1. Vietnam Osteoporosis Workshop, HCMC 2006 RISK FACTORS FOR OSTEOPOROTIC FRACTURE IN THE ELDERLY Tuan Van Nguyen and Nguyen Dinh Nguyen Garvan Institute of Medical Research Sydney, Australia

2. Vietnam Osteoporosis Workshop, HCMC 2006 Overview Background Risk factors for fracture risk Summary

3. Vietnam Osteoporosis Workshop, HCMC 2006 Background Aging population: fastest growing age group Osteoporosis and osteoporotic fracture: age- related disorders Osteoporosis and osteoporotic fracture: –Common –Cause serious disability and excess mortality –Major economic burden on healthcare system

4. Vietnam Osteoporosis Workshop, HCMC 2006 Incidence of common diseases (Sources: Riggs BL et al., 1995; American Heart Foundation, 1998; American Cancer Society, 1998)

5. Vietnam Osteoporosis Workshop, HCMC 2006 Survival probability and fracture Age (y) WomenMen Cumulative survival rate (Soure: Center J, Nguyen TV et al., Lancet 1999;353:878-82)

6. Vietnam Osteoporosis Workshop, HCMC 2006 Burden of Osteoporotic fractures Annual cost of all osteoporotic fractures: $20 billion in USA and ~$30 billion on EU 1. Worldwide direct and indirect cost of hip fracture: US$131.5 billion 2. Australia: Total health system costs of osteoporosis, $1.9 billion (2000-2001). (Sources: 1 Cummings et al., Lancet 2002;359:1761-67; 2 Johnell O, Am J Med 1997;103:20S-26)

7. Vietnam Osteoporosis Workshop, HCMC 2006 A systematic skeleton disease characterized by: -low bone mass -microarchitectural deterioration of bone tissue -consequent increase in bone fragility and susceptibility to fracture Definition of Osteoporosis (WHO) Consensus Development Conference: Diagnosis, Prophylaxis, and Treatment of Osteoporosis, Am J Med 1993;94:646-650. WHO Study Group 1994.

8. Vietnam Osteoporosis Workshop, HCMC 2006 (VN 2006, unpublished data) Relationship between BMD and Age

9. Vietnam Osteoporosis Workshop, HCMC 2006 Measure of association: Relative risk (RR) The ratio of the incidence of disease (fracture) in exposed individuals to that in unexposed individuals. In longitudinal studies: the hazards ratio equivalent to relative risk or risk ratio.

10. Vietnam Osteoporosis Workshop, HCMC 2006 Measure of association: Relative risk (RR) RR > 1:  risk RR = 1: no difference RR < 1:  risk Relative risk (95% confidence interval) RR (95%CI) Example:

11. Vietnam Osteoporosis Workshop, HCMC 2006 Bone mineral density: the best predictor of osteoporotic fracture StudyType of studyNUnitRR (95% CI) Nguyen TV et al., 1993 Cohort1080-1SD2.4 (1.9 - 3.0) Marshall D et al., 1996 Meta-analysis11 cohorts-1SD Any fracture1.5 (1.4 - 1.6) Hip2.6 (2.0 - 3.5) Vertebrae2.3 (1.9 - 2.8) Johnell O el al., 2005 Meta-analysis29082-1SD Any fracture1.5 (1.4 - 1.6) Hip2.0 (1.9 – 2.2) WOMEN

12. Vietnam Osteoporosis Workshop, HCMC 2006 Bone mineral density: the best predictor of osteoporotic fracture StudyType of studyNUnitRR (95% CI) Nguyen TV et al., 1993 Cohort790-1SD2.0 (1.5-2.6) Johnell O el al., 2005 Meta-analysis9785-1SD Any fracture1.6 (1.4 - 1.8) Hip2.4 (1.9 – 3.1) MEN

13. Vietnam Osteoporosis Workshop, HCMC 2006 Other bone-related risk factors Outcome/Risk factorUnitRR (95% CI) WomenMen Hip fracture Hip strength* CSMI-1SD1.8 (1.1-3.2)1.6 (1.0-2.5) Section modulus-1SD1.6 (1.1-5.1)2.3 (1.4-2.9) Volumetric BMD**-1SD2.4 (1.8-3.2)3.2 (2.0-5.0) Bone loss*-5%/y1.4 (1.1-1.8)NA * Adjusted for femoral neck BMD; **adjusted for age (Sources: Nguyen TV et al., 2005; Ahlborg H, Nguyen TV et al, 2005; Center J, Nguyen TV et al. 1998 and 2004)

14. Vietnam Osteoporosis Workshop, HCMC 2006 (n=29188)(n=9875) (Adapted from Johnell O el al., JBMR 2005;20:1185-94) Association between age and fracture

15. Vietnam Osteoporosis Workshop, HCMC 2006 BMD: primary predictor of fracture but not good discriminator (Calculation based on Nguyen TV et al., BMJ, 1993;307:1111-15)

16. Vietnam Osteoporosis Workshop, HCMC 2006 Prior fracture OutcomeGenderRR (95% CI)*Increment (%) Any fractureMen2.04 (1.67-2.48)104 Women1.73 (1.59-1.88)73 Osteoporotic fxMen1.91 (1.50-2.43)91 Women1.74 (1.57-1.92)74 Hip fractureMen1.97 (1.12-3.48)97 Women1.56 (1.23-1.98)56 (Kanis J et al., Bone 2004;35:375-82) Results from meta-analysis *RRs were adjusted for BMD

17. Vietnam Osteoporosis Workshop, HCMC 2006 Fall and fall-related factors Risk factor/OutcomeGenderRR (95% CI)*Increment (%) Fall Hip fractureMen2.0 (1.0-4.2)100 Women2.0 (1.3-3.2)100 Postural sway (+1SD) Osteoporotic fxMenSex combined Women1.90 (1.63-2.21)90 Hip fractureMen2.1 (1.6-2.6)110 Women1.6 (1.4-1.8)60 Quadriceps strength (-1SD) Osteoporotic fxMenSex combined Women1.83 (1.49-2.24)83 Hip fractureMen2.3 (1.7-3.2)130 Women2.6 (1.9-3.6)160 (Nguyen TV el al., BMJ 1993;307:1111-5; Nguyen ND et al., JBMR 2005; 20:1921-8)) *RRs were adjusted for BMD

18. Vietnam Osteoporosis Workshop, HCMC 2006 Corticosteroids use OutcomeGenderRR (95% CI)Increment (%) Any fractureMen1.67 (1.10-2.51)67 Women1.39 (1.18-1.64)39 Osteoporotic fxMen2.16 (1.42-3.27)116 Women1.42 (1.18-1.70)42 Hip fractureMen2.62 (0.91-7.51)162 Women2.07 (1.38-3.10)107 (Kanis J et al., JBMR 2004;19:893-99) Results from meta-analysis

19. Vietnam Osteoporosis Workshop, HCMC 2006 Lifestyle: Smoking OutcomeGenderRR (95% CI)Increment (%) Any fractureMen1.27 (1.07-1.51)27 Women1.18 (1.10-1.26)18 Osteoporotic fxMen1.34 (1.10-1.63)34 Women1.15 (1.07-1.25)15 Hip fractureMen1.42 (1.18-1.72)42 Women1.38 (1.15-1.65)38 (Kanis J et al., Osteoporos Int 2005;16:155-62) Association between smoking and fracture Results from meta-analysis Although the magnitude of the association was modest, but the impact of smoking on the community with high prevalence of smoking could be significant

20. Vietnam Osteoporosis Workshop, HCMC 2006 Lifestyle: Alcohol consumption OutcomeLevel (U/d)RR (95% CI)*Increment (%) Any fracture>21.24 (1.06-1.45)24 >31.34 (1.11-1.62)34 >41.51 (1.19-1.93)51 Osteoporotic fx>21.36 (1.13-1.63)36 >31.53 (1.23-1.91)53 >41.64 (1.24-2.17)64 Hip fracture>21.70 (1.20-2.42)70 >32.05 (1.35-3.11)105 >42.39 (1.39-4.09)139 (Kanis J et al., Bone 2004;35:1029-37)) Results from meta-analysis (men and women combined) *RRs were adjusted for BMD 1U/d ~ 8g pure alcohol

21. Vietnam Osteoporosis Workshop, HCMC 2006 Family history of fracture Parental historyOutcomeRR (95% CI)*Increment (%) Any fracture 1.18 (1.07-1.31)18 Osteoporotic fx1.22 (1.08-1.38)22 Hip fracture1.63 (1.24-2.13)63 Hip fractureAny fracture1.41 (1.17-1.71)42 Osteoporotic fx1.54 (1.25-1.88)54 Hip fracture2.28 (1.48-3.15)128 (Kanis J et al., Bone 2004;35:1029-1037) Results from meta-analysis (men and women combined) *RRs were adjusted for BMD

22. Vietnam Osteoporosis Workshop, HCMC 2006 Genetic factor: COLIA1 and VDR genes and fracture GenesOutcomeRR (95% CI)*Increment (%) Meta-analysis* COLIA1 (vs. SS)Any fracture Ss genotype1.26 (1.09-1.46)26 ss genotype1.78 (1.30-2.43)78 Ss genotypeVert. fracture1.37 (1.15 (1.64)37 ss genotype2.48 (1.49-3.65)148 Observational study** COLIA1 (TT)Hip fracture3.8 (1.4-10.8)280 VDR (CC)Hip fracture2.6 (1.2-5.3)160 (*Mann V and Ralston SH, Bone 2003;32:711-17; **Nguyen TV et al., JCEM 2005; 90:6575-9) *RRs were adjusted for BMD

23. Vietnam Osteoporosis Workshop, HCMC 2006 -Medication: Corticosteroids Modifiable risk factors Non-modifiable risk factors Fracture - Bone-related factors: BMD, bone strength indice… - Fall and fall-related factors - Prior fracture - Lifestyle: smoking, alcohol - Advancing age - Family history - Genetics Intervention strategies Identify high-risk group

24. Vietnam Osteoporosis Workshop, HCMC 2006 Association between risk factors and fracture risk: summary

25. Vietnam Osteoporosis Workshop, HCMC 2006 RR of risk factors for fracture Measure of population risk (as a group), but not for an individual patient  useful in the investigation of etiological relationships. Uninformative in clinical decision making, because it obscures the background risk of the outcome interest in the study population. How to translate into individual patient’s interests? Moving towards ABSOLUTE RISK

26. Vietnam Osteoporosis Workshop, HCMC 2006 Residual lifetime risk of fractures (unadjusted and adjusted for competing risk of death) 5 10 15 20 25 30 35 40 45 50 Men, death-adjusted Men, unadjusted Women, unadjusted Women, death-adjusted Years of risk from age 50 Cumulative risk of fracture (%) 0 10 20 30 40 50 60 70 (68) (54) (50) (32) Source: Nguyen et al. 2006, unpublished data

27. Vietnam Osteoporosis Workshop, HCMC 2006 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(at age >50 yrs) 02 13 Number of falls (past 12 mo) 02 13 Total Points 0 20 40 60 80100120140160180 5-year risk 0.010.050.10.20.30.40.50.60.70.80.9 10-year risk 0.050.10.20.30.40.50.60.70.80.90.99 Nomogram for predicting fracture in Women 16 65 14 5 100 The risk for this woman sustaining any fracture within next 5 years = 25% 10 years = 45% A woman of 75 yrs old, Femoral neck BMD T-score = -2.5 Had a fracture when she was 67 yrs Had a fall last year What is the probability for her sustaining a fracture within the next 5 and 10 years?

28. Vietnam Osteoporosis Workshop, HCMC 2006 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(at age >50 yrs) 02 1>=3 Number of falls (past 12 mo) 02 13 Total Points 0 20 40 60 80100120140160180 5-year risk 0.010.050.10.20.30.40.50.60.70.80.9 10-year risk 0.010.050.10.20.30.40.50.60.70.80.90.99 Nomogram for predicting fracture in Men

29. Vietnam Osteoporosis Workshop, HCMC 2006 Key messages Osteoporotic fracture is a multifactorial event No single best predictor BMD is the best predictor but not good discriminator Interaction between risk factors Measure of the association: –Relative risk scale  population risk –Absolute risk scale  individual risk  more clinical relevant

30. Vietnam Osteoporosis Workshop, HCMC 2006 Lời Cảm tạ Chúng tôi xin chân thành cám ơn Công ty Dược phẩm Bridge Healthcare, Australia là nhà tài trợ cho hội thảo.

31. Vietnam Osteoporosis Workshop, HCMC 2006 Thank you!

32. Vietnam Osteoporosis Workshop, HCMC 2006 BMD and the prediction of Osteoporosis and Incident fracture OsteoporosisFracture (Source: Nguyen TV et al, Osteoporos Int 2004;15:49-55)