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. 2020 Dec 3;12(12):CD013020.
doi: 10.1002/14651858.CD013020.pub2.

Bisphosphonates or RANK-ligand-inhibitors for men with prostate cancer and bone metastases: a network meta-analysis

Tina Jakob  1 , Yonas Mehari Tesfamariam  1 , Sascha Macherey  2 , Kathrin Kuhr  3 , Anne Adams  3 , Ina Monsef  1 , Axel Heidenreich  4 , Nicole Skoetz  5
Affiliations

Bisphosphonates or RANK-ligand-inhibitors for men with prostate cancer and bone metastases: a network meta-analysis

Tina Jakob et al. Cochrane Database Syst Rev. .

Abstract

Background: Different bone-modifying agents like bisphosphonates and receptor activator of nuclear factor-kappa B ligand (RANKL)-inhibitors are used as supportive treatment in men with prostate cancer and bone metastases to prevent skeletal-related events (SREs). SREs such as pathologic fractures, spinal cord compression, surgery and radiotherapy to the bone, and hypercalcemia lead to morbidity, a poor performance status, and impaired quality of life. Efficacy and acceptability of the bone-targeted therapy is therefore of high relevance. Until now recommendations in guidelines on which bone-modifying agents should be used are rare and inconsistent.

Objectives: To assess the effects of bisphosphonates and RANKL-inhibitors as supportive treatment for prostate cancer patients with bone metastases and to generate a clinically meaningful treatment ranking according to their safety and efficacy using network meta-analysis.

Search methods: We identified studies by electronically searching the bibliographic databases Cochrane Controlled Register of Trials (CENTRAL), MEDLINE, and Embase until 23 March 2020. We searched the Cochrane Library and various trial registries and screened abstracts of conference proceedings and reference lists of identified trials.

Selection criteria: We included randomized controlled trials comparing different bisphosphonates and RANKL-inihibitors with each other or against no further treatment or placebo for men with prostate cancer and bone metastases. We included men with castration-restrictive and castration-sensitive prostate cancer and conducted subgroup analyses according to this criteria.

Data collection and analysis: Two review authors independently extracted data and assessed the quality of trials. We defined proportion of participants with pain response and the adverse events renal impairment and osteonecrosis of the jaw (ONJ) as the primary outcomes. Secondary outcomes were SREs in total and each separately (see above), mortality, quality of life, and further adverse events such as grade 3 to 4 adverse events, hypocalcemia, fatigue, diarrhea, and nausea. We conducted network meta-analysis and generated treatment rankings for all outcomes, except quality of life due to insufficient reporting on this outcome. We compiled ranking plots to compare single outcomes of efficacy against outcomes of acceptability of the bone-modifying agents. We assessed the certainty of the evidence for the main outcomes using the GRADE approach.

Main results: Twenty-five trials fulfilled our inclusion criteria. Twenty-one trials could be considered in the quantitative analysis, of which six bisphosphonates (zoledronic acid, risedronate, pamidronate, alendronate, etidronate, or clodronate) were compared with each other, the RANKL-inhibitor denosumab, or no treatment/placebo. By conducting network meta-analysis we were able to compare all of these reported agents directly and/or indirectly within the network for each outcome. In the abstract only the comparisons of zoledronic acid and denosumab against the main comparator (no treatment/placebo) are described for outcomes that were predefined as most relevant and that also appear in the 'Summary of findings' table. Other results, as well as results of subgroup analyses regarding castration status of participants, are displayed in the Results section of the full text. Treatment with zoledronic acid probably neither reduces nor increases the proportion of participants with pain response when compared to no treatment/placebo (risk ratio (RR) 1.46, 95% confidence interval (CI) 0.93 to 2.32; per 1000 participants 121 more (19 less to 349 more); moderate-certainty evidence; network based on 4 trials including 1013 participants). For this outcome none of the trials reported results for the comparison with denosumab. The adverse event renal impairment probably occurs more often when treated with zoledronic acid compared to treatment/placebo (RR 1.63, 95% CI 1.08 to 2.45; per 1000 participants 78 more (10 more to 180 more); moderate-certainty evidence; network based on 6 trials including 1769 participants). Results for denosumab could not be included for this outcome, since zero events cannot be considered in the network meta-analysis, therefore it does not appear in the ranking. Treatment with denosumab results in increased occurrence of the adverse event ONJ (RR 3.45, 95% CI 1.06 to 11.24; per 1000 participants 30 more (1 more to 125 more); high-certainty evidence; 4 trials, 3006 participants) compared to no treatment/placebo. When comparing zoledronic acid to no treatment/placebo, the confidence intervals include the possibility of benefit or harm, therefore treatment with zoledronic acid probably neither reduces nor increases ONJ (RR 1.88, 95% CI 0.73 to 4.87; per 1000 participants 11 more (3 less to 47 more); moderate-certainty evidence; network based on 4 trials including 3006 participants). Compared to no treatment/placebo, treatment with zoledronic acid (RR 0.84, 95% CI 0.72 to 0.97) and denosumab (RR 0.72, 95% CI 0.54 to 0.96) may result in a reduction of the total number of SREs (per 1000 participants 75 fewer (131 fewer to 14 fewer) and 131 fewer (215 fewer to 19 fewer); both low-certainty evidence; 12 trials, 5240 participants). Treatment with zoledronic acid and denosumab likely neither reduces nor increases mortality when compared to no treatment/placebo (zoledronic acid RR 0.90, 95% CI 0.80 to 1.01; per 1000 participants 48 fewer (97 fewer to 5 more); denosumab RR 0.93, 95% CI 0.77 to 1.11; per 1000 participants 34 fewer (111 fewer to 54 more); both moderate-certainty evidence; 13 trials, 5494 participants). Due to insufficient reporting, no network meta-analysis was possible for the outcome quality of life. One study with 1904 participants comparing zoledronic acid and denosumab showed that more zoledronic acid-treated participants than denosumab-treated participants experienced a greater than or equal to five-point decrease in Functional Assessment of Cancer Therapy-General total scores over a range of 18 months (average relative difference = 6.8%, range -9.4% to 14.6%) or worsening of cancer-related quality of life.

Authors' conclusions: When considering bone-modifying agents as supportive treatment, one has to balance between efficacy and acceptability. Results suggest that Zoledronic acid likely increases both the proportion of participants with pain response, and the proportion of participants experiencing adverse events However, more trials with head-to-head comparisons including all potential agents are needed to draw the whole picture and proof the results of this analysis.

Trial registration: ClinicalTrials.gov NCT00079001 NCT00003232 NCT00019695 NCT00104650 NCT00321620 NCT00216060 NCT00181558 NCT00268476 NCT00554918 NCT00685646.

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Conflict of interest statement

Tina Jakob: none known

Yonas Mehari Tesfamariam: none known

Sascha Macherey: none known

Kathrin Kuhr: none known

Anne Adams: none known

Ina Monsef: none known

Axel Heidenreich: none known

Nicole Skoetz: none known

Figures

1
1
Ideal network diagram of all comparisons.
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2
Study flow diagram.
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Risk of bias summary: review authors' judgements about each risk of bias item for each included study. Spaces are left blank in the case a judgement is not applicable (e.g. study reports only outcomes subjective to participants).
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4
Network diagram for outcome pain response. Any two treatments are connected by a line when there is at least one study comparing the two treatments. Line width: number of participants.
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Forest plot for outcome pain response: random‐effects model. Reference treatment: no treatment/placebo. Treatments are ordered by P‐score (descending). The fixed‐effect model yields similar results.
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6
Leaguetable of network meta‐analysis for the outcome proportion of participants with pain response. Treatment options are ranked as indicated by the arrow from top: greater chance of being the best treatment (higher P‐scores) to bottom: lower chance of being the best treatment (lower P‐score). Network estimates with 95% confidence intervals indicating an effect between two of the treatment options are marked in yellow: treatment option in column better than treatment option in row. No. of studies: 4. No. of treatments: 5. No. of pairwise comparisons: 4. No. of designs: 4 Heterogeneity/inconsistency: Qtotal = 0, P = not available; I2 = not available; Tau2 = not available
Treatment effects + 95% confidence intervals (risk ratios, random‐effects model)
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Forest plot for sensitivity analysis for outcome pain response (risk of bias (RoB) low): random‐effects model. Reference treatment: no treatment/placebo. Treatments are ordered by P‐score (descending). The fixed‐effect model yields similar results.
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8
Leagutetable of sensitivity network meta‐analysis including only studies with low risk of bias for outcome proportion of participants with pain response. Treatment options are ranked as indicated by the arrow from top: greater chance of being the best treatment (higher P‐scores) to bottom: lower chance of being the best treatment (lower P‐score). Network estimates with 95% confidence intervals indicating an effect between two of the treatment options are marked in yellow: treatment option in column better than treatment option in row. No. of studies: 3. No. of treatments: 4. No. of pairwise comparisons: 3. No. of designs: 3 Heterogeneity/inconsistency: Qtotal = 0, P = not available; I2 = not available; Tau2 = not available
Treatment effects + 95% confidence intervals (risk ratios, random‐effects model)
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Network diagram for outcome adverse event: renal impairment. Any two treatments are connected by a line when there is at least one study comparing the two treatments. Line width: number of participants.
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Forest plot for the outcome adverse events: renal impairment. Random‐effects model. Reference treatment: no treatment/placebo. Treatments are ordered by P‐score (descending). The fixed‐effect model yields similar results.
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Leaguetable of network meta‐analysis for outcome adverse event: renal impairment. Treatment options are ranked as indicated by the arrow from top: greater chance of being the best treatment (higher P‐scores) to bottom: lower chance of being the best treatment (lower P‐score). Network estimates with 95% confidence intervals indicating an effect between two of the treatment options are marked in yellow: treatment option in column better than treatment option in row. Global approach to check inconsistency/heterogeneity: Q‐statistics, I2. No. of studies: 6. No. of treatments: 4. No. of pairwise comparisons: 6. No. of designs: 4 Qtotal = 0.92, P = 0.82/Qwithin = 0.56; P = 0.76/Qbetween = 0.36, P = 0.55; I2 = 0.0%, Tau2 = 0
Treatment effects + 95% confidence intervals (risk ratios, random‐effects model)
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Forest plot of splitting direct and indirect evidence for the outcome adverse event: renal impairment. In addition to the confidence interval for the network estimate, prediction intervals are shown as bars for each comparison. Local approach to check inconsistency—comparison of direct and indirect estimates for closed loops. As presented in Figure 9, there is one closed loop in the network (zoledronic acid—clodronate—no treatment/placebo). There is no significant difference between direct and indirect estimate (P value of test for disagreement: P = 0.547).
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Net heat plot for outcome adverse events: renal impairment (random‐effects model). There are negligible signs of inconsistency in the net heat plot. Local approach to check inconsistency—comparison of direct and indirect estimates for closed loops.
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Forest plot for sensitivity analysis of the primary outcome adverse event: renal impairment (risk of bias (RoB) low): random‐effects model. Reference treatment: no treatment/placebo. Treatments are ordered by P‐score (descending). The fixed‐effect model yields similar results.
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Leaguetable of sensitivity network meta‐analysis including only studies with low risk of bias for outcome adverse event: renal impairment. Treatment options are ranked as indicated by the arrow from top: greater chance of being the best treatment (higher P‐scores) to bottom: lower chance of being the best treatment (lower P‐score). Network estimates with 95% confidence intervals indicating an effect between two of the treatment options are marked in yellow: treatment option in column better than treatment option in row. No. of studies: 4. No. of treatments: 3. No. of pairwise comparisons: 4. No. of designs: 3 Qtotal = 0.38, P = 0.83/Qwithin = 0.00, P = 0.95/Qbetween = 0.38, P = 0.54; I2 = 0.0%, Tau2 = 0
Treatment effects + 95% confidence intervals (risk ratios, random‐effects model).
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Forest plot of splitting direct and indirect evidence for outcome adverse event: renal impairment (risk of bias: low). In addition to the confidence interval for the network estimator, a prediction interval is shown. Local approach to check inconsistency—comparison of direct and indirect estimate for closed loops. There is one closed loop in the network (graph not shown; zoledronic acid—clodronate—no treatment/placebo). There is no significant difference between direct and indirect estimate (P value of test for disagreement: P = 0.538).
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Network diagram for the outcome adverse event: osteonecrosis of the jaw. Any two treatments are connected by a line when there is at least one study comparing the two treatments. Line width: number of participants.
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Forest plot for the outcome adverse event: osteonecrosis of the jaw. Random‐effects model. Reference treatment: no treatment/placebo. Treatments are ordered by P‐score (descending). The fixed‐effect model yields similar results. Since there are no closed loops in the network, no local approach to check inconsistency comparing direct and indirect estimates was done. Also, prediction intervals could not be calculated.
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Leaguetable of network meta‐analysis for outcome adverse event: osteonecrosis of the jaw. Treatment options are ranked as indicated by the arrow from top: greater chance of being the best treatment (higher P‐scores) to bottom: lower chance of being the best treatment (lower P‐score). Network estimates with 95% confidence intervals indicating an effect between two of the treatment options are marked in yellow: treatment option in column better than treatment option in row. Global approach to check inconsistency/heterogeneity: Q‐statistics, I2. No. of studies: 4. No. of treatments: 4. No. of pairwise comparisons: 4. No. of designs: 3 Heterogeneity/inconsistency: Qtotal = 0.45, P = 0.50; I2 = 0.0%, Tau2 = 0
Treatment effects + 95% confidence intervals (risk ratios, random‐effects model)
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Forest plot for sensitivity analysis of outcome adverse event: osteonecrosis of the jaw (risk of bias (RoB) low): random‐effects model. Reference treatment: no treatment/placebo. Treatments are ordered by P‐score (descending). The fixed‐effect model yields similar results.
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Leaguetable of sensitivity network meta‐analysis including only studies with low risk of bias for outcome adverse event: osteonecrosis of the jaw. Treatment options are ranked as indicated by the arrow from top: greater chance of being the best treatment (higher P‐scores) to bottom: lower chance of being the best treatment (lower P‐score). Network estimates with 95% confidence intervals indicating an effect between two of the treatment options would have been marked in yellow: treatment option in column better than treatment option in row. No. of studies: 3. No. of treatments: 4. No. of pairwise comparisons: 3. No. of designs: 3 Heterogeneity/inconsistency: Qtotal = 0, P = not available; I2 = not available, Tau2 = not available
Treatment effects + 95% confidence intervals (risk ratios, random‐effects model)
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Network diagram for outcome total number of skeletal‐related events. Any two treatments are connected by a line when there is at least one study comparing the two treatments. Line width: number of participants.
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Forest plot for the outcome total number of skeletal‐related events (SREs). Random‐effects model. Reference treatment: no treatment/placebo. Treatments are ordered by P‐score (descending). The fixed‐effect model yields slightly different results (Figure 99).
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Leaguetable of network meta‐analysis for outcome total number of skeletal‐related events. Treatment options are ranked as indicated by the arrow from top: greater chance of being the best treatment (higher P‐scores) to bottom: lower chance of being the best treatment (lower P‐score). Network estimates with 95% confidence intervals indicating an effect between two of the treatment options are marked in yellow: treatment option in column better than treatment option in row. Global approach to check inconsistency/heterogeneity: Q‐statistics, I2. No. of studies: 12. No. of treatments: 6. No. of pairwise comparisons: 12. No. of designs: 6 Qtotal = 11.48, P = 0.12/Qwithin = 11.38, P = 0.077/Qbetween = 0.09, P = 0.76; I2 = 39%, Tau2 = 0.0124
Treatment effects + 95% confidence intervals (risk ratios, random‐effects model)
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Forest plot for the outcome: total number of skeletal‐related events (SREs). Fixed‐effect model.
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26
Forest plot of splitting direct and indirect evidence for the outcome total number of skeletal‐related events. In addition to the confidence interval for the network estimate, prediction intervals are shown as bars for each comparison. Local approach to check inconsistency—comparison of direct and indirect estimates for closed loops. As presented in Figure 22, there is one closed loop in the network (zoledronic acid—clodronate—no treatment/placebo). There is no significant difference between direct and indirect estimate (P value of test for disagreement: P = 0.847).
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Net heat plot for outcome total number of skeletal‐related events (random‐effects model). There are no signs of inconsistency in the net heat plot.
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Forest plot for sensitivity analysis of outcome total number of skeletal‐related events (SREs) (risk of bias (RoB) low). Random‐effects model. Reference treatment: no treatment/placebo. Treatments are ordered by P‐score (descending). The fixed‐effect model yields similar results.
29
29
Leaguetable of sensitivity network meta‐analysis including only studies with low risk of bias for outcome total number of skeletal‐related events. Treatment options are ranked as indicated by the arrow from top: greater chance of being the best treatment (higher P‐scores) to bottom: lower chance of being the best treatment (lower P‐score). Network estimates with 95% confidence intervals indicating an effect between two of the treatment options are marked in yellow: treatment option in column better than treatment option in row. Global approach to check inconsistency/heterogeneity: Q‐statistics, I2. No. of studies: 7. No. of treatments: 5. No. of pairwise comparisons: 7. No. of designs: 5 Qtotal = 2.09, df = 3, P = 0.55/Qwithin = 1.95, df = 2, P = 0.38/Qbetween = 0.14, df = 1, P = 0.71; I2 = 0%, Tau2 = 0
Treatment effects + 95% confidence intervals (risk ratios, random‐effects model)
30
30
Forest plot of sensitivity analysis of splitting direct and indirect evidence for the outcome total number of skeletal‐related events (risk of bias low). In addition to the confidence interval for the network estimator, a prediction interval is shown. Local approach to check inconsistency—comparison of direct and indirect estimate for closed loops. There is one closed loop in the network (graph not shown; zoledronic acid—clodronate—no treatment/placebo). There is no significant difference between direct and indirect estimate (P value of test for disagreement: P = 0.710).
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Results of pairwise meta‐analysis of denosumab versus zoledronic acid for the outcome total number of skeletal‐related events (SREs).
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Network diagram for outcome skeletal‐related event: pathological fractures. Any two treatments are connected by a line when there is at least one study comparing the two treatments. Line width: number of participants.
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Forest plot for the outcome skeletal‐related event (SRE): pathological fractures. Random‐effects model. Reference treatment: no treatment/placebo. Treatments are ordered by P‐score (descending). The fixed‐effect model yields similar results.
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34
Leaguetable of network meta‐analysis for the outcome skeletal‐related event: pathological fractures. Treatment options are ranked as indicated by the arrow from top: greater chance of being the best treatment (higher P‐scores) to bottom: lower chance of being the best treatment (lower P‐score). Network estimates with 95% confidence intervals indicating an effect between two of the treatment options are marked in yellow: treatment option in column better than treatment option in row. Global approach to check inconsistency/heterogeneity: Q‐statistics, I2. No. of studies: 8. No. of treatments: 5. No. of pairwise comparisons: 8. No. of designs: 5 Qtotal = 1.73, df = 4, P = 0.78/Qwithin = 1.73, df = 3, P = 0.63/Qbetween = 0.00, df = 1, P = 0.96; I2 = 0.0%, Tau2 = 0 Treatment effects + 95% confidence intervals (risk ratios, random‐effects model)
35
35
Forest plot of splitting direct and indirect evidence for outcome skeletal‐related event: pathological fractures. In addition to the confidence interval for the network estimator, a prediction interval is shown. Local approach to check inconsistency—comparison of direct and indirect estimate for closed loops. As presented in Figure 32, there is one closed loop in the network (zoledronic acid—clodronate—no treatment/placebo). There is no significant difference between direct and indirect estimate (P value of test for disagreement: P = 0.958).
36
36
Net heat plot for outcome skeletal‐related event: pathological fractures (random‐effects model). There are no signs of inconsistency in the net heat plot.
37
37
Network diagram for outcome skeletal‐related event: spinal cord compression. Any two treatments are connected by a line when there is at least one study comparing the two treatments. Line width: number of participants.
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38
Forest plot for outcome skeletal‐related event (SRE): spinal cord compression. Random‐effects model. Reference treatment: no treatment/placebo. Treatments are ordered by P‐score (descending). The fixed‐effect model yields similar results.
39
39
Leaguetable of network meta‐analysis for the outcome skeletal‐related event: spinal cord compression. Treatment options are ranked as indicated by the arrow from top: greater chance of being the best treatment (higher P‐scores) to bottom: lower chance of being the best treatment (lower P‐score). Network estimates with 95% confidence intervals indicating an effect between two of the treatment options are marked in yellow: treatment option in column better than treatment option in row. Global approach to check inconsistency/heterogeneity: Q‐statistics, I2. No. of studies: 9. No. of treatments: 5. No. of pairwise comparisons: 9. No. of designs: 5 Qtotal = 2.43, P = 0.79/Qwithin = 2.38, P = 0.67/Qbetween = 0.05, P = 0.82; I2 = 0.0%, Tau2 = 0 Treatment effects + 95% confidence intervals (risk ratios, random‐effects model).
40
40
Forest plot of splitting direct and indirect evidence for the outcome skeletal‐related event: spinal cord compression. In addition to the confidence interval for the network estimator, a prediction interval is shown. Local approach to check inconsistency—comparison of direct and indirect estimate for closed loops. As presented in Figure 37, there is one closed loop in the network (zoledronic acid—clodronate—no treatment/placebo). There is no significant difference between direct and indirect estimate (P value of test for disagreement: P = 0.822).
41
41
Net heat plot for the outcome skeletal‐related event: spinal cord compression (random‐effects model). There are no signs of inconsistency in the net heat plot.
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42
Network diagram for the outcome skeletal‐related event: radiotherapy. Any two treatments are connected by a line when there is at least one study comparing the two treatments. Line width: number of participants.
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Forest plot for the outcome skeletal‐related event (SRE): radiotherapy. Random‐effects model. Reference treatment: no treatment/placebo. Treatments are ordered by P‐score (descending). The fixed‐effect model yields similar results.
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44
Leaguetable of network meta‐analysis for the outcome skeletal‐related event: radiotherapy. Treatment options are ranked as indicated by the arrow from top: greater chance of being the best treatment (higher P‐scores) to bottom: lower chance of being the best treatment (lower P‐score). Network estimates with 95% confidence intervals indicating an effect between two of the treatment options are marked in yellow: treatment option in column better than treatment option in row. Global approach to check inconsistency/heterogeneity: Q‐statistics, I2. No. of studies: 8. No. of treatments: 5. No. of pairwise comparisons: 8. No. of designs: 5 Qtotal = 0.29, P = 0.99/Qwithin = 0.28, P = 0.96/Qbetween = 0.00, P = 0.95; I2 = 0.0%, Tau2 = 0 Treatment effects + 95% confidence intervals (risk ratios, random‐effects model)
45
45
Forest plot of splitting direct and indirect evidence for the outcome skeletal‐related event: radiotherapy. In addition to the confidence interval for the network estimator, a prediction interval is shown. Local approach to check inconsistency—comparison of direct and indirect estimate for closed loops. As presented in Figure 42, there is one closed loop in the network (zoledronic acid—clodronate—no treatment/placebo). There is no significant difference between direct and indirect estimate (P value of test for disagreement: P = 0.955).
46
46
Net heat plot for the outcome skeletal‐related event: radiotherapy (random‐effects model). There are no signs of inconsistency in the net heat plot.
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47
Network diagram for the outcome skeletal‐related event: bone surgery. Any two treatments are connected by a line when there is at least one study comparing the two treatments. Line width: number of participants.
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Forest plot for the outcome skeletal‐related event: surgery. Random‐effects model. Reference treatment: no treatment/placebo. Treatments are ordered by P‐score (descending). The fixed‐effect model yields slightly different confidence intervals (Figure 50).
49
49
Leaguetable of network meta‐analysis for the outcome skeletal‐related event: surgery. Treatment options are ranked as indicated by the arrow from top: greater chance of being the best treatment (higher P‐scores) to bottom: lower chance of being the best treatment (lower P‐score). Network estimates with 95% confidence intervals indicating an effect between two of the treatment options are marked in yellow: treatment option in column better than treatment option in row. Global approach to check inconsistency/heterogeneity: Q‐statistics, I2. No. of studies: 6. No. of treatments: 5. No. of pairwise comparisons: 6. No. of designs: 4 Heterogeneity/inconsistency: Qtotal = 2.11, P = 0.35; I2 = 5.3%, Tau2 = 0.0216 Treatment effects + 95% confidence intervals (risk ratios, random‐effects model)
50
50
Forest plot for outcome skeletal‐related event (SRE): surgery. Fixed‐effect model. Reference treatment: no treatment/placebo. Treatments are ordered by P‐score (descending). Since there are no closed loops in the network, no local approach to check inconsistency was conducted.
51
51
Network diagram for the outcome skeletal‐related event: hypercalcemia. Any two treatments are connected by a line when there is at least one study comparing the two treatments. Line width: number of participants.
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Forest plot for the outcome skeletal‐related event (SRE): hypercalcemia. Random‐effects model. Reference treatment: no treatment/placebo. Treatments are ordered by P‐score (descending). The fixed‐effect model yields similar results. Since there are no closed loops in the network, no local approach to check inconsistency was conducted.
53
53
Leaguetable of network meta‐analysis for the outcome skeletal‐related event: hypercalcemia. Treatment options are ranked as indicated by the arrow from top: greater chance of being the best treatment (higher P‐scores) to bottom: lower chance of being the best treatment (lower P‐score). Network estimates with 95% confidence intervals indicating an effect between two of the treatment options would have been marked in yellow: treatment option in column better than treatment option in row. Global approach to check inconsistency/heterogeneity: Q‐statistics, I2. No. of studies: 4. No. of treatments: 4. No. of pairwise comparisons: 4. No. of designs: 3 Heterogeneity / inconsistency: Qtotal = 0.57, P = 0.45; I2 = 0.0%, Tau2 = 0 Treatment effects + 95% confidence intervals (risk ratios, random‐effects model)
54
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Network diagram for the outcome mortality. Any two treatments are connected by a line when there is at least one study comparing the two treatments. Line width: number of participants.
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Forest plot for the outcome mortality. Random‐effects model. Reference treatment: no treatment/placebo. Treatments are ordered by P‐score (descending). The fixed‐effect model yields similar results.
56
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Leaguetable of network meta‐analysis for the outcome mortality. Treatment options are ranked as indicated by the arrow from top: greater chance of being the best treatment (higher P‐scores) to bottom: lower chance of being the best treatment (lower P‐score). Network estimates with 95% confidence intervals indicating an effect between two of the treatment options are marked in yellow: treatment option in column better than treatment option in row. Global approach to check inconsistency/heterogeneity: Q‐statistics, I2. No. of studies: 13. No. of treatments: 6. No. of pairwise comparisons: 13. No. of designs: 6 Qtotal = 3.35, P = 0.91/Qwithin = 3.15, P = 0.87/Qbetween = 0.20, P = 0.65; I2 = 0.0%, Tau2 = 0 Treatment effects + 95% confidence intervals (risk ratios, random‐effects model)
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Forest plot of splitting direct and indirect evidence for the outcome mortality. In addition to the confidence interval for the network estimator, a prediction interval is shown. Local approach to check inconsistency—comparison of direct and indirect estimate for closed loops. As presented in Figure 54, there is one closed loop in the network (zoledronic acid—clodronate—no treatment/placebo). There is no significant difference between direct and indirect estimate (P value of test for disagreement: P = 0.654).
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58
Net heat plot for outcome mortality (random‐effects model). There are negligible signs of inconsistency in the net heat plot.
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Forest plot for sensitivity analysis of outcome: mortality (low risk of bias (RoB)). Random‐effects model. Reference treatment: no treatment/placebo. Treatments are ordered by P‐score (descending). The fixed‐effect model yields similar results.
60
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Leaguetable of sensitivity network meta‐analysis including only studies with low risk of bias for the outcome mortality. Treatment options are ranked as indicated by the arrow from top: greater chance of being the best treatment (higher P‐scores) to bottom: lower chance of being the best treatment (lower P‐score). Network estimates with 95% confidence intervals indicating an effect between two of the treatment options would have been marked in yellow: treatment option in column better than treatment option in row. Global approach to check inconsistency/heterogeneity: Q‐statistics, I2. No. of studies: 9. No. of treatments: 5. No. of pairwise comparisons: 9. No. of designs: 5 Qtotal = 2.98, P = 0.70/Qwithin = 2.85, P = 0.58/Qbetween = 0.13, P = 0.72; I2 = 0%, Tau2 = 0 Treatment effects + 95% confidence intervals (risk ratios, random‐effects model)
61
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Forest plot for sensitivity analysis of splitting direct and indirect evidence for the outcome mortality (low risk of bias). In addition to the confidence interval for the network estimator, a prediction interval is shown. Local approach to check inconsistency—comparison of direct and indirect estimate for closed loops. There is one closed loop in the network (graph not shown; zoledronic acid—clodronate—no treatment/placebo). There is no significant difference between direct and indirect estimate (P value of test for disagreement: P = 0.721).
62
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Net heat plot for sensitivity analysis of the outcome mortality (low risk of bias; random‐effects model). There are negligible signs of inconsistency in the net heat plot. The fixed‐effect model yields the same results.
63
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Network diagram for the outcome adverse event: grade 3 to 4. Any two treatments are connected by a line when there is at least one study comparing the two treatments. Line width: number of participants.
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Forest plot for the outcome adverse event: grade 3 to 4. Random‐effects model. Reference treatment: no treatment/placebo. Treatments are ordered by P‐score (descending). The fixed‐effect model yields similar results. Since there are no closed loops in the network, no local approach to check inconsistency was conducted.
65
65
Leaguetable of network meta‐analysis for the outcome adverse event: grade 3 to 4. Treatment options are ranked as indicated by the arrow from top: greater chance of being the best treatment (higher P‐scores) to bottom: lower chance of being the best treatment (lower P‐score). Network estimates with 95% confidence intervals indicating an effect between two of the treatment options are marked in yellow: treatment option in column better than treatment option in row. Global approach to check inconsistency/heterogeneity: Q‐statistics, I2. No. of studies: 8. No. of treatments: 7. No. of pairwise comparisons: 8. No. of designs: 6 Heterogeneity/inconsistency: Qtotal = 0.44, P = 0.80; I2 = 0.0%, Tau2 = 0 Treatment effects + 95% confidence intervals (risk ratios, random‐effects model)
66
66
Results of pairwise meta‐analysis for the outcome adverse event: grade 3 to 4 (random‐effects model).
67
67
Network diagram for the outcome adverse event: hypocalcemia. Any two treatments are connected by a line when there is at least one study comparing the two treatments. Line width: number of participants.
68
68
Forest plot for secondary outcome: adverse event: hypocalcemia. Random‐effects model. Reference treatment: no treatment/placebo. Treatments are ordered by P‐score (descending). There are strong differences between the fixed‐effect and random‐effects estimates and confidence intervals. In addition, the treatments are ranked in a different order (Figure 70).
69
69
Leaguetable of network meta‐analysis for the outcome adverse event: hypocalcemia. Treatment options are ranked as indicated by the arrow from top: greater chance of being the best treatment (higher P‐scores) to bottom: lower chance of being the best treatment (lower P‐score). Network estimates with 95% confidence intervals indicating an effect between two of the treatment options would have been marked in yellow: treatment option in column better than treatment option in row. Global approach to check inconsistency/heterogeneity: Q‐statistics, I2. No. of studies: 7. No. of treatments: 5. No. of pairwise comparisons: 7. No. of designs: 5 Qtotal = 6.90, P = 0.075/Qwithin = 2.39, P = 0.30/Qbetween = 4.51, P = 0.034; I2 = 56.5%, Tau2 = 1.0252 Treatment effects + 95% confidence intervals (risk ratios, random‐effects model)
70
70
Forest plot for secondary outcome adverse event: hypocalcemia. Fixed‐effect model. Reference treatment: no treatment/placebo. Treatments are ordered by P‐score (descending).
71
71
Forest plot of splitting direct and indirect evidence for the secondary outcome adverse event: hypocalcemia. In addition to the confidence interval for the network estimator, a prediction interval is shown. Local approach to check inconsistency—comparison of direct and indirect estimate for closed loops. As presented in Figure 67, there is one closed loop in the network (zoledronic acid—clodronate—no treatment/placebo). There is no significant difference between direct and indirect estimate (P value of test for disagreement: P = 0.20).
72
72
Net heat plot for secondary outcome adverse event: hypocalcemia (random‐effects model). There are signs of inconsistency in the net heat plot in the comparison clodronate versus no treatment/placebo. The fixed‐effect model shows even stronger inconsistency (not shown).
73
73
Results of pairwise meta‐analysis for secondary outcome adverse event: hypocalcemia (random‐effects model).
74
74
Network diagram for secondary outcome adverse event: fatigue. Any two treatments are connected by a line when there is at least one study comparing the two treatments. Line width: number of participants.
75
75
Forest plot for the secondary outcome adverse event: fatigue. Random‐effects model. Reference treatment: no treatment/placebo. Treatments are ordered by P‐score (descending). The fixed‐effect model yields similar results.
76
76
Leaguetable of network meta‐analysis for the outcome adverse event: fatigue. Treatment options are ranked as indicated by the arrow from top: greater chance of being the best treatment (higher P‐scores) to bottom: lower chance of being the best treatment (lower P‐score). Network estimates with 95% confidence intervals indicating an effect between two of the treatment options would have been marked in yellow: treatment option in column better than treatment option in row. Global approach to check inconsistency/heterogeneity: Q‐statistics, I2. No. of studies: 7. No. of treatments: 5. No. of pairwise comparisons: 7. No. of designs: 4 Heterogeneity/inconsistency: Qtotal = 2.36, P = 0.50; I2 = 0.0%, Tau2 = 0 Treatment effects + 95% confidence intervals (risk ratios, random‐effects model)
77
77
Network diagram for the secondary outcome adverse event: diarrhea. Any two treatments are connected by a line when there is at least one study comparing the two treatments. Line width: number of participants.
78
78
Forest plot for secondary outcome adverse event: diarrhea. Random‐effects model. Reference treatment: no treatment/placebo. Treatments are ordered by P‐score (descending). There are slight differences between the fixed‐effect and random‐effects estimates and confidence intervals (Figure 80).
79
79
Leaguetable of network meta‐analysis for the outcome adverse event: diarrhea. Treatment options are ranked as indicated by the arrow from top: greater chance of being the best treatment (higher P‐scores) to bottom: lower chance of being the best treatment (lower P‐score). Network estimates with 95% confidence intervals indicating an effect between two of the treatment options are marked in yellow: treatment option in column better than treatment option in row. Global approach to check inconsistency/heterogeneity: Q‐statistics, I2. No. of studies: 6. No. of treatments: 6. No. of pairwise comparisons: 6. No. of designs: 5 Heterogeneity/inconsistency: Qtotal = 1.23, P = 0.27; I2 = 18.7%, Tau2 = 0.0197 Treatment effects + 95% confidence intervals (risk ratios, random‐effects model)
80
80
Forest plot for secondary outcome adverse event: diarrhea. Fixed‐effect model. Reference treatment: No treatment/placebo. Treatments are ordered by P‐score (descending).
81
81
Network diagram for the secondary outcome adverse event: nausea. Any two treatments are connected by a line when there is at least one study comparing the two treatments. Line width: number of participants.
82
82
Forest plot for secondary outcome adverse event: nausea. Random‐effects model. Reference treatment: no treatment/placebo. Treatments are ordered by P‐score (descending). The fixed‐effect model yields similar results.
83
83
Leaguetable of network meta‐analysis for the outcome adverse event: nausea. Treatment options are ranked as indicated by the arrow from top: greater chance of being the best treatment (higher P‐scores) to bottom: lower chance of being the best treatment (lower P‐score). Network estimates with 95% confidence intervals indicating an effect between two of the treatment options are marked in yellow: treatment option in column better than treatment option in row. Global approach to check inconsistency/heterogeneity: Q‐statistics, I2. No. of studies: 9. No. of treatments: 7. No. of pairwise comparisons: 9. No. of designs: 6 Heterogeneity/inconsistency: Qtotal = 2.33, P = 0.51; I2 = 0.0%, Tau2 = 0 Treatment effects + 95% confidence intervals (risk ratios, random‐effects model).
84
84
Results of pairwise meta‐analysis for outcome adverse event: nausea (fixed‐effect and random‐effects).
85
85
Ranking plot representing simultaneously the efficacy (x axis, total number of skeletal‐related events (SREs)) and the acceptability (y axis, adverse event: renal impairment) of all bone‐modifying agents for patients with prostate cancer and bone metastases. Optimal treatment should be characterized by both high efficacy and acceptability and should be in the right upper corner of this graph. Only studies reporting both efficacy (total numbers of SREs) and acceptability (adverse event: renal impairment) are considered in the ranking plot. Studies reporting only one of the two are not included in the statistical analysis for this plot.
86
86
Leaguetable with network estimates of all pairwise comparisons for efficacy (total number of skeletal‐related events) and acceptability (adverse event: renal impairment). Treatments are presented in alphabetical order. Data are risk ratios (RRs) with corresponding 95% confidence intervals. For both efficacy and acceptability, RRs lower than 1 favor the first treatment in alphabetical order. To obtain RRs for comparisons in the opposite direction, reciprocals should be taken. Results not including the line of no effect in their confidence intervals and therefore suggesting evidence for a difference, are marked bold.
87
87
Ranking plot representing simultaneously the efficacy (x axis, total number of skeletal‐related events (SREs)) and the acceptability (y axis, adverse event: osteonecrosis of the jaw) of all bone‐modifying agents for patients with prostate cancer and bone metastases. Optimal treatment should be characterized by both high efficacy and acceptability and should be in the right upper corner of this graph. Only studies reporting both efficacy (total numbers of SREs) and acceptability (adverse event: osteonecrosis of the jaw) are considered in the ranking plot. Studies reporting only one of the two are not included in the statistical analysis for this plot.
88
88
Leaguetable with network estimates of all pairwise comparisons for efficacy (total number of skeletal‐related events) and acceptability (adverse event: osteonecrosis of the jaw). Treatments are presented in alphabetical order. Data are risk ratios (RRs) with corresponding 95% confidence intervals. For both efficacy and acceptability, RRs lower than 1 favor the first treatment in alphabetical order. To obtain RRs for comparisons in the opposite direction, reciprocals should be taken. Results not including the line of no effect in their confidence intervals and therefore suggesting evidence for a difference, are marked bold.
89
89
Ranking plot representing simultaneously the efficacy (x axis, total number of skeletal‐related events (SREs)) and the acceptability (y axis, grade 3 to 4 adverse events) of all bone‐modifying agents for patients with prostate cancer and bone metastases. Optimal treatment should be characterized by both high efficacy and acceptability and should be in the right upper corner of this graph. Only studies reporting both efficacy (total numbers of SREs) and acceptability (grade 3 to 4 adverse events) are considered in the ranking plot. Studies only reporting one of the two are not included in the statistical analysis for this plot. Results not including the line of no effect in their confidence intervals and therefore suggesting evidence for a difference, are marked bold.
90
90
Leaguetable with network estimates of all pairwise comparisons for efficacy (total number of skeletal‐related events) and acceptability (grade 3 to 4 adverse events). Treatments are presented in alphabetical order. Data are risk ratios (RRs) with corresponding 95% confidence intervals. For both efficacy and acceptability, RRs lower than 1 favor the first treatment in alphabetical order. To obtain RRs for comparisons in the opposite direction, reciprocals should be taken. Results not including the line of no effect in their confidence intervals and therefore suggesting evidence for a difference, are marked bold.
91
91
Ranking plot representing simultaneously the efficacy (x axis, total number of skeletal‐related events (SREs)) and the acceptability (y axis, adverse event: hypocalcemia) of all bone‐modifying agents for patients with prostate cancer and bone metastases. Optimal treatment should be characterized by both high efficacy and acceptability and should be in the right upper corner of this graph. Only studies reporting both efficacy (total numbers of SREs) and acceptability (adverse event: hypocalcemia) are considered in the ranking plot. Studies reporting only one of the two are not included in the statistical analysis for this plot.
92
92
Leaguetable with network estimates of all pairwise comparisons for efficacy (total number of skeletal‐related events) and acceptability (adverse event: hypocalcemia). Treatments are presented in alphabetical order. Data are risk ratios (RRs) with corresponding 95% confidence intervals. For both efficacy and acceptability, RRs lower than 1 favor the first treatment in alphabetical order. To obtain RRs for comparisons in the opposite direction, reciprocals should be taken.
93
93
Overview of included studies and comparisons for outcome proportion of participants with pain response (A) and adverse event: renal impairment (B).
94
94
Overview of included studies and comparisons for the outcome adverse event: osteonecrosis of the jaw (A) and total number of skeletal‐related events (SREs) (B).
95
95
Overview of included studies and comparisons for the outcome skeletal‐related event (SRE): pathological fractures (A) and SRE: spinal cord compression (B).
96
96
Overview of included studies and comparisons for the outcome skeletal‐related event (SRE): bone surgery (A) and SRE: hypercalcemia (B).
97
97
Overview of included studies and comparisons for the outcome mortality (A) and grade 3 to 4 adverse events (B).
98
98
Overview of included studies and comparisons for the outcome adverse event: hypocalcemia (A) and adverse event: fatigue (B).
99
99
Overview of included studies and comparisons for the outcome adverse event: diarrhea (A) and adverse event: nausea (B).
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References

References to studies included in this review

Abetz 2006 {published data only}
    1. *Abetz L, Barghout V, Arbuckle R, Bosch V, Shirina N, Saad F. Impact of zoledronic acid (Z) on pain in prostate cancer patients with bone metastases in a randomised placebo-control trial. Journal of Clinical Oncology 2006;24:4638.
    1. Barghout V, Abetz L, Arbuckle R, Bosch V, Hei Y, Saad F. Effect of zoledronic acid (Z) on pain in prostate cancer patients with bone metastases based on performance status. Journal of Clinical Oncology - Supplement 2006;24(18):14544.
CALGB 90202 {published data only}
    1. *Smith MR, Halabi S, Ryan CJ, 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). Journal of Clinical Oncology 2014;32:1143-50. - PMC - PubMed
    1. Cook RJ, Coleman R, Brown J, Lipton A, Major P, Hei YJ, et al. Markers of bone metabolism and survival in men with hormone-refractory metastatic prostate cancer. Clinical Cancer Research 2006;12:3361-7. - PubMed
    1. Smith MR. CALGB 90202: a randomized double-blind, placebo-controlled phase III study of early vs standard zoledronic acid to prevent skeletal-related events in men with prostate cancer metastatic to the bone. Clinical Advances in Hematology and Oncology 2006;4:897-8.
Elomaa 1992 {published data only}
    1. *Elomaa I, Kylmata T, Tammela T, Vitanen J, Ottelin M, Ruutu K, et al. Effect of oral clodronate on bone pain: a controlled study in patients with metastatic prostate cancer. International Journal of Urology and Nephrology 1992;24(2):159-66. - PubMed
    1. Taube T, Kylmala T, Lamberg-Allardt C, Tammela TLJ, Elomaa I. The effect of clodronate on bone in metastatic prostate cancer. Histomorphometric report of a double-blind randomised placebo-controlled study. European Journal of Cancer Part A: General Topics 1994;30:751-8. - PubMed
Ernst 2003 {published data only}
    1. *Ernst DS, Tannock IF, Winquist EW, Venner PM, Reyno L, Moore MJ, et al. Randomized, double-blind, controlled trial of mitoxantron/prednisone and clodronate versus mitoxantrone/prednisone and placebo in patients with hormone-refractory prostate cancer and pain. Journal of Clinical Oncology 2003;21(17):3335-42. - PubMed
Figg 2005 {published data only}
    1. *Figg WD, Liu Y, Arlen P, Gulley J, Steinberg SM, Liewehr DJ, et al. A randomized, phase II trial of ketoconazole plus alendronate versus ketoconazole alone in patients with androgen independent prostate cancer and bone metastases. Journal of Urology 2005;173:790-6. - PubMed
Fizazi 2009 {published data only}
    1. *Fizazi K, Lipton A, Mariette X, Body JJ, Rahim Y, Gralow JR, et al. Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. Journal of Clinical Oncology 2009;27:1564-71. - PubMed
    1. Fizazi K, Bosserman L, Gao G, Skacel T, Markus R. Denosumab in patients with bone metastases from castration-resistant prostate cancer and elevated bone resorption despite intravenous bisphosphonate (IV BP) therapy: analysis of a randomised phase II trial. Annals of Oncology 2008;19:viii153.
    1. Fizazi K, Bosserman L, Gao G, Skacel T, Markus R. Denosumab treatment of prostate cancer with bone metastases and increased urine N-telopeptide levels after therapy with intravenous bisphosphonates: results of a randomized phase II trial. Journal of Urology 2009;182:509-16. - PubMed
    1. Fizazi K, Bosserman L, Gao G, Skacel T, Markus R. Denosumab treatment of prostate cancer with bone metastases and increased urine N-telopeptide levels after therapy with intravenous bisphosphonates: results of a randomized phase II trial. Journal of Urology 2013;189:51-8. - PubMed
Fizazi 2011 {published data only}
    1. *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. Lancet 2011;377:813-22. - PMC - PubMed
    1. Brown J, Carducci M, Fizazi K, Smith M, Damião DR, Karsh L, et al. Denosumab versus zoledronic acid in patients with bone metastases from castration-resistant prostate cancer: results from a phase 3 randomized trial. Bone 2011;48(1):S16.
    1. Fizazi K, Brown JE, Carducci M, Shore ND, Sieber P, Kueppers F, et al. Denosumab in patients with metastatic prostate cancer previously treated with denosumab or zoledronic acid: 2-year open-label extension phase results from the pivotal phase 3 study. Annals of Oncology 2012;23:ix309.
    1. Fizazi K, Carducci MA, Smith MR, Damiao R, Brown JE, Karsh L, et al. A randomized phase III trial of denosumab versus zoledronic acid in patients with bone metastases from castration-resistant prostate cancer [abstract no. LBA4507]. Journal of Clinical Oncology 2010;28(18):951.
    1. Fizazi K, Massard C, Smith MR, Rader ME, Brown JE, Milecki P, et al. Baseline covariates impacting overall survival (OS) in a phase III study of men with bone metastases from castration-resistant prostate cancer. Journal of Clinical Oncology 2012;30:4642.
GU02‐4 {published data only}
    1. *Hahn NM, Yiannoutsos CT, Kirkpatrick K, Sharma J, Sweeney CJ. Failure to suppress markers of bone turnover on first-line hormone therapy for metastatic prostate cancer is associated with shorter time to skeletal-related event. Clinical Genitourinary Cancer 2014;12(1):33-40. - PubMed
    1. Sharma J, Yiannoutsos CT, Hahn NM, Sweeney C. Prognostic value of suppressed markers of bone turnover (BTO) after 6 months of androgen deprivation therapy (ADT) in prostate cancer. Journal of Clinical Oncology 2011;29:4594.
    1. Sweeney C, Dugan WM, Dreicer R, Chu F, Parks G, Baker K, et al. A randomized placebo-controlled trial of daily high-dose oral risedronate in men with metastatic prostate cancer commencing androgen deprivation therapy (ADT). Journal of Clinical Oncology 2010;28:e15000.
Kylmala 1993 {published data only}
    1. *Kylmala T, Tammela T, Risteli L, Risteli J, Taube T, Elomma I. Evaluation of the effect of oral clodronate on skeletal metastases with type I collagen metabolites. A controlled trial of the Finnish Prostate Cancer Group. European Journal of Cancer 1993;29(6):821-5. - PubMed
Kylmala 1997 {published data only}
    1. *Kylmala T, Taube T, Tammela TL. Concomitant i.v. and oral clodronate in the relief of bone pain: a double-blind placebo-controlled study in patients with metastatic prostate cancer. British Journal of Cancer 1997;76:939-42. - PMC - PubMed
Meulenbeld 2012 {published data only}22844568
    1. *Meulenbeld HJ, Werkhoven ED, Coenen JLLM, Creemers GJ, Loosveld OJL, Jong PC, et al. Randomised phase II/III study of docetaxel with or without risedronate in patients with metastatic Castration Resistant Prostate Cancer (CRPC), the Netherlands Prostate Study (NePro). European Journal of Cancer 2012;48:2993-3000. - PubMed
Michaelson 2012 {published data only}
    1. *Michaelson MD, Kaufman DS, Kantoff P, Oh WK, Smith MR. Randomized phase II study of atrasentan alone or in combination with zoledronic acid in men with metastatic prostate cancer. Cancer 2012;107(3):530-5. - PubMed
Pan 2014 {published data only}
    1. *Pan Y, Jin H, Chen W, Yu Z, Ye T, Zheng Y, et al. Docetaxel with or without zoledronic acid for castration-resistant prostate cancer. International Urology and Nephrology 2014;46:2319-26. - PubMed
PR05 {published data only}38477744
    1. *Dearnaley DP, Mason MD, Parmar MKB, Sanders K, Sydes MR. 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. Lancet Oncology 2009;10:872-6. - PMC - PubMed
    1. Dearnaley DP, Sydes MR, Mason MD, Stott M, Powell CS, Robinson ACR, et al. A double-blind, placebo-controlled, randomised trial of oral sodium clodronate for metastatic prostate cancer (MRC PRO5 Trial). Journal of the National Cancer Institute 2003;95(17):1300-11. - PubMed
Robertson 1995 {published data only}
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Ryan 2007 {published data only}
    1. *Ryan CW, Huo D, Bylow K, Demers LM, Stadler WM, Henderson TO, et al. Suppression of bone density loss and bone turnover in patients with hormone-sensitive prostate cancer and receiving zoledronic acid. BJU International 2007;100:70-5. - PubMed
Saad 2010 {published data only}
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    1. Saad F, Chen YM, Gleason DM, Chin J. Continuing benefit of zoledronic acid in preventing skeletal complications in patients with bone metastases. Clinical Genitourinary Cancer 2007;5:390-6. - PubMed
    1. Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. Journal of the National Cancer Institute 2004;96:879-82. - PubMed
    1. Saad F, Gleason DM, Murray R. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. Journal of the National Cancer Institute 2002;94(19):1458-68. - PubMed
    1. Saad F, Perez J, Cook R, Segal S. Evaluation of prostate-specific antigen kinetics during zoledronic acid therapy for bone metastases in patients with castration-resistant prostate cancer. Journal of Urology 2011;185:e288.
Small 2003 {published data only}
    1. *Small EJ, Matthew RS, Seaman JJ, Petrone S, Kowalski MO. Combined analysis of two multicenter, randomized, placebo-controlled studies of pamidronate disodium for the palliation of bone pain in men with metastatic prostatic cancer. Journal of Clinical Oncology 2003;21(23):4277-84. - PubMed
Smith 1989 {published data only}
    1. *Smith JAJ. Palliation of painful bone metastases from prostate cancer using sodium etidronate: results of a randomized, prospective, double-blind, placebo-controlled study. Journal of Urology 1989;141:85-7. - PubMed
STAMPEDE {published data only}
    1. *Mason MD, Clarke NW, James ND, Dearnaley DP, Spears MR, Ritchie AWS, et al. Adding celecoxib with or without zoledronic acid for hormone-naïve prostate cancer: long-term survival results from an adaptive, multiarm, multistage, platform, randomized controlled trial. Journal of Clinical Oncology 2017;35:1530-41. - PMC - PubMed
    1. James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Anderson J, et al. STAMPEDE: Systemic Therapy for Advancing or Metastatic Prostate Cancer—A Multi-Arm Multi-Stage Randomised Controlled Trial. Clinical Oncology 2008;20:577-81. - PubMed
    1. James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Spears MR, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 2016;387:1163-77. - PMC - PubMed
    1. James ND, Sydes MR, Mason MD, Clarke NW, Anderson J, Dearnaley DP, et al. Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: first results from STAMPEDE (MRC PR08, CRUK/06/019), a randomized controlled trial. Journal of Clinical Oncology 2012;30:26. - PMC - PubMed
    1. James ND, Sydes MR, Mason MD, Clarke NW, Anderson J, Dearnaley DP, et al. Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: first results from the STAMPEDE multiarm, multistage, randomised controlled trial. Lancet Oncology 2012;13:549-58. - PMC - PubMed
Strang 1997 {published data only}
    1. *Strang P, Nilsson S, Brandstedt S. The analgesic efficacy of clodronate compared with placebo inpatients with painful bone metastases from prostatic cancer. Anticancer Research 1997;17:4717-21. - PubMed
TRAPEZE 2016 {published data only}12808747
    1. *James N, Pirrie S, Pope A, Barton D, Andronis L, Goranitis I, et al. TRAPEZE: A randomised controlled trial of the clinical effectiveness and cost-effectiveness of chemotherapy with zoledronic acid, strontium-89, or both, in men with bony metastatic castration-refractory prostate cancer. Health Technology Assessment 2016;20(53):1-127. - PMC - PubMed
    1. James ND, Andronis L, Goranitis I, Pirrie S, Pope A, Barton D, et al. Cost-effectiveness of zoledronic acid and strontium-89 as bone protecting treatments in addition to chemotherapy in patients with metastatic castrate-refractory prostate cancer. (ISRCTN 12808747) TRAPEZE. Journal of Clinical Oncology 2015;33:e16108. - PubMed
    1. James ND, Pirrie S, Barton D, Brown JE, Billingham L, Collins SI, et al. Clinical outcomes in patients with castrate-refractory prostate cancer (CRPC) metastatic to bone randomized in the factorial TRAPEZE trial to docetaxel (D) with strontium-89 (Sr89), zoledronic acid (ZA), neither, or both (ISRCTN 12808747). Journal of Clinical Oncology 2013;31(18):5000.
    1. James ND, Pirrie SJ, Pope AM, 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. JAMA Oncology 2016;2(4):493-9. - PubMed
    1. Porfiri E, Collins SI, Barton D, Billingham L, McLaren D, Nixon GG, et al. Initial feasibility and safety results from a phase II/III clinical trial to evaluate docetaxel (D) therapy in combination with zoledronic acid (ZA) {+/-} strontium-89 (Sr89) in hormone-refractory prostate cancer patients: ISRCTN12808747. Journal of Clinical Oncology 2010;28:4677.
Wang 2013 {published data only}
    1. *Wang F, Chen W, Chen H, Mo L, Jin H, Yu Z, et al. Comparison between zoledronic acid and clodronate in the treatment of prostate cancer patients with bone metastases. Medical Oncology 2013;30:657. - PubMed
ZABTON‐PC {published data only}
    1. *Ueno S, Mizokami A, Fukagai T, Fujimoto N, Oh-Oka H, Kondo Y, et al. Efficacy of combined androgen blockade with zoledronic acid treatment in prostate cancer with bone metastasis: the ZABTON-PC (zoledronic acid/androgen blockade trial on prostate cancer) study. Anticancer Research 2013;33:3837-44. - PubMed
ZAPCA {published data only}
    1. *Kamba T, Kamoto T, Maruo S, Kikuchi T, Shimizu Y, Namiki S, et al. A phase III multicenter, randomized, controlled study of combined androgen blockade with versus without zoledronic acid in prostate cancer patients with metastatic bone disease: results of the ZAPCA trial. International Journal of Clinical Oncology 2017;22:166-73. - PubMed
    1. Kamba T, Kamoto T, Shimizu Y, Namiki S, Fujimoto K, Kawanishi H, et al. A phase III, multicenter, randomized, controlled study of maximum androgen blockade with versus without zoledronic acid in treatment-naive prostate cancer patients with bone metastases: results of ZAPCA study. Journal of Clinical Oncology 2015;33:150. - PubMed

References to studies excluded from this review

Beer 2007 {published data only}
    1. Beer TM, Ryan CW, Venner PM, Petrylak DP, Chatta GS, Ruether JD, et al. Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT investigators. Journal of Clinical Oncology 2007;25(6):669-74. - PubMed
Body 2010 {published data only}
    1. Body JJ, Lipton A, Gralow J, Steger GG, Gao G, Yeh H, et al. Effects of denosumab in patients with bone metastases with and without previous bisphosphonate exposure. Journal of Bone and Mineral Research 2010;25(3):440-6. - PubMed
Brown 2011 {published data only}
    1. Brown JE, Barrios CH, Diel IJ, Facon T, Fizazi K, Ibrahim T, et al. Incidence and outcomes of osteonecrosis of the jaw from an integrated analysis of three pivotal randomized double-blind, double-dummy phase 3 trials comparing denosumab and zoledronic acid for treatment of bone metastases in advanced cancer patients or myeloma. Bone 2011;48(1):18-9.
Doria 2016 {published data only}
    1. Doria C, Leali PT, Solla F, Maestretti G, Balsano M, Scarpa RM. Denosumab is really effective in the treatment of osteoporosis secondary to hypogonadism in prostate carcinoma patients? A prospective randomized multicenter international study. Clinical Cases in Mineral and Bone Metabolism 2016;13(3):195-9. - PMC - PubMed
Doria 2017 {published data only}
    1. Doria C, Mosele GR, Solla F, Maestretti G, Balsano M, Scarpa RM. Treatment of osteoporosis secondary to hypogonadism in prostate cancer patients: a prospective randomized multicenter international study with denosumab vs. alendronate. Minerva Urologica e Nefrologica 2017;69(3):271-7. - PubMed
Heidenreich 2001 {published data only}
    1. Heidenreich A, Hofmann R, Engelmann UH. The use of bisphosphonate for the palliative treatment of painful bone metastasis due to hormone refractory prostate cancer. Journal of Urology 2001;165(1):136-40. - PubMed
Heidenreich 2002 {published data only}
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Lang 2011 {published data only}
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NTR503 {published data only}
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Patrick 2013 {published data only}
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References to studies awaiting assessment

EUCTR2013‐001146‐34‐FR {published data only}
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JPRN‐UMIN000002577 {published data only}
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JPRN‐UMIN000012967 {published data only}
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References to ongoing studies

NCT03336983 {published data only}
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References to other published versions of this review

Tesfamariam 2018
    1. Tesfamariam YM, Macherey S, Kuhr K, Becker I, Monsef I, Jakob T, et al. Bisphosphonates or RANK‐ligand‐inhibitors for men with prostate cancer and bone metastases: a Cochrane Review and network meta‐analysis. Cochrane Database of Systematic Reviews 2018, Issue 5. Art. No: CD013020. [DOI: 10.1002/14651858.CD013020] - DOI - PMC - PubMed

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