Workshop Osteogenesis Imperfecta in Adults Malachi J Mc

Workshop: Osteogenesis Imperfecta in Adults Malachi J Mc. Kenna & Susan van der Kamp DXA Unit & Department of Endocrinology St. Vincent’s University Hospital Dublin, 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 Imperfecta Type Classical Sillence types I: Mild II: Perinatal lethal III: Severely deforming Affected gene Mode of inheritance COL 1 A 1 AD COL 1 A 1 or COL 1 A 2 AD IV: Moderately deforming COL 1 A 1 or COL 1 A 2 AD AD Phenotype Normal stature, few fractures, blue sclera, hearing loss in 50% Severe, multiple fractures, blue or grey sclerae, soft cranium Severe, short stature, scoliosis with vertebral fractures, triangular face, multiple fractures, blue or grey sclera, frequent hearing loss, platybasia, dentinogenesis imperfecta Moderately short stature, mild to moderate scoliosis, white or grey sclerae Distinctive histology V: Moderately deforming IFITM 5 AD Mild to moderate short stature, dislocation of radial head, hyperplastic callus, white sclerae Mineralisation defect VI: Severe SERPINF 1 AR Moderately short, scoliosis, fish-scale pattern of bone lamellation, white sclera 3 -hydroxylation defects VII: Severe CRTAP AR VIII: Severe LEPRE 1 AR Rhizomelia, short stature, white sclera, undertubulated long bones 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 Formation s. CTX Procollagen I aminopropeptide ur. NTX Bone specific alkaline phosphatase s. TRAP 5 b Osteocalcin

Collagen-based Markers of Bone Remodelling

Origin of Collagen Cross Links N-TELOPEPTIDE REGION HELICAL REGION C-TELOPEPTIDE REGION CTx NTx Pyr Dpd 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) • Bisphonates – Alendronate – Risedronate – Ibandronate – Zoledronate • Parathyroid hormone – rh. PTH 1 -34 • RANKL inhibitor – Denosumab

Cochrane Review on Bisphonates in OI Dwan K, Phillipi CA, Steiner RD, Basel D. The Cochrane Library 2014, Issue 7 • Current evidence demonstrates that oral or intravenous bisphonates 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 bisphonates 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 bisphonate 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, 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/JCI 71101

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