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)

Cultures of a cell line derived from a murine mammary carcinoma that induces hypercalcemia were examined for soluble products that could induce osteoclasts to differentiate from murine bone marrow cells. The serum-free culture supernatant of this cell line stimulated growth of colonies from bone marrow cells that exhibited tartrate-resistant acid phosphatase (TRAPase) activity. These TRAPase-positive cells demonstrated essential features of osteoclasts when cultured with mineralized bone or dentin. The culture period required for colony development and the frequency of colony-forming cells indicated that relatively primitive marrow progenitors were stimulated by a tumor-derived factor(s) to form immature osteoclasts. Other colony-stimulating factors (CSFs), including granulocyte CSF, macrophage CSF, granulocyte-macrophage CSF and interleukin 3, were ruled out as the source of the activity produced by the tumor cells. The biological activity was successfully purified by gel filtration chromatography and reverse-phase HPLC. By SDS/PAGE, the activity was traced to a protein of approximately 17 kDa. Functional and biochemical studies of the purified factor suggest that it is distinct from any known CSF of myeloid cells. This protein appears to be a CSF for the osteoclast lineage, osteoclast CSF (O-CSF).
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PMID:Isolation of a murine osteoclast colony-stimulating factor. 192 9

The effect of a low calcium diet, mithramycin, or dichlorodimethylene bisphosphonate were evaluated in nude mice with humoral hypercalcemia of malignancy associated with the transplanted canine adenocarcinoma (CAC-8). Low calcium (0.01%) diet significantly reduced serum calcium levels in hypercalcemic nude mice and reduced urine calcium excretion to control levels. Mithramycin (8 mg/kg) decreased serum calcium concentration and urine calcium excretion to the range of control non-tumor-bearing nude mice at day 5 after a single injection, but there was no change in the number of tartrate-resistant acid phosphatase-positive osteoclasts in lumbar vertebrae. Osteoclasts from CAC 8-bearing nude mice after mithramycin administration were decreased in size, had small ruffled borders, and increased relative size of clear zones. Dichlorodimethylene bisphosphonate (Cl2MDP) (45 mg/kg) partially reduced serum calcium concentration of hypercalcemic tumor-bearing nude mice, decreased urine calcium excretion to control levels, and markedly reduced the numbers of tartrate-resistant acid phosphatase-positive osteoclasts in lumbar vertebrae. Osteoclasts from Cl2MDP-treated nude mice were smaller and had a reduced frequency of ruffled borders than saline-treated hypercalcemic nude mice. In vitro bone resorption induced by CAC-8 extract was significantly reduced by Cl2MDP and mithramycin. The results of these investigations suggest that the hypercalcemia and hypercalciuria associated with HHM in nude mice with CAC-8 are the combined result of altered calcium homeostasis in the bone, kidney, and intestine. Chemotherapeutic agents that specifically affect only bone or feeding a low calcium diet alone may not completely ameliorate the hypercalcemia of HHM.
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PMID:The effect of low calcium diet, mithramycin, and dichlorodimethylene bisphosphonate on humoral hypercalcemia of malignancy in nude mice transplanted with the canine adenocarcinoma tumor line (CAC-8). 297 5

Tumors frequently induce the multifunctional cytokine IL-6, which has been linked to several paraneoplastic syndromes, most notably cachexia. IL-6 stimulates osteoclast formation, causes mild hypercalcemia, and is produced by bone cells in vitro upon exposure to systemic hormones. Since IL-6 is produced together with parathyroid hormone-related protein (PTH-rP) in some patients with cancer, we tested the hypothesis that production of IL-6 potentiates the effects of PTH-rP on Ca2+ homeostasis and osteoclastic bone resorption and examined potential mechanisms for these interactions in vivo. Chinese hamster ovarian (CHO) cells stably transfected with cDNAs for IL-6 (CHO/IL-6) and PTH-rP sense (CHO/PTH-rP) or antisense (CHO/PTH-rP AS) were inoculated intramuscularly into nude mice. Experimental groups included CHO/IL-6 plus CHO/PTH-rP; CHO/IL-6 plus CHO/PTH-rP AS; CHO/IL-6 alone; and CHO/PTH-rP alone. Blood ionized Ca2+ was measured on days 0, 7, 10, 12, and 13. Three different developmental stages in the osteoclast lineage were examined at day 13: the early multipotential precursor, granulocyte macrophage colony-forming units (CFU-GM); more mature mononuclear osteoclast precursors, assessed by their capacity to form tartrate-resistant acid phosphatase-positive multinucleated cells in marrow cultures; and mature osteoclasts, assessed by histomorphometry. IL-6 increased CFU-GM but not bone resorption or Ca2+. In contrast, PTH-rP induced hypercalcemia and bone resorption and increased multinucleated osteoclasts and more mature precursors cells, but not CFU-GM. However, mice treated with both IL-6 and PTH-rP had very marked hypercalcemia and osteoclastosis as well as an increase in the number of both CFU-GM and mature osteoclast precursors. These data demonstrate that IL-6 enhances PTH-rP-mediated hypercalcemia and bone resorption, most likely by increasing the pool of early osteoclast precursors that in turn can differentiate to mature osteoclasts. We conclude that IL-6 stimulatory effects on osteoclast precursors may enhance the effects of other bone resorption factors that act at later stages in the osteoclast lineage.
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PMID:Interleukin-6 enhances hypercalcemia and bone resorption mediated by parathyroid hormone-related protein in vivo. 776 25

A 56-year-old white man was referred for evaluation of severe hypercalcemia following a three-week history of progressive weakness, nausea, and depression. Initial laboratory results showed serum total and ionized calcium (Ca++) values of 5.3 and 2.6 mmol/l, respectively. A short intact PTH assay was immediately performed and an extremely high value was obtained in just 30 min (1315 ng/l, normal values 6.4-70.4). The patient was therefore treated with saline solution and with salmon calcitonin (1200 IU/day, half by continuous i.v. infusion and half by i.m. route) for 10 days. There was a sudden decrease of both Ca++ and intact PTH during the first six days; then there was a trend to reach a steady-state until parathyroidectomy was performed. After withdrawal of calcitonin therapy it was possible to observe a positive uncoupling between bone formation (serum alkaline phosphatase and osteocalcin) and resorption (serum tartrate-resistant acid phosphatase) markers. On day 35 the patient underwent neck exploration, and an enlarged lower left parathyroid gland was removed that on macroscopic examination revealed the presence of a haemorrhagic cyst; microscopic appearance was suggestive of a previous glandular infarction. This is the first time the daily clinical course of a parathyroid crisis has been documented. Furthermore, changes of biomarkers of bone turnover following calcitonin therapy show that high doses of the hormone may cause a prolonged positive uncoupling of the two processes of bone remodeling.
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PMID:Parathyroid storm: immediate recognition and pathophysiological considerations. 826 42

In the last years, a parathyroid hormone (PTH)-related peptide (PTHrP) has been isolated from tumors associated with humoral hypercalcemia with malignancy (HHM). In the present work, we studied the effect of bovine PTH (bPTH)(1-34) and PTHrP(1-34) on tartrate-resistant acid phosphatase (TRAP), a marker of bone resorption, and alkaline phosphatase (AP) activities, and basal and vitamin D-stimulated osteocalcin (BGP) synthesis (markers of bone formation) in fetal rat calvaria cultures. After a 48-hour incubation period, both bPTH(1-34) and PTHrP(1-34) caused an increase in TRAP activity liberated in the medium with respect to control cultured calvaria. On the other hand, while after 2 or 4 h of incubation both bPTH(1-34) and PTHrP(1-34) caused a decrease in the AP activity liberated in the medium, after 48 h of incubation both peptides caused a significant increase in the AP liberated in the medium with respect to control cultures. With respect to BGP synthesis, both bPTH(1-34) and PTHrP(1-34) antagonized the 1,25-dihydroxyvitamin D3 stimulatory effect in calvaria cultures. We conclude that PTHrP(1-34) causes similar effects on bone, in organ cultures, to those caused by bPTH(1-34), namely an increase in both bone resorption and formation and a decrease in the vitamin D-stimulated BGP synthesis.
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PMID:Effects of the (1-34) fragment of synthetic parathyroid hormone-related protein on tartrate-resistant acid phosphatase and alkaline phosphatase and alkaline phosphatase activities, and on osteocalcin synthesis, in cultured fetal rat calvaria. 837 26

The objective of the present work has been to study some aspects of bone and intestinal compartments in rats with Walker 256 carcinosarcoma, an experimental model of humoral hypercalcemia of malignancy (HHM). The results have been compared to those obtained in control animals and, also, to those obtained in Yoshida sarcoma-bearing rats, which were used as tumoral controls without hypercalcemia. Urinary hydroxyproline/creatinine ratio (OHProl/creat) is increased, in both Walker 256 and Yoshida tumor-bearing animals, showing the nonspecifity of this bone marker. However, serum tartrate-resistant acid phosphatase (TRAP) levels are increased in Walker 256 tumor-bearing animals, but they are normal in Yoshida tumor-bearing animals, indicating that TRAP is a better index of bone resorption than OHProl/creat in the HHM syndrome. The decrease of bone calcium content in Walker 256 tumor-bearing rats, not shown by Yoshida-bearing rats, also reflects an increased bone resorption due to HHM. Serum and bone osteocalcin levels are similar in control, Walker 256 and Yoshida tumor-bearing rats, but we observed a decrease in serum alkaline phosphatase levels in Walker 256 and Yoshida tumor-bearing animals, which could also be a nonspecific tumor effect, due to the presence of the neoplasia. Our results support the convenience of the employment of a nonhypercalcemic tumor group as control in the HHM study, in addition to the healthy controls. We have also observed higher 1,25-dihydroxyvitamin D serum levels in Walker 256 tumor-bearing rats than in control and Yoshida tumor-bearing rats. On the other hand, we have found normal levels in the fractional rate of intestinal calcium absorption in Walker-256 tumor-bearing rats, in spite of their high calcium levels, and a significant decrease of this parameter in Yoshida sarcoma-bearing animals. These results support the concomitant contribution of intestinal compartment to hypercalcemia, in the experimental model of HHM studied.
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PMID:Osseous and intestinal compartments in the humoral hypercalcemia of malignancy associated to Walker 256 tumor in rats. 845 Oct 38

Intermittent high dose administration of calcitriol or alfacalcidol is effective in suppressing secondary hyperparathyroidism in chronic dialysis patients, however calcaemic action of these vitamin D derivatives is a major obstacle. 22-Oxacalcitriol (OCT) has been reported to have less calcaemic action than calcitriol, while preserving a comparable suppressive effect on parathyroid hormone (PTH) secretion. This preliminary study was conducted to examine the effects of OCT on secondary hyperparathyroidism in chronic dialysis patients. OCT was administrated intravenously immediately after every haemodialysis session three times a week for 12 weeks to three haemodialysis patients with secondary hyperparathyroidism. An initial dose of OCT of 5.5 micrograms/haemodialysis session was increased stepwise by 5.5 micrograms/haemodialysis up to 22 micrograms/haemodialysis according to the suppression of PTH and calcaemic action. OCT was discontinued for at least a week when serum calcium adjusted to albumin concentration measured just before haemodialysis exceeded 11.5 mg/dl. Marked reduction in plasma PTH, alkaline phosphatase and tartrate-resistant acid phosphatase was observed in all three patients. Although the dose of OCT was increased to 22 micrograms/haemodialysis in one patient, the final dose of OCT remained 5.5 micrograms/haemodialysis in the other two patients because of hypercalcaemia. It is concluded that OCT is highly effective in suppressing PTH in dialysis patients with secondary hyperparathyroidism. Hypercalcaemia may be a major factor which limits the use of OCT, though it may occur with higher doses of OCT than those of calcitriol usually given to suppress PTH hypersecretion.
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PMID:Effect of 22-oxacalcitriol on hyperparathyroidism of dialysis patients: results of a preliminary study. 884 Mar 26

A 64-year-old woman with adult T cell leukemia (ATL) was admitted to our hospital with severe hypercalcemia. The serum calcium level was elevated to 14.9 mg/dl. Biochemical parameters for bone formation including serum osteocalcin (bone Gla protein, BGP) and alkaline phosphatase (ALP) were normal. The serum levels of tartrate-resistant acid phosphatase (TRAP), a parameter for bone resorption, were increased (4.6 KAU). The serum level of parathyroid hormone-related protein (PTHrP) was elevated (343 pmol/l). The cytokines with stimulatory effects on bone resorption, such as interleukin (IL)-1alpha, IL-1beta, IL-6, and tumor necrosis factor-alpha, were not detected. Serum Ca levels, PTHrP levels, and TRAP levels decreased with the decrease in ATL cells after chemotherapy, while serum BGP levels and ALP levels increased. On the 29th hospital day, ATL cells began to increase again. Then serum PTHrP levels, Ca levels, and TRAP levels increased, while serum BGP levels and ALP levels decreased. A marked excessive bone resorption with suppressed bone formation (uncoupling) occurred in this patient. The ATL cells produced not only PTHrP but also IL-1alpha and IL-1beta. These results suggest that PTHrP may act as a humoral factor and IL-1 may act as a local factor in bone metabolism of ATL patients.
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PMID:Bone resorption associated with uncoupling of osteoclastic and osteoblastic activities in adult T cell leukemia with hypercalcemia: case report. 1152 70

Maxacalcitol (22-oxacalcitriol [OCT]) is a newly developed vitamin D analogue in Japan. OCT has shown less calcemic action and a strong suppressive effect on parathyroid hormone (PTH) in uremic rats and dogs. In uremic patients with secondary hyperparathyroidism, OCT dose-dependently suppressed PTH secretion and increased serum calcium levels. However, more than 60% of patients achieved a greater than 30% decrease in intact PTH level from baseline with long-term OCT treatment up to 1 year without an unphysiological increase in mean serum calcium levels. Long-term treatment also brought about a reduction in bone metabolic markers, including bone alkaline phosphatase, tartrate-resistant acid phosphatase, and bone gra-protein. These results suggest that although careful attention should be paid to the onset of hypercalcemia and oversuppression of PTH, OCT is one of the effective tools for the treatment of secondary hyperparathyroidism.
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PMID:Clinical effects of maxacalcitol on secondary hyperparathyroidism of uremic patients. 1157 42

A trial on the long-term administration of 1,25-dihydroxy-22-oxavitamin D(3) (22-oxacalcitoriol, OCT) was conducted among 124 patients with chronic renal failure on maintenance haemodialysis (HD) complicated with secondary hyperparathyroidism (2HPT). In the trial, OCT was administered three times weekly for 26 weeks subsequent to a 26-week pre-trial. As a result, intact-parathyroid hormone (PTH) levels fell significantly after the start of administration and, at the end of the trial, PTH was decreased by over 30% in 51.6% (64/124) of the patients, and the levels of bone metabolism markers such as alkaline phosphatase (ALP), bone ALP, and tartrate-resistant acid phosphatase (TRACP) were significantly decreased compared with those at the start of administration, suggesting a correction of high-turnover bone disease. Serum calcium (Ca) levels rose significantly following OCT administration, but were successfully maintained within a physiological level. Hypercalcaemia, which was diagnosed in 33.1% of patients, was found to resolve or ameliorate immediately after the withdrawal or dose reduction of OCT. OCT can be administered for as long as 1 year without any major problems other than hypercalcaemia. The final doses ranged from 2.5 to 20.0 microg/HD, and the optimal dose varied among patients depending on the intact-PTH and adjusted serum Ca levels. These results suggest that OCT is a highly effective drug for the suppression of PTH levels in 2HPT, and is an overall safe drug if the dosage is adjusted for serum Ca and intact-PTH levels. This study confirmed that the long-term (1-year) administration of OCT is very useful for the treatment of 2HPT.
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PMID:Long-term effect of 1,25-dihydroxy-22-oxavitamin D(3) on secondary hyperparathyroidism in haemodialysis patients. One-year administration study. 1238 66


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