Carboxyterminal Telopeptide Of Type Research Articles

Association between polymorphisms in period genes and bone density in postmenopausal Korean women

Objective In the present study, we aimed to investigate the association between genetic polymorphisms in period (PER) genes and bone mineral density (BMD) in postmenopausal Korean women.Methods The PER1 c.2247C> T and c.2884C> G polymorphisms; the PER2 c.661G> A and c.3731G> A polymorphisms; the PER3 c.2592G> A, c.3029C> T, c.3035C> T, and c.3083T> C polymorphisms, and the 54 bp variable number tandem repeats polymorphism were analyzed in 551 postmenopausal Korean women. Serum leptin, soluble leptin receptor, osteoprotegerin, soluble receptor activator of the nuclear factor-κB ligand, and bone markers including bone alkaline phosphatase and carboxy-terminal telopeptide of type I collagen were measured, and the lumbar spine and femoral neck BMDs were also determined.Results The PER2 c.661G> A, PER3 c.3029C> T and c.3035C> T polymorphisms were not observed. The PER2 and PER3 polymorphisms evaluated were not related to BMD, whereas associations of the c.2247C> T and c.2884C> G polymorphisms in PER1 with the lumbar spine BMD were observed both singly and in combination. The CC haplotype homozygotes showed significantly lower lumbar spine BMD than participants with other genotypes. Additionally, 2.01-fold higher odds for osteoporosis of the lumbar spine were found in the CC haplotype homozygotes compared to women not carrying the haplotype CC allele. No significant differences in bone markers were detected according to the PER1 haplotype genotype.Conclusions Our results suggest that both the PER1 c.2247C> T and c.2884C> G polymorphisms may be genetic factors affecting the lumbar spine BMD in postmenopausal Korean women.

SP0179 Biological Changes in Early Systemic Sclerosis

Early systemic sclerosis (SSc) is a newly identified condition characterized by the association of Raynaud's phenomenon (RP) with SSc marker autoantibodies and/or with a scleroderma pattern at nailfold videocapillaroscopy (NVC),...

Increased low-density lipoprotein cholesterol level is associated with non-vertebral fractures in postmenopausal women.

Although a high serum low-density lipoprotein cholesterol (LDL-C) level is an established risk factor for atherosclerosis, it is unclear whether it is associated with osteoporosis. In this study, the associations between the serum LDL-C level and bone mineral density (BMD), bone metabolic markers, and the presence of prevalent vertebral or non-vertebral fractures were examined. A total of 211 healthy postmenopausal women (age range, 46-80 years) who visited a community health center were recruited consecutively. Their radiographic and biochemical characteristics were collected. Prevalent vertebral and non-vertebral fractures were found in 49 (23.2%) and 36 (17.1%) subjects, respectively. Simple regression analyses showed that the serum LDL-C level was not significantly correlated with lumbar or femoral BMD or serum levels of total amino-terminal propeptide of type I collagen (PINP) or carboxy-terminal telopeptide of type I collagen (CTX). Logistic regression analyses adjusted for age and BMI showed that the increased serum LDL-C level was selected as an index affecting the presence of prevalent non-vertebral fractures, but not vertebral fractures. This result was still significant after additional adjustments for years since menopause, physical activity, previous cardiovascular events, bone markers, BMD, serum Ca, P, Cr, 25(OH)D, grip strength, tandem gait test, and use of drugs for hyperlipidemia [odds ratio 1.76 (1.13-2.73), p=0.012]. These findings suggest that a high serum LDL-C level may be a risk factor for prevalent non-vertebral fragility fractures independent of bone turnover, bone mass, vitamin D insufficiency, or frail status in postmenopausal women, and that it may be detrimental to bone, as well as blood vessels.

Early Changes in Bone Density, Microarchitecture, Bone Resorption, and Inflammation Predict the Clinical Outcome 12 Weeks After Conservatively Treated Distal Radius Fractures: An Exploratory Study

Fracture healing is an active process with early changes in bone and inflammation. We performed an exploratory study evaluating the association between early changes in densitometric, structural, biomechanical, and biochemical bone parameters during the first weeks of fracture healing and wrist-specific pain and disability at 12 weeks in postmenopausal women with a conservatively treated distal radius fracture. Eighteen patients (aged 64 ± 8 years) were evaluated at 1 to 2 and 3 to 4 weeks postfracture, using high-resolution peripheral quantitative computed tomography (HR-pQCT), micro-finite element analysis, serum procollagen type-I N-terminal propeptide (P1NP), carboxy-terminal telopeptide of type I collagen (ICTP), and high-sensitive C-reactive protein (hsCRP). After 12 weeks, patients rated their pain and disability using Patient Rated Wrist Evaluation (PRWE) questionnaire. Additionally, Quick Disability of the Arm Shoulder and Hand (QuickDASH) questionnaire and active wrist range of motion was evaluated. Linear regression models were used to study the relationship between changes in bone parameters and in hsCRP from visit 1 to 2 and PRWE score after 12 weeks. A lower PRWE outcome, indicating better outcome, was significantly related to an early increase in trabecular bone mineral density (BMD) (β -0.96 [95% CI -1.75 to -0.16], R(2) = 0.37), in torsional stiffness (-0.14 [-0.28 to -0.004], R(2) = 0.31), and to an early decrease in trabecular separation (209 [15 to 402], R(2) = 0.33) and in ICTP (12.1 [0.0 to 24.1], R(2) = 0.34). Similar results were found for QuickDASH. Higher total dorsal and palmar flexion range of motion was significantly related to early increase in hsCRP (9.62 [3.90 to 15.34], R(2) = 0.52). This exploratory study indicates that the assessment of early changes in trabecular BMD, trabecular separation, calculated torsional stiffness, bone resorption marker ICTP, and hsCRP after a distal radius fracture provides valuable information regarding the 12-week clinical outcome in terms of pain, disability, and range of motion and validates its use in studies on the process of early fracture healing. © 2014 American Society for Bone and Mineral Research.

Relationship of bone scan index and progression-free survival after docetaxel treatment for CRPC patients with bone metastases.

280 Background: A computer-aided diagnosis system for bone scintigraphy using semiquantitative index [Bone Scan Index (BSI)] has been used to measure the tumor burden of bone metastases. We examined relationships of BSI, bone turnover marker, and prostate-specific antigen (PSA)-progression free survival (PFS) after docetaxel-treatment for castration resistant prostate cancer (CRPC) with bone metastasis. Methods: Sixteen CRPC patients with bone metastases (median age 72, range 52 to 82) were treated with docetaxel. We evaluated bone metastasis by bone scintigraphy before or around six months after docetaxel-treatment retrospectively. BSI was automatically calculated by BONENAVI software version 1 (FUJIFILM RI Pharma, Co. Ltd., Tokyo, Japan; Exini Bone, Exini Diagnostics, Sweden). Serum PSA, bone alkaline phosphatase (BAP), carboxyterminal telopeptide of type I collagen (I-CTP) were examined every months. PSA-PFS was evaluated after docetaxel-treatment and compared with baseline of BSI, BAP, I-CTP, and change of these value after treatment. Overall survival (OS) was also evaluated by these markers. The rate of patients with PFS and OS was estimated by the Kaplan-Meier method. Results: Baseline of BSI, the serum BAP, and I-CTP before docetaxel-treatment did not affect PFS. The change of BAP and I-CTP by the docetaxel-treatment also did not affect PFS. Only the change of BSI affected PFS and the median PFS of CRPC patients with increased BSI and decreased BSI was 5.5 months and 10 months, respectively (p=0.026). Although OS showed a longer tendency in CRPC patients with decreased BSI than with increased BSI, there was not the significant difference (p=0.12). Conclusions: The change of BSI affected PFS in CRPC patients with bone metastases. Bone scan and its evaluation with BONENAVI was effective to monitor the clinical course during chemotherapy.

Association between polymorphisms in leptin, leptin receptor, and β-adrenergic receptor genes and bone mineral density in postmenopausal Korean women

The purpose of this study was to investigate the association between single nucleotide polymorphisms in leptin (LEP), leptin receptor (LEPR), and β-adrenergic receptor (ADRB) genes and bone mineral density (BMD) in postmenopausal Korean women. LEP c.280G>A, LEPR c.326A>G, LEPR c.668A>G, LEPR c.1968G>C, LEPR c.2096C>T, ADRB2 c.46A>G, ADRB2 c.79C>G, ADRB2 c.718T>C, ADRB2 c.741G>T, ADRB2 c.769G>A, and ADRB3 c.190T>C polymorphisms were analyzed in 592 postmenopausal Korean women. Serum levels of leptin, soluble leptin receptor, osteoprotegerin, soluble receptor activator of the nuclear factor-κB ligand, bone alkaline phosphatase, and carboxy-terminal telopeptide of type I collagen were measured, and BMDs at the lumbar spine and femoral neck were also examined. Among the polymorphisms measured, only the LEPR c.1968G>C polymorphism was found to be associated with BMD at the femoral neck, and higher BMD was observed with increasing number of G alleles (P = 0.04). Osteoporosis at the femoral neck was 3.27 and 3.89 times more frequently observed in the AG and GG genotypes than in the AA genotype in the ADRB2 c.46A>G polymorphism (P = 0.024 and P = 0.015, respectively). However, no significant differences in serum levels of leptin, soluble leptin receptor, free leptin index, osteoprotegerin, soluble receptor activator of the nuclear factor-κB ligand, and bone turnover markers were detected among single and haplotype genotypes. These results suggest that the LEPR c.1968G>C polymorphism may be one of the genetic factors affecting femoral neck BMD in postmenopausal Korean women and that an analysis of the ADRB2 c.46A>G polymorphism may be useful in identifying women at risk for osteoporosis at the femoral neck.

Investigation of pyridinolne cross linked carboxyterminal telopeptide of type I collagen on carcinomaofrectum

Objective To investigate the clinical usefulness of determination of serum pyridinoline cross linked carboxyterminal telopeptide of type Ⅰ collagen (ICTP) in patients with carcinomaofrectum.Methods 75 malignant carcinomaofrectum patients in group A with 71 primary malignant carcinomaofrecrum patients and 4 metastatic carcinomaofrectum patients were analyzed,43 benign carcinomaofrectum patients were including group B,52 normal persons were chosen in group C,Serum ICTP in everybody was determined by enzyme immunoassay (EIA).Results The serum level of ICTP in group A was (14.84 ±8.49) μg/L,and the serum level of primary malignant carcinomaofrectum,and metastatic tumor of bone in group A were (17.47 ± 10.86) μg/L and (8.14 ± 5.45) μg/L,the serum level of ICTP in group B and C were (6.75 ±3.34) μg/L and (4.68 ±2.91) μg/L.The serum level in group A was significantly higher than that in group B and C (P ＜ 0.05),At the same time,the serum level in primary malignant carcinomaofrectum patients were significantly higher than that of metastatic carcinomaofrectum patients (P ＜ 0.05).Conclusion Serum ICTP was a sensitive and convenient biochemical index which could diagnose and identify carcinomaofrectum. Key words: Benign carcinomaofrectum ; Primary carcinomaofrectum; Metastatic tumor; Pyridinoline cross linked carboxyterminal telopeptide of type Ⅰ collagen

Reference intervals for serum concentrations of three bone turnover markers for men and women

ObjectiveBone turnover markers (BTMs) reflect the metabolic activity of bone tissue and can be used to monitor osteoporosis therapy. To adequately interpret BTMs, method-specific reference intervals are needed. We aimed to determine reference intervals for serum concentrations of intact amino-terminal propeptide of type I procollagen (PINP), bone-specific alkaline phosphatase (BAP) and carboxy-terminal telopeptide of type I collagen (CTX). Material and methodsWe established a healthy reference population of 1107 men as well as 382 pre- and 450 postmenopausal women, who participated in the first follow-up of the Study of Health in Pomerania. Serum PINP, BAP and CTX concentrations were measured on the IDS-iSYS Automated System (Immunodiagnostic Systems, Frankfurt am Main, Germany). The reference interval was defined as the central 95% range. We determined age-specific reference intervals for PINP, BAP, and CTX for men by quantile regression. Reference intervals for women were age-independent. ResultsReference intervals for men for PINP and CTX decreased with age (25–29year-old men: PINP 31.1–95.9ng/mL, CTX 0.12–0.83ng/mL; 75–79year-old men: PINP 15.7–68.1ng/mL, CTX 0.05–0.58ng/mL). The reference interval for men for BAP did not significantly change with age (25–29year-old men: 7.4–27.7ng/mL; 75–79year-old men: 7.6–24.4ng/mL). The reference intervals for 30–54year-old premenopausal women were: PINP 19.3–76.3ng/mL, BAP 6.0–22.7ng/mL, and CTX 0.05–0.67ng/mL. The reference intervals for 50–79year-old postmenopausal women were: PINP 18.2–102.3ng/mL, BAP 8.1–31.6ng/mL, and CTX 0.09–1.05ng/mL. ConclusionAn intensively characterized, large reference population free of bone-related diseases allowed us to determine robust reference intervals for serum concentrations of PINP, BAP and CTX. Our normative data may aid to interpret bone turnover in adult men and pre- and postmenopausal women.

SAT0476 The Role of Vitamin D Receptor Gene Polymorphism (VDR) in Pathogenesis of Juvenile Idiopathic Arthritis and Bone Metabolism Disturbances.

BackgroundJuvenile idiopathic arthritis (JIA) – chronic articular disease related to immune system dysfunctions. JIA course and complications have genetic background.ObjectivesWe evaluated features of JIA and related bone mineralization and metabolism...

A new parameter of bone scintigraphy: Relation between bone scan index and bone metabolic markers in prostate cancer patients with bone metastases.

e16072 Background: A computer-aided diagnosis system for bone scan with semiquantitative index of Bone Scan Index (BSI) may be used to quantify the spread of bone metastases. This retrospective study aimed to examine associations between BSI, bone metabolic markers, and prostate specific antigen (PSA) in prostate cancer patients with bone metastases. Methods: A total of 158 scintigraphy of 52 patients (mean examinations/person 3, range 1-8; mean age 71 years, range 46 to 86) were studied. The intervals between bone scan and blood examinations were 0 to 16 days (median 0 day). Subjects were divided into 4 groups according to BSI; Group A: 0 - <2, Group B: 2 - <4, Group C: 4 - <8, and Group D: 8<. The markers of PSA, pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (1-CTP), bone alkaline phosphatase (BAP), and tartate resistant acid phosphatase-5b (TRAP-5b) were examined. As the values of PSA, BAP, and TRAP-5b covered a large range of scales, we also used the logarithms of the variables. BSI, which corresponded amount of metastatic lesions, was automatically calculated by BONENAVI software (FUJIFILM RIPharma, Co. Ltd., Tokyo, Japan; Exini Bone, Exini Diagnostics, Sweden). Results: All scans showed increased uptake at bone metastases. BSI correlated significantly with 1-CTP, BAP, logBAP, TRAP-5b, logTRAP-5b, and logPSA (r=0.39, 0.66, 0.71, 0.69, 0.61 and 0.41, respectively). Statistical F value was 11 in 1-CTP, 31 in BAP, 29 in logBAP, 19 in TRAP-5b, 14 in logTRAP-5b, 3 in PSA, and 9 in logPSA by ANOVA, respectively. Comparison by Dunnett’s test showed significantly higher values in Group D for all bone metabolic markers and logPSA, Group C for BAP, logBAP, TRAP-5b, and logTRAP-5b, and Group B for logTRAP-5b compared with Group A, respectively. However, PSA did not correlate significantly with extent of bone metastases as assessed by BSI. Conclusions: The changes in BSI showed close relationship with all bone metabolic markers but not with PSA. The BSI reflected the activity and extent of bone metastases, and might be used as an imaging biomarker.

Improvement in collagen metabolism after 12 weeks’ cardiac resynchronization therapy in patients with ischaemic cardiomyopathy

To investigate the effects of cardiac resynchronization therapy (CRT) on collagen metabolism biomarkers and their relationship to cardiac function, in patients with ischaemic cardiomyopathy (ICM). Serum levels of matrix metalloproteinase (MMP)-9, tissue inhibitor of MMP-9 (TIMP-1), carboxyterminal propeptide of type I procollagen (PICP) and carboxyterminal telopeptide of type I collagen (ICTP) were quantified before and after 12 weeks' treatment, in patients with ICM receiving CRT and standard medical therapy (CRT group) or standard medical therapy alone (non-CRT group), and in controls. Cardiac function was measured echocardiographically. MMP-9, TIMP-1, ICTP and the MMP-9/TIMP-1 ratio were significantly higher, and the PICP/ICTP ratio significantly lower, in patients with ICM (n = 27) compared with controls (n = 20). After 12 weeks' treatment, MMP-9, TIMP-1, ICTP and the MMP-9/TIMP-1 ratio were significantly higher, and the PICP/ICTP ratio significantly lower, in the non-CRT group (n = 15) compared with the CRT group (n = 12). The PICP/ICTP ratio correlated positively with TIMP-1 and negatively with MMP-9. The early/atrial ratio and left ventricular ejection fraction correlated positively and negatively, respectively, with the MMP-9/TIMP-1 ratio. Echocardiographic measurements of cardiac function were significantly worse in patients with ICM compared with controls and improved significantly after treatment in the CRT group. In ICM, collagen degradation biomarkers were elevated and correlated positively with cardiac function. CRT partially reversed the deterioration in collagen metabolism and enhanced cardiac function.

Application of Data Mining Technology on Analyzing a Series of Biomarkers for Diagnosis of Bone Metastasis from Different Cancers

The aim of this study was to evaluate the value index of tumor biomarkers for diagnosis and prediction of bone metastasis by combining pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen (ICTP) in serum with other biochemical markers in patients with several cancers. All of 1253 patients and biomarkers data with cancers and the related benign diseases and 312 healthy controls were included in the study. Bioinformatics, data mining technology and statistics were carried out to calculate sum of direct positive index (SDPI) and sum of indirect positive index (SIPI). The average ICTP was higher in patients with bone metastasis from liver, gastric, lung, colorectal and pancreatic cancer, than in cancer patients without bone metastasis. For those cancers patients with bone metastasis, which could not be differentiated by single ICTP, combining with SDPI and SIPI would distinguish types of carcinama in situ from similar symptoms. The measurement of multiple tumor markers was very useful in complementary diagnosis and prediction of different carcinoma with bone metastasis bottom.

Effect of glucagon-like peptide-2 exposure on bone resorption: Effectiveness of high concentration versus prolonged exposure

ObjectiveIn healthy subjects, subcutaneous injections of GLP-2 have been shown to elicit dose-related decrease in the bone resorption marker, carboxy-terminal telopeptide of type I collagen (CTX), and have been proposed for the treatment of osteoporosis. This study investigated the relation between GLP-2 exposure and decreases in CTX in order to determine whether high concentrations or prolonged exposure was the most effective mode of administration. High GLP-2 concentrations resulted from iv bolus injections, whereas a more protracted stimulation was obtained by subcutaneous injections and the addition of an inhibitor of GLP-2 degradation, a DPP-4 inhibitor, sitagliptin. Materials and methodsEight healthy subjects were given: a) three intravenous injections of GLP-2 of 0.1, 0.4 and 0.8nmol/kg, b) one subcutaneous injection of 1.6mg GLP-2 and c) one subcutaneous injection of 1.6mg GLP-2 preceded by an intake of sitagliptin. Blood was sampled for measurements of GLP-2 and p-CTX after each intervention. ResultsThe 0.1, 0.4 and 0.8nmol/kg GLP-2 injections dose-dependently elevated plasma GLP-2 concentrations and decreased CTX, but the decrease was similar regardless of dose. Subcutaneous GLP-2 caused a much more prolonged exposure (with a peak concentration corresponding to 0.4nmol/kg IV) and was associated with a stronger and a more prolonged suppression of CTX, but in spite of significantly increasing exposure, the administration of sitagliptin, had no additional effect. ConclusionThe high concentrations obtained by iv administration were less effective with respect to CTX suppression than the prolonged exposure (with much lower peak concentrations). GLP-2 agonists for osteoporosis treatment should therefore be long-acting for best efficacy.

Plasma osteoprotegerin is associated with testosterone levels but unaffected by pioglitazone treatment in patients with polycystic ovary syndrome.

Increased osteoprotegerin (OPG) levels are associated with increased cardiovascular risk and decreased bone resorption. Pioglitazone treatment reduces the inflammatory state but may decrease bone mineral density (BMD). OPG levels during pioglitazone treatment have not previously been evaluated in polycystic ovary syndrome (PCOS). Plasma OPG levels were measured in 30 PCOS patients before and after randomized treatment with 30 mg pioglitazone/placebo for 16 weeks. Fourteen age- and body mass index-matched healthy women were included as controls. Clinical and hormonal evaluations and whole body dual-energy X-ray absorptiometry scans were performed in all participants. OPG levels were comparable in PCOS patients [12.0 (10.5-14.6) ng/ml] and controls [12.9 (11.7-14.9) ng/ml]. In PCOS patients (no.=30), OPG levels were positively associated with testosterone (r=0.43), PRL (r=0.47), Pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (r=0.43), and hip BMD, whereas inverse associations were found between OPG levels and triglyceride (r=-0.49) and free fatty acid levels during euglycemic clamps (r=-0.38), all p<0.05. Pioglitazone treatment significantly decreased inflammatory markers, insulin sensitivity, and BMD without affecting OPG levels. OPG levels were comparable in PCOS patients and controls and unchanged during insulin sensitizing treatment with pioglitazone. OPG levels were associated with BMD in PCOS. Future studies need to evaluate OPG as a marker of cardiovascular disease in PCOS.

89Sr Imaging With Bremsstrahlung in Patients With Metastatic Breast Cancer

In this study, we investigated the clinical and laboratory factors that may enhance (89)Sr uptake to strengthen its tumoricidal effect. We enrolled 21 patients with multiple bone metastases (n = 23) from breast cancer and classified them into 2 groups according to their zoledronic acid (ZOL) treatment history. (89)Sr imaging with bremsstrahlung was performed 2 to 6 weeks after administration and (89)Sr index was measured using combined imaging with bone scintigraphy. We compared the Sr index with the levels of alkaline phosphatase, bone-specific alkaline phosphatase, serum cross-linked N-telopeptides, carboxy-terminal telopeptide of type 1 collagen, C-reactive protein, calcium, and hemoglobin on administration and evaluated the differences among the groups. The (89)Sr index ranged from 0.01 to 2.0 and was significantly correlated with C-reactive protein and alkaline phosphatase and moderately correlated with carboxy-terminal telopeptide of type 1 collagen, serum cross-linked N-telopeptides, and bone-specific alkaline phosphatase. The (89)Sr index was not significantly correlated with calcium or hemoglobin. The group with less than 1 year of ZOL treatment demonstrated a mean (SD) (89)Sr index of 1.11 (0.59), and the group with 1 or more years of ZOL treatment showed a mean (89)Sr index of 0.36 (0.26). The Wilcoxon signed-rank test demonstrated a significant difference between the 2 groups (P < 0.001). (89)Sr accumulation seemed to be associated with bone turnover, in particular bone resorption, and vascularization due to inflammation or tumor growth. Long-term ZOL treatment may reduce bone resorption and vascularization. To enhance the tumoricidal effect and palliation of bone pain by (89)Sr, combined therapy must be established.

Sclerostin Levels Associated with Inhibition of the Wnt/β-Catenin Signaling and Reduced Bone Turnover in Type 2 Diabetes Mellitus

Patients with type 2 diabetes (T2DM) have low bone turnover, poor bone quality, and circulating levels of sclerostin significantly higher than non-T2DM controls. There are no data on the possible association of sclerostin with β-catenin, a key component of the Wnt/β-catenin canonical signaling. The aim of the study was to evaluate the circulating β-catenin levels in T2DM patients and to analyze their relationship with sclerostin and bone turnover markers. This was a cross-sectional study. The study was conducted at a clinical research center. Forty T2DM postmenopausal women were studied and compared with 40 healthy controls. Bone status was assessed by dual-energy x-ray absorptiometry measurements (bone mineral density) and by measuring bone alkaline phosphatase and carboxy-terminal telopeptide of type 1 collagen. Sclerostin and β-catenin were evaluated by an immunoenzymetric assay. Consistent with previous reports in T2DM subjects, we found sclerostin levels higher and bone turnover markers lower than controls. In our cohort of T2DM patients, β-catenin levels are significantly lower than in controls (median 1.22 pg/ml, 25th to 75th percentiles 0.50-2.80; and median 4.25 pg/ml, 25th to 75th percentiles 2.20-7.62, respectively; P=0.0002). β-Catenin correlated negatively with sclerostin (P<0.0001) and positively with bone alkaline phosphatase (P=0.0030) only in T2DM patients and negatively with age in both groups. Eight of the 40 T2DM patients had vertebral fractures. These results show for the first time that T2DM patients have serum concentrations of β-catenin lower than controls. The negative association of β-catenin with sclerostin suggests a biological effect of increased sclerostin on the Wnt signaling, which appears impaired in T2DM.

P-0264 Carboxy-Terminal Telopeptide of Type I Collagene and Tartrate-Resistant Acid Posphatase Measurement in Patients with Colorectal Cancer and Bone Metastases

ABSTRACT Introduction Despite significant advances in detection and treatment, colorectal cancer (CRC) still remains one of the most prevalent cancers, and one of the leading causes of mortality due to malignancy. In patients with stage I-II CRC surgical resection usually represents the sole treatment, while in those with metastasized tumor (stage IV) any therapy is rarely successful. Unfortunately, up to 60% of patients with CRC undergoing primary surgery with curative intention die from metastatic disease. Thus, occult tumor cells, not detected preoperatively, likely colonize and remain vital in different tissues of these patients, such as lymph nodes, blood, and bone marrow. Usually, CRC metastasizes to the liver and lungs more frequently than to bone. Isolated bone metastasis (BM) is considered truly rare, but it has been observed that the improved survival for patients with metastatic CRC following expanded treatment options is associate with an increased incidence of BMs. Because metastases in uncommon sites often indicates the terminal phase of CRC, clinicians should be more vigilant about possible BMs. For this purpose, several serum biomarkers have been tested for early detection of BMs, such as carboxy-terminal telopeptide of type I collagen (ICTP), a cross-link product of collagen I degradation, and tartrate-resistant acid phosphatase 5b (TRACP), specifically derived from osteoclasts. Recent studies showed that TRACP activity and ICTP were increased in up to 90% of patients with breast cancer and BM. The aim of this study was to evaluate the usefulness of TRACP, ICTP, and bone alkaline phosphatase (BAP) measurements in patients with CRC and BM. Methods Fourteen patients (9 men, 5 women, mean age 56.1±4.8, range 49-63 years) with CRC and confirmed BMs (cases), and a group of 15 age- and gender matched (10 men, 4 women, age 57.1±4.9 years, p=0.08) patients (controls) without BM (negative F-18 FDG PET/CT) underwent serum TRACP, ICTP, and BAP measurements. Written informed consent was obtained from all the participants. TRACP and BAP were measured by two-site enzyme-linked immunosorbent assay (ELISA), while ICTP was measured by commercially available radioimmunoassay. The sensitivity and specificity of serum TRACP, ICTP, and BAP as a marker for BM were estimated by receiver operator characteristic (ROC) curves. Results The mean levels of TRACP, ICTP, and BAP (cases vs. controls) were: 5.9±1.6 vs. 4.8±1.3 U/L (95% CI 0.11-2.11, p=0.08), 6.9±1.4 vs. 5.9±1.3 U/L (95% CI 0.94-3.04, p=0.0003), and 82.6±18.2 vs. 79.3±16.2 (95% CI 9.81-16.39, p=0.59). ROC analysis established a cutoff value for ICTP of 4.51 U/mL to identify patients with extensive BM with a specificity of 97% and a sensitivity of 92% (area under the curve=0.97; 95% CI=0.95-0.98). A strong relationship was found only between TRACP and ICTP (R=0.95, p Conclusion Serum ICTP is a useful diagnostic marker in the detection of BMs in patients with CRC, more accurate than TRACP and BAP.

Biologicals and bone loss

Inflammatory joint diseases like rheumatoid arthritis (RA), as well as other rheumatic conditions such as ankylosing spondylitis and systemic lupus erythematosus, comprise a heterogeneous group of joint disorders that are all associated with extra-articular side effects, including bone involvement. Disease activity, immobility and treatment with glucocorticoids are the main factors that increase the risk of osteoporotic fractures, on top of the background fracture risk based on, amongst others, age, body mass index and gender. It is thought that the pathogenesis of both peri-articular and generalized osteoporosis and local bone erosions share common pathways. This hypothesis has been strengthened by the discovery that osteoclasts, stimulated mostly by the receptor activator of nuclear factor kappa B ligand (RANKL) pathway, play a central role in all of these processes. Generalized bone loss has been documented in cross-sectional studies: a 2-fold increase in osteoporosis, defined as a T-score <-2.5 in females and Z-score <-1 was found in 394 postmenopausal RA-patients and 192 male RA-patients [1]. Before the introduction of biologicals, a high bone loss was also observed in a longitudinal study in early RA: -2.4% at the spine and -4.3% at the trochanter [2]. Against that background, it is relevant that we investigated whether treatment with anti-TNF-α prevents loss of bone mineral density at the spine and hip (generalized) and in the hands (local) in patients with rheumatoid arthritis (RA) and during anti-TNF treatment [3]. 102 patients with active RA, who were treated with infliximab during one year, were included into this open cohort study. The BMD of the spine and hip was unchanged during treatment with infliximab, whereas BMD of the hand decreased significantly by 0.8% (p < 0.001). The BMD of the hip in patients with an EULAR good response showed a favorable change compared with patients not achieving such a response. This is a proof that the usually occurring generalized bone loss in patients with RA can be arrested by the use of aggressive antirheumatic drugs, such as anti-TNF. Next to BMD changes upon anti-TNF, we investigated the changes in bone markers, to elucidate the underlying mechanism of the favourable effect of anti-TNF. Bone formation was measured by osteocalcin (OC) and bone resorption was determined by b-isomerized carboxy terminal telopeptide of type 1 collagen (b-CTx); osteoclast regulating proteins including the soluble receptor activator of Nfκb (s-RANKL) and osteoprotegerin (OPG) were determined in serum using an ELISA from Immun-diagnostik. Serum β-CTx and RANKL were both significantly decreased compared to baseline at all time points. The decrease in β-CTx was associated to the decrease in DAS-28 and CRP during the 0 to 14 weeks interval. No changes were observed in serum osteocalcin and OPG. These data on bone mineral density emphasizes that the arrested bone loss at the spine and hips can be described to a large extent to a decrease in disease activity. Later on, it was also shown that bone loss could be arrested in RA-patient treated with adalimumab [4], and the favourable effects of anti-TNF on bone markers were also observed during treatment with rituximab [5].

The Detection of Myocardial Fibrosis

Both type 1 and type 2 diabetes mellitus (DM) are associated with a significant increase in cardiovascular risk. Glycemic control has, unfortunately, not been convincingly shown to reduce cardiovascular risk.1–3 The level at which blood pressure should be controlled also is controversial.4 Thus, there may be a need to focus on new therapeutic targets if we are to reduce cardiovascular risk in patients with either type 1 or type 2 DM. Cardiac and large arteries fibrosis is a frequent occurrence in patients with DM and one of the major factors predisposing to the development of heart failure (HF). Cardiac fibrosis is the consequence of extracellular cardiac matrix remodeling resulting from pathological processes, including ischemia; stretch; inflammation; and specifically in DM, oxidative stress, advanced glycation end products, and several neurohormonal mediators. Cardiac fibrosis may cause myocyte slippage, tissue heterogeneity and dyssynchrony, ventricular dilatation, and contractile dysfunction. Myocardial fibrosis alters myocardial compliance, and associated fibrosis-related large artery stiffness may predispose to diastolic dysfunction and HF with a preserved left ventricular ejection fraction. Cardiac fibrosis also may result in alteration of gap junctions and predispose to arrhythmias and sudden cardiac death.5 Bioimaging and biomarkers of cardiac fibrosis, therefore, may become clinically useful tools, particularly given the potential for cardioprotective and cardioreparative pharmacological strategies.6,7 Article see p 51 The measurement of various serum peptides arising from the metabolism of collagen types I and III, of degradation fragments (carboxy-terminal telopeptide of type I collagen), and of specific metalloproteinases may provide a noninvasive assessment of fibrosis.8–10 A strong correlation exists between changes in serum levels of biomarkers for the turnover of extracellular cardiac matrix proteins and ongoing cardiac remodeling. Diagnostic approaches for diabetic cardiomyopathy …

Myocardial collagen turnover after surgical ventricular restoration in heart failure patients

Surgical ventricular restoration (SVR) aims to normalize left ventricular (LV) volume and shape in patients with ischaemic cardiomyopathy and anterior wall scar. The chronic effects on LV function may depend on alterations in myocardial collagen metabolism. The present study evaluated myocardial collagen synthesis and degradation rates at baseline and at 6 months follow-up after SVR. We hypothesize that the chronic effects of SVR on LV function and clinical outcome depend on alterations in myocardial collagen metabolism. Serum levels of aminoterminal propeptides of type I and III collagen (PINP, PIIINP), carboxyterminal telopeptide of type I collagen (ICTP), and tenascin-C (TNC) were measured at baseline and 6 months after SVR in 24 patients. In addition, New York Heart Association (NYHA) functional class, LV volumes and function were evaluated. At follow-up, a significant improvement in NYHA class (from 3.2 ± 0.8 to 1.4 ± 0.6, P< 0.001) and LV ejection fraction (from 28 ± 9 to 35 ± 7%, P< 0.001) was found, whereas E/A ratio tended to increase (from 1.4 ± 1.1 to 1.9 ± 1.1, P= 0.064). Serum levels of PINP, PIIINP, ICTP, and TNC increased significantly (PINP: from 37 ± 15 to 67 ± 26 μg/L, P< 0.001; PIIINP: from 4.9 ± 1.7 to 7.9 ± 4.0 μg/L, P< 0.001; ICTP: from 5.9 ± 3.7 to 10.0 ± 5.3 μg/L, P< 0.001; TNC: from 30 ± 20 to 44 ± 23 μg/L, P= 0.020). At follow-up, an LV ejection fraction <34% and E/A ratio ≥ 2.0 were significantly associated with increased serum levels of PIIINP and ICTP. In patients who underwent SVR, myocardial collagen metabolism was significantly enhanced 6 months after surgery. Serum levels of myocardial collagen turnover biomarkers were related to post-surgical LV systolic and diastolic function.