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August 2011, Supplement to Volume 15, Number 4
Article
Maintaining Bone Health in Patients With Multiple Myeloma: Survivorship
Care Plan of the International Myeloma Foundation Nurse Leadership Board
Teresa S. Miceli, RN, BSN,
OCN®, Kathleen Colson, RN, BSN, BS,
Beth M. Faiman, MSN,
APRN-BC, AOCN®, Kena Miller, RN, MSN, FNP,
Joseph D. Tariman, PhD,
APRN, BC, and the International Myeloma
Foundation Nurse Leadership
Board
About 90% of individuals with
multiple myeloma will develop osteolytic bone lesions from increased
osteoclastic and decreased osteoblastic activity. Severe morbidities from
pathologic fractures and other skeletal events can lead to poor circulation,
blood clots, muscle wasting, compromised performance status, and overall poor
survival. Supportive care targeting bone disease is an essential adjunct to
antimyeloma therapy. In addition, the maintenance of bone health in patients
with multiple myeloma can significantly improve quality of life. Oncology
nurses and other healthcare providers play a central role in the management of
bone disease and maintenance throughout the course of treatment. Safe
administration of bisphosphonates, promotion of exercise, maintenance of
adequate nutrition, vitamin and mineral supplementation, scheduled radiographic
examinations, and monitoring of bone complications are among the important
functions that oncology nurses and healthcare providers perform in clinical
practice.
At a Glance
·
Most patients
with multiple myeloma will develop osteolytic bone lesions. Pathologic
fractures and other skeletal events can result in poor circulation, blood
clots, muscle wasting, and decreased survival.
·
Supportive care
targeting bone disease is an essential part of myeloma therapy.
·
Oncology nurses
play a key role in the management of bone disease and maintenance of adequate
bone health throughout the course of myeloma.
A main feature of multiple
myeloma (MM) is bone destruction, and many patients will initially present with
pain related to osteolytic lesions or vertebral compression fractures (Sezer,
2009). Destructive bone lesions and diffuse osteopenia are secondary to the
stimulation of osteoclast-activating growth factors, cytokine release, and the
lack of osteoblastic response (Esteve & Roodman, 2007). The clinical
consequences of osteolytic bone lesions—fractures, severe bone pain, spinal
cord compression, hypercalcemia, and renal insufficiency—can be devastating for
patients, negatively affecting immediate and ongoing quality of life and
worsening survival prospects (Kyle, Gertz, et al., 2003).
Pathophysiology
of Myeloma Bone Disease
Bone disease is the major
cause of morbidity and mortality in patients with MM (Coleman, 2006).
Osteolytic lesions found with MM are caused by rapid bone turnover, which
occurs as a result of increased osteoclastic resorption that is not accompanied
by a comparable increase in bone formation (Berenson, Rajdev, & Border,
2006; Epstein & Walker, 2006). Normal bone formation is initiated by
osteoblasts, and bone resorption is initiated by osteoclasts. Osteoprotegerin
is a cytokine that inhibits production of osteoclasts. Osteoprotegerin
maintains the balance between bone resorption and formation. Bone destruction in
MM is believed to be multifactorial, resulting from an interaction of bone
marrow stromal cells and myeloma tumor cells within the microenvironment of the
bone marrow (Coleman, 2001). Bone destruction is characterized by
overproduction of osteoclasts and reduced stimulation of osteoblasts resulting
in unbalanced bone turnover.
Bone pain and the incidence
of pathologic fracture are high among patients living with MM as a result of
osteolytic bone lesions and bone turnover related to excess cytokine levels. Fractures
typically occur near the time of diagnosis or relapse and are pathologic in
nature. The most common locations of fracture are within the vertebral bodies
(55%–70%), particularly in the lumbar vertebral bodies, flat and long bones
(including the ribs), the extremities, and pelvis (Melton, Kyle, Achenbach,
Oberg, & Rajkumar, 2005).
Long-Term
Effects of Bone Disease
As noted, the majority of
patients with MM will experience a pathologic fracture over the natural
duration of their illness. As a result, 80% of patients will experience pain
and altered quality of life (Roodman, 2008). The severity of bone disease and
number of lesions present at the time of the diagnosis help to classify
patients who are considered high risk. The Durie/Salmon PLUS staging system has
integrated the quantification of bone lesions by magnetic resonance imaging
(MRI) and positron-emission tomography (PET) to better define the treatment
plan for patients newly diagnosed with early disease (Durie, 2006). Two staging
systems are used to standardize treatment approaches. The International Staging
System was introduced in 2005 by the International Myeloma Working Group and is
based on two factors, serum beta-2 microglobulin and serum albumin levels
(Greipp et al., 2005). This system divides cases of myeloma into three stages,
providing a reliable prognostic tool. The Durie-Salmon staging system (Durie
& Salmon, 1975) is based on the following criteria: percentage of marrow
involved by monoclonal plasma cells; level of abnormal monoclonal
immunoglobulin in the blood and/or urine; and level of serum calcium, renal
dysfunction, degree of anemia, and presence of bone damage (CRAB) as later
defined by the International Myeloma Working Group (Kyle, Child, et al., 2003).
Although both systems provide valuable diagnostic and prognostic information,
neither system describes how the severity of bone disease affects long-term
outcomes.
The Durie/Salmon PLUS staging
system (Durie, 2006) assimilates imaging methods into a new generation of anatomic
and functional myeloma staging. Table 1 outlines the
diagnostic imaging commonly used for patients with MM. With the use of MRI,
whole body fluorodeoxyglucose (FDG) PET scanning and whole body computed
tomography (CT), combined with PET directly or by fusion, the Durie-Salmon
staging system has now been enhanced to include anatomic and functional
staging. The new system may provide better classification of early disease. The
Durie/Salmon PLUS staging system provides the following advantages.
·
Assessment of
cell mass
·
More accurate
staging for patients who lack traditional biomarkers because of hyposecretory
or nonsecretory disease
·
Identifies
patients at poor risk who have more than 20 focal lesions and/or extramedullary
disease
·
Confirms stage I
active disease for patients with negative x-rays
·
Provides a more
detailed discernment between those diagnosed with stage II and III disease
The degree of bone
involvement affects quality of life as well as prognosis. Compromised skeletal
structure because of lytic lesions and vertebral compression fracture can
result in altered mobility and function; therefore, early detection can offer
potential benefits to patients. The life-altering mobility and functional
aspects of myeloma are further described in Rome, Jenkins, Lilleby, and the
International Myeloma Foundation Nurse Leadership Board (2011).
Assessment
of Myeloma Bone Disease
Laboratory Testing
Laboratory tests to assess
bone include calcium, vitamin D, fractionated alkaline phosphatase, and
creatinine. Hypercalcemia, defined as a corrected serum calcium greater than
11.5 mg/dl, is seen in 10%–15% of patients at presentation and is considered an
oncologic emergency. Alkaline phosphatase will be elevated with a high bone
fraction and can indicate an increased rate of bone growth. Vitamin D levels
can provide additional baseline evaluation of bone health because vitamin D
deficiency can interrupt calcium metabolism, leading to weakened bones.
Adequate vitamin D is crucial in preventing bone loss (Bischoff-Ferrari, 2007;
Cashman, 2007; Guise, 2006; Mauck & Clarke, 2006; Roodman, 2004).
A variety of laboratory
markers are used to monitor bone resorption in patients with MM. These markers
can predict the development of new skeletal events. If the parathyroid hormone
(PTH) level is low, bones will release more calcium in the blood, leading to
hypercalcemia, and weakening of the bones, as well as resulting in fractures
and pain. Some common symptoms of hypercalcemia include polyuria, polydipsia,
constipation, confusion, somnolence, fatigue, vomiting, dehydration, weakness,
and renal insufficiency. N-telopeptides are fragments of collagen released by
the bone during bone turnover. When bone is broken down, this collagen is
released in the urine; high levels of N-telopeptides in the urine can be
indicative of active bone disease. Endocrine evaluation that includes thyroid,
parathyroid, and testosterone levels may be indicated throughout the course
(Bischoff-Ferrari, 2007; Cashman, 2007; Coleman, 2006; Guise, 2006; Mauck &
Clarke, 2006; Roodman, 2004).
Diagnostic Imaging
Bone imaging is an important
tool for diagnosis and monitoring bone disease in patients with myeloma.
Patients often are initially diagnosed because of the onset of acute bone pain
or pathologic fracture. Any bone may be affected in MM; the bones with the
highest chance of being affected are the spine with more than a 49% risk, the
skull with more than a 35% risk, the pelvis at 34% risk, the humeri with 22%
risk, the femora at 13% risk, and the mandible at 10% (Roodman, 2008) (see Figure 1). Of note, bone disease in myeloma is caused
by an imbalance of osteoblast and osteoclast activity causing bone destruction
and absence of bone formation. Therefore, bone scans are not the imaging
technique of choice because the degree of bone disease may be underestimated
(Roodman, 2008). A complete skeletal survey, the standard method of imaging in
patients with MM, detects fractures, tumors, or degenerative changes in the
bone. Metastatic bone surveys show that skeletal abnormalities are present in
79% of newly diagnosed patients. Osteosclerotic lesions are rarely seen (Kyle,
Gertz, et al., 2003).
Metastatic bone survey, the
gold standard for assessing bone disease in myeloma, is able to only identity
the lytic disease where a minimum of 30% of the trabecular bone has been
destroyed, which basically renders the method somewhat insensitive. In
addition, this technique does not demonstrate response to therapy (Roodman,
2008). These limitations of the skeletal survey have led to the use of three
additional imaging techniques: CT, PET, and MRI. These three are not considered
standard of care in the diagnosis of myeloma bone disease, but can be helpful
in discerning suspicious lesions or areas of focal bone destruction. The more
sensitive CT may reveal bone lesions not seen on a metastatic bone survey,
particularly for patients who are experiencing pain. An MRI may reveal the
presence of bone marrow involvement or spinal cord compression. For patients
with nonsecretory or oligosecretory myeloma, MRI may reveal the presence and
progression of disease and provide prognostic information as discussed in the
Durie/Salmon PLUS staging system. For patients with renal insufficiency, which
occurs in 20%–60% of patients throughout their disease, care should be taken to
avoid the use of gadolinium (Angtuaco, Fassas, Walker, Sethi, & Barlogie,
2004; Kyle, Schreiman, McLeod, & Beabout, 1985; Mariette et al., 1999;
Tariman & Faiman, 2011; Tryciecky, Gottschalk, & Ludema, 1997).
Although MRI has a higher
sensitivity compared to a typical radiograph in providing anatomic information
about the bone marrow, it lacks specificity because of the small signal
strength on T1- and T2-weighted images. MRI is the diagnostic tool of choice
for spinal cord compression. CT has a higher sensitivity for smaller lesions
and is useful in detecting extraosseous extensions of the disease and to
determine bone destruction. PET scans are useful in detecting bone disease,
bone marrow infiltration, and extramedullary disease. Whole-body PET scans are
much more sensitive than x-rays and other diagnostic imaging tools. The PET
scan uses a radio-labeled sugar-based tracer called 18F-fluorodeoxyglucose
(18F-FDG) that identifies metabolically active cells. FDG is absorbed but not metabolized in the
cells and, therefore, accumulates. Areas of malignancy and infection are
metabolically more active and typically uptake the tracer at greater rates.
This provides a mechanism for imaging areas of infection or malignancy (Tryciecky
et al., 1997). The use of whole-body 18F-FDG PET, combined with either CT alone
or PET/CT, has been found to be useful in the detection of residual disease for
myeloma that has been treated and is the imaging of choice for evaluation of
extramedullary disease (Bartel et al., 2009). However, critics warn that the
PET/CT tool requires additional study before it becomes part of the standard of
care in patients with MM for the following reasons (Dimopoulos, Moulopoulos,
& Terpos, 2009).
·
PET/CT may miss small
lytic lesions and diffuse spinal involvement readily detected through use of an
MRI.
·
PET/CT have been
known to provide “false-positive” results, particularly in areas of
inflammation and infection, post-surgical sites, and vertebroplasty or other metastatic
disease.
·
Reimbursement
remains an issue.
Treatment
of Myeloma Bone Disease
The management of MM-related
bone disease involves treatment of the disease itself, which controls the
myeloma and the underlying manifestations of the disease. The most common forms
of treatment are chemotherapy and autologous stem cell transplantation (for
eligible patients). For patients with bone involvement who do not experience
bone-related pain, systemic therapy often is the primary treatment choice.
Adjuvant therapies include localized radiation, orthopedic surgical
interventions including kyphoplasty or vertebroplasty for vertebral fractures,
and the use of agents that can inhibit bone resorption, such as
bisphosphonates.
Novel Antimyeloma Agents
Novel agents used today in
the treatment of MM may positively affect bone metabolism. Management of active
MM with effective antimyeloma therapies will help to decrease the risk of
worsening bone structure and risk of fracture. However, these therapies are far
from perfect, and it now is clear that skeletal disease may progress despite
the achievement of stable disease (Kanis & McCloskey, 2000).
The proteasome inhibitor
bortezomib appears to have an effect on myeloma bone disease. It inhibits
nuclear factor kappa-B (NF-kB) activity, a critical factor for osteoclast
formation and survival. It appears to act during the initial and ending stages
of osteoclast differentiation. Several clinical trials conducted with
bortezomib have demonstrated that it may increase osteoblast activity, leading
to new bone formation, as researchers have reported an increase in bone
formation markers in some patients (Pennisi, Li, Ling, Khan, Zangari, &
Yaccoby, 2009).
The novel agent thalidomide
may halt receptor activator of NF-kB ligand (RANKL)-induced osteoclast
formation in vitro (Terpos et al., 2008). Lenalidomide, an immunomodulatory
drug (IMiD) and an analog of thalidomide that is more active with an improved
side-effect profile, decreases osteoclast formation and activity (Bolzoni et al.,
2010; Breitkreutz et al., 2008; Terpos et al., 2009). In vitro studies
demonstrate that thalidomide and the currently investigational immunomodulatory
drug pomalidomide can inhibit the osteoclast activation process (Bolzoni et
al., 2010). The effect of thalidomide combined with dexamethasone reduces bone
resorption (Roodman, 2008). The combination of bortezomib, thalidomide, and
dexamethasone reduces bone resorption and the RANKL/osteoprotegerin ratio;
however, no impact on the formation of bones was observed (Terpos et al.,
2009). Whether combining lenalidomide with bortezomib would enhance the osseous
effects of each agent alone is unknown; potentially this is a topic for future
study. As the understanding of myeloma bone biology develops, more targeted
therapies have the potential to emerge (Yeh & Berenson, 2006).
Bisphosphonates
Bisphosphonates are strong
inhibitors of bone resorption and are effective in the management of
hypercalcemia of malignancy, decrease risk of fractures, and may decrease pain
in some patients. Bisphosphonates bind to mineralized bone throughout
resorption as well as inhibit osteoclast maturation. They cause osteoclast
apoptosis as well as prevent attachment to the bone. The bisphosphonates that
generally are administered to patients with MM in the United States include
pamidronate and zoledronic acid. Both are given via IV, but the time of
infusion differs for each. Skeletal-related events can be reduced with
bisphosphonates, which decrease bone complications and improve quality of life
(Fitch & Maxwell, 2008). It also has been suggested that pamidronate has an
antimyeloma effect (Terpos & Dimopoulos, 2005); an antimyeloma effect has
recently been shown for zoledronic acid (Morgan et al., 2010).
Radiation
Myeloma cells have a high
level of sensitivity to radiation, and radiation to affected areas of bone is a
useful management modality for some patients with MM, providing local pain and
tumor control as well as preventing or treating skeletal fractures. Radiation
may be curative in patients with solitary bone plasmacytomas (Yeh &
Berenson, 2006). Unfortunately, solitary bone plasmacytoma will evolve to MM in
the majority of patients within two to three years. Fortunately, about 15%–45%
of patients will remain disease free at 10 years following diagnosis with an
overall median survival of 7–12 years (Weber, 2005). Total body irradiation was
used in the past to treat MM but, because of its severe toxicities and modest
benefit, this treatment modality is rarely used today (Hu & Yahalom, 2000).
The use of radiation should be limited as it may cause permanent bone marrow
damage in the treatment areas and compromise organ function within the
treatment fields (National Comprehensive Cancer Network, 2010; Roodman, 2008;
Yeh & Berenson, 2006).
Surgical Procedures
A large lytic lesion that is
present but has not yet progressed to a pathologic fracture may require
stabilization to prevent a fracture. A surgical procedure may become a
necessity to decrease the size of the tumor, control pain, and prevent or treat
fractures. The spine, long bones, and pelvis are the most common areas
affected. Patients with tumors affecting the long bones or weight-bearing
joints may benefit from prophylactic surgery to stabilize and restore function
to the affected bone. Intramedullary rod placement in the femur or pins and
screws may be used for surgical fixation if the bone quality is good enough to
support such hardware. Open surgical repairs, despite the invasiveness of these
procedures, may be considered even at an advanced stage of disease to prevent
impending fracture (Cady, Easson, Aboulafia, & Ferson, 2005). Stabilizing
bone before a fracture occurs is far easier, and doing so will result in less
pain and morbidity (Awan, Azer, Harrani, & Cogley, 2002).
Vertebral compression
fractures are common among patients with MM. Two additional surgical techniques
specific to the spine include percutaneous vertebroplasty and balloon
kyphoplasty. Both are minimally invasive procedures and are performed on an
outpatient basis by an interventional radiologist, orthopedic surgeon, or a
neurosurgeon. Both procedures involve using contrast guided-imaging under CT or
CT fluoroscopy and an incision of less than 1 cm to reach the anterior and
paramedian aspect of the vertebral body. In vertebroplasty, a hollow needle is
passed through the skin into the fractured vertebra and bone cement
(polymethylmethacrylate) is injected through the hollow needle into the
compressed or fractured area. Kyphoplasty is similar to verteboplasty, but a
balloon tamp is inserted into the fractured vertebral body, which then is
inflated in an attempt to restore vertebral height. The balloon is then
deflated and withdrawn, forming a cavity in the vertebral body; the cavity is
then filled with bone cement. Using balloon kyphoplasty instead of
vertebroplasty can decrease the chance of cement extravasation; vertebroplasty
does not involve restoring the structure of the collapsed vertebral body and
requires a high-pressure cement fill that can lead to leakage (Roodman, 2008).
Both procedures can provide immediate pain relief in some patients along with
improvements in functional stability and spine stabilization. A recent
randomized, controlled, open-label trial compared balloon kyphoplasty with
usual nonsurgical care in patients with cancer, including patients with MM, who
had vertebral compression fractures. Patients receiving kyphoplasty had
improved back-specific physical function, more rapid back pain relief, and
improved quality of life. Potential serious complications include cement
leakage (Berenson et al., 2011). The risk for future fractured vertebral bodies
rises in those opting for vertebroplasty or kyphoplasty as compared with
individuals not undergoing either procedure (Ludwig & Zojer, 2007).
Emerging Treatments
RANKL is required for
production and survival of osteoclasts and appears to play a role in the
process of bone destruction (Roodman, 2008). The human monoclonal antibody
denosumab binds to RANKL, preventing it from activating its receptor, RANK,
thereby blocking its effects. Denosumab is approved for use in preventing
skeletal-related events in solid tumors and is indicated for the management of
postmenopausal osteoporosis in women at increased risk for fractures. Denosumab
is not approved in the United States for administration to patients with MM,
although it currently is used in clinical trials, as are Dickkopf-related
protein 1 (DKK1) inhibitors. DKK1 and other members of the Wnt signaling
pathway are logical therapeutic targets (Roodman, 2008).
Risk
Factors Adversely Affecting Bone Health
In addition to the diagnosis
of MM, patients can have comorbid conditions that may place them at risk for
poor bone health, such as osteoporosis, metastatic malignancies, immobility,
side effects from long-term steroid and other drug use, and hormone changes.
Factors contributing to osteoporosis include renal disease, natural or
therapy-induced gonadal failure, depression, diabetes, and vitamin deficiencies
(Mauck & Clarke, 2006; Mezuk, Eaton, & Golden, 2008).
Osteoporosis and Risk of Fracture
Risk factors for osteoporosis
are numerous and can be classified as primary or secondary (Mauck & Clarke,
2006) (see Table 2). Primary causes are those that
cannot be modified (Cashman, 2007), and include female gender, increased age,
family history of osteoporosis or fracture, small or thin frame, and low levels
of sex hormones (Mauck & Clarke, 2006). Secondary causes are potentially
modifiable through medical intervention and behavioral changes; they include
nutritional deficits, chronic medical conditions, inactivity, smoking, alcohol
abuse, and certain medications (Cashman, 2007; Mauck & Clarke, 2006).
Thirty to 60% of men experience osteoporosis related to decreased gonadal
function, use of glucocorticosteroids, and alcoholism; 50% of women will
experience osteoporosis related to primary and secondary risk factors such as
decreased estrogen, glucocorticosteroid use, and hyperthyroidism (Mauck &
Clarke, 2006).
About 55% of the U.S.
population older than age 50 is at high risk for the development of
osteoporosis. An estimated 10 million individuals are affected by the disease,
with more than 34 million at risk as evidenced by low bone mass. Osteoporosis
is a chronic and progressive disease characterized by decreased bone mass,
leading to structural changes within the bone, placing an individual at a
higher risk for developing a fracture, particularity of the spine, wrist, or
hip. Osteoporosis affects four times as many women as it does men, with
significant risk seen among all ethnic backgrounds (Mauck & Clarke, 2006).
The National Osteoporosis
Foundation ([NOF], 2010) estimates that 80% of women and 20% of men older than
age 50 are affected by osteoporosis. In addition, one in two women and one in
four men will experience a fracture secondary to osteoporosis. Studies have
shown that not only does the risk for subsequent fractures increase after the
first event, but the quality of life and impact on independent activities of
daily living is dramatically reduced following a fracture (NOF, 2010). The
median age for diagnosis of MM is 66 years (Kyle & Rajkumar, 2007). MM and
other comorbid conditions (see Figure 2) increase
the risk of age-related osteoporosis and fracture.
Other Comorbid Conditions
Renal osteodystrophy: Bone loss associated with chronic renal disease is
one of the most common osseous complications of patients with MM. The bone
changes from chronic kidney disease or renal osteodystrophy can begin in adults
several years prior to the appearance of any symptoms. Management of
myeloma-related renal complications are described in Faiman, Mangan, Spong,
Tariman, and the International Myeloma Foundation Nurse Leadership Board
(2011). Patients with either osteoporosis or renal osteodystrophy experience
increased risk of fractures and resultant joint and bone pain, but renal
osteodystrophy does not necessarily respond to bisphosphonates (Legg, 2005).
Kidneys have a significant
role in the maintenance of bone mass throughout one’s life by maintaining calcium
and phosphorus levels in the blood. Patients with kidney disease may develop
hypocalcemia leading to increased stimulation of the parathyroid glands to
release PTH. The excess PTH results in osteopenia, and constant removal of
calcium over time will weaken the bones (Legg, 2005).
The kidneys also regulate
serum calcium by producing calcitriol, a form of vitamin D produced by healthy
kidneys that helps the body absorb dietary calcium. In kidney failure,
calcitriol production is decreased and the resulting hypocalcemia stimulates
the parathyroid gland to release more PTH, which contributes to further osseous
calcium loss. Nurses need to be aware that routine monitoring for serum PTH and
vitamin D should take place in patients with chronic kidney disease (Legg, 2005).
Gonadal insufficiency: Gonadal failure can be a natural part of aging or
therapy related and can affect both men and women. Postmenopausal women have a
higher risk of developing osteoporosis and risk of fracture. The loss of
estrogen results in a higher rate of bone loss (Everitt et al., 2006). Bone
mineral density (BMD) in women is estimated to decrease at over 2% annually for
the first five years following menopause, and then the rate slows, whereas the
rate of bone loss in men begins in midlife and is further reduced from 0.5%–1%
per year (Guise, 2006). Selected therapies, both surgical and medical, that
result in gonad failure and contribute to the risk of osteoporosis and risk of
fracture are listed in Table 3.
Depression:
Major depressive disorders occur in about 16% of the general population, but
more frequently in those diagnosed with cancer (Mezuk, Eaton, & Golden,
2008; Mezuk, Eaton, Golden, Wand, & Lee, 2008). People who suffer from
major depressive disorders have a lower BMD than those in control groups. The
association of depression, osteoporosis, and risk of fracture is unclear.
Physiologically, hormone levels that promote osteoclastic function and decrease
osteoblastic function, including interleukin-6, tumor necrosis factor-alpha,
PTH, C-reactive protein, and cortisol, also are elevated in those who have
major depressive disorders. Secondary risk factors may play the greatest role
because an association exists between depression and unhealthy behaviors (e.g.,
smoking, alcohol use, fatigue resulting in inactivity) (Mezuk, Eaton, &
Golden, 2008).
Diabetes:
People suffering from type 1 diabetes have decreased BMD and increased risk of
fracture, and those with type 2 diabetes also are at a higher risk for
suffering a fracture even if their BMD is normal or increased (Adami, 2009).
However, the mechanism for bone loss in these patients is not well understood
(Chau & Edelman, 2002). Patients with MM undergoing treatment with
high-dose steroids have an increased risk of developing steroid-induced
diabetes which, in turn, increases the risk of osteoporosis (Faiman, Bilotti,
Mangan, Rogers, & the International Myeloma Foundation Nurse Leadership
Board, 2008).
Cardiovascular disease: The association of osteoporosis and cardiovascular
disease in men is not well understood and may be a culmination of comorbid
conditions that place a person at risk for both conditions (e.g., inactivity,
low testosterone levels, end-stage renal disease) (Szulc, Kiel, & Delmas,
2008).
Medications
Many cancer treatment
regimens can have adverse effects on bones, resulting in more rapid and severe
bone loss than seen in primary causes of osteoporosis in men and women (Guise,
2006; Melton et al., 2005). In addition,
many comorbid conditions are treated with pharmacotherapy, which also may
contribute to osteoporosis and risk of fracture. Figure
3 lists drugs that may predispose patients to osteoporosis, putting them at
a higher risk for fracture.
Steroids:
Glucocorticoids (dexamethasone or prednisone) remain a backbone of antimyeloma
therapy. Steroids kill myeloma cells directly and may enhance the efficacy of
other myeloma drugs when used in combination. However, steroid use may result
in osteopenia or osteoporosis by inhibiting or killing osteoblasts, stimulating
bone resorption, inhibiting calcium absorption, and increasing calcium
excretion. Steroid use also is associated with avascular necrosis or
osteonecrosis (Faiman et al., 2008).
Antidepressants: Antidepressant medications such as selective serotonin reuptake
inhibitors and tricyclic antidepressants have been implicated in increased risk
of fractures. Current use of antidepressants plays a greater role in risk of
fracture than previous use and may be age- and life-stage dependent (Mezuk,
Eaton, & Golden, 2008).
Bone Marrow Transplantation
Multiple small studies
evaluating BMD following autologous and allogeneic bone marrow transplantation
report that bone loss is a common side effect. Few long-term studies are
available, but disturbance in bone metabolism and reduced BMD is measurable
years after the procedure. The mechanism is not completely understood, however,
alteration of the osteoprotegerin/RANKL system may play a significant role
(Ebeling et al., 1999; Kang et al., 2000; Kerschan-Schindl et al., 2004; Lee,
Cho, et al., 2002, Lee, Kang, et al., 2002). Interestingly, one small study
(Kielholz et al., 1997) of 29 patients who underwent autologous bone marrow or
peripheral blood transplantation following high-dose chemotherapy showed that
they did not have significant osteopenia despite high-dose steroids, prolonged
inactivity, and decreased estrogen levels. The lowest BMD was seen in men who
had the lowest testosterone levels. Because this was a follow-up study of
patients who were five years post-transplantation, these unexpected results may
be from recovery of endocrine function during that time. With such a small
cohort of patients, however, additional investigation is warranted before
making any conclusions (Kielholz et al., 1997).
Diet
Although diet is considered a
secondary risk factor for osteoporosis and risk of fracture, the peak bone
mass, which is reached in youth, is not modifiable in adults. About 90% of bone
mass is established within the first two decades of life and, most
significantly, during puberty (Cashman, 2007). Vitamins and nutrients important
for bone mineralization and skeletal development are listed in Table 4. Vitamin D and calcium are required during
development and throughout life to promote bone health (Everitt et al., 2006).
Maximizing serum vitamin D levels, as measured by 25-hydroxyvitamin D (25-OHD),
contributes to an increase in BMD and is associated with improved muscle
strength, resulting in a 20% decreased risk of fracture in older adults.
Bischoff-Ferrari (2007) stated that optimal levels of serum 25-OHD are between
90 and 100 nmol/L. Inadequate levels of vitamin D cause elevation of PTH that
can lead to decreased BMD (Bischoff-Ferrari, 2007; Mauck & Clarke, 2006).
Evidence shows that increased levels of vitamin K reduce the risk of fracture.
Phytoestrogens, found naturally in plant-based products such as soy, are a
nonsteroidal compound that may act as a safe hormone replacement therapy for
postmenopausal women (Cashman, 2007). Smoking and use of alcohol (more than two
drinks per day) are both associated with decreased bone cell proliferation
related to impaired absorption of calcium in the intestine (Mauck & Clarke,
2006; Mezuk, Eaton, Golden, Wand, et al., 2008). Consumption of excess or
insufficient amounts of protein, vitamin A, and phosphorus can have positive or
negative effects on bone health, depending on their renal effects.
Paradoxically, obesity has a positive effect on BMD (Cashman, 2007; Everitt et
al., 2006), even in those patients considered to be inactive. Weight-bearing
activity promotes bone density, so the additional body mass contributes to bone
strength (Everitt et al., 2006; Mauck & Clarke, 2006; Mezuk, Eaton, &
Golden, 2008). However, the comorbid conditions associated with obesity make this
a counterproductive approach to promoting bone health.
MM occurs more frequently in
African Americans than in other racial or ethnic groups (Kyle & Rajkumar,
2007). African Americans have lower serum levels of vitamin D, which may place
individuals at increased risk of fracture. Although the risk of falling is
similar to Caucasians, the risk of fracture is lower. This process is not fully
understood, but possible elements protecting African Americans include
increased rates of obesity, bone composition, remodeling, and inherited factors
(Aloia, 2008).
Evidence-Based
Recommendations to Manage and Maintain Bone Health
Comorbidities and concomitant
risk factors, such as age, gender, medications, and mobility, should be
considered when developing a treatment plan and will influence the approach
taken for each patient (see Figure 4). In addition
to mobility and exercise, which are discussed in depth in another article in
this supplement (Rome et al., 2011), nurses can assist patients to manage their
bone health by maintaining proper diet and nutrition, undergoing radiation
treatment or surgical procedures when necessary, and safely taking
bisphosphonates and pain medications where appropriate.
Diet and Supplements
Only general recommendations
exist in regard to diet, supplements, and bone health in MM. Clinicians should
encourage patients to eat well-balanced diets comprising fruits, vegetables,
protein, and carbohydrates. Most nutritional supplements are safe in
moderation; however, based on preclinical evidence, the Nurse Leadership Board
suggests the following compounds be used with caution by patients receiving
bortezomib. Vitamin C interferes with the ability of bortezomib to kill human
cancer cell lines in culture, apparently by binding to bortezomib and inactivating
it (Zou et al., 2006). Alpha lipoic acid, often recommended for the treatment
of peripheral neuropathy, has been shown to interfere with antimyeloma effects
of bortezomib in myeloma cell lines (Steinberg et al., 2009). In addition,
preclinical (in vitro and in vivo) research demonstrated tumor cell death
caused by bortezomib may be negated by the use of green tea (Golden et al.,
2009). Although additional research is warranted, and no clinical evidence
exists, the International Myeloma Foundation Nurse Leadership Board recommends
avoidance of vitamin C, alpha lipoic acid, and green tea on the day of
bortezomib therapy.
Calcium and vitamin D
supplementation is advised for all patients with osteopenia or osteoporosis,
particularly if they are receiving bisphosphonates such as pamidronate or
zoledronic acid. The NOF’s recommendations for calcium and vitamin D
supplementation are provided at
http://nof.org/aboutosteoporosis/prevention/calcium.
In summary, for people older
than age 50, 1,200 mg of calcium and 800–1,000 IU of vitamin D daily are
recommended. Those younger than age 50 do no require as much, with 1,000 mg of
calcium and 400–800 IU of vitamin D daily recommended. Of note, however,
individuals with hypercalcemia or renal insufficiency should not take calcium
replacement (NOF, 2010), both of which may be concerns for patients with MM. A
discussion with a healthcare provider should take place.
Radiation as Treatment for Bone Disease
Care of patients receiving
radiation for local pain and tumor control includes alleviating side effects
related to the radiated field. The potential for side effects is dose
dependent. External beam doses can range from 600–800 cGy hemi-body irradiation
for palliation of generalized pain, 3,000 cGy for a localized painful bone
lesion, and to 4,500 cGy for tumor control. Patients receiving lower-dose
radiation for pain palliation have less potential for side effects, but all
should be monitored closely (Terpos & Dimopoulos, 2005). For example,
patients with head and neck radiation may have trouble eating and swallowing
and may experience mouth sores. For these patients, good oral hygiene is
necessary to prevent mouth sores and decrease the risk of infections. Pain
medication may be indicated if severe mouth sores or radiation burns to the
skin develop. Individuals who receive mediastinal, thoracic, or lumbar spine
radiation may develop nausea, loss of appetite, or vomiting. Assessment of
hydration and calorie counts and evaluation by a dietitian may be necessary if
intake is compromised. All patients receiving cumulative external beam
radiation therapy may be at risk for radiation dermatitis and are encouraged to
keep their skin well hydrated with nonalcohol lotions applied after radiation
(Berkey, 2010).
Other common side effects of
radiation include fatigue and pain. Patients should be made aware of fatigue as
a side effect and be educated about managing their activities. Pain medication
may be warranted because individuals are required to remain in an uncomfortable
position during the radiation treatment. Opioid or nonopioid analgesics may
enhance comfort during and after radiation treatment. A baseline and ongoing
pain assessment is integral to the patient’s plan of care.
Vertebroplasty or Kyphoplasty
Several studies suggest
balloon kyphoplasty and vertebroplasty are effective in reducing pain scores
associated with vertebral compression fracture, but each procedure has
associated risks. Potential risk is related to the cement injection resulting
in extravasation and causing nerve damage or other neurologic issues. General
risks include those associated with any surgical procedure, namely increased
risk of bleeding and infection. Although minimal blood loss occurs with
vertebroplasty and balloon kyphoplasty, this risk increases if patients are
thrombocytopenic or are receiving low molecular weight heparin, heparin,
warfarin, or antiplatelet agents, aspirin, or nonsteroidal anti-inflammatory
drugs (NSAIDs). Although specific recommendations are not documented, practices
followed by Nurse Leadership Board members at their institutions include
stopping aspirin and NSAIDs seven days prior to the procedure. Management
should be patient specific. Therapeutic anticoagulation should be bridged from
warfarin to low molecular weight heparin or heparin, and this should be stopped
within six hours of the procedure. Baseline complete blood count, including
platelets, white blood count differential, and coagulation studies such as
prothrombin time, international normalized ratio, and partial thromboplastin
time may be indicated.
Infection risk could rise
because of a low white blood cell count as a result of marrow infiltration by
myeloma or as a result of the treatment itself. Clinicians should assess
complete blood count with white blood cell differential if patients are
receiving myelosuppressive antimyeloma treatment.
Mobility and exercise can be
encouraged almost immediately after the procedure. The cement used creates an
internal cast that hardens within minutes. Patients can resume their usual
activities and, if this procedure proves effective at decreasing pain, patients
can be weaned off pain medications gradually. The use of slings and orthotic
braces are not usually encouraged unless used in preparation for planned
surgical intervention because they may reduce mobility and lead to osteopenia
(Tariman & Estrella, 2005).
Bisphosphonates
Bisphosphonates should be
administered monthly for a total duration of two years in individuals with
lytic lesions or osteoporosis. The International Myeloma Working Group suggests
that using pamidronate or zoledronic acid decreases the risk of
skeletal-related events, but the optimal duration of bisphosphonates therapy is
unknown (Durie et al., 2007). In patients achieving very good partial response
or better from their initial treatment as defined as greater than a 90%
reduction in serum or urine paraprotein, bisphosphonates should be given on a
monthly basis for one year. Although clear evidence does not exist for modified
administration, the International Myeloma Working Group members have agreed
that patients should continue bisphosphonates use if they have active bone
disease or achieve less than a very good partial response to treatment. If,
after two years, the patient does not have evidence of active bone disease,
bisphosphonate use may be discontinued. Bisphosphonates should be resumed at
the time of relapse if they were discontinued (Durie et al., 2007; Kyle et al.,
2007).
Although the aim is to reduce
skeletal-related events, bisphosphonates can have adverse effects. Side effects
of bisphosphonates include acute phase reactions, a small but increased risk of
osteonecrosis of the jaw (ONJ), and renal impairment (Maxwell, Swift, Goode,
Doane, & Rogers, 2003). Acute phase reactions present as flu-like symptoms
after the bisphosphonate infusion. These symptoms can be decreased with the use
of acetaminophen. Other side effects include nausea, fatigue, and bone pain.
Monitoring and surveillance
for ONJ is necessary. ONJ is an uncommon but serious condition usually
involving the maxilla or mandible that may occur with prolonged use of
bisphosphonates. The incidence is relatively low, at 2%–10%. Signs of ONJ may
include jaw or tooth pain, and exposed bone may be identified on physical
examination. If ONJ symptoms occur, initial treatment should be with antibiotic
therapy and not surgical procedures (Cafro et al., 2008). ONJ is thought to be
an infectious process, and the use of antibiotic prophylaxis for dental
procedures has been studied. The Italian Myeloma Group evaluated patients
receiving either amoxicillin-clavulanate 2 g per day by mouth, levofloxacin 500
mg per day by mouth, beginning a day prior, up to three days after a dental
procedure, or standard care (no antibiotics). In patients receiving antibiotic
prophylaxis with amoxicillin-clavulanate, a decreased incidence of infection
with dental procedures such as cleaning, implants, and extractions was noted.
More studies are required to validate these findings (Montefusco et al., 2008).
Prevention of ONJ is
important, and good dental hygiene is integral to the prevention of ONJ in
patients with MM. Patients should receive baseline and routine dental
examinations every six months. In addition, dentures should fit well because
poor-fitting dentures increase the risk of ONJ (Vahtsevanos et al., 2009).
Patients should advise their dental care providers when they are receiving
bisphosphonates.
Renal impairment is common in
patients with MM. Precautions concerning the use of bisphosphonates in patients
with renal impairment are discussed in Faiman et al. (2011).
Pain Management
Damage to bones as a result
of MM often causes pain; effective doses of analgesia should be administered
for patient comfort and to increase mobility and quality of life. A good pain
history is essential to assessing the quality and character of a patient’s
pain. The pain assessment includes asking a patient about the following.
· Onset: When did it start? Was trauma involved?
· Location: Where is it located?
· Quality: Dull, sharp, burning, or stabbing?
· Duration: How long have you had this pain?
· Character: Is it present when you sit or move? All the
time or some of the time?
In addition, patients should
be asked to rate their pain according to a pain scale. One of the most common
scales is a 1–10 rating system with 1 as minimal pain and 10 as the worst pain.
Treatment of the pain with analgesics can be accomplished by using the World
Health Organization (2009) pain ladder. Additional management strategies
include the use of bisphosphonates and systemic antimyeloma therapy that may
have a marked effect on bone pain.
Bone pain from MM can be
challenging to control because it usually occurs when patients change position
or walk and is often called “incident pain.” Three main types of analgesia are
used to treat bone pain and other types of pain related to MM and include
nonopioid analgesics, opioid analgesics, and adjunct medications. Nonopioid
analgesia includes acetaminophen, NSAIDs, and aspirin. Use of NSAIDs is
discouraged because of the risk of renal injury. Many opioid analgesics exist
and also can decrease pain, but at the expense of sedation and the risk of
constipation. Neuropathic pain often is present after nerve-related injuries
such as in peripheral neuropathy, post-herpetic neuralgia, or spinal canal
compromise and often is described as “burning or shooting” in character.
Medications such as gabapentin or pregabalin, or tricyclic antidepressants such
as amitriptyline, can be helpful in decreasing this type of pain (Levy, 1996).
Systemic antimyeloma therapy and the use of bisphosphonates will not be
effective in reducing pain in some patients, and this group may require bracing
or surgical intervention.
Effective pain management is
imperative because the psychosocial aspects of pain can lead to depression and
anxiety. In addition, uncontrolled pain will result in immobility and muscle
and bone wasting, in turn leading to increased risks of atelectasis, pneumonia,
and venous thromboembolism. Healthcare providers must recognize this,
diligently monitor pain scores, and prescribe analgesia to combat these
deleterious side effects (Coleman, 2000).
Patient
and Family Education
Nurses play an important role
in educating patients as well as promoting functional independence. Activity
can decrease fatigue as well as improve mood and prevent insomnia. However,
even simple activities can be difficult for patients with pain. All patients
must have effective pain management. Patients should be educated regarding the
use of NSAIDs and narcotics as educated patients are more likely to adhere to
their therapy. Because bone disease can be debilitating throughout the
continuum of treatment, a dire need exists to instruct and educate patients and
their caregivers regarding the signs and symptoms of depression and anxiety.
Interdisciplinary collaboration may be required in the education of the
patient. All patients will have varying needs for education regarding their
bone health; emphasis on the benefits of treatment will assist patients in
adhering to their therapy.
Educational opportunities
include the following.
·
Using
evidence-based recommendations to promote behaviors that enhance bone health
·
Instructing
patients on how to rate pain using a pain scale
·
Informing
patients about symptoms of hypercalcemia, a complication of bone disease that
includes lethargy, nausea, confusion, thirst, and constipation
·
Enforcing the
need for bisphosphonate use; advocating good oral hygiene while patients are
receiving bisphosphonates
·
Referring patients
to a clinical social worker or psychiatrist to identify anxiety and depression
if necessary
·
Counseling to
encourage continued adherence to pharmacologic regimens and exercise programs
Useful resources and tools
for patients and caregivers, as well as nurses and other healthcare providers,
can be obtained from the International Myeloma Foundation at www.myeloma.org.
Conclusion
Recent research in myeloma
and the advent of novel agents has led to increased response rates and improved
survival. Bone disease as a prognostic indicator and therapies directed at bone
disease may alter future treatment regimens and outcomes. Supportive care and
the management of bone disease are of the utmost importance to alleviate
bone-related sequelae, enhance mobility and disease response, and promote
quality of life. Oncology nurses and other healthcare providers play a crucial
part in assessing and managing myeloma, along with educating patients, as they
live longer and continue to experience both disease- and treatment-related
complications.
The authors gratefully acknowledge Brian G.M. Durie,
MD, and Robert A. Kyle, MD, for critical review of the manuscript; Lynne
Lederman, PhD, medical writer for the International Myeloma Foundation, for
preparation of the manuscript; and Lakshmi Kamath, PhD, at ScienceFirst, LLC,
for assistance in preparation of the manuscript.
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Teresa S. Miceli, RN, BSN, OCN®, is the
bone marrow transplant RN coordinator at the Mayo Clinic in Rochester, MN;
Kathleen Colson, RN, BSN, BS, is a clinical research nurse in the Jerome Lipper
Multiple Myeloma Center at Dana-Farber Cancer Institute in Boston, MA; Beth M.
Faiman, MSN, APRN-BC, AOCN®, is a nurse practitioner in the
Hematology and Medical Oncology Department at the Cleveland Clinic in Ohio;
Kena Miller, RN, MSN, FNP, is a nurse practitioner in the Department of
Medicine, Lymphoma/Myeloma Division, at Roswell Park Cancer Institute in
Buffalo, NY; and Joseph D. Tariman, PhD, APRN, BC, is an advanced practice
nurse in the myeloma program at Northwestern University in Chicago, IL. The
authors take full responsibility for the content of this article. Publication
of this supplement was made possible through an unrestricted educational grant
to the International Myeloma Foundation from Celgene Corp. and Millennium: The
Takeda Oncology Company. Colson is a consultant with Merck & Co., Inc., and
Millennium: The Takeda Oncology Company; Faiman is a consultant and on the
speakers bureau at Celgene Corp. and Millennium: The Takeda Oncology Company;
Miller is on the advisory board and speakers bureau at Celgene Corp. and
Millennium: The Takeda Oncology Company; and Tariman is a consultant with
Millennium: The Takeda Oncology Company. The content of this article has been
reviewed by independent peer reviewers to ensure that it is balanced,
objective, and free from commercial bias. No financial relationships relevant
to the content of this article have been disclosed by independent peer
reviewers or editorial staff. (First submission February 2011. Revision submitted
March 30, 2011. Accepted for publication April 5, 2011.)
Author Contact: Teresa S.
Miceli, RN, BSN, OCN®, can be reached at miceli.teresa@mayo.edu, with copy to
editor at CJONEditor@ons.org.
