Page 1 of 47
Accepted Preprint first posted on 3 June 2015 as Manuscript EJE-14-0865
1
Osteoporosis in Children: Diagnosis and Management
2 3
Vrinda Saraff and Wolfgang Högler
4
Department of Endocrinology and Diabetes, Birmingham Children’s Hospital,
5
Birmingham, United Kingdom
6 7 8 9
Corresponding author:
10
PD Dr Wolfgang Högler
11
Birmingham Children’s Hospital
12
Steelhouse Lane
13
Birmingham
14
B4 6NH, United Kingdom
15
Phone: +44 121 333 8197
16
Fax: ++44 121 333 8191
17
Email: [email protected]
18 19 20
Keywords: Osteoporosis, Bisphosphonates, Dual Energy Absorptiometry,
21
Osteogenesis Imperfecta, Fractures.
22
1
Copyright © 2015 European Society of Endocrinology.
Page 2 of 47
23
Abstract
24 25
Osteoporosis in children can be primary or secondary due to chronic disease.
26
Awareness among paediatricians is vital to identify patients at risk of developing
27
osteoporosis. Previous fractures and backache are clinical predictors, and low
28
cortical thickness and low bone density are radiological predictors of fractures.
29
Osteogenesis Imperfecta (OI) is a rare disease and should be managed in tertiary
30
paediatric units with the necessary multidisciplinary expertise. Modern OI
31
management focuses on functional outcomes rather than just improving bone
32
mineral density. Whilst therapy for OI has improved tremendously over the last
33
few decades, this chronic genetic condition has some unpreventable, poorly
34
treatable and disabling complications.
35
In children at risk of secondary osteoporosis, a high degree of suspicion needs to
36
be exercised. In affected children, further weakening of bone should be avoided
37
by minimising exposure to osteotoxic medication and optimising nutrition
38
including calcium and vitamin D. Early intervention is paramount. However, it is
39
important to identify patient groups in whom spontaneous vertebral reshaping
40
and resolution of symptoms occur in order to avoid unnecessary treatment.
41
Bisphosphonate therapy remains the pharmacological treatment of choice in
42
both primary and secondary osteoporosis in children, despite limited evidence
43
for its use in the latter. The duration and intensity of treatment remain a concern
44
for long-term safety. Various new potent antiresorptive agents are being studied,
45
but more urgently required are studies using anabolic medications that stimulate
46
bone formation. More research is required to bridge the gaps in the evidence for
47
management of paediatric osteoporosis.
2
Page 3 of 47
48
Introduction
49 50
The skeletal system provides a frame to protect internal organs and aid
51
movement. Bone is a dynamic tissue comprising mostly of type I collagen fibers
52
packed with hydroxyapatite crystals that ensures resistance to fracture through
53
an optimal balance of flexibility and stiffness. A child’s bone undergoes constant
54
bone growth at the epiphyseal growth plates and modeling (bone formation and
55
shaping). In addition, the process of remodeling replaces old bone with new bone
56
and is a lifelong process. Remodeling occurs by a unique cooperation of
57
osteoclasts resulting in bone resorption and osteoblasts subsequently replacing
58
this with unmineralised osteoid, that is later mineralised.1 Bone is also unique in
59
adapting modeling based on exposure to mechanical forces. Osteocytes play a
60
central role in sensing biomechanical strains, and activating signaling through
61
sclerostin, an inhibitor of the WNT signaling pathway, the RANK- RANKL system
62
and other poorly understood mechanisms that regulate bone resorption and
63
formation.2, 3 Osteocytes secrete hormones such as osteocalcin and FGF23, with
64
the latter involved in maintaining phosphate homeostasis.
65 66
Osteoporosis is characterized by low bone mass and microarchitectural
67
deterioration of bone structure resulting in increased bone fragility. According to
68
the revised paediatric position papers by the International Society for Clinical
69
Densitometry (ISCD), the diagnosis of osteoporosis in children can be made in
70
the presence of 1) combination of size corrected low bone mineral density
71
(BMD) of more than 2 SD below the mean and a significant history of low trauma
72
fractures, arbitrarily defined as the presence of either two or more long bone
3
Page 4 of 47
73
fractures by the age of 10 years or three or more long bone fractures at any age,
74
up to the age of 19 years or 2) or one or more vertebral fractures (VF), in the
75
absence of high energy trauma or local disease, independent of BMD.4
76 77
Clinical signs and risk factors for osteoporosis in children
78 79
Children with symptomatic osteoporosis typically present with a history of
80
recurrent low impact fractures or moderate to severe backache. Asymptomatic
81
osteoporosis is increasingly being detected through surveillance for VFs in at
82
risk children, such as those on high dose glucocorticoid (GC) therapy, or through
83
incidental osteopenia found on X-ray. While primary osteoporosis mainly occurs
84
in an otherwise healthy child due to an underlying genetic condition, with a
85
typical family history, secondary osteoporosis occurs as a result of chronic illness
86
or its treatment.
87
Risk factors for fractures in an otherwise healthy child include age, gender,
88
previous fractures, 5 genetic predisposition, poor nutrition, total body mass 6,
89
vigorous physical activity 7 and equally lack of physical activity.8
90 91
Diagnostic tools
92 93
Every child referred for bone assessment deserves routine measurement of bone
94
metabolism including serum alkaline phosphatase, calcium, phosphate, vitamin
95
D, and urinary bone mineral excretion, as a minimum, in addition to a detailed
96
history of growth and nutrition. Measurement of bone turnover markers is
4
Page 5 of 47
97
reserved for specific cases and research.9 Here, we describe the specific tools
98
that are useful in the diagnosis of osteoporosis.
99 100
1. Assessment of Bone Mass and Structure
101
Dual energy X-ray Absorptiometry (DXA) remains the technique of choice to
102
measure bone mass as it is highly reproducible, commonly available, relatively
103
inexpensive and has low radiation exposure. Lumbar spine and total body less
104
head are the preferred sites for measuring bone mineral content (BMC, in grams)
105
or areal BMD (in grams/cm2) in children.10 BMD values for children are
106
expressed as age- and sex-specific standard deviation scores (Z-scores) but also
107
depend on body size, ethnicity, pubertal staging, and skeletal maturity. As a
108
result of DXA’s two-dimensional measurement, BMD can be grossly
109
underestimated in children with short stature.11, 12 Hence in children with short
110
stature, BMD requires adjustment for height or bone volume such as bone
111
mineral apparent density (BMAD, in g/cm3) to avoid gross overestimation of
112
osteoporosis 13. BMAD is the most accurate method to predict VFs.14 Despite its
113
pitfalls, DXA is recommended as a monitoring tool in children with chronic
114
disease, who are at a risk of developing osteoporosis and those already on
115
treatment to guide future management.15 An alternate technique used in children
116
with spinal deformity or contractures is the lateral femur DXA scan.16 A large
117
cross sectional study demonstrated an association of increased fracture risk (6-
118
15%) with every 1 SD reduction in distal femur BMD.17
119 120
VFs in children can present with backache but are often asymptomatic. They are
121
a significant cause of morbidity and an indicator of future incident VFs in
5
Page 6 of 47
122
children 18, 19 and adults.20 Children also have the unique ability of bone
123
reshaping due to their growth potential. Given their importance in the diagnosis
124
of osteoporosis, and that they can be asymptomatic and go undetected,
125
assessment of vertebral morphometry is essential. Lateral Spine X-ray currently
126
is the most commonly used imaging technique to evaluate VFs in children but
127
radiation exposure is high. The Genant semiquantitative method is a technique
128
used to grade VF in adults21, with good reproducibility in children.22 The newest
129
generation of DXA scanners allows Vertebral Fracture Assessment (VFA)
130
performed on lateral scanning. Although radiation dose vary with different scan
131
modes, in comparison to spine X-rays,23 it only uses a fraction (approx.1%) of
132
radiation exposure and compares with the daily dose of natural background
133
radiation.24 Although VFA may not have the spatial resolution of lateral spine X-
134
rays and paediatric VFA on older Hologic models was not satisfactory,25 the
135
image quality on the new Lunar iDXA scanner appears promising (Figure 1).
136
Validation studies for VF detection in children using this technique are
137
underway.
138
139
Quantitative computed tomography (QCT) and peripheral QCT (pQCT) have the
140
advantage of measuring cortical geometry and volumetric densities of both
141
trabecular and cortical bone, thus providing information not attainable on DXA.
142
Using pQCT in children with cerebral palsy demonstrated smaller and thinner
143
bones rather than lower cortical BMD.26 pQCT also identified that cortical
144
thickness, and not density is the main bone variable affected by growth hormone
145
deficiency and treatment.27 Reproducibility and positioning remain a problem
146
with pQCT. It is specifically useful for children with spinal deformities,
6
Page 7 of 47
147
contractures or metallic implants where DXA imaging can prove challenging. The
148
newest technique is high-resolution peripheral QCT, which has the spatial
149
resolution to measure trabecular geometry and microarchitectural changes
150
resulting from treatment. However it is expensive, limited to imaging extremities
151
and currently mainly used for research purposes.28
152
Another method used to measure peripheral bone geometry and density is
153
digital X-ray radiogrammetry, which estimates BMD by hand radiographs in
154
children. 29 However, this technique, as well as quantitative ultrasound and
155
magnetic resonance imaging, are less commonly used in clinical practice since
156
validation studies establishing their association with VF or non-VF are missing.
157
158
Trans-iliac bone biopsy with tetracycline labeling provides the ultimate, invasive,
159
diagnostic information on bone material properties, bone formation and
160
resorption activities as well as histomorphometry. Biopsies are useful in
161
establishing the diagnosis and defining bone tissue characteristics and metabolic
162
activity in some cases such as Idiopathic Juvenile Osteoporosis (IJO).30, 31
163
However it is used infrequently as a treatment monitoring tool in children since
164
it requires general anaesthesia, and response to therapy, in most cases, can be
165
adequately assessed using imaging or fracture history. As such, biopsies are
166
limited to highly specialist centers and research.
167 168
2. Mobility, muscle and functional tests
169
Increasing emphasis is being placed on improving functional outcomes, muscle
170
strength and mobility in children with osteoporosis. There are various functional
171
tests used, for example the 6-minute walk test (6MWT) 32, Bruininks Oseretsky
7
Page 8 of 47
172
Test of Motor Proficiency (BOT-2) 33, gross-motor function measure (GMFM) 34,
173
Childhood Health Assessment Questionnaire (CHAQ) score 35, and the widely
174
used faces pain scale. 36 Specific muscle force and power tests include the chair-
175
rise test, mechanography (legs) 37, 38 and grip force testing by dynamometry 39
176
amongst others. Since these tests measure different functional variables,
177
selection depends on disease-specific or case-specific deficits and protocols need
178
to be established.
179 180
Primary Osteoporosis
181 182
Primary osteoporosis occurs due to an intrinsic skeletal defect of genetic or
183
idiopathic origin. Osteogenesis Imperfecta (OI) is the most common condition,
184
with an incidence of 1 in 25,000 births 40, equally affecting both sexes. Recent
185
genetic advances have identified many new subtypes of this condition that is
186
caused by quantitative or qualitative type I collagen defects, with various new
187
classification attempts.41-43 The original classification by Sillence 44 is still used
188
on a clinical basis, as it categorizes the severity of the condition in the individual
189
child quite well, into Type I (mild), IV (moderate), II (lethal) and III (severe).
190
Whilst Type I patients have an increased fracture rate but deformity or final
191
height reduction is uncommon, more severe perinatal forms (Type III) present
192
with multiple intrauterine fractures that heal with residual bony deformity
193
leading to significant disability. The most severe form (Type II) is not compatible
194
with life due to pulmonary hypoplasia. Children with OI can have both skeletal as
195
well as extra-skeletal manifestations such as blue sclera, hypermobility,
196
abnormalities of the cranio-cervical junction including basilar invagination, flat
8
Page 9 of 47
197
feet, dentinogenesis imperfecta and hearing loss. Diagnosis of OI is primarily
198
based on clinical and radiological findings. Typical X ray findings include VFs,
199
scoliosis, deformities and low bone mass, confirmed by low BMD on DXA.
200
Material bone density on biopsy in OI is however high 45 and the low BMD on
201
DXA is only a reflection of the deficit in bone volume and mass (low tissue
202
density), rather than a problem with bone mineralization . Genetic confirmation
203
of the condition is not routinely sought when there is a typical family history of
204
autosomal dominant inheritance 46, as genetic confirmation remains expensive
205
and currently would not change medical management.
206 207
Recent advances in genetics have identified a number of gene defects causing
208
early onset osteoporosis. Mutations in PLS3, which encodes plastin 3, a bone
209
regulatory protein, were reported in five families with early onset X-linked
210
osteoporosis with axial and appendicular fractures developing during childhood.
211
Although the exact mechanism remains unknown, osteoporosis is proposed to
212
occur secondary to defects in mechanosensing in the osteocytes, resulting in
213
effects on bone remodeling.47
214
Other forms of early-onset osteoporosis involve the WNT signaling pathway,
215
which is essential for normal skeletal homeostasis by inducing osteoblast
216
proliferation and differentiation. Defects in this complex signaling pathway
217
predominantly affect bone formation.48 Low-density lipoprotein receptor-related
218
protein 5 (LRP5), a coreceptor of WNT located on the osteoblast membrane is
219
the most widely studied. Biallelic mutations in LRP5 cause osteoporosis-
220
pseudoglioma syndrome (OPPG), a very rare condition characterized by
221
generalized osteoporosis and ocular involvement.49 Heterozygous LRP5
9
Page 10 of 47
222
mutations cause early onset osteoporosis.50 More recently, WNT1 mutations,
223
which affect canonical WNT signaling, have been identified to cause early onset
224
osteoporosis in the heterozygous state and OI in the biallelic state. 51 Several
225
other components of the WNT signaling pathway 49, including LGR4 52 and
226
WNT16 53 have also been associated with osteoporosis.
227
With the discovery of these new genetic conditions, explaining many more cases
228
of primary osteoporosis previously labeled as IJO, this diagnosis is becoming
229
increasingly rare. IJO affects both sexes equally 54, typically presents before
230
puberty with difficulty in walking, back pain and VFs. Decreased BMD, especially
231
in the spine, is associated with evidence of reduced bone turnover on bone
232
histomorphometry.55 Although spontaneous resolution of symptoms occurs in
233
most children, only partial resolution of lumbar spine BMD was recorded.56
234
Some other rare genetic conditions (non-OI, non-WNT) associated with primary
235
osteoporosis include Cleidocranial dysplasia, Marfan, Ehlers Danlos and Hadju-
236
Cheney syndrome (HCS). HCS occurs due to NOTCH2 mutations that impair the
237
NOTCH signaling, which is required in the differentiation and functioning of
238
osteoblasts and osteoclasts.57 Due to rapid advances in genetics, even the most
239
recent list of osteoporotic conditions will never be exhaustive.
240 241
Secondary Osteoporosis
242 243
Secondary osteoporosis ensues chronic systemic illnesses in children either due
244
to the effects of the disease process on the skeleton or their treatment. With
245
advances in medical knowledge leading to improved survival rates and long term
246
outcomes, complications such as secondary osteoporosis are on the rise in these
10
Page 11 of 47
247
children. The most important causes for secondary osteoporosis are immobility,
248
leukaemia, inflammatory conditions, GC therapy, hypogonadism and poor
249
nutrition.
250 251
In contrast to extremity bones, vertebrae contain a higher proportion of
252
trabecular bone, which is more metabolically active than cortical bone and thus
253
more exposed to the osteotoxic effect of drugs such as GC. Not all vertebrae are
254
equally vulnerable, with most fractures in children located in the upper thoracic
255
(T6/7) and lumbar spine (L1/2).58 (Figure 2)
256
257
Immobility induced osteoporosis
258
According to the mechanostat concept 59, mechanical factors such as muscle
259
force regulate bone mass and shape. Disruption in this equilibrium due to lack of
260
physical activity affects the integrity of the muscle bone unit. Conditions
261
associated with immobility demonstrate why the mechanostat concept is
262
superior to the peak bone mass concept.60 Complete spinal cord transection not
263
only leads to severe sudden immobility but also massive bone loss in the first
264
years following the insult and bone mass reaches a much lower steady state by 3-
265
8 years post trauma.61 Similarly, osteoporosis in children with cerebral palsy is a
266
result of chronic immobility, sometimes exaggerated by poor nutrition
267
secondary to feeding difficulties. The risk of fracture in these children is reported
268
to be between 4-12 %.62 The lack of muscle pull leads to reduced periosteal
269
apposition in lower extremity bones, resulting in reduced cortical thickness.26
270
Therefore, in children and adults with prolonged immobility, fractures
11
Page 12 of 47
271
commonly occur in the distal femur and proximal tibia following minimal
272
trauma, further impairing mobility and worsening the quality of life.63
273 274
Neuromuscular conditions like Duchenne Muscular Dystrophy (DMD) and spinal
275
atrophy are associated with progressive skeletal muscle weakness leading to
276
progressive immobility. Again, the decreasing muscle forces weaken bones,
277
which sense and respond to the lower biomechanical stress (lower set-point).
278
GC therapy, used to improve quality of life and ambulation in DMD, exerts
279
additional skeletal toxicity. Studies have shown reduced height- adjusted BMD z
280
scores and long bone fracture prevalence of 20-44% 64, 65 prior to starting GC and
281
an increased VF prevalence of 19-32% following GC exposure. 64, 66, 67 Although
282
no difference in long bone fractures was noted during GC therapy, a significant
283
decline in BMD occurred as they lost their ability to walk.67 (Figure 3)
284
285
Leukaemia
286
Acute Lymphocytic Leukaemia (ALL), the most common paediatric malignancy is
287
associated with an increased risk of fracture both at diagnosis, as well as first few
288
years following diagnosis.68 The Canadian STOPP study prospectively studies GC
289
treated conditions and reported a VF prevalence of 16% in children with ALL at
290
diagnosis, 69 with another 16% of new VFs following 12 months of ALL
291
treatment.18 BMD correlated well with VFs, with an 80% increase in VF risk with
292
every 1 SD reduction in lumbar spine (LS) BMD. Presence of VFs at diagnosis and
293
baseline LS BMD z scores were good predictors of VFs at 12 months. 18 Similarly,
294
patients with fractures during the first 3 years after diagnosis had lower LS BMD
295
at diagnosis than those without fractures. 70 The cause of secondary osteoporosis
12
Page 13 of 47
296
in ALL is believed to be the disease itself at start, by increasing bone resorption
297
via osteoclast-activating cytokines, followed by treatment with osteotoxic drugs
298
such as GC and methotrexate.18 Some studies have suggested older age 70 and
299
type of GC used 71 as predictors of skeletal morbidity, while the others have not
300
18.
301
demonstrate skeletal recovery either spontaneously or through BP therapy
302
related vertebral reshaping,72 especially in those with growth potential, also
303
improvement in trabecular and cortical BMD as measured by pQCT.73
Most survivors of childhood leukaemia unlike other chronic illnesses,
304
305
Chronic inflammatory conditions and GC therapy
306
Steroid-induced osteoporosis summarizes a variety of conditions where GCs are
307
commonly blamed for bone loss and fragility. GCs are widely used in the
308
management of chronic inflammatory childhood illnesses such as rheumatoid
309
disorders and Crohn’s disease. Use of GC has led to improved outcomes and
310
survival rates, however at the cost of substantial adverse effects such as
311
osteoporosis, obesity and diabetes 74. Studies have shown a 7-34% prevalence of
312
VFs in children with rheumatic disorders treated with GCs 19. Similar to their ALL
313
cohort, the STOPP study consortium found that the rheumatic disease process
314
itself had led to a 7% prevalence of VF at diagnosis,75 with another 6% of
315
patients developing new VFs in the first 12 months, likely secondary to GC
316
exposure. VFs were associated with greater weight gain, more significant
317
reduction in LS BMD and higher GC exposure.19
318
Questions arise whether cytokines are the main culprit in causing secondary
319
osteoporosis rather than GC alone. Infliximab, a chimeric monoclonal antibody
320
used in the treatment of chronic inflammatory conditions such as inflammatory
13
Page 14 of 47
321
bowel disease and rheumatic disorders has shown improvements in BMD 76 and
322
bone resorption 77 by suppressing TNF α mediated inflammation.
323
GC therapy is also used in nephrotic syndrome, yet this condition comes without
324
elevated inflammatory cytokines and thus is regarded as a model to study true
325
GC effects on bone. At diagnosis, 8% of children had anterior vertebral wedging,
326
78
327
patients developed incident VF, which mostly constituted mild vertebral
328
deformities and were asymptomatic in nature.79 The lower prevalence of bone
329
pathology in nephrotic syndrome compared to other GC treated conditions
330
suggests that cytokines may be the main cause of fractures in inflammatory
331
conditions, as they activate osteoclasts through the RANKL-OPG system.
and normal BMD.16 12 months following initiation of GC treatment, 6% of
332
333
Poor nutrition, female hypogonadism and anorexia nervosa
334
Anorexia Nervosa (AN) leads to underweight and a relative state of
335
hypogonadotrophic hypogonadism. AN is also characterized by reduced bone
336
mass leading to an increased risk of fractures with a reported incidence of at
337
least one fracture in 50% of the girls with more severe trabecular, rather than
338
cortical, bone loss.80 Faje et al 81 demonstrated a fracture prevalence of 31% in
339
adolescent girls with AN despite relatively normal BMAD (z scores of
Accepted Preprint first posted on 3 June 2015 as Manuscript EJE-14-0865
1
Osteoporosis in Children: Diagnosis and Management
2 3
Vrinda Saraff and Wolfgang Högler
4
Department of Endocrinology and Diabetes, Birmingham Children’s Hospital,
5
Birmingham, United Kingdom
6 7 8 9
Corresponding author:
10
PD Dr Wolfgang Högler
11
Birmingham Children’s Hospital
12
Steelhouse Lane
13
Birmingham
14
B4 6NH, United Kingdom
15
Phone: +44 121 333 8197
16
Fax: ++44 121 333 8191
17
Email: [email protected]
18 19 20
Keywords: Osteoporosis, Bisphosphonates, Dual Energy Absorptiometry,
21
Osteogenesis Imperfecta, Fractures.
22
1
Copyright © 2015 European Society of Endocrinology.
Page 2 of 47
23
Abstract
24 25
Osteoporosis in children can be primary or secondary due to chronic disease.
26
Awareness among paediatricians is vital to identify patients at risk of developing
27
osteoporosis. Previous fractures and backache are clinical predictors, and low
28
cortical thickness and low bone density are radiological predictors of fractures.
29
Osteogenesis Imperfecta (OI) is a rare disease and should be managed in tertiary
30
paediatric units with the necessary multidisciplinary expertise. Modern OI
31
management focuses on functional outcomes rather than just improving bone
32
mineral density. Whilst therapy for OI has improved tremendously over the last
33
few decades, this chronic genetic condition has some unpreventable, poorly
34
treatable and disabling complications.
35
In children at risk of secondary osteoporosis, a high degree of suspicion needs to
36
be exercised. In affected children, further weakening of bone should be avoided
37
by minimising exposure to osteotoxic medication and optimising nutrition
38
including calcium and vitamin D. Early intervention is paramount. However, it is
39
important to identify patient groups in whom spontaneous vertebral reshaping
40
and resolution of symptoms occur in order to avoid unnecessary treatment.
41
Bisphosphonate therapy remains the pharmacological treatment of choice in
42
both primary and secondary osteoporosis in children, despite limited evidence
43
for its use in the latter. The duration and intensity of treatment remain a concern
44
for long-term safety. Various new potent antiresorptive agents are being studied,
45
but more urgently required are studies using anabolic medications that stimulate
46
bone formation. More research is required to bridge the gaps in the evidence for
47
management of paediatric osteoporosis.
2
Page 3 of 47
48
Introduction
49 50
The skeletal system provides a frame to protect internal organs and aid
51
movement. Bone is a dynamic tissue comprising mostly of type I collagen fibers
52
packed with hydroxyapatite crystals that ensures resistance to fracture through
53
an optimal balance of flexibility and stiffness. A child’s bone undergoes constant
54
bone growth at the epiphyseal growth plates and modeling (bone formation and
55
shaping). In addition, the process of remodeling replaces old bone with new bone
56
and is a lifelong process. Remodeling occurs by a unique cooperation of
57
osteoclasts resulting in bone resorption and osteoblasts subsequently replacing
58
this with unmineralised osteoid, that is later mineralised.1 Bone is also unique in
59
adapting modeling based on exposure to mechanical forces. Osteocytes play a
60
central role in sensing biomechanical strains, and activating signaling through
61
sclerostin, an inhibitor of the WNT signaling pathway, the RANK- RANKL system
62
and other poorly understood mechanisms that regulate bone resorption and
63
formation.2, 3 Osteocytes secrete hormones such as osteocalcin and FGF23, with
64
the latter involved in maintaining phosphate homeostasis.
65 66
Osteoporosis is characterized by low bone mass and microarchitectural
67
deterioration of bone structure resulting in increased bone fragility. According to
68
the revised paediatric position papers by the International Society for Clinical
69
Densitometry (ISCD), the diagnosis of osteoporosis in children can be made in
70
the presence of 1) combination of size corrected low bone mineral density
71
(BMD) of more than 2 SD below the mean and a significant history of low trauma
72
fractures, arbitrarily defined as the presence of either two or more long bone
3
Page 4 of 47
73
fractures by the age of 10 years or three or more long bone fractures at any age,
74
up to the age of 19 years or 2) or one or more vertebral fractures (VF), in the
75
absence of high energy trauma or local disease, independent of BMD.4
76 77
Clinical signs and risk factors for osteoporosis in children
78 79
Children with symptomatic osteoporosis typically present with a history of
80
recurrent low impact fractures or moderate to severe backache. Asymptomatic
81
osteoporosis is increasingly being detected through surveillance for VFs in at
82
risk children, such as those on high dose glucocorticoid (GC) therapy, or through
83
incidental osteopenia found on X-ray. While primary osteoporosis mainly occurs
84
in an otherwise healthy child due to an underlying genetic condition, with a
85
typical family history, secondary osteoporosis occurs as a result of chronic illness
86
or its treatment.
87
Risk factors for fractures in an otherwise healthy child include age, gender,
88
previous fractures, 5 genetic predisposition, poor nutrition, total body mass 6,
89
vigorous physical activity 7 and equally lack of physical activity.8
90 91
Diagnostic tools
92 93
Every child referred for bone assessment deserves routine measurement of bone
94
metabolism including serum alkaline phosphatase, calcium, phosphate, vitamin
95
D, and urinary bone mineral excretion, as a minimum, in addition to a detailed
96
history of growth and nutrition. Measurement of bone turnover markers is
4
Page 5 of 47
97
reserved for specific cases and research.9 Here, we describe the specific tools
98
that are useful in the diagnosis of osteoporosis.
99 100
1. Assessment of Bone Mass and Structure
101
Dual energy X-ray Absorptiometry (DXA) remains the technique of choice to
102
measure bone mass as it is highly reproducible, commonly available, relatively
103
inexpensive and has low radiation exposure. Lumbar spine and total body less
104
head are the preferred sites for measuring bone mineral content (BMC, in grams)
105
or areal BMD (in grams/cm2) in children.10 BMD values for children are
106
expressed as age- and sex-specific standard deviation scores (Z-scores) but also
107
depend on body size, ethnicity, pubertal staging, and skeletal maturity. As a
108
result of DXA’s two-dimensional measurement, BMD can be grossly
109
underestimated in children with short stature.11, 12 Hence in children with short
110
stature, BMD requires adjustment for height or bone volume such as bone
111
mineral apparent density (BMAD, in g/cm3) to avoid gross overestimation of
112
osteoporosis 13. BMAD is the most accurate method to predict VFs.14 Despite its
113
pitfalls, DXA is recommended as a monitoring tool in children with chronic
114
disease, who are at a risk of developing osteoporosis and those already on
115
treatment to guide future management.15 An alternate technique used in children
116
with spinal deformity or contractures is the lateral femur DXA scan.16 A large
117
cross sectional study demonstrated an association of increased fracture risk (6-
118
15%) with every 1 SD reduction in distal femur BMD.17
119 120
VFs in children can present with backache but are often asymptomatic. They are
121
a significant cause of morbidity and an indicator of future incident VFs in
5
Page 6 of 47
122
children 18, 19 and adults.20 Children also have the unique ability of bone
123
reshaping due to their growth potential. Given their importance in the diagnosis
124
of osteoporosis, and that they can be asymptomatic and go undetected,
125
assessment of vertebral morphometry is essential. Lateral Spine X-ray currently
126
is the most commonly used imaging technique to evaluate VFs in children but
127
radiation exposure is high. The Genant semiquantitative method is a technique
128
used to grade VF in adults21, with good reproducibility in children.22 The newest
129
generation of DXA scanners allows Vertebral Fracture Assessment (VFA)
130
performed on lateral scanning. Although radiation dose vary with different scan
131
modes, in comparison to spine X-rays,23 it only uses a fraction (approx.1%) of
132
radiation exposure and compares with the daily dose of natural background
133
radiation.24 Although VFA may not have the spatial resolution of lateral spine X-
134
rays and paediatric VFA on older Hologic models was not satisfactory,25 the
135
image quality on the new Lunar iDXA scanner appears promising (Figure 1).
136
Validation studies for VF detection in children using this technique are
137
underway.
138
139
Quantitative computed tomography (QCT) and peripheral QCT (pQCT) have the
140
advantage of measuring cortical geometry and volumetric densities of both
141
trabecular and cortical bone, thus providing information not attainable on DXA.
142
Using pQCT in children with cerebral palsy demonstrated smaller and thinner
143
bones rather than lower cortical BMD.26 pQCT also identified that cortical
144
thickness, and not density is the main bone variable affected by growth hormone
145
deficiency and treatment.27 Reproducibility and positioning remain a problem
146
with pQCT. It is specifically useful for children with spinal deformities,
6
Page 7 of 47
147
contractures or metallic implants where DXA imaging can prove challenging. The
148
newest technique is high-resolution peripheral QCT, which has the spatial
149
resolution to measure trabecular geometry and microarchitectural changes
150
resulting from treatment. However it is expensive, limited to imaging extremities
151
and currently mainly used for research purposes.28
152
Another method used to measure peripheral bone geometry and density is
153
digital X-ray radiogrammetry, which estimates BMD by hand radiographs in
154
children. 29 However, this technique, as well as quantitative ultrasound and
155
magnetic resonance imaging, are less commonly used in clinical practice since
156
validation studies establishing their association with VF or non-VF are missing.
157
158
Trans-iliac bone biopsy with tetracycline labeling provides the ultimate, invasive,
159
diagnostic information on bone material properties, bone formation and
160
resorption activities as well as histomorphometry. Biopsies are useful in
161
establishing the diagnosis and defining bone tissue characteristics and metabolic
162
activity in some cases such as Idiopathic Juvenile Osteoporosis (IJO).30, 31
163
However it is used infrequently as a treatment monitoring tool in children since
164
it requires general anaesthesia, and response to therapy, in most cases, can be
165
adequately assessed using imaging or fracture history. As such, biopsies are
166
limited to highly specialist centers and research.
167 168
2. Mobility, muscle and functional tests
169
Increasing emphasis is being placed on improving functional outcomes, muscle
170
strength and mobility in children with osteoporosis. There are various functional
171
tests used, for example the 6-minute walk test (6MWT) 32, Bruininks Oseretsky
7
Page 8 of 47
172
Test of Motor Proficiency (BOT-2) 33, gross-motor function measure (GMFM) 34,
173
Childhood Health Assessment Questionnaire (CHAQ) score 35, and the widely
174
used faces pain scale. 36 Specific muscle force and power tests include the chair-
175
rise test, mechanography (legs) 37, 38 and grip force testing by dynamometry 39
176
amongst others. Since these tests measure different functional variables,
177
selection depends on disease-specific or case-specific deficits and protocols need
178
to be established.
179 180
Primary Osteoporosis
181 182
Primary osteoporosis occurs due to an intrinsic skeletal defect of genetic or
183
idiopathic origin. Osteogenesis Imperfecta (OI) is the most common condition,
184
with an incidence of 1 in 25,000 births 40, equally affecting both sexes. Recent
185
genetic advances have identified many new subtypes of this condition that is
186
caused by quantitative or qualitative type I collagen defects, with various new
187
classification attempts.41-43 The original classification by Sillence 44 is still used
188
on a clinical basis, as it categorizes the severity of the condition in the individual
189
child quite well, into Type I (mild), IV (moderate), II (lethal) and III (severe).
190
Whilst Type I patients have an increased fracture rate but deformity or final
191
height reduction is uncommon, more severe perinatal forms (Type III) present
192
with multiple intrauterine fractures that heal with residual bony deformity
193
leading to significant disability. The most severe form (Type II) is not compatible
194
with life due to pulmonary hypoplasia. Children with OI can have both skeletal as
195
well as extra-skeletal manifestations such as blue sclera, hypermobility,
196
abnormalities of the cranio-cervical junction including basilar invagination, flat
8
Page 9 of 47
197
feet, dentinogenesis imperfecta and hearing loss. Diagnosis of OI is primarily
198
based on clinical and radiological findings. Typical X ray findings include VFs,
199
scoliosis, deformities and low bone mass, confirmed by low BMD on DXA.
200
Material bone density on biopsy in OI is however high 45 and the low BMD on
201
DXA is only a reflection of the deficit in bone volume and mass (low tissue
202
density), rather than a problem with bone mineralization . Genetic confirmation
203
of the condition is not routinely sought when there is a typical family history of
204
autosomal dominant inheritance 46, as genetic confirmation remains expensive
205
and currently would not change medical management.
206 207
Recent advances in genetics have identified a number of gene defects causing
208
early onset osteoporosis. Mutations in PLS3, which encodes plastin 3, a bone
209
regulatory protein, were reported in five families with early onset X-linked
210
osteoporosis with axial and appendicular fractures developing during childhood.
211
Although the exact mechanism remains unknown, osteoporosis is proposed to
212
occur secondary to defects in mechanosensing in the osteocytes, resulting in
213
effects on bone remodeling.47
214
Other forms of early-onset osteoporosis involve the WNT signaling pathway,
215
which is essential for normal skeletal homeostasis by inducing osteoblast
216
proliferation and differentiation. Defects in this complex signaling pathway
217
predominantly affect bone formation.48 Low-density lipoprotein receptor-related
218
protein 5 (LRP5), a coreceptor of WNT located on the osteoblast membrane is
219
the most widely studied. Biallelic mutations in LRP5 cause osteoporosis-
220
pseudoglioma syndrome (OPPG), a very rare condition characterized by
221
generalized osteoporosis and ocular involvement.49 Heterozygous LRP5
9
Page 10 of 47
222
mutations cause early onset osteoporosis.50 More recently, WNT1 mutations,
223
which affect canonical WNT signaling, have been identified to cause early onset
224
osteoporosis in the heterozygous state and OI in the biallelic state. 51 Several
225
other components of the WNT signaling pathway 49, including LGR4 52 and
226
WNT16 53 have also been associated with osteoporosis.
227
With the discovery of these new genetic conditions, explaining many more cases
228
of primary osteoporosis previously labeled as IJO, this diagnosis is becoming
229
increasingly rare. IJO affects both sexes equally 54, typically presents before
230
puberty with difficulty in walking, back pain and VFs. Decreased BMD, especially
231
in the spine, is associated with evidence of reduced bone turnover on bone
232
histomorphometry.55 Although spontaneous resolution of symptoms occurs in
233
most children, only partial resolution of lumbar spine BMD was recorded.56
234
Some other rare genetic conditions (non-OI, non-WNT) associated with primary
235
osteoporosis include Cleidocranial dysplasia, Marfan, Ehlers Danlos and Hadju-
236
Cheney syndrome (HCS). HCS occurs due to NOTCH2 mutations that impair the
237
NOTCH signaling, which is required in the differentiation and functioning of
238
osteoblasts and osteoclasts.57 Due to rapid advances in genetics, even the most
239
recent list of osteoporotic conditions will never be exhaustive.
240 241
Secondary Osteoporosis
242 243
Secondary osteoporosis ensues chronic systemic illnesses in children either due
244
to the effects of the disease process on the skeleton or their treatment. With
245
advances in medical knowledge leading to improved survival rates and long term
246
outcomes, complications such as secondary osteoporosis are on the rise in these
10
Page 11 of 47
247
children. The most important causes for secondary osteoporosis are immobility,
248
leukaemia, inflammatory conditions, GC therapy, hypogonadism and poor
249
nutrition.
250 251
In contrast to extremity bones, vertebrae contain a higher proportion of
252
trabecular bone, which is more metabolically active than cortical bone and thus
253
more exposed to the osteotoxic effect of drugs such as GC. Not all vertebrae are
254
equally vulnerable, with most fractures in children located in the upper thoracic
255
(T6/7) and lumbar spine (L1/2).58 (Figure 2)
256
257
Immobility induced osteoporosis
258
According to the mechanostat concept 59, mechanical factors such as muscle
259
force regulate bone mass and shape. Disruption in this equilibrium due to lack of
260
physical activity affects the integrity of the muscle bone unit. Conditions
261
associated with immobility demonstrate why the mechanostat concept is
262
superior to the peak bone mass concept.60 Complete spinal cord transection not
263
only leads to severe sudden immobility but also massive bone loss in the first
264
years following the insult and bone mass reaches a much lower steady state by 3-
265
8 years post trauma.61 Similarly, osteoporosis in children with cerebral palsy is a
266
result of chronic immobility, sometimes exaggerated by poor nutrition
267
secondary to feeding difficulties. The risk of fracture in these children is reported
268
to be between 4-12 %.62 The lack of muscle pull leads to reduced periosteal
269
apposition in lower extremity bones, resulting in reduced cortical thickness.26
270
Therefore, in children and adults with prolonged immobility, fractures
11
Page 12 of 47
271
commonly occur in the distal femur and proximal tibia following minimal
272
trauma, further impairing mobility and worsening the quality of life.63
273 274
Neuromuscular conditions like Duchenne Muscular Dystrophy (DMD) and spinal
275
atrophy are associated with progressive skeletal muscle weakness leading to
276
progressive immobility. Again, the decreasing muscle forces weaken bones,
277
which sense and respond to the lower biomechanical stress (lower set-point).
278
GC therapy, used to improve quality of life and ambulation in DMD, exerts
279
additional skeletal toxicity. Studies have shown reduced height- adjusted BMD z
280
scores and long bone fracture prevalence of 20-44% 64, 65 prior to starting GC and
281
an increased VF prevalence of 19-32% following GC exposure. 64, 66, 67 Although
282
no difference in long bone fractures was noted during GC therapy, a significant
283
decline in BMD occurred as they lost their ability to walk.67 (Figure 3)
284
285
Leukaemia
286
Acute Lymphocytic Leukaemia (ALL), the most common paediatric malignancy is
287
associated with an increased risk of fracture both at diagnosis, as well as first few
288
years following diagnosis.68 The Canadian STOPP study prospectively studies GC
289
treated conditions and reported a VF prevalence of 16% in children with ALL at
290
diagnosis, 69 with another 16% of new VFs following 12 months of ALL
291
treatment.18 BMD correlated well with VFs, with an 80% increase in VF risk with
292
every 1 SD reduction in lumbar spine (LS) BMD. Presence of VFs at diagnosis and
293
baseline LS BMD z scores were good predictors of VFs at 12 months. 18 Similarly,
294
patients with fractures during the first 3 years after diagnosis had lower LS BMD
295
at diagnosis than those without fractures. 70 The cause of secondary osteoporosis
12
Page 13 of 47
296
in ALL is believed to be the disease itself at start, by increasing bone resorption
297
via osteoclast-activating cytokines, followed by treatment with osteotoxic drugs
298
such as GC and methotrexate.18 Some studies have suggested older age 70 and
299
type of GC used 71 as predictors of skeletal morbidity, while the others have not
300
18.
301
demonstrate skeletal recovery either spontaneously or through BP therapy
302
related vertebral reshaping,72 especially in those with growth potential, also
303
improvement in trabecular and cortical BMD as measured by pQCT.73
Most survivors of childhood leukaemia unlike other chronic illnesses,
304
305
Chronic inflammatory conditions and GC therapy
306
Steroid-induced osteoporosis summarizes a variety of conditions where GCs are
307
commonly blamed for bone loss and fragility. GCs are widely used in the
308
management of chronic inflammatory childhood illnesses such as rheumatoid
309
disorders and Crohn’s disease. Use of GC has led to improved outcomes and
310
survival rates, however at the cost of substantial adverse effects such as
311
osteoporosis, obesity and diabetes 74. Studies have shown a 7-34% prevalence of
312
VFs in children with rheumatic disorders treated with GCs 19. Similar to their ALL
313
cohort, the STOPP study consortium found that the rheumatic disease process
314
itself had led to a 7% prevalence of VF at diagnosis,75 with another 6% of
315
patients developing new VFs in the first 12 months, likely secondary to GC
316
exposure. VFs were associated with greater weight gain, more significant
317
reduction in LS BMD and higher GC exposure.19
318
Questions arise whether cytokines are the main culprit in causing secondary
319
osteoporosis rather than GC alone. Infliximab, a chimeric monoclonal antibody
320
used in the treatment of chronic inflammatory conditions such as inflammatory
13
Page 14 of 47
321
bowel disease and rheumatic disorders has shown improvements in BMD 76 and
322
bone resorption 77 by suppressing TNF α mediated inflammation.
323
GC therapy is also used in nephrotic syndrome, yet this condition comes without
324
elevated inflammatory cytokines and thus is regarded as a model to study true
325
GC effects on bone. At diagnosis, 8% of children had anterior vertebral wedging,
326
78
327
patients developed incident VF, which mostly constituted mild vertebral
328
deformities and were asymptomatic in nature.79 The lower prevalence of bone
329
pathology in nephrotic syndrome compared to other GC treated conditions
330
suggests that cytokines may be the main cause of fractures in inflammatory
331
conditions, as they activate osteoclasts through the RANKL-OPG system.
and normal BMD.16 12 months following initiation of GC treatment, 6% of
332
333
Poor nutrition, female hypogonadism and anorexia nervosa
334
Anorexia Nervosa (AN) leads to underweight and a relative state of
335
hypogonadotrophic hypogonadism. AN is also characterized by reduced bone
336
mass leading to an increased risk of fractures with a reported incidence of at
337
least one fracture in 50% of the girls with more severe trabecular, rather than
338
cortical, bone loss.80 Faje et al 81 demonstrated a fracture prevalence of 31% in
339
adolescent girls with AN despite relatively normal BMAD (z scores of
