Understanding
Bisphosphonate
Therapy
"Until There is a Cure...There is the IMF"

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Table of Contents
Introduction
5
What Are Bisphosphonates?
6
Are Bisphosphonates a Type
of Chemotherapy?
7
Who Benefits From Bisphosphonates?
8
What Are the Different Types
of Bisphosphonates?
9
What Are the Possible Side Effects of
Bisphosphonates?
11
Who Should Not Take Bisphosphonates?
15
How Are Bisphosphonates Given?
16
Can Bisphosphonates Be Combined
With Other Therapies?
17
Will Insurance Cover the Costs of
Bisphosphonates?
17
What Other Approaches to Bone Care
Are Available?
17
What Does the Future Hold?
19
Questions to Ask Your Doctor
19
About the IMF
20
Sponsored by an unrestricted educational grant
from Novartis.
Glossary
23
©2003, International Myeloma Foundation,
North Hollywood, California

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Introduction
Many patients with myeloma develop bone dis-
ease. Bone disease can cause the bones to
become thinner and weaker (osteoporosis),
and it can make holes appear in the bone (lytic
lesions). The weakened bone that results is
more likely to break under minor pressure or
injury (pathologic fracture). The bones most
commonly affected are the axial skeleton
(spine, pelvis, ribs, and skull) and the upper
ends of the long bones of the arms and legs.
Myeloma cells cause bone disease by sending
signals to certain bone cells called osteoclasts,
causing them to break down bone. In addition
to giving rise to bone disease, this process also
releases calcium; if this release happens too
quickly, a condition called hypercalcemia can
occur. Both myeloma bone disease and hyper-
calcemia can be treated with a group of drugs
called bisphosphonates.
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What Are Bisphosphonates?
Are Bisphosphonates a Type
Bisphosphonates are small inorganic molecules
of Chemotherapy?
that bind to a substance called hydroxyapatite
Bisphosphonates are not a type of chemotherapy.
on the surface of damaged bones. At the sites
They were first introduced over 20 years ago
of bone damage, osteoclasts are inhibited and
as an additive for toothpaste to reduce
destroyed. Since bone damage is caused by
dental decay.
increased numbers and activity of these osteo-
Bisphosphonates are generally very safe and
clast bone cells, bisphosphonates reduce new
do not have the types of risks or side effects
bone damage and allow an opportunity for
associated with chemotherapy, which is used to
bone healing to occur.
directly attack the myeloma. Bisphosphonates
Bisphosphonates therefore have several benefi-
are used to treat several types of bone disease,
cial effects, including:
including osteoporosis in women, as well as the
bone-thinning effects of steroid treatment.
s Preventing further bone damage
s Reducing bone pain and the need
for painkillers
s Correcting and preventing hypercalcemia
(higher than normal levels of calcium in
the blood)
s Reducing the need for radiotherapy
s Reducing pathologic fractures due to
myeloma (i.e., fracture at a site where
myeloma has weakened the bone)
s Improving quality of life
s Improving the chances of healing and
recovery of strength of the bone
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Bisphosphonates are particularly helpful for
patients being treated with steroids, such as
prednisone or dexamethasone. Steroids
reduce bone mass or density. Bisphosphonate
use improves this negative effect on bones.
What Are the Different Types of
Bisphosphonates?
Several bisphosphonates are commercially
available, and more potent products have been
developed over the years in an effort to
achieve better bone healing. Thus far, the
various products available have produced
"equivalent" major benefits. However, these
products are associated with several important
differences in:
s Administration: intravenous versus oral
delivery and the length of intravenous
infusion time
Who Benefits From Bisphosphonates?
s Potential side effects: e.g., fever or possible
Bisphosphonates are recommended for all
kidney toxicity
patients with myeloma-related bone disease.
s Potential longer-term benefits: newer, more
The American Society of Clinical Oncology has
potent bisphosphonates such as Zometa®
established guidelines, which recommend
may have added longer term benefits
ongoing use of bisphosphonates for all
myeloma patients with documented bone dis-
The bisphosphonates currently approved by
ease who start on systemic treatment for
the Food and Drug Administration (FDA) for
the myeloma.
use in multiple myeloma in the United States
are pamidronate (Aredia®) and zoledronic
A randomized study published in the New
acid (Zometa®).
England Journal of Medicine in 1996 docu-
mented a reduction in what are called
Aredia® was approved based upon the results
"skeletal-related events" or "SREs" (i.e., new
of the 1996 study in the New England Journal
bone damage or fractures), as well as pain
of Medicine. Use of Aredia® by monthly
reduction and improved quality of life. The
intravenous infusion became the standard of
bisphosphonate used in this study was
care for myeloma patients. It has become
Aredia® (pamidronate).
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established as a very safe, helpful drug for the
What Are the Possible Side Effects of
treatment of myeloma bone disease.
Bisphosphonates?
Zometa® was approved in 2001 based upon
Bisphosphonates are generally very well toler-
study results comparing it with Aredia®.
ated. The most common side effects are fever,
Zometa® produces more rapid and prolonged
vein irritation, general aches and pains, and
reduction in elevated blood calcium, when ele-
kidney dysfunction.
vated levels are present. However, results eval-
Fever
uating effect on SREs showed that Zometa® and
Fever associated with bisphosphonates is typi-
Aredia® affect SREs equivalently. The major dif-
cally mild (i.e., 100° to 101° F), occurring
ference with Zometa®, therefore, proved to be
a few hours after the intravenous infusion
its much shorter infusion time of 15 minutes
and lasting for a few hours at most. Fever
versus 2 to 4 hours for Aredia® (see p.16, How
is usually easily treated or prevented with
Are Bisphosphonates Given).
1 or 2 Tylenol (325 mg).
Vein Irritation
Vein irritation (mild phlebitis) occurs at the site
of the infusion. It is usually mild and patients
typically recover within 1 to 2 days. Careful
infusion is recommended to avoid any leakage
of medication around the vein. Also, a short
infusion of saline at the end of the bisphospho-
nate infusion can clear the Aredia® or Zometa®
from the area and reduce the chance
of phlebitis.
General Aches and Pains
These effects sometimes occur briefly, along
with fever.
Kidney Dysfunction
The main additional concern relates to kidney
side effects. All bisphosphonates are potential
toxins for the kidneys. Since myeloma can
impact kidney function (e.g., due to myeloma
protein damage or elevated blood calcium),
the possibility of kidney-related side effects is of
particular concern.
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Aredia® has been used widely for almost
long-standing high blood pressure, or in
10 years, including the initial trials period. The
elderly or frail patients). Zometa® should not
main toxicity that has emerged is an excess of
be used in patients with known kidney
a serum protein, called albumin, in the urine
deterioration as determined by creatinine
(known as albuminuria or nephrotic syndrome).
level over 3 mg/dl.
This toxicity has occurred predominantly with
s Your doctor should check your serum creati-
uses of higher than recommended doses
nine level before each dose of Zometa®.
(e.g., 180 mg versus 90 mg) and/or more
frequent than recommended dosing schedules
­ If the serum creatinine value has increased
(e.g., every 2 weeks versus once/month). This
by 0.5 mg/dl in a patient with normal
side effect is usually reversible with dose
renal function at the outset, the doctor
and/or schedule adjustments or, in occasional
should hold the next dose until the value
severe cases, discontinuing Aredia®. Very rare
returns to within 10% of baseline.
irreversible damage has occurred. Periodic
­ If the serum creatinine value has increased
monitoring (e.g., every 3 to 6 months) of urine
by 1.0 mg/dl in a patient with abnormal
protein levels with 24-hour urine collection is
renal function at the outset, the doctor
recommended to prevent any significant
should hold the next dose until the value
kidney damage.
returns to within 10% of baseline.
Zometa® has also been used for about
10 years, including the clinical trial period. The
major toxicity-related concern that has
emerged with Zometa® is an increase in serum
creatinine, which is an indication of kidney dys-
function. Reports of both increased creatinine
and occasionally more severe kidney damage
have raised concern that this much more potent
bisphosphonate must be used more cautiously
with respect to kidney function.
To minimize the potential for kidney-related
problems,
your
doctor
should
follow
several recommendations:
s Your doctor should be especially cautious
with the use of Zometa® if there is concern
from the outset for kidney dysfunction
(i.e., with Bence Jones myeloma, diabetes,
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­ In a patient who has experienced a mild
Who Should Not Take Bisphosphonates?
elevation in serum creatinine value that
s Patients without documented myeloma-related
has returned to 10% of baseline, the
bone disease should not take bisphospho-
doctor may consider adjustments to the
nates. This means that, in general, patients
treatment schedule. Adjustments may
with monoclonal gammopathy of undeter-
include increasing the time of infusion from
mined significance (MGUS) and smoldering
15 to 30 minutes or more, using a larger
myeloma without bone disease do not need
volume of diluting fluids, or delaying the
or benefit from bisphosphonates. However,
administration of the next dose. The doctor
this remains an area of ongoing research and
should use his or her judgment to deter-
clinical trials.
mine which option is the most appropriate
s As noted, bisphosphonates must be used
for an individual patient.
with caution in patients with pre-existing kid-
s Your doctor should be aware that certain
ney disease or known elevation in serum cre-
medications with the potential to affect
atinine, especially >3.0 mg/dl but also any
kidney function may be more likely to do so
value above the normal range.
if they are given at the same time
s Patients who have allergic reactions or are
as bisphosphonates. Some examples of
intolerant to bisphosphonate treatment
these medications are nonsteroidal anti-
should not take bisphosphonates.
inflammatory drugs (NSAIDs), thalidomide,
and certain antibiotics.
Other Side Effects
Other side effects are generally rare. As with
most drugs, however, other reactions occasion-
ally occur and may include rash, stomach
upset, blurred vision, headache, and shortness
of breath. Severe allergic reactions are very
rare, although possible.
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How Are Bisphosphonates Given?
can be considered. Administering the oral
Both Aredia® and Zometa® are given intra-
bisphosphonates Fosamax® (e.g., once per
venously on a monthly basis. Aredia® is given
week by mouth) and/or Actonel® (daily dosing
over 2 to 4 hours by intravenous infusion, and
by mouth) is not approved specifically for
premedication with 1 or 2 Tylenol® (325 mg)
myeloma by the FDA. Nonetheless, occasional
can be helpful. Zometa® is given over 15 to
patients can benefit from oral bisphosphonates,
45 minutes by intravenous infusion, and pre-
especially patients who are intolerant of intra-
medication may also be beneficial.
venous infusion, have nephrotoxicity, and/or
are concomitantly using steroids. Oral bisphos-
Toxicities associated with both medications,
phonates can cause esophagitis and/or other
especially potential renal toxicities, are related
gastrointestinal complaints, which preclude use.
to dose, time of infusion, and frequency of infu-
sion. If kidney toxicity is a concern, the infusion
Can Bisphosphonates Be Combined
time of Aredia® can be increased to 4 hours
With Other Therapies?
and the infusion time of Zometa® can be
In general, bisphosphonates can be safely
increased from 15 minutes to 30 to 45 minutes.
combined with most other therapies. Your
If, for any reason, difficulty with intravenous
physician may decide not to give Aredia® or
bisphosphonates exists, oral bisphosphonates
Zometa® on or close to the same day as admin-
istration of intravenous chemotherapy. Caution
about potential nephrotoxicity has been
noted above.
Will
Insurance
Cover
the
Costs
of Bisphosphonates?
Since Aredia® and Zometa® are FDA, commer-
cially approved medications, Medicare and
most insurance programs reimburse for
bisphosphonate use. Any problems with reim-
bursement should be brought to the attention of
your physician and/or Novartis.
What Other Approaches to Bone Care
Are Available?
Kyphoplasty provides a new tool that may
impact bone care for myeloma patients. This
procedure involves the injection of liquid
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cement using the balloon technique in an
What Does the Future Hold?
attempt to provide acute pain relief and
Considerable new research is ongoing to inves-
improvement in the structural integrity of col-
tigate myeloma bone disease. Of particular
lapsed vertebrae or other damaged bones.
interest is treatment that can improve bone cell
Although results from large studies are not
function with activation of osteoblasts to pro-
available, the procedure has been found safe
mote bone healing. The future looks promising
and effective in selected patients.
for useful new drug treatments.
General measures to improve bone health are
Questions to Ask Your Doctor
recommended, including:
Some questions you may want to ask your
s Adequate pain control to allow ambulation
doctor about your medication are:
and exercise.
s For how long will I be taking bisphosphonates?
s Radiation therapy and/or orthopedic sur-
s How do I get repeat prescriptions?
gery to restore structural integrity of bones
and recovery of full mobilization. Radiation
s What side effects should I be aware of?
therapy should be used sparingly for acute
s Is there anything I need to avoid while
problems such as spinal cord compression,
taking bisphosphonates?
severe refractory pain, and treatment or
s May I see a patient information leaflet about
prevention of pathologic fracture. Since
my medicine?
radiation therapy can impair local bone
healing, many physicians prefer to use sys-
temic steroids and/or other antimyeloma
therapy. Orthopedic surgery should be used
as necessary.
s Exercise, especially walking and/or swim-
ming, to enhance bone strength, flexibility,
and endurance.
s Avoidance of risky activities (e.g., climbing
ladders), which can increase the likelihood
of falls and/or fractures.
s Regular re-evaluation and follow-up testing of
bones by x-ray/scan/bone density testing to
rule out new bone disease and assess the
impact of treatment.
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We care for patients today, while working
About the IMF
toward tomorrow's cure.
"One person can make a difference,
Two can make a miracle."
How Can the IMF Help You?
Brian D. Novis
PATIENT EDUCATION
IMF Founder
INFORMATION PACKAGE
Myeloma is a little-known, complex, and often
Our free IMF InfoPack provides comprehensive
misdiagnosed bone marrow cancer that
information about myeloma, treatment options,
attacks and destroys bone. Myeloma affects
disease management, and IMF services.
approximately 75,000 to 100,000 people in
It includes our acclaimed Patient Handbook.
the United States, with more than 14,500 new
cases diagnosed each year. While there is
INTERNET ACCESS
presently no known cure for myeloma, doctors
Log on to www.myeloma.org for 24-hour
have many approaches to help myeloma
access to information about myeloma, the IMF,
patients live better and longer.
education, and support programs.
The International Myeloma Foundation (IMF)
ONLINE MYELOMA FORUM
was founded in 1990 by Brian and Susie
Join the IMF Internet Discussion Group at
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www.myeloma.org/listserve.html to share your
at the age of 33. It was Brian's dream that
thoughts and experiences.
future patients would have easy access to med-
ical information and emotional support
MYELOMA MINUTE
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lished the IMF with the 3 goals of treatment,
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education, and research. He sought to provide
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Meet with leading experts in myeloma treat-
Although Brian died 4 years after his initial
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reaches out to an international membership of
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20
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SUPPORT
Glossary
MYELOMA HOTLINE: 800-452-CURE
Albuminuria: The presence of an excess of serum
Toll-free throughout the United States and
protein in the urine.
Canada, the IMF Hotline is staffed by
Axial skeleton: Spine, pelvis, ribs, and skull. Along
specialists trained at the National Cancer
with the upper ends of the long bones of the arms and
legs, the axial skeleton is most commonly affected by
Institute (NCI).
pathologic fracture.
SUPPORT GROUPS
Bence Jones myeloma: Myeloma characterized by
the presence of Bence Jones protein, an abnormal protein
A worldwide network of more than 90 myeloma
in urine or plasma.
support groups hold regular meetings for
Bisphosphonate: A small inorganic molecule that
members of the myeloma community. The IMF
binds to the surface of damaged bones. Bisphosphonate
conducts annual retreats for myeloma support
therapy is used in patients with bone disease to reduce
group leaders.
new bone damage and allow an opportunity for bone
healing to occur.
RESEARCH
Chemotherapy: Drugs that are used to kill cancer cells.
Creatinine: A compound excreted in the blood and
BANK ON A CURETM
urine. A high level of creatinine is an indication of
This DNA bank will provide genetic data
kidney dysfunction.
research in new drug development.
Esophagitis: Inflammation of the esophagus (the tube
that transports food from the mouth to the stomach).
THE INTERNATIONAL PROGNOSTIC INDEX (IPI)
Hydroxyapatite: A compound found on the surface of
This updated staging system for myeloma will
bones that gives them rigidity.
enhance physicians' ability to select the most
Hypercalcemia: Higher than normal levels of calcium
appropriate treatment for each patient.
in the blood.
Kyphoplasty: The injection of liquid cement into dam-
RESEARCH GRANTS
aged bone using a balloon technique. This procedure
Leading the world in collaborative research and
may provide acute pain relief and improvement in
achieving extraordinary results, the IMF Grant
structural integrity of collapsed vertebrae or other dam-
Program supports both junior and senior
aged bones.
researchers working on a broad spectrum of
Lytic lesions: Holes in the bone.
projects. The IMF has attracted many young
Monoclonal gammopathy of undetermined sig-
nificance (MGUS): A category of myeloma character-
investigators into the field of myeloma, and they
ized by comparatively low amounts of myeloma-
have remained in the field and are actively
associated protein levels and bone marrow plasma cells
pursuing a cure for this disease.
as well as an absence of certain myeloma-related
symptoms (i.e., anemia, renal failure, hypercalcemia,
and lytic lesions).
Myeloma: A cancer of bone marrow plasma cells.
Cancerous plasma cells are called myeloma cells.
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Nephrotic syndrome: A group of diseases character-
ized by a massive excess of serum protein in the urine.
Nephrotoxicity: The quality of being toxic or destruc-
tive to kidney cells.
Nonsteroidal anti-inflammatory drug (NSAID):
A drug used to reduce fever, swelling, pain, and redness.
Osteoblast: An immature cell that is associated with
bone production as it matures.
Osteoclast: A cell that destroys the bone.
Osteoporosis: Thinning and weakening of the bone.
Pathologic fracture: Fracture due to weakening of the
bone structure from disease.
Phlebitis: Inflammation of a vein.
Skeletal-related event (SRE): New bone damage
or fracture.
Smoldering myeloma: A category of myeloma char-
acterized by comparatively low amounts of myeloma-
associated protein levels and bone marrow plasma cells
as well as an absence of certain myeloma-related symp-
toms (i.e., anemia, renal failure, hypercalcemia, and lytic
lesions). Although the quantities of protein levels and
plasma cells are relatively low, they are higher than in
patients with monoclonal gammopathy of undetermined
significance (MGUS).
Steroid: A type of drug that is used to reduce swelling
and inflammation. A negative effect of steroid treatment
is the reduction of bone mass.
Systemic treatment: Treatment using substances that
travel through the bloodstream to reach and affect cells in
the entire body.
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Appointments
Date
Time
Important Notes
Date
Time
Important Notes

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International Myeloma Foundation
12650 Riverside Drive, Suite 206
North Hollywood, CA 91607 USA
Telephone:
800-452-CURE (United States and Canada)
818-487-7455
FAX:
818-487-7454
TheIMF@myeloma.org
www.myeloma.org
10/03

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