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Early identification and intervention matters: A comprehensive review of current evidence and recommendations for the monitoring of bone health in patients with cancer

Open AccessPublished:October 17, 2017DOI:https://doi.org/10.1016/j.ctrv.2017.09.008

      Highlights

      • Bone metastases and skeletal-related events (SREs) are common in advanced cancer.
      • Agents such as denosumab and bisphosphonates can prevent SREs.
      • Early detection of bone metastases is vital for early intervention.
      • Across tumor types, guidelines differ in their recommendations on bone assessment.
      • Regular bone health monitoring is important in patients with advanced cancer.

      Abstract

      Bone metastases are common in patients with advanced solid tumors, and many individuals experience debilitating skeletal-related events (SREs; e.g. pathologic fracture, hypercalcemia, radiotherapy or surgery to bone, and spinal cord compression). These events substantially affect disease outcomes, including survival and quality of life, and healthcare systems. Plain radiography is the most widely used imaging modality for the detection of bone metastases; skeletal scintigraphy, computed tomography, positron emission tomography and magnetic resonance imaging offer greater sensitivity but their use in routine practice is restricted by high costs and limited availability. Biomarkers of bone turnover may also have a role in the early detection of bone metastases and can provide valuable prognostic information on disease progression. SREs can be delayed or prevented using agents such as the receptor activator of nuclear factor kappa B ligand (RANKL) inhibitor, denosumab, and bisphosphonates. Painful bone metastases can be treated with radiofrequency ablation, radiotherapy, or radionuclides such as radium-223 dichloride, which has been shown to delay the onset of SREs in men with castration-resistant prostate cancer. Close monitoring of bone health in patients with advanced cancer may lead to early identification of individuals with bone metastases who could benefit from early intervention to prevent SREs. This review examines current guideline recommendations for assessing and monitoring bone health in patients with advanced cancer, use of biomarkers and treatment of patients with bone metastases. The emerging evidence for the potential survival benefit conferred by early intervention with denosumab and bisphosphonates is also discussed, together with best practice recommendations.

      Keywords

      Introduction

      Bone metastases are common in patients with advanced solid tumors [
      • Coleman R.E.
      Metastatic bone disease: clinical features, pathophysiology and treatment strategies.
      ]. Cancers particularly associated with bone metastases include those of the prostate and breast (65–75% of patients) [
      • Coleman R.E.
      Metastatic bone disease: clinical features, pathophysiology and treatment strategies.
      ], and those affecting the lung (30–40%) [
      • Coleman R.E.
      Metastatic bone disease: clinical features, pathophysiology and treatment strategies.
      ] and kidney (20–32%) [
      • Coleman R.E.
      Metastatic bone disease: clinical features, pathophysiology and treatment strategies.
      ,
      • Woodward E.
      • Jagdev S.
      • McParland L.
      • Clark K.
      • Gregory W.
      • Newsham A.
      • et al.
      Skeletal complications and survival in renal cancer patients with bone metastases.
      ]. A substantial proportion of patients with advanced cancer and bone metastases will develop skeletal complications known collectively as skeletal-related events (SREs); these include pathologic fracture, spinal cord compression and hypercalcemia, as well as radiation or surgery to bone, which are surrogate markers for skeletal pain and fractures [
      • Coleman R.E.
      Clinical features of metastatic bone disease and risk of skeletal morbidity.
      ]. On average, patients with untreated bone metastases experience an SRE every 3–6 months [
      • Coleman R.E.
      Clinical features of metastatic bone disease and risk of skeletal morbidity.
      ], placing a considerable burden on both patients and healthcare systems [
      • Carter J.A.
      • Ji X.
      • Botteman M.F.
      Clinical, economic and humanistic burdens of skeletal-related events associated with bone metastases.
      ]. A pooled analysis of data from phase 3 trials found that moderate/severe pain and strong opioid analgesic use generally increased in the 6 months preceding an SRE and remained elevated once the SRE had occurred [
      • von Moos R.
      • Body J.J.
      • Egerdie B.
      • Stopeck A.
      • Brown J.
      • Fallowfield L.
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      Pain and analgesic use associated with skeletal-related events in patients with advanced cancer and bone metastases.
      ]; pain interfered with daily living and reduced emotional wellbeing [
      • von Moos R.
      • Body J.J.
      • Egerdie B.
      • Stopeck A.
      • Brown J.
      • Fallowfield L.
      • et al.
      Pain and analgesic use associated with skeletal-related events in patients with advanced cancer and bone metastases.
      ]. Furthermore, SREs have been associated with decreased survival [
      • Cetin K.
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      • Jacobsen J.B.
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      Do skeletal-related events predict overall survival in men with metastatic castration-resistant prostate cancer?.
      ]. Early detection of bone metastases is therefore important to enable optimal management of patients with bone complications secondary to cancer.
      The risk of SREs can be reduced through the use of agents such as the receptor activator of nuclear factor kappa B (RANK) ligand (RANKL) inhibitor denosumab (120 mg administered by subcutaneous injection every 4 weeks) [] and bisphosphonates, such as zoledronic acid (4 mg administered by intravenous infusion every 3–4 weeks) [

      Novartis Europharm Limited. Zometa summary of product characteristics, http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000336/WC500051730.pdf; 2006 [accessed 17.05.2016].

      ]. Pamidronate, ibandronate and clodronate are also indicated for the prevention of SREs but only for patients with breast cancer (pamidronate and clodronate are also indicated for patients with multiple myeloma) [

      Hospira UK Ltd. Pamidronate disodium summary of product characteristics, https://www.medicines.org.uk/emc/medicine/21442; 2016 [accessed 06.01.2017].

      ,

      Accord Healthcare Ltd. Ibandronic acid Accord summary of product characteristics, http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002638/WC500135847.pdf; 2012 [accessed 06.01.2017].

      ,

      Beacon Pharmaceuticals. Sodium clondronate (CLASTEON®) summary of product characteristics, https://www.medicines.org.uk/emc/medicine/26774; 2016 [accessed 06.01.2017].

      ]. Studies have shown that tumor-specific androgen pathway inhibitors, such as abiraterone acetate and enzalutamide, also have beneficial effects on bone in patients with prostate cancer, although this effect is likely to be due to their role in controlling the underlying disease rather than a direct effect on bone [
      • Logothetis C.J.
      • Basch E.
      • Molina A.
      • Fizazi K.
      • North S.A.
      • Chi K.N.
      • et al.
      Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial.
      ,
      • Scher H.I.
      • Fizazi K.
      • Saad F.
      • Taplin M.E.
      • Sternberg C.N.
      • Miller K.
      • et al.
      Increased survival with enzalutamide in prostate cancer after chemotherapy.
      ,
      • Fizazi K.
      • Scher H.I.
      • Miller K.
      • Basch E.
      • Sternberg C.N.
      • Cella D.
      • et al.
      Effect of enzalutamide on time to first skeletal-related event, pain, and quality of life in men with castration-resistant prostate cancer: results from the randomised, phase 3 AFFIRM trial.
      ]. However, some patients in these studies received concomitant bisphosphonates. In addition, radium-223 dichloride (radium-223) has been shown to improve overall survival (OS) significantly compared with placebo in men with castration-resistant prostate cancer and bone metastases [
      • Parker C.
      • Nilsson S.
      • Heinrich D.
      • Helle S.I.
      • O'Sullivan J.M.
      • Fossa S.D.
      • et al.
      Alpha emitter radium-223 and survival in metastatic prostate cancer.
      ].
      Early identification of patients with bone metastases is critical if the treatment options are to be best used to shift the balance from palliative treatment towards prevention of SREs, thus maintaining patients’ quality of life. However, numerous factors hinder the detection of bone metastases in patients with advanced cancer, including a lack of established screening programs and differences across patient groups in terms of who seeks medical advice. For example, men are less likely than women to visit their doctor if they experience pain [
      • Hoffmann D.E.
      • Tarzian A.J.
      The girl who cried pain: a bias against women in the treatment of pain.
      ], which may delay the identification of symptomatic bone metastases in these patients. With the exception of breast cancer, general screening for bone metastases for all patients with solid tumors is not recommended (Table 1). For example, bone imaging is recommended in patients with non-small-cell lung cancer (NSCLC) or renal cell carcinoma only if symptoms suggest the presence of bone metastases [
      • Escudier B.
      • Porta C.
      • Schmidinger M.
      • Rioux-Leclercq N.
      • Bex A.
      • Khoo V.
      • et al.
      Renal cell carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ,
      • Novello S.
      • Barlesi F.
      • Califano R.
      • Cufer T.
      • Ekman S.
      • Levra M.G.
      • et al.
      Metastatic non-small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ]. In contrast, it is recommended that all patients with locally advanced breast cancer undergo bone imaging, regardless of whether symptoms of bone metastases are present [
      • Cardoso F.
      • Costa A.
      • Norton L.
      • Senkus E.
      • Aapro M.
      • Andre F.
      • et al.
      ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2).
      ,
      • Senkus E.
      • Kyriakides S.
      • Ohno S.
      • Penault-Llorca F.
      • Poortmans P.
      • Rutgers E.
      • et al.
      Primary breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ]. The European School of Oncology (ESO)–European Society for Medical Oncology (ESMO) joint guidelines for advanced breast cancer recommend bone imaging as part of a full staging workup for patients with advanced breast cancer, preferably with computed tomography (CT) or positron emission tomography (PET) coupled with CT (PET/CT) [
      • Cardoso F.
      • Costa A.
      • Norton L.
      • Senkus E.
      • Aapro M.
      • Andre F.
      • et al.
      ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2).
      ]. The guidelines also recommend that patients are managed by a multidisciplinary team that includes imaging experts [
      • Cardoso F.
      • Costa A.
      • Norton L.
      • Senkus E.
      • Aapro M.
      • Andre F.
      • et al.
      ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2).
      ].
      Table 1European guideline recommendations for the assessment for bone metastases at diagnosis of different tumor types.
      Tumor typeAgencySummary of guidance
      ProstateEAU

      Mottet N, Bellmunt N, Briers E, van den Bergh R, Bolla M, van Casteren N, et al. European Association of Urology guidelines on prostate cancer, http://uroweb.org/wp-content/uploads/09-Prostate-Cancer_LR.pdf; 2015 [accessed 18.05.2016].

      • Bone scintigraphy or radiography is recommended during routine disease staging, except in low-risk disease
        • Low-risk disease: no routine bone scintigraphy; additional imaging only required if it changes patient management
        • Intermediate-risk disease: bone scintigraphy and cross-sectional imaging
        • High-risk disease (localized/locally advanced): CT/MRI and bone scintigraphy
      • Bone scintigraphy or radiography should be performed in all patients with signs and symptoms of bone metastases
      • PET should not be used for upfront staging
      • 18F-PET, PET/CT or diffusion-weighted whole-body or axial MRI are more sensitive than bone scintigraphy and targeted radiography, but bone scintigraphy is preferred owing to lower cost and greater availability
      • Elevated B-ALP and PSA are indicators of bone metastases
      ProstateESMO
      • Parker C.
      • Gillessen S.
      • Heidenreich A.
      • Horwich A.
      Cancer of the prostate: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      • Imaging techniques recommended for patients with intermediate- or high-risk disease:
        • Bone scintigraphy and thoraco-abdominal CT
        • Whole-body MRI
        • Choline PET/CT
      Breast (primary)ESMO
      • Senkus E.
      • Kyriakides S.
      • Ohno S.
      • Penault-Llorca F.
      • Poortmans P.
      • Rutgers E.
      • et al.
      Primary breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      • Asymptomatic distant metastases are rare in patients with primary breast cancer; tests for metastases are recommended only for patients with locally advanced or symptomatic disease
      • Bone scintigraphy, CT and abdominal ultrasonography can be considered for patients with:
        • Clinically positive axillary nodes
        • Tumors ≥ 5 cm along longest axis
        • Aggressive tumor biology
        • Clinical signs or symptoms, or laboratory values suggesting the presence of metastases
      • Dual imaging methods combining functional and anatomical information, such as 18FDG–PET/CT, may be used when conventional methods are inconclusive
      • PET/CT should not be used for staging loco-regional disease but can be used to stage high-risk, locally advanced or inflammatory disease because these patients are at a high risk of metastases
      Breast (advanced)ESO–ESMO
      • Cardoso F.
      • Costa A.
      • Norton L.
      • Senkus E.
      • Aapro M.
      • Andre F.
      • et al.
      ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2).
      • Patients with locally advanced breast cancer have a significant risk of metastatic disease; a full staging workup, including bone imaging, is highly recommended
      • Thoracic and abdominal CT are preferred to thoracic radiography
      • PET/CT, if available, may be used instead of (not in addition to) CT and bone scintigraphy
      • Given the high risk of concomitant distant metastases, patients with chest wall or regional (nodal) recurrence should undergo full re-staging, including bone imaging
      NSCLC (metastatic)ESMO
      • Novello S.
      • Barlesi F.
      • Califano R.
      • Cufer T.
      • Ekman S.
      • Levra M.G.
      • et al.
      Metastatic non-small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      • Standard staging includes routine bone biochemistry tests (not specified) and CT of the chest and upper abdomen
      • If bone metastases are suspected, recommended bone imaging techniques are:
        • PET ± CT
        • Bone scintigraphy
        • 18FDG–PET
      • MRI can be used to document localized bone metastases
      • PET/CT and 18FDG–PET are more sensitive than bone scintigraphy
      Renal cell carcinomaESMO
      • Escudier B.
      • Porta C.
      • Schmidinger M.
      • Rioux-Leclercq N.
      • Bex A.
      • Khoo V.
      • et al.
      Renal cell carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      • Contrast-enhanced chest, abdominal and pelvic CT is mandatory
      • Bone scintigraphy is not recommended unless indicated by signs and symptoms of bone metastases
      • Bone scan is not recommended unless indicated by clinical or laboratory signs or symptoms
      • 18FDG–PET is not recommended for diagnosis or staging
      Abbreviations: B-ALP, bone-specific alkaline phosphatase; CT, computed tomography; EAU, European Association of Urology; ESMO, European Society for Medical Oncology; ESO, European School of Oncology; F, fluorine; FDG, fluorodeoxyglucose; MRI, magnetic resonance imaging; NSCLC, non-small-cell lung cancer; PET, positron emission tomography; PSA, prostate-specific antigen.
      In the case of prostate cancer, European guidelines recommend that only patients with intermediate- or high-risk disease should be assessed using advanced imaging techniques [

      Mottet N, Bellmunt N, Briers E, van den Bergh R, Bolla M, van Casteren N, et al. European Association of Urology guidelines on prostate cancer, http://uroweb.org/wp-content/uploads/09-Prostate-Cancer_LR.pdf; 2015 [accessed 18.05.2016].

      ,
      • Parker C.
      • Gillessen S.
      • Heidenreich A.
      • Horwich A.
      Cancer of the prostate: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ]. The risk of bone metastases in these patients may be assessed on the basis of prostate-specific antigen (PSA) level, disease stage and Gleason score (all at diagnosis) [
      • Briganti A.
      • Suardi N.
      • Gallina A.
      • Abdollah F.
      • Novara G.
      • Ficarra V.
      • et al.
      Predicting the risk of bone metastasis in prostate cancer.
      ]. Guidance from the European Association of Urology (EAU) and ESMO defines the following categories of disease risk: intermediate risk – PSA level 10–20 ng/mL or Gleason score of 7 or stage cT2b disease; high risk – PSA level greater than 20 ng/mL or Gleason score of more than 7 or stage cT2c disease or higher [

      Mottet N, Bellmunt N, Briers E, van den Bergh R, Bolla M, van Casteren N, et al. European Association of Urology guidelines on prostate cancer, http://uroweb.org/wp-content/uploads/09-Prostate-Cancer_LR.pdf; 2015 [accessed 18.05.2016].

      ,
      • Parker C.
      • Gillessen S.
      • Heidenreich A.
      • Horwich A.
      Cancer of the prostate: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ].
      Many imaging techniques are available for the detection of bone metastases, although cost, availability and expertise may vary across regions, meaning that patients may not have access to regular highly sensitive screening. New technologies for the detection of bone metastases are being developed, such as biomarkers of bone turnover, but these are not yet recommended in clinical practice. In this review, we discuss imaging and other techniques for the early identification of bone metastases, and recommendations for the early treatment of bone metastases immediately following diagnosis.

      Imaging modalities and assessment of bone metastases

      The different imaging methods have advantages and disadvantages in clinical practice (Table 2) [
      • Bombardieri E.
      • Setti L.
      • Kirienko M.
      • Antunovic L.
      • Guglielmo P.
      • Ciocia G.
      Which metabolic imaging, besides bone scan with 99mTc-phosphonates, for detecting and evaluating bone metastases in prostatic cancer patients? An open discussion.
      ,
      • Cook G.J.
      • Azad G.K.
      • Goh V.
      Imaging bone metastases in breast cancer: staging and response assessment.
      ,
      • Jehn C.F.
      • Diel I.J.
      • Overkamp F.
      • Kurth A.
      • Schaefer R.
      • Miller K.
      • et al.
      Management of metastatic bone disease algorithms for diagnostics and treatment.
      ,
      • O'Sullivan G.J.
      • Carty F.L.
      • Cronin C.G.
      Imaging of bone metastasis: an update.
      ]. Plain radiography detects increased blood flow and reactive bone formation at the site of metastases but has low sensitivity and specificity. Bone scintigraphy is more sensitive than plain radiography for detecting skeletal pathology but has low specificity [

      Coleman R, Body JJ, Aapro M, Hadji P, Herrstedt J. Bone health in cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol 2014; 25 Suppl 3: iii124–37.

      ]. These techniques are relatively inexpensive and are available at most hospitals; however, the low sensitivity and specificity necessitate confirmation using other imaging modalities in patients with equivocal findings of bone metastases or a small number of hot spots [
      • Jehn C.F.
      • Diel I.J.
      • Overkamp F.
      • Kurth A.
      • Schaefer R.
      • Miller K.
      • et al.
      Management of metastatic bone disease algorithms for diagnostics and treatment.
      ]. Magnetic resonance imaging (MRI) is more sensitive than bone scintigraphy [
      • O'Sullivan G.J.
      • Carty F.L.
      • Cronin C.G.
      Imaging of bone metastasis: an update.
      ] and is the preferred method for early detection of spinal cord metastases. CT can readily distinguish osteolytic, sclerotic and soft tissue lesions, and is therefore useful during localization for biopsy and to detect bone metastases that extend into soft tissue [
      • Jehn C.F.
      • Diel I.J.
      • Overkamp F.
      • Kurth A.
      • Schaefer R.
      • Miller K.
      • et al.
      Management of metastatic bone disease algorithms for diagnostics and treatment.
      ]. Given the strengths and weaknesses of individual imaging modalities, there is increasing interest in hybrid techniques such as single-photon emission CT/CT, PET/CT and PET/MRI, which combine anatomical and functional information. It must be noted, however, that hybrid methods involving CT increase a patient’s exposure to radiation [
      • O'Sullivan G.J.
      • Carty F.L.
      • Cronin C.G.
      Imaging of bone metastasis: an update.
      ]; the risk–benefit profile should therefore be considered for each patient.
      Table 2Advantages and disadvantages of imaging modalities for the detection of bone metastases
      • Bombardieri E.
      • Setti L.
      • Kirienko M.
      • Antunovic L.
      • Guglielmo P.
      • Ciocia G.
      Which metabolic imaging, besides bone scan with 99mTc-phosphonates, for detecting and evaluating bone metastases in prostatic cancer patients? An open discussion.
      ,
      • Cook G.J.
      • Azad G.K.
      • Goh V.
      Imaging bone metastases in breast cancer: staging and response assessment.
      ,
      • Jehn C.F.
      • Diel I.J.
      • Overkamp F.
      • Kurth A.
      • Schaefer R.
      • Miller K.
      • et al.
      Management of metastatic bone disease algorithms for diagnostics and treatment.
      ,
      • O'Sullivan G.J.
      • Carty F.L.
      • Cronin C.G.
      Imaging of bone metastasis: an update.
      .
      Imaging modalityAdvantagesDisadvantages
      Plain radiography
      • Widely available and inexpensive
      • Insensitive for detection of metastases
      Radionuclide bone scintigraphy
      • Relatively inexpensive
      • Evaluates whole skeletal system
      • Provides information on osteoblastic activity and skeletal vascularity
      • More sensitive than plain radiography
      • Low specificity for bone metastases
      • Cannot directly detect osteolytic metastases
      CT
      • Higher resolution than plain radiography and provides three-dimensional anatomical information
      • Modality of choice for evaluating cortical bone (e.g. the ribs)
      • Excellent soft tissue and contrast resolution; soft tissue extension of bone metastases is easily visualized
      • Useful to localize lesions for biopsy
      • Low specificity for bone metastases
      MRI
      • Higher resolution than plain radiography and additional three-dimensional anatomical information
      • Highly sensitive (95%) for detection of bone metastases
      • Multi-planar images permit imaging of the entire spine in the sagittal plane
      • Excellent for demonstrating bone marrow infiltration
      • Preferred imaging method for spinal cord compression and subsequent planning of surgery or radiation therapy
      • Superior to 11C-choline PET/CT for detecting bone metastases
      • Not suitable for evaluating cortical bone
      • Cost-effectiveness of newer MRI modalities (e.g. whole-body or axial MRI) unclear
      SPECT
      • Superior sensitivity and specificity to bone scintigraphy
      • Axial slices provide better localization of radionuclide uptake than bone scintigraphy
      • Cannot generate absolute quantification values
      • Whole-body scanning not possible in a reasonable time frame
      • Less widely available and more costly than other imaging modalities
      18FDG–PET
      • Superior sensitivity to bone scintigraphy
      • Allows visualization of functional aspects
      • Role in routine practice unclear
      • Less widely available and more costly than other imaging modalities
      11C-choline PET/CT
      • Higher specificity than bone scintigraphy and MRI, with fewer indeterminate lesions
      • May not provide greater sensitivity than bone scintigraphy
      • Cost-effectiveness unclear
      • Less widely available and more costly than other imaging modalities
      Abbreviations: C, carbon; CT, computed tomography; FDG, fluorodeoxyglucose; MRI, magnetic resonance imaging; PET, positron emission tomography; SPECT, single-photon emission computed tomography.
      Imaging is usually recommended by European guidelines only as part of disease staging, and only if there are signs or symptoms of bone metastases. Bone scintigraphy is the preferred method for detecting bone metastases (Table 1 and Fig. 1) [
      • Escudier B.
      • Porta C.
      • Schmidinger M.
      • Rioux-Leclercq N.
      • Bex A.
      • Khoo V.
      • et al.
      Renal cell carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ,
      • Novello S.
      • Barlesi F.
      • Califano R.
      • Cufer T.
      • Ekman S.
      • Levra M.G.
      • et al.
      Metastatic non-small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ,
      • Cardoso F.
      • Costa A.
      • Norton L.
      • Senkus E.
      • Aapro M.
      • Andre F.
      • et al.
      ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2).
      ,
      • Senkus E.
      • Kyriakides S.
      • Ohno S.
      • Penault-Llorca F.
      • Poortmans P.
      • Rutgers E.
      • et al.
      Primary breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ,

      Mottet N, Bellmunt N, Briers E, van den Bergh R, Bolla M, van Casteren N, et al. European Association of Urology guidelines on prostate cancer, http://uroweb.org/wp-content/uploads/09-Prostate-Cancer_LR.pdf; 2015 [accessed 18.05.2016].

      ,
      • Parker C.
      • Gillessen S.
      • Heidenreich A.
      • Horwich A.
      Cancer of the prostate: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ] and recommendations for use of other imaging techniques vary among guidelines. PET is recommended as an alternative to bone scintigraphy in some guidelines [
      • Novello S.
      • Barlesi F.
      • Califano R.
      • Cufer T.
      • Ekman S.
      • Levra M.G.
      • et al.
      Metastatic non-small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ,
      • Cardoso F.
      • Costa A.
      • Norton L.
      • Senkus E.
      • Aapro M.
      • Andre F.
      • et al.
      ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2).
      ,
      • Parker C.
      • Gillessen S.
      • Heidenreich A.
      • Horwich A.
      Cancer of the prostate: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ] whereas other guidelines suggest that it should be used only if bone scintigraphy is inconclusive [
      • Senkus E.
      • Kyriakides S.
      • Ohno S.
      • Penault-Llorca F.
      • Poortmans P.
      • Rutgers E.
      • et al.
      Primary breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ] or that it should not be used in routine practice [
      • Escudier B.
      • Porta C.
      • Schmidinger M.
      • Rioux-Leclercq N.
      • Bex A.
      • Khoo V.
      • et al.
      Renal cell carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ,

      Mottet N, Bellmunt N, Briers E, van den Bergh R, Bolla M, van Casteren N, et al. European Association of Urology guidelines on prostate cancer, http://uroweb.org/wp-content/uploads/09-Prostate-Cancer_LR.pdf; 2015 [accessed 18.05.2016].

      ]. MRI and CT are recommended for clinical staging in patients with high- or intermediate-risk prostate cancer [

      Mottet N, Bellmunt N, Briers E, van den Bergh R, Bolla M, van Casteren N, et al. European Association of Urology guidelines on prostate cancer, http://uroweb.org/wp-content/uploads/09-Prostate-Cancer_LR.pdf; 2015 [accessed 18.05.2016].

      ,
      • Parker C.
      • Gillessen S.
      • Heidenreich A.
      • Horwich A.
      Cancer of the prostate: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ], and PET/CT is recommended for screening for bone metastases in patients with advanced NSCLC or breast cancer [
      • Novello S.
      • Barlesi F.
      • Califano R.
      • Cufer T.
      • Ekman S.
      • Levra M.G.
      • et al.
      Metastatic non-small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ,
      • Cardoso F.
      • Costa A.
      • Norton L.
      • Senkus E.
      • Aapro M.
      • Andre F.
      • et al.
      ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2).
      ]. PET/CT may also be used in place of CT and bone scintigraphy in some patients with primary breast cancer (those with large tumors, aggressive biology, and signs or symptoms of metastases) [
      • Senkus E.
      • Kyriakides S.
      • Ohno S.
      • Penault-Llorca F.
      • Poortmans P.
      • Rutgers E.
      • et al.
      Primary breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ]. The guidelines for renal cell carcinoma recommend bone scintigraphy only in patients with suspected bone metastases, and advanced imaging techniques such as MRI or CT should be used only during staging [
      • Escudier B.
      • Porta C.
      • Schmidinger M.
      • Rioux-Leclercq N.
      • Bex A.
      • Khoo V.
      • et al.
      Renal cell carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ]. Biochemical methods for detecting bone metastases are mentioned in the ESMO clinical practice guidelines for metastatic NSCLC, although the precise tests are not specified [
      • Novello S.
      • Barlesi F.
      • Califano R.
      • Cufer T.
      • Ekman S.
      • Levra M.G.
      • et al.
      Metastatic non-small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ]. The only other guideline that recommends biochemical tests for metastases is the EAU guideline on prostate cancer, which lists bone-specific alkaline phosphatase (B-ALP) and PSA as indicators for bone metastases [

      Mottet N, Bellmunt N, Briers E, van den Bergh R, Bolla M, van Casteren N, et al. European Association of Urology guidelines on prostate cancer, http://uroweb.org/wp-content/uploads/09-Prostate-Cancer_LR.pdf; 2015 [accessed 18.05.2016].

      ].
      Figure thumbnail gr1
      Fig. 1European guideline recommendations for the assessment of bone metastases and use of bone-protective agents at different disease stages [
      • Escudier B.
      • Porta C.
      • Schmidinger M.
      • Rioux-Leclercq N.
      • Bex A.
      • Khoo V.
      • et al.
      Renal cell carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ,
      • Novello S.
      • Barlesi F.
      • Califano R.
      • Cufer T.
      • Ekman S.
      • Levra M.G.
      • et al.
      Metastatic non-small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ,
      • Cardoso F.
      • Costa A.
      • Norton L.
      • Senkus E.
      • Aapro M.
      • Andre F.
      • et al.
      ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2).
      ,
      • Senkus E.
      • Kyriakides S.
      • Ohno S.
      • Penault-Llorca F.
      • Poortmans P.
      • Rutgers E.
      • et al.
      Primary breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ,

      Coleman R, Body JJ, Aapro M, Hadji P, Herrstedt J. Bone health in cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol 2014; 25 Suppl 3: iii124–37.

      ]. aPSA level 10–20 ng/mL or Gleason score ≤7 or stage cT2b or higher. bPSA level >20 ng/mL or Gleason score >7, or locally advanced disease with any PSA level and stage cT3–4 or lymph-node-positive disease. c Calcium and vitamin D supplementation recommended. dAsymptomatic distant metastases are rare in primary breast cancer. eApproved but not recommended by the guideline. Abbreviations: ADT, androgen-deprivation therapy; AI, aromatase inhibitor; B-ALP, bone-specific alkaline phosphatase; BMD, bone mineral density; CT, computed tomography; FDG, fluorodeoxyglucose; MRI, magnetic resonance imaging; NA, not applicable; NSCLC, non-small-cell lung cancer; PET, positron emission tomography; PSA, prostate-specific antigen; Ra-223, radium-223 dichloride; SRE, skeletal-related event.
      In line with the recommendations in European guidelines, randomized phase 3 trials in patients with breast or prostate cancer generally used bone scintigraphy and CT/MRI to identify bone metastases and SREs (spinal cord compression and pathologic fracture), although other methods, such as radiographic bone survey or clinical assessment of symptomatic SREs, have occasionally been used. Bone turnover markers were assessed in only five of the identified phase 3 clinical trials (Table 3) [
      • Logothetis C.J.
      • Basch E.
      • Molina A.
      • Fizazi K.
      • North S.A.
      • Chi K.N.
      • et al.
      Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial.
      ,
      • Scher H.I.
      • Fizazi K.
      • Saad F.
      • Taplin M.E.
      • Sternberg C.N.
      • Miller K.
      • et al.
      Increased survival with enzalutamide in prostate cancer after chemotherapy.
      ,
      • Fizazi K.
      • Scher H.I.
      • Miller K.
      • Basch E.
      • Sternberg C.N.
      • Cella D.
      • et al.
      Effect of enzalutamide on time to first skeletal-related event, pain, and quality of life in men with castration-resistant prostate cancer: results from the randomised, phase 3 AFFIRM trial.
      ,
      • Amadori D.
      • Aglietta M.
      • Alessi B.
      • Gianni L.
      • Ibrahim T.
      • Farina G.
      • et al.
      Efficacy and safety of 12-weekly versus 4-weekly zoledronic acid for prolonged treatment of patients with bone metastases from breast cancer (ZOOM): a phase 3, open-label, randomised, non-inferiority trial.
      ,
      • Barrett-Lee P.
      • Casbard A.
      • Abraham J.
      • Hood K.
      • Coleman R.
      • Simmonds P.
      • et al.
      Oral ibandronic acid versus intravenous zoledronic acid in treatment of bone metastases from breast cancer: a randomised, open label, non-inferiority phase 3 trial.
      ,
      • Fizazi K.
      • Carducci M.
      • Smith M.
      • Damiao R.
      • Brown J.
      • Karsh L.
      • et al.
      Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study.
      ,
      • Gnant M.
      • Baselga J.
      • Rugo H.S.
      • Noguchi S.
      • Burris H.A.
      • Piccart M.
      • et al.
      Effect of everolimus on bone marker levels and progressive disease in bone in BOLERO-2.
      ,
      • James N.D.
      • Pirrie S.J.
      • Pope A.M.
      • Barton D.
      • Andronis L.
      • Goranitis I.
      • et al.
      Clinical outcomes and survival following treatment of metastatic castrate-refractory prostate cancer with docetaxel alone or with strontium-89, zoledronic acid, or both: the TRAPEZE randomized clinical trial.
      ,
      • Loriot Y.
      • Miller K.
      • Sternberg C.N.
      • Fizazi K.
      • De Bono J.S.
      • Chowdhury S.
      • et al.
      Effect of enzalutamide on health-related quality of life, pain, and skeletal-related events in asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer (PREVAIL): results from a randomised, phase 3 trial.
      ,
      • Rosen L.S.
      • Gordon D.
      • Kaminski M.
      • Howell A.
      • Belch A.
      • Mackey J.
      • et al.
      Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial.
      ,
      • Sartor O.
      • Coleman R.
      • Nilsson S.
      • Heinrich D.
      • Helle S.I.
      • O'Sullivan J.M.
      • et al.
      Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial.
      ,
      • Smith M.R.
      • Halabi S.
      • Ryan C.J.
      • Hussain A.
      • Vogelzang N.
      • Stadler W.
      • et al.
      Randomized controlled trial of early zoledronic acid in men with castration-sensitive prostate cancer and bone metastases: results of CALGB 90202 (alliance).
      ,
      • Stopeck A.T.
      • Lipton A.
      • Body J.J.
      • Steger G.G.
      • Tonkin K.
      • de Boer R.H.
      • et al.
      Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study.
      ].
      Table 3Methodologies used in phase 3 trials to identify bone metastases and SREs in patients with breast or prostate cancer.
      Trial name and authorTumor typeTreatment vs comparatorImaging methodology usedBiomarker measurements taken
      TRAPEZE; James et al.
      • James N.D.
      • Pirrie S.J.
      • Pope A.M.
      • Barton D.
      • Andronis L.
      • Goranitis I.
      • et al.
      Clinical outcomes and survival following treatment of metastatic castrate-refractory prostate cancer with docetaxel alone or with strontium-89, zoledronic acid, or both: the TRAPEZE randomized clinical trial.
      ProstateDocetaxel vs docetaxel plus strontium-89 or zoledronic acid, or both
      • ‘Clinical assessment’ of symptomatic SREs
      • No protocol-mandated radiological assessment
      • None
      PREVAIL; Loriot et al.
      • Loriot Y.
      • Miller K.
      • Sternberg C.N.
      • Fizazi K.
      • De Bono J.S.
      • Chowdhury S.
      • et al.
      Effect of enzalutamide on health-related quality of life, pain, and skeletal-related events in asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer (PREVAIL): results from a randomised, phase 3 trial.
      ProstateEnzalutamide vs placebo
      • Assessment of SREs not specified
      • None
      AFFIRM; Scher et al.
      • Scher H.I.
      • Fizazi K.
      • Saad F.
      • Taplin M.E.
      • Sternberg C.N.
      • Miller K.
      • et al.
      Increased survival with enzalutamide in prostate cancer after chemotherapy.
      and Fizazi et al.
      • Fizazi K.
      • Scher H.I.
      • Miller K.
      • Basch E.
      • Sternberg C.N.
      • Cella D.
      • et al.
      Effect of enzalutamide on time to first skeletal-related event, pain, and quality of life in men with castration-resistant prostate cancer: results from the randomised, phase 3 AFFIRM trial.
      ProstateEnzalutamide vs placebo
      • CT or MRI of soft tissue to assess progression
      • Radionuclide bone scan to assess bone lesions and metastases
      • None
      ALSYMPCA; Sartor et al.
      • Sartor O.
      • Coleman R.
      • Nilsson S.
      • Heinrich D.
      • Helle S.I.
      • O'Sullivan J.M.
      • et al.
      Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial.
      ProstateRadium-223 vs placebo
      • Bone metastases confirmed using bone scintigraphy and CT
      • ‘Clinical assessment’ of symptomatic SREs
      • None
      CALGB 90202 (Alliance); Smith et al.
      • Smith M.R.
      • Halabi S.
      • Ryan C.J.
      • Hussain A.
      • Vogelzang N.
      • Stadler W.
      • et al.
      Randomized controlled trial of early zoledronic acid in men with castration-sensitive prostate cancer and bone metastases: results of CALGB 90202 (alliance).
      ProstateZoledronic acid vs placebo
      • Bone metastases confirmed by bone scintigraphy, MRI, CT or plain radiography
      • ‘Clinical assessment’ of symptomatic SREs and new bone metastases (radiographic assessment was not required)
      • None
      COU-AA-301; Logothetis et al.
      • Logothetis C.J.
      • Basch E.
      • Molina A.
      • Fizazi K.
      • North S.A.
      • Chi K.N.
      • et al.
      Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial.
      ProstateAbiraterone acetate and prednisone vs placebo and prednisone
      • Bone scintigraphy scheduled throughout the study
      • Radiographic assessment for pathologic fracture and spinal cord compression
      • None
      Fizazi et al.
      • Fizazi K.
      • Carducci M.
      • Smith M.
      • Damiao R.
      • Brown J.
      • Karsh L.
      • et al.
      Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study.
      ProstateDenosumab vs zoledronic acid
      • Radiographic evidence of bone metastases required
      • Skeletal survey (including radiographic assessment) to identify SREs and new bone metastases
      • Urinary type 1 collagen NTx
      • B-ALP
      Stopeck et al.
      • Stopeck A.T.
      • Lipton A.
      • Body J.J.
      • Steger G.G.
      • Tonkin K.
      • de Boer R.H.
      • et al.
      Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study.
      BreastDenosumab vs zoledronic acid
      • Bone metastases confirmed by radiography, CT or MRI
      • Pathologic fracture assessed by radiography, CT or MRI
      • Urinary type 1 collagen NTx
      • B-ALP
      ZICE; Barrett-Lee et al.
      • Barrett-Lee P.
      • Casbard A.
      • Abraham J.
      • Hood K.
      • Coleman R.
      • Simmonds P.
      • et al.
      Oral ibandronic acid versus intravenous zoledronic acid in treatment of bone metastases from breast cancer: a randomised, open label, non-inferiority phase 3 trial.
      BreastZoledronic acid vs ibandronate
      • Radiographic evidence of ≥1 bone metastasis required
      • Plain radiography to identify SREs
      • None
      ZOOM; Amadori et al.
      • Amadori D.
      • Aglietta M.
      • Alessi B.
      • Gianni L.
      • Ibrahim T.
      • Farina G.
      • et al.
      Efficacy and safety of 12-weekly versus 4-weekly zoledronic acid for prolonged treatment of patients with bone metastases from breast cancer (ZOOM): a phase 3, open-label, randomised, non-inferiority trial.
      BreastZoledronic acid Q12W vs zoledronic acid Q4W
      • Radiographic evidence of ≥1 bone metastasis required
      • Radiography or CT to identify pathologic fractures
      • Type 1 collagen NTx
      BOLERO-2; Gnant et al.
      • Gnant M.
      • Baselga J.
      • Rugo H.S.
      • Noguchi S.
      • Burris H.A.
      • Piccart M.
      • et al.
      Effect of everolimus on bone marker levels and progressive disease in bone in BOLERO-2.
      BreastEverolimus vs placebo
      • Bone scintigraphy or skeletal survey to identify bone metastases
      • Patients with bone metastases also assessed by radiography, CT or MRI
      • Serum B-ALP
      • Serum P1NP
      • Serum type 1 collagen CTx
      Rosen et al.
      • Rosen L.S.
      • Gordon D.
      • Kaminski M.
      • Howell A.
      • Belch A.
      • Mackey J.
      • et al.
      Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial.
      Breast or multiple myelomaZoledronic acid vs pamidronate
      • Bone metastases confirmed by bone scintigraphy
        In patients with breast cancer only.
        and bone survey
      • SREs identified by ‘clinical assessment’
      • Serum B-ALP and PTH
      • Urinary pyridinoline, deoxypyridinoline and type 1 collagen NTx
      Abbreviations: B-ALP, bone-specific alkaline phosphatase; CT, computed tomography; CTx, C-terminal telopeptides; MRI, magnetic resonance imaging; NSCLC, non-small-cell lung cancer; NTx, N-terminal telopeptides; P1NP, procollagen type 1 N-terminal propeptides; PTH, parathyroid hormone; Q, every; SRE, skeletal-related event; W, weeks.
      a In patients with breast cancer only.
      With regard to follow-up, the guidelines differ in their recommendations on how often tumors should be re-staged and whether this should include skeletal assessment. There is a lack of guidance on regular assessment for bone metastases. The EAU recommends that, for patients with prostate cancer who have received treatment with curative intent, PSA levels should be assessed 3, 6 and 12 months after treatment, then every 6 months for 3 years, and annually thereafter [

      Mottet N, Bellmunt N, Briers E, van den Bergh R, Bolla M, van Casteren N, et al. European Association of Urology guidelines on prostate cancer, http://uroweb.org/wp-content/uploads/09-Prostate-Cancer_LR.pdf; 2015 [accessed 18.05.2016].

      ]. Routine bone imaging is not recommended if there are no signs of biochemical relapse, except in individuals with bone pain or other symptoms of disease progression, for whom re-staging should be considered [

      Mottet N, Bellmunt N, Briers E, van den Bergh R, Bolla M, van Casteren N, et al. European Association of Urology guidelines on prostate cancer, http://uroweb.org/wp-content/uploads/09-Prostate-Cancer_LR.pdf; 2015 [accessed 18.05.2016].

      ]. The ESMO clinical practice guidelines for prostate cancer suggest that regular imaging should be undertaken to monitor response to treatment, although conventional imaging such as CT and bone scintigraphy are not suitable for assessing response or progression in patients with metastatic bone disease, and alternative techniques should be used, such as whole-body MRI [
      • Parker C.
      • Gillessen S.
      • Heidenreich A.
      • Horwich A.
      Cancer of the prostate: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ]. Bone health is an under-recognized issue in men, who can also experience a steady loss of bone mineral density (BMD) with aging, which increases their risk of pathologic fracture [
      • Body J.J.
      • Terpos E.
      • Tombal B.
      • Hadji P.
      • Arif A.
      • Young A.
      • et al.
      Bone health in the elderly cancer patient: a SIOG position paper.
      ]. Many men receive androgen-deprivation therapy (ADT) and are therefore at particularly high risk of pathologic fracture, so should receive regular BMD monitoring [
      • Parker C.
      • Gillessen S.
      • Heidenreich A.
      • Horwich A.
      Cancer of the prostate: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ,
      • Body J.J.
      • Terpos E.
      • Tombal B.
      • Hadji P.
      • Arif A.
      • Young A.
      • et al.
      Bone health in the elderly cancer patient: a SIOG position paper.
      ].
      Follow-up recommendations for patients with advanced breast cancer lack clarity. The ESO–ESMO guidelines recommend radiological assessments in patients with persistent and localized pain due to bone metastases, in order to identify any impending (or actual) pathologic fracture. In addition, full re-staging (including bone imaging) is recommended in patients with chest wall or nodal recurrence [
      • Cardoso F.
      • Costa A.
      • Norton L.
      • Senkus E.
      • Aapro M.
      • Andre F.
      • et al.
      ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2).
      ]. No other recommendations are provided on the frequency of disease staging or skeletal assessment [
      • Cardoso F.
      • Costa A.
      • Norton L.
      • Senkus E.
      • Aapro M.
      • Andre F.
      • et al.
      ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2).
      ]. A large proportion of women with breast cancer are aged 50 years or older [

      International Agency for Research on Cancer. GLOBOCAN estimated breast cancer incidence by age, http://globocan.iarc.fr/old/age-specific_table_r.asp?selection=62968&title=Europe&sex=2&type=0&stat=0&window=1&sort=0&submit=%C2%A0Execute%C2%A0; 2012 [accessed 17.01.2017].

      ] and are therefore likely to be peri- or postmenopausal. This puts them at risk of low BMD, which is exacerbated by the endocrine therapies often used to treat breast cancer (e.g. aromatase inhibitors and gonadotropin-releasing hormone analogs), and they are therefore vulnerable to pathologic fracture [
      • Body J.J.
      • Terpos E.
      • Tombal B.
      • Hadji P.
      • Arif A.
      • Young A.
      • et al.
      Bone health in the elderly cancer patient: a SIOG position paper.
      ,
      • Biganzoli L.
      • Wildiers H.
      • Oakman C.
      • Marotti L.
      • Loibl S.
      • Kunkler I.
      • et al.
      Management of elderly patients with breast cancer: updated recommendations of the International Society of Geriatric Oncology (SIOG) and European Society of Breast Cancer Specialists (EUSOMA).
      ]. A position paper on the treatment of elderly patients with cancer from the International Society of Geriatric Oncology recommends that patients with breast cancer have their BMD monitored every 1–2 years [
      • Body J.J.
      • Terpos E.
      • Tombal B.
      • Hadji P.
      • Arif A.
      • Young A.
      • et al.
      Bone health in the elderly cancer patient: a SIOG position paper.
      ]. For patients receiving endocrine treatment for breast cancer, the ESMO clinical practice guidelines recommend regular follow-up: every 3–4 months for the first 2 years following treatment, then every 6 months in years 3–5, and annually thereafter [
      • Senkus E.
      • Kyriakides S.
      • Ohno S.
      • Penault-Llorca F.
      • Poortmans P.
      • Rutgers E.
      • et al.
      Primary breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ]. It is important to note that fracture risk is high even in individuals with normal BMD. In the placebo arm of the ABCSG–18 (‘Adjuvant denosumab in breast cancer’) trial in postmenopausal women with early stage breast cancer, the incidence of pathologic fracture was 10% in individuals with normal BMD and 11% in those with low BMD [
      • Gnant M.
      • Pfeiler G.
      • Dubsky P.C.
      • Hubalek M.
      • Greil R.
      • Jakesz R.
      • et al.
      Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial.
      ].
      For patients who have undergone surgery for localized renal cell carcinoma, CT assessment every 3–6 months for 2 years is recommended in those with high-risk disease, and annually for those with low-risk disease [
      • Escudier B.
      • Porta C.
      • Schmidinger M.
      • Rioux-Leclercq N.
      • Bex A.
      • Khoo V.
      • et al.
      Renal cell carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ]. The ESMO clinical practice guidelines for metastatic NSCLC recommend follow-up every 6–12 weeks after first-line treatment but do not state what this should entail [
      • Novello S.
      • Barlesi F.
      • Califano R.
      • Cufer T.
      • Ekman S.
      • Levra M.G.
      • et al.
      Metastatic non-small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ].
      Clinical practice patterns may vary between countries as a consequence of differing national guideline recommendations and other factors, such as local institutional practices. A patient chart survey in five European countries showed that individuals in Germany were more likely to have asymptomatic bone lesions detected during routine imaging than were patients in the other countries [
      • Lebret T.
      • Casas A.
      • Cavo M.
      • Woll P.J.
      • Deleplace C.
      • Kennedy C.
      • et al.
      The use of bisphosphonates in the management of bone involvement from solid tumours and haematological malignancies – a European survey.
      ]. There is a need for clear and consistent guidelines regarding regular assessment of bone metastases in individuals with cancer. Current guidelines generally do not recommend routine bone surveys in asymptomatic patients. However, recent real-world evidence from patients with advanced breast cancer has shown that over half (58%) of bone metastases were identified while they were asymptomatic [
      • Kuchuk I.
      • Hutton B.
      • Moretto P.
      • Ng T.
      • Addison C.L.
      • Clemons M.
      Incidence, consequences and treatment of bone metastases in breast cancer patients – experience from a single cancer centre.
      ]. Data from another real-world study indicate that only 38% of patients with advanced solid tumors and bone metastases had their bone metastases identified during routine staging [
      • Lebret T.
      • Casas A.
      • Cavo M.
      • Woll P.J.
      • Deleplace C.
      • Kennedy C.
      • et al.
      The use of bisphosphonates in the management of bone involvement from solid tumours and haematological malignancies – a European survey.
      ]. Early detection of bone metastases alone does not improve survival [
      • Ghezzi P.
      • Magnanini S.
      • Rinaldini M.
      • Berardi F.
      • Di Biagio G.
      • Testare F.
      • et al.
      Impact of follow-up testing on survival and health-related quality of life in breast cancer patients. A multicenter randomized controlled trial. The GIVIO Investigators.
      ]; it is early intervention that results in better outcomes for patients [
      • Ahn S.G.
      • Lee H.M.
      • Cho S.H.
      • Lee S.A.
      • Hwang S.H.
      • Jeong J.
      • et al.
      Prognostic factors for patients with bone-only metastasis in breast cancer.
      ,
      • Meng T.
      • Chen R.
      • Zhong N.
      • Fan T.
      • Li B.
      • Yin H.
      • et al.
      Factors associated with improved survival following surgical treatment for metastatic prostate cancer in the spine: retrospective analysis of 29 patients in a single center.
      ].

      Biomarkers of bone health and tumor-specific factors

      Emerging evidence indicates that bone markers measured in urine or plasma could be used to aid the early identification of patients with asymptomatic bone metastases and those at risk of bone lesion progression [
      • Coleman R.
      • Costa L.
      • Saad F.
      • Cook R.
      • Hadji P.
      • Terpos E.
      • et al.
      Consensus on the utility of bone markers in the malignant bone disease setting.
      ]. Several markers of bone turnover have been identified as potential predictive biomarkers for bone metastases, and the laboratory tests for these markers are generally inexpensive [
      • Seibel M.J.
      Clinical use of markers of bone turnover in metastatic bone disease.
      ]. In the United Kingdom, for example, the cost of measuring bone turnover markers in patients with osteoporosis is approximately one-third of the cost of a dual-energy X-ray absorptiometry scan [
      • Burch J.
      • Rice S.
      • Yang H.
      • Neilson A.
      • Stirk L.
      • Francis R.
      • et al.
      Systematic review of the use of bone turnover markers for monitoring the response to osteoporosis treatment: the secondary prevention of fractures, and primary prevention of fractures in high-risk groups.
      ]. A consensus paper from the Belgian Bone Club recommends that bone turnover markers are used as a cost-conscious option to monitor bone dynamics [
      • Cavalier E.
      • Bergmann P.
      • Bruyere O.
      • Delanaye P.
      • Durnez A.
      • Devogelaer J.P.
      • et al.
      The role of biochemical of bone turnover markers in osteoporosis and metabolic bone disease: a consensus paper of the Belgian Bone Club.
      ].
      Several factors must be considered when using biomarkers to aid the identification of bone metastases and those patients at risk of SREs. It is essential that biomarker assessments are performed consistently at the same time of day for each individual, because serum levels of bone markers vary according to circadian rhythms, with levels generally peaking in the morning [
      • Generali D.
      • Berruti A.
      • Tampellini M.
      • Dovio A.
      • Tedoldi S.
      • Bonardi S.
      • et al.
      The circadian rhythm of biochemical markers of bone resorption is normally synchronized in breast cancer patients with bone lytic metastases independently of tumor load.
      ]. Endocrine treatments for breast cancer [
      • Gallicchio L.
      • MacDonald R.
      • Wood B.
      • Rushovich E.
      • Fedarko N.S.
      • Helzlsouer K.J.
      Changes in bone biomarker concentrations and musculoskeletal symptoms among breast cancer patients initiating aromatase inhibitor therapy and women without a history of cancer.
      ] and alterations in bone turnover resulting from the menopause [
      • Garnero P.
      • Sornay-Rendu E.
      • Chapuy M.C.
      • Delmas P.D.
      Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis.
      ] can affect levels of bone biomarkers in the absence of bone metastases. Similarly, ADT for the treatment of patients with prostate cancer can also result in aberrations in bone biomarkers in metastases-free individuals [
      • Saad F.
      • Eastham J.A.
      • Smith M.R.
      Biochemical markers of bone turnover and clinical outcomes in men with prostate cancer.
      ]. Additionally, it has been shown that, in patients with solid tumors, denosumab and bisphosphonates may alter the levels of certain biomarkers despite the presence of bone metastases [
      • Seibel M.J.
      Clinical use of markers of bone turnover in metastatic bone disease.
      ]; therefore, care should be taken when interpreting such results.
      One such bone marker is alkaline phosphatase (ALP), a membrane-associated enzyme found at high concentrations in osteoblasts as well as in the liver, intestines and placenta. It can be used to assess the presence of bone metastases, particularly in patients with prostate cancer [
      • Kamiya N.
      • Suzuki H.
      • Endo T.
      • Yano M.
      • Naoi M.
      • Nishimi D.
      • et al.
      Clinical usefulness of bone markers in prostate cancer with bone metastasis.
      ]. Several isoforms of ALP are secreted by various organs into the blood, and B-ALP is a sensitive predictive marker of bone turnover and bone metastases in patients with advanced solid tumors [
      • Zhao H.
      • Han K.L.
      • Wang Z.Y.
      • Chen Y.
      • Li H.T.
      • Zeng J.L.
      • et al.
      Value of C-telopeptide-cross-linked type I collagen, osteocalcin, bone-specific alkaline phosphatase and procollagen type I N-terminal propeptide in the diagnosis and prognosis of bone metastasis in patients with malignant tumors.
      ]. Both total ALP and B-ALP are significantly elevated in patients with prostate cancer and bone metastases compared with patients without bone metastases and healthy controls [
      • Garnero P.
      • Buchs N.
      • Zekri J.
      • Rizzoli R.
      • Coleman R.E.
      • Delmas P.D.
      Markers of bone turnover for the management of patients with bone metastases from prostate cancer.
      ], and predict poor prognosis in patients with bone metastases secondary to solid tumors [
      • Lipton A.
      • Smith M.R.
      • Fizazi K.
      • Stopeck A.T.
      • Henry D.
      • Brown J.
      • et al.
      Changes in bone turnover marker levels and clinical outcomes in patients with advanced cancer and bone metastases treated with bone antiresorptive agents.
      ,
      • Sonpavde G.
      • Pond G.R.
      • Berry W.R.
      • de Wit R.
      • Armstrong A.J.
      • Eisenberger M.A.
      • et al.
      Serum alkaline phosphatase changes predict survival independent of PSA changes in men with castration-resistant prostate cancer and bone metastasis receiving chemotherapy.
      ]. An analysis of data from three identically designed blinded phase 3 trials that compared denosumab and zoledronic acid showed that high B-ALP levels were associated with an increased risk of disease progression at the primary site and in bone, as well as reduced OS in both treatment arms [
      • Lipton A.
      • Smith M.R.
      • Fizazi K.
      • Stopeck A.T.
      • Henry D.
      • Brown J.
      • et al.
      Changes in bone turnover marker levels and clinical outcomes in patients with advanced cancer and bone metastases treated with bone antiresorptive agents.
      ]. In patients with prostate cancer and bone metastases receiving zoledronic acid, early increases in serum B-ALP levels have been shown to predict short SRE-free survival and reduced OS [
      • Izumi K.
      • Mizokami A.
      • Itai S.
      • Shima T.
      • Shigehara K.
      • Miwa S.
      • et al.
      Increases in bone turnover marker levels at an early phase after starting zoledronic acid predicts skeletal-related events in patients with prostate cancer with bone metastasis.
      ]. Multivariate analysis of data from patients with prostate cancer enrolled in a phase 3 trial identified ALP, B-ALP and PSA as significant predictors of OS [
      • Fizazi K.
      • Massard C.
      • Smith M.
      • Rader M.
      • Brown J.
      • Milecki P.
      • et al.
      Bone-related parameters are the main prognostic factors for overall survival in men with bone metastases from castration-resistant prostate cancer.
      ].
      The predominant protein in bone is type 1 collagen, and numerous studies have shown that markers of collagen breakdown are correlated with the presence of bone metastases [
      • Brown J.E.
      • Thomson C.S.
      • Ellis S.P.
      • Gutcher S.A.
      • Purohit O.P.
      • Coleman R.E.
      Bone resorption predicts for skeletal complications in metastatic bone disease.
      ]. Serum type 1 collagen C-terminal telopeptides (CTx), B-ALP, osteocalcin and procollagen type 1 N-terminal propeptides (P1NP) have been identified as sensitive predictors of bone metastases in patients with advanced tumors [
      • Zhao H.
      • Han K.L.
      • Wang Z.Y.
      • Chen Y.
      • Li H.T.
      • Zeng J.L.
      • et al.
      Value of C-telopeptide-cross-linked type I collagen, osteocalcin, bone-specific alkaline phosphatase and procollagen type I N-terminal propeptide in the diagnosis and prognosis of bone metastasis in patients with malignant tumors.
      ]. Patients with bone metastases and high levels of N-terminal telopeptides (NTx) have a significantly increased relative risk of SREs, disease progression and death compared with patients with low levels of NTx [
      • Brown J.E.
      • Cook R.J.
      • Major P.
      • Lipton A.
      • Saad F.
      • Smith M.
      • et al.
      Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors.
      ,
      • Ferreira A.R.
      • Alho I.
      • Shan N.
      • Matias M.
      • Faria M.
      • Casimiro S.
      • et al.
      N-telopeptide of type I collagen long-term dynamics in breast cancer patients with bone metastases: clinical outcomes and influence of extraskeletal metastases.
      ]. Other collagen markers that may have diagnostic value include serum procollagen type 1 C-terminal propeptides and type 1 collagen degradation products; both have been found to be significantly elevated in patients with prostate cancer and bone metastases compared with those without bone metastases and healthy controls [
      • Garnero P.
      • Buchs N.
      • Zekri J.
      • Rizzoli R.
      • Coleman R.E.
      • Delmas P.D.
      Markers of bone turnover for the management of patients with bone metastases from prostate cancer.
      ,
      • Koopmans N.
      • de Jong I.J.
      • Breeuwsma A.J.
      • van der Veer E.
      Serum bone turnover markers (PINP and ICTP) for the early detection of bone metastases in patients with prostate cancer: a longitudinal approach.
      ]. Similarly, in patients with NSCLC, those with bone metastases had higher levels of serum type 1 collagen CTx and P1NP than those without bone metastases [
      • Lumachi F.
      • Santeufemia D.A.
      • Del Conte A.
      • Mazza F.
      • Tozzoli R.
      • Chiara G.B.
      • et al.
      Carboxy-terminal telopeptide (CTX) and amino-terminal propeptide (PINP) of type I collagen as markers of bone metastases in patients with non-small cell lung cancer.
      ]. Early increases in levels of serum type 1 collagen CTx after starting zoledronic acid treatment have been shown to predict short SRE-free survival and reduced OS in patients with prostate cancer and bone metastases [
      • Izumi K.
      • Mizokami A.
      • Itai S.
      • Shima T.
      • Shigehara K.
      • Miwa S.
      • et al.
      Increases in bone turnover marker levels at an early phase after starting zoledronic acid predicts skeletal-related events in patients with prostate cancer with bone metastasis.
      ]. P1NP alone [
      • Dean-Colomb W.
      • Hess K.R.
      • Young E.
      • Gornet T.G.
      • Handy B.C.
      • Moulder S.L.
      • et al.
      Elevated serum P1NP predicts development of bone metastasis and survival in early-stage breast cancer.
      ] and the combination of P1NP, B-ALP and tartrate-resistant acid phosphatase 5b, have been shown to be significant predictors of the development of bone metastases in patients with early breast cancer [
      • Lumachi F.
      • Basso S.M.
      • Camozzi V.
      • Tozzoli R.
      • Spaziante R.
      • Ermani M.
      Bone turnover markers in women with early stage breast cancer who developed bone metastases. A prospective study with multivariate logistic regression analysis of accuracy.
      ].
      The use of bone markers to guide treatment decisions has been investigated in the BISMARK study (‘Cost-effective use of BISphosphonates in metastatic bone disease – a comparison of bone MARKer directed zoledronic acid therapy to a standard schedule’). In this study, patients with bone metastases secondary to breast cancer received standard treatment with zoledronic acid (one infusion every 3–4 weeks) or marker-directed treatment, in which the frequency of treatment depended on levels of urinary type 1 collagen NTx [
      • Coleman R.
      • Wright J.
      • Houston S.
      • Agrawal R.
      • Purohit O.
      • Hayward L.
      • et al.
      Randomized trial of marker-directed versus standard schedule zoledronic acid for bone metastases from breast cancer.
      ]. Unfortunately, the study was terminated early because of slow recruitment; this meant that non-inferiority of marker-directed treatment compared with standard treatment could not be demonstrated. The authors suggested that basing zoledronic acid dosing on levels of urinary type I collagen NTx alone was likely to result in suboptimal treatment [
      • Coleman R.
      • Wright J.
      • Houston S.
      • Agrawal R.
      • Purohit O.
      • Hayward L.
      • et al.
      Randomized trial of marker-directed versus standard schedule zoledronic acid for bone metastases from breast cancer.
      ].
      RANKL is a key mediator of osteoclast function and survival, and has been linked to bone metastases. Elevated levels of RANKL have been found in biopsies from aggressive prostate, lung and kidney tumors [
      • De Castro J.
      • Garcia R.
      • Garrido P.
      • Isla D.
      • Massuti B.
      • Blanca B.
      • et al.
      Therapeutic potential of denosumab in patients with lung cancer: Beyond prevention of skeletal complications.
      ,
      • Mikami S.
      • Oya M.
      • Mizuno R.
      • Kosaka T.
      • Katsube K.
      • Okada Y.
      Invasion and metastasis of renal cell carcinoma.
      ,
      • Li X.
      • Liu Y.
      • Wu B.
      • Dong Z.
      • Wang Y.
      • Lu J.
      • et al.
      Potential role of the OPG/RANK/RANKL axis in prostate cancer invasion and bone metastasis.
      ]. Furthermore, elevated serum RANKL has been shown to be a significant risk factor for biochemical recurrence in patients undergoing radical prostatectomy for localized prostate cancer [
      • Todenhofer T.
      • Hennenlotter J.
      • Leidenberger P.
      • Wald A.
      • Hohneder A.
      • Kuhs U.
      • et al.
      Serum receptor activator of nuclear factor kappaB ligand (RANKL) levels predict biochemical recurrence in patients undergoing radical prostatectomy.
      ], and RANK-positive breast tumors have been associated with an increased risk of bone metastases [
      • Ibrahim T.
      • Sacanna E.
      • Gaudio M.
      • Mercatali L.
      • Scarpi E.
      • Zoli W.
      • et al.
      Role of RANK, RANKL, OPG, and CXCR4 tissue markers in predicting bone metastases in breast cancer patients.
      ]. Similar links between high levels of RANK and reduced disease-free survival and OS in patients with breast cancer were reported in the phase 3 GeparTrio study, even though high RANK levels were associated with increased sensitivity to chemotherapy [

      Pfitzner B, Branstetter D, Mergler B, Loibl S, Denkert C, Fasching P, et al. RANK expression is prognostic and predictive in primary breast carcinoma: analysis of samples from the GeparTrio study. In: Poster presented at the 36th Annual San Antonio Breast Cancer Symposium, 10–14 December 2013, San Antonio, TX, USA.

      ]. Breast tumors that are positive for the chemokine receptor type 4, alone or in combination with RANK, are more likely to metastasize to bone than are tumors that are negative for these markers [
      • Ibrahim T.
      • Sacanna E.
      • Gaudio M.
      • Mercatali L.
      • Scarpi E.
      • Zoli W.
      • et al.
      Role of RANK, RANKL, OPG, and CXCR4 tissue markers in predicting bone metastases in breast cancer patients.
      ].
      A diagnostic algorithm designed to consolidate current procedures for the detection of bone metastases in practice was published in 2016 [
      • Jehn C.F.
      • Diel I.J.
      • Overkamp F.
      • Kurth A.
      • Schaefer R.
      • Miller K.
      • et al.
      Management of metastatic bone disease algorithms for diagnostics and treatment.
      ]. Fig. 2 shows a modified version of this algorithm to reflect potential strategies by which early detection of bone pathology might be improved. New developments in biomarkers and tumor-specific factors have the potential to contribute to risk assessment, although further evidence is needed on their prognostic value. Once established, however, it is possible that biomarkers could in future replace, or complement, imaging modalities as diagnostic tools. Biomarker assessment may be faster, less invasive and cheaper than imaging, which would reduce the burden on healthcare systems. These assessments could be performed more regularly than imaging and could help to identify patients who may be at risk of developing bone metastases, or to detect bone metastases at an early stage, before they become established and symptomatic.
      Figure thumbnail gr2
      Fig. 2Diagnostic algorithm for bone pathology in patients with cancer, with potential strategies to improve early diagnosis. aLevels of alkaline phosphatase, lactate dehydrogenase, hemoglobin, leukocytes, thrombocytes, calcium, etc. Abbreviations: ADT, androgen-deprivation therapy; B-ALP, bone-specific alkaline phosphatase; BC, breast cancer; BMD, bone mineral density; BTA, bone-targeted agent; CT, computed tomography; CTIBL, cancer treatment-induced bone loss; CTx, C-terminal telopeptides; DXA, dual-energy X-ray absorptiometry; ICTP, type 1 collagen degradation products; MRI, magnetic resonance imaging; NTx, N-terminal telopeptides; P1CP, procollagen type 1 C-terminal propeptides; P1NP, procollagen type 1 N-terminal propeptides; PC, prostate cancer; PET, positron emission tomography; PSA, prostate-specific antigen; RANK, receptor activator of nuclear factor kappa B; RANKL, receptor activator of nuclear factor kappa B ligand; SPECT, single-photon emission computed tomography; TRACP5b, tartrate-resistant acid phosphatase 5b.

      Treatment of patients with bone metastases

      Early identification of bone metastases means that treatment can be initiated to prevent or delay the development of SREs, which can be debilitating and painful and have a significant impact on patients’ lives [
      • von Moos R.
      • Body J.J.
      • Egerdie B.
      • Stopeck A.
      • Brown J.
      • Fallowfield L.
      • et al.
      Pain and analgesic use associated with skeletal-related events in patients with advanced cancer and bone metastases.
      ,
      • Diel I.J.
      Prognostic factors for skeletal relapse in breast cancer.
      ,
      • von Moos R.
      • Body J.J.
      • Egerdie B.
      • Stopeck A.
      • Brown J.E.
      • Damyanov D.
      • et al.
      Pain and health-related quality of life in patients with advanced solid tumours and bone metastases: integrated results from three randomized, double-blind studies of denosumab and zoledronic acid.
      ,
      • Weinfurt K.P.
      • Li Y.
      • Castel L.D.
      • Saad F.
      • Timbie J.W.
      • Glendenning G.A.
      • et al.
      The significance of skeletal-related events for the health-related quality of life of patients with metastatic prostate cancer.
      ]. SREs are also associated with substantial healthcare resource utilization, including hospitalization and surgery [
      • Hoefeler H.
      • Duran I.
      • Hechmati G.
      • Garzon Rodriguez C.
      • Luftner D.
      • Ashcroft J.
      • et al.
      Health resource utilization associated with skeletal-related events in patients with bone metastases: results from a multinational retrospective–prospective observational study – a cohort from 4 European countries.
      ]. Therefore, prevention or delay of SREs will benefit both patients and healthcare systems. Denosumab and bisphosphonates have been widely studied for the prevention of SREs in patients with advanced cancer. In a long-term follow-up study, zoledronic acid significantly delayed the median time to first SRE compared with placebo (236 vs 155 days; p = 0.009) and reduced the proportion of patients who experienced an on-study SRE (21 months: 36% vs 46%; p = 0.023) [
      • Rosen L.S.
      • Gordon D.
      • Tchekmedyian N.S.
      • Yanagihara R.
      • Hirsh V.
      • Krzakowski M.
      • et al.
      Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, phase III, double-blind, placebo-controlled trial.
      ]. Zoledronic acid is the bisphosphonate that features most prominently in clinical recommendations. Comparative studies have failed to identify an alternative bisphosphonate that is more effective in delaying SREs [
      • Barrett-Lee P.
      • Casbard A.
      • Abraham J.
      • Hood K.
      • Coleman R.
      • Simmonds P.
      • et al.
      Oral ibandronic acid versus intravenous zoledronic acid in treatment of bone metastases from breast cancer: a randomised, open label, non-inferiority phase 3 trial.
      ,
      • Rosen L.S.
      • Gordon D.
      • Kaminski M.
      • Howell A.
      • Belch A.
      • Mackey J.
      • et al.
      Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial.
      ], and it is the only bisphosphonate that reduces the risk of SREs in patients with prostate cancer and bone metastases [
      • Saad F.
      • Gleason D.M.
      • Murray R.
      • Tchekmedyian S.
      • Venner P.
      • Lacombe L.
      • et al.
      A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma.
      ]. In contrast, denosumab has shown superiority over zoledronic acid in three identically designed phase 3 studies involving 5723 patients with breast cancer, prostate cancer and other advanced solid tumors: time to first on-study SRE was extended by a median of 8.2 months and the risk of a first on-study SRE was reduced by 17% (p < 0.001) [
      • Lipton A.
      • Fizazi K.
      • Stopeck A.T.
      • Henry D.H.
      • Brown J.E.
      • Yardley D.A.
      • et al.
      Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials.
      ].
      Once a patient has experienced a SRE, they are at risk of subsequent SREs, which impose a further burden on patient quality of life and put pressure on healthcare resources. Zoledronic acid significantly reduces the risk of multiple SREs in patients with advanced solid tumors and multiple myeloma [
      • Rosen L.S.
      • Gordon D.
      • Tchekmedyian N.S.
      • Yanagihara R.
      • Hirsh V.
      • Krzakowski M.
      • et al.
      Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, phase III, double-blind, placebo-controlled trial.
      ,
      • Rosen L.S.
      • Gordon D.
      • Kaminski M.
      • Howell A.
      • Belch A.
      • Mackey J.
      • et al.
      Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial.
      ]. Denosumab significantly reduced the risk of multiple SREs in patients with advanced solid tumors, and was superior to zoledronic acid at preventing first and subsequent SREs in a pooled analysis of the three phase 3 trials (p < 0.001) [
      • Lipton A.
      • Fizazi K.
      • Stopeck A.T.
      • Henry D.H.
      • Brown J.E.
      • Yardley D.A.
      • et al.
      Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials.
      ]. Bone metastases and SREs are also linked to reduced survival. In a Danish study of 2427 women with breast cancer, the risk of death in the year following a diagnosis of bone metastases was double that in patients with localized disease (hazard ratio [HR] 2.12; 95% confidence interval [CI] 1.71–2.62) [
      • Cetin K.
      • Christiansen C.F.
      • Svaerke C.
      • Jacobsen J.B.
      • Sorensen H.T.
      Survival in patients with breast cancer with bone metastasis: a Danish population-based cohort study on the prognostic impact of initial stage of disease at breast cancer diagnosis and length of the bone metastasis-free interval.
      ]. Furthermore, 1–year survival increased with longer bone-metastases-free intervals (1 to <3-year interval 39.9%; ≥5-year interval 52.6%) [
      • Cetin K.
      • Christiansen C.F.
      • Svaerke C.
      • Jacobsen J.B.
      • Sorensen H.T.
      Survival in patients with breast cancer with bone metastasis: a Danish population-based cohort study on the prognostic impact of initial stage of disease at breast cancer diagnosis and length of the bone metastasis-free interval.
      ]. SREs have also been shown to be associated with significantly increased mortality in men with metastatic castration-resistant prostate cancer (HR 1.67; 95% CI 1.22–2.30; p = 0.001) [
      • Howard L.E.
      • De Hoedt A.M.
      • Aronson W.J.
      • Kane C.J.
      • Amling C.L.
      • Cooperberg M.R.
      • et al.
      Do skeletal-related events predict overall survival in men with metastatic castration-resistant prostate cancer?.
      ].
      Painful bone metastases can be palliated with radionuclides (e.g. radium-223) [
      • Tunio M.
      • Al Asiri M.
      • Al Hadab A.
      • Bayoumi Y.
      Comparative efficacy, tolerability, and survival outcomes of various radiopharmaceuticals in castration-resistant prostate cancer with bone metastasis: a meta-analysis of randomized controlled trials.
      ], radiofrequency ablation [
      • Belfiore G.
      • Tedeschi E.
      • Ronza F.M.
      • Belfiore M.P.
      • Della Volpe T.
      • Zeppetella G.
      • et al.
      Radiofrequency ablation of bone metastases induces long-lasting palliation in patients with untreatable cancer.
      ], or radiotherapy [
      • Chow R.
      • Hoskin P.
      • Chan S.
      • Mesci A.
      • Hollenberg D.
      • Lam H.
      • et al.
      Efficacy of multiple fraction conventional radiation therapy for painful uncomplicated bone metastases: a systematic review.
      ]; however, preventing or delaying the onset of pain is preferable to treating pain itself. Tumor-specific treatments can benefit bone through control of the underlying disease, and the effects of denosumab, bisphosphonates and radionuclides on bone have been shown to prevent SREs and delay the onset of pain; early intervention is therefore important to minimize patient morbidity. Another analysis of the pooled phase 3 data showed that denosumab significantly delayed the onset of moderate-to-severe pain by 1.8 months and the time to overall pain interference by 2.6 months (both p < 0.001) in patients with advanced solid tumors [
      • von Moos R.
      • Body J.J.
      • Egerdie B.
      • Stopeck A.
      • Brown J.E.
      • Damyanov D.
      • et al.
      Pain and health-related quality of life in patients with advanced solid tumours and bone metastases: integrated results from three randomized, double-blind studies of denosumab and zoledronic acid.
      ]. These effects on pain delay and interference were also observed in patients with no or mild pain at baseline, indicating that early treatment is clinically meaningful. In the same analysis, health-related quality of life was also improved in patients who received denosumab relative to those who received zoledronic acid [
      • von Moos R.
      • Body J.J.
      • Egerdie B.
      • Stopeck A.
      • Brown J.E.
      • Damyanov D.
      • et al.
      Pain and health-related quality of life in patients with advanced solid tumours and bone metastases: integrated results from three randomized, double-blind studies of denosumab and zoledronic acid.
      ].
      Evidence is emerging of potential survival benefits with denosumab and bisphosphonates in some patients with bone metastases secondary to solid tumors. In exploratory analyses, patients with elevated baseline levels of urinary type 1 collagen NTx had a significantly reduced risk of death if they received zoledronic acid rather than placebo (risk reduction: 31%; p = 0.0028) [
      • Coleman R.E.
      • Lipton A.
      • Costa L.
      • Cook R.J.
      • Lee K.A.
      • Saad F.
      • et al.
      Possible survival benefits from zoledronic acid treatment in patients with bone metastases from solid tumours and poor prognostic features – an exploratory analysis of placebo-controlled trials.
      ]. In the same study, multivariate analyses indicated a survival benefit with zoledronic acid in patients who had a history of SREs and in those in whom time since diagnosis was shorter than the median [
      • Coleman R.E.
      • Lipton A.
      • Costa L.
      • Cook R.J.
      • Lee K.A.
      • Saad F.
      • et al.
      Possible survival benefits from zoledronic acid treatment in patients with bone metastases from solid tumours and poor prognostic features – an exploratory analysis of placebo-controlled trials.
      ]. In an exploratory analysis of patients with metastatic lung cancer, denosumab was associated with significantly improved median OS compared with zoledronic acid (8.9–9.5 vs 7.7–8.0 months; p = 0.01) [
      • Scagliotti G.V.
      • Hirsh V.
      • Siena S.
      • Henry D.H.
      • Woll P.J.
      • Manegold C.
      • et al.
      Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: subgroup analysis from a randomized phase 3 study.
      ]. An ongoing open-label, phase 3 trial (SPLENDOUR; ‘Survival improvement in lung cancer induced by denosumab therapy’; NCT02129699) is investigating the effect on survival of adding denosumab to first-line standard of care for patients with advanced NSCLC. Radionuclides may also be valuable in the management of bone metastases and prevention of SREs, particularly radium-233, which has been evaluated extensively in men with prostate cancer, and may also confer a survival benefit [
      • Parker C.
      • Nilsson S.
      • Heinrich D.
      • Helle S.I.
      • O'Sullivan J.M.
      • Fossa S.D.
      • et al.
      Alpha emitter radium-223 and survival in metastatic prostate cancer.
      ,
      • Humm J.L.
      • Sartor O.
      • Parker C.
      • Bruland O.S.
      • Macklis R.
      Radium-223 in the treatment of osteoblastic metastases: a critical clinical review.
      ]. However, radium-223 cannot be used in patients with visceral metastases [

      Bayer Pharma AG. Xofigo summary of product characteristics, http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002653/WC500156172.pdf; 2013 [accessed 21.09.2016].

      ]; therefore, early identification of patients with metastases only to bone may allow initiation of radium-223 treatment while patients are still eligible to receive it.
      While there is strong evidence to support early intervention in patients with bone metastases, some data suggest that treatment with bisphosphonates may not benefit all patient populations equally. Exploratory interaction analyses of data from the PR05 trial of the use of sodium clodronate in men with bone metastases secondary to prostate cancer suggest that early therapy may be associated with a greater relative survival benefit in men with poorer prognostic features, such as raised serum alkaline phosphatase and creatinine levels [
      • Dearnaley D.P.
      • Mason M.D.
      • Parmar M.K.B.
      • Sanders K.
      • Sydes M.R.
      Adjuvant therapy with oral sodium clodronate in locally advanced and metastatic prostate cancer: long-term overall survival results from the MRC PR04 and PR05 randomised controlled trials.
      ]. A raised alkaline phosphatase level is likely to be associated with increased osteoblastic activity, and early bisphosphonate treatment may modify osteoclast activation and bone lysis. In addition, a raised creatinine level may be associated with decreased bisphosphonate excretion, and relatively greater drug exposure and enhanced biological effect [
      • Dearnaley D.P.
      • Mason M.D.
      • Parmar M.K.B.
      • Sanders K.
      • Sydes M.R.
      Adjuvant therapy with oral sodium clodronate in locally advanced and metastatic prostate cancer: long-term overall survival results from the MRC PR04 and PR05 randomised controlled trials.
      ]. Moreover, the lack of a statistically significant benefit with early bisphosphonate therapy on symptomatic bone progression-free survival in patients with metastases [
      • Dearnaley D.P.
      • Sydes M.R.
      • Mason M.D.
      • Stott M.
      • Powell C.S.
      • Robinson A.C.
      • et al.
      A double-blind, placebo-controlled, randomized trial of oral sodium clodronate for metastatic prostate cancer (MRC PR05 Trial).
      ] may suggest the involvement of other mechanisms in the development (and survival) of bone metastases in these patients, such as up-regulation of human epidermal growth factor 2 and endothelial growth factor receptor, in response to ADT [
      • Day K.C.
      • Hiles G.L.
      • Kozminsky M.
      • Dawsey S.J.
      • Paul A.
      • Broses L.J.
      • et al.
      HER2 and EGFR overexpression support metastatic progression of prostate cancer to bone.
      ]. Given its distinct mechanism of action and pharmacology, bisphosphonate data cannot be used to infer whether denosumab will benefit some patient groups more than others.
      European guidelines provide recommendations for the assessment of bone metastases and use of bone-protective agents at different disease stages (Fig. 1). Some guidelines recommend that treatment for the prevention of SREs is initiated as soon as bone metastases have been identified, regardless of whether they are symptomatic [
      • Cardoso F.
      • Costa A.
      • Norton L.
      • Senkus E.
      • Aapro M.
      • Andre F.
      • et al.
      ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2).
      ,

      Coleman R, Body JJ, Aapro M, Hadji P, Herrstedt J. Bone health in cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol 2014; 25 Suppl 3: iii124–37.

      ], whereas others recommend treatment only for patients at high risk of SREs [
      • Parker C.
      • Gillessen S.
      • Heidenreich A.
      • Horwich A.
      Cancer of the prostate: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ], pointing out that the risk–benefit ratio should be taken into account when offering patients denosumab or bisphosphonates [

      Mottet N, Bellmunt N, Briers E, van den Bergh R, Bolla M, van Casteren N, et al. European Association of Urology guidelines on prostate cancer, http://uroweb.org/wp-content/uploads/09-Prostate-Cancer_LR.pdf; 2015 [accessed 18.05.2016].

      ]. The variation in guideline recommendations leads to differences in clinical practice, and many patients who might benefit from these agents are not receiving them. In a European patient chart survey, almost one-fifth of patients with bone metastases would never receive bisphosphonates, even though most had a moderate-to-high risk of developing a SRE [
      • Lebret T.
      • Casas A.
      • Cavo M.
      • Woll P.J.
      • Deleplace C.
      • Kennedy C.
      • et al.
      The use of bisphosphonates in the management of bone involvement from solid tumours and haematological malignancies – a European survey.
      ]. Furthermore, bisphosphonate treatment was often delayed, a common reason being safety concerns [
      • Lebret T.
      • Casas A.
      • Cavo M.
      • Woll P.J.
      • Deleplace C.
      • Kennedy C.
      • et al.
      The use of bisphosphonates in the management of bone involvement from solid tumours and haematological malignancies – a European survey.
      ]. It has been established that the long-term safety profiles of denosumab and bisphosphonates are generally good, although a small proportion of patients may experience osteonecrosis of the jaw (ONJ) [
      • Stopeck A.T.
      • Fizazi K.
      • Body J.J.
      • Brown J.E.
      • Carducci M.
      • Diel I.
      • et al.
      Safety of long-term denosumab therapy: results from the open label extension phase of two phase 3 studies in patients with metastatic breast and prostate cancer.
      ], so dental monitoring is required during treatment.
      Early intervention may result in longer treatment exposure for patients and an associated increase in the potential for adverse events. However, this risk should be minimized and weighed against the benefits of early intervention, such as preventing SREs and reducing the burden of SREs on patients and healthcare systems. While a growing body of evidence suggest potential non-inferiority between 12- and 4-weekly zoledronic acid regimens with respect to SREs in patients with bone involvement [
      • Amadori D.
      • Aglietta M.
      • Alessi B.
      • Gianni L.
      • Ibrahim T.
      • Farina G.
      • et al.
      Efficacy and safety of 12-weekly versus 4-weekly zoledronic acid for prolonged treatment of patients with bone metastases from breast cancer (ZOOM): a phase 3, open-label, randomised, non-inferiority trial.
      ,
      • Himelstein A.L.
      • Foster J.C.
      • Khatcheressian J.L.
      • Roberts J.D.
      • Seisler D.K.
      • Novotny P.J.
      • et al.
      Effect of longer-interval vs standard dosing of zoledronic acid on skeletal events in patients with bone metastases: a randomized clinical trial.
      ,
      • Hortobagyi G.N.
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      • Harker W.
      • et al.
      Continued treatment effect of zoledronic acid dosing every 12 vs 4 weeks in women with breast cancer metastatic to bone: the OPTIMIZE-2 randomized clinical trial.
      ], optimal trade-offs must balance the risk of adverse events against efficacy (as well as considering convenience and cost), and will be informed and guided by emerging evidence and patient preferences. Although rare, significant adverse events, such as ONJ, should continue to be evaluated in clinical studies, and steps taken to prevent such complications and to diagnose and treat them early in clinical practice [
      • Beth-Tasdogan N.H.
      • Mayer B.
      • Hussein H.
      • Zolk O.
      Interventions for managing medication-related osteonecrosis of the jaw (MRONJ) (Protocol).
      ]. It should be noted that, given their distinct mechanisms of action, the non-inferiority evidence for zoledronic acid cannot be extrapolated to denosumab; trials evaluating the effect of denosumab administration frequency on the prevention of symptomatic skeletal events are in progress [

      Swiss Group for Cancer Research. Prevention of symptomatic skeletal events with denosumab administered every 4 weeks versus every 12 weeks. NCT02051218. https://clinicaltrials.gov/ct2/show/NCT02051218; 2017 [accessed 11.07.17].

      ].
      Interest in the adjuvant use of denosumab and bisphosphonates in patients with non-metastatic cancer (and without cancer treatment-induced bone loss) is also increasing in light of the potential survival benefit that these agents may confer. Evidence from patients with breast cancer suggests that adjuvant bisphosphonate therapy may improve survival [
      • Coleman R.
      • Powles T.
      • Paterson A.
      • Gnant M.
      • Anderson S.
      • Diel I.
      • et al.
      Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials.
      ] and other outcomes, including the prevention of breast cancer recurrence in bone [
      • Coleman R.
      • Powles T.
      • Paterson A.
      • Gnant M.
      • Anderson S.
      • Diel I.
      • et al.
      Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials.
      ,
      • Coleman R.
      • Cameron D.
      • Dodwell D.
      • Bell R.
      • Wilson C.
      • Rathbone E.
      • et al.
      Adjuvant zoledronic acid in patients with early breast cancer: final efficacy analysis of the AZURE (BIG 01/04) randomised open-label phase 3 trial.
      ], in selected populations, particularly postmenopausal women. A meta-analysis has suggested that patients receiving low- or high-dose bisphosphonate regimens (e.g. 6-monthly or 3–4-weekly zoledronic acid) experience similar benefits with respect to bone recurrence [
      • Coleman R.
      • Powles T.
      • Paterson A.
      • Gnant M.
      • Anderson S.
      • Diel I.
      • et al.
      Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials.
      ]. Furthermore, low-dose zoledronic acid improved disease-free survival in patients with early stage breast cancer receiving adjuvant endocrine therapy [
      • Gnant M.
      • Mlineritsch B.
      • Stoeger H.
      • Luschin-Ebengreuth G.
      • Heck D.
      • Menzel C.
      • et al.
      Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial.
      ,
      • Gnant M.
      • Mlineritsch B.
      • Stoeger H.
      • Luschin-Ebengreuth G.
      • Knauer M.
      • Moik M.
      • et al.
      Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozole plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12.
      ,
      • Coleman R.
      • de Boer R.
      • Eidtmann H.
      • Llombart A.
      • Davidson N.
      • Neven P.
      • et al.
      Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study): final 60-month results.
      ]. Comparable results have been reported with low-dose denosumab (60 mg every 6 months) [

      Gnant M, Pfeiler G, Dubsky PC, Hubalek M, Greil R, Jakesz R, et al. The impact of adjuvant denosumab on disease-free survival: results from 3,425 postmenopausal patients of the ABCSG-18 trial. [abstract]. Cancer Res 2016; 76 Suppl 4: Abstract S2–02.

      ]. Data on early intervention with denosumab and bisphosphonates in other tumor types are limited, but some benefit has been observed in patients with prostate cancer. In a randomized, placebo-controlled phase 3 trial of 1432 men with non-metastatic castration-resistant prostate cancer, denosumab significantly improved bone-metastases-free survival by a median of 4.2 months compared with placebo (HR 0.85; 95% CI 0.73–0.98; p = 0.028) [
      • Smith M.R.
      • Saad F.
      • Coleman R.
      • Shore N.
      • Fizazi K.
      • Tombal B.
      • et al.
      Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial.
      ]. Median OS was, however, similar in both treatment groups. Time to first bone metastases was also significantly delayed in the denosumab group compared with the placebo group (HR 0.84; 95% CI 0.71–0.98; p = 0.032) [
      • Smith M.R.
      • Saad F.
      • Coleman R.
      • Shore N.
      • Fizazi K.
      • Tombal B.
      • et al.
      Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial.
      ]. Further investigations into the adjuvant use of denosumab and bisphosphonates, and the potential antitumor effects of these agents, are ongoing.
      As with any targeted intervention, the risks associated with denosumab and bisphosphonates can be minimized by identifying patients most likely to benefit from early intervention and by limiting exposure as far as possible. With respect to identifying patients most likely to benefit, understanding which patients are likely to develop bone metastases will help to inform treatment decisions and potentially improve outcomes. Unfortunately, there are currently no algorithms that reliably predict which patients will develop bone metastases and would therefore benefit most from the early use of denosumab and bisphosphonates in an adjuvant setting. However, several general prognostic factors that increase the risk of developing bone metastases in breast cancer have been identified, including: tumor subcategory, age at diagnosis, histological subtype, grade, lymph node involvement and tumor size [
      • Diessner J.
      • Wischnewsky M.
      • Stuber T.
      • Stein R.
      • Krockenberger M.
      • Hausler S.
      • et al.
      Evaluation of clinical parameters influencing the development of bone metastasis in breast cancer.
      ,
      • Korde L.A.
      • Gralow J.R.
      Can we predict who's at risk for developing bone metastases in breast cancer?.
      ]. In prostate cancer, PSA levels have been found to correlate with the presence of bone metastases [
      • Kamaleshwaran K.K.
      • Mittal B.R.
      • Harisankar C.N.
      • Bhattacharya A.
      • Singh S.K.
      • Mandal A.K.
      Predictive value of serum prostate specific antigen in detecting bone metastasis in prostate cancer patients using bone scintigraphy.
      ], and PSA kinetics have been shown to be a useful indicator of bone metastases during treatment [
      • Briganti A.
      • Suardi N.
      • Gallina A.
      • Abdollah F.
      • Novara G.
      • Ficarra V.
      • et al.
      Predicting the risk of bone metastasis in prostate cancer.
      ]. With respect to limiting exposure, it is currently unclear for how long patients may benefit from treatment with denosumab and bisphosphonates during their clinical course. It should be noted, however, that the doses of denosumab and bisphosphonates used for the prevention of osteoporosis and cancer treatment-induced bone loss [
      • Gnant M.
      • Pfeiler G.
      • Dubsky P.C.
      • Hubalek M.
      • Greil R.
      • Jakesz R.
      • et al.
      Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial.
      ,
      • Smith M.R.
      • Egerdie B.
      • Hernandez Toriz N.
      • Feldman R.
      • Tammela T.L.
      • Saad F.
      • et al.
      Denosumab in men receiving androgen-deprivation therapy for prostate cancer.
      ] are considerably lower than those used for the prevention of SREs in metastatic bone disease [,

      Novartis Europharm Limited. Zometa summary of product characteristics, http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000336/WC500051730.pdf; 2006 [accessed 17.05.2016].

      ]; and it should be possible to use lower doses in the adjuvant setting and therefore reduce the risk of complications such as ONJ.
      The balance between adverse event risks and efficacy should favor the early use of denosumab and bisphosphonates in an adjuvant setting in patients considered to be at risk of bone metastasis [
      • Coleman R.
      • Powles T.
      • Paterson A.
      • Gnant M.
      • Anderson S.
      • Diel I.
      • et al.
      Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials.
      ,
      • Smith M.R.
      • Saad F.
      • Coleman R.
      • Shore N.
      • Fizazi K.
      • Tombal B.
      • et al.
      Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial.
      ] or low BMD [
      • Gnant M.
      • Pfeiler G.
      • Dubsky P.C.
      • Hubalek M.
      • Greil R.
      • Jakesz R.
      • et al.
      Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial.
      ,
      • Smith M.R.
      • Egerdie B.
      • Hernandez Toriz N.
      • Feldman R.
      • Tammela T.L.
      • Saad F.
      • et al.
      Denosumab in men receiving androgen-deprivation therapy for prostate cancer.
      ]. The prescription of these agents should be considered in these settings, particularly when the risk is high. Recently, Cancer Care Ontario and the American Society of Clinical Oncology have published guidelines which recommend that adjuvant low-dose zoledronic acid (4 mg every 6 months) or clodronate (1600 mg a day) should be considered in postmenopausal women with breast cancer who are candidates for systemic therapy [
      • Dhesy-Thind S.
      • Fletcher G.G.
      • Blanchette P.S.
      • Clemons M.J.
      • Dillmon M.S.
      • Frank E.S.
      • et al.
      Use of adjuvant bisphosphonates and other bone-modifying agents in breast cancer: a Cancer Care Ontario and American Society of Clinical Oncology clinical practice guideline.
      ]. The guideline authors conclude that data for denosumab are promising but currently insufficient to support a recommendation for adjuvant use in breast cancer. However, the authors also recognize the need for more research to compare agents, dose regimens and treatment duration. These guidelines do not cover the use of denosumab and bisphosphonates for the prevention of pathologic fractures in patients at risk of cancer treatment-induced bone loss, or in other cancers [
      • Dhesy-Thind S.
      • Fletcher G.G.
      • Blanchette P.S.
      • Clemons M.J.
      • Dillmon M.S.
      • Frank E.S.
      • et al.
      Use of adjuvant bisphosphonates and other bone-modifying agents in breast cancer: a Cancer Care Ontario and American Society of Clinical Oncology clinical practice guideline.
      ].
      When prescribing denosumab and bisphosphonates, attention should also be paid to renal function, in the case of bisphosphonates, and to risk factors for osteonecrosis and hypocalcemia, particularly in elderly populations [
      • Body J.J.
      • Terpos E.
      • Tombal B.
      • Hadji P.
      • Arif A.
      • Young A.
      • et al.
      Bone health in the elderly cancer patient: a SIOG position paper.
      ]. Ultimately, treatment decisions should be evidence based, and shared with patients and guided by their personal preferences and individual clinical circumstances.

      Best practice recommendations and conclusions

      Early detection of bone metastases is critical in order that treatment is initiated early; this will help to improve outcomes in patients with advanced cancer. Radiography is the most widely used imaging technique for the detection of bone metastases, reflecting its wide availability and low cost. Bone scintigraphy is, however, the imaging modality of choice recommended by European guidelines. While CT, PET and MRI each offer advantages over bone scintigraphy, their roles in routine practice are unclear given high cost and limited availability. Guidelines differ in their recommendations on how often disease stage should be re-assessed in different tumor types, and whether patients should have regular skeletal assessment.
      Interest in biomarkers for monitoring bone health in patients with cancer is growing in the medical community. Numerous biochemical markers of bone turnover have been evaluated in patients with and without bone metastases; serum and urinary levels of type 1 collagen CTx and P1NP in particular provide good predictive and prognostic power. Their use in combination with imaging modalities may improve the early identification of patients at risk of developing bone metastases, individuals who already have asymptomatic bone metastases, and those who may be at imminent risk of a SRE. Expression of RANKL also predicts outcomes in several tumor types. Bone metastases can lead to SREs, which are painful and debilitating, but the risk of such events can be reduced with denosumab or bisphosphonates. However, in clinical practice patients are often not prescribed these agents [
      • Lebret T.
      • Casas A.
      • Cavo M.
      • Woll P.J.
      • Deleplace C.
      • Kennedy C.
      • et al.
      The use of bisphosphonates in the management of bone involvement from solid tumours and haematological malignancies – a European survey.
      ] or do not persist with treatment [
      • Hadji P.
      • Ziller V.
      • Kyvernitakis J.
      • Schmidt N.
      • Kostev K.
      Persistence with bisphosphonates in patients with metastatic breast cancer: a retrospective database analysis.
      ]. Radium-223 may also be used to delay the onset of symptoms of SREs in men with metastatic prostate cancer, although it is not licensed for use in individuals with visceral metastases [
      • Parker C.
      • Nilsson S.
      • Heinrich D.
      • Helle S.I.
      • O'Sullivan J.M.
      • Fossa S.D.
      • et al.
      Alpha emitter radium-223 and survival in metastatic prostate cancer.
      ,

      Bayer Pharma AG. Xofigo summary of product characteristics, http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002653/WC500156172.pdf; 2013 [accessed 21.09.2016].

      ]. Emerging and future evidence will further inform administration regimens to optimize the benefit–risk profile.
      Common treatments for prostate and breast cancer, such as ADT and aromatase inhibitors, may induce bone loss; therefore, patients receiving such treatments should be closely monitored for changes in BMD. The use of low-dose denosumab (60 mg as a single injection every 6 months []) or bisphosphonates (annual infusions or daily/weekly/monthly tablets, in line with license particulars) can be discussed with such patients, as this may reduce the risk of pathologic fracture [
      • Senkus E.
      • Kyriakides S.
      • Ohno S.
      • Penault-Llorca F.
      • Poortmans P.
      • Rutgers E.
      • et al.
      Primary breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ,

      Coleman R, Body JJ, Aapro M, Hadji P, Herrstedt J. Bone health in cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol 2014; 25 Suppl 3: iii124–37.

      ,
      • Body J.J.
      • Terpos E.
      • Tombal B.
      • Hadji P.
      • Arif A.
      • Young A.
      • et al.
      Bone health in the elderly cancer patient: a SIOG position paper.
      ]. Close monitoring of bone health in patients with cancer may lead to early identification and treatment of bone loss and/or bone metastases, which may result in improved outcomes for patients and a reduced burden on healthcare systems.

      Acknowledgement

      Writing support was provided by Liz Hartfield PhD of Oxford PharmaGenesis, Oxford, United Kingdom, and was funded by Amgen (Europe) GmbH.

      Role of the funding source

      Amgen (Europe) GmbH set up the initial meeting in which the manuscript concept was discussed, and provided funding for medical writing support and manuscript submission.

      Disclosure

      Thomas Brodowicz has participated in advisory boards for, and has received honoraria from, Amgen, Bayer, Eisai, Eli Lilly, Novartis, PharmaMar and Roche.
      Peyman Hadji has participated in advisory boards for, and has received honoraria from, Amgen, Eli Lilly, Novartis, Pfizer, Roche and UCB.
      Daniela Niepel is an employee of Amgen.
      Ingo Diel has acted as a consultant for Amgen and has received honoraria from Amgen and Teva.

      Author contributions

      All authors contributed to the conception of the article, were involved in drafting the article and revising it critically for important intellectual content. All authors approved the final article and agree to be accountable for all aspects of the work.

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