Osteogenesis Imperfecta (OI), also known as brittle bone disease, is a genetic disorder characterized by fragile bones that break easily. The document discusses the various types of OI, from the mildest Type I to the most severe Type II which is often lethal. Type I is the most common and involves increased bone fragility without severe deformity. Type II causes bone fractures in the womb and death shortly after birth. Type III is progressively deforming and causes multiple fractures leading to short stature and wheelchair dependence. Treatment involves physiotherapy, orthopedic care, and bisphosphonates which increase bone density and reduce fractures in children but not adults. More research is being done on drugs like terip

1. Osteogenesis Imperfecta
Dr Anton A.M. Franken
Isala Zwolle
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2. Osteogenesis Imperfecta (OI)
brittle bone disease
• heterogeneous (clinical and genetic) group of
inherited connective tissue syndromes
characterized primarily by liability to fractures
• predominantly defect in biosynthesis of collagen
type I
• prevalence 6-7 :100.000
• 17 genetic causes, 90% autosomal dominant
• clinical classification of OI (type 1-5)
• revised according Sillence (1979)
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3. OI clinical diagnosis, nomenclature and severity assesment
van Dijk , Sillence. Am J Med Genet 2014
OI syndrome name
Type
Gene
Inheritance
Non-deforming OI with Blue Sclerae
1
COL1A1
COL1A2
AD
AD
Common Variable OI with Normal
Sclerae
4
COL1A1
COL1A2
WNT1
CRTAP
PPIB
SP7
PLS3
AD
AD
AD
AR
AR
AR
XL
OI with Calcification in Interosseous
Membranes
5
IFITM5
AD
Progressively Deforming
3
COL1A1
COL1A2
BMP1
CREB3L1
CRTAP
FKBP10
LEPRE1
PLOD2
PPIB
SERPINF1
SERPINH1
TMEM38B
WNT1
AD
AD
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
AR
Perinatally lethal
2
COL1A1
COL1A2
CRTAP
LEPRE1
PPIB
AD
AD
AR
AR
AR
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4. OI type I
non-deforming OI with blue sclerae
• most frequent, mildest form,
• autosomal dominant, COL1A1, 50% reduction
synthesis of type 1 procollagen
• increased bone fragility with low bone mass
• blue sclerae
• deformity of long bones or spine uncommon
• normal posture
• hearing loss
• dentinogenesis imperfecta (DI)
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7. OI type II
perinatally lethal OI syndromes
• prematurity, small for gestational age, perinatal
lethality
• in utero fractures (rib), abnormal modeling,
• Legs in frog position
• skull severely undermineralized with open
fontanels
• cardiopulmonal dysplasia
• blue sclerae
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8. OI type II
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9. OI type III
progressive deforming
• severe, non-lethal
• multiple fractures (100, also antenatal)
• progressive deformity skeleton
• short stature, scoliosis,
• dentinogenesis imperfecta
• respiratory insufficiency
• wheelchair dependent
• 11 genes both AD/AR
Michel Petrucciani
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13. OI type IV
common variable OI
• moderately severe
• normal sclerae, short final stature
• recurrent fractures
• variable degree of deformity
• dentinogenesi imperfecta
• basilar impression (30%)
• Inheritance: AD, AR, X-linked
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16. OI type V
OI with calcification in interosseous membranes
• moderate severe
• normal sclerae, normal teeth
• calcification inter-osseous membrane leads
restriction pronation ans supination
• Specific bone histomorphometry
• Inheritance : AD, IFITM5
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17. D
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18. treatment
• Early and consistent rehabilitation intervention
• fysiotherapy
• ergotherapy
• rehabilitation
• Orthopedic care
• Pharmacological treatment
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19. pharmacological treatment
• Bisphosphonates:
– children: standard care: BP increase BMD and reduce
fracture rate (Glorieux 1998 iv pamidronate; Gatti 2005 iv
neridronate : Sakkers 2004 oral olpradonate, Bishop 2013, oral
risedronate)
– Adults: BP increase BMD, no fracure rate reduction
• Teriparatide:
– Adults: increas BMD, no data on fracture reduction
(Orwoll 2014)
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20. Figure 1. Meta-analysis of placebo controlled trials of oral
bisphosphonates in osteogenesis imperfecta
Hald JD, Evangelou E, Langdahl BL, Ralston SH (2014) Bisphosphonates for the
prevention of fractures in Osteogenesis Imperfecta: Meta-analysis of placebo-
controlled trials. Journal of Bone and Mineral Research Submitted:
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21. pharmacological treatment
• Bisphosphonates:
– children: standard care: BP increase BMD and reduce
fracture rate (Glorieux 1998 iv pamidronate; Gatti 2005 iv
neridronate : Sakkers 2004 oral olpradonate, Bishop 2013, oral
risedronate)
– Adults: oral BP increase BMD, no fracure rate
reduction
• Teriparatide:
– Adults: increas BMD, no data on fracture reduction
(Orwoll 2014)
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22. The Effect of Treatment with Teriparatide and
Zoledronic acid in Patients with Osteogenesis
Imperfecta
“TREAT-OI”
• Principal Investigator: Bente Lomholt Langdahl, Arhus DK.
Treatment
The participants will be randomized to one of the following treatment
regimens:
Daily subcutaneous injections of placebo for two years and annual intravenous
infusions of ZA 5 mg for 3 years.
Daily subcutaneous injections of TPTD 20 µg for two years and annual
intravenous infusions of placebo for two years followed by an intravenous
infusion of zoledronic acid 5 mg in year 3.
Daily subcutaneous injections of placebo for two years, and annual intravenous
infusions of placebo for 3 years.
Primary endpoint:
1. Clinical fractures
Secondary endpoints:
1. Bone mineral density (BMD) at the hip (femoral
neck and total hip) and lumbar spine
2. Bone structure assessed by QCT and HRpQCT
3. Bone turnover assessed by biochemical markers
4. Bone architecture and material properties evaluated
by histomorphometry and nanotechnology based
techniques after treatment for 1 year.
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23. Dutch OI-team
Children’s team (250 patients)
University Medical Centre Utrecht
Adult team (230 patients)
Isala Zwolle
Genetic diagnostics (500
mutations)
VU University Medical Centre Amsterdam
Meeting every 3 months
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24. Multidisciplinary adult care
one-stop-shop consultation
Basic team
• Orthopaedic surgery
• Rehabilitation medicine
• Internal medicine
• Physiotherapy/Ergo
therapy
• Clinical genetics
(Amsterdam)
Specialists “a la carte”
• Pulmonology
• Cardiology
• Neurology
• Radiology
• Gynaecology
• ENT
• Specialized dentist
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25. Adult OI expert centre Zwolle
one-stop-shop consultation
• basic lab + vit D and bonemarkers
• DNA analysis
• Skeletal radiographs and DXA
• Lung function test
• Cardiac ultrasound
• SF-36 questionaire
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26. Database
• retrospective, cross-sectional explorative study
in the first 149 adult OI patients
• demographics features
• BMD
• Total lifetime fractures
• Fractures in relation to BP use
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27. Cohort charatheristics
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28. Table 1. Characteristics of the study population.
Type OI I III IV
Total patients 106 20 23
Fracture total
Median, 1st
quart – 3rd
quart. (min-max)
15, 8-25
(0-100)
55, 36-100
(5-300)
20, 5-40
(0-51)
Total suffered fractures at the time of visit
(% of all)
0-15 58.7% 10.5% 39.2%
16-25 17.3% 5.3% 21.7%
26-35 9.6% 5.3% 13%
36-45 3.8% 10.5% 8.7%
45 10.6% 68.4% 17.4%
Surgery necessary for at least 1 fracture (% of all) 88.2% 90% 94.4%
* In type III length/weight relations are disturbed and BMI is not useable.
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29. BMD
Significant difference in T-score between LS and HR in type I patiënts
(p0.001) and type IV patiënts (p0.004)
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30. Table 3. Z-Scores of all patients per type OI according to the WHO Classification. In percentages
(number of all)
Type I III IV
DXA
location
LS
(n=100)
HR
(n=106)
LS
(n=4)
HR
(n=5)
LS
(n=20)
HR
(n=19)
Normal
Z-score ≥
-1.0
25%
(n=25)
54.6%
(n=53)
- 20%
(n=1)
20%
(n=4)
42.1%
(n=8)
Osteopenia
-2.5 Z-
score -1.0
41%
(n=41)
39.2%
(n=38)
- 40%
(n=2)
20%
(n=8)
36.8%
(n=7)
Osteoporosis
Z-score ≤
-2.5
34%
(n=34)
6.2%
(n=6)
100%
(n=4)
40%
(n=2)
40%
(n=8)
21.2%
(n=4)
LS= Lumbar Spine, HR=Hip Region
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31. Total fractures at time of visit vs age
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32. Table 4. Total suffered fractures at the time of visit (% of all patients).
Type I patients who never (NEVER) used BP vs. patients who use BP
now or used BP in the past (EVER).
Fracture total NEVER
(n=39)
EVER
(n=55)
0-15 64.1% 54.6%
16-25 17.9% 20%
26-35 10.3% 9.1%
36-45 2.6% 3.6%
45 5.1% 12.7%
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33. fractures and BP use in type 1 patients
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34. Discussion
• BMD of adult OI patients varies greatly per measured
location bij DXA. BMD at LS is lower opposed to HR
• Adults with type I and IV there is low fracure rate.
• Most fractures occur before adulthood
• In type III patients fracure total increases with age
• Half of type I and IV patients have never used BP
• many patients which had used BP seem to have equal
fracture rates as patients which did not use BP
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35. Excessive transforming growth factor-β signaling is a
common mechanism in osteogenesis imperfecta
Ingo Grafe1 et al
Nature Medicine june 2014
• TGF-beta: coordinator bone-remodeling by coupling osteoclast and
osteoblast, modulates bioactivity of protoglycans in association with
collagen fibrils
• TGF-ß produced by osteoblasts, secreted in in-active form and
depositedinto bone matrix and activated during bone resorption
• OI :dysregulated/ excessieve TGF-Beta signaling both in recessive and
dominant OI mouse models both in bone and lungs
• Anti-TGF-beta neutrallizing antibody treatment corrects the bone
phenotype in both forms of OI and improves lungabnormaliteits
•
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