BODRONAT

Optimizing Management of
Metastases Bone Disease and

Hypercalcemia in Malignancy
with Ibandronate
Bone Metastases
Incidence
Cancer
Incidence rate for

bone metastases
Breast
Most patients (73%)
Prostate
Most patients (68%)
Thyroid
Frequent (42%)
Lung
Frequent (36%)
Kidney
Frequent (35%)
GI tract
Very few patients (5%)
Coleman, RE. 2006. Clin Cancer Res 12: 6243s-6249s
Bone Metastases
Cancer most commonly spreads to the

bones that are close to the center of the
body. The spine is the most
common place for a bone

metastasis to form. Other common
areas for bone metastases include the
thigh bone, upper arm bone, ribs, hips,
and skull
Stoppler, M. 2014. Cancer 101: A Visual Guide to Understanding Cancer.

http://www.medicinenet.com/cancer_101_pictures_slideshow/article.htm, accessed on
th
October
2015
Ratini, M.12
2014.
Understanding Cancer and Bone Metastasis.
http://www.webmd.com/cancer/bone-metastasis-11/slideshow-cancer-bone-metastasis, accessed on
th
Bone Metastasis in Breast

Cancer
NORMAL
BREAST CANCER
Chen et al. 2010. Breast Cancer Research 12: 215
Bone Pain is The Most Common

Symptom of Metastatic Bone
Disease
Pain
Up to 79% of patients
with metastatic bone
disease experience
severe pain before
palliative therapy
Janjan, N. 2001. Semin Oncol 28: 2834
Current Paradigm in Bone

Metastases Management
Wong and Pavalkis. 2011. Breast Cancer: Targets and Therapy 3:

3560
Treating Metastatic Bone

Disease:
Immediate Opportunities Long-term
Relieve
Prevent
Metastatic Bone
bone events
Pain
Improve quality of life with tolerable adverse events
Consider patient lifestyle and
type of antineoplastic therapy
Reduce healthcare costs
Nitrogen-containing Bisphosphonate Inhibit

FPP synthase, thus prevent synthesis of
prenylated proteins required for osteoclast
function and survival
Russell et al. 2011. Bone 49: 219
Treating bone metastases

Do we have the best bisphosphonate?
What are the limitations of
bisphosphonate use?
Can we use bisphosphonates more
effectively?
The current reality:

are we missing an
opportunity?
Prevent bone loss
Preventing
metastases
Current and future trials
Bondronat phase III studies:

standard dosing
BONDRONAT PIVOTAL STUDIES

Phase III studies
Oral dosing
MF 4414/44342
Intravenous infusion
MF 42651
Intravenous
Bondronat
6mg
(n=154)
Oral
Bondronat
50mg
(n=287)
Placebo
(n=158)
Body JJ, et al. 2003. Ann Oncol 14:1399405

Body JJ, et al. 2004. British Journal of Cancer 90: 11331137
1
Placebo
(n=277)
Studi Body et al (2003)

Bondronat Phase III Studies:
Endpoints
Primary
SREs measured as Skeletal
Morbidity Period Rate (SMPR)
Secondary
Bone pain
Body JJ, et al. 2003. Ann Oncol 14: 1399405
Intravenous Bondronat
Significantly Reduced Skeletal
Morbidity
2.0
Mean SMPR
1.5
SMPR: 1.48 vs 1.19, p=0.004

p=0.004
1.0
p=0.011
p=0.023
p=0.396
0.5
p=0.075
0
w
e
s
ll n nt
A ve
e
e
n
o
b
al
al
r
r
eb res
eb res
t
t
r tu
r tu
e
e
V ac
-v rac
n
r
f
o f
N
Trial not powered for individual

composite endpoints
r
fo y
d p
ee era
N h
ot
i
d
ra
r
fo y
d er
e
e g
N ur
s
Body JJ, et al. 2003. Ann Oncol 14: 1399405
Oral Bondronat Significantly

Reduced Skeletal Morbidity
2.0
Mean SMPR
1.5
SMPR: 1.18 vs 0.95, p=0.004
1.0
p=0.041
p<0.004
p=0.330
p=0.145
0.5
p=0.098
Trial not powered for individual

composite endpoints
N
e
su ed
rg fo
er r
y
N
e
th ed
er f o
ap r
y
io
ra
d
-v
fr erte
ac b
tu ra
re l
s
N
on
Ve
fr rte
ac b
tu ra
re l
s
bo
n
Al
ev l ne
en w
ts
Body JJ, et al. 2004. British Journal of Cancer 90: 11331137
Intravenous Bondronat Reduces

MBP
*Maintained below baseline for 96 weeks with Bondronat 6mg

**Not significant
Diel I, et al. 2004. Eur J Cancer 40:170412
Journal Study: Oral Ibandronate

has similar efficacy with IV
Multicenter, open-label,
12-week, bone markerAcid
trial in breast cancer patients
Zoledronic
Ibandronate 50mg
0.8
Zoledronic acid 4mg
76%
73%
S-CTX (ng/mL)
0.6
0.4
0.2
0
Baseline
Week 12
Baseline
Week 12
Body JJ, et al. 2006. Bone 38(Suppl. 1): S69
Mean Reductions in Bone Turnover

Markers
Oral IBANDRONATE was NON-INFERIOR to zolendronic acid for

the primary endpoint S-CTX, OC, BAP, and P1NP
Body JJ, et al. 2006. Bone 38(Suppl. 1): S69
Ibandronate Maintains Quality of

Life
1
2
Intravenous
Placebo
(n=143)
Ibandronate
6mg
(n=137)
Oral
Placebo
(n=277)
Ibandronate
50mg
(n=287)
Change from baseline

(global assessment,
EORTC QLQ-C30)
Better
10
20
30
p=0.032
40
50
Worse
p=0.005
1
Diel I, et al. 2004. Eur J Cancer 40: 170412

2
Body JJ, et al. 2004. Pain 111: 30612
Oral Ibandronate Reduces MBP

and Analgesic Use
B
o
n
d
r
o
n
a
t
M
e
a
n
c
h
a
n
g
e
f
r
o
m
b
a
s
e
l
i
n
e
P
l
a
c
e
b
o
5
0
m
g
B
o
n
e
p
a
i
n
s
c
o
r
e
*
0
.
2
0
0
.
1
0
p
=
1
A
n
a
l
g
e
s
i
c
u
s
e
0
.
8
5
0
.
6
0
p
=
1
9
Q
u
alityo
flife 26.8 p
.=00
8
32
*Maintained below baseline for 96 weeks with Bondronat 50mg
Gralow and Tripathy. 2007. Journal of Pain and Symptom Management 33: 462-472
Intravenous Bondronat Maintains

Bone Pain Significantly Below
Baseline for 2 Years
Standard dosing = pain relief at 12 weeks
Mean change in pain score

from baseline
0.3
Placebo
Ibandronat 6mg
0.2
0.1
0
0.1
0.2
p<0.001
0.3
0.4
0.5
0
12
24
36
48
60
Time (weeks)
72
84
96
Heidenreich, et al. 2004. Semin Oncol 31: 67-72
Efficacy of Oral Ibandronate in

Bone Pain and Maintain MBP
Significantly Below Baseline for 2
Years
Standard dosing
= pain relief at 12 weeks
Mean change in pain score
from baseline
0.3
Placebo
Ibandronat 50mg
0.2
0.1
0
0.1
p=0.001
0.2
0.3
12
24
36
48
60
Time (weeks)
72
84
96
Heidenreich, et al. 2004. Semin Oncol 31: 67-72
Nephrotoxic Potential of
Bisphosphonates
One of concern arise in relation to bisphosphonate use in

patients with renal disease is fairly convincing evidence of
direct nephrotoxicity of some bisphosphonates, particularly at
high dose when used in oncological settings 1
Bisphosphonates inhibit osteoclast function and cause

apoptosis. Osteoclast are not the only cells that take up
bisphosphonate, but there is a moderate amount of evidence
that other cells including perhaps tubular cells may take up
bisphosphonate too 2
However, renal toxicity is NOT CLASS EFFECT 3
Cunningham. 2007. Nephrol Dial Transplant 22: 15051507

Hirschberg. 2012. Curr Opin Support Palliat Care 6: 342
347
1
Renal Toxicity is Not a Class

Effect
Ibandronate
Zolendronic
Acid
87%
56%
25 days
150-200 days
Cumulative renal
toxicity
No
Yes
Renal safety
comparable to placebo
Yes
No
Protein binding
Renal half-life
Diel IJ et al. 2007. J Support Oncol 5(10): 475-482
RENAL SAFETY OF IV
IBANDRONATE COMPARABLE
WITH PLACEBO
Deterioration with Ibandronate 6mg consistent with placebo (p=0.22, ns)
at 1 year: 2% vs 4%; at 2 years: 6% vs 12%
Patients without renal
function deterioration (%)
100
94%
88%
80
60
40
20
Ibandronate 6mg
Placebo
0
0
12
24
36
48
60
72
Study duration (weeks)
84
96
Body JJ, et al. 2006. Eur J Cancer Care 15: 299-302
Safety Profile Comparison of

Bisphosphonates
Renal
toxicity
Acutephase
reaction
s
Upper
GI AR
Diarrhe
a
ONJ
i.v.
Clodronate 800 mg
Oral
++
Clodronate 520 mg
Oral
++
Ibandronate 6 mg
i.v.
Oral
i.v.
++
++
++
Compound
Clodronate 1,500 mg
Ibandronate 50
mg
Zoledronic acid 4 mg
Route of
Administrati
on
Diel IJ et al. 2007. J Support Oncol 5(10):475-482
Comparison in Safety: Lower Incidence

of Pyrexia and Flu-Like Symptoms
with Intravenous Bondronat
Multicenter, open-label, bone marker study, 12week trial in breast cancer or multiple
myeloma patients
50
Patients (%)
40
Intravenous
Bondronat
30
Intravenous
zoledronic acid
26%
20
10
13%
0
Pyrexia and flu-like symptoms (Days 13)
Possibly or probably
related to treatment
Bergstrm B, et al. 2006. Bone 38(Suppl. 1): S68
Cancer-induced hypercalcemia (CIH) occurs in 5% to 30% of

patients with cancer during the course of their disease,
depending on the type of tumor.
Enhanced bone resorption is the primary cause of CIH and the

release of tumor-derived mediators induces this increase in
osteoclast-mediated resorption.
There are two different therapeutic approaches for treating

CIH, to increase the urinary excretion of calcium, or to inhibit
osteoclastic bone resorption, RANKL or the action of
PTHrP.
Lumachi et al. 2009. Anticancer research 29:

1551-1556
HYPERCALCEMIA IN MALIGNANCY
Bisphosphonates (BP) represent at present the drugs of

choice for treating patient with CIH. They inhibit osteoclasts,
induce apoptosis in these cells and bind to bone, blocking
osteoclastic
resorption
and
osteolysis.
Once
inside
osteoclasts, BPs hamper adhesion to the mineralized matrix,
reduce lysosomial enzymes and activate a pro-apoptotic
pathway.
Ibandronate has an extremely low rate of nephrotoxicity and

represents the compound of choice for patients with
moderate renal impairment or those treated with concomitant
nephrotoxic therapies and no dose reductions are needed.

1551-1556
Interactions between osteoclast and cancer cells

1551-1556
Diagnostics & laboratory work

up
Total serum calcium, corrected for albumin

(Formula: [(4 - albumin) x 0.8] + Ca++])
Ionized calcium.
Renal function, phosphate, magnesium and
potassiummonitor during treatment.
Siddiqui F and Weissman. 2010. Journal of Palliative Medicine 13: 77-78
Supportive Management
Saline hydration and loop diuretics: Normal Saline 200-500 ml/hr

increases GFR, increases filtered load of calcium, and is calciuretic.
Loop diuretics (e.g. furosemide) blocks calcium resorption in the
loop of Henle. Note: only use diuretics once dehydration has been
corrected.
Discontinue medications that can increase serum calcium (e.g.

lithium, Vitamin D, supplements containing calcitriol, thiazides,
calcium antacids); removal of calcium from TPN.
Increase mobility if possible
Bisphosphonates :
drug class of choice for most patients.
work via blocking osteoclastic bone resorption.
Supportive management
Other Agents:
Glucocorticoids are useful in lymphoid malignancies that secrete
1,25(OH)2 Vitamin D.
Calcitonin may lead to acute reductions in serum calcium (12-24
hours) but reductions are small and transient. Calcitonin is
administered intramuscularly or subcutaneously; initially 4
units/kg every 12 hours; may increase up to 8 units/kg every 12
hours to a maximum of every 6 hours.
Mithramycin was the standard agent prior to bisphosphonates;
now it is used only rarely due to a higher side effect profile.
Gallium nitrate is usually impractical due to the need for a 5 day
IV infusion.
Renal Dialysis can be used in cases of acute/chronic renal
failure.
Bondronat Decrease Albumin

Corrected Serum Calcium
Median course of albumin-corrected serum calcium during 28 days of observation period after a
single treatment on day 0 with higher doses of ibandronate.
Hermann, S. 1999. Onkologie 22: 208-211
NUMBER (PERCENTAGE) OF PATIENTS REPORTING

ADVERSE REACTIONS IN CONTROLLED CLINICAL TRIALS
IN TUMOUR-INDUCED HYPERCALCAEMIA AFTER
TREATMENT WITH BONDRONAT
BPOM. (2012). Product information Bondronat infusion approved 23 May 2012

BPOM (2012). Product information Bondronat Oral approved 26 March 2012
OTHER REACTIONS REPORTED AT LOWER FREQUENCY ARE AS

FOLLOWS:

ADVERSE REACTIONS OCCURRING COMMONLY AND

GREATER THAN PLACEBO IN PATIENTS WITH METASTATIC
BONE DISEASE DUE TO BREAST CANCER TREATED WITH
BONDRONAT 6 MG ADMINISTERED INTRAVENOUSLY





OTHER ADVERSE REACTIONS REPORTED AT A LOWER

FREQUENCY ARE AS FOLLOWS:

OTHER ADVERSE REACTIONS REPORTED AT A LOWER

FREQUENCY ARE AS FOLLOWS:

DRUG - FOOD INTERACTION
Products containing calcium and other multivalent cations (such as

aluminium, magnesium, iron), including milk and food, are likely to
interfere with absorption of Bondronat tablets, which is consistent with
findings in animal studies. Therefore, with such products, including food,
intake must be delayed 60 minutes following oral administration.
Bioavailability was reduced by approximately 75% when Bondronat tablets

were
administered
hours
after
standard
meal.
Therefore,
it
is
recommended that the tablets should be taken after an overnight fast (at
least 6 hours) and fasting should continue for at least 60 minutes after the
dose has been taken.

DRUG - DRUG INTERACTION
When co-administered with melphalan/prednisolone

multiple myeloma no interaction was observed.
Other interaction studies in postmenopausal women have demonstrated

the absence of any interaction potential with tamoxifen or hormone
replacement therapy (oestrogen).
In healthy male volunteers and postmenopausal women, i.v. ranitidine

caused an increase in ibandronic acid bioavailability of about 20 % (which
is within the normal range of the bioavailability of ibandronic acid),
probably as a result of reduced gastric acidity. However, no dosage
adjustment is required when Bondronat is administered with H2antagonists or other drugs that increase gastric pH.
In relation to disposition, no drug interactions of clinical significance

likely. Ibandronic acid is eliminated by renal secretion only and does
undergo any biotransformation. The secretory pathway appears does
appear to include known acidic or basic transport systems involved in
excretion of other active substance.
in
patients
with
are
not
not
the

SAFETY INFORMATION
KONTRAINDIKASI
Bondronat kontraindikasi pada pasien dengan hipersensitivitas terhadap

asam ibandronat atau ke eksipien. Perhatian diindikasikan pada pasien
dengan
hipersensitivitas
terhadap
bifosfonat
lain.
Bondronat
tidak
seharusnya dikonsumsi saat kehamilan dan menyusui karena tidak ada

pengalaman klinis yang memadai pada kehamilan manusia dan studi pada
hewan telah menunjukkan transfer asam ibandronat ke dalam susu pada
tikus menyusui. Bondronat tidak boleh digunakan pada anak-anak karena
kurangnya pengalaman klinis.

SAFETY INFORMATION
PERINGATAN DAN PERHATIAN
Hipokalsemia dan gangguan tulang dan metabolisme mineral lainnya

seharusnya diobati sebelum memulai terapi Bondronat. Asupan kalsium
dan vitamin D yang cukup penting pada semua pasiem. Pasien harus
menerima kalsium atau vitamin D tambahan jika asupan diet tidak
memadai. Hipokalsemia dapat terjadi dan tingkat kalsium serum pasien
harus diperbaiki secara sesuai. Bifosfonat oral telah dikaitkan dengan
disfagia, esofagitis dan esofagus atau ulkus lambung. Oleh karena itu,
pasien harus memberi perhatian khusus untuk petunjuk dosis.
Dokter harus waspada terhadap tanda-tanda atau gejala yang

menandakan reaksi esofagus selama terapi, dan pasien harus
diinstruksikan untuk menghentikan Bondronat dan mencari bantuan medis
jika mereka mengembangkan gejala iritasi esofagus seperti disfagia yang
baru atau memburuk, nyeri pada saat menelan, nyeri retrosternal, atau
mulas. Sejak NSAID berhubungan dengan iritasi gastrointestinal,
peringatan harus diambil selama obat oral yang bersamaan dengan
Bondronat. Karena administrasi intra-arteri yang tidak hati-hati tidak
direkomendasikan secara tegas untuk tujuan ini seperti administrasi
paravena yang dapat menyebabkan kerusakan jaringan, perawatan harus
dilakukan untuk memastikan bahwa konsentrat Bondronat untuk larutan
untuk infus diberikan secara intravena.
SAFETY INFORMATION
PERINGATAN DAN PERHATIAN
Osteonekrosis rahang, umumnya terkait dengan pencabutan gigi dan / atau

infeksi lokal (termasuk osteomyelitis) telah dilaporkan pada pasien kanker
yang menerima rejimen pengobatan termasuk bifosfonat terutama intravena.
Banyak dari pasien ini juga menerima kemoterapi dan kortikosteroid.
Osteonekrosis rahang juga telah dilaporkan pada pasien dengan osteoporosis
yang menerima bifosfonat oral. Pemeriksaan gigi dengan pencegahan yang
tepat harus dipertimbangkan sebelum pengobatan dengan bifosfonat pada
pasien dengan faktor risiko bersamaan (misalnya kanker, kemoterapi,
radioterapi, kortikosteroid, kebersihan mulut yang buruk). Sementara pada
pengobatan, pasien tersebut harus menghindari prosedur invasif gigi jika
memungkinkan. Untuk pasien yang mengembangkan osteonekrosis rahang
saat terapi bifosfonat, operasi gigi dapat memperburuk kondisi. Untuk pasien
yang membutuhkan prosedur gigi, tidak ada data yang tersedia untuk
menyarankan apakah penghentian pengobatan bisfosfonat mengurangi risiko
osteonekrosis rahang. Penilaian klinis dari dokter yang merawat harus
memandu rencana pengelolaan setiap pasien berdasarkan penilaian manfaat /
risiko individu.
Studi klinis belum menunjukkan bukti penurunan ginjal dengan jangka panjang
terapi Bondronat. Namun demikian, menurut penilaian klinis pasien individu,
direkomendasikan bahwa fungsi ginjal, kalsium serum, fosfat dan magnesium
harus dipantau pada pasien yang diobati dengan Bondronat. Karena tidak ada
data klinis yang tersedia,BPOM
rekomendasi
dosis tidak
dapat
diberikan
untuk
(2012). Product information
Bondronat
Oral approved
26 March
2012
pasien dengan insufisiensi hati yang berat Hidrasi berlebihan harus dihindari
Summary
Bisphosphonate has a good efficacy to reduce Skeletal

related events, metastatic bone pain, and improve
quality of life in patients with metastatic bone disease
The selection of the right Bisphosphonate should

considering
EFFICACY,
SAFETY,
and
PATIENTS
COMFORT, to brings best palliative care for patients
Ibandronate has a good efficacy for Metastatic Bone

Disease and has a good renal safety profile.
Mitra Dokter, Solusi untuk Pasien
Penjelasan umum
mengenai penyakit
melalui
www.solusiterapiku.c
om
Bagi pasien yang

mendapatkan
rekomendasi dari
dokter
Layanan telepon
berkala agar pasien
senantiasa
berkonsultasi dengan
dokter
Layanan informasi dan website Solusi Terapiku TIDAK bertujuan menggantikan konsultasi dengan
Mitra Dokter, Solusi untuk Pasien
REPORTING ADVERSE EVENT

Adverse Event
Any untoward medical occurrence in a patient or clinical investigation subject
administered a pharmaceutical drug and which does not necessarily have a
causal relationship with this treatment.
Example: any unfavorable and unintended sign (including an abnormal laboratory
finding), symptom, pregnancy.
REPORTING ADVERSE EVENT IS MANDATORY ACCORDING TO INDONESIAN REGULATORY AUTHORITY
(REGULATION HEAD OF BPOM RI No HK.03.1.23.11.10690 Year 2011 ON PHARMACOVIGILANCE
IMPLEMENTATION BY PHARMACEUTICALS)
Reporting Channels :
1. Email : indonesia.safety@roche.com
ALL THE DATA
2. Phone : +62 21 3041 3090
COLLECTED WILL BE
USED FOR ADVERSE
3. Fax : +62 21 514 00 112
EVENT PROCESSING
ONLY
OTH-OTH-Q4-15-169
PELAPORAN KEJADIAN TIDAK DIINGINKAN

Kejadian Tidak Diinginkan (KTD)
Adverse event (Kejadian Tidak Diinginkan/ KTD) adalah semua kejadian medis yang tidak diinginkan
yang dialami oleh pasien atau subyek uji klinik selama terapi menggunakan obat tetapi belum tentu
disebabkan oleh obat tersebut.
Contoh: tanda/ gejala yang tidak diinginkan (termasuk hasil laboratorium yang abnormal) dan kehamilan.
PELAPORAN ADVERSE EVENT DIWAJIBKAN SESUAI PERATURAN KEPALA BPOM RI No
HK.03.1.23.11.10690 Tahun 2011 TENTANG PENERAPAN FARMAKOVIGILANS BAGI INDUSTRI
FARMASI
Kontak Pelaporan Adverse event:

Email : indonesia.safety@roche.com
Phone : +62 21 3041 3090
Fax : +62 21 514 00 112
DATA YANG DILAPORKAN HANYA AKAN DIGUNAKAN UNTUK

PEMANTAUAN KEAMANAN OBAT
THANK YOU

BODRONAT

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Optimizing Management of

Metastases Bone Disease and

Incidence rate for

Most patients (73%)

Most patients (68%)

Very few patients (5%)

Coleman, RE. 2006. Clin Cancer Res 12: 6243s-6249s

Cancer most commonly spreads to the

common place for a bone

Stoppler, M. 2014. Cancer 101: A Visual Guide to Understanding Cancer.

Bone Metastasis in Breast

Chen et al. 2010. Breast Cancer Research 12: 215

Bone Pain is The Most Common

Janjan, N. 2001. Semin Oncol 28: 2834

Current Paradigm in Bone

Wong and Pavalkis. 2011. Breast Cancer: Targets and Therapy 3:

Treating Metastatic Bone

Nitrogen-containing Bisphosphonate Inhibit

Russell et al. 2011. Bone 49: 219

Treating bone metastases

The current reality:

Bondronat phase III studies:

BONDRONAT PIVOTAL STUDIES

Body JJ, et al. 2003. Ann Oncol 14:1399405

Studi Body et al (2003)

Body JJ, et al. 2003. Ann Oncol 14: 1399405

SMPR: 1.48 vs 1.19, p=0.004

Trial not powered for individual

Body JJ, et al. 2003. Ann Oncol 14: 1399405

Oral Bondronat Significantly

SMPR: 1.18 vs 0.95, p=0.004

Trial not powered for individual

Body JJ, et al. 2004. British Journal of Cancer 90: 11331137

Intravenous Bondronat Reduces

*Maintained below baseline for 96 weeks with Bondronat 6mg

Diel I, et al. 2004. Eur J Cancer 40:170412

Journal Study: Oral Ibandronate

Zoledronic acid 4mg

Body JJ, et al. 2006. Bone 38(Suppl. 1): S69

Mean Reductions in Bone Turnover

Oral IBANDRONATE was NON-INFERIOR to zolendronic acid for

Ibandronate Maintains Quality of

Change from baseline

Diel I, et al. 2004. Eur J Cancer 40: 170412

Oral Ibandronate Reduces MBP

Intravenous Bondronat Maintains

Mean change in pain score

Heidenreich, et al. 2004. Semin Oncol 31: 67-72

Efficacy of Oral Ibandronate in

Heidenreich, et al. 2004. Semin Oncol 31: 67-72

One of concern arise in relation to bisphosphonate use in

Bisphosphonates inhibit osteoclast function and cause

Cunningham. 2007. Nephrol Dial Transplant 22: 15051507

Renal Toxicity is Not a Class

Diel IJ et al. 2007. J Support Oncol 5(10): 475-482

Body JJ, et al. 2006. Eur J Cancer Care 15: 299-302

Safety Profile Comparison of

Diel IJ et al. 2007. J Support Oncol 5(10):475-482

Comparison in Safety: Lower Incidence

Bergstrm B, et al. 2006. Bone 38(Suppl. 1): S68

Cancer-induced hypercalcemia (CIH) occurs in 5% to 30% of

Enhanced bone resorption is the primary cause of CIH and the

There are two different therapeutic approaches for treating