Fracture Patterns Differ Between Osteogenesis Imperfecta

ORIGINAL ARTICLE
Fracture Patterns Differ Between Osteogenesis Imperfecta
and Routine Pediatric Fractures
Kranti V. Peddada, BS, Brian T. Sullivan, BS, Adam Margalit, MD,
and Paul D. Sponseller, MD, MBA
Background: It is important to estimate the likelihood that a pediatric
fracture is caused by osteogenesis imperfecta (OI), especially the least
severe type of OI (type 1).
Methods: We reviewed records of 29,101 pediatric patients with
fractures from 2003 through 2015. We included patients with
closed fractures not resulting from motor vehicle accidents, gunshot wounds, nonaccidental trauma, or bone lesions. Patients with
OI of any type were identified through International Classification
of Diseases-9 code. We randomly sampled 500 pediatric patients
in whom OI was not diagnosed to obtain a control (non-OI)
group. We reviewed age at time of fracture, sex, fracture type,
laterality, and bone and bone region fractured. Bisphosphonate
use and OI type were documented for OI patients. Subanalysis of
patients with type-1 OI was performed. The Fisher exact and
χ2 tests were used to compare fracture rates between groups.
P < 0.05 was considered significant. Positive likelihood ratios for
OI were calculated by fracture pattern.
Results: The non-OI group consisted of 500 patients with 652
fractures. The OI group consisted of 52 patients with 209 fractures. Non-OI patients were older at the time of fracture (mean,
9.0 ± 5.0 y) than OI patients (mean, 5.5 ± 4.4 y) (P < 0.001). OI
patients had more oblique, transverse, diaphyseal, and bilateral
long-bone fractures than non-OI patients (all P < 0.001). Non-OI
patients had more buckle (P = 0.013), metaphyseal (P < 0.001),
and physeal (P < 0.001) fractures than OI patients. For patients
with type-1 OI and long-bone fractures (n = 18), rates of transverse and buckle fractures were similar compared with controls.
Transverse humerus (15.2), olecranon (13.8), and diaphyseal
humerus (13.0) fractures had the highest positive likelihood ratios for OI, and physeal (0.09) and supracondylar humerus (0.1)
fractures had the lowest.
Conclusions: Transverse and diaphyseal humerus and olecranon
fractures were most likely to indicate OI. Physeal and supracondylar
humerus fractures were least likely to indicate OI. Radiographic
fracture pattern is useful for estimating likelihood of OI.
Level of Evidence: Level III.
From the Department of Pediatric Orthopaedic Surgery, The Johns
Hopkins University School of Medicine, Baltimore, MD.
No funding was received in support of this study.
The authors declare no conflicts of interest.
Reprints: Paul D. Sponseller, MD, MBA, Department of Pediatric
Orthopaedic Surgery, The Johns Hopkins Bloomberg Children’s Center,
1800 Orleans Street, 7359A, Baltimore, MD 21287. E-mail: psponse@
jhmi.edu.
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/BPO.0000000000001137
J Pediatr Orthop
Volume 00, Number 00, ’’ 2018
Key Words: fracture pattern, likelihood ratio, osteogenesis
imperfecta, routine fracture
(J Pediatr Orthop 2018;00:000–000)
O
steogenesis imperfecta (OI) is a heterogenous group
of genetic disorders that affect the quantity and/or
quality of collagen the body produces. OI occurs in 1 of
10,000 to 20,000 children1 and varies in severity, which is
most commonly categorized using the modified Sillence
classification system.2 Type-1 OI is the most common and
mildest form; patients have no deformity of long bones or
the spine but often have blue sclerae. Type-2 OI is the
most severe form and is often lethal in utero. Type-3 OI is
characterized by progressively deforming bones. Type-4
OI involves variable deformity and normal sclerae. Type-5
OI is a newer category that involves interosseous membrane calcifications and hyperplastic callus development.
When treating fractures in pediatric patients, it can
be difficult to distinguish patients with normal bone
quality from those with milder types of OI, especially type
1. Clinical and radiographic findings traditionally used to
diagnose OI have limited sensitivity and specificity. Blue
sclerae are a classic finding but are consistently present in
only type-1 OI and may be a benign finding at birth.2,3 A
family history of OI is not a sensitive diagnostic indicator
because 25% of children are born with new mutations, and
<50% of children with OI have a family history of the
disease.4,5 Age at the time of fracture has limited reliability
because up to 10% of patients with type-1 OI do not experience long-bone fracture during childhood.2
We sought to identify differences in radiographic
fracture patterns between children with OI and those with
normal bone quality. If identified, such differences could
help providers estimate the likelihood of a patient having
OI and could guide additional examination and testing.
METHODS
Data Collection
The study was approved by our institutional review
board. We reviewed data for 29,101 patients who presented
to our institution with fractures of any bone (International
Classification of Diseases-96 codes 800-829) and with
or without OI diagnosis (International Classification of
Diseases-9 code 756.1) from 2003 through 2015. Four
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Peddada et al
patients who were undiagnosed with OI at initial presentation received OI diagnoses within 2 years. Fractures
were identified through visits to the emergency department
or clinic or from operative notes. We excluded patients
whose fractures occurred at age 21 years or older; those
whose fractures were presumed to be caused by bone lesions; those with open fractures; and those with fractures
resulting from motor vehicle accidents, gunshot wounds, or
nonaccidental trauma. For OI patients, fractures of a bone
containing an intramedullary rod were excluded.
To derive the control group, we identified 635 patients
through a simple random sample of all non-OI patients who
were younger than 22 years when they underwent surgery or
were seen in the emergency department or clinic for fracture
care (Fig. 1). The age restriction was implemented to narrow
the population from which we drew the random sample.
After applying our exclusion criteria, 500 patients remained
in the control group. We reviewed data on patient age at
time of fracture, sex, and (for the OI group) OI type
and bisphosphonate use. Fractures were classified according
to laterality, the involved bone (clavicle, femur, fibula, foot,
hand, humerus, pelvis, radius, skull, spine, tibia, ulna, or
other), bone region (diaphysis; epiphysis; metaphysis,
including metadiaphysis; physis; or other), and fracture type
(avulsion, buckle, greenstick, oblique, spiral, stress, transverse,
or other). Fracture types were determined by 2 authors using
radiographs, provider notes, and radiology reports. The
senior author made the final determination of classification
when discrepancies existed between authors and/or clinical
documentation. Oblique, spiral, and transverse fracture types
applied only to diaphyseal fractures. Physeal fractures did not
include fractures through an apophyseal growth plate.
Olecranon fractures were defined as proximal to the ulnar
shaft and on the posterior aspect of the trochlear notch.
J Pediatr Orthop
Volume 00, Number 00, ’’ 2018
Statistical Analysis
The mean ages at time of fracture were compared
between groups using a 2-sample t test. This statistic represents mean age at time of fracture documentation but not
at initial fracture, because fractures may have occurred before the study period. Distribution of sex, laterality, fracture
type, and bone region were compared using the χ2 or the
Fisher exact tests. Statistical significance was set at P < 0.05.
Fracture type and bone region were categorized only for
long-bone fractures.
We used 3 methods to compare fractures between the
OI and control groups. First, age at time of fracture and
differences in fracture type and bone region were compared
between all patients with OI and the control group. Second,
subgroup analyses of the same parameters were performed
between patients with type-1 OI and the control group to
note any differences in this milder OI type. Third, we compared fracture type and bone region between all patients with
OI and the control group, controlling for each of the 9 types
of long bones fractured (ie, clavicle, femur, fibula, long bones
of the foot, long bones of the hand, humerus, radius, tibia,
and ulna). Physeal fractures were excluded from the third
analysis because very few were observed in patients with OI.
We calculated the positive likelihood ratio (PLR) for
OI of the fracture type and/or bone region specific to each
long-bone fracture that showed statistically significant differences and had at least 1 fracture in the OI and control
group (to avoid undefined PLR values of 0 and ∞). We
calculated the PLR of physeal fractures among all long
bones. We categorized fractures as indicating a small increase (PLR, 2 to 4), moderate increase (PLR, 5 to 10), or
large increase (PLR ≥ 11) in OI likelihood; or a small decrease (PLR, 0.20 to 0.49), moderate decrease (PLR, 0.10
to 0.19), or large decrease (PLR ≤ 0.09) in OI likelihood.7
FIGURE 1. Selection flow chart of patients with and without OI. ICD indicates International Classification of Diseases; OI,
osteogenesis imperfecta.
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J Pediatr Orthop
Volume 00, Number 00, ’’ 2018
RESULTS
Patient Characteristics
The control group consisted of 500 patients with 652
fractures. The OI group consisted of 52 patients with 209
fractures. There was no significant difference in sex distribution between groups (P = 0.073). Patients were older at
the time of fracture in the control group (mean, 9.0 ± 5.0 y)
than in the OI group (mean, 5.5 ± 4.4 y) (P < 0.001). The
mean age at the time of fracture for patients with type-1 OI
was 6.9 ± 5.0 years, which was younger than that of the
control group (P < 0.001) but older than that of all patients
with OI (P = 0.03).
Type-1 OI was diagnosed in 19 patients (37%) who
had 70 (33%) fractures; type-3 OI was diagnosed in 15
patients (29%) who had 97 fractures (46%); type-4 OI was
diagnosed in 3 patients (5.8%) who had 19 fractures (9.1%);
and type-5 OI was diagnosed in 2 patients (3.8%) who had 4
fractures (1.9%). There were 13 patients (25%) whose OI
type was unreported, and these patients had 19 fractures
(9.1%). In total, 31 (60%) of OI patients were being treated
with bisphosphonates. The mean age at the time of fracture
for patients with type-1 OI was 6.9 ± 5.0 years, which was
younger than that of the control group (P < 0.001) but older
than that of all patients with OI (P = 0.03).
Fracture Patterns in OI and Routine Fractures
TABLE 2. Distribution of 813 Long-Bone Fractures in 500
Patients Without OI and 52 Patients With OI, Including
a Subgroup of 18 Patients With Type-1 OI, 2003 to 2015
No. Fractures (%)
Fracture
Parameters
Fracture type
Avulsion
Buckle
Greenstick
Oblique
Spiral
Stress
Transverse
Other
Missing
Bone region
Diaphysis
Epiphysis
Metaphysis
Physis
Other
Missing
Patients
Without
OI
Patients
With OI
P*
Type-1
OI
[n (%)]
P*
27
66
14
23
25
4
84
262
115
(4.4)
(11)
(2.3)
(3.7)
(4.0)
(0.65)
(14)
(42)
(19)
6
9
2
25
7
2
72
31
39
(3.1)
(4.7)
(1.0)
(13)
(3.6)
(1.0)
(37)
(16)
(20)
0.444
0.012
0.383
< 0.001
0.800
0.632
< 0.001
< 0.001
0.608
4
4
1
13
5
1
10
10
13
(6.6)
(6.6)
(1.6)
(21)
(8.2)
(1.6)
(16)
(16)
(21)
0.513
0.316
1
< 0.001
0.177
0.375
0.539
< 0.001
0.598
171
50
206
115
33
45
(28)
(8.1)
(33)
(19)
(5.3)
(7.3)
127
8
24
3
7
24
(66)
(4.1)
(12)
(1.6)
(3.6)
(12)
< 0.001
0.065
< 0.001
< 0.001
0.342
0.024
32
3
10
3
4
9
(52)
(4.9)
(16)
(4.9)
(6.6)
(15)
< 0.001
0.614
0.0073
0.0073
0.564
0.047
OI indicates osteogenesis imperfecta.
*P < 0.05 (considered statistically significant).
Bones Fractured
Fracture Type
Upper-extremity and lower-extremity fractures accounted for 62% of fractures in the OI group and 66% of
fractures in the control group (Table 1). There were 19
fractures (9.1%) of the clavicle, pelvis, skull, spine, and
other nonextremity bones in the OI group and 44 such
fractures (6.7%) in the control group. Most fractures in
the OI group (92%) and control group (95%) occurred in
long bones. Bilateral fractures of long bones were more
commonly observed in OI patients (n = 10; 5.1%); they
included fractures of the humerus, femur, tibia, and radius.
In controls, there were 6 (1.0%) bilateral fractures of long
bones, which included the femur and radius (P < 0.001).
Oblique fractures were more common in the OI group
(13%) than in the control group (3.7%), as were transverse
fractures (OI group, 37%; control group, 14%) (both P < 0.001)
(Table 2). Buckle fractures were more common in the control
group (11%) than in the OI group (4.7%) (P = 0.013) (Table 2).
Among patients with type-1 OI, the frequencies of transverse
fractures (P = 0.539) and buckle fractures (P = 0.316) were
similar to those of the control group. Oblique fractures were
significantly more common in patients with type-1 OI (21%)
than in the control group (3.7%) (P < 0.001). Other fracture
types not described in this study were more common in the
controls compared with all OI and type-1 OI patients (both
P < 0.001). We repeated the analysis after excluding
supracondylar humerus and physeal fractures from this group
and found no significant difference between controls and all OI
(P = 0.930) and type-1 OI (P = 0.451) patients.
TABLE 1. Distribution of Fractures in 500 Patients Without OI
and 52 Patients With OI, 2003 to 2015
No. Fractures (%)
Fracture Type
Clavicle
Femur
Fibula
Foot
Hand
Humerus
Pelvis
Radius
Skull
Spine
Tibia
Ulna
Other
Total
Patients Without OI
22
33
42
36
83
110
2
151
11
4
69
84
5
652
(3.4)
(5.1)
(6.4)
(5.5)
(13)
(17)
(0.31)
(23)
(1.7)
(0.61)
(11)
(13)
(0.77)
(100)
Patients With OI
4
45
25
20
4
30
1
13
4
8
39
14
2
209
(1.9)
(22)
(12)
(9.6)
(1.9)
(14)
(0.48)
(6.2)
(1.9)
(3.8)
(19)
(6.7)
(0.96)
(100)
OI indicates osteogenesis imperfecta.
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Bone Region
A higher rate of diaphyseal fractures was observed in
patients with OI (66%) compared with the control group
(28%) (P < 0.001) (Table 2). Metaphyseal fractures were
more common in the control group (33%) than in the OI
group (12%), as were physeal fractures (control group,
19%; OI group, 1.6%) (both P < 0.001). Notably, there
were only 3 physeal fractures in the OI group. The rates of
epiphyseal fractures were not significantly different
between the OI and control groups. These findings were
consistent in our subanalysis of patients with type-1 OI.
OI Likelihood Analysis
Transverse humerus (PLR, 15.2), olecranon (PLR,
13.8), and diaphyseal humerus fractures (PLR, 13.0) were
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J Pediatr Orthop
Peddada et al
TABLE 3. Fractures With Corresponding PLRs of OI
Categorized by Degree of Likelihood of OI
Degree of Likelihood by Fracture Type
Large increase
Transverse, humerus
Olecranon
Diaphysis, humerus
Moderate increase
Transverse, fibula
Transverse, tibia
Small increase
Diaphysis, fibula
Metaphysis, foot
Diaphysis, tibia
Transverse, femur
Moderate decrease
Supracondylar humerus
Large decrease
Physis
PLR of OI
15.2
13.8
13.0
7.6
7.3
3.7
2.7
2.3
2.2
0.1
0.09
PLR ranges for each category of likelihood changes: small increase in likelihood of OI, PLR 2 to 4; moderate increase, PLR 5 to 10; large increase, PLR ≥ 11;
small decrease in likelihood of OI, PLR 0.20 to 0.49; moderate decrease, PLR 0.10
to 0.19; and large decrease, PLR ≤ 0.09. There were no fractures with a small
decrease in the likelihood of OI.
OI indicates osteogenesis imperfecta; PLR, positive likelihood ratio.
associated with large increases in OI likelihood (Table 3).
Transverse fibula fractures (PLR, 7.6) and tibia fractures
(PLR, 7.3) were associated with moderate increases in OI
likelihood, whereas diaphyseal fibula fractures (PLR, 3.7),
metaphyseal foot fractures (PLR, 2.7), diaphyseal tibia
fractures (PLR, 2.3), and transverse femur fractures (PLR, 2.2)
were associated with small increases in OI likelihood. Physeal
fractures (PLR, 0.09) and supracondylar humerus fractures
Volume 00, Number 00, ’’ 2018
(PLR, 0.1) were associated with large and moderate decreases
in OI likelihood, respectively (Fig. 2). Notably, olecranon and
supracondylar humerus fractures are subsets of epiphyseal ulna
and metaphyseal humerus fractures, respectively. The PLRs
of the former were reported to increase fracture pattern
specificity. All olecranon fractures were unilateral; there were
no apophyseal avulsion fractures, and none involved radial
head dislocations. Two olecranon fractures occurred in the OI
group and 1 occurred in the control group.
DISCUSSION
Our primary aim was to determine the radiographic
differences between fractures in pediatric patients with OI
and routine fractures in patients with normal bone quality.
We found that oblique, transverse, diaphyseal, and bilateral long-bone fractures were more common in patients
with OI, whereas buckle, metaphyseal, and physeal fractures were more common in patients with normal bone
quality. These findings were consistent in patients with
type-1 OI, except for transverse and buckle fracture rates,
which did not differ significantly from those of patients
without OI. Fractures associated with the greatest increase
in OI likelihood were diaphyseal humerus, olecranon, and
transverse fractures of the humerus, tibia, and fibula.
Physeal and supracondylar humerus fractures were associated with the greatest decrease in OI likelihood.
Molecular and biomechanical differences between
the bone of patients with OI and normal bone help explain
several of our findings. In normal bone, the diaphysis is
the strongest region (eg, higher elastic modulus and fatigue
strength of cortical bone compared with trabecular bone
FIGURE 2. OI fracture pattern likelihood tree. ↑OI = positive likelihood ratio of 2 to 10 (small to moderate increase); ↓OI = positive
likelihood ratio of 0.10 to 0.49 (small to moderate decrease); ↑↑OI = positive likelihood ratio of ≥ 11 (large increase); and
↓↓OI = positive likelihood ratio of ≤ 0.09 (large decrease). Fracture patterns not depicted were associated with minimal to no
changes in the likelihood of OI. OI indicates osteogenesis imperfecta.
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J Pediatr Orthop
Volume 00, Number 00, ’’ 2018
in the metaphysis and epiphysis).8 However, the cortical
bone in patients with OI is thinner and more porous and
has more vascular channels.9–11 These factors reduce the
strength of the diaphysis in patients with OI and help
explain the higher rate of diaphyseal fractures we observed
in these patients. Furthermore, bowing of the tibia and
femur is common in OI, as seen in several patients in this
study, and bowing predisposes to fracture at the apex of
angulation in the diaphysis. Finite element analysis of the
tibia has demonstrated substantially higher fracture risk at
15 and 16 degrees of sagittal and coronal angulation,
respectively.12
When comparing fracture types, we found higher
rates of transverse and oblique fractures in patients with OI
compared with controls. Transverse fractures commonly
occur because of failure to support a tensile stress, often
generated by trauma that causes a bending moment in
bone.13 Collagen is the primary contributor to tensile
strength in bones, and the reduction in quantity and/or
quality of collagen in patients with OI may explain their
increased susceptibility to transverse fractures. In fact,
studies using a mouse model of OI have shown up to a 20%
reduction in collagen content and an increased tendency of
tropocollagen kinking.14,15 In contrast to transverse fractures, oblique fractures typically result from shear forces
generated by a compressive load.16 Bones of patients with
OI have a reduced capacity to dissipate energy from these
shear forces, likely because of increased nonenzymatic
cross-links of collagen that hinder sacrificial bond breakage,
as well as a higher density and disoriented organization of
hydroxyapatite mineral platelets that prevent shearing between platelets and collagen fibrils.17–20 The weakness of OI
bones also helps explain their greater propensity to fracture
bilaterally compared with controls.
The difference in the rate of transverse fractures
between patients with type-1 OI versus all patients with OI
might be related to genetic mutations unique to each OI
type. Inactivating a single allele of COL1A1 (collagen type
I α 1 chain) leads to reduced production of structurally
normal collagen in type-1 OI. By contrast, dominant
negative mutations of COL1A1 or COL1A2 (collagen type
I α 2 chain) lead to expression of structurally abnormal
collagen in more severe and lethal types of OI.21 The
structurally normal collagen likely results in improved
tensile strength of bones in type-1 OI compared with other
forms of OI, reducing the risk of transverse fractures.
Similar to all patients with OI, patients with type-1
OI had higher rates of oblique and diaphyseal fractures
and a younger mean age at fracture compared with the
control group. Factors contributing to bone weakness in
OI such as osteoporosis, cortical weakening, and mineralization defects may help explain these common fracture
patterns in patients with OI of all types.2
Likelihood ratio analyses showed specific fractures
that should increase or decrease suspicion for OI. We
found that diaphyseal humerus, especially transverse,
fractures were strongly associated with OI, whereas supracondylar humerus fractures were more common in
patients with normal bone quality. Epidemiologic studies
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Fracture Patterns in OI and Routine Fractures
of humerus fractures in children support this observation.
Supracondylar humerus fractures are common in childhood, constituting ∼16% of all fractures in children,
whereas humeral diaphysis fractures represent <10% of
humerus fractures in children.22,23 Furthermore, olecranon fractures had a large PLR for OI. This finding is
consistent with a previous study documenting the high
specificity of olecranon fractures, especially avulsion
fractures of the olecranon apophysis, for OI.24 Olecranon
fractures are uncommon in patients with healthy bone,
likely because of its relative thickness and proximity to
weaker structures (eg, the distal humerus) that are more
likely to fracture. Conversely, physeal fractures were rare
in patients with OI, likely because of weakness across the
entire length of OI bones instead of just the physis, which,
in normal bone, is most prone to fracture because it is
uncalcified. Findings from the likelihood ratio analyses are
shown in Figure 2 as an algorithm to enable providers to
assess whether a particular fracture pattern should raise
suspicion for OI.
Interestingly, we noted few vertebral fractures in OI
patients (3.8%), even though the reported prevalence of
vertebral compression fractures in OI is as high as 70%.25
One reason for this discrepancy could be that most of our
patients were receiving bisphosphonate therapy. Palomo
et al26 showed that although patients on long-term bisphosphonate therapy still had high rates of long-bone
fracture, significant improvements in lumbar spine bone
mineral density and remodeling of compressed vertebrae
were noted.
Our study was limited by its retrospective design.
Some patients we identified in this study as having OI may
have been treated at other institutions for fractures they
sustained at other times, precluding an estimation of
fracture incidence and potentially biasing the cohort toward patients who came more frequently or with more
severe fractures to our referral center. By including a relatively large sample of patients with OI, we hoped to
negate this bias. To maximize our sample size for this rare
condition, we included all documented fractures sustained
by each patient. Although this methodology leads to
correlated data, we assumed that the data were largely
independent because the underlying bone pathology in OI
patients would likely play a larger role in determining
fracture pattern than factors unique to each patient that
might predispose them to fracture (eg, activity level, diet).
Our findings may not be generalizable to patients with
open fractures or fractures from motor vehicle accidents
or gunshot wounds because these were excluded from our
study. However, fractures involving such high-energy
trauma are not typically the context in which underlying
bone abnormality is questioned. Finally, OI subtype was
unknown for 9.1% of the fractures in OI patients in our
study, potentially leading us to miss fractures in patients
with type-1 OI that would have been included in the
subgroup analysis. A prospective, multicenter study of
fractures in patients with unknown OI diagnosis and sufficient length of follow-up would be needed to validate our
findings.
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J Pediatr Orthop
Peddada et al
Strengths of our study included a large number of
fractures for a rare condition and analysis of a wide range
of radiographic parameters. Although previous studies of
OI fracture epidemiology have focused on bones frequently fractured in patients with OI, we also studied
fracture type and bone region to identify more specific
fracture patterns to help distinguish OI from normal
bone.27,28 Furthermore, we were able to categorize these
patterns by degree of likelihood of OI. To our knowledge,
only one other study has investigated differences in radiographic fracture patterns between patients with OI and
those with normal bone quality; it included only patients
younger than 5 years and did not include inferential statistical analysis.29
CONCLUSIONS
Olecranon fractures and transverse and diaphyseal
fractures, especially of the humerus, should increase suspicion of OI. Conversely, physeal and supracondylar humerus fractures were associated with low likelihood of OI.
Radiographic fracture patterns provide useful information
when estimating the likelihood of OI in pediatric patients
presenting with equivocal clinical signs or repeated fractures. Although fracture patterns alone cannot provide a
conclusive diagnosis of OI, patients with fractures that
raise suspicion for OI can undergo definitive testing, which
may lead to earlier diagnosis.
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3. Byers PH, Krakow D, Nunes ME, et al. Genetic evaluation of
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