Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020437 (hypercalcemia)
 10,293 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

ED-71 is a potent analog of active vitamin D, 1,25 (OH) (2)D(3), bearing a hydroxypropoxy substituent at the 2beta-position. In ovariectomized rats, ED-71 prevented the reduction in bone mass and strength of lumber spine without causing hypercalcemia. From those results, it was suggested that ED-71 preferentially enhances bone formation with less effects on intestinal calcium absorption. In osteoporotic patients, oral daily administration of ED-71 (0.25, 0.5, 0.75 and 1.0 microg) for 6 months increased bone mineral density (BMD) at L(2-4) in a dose-dependent manner. ED-71 also exhibited a dose-depend suppression of urinary deoxypyridinoline with no significant reduction in serum osteocalcin. These results demonstrate that ED-71 can effectively increase bone mass without causing hypercalcemia, and suggest that ED-71 can be a promising candidate for the treatment of osteoporosis with prominent effect on bone formation.
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PMID:[ED-71]. 1577 13

Loss of renal function perturbs bone metabolism because kidney is a vital organ maintaining homeostasis of calcium and phosphate. In hemodialysis patients, bone diseases are serious complications resulting in fractures and extraosseous calcification. The latest clinical practice guidelines by the National Kidney Foundation (New York, US) recommend a dialysate calcium concentration (D-Ca) of 2.5 mEq/L rather than 3.0 mEq/L to avoid excess calcium load and to prevent subsequent vascular calcification. However, there is no perfect agreement yet about which concentration should be chosen because lowering D-Ca might enhance uncoupled bone resorption. Here, we studied effects of lowering D-Ca from 3.0 to 2.5 mEq/L on bone metabolism in 67 patients. Doses of vitamin D and phosphate binders were kept constant for a 2-month period beginning 1 month before the change in D-Ca, and were adjusted thereafter. In group A [intact parathyroid hormone (iPTH) < 100 pg/ml before the study], serum cross-linked N-terminal telopeptide of type I collagen (NTx) increased immediately after lowering D-Ca and then remained stable. Intact osteocalcin (iOC) increased later along with iPTH, suggesting the improvement of adynamic bone disease which shows a marked decrease in bone turnover without osteoid accumulation. Vitamin D was not dosed up in this group. In group B (100 < or = iPTH < 300), serum NTx increased transiently, which is followed by an increase of iOC but not by a change of iPTH. In group C (300 < or = iPTH), lowering D-Ca allowed us to increase the dose of vitamin D without hypercalcemia, leading to a significant decrease in NTx and iPTH. Overall, serum phosphate increased from 5.4 +/- 1.6 to 6.1 +/- 1.6 mg/dL (P < 0.0001) and serum NTx increased by 1.5-fold (P < 0.0001) 1 month after lowering D-Ca. Over a 3-month period after that, serum phosphate and serum NTx decreased to their basal levels. These indicate that bone resorption predominated over formation for only a short period. In conclusion, a D-Ca of 2.5 mEq/L with adjustment of vitamin D ameliorates metabolic abnormalities of bone which develop under 3.0 mEq/L.
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PMID:Impact of lowering dialysate calcium concentration on serum bone turnover markers in hemodialysis patients. 1579 28

A 78-year-old male was urgently admitted to our hospital because of consciousness disturbance. Laboratory data showed marked hypercalcemia (17.0 mg/dl), hypophosphatemia, low intact PTH level, high PTH relating peptide (PTHrP) level, normal osteocalcin and normal 1-25(OH)2D level. Computed tomography revealed a right renal tumor with extracapsular extension. Bone scintigram appeared normal. We performed right nephrectomy under the diagnosis of right renal tumor. Pathological diagnosis was poorly differentiated squamous cell carcinoma (SCC) of the right pelvis. Immunohistochemical study of the resected specimen for PTHrP was positive. Therefore, we diagnosed it as renal pelvic SCC with humoral hypercalcemia of malignancy (HHM). After nephrectomy, serum calcium returned to normal, but 5 months after nephrectomy, local recurrence appeared and serum calcium was re-elevated. She died 7 months after nephrectomy.
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PMID:[A case of renal pelvic squamous cell carcinoma accompanied with humoral hypercalcemia of malignancy (HHM)]. 1591 87

Parathyroid hormone (PTH) stimulates bone resorption as well as bone formation in vivo and in organ culture. The catabolic actions of PTH have been recognized in patients with hyperparathyroidism, or with acute infusion of the N-terminal 1-34 fragment of human PTH (hPTH1-34). Whereas the anabolic actions of daily injection with PTH have been well studied in both humans and mice, the catabolic actions of PTH on murine bone remain to be defined. To do this we sought to create a model with short-term, sustained hyperparathyroidism using osmotic infusion pumps. We treated 10-week-old female C57BL/J6 mice with continuous infusion of hPTH1-34 (8.1 pmol/0.25 microl per h, equivalent to 40 microg/kg per day) or vehicle for 2 weeks, using Alzet osmotic pumps. Bone mineral density (BMD), serum total calcium, hPTH1-34, mouse intact PTH (mPTH1-84), osteocalcin and mouse tartrate-resistant acid phosphatase (mTRAP) activity, and microarchitectural variables of the distal femur were measured. Separately, we compared the effects of intermittent daily injection of hPTH1-34 (40 microg/kg per day) with continuous infusion of hPTH1-34 on BMD and bone markers. Exogenous hPTH1-34 was detected only in the PTH-infused mice. Both intermittent and continuous treatment with hPTH1-34 markedly suppressed endogenous mPTH1-84, but only the latter induced hypercalcemia. Daily PTH injection significantly increased both serum osteocalcin and mTRAP, while continuous PTH infusion showed a strong trend to stimulate mTRAP, with a slight but non-significant increase in osteocalcin. There were significant differences in BMD at all sites between animals treated with the same daily dose of intermittent and continuous hPTH1-34. Micro-computed tomography (muCT) analysis of the distal femurs revealed that hPTH1-34 infusion significantly decreased trabecular connectivity density (P<0.05). Thus, the murine bone response to continuous PTH infusion was quite different from that seen with daily PTH injection. Short-term infusion of hPTH1-34 appears to be a good model to study the mechanisms underlying the catabolic action of PTH in mice.
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PMID:Short-term continuous infusion of human parathyroid hormone 1-34 fragment is catabolic with decreased trabecular connectivity density accompanied by hypercalcemia in C57BL/J6 mice. 1613 74

To investigate the relationship between ionized calcium and disease activity, parameters of bone metabolism and bone mineral density (BMD) at the lumbar spine (BMD-LS) and the femoral neck (BMD-FN) measured by dual X-ray absorptiometry in rheumatoid arthritis (RA). In 146 patients with RA, the following parameters were investigated: serum levels of ionized calcium, total calcium, vitamin D metabolites 25-hydroxyvitamin D3 (25D3) and 1,25-dihydroxyvitamin D3 (1,25D3), intact parathyroid hormone (iPTH), interleukin-6, osteocalcin, erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP); renal excretion of pyridinolin (PYD)- and desoxypyridinolin (DPD)-crosslinks. A total of 30.1% of the patients were hypercalcemic (ionized calcium >1.30 mmol/l). In comparison with normocalcemic patients, those with hypercalcemia had significantly higher ESR (P<0.01) and CRP values (P<0.05) and significantly lower serum levels of both iPTH (P<0.01) and 1,25D3 (P<0.05) and a significantly lower BMD-LS (P<0.05). The results indicate that a substantial part of RA patients is hypercalcemic. Hypercalcemia is associated with high disease activity and may contribute to suppression of PTH secretion and vitamin D hormone synthesis. High levels of ionized calcium may be a reflection of disease-activity-related systemic bone loss, and could be a predictor of BMD at the lumbar spine in RA.
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PMID:Hypercalcemia in rheumatoid arthritis: relationship with disease activity and bone metabolism. 1640 62

Global gene expression profiling has been used to study the molecular mechanisms of increased bone remodeling caused by PHPT. This disease is a model for chronic over-stimulation of target organs by PTH due to an inappropriate overproduction of the hormone. Hyperactivity of osteoblasts and osteoclasts lead to increased calcium and phosphate mobilization from the skeleton and hypercalcaemia. The ensemble of genes that alter expression and thus is responsible for the effects of chronic PTH stimulation is today largely unknown. The differentiated gene expression profiles revealed characteristic molecular disease modalities which define the bone remodeling abnormalities occurring in PTH dependent osteodystrophy. We analyzed mRNAs in transiliacal bone biopsies from 7 patients with PHPT using Affymetrix HG-U133A Gene Chips containing more than 22000 different probe sets. Similar analyses of the global transcriptional activity were repeated in a second bone biopsy from the same patient taken one year after surgery and reversal of disease parameters. Real time PCR was carried out on many genes for corroboration of the results. Out of more than 14500 different genes examined, 99 which were related to bone and extra-cellular matrix, showed altered expression. Of these were 85 up- and 14 down-regulated before operation. The majority of regulated genes represented structural and adhesion proteins, but included also proteases and protease regulators which promote resorption. Increased expressions of collagen type 1 and osteocalcin mRNAs in disease reflecting the PTH anabolic action were paralleled by increased concentrations of these proteins in serum. In addition, genes encoding transcriptional factors and their regulators as well as cellular signal molecules were up-regulated during disease. The identified genetic signature represents the first extensive description of the ensemble of bone and matrix related mRNAs, which are regulated by chronic PTH action. These results identify the molecular basis for this skeletal disease, and provide new insight into this clinical condition with potential bearing on future treatment.
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PMID:Gene expression profiles give insight into the molecular pathology of bone in primary hyperparathyroidism. 1651 70

black triangle An oral formulation of paricalcitol has been developed for the prevention and treatment of secondary hyperparathyroidism in patients with stage 3 or 4 chronic kidney disease.black triangle Paricalcitol is a synthetic vitamin D analog that binds to the vitamin D receptor inducing suppression of parathyroid hormone (PTH) secretion.black triangle Oral paricalcitol was significantly more effective than placebo in treating secondary hyperparathyroidism in patients with stage 3 or 4 chronic kidney disease. In a pooled analysis of three well designed, 24-week trials, two consecutive reductions from baseline in intact PTH levels of >/=30% were achieved by significantly more paricalcitol than placebo recipients (91% vs 13%).black triangle In addition, mean levels of the biochemical bone markers serum bone-specific alkaline phosphatase, serum osteocalcin, and urinary pyridinoline were reduced from baseline to a significantly greater extent with paricalcitol than with placebo, indicating a reduction in bone turnover.black triangle Oral paricalcitol was well tolerated; there was no significant difference between paricalcitol and placebo recipients in the incidence of hypercalcemia, hyperphosphatemia, or elevated calcium-phosphorus product.
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PMID:Oral paricalcitol. 1700 90

The purpose of this crossover comparison study is to elucidate the differences between the effects of a novel calcitriol analog, 22-oxacalcitriol, and calcitriol on parathyroid hormone (PTH) and bone mineral metabolism in hemodialysis patients with secondary hyperparathyroidism (SHPT). Twenty-three patients with moderate to severe SHPT were included in a random 2 x 2 crossover trial with two vitamin D analogs (12 weeks for each treatment). Two patients withdrew during the run-in period for personal reasons. Serum electrolyte, bone metabolic marker, intact PTH (iPTH) and whole PTH (wPTH) levels were measured periodically. The primary endpoint measure was a decrease in serum iPTH level, and the secondary outcome measures included changes in serum calcium (Ca), phosphate (P), and metabolic bone marker levels. Both treatments decreased iPTH and wPTH levels by similar degrees. Serum Ca, P, and Ca x P product levels at the end of each treatment were comparable and the frequencies of hypercalcemia and hyperphosphatemia were also similar during each treatment period. 22-Oxacalcitriol significantly decreased the levels of bone metabolic markers, namely, bone-specific alkaline phosphate, intact osteocalcin, pyridinoline, and cross-linked N-telopeptide of type I collagen, after a 12-week treatment. In contrast, calcitriol did not change any of the levels of bone metabolic markers. The present study showed that 22-oxacalcitriol is equally effective for PTH suppression, and Ca and P metabolism. In addition, 22-oxacalcitriol might have putative actions on bone remodeling independent of its PTH suppression. Further study is necessary to confirm the effects of 22-oxacalcitriol on bone metabolism in SHPT.
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PMID:Effects of 22-oxacalcitriol and calcitriol on PTH secretion and bone mineral metabolism in a crossover trial in hemodialysis patients with secondary hyperparathyroidism. 1749 2

Hypercalcemia in persistent secondary hyperparathyroidism after kidney transplantation is considered to result from increased bone resorption. Bone biopsies' studies, however, have never been performed in these patients. Bone biopsies after double tetracycline labeling were obtained from 17 patients with hypercalcemic hyperparathyroidism and an estimated glomerular filtration rate > 30 mL/min/1.73 m2. Serologic bone markers, calcitriol, intact fibroblast growth factor-23 (iFGF-23), and serum and 24h urine concentration of calcium and phosphate were measured in all patients. Tubular maximum for phosphate corrected for GFR (TmP/GFR), and the fractional excretion of calcium (FeCa) were calculated. High-turnover renal osteodystrophy (ROD) was present in nine and low-turnover ROD in eight patients. The bone formation rate was significantly associated with bone alkaline phosphatase, c-telopeptide and osteocalcin. In patients with high turnover ROD, osteocalcin was also significantly higher than in patients with decreased bone formation. The FeCa was normal or below normal in 14/17 patients. TmP/GFR was below normal in all patients. Neither intact PTH nor iFGF-23 was associated with TmP/GFR, FeCa or any histomorphometric bone parameter. We conclude that hypercalcemia of posttransplant hyperparathyroidism can be associated with high or low turnover bone disease. Decreased calcium excretion suggests an additive tubular effect on hypercalcemia.
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PMID:Low-turnover bone disease in hypercalcemic hyperparathyroidism after kidney transplantation. 1772 80

PTH and 1,25(OH)(2)D each exert dual anabolic and catabolic skeletal effects. We assessed the potential interaction of PTH and 1,25(OH)(2)D in promoting skeletal anabolism by comparing the capacity of exogenous, intermittently injected PTH(1-34) to produce bone accrual in mice homozygous for the 1 alpha(OH)ase-null allele [1 alpha(OH)ase(-/-) mice] and in wildtype mice. In initial studies, 3-mo-old wildtype mice were either injected once daily (40 microg/kg) or infused continuously (120 microg/kg/d) with PTH(1-34) for up to 1 mo. Infused PTH reduced BMD, increased the bone resorption marker TRACP-5b, and raised serum calcium but did not increase serum 1,25(OH)(2)D. Injected PTH increased serum 1,25(OH)(2)D and BMD, raised the bone formation marker osteocalcin more than did infused PTH, and did not produce sustained hypercalcemia as did PTH infusion. In subsequent studies, 3-mo-old 1 alpha(OH)ase(-/-) mice, raised on a rescue diet, and wildtype littermates were injected with PTH(1-34) (40 microg/kg) either once daily or three times daily for 1 mo. In 1 alpha(OH)ase(-/-) mice, baseline bone volume (BV/TV) and bone formation (BFR/BS) were lower than in wildtype mice. PTH administered intermittently increased BV/TV and BFR/BS in a dose-dependent manner, but the increases were always less than in wildtype mice. These studies show that exogenous PTH administered continuously resorbs bone without raising endogenous 1,25(OH)(2)D. Intermittently administered PTH can increase bone accrual in the absence of 1,25(OH)(2)D, but 1,25(OH)(2)D complements this PTH action. An increase in endogenous 1,25(OH)(2)D may therefore facilitate an optimal skeletal anabolic response to PTH and may be relevant to the development of improved therapeutics for enhancing skeletal anabolism.
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PMID:Exogenous PTH and endogenous 1,25-dihydroxyvitamin D are complementary in inducing an anabolic effect on bone. 1834 99


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