BACKGROUND

Persistent (tertiary) hyperparathyroidism (TH) after renal transplantation may cause considerable morbidity and necessitate parathyroidectomy. This study investigated the characteristics of this patient subgroup.

METHODS

The medical data and pathology specimens of 20 kidney transplant recipients who underwent parathyroidectomy for TH in 2001 to 2004 were reviewed.

RESULTS

Treatment consisted of subtotal resection of 3.5 glands in 13 patients, resection of 3 to 3.5 glands under intraoperative parathyroid hormone monitoring (iPTH) in 5 patients, and selective resection in 2 patients with markedly asymmetric gland enlargement. Eighteen patients had hyperplasia-diffuse in 10, nodular in 4, or both in 2; 2 patients had 1 large nodule in every gland. Six patients had postoperative complications. Follow-up of 2 years revealed recurrent hypercalcemia in 1 patient and a high level of PTH (>60 pg/mL) in 12.

CONCLUSIONS

Subtotal resection for TH may be insufficient. The use of iPTH monitoring is recommended. Renal transplant recipients have distinctive characteristics and require special perioperative attention.

BACKGROUND

Disorders in mineral metabolism are associated with risk for cardiovascular disease (CVD) events in patients with kidney disease as well as in the general population. This risk is thought to be mediated, in part, through the mechanism of stiffening of the arteries.

METHODS

The objective of this study was to evaluate the relationships between serum calcium, phosphorus, intact parathyroid hormone (iPTH), and 25-hydroxyvitamin D levels and arterial pulse wave velocity (aPWV) among 2,229 community-dwelling elderly persons participating in the Health Aging and Body Composition (Health ABC) study.

RESULTS

The mean age of the participants was 72 years; 52% were woman, 39% were black, and 17% had chronic kidney disease (CKD) (estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2)). In parallel unadjusted analyses, the following associations were observed: 2.86% greater aPWV per 12 ng/ml (s.d.) lower 25-hydroxyvitamin D (95% confidence interval -4.38%, -1.31%), 3.04% greater aPWV per 28 pg/ml (s.d.) higher iPTH (95% confidence interval 1.42-4.68%), and 2.37% lower aPWV per 0.5 mg/dl (s.d.) higher phosphorus (95% confidence interval -3.90% to - 0.81%). Except for phosphorus, these associations were attenuated and rendered no longer statistically significant after adjustment for demographic risk factors, clinical site, season, medications and other CVD risk factors. The results were similar in men and women and were not dependent on the presence of CKD.

CONCLUSIONS

Among well-functioning community-dwelling elderly persons, only serum phosphorus was associated with aPWV; and this association was in the opposite direction of the one hypothesized. Factors other than vascular stiffening may mediate the relationship between disordered mineral metabolism and CVD events in community-living elders.

OBJECTIVE

The goal of this study was to determine whether intraoperative intact parathyroid hormone (IOiPTH) levels can predict the functional status of remaining parathyroids at the end of total thyroidectomy and thereby be a guide for parathyroid autotransplantation when glands are deemed not functional.

METHODS

Prospective study involving 23 patients undergoing either total thyroidectomy or completion thyroidectomy

METHODS

During surgery, an attempt was made to identify all four parathyroid glands. Normal size vascular glands were preserved, whereas avascular glands were microdissected and reimplanted. Serial IOiPTH was measured preoperatively after each parathyroid was identified, manipulated, or removed and serum iPTH measurements were done postoperatively up to 56 days.

RESULTS

The sensitivity of low IOiPTH in identifying a devascularized gland was 88.9%, and specificity was 92.9%. A normal IOiPTH level indicates at least two functioning glands. IOiPTH levels between 1.5 and 10 pg/mL indicate only one functional gland. Undetectable IOiPTH levels indicate no residual functioning gland.

CONCLUSIONS

For patients undergoing total or completion thyroidectomy, IOiPTH should be routinely measured at the end of the procedure, and a level less than 10 pg/mL requires reassessment of remaining parathyroid glands. Vascularized glands should be preserved regardless of IOiPTH levels. Devascularized glands or glands of questionable vascularity should be considered for autotransplantation.

OBJECTIVE

Intraoperative parathyroid hormone measurement (iPTH) has strengthened the successful use of minimal-invasive approaches in surgery of primary hyperparathyroidism (pHPT). The aim of the study was to evaluate the efficacy of iPTH monitoring in treating pHPT resulting from multiple gland disease.

METHODS

In this retrospective study, 58 patients with pHPT underwent surgery (minimally invasive or open exploration) between January 2003 and July 2005. iPTH levels were routinely measured at the start of anesthesia, in any case before skin incision, and 10 as well as 15 min after removal of abnormal gland(s). A drop in iPTH >50% after 10 min and >60% after 15 min was considered adequate to prove the success of the removal of the abnormal gland(s). The removed tissue was examined histologically by immediate frozen section.

RESULTS

A single gland disease was found in 51 (88%) cases, a multiple gland disease (double adenoma or hyperplasia) in 7 (12%) cases. In all cases of single adenoma, an adequate drop of iPTH was seen after removal of the pathologic gland. In contrast, in all cases with a second adenoma, an adequate drop in iPTH was detected only after removal of both adenoma/hyperplasia. Immediate sectioning was only helpful for identification of removed tissue, but was no help in deciding whether to search for an additional gland. The follow-up showed no late disease recurrence.

CONCLUSIONS

The measurement of iPTH is an effective and safe means in treating single gland disease as well as multiple gland disease (adenoma/hyperplasia) causing pHPT and also allows a successful limited dissection via minimally invasive parathyroidectomy.

BACKGROUND

Drug treatment for secondary hyperparathyroidism caused by chronic renal failure may be available at the early stage of the disease, but it is not as effective for serious patients. The aim of the study was to evaluate the effect of total parathyroidectomy combined with forearm autotransplantation in the uremic patients with secondary hyperparathyroidism.

METHODS

From September 1999 through September 2006, parathroidectomy and autotransplantation was performed in 20 patients. The coherence between the results of preoperative parathyroid ultrasonography and surgical exploration were compared. The serum calcium concentration and intact parathyroid hormone (iPTH) were monitored preoperatively, intraoperatively, and postoperatively.

RESULTS

A total of 71 hyperplastic parathyroid glands were resected in the 20 patients. The accordance rate of parathyroid localization between B-ultrasonography and intraoperative exploration was 94.4%. The average iPTH value was (110.90 +/- 67.42) ng/L, (433.80 +/- 243.72) ng/L, (48.80 +/- 42.69) ng/L, (229.04 +/- 172.68) ng/L and (232.39 +/- 224.05) ng/L at day 1, 2, 3, 7, 30 after operation respectively. The clinical symptoms were ameliorated and the levels of serum calcium concentration were controlled within the normal range after operation. Recurrent secondary hyperparathyroidism had happened in 1 case, 4 years postoperatively because of the development of autograft hyperplasia, and in another case 2 years postoperatively due to remnant of neck parathyroid glands. The clinical symptoms were all alleviated after re-operation. No surgical complication had occurred in any of the patients.

CONCLUSIONS

The total parathyroidectomy with forearm autotransplantation is feasible, safe, and effective for patients with secondary hyperparathyroidism in the short term. The long-term effects should be further investigated.

Immunostaining with antiserum to bovine parathyroid hormone (PTH) was used to delineate the immunoreactive PTH (iPTH)-containing cells of parathyroid glands from 1 anencephalic and 29 normal human fetuses. The antiserum (GPO 3) cross-reacted with human PTH and recognized the carboxyl-terminal fragments of the PTH molecule. No iPTH-containing cells were observed in the parathyroid glands of the 6 fetuses younger than 10 weeks, in spite of the fact that organized parathyroid glands were identified by histological methods. By contrast, iPTH-containing cells were observed in all fetuses older than 10 weeks of gestation, including the anencephalic fetus. All cells were immunoreactive either at the cellular periphery or as a more diffuse cytoplasmic staining around the nucleus. No immunoreactive cells were observed in the thyroid or thymic parenchyma. The specificity of the immunocytological reaction was tested by the usual procedures. Previous in vitro studies suggested that parathyroid function might be active at 12 weeks of gestation. Our data suggest that iPTH is synthetized by parathyroid glands as as early as 10 weeks of gestation and is also present in the anencephalic fetus. The physiological significance of the early presence of PTH within the fetal parathyroid glands remains to be established.

BACKGROUND

Others have reported a clear distinction between patients with primary hyperparathyroidism (PHPT) and normal subjects using the intact PTH (iPTH) assay.

OBJECTIVE

We reviewed our last 60 surgically proven cases of PHPT, who had adequate preoperative biochemical assessment, to determine the usefulness of the iPTH assay, ionised calcium and other biochemical criteria in differentiating between normal subjects and patients with PHPT.

METHODS

We conducted a retrospective cross-sectional study of all patients with surgically proven PHPT who had been referred to Sir Charles Gairdner Hospital, Perth, Western Australia for preoperative biochemical assessment. All cases had fasting preoperative blood and urine samples collected for ionised calcium, plasma total calcium, albumin, urine calcium excretion, renal phosphate threshold and iPTH.

RESULTS

Fifty cases had a single or double adenoma and ten had hyperplasia. All except one had ionised hypercalcaemia but only 47 (78%) had an elevated corrected total calcium (cCa). Therefore 13 cases (22%) had a normal cCa and five of those patients (8%) had both an iPTH and cCa within the reference range. Forty-nine (82%) had an elevated ionised calcium (iCa) and iPTH; the remaining 11 (18%) had an iPTH within the reference range. Of this latter 18%, ten (91%) had a low renal phosphate threshold and five (45%) had significant renal calcium conservation: all 11 cases had at least one abnormality in the renal handling of calcium or phosphate and all normalised their plasma calcium postoperatively (ionised and corrected total calcium).

CONCLUSIONS

One in five patients with proven PHPT have a non-elevated cCa and/or intact PTH. Ionised calcium should be measured in all suspected cases. Additional studies of renal calcium and phosphate handling are helpful to establish a diagnosis where any uncertainty exists.

OBJECTIVE

To find out if the whole parathyroid hormone (wPTH) assay has practical advantages over the intact (iPTH) assay in patients with Graves' disease.

METHODS

We measured iPTH and wPTH levels before and after subtotal thyroidectomy in 111 consecutive patients (94 women and 17 men) with Graves' disease. Blood samples for assays were obtained after the induction of anesthesia (basal) and following skin closure (postoperative).

RESULTS

There was a significant correlation between wPTH and iPTH in both the basal and postoperative levels. Logistic regression analyses examining the relationship between the reduction in parathyroid hormone (PTH) levels and the incidence of tetany revealed that both the wPTH and iPTH assays were significantly equally predictive of postoperative tetany.

CONCLUSIONS

We found that both the wPTH and iPTH assays were useful for predicting postoperative tetany in patients with Graves' disease, yielding similar results.

The purpose of this study was to investigate the frequency and risk factors for low bone mineral density (BMD) among patients awaiting liver transplantation. BMD of the lumbar spine (LS) and femoral neck (FN), measured by dual-energy X-ray absorptiometery (DEXA), were obtained in 64 pretransplant patients. We measured markers of bone metabolism including serum calcium, phosphorus, serum 25-hydroxyvitamin D (25-OH D), intact parathyroid hormone (iPTH), bone alkaline phosphatase (BAP), osteocalcin (OC), and urinary deoxypyridinoline/creatinine (DPD/Cr) ratio. Osteoporosis and osteopenia (low BMD) were observed in 36 patients (36/64, 56.2%), including 6 cases of osteoporosis (6/64, 9.3%) and 30 cases of osteopenia (30/64, 46.9%). Of all variables, cholestatic liver disease and elevated levels of iPTH were significantly associated with low BMD. Moreover, elevated iPTH level was identified as an independent risk factor for low BMD (P<.05, OR=1.017, 95% CI=1.001-1.032) by multivariate analysis. The median level of iPTH was increased to 55.6 pg/mL (range, 7.8-337 pg/mL) in the low BMD group, while the median level was 33 pg/mL (range, 3-162 pg/mL) in the normal BMD group (P<.05). This study revealed a high incidence of low BMD in the pretransplant patients with liver diseases. The elevated iPTH level was the predominant risk factor for low BMD. We suggest that both BMD and iPTH examinations be considered routine tests to identify the status of bone mass and bone metabolism among recipients prior to liver transplantation.

Sexual hormone concentrations are commonly affected in chronic renal failure. The contribution of sex steroids to bone turnover regulation implies that sex steroid's dysfunction may be implicated in the emergence of renal osteodystrophy. This study was conducted to evaluate sex steroids and gonadotrophins in hemodialysis (HD) patients and to investigate their role in bone homeostasis in concert with other hormones and cytokines. Bone mineral density (BMD) at the proximal femur and intact parathyroid hormone (iPTH), osteoprotegerin, soluble receptor activator of NF-kappaB ligand (sRANKL), prolactin, total testosterone, estradiol, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were measured in serum samples in 42 patients, 21 men and 21 women, on maintenance HD therapy. Possible associations between clinical characteristics, biochemical parameters, and BMD values were investigated. In male HD patients, the testosterone concentration declined significantly with aging, whereas the estradiol level increased with longer duration of HD. Concurrently, testosterone correlated negatively with sRANKL concentrations (r=-0.520, p=0.016). Luteinizing hormone levels in male patients demonstrated statistically significant negative correlations with BMD values of the proximal femur. In the entire cohort of patients, FSH and LH were negatively associated with absolute values of proximal femur BMD. Gonadotrophin and sexual hormone concentrations in HD patients are associated with bone mineral status and consequently their derangements appear to contribute to the development of bone composition abnormalities in different types of renal osteodystrophy. Furthermore, testosterone's association with sRANKL levels in male HD patients suggests that RANKL may mediate the effect of testosterone on bone metabolism in these patients.

We performed retrospective, multi-center study of the impacts of parathyroidectomy (PTX) after or before kidney transplantation on allograft outcomes. A total of 63 patients who underwent PTX after kidney transplantation were identified. Deterioration in eGFR by more than 25% at 1 month after PTX occurred in 20% of the patients. The baseline eGFR was significantly lower in impairment group than nonimpairment group [adjusted odds ratio (OR) 0.87, 95% confidence interval (CI) 0.77-0.99, P = 0.033]. Low iPTH concentration after PTX was also a significant risk factor for the renal impairment (OR 0.96, CI 0.94-0.99, P = 0.009). A total of 37 patients who underwent PTX before transplantation were identified. Thirty-six percent of the patients had persistent hyperparathyroidism by 1 year after transplantation. A high iPTH level before PTX was a significant risk factor for persistent post-transplant hyperparathyroidism (adjusted OR 1.002, CI 1.000-1.005, P = 0.039). Finally, eGFR values during the first 5 years after transplantation were significantly lower in the patients who underwent PTX at less than 1 year after transplantation, than the pretransplant PTX patients (P = 0.032). As PTX after kidney transplantation has a risk of deterioration of allograft function, pretransplant PTX should be considered for patients with severe hyperparathyroidism, who could undergo post-transplant PTX.

OBJECTIVE

Secondary hyperparathyroidism (sHPT) is associated with elevated levels of FGF-23, which in turn are connected to adverse outcomes in ESRD patients. The relationship between FGF-23 and bone metabolism in patients with sHPT treated with cinacalcet has not been studied.

METHODS

Thirty-four stable chronically hemodialyzed patients with sHPT were prospectively followed during the treatment with cinacalcet without any changes in concurrent vitamin D or phosphate binder dose. Blood samples were collected at the start and after 6 months of study. Levels of osteocalcin (OC), cross-linked C-telopeptide of type I collagen (CTX), and FGF-23 were measured.

RESULTS

Eighteen patients finished the study. Levels of calcium, phosphate, and iPTH decreased during 6 months of treatment with cinacalcet. Serum level of FGF-23 decreased significantly (log FGF-23 from 7.58 ± 1.7 to 6.61 ± 1.7 pg/ml) (P < 0.001). Cinacalcet lowered the concentration of CTX from 3.1 ± 0.6 ng/ml to 2.6 ± 0.9 ng/ml (P < 0.05) and OC from 91.8 (41.5-558.6) to 70.3 (11.3-419.7) ng/ml (P < 0.05). The magnitude of change in FGF-23 concentration before and after treatment correlated significantly with suppression of osteoblasts' function assessed by ΔOC (r = 0.5, P < 0.05) but not with changes in bone resorption marker ΔCTX.

CONCLUSIONS

Cinacalcet treatment of sHPT results in reduction of FGF-23 levels, probably due to the suppression of osteoblasts function.

BACKGROUND

Cardiovascular disease is the leading cause of death in patients with chronic kidney disease (CKD). Recent data implicate disordered bone and mineral metabolism, including changes in serum levels of calcium, phosphate, parathyroid hormone (PTH), vitamin D, fibroblast growth factor-23 (FGF-23), and fetuin A, as novel risk factors for arterial calcification. The potential role of calcitonin, another hormonal regulator of mineral and bone metabolism, has not been studied in detail.

METHODS

We investigated the link between serum calcitonin and the total burden of coronary artery disease (CAD) using the validated Gensini score, in a cross-sectional study of 88 patients with estimated GFR (eGFR) between 46 and 87 ml/min/1.73 m² who underwent coronary angiography. We evaluated the associations between serum calcitonin, minerals (calcium, phosphate), calcium × phosphate product, and other factors that regulate mineral metabolism (intact PTH, 25-OH-vitamin D, FGF-23, and fetuin A) and the severity of CAD.

RESULTS

The mean serum calcitonin was 11.5 ± 7.8 pg/ml. In univariate analysis, the Gensini CAD severity score correlated significantly with male gender, eGFR, and serum levels of 25-OH-vitamin D, iPTH, FGF-23, fetuin A, and calcitonin (R = 0.474, P = 0.001 for the latter). In multivariate analysis adjusted for calcium, phosphate, 25-OH-vitamin D, iPTH, FGF 23, fetuin A, and calcitonin, only calcitonin (β = 0.20; P = 0.03), FGF-23, fetuin A, and 25-OH-vitamin D emerged as independent predictors of Gensini score. In the second step, we adjusted for the presence of traditional risk factors, proteinuria, and GFR. After these adjustments, the FGF-23 and fetuin A remained statistically significant predictors of the Gensini score, while calcitonin did not.

CONCLUSIONS

Our study suggests that, in addition to other well-known components of mineral metabolism, increased calcitonin levels are associated with greater severity of CAD. However, this relation was not independent of traditional and nontraditional cardiovascular risk factors. Longitudinal studies in larger populations including patients with more advanced CKD are needed.

A 7-month-old male infant was referred for investigation after a documented febrile urinary tract infection. His past medical history was characterized by episodes of unexplained fever and mild dehydration. The ultrasound examination of his kidneys demonstrated bilateral diffuse medullary nephrocalcinosis. His serum and urine biochemistry revealed hypomagnesemia (0.4 mmol/l), hyperuricaemia (506 micromol/l), mildly increased iPTH (71 pg/ml) and hypercalciuria (16.0 mg/kg/day). The diagnosis of familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) was confirmed by mutational analysis of the CLDN16 gene, encoding paracellin-1. Sequencing displayed a homozygous Leu151Phe exchange affecting the first extracellular loop of paracellin-1. There were eight family relatives who underwent biochemical analysis, renal ultrasound and genetic investigation for CLDN16 mutations. Five of them were found to be heterozygous for the Leu151Phe mutation. Two heterozygotes (the mother and the maternal grandfather) presented with hypercalciuria. The grandfather had a history of recurrent passage of calculi. These findings point to the role of heterozygous CLDN16 gene mutations in renal pathophysiology. In conclusion, patients suspected of having FHHNC should be screened for CLDN16 mutations, especially with respect to genetic counseling. In addition, heterozygotes at risk should be clinically assessed in order to prevent renal complications of hypercalciuria.

Forty 5-week-old rats were randomly divided into 1 control group given a normal diet and water low in fluoride (0.026 mM/1) and experimental group receiving the same basic diet and a fluoride supplement of 2.6 mMol/l in the drinking water. After 30 weeks, half of the fluoride-supplemented and half of the nonsupplemented animals were given a calcium-deficient diet for another 16 weeks. Parathyroid activity was estimated by determinations of serum levels of parathyroid hormone and by light microscopic, morphometric evaluation of randomized sections of the parathyroid glands. Serum iPTH and parathyroid nuclear size were significantly increased in the calcium-deficient animals without any fluoride supplement. Fluoride administration to animals on a normal diet did not cause any increase in the serum iPTH levels or in the morphometric parameters for nuclear size. Calcium-deficient animals given a fluoride supplement also showed normal serum iPTH levels and normal parathyroid nuclear size. It is therefore concluded that fluoride does not induce hyperparathyroidism and, further, that fluoride seems to inhibit increased parathyroid activity caused by calcium deficiency.

OBJECTIVE

The aim of this study is to analyse the percentage of hypovitaminosis D, as well as its relationship with the various parameters of calcium-phosphate metabolism.

METHODS

A case control study was conducted on 366 patients, divided into two groups: Group 1: 127 non-stone-forming patients, and Group 2: 239 calcium stone forming. A study was performed on calcium-phosphate metabolism and urinary lithogenic factors. The percentage of vitamin D deficiency (25-OH-vitamin D levels <20 ng/ml) between the groups was analysed and compared. The SPSS 20.0 statistics program was used for the analysis, with a p ≤ .05 being considered significant.

RESULTS

The mean age of Group 1 was 52.1 years compared to 49.6 years in Group 2, with no significant differences (p = .07). Vitamin D levels were lower in Group 2 compared to Group 1 (25.7 vs. 28.4 ng/ml, p = .02). A vitamin D deficiency was observed in 28 % of the Group 2 stone-forming patients versus 15.7 % in Group 1 (p = .009), with an odds ratio (OR) of 2.09 (95 % CI; 1.19-3.63). In the stone-forming patients with a vitamin D deficiency, the only difference observed was the higher levels of iPTH compared to those stone-formers with a normal vitamin D (56.9 vs. 45.5 pg/ml, respectively; p = .0001).

CONCLUSIONS

Calcium stone-forming patients have lower mean levels of vitamin D and a higher percentage of hypovitaminosis D than in non-stone-forming patients. This was only related to increased iPTH levels, with urine calcium and other lithogenic parameters having no obvious effect.

BACKGROUND

For diagnosing of specific types of bone lesions in hemodialysis (HD) patients, it is necessary to conduct a bone biopsy as the gold standard method. However, it is an invasive procedure. While different markers have been suggested as alternative methods, none of them has been selected. The frequency of hip fractures is 80 fold in HD patients who have two-fold mortality as compared with general population.

OBJECTIVE

Recently, serum leptin has been suggested as a bone density marker. This study tries to confirm this proposal.

METHODS

In this study about 104 HD patients (53.8% male and 46.2% female) were enrolled. The average age was 38.28±7.89 years. Serum leptin, bone alkaline phosphatase, intact parathyroid hormone (iPTH), 25(OH)D, calcium, phosphorus and bone mineral density (BMD) (at the femoral neck and lumbar spine, as measured by dual-energy x-ray absorptiometry [DXA]) were assessed.

RESULTS

Analysis by polynomial regression revealed no correlation between BMD Z-score at two points and serum leptin level. According to the thresholds of 25 ng/mL and 18-24 ng/mL in some studies, we detected 25 ng/mL as the threshold in our patients. Under this threshold, the leptin effect on bone mass was negative, and above the threshold of 25 ng/mL, we found leptin had positive effect on bone mass.

CONCLUSIONS

In this investigation, we found, leptin has a bimodal effect on bone mass. Cortical bones assessment may be a better option for assessment.

During a review of 42 metabolic studies in healthy women and men we observed that serum 1,25-(OH)2-D concentrations were directly correlated to the observed daily changes in body weight (r = 0.68; P less than 0.001) and to caloric intake/kg/day (r = 0.39; P = 0.01). These relationships could not be accounted for by related and physiologically expected changes in serum Ca or iPTH concentrations. However, serum 1,25-(OH)2-D concentrations were observed to be inversely correlated to serum PO4 levels (r = -0.44; P = 0.004). In addition, serum PO4 levels were inversely correlated to the daily changes in body weight (r = -0.40; P = 0.009). Since dietary sodium intake averaged 142 mmol/day, it is unlikely that the observed changes in weight were the result of changes in salt and water balance. Thus it seems reasonable to speculate that serum 1,25-(OH)2-D concentrations may vary directly with energy balance, as reflected by changes in body weight. This effect may be mediated by alterations in PO4 metabolism. The accurate assessment of serum 1,25-(OH)2-D levels thus appears to require several measurements over time periods during which body weight is stable.

A newly identified cytokine, osteoprotegerin (OPG) appears to be involved in the regulation of bone remodeling. In vitro studies suggest that OPG, a soluble member of the TNF receptor family of proteins, inhibits osteoclastogenesis by interrupting the intercellular signaling between osteoblastic stromal cells and osteoclast progenitors. As patients with chronic renal failure (CRF) often have renal osteodystrophy (ROD), we investigated the role of osteoprotegerin (OPG) in ROD, and investigated whether there was any relationship between serum OPG, intact parathyroid (PTH) (iPTH), vitamin D, and trabecular bone. Serum OPG combined with iPTH might be a useful tool in the noninvasive diagnosis of ROD, at least in cases in which the range of PTH values compromises reliable diagnosis. Thirty-six patients on maintenance hemodiafiltration (HDF) and a control group of 36 age and sex matched healthy subjects with no known metabolic bone disease were studied. The following assays were made on serum: iPTH, osteocalcin (BGP), bone alkaline phosphatase, 25(OH)-cholecalciferol, calcium, phosphate, OPG, IGF-1, estradiol, and free testosterone. Serum Ca++, P, B-ALP, BGP, IGF-1, iPTH, and OPG levels were significantly higher in HDF patients than in controls, while DXA measurements and quantitative ultrasound (QUS) parameters were significantly lower. On grouping patients according to their mean OPG levels, we observed significantly lower serum IGF-1, vitamin D3 concentrations, and lumbar spine and hip bone mineral density in the high OPG groups. No correlation was found between OPG and bone turnover markers, whereas a negative correlation was found between serum OPG and IGF-1 levels (r=-0.64, p=0.032). Serum iPTH concentrations were positively correlated with bone alkaline phosphatase (B-ALP) (r=0.69, p=0.038) and BGP (r=0.92, p<0.001). The findings made suggest that an increase in OPG levels may be a compensatory response to elevated bone loss. The low bone mineral density (BMD) levels found in the high OPG group might have been due to the significant decrease in serum IGF-1 and vitamin D3 observed. In conclusion, the findings made in the present study demonstrate that increased OPG in hemodiafiltration patients is only partly due to decreased renal clearance. As it may partly reflect a compensatory response to increased bone loss, this parameter might be helpful in the identification of patients with a marked reduction in trabecular BMD.

BACKGROUND

To optimize the noninvasive evaluation of bone remodeling, we evaluated, besides routine serum markers, serum levels of several cytokines involved in bone turnover.

METHODS

A transiliac bone biopsy was performed in 47 hemodialysis patients. Serum levels of intact parathyroid hormone (iPTH; 1-84), total alkaline phosphatases (tAP), calcium, phosphate and aluminum (Al) were measured. Circulating levels of interleukin-6 (IL-6), IL-1 receptor antagonist (IL-1Ra) and soluble IL-6 receptor (sIL-6r) were determined using ELISA. Circulating IL-1beta, IL-6, IL-8, IL-10, IL-12p70 and tumor necrosis factor-alpha (TNF-alpha) were simultaneously quantified by flow cytometric immunoassay.

RESULTS

Patients with low/normal bone formation rate (L/N-BFR) had significantly lower serum iPTH (p<0.001) and tAP (p<0.008) and significantly higher Al (p<0.025) than patients with high BFR. Serum calcium and phosphorus, however, did not differ (p=NS). An iPTH >300 pg/mL in association with tAP >120 U/L showed low sensitivity (58.8%) and low negative predictive value (44.0%) for the diagnosis of high BFR disease. An iPTH <300 pg/mL in association with normal or low tAP, <120 U/L, was associated with low sensitivity (66.7%) but high specificity (97.1%) for the diagnosis of L/N-BFR. Serum IL-1, IL-6, IL-12p70 and TNF-alpha were positively correlated with BFR, serum IL1-Ra and IL-10 with bone area, and by multiple regression analysis, tAP and IL-6 were independently predictive of BFR.

CONCLUSIONS

Significant associations were found between several circulating cytokines and bone histomorphometry in dialysis patients. The usefulness of these determinations in the noninvasive evaluation of bone remodeling needs to be confirmed in larger dialysis populations.

Two antisera which were raised against bovine parathyroid hormone (bPTH), and which cross-reacted with the human hormone, have been characterized. The antisera which originated from rooster and guinea-pig, were found to contain several populations of antibodies directed against both N-terminal and C-terminal sequences of the hormone. However, at proper dilutions the rooster antiserum did not bind the N-terminal fragment nor could this fragment displace the [125I] bPTH (1--84 amino acid residue) from binding to the antiserum. Furthermore, preincubation experiments with excess N-terminal fragment showed only a negligible reduction in maximal binding of the iodinated intact hormone using the rooster antiserum. In contrast, the guinea-pig antiserum reacted equally well with the N-terminal fragment and the intact hormone, and preincubation with this fragment reduced the binding of the [125I]bPTH (1--84 amino acid residues) by 75%. Gel filtration of hyperparathyroid serum on Bio-Gel P-60 showed immunoreactive material which was measured with both antisera, eluting at a position similar to the intact hormone. However, in the C-terminal specific, but not in the N-terminal specific radioimmunoassay the major component eluted together with or somewhat earlier than the N-terminal bPTH fragment (1--34 amino acid residue), and this peak represented more than 90% of total immunoreactive PTH (iPTH) in serum. This major iPTH component must therefore represent fragment(s) with intact carboxy-terminal sequences. The N-terminal specific radioimmunoassay was unable to measure iPTH in about 80--90% of healthy individuals while the C-terminal specific assay detected iPTH in about 88% of these sera (equal to or above 0.1 micrograms/l). Similarly, the N-terminal specific antiserum measured consistently lower serum iPTH concentrations in patients with primary hyperparathyroidism. In thirty-four out of forty-one patients with surgically verified primary hyperparathyroidism, serum iPTH concentrations equal to or above 0.60 micrograms/l were demonstrated using the C-terminal, specific radioimmunoassay.

Fourteen patients with medullary carcinoma of the thyroid (MCT) and hypercalcitoninemia were studied. Serum concentrations of calcium, phosphorus and iPTH (C-terminal) were normal. Serum 1,25-dihydroxyvitamin D (1,25-(OH)2D) levels were increased (p less than 0.001) in spite of reduced serum 25-hydroxyvitamin D (25-OHD) levels (p less than 0.02) indicating an enhanced activity of the renal 1 alpha-hydroxylase. Serum 24,25-dihydroxyvitamin D levels were normal and correlated positively with serum 25-OHD. Histomorphometric analyses of iliac crest bone biopsies after in vivo tetracycline double-labelling were performed in patients and controls. The patients showed a normal trabecular bone volume. The mean size of the cortical osteocytic lacunae was increased (p less than 0.001). Significant increases were found in fractional formation surfaces (p less than 0.05), fractional labelled surfaces (p less than 0.01) and fractional resorption surfaces (p less than 0.005) in trabecular bone. The appositional rate of newly mineralized bone was reduced (p less than 0.025). The mean osteoid seam width was normal due to an unchanged mineralization lag time and a normal osteoid appositional rate. The bone formation rate at tissue level was high normal. The altered vitamin D metabolism may be caused by a direct effect of hypercalcitoninemia on the renal l alpha-hydroxylase or may represent an adaptive change in calcium-phosphorus homeostasis. The dynamic bone changes are similar to those found in primary hyperparathyroidism and may be caused by an enhanced sensitivity to circulating PTH induced by the increased 1,25-(OH)2D.

The change in circulating levels of immunoreactive parathyroid hormone (iPTH), measured with an N-terminal specific radioimmunoassay, was examined during lactation in rats. In lactating rats consuming a diet containing 0.4% Ca (basic diet), serum iPTH was a) increased by an average of 53% between days 10 and 18 compared to the level of age-matched nonlactating rats (24.7 +/- 2.1 pg/ml vs 16.1 +/- 0.8 pg/ml, mean +/- SE, p less than 0.01) and b) significantly higher in dams suckling large litters (10-15 pups) than in dams suckling small litters (3 pups) over the period 3-13 days of lactation. Lactating rats consuming a low calcium diet (0.04% Ca), had serum iPTH levels on days 16-18 of lactation approximately twice those of nonlactating rats fed the same diet and 73% higher than those of lactating rats fed the basic diet. Serum Ca concentrations were 22% and 10% lower in dams consuming the 0.04 and 0.4% Ca diets, respectively, than in the nonlactating controls fed the same diets. Regression analysis showed a significant (p less than 0.001) negative correlation between iPTH and total serum calcium. Compared with nonmated controls, net mineral loss from femurs of dams consuming the 0.4% Ca diet was a) insignificant at day 6, b) 27% at day 15, and c) 34% at day 21 of lactation. Our data demonstrate that lactation in the rat is characterized by hyperparathyroidism that appears to be related to lactational intensity and that is accentuated when dietary calcium intake is restricted.(ABSTRACT TRUNCATED AT 250 WORDS)

The roles of parathyroid hormone (PTH) and calcitonin (CT) in the pathogenesis of familial benign hypercalcemia (FBH, or hypocalciuric hypercalcemia) are uncertain. Thus we performed studies in 26 patients with FBH, 12 patients with primary hyperparathyroidism (HPT), and 20 normal volunteers, to answer these questions: are plasma levels of intact or biologically active PTH frequently elevated in FBH? Is plasma intact PTH nonsuppressible during calcium infusion? Is there blunting of the C cell CT response to calcium infusion as occurs in primary HPT? We used three methods for measurement of PTH: a mid region-specific radioimmunoassay (iPTH, antiserum GP-1M), an extraction-concentration bioassay (bioPTH, stimulation of cAMP generation in osteoblastlike cells), and a two-site immunoradiometric assay (IRMA) for intact PTH. PTH levels were significantly elevated in primary HPT by all three methods, but mean PTH was normal in FBH and 85-92% of values overlapped the normal range. During 5 minute calcium infusions (2 mg Ca2+ per kg) iPTH values fell little, but bioPTH and intact PTH fell sharply in all three groups. Mean calcium-induced decreases of intact and bioPTH were indistinguishable from normal in FBH, but PTH levels generally remained elevated at 5 minutes in primary HPT. In FBH basal and postinfusion CT levels were normal. The data show that, in the majority of patients with FBH, PTH concentrations and bioactivity in blood are within the normal range and are suppressed rapidly to very low levels with further increases of calcium. The data suggest that the abnormality of parathyroid function in FBH differs from that in primary HPT.(ABSTRACT TRUNCATED AT 250 WORDS)