Bone metabolism and circulating IGF-I and IGFBPs in dexamethasone-treated preterm infants

Abstract

Aim: To characterize the ontogeny of circulating IGF-I, the IGF binding proteins (IGFBPs) and biochemical markers of bone turnover in dexamethasone (DEX)-treated preterm infants with chronic lung disease. Methods: Plasma and urine samples from 17 infants were obtained prior to DEX, after 9–12 days of DEX and 10 days after the completion of DEX to assess plasma IGF-I, IGFBPs, osteocalcin and urinary N-telopeptide. Nutrient intakes and growth were monitored from birth until term corrected age at which time body composition was evaluated by dual energy X-ray absorptiometry. Results: Although nutrient intakes did not differ during or after DEX, weight gain (115 vs. 174 g/week) and length gain (0.7 vs. 1.0 cm/week) were higher after DEX treatment. Plasma IGF-I, IGFBP-3 and osteocalcin increased over time. N-telopeptide was the only biochemical parameter which appeared to be suppressed during DEX (1342 nM bone collagen equivalents/mM creatinine vs. 2486 (pre-DEX) and 2292 (post-DEX)). At term corrected age, bone mineral content was lower in dexamethasone-treated infants compared to preterm and term reference infants. Conclusion: Changes in circulating IGFBP-2 and IGFBP-3 paralleled the changes reported in non-steroid-treated infants; however, it remains uncertain whether the natural rise in IGF-I was suppressed by DEX treatment. Assessment of these circulating components provided limited insight into the mechanisms by which DEX alters growth and bone turnover.

Introduction

Infants born very prematurely with a birth weight less than 1200 g exhibit growth rates and bone mass accretion which are substantially lower than intrauterine growth. Administration of dexamethasone (DEX), which is an accepted therapy for bronchopulmonary dysplasia (BPD) [15], [22], [29], imposes an additional impediment to growth and skeletal development in this population. DEX treatment is associated with reduced weight and length growth during treatment, with a delay in length growth still apparent at 6 months corrected age [37]. The gain in radial bone mineral content (BMC) from recruitment through to term corrected age was lower in DEX-treated infants compared to infants of similar birth weight and gestational age [37].

There is speculation that interference with the GH-IGF-I axis is responsible for the growth delay and altered bone mineral status in DEX-treated very low birth weight (VLBW) infants; however, the mechanism of steroid action remains to be determined. Studies in older children [1], [33], [41] and animals [2], [10], [36] provide evidence that steroids can alter the circulating components of the GH-IGF-I axis and, thereby, mediate the negative effects of steroids on growth and/or bone mineral homeostasis. A functional GH-IGF-I axis is essential for tissue growth, particularly the acquisition of bone during development. Children who are GH deficient or have Laron syndrome experience significant delays in postnatal weight, height and bone growth, providing direct evidence that interference with the GH-IGF-I axis can have deleterious effects on normal human development [23], [25]. In a case report, a male infant with an IGF-I gene deletion presented with profound weight (−3.9 standard deviations) and length (−5.4 standard deviations) growth retardation at birth [41]. On follow-up from birth through to age 15, weight and length growth failure persisted and was accompanied by severe osteopenia in the lumbar spine [41]. IGF-I has also been proven critical for growth and bone development during both fetal and postnatal life in the transgenic mouse model [4], [27]. Mice carrying a null mutation for the gene encoding IGF-I may die within 6 h of birth [27] while those surviving into adulthood have a significantly slower rate of long bone ossification and an adult body weight that is 30% that of wild-type littermates [4]. These findings, in addition to the developmental changes in the tissue expression of IGF-I receptors and IGF binding proteins (IGFBPs), as well as circulating concentrations of IGF-I and the IGFBPs, provide evidence that IGF-I is important for normal intrauterine development [5], [18].

The ontogeny of circulating GH, IGF-I and the IGFBPs in prematurely born infants has been described [7], [19], [26], [30], [31]. Most studies have reported increases in circulating IGF-I [19], [26], [30], [31] and IGFBP-3 [26], [30], [31] and a decrease in circulating IGFBP-2 with increasing postnatal age [19], [26], [30]. There are no published reports defining how DEX might alter the natural ontogeny of the GH-IGF-I axis in VLBW infants, nor the relationship of these proteins to changes in somatic growth and bone metabolism during early development at known nutrient intakes.

The objective of this study was to characterize the changes in the concentrations of the circulating components of the GH-IGF-I axis, specific biochemical markers of bone metabolism, dietary intakes, and growth velocities during and after the completion of DEX treatment. Measurements of bone mineral mass at term corrected age in steroid-treated VLBW infants were compared with appropriate reference values from non-steroid treated preterm and term-born infants.