Published online September 30, 2005
PEDIATRICS Vol. 116 No. 4 October 2005, pp. 943-949 (doi:10.1542/peds.2004-2582)
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Bone Area and Bone Mineral Content Deficits in Children With Sickle Cell Disease

Anne M. Buison, PhD*, Deborah A. Kawchak, MS, RD*, Joan I. Schall, PhD*, Kwaku Ohene-Frempong, MD{ddagger}, Virginia A. Stallings, MD*, Mary B. Leonard, MD, MSCE§ and Babette S. Zemel, PhD*

* Gastroenterology and Nutrition
{ddagger} Divisions of Hematology
§ Divisions of Nephrology, Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Objective. Children with sickle cell disease (SCD) experience poor growth, altered body composition, and delayed maturation. Deficits in bone mineral content (BMC) and bone area (BA) have not been well characterized. The objectives of this study were to assess whole-body BMC (WBBMC) and WBBA in children with SCD, type SS (SCD-SS), compared with healthy control subjects, adjusted for growth and body composition, and to determine the relationships of WBBMC and WBBA to bone age and hematologic parameters in children with SCD-SS.

Methods. WBBMC, WBBA, and lean mass were measured by dual-energy x-ray absorptiometry in children who were aged 4 to 19 years. Growth, sexual development, and bone age were assessed. Gender-specific z scores for WBBMC relative to age and height were generated from control data.

Results. Ninety children with SCD-SS and 198 healthy control subjects were evaluated. SCD-SS was associated with poor growth. WBBMC was significantly decreased in SCD-SS compared with control subjects, adjusted for age, height, pubertal status, and lean mass. WBBMC relative to age and WBBMC relative to height z scores were –0.95 ± 0.99 and –0.54 ± 0.97, respectively, and were associated with hemoglobin and hematocrit levels and history of delayed bone age.

Conclusions. Children with SCD-SS have significant deficits in WBBMC that persist despite adjustment for poor growth and decreased lean mass. These children may be at increased risk for fragility fractures and suboptimal peak bone mass.

Key Words: bone health • growth and nutrition • sickle cell disease

Abbreviations: SCD, sickle cell disease • SCD-SS, sickle cell disease type SS • BMD, bone mineral density • DXA, dual-energy x-ray absorptiometry • WBBMC, whole-body bone mineral content • WBBA, whole-body bone area • CHOP, Children's Hospital of Philadelphia • WBBMC-age-z, WBBMC z score relative to age • WBBA-age-z, WBBA z score relative to age • WBBMC-ht-z, WBBMC z score relative to height • WBBA-ht-z, WBBA z score relative to height

Sickle cell disease (SCD) is a hereditary disorder characterized by chronic hemolytic anemia and tissue infarction caused by vaso-occlusion by sickle-shaped erythrocytes. Poor growth status, altered body composition, delayed skeletal and sexual maturation, and nutritional deficiencies have long been recognized in children with SCD, particularly with type SS (SCD-SS).1–3 Possible explanations for poor growth, development, and nutritional status include lack of appetite, suboptimal dietary intake, increased energy expenditure, increased catabolism of specific nutrients, and abnormal endocrine function.4–7

SCD is known to have an adverse effect on the growing skeleton. The impact of SCD-SS on bone mineral accrual has not been well characterized. Two early dual-photon absorptiometry studies in small numbers of children with SCD reported decreased areal bone mineral density (BMD) in the lumbar spine and proximal femur.8, 9 However, both of these studies failed to consider the potential confounding effects of decreased stature and delayed maturation on BMD.

Decreased areal BMD (g/cm2) as measured by dual-energy x-ray absorptiometry (DXA) is the accepted method to assess and monitor treatment for osteoporosis in adults.10 Measures of areal BMD for age are flawed in children because of the confounding effect of bone size as children grow.11, 12 DXA areal BMD is not a measure of true volumetric density (g/cm3) because it provides no information about the depth of bone. For whole-body DXA measures, this is especially problematic as the depth of bone varies considerably throughout the skeleton. Adjustment of whole-body BMC and bone area for height is the preferred approach for interpreting DXA measurements in children. Adjustment for weight does not correlate with bone strength, as measured by computed tomography.13

The primary objective of this study was to determine the impact of SCD-SS on whole-body bone mineral content (WBBMC) and whole-body bone area (WBBA), relative to height and body composition, in a large cohort of children and adolescents, compared with healthy control subject. Secondary objectives were to determine the relationships between WBBMC and WBBA to bone age and hematologic factors related to SCD-SS.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
Children with SCD-SS were recruited from the Comprehensive Sickle Cell Center at Children's Hospital of Philadelphia (CHOP) for a 5-year longitudinal growth study. Here we report on cross-sectional evaluations of growth, body composition, and bone mineral from the fourth or fifth year of the study, depending on when the DXA evaluation was conducted. Bone age was obtained in the second year of the study. The participants (4–19 years of age) were not taking medications that are known to alter nutritional or growth status, were not on hydroxyurea therapy, and had no hospitalizations or acute illnesses within 2 weeks of the study visit.

Concurrent control data were obtained from healthy children (aged 4–19 years) who were enrolled for ongoing bone health studies in the Nutrition and Growth Laboratory at CHOP. These healthy children were recruited from general pediatric clinics at CHOP, as well as from the surrounding community, using fliers and newspaper advertisements. Children who had chronic medical conditions or were taking medications that are known to affect growth, sexual development, nutritional status, or dietary intake were excluded. Informed consent for both healthy children and children with SCD-SS was obtained from the parent or guardian of each child, and assent was obtained from children who were older than 7 years. This protocol was approved by the Committee for the Protection of Human Subjects Internal Review Board at CHOP.

Assessments of Growth Status and Maturation
For children with SCD-SS and healthy children, height was assessed using a digital stadiometer (Holtain, Crymych, United Kingdom) and weight was assessed using a digital electronic scale (Scaletronix, White Plains, NY), as described by Lohman et al.14 BMI (kg/m2) was calculated. Height, weight, and BMI were compared with the Centers for Disease Control and Prevention 2000 reference standards,15 and age- and gender-specific z scores were calculated in children with SCD-SS and healthy children.

Pubertal status in children with SCD-SS was determined using a self-assessment pictorial questionnaire16 that illustrated the 5 stages of development as described by Tanner.17 The self-assessment method was previously validated in our laboratory in children with Crohn's disease.18 The control subjects were assessed by physical examination. Children in stage 1 pubertal development were classified as prepubertal, and stages >1 were classified as pubertal. For children with SCD-SS, bone age was determined by 1 reader (B.S.Z.) using a left-wrist radiograph and was assessed according to Tanner et al.19 Relative bone age (in years) was calculated as bone age – chronological age (at the time of the hand-wrist radiograph).

Whole-Body DXA
Children with SCD-SS and healthy children had a whole-body DXA scan (Hologic QDR 2000, Waltham, MA) in the array mode. In our laboratory, the long-term in vitro coefficient of variation of BMD is <0.6%, and the in vivo coefficient of variation is <1%.20 Two investigators (A.M.B. and B.S.Z.) concurrently reviewed all scans to determine acceptability. WBBA (cm2), WBBMC (g), lean body mass (excluding bone; kg), and fat mass (kg) were determined from the DXA scans. Because of the variability in children's skull sizes, all results exclude the skull, as suggested by Taylor et al.21

Hematologic and Dietary Measures in Children With SCD-SS
Disease-related measures, serum vitamin D, and dietary intake were obtained in the SCD-SS sample only. Blood samples were obtained for determination of total hemoglobin, hematocrit, fetal hemoglobin, reticulocyte count, and platelets using standard techniques (Clinical Laboratory, CHOP). Children who were receiving transfusion therapy had blood samples obtained just before transfusion. Information regarding hospitalizations was obtained from the Comprehensive Sickle Cell Center. Total number of hospitalizations in the year before the study visit were calculated.

Serum 25-hydroxyvitamin D concentrations were determined by using a radioiodinated tracer (Bruce Hollis, PhD, Medical University of South Carolina, Charleston, SC) as reported previously.22 Dietary intake assessment was performed with a 24-hour recall by a research pediatric dietitian, with the parent and child using food portion booklets to estimate serving size. Nutrient analysis was performed (Food Processor Plus software, version 7.0; ESHA Research, Salem, OR) to determine total energy, calcium, and vitamin D intakes. Dietary vitamin D and calcium intakes were compared with the dietary reference intakes (adequate intakes).23, 24 Energy intake was compared with the estimated energy requirement for low active children.25 Children with SCD-SS were considered "low active" on the basis of a previous energy expenditure study.5

Statistics
All values are expressed as means ± SD unless otherwise noted. Analyses were performed using Stata 7.0 software (Stata Corp, College Station, TX) using a multistage approach, which included both descriptive statistics and inferential analyses that described these bone data in 3 steps. In step 1, we compared unadjusted bone measures, WBBMC, and WBBA from children with SCD-SS with that in healthy control subjects. In step 2, we generated gender-specific WBBMC and WBBA z scores relative to age (WBBMC-age-z and WBBA-age-z) and height (WBBMC-ht-z and WBBA-ht-z), as well as gender-specific scores for lean body mass and fat mass relative to height, from the healthy children data in the study using the LMS method.26 LMS software (version 1.22) was used to create best-fit centile curves as suggested by Cole and Green.26 Low bone status was defined as a z score <–2.0. In step 3, we developed multiple linear-regression models to determine significant predictors of WBBMC, WBBA, and lean body mass. Continuous variables were natural log transformed for improved fit of linear models. The regression models tested known determinants of WBBMC and WBBA that may confound the comparison of SCD-SS and healthy control subjects, such as height, pubertal status, lean body mass, age, and race. Lean body mass or muscle creates forces on bone that affect bone mass, size, and strength.27 Thus, the relationship between bone and lean mass was examined. Models were adjusted for puberty stage (prepubertal, Tanner stage 1 vs pubertal, Tanner stages 2–5). Within each model, tests for interaction between gender and other covariates were included as needed. Exponentiation of the regression coefficient for the SCD group effect represents the ratio of dependent variable (WBBA or WBBMC) in SCD relative to control subjects after adjustment for the independent variables in the regression model. The fit of each model was assessed via the adjusted R2 value.

This study was powered to detect a –0.5 difference in WBBMC-ht-z in the children with SCD-SS compared with healthy control subjects. For detecting this difference, the number of children needed was 85 per group at 90% power. Student's t test was used to assess differences in growth status, unadjusted bone measures, bone z scores, and body composition components among children with SCD-SS and healthy children. Pearson's correlation coefficient was used to assess the strength of the relationship between WBBMC-age-z, WBBMC-ht-z, and WBBA-ht-z in children with SCD-SS and growth status, dietary intake, vitamin D status, and hematologic measures. Spearman's correlation coefficient was used to assess the strength of the relationship between bone z scores and relative bone age, which had a skewed distribution. Student's t test was used to identify gender differences in WBBMC-age-z and WBBA-age-z. Statistical significance was considered at P < .05.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Ninety children with SCD-SS (44 female) were evaluated (Table 1). All were of African, Afro-Caribbean, or African American ancestry on the basis of self-report. The multiethnic sample of 198 healthy control children had a similar age and gender distribution. Among the healthy control children, 67 were African American (34%; aged 4–18 years; 40 female). Sixteen percent of participants with SCD-SS (n = 14; 5 girls) received chronic transfusion therapy. There were no differences in age, gender, and pubertal status between children with SCD-SS and healthy children.


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  		TABLE 1. Characteristics of Healthy Children and Children With SCD-SS

 
Dietary Intake and Serum Vitamin D Concentrations
The children (n = 80) with SCD-SS consumed 1980 ± 831 kcal/day, equivalent to 115% of the estimated energy requirement. Mean vitamin D and calcium intakes were below recommended levels: vitamin D (n = 78): 3.5 ± 3.6 µg/day (71% of adequate intake); and calcium (n = 80): 645 ± 426 mg/day (60% of adequate intake). A total of 77% of children with SCD-SS consumed <100% of the adequate intake for vitamin D, and 75% consumed <100% of the adequate intake for calcium. Of note, we previously reported that the mean serum vitamin D concentrations were 25.6 ± 12.7 nmol/L (n = 64), and 66% of children with SCD-SS had a level <27.5 nmol/L,28 considered indicative of vitamin D deficiency.23

Growth Status and SCD-Related Measures
Children with SCD-SS were similar in height but had significantly lower weight and BMI (Table 1) than healthy children (P < .05). The distributions of height, weight, and BMI z scores in the healthy children were consistent with the current literature.29 Children with SCD-SS had significantly lower z scores for height, weight, and BMI compared with healthy children (all P < .01; Table 1). Among children with SCD-SS, boys had significantly lower z scores for height, weight, and BMI compared with girls (data not shown, all P < .05).

All hematologic measures reflected the SCD diagnosis, with reduced hematocrit (23.7 ± 4.2%; median: 23.4; n = 87) and total hemoglobin concentrations (8.1 ± 1.3 mg/dL; median: 7.8 mg/dL; n = 87), elevated fetal hemoglobin production (7.9 ± 7.1%; median: 6.3; n = 68), and elevated reticulocyte count (11.6 ± 4.7%; median: 11.9; n = 81). Participants had a normal platelet count (374.4 ± 136.8 x 103/mm3; median: 358; n = 87). In this sample, participants had an average of 1 SCD-related hospitalization in the previous year (median: 0 times; range: 0–15 times; n = 90).

Body Composition
Children with SCD-SS had significantly lower z scores for both lean and fat mass, adjusted for height, compared with healthy children (both P < .01; Table 2). Height, gender, pubertal status, and race were significant predictors of lean body mass in all children. After adjustment for these significant predictors, children with SCD-SS had significant deficits in lean body mass compared with healthy children (R2 = 0.94). The regression coefficient of –0.06 in the log linear model indicates that the ratio of lean body mass in children with SCD-SS compared with control children was 0.95 (95% confidence interval: –0.09 to –0.02; P < .01), representing a 5% reduction in lean body mass, after adjustment for height, gender, puberty, and race.


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  		TABLE 2. Bone Mineral Measures and Body Composition of Healthy Children and Children With SCD-SS as Determined by DXA

 
Bone Measures
Unadjusted WBBA and WBBMC (Fig 1) were significantly reduced in children with SCD-SS compared with healthy children (P < .05; Table 2). Age- and height-adjusted bone z scores confirmed reduction in WBBMC and WBBA in the children with SCD-SS and quantified the magnitude of the deficit (Table 2).


Figure 1
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  		Fig 1. WBBMC for age for children with SCD-SS compared with reference percentiles from healthy children. A, females with SCD; B, males with SCD.

 
Among children with SCD-SS, the prevalence of low bone status (at or below the third percentile) was 14% for WBBMC-age (n = 13; 10 boys), 9% for WBBA-age (n = 8; 5 boys), 6% for WBBMC-ht (n = 5; 2 boys), and 6% for WBBA-ht (n = 5; 1 boy). Three girls had low WBBMC-age (7% of girls). Among boys, low bone WBBMC-age was more common, occurring in 17% of the boys with SCD-SS (see Fig 1). Boys with low WBBMC-age weighed less, were shorter (both P < .01), were older (16 ± 3 vs 11 ± 4; P < .01), and had more delayed bone age (–2.1 ± 1.3 vs –0.5 ± 1.3; P < .05) but did not show signs of greater disease severity compared with boys with normal WBBMC-age. There was insufficient power to detect delayed puberty in children with low bone status because the 10 boys were distributed across 5 Tanner stages. However, the growth and skeletal age data suggest that low WBBMC-age in boys is associated with delayed growth and maturation.

Multiple linear-regression models were developed to estimate deficits in WBBMC and WBBA in children with SCD-SS compared with control children after adjustment for potential confounders (Table 3). All models were adjusted for gender and race. The initial model showed that age was a good predictor of WBBMC; after adjustment for age, the ratio of WBBMC in children with SCD-SS compared with control children was 0.68, representing a 32% reduction in WBBMC-age. After adjustment for height, the children with SCD-SS had a 16% reduction in WBBMC-ht. Height, puberty-gender interaction, race, and lean body mass were also significant predictors of WBBMC. After adjustment for these predictors, children with SCD-SS still had a 7% reduction in WBBMC compared with healthy control children.


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  		TABLE 3. Linear Regression Models for WBBMC and WBBA*

 
A similar pattern emerged for WBBA (Table 3). After adjustment for age, the children with SCD-SS had a 24% reduction in WBBA-age. After adjustment for height, puberty-gender interaction, and lean body mass, children with SCD-SS had a 6% reduction in WBBA relative to control children.

Clinical Correlates of Bone Deficits Within Children With SCD-SS
Secondary analyses comparing the whole-body bone z scores with SCD-related measures were performed. For children with SCD-SS, WBBMC-ht-z and WBBA-ht-z were significantly associated with relative bone age (r = 0.57 and r = 0.54. respectively; both P < .001) and modestly associated with hematocrit (r = 0.22, P < .05; r = 0.29, P < .001, respectively) and total hemoglobin (r = 0.22, P < .05; r = 0.29, P < .001, respectively). There were no associations between WBBMC-ht-z and WBBA-ht-z and history of transfusion therapy, fetal hemoglobin concentrations, reticulocyte count, platelet count, and number of hospitalizations as a result of SCD in the past year. Serum 25-hydroxyvitamin D concentrations and vitamin D and calcium intakes were not associated with WBBA-ht-z, WBBMC-ht-z, WBBA-age-z, or WBBMC-age-z.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Children with SCD-SS have markedly lower WBBMC and WBBA compared with other healthy children of the same age. These deficits were not fully explained by short stature, delayed puberty, or reduced lean body mass, suggesting that these children have narrow bones (shown by low WBBA-ht) and low bone mass (shown by low WBBMC-ht)13 beyond what is expected for their growth and body composition deficits. Relative to age, bone mineral accrual was most affected in adolescent boys. Moreover, all bone z scores were positively associated with hematocrit and hemoglobin concentrations. Although the associations between bone z scores and hematocrit and hemoglobin concentrations were modest, they give strength to the possibility that disease severity (measured by anemia) is associated with bone mass.

Cortical bone comprises 80% of the skeletal bone mass; therefore, WBBMC derived from DXA reflects predominantly cortical bone mass. The primary function of cortical bone is mechanical strength. A recent study in healthy children demonstrated that DXA estimates of WBBMC and WBBA, adjusted for height, correlated well with cortical BMC, dimensions, and strength, as measured by peripheral quantitative computed tomography.13 Thus, the low WBBA- and WBBMC-ht in children with SCD may represent loss of normal resistance to bending and torsion and reduced bone strength. This may increase lifelong risk for fracture.

SCD has profound effects on bone health. Spine radiographs of children with SCD-SS typically show the vertebral bodies with smooth endplate biconcavities, which is attributed to decreased osteoblast activity. In addition, dactylitis (hand-foot syndrome) during childhood is a consequence of necrosis of the epiphyses and bone marrow within the fingers, resulting in permanent shortening of the carpals and metacarpals. Children and adolescents with SCD-SS are at high risk for necrosis of the femoral head.30 Moreover, SCD causes bone marrow hyperplasia, which expands the marrow space in long bones (eg, radius, tibia, femur), thinning cortical bone and likely resulting in increasing bone fragility.30 This marrow expansion and cortical thinning may have a direct impact on bone strength in children with SCD-SS. Despite the profound impact of this disease on WBBA, WBBMC, and potentially bone strength, there are no reports on childhood and adult fracture rates and osteoporosis in individuals with SCD-SS. Severe osteopenia, fracture, and osteoporosis31–33 have been reported in adults with thalassemia, another hematologic disorder that includes chronic anemia. Additional investigation is warranted in patients with SCD-SS.

African American children and adults have significantly higher WBBMC compared with non–African American children.34 However, ethnic-specific data are not available, and we chose to compare the children with SCD-SS with a multiethnic sample (34% African American) of healthy children. Our results likely underestimate the deficits in this sample of African American children with SCD-SS relative to healthy African American children.

Multiple factors may contribute to decreased WBBMC in children with SCD-SS. Dietary calcium and vitamin D intakes were well below recommended levels in our children. They also had low serum vitamin D status, as defined as 25-hydroxyvitamin D levels <27.5 nmol/L. We previously reported a high prevalence of vitamin D insufficiency in this sample of children with SCD-SS,28 which is likely to affect calcium absorption and bone health. In the current study, we did not observe an association between serum vitamin D concentrations or dietary calcium with WBBMC. Because serum vitamin D and dietary calcium intake are measures taken at 1 point in time, we did not expect to observe associations with WBBMC, which is a measure of long-term bone mineral accrual. However, the duration of vitamin D deficiency or duration of inadequate calcium intake may have greater impact on the WBBMC. Other nutritional factors, such as deficiencies in zinc,35 magnesium, and vitamin K,36 are known to affect skeletal health. Additional research is needed to determine the effects of these and other nutritional factors on WBBMC and WBBA in children with SCD-SS.

In the current study, low WBBMC-age was more common in boys than in girls and was associated with bone age delay (relative bone age), older age, and poor growth status. We speculate that delays in puberty and skeletal maturation may have contributed to low bone mineral accrual in our sample, especially in the boys. Children with SCD-SS commonly have delays in the onset of puberty and skeletal maturation,1, 37, 38 which may affect bone mineral accrual and peak bone mass. In girls with SCD-SS, menarche is often delayed, and the degree of delay is commensurate with low weight status.1, 39, 40 In boys with SCD-SS, reduced testicular size,41 low serum testosterone concentrations,4, 42 and delayed onset of secondary sexual characteristics have been reported. Delayed skeletal and sexual maturation/hypogonadism were associated with lower BMD in male adults with a history of constitutionally delayed puberty,43 children with Crohn's disease,44 and children and adults with thalassemia.33, 45 The effects of delayed puberty and skeletal maturation on bone mineral accrual and peak bone mass in children with SCD-SS require additional study.

A potential limitation of this study was that pubertal assessment was determined by a self-report using a pictorial questionnaire in the children with SCD-SS, whereas the healthy control subjects were assessed by physical examination. However, the pictorial questionnaire was previously reported to be a reliable and valid measure of pubertal assessment compared with physical examination in our laboratory.18 An additional limitation was that bone age was assessed 2 to 3 years before DXA assessment and thereby indicates a history of delayed skeletal maturation rather than current status. However, that delayed bone age (relative bone age) was strongly and significantly associated with WBBMC-ht-z suggests that delayed skeletal maturation may have long-lasting effects on bone mineral accrual.

Barden et al2 observed that children with SCD-SS had reductions in fat-free mass assessed by multiple methods, which suggested lack of muscle accretion, low physical activity levels, or both. In the present study, children with SCD-SS also had reduced lean body mass relative to height compared with healthy children. Forces produced by muscle contractions signal bone's structural adaptation to mechanical loading. Under this concept of a "muscle-bone unit," changes in muscle mass and strength affect bone mass, size, and strength.27 Lean body mass reductions in children with SCD then would contribute to deficits in BMC. However, the regression models described here indicate continued, clinically significant deficits in WBBMC after taking into account deficits in stature and lean body mass. Thus, poor bone mineral accrual in children with SCD was not fully explained by growth failure, delayed maturation, and altered body composition, although these factors all contribute to the bone deficits.

The profound bone deficits observed in this sample of children with SCD-SS give cause for concern for potential fracture and osteoporosis in individuals during childhood and over the lifespan. The reported gender differences in bone mineral accrual may have additional implications on risk for fracture, osteoporosis, and prevention as well. Children with SCD-SS are prone to poor nutritional status and reduced physical activity-related energy expenditure,5, 46 both of which contribute to bone deficits. Thus, additional research is needed to determine the implications of low bone mass in children with SCD in terms of current and future fracture risk and, if appropriate, to develop intervention strategies to improve bone mineral accrual in children with SCD, optimize peak bone mass, and prevent fractures and osteoporosis later in life.


   ACKNOWLEDGMENTS
 
This study was supported by the General Clinical Research Center (National Institutes of Health/National Center for Research Resources grant M01-RR00240), the Comprehensive Sickle Cell Center (National Institutes of Health HL 38633), and the Nutrition Center of Children's Hospital of Philadelphia. Dr Buison is supported by Children’s Hospital of Philadelphia Institutional Training grant HL 07443.

We express our most sincere appreciation to the children and their families for participation in and commitment to this research effort.


   FOOTNOTES
 
Accepted May 5, 2005.

Reprint requests to (B.S.Z.) Division of Gastroenterology and Nutrition, Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, CHOP North, Room 1560, Philadelphia, PA 19104. E-mail: zemel{at}email.chop.edu

No conflict of interest declared.


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
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PEDIATRICS (ISSN 1098-4275). ©2005 by the American Academy of Pediatrics




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