1. Update on Alendronate and Raloxifene in Osteoporosis
Contents
EFficacy of Fosamax® vs. Evista® Comparison Trial (EFFECT)
Context: Osteoporosis and Experience with Alendronate and Raloxifene
Slide 2 Osteoporosis Is an Increasingly Important Health Issue Worldwide
Slide 3 Current Knowledge of Alendronate and Raloxifene
Slide 4 Meta-Analyses of RCT Data for Raloxifene and Alendronate
Slide 5 Johnell O et al, J Clin Endocrinol Metab 2002;87(3):
EFFECT–International Trial
Slide 6 EFficacy of Fosamax™ (alendronate) vs. Evista® (raloxifene) Comparison Trial
Slide 7 Study Design
Slide 8 Entry Criteria
Slide 9 Study Endpoints
Slide 10 Baseline Characteristics
Slide 11 Lumbar Spine BMD
Slide 12 Total Hip BMD
Slide 13 Hip Trochanter BMD
Slide 14 Markers of Bone Turnover: Absolute Values
Slide 15 Safety and Tolerability Profiles
Slide 16 Summary
Slide 17 Conclusions
EFFECT–International Is Consistent with ORAG Meta-Analyses
Slide 18 ORAG Meta-Analyses: BMD Changes Reported for Alendronate and Raloxifene
Slide 19 ORAG Meta-Analyses: Fracture Risk Reductions Reported for Alendronate and Raloxifene
Slide 20 ORAG Meta-Analyses: Relative Risk Reductions with Therapies for Postmenopausal Osteoporosis
Slide 21 Alendronate vs. Raloxifene: Overall Summary
Slide 22 Bibliography
FOSAMAX ® (alendronate) is a registered trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
EVISTA (raloxifene) is a registered trademark of Eli Lilly and Company, Indianapolis, IN.
FOSAMAX is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
EVISTA is a registered trademark of Eli Lilly and Company, Indianapolis, IN.

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
Slide 2
Osteoporosis is a major and increasingly important health issue for postmenopausal women around the world.1 This progressive disease is characterized by an age-related decline in bone mineral density (BMD) and increased risk of fracture and associated morbidity and mortality.2 Currently, osteoporosis is one of the most common and serious health risks to postmenopausal women, as well as all aging women and men.1 The lifetime risk of fracture is 40 percent for 50-year-old women worldwide.1,3
The incidence of osteoporosis is expected to rise substantially in developing countries due to the rapid aging of populations.1 Since bone loss is known to accelerate rapidly in women after menopause and cessation of hormone replacement therapy,4,5 it is also expected that the risk of fractures and related morbidity/mortality will become increasingly important concerns worldwide.
Several therapies are available for the treatment of osteoporosis in postmenopausal women. Evidence-based analyses of data from randomized controlled trials (RCTs) provide a framework for evaluating these treatment options.
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:
References
Riggs BL, Melton LJ III. The worldwide problem of osteoporosis: Insights afforded by epidemiology. Bone 1995;17(5 suppl):505S-511S.
International Osteoporosis Foundation. What is osteoporosis? Available at: osteoporosis/about_osteoporosis.html. Accessed June 11, 2003.
Melton LJ III, Chrischelles EA, Cooper C et al. How many women have osteoporosis? J Bone Miner Res 1992;7:
Ascott-Evans BH, Guanabens N, Kiviven S et al. Alendronate prevents loss of bone density associated with discontinuation of hormone replacement therapy. Arch Intern Med 2003;163:
Tremollieres FA, Pouilles J-M, Ribot C. Withdrawal of hormone replacement therapy is associated with significant vertebral bone loss in postmenopausal women. Osteoporos Int 2001;12:

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
Slide 3
Currently, the bisphosphonate alendronate and the selective estrogen receptor modulator raloxifene are used for postmenopausal osteoporosis. Recent meta-analyses by Cranney et al evaluated clinical data for these agents to aid practicing clinicians in managing osteoporosis.1,2 Such analyses can provide objective, comprehensive summaries of available data. Statistically significant anti-fracture differences between two active treatments can only be detected in specially designed fracture endpoint studies. These studies require large patient populations, potentially tens of thousands of patients, and evaluations over long durations of at least three years of treatment.3 However, changes in BMD and bone turnover have been shown to be highly predictive of the anti-fracture efficacy of osteoporosis therapies4,5 and can provide clinically relevant information about the relative efficacies of these therapies.4 This information can be valuable to physicians in selecting a therapy that provides the greatest improvements in BMD or bone turnover and accordingly the best reduction in fracture risk.4
To date, only one published RCT has provided data on the clinical response of post-menopausal women to alendronate 10 mg once daily or raloxifene 60 mg once daily.6 The purpose of the study was to assess the additive effects of alendronate and raloxifene. Two large, similarly designed RCTs, the EFficacy of FOSAMAX™ vs. Evista® Comparison Trial, known as EFFECT–US and EFFECT–International, were conducted to provide additional head-to-head data for alendronate versus raloxifene in postmenopausal osteoporosis.7
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.
References
Cranney A, Guyatt G, Griffith L et al. IX. Summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev 2002;23(4):
Cranney A, Tugwell P, Wells G et al. I. Systematic reviews of randomized trials in osteoporosis: Introduction and methodology. Endocr Rev 2000;23(4):
Kanis JA, Oden A, Johnell O et al. Uncertain future of trials in osteoporosis. Osteoporos Int 2002;13:
Hochberg MC, Greenspan S, Wasnich RD et al. Changes in bone density and turnover explain the reductions in incidence of nonvertebral fractures that occur during treatment with antiresorptive agents. J Clin Endocrinol 2002;87:
Looker AC, Bauer DC, Chesnut CH III et al. Clinical use of biochemical markers of bone remodeling: Current status and future directions. Osteoporos Int 2000;11:
Johnell O, Scheele WH, Lu Y et al. Additive effects of raloxifene and alendronate on bone density and biochemical markers of bone remodeling in postmenopausal women with osteoporosis. J Clin Endocrinol Metab 2002;87(3):
Sambrook P, Geusens P, Keraudren V et al. Efficacy of Fosamax vs. Evista Comparison Trial (EFFECT–International): Results at 6 and 12 months. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.

4. Meta-Analyses of RCT Data for Raloxifene and Alendronate
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)
Slide 4
The recent meta-analyses by Cranney et al provide a vigorous analysis and summary of the data for raloxifene and alendronate.1
Results of the meta-analysis of RCTs of raloxifene showed that this agent increased mean lumbar spine BMD by 2.5% from baseline. Corresponding increases of 2.1% at the combined hip, 0.65% at the forearm, and 1.3% over the total body were observed in RCTs of one to three years’ duration.1 All these increases with raloxifene were statistically significant (p<0.01) versus pretreatment baseline except for the increase at the forearm. Raloxifene reduced the risk of vertebral fracture by 40% (p=0.01) in one major RCT evaluated in this meta-analysis (no pooled results for fractures were provided due to differences in trial size).1 Raloxifene was shown to have no effect on nonvertebral fracture in this meta-analysis.1
In the meta-analysis of RCTs of alendronate, this agent increased lumbar spine BMD by 7.5% from pretreatment baseline. Corresponding increases were 4.2% at the combined hip, 2.1% at the forearm, and 2.7% over the total body through two to four years of treatment.1 All of these BMD increases with alendronate were statistically significant (p<0.01) versus baseline. This meta-analysis also showed that alendronate, at doses of 10 to 40 mg/day, reduced the risk of vertebral fracture by 48% and reduced the risk of nonvertebral fracture by 49%.1 Both of these risk reductions were statistically significant (p<0.01).
Adapted from Cranney A et al Endocr Rev 2002;23(4):
Reference
Cranney A, Guyatt G, Griffith L et al. IX. Summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev 2002;23(4):

5. Johnell O et al, J Clin Endocrinol Metab 2002;87(3):985-992
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
BMD
Bone Turnover
Slide 5 6 20 5 *
Placebo-controlled trials have established the efficacy and safety profiles of alendronate and raloxifene in the prevention and treatment of osteoporosis.1-3 To date, however, few head-to-head comparative data have been available to aid in the choice between these agents in clinical practice.
The recent clinical trial by Johnell et al evaluated the effects of daily alendronate and raloxifene, alone and in combination, versus placebo on BMD and biochemical markers of bone turnover.4 Bone resorption was assessed by the ratio of urinary N-telopeptide to creatinine (NTx/Cr) and bone formation by bone-specific alkaline phosphatase (BSAP). This randomized, double-blind, 12-month study involved 331 postmenopausal women with osteoporosis (femoral neck BMD >2.0 standard deviations below peak bone mass for healthy premenopausal women).4 The patients were assigned to receive placebo, raloxifene 60 mg once daily, alendronate 10 mg once daily, or the combination of alendronate and raloxifene. All patients also received calcium and vitamin D supplementation.
Through 12 months of study, treatment with alendronate produced significantly greater increases in BMD at the spine and femoral neck than did raloxifene alone (p0.05 for both sites).4 Alendronate was also associated with significantly greater reductions in biochemical markers of bone turnover compared with raloxifene therapy (p0.05 for both NTx/Cr and BSAP).4 Combination therapy with alendronate plus raloxifene was more effective than raloxifene alone on all BMD and bone marker endpoints. Combination therapy was not more effective than alendronate alone on any parameter other than femoral neck BMD. Alendronate and raloxifene were well tolerated, with no significant differences in the incidence of drug-related adverse experiences among patients receiving either agent alone.4
This study was designed to evaluate additive effects.4 4 *
% Change at 12 months 3
% Change at 12 months
–20 2
–40 1
–60 * * –1
Spine
Femoral neck
NTx/Cr
BSAP
–80
Placebo Raloxifene Alendronate Alendronate + raloxifene
(n=82) (n=82) (n=83) (n=84)
*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):
References
Black DM, Cummings SR, Karpf DB et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996;348:
Cummings SR, Black DM, Thompson DE et al. 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):
Ettinger B, Black DM, Mitlak BH et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene. Results from a 3-year randomized clinical trial. JAMA 1999;282(7):
Johnell O, Scheele WH, Lu Y et al. Additive effects of raloxifene and alendronate on bone density and biochemical markers of bone remodeling in postmenopausal women with osteoporosis. J Clin Endocrinol Metab 2002;87(3):

6. EFficacy of Fosamax™ (alendronate) vs
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
Slide 6
Alendronate once weekly and raloxifene are prescribed for postmenopausal osteoporosis but have not been compared in terms of efficacy and safety profiles in a large-scale RCT.1 Such data are needed to provide clinicians with useful evidence on the relative efficacy and safety profile of both agents.
EFFECT was conducted to compare the clinical effects of alendronate 70 mg once weekly versus raloxifene 60 mg once daily on improvements in BMD and markers of bone resorption in postmenopausal women with osteoporosis.1
This is the first clinical comparison of alendronate once weekly 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.
Reference
Sambrook P, Geusens P, Keraudren V et al. Efficacy of Fosamax vs. Evista Comparison Trial (EFFECT–International): Results at 6 and 12 months. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.

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 12
487 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)
Slide 7
EFFECT–International was a randomized, double-blind, double-dummy, active-comparator–controlled trial conducted at 50 sites in 16 countries outside the United States.1 A separate, similarly designed study was also conducted in the United States.1 The key efficacy endpoints, BMD and bone turnover, were evaluated before patients began study therapy and again at study months 6 and 12.1
A total of 487 patients were randomized to either alendronate 70 mg once weekly plus a raloxifene dummy once daily as placebo (n=246) or raloxifene 60 mg once daily plus an alendronate dummy once weekly as placebo (n=241).1 Calcium and vitamin D supplements were added according to local standards.1
Adapted from Sambrook P et al. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.
Reference
Sambrook P, Geusens P, Keraudren V et al. Efficacy of Fosamax vs. Evista Comparison Trial (EFFECT–International): Results at 6 and 12 months. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.

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)
Slide 8
Women enrolled in EFFECT–International were community dwelling and ambulatory, at least 40 years of age, and at least six months postmenopausal.1 Osteoporosis was defined as a BMD T-score of –2.0 or less at either the lumbar spine or total hip.1
Enrolled women had not taken estrogen, an estrogen analogue, a selective estrogen-receptor modulator, a bisphosphonate, or parathyroid hormone within the previous year.1
Additional reasons for exclusion were a history of breast or uterine cancer and contraindications to the study medications, such as venous thromboembolic disease or esophageal motility disorders, as stated in the product labels.1
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.
Reference
Sambrook P, Geusens P, Keraudren V et al. Efficacy of Fosamax vs. Evista Comparison Trial (EFFECT–International): Results at 6 and 12 months. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.

9. EFFECT–International Study Endpoints
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
Slide 9
The EFFECT–International study was designed to compare the efficacy and tolerability of alendronate 70 mg once weekly with raloxifene 60 mg once daily. The primary efficacy endpoint was the percent change from baseline in lumbar spine BMD at 12 months of therapy.1
Several secondary efficacy endpoints were also evaluated:1
Percent change from baseline in total hip BMD at 12 months
Hip trochanter BMD at 12 months
Lumbar spine, total hip, and hip trochanter BMD at six months
Percentage of patients who maintained or increased spine BMD
Percent change in markers of bone turnover, specifically NTx/Cr and BSAP
Tolerability, including upper gastrointestinal (GI) and vasomotor adverse experiences
Adapted from Sambrook P et al. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.
Reference
Sambrook P, Geusens P, Keraudren V et al. Efficacy of Fosamax vs. Evista Comparison Trial (EFFECT–International): Results at 6 and 12 months. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.

10. EFFECT–International Baseline Characteristics
Alendronate Raloxifene 70 mg 60 mg once weekly once daily Overall (n=246) (n=241) (N=487)
Age (years)
Race (%) White Multiracial Hispanic Asian 3 5 4
Body mass index (kg/m2)
Years since last menses
BMD T-score Lumbar spine –2.89 –2.86 –2.88
Total hip –1.55 –1.55 –1.55
Slide 10
In all, 487 postmenopausal women with osteoporosis were enrolled and randomized to therapy with alendronate 70 mg once weekly or raloxifene 60 mg once daily.1 Baseline demographic and clinical characteristics were comparable in the two treatment groups.1,2
The mean age in both groups was 62 years, and 79% of patients were white.1 The average time since last menses was 15 years in both treatment groups, and baseline BMD values at the lumbar spine and total hip were similar.1,2
Adapted from Sambrook P et al. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.
References
Sambrook P, Geusens P, Keraudren V et al. Efficacy of Fosamax vs. Evista Comparison Trial (EFFECT–International): Results at 6 and 12 months. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.
Data on file, MSD __________.

11. EFFECT–International Lumbar Spine BMD
Percent change from baseline (mean ± SE)
Months
4.8
2.2 1 2 3 4 5 6 12
Alendronate (n=226)
Raloxifene (n=219)
p<0.001
Slide 11
In EFFECT–International, alendronate increased lumbar spine BMD by 4.8% from baseline to month 12, compared with an increase of 2.2% with raloxifene.1 The increase in lumbar spine BMD with alendronate was more than two times greater than the increase with raloxifene at 12 months. The difference between alendronate and raloxifene was highly significant at 12 months (p<0.001), as well as at month 6 (p<0.001), the first measurement point in the study.2
Adapted from Sambrook P et al. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.
References
Sambrook P, Geusens P, Keraudren V et al. Efficacy of Fosamax vs. Evista Comparison Trial (EFFECT–International): Results at 6 and 12 months. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.
Data on file, MSD __________.

12. EFFECT–International Total Hip BMD
Months
2.3
0.8 1 2 3 4 6 12
Alendronate (n=224)
Raloxifene (n=220)
Percent change from baseline (mean ± SE)
p<0.001
Slide 12
In EFFECT–International, alendronate was associated with a 2.3% increase in total hip BMD from baseline to month 12, compared with an increase of 0.8% with raloxifene.1,2 The increase in total hip BMD with alendronate was nearly three times greater than the increase with raloxifene. The difference between the two treatments was highly significant at month 12 (p<0.001), as well as at month 6 (p<0.001).2
Adapted from Sambrook P et al. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.
References
Sambrook P, Geusens P, Keraudren V et al. Efficacy of Fosamax vs. Evista Comparison Trial (EFFECT–International): Results at 6 and 12 months. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.
Data on file, MSD __________.

13. EFFECT–International Hip Trochanter BMD
Months
2.9
1.0 1 2 3 4 6 12
Alendronate (n=224)
Raloxifene (n=220)
Percent change from baseline (mean ± SE)
p<0.001
Slide 13
In EFFECT–International, the increase in hip trochanter BMD from baseline to month 12 was 2.9% with alendronate, compared with an increase of 1.0% with raloxifene.1,2 This difference was highly significant in favor of alendronate (p<0.001) at month 12 as well as at month 6 (p<0.001).2 The increase in hip trochanter BMD with alendronate was nearly three times greater than the increase observed with raloxifene at 12 months.2
Adapted from Sambrook P et al. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.
References
Sambrook P, Geusens P, Keraudren V et al. Efficacy of Fosamax vs. Evista Comparison Trial (EFFECT–International): Results at 6 and 12 months. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.
Data on file, MSD __________.

14. EFFECT–International Markers of Bone Turnover: Absolute Values
NTx/Cr
BSAP 60 20 50
Slide 14
13.5
38.8 15
Premenopausal range 40
Premenopausal range
Several biochemical markers of bone turnover may provide additional information about patients’ risks for osteoporotic fractures.1,2 In EFFECT–International, changes in bone resorption were monitored on the basis of the ratio of N-telopeptide to creatinine in the urine (NTx/Cr).1,3,4 Changes in bone formation were monitored on the basis of bone-specific alkaline phosphatase in serum (BSAP).1,3,4
Treatment effects on NTx/Cr and BSAP were analyzed in terms of absolute values to provide a gauge of how bone turnover rates in these postmenopausal women treated with alendronate or raloxifene compare with normal premenopausal levels. The normal ranges for these bone turnover markers in premenopausal women, indicated by the shaded areas in the graphs, span from 3.4 to 40.2 nmol/mmol for NTx/Cr and from 3.3 to 14.1 ng/ml for BSAP.5 These ranges represent levels two standard deviations above and below mean values for NTx/Cr and BSAP in premenopausal women.
Through six and 12 months of the study, the absolute values decreased with alendronate 70 mg once weekly and raloxifene 60 mg once daily, but the reductions were significantly greater with alendronate (p<0.001 at six and 12 months).4 Moreover, the mean absolute values of both NTx and BSAP were near the middle of the premenopausal range with alendronate but were much closer to the upper limit with raloxifene, suggesting that alendronate reduced bone turnover to premenopausal levels for most patients.
Additionally, alendronate was associated with a significantly greater percent reduction in NTx/Cr versus raloxifene at six months (65% vs. 30%) and at month 12 (68% vs. 29%) (p<0.001 at both time points).3,4 Similarly, alendronate was associated with a significantly greater percentage reduction in BSAP versus raloxifene at six months (48% vs. 10%) and at 12 months (51% vs. 12%) (p<0.001 at both time points).4
p<0.001
p<0.001
Absolute value (nmol/mmol) 30
p<0.001
Absolute value (ng/ml)
p<0.001 10 20
8.1 5
17.7 10 6 12 6 12
Months
Months
Alendronate (n=161)
Raloxifene (n=154)
Alendronate (n=175)
Raloxifene (n=166)
N values refer to month 12
Adapted from Garnero P et al J Bone Miner Res 1996;11(3):
References
Hochberg MC, Greenspan S, Wasnich RD et al. Changes in bone density and turnover explain the reductions in incidence of nonvertebral fractures that occur during treatment with antiresorptive agents. J Clin Endocrinol Metab 2002;87:
Looker AC, Bauer DC, Chesnut CH III et al. Clinical use of biochemical markers of bone remodeling: Current status and future directions. Osteoporos Int 2000;11:
Sambrook P, Geusens P, Keraudren V et al. Efficacy of Fosamax vs. Evista Comparison Trial (EFFECT–International): Results at 6 and 12 months. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.
Data on file, MSD __________.
Garnero P, Sornay-Rendu E, Chapuy M-C et al. Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. J Bone Miner Res 1996;11(3):

15. EFFECT–International Safety and Tolerability Profiles
Percent of patients Alendronate Raloxifene 70 mg 60 mg
Adverse once weekly once daily Experience (AE) (n=246) (n=241) p Value
Any AE NS
Drug-related* AE NS
Discontinued due to AE 6 8 NS
Upper GI AE NS Drug related
Vasomotor AE Drug related
Slide 15
Overall, the safety and tolerability profiles of alendronate and raloxifene were similar in EFFECT–International.1 No significant differences were noted between groups in the proportion of patients reporting any adverse experience, any drug-related adverse experience, or discontinuing treatment because of an adverse experience.1,2
There were no significant differences between the treatment groups with respect to upper GI adverse experiences. However, significantly fewer patients taking alendronate 70 mg once weekly (9%) reported a drug-related upper GI adverse experience compared with patients taking raloxifene 60 mg once daily (16%) (p=0.029).2
Additionally, significantly more patients taking raloxifene (10%) experienced vasomotor adverse effects compared with patients receiving alendronate (4%) (p=0.01).2
Adapted from Sambrook P et al. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.
References
Sambrook P, Geusens P, Keraudren V et al. Efficacy of Fosamax vs. Evista Comparison Trial (EFFECT–International): Results at 6 and 12 months. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.
Data on file, MSD __________.

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)
Alendronate decreased markers of bone turnover to well within the premenopausal ranges
Similar tolerability observed with alendronate and raloxifene
Slide 16
In summary, the EFFECT–International study showed that alendronate 70 mg once weekly had greater efficacy compared with raloxifene 60 mg once daily and similar tolerability in the treatment of osteoporosis in postmenopausal women. Increases in spine and hip BMD were two- to threefold greater with alendronate than with raloxifene at 12 months.1,2 Percent increases in lumbar spine BMD were 4.8% with alendronate versus 2.2% with raloxifene. Total hip BMD rose by 2.3% with alendronate and by 0.8% with raloxifene; respective increases at the hip trochanter were 2.9% (alendronate) and 1.0% (raloxifene). These differences were all highly significant in favor of alendronate (p<0.001).
Significant differences between alendronate and raloxifene on BMD at all sites evaluated were already evident at month 6, the first evaluation point in this study.1
Alendronate decreased bone turnover, as measured by a urinary marker of resorption, NTx/Cr, and a serum marker of formation, BSAP, significantly more than raloxifene (p<0.001).2 The mean absolute values of these markers of bone turnover were rapidly reduced to well within the premenopausal ranges in the alendronate group, and the mean was close to the upper limit in the raloxifene group.1,3
The overall tolerability profiles of alendronate and raloxifene were similar, with no significant difference in the overall incidence of adverse experiences.2
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):
References
Data on file, MSD __________.
Sambrook P, Geusens P, Keraudren V et al. Efficacy of Fosamax vs. Evista Comparison Trial (EFFECT–International): Results at 6 and 12 months. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.
Garnero P, Sornay-Rendu E, Chapuy M-C et al. Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. J Bone Miner Res 1996;11(3):

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
Slide 17
In conclusion, EFFECT–International showed that alendronate 70 mg once weekly was consistently and substantially more efficacious than raloxifene 60 mg once daily in improving BMD in postmenopausal women.1 Notably, alendronate produced increases in both lumbar spine and hip BMD that were two to three times larger than those observed with raloxifene at six and 12 months of therapy.1 Additionally, alendronate rapidly provided significantly greater reductions in bone turnover that were sustained throughout the study period (p<0.001 vs. raloxifene).1 These findings are consistent with those of a separate, similarly designed study conducted in the United States.1,2
Adapted from Sambrook P et al. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.
References
Sambrook P, Geusens P, Keraudren V et al. Efficacy of Fosamax vs. Evista Comparison Trial (EFFECT–International): Results at 6 and 12 months. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.
Bone H, Greenspan SL, Miller P et al. Efficacy of Fosamax® vs Evista® Comparison Trial (EFFECT): Results of a randomized, multicenter study. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.

18. ORAG Meta-Analyses: BMD Changes Reported for Alendronate and Raloxifene
Meta-Analyses of Percent Change from Baseline BMD in Separate RCTs of Alendronate or Raloxifenea
7.5b
4.2b
2.1b
2.7b
2.5b
0.7
1.3c 1 2 3 4 5 6 7 8
Spine
Combined hipd
Forearm
Total body
Mean % change
Alendronate
Raloxifene NS
n=1613
n=6053
n=1443
n=6033
n=565
n=359
n=469
n=511
Slide 18
On behalf of the Osteoporosis Research Advisory Group (ORAG), Cranney et al recently published the results of meta-analyses of therapies for postmeno-pausal osteoporosis.1 This slide summarizes the findings from the meta-analyses of alendronate and raloxifene. All available clinical trials for each drug were analyzed to provide the best estimate of efficacy in increasing BMD with alendronate 10 to 40 mg once daily or raloxifene. These data are grouped by body site in this slide for ease of viewing. They were not, however, obtained from head-to-head comparisons between alendronate and raloxifene.
The meta-analysis of alendronate showed significant increases from pretreatment BMD at all sites evaluated (p<0.01) in studies of two to four years’ duration. Lumbar spine BMD increased by a mean of 7.5% with alendronate in RCTs evaluated. Alendronate also provided mean BMD increases of 4.2% at combined hip sites, 2.1% at the forearm, and 2.7% over the total body.1
The meta-analysis of raloxifene also showed increases from pretreatment BMD at all sites evaluated in studies of two to three years’ duration. Lumbar spine BMD increased by a mean of 2.5% from pretreatment levels (p<0.01) with raloxifene in RCTs. Raloxifene was also associated with mean BMD increases of 2.1% at the combined hip (p<0.01), 0.7% at the forearm (p=0.07), and 1.3% over the total body (p=0.01).1
The BMD changes at various sites with alendronate and raloxifene in these meta-analyses are fully consistent with the BMD increase observed in the EFFECT–International study.2
aThese are not head-to-head data. Data shown together for ease of comparison; bp<0.01 vs. baseline; cp=0.01 vs. baseline; dhip and femoral neck
ORAG=Osteoporosis Research Advisory Group
Adapted from Cranney A et al Endocr Rev 2002;23(4):
References
Cranney A, Guyatt G, Griffith L et al. IX. Summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev 2002;23(4):
Sambrook P, Geusens P, Keraudren V et al. Efficacy of Fosamax vs. Evista Comparison Trial (EFFECT–International): Results at 6 and 12 months. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.

19. Meta-Analyses of Relative Risk of Fracture versus Placebo at 3 yearsa
ORAG Meta-Analyses: Fracture Risk Reductions Reported for Alendronate and Raloxifene
Meta-Analyses of Relative Risk of Fracture versus Placebo at 3 yearsa
Vertebral
Nonvertebral
8 studies
(n=9360)
1 study
(n=6828)
6 studies
(n=3723)
2 studies
(n=6961)
–10 –9 NS
–20
Slide 19
Mean % change
–30
The ORAG meta-analyses also assessed efficacy of alendronate and raloxifene in reducing the risk of vertebral and nonvertebral fractures in RCTs in separate trials. These trials were not head-to-head comparisons of alendronate versus raloxifene. The data are grouped by vertebral or nonvertebral fracture for ease of viewing.
As the slide shows, alendronate significantly reduced the risk of both vertebral and nonvertebral fractures versus placebo (p<0.01).1
The reduction in risk of both vertebral and nonvertebral fracture approached 50% with alendronate. Raloxifene reduced the risk of vertebral fractures by 40% versus placebo (p=0.01) and of nonvertebral fractures by a nonsignificant 9%.
–40
–40c
–50
–48b
–49b
Alendronated
Raloxifene
–60
aThese are not head-to-head data. Data shown together for ease of comparison; bp<0.01 vs. baseline; cp=0.01 at baseline; dAlendronate 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):
Reference
1. Cranney A, Guyatt G, Griffith L et al. IX. Summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev 2002;23(4):

20. ORAG Meta-Analyses: Relative Risk Reductions with Therapies for Postmenopausal Osteoporosis
Relative Risk Reductions for Vertebral and Nonvertebral Fractures
alendronate* (48% V, 49% NV) 50 40
Relative risk reduction in nonvertebral fractures
risedronate (36% V, 27% NV) 30
Slide 20
calcitonin (21% V, 20% NV)
vitamin D (37% V, 23% NV)
The meta-analyses of therapies for the treatment of postmenopausal osteoporosis, which assessed the results of RCTs for each therapy, show that alendronate provided the greatest risk reductions for both vertebral and nonvertebral fractures.
The reductions in relative risk of 48% for vertebral fractures, along the horizontal axis, and 49% for nonvertebral fractures, along the vertical axis, with alendronate versus placebo were substantially greater than those reported for any other agent evaluated.1 The strength of evidence therefore supports alendronate as the most efficacious treatment of postmenopausal osteoporosis. 20
HRT (34% V, 13% NV) 10
calcium (23% V, 14% NV)
raloxifene (40% V, 9% NV)
etidronate (37% V, 1% NV) 10 20 30 40 50 60
Relative risk reduction in vertebral fractures
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):
Reference
1. Cranney A, Guyatt G, Griffith L et al. IX. Summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev 2002;23(4):

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
Slide 21
Large-scale, head-to-head comparative trials provide useful information about the relative efficacy, safety, and tolerability of pharmacotherapies.
EFFECT–International demonstrated that alendronate was two to three times more effective than raloxifene for increasing lumbar spine and hip BMD, with a similar tolerability profile.1 The results of EFFECT–International are supported by similar findings in the similarly designed EFFECT trial conducted in the US.2
These results are consistent with those of an independent meta-analysis of data for alendronate and raloxifene from other RCTs. In this meta-analysis, alendronate outperformed raloxifene by increasing BMD at key body sites.3
In the ORAG meta-analysis, alendronate also outperformed raloxifene in lowering the risk of both vertebral and nonvertebral fractures.3
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):
References
Sambrook P, Geusens P, Keraudren V et al. Efficacy of Fosamax vs. Evista Comparison Trial (EFFECT–International): Results at 6 and 12 months. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.
Bone H, Greenspan SL, Miller P et al. Efficacy of Fosamax® vs. Evista® Comparison Trial (EFFECT): Results of a randomized, multicenter study. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.
Cranney A, Guyatt G, Griffith L et al. IX. Summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev 2002;23(4):

22. Bibliography Bibliography
Ascott-Evans BH, Guanabens N, Kiviven S et al. Alendronate prevents loss of bone density associated with discontinuation of hormone replacement therapy. Arch Intern Med 2003;163:
Black DM, Cummings SR, Karpf DB et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996;348:
Bone H, Greenspan SL, Miller P et al. EFficacy of Fosamax® vs. Evista® Comparison Trial (EFFECT): Results of a randomized, multicenter study. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.
Cranney A, Guyatt G, Griffith L et al. IX. Summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev 2002;23(4):
Cranney A, Tugwell P, Wells G et al. I. Systematic reviews of randomized trials in osteoporosis: Introduction and methodology. Endocr Rev 2000;23(4):
Cummings SR, Black DM, Thompson DE et al. 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):
Data on file, MSD __________________.
Ettinger B, Black DM, Mitlak BH et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene. Results from a 3-year randomized clinical trial. JAMA 1999;282(7):
Garnero P, Sornay-Rendu E, Chapuy M-C et al. Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. J Bone Miner Res 1996;11(3):
Hochberg MC, Greenspan S, Wasnich RD et al. Changes in bone density and turnover explain the reductions in incidence of nonvertebral fractures that occur during treatment with antiresorptive agents. J Clin Endocrinol 2002;87:
International Osteoporosis Foundation. What is osteoporosis? Available at: osteoporosis/about_osteoporosis.html. Accessed June 11, 2003.
Johnell O, Scheele WH, Lu Y et al. Additive effects of raloxifene and alendronate on bone density and biochemical markers of bone remodeling in postmenopausal women with osteoporosis. J Clin Endocrinol Metab 2002;87(3):
Kanis JA, Oden A, Johnell O et al. Uncertain future of trials in osteoporosis. Osteoporos Int 2002;13(6):
Looker AC, Bauer DC, Chesnut CH III et al. Clinical use of biochemical markers of bone remodeling: Current status and future directions. Osteoporos Int 2000;11:
Melton LJ III, Chrischelles EA, Cooper C et al. How many women have osteoporosis? J Bone Miner Res 1992;7:
Riggs BL, Melton LJ III. The worldwide problem of osteoporosis: Insights afforded by epidemiology. Bone 1995;17(5 suppl):505S-511S.
Sambrook P, Geusens P, Keraudren V et al. Efficacy of Fosamax vs. Evista Comparison Trial (EFFECT–International): Results at 6 and 12 months. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.
Tremollieres FA, Pouilles J-M, Ribot C. Withdrawal of hormone replacement therapy is associated with significant vertebral bone loss in postmenopausal women. Osteoporos Int 2001;12:
Ascott-Evans BH, Guanabens N, Kiviven S et al. Alendronate prevents loss of bone density associated with discontinuation of hormone replacement therapy. Arch Intern Med 2003;163:
Black DM, Cummings SR, Karpf DB et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996;348:
Bone H, Greenspan SL, Miller P et al. EFficacy of Fosamax® vs. Evista® Comparison Trial (EFFECT): Results of a randomized, multicenter study. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.
Cranney A, Guyatt G, Griffith L et al. IX. Summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev 2002;23(4):
Cranney A, Tugwell P, Wells G et al. I. Systematic reviews of randomized trials in osteoporosis: Introduction and methodology. Endocr Rev 2000;23(4):
Cummings SR, Black DM, Thompson DE et al. 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):
Ettinger B, Black DM, Mitlak BH et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene. Results from a 3-year randomized clinical trial. JAMA 1999;282(7):
Garnero P, Sornay-Rendu E, Chapuy M-C et al. Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. J Bone Miner Res 1996;11(3):
Hochberg MC, Greenspan S, Wasnich RD et al. Changes in bone density and turnover explain the reductions in incidence of nonvertebral fractures that occur during treatment with antiresorptive agents. J Clin Endocrinol 2002;87:
International Osteoporosis Foundation. What is osteoporosis? Available at: osteoporosis/about_osteoporosis.html. Accessed June 11, 2003.
Johnell O, Scheele WH, Lu Y et al. Additive effects of raloxifene and alendronate on bone density and biochemical markers of bone remodeling in postmenopausal women with osteoporosis. J Clin Endocrinol Metab 2002;87(3):
Kanis JA, Oden A, Johnell O et al. Uncertain future of trials in osteoporosis. Osteoporos Int 2002;13(6):
Looker AC, Bauer DC, Chesnut CH III et al. Clinical use of biochemical markers of bone remodeling: Current status and future directions. Osteoporos Int 2000;11:
Melton LJ III, Chrischelles EA, Cooper C et al. How many women have osteoporosis? J Bone Miner Res 1992;7:
Riggs BL, Melton LJ III. The worldwide problem of osteoporosis: Insights afforded by epidemiology. Bone 1995;17(5 suppl):505S-511S.
Sambrook P, Geusens P, Keraudren V et al. Efficacy of Fosamax vs. Evista Comparison Trial (EFFECT–International): Results at 6 and 12 months. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.
Tremollieres FA, Pouilles J-M, Ribot C. Withdrawal of hormone replacement therapy is associated with significant vertebral bone loss in postmenopausal women. Osteoporos Int 2001;12:

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.
Slide 23
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
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