Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0005940 (bone disease)
 7,459 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In patients with adynamic bone disease, the bone contains few osteoblasts or osteoclasts and bone turnover is slow, so the risk of fracture is increased. The decrease of bone remodeling may also decrease the capacity of bone to buffer calcium, leading to an increase of the calcium x phosphate product and an increased risk of arterial calcification. Such findings emphasize that an effective treatment for adynamic bone disease is required. The present study investigated the influence of vitamin K2 (menatetrenone) on hemodialysis patients with low serum parathyroid hormone levels by using bone metabolism markers. The subjects were 32 hemodialysis patients (19 men and 13 women) aged from 27 to 76 years with an intact parathyroid hormone (PTH) level of less than 65 pg/ml and an intact osteocalcin level below 20 ng/ml. All patients received oral menatetrenone therapy (45 mg/day) for 12 months. To obtain control data on bone metabolism markers in hemodialysis patients with normal bone turnover, we selected 50 patients who had intact PTH levels within the range that maintains relatively normal bone turnover, that is, from 120 to 250 pg/ml. The baseline levels of all bone metabolism markers were significantly lower in our patients than in the normal PTH control group. There was a significant increase of gamma-carboxyglutamate (Gla) osteocalcin, bone alkaline phosphatase (B-ALP), tartrate-resistant acid phosphatase (TRACP), and cross-linked N-terminal telopeptide of type 1 collagen (NTx) levels after vitamin K2 administration. Type 1 procollagen carboxyterminal propeptide (P1CP) and intact osteocalcin both showed a significant increase after 12 months of treatment. Although there was no significant change of the alkaline phosphatase (ALP) level during the 12 months before the start of vitamin K2 therapy, there was a significant increase of alkaline phosphatase after vitamin K2 administration. Adjusted calcium, serum phosphate, and intact PTH showed no significant changes throughout the study. These changes of bone metabolism markers suggested that vitamin K2 therapy can improve bone remodeling in hemodialysis patients with low serum PTH levels.
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PMID:Effects of vitamin K2 in hemodialysis patients with low serum parathyroid hormone levels. 1500 6

The osteoprotegerin (OPG)/receptor activator of NF-kappa B ligand (RANKL) system has a major role in the pathogenesis of bone disease in myeloma (MM). The effect of autologous stem cell transplantation (ASCT) on bone turnover in MM was evaluated in 51 patients (35M/16F). Markers of bone resorption (NTX, TRACP-5b), bone formation (bone-alkaline phosphatase (bALP), osteocalcin), OPG and sRANKL were measured pre- and every month post-ASCT. The median follow-up period was 12 months. Four patients were transplanted in CR, 44 were transplanted in PR and three patients had progressive/resistant disease. All patients received bisphosphonates both pre- and post-ASCT. At baseline the majority of patients had increased NTX, TRACP-5b levels, and sRANKL/OPG ratio, while markers of bone formation were strongly suppressed. ASCT produced a significant reduction of sRANKL/OPG ratio, with a concomitant decrease of NTX, and TRACP-5b levels, starting the second month post-ASCT. Bone formation markers, osteocalcin and bALP, started to increase after the 9th and 11th month post-ASCT, respectively, while the increase of OPG preceded this. These results provide biochemical evidence that ASCT normalizes the abnormal bone resorption in MM patients possibly through the decrease of RANKL/OPG ratio, while bone formation requires a longer period to return to normal.
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PMID:Autologous stem cell transplantation normalizes abnormal bone remodeling and sRANKL/osteoprotegerin ratio in patients with multiple myeloma. 1521 75

This study was designed to evaluate the utility of the bone markers total alkaline phosphatase (TAP), bone-specific alkaline phosphatase (BAP), aminoterminal propeptide of type I collagen (PINP), carboxyterminal propeptide of type I collagen (PICP), pyridinoline crosslinks (PYD), deoxypyridinoline crosslinks (DPD), cross-linked carboxyterminal telopeptide of type I collagen (ICTP), cross-linked carboxyterminal telopeptide of type I collagen (CTx, beta-CrossLaps) and tartrate-resistant acid phosphatase 5b (TRAP 5b) in comparison with bone scintigraphy for the diagnosis of bone metastasis in lung carcinoma patients. The study population consisted of 49 patients with bone metastasis confirmed by plain radiography and/or computed tomography, 89 patients without bone metastasis, 12 patients with benign lung diseases and 18 healthy persons. All patients were of male gender. The bone markers were measured using commercially available tests. Serum and urine were collected from fasting patients at the time of bone scan between 7.00 and 8.00 a.m. The sensitivity of bone scintigraphy was 100%, its specificity 76.4%, resulting in a diagnostic efficiency of 84.8%. The positive predictive value was calculated to be 70% and the negative one to be 100%. The concentrations of the bone markers TAP, BAP, PINP, PYD, DPD and ICTP were significantly higher in patients with bone metastasis than in those without bone metastasis (p<0.01). The levels of PICP and CTx only tended to be higher in the patients with bone metastasis compared to those without bone metastasis. There was no significant difference in the TRAP 5b levels between the two groups. There was also no difference in the marker levels between osteoblastic, osteolytic and mixed osteoblastic-osteolytic lesions. Contrary to BAP, PICP, CTx and TRAP 5b, the markers TAP, PINP, PYD, DPD and ICTP were found to be higher (p<0.01-0.05) in patients with bone metastasis than in patients with benign lung diseases. In addition, PYD, DPD and ICTP differentiated patients with benign lung diseases from the healthy controls. Based on cut-off values that correspond to 95% specificity in the group of healthy persons, the sensitivity of the marker assays were as follows (specificity in brackets): TAP 33.3% (97.5%), BAP 22% (100%), PINP 18.4% (97.5%), PICP 2.1% (95.2%), PYD 91.8% (24.1%), DPD 83.7% (34.5%), ICTP 75.5% (44.6%), CTx 45.8% (77.5%) and TRAP 5b 14% (84%). The corresponding data for the diagnostic efficiency were as follows: TAP 73.6%, BAP 77.1%, PINP 67.7%, PICP 61.1%, PYD 48.5%, DPD 55.2%, ICTP 56.1%, CTx 65.6% and TRAP 5b 58.7%, respectively. The positive predictive values ranged from 20% (PICP) to 100% (BAP) and the negative values from 62.7% (PICP) to 84% (PYD). In the ROC analysis, TAP, followed by RAP, PINP and PYD, showed the best performance. The levels of TAP, BAP, PINP, PYD, DPD and ICTP were found to be higher in the patients with bone metastasis compared to those with metastastic lesions in other sites (p<0.01, except for ICTP having a p value of < 0.05). The levels of TAP, BAP, PYD, DPD and ICTP increased significantly with the number of metastases. There was also a steady increase in T scores of the markers PINP, PYD, DPD and ICTP with the extent of the metastatic bone disease. It is concluded that the currently available bone markers cannot replace bone scintigraphy, either for screening or in the diagnosis of bone metastasis, in lung carcinoma patients. However, a panel consisting of TAP, BAP, PINP, PYD, DPD and ICTP may be of some value as an adjunct tool to bone scintigraphy for this purpose.
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PMID:Comparison of bone scintigraphy with bone markers in the diagnosis of bone metastasis in lung carcinoma patients. 1551 Jun 10

Bone disease, a hallmark of multiple myeloma occurs in the majority of the patients, is associated with bone pain, fractures, hypercalcemia and has major impacts on quality of life. Myeloma is characterized by a unique form of bone disease with osteolytic bone destruction that is not followed by reactive bone formation, resulting in extensive lytic lesions. This review will focus on the pathophysiology of osteoclast activation and osteoblast inhibition in multiple myeloma and on biochemical markers of bone turnover. Since osteolytic lesions do not rapidly heal in myeloma, X-rays cannot reflect the activity of bone disease during antimyeloma treatment. Activity in bone turnover does not parallel changes in monoclonal protein levels. Thus, there is a need for biochemical markers reflecting disease activity in bone. The utility, prognostic implications and limitations of classical and novel markers of bone remodeling (e.g. ICTP, NTx, TRACP-5b, osteoprotegerin, sRANKL) will be discussed in this overview.
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PMID:Bone markers in multiple myeloma. 1676 40

The bone alkaline phosphatase (BALP) B1x isoform has previously only been identified in some adults with chronic kidney disease on dialysis and in human bone tissue. Twenty-nine patients, 3-20 years of age, with reduced renal function due to a variety of kidney diseases were examined. We measured parathyroid hormone (PTH), biointact (whole 1-84) PTH, osteoprotegerin (OPG), CrossLaps (CTX), tartrate-resistant acid phosphatase isoform 5b (TRACP 5b) type I procollagen intact amino-terminal propeptide (PINP), osteocalcin, total alkaline phosphatase (ALP), and BALP isoforms B/I, B1x, B1, and B2. Fifty percent higher levels were detected of PTH vs. biointact PTH, demonstrating non-(1-84) PTH fragments detected by the PTH assay. Increased activities were found in five, four, and three patients for total ALP, B1, and B2, respectively. Sixteen (55%) patients had increased B/I levels. B1x was identified in two (7%) patients, who had OPG levels in the higher range independently of age, glomerular filtration rate (GFR), and biointact PTH. B1x was identified prior to and after 9 days of growth hormone (GH) therapy in one patient but not after 1, 3, 6, and 12 months, however. In conclusion, our study demonstrates that the novel BALP B1x isoform is occasionally found to be present in children with kidney disease but to a lesser degree in comparison with adults with chronic kidney disease on dialysis. It is essential to perform bone histomorphometry for future investigations in order to elucidate the exact nature of circulating B1x in patients with kidney disease for accurate classification of type of renal bone disease.
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PMID:The novel bone alkaline phosphatase B1x isoform in children with kidney disease. 1693 97

The effect of bortezomib on bone remodelling was evaluated in 34 relapsed myeloma patients. At baseline, patients had increased serum concentrations of dickkopf-1 (DKK-1), soluble receptor activator of nuclear factor-kappaB ligand (sRANKL), sRANKL/osteoprotegerin ratio, C-telopeptide of type-I collagen (CTX) and tartrate-resistant acid phosphatase isoform-5b (TRACP-5b); bone-alkaline phosphatase and osteocalcin were reduced. Serum DKK-1 correlated with CTX and severe bone disease. Bortezomib administration significantly reduced serum DKK-1, sRANKL, CTX, and TRACP-5b after four cycles, and dramatically increased bone-alkaline phosphatase and osteocalcin, irrespective of treatment response. This is the first study showing that bortezomib reduces DKK-1 and RANKL serum levels, leading to the normalisation of bone remodelling in relapsed myeloma.
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PMID:Bortezomib reduces serum dickkopf-1 and receptor activator of nuclear factor-kappaB ligand concentrations and normalises indices of bone remodelling in patients with relapsed multiple myeloma. 1710 51

Osteolytic bone disease in multiple myeloma (MM) is associated with upregulation of osteoclast (OCL) activity and constitutive inhibition of osteoblast function. The extracellular signal-regulated kinase 1/2 (ERK1/2) pathway mediates OCL differentiation and maturation. We hypothesized that inhibition of ERK1/2 could prevent OCL differentiation and downregulate OCL function. It was found that AZD6244, a mitogen-activated or extracellular signal-regulated protein kinase (MEK) inhibitor, blocked OCL differentiation and formation in a dose-dependent manner, evidenced by decreased alphaVbeta3-integrin expression and tartrate-resistant acid phosphatase positive (TRAP+) cells. Functional dentine disc cultures showed inhibition of OCL-induced bone resorption by AZD6244. Major MM growth and survival factors produced by OCLs including B-cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL), as well as macrophage inflammatory protein (MIP-1alpha), which mediates OCL differentiation and MM, were also significantly inhibited by AZD6244. In addition to ERK inhibition, NFATc1 (nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1) and c-fos were both downregulated, suggesting that AZD6244 targets a later stage of OCL differentiation. These results indicate that AZD6244 inhibits OCL differentiation, formation and bone resorption, thereby abrogating paracrine MM cell survival in the bone marrow microenvironment. The present study therefore provides a preclinical rationale for the evaluation of AZD6244 as a potential new therapy for patients with MM.
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PMID:Targeting MEK1/2 blocks osteoclast differentiation, function and cytokine secretion in multiple myeloma. 1785 7

Osteolytic bone disease in multiple myeloma (MM) is caused by enhanced osteoclast (OCL) activation and inhibition of osteoblast function. Lenalidomide and bortezomib have shown promising response rates in relapsed and newly diagnosed MM, and bortezomib has recently been reported to inhibit OCLs. We here investigated the effect of lenalidomide on OCL formation and osteoclastogenesis in comparison with bortezomib. Both drugs decreased alpha V beta 3-integrin, tartrate-resistant acid phosphatase-positive cells and bone resorption on dentin disks. In addition, both agents decreased receptor activator of nuclear factor-kappaB ligand (RANKL) secretion of bone marrow stromal cells (BMSCs) derived from MM patients. We identified PU.1 and pERK as major targets of lenalidomide, and nuclear factor of activated T cells of bortezomib, resulting in inhibition of osteoclastogenesis. Furthermore, downregulation of cathepsin K, essential for resorption of the bone collagen matrix, was observed. We demonstrated a significant decrease of growth and survival factors including macrophage inflammatory protein-alpha, B-cell activating factor and a proliferation-inducing ligand. Importantly, in serum from MM patients treated with lenalidomide, the essential bone-remodeling factor RANKL, as well as the RANKL/OPG ratio, were significantly reduced, whereas osteoprotegerin (OPG) was increased. We conclude that both agents specifically target key factors in osteoclastogenesis, and could directly affect the MM-OCL-BMSCs activation loop in osteolytic bone disease.
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PMID:Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma. 1859 40

Myeloma bone disease (MBD) leads to progressive destruction of the skeleton and is the most severe cause of morbidity in multiple myeloma. Its pathogenetic mechanisms are not fully understood, though the current evidence points to osteoclast (OC) hyperactivity coupled with defective osteoblast function unable to counteract bone resorption. OCs are generated in bone marrow by myeloid progenitors through increased levels of receptor activator of nuclear factor kappaB ligand and M-CSF, whose intracellular pathways propagate signals that activate sequential transcription factors, resulting in the production of major OC enzymes that drive specific functions such as acidification and degradation of the bone matrix. Osteolytic lesions, however, are not characterized by massive OC content, whereas malignant plasma cells, which are usually present in a high number, may occur as large multinucleated cells. The possibility that myeloma cells fuse and generate polykaryons in vivo is suggested by the in vitro formation of multinuclear cells that express tartrate-resistant acid phosphatase and produce pits and erosive lacunae on experimental osteologic substrates. Further, the detection in vivo of polykaryons with chromosome translocations typical of myeloma cells lends support to the view that myeloma polykaryons may act as functional OCs and participate in the skeletal destruction by resorbing bone.
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PMID:Bone-resorbing cells in multiple myeloma: osteoclasts, myeloma cell polykaryons, or both? 1928 60

Chronic inflammation affects bone metabolism and is commonly associated with the presence of osteoporosis. Bone loss is directed by various immune mediators such as the pro-inflammatory cytokines tumour necrosis factor-alpha, interleukin 1-beta or interferon-gamma. Pre-B cell colony enhancing factor (PBEF)/nicotinamide phosphoribosyl transferase (NAMPT)/visfatin is a pleiotropic mediator acting as growth factor, cytokine and enzyme involved in energy and nicotinamide adenine dinucleotide (NAD) metabolism. PBEF/NAMPT/visfatin has been recently demonstrated to exert several pro-inflammatory functions. We studied serum levels of PBEF/NAMPT/visfatin in patients with inflammatory bowel diseases (IBD) and their relation with bone mineral density (BMD). Furthermore, we were interested whether PBEF/NAMPT/visfatin affects osteoclastogenesis and involved mediators. PBEF/NAMPT/visfatin serum levels were increased in patients with IBD, correlated positively with disease activity and negatively with BMD, especially in the lumbar spine. Osteoclast precursor cells were generated from peripheral blood mononuclear cells after stimulation with various growth factors such as macrophage colony-stimulating factor (M-CSF) and soluble ligand of receptor activator of nuclear factor kappa B (RANK). In these in vitro studies, PBEF/NAMPT/visfatin suppressed osteoclastogenesis and inhibited the differentiation of osteoclast precursors into tartrate-resistant acid phosphatase positive multinucleated cells. These effects were paralleled by the suppression of the osteoclast typical markers RANK, nuclear factor of activated T-cells c1 (NFATc1) and cathepsin-K. This is the first report demonstrating a potential role for this important cytokine/enzyme in inflammation-related bone disease.
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PMID:Pre-B cell colony enhancing factor/NAMPT/visfatin and its role in inflammation-related bone disease. 1958 71


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