Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0153690 (bone metastases)
 6,382 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypercalcemia is the most common paraneoplastic syndrome associated with cancer. This paper addresses the etiology and pathogenesis of hypercalcemia of malignancy and discusses the relative contributions of local and humoral effects on bone and renal calcium homeostasis. The roles of parathyroid hormone-related protein and other osteolytic cytokines are outlined. New biochemical markers that enable more specific monitoring of the response of bone metastases to treatment are introduced, including urinary excretion of the collagen crosslinks pyridinoline and deoxypyridinoline. The clinical management and prevention of hypercalcemia is systemically outlined, including indications for bisphosphonate, glucocorticoid, and calcitonin therapy. The results of recent trials of bisphosphonate therapy for the prevention of tumor progression and its subsequent problems such as bone pain, fracture, and hypercalcemia also are discussed.
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PMID:Hypercalcemia and bone resorption in malignancy. 763 18

Hypercalcemia of malignancy is due either to local osteolysis at the site of bone metastases or to production by the malignancy of parathyroid hormone-related peptide, which shares some of the effects of parathyroid hormone. We used a radioimmunoassay (antiserum specific to the amino-terminus) to measure serum parathyroid hormone-related peptide levels in controls (n = 61), chronic renal failure patients (n = 10), patients with primary hyperparathyroidism (n = 19), cancer patients with (n = 35) or without (n = 57) hypercalcemia and/or bone metastases (n = 53 and n = 39, respectively), and patients with hematologic malignancies (n = 15). We set the upper limit of normal of the parathyroid hormone-related peptide assay at 2.7 pmol/L. The peptide was undetectable in two-thirds of healthy controls. Renal failure did not interfere with the assay. Eighteen of the 19 patients with primary hyperparathyroidism had normal levels. In contrast, 82% of patients with humoral hypercalcemia of malignancy (i.e., without detectable bone metastases) had increased levels; in this subgroup there was a significant inverse correlation between serum levels of the peptide and phosphorus. Elevation of parathyroid hormone-related peptide levels was less common among hypercalcemic patients with metastatic bone disease (38%). Four of the seven hypercalcemic patients with hematologic malignancies had elevated parathyroid hormone-related peptide levels. In our overall study population, serum calcium levels were weakly but significantly correlated with parathyroid hormone-related peptide levels. In conclusion, elevated parathyroid hormone-related peptide in a patient with hypercalcemia suggests a malignant disease.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Contribution of parathyroid hormone-related peptide to the evaluation of hypercalcemia. 778 31

Circulating interleukin-6 (IL-6) concentrations correlate with disease activity in severe inflammatory conditions, in sepsis and in some hematological malignancies. On the other hand, IL-6 is a potent stimulator of osteoclastogenesis and has been implicated as a contributory factor in the genesis of osteopenic conditions. We measured circulating IL-6 levels by a sensitive (detection limit of 10 U/ml) and specific bioassay in 103 patients with advanced cancer, including 41 with tumor-induced hypercalcemia before any specific hypocalcemic therapy. We related IL-6 concentrations to clinical features and to biochemical parameters of bone metabolism, including blood Ca, Ca2+, Pi, intact parathyroid hormone, parathyroid hormone-related protein, osteocalcin, 1,25-(OH)2-vitamin D and, as markers of bone resorption, the fasting urinary excretion of calcium (Ca/creatinine) and hydroxyproline. IL-6 levels were increased, i.e. detectable, in 23% of the patients, 8/41 (20%) hypercalcemic and 16/62 (26%) normocalcemic patients (NS); the distribution of the values was similar in the two groups. The presence of increased IL-6 concentrations was not related to any clinical characteristic, notably not to the survival nor to the existence of bone metastases, whether in hypercalcemic or normocalcemic patients; e.g., only 3/12 (25%) hypercalcemic subjects without bone metastases had elevated IL-6 levels. We found no significant correlations between IL-6 concentrations and any of the biochemical parameters studied. Hypercalcemic subjects with increased IL-6 had higher urinary Ca/creatinine levels than patients with normal IL-6 levels (P < 0.005) but this was not the case in normocalcemic subjects. Mean concentrations of inflammatory or other bone metabolism markers were not significantly different between patients with normal or with elevated IL-6 levels. In summary, circulating IL-6 levels were increased in 23% of 103 patients with advanced cancer, but the frequency of increased IL-6 concentrations was not related to the presence of hypercalcemia or to any marker of calcium metabolism or bone turnover. The pathogenic importance of circulating IL-6 in patients with solid tumors remains to be demonstrated and our data indicate that increased circulating levels of IL-6, possibly reflecting the activation of the immune system, only contribute in a minor way to the osteolytic process in patients with tumor-induced hypercalcemia.
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PMID:Circulating concentrations of interleukin-6 in cancer patients and their pathogenic role in tumor-induced hypercalcemia. 798 59

To find out if the concentration of parathyroid hormone-related protein (PTHrP) predicts the response of tumour-inducing hypercalcaemia (TIH) to pamidronate, we studied 44 patients. Pretreatment measurements of serum PTHrP, calcium and phosphate, nephrogenous cyclic AMP, tubular threshold for calcium and phosphate (TmP), and the presence of bone metastases were correlated with response to pamidronate. Response was considered good (normal calcium concentration corrected for albumin [CCa] for > 14 days), or poor (failure of CCa to fall, or a rise above normal < or = 14 days). PTHrP correlated significantly with response (good vs poor, p = 0.02). Undetectable PTHrP (< 2 pmol/L) was associated with a good response in all seven treatments, PTHrP in the range 2-12 pmol/L was associated with good response in 10 of 14 treatments, while PTHrP > or = 12 pmol/L was associated with a poor response in all 11 treatments. Tubular threshold for calcium correlated with the fall in CCa by day 6 after treatment (p = 0.02). Urinary clearance estimations in poor responders suggested that there was an incomplete reversal of the renal tubular component of hypercalcaemia. Serum PTHrP correlates with response to pamidronate in the treatment of TIH; which may be associated with a renal tubular mechanism not significantly affected by currently available treatment. Drugs that inhibit tubular reabsorption of calcium or PTHrP secretion may help in patients who do not respond to pamidronate.
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PMID:Parathyroid hormone-related protein and response to pamidronate in tumour-induced hypercalcaemia. 810 20

Parathyroid hormone-related protein (PTHrP) is associated with the syndrome of humoral hypercalcemia of malignancy. A high incidence of positive staining for PTHrP is observed in breast cancer and positivity is more frequent in patients who develop bone metastases. We assessed the presence of PTHrP mRNA by using the polymerase chain reaction in 38 normocalcemic breast cancer patients with long-term follow-up (minimum, 5 years) selected for the presence or absence of later bone metastasis development. In all the patients except one, the PTHrP gene was expressed in the breast tumor. The level of amplified PTHrP complementary DNA was inversely related to age (P < 0.02) and positively related to the proportion of invaded nodes (P < 0.02) but was not related to the other usual prognostic factors. The level of PTHrP mRNA was not different between the group of patients without recurrence or metastases (n = 11) and the group of patients who later developed metastases in soft tissues (n = 10). By contrast, patients who subsequently developed bone metastases (n = 17) showed higher PTHrP gene expression than patients in the other two groups (P < 0.001). This study suggests that strong PTHrP gene expression in breast tumors is associated with the onset of bone metastases.
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PMID:Polymerase chain reaction analysis of parathyroid hormone-related protein gene expression in breast cancer patients and occurrence of bone metastases. 822 37

Hypercalcemia is relatively frequent in malignancy with or without osteolytic bone metastases. It is thought that neoplastic cells may secrete substances which not only stimulate osteoclastic activity but are also capable of modifying the absorption, excretion, and resorption of calcium and phosphate ions. Since 1987, we have studied 24 breast cancer patients with hypercalcemia (22 with bone metastases and two without). The group of 22 patients with bone metastases were divided into two subgroups. The first consisted of 10 patients with high serum levels of humoral factors, such as parathyroid hormone-related protein (PTHrP), and/or prostaglandin E2 (PGE2) and/or interleukin 1 (IL-1), and high levels of bone markers, such as alkaline phosphatase, bone Gla protein and urinary hydroxyproline. The second subgroup consisted of 12 patients with high levels of bone markers alone. Bone histologic analysis showed an osteoclastic activation surrounding metastatic tumor tissue in six out of 10 patients of the first subgroup, while an evident osteolysis caused by the tumor cells was noted in seven out of 12 patients of the second subgroup. The two patients without bone metastases showed normal biochemistry and bone histologic examination. The authors, having tried to explain the pathogenesis of hypercalcemia, emphasize the importance of humoral factors secreted by tumor cells as a direct or indirect cause of hypercalcemia. The origin of hypercalcemia remains unclear in two patients without bone metastases.
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PMID:Hypercalcemia in breast cancer. 837 11

Hypercalcaemia is the most common metabolic complication of malignant disease. It is an important cause of morbidity in cancer patients and is potentially amendable to treatment. Bone metastases are rarely the cause of hypercalcaemia in malignancy, the elevation in calcium concentrations usually resulting from the effects of humoral mediators released by the tumour. Many factors isolated from tumours have the potential to cause hypercalcaemia, but the most important is parathyroid hormone related protein (PTHrP), a peptide which mimics the effect of PTH. Treatment of cancer associated hypercalcaemia is based on an initial phase of volume repletion with isotonic saline, followed by drug treatment to inhibit bone resorption. Bisphosphonates are the most widely used agents in the treatment of such bone resorption, are very effective and have minimal toxicity. Gallium nitrate is also effective but less widely used. The combination of bisphosphonates and calcitonin has been found to be particularly useful in patients with severe hypercalcaemia, since this gives a more rapid reduction in serum calcium values than can be achieved with bisphosphonate alone. In the longer term, effective control of hypercalcaemia depends on treating the primary tumour. In the majority of cases this is not possible, however, because of the state of disease progression or the nature of the tumour. Anti-hypercalcaemic therapy is an important palliative measure in cancer patients who have symptoms of hypercalcaemia. Treatment does little to alter the long term prognosis but often results in an improvement in symptoms such that the majority may be made well enough to be discharged from hospital care.
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PMID:Pathogenesis and management of cancer associated hypercalcaemia. 856 93

In the formation of bone metastasis, osteoclastic bone resorption is necessary before the expansion of tumor cells from bone marrow to bone, and several cytokines, which possess osteoclast-stimulating activity, could be involved in this step. In this paper, we describe a bone metastasis model in nude mice using human lung squamous cell carcinoma-derived cells (HARA), in which the parathyroid hormone-related protein (PTHrP) gene, one of the most potent osteoclast-activating factors, is strongly expressed. The injection of HARA cells (1 x 10(5)) into the left cardiac ventricle resulted in tumor colonies exclusively in the skeletal system at 4 and/or 8 weeks after inoculation. An anti-PTHrP antibody injected via a tail vein reduced the incidence of bone metastases, number of tumor colonies, and tumor volume after the inoculation of HARA cells. The injection of another line of human lung squamous cell carcinoma-derived cells (QG-56), in which the PTHrP gene is not expressed, resulted in no bone metastasis. These findings suggest that PTHrP plays an important role in the formation of bone metastasis.
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PMID:An experimental model of bone metastasis by human lung cancer cells: the role of parathyroid hormone-related protein in bone metastasis. 875 76

Breast cancer almost invariably metastasizes to bone in patients with advanced disease and causes local osteolysis. Much of the morbidity of advanced breast cancer is a consequence of this process. Despite the importance of the problem, little is known of the pathophysiology of local osteolysis in the skeleton or its prevention and treatment. Observations in patients with bone metastases suggest that breast cancer cells in bone express parathyroid hormone-related protein (PTHrP) more frequently than in soft tissue sites of metastasis or in the primary tumor. Thus, the role of PTHrP in the causation of breast cancer metastases in bone was examined using human breast cancer cell lines. Four of eight established human breast cancer cell lines expressed PTHrP and one of these cell lines, MDA-MB-231, was studied in detail using an in vivo model of osteolytic metastases. Mice inoculated with MDA-MB-231 cells developed osteolytic bone metastasis without hypercalcemia or increased plasma PTHrP concentrations. PTHrP concentrations in bone marrow plasma from femurs affected with osteolytic lesions were increased 2.5-fold over corresponding plasma PTHrP concentrations. In a separate experiment, mice were treated with either a monoclonal antibody directed against PTHrP(1-34), control IgG, or nothing before tumor inoculation with MDA-MB-231 and twice per week for 26 d. Total area of osteolytic lesions was significantly lower in mice treated with PTHrP antibodies compared with mice receiving control IgG or no treatment. Histomorphometric analysis of bone revealed decreased osteoclast number per millimeter of tumor/bone interface and increased bone area, as well as decreased tumor area, in tumor-bearing animals treated with PTHrP antibodies compared with respective controls. These results indicate that tumor-produced PTHrP can cause local bone destruction in breast cancer metastatic to bone, even in the absence of hypercalcemia or increased circulating plasma concentrations of PTHrP. Thus, PTHrP may have an important pathogenetic role in the establishment of osteolytic bone lesions in breast cancer. Neutralizing antibodies to PTHrP may reduce the development of destructive bone lesions as well as the growth of tumor cells in bone.
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PMID:Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. 883 2

Parathyroid hormone-related protein (PTHrP) has been shown to be the primary factor responsible for humoral hypercalcemia of malignancy. Recently PTHrP has been shown to be an early-response gene that may be involved in cellular proliferation or differentiation. In addition, PTHrP has been implicated in the pathogenesis of bone metastases. Bone metastases are a significant complication in patients with prostate cancer. We compared the expression of PTHrP by immunohistochemical staining using a monoclonal antibody directed against epitope between amino acids [53-64] in benign prostatic hyperplasia (BPH) with that in various stages of prostate cancer. Tissue sections were obtained on formalin-fixed paraffin-embedded blocks from BPH, well-differentiated prostate cancer, poorly differentiated prostate cancer, lymph node metastases (n = 15 each), and normal prostate (n = 2). In the normal prostate tissue there was no staining observed. In BPH, 13 of 15 tissue samples were positive for PTHrP immunoreactivity. An average of 33% of the cells stained positive with 1+ intensity. All samples from prostate cancer stained positive for PTHrP. In the samples from well-differentiated prostate cancer, an average of 87% of cells stained positive for PTHrP, whereas 100% of cells were positive in poorly differentiated and metastatic tumors. The intensity of staining was 3+ in well-differentiated tumors and 4+ in poorly differentiated tumors. Therefore, the expression of PTHrP is enhanced in prostate cancer as compared with BPH and is greater in poorly differentiated carcinoma as compared with the well-differentiated tumors. The role of PTHrP in the pathogenesis of prostate cancer deserves further study.
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PMID:Enhanced expression of parathyroid hormone-related protein in prostate cancer as compared with benign prostatic hyperplasia. 895 5


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