1. 1 Ipriflavone in the Treatment of Postmenopausal Osteoporosis Randomized placebo-controlled, 4-year study conducted Europe 475 postmenopausal white women, 45 to 75 years, with BMD < 0.86 g/cm 2 Ipriflavone did not prevent bone loss or affect biochemical markers of bone metabolism. JAMA. 2001;285:1482-1488

2. 2 Purpose: determine the effect of progesterone skin cream on BMD and vasomotor symptoms Design: 102 recently postmenopausal women, randomized to 1/4 tsp cream with either 20 mg P vs Placebo for 12 months; all took 1200 Ca++ Results: –no effect on BMD –helpful for hot flashes (83% improved vs. 19% placebo) Study of Progesterone Skin Cream

3. 3 RALOXIFENE The first SERM to be approved for the prevention and the treatment of postmenopausal osteoporosis Estrogen agonist in bone (Prevents bone loss) Estrogen antagonist in the breast and the uterus

4. 4 Effect of Raloxifene on Spine and Femoral Neck BMD MORE Trial - 48 Months Months 012243648 -2 0 1 2 3 4 * * * * Placebo Raloxifene 60 mg/d Months 012243648 -2 0 1 2 3 4 * * * * Femoral NeckLumbar Spine 1.9 1.3 2.1 2.0 2.6 2.7 2.6

5. 5 0 5 10 15 20 25 30 35 40 Effects of Raloxifene on New Vertebral Fractures MORE Trial - 48 Months % 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) Placebo Raloxifene 60 mg/d 49% 34%

6. 6 Wrist Ankle Hip Any nonvertebral No. (%) of Women Placebo (N=2576) Raloxifene (pooled) (N=5129) 0.9(0.7-1.1) 0.6(0.4-1.0) 1.1(0.6-1.9) 0.9(0.8-1.1) Effect of Raloxifene on Nonvertebral Fractures MORE Trial - 3 Years 151(2.9) 34(0.7) 40(0.8) 437(8.5) 86(3.3) 28(1.1) 18(0.7) 240(9.3) Relative Risk (95% CI) Fractures

7. 7 BCPT: Relative Risk of Fracture by Tamoxifen use HIP Spine Radius, Colles Other Total  <49 years at entry  >50 years at entry 0.55 (0.25-1.15) 0.74 (0.41-1.32) 0.61 (0.29-1.23) 1.05 (0.73-1.51) 0.81 (0.63-1.05) 0.88 (0.46-1.68) 0.79 (0.60-1.05) RR (95% CI) Fisher B, et al. JNCI 1998;90:1371-88.

8. 8  Prevent vertebral fractures  No effect on other clinical fractures  Prevent Breast Cancer in average risk women  ? High Risk Women (STAR)  No effect on endometrium  ? Prevent CVD in high risk women: RUTH  Increase in VTE Long-term effects: CORE – Increase in ER(-) tumors? – Immunity to anti-estrogen effects ? Summary: Raloxifene

9. 9 Bisphosphonates Alendronate (Fosamax ® ) Risedronate (Actonel ® ) Zoledronic Acid (Zometa ® ) (not FDA approved) Pamidronate (Aredia ® ) (not FDA approved)

10. * p<0.05 Results from Separate Risedronate and Alendronate BMD Trials Lumbar Spine BMD Mean Change vs. Baseline Risedronate Lumbar Spine BMD Mean Change vs. Baseline Alendronate * * * * * * * * * * * * * *

11. 11 Efficacy at the Spine: Radiographic Vertebral Fractures at 3 years Alendronate (n=2027; 71y) + Risedronate (n=2458; 69y)* 47% reduction p<0.001 41% reduction p=0.003 + Black et al. Lancet 1996. *Harris S. JAMA 1999. % with fracture

12. 12 Efficacy of Oral Bisphosphonates on Hip Fracture Alendronate + –Women with vertebral fractures: 50% reduction, p<0.05 –Women without vertebral fractures: T< -2.5: 56% reduction, p<0.05 T> -2.5: Not significant Risedronate* Age 70 – 79 –Women with osteoporosis (t-score < -2.5) 39% reduction (p=0.02) –Women with vertebral fractures 58% reduction (p<0.01) Age 80+ –Women with osteoporosis (t-score < -2.5) 25% reduction, p=0.14 –Women with risk factors Not significant

13. 13 Once-Weekly Alendronate for the Treatment of Osteoporosis: Effect on BMD Month Lumbar Spine

14. 14 Effects of Zoledronic Acid on BMD in Lumbar Spine Month of Scan

15. 15 Bisphosphonates: Alendronate and Residronate –Prevent vertebral fractures –Prevent clinical fractures Alendronate: Hip Fracture indication –Both approved for weekly administration –RCTs >3 years duration –No other systemic effects –Long term effect Alendronate :10 years of use: BMD

16. 16 Salmon Calcitonin

17. 17 Effect of Nasal Spray Salmon Calcitonin on BMD 1 -0.5 0.0 0.5 1.0 1.5 2.0 012345 1 No effect of any dose of calcitonin on femoral neck BMD *p<0.05 vs placebo for all dose groups **p<0.01 vs placebo for 400 IU group only Change in Lumbar Spine BMD (%) Year Placebo 100 IU 200 IU 400 IU * * **

18. 18 Effect of Nasal Spray Salmon Calcitonin on Risk of Vertebral Fracture 0 5 10 15 20 25 30 *RR = 0.67 (0.47-0.97), p<0.05 vs placebo Patients with  1 Incident Fracture (%) Placebo100 IU200 IU400 IU *

19. 19 Effect of Nasal Spray Salmon Calcitonin on the Risk of Nonvertebral Fracture Type of Fracture All nonvertebral Hip or femoral Arm 16 3 5 NS Placebo (N=305) P Calcitonin (200 IU) (N=315) 15 2 4 Women with  1 Fracture (%) Chesnut CH, et al. Am J Med. 2000;109:267-276.

20. 20 PTH: Mode of Delivery Determines Bone Activity Intermittent doses of PTH are anabolic and lead to increased bone formation whereas continuous exposure to PTH leads to increased bone resorption and a net bone loss. Tam et al. Endocrinology 1982

21. 21 Effect of rhPTH(1-34) on the Risk of New Vertebral Fractures * p <0.001 vs. Placebo Risk Reduction (RR) Placebo (n=448) rhPTH 20 (n=444) rhPTH 40 (n=434) 6422 19 100% 75% 50% 0% 25% % of Women 8 0 2 4 6 10 12 14 RR 0.31 (95% CI, 0.19 to 0.50)* RR 0.35 (95% CI, 0.22 to 0.55)* 65%69% No. of women who had > 1 fracture

22. 22 Effect of rhPTH(1-34) on the Risk of Nonvertebral Fragility Fractures * p = 0.02 vs. Placebo ** p = 0.01 vs. Placebo 3014 53% 54% (n=544)(n=552)(n=541) No. of women who had > 1 fragility fracture RR 0.46 (95% CI, 0.25 to 0.86)** RR 0.47 (95% CI, 0.25 to 0.88)*

23. 23 Effect of rhPTH(1-34) on BMD % Change from Baseline to Last Visit ( + SD ) rhPTH 20 rhPTH 40 Lumbar Spine9.7 ± 7.4* 13.7 ± 9.7* Femoral Neck2.8 ± 5.7* 5.1 ± 6.7* Total Hip2.6 ± 4.9* 3.6 ± 5.4* *p <0.001 vs. Placebo

24. 24 WHO SHOULD BE TREATED WITH WHAT? HOT FLASHES HIP FRACTURES ESTROGEN???? ALENDRONATE RISEDRONATE RALOXIFENE, ALENDRONATE, RISEDRONATE FIRST VERTEBRAL FRACTURE CALCITONIN ?? 50 80 70 60 AGE

25. 25 Anti-fracture Efficacy of Selected Therapies Alendronate+++++ Calcitonin+0 Etidronate+0 Fluoride+- HRT++++ PTH+++++ Raloxifene+++0 Risedronate+++++ Vit D derivatives+ 0 DrugVertebral F xHip fx

26. What are the effects of aromatase inhibitors on bone density?

27. 27 Arimidex versus Tamoxifen: women with advanced breast cancer ArimidexTamoxifen Bone fractures5.8%3.7% Cancer of the uterus 0.1%0.5% Deep vein thrombosis 1.0%1.7%