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Diagnosis and treatment of bone metastasis: comprehensive guideline of the Japanese Society of Medical Oncology, Japanese Orthopedic Association, Japanese Urological Association, and Japanese Society for Radiation Oncology
  1. H Shibata1,
  2. S Kato2,
  3. I Sekine3,
  4. K Abe4,
  5. N Araki5,
  6. H Iguchi6,
  7. T Izumi7,
  8. Y Inaba8,
  9. I Osaka9,
  10. S Kato10,
  11. A Kawai11,
  12. S Kinuya12,
  13. M Kodaira13,
  14. E Kobayashi11,
  15. T Kobayashi14,
  16. J Sato15,
  17. N Shinohara16,
  18. S Takahashi17,
  19. Y Takamatsu18,
  20. K Takayama19,
  21. K Takayama20,
  22. U Tateishi21,
  23. H Nagakura22,
  24. M Hosaka23,
  25. H Morioka24,
  26. T Moriya25,
  27. T Yuasa26,
  28. T Yurikusa27,
  29. K Yomiya28,
  30. M Yoshida29
  1. 1Department of Clinical Oncology, Akita University Graduate School of Medicine, Akita, Japan
  2. 2Department of Clinical Oncology, Juntendo University, Tokyo, Japan
  3. 3Department of Clinical Oncology, University of Tsukuba, Tsukuba, Japan
  4. 4Department of Rehabilitation, Chiba Prefectural University of Health Sciences, Chiba, Japan
  5. 5Department of Orthopedic Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
  6. 6Department of Gastroenterology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan
  7. 7Division of Hematology, Tochigi Cancer Center, Utsunomiya, Japan
  8. 8Department of Diagnostic and Interventional Radiology, Aichi Cancer Center Hospital, Nagoya, Japan
  9. 9Division of Palliative Medicine, Shizuoka Cancer Center, Sunto-gun, Japan
  10. 10Department for Cancer Chemotherapy, Iwate Prefectural Central Hospital, Morioka, Japan
  11. 11Division of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, Japan
  12. 12Department of Nuclear Medicine, Kanazawa University Hospital, Kanazawa, Japan
  13. 13Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
  14. 14Department of Diagnostic and Interventional Radiology, Ishikawa Prefectural Central Hospital, Kanazawa, Japan
  15. 15Department of Clinical Pharmaceutics, School of Pharmacy, Iwate Medical University, Morioka, Japan
  16. 16Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
  17. 17Department of Medical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
  18. 18Division of Medical Oncology, Hematology and Infectious Diseases, Fukuoka University Hospital, Fukuoka, Japan
  19. 19Seirei Christopher University, Hamamatsu, Japan
  20. 20Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
  21. 21Department of Diagnostic Radiology and Nuclear Medicine, Tokyo Medical and Dental University, Tokyo, Japan
  22. 22Department of Radiology, KKR Sapporo Medical Center, Sapporo, Japan
  23. 23Department of Orthopaedic Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
  24. 24Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan
  25. 25Department of Pathology 2, Kawasaki Medical School, Kurashiki, Japan
  26. 26Department of Urology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
  27. 27Division of Dentistry and Oral Surgery, Shizuoka Cancer Center, Sunto-gun, Japan
  28. 28Department of Palliative Care, Saitama Cancer Center, Kitaadachi-gun, Japan
  29. 29Department of Hemodialysis and Surgery, Chemotherapy Research Institute, International University of Health and Welfare, Ichikawa, Japan
  1. Correspondence to Professor Hiroyuki Shibata; hiroyuki{at}


Diagnosis and treatment of bone metastasis requires various types of measures, specialists and caregivers. To provide better diagnosis and treatment, a multidisciplinary team approach is required. The members of this multidisciplinary team include doctors of primary cancers, radiologists, pathologists, orthopaedists, radiotherapists, clinical oncologists, palliative caregivers, rehabilitation doctors, dentists, nurses, pharmacists, physical therapists, occupational therapists, medical social workers, etc. Medical evidence was extracted from published articles describing meta-analyses or randomised controlled trials concerning patients with bone metastases mainly from 2003 to 2013, and a guideline was developed according to the Medical Information Network Distribution Service Handbook for Clinical Practice Guideline Development 2014. Multidisciplinary team meetings are helpful in diagnosis and treatment. Clinical benefits such as physical or psychological palliation obtained using the multidisciplinary team approaches are apparent. We established a guideline describing each specialty field, to improve understanding of the different fields among the specialists, who can further provide appropriate treatment, and to improve patients’ outcomes.

  • bone metastasis
  • multidisciplinary team approach
  • a diagnosis and treatment guideline

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Bone metastasis is a devastating condition that can have a negative impact on the lives of patients with advanced cancer in many ways. Patients may experience limitations in the activities of daily living (ADL), decreases in quality of life (QOL), threat of survival and increases in medical expenses. Large-scale aetiological studies on the prevalence or incidence of bone metastasis have not been conducted in Japan or in other countries. A smaller study on autopsy cases over the period from 1959 to 1997 recorded by the Shikoku Cancer Center in Japan indicated that the frequencies of bone metastasis varied among cancers; they were as high as 75% in cancers such as of the breast and prostate, and as low as 22% in stomach and colon cancers.

Recently, the number of cancer survivors pertaining to breast and colorectal cancers has globally increased, and the 5-year survival rates are ≥60% and ≥85%, respectively. In many countries, the 5-year survival rate for prostate cancer is ≥95%.1 An increase in the survival time may increase the incidence of bone metastasis.

Recently, cancer chemotherapy has also made considerable progress in increasing survival of patients with far-advanced cancer. For example, gefitinib improved disease-free survival of epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC).2 Pertuzumab and trastuzumab increased the median overall survival (OS) of patients with EGFR 2-positive metastatic breast cancer.3

In addition to these therapeutic measures, agents that target bone metastatic lesions have provided clinical benefits to patients. Medicines targeting bone metastasis include bone-modifying agents (BMAs) and radiopharmaceuticals. To date, zoledronic acid (ZA) is the most promising of the bisphosphonates (BPs). Denosumab (D-mab), another potent BMA, which targets the receptor activator of nuclear factor κ-B ligand, has also been approved for skeletal-related events (SREs). β Emitters such as strontium-89 (89Sr) and samarium-153 (153Sm) have been shown to be effective for palliation of cancer pain induced by bone metastases.

Furthermore, surgical and interventional measures such as vertebroplasty and ablation have been developed. Caregivers should consider comprehensive strategies to treat patients with bone metastasis, using multimodal measures.


The guideline was developed according to the Medical Information Network Distribution Service (MINDS) Handbook for Clinical Practice Guideline Development 2014. The clinical algorithm is depicted in figure 1, and clinical questions (box 1) were derived on the basis of this algorithm.

Box 1

Table Clinical Questions and Answers

CQ 1. What are the symptoms induced by bone metastasis that necessitate emergent treatment?

A. Spinal cord compression and hypercalcemia need to be treated emergently.

CQ 2. What kinds of imaging are useful to diagnose bone metastasis?

A. Bone scintigraphy, 18F-fluorodeoxyglucose positron emission tomography/CT and MRI are useful to diagnose bone metastasis.

CQ 3. When is pathological examination needed?

A. It is needed when diagnosis is difficult, in primary unknown cancers, or in cases with multiple cancers.

CQ 4. Does the presence of bone metastasis affect the patient's prognosis?

A. Bone metastasis at diagnosis might affect the prognosis.

CQ 5. Is surgery beneficial to treat spinal metastasis with spinal cord compression?

A. Surgery is effective for functional improvement.

(Weak, Evidence B)

CQ 6. Is surgery beneficial to treat long bone metastasis with pathological fracture or those at risk?

A. Surgery is beneficial for pain relief and/or functional improvement.

(Strong, Evidence C)

CQ 7. Is the use of instrumentation beneficial in bone metastasis?

A. Instruments are beneficial for treatment and prevention of pathological fracture.

(Strong, Evidence C)

CQ 8. Is external beam radiation beneficial in bone metastasis?

A. External beam radiation is beneficial for relief from pain.

(Strong, Evidence A)

CQ 9. Is vertebroplasty beneficial in bone metastasis?

A. Vertebroplasty is beneficial for inoperable cases to sooner relieve pain on movement.

(Weak, Evidence C)

CQ 10. Is ablation is beneficial in bone metastasis?

A. Ablation is beneficial to relieve pain.

(not approved in Japan, Evidence C)

CQ 11. Are bone-modifying agents (BMAs) beneficial in bone metastasis of lung cancer?

A. Zoledronic acid (ZA) and denosumab (D-mab) are beneficial to SREs, regardless of symptoms.

(Strong, Evidence A)

CQ 12. Are BMAs beneficial in bone metastasis of breast cancer?

A. ZA, pamidronic acid and D-mab are beneficial in treating SREs.

(Strong, Evidence A)

CQ 13. Are BMAs beneficial in bone metastasis of prostate cancer?

A. ZA and D-mab are beneficial in treating SREs among castration resistant cases.

(Strong, Evidence A)

CQ 14. Are BMAs beneficial in bone lesions of multiple myeloma?

A. Bisphosphonates are beneficial in treating SREs.

(Strong, Evidence A)

CQ 15. Are BMAs beneficial in bone metastasis of the other cancers?

A. BMAs are beneficial in treating SREs of the other cancers.

(Weak, Evidence C)

CQ 16. What are the adverse events with BMAs to be cautious of?

A. Osteonecrosis of the jaw, renal toxicity, hypocalcaemia and flu-like illness should raise caution.

CQ 17. What kinds of biomarkers are useful to monitor the effects?

A. No biomarkers are recommended for practice.

CQ 18. What kinds of imaging are useful to monitor the effects of therapeutic measures to bone metastasis?

A. Osteolytic or mixed bone metastases with soft tissue components can be monitored with CT or MRI.

CQ 19. Are non-opioids effective to relieve pain of bone metastasis?

A. Non-opioids are effective to relieve pain.

(Strong, Evidence C)

CQ 20. Are opioids effective to relieve pain of bone metastasis?

A. Opioids are effective to relieve pain.

(Strong, Evidence C)

CQ 21. Are radiopharmaceuticals effective to relieve pain of bone metastasis?

A. Radiopharmaceuticals are beneficial to relieve pain in valid cases with the other measures.

(Weak, Evidence B).

CQ 22. Is Rehabilitation beneficial in bone metastasis?

A. Rehabilitation is beneficial to improve activities of daily living and quality of life, and to prevent disuse syndrome.

(Weak, Evidence C).

CQ 23. Is patient education beneficial in bone metastasis?

A. Patient education is beneficial in bone metastasis.

Figure 1

Clinical algorithm of diagnosis and treatment of bone metastasis guideline. BMA, bone-modifying agent; CQ, Clinical Question; DIC, disseminated intravascular coagulation; EBR, external beam radiation; PVP, percutaneous vertebroplasty; RCC, renal cell carcinoma; RECIST, Response Evaluation Criteria in Solid Tumor; RFA, radiofrequency ablation; thy CA, thyroid cancer.

Medical evidence was extracted from published articles describing meta-analyses or randomised controlled trials (RCTs) in PubMed, the Cochrane Library, CINAHL and the Japan Medical Abstracts Society. A systematic literature search was performed by Japan Library Association, mainly from 2003 to 2013. Medical evidence was evaluated critically and divided into four levels, A–D, covering estimated effects with higher reliability (A) to those that were mere speculations (D). On the basis of these levels, preliminary recommendations were elicited. Forward questions were fundamentally written in Patient, Intervention, Comparison, Outcome style. For forward questions, the synopsis of recommendations was assessed as strong or weak. To achieve consensus, majority voting (>70%) of the conference was adopted according to the Delphi technique.


Diagnostic procedures

Symptoms (CQ 1)

‘Spinal cord compression (SpCC) and hypercalcaemia need to be treated emergently’. Among SREs, SpCC and malignant hypercalcaemia (MHC) should be emergently treated. The frequencies of SpCC and MHC are reported to be 3% and 13% in breast cancer, 8% and 1% in prostate cancer, and 4% and 4% in lung cancer, and other cancers, respectively.4–6 These cancers are asymptomatic in the very early stage; therefore, careful examination is required. Symptoms of SpCC are back pain, listlessness of the lower limb and cauda equina syndrome.7 ,8 Symptoms of MHC are anorexia, nausea, fatigue, polyuria, muscle weakness, hyporeflexia, confusion, tremor, torpor, etc.9

Imaging (CQ 2)

‘Bone scintigraphy (BS), 18F-fluorodeoxyglucose positron emission tomography (PET) and magnetic resonance imaging (MRI) are useful to diagnose bone metastasis’. BS, 18F-fluorodeoxyglucose PET, and MRI are recommended as practical imaging measures to detect bone metastasis. A meta-analysis of BS combined with single-photon emission CT (SPECT) indicated that the sensitivity was 86% and specificity was 81%.10 A meta-analysis showed that the sensitivity of PET combined with CT (PET/CT) was 90% and the specificity of this combination was 97%.10 For cancers with a high risk of metastasis, including breast cancer, PET/CT is recommended in the National Comprehensive Cancer Network (NCCN) guideline.11 PET is better than CT in diagnosing osteolytic lesions; however, when combined with CT, its ability to detect osteoplastic lesions increases.12 MRI, particularly whole-body MRI, can detect bone metastasis with sensitivity and specificity of 91% and 95%, respectively.13 Using diffusion-weighted MRI (DW-MRI), the specificity increases to 96%.13 Radiography and CT are useful in evaluating the size of lesions or the rigidity of skeletal structures;14 sodium 18F-fluoride has high diagnostic potential and accuracy.15

Histopathology (CQ 3)

‘Histopathology is needed when diagnosis is difficult, and in primary unknown cancers or in cases with multiple cancers’. In many cases where bone metastasis is confirmed based on the patient's clinical course, histopathological analysis is often omitted; however, in case of an unknown primary and ≥2 synchronous or metachronous cancers, it is necessary.16 Tissue materials can be obtained using CT-guided percutaneous needle or open biopsy; aspiration cytology, despite the lower accuracy, is an alternative.17 ,18

Prognosis (CQ 4)

‘Bone metastasis at diagnosis might affect the prognosis’. In the Danish National Patient Registry (DNPR; 1997–2007), the 5-year survival rates of patients with prostate cancer with and without bone metastasis at diagnosis were 3% and 56%, respectively.19 Among registrants in the Surveillance Epidemiology, and End Results programme in the USA (1999–2005), the HRs for risk of death in patients with prostate cancer with and without SREs were 10.2 and 6.6, respectively.20 In DNPR, the 5-year survival rates of patients with breast cancer with and without bone metastasis at diagnosis were 8.3% and 75.8%, respectively.21 Katagiri et al22 proposed a scoring system that correlated with prognosis.



Metastatic spinal tumour (CQ 5)

‘It is weakly suggested that surgery is effective for functional improvement’. Surgery for spinal metastasis is beneficial for tumour resection as well as for relieving pain and improving neurological manifestations. Significant improvement pertaining to walking was observed in patients treated with surgery plus radiation compared with that in patients treated with radiation alone;23 however, a report by Rades et al24 did not confirm these results. Surgery for spinal metastases because of radiosensitive tumours such as multiple myeloma, malignant lymphoma and leukaemia, should be avoided.23–25 Surgery is not recommended in cases where ≥48 h are passed since complete paralysis or when prognosis is predicted within 6 months.23 ,26 For spinal metastasis of breast or prostate cancer, hormonal treatment or radiation is the first choice before surgery.23 ,27 Operative methods for spinal metastasis differ according to the sites and sizes of metastases. A posterior approach, decompression by laminectomy and spinal fixation, are the most common procedures. Total en bloc spondylectomy may be beneficial when the lesion is single and long survival is expected.26

Metastasis to long bones (CQ 6)

‘It is strongly suggested that surgery is beneficial for pain relief and/or functional improvement’. Surgery is beneficial to repair mechanical ruptures, relieve pain, and improve diseased limb function and QOL during pathological fractures or at risk fractures.28–30 The outcomes of surgery for at risk fractures are better than those of surgery for pathological fractures in many aspects such as those concerning blood loss, period of hospitalisation and functional recovery.31 ,32 Mirels reported a scoring system for risk of fracture.33–35 Linden claimed that axial cortical involvement >30 mm and circumferential cortical involvement >50% are predictive of fracture.36 Operative methods are divided into two types: internal fixation and prosthesis replacement.

External fixation (CQ 7)

‘It is strongly suggested that instruments are beneficial for treatment and prevention of pathological fractures’. Braces are used for various purposes such as relief from pain, and preservation and stabilisation of diseased bone. Braces are appropriate for postoperative fixation. For pathological and at risk fractures, surgery is superior to non-surgical conservative treatment in increasing QOL. Among conservative approaches such as resting and rehabilitation, braces and body casts, braces are best for thoracic and lumbar spinal compression (compression rate <50%) without neurological symptoms.37 Emergently, external fixation using splint and weight-bearing orthoses such as crutches are suitable for long-bone metastasis.

External beam radiotherapy (CQ 8)

‘It is strongly suggested that external beam radiation (EBR) is beneficial for relief from pain’. EBR can relieve pain caused by bone metastasis without SpCC or pathological fracture in 59–73% of cases,38–40 and neuropathic pain in 53–61% of cases.41 Dose fractionation is performed using multifractionated radiation (MFR) such as 30 Gy divided into 10 fractions (30 Gy/10 Fr or 20 Gy/5 Fr). Single-dose irradiation (SDI) such as 8 Gy is also performed. In some studies, the effects on pain using either MFR or SDI were identical; pain relief was achieved in 60–73% patients using SDI and in 59–73% patients using MFR.38–40 Pain relief was achieved within 3 weeks in half the total number of cases where the treatment was effective. Neuropathic pain was relieved in 53% of patients treated using SDI and in 61% of patients treated using MFR.41 Regarding the duration of pain relief, there was no significant difference between SDI and MFR; the median time for recurrence was 2.4 months after SDI and 3.7 months after MFR.41 The average duration of pain relief was 29 weeks after SDI and 30 weeks after MFR.42 Additional radiation is performed in 7–8% of MFR patients and in 20–22% of SDI patients.38–40 Additional radiation relieved pain in 58% of patients in another study comprising 33–66% of patients in whom the first radiation treatment was not effective.43 Additional SDI and MFR relieved pain in 66–70% and 33–57% of patients, respectively.43 It is not clear whether EBR can completely prevent pathological fracture. The incidence of fracture was identical by both methods (SDI=3.3% vs MFR=3.0%).40 Thus, fixation of the damaged cortex of a femoral metastasis >30 mm in longitudinal length is necessary before irradiation.44 The frequency of SpCC after EBR is reduced to 2.8–3.0% using SDI, and 1.6–1.9% using MFR.39 ,40

Vertebroplasty (CQ 9)

‘It is weakly suggested that vertebroplasty is beneficial for inoperable cases to sooner relieve pain on movement’. Percutaneous vertebroplasty (PVP) can relieve pain associated with movement of weighted vertebrae or relieve neuropathic pain when surgery is not indicated. Complications such as acute phase of infection, haemorrhagic diathesis and severe heart disease, are contraindicative.45 PVP is applicable for radio-resistant patients, and an additive effect is obtained by combining it with radiotherapy. PVP relieves pain within 1–3 days.46 Polymethyl methacrylate is commonly used as cement. Extreme care should be taken to not leak cement out of the targeted vertebral body. As the therapeutic effect does not correlate with cement volume, it is recommended that only the minimum amount needed should be used. Balloon kyphoplasty is performed to attempt kyphosis of the diseased vertebra to avoid leakage.47

Ablation (CQ 10)

‘Ablation is beneficial for pain relief’. Radiofrequency ablation (RFA) is used to kill tumours by heating, using image-guided needle centesis. RFA is one measure to relieve pain from bone metastasis, based on results from two RCTs.47 ,48 RFA is used to treat resistant patients or patients unresponsive to radiotherapy; however, in Japan, it is not covered by medical insurance. Cryoablation is an alternative method to relieve pain.49

Bone modifying agents

Lung cancer (CQ 11)

‘It is strongly suggested that zoledronic acid (ZA) and denosumab (D-mab) are beneficial to SREs, regardless of symptoms’. RCTs comparing ZA with placebo that target NSCLC (50% of total participants) and small cell lung cancer (8%) have shown the occurrence rate of SRE treated with ZA to be 38.9% and that with placebo to be 48.0% (p=0.039).50 ,51 RCT comparing ZA with D-mab showed that the duration of the first SRE was 16.3 months using ZA and 20.6 months using D-mab (40% were NSCLC).52 Non-inferiority of D-mab to ZA is proven (p=0.06). For SREs that needed radiotherapy, the grade of pain and dosage of opioids were significantly suppressed in the D-mab group.53 Exploratory analysis of this trial indicated that OS was prolonged in the D-mab group.54

Breast cancer (CQ 12)

‘It is strongly suggested that ZA, pamidronic acid (PA) and D-mab are beneficial to SREs’. An RCT comparing PA with placebo showed that PA could significantly decrease SREs of breast cancer from 4.0 to 2.5 per person-year. PA was effective with chemotherapy or hormonal treatment.55 In the breast cancer subgroup, ZA significantly decreased SREs by 20%.56 Improvements in QOL score, progression free survival (PFS) and OS were not achieved. Ibandronate decreased SREs and improved pain and QOL scores.57–60 An RCT comparing ZA with D-mab showed that D-mab significantly decreased the first SREs by 18% and the second SREs by 23%.61 ,62 Improvement in QOL score was achieved in 37.1% of the D-mab group and in 31.4% of the ZA group.61 ,62 No improvements were observed in PFS and OS. A meta-analysis showed 8 of 10 papers reporting BPs to significantly reduce SREs (relative risk (RR) = 0.85). ZA significantly reduced SREs compared with PA (RR=0.80).63 D-mab significantly reduced SREs compared with ZA (RR=0.78).

Prostate cancer (CQ13)

‘It is strongly suggested that ZA and D-mab are beneficial to SREs of castration resistant cases’. Hormonal treatment is effective in most prostate cancers, regardless of bone metastasis. In many cases, combined androgen blockade with lutenising hormone-releasing hormone analogue, antagonist and a non-steroidal antiandrogen agent, is used.64 Prostate cancer is sensitive to hormonal treatment in the first 2 years on average, but finally turns into castration-resistant prostate cancer (CRPC).65 ,66 Clodronate combined with hormonal treatment prolongs survival compared with placebo (RR=0.77).67 The survival benefit of ZA or D-mab with hormonal treatment is controversial. An RCT comparing ZA with placebo against CRPC indicated that the frequency of SREs was 33.2% in the ZA group and 44.2% in the placebo group (p=0.021). OS was longer in the ZA group than in the placebo group (546 vs 464 days, p=0.094).5 ,68 An RCT comparing D-mab with ZA against CRPC showed that the duration to the first SRE was 20.7 months in the D-mab group and 17.1 months in the ZA group (p=0.0085).69

Multiple myeloma (CQ 14)

‘It is strongly suggested that BPs are beneficial to SREs’. Combination therapy of PA with chemotherapy for bone lesions reduced the occurrence of SREs compared with chemotherapy alone (24% vs 41%, p<0.001).70 Clodronate with chemotherapy inhibited the progression of osteolytic lesions compared with chemotherapy alone (12% vs 24%, p=0.026).71 An RCT comparing PA with ZA to treat breast cancer and multiple myeloma showed that they had similar effects.72 An RCT comparing the first-line treatment using ZA plus chemotherapy with that of clodronate plus chemotherapy showed that SREs were significantly suppressed in the ZA group (HR=0.74, p=0.0004).73 A meta-analysis comparing BPs with placebo showed that BPs significantly suppressed pathological fracture of vertebrae (RR=0.74) and occurrence of SREs (RR=0.80), and improved pain (RR=0.75).74 A better survival benefit with ZA was achieved compared with clodronate (HR=0.84, p=0.0118).73 A meta-analysis comparing all types of BPs to placebo showed that BPs had no survival benefits. However, ZA showed a survival benefit (HR=0.61).74 An RCT comparing ZA with D-mab showed that D-mab significantly prolonged the duration to the first SRE (14.4 vs 19.0 months, p=0.022).75 However, the survival benefit with D-mab was inferior to that with ZA (HR=2.26).

An RCT comparing melphalan plus prednisone (MP) with MP plus bortezomib (VMP) showed that VMP suppressed the progression of bone lesions and decreased the need for radiation.76 ,77

Other cancers (CQ 15)

‘It is weakly suggested that BMAs are beneficial to SREs of the other cancers’. In an RCT comparing ZA with placebo, other cancers such as gastrointestinal cancer accounted for 10% of the total.50 Subset analysis showed that ZA had a similar effect on SREs. A meta-analysis of three RCTs comparing ZA with D-mab showed that D-mab significantly suppressed SREs.75 No survival benefit of D-mab was observed.

Combination with radiotherapy

There are no meta-analyses of combination treatment with BMAs and radiation; however, >200 retrospective studies have been reported,78–82 where radiation with BPs has been effective. The American Society of Clinical Oncology (ASCO) guideline for bone metastasis of breast cancer recommends radiation with BPs for SREs.83 ,84

Adverse events (CQ 16)

‘Osteonecrosis of the jaw (ONJ), renal toxicity, hypocalcaemia and flu-like illness should be cautious’.

Osteonecrosis of the jaw

The frequency of ONJ induced by BPs varies from 1% to 10%.85 D-mab induces ONJ with the same frequency.61 Longer duration of BP injection increases the risk; the incidence at 4–12 months is 1.5%, whereas that at 27–48 months is 7.7%.85 Appropriate oral hygiene decreases ONJ.86 ,87 Patients should maintain good oral hygiene, and have dental examinations and preventive dental treatment prior to initiating therapy.83 Tooth extraction, oral infection and artificial dentures are risk factors.88 Extraction should be completed before administration and takes 14–21 days to recover from.89

Renal toxicities

The frequency of renal toxicities with ZA is 4.9–44.5%.6 ,51 ,52 ,61 ,69 ,90–93 However, many of these toxicities remain within grade 1 or 2 and are reversible. Risk factors are older age (>65 years), combination use with non-steroidal anti-inflammatory drugs (NSAIDs) or cis-platinum, diabetes mellitus and multiple myeloma. Multiplicity and longer duration (>2 years) increase the risk.93 The median time to occurrence is 4.7–5.4 months.94 ,95 The risk for acute renal failure increases in low creatinine clearance rates (CCR, <60 mL/min).52 ,61 Dose modification according to CCR is recommended. The frequency of renal toxicities with D-mab is 3.3–14.7% for all grades and 0.4% for grades >3.52 ,61 ,69


The frequency of hypocalcaemia with ZA is 3.3–9.0%.53 ,61 ,69 ,75 ,94 The frequency of clinical symptoms or for grades >3 is 1.0–4.7%.53 ,69 ,74 ,96 The frequency with D-mab is 1.7–10.8% for all grades and 1.3–5.1% for grades >3.53 ,61 ,68 ,75 Administration of BMA without vitamin D and oral calcium elevates the frequency of hypocalcaemia by 5–6 times.53 ,61 ,68 In case of D-mab, a daily supply of vitamin D (natural form; 400 IU) and oral calcium (500 mg) is necessary. Risk factors are low serum calcium before treatment, and renal dysfunction.97 ,98 The onset is ≤10 days in most cases and early monitoring is important.


Other adverse events include flu-like reactions, which occur within 3 days; their frequencies are 17.7–22.0% with ZA and 8.4–10.4% with D-mab.61 ,68 ,92 Atypical femoral fractures are rare severe adverse events associated with ZA.99

Monitoring of treatment

Biomarkers (CQ 17)

‘No biomarkers are suggested for practice’. Broun reported that elevation of type I collagen cross-linked N-telopeptide (NTx) or bone-specific alkaline phosphatase during treatment indicated poor prognosis of lung and prostate cancers with bone metastases.100 Coleman et al101 reported that, in cases with high urine NTx (uNTx), SRE or disease progression risks were 4–6 times higher than those with low uNTx. The prognostic value of uNTx is apparent, but the predictive value for therapeutic effects is not. Longer survival was achieved in cases where uNTx was normalised using ZA compared with cases where uNTx was not normalised (RR=0.52).102 Clinical events such as death or SREs were preceded by elevation of bone turnover markers (BTMs) in >90% of cases. Inverse phenomena were observed only in 5.6% of breast cancers and 5.9% of prostate cancers.103 The ASCO guideline does not recommend measurement of BTMs to monitor BMA effects.87

Imaging (CQ 18)

‘Osteolytic or mixed bone metastases with soft tissue components can be monitored with CT or MRI’. Evaluation using radiography, BS, or PET is not suitable for bone metastasis, according to the Response Evaluation Criteria in Solid Tumor V.1.1.104 Osteolytic and mixed lesions can be evaluated by CT or MRI. There are no imaging devices for evaluating osteoplastic lesions. The Prostate Cancer Working Group 2 in the USA set the criteria for progressive disease of osteoplastic new lesions using BS.105 The bone scan index (BSI) is a quantitative method for detecting possible metastatic lesions as a percentage of total bone quantity. Changes in BSI before and after treatment show better correlation with prognosis than changes in prostate specific antigen (PSA).106 DW-MRI can measure water diffusion, which reflects cellularity as an apparent diffusion coefficient (ADC).107 The possibility of ADC to predict tumour response clinically is now under verification.


The patient-reported outcome (PRO) measures a patients’ own health condition by self-reporting. PRO has recently been considered to provide a real benefit to patients; for example, McGill-Melzack reported benefits of using the pain intensity scale and brief pain inventory scale.108 ,109


Non-opioids (CQ 19)

‘It is strongly suggested that non-opioids are effective to relieve pain’. The WHO has developed a three-step ladder for cancer pain, and non-opioids are the first choice. No RCTs have compared non-opioids on a large scale.110 ,111 Joishy and Walsh112 reported that the dosage of morphine could be reduced by ketorolac. Combined effects of opioids and non-opioids are still controversial.110 ,111 Other reviews have concluded that acetaminophen, NSAIDs and steroids are effective. Steroids are not analgaesics but are effective for reducing pain flare induced by radiation.113

Opioids (CQ 20)

‘It is strongly suggested that opioids are effective to relieve pain’. Many observational studies indicate that opioids are effective for pain of bone metastases.114 ,115 Comparison between the fentanyl patch and codeine–acetaminophen combination indicated that fentanyl had significantly superior effects.116 Bone metastatic pains are divided into two types: continuous pain at rest and breakthrough pain. The treatment strategy differs for each type. A systemic review found that the utility of rescue drugs for breakthrough pain and the dosage should be individually adjusted.117 For neuropathic pain, when not fully relieved by opioids, combination use with adjuvant analgaesics should be considered.

Radiopharmaceuticals (CQ 21)

‘It is weakly suggested that radiopharmaceuticals are beneficial to relieve pain in valid cases with the other measures’. A meta-analysis showed that radiopharmaceuticals were effective for 1–6 months.118 Two-thirds of patients treated using 89Sr showed pain relief.119 ,120 89Sr contributed to reducing the dosage of analgaesics and improving patients’ QOL.118 In Japan, 153Sm and rhenium-186 are not covered by medical insurance. 89Sr is particularly effective for prostate cancer because it is highly taken up by osteoplastic lesions as calcium mimetics.118 ,120 In many reports, the effect of 89Sr is identical to that of EBR, but the incidences of nausea and vomiting are lower using 89Sr.119 The effect of a combination of 89Sr and EBR remains controversial.118 ,119 The combination of 89Sr and ZA was effective for prostate cancer.121 An RCT comparing the combination of 89Sr and ZA with 89Sr alone for asymptomatic bone metastasis of NSCLC showed that the combination reduced the occurrence of SREs and improved OS.122 The antitumour effects of 89Sr, including reduction of PSA levels or improved survival in prostate cancer, are reported in a few cases.123 89Sr can be administered every 3 months. Reported adverse events include bone marrow suppression; thrombocytopaenia is most common (15–50%), but the grade is <2 in most cases.118–120 Leucocytopaenia is less frequent; however, caution is required when 89Sr is combined with chemotherapy. An RCT showed that 223Ra significantly increased OS and the time to occurrence of SREs with low toxicities compared with placebo.124

Rehabilitation and patient education (CQ 22, 23)

‘It is weakly suggested that rehabilitation is beneficial to improve ADL and QOL, and to prevent disuse syndrome’. Rehabilitation is beneficial in terms of providing pain relief, prevention of degeneration, improvement of ADL and QOL, and increased survival. An RCT comparing treatment plus rehabilitation with treatment alone of symptomatic spinal metastasis showed significant improvements in pain score (p<0.001), dosage of analgaesics (p<0.001) and depression status.125 Tang retrospectively showed that rehabilitation for spinal metastasis significantly improved the scores of functional independence measures and recovered function.126 Resting in bed is good for preventing SREs but leads to reduction of ADL and QOL, and results in disuse syndrome, which can cause sepsis or respiratory failure and increase the risk of death.

‘Patient education is beneficial to bone metastasis’. PRO-SELF is an education programme provided in the patient's home and by telephone. An RCT comparing PRO-SELF with normal care showed that knowledge of cancer pain reduced pain scores.127–129 A systematic review of educational intervention showed that it could reduce pain scores but could not improve patient's QOL.130


Diagnosis to treatment for bone metastasis needs various types of measures, specialists and caregivers. Consideration of the status of diseases, as well as of the background of patients, should be taken. For this purpose, a multidisciplinary team is necessary. In treating, multidisciplinary meetings are helpful. To collaborate with other specialists, a guideline describing each specialty field is necessary. The clinical benefits, such as physical or psychological palliation, obtained by the multidisciplinary team approaches, are described in some papers.131–133 Further, registration in addition to multidisciplinary team approaches could be advantageous to monitor the therapeutic outcomes according to the guideline.


The authors thank the members of the guideline committee and the JSMO guideline evaluation committee for their reviews. In particular, they acknowledge Kei Muro, Takayuki Yoshino and Yutaka Fujiwara, for their critical reviews of the final manuscript in Japanese. They also thank Chiharu Tada and Hiromi Nishizawa, secretaries of the JSMO, and Yuji Tatsugami, for their help with editing the Japanese version of the guideline, and ENAGO for their English language review.


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  • Twitter Follow Hiroyuki Shibata at @Shibacchi

  • Funding The total cost of developing this guideline was borne by JSMO.

  • Competing interests S Kato, sponsored research (Chugai Pharmaceutical Co, Ltd); IO, honoraria (Taiho Pharmaceutical Co, Ltd); S Kinuya, data and safety monitoring board (Bayer Yakuhin, Ltd); NS, honoraria (Novartis Pharma); ST, honoraria (Astellas Pharma Inc, AstraZeneca plc, Daiichi Sankyo Co, Ltd, Novartis Pharma), sponsored research (Sanofi, Zenyaku Kogyo Co, Ltd, Taiho Pharmaceutical Co, Ltd, Boehringer Ingelheim Japan, Chugai Pharmaceutical Co, Ltd, Novartis Pharma); YT, honoraria (Janssen Pharma); K Takayama20, consultation and honoraria (Clinical Research Support Center Kyushu, AstraZeneca plc, Chugai Pharmaceutical Co, Ltd, Eli Lilly Japan, PfizerJapan Inc), sponsored research (Kyowa Hakko Kirin Co, Ltd, plc, Daiichi Sankyo Co, Ltd, Chugai Pharmaceutical Co, Ltd, Eli Lilly Japan, Novartis Pharma, Bristol-Myers Squibb); UT, consultation and honoraria (Micron Inc, SymBio Pharmaceutical Co, Ltd, Chugai Pharmaceutical Co, Ltd, Nihon Medi-Physics Co, Ltd); HM, sponsored research (Eisai Co, Ltd, Taiho Pharmaceutical Co, Ltd); T Yuasa, honoraria (Novartis Pharma, PfizerJapan Inc).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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