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

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

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 Direct costs in US in 2001 = $ 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

Hip Fracture Worldwide Projections Gullberg, Johnell & Kanis 1997 Osteoporosis Int 7: All Europe Asia Africa N America Latin America Oceania Hip fractures 1000/yr in 80+ yr olds 2008

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: Teede et al, 2007 Int Med J 37: Sambrook et al, OI 2008 (Epub)

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

Garvan Institute of Medical Research Osteoporotic fractures by site in Dubbo: Women 809 n = 809 Men 306 n = 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 Pelvis 7 Chang et al, 2004 JBMR 19:

Garvan Institute of Medical Research Women MenWomen MenWomen 80+ Men First Fracture Re-Fracture Age Risk per 1000 P-yrs Center et al (2007) JAMA 297: Absolute Risk of Subsequent Fracture

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

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 Vertebral Other major Center et al, Lancet 1999

Garvan Institute of Medical Research Standardized Mortality Ratio of First and Subsequent Fractures Over Time SMR WomenMen First fracture (0-5yr) First fracture (>5yr) Bliuc et al (2006) ANZBMS/IOF

Garvan Institute of Medical Research Standardized Mortality Ratio of First and Subsequent Fractures Over Time SMR WomenMen First fracture (0-5yr) First fracture (>5yr) Subsequent fracture (0-5yr) Subsequent fracture (>5yr) Bliuc et al (2006) ANZBMS/IOF

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

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

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

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

Garvan Institute of Medical Research 1 Rossouw & WHI, 2002 JAMA 288: Banks et al, 2004 JAMA 291: 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 ( ) (5/1,000 w.yr) irrespective of HRT type Current users, rapid (≤ 1 year) onset and offset of benefit Sex Hormone Therapy & Fractures

MORE Trial - 4 Years Eastell et al 2000 JBMR 15:S229 % of Women With Incident Vertebral Fracture 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

Incidence of Invasive Breast Cancer Years in Study HR 0.34 (95% CI = ) 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: women over 8 years

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

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

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: Months Percent of Patients PLB RIS

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 Lumbar Spine Total Hip

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: Bagger et al, 2003, Bone 33: Watts et al, ISCD 2004, 2005

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 ( ) AND mild osteoporosis (T-score -1.3 to -2.2) Black et al, JAMA 2006, 296:

Urinary NTx /Cr * p<0.05 from baseline # p<0.05 from placebo Risedronate Offset After 3-Yr Exposure Reversal of Antiresorptive Effect Placebo RIS 5mg Month % change from baseline * * * * # # # Serum BSAP Placeb o RIS 5mg Month * # * # * # * # RIS removed Watts et al ISCD 2004

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: Placebo Zoled Hazard ratio 0.30 ( ) 0.11 ( ) 0.23 ( ) 0.59 ( ) 0.75 ( ) 0.67 ( ) SAE Atrial fibrillation

RELATIVE RISKS AND 95% CI * humerus, pelvis-sacrum ribs-sternum, hip, clavicle, wrist Relative risk reduction 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: Strontium ranelate & non-spine fractures

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

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: Kaufman et al 2005 Osteopor Int 16:510-6

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% †

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

Garvan Institute of Medical Research Absolute Fracture Risk & NNT Number Needed to be Treated per yr Fractures per 1000 person.yr Fracture Relative Risk Reduction yr Man No prior fracture 80+ yr Man Prior fracture

Garvan Institute of Medical Research Absolute fracture risk in a woman Points Age (years) FNBMD T-scores Prior fracture (>50 yrs) 02 1≥3 Number of falls (past 12 mo) 02 1≥3 Total Points year risk year risk % 22 % % 52% Nguyen et al, Osteoporosis Intentional 2007 & 2008 www. FractureRiskCalculator.com

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

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