Management of osteoporosis in children Nicholas J Shaw

European Journal of Endocrinology (2008) 159 S33–S39
ISSN 0804-4643
Management of osteoporosis in children
Nicholas J Shaw
Department of Endocrinology, Birmingham Children’s Hospital, Steelhouse Lane, Birmingham B4 6NH, UK
(Correspondence should be addressed to N J Shaw; Email: [email protected])
Abstract
Osteoporosis is being increasingly recognised in paediatric practice as a consequence of several factors.
These include the increasing complexity of chronic conditions and the associated treatments managed
by paediatricians. In addition, the improved care provided to children with chronic illness has led to
many of them living long enough to develop osteoporosis. The availability of methods to assess bone
density in children as a surrogate marker of bone strength and the possibility of medical treatment to
increase bone density have also resulted in an increased awareness of groups of children who may be at
risk of osteoporosis. This article reviews the current definition of osteoporosis in children, aetiological
factors and the evidence for effective treatment.
European Journal of Endocrinology 159 S33–S39
What is osteoporosis?
Osteoporosis is defined by the World Health Organization as a systemic skeletal disorder characterised by
low bone mass and micro-architectural deterioration of
bone tissue with a consequent increase in bone fragility
and susceptibility to fracture (1). However, in adult
practice, osteoporosis is usually defined on the assessment of bone density alone in the absence of any
fractures. This is because large epidemiological studies
have demonstrated a link between measurements of
bone density using dual energy X-ray absorptiometry
(DXA) at the spine, hip and wrist with a subsequent risk
of future fractures. Here, comparison of an individual’s
bone density is against the peak bone mass seen in a
young adult with the T-score representing the number
of S.D. from this value. Thus, a T-score more than 2.5
S.D.s below the mean is defined as osteoporosis while a
T-score between 1 and 2.5 S.D.s below the mean is
defined as osteopaenia. Although this definition was
originally intended for the management of postmenopausal osteoporosis, it has been applied uncritically to
other groups.
Currently, it is not possible to define osteoporosis in
children on the basis of bone density measurements
alone. Although there are now several studies that have
examined the relationship between bone density in
healthy children and fractures (2, 3), the relationship
between bone density and fracture risk in children with
chronic disease is currently unknown and therefore it is
This paper was presented at the 5th Ferring International Paediatric
Endocrinology Symposium, Baveno, Italy (2008). Ferring Pharmaceuticals has supported the publication of these proceedings.
q 2008 European Society of Endocrinology
not possible to define thresholds below which there is an
increased fracture risk. An additional reason is that
bone density measurements in children using DXA are
affected by body size. This is because the bone density
value produced in gm/cm2 is an areal bone density, i.e.
the bone mineral content of the bone being scanned is
divided by its bone area. This fails to take account of the
third dimension and does not provide a volumetric bone
density where bone mineral content is divided by bone
volume to produce a result in gm/cm3.
There is a strong correlation between areal bone
density and bone size and thus height. This means in
practice that a child who is short for their age will have
smaller bones and therefore their areal bone density will
be below the mean value for a child of the same age due
entirely to their short stature. The worst case scenario is
that a small child is inappropriately diagnosed as having
‘osteoporosis’ with a resultant change in their lifestyle
and potentially inappropriate treatment to improve
their low bone density. This is well illustrated in a paper
by Gafni et al. (4) where up to 50% of children had
received an inappropriate diagnosis of osteoporosis due
to errors in interpretation of their DXA scan results.
The International Society for Clinical Densitometry
has recently produced a position statement on bone
densitometry in children, which states that the
diagnosis of osteoporosis in children and adolescents
should not be made on the basis of densitometric criteria
alone (5). It states that the diagnosis of osteoporosis
requires the presence of a clinically significant fracture
history and low bone mineral content or density. A
clinically significant fracture history is defined as one or
more of the following: long bone fracture of the lower
extremities, vertebral compression fracture or two or
DOI: 10.1530/EJE-08-0282
Online version via www.eje-online.org
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N J Shaw
more long bone fractures of the upper extremities. Low
bone mineral content (BMC) or density (BMD) is defined
as a BMC or areal BMD Z-score that is less than or equal
to K2.0, adjusted for age, gender and body size, as
appropriate. A Z-score between K1.0 and K2.0 is
defined as the low range of normality.
There are many childhood conditions in which low
bone mineral density has been demonstrated often in
studies using DXA. However, in many of these
conditions, there is a lack of evidence that there is an
increased fracture risk and therefore it is inappropriate
to label them as causing osteoporosis.
Clinical presentation
Children with osteoporosis may present in a variety of
different ways. Recurrent long bone fractures, particularly
if associated with low impact trauma, are a common
presentation. This may be in the context of an existing
chronic disease such as juvenile idiopathic arthritis or in
the absence of a previously identified condition. The latter
is for example a common presentation of a mild form of
osteogenesis imperfecta (OI).
Vertebral compression fractures often present with
symptoms of back pain and potential loss of height and
spinal deformity. They may be the first manifestation of
an underlying chronic disease such as leukaemia or
Crohn’s disease. Occasionally, vertebral compression
fractures may be asymptomatic and may only be
identified when a spinal X-ray is performed in a child
who is being investigated for a low bone density.
Idiopathic juvenile osteoporosis will often present with
progressive symptoms of back pain and difficulty
walking. A known family history of OI may lead to the
identification of an affected child. However, it is
sometimes the case that a family history is not
recognised until the diagnosis of OI in a child leads to
the identification of an affected parent or other family
members.
Classification
Osteoporosis in children may be primary due to an
intrinsic bone abnormality (usually genetic in origin) or
secondary due to an underlying medical condition
and/or its treatment (Table 1).
Primary osteoporosis
The most common condition in this category is OI in
which there is an underlying abnormality in bone
matrix composition, usually due to defective synthesis of
type I collagen. It has an estimated incidence of 1 in
10 000–20 000 births. In addition to evidence of low
trauma fractures, affected individuals often have
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EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 159
Table 1 Classification of childhood osteoporosis.
Primary osteoporosis
Osteogenesis imperfecta
Idiopathic juvenile osteoporosis
Osteoporosis pseudoglioma syndrome
Secondary osteoporosis
Reduced mobility
Cerebral palsy
Spinal cord injury and spina bifida
Duchenne muscular dystrophy
Spinal muscle atrophy
Head injury
Unknown neurodisability
Inflammatory cytokines
Juvenile idiopathic arthritis
Systemic lupus erythematosis
Dermatomyositis
Inflammatory bowel disease
Systemic glucocorticoids
Rheumatological conditions
Inflammatory bowel disease
Nephrotic syndrome
Duchenne muscular dystrophy
Cystic fibrosis
Leukaemia
Organ and bone marrow transplantation
Disordered puberty
Thalassaemia major
Anorexia nervosa
Gonadal damage due to radiotherapy/chemotherapy
Klinefelter’s syndrome
Galactosaemia
Poor nutrition/low body weight
Anorexia nervosa
Chronic systemic disease
Inflammatory bowel disease
Cystic fibrosis
Malignancy
evidence of joint hypermobility, easy bruising, flat feet
and a blue-grey scleral hue. The original classification
on the basis of phenotypic features by David Sillence
consisted of four types varying in severity. Type I is the
most frequent form encountered and its characteristics
include recurrent fractures in childhood with a
reduction in fracture risk in adolescence, blue sclera,
healing of fractures without residual deformity and the
variable presence of abnormalities of tooth composition,
dentinogenesis imperfecta. Type II is the most severe
form with multiple fractures present in utero or at birth
often with associated respiratory distress due to chest
deformity. Such infants usually do not survive the
neonatal period. Type III is another severe type with
multiple fractures present at birth or early life. Such
fractures usually heal with significant residual deformity and historically children with this type were often
unable to walk and were wheelchair dependent.
Significant short stature is a common feature of this
type as is dentinogenesis imperfecta. Type IV is a form
that is intermediate in severity between types I and III
with a variable fracture frequency, and the possibility of
bone deformity. Stature is often normal in this type and
characteristically the colour of the sclera is white.
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EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 159
In these four types, abnormalities in synthesis of type
I collagen can often be demonstrated with either a
reduction in amount (type I) or quality (types II, III and
IV). It is recognised that some children with OI do not
clearly fall into one of these four types.
In recent years, three additional forms of OI have been
identified based on a combination of phenotypic and bone
histological features (6). Individuals with type V often
exhibit exuberant hypertrophic callus formation following
a fracture and have evidence of calcification of the
interosseous membrane between the radius and ulna on
X-ray. Individuals with type VI have evidence of fish
scale-like lamellation on bone histology. Type VII has only
been reported in a Native American community in Quebec
and is characterised by rhizomelia and coxa vara and in
contrast to the autosomal dominant inheritance seen in
most types of OI it is recessive. In each of these additional
types, abnormalities in the two genes coding for the
synthesis of type I collagen have not been described.
Recently, mutations in cartilage-associated protein
(CRTAP) have been shown to be the cause of OI type VII (7).
Idiopathic juvenile osteoporosis is a rare condition
with an estimated incidence of 1 in 100 000 which
characteristically presents in early puberty with back
pain, difficulty walking and vertebral compression
fractures (Fig. 1). Its precise aetiology is unclear
although there is an evidence of reduced bone
formation on bone histology. Spontaneous resolution
S35
has been reported in this condition in some individuals
while others go on to have a severe disabling condition
with a potential loss of the ability to walk. A precise
genetic cause for this condition has not yet been
identified although there is a report of 3 out of 20
individuals with idiopathic juvenile osteoporosis having
heterozygous mutations in the gene for low-density
lipoprotein receptor-related protein LRP5 (8).
Osteoporosis pseudoglioma syndrome is a very rare
condition in which there is a combination of osteoporosis, usually with vertebral compression fractures,
and congenital blindness due to failure of vascularisation of the peripheral retina. This condition has now
been identified as due to homozygous loss of function
mutations in the gene LRP5.
Secondary osteoporosis
There are several aetiological factors that act either
singly or in combination adversely on the bone
development of a child with a chronic condition to
increase their chances of developing osteoporotic
fractures. These are:
i.
ii.
iii.
iv.
Reduced mobility,
Inflammatory cytokines,
Systemic glucocorticoids, and
Disordered puberty and low body weight.
Reduced mobility
Figure 1 Vertebral compression fractures in the lumbar spine of a
child with idiopathic juvenile osteoporosis.
A number of chronic childhood conditions are associated
with reduced mobility such as cerebral palsy, spinal cord
injury, head injury, muscular dystrophy, spinal muscular
atrophy and neurodisability conditions with an
unknown aetiology. A key influence on bone development is muscle force and function with mechanical
loading being essential for the maintenance of bone
strength. This has been termed the functional muscle–
bone unit. During childhood, bones not only grow in
length but also are dependent on growth in width due to
periosteal expansion, which is driven by mechanical
loading by muscle force (9). Thus, conditions where this
mechanical stimulus is removed during growth such as
cerebral palsy are associated with long narrow bones
that are weaker and more vulnerable to fracture (Fig. 2).
A study using peripheral quantitative computed
tomography (pQCT) of the tibia in children with cerebral
palsy showed the failure of the normal increase in
periosteal circumference with growth (10).
Characteristically, the typical fractures seen in
individuals with these conditions are in the distal
femur or proximal tibia and appear to occur with
minimal trauma. The unexplained finding of a swollen
thigh in such children may on occasion lead to the
suspicion of non-accidental injury. Children with
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EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 159
wasting, thus compromising the mechanical loading on
the skeleton. A study of children and young adults with
Crohn’s disease identified significant deficits in lean body
mass which is predominantly muscle (15). The potential
impact of inflammatory cytokines has been demonstrated
in studies in adults with Crohn’s disease treated with
infliximab, a monoclonal antibody to TNFa, where
increases in bone density and markers of bone formation
have been observed (16).
Glucocorticoids
Figure 2 The femur of a child with spinal muscular atrophy.
cerebral palsy have been the most well studied in this
group with one study demonstrating a 4% fracture
incidence per year (11). Boys with Duchenne muscular
dystrophy progressively lose mobility in mid to late
childhood and are recognised to have an increased risk
of long bone fractures in the arms or legs, with one
study quoting an incidence of 44% (12).
Inflammatory cytokines
Increased circulating levels of cytokines such as interleukin
(IL)1A, IL6, IL7, tumour necrosis factor a (TNFa) and
TNFb cause suppression of osteoblast recruitment and
stimulate osteoclastogenesis producing an imbalance in
bone turnover. Several chronic inflammatory childhood
conditions are associated with osteoporosis such as juvenile
idiopathic arthritis, systemic lupus erythematosis and
Crohn’s disease. Activated T-cells in children with Crohn’s
disease have been shown to produce higher levels of TNFa
than those from controls (13). Many of these conditions are
treated with glucocorticoids, which can make it difficult to
distinguish the impact of the inflammatory condition on
bone. However, in some of these conditions, osteoporotic
fractures can occur early in disease presentation in the
absence of the use of glucocorticoids (14). In addition to the
impact on bone metabolism, inflammatory cytokines can
have adverse effects on skeletal muscle causing muscle
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These are known to have a variety of effects on calcium
and bone metabolism, including a direct effect on
osteoblasts causing a reduction in bone formation, an
inhibition of osteoprotegerin leading to increased bone
resorption by stimulating osteoclastogenesis, a
reduction in intestinal calcium absorption and an
increased renal tubular calcium excretion. They are
used in many chronic childhood conditions because of
their potent anti-inflammatory actions. They have a
predilection for affecting trabecular bone and therefore
vertebral compression fractures are the commonest
form of osteoporotic fracture seen in treated individuals.
One study in children with juvenile idiopathic arthritis
showed that a prednisolone dose of 0.62 mg/kg per day
was associated with a mean time to vertebral fracture of
2.6 years (17). A study utilising the UK GP Research
database has shown that children receiving four or
more courses of systemic steroids had an increased odds
ratio for fracture of 1.32 (18). However, glucocorticoids
are often used in inflammatory conditions which
themselves are associated with an increased risk of
fractures. It is becoming evident that their impact on the
growing skeleton is often dependent on the underlying
condition. For example, a study of children with steroid
sensitive nephrotic syndrome, who had received a mean
dose of prednisolone of 0.65 mg/kg per day for 53
months (19), demonstrated that bone mineral content
of the lumbar spine and whole body was not different
from controls. In adults who are receiving prednisolone
in doses of 7.5 mg or more per day for at least 3 months
and have a bone density T-score of K1.5 or less, it is
recommended that they are treated with an oral
bisphosphonate to provide protection to the skeleton.
Such a practice if adopted in paediatrics would mean
that many groups of children with chronic disease could
receive similar treatment. This is not currently justified
until there is good evidence that there is an increased
fracture risk in the childhood condition for which
steroids are being used and that bisphosphonates used
prophylactically can reduce this risk.
Disordered puberty and low body weight
Many chronic childhood illnesses are associated with
delayed puberty and low body weight although it is not
clear whether they have an additional compromise on
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EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 159
bone development other than the effect of the
underlying condition. Failure to enter puberty or
pubertal arrest can also occur as a consequence of
primary gonadal damage; e.g. chemotherapy or secondary to gonadotrophin deficiency due to pituitary
damage, e.g. as a consequence of iron overload in
thalassaemia major treated with regular blood
transfusions.
A study undertaken in children and young adults
with thalassaemia demonstrated that disordered puberty was the key factor causing a reduction in bone
density (20). Anorexia nervosa is a condition associated
with low bone density where the impact of low body
weight on bone is augmented by the associated
hypogonadism. Other disorders where nutrition is
impaired include inflammatory bowel disease, malignancy and cystic fibrosis. Although disordered puberty
and low body weight are important aetiological factors
for reducing bone density, there is little evidence
currently that they independently cause an increased
fracture risk in childhood and adolescence. In many
conditions associated with osteoporosis in children,
there is often a combination of several factors acting
together to compromise the skeleton, e.g. juvenile
idiopathic arthritis where inflammatory cytokines,
glucocorticoids, reduced mobility and poor nutrition
are common features.
S37
therapy will improve bone density (24). Bisphosphonates have also been studied as a potential preventive
measure. In a study of six pairs of subjects with
quadriplegic cerebral palsy, who were randomised to
receive i.v. pamidronate or saline every 3 months for a
year, there was an 89% increase in distal femur bone
density in the bisphosphonate group compared with 9%
in the controls (25). This study was too small to
demonstrate that these changes led to a reduction in
fracture risk. Although the use of growth hormone has
been shown to increase total and cortical crosssectional area in the radius in children with juvenile
idiopathic arthritis (26), there is currently no other
good evidence to suggest its use in the prevention of
osteoporosis in children.
In a situation where a child is identified as having a
significantly reduced lumbar spine bone density in the
absence of a history of fractures, it is worth considering
performing an X-ray of the lateral thoracic and lumbar
spine to identify asymptomatic vertebral compression
fractures or earlier changes with loss of vertebral height
and shape. In the absence of such changes, it is worth
considering whether it is possible to change factors that
may be compromising bone density such as adjustment
of corticosteroid dose or inducing puberty in an
adolescent with delayed puberty. A follow-up bone
density assessment after an interval of 1 year would be
recommended.
Prevention
Currently, the evidence base for interventions that will
potentially prevent osteoporosis in children is limited in
contrast to the situation in adult practice. Calcium and
vitamin D supplementation is instinctively felt to be an
appropriate response to a child with low bone density.
However, there is no good evidence in paediatric
practice to support such an approach. If there is
evidence of vitamin D deficiency and/or poor dietary
calcium intake it would be appropriate to replace such
deficits, but routine calcium and vitamin D supplementation is not recommended. In children with
conditions with reduced mobility, who are able to
stand, there is evidence that an increased duration of
standing or physical activity will improve bone density
in the spine and femur (21, 22). An additional potential
intervention in such a group is the use of a vibrating
platform to stimulate muscle activity and consequently
bone strength. A study undertaken in 20 children with
disabling conditions randomised them to stand on
active or placebo vibrating platforms for 10 min a day,
five times a week for 6 months (23). The active
intervention group had an increase in tibial bone
density of 18.2 mg/cm3 compared with placebo in this
relatively short time period, but further larger studies
are needed to confirm this effect before it is routinely
recommended. In individuals with hypogonadism, there
is evidence that compliance with hormone replacement
Treatment
In the management of children who have sustained
osteoporotic fractures, the treatment for which currently there is the most evidence of benefit are
bisphosphonates (27). These are chemical analogues
of pyrophosphate, a natural inhibitor of bone mineralisation. The more recent nitrogen-containing bisphosphonates inhibit the enzyme farnesyl diphosphate
synthase within the mevalonate pathway resulting in
impairment of osteoclast-induced bone resorption.
Although there are many different bisphosphonates
that are now available, which vary in potency and
method of administration, most of the studies undertaken in children have utilised the i.v. preparation,
pamidronate. Most of the studies to date have been
observational with relatively few randomised controlled
trials (28).
Many of the studies in children with different
conditions have used change in bone density as the
primary outcome, often with evidence of improvement,
but few so far have examined fracture incidence as an
outcome. In an observational study of pamidronate in a
group of 30 children with moderate to severe OI, there
was a mean annual increase in lumbar spine bone
density of 42% and a reduction in fracture risk of 1.7 per
year (29). In a randomised 2-year study using the oral
bisphosphonate olpadronate in children with OI, there
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N J Shaw
was a 31% reduction in fracture risk (30). In a group of
38 children with OI and 18 children with cerebral palsy,
the use of i.v. pamidronate at intervals of 2–8 months
was associated with a reduction in fracture frequency of
79 and 88% respectively (31).
The impact of pamidronate on bone biopsies in a
group of children with OI treated for at least 2 years has
shown an increase in cortical width by 88%, an
increase in trabecular bone volume by 44% and
increased trabecular number (32). Several other patient
groups have also shown beneficial effects from the use of
bisphosphonates on bone density and fracture frequency as summarised in the Cochrane Review on
bisphosphonate therapy in children and adolescents
with secondary osteoporosis (30) Most of these studies
have used i.v. pamidronate in doses ranging from
2–15/mg per kg per year.
Intravascular bisphosphonates such as pamidronate
are also effective at relieving pain associated with
vertebral compression fractures.
There are a number of potential side effects of
bisphosphonates including the acute-phase reaction
seen on first exposure and gastrointestinal upset seen
with some oral bisphosphonates. They can cause
symptomatic hypocalcaemia if used where there is preexisting Vitamin D deficiency or hypoparathyroidism.
They have been shown to delay bone healing after elective
osteotomies in children with OI (33). There is no evidence
that they compromise longitudinal bone growth although
they have a long half-life in the skeleton with evidence of
urinary excretion up to 8 years following their cessation
(34). In view of this, there are concerns about potential
teratogenicity if taken by women of child-bearing age
although as yet there is no evidence of this. There is
emerging evidence of fractures occurring at the interface
between treated and untreated (bisphosphonate naive)
zones of long bones in children with OI (35). There have
now been numerous reports of the development of
osteonecrosis of the jaw in individuals on bisphosphonates
(36). This is a condition where necrotic painful lesions in
the jaw show delayed healing. These reports which to date
have only been in adults are in individuals who usually
have malignancies or poor dental hygiene and have
received high doses of potent i.v. bisphosphonates such as
pamidronate or zoledronate, although there are some
reports of this with oral bisphosphonates. Bisphosphonate
induced osteopetrosis has also been reported in a child
who was treated inappropriately (37). He received at least
2800 mg of pamidronate, which is more than four times
the amount often given to a child with OI over the same
time period. Such reports demonstrate the potential for
serious adverse effects and clinicians contemplating their
use in a child should discuss these potential risks and
provide appropriate written information.
Although this article has focused on the medical
management of a child with osteoporosis, it is important
to recognise that a multi-disciplinary approach is often
required. In addition to a paediatrician who is familiar
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EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 159
with paediatric bone disease, there is a need for
radiographers who are experienced in undertaking
and interpreting bone density scans in children.
Physiotherapists and occupational therapists are
necessary for rehabilitation following surgery or
fractures. Liaison with an orthopaedic surgeon is often
important for elective surgery to correct limb deformity
or the placement of intramedullary rods in children
with OI to provide internal strength to bones that are
frequently fracturing. A specialist nurse is another
important member of the team to provide education
about the condition and treatments and to liaise with
schools as to the appropriate management of a child
with osteoporosis.
Disclosure
This article forms part of a European Journal of Endocrinology supplement,
supported by ferring pharmaceuticals. The author discloses no potential
conflicting relationship with Ferring. This article was subject to rigorous
peer review before acceptance and publication.
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Received 31 August 2008
Accepted 2 September 2008
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