1. Workshop: Osteogenesis Imperfecta in Adults Malachi J McKenna & Susan van der Kamp DXA Unit & Department of Endocrinology St. Vincent’s University Hospital Dublin, Ireland

2. Disclosures No disclosures or conflicts of interest

3. 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

4. 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

5. OI Phenotypes

6. Nosology of Osteogenesis Imperfecta TypeAffected geneMode of inheritance Phenotype Classical Sillence types I: MildCOL1A1ADNormal stature, few fractures, blue sclera, hearing loss in 50% II: Perinatal lethalCOL1A1 or COL1A2 ADSevere, multiple fractures, blue or grey sclerae, soft cranium III: Severely deformingCOL1A1 or COL1A2 ADSevere, short stature, scoliosis with vertebral fractures, triangular face, multiple fractures, blue or grey sclera, frequent hearing loss, platybasia, dentinogenesis imperfecta IV: Moderately deformingCOL1A1 or COL1A2 ADModerately short stature, mild to moderate scoliosis, white or grey sclerae Distinctive histology V: Moderately deformingIFITM5 ADMild to moderate short stature, dislocation of radial head, hyperplastic callus, white sclerae Mineralisation defect VI: SevereSERPINF1ARModerately short, scoliosis, fish-scale pattern of bone lamellation, white sclera 3-hydroxylation defects VII: SevereCRTAPARRhizomelia, short stature, white sclera, undertubulated long bones VIII: SevereLEPRE1ARRhizomelia, white sclera, undertubulated long bones, seen in Irish Travellers IX: SeverePPIBARSimilar 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

7. 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

8. Mechanism of disease in OI type I

9. Mechanism of disease in OI type III & IV

10. Abnormal folding of collagen molecule

11. Approach to Genetic Testing

12. 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

13. 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

14. 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

15. Challenges of DXA in OI Type I

16. Challenges of DXA in OI Type III

17. Panel of Bone Turnover Markers Resorption sCTXurNTXsTRAP5b Formation Procollagen I aminopropeptide Bone specific alkaline phosphatase Osteocalcin

18. Collagen-based Markers of Bone Remodelling

19. Origin of Collagen Cross Links Watts, N. B. Clin Chem 1999 45:1359-68, with permission.

20. 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

21. Medications for OI (off-label use of medications) Bisphosphonates – Alendronate – Risedronate – Ibandronate – Zoledronate Parathyroid hormone – rhPTH1-34 RANKL inhibitor – Denosumab

22. Cochrane Review on Bisphosphonates in OI Dwan 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.

23. 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

24. Study of Teriparatide in Adults with OI

25. BMD Response to Teriparatide

26. BTM Response to Teriparatide

27. Bone Strength Response to Teriparatide

28. 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