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Effects of Dexamethasone Treatment on Bone and Collagen Turnover in Preterm Infants with Chronic Lung Disease

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Effects of Dexamethasone Treatment on Bone and Collagen Turnover in Preterm Infants with Chronic Lung Disease 0031-3998/00/4802-0155 PEDIATRIC RESEARCH Vol. 48, No. 2, 2000 Copyright © 2000 International Pediatric Research Foundation, Inc. Printed in U.S.A. Effects of Dexamethasone Treatment on Bone and Collagen Turnover in Preterm Infants with Chronic Lung Disease PATRICIA M. CROFTON, ANOUPAM SHRIVASTAVA, JEAN C. WADE, RHONA STEPHEN, CHRISTOPHER J.H. KELNAR, NEIL MCINTOSH, AND ANDREW J. LYON Department of Paediatric Biochemistry, Royal Hospital for Sick Children, Edinburgh, United Kingdom [P.M.C.]; Department of Child Life and Health, University of Edinburgh, Edinburgh, United Kingdom [P.M.C., A.S., J.C.W., R.S., C.J.H.K., N.M., A.J.L.]; and Simpson Memorial Maternity Pavilion, Royal Infirmary, Edinburgh, United Kingdom [N.M., A.J.L.] ABSTRACT Dexamethasone is used commonly in the treatment of chronic were also seen in most individual babies, although the slopes of lung disease of prematurity, but there are concerns about possible individual regression lines varied by a factor of 2. Weight gain at deleterious effects on growth and bone. Our aim in this study was 12 wk was correlated with PICP, expressed as the mean SD score to examine the effects of dexamethasone treatment on bone and over 12 wk for each baby, (r ϭ 0.69, p Ͻ 0.01) but not with other collagen turnover in preterm infants. Bone-specific alkaline markers or cumulative dose of dexamethasone. We conclude that phosphatase, the C-terminal propeptide of type I collagen (PICP, dexamethasone markedly suppressed collagen turnover in pre- reflecting whole-body type I collagen synthesis), and the N- term infants in a dose-dependent fashion, although some babies terminal propeptide of type III procollagen (P3NP, reflecting soft were more affected than others. The degree of suppression of tissue collagen turnover), together with the C-terminal telopep- type I collagen synthesis was a strong independent predictor of tide of type I collagen (ICTP), urinary pyridinoline (Pyd), and overall weight gain over the first 12 wk of life. (Pediatr Res 48: deoxypyridinoline (all markers of collagen breakdown) were 155–162, 2000) measured at weekly intervals over the first 12 wk of life in 14 preterm infants with chronic lung disease treated with dexameth- Abbreviations asone. Results were expressed as SD scores relative to preterm CLD, chronic lung disease control infants not treated with dexamethasone. PICP, P3NP, ALP, alkaline phosphatase ICTP, and Pyd all showed marked decreases (Ϫ2.1 to Ϫ3.7 SD PICP, C-terminal propeptide of type I collagen scores) during the first week of treatment (p Ͻ 0.001), returning P3NP, N-terminal propeptide of type III collagen to pretreatment levels after stopping dexamethasone. In the group ICTP, the cross-linked telopeptide of type I collagen as a whole, these collagen markers were negatively correlated Pyd, pyridinoline with dexamethasone dose (p Ͻ 0.0001); negative correlations Dpd, deoxypyridinoline Steroids are used commonly in the management of preterm and reduced phosphate retention, compared with infants who infants with developing chronic lung disease (CLD). Dexa- did not receive steroids (11). methasone has been shown to improve pulmonary compliance Biochemical markers of bone and soft tissue turnover may and help to wean infants from the ventilator, but there are give insight into the dynamic effects of therapeutic interven- concerns about side effects (1–3). Glucocorticoids impair tions on bone and growth (12). For the present study, we chose growth and bone formation in children (4–8). We and others a panel of markers that would reflect various aspects of bone have demonstrated that infants treated with dexamethasone and soft tissue turnover and that have already been validated as have short-term reductions in linear growth, weight velocity, markers of growth in older children and as markers of bone radial length velocity, and bone mineralization compared with formation and resorption by histomorphometry and calcium those not so treated (9–11). We have also demonstrated that kinetic studies in adults (12). Bone alkaline phosphatase (ALP) these infants have reduced calcium absorption and retention, is a marker of the differentiated osteoblast and also of hyper- trophic chondrocytes in the growth plate. The C-terminal propeptide of type I collagen (PICP) quantitatively reflects type Received June 8, 1999; accepted February 2, 2000. Correspondence: Dr. P.M. Crofton, Department of Paediatric Biochemistry, Royal I collagen synthesis; it is produced principally by the osteoblast Hospital for Sick Children, Sciennes Road, Edinburgh EH9 1LF, United Kingdom. in its proliferative phase but may also, to a lesser extent, reflect 155 156 CROFTON ET AL. type I collagen synthesis elsewhere in the body. The N- during mid-morning to minimize the effect of any circadian terminal propeptide of type III collagen (P3NP) is purely a variation on the markers of bone turnover. In addition, we marker of type III collagen synthesis in soft tissue. The cross- collected an extra blood and urine sample 3 d after commenc- linked telopeptide of type I collagen (ICTP) reflects the deg- ing dexamethasone. Samples were stored at Ϫ70°C until anal- radation of type I collagen, largely, but not exclusively, of bone ysis. The study was approved by the local ethics committee and origin. Pyridinoline (Pyd), measured in urine, reflects whole informed parental consent was obtained in all cases. body collagen degradation (excluding that in skin) whereas deoxypyridinoline (Dpd) is thought to be more specific for Analytical Methods bone collagen. We have already demonstrated that in preterm infants not treated with glucocorticoids, PICP and P3NP in- Collagen assays. PICP, P3NP, and ICTP were measured in crease after birth, whereas ICTP decreases, reflecting postnatal plasma by RIA (Orion Diagnostica, Espoo, Finland), using growth (13). P3NP was correlated with rate of weight and methods previously described (14–16). Before analysis, we length gain in these infants, whereas PICP was highly corre- diluted samples appropriately in 154 mM sodium chloride to lated with bone mineral content. achieve concentrations within the calibration curve; typical We report here a longitudinal prospective study on a sepa- dilutions were 1 in 30 for PICP and 1 in 20 for P3NP and ICTP. rate group of preterm infants treated with high-dose dexameth- All samples were analyzed in duplicate. As far as possible, asone. Our aim was to explore its effects on bone and soft samples from each infant were analyzed in a single run to tissue turnover in these infants, to determine whether these minimize analytical variation. Between-run coefficients of vari- effects were dose-related, and to examine their relationship ation for manufacturer’s controls were 7.8% and 5.2% at 94 with growth over the first 12 wk of life. ␮g/L and 320 ␮g/L for PICP, 5.6% at 4.6 ␮g/L for P3NP, and 6.3% and 9.2% at 8.7 ␮g/L and 33.8 ␮g/L for ICTP. For PATIENTS AND METHODS pooled plasma from preterm infants, diluted as above, they were 4.4% at 3990 ␮g/L for PICP, 6.4% at 208 ␮g/L for P3NP, Subjects and 11.7% at 118 ␮g/L for ICTP. All infants admitted sequentially to the neonatal intensive Bone ALP. Bone ALP was measured in plasma by an ௢ care unit over a 15-mo period from August 1993 to November ELISA (Alkphase-B from Metra Biosystems Inc., Mountain 1994 with a birthweight less than 1500 g, gestational age at View, CA, U.S.A.). The assay uses a monoclonal anti-bone birth less than 34 wk, and who were treated with dexametha- ALP antibody coated on a microtitre plate to capture bone ALP sone for developing CLD were eligible to participate in the in the samples. This assay gives approximately 10% cross- study. CLD was defined retrospectively as persisting oxygen reactivity with the liver isoform, but this is not present in dependence at 28 d postnatal age in the presence of an abnor- plasma from preterm infants (17). Using plasma samples from mal chest radiograph. The decision to treat with dexametha- preterm infants containing high activities of fetal intestinal sone was made on clinical grounds by the team caring for the ALP, and also amniotic fluid and extracts of meconium from infant. The policy on the unit at that time was to start dexa- preterm infants (both of which contain only fetal intestinal methasone during the third postnatal week if an infant could ALP), we confirmed that the assay gave no cross-reaction with not be weaned from the ventilator and had signs of developing fetal intestinal ALP, which may comprise up to half the total CLD on chest radiograph. Dexamethasone was commenced at plasma ALP activity in preterm infants (18). Before analysis, 500 ␮g/kg body weight/d for 3 d, followed by gradually we diluted samples 1 in 3 in 154 mM sodium chloride to decreasing doses for a total treatment period of 3 wk. There achieve concentrations within the calibration curve. Between- was, however, some variation in the timing and duration of run coefficients of variation for manufacturer’s controls were dexamethasone treatment, for clinical reasons. Subsequent 6.7% and 5.4% at 15.1 U/L and 70.5 U/L, respectively. For courses of dexamethasone were used as clinically indicated. In pooled plasma from preterm infants, diluted as above, it was practice, all infants in this study who were treated with dexa- 6.6% at 126 U/L. methasone had CLD, as assessed at 28 d postnatal age. Pyridinium cross-links. Pyridinium cross-links were mea- All infants were fed on mother’s breast milk with preterm sured in urine by HPLC using a modification of the method of formula (Prematil, Milupa, Trowbridge, U.K.) added if the Pratt et al.
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