BACKGROUND

The use and effectiveness of cinacalcet in 'real-world' clinical practice was investigated in a pan-European observational study in dialysis patients with secondary hyperparathyroidism (SHPT) of varying severity.

METHODS

Adult patients with chronic kidney disease on dialysis who had initiated cinacalcet treatment were enrolled. Data were collected 6 months before initiating cinacalcet, at baseline (initiation of cinacalcet) and up to 12 months after cinacalcet initiation.

RESULTS

A total of 1865 patients [mean (SD) age 58 (15) years] were enrolled from 187 sites in 12 countries. Most patients had a dialysis vintage of>> or =1 year (1-5 years, n = 833; >5 years, n = 748 versus <1 year, n = 265). The patients generally had severely uncontrolled intact parathyroid hormone (iPTH) serum levels (median 721 pg/ml) and elevated phosphorus (median 5.9 mg/dl) and calcium (median 9.6 mg/dl) at baseline, despite being prescribed conventional therapies. The proportions of patients achieving the recommended [NKF-K/DOQI(TM) (KDOQI(TM))] targets increased from baseline [4%, 39%, 40% and 46% for iPTH, phosphorus, calcium and calcium-phosphorus product (Ca x P), respectively] to Month 12 (28%, 48%, 51% and 68%, respectively). At Month 12, 18% of patients had achieved the combined target for iPTH + Ca x P compared with 2% at baseline. Most patients (65%) received <60 mg/day cinacalcet at Month 12. Vitamin D sterol use remained fairly stable throughout the study. There was a 13% decrease in prescribed sevelamer; use of calcium-based phosphate binders increased by 5.6%. There was no unexpected safety or tolerability concerns.

CONCLUSIONS

This analysis of current European clinical practice shows that-consistent with findings from randomized controlled trials and retrospective observational studies-cinacalcet improves attainment of KDOQI bone metabolism targets in dialysis patients with various stages of SHPT.

Parathyroid hormone (PTH), the major calcium-regulating hormone, and norepinephrine (NE), the principal neurotransmitter of sympathetic nerves, regulate bone remodeling by activating distinct cell-surface G protein-coupled receptors in osteoblasts: the parathyroid hormone type 1 receptor (PTHR) and the β(2)-adrenergic receptor (β(2)AR), respectively. These receptors activate a common cAMP/PKA signal transduction pathway mediated through the stimulatory heterotrimeric G protein. Activation of β(2)AR via the sympathetic nervous system decreases bone formation and increases bone resorption. Conversely, daily injection of PTH (1-34), a regimen known as intermittent (i)PTH treatment, increases bone mass through the stimulation of trabecular and cortical bone formation and decreases fracture incidences in severe cases of osteoporosis. Here, we show that iPTH has no osteoanabolic activity in mice lacking the β(2)AR. β(2)AR deficiency suppressed both iPTH-induced increase in bone formation and resorption. We showed that the lack of β(2)AR blocks expression of iPTH-target genes involved in bone formation and resorption that are regulated by the cAMP/PKA pathway. These data implicate an unexpected functional interaction between PTHR and β(2)AR, two G protein-coupled receptors from distinct families, which control bone formation and PTH anabolism.

In this study of 242 patients with renal failure, women, patients with diabetes, and patients on peritoneal dialysis had the highest risk of 25-hydroxyvitamin D deficiency. Levels correlated positively to BMD Z scores, and hip BMD was inversely related to prevalent fracture. Increasing 25-hydroxyvitamin D levels may benefit these patients.

BACKGROUND

25-Hydroxyvitamin D deficiency (<37 nM) is common in patients with chronic kidney disease (CKD) stage 5 (glomerular filtration rate < 15 ml/min/1.73 m(2) or on dialysis), but it is unclear if this deficiency is associated with bone disease and if supplementation is warranted.

METHODS

Blood samples were collected on 242 patients with CKD stage 5 caused by type 1 diabetes (33%), type 2 diabetes (2%), and other causes (65%), who were about to undergo kidney or kidney pancreas transplantation. Prevalent spinal fracture was assessed by X-ray and BMD by DXA.

RESULTS

25-Hydroxyvitamin D deficiency was present in 28% of patients with diabetes versus 12% without (p < 0.0001). Patients on peritoneal dialysis (PD) had lower levels of 25-hydroxyvitamin D than patients on hemodialysis (HD; 49 +/- 26 versus 77 +/- 34 nM; p < 0.0001), and women had lower levels than men (51 +/- 25 versus 77 +/- 35 pM; p < 0.0001). BMD Z scores were within 1 SD of the mean at all sites, except in patients with diabetes (femoral neck Z score, -1.07 +/- 1.2; p < 0.0001) and patients who had undergone parathyroidectomy (lumbar spine Z score, 1.03 +/- 1.34, femoral neck Z score, 1.24 +/- 1.35; p < 0.001 and p < 0.0001, respectively). In multiple stepwise linear regression analysis, levels of 25-hydroxyvitamin D correlated positively and intact PTH (iPTH) correlated negatively to Z scores at the lumbar spine and wrist. Time on dialysis correlated positively to Z scores at the femoral neck and lumbar spine. Diabetes and serum alkaline phosphatase levels correlated negatively with Z scores at the femoral neck. Lower femoral neck BMD was associated with an increased prevalence of vertebral fracture and fragility fracture at any site (p = 0.03 and p < 0.03, respectively).

CONCLUSIONS

This study of patients with CKD stage 5 identifies women, patients with diabetes, and patients on PD as being at particular risk of 25-hydroxyvitamin D deficiency. We describe positive associations of 25-hydroxyvitamin D levels and BMD Z scores and an association between femoral neck BMD and fragility fracture at any site. Treatment to improve 25-hydroxyvitamin D levels may benefit these patients.

BACKGROUND

Vitamin D (25-hydroxyvitamin D, 25(OH)D) deficiency, hypovitaminosis D, is highly prevalent in chronic kidney disease patients and is potentially involved with complications in the hemodialysis (HD) population. The aim of this study was to evaluate the impact of cholecalciferol supplementation on biomarkers of mineral metabolism, inflammation, and cardiac function in a group of HD patients presenting with hypovitaminosis D and low intact parathyroid hormone (iPTH) levels.

METHODS

HD patients with iPTH levels of <300 pg/mL, not receiving vitamin D therapy, and presenting with 25(OH)D levels of <30 ng/mL were enrolled in this prospective study. Oral cholecalciferol was prescribed once a week in the first 12 weeks (50,000 IU) and in the last 12 weeks (20,000 IU) of the study. High-sensitivity C-reactive protein, interleukin-6, and serum albumin were used as inflammatory markers. Echocardiograms were performed on a midweek interdialytic day at baseline and after 6 months of cholecalciferol supplementation.

RESULTS

In all, 30 patients were included in the final analysis. We observed a significant increase in serum 25(OH)D levels after 3 months (46.2 ± 14.4 ng/mL vs. 18.1 ± 6.6 ng/mL; P < .001) and after 6 months (40.4 ± 10.4 ng/mL vs. 18.1 ± 6.6 ng/mL; P < .001) of cholecalciferol supplementation. There were no significant changes in alkaline phosphatase, iPTH, phosphorus, and serum albumin levels, but there was a slight but significant increase in calcium levels after 6 months of cholecalciferol supplementation (9.4 ± 0.6 mg/dL vs. 9.0 ± 0.6 mg/dL; P = .02). Additionally, we observed a significant reduction in high-sensitivity C-reactive protein levels after 3 months (median: 0.62 [0.05 to 29.6] mg/L vs. 0.32 [0.02 to 3.13] mg/L; P = .02) and after 6 months (median: 0.62 [0.05 to 29.6] mg/L vs. 0.50 [0.02 to 5.66] mg/L; P = .04) of cholecalciferol supplementation, as well as a significant reduction in interleukin-6 levels (median: 6.44 pg/mL vs. 3.83 pg/mL; P = .018) after 6 months of supplementation. Left ventricular mass index was significantly reduced at the end of supplementation (159 ± 55 g/m(2) vs. 175 ± 63 g/m(2); P = .03).

CONCLUSIONS

Cholecalciferol supplementation in HD patients was found to be safe and efficient to correct hypovitaminosis D and established little impact on mineral metabolism markers. Additionally, we observed a reduction in important surrogate markers of cardiovascular risk, namely systemic inflammation and left ventricular hypertrophy, suggesting an anti-inflammatory action and possibly an improvement of cardiac dysfunction.

BACKGROUND

Vitamin D insufficiency is common in elderly adults, and leads to secondary hyperparathyroidism, bone loss, muscle weakness, and osteoporotic fractures.

OBJECTIVE

To evaluate the relation between vitamin D nutritional status and muscle function and muscle strength in women aged over 65 years.

METHODS

Fifty-four postmenopausal women from Buenos Aires (latitude 34° S), average age (X±DS) 71±4, were included in the study. Determinations of serum calcium, phosphate, 25 hydroxyvitamin D (25OHD), intact parathormone (iPTH) and calciuria / creatininuria ratio in 24-hour urine samples were performed. Muscle function was assessed by means of walking-speed test, standing balance, and sit-to-stand tests. Lower extremity muscle strength was determined using a manual dynamometer.

RESULTS

25OHD levels ≥20 ng/ml were found to be associated with better lower extremity muscle function and strength. Forty- six % of participants had 25OHD levels ≥20 ng/ml. Women with 25OHD levels ≥20 ng/ml scored higher on the muscle function tests (11.2±0.9 vs.10.0±2.1; p<0.003) and had stronger knee extensor (13.4±2.7 vs.11.6±2.5 Kg.; p<0.03) and hip abductor (8.3±2.7 vs. 7.3±3.1 Kg; p<0.04) muscles; strength of their hip flexors tended to be higher but did not reach significantly different values (17.0±3.3 vs. 15.4±2.8 Kg.; 0.1>p>0.05). Negative correlation was observed between iPTH and muscle function (r= -0.436; p<0.02).

CONCLUSIONS

25OHD levels ≥20 ng/ml are needed for a better muscle function and strength. Assessing vitamin D nutritional status in adults aged ≥ 65 years would allow correcting hypovitaminosis D and improve muscle function and strength.

Vitamin D deficiency, which is usually detected by using immunoassays or the more reliable liquid chromatography tandem mass spectrometry (LC-MS/MS) methods, has recently been considered a public health problem worldwide. However, the vitamin D status in Chinese populations, as measured using the LC-MS/MS method, is not available. The objective of this multicenter study was to determine the vitamin D status and prevalence of vitamin D deficiency by using a reliable method in 5 large cities in China. From May 1 to September 31, 2013, we conducted a multicenter study on 2173 apparently healthy adults who were recruited from 5 Chinese cities. The 25-hydroxyvitamin D 25OHD2 and 25OHD3 levels were measured using the LC-MS/MS method. Intact parathyroid hormone (iPTH), calcium, phosphorus, and alkaline phosphate levels were also measured using an automatic analyzer. The mean 25OHD level of all participants was 19.4 ± 6.4 ng/mL (2.5-97.5%: 7.9-32.6 ng/mL), and only 109 (5.0%) participants had a 25OHD2 level >2.5 ng/mL (maximum, 22.4 ng/mL). In this study, the prevalence of severe vitamin D deficiency (<10 ng/mL), vitamin D deficiency (10-20 ng/mL), vitamin D insufficiency (20-30 ng/mL), and vitamin D sufficiency (>30 ng/mL) was 5.9%, 50.0%, 38.7%, and 5.4%, respectively. Women had a significant higher rate of deficiency than men (66.3% vs 45.3%, P < 0.01). Participants aged 18 to 39 years had a lower 25OHD level than elderly individuals (>59 years). Lifestyle may influence the 25OHD level more than the latitude, with participants in Dalian having the highest 25OHD level and the lowest deficiency rate. The serum iPTH level showed a significant negative correlation with the 25OHD level (r = -0.23, P < 0.01) after correcting for age and sex. In conclusion, the present study evaluated the vitamin D status using a reliable method, and our results indicate that vitamin D deficiency is prevalent among all age groups in China, especially among younger adults. We also observed significant differences in the 25OHD levels according to sex, age, and region among apparently healthy individuals.

Parathyroid carcinoma is a rare tumor and its clinical course is variable. Differentiation of patients with parathyroid carcinoma from those with parathyroid adenoma is often difficult both preoperatively and at operation. For good results, the surgeon must recognize this disorder and perform an en bloc resection at the initial surgery. A neck dissection is necessary only when there is evidence of regional node metastases. After surgery, periodic follow-up of the serum calcium and iPTH levels is essential. When hypercalcemia recurs or the serum iPTH increases, localization studies with the use of thallium-201 scanning help detect local recurrence and regional lymph node metastases, but unfortunately, this method often fails to localize pulmonary metastases. Chest radiographs and CT scanning are useful for delineating pulmonary metastases. A wide excision of locally recurrent tumor, an en bloc radical neck dissection and mediastinum dissection for lymphatic metastases, and an aggressive surgical resection of lung metastases are recommended. Although these operations are rarely curative, they usually offer definite palliation of the marked hypercalcemia, often for a considerable period. Drugs to lower the serum calcium level and systemic chemotherapy are currently of only limited benefit, and radiation therapy is generally ineffective.

Previous studies suggested that estrogen administration leads to an increase in circulating immunoreactive PTH (iPTH), thought to be secondary to a slight decrease in serum calcium resulting from inhibition of bone resorption. Using three different RIAs, we measured iPTH in serum from 10 postmenopausal women before and after 14 days of ethinyl estradiol administration. In 2 sensitive RIAs directed at the midregion of the PTH molecule, iPTH values fell or remained unchanged in each subject, with average decreases of 23% (P less than 0.001) and 28% (P less than 0.005) in the two assays. Total urinary cAMP, the tubular maximum for urinary phosphate excretion, and serum iPTH measured with the third RIA did not change after estrogen treatment. Fasting urinary calcium and hydroxyproline and serum calcium, phosphorus, albumin, alkaline phosphatase, and osteocalcin all decreased after treatment, and serum 1,25-dihydroxyvitamin D increased in each subject. In a second cohort of 5 women given ethinyl estradiol for 8 weeks, similar changes were found at 2 weeks, but there was a trend toward increasing serum iPTH, increasing total urinary cAMP excretion, and decreasing the tubular maximum for urinary phosphate excretion by 8 weeks. The increase in serum 1,25-dihydroxyvitamin D and the decrease in serum osteocalcin were again found after 2 weeks of estrogen and did not change further despite continued treatment. These results indicate multiple effects of a 2-week course of estrogen treatment on mineral metabolism in the absence of an increase in serum iPTH or several biological indices of PTH activity.

BACKGROUND

The features of primary hyperparathyroidism (PHPT) in developing countries have rarely been examined. This study explored the clinical characteristics of PHPT in India with the hypothesis that this may improve understanding of the pathogenesis of the disease worldwide.

METHODS

Consecutive patients with PHPT (24 women, five men) were examined prospectively before and after parathyroidectomy.

RESULTS

All patients had osteitis fibrosa cystica with a median symptom duration of 2.5 (range 1-26) years. Single or multiple fragility fractures were present in 14 patients (eight were bedridden); 20 had brown tumours. Mean preoperative serum calcium was 3.1 mmol/l, while mean serum intact parathyroid hormone (iPTH) and total alkaline phosphatase (ALP) levels were 17-fold and 12-fold higher than normal respectively. Nine patients had overt renal damage, mainly nephrocalcinosis. Parathyroidectomy invariably resulted in severe hypocalcaemia, necessitating long-term vitamin D treatment. The mean parathyroid gland weight was 8.6 (range 2.0-36.6) g and features of carcinoma were found in four patients. Serum calcidiol level correlated inversely (P < 0.05) with serum iPTH and ALP, and parathyroid gland weight.

CONCLUSIONS

PHPT in Indians is a severe, symptomatic disorder with skeletal, muscular and renal manifestations at a young age. The presence of this severe variant of PHPT in vitamin D-sufficient Indians, and the lack of skeletal disease in other vitamin D-deficient populations, raises the possibility of additional pathogenetic factors.

Parathyroid function was assessed by calcium infusions (4-8 h) in 16 patients with chronic renal insufficiency being treated by long-term hemodialysis. The concentrations of two immunoreactive species of parathyroid hormone in plasma (iPTH-9, mol wt 9500; iPTH-7, mol wt 7000) were estimated by radioimmunoassays utilizing two relatively specific antisera. Control values of the smaller species, iPTH-7, were uniformly high, whereas values of iPTH-9 were normal in 12 of 19 studies. Response of iPTH-7 to calcium infusions was variable, with significant decreases occurring only five times in 27 infusions. Concentrations of iPTH-9, however, decreased during every calcium infusion. In contrast to these acute responses, five of six patients studied during periods of dialysis against both low (< 6 mg/100 ml) and high (7-8 mg/100 ml) calcium concentrations in the dialyzate showed a decrease in values of iPTH-7 during the period of dialysis against the higher calcium concentration. It is concluded that plasma concentrations of iPTH-9 reflect primarily the moment-to-moment secretory status of the parathyroid glands, while concentrations of iPTH-7 reflect more closely chronic parathyroid functional status. It is further concluded that the failure of iPTH-7 to decrease during induced hypercalcemia should not be equated with autonomy of parathyroid gland function.

BACKGROUND

Incidence rates of hypoparathyroidism and vocal cord paralysis are high following central compartment reoperation, but few prospective studies have assessed morbidities and factors predictive of hypocalcemia after reoperation. We investigated recurrence patterns, morbidity, and factors predictive of postoperative hypocalcemia in patients undergoing central compartment reoperation for recurrent/persistent differentiated thyroid cancer (DTC).

METHODS

We prospectively evaluated 45 consecutive patients with recurrent/persistent DTC. Thyroid remnants or recurrent cancers were removed in 16 patients, the unilateral or bilateral central compartment was cleared in all patients, and the lateral compartment on the diseased side was comprehensively removed from 24 patients. Recurrence patterns were assessed histopathologically, morbidities were monitored, and serum concentrations of calcium and intact parathyroid hormone (iPTH) were measured in all patients.

RESULTS

Eleven patients (24.4%) had tumor invasion into the recurrent laryngeal nerve and/or the tracheoesophagus. Central nodal involvement occurred frequently (86.7%), and the ipsilateral jugular nodes of the lateral compartment were frequently involved. Temporary and permanent vocal cord paralysis developed in 10 (22.2%) and 8 (17.8%) patients, respectively, due primarily to intentional nerve resection following tumor invasion. Of 41 patients without preoperative hypoparathyroidism, 21 (46.3%) had temporary and 2 (4.9%) had permanent hypocalcemia. Multivariate analysis showed that bilateral central compartment dissection and low iPTH levels (<12.0 pg/ml) were independent predictors of postoperative hypocalcemia.

CONCLUSIONS

Most patients with recurrent/persistent DTC harbor lesions in the central compartment. Central compartment reoperation may lead to high rates of morbidity, including hypoparathyroidism, which can be predicted by surgical extent and low serum iPTH levels.

OBJECTIVE

This study aims to determine the prevalence and significance of vitamin D deficiency and insufficiency among apparently healthy adults.

METHODS

A total of 123 subjects, 56.9% males and 43.1% females, were recruited from a tertiary care hospital in Karachi, Pakistan. Questionnaires were administered to gather demographics; height, weight, and blood samples were also taken. For staging serum 25OHD, the cutoff values ≤50 nmol/L and 50.1-74.9 nmol/L were defined as deficiency and insufficiency, respectively.

RESULTS

The mean vitamin D level in the study subjects was 41.1±9.6 nmol/L. Of them, 90% had low serum 25OHD levels: 69.9% were deficient and 21.1% had insufficient levels of 25OHD. There was a significant negative correlation between serum 25OHD and iPTH levels.

CONCLUSIONS

The high prevalence of vitamin D deficiency and insufficiency showed that a high proportion of apparently healthy adults are at risk of developing musculoskeletal and other chronic diseases. Serum iPTH and serum 25OHD levels are better markers of this deficiency as compared to other markers.

Two hundred and twenty-nine consecutive subjects, 202 women and 27 men, referred for evaluation of osteoporosis or low bone mineral density (BMD) had serum measurements of immunoreactive PTH (iPTH) and 25-hydroxyvitamin D (25OHD) performed. Fifteen individuals (mean age +/- SE, 75+/-2.4 yr) had depressed serum 25OHD (<15 pg/mL) and concomitantly elevated (>65 pg/mL) iPTH levels. After successful treatment of vitamin D insufficiency in all subjects, iPTH remained inappropriately high or frankly elevated in 5, describing a 2.2% prevalence rate of coexistent primary hyperparathyroidism and vitamin D insufficiency in our population. Despite persistent primary hyperparathyroidism, normalization of serum 25OHD levels in these 5 subjects increased their BMD at an annual rate of 6.3% and 8.2% in spine and hip, respectively. Our results suggest that coexistent vitamin D insufficiency can obscure the diagnosis of primary hyperparathyroidism and, when treated effectively, can result in substantial short-terms gains in BMD despite persistence of the inappropriate production of PTH.

BACKGROUND

First-generation immunometric assays for "intact" parathyroid hormone (iPTH) also measure large N-terminally truncated PTH fragments, whereas second-generation assays, such as the "bio-intact" PTH (biPTH) assay, measure only full-length biologically active PTH(1-84). This study compared iPTH and biPTH assays during cinacalcet treatment in subjects with secondary HPT receiving dialysis.

METHODS

Four hundred and ten subjects were enrolled in a 26-week randomized, double-blind, placebo-controlled trial of oral cinacalcet (or placebo), 30 to 180 mg once daily, and efficacy was assessed using biPTH and iPTH assays.

RESULTS

Compared with control treatment, cinacalcet improved the management of secondary HPT. Both biPTH and iPTH decreased by 38%+/- 3% during weeks 13 to 26 in the cinacalcet group; biPTH increased by 23%+/- 4% and iPTH increased by 9.5%+/- 3% in the control group (P < 0.001). Fifty-six percent of cinacalcet subjects and 10% of control subjects had a>> or = 30% reduction in biPTH, and 61% and 11%, respectively, had a>> or = 30% reduction in iPTH. Significant correlations between biPTH and iPTH levels were observed throughout the study. Both assays correlated similarly with bone-specific alkaline phosphatase levels. The ratio of biPTH to iPTH was maintained at 56% +/- 1% after treatment in both treatment groups. Increasing serum calcium levels were associated with a decreasing ratio of biPTH to (iPTH-biPTH).

CONCLUSIONS

These data show that PTH can be monitored with either iPTH or biPTH assays during therapy with cinacalcet, and that cinacalcet therapy does not exert a major influence on the ratio between PTH(1-84) and large, N-terminally truncated PTH fragments.

Bones' functionally adaptive responses to mechanical loading can usefully be studied in the tibia by the application of loads between the knee and ankle in normal and genetically modified mice. Such loading also deforms the fibula. Our present study was designed to ascertain whether the fibula adapts to loading in a similar way to the tibia and could thus provide an additional bone in which to study functional adaptation. The right tibiae/fibulae in C57BL/6 mice were subjected to a single period of axial loading (40 cycles at 10 Hz with 10-second intervals between each cycle; approximately 7 min/day, 3 alternate days/week, 2 weeks). The left tibiae/fibulae were used as non-loaded, internal controls. Both left and right fibulae and tibiae were analyzed by micro-computed tomography at the levels of the mid-shaft of the fibula and 25% from its proximal and distal ends. We also investigated the effects of intermittent parathyroid hormone (iPTH) on the (re)modelling response to 2-weeks of loading and the effect of 2-consecutive days of loading on osteocytes' sclerostin expression. These in vivo experiments confirmed that the fibula showed similar loading-related (re)modelling responses to those previously documented in the tibia and similar synergistic increases in osteogenesis between loading and iPTH. The numbers of sclerostin-positive osteocytes at the proximal and middle fibulae were markedly decreased by loading. Collectively, these data suggest that the mouse fibula, as well as the tibia and ulna, is a useful bone in which to assess bone cells' early responses to mechanical loading and the adaptive (re)modelling that this engenders.

OBJECTIVE

The prevalence of mineral metabolism abnormalities is almost universal in stage 5 chronic kidney disease (CKD), but the presence of abnormalities in milder CKD is not well characterized.

METHODS

Data on adults>> or =20 yr of age from the National Health and Nutrition Examination Survey 2003-2004 (N = 3949) were analyzed to determine the association between moderate declines in estimated GFR (eGFR), calculated using the Modfication of Diet in Renal Disease formula, and serum intact parathyroid hormone (iPTH)>> or = 70 pg/ml.

RESULTS

The geometric mean iPTH level was 39.3 pg/ml. The age-standardized prevalence of elevated iPTH was 8.2%, 19.3%, and 38.3% for participants with eGFR>> or = 60, 45 to 59, and 30 to 44 ml/min/1.73 m(2), respectively (P-trend < 0.001). After adjustment for age; race/ethnicity; sex; menopausal status; education; income; cigarette smoking; alcohol consumption; body mass index; hypertension; diabetes mellitus; vitamin D supplement use; total calorie and calcium intake; and serum calcium, phosphorus, and 25-hydroxyvitamin D levels-and compared with their counterparts with an eGFR>> or = 60 ml/min/1.73 m(2)-the prevalence ratios of elevated iPTH were 2.30 and 4.69 for participants with an eGFR of 45 to 59 and 30 to 44 ml/min/1.73 m(2), respectively (P-trend < 0.001). Serum phosphorus>> or = 4.2 mg/dl and 25-hydroxyvitamin D < 17.6 ng/ml were more common at lower eGFR levels. No association was present between lower eGFR and serum calcium < 9.4 mg/dl.

CONCLUSIONS

This study indicates that elevated iPTH levels are common among patients with moderate CKD.

BACKGROUND

For many years bilateral neck exploration (BNE) was the gold standard operation for primary hyperparathyroidism (pPHP). With advances in preoperative pathological gland localization and intraoperative parathyroid hormone (IPTH) monitoring, minimally invasive approaches have evolved. This study is aimed to compare BNE and focused parathyroidectomy (FP) in a prospective, randomized, blind trial.

METHODS

Between 2005 and 2007, 48 patients with pPHP were enrolled in our study. Twenty three patients were randomized to the BNE group and 24 to the FP group. Patients in the FP group underwent preoperative localization studies. All parathyroidectomies were guided by intraoperative intact parathyroid hormone (IIPTH) monitoring. In the BNE group, neither IIPTH nor preoperative localization studies were performed.

RESULTS

All patients were cured by the primary operation. Overall, the operative time was similar in both groups. In the focused exploration (FE) group, compared to the BNE group, there was lower pain intensity at 4, 8, 16, 24, 36 and 48 h after surgery (p < 0.001), lower consumption of analgesics (p < 0.001), lower analgesia request rate (p < 0.001), shorter scar length (p < 0.001), higher cosmetic satisfaction rate 2 days, 1 month (p < 0.001) and 6 months after surgery (p < 0.05), but after 1 year cosmetic satisfaction rate became not significant (p = 0.38). Focused exploration (FE) was more expensive (p < 0.05). We did not find any difference in quality of life after 1 month and 6 months after surgery in both groups.

CONCLUSIONS

Both methods of parathyroidectomy for PHP are safe and effective. Focused exploration (FE) has several advantages: lower postoperative pain, lower analgesic request rate, lower analgesic consumption, shorter scar length, better cosmetic satisfaction rate in a short time period.

BACKGROUND

Control of dietary phosphate absorption in end-stage renal disease patients is essential to prevent the deleterious sequelae of phosphorus retention. Efficacy of currently available calcium- and aluminium-containing phosphate binders is constrained by the side-effects associated with the absorption of calcium and aluminium. The current study examined the efficacy of RenaGel, a calcium- and aluminium-free, polymeric phosphate binder, in end-stage renal disease patients.

METHODS

Administration of calcium- or aluminium-containing phosphate binders ceased during a 2-week washout period. RenaGel, at starting doses of one, two, or three 500-mg capsules three times per day with meals, was administered for 8 weeks. RenaGel dose was titrated up 1 capsule per meal at the end of each 2-week period if necessary to achieve phosphorus control. A second 2-week washout period followed the end of RenaGel treatment.

RESULTS

Mean serum phosphorus rose from a pre-washout level of 6.9 mg/dl (2.23 mmol/l) to 8.1 mg/dl (2.62 mmol/l) at the end of the initial 2-week washout. With RenaGel treatment, serum phosphorus declined and returned to pre-washout levels after 4 weeks. Serum phosphorus reached a nadir of 6.5 mg/dl (2.10 mmol/l) after 7 weeks of RenaGel treatment. Serum phosphorus rose to 8.2 mg/dl (2.65 mmol/l) 2 weeks after cessation of RenaGel treatment. As anticipated, calcium declined during the initial washout period when calcium-based phosphate binders were stopped for the majority of patients. The rise in serum phosphorus and decline in serum calcium during washout resulted in an increase in median intact parathyroid hormone (iPTH) levels from 292 pg/ml to 395 pg/ml. iPTH fell to 283 pg/ml after 6 weeks of RenaGel treatment despite a persistently lower serum calcium. RenaGel treatment also reduced serum total and LDL cholesterol by 25 mg/dl (0.65 mmol/l) and 23 mg/dl (0.59 mmol/l) respectively.

CONCLUSIONS

RenaGel appears to be an effective phosphate binder free of calcium and aluminium. Phosphorus control with two to four RenaGel capsules per meal appears to result in comparable phosphorus lowering seen with calcium- or aluminium-based phosphate binders. RenaGel may offer an alternative for the control of phosphorus retention in end-stage renal disease patients.

Bone biopsies were studied in 73 patients to determine if a two-site radioimmunometric assay for serum bone alkaline phosphatase (BAP), total serum alkaline phosphatase (ALP), serum intact parathyroid hormone (iPTH), hand X-rays, regional bone mineral density (BMD) measurements and parathyroid enlargement detected by ultrasonography could accurately predict renal osteodystrophy. In the patients studied 57 had hyperparathyroid bone disease, 4 mixed renal osteodystrophy, 3 adynamic bone disease, 1 osteomalacia and 8 normal histology. Serum BAP, ALP and iPTH correlated positively with mineral apposition rate, osteoblastic, osteoid and eroded surface. In the diagnosis of hyperparathyroid bone disease serum iPTH was the most sensitive investigation, detecting 81% of patients at a level>> 100 pg/ml but with a specificity of only 66%. Serum BAP was more sensitive, 70% at a level of>> 10 ng/ml, than serum total ALP, 30% at a level of 300 IU/l, with similar specificities, 92 and 100%, respectively. Ultrasound detection of an enlarged parathyroid gland had a sensitivity of 64% and a specificity of 100% for the diagnosis of hyperparathyroid bone disease. Hand X-rays had a poor sensitivity, 47%, but a high specificity, 92%, for the detection of hyperparathyroid bone disease. The majority of patients had regional BMD values within the normal reference range and this test was of poor discriminatory value. The non-invasive markers were unable to distinguish between patients with low turnover, mild hyperparathyroidism and patients with normal histology. In conclusion the measurement of serum iPTH is a useful screening tool for the detection of hyperparathyroid bone disease which can be confirmed by the finding of a raised serum BAP or parathyroid enlargement. For definitive diagnosis, however, the gold standard remains bone biopsy and at present one cannot recommend any non-invasive method as an adequate substitute.

OBJECTIVE

Secondary hyperparathyroidism is a common complication of chronic kidney disease, resulting from inactivation of vitamin D receptor signaling and phosphate retention. Selective activation of vitamin D receptors with intravenous paricalcitol significantly reduced parathyroid hormone (PTH) levels with no significant hypercalcemia or hyperphosphatemia in predialysis and hemodialysis (HD) patients. This study investigates the effects of oral paricalcitol to reduce PTH in patients receiving chronic HD and peritoneal dialysis (PD).

METHODS

Eighty-eight patients were randomized in double-blind fashion to receive paricalcitol or placebo for 12 weeks. The dose of the study drug was adjusted weekly using the previous week's intact PTH (iPTH) level as well as calcium and Ca x P product levels. The primary end points were efficacy (two consecutive iPTH decreases of>>or=30%) and safety (two consecutive calcium measurements >11.0 mg/dl). Markers of biochemical bone activity were followed.

RESULTS

Demographic characteristics were similar between treatment groups. The mean paricalcitol doses (three times a week) over the entire treatment period for subjects with baseline <em>iPTH</em> <or=500 pg/ml and <em>iPTH</em> >500 pg/ml were 3.9 and 7.6 microg, respectively. A statistically significant decrease in <em>iPTH</em> was seen after week 1, with a mean 30% reduction occurring by week 3. A significantly greater proportion of both HD and PD paricalcitol subjects [83% (33/40) and 100% (18/18), respectively] achieved two consecutive>>or=30% decreases in <em>iPTH</em>. The treatment groups were not statistically different in regard to the hypercalcemia safety end point. Phosphate binder use and mean serum phosphorus levels were not different between the treatment groups. The markers of bone activity improved in the treated subjects and worsened in those on placebo.

CONCLUSIONS

Paricalcitol provides a rapid and sustained reduction of PTH in both HD and PD patients with minimal effect on serum calcium and phosphorus and no significant difference in adverse events as compared with placebo.

BACKGROUND

Changes in serum vitamin D metabolites and calcium absorption with varying doses of oral vitamin D₃ in healthy children are unknown.

OBJECTIVE

Our objective was to examine the dose-response effects of supplemental vitamin D₃ on serum vitamin D metabolites and calcium absorption in children living at two U.S. latitudes.

METHODS

Black and white children (n = 323) participated in a multisite (U.S. latitudes 34° N and 40° N), triple-masked trial. Children were randomized to receive oral vitamin D₃ (0, 400, 1000, 2000, and 4000 IU/d) and were sampled over 12 weeks in winter. Serum 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)₂D) were measured using RIA and intact PTH (iPTH) by immunoradiometric assay. Fractional calcium absorption was determined from an oral stable isotope ⁴⁴Ca (5 mg) in a 150-mg calcium meal. Nonlinear and linear regression models were fit for vitamin D metabolites, iPTH, and calcium absorption.

RESULTS

The mean baseline 25(OH)D value for the entire sample was 70.0 nmol/L. Increases in 25(OH)D depended on dose with 12-week changes ranging from -10 nmol/L for placebo to 76 nmol/L for 4000 IU. Larger 25(OH)D gains were observed for whites vs blacks at the highest dose (P < .01). Gains for 1,25(OH)₂D were not significant (P = .07), and decreases in iPTH were not dose-dependent. There was no dose effect of vitamin D on fractional calcium absorption when adjusted for pill compliance, race, sex, or baseline 25(OH)D.

CONCLUSIONS

Large increases in serum 25(OH)D with vitamin D₃ supplementation did not increase calcium absorption in healthy children living at 2 different latitudes. Supplementation with 400 IU/d was sufficient to maintain wintertime 25(OH)D concentrations in healthy black, but not white, children.

OBJECTIVE

To examine the distribution of bone mineral density (BMD) in different histological groups of renal osteodystrophy.

METHODS

We prospectively studied 62 patients, 41 men and 21 women, aged 57+/-11.5 years, who had been on hemodialysis for 60+/-55 months. The women had been amenorrheic for 13+/-4 years and 7 patients (11%) had a positive fracture history.

METHODS

A bone biopsy was taken after tetracycline labelling and BMD of the lumbar spine and proximal femur was measured by dual-energy X-ray absorptiometry (DEXA); serum intact parathyroid hormone (iPTH), bone Gla protein (BGP), phosphorus, calcium and alkaline phosphatase (ALP) were also determined.

RESULTS

Histologically, 40 patients showed secondary hyperparathyroidism (sHPT), 6 mixed bone disease, 14 adynamic bone disease (A) and 2 osteomalacia. BMD of the lumbar spine was decreased in 43 patients (69%) and in 9 (14.5%) it was lower than -2 Z score units. BMD of the femoral neck was low in 55 patients (89%) and in 22 (35.5%) it was lower than -2 Z scores. BMD was lower in patients with sHPT than in those with adynamic bone disease (p<0.05) in which it was close to normal. BMD in both these sites correlated inversely with the biochemical markers (serum iPTH, BGP and ALP) and the histomorphometric indices of bone turnover.

CONCLUSIONS

Osteopenia is frequent in patients on hemodialysis, especially those with biochemical and histological findings of sHPT.

BACKGROUND

Children burned>> 40% total body surface area (TBSA) have chronically low bone mineral density (BMD) and increased risk for fractures and adult-onset osteoporosis. Because they are advised to avoid sunlight to prevent burn scar hyperpigmentation, we hypothesized that they develop vitamin D depletion, which could contribute to post-burn osteopenia.

METHODS

We studied 24 children, ages 5-20 years, burned>> or = 40% TBSA 7.1 +/- 3.8 (SD) years, range 1.9-13.3 years, previously (n = 12) and 2.0 +/- 0.2, range 1.4-2.1 years, previously (n = 12), of which half received recombinant human growth hormone during the first post-burn year. We measured lumbar spine BMD, serum 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)2D), intact PTH (iPTH), and osteocalcin.

RESULTS

Serum 25(OH)D was low in 10/11 patients and 1,25(OH)2D was low in 5/11 at 7 years post-burn. Serum 25(OH)D was low in 10/12, while 1,25(OH)2D was low in 0/12 at 2 years; osteocalcin was low in 9/12 in the 7-year group; iPTH levels were in the lowest quartile in 5/12 patients at 7 years and 10/12 patients at 2 years. Serum 25(OH)D levels correlated with BMD z-scores, r = 0.53, p < 0.05, and inversely with iPTH levels, r = -0.66, p < 0.05, in the 7-year group.

CONCLUSIONS

Burned children have low circulating levels of 25(OH)D which correlated with BMD z-scores, suggesting that post-burn vitamin D depletion may play a role in the chronically low bone density observed in these children.

OBJECTIVE

Observational data indicate that newer vitamin D compounds such as paricalcitol can suppress serum intact parathyroid hormone (iPTH) and reduce proteinuria in patients with CKD. To systematically evaluate the efficacy and safety of paricalcitol for CKD, we conducted a meta-analysis of the published randomized controlled trials (RCTs).

METHODS

MEDLINE, Embase, the Cochrane Library, and article reference lists were searched for RCTs that compared paricalcitol with placebo in the treatment of patients with stage 2-5 CKD. The quality of the studies was evaluated using the Jadad method. The results are summarized as risk ratios (RRs) for dichotomous outcomes or mean differences for continuous outcomes.

RESULTS

Nine studies (832 patients) were included. Compared with placebo, paricalcitol suppressed serum iPTH (RR, 6.37; 95% confidence interval [95% CI], 4.64-8.74; P<0.001) and reduced proteinuria (RR, 1.68; 95% CI, 1.25-2.25; P<0.001). Compared with the control group, the RR for hypercalcemia associated with paricalcitol use was 2.25 (95% CI, 0.81-6.26; P=0.12). Patients receiving paricalcitol therapy did not have an increased risk of endocrine system and cardiovascular system adverse effects (RR, 1.07; 95% CI, 0.84-1.36; P=0.58).

CONCLUSIONS

We confirm that paricalcitol suppresses iPTH and lowers proteinuria in patients with stage 2-5 CKD without an increased risk of adverse events. A trend toward increased hypercalcemia did not reach statistical significance, but may be clinically relevant. A randomized trial is needed to determine if paricalcitol affects the development of ESRD or mortality.