Skeletal sequelae of cancer and cancer treatment
Charles J. Stava & Camilo Jimenez & Mimi I. Hu &
Received: 10 September 2008 /Accepted: 5 March 2009
# Springer Science + Business Media, LLC 2009
Introduction Survivors of cancer may experience lingering
adverse skeletal effects such as osteoporosis and osteoma-
lacia. Skeletal disorders are often associated with advancing
age, but these effects can be exacerbated by exposure to
cancer and its treatment. This review will explore the cancer
and cancer treatment-related causes of skeletal disorders.
Methods We performed a comprehensive search, using
various Internet-based medical search engines such as
PubMed, Medline Plus, Scopus, and Google Scholar, for
published articles on the skeletal effects of cancer and
Results One-hundred-forty-two publications, including jour-
nal articles, books, and book chapters, met the inclusion
criteria. They included case reports, literature reviews,
systematic analyses, and cohort reports. Skeletal effects
resulting from cancer and cancer therapies, including hypo-
gonadism, androgen deprivation therapy, estrogen suppres-
sion, glucocorticoids/corticosteroids, methotrexate, megestrol
acetate, platinum compounds, cyclophosphamide, doxorubi-
cin, interferon-alpha, valproic acid, cyclosporine, vitamin A,
NSAIDS, estramustine, ifosfamide, radiotherapy, and com-
bined chemotherapeutic regimens, were identified and
described. Skeletal effects of hyperparathyroidism, vitamin D
deficiency, gastrectomy, hypophosphatemia, and hyperprolac-
tinemia resulting from cancer therapies were also described.
Discussion/Conclusions The publications researched during
this review both highlight and emphasize the association
between cancer therapies, including chemotherapy and
radiotherapy, and skeletal dysfunction.
Implications for cancer survivors These studies confirm
that cancer survivors experience a more rapid acceleration
of bone loss than their age-matched peers who were never
diagnosed with cancer. Further studies are needed to better
address the skeletal needs of cancer survivors.
Cancer survivors have become an important component of
mainstream society, as nearly 4% of the United States
population has been diagnosed with cancer and survived
. Following great innovations in therapy and detection,
the number of cancer survivors has grown to more than 10.8
million individuals. Therapy regimens used to treat cancer
have undergone tremendous change over the past four
decades, and adjuvant chemotherapy and hormone therapy
have become more widely used. Toxic chemotherapeutic
drugs, radiotherapy, surgery, hormone therapy, and tumor
activity itself may result in undesired long-term effects,
including cardiovascular, neurologic, integumentary, pulmo-
nary, musculoskeletal, gastrointestinal, and endocrinologic
In recognition of the challenges facing cancer survivors,
the Institute of Medicine and the National Research Council
released recommendations for long-term follow-up care and
researchinthisfield. The Life After Cancer Care (LACC)
program at The University of Texas M. D. Anderson Cancer
Center was established to study the long-term health profiles
of cancer survivors and to develop recommendations for
J Cancer Surviv
C. J. Stava:C. Jimenez:M. I. Hu:R. Vassilopoulou-Sellin (*)
Department of Endocrine Neoplasia and Hormonal Disorders,
The University of Texas M. D. Anderson Cancer Center,
Unit 1461, 1515 Holcombe Boulevard,
Houston, TX 77030, USA
their health care. Several studies on the long-term health
effects of cancer survivors have been published by the
LACC team [3–12].
One of the most prevalent long-term health effects in
cancer survivors is bone loss, including osteoporosis and
osteomalacia. Osteoporosis is a systemic skeletal disorder
defined by low bone mineral density and deterioration of
the bone tissue microarchitecture, which may result in an
increased propensity to fracture [13, 14]. It has been
recognized as a major health threat for an estimated
44 million Americans, or 55% of people 50 years of age
osteoporosis, and an additional 34 million are estimated to
have low bone mass, placing them at increased risk for
osteoporosis [15, 16] . Of the 10 million people estimated to
have osteoporosis, 80% are women. Osteopenia is defined
as bone mineral density (BMD) values between 1 and 2.5
standard deviations (SD) below the young adult mean
value. Osteoporosis reflects BMD values more than 2.5
SD below the young adult mean value, and severe osteo-
porosis includes BMD values more than 2.5 SD below the
young adult mean value in the presence of one or more
fragility fractures .
Osteomalacia is a condition defined by incomplete
mineralization of bone structure , otherwise known
as softening of the bones. There are several groups of
survivors who have been recognized to be at particularly
high risk for osteoporosis. Women with breast cancer
treated with cytotoxic chemotherapy frequently experience
early menopause and cannot receive estrogen replacement
therapy. Men with prostate cancer who are on antiandro-
genic therapy and become hypogonadal are at equivalent
risk for developing osteoporosis. A third group at risk
for bone loss is patients with lymphoma, myeloma, or
leukemia. The common mechanisms shared by these
groups include the production of bone-resorbing cytokines
secreted by neoplastic cells and the use of high-dose
glucocorticoids in treatment regimens . A number of
other drugs can induce osteoporosis, including methotrex-
ate and various cytotoxic drugs that cause renal loss of
calcium, magnesium, or phosphorous (e.g., platinum com-
pounds, cyclophosphamide, and ifosfamide). These agents
can have significant impact on bone density, especially at
high dosages . In most cases, it is undetermined
whether bone loss in cancer survivors stems directly from
the therapy itself, from the underlying disease process
(including the impact of cachexia, malnutrition, and poor
calcium and vitamin D intake), or from a combination of
the two . In addition to hormone therapy and cytotoxic
drugs, radiation therapy and surgical castration can lead to
loss of bone density .
Accelerated loss of bone mineral density, with conse-
quential complications of pain, risk of compression, and
pathological and traumatic fractures, becomes more impor-
tant with increased duration of survival . Disease-
related skeletal complications are associated with shorter
overall survival and a decreased quality of life .
The health effects reported by cancer survivors are
numerous, but medical research and published literature
on the topic are scarce, especially for adult survivors.
Published literature on the risk, incidence, and detection of
cancer treatment-induced bone loss in survivors of cancers
other than breast or prostate cancer remains limited .
Most studies of cancer treatment-induced bone loss focused
on survivors of childhood cancers. Those studies show
varied, sometimes conflicting, results, and it is, therefore,
challenging for researchers to reach explicit conclusions.
This review focuses on the skeletal sequelae of cancer
and cancer treatments in survivors of pediatric and adult
cancers. We conducted an intensive and current search
using several medical Internet search engines, including
PubMed, Medline Plus, Scopus, and Google Scholar. Since
we wanted to focus on skeletal effects of cancer and cancer
therapies, our criteria included search terms such as
osteoporosis, osteomalacia, effects of cancer therapies,
drug-induced skeletal disorders, effects of hormone replace-
ment therapies, and skeletal effects of endocrine disorders.
We excluded effects of bone metastases and skeletal effects
of endocrine disorders not attributed to cancer therapies.
One-hundred-forty-two publications, mostly journal
articles, met the inclusion criteria and were used for this
review. The following analysis chronicles the many skeletal
complications experienced by cancer survivors and observed
in clinical studies.
The primary cause of cancer treatment-induced bone loss in
both men and women survivors is hypogonadism induced
by chemotherapy, irradiation, hormone therapy, or surgical
castration . Osteoporosis stemming from hypogonadism
is frequently seen in survivors of breast and prostate cancer,
as therapeutic hypogonadism is an important strategy for
controlling these hormone-dependent tumors . The risk
of osteoporosis induced by hypogonadism is not limited to
survivors of these cancers, however. Bone loss has been
observed in lymphoma survivors who received therapy
regimens including corticosteroids, alkylating agents, and
radiation therapy, all of which can cause hypogonadism
[13, 16]. Bone loss was also observed in patients made
hypogonadic by cytotoxic drugs used in hematopoietic stem
cell transplantations as part of their treatment regimens for
certain cancers .
Researchers began highlighting the association between
estrogen deficiency and lower bone mass in postmenopausal
J Cancer Surviv
women as early as 1941 . Estrogen deficiency, either
due to menopause or surgical castration, can lead to in-
creased osteoclastic bone resorption resulting in significant
bone loss [13, 26]. The association between hypogonadism
and osteoporosis has been more extensively studied in
women than in men. Approximately 20% of men with
spinal osteoporosis have hypogonadism , but the exact
mechanism by which hypogonadism causes bone loss in
men treated for prostate cancer is less clear. However, in
hypogonadal prostate cancer patients, decreased circulating
testosterone and estrogen levels cause a decrease in osteo-
blastic bone formation and an increase in osteoclastic bone
resorption, resulting in accelerated bone loss . (Table 1)
Chemotherapy-induced menopause and hypogonadism
Chemotherapy-induced menopause has been determined to be
a more important cause of osteoporosis than the direct effects
of cytotoxic agents and glucocorticoids . Cytotoxic drugs
used as adjuvant therapy for breast cancer may induce
ovarian failure, which can ultimately hasten loss of bone
mineral density in postmenopausal patients. Permanent
ovarian failure was observed following individual therapeutic
doses of cyclophosphamide, L-phenylalanine mustard, busul-
fan, chlorambucil, and mitomycin-C. Bines et al. reported that
cyclophosphamide is the most common agent implicated in
chemotherapy-related amenorrhea and that premature meno-
pause was dependent on its cumulative dose .
The use of chemotherapy for prostate cancer is usually
studies on its effect on bone density are limited. However,
chlorambucil and cyclophosphamide taken individually have
been observed to cause prolonged azoospermia in male
patients . In addition, gonadal toxicity was evident in
patients, especially those with testicular cancer, receiving a
cumulative dose of cisplatinum greater than 400 mg/m2
. The effects of cyclophosphamide and cisplatinum on
bone will be discussed later in this review.
Both female and male cancer survivors who received
irradiation to the cranium [29, 31], ovaries, or testes have
displayed hypogonadism [20, 27, 32–35]. Daniell et al.
highlighted the association between male hypogonadism
and osteoporosis through reports of fractures occurring after
external-beam radiation therapy to the prostate bed for
prostate cancer [27, 34]. An older report by Grigsby et al.
also demonstrated hypogonadism following radiation to the
prostate bed .
Hormone treatment-induced hypogonadism
Treatment regimens for metastatic or locally advanced non-
metastatic prostate cancer increasingly involve the use of
hormone therapy such as androgen deprivation therapies
(ADT; i.e., bilateral orchiectomy, leuprolide, and other GnRH
analogues). ADTinduces severe hypogonadism characterized
by loss of libido, impotence, gynecomastia, reduction of
muscle mass, and lossof bone mineral density . The most
common type of ADT is the use of gonadotropin-releasing
hormone (GnRH) agonists [37, 38]. The use of ADTs,
particularly GnRH agonists, instead of surgical castration as
part of the treatment regimen for cancer has been and is
preferred by a large number of patients, especially those with
prostate cancer [39–43].
Direct effects of cancer therapies
Androgen deprivation therapy (ADT)
Like many hormone replacement therapies, ADT is used as
a palliative agent rather than as a treatment to cure the
cancer itself and is taken over an extended period of
time. Numerous studies, including retrospective audits, have
Table 1 Cancer treatment regimens directly and indirectly associated
with bone loss
Androgen Deprivation Therapy
Combination Chemotherapy Regimens
Vitamin D Deficiency
J Cancer Surviv
demonstrated the association between ADTand osteoporosis
[14, 40, 43–47].
The rate of BMD loss that occurs with ADT is signif-
icantly greater (as much as 10-fold higher) than that due to
normal aging or female menopause [16, 39]. Kiratli et al.
reported a trend towards decreased hip BMD with
increasing years of ADT; this increase was more dramatic
in patients who had undergone surgical castration than in
those receiving medical ADT .
GnRH analogues were reported in a study by Smith et al.
 to be an independent risk factor for fracture and were
associated with an increased risk of any clinical fractures,
with an odds ratio of 1.13 (95% CI, 1.02–2.26, p=0.024).
Maillefert et al. reported reductions in bone density from
3% to as high as 10% after 18 months of therapy with
GnRH agonists .
Homes-Walker et al. demonstrated that the frequency of
fractures in prostate cancer patients was dependent on the
number of doses of gonadotropin-releasing hormone re-
ceived during the first 12 months after diagnosis of cancer
and on the age of the patient . GnRH analogues
suppress the secretion of follicle-stimulating hormone (FSH)
and luteinizing hormone (LH) by the pituitary gland. These
effects and hypoestrogenemia may result in decreased BMD
andosteoporosis. However, the review by McLeod et al.
demonstrates that the mechanism of bone loss due to ADT in
male survivors of cancer is not well understood. Theories
include the absence of circulating testosterone, which bonds
to androgen receptors on osteoblasts, mediating their
proliferation, and reduced substrate for the peripheral
conversion of testosterone to estrogen, which positively
maintains bone mass .
Aromatase inhibitors (AIs)
The most common estrogen suppressors used in the treatment
of cancer are aromatase inhibitors (AIs). AIs do not exert
estrogen agonist or antagonist activity; they can, however,
cause bone loss by suppressing aromatase activity and
interfering with the conversion of adrenal and other andro-
gens to estrogen, thereby reducing both circulating and tissue
levels of estrogen [16, 53]. A retrospective longitudinal
analysis of a large cohort of patients with breast cancer
determined that AIs were independently associated with a
27% increase in risk of bone loss and a 21% increase in
clinical fractures, after controlling for age, comorbidities,
income, geographic location, and health plan type .
Nonsteroidal (anastrozole and letrozole) and steroidal
(exemestane) AIs may have different effects on bone.
Exemestane has a structure similar to androstenedione, an
androgen precursor. It is presumed to have more bone-
protective qualities than anastrozole or letrozole because of
the increased bone formation seen with androgen excess .
However, both types of AIs may result in similar degrees of
bone loss regardless of whether they are steroidal or non-
steroidal. The overall effects of nonsteroidal versus steroidal
AIs on bone health are controversial . Osteoporosis was
more frequent in patients receiving exemestane, but the
fracture rate was only slightly higher than in those taking
tamoxifen, and the difference did not reach statistical sig-
nificance. A British study also found no statistically signif-
icant differences between the three agents in terms of effects
on bone turnover markers in postmenopausal women .
Tamoxifen, a selective estrogen receptor modulator
(SERM), has been shown to both cause and prevent bone
loss, depending on the menopausal status of the woman. In
premenopausal women with high estrogen levels, it works
as a bone antagonist, whereas in postmenopausal women
with low estrogen levels, it works as a bone agonist and
seemingly protects against bone loss [57, 58].
Powles et al. determined that while tamoxifen treatment
has been associated with a significant loss of BMD in
premenopausal women, the effects of tamoxifen on bone
actually have not been adequately studied in these women
. Many treatment regimens for breast cancer involve
adjuvant therapy with aromatase inhibitors after two or
three years of tamoxifen therapy, and measuring the effect
of both therapies on bone health has posed challenges for
researchers studying bone turnover because prior, or
concurrent, administration of tamoxifen exerts a protective
effect on bone in postmenopausal women treated with AIs.
Glucocorticoids, cytotoxic chemotherapy, and other agents
The majority of therapeutic regimens for many hematopoietic
based malignancies involve high-dose glucocorticoids, usually
administered over extended periods of time. Glucocorticoids,
which are often used as a pain adjuvant, palliative agent,
antiemetic, or as part of the treatment, suppress the activity of
osteoblasts and, therefore, reduce bone formation .
Prolonged exposure to corticosteroids is the third leading
cause of osteoporosis, after loss of sex steroids and old age in
the normal population . Osteoporosis develops in approx-
imately half of the patients on long-term treatment with
glucocorticoids [13, 60]. In fact, the risk of fracture increases
by 50–100% in recipients of oral corticosteroids [61, 62].
The mechanisms underlying the negative effects of
glucocorticoids on bone include (i) direct inhibitory effects
on osteoblast function, (ii) reduction in the production of
J Cancer Surviv
estrogen and testosterone along with the inhibition of
anabolic action of sex steroids, and (iii) enhanced effects
of parathyroid hormone .
There appears to be a defined relationship between the
rate of bone loss and the dose of corticosteroid drug. The
risk of corticosteroid-induced osteoporosis increases as
the cumulative corticosteroid dose increases .
The association between methotrexate and bone loss was
reported as early as 1970 in a study of children on long-
term methotrexate therapy for acute leukemia , and
several publications have since confirmed the association
[65, 66]. The review by Pfeilschifter et al. documented
incidences of skeletal fractures in leukemic children
ranging from 12% to 45% . Methotrexate increases
bone resorption and suppresses matrix mineralization,
which reduces bone formation [20, 67].
Megestrol acetate, a progestational agent used to treat
metastatic breastcancer and endometrial carcinoma,has been
implicated in osteoporosis and fractures in some patients. Its
glucocorticoid-like activity may lead to the development of
osteoporosis as well as other comorbidities. Wermers et al.
documented the first possible association between megestrol
and osteoporosis in two patients. This finding suggested that
megestrol, especially at higher doses, may negatively affect
bone density and potentially be associated with bone loss and
the development of fractures .
Platinum-based therapy regimens
Published literature on the effects of platinum-based therapy
regimens on bone is limited and primarily focused on animal
studies. Platinum compounds are often administered in
conjunction with other cytotoxic agents, so it has been
challenging for researchers to differentiate between their
effects on bone turnover and those of other agents. Cisplati-
num is known for its hypomagnesemic effects, which include
cessation of bone growth with suppressed osteoblast activity,
inhibited bone formation, and osteopenia [18, 69, 70]. A
Welsh study concluded that exposure to 6-mercaptopurine
and cisplatin was associated with a reduction in hip bone
mineral content in children treated for acute lymphoblastic
Besides its role in hypogonadism, cyclophosphamide
suppresses bone formation and resorption by directly
arresting the cell division of preosteoblasts and osteo-
clasts, which in turn, results in fewer osteoblasts and osteo-
clasts on the bone surface [13, 16, 20]. This mechanism
was also observed in an older study involving rats . At
the time of Wang’s writing (1986), the long-term effects of
cyclophosphamide on the human skeleton had not yet
been determined . While adjuvant taxane-containing
regimens (e.g., AC [doxorubicin/cyclophosphamide] fol-
lowed by paclitaxel) may elicit menopause, it remains
unknown whether cyclophosphamide or the combination
of a taxane and alkylating agent causes the loss of bone
Both in vitro studies and animal studies of doxorubicin
have demonstrated that the agent inhibits the proliferation
and differentiation of osteoblasts and selectively reduces
the rate of bone formation by altering the interaction of
parathyroid hormone with the osteoblast receptor [16, 20,
73, 74]. Studies demonstrating doxorubicin’s effect on
bone’s biomechanical properties are limited .
Interferon-alpha (INF-α), one of the earliest known cytokine
agents, is used to treat certain cancers such as hematologic
malignancies, especially hairy cell leukemia, and solid
tumors. Treatment with this agent may suppress bone
formation; however, the consequences of its effects on bone
mass remain undetermined. The review by Pfeischifter et al.
described that recombinant INF-α transformed the cellular
functions of both osteoblastic and osteoclastic lineages .
Beresford et al. suggested that INF-α suppressed prolifer-
ation of normal human bone-derived cells but did not
appear to enhance differentiation . The majority of
studies demonstrating interferon’s effects on bone were
conducted in in vitro models, and the exact mechanism
remains incompletely understood [76, 77]. However, some
of the in vitro studies suggest that INF-α causes decreased
bone turnover, with decreased resorption by osteoclasts but
increased differentiation of osteoblasts .
Solis-Herruzo et al. observed severe osteoporosis in a
patient treated with ribavirin plus interferon for a year. This
was the first published report of the effect of this therapy on
bone mineral metabolism . Another study concluded
that male patients treated with interferon for multiple
sclerosis demonstrated a decrease in bone mineral density
. In contrast, Lehmann et al. reported a case in which
INF-α was instrumental in reversing some of the osteo-
porotic effects brought about by systemic mast cell disease
 whereas it was suggested that INF-α inhibited the
accretion of mast cells in bone marrow.
J Cancer Surviv
In addition to its role as a mood stabilizer and anti-
convulsant, the role of valproic acid (valproate) as a
histone-deacetylase inhibitor renders it cytotoxic to many
different types of cancer, including multiple myeloma,
glioma, and melanoma. Osteopenia and osteoporosis were
often reported in patients with chronic mental illness treated
with long-term valproate therapy . Sato et al. found that
37% of patients on valproate for epilepsy displayed
osteopenia . Sixty-eight percent of patients receiving
chronic treatment with valproate in a study showed either
osteoporosis or osteopenia compared to 22% in the control
group. Furthermore, the longer an individual was on
valproate, the worse the bone health; at 6-month follow-
up, all lumbar spine and femoral bone density measures had
The mechanism behind how valproate adversely affects
bone microarchitecture remains unidentified . Valproate
has, however, been associated with reversible Fanconi
syndrome, suggesting that valproate may cause renal
tubular dysfunction with increased urinary loss of calcium
and phosphorus, leading to decreased mineral substrates for
bone formation .
The immunosuppressant cyclosporine has been shown to
stimulate osteoclasts, suppress osteoblasts, and inhibit
mineral apposition and bone formation rates . It has
been hard to pinpoint the actual role of cyclosporine in
bone density because it is almost always used in con-
junction with other agents, such as corticosteroids, that are
known to induce bone loss. Severe bone loss is often
experienced by patients who undergo allogeneic or
autologous hematopoietic stem cell transplantation. While
post-transplantation osteopenia was brought about in part
by hypogonadism, which can be prevented by hormone
replacement, glucocorticoids and cyclosporine appear
to be major components of bone loss in recipients, as
bone loss was shown to be dependent on both the gluco-
corticoid dose and duration of cyclosporine therapy
Furthermore, in renal transplant patients, histomorpho-
metric studies demonstrated increased bone turnover and
delayed repair of renal osteodystrophy, suggesting that the
effect of cyclosporine on bone turnover is independent of
corticosteroids . In addition, a follow-up study of
patients more than six years after allogeneic bone marrow
transplantation demonstrated that increased bone turnover
was mainly present in patients who took cyclosporine
during treatment .
Excessive intake of vitamin A or retinoic acid was shown to
be effective in the treatment of certain cancers and is
suspected of inducing osteoporosis in humans [90, 91], but
data are limited. In multivariate analysis, retinol intake was
negatively associated with bone mineral density. For every
1-mg increase in daily intake of retinol, risk for hip fracture
increased by 68% .
Nonsteroidal anti-inflammatory drugs
There are conflictingreports onthe effectofnonsteroidalanti-
inflammatory drugs (NSAIDs) on bone health. NSAIDs,
which are used in various cancer therapies, inhibit the pro-
duction of prostaglandins that modulate bone metabolism.
Most published studies on NSAIDs’ effects on bone were
performed in uncontrolled settings or in animals. A study of
ovariectomized rats on long-term indomethacin treatment
demonstrated reduced lumbar vertebral bone mass and
compressive strength . In another study, Goodman et
al.  reported that NSAIDs were associated with delayed
fracture healing and bone growth in humans; however,
these effects may be reversible after discontinuation of
treatment. Van Staa et al. showed that regular NSAID users
experienced a higher risk of fracture compared with non-
NSAID controls . A Japanese study demonstrated that
60% of women taking NSAIDs had BMD scores less than
80% of the nation’s age-matched mean values .
In contrast to most data highlighting the negative effect
of NSAIDs on bone health, a cohort study suggested that the
use of COX-2-selective NSAIDs with aspirin was associated
with higher BMD levels in various skeletal sites in both men
and women . Likewise, Bauer et al. found that regular
use of aspirin or NSAIDs may exert a modest but beneficial
effect on BMD in postmenopausal women .
Estramustine, an estrogen derivative used in prostate cancer
therapy regimens, has been reported to increase bone
resorption and at the same time induce hypocalcemia, hypo-
phosphatemia, secondary hyperparathyroidism, and osteo-
malacia [18, 99]. It has been suggested that estramustine
owes part of its therapeutic action and toxicity to a high-dose
estrogen effect. Citrin et al. confirmed that estramustine was
associated with significant changes in calcium and phosphate
metabolism similar to those previously observed with high-
dose estrogen therapy . It was suggested that castration
resulted in increased bone turnover and decreased BMD, but
these changes may be exacerbated by using estramustine
phosphate rather than bicalutamide .
J Cancer Surviv
Ifosfamide, used in many different cancer therapeutic
regimens, including those for solid tumors in children,
induces more sex-hormone-independent negative effects on
the skeletal system than any other alkylating agent .
The effects of ifosfamide on the skeletal and renal systems
have been well studied in the pediatric population, but a
dearth of literature exists on its effects in adults .
Toxic effects of ifosfamide include tubular damage (e.g.,
Fanconi syndrome) that leads to renal phosphate wasting,
hypophosphatemia, and rickets/osteomalacia [18, 103,
104]. Other associations between hypophosphatemia and
Fanconi syndrome resulting from cancer therapies and bone
health will be discussed later in this review.
Skeletal effects of radiation therapy may include altered
bone growth and damaged or necrotic osteoblasts, which
can result in secondary or uncontrolled resorption of the
bone matrix [105, 106]. Bone alterations or damages caused
by radiation are called radiation osteitis and radiation
osteonecrosis, or osteoradionecrosis . The study by
Williams et al., conducted in Britain , suggests that
radiation damage to bone in children usually involves
altered bone growth patterns, wherein radiation affects the
immature skeleton by disrupting the chondrogenesis and
reabsorption of calcified cartilage. The authors of that study
also reported that in adult skeletons, radiation may result in
decreased matrix formation resulting from affected osteo-
blasts. However, Hopewell did not find a direct association
between local radiotherapy to bone and reduced bone
density in childhood cancer patients, even though the
review documented other investigations that suggested
reduced bone mineral density and increased fragility in
mature bone .
Risk factors for developing radiation-associated fractures
include radiation doses higher than 3,000 cGy, high-energy
radiation beams, and underlying osteoporosis, especially in
postmenopausal patients . The effect of radiation
therapy is dependent on the field of radiation, as cranial,
rib, and pelvic irradiation each may result in different
Cranial irradiation has been studied as a prominent cause
of osteopenia , and osteopenia was observed amongst
26 long-term survivors of cancer who were treated with
cranial irradiation . Therapy for tumors requiring
radiation to the cranium, including acute lymphoblastic
leukemia and nasopharyngeal carcinomas, can often inhibit
the secretion of growth hormone and gonadotropins, which
may result in hypogonadism. However, depending on the age
at which treatment was received, hypopituitarism brought
about by radiation can result in lack of skeletal growth and
reducedBMD. The mandible is particularly vulnerable
to the effects of radiation, and osteoradionecrosis may occur
within a year of treatment [106, 110]. As mentioned in this
review, gonadotropin deficiency has been observed in
patients treated with cranial irradiation, and subsequent
hypogonadism may affect bone mineral density.
The literature suggests that radiation to the chest area for
breast cancer and other cancers, including Hodgkin’s lym-
phoma, can result in radiation osteotitis involving the ribs,
clavicles, and scapulae [107, 111, 112]. Pierce et al. deter-
mined that among a cohort of 1624 patients treated with
irradiation for early-stage breast cancer, 1.8% experienced
rib fractures an average of 12 months after treatment .
However, a Danish study demonstrated that 19% of post-
mastectomy patients treated with a large dose per fraction of
radiation experienced bone damage between one and six
years after treatment .
Pelvic irradiation for ovarian/cervical cancer and prostate
cancer is a common predisposing factor for sacral and
femoral neck fractures [110, 115]. Bonfiglio  reported
back in 1953 that femoral neck fractures were observed in
2% of cervical cancer patients who received orthovoltage
radiation therapy. Another study published in 1981 reported
several cases of slipped upper femoral epiphysis among
childhood cancer patients treated with pelvic irradiation
. The effects of pelvic irradiation on bones, including
demineralization and osteopenia, may develop following
one year after therapy, and the effects may be progressive
. Bone changes resulting from pelvic irradiation may
not be a direct consequence of the radiation itself but rather
an indirect effect of radiation-induced hypogonadism.
Combination therapy regimens can also exert negative
effects on bone. As mentioned previously, it has been a
challenge for researchers to study the toxicity of individual
agents because most cancer treatments are administered as
multi-agent regimens. Determining the actual incidences of
skeletal damage for individual cancer therapies is often not
possible because most protocols contain multiple agents
and are subject to frequent revisions, and studies involving
large numbers of patients and long-term follow-up remain
scarce. In childhood cancer patients, van Leeuwen et al.
concluded that it was difficult to distinguish the effect of
one single agent on the growing skeleton . However,
some combination adjuvant chemotherapy regimens
(including regimens with 5-fluorouracil, cyclophospha-
mide, and doxorubicin or methotrexate) have been associ-
ated with low bone mass .
J Cancer Surviv
Effect of age
While bone loss and osteoporosis are common signs of
advancing age, survivors of cancer may experience bone loss
at a more accelerated rate than their age-matched controls.
Estrogen and androgen production decreases with age, and
most anti-cancer therapeutic regimens leave cancer patients
with little or no remaining estrogen and/or androgen. If these
levels are not increased by ongoing estrogen replacement
therapy, the patient’s rate of bone loss will rapidly accelerate
with age. The Women’s Health Initiative Observational Study
showed that female survivors of breast cancer had a 15%
higher rate of all fractures, regardless of treatment received,
The rate of bone loss in a study of prostate cancer survivors
was nearly 10-fold greater than that reported for a group of
age-matched healthy elderly men .
Indirect effects of cancer therapies
It has been noted in this review that chemotherapy,
irradiation, and hormone therapy may indirectly affect the
skeleton through the mechanism of hypogonadism. There
are, however, other indirect effects on bone health that
result from cancer therapies. These effects include hyper-
parathyroidism, hypovitaminosis D, hypophosphatemia/
Fanconi syndrome, gastrointestinal complications, and
Hyperparathyroidism has long been associated with osteo-
porosis in which the parathyroid hormone (PTH) activates
osteoblasts, which in turn matures the osteoclasts. Osteo-
clasts release hydrochloric acid, which dissolves bone
mineral, causing osteopenia and osteoporosis [120, 121].
Incidences of secondary hyperparathyroidism associated
with glucocorticoid intake have been demonstrated variably
in both human and animal studies. The review by Reid
showed that in some studies, patients receiving long-term
glucocorticoid therapy exhibited PTH levels 50–100%
higher than those of control subjects . On the other
hand, Pearce et al.  could not determine an effect of
hyperparathyroidism on bone amongst a cohort of men
treated with prednisolone to reduce antisperm antibodies.
Nonetheless, the role of hyperparathyroidism on bone
mineral density in patients who have undergone organ
transplantation, including autologous stem cell trans-
plantation, has not been fully studied . Heaf et al.
concluded that ongoing hyperparathyroidism was a major
cause of bone loss after renal transplantation . In the
review by Conde et al.  corticosteroid-related hypo-
calcemia directly stimulates PTH secretion, which can lead
to increased osteoclastic bone resorption. Immunosuppres-
sive therapy involving cyclosporine and tacrolimus can
both directly and indirectly influence bone health, resulting
in secondary hyperparathyroidism and increased bone
Radiotherapy has been associated with hyperparathy-
roidism, but few studies have been published on its effect
on bone density [126–128]. In a study of patients with
radiation-associated hyperparathyroidism, mean lumbar
spine bone mineral density was found to be lower in women
whose hyperparathyroidism was induced by radiation than
in women with no history of radiation exposure .
Vitamin D deficiency
Hypovitaminosis D, or vitamin D deficiency, can lead to
alterations in calcium intake and phosphorous homeostasis,
secondary hyperparathyroidism, osteomalacia, and osteo-
porosis, as well as an increase in fracture risk [43, 50, 79,
130–133]. The association between hypovitaminosis D and
high-dose or long-term glucocorticoid therapy has been
pointed out in recent studies [134, 135]. Fifteen percent of a
cohort of patients treated with bone marrow transplantation
displayed hypovitaminosis D more than five years after
treatment , and associated secondary hyperparathy-
roidism leading to increased bone turnover was evident in
Varying degrees of hypophosphatemia, with associated
in up to 45% of patients taking tyrosine kinase inhibitors
such as imatinib, sunitinib, and sorafenib [136–140]. How-
ever, Grey et al. suggested that hypophosphatemia from
imatinib use resulted from secondary hyperparathyroidism
. One suggested explanation for the abnormalities in
bone and mineral metabolism seen in patients taking
imatinib is that the drug itself affects the formation and
resorption of bone by inhibiting the platelet-derived growth
factor receptor .
Hypophosphatemia, due to vitamin D deficiency and
secondary hyperparathyroidism or primary renal tubular
defects with phosphate wasting, is the most common cause
of osteomalacia . Hypophosphatemic osteomalacia has
been reported among prostate cancer patients, which
suggests that prostate cancer itself may be a cause of
tumor-induced osteomalacia .
Osteomalacia resulting from hypophosphatemia associ-
ated with Fanconi syndrome has been observed in patients
, and that study suggested that cisplatin and ifosfamide
were well-recognized etiologies of the syndrome. Ifosfamide
J Cancer Surviv
has beena well-recognizedrisk factorfor Fanconi syndrome,
and tubular damage was most commonly associated with
doses of ifosfamide greater than 50 g/m2and with con-
current use of cisplatin [19, 102, 103].
Patients who undergo gastrectomy for gastric carcinoma
may develop osteoporosis or osteomalacia [141–144]. A
German study documented that the overall rate of vertebral
fractures or osteopenia in a cohort of post-gastrectomy
patients was as high as 55% . It has been suggested
that patients who undergo gastrectomy may experience
hypocalcemia and low vitamin D levels because their intake
of dairy products is limited and essential nutrients are
malabsorbed as a result of the adverse effects of the surgery,
which may result in bone loss, and ultimately, fracture [142,
144, 145]. A recently published study conducted in Korea
confirmed a high rate of osteoporosis amongst patients with
gastric adenocarcinoma following gastrectomy .
Hyperprolactinemia and subsequent central hypogonadism
have been associated with the development of osteoporosis
[147–150]. Hyperprolactinemia caused by prolactinomia in
women influences bone metabolism unfavorably, primarily
owing to the impact on the activity of bone turnover
Cranial irradiation for brain malignancies may result in
hyperprolactinemia, as dopamine released from the cellular
damage and degeneration of the hypothalamus is unable to
inhibit prolactin secretion from the pituitary gland. Hyper-
prolactinemia can be observed following radiotherapy
doses of greater than 40 Gy  and is more common in
young women [152, 153]. In one study, seven of eight
patients who received chemotherapy including carmustine,
vincristine, and methotrexate concurrent with radiotherapy
for brain malignancies exhibited hyperprolactinemia .
This is a descriptive and inclusive review of scientific
literature on bone and mineral metabolic disorders to which
cancer survivors are prone. This review demonstrates that
dysfunctions of the skeletal system are amongst the adverse
effects of anti-cancer therapy. Some effects may not
develop immediately after completion of therapy, and may
be compounded with advancing age. Bone loss that occurs
with cancer therapy is generally more rapid and severe than
postmenopausal bone loss in women or normal age-related
osteoporosis in men.
Bone recovery is poor once bone loss has occurred.
Therefore early intervention is crucial to improving out-
comes as osteoporosis therapy, or bone maintenance therapy,
is most effective at preventing deterioration of bone.
The American Society of Clinical Oncology (ASCO) in
2003 established evidence-based guidelines for clinicians
for the treatment of cancer-treatment-induced bone loss in
patients with breast cancer. However, guidelines still do not
exist for survivors of other cancers who are experiencing
bone loss, including men who survived prostate cancer. At
the time of this writing, no consensus statement or societal
recommendation exists advising clinicians which men
should receive therapy. The lack of guidelines for survivors
of cancers other than breast cancer is due, in part, to the
dearth of published evidence on cancer survivorship and its
follow-up strategies . As of 2004, there have been 374
PubMed citations on adult cancer survivorship research
compared to 23,736 citations on adult cancer treatment
research . However, there has been a recent surge in
published studies on bone loss caused by anti-cancer
therapies, and it is with hope that successful follow-up
strategies will encourage more guidelines on treatment-
induced bone loss in survivors of other cancers such as
prostate and ovarian cancer, multiple myeloma, and other
hematologic malignancies. One of the recommendations
issued by the Institute of Medicine in 2005 was to refine
existing guidelines on the late effects of cancer and its
treatment, and to develop new ones . In fact, in 2005,
one of the topics that ASCO assigned several panel
subgroups was to study osteoporosis in long-term cancer
survivorship. Hopefully the findings from the subgroups
will be published in the near future .
As indicated in this review, further studies on cancer
treatment-induced bone loss to answer these questions and
to help clinicians better address the skeletal needs of cancer
survivors are highly encouraged. Studies that isolate the
effects of cancer and its treatments from the effects of
normal aging on bone will be extremely useful. Hopefully
with new cancer survivorship programs established at
various referral cancer centers, researchers will be able to
follow survivors over even longer periods of time. In the
meantime until appropriate guidelines are developed,
clinicians and other health care providers who treat cancer
survivors should: (1) be aware of the patient’s full treatment
history and exposure to cytotoxic agents, (2) identify the
potential side effects of treatment agents/regimens, (3)
identify other common risk factors not related to their
treatments such as aging, family history of osteoporosis,
lack of estrogen replacement therapy, a previous history of
fractures, and others that may suggests an increased risk for
bone loss, (4) provide diligent surveillance of patients’ bone
density evaluation and measurements of kidney, liver, and
thyroid function studies, a complete evaluation of mineral
J Cancer Surviv
metabolism including serum measurements of parathyroid
hormone, vitamin D metabolites, calcium, phosphate,
albumin, and markers of bone turnover, and other hormones
such as testosterone in men, (5) educate the individual
patient on how to prevent bone loss and fractures by having
adequate dietary calcium and vitamin D intake, sun
exposure, exercise, prevention of falls, and the elimination
of important risk factors for osteoporosis such as alcohol
abuse and smoking, and (6) finally, if necessary, refer the
patient to a cancer survivorship clinic.
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