Understanding
Bisphosphonate
Therapy
International Myeloma Foundation
12650 Riverside Drive, Suite 206
North Hol ywood, CA 91607 USA
Telephone:
800-452-CURE
(USA & Canada)
818-487-7455
Fax: 818-487-7454
TheIMF@myeloma.org
myeloma.org
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Table of Contents
Introduction
5
What Are Bisphosphonates?
6
Are Bisphosphonates a Type
of Chemotherapy?
6
Who Benefits From Bisphosphonates?
7
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?
19
Can Bisphosphonates Be Combined
With Other Therapies?
20
Will Insurance Cover the Costs
of Bisphosphonates?
20
What Other Approaches to Bone Care
Are Available?
20
What Does the Future Hold?
22
Questions to Ask Your Doctor
22
About the IMF
23
Glossary
26
©2011, International Myeloma Foundation, North Hollywood, California (V11)

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Introduction
Approximately 80% of al patients with
myeloma* develop bone disease. 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 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 send-
ing signals to certain bone cel s cal ed osteo-
clasts, causing them to break down bone. In
addition to giving rise to bone disease, this
process also releases calcium from the bones
into the bloodstream; if this release happens
too quickly, a condition cal ed hypercalcemia
can occur. Both myeloma bone disease and
hypercalcemia can be treated with a group
of drugs cal ed bisphosphonates.
*Al words that appear in bold type are defined in
a glossary at the end of this booklet.
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What are Bisphosphonates?
is used to directly at ack the myeloma.
Bisphosphonates are smal inorganic mole-
Bisphosphonates are used to treat sever-
cules that bind to a substance cal ed hydroxy-
al types of bone disease, including osteo-
apatite on the surface of damaged bones. At
porosis and the bone-thinning ef ects of
steroid
the sites of bone damage, bisphosphonates
treatment.
inhibit and destroy osteoclasts. Since bone
Who Benefits from Bisphosphonates?
damage is caused by the increased numbers
Bisphosphonates are recommended for al
and activity of these osteoclasts, treatment
patients with myeloma-related bone disease.
with bisphosphonates reduces bone damage
The American Society of Clinical Oncology
and al ows bone healing to occur.
has guidelines that recommend ongoing use
Bisphosphonates therefore have several
of bisphosphonates for al myeloma patients
beneficial ef ects, including:
with documented bone disease who start on
Preventing further bone damage
systemic treatment for myeloma.
Reducing bone pain and the need
for painkil ers
Correcting and preventing hypercalcemia
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
and recovering bone strength
are Bisphosphonates a type
of Chemotherapy?
Bisphosphonates are not a type of chemo-
therapy. They were first introduced over
twenty years ago as an additive to tooth-
paste to reduce dental decay.
Bisphosphonates are general y very safe
and do not have the types of risks or side
ef ects associated with chemotherapy, which
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zoledronic acid was not only superior to
clodronate in preventing SREs but also pro-
vided a survival benefit independent of SRE
reduction, suggesting that zoledronic acid
may also have anti-myeloma activity. Ful
results of this trial were published recently in
the journal Lancet Oncology.
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
A randomized study published in the New
products are associated with several impor-
England Journal of Medicine documented
tant dif erences in:
that bisphosphonate use leads to a reduction

in what are cal ed skeletal-related events or
Administration: intravenous versus oral
SREs (i.e., new bone damage or fractures),
delivery and the length of intravenous
infusion time
as wel as pain reduction and improved qual-
ity of life. The bisphosphonate used in this
Potential side ef ects: e.g., fever, possible
study was Aredia® (pamidronate).
kidney toxicity, or bone disease in the jaw
Bisphosphonates are particularly helpful for
The bisphosphonates currently approved by
patients being treated with steroids, such
the Food and Drug Administration (FDA) for
as prednisone or dexamethasone. Steroids
use in multiple myeloma in the United States
reduce bone mass or density. Bisphosphonate
are pamidronate (Aredia®) and zoledron-
use improves this negative ef ect on bones.
ic acid (Zometa®). Clodronate (Clasteon®,
Bonefos®) is approved for use in Canada
At the 2010 annual meeting of the American
and other countries.
Society of Hematology (ASH), a randomized
comparison of zoledronic acid (Zometa®)
Aredia® was approved based upon the
with clodronate (Clasteon®, Bonefos®) as
results of the 1996 study published in the
part of the British MRC (Medical Research
New England Journal of Medicine. Use of
Council) Myeloma IX trial showed that
Aredia® by monthly intravenous infusion
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became the standard of care for myeloma
What are the possiBle siDe effeCts of
patients. It has become established as a safe,
Bisphosphonates?
helpful drug for the treatment of myeloma
Bisphosphonates are general y very wel
bone disease.
tolerated. The most common side ef ects
Zometa® was approved in 2001 based
are fever, vein irritation, general aches and
upon study results comparing it with Aredia®.
pains, kidney dysfunction, and osteonecrosis
Zometa® produces more rapid and pro-
of the jaws (ONJ).
longed reduction in elevated blood cal-
fever
cium, when elevated levels are present.
Fever associated with bisphosphonates is
However, results evaluating ef ect on SREs
typical y mild (i.e., 100° to 101° F), occurring
showed that Zometa® and Aredia® af ect
a few hours after the intravenous infusion
SREs equivalently. The major dif erence with
and lasting for a few hours at most. Fever
Zometa®, therefore, proved to be its much
is usual y easily treated or prevented with
shorter infusion time of 15 to 30 minutes
1 or 2 acetaminophen (such as Tylenol®) of
versus 2 to 4 hours for Aredia® (see p.19,
325 mg.
How Are Bisphosphonates Given).
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.
Kidney Dysfunction
The main additional concern relates to
kidney side effects. Al bisphosphonates
are potential toxins for the kidneys. Since
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myeloma can impact kidney function (e.g.,
To minimize the potential for kidney-relat-
due to myeloma protein damage or elevated
ed problems, your doctor should fol ow
blood calcium), the possibility of kidney-
several recommendations:
related side ef ects is of particular concern.
Your doctor should be especial y cautious
Aredia® has been used widely for fif-
with the use of Zometa® if there is concern
teen years, including the initial trials peri-
from the outset for kidney dysfunction
od. The type of kidney toxicity that has
(i.e., with Bence Jones myeloma, diabetes,
emerged is an excess of a serum protein,
long-standing high blood pressure, or in
cal ed albumin, in the urine (known as
elderly or frail patients). Zometa® should
albuminuria or nephrotic syndrome). This
not be used in patients with known kidney
toxicity has occurred predominantly with
deterioration as determined by creatinine
uses of higher than recommended doses
level over 3 mg/dL.
(e.g., 180 mg versus 90 mg) and/or more
Your doctor should check your serum
frequent than recommended dosing sched-
creatinine level before each dose of
ules (e.g., every 2 weeks versus once/
Zometa®.
month). This side ef ect is usual y revers-
· If the serum creatinine value has
ible with dose and/or schedule adjustments
increased by 0.5 mg/dL in a patient
or, in occasional severe cases, by 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 more
than 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
both increased creatinine and occasional y
more severe kidney damage have raised
concern that this much more potent bisphos-
phonate must be used more cautiously with
respect to kidney function.
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with normal renal function at the outset,
next dose. The doctor should use his
the doctor should hold the next dose
or her judgment to determine which
until the value returns to within 10% of
option is the most appropriate for an
baseline.
individual patient.
· If the serum creatinine value has
Your doctor should be aware that certain
increased by 1.0 mg/dL in a patient
medications with the potential to af ect
with abnormal renal function at the out-
kidney function may be more likely to
set, the doctor should hold the next dose
do so if they are given at the same time
until the value returns to within 10%
as bisphosphonates. Some examples of
of baseline.
these medications are nonsteroidal anti-
· In a patient who has experienced a
inflammatory drugs (NSAIDs), thalido-
mild elevation in serum creatinine value
mide, and certain antibiotics.
that has returned to 10% of baseline,
osteonecrosis of the Jaws
the doctor may consider adjustments
Osteonecrosis of the Jaws (ONJ) is a jaw
to the treatment schedule. Adjustments
problem that occurs in a smal percentage
may include increasing the time of infu-
of of patients with myeloma or other cancers
sion from 15 to 30 minutes or more,
who have been treated with Aredia® or
using a larger volume of diluting fluids,
Zometa®. In the recent MRC trial (discussed
or delaying the administration of the
above), 3.5% of patients developed ONJ
associated with the use of Zometa® (0.6%
developed ONJ associated with clodronate
(Bonefos®). In the recent MRC trial (discussed
above), 3.5% of patients developed ONJ
associated with the use of Zometa® (0.6%
developed ONJ associated with clodronate
(Bonefos®). This condition produces pain,
swel ing, and bone damage around the
tooth sockets in the jaws. There is bone
necrosis or loss of bone which can lead to
loose teeth, sharp edges of exposed bone,
bone spurs, and the breaking loose of smal
bone spicules or dead bone. Symptoms may
not be obvious at first, or may include pain,
swel ing, numbness or a "heavy jaw" feel-
ing, or loosening of a tooth.
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Consultation with an oral surgeon or den-
If surgery is absolutely required, interrup-
tal oncologist familiar with osteonecrosis
tion of bisphosphonate therapy is strongly
is strongly recommended for patients
recommended. Current data indicate very
who suspect that they may have ONJ.
poor healing with continued bisphospho-
Management without surgery is recom-
nates in this set ing.
mended as a first step. Minor dental work
Dentures can be worn, but many need
to reduce sharp edges or remove injured
adjustment. Placement of dental implants
tissue may be required. A protective
appears to be contraindicated. Use of
mouth guard may also be helpful.
hyperbaric oxygen does not appear to
Antibiotic treatment is recommended if
be helpful.
there is infection. The type of therapy
Careful monitoring and fol ow-up are
selected depends upon the type of infec-
required.
tion that is documented. Oral rinses can
also be used.
Prevention can help patients avoid or
reduce the scope of the problem. Be
If problems persist and/or if healing is
aware and inform your dentist about
slow, consideration can be given to stop-
this potential risk for patients who take
ping bisphosphonate therapy for two
bisphosphonates; maintain excel ent oral
to four months to facilitate recovery.
hygiene, and make sure that you have
Although study results are lacking, there
regular visits to the dentist. Avoid tooth
are anecdotal reports of benefit with
extraction and/or any elective jaw sur-
brief interruption of Aredia® or Zometa®
gery if at al possible. If there is an
treatment.
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. It is encouraging
that at the 2009 annual meeting of the
American Society of Hematology (ASH),
key opinion leaders noted that the inci-
dence of ONJ appears to have decreased
dramatical y, probably due to improved
dental practice.
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other side effects
benefit from bisphosphonates. However,
Other side ef ects are general y rare. As
this remains an area of ongoing research
with most drugs, however, other reactions
and clinical trials.
occasional y occur and may include rash,
As noted, bisphosphonates must be used
stomach upset, blurred vision, headache,
with caution in patients with pre-existing
and shortness of breath. Severe al ergic
kidney disease or known elevation in
reactions are very rare, although possible.
serum creatinine, especial y >3.0 mg/dL
but also any value above the normal
Two additional concerns have emerged
range.
with long-term use of bisphosphonates that

bear noting. Atypical fractures of the femur
Patients who have al ergic reactions or
are intolerant to bisphosphonate treat-
(known as subtrochanteric and diaphyseal
ment should not take bisphosphonates.
femur fractures) are rare, and an association
with five or more years of bisphosphonate
hoW are Bisphosphonates GiVen?
treatment has been documented. The FDA
Both Aredia® and Zometa® are given intra-
reviewed the data on the occurrence of
venously on a monthly basis. Aredia® is
these atypical femur fractures and issued
given over 2 to 4 hours by intravenous
a safety announcement on October 13,
infusion, and premedication with 1 or 2
2010, which was then added to Warnings
acetaminophen (such as Tylenol®) of 325 mg
and Precautions section of the labels of al
can be helpful. Zometa® is given over 15 to
approved bisphosphonate drugs. Two recent
45 minutes by intravenous infusion, and pre-
publications discuss the possible association
medication may also be beneficial.
between oral bisphosphonates and cancer
of the esophagus. Using the same database,
Toxicities associated with both medications,
one group found an association whereas the
especial y potential renal toxicities, are
other group did not. These findings require
related to dose, duration of infusion, and
further examination and may not apply to
frequency of infusion. If kidney toxicity is a
bisphosphonates administered by infusion.
concern, the infusion time of Aredia® can be
increased to 4 hours and the infusion time of
Who shoulD not taKe Bisphosphonates?
Zometa® can be increased from 15 minutes
Patients without documented myeloma-
to 30 to 45 minutes.
related bone disease should not take
If, for any reason, dif iculty with intravenous
bisphosphonates. This means that,
in general, patients with monoclonal
bisphosphonates exists, oral bisphosphonates
gammopathy of undetermined significance
can be considered. Administering the oral
(MGUS) and asymptomatic myeloma
bisphosphonates Fosamax® (e.g., once
without bone disease do not need or
per week by mouth) and/or Actonel®
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(daily dosing by mouth) is not approved
This procedure involves the injection of
specifical y for myeloma by the FDA.
liquid cement using the bal oon technique
Nonetheless, occasional patients can ben-
in an at empt to provide acute pain relief
efit from oral bisphosphonates, especial y
and improvement in the structural integrity
patients who are intolerant of intravenous
of col apsed vertebrae or other damaged
infusion, have nephrotoxicity, and/or are
bones. The results of a randomized study
concomitantly using steroids. Oral bisphos-
(the CAFE study) of kyphoplasty versus
phonates can cause esophagitis and/or
non-surgical intervention were published in
other gastrointestinal complaints, which
Lancet in February, 2011. The study included
precludes their use.
134 patients with vertebral compression frac-
tures who also had various types of cancer
Can Bisphosphonates Be ComBineD With
such as breast, lung, prostate, or multiple
other therapies?
myeloma, and took place at 22 sites in the
In general, bisphosphonates can be safely
U.S., Europe, Australia and Canada. The
combined with most other therapies. Your
study concluded that patients randomized
physician may decide not to give Aredia® or
to have kyphoplasty rather than non-surgical
Zometa® on or close to the same day as admin-
intervention had improved pain relief, back
istration of intravenous chemotherapy. Caution
function, and quality of life.
about potential nephrotoxicity has been
noted above.
General measures to improve bone health
are recommended, including:
Will insuranCe CoVer the Costs
Adequate pain control to al ow for move-
of Bisphosphonates?
ment and exercise.
Since Aredia® and Zometa® are FDA
Radiation therapy and/or orthopedic
approved medications, Medicare and
surgery to restore structural integrity of
most insurance programs reimburse for
bones and recovery of ful mobilization.
their use. Any problems with reimbursement
Radiation therapy should be used sparing-
should be brought to the at ention of your
ly for acute problems such as spinal cord
physician and/or Novartis, the manufacturer
compression, severe refractory pain, and
of both medications.
treatment or prevention of pathologic frac-
ture. Since radiation therapy can impair
What other approaChes to Bone Care
local bone healing, many physicians pre-
are aVailaBle?
fer to use systemic steroids and/or other
Kyphoplasty provides a new tool that may
antimyeloma therapy. Orthopedic surgery
impact bone care for myeloma patients.
should be used as necessary.
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Exercise, especial y walking and/or swim-
About the IMF
ming, to enhance bone strength, flexibil-
ity, and endurance.
"One person can make a dif erence,
Avoidance of risky activities (e.g., climb-
Two can make a miracle."
ing ladders), which can increase the likeli-
Brian D. Novis
hood of fal s and/or fractures.
IMF Founder
Regular re-evaluation and fol ow-up test-
Myeloma is a lit le-known, complex, and
ing of bones by x-ray/scan/bone density
often misdiagnosed bone marrow cancer that
testing to rule out new bone disease and
at acks and destroys bone. Myeloma af ects
assess the impact of treatment.
approximately 75,000 to 100,000 people
What Does the future holD?
in the United States, with approximately
20,000 new cases diagnosed each year.
Considerable new research is ongoing
Although there is presently no known cure for
to investigate myeloma bone disease. Of
myeloma, doctors have many approaches to
particular interest is treatment that can
help myeloma patients live bet er and longer.
improve bone cel function with activation
of osteoblasts to promote bone healing.
The International Myeloma Foundation (IMF)
The future looks promising for useful new
was founded in 1990 by Brian and Susie
drug treatments.
Novis shortly after Brian's myeloma diagno-
sis at the age of 33. It was Brian's dream that
Questions to asK your DoCtor
future patients would have easy access to
Some questions you may want to ask your
medical information and emotional support
doctor about your medication are:
throughout their bat le with myeloma. He
For how long wil I be taking
established the IMF with the 3 goals of treat-
bisphosphonates?
ment, education, and research. He sought
How do I get repeat prescriptions?
to provide a broad spectrum of services for
patients, their families, friends, and health
Of which side ef ects should I be aware?
care providers. Although Brian died 4 years
Is there anything I need to avoid while
after his initial diagnosis, his dream didn't.
taking bisphosphonates?
Today, the IMF reaches out to an interna-

tional membership of more than 195,000.
May I see a patient information leaflet
The IMF was the first organization dedicated
about my medicine?
solely to myeloma, and today it remains
the largest.
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The IMF provides programs and services to
support
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bers of our Scientific Advisory Board.
We care for patients today, while working
support Groups
toward tomorrow's cure.
A worldwide network of more than 100 myeloma
support groups holds regular meetings for mem-
How Can the IMF Help?
bers of the myeloma community. The IMF con-
ducts annual retreats for myeloma support group
patient eDuCation
leaders.
information paCKaGe
researCh
Our free IMF InfoPack provides comprehensive
BanK on a Cure®
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This DNA bank wil provide genetic data for
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research in new drug development.
internet aCCess
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Log on to myeloma.org for 24-hour access to
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With a goal to improve myeloma treatment
Join the IMF Internet Discussion Group at www.
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es on protocols to provide a more durable
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Glossary
Kyphoplasty: The injection of liquid cement into damaged
bone using a bal oon technique. This procedure may
Albuminuria: The presence of an excess of serum protein
provide acute pain relief and improvement in structural
in the urine.
integrity of col apsed vertebrae or other damaged bones.
Asymptomatic myeloma: A category of myeloma character-
Lytic lesions: Holes in the bone.
ized by comparatively low amounts of myeloma-associat-
Monoclonal gammopathy of undetermined signifi-
ed protein levels and bone marrow plasma cel s as wel
cance (MGUS): A category of myeloma character-
as an absence of certain myeloma-related symptoms (i.e.,
ized by comparatively low amounts of myeloma-
anemia, renal failure, hypercalcemia, and lytic lesions).
associated protein levels and bone marrow plasma
Although the quantities of protein levels and plasma cel s
cel s as wel as an absence of certain myeloma-related
are relatively low, they are higher than in patients with
symptoms (i.e., anemia, renal failure, hypercalcemia,
monoclonal gammopathy of undetermined significance
and lytic lesions).
(MGUS).
Myeloma: A cancer of bone marrow plasma cel s.
Axial skeleton: Spine, pelvis, ribs, and skul . Along with the
Cancerous plasma cel s are cal ed myeloma cel s.
upper ends of the long bones of the arms and legs, the
axial skeleton is most commonly af ected by pathologic
Nephrotic syndrome: A group of diseases characterized by
fracture.
a massive excess of serum protein in the urine.
Bence Jones myeloma: Myeloma characterized by the pres-
Nephrotoxicity: The quality of being toxic or destructive to
ence of Bence Jones protein, an abnormal protein in urine
kidney cel s.
or plasma.
Nonsteroidal anti-inflammatory drug (NSAID): A drug used to
Bisphosphonate: A smal inorganic molecule that binds to
reduce fever, swel ing, pain, and redness.
the surface of damaged bones. Bisphosphonate therapy
Osteoblast: An immature cel that is associated with bone
is used in patients with bone disease to reduce new bone
production as it matures.
damage and al ow an opportunity for bone healing to
occur.
Osteoclast: A cel that destroys the bone.
Chemotherapy: Drugs that are used to kil cancer cel s.
Osteoporosis: Thinning and weakening of the bone.
Creatinine: A compound excreted in the blood and urine.
Pathologic fracture: Fracture due to weakening of the bone
A high level of creatinine is an indication of kidney
structure from disease.
dysfunction.
Phlebitis: Inflammation of a vein.
Esophagitis: Inflammation of the esophagus (the tube that
Skeletal-related event (SRE): New bone damage or fracture.
transports food from the mouth to the stomach).
Steroid: A type of drug that is used to reduce swel ing and
Hydroxyapatite: A compound that helps form bones and
inflammation. A negative ef ect of steroid treatment is the
gives them rigidity and strength.
reduction of bone mass.
Hypercalcemia: Higher than normal levels of calcium in
Systemic treatment: Treatment using substances that travel
the blood.
through the bloodstream to reach and af ect cel s in the
entire body.
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