss in the first year of renal transplantation were included. Methods reported in the "Cochrane Handbook for Systematic Reviews of Interventions 5.0.2" were used to evaluate changes of lumbar spine and femoral neck BMD, and serum creatinine, calcium and intact parathyroid hormone (iPTH) levels. Fixed or random effect models were used as appropriate.

RESULTS

Six randomized trials evaluating 281 patients were identified. One hundred forty-four were treated with pamidronate and 137 were control patients. Administration of pamidronate was associated with significant reduction of bone loss in the lumbar spine, compared to the control group (standardized mean difference (SMD) = 24.62 [16.25, 32.99]). There was no difference between the pamidronate treated and control femoral neck BMD (SMD = 3.53 [-1.84, 8.90]). A significant increase in the serum creatinine level of the intervention group was seen, compared to the control group. The serum calcium and iPTH of the pamidronate and control groups were not different after 1 year (serum creatinine: SMD = -3.101 [-5.33, -0.89]; serum calcium: SMD = 2.18 [-0.8, 5.16]; serum iPTH: SMD = 0.06 [-0.19, 0.31]). Heterogeneity was low for serum calcium and iPTH and high for serum creatinine.

CONCLUSIONS

This meta-analysis demonstrated the beneficial clinical efficacy of pamidronate on BMD with no association with any alteration in graft function during the first year of renal transplantation. Significant heterogeneity precludes the conclusion of the relationship between serum creatinine and pamidronate.

The aim of this work was to analyze patients suffering from primary hyperparathyroidism (HPT) treated by traditional and miniaccess surgery, to demonstrate the validity and limits of intraoperative assay of PTH (iPTH). Between January 2000 and December 2001, at the Surgical Science Department of "La Sapienza" University of Rome, 29 patients affected by HPT, one of whom was a recidivist, underwent surgery for HPT and had a mean follow-up of 15 months (range, 6-24 months). The research showed that a decrease of >50% in iPTH values is indicative of resolution of clinical signs in 95% of cases. The use of iPTH in HPT for solitary adenoma in both classical and mini-invasive surgery yields a 100% success rate in terms of persistence, recidivism, and postoperative normocalcemia. iPTH is of assistance to the surgeon and allows treatment through mini-invasive access. In the case of solitary adenoma, iPTH is not only a biochemical histological examination but also a predictive test of normocalcemia.

Calcimimetic agents increase the sensitivity of calcium sensing receptors of parathyroid glands and suppress both serum calcium levels and parathyroid hormone. There are still limited data on the treatment of renal transplant patients with severe hypercalcemia and hyperparathyroidism with calcimimetics (cinacalcet). We describe two such renal transplant patients with chronic kidney disease Stage 3 who presented with persistent hypercalcemia (serum calcium 11.5-12 mg/dl) and refractory hyperparathyroidism (iPTH 194-547 pg/ml). Control of hypercalcemia with cinacalcet (serum calcium <10 mg/dl) resulted also in an improvement of hyperparathyroidism, but with a slower rate than that of the lowering of serum calcium. Addition of a vitamin D analog together with the calcimimetic agent resulted in faster control of the resistant hyperparathyroidism in both patients (iPTH <145 pg/ml) with clinical improvement and without any side effect. It seems that this new agent will improve our clinical approach of renal bone disease permitting a more integrated and successful treatment of hyperparathyroidism and its consequences on patients with chronic kidney disease.

Severe renal osteodystrophy with metaphyseal fractures developed in two children with hypoplastic-dysplastic kidneys and chronic renal failure despite therapy with vitamin D, CaCO3, phosphate-binding agents, and protein restriction. Serum immunoreactive parathyroid hormone (iPTH) levels were elevated to 709 and 1,537 pg/mL (N = 255 +/- 92 pg/mL). Total parathyroidectomy and then autotransplantation of a small portion of parathyroids into the left brachioradialis muscle resulted in complete healing of renal osteodystrophy with the same dose of vitamin D. Serum iPTH and histological studies have demonstrated functioning parathyroid autotransplants, 19 and 20 months postoperatively in these two patients. Advantage of such a procedure over 3 3/4 parathyroidectomy is that this transplanted parathyroid tissue is easily accessible for partial removal in case of recurrence of uncontrollable hyperparathyroidism. We believe that total parathyroidectomy and autotransplantation can be successfully performed even in small children.

Role of parathyroid hormone in the phosphaturia of extracellular fluid volume expansion. Acute expansion of the extracellular fluid volume increases the urinary excretion of phosphate. The present study examined the importance of increased plasma parathyroid hormone concentration in the phosphaturia accompanying acute extracellular fluid volume expansion (ECVE). Infusion of a calcium-free Ringer's solution into dogs was associated with increased urinary phosphateexcretion and serum immunoreactive parathyroid hormone concentration (iPTH), the latter being significantly correlated with a decrease in plasma ionized calcium concentration. Prevention of the fall in plasma ionized calcium concentration by infusion of a calcium containing Ringer's solution prevented the increase in serum iPTH but the magnitude of the phosphaturia was not affected.

A significant contribution of the forestomachs in net calcium (Ca2+) absorption from the gastrointestinal tract has been postulated from in vivo and in vitro studies in different ruminant species. However, the potential role of vitamin D3 and its metabolites in controlling these mechanisms is still under discussion. It was therefore the aim of the present study to investigate the effectiveness of treatment with vitamin D3 in stimulating active Ca2+ absorption from sheep rumen. Four mature, non-lactating, non-pregnant sheep that had been treated 7 and 4 days before the Ca2+ flux rate measurements with intramuscular injections of 300000 IU of vitamin D3 each in aqueous solution were used. Two female and three male placebo-treated sheep served as controls. To characterize the effects of vitamin D3 application on plasma parameters the time courses of total calcium, inorganic phosphate, calcitriol and intact parathyroid hormone (iPTH) were recorded. In vitro studies of unidirectional Ca2+ flux rates across isolated, intact rumen wall epithelia were carried out by applying the Ussing-chamber technique. Western blot analysis and reverse transcriptase-polymerase chain reaction analysis (RT-PCR) were applied to identify vitamin D receptors (VDR) in ruminal and jejunal tissues. In addition, Western blot analysis for qualitative examination of epithelial calbindin D9k levels was carried out in these tissues. Total calcium and phosphate levels in plasma were not significantly affected treatment with vitamin whereas calcitriol concentrations significantly increased by about 130 and 63% after the first and second application, respectively. In contrast, iPTH tended to decrease by about 60% indicating regulatory effects of calcitriol on systemic Ca homeostasis. The Ca2+ flux rate measurements in Ussing-chambers revealed significant net Ca2+ absorption indicating the contribution of active mechanisms for Ca2+ transport in rumen epithelia. This, however, was not significantly affected by increased calcitriol concentrations in plasma. Western blot analysis on the basis of a human recombinant VDR protein and RT-PCR clearly indicated the presence of VDR in ruminal and jejunal epithelia, but, in contrast to jejunum, this was not reflected by respective amounts of calbindin-D9k in ruminal tissues. The results suggest the absence of classical calbindin-D9k-mediated mechanisms for active Ca2+ transport in sheep rumen.

Data on the effect of estrogen on immunoreactive parathyrin (iPTH) in postmenopausal women are conflicting. We administered estrogen or placebo to 21 postmenopausal women for 12 weeks and measured PTH bioactivity (bioPTH), using the renal cytochemical bioassay. Before treatment, there was a negative correlation between nephrogenous cAMP and the tubular maximum for urinary phosphate excretion and a positive correlation between values measured by a mid-region-specific PTH RIA and those measured in an immunoradiometric assay for intact PTH. Values measured by the midregion-specific RIA were also positively correlated with nephrogenous cAMP. BioPTH values were not correlated with other indices of PTH activity but were increased compared with values for younger subjects. After estrogen treatment there was no change in bioPTH activity despite an early decrease in serum osteocalcin and a later increase in nephrogenous cAMP. PTH concentrations measured by mid-region-specific or intact RIAs were unchanged, but sample size may have been insufficient to exclude the possibility of significant changes in these values. The effects of estrogen on mineral metabolism in postmenopausal women are time-dependent. Early effects are independent of PTH, and later effects are variably associated with increased PTH activity.

In sham-operated and TPTX animals, F treatment did not affect final body weight, or serum Ca and P. In sham-treated rats, serum iPTH was not affected by F treatment. At the periosteum, F increased bone formation rate and bone and matrix apposition rates. At the endosteum, F treatment decreased forming surface, bone formation rate, bone and matrix apposition rates, and osteoid maturation rate; and increased endosteal resorbing surface and medullary area. The above-described F effects on bone were observed in TPTX as well as sham-treated animals. The effect of F treatment to stimulate periosteal matrix apposition was enchanced by TPTX. These results indicate that bone changes seen in animals treated with large amounts of F are not due to increased parathyroid activity.

Ten patients with subtle primary hyperparathyroidism and intermittent hypercalcaemia were followed serially for periods of 2--18 months (mean 10 months). Fasting serum calcium was elevated (greater than 10.6 mg/dl) in only 20% of determinations and fluctuated widely (9.1--11.2 mg/dl), yet the patients displayed a continuous, rather than episodic, basic disease process as defined by increases in nephrogenous cyclic AMP and serum iPTH. Identical findings were noted in short-term (2--3 successive days) studies in twelve patients. In response to a 1000 mg oral calcium tolerance test, twelve patients with primary hyperparathyroidism and intermittent hypercalcaemia (basal serum calcium 10.2 +/- 0.2 mg/dl, mean +/- SD) displayed: (1) hyperabsorption of calcium (mean calciuric response twice normal); (2) induced-hypercalcaemia (mean serum calcium 11.4 mg/dl, with a mean increase of 1.2 mg/dl versus 0.2 mg/cl in normal subjects); and (3) abnormal parathyroid suppressibility (nephrogenous cyclic AMP 2.66 +/- 0.57 nmol/100 ml GF versus 0.95 +/- 0.40 nmol/100 ml GF in normal subjects, mean +/- SD). The patients demonstrated striking hypercalciuria (452 +/- 123 mg/24 h) on a 1000 mg metabolic calcium diet. Serum levels of 1,25(OH)2D3, measured in ten patients, were markedly elevated at 90 +/- 20 pg/ml (mean +/- SD), and there was a strong positive correlation between the values for 1,25(OH)2D3 and the calciuric response to the calcium tolerance test (r = 0.75, P less than 0.001). These results (1) indicate that the calcium tolerance test is a simple and reliable technique for diagnosis of patients with primary hyperparathyroidism and intermittent hypercalcaemia, and (2) emphasize the important pathophysiologic features of this subtle clinical variant of primary hyperparathyroidism.