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)

Vitamin D and its metabolites are best known for their actions in calcium and bone metabolism. However, epidemiological studies have suggested that an increased prostate cancer risk is associated with decreased production of vitamin D. In vitro and in vivo studies have shown that the biologically active form of vitamin D, 1alpha,25-dihydroxyvitamin D3 (1,25D), inhibits proliferation of cancer cells derived from multiple tissues, including the prostate. Although the mechanisms underlying the growth inhibitory effects of 1,25D have not been fully elucidated, in prostate cancer cells 1,25D reduces cell growth via a number of cellular pathways, including cell cycle arrest, induction of apoptosis, and altered activation of growth factor signaling. The hypercalcemia induced by 1,25D in vivo limits its use clinically as a therapeutic agent. However, several 1,25D analogs have been developed that reduce prostate tumor growth in rodent xenograft models without causing hypercalcemia. Additional studies are required in order to determine whether these 1,25D analogs will be useful therapeutic agents for the treatment of prostate cancer.
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PMID:Vitamin D and prostate cancer. 1504 10

Vitamin D therapy for patients with chronic kidney disease has until recently comprised alfacalcidol or calcitriol, both of which effectively attenuate secondary hyperparathyroidism and the target organ consequences thereof. Unfortunately, both these agents also have significant calcaemic and phosphataemic actions leading to frequent episodes of hypercalcaemia, hyperphosphataemia and an increase in the CaxP product. It is likely that these in turn have adverse effects on cardiovascular and survival outcomes by promoting soft tissue and vascular calcification. These drawbacks have fuelled a search for vitamin D compounds with a wider therapeutic window. Experimentally, some of these have exhibited remarkable dissociation between their ability to suppress parathyroid hormone (PTH) and concomitant calcaemic actions. In the case of 22-oxacalcitriol, the calcaemic potency relative to parathyroid suppression is 100th of that of calcitriol. 22-oxacalcitriol, with paricalcitol and doxercalciferol, are now widely used. Clinical studies of these agents, while confirming efficacy that is at least as good as alfacalcidol/calcitriol, have not consistently shown benefit in head to head comparison. Experience with these agents in the paediatric arena is very limited. One placebo-controlled study has now been completed in children-paricalcitol appeared effective and well tolerated. Calcimimetics, which simultaneously lower PTH, calcium and the CaxP product are about to enter the clinical arena-early studies in adults look promising, although they will need careful evaluation in children. These two therapies are likely to be additive and will probably complement one another effectively.
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PMID:New Vitamin D analogues for osteodystrophy in chronic kidney disease. 1514 42

The steroid hormone 1alpha,25(OH)(2)-Vitamin D(3) [1alpha,25(OH)(2)D(3)] exerts a wide variety of biological actions through one or more receptors/binding proteins. The nuclear Vitamin D receptor (VDR) when bound to its natural ligand, 1alpha,25(OH)(2)D(3), can stimulate transcription of a wide variety of genes. The synthesis of 1alpha,25(OH)(2)D(3) analogs allows the study of structure-function relationships between ligand and the VDR. 1alpha,25(OH)(2)D(3) is a conformationally flexible molecule; specifically the side-chain of the hormone can display a large variety of shapes for its receptor. Here, we describe and analyze the properties of 10 1alpha,25(OH)(2)D(3) analogs modified at the side-chain of which five lack carbon-19 (19-nor) but have a novel 20-cyclopropyl functionality. Analog NG [20,21-methylene-23-yne-26,27-F(6)-19-nor-1alpha,25(OH)(2)D(3)] possesses a respectable binding affinity for the VDR and exhibits a high transcriptional activity (EC(50) approximately 10pM), while retaining low induction of hypercalcemia in vivo in the mouse, making it a primary candidate for further analyses of its anti-proliferative and/or cell differentiating properties.
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PMID:Characterization of five 19-nor-analogs of 1alpha,25(OH)2-Vitamin D3 with 20-cyclopropyl-modified side-chains: implications for ligand binding and calcemic properties. 1522 54

1,25-Dihydroxycholecalciferol (calcitriol) is recognized widely for its effects on bone and mineral metabolism. Epidemiological data suggest that low Vitamin D levels may play a role in the genesis of prostate cancer and perhaps other tumors. Calcitriol is a potent anti-proliferative agent in a wide variety of malignant cell types. In prostate, breast, colorectal, head/neck and lung cancer as well as lymphoma, leukemia and myeloma model systems calcitriol has significant anti-tumor activity in vitro and in vivo. Calcitriol effects are associated with an increase in G0/G1 arrest, induction of apoptosis and differentiation, modulation of expression of growth factor receptors. Glucocorticoids potentiate the anti-tumor effect of calcitriol and decrease calcitriol-induced hypercalcemia. Calcitriol potentiates the antitumor effects of many cytotoxic agents and inhibits motility and invasiveness of tumor cells and formation of new blood vessels. Phase I and II trials of calcitriol either alone or in combination with carboplatin, taxanes or dexamethasone have been initiated in patients with androgen dependent and independent prostate cancer and advanced cancer. Data indicate that high-dose calcitriol is feasible on an intermittent schedule, no dose-limiting toxicity has been encountered and optimal dose and schedule are being delineated. Clinical responses have been seen with the combination of high dose calcitriol+dexamethasone in androgen independent prostate cancer (AIPC) and apparent potentiation of the antitumor effects of docetaxel have been seen in AIPC. These results demonstrate that high intermittent doses of calcitriol can be administered to patients without toxicity, that the MTD is yet to be determined and that calcitriol has potential as an anti-cancer agent.
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PMID:Anti-tumor activity of calcitriol: pre-clinical and clinical studies. 1522 31

Bone metastasis are a frequent complication of cancer, occurring in up to 70% of patients with advanced breast or prostate cancer. The consequences of bone metastasis are often devastating. Osteolytic metastasis can cause different kinds of skeletal related events including severe pain, pathologic fractures, life-threatening hypercalcemia, spinal cord compression, and other nerve-compression syndromes. These skeletal-related events are the result of the resorption of mineralized bone by osteoclasts. Bisphosphonates are synthetic analogues of naturally occurring pyrophosphate compounds that inhibit bone resorption. Potent bisphosphonates, pamidronate and, more importantly zoledronic acid may cause hypocalcemia, but mostly asymptomatic, mild, transient in most cases. Sufficient calcium and vitamin D intake needs to be ensured in patients with malignancy who have borderline or low levels of calcium when commencing treatment with bisphosphonates. Vitamin D itself induce the formation of osteoclasts by increasing the expression of RANKL on marrow stromal cells. Local calcium also promotes tumor growth and the production of parathyroid hormone-related peptide which in turn stimulates bone resorption. Vitamin D and calcium supplementation during bisphosphonate administration for the purpose of elimination of the side effects related to hypocalcemia in patients with bone metastasis may increase the bone resorption and decrease the efficacy of bisphosphonates. Therefore, vitamin D and calcium supplementation must not be routinely recommended during bisphosphonate administration.
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PMID:Calcium and vitamin D supplementation during bisphosphonate administration may increase osteoclastic activity in patients with bone metastasis. 1569 11

Vitamin D and its analogues are administered to patients with secondary hyperparathyroidism (SHPT) in chronic renal failure (CRF). Hypercalcemia is one of the complications of this therapy, and is thought to be not rare, though its frequency is not clearly documented. There is a need to monitor serum corrected (ionized) calcium concentration and parathyroid hormone (PTH) in order to administer vitamin D and its analogues safely. Intravenous administration of vitamin D provides advantages over oral administration, though no definite evidence could show which is better. Calcitriol and maxacalcitol are administered intravenously, and the latter is more likely to increase serum calcium concentration than the former. It must be very careful to administer vitamin D to patients with predialysis CRF because hypercalcemia can accelerate progression of renal dysfunction.
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PMID:[Serum calcium concentration and the safety of vitamin D therapy]. 1557 16

Primary hyperparathyroidism (PHPT) is characterized most commonly now as an asymptomatic disorder with hypercalcaemia and elevated levels of parathyroid hormone (PTH). The elevation in PTH is detected by both the standard immunoradiometric assays (IRMA) and a more recent IRMA that detects only the 1-84 full-length PTH molecule. The serum calcium concentration is usually <1 mg dL(-1) above normal. Recently, another variant of PHPT (normocalcaemic PHPT) has been described in which the serum calcium is normal but the serum PTH is elevated, in the absence of any secondary cause for PTH elevation. Although usually sporadic, PHPT also occurs in inherited syndromes. Skeletal manifestations are appreciated by densitometry showing a typical pattern in which cancellous bone of the lumbar spine is reasonably well preserved whilst the cortical bone of the distal third of the radius is preferentially reduced. Although reduced in incidence, renal stones remain the most common overt complication of PHPT. Other organs are theoretical targets of PHPT such as the neurobehavioural axis and the cardiovascular system. Vitamin D looms as an important determinant of the activity of the PHPT state. The 2002 NIH Workshop on asymptomatic PHPT has led to revised guidelines to help doctors determine who is best advised to have parathyroid surgery and who can be safely followed without surgery. New information about the natural history of PHPT in those who did not undergo surgery has helped to define more precisely who is at-risk for complications. At the NIH workshop, a number of items were highlighted for further investigation such as pharmacological approaches to controlling hypercalcaemia, elevated PTH levels and maintaining bone density.
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PMID:Primary hyperparathyroidism: new concepts in clinical, densitometric and biochemical features. 1560 72

Vitamin D insufficiency is common in patients with primary hyperparathyroidism (PHPT) and may be associated with more severe and progressive disease. Uncertainty exists, however, as to whether repletion of vitamin D should be undertaken in patients with PHPT. Here we report the effects of vitamin D repletion on biochemical outcomes over 1 yr in a group of 21 patients with mild PHPT [serum calcium <12 mg/dl (3 mmol/liter)] and coexistent vitamin D insufficiency [serum 25 hydroxyvitamin D [25(OH)D] <20 microg/liter (50 nmol/liter)]. In response to vitamin D repletion to a serum 25(OH)D level greater than 20 microg/liter (50 nmol/liter), mean levels of serum calcium and phosphate did not change, and serum calcium did not exceed 12 mg/dl (3 mmol/liter) in any patient. Levels of intact PTH fell by 24% at 6 months (P < 0.01) and 26% at 12 months (P < 0.01). There was an inverse relationship between the change in serum 25(OH)D and that in intact PTH (r = -0.43, P = 0.056). At 12 months, total serum alkaline phosphatase was significantly lower, and urine N-telopeptides tended to be lower than baseline values (P = 0.02 and 0.13, respectively). In two patients, 24-h urinary calcium excretion rose to exceed 400 mg/d, but the group mean 24-h urinary calcium excretion did not change. These preliminary data suggest that vitamin D repletion in patients with PHPT does not exacerbate hypercalcemia and may decrease levels of PTH and bone turnover. Some patients with PHPT may experience an increase in urinary calcium excretion after vitamin D repletion.
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PMID:Vitamin D repletion in patients with primary hyperparathyroidism and coexistent vitamin D insufficiency. 1564

Vitamin D plays a pivotal role in the pathogenesis and treatment of renal bone disease. Vitamin D levels decline in the early phase of renal failure; however, through a compensatory mechanism parathyroid hormone (PTH) stimulates the production of calcitriol to return it to normal circulating concentrations. Nevertheless, resistance to calcitriol is observed and may be related to the decreased presence of the heterodimeric, DNA-binding partner for the vitamin D receptor protein. In end-stage kidney disease (ESKD) the circulating levels of calcitriol are invariably low. The indications of vitamin D therapy are the replacement of the missing hormone versus suppression of hyperparathyroidism requiring daily low-dose oral versus intermittent pulse or oral administration. However, this therapy must be accompanied by careful patient monitoring to avoid hypercalcemia and low bone turnover. Low bone turnover is not merely a histologic entity, but a clinical condition associated with high risk of extraosseous calcifications, in particular in the cardiovascular system, leading to increased morbidity. Thus, determination of bone turnover in patients with ESKD is essential. Bone biopsy is the gold standard to assess bone turnover, however, it is not always available and nephrologists rely on PTH levels. The intact PTH assay measures PTH (1-84) and large C-PTH fragments, which may antagonize the PTH (1-84) effects on bone. An assay that measures exclusively PTH (1-84) has recently become available and a calculated PTH (1-84) /C-PTH fragment ratio has been shown to be the best predictor of bone turnover in patients with ESKD not treated with vitamin D or with other medications known to affect bone metabolism. 22-Oxacalcitriol is a vitamin D analogue that could control serum PTH concentrations without deleterious effects on bone.
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PMID:[Use and indication of vitamin D and vitamin D analogues in patients with renal bone disease]. 1577 57

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


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