Clinical and Translational Oncology

https://doi.org/10.1007/s12094-022-02872-1

SPECIAL ARTICLE

Bone loss induced by cancer treatments in breast and prostate cancer

patients
Santos Castañeda1 · Ana Casas2 · Aránzazu González‑del‑Alba3 · Guillermo Martínez‑Díaz‑Guerra4 · Xavier Nogués5 ·
Cristina Ojeda Thies6 · Óscar Torregrosa Suau7 · Álvaro Rodríguez‑Lescure8 

Received: 9 February 2022 / Accepted: 5 June 2022

© The Author(s) 2022

Abstract
Cancer and cancer therapies are a major factor risk for osteoporosis due to bone loss and deterioration of bone microarchi-
tecture. Both factors contribute to a decrease in bone strength and, consequently, increased bone fragility and risk of frac-
ture. Cancer-associated bone loss is a multifactorial process, and optimal interdisciplinary management of skeletal health,
accurate assessment of bone density, and early diagnosis are essential when making decisions aimed at reducing bone loss
and fracture risk in patients who have received or are receiving treatment for cancer. In this document, a multidisciplinary
group of experts collected the latest evidence on the pathophysiology of osteoporosis and its prevention, diagnosis, and treat-
ment with the support of the Spanish scientific societies SEOM, SER, SEIOMM, and SECOT. The aim was to provide an
up-to-date and in-depth view of osteoporotic risk and its consequences, and to present a series of recommendations aimed
at optimizing the management of bone health in the context of cancer.

Keywords  Osteoporosis · Bone health · Cancer · Diagnosis · Bone turnover marker · Fragility fracture · Hormone therapy ·
Hormone deprivation therapy · Antiresorptive agents

Introduction
* Álvaro Rodríguez‑Lescure
[email protected] Osteoporosis is defined as a systemic skeletal disease charac-
terized by low bone mass and a deterioration in bone micro-
1
Department of Rheumatology, Hospital Universitario de La architecture, resulting in an increase in bone fragility and
Princesa, IIS-Princesa, Catedra UAM-Roche, EPID-Future,
Universidad Autónoma de Madrid, Madrid, Spain predisposition to fractures [1].
2 Cancer treatments can have significant negative effects on
Department of Medical Oncology, Hospital Virgen del
Rocío, Seville, Spain bone health and cause bone loss or secondary osteoporosis
3 that increases the risk of fractures [2–4]. Moreover, cancer
Department of Medical Oncology, Hospital Universitario
Puerta de Hierro-Majadahonda, Madrid, Spain accentuates age-related loss of muscle mass, or sarcopenia,
4 which increases the risk of falls and osteoporotic fractures
Department of Endocrinology and Nutrition, Instituto de
Investigación imas12, Universidad Complutense, Hospital 12 [5]. This compromises the patient’s functional status, their
de Octubre, Madrid, Spain quality of life, and their very survival.
5
Department of Internal Medicine, Hospital del Mar, Hospital The aim of this document, drawn up by a group of experts
del Mar Research Institute (IMIM), Centro de Investigación from the Spanish Society of Medical Oncology (SEOM), the
Biomédica en Red de Fragilidad y Envejecimiento Saludable Spanish Society for Bone and Mineral Metabolism Research
(CIBERFES), Universidad Pompeu Fabra, Barcelona, Spain (SEIOMM), the Spanish Society of Rheumatology (SER),
6
Department of Traumatology and Orthopedic Surgery, and the Spanish Society of Orthopedic Surgery and Trau-
Hospital Universitario, 12 de Octubre, Madrid, Spain matology (SECOT) is to provide an up-to-date review of the
7
Department of Internal Medicine, Hospital General pathophysiology of the metabolic bone comorbidity osteo-
Universitario de Elche, Alicante, Spain porosis in cancer patients. We discuss the biomarkers most
8
Department of Medical Oncology, Hospital General widely used in the diagnosis and monitoring of osteoporo-
Universitario de Elche, Camino de la Almazara, 11, sis, and the main pharmacological and non-pharmacological
03202 Alicante, Spain

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 Clinical and Translational Oncology

measures aimed at preventing and treating bone loss and osteoporosis, and fractures [2–4]. There are also other
fractures. We also present advances in surgical and rehabili- factors that alter bone health, such as prolonged immobi-
tation techniques and a series of recommendations based on lization and/or sedentary lifestyle, primary bone cancer,
our clinical experience and expertise to provide a practical and bone metastases associated with other types of cancer.
up-to-date framework for specialists who routinely monitor Although osteoporosis is a common manifestation in these
these patients. patients, the pathogenic mechanisms are largely unknown,
and most studies focus on patients with breast (BC) and
prostate cancer (PC).
Pathophysiology of osteoporosis in cancer It is important to differentiate between osteoporosis and
patients fractures, because although they share a number of mecha-
nisms and risk factors, others are more specific to each
The pathophysiology of osteoporosis is multifactorial and process, such as falls in the case of fractures.
varies depending on the underlying disorder. There are
multiple risk factors involved in bone loss and fracture
(called “osteoporotic, fragility, or low-impact fractures”) General risk factors for osteoporosis
(Table  1). Cancer itself and many treatments used in
oncology (chemotherapy [CT], radiotherapy [RT], glu- Figure 1 summarizes the main risk factors, treatments, and
cocorticoids [GC], or hormone therapies [HT]) are inde- pathogenic mechanisms involved in osteoporosis in cancer
pendent risk factors for the development of bone loss, patients, particularly in patients with BC and PC.

Table 1  General factors that increase the risk of osteoporosis and fractures

Non-modifiable risk factors

 Age Personal history of previous fracture
 Female sex Genetic (family history)
 Ethnicity (Asian or Caucasian) Hip fractures in first-degree relatives
Modifiable risk factors
 Low levels of physical activity (prolonged immobilization and/or Estrogen deficiency (early menopause, prolonged amenorrhea periods)
sedentary lifestyle)
 Smoking Low calcium intake or malnutrition
 Alcohol consumption (≥ 3 units per day) Osteoporosis secondary to chronic or consumptive diseases
 Low weight (< 58 kg or 127 lb) Chronic glucocorticoid use
Drugs used in oncology
 Aromatase inhibitors (BC) Chemotherapy
 Steroidal (exemestane) Alkylating agents
 Non-steroidal (anastrozole, letrozole) Anthracyclines Docetaxel
 GnRH agonists (BC: goserelin, triptorelin) Doxorrubicin
 Selective ER Modulators (BC) 5-fluorouracil
 Androgen deprivation therapy (PC) Other
 LHRH analogues (goserelin, buserelin, leuprorelin, triptorelin) Other drugs
 LHRH antagonists (goserelin) Antidepressants and serotonin reuptake inhibitors
 Antiandrogens (enzalutamide, bicalutamide, flutamide, nilutamide) Oral antidiabetics (thiazolidinediones)
Other osteopenizing drugs
 Methotrexate NSAIDs
 Megestrol acetate Estramustine
 Platinum compounds Ifosfamide
 Cyclophosphamide Radiotherapy
 Interferon-alfa Combination of chemotherapy regimens
 Cyclosporine Valproic acid
 Vitamin A

ADT androgen deprivation therapy, BC breast cancer, ER estrogen receptor, GnRH gonadotropin-releasing hormone, kg kilograms, lb pounds,
LHRH luteinizing hormone-releasing hormone, NSAIDs non-steroidal anti-inflammatory drugs, PC prostate cancer

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Clinical and Translational Oncology

Fig. 1  Clinical risk factors and main pathogenic mechanisms of luteinizing hormone-releasing hormone, PTHrP parathyroid hor-
osteoporosis in patients with breast cancer and prostate cancer. ADT mone-related protein, RANKL/RANK receptor activator of the NF-κB
androgen deprivation therapy, AI aromatase inhibitors, BMD bone (L: ligand), TGFβ transforming growth factor beta
mineral density, BMI body mass index, GC glucocorticoids, LHRH

Non‑modifiable risk factors [8]. A history of previous fragility or low-impact fractures

is another important determinant of new fractures, with a
The main non-modifiable risk factors are shown in Table 1. previous vertebral fracture increasing the risk of hip fracture
Age is one of the main risk factors for both osteoporosis (RR: 2.5 [95%CI 1.9–3.2]), new vertebral fracture (RR: 1.7
and fracture. In general, the risk of fracture at any location [95%CI 1.4–2]), and proximal humerus fracture (RR: 1.9
is greater the older the individual [6]. Sex and ethnicity are [95%CI 1.5–2.4]) [9–12].
also important risk factors [6, 7]. Genetics is another funda-
mental determinant that increases the risk of osteoporosis. Modifiable risk factors
In fact, 60%–70% of an individual’s bone mass is estimated
to be genetically determined. A history of hip fracture in The presence of associated comorbidities and treatment with
a first-degree relative doubles the risk of hip fracture in GC or other osteopenizing drugs are particularly relevant
women (relative risk [RR]: 2 [95% confidence interval, CI in the case of cancer patients, who are usually polymedi-
1.4–2.9]), regardless of their bone mineral density (BMD) cated (Table 1). The higher the cumulative dose of GC, the

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 Clinical and Translational Oncology

higher the risk of osteoporosis. In general, maintaining doses the proliferation of estrogen receptor-positive (ER +) cells.
of ≥ 7.5 mg/day, or even ≥ 5 mg/day for more than 3 months, In addition, they stimulate osteoclastogenesis via receptor
is a risk factor. activator of nuclear factor-κB (RANK), although their effect
Fragility fractures are usually triggered by low-energy on bone formation is less well known. Inhibins are heter-
trauma that would not ordinarily cause a fracture, such as a odimeric proteins also secreted by breast cells that mediate
fall from standing height or less, and are a sign of underlying opposite effects in carcinogenesis. At bone level, they cause
osteoporosis or low bone quality. In osteoporosis, the risk a bone turnover disorder by inhibiting both osteoblastogen-
of fragility fractures is also related to the individual’s BMD esis and osteoclastogenesis (Fig. 1) [18, 22].
and likelihood of falling, since the fall itself is a fundamental
precipitating factor, especially of major non-vertebral frac- Prostate cancer
tures (radius, femur, and humerus). In general, the lower the
BMD and the higher the number of falls, the greater the risk As with estrogen in women, androgens are fundamental in
of a fragility fracture [6, 7, 13, 14]. maintaining bone homeostasis in men. Androgens have a
double/triple effect on bone tissue. In fact, they increase
bone formation and decrease resorption through a direct
Specific risk factors for osteoporosis effect mediated by androgen receptors (AR). Moreover,
some androgens are transformed into estrogens at the
Breast cancer peripheral level and act through ERα, which is an additional
benefit. Thus, low androgen levels are associated with ele-
Osteoporosis associated with BC is mainly linked to estro- vated RANKL levels and greater bone resorption [18, 23].
gen deprivation induced by chemotherapy (CT) and hor- Osteoporosis is present at diagnosis in 25–40% of patients
mone therapy (HT), and more specifically, to the use of non- with prostate cancer (PC). Treatment based on surgical or
steroidal aromatase inhibitors (AI) [15, 16]. Estrogens play pharmacological hormone deprivation (androgen depriva-
an essential role in bone homeostasis by binding to estro- tion therapy [ADT], which includes the use of luteinizing
gen receptors alpha and beta (ERα and ERβ, respectively), hormone-releasing hormone [LHRH] analogues), reduces
which are expressed in both osteoblasts (OB) and osteo- testosterone levels to 20% below baseline after 2–4 weeks
clasts (OC), thereby decreasing bone resorption and bone [18]. This results in rapid losses in BMD (already detect-
loss [17]. Estrogens promote the proliferation and activity able 6–9 months after the start of treatment), ranging from
of OBs, decrease the apoptosis of osteocytes (involved in 5% to 10% in the first year, especially in the radius and spine,
bone formation), and reduce the differentiation and matura- which increases the risk of fractures [18, 24, 25]. Fragility
tion of osteoclastic precursors by increasing the production fractures appear in up to 20% of patients in the first 5 years
of osteoprotegerin (OPG) and decreasing the synthesis of of ADT and the risk increases with time and number of
osteoclast differentiation and proliferation factor (receptor doses administered [25, 26]. ADT can increase the risk of
activator of nuclear factor-κB ligand [RANKL]) [18, 19] osteoporosis from 10%–40% to 80% after 10 years of treat-
(Fig. 1). ment exposure [18, 27], and 35% of patients experience skel-
Bone loss caused by CT (especially CT involving alkylat- etal fractures. Other factors that enhance this effect are age
ing agents and/or 5-fluorouracil) or after HT (especially HT and low body mass.
using non-steroidal AIs) is rapid, and can reach 6–8% dur- Androgens also have a positive effect at muscle level,
ing the first year, especially in trabecular bone. CT-induced while the use of ADT causes an increase in total body fat at
ovarian failure has more immediate and difficult-to-reverse the expense of a decrease in lean mass [28, 29]. Therefore,
effects, while hormone-induced failure can be reversed ADT produces sarcopenia with rapid loss of muscle mass
months after discontinuation, especially in young women. and increased risk of falls [28, 30].
The risk level for osteoporosis in decreasing order is as fol- Other factors that increase the risk of osteoporosis in PC
lows: premenopausal women with CT-induced menopause patients are CT (e.g. docetaxel), RT, prolonged use of GC,
treated with gonadotropin-releasing hormone (GnRH) and interventions such as orchiectomy. In patients with PC
agonists; women initially treated with tamoxifen and sub- treated with 10–12 mg/day prednisone or equivalent for
sequently treated with AI; and finally, women treated only more than 3 months, a 7-to-17-fold increase in the risk of
with AI, particularly those aged < 70 years [14, 20, 21]. vertebral or hip fracture has been shown [31].
Activins and inhibins are other mediators of interest in PC may induce osteoporosis independently of hormone
osteoporosis in cancer patients. Both belong to the trans- treatment, due to an increase in the expression of TGFβ and
forming growth factor β (TGFβ) superfamily, whose func- parathyroid hormone-related protein (PTHrP) [32]. PTHrP
tions are only partially known [18]. Activins are homodi- increases the growth and survival of prostate tumor cells
meric peptides secreted by breast tumor cells that inhibit in vitro (Fig. 1) [33].

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Another tumor that can cause osteoporosis through the BRMs show variations within the first 3 months of treat-
aforementioned mechanisms is testicular cancer. In this case, ment, so they can be used to assess the response to a given
the appearance of osteoporosis is related to age and time antiresorptive therapy. A positive treatment outcome is
from orchiectomy. reflected in a reduction in these markers. At the end of treat-
ment (approximately 3–6 months later), the markers return to
their baseline levels. The best BRMs for treatment monitoring
Other tumors
are NTX and CTX in urine, and CTX in blood. Response to
antiresorptive drugs has been defined as a reduction in BTM
Hematology patients undergoing bone marrow transplanta-
levels of more than the least significant change or to a value
tion merit special mention. In many cases, these are young
below the mean levels of the premenopausal reference range
women who have received multiple cycles of CT, immu-
[41]. A 25–30% decrease in CTX or PINP has been associ-
nosuppressant and GC before and after transplantation,
ated with a reduction in vertebral fracture (nearly a 40%) [42],
with frequent gonadal failure, often permanent [34–36]. In
so this may be a good threshold for use in clinical practice to
patients undergoing allogeneic and autologous transplanta-
evaluate the response of patients to antiresorptive therapies.
tion, graft-versus-host-disease and its treatment appear to
The most widely used BFMs in clinical practice are BALP,
play an important role in osteoporosis [37]. In general, these
osteocalcin and PINP [43].
patients are at increased risk for osteoporosis, and treatment
There are certain considerations with respect to BRMs as
options often include hormone replacement therapy (HRT)
follows:
with estrogens.
• BRMs measure functional activity and do not quantify
bone mass, so they should not be used for the diagnosis of
Diagnosis and monitoring of osteoporosis osteoporosis.
in cancer patients • Collagen-dependent BRMs may be altered due to non-bone
pathologies, such as chronic liver disease of any origin.
Role of bone biomarkers in treatment monitoring • BALP may be altered depending on the liver ALP values.
and evaluation • Chronic renal failure may alter the concentration of
BRMs.
It is essential to measure bone mass to estimate fracture risk. • Bone fractures may alter BRM values for several months.
The main techniques available for quantifying bone mass • In general, it is preferable to measure BRMs in serum
include dual-energy X-ray absorptiometry (DXA), quanti- instead of in urine, due to their lower variability.
tative computed tomography, and measurements of bone
microarchitecture such as the trabecular bone score (TBS). Diagnostic and monitoring tests: recommendations
According to the World Health Organization (WHO), DXA and frequency
is the gold standard for the study of osteoporosis [38].
Bone turnover markers (BTM) are proteins or enzymes Assessing the risk of low BMD is important in cancer
secreted by OBs or OCs during the formation or degrada- patients, since they often present premature loss of bone
tion of matrix protein collagen. They are released into the mass that contributes to the risk of osteoporosis, even in
bloodstream, so their detection is useful for the diagno- the absence of menopause. Recommendations for patient
sis and monitoring of osteoporosis, and for the individual assessment are summarized in Table 2.
assessment of fracture risk [39, 40]. There are two types of
BTMs as follows: Prevention and treatment of osteoporosis in cancer
patients
• Bone formation markers (BFMs), which derive from
formation processes and reflect osteoblastic activity: This section will discuss in detail the main pharmacologi-
alkaline phosphatase (ALP), bone-specific alkaline phos- cal and non-pharmacological measures to prevent and treat
phatase (BALP), procollagen type I carboxy-(PICP) and osteoporosis (Table 3).
amino-terminal propeptides (PINP), and osteocalcin.
• Bone resorption markers (BRMs), which derive from Non‑pharmacological measures
the resorption processes and reflect osteoclastic activity:
cross-linked carboxy- and amino-terminal telopeptides of Dietary supplements: amino acids, calcium and vitamin D
type I collagen (CTX and NTX), tartrate-resistant acid
phosphatase (TRAP), pyridinolines and deoxypyridino- Age and cancer treatments can impair protein synthesis with
lines, hydroxyproline and sialoprotein. decreased response to amino acids and insulin resistance.

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Table 2  Recommendations for patient diagnostic and monitoring screening

Patient assessment Comments

Medical history Fracture history Previous fractures increase the risk of future fractures, regardless of BMD. It is useful to perform a
spinal x-ray before starting treatment in order to detect previous asymptomatic fractures. Tech-
niques such as CT, MRI and/or PET can be very useful in determining whether an acute fracture is
a bone metastasis
Classic risk factors Family history of osteoporosis should be included. The FRAX® is an easily reproducible diagnos-
tic tool developed by the University of Sheffield from a meta-analysis of a wide variety of risk
factors for osteoporotic fractures (https://​www.​sheff​i eld.​ac.​uk/​FRAX/). It allows the estimation
of the 10-year risk of hip fracture and major osteoporotic fracture, with or without concomitant
determination of BMD, although it may underestimate the risk in cancer patients. When using the
FRAX® tool in cancer patients, cancer can be considered a “secondary osteoporosis”. One limita-
tion is that this tool does not weigh the number, severity, or location of previous fractures, or the
total or cumulative GC treatment
Medications Treatment review for potentially osteopenizing drugs
Fall risk estimation Estimation of fall risk
Vitamin D Vitamin D deficiency is an independent risk factor for low bone mass, falls, and fractures [112].
Determination of 25-hydroxyvitamin D levels allows patients to be classified as normal (> 30 ng/
ml), insufficient (20–30 ng/ml) or deficient (< 20 ng/ml)
Physical & comple- Height Height should be measured at least once a year and whenever there is suspicion of a new vertebral
mentary examina- compression fracture
tions
BRMs Variations throughout the day explain why their reproducibility is not a critical factor in the assess-
ment of FR in cancer patients. However, it may be useful to determine BRMs at the beginning
of diagnosis or once treatment has started to gain insight into the status of bone metabolism and,
above all, to monitor treatment
BMD DXA is recommended to measure and compare BMD with previous DXA to assess the progres-
sion of osteoporosis. The WHO recommends performing these measurements every 2 years from
menopause. The standardized recommendation for menopausal women treated with AI was an
annual BMD assessment for the duration of treatment, especially if there is baseline osteopenia or
osteoporosis [113]. The ASCO recommends increasing the frequency of DXA follow-up screening
if deemed medically necessary based on the results of BMD testing and expected bone loss [84]
Fig. 2

AI aromatase inhibitors, ASCO American Society of Clinical Oncology, BMD bone mineral density, BRMs bone resorption markers, CT com-
puted tomography, DXA dual energy X-ray absorptiometry, FRAX Fracture Risk Assessment Tool, GC glucocorticoid; FR fracture risk, MRI
magnetic resonance imaging, PET positron emission tomography, PMW postmenopausal women, PrMW premenopausal women, WHO World
Health Organization

This is often compounded by the physical or psychologi- (NCCN) guidelines recommend calcium (1200 mg daily)
cal difficulty of achieving adequate intake, a result of the and vitamin D (800–1000 IU daily) supplements for young
disease itself or the therapeutic sequelae. Adequate protein, women at risk of losing BMD and for women over 50 years
calcium, and vitamin D levels are essential for proper bone of age. For men with PC, calcium (1000 mg daily) and vita-
homeostasis, so it is recommended that they be added to min D (800–1000 IU daily) supplements are recommended
the diet, preferably as dietary supplements because of their from the age of 50 [49, 50]. The European Association of
greater efficacy and tolerance [44, 45]. Vitamin D plays a Urology (EAU) mentions the protective role of calcium sup-
fundamental role in calcium and phosphorus homeostasis plements in patients with PC, of whom 71% receive ADT
and is essential to maintain skeletal muscle health, muscle [51]. Several studies and reviews have confirmed the role
mass and strength, and balance [46]. Vitamin D levels higher of dietary supplements in alleviating the adverse events of
than 50 nmol/L (20 ng/mL) are recommended in the gen- ADT on BMD [52]. Monitoring by bone densitometry every
eral population. Levels above 100 nmol/L (40 ng/mL) have 1–2 years (or lengthening the scan interval in the case of
been shown to reduce AI-associated arthralgias [47, 48]. As stabilization) is also recommended in these patients. BRMs
regards calcium, the necessary dietary intake is estimated to such as serum CTX or urine NTX, or BFMs such as serum
be 1200–1500 mg/day. PINP every 3–6 months from the start of treatment may be
All patients starting treatment for osteoporosis should considered.
have normal calcium and vitamin D levels at the start of Obesity and vitamin D deficiency are global health issues.
treatment. The National Comprehensive Cancer Network Although evidence from meta-analyses has consistently

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supported an association between body weight and fat mass research is needed to determine the role and effect of these
and low levels of vitamin D, the underlying pathophysi- nutrients in the prevention of events, especially fractures.
ological mechanisms are complex and many potential con-
founding factors should be taken into account. Patients with Pharmacological measures
obesity frequently present decreased levels of vitamin D in
serum, as this parameter correlates inversely with BMI, body Table 3 lists the most used drugs, while the most relevant
weight or abdominal fat, irrespective of gender, likely lead- efficacy and safety clinical trials in patients with BC and PC
ing to an increased risk of osteoporosis [53]. The potential are presented in Online Resource 1.
benefit of vitamin D supplementation in obese people has
been reported in several studies [54, 55], so the assessment Bisphosphonates: breast cancer
of vitamin D levels in patients with osteoporosis and high
BMI is advisable in order to prescribe vitamin D supplemen- Several randomized clinical trials have shown that bispho-
tation when necessary. sphonates prevent or reduce bone mineral loss in women
with BC treated with AI, although they do not significantly
reduce the overall incidence of fractures. A systematic
Physical exercise
review of six studies confirmed with moderate-quality evi-
dence that the RR of skeletal events was not significantly
Exercise has been shown to improve a wide spectrum of
reduced in patients treated with bisphosphonates compared
cancer-related adverse events. Several clinical practice
to the placebo or the no bisphosphonate group [66].
guidelines currently recommend exercise as a key element
The studies with the largest number of patients are the
in the management of cancer patients. The SEOM recently
Z-FAST and the ZO-FAST trials (Zometa-Femara Adju-
published a position statement on physical exercise and can-
vant Synergy Trials). Both evaluated the efficacy of intrave-
cer due to its possible impact on the prevention and reduc-
nous zoledronic acid (ZOL) in preventing AI-induced bone
tion of complications and relapses [56]. However, there are
loss. All patients received calcium (500 mg) and vitamin D
no specific guidelines for a particular type of exercise, and
(400–800 IU) supplements. In the Z-FAST study, 602 post-
little is known about the extent to which physical exercise
menopausal women with early BC who received adjuvant
can prevent bone loss.
letrozole were randomized to receive upfront or delayed-
The results of different randomized trials on the effect
start intravenous ZOL treatment. At 12 months, BMD was
of exercise on BMD in cancer survivors have not shown a
higher in the group that received ZOL up front compared to
significant overall improvement in lumbar spine or femoral
the delayed-start group, and a significant reduction in NTX
neck BMD (exercise versus placebo) [57, 58].
and BALP was observed in the first group [67] (Online
In women with BC on treatment, the results of programs
Resource 1). In the 5-year extension study, a progressive
combining moderate intensity strength and resistance exer-
increase in BMD was observed in the upfront treatment
cises are inconclusive, largely due to the limitations and
group, with significant differences between both groups and
heterogeneity of the patient sample and poor adherence to
no significant differences in the incidence of fractures [68].
exercise programs [59]. Although not all types of exercise
One quarter of patients (25%) in the delayed treatment group
are equally osteogenic, moderate-intensity aerobic exercise
required ZOL treatment. This suggests that not all women
has beneficial effects on the lumbar spine BMD in women
need antiresorptive treatment, and patients should preferably
with BC, and it is also important to encourage adherence to
be pre-selected individually on the basis of their fracture
training programs [57, 60–62].
risk identified from the BMD and clinical risk factors. In
There is still no evidence on the effect of exercise in pre-
the similarly designed ZO-FAST study, the lumbar spine
venting fractures [63] in men with PC undergoing ADT,
BMD increased at 36 months in the upfront treatment group,
although positive effects have been observed on other
while loss of BMD was observed in the delayed-start group.
aspects such as anxiety, bone loss and sexual dysfunction
Twenty-one percent of patients in the delayed group required
[64].
ZOL treatment during the study [69] (Online Resource 1).
Very similar results were obtained in the N03CC trial [70,
Fatty acids 71]. It should be noted that the regimen commonly used in
non-BC-related menopausal osteoporosis is 5 mg intrave-
Omega-3 fatty acids have anti-inflammatory potential and nous ZOL annually, which is likely to also be effective in
are related to PC. It has been suggested that daily use of the treatment of AI-induced osteoporosis, although this has
omega-3 and omega-6 combined with calcium has a posi- not been studied.
tive effect on bone health [65]. However, the results of the With regard to oral bisphosphonates, various trials
various studies analyzed were inconclusive, so larger-scale have assessed their effect on the prevention of AI-induced

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osteoporosis. The doses studied are the same as those rec- a very rare problem that is more common in cancer patients
ommended in postmenopausal osteoporosis. Of these, the with bone metastases who receive monthly doses of intra-
most extensively studied is risedronate (35 mg/week). In the venous ZOL for long periods. In early BC, the incidence of
SABRE trial, 154 postmenopausal patients with BC treated ONJ is 0.25%. The Z-FAST trial reported two unconfirmed
with the AI anastrozole as adjuvant therapy and who had cases of ONJ, and generalized bone pain was most com-
moderate risk of osteoporotic fracture were randomized to monly seen in the group randomized to upfront intravenous
receive risedronate or placebo for 2 years. In the risedronate ZOL versus the delayed-start group [62].
group, the lumbar spine and total hip BMD increased signifi-
cantly, but decreased in the placebo group [72]. In a more
recent placebo-controlled trial that recruited 109 women Denosumab
with low BMD treated with different AIs (anastrozole, letro-
zole, or exemestane), risedronate achieved greater increases Denosumab is a human monoclonal antibody directed
in spine and hip BMD at 24 months compared with placebo against RANKL, thus inhibiting the differentiation, prolif-
[73]. All women received supplemental calcium and vitamin eration and activity of OCs and, therefore, reducing bone
D. Greater reduction in CTX and PINP correlated with a resorption. In clinical trials in postmenopausal women
better response in spinal BMD. Risedronate also achieved with osteoporosis, denosumab treatment for up to 10 years
better conservation of lumbar bone microarchitecture esti- increased lumbar spine and femoral neck BMD, and reduced
mated using the TBS [74] (Online Resource 1). the risk of osteoporotic vertebral, hip and non-vertebral frac-
A recent large observational cohort study to evaluate the tures [78, 79]. The most common adverse events associated
efficacy of oral bisphosphonates under clinical practice con- with denosumab are hypocalcemia, diarrhea, eczema and
ditions in 36 472 women diagnosed with BC and treated skin infections; the occurrence of hypophosphatemia and
with tamoxifen and/or AI showed that in the subgroup of ONJ, among other effects, has also been described, albeit
women treated with AI who had high fracture risk, treatment relatively less frequently [80].
with oral bisphosphonates reduced the risk of fractures by
30% compared to the group that did not receive bisphospho- Denosumab: breast cancer
nates. This is the first real-world study to confirm positive
data from previous clinical trials with bisphosphonates, and In a placebo-controlled clinical trial in women with non-
to report a positive effect on fractures [47]. metastatic BC treated with AI and low BMD, the use of
denosumab (according to the recommended regimen for
Bisphosphonates: prostate cancer postmenopausal osteoporosis) led to a significant increase
in lumbar spine, hip and femoral neck BMD and a reduc-
A recent systematic review and meta-analysis of 14 clinical tion in BTMs. This effect was independent of the duration
trials has shown the protective effects of bisphosphonates of AI therapy. There was no significant effect on the number
on BMD loss in men with non-metastatic PC receiving of fractures [81]. The ABCSG-18 (Adjuvant Denosumab in
ADT, resulting in a significant increase in lumbar, femoral Breast Cancer Trial) study, which evaluated the protective
neck and total hip BMD after 12 months of treatment [75] effect of denosumab against fractures in women with non-
(Table 3). Most of the trials analyzed included administra- metastatic BC on AI, found a 50% reduction in the risk of
tion of intravenous ZOL, alendronate, and to a lesser extent, clinical fracture in women treated with denosumab com-
risedronate. Despite this, it has not been possible to dem- pared to placebo. In addition, a decrease in the risk of new
onstrate a reduction in the fracture risk with oral or intra- vertebral fractures and worsening of existing fractures, and
venous bisphosphonates in these patients, since the number a significant increase in lumbar spine, total hip and femoral
of fractures recorded in the trials was extremely low [76]. neck BMD were confirmed. The benefits of denosumab were
For this reason, ASCO clinical guidelines consider oral or independent of baseline BMD and age [82] (Table 3).
intravenous bisphosphonates to be a reasonable option to
reduce the fracture risk in patients with non-metastatic PC
and ADT [77]. Denosumab: prostate cancer

Adverse events of bisphosphonates In a trial in patients with PC (> 70 years, or low bone mass
with T-score < -1) undergoing surgical castration or ADT
Bisphosphonates are generally well tolerated. In prolonged with GnRH agonists, a reduction in the risk of new verte-
treatment with intravenous ZOL, the appearance of flu-like bral fractures was observed after 12 months of denosumab
symptoms, renal failure, hypocalcemia and osteonecrosis of treatment (compared to placebo). In addition, a significant
the jaw (ONJ) should be monitored, among others. ONJ is and progressive increase in BMD at the lumbar spine, total

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Clinical and Translational Oncology

hip, femoral neck and distal third of the radius was con- Selective estrogen receptor modulators
firmed from the first month of treatment. The incidence of and calcitonin
adverse events was similar in both groups, with no cases
of ONJ or atypical fractures reported. Cataracts were more Selective estrogen receptor modulators (SERMs) are a group
frequent in the denosumab group, while the occurrence of of drugs that have either proestrogenic (mainly cardiovas-
bone metastases was more frequent in the placebo group cular, liver, and bone) or antiestrogenic activities (breast,
[83] (Online Resource 1). uterus) depending on the target tissue on which they act.
Different clinical guidelines recommend denosumab Raloxifene has estrogenic activity in the bone and no
as the drug of choice for the prevention of bone loss in proestrogenic activity in the endometrium, unlike other
patients with non-metastatic PC on ADT [84]. SERMs. It has, therefore, been approved for the prevention
and treatment of osteoporosis in postmenopausal women.
Tamoxifen, in contrast, has agonist activity at the endome-
Other treatments trial level, and has been associated with an increased risk
of endometrial cancer. Although not used as a treatment for
Bone‑forming agents osteoporosis, tamoxifen contributes to the improvement of
bone health in postmenopausal patients who receive it as
Osteoanabolic agents stimulate the differentiation, func- treatment or prophylaxis against BC [91].
tion and survival of OBs. These include teriparatide All these drugs carry a slight increase in the risk of
(recombinant form of parathyroid hormone [PTH]), aba- thromboembolic events due to their estrogenic agonist
loparatide (PTHrP analogue), and romosozumab. After a activity at the cardiovascular level, as well as climacteric
certain period of time, the conventional treatment for post- symptoms.
menopausal osteoporosis applied in the general population New agents have been added to classic SERMs, such
should be administered according to the usual risk factors. as bazedoxifene, a third-generation SERM that has been
Chronic exposure to PTH or PTHrP analogues causes approved for the treatment of postmenopausal osteoporosis
bone resorption, although intermittent administration with increased risk of fractures. The use of these drugs is
has been shown to stimulate bone formation more than associated with a lower risk of BC, and they are approved
resorption in postmenopausal women [85, 86]. Their use for chemoprevention treatment in patients at high risk of BC.
in cancer patients on ADT is usually restricted or con- Calcitonin is a hormone that acts on OCs and inhibits
traindicated. However, they can be used in patients with bone resorption. In Spain, it is marketed as salmon calcitonin
osteoporosis with high fracture risk and in cases of ONJ or or eel calcitonin [92]. The former is the most frequently used
atypical femoral fracture, both antiresorptive-related com- and has a high affinity for the calcitonin receptor (up to 40
plications, as they can facilitate their rapid resolution [87]. times higher than human calcitonin). Intranasal, oral and
Bone-forming treatments are contraindicated in patients parenteral formulations have been developed [93, 94]. Cal-
with primary or secondary hyperparathyroidism, hyper- citonin has shown a benefit in increasing bone mass in the
calcemia, or patients at increased risk of osteosarcoma axial skeleton and in reducing the risk of fracture, although
(such as patients with Paget’s disease of bone and patients to a lesser extent compared with other agents such as bis-
who have received RT). A single course of treatment with phosphonates. Analysis of data from different studies evalu-
these drugs is generally recommended for up to 2 years. ating the safety of prolonged use of calcitonin in the treat-
Although they are usually well tolerated and no associated ment of osteoporosis identified an increase in the incidence
complications have been described, they can cause hyper- of cancer in patients receiving the drug compared to the
calcemia and hypercalciuria to a marginal extent. placebo group (with incidence rates of 0.7–2.4%). Accord-
Romosozumab (anti-sclerostin monoclonal antibody) ingly, EMA issued a statement explaining that the benefits of
is a new anabolic agent approved by the Food and Drug calcitonin as a treatment for osteoporosis did not outweigh
Administration (FDA) in 2019 and the European Medi- the risk identified in the safety analyses and recommended
cines Agency (EMA) in 2020, after having demonstrated limiting its indication to acute periods of the disease. The
a reduction in vertebral and non-vertebral fractures main adverse events associated with administration of this
compared to placebo and alendronate. Romosozumab is treatment are nausea, vomiting, and hot flushes. Calcitonin
approved for the treatment of severe osteoporosis in post- is not used as a first-line therapy due to the existence of
menopausal women with high fracture risk [88, 89]. There other drugs that are more effective in preventing bone loss
is no formal contraindication for the romosozumab use and reducing fracture risk. It is mainly indicated in patients
in cancer patients, despite one of the criteria for patient with recent osteoporotic fracture, but should only be admin-
exclusion in the pivotal clinical trial was a previous history istered for 2–5 weeks at the lowest effective dose for the
of cancer [90]. patient, or until resolution of pain. After the acute episode, it

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 Clinical and Translational Oncology

is recommended to switch calcitonin to other more effective these principles, and can be summarized as angular-stable
osteoporosis medications. implants, augmentation, and minimally invasive techniques
that allow optimal application of biomechanical principles
Sequential treatment to protect the entire bone [98].

Oral bisphosphonates are recommended as first-line treat- Surgical management

ment of osteoporosis due to their efficacy, safety, accessi-
bility and cost-effectiveness. In patients contraindicated for Implants and devices
oral or even intravenous bisphosphonates (as is the case in
patients with gastrointestinal disturbances or renal failure) Angular-stable implants have an additional fixation point
or patients with high fracture risk who have new fracture between the screw and the implant itself to increase resist-
events despite bisphosphonate treatment (which should be ance to shearing in fragile or comminuted bone. This added
switched to an anabolic agent), other alternatives may be point of fixation is achieved in plates by using locking screw
offered based on the fracture risk, efficacy, safety and patient heads that lock into the plate itself through threaded screw
preference. One of these alternatives is denosumab. heads or locknuts (Fig. 3); in nails, the holes for the locking
The denosumab discontinuation effect has been the sub- bolts are threaded or lined with polyethylene or a similar
ject of recent attention, given the risk of fracture following material to lock the screws in place. Locking plates do not
discontinuation due to a rebound effect on bone resorption rely on bone-to-plate contact for stability, acting as “internal
observed in clinical series, although this has not been con- fixators” without excessive periosteal stripping or soft tis-
firmed with high-level evidence. In this respect, a recent sue dissection. This allows for indirect reduction and plating
systematic review by the European Calcified Tissue Soci- using minimally invasive surgery and plate constructs with
ety (ECTS) working group suggests that patients with high long working distances that are less stiff and distribute loads
fracture risk can maintain denosumab beyond 5 years and across the bone. The trend is towards using longer implants
even continue treatment for up to 10 years [95]. In case of that protect the entire bone (i.e., long cephalomedullary
discontinuation, close patient follow-up or switching to bis- nails), especially in cases with a possibility of metastatic
phosphonates is recommended, although there is no high- disease [99, 100].
level evidence to date to support the regimen to be followed A recent survey of French physicians showed a willing-
and its duration. ness to use implantable devices to prevent contralateral hip
Finally, romosozumab, a more potent bone-forming agent fractures, particularly in oncologic indications [101]. Several
than PTH, has been shown to be more effective than teri- techniques have been developed, but experience is limited to
paratide after prolonged treatment with oral bisphosphonates small case series and preliminary trials [102], and the cost-
in postmenopausal women, according to the STRU​CTU​RE effectiveness of these interventions has not been evaluated
study [88], although there is still no experience with this yet [103].
drug in cancer patients.
Augmentation techniques
Osteoporotic fractures in cancer patients:
prevention and treatment Augmentation is the injection of bone cement or bone sub-
stitutes in the area of the screws to increase purchase in
The burden of osteoporotic fractures has been growing poor bone and assist load transfer through fenestrations in
despite the development of bone-protecting medication, specially designed cannulated screws (Fig. 2A and B). This
mainly due to population aging. Furthermore, as long-term technique is also used in vertebral kyphoplasty [104], where
survival of oncologic disease increases, more patients with bone cement is injected into a cavity in the vertebral body
osteoporotic fractures will be likely to have a history of can- created by balloon expansion (Fig. 2C) to reduce micromo-
cer, particularly breast cancer [96]. tion at the fracture site and increase trabecular bone resist-
Surgical management of fractures follows a series of prin- ance to compression. Osteoplasty is the application of this
ciples published by the AO Society (Arbeitsgemeinschaft technique to bones other than spine and has been used percu-
für Ostheosynthesefragen) [97]: (1) restoration of anatomi- taneously in combination with internal fixation for traumatic
cal relationships; (2) fixation providing stability as required injuries [105] as well as lytic bone lesions [106].
by the type of fracture, patient and injury; (3) preservation
of blood supply to tissues and bones; and (4) early and Rehabilitation
safe mobilization of the injured part and the patient as a
whole. Several technological innovations in recent decades The fracture fixation construct should be sufficiently stable
have helped stabilize osteoporotic fractures while fulfilling to enable early mobilization and weight bearing. There is

13
Clinical and Translational Oncology

Fig. 2  Proposed therapeutic approach to cancer patients with bone number of aforementioned clinical risk factors and clinical guideline
loss induced by hormone deprivation therapy. Non-pharmacological followed. In addition, dorsolumbar X-ray may be necessary if axial
measures include the following: regular exercise, calcium 1200  mg/ pain appears or a vertebral fracture is suspected. Pharmacological
day and vitamin D 800–1000 IU/day or supplements to reach 25(OH) treatment is mandatory in any of the three scenarios mentioned if a
Vit D levels > 50–75  nmol/L (20–30  ng/ml,) if necessary, smoking prevalent major osteoporotic fracture is confirmed. DXA dual energy
and alcohol cessation and training to avoid falls. Pharmacological X-ray absorptiometry, FRAX Fracture Risk Assessment Tool, MOF
measures are indicated when T-score < -1.5 or < -2 depending on the major osteoporotic fracture, yrs years

Table 3  Pharmacological and Non-pharmacological measures Pharmacological measures

non-pharmacological measures
for the prevention and treatment Smoking cessation Hormone replacement therapies
of osteoporosis in patients with
Avoid excess alcohol intake Antiresorptive agents
cancer
Avoid excess caffeine intake Selective estrogen receptor modulators (SERMs)
Avoid sedentary lifestyle Calcitonin
Prevent falls Bisphosphonates (alendronate, risedronate,
ibandronate, zoledronate)
Balanced diet Denosumab (anti-RANKL biologic)
Adequate intake of:
Trace minerals
Proteins
Vitamin D
Calcium
Combination of calcium and vitamin D
Physical therapy (improve muscle strength and balance)

RANKL receptor activator of NF-κB ligand, SERMs selective estrogen receptor modulators

13
 Clinical and Translational Oncology

Fig. 3  Augmentation technique. A Angular stable locking screw and with cement augmentation. Note the filling of the lytic lesion in the
conventional screw. The threaded screw head locks in the plate hole, femoral head (black asterisk). C Fracture of the 11th dorsal and 3rd
providing angular stability and reducing shearing (red arrow). This lumbar vertebra (asterisks) in a patient with multiple myeloma [1];
stability reduces the dependence on the bone–plate interface for sta- lateral [2] and anteroposterior [3] intraoperative fluoroscopy of bal-
bility, protecting periosteal tissue; B Lytic metastatic lesion (white loon kyphoplasty of the affected vertebrae; lateral [4] and anteropos-
asterisk) of the postero-inferior aspect of the femoral head in a patient terior postoperative radiographs [5]. Clinical case courtesy of Dr.
with metastatic renal cancer: [1] AP and [2] axial view in conven- Rodrigo Merino, Orthopedic Department, Hospital Universitario 12
tional radiographs; [3] axial computed tomography; [4] AP and [5] de Octubre, Madrid
axial view following internal fixation using a cephalomedullary nail

evidence that frail elderly patients are unable to comply with about the importance of monitoring bone health. Many sectors
partial weight-bearing [107]; furthermore, early weight- of the healthcare system still remain oblivious to the tremen-
bearing reduces morbidity and mortality [108, 109]. Early dous impact on quality of life and functional status caused
intervention has been shown to improve physical function by bone loss from mild fractures and vertebral compression.
following fracture, particularly hip fractures, though it The healthcare system also plays an essential role in improv-
remains unclear which types of exercise are superior [110]. ing understanding among patients of the available treatments,
The effect of exercise interventions seems less marked in the risks of fracture and bone weakness associated with some
patients who have already experienced fractures, although therapies, and the diet and lifestyle changes that are most effec-
benefits were observed for measures of balance and mobility, tive in preventing bone loss and fractures. There is still limited
fall risk, physical activity, mood, and community outings knowledge about the risk of osteoporosis associated with a
[111]. wide range of medical and surgical treatments for cancer. More
research is needed to increase the effectiveness and number
of available antiresorptive and bone-forming therapies, and
Conclusions more evidence on the effectiveness of combined bone resorp-
tion and formation treatments is needed. Other areas, such as
Steady improvements in the effectiveness of cancer treatments the management of severe osteoporosis, early identification of
have not been accompanied by equally optimal management of patients with increased or imminent risk of fracture after recent
skeletal health, which is badly affected by the disease and the fractures and patient adherence to long-term treatments, also
treatments themselves. Efforts are needed to raise awareness need to be improved. The emergence of new bone-forming
among physicians and specialists in the care of cancer patients therapies and the application of more personalized precision

13
Clinical and Translational Oncology

medicine may represent an important advance in the manage- included in the article's Creative Commons licence, unless indicated
ment of bone health in patients with cancer. otherwise in a credit line to the material. If material is not included in
the article's Creative Commons licence and your intended use is not
Until these issues have been resolved, efforts should be permitted by statutory regulation or exceeds the permitted use, you will
focused on promoting the identification of cancer patients at need to obtain permission directly from the copyright holder. To view a
risk of morbidity due to bone loss and their proper follow-up. copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/.
In this context, BMD is currently one of the most important
tools in the diagnosis and monitoring of these patients.
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