Download from Slide 1 Update on Alendronate and Raloxifene in Osteoporosis EFficacy of Fosamax ™ vs. Evista ® Comparison Trial (EFFECT) FOSAMAX (alendronate) is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. EVISTA (raloxifene) is a registered trademark of Eli Lilly and Company, Indianapolis, IN.

Download from Slide 2 Osteoporosis Is an Increasingly Important Health Issue Worldwide Osteoporosis is a progressive disease characterized by age- related decline in BMD –Bone loss accelerates rapidly after menopause –Bone loss accelerates rapidly in postmenopausal women after cessation of hormone replacement therapy Loss of bone mass increases fracture risk and associated morbidity/mortality 40% lifetime risk of fracture for women over 50 worldwide Incidence/impact expected to increase in the future with the aging population Several therapies available for treatment of osteoporosis BMD=bone mineral density Adapted from Riggs BL, Melton LJ III Bone 1995;17(5 suppl):505S-511S; International Osteoporosis Foundation. Available at: Accessed June 11, 2003; Melton LJ III et al J Bone Miner Res 1992; 7: ; Tremollieres FA et al Osteoporos Int 2001;12:

Download from Slide 3 Current Knowledge of Alendronate and Raloxifene Both alendronate and raloxifene are used for postmenopausal osteoporosis Meta-analyses of clinical data for each agent have recently been performed [Cranney A et al Endocr Rev 2002;23(4): ] No head-to-head fracture trial data currently available –Requires large patient population (tens of thousands) –Long duration (>3 years) One study assessed the individual and additive effects of alendronate and raloxifene [Johnell O et al J Clin Endocrinol Metab 2002;87(3): ] EFFECT was conducted to provide head-to-head data for alendronate once weekly vs. raloxifene in postmenopausal osteoporosis RCT=randomized clinical trial Adapted from Cranney A et al Endocr Rev 2002;23(4): ; Cranney A et al Endocr Rev 2000;23(4): ; Johnell O et al J Clin Endocrinol Metab 2002;87(3): ; Sambrook P et al. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.

Download from Slide 4 Meta-Analyses of RCT Data for Raloxifene and Alendronate Raloxifene BMD increases at spine (2.5%), combined hip (2.1%), forearm (0.65%), and total body (1.3%) (1–3 yrs) 40% risk reduction in vertebral fractures No effect on nonvertebral fractures Alendronate BMD increases at spine (7.5%), combined hip (4.2%), forearm (2.1%), total body (2.7%) (10–40 mg, 2–4 yrs) 48% risk reduction in vertebral fractures (5–40 mg) 49% risk reduction in nonvertebral fractures (10–40 mg) Adapted from Cranney A et al Endocr Rev 2002;23(4):

Download from Slide 5 Placebo Raloxifene AlendronateAlendronate + raloxifene (n=82) (n=82) (n=83)(n=84) Johnell O et al, J Clin Endocrinol Metab 2002;87(3): Randomized, double-blind, 12-month study Postmenopausal women with osteoporosis (FN –2.0 or lower), N=331 Greater spine and FN increases with alendronate than raloxifene Similar tolerability *p≤0.05 alendronate vs. raloxifene FN=femoral neck (T-score); NTx/Cr=ratio of N-telopeptide to creatinine; BSAP=bone-specific alkaline phosphatase Adapted from Johnell O et al J Clin Endocrinol Metab 2002;87(3): % Change at 12 months * * – SpineFemoral neck * * –80 –60 –40 – NTx/CrBSAP BMDBone Turnover % Change at 12 months

Download from Slide 6 EFficacy of Fosamax ™ (alendronate) vs. Evista ® (raloxifene) Comparison Trial (EFFECT–International) Rationale –Alendronate once weekly and raloxifene are prescribed for postmenopausal osteoporosis but have not been compared in a large-scale RCT Objective –Compare effects of alendronate 70 mg once weekly vs. raloxifene 60 mg once daily on improvements in BMD and inhibition of bone resorption in postmenopausal women with osteoporosis Adapted from Sambrook P et al. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.

Download from Slide 7 EFFECT–International Study Design Randomized, double-blind, double-dummy, active-comparator–controlled, 12-month study 50 sites in 16 countries (non-US) BMD and bone turnover evaluated before treatment and at months 6 and patients randomized to alendronate 70 mg once weekly plus raloxifene placebo once daily (n=246) or raloxifene 60 mg once daily plus alendronate placebo once weekly (n=241) Adapted from Sambrook P et al. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.

Download from Slide 8 EFFECT–International Entry Criteria Community-dwelling, ambulatory women ≥40 years of age and ≥6 months postmenopausal Osteoporosis defined by a BMD T-score –2.0 or lower at either lumbar spine or total hip No estrogen, estrogen analogue, SERM, bisphosphonate, or PTH taken within the previous year No history of breast or uterine cancer No contraindications as stated in the product labels (e.g., venous thromboembolic disease, esophageal motility disorders) SERM=selective estrogen-receptor modulator; PTH=parathyroid hormone Adapted from Sambrook P et al. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.

Download from Slide 9 Primary –Percent change from baseline in lumbar spine BMD at 12 months Secondary –Percent change from baseline in Total hip BMD at 12 months Hip trochanter BMD at 12 months Lumbar spine, total hip, hip trochanter BMD at 6 months –Percentage of patients who maintained or increased spine BMD –Percent change in markers of bone turnover (NTx/Cr and BSAP) –Tolerability, including upper GI and vasomotor events EFFECT–International Study Endpoints Adapted from Sambrook P et al. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.

Download from Slide 10 EFFECT–International Baseline Characteristics AlendronateRaloxifene 70 mg60 mg once weeklyonce daily Overall (n=246)(n=241)(N=487) Age (years) Race (%) White Multiracial999 Hispanic888 Asian354 Body mass index (kg/m 2 ) Years since last menses BMD T-score Lumbar spine–2.89–2.86–2.88 Total hip–1.55–1.55–1.55 Adapted from Sambrook P et al. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.

Download from Slide 11 EFFECT–International Lumbar Spine BMD Adapted from Sambrook P et al. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, Percent change from baseline (mean ± SE) Months Alendronate (n=226) Raloxifene (n=219) p<0.001

Download from Slide 12 Adapted from Sambrook P et al. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, EFFECT–International Total Hip BMD Months Alendronate (n=224) Raloxifene (n=220) Percent change from baseline (mean ± SE) p<0.001

Download from Slide 13 EFFECT–International Hip Trochanter BMD Adapted from Sambrook P et al. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, Months Alendronate (n=224) Raloxifene (n=220) Percent change from baseline (mean ± SE) p<0.001

Download from Slide 14 Premenopausal range EFFECT–International Markers of Bone Turnover: Absolute Values Months Absolute value (nmol/mmol) NTx/CrBSAP Alendronate (n=161) Raloxifene (n=154) N values refer to month 12 Adapted from Garnero P et al J Bone Miner Res 1996;11(3): Absolute value (ng/ml) p<0.001 Alendronate (n=175) Raloxifene (n=166)

Download from Slide 15 EFFECT–International Safety and Tolerability Profiles Adapted from Sambrook P et al. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, Percent of patients AlendronateRaloxifene 70 mg60 mg Adverseonce weeklyonce daily Experience (AE)(n=246)(n=241)p Value Any AE6365NS Drug-related* AE2327NS Discontinued due to AE 68NS Upper GI AE1522NS Drug related Vasomotor AE Drug related

Download from Slide 16 EFFECT–International Summary Alendronate produced two to three times greater increases in hip and spine BMD than did raloxifene at 12 months (p<0.001) –Differences were significant at 6 months (p<0.001) Alendronate reduced bone turnover significantly more than raloxifene at 12 months (p<0.001) –Differences were significant at 6 months (p<0.001) Alendronate decreased markers of bone turnover to well within the premenopausal ranges Similar tolerability observed with alendronate and raloxifene Adapted from Sambrook P et al. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003; Garnero P et al J Bone Miner Res 1996;11(3):

Download from Slide 17 EFFECT–International Conclusions Alendronate 70 mg once weekly was significantly more efficacious than raloxifene 60 mg –Increases in spine and hip BMD two to three times greater with alendronate vs. raloxifene (p<0.001) at 12 months –Alendronate produced greater reductions in bone turnover than raloxifene at 12 months (p<0.001) –Alendronate was similarly well tolerated Adapted from Sambrook P et al. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.

Download from Slide 18 Meta-Analyses of Percent Change from Baseline BMD in Separate RCTs of Alendronate or Raloxifene a a These are not head-to-head data. Data shown together for ease of comparison; b p<0.01 vs. baseline; c p=0.01 vs. baseline; d hip and femoral neck ORAG=Osteoporosis Research Advisory Group Adapted from Cranney A et al Endocr Rev 2002;23(4): b 4.2 b 2.1 b 2.7 b 2.5 b 2.1 b c SpineCombined hip d ForearmTotal body Mean % change Alendronate Raloxifene NS n=1613n=6053n=1443n=6033n=565n=359n=469n=511 ORAG Meta-Analyses: BMD Changes Reported for Alendronate and Raloxifene

Download from Slide 19 ORAG Meta-Analyses: Fracture Risk Reductions Reported for Alendronate and Raloxifene –48 b –49 b –40 c –9 –60 –50 –40 –30 –20 –10 0 VertebralNonvertebral Mean % change Meta-Analyses of Relative Risk of Fracture versus Placebo at 3 years a NS 8 studies (n=9360) 1 study (n=6828) 6 studies (n=3723) 2 studies (n=6961) Alendronate d Raloxifene a These are not head-to-head data. Data shown together for ease of comparison; b p<0.01 vs. baseline; c p=0.01 at baseline; d Alendronate doses evaluated were 5–40 mg (vertebral fracture) and 10–40 mg (nonvertebral) ORAG=Osteoporosis Research Advisory Group Adapted from Cranney A et al Endocr Rev 2002;23(4):

Download from Slide 20 Relative Risk Reductions for Vertebral and Nonvertebral Fractures ORAG Meta-Analyses: Relative Risk Reductions with Therapies for Postmenopausal Osteoporosis ORAG=Osteoporosis Research Advisory Group; V=vertebral; NV=nonvertebral *Alendronate doses evaluated were 5–40 mg (vertebral fracture) and 10–40 mg (nonvertebral) Adapted from Cranney A et al Endocr Rev 2002;23(4): alendronate* (48% V, 49% NV) Relative risk reduction in nonvertebral fractures vitamin D (37% V, 23% NV) calcitonin (21% V, 20% NV) calcium (23% V, 14% NV) risedronate (36% V, 27% NV) HRT (34% V, 13% NV) raloxifene (40% V, 9% NV) etidronate (37% V, 1% NV) Relative risk reduction in vertebral fractures

Download from Slide 21 Alendronate vs. Raloxifene: Overall Summary Large-scale, head-to-head BMD trials can provide clinicians with useful information EFFECT–International demonstrated –Alendronate 2–3 times more effective than raloxifene once daily for increasing lumbar spine and hip BMD –Similar tolerability Results from EFFECT–International consistent with independent meta-analyses –Alendronate outperformed raloxifene in increasing BMD –In the ORAG meta-analysis, alendronate also outperformed raloxifene in lowering risk of both vertebral and nonvertebral fractures Adapted from Sambrook P et al. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003; Cranney A et al Endocr Rev 2002;23(4):

Download from Slide 22 Bibliography Please see notes page.

Download from Slide 23 Update on Alendronate and Raloxifene in Osteoporosis Before prescribing any of the products mentioned in this slide presentation, please consult the manufacturers’ prescribing information. Copyright © 2003 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved FSM 2003-W-6999-SS VISIT US ON THE WORLD WIDE WEB AT