Botmetastasen komen bij verschillende tumorsoorten voor (vooral bij prostaat- en borstkanker) en kunnen leiden tot ernstige problemen zoals botbreuken, pijn en verminderde kwaliteit van leven. Bij sommige tumorsoorten worden, wanneer men botmetastasen constateert, medicijnen voorgeschreven die de botafbraak bij botmetastasen remmen, zoals bisfosfonaten, denosumab en calcium/vitamine D.

Overview of findings regarding medication for bone metastases when compared to placebo.

¹ Based on a study population including patients with various tumor types (Wang 2015, Geng 2015, Machado 2009)

² Based on a study population including lung cancer patients (Bozzo 2021)

³ Based on a study population including prostate cancer patients (Jakob 2020)

⁴ Based on a study population including breast cancer patients (Tesfamariam 2019)

⁵ Based on a study population including renal cell cancer patients (Van Broekhoven 2023)

Overview of findings regarding zoledronate compared to denosumab for bone metastases.

¹ Based on a study population including patients with various tumor types (Wang 2015, Geng 2015, Machado 2009)

² Based on a study population including patients with various tumor types (Von Moos 2013)

GENERIC

Description of studies not focusing on a specific tumortype

Zoledronate, pamidronate, ibandronate and denosumab compared to each other and placebo

Systematic review

Wang 2015 compared the effectiveness of pamidronate, ibandronate, zoledronate, denosumab and placebo in reducing the morbidity of SREs in cancer patients with bone metastases. They conducted a network meta-analysis (NMA) that included 14 trials with 10,192 patients. Wang 2015 used a quality score proposed by Higgins 2011 to assess the methodological quality of the studies and the consistency of the available evidence. According to Wang 2015, the quality of the studies included in the NMA was high. There was a low risk of bias for the majority of risk of bias domains. Wang 2015 concluded that the results were of moderate to good quality.

Nine studies included patients with breast cancer, three included patients with prostate cancer, and two included patients with non-small cell lung carcinoma and other solid tumors. Three studies compared denosumab with zoledronate, three compared zoledronate with placebo, two compared zoledronate with pamidronate, one compared zoledronate with ibandronate, and four compared pamidronate with placebo.

RCT (zoledronate versus ibandronate versus pamidronate)

Choudhury 2011 included 256 patients with painful bone metastases in solid tumors (primary sites were lung, breast, prostate, GI, bone and soft tissue and other). They were randomized into three arms: zoledronate (4 mg, i.v.), ibandronate (6 mg, i.v.) and pamidronate (90 mg, i.v.). Despite unclear reporting of some methodological aspects of the study, the study was overall considered to be at low risk of bias for SREs. Blinding of patients, clinicians and outcome assessors was not reported. As this was considered a key element in the potential risk of bias of pain outcomes, the study was considered to be at high risk of bias for pain outcomes.

Choudhury 2011 was included in the systematic review of Geng 2015 for the comparison of zoledronate with ibandronate.

Ibandronate versus zoledronate or placebo

Systematic review

Geng 2015 conducted a systematic review and meta-analysis of studies that compared ibandronate with placebo or zoledronate with respect to SREs and bone pain. Geng 2015 included 10 RCTs involving 3,474 patients: six RCTs were placebo-controlled and four compared ibandronate with zoledronate. Geng 2015 included studies with patients with bone metastases or multiple myeloma. Only Barrett-Lee 2014 was included in both Wang 2015 and Geng 2015. This trial compared ibandronate with zoledronate.

The quality of the six placebo-controlled studies was high (indicated by a Jadad score ≥3). The quality of the four trials comparing ibandronate and zoledronate was lower because the studies were open label.

Clodronate, pamidronate, zoledronate versus placebo

Systematic review

Machado 2009 compared the efficacy of clodronate, pamidronate, and zoledronate with that of placebo in reducing morbidity and overall mortality in cancer patients with bone metastases. Some of the studies included by Wang 2015 that compared pamidronate with placebo (Conte 1996; Hortobagyi 1996; Hultborn 1996; Theriault 1999) and zoledronate with placebo Kohno 2005; Rosen 2003; Saad 2002) were also included by Machado 2009. Therefore, particularly the analysis of studies about the effects of clodronate are unique to the systematic review of Machado and therefore reported. Seven studies evaluated oral forms of clodronate (dose range: 1600–2080 mg daily.

Zoledronate versus pamidronate

Systematic review

Yang 2015 included 20 controlled clinical trials that compared the effect of treatment with zoledronate and pamidronate disodium on pain response. A total of 3025 patients were included. The outcome complete pain response rate was reported in 10 trials. The quality of this SR was very low, due to several limitations. For example, Yang 2015 did not assess the risk of bias in the included studies and characteristics of the study population were not reported. Due to this limitations, the studies were not added to Table 1.

Table 1. Study characteristics of RCTs that are included in Wang 2015, Geng 2015 and Machado 2009. Studies are ranked from oldest to newest. Studies comparting denosumab and zoledronate are presented in Table 2.

¹ Included in Wang 2015

² Included in Geng 2015

³ Included in Machado 2009

Denosumab versus zoledronate

Systematic reviews

Jiang 2021 compared the efficacy and safety between denosumab and zoledronate for various advanced solid tumors and multiple myeloma with bone metastases. They included four RCTs involving 7,201 patients (Table 2). The risk of bias assessment of Jiang 2021 revealed a low risk of bias among the included four studies. Jiang 2021 compared the following outcomes: time to first SRE, time to first-and-subsequent SREs, overall survival, disease progression, incidence of treatment-emergent adverse events (AEs) and serious AEs.

Menshawy 2018 included six RCTs with a total of 7722 patients. They compared the efficacy of denosumab versus bisphosphonates in preventing SREs in patients with advanced cancer (including patients with prostate cancer, solid tumors excluding breast and prostate cancer), and various tumortypes (except lung) or multiple myeloma (Table 1). The quality of the included RCTs was moderate to high quality according to the Cochrane risk of bias assessment tool, but it was noted that there was a high risk of bias at the funding of the trials, as all the included clinical trials in the meta-analysis were funded by drug companies. Menshawy 2018 compared time to first on-study SRE, time to first and subsequent on-study SRE, time to disease progression, overall survival, and safety outcomes.

Individual patient data analysis

Von Moos 2013 included three identically designed double-blind phase III RCTs across three comparative studies of denosumab and zoledronate (Table 2). Von Moos 2013 analyzed individual patient data about pain and health-related quality of life in patients with advanced solid tumors (breast cancer (n=2046), castration-resistant prostate cancer (n=1901), and other solid tumors (n=1597)) and bone metastases. Patients with multiple myeloma in the studies were excluded from this pooled analysis.

Table 2. Study characteristics of RCTs directly comparing denosumab and zoledronate and that are included in Jiang 2021, Menshawy 2018 and Von Moos 2013.

¹ Included in Jiang 2021

² Included in Menshawy 2018

³ Included in Von Moos 2013

Results

Zoledronate versus denosumab versus pamidronate versus ibandronate and clodronate versus placebo (direct and indirect comparisons)

SRE

Wang 2015 found, based on a network meta-analysis (NMA) that three medication types were associated with significant reductions in SREs overall compared with the placebo: Denosumab was superior to placebo in significantly reducing the risk of SREs (odds ratio [OR]: 0.49; 95% CI: 0.31–0.75), followed by zoledronate (OR: 0.57; 95% CI: 0.41–0.77) and pamidronate (OR: 0.55; 95% CI: 0.41–0.72).

The NMA model of Wang 2015 converged, and there were no significant inconsistencies between the direct and indirect evidence within the NMA.

Wang 2015 found that ibandronate compared with placebo could not significantly reduce the risk of SREs overall. In contrast, Geng 2015 found a lower SRE incidence with ibandronate than with placebo (RR 0.87, 95% CI 0.80 to 0.96; six trials). Subgroup analyses  revealed no differences between intravenous ibandronate (2 mg) and placebo (RR 1.02, p=0.82), while intravenous ibandronate (6 mg) every 3–4 weeks or daily oral ibandronate (50 mg) was associated with significantly lower incidence than placebo (RR 0.80, p=0.002).

Geng 2015 found a similar incidence of SREs when comparing ibandronate with zoledronate (RR 1.02, 95% CI 0.82 to 1.26; two trials).

Machado 2009 found that clodronate reduces the SREs when compared to placebo (RR 0.87 (95% CI, 0.75–1.00), but this difference is unlikely to be clinically relevant.

Pain

The outcome pain as such was not analysed by Wang 2015. Initial meta-analysis of Geng 2015 indicated that placebo might be associated with a significantly greater reduction in bone pain score from baseline than was ibandronate at 96 weeks follow-up. However, subgroup analyses (without the data for patients who received intravenous ibandronate 2 mg) showed that intravenous ibandronate 6 mg every 3–4 weeks or daily oral ibandronate 50 mg was associated with a greater reduction in bone pain score from baseline than was placebo at 96 weeks (mean difference =−0.41, 95% CI −0.56 to −0.27; two trials; measured on a scale of 0 (none), to 4 (intolerable).

Geng 2015 found four trials that compared ibandronate with zoledronate regarding the outcome pain, but due to heterogeneity in measurement methods their data could not be pooled in a meta-analysis. Three RCTs showed no difference between the two drugs in reducing bone pain. One RCT involving 65 patients in the ibandronate group and 60 in the zoledronate group found that zoledronate might be superior to ibandronate at 6 months, but no difference at 3 months or at the end of the study.

Machado 2009 did not analyse the outcome pain as such.

Toxicity

The outcome toxicity was not analysed by Wang 2015. Geng 2015 found that the four placebo controlled trials showed a higher incidence of abdominal pain in the ibandronate group (7.0%) than in the placebo group (1.5%) (RR 2.26, 95% CI 1.09 to 4.70. For other adverse events the findings were very imprecise (very wide confidence intervals) and therefore show uncertainty about differences, if any, in diarrhoea, nausea, and renal toxicity.

The two trials that compared ibandronate and zoledronate found that the incidence of renal toxicity was lower in the ibandronate group (23.7%) than the zoledronate group (31.8%) (RR 0.74, 95% CI 0.63 to 0.88). Full details about all adverse events can be found in Geng 2015.

Quality of life

The outcome quality of life was analysed by Wang 2015 nor Geng 2015.

Denosumab versus zoledronate (direct comparison)

SREs

The meta-analyses of Jiang 2021 and Menshawy 2018 showed that denosumab may be superior to zoledronate in delaying time to first SRE (HR 0.86; 95% CI 0.80 to 0.93 and HR 0.92, 95% CI 0.86 to 0.98), and time to first-and subsequent SREs (risk ratio (RR) 0.87; 95% CI 0.81 to 0.93 and RR 0.92, 95% CI 0.86 to 0.99), but these differences might not be clinically relevant. When Jiang 2021 excluded the multiple myeloma study from the analysis, similar results were found for the effect of denosumab versus zoledronate in patients with solid tumors with bone metastases.

Pain

Van Moos 2013 reported several different outcome measures for pain. Small differences in pain severity were found, but those differences were not clinically relevant (for example: a 13% difference in analgesic use favouring denosumab over zoledronate).

Toxicity

All four studies included in Jiang 2021 presented information about adverse events (treatment-emergent AEs), serious adverse events (all AEs were coded using Medical Dictionary for Regulatory Activities v12.0 system), acute-phase reactions, renal toxicity, osteonecrosis of the jaw, and hypocalcaemia. No significant differences were found in the incidence of (serious) adverse events. Pooled results showed that denosumab may be associated with lower incidence of renal toxicity and acute phase reaction. However, denosumab may also be associated with higher incidence of hypocalcemia and osteonecrosis of the jaw. Full details of the meta-analyses can be found in Jiang 2021. The authors noted that the small number of included studies was the main limitation of their meta-analysis. No data about long-term efficacy and long-term safety were available yet.

Table 3. Adverse and serious adverse events reported in two studies (Stopeck 2010 and Henry 2014) comparing denosumab and zoledronate.

Quality of life

Von Moos 2013 found that health-related quality of life, as measured by FACT-G total score, was not different between the denosumab and zoledronate groups (average relative difference of +8.2 % favouring denosumab over zoledronate, p = 0.109).

Other outcomes, such as overall survival

Both Jiang 2021 and Menshawy 2018 found no differences between the two groups in overall survival (HR 0.96; 95% CI 0.89 to 1.04) or time to disease progression (HR 0.98; 95% CI 0.93 to 1.05).

SPECIFIC TUMOR TYPES

List of included studies focusing on a specific tumor type:

A total of six SRs were included that focused on a specific tumor type and performed analyses across patients with breast cancer, lung cancer, prostate cancer or renal cell cancer and bone metastases.

Description of systematic reviews focusing on a specific tumor type

Breast cancer

Bone-modifying agents

Tesfamariam 2019 included 21 RCTs with a total of 9048 patients. The aim of their systematic review was to provide a comprehensive overview on the benefits and harms of different bisphosphonates and RANK-L inhibitors and establish a hierarchy of therapeutic options for patients with breast cancer and bone metastases. For more details about the included studies, please see Tesfamariam 2019. Overall survival was the primary outcome. Quality of life and pain were assessed as secondary outcomes along with osseous complications such as pathologic fractures, spinal cord compression and hypercalcemia, which were recorded within the outcome SREs. In addition, adverse events were evaluated.

Allocation concealment, blinding of participants, personnel and outcome assessors and selective reporting were the domains that were judged as “unclear risk of bias” for most of the included studies. Only few of the included studies were judged as low risk of bias.

Bone-modifying agents – effects of long-term use

Ng 2021 included three RCTs and nine retrospective studies. The RCTs can be found in table 2. The aim of Ng 2021 was to review the literature on the efficacy and toxicity of bone-modifying agents after administering this medication for two years or longer in patients with bone metastases from breast or castration-resistant prostate cancer. More details about all included studies can be found in Ng 2021. Ng 2021 reviewed the following outcomes: the proportion of patients with ≥ 1 SRE; total number of SRE; time to first SRE; skeletal morbidity rate (SMR); and any QoL metrics. Outcomes regarding BMA toxicity included the incidence of osteonecrosis of the jaw (ONJ), hypocalcaemia, renal toxicity, and atypical femoral fracture.

Lung cancer

Bone-Modifying Agents

Bozzo 2021 included 131 RCTs that evaluated 11,105 patients with skeletal metastases from lung cancer. They performed a network meta-analysis to identify the bone modifying agent that is associated with the (1) highest overall survival, (2) longest time to SRE, (3) lowest SRE incidence, and (4) greatest likelihood of pain resolution. For more details about the included studies, please see Bozzo 2021. Methodological limitations of the included trials were related to their method for concealing allocation, and the lack of blinding of participants and outcome assessors.

Prostate cancer

Bone-Modifying Agents

Jakob 2020 assessed in their Cochrane review the effects of bisphosphonates and RANKL-inhibitors as supportive treatment for patients with prostate cancer with bone metastases. They generated a clinically meaningful treatment ranking according to safety and efficacy by using a network meta-analysis. They included twenty-five trials of which twenty-one trials could be considered in the quantitative analysis, of which bisphosphonates (zoledronate, risedronate, pamidronate, alendronate, etidronate, or clodronate) were compared with each other, the RANKL-inhibitor denosumab, or no treatment/placebo. The risk of bias in the included studies was low to unclear, with 11 studies showing high risk of bias in 2 or more domains, which was due mostly to unblinded trials. For more information about the included studies, please see Jakob 2020.

Renal cell cancer

Bone-Modifying Agents

Broekhoven 2023 systematically reviewed the literature to assess whether the use of bisphosphonates in patients with renal cell cancer and metastases in the long bones resulted in reduced SRE rate. They excluded studies on spinal metastases. They included a total of 13 studies: two studies using data from a subset of renal cell cancer patients in the same phase III, double-blind, randomized controlled trial (Lipton 2003 and Saad 2005). The other included studies were 7 retrospective studies and 4 prospective studies. For more information about the included studies, please see Broekhoven 2023.

Omae 2017 conducted a systematic review to compare the efficacy and safety of all available bone-modifying agents for the treatment of bone metastases in patients with advanced renal cell carcinoma. They included three RCTs (259 patients): Broom 2015, Henry 2014, and Lipton 2003 for data analysis and excluded one eligible study in which only 1 patient with renal cell carcinoma participated (Vinholes 1997).

Results:

Breast cancer

Bone-modifying agents

Tesfamariam 2019 compared, directly or indirectly, seven different treatment options. The network meta-analysis showed that denosumab (RR: 0.62; 95% CI 0.50 to 0.76), zoledronate (RR: 0.72; 95% CI 0.61 to 0.84) and pamidronate (RR: 0.76; 95% CI 0.67 to 0.85) were all superior to placebo in reducing SREs.

The authors pointed out that quality of life and pain data were available from a number of the included studies (7 and 11, respectively), but overall conclusions were not possible due to heterogeneity in methods of measurement used and measuring time points.

An overall network meta-analysis for different adverse events was impossible, but based on the data, Tesfamariam 2019 concluded that significant adverse events appear to be uncommon, with the risk of osteonecrosis of the jaw for example likely being about 1% for zoledronate and about 2% for denosumab.

Bone-modifying agents – effects of long-term use

Ng 2021 summarized the available data on the efficacy and toxicity of bone-modifying agents after 2 or more years of exposure. They found that the conclusions from their systematic review were restricted by the quality of data available.

Data beyond 2 years was limited to subgroup analyses in all studies. Ng 2021 found:

• Only one study (n = 181) reported SRE rates based on bisphosphonate exposure, with decreased rates from 27.6% (0 to 24 months) to 15.5% (> 24 months).
• None reported on quality of life.
• Seven bisphosphonate studies (n = 1077) and one denosumab study (n = 948) reported on osteonecrosis of the jaw. Across three studies (n = 1236), osteonecrosis of the jaw incidence ranged from 1 to 4% in the first 2 years to 4–18% after 2 years. Clinically significant hypocalcemia ranged from 1 to 2%. Atypical femoral fractures were rare.

According to Ng 2021, the data suggests that the benefit-to-risk ratio of continuing bone-modifying agents seems to decrease over time, with a drop in SREs after 2 years and a steady rise in potentially debilitating adverse events such as osteonecrosis of the jaw.

Lung cancer

Bone-Modifying Agents

Bozzo 2021 found that for the time to SRE, denosumab was ranked first with a mean of 9.1 additional SRE-free months (95% CI 6.7 to 11.5) compared with untreated patients (no placebo), while zoledronate conferred an additional 4.8 SRE-free months (95% CI 3.6-6.1). The reduction in the incidence of SREs was not different between patients treated with denosumab (RR 0.54; 95% CI 0.33 to 0.87) and those treated with zoledronate (RR 0.56; 95% CI 0.46 to 0.67). Patients treated with the combination of ibandronate and systemic therapy (not further specified) were more likely to experience successful pain resolution than untreated patients (RR 2.4; 95% CI 1.8-3.2).

Prostate cancer

Bone-Modifying Agents

Jakob 2020 found that zoledronate (RR 0.84; 95% CI 0.72 to 0.97) and denosumab (RR 0.72; 95% CI 0.54 to 0.96) appeared to be the most effective for a reduction in SREs, but also seemed to cause the most and worst adverse events [like renal impairment for treatment with zoledronate (RR 1.63; 95% CI 1.08 to 2.45) and osteonecrosis of the jaw for denosumab (RR 3.45; 95% CI 1.06 to 11.24)].

Jakob 2020 suggests that zoledronate, compared to placebo, likely increases both the proportion of participants with pain response (RR 1.46; 95% CI 0.93 to 2.32). Most of the included studies did not report data on quality of life or reported it very poorly, so that data from different studies could not be combined. One trial analyzed the effects of zoledronate and denosumab on cancer-related quality of life in an abstract.

Jakob 2020 compared their findings to those of Tesfamariam 2019. Jakob 2020 concluded that the effects of bisphosphonates as supportive treatment for women with breast cancer are similar to the effects found for men with prostate cancer. The only exception was that Jakob 2020 did not find an effect for pamidronate.

Although the NMA of Jakob 2020 provided useful information, they pointed out that head-to-head comparisons of the different bone-modifying agents are needed to provide more robust evidence.

Renal cell cancer

Bisphosphonates

Van Broekhoven 2023 found evidence from numerous retrospective series and a few small randomized studies. The studies seem to support the hypothesis that bisphosphonates reduce the SRE rate in patients with renal cell cancer and bone metastases, but the overall quality and quantity of evidence was not convincing. When combined with radiotherapy, the use of bisphosphonates may decrease the risk of SREs with 55%.

The authors pointed out that it is difficult to determine the effect of bisphosphonates because the present literature is limited about the timing of bisphosphonates, time to disease progression and follow-up time. Furthermore, the authors drew attention to the fact that patients with renal cell cancer receive targeted therapy and/or immunotherapy, making .it difficult to determine the effect of bisphosphonates.

Level of evidence of the literature

We did not assess the certainty of the evidence for each outcome separately based on the individual studies by using GRADE, but instead adopted the GRADE from the systematic review authors when available (Bozzo 2021; Jakob 2020) or described the main limitations of the systematic reviews or the studies included in the systematic reviews (see description of included studies). The working group noted that many trials were industry-funded, but if and to what extent this affects the results is difficult to substantiate.

Bozzo 2021 reported a “high” GRADE, i.e. high certainty of the evidence, for lower SRE incidence among lung cancer patients with zoledronate and denosumab. Jakob 2020 reported a “moderate” GRADE for lower SRI incidence among prostate cancer patients. Their findings are consistent with the findings from Wang 2015 based on a generic patient population with bone metastases and the findings from Tesfamariam 2019 regarding breast cancer patients. The working group considered the estimated treatment effects to be clinically relevant and consistent with a strong recommendation in favour of denosumab or bisphosphonates.

The risk of pain remission was higher with zoledronate compared with untreated patients (Bozzo 2021, High GRADE; Jakob 2020, Moderate GRADE). No data was available for denosumab. The working group considered the findings regarding pain remission to be clinically relevant and, together with the evidence on SRI incidence, consistent with a recommendation in favour of bone-modifying agents in general.

A systematic review of the literature was performed to answer the following question:

What are the effects of medication in patients with bone metastases, independent of the primary tumor, on skeletal-related events (SREs) and pain)?

P: Patients with bone metastases, any primary tumor

I: Medication (denosumab, bisphosphonates, for example zoledronate, RANK-ligand-inhibitors, bone-modifying agents)

C: Another pain intervention, placebo, another medication, or no intervention

O: Crucial: fractures; skeletal-related events (SREs), pain; important: toxicity (incl. bone necrosis, jaw and tooth problems, nausea, a full feeling/bloating), quality of life)

The primary focus in answering the literature review question is generic (i.e. not tumor-specific) and the secondary focus is tumor-specific.

Relevant outcome measures

The guideline development group considered fractures as such or all SREs (pathological fractures, myelum compression, need for surgery or radiotherapy, hypercalcemia, neurological complaints, neurological deficit) and pain as critical outcome measures for decision making. Following international criteria (Chow 2012), a clinically important pain response was defined as:

• a decrease in the initial pain score by at least 2 points (on a Visual Analogue Scale (VAS) from 0-10), without analgesic increase

or

• an analgesic decrease of ≥25% without an increase in pain score.

The working group did not define a minimal clinically important difference for fractures and SREs, because they felt that any (statistically significant) difference could be clinically relevant and should be weighed against toxicity. There is no agreed minimal clinically relevant difference for fractures or SREs.

Search and select (Methods)

The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms until 18^th of July 2022. This search was updated on 21^st February 2023. The detailed search strategy is depicted under the tab Methods. The systematic literature search resulted in 1227 hits. Studies were selected based on the following criteria:

• Systematic review;
• Includes patients with bone metastases;
• Intervention is medication (denosumab, bisphosphonates, for example zoledronate, RANK-ligand-inhibitors, bone-modifying agents) as monotherapy;
• Comparator is other medication, placebo or another pain intervention (radiation, another combination or another treatment strategy).

Systematic reviews describing studies that also contained patients with vertebral metastases and/or multiple myeloma were included. Original research focusing on those patients were excluded from the literature analysis. Studies comparing medication with another pain intervention (such as the study of Seider 2018) were, when relevant, described in the guideline modules focusing on that type of intervention (i.e. the module Radiotherapy or Radionuclides).

Results

Twenty-six systematic reviews (SRs) were initially selected based on title and abstract screening. After reading the full text of those articles, the working group decided to limit the literature summary for this guideline module to the systematic reviews with 1) a unique contribution in answering the research question, 2) the most recent search strategy, 3) the better quality as assessed with the AMSTAR instrument. Excluded studies and reason for exclusion can be found in the table under the tab Methods.

List of included studies not focusing on a specific tumortype:

A total of six SRs, one individual patient data (IPD) analysis and one original RCT were included that did not focus on a specific tumor type and performed analyses across a heterogenous cohort of patients with bone metastases:

Zoledronate, pamidronate, ibandronate and denosumab compared to each other and placebo:

Wang 2015 (SR, search date up to January 2014), Choudhury 2011 (RCT)

Ibandronate versus zoledronate or placebo:

Geng 2015 (SR, search date up to March 2015)

Clodronate, pamidronate, and zoledronate versus placebo:

Machado 2009 (SR, search date up to January 2009)

Denosumab versus zoledronate:

Jiang 2021 (SR, search date up to December 2020), Menshawy 2018 (SR, search date up to January 2017) and Von Moos 2013 (individual patient data analysis of three RCTs).

Zoledronate versus pamidronate:

Yang 2015 (SR, search date up to March 2015)