Calcimimetic and Calcilytic Drugs: Feats, Flops, and Futures.

The actions of extracellular Ca(2+) in regulating parathyroid gland and kidney functions are mediated by the extracellular calcium receptor (CaR), a G protein-coupled receptor. The CaR is one of the essential molecules maintaining systemic Ca(2+) homeostasis and is a molecular target for drugs useful in treating bone and mineral disorders. Ligands that activate the CaR are termed calcimimetics and are classified as either agonists (type I) or positive allosteric modulators (type II); calcimimetics inhibit the secretion of parathyroid hormone (PTH). Cinacalcet is a type II calcimimetic that is used to treat secondary hyperparathyroidism in patients receiving dialysis and to treat hypercalcemia in some forms of primary hyperparathyroidism. The use of cinacalcet among patients with secondary hyperparathyroidism who are managed with dialysis effectively lowers circulating PTH levels, reduces serum phosphorus and FGF23 concentrations, improves bone histopathology, and may diminish skeletal fracture rates and the need for parathyroidectomy. A second generation type II calcimimetic (AMG 416) is currently under regulatory review. Calcilytics are CaR antagonists that stimulate the secretion of PTH. Several calcilytic compounds have been evaluated as orally active anabolic therapies for postmenopausal osteoporosis but clinical development of all of them has been abandoned because they lacked clinical efficacy. Calcilytics might be repurposed for new indications like autosomal dominant hypocalcemia or other disorders beyond those involving systemic Ca(2+) homeostasis.

The effects of cinacalcet on blood pressure, mortality and cardiovascular endpoints in the EVOLVE trial.

Patients with end-stage renal disease often have derangements in calcium and phosphorus homeostasis and resultant secondary hyperparathyroidism (sHPT), which may contribute to the high prevalence of arterial stiffness and hypertension. We conducted a secondary analysis of the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial, in which patients receiving hemodialysis with sHPT were randomly assigned to receive cinacalcet or placebo. We sought to examine whether the effect of cinacalcet on death and major cardiovascular events was modified by baseline pulse pressure as a marker of arterial stiffness, and whether cinacalcet yielded any effects on blood pressure. As reported previously, an unadjusted intention-to-treat analysis failed to conclude that randomization to cinacalcet reduces the risk of the primary composite end point (all-cause mortality or non-fatal myocardial infarction, heart failure, hospitalization for unstable angina or peripheral vascular event). However, after prespecified adjustment for baseline characteristics, patients randomized to cinacalcet experienced a nominally significant 13% lower adjusted risk (95% confidence limit 4-20%) of the primary composite end point. The effect of cinacalcet was not modified by baseline pulse pressure (Pinteraction=0.44). In adjusted models, at 20 weeks cinacalcet resulted in a 2.2 mm Hg larger average decrease in systolic blood pressure (P=0.002) and a 1.3 mm Hg larger average decrease in diastolic blood pressure (P=0.002) compared with placebo. In summary, in the EVOLVE trial, the effect of cinacalcet on death and major cardiovascular events was independent of baseline pulse pressure.

Calcium-mediated parathyroid hormone suppression to assess progression of secondary hyperparathyroidism during treatment among incident dialysis patients.

CONTEXT: Parathyroid gland function is affected adversely by tissue hyperplasia and gland enlargement in hyperparathyroidism. OBJECTIVE: We examined the effects of 2 treatment strategies on the progression of secondary hyperparathyroidism using measurements of the nonsuppressible component of calcium-regulated PTH secretion as an index of parathyroid mass. DESIGN, SUBJECTS, AND INTERVENTION: In this randomized, open-label study, subjects managed with hemodialysis for >3 but <12 months before entering the trial (mean, 7.2 months) who had baseline plasma PTH levels >300 pg/mL received cinacalcet and low-dose vitamin D sterols (Cin-D, n = 153) or larger, varying doses of calcitriol, or other vitamin D analogs (Flex-D, n = 151). Study drug doses were adjusted periodically based on PTH and serum total calcium determinations. MAIN OUTCOME MEASURES: The exploratory endpoint was calcium-regulated PTH release, assessed using a standardized PTH suppression test before and after 52 weeks of treatment and 4 weeks after withdrawing treatment. PTH and serum total calcium were measured before hemodialysis using high-calcium (3.5 mEq/L or 1.75 mmol/L) dialysate and after 150 and 180 minutes. RESULTS: Mean (95% confidence interval) nonsuppressible calcium-regulated PTH release at baseline did not differ between Cin-D, 33.4% (25.9%, 40.9%), and Flex-D, 28.1% (23.2%, 32.9%). Corresponding values after 52 weeks of treatment were 34.3% (29.7%, 38.9%) and 42.0% (32.7%, 51.3%), not significant, and did not change measurably in either group when reevaluated 4 weeks after treatments were withdrawn. CONCLUSION: Disease progression over 12 months was not documented using a PTH suppression test in this population. Calcium-mediated PTH suppression was maintained fully, however, in Cin-D despite reductions in serum total calcium concentration, whereas values did not increase in Flex-D despite substantial increases in serum calcium.

An assessment of cinacalcet HCl effects on bone histology in dialysis patients with secondary hyperparathyroidism.

AIMS: Cinacalcet lowers plasma parathyroid hormone (PTH) levels in patients with secondary hyperparathyroidism (sHPT), but the bone histologic response has not been described. This prospective, double-blind, placebo-controlled trial assessed the effects of cinacalcet on bone histology and serum markers of bone metabolism in dialysis patients with sHPT. METHODS: Patients with intact PTH (iPTH) > or = 300 pg/ml were randomly assigned 2:1 to receive cinacalcet or placebo with concurrent vitamin D and/or phosphate binder therapy. Cinacalcet (30 - 180 mg/day) was used to achieve iPTH levels < or = 200 pg/ml. Bone biopsies were performed before and after one year of treatment. RESULTS: Baseline and end-of-study data were available from 32 patients (19 cinacalcet, 13 placebo). Baseline bone turnover was elevated in 27, reduced in 3 and normal in 2 patients. Serum bone-specific alkaline phosphatase (BSAP) and N-telopeptide (NTx) were elevated. Cinacalcet treatment decreased PTH and diminished activation frequency, bone formation rate/bone surface, and fibrosis surface/bone surface. Adynamic bone was observed in three patients receiving cinacalcet; in two of these, PTH levels were persistently low (< 100 pg/ml). The histomorphometric parameter changes in bone corresponded to PTH, BSAP and NTx reductions. Bone mineralization parameters remained normal. CONCLUSIONS: Treatment with cinacalcet lowered PTH and reduced bone turnover and tissue fibrosis among most dialysis patients with biochemical evidence of sHPT.

Sequence, structure and expression of the hemolymph juvenile hormone binding protein gene in the tobacco hornworm, Manduca sexta.

The hemolymph juvenile hormone binding protein (hJHBP) gene of Manduca sexta is a key target of its specific ligand, juvenile hormone (JH). While the cDNA for hJHBP has been partially characterized, little is known about the hJHBP gene structure or its promoter(s) and enhancers(s). Previous studies have demonstrated that JH stimulates a rapid accumulation of hJHBP mRNA in the fat body. To better understand the underlying molecular events affecting regulation, we sequenced the M. sexta hJHBP gene and its mRNA transcript, characterized its genomic organization, and determined the spatial and temporal expression patterns of the hJHBP gene. The gene is composed of 5 exons spanning 6.7 kb. Southern blot analysis indicates that the gene is present as a single copy. The earliest expression of hJHBP occurs 24 to 48 h after fertilization. Distribution studies indicate that fat body is the only site for hJHBP expression. Elements displaying similarity with sequences of other lepidopteran genes were discovered outside the open reading frame and may represent mobile insertion elements.

Biosynthetic pathway of insect juvenile hormone III in cell suspension cultures of the sedge Cyperus iria.

In most insect species, juvenile hormones regulate critical physiological processes such as metamorphosis and reproduction. In insects, these sesquiterpenoids are synthesized by retrocerebral endocrine organs, the corpora allata, via the classical mevalonate (MVA) pathway. One of these compounds, juvenile hormone III (JH III), has also been identified in the sedge Cyperus iria. In higher plants, biosynthesis of the sesquiterpenoid backbone may proceed through two distinct pathways: the MVA pathway or the 2C-methyl erythritol 4-phosphate pathway or through a combination of both pathways. Cell suspension cultures of C. iria were used to elucidate the biosynthetic pathway of JH III in the plant. Enzyme inhibition and labeling studies conclusively demonstrated that the biosynthesis of the sesquiterpenoid backbone of JH III proceeds via the MVA pathway. Inhibitor and precursor feeding studies also suggest that later steps of JH III biosynthesis in C. iria are similar to the insect pathway and that the final enzymatic reaction in JH III biosynthesis is catalyzed by a cytochrome P(450) monooxygenase.

Calcimimetic agents for the treatment of hyperparathyroidism.

Calcimimetic agents are small organic molecules that act as allosteric activators of the calcium sensing receptor. They lower the threshold for receptor activation by extracellular calcium ions and, in parathyroid cells, diminish parathyroid hormone secretion. Calcimimetic compounds represent a novel class of therapeutic agents that may provide a way of controlling excess parathyroid hormone secretion in several clinical disorders. Although experience from clinical trials in humans is limited, available data suggest that calcimimetic agents effectively lower plasma parathyroid hormone levels in patients with primary hyperparathyroidism and those with secondary hyperparathyroidism caused by end-stage renal disease. Calcimimetic compounds thus have considerable potential as a new approach to the medical management of several important clinical disorders of bone and mineral metabolism.

Non-invasive assessments of cardiovascular disease in patients with renal failure.

Vascular calcification is common in patients with chronic renal failure, and it may contribute to the very high mortality rate from cardiovascular causes in the end-stage renal disease population. Vascular calcification in chronic renal failure can arise from the calcification of the intimal layer of arteries as a result of atherosclerosis or from medial wall calcification due largely to alterations in mineral metabolism. Although several reports indicate that coronary artery calcification, as measured by electron-beam computed tomography, is quite common in patients with end-stage renal disease who are treated with dialysis, the clinical significance of these findings remain uncertain. In the general population, electron-beam computed tomography evidence of coronary calcification serves as a useful index of atherosclerotic burden and has value as a predictor of adverse coronary events. The relationship between coronary artery calcification and atherosclerotic cardiovascular disease has not been adequately studied, however, in patients with end-stage renal disease, and calcification scores in this population may reflect both intimal and medial wall calcification. Assessments using coronary angiography are needed to determine the diagnostic value of electron-beam computed tomography as a predictor of atherosclerotic cardiovascular disease in patients with chronic renal failure. Nevertheless, electron-beam computed tomography makes it possible to detect the presence and monitor the progression of coronary calcification in those undergoing long-term dialysis. The technique may provide important information about the impact of new therapeutic strategies aimed at reducing the risks of vascular calcification in those with chronic renal failure.

Efficacy and side effects of intermittent intravenous and oral doxercalciferol (1alpha-hydroxyvitamin D(2)) in dialysis patients with secondary hyperparathyroidism: a sequential comparison.

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.

Neuroendocrine factors affecting the steady-state levels of early trypsin mRNA in Aedes aegypti.

Transcription of the early trypsin gene occurs in the midgut after adult emergence under control of juvenile hormone (JH). We tested the hypothesis that factors that affect the steady-state levels of early trypsin mRNA do so by influencing the levels of JH. We investigated the effect of ingesting different meals on early trypsin mRNA levels as well as on JH levels. We also studied how early trypsin mRNA levels changed when the midgut was isolated from different components of the neuroendocrine system by abdominal ligation and decapitation. Early trypsin transcripts levels are high in unfed females; feeding different meals had three distinct effects on the changes of steady-state levels of early trypsin mRNA: (1) blood and protein meals caused the level to decrease drastically and remained low for at least 24 h; (2) amino acid meals caused a transient decrease in the mRNA level, but it returned to high levels after 12-18 h; and (3) sugar, latex and saline meals had no effect on the early trypsin mRNA steady-state levels. The changes in JH levels after ingesting blood and amino acid meals show profiles resembling the changes in early trypsin mRNA levels for the corresponding meal. Decapitation at 1, 2 and 3 days after emergence does not affect the steady-state levels of early trypsin in unfed females. In contrast, 24 h after feeding, transcript levels were significantly higher in decapitated females when compared with non-decapitated fed females. We propose that the changes in the steady-state levels of early trypsin mRNA observed after the ingestion of different meals, ligations and decapitations are generated by changes in the levels of juvenile hormone.

Intermittent doxercalciferol (1alpha-hydroxyvitamin D(2)) therapy for secondary hyperparathyroidism.

Hypercalcemia and hyperphosphatemia frequently necessitate vitamin D withdrawal in hemodialysis patients with secondary hyperparathyroidism. In short-term trials, doxercalciferol (1alpha-hydroxyvitamin D(2) [1alphaD(2)]) suppressed intact parathyroid hormone (iPTH) effectively with minimal increases in serum calcium and phosphorus (P) levels. This modified, double-blinded, controlled trial examined the efficacy and safety of 1alphaD(2) use in 138 hemodialysis patients with moderate to severe secondary hyperparathyroidism by using novel dose titration; 99 patients completed the study. Hemodialysis patients with secondary hyperparathyroidism were enrolled onto this study, consisting of washout (8 weeks), open-label 1alphaD(2) treatment (16 weeks), and randomized, double-blinded treatment with 1alphaD(2) or placebo (8 weeks). Oral 1alphaD(2) was administered at each hemodialysis session, with doses titrated to achieve target iPTH levels of 150 to 300 pg/mL. Baseline iPTH levels (897 +/- 52 [SE] pg/mL) decreased by 20% +/- 3.4% by week 1 (P: < 0.001) and by 55% +/- 2.9% at week 16; iPTH levels returned to baseline during placebo treatment but remained suppressed with 1alphaD(2) treatment. In 80% of the patients, iPTH level decreased by 70%, reaching the target level in 83% of the patients. Grouping patients by entry iPTH level (<600, 600 to 1,200, and >1,200 pg/mL) showed rapid iPTH suppression in the group with the lowest level; greater doses and longer treatment were required in the group with the highest level. During open-label treatment, serum calcium and P levels were 9.2 +/- 0.84 (SD) to 9.7 +/- 1.05 mg/dL and 5.4 +/- 1.10 to 5.9 +/- 1.55 mg/dL, respectively. During double-blinded treatment, serum calcium levels were slightly greater with 1alphaD(2) than placebo, but P levels did not differ. During double-blinded treatment, 3.26% and 0.46% of serum calcium measurements exceeded 11.2 mg/dL with 1alphaD(2) and placebo, respectively (P: < 0.01); median level was 11.6 mg/dL during hypercalcemia. Intermittent oral 1alphaD(2) therapy effectively suppresses iPTH in hemodialysis patients with secondary hyperparathyroidism, with acceptable mild hypercalcemia and hyperphosphatemia.

A calcimimetic agent lowers plasma parathyroid hormone levels in patients with secondary hyperparathyroidism.

BACKGROUND: The calcimimetic agent R-568 lowers plasma parathyroid hormone (PTH) levels in hemodialysis patients with mild secondary hyperparathyroidism, but its efficacy in those with more severe secondary hyperparathyroidism has not been studied. METHODS: Twenty-one patients undergoing hemodialysis three times per week with plasma PTH levels between 300 and 1200 pg/mL were randomly assigned to 15 days of treatment with either 100 mg of R-568 (N = 16) or placebo (N = 5). Plasma PTH and blood ionized calcium levels were measured at intervals of up to 24 hours after oral doses on days 1, 2, 3, 5, 8, 11, 12, and 15. RESULTS: Pretreatment PTH levels were 599 +/- 105 (mean +/- SE) and 600 +/- 90 pg/mL in subjects given R-568 or placebo, respectively, and values on the first day of treatment did not change in those given placebo. In contrast, PTH levels fell by 66 +/- 5%, 78 +/- 3%, and 70 +/- 3% at one, two, and four hours, respectively, after initial doses of R-568, remaining below pretreatment values for 24 hours. Blood ionized calcium levels also decreased after the first dose of R-568 but did not change in patients given placebo. Despite lower ionized calcium concentrations on both the second and third days of treatment, predose PTH levels were 422 +/- 70 and 443 +/- 105 pg/mL, respectively, in patients given R-568, and values fell each day by more than 50% two hours after drug administration. Predose PTH levels declined progressively over the first nine days of treatment with R-568 and remained below pretreatment levels for the duration of study. Serum total and blood ionized calcium concentrations decreased from pretreatment levels in patients given R-568, whereas values were unchanged in those given placebo. Blood ionized calcium levels fell below 1.0 mmol/L in 7 of 16 patients receiving R-568; five patients withdrew from study after developing symptoms of hypocalcemia, whereas three completed treatment after the dose of R-568 was reduced. CONCLUSIONS: The calcimimetic R-568 rapidly and markedly lowers plasma PTH levels in patients with secondary hyperparathyroidism caused by end-stage renal disease.

Implications of intermittent calcitriol therapy on growth and secondary hyperparathyroidism.

Secondary hyperparathyroidism is the most common skeletal lesion in pediatric patients undergoing maintenance dialysis. The present review summarizes a prospective randomized study that evaluated the biochemical and skeletal responses to intermittent calcitriol therapy in 33 pediatric patients on peritoneal dialysis with secondary hyperparathyroidism. Also, the effect of intermittent calcitriol therapy on linear growth was evaluated in 16 of 33 patients who had completed the clinical trial. Serum parathyroid hormone levels decreased by 62% from 648+/-125 pg/ml in patients treated with intermittent intraperitoneal (IP) calcitriol, and values remained unchanged from pre-treatment levels of 670+/-97 pg/ml with oral calcitriol therapy. Overall serum total and ionized calcium levels were higher in patients treated with IP calcitriol during the study. In contrast to these biochemical findings, the skeletal lesions of secondary hyperparathyroidism improved after 12 months of treatment in both groups and adynamic bone occurred in 33% of the patients. Z-scores for height decreased from -1.80 /-0.3 to -2.00+/-0.3, P<0.01, after 12 months of intermittent calcitriol therapy. Such findings suggest that an intermittent schedule of calcitriol administration adversely affects chondrocyte activity within epiphyseal cartilage in pre-pubertal children with end-stage renal disease.

Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis.

BACKGROUND: Cardiovascular disease is common in older adults with end-stage renal disease who are undergoing regular dialysis, but little is known about the prevalence and extent of cardiovascular disease in children and young adults with end-stage renal disease. METHODS: We used electron-beam computed tomography (CT) to screen for coronary-artery calcification in 39 young patients with end-stage renal disease who were undergoing dialysis (mean [+/-SD] age, 19+/-7 years; range, 7 to 30) and 60 normal subjects 20 to 30 years of age. In those with evidence of calcification on CT scanning, we determined its extent. The results were correlated with the patients' clinical characteristics, serum calcium and phosphorus concentrations, and other biochemical variables. RESULTS: None of the 23 patients who were younger than 20 years of age had evidence of coronary-artery calcification, but it was present in 14 of the 16 patients who were 20 to 30 years old. Among those with calcification, the mean calcification score was 1157+/-1996, and the median score was 297. By contrast, only 3 of the 60 normal subjects had calcification. As compared with the patients without coronary-artery calcification, those with calcification were older (26+/-3 vs. 15+/-5 years, P<0.001) and had been undergoing dialysis for a longer period (14+/-5 vs. 4+/-4 years, P< 0.001). The mean serum phosphorus concentration, the mean calcium-phosphorus ion product in serum, and the daily intake of calcium were higher among the patients with coronary-artery calcification. Among 10 patients with calcification who underwent follow-up CT scanning, the calcification score nearly doubled (from 125+/-104 to 249+/-216, P=0.02) over a mean period of 20+/-3 months. CONCLUSIONS: Coronary-artery calcification is common and progressive in young adults with end-stage renal disease who are undergoing dialysis.

Impaired growth, delayed ossification, and reduced osteoclastic activity in the growth plate of calcium-supplemented rats with renal failure.

Linear growth is reduced in prepubertal children with adynamic renal osteodystrophy, suggesting that the proliferation and/or differentiation of epiphyseal growth plate chondrocytes is abnormal in this disorder. To examine this issue, in situ hybridization and histochemistry were used to measure selected markers of endochondral bone formation and bone resorption in the proximal tibia of subtotally nephrectomized rats fed a high calcium diet to induce biochemical changes consistent with adynamic osteodystrophy. Blood ionized calcium concentrations were higher and serum PTH levels were lower in nephrectomized, calcium-supplemented rats than in either intact or nephrectomized control animals. Linear growth and tibial length were reduced, but messenger RNA levels for type II collagen, type X collagen, and the PTH/PTHrP receptor did not differ from control values in nephrectomized rats given supplemental calcium. In contrast, both the width of epiphyseal cartilage and the height of the zone of hypertrophic chondrocytes were greater in calcium-supplemented nephrectomized rats. These morphological changes were associated with decreases in histochemical staining for tartrate-resistant acid phosphatase and lower levels of messenger RNA expression for the matrix metalloproteinase MMP-9/gelatinase B immediately adjacent to the epiphyseal growth plate. Diminished chondroclastic/osteoclastic activity alters growth plate morphology and adversely affects linear bone growth in calcium-supplemented, nephrectomized rats.

Increased bone strontium levels in hemodialysis patients with osteomalacia.

BACKGROUND: In this study, we report on the association between increased bone strontium levels and the presence of osteomalacia in end-stage renal failure patients treated by hemodialysis. METHODS: We performed a histologic examination and determined the strontium content and strontium/calcium ratios in bone biopsies of 100 hemodialysis patients recruited from various centers all over the world. Aside from the bone strontium concentration, the bone aluminum content was assessed. The bone zinc concentration, a nonrelevant element for bone toxicity, was also measured. RESULTS: Bone strontium levels and bone strontium/calcium ratios were increased in subjects with osteomalacia when compared with those with the other types of renal osteodystrophy. Bone strontium and bone calcium levels correlated with each other. The slope of the linear regression curve correlating these parameters was much steeper in the osteomalacic group (Y = 2.22X - 120) as compared with the other types of renal osteodystrophy (Y = 0.52X - 5.7). Within the group of patients with osteomalacia, bone strontium levels also significantly correlated with the bone aluminum content (r = 0.72, P = 0.018). No such correlation was found for the other types of renal osteodystrophy. The bone zinc concentration of subjects with normal renal function did not differ significantly from the values noted for the various types of renal osteodystrophy taken as separate groups, nor could increased bone zinc concentrations be associated with a particular bone lesion. CONCLUSIONS: Our data demonstrate an association between osteomalacia and increased bone strontium concentrations in dialysis patients. Further studies are warranted to establish whether strontium plays either a primary, secondary, or contributive role in the development of the latter type of renal osteodystrophy.

Altered diurnal regulation of blood ionized calcium and serum parathyroid hormone concentrations during parenteral nutrition.

BACKGROUND: Little is known about parathyroid gland function in patients receiving total parenteral nutrition (TPN). OBJECTIVE: Our objective was to determine whether parathyroid gland function is abnormal in TPN recipients. DESIGN: Six patients with a mean (+/-1 SD) age of 45.5 +/- 8.0 y who had been receiving TPN for 18.7 +/- 2. 8 y underwent bone biopsy, bone mass measurements with dual-energy X-ray absorptiometry, and dynamic tests of parathyroid gland function. Diurnal variations in blood ionized calcium (iCa(2+)) and serum parathyroid hormone (PTH) concentrations were also assessed. Results were compared with those of healthy volunteers. RESULTS: Bone mass and bone formation were subnormal in all patients. Basal serum PTH concentrations were moderately higher in the TPN recipients than in healthy volunteers, and values obtained every 30 min over 24 h were significantly higher (P < 0.001) in TPN recipients (5.0 +/- 0.9 pmol/L) than in healthy volunteers (2.6 +/- 0.6 pmol/L). The percentage increase in serum PTH during citrate-induced hypocalcemia was lower in the TPN recipients, consistent with secondary hyperparathyroidism. Evening infusions of calcium-containing TPN eliminated the nocturnal rise in serum PTH, increased the amplitude of change for iCa(2+) and PTH over 24 h, increased the orderliness of change for iCa(2+) and PTH as measured by approximate entropy (ApEn), and enhanced the synchrony of change between iCa(2+) and PTH. Treatment for 10 d with calcium-free TPN restored the nocturnal rise in serum PTH and increased ApEn for PTH. ApEn for iCa(2+) remained low, suggesting that a component of nutrient solutions, but not calcium per se, enhances the regularity of PTH release in TPN recipients. CONCLUSION: Parathyroid gland function is abnormal in long-term TPN recipients, which may contribute to disturbances in bone metabolism.