Specific inhibition of iNOS decreases the intestinal mucosal peroxynitrite level and improves the barrier function after thermal injury

BACKGROUND: Patients with Crohn's disease are at risk of osteoporosis and premature fracture. However, the pathophysiology underlying bone loss remains poorly understood and the optimum treatment has not been established. AIM: To investigate mechanisms of bone loss in Crohn's disease using biochemical markers of bone turnover. METHODS: Bone mineral density was measured at the hip and spine using dual-energy X-ray absorptiometry in 117 patients (48 male) with Crohn's disease. Bone turnover was assessed by measuring serum osteocalcin (BGP), pro-collagen carboxy-terminal propeptide (PICP), bone specific alkaline phosphatase (BALP) and urinary deoxypyridinoline (DPD); and compared to age-matched healthy controls (n = 28). RESULTS: Bone mineral density was reduced (z-score < -1) in 48 (41%) patients with Crohn's disease. Mean values for bone formation markers in patients with Crohn's disease were all within the normal reference range (BGP 8.92 (+/- 3.23) ng/mL (normal range 3.4-10.0), BALP 17.6 (+/- 12.6) U/L (normal range 11.6-43.3), PICP 95.1 (+/- 46.5) ng/mL (normal range 69-163)) and were not significantly different to the control population. However, mean urinary DPD was significantly higher in patients with Crohn's disease compared to healthy controls (10.97 (+/- 9.22) nM DPD/mM creatinine vs. 5.02 (+/- 1.03) nM DPD/mM creatinine, difference in means = 5.95, 95% CI: -9.6 to -2.3, P = 0.00001) and compared to the UK reference range DPD levels were increased in 74 (63%) patients. CONCLUSIONS: Bone resorption as evidenced by urinary DPD was frequently increased in patients with Crohn's disease and was significantly higher than in an age-matched control population. The high levels of urinary DPD suggest increased bone collagen degradation may contribute to osteoporosis in patients with Crohn's disease. These results suggest anti-resorptive agents such as the bisphosphonates may be effective treatment for osteoporosis in Crohn's disease.     

Livestock improvement: art, science, or industry?

BACKGROUND: Renal osteodystrophy includes a number of low and high turnover bone histologic patterns which require a bone biopsy for their full identification. The role of intact PTH and several classical and more recent bone markers in the non-invasive diagnosis of renal bone disease in patients with CRF in HD requires further definition since available published data are limited. METHODS: In addition to intact PTH, alkaline phosphatase (AP) and osteocalcin (BGP), bone alkaline phosphatase isoenzyme (BALP), tartrate resistant acid phosphatase (TRAP), C-terminal cross-linked peptide of collagen type 1 (ICTP) and deoxypyridinoline (DPD) were measured in the serum of 41 patients on haemodialysis, subjected at the same time to transiliac bone biopsy for histomorphometric, histodynamic and aluminium histochemical examination. Histodynamic evaluation following double tetracycline label, was carried out in 37 patients. The patients had no evidence of active cytolytic and cholestatic liver disease and a history of very limited aluminium exposure. RESULTS: The patients had differing degrees of hyper-parathyroidism, with intact PTH ranging from normal to very elevated levels. Serum values of the markers BGP, ICTP and DPD, normally excreted through the kidneys, were on average very high. The correlation coefficients of the humoral parameters vs dynamic variables, such as BFR/BS, were high. The highest values were: intact PTH 0.798, AP 0.900, BALP 0.891, ICTP 0.807. The patients, grouped in low turnover osteodystrophy (LTO; 9), mixed osteodystrophy (MO; 9) and prevalent hyperparathyroidism (HP; 23), showed significant difference in the levels of most humoral and static and dynamic parameters (ANOVA). Bone aluminium histochemistry was negative in all cases. Discrimination of LTO patients from the other groups by humoral parameters, at the highest value of accuracy, showed 100% sensitivity and 93.7% specificity with a cut-off of 12.9 ng/ml for BALP; 88.9% sensitivity and 93.7% specificity with a cut-off of 21.5 ng/ml for DPD, and 88.9% sensitivity and 90.6% specificity with a cut-off of 79.7 pg/ml for intact PTH. The other markers had lower values. A standardized z-score approach for evaluation of all humoral parameters was also carried out. Using all variables, a correct classification of MO/HP and of LTO was possible in 93.8 and 88.9% of the cases, respectively. Predictive power was 96.8 and 80%, respectively for MO/HP and LTO. When the only variables used were intact PTH and BALP, a correct classification of MO/HP and LTO was possible in 90.6% and 88.9%, respectively. Predictive value of MO/HP was 96.7% and for LTO 72.7%. Predictive values using PTH and AP were 96.3% and 57.2%, respectively. CONCLUSION: Intact PTH and several relatively new bone markers are of certain value in the non-invasive diagnosis of renal osteodystrophy. However some of the humoral markers carry the same quality of information and the use of intact PTH and BALP may be adequate in the discrimination of bone histologic patterns. In cases exempt from liver disease, PTH and AP may be used as a less costly alternative. Bone biopsy could be chiefly limited to cases with borderline humoral values and to all those with a suspected aluminium overload.     

Diagnostic validity of bone metabolic markers for bone metastasis

We measured bone resorption markers in tumor patients with and without bone metastases and evaluated the diagnostic validity of these biochemical parameters in the diagnosis of neoplastic bone involvement. On the basis of radiography and bone scintigraphy findings, subjects were divided into 3 groups, 83 patients without bone metastases (META(-)), 22 patients with 1 or 2 bone metastases (META(+)) and 22 patients with more than 3 bone metastases (META(++)). Among the biochemical markers, urinary pyridinoline (PYR), circulating C-terminal telopeptide of type I collagen (ICTP) and urinary N-terminal telopeptide of type I collagen (NTx) were especially sensitive and specific and increased significantly not only in META(++) but also even in META(+). The efficacy of several bone metabolic markers in differentiating between patients with and without bone metastases was evaluated by receiver-operating characteristic (ROC) analysis, and PYR, ICTP and NTx were proved to have high diagnostic validity (area under the ROC curve; 0.75 for PYR, 0.77 for ICTP and 0.77 for NTx). Furthermore, their odds ratios showed significantly high values for both META(+) and META(++)(to META(++); 7.91 for PYR, 5.33 for ICTP and 5.70 for NTx). On the other hand, urinary deoxypyridinoline (DPYR) and serum total alkaline phosphatase (ALP) showed relatively low sensitivities, the odds ratio of ALP in particular being insignificant. In conclusion, several bone metabolic markers were proved to be useful in the diagnosis of bone metastases in patients with malignancies, particularly PYR, ICTP and NTx had rather high diagnostic validities among all markers examined in this study.     

Carcinogenic responses of transgenic heterozygous p53 knockout mice to inhaled 239PuO2 or metallic beryllium

BACKGROUND: To investigate if serum levels of carboxyterminal propeptide of type I procollagen (PICP), cross-linked carboxyterminal telopeptide of type I collagen (ICTP) and urinary levels of deoxypyridinoline (D-Pyr) are useful markers of bone metastasis in patients with prostate carcinoma, we measured these markers in patients with untreated benign prostatic hyperplasia (BPH) and untreated prostate carcinoma (PCA). METHODS: Serum PICP, ICTP and urinary D-Pyr levels were determined in 53 patients; 16 patients with BPH, 15 patients with PCA without bone metastasis (stage A, B, C and D1) and 22 patients with PCA with bone metastasis (stage D2). At the same time correlations among these markers and serum total alkaline phosphatase (ALP) activity were studied. RESULTS: Serum PICP, ICTP and urinary D-Pyr levels in the PCA patients with bone metastasis were significantly higher than those of BPH. The serum levels of PICP in patients with PCA with bone metastasis group were significantly higher than those of without bone metastasis group. The serum levels of ICTP in patients with PCA without bone metastasis group were significantly higher than those of BPH group, while no significant difference was observed between PCA group with and without bone metastasis. In the PCA patients with bone metastasis, serum PICP and serum total alkaline phosphatase (ALP) activity were significantly correlated (r = 0.80). In these patients, serum ICTP and urinary D-Pyr levels were also significantly correlated (r = 0.70). CONCLUSION: These results suggest that serum PIPC, ICTP and urinary D-Pyr are the useful markers to quantitate bone metastasis in the patients with PCA. Moreover, the determination of serum ICTP levels may be significant for detecting occult bone metastasis in the patients with PCA.     

Quantitative bone scintigraphy in the management of monostotic Paget's disease of bone

OBJECTIVE: To assess the use of quantitative bone scanning (QBS) in the monitoring of patients with intravenous pamidronate-treated symptomatic monostotic Paget's disease of bone in whom biochemical markers of bone turnover are relatively normal. METHODS: QBS was performed in 9 patients and the results were expressed as a ratio, obtained by comparing isotope uptake at an affected and a control (unaffected) site. RESULTS: Serum alkaline phosphatase levels were normal in 7 of the 9 patients and changed minimally with treatment. The median QBS ratio was 2.72 (range 1.69-24.6) at baseline and 1.49 (range 0.63-4.18) posttreatment (P = 0.008). The median symptom score decreased with treatment, but QBS ratios provided the only objective measure of disease activity by which response to pamidronate therapy could be judged. CONCLUSION: QBS may be a useful technique for evaluating the effects of treatment in patients with Paget's disease of bone.     

The usefulness of early whole body bone scintigraphy in the detection of bone metastasis from prostatic cancer

Early whole body bone scintigraphy was performed on 25 patients with prostatic cancer (15 cases with bone metastases and 10 cases without bone metastasis) to obtain anterior and posterior whole body images five minutes after administration of 99mTc-HMDP. The results were compared with the findings of routine bone scintigraphy after three hours, and the usefulness of the above method for the diagnosis of bone metastasis from prostatic cancer was evaluated. In cases in which increased activity was found in the upper and lower lumbar vertebrae by routine bone scintigraphy but no abnormality was seen by early whole body bone scintigraphy, senile degenerative bone changes such as spondylosis deformans were observed by bone radiography. In cases with multiple bone metastases, abnormal multiple accumulations were found by both early whole body bone scintigraphy and routine bone scintigraphy. In addition, in cases showing super bone scan, high accumulation in the skeletal system had already been detected by early whole body bone scintigraphy. When the courses before and after treatment in nine cases of multiple bone metastases were passaged from the results of early whole body bone scintigraphy and from changes in tumor markers (prostatic specific antigen, gamma-semino protein and prostatic acid phosphatase), increased activity and the appearance of new hot spots as well as an increase in tumor markers were detected by early whole body scintigraphy in three of the four advanced cases, whereas decreased accumulations and a decrease in and normalization of tumor markers were observed in five improved cases.     

Markers of bone remodeling in the elderly subject: effects of vitamin D insufficiency and its correction

The elderly subject is prone to both vitamin B insufficiency and calcium insufficiency due to a low calcium intake and calcium malabsorption. These two alterations may lead to secondary hyperparathyroidism, and thus to increased bone loss. We investigated 72 elderly subjects (16 men and 56 women) with vitamin D insufficiency and 25 healthy elderly women with normal vitamin D status, with respect to their indices of calcium metabolism and of bone remodeling: serum total alkaline phosphates (phosphatases), bone AP (BAP), osteocalcin (BGP), tartrate-resistant acid phosphatase (TRAP), urine hydroxyproline (HYP), and the 3-OH-pyridinium derivatives pyridinoline (PYD) and deoxypyridinoline (DPD), which are new markers of bone resorption. We then studied the modifications of these markers in the patients with vitamin D insufficiency at 3 months and 6 months after onset of a daily vitamin D and calcium supplementation. When compared with elderly subjects with normal vitamin D status, patients with vitamin D insufficiency had increased intact parathyroid hormone (iPTH) levels (60.1 +/- 10.2 vs 30.2 +/- 4.5, p < 0.001) and a high bone turnover as reflected by increased values of most serum and urine markers of bone remodeling. PYD and DPD levels were significantly correlated with all indices of bone turnover, unlike HYP, which showed no correlation with bone formation markers (AP, BAP, and BGP). A daily supplement of 800 IU vitamin D3 and 1 g of elemental calcium increased 25(OH)D levels and induced a dramatic decrease of iPTH levels; at 3 and 6 months, the mean iPTH level decreased by 50% (p < 0.0001), reaching the mean value of healthy vitamin D sufficient elderly women. All markers of bone turnover, except TRAP, decreased significantly at 3 and 6 months. The PYD/DPD ratio increased significantly at 3 and 6 months. The decrease of bone markers was more marked in patients with more severe hyperparathyroidism, the greatest variations being obtained with BAP (45%, p = 0.006) and DPD (43%, p = 0.036) levels. Most markers of bone remodeling are increased in elderly subjects with vitamin D insufficiently and vary with its correction. However, BAP and DPD are the most sensitive indicators of increased bone turnover due to secondary hyperparathyroidism.     

A simple combination of Rf value and melting-point determination for the identification of barbiturates

Patients (219) with prostatic adenocarcinoma were classified on the basis of whether or not their bone scans were positive for metastasis. Acid and alkaline phosphatase determinations and clinical evaluations for bone metastases were reviewed. Of those with proved metastases, 43% had no bone pain, 39% had normal acid phosphatase levels, 23% normal alkaline phosphatase levels, 19% normal levels of both enzymes, and 15% normal enzyme levels without bone pain. Twenty-four per cent of the patients with normal enzyme levels and clinically unsuspected bone metastases had bone scans which proved positive for metastasis; 62% of these had normal radiographs.     

Identification of metabolic bone disease in patients with endogenous hyperthyroidism: role of biological markers of bone turnover

Active hyperthyroidism is associated with reduced bone mass. Nevertheless, not all patients show the same risk for developing osteoporosis. Our aim was to analyze some clinical and biochemical potential predictors of low bone mass in hyperthyroid patients. We studied 127 consecutive hyperthyroid patients (110 females, 17 males; aged 42 +/- 16 years). Bone mineral density (BMD) was measured by dual X-ray absorptiometry (DXA) at lumbar spine (LS; L2-L4) and femoral neck (FN). Data were expressed as g/cm2 and T-score. Patients were placed into two groups based on recent WHO criteria: Group A, no osteoporosis (n = 98); and group B, lumbar or femoral osteoporosis (n = 29). Study protocol included evaluation of osteoporosis risk factors, anthropometrical variables, thyroid function, and bone turnover markers. Receiver-operating characteristic (ROC) plots for the precision of bone markers and multivariate analysis for the prediction of BMD and osteoporosis were performed. Group B showed greater age and proportion of menopausal females; lower weight, height, and calcium intake; longer duration of menopause; and greater levels of total and bone alkaline phosphatase and of urine hydroxyproline. No differences in thyroid function, osteocalcin, tartrate-resistant acid phosphatase, and type I collagen C-telopeptide (ICTP) were found. The best predictive model accounted for 46% and 62% of the variability of lumbar and femoral BMD respectively and correctly classified 89% of the osteoporotic hyperthyroid patients. No significant difference in ROC plots was observed. It is concluded that hyperthyroid patients with lumbar or femoral osteoporosis show a typical clinical and biochemical profile illustrating that the relationship between BMD and bone markers is better in high turnover states. Classical bone turnover markers show high performance in the evaluation of hyperthyroid bone disease.     

Biochemical markers of bone metabolism: an overview

OBJECTIVES: An overview of biochemical markers of bone metabolism is presented along with indications for their clinical utilization. DESIGN AND METHODS: The structure, cyclical metabolism, and hormone regulation of bone is reflected by markers of resorption, formation and/or turnover. Markers of resorption representing degradation of type 1 collagen, include N-telopeptides, C-telopeptides, hydroxyproline, and the collagen crosslinks pyridinoline and deoxypyridinoline; acid phosphatase, a marker of osteoclast activity, and urinary calcium are also indicators of bone resorption. Bone formation markers indicate osteoblast activity; bone-specific alkaline phosphatase and the N-terminal and C-terminal extension peptides of procollagen reflect formation of organic matrix in bone. Osteocalcin, produced by osteoblasts but also released during osteoclastic degradation, may indicate either formation when resorption and formation are coupled or turnover when they are uncoupled. RESULTS: Bone markers respond to intervention more rapidly than techniques such bone mineral density. Resorption markers respond approximately 1 to 3 months after intervention; markers of formation respond later, after 6 to 9 months. Bone markers may add useful information for assessing fracture risk and for monitoring osteoporosis, Paget's disease of bone, cancer metastasis, and metabolic disease. Various therapeutic interventions may affect release of some bone markers. CONCLUSION: Bone disease has high prevalence in adults so bone markers will become even more important for assessing fracture risk and monitoring therapy as populations age. Characteristics of bone markers are dependent on biology and the assay used. Substantial work remains in characterizing existing assays, identifying better markers and performing the clinical studies to define which bone markers should be measured and when.