Vitamin D therapy for patients with end-stage renal disease (ESRD) on hemodialysis therapy has relied on patient dry weight to determine the initial dose of medication. Obtaining a patient's dry weight can be difficult, and no correlation has been established between a patient's body weight and severity of secondary hyperparathyroidism. We conducted a double-blind, double-dummy, randomized, 12-week, multicenter trial to compare the incidence of hypercalcemia (single occurrence) between two dosing regimens: one regimen based on baseline intact parathyroid hormone (iPTH; PTH/80) level, and the other regimen based on patient body weight (0.04 microgram/kg). One hundred twenty-five adult patients with ESRD on maintenance hemodialysis therapy were enrolled at multiple sites. Before treatment, all patients were required to have PTH levels of 300 pg/mL or greater, calcium levels of 8.0 mg/dL or greater and 10.5 mg/dL or less, and a calcium x phosphorus (Ca x P) product of 70 or less. Patients were randomized to one of two regimens: the nonrandomized treatment was also administered as a placebo dummy. No incidence of hypercalcemia occurred in either treatment group during the study. Patients treated according to the formula iPTH/80 required fewer dose adjustments and achieved the first of four consecutive reductions from baseline PTH level of 30% or greater more rapidly than patients treated based on body weight (P = 0.0306). Incidences of elevated Ca x P product levels were similar between treatment groups. Treatment with paricalcitol injection based on degree of secondary hyperparathyroidism incurred no greater risk for hypercalcemia and achieved meaningful therapeutic results with fewer dose adjustments than dosing based on patient body weight.

Most reports on the effectiveness and side effects of oral versus parenteral calcitriol or alfacalcidol in hemodialysis patients with secondary hyperparathyroidism show no advantage of parenteral treatment. The efficacy and safety of intravenous doxercalciferol (1alphaD(2)) were studied in hemodialysis patients with secondary hyperparathyroidism (plasma intact parathyroid hormone [iPTH]: range, 266 to 3,644 pg/mL; median, 707 pg/mL). These results were compared with those of a previous trial using intermittent oral 1alphaD(2); the same 70 patients were entered onto both trials, and 64 patients completed both trials per protocol. Twelve weeks of open-label treatment in both trials were preceded by identical 8-week washout periods. Degrees of iPTH suppression from baseline were similar in the two trials, with iPTH level reductions less than 50% in 89% and 78% of patients during oral and intravenous treatment, respectively. Grouping patients according to entry iPTH levels (<750 and>>/=750 pg/mL) showed similar but more rapid iPTH suppression in the low-iPTH groups, whereas longer treatment and larger doses were required by the high-iPTH groups. Highest serum calcium levels averaged 9.82 +/- 0.14 and 9.67 +/- 0.11 mg/dL during oral and intravenous 1alphaD(2) treatment, respectively (P: = not significant [NS]). Prevalences of serum calcium levels greater than 11.2 mg/dL during oral and intravenous treatment were 3.62% and 0.86% of calcium measurements, respectively (P: < 0.001). Highest serum phosphorus levels during oral and intravenous treatment averaged 5.82 +/- 0.21 and 5.60 +/- 0.21 mg/dL, respectively (P: = NS). The percentage of increments in serum phosphorus levels during oral treatment exceeded that during intravenous treatment during 5 of 12 treatment weeks. Thus, intermittent oral and intravenous therapy with 1alphaD(2) reduced iPTH levels effectively and similarly, hypercalcemia was less frequent, and serum phosphorus levels increased less during intravenous than oral 1alphaD(2) therapy, suggesting that intravenous 1alphaD(2) therapy may be advantageous in patients prone to hypercalcemia or hyperphosphatemia.

BACKGROUND

Symptomatic (SX) hypocalcemia after thyroidectomy is a barrier to same day surgery and the cause of emergency room visits. A standard protocol of calcium and vitamin D supplementation, dependent on intact parathyroid hormone (iPTH) levels, can address this issue. How effective is it? When does it fail?

METHODS

We performed a retrospective review of the prospective Thyroid database from January 2006 to December 2010. Six hundred twenty patients underwent completion thyroidectomy or total thyroidectomy and followed our postoperative protocol of calcium carbonate administration for iPTH levels ≥10 pg/mL and calcium carbonate and 0.25 μg calcitriol twice a day for iPTH <10 pg/mL. Calcium and iPTH values, pathology, and medication were compared to evaluate protocol efficacy. A P value <0.05 was considered statistically significant.

RESULTS

Using the protocol, sixty-one (10.2%) patients were chemically hypocalcemic but never developed symptoms and 24 (3.9%) patients developed breakthrough SX hypocalcemia. The SX and asymptomatic groups were similar with regard to gender, cancer diagnosis, and preoperative calcium and iPTH. The SX group was significantly younger (39.6 ± 2.8 versus 49 ± 0.6 y, P = 0.01), with lower postoperative iPTH levels. Thirty-three percent (n = 8) of SX patients had an iPTH ≤5 pg/mL versus only 6% (n = 37) of ASX patients. Although the majority of patients with a iPTH ≤5 pg/mL were asymptomatic, 62.5% (n = 5) of SX patients with iPTH levels ≤5 pg/mL required an increase in calcitriol dose to achieve both biochemical correction and symptom relief.

CONCLUSIONS

Prophylactic calcium and vitamin D supplementation based on postoperative iPTH levels can minimize SX hypocalcemia after thyroidectomy. An iPTH ≤5 pg/mL may warrant higher initial doses of calcitriol to prevent symptoms.

Bone mineral density (BMD) at lumbar spine (L2-L4) was measured by dual-energy X-ray absorptiometry (DEXA) in 21 children with predialysis chronic renal failure (CRF) and 44 children with end-stage renal failure (ESRF) on regular hemodialysis. BMD results were expressed as Z-scores. Osteopenia was documented in 13 predialysis patients (61.9%) and 26 patients (59.1%) with ESRF. No significant correlation was observed between Z-scores and the duration of CRF or estimated creatinine clearance. In osteopenic children there was a negative correlation between Z-scores and serum phosphorus (r=-0.61, P=0.004), intact parathyroid hormone (iPTH) (r=-0.47, P=0.03), and bone-specific alkaline phosphatase (r=-0.52, P=0.02) and a positive correlation with total calcium (r=0.41, P=0.07) and 25-hydroxycholecalciferol (r=0.53, P=0.02). Osteopenic children who had iPTH values>> or = 200 pg/ml were more osteopenic than those who had lower iPTH levels (P=0.006). In conclusion, osteopenia, assessed by DEXA, is frequent in children with CRF. It occurs early irrespective of the duration or the severity of CRF. In children with ESRF the degree of osteopenia is correlated with laboratory markers of renal osteodystrophy and patients with biochemical findings of secondary hyperparathyroidism are more osteopenic than the others.

BACKGROUND

The existence of adynamic bone disease (ABD) as most prevalent form of renal osteodystrophy in recent years and its reduced ability to handle an exogenous calcium load has implied a higher risk for vascular and soft-tissue calcifications. The effect of low dialysate calcium (LCD) on parathyroid hormone (PTH) secretion in ABD patients has not yet sufficiently been clarified. This randomized, prospective study aimed to compare the effects of LCD and high calcium dialysate (HCD) on the evolution of bone and mineral parameters related to ABD in dialysis patients.

METHODS

52 out of 60 patients with predialysis intact PTH<100 pg/ml completed this study and were equally distributed over LCD (1.25 mmol/l) or HCD (1.75 mmol/l) treatment. The duration of the study was 6 months and the only peroral phosphate binder administered was calcium carbonate. Total and ionised calcium were measured monthly in serum before and after dialysis while serum parameters relevant to bone were measured at the enrollment and at 3-month intervals.

RESULTS

There were no differences in predialysis mean phosphate or calcium x phosphorus product (Ca x P). The most common side effects of both treatments were comparable. Hypotension occurred in 16% and 17% and cramps in 6% and 8% of the dialysis sessions, in the HCD and LCD group, respectively. The groups did not differ in the mean tCa before dialysis, but this parameter was significantly higher in the HCD group vs. LCD at the end of dialysis (2.59+/-0.18 vs. 2.44+/-0.19 mmol/l; p<0.01). The patients of the HCD group also had a significantly higher mean iCa both before (1.08+/-0.05 vs. 1.04+/-0.06 mmol/l; p=0.02) and at the end of dialysis (1.18+/-0.04 vs. 1.48+/-0.04 mmol/l; p<0.01). There were no differences within the LCD group between baseline and end of dialysis treatment values of tCa and iCa. However, the mean tCa and iCa were markedly increased at the end of dialysis in the HDC group [2.40+/-0.21 vs. 2.59+/-0.18 mmol/l (p<0.01); 1.08+/-0.05 vs. 1.18+/-0.04 mmol/l (p<0.01)]. Mean serum levels of iPTH and total alkaline phosphatase in the LCD group were increased at 3 months and at the end of the study compared with the baseline levels [(38.6+/-22.9 vs. 63.3+/-46.0 vs. 78.6+/-44.7 pg/ml); (59.5+/-18.7 vs. 75.9+/-26.7 vs. 84.0+/-35.4 U/l)], respectively, and bone alkaline phosphatase increased also only after 6 months of treatment (23.4+/-7.3 U/l vs. 35.6+/-22.3). The bone markers in the HCD group did not change. At the end of the study all bone parameters in the LCD group were significantly higher than in the HCD group.

CONCLUSIONS

There was an evolution towards parameters reflecting higher bone turnover in patients treated with dialysate calcium of 1.25 mmol/l, probably by prevention of a positive calcium balance and enabling sustained stimulation of PTH secretion. Hence, LCD might be considered a valuable therapeutic option for ABD patients.

Diabetic bone disease is characterized by low bone turnover resulting from either impaired secretion of parathyroid hormone (PTH) or refractoriness of osteoblasts to PTH. The present study was performed to elucidate which factor contributes more to the reduction in bone turnover by comparison between 64 hemodialyzed patients with diabetes mellitus and 106 hemodialyzed patients without diabetes mellitus. Only men were enrolled to avoid the influence of the menstrual cycle on bone metabolism. Serum intact PTH (iPTH) levels were significantly lower in hemodialyzed patients with diabetes than those without diabetes, although no significant difference existed in age, duration of hemodialysis therapy, or serum calcium or phosphate levels. Of the biochemical markers measured, serum intact osteocalcin (iOC) and deoxypyridinoline levels were significantly lower in patients with diabetes, although serum bone-specific alkaline phosphatase (BAP) and pyridinoline levels did not differ significantly between the two groups of patients. When patients were restricted to those with serum iPTH levels greater than 180 pg/mL, this parameter correlated significantly in a positive manner with both serum iOC and BAP levels and negatively with bone mineral density at distal radius 1/3. Regression slopes between iPTH levels and these parameters were not significantly different between the two groups of patients, indicating the absence of refractoriness of bone to PTH in patients with diabetes. In conclusion, our findings suggest that impaired PTH secretion, but not refractoriness of osteoblasts to PTH, may be responsible for the low bone turnover in hemodialyzed patients with diabetes.

The impact of dialysis intensity on erythropoietin (EPO) requirements is unclear. Previous work suggests that increased dialysis is associated with increased erythropoietin responsiveness (ERSP), but average dialysis intensity has increased since those publications. We hypothesized that ERSP would be independent of delivered Kt/V(urea) at current intensities of hemodialysis. We prospectively studied 135 stable chronic hemodialysis patients who receive iron and subcutaneous EPO dosed according to current guidelines. We collected biochemical, hematologic, and single pool urea kinetics data. ERSP was expressed as units per kilogram per week of EPO administered. Simple and multiple linear regression were used to identify characteristics predictive of ERSP. The mean age of the patients was 62 +/- 17 years (range, 17-90 years); 68 of 135 (50.3%) were women, and 120 of 135 (88.9%) were Caucasian. Mean delivered Kt/V(urea) was 1.60 +/- 0.49, with 102 of 135 (75.6%) of patients with a delivered Kt/V(urea)>> 1.3. Univariate linear regression showed seven significant independent predictors of erythropoietin requirements. Low serum albumin (p < 0.001), low serum calcium (p = 0.002), high serum phosphate (p = 0.004), and high serum iPTH (p = 0.007) were all associated with lower levels of ERSP. Lower ERSP was also correlated with lower hemoglobin and lower serum iron and transferrin saturation. Delivered dialysis (Kt/ V(urea)) was not a significant predictor of ERSP (p = 0.61). Multivariate regression confirmed low serum albumin (p < 0.01), high serum phosphate (p = 0.001), high immunoreactive parathyroid hormone (p = 0.025), and low transferrin saturation (p < 0.0005) as predictors of low ERSP, and also found high serum ferritin to be correlated with low ERSP (p = 0.016). We found no relationship between erythropoietin responsiveness and intensity of hemodialysis in this population of patients with a mean delivered Kt/V(urea) of 1.6. This may indicate a threshold effect beyond which more dialysis will not improve ERSP. However, markers of an underlying inflammatory state and of secondary hyperparathyroidism were associated with decreased response to erythropoietin.

Denosumab is a fully human monoclonal antibody that has high affinity for RANK ligand (RANKL). RANKL is the essential mediator of osteoclast formation, function and survival. The safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of denosumab in healthy postmenopausal Japanese women were assessed. This was a randomized, double-blind, dose-escalation study in which 40 subjects received denosumab at doses of 0.03, 0.1, 0.3, 1.0 or 3.0mg/kg, or placebo administered subcutaneously. Blood and urine samples for determination of serum denosumab, CTX-I, NTX-I/Cr, bone specific alkaline phosphatase (bone ALP) and intact parathyroid hormone (iPTH) were collected. The PK and PD time profiles were compared to those obtained in separate studies conducted in the US. No serious adverse events occurred and all subjects completed this study. Denosumab demonstrated nonlinear PK and dose- and concentration-dependent dispositions. The maximum mean decrease from baseline ranged from 65% to 95% for CTX-I concentrations and from 50% to 85% for NTX-I/Cr. Additionally, the changes were dose-dependent. The suppression of bone turnover markers was rapid (within 2 days after dosing) and duration of suppression was dose-dependent. No marked differences in the PK and PD profiles between Japanese and non-Japanese subjects were noted. The observed results indicate that denosumab may have therapeutic potential for conditions resulting from increased bone turnover, such as osteoporosis in Japanese.

Hyperphosphatemia and dyslipidemia are common clinically significant conditions in end-stage renal disease (ESRD). Hyperphosphatemia management is essential; however, use of calcium-based phosphate binder has been associated with elevated risk of cardiac calcification in ESRD, increasing risks for cardiovascular disease and death. An alternative to calcium-based phosphate binders is sevelamer hydrochloride, a calcium-free, metal-free, nonabsorbed polymer that binds phosphate effectively. We conducted a meta-analysis on the effects of sevelamer hydrochloride on parameters of mineral metabolism (serum phosphorous, calcium, Ca x P, and iPTH) and the lipid profile (total, LDL, HDL, and non-HDL cholesterol, and triglycerides) in dialysis patients. After application of inclusion/exclusion criteria, 17 core studies were statistically analyzed to determine the sevelamer treatment effect on the study parameters as demonstrated by simple, n-weighted, and inverse variance-weighted mean changes. Analysis of inverse variance-weighted mean changes indicated that sevelamer treatment was associated with a 2.14 mg/dL drop in serum phosphorus (P <.001), no significant overall effect on calcium (0.09 mg/dL, P =.364), significant decline in Ca x P product (15.91 mg(2)/dL(2), P <.001), 35.99 pg/mL reduction in iPTH (P =.026), significant reduction in total cholesterol (30.58 mg/dL, P <.001), 31.38 mg/dL drop in LDL cholesterol (P <.001), significant increase in HDL cholesterol (4.09 mg/dL, P =.008), and a significant reduction in triglycerides (22.04 mg/dL, P x.001). This meta-analysis suggests that sevelamer offers a dual therapeutic benefit in dialysis patients-a population at high risk for cardiovascular disease-by improving phosphorus control and the lipid profile, without altering serum calcium.

BACKGROUND

Chronic kidney disease (CKD) is associated with elevations in serum phosphate, calcium-phosphorus product and bone-specific alkaline phosphatase (BAP), with attendant risks of cardiovascular and bone disorders. Active vitamin D can suppress parathyroid hormone (PTH), but may raise serum calcium and phosphate concentrations. Paricalcitol, a selective vitamin D activator, suppressed PTH in CKD patients (stages 3 and 4) with secondary hyperparathyroidism (SHPT) with minimal changes in calcium and phosphate metabolism.

METHODS

The VITAL study enrolled patients with CKD stages 2-4. We examined the effect and relationship of paricalcitol to calcium and phosphate metabolism and bone markers in a post hoc analysis of VITAL. The study comprised patients with diabetic nephropathy enrolled in a double-blind, placebo-controlled, randomized trial of paricalcitol (1 or 2 μg/day). Urinary and serum calcium and phosphate, serum BAP, and intact PTH (iPTH) concentrations were measured throughout the study.

RESULTS

Baseline demographics and calcium, phosphate, PTH (49% with iPTH <70 pg/mL), and BAP concentrations were similar between groups. A transient, modest yet significant increase in phosphate was observed for paricalcitol 2 μg/day (+0.29 mg/dL; P < 0.001). Dose-dependent increases in serum and urinary calcium were observed; however, there were few cases of hypercalcemia: one in the 1-μg/day group (1.1%) and three in the 2-μg/day group (3.2%). Significant reductions in BAP were observed that persisted for 60 days after paricalcitol discontinuation (P < 0.001 for combined paricalcitol groups versus placebo). Paricalcitol dose-dependent reductions in iPTH were observed. Paricalcitol in CKD patients (±SHPT) was associated with modest increases in calcium and phosphate.

CONCLUSIONS

Paricalcitol reduces BAP levels, which may be beneficial for reducing vascular calcification.

BACKGROUND

Trial is registered with ClinicalTrials.gov, number NCT00421733.

Plasma bicarbonate decreases during normal pregnancy. To assess what roles increased extra cellular volume or alterations in parathyroid hormone levels (iPTH) have in the maintenance of this decrement, we evaluated acid-base metabolism in eleven 3rd-trimester women. Base-line pH and PCO2 were 7.44 and 27.3 mmHg, respectively. Mean tubular reabsorption of phosphate was 93% and baseline iPTH levels were similar to those of nonpregnant subjects. During the slow infusion of hypertonic NaHCO3, a urinary threshold of HCO3- (THCO3) appeared at a mean plasma level of 18.9 meq/liter, but as plasma HCO3- increased progressively, its renal reclamation was almost complete and there was no evidence of either splay or tubular maximum, even when filtered loads of HCO3- reached 5 meq/min. Urine acidification was normal and distal [H+] secretory ability( deltaidification was normal and distal [H+] secretory ability (delta urinary PCO2) was similar to that reported in nongravid subjects. In metabolic balance studies blood pH and plasma HCO3- increased (P less than .01 and less than .02, respectively) when the women changed from a high- to a low-sodium diet. Mechanisms by which decreased plasma bicarbonate levels are maintained during gestation are discussed.

Vitamin D insufficiency and secondary hyperparathyroidism (SHPT) are associated with increased morbidity and mortality in chronic kidney disease (CKD) and are poorly addressed by current treatments. The present clinical studies evaluated extended-release (ER) calcifediol, a novel vitamin D prohormone repletion therapy designed to gradually correct low serum total 25-hydroxyvitamin D, improve SHPT control and minimize the induction of CYP24A1 and FGF23.

Two identical multicenter, randomized, double-blind, placebo-controlled studies enrolled subjects from 89 US sites. A total of 429 subjects, balanced between studies, with stage 3 or 4 CKD, SHPT and vitamin D insufficiency were randomized 2:1 to receive oral ER calcifediol (30 or 60 µg) or placebo once daily at bedtime for 26 weeks. Most subjects (354 or 83%) completed dosing, and 298 (69%) entered a subsequent open-label extension study wherein ER calcifediol was administered without interruption for another 26 weeks.

ER calcifediol normalized serum total 25-hydroxyvitamin D concentrations (>30 ng/ml) in >95% of per-protocol subjects and reduced plasma intact parathyroid hormone (iPTH) by at least 10% in 72%. The proportion of subjects receiving ER calcifediol who achieved iPTH reductions of ≥30% increased progressively with treatment duration, reaching 22, 40 and 50% at 12, 26 and 52 weeks, respectively. iPTH lowering with ER calcifediol was independent of CKD stage and significantly greater than with placebo. ER calcifediol had inconsequential impact on serum calcium, phosphorus, FGF23 and adverse events.

Oral ER calcifediol is safe and effective in treating SHPT and vitamin D insufficiency in CKD.

The aim of the current investigation was to study the effects of sevelamer hydrochloride (RenaGel) on serum phosphate, intact parathyroid hormone levels (iPTH), and lipid profiles in stable hemodialysis patients. Hemodialysis patients maintained on calcium containing phosphate binders were enrolled in this study. Following two weeks of washout of the phosphate binders, serum phosphate rose from 6.4 +/- 0.6 to 10.5 +/- 0.7 mg/dl (p <0.001). After 8 weeks of titration with sevelamer hydrochloride, serum phosphate fell by 4.5 +/- 0.3 to 6.3 +/- 0.7 mg/dl (p <0.0001). Serum calcium levels fell during washout (9.8 +/- 0.4 to 8.9 +/- 0.3 mg/dl, p <0.004) and were unaffected by sevelamer hydrochloride. Sevelamer hydrochloride administration was associated with a 23.0 +/- 3.1% fall in total cholesterol, a 35.9 +/- 3.0% fall in LDL cholesterol, and a 35.2 +/- 5.3% fall in the LDL:HDL cholesterol ratio (p <0.001). There was no change in HDL cholesterol, triglycerides or the concentration of fat soluble vitamins. Sevelamer hydrochloride is a well tolerated alternative to calcium or aluminum containing phosphate binders and may offer an advantage to patients who become hypercalcemic on calcium-containing antacids and vitamin D supplementation. Furthermore, sevelamer hydrochloride lowers LDL cholesterol without affecting HDL cholesterol. The potential usefulness of the lipid lowering effects of sevelamer hydrochloride needs to be determined in additional prospective studies.

OBJECTIVE

To evaluate the effect of strenuous exercise on bone metabolism and related hormones in elderly subjects.

METHODS

Twenty one active elderly subjects (11 men and 10 women; mean age 73.3 years) showing a mean theoretical Vo2max of 151.4% participated. Concentrations of plasma ionised calcium (iCa), serum intact parathyroid hormone (iPTH), 25-hydroxyvitamin D (25(OH)D), and 1.25-dihydroxy-vitamin D3 (1.25(OH)2D3), as well as the bone biochemical markers type I collagen C-telopeptide for bone resorption and osteocalcin and bone alkaline phosphatase for bone formation, were analysed before and after a maximal incremental exercise test.

RESULTS

At basal level, iPTH was positively correlated with age (r = 0.56, p < 0.01) and negatively correlated with 25(OH)D (r = -0.50; p < 0.01) and 1.25(OH)2D3 (r = -0.47; p < 0.05). Moreover, 25(OH)D and 1.25(OH)2D3 levels were negatively correlated with age (r = -0.50, p < 0.01 and r = -0.53, p < 0.01, respectively). After exercise, iCa and 25(OH)D decreased (p < 0.001 and p = 0.01, respectively) while iPTH increased (p < 0.001). The levels of 1.25(OH)2D3, bone biochemical markers, haematocrit, and haemoglobin were unchanged. The variations in iCa and 25(OH)D were not related to age and/or sex. The iPTH variation was directly related to basal iPTH levels (p < 0.01) and indirectly related to age.

CONCLUSIONS

In active elderly subjects, strenuous exercise disturbed calcium homeostasis and bone related hormones without immediate measurable effect on bone turnover. Although an increase in iPTH could have an anabolic action on bone tissue, our findings from our short term study did not allow us to conclude that such action occurred.

The diagnostic and predictive value of serum intact parathyroid hormone (iPTH) and osteocalcin (bone Gla protein, BGP), alone or in combination, have been examined in only a small number of haemodialysis patients.

METHODS

We studied prospectively 114 patients (46 women, 68 men; mean age 52 +/- 12 years) on regular haemodialysis for a mean of 55 (6-185) months. All patients underwent labelled transiliac bone biopsy, and serum levels of iPTH, BGP and alkaline phosphatase were determined.

RESULTS

Seventy-one patients (62%) showed histological findings of hyperparathyroid bone disease, 24 (21%) mixed bone disease, six (5.5%) osteomalacia and 13 (11.5%) adynamic bone. Bone aluminium deposition over more than 25% of the trabecular bone interface was found in 66 patients (58%). Serum iPTH and BGP correlated with the majority of histomorphometric indices of bone formation, mineralization and resorption (r>> 0.5, P < 0.01). iPTH levels>> or = 200 pg/ml and BGP>> or = 50 ng/ml were found to be indicative of hyperparathyroid bone disease, whilst iPTH levels < 65 pg/ml and BGP < 20 ng/ml were indicative of adynamic bone. However, the positive predictive value of these indices was limited (less than 80%), although their negative predictive value, especially when used in combination, was good (more than 90%) and the exclusion of hyperparathyroid bone disease and adynamic bone was possible. The diagnostic and predictive value of these bone markers were improved when patients with bone aluminium deposition were excluded.

CONCLUSIONS

Diagnosis of hyperparathyroid bone disease and adynamic bone is difficult on the basis of iPTH and BGP, especially when bone aluminium deposition is prevalent. However, using these bone markers, preferably in combination, the exclusion of these lesions is feasible.

BACKGROUND

To describe a standardized, efficient, and cost-effective protocol for the diagnosis of temporary/persisting postoperative hypoparathyroidism after (total) thyroidectomy.

METHODS

We included 237 consecutive patients who underwent (total) thyroidectomy without central neck dissection for various indications. Serum calcium (sCa) and intact parathyroid hormone (iPTH) levels were measured prospectively on the morning of postoperative day 1 to predict the long-term parathyroid metabolism. On the morning of postoperative day 2, measurements were repeated. Follow-up was performed at 1 and 6 months postoperatively.

RESULTS

On the morning of postoperative day 1, patients with iPTH ≥ 15 pg/mL (178/237; 75%) and sCa>> 2.0 mmol/L were normocalcemic, and "normal" parathyroid metabolism was predicted. iPTH levels of <10 pg/mL and sCa levels of ≤2.0 mmol/L were present in 33 of the 237 patients ("disturbed" parathyroid metabolism; 14%). A "gray zone" included patients with "uncertain" parathyroid metabolism demonstrating iPTH levels between 10 and 15 pg/mL (26/237; 11%). Patients with "disturbed" and "uncertain" parathyroid metabolism were given oral calcium and vitamin D. On the morning of the second postoperative day, iPTH turned to "normal" in 10 of those 26 (38%) patients, and no further calcium or vitamin D was given. During follow-up, supplemental calcium and vitamin D was able to be stopped in all but 2 patients ("permanent" hypoparathyroidism; 2/237; 0.8%).

CONCLUSIONS

Measurement of iPTH on the morning after operation allows accurate prediction of postoperative parathyroid function in ≥99% of cases. This simple recommendation is practicable in all surgical units, and is an efficient and cost-effective way to recognize patients who require calcium and vitamin D supplementation.

Daily bisphosphonate is effective in preventing and treating corticosteroid-induced osteoporosis in renal transplant recipients, although it frequently has gastrointestinal side effects. The aim was to assess efficacy and side effect profile of weekly oral risedronate. Eighty-four renal transplant patients, receiving either cyclosporin A or tacrolimus and steroids were prospectively included. The study group (39 patients) received 35 mg risedronate weekly, vitamin D and calcium, while control group (45 patients) only vitamin D and calcium. At baseline, 6 and 12 months, creatinine, calcium, phosphorus, alkaline phosphatase and iPTH were determined. Fractures and bone mineral densities were assessed by X-rays and dual-energy X-ray absorptiometry, respectively. Pain was assessed by clinical interview. Mineral bone density score increased significantly in risedronate group after 1 year. There were no differences in the incidence of fractures, although, anamnestic pain assessment revealed that 3% of treatment group reported to have bone pain compared with 18% in nontreatment group (P < 0.05). Follow-up calcium, phosphorus, alkaline phosphatases, and iPTH levels showed no differences from basal measures. Risedronate was well tolerated with no major side effects. Weekly oral risedronate in renal transplanted patients reduces bone mineral loss and bone pain and has an excellent side effect profile.

BACKGROUND

Arterial thickening contributes to elevated cardiovascular risk in patients on maintenance renal replacement therapy. The common carotid artery intima-media thickness (CCA-IMT) is an early atherosclerotic marker and may be used to assess the stratification of atherosclerotic advancement and resultant arterial calcification.

OBJECTIVE

The aim of the study was to evaluate the associations between atherosclerotic changes in the common carotid arteries expressed as the CCA-IMT and the body mass index (BMI), serum lipid levels, C‑reactive protein (CRP), and selected bone metabolism parameters including phosphorus, calcium, intact parathormone (iPTH), alkaline phosphatase, osteopontin, osteoprotegerin, osteocalcin, fetuin A, and fibroblast growth factor‑23 (FGF‑23) in patients treated with peritoneal dialysis.

METHODS

The study included 67 patients with chronic kidney disease (36 men and 31 women) aged 53 ±13 years (range, 19-75 years) treated with peritoneal dialysis for 30 ±24 months. The CCA‑IMT was assessed by ultrasonography using Acuson 128/10 XP. The BMI was calculated using the Quetelet formula. Serum lipid levels, phosphorus, calcium, iPTH, alkaline phosphatase, and CRP were measured using standard laboratory methods, while fetuin A, osteocalcin, osteoprotegerin, osteopontin, and FGF‑23 using commercial enzyme‑linked immunosorbent assay kits.

RESULTS

Positive correlations were observed between CCA-IMT and age (r = 0.54, P <0.0001), BMI (r = 0.39, P = 0.003), and osteoprotegerin (r = 0.38, P = 0.004). In a multiple regression analysis, age (r = 0.41, P = 0.01), osteocalcin (r = 0.34, P = 0.04), and log‑transformed osteoprotegerin values (r = 0.38, P = 0.02) remained independently associated with the CCA-IMT. The highest CCA‑IMT values (0.85 ±0.21) were observed in patients with osteoprotegerin concentrations in the upper tertile. Osteoprotegerin concentrations strongly and positively correlated with the duration of dialysis treatment (r = 0.55, P <0.0001).

CONCLUSIONS

The CCA‑IMT has been shown to be a reliable noninvasive measure of subclinical atherosclerosis and, therefore, of associated increased vascular risk. Elevated serum osteoprotegerin levels may be useful as a prognostic marker of cardiovascular risk in dialyzed patients.

Calcium metabolism across one menstrual cycle was studied in 12 healthy, premenopausal women. Seven women had documented premenstrual syndrome (PMS), and five were asymptomatic controls. Fasting blood samples were drawn at six points throughout the ovulatory cycle. In both the asymptomatic and the PMS groups, total and ionized calcium declined significantly at midcycle with the increase of estradiol. In the PMS group only, peak midcycle intact PTH was significantly elevated by approximately 30% compared with early follicular levels (49 +/- 25 vs. 37 +/- 22 ng/L, t = 3.79, P = 0.009). In the asymptomatic group, iPTH did not vary during the menstrual cycle. Midcycle iPTH was significantly higher in the PMS group compared with that of the control group (49 +/- 25 vs. 26 +/- 7 ng/L, Wilcoxon Z = 2.28, P = 0.02). Multivariate analysis showed that total and ionized calcium both varied significantly across the menstrual cycle. Significant differences between groups were found for total calcium, 25OHD, and 1,25-(OH)2D. One woman with PMS was treated with oral elemental calcium and cholecalciferol daily for 3 months, with amelioration of her symptoms. Midcycle iPTH and 1,25-(OH)2D declined after repletion of 25OHD. In conclusion, we found that concentrations of total and ionized calcium significantly fluctuate during the menstrual cycle both in symptomatic and in asymptomatic women. We also found that concentrations of iPTH, 25OHD, and 1,25-(OH)2D differed between groups during specific phases of the menstrual cycle. Our data suggest that women with PMS have midcycle elevations of iPTH with a transient, secondary hyperparathyroidism.

BACKGROUND

Chronic kidney disease (CKD) is associated with markedly increased cardiovascular (CV) risk. This increase is not fully explained by traditional CV risk factors but may in part be mediated by nontraditional risk factors, such as inadequate vitamin D (vit D) levels and insulin resistance (IR). Although IR is shown in nondiabetic CKD, its association with vit D deficiency and vascular disease in this population is unknown and what this study aims to investigate.

METHODS

The study comprised 67 patients with CKD (eGFR ≥ 30 mL/min) and 15 healthy controls matched for age and sex. The phlogosis indexes, vit D levels, IR, carotid intima-media thickness (cIMT), and left ventricular mass index (LVMI) were measured.

RESULTS

In our study, the mean value of LVMI and cIMT was significantly higher in patients with eGFR ≥ 30 mL/min compared with controls (p = 0.037 and p < 0.001). The IR and intact parathyroid hormone (iPTH) levels were increased in CKD patients, whereas the serum levels of vit D were significantly reduced (p = 0.044, p = 0.012, p = 0.038). A positive correlation was found between LVMI and IR (r = 0.704, p = 0.041) and a negative correlation was found between IR and vit D levels (r = -0.238, p = 0.031).

CONCLUSIONS

In our study, IR and vit D deficiency were found to be independent predictors of left ventricular hypertrophy and atherosclerotic disease. Vitamin D deficiency and IR are thus associated with increased CV risk. More novel approaches to improving IR and vit D supplementation in the CKD population might lead to potential strategies for preventing excess CV mortality.

OBJECTIVE

To determine the risk factors for the presence of moderate/severe vertebral fracture, specifically 25-hydroxyvitamin D (25-OHD).

METHODS

Cross-sectional study conducted for 2 years in the city of São Paulo, Brazil including community-dwelling elderly women.

METHODS

Bone mineral density (BMD), serum 25-OHD, intact parathyroid hormone (iPTH), calcium and estimated glomerular filtration rate (eGFR) were examined in 226 women without vertebral fractures (NO FRACTURE group) and 189 women with at least one moderate/severe vertebral fracture (FRACTURE group). Vertebral fracture assessment (VFA) was evaluated using both the Genant semiquantitative (SQ) approach and morphometry.

RESULTS

Patients in the NO FRACTURE group had lower age, increased height, higher calcium intake, and higher BMD compared to those patients in the FRACTURE group (p<0.05). Of interest, serum levels of 25-OHD in the NO FRACTURE group were higher than those observed in the FRACTURE group (51.73 nmol/L vs. 42.31 nmol/L, p<0.001). Reinforcing this finding, vitamin D insufficiency (25-OHD<75 nmol/L) was observed less in the NO FRACTURE group (82.3% vs. 93.65%, p=0.001). After adjustment for significant variables within the patient population (age, height, race, calcium intake, 25-OHD, eGFR and sites BMD), the logistic-regression analyses revealed that age (OR=1.09, 95% CI 1.04-1.14, p<0.001) femoral neck BMD (OR=0.7, 95% CI 0.6-0.82, p<0.001) and 25-OHD <75 nmol/L (OR=2.38, 95% CI 1.17-4.8, p=0.016) remains a significant factor for vertebral fracture.

CONCLUSIONS

Vitamin D insufficiency is a contributing factor for moderate/severe vertebral fractures. This result emphasizes the importance of including this modifiable risk factor in the evaluation of elderly women.

BACKGROUND

Calcium is a major component of mineralized tissues and is required for normal growth and maintenance of bone. Epidemiologic studies showed that a large percentage of the population fails to meet the currently recommended guidelines for optimal calcium intake.

OBJECTIVE

The present study was designed to determine whether high-calcium mineral water is an efficient additional source of dietary calcium.

METHODS

Twelve healthy young men (mean +/- SD age: 21.1 +/- 1.2 y) ingested in a randomized order either 0.5 L of a mineral water containing 344 mg Ca/L or 0.5 L of a mineral water with a very low concentration of calcium (<10 mg/L) as a control. Blood samples were drawn before and 1, 2, 3, and 4 h after intake of the water. Urine was collected for 2 h before and every 2 h for 4 h after ingestion of the water. Serum concentrations of intact parathyroid hormone (iPTH) and serum concentrations and urinary excretion of a recently developed biochemical marker of bone resorption, type 1 collagen cross-linked C-telopeptide (CTx), were measured.

RESULTS

Serum iPTH was significantly (P < 0.002) lower after ingestion of high-calcium water than after ingestion of the control. There was a significant (P = 0.01) progressive decrease in urinary CTx after ingestion of the high-calcium water, whereas after ingestion of low-calcium water the changes were modest and not significant. The fall in serum CTx concentrations was 34.7% 3 h after ingestion of high-calcium water, compared with 17.6% with the control. The decreases in serum CTx concentrations were significantly (P < 0.05) lower 1, 2, 3, and 4 h after ingestion of high-calcium water than after ingestion of the control.

CONCLUSIONS

The present study showed that one oral intake of water containing a very moderate dose of calcium (172 mg) acutely inhibited iPTH secretion and bone resorption.

The incidence of parathyroid carcinoma is rare. We recently encountered a case of double carcinoma, located in the right and left upper parathyroid glands. A 67-year old man came to the Teikyo University Hospital because of his bilateral parathyroid masses with hypercalcemia and high parathyroid hormone (PTH). Preoperative diagnoses were parathyroid adenoma in the left lobe and papillary thyroid carcinoma or parathyroid carcinoma in the right lobe. First, the left tumor was removed; however, iPTH was still high. The right mass was then resected and iPTH fell to normal range. Histological examination revealed both tumors were parathyroid carcinoma. To the best of our knowledge, this is the first report of double parathyroid carcinoma confirmed histologically.

OBJECTIVE

In contrast to that in patients with primary hyperparathyroidism, the value of intraoperative intact parathyroid hormone (iPTH) measurement is still unclear in patients with renal hyperparathyroidism and was, therefore, evaluated in a large cohort of patients.

METHODS

Intraoperative iPTH measurement was performed in 153 patients with renal hyperparathyroidism (129 with terminal renal failure and 24 with functioning kidney graft). Subtotal and total parathyroidectomy were performed in 123 and 13 patients, respectively, during initial surgery. In patients with recurrent disease (17), the respective hyperfunctioning tissue was removed. Intraoperative blood samples were obtained by puncture of the internal jugular vein before preparation of the parathyroids (PTH0) and 15 min after parathyroidectomy (PTH15). iPTH was measured with the Elecsys 2010 system. Postoperative iPTH levels (PTH(post)) were determined at postoperative days 1 to 3 and at week 2. Patients were arbitrarily divided in four groups according to the postoperative iPTH values: 0-25 pg/ml (group 1), 26-65 pg/ml (group 2), 66-150 pg/ml (group 3) and more than 150 pg/ml (group 4).

RESULTS

The mean PTH0 value was 869+/-57 pg/ml, which decreased to 167+/-15 pg/ml at PTH15. The mean relative PTH15 value was 21.6+/-1.7%. Postoperatively, iPTH decreased to 42+/-9 pg/ml. The postoperative iPTH value of the 129 patients with terminal renal failure was 25 pg/ml or less in 99 patients, 26-65 pg/ml in 11 patients, 66-150 pg/ml in eight patients and higher than 150 pg/ml in 11 patients. Two successive criteria of iPTH decrease were used: first, a PTH15 of < or =150 pg/ml or, second, a relative PTH15 of < or =30% less was used. Fifteen patients did not fulfil both criteria. In 13 of them (86.7%) iPTH(post) was higher than 65 pg (true failure to decline). Of 114 patients who fulfilled the criteria, 108 (94.7%) had normal postoperative iPTH values (true decline). Absolute PTH15 values of less than 150 pg/ml predicted normal postoperative iPTH levels in 77 of 78 patients.

CONCLUSIONS

A PTH15 value of 150 pg/ml or less predicts operative success in patients with renal failure in 98.7% of cases, independently of the relative decay. In contrast, if the relative PTH15 is higher than 30%, high postoperative PTH values are predicted with a probability of 86.7%. Although there remain some borderline cases, intraoperative iPTH measurement is accurate and also can be useful in patients with renal hyperparathyroidism.