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Ibandronate roles for Osteoporosis

Definition of Osteoporosis

NORMAL

OSTEOPOROTIC

a systemic skeletal disease characterized by


low bone mass and microarchitectural
deterioration of bone tissue leading to enhanced
bone fragility and a consequent increase in

fracture risk.
World Health Organization (WHO), 1994

Kriteria WHO untuk diagnosis


osteoporosis

Projected ASIAN Increase


osteoporosis Fracture Number
668

742
378

3250

400

1,5 X

2X

1990 2050

1990 2050

(?)

Osteopenia 41.8%(m) 90%(f)


629
100
1990 2050

600

Do something
Low cost

ASIAN
5X

1990 2050

www.iofbonehealth.org/health-professionals/about-osteoporosis/epidemiology.html

Fraktur yang disebabkan benturan


ringan merupakan tanda
osteoporosis

Osteoporosis Increase Morbidity


Back pain
Loss of height
Deformity (kyphosis,
protuberant abdomen)
Reduced pulmonary function
Diminished quality of life: loss of
self-esteem, distorted body image,
dependence on narcotic analgesics,
sleep disorder, depression,
loss of independence

OSTEOPOROSIS PATIENTS REQUIRE


LONG-TERM PROTECTION
Long-term protection

Sustained
fracture
risk
reduction

Vertebral
and nonvertebral
fracture
prevention

Bone strength

Rekomendasi durasi terapi


International Osteoporosis Foundation

Recommend Treatment for Osteoporosis should be


maintained at least 1 year
For Individual at high risk, should be continued
without a drug holiday.
Recommendation

Grade

Individuals at high risk for fracture should continue osteoporosis therapy without a
drug holiday

1. Black DM, et al. JAMA 2006; 296(24):2927-2938.


2. Watts NB, et al. Osteoporos Int 2008; 19(3):365-372.

Terapi yang disetujui oleh US FDA yang


terbukti dalam mencegah fraktur pada
wanita post menopause*
Bone
Antiresorptive therapy
Type of
Fractur
e<

Bisphosphonates
(As first line therapy)
Ibandronate,Risedronate,
Alendronate,
Zolendronic Acid

formati
on
therap
y

Hormo
ne
Calcit Raloxi therap Teripar
onin
fene
y
atide
(Estro
gen)**

Vertebr

al

Hip
Non

vertebr

+
* For al
postmenopausal women, indicates first line therapies and Grade A recommendation. For men requiring treatment,
alendronate, risedronate, and zoledronic acid can be used as first line therapies for prevention of fractures [Grade D].
+ In clinical trials, non-vertebral fractures are a composite endpoint including hip, femur, pelvis, tibia, humerus, radius, and clavicle.
** Hormone therapy (estrogen) can be used as first line therapy in women with menopausal symptoms.

Clinical approach to Managing


Osteoporosis in PostMenopausal Women
and Men Age 50 and Older

Sumber: National Osteoporosis Foundation Guideline 2013

Phillips, B. B., 2008. Osteoporosis, in : Pharmacotherapy A Pathophysiologic Approach, 7th edition. J. T.


DiPiro, et. al.(Eds). New York. Mc Graw Hill Medical. pp. 853-866

Bisphosphonate
First line drug of osteoporosis treatment
Bisphosponates oral is poorly absorbed
Associated with Gatroesophagealo reflux
disease
Antiresorptive agent
To inhibit osteoclastic bone resorption

1960s Herbert Fleisch discovers bisphosphonates


1970s The first studies of a bisphosphonate are
published
1980s Etidronate is licensed to treat
PMO
1995 Alendronate (daily) is licensed to treat
PMO
1998 Molecular MOA for nitrogen-containing
bisphosphonates established
1

PMO = postmenopausal osteoporosis


MOA = mode of action
1
Jowsey J, et al. J Lab Clin Med 1973;82:56775
2
Luckman SP, et al. J Bone Miner Res 1998;13:5819

2000 Risedronate (daily) and alendronate


(weekly)
are licensed to treat PMO
2002 Risedronate (weekly) and ibandronate
(daily) are licensed to treat PMO
2004 The first study of an intermittent vs daily
bisphosphonate (ibandronate) is
published1
2005 Ibandronate (once-monthly) is
licensed
to treat PMO

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

MEKANISME KERJA
Bonviva bekerja dengan cara
Menghambat aktivitas osteoklas
Menghambat pembentukan osteoklas
Menghambat pematangan ( maturation ) osteoklas

BonAdAsia
Pengaruh Bone Marker Feedback (BMF) Terhadap
Kepatuhan Pengobatan Bonviva Sekali Sebulan Untuk
PMO

Total patients 200 :


Jakarta : 100
Surabaya : 50
Makassar : 50
100 patients in BMF arm and 100 patients in non-BMF arm

Hasil
Bonviva menurunkan CTX serum secara signifikan, dengan profil
keamanan yang baik
Pasien merasa lebih nyaman & lebih memiliki kualitas hidup
dengan mengasup IBN sekali sebulan daripada BP mingguan
Pasien patuh tehadap asupan Bonviva tanpa ada kaitannya
dengan BMF

Ibandronate
Complete fracture protection
BONE

VIBE

BONE: iBandronate Osteoporosis trial in North America and Europe


VIBE:eValuation of iBandronate Efficacy

Primary endpoint: Ibandronate significantly


reduces vertebral fracture risk at 3 years

Fracture incidence (%)

10
62% RRR
(95% CI: 4175
p=0.0001 vs.
placebo)

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

VIBE STUDY

Ibandronate terbukti menurunkan resiko fraktur vertebra yang


lebih tinggi dan memiliki resiko fraktur non vertebra yang

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:Monthly Oral iBandronate in LadiEs Long Term Extension


DIVA: Dosing IntraVenous Administration Long-Term Extension

MOBILE STUDY

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)

BONVIVA TABLET TERBUKTI MEMPERTAHANKAN KENAIKAN BMD


SELAMA 5 TAHUN

Ibandronate maintains increases


in total hip BMD over 5 years
Relative change from MOBILE
baseline (%)

10

MOBILE

MOBILE LTE

8
150mg monthly (n=171)
100mg monthly (n=173)

6
4
2
0

3
Years

ITT population
Pooled data; subgroups of patients on the same dose of ibandronate continuously for 5 years

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

Swallowing
difficulties

Have cognitive
difficulties
Do not respond
to oral therapy

The DIVA LTE study: 5 years 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)

Significant greater increase of mean change (%) in IV group from baseline in


lumbar spine BMD at first year (primary endpoint);
lumbar spine and proximal femur BMD at second year (secondary endpoints)
q3mo = every 3 months; q2mo = every 2 months

DIVA STUDY

Ibandronat terbukti mempertahankan kenaikan


BMD selama 5 TAHUN

IV ibandronate injection is well tolerated


Incidence of adverse events and adverse events leading to
withdrawal similar with daily oral and i.v. ibandronate
The number of patients with renal and urinary disorders was low
and similar between the oral and i.v. arms (<5%)
DIVA LTE ibandronate IV injection continued to be well tolerated
low incidence of flu-like illness, good renal safety profile
no evidence for late or cumulative toxicity after 3 years of i.v. ibandronate
therapy

Emkey R, et al. Arthritis Rheum 2005;52:4060 (Abstract L8)


Lewiecki M, et al. Bone 2007;40(Suppl. 2):S301 (Abstract 307Th)

IV ibandronate is well tolerated


3mg q3mo IV
(n=400, %)
Any adverse event
Any drug-related adverse event
Any adverse event leading to
withdrawal

270 (68.0)
37 (9.0)
0

Low Incidence of flu-like illness


with IV ibandronate regimens

Switched from placebo


to IV ibandronate
3mg q3mo (n=137, %)
Flu-like illness

1 (0.7)

Received continuous IV
ibandronate
3mg q3mo
(n=263, %)
1 (0.4)

Ibandronates superior renal safety profile


Enables to be given as IV Bolus
Ibandronate renal safety comparable to placebo
Ibandronate renal safety superior to zoledronic acid
Ibandronate does not require renal monitoring
Ibandronate does not require co-medication awareness
to lessen renal toxicity

Patients without renal


function deterioration (%)

Renal Function with Intravenous Ibandronat


Comparable with Placebo
100

94%
88%

80
60
40
Ibandronat 6mg
Placebo

20
0

12

24

36
48
60
72
Study duration (weeks)

Diel IJ, et al. Ann Oncol 2004;15(Suppl. 3):iii224

84

96

Preclinical differences
Effects

Ibandronat

zoledronate

Tissue damage

renal cortex

renal cortex +
outer medulla

Margin of safety
(Ratio between renal
LOEL & LLD)

25

3.3

Terminal renal tissue


half-life

24 days

150+ days

Accumulation renal damage


at 3-weekly dosing interval

No

Yes

LOEL - Lowest Observed Effect Level


LLD - Lowest Lethal Dose

Inter-study comparison
of renal deterioration

Patients without renal


function deterioration (%)

100
80
60
40
20
0

Ibandronat 6mg

12

24

Zoledronic acid 4mg

36
48
60
72
Study duration (weeks)

84

96

Rosen LS, et al. Cancer J 2001;7:37787

Renal safety considerations with


the use of Ibandronat
Renal function monitoring is at the physicians
discretion
No dosage adjustment needed in patients with
creatinine clearance 30mL/min or blood creatinine
2.3 mg/dL
No restrictions on use with nephrotoxic medications

European Bondronat SmPC. F. Hoffmann-La Roche Ltd

Intravenous Ibandronate Safety:


The benefits associated with bisphosphonate use OUTWEIGH the risk of
rare adverse events, such as atypical fracture and ONJ

Perceived issues: renal events, ONJ, flu-like illness


Fact: only rare occurrences with i.v. ibandronate
injection in patients with PMO
Renal events
No cases of acute renal
failure in >3,000 women
with PMO

PMO= postmenopausal osteoporosis


PM= Post-Marketing

ONJ
No cases reported with
ibandronate for PMO
in the clinical
development programme;
CCR: 2.9:1.000.000 pts exposed
in Post Marketing Surveillance

Flu-like illness
First-dose related,
transient mild-tomoderate intensity,
most cases resolve
spontaneously.

Monthly oral and quarterly IV ibandronate are


effective for postmenopausal osteoporosis
Both regimens have demonstrated17

consistent BMD gains following up to 5 years oftreatment


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

Monthly oral and quaterly IV


Ibandronate have demonstrated as a
complete fracture protection

Ibandronate is proven for long term


fracture protection