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

2. 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

3. 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

4. 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

5. 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= ).’
Non-persistent patients Persistent patients*
*No gap in refills longer than 30 days
Siris E, et al Mayo Clin Proc 2006

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

7. 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

8. 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

9. 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

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

11. 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): (2004)

12. 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: (1998)

13. 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= P<0.0001
r= 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)

14. Ibandronate Fracture efficacy
Strong
Rapid
Consistent

15. 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

16. 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

17. Daily ibandronate reduces vertebral fracture risk10 8 6 4 2
62% RRR (p= vs placebo)
Fracture rate at 3 years (%)
Placebo Daily ibandronate
Chesnut CH, et al. J Bone Miner Res 2004;19:1241–9

18. 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

19. 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

20. 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 ;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
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

21. 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.

22. 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= between groups for fracture incidence) Chesnut CH, et al. J Bone Miner Res 2004;19:1241–9

23. 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

24. 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

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

26. 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

27. 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

28. 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

29. 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

30. Monthly ibandronate provides larger gains in spinal bone density than daily ibandronate7 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
Year

31. 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

32. 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:

33. 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 –
BMD change (%)
Moving average plot of 250 patients (using the mean) in patients with BMD lumbar spine T-score <–2
Adami ECTS 2007

34. Monthly ibandronate provides marked reductions in sCTX20 40 60 80
Daily
Monthly (150mg)
Change (%)
Miller PD, et al. J Bone Miner Res 2005;20:1315–22 Reginster JY, et al. Ann Rheum Dis 2006;65:654–61

35. Once-monthly ibandronate is well tolerated80 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

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

37. 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

38. 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

39. 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

40. 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

41. 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%

42. 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
(0.395, 0.973)
(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

43. 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).
Time (days)
ACE = annual cumulative exposure

44. 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)

45. 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)

46. 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)

47. 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)

48. 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)

49. 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

50. 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