BACKGROUND

Uremic tumoral calcinosis (UTC) has been analyzed in uremic patients on hemodialysis, but little is known about UTC in peritoneal dialysis (PD). In this study, we aimed to characterize UTC in uremic patients on PD.

METHODS

We retrospectively reviewed uremic patients on PD who developed UTC over a 9-year period. Clinical, radiologic, and laboratory features; treatments; and outcomes in those patients were assessed. One of the patients (case 7) is described as a case example.

RESULTS

The study enrolled 7 patients with a mean age of 41 years. Mean time from PD to UTC was 45.3 months. All patients were anuric but adequately dialyzed. Cardinal symptoms were local tenderness and limited range of joint motion. Lesions were mostly multifocal (n=6) and predominantly involved shoulders, hands, feet, hips, and wrists. Metatarsophalangeal joint UTC was misdiagnosed as tophaceous gout in 2 patients. Main laboratory findings were hyperphosphatemia (7.9 ± 0.8 mg/dL), high Ca×P product [>65 mg(2)/dL(2) (range: 81.1 ± 11.5 mg(2)/dL(2))], secondary hyperparathyroidism (SHPT) with various levels of intact parathyroid hormone (iPTH: 592.2 ± 315.2 pg/mL; <250 pg/mL in 2 patients). Medical treatments for UTC included P restriction, non-Ca-based phosphate binders, and adequate dialysis with low-Ca dialysate, but all treatments were ineffective. Parathyroidectomy (n=3) can partially ameliorate UTC, but only 1 patient (case 7), who had extremely high iPTH (1085 pg/mL), manifested hungry bone syndrome (HBS) and had remarkable resolution of UTC. By contrast, in patients who underwent renal transplantation (n=3), UTC completely resolved by about 1 year after surgery.

CONCLUSIONS

Uremic tumoral calcinosis develops in anuric PD patients with uncontrolled hyperphosphatemia; it is usually multifocal, occurring around the weight-bearing joints or overused smaller joints. Aggressive medical therapy alone is ineffective, and parathyroidectomy appears to be unsatisfactory except in the presence of severe SHPT with postoperative HBS.

Calcium (Ca) overload by Ca-containing phosphorus (P) binder has been suggested to be implicated in the pathogenesis of soft tissue and vascular calcification, which contribute to increased morbidity and mortality of cardiovascular disease in patients undergoing dialysis. Recently, a noncalcium P binder, sevelamer hydrochloride (sevelamer), has become available in Japan. However, Japanese patients undergoing dialysis might be less tolerant of sevelamer treatment, and it is likely to cause hypocalcemia because their dietary Ca intake is less than that in European and American patients. We evaluated the effects of combination therapy with sevelamer and calcium carbonate (CC) on mineral metabolism in Japanese hemodialysis patients, as an alternative form of P management. A total of 210 hemodialysis patients were enrolled, and were given a small dose of sevelamer (0.75-1.5 g/day) on CC treatment. Sevelamer dose was gradually increased, while CC decreased during 24 weeks. Five patients discontinued sevelamer treatment because of severe constipation, anorexia, and parathyroidectomy for severe secondary hyperparathyroidism. After 24 weeks, the dose of sevelamer was significantly increased to 3.29 g/day (initial dose: 1.47 g/day), while CC was decreased by 54%. Adjusted serum Ca significantly decreased (9.63 +/- 0.57-9.45 +/- 0.67 mg/dL; P = 0.0012), although serum P increased (5.89 +/- 1.32-6.25 +/- 1.32 mg/dL; P = 0.017). Serum intact PTH (iPTH) significantly increased in patients with a low or normal iPTH level (< or =300 pg/mL), while it did not change in patients with secondary hyperparathyroidism (>300 pg/mL). The results suggest that the therapeutic regimen is more tolerant and reduces Ca load in Japanese hemodialysis patients while avoiding hypocalcemia. In addition, the mitigated Ca overload could improve PTH hyposecretion in patients with adynamic bone disease, which is associated with soft tissue calcification and higher mortality in uremia.

This study compared the effects of oral and intravenous calcitriol on serum biochemistry parameters and levels of bone-resorptive cytokines in haemodialysis patients. Patients were randomized to receive oral (n = 18) or intravenous (n = 16) calcitriol treatment for 6 months. Serum levels of total calcium, ionized calcium, intact parathyroid hormone (iPTH), magnesium, alkaline phosphatase, tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 and IL-6 were measured at baseline and after 3 and 6 months of treatment. After treatment, serum levels of iPTH, total calcium, ionized calcium, TNF-alpha, IL-1 and IL-6 were not significantly different from baseline. The intravenous calcitriol treatment group showed significant decreases in levels of iPTH, TNF-alpha, IL-1 and IL-6 and a significant increase in total calcium level after 3 and 6 months. There was no significant change in serum ionized calcium levels. Significantly decreased serum alkaline phosphatase and magnesium levels were found in both treatment groups after 3 and 6 months. In conclusion, intravenous calcitriol treatment has a significant depressive effect on iPTH and bone-resorptive cytokines in patients undergoing haemodialysis.

Secondary hyperparathyroidism (SHPT) is a common, important, and treatable complication of end-stage renal disease. This study was conducted to investigate the role of serum magnesium (Mg) in regulating the secretion of parathyroid hormone (PTH) by the parathyroid gland in patients on maintenance hemodialysis (HD). Pre-dialysis serum levels of calcium (Ca), phosphorus (P), Mg, alkaline phosphatase (ALP), intact serum PTH (iPTH), serum 25-hydroxy Vitamin D (25-OH Vit D) and plasma bicarbonate (HCO3) were measured. The Urea Reduction Rate as well as duration and dosage of HD treatment were noted. Our study did not show any significant correlation between serum Mg levels and duration of HD treatment, levels of serum ALP, and plasma HCO3, Ca and P. An inverse correlation, albeit insignificant, was found between the serum Mg levels and iPTH (r = -0.30 p = 0.079); also, a significant positive correlation was found between serum Mg levels and serum 25-OH Vit D levels (r = 0.40 p = 0.009). Our findings are in agreement with previous data, which suggest that factors other than serum Mg are more important in the regulation of PTH secretion in HD patients. A positive and strong association between serum Mg with 25-OH Vit D needs to be studied in greater detail.

BACKGROUND

The management of anemia with erythropoietin (EPO) is important in the global treatment of dialysis patients. There is a general impression that anemia control with EPO is obtained more easily in peritoneal dialysis (PD) patients than in hemodialysis (HD) patients. The EPO administration route has to be the same to compare the two techniques adequately.

METHODS

To compare EPO action by subcutaneous (SC) route in HD and PD, 132 stable patients were recruited (HD: 69, PD: 63) from six centers, with adequate dialysis criteria (Kt/V in HD >1.3; weekly Kt/V in PD >1.8). In a cross-sectional study, the EPO dose/week, the number of EPO doses/week, hemoglobin (Hb), ferritin, transferrin saturation index (TS), albumin and intact parathyroid hormone (iPTH) were analyzed. Iron treatment, comorbidity and ACE inhibitors (ACEI) and angiotensin II antagonist (AIIA) treatment were recorded. A multivariate regression model was used in the statistical analysis.

RESULTS

The mean Hb level was the same in both groups, HD 11.6 (1.3) g/dL, PD 11.4 (1.4) g/dL, p=0.3. The SC, EPO doses required to obtain the Hb levels were higher in HD than in PD patients, with a difference of 64.3 u/Kg/week, statistically significant in the multivariate regression model (p=0.001, 95% CI 42.6-86.0). The number of EPO doses/week was also higher in HD patients (65% of HD patients with>> or = 3 doses, 19% of PD patients with three or more doses, p<0.001). TS was similar in both groups, while ferritin was higher in HD patients, with a higher percentage of HD patients using intravenous (i.v.) iron (HD 77% vs. PD 49%, p=0.001). Serum albumin and iPTH were lower in PD patients (p<0.001 and p=0.04, respectively), but the percentage of patients with intact parathyroid hormone (iPTH) >500 pg/mL was similar in both groups (HD 17%, PD 14%).

CONCLUSIONS

With the same administration route, PD patients showed a reduced EPO requirement, and less frequent EPO administration than HD patients, to obtain the same Hb level. No other factors, except those involved in better depuration of erythropoiesis inhibitors in PD, seemed responsible for the different EPO requirements.

OBJECTIVE

Postoperative hypocalcemia is common after total thyroidectomy, and perioperative monitoring of serum calcium levels is arguably the primary reason for overnight hospitalization. Confidently predicting which patients will not develop significant hypocalcemia may allow for a safe earlier discharge.

OBJECTIVE

To examine associations of patient characteristics with hypocalcemia, duration of hospitalization, and postoperative intact parathyroid hormone (IPTH) level after total thyroidectomy.

METHODS

Retrospective study of consecutive patients who underwent total thyroidectomy by a single high-volume surgeon between February 1, 2010, and November 30, 2012. Postoperative serum 25-hydroxyvitamin D (vitamin D), calcium, and IPTH levels were tested within 6 to 8 hours after surgery. Mild hypocalcemia was defined as any postoperative serum calcium level of less than 8.4 to 8.0 mg/dL. Significant hypocalcemia was defined as any postoperative serum calcium level of less than 8.0 mg/dL or the development of hypocalcemia-related symptoms.

METHODS

Total thyroidectomy.

METHODS

Associations of patient demographic and clinical characteristics and laboratory values with postoperative mild and significant hypocalcemia were examined using univariate analysis, and independent predictors of hypocalcemia, duration of hospitalization, and IPTH level were determined using multivariate analysis.

RESULTS

Overall, 304 total thyroidectomies were performed. Mild and significant hypocalcemia occurred in 68 (22.4%) and 91 (29.9%) patients, respectively, of which the majority were female (P = .003). The development of significant hypocalcemia was associated with postoperative IPTH level (P < .001). On multivariate analysis, males had a decreased risk of developing mild (odds ratio, 0.37 [95% CI, 0.16-0.85]) and significant (odds ratio, 0.57 [95% CI, 0.09-0.78]) hypocalcemia. Every 10-pg/mL increase in postoperative IPTH level predicted a 43% decreased risk of significant hypocalcemia (P < .001) and an 18% decreased risk of hospitalization beyond 24 hours (P = .03). Presence of malignant neoplasm carried a 27% risk of mild hypocalcemia (P = .02). There was a progressively increasing risk of lower IPTH levels for each parathyroid gland inadvertently resected or autotransplanted. Male sex and African American race were independently predictive of higher IPTH levels.

CONCLUSIONS

Low postoperative IPTH level, female sex, and presence of malignant neoplasm are all significant, independent predictors of hypocalcemia after total thyroidectomy. Clinicians should consider these variables when deciding how to best manage or prevent postoperative hypocalcemia.

OBJECTIVE

To assess (a) plasma osteopontin (pOPN) in a cohort of chronic kidney disease (CKD) patients; (b) the relationship between pOPN and aortic calcification and stiffness, and (c) the association between pOPN and the overall and cardiovascular mortality risk.

METHODS

pOPN, the abdominal aortic calcification score and pulse wave velocity (PWV) were determined in 94 CKD patients (68 ± 13 years; 60% males; 31% at CKD stages 2-3, 31% at stages 4-5, 38% at stage 5D), prospectively followed for mortality.

RESULTS

pOPN was higher in CKD patients than in controls. Interleukin (IL)-6 (r(2) = 0.086; p = 0.004), CRP (r(2) = 0.046; p = 0.038), iPTH (r(2) = 0.065; p = 0.014), albumin (r(2) = 0.210; p < 0.0001) and statin use (r(2) = 0.038; p = 0.059) were associated with pOPN. There was no association between pOPN and the aortic calcification score or PWV. During follow-up (969 ± 405 days), 32 patients died. In crude analysis, pOPN >167 ng/ml predicted overall and cardiovascular mortality (p = 0.02 and 0.01, respectively), but this effect was lost after adjustment for albumin or IL-6.

CONCLUSIONS

pOPN is elevated from the early stages of CKD onward. We found no associations between pOPN and the aortic calcification score or the PWV. The positive association between pOPN and clinical outcomes was dependent of the patients' inflammatory status.

BACKGROUND

Loss of renal function is accompanied by progressive increase in serum levels of intact parathyroid hormone (iPTH) in patients with end-stage renal disease (ESRD). There is a paucity of data regarding levels of PTH-(1-84) and its large carboxyl-terminal fragments (large C-PTH fragments) and progressive loss of kidney function in patients with chronic kidney disease (CKD). The current study was undertaken to describe the glomerular filtration rate (GFR)-dependent plasma concentrations of PTH-(1-84) and related large C-PTH fragments in adult patients with CKD by using different commercially available PTH assays.

METHODS

We studied 80 Caucasian patients with CKD stages 1-5 without renal replacement therapy. Creatinine clearance was calculated by the Modification of Diet in Renal Disease (MDRD) formula. Levels of iPTH were determined by second-generation assays (iPTH Elecsys system, Roche Diagnostics; DUO total iPTH, Scantibodies Laboratory, Inc.; iPTH, Nichols Institute Diagnostics). Third-generation assays were used to measure PTH-(1-84) (CAP (cyclase activating PTH), Scantibodies; Bio-Intact PTH, Nichols). Levels of large C-PTH fragments and ratios of PTH-(1-84)/large C-PTH fragments were calculated and statistical analyses performed.

RESULTS

Levels of iPTH and PTH-(1-84) showed CKD stage-dependent increases. Variations among the assays increased with progressive loss of kidney function. The assay from Scantibodies showed a GFR-dependent decrease of the ratio 1-84 PTH / large C-PTH fragment that was not observed with the Nichols assay.

CONCLUSIONS

Increasing variations among the assays with progression of CKD emphasize the fact that the interpretation of measurements must take into consideration the specific assay. We found evidence for a possible preferential increase of the level of large C-PTH fragments over 1-84 PTH in a CKD stage-dependent manner (Scantibodies). The clinical implications of this finding have to be further evaluated by bone biopsy studies.

UNASSIGNED

Secondary hyperparathyroidism (SHPT) is a major complication associated with chronic kidney disease. We evaluated the efficacy and safety of etelcalcetide (ONO-5163/AMG 416), a novel intravenous calcimimetic, in Japanese haemodialysis patients with SHPT.

UNASSIGNED

In this phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel-group study, etelcalcetide was administered three times per week at an initial dose of 5 mg, and subsequently adjusted to doses between 2.5 and 15 mg at 4-week intervals for 12 weeks. A total of 155 SHPT patients with serum intact parathyroid hormone (iPTH) levels ≥300 pg/mL were assigned to receive etelcalcetide (n = 78) or placebo (n = 77). The primary endpoint was the proportion of patients with decreased serum iPTH to the target range proposed by the Japanese Society for Dialysis Therapy (60-240 pg/mL). The major secondary endpoint was the proportion of patients with ≥30% reductions in serum iPTH from baseline.

UNASSIGNED

The proportion of patients meeting the primary endpoint was significantly higher for etelcalcetide (59.0%) versus placebo (1.3%). Similarly, the proportion of patients meeting the major secondary endpoint was significantly higher for etelcalcetide (76.9%) versus placebo (5.2%). Serum albumin-corrected calcium, phosphorus and intact fibroblast growth factor-23 levels were decreased in the etelcalcetide group. Nausea, vomiting and symptomatic hypocalcaemia were mild with etelcalcetide. Serious adverse events related to etelcalcetide were not observed.

UNASSIGNED

This study demonstrated the efficacy and safety of etelcalcetide. As the only available intravenous calcium-sensing receptor agonist, etelcalcetide is likely to provide a new treatment option for SHPT in haemodialysis patients.

Osteopontin (OPN) and bone sialoprotein (BSP) are coexpressed in osteoblasts and osteoclasts, and display overlapping properties. We used daily injection of parathyroid hormone 1-84 (iPTH) over the calvaria of BSP knockout (-/-) mice to investigate further their functional specificity and redundancy. iPTH stimulated bone formation in both +/+ and -/- mice, increasing to the same degree periosteum, osteoid and total bone thickness. Expression of OPN, osterix, osteocalcin (OCN) and DMP1 was also increased by iPTH in both genotypes. In contrast to +/+, calvaria cell cultures from -/- mice revealed few osteoblast colonies, no mineralization and little expression of OCN, MEPE or DMP1. In contrast, OPN levels were 5× higher in -/- versus +/+ cultures. iPTH increased alkaline phosphatase (ALP) activity in cell cultures of both genotypes, with higher OCN and the induction of mineralization in -/- cultures. siRNA blocking of OPN expression did not alter the anabolic action of the hormone in BSP +/+ calvaria, while it blunted iPTH effects in -/- mice, reduced to a modest increase in periosteum thickness. In -/- (not +/+) cell cultures, siOPN blocked the stimulation by iPTH of ALP activity and OCN expression, as well as the induction of mineralization. Thus, full expression of either OPN or BSP is necessary for the anabolic effect of PTH at least in the ectopic calvaria injection model. This suggests that OPN may compensate for the lack of BSP in the response to this hormonal challenge, and provides evidence of functional overlap between these cognate proteins.

The vitamin D status of vegetarians was studied in the winter. The groups studied were strict vegetarians (G1), lactovegetarians (G2), lactoovovegetarians eating some fish (G3), and vegetarians who were taking vitamin D supplements or who had been exposed to abundant sunlight during the last 6 mo (G4). A group of healthy women served as control subjects (C). The serum 25-hydroxyvitamin D [25(OH)D] concentration was significantly lower, the serum intact parathyroid hormone (S-iPTH) concentration significantly higher, and the dietary vitamin D intake significantly lower in G1 than in C. S-iPTH correlated negatively with serum 25(OH)D and dietary calcium intake. In conclusion, white strict vegetarians are at risk of vitamin D deficiency, at least in the winter, primarily because of a low dietary vitamin D intake, despite a normal sunlight exposure in summer. Low serum 25(OH)D concentrations are accompanied by high S-iPTH concentrations, which also are affected by a low calcium intake. The effect of these changes on bone health remains to be evaluated.

Duchenne Muscular Dystrophy (DMD) is a progressive muscle disorder caused by genetic mutations of the dystrophin encoding gene. In the absence of functional dystrophin, DMD patients suffer from muscle inflammation and wasting, as well as compromised bone health with increased risk of fracture. The use of high dose glucocorticoids (GC) as the standard therapy also contributes to bone fragility. This study examined the effects of intermittent, daily administered parathyroid hormone (iPTH), an approved bone anabolic therapy, on growing bone and dystrophic muscle in the presence and absence of prednisone treatment using the Mdx mouse model of DMD. Five-weeks of prednisone treatment in Mdx mice decreased cortical bone thickness and area (p < 0.001), with a large increase in endocortical osteoclasts that were significantly improved by PTH treatment (p < 0.001). GC-induced decreases in cortical bone toughness and modulus were improved with iPTH therapy (p < 0.05). Mdx mice showed significantly less bone mass in trabecular compartments of lumbar vertebrae and iPTH treatment, with or without glucocorticoids, significantly improved structural and material properties of this bone. Prednisone improved grip strength and endurance of treadmill running, which were maintained and further improved, respectively, in co-treated Mdx mice. Altogether, our study demonstrates that iPTH therapy significantly ameliorated GC-induced bone loss and maintained or further enhanced the positive effects of GCs on dystrophic muscle function. These findings give insight into the potential for use of teriparatide to treat growing bone in children with DMD.

Teriparatide is a bone anabolic treatment for osteoporosis, modeled in animals by intermittent PTH (iPTH) administration, but the cellular and molecular mechanisms of action of iPTH are largely unknown. Here, we show that Teriparatide and iPTH cause a ~two-threefold increase in the number of regulatory T cells (Tregs) in humans and mice. Attesting in vivo relevance, blockade of the Treg increase in mice prevents the increase in bone formation and trabecular bone volume and structure induced by iPTH Therefore, increasing the number of Tregs is a pivotal mechanism by which iPTH exerts its bone anabolic activity. Increasing Tregs pharmacologically may represent a novel bone anabolic therapy, while iPTH-induced Treg increase may find applications in inflammatory conditions and transplant medicine.

OBJECTIVE

The objective of the study was to compare the efficacy and safety of oral paricalcitol with oral calcitriol for treating secondary hyperparathyroidism.

METHODS

We conducted the first multicenter open-labelled parallel group randomized controlled trial in 66 patients on dialysis. Patients were randomized to paricalcitol or calcitriol at a 3:1 dose ratio and adjusted to maintain intact parathyroid hormone (iPTH) level between 150-300 pg/mL, serum calcium ≤2.74 mmol/L and calcium-phosphate product ≤5.63 mmol(2) /L(2). The primary end point was the proportion of patients who achieved >30% reduction in iPTH.

RESULTS

At 24 weeks, 22 (61.1%) patients in the paricalcitol and 22 (73.3%) in the calcitriol group had achieved the primary end-point (P-value = 0.29). The cumulative proportion of patients who achieved the end-point at 6 weeks, 12 weeks and 24 weeks were 50%, 80.6% and 86.1%, respectively, in paricalcitol and 53.3%, 86.7% and 86.7%, respectively, in the calcitriol group (P-value = 0.67). Median time to the end-point was 6 weeks in both groups. There were no significant differences in iPTH level at any time during the study. The median reduction in iPTH at 24 weeks was 48.4% in the paricalcitol group and 41.9% in the calcitriol group (P-value = 0.6). The median maximal iPTH reduction was 77.1% (paricalcitol) and 83.7% (calcitriol), P-value = 0.3. Serum calcium and incidence of hypercalcaemia did not differ between groups. 16.7% of patients in both groups had at least one episode of hypercalcaemia (serum calcium >2.74 mmol/L). Other adverse events were similar between groups.

CONCLUSIONS

Our study suggests that oral paricalcitol has similar efficacy and safety to oral calcitriol.

OBJECTIVE

Data are limited regarding the use of paricalcitol in calcitriol-resistant patients with secondary hyperparathyroidism (SHPT). We aimed to evaluate the effects of paricalcitol in calcitriol-resistant hemodialysis patients with SHPT.

METHODS

This is a 12-month, open-label, prospective study. Forty patients with calcitriol-resistant and/or calcitriol-intolerant SHPT were included. After a washout period, all patients converted to paricalcitol with a 1:3 conversion ratio. Serum calcium and phosphorus were monitored monthly, while serum intact parathyroid hormone (iPTH) once in every 3 months. Paricalcitol dose was reduced or discontinued in case of hypercalcemia and/or hyperphosphatemia. Pre- and posttreatment electrolyte and iPTH values were compared with Student's t-test and Wilcoxon signed-rank test, respectively.

RESULTS

Forty patients completed the study. Mean initiation dose of paricalcitol was 23 ± 7 μg/week. Mean serum calcium was 8.9 ± 0.8 mg/dL at baseline and 9.4 ± 0.7 mg/dL at study end (p = 0.07). Mean monthly serum phosphorus levels stayed stable. Paricalcitol was effective in reducing iPTH levels when compared with pretreatment values (747.9 ± 497.2 pg/mL, 307.3 ± 417.1 pg/mL, respectively; p < 0.001). Thirty-two patients had to discontinue intravenous (IV) paricalcitol at some time during their treatment. Main reasons for discontinuation were as follows: hyperphosphatemia (58%), hypercalcemia (25%), and iPTH < 150 pg/mL (17%).

CONCLUSIONS

Paricalcitol was found to be effective in reducing iPTH levels in calcitriol-resistant patients with SHPT despite relatively frequent drug discontinuation rates.

OBJECTIVE

To evaluate the relationship between the severity of secondary hyperparathyroidism (SHPT) - defined in terms of baseline plasma intact parathyroid hormone (iPTH) level - and the magnitude of response to cinacalcet.

METHODS

In this post hoc analysis, data were pooled from three randomized, placebo-controlled trials in which dialysis patients with iPTH ≥ 300 pg/ml were dose-titrated with cinacalcet or placebo in addition to conventional treatment to achieve iPTH ≤ 250 pg/ml. In 953 patients analyzed (cinacalcet, 545; placebo, 408), baseline iPTH levels were categorized in 100 pg/ml intervals (300 - ≥ 1,000 pg/ml), and the impact of baseline iPTH on changes in iPTH, phosphate (P), calcium (Ca) and calcium- phosphate product (Ca × P) was evaluated.

RESULTS

Cinacalcet reduced iPTH (47% reduction), P (9%), Ca (7%), and Ca × P (15%) across all subgroups. For patients receiving cinacalcet, the mean percentage reduction from baseline in iPTH varied from 35 to 55%, being consistently decreased across the severity subgroups. The mean absolute change in iPTH was more pronounced in patients with higher baseline iPTH levels, particularly in the ≥ 1,000 pg/ml subgroup vs. the other subgroups. However, as baseline iPTH levels increased, iPTH ≤ 250 pg/ml was achieved in fewer patients. A trend towards greater absolute change from baseline was observed for P in patients with more severe disease (iPTH ≥ 800 pg/ml) treated with cinacalcet compared with patients with less severe disease (iPTH 300 - < 800 pg/ml).

CONCLUSIONS

Cinacalcet lowers plasma iPTH and serum P, Ca and Ca × P levels in dialysis patients with SHPT, regardless of disease severity. Patients with more severe disease experienced greater reductions in PTH and P, but fewer achieved iPTH ≤ 250 pg/ml by the efficacy assessment phase. Use of cinacalcet when baseline PTH is lower may result in more stable control of SHPT and help to control bone and mineral alterations.

Pentosidine is an advanced glycation end product (AGE). The present study was undertaken to investigate the association of serum pentosidine with carotid distensibility as a measure of arterial stiffness in hemodialysis patients. One hundred and three patients on maintenance hemodialysis were recruited. The distensibility coefficient of the common carotid artery was evaluated by an ultrasonic phase-locked echo-tracking system. Serum pentosidine was measured by competitive enzyme-linked immunosorbent assay. Serum albumin, lipid profile, calcium, phosphorus, intact parathyroid hormone (iPTH), high-sensitivity C-reactive protein (hs-CRP), and oxidized low-density lipoprotein (ox-LDL) levels were also measured. Correlation was determined by linear and multiple stepwise regression analysis. Serum pentosidine level studied in hemodialysis patients was 0.54 +/- 0.13 microg/mL. No significant difference in serum pentosidine level was noted between patients with and without diabetes (0.59 +/- 0.10 microg/mL vs. 0.53 +/- 0.13 microg/mL, P = 0.062) as well as between patients with and without prior cardiovascular disease (CVD) history (0.56 +/- 0.14 microg/mL vs. 0.53 +/- 0.12 microg/mL, P = 0.206). In multivariate regression analysis, only age (beta = 0.363, P < 0.001) and ox-LDL (beta = 0.262, P = 0.004) were identified as independent determinants for serum pentosidine. Serum pentosidine was significantly correlated with carotid distensibility (r = -0.387, P < 0.001), as well as age, ox-LDL, and hs-CRP. After adjustment for age, blood pressure, history of diabetes, prior CVD history, lipid profile, calcium, phosphorus, iPTH, hs-CRP, and ox-LDL, serum pentosidine was still negatively correlated with distensibility (beta = -0.175, P = 0.044). Serum pentosidine was independently associated with carotid distensibility in hemodialysis patients. This finding suggested that the accumulation of AGE might be an important pathway in the development of arterial stiffness in end-stage renal disease.

Degenerative disc disease (DDD) is associated with intervertebral disc degeneration of spinal instability. Here, we report that the cilia of nucleus pulposus (NP) cells mediate mechanotransduction to maintain anabolic activity in the discs. We found that mechanical stress promotes transport of parathyroid hormone 1 receptor (PTH1R) to the cilia and enhances parathyroid hormone (PTH) signaling in NP cells. PTH induces transcription of integrin αvβ6 to activate the transforming growth factor (TGF)-β-connective tissue growth factor (CCN2)-matrix proteins signaling cascade. Intermittent injection of PTH (iPTH) effectively attenuates disc degeneration of aged mice by direct signaling through NP cells, specifically improving intervertebral disc height and volume by increasing levels of TGF-β activity, CCN2, and aggrecan. PTH1R is expressed in both mouse and human NP cells. Importantly, knockout PTH1R or cilia in the NP cells results in significant disc degeneration and blunts the effect of PTH on attenuation of aged discs. Thus, mechanical stress-induced transport of PTH1R to the cilia enhances PTH signaling, which helps maintain intervertebral disc homeostasis, particularly during aging, indicating therapeutic potential of iPTH for DDD.

Ageing is associated with a gradual bone loss and physical activity has been suggested as practical strategy for a non-pharmacological prevention of osteoporosis. However, until now, the specific mechanism by which physical activity affects bone tissue is not thoroughly understood. The aim of this study was to evaluate the effect of strenuous exercise on bone metabolism as a function of age and fitness level. Eighteen physically highly active elderly participants (mean age 71.7+/-7.3 years, HAcEl group), 18 moderately active elderly participants (mean age 71.9+/-8.6 years, ModEl group) and 9 young physically active participants (mean age 25.8+/-2.3 years, AcYo) participated in this study. Concentrations of plasma ionised calcium (iCa), serum parathyroid hormone (iPTH), 25-hydroxy-vitamin D [25(OH)D], and 1,25-dihydroxy-vitamin D3 [1,25(OH)(2)D3] as well as the bone biochemical markers type-I collagen C-telopeptide (CTX) for bone resorption and osteocalcin (OC) and bone alkaline phosphatase (B-ALP) for bone formation, were analyzed before and after a maximal incremental exercise test. In all groups, iCa decreased significantly (p<0.05 for ModEl and AcYo and p<0.001 for HAcEl) while iPTH increased significantly (p<0.01 for ModEl and HAcEl and p<0.001 for AcYo) after exercise. The levels of 1,25(OH)(2)D3, OC and CTX remained unchanged, while 25(OH)D decreased only in HAcEl group while B-ALP increased in ModEl group. In conclusion, strenuous exercise disturbed calcium homeostasis, mainly the iCa/iPTH equilibrium independently of gender, age or fitness level of the participants while no immediate effect on bone turnover was observed.

OBJECTIVE

The study aimed to investigate the effect of high dose radioactive iodine (RAI) on parathyroid function in patients with differentiated thyroid cancer.

METHODS

Nineteen patients (8 men/11 women, age 46.5 +/- 13.2 years) undergoing RAI for thyroid remnant ablation were enrolled in the study. The biochemical parameters related to parathyroid function [serum calcium (Ca), phosphate (P), creatinine (Cr), alkaline phosphatase (ALP), intact parathyroid hormone (iPTH), urinary Ca, cAMP concentrations and the maximum tubular capacity for phosphate per unit volume of glomerular filtrate (TmP/GFR)] were evaluated at baseline and at the 1st, 3rd, 6th and 12th months of RAI administration. SPSS 15.0 was used for statistical analysis.

RESULTS

For all patients, thyroid-stimulating hormone levels were >30 U/ml at baseline and <0.1 U/ml at the following visits. Serum iPTH levels were decreased significantly at the 6th month and reached basal levels at the 12th month (baseline vs. 6th p = 0.027, 1st vs. 6th p = 0.011, 3rd vs. 6th p = 0.047, 3rd vs. 12th p = 0.014, 6th vs. 12th p = 0.001). At the 6th month, P and TmP/GFR levels were higher (p = 0.036, 0.017, respectively), and urinary cAMP measurements were lower (p = 0.020) compared to those of the 1st month. No difference was detected concerning the other parameters. Serum Ca levels decreased below 2.1 mmol/l in several patients (n = 5 at 1st month, n = 4 at 3rd month, n = 8 at 6th month and n = 3 at 12th month) without clinical symptoms.

CONCLUSIONS

The study indicated a transient decline in PTH levels at the 6th month following RAI therapy. Although this decrease did not cause symptoms in any of the present cases, this pattern might be important especially in individuals with diminished parathyroid background.

There is a close relationship between hematopoietic bone marrow and bone cells. Thus, the profound derangement of hematopoiesis in myelodysplastic syndromes (MDS) might be expected to affect bone cell function. We studied the dynamic histomorphometric changes in bone in 22 MDS patients to examine this relationship and analyze the influence of hematological disease on bone remodeling. Bone-regulating hormones and histomorphometry of undecalcified transiliac bone biopsies, after double tetracycline labeling, were studied. Serum calcium, phosphorus, creatinine, alkaline phophatase, osteocalcin, iPTH, 25(OH)D3, 1,25(OH)2D3, hydroxyprolinuria, and calcium/creatinine ratio in urine were normal compared with controls. Histomorphometry showed a significant decrease in osteoblast surface (Ob.S/BS) (0.30 +/- 0.40 vs. 0.8 +/- 1.1, p = 0.031), wall thickness (W.Th), (22.03 +/- 5.5 vs. 31.8 +/- 5.8, p < 0.005), osteoclast number (N.Oc/T.Ar) (0.004 +/- 0.01 vs. 0.017 +/- 0.01, p = 0.03), mineral apposition rate (MAR) (0.16 +/- 0.15 vs. 0.53 +/- 0.19, p < 0.005), bone formation rate, surface referent (BFR/BS) (0.004 +/- 0.10 vs. 0.016 +/- 0.016, p = 0.009), and activation frequency (Ac.f) (0.06 +/- 0.07 vs. 0.21 +/- 0.23, p = 0.008). An increase in mineralization lag time (MLT) (119.2 +/- 78.6 vs. 29.6 +/- 77, p < 0.005), (mean +/- SD, unpaired Student t-test) was observed. Bone volume (BV/ TV), eroded surfaces (ES/BS), and osteoid thickness (O.Th) remained unchanged. This picture of adynamic bone with decreased mineral apposition rate and markedly decreased osteoclast number is a characteristic finding in MDS patients. Thus, bone histomorphometric finding in MDS patients show the relationships and interactions between hematopoietic and bone cells.

OBJECTIVE

Blood levels of 25-hydroxyvitamin D [25(OH) D] are reduced in patients with nephrotic syndrome (NS). The lowering is thought to be due to urinary loss of vitamin D binding protein (DBP). A link between vitamin D deficiency and bone disease or markers of mineral metabolism has not yet been shown in NS. We hypothesized that alterations in bioavailable vitamin D levels might be linked to these abnormalities in NS.

METHODS

We measured circulating levels of 25(OH)D, 1,25-dihydroxyvitamin D [1,25(OH)2 D], DBP, serum albumin and intact parathyroid hormone (iPTH) in 106 adults with sporadic idiopathic NS and 40 healthy controls. Bioavailable vitamin D was calculated from previously validated formulae. Bone mineral density (BMD) was measured at left hip (neck of femur) by DEXA.

RESULTS

Compared to healthy controls, total and bioavailable 25(OH)D levels were significantly reduced in patients with NS as compared to healthy controls. Among the nephrotic patients, BMD was positively correlated with bioavailable 25(OH)D (r = 0.358; P = 0.0002) but not with total 25(OH)D (r = 0.174; P = 0.079). Total 1,25(OH)2 D and bioavailable 1,25(OH)2 D did not correlate with BMD (r = 0.131; P = 0.206 and r = 0.107, P = 0.295). Bioavailable 25(OH)D levels showed a strong inverse correlation with iPTH on univariate (r = -0.457; P < 0.0001) and multivariate (β=-0.453, P < 0.0001) analyses.

CONCLUSIONS

We conclude that bioavailable 25(OH)D is a better measure of vitamin D status with respect of BMD and mineral metabolism in patients of nephrotic syndrome.

We explored the effects of atorvastatin on BMD and biochemical markers of bone metabolism in a 1-year, prospective, randomized controlled study. 64 male patients with osteopenia and mild dyslipidemia (mean age 80.1±6.6 years) were randomized to a 1-year atorvastatin treatment or control. BMD of hip and lumbar spine was measured with dual-energy X-ray absorptionmetry (DXA). Bone metabolic markers including resorption markers β-c-terminal telopeptide of type I collagen (CTx), formative markers osteocalcin (OC), 25-hydroxyvitamin D (25(OH)D) were measured with electrochemiluminescence immunoassay (ECLIA). Other bone metabolism markers including intact parathyroid hormone (iPTH) and testosterone were measured with chemiluminescence enzyme immunoassay (CLEIA). Levels of serum lipid and biochemical parameters were measured with automatic biochemical analyzer. All the parameters were recorded at baseline, and at 6 and 12 months, respectively. Compared with the control group, the atorvastatin treatment group showed significant reduction of triglyceride (TG, P<0.01) and low-density lipoprotein cholesterol (LDL-C, P<0.01). At 12 month, total hip BMD in atorvastatin group was significantly higher (P<0.01) compared with the control group, while there were no similar effect on femoral neck or lumbar spine between the two groups (P=0.48 and 0.53 respectively). Meanwhile, CTx significantly reduced in atorvastatin treatment group (P<0.001) compared with baseline. Our findings suggest that in elderly male patients with osteopenia and mild dyslipidemia, therapeutic doses of atorvastatin were associated with positive effects on BMD, probably mediated by suppressed bone resorption.

Preclinical studies in cell culture systems as well as in whole animal chronic kidney disease (CKD) models showed that parathyroid hormone (PTH), oxidized at the 2 methionine residues (positions 8 and 18), caused a loss of function. This was so far not considered in the development of PTH assays used in current clinical practice. Patients with advanced CKD are subject to oxidative stress, and plasma proteins (including PTH) are targets for oxidants. In patients with CKD, a considerable but variable fraction (about 70 to 90%) of measured PTH appears to be oxidized. Oxidized PTH (oxPTH) does not interact with the PTH receptor resulting in loss of biological activity. Currently used intact PTH (iPTH) assays detect both oxidized and non-oxPTH (n-oxPTH). Clinical studies demonstrated that bioactive, n-oxPTH, but not iPTH nor oxPTH, is associated with mortality in CKD patients.