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MED 240601

REVIEW

CURRENT
OPINION Osteogenesis imperfecta: diagnosis and treatment
Telma Palomo a, Tatiane Vilaça a,b, and Marise Lazaretti-Castro a

Purpose of review
Here we summarize the diagnosis of osteogenesis imperfecta, discuss newly discovered genes involved in
osteogenesis imperfecta, and review the management of this disease in children and adults.
Recent findings
Mutations in the two genes coding for collagen type I, COL1A1 and COL1A2, are the most common cause
of osteogenesis imperfecta. In the past 10 years, defects in at least 17 other genes have been identified as
responsible for osteogenesis imperfecta phenotypes, with either dominant or recessive transmission.
Intravenous bisphosphonate infusions are the most widely used medical treatment. This has a marked effect
on vertebra in growing children and can lead to vertebral reshaping after compression fractures. However,
bisphosphonates are less effective for preventing long-bone fractures. At the moment, new therapies are
under investigation.
Summary
Despite advances in the diagnosis and treatment of osteogenesis imperfecta, more research is needed.
Bisphosphonate treatment decreases long-bone fracture rates, but such fractures are still frequent. New
antiresorptive and anabolic agents are being investigated but efficacy and safety of these drugs, especially
in children, need to be better established before they can be used in clinical practice.
Keywords
bisphosphonate, bone fragility, collagen, fragility fractures, osteogenesis imperfecta

INTRODUCTION and trauma [4]. In addition to the low-bone mass

Osteogenesis imperfecta, also known as brittle bone
disease, is a heritable disorder of the extracellular
&
matrix [1 ]. This disorder manifests mainly as bone
fragility, although other organs can be involved.
Abnormalities of the teeth, known as dentinogen-
esis imperfecta, and soft tissues, such as discolor-
ation of the sclera and joint hyperlaxity are often
observed [2 ].
&&
The new gene discoveries in the past years have
achieved, patients with osteogenesis imperfecta
experience age-associated bone loss, increasing even
more the risk of fractures [5]. Women undergo
perimenopause loss and the rate of fractures in
postmenopausal women with osteogenesis imper-
fecta is twice as high as that of osteogenesis imper-
fecta in premenopausal women [6].
The predominant cause of osteogenesis imper-
fecta are mutations in the two genes that encode
&&

contributed to better explanation of the pathophys-
iology of osteogenesis imperfecta, providing oppor-
tunities for the development of new therapies. In
this review, we will outline the clinical and molecu-
lar diagnosis of osteogenesis imperfecta, mention
the novel causative genes and review the treatment
options.
EPIDEMIOLOGY AND PATHOPHYSIOLOGY
Osteogenesis imperfecta affects approximately 1 in
10 000 to 20 000 births [3]. It is a genetically hetero-
geneous skeletal dysplasia with higher mortality
than general population. In a recent cohort, people
with osteogenesis imperfecta had higher risk of
death from respiratory and gastrointestinal diseases
type I collagen [2 ,3]. The protein is a heterotrimer,
containing two a1(I) and one a2(I) chains [7]. It is
synthesised as a procollagen molecule, and under-
goes multiple posttranslational modifications.
Flanking propeptides are removed by specific pro-
teases, then, the molecule spontaneously assembles
a
Bone and Mineral Unit, Division of Endocrinology, Universidade Federal
de São Paulo, Brazil and bAcademic Unit of Bone Metabolism, University
of Sheffield, Sheffield, United Kingdom
Correspondence to Telma Palomo, MD, PhD, Universidade Federal de
São Paulo (UNIFESP), Rua Botucatu 806, Vila Clementino, São Paulo,
SP, CEP 04023-062 Brazil. Tel: +55 11 55748432;
e-mail: telmapalomo@yahoo.com.br
Curr Opin Endocrinol Diabetes Obes 2017, 24:000–000
DOI:10.1097/MED.0000000000000367

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Parathyroids, bone and mineral metabolism
KEY POINTS
 Osteogenesis imperfecta is the most prevalent heritable
bone fragility disorder in children.
 COL1A1 and COL1A2 are the most frequent causative
mutations, but recently, mutations on 15 other genes
have been identified, either with autosomal dominant
or autosomal recessive inheritance.
 Intravenous bisphosphonate is the most used therapy
for osteogenesis imperfecta and increases bone mass,
has a marked effect on vertebra reshaping in growing
children but little effect on the development of scoliosis.
 Bisphosphonate treatment decreases long-bone fracture
rates, but such fractures are still frequent.
 Novel promising osteogenesis imperfecta treatments in
preclinical studies may provide a promising approach
to treat patients with osteogenesis imperfecta.
into fibrils in tissue, and is further stabilised by
crosslinks. Mutations that affect the propeptide
cleavage sites cause specific variants of osteogenesis
&&
imperfecta with unique phenotypes [7,8 ].
CLASSIFICATION
Osteogenesis imperfecta is a heterogeneous disease,
and the severity ranges from subtle increase in frac-
ture frequency to death in the perinatal period
[9,10]. A classification based in the severity of bone
fragility, according to clinical/radiological features,
was proposed by Sillence et al. in 1979. He suggested
four phenotypic categories: osteogenesis imperfecta
type I, ‘nondeforming with blue sclera’; osteogene-
sis imperfecta type II, ‘perinatally lethal osteogene-
sis imperfecta’; osteogenesis imperfecta type III,
‘progressively deforming osteogenesis imperfecta’;
and osteogenesis imperfecta type IV, ‘moderate
severe osteogenesis imperfecta’ [9]. Additional oste-
ogenesis imperfecta types (V and higher) were
described, based on specific phenotypic character-
istics and on the genetic findings.
Osteogenesis imperfecta type V is characterised
by moderate-to-severe bone fragility, and a calci-
fied interosseous membrane at the forearm that
can lead to secondary dislocation of the radial
head. Osteogenesis imperfecta type V has an auto-
somal dominant pattern, and a hyperplastic callus
can develop after fractures or surgical interventions
[11]. Additional osteogenesis imperfecta types were
described, such as osteogenesis imperfecta types VI
and VII [10,12]. The discovery of multiple new
genes spread out the field of osteogenesis imper-
fecta, and many additional osteogenesis imperfecta
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types have been proposed based on genetic find-
ings. The several mutations are listed in the
OMIM Database.
The new genetic discoveries provided a contro-
versial classification, merging clinic and genetic
findings. Each new gene affected, defined a new
osteogenesis imperfecta type, beyond the Sillence
&&
original 4 types [8 ]. This system was criticised by
&& &
clinicians and researchers [8 ,13 ]. The Nosology
and Classification of Genetic Skeletal Disorders,
published in 2015, adopted a phenotypic criterion
to classify osteogenesis imperfecta types, limiting to
five types (osteogenesis imperfecta types I–V)
&& &
[2 ,13 ,14]. In our opinion, it is more useful to
describe osteogenesis imperfecta types by stating
the phenotypic severity and the involved gene, as
&&
proposed by Van Dijk et al. [2 ,7].
GENES ASSOCIATED WITH
OSTEOGENESIS IMPERFECTA
Almost all individuals with osteogenesis imperfecta
type I and close to 80% of patients with moderate-
to-severe osteogenesis imperfecta types have an
autosomal dominant form of osteogenesis imper-
fecta that is caused by heterozygous mutations in
one of the two genes encoding type I collagen,
&&
COL1A1 and COL1A2 [2 ]. Mutations can be inher-
ited from an affected parent or arise de novo [15].
Although there is not a straight genotype–pheno-
type correspondence, mutations’ type and position
influence the phenotype and there is a relation to
some extent. The most frequent abnormality is a
mutation in a glycine residue in one of the two
collagen genes [10]. These mutations can be divided
in two categories: quantitative defects and muta-
tions that affect type I collagen structure. The first
category results in haploinsuficiency of the gene,
leading to the production of structurally normal
collagen, however, in about half of the normal
amount. This is the cause of osteogenesis imperfecta
type I. In the second category, the mutations usu-
ally replace a glycine by another amino acid result-
ing in an abnormal collagen molecule [16,17 ].
&
Recessive mutations in genes that regulate post-
translational type I collagen processing, and genes
that modulate osteoblast differentiation or bone
mineralization cause about 10% of moderate-to-
severe osteogenesis imperfecta cases. Collagen fold-
ing, secretion and processing might be affected.
These noncollagen mutations usually cause moder-
ate-to-severe osteogenesis imperfecta phenotype
but mild phenotype similar to osteogenesis imper-
&&
fecta type I has been described [2 ,3,18]. Table 1
and Fig. 1 summarises genetic findings and its
&& &&
mechanisms [2 ,8 ,18].
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Osteogenesis imperfecta: diagnosis and treatment Palomo et al.

Table 1. Genes and clinical classification of osteogenesis imperfectaa

Defective Clinical Defective

gene OI typeb Inheritance protein Protein full name Mechanism Frequency

COL1A1 I, II, III, IV AD COL1A1 Collagen type I alpha 1 chain Defects in collagen 85–90% of
synthesis and OI cases
structure
COL1A2 I, II, III, IV AD COL1A2 Collagen type I alpha 2 chain
CRTAP III, IV AR CRTAP Cartilage-associated protein Defects in collagen 10–15% of
type I processing OI cases
P3H1 III AR P3H1 Prolyl-3-hydroxlase 1
PPIB III AR CypB Cyclophyllin B
FKBP10 III, IV AR FKBP65 FK506 binding protein, 65
kDa
SERPINH1 III, IV AR HSP47 Heat-shock protein 47
PLOD2 III, IV AR LH2 Lysyl hydroxylase 2
BMP1 I, III, IV AR BMP1 Bone morphogenetic protein 1
SPARC IV AR SPARC Secreted protein, acidic,
cysteine-rich
TMEM38B IV AR TMEM38B Transmembrane protein 38B
SEC24D III, IV AR SEC24D SEC24D
P4HB III AR PDI Protein disulfide isomerase
IFITM5 V AD BRIL Bone-restricted ifitm-like Defects in bone
mineralization
SERPINF1 III, IV AR PEDF Pigment-epithelium derived
factor
WNT1 IV AR/AD WNT1 WNT1 Defects in osteoblast
development
SP7 III AR SP7 Osterix; transcription factor
Sp7
CREB3L1 II AR OASIS Old astrocyte specifically
induced substance

All data of osteogenesis imperfecta (OI) mutations is from the OI Variant Database (https://oi.gene.le.ac.uk). AD, autosomal dominant pattern; AR, autosomal
recessive pattern.
a && &&
Adapted from Trejo et al. [2 ] and Forlino et al. [8 ].
b
The 2015 Nosology and Classification of Genetic Skeletal Disorders has been followed.

DIAGNOSIS of long bones or spine and dentinogenesis imper-

Osteogenesis imperfecta diagnosis is based on history,
clinical examination, lumbar spine bone mineral
density (BMD), bone biochemistry and radiographic
&&
findings (Fig. 2) [2 ]. The exclusion of metabolic
causes of osteoporosis is important at baseline.
The single most important clinical feature is bone
fragility, that is common to all osteogenesis imper-
fecta types but other extra-skeletal features might be
present. The most common features of each osteo-
genesis imperfecta type will be described according to
the clinical classification proposed by Van Dijk and
Sillence [7].
Osteogenesis imperfecta type I is associated with
low-bone mass. Fractures are rare at birth, but there
is an increase in the rate of long-bone fractures [19].
Blue or grey sclera and an increased risk of preco-
cious hearing loss are common features. Deformities
fecta are uncommon [7].
In osteogenesis imperfecta type II, the bones are
extremely affected. Short and severely deformed
long bones, and poor ossification of facial and skull
bones are detected in 18–20 weeks’ foetal ultra-
sounds. Multiple rib fractures are observed in utero
and perinatal lethality is almost a rule, with 90% of
the affected babies dying by 4 weeks of age [7].
Osteogenesis imperfecta type III is characterised
by severe bone fragility and progressive skeletal defor-
mity. Generalised osteopenia and fractures are seen
in radiographic studies at birth. Blue sclera and den-
tinogenesis imperfecta might be present, but the
sclera tends to become less blue with ageing. Short
stature is a rule and progressive kyphoscoliosis starts
in childhood and progresses with growth. Hearing
impairment might develop in adulthood [7].

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Parathyroids, bone and mineral metabolism

FIGURE 1. Genes and molecular mechanisms involved in osteogenesis imperfecta. (a) Abnormal structure in collagen a
chains because of mutations in COL1A1 or COL1A2. (b) Procollagen posttranslational modification in the endoplasmic
reticulum : trimeric complex (P3H1, prolyl-3-hydroxylase 1; CRTAP, cartilage-associated protein and CypB, cyclophillin B) for
hydroxylation of the proline residues. (c) FKBP10 and HSP47 stabilize the triple helix and accelerate its folding. Lysyl
hydroxylase 2 (LH2) hydroxylates collagen telopeptide lysines. After being secreted, the C-propeptides and N-propeptides are
cleaved. BMP1 cleaves the procollagen C-propeptide. Adapted from Forlino et al. [8 ] and Marini et al. [18].
&&

Patients with osteogenesis imperfecta type IV
have recurrent fractures and the deformity is vari-
able. Most of them have normal sclera and hearing
impairment is rare. Severity is also variable within
families, with some individuals presenting mild
osteogenesis imperfecta and others with more severe
forms in the same family [7].
Finally, osteogenesis imperfecta type V is char-
acterised by progressive calcification of the inter-
osseous membrane and hyperplastic callus, as
previously described. The bone fragility is moder-
ate-to-severe and there is no blue sclera or dentino-
genesis imperfecta [7].
The diagnosis of osteogenesis imperfecta can be
difficult. Some primary skeletal disorders can be
mixed up with osteogenesis imperfecta. The exclu-
sion of idiopathic or juvenile osteoporosis might be
&
a challenge [20 ]. Children with mild bone fragility
and no extra-skeletal features of osteogenesis imper-
fecta, and children with fractures at birth may also
demand careful assessment. Child abuse is a remark-
able cause of fractures, and the highest incidence is
in the first year of life [10]. The most common signs
are rib fractures, and classic metaphyseal lesions of
the femur. The incidence of osteogenesis imperfecta
in this context is between 2 and 5% [21]. These
uncertain cases may still be caused by mutations
in COL1A1 or COL1A2 [22,23].
Although the diagnosis is mainly based in clinical
and radiological features, genetic tests may establish
the exact cause of the disease and provide helpful
&
information in unclear cases [20 ,24]. Molecular diag-
nosis also allows information about recurrent risk
(dominant versus recessive osteogenesis imperfecta)
and the identification of affected family members
&&
[2 ]. This could be interesting especially in very mild
forms of osteogenesis imperfecta type I, wherever
clinical signs can be very subtle. On the other hand,
molecular diagnosis has low impact in the evaluation
of suspected child abuse and in infants in whom
careful examination has not shown clinical charac-
teristics of osteogenesis imperfecta [21,25].
Currently, molecular diagnosis is performed
by sequencing the DNA of target gene panels

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Osteogenesis imperfecta: diagnosis and treatment Palomo et al.

FIGURE 2. Lateral lumbar spine and lower extremities radiographs of three patients with osteogenesis imperfecta type I
(milder form), type III (most severe type of osteogenesis imperfecta) and type IV (intermediate in severity between types I and
III). (A1 and A2) Spiral right femur healing fracture in a osteogenesis imperfecta type I patient without vertebral fractures. (B1
and B2) Osteogenesis imperfecta type III patient with severe vertebral compression fractures, protrusion of the acetabulum,
fracture healing of the right femur and deformities in both femurs and tibias (small diameter and thin cortices). (C1 and C2)
Full community ambulator osteogenesis imperfecta type IV patient with several vertebral compression fractures, bilateral
femoral bowing and straight tibias. Vertebral fractures are indicated by asterisks.

(‘next-generation sequencing’) [26,27]. The evalu-
ation of this known disease-causing genes identi-
fies mutations in 97% of individuals with a clinical
diagnosis of ‘typical osteogenesis imperfecta’ [14].
TREATMENT
The therapeutic approach to osteogenesis imper-
fecta patients will vary with age, severity of the
disease and functional status. Individuals with mild
disease may require subtle restrictions, such as
avoiding contact sports, and orthopaedic therapy
&&
is reserved to the management of fractures [2 ].
Conversely, moderate-to-severe osteogenesis imper-
fecta patients demand rehabilitation and orthopae-
dic interventions not only in acute fractures, but
also to address reduced mobility, long-bone defor-
&&
mities and scoliosis [2 ,28].
In severe forms of osteogenesis imperfecta, intra-
medullary rodding surgery may be required for
&
straightening bowed femurs and tibias [29 ,30]. Mul-
tiple fractures may result in deformities and repeated
periods of immobilization, which may compromise
the functional status and mobility. In this scenario, a
multidisciplinary approach is the best option and
physical rehabilitation plays an important role in
improving individual’s function and promoting
independence [28,30].
For many years, intravenous bisphosphonate
therapy has been the most widely used approach to
treat bone fragility in children with osteogenesis
imperfecta. In a systematic review, all the randomised

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Parathyroids, bone and mineral metabolism
studies that evaluated areal BMD reported an increase
with bisphosphonates [31–34], and some studies
reported a decrease in the incidence of fractures
[33]. However, two recent meta-analyses that
assessed the effects of bisphosphonates on fracture
in osteogenesis imperfecta reported different find-
ings: Hald et al. [31] observed inconclusive results,
whereas Shi et al. [34] reported a decrease in the risk of
fractures in children, but not in adults. Studies to
better define the role of bisphosphonates in fracture
prevention in this population are needed, however, a
long randomised controlled trial is unlikely to take
&&
place [2 ].
Bisphosphonates have a remarkable effect on
vertebra during growth and can induce reshaping
in vertebral compression fractures in growing chil-
&
dren with osteogenesis imperfecta [1 ]. It is impor-
tant to highlight that vertebral reshaping is
associated with growth. Reshaping will depend on
the amount of growth in use of bisphosphonates. In
addition to the striking outcome in vertebra com-
pression fractures, the effect of this therapy is small
& &&
on the scoliosis development [1 ,2 ]. The effects of
bisphosphonates are also less pronounced in long
bones. Although bisphosphonates decrease long-
bone fracture, the rates are still very high in children
with osteogenesis imperfecta. This finding is proba-
bly associated with abnormal bone geometry (small
&
bone cross-section area) and deformities [1 ].
Multiple different protocols have been proposed
&
for bisphosphonate use [17 ]. Table 2 summarises
& &&
the most widely used [1 ,2 ,10]. Other modified
protocols have been proposed, such as by Palomo
et al. [37] that showed the safety of pamidronate in a
shorter single infusion over a 2-h period what could
be suitable for countries with reduced number of
hospital beds.
Although intravenous bisphosphonates have
shown positive results, the same was not observed
&&
with oral bisphosphonates [2 ]. Two large random-
ised placebo-controlled trials on oral alendronate
(n ¼ 139) and risedronate (n ¼ 147) did not observe
Table 2. Most widely used intravenous bisphosphonates protocol
Bisphosphonate (IV) Less than 2 years
Pamidronate on 3 successive 0.5 mg/kg every 2 months
days (maximum dose
60 mg/day)
Zoledronate (single infusion) Only in studies

The first exposure to intravenous bisphosphonate occurs at a lower dose to minimize adverse events (in particular, the acute phase reaction and hypocalcaemia)
[10,35]. The initial annual dose (’full-dose’) of pamidronate is 9 mg/kg of body weight and of zoledronic acid is 0.1 mg/kg of body weight. These annual doses
of both bisphosphonates should be reduced to half of the ‘full-dose’ schedules whenever the lumbar spine areal bone mineral density (BMD) z-score exceeded 2
&
[1 ]. Bisphosphonate infusions were discontinued once longitudinal growth ceased [36].
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improvements on vertebral fractures [38,39]. Possi-
bly because the observation periods were not long
enough to show vertebral reshape. Oral alendronate
did not decrease fracture incidence in children with
moderate and severe osteogenesis imperfecta [38].
Nevertheless, oral risedronate showed a significant
reduction in the risk of clinical fracture in children
with osteogenesis imperfecta [39]. Although some
studies reported positive results with the use of oral
bisphosphonate, there is better evidence on the
benefit of intravenous bisphosphonate and this
should be the treatment of choice.
The benefits of bisphosphonates in adults is less
clear. Two randomised controlled trials and few
observational nonrandomised studies have shown
an increase in BMD but few evidence to support a
positive effect in fracture risk [40]. Many of these
studies showed increase in lumbar spine areal bone
mineral density (LS-aBMD) with less effective bene-
fits on the total hip [41]. Recently, Viapiana et al.
[42] showed a positive effect of neridronate on BMD
and bone turnover markers in adults with osteogen-
esis imperfecta, albeit there was no significant effect
on the risk of fracture.
The bisphosphonate therapy is considered as
well tolerated. Intravenous bisphosphonates can
lead to a decrease in serum calcium immediately
after infusion, however, this decrease is transient in
calcium and vitamin D-replete patients [10,35]. The
main adverse effect is reported in the first infusion:
an influenza-like syndrome, characterised by fever,
muscle pain and vomiting. This reaction should be
treated with standard antipyretics and often does
not recur [10].
Osteonecrosis of the jaw is an adverse effect
associated with high doses of bisphosphonates,
and has never been reported in osteogenesis imper-
&&
fecta [2 ,43]. Atypical femoral fractures are sub-
trochanteric or diaphyseal fractures described in
postmenopausal women associated with long-term
use of bisphosphonates [44]. Although considered
atypical in this female population, transverse
Dose according to age
2–3 years More than 3 years
0.75 mg/kg every 3 months 1.0 mg/kg every 4 months
0.05 mg/kg every 6 months
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Osteogenesis imperfecta: diagnosis and treatment Palomo et al.
diaphyseal femoral fractures were already common
in osteogenesis imperfecta, even before the use of
&
bisphosphonates [29 ]. These fractures have been
associated with the severity of osteogenesis imper-
fecta, but not with bisphosphonate use. Therefore,
in osteogenesis imperfecta these fractures cannot be
considered ‘atypical’ and more studies are needed to
&
assess the association with bisphosphonates [29 ,44].
The bisphosphonate-therapy benefits for
patients with osteogenesis imperfecta are clearly
established, but other treatment options would be
desirable. Denosumab is an antiresorptive therapy
currently approved for postmenopausal osteopo-
rosis treatment. The use of denosumab has been
reported in children with osteogenesis imperfecta
caused by SERPINF1 and COL1A1 and COL1A2
mutations and resulted in a decrease in bone
turnover markers and in an increase in areal
BMD [45,46].
Differently from bisphosphonates, which has a
long half-life in bone, the effect of denosumab is
limited to a few months, which seemed to be inter-
esting in some cases. However, there is a potential
rebound effect described after interruption of treat-
ment, leading to hypercalcemia, which cannot be
neglected [46,47]. Nevertheless, this was not
observed in the study of children with osteogenesis
imperfecta treated with denosumab who had been
previously treated with bisphosphonates [46]. More
studies about the efficacy and, especially, safety of
denosumab in osteogenesis imperfecta patients
are required.
Anabolic therapies seem attractive in osteogen-
esis imperfecta setting. A randomised controlled
trial on teriparatide in adults with osteogenesis
imperfecta showed an increase in BMD in the milder
form of osteogenesis imperfecta (type I), but no
benefit in more severe forms of the disease [48].
Antisclerostin antibodies decrease the inhibitory
effect of sclerostin, which results in an increase in
BMD. Effects were promising in osteogenesis imper-
fecta mouse models and preliminary results in
adults with moderate osteogenesis imperfecta were
positive [49]. However, long-term phase 3 studies
are required to evaluate efficacy and safety in
this population.
CONCLUSION
The diagnosis and treatment of patients with oste-
ogenesis imperfecta have advanced recently. It is
clear that current medical treatment (intravenous
bisphosphonate) have a beneficial effect on bone
density, fracture rates and in the reshape of verte-
bras after compression fractures. A multidisciplin-
ary approach has been improving patient care,
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producing remarkable gains in functionality and
mobility. The safety and efficacy of new antiresorp-
tive and anabolic treatments need to be established
along with new approaches in children with osteo-
genesis imperfecta. The aim is to reduce the disease
burden carried by children and adults with osteo-
genesis imperfecta. An individualised mutation-
specific approach is a visionary target for the future.
Acknowledgements
We thank Frank Rauch, from the Shriners Hospital for
Children in Montreal, Canada, for helpful suggestions.
Financial support and sponsorship
T.V. is funded by Conselho Nacional de Desenvolvi-
mento Cientı´fico e Tecnológico (CNPq), Brazil.
Conflicts of interest
There are no conflicts of interest.
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Volume 24  Number 00  Month 2017