Rebecca D. Jackson, M.D., The Ohio State University

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Rebecca D. Jackson, M.D., The Ohio State University

  1. 1. Risk of Fractures Rebecca D. Jackson, M.D. Associate Professor of Internal Medicine Division of Endocrinology, Diabetes and Metabolism The Ohio State University Vice-Chair, WHI Steering Committee
  2. 2. <ul><li>A condition of skeletal fragility characterized by reduced bone mass and microarchitectural deterioration </li></ul>WHO, Guidelines for Preclinical Evaluation and Clinical Trials in Osteoporosis,1998 Normal Bone Osteoporosis Definition of Osteoporosis
  3. 3. Epidemiology of Osteoporosis <ul><li>Major public health threat for 44 million Americans </li></ul><ul><ul><li>10 million women and men already have osteoporosis </li></ul></ul><ul><ul><li>34 million have low bone mass </li></ul></ul><ul><li>One in every two women will have an osteoporosis-related fracture in their lifetime </li></ul><ul><li>Responsible for more than 1.5 million fractures annually </li></ul><ul><ul><li>300,000 hip fractures </li></ul></ul><ul><ul><li>700,000 vertebral fractures </li></ul></ul><ul><ul><li>250,000 wrist fractures </li></ul></ul><ul><ul><li>~ 300,000 other fractures </li></ul></ul><ul><li>Estimated direct expenditures for osteoporosis and fractures is $14 billion each year </li></ul>
  4. 4. Survival Rates After Fractures Adapted from Cooper C et al. Am J Epidemiol. 1993;137:1001-1005 % Survival Time After Fracture (Years) Expected Observed 100 80 60 40 20 0 1 2 3 4 5 Vertebral Fracture (Relative Survival = 0.81) 100 80 60 40 20 0 1 2 3 4 5 Hip Fracture (Relative Survival = 0.82)
  5. 5. 0 1000 2000 3000 4000 35–39 85+ Age Fracture Incidence per 100,000 Person-Years Riggs BL, Melton LJ. N Engl J Med. 1986;314:1676–1686. Faulkner, KG. J Clin Densitometry. 1998;1:279–285. 60% 70% 80% 90% 100% 30 40 50 60 70 80 90 Age Relative BMD Wrist Vertebrae Hip Bone Density and Bone Strength Decreases in BMD and Increases in Fractures as a Function of Age in Women Forearm Hip and Heel Spine
  6. 6. CEE: conjugated equine estrogen; MPA: medroxyprogesterone acetate; MP: micronized progesterone; cyc: cyclic admin. (days 1–12 of each month); and con: continuous admin. (daily throughout the month) Writing Group for the PEPI Trial. JAMA, 1996;276:1389–96. Percent Change from Baseline Baseline 12 mo 36 mo Spine Hip Baseline 12 mo 36 mo Placebo CEE Only CEE-MPA (cyc) CEE-MPA (cont) CEE-MP Estrogen and Progestin Effect on BMD The PEPI Trial – 6 – 4 – 2 0 2 4 6 – 6 – 4 – 2 0 2 4 6
  7. 7. Prior Positive Fracture Prevention Trials with Hormones <ul><li>Nachtigall LE et al, Ob& Gyn 1979;53:277-81 </li></ul><ul><ul><li>Ten years in 84 pairs of women, 7 FX vs 0 </li></ul></ul><ul><li>Lindsay R et al, Lancet 1980;2:1151-53. </li></ul><ul><ul><li>100 oophorectomized women, mestranol, 9 yr f/u, significantly reduced the incidence of vertebral compression. </li></ul></ul><ul><li>Lufkin EG et al, . Ann Intern Med 1992;117:1-9 </li></ul><ul><ul><li>Transderm estrogen, 75 women, 40% reduction in radiographic vertebral fracture rate </li></ul></ul><ul><li>Komulainen MH et al, Maturitas 1998;31:45-54 </li></ul><ul><ul><li>5 yrs, Finland, 47 to 56 yrs old, reduced the risk of non-vertebral fractures by about 60% </li></ul></ul>
  8. 8. Metanalysis of the Effect of Hormone Therapy on Non-vertebral Fracture Rates JAMA 2001; 285: 2891-2897 0.71-1.08 0.88 Women > 60 y.o. 0.46-0.98 0.67 Women < 60 y.o. 0.56-0.94 0.73 All Trials 95% CI Hazard Ratio
  9. 9. Baseline Characteristics of Women In the WHI E+P Trial .87 13.6 13.5 Fracture at > 55 .18 32.5 33.8 >1 Fall in last 12 mo .49 74.4 73.9 No Prior Hormone Use .67 10.3 10.1 Nulliparity .85 10.5 10.5 Current Smoking .89 30.8 30.4 BMI (kg/m 2 ) < 25 21.7 21.3 70-79 .80 45.1 45.3 60-69 33.1 33.4 50-59 Age at screening (%) P value Placebo E+P Characteristic
  10. 10. Prevalence of Osteoporosis at the Total Hip among E+P Participants* by Age Age Percent * BMD subset of E+P cohort (n= 1025)
  11. 11. Clinical Fracture Outcomes as Annualized Percentage 60 41 788 650 # of FX 62 44 Annualized Percent 701 * * * All comparisons are significant * * 579
  12. 12. Kaplan-Meier Estimates of Cumulative Hazards for Hip Fracture E+P Placebo E+P 8506 8382 8299 8190 7073 4305 2116 826 Placebo 8102 8009 7915 7807 6659 3958 1763 525 HR 0.66 CI (0.45, 0.98) Number of women at risk 0.0 0.01 0.02 0.03 0.04 0.05 0 1 2 3 4 5 6 7 Time (years)
  13. 13. Kaplan-Meier Estimates of Cumulative Hazards for Total Fractures E+P Placebo E+P 8506 8236 8042 7827 6676 3991 1943 745 Placebo 8102 7856 7627 7361 6163 3593 1574 448 HR 0.76 CI (0.69, 0.85) Number of women at risk 0.0 0.05 0.10 0.15 0 1 2 3 4 5 6 7 Time (years)
  14. 14. Hip Fracture Rate/1,000 women years As a Function of Age Group 19 15 40 27 # of FX 3 2 P >0.5 (33%) (45%) (22%) (age distribution)
  15. 15. All Fracture Rate/1,000 women years As a Function of Age Group * **p<0.01 ** 189 171 372 295 227 184 # of FX (33%) (45%) (22%) (age distribution) *p<0.05
  16. 16. Hip Fracture Rate/1,000 women years As a Function of BMI * *p<0.05 BMI kg/m2 29 16 23 14 10 14 # of FX
  17. 17. All Fracture Rate/1,000 women years As a Function of BMI * *p<0.01 * BMI kg/m2 272 215 275 208 235 222 # of FX
  18. 18. Overall Efficacy of E+P on Risk for Osteoporotic Fracture <ul><li>Estrogen +progestin reduces the rate of hip and clinical vertebral fractures by approximately one-third </li></ul><ul><li>There was also an approximate one-fourth reduction for other osteoporotic fractures and total fractures </li></ul><ul><li>There was a trend toward a larger treatment effect in older women but this was only significant for total fractures </li></ul><ul><li>There is a stronger treatment effect in women with lower BMI for both hip and total fractures </li></ul>
  19. 19. Prevention and Treatment Options for Osteoporosis
  20. 20. Conclusion <ul><ul><ul><ul><ul><li>Although estrogen and progestin are effective for the prevention and treatment of osteoporosis, the substantial risks for CVD and breast cancer must be weighed against the benefit for fracture reduction in selecting from among the therapeutic agents that can prevent and treat osteoporosis </li></ul></ul></ul></ul></ul>

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