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      Analysis of Bone Mineral Density and Turnover in Patients with Cystic Fibrosis: Associations between the IGF System and Inflammatory Cytokines

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          Abstract

          Background: Cystic fibrosis (CF) patients present an increased risk of osteoporosis, and increased fracture rate. Several factors have been identified as modulators of bone metabolism and bone mineral density (BMD). Aims: To evaluate BMD and serum markers of bone turnover and establish their relationships with serum concentrations of interleukin (IL)-1β, IL-6, tumour necrosis factor (TNF)-α, IGF-I, IGF-II, IGF binding protein (IGFBP)-2, IGFBP-3, and parathyroid hormone (PTH) in young adult CF patients. Methods: Seventeen young adult CF patients (4 M, 13 F; mean age: 26.6 ± 1.1 years) were enrolled in the study and analysed as a whole and as two subgroups according to the Shwachman-Kulczycki score. BMD was assessed at the lumbar spine (L1–L4) by dual energy X-ray absorptiometry (DXA Hologic QDR 2000). Bone turnover was assessed by measuring serum levels of osteocalcin (OC) and serum carboxyterminal propeptide of type I collagen (PICP) as markers of bone formation, and serum cross-linked carboxyterminal telopeptide of type I collagen (ICTP) as a marker of bone resorption. Serum IGFs, IGFBPs, and cytokines were assayed using special commercial kits. Daily calcium intake and weekly physical activity were estimated by questionnaires. Forced expiratory volume in one second was used to assess pulmonary function. Results: Lumbar BMD was normal, although there was a tendency to be lower in the patients with a lower clinical score. Both OC and PICP were increased, whereas ICTP was normal. Lumbar BMD was positively correlated with pulmonary function. IL-6 and C-reactive protein (markers of inflammation) were inversely correlated with PICP. Serum ICTP levels were correlated with serum IGF-I levels.No significant relationship was detected among lumbar BMD, markers of bone turnover and PTH, IGF-I, IGF-II, IGFBP-2, IGFBP-3, TNF-α, IL-1β, and body mass index Z-score. Conclusions: Bone turnover is abnormal in CF patients. Young adult CF patients with satisfying clinical status and nutritional conditions have normal BMD and increased serum OC and PICP levels.

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          Most cited references 23

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          Italian cross-sectional growth charts for height, weight and BMI (6-20 y).

          To trace growth charts for height, weight and body mass index (BMI) that apply to the whole Italian population. Different charts were drawn for central-north and south Italy since children in central-north regions are known to be taller and leaner. Cross-sectional study. A sample of schoolchildren covering 16 of the 20 Italian regions, with data collected between 1994 and 2000. A total of 27 421 girls and 27 374 boys, aged 6-20 y. Height and weight were measured using portable Harpenden stadiometers and properly calibrated scales, respectively. SIEDP references are presented both as centiles and as LMS curves for the calculation of standard deviation scores. According to International Obesity Task Force, SIEDP charts for BMI include the limits for overweight and obesity, ie the centiles having, at 18 y of age, the value of 25 and 30 kg/m(2), respectively. The comparison between SIEDP and Tanner et al's charts for height, still in use among most Italian paediatricians, shows that before puberty Italian children are 2-4 cm taller than their English peers. Because of these differences, Tanner's charts fail to detect, when applied to Italian children, 50-90% of short children aged 6-11 y, ie with stature below the 3rd centile of their reference population. Rolland-Cachera et al's centiles for BMI are lower than those of SIEDP standards, mainly during adolescence (up to 6.6 kg/m(2) for the 97th centile), and apply poorly to Italian children. The prevalence of overweight is 27 (boys) and 19% (girls) in south Italy vs 17 (boys) and 10% (girls) in central-north Italy. These references intend to supply Italian paediatricians with a tool that avoids the use of outdated or inadequate charts, and thus should be suitable for monitoring their patients' growth. Italian Society for Pediatric Endocrinology and Diabetes (SIEDP).
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            Role of physical activity in the development of skeletal mass in children.

            A group of 118 children, aged 5.3-14 years, were enrolled in a prospective study of calcium supplementation and bone mass. At entry to the study, questionnaires regarding the child's usual physical activity were administered to the children and their mothers. Repeated activity assessments at 6 month intervals indicated good within-person agreement for total activity and for most individual activities. Consistent positive associations were observed between bone mineral densities (BMD) in the radius, spine, and hip and most activities. A summary measure (total hours of weight-bearing activity) was significantly related to BMD in the radius and hip, independently of age or gender effects. Self-reported sports and play activities were associated with BMD, but neither time spent watching television nor hours of physical education classes were associated either positively or negatively with skeletal mass. These data suggest that important increments in skeletal mass may result from physical activity during childhood.
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              Inflammation is a modulator of the insulin-like growth factor (IGF)/IGF-binding protein system inducing reduced bioactivity of IGFs in cystic fibrosis.

              In inflammatory bowel diseases, increased serum interleukin (IL)-6 levels are associated with high serum insulin-like growth factor-binding protein 2 (IGFBP-2) levels, and cytokines modify the insulin-like growth factor (IGF)/IGFBP system in models in vitro. In cystic fibrosis (CF) the IGF/IGFBP system has not been extensively studied, and relationships with proinflammatory cytokines have not been explored. The aim of this study was to investigate the IGF/IGFBP system and verify changes dependent on IL-1beta, IL-6, tumour necrosis factor alpha (TNFalpha), and insulin. Eighteen subjects with CF (mean age 26.6 +/- 1.1 years) and 18 controls, comparable for age, sex, and body mass index, were enrolled. Serum IGF-I, IGF-II, IGFBP-2, IGFBP-3, IL-1beta, IL-6, TNFalpha, insulin and C-peptide were measured. Different molecular forms of IGFBP-2 and IGFBP-3 were investigated by Western immunoblotting. The patients were analysed as a whole and as two subgroups depending on established clinical criteria (Swachman-Kulczycki score). Patients had higher serum concentrations of IL-1beta, IL-6, TNFalpha and IGFBP-2 than controls. Serum concentrations of IGF-I and IGF-II were significantly lower and insulin and C-peptide levels significantly increased in CF compared with healthy controls whereas IGFBP-3 serum concentrations were similar, with comparable IGF-I/IGFBP-3 and decreased IGF-I/IGFBP-2 and IGF-II/IGFBP-2 molar ratios. From correlation analysis we detected a significant positive correlation between IGFBP-2 and IL-6 and a negative correlation between IGFBP-2 and IGFBP-3. Our findings suggest that inflammation is an important modulator of the IGF/IGFBP system with an overall reduction in IGF bioactivity in CF.
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                Author and article information

                Journal
                HRE
                Horm Res Paediatr
                10.1159/issn.1663-2818
                Hormone Research in Paediatrics
                S. Karger AG
                1663-2818
                1663-2826
                2006
                September 2006
                20 September 2006
                : 66
                : 4
                : 162-168
                Affiliations
                aDepartment of Pediatrics, University of Parma, Parma, bDepartment of Pediatrics, University of Pisa, Pisa, Italy
                Article
                94143 Horm Res 2006;66:162–168
                10.1159/000094143
                16804317
                © 2006 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 1, Tables: 2, References: 35, Pages: 7
                Categories
                Original Paper

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