Understanding
Bisphosphonate
Therapy
International Myeloma Foundation
12650 Riverside Drive, Suite 206
North Hol ywood, CA 91607 USA
Telephone:
800-452-CURE (United States and Canada)
818-487-7455
FAX:
818-487-7454
TheIMF@myeloma.org
www.myeloma.org
28
1/06

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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?
18
How Are Bisphosphonates Given?
18
Can Bisphosphonates Be Combined
With Other Therapies?
19
Will Insurance Cover the Costs of
Bisphosphonates?
19
What Other Approaches to Bone Care
Are Available?
20
What Does the Future Hold?
21
Questions to Ask Your Doctor
21
About the IMF
22
Glossary
25
©2006, International Myeloma Foundation,
North Hollywood, California

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Introduction
Many patients with myeloma develop bone
disease. Bone disease can cause the bones
to become thinner and weaker (osteoporo-
sis), 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 af ected are the axial
skeleton (spine, pelvis, ribs, and skul ) and
the upper ends of the long bones of the
arms and legs. Myeloma cel s cause bone
disease by sending signals to certain bone
cel s cal ed 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 cal ed hypercalcemia can occur.
Both myeloma bone disease and hypercal-
cemia can be treated with a group of drugs
cal ed bisphosphonates.
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WHAT ARE BISPHOSPHONATES?
ARE BISPHOSPHONATES A TYPE
Bisphosphonates are smal inorganic mol-
OF CHEMOTHERAPY?
ecules that bind to a substance cal ed
Bisphosphonates are not a type of chemo-
hydroxyapatite on the surface of damaged
therapy. They were first introduced over 20
bones. At the sites of bone damage, osteo-
years ago as an additive for toothpaste to
clasts are inhibited and destroyed. Since
reduce dental decay.
bone damage is caused by increased num-
Bisphosphonates are general y very safe
bers and activity of these osteoclast bone
and do not have the types of risks or side
cel s, bisphosphonates reduce new bone
ef ects associated with chemotherapy, which
damage and al ow an opportunity for bone
is used to directly at ack the myeloma.
healing to occur.
Bisphosphonates are used to treat several
Bisphosphonates therefore have several ben-
types of bone disease, including osteoporosis
eficial ef ects, including:
in women, as wel as the bone-thinning ef ects

of steroid treatment.
Preventing further bone damage
Reducing bone pain and the need
for painkil ers
Correcting and preventing hypercalcemia
(higher than normal levels of calcium in
the blood)
Reducing the need for radiotherapy
Reducing pathologic fractures due to
myeloma (i.e., fracture at a site where
myeloma has weakened the bone)
Improving quality of life
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 ef ect on bones.
WHAT ARE THE DIFFERENT TYPES OF
BISPHOSPHONATES?
Several bisphosphonates are commercial y
available, and more potent products have
been developed over the years in an ef ort
to achieve bet er bone healing. Thus far, the
various products available have produced
"equivalent" major benefits. However, these
products are associated with several impor-
tant dif erences in:
Administration: intravenous versus oral
delivery and the length of intravenous
WHO BENEFITS FROM BISPHOSPHONATES?
infusion time
Bisphosphonates are recommended for al

patients with myeloma-related bone disease.
Potential side ef ects: e.g., fever, possible
The American Society of Clinical Oncology
kidney toxicity, or bone disease in the jaw
has established guidelines, which recom-
Potential longer-term benefits: newer,
mend ongoing use of bisphosphonates for al
more potent bisphosphonates such as
myeloma patients with documented bone
Zometa® may have added longer-term
disease who start on systemic treatment for
benefits
the myeloma.
The bisphosphonates currently approved by
A randomized study published in the New
the Food and Drug Administration (FDA) for
England Journal of Medicine in 1996 docu-
use in multiple myeloma in the United States
mented a reduction in what are cal ed
are pamidronate (Aredia®) and zoledronic
"skeletal-related events" or "SREs" (i.e.,
acid (Zometa®).
new bone damage or fractures), as wel as
Aredia® was approved based upon the results
pain reduction and improved quality of life.
of the 1996 study in the New England Journal
The bisphosphonate used in this study was
of Medicine. Use of Aredia® by monthly
Aredia® (pamidronate).
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intravenous infusion became the standard
its much shorter infusion time of 15 minutes
of care for myeloma patients. It has become
versus 2 to 4 hours for Aredia® (see p.16,
established as a safe, helpful drug for the
How Are Bisphosphonates Given).
treatment of myeloma bone disease.
WHAT ARE THE POSSIBLE SIDE EFFECTS OF
Zometa® was approved in 2001 based
BISPHOSPHONATES?
upon study results comparing it with
Bisphosphonates are general y very wel
Aredia®. Zometa® produces more rapid
tolerated. The most common side ef ects
and prolonged reduction in elevated blood
are fever, vein irritation, general aches and
calcium, when elevated levels are pres-
pains, kidney dysfunction, and osteonecro-
ent. However, results evaluating ef ect on
sis of the jaws (ONJ).
SREs showed that Zometa® and Aredia®
Fever
af ect SREs equivalently. The major dif er-
ence with Zometa®, therefore, proved to be
Fever associated with bisphosphonates is typ-
ical y mild (i.e., 100° to 101° F), occurring
a few hours after the intravenous infusion
and lasting for a few hours at most. Fever
is usual y easily treated or prevented with
1 or 2 Tylenol® (325 mg).
Vein Irritation
Vein irritation (mild phlebitis) can occur
at the site of the infusion. It is usual y mild
and patients typical y 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 bisphosphonate infu-
sion can clear the Aredia® or Zometa®
from the area and reduce the chance
of phlebitis.
General Aches and Pains
These ef ects sometimes occur briefly, along
with fever.
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Kidney Dysfunction
both increased creatinine and occasional y
The main additional concern relates to kid-
more severe kidney damage have raised
ney side ef ects. Al bisphosphonates are
concern that this much more potent bisphos-
potential toxins for the kidneys. Since myelo-
phonate must be used more cautiously with
ma can impact kidney function (e.g., due to
respect to kidney function.
myeloma protein damage or elevated blood
To minimize the potential for kidney-relat-
calcium), the possibility of kidney-related
ed problems, your doctor should fol ow
side ef ects is of particular concern.
several recommendations:
Aredia® has been used widely for over
Your doctor should be especial y cautious
ten years, including the initial trials peri-
with the use of Zometa® if there is concern
od. The type of kidney toxicity that has
from the outset for kidney dysfunction
emerged is an excess of a serum protein,
(i.e., with Bence Jones myeloma, diabetes,
cal ed albumin, in the urine (known as
long-standing high blood pressure, or in
albuminuria or nephrotic syndrome). This
elderly or frail patients). Zometa® should
toxicity has occurred predominantly with
not be used in patients with known kidney
uses of higher than recommended doses
deterioration as determined by creatinine
(e.g., 180 mg versus 90 mg) and/or more
level over 3 mg/dl.
frequent than recommended dosing sched-
ules (e.g., every 2 weeks versus once/
month). This side ef ect is usual y revers-
ible with dose and/or schedule adjust-
ments or, in occasional severe cases, dis-
continuing Aredia®. Very rare irreversible
damage has occurred. Periodic monitoring
(e.g., every 3 to 6 months) of urine pro-
tein levels with 24-hour urine col ection is
recommended to prevent any significant
kidney damage.
Zometa® has also been used for about
10 years, including the clinical trial period.
The major kidney toxicity-related concern
that has emerged with Zometa® is an
increase in serum creatinine, which is an
indication of kidney dysfunction. Reports of
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Your doctor should check your serum
Osteonecrosis of the Jaws
creatinine level before each dose of
Osteonecrosis of the Jaws (ONJ) is a previ-
Zometa®.
ously rare jaw problem now being observed
· If the serum creatinine value has
in a smal percentage of myeloma patients
increased by 0.5 mg/dl in a patient
taking Aredia® and Zometa®. This condition
with normal renal function at the outset,
produces pain, swel ing, and bone damage
the doctor should hold the next dose
around the tooth sockets in the jaws. There
until the value returns to within 10% of
is bone necrosis or loss of bone which can
baseline.
lead to loose teeth, sharp edges of exposed
· If the serum creatinine value has
bone, bone spurs, and the breaking loose of
increased by 1.0 mg/dl in a patient
smal bone spicules or dead bone. Symptoms
with abnormal renal function at the
may not be obvious at first, or may include
outset, the doctor should hold the next
pain, swel ing, numbness or a "heavy jaw"
dose until the value returns to within
feeling, or loosening of a tooth.
10% of baseline.
Consultation with an oral surgeon or den-
· In a patient who has experienced a
tal oncologist familiar with osteonecrosis
mild elevation in serum creatinine value
is strongly recommended for patients
that has returned to 10% of baseline,
who suspect that they may have ONJ.
the doctor may consider adjustments
to the treatment schedule. Adjustments
may include increasing the time of infu-
sion from 15 to 30 minutes or more,
using a larger volume of diluting fluids,
or delaying the administration of the
next dose. The doctor should use his
or her judgment to determine which
option is the most appropriate for an
individual patient.
Your doctor should be aware that certain
medications with the potential to af ect
kidney function may be more likely to
do so if they are given at the same time
as bisphosphonates. Some examples of
these medications are nonsteroidal anti-
inflammatory drugs (NSAIDs), thalido-
mide, and certain antibiotics.
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Management without surgery is recom-
If surgery is absolutely required, inter-
mended as a first step. Minor dental work
ruption of bisphosphonate therapy is
to reduce sharp edges or remove injured
strongly recommended. Current data
tissue may be required. A protective
indicate very poor healing with contin-
mouth guard may also be helpful.
ued bisphosphonates in this set ing.
Antibiotic treatment is recommended if
Dentures can be worn, but many need
there is infection. The type of therapy
adjustment. Placement of dental implants
selected depends upon the type of infec-
appears to be contraindicated. Use of
tion that is documented. Oral rinses can
hyperbaric oxygen does not appear to
also be used.
be helpful.
If problems persist and/or if healing
Careful monitoring and fol ow-up are
is slow, consideration can be given to
required.
stopping bisphosphonate therapy for 2-4
months to facilitate recovery. Although
Prevention can help patients avoid or
reduce the scope of the problem. Be
study results are lacking, there are anec-
aware and inform your dentist about
dotal reports of benefit with brief interrup-
this potential risk for patients who take
tion of Aredia® or Zometa® treatment.
bisphosphonates; maintain excel ent oral
hygiene, and make sure that you have
regular visits to the dentist. Avoid tooth
extraction and/or any elective jaw sur-
gery if at al possible. If there is an
opportunity, proceed with careful dental
evaluation and any required preventative
dental care before starting bisphospho-
nate therapy.
There is every reason to hope that with
appropriate awareness and early man-
agement, serious problems from osteone-
crosis can be avoided.
Other Side Effects
Other side ef ects are general y rare. As
with most drugs, however, other reactions
occasional y occur and may include rash,
stomach upset, blurred vision, headache,
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and shortness of breath. Severe al ergic
increased to 4 hours and the infusion time of
reactions are very rare, although possible.
Zometa® can be increased from 15 minutes
to 30 to 45 minutes.
WHO SHOULD NOT TAKE BISPHOSPHONATES?

If, for any reason, dif iculty with intravenous
Patients without documented myeloma-
related bone disease should not take
bisphosphonatesexists,oralbisphosphonates
bisphosphonates. This means that, in
can be considered. Administering the oral
general, patients with monoclonal gam-
bisphosphonates Fosamax® (e.g., once per
mopathy of undetermined significance
week by mouth) and/or Actonel® (daily
(MGUS) and smoldering myeloma without
dosing by mouth) is not approved specifi-
bone disease do not need or benefit from
cal y for myeloma by the FDA. Nonetheless,
bisphosphonates. However, this remains
occasional patients can benefit from oral
an area of ongoing research and clinical
bisphosphonates, especial y patients who
trials.
are intolerant of intravenous infusion, have
As noted, bisphosphonates must be used
nephrotoxicity, and/or are concomitantly
with caution in patients with pre-existing
using steroids. Oral bisphosphonates can
kidney disease or known elevation in
cause esophagitis and/or other gastrointes-
serum creatinine, especial y >3.0 mg/dl
tinal complaints, which preclude use.
but also any value above the normal
range.
CAN BISPHOSPHONATES BE COMBINED WITH
Patients who have al ergic reactions or
OTHER THERAPIES?
are intolerant to bisphosphonate treat-
In general, bisphosphonates can be safely
ment should not take bisphosphonates.
combined with most other therapies. Your
HOW ARE BISPHOSPHONATES GIVEN?
physician may decide not to give Aredia® or
Zometa® on or close to the same day as admin-
Both Aredia® and Zometa® are given intrave-
istration of intravenous chemotherapy. Caution
nously on a monthly basis. Aredia® is given
about potential nephrotoxicity has been
over 2 to 4 hours by intravenous infusion, and
noted above.
premedication with 1 or 2 Tylenol® (325 mg)
can be helpful. Zometa® is given over 15 to
WILL INSURANCE COVER THE COSTS
45 minutes by intravenous infusion, and pre-
OF BISPHOSPHONATES?
medication may also be beneficial.
Since Aredia® and Zometa® are FDA, com-
Toxicities associated with both medica-
mercial y approved medications, Medicare
tions, especial y potential renal toxicities,
and most insurance programs reimburse for
are related to dose, time of infusion, and
bisphosphonate use. Any problems with reim-
frequency of infusion. If kidney toxicity is a
bursement should be brought to the at ention
concern, the infusion time of Aredia® can be
of your physician and/or Novartis.
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WHAT OTHER APPROACHES TO BONE CARE
Regular re-evaluation and fol ow-up test-
ARE AVAILABLE?
ing of bones by x-ray/scan/bone density
testing to rule out new bone disease and
Kyphoplasty provides a new tool that may
assess the impact of treatment.
impact bone care for myeloma patients. This
procedure involves the injection of liquid
WHAT DOES THE FUTURE HOLD?
cement using the bal oon technique in an
Considerable new research is ongoing to
at empt to provide acute pain relief and
investigate myeloma bone disease. Of par-
improvement in the structural integrity of col-
ticular interest is treatment that can improve
lapsed vertebrae or other damaged bones.
bone cel function with activation of osteo-
Although results from large studies are not
blasts to promote bone healing. The future
available, the procedure has been found
looks promising for useful new drug treat-
safe and ef ective in selected patients.
ments.
General measures to improve bone health
QUESTIONS TO ASK YOUR DOCTOR
are recommended, including:
Some questions you may want to ask your
Adequate pain control to al ow moving
doctor about your medication are:
about and exercise.
For how long wil I be taking bisphospho-
Radiation therapy and/or orthopedic
nates?
surgery to restore structural integrity of
bones and recovery of ful mobilization.
How do I get repeat prescriptions?
Radiation therapy should be used sparing-
Of which side ef ects should I be aware?
ly for acute problems such as spinal cord
Is there anything I need to avoid while
compression, severe refractory pain, and
taking bisphosphonates?
treatment or prevention of pathologic frac-
ture. Since radiation therapy can impair
May I see a patient information leaflet
local bone healing, many physicians pre-
about my medicine?
fer to use systemic steroids and/or other
antimyeloma therapy. Orthopedic surgery
should be used as necessary.
Exercise, especial y walking and/or swim-
ming, to enhance bone strength, flexibil-
ity, and endurance.
Avoidance of risky activities (e.g., climb-
ing ladders), which can increase the likeli-
hood of fal s and/or fractures.
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The IMF provides programs and services to
About the IMF
aid in the research, diagnosis, treatment, and
"One person can make a difference,
managementofmyeloma.TheIMFensuresthat
Two can make a miracle."
no one must brave the myeloma bat le alone.
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We care for patients today, while working
IMF Founder
toward tomorrow's cure.
Myeloma is a lit le-known, complex, and
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often misdiagnosed bone marrow cancer
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af ects approximately 75,000 to 100,000
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MYELOMA MATRIX
researchers working on a broad spectrum of
On our website and in print, this document is a
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comprehensive guide to drugs in development
investigators into the field of myeloma, and
for myeloma.
they have remained in the field and are actively
pursuing a cure for this disease.
MYELOMA TODAY NEWSLETTER
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Glossary
Albuminuria: The presence of an excess of serum
SUPPORT
protein in the urine.
MYELOMA HOTLINE: 800-452-CURE (2873)
Axial skeleton: Spine, pelvis, ribs, and skul . Along
with the upper ends of the long bones of the arms and
Tol -free throughout the United States and
legs, the axial skeleton is most commonly af ected by
Canada, the IMF hotline is staf ed by trained
pathologic fracture.
information specialists and is in frequent inter-
Bence Jones myeloma: Myeloma characterized
action with members of our Scientific Advisory
by the presence of Bence Jones protein, an abnormal
Board.
protein in urine or plasma.
SUPPORT GROUPS
Bisphosphonate: A smal inorganic molecule that
binds to the surface of damaged bones. Bisphosphonate
A worldwide network of more than 100 myelo-
therapy is used in patients with bone disease to reduce
ma support groups hold regular meetings for
new bone damage and al ow an opportunity for bone
members of the myeloma community. The IMF
healing to occur.
conducts annual retreats for myeloma support
Chemotherapy: Drugs that are used to kil cancer
group leaders.
cel s.
Creatinine: A compound excreted in the blood and
RESEARCH
urine. A high level of creatinine is an indication of
kidney dysfunction.
BANK ON A CURE®
Esophagitis: Inflammation of the esophagus (the tube
This DNA bank wil provide genetic data
that transports food from the mouth to the stomach).
research in new drug development.
Hydroxyapatite: A compound found on the surface
THE INTERNATIONAL STAGING SYSTEM
of bones that gives them rigidity.
Hypercalcemia: Higher than normal levels of calcium
This updated staging system for myeloma wil
in the blood.
enhance physicians' ability to select the most
Kyphoplasty: The injection of liquid cement into dam-
appropriate treatment for each patient.
aged bone using a bal oon technique. This procedure
RESEARCH GRANTS
may provide acute pain relief and improvement in
structural integrity of col apsed vertebrae or other dam-
Leading the world in col aborative research
aged bones.
and achieving extraordinary results, the IMF
Lytic lesions: Holes in the bone.
Grant Program supports both junior and senior
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Monoclonal gammopathy of undetermined
Appointments
significance (MGUS): A category of myeloma char-
acterized by comparatively low amounts of myeloma-
Date
Time
Important Notes
associated protein levels and bone marrow plasma
cel s as wel as an absence of certain myeloma-related
symptoms (i.e., anemia, renal failure, hypercalcemia,
and lytic lesions).
Myeloma: A cancer of bone marrow plasma cel s.
Cancerous plasma cel s are cal ed myeloma cel s.
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 cel s.
Nonsteroidal anti-inflammatory drug (NSAID):
A drug used to reduce fever, swel ing, pain, and
redness.
Osteoblast: An immature cel that is associated with
bone production as it matures.
Osteoclast: A cel 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 cel s
as wel 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 cel s 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 swel ing
and inflammation. A negative ef ect of steroid treatment
is the reduction of bone mass.
Systemic treatment: Treatment using substances that
travel through the bloodstream to reach and af ect cel s
in the entire body.
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