Whole Body BMC in Pediatric Crohn Disease: Independent Effects of
Altered Growth, Maturation, and Body Composition
Jon M Burnham,1,2Justine Shults,2Edisio Semeao,1Bethany Foster,1,2Babette S Zemel,1
Virginia A Stallings,1and Mary B Leonard1,2
ABSTRACT: Whole body BMC was assessed in 104 children and young adults with CD and 233 healthy
controls. CD was associated with significant deficits in BMC and lean mass, relative to height. Adjustment for
lean mass eliminated the bone deficit in CD. Steroid exposure was associated with short stature but not bone
deficits relative to height.
Introduction: Children with Crohn disease (CD) have multiple risk factors for impaired bone accrual. The
confounding effects of poor growth and delayed maturation limit the interpretation of prior studies of bone health in
CD. The objective of this study was to assess BMC relative to growth, body composition, and maturation in CD
compared with controls.
Materials and Methods: Whole body BMC and lean mass were assessed by DXA in 104 CD subjects and 233
healthy controls, 4–26 years of age. Multivariable linear regression models were developed to sequentially adjust for
differences in skeletal size, pubertal maturation, and muscle mass. BMC-for-height z scores were derived to
determine CD-specific covariates associated with bone deficits.
Results: Subjects with CD had significantly lower height z score, body mass index z score, and lean mass relative
to height compared with controls (all p ? 0.0001). After adjustment for group differences in age, height, and race,
the ratio of BMC in CD relative to controls was significantly reduced in males (0.86; 95% CI, 0.83, 0.94) and females
(0.91; 95% CI, 0.85, 0.98) with CD. Adjustment for pubertal maturation did not alter the estimate; however, addition
of lean mass to the model eliminated the bone deficit. Steroid exposure was associated with short stature but not bone
Conclusion: This study shows the importance of considering differences in body size and composition when
interpreting DXA data in children with chronic inflammatory conditions and shows an association between deficits
in muscle mass and bone in pediatric CD.
J Bone Miner Res 2004;19:1961–1968. Published online on September 20, 2004; doi: 10.1359/JBMR.040908
Key words: Crohn disease, osteoporosis, child, DXA, body composition
anemia, pubertal delay, growth failure, and impaired bone
mineral accretion in children and adolescents. The patho-
genesis of osteopenia in children with CD is multifactorial,
including increased production of bone-resorptive inflam-
matory cytokines, delayed pubertal maturation, decreased
physical activity, vitamin D deficiency, and glucocorticoid
exposure.(1–4)Osteopenia in children and adolescents with
CD poses an immediate fracture risk and compromises peak
bone mass in early adulthood, resulting in skeletal fragility
later in life.(5,6)
Numerous studies have shown decreased areal BMD
(aBMD) using DXA in children and adults with CD.(2,3,7–10)
ROHN DISEASE (CD) is characterized by gastrointestinal
tract inflammation with malabsorption, malnutrition,
While decreased aBMD is the accepted measure of osteo-
porosis in adults,(11)it is well recognized that aBMD is
confounded by bone size in children and adolescents.(12–14)
The use of aBMD in children with CD may lead to spurious
associations with other body size–dependent measures,
such as corticosteroid exposure, muscle mass, or dietary
Alternative strategies have been proposed for the analysis
and interpretation of DXA results in children with abnormal
growth and body composition.(16–18)A recent study showed
that DXA estimates of whole body BMC, adjusted for
height, correlated with cortical BMC, dimensions, and
strength, as measured by pQCT.(17)In contrast, adjustment
of whole body BMC for bone area was not correlated with
bone strength. Schoenau et al.(18)proposed that the func-
tional assessment of bone deficits should determine whether
muscle mass is reduced relative to body size (height) and
whether bone mass is normally adapted to muscle mass.
The authors have no conflict of interest.
1Children’s Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania, USA;
2Department of Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
JOURNAL OF BONE AND MINERAL RESEARCH
Volume 19, Number 12, 2004
Published online on September 20, 2004; doi: 10.1359/JBMR.040908
© 2004 American Society for Bone and Mineral Research
These approaches have been described in small series of
children with varied chronic diseases.(16,18,19)
The objective of this study was to assess whole body
BMC relative to height and muscle mass in children and
young adults with CD compared with healthy controls and
to determine the independent effects of growth, maturation,
body composition, and disease characteristics on BMC def-
MATERIALS AND METHODS
Individuals with CD, 4–25 years of age, treated at the
Children’s Hospital of Philadelphia or the University of
Pennsylvania Medical Center, were eligible for the study.
Diagnosis was confirmed by radiographic, histological, and
clinical information. Individuals with CD were excluded for
other medical conditions unrelated to CD that could poten-
tially affect growth or bone health. Lumbar spine aBMD,
vitamin D levels, growth, and maturation have been re-
ported in these subjects.(1–4)
Healthy control subjects were recruited from general pe-
diatric clinics in the surrounding community and through
newspaper advertisements. Control subjects were excluded
for any co-existing conditions known to affect growth,
nutritional status, dietary intake, pubertal development, or
bone mineralization. The protocol was approved by the
Institutional Review Board at the Children’s Hospital of
Philadelphia. Informed consent was obtained from the
young adult participants and the parents or guardians of
those ?18 years of age. Assent was obtained from those
?18 years old.
Medical records were reviewed for age at disease onset,
disease characteristics, medical, nutritional, and surgical
interventions, and hematologic and biochemical abnormal-
ities since diagnosis. Site of disease was coded as upper
gastrointestinal tract only, colon only, or both. Laboratory
abnormalities were defined as one or more values below the
normal reference range (based on age and gender) after the
diagnosis of CD had been established. Among subjects ?18
years of age, CD severity was assessed using the Pediatric
Crohn’s Disease Activity Index (PCDAI), which is based on
history (30%), physical examination (30%), laboratory data
(20%), and height velocity (20%).(20,21)Scores are catego-
rized as follows: no disease activity (0–10) mild disease
activity (11–30), and moderate to severe disease activity
Use of the following medications was documented:
6-mercaptopurine, azulfidine, mesalamine (Pentasa or
Asacol), metronidazole, calcium supplementation, and cor-
ticosteroid enemas. All doses of enteral and parenteral cor-
ticosteroids were noted and were converted to prednisone
equivalents. Corticosteroid exposure was summarized as
lifetime cumulative prednisone dose (g) and cumulative
milligram per kilogram body weight at the time of the dose
(mg/kg). Average doses during intervals of corticosteroid
therapy were summarized as milligrams per day and milli-
grams per kilograms per day. This study was conducted
before the use of TNF-? inhibitors in pediatric CD.
Anthropometry and pubertal development
Weight and height were measured using a digital scale to
the nearest 0.1 kg (Scaltronix, White Plains, NY, USA) and
a stadiometer to the nearest 0.1 cm (Holtain, Croswell,
Crymych, UK), respectively. Age- and gender-specific SD
scores (z scores) for weight, height, and body mass index
(BMI) were calculated using the National Center for Health
Statistics (NCHS) 2000 Center for Disease Control growth
data using the LMS method.(22)Pubertal stage was assessed
according to the method of Tanner et al.(23)
Whole body DXA scans were performed using a Hologic
QDR 2000 bone densitometer (Hologic, Bedford, MA,
USA) with a fan beam in the array mode in all subjects. The
measurements were performed using standard supine posi-
tioning techniques and were analyzed to generate estimates
of BMC (g), lean mass (kg), and fat mass (kg). All whole
body DXA measures excluded the skull (post-cranial). The
instrument was calibrated daily with a hydroxyapatite phan-
tom, and the in vitro CV at our institution is ?0.6%. The in
vivo CV is ?1% when measured in adults.
Blood samples were obtained from individuals with CD
at the time of the study visit. Serum albumin (g/dl), total
protein (g/dl), hemoglobin (g/dl), and erythrocyte sedimen-
tation rate (mm/h) were measured in the Clinical Laboratory
at the Children’s Hospital of Philadelphia using standard
techniques. Serum 25(OH)vitamin D levels were measured
by radioimmunoassay with a radioiodinated tracer.(24)
Descriptive analyses included means, SDs, median, and
ranges of continuous variables and distributions of categor-
ical variables. Differences of means were assessed using
Student’s t-test if the variable was normally distributed. The
Wilcoxon rank-sum test was used if these data were not
normally distributed. Group differences in categorical vari-
ables were assessed using the ?2or Fisher’s exact test,
where appropriate. Analyses were conducted using Stata 8.2
(Stata Corp., College Station, TX, USA). Two-sided tests of
hypotheses were used, and a p value ?0.05 was considered
to be statistically significant.
The primary outcome was whole body BMC. DXA re-
sults are traditionally expressed relative to age and gender.
However, assessment of BMC in children and adolescents
requires adjustment for bone size. Natural log transforma-
tion of BMC and height results in a linear relationship
between the two measures that does not exist in nontrans-
formed models. A prediction model using this approach has
been described in children(16)and validated with QCT.(17)
A series of log-transformed models for whole body BMC
relative to height were sequentially adjusted for known
determinants of BMC that may confound the comparison of
1962 BURNHAM ET AL.
individuals with CD and healthy controls. Given the known
gender differences in bone mineral accretion during
growth,(25)all results are presented stratified on gender. All
models were adjusted for race (black versus all others).
Models were subsequently adjusted for Tanner stage of
pubertal maturation (stage 1 as the referent group, with
indicator variables for Tanner stages 2–5) and lean mass. To
compare the relationship between lean mass and BMC in
subjects with CD and in healthy controls, a CD–lean mass
interaction term was added to a multivariable regression
model of BMC on CD, height, age, and race. The fit of each
model was assessed through the adjusted R2value. The
assumptions of the regression models were assessed through
graphical checks, the Shapiro-Wilk test of normality of the
residuals, the Ramsey omitted variable test, and the Cook-
Weisburg test for heteroscedasticity.
Because the outcome variable was log-transformed, the
independent effect of CD in each multivariate model was
summarized as the adjusted ratio of the outcome measure in
the subjects with CD divided by the outcome measure in the
control subjects; we note that the ratios have no units. The
adjusted ratio and 95% CI for each covariate were calcu-
lated as the exponentiated estimate of the regression param-
eter and the 95% confidence limits of the regression param-
To aid the clinical interpretation of the magnitude of the
deficits in CD in the series of multivariable models and to
assess the impact of CD-specific effects on bone within the
subjects with CD, the whole body BMC results were con-
verted to gender-specific BMC z scores. Data from the
control subjects were used to derive the predicted value of
BMC relative to either age or height using linear regression.
The residuals from each of the models were not heterosce-
dastic; therefore, the root mean square error served as the
SD at all levels of the predictor variable. The z scores were
calculated as follows: ([Observed ? Predicted]/SD). For
example, a BMC-for-height z score of ?1.0 indicates a
whole body BMC that was 1 SD below that of control
subjects of the same height and gender. Lean mass-for-
height z score, a secondary outcome, was derived in a
similar manner. The z scores were compared between sub-
jects with CD versus controls in regression models that also
included other explanatory variables.
Bivariate analyses of CD-specific factors and anthropo-
metric measures associated with low BMC-for-height z
scores within the subjects with CD were identified using
simple logistic regression. BMC-for-height z score was
considered abnormal if ? ?1.0 (equivalent to the 16th
percentile). The correlations between glucocorticoid expo-
sure, BMC-for-height z score, and height-for-age z score
were assessed using Pearson product-moment estimates.
Subject characteristics and body composition
A total of 104 subjects with CD and 233 healthy controls
completed the study. Subject characteristics are summarized
in Table 1. Controls were significantly younger and less
mature than the subjects with CD. The white predominance
among the subjects with CD was consistent with the demo-
graphics of the disease. Comparison of age distributions
within Tanner stages suggested that CD was associated with
delayed pubertal maturation: within Tanner stages 2 and 4,
individuals with CD were an average of 1.4 and 1.5 years
older than controls (p ? 0.05 and p ? 0.01, respectively),
adjusted for gender and race. There were no gender differ-
ences in age, Tanner stage, height, or BMI z score within the
participants with CD.
Individuals with CD had significantly lower height,
weight, BMI-for-age, and lean mass-for-height z scores than
healthy controls (all p ? 0.0001). The BMI z score distri-
bution within the control subjects was consistent with a
recent report in the U.S. population.(26)The mean lean
mass-for-height z score, adjusted for age and race, was
significantly decreased in the subjects with CD (p ? 0.001).
Disease characteristics, medications, and laboratory val-
ues were available in 76–88% of individuals with CD and
are detailed in Table 2. Among the 88% with complete
medication data, 90% were treated with glucocorticoids.
Treatment and disease characteristics were compared be-
tween the male and female subjects with CD to determine
possible differences in disease severity. Males were exposed
to glucocorticoids for a significantly greater duration than
females (median duration, 15.2 months; [range, 0–128.3
TABLE 1. SUBJECT CHARACTERISTICS IN CROHN DISEASE AND CONTROL PARTICIPANTS
Variable Crohn disease (n ? 104)Controls (n ? 233)
Gender (% male)
Race (% black)
Tanner distribution (n at stages 1, 2, 3, 4, 5)
Height z score*
Weight z score*
BMI z score*
Lean mass z score†
15.4 ? 4.3 11.9 ? 5.7
17, 16, 22, 18, 31
?0.74 ? 1.2
?0.66 ? 1.1
19.42 ? 3.2 (12.5–31.7)
?0.35 ? 1.0
?0.61 ? 0.92
117, 24, 16, 33, 43
0.28 ? 1.1
0.36 ? 1.1
19.55 ? 4.9 (13.0–40.9)
0.27 ? 1.12
0.0 ? 0.99
Mean ? SD.
* Relative to age, derived from CDC growth data.(22)
†Relative to height, derived from control subjects.
1963BMC IN PEDIATRIC CROHN DISEASE
months] versus 8.4 months [0–79.5 months]; p ? 0.01),
receiving a greater total dose over the course of their disease
(median dose, 7.9 g [range, 0–74.0 g] versus 6.2 g [range,
0–41.7 g]; p ? 0.01). However, during the exposure to
glucocorticoids, the doses (mg/day and mg/kg/day) were
similar. Males were more frequently treated with me-
salamine (Pentasa) than females (32.7% versus 16.2%, p ?
0.01) and were more likely to have had hypoalbuminemia
(27.3% versus 8.1%, p ? 0.02).
Whole body BMC
A series of models were developed to assess BMC in CD
compared with control subjects. All models were adjusted
for the confounding effects of age and race, given the
differences between the subjects with CD and the controls.
Because delayed pubertal maturation is associated with de-
creased bone mass,(27)adjusting for pubertal stage may
mask clinically important differences in whole body BMC
between CD and controls. Accordingly, gender-specific sta-
tistical models are presented with and without adjustment
for Tanner stage of pubertal maturation. Table 3 summa-
rizes four sequential models in males and females. The ratio
in each model represents the expected BMC in a subject
with CD divided by the BMC in a control subject with the
same values for the stated covariates (e.g., the ratio of BMC
in CD subjects versus controls of the same age and race).
The least adjusted models assessed whole body BMC in
CD compared with controls, adjusted for age and race, and
revealed substantial deficits. The ratio of BMC in males
with CD compared with controls was 0.74 (95% CI, 0.68,
0.82), representing a 26% reduction in BMC on average.
Assessment of BMC without consideration of the decreased
skeletal size for age (decreased height z scores) in subjects
with CD group may overestimate bone deficits. Accord-
ingly, the second model was also adjusted for height (Table
3). Figure 1 shows the distribution of bone measures ex-
pressed relative to age and relative to height. Log transfor-
mation improved model fit. Adjustment for height attenu-
ated the CD effect; however, significant BMC deficits
persisted in males and females with CD compared with
TABLE 2. DISEASE CHARACTERISTICS, MEDICATION EXPOSURE, AND LABORATORY ASSESSMENT IN PARTICIPANTS WITH CROHN DISEASE
VariableMean ? SD Range VariablePercentage
Age at diagnosis (years)
Duration of disease (years)
Age at symptom onset (years)
PCDAI, at study visit
Total hospital admissions
Total hospital days
Site of disease
Isolated upper tract
Upper tract and colonic
12.0 ? 3.8
4.0 ? 3.4
10.9 ? 3.7
12.0 ? 11.9
13.5 ? 9.7
2.4 ? 1.9
24.7 ? 37.0
20.910.3 ? 12.1
19.0 ? 12.2
0.5 ? 0.3
19.6 ? 24.5
Laboratory values at the time of the study visit
25(OH) Vitamin D (nM)
4.0 ? 0.6
12.9 ? 1.1
17.2 ? 17.0
60.1 ? 27.4
TABLE 3. SEQUENTIAL LINEAR REGRESSION MODELS OF THE INDEPENDENT EFFECT OF CROHN DISEASE ON WHOLE BODY BMC
Covariates Ratio (95% CI)
Height, age, race
Height, age, race, Tanner stage
Height, age, race, Tanner stage, lean mass
0.74 (0.68, 0.82)
0.88 (0.83, 0.94)
0.89 (0.83, 0.96)
0.96 (0.91, 1.01)
Height, age, race
Height, age, race, Tanner stage
Height, age, race, Tanner stage, lean mass
0.83 (0.75, 0.92)
0.91 (0.85, 0.98)
0.92 (0.86, 0.99)
0.98 (0.93, 1.04)
The Ratio represents the BMC in Crohn Disease compared with Controls adjusted for the Covariates.
1964 BURNHAM ET AL.
controls. To determine if delayed pubertal maturation for
age contributed to the decreased BMC observed relative to
height and age in subjects with CD, the third model adjusted
for Tanner stage. Adjustment for delayed pubertal matura-
tion did not appreciably change the estimate of BMC defi-
cits in CD. Tanner stage was not independently associated
with BMC in males after adjustment for age and height (p ?
0.16 for Tanner stages 2–5); however, Tanner stage was
independently associated with BMC in females, adjusted for
age and height (p ? 0.05 for Tanner stages 4 and 5, p ?
0.08 for Tanner stages 2 and 3).
The fourth and final model was also adjusted for whole
body lean mass to determine if the significant deficits in
BMC in CD were associated with the lean mass deficits.
Lean mass was independently associated with BMC in
subjects with CD and healthy control subjects (both p ?
0.001). This relationship between lean mass and BMC was
conserved in subjects with CD (interaction p ? 0.2). No
significant differences in BMC were detected between sub-
jects with CD and controls when lean mass was included in
the model. In males, results were unchanged in a model
adjusted for height, age, and lean mass (0.96; 95% CI, 0.91,
1.01; p ? 0.09), but omitting Tanner stage, consistent with
the insignificant relationship between Tanner stage and
BMC in males in model 3.
BMC z score models produced similar results (Table 4).
There were significant deficits in BMC in males and females
relative to age and relative to height. These deficits were
attenuated by adjustment of the BMC-for-height z score for
age, race, Tanner stage, and lean mass.
The gender-specific BMC-for-height z scores are shown
in Fig. 2. The mean unadjusted BMC-for-height z scores
were ?0.65 ? 0.85 in males and ?0.45 ? 0.95 in females.
The z scores were less than ?1.0 in 34% of individuals with
CD. By definition, the z scores were 0.0 ? 1.0 in controls,
with 16% less than ?1.0.
CD-specific factors and bone health
Having established group differences in whole body
BMC between individuals with CD and controls, models
and height in individuals with CD and control
subjects. An age2polynomial term was added to
z score models of ln(BMC) relative to age, given
the nonlinearity of the relationship. Natural log
transformation of BMC and height improved
model fit relative to a nontransformed model.
Distribution of BMC relative to age
TABLE 4. MULTIPLE LINEAR REGRESSION MODELS SUMMARIZING THE INDEPENDENT EFFECT OF CD ON WHOLE BODY BMC Z SCORES
Outcome Covariatesz Score in CD (95% CI)
Race, age, Tanner stage
Race, age, Tanner stage, lean mass*
?1.16 (?1.51, ?0.82)
?0.63 (?0.95, ?0.30)
?0.50 (?0.85, ?0.15)
?0.19 (?0.43, 0.06)
Race, age, Tanner stage
Race, age, Tanner stage, lean mass*
?0.61 (?0.95, ?0.27)
?0.44 (?0.81, ?0.06)
?0.35 (?0.72, 0.02)
?0.05 (?0.34, 0.25)
* Lean mass-for-height Z score, derived from control subjects.
1965BMC IN PEDIATRIC CROHN DISEASE
were designed to examine the association of BMC-for-
height z scores with anthropometric measures and the CD-
specific variables summarized in Table 2. Factors that were
found to be significantly associated with a BMC-for-height
z score less than ?1.0 in bivariate analyses are listed in
Table 5. Serum vitamin D levels were not correlated with
bone deficits. Many of these covariates were co-linear and
indicative of severe disease. For example, use of me-
salamine (Pentasa) was predictably associated with hy-
poalbuminemia (p ? 0.05) and site of disease (p ? 0.03),
because it is generally used to target inflammation in the
upper gastrointestinal tract. Individuals with a history of
hypoalbuminemia were more likely to have received naso-
gastric feeding (p ? 0.02). A 1 SD decrease in the BMI z
score was associated with an increased odds of exposure to
parenteral nutrition (OR, 1.6; 95% CI, 1.03, 2.54; p ? 0.04).
Corticosteroid exposure and bone health
The relationshipsbetween corticosteroid exposure,
growth, and BMC-for-height z scores were examined. None
of the corticosteroid measures summarized in Table 2 were
significantly correlated with BMC-for-height z scores.
However, height z score was negatively and significantly
associated with duration of exposure to corticosteroids (r ?
?0.24, p ? 0.02), cumulative corticosteroid dose (g; r ?
?0.23, p ? 0.03), and cumulative mg/kg (r ? ?0.36, p ?
0.001). Height z score was not associated with the duration
of disease or average corticosteroid exposure in milligrams
per kilograms per day. The correlation of cumulative PC-
DAI and height z score approached statistical significance
(r ? ?0.27; p ? 0.06).
This examination of 104 individuals with CD showed
significant deficits in whole body BMC compared with a
concurrent group of 233 healthy controls. Adjustment for
the confounding effects of stature, race, and delayed puber-
tal maturation attenuated, but did not fully explain, the bone
deficits. However, adjustment for the decreased lean mass in
CD eliminated the BMC deficits in males and females.
These analyses show the importance of a concurrent com-
parison group of healthy subjects to adjust for differences in
growth and body composition across the broad age range of
Cortical bone comprises 80% of the skeletal bone mass;
therefore, whole body DXA BMC reflects predominantly
cortical bone mass and dimensions. The primary function of
cortical bone is mechanical strength. Our recent study
showed that measures of DXA whole body BMC relative to
height correlated with cortical bone mass, dimensions, and
strength, as validated by pQCT.(17)Lean mass was not
included in our recent study because children with disease
states may have abnormal body composition, which may
independently impact bone strength. The BMC deficits in
CD reported here likely represent structurally significant
deficits in cortical bone, which are associated with deficits
in lean mass and consistent with increased fracture risk in
Cowan et al.(28)reported whole body DXA results in 32
subjects with CD compared with 58 healthy children. The
BMC results were adjusted for bone area, age, height,
weight, pubertal stage, and gender and showed a 4% dec-
rement compared with controls. However, a recent study
suggested that whole body BMC adjusted for bone area is
not correlated with bone strength.(17)Furthermore, the final
adjusted model may have masked clinically significant def-
icits in bone strength, as detailed below. In contrast, our
multistaged approach revealed the contributions of each
confounding variable to structurally significant bone defi-
It is critical to note that the absence of a bone deficit after
adjustment for lean mass does not imply that the bones are
normal or adequate. As muscles increase in size and
strength during growth, bones adapt by increasing mass,
dimensions, and strength.(29)Growth, in the absence of
normal loading, results in bones that are adapted to their
diminished functional requirement, with decreased mass,
size, and strength. These bones may be inadequate to with-
stand even minor trauma. This is evident is disorders such as
cerebral palsy that are characterized by decreased muscle
mass, decreased bone dimensions, and propensity to frac-
ture with minimal trauma.(30)Moreover, a recent study
showed significantly increased risk of hip fracture (OR,
1.86; 95% CI, 1.08, 3.21) in adults with CD.(6)Disease
severity, assessed by the number of symptoms, predicted
fracture even after adjusting for corticosteroid use.
While the bone and muscle deficits are highly correlated,
this does not prove a causal relationship. This close asso-
ciation may be mediated by nutritional, hormonal, or in-
flammatory factors that influence muscle and bone. For
example, the cytokines TNF-? and interleukin (IL)-1 were
and control subjects.
BMC-for-height z score distributions in individuals with CD
TABLE 5. BIVARIATE ANALYSES OF FACTORS ASSOCIATED WITH
DECREASED BMC-FOR-HEIGHT Z SCORE IN CD
OR for z score ? ?1.0
Isolated upper tract disease
Mesalamine (Pentasa) therapy
BMI z score ? ?1
3.4 (1.4, 8.5)
2.9 (1.1, 7.4)
3.4 (1.2, 9.8)
11.3 (1.6, 80.3)
3.5 (1.3, 9.4)
2.7 (1.0, 7.2)
1966 BURNHAM ET AL.
independently associated with cachexia in adults with in-
flammatory disorders.(31,32)Inflammatory cytokines are also
known to promote bone resorption. Recent developments in
the understanding of bone loss in inflammatory conditions
have highlighted the critical role of TNF-?, IL-1, and IL-6,
which stimulate RANKL expression by osteoblasts.(33)
Alternatively, physical activity may be decreased in those
with CD, resulting in decreased muscle forces, with a con-
sequent reduction in bone mass. Some observational studies
in healthy athletes and randomized trials with modest inter-
ventions in healthy children (e.g., jumping activities three
times per week) have shown significant beneficial effects on
bone mass and size.(34–36)In addition, a recent weight-
bearing intervention in non-ambulatory children with cere-
bral palsy resulted in increased bone mass.(37)We did not
measure physical activity in this study, which precludes an
assessment of the relationship between lean mass in CD and
physical activity levels. However, the independent relation-
ship between lean mass and BMC was highly significant
and was comparable in subjects with CD and in healthy
controls. That is, the magnitude of the bone deficit associ-
ated with a given reduction in muscle mass in CD was the
same as in healthy controls.
Studies have yielded differing conclusions concerning the
role of corticosteroids in the pathogenesis of osteopenia in
children with CD. Most,(3,7,10)but not all,(28)have shown a
relationship between cumulative corticosteroid dose and
bone outcomes. Cowan et al.(28)showed a difference in
BMC between corticosteroid-treated and corticosteroid-
naı ¨ve subjects with pediatric CD. Reports of correlations
between bone deficits and corticosteroid exposure in prior
studies may be explained by two types of confounding:
confounding by indication and confounding by short stat-
ure. First, subjects with severe inflammation are more likely
to receive corticosteroids and were more likely to suffer
bone deficits; therefore, corticosteroids may be a marker of
disease severity. Second, corticosteroids are associated with
decreased stature, and DXA measures relative to age are
systematically underestimated in shorter subjects.(38)DXA
outcomes expressed relative to age are subject to confound-
ing by skeletal size and are poorly suited to assess the
impact of corticosteroids on bone mass.
Our data did not show differences in BMC-for-height z
scores between corticosteroid-treated and corticosteroid-
naı ¨ve individuals with CD. However, there were few indi-
viduals with no steroid exposure (10%). BMC-for-height z
scores were not associated with any of the corticosteroid
measures. In contrast, these data showed markedly de-
creased stature for age in the subjects with CD, consistent
with the disease process and with corticosteroid effects.
While retrospective collection of lifetime corticosteroid ex-
posure may result in misclassification of exposure status, the
significant correlation between height deficits and glucocor-
ticoids supported the validity of these estimates.
This study aimed to address cortical bone deficits inde-
pendently associated with CD. Prior studies of lumbar spine
aBMD, a trabecular site, in pediatric CD have noted signif-
icant deficits in age-adjusted z scores, which were, in part,
attributable to delayed maturation.(2,7,10)However, these
analyses did not fully account for the confounding effect of
decreased stature on aBMD results. Therefore, reports of an
association between decreased lumbar spine aBMD and
glucocorticoids may be confounded by glucocorticoid-
induced short stature.
The clinical significance of poor bone health in CD lies in
the occurrence of fractures during childhood and be-
yond.(5,6)The data presented here highlight the relationship
between bone and muscle deficits in CD. Prospective stud-
ies are needed to evaluate the relationship between de-
creased muscle mass, muscle strength, physical activity
level, and bone mass in CD. Weight-bearing physical ac-
tivity may represent a powerful and safe intervention to
improve bone health and lean mass in CD and should be
explored in future clinical trials.
We thank David Piccoli, Robert Baldassano, and the
Center for Pediatric Inflammatory Bowel Disease at the
Children’s Hospital of Philadelphia for support. We greatly
appreciate the dedication and enthusiasm of the children and
their families who participated in this study. This work was
supported by the American College of Rheumatology Re-
search and Education Foundation (JMB), the General Clin-
ical Research Center (M01RR00240), and the Nutrition and
Growth Center at the Children’s Hospital of Philadelphia.
1. Sentongo TA, Semeao EJ, Piccoli DA, Stallings VA, Zemel BS
2000 Growth, body composition, and nutritional status in children
and adolescents with Crohn’s disease. J Pediatr Gastroenterol Nutr
2. Semeao EJ, Jawad AF, Zemel BS, Neiswender KM, Piccoli DA,
Stallings VA 1999 Bone mineral density in children and young
adults with Crohn’s disease. Inflamm Bowel Dis 5:161–166.
3. Semeao EJ, Jawad AF, Stouffer NO, Zemel BS, Piccoli DA,
Stallings VA 1999 Risk factors for low bone mineral density in
children and young adults with Crohn’s disease. J Pediatr 135:
4. Sentongo TA, Semaeo EJ, Stettler N, Piccoli DA, Stallings VA,
Zemel BS 2002 Vitamin D status in children, adolescents, and
young adults with Crohn disease. Am J Clin Nutr 76:1077–1081.
5. Semeao EJ, Stallings VA, Peck SN, Piccoli DA 1997 Vertebral
compression fractures in pediatric patients with Crohn’s disease.
6. van Staa TP, Cooper C, Brusse LS, Leufkens H, Javaid MK, Arden
NK 2003 Inflammatory bowel disease and the risk of fracture.
7. Gokhale R, Favus MJ, Karrison T, Sutton MM, Rich B, Kirschner
BS 1998 Bone mineral density assessment in children with inflam-
matory bowel disease. Gastroenterology 114:902–911.
8. Ardizzone S, Bollani S, Bettica P, Bevilacqua M, Molteni P,
Bianchi Porro G 2000 Altered bone metabolism in inflammatory
bowel disease: There is a difference between Crohn’s disease and
ulcerative colitis. J Intern Med 247:63–70.
9. Dinca M, Fries W, Luisetto G, Peccolo F, Bottega F, Leone L,
Naccarato R, Martin A 1999 Evolution of osteopenia in inflam-
matory bowel disease. Am J Gastroenterol 94:1292–1297.
10. Boot AM, Bouquet J, Krenning EP, de Muinck Keizer-Schrama
SM 1998 Bone mineral density and nutritional status in children
with chronic inflammatory bowel disease. Gut 42:188–194.
11. World Health Organization 1994 The WHO Study Group: Assess-
ment of Fracture Risk and Its Application to Screening for Post-
menopausal Osteoporosis. World Health Organization, Geneva,
12. Carter DR, Bouxsein ML, Marcus R 1992 New approaches for
interpreting projected bone densitometry data. J Bone Miner Res
1967BMC IN PEDIATRIC CROHN DISEASE
13. Heaney RP 2003 Bone mineral content, not bone mineral density, Download full-text
is the correct bone measure for growth studies. Am J Clin Nutr
14. Nevill AM, Holder RL, Maffulli N, Cheng JC, Leung SS, Lee WT,
Lau JT 2002 Adjusting bone mass for differences in projected bone
area and other confounding variables: An allometric perspective.
J Bone Miner Res 17:703–708.
15. Prentice A, Parsons TJ, Cole TJ 1994 Uncritical use of bone
mineral density in absorptiometry may lead to size-related artifacts
in the identification of bone mineral determinants. Am J Clin Nutr
16. Ellis KJ, Shypailo RJ, Hardin DS, Perez MD, Motil KJ, Wong
WW, Abrams SA 2001 Z score prediction model for assessment of
bone mineral content in pediatric diseases. J Bone Miner Res
17. Leonard MB, Shults J, Elliott DM, Stallings VA, Zemel BS 2004
Interpretation of whole body dual energy x-ray absorptiometry
measures in children: Validation with peripheral quantitative com-
puted tomography. Bone (in press).
18. Schoenau E, Neu CM, Beck B, Manz F, Rauch F 2002 Bone
mineral content per muscle cross-sectional area as an index of the
functional muscle-bone unit. J Bone Miner Res 17:1095–1101.
19. Bechtold S, Rauch F, Noelle V, Donhauser S, Neu CM, Schoenau
E, Schwarz HP 2001 Musculoskeletal analyses of the forearm in
young women with Turner syndrome: A study using peripheral
quantitative computed tomography. J Clin Endocrinol Metab 86:
20. Hyams JS, Ferry GD, Mandel FS, Gryboski JD, Kibort PM,
Kirschner BS, Griffiths AM, Katz AJ, Grand RJ, Boyle JT,
Michener WM, Levy JS, Lesser ML 1991 Development and val-
idation of a pediatric Crohn’s disease activity index. J Pediatr
Gastroenterol Nutr 12:439–447.
21. Hyams JS, Mandel F, Ferry GD, Gryboski JD, Kibort PM, Kirsch-
ner BS, Griffiths AM, Katz AJ, Boyle JT 1992 Relationship of
common laboratory parameters to the activity of Crohn’s disease in
children. J Pediatr Gastroenterol Nutr 14:216–222.
22. Ogden CL, Kuczmarski RJ, Flegal KM, Mei Z, Guo S, Wei R,
Grummer-Strawn LM, Curtin LR, Roche AF, Johnson CL 2002
Centers for Disease Control and Prevention 2000 growth charts for
the United States: Improvements to the 1977 National Center for
Health Statistics version. Pediatrics 109:45–60.
23. Tanner J, Whitehouse R, Marshall W, Healy M, Goldstein H 1975
Assessment of Skeletal Maturity and Prediction of Adult Height
(TW2 Method). Academic Press, London, UK.
24. Hollis BW 1997 Quantitation of 25-hydroxyvitamin D and 1,25-
dihydroxyvitamin D by radioimmunoassay using radioiodinated
tracers. Methods Enzymol 282:174–186.
25. Gilsanz V, Kovanlikaya A, Costin G, Roe TF, Sayre J, Kaufman F
1997 Differential effect of gender on the sizes of the bones in the
axial and appendicular skeletons. J Clin Endocrinol Metab 82:
26. Ogden CL, Flegal KM, Carroll MD, Johnson CL 2002 Prevalence
and trends in overweight among US children and adolescents,
1999–2000. JAMA 288:1728–1732.
27. Finkelstein JS, Neer RM, Biller BM, Crawford JD, Klibanski A
1992 Osteopenia in men with a history of delayed puberty. N Engl
J Med 326:600–604.
28. Cowan FJ, Warner JT, Dunstan FD, Evans WD, Gregory JW,
Jenkins HR 1997 Inflammatory bowel disease and predisposition
to osteopenia. Arch Dis Child 76:325–329.
29. Frost HM, Schonau E 2000 The “muscle-bone unit” in children
and adolescents: A 2000 overview. J Pediatr Endocrinol Metab
30. Henderson RC, Lark RK, Gurka MJ, Worley G, Fung EB, Con-
away M, Stallings VA, Stevenson RD 2002 Bone density and
metabolism in children and adolescents with moderate to severe
cerebral palsy. Pediatrics 110:E5.
31. Walsmith J, Abad L, Kehayias J, Roubenoff R 2004 Tumor ne-
crosis factor-alpha production is associated with less body cell
mass in women with rheumatoid arthritis. J Rheumatol 31:23–29.
32. Roubenoff R, Roubenoff RA, Cannon JG, Kehayias JJ, Zhuang H,
Dawson-Hughes B, Dinarello CA, Rosenberg IH 1994 Rheuma-
toid cachexia: Cytokine-driven hypermetabolism accompanying
reduced body cell mass in chronic inflammation. J Clin Invest
33. Teitelbaum SL, Ross FP 2003 Genetic regulation of osteoclast
development and function. Nat Rev Genet 4:638–649.
34. Bass SL, Saxon L, Daly RM, Turner CH, Robling AG, Seeman E,
Stuckey S 2002 The effect of mechanical loading on the size and
shape of bone in pre-, peri-, and postpubertal girls: A study in
tennis players. J Bone Miner Res 17:2274–2280.
35. Petit MA, McKay HA, MacKelvie KJ, Heinonen A, Khan KM,
Beck TJ 2002 A randomized school-based jumping intervention
confers site and maturity-specific benefits on bone structural prop-
erties in girls: A hip structural analysis study. J Bone Miner Res
36. Specker B, Binkley T 2003 Randomized trial of physical activity
and calcium supplementation on bone mineral content in 3- to
5-year-old children. J Bone Miner Res 18:885–892.
37. Caulton JM, Ward KA, Alsop CW, Dunn G, Adams JE, Mughal
MZ 2004 A randomised controlled trial of standing programme on
bone mineral density in non-ambulant children with cerebral palsy.
Arch Dis Child 89:131–135.
38. Katzman DK, Bachrach LK, Carter DR, Marcus R 1991 Clinical
and anthropometric correlates of bone mineral acquisition in
healthy adolescent girls. J Clin Endocrinol Metab 73:1332–1339.
Address reprint requests to:
Jon M Burnham, MD
The Children’s Hospital of Philadelphia
34th Street and Civic Center Boulevard
Philadelphia, PA 19104, USA
Received in original form March 8, 2004; in revised form June 29,
2004; accepted July 15, 2004.
1968 BURNHAM ET AL.