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Parathyroid Hormone (parathyroid + hormone)
Kinds of Parathyroid Hormone Terms modified by Parathyroid Hormone Selected AbstractsPARATHYROID HORMONE HAS A PROSCLEROTIC EFFECT ON VASCULAR SMOOTH MUSCLE CELLSNEPHROLOGY, Issue 1 2002Vlado Perkovic [source] IGF-I Receptor Is Required for the Anabolic Actions of Parathyroid Hormone on Bone,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 9 2007Yongmei Wang Abstract We showed that the IGF-IR,null mutation in mature osteoblasts leads to less bone and decreased periosteal bone formation and impaired the stimulatory effects of PTH on osteoprogenitor cell proliferation and differentiation. Introduction: This study was carried out to examine the role of IGF-I signaling in mediating the actions of PTH on bone. Materials and Methods: Three-month-old mice with an osteoblast-specific IGF-I receptor null mutation (IGF-IR OBKO) and their normal littermates were treated with vehicle or PTH (80 ,g/kg body weight/d for 2 wk). Structural measurements of the proximal and midshaft of the tibia were made by ,CT. Trabecular and cortical bone formation was measured by bone histomorphometry. Bone marrow stromal cells (BMSCs) were obtained to assess the effects of PTH on osteoprogenitor number and differentiation. Results: The fat-free weight of bone normalized to body weight (FFW/BW), bone volume (BV/TV), and cortical thickness (C.Th) in both proximal tibia and shaft were all less in the IGF-IR OBKO mice compared with controls. PTH decreased FFW/BW of the proximal tibia more substantially in controls than in IGF-IR OBKO mice. The increase in C.Th after PTH in the proximal tibia was comparable in both control and IGF-IR OBKO mice. Although trabecular and periosteal bone formation was markedly lower in the IGF-IR OBKO mice than in the control mice, endosteal bone formation was comparable in control and IGF-IR OBKO mice. PTH stimulated endosteal bone formation only in the control animals. Compared with BMSCs from control mice, BMSCs from IGF-IR OBKO mice showed equal alkaline phosphatase (ALP)+ colonies on day 14, but fewer mineralized nodules on day 28. Administration of PTH increased the number of ALP+ colonies and mineralized nodules on days 14 and 28 in BMSCs from control mice, but not in BMSCs from IGF-IR OBKO mice. Conclusions: Our results indicate that the IGF-IR null mutation in mature osteoblasts leads to less bone and decreased bone formation, in part because of the requirement for the IGF-IR in mature osteoblasts to enable PTH to stimulate osteoprogenitor cell proliferation and differentiation. [source] Recombinant Human Parathyroid Hormone (1,34) [Teriparatide] Improves Both Cortical and Cancellous Bone StructureJOURNAL OF BONE AND MINERAL RESEARCH, Issue 11 2003Yebin Jiang MD Abstract Histomorphometry and ,CT of 51 paired iliac crest biopsy specimens from women treated with teriparatide revealed significant increases in cancellous bone volume, cancellous bone connectivity density, cancellous bone plate-like structure, and cortical thickness, and a reduction in marrow star volume. Introduction: We studied the ability of teriparatide (rDNA origin) injection [rhPTH(1,34), TPTD] to improve both cancellous and cortical bone in a subset of women enrolled in the Fracture Prevention Trial of postmenopausal women with osteoporosis after a mean treatment time of 19 months. This is the first report of a biopsy study after treatment with teriparatide having a sufficient number of paired biopsy samples to provide quantitative structural data. Methods: Fifty-one paired iliac crest bone biopsy specimens (placebo [n = 19], 20 ,g teriparatide [n = 18], and 40 ,g teriparatide [n = 14]) were analyzed using both two-dimensional (2D) histomorphometry and three-dimensional (3D) microcomputed tomography (,CT). Data for both teriparatide treatment groups were pooled for analysis. Results and Conclusions: By 2D histomorphometric analyses, teriparatide significantly increased cancellous bone volume (median percent change: teriparatide, 14%; placebo, ,24%; p = 0.001) and reduced marrow star volume (teriparatide, ,16%; placebo, 112%; p = 0.004). Teriparatide administration was not associated with osteomalacia or woven bone, and there were no significant changes in mineral appositional rate or wall thickness. By 3D cancellous and cortical bone structural analyses, teriparatide significantly decreased the cancellous structure model index (teriparatide, ,12%; placebo, 7%; p = 0.025), increased cancellous connectivity density (teriparatide, 19%; placebo, ,14%; p = 0.034), and increased cortical thickness (teriparatide, 22%; placebo, 3%; p = 0.012). These data show that teriparatide treatment of postmenopausal women with osteoporosis significantly increased cancellous bone volume and connectivity, improved trabecular morphology with a shift toward a more plate-like structure, and increased cortical bone thickness. These changes in cancellous and cortical bone morphology should improve biomechanical competence and are consistent with the substantially reduced incidences of vertebral and nonvertebral fractures during administration of teriparatide. [source] Identification of a Parathyroid Hormone in the Fish Fugu rubripes,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2003Janine A Danks Abstract A PTH gene has been isolated from the fish Fugu rubripes. The encoded protein of 80 amino acid has the lowest homology with any of the PTH family members. Fugu PTH(1,34) had 5-fold lower potency than human PTH(1,34) in a mammalian cell system. Introduction: Parathyroid hormone (PTH) is the major hypercalcemic hormone in higher vertebrates. Fish lack parathyroid glands, but there have numerous attempts to identify and isolate PTH from fish. Materials and Methods: Polymerase chain reaction (PCR) was performed with primers based on preliminary data from the Joint Genome Institute database. PCR amplification was performed on genomic DNA isolated from Fugu rubripes. PCR products were purified and DNA was sequenced. All sequence was confirmed from more than one independently amplified PCR product. Multiple sequence alignments were carried out, and the percentage of identities and similarities were calculated. An unrooted phylogenetic tree, using all the known PTH and PTH-related protein (PTHrP) amino acid sequences, was determined. Synthetic peptides were tested in a biological assay that measured cyclic adenosine 3,,5,-monophosphate formation in UMR106.1 cells. Rabbit polyclonal antisera specific for N-terminal human PTHrP and one rabbit polyclonal antiserum specific for N terminus hPTH were used to test the cross-reactivity with fPTH(1,34) in immunoblots. [source] Induction of Transcriptional Activity of the Cyclic Adenosine Monophosphate Response Element Binding Protein by Parathyroid Hormone and Epidermal Growth Factor in Osteoblastic Cells,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 8 2002John T. Swarthout Abstract Previously, we have shown that parathyroid hormone (PTH) transactivation of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) requires both serine 129 (S129) and serine 133 (S133) in rat osteosarcoma cells UMR 106-01 (UMR) cells. Furthermore, although protein kinase A (PKA) is responsible for phosphorylation at S133, glycogen synthase kinase 3, (GSK-3,) activity is required and may be responsible for phosphorylation of CREB at S129. Here, we show, using the GAL4-CREB reporter system, that epidermal growth factor (EGF) can transactivate CREB in UMR cells in addition to PTH. Additionally, treatment of UMR cells with both PTH and EGF results in greater than additive transactivation of CREB. Furthermore, using mutational analysis we show that S129 and S133 are required for EGF-induced transcriptional activity. EGF activates members of the MAPK family including p38 and extracellular signal,activated kinases (ERKs), and treatment of UMR cells with either the p38 inhibitor (SB203580) or the MEK inhibitor (PD98059) prevents phosphorylation of CREB at S133 by EGF but not by PTH. Treatment of cells with either SB203580 or PD98059 alone or together significantly inhibits transactivation of CREB by EGF but not by PTH, indicating that EGF regulates CREB phosphorylation and transactivation through p38 and ERKs and PTH does not. Finally, the greater than additive transactivation of CREB by PTH and EGF is significantly inhibited by the PKA inhibitor H-89 or by cotreatment with SB203580 and PD98059. Thus, several different signaling pathways in osteoblastic cells can converge on and regulate CREB activity. This suggests, in vivo, that circulating agents such as PTH and EGF are acting in concert to exert their effects. [source] Development of a Novel Immunoradiometric Assay Exclusively for Biologically Active Whole Parathyroid Hormone 1,84: Implications for Improvement of Accurate Assessment of Parathyroid FunctionJOURNAL OF BONE AND MINERAL RESEARCH, Issue 4 2001Ping Gao Abstract We developed a novel immunoradiometric assay (IRMA; whole parathyroid hormone [PTH] IRMA) for PTH, which specifically measures biologically active whole PTH(1,84). The assay is based on a solid phase coated with anti-PTH(39,84) antibody, a tracer of125I-labeled antibody with a unique specificity to the first N-terminal amino acid of PTH(1,84), and calibrators of diluted synthetic PTH(1,84). In contrast to the Nichols intact PTH IRMA, this new assay does not detect PTH(7,84) fragments and only detects one immunoreactive peak in chromatographically fractionated patient samples. The assay was shown to have an analytical sensitivity of 1.0 pg/ml with a linear measurement range up to 2300 pg/ml. With this assay, we further identified that the previously described non-(1,84)PTH fragments are aminoterminally truncated with similar hydrophobicity as PTH(7,84), and these PTH fragments are present not only in patients with secondary hyperparathyroidism (2° -HPT) of uremia, but also in patients with primary hyperparathyroidism (1° -HPT) and normal persons. The plasma normal range of the whole PTH(1,84) was 7,36 pg/ml (mean ± SD: 22.7 ± 7.2 pg/ml, n = 135), whereas over 93.9% (155/165) of patients with 1° -HPT had whole PTH(1,84) values above the normal cut-off. The percentage of biologically active whole PTH(1,84) (pB%) in the pool of total immunoreactive "intact" PTH is higher in the normal population (median: 67.3%; SD: 15.8%; n = 56) than in uremic patients (median:53.8%; SD: 15.5%; n = 318; p < 0.001), although the whole PTH(1,84) values from uremic patients displayed a more significant heterogeneous distribution when compared with that of 1° -HPT patients and normals. Moreover, the pB% displayed a nearly Gaussian distribution pattern from 20% to over 90% in patients with either 1° -HPT or uremia. The specificity of this newly developed whole PTH(1,84) IRMA is the assurance, for the first time, of being able to measure only the biologically active whole PTH(1,84) without cross-reaction to the high concentrations of the aminoterminally truncated PTH fragments found in both normal subjects and patients. Because of the significant variations of pB% in patients, it is necessary to use the whole PTH assay to determine biologically active PTH levels clinically and, thus, to avoid overestimating the concentration of the true biologically active hormone. This new assay could provide a more meaningful standardization of future PTH measurements with improved accuracy in the clinical assessment of parathyroid function. [source] Intermittently Administered Human Parathyroid Hormone(1,34) Treatment Increases Intracortical Bone Turnover and Porosity Without Reducing Bone Strength in the Humerus of Ovariectomized Cynomolgus MonkeysJOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2001David B. Burr Abstract Cortical porosity in patients with hyperparathyroidism has raised the concern that intermittent parathyroid hormone (PTH) given to treat osteoporotic patients may weaken cortical bone by increasing its porosity. We hypothesized that treatment of ovariectomized (OVX) cynomolgus monkeys for up to 18 months with recombinant human PTH(1,34) [hPTH(1,34)] LY333334 would significantly increase porosity in the midshaft of the humerus but would not have a significant effect on the strength or stiffness of the humerus. We also hypothesized that withdrawal of PTH for 6 months after a 12-month treatment period would return porosity to control OVX values. OVX female cynomolgus monkeys were given once daily subcutaneous (sc) injections of recombinant hPTH(1,34) LY333334 at 1.0 ,g/kg (PTH1), 5.0 ,g/kg (PTH5), or 0.1 ml/kg per day of phosphate-buffered saline (OVX). Sham OVX animals (sham) were also given vehicle. After 12 months, PTH treatment was withdrawn from half of the monkeys in each treatment group (PTH1-W and PTH5-W), and they were treated for the remaining 6 months with vehicle. Double calcein labels were given before death at 18 months. After death, static and dynamic histomorphometric measurements were made intracortically and on periosteal and endocortical surfaces of sections from the middiaphysis of the left humerus. Bone mechanical properties were measured in the right humeral middiaphysis. PTH dose dependently increased intracortical porosity. However, the increased porosity did not have a significant detrimental effect on the mechanical properties of the bone. Most porosity was concentrated near the endocortical surface where its mechanical effect is small. In PTH5 monkeys, cortical area (Ct.Ar) and cortical thickness (Ct.Th) increased because of a significantly increased endocortical mineralizing surface. After withdrawal of treatment, porosity in PTH1-W animals declined to sham values, but porosity in PTH5-W animals remained significantly elevated compared with OVX and sham. We conclude that intermittently administered PTH(1,34) increases intracortical porosity in a dose-dependent manner but does not reduce the strength or stiffness of cortical bone. [source] Teriparatide (Biosynthetic Human Parathyroid Hormone 1,34): A New Paradigm in the Treatment of OsteoporosisBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 6 2004Kim T. Brixen Biosynthetic human parathyroid hormone 1,34 (teriparatide) was recently approved in the EU and the USA as the first anabolic treatment of osteoporosis. The effects of teriparatide are mediated by the G-protein-dependent, parathyroid hormone receptor-1 in the cell membrane. The binding of the ligand to the receptor activates adenylate cyclase and a number of phospholipases (A, C, and D) and increases intracellular levels of cAMP and calcium. Intermittent teriparatide increases the number of osteoblasts and bone formation by activation of pre-existing osteoblasts, increased differentiation of lining cells, and reduced osteoblast apoptosis. Anabolic effects of teriparatide on bone have been demonstrated in several species. It increases bone mass, structural integrity, bone diameter, and bone strength. Clinical efficacy was demonstrated in a randomized study comprising 1637 post-menopausal women with osteoporosis showing a 65% and 35% reduction of the relative risk of vertebral and appendicular fractures, respectively, during 18 months of treatment. Moreover, bone mineral density in the lumbar spine and hip increased by 9.7% and 2.6%, respectively. Similar effects on bone mineral density have been reported in men with osteoporosis and in glucocorticoid-induced osteoporosis, however, fracture data are limited in these groups. Direct comparison with alendronate revealed that teriparatide has a more pronounced effect on bone mineral density. Teriparatide should be used in combination with calcium plus vitamin D, and may be combined with hormonal replacement therapy. In contrast, alendronate attenuates the effect of teriparatide. The efficacy of other combinations remains uncertain. After termination of teriparatide, bone mineral density of the lumbar spine is reduced by approximately 2,3% after 2 1/2 years. This decrease is prevented by treatment with bisphosphonates. The most frequent adverse effects with teriparatide are nausea, headache, dizziness, and leg cramps, however, only the latter two differed significantly between the groups receiving teriparatide 20 ,g/day and placebo. In the pivotal clinical study, reduced dosage or termination of therapy due to hypercalcaemia was necessary in 3% and 0.2%, respectively. In a rat toxicology study, in which teriparatide was administered in high dosages for an extended period of time, osteosarcoma was seen in a significant number of animals. However, none of the approximately 2800 patients in clinical trials has developed osteosarcoma. Teriparatide constitutes a break-through in the treatment of severe osteoporosis, although a number of issues about the optimal use of teriparatide remains unsettled. The published data provide proof of concept on anabolic therapy which changes several paradigms of bone physiology. Other parathyroid hormone analogues are being investigated in clinical trials and the development of non-peptide, small molecules targeted at the parathyroid hormone receptor may be envisaged. [source] Validation and clinical utility of a novel immunoradiometric assay exclusively for biologically active whole parathyroid hormone in the horseEQUINE VETERINARY JOURNAL, Issue 3 2003J. C. ESTEPA Summary Reasons for performing study: Parathyroid hormone (PTH) plays a critical role in the regulation of mineral metabolism in mammals. Until recently, the standard method for PTH measurement has been the 2nd generation intact-PTH (I-PTH) assay. Current evidence indicates that the I-PTH assay binds to the PTH molecule and to an inactive N-terminally truncated PTH fragment that tends to accumulate in the blood of uraemic patients. Therefore, a new 3rd generation PTH assay that detects only the whole PTH molecule (W-PTH; cyclase-activating PTH [CAP]) has been developed. Objectives: To validate this more specific W-PTH assay for measurement of equine PTH and evaluate its clinical utility. Methods: W-PTH and I-PTH were measured in plasma samples from normal horses (adults and foals) and horses with nutritional secondary hyperparathyroidism (N2HPT) and with chronic renal failure (CRF). Replicate measurements and dilutional paralellism were used for assay validation. Changes in blood ionized calcium were induced by EDTA and CaCl2 administration. Results: Performance of the W-PTH assay (accuracy, sensitivity, specificity and ability to detect changes in PTH in response to changes in calcium) was similar to that of the I-PTH assay. Surprisingly, the relative W-PTH concentration in normal horses and foals was higher than the relative I-PTH concentration. W-PTH values remained higher than I-PTH during acute hypo- and hypercalcaemia. An increase in both W-PTH and I-PTH concentrations was found in horses with N2HPT. In horses with CRF, W-PTH and I-PTH values were very low and no increase in I-PTH was observed. Conclusions: The W-PTH assay can be used for measurement of equine PTH. Potential relevance: The use of W-PTH assay is likely to improve the diagnosis of mineral metabolism in horses. [source] Parathyroid hormone stimulates the endothelial expression of vascular endothelial growth factorEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 11 2008G. Rashid ABSTRACT Background, We showed previously that parathyroid hormone (PTH) may stimulate the endothelial expression of pro-atherosclerotic and pro-inflammatory markers. Considering the impact of PTH on vasculature, we decided to evaluate its effect on mRNA and intra-cellular protein expressions of endothelial vascular endothelial growth factor (VEGF) taking into account that VEGF may play a role in the pathogenesis of endothelial dysfunctions. Materials and methods, Human umbilical vein cords endothelial cells (HUVEC) were stimulated for 24 h with 10,12,10,10 mol L,1 PTH. The VEGF-165 mRNA expression (critical in stimulating endothelial cell proliferation) was evaluated by RT/PCR and the intra-cellular VEGF protein expression by flow cytometry. The pathways by which PTH may have an effect on VEGF expression were also evaluated. Results, PTH (10,10 mol L,1) significantly increased VEGF-165 mRNA expression (P < 0·05). The addition of 50 nmol L,1 protein kinase C (PKC) and 10 µmol L,1 protein kinase A (PKA) inhibitors significantly reduced the VEGF-165 mRNA expression (P = 0·01). We also examined whether nitric oxide (NO) may be involved in the PTH-induced stimulation of VEGF-165 expression. Pre-treatment of the cells with 200 µmol L-nitro arginine methyl ester (L-NAME, NO synthase inhibitor) was found to inhibit VEGF-165 mRNA expression (P = 0·006). VEGF protein could not be detected in the medium of HUVEC but it was present in the cell cytoplasm. PTH had no significant effect on cytoplasmatic VEGF protein expression. Conclusion, The stimulatory effect of PTH on endothelial VEGF-165 mRNA expression is partly through PKC and PKA pathways and is also NO dependent. [source] Prediction of hypocalcemia after using 1- to 6-hour postoperative parathyroid hormone and calcium levels: An analysis of pooled individual patient data from 3 observational studiesHEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 4 2010Jeffrey Saad Jumaily BS Abstract Background. Parathyroid hormone (PTH) levels up to 6 hours postthyroidectomy have been shown to have excellent predictive power in determining hypocalcemia. In this study, we investigate the usefulness of combining calcium and PTH to increase the predictive power. Methods. Individual patient data were obtained from 3 studies (152 patients) that fulfilled our criteria (using PTH assay within hours postthyroidectomy to predict symptomatic hypocalcemia). Results. Changes in combined PTH and calcium threshold levels checked 1 to 6 hours after thyroidectomy were excellent in predicting postoperative hypocalcemia. A decrease in PTH of 60%, coupled with a simultaneous decrease in calcium of 10%, 5 to 6 hours postoperatively resulted in a sensitivity and specificity of 100%. However, combined PTH and calcium threshold changes were not significantly better than using PTH threshold changes alone. Conclusions. Threshold changes in serum calcium and PTH, checked hours after surgery, can be used together to accurately predict whether a patient will become hypocalcemic after thyroidectomy. © 2009 Wiley Periodicals, Inc. Head Neck, 2010 [source] Comparison between different dialysate calcium concentrations in nocturnal hemodialysisHEMODIALYSIS INTERNATIONAL, Issue 2 2007Nigel D. TOUSSAINT Abstract Benefits of dialysate with greater calcium (Ca) concentration are reported in nocturnal hemodialysis (NHD) to prevent Ca depletion and subsequent hyperparathyroidism. Studies with patients dialyzing against 1.25 mmol/L Ca baths demonstrate increases in alkaline phosphatase (ALP) and parathyroid hormone (PTH) and increasing dialysate Ca subsequently corrects this problem. However, whether 1.5 or 1.75 mmol/L dialysate Ca is most appropriate for NHD is yet to be determined, and differences in the effect on mineral metabolism of daily vs. alternate daily NHD have also not been well defined. We retrospectively analyzed mineral metabolism in 48 patients, from 2 institutions (30 at Monash and 18 at Geelong), undergoing home NHD (8 hr/night, 3.5,6 nights/week) for a minimum of 6 months. Thirty-seven patients were dialyzed against 1.5 mmol/L Ca bath and 11 patients against 1.75 mmol/L. We divided patients into 4 groups, based on dialysate Ca and also on the hours per week of dialysis, <40 (1.5 mmol/L, n=29 and 1.75 mmol/L, n=8) or ,40 (n=4 and 7). We compared predialysis and postdialysis serum markers, time-averaged over a 6-month period, and the administration of calcitriol and Ca-based phosphate binders between 1.5 and 1.75 mmol/L Ca dialysate groups. Baseline characteristics between all groups were similar, with a slightly longer, but nonsignificant, duration of NHD in both 1.75 mmol/L dialysate groups compared with 1.5 mmol/L. The mean predialysis Ca, phosphate, and Ca × P were similar between the 1.5 and 1.75 mmol/L groups, regardless of NHD hr/week. Postdialysis Ca was significantly greater, with 1.75 vs. 1.5 mmol/L in those dialyzing <40 hr/week (2.64±0.19 vs. 2.50±0.12 mmol/L, p=0.046), but postdialysis Ca × P were similar (2.25±0.44 vs. 2.16±0.29 mmol2/L2, p=0.60). Parathyroid hormone was also lower with 1.75 vs. 1.5 mmol/L baths in the <40 hr/week groups (31.99±26.99 vs. 14.47±16.36 pmol/L, p=0.03), although this difference was not seen in those undertaking NHD ,40 hr/week. Hemoglobin, ALP, and albumin were all similar between groups. There was also no difference in vitamin D requirement when using 1.75 mmol/L compared with the 1.5 mmol/L dialysate. Multivariate analysis to determine independent predictors of postdialysis serum Ca showed a statistically significant positive association with predialysis Ca, dialysate Ca, and total NHD hr/week. An elevated dialysate Ca concentration is required in NHD to prevent osteopenia but differences in serum markers of mineral metabolism between 1.5 and 1.75 mmol/L Ca dialysate in NHD in our study were few. This was similar for patients undertaking NHD <40 or ,40hr/week, although differences in the frequency of NHD may also be as important as dialysate Ca with regard to serum Ca levels. With concerns that prolonged higher Ca levels contribute to increased cardiovascular mortality, the optimal Ca dialysate bath is still unknown and further studies addressing bone metabolism with larger NHD numbers are required. [source] Parathyroid hormone (PTH),induced bone gain is blunted in SOST overexpressing and deficient miceJOURNAL OF BONE AND MINERAL RESEARCH, Issue 2 2010Ina Kramer Abstract Intermittent parathyroid hormone (PTH) treatment is a potent bone anabolic principle that suppresses expression of the bone formation inhibitor Sost. We addressed the relevance of Sost suppression for PTH-induced bone anabolism in vivo using mice with altered Sost gene dosage. Six-month-old Sost overexpressing and 2-month-old Sost deficient male mice and their wild-type littermates were subjected to daily injections of 100,µg/kg PTH(1,34) or vehicle for a 2-month period. A follow-up study was performed in Sost deficient mice using 40 and 80,µg/kg PTH(1,34). Animals were sacrificed 4 hours after the final PTH administration and Sost expression in long bone diaphyses was determined by qPCR. Bone changes were analyzed in vivo in the distal femur metaphysis by pQCT and ex vivo in the tibia and lumbar spine by DXA. Detailed ex vivo analyses of the femur were performed by pQCT, µCT, and histomorphometry. Overexpression of Sost resulted in osteopenia and Sost deletion in high bone mass. As shown before, PTH suppressed Sost in wild-type mice. PTH treatment induced substantial increases in bone mineral density, content, and cortical thickness and in aging wild-type mice also led to cancellous bone gain owing to amplified bone formation rates. PTH-induced bone gain was blunted at all doses and skeletal sites in Sost overexpressing and deficient mice owing to attenuated bone formation rates, whereas bone resorption was not different from that in PTH-treated wild-type controls. These data suggest that suppression of the bone formation inhibitor Sost by intermittent PTH treatment contributes to PTH bone anabolism. © 2010 American Society for Bone and Mineral Research [source] Bone mineralization defects and vitamin D deficiency: Histomorphometric analysis of iliac crest bone biopsies and circulating 25-hydroxyvitamin D in 675,patientsJOURNAL OF BONE AND MINERAL RESEARCH, Issue 2 2010Matthias Priemel Abstract Parathyroid hormone (PTH) is only one measurable index of skeletal health, and we reasoned that a histomorphometric analysis of iliac crest biopsies would be another and even more direct approach to assess bone health and address the required minimum 25-Hydroxyvitamin D [25(OH)D] level. A cohort from the northern European population with its known high prevalence of vitamin D deficiency therefore would be ideal to answer the latter question. We examined 675 iliac crest biopsies from male and female individuals, excluding all patients who showed any signs of secondary bone diseases at autopsy. Structural histomorphometric parameters, including osteoid indices, were quantified using the Osteomeasure System according to ASBMR standards, and serum 25(OH)D levels were measured for all patients. Statistical analysis was performed by Student's t test. The histologic results demonstrate an unexpected high prevalence of mineralization defects, that is, a pathologic increase in osteoid. Indeed, 36.15% of the analyzed patients presented with an osteoid surface per bone surface (OS/BS) of more than 20%. Based on the most conservative threshold that defines osteomalacia at the histomorphometric level with a pathologic increase in osteoid volume per bone volume (OV/BV) greater than 2% manifest mineralization defects were present in 25.63% of the patients. The latter were found independent of bone volume per trabecular volume (BV/TV) throughout all ages and affected both sexes equally. While we could not establish a minimum 25(OH)D level that was inevitably associated with mineralization defects, we did not find pathologic accumulation of osteoid in any patient with circulating 25(OH)D above 75,nmol/L. Our data demonstrate that pathologic mineralization defects of bone occur in patients with a serum 25(OH)D below 75,nmol/L and strongly argue that in conjunction with a sufficient calcium intake, the dose of vitamin D supplementation should ensure that circulating levels of 25(OH)D reach this minimum threshold (75,nmol/L or 30,ng/mL) to maintain skeletal health. © 2010 American Society for Bone and Mineral Research [source] Identification of a Parathyroid Hormone in the Fish Fugu rubripes,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2003Janine A Danks Abstract A PTH gene has been isolated from the fish Fugu rubripes. The encoded protein of 80 amino acid has the lowest homology with any of the PTH family members. Fugu PTH(1,34) had 5-fold lower potency than human PTH(1,34) in a mammalian cell system. Introduction: Parathyroid hormone (PTH) is the major hypercalcemic hormone in higher vertebrates. Fish lack parathyroid glands, but there have numerous attempts to identify and isolate PTH from fish. Materials and Methods: Polymerase chain reaction (PCR) was performed with primers based on preliminary data from the Joint Genome Institute database. PCR amplification was performed on genomic DNA isolated from Fugu rubripes. PCR products were purified and DNA was sequenced. All sequence was confirmed from more than one independently amplified PCR product. Multiple sequence alignments were carried out, and the percentage of identities and similarities were calculated. An unrooted phylogenetic tree, using all the known PTH and PTH-related protein (PTHrP) amino acid sequences, was determined. Synthetic peptides were tested in a biological assay that measured cyclic adenosine 3,,5,-monophosphate formation in UMR106.1 cells. Rabbit polyclonal antisera specific for N-terminal human PTHrP and one rabbit polyclonal antiserum specific for N terminus hPTH were used to test the cross-reactivity with fPTH(1,34) in immunoblots. [source] Insulin-Like Growth Factor I Is Required for the Anabolic Actions of Parathyroid Hormone on Mouse Bone,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 9 2002Daniel D. Bikle M.D., Ph.D. Abstract Parathyroid hormone (PTH) is a potent anabolic agent for bone, but the mechanism(s) by which it works remains imperfectly understood. Previous studies have indicated that PTH stimulates insulin-like growth factor (IGF) I production, but it remains uncertain whether IGF-I mediates some or all of the skeletal actions of PTH. To address this question, we examined the skeletal response to PTH in IGF-I-deficient (knockout [k/o]) mice. These mice and their normal littermates (NLMs) were given daily injections of PTH (80 ,g/kg) or vehicle for 2 weeks after which their tibias were examined for fat-free weight (FFW), bone mineral content, bone structure, and bone formation rate (BFR), and their femurs were assessed for mRNA levels of osteoblast differentiation markers. In wild-type mice, PTH increased FFW, periosteal BFR, and cortical thickness (C.Th) of the proximal tibia while reducing trabecular bone volume (BV); these responses were not seen in the k/o mice. The k/o mice had normal mRNA levels of the PTH receptor and increased mRNA levels of the IGF-I receptor but markedly reduced basal mRNA levels of the osteoblast markers. Surprisingly, these mRNAs in the k/o bones increased several-fold more in response to PTH than the mRNAs in the bones from their wild-type littermates. These results indicate that IGF-I is required for the anabolic actions of PTH on bone formation, but the defect lies distal to the initial response of the osteoblast to PTH. [source] PTH-dependent adenylyl cyclase activation in SaOS-2 cells: Passage dependent effects on G protein interactionsJOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2002Hong Gao Parathyroid hormone (PTH) sensitive adenylyl cyclase activity (ACA) in SaOS-2 cells varies as a function of cell passage. In early passage (EP) cells (<,6), ACA in response to PTH and forskolin (FOR) was relatively low and equivalent, whereas in late passage (LP) cells (>,22), PTH exceeded FOR dependent ACA. Potential biochemical mechanisms for this passage dependent change in ACA were considered. In EP, prolonged exposure to pertussis toxin (PT) markedly enhanced ACA activity in response to PTH, Isoproterenol and Gpp(NH)p, whereas ACA in response to FOR was decreased. In contrast, the identical treatment of LP with PT diminished all ACA in response to PTH, Gpp(NH)p, and FOR. The dose dependent effects of PT on subsequent [32P]ADP-ribosylation of its substrates, GTPase activity, as well as FOR-dependent ACA, were equivalent in EP and LP. The relative amounts of G,i and G,s proteins, as determined both by Western blot, PT and cholera toxin (CT) dependent [32P]ADP-ribosylation, were quantitatively similar in EP and LP. Western blot levels of G,s and G,i proteins were not influenced by prior exposure to PT. Both PT and CT dependent [32P]ADP-ribosylation were dose-dependently decreased following exposure to PT. However, the PT-dependent decline in CT-dependent [32P]ADP-ribosylation occurred with enhanced sensitivity in LP. The protein synthesis inhibitor cycloheximide partially reversed the PT associated decrease in FOR dependent ACA in EP. In contrast, cycloheximide completely reversed the PT associated decrease in FOR and as well as PTH dependent ACA in LP. G,s activity, revealed by cyc, reconstitution, was not altered either by cell passage or exposure to PT. The results suggest that the coupling between the components of the complex may be pivotally important in the differential responsiveness of early and late passage SaOS-2 cells to PTH. J. Cell. Physiol. 193: 10,18, 2002. © 2002 Wiley-Liss, Inc. [source] Decreased oxidative stress and greater bone anabolism in the aged, when compared to the young, murine skeleton with parathyroid hormone administrationAGING CELL, Issue 5 2010Robert L. Jilka Summary Because of recent insights into the pathogenesis of age-related bone loss, we investigated whether intermittent parathyroid hormone (PTH) administration antagonizes the molecular mechanisms of the adverse effects of aging on bone. Parathyroid hormone produced a greater increase in vertebral trabecular bone mineral density and bone volume as well as a greater expansion of the endocortical bone surface in the femur of 26- when compared to 6 -month-old female C57BL/6 mice. Moreover, PTH increased trabecular connectivity in vertebrae, and the toughness of both vertebrae and femora in old, but not young, mice. Parathyroid hormone also increased the rate of bone formation and reduced osteoblast apoptosis to a greater extent in the old mice. Most strikingly, PTH reduced reactive oxygen species, p66Shc phosphorylation, and expression of the lipoxygenase Alox15, and it increased glutathione and stimulated Wnt signaling in bone of old mice. Parathyroid hormone also antagonized the effects of oxidative stress on p66Shc phosphorylation, Forkhead Box O transcriptional activity, osteoblast apoptosis, and Wnt signaling in vitro. In contrast, administration of the antioxidants N -acetyl cysteine or pegylated catalase reduced osteoblast progenitors and attenuated proliferation and Wnt signaling. These results suggest that PTH has a greater bone anabolic efficacy in old age because in addition to its other positive actions on bone formation, it antagonizes the age-associated increase in oxidative stress and its adverse effects on the birth and survival of osteoblasts. On the other hand, ordinary antioxidants cannot restore bone mass in old age because they slow remodeling and attenuate osteoblastogenesis by interfering with Wnt signaling. [source] Calciphylaxis: Is There a Role for Parathyroidectomy?,THE LARYNGOSCOPE, Issue 4 2000Mark D. Kriskovich MD Abstract Objective Calciphylaxis, a rare disorder typically affecting renal failure patients, results in vascular calcification with subsequent skin necrosis, gangrene, and often death from sepsis. Parathyroid hormone is thought to act as a tissue sensitizer leading to these soft tissue changes. As such, parathyroidectomy is often advocated to control this complicated condition. A discussion of calciphylaxis does not exist in the otolaryngology literature, and head and neck surgeons performing parathyroidectomy should be aware of this phenomenon. This study evaluates the success of parathyroidectomy in reversing the ill effects of calciphylaxis in both our patient population and the literature. Study Design Retrospective study and review of the literature. Methods Five patients with calciphylaxis treated at our institution were evaluated for mortality, surgical and perioperative complications, wound healing, and predictors of patient outcomes. Results Two patients died from sepsis and infectious complications of their calciphylaxis shortly after surgery. Of the three survivors, two later died (15 and 18 mo after surgery) from causes not directly related to calciphylaxis. The other long-term survivor required partial amputation of a leg for osteomyelitis. There was one operative complication, a wound infection requiring antibiotic therapy, drainage, and packing. Postoperative hypocalcemia required treatment in two patients. Immediate perioperative survival was more likely in patients with leukocyte counts less than 20,000 cells/mL. Conclusions Calciphylaxis is a serious disease and patients often succumb to sepsis and infectious complications. Patients with extremely high leukocyte counts from coexistent infections may have a worse prognosis. Although a conclusive effective therapy does not exist, parathyroidectomy can be safely performed and may benefit some patients with what is often an otherwise fatal disease. The literature to date generally confirms our findings. [source] Parathyroid hormone 1,34 inhibits terminal differentiation of human articular chondrocytes and osteoarthritis progression in ratsARTHRITIS & RHEUMATISM, Issue 10 2009Je-Ken Chang Objective Parathyroid hormone 1,34 (PTH[1,34]), a parathyroid hormone analog, shares the same receptor, PTH receptor 1, with parathyroid hormone,related peptide (PTHrP). This study was undertaken to address the hypothesis that PTH(1,34) inhibits terminal differentiation of articular chondrocytes and in turn suppresses the progression of osteoarthritis (OA). Methods We studied the effect of PTH(1,34) on human articular chondrocytes with azacytidine (azaC),induced terminal differentiation in vitro and on papain-induced OA in the knee joints of rats. In the in vitro study, we measured the levels of messenger RNA for SOX9, aggrecan, type II collagen, type X collagen, alkaline phosphatase (AP), Indian hedgehog (IHH), Bcl-2, and Bax by real-time polymerase chain reaction, levels of glycosaminoglycan (GAG) by dimethylmethylene blue assay, and rate of apoptosis by TUNEL staining. In the in vivo study, we evaluated the histologic changes in GAG, type II collagen, type X collagen, and chondrocyte apoptosis in the articular cartilage of rat knees. Results AzaC induced terminal differentiation of human chondrocytes, including down-regulation of aggrecan, type II collagen, and GAG and up-regulation of type X collagen, alkaline phosphatase, and IHH. Apoptosis was reversed by 3,10 days of treatment with 10 nM PTH(1,34). SOX9 expression was not changed by either azaC or PTH(1,34) treatment. Bcl-2 and Bax were up-regulated on day 10 and day 14, respectively, after azaC induction of terminal differentiation, but PTH(1,34) treatment did not reverse this effect. Furthermore, PTH(1,34) treatment reversed papain-induced OA changes (decreasing GAG and type II collagen, and increasing type X collagen and chondrocyte apoptosis) in the knee joints of rats. Conclusion Our findings indicate that PTH(1,34) inhibits the terminal differentiation of human articular chondrocytes in vitro and inhibits progression of OA in rats in vivo, and may be used to treat OA. [source] Parathyroid hormone inhibits phosphorylation of mitogen-activated protein kinase (MAPK) ERK1/2 through inhibition of c-Raf and activation of MKP-1 in osteoblastic cellsCELL BIOCHEMISTRY AND FUNCTION, Issue 5 2009Lick Pui Lai Abstract Parathyroid hormone (PTH) regulation of mitogen-activated protein kinases (MAPK) ERK1/2 contributes to PTH regulation of osteoblast growth and apoptosis. We investigated the mechanisms by which PTH inhibits ERK1/2 activity in osteoblastic UMR 106-01 cells. Treatment with PTH significantly inhibited phosphorylated ERK1/2 between 5 and 60,min. Transient transfection of cells with a cDNA encoding MAPK phosphatase-1 (MKP-1) resulted in 30,40% inhibition of pERK1/2; however MKP-1 protein levels were only significantly stimulated by PTH after 30,mins, suggesting another mechanism for the early phase of pERK1/2 inhibition. The active upstream kinase c-Raf phosphorylation at serine 338 (ser338) was significantly inhibited by PTH treatment within 5,min and transfection of the cells with constitutively-active c-Raf blocked PTH inhibition of pERK1/2. Inhibition of pERK1/2 and phosphor-c-Raf were seen when cells were treated with PTH(1-34) or PTH(1-31) analogues that stimulate cAMP, but not with PTH(3-34), PTH(7-34) or PTH(18-48) that do not stimulate cAMP. Stimulation of the cells with forskolin or 8BrcAMP also inhibited pERK1/2 and c-Raf.p338. Our results suggest that rapid PTH inhibition of ERK1/2 activity is mediated by PKA dependent inhibition of c-Raf activity and that stimulation of MKP-1 may contribute to maintaining pERK1/2 inhibition over prolonged time. Copyright © 2009 John Wiley & Sons, Ltd. [source] Vacuolar H+ -ATPase expression is increased in acid-secreting intercalated cells in kidneys of rats with hypercalcaemia-induced alkalosisACTA PHYSIOLOGICA, Issue 4 2007W. Wang Abstract Aims:, Hypercalcaemia is known to be associated with systemic metabolic alkalosis, although the underlying mechanism is uncertain. Therefore, we aimed to examine whether hypercalcaemia was associated with changes in the expression of acid,base transporters in the kidney. Methods:, Rats were infused with human parathyroid hormone (PTH, 15 ,g kg,1 day,1), or vehicle for 48 h using osmotic minipumps. Results:, The rats treated with PTH developed hypercalcaemia and exhibited metabolic alkalosis (arterial HCO: 31.1 ± 0.8 vs. 28.1 ± 0.8 mmol L,1 in controls, P < 0.05, n = 6), whereas the urine pH of 6.85 ± 0.1 was significantly decreased compared with the pH of 7.38 ± 0.1 in controls (P < 0.05, n = 12). The observed alkalosis was associated with a significantly increased expression of the B1-subunit of the H+ -ATPase in kidney inner medulla (IM, 233 ± 45% of the control level). In contrast, electroneutral Na+ -HCO cotransporter NBCn1 and Cl,/HCO anion exchanger AE2 expression was markedly reduced in the inner stripe of the outer medulla (to 26 ± 9% and 65 ± 6%, respectively). These findings were verified by immunohistochemistry. Conclusions:, (1) hypercalcaemia-induced metabolic alkalosis was associated with increased urinary excretion of H+; (2) the increased H+ -ATPase expression in IM may partly explain the enhanced urinary acidification, which is speculated to prevent stone formation because of hypercalciuria and (3) the decreased expression of outer medullary AE2 suggests a compensatory reduction of the transepithelial bicarbonate transport. [source] Fine-needle aspiration of brown tumor of bone: Cytologic features with radiologic and histologic correlationDIAGNOSTIC CYTOPATHOLOGY, Issue 2 2009Ph.D., Sasha Pavlovic M.D. Abstract We report the case of a 40-year-old man with tertiary hyperparathyroidism due to end stage renal disease who initially presented with acute-onset paraplegia, elevated serum parathyroid hormone, and multiple bone abnormalities, including a large extradural intraspinal mass seen by magnetic resonance imaging. In contrast with imaging features, fine-needle aspiration cytology showed numerous benign-appearing multinucleated osteoclast-type giant cells that are the characteristics of either brown tumor or benign giant cell tumor of bone. Sheets of mononuclear spindled stromal cells were also noted. A core-needle biopsy confirmed the diagnostic features of brown tumor of hyperparathyroidism. Diagn. Cytopathol. 2009. © 2008 Wiley-Liss, Inc. [source] Vitamin D Levels and Bone Turnover in Epilepsy Patients Taking Carbamazepine or OxcarbazepineEPILEPSIA, Issue 3 2006Scott Mintzer Summary:,Purpose: Evidence suggests that enzyme-inducing antiepileptic drugs (AEDs) may decrease serum 25-hydroxyvitamin D (25-OHD) levels and increase bone turnover. We sought to determine whether these are affected by treatment with carbamazepine (CBZ) or oxcarbazepine (OXC). Methods: We measured serum levels of 25-OHD, parathyroid hormone (PTH), osteocalcin (OCLN), bone alkaline phosphatase (BAP), and urinary N-telopeptides of type I collagen cross-links (NTX) in normal controls (n = 24) and in epilepsy patients taking CBZ (n = 21) or OXC (n = 24) in monotherapy. CBZ patients were subsequently switched overnight to OXC monotherapy, and after 6 weeks, the tests were repeated. Results: 25-OHD levels were lower in each drug-treated group (OXC, 19.4 ± 2.3 pg/ml; CBZ, 20.4 ± 2.4) than in the controls (27.5 ± 2.8) (ANOVA, p = 0.052). This difference was significant for the OXC group (p < 0.05). PTH, BAP, and NTX did not differ significantly among groups. OCLN levels were somewhat elevated in the OXC group (2.79 ± 0.47 ng/ml) and more clearly and significantly elevated in the CBZ group (3.63 ± 0.36) compared with controls (2.38 ± 0.41) (p = 0.053). Because the data were very similar between OXC and CBZ groups, they were combined to increase statistical power. The combined drug-treatment group had significantly higher BAP (p = 0.02) and lower 25-OHD (p = 0.015) than did controls. The latter remained significant even after accounting for the confounding effects of age on 25-OHD levels (p < 0.05). No significant differences were found after CBZ patients were switched to OXC. Conclusions: Epilepsy patients taking OXC or CBZ have significantly lower 25-OHD than do normal controls, with a pattern of changes in other bone biomarkers suggestive of secondary hyperparathyroidism. It may be prudent for patients taking CBZ or OXC to be prescribed 25-OHD replacement. [source] Validation and clinical utility of a novel immunoradiometric assay exclusively for biologically active whole parathyroid hormone in the horseEQUINE VETERINARY JOURNAL, Issue 3 2003J. C. ESTEPA Summary Reasons for performing study: Parathyroid hormone (PTH) plays a critical role in the regulation of mineral metabolism in mammals. Until recently, the standard method for PTH measurement has been the 2nd generation intact-PTH (I-PTH) assay. Current evidence indicates that the I-PTH assay binds to the PTH molecule and to an inactive N-terminally truncated PTH fragment that tends to accumulate in the blood of uraemic patients. Therefore, a new 3rd generation PTH assay that detects only the whole PTH molecule (W-PTH; cyclase-activating PTH [CAP]) has been developed. Objectives: To validate this more specific W-PTH assay for measurement of equine PTH and evaluate its clinical utility. Methods: W-PTH and I-PTH were measured in plasma samples from normal horses (adults and foals) and horses with nutritional secondary hyperparathyroidism (N2HPT) and with chronic renal failure (CRF). Replicate measurements and dilutional paralellism were used for assay validation. Changes in blood ionized calcium were induced by EDTA and CaCl2 administration. Results: Performance of the W-PTH assay (accuracy, sensitivity, specificity and ability to detect changes in PTH in response to changes in calcium) was similar to that of the I-PTH assay. Surprisingly, the relative W-PTH concentration in normal horses and foals was higher than the relative I-PTH concentration. W-PTH values remained higher than I-PTH during acute hypo- and hypercalcaemia. An increase in both W-PTH and I-PTH concentrations was found in horses with N2HPT. In horses with CRF, W-PTH and I-PTH values were very low and no increase in I-PTH was observed. Conclusions: The W-PTH assay can be used for measurement of equine PTH. Potential relevance: The use of W-PTH assay is likely to improve the diagnosis of mineral metabolism in horses. [source] Renal phosphate handling in human , what can we learn from hereditary hypophosphataemias?EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 6 2010Stefan Amatschek Eur J Clin Invest 2010; 40 (6): 552,560 Abstract Background, Renal reabsorption of inorganic phosphate is critical for the maintenance of phosphate homeostasis. The sodium dependent phosphate cotransporters NaPi-IIa and NaPi-IIc have been identified to fulfill this task at the brush border membrane of proximal tubule cells. Various factors including dietary phosphate intake, parathyroid hormone, or the so called phosphatonins such as FGF23 have been shown to regulate activity of these transporters. Design, This review seeks to give an update on our current knowledge about regulatory mechanisms involved in human renal phosphate reabsorption. Results, Recently, an increasing number of genes have been identified that are directly associated with inherited phosphate wasting disorders (Klotho, PHEX, DMP1 and NHERF1). Several of these genes are predominantly expressed by osteocytes and osteoclasts in the bone suggesting indispensable signalling pathways between kidneys and the skeleton. Conclusion, In this review, the affected gene products in these inherited hypophosphataemias and their contribution to phosphate homeostasis are discussed. [source] Parathyroid hormone stimulates the endothelial expression of vascular endothelial growth factorEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 11 2008G. Rashid ABSTRACT Background, We showed previously that parathyroid hormone (PTH) may stimulate the endothelial expression of pro-atherosclerotic and pro-inflammatory markers. Considering the impact of PTH on vasculature, we decided to evaluate its effect on mRNA and intra-cellular protein expressions of endothelial vascular endothelial growth factor (VEGF) taking into account that VEGF may play a role in the pathogenesis of endothelial dysfunctions. Materials and methods, Human umbilical vein cords endothelial cells (HUVEC) were stimulated for 24 h with 10,12,10,10 mol L,1 PTH. The VEGF-165 mRNA expression (critical in stimulating endothelial cell proliferation) was evaluated by RT/PCR and the intra-cellular VEGF protein expression by flow cytometry. The pathways by which PTH may have an effect on VEGF expression were also evaluated. Results, PTH (10,10 mol L,1) significantly increased VEGF-165 mRNA expression (P < 0·05). The addition of 50 nmol L,1 protein kinase C (PKC) and 10 µmol L,1 protein kinase A (PKA) inhibitors significantly reduced the VEGF-165 mRNA expression (P = 0·01). We also examined whether nitric oxide (NO) may be involved in the PTH-induced stimulation of VEGF-165 expression. Pre-treatment of the cells with 200 µmol L-nitro arginine methyl ester (L-NAME, NO synthase inhibitor) was found to inhibit VEGF-165 mRNA expression (P = 0·006). VEGF protein could not be detected in the medium of HUVEC but it was present in the cell cytoplasm. PTH had no significant effect on cytoplasmatic VEGF protein expression. Conclusion, The stimulatory effect of PTH on endothelial VEGF-165 mRNA expression is partly through PKC and PKA pathways and is also NO dependent. [source] The role of calcimimetics in the treatment of hyperparathyroidismEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 12 2007R. P. Wüthrich Abstract Calcimimetics reduce serum levels of parathyroid hormone (PTH) and calcium, with a leftward shift in the set-point for calcium-regulated PTH secretion. The aim of this publication is to review the data available for calcimimetics in primary, secondary and tertiary hyperparathyroidism (HPT). Parathyroidectomy (PTX) is currently the only curative treatment for primary HPT, and recommended for patients with moderate-to-severe disease, as defined by a 2002 National Institute's of Health summary statement. In general, patients with primary HPT not meeting these surgical criteria, as well as those with contraindication or refusal for surgery, are monitored for signs and symptoms of primary HPT. There are currently no non-surgical therapies approved for use in primary HPT, although bisphosphonates are used in some patients, in an effort to control serum calcium levels. Calcimimetics decrease PTH and calcium levels and are a potential alternative for patients contraindicated for PTX, or who have failed previous PTX and have recurrent primary HPT. Secondary HPT develops early in chronic kidney disease and is present virtually in all patients with end-stage renal disease (ESRD). Secondary HPT is a progressive disease and is associated with several systemic complications, including renal osteodystrophy, soft tissue and vascular calcifications, and adverse cardiovascular outcomes. In ESRD patients, calcimimetics were shown to simultaneously reduce PTH, calcium, phosphate and calcium × phosphate product. In addition, observational analyses of use of calcimimetics in the ESRD population have shown a reduction of important clinical outcomes. In renal allograft recipients with tertiary HPT and hypercalcaemia, calcimimetics are a promising treatment option to control the parameters of calcium phosphate metabolism and may be a valid alternative to PTX. Based on its unique mechanism of action, the calcimimetic cinacalcet may play a role in the medical treatment of primary and tertiary forms of HPT, in addition to the registered indication for the treatment of secondary HPT. [source] Mineral metabolism disturbances in patients with chronic kidney diseaseEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 8 2007B. Kestenbaum Abstract Background Kidney disease, especially chronic kidney disease (CKD), is a worldwide public health problem with serious adverse health consequences for affected individuals. Secondary hyperparathyroidism, a disorder characterized by elevated serum parathyroid hormone levels, and alteration of calcium and phosphorus homeostasis are common metabolic complications of CKD that may impact cardiovascular health. Materials and methods Here, we systematically review published reports from recent observational studies and clinical trials that examine markers of altered mineral metabolism and clinical outcomes in patients with CKD. Results Mineral metabolism disturbances begin early during the course of chronic kidney disease, and are associated with cardiovascular disease and mortality in observational studies. Vascular calcification is one plausible mechanism connecting renal-related mineral metabolism with cardiovascular risk. Individual therapies to correct mineral metabolism disturbances have been associated with clinical benefit in some observational studies; clinical trials directed at more comprehensive control of this problem are warranted. Conclusions There exists a potential to improve outcomes for patients with CKD through increased awareness of the Bone Metabolism and Disease guidelines set forth by the National Kidney Foundation,Kidney Disease Outcomes Quality Initiative. Future studies may include more aggressive therapy with a combination of agents that address vitamin D deficiency, parathyroid hormone and phosphorus excess, as well as novel agents that modulate circulating promoters and inhibitors of calcification. [source] Development of renal bone diseaseEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2006A. Ferreira Abstract Renal osteodystrophy (ROD) develops as the early stages of chronic renal failure (CRF) and covers a spectrum of bone changes observed in the uraemic patient, which extend from high remodelling bone disease (frequently known as osteitis fibrosa) to low turnover, or adynamic disease. Between these two extremes there are also cases of bone mineralization compromised in variable degrees, as is the case of ,mixed bone disease' and osteomalacia. The dynamic process of bone remodelling is compromised in CRF, and a positive or negative bone balance can be observed in uraemic patients. In addition to the classic modulators of bone remodelling, like parathyroid hormone, calcitriol and calcitonin, other factors were recently identified as significant modulators of osteoblast and osteoclast activation in uraemic patients. In fact, different cytokines and growth factors, acting at an autocrine or paracrine level, seem to play a relevant role in the bone and mineral changes observed in uraemia. Recently, observations have been made of the development of more sensitive and specific techniques to assay different biochemical markers of bone turnover and mineral metabolism. Analogously, new contributions of conventional bone histology, bone immunocytochemistry and molecular biology, which enabled the understanding of some etiopathogenic mechanisms of ROD, were observed. [source] | ||||||||||||||||||||||||||||||||||