Osteogenesis Imperfecta

Dr Anton A.M. Franken Isala Zwolle

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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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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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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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Dr. A.M

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Dr. A.M

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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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OI type II

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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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Dr. A.M

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Dr. A.M

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Dr. A.M

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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 Dr. A

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Dr. A.M

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Dr. A.M

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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

•  Overige typen

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Dr. A.M

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treatment

•  Early and consistent rehabilitation intervention •  fysiotherapy •  ergotherapy •  rehabilitation

•  Orthopedic care

•  Pharmacological treatment Dr. A.M

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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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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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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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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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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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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 Dr. A.M

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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 Dr. A

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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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Cohort charatheristics

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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. Dr. A.M

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BMD

Significant difference in T-score between LS and HR in type I patiënts (p<0.001) and type IV patiënts (p<0.004)

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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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Total fractures at time of visit vs age

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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% Dr. A

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fractures and BP use in type 1 patients

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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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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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Dr. A.M

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Dr. A.M

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