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IBANDRONATE

High Efficacy to
Reduce Fracture
Risk in Osteoporosis

Disclaimer: This scientific information and event supported by PT. Roche Indonesia

Definition
1). Old
definition: a reduced amount of bone that is qualitatively
Osteoporosis
normal. (Albright F. Ann Intern Med. 1947; 27:861)
2). Modern definition: A systemic skeletal disease characterized
by low bone mass and microarchitectural deterioration of
bone tissue, with a consequent increase in bone fragility and
susceptibility to fracture. (1991)
3). Newest definition: Osteoporosis is a skeletal disorder
characterized by compromised bone strength predisposing
to an increased risk of fracture. Bone strength reflects the
integration of two main features: bone density and bone
quality. (2001)

Prevalensi
WHO 200.000.000 orang menderita Osteoporosis di
Osteoporosis
seluruh dunia. Tahun 2050, angka hip fracture
meningkat dua kali lipat pada wanita dan tiga lipat
pada pria.
Di dunia, 1 dari 3 wanita usia 50tahun akan
mengalami fraktur
akibat osteoporosis dan di pria adalah 1 dari 5.
PEROSI (2006) meningkat 23% pada usia 50-80
tahun dan menjadi 53% usia 70-80 tahun
Sistem Informasi Rumah Sakit (SIRS) 2010,
insiden fraktur tulang paha atas sekitar 200/100.000
kasus pada wanita dan pria usia 40 tahun
50% fraktur tulang paha atas: cacat seumur hidup,

As Women Age, BMD Decreases


and Fracture Risk Increases
Spine BMD
(g/cm2)

Colles'

Hip

Fracture Incidence
per 100,000 Person-Years

Spine

4000
3000
2000
1000
0
35-39

85+

Age

Economic cost of
Osteoporosis
Direct cost: estimated $13.8 billion
(1995) for hospitalization, rehabilitation,
and nursing home care. In 2003 will be
$17 billion
Indirect cost due to loss of productivity
and wages are difficult to measure but it
will very substantial things
By 2025 is expected to be 25 billion
annualy1

Burge R et al J Bone Miner Res, 2007; 22:465-475

NON-VERTEBRAL FRACTURE :
SATU TAHUN SETELAH PATAH TULANG PANGGUL
Tidak dapat melakukan
paling tidak 1 kegiatan
sehari-hari

Pasien (%)

80%
Tidak dapat
berjalan sendiri
Cacat tetap
Meninggal
dalam 1 tahun

40%

30%

20%
Cooper C, Am J Med, 1997;103(2A):12S-17S

The ultimate treatment goal for


bisphosphonates in osteoporosis
Increasing
BMD

Reducing
bone remodelling

Maintaining
structural properties

BMD = bone mineral density

Bone
strength

Fracture
risk

Ibandronate
Complete fracture protection
BONE
Meta-Analyses
VIBE

Ibandronate
Complete fracture protection
BONE

Primary endpoint: Ibandronate significantly


reduces vertebral fracture risk at 3 years
10
62% RRR
(95% CI: 4175
p=0.0001 vs.
placebo)

Fracture incidence (%)

8
6
4
2
0

n=975

n=977

Placebo

Ibandronate
2.5mg daily

RRR = relative risk reduction; CI = confidence interval;


BONE study Intent-to-treat (ITT) at 3 years;
Relative risk = 0.38 (95% CI: 0.250.57) for 2.5mg daily vs. placebo at 3 years
Chesnut CH, et al. J Bone Miner Res 2004;19:12411249

BONE STUDY: Vertebral Fracture Risk Reduction

Ibandronate reduces non-vertebral


fractures in high-risk patients
Overall population

Baseline femoral neck BMD


T-score <3.0*
20

15
p=NS
10

n=975

n=977

Placebo

Ibandronate
2.5mg daily

*Post-hoc subgroup analysis


BMD = bone mineral density
Chesnut CH, et al. J Bone Miner Res 2004;19:12411249

Incidence of non-vertebral
fractures at 3 years (%)

Incidence of non-vertebral
fractures at 3 years (%)

20

15
69% RRR
p=0.012

10

n=124

n=123

Placebo

Ibandronate
2.5mg daily

BONE STUDY: Non-Vertebral Fracture Risk Reduction

Bone quality maintenance has also been


demonstrated with ibandronate

Placebo

Ibandronate

Qualitative histological
analysis of bone biopsies

Recker R, et al. J Clin Densitom 2009;12:7176


Chesnut CH, et al. J Bone Miner Res 2004;19:12419

Ibandronate
Complete fracture protection
Meta-Analyses

Non-vertebral fracture data


Two separate meta-analyses confirm non-vertebral
protection with ibandronate

Harris et al. 20081


Data from BONE, IV Pivotal Fracture Trial, MOBILE and DIVA
Individual patient level data from ITT population
Higher dose vs. placebo comparison for non-vertebral
fractures

Cranney et al. 20092


Data from eight randomised trials reviewed
Individual patient data from ITT population
Higher vs. lower doses comparison for key non-vertebral
fractures
1. Harris ST, et al. Curr Med Res Opin 2008;24:237245
2. Cranney A, et al. Osteoporos Int 2009;20:291297

Meta-analysis comparison of higher vs.


lower dose groups
Higher doses
(ACE* 10.8mg)
Monthly oral
150mg

Cranney

Lower dose
(ACE* 5.5mg)
Daily oral
2.5mg

Quarterly IV
3mg

Placebo
Bimonthly IV 2mg
NOT LICENSED

Harris

Placebo

*ACE = annual cumulative exposure = dose x doses/year x absorption (e.g. 2.5 x 365 x 0.6% = 5.5mg ACE)

Absorption for oral ibandronate = 0.6%


Barrett J, et al. J Clin Pharmacol 2004;44:951965
Harris ST, et al. Curr Med Res Opin 2008;24:237245
Cranney A, et al. Osteoporosis Int 2009;20:291297

Cranney et al.
Time to non-vertebral fracture is extended with
ibandronate ACE 10.8mg vs. low dose
Daily ibandronate (ACE=5.5mg)
Estimated fracture rate (%)

High-dose ibandronate (ACE10.8mg)


38% relative
risk reduction

Time (days)
Adachi JD, et al. ASBMR Annual Meeting, 1619 September 2007; Honolulu, HI. Poster M428.
Cranney A, et. al. Osteoporos Int 2009;20:291297

Harris et al.

Patients with fracture (%)

Time to non-vertebral fracture is extended with


ibandronate ACE 10.8mg vs. placebo
Ibandronate high doses (ACE10.8mg)
Placebo

10
9
8
7
6
5
4
3
2
1
0

p=0.025 (Log-rank)

50

150

250

350
450
Time (days)

Harris ST, et al. Curr Med Res Opin 2008;24:237245

550

650

750

Meta-analyses: Ibandronate significantly


reduced the risk of non-vertebral fractures
Ibandronate at higher dose levels, provided by the
licensed monthly oral and quarterly IV dose,
significantly reduced the risk of non-vertebral fractures
Ibandronate is the first bisphosphonate to demonstrate
non-vertebral antifracture efficacy with doses used in
clinical practice vs. an active comparator

1. Cranney A, et al. Osteoporos Int 2009;20:291297


2. Harris ST, et al. Curr Med Res Opin 2008; 24: 237245

VIBE STUDY

Ibandronate terbukti menurunkan resiko fraktur vertebra yang


lebih tinggi dan

VIBE study: Comparable rates of hip and


non-vertebral fractures
Comparable rates of hip and non-vertebral fractures
for monthly ibandronate and weekly bisphosphonates
The rates of vertebral fractures were statistically
significantly lower with monthly ibandronate vs. weekly
bisphosphonates
Sensitivity analyses support primary conclusions

Harris ST, et al. Bone 2009;44:758765

Ibandronate
long term fracture protection
MOBILE LTE

DIVA

Mobile LTE: IBandronate meningkatkan BMD


secara berkesinambungan hingga >5 tahun

Miller PD et al. Osteoporos Int. 2012


Jun;23(6):1747-56.

Monthly ibandronate maintained increases


in proximal femur BMD over 5 years
10
9
8
7
6
5
4
3
2
1
0

Femoral neck
150mg monthly (n=346)
2.5mg daily (n=349)

n=167

n=164
n=156

p<0.05

Mean change from baseline (%)

Mean change from baseline (%)

Total hip

10
9
8
7
6
5
4
3
2
1
0

Year

n=167

p<0.05

Year

MOBILE ITT analysis; *p<0.05 vs. MOBILE baseline; **95% CI; At 2 years; LTE = long-term extension
Miller PD, et al. J Bone Miner Res 2005;20:13151322
Reginster JY, et al. Ann Rheum Dis 2006;65:654661
Felsenberg D, et al. Osteoporos Int 2009;20(Suppl.1):S15 (Abstract OC32)

n=164

n=156

The need for I.V. bisphosphonates


in osteoporosis
Postmenopausal osteoporosis patients best
suited for i.v. administration are those who
Cannot tolerate
oral administration

Are taking
multiple oral
medications

Cannot follow
Dosing instructions
e.g. bedridden
Have problems with
adherence to oral
bisphosphonates
i.v. = intravenous

Have abnormalities
delaying oesophageal
emptying

Have cognitive
difficulties
Do not respond
to oral therapy

The DIVA trial :


Demonstrating the robust
Ibandronate i.v 3mg proven long-term safety

The DIVA study: evaluation of


i.v. ibandronate injection
Randomised, double-blind, double-dummy, non-inferiority study
Women (n=1,395), 5580 years; 5 years postmenopause;
lumbar spine (L2L4) BMD T-score <2.5 and 5.0
Daily calcium (500mg) and vitamin D (400IU)
2.5mg daily
oral ibandronate
(n=465)

2mg q2mo i.v.


ibandronate injection
(n=448)

3mg q3mo i.v.


ibandronate injection
(n=469)

Mean change (%) from baseline in


lumbar spine BMD at 1 year (primary endpoint); lumbar spine and
proximal femur BMD, and serum CTX at 2 years (secondary endpoints)
q3mo = every 3 months; q2mo = every 2 months

Greater increases in BMD with quarterly IV


injection versus daily ibandronate: lumbar spine
Mean change from baseline (%)

8
7
6
5
4
3
2
1
0

3mg quarterly IV injection (n=334)


2.5mg daily (n=334)
0

Year
PP population; *p<0.001 vs daily ibandronate (2.5mg); At 2 years
Delmas PD, et al. Arthritis Rheum 2006;54:183846
Eisman JA, et al. J Rheumatol 2007. In press

Total hip

Mean change from


baseline (%)

Mean change from


baseline (%)

Greater increases in BMD with quarterly IV injection


versus daily ibandronate: proximal femur

PP population
*p<0.05 vs ibandronate daily (2.5mg)

p=0.08 vs ibandronate daily (2.5mg); At 2 years


Delmas PD, et al. Arthritis Rheum 2006;54:183846
Eisman JA, et al. J Rheumatol 2007. In press

Year
Mean change from
baseline (%)

Year

3mg quarterly IV injection (n=333)


2.5mg daily (n=330)

Femoral neck

Trochanter

Year

Monthly oral and quarterly IV ibandronate produce


similar BMD gains: non-comparative studies

Mean change from


baseline (%) at 2 years

6.6

6.3

Lumbar spine
Total hip

5
4.2

3.1

3
2
1
0

n=289

n=289

150mg monthly oralIbandronate1


PP population; 2-year data
1
Reginster J-Y, et al. Ann Rheum Dis 2006;65:65461
2
Eisman JA, et al. J Rheumatol 2007. In press.

n=333

n=333

3mg quarterly IV ibandronate


injection2

DIVA LTE study: long-term evaluation


of quarterly IV ibandronate injection
Randomised for DIVA
LTE

Ibandronate 2mg q2mo i.v.


DIVA study
2.5mg daily,
2mg q2mo, 3mg q3mo

Follow-up

Ibandronate 3mg q3mo i.v.

2 years

3 years

12 months

15 days

24 months
BMD and BTM assessment

LTE = long-term extension


BTM = bone turnover marker

36 months

BMD
Lumbar
Spine

Serum
CTX

33

BMD
Total
Hip

Biochemical
Bone
Turnover
Marker

DIVA STUDY
Ibandronate Injection 3 mg quaterly
showed impressive BMD increases
from baseline1

Significant BMD
increases delivered
in as few as 2
years and
consistenly
maintained over 5
years.2,3

BMD is a major determinant of increased


fracture risk2

Monthly oral and quarterly IV ibandronate are


effective for postmenopausal osteoporosis
Both regimens have demonstrated17

consistent BMD gains following up to 5 years of treatment


consistent reductions in markers of bone turnover
A large number of patients respond to treatment above baseline and at prespecified
cut-offs that are indicative of fracture efficacy2,4

Monthly oral and quarterly IV ibandronate are generally well tolerated, with
similar tolerability to daily2,4
Ibandronats superior renal safety profile enables to be given as IV Bolus

Miller PD, et al. J Bone Miner Res 2005;20:131522; 2Reginster J-Y, et al. Ann Rheum Dis 2006;65:65461; 3Delmas PD,
et al. Arthritis Rheum 2006;54:183846; 4Eisman JA, et al. J Rheumatol 2007. In press; 5Eisman JA, et al. Osteoporos Int
2006;17(Suppl. 2);S212 (Abstract P316SA); 6Lewiecki M, et al. Bone 2007;40(Suppl. 2):S302 (Abstract 309Th); 7Lewiecki
M, et al. Bone 2007;40(Suppl. 2):S301 (Abstract 307Th);
1

Summary

Osteoporosis is a significant
problem

Ibandronate as a complete fracture


protection

Ibandronate is proven for long term


fracture protection

Ibandronate is flexible and simple to