1. Slide 1 FOSAMAX ™ Once Weekly ACTONEL ™ Once A Week Comparison Trial FOSAMAX™ (alendronate) is a trademark of Merck & Co., Inc, Whitehouse Station, NJ, USA. ACTONEL™ (risedronate) is a trademark of Procter & Gamble Pharmaceuticals.

2. Slide 2 Introduction Both alendronate and risedronate are commonly used bisphosphonates for the treatment of postmenopausal osteoporosis Head-to-head clinical trial data are needed to help clinicians make decisions regarding these treatment options for postmenopausal women with osteoporosis Adapted from National Osteoporosis Foundation. Physician's Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2003; Cummings SR et al JAMA 1998;280(24):2077–2082; Black DM et al J Clin Endocrinol Metabol 2000;85(11):4118–4124; Reginster J et al Osteoporos Int 2000;11(1):83–91; Harris ST et al JAMA 1999; 282(14):1344–1352; McAlister FA et al JAMA 1999;282(14):1371–1377.

3. Slide 3 How Bisphosphonates Work in Osteoporosis Adapted from Rodan GA, Fleisch HA J Clin Invest 1996;97:2692–2696; Chesnut CH III et al Am J Med 1995;99:144–152; Garnero P et al J Clin Endocrinol Metab 1994;79(6):1693–1700; Wasnich RD, Miller PD J Clin Endocrinol Metab 2000;85(1):231–236; Chavassieux PM et al J Clin Invest 1997;100(6):1475–1480; Adami S Bone 1995;17(4):383–390. Altered microarchitecture and mineralization Bone Turnover Bone Mineral Density Fracture Risk Bone Strength

4. Slide 4 FOSAMAX ™ ACTONEL ™ Comparison Trial (FACT) Study Design FOSAMAX Once Weekly vs. ACTONEL Once A Week Randomized, double-blind, double-dummy, active-comparator study 1053 postmenopausal women from 78 US sites randomized (1:1) to –alendronate 70 mg (n = 520) and risedronate placebo or –risedronate 35 mg (n = 533) and alendronate placebo Calcium ≥1000 mg and vitamin D 400 IU daily Central Lab and Quality Assurance centers used for all lab and DXA evaluations (DXA at 0, 6, and 12 months) DXA=dual-energy x-ray absorptiometry FOSAMAX™ (alendronate) is a trademark of Merck & Co., Inc, Whitehouse Station, NJ, USA. ACTONEL® (risedronate) is a registered trademark of Procter & Gamble Pharmaceuticals.

5. Slide 5 Entry Criteria Community-dwelling, ambulatory women  40 years of age (  25 years if surgically menopausal) and  6 months postmenopausal Osteoporosis (BMD T-score  –2.0) at either the trochanter, femoral neck, total hip, or lumbar spine No bisphosphonates within previous year or for more than two years within past five years No estrogen or estrogen analogues (SERMs) within the previous six months, or PTH within the previous year No abnormality of the esophagus that would delay emptying (i.e., stricture, achalasia) SERMs=selective estrogen receptor modulators; PTH=parathyroid hormone

6. Slide 6 Study Endpoints Study Endpoints Primary –Hip trochanter BMD at 12 months Secondary –Total hip, femoral neck, and lumbar spine BMD at 12 months –Biochemical markers of bone turnover (serum BSAP, P1NP, CTx, and urinary NTx) at 3, 6, and 12 months –Percentage of patients with BMD gains  0% and  3% –Change in BMD at all sites at 6 months –Tolerability and safety profile, including percentage of patients with any upper-GI adverse events at 12 months BMD=bone mineral density; BSAP=serum bone-specific alkaline phosphatase; P1NP=N-terminal Propeptide of type 1 Procollagen; CTx=serum C-telopeptide; NTx=N-telopeptide corrected for creatinine; GI=gastrointestinal

7. Slide 7 Statistical Methods Primary analysis for BMD –Modified intention-to-treat (mITT) Primary analysis for biochemical markers –Per protocol (PP) 90% power to detect a 1.2% difference between alendronate and risedronate at a statistically significant alpha level of 0.05

8. Slide 8 454 completed (85.2%)438 completed (84.2%) Patient Accounting 1759 patients screened 706 excluded Alendronate 520 randomized 515 treated Risedronate 533 randomized 527 treated 82 discontinued (15.8%) Clinical adverse event=33 (6.3%) Lost to follow-up=14 Moved=4 Withdrew consent=29 Deviation from protocol=2 Lab adverse event=0 79 discontinued (14.8%) Clinical adverse event=33 (6.2%) Lost to follow-up=9 Moved=3 Withdrew consent=28 Deviation from protocol=5 Lab adverse event=1 1053 patients randomized

9. Slide 9 Baseline Demographics Alendronate 70 mg OW (n=520) Risedronate 35 mg OW (n=533) Total (n=1053) Age (years)64.264.864.5 Years since menopause18.318.718.5 Race (% Caucasian)94.496.195.3 Upper-GI disorder (%) Fracture* after age 45 (%) 125 (24) 60 (11.5) 139 (26.1) 66 (12.4) 264 (25.1) 126 (12.0) *Hip, spine or wrist OW=once weekly

10. Slide 10 Baseline BMD T-scores* Site Alendronate (n=520) Risedronate (n=533) Total (n=1053) Trochanter–1.58 Total hip–1.76–1.78–1.77 Femoral neck–2.12–2.16–2.14 Lumbar spine–2.26–2.23–2.24 *mean scores

11. Slide 11 Hip Trochanter BMD 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 BaselineMonth 6Month 12 p<0.001 3.4% 2.1% Mean % change p<0.001 Treatment difference=1.4 %, p<0.001. Alendronate (n=464) Risedronate (n=481)

12. Slide 12 Total Hip BMD Total Hip BMD 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 BaselineMonth 6Month 12 p<0.001 2.2% 1.2% Mean % change p<0.001 Treatment difference=1.1%, p<0.001. Alendronate (n=464) Risedronate (n=481)

13. Slide 13 Femoral Neck BMD Femoral Neck BMD 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 BaselineMonth 6Month 12 p=0.035 1.6% 0.9% Mean % change p=0.005 Treatment difference=0.7%, p=0.005. Alendronate (n=464) Risedronate (n=481)

14. Slide 14 Lumbar Spine BMD 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 BaselineMonth 6Month 12 p=0.002 3.7% 2.6% Mean % change p<0.001 Treatment difference=1.2 %, p<0.001. Alendronate (n=464) Risedronate (n=481)

15. Slide 15 BMD Response at Lumbar Spine 0 100 20 40 60 80 % Change in BMD % Patients  –3% 4% 1% p=0.008  0% 87% 76% p<0.001  3% 60% 41% p<0.001  5% 35% 23% p<0.001 Alendronate (n=464) Risedronate (n=481)

16. Slide 16 % Patients % Change in BMD 0 100 20 40 60 80 85% 68% 51% 41% 31% 20% 5% 11% p=0.002 p<0.001  –3%  0%  3%  5% BMD Response at Hip Trochanter Alendronate (n=464) Risedronate (n=481)

17. Slide 17 Bone Resorption Markers –100 –80 –60 –40 –20 0 BaselineMonth 6Month 12 Mean % change Urine NTx Serum CTx p<0.001 –40% –53% –55% –74% p<0.001 Month 3 p<0.001 Treatment difference 13% p<0.001 Treatment difference 19% Alendronate n = 442429414365449443423382 Risedronate n = 457449426375459455433387 Alendronate 70 mg OW Risedronate 35 mg OW –100 –80 –60 –40 –20 0 BaselineMonth 6Month 12Month 3

18. Slide 18 Bone Formation Markers Serum BSAP Serum P1NP p<0.001 –28% –41% –48% –64 % p<0.001 Treatment difference 13% p<0.001 Treatment difference 16% Alendronate n = 449441422382447440419378 Risedronate n = 458454430387459455432387 –100 –80 –60 –40 –20 0 BaselineMonth 6Month 12 Mean % change Month 3 –100 –80 –60 –40 –20 0 BaselineMonth 6Month 12Month 3 Alendronate 70 mg OW Risedronate 35 mg OW

19. Slide 19 Adverse Experiences Adverse Experiences Number (%) of patients Alendronate 70 mg OW (n=515) Risedronate 35 mg OW (n=527)  1 clinical adverse experience 394 (76.5)399 (76.1) Serious adverse experience45 (8.7)41 (7.8) Discontinued due to adverse experience33 (6.4)33 (6.3) No significant differences between treatment groups

20. Slide 20 UGI Adverse Experiences No significant differences between treatment groups Number (%) of patients Alendronate 70 mg OW (n=515) Risedronate 35 mg OW (n=527)  1 Upper-GI adverse experience 116 (22.5)106 (20.1) Discontinued due to upper-GI adverse experience13 (2.5)16 (3.0)

21. Slide 21 Summary Summary At 6 and 12 months, alendronate produced significantly greater BMD increases at hip trochanter,* total hip,* femoral neck,** and lumbar spine*** than did risedronate Greater decreases in indices of bone turnover (BSAP, P1NP, CTx, and urinary NTx) were seen with alendronate as compared to risedronate at 3, 6, and 12 months Significantly more patients experienced gains in BMD ≥3% at the hip trochanter (p=0.002) and lumbar spine (p<0.001) with alendronate than with risedronate Overall (including upper-GI) safety profile and tolerability of alendronate and risedronate were similar *p<0.001 at months 6 and 12; **p=0.035 at month 6 and p=0.005 at month 12; ***p=0.002 at month 6 and p<0.001 at month 12

22. Slide 22 Conclusions In this head-to-head study, alendronate 70 mg OW produced larger increases in BMD and greater reductions in markers of bone turnover than did risedronate 35 mg OW. The superior antiresorptive effect of alendronate was seen as early as three months. These results are consistent with results of previous clinical trials and are important for physicians to consider when evaluating treatment options for postmenopausal women with osteoporosis. Adapted from McAlister FA et al JAMA 1999;282(14):1371–1377; Hosking D et al Curr Med Res Opin 2003;19:383–394; Cranney A et al Endocr Rev 2002;23(4):570–578.

23. Slide 23 References 1.National Osteoporosis Foundation. Osteoporosis: Physician's Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2003. 2.Cummings SR, Black DM, Thompson DE et al, for the Fracture Intervention Trial Research Group. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: Results from the Fracture Intervention Trial. JAMA 1998;280(24):2077–2082. 3.Black DM, Thompson DE, Bauer DC et al, for the FIT Research Group. Fracture risk reduction with alendronate in women with osteoporosis: The Fracture Intervention Trial. J Clin Endocrinol Metab 2000;85(11):4118–4124. 4.Reginster J, Minne HW, Sorensen OH et al. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporos Int 2000;11(1):83–91. 5.Harris ST, Watts NB, Genant HK et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: A randomized controlled trial. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. JAMA 1999;282(14):1344–1352. 6.Schnitzer T, Bone, H, Crepaldi G et al. Therapeutic equivalence of alendronate 70 mg once weekly and alendronate 10 mg daily in the treatment of osteoporosis. Aging (Milano) 2000;12(1):1–12. 7.Brown JP, Kendler DL, McClung MR et al. The efficacy and tolerability of risedronate once a week for the treatment of postmenopausal osteoporosis. Calcif Tissue Int 2002;71(2):103–111. 8.McAlister FA, Laupacis A, Wells GA et al. Users' Guides to the Medical Literature: XIX. Applying clinical trial results B. Guidelines for determining whether a drug is exerting (more than) a class effect. JAMA 1999; 282(14):1371–1377. 9.Hosking D, Adami S, Felsenberg D et al. Comparison of change in bone resorption and bone mineral density with once-weekly alendronate and daily risedronate. Curr Med Res Opin 2003;19:383–394. 10.Rosen, CJ, Hochberg M, Bonnick S et al. Treatment with once-weekly alendronate 70 mg compared to once- weekly risedronate 35 mg in women with postmenopausal osteoporosis: A randomized, double-blind study. J Bone Min Res Web First September 29, 2004; 1–51. 11.Data on file, MSD ____________.

24. Slide 24 References (cont’d) 12.Rodan GA, Fleisch HA. Bisphosphonates: Mechanisms of action. J Clin Invest 1996;97:2692–2696. 13.Chesnut CH III, McClung MR, Ensrud KE et al. Alendronate treatment of the postmenopausal osteoporotic woman: Effect of multiple dosages on bone mass and bone remodeling. Am J Med 1995;99:144–152. 14.Garnero P, Shih WJ, Gineyts E et al. Comparison of new biochemical markers of bone turnover in late postmenopausal osteoporotic women in response to alendronate treatment. J Clin Endocrinol Metab 1994;79(6):1693–1700. 15.Wasnich RD, Miller PD. Antifracture efficacy of antiresorptive agents are related to changes in bone density. J Clin Endocrinol Metab 2000;85(1):231–236. 16.Chavassieux PM, Arlot ME, Reda C et al. Histomorphometric assessment of the long-term effects of alendronate on bone quality and remodeling in patients with osteoporosis. J Clin Invest 1997;100(6):1475–1480. 17.Adami S, Passeri M, Ortolani S et al. Effects of oral alendronate and intranasal salmon calcitonin on bone mass and biochemical markers of bone turnover in postmenopausal women with osteoporosis. Bone 1995;17(4):383– 390. 18.Cranney A, Guyatt G, Griffith L et al. Meta-analyses of therapies for postmenopausal osteoporosis. IX: Summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev 2002;23(4):570–578.

25. FACT (FOSAMAX™ ACTONEL ® Comparison Trial) Year-1 Results Before prescribing, please consult the manufacturers’ prescribing information. Merck does not recommend the use of any product in any different manner than as described in the prescribing information. Copyright © 2004 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved. 10-05 FSM 2004-W-7082-SS VISIT US ON THE WORLD WIDE WEB AT http://www.merck.com