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)

Tumour-induced hypercalcaemia (TIH) is a frequent complication of advanced cancer but has been rarely reported in patients with malignant melanoma, and its pathogenesis remains unexplored. We studied eight patients with TIH and melanoma. We determined the incidence and pathogenesis of this complication and the effects of bisphosphonate therapy. The incidence of TIH in 751 patients with melanoma was 1.1%. All patients had liver and bone metastases at the time of hypercalcaemia. All patients had osteolytic lesions, most often multiple. The median survival was 30 days (range 4-136 days). After rehydration, the mean (+/- SEM) corrected calcium was 3.42 +/- 0.17 mmol/l. Parathyroid hormone levels were adequately suppressed and vitamin D concentrations were normal. Serum osteocalcin, a marker of bone formation, was low, except in the two patients with renal insufficiency, whereas fasting urinary calcium and hydroxyproline were increased, indicating inhibition of bone formation and stimulation of bone resorption. Increased parathyroid hormone-related protein secretion was noted in only one patient. Three of four patients became normocalcaemic after bisphosphonate therapy for a median duration of 2 weeks. In conclusion, hypercalcaemia is a rare complication of melanoma. It occurs in the context of far advanced disease and is essentially due to aggressive lytic bone metastases with an uncoupling in bone turnover. Bisphosphonates can offer short-term palliation.
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PMID:Hypercalcaemia of melanoma: incidence, pathogenesis and therapy with bisphosphonates. 1159 84

The hormone 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3), the active form of vitamin D3, is an important regulator of calcium homeostasis, exerts antiproliferative effects on various cell systems and can induce differentiation in some kinds of hematopoietic cells. These effects are triggered by its receptor, vitamin D receptor (VDR), a phosphoprotein member of the nuclear receptor superfamily, which functions as a transcriptional factor. VDR binds as a heterodimer with retinoid X receptor (R X R) to hexameric repeats, characterized as vitamin D-responsive elements present in the regulatory region of target genes such as osteocalcin, osteopontin, calbindin-D28K, calbindin-D9K, p21WAF1/CIP1, TGF-beta2 and vitamin D 24-hydroxylase. Many factors such as glucocorticoids, estrogens, retinoids, proliferation rate and cell transformation can modulate VDR levels. VDR is expressed in mammary tissue and breast cancer cells, which are potential targets to hormone action. Besides having antiproliferative properties, vitamin D might also reduce the invasiveness of cancer cells and act as an anti-angiogenesis agent. All of these antitumoral features suggest that the properties of vitamin D could be explored for chemopreventive and therapeutic purposes in cancer. However, hypercalcemia is an undesirable side effect associated with pharmacological doses of 1,25-(OH)2D3. Some promising 1,25-(OH)2D3 analogs have been developed, which are less hypercalcemic in spite of being potent antiproliferative agents. They represent a new field of investigation.
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PMID:Antiproliferative effects of 1,25-dihydroxyvitamin D3 on breast cells: a mini review. 1174 8

We have examined several analogs of 1alpha,25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] in an animal model of osteoporosis (ovariectomized rats) to identify a compound with a greater therapeutic range than 1,25-(OH)(2)D(3) for treatment of this bone disease. Here, we report that one analog, Ro-26-9228, had a bone-protecting effect but did not induce hypercalcemia at a wide concentration range. Analysis of biochemical markers and the bone histomorphometry of analog-treated rats suggested that Ro-26-9228 acted by inhibiting bone resorption and increasing the number of differentiated osteoblasts. To determine the basis for the segregation between hypercalcemia and bone-protecting action, we examined gene expression in tissues that regulate calcium homeostasis. We found that 1,25-(OH)(2)D(3) induced 24-hydroxylase mRNA expression in the duodena of ovariectomized rats, but Ro-26-9228 did not. Furthermore, in the duodena of intact animals, 1,25-(OH)(2)D(3) induced a significant increase in calbindin D 9K and plasma membrane calcium pump 1 mRNAs, but Ro-26-9228 had no effect on these mRNAs. On the other hand, the osteoblast-specific gene products osteocalcin and osteopontin were significantly up-regulated in trabecular bone by both the natural hormone and Ro-26-9228. Further investigation of gene-regulatory events in trabecular bone revealed that both 1,25-(OH)(2)D(3) and Ro-26-9228 up-regulated TGF beta1 and beta2 mRNAs. We concluded that the unique properties of Ro-26-9228 include preferential gene regulation in osteoblasts over duodenum and effective induction of growth factors in bone.
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PMID:Cellular and molecular events associated with the bone-protecting activity of the noncalcemic vitamin D analog Ro-26-9228 in osteopenic rats. 1195 43

Significant reduction in bone mineral density (BMD) occurs in patients with Parkinson's disease (PD), correlating with immobilization and with vitamin D deficiency, and increasing the risk of hip fracture, especially in elderly women. As a biological indicator of compromised vitamin K status, an increased serum concentration of undercarboxylated osteocalcin (Oc) has been associated with reduced BMD in the hip and an increased risk of fracture in otherwise healthy elderly women. We evaluated treatment with vitamin K(2) (menatetrenone; MK-4) in maintaining BMD and reducing the incidence of nonvertebral fractures in elderly female patients with PD. In a random and prospective study of PD patients, 60 received 45 mg of MK-4 daily for 12 months, and the remaining 60 (untreated group) did not. At baseline, patients of both groups showed vitamin D and K(1) deficiencies, high serum levels of ionized calcium, and glutaminic residue (Glu) Oc, and low levels of parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D [1,25-(OH)(2)D], indicating that immobilization-induced hypercalcemia inhibits renal synthesis of 1,25-(OH)(2)D and compensatory PTH secretion. BMD in the second metacarpals increased by 0.9% in the treated group and decreased by 4.3% in the untreated group (p < 0.0001). Vitamin K(2) level increased by 259.8% in the treated group. Correspondingly, significant decreases in Glu Oc and calcium were observed in the treated group, in association with an increase in both PTH and 1,25-(OH)(2)D. Ten patients sustained fractures (eight at the hip and two at other sites) in the untreated group, and one hip fracture occurred among treated patients (p = 0.0082; odds ratio = 11.5). The treatment with MK-4 can increase the BMD of vitamin D- and K-deficient bone by increasing vitamin K concentration, and it can also decrease calcium levels through inhibition of bone resorption, resulting in an increase in 1,25-(OH)(2)D concentration.
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PMID:Amelioration of osteoporosis by menatetrenone in elderly female Parkinson's disease patients with vitamin D deficiency. 2927 15

Time-dependent differences in adverse reactions and efficacy by a repeated administration of 1,25(OH)2 vitamin D3 (vit D, 0.3 microg/Kg/day for 12 weeks) were examined in 5/6 nephrectomized rats under a condition of 12-hour light-dark cycle. The 5/6 nephrectomy increased serum concentrations of phosphate, osteocalcin and PTH, and urinary excretions of phosphate and deoxypyridinoline (DPD) while the maneuver reduced serum Ca concentration and its urinary excretion. Animals with a dosing of the drug at 2 hours after light on (HALO) had more grade of hypercalcemia and hyperphosphatemia than those at 14 HALO. Reduction of serum intact PTH and increase of serum vit D were observed in both groups with a similar extent. Increase of osteocalcin by the drug was greater in 14 HALO trial. Urinary excretion of DPD was not influenced by the treatment. The increase in bone density of femur was greater in 14 HALO than in 2 HALO trials. These results suggest that adverse reactions of vit D were ameliorated and its efficacy was enhanced after the repeated dosing of the drug at 14 HALO. Time-dependent variation in the sensitivity of the drug to osteoblast was involved in the mechanism of these events, while the roles of pharmacokinetic alteration and renal response were small, if any.
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PMID:Time of day improves efficacy and reduces adverse reactions of vitamin D3 in 5/6 nephrectomized rat. 1215 Oct 58

Incadronate is a highly effective inhibitor of stimulated bone resorption as demonstrated in a hypercalcemia model in rats, bone metastasis models in mice and rats, and an osteoporosis model in dogs. In this study, the effect of incadronate on osteoporosis in ovariectomized rats was examined. Incadronate dose-dependently inhibited decreases in second lumbar vertebrae bone mineral density (BMD) following oral administration for 4 or 12 weeks. Significant inhibition was observed at doses of more than 0.3 mg/kg. Incadronate dose-dependently inhibited the loss of distal femur metaphyseal compressive strength following 12 weeks of oral administration, and this was significant at a 3 mg/kg daily dose. Incadronate also dose-dependently inhibited the increases in urinary deoxypyridinoline levels after 4-or 12-week oral administrations. While incadronate had no effect on serum osteocalcin levels after 4 weeks of oral administration, it did dose-dependently reduce levels after 12 weeks of oral administration. These results suggested that incadronate may be a useful drug for osteoporosis due to stimulated bone resorption.
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PMID:Incadronate inhibits osteoporosis in ovariectomized rats. 1246 Jun 43

As a candidate for active vitamin D analogs that have selective effects on bone, 1alpha,25-dihydroxy-2beta-(3-hydroxypropoxy)vitamin D3 (ED-71) has been synthesized and is currently under clinical trials. In ovariectomized rat model for osteoporosis, ED-71 caused an increase bone mass at the lumbar vertebra to a greater extent than 1alpha-hydroxyvitamin D3 (alfacalcidol), while enhancing calcium absorption and decreasing serum parathyroid hormone levels to the same degree as alfacalcidol. ED-71 lowered the biochemical and histological parameters of bone resorption more potently than alfacalcidol, while maintaining bone formation markers. An early phase II clinical trial was conducted with 109 primary osteoporotic patients. The results indicate that oral daily administration of ED-71 (0.25, 0.5, 0.75, and 1.0 microgram) for 6 months increased lumbar bone mineral density in a dose-dependent manner without causing hypercalcemia and hypercalciuria. ED-71 also exhibited a dose-dependent suppression of urinary deoxypyridinoline with no significant reduction in serum osteocalcin. These results demonstrate that ED-71 has preferential effects on bone with diminished effects on intestinal calcium absorption. ED-71 offers potentially a new modality of therapy for osteoporosis with selective effects on bone.
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PMID:A new active vitamin D analog, ED-71, causes increase in bone mass with preferential effects on bone in osteoporotic patients. 1252 May 28

Patients with primary hyperparathyroidism (pHPT) are sometimes treated with bisphosphonates (BPs) as an alternative to surgery despite sparse documentation of the efficacy in this disorder. It is therefore of interest to study the biochemical effects from BPs in patients with pHPT. A series of 21 pHPT patients with serum calcium levels > 2.8 mmol/L were included. One month before surgery the patients underwent intravenous infusions of 30 to 40 mg pamidronate. Study parameters were total and ionized serum calcium, intact parathormone (PTH), alkaline phosphatase (ALP) and isoenzymes, creatinine, osteocalcin, 25-OH vitamin D(3), 1,25-OH(2 )vitamin D(3), urine calcium/creatinine, and osmolality. Registration of hypercalcemia-related symptoms were done by questionnaire. After pamidronate there was a temporary reduction in serum calcium with a nadir at 6 to 10 days. Normalization of serum calcium was achieved only by surgery. Intact PTH rose after pamidronate, with a maximum on day 6. Urinary calcium excretion was reduced after both pamidronate and surgery. ALP was reduced 30 days after pamidronate and also after surgery. Serum osteocalcin was not influenced by pamidronate. No statistically significant differences in symptoms were reported after treatment. In conclusion, there was a short, limited calcium-lowering effect from pamidronate in pHPT patients and a transient increase in PTH corresponding to the reduced calcium concentration. An obvious change in bone markers was found only after surgery. Treatment with BPs should not be considered an alternative to surgery, which is still the only method to cure patients with pHPT.
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PMID:Biochemical effects from treatment with bisphosphonate and surgery in patients with primary hyperparathyroidism. 1551 86

The effect of treatment with alfacalcidol on post-transplantation bone loss in children and adolescents was investigated. Of the 63 young patients who received renal transplant and were subjected to dual-energy x-ray absorptiometry (DEXA), 30 patients had low-bone mineral density (BMD) (z-score < or = -1) and were enrolled into the study. Their mean age at the time of transplantation was 14.5 +/- 4.0 years and the mean duration after transplantation was 48 +/- 34 months. Patients with low BMD were randomized into two equal homogeneous groups: group 1 (control) received placebo and group 2 received daily alfacalcidol 0.25 microg by mouth. Parameters of bone metabolism (intact parathyroid hormone, serum osteocalcin and urinary deoxypyridinoline) and BMD were assessed before and after the study period. After 12 months of treatment BMD at the lumber spine decreased from -2.2 to -2.5 in group 1 while it increased from -2.1 to -0.6 in group 2 (p < 0.001). Serum intact parathyroid hormone level decreased significantly in group 2 (p = 0.042). Apart from transient hypercalcemia in 1 patient in group 2, no other significant adverse effects were noted. This study suggested the value of alfacalcidol in the treatment of bone loss in young renal transplant recipients.
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PMID:A prospective randomized study for the treatment of bone loss with vitamin d during kidney transplantation in children and adolescents. 1557 9

We studied bone mineral metabolism changes complicated by acute gastroenteritis in a clinical acute metabolic acidosis milieu where we observed hypercalcemia, hypercalciuria, and elevated urinary hydroxyproline excretion. Serum magnesium and plasma osteocalcin, alkaline phosphatase, and IGF-1 levels were decreased. No significant changes in serum inorganic phosphate and plasma PTH, calcitonin, or 25-hydroxy vitamin D3 levels were detected. All abnormalities disappeared with the correction of acidosis. Observed hypercalcemia seems to be the result of increased calcium efflux from bone due to metabolic acidosis-induced catabolism of type 1 collagen and decreased osteoblastic activity. This study provides data regarding acute metabolic acidosis-induced changes in noninvasive parameters of bone modeling, assessed for the first time in humans.
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PMID:Bone mineral changes in acute metabolic acidosis due to acute gastroenteritis. 1559 94


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