1. What To Do After Starting Treatment E. Michael Lewiecki, MD, FACP, FACE New Mexico Clinical Research & Osteoporosis Center Albuquerque, NM

2. Fracture Risk Assessment Will I end up like my mother? Fracture Risk Reporting Intervention Thresholds Follow-up Strategies Treatment Decisions Clinical Factors

4. Evidence Based Medicine

12. Eligibility for Treatment or RCT Dowd R et al. Osteoporos Int. 2000;11:533-536. Standard Criteria for Drug Therapy Eligible for Participation in Drug Study A B C D 100% 3% 4% 21% 7% Reasons for Exclusion from Drug Studies Too young 28% Too old 8% Disease too severe 19% Co-morbid conditions 60% Medications 60% Other 3%

13. Adherence in Clinical Trials * Definition of adherence and dropout varies by study Study Drug Time Adherence* Dropout* FIT-I + FIT-II Alendronate 3-4 yrs 86% 4% VERT-NA Risedronate 3 yrs >85% 42% MORE Raloxifene 3 yrs 92% 23% PROOF Calcitonin 5 yrs >90% 59% PEPI Estrogen 3 yrs 77% 3% Neer Teriparatide 1.8 yrs 82% 19%

14. Seeman E et al. Osteoporos Int. 2007;18;711-719. Cramer JA et al. Curr Med Res Opin.2005;21:1453-1460.

15. Lewiecki EM. South Med J. 2007;100:1190-1191.

17. Fracture Risk Decreases with Improved Compliance Adapted from Siris E et al. Mayo Clin Proc. 2006;81:1013-1022, in Seeman E et al. Osteoporos Int. 2007;18;711-719.

22. Impact of Nurse Visits on Adherence Postmenopausal Women Treated with Raloxifene Clowes JA et al. J Clin Endocrinol Metab. 2004;1117-1123. (Refill at 6 mo.) (Nurse visit at 3,6,9 mo.) (Nurse visit with markers at 3,6,9 mo.) Adherence = > 75% of pills taken P<0.05 P<0.05 Adherent patients had better BMD and marker response than non-adherent patients.

23. Typical Responses in Treatment and Placebo Arms of Successful Clinical Trials BMD Fracture Risk BTM, Antiresorptive Rx BTM, Anabolic Rx Percent Change Percent Change Percent Change Fracture Rate (%)

24. BMD Response to Alendronate Concept from EPIC data. Personal communication Dr. Mike McClung. Shaded area shows estimated least significant change (LSC).

25. BMD Change & VF Risk Relative Risk of Vertebral Fracture Wasnich RD, Miller PD. J Clin Endo Metab. 2000;85(1):231-236. A - Alendronate H - Hormone Replacement C - Calcitonin R - Raloxifene E - Etidronate T - Tiludronate T A A A A A H E E R R R C C C T T T 22% 54% Risk Reduction Line = No effect C 13 RCT’s with alendronate, risedronate, ERT, calcitonin, etidronate, raloxifene, tiludronate.

26. Change in BTM & Fracture Risk Pooled data in 6186 women from FIT1 + FIT2 Bauer DC et al. J Bone Miner Res. 2004;19:1250-1258. * * * * * P < 0.01 compared to placebo. Change in BSAP at 1-Year Predicts Fracture Risk over 3.6 Years. Type of Fracture

27. Biomarker Change and Fracture Risk Reduction with Treatment Bouxsein ML, Delmas PD. J Bone Miner Res. 2008;23:1155-1167. NR = No relationship, data exist ND = No data QCT = quantitative computed tomography Micro-arch = micro-architecture hr = high resolution pCT = peripheral computed tomography MRI = magnetic resonance imaging FEA = finite element analysis DXA BMD BTM QCT Micro-arch (hr pCT or MRI) QCT FEA Raloxifene NR + ND ND ND Bisphosphonates ++ +++ ND ND ND Teriparatide + ND ND ND ND Strontium ranelate ++ ND ND ND ND

31. Clinical Considerations for Biomarkers *Least Significant Change = smallest change in a measurement that is likely to represent a genuine change and not a measurement error or biological variation DXA BMD BTM LSC* with 95% CI ~3% (Must be measured for each facility) ~20-40% (biological and analytical variability) Signal-Noise Ratio (biological change/LSC) >1 (varies by skeletal site and drug) >1 (not clear which BTM best for which drug) Time to reach LSC 1-2 years (varies by skeletal site and drug) 3 months (within several days for some drugs) Medicare coverage 1-2 years (varies by Medicare carrier) 2 baseline, 1 f/u per yr Guidelines for clinical use Yes No

35. Bisphosphonate Bone-Losers in Clinical Practice Lewiecki EM, Rudolph LA. J Bone Miner Res. 2002;17(Suppl 1):S367. 90.4% Stable or Increased BMD 9.6% Bone Losers 50% Contributing Factors Identified 50% No Contributing Factors Identified 104 patients age 65 and over with baseline and F/U DXA

38. L1-L4 Scans Baseline 0.729 g/cm 2 Follow-up #1 +0.038 (+5.3%) Follow-up #2 -0.037 (-5.1%)

43. How Long to Treat

45. FLEX: Lumbar Spine BMD 2 4 6 8 10 12 14 3.7% Year P <0.001 Mean Percent Change From FIT Baseline, % 16 FL 0 FL 1 FL 2 FL 3 FL 4 FL 5 0 F 0 F 1 F 2 F 3 F 4 FLEX 5 years Time Between FIT and FLEX 1 to 2 years FIT 3 to 4.5 years Black DM et al. JAMA. 2006;296:2927-2938. = ALN/placebo (n = 437) = ALN/ALN (pooled 5-mg and 10-mg groups: n = 662)

46. FLEX: Serum CTX 0.05 0.25 0.10 0.15 0.20 Mean Absolute Value, ng/mL 0.00 FL 0 FL 1 FL 2 FL 3 FL 4 FL 5 F 0 F 1 F 2 F 3 F 4 Year 56% P <0.0001 FLEX 5 years Time Between FIT and FLEX 1 to 2 years FIT 3 to 4.5 years Black DM et al. JAMA. 2006;296:2927-2938. = ALN/placebo (n = 97) = ALN/ALN (pooled 5-mg and 10-mg groups: n = 139)

47. FLEX: Incidence of Fractures ARR = 2.9% P = 0.013 RR = 0.9 CI (0.6, 1.2) RR = 1.0 CI (0.8, 1.3) 5% 2% 11% 10% 19% 19% Fracture Incidence, % Clinical Vertebral Vertebral Morphometric Nonvertebral RR = 0.45 CI (0.2, 0.8) Hip 3% 3% RR = 1.0 CI (0.5, 2.1) Black DM et al. JAMA. 2006;296:2927-2938. ALN/PLB (n = 437) ALN/ALN (n = 662)

52. Selected Adverse Events Bisphosphonates Raloxifene Teriparatide Calcitonin GI irritation VTE Osteosarcoma in rats Nasal irritation Acute phase reaction Fatal stroke Leg cramps Chronic muscle and bone pain Leg cramps Nausea Renal effects Vasomotor symptoms Headaches Uveitis/iritis/scleritis Fatal stroke Hypercalcemia Hypocalcemia ONJ Unusual fractures? Atrial fib?

53. Comparative Risks Kanis JA et al. Osteoporos Int. 2001;12:417-427. Pharmcoepidemiol Drug Saf. 2003;12:195-202. National Center for Health Statistics. JADA. 2006;137:1144-1150. www.nssl.noaa.gov/papers/techmemos/NWS-SR-193/techmemo-sr193-4.html (1) Women age 65-69 (from Swedish National Bureau of Statistics and database of Olmsted County, MN, USA.)