Mike Stone Llandough Hospital Cardiff, UK Ibandronate: a new oral bisphosphonate for once-monthly administration in postmenopausal osteoporosis Mike Stone Llandough Hospital Cardiff, UK

Bisphosphonates: the gold standard of osteoporosis treatment Strontium ranelate SERMs HRT Calcium + Vitamin D Para- thyroid hormone Calci- tonin Patient preference for less frequently dosed regimens1–3 should be considered alongside efficacy and tolerability when prescribing a bisphosphonate 1Simon JA, et al. Clin Ther 2002;24:1871–86; 2Kendler D, et al. Maturitas 2004;48:243–51; 3Emkey R, et al. Curr Med Res Opin 2005;21:1895–61

Ibandronate: unique once-monthly regimen Significant vertebral fracture efficacy*1 nonvertebral fracture efficacy† 1 increases in bone mineral density (BMD)2,3 reduction in levels of bone markers2,3 Well tolerated tolerability similar to daily ibandronate, which is similar to placebo1–3 *Daily ibandronate vs placebo †With daily ibandronate vs placebo in patients at higher osteoporotic risk 1Chesnut CH, et al. J Bone Miner Res 2004;19:1241–9 2Miller PD, et al. J Bone Miner Res 2005;20:1315–22 3Reginster JY, et al. Ann Rheum Dis 2006;65:654–61

Oral bisphosphonates reduce bone turnover, improve bone density and decrease fracture risk RESTING RESORPTION osteoclast FORMATION osteoblasts BISPHOSPHONATES INHIBIT OSTEOCLAST -MEDIATED BONE Treatment and prevention of osteoporosis Bisphosphonates inhibit osteoclast activity and reduce the rate of bone resorption. This shifts the balance in favour of bone formation, and bone mass increases (Russell et al. 1999). Bisphosphonates achieve this by: Interfering with osteoclast cytoskeleton Inhibiting mevalonate pathway enzymes Decreasing protein-tyrosine phosphatases Stimulating apoptosis of osteoclasts Inhibiting osteoclast attachment to bone Inhibiting secretion of matrix metalloproteinases Adapted from Bone H, et al. Clin Ther 2000;22:15–25

Adherence with daily and weekly bisphosphonates reduces fracture risk 29% fracture risk reduction for persistent versus non-persistent users (p<0.001) 14 12 10 8 6 4 2 Fracture rate at 24 months (%) Adherence(9) Graph drawn from data in Coronary drug project. N Engl J Med 1980;303:1038–41 Poor adherence can result in a significantly higher 5-year mortality rate in patients with coronary heart disease compared with those patients who adhered well to treatment. ‘Good adherers to clofibrate, described as patients who took 80% or more of the protocol prescription during the five-year follow-up period, had a substantially lower 5-year mortality rate than poor adherers to clofibrate (15 vs 24.6%; p=0.00011).’ Non-persistent patients Persistent patients* *No gap in refills longer than 30 days Siris E, et al Mayo Clin Proc 2006

Adherence with oral bisphosphonates is currently suboptimal 100 80 60 40 20 Weekly alendronate Daily alendronate or risedronate Persistent patients (%) 44.2%* 31.7% 0 133.5 269 365 Days *p≤0.0001 vs daily Cramer JA, et al. Curr Med Res Opin 2005;21:1453–60.

Ibandronate is a N-containing Bisphosphonate NON-Nitrogen-containing BPs Nitrogen-containing BPs HO N O = P OH alendronate risedronate etidronate tiludronate pamidronate zoledronic acid clodronate ibandronate

Ibandronate is a new bisphosphonate that can be given less frequently than weekly OH OH OH OH group at R1 increases affinity for bone mineral2 O P C P O OH CH2 OH CH2 N-containing group within R2 increases potency3–5 N CH3 C5H11 1Mühlbauer RC, et al. J Bone Miner Res 1991;6:1003–11 2Van Beek E, et al. J Bone Miner Res 1994;9:1875–82 3Shinoda H, et al. Calcif Tissue Int 1983;35:87–99 4Geddes AD, et al. J Bone Miner Res 1994;8:265–306 5Russell RGG, Rogers MJ. Bone 1999;25:97–106

Ibandronate is a potent bisphosphonate Relative in vivo and in vitro potencies of bisphosphonates Zoledronic acid 103 Ibandronate Risedronate 102 Relative potency in vitro IC50 Dimethyl-APD Alendronate Pamidronate 101 Clodronate Neridronate 100 Etidronate 100 101 102 103 104 105 Relative potency in vivo (rat) ED50 Green J, et al. J Bone Miner Res 1994;9:745–51

Parameters for Bone Strength Bone Quantity Bone Quality - BMD - bone diameter - cortical thickness micro-architecture - bone turnover mineral properties collagen changes

Extensive Bone Quality testing with Ibandronate Increased trabecular volume Shift to plate like structure Two- and 3-dimensional Bone Architecture of Lumbar Vertebrae (L1): Micro-Tomographic Fan-Beam Imaging System (Cynomolgus Monkeys) Müller R, et al., J Bone Miner Res 19 (11): 1787-1796 (2004)

Treatment with Ibandronate increases Bone Strength 2-year Daily oral Treatment with Ibandronate in Rats Ultimate load (L4) **** 900 15mg/kg/d = 900mg/d per 60 kg-Patient 800 700 600 Control 3 mg/kg/d 7 mg/kg/d 15 mg/kg/d N 500 400 300 200 sign. vs. control 100 **** p<0.0001 female Lalla S, et al., Osteoporosis Int 8:97-103 (1998)

BMD increases with Ibandronate result in increased Bone Strength 200 300 400 500 600 700 3500 3000 2500 2000 1500 1000 L1 Whole Vertebrae L5 Vertebral Cores 120 100 80 60 40 20 BMD (mg/cm3) (pQCT) Ultimate Load (N) r=0.65730 P<0.0001 r=0.75794 P<0.0001 This slide shows the relationship of increasing BMD and ability to resist fracture (ultimate load) in the ovx monkey. This slide shows the relationship of increasing BMD and ability to resist fracture (ultimate load) in the OVX monkey. Sham controls OVX controls IBN 10 ug/kg/dpse IBN 30 ug/kg/dose IBN 150 ug/kg/dose Regression line Smith SY, et al. Bone 32:45-55 (2003)

Ibandronate Fracture efficacy Strong Rapid Consistent

Antifracture efficacy of all oral regimens has been established using daily dosing* Bisphosphonate Fracture Studies (daily dosing) Weekly and monthly oral regimens were approved based on demonstrating BMD gains comparable to daily dosing FIT11 Alendronate VERT NA2 VERT MN3 Risedronate BONE4 Ibandronate Several clinical trials have shown that oral bisphosphonate therapy is associated with antifracture efficacy at vertebral and non-vertebral sites. However, all these studies have been performed with the daily formulations, with the exception of ibandronate in which an intermittently dosed regimen has also demonstrated fracture efficacy. However, there are no data available that demonstrate antifracture efficacy for weekly oral, monthly oral or quarterly intravenous (i.v.) dosing with any bisphosphonate. These regimens have been assessed in studies evaluating bone mineral density (BMD) gains as the primary endpoint. Monthly oral ibandronate 150mg and quarterly i.v. ibandronate injection 3mg are associated with superior BMD gains when compared with a daily oral dose of known antifracture efficacy (2.5mg). Black DM, et al. Lancet 1996;348:1535–41 Chesnut CH, et al. J Bone Miner Res 2004;19:241–9 Harris ST, et al. JAMA 1999;282:1344–52 Miller PD, et al. J Bone Miner Res 2005;20:1315–22 Reginster J-Y, et al. Ann Rheum Dis 2006;65:654–61 Delmas PD, et al. Arthritis Rheum 2006;54:1838–46 *In patients with one or more prevalent vertebral fractures FIT = Fracture Intervention Trial; VERT NA = Vertebral Efficacy with Risedronate Therapy North America study VERT MN = Vertebral Efficacy with Risedronate Therapy MultiNational study BONE = oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe 1Black DM, et al. Lancet 1996;348:1535–41; 2Harris ST, et al. JAMA 1999;282:1344–52 3Reginster J-Y, et al. Osteoporos Int 2000;11:83–91; 4Chesnut CH, et al. J Bone Miner Res 2004;19:241–9

BONE explored daily and intermittent oral ibandronate administrations in osteoporosis Osteoporotic women* (n=2,946) Osteoporotic women* (n=2,946) Daily or intermittent placebo (n=982) Daily or intermittent placebo (n=982) Daily ibandronate (2.5mg) (n=982) Daily ibandronate (2.5mg) (n=982) Intermittent ibandronate (20mg every other day for 12 doses every 3 months) (n=982) Intermittent ibandronate (20mg every other day for 12 doses every 3 months) (n=982) Calcium (500mg) + vitamin D (400IU) Primary endpoint: rate of new vertebral fracture at 3 years *Aged 55–80 years, ≥5 years since menopause, BMD T-score ≤–2 in ≥1 lumbar vertebra (L1–L4), 1–4 prevalent vertebral fractures Chesnut CH, et al. J Bone Miner Res 2004;19:1241–9

Daily ibandronate reduces vertebral fracture risk 10 8 6 4 2 62% RRR (p=0.0001 vs placebo) Fracture rate at 3 years (%) Placebo Daily ibandronate Chesnut CH, et al. J Bone Miner Res 2004;19:1241–9

Fast and consistent efficacy of Ibandronate over time 62% Year 3 61% Year 2 58% Year 1 0.25 0.5 0.75 1 Relative risk (95% CI) for new vertebral fractures Data in: Chesnut CH, et al. J Bone Miner Res 2004;19:1241–9

Antifracture efficacy of Risedronate over time 41% Year 3 55% Year 2 65% Year 1 0.25 0.5 0.75 1 New Morphometric Vertebral Fractures Risedronate USPI Harris ST, et al. JAMA 1999;282:1344–52

Rapid and consistent effect of ibandronate on vertebral fractures 59.0% RRR p<0.0001 12 10 8 6 4 2 Placebo Ibandronate* 58.7% RRR p=0.0004 Incidence of new, moderate and severe vertebral fractures (%) 59.5% RRR p=0.016 Study: MF4411/BONE(14) Reference: Chesnut CH, et al. J Bone Miner Res 2004;19:1241–9 The placebo group exhibited an unusually low fracture incidence at year 1. Nevertheless, a 58% RRR was reported for the daily treatment. However, significance was narrowly missed, with a p-value of 0.056. 3-year fracture incidence: Placebo = 9.6% 2.5mg ibandronate = 4.7% 20mg ibandronate = 4.9% 1 2 3 Years *2.5mg daily Semiquantitative analysis (moderate and severe vertebral fractures) ITT population Felsenberg D, et al. Bone 2005;37:651–4

Study n Inclusion criteria Pbo non-vert fx incidence [%] 3 years Non-vert fracture risk reduction ALN Phase III 994 < -2.5 LS 10.7 n.s. FIT1 2027 < -2.0 LS Vert fx ≥1 14.7 FIT2 4432 Vert fx - 13.3 (4 ys) BONE 2946 8.9 RIS – MN 1226 Vert fx ≥2 16.0 (selected fractures) 17% (all non-vert fractures) RIS – US 2458 8.4 (selected fractures) 13% (all non-vert fractures) p< 0.05 This slide just summarizes the pivotal studies, showing the inconsistency with regards to non-vertebral fracture risk reduction across these trials.

Fracture incidence (%) First demonstration of fracture efficacy for a non-daily* bisphosphonate: ibandronate 10 8 6 4 2 62% RRR p=0.0001 50% RRR p=0.0006 ns Fracture incidence (%) Placebo Ibandronate Ibandronate daily >2 months treatment free interval ITT population at 3 years ns = not significant (p=0.2785 between groups for fracture incidence) Chesnut CH, et al. J Bone Miner Res 2004;19:1241–9

Patients with baseline femoral neck T-score <–3.0 Significant reduction in nonvertebral fractures with ibandronate in patients at higher risk Patients with baseline femoral neck T-score <–3.0 20 16 12 8 4 69% RRR (p=0.012 vs placebo) Fracture incidence (%) Study: MF4411/BONE(22) Reference: MF4411 data on file (Roche/GSK) Placebo Ibandronate* *2.5mg daily Chesnut CH, et al. J Bone Miner Res 2004;19:1241–9

Fracture incidence (%) Significant reduction in nonvertebral fractures with ibandronate in patients at higher risk Patients with baseline lumbar spine T-score <–2.5 and a history of clinical fracture within last 5 years 20 16 12 8 4 60% RRR (p=0.037 vs placebo) Fracture incidence (%) Placebo Ibandronate* *2.5mg daily Bauss F, Schimmer R. Ther Clin Risk Manage 2006;2:3–18

Bonviva preserves bone structure Ibandronate Placebo Recker ECTS 2007 Chesnut CH, et al. J Bone Miner Res 2004;19:1241–9

Daily and intermittent* ibandronate are well tolerated 100 80 60 40 20 Placebo Daily Incidence (%) Any AE Any related Any SAE Any related Any upper AE SAE GI AE *20mg every other day for 12 doses every 3 months Chesnut CH, et al. J Bone Miner Res 2004;19:1241–9 Rosen C, et al. Arthritis Rheum 2003;48(Suppl. 9):Abstract 102

Frequency of GI AEs (>5%) in patients taking concomitant NSAIDs* 20 15 10 5 Placebo 2.5mg daily Frequency (% patients) Study: MF4411/BONE(39) Data sources: MF4411 data on file (Roche/GSK); Delmas PD, et al. Osteoporosis Int 2003;14(Suppl. 7):S74[poster] Oral ibandronate was associated with excellent upper gastrointestinal tolerability in patients taking concomitant non-steroidal anti-inflammatory agents (NSAIDs). Dyspepsia Constipation Gastroenteritis Nausea After Epstein s Maturitas; Vol 54, Issue 1, 1-10 *All patients received oral ibandronate and concomitant therapies: analgesics/antipyretics (36–38%), anti-inflammatory/antirheumatic (35–37%; mainly aspirin and non-steroidal anti-inflammatory drugs [NSAIDs]) (21–24%) Placebo 2.5mg daily 20mg intermittent Dyspepsia 11.1 15.1 11.7 Constipation 7.4 5.1 Gastroenteritis 6.5 6.3 7.3 Nausea 6 4.3 7.1

Lumbar spine BMD with daily and weekly oral bisphosphonates 10mg daily 70mg weekly 5mg daily 35mg weekly 8 7 6 5 4 3 2 1 8 7 6 5 4 3 2 1 Change in lumbar spine BMD (%) from baseline Change in lumbar spine BMD (%) from baseline 1 year 2 years 1 year 2 years Alendronate1,2 Risedronate3,4 1Schnitzer T, et al. Aging Clin Exp Res 2000;12:1–12; 2Rizzoli R, et al. J Bone Miner Res 2002;17:1988–96; 3Brown JP, et al. Calcif Tissue Int 2002;71:103–11; 4Harris ST, et al. Curr Med Res Opin 2004;20:757–64

MOBILE explored once-monthly oral ibandronate administrations in osteoporosis Osteoporotic women* (n=1610) Osteoporotic women* (n=1,609) Daily ibandronate (2.5mg) (n=402) Monthly ibandronate (50+50mg) (n=404) Monthly ibandronate (100mg) (n=402) Monthly ibandronate (150mg) (n=402) Calcium (500mg) + vitamin D (400IU) Primary endpoint: change (%) in lumbar spine BMD at 1 year *Aged 5580 years, 5 years since menopause, lumbar spine (L2L4) BMD T-score <2.5 Miller PD, et al. J Bone Miner Res 2005;20:1315–22 Reginster JY, et al. Ann Rheum Dis 2006;65:654–61

Monthly ibandronate provides larger gains in spinal bone density than daily ibandronate 7 6 5 4 3 2 1 6.6%† Daily Monthly (150mg) 5.0%* 4.9% 3.9% Change (%) *p=0.002 vs daily †p<0.001 vs daily Miller PD, et al. J Bone Miner Res 2005;20:1315–22 Reginster JY, et al. Ann Rheum Dis 2006;65:654–61 1 2 Year

Mean change from baseline at 2 years (%) Further increases in proximal femur BMD with monthly versus daily ibandronate 7 6 5 4 3 2 1 2.5mg daily 6.2* 150mg monthly 4.2* 4.0 Mean change from baseline at 2 years (%) 3.1* 2.5 1.9 Total hip Femoral neck Hip trochanter *Superior (p<0.05) to 2.5mg daily PP population Miller PD, et al. J Bone Miner Res 2005;20:1315–22 Reginster JY, et al. Ann Rheum Dis 2006;65:654–61

The anti-fracture efficacy with BPs is related to increases in BMD RR of new non-vertebral fracture vs change in hip BMD at 1y RR of new non-vertebral fracture vs change in spine BMD at 1y Hochberg MC, et al. J Clin Endocrinol Metab 2002;87:1586-92

Fracture rate (fractures) Lower fracture rates reported with higher hip BMD gains in patients who received oral ibandronate 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 Placebo 2.5mg and 20mg oral ibandronate Fracture rate (fractures) p=0.0084 –4 –3 –2 –1 0 1 2 3 4 5 6 7 8 9 BMD change (%) Moving average plot of 250 patients (using the mean) in patients with BMD lumbar spine T-score <–2 Adami ECTS 2007

Monthly ibandronate provides marked reductions in sCTX 20 40 60 80 Daily Monthly (150mg) Change (%) 0 6 12 18 24 Miller PD, et al. J Bone Miner Res 2005;20:1315–22 Reginster JY, et al. Ann Rheum Dis 2006;65:654–61

Once-monthly ibandronate is well tolerated 80 70 60 50 40 30 20 10 Year 1 Year 2 2.5mg daily 150mg monthly Overall adverse event profile of daily ibandronate was similar to that of placebo in BONE3 Incidence (%)1,2 Any AE Any drug- Any drug- Any SAE Any drug- Any drug- related AE related AE related SAE related SAE leading to leading to withdrawal withdrawal AE = adverse event; SAE = serious adverse event 1Reginster JY, et al. Ann Rheum Dis 2006;65:654–61 2Miller PD, et al. J Bone Miner Res 2005;20:1315–22 3Chesnut CH, et al. J Bone Miner Res 2004;19:1241–9

Effect of ibandronate on non-vertebral fractures: Meta-analysis of patient data Investigated for different doses of ibandronate – including licensed doses

Meta-analysis conducted by experts in systematic review and osteoporosis Led by A Cranney, G Wells and JD Adachi Previously published a series of meta-analyses for osteoporosis therapies in Endocrine Reviews1 Full ibandronate clinical trial datasets were provided to, and all analyses conducted by, external expert group at the University of Ottawa Guidance was also provided by a steering committee - SCIENCE (Steering Committee for IbandronatE and Non-vertebral fraCture Endpoints) Silvano Adami Cyrus Cooper Pierre D Delmas Paul D Miller Socrates E Papapoulos Jean-Yves Reginster Philip Sambrook Stuart Silverman Ethel Siris 1Cranney A, et al. Endocr Rev 2002;23:496–507

Objective Investigate the non-vertebral efficacy of ibandronate by examining evidence from clinical trials of PMO patients with at least two years of fracture data Increase power and sample size to detect differences in fracture rates

Methods1 Meta-analysis of ibandronate registration trials to increase sample size and power Evaluated 8 ibandronate registration trials for PMO Selected trials with at least 2 years fracture data on marketed doses Two pivotal phase III clinical trials met criteria Identical designs: BMD bridging studies for oral (MOBILE) and IV (DIVA) Nonvertebral fracture data collected same as in pivotal fracture trials using x-ray (to confirm adverse event data) Individual patient data (IPD) analysis more robust2 than study level summary data for fracture studies Primary endpoint: non-vertebral fractures as standard in the osteoporosis literature3 (clavicle, humerus, wrist, pelvis, hip, leg) Compare higher doses, including currently marketed doses vs active comparator (2.5 mg daily oral) Old version (didn’t include green highlight): Meta-analysis included MOBILE and DIVA Pivotal phase III trials in PMO with at least 2 years fracture data Identical study designs concurrently implemented Registration studies for marketed doses vs active comparator (2.5mg daily) Used individual patient data (IPD) Primary endpoint: Key non-vertebral fractures The standard 6 osteoporotic nonvertebral fractures Clavicle, humerus, wrist, pelvis, hip, leg 1Adachi R. EULAR 2007

Statistical Analysis Compare patients on high doses versus daily doses Time to fracture using Kaplan-Meier methods (cumulative fracture rate) Relative risk of fracture using Cox regression to control for baseline differences (age, BMD, prior clinical fracture) Compare patients within trials, rather than across trials Maintains study randomisation and increases validity of results Group patients on similar therapeutic doses Patients grouped according to annual cumulative exposure (ACE) to increase sample size – this allowed grouping of oral and IV dose Old version: Compare patients on higher doses versus lower doses Time to fracture using Kaplan-Meier methods Relative risk of fracture using Cox regression to control for baseline differences (age, BMD, prior clinical fracture) Compare patients within a trial, rather than across trials Maintains study randomisation Doses grouped based on the total absorbed dose the annual cumulative exposure (ACE) what a patient is systemically exposed to in a year

Doses grouped to increase sample size Higher Doses ACE ~ 11 mg Daily / Low Dose ACE = 5.5mg Daily Oral: 2.5mg Monthly Oral: 150mg Quarterly IV: 3mg Bi-Monthly IV: 2mg NOT LICENSED Annual Cumulative Exposure (ACE) = dose X doses/year X absorption (E.g. 2.5 x 365 x 0.6% = 5.5mg ACE) Absorption for oral 150mg = 0.6%

Results: Bonviva Reduced Nonvertebral Fracture Risk Ibandronate at higher doses (including the licensed doses) significantly reduced non-vertebral fractures compared with daily dosing over 2 years 43% RRR p=0.0489 38% RRR p=0.0375 0.620 (0.395, 0.973) 0.569 (0.324, 0.997) n=1,355 n=2,137 12mg vs 5.5mg ≥10.8mg vs 5.5mg ACE * Marketed doses are 150mg monthly (ACE 10.8mg) and 3mg IV quarterly (ACE 12mg). 2mg bimonthly dose (ACE 12mg; not licensed) with identical ACE as 3mg IV also included in analysis. ACE of 5.5mg refers to 2.5mg daily Cranney A, et al. Ann Rheum Dis 2007;66(Suppl. 11):681

Time to non-vertebral fracture is extended with ibandronate ACE ≥10 Time to non-vertebral fracture is extended with ibandronate ACE ≥10.8mg vs daily dose 6 5 4 3 2 1 ACE 10.8mg ACE 5.5mg RRR 38% p<0.05† p=0.036 (log-rank) Estimated fracture rate (%) This corresponds to row 2 in the table. Kaplan-Meier plot shows the cumulative incidence of fractures is significantly lower (log-rank statistic p=0.036) for the pooled doses with ACE>=10.8 in the MOBILE and DIVA trials (150mg, 3mg IV q 3 months and 2mg IV q 2 months), compared to the subjects receiving ACE=5.5 mg (2.5mg oral daily dose). 0 100 200 300 400 500 600 700 Time (days) ACE = annual cumulative exposure

Assessment of preference BALTO studies: patient preference after once-monthly ibandronate and weekly alendronate Assessment of preference Randomisation Crossover Ibandronate for 3 months Alendronate for 12 weeks Patients screened and informed* consent obtained Follow-up Alendronate for 12 weeks Ibandronate for 3 months 5 months 15 days *All patients were informed that both drugs are indicated for the treatment of osteoporosis Emkey R, et al. Curr Med Res Opin 2005;21:1895–903 Hadji P, et al. Osteoporos Int 2006;17(Suppl. 1):S69 (Abstract P259)

The majority of patients prefer the monthly regimen of ibandronate 100 80 60 40 20 100 80 60 40 20 BALTO I1 BALTO II2 71.4* 70.6* Proportion of patients (%) Proportion of patients (%) 28.6 29.4 Monthly ibandronate Weekly alendronate Monthly ibandronate Weekly alendronate Patients expressing a preference (93%), modified intent-to-treat (mITT) populations=298 (BALTO I), 321 (BALTO II) *Preference rate for monthly was significant (p<0.0001) 1Emkey R, et al. Curr Med Res Opin 2005;21:1895–903 2Hadji P, et al. Osteoporos Int 2006;17(Suppl. 1):S69 (Abstract P259)

The majority of patients find the monthly regimen of ibandronate more convenient 100 80 60 40 20 100 80 60 40 20 BALTO I1 BALTO II2 76.6* 74.6* Proportion of patients (%) Proportion of patients (%) 25.4 23.4 Monthly ibandronate Weekly alendronate Monthly ibandronate Weekly alendronate Patients expressing a preference (93%), mITT=298 (BALTO I), 321 (BALTO II) *Preference rate for monthly was significant (p<0.0001) 1Emkey R, et al. Curr Med Res Opin 2005;21:1895–903 2Hadji P, et al. Osteoporos Int 2006;17(Suppl. 1):S69 (Abstract P259)

HealthCore database n=6,127 Patients on monthly ibandronate more likely to persist than those on weekly bisphosphonates HealthCore database n=6,127 Covariates significantly (p<0.0001) affecting persistence co-pay per day* Deyo-Charlson Comorbidity Index (DCI) score treatment supply over 30 days Monthly vs weekly: 27.2% increase in persistence *Continuous Analysed using Cox proportional hazards regression Silverman S, et al. ASBMR 2006 (Abstract SU335)

MOTION: study to demonstrate non-inferiority between ibandronate and alendronate on BMD Superior efficacy in terms of BMD gains with alendronate versus risedronate has been demonstrated1 Objective: to demonstrate non-inferiority of lumbar spine and total hip BMD changes with ibandronate versus alendronate2 Women aged 55–84 years and 5 years postmenopause Mean lumbar spine (L2–L4) BMD T-score <–2.5 and –5.0 n=1,760 Daily calcium (500mg) and vitamin D (400IU) Once-monthly oral ibandronate (150mg) Weekly oral alendronate (70mg) MOTION = Monthly Oral Therapy with Ibandronate for Osteoporosis iNtervention 1Rosen CJ, et al. J Bone Miner Res 2005;20:141–51 2Cosman F, et al. J Bone Miner Res 2005;20(Suppl. 1):S398 (Abstract M359)

Secondary/exploratory endpoints Mean change from baseline (%; 95% CI) Comparable improvements in hip and spine BMD with monthly ibandronate and weekly alendronate Ibandronate 150mg monthly Alendronate 70mg weekly Co-primary endpoints Secondary/exploratory endpoints Mean change from baseline (%; 95% CI) The improvements at the four BMD sites: total hip, lumbar spine, trochanter and femoral neck, were all clinically comparable with monthly ibandronate 150mg and weekly alendronate 70mg. n=717 n=721 n=714 n=720 n=714 n=720 n=714 n=720 Lumbar spine Total hip Hip trochanter* Femoral neck† PP population *Secondary endpoint; †exploratory endpoint Miller P et al ASBMR 2007

Summary and conclusions Ibandronate is a highly potent aminobisphosphonate Daily and intermittent oral ibandronate provide strong antifracture efficacy and have a tolerability profile similar to placebo Once-monthly ibandronate (150mg) is at least as effective and well tolerated as daily dosing Non vertebral fracture data for once-monthly ibandronate (150mg) from individual patient data metaanalysis Once-monthly ibandronate (150mg) is a preferred option for postmenopausal osteoporosis