Evidence for a role of intracellular stored parathyroid hormone in producing hysteresis of the PTH-calcium relationship in normal humans.

OBJECTIVE: Despite the clear recognition that extracellular ionized calcium controls PTH secretion, there have been suggestions of hysteresis in the relationship between extracellular ionized calcium and PTH during recovery from induced hypo- and hypercalcaemia in vivo in humans. In this study, we examined the possibility that release of intracellular stored PTH during induced hypocalcaemia may explain hysteresis. VOLUNTEERS: Eleven volunteers, five women and six men, were recruited to participate in the study. DESIGN: A series of three protocols of repeated induction of hypocalcaemia or sequential induction of hypo- and hypercalcaemia. RESULTS: We observed in a total of 13 trials that a drastic lowering of blood ionized calcium by 0.20 mmol/l within 30 min elicited an immediate large, transient peak release of PTH amounting to 6-16 times the baseline concentration. However, following a steady-state period of hypocalcaemia, a subsequent lowering of blood ionized calcium either following a brief return to normocalcaemia (protocol 1), from the initial hypocalcaemic level of blood ionized calcium (protocol 2) or after a brief period of induced hypercalcaemia (protocol 3) gave either no peak release of PTH or a markedly blunted peak. Thus, the PTH response during the initial induction of and the first recovery from hypocalcaemia in our protocol 3 showed significant hysteresis in the relationship between blood ionized calcium and PTH (P < 0.001), whereas, no hysteretic relationship could be shown during the second recovery from induced hypocalcaemia in four of five cases (NS). Moreover, no hysteretic relationship was observed during induction, recovery and re-induction of hypercalcaemia in protocol 3 (NS). CONCLUSION: We believe that the release of what might be preformed, intracellular stored depot PTH can explain, at least in part, the observed hysteretic PTH-calcium relationship in normal humans.

Within-centre evaluation of hypercalcaemia discriminant functions 5 years after their development.

Diagnostic hypercalcaemia discriminant functions, discriminating between clinically significant and non-significant hypercalcaemia, were tested 5 years after their development in order to evaluate the impact of time on their diagnostic capacity. Two populations, consisting of 257 and 129 patients with hypercalcaemia, were consecutively recorded, during six and three months respectively, 5 years apart under similar circumstances. The prevalence of hypercalcaemia was comparable in both populations, being 2.57 and 2.38% respectively (non-significant) (NS). The female/male ratio was 1.9 and 1.7 (NS). The discriminant functions correctly classified 81 and 80% of the women, respectively (NS) and respectively 75% and 64% of the men (NS) in the first and second recorded populations.

Inter-relations between the calcium set-points of Parfitt and Brown in primary hyperparathyroidism: a sequential citrate and calcium clamp study.

The objective of the present study was to compare the calcium set-points of E. M. Brown and A. M. Parfitt obtained by sequential citrate and calcium clamp in patients with primary hyperparathyroidism and healthy controls. Twenty-six patients with primary hyperparathyroidism were investigated and compared to 22 healthy volunteers. All participants were investigated by sequential calcium lowering and raising comprising the following four phases: Phase (1) blood ionized calcium lowering of about 0.20 mmol l-1; phase (2) steady-state (relative) hypocalcaemia of blood ionized calcium 0.20 mmol l-1 below baseline; phase (3) blood ionized calcium is raised to about 0.20 mmol l-1 above baseline; and phase (4) (relative) hypercalcaemia of blood ionized calcium 0.20 mmol l-1 above baseline. Serum parathyroid hormone (1-84) was measured by an immunoradiometric assay. Blood ionized calcium was measured by a calcium selective electrode. We found the calcium set-points of Parfitt to be 1.42 mmol l-1 (SD 0.12, n = 52) vs. 1.25 mmol l-1 (SD 0.04, n = 44) in patients and controls, respectively (P < 0.001). The calcium set-points of Brown were 1.32 mmol l-1 (SD 0.10, n = 26) vs. 1.13 mmol l-1 (SD 0.04, n = 22), respectively (P < 0.001). By comparing the calcium set-points of Parfitt and Brown, a strikingly good correlation was observed, in patients (r = 0.91, P < 0.001) and in controls (r = 0.85, P < 0.001). We demonstrate in this paper in vivo that Brown's and Parfitt's calcium set-points are raised in primary hyperparathyroidism and return to normal following parathyroidectomy.(ABSTRACT TRUNCATED AT 250 WORDS)

Tamoxifen and bone metabolism in postmenopausal low-risk breast cancer patients: a randomized study.

PURPOSE: This trial was undertaken to evaluate the effect of adjuvant tamoxifen on bone metabolism in postmenopausal women undergoing surgery for low-risk breast cancer. PATIENTS AND METHODS: In an open trial, 25 women were randomized to receive tamoxifen 30 mg/d for 2 years, and 25 women constituted the control group. Twenty women treated with tamoxifen and 23 women in the control group provided data for the analysis. Inclusion criteria were operation for low-risk breast cancer and cessation of menstruations for more than 1 year. Exclusion criteria were presence of metastases, disorders of bone metabolism, contraindications against tamoxifen, use of drugs with influence on bone metabolism, ailments that made bone mineral measurements impossible, and age greater than 65 years. Repeated measurements of bone mineral density and content at the lumbar spine and forearms, serum alkaline phosphatase, phosphate, and ionized calcium were performed in all patients. RESULTS: Lumbar spine bone mineral density increased during the first year in women treated with tamoxifen and then stabilized, compared with decreased bone mineral density in the control group (P = .00074). Bone mineral content at the forearms remained almost stable in tamoxifen-treated women compared with a decrease in the control group (P = .024). Serum alkaline phosphatase, phosphate, and ionized calcium decreased in the tamoxifen group (P < .00001, P = .002, and P = .002, respectively). CONCLUSION: Tamoxifen has estrogen-like effects on bone metabolism that result in an increase and stabilization of bone mineral density in the axial skeleton and a stabilization of bone mineral content in the appendicular skeleton.

Progressive escape from parathyroid suppression: a common phenomenon in primary hyperparathyroidism (a calcium clamp study).

OBJECTIVE: Induced aggravation of hypercalcaemia in vivo and in vitro causes partial suppression of parathyroid hormone (PTH) secretion in primary hyperparathyroidism (PHP). Furthermore, one in-vitro study also demonstrates progressive escape from such action. The aim of the present in-vivo study was to examine whether escape from suppression is a common feature of PHP. DESIGN: A rapid increment in blood ionized calcium (B-Ca2+) to 0.25-0.30 mmol/l above individual baselines was achieved by intravenous calcium infusions. This induced or aggravated hypercalcaemia was kept constant for 2 hours (controls) or 4 hours (patients). PATIENTS AND CONTROLS: The study of PHP comprised 19 patients (18 females and one male) aged 39-85 years (geometric mean 66). For comparison we included the results obtained in a control group of 24 healthy subjects (11 women and 13 men) aged 20-68 years (geometric mean 32). MEASUREMENTS: The individual levels of B-Ca2+ were controlled by frequent bedside measurements of B-Ca2+. The changes in serum intact parathyroid hormone (S-PTH(1-84)) were registered. RESULTS: After 30 minutes of calcium infusion average concentrations of S-PTH(1-84) had decreased from 7.9 (6.7-9.4) pmol/l in PHP and 2.5 (2.1-2.9) pmol/l in controls to their respective nadir values of 2.9 (2.1-4.1) pmol/l and 0.6 (0.5-0.8) pmol/l. While S-PTH(1-84) remained suppressed at a stable level for 120 minutes in controls, in PHP it started to escape progressively after 30 minutes to a level of 4.2 (3.0-5.8) pmol/l (P < 0.001). Linear regression analysis of the individual S-PTH(1-84) observations in PHP, from 30 to 240 minutes of study, revealed that five patients did not escape (group A) while the remainder 14 patients escaped progressively (group B). Within group B, seven patients escaped significantly after 120 minutes, 10 after 180 minutes and 14 after 240 minutes. Although comparable respecting B-Ca2+ before and during calcium infusion, group A and B presented different S-PTH(1-84) curves. Thus, at times zero, 30, 120 and 240 minutes their respective average concentrations of S-PTH(1-84) measured 9.9 (9.1-10.9) vs 7.3 (5.9-9.0) (P < 0.02), 4.6 (3.7-5.7) vs 2.5 (1.6-3.9) (P < 0.01), 5.0 (3.9-6.5) vs 3.0 (1.9-4.8) (P < 0.05) and 5.2 (3.6-7.4) vs 3.9 (2.6-6.0) (NS) pmol/l. CONCLUSIONS: We hypothesize that two different mechanisms are involved in the parathyroid response to the calcium clamp, an initial and fast inhibition of PTH release, while the subsequent course depends on the balance between the intra-glandular secretion rate of PTH and the intra-glandular capacity for PTH degradation. The escape from parathyroid suppression during a sustained stable increment in B-Ca2+ suggests that the basal secretion over-rides degradation in a majority of the patients with PHP.

Effect of oral calcium on noninvasive indices of bone formation and bone mass in hemodialysis patients: a randomized double-blind placebo-controlled study.

The purpose of this study was to evaluate the effect of high-dose oral calcium on biochemical indices of bone formation, bone bisphosphonate clearance (BBC) and bone mineral content (BMC) of the distal forearm in patients undergoing hemodialysis. Eighteen patients agreed to participate and were randomized in a double-blind manner to receive either 2 g elemental calcium/day (n = 9) or placebo (n = 9) for 6 months. Previous treatment with aluminum-containing phosphate binders was continued unchanged throughout the study. In the placebo group, serum alkaline phosphatase and osteocalcin tended to increase by 8.0 and 10.2%, respectively, while BBC changed significantly by 49.5% (p < 0.05). In the calcium group the opposite was observed with small decreases in alakline phosphatase and osteocalcin by 8.2 and 11.0%, respectively, and no change in BBC. BMC decreased by 5.0% in the placebo group, but increased by 5.2% in the calcium group, resulting in a difference of 10.2% (p < 0.05). The present study demonstrates that high-dose oral calcium tends to reduce bone turnover and seems able to prevent bone loss in hemodialyzed patients.

Cica clamp evaluation of parathyroid responsiveness in chronic hypoparathyroidism: a sequential citrate and calcium clamp study.

The objective of this study was to examine if the Cica clamp technique, sequential citrate and calcium administration sufficient to promote steady-state-blood-ionized calcium concentrations (B-Ca2+) of about 0.20 mmol/l below and above the individual baseline concentrations, was able to produce reciprocal changes in serum intact parathyroid hormone [S-PTH(1-84)] in chronic surgical hypoparathyroidism (HP; n = 10) and chronic idiopathic HP (n = 2). The calcium set point according to Brown [J Clin Endocrinol Metab 1993;56:572-581] was calculated when possible. Data from 22 controls were included for comparison. Within 5-10 min B-Ca2+ lowering in responding patients with surgical HP (n = 7) and controls demonstrated transient S-PTH(1-84) peaks from 1.3 +/- 0.7 to 3.5 +/- 3.2 pmol/l (p < 0.05) and from 3.4 +/- 1.2 to 19.1 +/- 6.7 pmol/l (p < 0.001), respectively. Subsequently S-PTH(1-84) declined to steady-state hypersecretion levels of about 1.9 +/- 1.2 and 8.6 +/- 2.6 pmol/l, respectively. An increase of B-Ca2+ made S-PTH(1-84) unmeasurable in all HP responders except one, while S-PTH(1-84) remained measurable, 0.9 +/- 0.4 pmol/l, in all controls. In responding patients with surgical HP and controls the respective calcium set points averaged 1.05 +/- 0.06 and 1.13 +/- 0.04 mmol/l, respectively (p < 0.001). The remaining nonresponders with surgical and idiopathic HP did not respond at all. To summarize, 7 out of 10 patients with surgical HP demonstrated a normal pattern of parathyroid response to sequential B-Ca2+ decreases and increases.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone metabolism in obesity: changes related to severe overweight and dietary weight reduction.

A non-invasive evaluation of bone metabolism was performed in 44 morbidly obese patients before and after a mean weight loss of 22.4 kg (range 7.9-43.4 kg) after 2 months and a further weight loss of 7.3 kg after 8 months (0.8-20.0 kg). This weight reduction was obtained by a nutritionally adequate very-low-calorie diet. Before treatment the bone mineral content of the distal forearm was increased compared to normals (51.9 U vs. 43.7 U, p < 0.001). Bone formation was evaluated by serum alkaline phosphatase and serum osteocalcin. Serum alkaline phosphatase was increased (187.8 U/l vs 147.4 U/l, p < 0.001) while serum osteocalcin was lower than in the controls (0.67 nmol/l vs 0.98 nmol/l, p < 0.01). Bone resorption, as measured by the urinary hydroxyproline/creatinine ratio, was not increased in the obese patients (19.2 molar ratio x 10(-3) vs 16.7 molar ratio x 10(-3), NS). After 2 months, the bone mineral content had declined by 3.3%. Serum alkaline phosphatase remained unchanged (187.8 U/l vs 186.9 U/l, NS) but serum osteocalcin demonstrated a significant rise (3.94 nmol/l vs 10.53 nmol/l, p < 0.001), parallel to changes in the hydroxyproline/creatinine ratio (19.2 molar ratio x 10(-3) vs 25.2 molar ratio x 10(-3), p < 0.001). At 8 months, no further change in the bone mineral content was seen. The hydroxyproline/creatinine ratio did still increase (from 25.8 molar ratio x 10(-3) to 30.1 molar ratio x 10(-3), p < 0.05), while serum alkaline phosphatase and serum osteocalcin remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Cica-clamp technique: a method for quantifying parathyroid hormone secretion: a sequential citrate and calcium clamp study.

Objectives of the present study were to establish and investigate a standardized method for quantifying of intact parathyroid hormone secretion during sequential induction of hypo- and hypercalcaemia, and to explore the applicability to these data of a mathematical model derived from in vitro studies as presented in the literature. Twenty-two healthy volunteers aged 20-80 years participated in one or more experiments. The experiments comprised three different protocols of sequential induction of a regular hypocalcaemic (citrate) clamp followed by increases in blood ionized calcium, ending in a regular hypercalcaemic (calcium) clamp. During protocol I, the induction of hypocalcaemia, blood ionized calcium 0.21 mmol l-1 (SD 0.01, n = 76) below baseline, the release of serum parathyroid hormone rapidly increased to a concentration of four to seven times above baseline. The serum parathyroid hormone declined gradually to a steady state of about two to three times above baseline. During stepwise increases in blood ionized calcium, the serum parathyroid hormone rapidly declined to new steady state concentrations. When a hypercalcaemia of 0.20 mmol l-1 (SD 0.02, n = 76) above baseline was reached, serum parathyroid hormone was suppressed to about one-fourth of baseline concentration. Protocol II, the Cica-clamp, and protocol III, are short versions of protocol I using a slow and gradual increase in blood ionized calcium from hypo- to hypercalcaemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Changing incidence and residual lifetime risk of common osteoporosis-related fractures.

Changes in incidence and lifetime risk of fractures are of major importance in the epidemiology of osteoporosis. We focused on hip fractures in women and men and on radial and humeral fractures in women. The study subjects comprised 4500 women and men 20 years old or more with fractures. In women 1735 fractures of the distal radius, 747 fractures of the proximal humerus, 878 cervical and 635 trochanteric hip fractures were included. In men 273 cervical and 232 trochanteric hip fractures were included. The fractures were registered during the period 1976 to 1984 and changes in age-specific incidence were calculated (chi-squared test for linear trend; p-values less than 0.05 were considered significant). On the basis of life tables and population background data, the lifetime risk was estimated. The incidence of cervical hip fractures in women aged 60-89 years decreased significantly (p < 0.05) during the observation period, while no significant decrease was found in the incidence of trochanteric fractures. No significant changes in incidence were observed in women with radial or humeral fractures, or in men with hip fractures. A women 60 years old with a life expectancy of 81 years had an estimated residual lifetime risk of radial, humeral or hip fracture of 17%, 8% and 14% respectively. A man 60 years of age with a life expectancy of 77 years had an estimated risk of hip fracture of 6%.(ABSTRACT TRUNCATED AT 250 WORDS)

Radial and humeral fractures as predictors of subsequent hip, radial or humeral fractures in women, and their seasonal variation.

Hip fractures are common in elderly women, and early risk assessment of future hip fractures is relevant in relation to prevention. We studied the predictive value of radial and humeral fractures in women. The influence of weather conditions on the risk was also studied. Women aged 20-99 years with a fracture of the distal radius (n = 1162) or proximal humerus (n = 406) were followed for 0 to 9 years. The relative risk (RR) and 95% confidence limits (CL) of subsequent fracture among women suffering radial or humeral fractures compared with the background population were calculated. Women 60-79 years of age who had suffered a fracture of the distal radius or proximal humerus had relative risks of sustaining a hip fracture of 1.9 (1.3-2.6, 95% CL) and 2.5 (1.3-3.6, 95% CL) respectively. The relative risk of hip fracture was highest within the first years following a fracture of the radius or the humerus. Women suffering an upper extremity fracture (radius or humerus) in snowy or icy weather had a marginally increased risk (RR = 1.3, 0.4-2.3, 95% CL and RR = 1.8, 0.3-3.4, 95% CL) for a later hip fracture. A woman 50 years old with a radial or a humeral fracture had an estimated residual lifetime risk of sustaining a subsequent hip fracture of 17% and 16% respectively compared with 11% for the background population.(ABSTRACT TRUNCATED AT 250 WORDS)

Oral calcium effectively reduces parathyroid hormone levels in hemodialysis patients: a randomized double-blind placebo-controlled study.

The objective of this study was to elucidate the effect of oral calcium supplement upon the severity of secondary hyperparathyroidism and hyperphosphatemia in patients undergoing hemodialysis. Twenty-three accepted to participate and were randomly allocated to receive in a double-blind manner either 2 g elemental calcium per day (n = 12) or placebo (n = 11) for 6 months. Three patients dropped out leaving 10 patients in each group. In the calcium group serum ionized calcium increased significantly during the 1st month from 1.15 +/- 0.02 to 1.29 +/- 0.04 mmol/l (mean +/- SE) and was then stabilized at an average of 1.26 +/- 0.02 mmol/l for the remaining 5 months. Serum intact parathyroid hormone (PTH) decreased in average by 54% within the 1st month and remained at that level for the following months. Hyperphosphatemia remained stable throughout. On the contrary, in the placebo group, serum concentrations of ionized calcium and intact PTH remained unchanged, while serum phosphate increased significantly. The present study demonstrates that oral calcium reduces secondary hyperparathyroidism and prevents the progression of hyperphosphatemia in patients undergoing hemodialysis.

Increasing parathyroid hormone concentrations in untreated primary hyperparathyroidism.

Twenty-four patients with mild to moderate primary hyperparathyroidism were followed for an average of 2.45 years with serial determinations of serum ionized calcium and intact parathyroid hormone (PTH). For the entire group serum ionized calcium remained stable, whereas serum PTH increased significantly. Eleven patients (group 1) demonstrated a significant increase in PTH with time. The remaining 13 patients formed group 2. Comparison of the changes (%) in each subgroup showed a small but significant increase in serum ionized calcium of 2.6% with time in group 1, while serum PTH increased by 78%. In group 2 serum ionized calcium remained stable whereas PTH increased modestly by 22%. Serum concentrations of creatinine were stable throughout the follow-up period in both groups. Despite the greater precision of serum ionized calcium, measurements of intact PTH are evidently more sensitive than measurements of serum ionized calcium for the detection of progression in primary hyperparathyroidism.

Normal pattern of parathyroid response to blood calcium lowering in primary hyperparathyroidism: a citrate clamp study.

OBJECTIVE: The objective of the present study was to elucidate the parathyroid responsiveness by measurements of blood ionized calcium and serum intact parathyroid hormone (PTH) concentrations, before and during trisodium citrate induced hypocalcaemia. PATIENTS AND CONTROLS: Sixteen patients with primary hyperparathyroidism and 32 healthy volunteers. DESIGN: Blood ionized calcium concentration was lowered by about 0.20 mmol/l and maintained at this level for 2 hours by blood ionized calcium controlled trisodium citrate infusion. MEASUREMENTS: Serum PTH(1-84) was measured by an immunoradiometric assay. RESULTS: In patients and controls, baseline measurements of blood ionized calcium were 1.39 +/- 0.07 vs 1.24 +/- 0.04 mmol/l (mean +/- SD) (P < 0.001) and of serum PTH (1-84) 9.7 +/- 5.4 vs 3.2 +/- 1.1 pmol/l (P < 0.001). During a trisodium citrate clamp, serum PTH(1-84) rose to a maximal concentration after 5-10 minutes in both groups, the patients to 2-10 times baseline, whereas controls rose to 4-7 times baseline values. In both groups the peak of serum PTH(1-84) declined to a steady state concentration around 2-4 times baseline. CONCLUSIONS: In conclusion, adenoma cells seem to react in almost the same way as normal parathyroid cells. They respond to initiation of hypocalcaemia by the release of preformed PTH(1-84), and continue to secrete increased amounts of PTH(1-84) during the maintenance of relative hypocalcaemia. The increased baseline concentrations of blood ionized calcium and serum PTH(1-84) and the serum PTH(1-84) response during blood ionized calcium lowering all suggest a shift upwards in the calcium set point.

Calcium clamp technique: suppression of serum intact PTH by induced hypercalcaemia in normal man and primary hyperparathyroidism.

The aim of the study was to investigate the interrelation between induced hypercalcaemia and serum intact parathyroid hormone (S-PTH(1-84)) in normal man and in patients with primary hyperparathyroidism (PHPT) by measuring blood ionized calcium (B-Ca++) and S-PTH(1-84) before and during a controlled calcium infusion. Guided by frequent measurements of B-Ca++, we adjusted the calcium infusion rate continuously, thereby keeping B-Ca++ in a steady state at a pre-determined level approximately 0.25 mmol l-1 above baseline values. This calcium clamp technique (CCT) applied to 14 normal volunteers for 120 min established a standardized reference for parathyroid suppression and the renal physiological PTH response. The reproducibility of the method and the results obtained by the CCT were satisfactorily assessed in six of the 14 normal subjects. In normal subjects B-Ca++ was raised from 1.25 +/- 0.3 mmol l-1 (mean +/- SD) to 1.49 +/- 0.02 mmol l-1 suppressing S-PTH(1-84) to 264 +/- 9.9% of pre-infusion levels. We applied the CCT to 10 patients with PHPT for 120 min raising B-Ca++ from 1.41 +/- 0.09 mmol l-1 to 1.69 +/- 0.08 mmol l-1, thereby suppressing S-PTH(1-84) to 47.9 +/- 16.3% of pre-infusion levels. The renal handling of calcium and phosphate during CCT demonstrates the biological effects of suppressed activity of PTH on the renal tubules showing increments in the maximal tubular phosphate reabsorption in relation to the glomerular filtration rate (TmP/GFR) and decreased tubular reabsorption fraction of calcium. The described CCT is a safe and reliable dynamic test.(ABSTRACT TRUNCATED AT 250 WORDS)

Prednisolone in the treatment of severe malignant hypercalcaemia in metastatic breast cancer: a randomized study.

To determine the effect of prednisolone on severe hypercalcaemia in women with metastatic breast cancer, 30 patients with serum ionized calcium above 1.60 mmol l-1 (reference range 1.15-1.35 mmol l-1) entered a randomized trial. Performance status before entry to the trial and survival time after hypercalcaemia were also noted. All patients received 4 l of isotonic saline daily and 80 mg intravenous furosemide three times daily for 2 d; thereafter they received 3 l of isotonic saline daily and 80 mg furosemide twice daily for 6 d. Fifteen patients were randomized to receive prednisolone, 25 mg orally, three times daily for 8 d. Serum ionized calcium decreased significantly in both groups, but most markedly in the prednisolone group. The median difference was 0.28 mmol l-1 (95% confidence interval (CI), 0.09-0.52) on day 4 and 0.21 mmol l-1 (95% CI, 0.12-0.44) on day 8. In seven prednisolone-treated patients serum ionized calcium normalized, compared to none in the control group (Fisher's exact test; P = 0.028). No severe adverse effects were observed. Prior to detection of hypercalcaemia all patients were severely immobilized, primarily due to bone pain. Only 10 patients were still living after 3 months. Prednisolone, furosemide and rehydration is superior to furosemide and rehydration alone in severely hypercalcaemic patients with metastatic breast cancer in whom immobilization appears to be an early warning sign of life-threatening hypercalcaemia. The short survival time was not influenced by prednisolone.

Regulation of acute parathyroid hormone release in normal humans: combined calcium and citrate clamp study.

The objective of the present study was to elucidate the dynamics of parathyroid hormone regulation, with particular reference to the mechanism controlling the acute parathyroid hormone release. Through utilization of the citrate clamp technique and the calcium clamp technique we were able, in a standardized way, to stimulate and suppress the parathyroid hormone secretion. Precise bedside measurements of blood ionized calcium and measurements of intact parathyroid hormone were performed. Twelve healthy young volunteers participated in two trials 6-12 wk apart, a citrate clamp (delta-blood ionized calcium -0.19 mmol/l) and a calcium plus citrate clamp (delta-blood ionized calcium +0.22 mmol/l and -0.19 mmol/l). During the citrate clamp, preceded by normal calcemia, serum intact parathyroid hormone peaked to a maximum after 5-10 min, four to six times above baseline concentration and then declined to a steady state two to three times above baseline concentration. During the citrate clamp, preceded by hypercalcemia induced by a calcium clamp, serum intact parathyroid hormone also peaked immediately to about five to nine times above its suppressed level, approximately two times above the baseline concentration. Subsequently, serum intact parathyroid hormone declined to a steady state just below the baseline concentration. In conclusion, within the range studied, the mechanism eliciting the acute serum intact parathyroid hormone release from its depot is a fall in blood ionized calcium, not the absolute concentration of ionized calcium.

Hypocalcemia and parathyroid hormone responsiveness in diabetes mellitus: a tri-sodium-citrate clamp study.

The aim of this study was to elucidate the diabetic hypocalcemia and PTH responsiveness, investigated by measuring blood ionized calcium and serum intact parathyroid hormone (S-PTH(1-84)) concentrations, before and during an induced and maintained controlled hypocalcemia. In 15 patients with insulin-dependent diabetes mellitus and 19 healthy volunteers the blood ionized calcium concentration was lowered by about 0.20 mmol/l and maintained at this level by blood ionized calcium controlled tri-sodium-citrate infusion. In patients vs controls, baseline measurements averaged for blood ionized calcium (mmol/l) 1.18 +/- 0.08 vs 1.24 +/- 0.03 (p less than 0.01), for S-magnesium (mmol/l) 0.73 +/- 0.07 vs 0.81 +/- 0.07 (p less than 0.01) and for S-PTH (1-84) (pmol/l) 3.0 +/- 1.0 vs 3.1 +/- 1.0 (p greater than 0.75). During the clamp, S-PTH (1-84) peaked to comparable maximums after 5-10 min in both groups and then declined to constant concentrations two to three times above their control levels. In conclusion, we found a diabetic hypocalcemia and hypomagnesemia, though baseline levels of PTH and PTH responsiveness were normal. This may be taken to indicate a mild shift downwards in the set-point for PTH secretion in patients with insulin-dependent diabetes mellitus.

Inappropriate hypercalcitriolemia in ileum-resected patients with Crohn's disease.

Twelve patients who had undergone ileal resection because of Crohn's disease were studied for measurements of serum 25-hydroxyvitamin D3 (25-OHD3), 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], intact parathyroid hormone (PTH), ionized calcium and phosphate in median 6 years after the intestinal resection. 24 normal subjects matched for age, sex and season served as controls. Despite a reduced level of 25-OHD3 (p less than 0.05) and normal levels of ionized calcium, PTH, phosphate and renal function the median level of 1,25(OH)2D3 was significantly raised (p less than 0.001). Further analysis showed that the inappropriately increased level of 1,25(OH)2D3 was significantly positive related to the concentrations of its substrate (25-OHD3) and PTH. The cause for inappropriate hypercalcitriolemia is uncertain. Contribution from extrarenal 1-hydroxylation of 25-OHD3 as in sarcoidosis is suggested.

[Basedow's disease and thyroid stimulating hormone producing pituitary adenoma in a patient]. / Mb. Basedowi og thyreoideastimulerende hormonproducerende hypofyseadenom hos samme patient.

TSH-producing adenomas of the pituitary gland are very rare. Synchronous combinations of TSH-producing adenomas with other causes of hyperthyroidism are certainly extremely rare. We present the second known case, reported in the literature, consisting of observations for 12 years in a woman aged 43 years, who presented with active Graves' disease and an apparently inactive pituitary macro-adenoma. However, after normalisation of serum T3 and serum T4 levels by antithyroid medication for one year, the serum TSH rose inappropriately and continued to rise for the following 11 years. Insidious growth of the adenoma also occurred. After one year of medical treatment, a huge goitre was resected (210 g) leaving the patient euthyroid, clinically and biochemically, for four years. Hereafter, hyperthyroidism developed again this time without Graves' disease. We conclude that the patient experienced hyperthyroidism on two occasions, the first caused by Graves' disease and then caused by a TSH-producing pituitary adenoma.