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Osteoporosis in Breast and Prostate Cancer Survivors

Osteoporosis in Breast and Prostate Cancer Survivors

ABSTRACT: Recent advances in treatment modalities for breast and prostate cancer have resulted in an increasing number of patients that are cured or that, despite residual disease, live long enough to start experiencing complications from cancer treatment. Osteoporosis is one such problem that has been increasingly identified in cancer patients. Hypogonadism and glucocorticoid use are the two major causes of bone loss in these patients. Osteoporosis is characterized by low bone mass and abnormal bone microarchitecture, which results in an increased risk of fractures. Vertebral body and hip fractures commonly result in a drastic change of quality of life as they can result in disabling chronic pain, loss of mobility, and loss of independence in performing routine daily activities, as well as in increased mortality. In patients with prostate carcinoma, androgen-deprivation therapy by either treatment with a gonadotropin-releasing hormone (GnRH) or bilateral orchiectomy results in increased bone turnover, significant bone loss, and increased risk of fractures. Patients with breast cancer are at increased risk for estrogen deficiency due to age-related menopause, ovarian failure from systemic chemotherapy, or from the use of drugs such as aromatase inhibitors and GnRH analogs. Several studies have indicated that the prevalence of fractures is higher in breast and prostate cancer patients compared to the general population. Therefore, patients at risk for bone loss should have an assessment of their bone mineral density so that prevention or therapeutic interventions are instituted at an early enough stage to prevent fractures. This article will address the characteristics of bone loss observed in breast and prostate cancer patients and potential treatments.

Advances in the medical treatment
of breast and prostate
cancer have improved cure
rates or disease-free survival. Increasing
longevity has resulted in the emergence
of medical problems associated
with the malignancy or caused by the
oncologic treatment. Bone loss is one
such complication. In breast and prostate
cancer patients, hypogonadism is
the predominant cause of bone loss.
In breast cancer patients, estrogen deficiency
caused by premature ovarian
failure, a result of systemic chemotherapy,
or from drugs such as aromatase
inhibitors or GnRH analogs
causes bone loss.[1-5] Acute estrogen
deficiency results in higher bone turnover
and rapid bone loss, at a rate greater
than that seen during natural menopause.[
4] In patients with prostate cancer,
hypogonadism as a result of
androgen-deprivation therapy also leads
to higher bone turnover, bone loss, and
increased risk of fractures.[6-8]

The aim of this review is to discuss
the known frequency, magnitude, and
mechanisms of bone loss observed in
breast and prostate cancer patients, as
well as to summarize the current recommendations
on how to prevent bone
loss or treat patients with osteoporosis.

Definition and Diagnosis of
Osteoporosis

Osteoporosis is defined as a metabolic
bone disease characterized by
low bone mass and microarchitectural
deterioration of bone tissue, leading
to enhanced bone fragility and
increased risk of fractures.[9] Vertebral
body and hip fractures commonly
result in a significant change in
quality of life; they cause chronic pain,
loss of mobility, and loss of independence
in performing daily activities.
Hip fracture is the most devastating
complication of osteoporosis. Epidemiologic
studies show clearly that survival
probability is reduced
dramatically, at any age over 60
years,[10] suggesting that untreated
osteoporosis could have an independent
effect on survival in women with
breast cancer. There are similar and
even more striking results for men
with hip or vertebral fractures.[10]
Therefore it is important to evaluate
bone mass in hypogonadal patients
and initiate therapy for those at risk.

Bone mass can be measured by
several noninvasive methods. These
include dual-energy x-ray absorptiometry
(DXA), quantitative computed
tomography scan (QCT), and
ultrasound. The method of choice is
DXA, as it is easily accessible, provides
low radiation exposure, and has
good precision. It can be used to diagnose
osteopenia or osteoporosis, to
determine fracture risk, and to monitor
response to therapy.

The definition of normal bone
mass, osteopenia, or osteoporosis is
based on the World Health Organization
(WHO) criteria. Risk is defined
by comparing an individual patient's
bone mineral density (BMD) with an
age, sex, and ethnically appropriate
population. Osteoporosis is defined
as a BMD ≥ 2.5 standard deviations
(SD) below average peak adult bone
mass. This is designated as a T score
of -2.5 or less (Table 1). A higher
BMD, but one that is less than normal
(-1 to -2.5), is defined as osteopenia.
These patients do not currently have a
greater risk of fractures, but nevertheless
form a high-risk population for
future fractures.[11]

Both DXA and QCT can measure
BMD of the spine and hips (central
DXA or QCT) or BMD of peripheral
sites such as the forearm (pDXA or
pQCT). Measurement of spine and
hip BMD is the gold standard for diagnosis
and monitoring of osteoporosis,
while peripheral measurements are
performed mainly for screening purposes.
Quantitative computed tomography
is a more sensitive but less
precise method than DXA for diagnosing
osteoporosis in men. In older
men, osteophytes or facet sclerosis of
the posterior elements may increase
the spine BMD values.[12] Therefore,
whenever possible DXA measurements
of other sites or QCT of the
spine should be performed in older
individuals.

The most common cause of osteoporosis
in women, including women
with breast cancer, is estrogen
deficiency. In postmenopausal osteoporosis,
there is an increased rate
of bone remodeling and an imbalance
between bone resorption and bone formation
that results in a net loss of
bone.[13,14] Bone loss in postmenopausal
women occurs in two phases.[
15] In the first 5 years after
menopause there is a rapid phase of
bone loss (about 3%/yr in the spine)
followed by a phase of slower rate of
bone loss (about 0.5%/yr) that occurs
not only at the spine but also at other
sites. The slower phase of bone loss
starts at around age 55 in both men
and women.

Other than gonadal function, vitamin
D and calcium deficiencies are
common problems in older individuals.[
15] Approximately 30% to 50%
of older individuals have subnormal
plasma vitamin D concentration. Other
contributors to bone loss in cancer
patients that are less well-defined include
direct effects of chemotherapy
agents on bone cells, reduced physical
activity, exposure to corticosteroids,
and deficient dietary calcium
intake. It is important for the oncologist
or internist following this group
of patients to recognize that it is a
series of small but additive medical
and lifestyle changes that contribute
to the steady decline in bone mass.
The corollary is that it is not inevitable:
simple preventive measures will
have profound long-term effects.

The increased bone remodeling in
sex steroid hormone deficiency causes
deregulation of cytokines, hormones,
and growth factors present in the bone
microenvironment. These changes result
in activation of osteoclastic bone
resorption and bone loss. To better understand
the mechanisms of bone loss
and the rationale for the use of specific
pharmacologic agents to prevent and
treat osteoporosis, we will discuss how
bone is remodeled in normal and sex
steroid-deficient states.

Bone Remodeling

The adult skeleton is in a dynamic
state, constantly being renewed in a
continuous and coordinated fashion
throughout life to maintain the structure
and quality of bone. Bone remodeling,
also termed bone turnover, occurs
simultaneously in tens of thousands of
skeletal areas. Each of these areas is
called a bone-remodeling unit.[16]

The initiating event in remodeling
at each of these bone-remodeling units
is the differentiation of monocytic
cells into multinucleated cells called
osteoclasts. These cells bind tightly to
bone, produce acid and proteolytic
enzymes, and cause the resorption of
mineral and bone protein, creating a
resorption lacuna of uniform size and
depth. The osteoclast is then replaced
with scavenger cells to clean up resorbed
material, followed by osteoblasts
or bone-forming cells. These
cells lay down multiple layers of type 1
collagen that is mineralized to form
new bone. This entire process takes 3
to 4 months. Most importantly, this
process makes it possible to repair microfractures
that result from normal
minor trauma or other "wear and tear"
to the skeleton. Normal bone remodeling
is a balanced event: bone resorption
is equaled by bone formation.

The remodeling process occurs
under control of several hormones and
cytokines that are active within the
bone microenvironment.[13] These
include estrogen, testosterone, parathyroid
hormone, and growth hormone.
Other important factors include
vitamin D, interleukins (IL-1, IL-4,
IL-6, IL-7, IL-11, IL-17), transforming
growth factor-beta (TGF-beta),
tumor necrosis factor-alpha (TNF-alpha),
prostaglandin E2, and the receptor
activator of nuclear factor kappaB
ligand (RANKL).[17,18] RANKL is
a critical cytokine for osteoclastogenesis.
It is expressed by osteoblasts and
binds to the receptor activator of nuclear
factor kappaB (RANK) present
on the surface of osteoclasts precursors
and mature osteoclasts. The
RANKL/RANK interaction is responsible
for differentiation of monocytes
to osteoclasts and activates bone resorption
by the mature osteoclast.

Osteoprotegerin (OPG) is a decoy
receptor, expressed by osteoblasts, that
binds RANKL thereby preventing
RANKL from activating RANK.[19]
The balance between RANKL and
OPG is essential for normal bone remodeling.
Overexpression of RANKL
will result in increased bone resorption
and osteoporosis; overexpression
of OPG will result in inhibition of
bone resorption and osteopetrosis.[18]
Alteration in the RANKL/OPG ratio
has been observed in several conditions
associated with osteoporosis,
including estrogen deficiency, corticosteroid
use, hyperparathyroidism,
rheumatoid arthritis, multiple myeloma,
osteolytic bone metastases, and
humoral hypercalcemia of malignancy.[
18] In most of these disorders there
is overexpression of RANKL and
decreased production or increased
degradation of OPG.

Estrogen deficiency can result in
an increase of the RANKL/OPG ratio.
Eghbali-Fatourechi and colleagues
showed that the RANKL level was
higher in marrow stromal cells and
lymphocytes of postmenopausal women
as compared to premenopausal
women; RANKL expression was inversely
correlated with estrogen levels.[
20] These findings demonstrate
the important role of the OPG/
RANKL/RANK system in mediating
estrogen deficiency-induced bone resorption.
As estrogen deficiency is the
main cause of bone loss in breast cancer
patients, one could postulate that
the OPG/RANKL/RANK system
plays an important role in the mechanism
of bone loss in these patients. In
fact, the effect of a monoclonal antibody
against RANKL, which functions
to prevent the RANKL-RANK
interaction, is under investigation as a
therapeutic agent to inhibit bone loss
in estrogen-deficient breast cancer
patients.

In clinical practice, bone resorption
and formation are easily quantified.
Table 2 shows several readily
available markers of formation and
resorption. The formation markers include
bone proteins incorporated into
the matrix (osteocalcin or collagen)
or enzymes involved in mineralization
(alkaline phosphatase). All bone
resorption markers are fragments of
bone-specific collagen released by the
osteoclast.[21]

Bone Loss in Breast
Cancer Patients

Breast cancer is the most common
malignancy in women, with an estimated
40,410 new cases in the United
States predicted for 2005.[22] Early
detection and improved treatment modalities
have resulted in a significant
improvement of disease-free and overall
survival. More than 90% of patients
with early-stage breast cancer are alive
10 years after diagnosis,[23] a survival
improvement that is mainly due to advances
in adjuvant chemotherapy and
radiation therapy. Unfortunately, adjuvant
systemic chemotherapy can induce
ovarian failure in premenopausal
patients with early breast cancer and
exacerbate the expected bone loss in
postmenopausal patients.

Premature menopause occurs in
50% to 85% of patients treated with
adjuvant chemotherapy regimens that
include cyclophosphamide, metho
trexate, fluorouracil, and doxorubicin.[
1] The effect of chemotherapy
(cyclophosphamide-based) on ovarian
function is dose- and age-dependent.
The frequency of ovarian failure
rises as patients approach the natural
age of menopause, reaching nearly
100% by the age of 50 years.[1] A
few studies have investigated the magnitude
and frequency of bone loss in
patients undergoing adjuvant chemotherapy
(Table 3). All highlight the
tight correlation between development
of ovarian failure and bone loss.

Shapiro and colleagues investigated
the BMD and markers of bone
turnover (osteocalcin, bone alkaline
phosphatase) at baseline, 6 months,
and 12 months in 49 patients receiving
adjuvant systemic chemotherapy.
Patients who developed ovarian failure
lost 4% BMD in the lumbar spine
at 6 months and an additional 3.7%
bone loss at 12 months. The bone loss
was accompanied by a significant increase
of serum osteocalcin and bonespecific
alkaline phosphatase. In
contrast, no significant bone loss was
observed in patients who had maintained
normal ovarian function.[4]
This has been corroborated in other
studies.

Headley and colleagues evaluated
27 patients with breast cancer treated
with adjuvant chemotherapy who
were premenopausal at the time of
diagnosis.[2] The BMD was assessed
2 years after treatment with adjuvant
chemotherapy. Patients who became
amenorrheic (16) had a BMD 14%
lower than patients with intact ovarian
function.

Another study by Vehmanen and
colleagues evaluated the long-term
impact of chemotherapy-induced ovarian
failure on bone mineral density.[
3] This study involved 75 patients
who received adjuvant chemotherapy
for breast cancer. Patients who developed
ovarian failure suffered a 12%
reduction of lumbar spine BMD 5
years later, while patients who maintained
gonadal function lost 3%.[3]
Most of the other studies are retrospective
and involved fewer numbers
of patients. Collectively, these studies
have included a small number of
patients followed for short periods;
accordingly there is no substantial information
on fracture prevalence in
this group of patients.

One study by Kanis and colleagues[
24] investigated the incidence
of osteoporotic fractures in patients with
breast cancer as a subprotocol of two
trials designed to assess the effect of
clodronate on the incidence of skeletal
metastases. The authors followed three
groups of patients for 3 years: newly
diagnosed breast cancer patients (356),
healthy controls (776), and patients presenting
with soft-tissue recurrence (82).
They performed x-rays of the spine at
baseline and every 6 months. The annual
incidence of vertebral fracture was
higher in any of the breast cancer groups
compared to healthy controls: 19% in
patients with recurrent disease, 2.7% in
patients presenting with newly diagnosed
disease, and 0.5% in controls.[24]

Adjuvant hormonal treatment has
resulted in significant improvement
in disease-free and overall survival
for women with hormone receptor-
positive breast cancer.[25] For several
years tamoxifen was the standard
hormonal treatment in postmenopausal
women. Recently, several multicenter,
randomized, phase III adjuvant
trials have compared the new generation
of aromatase inhibitors to tamoxifen
or placebo following tamoxifen
therapy (5 or fewer years). These trials
include the ATAC trial, comparing
initial therapy with anastrozole
(Arimidex) to tamoxifen[26]; the MA-
17 trial, which evaluated the effects
of letrozole (Femara) vs placebo[27]
after 5 years of tamoxifen; and the
Intergroup Exemestane Study, which
included women treated with tamoxifen
for 2 to 3 years, randomized to
complete 5 years of tamoxifen or 2 to
3 years of exemestane (Aromasin).[
28] In all of these trials, treatment
with an aromatase inhibitor was
superior to tamoxifen, providing a
lower risk of tumor recurrence and
better disease-free survival.

Treatment with aromatase inhibitors
rather than tamoxifen has become
the preferred primary form of therapy
for women with hormone receptor-
positive breast cancer. As the aromatase
inhibitors cause a marked
reduction in the circulating levels of
estrogen, it is expected that they will
exacerbate bone loss in postmenopausal
patients. This is of concern as
many of these patients have already
suffered accelerated bone loss from
premature menopause, and rather than
being treated with tamoxifen-a drug
that maintains bone mass in postmenopausal
women-are placed on aromatase
inhibitors that result in further
bone loss.

Information regarding the effects
of aromatase inhibitors on bone mass
is still limited. The best information
available to date can be obtained from
a substudy of the ATAC trial.[5] In
this study 308 patients underwent a
BMD study at baseline and after 1
and 2 years of treatment. Patients who
received anastrozole lost 4% of bone
mass at the lumbar spine at 2 years
while no bone loss was observed in
other groups. In addition, the number
of fractures was higher in patients who
received anastrozole.[5] Therefore, in
contrast to tamoxifen, which has beneficial
effects to the bone mass of
postmenopausal women,[29-31] anastrozole
has been shown to result in
bone loss and to increase the risk of
fractures.[5]

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