FUTURE DIRECTIONS IN OSTEOPOROSIS

1. FUTURE DIRECTIONS IN OSTEOPOROSIS Sundeep Khosla, M.D. College of Medicine, Mayo Clinic

2. KEY CLINICAL ISSUES IN OSTEOPOROSIS • Better identification of patients in whom to use pharmacological therapy • New approaches to reverse bone loss • Customizing treatment: which drug(s) and when?

3. KEY CLINICAL ISSUES IN OSTEOPOROSIS • Better identification of patients in whom to use pharmacological therapy • New approaches to reverse bone loss • Customizing treatment: which drug(s) and when?

4. DUAL ENERGY X-RAY ABSORPTIOMETRY (DXA)Limitations in Assessment of Fracture Risk • Although DXA is the keystone for clinical assessment of fracture risk, epidemiologic studies and drug trials, it has some limitations • DXA measures areal BMD which overestimates true volumetric BMD, is confounded by osteophytes and extraskeletal calcification, fails to separate cortical and trabecular bone, and fails to capture important elements of bone strength • Patients with “osteopenia” constitute the largest group of all patients who fracture

5. CURRENTLY AVAILABLE IN VIVO TECHNIQUES TO ASSESS BONE STRUCTURE • Central QCT • HRpQCT • MRI

6. VOXEL QCT-BASED FE MODELS OF A LUMBAR VERTEBRA IN A TREATED PATIENT Keaveny et al. JBMR 21:149, 2007

7. HRpQCT (Xtreme CT) • With a voxel size of 82 μm, can define trabecular and cortical microstructure and correlates highly with ex vivoμCT: • R ≥ 0.96 for BV/TV, Tb.N., Tb.Th., and Tb.Sp. (Laib et al. Bone 24:35, 1999); R = 0.98 for Ct.Th. (MacNeil et al. Med Eng Phys 29:1096, 2007) • Can be used to construct μFE models of bone strength (Pistoia et al. Bone 30:842, 2002)

8. HRpQCT IMAGING (Cont’d)

9. WRIST MRI Chesnut et al. JBMR 20:1548, 2005

10. µMRI • Image processing to extract microstructural information • Architectural parameters: • Bone volume fraction • Trabecular thickness • Surface to curve ratio (ratio of all surface voxels to all curve voxels; higher ratio indicates more intact trabecular network) • Topological erosion index (ratio of parameters expected to increase with trabecular deterioration to those expected to decrease; lower ratio indicates less trabecular deterioration) Wehrli et al. JBMR 16:1520, 2001; Gomberg et al. IEEE Trans Med Imaging 19:166, 2000

11. TRABECULAR STRUCTURE BEFORE AND AFTER T REPLACEMENT Benito et al. JBMR 20:1785, 2005

12. NOVEL IMAGING APPROACHES FOR DETERMINING OSTEOPOROSIS RISK: SUMMARY • Clearly provide important information on changes in bone structure with aging and the structural basis for fractures • While magnitude of differences between fracture and control subjects tends to be greater than with DXA, improvements in predictive ability for fracture risk are modest using current approaches • Future: • Improvements in resolution, image analysis, fidelity of FE models (eg, compression vs torsion, non-linear models) • Microstructural changes may be more relevant in the early phases of bone loss

13. KEY CLINICAL ISSUES IN OSTEOPOROSIS • Better identification of patients in whom to use pharmacological therapy • New approaches to reverse bone loss • Customizing treatment: which drug(s) and when?

14. EFFECT OF DIFFERENT THERAPEUTIC REGIMENS ON LUMBAR SPINE BMD IN POSTMENOPAUSAL OSTEOPORSIS 40 FS regimen 30 AR regimen high turnover 20 D BMD, % of basal 10 AR regimen low turnover 0 No treatment -10 0 1 2 3 4 Treatment, yr 1778

15. Anti-resorptive Drugs Estrogen, SERMs Bisphosphonates Calcitonin Strontium Cathepsin K inhibitors RANKL antibody APPROVED AND PENDING DRUGS

16. Anti-resorptive Drugs Estrogen, SERMs Bisphosphonates Calcitonin Strontium Cathepsin K inhibitors RANKL antibody Formation Stimulating Drugs Teriparatide SOST antibody Others APPROVED AND PENDING DRUGS

17. Anti-resorptive Drugs Estrogen, SERMs Bisphosphonates Calcitonin Strontium Cathepsin K inhibitors RANKL antibody Formation Stimulating Drugs Teriparatide SOST antibody Others APPROVED AND PENDING DRUGS

18. TERIPARATIDE • Approved at a dose of 20 μg/d for a maximum of 2 years for the treatment of postmenopausal osteoporosis/male osteoporosis/GIOP • Decreases the risk of vertebral fractures by 65% and non-vertebral fractures by 53% after an average of 18 months of therapy

19. TIME COURSE OF CHANGES IN BONE TURNOVER WITH PTH Serum Osteocalcin Serum P1NP Serum N-telopeptide 400 1400 300 1200 300 1000 200 800 100 600 Percent change 100 100 400 200 0 0 0 -200 -100 -100 0 6 12 18 24 30 0 6 12 18 24 30 0 6 12 18 24 30 Time, months Time, months Time, months Alendronate Hu PTH(1-34) Finkelstein et al. JCEM 91:2882, 2006 Both

20. VARIABILITY IN THE RESPOSE TO PTH 60 40 Frequency, % 20 0 -16 -8 0 8 16 24 32 40 1 year change, % Sellmeyer et al. Osteoporosis Int 18:973, 2007

21. Anti-resorptive Drugs Estrogen, SERMs Bisphosphonates Calcitonin Strontium Cathepsin K inhibitors RANKL antibody Formation Stimulating Drugs Teriparatide SOST antibody Others APPROVED AND PENDING DRUGS

22. WNT SIGNALING IN BONE Khosla, Westendorf, and Oursler JCI 118:421, 2008

23. WNT SIGNALING IN BONE Khosla, Westendorf, and Oursler JCI 118:421, 2008

24. EFFECTS OF SOST Ab ON BONE MASS AND STRUCTURE Li et al. JBMR 24:578, 2009

25. KEY CLINICAL ISSUES IN OSTEOPOROSIS • Better identification of patients in whom to use pharmacological therapy • New approaches to reverse bone loss • Customizing treatment: which drug(s) and when?

26. Anti-resorptive Drugs Estrogen, SERMs Bisphosphonates Calcitonin Strontium Cathepsin K inhibitors RANKL antibody Formation Stimulating Drugs Teriparatide SOST antibody Others Which drug, when? Combinations? What sequence? Duration/drug holidays? APPROVED AND PENDING DRUGS