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Meta-Analysis
. 2017 Dec 26;12(12):CD006250.
doi: 10.1002/14651858.CD006250.pub2.

Bisphosphonates for advanced prostate cancer

Sascha Macherey  1 , Ina Monsef, Franziska Jahn, Karin Jordan, Kwok Keung Yuen, Axel Heidenreich, Nicole Skoetz
Affiliations
Meta-Analysis

Bisphosphonates for advanced prostate cancer

Sascha Macherey et al. Cochrane Database Syst Rev. .

Abstract

Background: The prevalence and incidence of pain and skeletal complications of metastatic bone disease such as pathologic fractures, spinal cord compression and hypercalcemia is high and an important contributor to morbidity, poor performance status and decreased quality of life. Moreover, pathologic fractures are associated with increased risk of death in people with disseminated malignancies. Therefore, prevention of pain and fractures are important goals in men with prostate cancer at risk for skeletal complications.

Objectives: To assess the effects of bisphosphonates in men with bone metastases from prostate cancer.

Search methods: We identified studies by electronic search of bibliographic databases including the Cochrane Controlled Trials Register and MEDLINE on 13 July 2017 and trial registries. We handsearched the Proceedings of American Society of Clinical Oncology (to July 2017) and reference lists of all eligible trials identified. This is an update of a review last published in 2006.

Selection criteria: We included randomized controlled studies comparing the effectiveness of bisphosphonates in men with bone metastases from prostate cancer.

Data collection and analysis: Two review authors independently extracted data and assessed the quality of trials. We defined the proportion of participants with pain response as the primary end point; secondary outcomes were skeletal-related events, mortality, quality of life, adverse events, analgesic consumption and disease progression. We assessed the quality of the evidence for the main outcomes using the GRADE approach.

Main results: We included 18 trials reporting on 4843 participants comparing the effect of bisphosphonate administration to control regimens.

Primary outcome: there was no clear difference in the proportion of participants with pain response (RR 1.15, 95% CI 0.93 to 1.43; P = 0.20; I2 = 0%; 3 trials; 876 participants; low quality evidence). In absolute terms, bisphosphonates resulted in a pain response in 40 more participants per 1000 (19 fewer to 114 more).

Secondary outcomes: bisphosphonates probably reduced the incidence of skeletal-related events in participants with prostate cancer metastatic to bone (RR 0.87, 95% CI 0.81 to 0.94; P = 0.27; I2 = 19%; 9 trials; 3153 participants; moderate quality evidence). In absolute terms, bisphosphonates resulted in 58 fewer SREs per 1000 (85 fewer to 27 fewer).We found no clinically relevant differences in mortality (RR 0.97, 95% CI 0.91 to 1.04; P = 0.43; I2 = 1%; 9 trials; 2450 participants; moderate quality evidence). In absolute terms, bisphosphonates resulted in 16 fewer deaths per 1000 (47 fewer to 21 more).Outcome definition of quality of life and the measurement tools varied greatly across trials and we were unable to extract any quantitative data for meta-analysis.Bisphosphonates probably increased the number of participants affected by nausea (RR 1.19, 95% CI 1.00 to 1.41; P = 0.05; I2 = 0%; 9 trials; 3008 participants; moderate quality evidence). In absolute terms, bisphosphonates resulted in seven more cases of nausea per 1000 (0 fewer to 14 more). Bisphosphonates probably increased the number of renal adverse events (RR 1.65, 95% CI 1.11 to 2.46; P = 0.01; I2 = 0%; 7 trials; 1794 participants; moderate quality evidence). In absolute terms, bisphosphonates resulted in 22 more renal adverse events per 1000 (4 more to 50 more). We found no clear difference in the number of participants with osteonecrosis of the jaw between groups (RR 1.92, 95% CI 0.75 to 4.90; P = 0.17; I2 = 0%; 5 trials; 1626 participants; very low quality evidence). In absolute terms, bisphosphonates resulted in seven more cases with osteonecrosis of the jaw per 1000 (2 fewer to 29 more). We observed no clinically relevant difference in the proportion of participants with decreased analgesic consumption (RR 1.19, 95% CI 0.87 to 1.63; P = 0.28; I2 = 37%; 4 trials; 416 participants). Statistical analysis revealed that bisphosphonates probably reduced the number of participants with disease progression (RR 0.94, 95% CI 0.90 to 0.98; P = 0.006; I2 = 0%; 7 trials; 2115 participants; moderate quality evidence). In absolute terms, bisphosphonates resulted in 36 fewer cases of disease progression per 1000 (71 fewer to 7 fewer).Findings of our predefined subgroup and sensitivity analyses were no different from those of the primary analyses.

Authors' conclusions: Based on low quality evidence, there may be no clinically relevant difference in the proportion of men with pain response between bisphosphonates and control regimens in men with bone metastases from prostate cancer. Bisphosphonates probably decrease the number of skeletal-related events and disease progression. These benefits need to be weighed against the increased risk of renal impairment and nausea in men receiving bisphosphonates. Future studies should explicitly evaluate patient important outcomes such as quality of life and pain by using standardized and comparable assessment tools.

PubMed Disclaimer

Conflict of interest statement

SM: none known.

IM: none known.

FJ: received payment for lectures from MSD, Riemser and Tesaro; received travel, accommodation or meeting expenses from Pfizer, Roche, Tesaro.

KJ: received payment for lectures from Amgen.

KKY: none known.

AH: none known.

NS: none known.

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgments about each risk of bias item for each included study.
3
3
Forest plot of comparison: 1 Bisphosphonates versus control, outcome: 1.1 Proportion of participants with pain response.
4
4
Forest plot of comparison: 1 Bisphosphonates versus control, outcome: 1.2 Skeletal‐related events: any.
5
5
Forest plot of comparison: 1 Bisphosphonates versus control, outcome: 1.9 Mortality.
6
6
Forest plot of comparison: 1 Bisphosphonates versus control, outcome: 1.11 Adverse events: renal.
1.1
1.1. Analysis
Comparison 1 Bisphosphonates versus control, Outcome 1 Proportion of participants with pain response.
1.2
1.2. Analysis
Comparison 1 Bisphosphonates versus control, Outcome 2 Skeletal‐related events: any.
1.3
1.3. Analysis
Comparison 1 Bisphosphonates versus control, Outcome 3 Skeletal‐related events: pathologic fracture.
1.4
1.4. Analysis
Comparison 1 Bisphosphonates versus control, Outcome 4 Skeletal‐related events: pathologic fractures: vertebral fracture.
1.5
1.5. Analysis
Comparison 1 Bisphosphonates versus control, Outcome 5 Skeletal‐related events: pathologic fractures: non‐vertebral fracture.
1.6
1.6. Analysis
Comparison 1 Bisphosphonates versus control, Outcome 6 Skeletal‐related events: spinal cord compression.
1.7
1.7. Analysis
Comparison 1 Bisphosphonates versus control, Outcome 7 Skeletal‐related events: bone radiation therapy.
1.8
1.8. Analysis
Comparison 1 Bisphosphonates versus control, Outcome 8 Skeletal‐related events: bone surgery.
1.9
1.9. Analysis
Comparison 1 Bisphosphonates versus control, Outcome 9 Mortality.
1.10
1.10. Analysis
Comparison 1 Bisphosphonates versus control, Outcome 10 Adverse events: nausea.
1.11
1.11. Analysis
Comparison 1 Bisphosphonates versus control, Outcome 11 Adverse events: renal.
1.12
1.12. Analysis
Comparison 1 Bisphosphonates versus control, Outcome 12 Adverse events: bone pain.
1.13
1.13. Analysis
Comparison 1 Bisphosphonates versus control, Outcome 13 Adverse events: osteonecrosis of the jaw.
1.14
1.14. Analysis
Comparison 1 Bisphosphonates versus control, Outcome 14 Proportion of participants with decreased analgesic consumption.
1.15
1.15. Analysis
Comparison 1 Bisphosphonates versus control, Outcome 15 Proportion of participants with disease progression.
1.16
1.16. Analysis
Comparison 1 Bisphosphonates versus control, Outcome 16 Sensitivity analysis: pain response (low risk of bias vs high risk of bias).
1.17
1.17. Analysis
Comparison 1 Bisphosphonates versus control, Outcome 17 Subgroup analysis: pain response (amino‐bisphosphonate vs non‐amino‐bisphosphonate).
1.18
1.18. Analysis
Comparison 1 Bisphosphonates versus control, Outcome 18 Subgroup analysis: pain response (route of administration).
1.19
1.19. Analysis
Comparison 1 Bisphosphonates versus control, Outcome 19 Sensitivity analysis: skeletal‐related events (low risk of bias vs high risk of bias).
1.20
1.20. Analysis
Comparison 1 Bisphosphonates versus control, Outcome 20 Sensitivity analysis: skeletal‐related events (full‐text vs abstract publication).
1.21
1.21. Analysis
Comparison 1 Bisphosphonates versus control, Outcome 21 Subgroup analysis: skeletal‐related events (amino‐bisphosphonate versus non‐amino‐bisphosphonate).
1.22
1.22. Analysis
Comparison 1 Bisphosphonates versus control, Outcome 22 Subgroup analysis: skeletal‐related events (route of administration).
1.23
1.23. Analysis
Comparison 1 Bisphosphonates versus control, Outcome 23 Sensitivity analysis: mortality (low risk of bias vs high risk of bias)).
1.24
1.24. Analysis
Comparison 1 Bisphosphonates versus control, Outcome 24 Sensitivity analysis: mortality (full‐text vs abstract publication).
1.25
1.25. Analysis
Comparison 1 Bisphosphonates versus control, Outcome 25 Subgroup analysis: mortality (amino‐bisphosphonate vs non‐amino‐bisphosphonate).
1.26
1.26. Analysis
Comparison 1 Bisphosphonates versus control, Outcome 26 Subgroup analysis: mortality (route of administration).
1.27
1.27. Analysis
Comparison 1 Bisphosphonates versus control, Outcome 27 Sensitivity analysis: adverse event: nausea (low risk of bias vs high risk of bias).
1.28
1.28. Analysis
Comparison 1 Bisphosphonates versus control, Outcome 28 Subgroup analysis: adverse event: nausea (amino‐bisphosphonate vs non‐amino‐bisphosphonate).
1.29
1.29. Analysis
Comparison 1 Bisphosphonates versus control, Outcome 29 Subgroup analysis: adverse event: nausea (route of administration).
1.30
1.30. Analysis
Comparison 1 Bisphosphonates versus control, Outcome 30 Sensitivity analysis: renal (low risk of bias vs high risk of bias).
1.31
1.31. Analysis
Comparison 1 Bisphosphonates versus control, Outcome 31 Subgroup analysis: renal (amino‐bisphosphonate vs non‐amino‐bisphosphonate).
1.32
1.32. Analysis
Comparison 1 Bisphosphonates versus control, Outcome 32 Subgroup analysis: renal (route of administration).
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