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Query: UMLS:C0020437 (hypercalcemia)
 10,293 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although hypercalcemia, osteoporosis, and increased bone turnover are associated with thyrotoxicosis, no direct effects of thyroid hormones on bone metabolism have been reported previously in organ culture. We have now demonstrated that prolonged treatment with thyroxine (T4) or triiodothyronine (T3) can directly increase bone resorption in cultured fetal rat long bones as measured by the release of previously incorporated 45Ca. T4 and T3 at 1 muM to 10 nM increased 45Ca release by 10-60% of total bone 45Ca during 5 days of culture. The medium contained 4 mg/ml of bovine serum albumin to which 90% of T4 and T3 were bound, so that free concentrations were less than 0.1 muM. The response to T4 and T3 was inhibited by cortisol (1 muM) and calcitonin (100 mU/ml). Indomethacin did not inhibit T4 response suggesting that T4 stimulation of bone resorption was not mediated by increased prostaglandin synthesis by the cultured bone. Matrix resorption was demonstrated by a decrease in extracted dry weight and hydroxyproline concentration of treated bones and by histologic examination which also showed increased osteoclast activity. The effects of thyroid hormones were not only slower than those of other potent stimulators of osteoclastic bone resorption (parathyroid hormone, vitamin D metabolites, osteoclast activating factor, and prostaglandins), but the maximum response was not as great. We conclude that T4 and T3 can directly stimulate bone resorption in vitro at concentrations approaching those which occur in thyrotoxicosis. This effect may explain the disturbances of calcium metabolism seen in hyperthyroidism.
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PMID:Direct stimulation of bone resorption by thyroid hormones. 18 21

Results of previous studies have shown that the VX2 carcinoma in rabbits synthesizes large amounts of prostaglandin E2 (PGE2). PGE2 secreted by the tumor is rapidly metabolized and can be measured in plasma as the metabolite 13,14-dihydro-15-keto-PGE2 (PGE2-M). We have previously proposed that the hypercalcemia that occurs in rabbits bearing the VX2 carcinoma is due to excessive secretion of PGE2 by the tumor and its subsequent action on the skeleton as a bone resorption-stimulating factor. In the course of these studies, we noted that the plasma of rabbits bearing the VS2 carcinoma became blue about 1 wk after tumor implantation. The intensity of the color increased markedly thereafter. We therefore measured ceruloplasmin in plasma by both chemical and immunological assay methods. Plasma ceruloplasmin and PGE2-M rose in parallel (within 7-10 days) and preceded by 7-10 days the development of hypercalcemia. 2 wk after tumor implantation, plasma PGE2-M and ceruloplasmin had risen about 20- and 6-fold, respectively, while the rise in plasma calcium was just beginning. Indomethacin, an inhibitor of prostaglandin synthesis, given from the time of tumor implantation prevented completely the hypercalcemia and largely inhibited the rise in ceruloplasmin. When given after hyperprostaglandinemia had developed, indomethacin produced a fall in both PGE2-M and ceruloplasmin. A rise in plasma haptoglobin concentrations similar to that seen for ceruloplasmin was also observed. No changes in plasma albumin concentrations occurred. We conclude that the acute phase reactants ceruloplasmin and haptoglobin rise rapidly in the plasma of rabbits bearing the VX2 carcinoma, and that this increase is related to arachidonic acid metabolism in these animals. It is possible that arachidonic acid metabolites also play a role in the elevations of these two plasma proteins observed in certain patients with malignant tumors.
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PMID:Acute phase reactants ceruloplasmin and haptoglobin and their relationship to plasma prostaglandins in rabbits bearing the VS2 carcinoma. 65 Jan 52

In rabbits bearing the prostaglandin-producing VX2 carcinoma, the plasma concentration of 13,14-dihydro-15-keto-PGE2 (PGE2-M) was elevated within one week after tumor implantation and preceded the development of hypercalcemia. Both the rate of rise and magnitude of the increase were greater for the metabolite than for PGE2; at the time of peak hyercalcemia (about 4 to 5 weeks after tumor implantation), the increase over basal in plasma PGE2-M was about 75 fold whereas it was previously shown that the increase in PGE2 was less than 2 fold. Indomethacin, which inhibits PGE2 synthesis in VX2 cells in culture, lowered in parallel plasma calcaium and PGE2-M in tumor-bearing rabbits. Administration of hydrocortisone to rabbits bearing the VX2 tumor prevented the development of hypercalcemia when given at the time of tumor implantation and reversed the elevated plasma calcium in previously untreated animals; the steroid hormone also lowered plasma concentrations of PGE2-M. These findings are consistent with our hypothesis that the hypercalcemic syndrome in VX2 tumor-bearing rabbits is due to the secretion of PGE2 by the tumor.
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PMID:Plasma concentrations of 13,14-dihydro-15-keto-prostaglandin E2 in rabbits bearing the VX2 carcinoma: effects of hydrocortisone and indomethacin. 89 22

Prostaglandin biosynthesis and metabolism were studied in the VX2 carcinoma-bearing rabbit, an animal model of prostaglandin-mediated hypercalcemia. All the identification and quantification of the prostaglandins were done by gas chromatography-mass spectrometry. The tumor incubated in vitro converted exogeneous arachidonic acid principally to PGE2. Biosynthesis from endogenous precursor lipids yields mainly PGE2 and PGF2alpha. The 100,000 x g supernatant fluid of the tumor did not contain any metabolizing enzymes. Significant hypercalcemia developed between the first and second week after tumor implantation. The levels of the major plasma metabolite of PGE2, 15-keto-13,14-dihydro-PGE2, became elevated at one week, had risen 25-fold by the end of the second week, and at the fourth week were elevated to 256 times the pre-incubation levels. The concentration of 15-keto-13,14-dihydro-PGF2alpha in plasma rose in parallell but to a lesser degree. 7alpha-hydroxy-5,11-diketotetranor-prostane-1,16-dioic acid, the major urinary metabolite of the E prostaglandins, was elevated two weeks after tumor implantation and rose until the fifth week. Indomethacin treatment lowered both serum calcium and the plasma level of 15-keto-13,14-dihydro-PGE2.
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PMID:Prostaglandin-mediated hypercalcemia in the VX2 carcinoma-bearing rabbit. 89 23

Prostaglandin synthetase inhibitors have, in the past, been shown to inhibit osteolysis caused by breast carcinoma tissue in vitro. We therefore assessed the effect of Indomethacin and aspirin on some parameters of calcium metabolism in patients with breast cancer. Neither drug reduced the serum calcium in pateints with hypercalcemia, nor reduced skeletal destruction as measured by the urinary hydroxy proline: creatinine ratio and urinary calcium in normocalcemic or hypercalcemic patients with osteolytic metastases. A possible reason for the discrepancy between results obtained in vitro and in vivo is that there are two phases of bone destruction in breast cancer; the early phase dependent and the late phase independent of prostaglandin synthesis.
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PMID:Failure of indomethacin to reduce hypercalcemia in patients with breast cancer. 100 35

We made a retrospective review of the patients with cancer of the digestive organs who died between January 1, 1975 and December 31, 1985, at Shinshu University Hospital. Of 183 patients with such cancers 15 (8.2%) had hypercalcemia. Hypercalcemia was defined as serum calcium level greater than 11.0 mg/dl on at least two determinations. The incidence of hypercalcemia by site was 5 of 74 (6.8%) liver, 1 of 16 (6.3%) biliary tract, 4 of 33 (12.1%) pancreas, 3 of 15 (20.0%) esophagus, 0 of 37 stomach, 0 of 2 duodenum, 2 of 5 colon, and 0 of 1 rectum carcinomas. There was no sexual or age predisposition to hypercalcemia. Bone scans and/or x-ray results were positive in three of eight, negative in five of eight, and were not evaluated in the remaining seven patients. Of five patients tested, four had low to normal serum parathyroid hormone (PTH) levels, and one had a serum PTH level high by C-terminal assay but normal by N-terminal assay. Serum chloride levels at the late stage of hypercalcemia were less than 102 mEq/L in all patients. Therefore, hyperproduction of PTH was unlikely to be a causative factor for hypercalcemia. Indomethacin was given to four patients with hypercalcemia with no effect on serum calcium levels in any cases. Survival from the diagnosis of hypercalcemia ranged from 2 to 96 days (mean 33 days). We conclude that hypercalcemia is a complication not infrequent at the late stages of cancers of the digestive organs, with the exception of gastric cancer, and a portent of a poor prognosis.
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PMID:Hypercalcemia of cancer in the digestive tract. 355 19

The interactions of calcium-regulating hormones, active forms of vitamin D and parathyroid hormone, and aspirin were studied in rats. Aspirin, a prostaglandin biosynthesis inhibitor, abolished the hypercalcemia induced by 1 alpha-hydroxyvitamin D3 at 20, 50 and 100 mg/kg p.o. in parathyroidectomized or thyroparathyroidectomized rats with or without vitamin D deficiency, and in thyroparathyroidectomized plus nephrectomized rats. Aspirin did not affect the stimulation of intestinal calcium absorption by 1 alpha-hydroxyvitamin D3. By contrast, indomethacin, another prostaglandin biosynthesis inhibitor, did not affect hypercalcemia or stimulation of intestinal calcium absorption by 1 alpha-hydroxyvitamin D3. Aspirin also abolished the hypercalcemic action of parathyroid hormone in rats with or without intact thyroparathyroid glands. Moreover, aspirin alone caused hypocalcemia in rats with intact thyroparathyroid glands. Indomethacin had no effect in either of these systems. These data suggest that aspirin may inhibit bone resorption by the active form of vitamin D or parathyroid hormone via a mechanism independent of prostaglandin biosynthesis inhibition.
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PMID:Aspirin inhibition of 1 alpha-hydroxyvitamin D3 or parathyroid hormone induced hypercalcemia in vivo in rats. A mechanism independent of prostaglandin biosynthesis inhibition. 400 6

A transplantable mouse fibrosarcoma, HSDM(1), produces a potent bone resorption-stimulating factor. The factor can be extracted from the tumor tissue and harvested from the medium of clonal strains of HSDM(1) tumor cells growing in monolayer culture. It has several chemical and biological properties of a prostaglandin. Using radioimmunoassay techniques, we have shown that HSDM(1) cells synthesize and secrete large quantities of prostaglandin E(2) (PGE(2)). The specific bone resorption-stimulating activity of the HSDM(1) factor extracted from the tumor is high and approximately equal to that of PGE(2) as measured in a bone tissue culture system in vitro. Indomethacin, a potent inhibitor of PGE(2) synthesis in HSDM(1) cells, also inhibits production by the cells of the bone resorption-stimulating factor, and has no detectable nonspecific effects on the bone culture assay system. Mice bearing the HSDM(1) tumor have higher levels of both calcium and PGE(2) in serum than control mice. We conclude that PGE(2) is the bone resorption-stimulating factor produced by HSDM(1) tumor cells, and that secretion of PGE(2) by the tumor in vivo accounts for the relative hypercalcemia observed in tumor-bearing animals. The HSDM(1) tumor cell system constitutes a new model for studying the pathogenesis of hypercalcemia associated with certain malignant tumors.
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PMID:Evidence that the bone resorption-stimulating factor produced by mouse fibrosarcoma cells is prostaglandin E 2 . A new model for the hypercalcemia of cancer. 434 6

The relative efficacy of five drugs in the treatment of hypercalcemia of malignancy was assessed in a randomized study. The drugs were oral phosphate, mithramycin, glucocorticoids, indomethacin, and ethane-1-hydroxy-1, 1-diphosphonate (EHDP). No single agent was universally effective. Oral phosphate and mithramycin were the most efficacious, each producing a decrease in serum calcium concentrations in four of five patients, although there were serious disadvantages with the use of each. Glucocorticoids were effective in only two of five patients who received randomized treatment. A further five patients received nonrandomized treatment with glucocorticoids, and only three of these showed response. Indomethacin was effective in only one of five patients to whom it was given, and EHDP was effective also in only one of five patients. The new diphosphonate, 3-amino-1-hydroxypropane-1, 1-diphosphonate (APD) was evaluated in the treatment of hypercalcemia in 13 patients with malignant disease and two with primary hyperparathyroidism. APD caused a significant decrease in serum calcium concentration in nine of 12 patients within 72 hours. These results indicate that there is no currently available pharmacologic agent that is entirely satisfactory in the treatment of hypercalcemia. The most effective agents were mithramycin, oral phosphate, and APD. Glucocorticoids and orally administered EHDP showed limited effectiveness, and indomethacin was ineffective in the majority of patients.
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PMID:Comparative study of available medical therapy for hypercalcemia of malignancy. 621 78

We examined the effect of parathyroid hormone (PTH), administrated for 24-48 h, on acid-base homeostasis in dogs. Parathyroid extract (PTH), 15 IU/kg/day, given subcutaneously, caused metabolic alkalosis (control vs. experimental; mean +/- SEM): plasma HCO3, 21.3 +/- 0.3 vs. 24.2 +/- 0.5 mEq/l (p less than 0.001); plasma H+, 37.7 +/- 1.1 vs. 35.7 +/- 1.4 nEq/l (p less than 0.05), and net acid excretion, 48.6 +/- 2.0 vs. 65.1 +/- 4.0 mmol/day (p less than 0.01). PTH administered by continuous intravenous infusion had similar effects (control vs. experimental): plasma HCO3, 21.4 +/- 0.4 vs. 23.6 +/- 0.7 mEq/l (p less than 0.001) and net acid excretion, 54.0 +/- 3.5 vs. 68.3 +/- 5.7 mmol/day (p less than 0.05). PTH, 8 IU/kg/day, had qualitatively similar but quantitatively less profound consequences. Bicarbonaturia was not observed in any group. The effects of PTH were similar in adrenalectomized dogs maintained on hormone replacement. Indomethacin (150 mg/day) prevented the renal effects of PTH so that no increase in net acid secretion occurred. However, metabolic alkalosis still developed: control vs. experimental plasma HCO3, 21.8 +/- 0.5 vs. 23.9 +/- 0.5 mEq/l (p less than 0.001). Dichloromethanediphosphonate blunted both the renal and nonrenal effects of PTH, such that hypercalcemia, metabolic alkalosis and increased net acid excretion were quantitatively less and delayed in onset. In summary, PTH administration for 24-48 h causes metabolic alkalosis in dogs, the result of renal and nonrenal mechanisms.
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PMID:Parathyroid-hormone-induced metabolic alkalosis in dogs. 622 Feb


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