Long-Term Effect of Early Vitamin D Supplementation on Bone Mineral Status in Prematurely Born Infants

To the editor: We read with interest the work of Bacström et al. (1) evaluating the effects of early mineral, vitamin D, and breast milk intake on bone mineral status in prematurely born infants at ages 9 to 11 years. Seventy preterm infants born 1985 through 1987 were randomized into four groups receiving 500 or 1000 IU/day of vitamin D and mineral-supplemented or unsupplemented breast milk. In 37 infants assessed at 3 months of chronological age (an approximately 50% withdrawal rate), bone mineral content (BMC) was higher in the distal third of the left forearm in mineral-supplemented subjects and in those receiving 500 IU/day vitamin D. The BMC and areal bone mineral density (BMD) were determined at the level of the lumbar spine, distal radius, and radial shaft by dual-energy X-ray absorptiometry in 35 infants from the original cohort at 9 to 11 years of age. After adjustment, by analysis of covariance, for duration of lactation and body weight, no association was found between vitamin D dose and long-term bone mineral variables. The authors conclude that vitamin D at a dose of 1000 IU/day provides no advantage for long-term bone mineral accretion compared with a lower dose of 500 IU/day. This study provides important information on the long-term impact of early nutritional interventions on bone mineral status of prematurely born infants. However, caution should be exercised before the conclusion is taken that a supplementation of 1000 IU/day vitamin D in preterm infants in early life has no advantage compared with a lower dose of 500 IU/day. The small number of subjects per group (n = 6–12) precludes firm conclusions to be generalized. There is evidence that specific skeletal sites respond differently to environmental factors (2,3). In a retrospective cohort study of term infants (3), we found that vitamin D supplementation during infancy was associated with higher BMD in prepubertal white girls at 7 to 9 years of age. Prepubertal girls supplemented in infancy with vitamin D (400 IU/day) had a significantly higher BMD than unsupplemented subjects at the level of radial metaphysis (0.301 ± 0.003 g/cm2 versus 0.283 ± 0.008 g/cm2; mean ± SEM), femoral neck (0.638 ± 0.007 g/cm2 versus 0.584 ± 0.021 g/cm2), and femoral trochanter (0.508 ± 0.006 g/cm2 versus 0.474 ± 0.016 g/cm2). Backström et al. did not determine BMD at the femoral level and can not therefore exclude an advantage of the higher vitamin D dose at this skeletal site. At the distal radius level, their data show higher BMD in the group receiving 1000 IU/day compared with the group receiving 500 IU/day (pooled mean: 0.315 versus 0.292), but this difference did not reach statistical significance. The magnitude of the difference at the distal radius level is similar to the one found in our retrospective cohort study of term subjects between 400 IU/day and no supplementation. However, the small sample (17 versus 18 subjects) studied by Backström et al. had only approximately a 30% power of detecting such a difference to be statistically significant. Beyond the statistical limitations, the small number of subjects available for the long-term follow-up does not guarantee the benefits of randomization. The negative finding regarding the two different doses of vitamin D supplementation could also be the results of unrecognized or recognized confounding factors (i.e., gender, calcium intake in later childhood). The appropriate dose of vitamin D supplementation in preterm infants remains to be determined by further randomized trials performed in larger cohorts of homogeneous subjects. Samuel A. Zamora *Rene Rizzoli Dominique C. Belli

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