Attaining PBM by early adulthood is necessary to reduce the risk of adult-onset osteoporosis Table 1, which is a worldwide public health problem and the most common metabolic bone dis-or
Trang 1Childhood and adolescence are
rec-ognized as critical periods for the
attainment of peak bone mass
(PBM) Attaining PBM by early
adulthood is necessary to reduce
the risk of adult-onset osteoporosis
(Table 1), which is a worldwide
public health problem and the
most common metabolic bone
dis-order in North America.1 Vitamin
D, calcium, and phosphorus intake
must be adequate for optimal bone
mass accrual; however, the diets of
most children do not provide
rec-ommended allowances of these
nutrients during the most critical
years of skeletal growth.2 Also,
recent investigation emphasizes
that peak bone mineralization is in
part genetically predetermined;
therefore, some children may be
predisposed to osteopenia.3 Prior
to the widespread use of
dual-ener-gy x-ray absorptiometry (DEXA),
low bone mineral density (BMD)
could only be inferred based on
nonspecific and insensitive bio-chemical measurements, a history
of fractures, or the appearance of bone on plain radiographs The recent use of DEXA and other modalities has enabled clinicians and researchers to understand more clearly the physiologic pro-cess of skeletal mineralization, define the extent of osteopenia in both the general population and in children with chronic disorders, and track the efficacy of specific interventions in enhancing BMD
Despite the emergence of poor bone mineralization in children as
a condition more prevalent than previously recognized, studies on this subject in the orthopaedic lit-erature are lacking Understand-ing bone mass accrual and tech-niques of measurement is critical for the effective evaluation and treatment of patients with subtle and severe presentations of re-duced BMD
Bone Mineral Density
Understanding the units of mea-surement and differences in types
of bone measured is important for drawing conclusions about study results and patient data Bone min-eral content (BMC) is a measure-ment of bone size and therefore tends to increase as bone grows BMD is calculated by dividing the BMC by the surface area of the re-gion of interest Often referred to
as areal BMD, this two-dimensional result is only an estimation of the true volumetric BMD, which is cal-culated by correlating BMD data obtained for both anteroposterior (AP) and lateral measurements Volumetric BMD is seldom
report-ed in the literature
Radiographs, which are typically the first tests ordered by orthopae-dic surgeons, cannot provide an ac-curate quantitative assessment of BMD Reductions in BMD do not become apparent until at least
ap-Dr Tortolani is Chief Resident, Department of Orthopaedic Surgery, Johns Hopkins Hospital, Baltimore, Md Dr McCarthy is Chief, Division of Bone Pathology, Johns Hopkins Hospital Dr Sponseller is Chief, Division of Pediatric Orthopaedic Surgery, Johns Hopkins Hospital.
Reprint requests: Dr Tortolani, Johns Hopkins Hospital, 601 North Caroline Street, Baltimore,
MD 21287-0881.
Copyright 2002 by the American Academy of Orthopaedic Surgeons.
Abstract
With the development of improved diagnostic and treatment options, reduced
bone mineral density in children is receiving increased attention The etiology
of osteopenia in healthy children is multifactorial and incompletely understood,
but poor calcium intake during the adolescent growth spurt may be an
impor-tant (and potentially reversible) factor Other clinically relevant causes of
reduced bone mineral density in children include osteogenesis imperfecta,
rick-ets, juvenile rheumatoid and other chronic arthritides, osteopenia associated
with neuromuscular disorders, and idiopathic osteoporosis To provide
effec-tive treatment, it is important to understand the process of normal skeletal
mineralization, the techniques of bone mineral density measurement, the
pathophysiology of osteopenia, and the evaluation and treatment options for
the general pediatric population as well as for patients with specific pediatric
disorders.
J Am Acad Orthop Surg 2002;10:57-66
P Justin Tortolani, MD, Edward F McCarthy, MD, and Paul D Sponseller, MD
Trang 2proximately 30% to 40% of the
min-eral has been lost.4 Certain childhood
diseases (e.g., rickets) do
demon-strate characteristic radiographic
findings, so radiographs may be
sufficient to diagnose these
condi-tions However, radiographs are
not a sensitive measure of BMD, so
clinicians should not rule out
osteo-penia based on an apparently
nor-mal mineralization pattern on
radio-graphs
During the past 10 years, DEXA
has emerged as a cost-effective, safe,
and accurate means to quantitate
skeletal mass The World Health
Organization has adopted
DEXA-derived BMD measurements to
define normal bone, osteopenia, and
osteoporosis (Table 1).5 Chronic
dis-eases often cause primary
osteope-nia in children, and as a result of
poor nutrition, steroid use, or a
combination of factors, these
chil-dren may develop osteoporosis
BMD standards for pediatric
popu-lations have been generated and are
incorporated into DEXA software
programs for comparisons with an
individual patient’s measurements.6
In general, individual or raw
mea-surements for a patient are of little
value except as compared with
these control values The typical
DEXA analysis therefore reports a Z
score, which is the number of
stan-dard deviations (SDs) that a
pa-tient’s BMD is above or below the
mean value for persons of the
pa-tient’s age and sex.7 The T score is
the number of SDs the patient’s
BMD is either above or below the mean value for young adults of the same gender (Fig 1).7 Normative data for neonates and younger chil-dren are somewhat limited, and some authors question the validity
of DEXA analysis for younger chil-dren However, Koo et al8and Ellis
et al9 have validated its accuracy and precision in infants and chil-dren
In contrast to single photon ab-sorptiometry, which permits analy-sis of the appendicular skeleton only, DEXA is able to measure both appendicular and axial bone min-eralization The radiation exposure
is approximately 5 mrem per scan (the exposure from a typical chest radiograph is 25 mrem), and the test takes approximately 20 min-utes to complete
Because bone strength and resis-tance to fracture depend not only on the amount of mineral present but also on the three-dimensional con-formation, some investigators have questioned the accuracy of BMD measurements in predicting fracture risk.10 Despite this theoretic limita-tion, DEXA remains a powerful modality for documenting develop-mental changes in BMD, and re-sponses to therapeutic interventions and its measurements have been shown to correlate well with frac-ture risk in adult patients.11
Quantitative computed tomogra-phy (QCT) provides true three-dimensional BMD measurements and is unique in that it can isolate
the area of interest from surround-ing tissues A purely trabecular area of a vertebral body can be iso-lated from the posterior elements, which may be involved with other processes, such as degenerative arthritis QCT is available with most
CT scanners, but the radiation dose
is approximately 10 times that of DEXA and the tests are more costly and time consuming
Recent reports12-14have suggested that quantitative ultrasound and magnetic resonance imaging (MRI) may accurately discriminate normal from osteopenic bone without ex-posing the patient to ionizing radia-tion In addition, these modalities may provide additional data, such
as trabecular thickness and other microarchitectural factors, that can-not be provided by DEXA.13 De-spite these potential benefits of quantitative ultrasound and MRI, population-derived norms have not been generated for these modalities, and documentation of their
accura-cy, especially in young children (younger than 6 years old), is lack-ing Neither quantitative ultra-sound nor MRI currently is used as
a screening tool for low BMD
Normal Skeletal Mineralization
The critical processes of skeletal growth and bone mineralization take place during childhood Or-thopaedic surgeons must have a thorough understanding of these processes for two reasons First, attainment of PBM by early adult-hood is a central element in the pre-vention of adult-onset osteoporosis Second, reduced BMD may increase the risk for fractures in children and adolescents Both bone mass accu-mulation and longitudinal growth
of bone are complex processes con-trolled by genetic and environmen-tal factors as well as hormonal sig-nals, many of which have become
Table 1
Definition of Terms Relating to Bone Mineral Density 5
fragility fractures
Trang 3better understood in the past 25
years Throughout most of
child-hood, bone mass accrual and
longi-tudinal growth are closely related:
as the skeleton increases in length
(height), it also increases in mass
During puberty, however, a
dispar-ity between these factors develops
whereby increases in bone mass lag
behind increases in height A
pro-spective study of 140 boys and girls
evaluated by DEXA demonstrated
that the rate of bone mineral uptake
in the femoral neck, lumbar spine,
and total body does not reach a
max-imum until at least 1 year after peak
height velocity (PHV) is achieved.2
Skeletal growth also has been
demonstrated to vary by anatomic
location During early childhood,
the rate of appendicular growth
outpaces the rate of axial bone
growth This relationship then
re-verses during puberty, when axial
skeletal growth accelerates while
appendicular growth remains
con-stant Hormonal factors such as
insulin-like growth factor 1 (IGF-1),
growth hormone, and sex hormones
likely mediate these mechanisms
via site-specific end organ receptors
Bone densitometry has demonstrated
that bone mass accumulation also
varies by region In a longitudinal
study of girls aged 11 to 14 years
and boys aged 13 to 17 years, in-creases in bone mass in the lumbar spine and femoral neck were three times that found in the midfemoral shaft.15 A clear distinction between bone mass (or content) and BMD is critical in analyzing developmental studies because simple bone mass increases may reflect the increased bone size (cortical shell thickness) that occurs during growth rather than increased density (mass per unit volume) The increase in BMC
of the lumbar spine during puberty, for example, is almost 10 times greater than the corresponding mean increase in volumetric trabecular den-sity of the vertebrae
To control for differences be-tween the sexes that occur during puberty, Bailey2examined the BMC
of healthy children at the age of PHV and demonstrated that, at the age of PHV, both boys and girls have achieved approximately 70%
of their adult BMC in the femoral neck and 60% of their adult BMC
in the lumbar spine as well as total body Bailey also showed that whereas boys have higher BMC at all skeletal sites because of their larger skeletons, the percentage of adult BMC attained did not differ between the sexes According to these data, it appears that boys enter
young adulthood with greater over-all skeletal mass because of their larger bone size, but BMD in boys is not drastically different from that in girls
Osteopenia and Fracture Risk in the General Pediatric Population
Fractures account for 25% of all pediatric injuries; the peak inci-dence of fractures in girls and boys occurs at 11 and 13 years of age, re-spectively.16,17 These age peaks typ-ically are attributed to risk-taking behavior, but recent work suggests that osteopenia that occurs during development may predispose chil-dren to fractures at specific skeletal locations In addition to the work
by Bailey,2 results from a popula-tion-based study of 236 Japanese children demonstrated differing rates of increase of BMD at the metaphysis and the diaphysis of the forearm.16 In particular, the ratio of metaphyseal to diaphyseal BMD is lowest in 11-year-old girls and in boys aged 12 to 13 years These age ranges parallel the ages at which the highest rate of distal radius frac-tures occurs Therefore, the authors concluded that low BMD at the dis-tal metaphysis may contribute to distal radius fractures during ado-lescence Similarly, girls aged 13 to
15 years with a history of a distal radius fracture are significantly more likely to have osteopenia than are fracture-free children.18 In their study of 100 affected children and
100 fracture-free children, Goulding
et al18used DEXA to analyze BMD
at the lumbar spine, ultradistal radius, radius, hip trochanter, and total body These findings identify the adolescent growth period as a critical period for bone mineraliza-tion and suggest that transient long bone weakness and increased frac-ture risk may follow PHV in boys and girls
1.4
1.3
1.2
1.1
1.0
0.9
0.8
0.3
0.4
0.5
0.6
0.7
0 5 10 15 20 25 30
Age (yr)
2 )
Region (g/cm 2 ) (SD) (%) Z score (%)
L1 0.895 −0.28 (97) — — L2 0.999 −0.27 (97) — — L3 1.011 −0.66 (93) — — L4 0.994 −1.11 (89) — — L1-L4 0.980 −0.61 (94) +0.74 (108)
* Normalized for a patient population of 30 years average age.
Figure 1 BMD of the lumbar spine in a healthy 14-year-old girl A, Reference database of
lumbar spine BMD as a function of age The dark middle line is the mean BMD The
shaded dark and light sections represent 1 SD above and below the mean, respectively.
The circle indicates the patient’s BMD of 0.980 g/cm 2 (the mean for spinal levels L1-L4)
B, Specific BMD values for individual lumbar vertebrae.
Trang 4We currently recommend DEXA
for healthy children who sustain
three or more fractures in 1 year
from low-energy mechanisms such
as falls and sports Children with a
Z score of >2 SDs below the mean
and a history of poor calcium intake
or generally poor nutrition should
be given calcium supplementation
Repeat DEXA scans are not
neces-sary unless the child continues to
sustain fractures or the clinician
sus-pects a different diagnosis, such as
osteogenesis imperfecta (OI) or
idio-pathic juvenile osteoporosis (IJO),
where further reductions in bone
mineralization could alter medical
management
The Role of Genetics
Although many of the molecular
mechanisms mediating bone mineral
accrual are unknown, genetic factors
likely account for approximately
70% to 80% of the variability
ob-served among individuals.3 Recent
landmark investigations have
iden-tified specific DNA polymorphisms
of the vitamin D receptor that
pre-dict differences in BMD in
prepu-bertal children as well as adults.3,19
Using DEXA to determine the BMD
of 250 healthy monozygotic and
dizygotic twins, Morrison et al3
clearly demonstrated a codominant
effect of two specific allelic variants,
which they designated B and b
BMD was significantly and
propor-tionately lower in homozygotic BB
and heterozygotic Bb individuals
than in homozygotic bb individuals
Morrison et al also examined 311
unrelated healthy postmenopausal
women and found that allelic
varia-tion at the vitamin D receptor is an
independent predictor of BMD at
both the femoral neck and the
lum-bar spine.3 Using multiple
regres-sion analysis, they calculated that
women would reach a fracture
threshold, defined as 2 SD below the
mean BMD of young normal women,
at varying rates after menopause depending on their particular geno-type Women with the BB genotype would reach this fracture threshold
at 18.4 years after menopause, Bb individuals at 22 years, and bb indi-viduals at 29 years.3
The importance of genotype in predicting BMD phenotype also has been corroborated in children.19
Specific allelic variations at the vita-min D receptor in prepubertal girls appeared to correlate with differ-ences in BMD when measured by QCT but not with cross-sectional area or cortical thickness Children with the bb genotype demonstrated significantly higher BMD in the femur and vertebrae than did chil-dren with the BB genotype.19 Impor-tantly, this genotypic variation does not correlate with any observable differences in developmental status
To date, no studies have investigated whether these gene-specific alter-ations in mineralization manifest clinically as increased fracture rates;
however, the implications of these findings are important both for eval-uation and treatment of children pre-senting with fractures Further research will enable physicians to identify a subgroup of children at risk and provide novel therapies both to optimize bone mineral
accru-al during childhood and possibly to reduce fracture risk
The Role of Calcium
As previously mentioned, low bone mineral density at age 11 in girls and age 13 in boys represents a de-velopmental phenomenon for which treatment is not currently available
Although the increased rate of frac-ture in children at these ages often has been attributed to risk-taking behavior, clearly some children at this age also have deficient calcium intake In a study of healthy Ameri-can children, Chan20 showed that only 15% of children >11 years of
age obtain the recommended daily allowance (RDA) for calcium and that intake of >1,000 mg daily corre-lated with higher BMC than did
lower intake (P = 0.001) Similarly,
the Centers for Disease Control and Prevention reported that females >12 years of age of almost all racial and ethnic groups consume less than the RDA for calcium.21 These figures are remarkable, given the amount of evidence unequivocally supporting adequate dietary calcium before, during, and after puberty as possi-bly the only modifiable factor for reaching peak BMD.22,23
By studying identical twin pairs, investigators have demonstrated that adequate dietary calcium intake
in prepubertal children leads to sig-nificantly increased BMD at the radius and at the lumbar spine.24 In
a 3-year, double-blind, prospective study of 45 twin pairs in which one child of each twin pair received cal-cium supplementation and the other received placebo, children receiving calcium had 2% to 5% greater in-creases in BMD at all skeletal sites measured.24 These findings have been corroborated by other random-ized, placebo-controlled studies in prepubertal children Bonjour et
al22 showed that the beneficial effects of calcium supplementation are more profound at appendicular skeleton locations Lee et al23found that children accustomed to a low-calcium diet had greater increases in BMD with calcium supplementation than did children with adequate cal-cium intake at baseline
Calcium intake follows a thresh-old pattern: increased intake corre-lates with increased calcium balance until a limit is reached at which in-creases do not result in further net increases in calcium storage.25 Be-cause this threshold was found to exceed previous RDAs, recommen-dations were modified in 1994 to
400 to 600 mg of calcium per day for infants from birth to 1 year of age,
800 to 1,200 mg per day in children
Trang 5aged 1 to 10 years, and 1,200 to 1,500
mg per day for adolescents and
young adults aged 11 to 24 years.26
Adequate amounts of dietary
calci-um are relatively easy to obtain,
with one 8-oz cup of milk containing
300 mg of calcium, and the risks
related to increased calcium intake
are minimal In addition to dairy
products, other good food sources of
calcium include certain green
veg-etables, such as broccoli and kale,
calcium-set tofu, seeds, nuts, and
fortified food products such as
orange juice
Calcium supplementation, either
through dietary sources or vitamins,
is recommended for children with
three or more fractures in 1 year or a
DEXA measurement of <2.0 SDs
Given the importance of adequate
calcium intake in achieving PBM,
the likelihood of poor intake during
adolescence, and the safety of
sup-plementation, increasing calcium
intake should be emphasized to all
teenage patients and their families
The National Institutes of Health
has identified low calcium intake as
a critical public health concern
re-quiring public education programs
as well as private and public sector
initiatives to address socioeconomic,
ethnic, age, sex, and regional
barri-ers to optimization.26
Osteopenia and
Osteoporosis in
Disorders of Childhood
Idiopathic Juvenile
Osteoporosis
Some children with reduced BMD
have genetic, hematologic, or
meta-bolic defects that can be identified
by thorough clinical examination
However, in a subset of otherwise
healthy children, severe bone
min-eral loss for which there is no known
cause develops between the ages of
4 and 16 years Remarkably, this
rare syndrome, IJO, reverses itself
completely in virtually every case
Clinically, IJO is characterized by five cardinal features: onset before puberty, multiple fractures, pain in the back and the extremities, radio-graphic evidence of osteoporosis in new bone, and metaphyseal com-pression fractures Children typi-cally present with an insidious onset
of pain in the back and legs The physical examination is normal, with the exception of bone tender-ness Severely affected children may have a mild kyphosis or pectus carinatum All serum biochemical measurements are normal, and radio-graphs are notable for severe osteo-penia with lower extremity meta-physeal impaction fractures The distal tibia is particularly suscepti-ble, and the vertebrae may be col-lapsed or wedged The clinician also must consider the diagnosis of leukemia in otherwise healthy chil-dren presenting with diffuse, sym-metric osteopenia and bone tender-ness, because these are common presenting signs.20 The presence of anemia, fever, or bleeding tenden-cies is suggestive of leukemia, and a peripheral blood smear helps to confirm the diagnosis
The cause of IJO is unknown;
however, several mechanisms have been theorized The reversibility of this disease at puberty suggests pre-pubertal hormone deficiency as a possible pathophysiologic mecha-nism In addition, qualitative abnor-malities in type I collagen have been observed in a subset of patients with IJO, suggesting a possible relation-ship to OI.27 Additional research likely will reveal multiple underly-ing mechanisms for IJO; currently, cases cannot be differentiated based
on their clinical characteristics alone
Supportive care is the most im-portant treatment for IJO Children and their families should be reas-sured that the symptoms will remit during puberty Physical activity should be curtailed to reduce frac-ture risk Children must be exam-ined by their physicians every 6
months to monitor pain and osseous deformity of both the spine and lower extremities Bracing may be considered for children with kypho-sis and back pain
Osteogenesis Imperfecta
OI is the most common genetic disease of the skeleton, affecting between 15,000 and 20,000 patients
in the United States Mutations in the synthesis of type I collagen lead
to reduced BMD, skeletal fragility, and chronic pain These symptoms are characteristic of this disease, which is marked by tremendous clinical heterogeneity Orthopaedic surgeons play a central role in the management of these patients be-cause osseous manifestations such
as fractures, long bone deformity, and growth retardation are com-mon Severe cases of OI are usually readily diagnosed; detailed charac-terization of the spectrum of this disorder has been the subject of pre-vious review articles The four-type classification scheme of Sillence is often used to classify OI by clinical, radiographic, and genetic factors Type I OI is the focus of this article because it is the most common phe-notype, and subtle manifestations may be overlooked
Type I OI accounts for approxi-mately 60% of all cases and is the least severe form of the disease It is transmitted as an autosomal domi-nant disorder Children with type I
OI have reduced bone volume, but because the bone is qualitatively normal, the phenotypic expression
of the disease is mild Compared to children with severe OI, children with type I OI have fewer fractures, less severe osteopenia, and little or
no skeletal deformity, although het-erogeneity exists within this pheno-type Some children with type I OI experience frequent fractures in infancy, with the rate decreasing during adolescence Others have milder disease that is not manifest until adulthood, when unexplained
Trang 6osteopenia occurs A child who
pre-sents to the emergency department
with a new fracture should be
examined for the presence of blue
sclerae because this feature is
pres-ent in almost all cases of type I OI
A family member with a history of
multiple fractures also is an
indica-tor for this diagnosis However,
almost 20% to 30% of patients have
apparently normal parents and so
may represent new mutations
Approximately 25% of patients with
type I OI have hearing impairments,
and dentinogenesis imperfecta
occurs in a subset of these patients
as well.28 Importantly, because
os-teopenia may not be profound and
skeletal deformity may be absent,
normal radiographic examination
does not rule out type I OI (Fig 2)
DEXA may aid in the diagnosis of
OI when clinical and radiographic
evidence is lacking Healthy
chil-dren who sustain three or more
low-energy fractures over a 1-year period
should have DEXA as part of the
workup for OI Children with type I
OI have been shown to have signifi-cantly reduced BMD in the femoral neck compared with age- and weight-matched healthy children.29
It has been postulated that pa-tients with OI have deficiencies in mineralization secondary to the ab-normalities in type I collagen syn-thesis Biochemical studies suggest that increased bone resorption and a reduced rate of osteogenesis also play a role.30 In support of this, bis-phosphonates, which are potent in-hibitors of bone resorption, have been found to lead to increased BMD and reduced fracture rates in children with OI.31 Although bis-phosphonates currently are not approved by the US Food and Drug Administration for use in children, their use in some children with OI and neuromuscular disorders ap-pears to be efficacious.31,32
Rickets and Osteomalacia
Rickets is a pediatric disorder characterized by deformity and growth retardation caused by defec-tive mineralization of the growth plate Osteomalacia is defective mineralization of osteoid; because osteoid is remodeled throughout life, this condition occurs in both children and adults Numerous causes of rickets and osteomalacia have been identified (Table 2); how-ever, the central theme is inadequate calcium or phosphate for normal skeletal mineralization In addition
to the pathognomonic widening of the physeal plate and cupping of the metaphysis, generalized osteopenia may be profound and demonstrable
by radiographs alone (Fig 3)
Vitamin D–dependent rickets is a continuing problem in North Am-erica.33-35 Children with dark skin pigmentation, those who have been breast-fed exclusively without addi-tional vitamin D supplementation, those who live in northern cities, those consuming a strict vegetarian diet, and those whose mothers
lacked calcium and vitamin D sup-plementation during pregnancy are particularly susceptible Other so-ciocultural factors, such as the Mus-lim custom of covering the skin, may drastically reduce the sunlight exposure required to synthesize ade-quate vitamin D.35 Highly pigmented children of Asian and African immi-grants should be evaluated carefully because the prevalence of vitamin D–dependent rickets approaches 40% in parts of these continents.36
Bowing of the lower extremities with shortening of the long bones and spinal kyphosis are the most common presenting signs in patients with vitamin D–dependent rickets; however, fractures often complicate the disease (Fig 4) Repeat clavicle fractures in infants below height and weight norms should alert the phy-sician to the possibility of rickets.37
In addition, stress fractures may be present in 20% of affected children Genetically caused rickets also is seen One example, type I vitamin D–dependent rickets, has been well characterized as a defect in the 1-alpha hydroxylase enzyme, which converts 25(OH) vitamin D to 1,25(OH)2vitamin D, the
biological-ly active form Type II vitamin
Figure 2 AP radiographs of the femur of
an 8-year-old patient with OI Osteopenia
is not obvious (A); however, this patient
had a fracture treated by intramedullary
fixation (B).
Table 2 Causes of Rickets and Osteomalacia in Children
Vitamin D deficiency Inadequate sun exposure Low dietary intake Congenital diseases Vitamin D–dependent rickets, type I
Vitamin D–dependent rickets, type II
X-linked hypophosphatemic rickets
Oncogenic osteomalacia Vitamin D metabolism abnormalities Renal failure
Phenytoin therapy
Trang 7D–dependent rickets is caused by
mutations in the vitamin D receptor
More than 10 mutations in the
vita-min D receptor have been
character-ized, all of which are manifested as
severe rickets The profound
physio-logic effects of rickets-inducing
vita-min D receptor mutations are in
sharp contrast to findings in the
studies by Morrison et al3and Sainz
et al,19 in which allelic variation at
the vitamin D receptor locus results
in only subtle phenotypic
manifes-tations of reduced BMD Further
investigation is warranted to
eluci-date more clearly the molecular
structure of the vitamin D receptor
gene and its associated regulatory
domains to explain this apparent
dichotomy
The key task for most
orthopae-dic surgeons is to identify patients
at risk for rickets and to establish
the diagnosis Orthopaedic
sur-geons should feel comfortable
initi-ating the work-up for this disease
by ordering and interpreting the
results of serum calcium, phate, vitamin D, and alkaline phos-phatase tests prior to referral to a pediatric endocrinologist Nutri-tional rickets responds in dramatic fashion to vitamin D supplementa-tion, and all exclusively breast-fed infants should receive oral supple-mentation with 400 IU of vitamin D daily and/or increased sunlight or ultraviolet light exposure For infants, exposure to 30 min of sun-light per week in the summer while wearing only a diaper, or 120 min per week while fully clothed with the head exposed, is sufficient.38
Metabolic control of this disorder is necessary before considering correc-tive osteotomy for angular
deformi-ty in these children Furthermore, prompt recognition and appropriate treatment of vitamin D deficiency enables these patients to reach their peak bone mineral status before entering adulthood
Juvenile Arthritis
Juvenile rheumatoid arthritis (JRA) is associated with poor linear growth, increased fracture rates, and reduced bone mineralization
A decrease in BMD has been dem-onstrated in almost 60% of children with juvenile chronic JRA, and limi-tation of function has been correlated with reduced BMD in these pa-tients.39 Although all skeletal sites may be involved, the appendicular skeleton appears to be more dramat-ically affected The severity of the condition is the most critical factor influencing BMD in children with JRA Although global reduction in bone turnover is apparent, reduced bone formation by osteoblasts is most likely the primary physiologic defect Prepubertal patients present-ing with chronic arthritis should be followed closely because JRA inter-rupts the normal hormonal signals that enhance skeletal mineralization during this period of development
Corticosteroid use accelerates BMD loss in children with chronic
arthritis The exact mechanisms of corticosteroid action are unknown, and therefore pharmacologic block-ade of this effect is not currently pos-sible The degree to which cortico-steroids impact bone mineralization depends both on cumulative dose and skeletal location Vertebral col-lapse is more common in children receiving a cumulative dose of at least 5 g.40 Trabecular bone in the lumbar spine is most sensitive to corticosteroids.39
Osteopenia should be suspected
in all children presenting with chronic arthritis The severity of the
Figure 3 Lateral radiograph of the knee of
a 6-year-old patient with rickets Diffuse
osteopenia is present in the metaphysis,
with widening of the physeal plate and
metaphyseal cupping.
and lower leg of a 7-year-old patient with rickets Metaphyseal cupping and widened physes can be recognized Note the patho-logic fracture in the distal tibia and fibula.
Trang 8disease and the cumulative dose of
steroids should alert the physician
to the possibility of profound
reduc-tions in BMD (Fig 5) Other factors,
such as poor calcium and vitamin D
intake and inadequate exercise, also
may exacerbate the degree of
osteo-penia Orthopaedic surgeons need
to be aware of these factors so that,
in addition to managing osseous
manifestations of the disease, they
can educate their patients and
iden-tify children in high-risk groups
Neuromuscular Disorders
Cerebral palsy and
myelomenin-gocele are the most common
neuro-muscular disorders overall and
affect approximately 0.4% of
new-borns Profound osteoporosis
devel-ops in many of these children This
loss of BMD leads to pain, additional
disability, and, ultimately, pathologic
fractures Inability to ambulate in general and prolonged immobiliza-tion after surgical procedures in particular are thought to explain much of the dramatically reduced BMD and increased risk of
patholog-ic fractures in these patients In one retrospective cohort study, fractures developed in the lower extremity in 29% of children within the 3 months following spica cast removal.41 The treatment of these fractures and as-sociated complications are costly aspects of the medical care of these patients
DEXA has enabled the identifica-tion of multiple factors that lead to defects in bone mineralization in children with cerebral palsy.42 Al-though the inability to ambulate cor-relates most strongly with low BMD, low calcium intake, nutritional sta-tus, immobilization, and pattern of
involvement are additional con-tributing factors.42 Prematurity and anticonvulsant use also may con-tribute to mineralization defects in these children An unpublished review of histomorphometric data from pediatric patients with neuro-muscular disorders at our institution revealed severe bone loss in virtually every patient (B Buch, MD, P Sponseller, MD, E McCarthy, MD, unpublished data, 1998) (Fig 6) Severe metabolic bone disease may
be obvious in severely affected pa-tients; however, orthopaedic sur-geons must be aware of this risk even in highly functioning patients
or patients in the early stages of the disease
Management of cerebral palsy and other neuromuscular disorders requires a multidisciplinary team approach with the orthopaedic sur-geon occupying a central role Lim-iting immobilization by combining surgical procedures, optimizing nu-tritional status, and maintaining cal-cium supplementation all have the potential to increase BMD during the childhood years Preliminary use
of bisphosphonates shows promise for reducing mineral loss in patients with neuromuscular disorders.32
Summary
As improved diagnostic modalities and treatment options have been developed, BMD deficiency in chil-dren has emerged as an important clinical problem Mutations in the vitamin D receptor gene have been identified that have a profound impact on bone mineral acquisition
In otherwise healthy children, these mutations result in subtle pheno-typic variations that may be mani-fested only later in life as an increased risk of
osteoporosis-relat-ed fractures Children with idio-pathic osteoporosis likely also carry mutations in the vitamin D receptor gene or some other signaling gene
Figure 5 AP radiograph of the pelvis of a 13-year-old patient with JRA Note the profound
deficiency of bone mineralization of the proximal femora as well as hip arthritis.
Trang 9critical for bone mineral deposition.
The potent hormonal effects
associ-ated with puberty, however, lead to
reversal of this condition in almost all cases On the other hand, most children with type II vitamin D–dependent rickets have clear-cut mutations in the vitamin D receptor that lead to obvious clinical and radiographic findings
DEXA has enabled investigators
to understand more clearly the determinants of peak bone mass accrual Adequate dietary intake of calcium, vitamin D, and phosphorus
is critical Most children in the United States consume inadequate amounts of calcium, especially dur-ing the most critical phases of growth Some investigators believe that this inadequate mineral intake, coincident with rapid linear bone growth, predisposes children to osteopenia and increased fracture risk during early adolescence
Public awareness of this problem is
increasing, and active participation
of parents, educators, and physi-cians is critical in improving the skeletal health of our younger popu-lation
Orthopaedic surgeons should understand the problems of osteo-penia in both otherwise healthy children and children with chronic disorders Children with neuro-muscular disorders, OI, and JRA may be severely affected, as evi-denced by repeat fractures, pain, and limitation of function In virtu-ally all of these conditions, the de-fects in bone metabolism are multi-factorial, involving inactivity, poor nutrition, and disease severity Awareness of symptoms and con-tributing factors will lead to timely diagnosis and appropriate treat-ment, ensuring the most rapid re-turn to skeletal health
Figure 6 Low-power photomicrograph of
undecalcified bone from the calcaneus of a
patient with myelomeningocele showing
severe osteopenia Trabeculae are reduced
to small, unconnected buttons (arrows)
(trichrome, original magnification × 60).
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