Managing Metastatic Bone Pain: New Perspectives, Different Solutions

Home , Bone metastasis, Bone pain

Biomedicine & Pharmacotherapy 93 (2017) 1277–1284

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Review

Managing metastatic bone pain: New perspectives, different solutions

a,b, b,c d

Iwona Zaporowska-Stachowiak *, Jacek Łuczak , Karolina Hoffmann ,

e d,f b,c

Katarzyna Stachowiak , Wiesław Bryl , Maciej Sopata

Chair and Department of Pharmacology, Poznan University of Medical Sciences, Poland

Palliative Medicine In-Patient Unit, University Hospital of Lord’s Transﬁguration, Poznan University of Medical Sciences, Poland

Department of Palliative Medicine, Poznan University of Medical Sciences, Poland

Arterial Hypertension and Metabolic Disorders In-patient Unit, University Hospital of Lord’s Transﬁguration, Poznan University of Medical Sciences, Poland

Institute of Applied Linguistics, University of Warsaw, Poland

Department of Internal Diseases, Metabolic Disorders and Arterial Hypertension, Poznan University of Medical Sciences, Poland

A R T I C L E I N F O A B S T R A C T

Article history:

Received 6 April 2017 Bone metastases are the most frequent cause of cancer-induced bone pain (CIBP). Although palliative

Received in revised form 28 June 2017 radiotherapy and pharmacotherapy conducted according to World Health Organization (WHO) analgesic

Accepted 5 July 2017

ladder are the treatment of choice for CIBP reduction, these methods are not always successful, especially

Keywords: with regard to alleviation of incidental pain. Antiresorptive drugs (bisphosphonates) are able to inhibit

Bone pain bone destruction (loss), proliferation of cancer cells and angiogenesis, but their prolonged use may lead

Bone metastases

to a spectrum of adverse effects. In this paper, types of bone metastases, their complications, as well as

Pathological fractures

diagnostic and therapeutic implications are presented. Moreover, the paper discusses presently used

Spinal cord compression

CIBP treatment methods and research directions for future methods, with special focus on bone

Antiresorptive drugs

metastases.

Contents

1. Introduction ...... 1277

1.1. Types of bone metastases ...... 1277

1.1.1. Osteolytic metastases ...... 1278

1.1.2. Osteosclerotic (osteoblastic) metastases ...... 1278

2. Diagnostics of cancer induced bone pain (CIBP) ...... 1279

3. Therapeutic implications of CIBP ...... 1280

4. Summary ...... 1281

References ...... 1282

1. Introduction

1.1. Types of bone metastases

Bone metastases can be categorized on the basis of radiological

and histopathological image data and divided into osteolytic,

* Corresponding author at: Chair and Department of Pharmacology, Poznan osteosclerotic and mixed types.

University of Medical Sciences, Rokietnicka 5A, 60-806, Poznan, Poland. Palliative Osteolytic metastases are responsible for bone destruction.

Medicine In-patient Unit, University Hospital of Lord’s Transﬁguration, Poznan

These types of lesions are related with breast, lung, thyroid, kidney

University of Medical Sciences, os. Rusa 55, 61-245, Poznan, Poland. Tel.: +48 609 26

and multiple myeloma cancer.

70 73; fax: +48 61 873 83 06.

E-mail address: [email protected] (I. Zaporowska-Stachowiak).

http://dx.doi.org/10.1016/j.biopha.2017.07.023

1278 I. Zaporowska-Stachowiak et al. / Biomedicine & Pharmacotherapy 93 (2017) 1277–1284

The second type of bone metastasis, referred to as the 1.1.1. Osteolytic metastases

osteosclerotic type is able to stimulate new bone tissue formation

and is associated with prostate and breast cancer. Osteoclasts are polynuclear cells adhered to the bone using

The third type, called mixed metastasis, occurs mainly with avb3 integrin. Due to the secretion of collagenases, proteases and

lymphoma, breast and lung cancer. This type of metastasis is hydrogen ions, they are able to demineralize the bone matrix.

related to local interactions of metastatic cells with osteoclasts and Osteoclasts’ main growth factors are called RANKL (Receptor

osteoblasts [1,2]. Activators of Nuclear Factor kb Ligand) and M-CSF (macrophage

Regardless of their type, metastases alter normal bone colony stimulating factor) [16,17]. RANKL activates osteoclasto-

architecture and increase the risk of complications referred to as genesis, prolongs the time of osteoclasts’ survival by binding on

skeletal-related events (SRE) [1–3]. The processes of bone these cells and their precursors’ surface [18–21]. In turn, M-CSF

resorption and formation are closely interrelated and, although increases RANKL expression on the surface of bone stromal cells,

they may be impaired due to ongoing cancerogenesis, they occur at has a chemotactic effect on osteoclasts and prolongs their life span

the site of the metastasis (independently of its type) in nearly all by inhibiting apoptosis [22].

types of cancer [4]. There are two exceptions from this rule. The IL-11 is another cellular factor that induces and escalates

ﬁrst is osteosarcoma (the 3rd most frequent type of cancer in osteoclastogenesis [23]. There are many other growth factors that

children and youth) which is related to pure osteosclerotic can directly or indirectly induce osteoclasts’ formation, stimulate

metastasis [5] and the second is multiple myeloma giving their activity or prolong their life span. One of them is Parathyroid

exclusively metastases of “purely” osteolytic character [6]. In all Hormone-Related Peptide (PTHRP1), produced by a majority of

other types of cancers, the process of bone formation is secondary solid tumor cells (e.g. breast cancers). PTHrP binds to PTHRP1

to osteolysis [7]. receptor (i.e. receptor of PTH) and induces RANKL expression on

Prostate and bladder cancers are responsible mainly for cells of stromal bone marrow (see Fig. 1) [24,25].

osteosclerotic (aka. osteoblastic) metastases [8], however intense TGFb, in turn, stimulates the production of PTHrP by breast

osteolysis is also observed in these types of cancers. Therefore, the cancer cells [26,27]. It has been found that PTHrP production was

application of antiresorptive drugs decreases pain and risk of increased in 92% of patients with metastases from breast to bone,

pathological fractures in patients with prostate cancer [9–11]. while the presence of this peptide was conﬁrmed in only 50% of

Breast and lung cancers and lymphomas lead to simultaneous patients suffering from breast cancer without metastasis to bone

osteosclerotic and osteolytic metastases. These types of lesions are tissue [28].

therefore referred to as mixed- type metastases. Phenotypic similarity of breast cancer cells to osteoblasts is the

In patients with breast and lung cancer, osteolytic lesions reason why breast cancer tends to metastasize to the bone. Barns

prevail. In 25% of patients suffering from breast cancer, blastic et al. have shown ectopic expression of the transcription factor

metastasis is also present, while osteosclerotic metastases prevail referred to as the RUNX2 protein (Runt-Related Transcription

in 15–20% of such patients [1,3,12]. In the case of thyroid, kidney Factor 2) that stimulates bone sialoprotein (BSP) synthesis in

and multiple myeloma cancers, osteolytic metastasis is the most breast cancers [29]. BSP level correlates positively with the

frequent type of lesion [13]. frequency of metastasis to the bone [30]. BSP plays a role in

Biochemical markers of bone turnover (i.e. cell-secreted angiogenesis, micro-calciﬁcation and protection from comple-

peptides and proteins as well as cellular products of degradation) ment-induced cell lysis [31]. RUNX2 protein also stimulates

are assessed for quick evaluation of cellular activity in the bone osteoblasts’ differentiation. Breast cancer and multiple myeloma

[14]. The levels of the above-mentioned markers may be increased cells produce cytokines that inhibit osteoblasts’ activity, namely

in female breast cancer patients even in the absence of clinical activin A and DKK-1 (dikkopf-related protein 1) [32,33]. DKK-1 is a

manifestations of metastases [15].

Fig. 1. A simpliﬁed scheme of osteolytic bone metastases.

I. Zaporowska-Stachowiak et al. / Biomedicine & Pharmacotherapy 93 (2017) 1277–1284 1279

soluble inhibitor of the Wnt signal path which is important for the Osteolytic metastases may be a reason of such para-neoplastic

process of growth and differentiation of osteoblasts. symptoms, such as hypercalcemia (nausea, vomiting, constipation,

abdominal pain, debilitation, anorexia, body mass loss, polyuria,

nephrolithiasis, oscitance, impaired consciousness, coma and

1.1.2. Osteosclerotic (osteoblastic) metastases

death). These symptoms occur predominately in the course of

myeloma myelitis (in 33% of patients), breast cancer (19% of

The cells of some cancer types, such as adenocarcinoma, secrete

patients) and lung cancer [53,54].

or induce the secretion of various factors stimulating osteoblasts’

Neurological impairments (due to pressure on the nerve) and

proliferation [34,35], such as transforming growth factor b (TGFb)

pathological bone fractures causing pain and spinal cord compres-

and urokinase [36]. Other factors responsible for the formation and

sion are the most frequent results/complications of osteolytic and

activation of osteoblasts are Wnt (wingless int) proteins that

osteosclerotic metastases. These complications concern mainly

stimulate these cells’ differentiation and activation, prolong their

such long bones as femur or humerus, which are exposed to weight

life span and suppress osteoclastic activity [37]. Also Platelet-

bearing. Less frequent complications include: limited mobility

Derived Growth Factor (PDGF) increases osteoblasts’ activity and

(resulting in bedsores, clots, embolism, infections, muscle dystro-

stimulates angiogenesis [38].

phy) and spinal cord instability. Not only do the above-mentioned

Osteoblasts produce Insulin-Growth Factors (IGFs; and so do

complications signiﬁcantly decrease the patients’ quality of life,

bone endothelial cells) and insulin-like growth factor-binding

but they are also life-threatening [55,56].

proteins (IGF-BPs). The IGF axis imbalance promotes tumor

invasion and tumor-induced angiogenesis. IGF balance depends

2. Diagnostics of cancer induced bone pain (CIBP)

on urokinase plasminogen activator (uPA), synthesized by tumor

and endothelial cells. IGF and uPA mutually boost their activity.

The majority (70–75%) of patients with metastases to the bone

High uPa levels are responsible for the degradation of IGF-BPs and

suffer from pain [57]. Thus, from the therapeutic point of view, pain

by the same token for the increase in IGFs. This in turn stimulates

diagnostics is of paramount importance.

the growth of metastatic cells and osteoblasts. IGF-1 also activates

Bone pain may be of localized nature and be present in one (in

metalloproteinases in cancer cells [39].

10% of patients) or a few areas of the bone system. It may also be

It was shown that Insulin-Growth Factors (IGF-1 and IGF-2)

generalized. The latter type of pain is frequent after bone marrow

stimulated the proliferation of osteoblasts and prolong their life

replacement and it is referred to as the bone marrow replacement

span [40]. Adrenomedulin (ADM) promotes angiogenesis. Prostate

syndrome [58–60]. The occurrence and intensity of CIBP depends

cancer cells were observed to produce osteogenic factors, including

among others on the location of the cancer and/or metastases and

Wnt proteins which are osteoinductive and oncogenic. DKK-1 is a

on the degree of bone tissue destruction [61]. However, some

Wnt antagonist and inhibits bone growth within osteoblastic

patients complain from CIBP weeks or months before bone

metastases [41]. Endothelin-1 (ET-1) stimulates ETAR and using N-

structure damage can be conﬁrmed by radiology or scintigraphy

terminal portion of PTHrP down-regulates DKK-1 produced by

[62]. On the other hand, only 25% patients with metastases to the

tumor cells. It leads to osteoblasts’ proliferation, drop of

bone do not feel CIBP [63].

osteoclasts’ activity, to an increase in bone mineralization and

A very important issue that must be addressed when treating

to the activation of other pro-osteosclerotic growth factors [42,43].

cancer patients is the question of permanent cancer-induced bone

This is rooted in the fact that the endothelin system is crucial for

pain (localized, frequently described as “deep” and “dull”. In the

numerous physiological and pathological processes, including

early stage of the disease it may be of occasional nature, but the

cancerogenesis and osteoblastic metastases. Endothelins inﬂuence

patient’s motion and weight-bearing activities may intensify it.

the following signaling pathways: Ras, b-catenin/T-cell factor/

Also night pain and pain at rest are characteristic for patients

lymphoid enhancer factor, mitogen activated protein kinases,

with bone cancer.

nuclear factor-kB (NFkB), mammalian target of rapamycin (mTOR)

CIPB can be also felt during palpation and percussion

and the zinc-ﬁnger transcriptional factors (Snail) [44].

examination. Other typical syndromes are backbone deformation,

Also another particle, described as Vascular Endothelial Growth

oedema, increased muscle tonus in the lesion area, radiating pain

Factor (VEGF) is able to stimulate osteoblasts’ differentiation and is

and synalgia (e.g. presence of lesion in Th12-L1 vertebrae may be

involved in osteolysis [45]. Its expression is dependent of the

felt as lateral/bilateral pain of wing of ilium/sacro-iliac joint; see

mentioned IGF-1 levels in serum [39]. Another growth factor À

Table 1).

Fibroblast Growth Factor [2,6,25,46–48] stimulates not only

If metastases to the bone are suspected, their diagnostics should

osteoblasts’ differentiation but also their proliferation.

be performed as soon as possible by means of:

During bone cancerogenesis, the activated osteoblasts secrete

various growth factors that are later used by cancer cells to

anamnesis and physical examination, imaging examination: x-

proliferate and to increase their odds for survival. These

ray, bone scintigraphy (displaying high sensitivity but low

proliferating cancer cells secrete increased numbers of pro-

speciﬁcity), computed tomography (CT), nuclear magnetic

osteoblastic factors that stimulate cancerogenesis. This path turns

resonance imaging (MRI, highly sensitive and speciﬁc, it is the

into a vicious circle [6]. Over a half a century ago, a theory was

diagnostic method of choice), positron emission tomography

proposed according to which all types of metastasis to the bone are

(PET),

preceded by osteolysis [49]. Although this theory has not been

conﬁrmed to this day, it has been proven that by stopping

laboratory tests: evaluation of peripheral blood morphology

osteolysis, cancer cells proliferation may be decreased (even in

(bone marrow cells suppression), assessment of plasma levels of:

cases of osteosclerotic metastases) thanks to the drop in the

ionized calcium, albumins (hipoalbuminemia À> increase of

secretion of cancer-inducing growth factors released from the

ionized calcium), urea, creatinine, alkaline phosphatase,

bone matrix [47].

biopsy – histological and pathological conﬁrmation of an

Apart from its impact on osteoclasts and osteoblasts, cancer

ongoing disease process.

cells in bone mobilize and modulate the function of bone marrow

cells (in particular platelets and white cells) as well as neurons and

One should be aware of non-symptomatic vertebral fractures

cells responsible for angiogenesis [50–52].

that are discovered only in bone imaging [67]. In case of metastases

1280 I. Zaporowska-Stachowiak et al. / Biomedicine & Pharmacotherapy 93 (2017) 1277–1284

Table 1

Characteristics of bone cancer pain [56,64–66]

Bone Cancer Pain Characteristics

Duration Permanent Pain (may be periodic at the beginning)

Incidental

1) Spontaneous at rest (pain without cause)

2) Breakthrough pain (BTP), dependent/independent of the patient (e.g. motion-induced/cough-induced)

So-called wandering pain (appears and disappears, sometimes completely, and shifts to another location; frequent in hematologic

cancers)

Nature Frequent descriptions:

1) Permanent – “dull”, “deep”

2) Incidental – “acute”, “throbbing”

Severity Severe (60% of patients), moderate (30%), weak (10%). Intensity of pain increases along with progression of disease

Site Backbone (in 13%, Th most frequently); generalized pain (metastases, multiple metastases in 10.2% of patients), pelvis bones (in 7.1%), thorax

(ribs in 6.8%), long bones (in 3.9%)

Radiation +

Synalgia +

(e.g. lesion in the pelvis is felt as a pain in the knee)

Other symptoms Paresthesia, mechanical and dynamical allodynia, hyper-/hipoalgesia

Pain triggers/aggravating Dependent and independent on the patient: motion, weight-bearing activities

factors

Alleviating factors See text below and Tables 2 and 3 (treatment)

ﬁ

to the bones, medical treatment is aimed to increase life quality The signi cance of bone resorption suppression in the

and to alleviate or to signiﬁcantly reduce pain. Moreover, it should prevention of occurrence of new and of progression of diagnosed

prevent bedsore formation, immobilization and provide anti- metastases to the bone is still not fully elucidated. There are reports

ﬁ –

clotting prophylaxis. indicating a bene cial impact of such suppression [71 74]. The

The treatment consists of: unique pathophysiology of metastases to the bone may be

conﬁrmed by the fact that the application of antiresorptive drugs

assessment of expected time of survival and physical ﬁtness, does not correlate with tumor growth in soft tissues [75].

assessment of fracture risk, Antiresorptive drugs used for the treatment of metastases are

surgical consultation: assessment of usefulness of such inter- presented in Table 3.

ventions as vertebroplasty, use of orthopedic appliances, The currently used antiresorptive drugs (osteoclastogenesis

radiotherapeutic consultation to assess the possibility of tele- inhibiting), i.e. bisphosphonates and denosumab (antibody bind-

radiotherapy and radioisotopic therapy. ing to the ligand of receptor activator of nuclear factor kappa-beta)

signiﬁcantly decrease the number of bone-related complications in

Bone pain decreases the patient's mobility, causes anxiety, cases of metastases to the bones and display an additional

–

depression, increased risk of respiratory system infection, throm- anticancer effect. However, in ca. 30 50% of patients with

boembolism and bedsore formation, thus decreasing the quality of metastases to the bone who use antiresorptive drugs, new

life [68]. metastases and complications are observed, as well as progression

of previously existing lesions [6,84,85]. The above clearly indicates

3. Therapeutic implications of CIBP a need for new therapeutic options. New drugs able to affect the

pathophysiology of metastasis to bone that are used currently or

The following procedures are applied in the prophylaxis and are at the stage of clinical trials are as follows:

treatment of metastases to the bone:

Recombined, RANKL-blocking OPG drugs (OPG analogs) [86],

1 Systemic treatment that consists of hormone therapy, chemo- Soluble RANK-Fc suppressing RANKL [21,87] ,

therapy, radio-isotopic therapy (Sr89, Sm 153, Ren 186 decrease Oligonucleotides that block P2 7 receptor of NK-kB and

pain and have a cytoreductive effect), application of drugs suppress its activation [88],

preventing bone loss, such as bisphosphonates and denosumab. Humanized anti-PTHrP antibodies that stop RANKL-induced

Radium-223 dichloride (Ra-223) is also considered a bone- osteolysis [25],

–

targeting agent whose intake results in pain decrease and, in Atrasentan inhibitor of endothelin ETA receptor able to stop

some patients, metastases stabilization or remission [70], osteosclerotic metastases in patients with prostate cancer [40],

2 Local treatment e.g. by means of palliative radiotherapy that Activin A (ACE-011) inhibitors [89,90] and inhibitors of metal-

leads to regression of metastases and to calciﬁcation of loproteinases of the bone matrix able to stop metastatic cells and

osteolytic lesions; another procedure is surgical treatment that the angiogenesis process [91]. In the case of metastases to the

ﬁ

is used to join bone shards, to introduce implants and bone, the bers of afferent CGRP and NF200 neurons undergo

endoprostheses, to perform vertebtoplasty and external ﬁxation pathological reorganization referred to as sprouting. Among

ﬁ

of bones, sprouting CGRP and NF200 bers surrounded by bone marrow

3 Symptomatic treatment: treatment of chronic and acute pain cancer cells colony, increased numbers of TrkA receptors (high

ﬁ

(according to the WHO three-step ladder for cancer pain relief it af nity to nerve growth factor receptor/tropomiosin receptor

is the so-called “fourth-step” i.e. invasive, anesthetic methods kinase A) [92] and of GAP43 protein (growth associated protein

Table 2), hypercalcemia and anemia treatment. 43) are observed. The TrkA receptor binds NGF (nerve growth

I. Zaporowska-Stachowiak et al. / Biomedicine & Pharmacotherapy 93 (2017) 1277–1284 1281

Table 2

Drugs used in Poland for the treatment of chronic and acute bone pain according to the WHO three-step pain relief ladder [69].

Group of drugs Drugs Comments

1 st choice drugs

Analgetics Nonsteroidal anti-inﬂammatory drugs KETOPROFEN, diclofenak, Efﬁcacy in 75% of patients

(NSAIDs) ibuprofen, naprokxen

Opioids Morphine sulphate or Morphine and oxycodone are not recommended for patients

hydrochloride, phentanyl, with renal insufﬁciency

oxycodone, buprenorphine,

methadone

Glucocorticosteroids Dexamethasone, prednisone Recommended in case of efﬁcacy or impaired efﬁcacy of

NSAIDs; always recommended in case of possible or

performed compression of spinal cord – very high initial

dosage should be decreased with time to the lowest efﬁcient

dose

2nd choice drugs

Antiresorptive drugs BISPHOSPHONATES Pamidronate, zolendronate Used depending on renal function and concentration of

ionized calcium level in blood

Antiepileptic drugs Gabapentin and other similar drugs gabapentin, pregabalin Recommended due to high neuropathic bone pain component

So-called 4th step of the Blocs of peripheral nerves and nerve Bupivacaine, lidocaine These local analgetics may be neurotoxic and cardiotoxic,

analgesic plexuses; other blocks: central, especially if used for prolonged periods of time!

ladderÀinvasive extradural, subarachnoid, paravertebral

anesthetic techniques

factor) which is essential for the survival of afferent and Bone Pain is responsible for patients’ limited mobility and negative

autonomic nerves, modulates neurotransmitter release and emotions, increased risk of respiratory system infection, embolism,

stimulates pathogenic proliferation of nerve ﬁbers [93,94], bedsore formation and it signiﬁcantly decreases the quality of life.

Tanezumab is an antibody against NGF; it displays an analgetic Therefore it is of paramount importance to provide patients

effect and is a promising drug for the treatment of metastases to with an early palliative care integrated with oncological treatment,

the bone [95]. Also the GAP43 protein plays a role in the which will ensure an optimum pain alleviation strategy, con-

sprouting of nerve ﬁbers and in the regeneration of central and sultations, treatments and physical therapy, offered simultaneous-

peripheral nerve ﬁbers [96]. ly with comprehensive care taking into account the psycho-social

and spiritual components of suffering, as well as will offer support

for the persons caring for the patient.

4. Summary In the treatment of CIBP, palliative radiotherapy and analgetic

drugs given to the patient according to the WHO three-step ladder

Bone pain, caused mainly by metastases to the bone system (use of drugs with various targets having an impact on the receptor

(that are unfavorable prognostics of survival time), occurs most and neuropathic component of pain) are the treatment of choice

frequently in patients with malignant tumors. Cancer Induced

Table 3

Antiresorptive drugs used in the treatment of bone metastases.

Group of drugs/ Mechanism of action Comments

Drug

Bisphosphonates pamidronate They have a direct and indirect effect: by preventing bone loss and Recommendations for pamidronate: osteolytic metastases;

(BPs) cancer cell proliferation they stop the vicious circle of cancer cell shorter T1/2, lower risk of nephrotoxicity and bone necrosis than

and osteoclasts interaction in the microenvironment of the bone for zoledronate

zoledronate tissue. Bisphosphonates stimulate the differentiation of T-cell Zoledronate – recommendations: osteoblastic and osteolytic

subpopulation (gd cells) responsible for the destruction of cancer metastases, signiﬁcant nephrotoxicity and risk of bone necrosis

cells – this effect is especially strong in zoledronate; they strongly [72]. Long-term effect; during application, temporary suppression

suppress osteoclastic activity, decrease cancer cells’ survival of bone formation may be observed leading to jaw necrosis (the

(complex mechanism); they stop angiogenesis and display effect is stronger in the case of zoledronate) Regular use of BPs as

immuno-modulative effect[76–79]. means of oncologic and palliative treatment leads to high

cumulative doses

Monoclonal denosumab It binds the ligand of receptor activator of nuclear factor kappa- Recommendations (apart from osteoporosis):

Human beta (RANKL). It leads to the suppression of formation, activity and Skeletal-Related Events Prevention in adult patients with solid

Antibody survival of osteoclasts and to the drop in the resorption of tumor metastases to the bones (pathological fractures, need of

(IgG2) trabecular and cortical bone. It prevents the formation and treats bone radiation, pressure on spinal cord, need of surgical treatment

metastases to the bone; it prevents Skeletal Related Events (more of bones. The drug is administered in the dose of 120 mg s.c 1Â/4

effectively than BPs) and displays anticancer effect (conﬁrmed in weeks. In case of treatment of adults or young people with a

patients with bone marrow cancer) [80–82] mature bone system and suffering from inoperable giant-cell

tumor of the bone, the dosage is 120 mg s.c. 1Â/4 weeks and on

day 8 and 15 of the treatment, additional doses of 120 mg are given

[83]. In comparison to zoledronate, the use of denosumab leads to

a longer delay in the occurrence of the ﬁrst skeletal-related event

in patients with metastases of breast or prostate cancer to the

bone [73].

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