1. Garvan Institute of Medical Research Osteoporosis Treatment: Why, Who, What & When ? John A Eisman AO MB BS PhD FRACP Director, Bone and Mineral Research Program, Garvan Institute of Medical Research; Endocrinologist, St Vincent's Hospital; Professor (Conjoint), University of New South Wales Consulting and Research Support from Amgen, deCode, Eli Lilly, GE-LUNAR, Interleukin Genetics, Merck Sharp and Dohme, Novartis, Organon, Roche-GSK, sanofi-aventis, Servier, WHO Ho Chi Minh City, July 2008

2. Garvan Institute of Medical Research Osteoporosis A major health care problem In Australia >1 in 2 older women and 1 in 3 older men will have an osteoporotic fracture during their lifetime 1-3 Mortality increased 2-3 fold in men and women after all types of Osteoporotic fractures 4,5 Major & increasing impact on well-being, mortality 3,6 & health care costs 1,7 1 Randell 1995, 2 Nguyen 2005, 3 Sanders 1999, 4 Center 1999, 5 Bliuc 2007, 6 Australian Consensus Statement 1997, 7 Access Economics 2000

3. Garvan Institute of Medical Research Osteoporosis Costs Affects 8 million Women and 2.5 million Men in USA Expected to increase by about 40% by 2020 1 Direct costs in US in 2001 = $ 12 - 17 billion annually estimated 1  $32 - $47 million every single day Direct + Indirect costs in Australia of $7 billion annually estimated 2  AUD 19 million every single day AUD $1/day for every person in Australia every single day 1 US Surgeon-Generals Report 2 Access Economics

4. Hip Fracture Worldwide Projections Gullberg, Johnell & Kanis 1997 Osteoporosis Int 7:407-13 0 200 400 800 19902025 2050 All Europe Asia Africa N America Latin America Oceania Hip fractures 1000/yr in 80+ yr olds 2008

5. Garvan Institute of Medical Research Osteoporosis prevalence & therapy in primary care 52,780 of 88,040 postmenopausal women from 927 Australian GPs 29% at least 1 fracture post-menopause 1 < 20% on any osteoporosis-specific treatment 1829 women & men with low trauma fractures from 16 Public hospitals around Australia 2 < 10% investigated & < 10% initiated on specific R x Of 37,957 GP patients (71 yrs), 12.6% had prior fracture & 30% prior spine # 3 Specific therapy in 29.7% with any # & 12.6% with prior spine # 1 Eisman et al, 2004 JBMR 19:1969-75 2 Teede et al, 2007 Int Med J 37:674-9 3 Sambrook et al, OI 2008 (Epub)

6. Garvan Institute of Medical Research Osteoporosis: Scope of the Problem Common in men as well as women Onset relatively early in older years Any fracture signals major increase in risk Major impact on morbidity, costs and mortality Majority at high risk, even after an osteoporotic fractures, are not treated to reduce risk of future fractures

7. Garvan Institute of Medical Research Osteoporotic fractures by site in Dubbo: 1989-2000 Women 809 n = 809 Men 306 n = 306 13 Clavicle/Sternum 58 Proximal Humerus 52 Rib 13 Distal Humerus 201 Spine 156 Forearm/Wrist 22 Hand 175 Hip 41 Distal Femur, Knee Proximal Tibia 40 Ankle 33 Foot 7 16 52 1 78 25 54 11 20 10 25 Pelvis 7 Chang et al, 2004 JBMR 19:532-536

8. Garvan Institute of Medical Research 0 20 40 60 80 100 Women 60-69 MenWomen 70-79 MenWomen 80+ Men First Fracture Re-Fracture Age Risk per 1000 P-yrs Center et al (2007) JAMA 297:387-394 Absolute Risk of Subsequent Fracture

9. Garvan Institute of Medical Research Subsequent Fracture according to Initial Fracture WomenMen Hip Major Minor Subsequent Fracture Center et al (2007) JAMA 297:387-394

10. Garvan Institute of Medical Research Osteoporosis-associated Mortality Age-standardised mortality risk increased 2-3 fold after all types of osteoporotic fracture Women Men Proximal femur 2.2 3.2 Vertebral1.72.4 Other major1.9 2.2 Center et al, Lancet 1999

11. Garvan Institute of Medical Research Standardized Mortality Ratio of First and Subsequent Fractures Over Time SMR 2.5 3.1 1.2 0.6 0 1 2 3 4 WomenMen First fracture (0-5yr) First fracture (>5yr) Bliuc et al (2006) ANZBMS/IOF

12. Garvan Institute of Medical Research Standardized Mortality Ratio of First and Subsequent Fractures Over Time SMR 2.5 3.1 1.2 0.6 2.7 3.5 1.4 1.8 0 1 2 3 4 WomenMen First fracture (0-5yr) First fracture (>5yr) Subsequent fracture (0-5yr) Subsequent fracture (>5yr) Bliuc et al (2006) ANZBMS/IOF

13. Garvan Institute of Medical Research Management of Osteoporosis Public Health Approaches –Regular physical activity –Adequate calcium & protein intake –Avoid smoking, excessive alcohol intake –Minimise falls risk Low bone density –Personal aspects eg age and low weight –Family history –Corticosteroid use Prior low trauma fractures –Increased future fracture risk  clear cost-benefit for treatment

14. Garvan Institute of Medical Research Management of Osteoporosis Public Health Approaches –Regular physical activity –Adequate calcium & protein intake –Avoid smoking, excessive alcohol intake –Minimise falls risk Low bone density –Personal aspects eg age and low weight –Family history –Corticosteroid use Prior low trauma fractures –Increased future fracture risk  clear cost-benefit for treatment Largely ignored Limited access Most untreated

15. Garvan Institute of Medical Research Osteoporosis: Options for Therapy Age Hormone therapy Bisphosphonates Strontium ranelate SERMs/tibolone 20406080 Vitamin D PTH Calcium Life Style Treatment choices Bone density Fracture risk

16. Garvan Institute of Medical Research Calcium and Vitamin D Adequate calcium intake - dairy ± supplements for “optimal” peak bone health Vitamin D deficiency common in institutionalized-housebound Current treatments validated ± calcium & vitamin D Vitamin D and calcium insufficient alone

17. Garvan Institute of Medical Research 1 Rossouw & WHI, 2002 JAMA 288:321-33 2 Banks et al, 2004 JAMA 291:2212-20 Women’s Health Initiative 1 Hip fracture RR 0.66 (1/1,000 w.yr) All fracture RR 0.76 (4/1,000 w.yr) Million Women's Study and Fractures 2 All fracture RR 0.62 (0.58 - 0.66) (5/1,000 w.yr) irrespective of HRT type Current users, rapid (≤ 1 year) onset and offset of benefit Sex Hormone Therapy & Fractures

18. MORE Trial - 4 Years Eastell et al 2000 JBMR 15:S229 % of Women With Incident Vertebral Fracture 0 10 20 30 WITH Prevalent Vertebral Fractures WITHOUT Prevalent Vertebral Fractures RR 0.51 (95% CI = 0.35, 0.73) RR 0.66 (95% CI = 0.55, 0.81) Raloxifene 60 mg/d Placebo 49% 34% SERM Raloxifene & spine fractures Spine but not non-spine fracture risk reduction

19. Incidence of Invasive Breast Cancer Years in Study 012345678 0.0 1.0 2.0 3.0 4.0 HR 0.34 (95% CI = 0.22-0.50) Placebo 4.2 per 1000 Women-Yrs Raloxifene 1.4 per 1000 Women-Yrs p <0.001 Cumulative Incidence (%) 66% 8 Years of MORE plus CORE Martino et al. J Natl Cancer Inst 2004;96:1751-61 7705 women over 8 years

20. Garvan Institute of Medical Research Bisphosphonate & Fracture Reduction Spine # 0 20 40 60 80 100 Wrist # 48% Hip # 51% Any # 28% Symptomatic 55% Multiple 90% Fracture Reduction % Black et al, 1996 Alendronate Lancet 348:1535–1541 47% Any Non-spine # Fracture reduction 50  30%

21. ALENDRONATE Onset of fracture risk reduction Clinical Vertebral Fractures * * 27%* Black DM et al. J Clin Endocrinol Metab 2000;85:4118-24 Nonvertebral Fractures * * * * 45%*

22. RISEDRONATE Onset of Fracture Risk reduction Clinical Vertebral Fractures * * 59%* Nonvertebral Fractures * * 69%* * * * * * * * * Roux et al. Curr Med Res Opin 2004; 4:433 Harrington et al. CTI 2004; 74:129 0 5 10 15 0 1836 Months Percent of Patients PLB RIS 0 6 12 18 24 30 36

23. Garvan Institute of Medical Research BMD with alendronate up to 10 Years Year % change from Bone et al 2004 NEJM;350:1189–99 ALN 5 mg (n=78) ALN 10 mg (n=86) ALN 20/5 mg/placebo (n=83) Year 012345678910 0 2 4 6 8 12 14 Lumbar Spine 012345678910 0 2 4 6 8 Total Hip

24. Garvan Institute of Medical Research Persistence of bisphosphonate effects Gradual loss of BMD & turnover effects over further 5 yrs following 5 years of alendronate 1 Effect on BMD, turnover & fracture risk after cessation  duration of use up to 7 yrs of alendronate 2 Shorter for Risedronate 3 ? 1 Bone et al, 2004 NEJM 350:1189-99 2 Bagger et al, 2003, Bone 33:301-7 3 Watts et al, ISCD 2004, 2005

25. Efficacy after stopping Alendronate FLEX (FIT Long-term Extension Study) Relative loss of BMD & bone turnover suppression but remains ‘better’ than base-line  NO  in overall fracture rate (morphometric spine & non-spine) over 4-5 years off Alendronate BUT  in clinical spine fractures 5.3% vs 2.4% RR = 0.45 (0.24-0.85) AND mild osteoporosis (T-score -1.3 to -2.2) Black et al, JAMA 2006, 296:2927-38

26. Urinary NTx /Cr * p<0.05 from baseline # p<0.05 from placebo Risedronate Offset After 3-Yr Exposure Reversal of Antiresorptive Effect 363648 -60 -50 -40 -30 -20 -10 0 Placebo RIS 5mg Month % change from baseline * * * * # # # Serum BSAP 136123648 -4040 -3030 -2020 -1010 0 1010 Placeb o RIS 5mg Month * # * # * # * # RIS removed Watts et al ISCD 2004

27. Garvan Institute of Medical Research Zoledronic Acid Yearly IV infusions Fracture Site Vertebral –Morphometric deformities –Multiple morphometric –Clinical Hip fracture Non-vertebral fractures Any clinical fracture Black et al, 2007 NEJM 356:1809-22 Placebo 310 66 84 88 388 456 Zoled 92 7 19 52 292 308 Hazard ratio 0.30 (0.24-0.38) 0.11 (0.05-0.23) 0.23 (0.14-0.37) 0.59 (0.42-0.83) 0.75 (0.64-0.87) 0.67 (0.58-0.77) SAE Atrial fibrillation

28. RELATIVE RISKS AND 95% CI * humerus, pelvis-sacrum ribs-sternum, hip, clavicle, wrist Relative risk reduction 00.511.5 Over 3 years Non-spine - 16% P=0.04 Hip - 36% P=0.046 Major non-spine * - 19% P=0.031  RR Reginster et al. JCEM 2005;90:2816-22. Strontium ranelate & non-spine fractures

29. Garvan Institute of Medical Research 00.511.5 Relative risk reduction Over 3 years - 32% P=0.013 Spine - 31% Non-spine P=0.011 - 32 % Hip fracture P=0.112  RR Seeman et al. 2004 JBMR;19:S57;Abs 1219. Strontium ranelate and fracture risk reduction RELATIVE RISKS AND 95% CI Elderly women

30. Garvan Institute of Medical Research Teriparatide (hPTH 1-34) & fracture outcomes BMD loss upon cessation of intermittent rhPTH1-34 but reduction of vertebral fracture risk persisted New vertebral fractures over further 18 months Women 1 Men 2 Prior placebo 19.0%11.7% Prior 20 mg PTH 11.3% 5.4% Prior 40 mg PTH 10.4% 6.0% 1 Lindsay et al 2004, Arch Int Med 164:2024-30 2 Kaufman et al 2005 Osteopor Int 16:510-6

31. Garvan Institute of Medical Research Effect of Teriparatide on the Risk of Nonvertebral Fragility Fractures Adapted from Neer et al. N Engl J Med 2001 *P = 0.02 vs. placebo † P = 0.01 vs. placebo RR = relative risk vs. placebo % of women with >1 fragility fracture RR  53%* RR  54% †

32. Garvan Institute of Medical Research Potential adverse treatment effects Suppressed turnover ?  microcracks Osteopetrosis ? unusual fractures Osteonecrosis of jaw (ONJ) Osteomalacia Osteosarcoma Breast cancer Cardiovascular events Cerebrovascular events DVT & pulmonary embolism Skin rash & Stevens-Johnson syndrome

33. Garvan Institute of Medical Research Absolute Fracture Risk & NNT 10 100 1000 10000 110100200502052 Number Needed to be Treated per yr Fractures per 1000 person.yr 0.2 0.4 0.6 1.0 Fracture Relative Risk Reduction 60-69 yr Man No prior fracture 80+ yr Man Prior fracture 500 20

34. Garvan Institute of Medical Research Absolute fracture risk in a woman Points 0 10 20 30 40 50 60 70 80 90100 Age (years) 556065707580859095100 FNBMD T-scores 43210-2-3-4-5-6 Prior fracture (>50 yrs) 02 1≥3 Number of falls (past 12 mo) 02 1≥3 Total Points 0 20 40 60 80100120140160180 5-year risk 0.010.05 0.1 0.20.40.60.8 10-year risk 0.050.10.20.40.60.80.99 78 11 % 22 % 4659 28 106 30 % 52% Nguyen et al, Osteoporosis Intentional 2007 & 2008 www. FractureRiskCalculator.com

35. Garvan Institute of Medical Research, Osteoporosis therapy BMD T score A B C Age 6080 - 1.0 - 2.5 Calcium, Protein intake Vitamin D, Exercise Moderate alcohol & not smoking

36. Garvan Institute of Medical Research Osteoporosis & Fracture Rational Intervention Why ? Large impact on health, mortality and costs Therapy effective (30-50%) and well tolerated Whom ? Prior fracture (    ), low BMD + older age (  ) When ? Reasonable life expectancy What ? Nutrition & lifestyle, specific-osteoporosis treatments Disease severity, rapidity and persistence of action How long ? Balance of benefits & risks Therapy interruption must be monitored