Use of calcimimetics in children with normal kidney function.

The calcium-sensing receptor (CaSR) plays an important role in the homeostasis of serum ionized calcium by regulating parathyroid hormone (PTH) secretion and tubular calcium handling. Calcimimetics, which act by allosteric modulation of the CaSR, mimic hypercalcemia resulting in suppression of PTH release and increase in calciuria. Mostly used in children to treat secondary hyperparathyroidism associated with advanced renal failure, we have shown that calcimimetics can also be successfully used in children with bone and mineral disorders in which elevated PTH plays a detrimental role in skeletal pathophysiology in the face of normal kidney function. The current review briefly discusses the role of the CaSR and calcimimetics in calcium homeostasis, and then addresses the potential applications of calcimimetics in children with normal kidney function with disorders in which suppression of PTH is beneficial.

[Hormonal and metabolic disorders as systemic factor for the formation of urinary calculi].

In patients suffering from urolithiasis, metabolic diagnostics often reveals abnormalities contributing to the formation of stones: hypocitraturia, hyper- and hypocalcemia, hypercalciuria, hypomagnesemia/hypomagnesuria, hyperoxalaturia, etc. Before surgery, complex biochemical examination of blood and 24-hourcollection urine in 82 patients with urolithiasis was performed. The analysis of the main laboratory parameters of carbohydrate, lipid, calcium and phosphorus and purine metabolism found the prevalence of violations of calcium and phosphorus metabolism in these patients. Dyslipidemia was diagnosed in 31 (37.8%) patients. There was a significant positive correlation between serum total cholesterol and serum total calcium (rs = 0.3315, P = 0.0103). Low serum calcium levels were associated with hyperoxalaturia (rs = -0.4270, P = 0.0295). There was a significant effect of natriuria on urinary excretion of oxalate (rs = 0.6107, P = 0.0001), Mg (rs = 0.4156, P = 0.0096) and K (rs = 0.5234, P = 0.00005). The study shows the role of magnesium in the prevention of recurrence and manifestation of urolithiasis. The combination of two or more types of hormonal and metabolic disorders increases the incidence of recurrent stones. Timely correction of hormonal-metabolic status allows to reduce the risk of stone formation, and hospitalization attributable to the complications associated.

[Clinical and laboratory parameters in patients with urolithiasis in the presence and absence of primary hyperparathyroidism].

The clinical and laboratory findings in 78 patients with various forms of urolithiasis depending on the presence of primary hyperparathyroidism (PHPT) were analyzed. PHPT was diagnosed in 17 patients. Group "without PHPT" and group "with PHPT" differed significantly in terms of parathyroid hormone (PTH) level, serum calcium, phosphorus, chloride, alkaline phosphatase, calciuria and kaliuria. In patients with staghorn calculi, PHPT was diagnosed in 12.5%, and staghorn calculi in the presence of PHPT were identified in 17.7% of cases. Hypercalciuria in the group "with PHPT" was detected in 82.4% of patients (all 3 patients with staghorn calculi), and in the group "without PHPT"--in 18% of patients (2 of 21 patients with staghorn calculi). Hyperoxaluria was observed in 42.3% of patients "without PHPT" and in 35.3% of patients "with PHPT", in 36.8% of patients with simple stones and in 57.2%--with staghorn calculi. In 39% of patients "without PHPT", secondary hyperparathyroidism (SHPT) was diagnosed. SHPT prevalence was 28% in patients with staghorn calculi, and 45% in patients with simple stones. In 87.5% of patients with hypomagnesemia, staghorn calculi were observed. Significant relationship between magnesium and triglycerides (r(s) = -0.296; P = 0.041), and magnesium and high-density lipoproteins (r(s) = 0.339; P = 0.032) in all patients with urolithiasis were revealed. Thus, the study found no association between staghorn nephrolithiasis and PHPT. Elevated PTH levels usually indicate SHPT rather than PHPT. In hypocalcemia, there was more strong association between PTH and calcium, in normocalcaemia--between PTH and magnesium.

Normocalcemic hyperparathyroidism in patients with recurrent kidney stones: a disease entity or vitamin D deficiency?

This retrospective data analysis was undertaken to examine the biochemical differences between renal stone formers with normocalcemic hyperparathyroidism (NHPT) and those with normal parathyroid hormone (PTH) levels. Our goal was to ascertain whether 25-hydroxyvitamin D (25(OH)D) status related to PTH levels in this patient cohort. Our findings among 74 patients with NHPT indicate that stone formers with NHPT had significantly lower 25(OH)D levels compared to 192 controls (p = 0.0001) and that 25(OH)D is positively correlated with 1,25-dihydroxyvitamin D values (R = 0.736, p = 0.015). Sequential measurements (after 3 - 5 years), among 11 patients with NHPT who did not receive vitamin D (VitD) preparations, showed a significant increase in urinary calcium (3.43 ± 1.96 vs. 5.72 ± 3.95, p = 0.0426) without a significant change in PTH levels. VitD supplementation, to 3 patients resulted in significant PTH decrease (11.8 ± 1.8 vs. 9.8 ± 1.3, p = 0.003). Prospective studies are needed to confirm the role of vitamin supplementation in renal stone formers with NHPT.

Phosphatemic effect of cinacalcet in kidney transplant recipients with persistent hyperparathyroidism.

BACKGROUND: In kidney transplant recipients, persistent hyperparathyroidism leads to hypercalcemia and increased urinary phosphorus excretion. The calcimimetic drug cinacalcet effectively decreases parathyroid hormone (PTH) levels and corrects hypercalcemia in these patients. The purpose of the present study is to examine the effect of cinacalcet treatment on determinants of renal phosphorus reabsorption under steady-state conditions. STUDY DESIGN: Open-label prospective uncontrolled trial. SETTING & PARTICIPANTS: 10 stable kidney transplant recipients with persistent hyperparathyroidism. INTERVENTION: Cinacalcet, 30 and 60 mg/d, for 2 weeks. OUTCOMES & MEASURES: Changes in urinary phosphorus excretion in timed urine samples, intact and carboxy-terminal (C-term) fibroblast growth factor 23 (FGF-23), intact PTH, venous pH, and bicarbonate values at defined intervals over 24 hours. RESULTS: Cinacalcet decreased renal phosphorus excretion in the first 8 hours by 30% to 40%, but not from 8 to 24 hours after drug administration. Serum phosphorus levels normalized in all patients. Cinacalcet markedly decreased plasma intact PTH levels (60%; P < 0.001). Cinacalcet also decreased mean intact FGF-23 levels from 67 +/- 8 (SE) to 51 +/- 5 and to 54 +/- 6 pg/mL (P < 0.001) and mean C-term FGF-23 levels from 108 +/- 15 to 87 +/- 9 and to 101 +/- 9 RU/mL (P < 0.01), respectively. There was high correlation between intact FGF-23 and C-term FGF-23 levels (r = 0.598; P < 0.001). Acid-base status was unchanged. LIMITATIONS: This is a small study and does not examine the long-term effect of cinacalcet treatment. CONCLUSIONS: Cinacalcet effectively corrected urinary phosphate wasting in kidney transplant recipients, resulting in normalization of serum phosphorus levels. The phosphatemic effects of cinacalcet correlated with a marked decrease in the phosphaturic hormone PTH, rather than with a change in FGF-23 levels or acid-base status, highlighting the importance of PTH in posttransplantation hypophosphatemia.

A study of urinary excretion of parathyroid hormone in man.

A procedure for bioassaying parathyroid hormone-like activity in human urine has been developed. 24-hr urine samples were concentrated with dry Sephadex G-25 and bioassayed in the young thyroparathyrocauterized mouse by the measurement of whole blood calcium. Recovery of biological activity and radioiodinated beef parathyroid hormone was over 80%. Normal subjects usually excreted less than 30 U (USP) of activity per day while 18 patients with proven primary hyperparathyroidism excreted a mean of 182 U/day (USP). The activity was not found in 7 patients with hypoparathyroidism or in 5 patients with carcinoma of the breast, but was present in 9 patients with uremia and in 5 with carcinoma of the lung and hypercalcemia.

The acute effect of chlorothiazide on serum-ionized calcium. Evidence for a parathyroid hormone-dependent mechanism.

The acute effects of chlorothiazide (CTZ) on total (TSCA) and ionized (SCA-plus 2) serum calcium concentrations were studied in three groups of people: (a) eight subjects with normal parathyroid function; (b) six patients with hypoparathyroidism; and (c) two patients with hyperparathyroidism. Most subjects were studied on four occasions; at least 3 days intervened between studies on an individual subject. During each experiment the subject received an i.v. influsion of 5% dextrose in water at 1 ml/min from 8 a.m. to 4 p.m. Additions to the infusions were (a) none; (b) CTZ to deliver 3.33 mg/kg/h; (c) parathyroid extract to deliver 1 U/kg/h; or (d) both CTZ and parathyroid extract at the rates previously indicated. CTZ, when used, was added to the infusion at 10 a.m., parathyroid extract at 8 a.m. When CTZ was infused, the diuretic-induced losses of Na and water were replaced by i.v. infusion. In normal subjects 2 h after the start of CTZ infusion, there was a transient increase in SCA-plus 2 which coincided in time of day with a transient decrease in SCA-plus 2 in control experiments. At that time of day SCA-plus 2 was 4.18 plus or minus 0.12 mg/100 ml in control experiments and 4.56 plus or minus 0.08 in experiments with CTZ, P smaller than 0.025. The corresponding values for (TSCA) were 9.32 plus or minus 0.15 and 9.80 plus or minus 0.30, P smaller than 0.01. Such differences were not observed in the group with hypoparathyroidism. In the two patients with hyperparathyroidism, CTZ produced sustained increases in TSCA and SCA-plus 2. In normal subjects and those with hypoparathyroidism, CTZ plus parathyroid extract infusion resulted in sustained increases in both SCA-plus 2 and TSCA throughout the periods of observation when compared to experiments in which only parathyroid extract was infused, P smaller than 0.01 in all instances. The results suggest that the acute hypercalcemic action of CTZ requires the presence of circulating parathyroid hormone.

The role of 1 alpha, 25-dihydroxyvitamin D in the mediation of intestinal hyperabsorption of calcium in primary hyperparathyroidism and absorptive hypercalciuria.

The cuase for the intestinal hyperabsorptionof calcium (Ca) in various forms of hypercalciurias was explored by a careful measurement of plasma 1 alpha, 25-dihydroxycholecalciferol [1 alpha, 25-(OH)I D] and by an assessment of intestinal Ca absorption and of parathyroid function. In 18 cases of primary hyperparathyroidism (PHPT), the mean plasma concentration of 1 alpha, 25-(OH)2D was significantly increased (4.9 +/- 2.2 SD ng/dl vs. 3.4 +/- 0.9 ng/dl for the control group), and was significantly correlated with fractional Ca absorption (alpha) (r = 0.80, P less than 0.001). Plasma 1 alpha, 25-(OH)2D was also correlated with urinary Ca (P less than 0.05), but not with serum Ca or phosphorus (P), P clearance, urinary cyclic AMP, or serum immunoreactive parathyroid hormone. In 21 cases of absorptive hypercalciuria (AH), plasma 1 alpha, 25-(OH)2D was elevated in one-third of cases, and the mean value of 4.5 +/- 1.1 ng/dl was significantly higher than that of the control group (P less than 0.01). Since relative hypoparathyroidism may be present, the normal absolute value of plasma 1 alpha, 25-(OH)2D, found in two-thirds of cases of AH, may be considered to be inappropriately high. Moreover, in the majority of cases of AH, the data points relating plasma 1 alpha, 25-(OH)2D and alpha fell within 95% confidence limits of values found in non-AH groups (including PHPT). The results suggest that the intestinal hyperabsorption of Ca in PHPT aw AH may be vitamin D dependent. However, the disturbance in vitamin D metabolism may not be the sole cause for the high Ca absorption in AH, since in some patients with AH, the intestinal Ca absorption appears to be inapp

Urinary polypeptides related to collagen synthesis.

Of the total urinary hydroxyproline in normal subjects and those with skeletal disorders, between 4 and 20% was nondialyzable. In some patients with Paget's disease of bone, hyperparathyroidism with osteitis fibrosa, hyperphosphatasia, and extensive fibrous dysplasia the total urinary hydroxyproline was sufficiently high to permit purification of this polypeptide hydroxyproline by gel filtration and ion exchange chromatography. The partially purified polypeptides had molecular weights between 4500 and 10,000 and amino acid compositions and physical properties resembling those of gelatin. The polypeptide fractions also contained neutral sugar and glucosamine. These fragments had been shown to be susceptible to cleavage by purified bacterial collagenase suggesting the presence of the sequence-Pro-X-Gly-Pro-Y-. After administration of proline-(14)C to patients with Paget's disease hydroxyproline-(14)C was excreted in the urine. The hydroxyproline-(14)C specific activity reached a peak in 2-4 hr and declined rapidly. The specific activity of the polypeptide (retentate) portion was severalfold greater than that of the raw urine and diffusate. When the labeled urines were subjected to gel filtration the hydroxyproline-(14)C fractions of highest molecular weight which were eluted first from the columns had the highest specific activities. Exposure of the hydroxyproline-(14)C-containing polypeptides to bacterial collagenase rendered them dialyzable. Four patients with hyperparathyroidism and osteitis fibrosa were studied before and after removal of a parathyroid adenoma, a period of transition from a predominance of bone collagen resorption to one of relatively increased bone collagen synthesis. The total urinary hydroxyproline fell rapidly after operation whereas the ratio of the polypeptide fraction to the total rose three- to fourfold. The results of these studies suggest that the urinary polypeptides represent fragments of collagen related to collagen synthesis. Changes in the ratio of these peptides to total hydroxyproline in the urine may serve as an index of new bone formation in patients with skeletal disorders.

Thiazide Treatment in Primary Hyperparathyroidism-A New Indication for an Old Medication?

Context: There is no therapy for control of hypercalciuria in nonoperable patients with primary hyperparathyroidism (PHPT). Thiazides are used for idiopathic hypercalciuria but are avoided in PHPT to prevent exacerbating hypercalcemia. Nevertheless, several reports suggested that thiazides may be safe in patients with PHPT. Objective: To test the safety and efficacy of thiazides in PHPT. Design: Retrospective analysis of medical records. Setting: Endocrine clinic at a tertiary hospital. Patients: Fourteen male and 58 female patients with PHPT treated with thiazides. Interventions: Data were compared for each patient before and after thiazide administration. Main Outcome Measures: Effect of thiazide on urine and serum calcium levels. Results: Data are given as mean ± standard deviation. Treatment with hydrochlorothiazide 12.5 to 50 mg/d led to a decrease in mean levels of urine calcium (427 ± 174 mg/d to 251 ± 114 mg/d; P < 0.001) and parathyroid hormone (115 ± 57 ng/L to 74 ± 36 ng/L; P < 0.001), with no change in serum calcium level (10.7 ± 0.4 mg/dL off treatment, 10.5 ± 1.2 mg/dL on treatment, P = 0.4). Findings were consistent over all doses, with no difference in the extent of reduction in urine calcium level or change in serum calcium level by thiazide dose. Conclusion: Thiazides may be effective even at a dose of 12.5 mg/d and safe at doses of up to 50 mg/d for controlling hypercalciuria in patients with PHPT and may have an advantage in decreasing serum parathyroid hormone level. However, careful monitoring for hypercalcemia is required.

The threshold of bone mineral density for vertebral fractures in female patients with primary hyperparathyroidism.

BACKGROUND AND OBJECTIVE: Primary hyperparathyroidism (pHPT) is one of the causal diseases that induce secondary osteoporosis. Although patients with pHPT have reduced bone mineral density (BMD) especially at the cortical bone, there have been controversies about risk of fracture. Moreover, no reports have been available about the threshold of BMD for fractures in pHPT patients. METHODS: BMD values were measured by dual-energy x-ray absorptiometry at lumbar spine, femoral neck and distal one third of radius. Various indices were compared in 116 female pHPT patients and 716 control subjects. Moreover, we analyzed relationship between the cut-off values of BMD and the prevalence of vertebral fractures in pHPT and control subjects. RESULTS: The prevalence of subjects with vertebral fractures was lower in pHPT patients, compared with that of control subjects. Age and body height were significantly higher and lower in pHPT women with vertebral fractures, respectively. Lumbar spine BMD was significantly lower in pHPT women with vertebral fractures, presumably due to their increased age. There were no differences in femoral neck and radius BMD or in bone metabolic indices between pHPT women with and without vertebral fractures. On the other hand, age-matched BMD was not significantly different between both groups at any measured site. Cut-off values of BMD at lumbar spine and femoral neck were lower in postmenopausal pHPT patients, compared with those of the postmenopausal control group. Moreover, cut-off values of BMD at radius was much lower in postmenopausal pHPT patients, compared with those of the postmenopausal control group (pHPT vs control (g/cm(2)): 0.670 vs 0.706 at lumbar spine; 0.549 vs 0.570 at femoral; 0.394 vs 0.474 at radius). Sensitivity and specificity of vertebral fractures was lower in pHPT patients, compared with those in control group. CONCLUSIONS: The present cross-sectional study demonstrated that thresholds of BMD for vertebral fractures were lower especially at radial bone in female patients with pHPT, compared with those in the control group.

Urinary calcium excretion in primary hyperparathyroidism: relationship to 25-hydroxyvitamin d status.

OBJECTIVE: To determine the prevalence of vitamin D deficiency in patients with primary hyperparathyroidism (PHPT) and evaluate the relationship between urinary calcium excretion and serum 25-hydroxyvitamin D (25-OH-D) levels in patients with PHPT. METHODS: We present a case report and a review of the medical records of patients with PHPT. Of 75 patients with PHPT substantiated by hypercalcemia and increased levels of intact parathyroid hormone (iPTH), 35 were identified with laboratory evaluation of vitamin D levels and 24-hour urinary calcium excretion. These study subjects were stratified as 25-OH-D deficient, insufficient, or replete (on the basis of serum values of <15, 15 to 25, or >25 ng/mL, respectively). Total 24-hour urinary calcium excretion and the fractional excretion of calcium (FECa) were analyzed as a function of 25-OH-D status. RESULTS: Of the 35 study subjects, 14 (40%) and 13 (37%) had 25-OH-D deficiency or insufficiency, respectively. Those patients with a 25-OH-D level <15 ng/mL had higher serum iPTH concentrations as well as lower urinary calcium excretion and FECa. No significant correlations were found, however, between 25-OH-D status and iPTH concentrations (r = -0.21; P = 0.23), total 24-hour urinary calcium excretion (r = 0.07; P = 0.7), or FECa (r = 0.04; P = 0.8). CONCLUSION: Vitamin D deficiency (25-OH-D levels <15 ng/mL) was common in our population of patients with PHPT. Urinary calcium excretion was not significantly altered by 25-OH-D deficiency in patients with newly recognized PHPT. Measurements of total urinary calcium excretion and FECa can be reliably used to rule out familial benign hypocalciuric hypercalcemia in the initial evaluation of PHPT, regardless of 25-OH-D status. Determining 25-OH-D concentrations best assesses the vitamin D status.

Nephrogenous cyclic AMP levels in primary hyperparathyroidism.

The clinical utility of urinary cyclic adenosine-3',5'-monophosphate (cAMP) determinations has been limited by the overlap between hyperparathyroid and normal patients. We evaluated the potential of the parathyroid hormone (PTH)-dependent, nephrogenous cAMP in the diagnosis of hyperparathyroidism. Twenty-three patients with primary hyperparathyroidism and 19 control subjects had two-hour urine collections and blood sampling at midpoint. Nephrogenous cAMP level was calculated as total urinary cAMP excretion minus the amount filtered. The total urinary cAMP excretion (micromols per gram of creatinine) was higher in hyperparathyroid patients (6.8 +/- .5 SE), but overlapped with values obtained in controls (2.9 +/- .15). The level of nephrogenous cAMP (percent of total) was also higher in hyperparathyroid patients (72.5 +/- 1.8) than controls (26.3 +/- 4.1) and clearly separated the groups. Determination of nephrogenous cAMP levels may be useful in the diagnosis of hyperparathyroidism.

Borderline-low serum thyrotropin level is correlated with increased fasting urinary hydroxyproline excretion.

BACKGROUND: Recent studies suggest that even mildly supraphysiologic thyroid hormonal status accelerates bone loss. In hyperthyroidism, increased bone resorption is the predominant mechanism for bone loss. We postulated that the changes in thyroid hormone status as reflected by low-normal and minimally subnormal serum thyrotropin level would have an effect on bone turnover and could be detected by a simple, noninvasive marker of bone resorption, fasting urinary total hydroxyproline-creatinine excretion (THP/Cr). METHODS: We retrospectively identified ambulatory patients with a restricted range of diagnoses who had had measurements of thyrotropin and THP/Cr performed within +/- 21 days. RESULTS: Of the 86 patients, 47 had thyrotropin levels greater than 1.0 mU/L. In these patients, no correlation was evident for thyrotropin and THP/Cr. Of the other 39 patients, 11 had suppressed thyrotropin levels (less than 0.1 mU/L) and showed clearly elevated values for THP/Cr, as expected from previous studies of hyperthyroidism. For 28 patients with thyrotropin in the borderline and low-normal range of 0.1 to 1.0 mU/L, a significant negative correlation with THP/Cr was found. The THP/Cr was positively correlated with serum alkaline phosphatase level, as expected with increased bone turnover. CONCLUSIONS: These results add further support to the hypothesis that even a minimal excess of thyroid hormones increases bone turnover and may contribute to accelerated bone loss.

Pretreatment clinical and laboratory findings in dogs with primary hyperparathyroidism: 210 cases (1987-2004).

OBJECTIVE: To evaluate pretreatment clinical and laboratory findings in dogs with naturally occurring primary hyperparathyroidism. DESIGN: Retrospective study. ANIMALS: 210 dogs with primary hyperparathyroidism and 200 randomly selected, age-matched control dogs that did not have primary hyperparathyroidism. PROCEDURE: Medical records for dogs with primary hyperparathyroidism were reviewed for signalment; clinical features; and results of clinicopathologic testing, serum parathyroid hormone assays, and diagnostic imaging. RESULTS: Mean age of the dogs with primary hyperparathyroidism was 11.2 years (range, 6 to 17 years). The most common clinical signs were attributable to urolithiasis or urinary tract infection (ie, straining to urinate, increased frequency of urination, and hematuria). Most dogs (149 [71%]) did not have any observable abnormalities on physical examination. All dogs had hypercalcemia, and most (136 [65%]) had hypophosphatemia. Overall, 200 of the 210 (95%) dogs had BUN and serum creatinine concentrations within or less than the reference range, and serum parathyroid hormone concentration was within reference limits in 135 of 185 (73%) dogs in which it was measured. Urolithiasis was identified in 65 (31 %) dogs, and urinary tract infection was diagnosed in 61 (29%). Mean serum total calcium concentration for the control dogs-was significantly lower than mean concentration for the dogs with primary hyperparathyroidism, but mean BUN and serum creatinine concentrations for the control dogs were both significantly higher than concentrations for the dogs with primary hyperparathyroidism. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that urolithiasis and urinary tract infection may be associated with hypercalcemia in dogs-with primary hyperparathyroidism, but that development of renal insufficiency is uncommon.

Markers of bone remodeling in the elderly subject: effects of vitamin D insufficiency and its correction.

The elderly subject is prone to both vitamin B insufficiency and calcium insufficiency due to a low calcium intake and calcium malabsorption. These two alterations may lead to secondary hyperparathyroidism, and thus to increased bone loss. We investigated 72 elderly subjects (16 men and 56 women) with vitamin D insufficiency and 25 healthy elderly women with normal vitamin D status, with respect to their indices of calcium metabolism and of bone remodeling: serum total alkaline phosphates (phosphatases), bone AP (BAP), osteocalcin (BGP), tartrate-resistant acid phosphatase (TRAP), urine hydroxyproline (HYP), and the 3-OH-pyridinium derivatives pyridinoline (PYD) and deoxypyridinoline (DPD), which are new markers of bone resorption. We then studied the modifications of these markers in the patients with vitamin D insufficiency at 3 months and 6 months after onset of a daily vitamin D and calcium supplementation. When compared with elderly subjects with normal vitamin D status, patients with vitamin D insufficiency had increased intact parathyroid hormone (iPTH) levels (60.1 +/- 10.2 vs 30.2 +/- 4.5, p < 0.001) and a high bone turnover as reflected by increased values of most serum and urine markers of bone remodeling. PYD and DPD levels were significantly correlated with all indices of bone turnover, unlike HYP, which showed no correlation with bone formation markers (AP, BAP, and BGP). A daily supplement of 800 IU vitamin D3 and 1 g of elemental calcium increased 25(OH)D levels and induced a dramatic decrease of iPTH levels; at 3 and 6 months, the mean iPTH level decreased by 50% (p < 0.0001), reaching the mean value of healthy vitamin D sufficient elderly women. All markers of bone turnover, except TRAP, decreased significantly at 3 and 6 months. The PYD/DPD ratio increased significantly at 3 and 6 months. The decrease of bone markers was more marked in patients with more severe hyperparathyroidism, the greatest variations being obtained with BAP (45%, p = 0.006) and DPD (43%, p = 0.036) levels. Most markers of bone remodeling are increased in elderly subjects with vitamin D insufficiently and vary with its correction. However, BAP and DPD are the most sensitive indicators of increased bone turnover due to secondary hyperparathyroidism.

Direct, enzyme-linked immunoassay for urinary deoxypyridinoline as a specific marker for measuring bone resorption.

Several studies in recent years have shown that the pyridinium crosslinks of collagen provide good urinary markers of collagen degradation, primarily reflecting bone resorption. Most studies, however, were based on time-consuming HPLC assays of the crosslinks. We now describe the development of an immunoassay (ELISA) based on a monoclonal antibody for free deoxypyridinoline (Dpd) and its use in healthy individuals and patients with bone-related disorders to measure the urinary excretion of Dpd as an improved assessment of bone resorption rate. The Dpd antibody exhibited less than 1% cross-reaction with free pyridinoline and was shown to react only with free Dpd in urine, having no significant interaction with peptide forms of the crosslinks. The intra- and interassay variations were less than 10 and 15%, respectively. A total of 402 urine samples from patients and healthy volunteers were analyzed by both the immunoassay and HPLC. The ELISA results were highly correlated with those for total Dpd measured by HPLC over the full range of sample groups (r = 0.95). In normal adults, the excretion of Dpd (mean +/- SD) was 4.7 +/- 1.6 nmol/mmol creatinine, with about fivefold higher excretion rates in children. For 31 osteoporotic patients, the ELISA Dpd values (median 6.7; range 3.0-13.5 nmol/mmol Cr) were significantly higher (p < 0.0001) than the corresponding values for age- and sex-matched controls (median 4.0; range 1.8-7.4). The difference between the groups was similar for total Dpd by HPLC (osteoporotic: mean 12.8, range 4.8-30.7; controls: 6.6, range 3.0-18.1; p < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Calciotropic hormones and bone markers in the elderly.

There is a lack of substantial data on changes in calciotropic hormones and bone markers in elderly subjects living in North America. Parathyroid hormone (PTH), serum 25-hydroxyvitamin D (25(OH)D) and bone markers (serum osteocalcin and urine N-telopeptide), were measured in 735 Caucasian subjects (235 men and 500 women) aged 65-87 years. There was a significant increase in serum osteocalcin and urine N-telopeptide with age in men, and a significant increase in serum osteocalcin with age in women. Serum PTH and 25(OH)D showed no significant change with age in men or women. After adjusting for age, calcium intake, serum creatinine, season, and weight, mean serum PTH (p = 0.01), serum osteocalcin (p = 0.0001) and 24 h urine N-telopeptide (p = 0.0001) were higher in women than men, and mean serum 25(OH)D (p = 0.0001) and 24 h urine calcium (p = 0.0001) were higher in men than women. Serum PTH was correlated with serum osteocalcin in men and women, r = 0.24, r = 0.17, p < 0.001, but not with urine N-telopeptide. Serum PTH was inversely correlated with serum 25(OH)D (r = -0.25, r = -034,p < 0.001), and positively correlated with serum creatinine (r = 0.14, r = 0.17,p < 0.01) in men and women. The prevalence of serum 25(OH)D levels below 12 ng/ml was only 33% in females and 0.4% in men. Thus vitamin D deficiency was very uncommon in the U.S.A. compared with Europe. Although mean serum PTH was increased in the elderly, only 4-6% had PTH levels above the normal range. In summary, the increase in serum PTH in the elderly can be explained more by changes in vitamin D status than by declining renal function. These data also show significantly higher (p = 0.001) bone remodeling markers in women.

Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia.

The calcium-sensing receptor (CASR) is a plasma membrane G protein coupled receptor that is expressed in the parathyroid hormone (PTH) producing chief cells of the parathyroid gland and the cells lining the kidney tubule. By virtue of its ability to sense small changes in circulating calcium concentration ([Ca(2+)](o)) and to couple this information to intracellular signaling pathways that modify PTH secretion or renal cation handling, the CASR plays an essential role in maintaining mineral ion homeostasis. Inherited abnormalities of the CASR gene located on chromosome 3p13.3-21 can cause either hypercalcemia or hypocalcemia depending upon whether they are inactivating or activating, respectively. Heterozygous loss-of-function mutations give rise to familial (benign) hypocalciuric hypercalcemia (FHH) in which the lifelong hypercalcemia is asymptomatic. The homozygous condition manifests itself as neonatal severe hyperparathyroidism (NSHPT), a rare disorder characterized by extreme hypercalcemia and the bony changes of hyperparathyroidism which occur in infancy. The disorder autosomal dominant hypocalcemia (ADH) is due to gain-of-function mutations in the CASR gene. ADH may be asymptomatic or present with neonatal or childhood seizures. A common polymorphism in the intracellular tail of the CASR, Ala to Ser at position 986, has a modest effect on the serum calcium concentration in healthy individuals.

Calcium potentiates the cyclic nucleotide and phosphaturic response to parathyroid hormone infusion.

To determine whether calcium modulates the action of PTH, we measured the cyclic nucleotide and phosphaturic response to PTH following a 4-h infusion of glucose (day 1) and calcium (day 2). The 12 subjects were selected to provide a range of low, normal, and high endogenous PTH function. PTH stimulated nephrogenous cAMP [185 +/- 31 nmol/100 ml glomerular filtrate (GF)], cyclic guanosine monophosphate (0.44 +/- 0.09 mumol/g creatinine), and phosphate (367 +/- 59 mg P/g creatinine) excretion. Calcium infusion stimulated nephrogenous cAMP excretion in the hypoparathyroid subjects (1.42 +/- 0.35 nmol/100 ml GF) but reduced it in subjects with normal parathyroid function (-2.22 +/- 0.46 nmol/100 ml GF). Calcium infusion stimulated cGMP (0.64 +/- 0.1 mumol/g creatinine) and phosphate (113 +/- 48 P/g creatinine) excretion in all subject groups. Calcium infusion led to a 2-fold increase in the cyclic nucleotide and phosphaturic response to PTH in the normal and hypoparathyroid subjects, but had little effect on the PTH response in hyperparathyroid subjects. The extent to which calcium potentiated the ability of PTH to stimulate nephrogenous cAMP excretion correlated negatively with the basal nephrogenous cAMP excretion (r = -0.685, P less than 0.01). We conclude that calcium potentiates the acute effects of PTH on renal cyclic nucleotide and phosphate excretion. This effect is modified by the basal levels of PTH stimulation of the kidney such that it is reduced in magnitude when basal PTH stimulation is increased.