Normalization of reversed bio-intact-PTH(1-84)/intact-PTH ratio after parathyroidectomy in a patient with severe secondary hyperparathyroidism

The conventional intact-PTH assay detects both (1-84)-PTH and C-terminal fragments. The newer PTH assays, bio-intact-PTH assay and whole-PTH assay, use an antibody that binds only if the first amino acid is present, making it specific for the complete molecule, (1-84)-PTH. Thus, the intact-PTH concentrations are theoretically higher than bio-intact-PTH concentrations, and the ratio of bio-intact-PTH/intact-PTH is usually less than 1. These findings are observed in normal subjects and patients with primary and secondary hyperparathyroidism. Here we present a hemodialysis patient with severe secondary hyperparathyroidism who was found to have abnormally higher plasma bio-intact-PTH concentrations than intact-PTH concentrations, and the abnormally high biointact-PTH/intact-PTH ratio improved after parathyroidectomy (PTx). The patient was a 67-year-old man on maintenance hemodialysis since 1995. Since 2003, he was found to have high plasma intact-PTH concentrations and two swollen parathyroid glands in the neck. PTx with forearm autograft was performed in October 2003. Before PTx, an abnormally high ratio of bio-intact-PTH/intact-PTH was detected (840 pg/ml/770 pg/ml, > 1), while the same ratio was improved to normal range (100 pg/ml/200 pg/ml, < 1). Recently, a few patients with parathyroid carcinoma have been found to have higher (1-84)-PTH concentrations than intact-PTH concentrations with abnormally high (1-84)-PTH/intact-PTH ratio. Moreover, a new molecular form of PTH distinct from (1-84)-PTH was detected in these patients. We speculate that the resected parathyroid gland in our patient might have produced a new molecular form of PTH that was less well detected by the conventional intact-PTH assay.     

Efficacy of whole PTH assay and 1-84/non-(1-84) PTH ratio in patients on hemodialysis or undergoing parathyroidectomy

For measurement of parathyroid hormone (PTH), the intact PTH (I-PTH) assay is generally used. However, I-PTH assay apparently detects PTH 7-84 fragments, in addition to PTH 1-84. The whole PTH (W-PTH) assay exhibits no cross-reactivity with PTH 7-84. Ratio of PTH 1-84 to non-(1-84) PTH has been proposed as a non-invasive indicator of bone turnover in patients with end-stage renal disease (ESRD). We evaluated the efficacy of W-PTH assay and 1-84/non-(1-84) PTH ratio in hemodialysis patients and patients who had undergone parathyroidectomy. PTH levels were measured using W-PTH and I-PTH assays in 138 hemodialysis patients, 27 healthy controls and 10 patients who were scheduled to undergo parathyroidectomy for secondary hyperparathyroidism. Alkaline phosphatase, bone alkaline phosphatase and intact osteocalcin were also measured for comparison with 1-84/non-(1-84) PTH ratio. W-PTH was strongly correlated with I-PTH in both groups, and with all three bone metabolic markers in hemodialysis patients. In hemodialysis patients, both PTH and bone metabolic markers were significantly lower in the subgroup with a PTH ratio < 1.0 than in the subgroup with a PTH ratio > or = 1.0. However, PTH ratio exhibited no significant correlation with bone metabolism markers. PTH ratio was higher after parathyroidectomy than before. W-PTH and I-PTH assays offer identical indicators of bone metabolism in ESRD patients. However, 1-84/non-(1-84) PTH ratio may be of limited diagnostic use regarding bone turnover if a cut-off value of 1.0 is used. PTH 1-84 may be secreted relatively more than non-(1-84) PTH after parathyroidectomy, due to decreases in serum calcium. As the W-PTH assay allows easy calculation of non-(1-84) PTH by subtracting the I-PTH value, this assay contributes to identification of the function of non-(1-84) PTH fragments in various conditions.     

Serum 1-84 and 7-84 parathyroid hormone concentrations and bone in patients with primary hyperparathyroidism

BACKGROUND AND AIMS: Parathyroid hormone (PTH) acts on bone as both anabolic and catabolic factor. It includes two fractions: 1-84 (cyclase activating PTH, CAP) which increases bone turnover and serum calcium, and 7-84 (cyclase inactivating PTH, CIP) acting the opposite way. The aim of this study was to establish whether bone mineral density (BMD) and turnover in patients' primary hyperparathyroidism (HPT) are dependent on CAP and CIP concentrations. PATIENTS/METHODS: Thirty-one patients with HPT and 29 appropriately matched controls were examined. Parameters of calcium-phosphate homeostasis and BMD were estimated. RESULTS: BMD of radius shaft was lower in patients with HPT as compared with controls, whereas BMD of spine and ultradistal radius were similar. Serum calcium, bone alkaline phosphatase, total PTH, 1-84 PTH, and 7-84 PTH were higher in HPT patients, whereas serum phosphate was lower and beta cross-laps similar. Both total PTH and CAP correlated significantly with BMD of radius shaft and serum calcium concentration, but not with other examined parameters. CONCLUSION: Total and 1-84 PTH are similarly associated with examined parameters in patients with HPT. Thus, determination of serum CAP concentration does not seem to have advantages over total PTH with regard to bone mineral density and bone turnover assessment in those patients.     

Influence of sevelamer hydrochloride on serum concentration of whole (1-84) and N-terminally truncated (7-84) parathyroid hormone fragments in hemodialysis uremic patients

Phosphate retention stimulates parathyroid hormone (PTH) secretion in uremic patients. Sevelamer hydrochloride is an aluminium- and calcium-free phosphate binder used in the treatment of secondary hyperparathyroidism in uremic patients. The influence of the phosphate lowering effect on serum levels of whole PTH-1-84 and N-terminally truncated PTH-7-84 has not been studied. Seventeen hemodialysis (HD) patients (nine male, eight female) with chronic renal failure and serum phosphorus concentrations, despite calcium carbonate treatment, >2.0 mmol/L were enrolled in this study. Patients did not receive aluminium containing binders. Blood samples for serum concentration assessments of calcium, phosphorus, PTH-1-84 and N-terminally truncated PTH-7-84, carboxyterminal cross-linked collagen fragments (Ctx), total (AP) and bone specific alkaline phosphatase activity (BAP) were drawn twice: before and after 5-week sevelamer administration (in addition to calcium carbonate). Sevelamer treatment was followed by a significant reduction in serum phosphorus level (from 2.46 +/- 0.09 to 2.07 +/- 0.10 mmol/L; p=0.009), PTH-1-84 level (from 396 +/- 75 to 298 +/- 64 pg/mL; p=0.03) and PTH-1-84/PTH-7-84 ratio (from 1.78 +/- 0.18 to 1.55 +/- 0.19; p=0.01), while serum PTH-7-84 levels declined only slightly (from 220 +/- 35 to 183 +/- 25 pg/mL; p=0.11). Serum calcium, Ctx concentrations, AP and BAP activity did not change markedly. There was a significant positive correlation between changes of phosphorus and PTH-1-84 (tau=0.48; p=0.007) or PTH-7-84 concentration (tau=0.43; p=0.02). A 5-week sevelamer treatment suppressed both PTH-1-84 (change statistically significant) and PTH-7-84 (change statistically non-significant) serum concentration in HD uremic patients seemingly related to changes in phosphatemia.     

The reversed ratio of 1-84 PTH (whole PTH)/intact PTH in a patient on hemodialysis associated with primary hyperparathyroidism

Intact PTH measures not only 1-84 PTH, but also other fragments such as 7-84 PTH. Lately, a measurement of 1-84 PTH has been available as whole PTH assay and the ratio of whole PTH/intact PTH is considered to be between 0.5 and 0.7 in patients on hemodialysis. Therefore, intact PTH should be higher than whole PTH. We present a 57-year-old male with chronic renal failure on hemodialysis whose whole PTH was higher than intact PTH (the reversed ratio of whole PTH/intact PTH). He showed one enlarged parathyroid gland by an ultrasonic test, CT examination and RI subtraction study. After this gland was removed by surgery, the ratio of whole PTH/intact PTH normalized. The size of the resected gland was 22 x 15 x 11 mm. The histologic examination revealed adenoma. This indicates that, if patients with chronic renal failure showed the reversed ratio of whole PTH/intact PTH, the possibility that they could have primary hyperparathyroidism in addition to secondary hyperparathyroidism should be considered.     

Structure of non-(1-84) PTH fragments secreted by parathyroid glands in primary and secondary hyperparathyroidism

BACKGROUND: Non-(1-84) parathyroid hormone (PTH) fragments are large circulating carboxyl-terminal (C) fragments with a partially preserved amino-terminal (N) structure. hPTH (7-84), a synthetic surrogate, has been demonstrated to exert biologic effects in vivo and in vitro which are opposite to those of hPTH (1-34) on the PTH/PTHrP type I receptor through a C-PTH receptor. We wanted to determine the N structure of non-(1-84) PTH fragments. METHODS: Parathyroid cells isolated from glands obtained at surgery from three patients with primary hyperparathyroidism and three patients with secondary hyperparathyroidism were incubated with 35S-methionine to internally label their secretion products. Incubations were performed for 8 hours at the patient-ionized calcium concentration and in the presence of various protease inhibitors. The supernatant was fractionated by high-performance liquid chromatography (HPLC) and fractions were analyzed with PTH assays having (1 to 4) and (12 to 23) epitopes, respectively. The serum of each patient was similarly analyzed. Peaks of immunoreactivity identified were submitted to sequence analysis to recover the 35S-methionine residues in positions 8 and 18. RESULTS: Three regions of interest were identified with PTH assays. They corresponded to non-(1-84) PTH fragments (further divided in regions 3 and 4), a peak of N-PTH migrating in front of hPTH (1-84) (region 2) and a peak of immunoreactivity corresponding to the elution position of hPTH (1-84) (region 1). The last corresponded to a single sequence starting at position 1. Region 2 gave similar results in all cases (a major signal starting at position 1) but also sometimes minor sequences starting at position 4 or 7. Regions 3 and 4 always identified a major sequence starting at positions 7 and minor sequences starting at positions 8, 10, and 15. Surprisingly, a major signal starting at position 1 was also present in region 3. The HPLC profile obtained from a given patient's parathyroid cells was qualitatively similar to the one obtained with his/her serum in each case. CONCLUSION: These results indicate that non-(1-84) PTH fragments are composed of a family of fragments which may be generated by specific or progressive cleavage at the N region. The longest fragment starts at position 4 and the shortest at position 15. A peptide starting at position 7 appears as the major component of non-(1-84) PTH fragments. The generation process is similar to the one described for smaller C-PTH fragments a number of years ago, suggesting a similar production mechanism and source for all C-PTH fragments.     

Variable parathyroid hormone(1-84)/carboxylterminal PTH ratios detected by 4 novel parathyroid hormone assays

AIM: Parathyroidhormone (PTH) measurement is important in the evaluation of bone disease in patients with chronic renal failure. Large carboxyl-terminal PTH fragments (C-PTH) cross-react with second-generation PTH assays, lead to an overestimation of biologically active PTH, and are evaluated by a combination of second- and third-generation PTH assays. The aim of our study was to examine whether the use of 4 different PTH assays of putatively same specificity leads to comparable results detecting C-PTH fragments. SUBJECTS AND METHODS: In 70 chronic dialysis patients, total PTH and PTH(1-84) were measured in parallel by 4 novel PTH assays (Nichols Advantage Intact PTH and Bio-Intact PTH Chemiluminescence Assay, Nichols Institute Diagnostics, USA, DUO Total and CAP PTH IRMA, Scantibodies Laboratory, USA). The C-PTH concentration was quantitated by subtracting PTH(1-84) from total PTH. Consecutively, the PTH(1-84)/C-PTH ratio was calculated. RESULTS: Nichols Intact PTH and DUO Total PTH assays were highly correlated (r = 0.985), as well as Nichols Bio-Intact and DUO CAP assays (r = 0.984). However, total PTH values measured by the Nichols assay were 30% higher (median (range): 185 (9.9 - 2,332) versus 130 (2.3 - 1,271.1) pg/ml, p < 0.01). PTH(1-84) values, measured by the Nichols Bio-Intact PTH assay were 8% higher compared to the Scantibodies CAP assay (median (range): 79.6 (7.5 - 1,060.9) versus 73.7 (4.4 - 918.9) pg/ml, p = NS). Thirty-six patients had a ratio < 1 measured by the Nichols assays, whereas only 8 patients showed the same ratio when measured by the Scantibodies assays. In 28 patients (40%), contradictory PTH(1-84)/C-PTH ratios were found, showing a ratio < 1 when measured by the Nichols assays, but > 1 when the Scantibodies assays were used. CONCLUSION: In conclusion, our results suggest that the PTH(1-84)/C-PTH ratio cannot be equally used as a predictor of bone turnover when different PTH assays are used. Depending on those assays, differences in total PTH values mathematically lead to varying amounts of C-PTH fragments resulting in variable, even contradictory PTH(1-84)/C-PTH ratios.     

Cancellous and cortical bone architecture and turnover at the iliac crest of postmenopausal osteoporotic women treated with parathyroid hormone 1-84

Treatment with parathyroid hormone [PTH(1-84)] increases lumbar spine bone mineral density and decreases vertebral fractures, but its effects on bone microarchitecture are unknown. We obtained iliac crest biopsies from postmenopausal osteoporotic women given placebo (n=8) or 100 microg PTH(1-84) for 18 (n=8) or 24 (n=7) months to assess cancellous and cortical bone formation and structure. At 18 months, cancellous bone volume (BV/TV) measured by microcomputed tomography and histomorphometry was 45-48% higher in subjects treated with PTH(1-84) versus placebo, a result of higher trabecular number (Tb.N) and thickness. The higher Tb.N appeared to result from intratrabecular tunneling. Connectivity density was higher and structure model index was lower, indicating a better connected and more plate-like trabecular architecture. Cancellous bone formation rate (BFR) was 2-fold higher in PTH(1-84)-treated subjects, primarily because of greater mineralizing surface. Osteoblast and osteoid surfaces were a nonsignificant 58% and 35%, respectively, higher with PTH(1-84) treatment. Osteoclast and eroded surface were unaffected by PTH(1-84). There were no effects of PTH(1-84) treatment on cortical thickness, or endocortical or periosteal BFR, but cortical porosity tended to be higher. Although cancellous BFR was lower at 24 than at 18 months, measures of cancellous and cortical bone structure were similar at both timepoints. The bone produced by PTH(1-84) had normal lamellar structure and mineralization with no abnormal histology. In conclusion, when compared with placebo, treatment of osteoporotic women with PTH(1-84) was associated with higher BV/TV and trabecular connectivity, with a more plate-like architecture, all consistent with the lower vertebral fracture incidence.     

Maintenance of cortical bone in human parathyroid hormone(1-84)-treated ovariectomized rats

The purpose of this cross-sectional study was to evaluate the effects of human parathyroid hormone(1-84) (hPTH) followed by maintenance treatment with 17beta-estradiol (E(2)), risedronate (Ris), or a reduced dose of hPTH (LowPTH) on cortical bone in the ovariectomized (ovx) rat. Eight groups of ovx and one group of intact female rats (3.5 months) were left untreated for 11 weeks. For the following 12 weeks, four groups received subcutaneous injections of hPTH (75 microg/kg per day on 3 days/week) and four groups received vehicle. Treatments were then changed to E(2) (10 microg/kg per day on 2 days/week), Ris (3 microg/kg per day on 3 days/week), LowPTH (25 microg/kg per day on 3 days/week), or vehicle. Bone tissue was collected at weeks -11 (baseline), 0 (ovx effect), 12 (hPTH effect), 24, 36, and 48 (maintenance effect). Bone mineral density (BMD) and bone mineral content (BMC) of the diaphyseal femur and total cross-sectional area (Tt.Ar), marrow area (Ma.Ar), cortical area (Ct.Ar), and periosteal and endocortical bone formation of the tibia were measured. Ovariectomy resulted in lower BMD (weeks 0-48), unaffected BMC, and greater Tt.Ar (weeks 12 and 36), Ma.Ar (week 48), and Ct.Ar (weeks 0 and 12) compared with intact rats. Endocortical and periosteal bone formation were greater in the ovx than in the intact rats up to 23 weeks postovariectomy. Treatment of ovx rats with hPTH for 12 weeks resulted in greater cortical BMD, BMC, and endocortical bone formation than in intact or ovx controls. In ovx rats pretreated with hPTH and then treated with Ris for 36 weeks, BMD and BMC were greater and Ma.Ar was smaller than in ovx controls. In ovx rats pretreated with hPTH and then treated with LowPTH, BMD, BMC, Ct.Ar, and endocortical bone formation were greater and Ma.Ar was smaller than in ovx controls. Treatment of hPTH-pretreated rats with E(2) for 36 weeks did not affect cortical BMD, BMC, and Ct.Ar, although periosteal bone formation was lower in the E(2) group compared with the ovx group. Thus, in ovariectomized rats, cortical bone gained by 12 weeks of hPTH treatment was maintained for up to 36 weeks by treatment with risedronate or low-dose hPTH, but not with 17beta-estradiol.     

Measurement of PTH fragments for assessment of renal bone disease in hemodialysis patients

BACKGROUND: Renal bone pathology involves a spectrum from 'high-turnover' to 'low-turnover bone disease' (adynamic bone disease, classical osteomalacia). The diagnosis of the latter usually requires bone biopsy. Inhibitory parathyroid hormone (PTH) fragments may be useful for its noninvasive diagnosis. METHODS: A cross-sectional study was performed in 54 patients on chronic hemodialysis which involved measurements of intact PTH (iPTH; Nichols assay), total PTH (tPTH; Scantibodies assay), and the cyclase-activating PTH fragment (CAP). The level of cyclase-inactive PTH fragment (CIP) was calculated. At the same time, serum calcium, phosphorus, and alkaline phosphatase levels as well as the current therapy for secondary hyperparathyroidism were recorded. In selected patients, bone radiographs were evaluated for osteitis fibrosa. RESULTS: A high correlation (r = 0.94) was found between iPTH and tPTH, with the tPTH levels being lower by 30-40%. A similar association was also found for CAP (r = 0.988) and for CIP (r = 0.93). 3 out of the 54 patients had a CAP/CIP ratio of < or =1 which has been associated with adynamic bone disease. A higher CIP ratio was significantly associated with the use of aluminum-hydroxide- and calcium-containing phosphate binders. CONCLUSIONS: iPTH and tPTH assays are highly correlated. In a general hemodialysis patient population, low-turnover bone disease appears to be rare, when the CAP/CIP ratio is used as a marker. A high CIP value was associated with therapy using aluminum hydroxide, a drug known to carry a risk of adynamic bone disease.     

Circulating 1-84 PTH and large C-terminal PTH fragment levels in uremia

Background. The so-called intact parathyroid hormone (iPTH) assay detects large C-terminal PTH fragments that are lacking several N-terminal amino acid residues in addition to 1-84 PTH molecules.Methods. Blood samples were obtained from 65 predialysis patients (male, 35; female, 30) and 109 dialysis patients (male, 73; female, 36). The plasma 1-84 PTH levels were determined by a specific immunoradiometric assay (IRMA).Results. The ratio of 1-84 PTH/iPTH did not show a significant correlation with glomerular filtration rate (GFR) among patients with a GFR of more than 80ml/min, while it showed a positive correlation with GFR among patients with a GFR of less than 80ml/min. The ratio of 1-84 PTH/iPTH demonstrated a significant tendency to decrease in the order of patients with normal renal function (0.928 ± 0.182), those with renal dysfunction (0.836 ± 0.186; P < 0.05 vs patients with GFR > 80ml/min [i.e., normal renal function]), and those with maintenance hemodialysis (0.618 ± 0.123; P < 0.01 vs patients with GFR > 80ml/min). The plasma levels of 1-84 PTH and conventional iPTH showed a close correlation in dialysis patients. Neither 1-84 PTH levels nor secondary parameters calculated from them showed a better correlation with bone metabolic markers than iPTH levels.Conclusions. Circulating large C-terminal PTH fragment levels are increased in uremic patients. However, this noninvasive study failed to demonstrate the superiority of the specific 1-84 assay compared with the conventional iPTH assay to evaluate bone metabolism.     

Specific measurement of PTH (1-84) in various forms of renal osteodystrophy (ROD) as assessed by bone histomorphometry

BACKGROUND: Parathyroid hormone (PTH) measurements serve as a noninvasive, diagnostic tool for the assessment of renal osteodystrophy (ROD). Their value has been questioned following reports indicating that all commercially available intact PTH (I-PTH) assays cross-react with amino terminally truncated PTH fragments. Because these fragments can account for 50% of total PTH, their detection will overestimate the true PTH concentration and may lead to diagnostic inaccuracies. The aim of this study was to evaluate the specific Bio-Intact PTH (1-84) Assay (BI-PTH) in patients with various types of ROD confirmed by bone biopsy. METHODS: Bone biopsies were taken from 132 patients with chronic kidney disease (CKD) stages 3 to 5, and quantitative bone histomorphometry was done. Plasma PTH levels were measured using both the BI-PTH and I-PTH assays on an automated analyzer. RESULTS: Patients with CKD stages 3/4 and low turnover skeletal lesions had BI-PTH values (pg/mL, mean +/- SD) of 35 (+/-34) and I-PTH values of 59 (+/- 63). Corresponding values for BI-PTH and I-PTH in those with high turnover lesions were 141 (+/-60) and 221 (+/-106). Patients with CKD stage 5 and low turnover skeletal lesions had BI-PTH and I-PTH levels of 51 (+/-38) and 90 (+/-60), respectively, whereas the corresponding results for BI-PTH and I-PTH in those with high turnover lesions were 237 (+/-214) and 461 (+/-437). The areas under the receiver operating characteristic (ROC) curves for distinguishing low turnover from high turnover lesions were 0.94 for BI-PTH and 0.91 for I-PTH in CKD stages 3/4 and 0.86 for BI-PTH and 0.85 for I-PTH in CKD stage 5. Among all patients, BI-PTH levels are approximately 50% lower than I-PTH levels, but the results of the two assays are correlated highly (R2 = 0.92). CONCLUSION: Plasma PTH measurements using either the BI-PTH or I-PTH assay effectively identify patients with reduced bone turnover and serve to distinguish this subgroup from those with high turnover lesions of renal bone disease. Both assays provide better diagnostic discrimination for this purpose than calculated values for the ratio of PTH (1-84)/amino terminally truncated PTH fragments.     

Study of intact (1-84) parathyroid hormone secretion in patients undergoing parathyroidectomy

Patterns of intact (1-84) parathyroid hormone (intact PTH) elimination and subsequent recovery of parathyroid function were studied in 12 patients undergoing parathyroidectomy. Nine patients had primary hyperparathyroidism (HPT), with single gland disease in 6 and multiple gland disease in 3. Two patients had subtotal parathyroidectomy for HPT secondary to chronic renal failure and 1 underwent excision of a hyperfunctioning parathyroid autograft. Using a sensitive 2-site immunochemiluminometric assay, serum intact PTH levels were measured preoperatively, intraoperatively, and postoperatively. A dual phase pattern of hormone clearance was found in 10 of the 12 patients, including the patient undergoing autograft excision. A monoexponential clearance pattern was seen in the remaining 2 patients, both of whom had subtotal parathyroidectomies for multiple gland disease. In the patients with primary HPT due to single gland disease, the early phase of intact PTH clearance had a half-life (T1/2) of 3.3 (+/- standard deviation 0.9) minutes and a late T1/2 of 96.4 (+/- standard deviation 92.7) minutes. Calculation of decay curves and half-lives for the patients undergoing subtotal parathyroidectomy was more difficult because of the inherent uncertainty in determining time zero. Nevertheless, in all but 2 patients, the clearance pattern was biexponential and the T1/2 measurements were very similar to those encountered in patients with single-gland disease. In the 2 patients with monoexponential clearance, the T1/2 figures were 86.7 minutes and 26.7 minutes, respectively. In the patients undergoing parathyroidectomy for primary HPT, levels of intact PTH were lowest at 1-3 hours after surgery, recovering to normal in the majority of patients by 18-40 hours.     

Changes in 3-dimensional bone structure indices in hypoparathyroid patients treated with PTH(1-84): a randomized controlled study

Hypoparathyroidism (hypoPT) is characterized by a state of low bone turnover and high bone mineral density (BMD) despite conventional treatment with calcium supplements and active vitamin D analogues. To assess effects of PTH substitution therapy on 3‐dimensional bone structure, we randomized 62 patients with hypoPT into 24 weeks of treatment with either PTH(1‐84) 100 µg/day subcutaneously or similar placebo as an add‐on therapy. Micro‐computed tomography was performed on 44 iliac crest bone biopsies (23 on PTH treatment) obtained after 24 weeks of treatment. Compared with placebo, PTH caused a 27% lower trabecular thickness (p < 0.01) and 4% lower trabecular bone tissue density (p < 0.01), whereas connectivity density was 34% higher (p < 0.05). Trabecular tunneling was evident in 11 (48%) of the biopsies from the PTH group. Patients with tunneling had significantly higher levels of biochemical markers of bone resorption and formation. At cortical bone, number of Haversian canals per area was 139% higher (p = 0.01) in the PTH group, causing a tendency toward an increased cortical porosity (p = 0.09). At different subregions of the hip, areal BMD (aBMD) and volumetric BMD (vBMD), as assessed by dual‐energy X‐ray absorptiometry (DXA) and quantitative computed tomography (QCT), decreased significantly by 1% to 4% in the PTH group. However, at the lumbar spine, aBMD decreased by 1.8% (p < 0.05), whereas vBMD increased by 12.8% (p = 0.02) in the PTH compared with the placebo group. © 2012 American Society for Bone and Mineral Research.     

Changes in total parathyroid hormone (PTH), PTH-(1-84) and large C-PTH fragments in different stages of chronic kidney disease

INTRODUCTION: Loss of renal function is accompanied by progressive increase in serum levels of intact parathyroid hormone (iPTH) in patients with end-stage renal disease (ESRD). There is a paucity of data regarding levels of PTH-(1-84) and its large carboxyl-terminal fragments (large C-PTH fragments) and progressive loss of kidney function in patients with chronic kidney disease (CKD). The current study was undertaken to describe the glomerular filtration rate (GFR)-dependent plasma concentrations of PTH-(1-84) and related large C-PTH fragments in adult patients with CKD by using different commercially available PTH assays. METHODS: We studied 80 Caucasian patients with CKD stages 1-5 without renal replacement therapy. Creatinine clearance was calculated by the Modification of Diet in Renal Disease (MDRD) formula. Levels of iPTH were determined by second-generation assays (iPTH Elecsys system, Roche Diagnostics; DUO total iPTH, Scantibodies Laboratory, Inc.; iPTH, Nichols Institute Diagnostics). Third-generation assays were used to measure PTH-(1-84) (CAP (cyclase activating PTH), Scantibodies; Bio-Intact PTH, Nichols). Levels of large C-PTH fragments and ratios of PTH-(1-84)/large C-PTH fragments were calculated and statistical analyses performed. RESULTS: Levels of iPTH and PTH-(1-84) showed CKD stage-dependent increases. Variations among the assays increased with progressive loss of kidney function. The assay from Scantibodies showed a GFR-dependent decrease of the ratio 1-84 PTH / large C-PTH fragment that was not observed with the Nichols assay. CONCLUSION: Increasing variations among the assays with progression of CKD emphasize the fact that the interpretation of measurements must take into consideration the specific assay. We found evidence for a possible preferential increase of the level of large C-PTH fragments over 1-84 PTH in a CKD stage-dependent manner (Scantibodies). The clinical implications of this finding have to be further evaluated by bone biopsy studies.