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

Abstract

Dexamethasone is used commonly in the treatment of chronic lung disease of prematurity, but there are concerns about possible deleterious effects on growth and bone. Our aim in this study was to examine the effects of dexamethasone treatment on bone and collagen turnover in preterm infants. Bone-specific alkaline phosphatase, the C-terminal propeptide of type I collagen (PICP, reflecting whole-body type I collagen synthesis), and the Nterminal propeptide of type III procollagen (P3NP, reflecting soft tissue collagen turnover), together with the C-terminal telopeptide of type I collagen (ICTP), urinary pyridinoline (Pyd), and deoxypyridinoline (all markers of collagen breakdown) were measured at weekly intervals over the first 12 wk of life in 14 preterm infants with chronic lung disease treated with dexamethasone. Results were expressed as SD scores relative to preterm control infants not treated with dexamethasone. PICP, P3NP, ICTP, and Pyd all showed marked decreases (Ϫ2.1 to Ϫ3.7 SD scores) during the first week of treatment (p Ͻ 0.001), returning to pretreatment levels after stopping dexamethasone. In the group as a whole, these collagen markers were negatively correlated with dexamethasone dose (p Ͻ 0.0001); negative correlations were also seen in most individual babies, although the slopes of individual regression lines varied by a factor of 2. Weight gain at 12 wk was correlated with PICP, expressed as the mean SD score over 12 wk for each baby, (r ϭ 0.69, p Ͻ 0.01) but not with other markers or cumulative dose of dexamethasone. We conclude that dexamethasone markedly suppressed collagen turnover in preterm infants in a dose-dependent fashion, although some babies were more affected than others. The degree of suppression of type I collagen synthesis was a strong independent predictor of overall weight gain over the first 12 wk of life. Steroids are used commonly in the management of preterm infants with developing chronic lung disease (CLD). Dexamethasone has been shown to improve pulmonary compliance and help to wean infants from the ventilator, but there are concerns about side effects (1-3). Glucocorticoids impair growth and bone formation in children (4 -8). We and others have demonstrated that infants treated with dexamethasone have short-term reductions in linear growth, weight velocity, radial length velocity, and bone mineralization compared with those not so treated (9 -11). We have also demonstrated that these infants have reduced calcium absorption and retention, and reduced phosphate retention, compared with infants who did not receive steroids (11).Biochemical markers of bone and soft tissue turnover may give insight into the dynamic effects of therapeutic interventions on bone and growth (12). For the present study, we chose a panel of markers that would reflect various aspects of bone and soft tissue turnover and that have already been validated as markers of growth in older children and as markers of bone formation and resorption by histomorphometry and calcium kinetic studies in adults (1...

Dexamethasone-induced changes in lung function are not prevented by concomitant treatment with retinoic acid

“…In the present study, we found no compelling histological evidence of differences in lung collagen at 1 mo. These observations suggest, as others have shown, that when treatment is stopped, rates of collagen turnover return to, or exceed, control levels (7,29).…”

“…In contrast, Dex alone is reported to suppress collagen synthesis and degradation (7,8,24). In the present study, we found no compelling histological evidence of differences in lung collagen at 1 mo.…”

“…Another possible explanation relates to the density of capillaries in the lung parenchyma. Although the absolute tissue volume was significantly decreased in Dex-treated rats during the first 2 wk of life, Tschanz et al (33) showed that mean absolute values for capillary blood volume and capillary surface area were consistently greater in Dex-treated rats than in controls on days 4,7,10,13, and 36. This increased vascularity was not statistically significant, perhaps because of the small number of rats studied at each age (n ϭ 4).…”

LPS-induced chorioamnionitis and antenatal corticosteroids modulate Shh signaling in the ovine fetal lung

“…Several studies have shown beneficial effects of corticosteroid treatment on attenuating fibrotic processes following lung injury (17,36,50). Preterm infants at risk of BPD patients showed a significant reduction in markers of collagen synthesis after prenatal corticosteroid treatment up to 7 days after administration (18,43). Surprisingly, corticosteroid treatment before the inflammatory stimulus stimulated collagen deposition although little pulmonary inflammation was noticed in these animals (29).…”

A Randomized, Placebo-Controlled GH Trial in Very Preterm Infants Who Were at Risk for Bronchopulmonary Dysplasia and Were Treated with Dexamethasone

“…DEXA treatment in very preterm infants has been associated with reduced cerebral cortical gray matter, an arrest of alveolarization of the lungs, catabolic effects, alteration of skeletal metabolism, and cessation of growth (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(25)(26)(27). Despite these substantial concerns, DEXA is still administered to very preterm infants to wean them from the ventilator when clinical and radiologic signs of BPD develop and conservative treatment such as increased ventilation settings, fluid restriction, diuretics, antibiotics, and inhalation therapy has failed (28).…”