Workshop:Osteogenesis Imperfecta in Adults

Malachi J McKenna & Susan van der KampDXA Unit & Department of Endocrinology

St. Vincent’s University HospitalDublin, Ireland

Disclosures

• No disclosures or conflicts of interest

Learning Objectives

•Overview of osteogenesis imperfecta in adults–Classification of OI–Bone health in adulthood•Investigation of OI–Role of DXA–Role of bone turnover markers•Medication options•Case Studies

Learning Objectives

• Overview of osteogenesis imperfecta in adults– Classification of OI– Bone health in adulthood

• Investigation of OI– Role of DXA– Role of bone turnover markers

• Medication options• Case Studies

OI Phenotypes

Nosology of Osteogenesis ImperfectaType Affected gene Mode of

inheritancePhenotype

Classical Sillence typesI: Mild COL1A1 AD Normal stature, few fractures, blue sclera, hearing

loss in 50%II: Perinatal lethal COL1A1 or

COL1A2 AD Severe, multiple fractures, blue or grey sclerae, soft

cranium

III: Severely deforming COL1A1 or COL1A2

AD Severe, short stature, scoliosis with vertebral fractures, triangular face, multiple fractures, blue or grey sclera, frequent hearing loss, platybasia, dentinogenesis imperfecta

IV: Moderately deforming COL1A1 or COL1A2

AD Moderately short stature, mild to moderate scoliosis, white or grey sclerae

Distinctive histologyV: Moderately deforming IFITM5

AD Mild to moderate short stature, dislocation of radial

head, hyperplastic callus, white sclerae

Mineralisation defectVI: Severe SERPINF1 AR Moderately short, scoliosis, fish-scale pattern of

bone lamellation, white sclera

3-hydroxylation defectsVII: Severe CRTAP AR Rhizomelia, short stature, white sclera,

undertubulated long bonesVIII: Severe LEPRE1 AR Rhizomelia, white sclera, undertubulated long bones,

seen in Irish Travellers

IX: Severe PPIB AR Similar to type VII & VIII but no rhizomelia

Modified from Forlino A, Cabral WA, Barnes AM, Marini JC. New perspectives on osteogenesis imperfecta. Nat Rev Endocrinol 2011;7:540-57

Critical steps in collagen type I biosynthesis and indication of genes known to be involved in OI. Type I collagen is the major

structural protein in bone, tendon, ligament, skin & cornea

Mechanism of disease in OI type I

Mechanism of disease in OI type III & IV

Abnormal folding of collagen molecule

Approach to Genetic Testing

Bone Health in Adulthood

• OI type I– Low or low-normal BMD– Stable BMD– Normal or high-normal bone turnover– Fragility fractures

• Variable prevalence• Less frequent than childhood

Bone Health in Adulthood

• OI type III & IV– Low BMD– Stable BMD– High-normal or high bone turnover– Fractures

• Fragility fractures are common but variable prevalence• Stress fractures may occur easily

– Problems related to bone deformity• Wheelchair-bound• Platybasia

Learning Objectives

• Overview of osteogenesis imperfecta in adults– Classification of OI– Bone health in adulthood

• Investigation of OI– Role of DXA– Role of bone turnover markers

• Medication options• Case Studies

Challenges of DXA in OI Type I

Challenges of DXA in OI Type III

Panel of Bone Turnover Markers

Resorption

sCTX

urNTX

sTRAP5b

Collagen-based Markers of Bone Remodelling

CTxNTx

N-TELOPEPTIDEREGION HELICAL REGION

C-TELOPEPTIDEREGION

Pyr Dpd

Origin of Collagen Cross Links

Watts, N. B. Clin Chem 1999 45:1359-68, with permission.

Learning Objectives

• Overview of osteogenesis imperfecta in adults– Classification of OI– Bone health in adulthood

• Investigation of OI– Role of DXA– Role of bone turnover markers

• Medication options• Case Studies

Medications for OI(off-label use of medications)

• Bisphosphonates– Alendronate– Risedronate– Ibandronate– Zoledronate

• Parathyroid hormone– rhPTH1-34

• RANKL inhibitor– Denosumab

Cochrane Review on Bisphosphonates in OIDwan K, Phillipi CA, Steiner RD, Basel D. The Cochrane Library 2014, Issue 7

• Current evidence demonstrates that oral or intravenous bisphosphonates increase bone mineral density in children and adults

• These were not shown to be different in their ability to increase bone mineral density.

• It is unclear whether treatment consistently decreases fractures, though multiple studies report this independently and no studies report an increased fracture rate.

• The studies did not show bisphosphonates conclusively improve clinical status (reduce pain; improve growth and functional mobility) in people with osteogenesis imperfecta.

• Given their current widespread and expected continued use, the optimal method, duration of therapy and long-term safety of bisphosphonate therapy require further investigation.

• In addition, attention should be given to long-term fracture reduction and improvement in quality of life indicators.

Study of Teriparatide in Adults with OI

• Evaluation of teriparatide treatment in adults with osteogenesis imperfecta. Eric S. Orwoll, Jay Shapiro, Sandra Veith, Ying Wang, Jodi Lapidus, Chaim Vanek, Jan L. Reeder, Tony M. Keaveny, David C. Lee, Mary A. Mullins, Sandesh C.S. Nagamani, and Brendan Lee

• Oregon Health and Science University, Portland, Oregon, USA. Kennedy Krieger Institute, Baltimore, Maryland, USA. ON Diagnostics, Berkeley, California, USA. Departments of Mechanical Engineering and Bioengineering, UC Berkeley, Berkeley, California, USA. Baylor College of Medicine, Houston, Texas, USA. Howard Hughes Medical Institute, Houston, Texas, USA.

• J Clin Invest. 2014;124(2):491–498. doi:10.1172/JCI71101

Study of Teriparatide in Adults with OI

BMD Response to Teriparatide

BTM Response to Teriparatide

Bone Strength Response to Teriparatide

Learning Objectives

• Overview of osteogenesis imperfecta in adults– Classification of OI– Bone health in adulthood

• Investigation of OI– Role of DXA– Role of bone turnover markers

• Medication options• Case Studies