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Query: UMLS:C0153690 (bone metastases)
 6,382 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bone scintigraphy plays a major role in the diagnosis of bone metastases. The clinical utility of new biochemical markers of bone metabolism has recently been investigated in various bone diseases. This study evaluated the role of some bone metabolism markers in comparison with bone scan in the follow-up of breast cancer patients. We studied 149 patients with breast cancer, 33 (22%) of whom had bone metastases. IRMAs were used for the evaluation of blood levels of osteocalcin, bone alkaline phosphatase (BAP), the C-terminal propeptide of type I procollagen and the C-terminal cross-linked telopeptide of type I collagen (ICTP). Multivariate regression analysis showed that menopausal status (P=0.007) and metastatic bone lesions (P=0.001) affected bone marker levels. When considering post-menopausal women, the only subset in which bone metabolism marker behaviour could be reliably investigated, we found a high degree of overlap in marker distribution for scan-positive and scan-negative patients. Discrimination between scan-negative and scan-positive patients based on the above markers, taken singly or jointly, was assessed by means of logistic discriminant analysis. The best discrimination was achieved with BAP, closely followed by ICTP. BAP and ICTP together gave a slight improvement over the use of the two markers separately. However, even in this case the degree of discrimination was poor and its clinical utility was limited. In fact, to achieve a specificity of 95%, the sensitivity of the test was about 20%; conversely, with a sensitivity of 95%, the specificity was below 10%. In conclusion, based on our findings, we believe that blood levels of the investigated markers cannot replace bone scintigraphy in the follow-up of breast cancer patients for the early detection of bone metastases.
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PMID:Can bone metabolism markers be adopted as an alternative to scintigraphic imaging in monitoring bone metastases from breast cancer? 937 66

The role of biochemical markers of bone metabolism in the diagnosis and monitoring of bone metastases in solid tumors is reviewed. Emphasis is on the recently developed markers, which may provide a more accurate quantitation of bone metabolism. In metastatic bone disease, bone formation and resorption become uncoupled processes, leading to predominantly osteoblastic or osteolytic metastases. In osteolytic metastases, bone resorption is enhanced without appropriate acceleration of bone formation. In osteolytic metastases the resorption markers are indicated for the detection of bone metastases. Urinary pyridinium cross-links and serum collagen telopeptides are sensitive and specific markers of bone resorption. These markers, can often identify bone metastases before visualization by imaging techniques. When osteolytic lesions are responding to treatment the physiologic coupling between bone resorption and formation is partly restored. An increase in formation markers, bone specific isoenzyme of alkaline phosphatase (BSAP), osteocalcin (OC) and carboxyterminal propeptide of collagen type I (PICP), will then closely reflect restoration of coupling. In osteoblastic metastases, bone formation markers can accurately indicate early and advanced bone involvement. Bone resorption markers are less sensitive in these osteoblastic lesions. The collagen telopeptides however, are resorption markers with the ability to detect early bone metastases. Osteoblastic lesions responding to therapy are indicated by declining values of formation as well as resorption markers. The precise role of the recently developed markers of bone metabolism in early diagnosis and monitoring of bone metastases needs further evaluation in longitudinal studies. Since the delicate derangements in bone metabolism may be obscured in mixed patient groups, these studies should address uniform patient groups with respect to the primary tumor type.
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PMID:Biochemical parameters of bone metabolism in bone metastases of solid tumors (review). 945 86

Osteolytic metastases are often associated with decreased renal tubular reabsorption of phosphate. There is, however, no specific data on phosphate metabolism in metastases from prostatic cancer, which are generally osteoblastic. The aim of the present study was to investigate renal handling of inorganic phosphate (Pi) in prostatic cancer, in patients without or with skeletal metastases of various extents. Forty-eight patients were the subjects of this study. There were 39 with malignant disease, of whom 27 had bony metastases. Nine other patients had benign prostate hyperplasia. Biochemical indexes of prostatic tumor, renal tubular reabsorption of calcium and Pi, biochemical markers of bone remodeling, and relevant calciotropic hormones were measured and analyzed in relation to the extent of skeletal metastases, as assessed by bone scintigraphy. A higher bone metastatic load was associated with significantly greater prostate-specific antigen and prostatic acid phosphatase levels (P < 0.05), increased levels of biochemical markers of bone formation (P < 0.05) and resorption (P < 0.001), higher maximal renal tubular reabsorption of Pi (TmPi/GFR; P < 0.05), and higher urinary cAMP excretion (P < 0.05). Nine patients among those with bone metastases (n = 27) had higher TmPi/GFR than metastasis-free patients. These had a greater value of osteocalcin (P < 0.001). Also, 8 of these had relatively more extensive skeletal metastatic load. In patients with prostatic cancer, high skeletal metastatic load was accompanied by increased TmPi/GFR despite higher urinary cAMP excretion, which is supposed to reduce the TmPi/GFR. These results support the hypothesis that renal tubular reabsorption of Pi is capable of adaptation to meet demands for minerals in the face of enhanced bone formation.
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PMID:Renal tubular reabsorption of phosphate is positively related to the extent of bone metastatic load in patients with prostate cancer. 958 51

Although increased bone formation is a prominent feature of patients with osteosclerotic metastases from prostate cancer, there is also some evidence for increased bone resorption. The aim of this study was to compare the clinical utility of new bone resorption markers to that of bone formation in patients with bone metastases from prostate cancer before and after bisphosphonate treatment. Thirty-nine patients with prostate cancer and bone metastasis, nine patients with prostate cancer without bone metastases, nine patients with benign prostatic hyperplasia and 355 healthy age-matched men were included. Urinary non-isomerized (alpha CTX) and beta isomerized (beta CTX) type I collagen C-telopeptides (CTX) and a new assay for serum CTX were used to assess bone resorption. Bone formation was determined by serum osteocalcin, serum total (T-ALP) and bone (BAP) alkaline phosphatase and serum type I collagen C-terminal propeptide (PICP). Fourteen patients with bone metastases were also evaluated 15 days after a single injection of the bisphosphonate pamidronate (120 mg). Levels of all bone formation and bone resorption markers were significantly (P < 0.006-0.0001) higher in patients with prostate cancer and bone metastasis than in patients with benign prostatic hyperplasia, patients with prostate cancer without bone metastases and healthy controls. In patients with bone metastases the median was increased by 67% for serum osteocalcin, 128% for T-ALP, 138% for BAP, 79% for PICP, 220% for urinary alpha CTX, 149% for urinary beta CTX and 214% for serum CTX. After bisphosphonate treatment all three resorption markers significantly decreased by an average of 65% (P = 0.001), 71% (P = 0.0010) and 61% (P = 0.0015) for urinary alpha CTX, urinary beta CTX and serum CTX, respectively, whereas no significant change was observed for any bone formation markers. Patients with prostate cancer and bone metastases exhibit a marked increase in bone resorption, which decreases within a few days of treatment with pamidronate. These findings suggest that these new resorption markers may be useful for the management of these patients.
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PMID:Markers of bone turnover for the management of patients with bone metastases from prostate cancer. 1073 59

Hypogonadism is associated with osteoporosis in men. GnRH- agonist-induced hypogonadism increases bone turnover and bone loss in men, but the mechanism underlying these changes is unknown. To determine whether gonadal steroid deprivation increases the skeletal sensitivity to PTH or blunts the ability of PTH to promote 1,25-dihydroxyvitamin D formation, we infused human PTH-(1-34) at a dose of 0.55 U/kg.h for 24 h, in 11 men (ages, 50-82 yr) with locally advanced, node-positive, or biochemically recurrent prostate cancer but no evidence of bone metastases. PTH infusions were performed before initiation of GnRH agonist therapy (leuprolide acetate, 22.5 mg im, every 3 months) and again after 6 months of confirmed GnRH agonist-induced hypogonadism. Serum osteocalcin (OC), bone- specific alkaline phosphatase (BSAP), N-telopeptide (NTX), whole-blood ionized calcium, and 1,25-dihydroxyvitamin D were measured at baseline and every 6 h during each PTH infusion. Urinary NTX and free deoxypyridinoline (DPD) were assessed on spot morning samples before PTH infusion and on 24-h samples collected during the PTH infusions. Sex steroid levels were lowered to the castrate range in all subjects. Baseline serum NTX levels (drawn before PTH infusion) increased from 9.1 +/- 3.7 before leuprolide therapy to 13.9 +/- 5.0 nmol bone collagen equivalents (BCE)/L after leuprolide therapy (P = 0.003). Spot urine NTX collected before PTH infusion increased from 28 +/- 8 before leuprolide therapy to 49 +/- 17 nmol BCE/mmol creatinine after leuprolide therapy (P < 0.001), and urinary DPD increased from 4.7 +/- 1.1 to 7.4 +/- 1.8 nmol BCE/mmol creatinine (P < 0.001). Baseline serum OC and BSAP levels drawn before each PTH infusion did not change before vs. after leuprolide therapy. Serum NTX levels increased significantly during PTH infusion pre-GnRH agonist therapy (P < 0.001), and the rate of increase was greater after 6 months of GnRH agonist-induced hypogonadism (P < 0.01 for the difference in rates of change before and after GnRH agonist administration). Serum OC and BSAP levels decreased during PTH infusion (P < 0.001 for OC and P = 0.002 for BSAP), but the rates of decrease did not differ before or after leuprolide therapy (P = 0.45 for OC and P: = 0.19 for BSAP). Whole-blood ionized calcium levels increased during PTH infusion (P < 0.001), and the rate of increase was greater after GnRH agonist-induced hypogonadism (P = 0.068). Serum 1,25-dihydroxyvitamin D levels increased in response to PTH infusion before leuprolide therapy (P = 0.022), but there was no difference in the rate of increase before or after leuprolide therapy (P = 0.66). The incremental increase in urinary NTX excretion, but not DPD, during PTH infusion was greater after 6 months of leuprolide therapy (P = 0.029 for NTX, P = 0.578 for DPD). We conclude that suppression of sex steroids in elderly men increases the skeletal responsiveness to the bone resorbing effects of PTH infusion but does not affect the response of bone formation markers or 1,25-dihydroxyvitamin D to PTH. Changes in skeletal sensitivity to PTH may play an important role in the pathogenesis of hypogonadal bone loss in men.
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PMID:Effects of gonadal steroid suppression on skeletal sensitivity to parathyroid hormone in men. 1115 1

Bone turnover is characterized both by the formation of new bone by the osteoblasts and the resorption of old tissue by the osteoclast. This process takes place only on the surface of bone and can be described in terms of spatio-temporal events that are the bone metabolic unit and the bone remodelling cycle. The former consists of a discrete group of cells (osteoblasts and osteoclasts) involved in a particular remodelling event while the latter represents the succession of resorption and formation. In a typical remodelling cycle, resorption takes 7-10 days, whereas formation requires 2-3 months. Remodelling is regulated either by local or systemic factors, including electrical and mechanical forces, hormones (e.g. parathyroid hormone, sexual steroids, calcitriol, cortisol, thyroid hormones, calcitonin), growth factors and cytokines. Recently different circulating biochemical markers have been proposed for the investigation of bone turnover. In addition to classical parameters such as serum alkaline phosphatase and urinary calcium and hydroxyproline, new markers have gained clinical attention because of their accuracy in assessing the dynamic changes in bone remodelling (bone alkaline phosphatase, osteocalcin, propeptides PICP and PINP, tartrate-resistant acid phosphatase, deoxypyridinoline, pyridinoline, telopeptide CTx and NTx). The aim of this review is to present the recent advances in this field and the clinical application of markers of bone turnover in patients with bone metastases from solid tumors. Also the cellular and molecular bases of bone remodelling are reported with details.
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PMID:Clinical utility of biochemical marker of bone remodelling in patients with bone metastases of solid tumors. 1145 78

Breast cancer is associated frequently with skeletal metastases, which cause significant morbidity. The main mechanism is an increase in osteoclast-mediated bone resorption. We postulated that osteoblasts could be other essential target cells and previously showed that conditioned medium (CM) of breast cancer cells (BCCs) inhibits the proliferation of osteoblast-like cells. In this study, we investigated the effects of BCC-secreted products on osteoprogenitor cells using a clonal fetal human bone marrow stromal preosteoblastic cell line (FHSO-6) that expresses alkaline phosphatase (ALP) activity, type I collagen (COLI), and increased osteocalcin (OC) and osteopontin under treatment with dexamethasone (Dex), 1,25-dihydroxyvitamin D [1,25(OH)2D], or recombinant human bone morphogenetic protein 2 (rhBMP-2). Treatment with MCF-7 CM inhibited FHSO-6 cell survival in a dose-dependent and irreversible manner. Morphological investigation indicated that MCF-7 CM increased both apoptotic and necrotic cell number. MCF-7 CM increased caspases activity and a broad inhibitor of caspase activity (benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethyl ketone [z-VAD-fmk]) partly reversed the CM-induced inhibition of FHSO-6 cell survival. Western blot analyses revealed an increased bax/bcl-2 ratio in MCF-7 CM-treated FHSO-6 cells. MCF-7 cells exhibit FasLigand as membrane-bound protein and as a soluble cytokine in the CM. Deprivation of MCF-7 CM from active FasLigand by saturation with a soluble Fas molecule suppressed the induction of FHSO-6 apoptosis, whereas fibroblast CM, which did not contain FasLigand, only weakly modified FHSO-6 cell survival because of increased cell necrosis. These data indicate that FasLigand secreted by BCCs induces apoptosis and necrosis of human preosteoblastic stromal cells through caspase cascade modulated by the bax and bcl-2 protein level. The induction of apoptosis in human bone marrow stromal cells by BCCs may contribute to the inappropriately low osteoblast reaction and bone formation during tumor-induced osteolysis in bone metastases.
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PMID:Breast cancer cells release factors that induced apoptosis in human bone marrow stromal cells. 1154 30

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

Delivery of therapeutic toxic genes to and their expression in tumor cells through the use of tissue-specific promoters could decrease their toxic effect on neighboring normal cells when virus-mediated gene delivery results in their infection. We have demonstrated the utility of two prostate cancer-specific promoters, long PSA and osteocalcin, for tissue-specific toxic gene therapy for prostate cancer. The two promoters were highly active in both androgen-dependent and androgen-independent prostate cancer cells. We also introduce the Phase I trial of osteocalcin promoter-based toxic gene therapy for bone metastases of prostate cancer, which is in progress at the University of Virginia.
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PMID:Tissue-specific promoters in gene therapy for the treatment of prostate cancer. 1200 46

Prostate cancer bone metastases are characterized by their ability to induce osteoblastic lesions and local bone formation. It has been suggested that bone metastatic prostate cancer cells are osteomimetic and capable of expressing genes and proteins typically expressed by osteoblasts. The ability of preosteoblasts to differentiate and express osteoblastic genes depends on several pathways, including Notch and MAPK. Here we show that notch1 expression is increased 4-5 times in C4-2B and MDA PCa 2b cells (osteoblastic skeletal prostate metastatic cancer cell lines) when compared with nonskeletal metastatic cell lines (LNCaP and DU145). Notch1 ligand, dll1, is expressed only in C4-2B cells. Immunohistochemical studies demonstrate that Notch1 is present in both human clinical samples from prostate cancer bone metastases and the C4-2B cell line. To determine whether prostate cancer bone metastases respond to osteogenic induction similar to osteoblasts, C4-2B cells were cultured in osteogenic medium that promotes mineralization. C4-2B cells mineralize and express HES-1 (a downstream target of Notch), an effect that is completely inhibited by L-685,458, a Notch activity inhibitor. Furthermore, osteogenic induction increases ERK activation, runx2 expression, and nuclear localization, independent of Notch signaling. Finally, we show that Notch and ERK activation are essential for Runx2 DNA binding activity and osteocalcin gene expression in C4-2B cells in response to osteogenic induction. These studies demonstrate that prostate cancer bone metastatic cell lines acquire osteoblastic properties through independent activation of ERK and Notch signaling; presumably, both pathways are activated in the bone microenvironment.
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PMID:Notch signaling and ERK activation are important for the osteomimetic properties of prostate cancer bone metastatic cell lines. 1460 22


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