Ten Years’ Experience with Alendronate for the Treatment of Osteoporosis in Postmenopausal Women Adapted from Bone HG, Hosking D, Devogelaer J-P, Tucci JR, Emkey RD, Tonino RP, Rodriguez-Portales JA, Downs RW, Gupta J, Santora AC, Liberman UA, for the Alendronate Phase III Osteoporosis Treatment Study Group. N Engl J Med 2004;350:1189–1199. Contents Osteoporosis and 10 Years’ Experience with Alendronate Slide #2 Introduction Slide #3 Study Objective Slide #4 Methods Slide #5 Phase III Osteoporosis Treatment Studies Slide #6 Statistical Analyses Slide #7 Baseline Characteristics Slide #8 Continuous Increases in Lumbar Spine BMD with Alendronate 10 mg over 10 Years Slide #9 Sustained Increase in Total Hip BMD with Alendronate 10 mg over 10 Years Slide #10 Bone Turnover Markers Slide #11 Sustained Reduction in Annual Height Loss with Alendronate 10 mg Slide #12 Nonvertebral Fracture Reduction Sustained through 10 Years Slide #13 Gastrointestinal Adverse Experiences Slide #14 Summary Slide #15 Conclusions Slide #16 Bibliography

Introduction Postmenopausal women have1 increased bone turnover higher rates of bone resorption than formation decreases in BMD greater susceptibility to fracture Alendronate is a potent bone resorption inhibitor2 3-Year study showed that alendronate1 increased BMD decreased bone turnover rate to within normal premenopausal range. reduced the risk of vertebral fractures The initial 3-year trials were extended for a total of 10 years – the longest study of any osteoporosis treatment3,4 Postmenopausal osteoporosis is a common disorder characterized by an increase in bone resorption relative to bone formation, generally in conjunction with an increased rate of bone turnover. The progressive decrease in bone mass leads to an increased susceptibility to fractures, which results in substantial morbidity and mortality.1 Alendronate is a potent inhibitor of bone resorption.2 The original 3-year study showed that daily treatment with alendronate progressively increases bone mass in the spine, hip, and total body, and reduces the incidence of vertebral fractures.1 The study was extended for a total of 10 years – the longest study of any osteoporosis treatment.3,4 Adapted from Liberman UA et al N Engl J Med 2004;333:1437–1443 and Bone HG et al N Engl J Med 2004;350:1189–1199.

Study Objective To examine the effects of prolonged alendronate therapy as well as its discontinuation, this multinational, randomized double-blind study was extended for a total of 10 years To investigate the effects of prolonged alendronate therapy as well as the drug’s discontinuation, the original trials were extended for a total of 10 years.4 Adapted from Bone HG et al N Engl J Med 2004;350:1189–1199.

Methods 994 Postmenopausal Osteoporotic Women (Initial 3-Year Study) First 2-Year, Double-Blind Extension (N = 727) Second 2-Year, Double-Blind Extension (N = 350) Third 3-Year, Double-Blind Extension (N = 247) Bone Mineral Density (BMD): DXA Lumbar Spine (Primary), Femoral Neck, Trochanter, Total Hip, Total Body, Forearm Biochemical Markers of Bone Turnover (BSAP, NTx) Stature (Stadiometer) Clinical and Laboratory Safety Evaluations The study was designed to assess the effects of oral alendronate, an aminobisphosphonate, on bone mineral density (BMD) and the incidence of fractures and height loss in women with postmenopausal osteoporosis.1 In the initial study, 994 postmenopausal women with osteoporosis were enrolled in two identical concurrent, 3-year, phase III studies, which were designed to permit pooling of the results. Three daily doses of alendronate were compared with placebo. The study was extended three times, maintaining randomized group assignments and blinding.1,4 The primary endpoint was the change in BMD at the lumbar spine. Secondary endpoints included changes in BMD at the femoral neck, trochanter, total proximal femur (total hip), total body, and forearm. Biochemical markers included urinary N–telopeptides of type 1 collagen (NTx) (a marker of bone resorption) and serum bone-specific alkaline phosphatase (BSAP) and total serum alkaline phosphatase (indicators of the rate of bone formation). 4 Safety endpoints included adverse clinical and laboratory events, vertebral and clinical fractures (reported as adverse experiences), and stature.4 DXA = Dual-energy x-ray NTx = urinary N-telopeptides of type I collagen BSAP = serum bone-specific alkaline phosphatase Adapted from Bone HG et al N Engl J Med 2004;350:1189–1199.

Phase III Osteoporosis Treatment Studies Alendronate Treatment Schedule The figure shows treatment assignments for the original study and the extensions. Women in the placebo group were given open-label alendronate for years 4 and 5 and then discharged from the study. The original 5 mg and 10 mg alendronate groups continued to receive the same doses in all three extensions of the study (years 4 and 5, 6 and 7, and 8 through 10). Those in the original 20 mg group received 5 mg for years 3 through 5 and placebo for years 6 through 10 (the discontinuation group).4 Adapted from Bone HG et al N Engl J Med 2004;350:1189–1199.

Statistical Analyses BMD: Percent Change at Year 10: From Baseline From Years 6 and 8 Modified Intention to Treat NTx, BSAP: Percent Change from Baseline Per-Protocol* Safety Profile: Adverse Experiences (Years 8–10) Stature (Years 6–10) Fractures Reported as Adverse Experiences (Years 6–10) The primary endpoint was the change in BMD at the lumbar spine. Secondary endpoints included changes in BMD at other sites. 4 The modified intention-to-treat analysis for BMD included all women with measurements at baseline, year 7, and at least one subsequent year in which a study drug was given. 4 Secondary endpoints included changes in the levels of urinary NTx — a biochemical marker of bone resorption; and changes in the levels of serum BSAP — an indicator of the rate of bone formation. 4 The analysis of biochemical markers was performed only in women who were compliant with the protocol (per-protocol analysis). 4 The proportions of women with clinical adverse events and laboratory adverse events were compared. 4 Data on morphometrically detected vertebral fractures, clinical fractures, and stature were collected as safety endpoints. 4 Annualized height loss was estimated primarily from the mean loss during years 6 through 10. 4 BMD = bone mineral density NTx = urinary N-telopeptides of type I collagen BSAP = serum bone-specific alkaline phosphatase *Included study participants compliant with protocol Adapted from Bone HG et al N Engl J Med 2004;350:1189–1199.

Baseline Characteristics* ALN 20/5/PBO ALN 5 mg ALN 10 mg n=83 n=78 n=86 Mean ±SD Mean ±SD Mean ±SD Age (years) 63 ±6.2 64 ±7.2 63 ±6.0 Years since Menopause 16 ±7.6 16 ±7.7 15 ±7.7 Body Mass Index (kg/m2) 25 ±3.5 24 ±3.6 24 ±2.9 Estimated Calcium Intake (mg/day) 704 ±459 838 ±516 747 ±563 Baseline Spine BMD (g/cm2)** -Hologic, Norland 0.71 ±0.1 0.70 ±0.1 0.70 ±0.1 -Lunar 0.81 ±0.1 0.80 ±0.1 0.82 ±0.1 The characteristics of the 247 women in the third extension of the study, at the time of their initial randomization, were similar among the groups.4 * Pre-treatment status of patients enrolled in the third, 3-year double-blind extension study, N = 247 ** Mean baseline T-score = -3.1 ALN = Alendronate; PBO = Placebo Adapted from Bone HG et al N Engl J Med 2004;350:1189–1199.

Mean Percent Change (±SE) Continuous Increases in Lumbar Spine BMD with Alendronate 10 mg over 10 Years 2 4 6 8 10 12 14 (13.7%) p<0.001 (9.3%) p<0.001 (9.3%) p<0.001 Mean Percent Change (±SE) ALN 5 mg (n=78) BMD at the lumbar spine continued to increase during years 6 through 10 and 8 through 10 in both alendronate 5 mg and 10 mg groups. The mean cumulative increase after 10 years of the 10 mg daily dose was 13.7% (p<0.001), as compared with the baseline value; smaller gains occurred in the 5 mg group.4 In the discontinuation group (ALN 20/5/PBO), BMD at the lumbar spine did not change significantly after year 5.4 ALN 10 mg (n=86) ALN 20 mg/ALN 5 mg/Placebo (n=83) 1 2 3 4 5 6 7 8 9 10 Year The mean percent change from baseline to year 10 appears in parentheses following each treatment group. Adapted from Bone HG et al N Engl J Med 2004;350:1189–1199.

Mean Percent Change (±SE) Sustained Increases in Total Hip BMD with Alendronate 10 mg over 10 Years 9 1 2 3 4 5 6 7 8 ALN 5 mg (n=78) ALN 20 mg/ALN 5 mg/Placebo (n=83) ALN 10 mg (n=86) (6.7%) p<0.001 Mean Percent Change (±SE) (3.4%) p<0.001 (2.9%) p<0.05 Treatment with 10 mg of alendronate daily for 10 years produced mean increases in bone mineral density of 6.7% at the total hip as compared with baseline values (p<0.001). Smaller gains occurred in the group given 5 mg daily (p<0.05). In the discontinuation group (ALN 20/5/PBO), BMD significantly decreased but remained above baseline values (p<0.001).4 1 2 3 4 5 6 7 8 9 10 Year The mean percent change from baseline to year 10 appears in parentheses following each treatment group. Adapted from Bone HG et al N Engl J Med 2004;350:1189–1199.

Bone Turnover Markers Urine NTx BSAP -90 -80 -70 -60 -50 -40 -30 -20 -10 -70 -60 -50 -40 -30 -20 -10 Mean Percent Change Alendronate reduced the levels of markers of bone remodeling to stable levels within the normal premenopausal range. This effect was sustained through 10 years of treatment.4 The mean level of urinary NTx in the 10 mg group declined from 66.6 nmol/mmol at baseline to 22 nmol/mmol at the end of year 10.4 The normal ranges for these bone turnover markers in premenopausal women is from 3.4 to 40.2 nmol/mmol for NTx/Cr.5 The mean serum BSAP level in the 10 mg group decreased from 17.8 ng/ml to 9.1 ng/ml at the end of year 10.4 The normal range in premenopausal women is from 3.3 to 14.1 ng/ml for BSAP.5 After discontinuation of alendronate, markers of bone remodeling increased within a year, but mean values remained below baseline values.4 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 Year Year ALN 10 mg ALN 20 mg/ALN 5 mg/Placebo ALN 5 mg Reduced turnover to within normal premenopausal range.4,5 NTx = urinary N-telopeptides of type I collagen BSAP = serum bone-specific alkaline phosphatase Adapted from Bone HG et al N Engl J Med 2004;350:1189–1199.

Height Loss with Alendronate 10 mg in Years 6–10 Was Similar to Alendronate in Years 1–3* 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 Height Loss (mm/year) Data on stature was collected as a safety endpoint. Height loss in the 10 mg group during years 6 through 10 was similar to that among all alendronate-treated women during the first three years. The height loss was slightly, but not significantly, greater in the 5 mg and discontinuation groups (ALN/20/5/PBO) than in the 10 mg group during years 6 through 10.4 Placebo (n=397) All ALN (n=597) ALN/20/5/PBO (n=65) ALN 5 mg (n=57) ALN 10 mg (n=73) *Years 1–3 included all alendronate-treated women Adapted from Bone HG et al N Engl J Med 2004;350:1189–1199

Nonvertebral Fracture Reduction Sustained through 10 Years 1 2 3 4 5 Women with Fracture per 100 Patient-Years Fracture data was collected as a safety endpoint, rather than an efficacy endpoint. In years 6–10, the rate of radiologically confirmed nonvertebral fractures in the 10 mg group was similar to that in the pooled alendronate groups during the first three years of the study.4 Although the differences were not statistically significant, the fewest morphometric vertebral fractures and lowest rate of non-vertebral fractures occurred in the group given 10 mg of alendronate, which also had the greatest cumulative exposure to alendronate.4 The “estimated” placebo group was estimated by calculating the increases in the incidence of fracture that would have been expected if the original placebo group (years 1–3) had continued with no treatment. The estimate was calculated using logistic-regression coefficients derived from the study of osteoporotic fractures.4 Placebo (n=397) All ALN (n=597) Estimated Placebo ALN 20/5/PBO (n=83) ALN 5 mg (n=78) ALN 10 mg (n=86) Adapted from Bone HG et al N Engl J Med 2004;350:1189–1199.

Gastrointestinal Adverse Experiences Years 8–10 24.1 1.2 2.4 7.2 0 ALN/20/5/PBO (n=83) 14.1 1.3 1.3 1.3 1.3 ALN 5 mg (n=78) 27.9 0 2.3 2.3 0 ALN 10 mg (n=86) % Of women with adverse experiences: Any Upper GI Serious Withdrawn Esophageal PUBs During years 8–10, the incidence of all upper gastrointestinal adverse experiences was similar among the three groups.4 PUBs = Perforations, Ulcers or Bleeds Adapted from Bone HG et al N Engl J Med 2004;350:1189–1199.

Summary Continuous treatment with daily oral alendronate 10 mg for 10 years resulted in the following: Significant increases in BMD from baseline up to 10 years Lumbar spine: 13.7% increase Total hip: 6.7% increase Sustained reduction of bone turnover to within the premenopausal range Nonvertebral fracture incidence in years 6–10 similar to that observed in patients treated with alendronate in years 1–3 In summary, continuous treatment with 10 mg of alendronate for 10 years was associated with sustained therapeutic effects on bone density and remodeling, with no indication that the anti-fracture efficacy of the drug was diminished.4 Adapted from Bone HG et al N Engl J Med 2004;350:1189–1199.

Conclusions Alendronate is the only osteoporosis therapy demonstrating 10 years of sustained efficacy3,4 Continuous alendronate for 10 years: Progressively increases lumbar spine BMD Increases, then maintains hip BMD Produces greater effects at 10 vs. 5 mg/day Maintains stable reduction of bone turnover Risk of nonvertebral fractures years 6–10 similar to years 1–3 (10 mg dose) Discontinuation of alendronate after 5 years: Is associated with only partial resolution of effect Does not lead to accelerated bone loss Continuous therapy yields greater skeletal benefits In conclusion, alendronate is the only osteoporosis therapy demonstrating 10 years of sustained efficacy.4 Adapted from Bone HG et al N Engl J Med 2004;350:1189–1199.

Bibliography 1. Liberman UA, Stuart RW, Broll J et al. Effect of alendronate on bone mineral density and the incidence of fractures in postmenopausal women. N Engl J Med 1995;333:1437–1443. 2. Tonino RP, Meunier PJ, Emkey R et al. Skeletal benefits of alendronate: 7-Year treatment of postmenopausal osteoporotic women. J Clin Endocrinol Metab 2000;85:3109–3115. 3. Data on file, MSD ________. 4. Bone HG, Hosking D, Devogelaer J-P et al. Ten years’ experience with alendronate for the treatment of osteoporosis in postmenopausal women. N Engl J Med 2004;350:1189–1199. 5. 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):337–349.

Phase III Osteoporosis Treatment Study Group Protocol 035 Investigators Mary Baker* Jeffrey Miller Norman Bell* Anthony Mulloy* Michael Bliziotes* Robert Recker* Henry Bone* Richard Tonino* Robert Downs* Joseph Tucci* Ronald Emkey* Richard Wasnich* Murray Favus* Nelson Watts* C. Conrad Johnston* Robert Weinstein Robert Marcus* Stuart Weiss* Harris McIlwain* * Participated in the 3rd Extension Protocol 037 Investigators Johann Bröll* J.M. Kaufman* Catherine Cormier M.O.R. Leite R. Correa-Rotter* Uri Liberman* David C. Cumming* Joel Menkes J. Dequeker * Pierre Meunier J-P. Devogelaer* Ian Reid* P. Geusens Jose Rodriguez-Portales* David Hosking* Ego Seeman* Phillippe Jaeger*

Ten Years’ Experience with Alendronate for the Treatment of Osteoporosis in Postmenopausal Women Before prescribing, please consult the manufacturers’ prescribing information. Copyright © 2004 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved. 4-05 FSM 2004-W-7083-SS Printed in USA VISIT US ON THE WORLD WIDE WEB AT http://www.merck.com