1. Osteoporosis: Moving Beyond Bone Mineral Density Tuan V. Nguyen Bone and Mineral Research Program Garvan Institute of Medical Research Sydney, Australia

2. Osteoporosis, Fracture and BMD Fracture is the ultimate outcome of osteoporosis Osteoporosis is defined by bone mineral density (BMD) BMD is a good predictor of fracture risk, but a poor discriminator of fracture There are BMD-independent predictors of fracture risk The current definition of osteoporosis is inadequate A probability-based definition is proposed

3. A Shift in Thinking Low bone mass, microarchitectural deterioration of bone tissue leading to enhanced bone fragility and a consequent increase in fracture risk (Consensus Development Conference, 1991) Osteoporosis: Risk factor Fracture: Outcome

4. Incidence of All-limb Fractures Donaldson, et al., J Epidemiol Comm Health 1990

5. Utility loss associated with fx

6. Risk of Death From Hip Fracture 50-year old women: Lifetime risk of mortality from: Hip Fracture: 2.8% Breast Cancer: 2.8% Endometrial Cancer: 0.7% Cummings et al. Arch Intern Med 1989; 149: 2445-8

7. Burden of Hip Fractures

8. Cost of Fractures DiseasePrevalenceAnnual Direct Cost (US$ Billion) Osteoporosis10 million13.8 Asthma15 million7.5 Chronic Heart Failure 4.6 million20.3 National Heart Lung and Blood Institute National Osteoporosis Foundation American Heart Association

9. Current Status BMD is a golden standard for assessment of osteoporosis BMD is used as (a) selection criteria, and (b) an endpoint in clinical trials BMD is the major focus of basic, clinical and epidemiological research in osteoporosis

10. BMD in the Medical Literature

11. Change in BMD with Age Peak bone density Puberty Menopause Osteopenia Osteoporosis Bone Mineral Density Age

12. Bone Mineral Density and Definition of “Osteoporosis” Gaussian distribution Constant standard deviation Decrease with advancing age T-score i = (BMD i – Peak BMD) / SD

13. The Use of T-scores Define “osteoporosis” and “osteopenia” T-score < -2.5 = “osteoporosis” -2.5 < T-scores < -1 = “osteopenia” Criteria for clinical trial entry Intervention threshold

14. BMD and Fracture Risk

15. 12-year Risk of Fracture by BMD and Age Women Age Data: n = 1287 women; No. of fractures: 328

16. 12-year Risk of Fracture by BMD and Age Men Age Data: n = 821 men; No. of fractures: 118

17. 12-year Risk of Hip Fracture by BMD and Age - Women Age Data: n = 1287 women; No. of hip fractures: 89

18. BMD and Prevalence of Osteoporosis

19. Prevalence of Low BMD WomenMen

20. U.S Preventive Services Taskforce "… recommendation that women 65 and older be routinely screened for osteoporosis to reduce the risk of fracture and spinal abnormalities often associated with the disease. … recommends that routine screening begin at 60 for those women identified as high risk because of their weight or estrogen use." Annals of Internal Medicine, Sept 17, 2002

21. 1287women Low BMD 345 (27%) Not Low BMD 942 (73%) Fx = 137 (40%) No Fx = 208 (60%) No Fx = 751 (80%) Fx = 191 (20%) 42% Low BMD (T<-2.5) and Fractures in Women

22. 1287 women Low BMD 562 (44%) Not Low BMD 725 (56%) Fx = 199 (35%) No Fx = 363 (65%) No Fx = 596 (82%) Fx = 129 (18%) 61% Low BMD (T<-2.0) and Fractures in Women

23. 821 men Low BMD N = 90 (11%) Not Low BMD 731 (89%) Fx = 27 (30%) No Fx = 63 (70%) No Fx = 640 (88%) Fx = 91 (12%) 23% Low BMD (T<-2.5) and Fractures in Men

24. 821 women Low BMD N = 173 (21%) Not Low BMD 648 (79%) Fx = 40 (23%) No Fx = 133 (77%) No Fx = 570 (88%) Fx = 78 (12%) 34% Low BMD (T<-2.0) and Fractures in Men

25. T-scoresSensitivitySpecificityPPV T < -2.5 Women Men 40 30 80 88 42 23 T < -2.0 Women Men 35 23 82 88 61 34 Specificity, Specificity, and PPV

26. Specificity, Specificity, and PPV (T<-2.5) SiteSensitivitySpecificityPPV Hip fx Women Men 19 16 97 72 41 Vertebral fx Women Men 20 24 93 96 51 42 Dist Rad & Hum Women Men 11 4 96 99 48 40

27. Specificity, Specificity, and PPV by age AgeSensitivitySpecificityPPV Less than 70 yr23.2 23.0 89.0 89.6 17.0 28.3 70 or older30.5 23.2 85.8 85.9 27.7 38.5 Low BMD: T<-2.5 Low BMD: T<-2.0

28. Can we identify "low-BMD women" by age, weight and prior fx? 100 women Low BMD N=27 Not Low BMD N=74 +ve (22, or 82%) -ve (5, or 18%) +ve (36, or 48%) -ve (38, or 52%) 37%

29. Can we identify low-BMD and fx women? AUC = 0.75 + 0.03AUC = 0.72 + 0.03 AUC = 0.48 + 0.04 T < -2.5 T < -2.0 Incident Fracture

30. Long-term Effect of Alendronate on BMD in Postmenopausal Women with Osteoporosis (PMO) Tonino RP, et al. J Clin Endocrinol Metab. 2000;85:3109-3115.

31. Relationships between Change in BMD and Fracture Risk Each standard deviation lowering in BMD is associated with a 2.5 (or higher)-fold increase in the risk of hip fracture. An increase by 3% would be predicted to reduce fracture risk by 12%.

32. Alendronate and Hip Fracture FractureRR (95% CI) Any non-vertebral fx0.80 (0.63 – 1.01) Hip fx0.49 (0.23 – 0.99) Wrist fx0.52 (0.31 – 0.87) Other fx0.99 (0.75 – 1.31) Black et al, Lancet 1996

33. Risedronate and Hip Fracture Risk in Women 70-79 yrs. with PMO McClung MR, et al. N Engl J Med. 2001;344:333-340.

34. BMD and Fracture: Summary BMD and fracture risk: Good predictor BMD and fracture event: Poor discrimination Moderate increase in BMD => larger-than- expected decrease in fracture risk BMD has been a major focus in osteoporosis research during the past 20 years

35. Osteoporotic Fractures

36. Beyond BMD Risk factorRelative risk Anticonvulsants2.0 History of maternal hip fx1.8 History of hyperthyroid1.7 On feet less than 4 hr/day1.7 Inability to raise from a chair1.7 Resting pulse >801.7 Benzodiazepines1.6 Age (>5 yrs)1.4 Height1.3 Cummings SR, et al. N Engl J Med. 1995;332(12):767-73.

37. Revisit Risk Factors Aetiologic risk factors –Genotypes –Lifestyle factors (eg smoking, alcohol, dietary habit, physical activity, etc) –Mechanical factors –Falls and fall-related factors Clinical risk factors –BMD –Quantitative ultrasound measurements (QUS) –History of fx

38. Genetics of Bone Mineral Density MZ DZ rMZ = 0.73 rMZ = 0.47 Nguyen et al., 1998

39. Candidate Genes for Bone Mineral Density OsteocalcinBGLAP1q25Dohi et al 1998 Interleukin 1 Receptor AntagonistCASR2q13Keen et al 1998 Calcium Sensing ReceptorCASR 3q21-24Cole et al 1998  2HS GlycoproteinAHSG3q27Zmuda et al 1998 Vitamin D binding proteinDBP/GCv4q11-13Papiha et 1996 OsteopontinSPP14q21Willing et al 1998 OsteonectinSPOCK5q31Kobayashi et al 1996 Estrogen receptor  ESR  6q25.1Qi et al 1995; Willing et al Interleukin-6IL-67p21Murray et al 1997 Calcitonin receptorCALCR7q21.3Taboulet et al, Masi et al Collagen type I  2COLIA27q22Willing et al Parathyroid hormonePTH11p15Gong et al Vitamin D receptorVDR12q13Morrison et al Collagen Type I  1COLIA117q22Grant et al Transforming growth factor  1TGF-  119q13Langdahl et al, Yamada et al Apolipoprotein EApoE19q13Kohlmeier et al

40. Potential Genes for Bone Mineral Density

41. Genetic Predictors of Hip Fracture VariableUnitRR (95% CI) Age+5 yr 1.4 (1.1 – 1.8) Femoral neck BMD-0.12 g/cm 2 3.4 (2.3 - 5.0) VDR Taq-1 genotypett vs TT & Tt 2.6 (1.2 - 5.3) COLIA1 Sp-1 genotype ss vs SS & Ss 3.8 (1.4 - 10.8) Nguyen et al., 2003

42. Quantitative Ultrasound as a Predictor of Fracture Risk VariableUnitRR (95% CI) Age+5 yr 1.2 (1.0 – 1.5) Femoral neck BMD-0.12 g/cm 2 1.9 (1.4 - 2.4) Speed of Sound – distal radius 150 m/s 1.8 (1.3 - 2.4) Nguyen et al., 2003

43. Effects of a History of Fx Athor and study designRelative riskRelative risk after adj for BMD Lindsay et al., 4 placebo-controlled trials 5.25.1 Klotzbuecher et al, review4.4? Melton et al, observational study12.6No BMD Black et al., SOF cohort5.44.1 Ross et al., cohort4.13.6 Nevitt et al, Placebo-controlled trial?3.0

44. Research Directions Improvement of models for long-term prediction of fractures –Etiologic risk factors Identification of high-risk individuals –Clinical risk factors

45. Long-term Prediction of Fractures “Remaining Lifetime Fracture Probability (RLFP): the sum of rates of fracture over an estimated remaining lifetime. Make use of etiological risk factors to construct models of prediction –> Risk Index.

46. Risk Profile and Remaining Lifetime Fracture Probability (RLFP) Risk IndexAgeRFLPRx RFLP 60 80 0.46 0.07 0.38 0.03 -2.060 80 2.5 0.50 1.98 0.19 -3.060 5.00 1.11 3.75 0.39

47. Individualisation of Fracture Risk 50 55 60 65 70 75 80 85 90 Risk Rx 0.5% 2.7 0.3 Age Risk Index

48. High-risk Individuals and The Definition of “Osteoporosis” Make use of clinical risk factors and long-term predictive models for diagnostic purpose. Toward a probability-based definition of osteoporosis. Toward a probabilisty-based entry criteria for clinical trials.

49. The Future: A risk score calculator www.RISKFx.com Welcome to the Garvan Institute's Risk Score Calculator for Osteoporotic Fracture. Please enter your information in the following boxes and press CALCULATE to obtain your risk score. To recalculate, please press RESET and repeat the above procedure. Thank you. Age: Sex: Your femoral neck BMD T-score: Your QUS T-score: Your genotype: Do you have a history of fracture (Y/N)? Are you a current smoker (Y/N): Have you had a fall during the past 12 months (Y/N)? Can you raise from a chair easily (Y/N)? CALCULATE RESET

50. Thank you Garvan team: –John Eisman –Jacqueline Center –Natasha Ivanovic –Jim McBride and "IT people" Dubbo team: –Janet Watters –Donna Reeves –Volunteers, participants