Childs Nerv Syst (2017) 33:625–630
DOI 10.1007/s00381-017-3346-9
ORIGINAL PAPER
Bone mineral density and insulin-like growth factor-1 in children
with spastic cerebral palsy
H Nazif 1 & R Shatla 2 & R Elsayed 3 & E Tawfik 4 & N Osman 5 & S Korra 6 & A Ibrahim 1
Received: 12 October 2016 / Accepted: 13 January 2017 / Published online: 24 February 2017
# Springer-Verlag Berlin Heidelberg 2017
Abstract
Background Children with cerebral palsy (CP) have signifi-
cant decrease linear growth rate and low bone mineral density
(BMD).
Aims This study is to evaluate BMD in children with CP and
its relation to the levels of insulin-like growth factor-1
(IGF-1).
Subjects and methods This cross-sectional study was carried
out on 58 children suffering from spastic CP with the age
range 4–12 years compared to 19 controls. All assessed by
dual energy x-ray absorptiometry (DXA) to measure BMD,
serum level of IGF-1, and serum vitamin D. The patients were
classified according to their GMFCS.
Results Fractures were reported in seven (12.1%) of cases.
Our study demonstrated that, IGF-1 level and BMD decrease
in correlation with the severity of CP. IGF-1correlates posi-
tively with serum vitamin D, BMI, and BMD. CP children
* R Elsayed
shewaka1971@yahoo.com
1
Department of Childhood Medical Studies, Institute of Postgraduate
Childhood Studies, Ain Shams University, Cairo, Egypt
2
Department of Pediatrics, Pediatric Neurology Unit, Faculty of
Medicine, Ain Shams University, Cairo, Egypt
3
Deparment of Pediatrics, Pediatric Neurology Unit, Faculty of
Medicine, Mansoura University, Mansoura 35516, Egypt
4
Department of Physical Medicine, Rheumatology and Rehabilitation
Faculty of Medicine, Ain Shams University, Cairo, Egypt
5
Department of Radio Diagnoses, Faculty of Medicine, Ain Shams
University, Cairo, Egypt
6
Department of Molecular Biology, National Center for Radiation
Research and Technology, Cairo, Egypt
with severe GMFCS level or who use anticonvulsive drugs
are at a high risk for low BMD and low levels of IGF-1.
Conclusion Both BMD and IGF-1 were significantly in low
children with spastic CP; IGF-1 negatively correlates with the
severity of osteopenia in children with spastic. Children with
CP who are not independently ambulant or with severe
GMFCS level or who use anticonvulsive drugs are at a high
risk for developing low BMD.
Keywords IGF-1 . Spastic CP . Bone mineral density .
Vitamin D
Background
Cerebral palsy (CP) is a catastrophic acquired disease occur-
ring during development of the fetal or infant brain. It mainly
affects the motor control centers of the developing brain, but
can also affect cognitive functions, and is usually accompa-
nied by a cohort of symptoms including lack of communica-
tion, epilepsy, and alterations in behavior [1].
Bone density is significantly decreased, and children with
CP often sustain painful fractures with minimal trauma that
impair their function and their quality of life. Preventing or
improving osteoporosis and maximizing bone accrual during
critical stages of growth will minimize the future lifelong risks
of fractures in children with CP [2]. Poor bone mineralization
in children with CP may be due to a variety of factors, for
example: limited weight bearing ambulation during skeletal
growth, temporary immobilization following orthopedic sur-
gical procedures, poor nutrition, and the use of anticonvulsant
drugs that interfere with vitamin D metabolism. There are
several lines of evidence that suggest that impairment of the
growth hormone-insulin-like growth factor (GH-IGF) axis
626
may be another factor that contributes to decreased BMD in
these children [3].
Growth hormone (GH) and its metabolite IGF-I are ana-
bolic hormones with an important role in the regulation of
bone remodeling. IGF-I mediates most of the effects of GH
on skeletal metabolism, increases bone formation by regulat-
ing the differentiated function of the osteoblast, and as a con-
sequence GH-IGF-I increase bone remodeling. Diseases af-
fecting the GH-IGF-I axis are frequently associated with sig-
nificant alterations in bone metabolism that often lead to bone
loss [4].
Many studies found that children with CP may have an
increased incidence of GH deficiency and their IGF-I level
[3–6].
The aim of this study is to assess BMD in children with CP
and its relation to the serum levels of IGF-1.
Subjects and methods
Study design Our study is a cross-sectional, case control
study.
Subjects
This study was carried out on 58 children suffering
from spastic cerebral palsy with the age range 6–
10 years. They were compared to 19 apparently healthy
age and sex-matched children as controls. The children
were recruited from both pediatric neurology outpatient
clinics in Pediatrics hospital, Ain shams University and
Institute of Postgraduate Childhood studies, Ain shams
University during the period from March 2013 to
March 2014.
Children with genetic disease or congenital CNS
malformations or any chronic diseases were excluded from
the study. The children on any medications other than antiep-
ileptic drugs (AEDS) and those receiving vitamin D, growth
hormone, or steroids supplementation were not included as
well.
Patients were divided into two groups: Group A:
those on anti-epileptic drugs with a dose that has not
been changed for the last 3 months before inclusion in
the study: 44 of which ten were receiving carbamaze-
pine, seven receiving sodium valproate, and four receiv-
ing other drugs. Twenty-three patients were on
polytherapy, and Group B:those not receiving antiepilep-
tic drugs, and included 14 patients.
They were also subdivided according to their Gross Motor
Function Classification System (GMFCS) into mild (1 and 2),
moderate (3), and severe (4 and 5) [7].
Childs Nerv Syst (2017) 33:625–630
Methods
All patients were subjected to full medical history, (perinatal
history, type of seizure, and frequency antiepileptic drugs used
and its dose and duration), detailed clinical examination, and
neurological examination with GMFSC was applied to all
patients. Growth assessment including weight percentage for
age, length percentage for age and body mass index (BMI).
3-investigations
A) Laboratory investigations
All serum blood samples from the 58 children were taken
to measure the following:
1. Complete blood picture, serum calcium, phosphorus, and
alkaline phosphatase.
2. Enzyme Linked Immunosorbent Assay (ELISA) tech-
nique was used to measure 25-OH vitamin D (vitamin
D) [8].
3. Serum IGF-1 concentration was analyzed by ELISA
using commercial reagents after extraction of the plasma
samples, and values will be measured. Serum IGF-1
values were compared to reference for age and sex [9].
B) Radiological investigations
Dual-emission x-ray absorptiometry (DXA) scan was done
to all cases and control children. BMD measurements (g/cm2)
were converted to age- and gender-normalized standard devi-
ation scores (z-scores) using our own series of normal pediat-
ric controls [10].
Ethical aspects
& Parents were informed about the aims and the procedures
of the study.
& A written informed consent was signed from parents to
enroll their children in the study as well as an ascent from
the patient.
& Study was approved by local ethical committee of our
hospital.
Statistical analysis
The data was collected and results analyzed on personal com-
puter using the Statistical Package for the Social Science
(SPSS) version number 12, Echosoft Corp; USA, 2005.
Description of quantitative variables was in the form of
mean ± standard deviation and range. Qualitative variables
were in the form of number and percentage. Student’s t test
Childs Nerv Syst (2017) 33:625–630 627

of two independent samples was used to compare two quan- Table 2 Comparing Laboratory parameters and BMD in cases and
control
titative variables. Pearson correlation coefficient test (r test)
was used to rank different variables against each other either Cases N = 58 Control N = 19 P value
directly or indirectly. A p value of <0.05 was considered Mean ± SD Mean ± SD
significant.
Calcium (mmol/l) 9.01 ± 0.50 9.39 ± 0.70 *0.012
Phosphorus (mmol/l) 4.70 ± 0.60 4.83 ± 0.55 0.395
Alkaline phosphatase 445.05 ± 89.147 329.11 ± 116.85 *0.000
(u/l)
Results Vitamin D (ng/ml) 20.0 ± 53.71 78.761 ± 8.47 *0.000
IGF-1 (ng/ml) 66.74 ± 44.78 73.79 ± 6.19 *0.025
The study included 58 children with cerebral palsy with Z-score (BMD) −0.79 ± 1.59 0.99 ± 1.14 *0.000
ages 8.4 ± 2.4 years, 65.5% were males, post anoxic CP
was the most common etiology 60.2%, and there were IGF-1 insulin-like growth factor-1, BMD bone mineral density, vitamin D
convulsions in 37 (63.8%) children controlled on 25–hydroxyl vitamin D
AEDS. Fractures were reported in seven (12.1%) of *P value <0.05 is considered significant
cases. There were 49 (84.5%) children on regular solid
diet and remaining on either liquid or mixed diet. There
were 19 apparently healthy age and sex-matched chil- Laboratory parameters and BMD according to GMFCS
dren as control group (Table 1).
We found that BMD in moderate stage being signifi-
cantly lowest. Vitamin D is significantly lower in severe
Laboratory parameters and BMD for patients stage of GMFCS than milder stages. Further, as we
and controls studied different laboratory results with levels of
GMFCS, we found that vitamin D was significantly
Serum IGF-1 was highly significantly lower in cases higher in mild cases and lowest in severe cases (p value
compared to controls, and also serum vitamin D was 0.000). Alkaline phosphatase, on the other hand, shows
significantly lower. Alkaline phosphatase was signifi- statistical significance being highest in moderate and
cantly higher in cases than in control, while there were severe cases (p value 0.000). IGF-1 was highly signifi-
no significant differences regarding serum calcium and cantly lower in severe cases of cerebral palsy (p value
phosphorus (Table 2). 0.012) (Table 3).

Table 1 Demographic data in

cerebral palsy cases and controls Cases no. =58 Control no. =19

Age Mean ± SD 8.40 ± 2.37 8.57 ± 2.38

Range 4.1–12 4.1–12
Sex, no. (%) Female 20 (34.5%) 8 (42.10%)
Male 38 (65.5%) 11 (57.90%)
Type of convulsions, no. (%) Absence 3 (5.2%) –
Focal 4 (6.9%) –
GTC 29 (50.0%) –
Myoclonic 1 (1.7%) –
No convulsions 21 (36.2%) –
Etiology of CP, no. (%) Post hemorrhagic 2 (3.4%) –
Post anoxic 35 (60.2%) –
Post infectious 15 (25.8%) –
Post kernicterus 4 (6.9%) –
Post traumatic 2 (3.4%) –
Feeding route, no. (%) Liquids 1 (1.7%) –
Solid 49 (84.5%) 19 (100%)
Puree 8 (13.8%) –
Fracture occurrence Positive 7 (12.1%) –
628 Childs Nerv Syst (2017) 33:625–630

Table 3 Comparison between

laboratory parameters in different Mild CP Moderate CP Severe CP P value
GMFCS levels
Mean ± SD Mean ± SD Mean ± SD
Calcium (mmol/l) 9.03 ± 0.50 9.11 ± 0.49 8.92 ± 0.51 0.067
Phosphorus (mmol/l) 4.71 ± 0.76 4.84 ± 0.26 4.60 ± 0.49 0.571
Alkaline phosphatase (u/l) 430.81 ± 78.18 457.75 ± 134.60 457.26 ± 68.54 *0.000
Vitamin D (ng/ml) 21.03 ± 3.93 20.23 ± 3.28 18.54 ± 3.28 *0.000
IGF-1 (ng/ml) 82.44 ± 48.76 56.58 ± 37.80 50.84 ± 36.54 *0.012

CP spastic cerebral palsy, GF-1 insulin-like growth factor-1, BMD bone mineral density, Vitamin D 25–hydroxyl
vitamin D
*p < .05 considered significant

Antiepileptic drugs and BMD in cerebral palsy patients

r=0.532
p=0.000
The conducted study showed that patients receiving no
AED had highest BMD followed by those on monother-
apy, while CP children on multiple AEDS have the
lowest BMD (Fig. 1).

Insulin-like growth factor-1 in cerebral palsy children

and its correlations
(a)
There was a positive correlation between IGF-1 and
r=0.635
vitamin D (Fig. 2a); also, there was a significant posi-
p=0.000
tive correlation between IGF-1 with BMI (Fig. 2b).
There was a significant positive correlation between
IGF-1 with BMD (Fig. 2c).

Factors affecting BMD in CP

By regression analysis, it was seen that in descending order of

significance as regard effect on BMD, GMFCS was most
significant, then nutritional status followed by vitamin D and
IGF-1, antiepileptic drugs and difficulty of feeding were of no
(b)
significance (Table 4).

BMD r=0.696
p=0.000

-0.2

-0.4

-0.6

-0.8

-1

-1.2

-1.4
(c)
No treatment Monotherapy Polytherapy
Fig. 2 Correlation between IGF1 and vitamin D (a), BM1 (b) and BMD
Fig. 1 Comparison between effects of antiepileptic drugs on BMD z- (c). The figure shows significant positive correlation between IGF-1 level
score in children with spastic CP with vitamin D, BMI, and BMD
Childs Nerv Syst (2017) 33:625–630 629

Table 4 Linear regression

analysis for the most affected Unstandardized coefficients Standardized coefficients T P value
parameters in BMD in spastic CP
children B SE Beta

GMFCS −0.615 0.146 −0.491 −4.213 *0.000

Weight (kg) 0.087 0.017 0.509 5.124 *0.000
BMI 0.193 0.037 0.517 5.233 *0.000
Vitamin D (ng/ml) 0.032 0.007 0.488 3.840 *0.010
IGF1 ng/ml 0.034 0.004 0.748 2.770 *0.015
Antiepileptic drugs −0.913 0.540 −0.220 −1.691 0.096
Difficulty of feeding −0.340 0.213 −0.507 −2.110 0.074

GMFCS gross motor function classification system, IGF-1 insulin-like growth factor-1, BMI body mass index
*P value <0.05 is considered significant

Discussion
The high prevalence of altered skeletal maturation and de-
creased BMD in children with CP can be of direct clinical
significance in situations where treatment decisions involve
issues of Bgrowth remaining^. DXA is the preferred technique
for measuring BMD. This test helps to predict risk of bone
fracture [11].
Malnutrition is a common health problem in patients with
CP, leading to significant morbidity in multiple organ systems.
The serious consequences of malnutrition include decreased
muscle strength, poor immune status, and depressed cerebral
functioning. CP patients were at risk for low body mass index
[12].
In our study, children with spastic CP had decreased BMD
compared to control group (z-score −0.79, p value 0.000).
These finding are similar to the finding of many previous
studies that reported low BMD in children with variable de-
grees of CP [13–16].
Our study also showed (12.1%) of our patients with frac-
tures at least once in their life which may attributed to low
BMD. Fracture rate was investigated by Stevenson and col-
leagues in a longitudinal cohort study of 245 patients with
moderate to severe CP. At baseline, 15.7% reported a history
of fractures [17].
The present study revealed that mean vitamin D level was
significantly lower in cases compared to controls (p value
0.000). This finding indicates that vitamin D deficiency is
one of contributing factors to osteopenia in CP children.
Jekovec-Vrhovsek et al. found low vitamin D and BMD in
non-supplemented group, and also, found improvement in
BMD other group of CP children after vitamin D supplemen-
tation [18]. We studied the effect of AEDS on BMD and our
results revealed that BMD was significantly decreased in CP
children receiving AEDs especially those on polytherapy.
In this study, IGF-1 was significantly lower in cases com-
pared to controls, and showed a positive correlation with
BMD, vitamin D, and BMI. In accordance with our study,
Mohan et al. [19]; Ali et al. [3], and Houlihan [20], they found
that BMD and IGF-1 decreased in children with CP compared
to normal controls.
According to the present study, both BMD and IGF-1 are
significantly lower with the severity of CP as graded by
GMFCS. This results were consistent with Henderson et al.
[15], who have studied bone density in children with moderate
to severe CP, finding that low BMD z-scores at initial evalu-
ation were associated with greater severity of CP (GMFCS
severity), and poorer growth and nutrition as judged by
weight. This is in agreement with Henderson et al. [13] and
Tasdemir et al. [21] who found that severity of neurologic
impairment as graded by GMFCS level contribute to low
BMD which is prevalent in children with moderate to severe
CP and is associated with significant fracture risk. In the cur-
rent study, regression analysis for factors affecting BMD in
CP showed that GMFCS was most significant, then nutritional
status followed by vitamin D and IGF-1. These findings were
similar to what are reported in many other studies [22–24]. Ali
et al. in a small pilot study suggests that 18 months of GH
therapy is associated with statistically significant improve-
ment in spinal BMD and linear growth [25].
In conclusion The present study showed that both BMD and
IGF-1 were significantly low in children with spastic CP, with
IGF-1 correlating with the severity of osteopenia in spastic CP
children, which may have diagnostic and therapeutic implica-
tions in this group of children. Further studies are still needed
to confirm the exact role of IGF-1 in pathogenesis of
osteopenia in children with spastic CP.
Compliance with ethical standards Parents were informed about the
aims and the procedures of the study. A written informed consent was
signed from parents to enroll their children in the study as well as an
ascent from the patient. The study was approved by the local ethical
committee of our hospital.
Conflict of interest All authors stated that no conflict of interest related
to this article.
630
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