골절 예방의 중요성과 비척추골절 예방 효과 정 호 연 경희대학교 동서신의학 병원

Annual Incidence in the US x 1000 Osteoporotic Fractures in Women: Comparison With Other Diseases Vertebral Fx: 70 만건 Hip Fx: 30 만건 Wrist Fx: 25 만건 기타: 25 만건 2000 1 500 0001 1500 Annual Incidence in the US x 1000 1000 500 0002 500 240 0003 180 0003 Osteoporotic Fractures Heart Attack Stroke Breast Cancer 1Osteoporosis Fast Facts. National Osteoporosis Foundation. 2000. 2 National Institutes of Health. Healthy Heart Handbook for Women. 2000. 3Statistical Information on Women and Women’s Health. US Department of Health and Human Services. 2000.

(5713 women aged between 50 and 85 years) Estimated prevalence of female osteoporosis, measured at the fermoral neck, by age band Data from UK (5713 women aged between 50 and 85 years) Br J Radiol 75:736, 2002

NHANES, source: NOF, 2002

Osteoporosis - An Epidemic Yet to Come Europe, USA, Oceania, Russia Asia, Middle East Lat America, Africa 3500 Hip Fractures in Asia Hip fracture incidence (HK): 300%  over 30 years In 2050, more than 50% of hip fractures will occur in Asia 3000 2500 Hip Fractures, x1000 2000 1990 2025 1500 2050 1000 500 Men Women Men Women

All fractures are associated with morbidity Unable to carry out at least one independent activity of daily living 80% One year after an hip fracture: Patients (%) Unable to walk independently 40% Permanent disability Death within one year 30% 20% Cooper C, Am J Med, 1997;103(2A):12S-17S

Mortality Following Hip and Vertebral Fractures Years after fracture Source: Cooper 1997. Am J Med 103(2A):12S-19S

FALLS AND FRACTURE The incidence of wrist fracture is parallel to the incidence of falls in women. Winner et al, Br med J 1989 The nature of the fall determines the type of fracture. Nevitt et al, JAGS 1993 forward: wrist sideways: hip 1/3 of people > 65 years old fall each year 6% of falls result in fracture 1% are associated with hip fracture (90% of hip fractures are associated with falls). Tinetti et al, N Engl J Med 1997

Number of Baseline Vertebral Fractures The Fracture Cascade Overall, 20% fractured again within the year following a new fracture Risk of fracture increased with the number of baseline fractures 30 * 25 20 % of Patients 15 10 5 Overall 1 2+ Number of Baseline Vertebral Fractures *p<0.05, vs patients with no prevalent vertebral fractures (12-fold increased risk). Lindsay R, et al. JAMA. 2001;285:320-323.

NON VERTEBRAL FRACTURE IS A RISK FACTOR FOR OTHER FRACTURES N = 2548 placebo patients Prior NON VERT FRACTURE Yes No Subsequent NON VERT Fracture Subsequent VERT Fracture

Increased risk of subsequent fracture following an initial fracture A Medline search was performed using the search terms “osteoporosis” and “fractures” to identify all articles in English from January 1966 up to September 1999. A total of 3576 articles were identified and performed a statistical synthesis of the risk of future fracture, given a history of prior fracture. JBMR 15:721, 2000

Risk factors for proximal humerus fracture Related to Femoral neck BMD Calcaneal SOS Maternal history of hip fracture History of falls Number of physical activities Static balance Ankle or foot pain 1.4 (1.1-1.7) 1.3 (1.0-1.6) 1.8 (1.0-3.0) 1.1 to 3.0 (1.5-6.1) 1.4 to 2.2 (1.1-4.4) 1.8 (1.1-2.9) 1.4 (1.0-2.1) Osteoporosis + - Fall Risk Score Low High Incidence per 1000 woman-years 5.1 3.8 5.3 12.1 Lee et al, JBMR 2002

INDIVIDUAL RISK ASSESSMENT ROTTERDAM STUDY Age (per 5 years) Gender (female) Height (5cm class) Use of walking aid (yes/no) Current cigarette smoking (yes/no) BMD (0.05g/cm²) OR (95% CI) 1.8 (1.5-2.3) 2.6 (1.0-6.4) 1.5 (1.1-1.9) 2.7 (1.4-5.2) 2.2 (1.1-4.4) 1.5 (1.3-1.7) Point 6 9 4 10 8 Burger et al Bone 1999

INDIVIDUAL RISK ASSESSMENT Black et al, Osteoporos Int 2001

Risk factors used in the calculation of 10-year risk of fracture Femoral neck T-score Age Previous low trauma fracture Low BMI Ever steroid exposure Family history of hip fracture Current cigarette smoking High alcohol intake (> 2 units/day)* *1 unit = 8 gm alcohol ~ ½ pt. beer ~ glass wine Kanis JA et al, Bone, 2002;30:251-258 Kanis JA et al, Osteoporos Int, 2005;16:581-589

Hierarchy of clinical evidence EBM and osteoporosis Decision making

Magnitude of effect on vertebral fractures Summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocrine Rev 2002; 23:570–8. ( without WHI data of hormone therapy)

Magnitude of effect on nonvertebral fractures Summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocrine Rev 2002; 23:570–8. ( without WHI data of hormone therapy)

Magnitude of therapy effect on fracture risk reduction 5

여성호르몬에 대한 장점과 위험성 Estrogen + progestin Estrogen only Benefit (RR) (WHI, JAMA 288:321, 2002) Estrogen only (WHI, JAMA 291:1701, 2004) Benefit (RR) Colon Ca: 0.63 (0.43-0.92) Hip fx: 0.66 (0.45-0.98) Colon Ca: 1.08 (0.75-1.55) Hip fx:0.61(0.41-0.91) Risk Breast Ca: 1.26(1.0-1.59) CHD: 1.29 (1.02-1.63) Stroke: 1.41(1.07-1.85) PE: 2.13 (1.39-3.25) Bresat Ca:0.77(0.59-1.01) CHD: 0.91:(0.75-1.12) PE:1.34 (0.87-2.06) Stroke: 1.39(1.1-1.77)

폐경후 골다공증 치료에서 새로운 약제의 비교 PTH Strontium Ibandronate Zoledro nate 투여방법 SC PO IV 투여 용량 20 mg 2 g 2.5 mg 150 mg 3 mg 5 mg 사용법 매일 q 1개월 q 3개월 q 1년 LS BMD +9.7% ( 18 개월 ) +14.4% (8.1%) ( 3년 ) +6.5% +6.6% ( 2년 ) +6.3% + FN +2.8% +8.3% >3% 척추 골절율 - 65% - 41% - 62% -70% 비척추 - 53% - 19% - 69% (고위험군) -25% 대퇴골 36% -40% 특징 FDA 공인 골생성 촉진제 골생성 촉진 골흡수 감소 사용 편리성 1년 간격 치료 기타 고 비용 간헐적 용법 골밀도 과대평가 위장관 장애 근육통 발열

How can we evaluate anti-fracture efficacy of Osteoporosis? EMEA ITT analysis over 3-years required Most studies have focused on prevention of vertebral fractures Non-vertebral fractures: often subgroup analysis European Agency for the Evaluation of Medicinal Products (EMEA) The gold standard for demonstration of anti-fracture efficacy in osteoporosis trials is the primary predetermined analysis of the intention to treat (ITT) population; this is highlighted by the requirement of fracture prevention efficacy in trials of at least 3-year duration for registration of new therapies The majority of these trials have focused on the prevention of vertebral fracture, with assessment of efficacy in the prevention of non-vertebral fracture relying largely on the analysis of subgroups. The use of subgroup analyses to demonstrate efficacy of a new treatment is not in line with recognized scientific standards and should be interpreted with caution.

New ITT and meta-analysis regarding non-vertebral antifracture efficacy Inclusion: 3-year clinical trials of ITT populations that met regulatory registration criteria Boonen S et al. Osteoporos Int 2005; 16:1291-98

Trials Included in the ITT Analysis Characteristics and Results Drug Trial Age Prevalent # Total N Length nv#incidence PBO nv#incidence Active P-value ARR ALN Libermann 64 21% 994 3J 10.7% 8.5% NA 2.2% FIT VFA 71 100% 2027 14.7% 11.9% 0.06 2.8% FIT CFV 68 0% 4432 4J 13.3% 11.8% 0.13 1.5% RIS VERT-MN 98% 812 16.0% 10.9% 5.1% VERT-NA 69 78% 1627 8.4% 5.2% 0.02 3.2% HIP 78 30% 9331 11.2% 9.4% 0.03 1.8% RAL MORE 66 37% 6828 9.3% Strontium TROPOS 77 34% 4932 12.9% 0.04 1.7% SOTI 1442 16.9% 15.6% 1.3% IBN BONE 94% 2929 8.2% 9.1%/ 8.9% -0.9/-0.7% Calcitonin PROOF 79% 620 5J 15.7% 14.6% 1.1% Boonen S et al. Osteoporos Int 2005; 16:1291-98

Anti-nonvertebral fracture efficacy of alendronate and risedronate in ITT

Funnel Plot of Six Trials with Alendronate and Risedronate ALN 10.000 9000 8000 Results of meta-analysis were significant for: Alendronate (RR=0.86; 95% CI 0.76-0.97) and Risedronate (RR=0.81; 95% CI 0.71-0.92) demonstrating non-vertebral anti-fracture efficacy 7000 6000 Sample size 5000 4000 3000 2000 1000 0.0 0.5 1.0 1.5 2.0 Relative risk Boonen S et al. Osteoporos Int 2005; 16:1291-98

Non-Vertebral Fracture Incidence by Treatment Libermann FIT VFA FIT CFV VERT-MN VERT-NA HIP MORE TROPOS SOTI BONE PROOF Alendronate Risedronate * * Raloxifene * Strontium Ibandronate Calcitonin 0.5 1.0 1.5 RR Boonen S et al. Osteoporos Int 2005; 16:1291-98

Fractures incidence (%) Effects of Treatments on Non-vertebral fractures * * * Fractures incidence (%) FIT 1, FIT 2 : The studies for Alendronate VERT-MN, VERT-NA, HIP : The studies for Risedronate MORE : The study for Raloxifene BONE : The study for Ibandronate TROPOS : The study for Strontium * placebo (No head to head studies) * p < 0.05 Anti-osteoporotic agent

Summary of ITT- and Meta-analysis on Non-Vertebral Fractures Out of 11 clinical trials meeting criteria for review 3 showed significant results within the trial 2x Risedronate 1x Strontium-ranelate Results of meta-analysis of Alendronate and Risedronate showed that both are comparably Efficacious in preventing non-vertebral fractures Boonen S et al. Osteoporos Int 2005; 16:1291-98

Need for Complete Fracture Protection Devastating impact of osteoporosis in terms of morbidity and mortality Identify individuals most at risk of sustaining vertebral and non-vertebral fractures Treat to reduce the risk of both vertebral and non-vertebral fractures