Downloaded from 1 Alendronate vs. Risedronate Comparison Trial

Downloaded from 2 Alendronate vs. Risedronate Comparison Trial Aim To compare the efficacy of alendronate 70 mg once weekly with risedronate 5 mg daily (alternate meal dosing) in post- menopausal women with osteoporosis Primary Endpoint Rate of bone resorption (urine NTx) at 3 months Secondary Endpoints Change in BMD at spine and hip at 6 and 12 months Rate of bone turnover (NTx and BSAP) at 6 and 12 months Safety and tolerability profile at 12 months NTx = N-telopeptides of type 1 collagen BSAP = bone-specific alkaline phosphatase Hosking et al Curr Med Res Opin 2003;19(5):

Downloaded from 3 First head-to-head study comparing alendronate and risedronate for treatment of osteoporosis Endpoints –Biochemical markers of bone turnover –BMD at spine and hip First head-to-head study comparing alendronate and risedronate for treatment of osteoporosis Endpoints –Biochemical markers of bone turnover –BMD at spine and hip Alendronate vs. Risedronate Comparison Trial Overview Hosking et al Curr Med Res Opin 2003;19(5):

Downloaded from 4 Alendronate vs. Risedronate Comparison Trial Participants Women aged 60-90, N = 549 At least 2 years postmenopausal at baseline 38 centers in 10 countries No vertebral fractures T score  2.5 (LS or hip) or T score  2.0 (LS and hip) Hosking et al Curr Med Res Opin 2003;19(5): LS = Lumbar spine

Downloaded from 5 Alendronate vs. Risedronate Comparison Trial Alendronate Risedronate Placebo Mean SD Mean SD Mean SD Age ( years ) Years since menopause BMI (kg/m 2 ) LS BMD (g/cm 2 ) (Hologic) LS = Lumbar Spine BMI = Bone mineral index BMD = Bone mineral density SD = Standard deviation Hosking et al Curr Med Res Opin 2003;19(5): Baseline Characteristics

Downloaded from 6  Randomized, double-blind, multicenter, multinational, placebo- controlled study  3 months: bone turnover  6- and 12-month extensions: BMD  549 postmenopausal women (age > 60) with osteoporosis T-score < -2.5 at either lumbar spine or total hip or T-score < -2.0 at both lumbar spine and total hip  Treatments (using approved dosing regimens)  Alendronate 70 mg OW (standard AM dosing)n=219  Risedronate 5 mg daily (post-meal dosing)n=222  Placebon=108  Randomized, double-blind, multicenter, multinational, placebo- controlled study  3 months: bone turnover  6- and 12-month extensions: BMD  549 postmenopausal women (age > 60) with osteoporosis T-score < -2.5 at either lumbar spine or total hip or T-score < -2.0 at both lumbar spine and total hip  Treatments (using approved dosing regimens)  Alendronate 70 mg OW (standard AM dosing)n=219  Risedronate 5 mg daily (post-meal dosing)n=222  Placebon=108 Alendronate vs. Risedronate Comparison Trial Study Design Hosking et al Curr Med Res Opin 2003;19(5): OW = Once weekly

Downloaded from 7 Alendronate vs. Risedronate Comparison Trial Dosing Regimens FOSAMAX (alendronate sodium) 70 mg once weekly At least 1/2 hour before the first food, beverage, or medication of the day, upon arising for the day ACTONEL (risedronate) 5 mg daily At least 2 hours from any food or drink at any other time of the day, and at least 30 minutes before going to bed FOSAMAX (alendronate sodium) 70 mg once weekly At least 1/2 hour before the first food, beverage, or medication of the day, upon arising for the day ACTONEL (risedronate) 5 mg daily At least 2 hours from any food or drink at any other time of the day, and at least 30 minutes before going to bed † Registered Trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA ‡ Trademark of Procter & Gamble, Cincinnati, OH Hosking et al Curr Med Res Opin 2003;19(5): ®†®† ™‡™‡

Downloaded from 8 Risedronate 30 mg Bioavailability EUSPC for ACTONEL™ Hours before breakfast 1 Hour before breakfast 1/2 Hour before breakfast 2 Hours after dinner Mean absolute bioavailability with 30 mg tablet = 0.63% Relative bioavailability (% of mean absolute) Risedronate 30 mg daily Alendronate 70 mg once weekly

Downloaded from 9 Alendronate vs. Risedronate Comparison Trial Markers of Bone Turnover at 1 and 3 Months p< 0.001: Alendronate vs. risedronate + p< 0.001: Alendronate vs. placebo Mean percent change Placebo, n = 108 RIS 5 mg daily, n = 222 ALN 70 mg once weekly, n = 219 BSAP Months * Urine NTx Months * * + + * + + Hosking et al Curr Med Res Opin 2003;19(5): ALN = Alendronate RIS = Risedronate 10 *

Downloaded from 10 Alendronate vs. Risedronate Comparison Trial at 3, 6, and 12 Months Alendronate vs. Risedronate Comparison Trial BSAP at 3, 6, and 12 Months Placebo, n = 108 RIS 5 mg daily, n = 222 ALN 70 mg once weekly, n = 219 Months Mean percent change p<0.001: Alendronate vs. risedronate + p<0.001: Alendronate vs. placebo * * Hosking et al Curr Med Res Opin 2003;19(5): * *

Downloaded from 11 Alendronate vs. Risedronate Comparison Trial Alendronate vs. Risedronate Comparison Trial Urine NTx Mean percent change p<0.001: Alendronate vs. risedronate + p<0.001: Alendronate vs. placebo Hosking et al Curr Med Res Opin 2003;19(5): * * * * Placebo, n = 336 RIS 5 mg daily n = 490 ALN 70 mg once weekly, n = 616 Months *

Downloaded from 12 Alendronate vs. Risedronate Comparison Trial Alendronate vs. Risedronate Comparison Trial Urine NTx Placebo, n = 108 RIS 5 mg daily, n = 222 ALN 70 mg once weekly, n = 219 Months Mean percent change * p<0.001: Alendronate vs. risedronate + p<0.001: Alendronate vs. placebo * Hosking et al Curr Med Res Opin 2003;19(5): * *

Downloaded from 13 Alendronate vs. Risedronate Comparison Trial Lumbar Spine BMD Months p<0.001: Alendronate vs. risedronate p<0.001: Alendronate vs. placebo Hosking et al Curr Med Res Opin 2003;19(5): Mean percent change ALN 70 mg Once weekly n = 219 RIS 5 mg daily n = 222 Placebo n = 108 * + * + * +

Downloaded from 14 Months p<0.001: Alendronate vs. risedronate + p<0.001: Alendronate vs. placebo ALN 70 mg Once weekly n = 219 RIS 5 mg Daily n = 222 Placebo n = 108 Mean percent change *+ Alendronate vs. Risedronate Comparison Trial Hip Trochanter BMD *+ Hosking et al Curr Med Res Opin 2003;19(5): *

Downloaded from 15 p<0.001: Alendronate vs. risedronate+ p<0.001: Alendronate vs. placebo Alendronate vs. Risedronate Comparison Trial Total Hip BMD Months Mean percent change Placebo, n = 108 RIS 5 mg daily, ALN 70 mg once weekly, 6 * n = 222 n = * Hosking et al Curr Med Res Opin 2003;19(5): * +

Downloaded from 16 ALN 70 mg once weekly, n = 219 Months Mean percent change Alendronate vs. Risedronate Comparison Trial Femoral Neck BMD * p  0.05 : Alendronate vs. risedronate + p < 0.001: Alendronate vs. placebo Hosking et al Curr Med Res Opin 2003;19(5): Placebo, n = 108 RIS 5 mg daily, n = * *

Downloaded from 17 Alendronate vs. Risedronate Comparison Trial Adverse Experiences Gastric or duodenal perforation, ulcer or bleed Similar tolerability seen in all three groups* Hosking et al Curr Med Res Opin 2003;19(5): *

Downloaded from 18  Significantly greater increases in BMD at both the hip and spine with alendronate compared to risedronate over 12 months (p ≤ 0.001)  70% greater at the lumbar spine (4.75% vs. 2.8%)  266% greater at the hip trochanter (3.3% vs. 0.9%)  200% greater at the total hip (2.7% vs. 0.9%)  Significantly greater increases in BMD with alendronate seen early (6 months) at spine, trochanter, and total hip (p ≤ 0.001)  Significantly greater increases in BMD at both the hip and spine with alendronate compared to risedronate over 12 months (p ≤ 0.001)  70% greater at the lumbar spine (4.75% vs. 2.8%)  266% greater at the hip trochanter (3.3% vs. 0.9%)  200% greater at the total hip (2.7% vs. 0.9%)  Significantly greater increases in BMD with alendronate seen early (6 months) at spine, trochanter, and total hip (p ≤ 0.001) Alendronate vs. Risedronate Comparison Trial Summary Hosking et al Curr Med Res Opin 2003;19(5):

Downloaded from 19 Alendronate vs. Risedronate Comparison Trial Summary Cont’d  Significantly greater effect on markers of bone resorption with alendronate compared to risedronate (months 3, 6, and 12) (p < 0.001)  Greater decrease in resorption marker urine NTx with alendronate seen early (at one month)  Similar tolerability was seen between alendronate and risedronate, including upper gastrointestinal adverse experiences  Significantly greater effect on markers of bone resorption with alendronate compared to risedronate (months 3, 6, and 12) (p < 0.001)  Greater decrease in resorption marker urine NTx with alendronate seen early (at one month)  Similar tolerability was seen between alendronate and risedronate, including upper gastrointestinal adverse experiences Hosking et al Curr Med Res Opin 2003;19(5):

Downloaded from 20 ConclusionsConclusions In this first head-to-head double-blind comparison of alendronate and risedronate for treatment of osteoporosis in postmenopausal women: Alendronate produced significantly greater increases in BMD at both spine and hip sites as early as 6 months (p ≤ 0.001) Alendronate produced significantly greater reduction in bone resorption at 3, 6, and 12 months (p < 0.001) Differences seen early, with greater effects of alendronate seen at 1 month for resorption marker urine NTx, and 6 months for BMD These differences may be due to superior efficacy of alendronate, reduced bioavailability of risedronate resulting from post-meal dosing, or both. Alendronate produced significantly greater increases in BMD at both spine and hip sites as early as 6 months (p ≤ 0.001) Alendronate produced significantly greater reduction in bone resorption at 3, 6, and 12 months (p < 0.001) Differences seen early, with greater effects of alendronate seen at 1 month for resorption marker urine NTx, and 6 months for BMD These differences may be due to superior efficacy of alendronate, reduced bioavailability of risedronate resulting from post-meal dosing, or both. Hosking et al Curr Med Res Opin 2003;19(5):

Downloaded from 21 Protocol 159 Investigators Hosking et al Curr Med Res Opin 2003;19(5):

Downloaded from 22 AddendumAddendum

Downloaded from 23 “Agents that produce larger increases in BMD tend to provide greater reductions in both vertebral and nonvertebral fracture risk.” M. Hochberg Hochberg M et al J Clin Endocrin & Metab 2002;87(4):

Downloaded from 24 Meta-analyses of Percent Change from Baseline BMD in Separate RCTs of Alendronate or Risedronate * * These are not head-to-head data. Data shown together for ease of comparison; **p<0.01 vs. baseline; ***hip and femoral neck ORAG=Osteoporosis Research Advisory Group RCTs = Randomized Clinical Trials Adapted from Cranney A et al Endocr Rev 2002;23(4):570– ** 4.2** 2.1** 2.7** 4.5** 2.7** Spine Combined hip*** ForearmTotal body Mean % change Alendronate 10 to 40 mg Risedronate 5 mg NS n= Trials n= Trials n= Trials n= Trials n=565 2 Trials n =648 1 Trial n=469 2 Trials ORAG Meta-analyses: BMD Changes Reported for Alendronate and Risedronate

Downloaded from 25 ORAG Meta-analyses: Fracture Risk Reductions Reported for Alendronate and Risedronate -48 b -49 b -36 c –60 –50 –40 –30 –20 –10 0 VertebralNonvertebral Mean % change Meta-analyses of Relative Risk of Fracture versus Placebo at 3 years a 8 Trials (n=9360) 5 Trials (n=2604) 6 Trials (n=3723) 7 Trials (n=12,958) Alendronate d Risedronate 5 mg 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 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):570– b

Downloaded from 26 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):570–578. 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

Downloaded from 27 Alendronate vs. Risedronate Comparison Trial 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-7006-SS VISIT US ON THE WORLD WIDE WEB AT