Methods

Recruitment period:

• not reported.

End points:

• pain response.

Pain assessment tool:

• pain severity scale score, pain interference scale score (McGill‐Melzack Pain Questionnaire).

Randomization:

• intervention vs control.

Participants

Eligibility criteria:

• not reported.

Exclusion criteria:

• not reported.

Participants randomized:

• 402 randomized, 201 zoledronic acid, 201 placebo.

Mean age:

• not reported.

Country of participants:

• not reported.

Interventions

Previous interventions:

• not reported.

Interventions during study period:

• intervention: zoledronic acid 4 mg;

• control: placebo.

Outcomes

Reported and analyzed in this review:

• pain response;

• QoL.

Funding sources

Funding sources:

• not reported.

Declarations of interest

Conflicts of interest: see meeting.ascopubs.org/cgi/content/abstract/24/18_suppl/4638?sid=2d509f53‐6021‐4c00‐8de9‐6bbec9c7cf92.

• Authors were employed at Novartis, received honoraria from Novartis or were consultants of Novartis.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information on sequence generation.

Allocation concealment (selection bias)

Unclear risk

Insufficient information on allocation concealment.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Placebo‐controlled trial.

Blinding of outcome assessment (detection bias)
Objective outcomes

Unclear risk

Insufficient information on outcome assessment.

Blinding of outcome assessment (detection bias)
Subjective outcomes

Unclear risk

Insufficient information on outcome assessment.

Incomplete outcome data (attrition bias)

Unclear risk

Information regarding discontinuations and ITT.

Selective reporting (reporting bias)

Unclear risk

No study protocol available.

Other bias

Unclear risk

Insufficient report on methods.

Methods

Recruitment period:

• January 2004 to May 2012.

End points:

• overall survival, disease progression, SREs, adverse events.

Pain assessment tool:

• not reported.

Randomization:

• intervention vs control.

Participants

Eligibility criteria:

• castration‐sensitive prostate cancer;

• age > 18 years;

• histologically confirmed prostate adenocarcinoma;

• ≥ 1 bone metastasis evident on radiographic imaging;

• ECOG performance status ≤ 2;

• creatinine clearance > 30 mL/minute.

Exclusion criteria:

• prior use of bisphosphonates, denosumab or radiopharmaceuticals;

• androgen‐deprivation therapy > 6 months before enrolment;

• external beam radiation therapy within 4 weeks prior to enrolment;

• corrected serum calcium < 8 mg/dL or ≥ 11.6 mg/dL.

Participants randomized:

• 645 randomized, 323 intervention, 322 control.

Mean age:

• intervention: 66.1 years;

• control: 66.7 years.

Country of participants:

• US and Canada.

Interventions

Previous interventions:

• not reported.

Interventions during study period:

• intervention: zoledronic acid 4 mg IV every 4 weeks (dose reduction for participants with creatinine clearance < 60 mL/minute), androgen‐deprivation therapy, supplemental calcium 500 mg, supplemental vitamin D 400‐500 IU;

• control: placebo IV every 4 weeks, androgen‐deprivation therapy, supplemental calcium 500 mg, supplemental vitamin D 400‐500 IU.

Outcomes

Reported and analyzed in this review:

• overall survival;

• SREs;

• PFS and disease progression;

• adverse events.

Funding sources

Funding sources:

• National Cancer Institute, Novartis Oncology and research awards from the Prostate Cancer Foundation.

Declarations of interest

Conflicts of interest:

• employment or leadership position: Nicholas Vogelzang, US Oncology Network;

• consultant or advisory role: Nicholas Vogelzang, Novartis, Dendreon, Janssen Pharmaceuticals, BayerHealthCare Pharmaceuticals, GlaxoSmithKline, Pfizer, Astellas Pharma/Medivation; Walter Stadler, Novartis (C); Fred Saad, Amgen (C), Novartis (C); Michael Morris, Millennium Pharmaceuticals (C), Bayer HealthCare Pharmaceuticals (U).

Notes

Prematurely completed after corporate supporter withdrew study drug supply.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomized block design was used."

Allocation concealment (selection bias)

Unclear risk

Insufficient information on allocation concealment.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote from protocol: "Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)."

Blinding of outcome assessment (detection bias)
Objective outcomes

Low risk

Quote from protocol: "Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)."

Blinding of outcome assessment (detection bias)
Subjective outcomes

Low risk

Quote from protocol: "Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)."

Incomplete outcome data (attrition bias)

Low risk

All participants with bone metastasis from prostate cancer were included in the analysis of efficacy and all participants on treatment were used for analysis of safety.

Selective reporting (reporting bias)

Low risk

Report on every end point (primary and secondary) mentioned in the original protocol.

Other bias

Low risk

No further information provided.

Methods

Recruitment period:

• not reported.

End points:

• overall survival, bone pain, analgesic consumption, performance status.

Pain assessment tool:

• not reported.

Randomization:

• intervention vs control.

Participants

Eligibility criteria:

• prostate cancer metastatic to bone;

• estimated life expectancy ≥ 3 months;

• intermittent or continuous bone pain with daily analgesic use;

• no radiation therapy 2 weeks before study enrollment or during study treatment.

Exclusion criteria:

• not reported.

Participants randomized:

• 75 randomized, 36 intervention, 39 control.

Mean age:

• intervention: 73 years;

• control: 72 years.

Country of participants:

• not reported.

Interventions

Previous interventions:

• 35 participants underwent orchiectomy, 17 in intervention group, 18 in control group;

• 21 participants received estrogens, 8 in intervention group, 13 in control group;

• 22 participants received LHRH agonists, 11 in intervention group, 11 in control group;

• 3 participants received antiandrogens, 2 in intervention group, 1 in control group;

• 5 participants underwent other previous treatment, 3 in intervention group, 2 in control group.

Interventions during study period:

• intervention: clodronate 3200 mg PO, estramustine 280 mg PO twice daily for 1 month, clodronate 1600 mg PO and estramustine 280 mg PO twice daily for 5 months;

• control: placebo and estramustine 280 mg PO twice daily.

Outcomes

Reported and analyzed in this review:

• overall survival;

• pain response;

• adverse events;

• analgesic consumption.

Funding sources

Funding sources:

• Finnish Cancer Foundation;

• Leiras Pharmaceutical Company.

Declarations of interest

Conflicts of interest:

• not reported.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information on sequence generation.

Allocation concealment (selection bias)

Unclear risk

Insufficient information on allocation concealment.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Placebo‐controlled trial.

Blinding of outcome assessment (detection bias)
Objective outcomes

Unclear risk

Insufficient information on outcome assessment.

Blinding of outcome assessment (detection bias)
Subjective outcomes

Unclear risk

Insufficient information on outcome assessment.

Incomplete outcome data (attrition bias)

Unclear risk

No information regarding discontinuations and ITT.

Selective reporting (reporting bias)

Unclear risk

No study protocol available.

Other bias

Unclear risk

Quote from the article: "We are grateful to the Finnish Cancer Foundation and to Leiras Pharmaceutical Company for their support of this work."

Methods

Recruitment period:

• October 1997 to May 2001.

End points:

• overall survival, pain response, disease progression and time to progression, SRE, QoL.

Pain assessment tool:

• PPI scale by McGill‐Melzack Pain Questionnaire, 0 = no pain to 5 = excruciating pain;

• analgesic score, 1 analgesic unit = standard doses of non‐opioids to 2 analgesic units = opioid doses of morphine 10 mg equivalents.

Randomization:

• intervention vs control.

Participants

Eligibility criteria:

• radiologically confirmed progressive bone disease (defined as increasing bone pain, new lesion on bone scan or increased isotope uptake at previous sites of disease);

• castrate levels of testosterone (3 nmol/L) by bilateral orchidectomy or therapy with LHRH agonist;

• intermittent or continuous bone pain with daily analgesic use;

• no radiation therapy 2 weeks before study enrollment or during study treatment;

• ECOG performance status < 3;

• withdrawal of antiandrogens with a minimum of 4 or 6 weeks;

• left ventricular ejection fraction > 50%;

• ability to complete pain and QoL scores;

• white blood cell count ≥ 3 × 10⁹/L;

• granulocyte count ≥ 1.5 × 10⁹/L;

• platelet count ≥ 100 × 10⁹/L;

• bilirubin ≤ 54 µmol/L;

• serum calcium ≤ 3.1 mmol/L;

• serum creatinine < 200 µmol/L.

Exclusion criteria:

• prior malignancy other than non‐melanoma skin cancer;

• ≥ 1 chemotherapy regimen or a previous chemotherapy regimen with mitoxantrone or a previous chemotherapy regimen with an anthracycline;

• previous use of bisphosphonates;

• radiation therapy within 4 weeks before study enrollment;

• radioisotope therapy within 8 weeks before study enrollment;

• radicular or back pain suggestive of epidural metastases;

• spinal cord or nerve root compression;

• impending pathologic fracture;

• uncontrolled cardiac failure;

• active infection.

Participants randomized:

• 227 randomized, 115 intervention, 112 control.

Median age:

• intervention: 70.1 years;

• control: 70.6 years.

Country of participants:

• Canada.

Interventions

Previous interventions:

• 22 participants received corticosteroids prior to study entry, 13 in intervention group, 9 in control group.

Interventions during study period:

• intervention: clodronate 1500 mg IV (until disease progression in responding participants), prednisone 5 mg twice a day, mitoxantrone 12 mg/m² IV every 3 weeks (until a cumulative dose of 140 mg/m²);

• control: saline IV (until disease progression), prednisone 5 mg twice a day, mitoxantrone 12 mg/m² IV every 3 weeks (until a cumulative dose of 140 mg/m²).

Outcomes

Reported and analyzed in this review:

• overall survival;

• PFS and disease progression;

• pain response;

• adverse events;

• QoL;

• analgesic consumption.

Funding sources

Funding sources:

• Immunex Corporation, Seattle, WA;

• Aventis Pharma, Laval, Quebec, Canada.

Declarations of interest

Conflicts of interest:

• not reported.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Patients were randomly assigned using a block‐randomization procedure with equal probability of assignment to either arm."

Allocation concealment (selection bias)

Low risk

"Patients were randomly assigned using a block‐randomization procedure with equal probability of assignment to either arm."

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

"The treating staff and patients were blinded to treatment allocation."

Blinding of outcome assessment (detection bias)
Objective outcomes

Low risk

"The treating staff and patients were blinded to treatment allocation."

Blinding of outcome assessment (detection bias)
Subjective outcomes

Low risk

"The treating staff and patients were blinded to treatment allocation."

Incomplete outcome data (attrition bias)

Unclear risk

Insufficient information regarding discontinuations and ITT.

Selective reporting (reporting bias)

Unclear risk

Protocol available (NCT00003232), but outcomes not prespecified in the protocol.

Other bias

Unclear risk

Quote: "Supported by a grant from Immunex Corporation, Seattle, WA, and Aventis Pharma, Laval, Quebec, Canada."

Methods

Recruitment period:

• not reported.

End points:

• overall survival, disease progression, adverse events.

Pain assessment tool:

• not reported.

Randomization:

• intervention vs control.

Participants

Eligibility criteria:

• men with castration‐resistant prostate adenocarcinoma metastatic to bone and progression after combined androgen blockade and antiandrogen withdrawal;

• ECOG performance status ≤ 2;

• increasing PSA despite continued testicular suppression or progression on CT/bone scan, or both.

Exclusion criteria:

• not reported.

Participants randomized:

• 72 randomized, 36 intervention, 36 control.

Mean age:

• intervention: 72 years;

• control: 70 years.

Country of participants:

• not clearly reported.

Interventions

Previous interventions:

• majority of participants received second‐line hormonal therapy;

• 15 participants received chemotherapy.

Interventions during study period:

• intervention: alendronate 40 mg daily, ketoconazole 1200 mg daily (dose reduction of alendronate and ketoconazole in participants with drug toxicity), hydrocortisone 30 mg daily;

• control: ketoconazole 1200 mg daily (dose reduction of ketoconazole in participants with drug toxicity), hydrocortisone 30 mg daily.

Outcomes

Reported and analyzed in this review:

• overall survival;

• PFS and disease progression;

• adverse events.

Funding sources

Funding sources:

• support from the National Cancer Institute (USA).

Declarations of interest

Conflicts of interest:

• not reported.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information on sequence generation.

Allocation concealment (selection bias)

Unclear risk

Insufficient information on allocation concealment.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "This was an open label, randomized, phase II study [...]"

Blinding of outcome assessment (detection bias)
Objective outcomes

Unclear risk

No information on blinding of outcome assessor.

Blinding of outcome assessment (detection bias)
Subjective outcomes

High risk

Quote: "This was an open label, randomized, phase II study [...]"

Incomplete outcome data (attrition bias)

Low risk

Complete analysis of all randomized participants.

Selective reporting (reporting bias)

Unclear risk

Protocol available (NCT00019695), more outcomes reported than prespecified in the protocol (e.g. overall survival).

Other bias

Low risk

No further information provided.

Methods

Recruitment period:

• December 2003 to August 2005.

End points:

• overall survival, disease progression, adverse events.

Pain assessment tool:

• not reported.

Randomization:

• intervention vs control.

Participants

Eligibility criteria:

• performance status: ECOG 0‐2;

• life expectancy: ≥ 12 weeks;

• histologically or cytologically confirmed adenocarcinoma of the prostate with metastatic bone disease (by CT, MRI or bone scan) with plans to start or be < 30 days from beginning androgen deprivation therapy;

• participants may have received palliative radiation therapy at the investigators discretion during the first 4 weeks of beginning protocol therapy.

Exclusion criteria:

• no neuroendocrine, small cell or transitional cell cancer of prostate;

• no abnormal bone metabolism (i.e. Paget disease, untreated hyperthyroidism, untreated hyperprolactinemia, untreated Cushing disease);

• no use of calcitonin within 14 days before being registered for protocol therapy or any previous use of bisphosphonates;

• no major surgery within 4 weeks of registration to protocol therapy;

• no adjuvant chemotherapy within 6 months of registration to protocol therapy;

• no previous chemotherapy for metastatic disease.

Participants randomized:

• 63 randomized, 32 intervention, 31 control.

Mean age:

• intervention: 70.5 years;

• control: 71 years.

Country of participants:

• not clearly reported.

Interventions

Previous interventions

• not reported.

Interventions during study period:

• intervention: risedronate PO daily combined with androgen deprivation;

• control: placebo PO daily combined with androgen deprivation.

Outcomes

Reported and analyzed in this review:

• overall survival;

• PFS;

• adverse events.

Funding sources

Funding sources:

• support from the National Cancer Institute (USA).

Declarations of interest

Conflicts of interest:

• not reported.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information on sequence generation.

Allocation concealment (selection bias)

Unclear risk

Insufficient information on allocation concealment.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Placebo‐controlled trial.

Blinding of outcome assessment (detection bias)
Objective outcomes

Unclear risk

No information on blinding of outcome assessor.

Blinding of outcome assessment (detection bias)
Subjective outcomes

Unclear risk

No information on blinding of outcome assessor.

Incomplete outcome data (attrition bias)

Unclear risk

Complete analysis of all randomized participants.

Selective reporting (reporting bias)

Unclear risk

Protocol available (NCT00019695), more outcomes reported than prespecified in the protocol (e.g. overall survival).

Other bias

Unclear risk

No information provided.

Methods

Recruitment period:

• not reported.

End points:

• overall survival, bone pain, analgesic consumption.

Pain assessment tool:

• not reported.

Randomization:

• intervention vs control.

Participants

Eligibility criteria:

• prostate cancer metastatic to bone;

• estimated life expectancy ≥ 3 months;

• intermittent or continuous bone pain with daily analgesic use;

• no radiation therapy 2 months before study enrollment or during study treatment.

Exclusion criteria:

• not reported.

Participants randomized:

• 99 randomized, 50 intervention, 49 control.

Mean age:

• intervention: 72 years;

• control: 71 years.

Country of participants:

• not reported.

Interventions

Previous interventions:

• 2 participants underwent orchiectomy, 20 in intervention group, 22 in control group;

• 35 participants received estrogens, 18 in intervention group, 17 in control group;

• 22 participants received LHRH agonists, 12 in intervention group, 10 in control group.

Interventions during study period:

• intervention: clodronate 3200 mg PO and estramustine 280 mg PO twice daily for 1 month, clodronate 1600 mg PO and estramustine 280 mg PO twice daily for 5 months;

• control: estramustine 280 mg PO twice daily.

Outcomes

Reported and analyzed in this review:

• overall survival;

• pain response;

• adverse events;

• analgesic consumption.

Funding sources

Funding sources:

• Finnish Cancer Foundation;

• Leiras Pharmaceutical Company.

Declarations of interest

Conflicts of interest:

• not reported.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information on sequence generation.

Allocation concealment (selection bias)

Unclear risk

Insufficient information on allocation concealment.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information provided.

Blinding of outcome assessment (detection bias)
Objective outcomes

Unclear risk

No information on blinding of investigated outcome.

Blinding of outcome assessment (detection bias)
Subjective outcomes

Unclear risk

No information on blinding of investigated outcome.

Incomplete outcome data (attrition bias)

Unclear risk

No information regarding discontinuations and ITT.

Selective reporting (reporting bias)

Unclear risk

No study protocol available.

Other bias

Unclear risk

Quote from the article: "We are grateful to [...] the Finnish Cancer Foundation and to Leiras Pharmaceutical Company for their support of this study."

Methods

Recruitment period:

• not reported.

End points:

• bone pain, analgesic consumption, performance status.

Pain assessment tool:

• VAS for pain assessment;

• verbal ordinal scale for pain assessment, 0 = no pain to 4 = intolerable pain.

Randomization:

• intervention vs control.

Participants

Eligibility criteria:

• prostate cancer metastatic to bone;

• estimated life expectancy ≥ 6 months;

• oral consent;

• no radiation therapy within 2 weeks before study enrollment;

• no peptic ulcer treated with antacids;

• no clinically relevant renal or hepatic insufficiency.

Exclusion criteria:

• not reported.

Participants randomized:

• 57 randomized, 28 intervention, 29 control.

Mean age:

• intervention: 72 years;

• control: 76 years.

Country of participants:

• not reported.

Interventions

Previous interventions:

• 42 participants underwent orchiectomy, 20 in intervention group, 22 in control group;

• 12 participants received estrogens, 5 in intervention group, 7 in control group;

• 6 participants received LHRH agonists, 1 in intervention group, 5 in control group;

• 4 participants received antiandrogens, 3 in intervention group, 1 in control group;

• 2 participants underwent radiation of prostate, 2 in intervention group, 0 in control group.

Interventions during study period:

• intervention: clodronate 300 mg IV daily and estramustine 280 mg PO twice daily for 5 days, clodronate 1600 mg PO daily and estramustine 280 mg PO twice daily for 5 months;

• control: placebo IV daily and estramustine 280 mg PO twice daily for 5 days, placebo PO daily and estramustine 280 mg PO twice daily for 5 months.

Outcomes

Reported and analyzed in this review:

• pain response;

• adverse events;

• disease progression/PFS;

• analgesic consumption.

Funding sources

Funding sources:

• Finnish Cancer Foundation;

• Leiras Clinical research;

• Finnish Academy of Sciences;

• Finnish Medical Society Duodecim;

• Reino Lathikari Foundation.

Declarations of interest

Conflicts of interest:

• not reported.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information on sequence generation.

Allocation concealment (selection bias)

Unclear risk

Insufficient information on allocation concealment.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Placebo‐controlled trial.

Blinding of outcome assessment (detection bias)
Objective outcomes

Unclear risk

No information on blinding of investigated outcome.

Blinding of outcome assessment (detection bias)
Subjective outcomes

Unclear risk

No information on blinding of investigated outcome.

Incomplete outcome data (attrition bias)

Unclear risk

No information regarding discontinuations and ITT.

Selective reporting (reporting bias)

Unclear risk

No study protocol available.

Other bias

Unclear risk

Quote: "This study was supported by the Finnish Academy of Sciences, Finnish Cancer Foundation, Finnish Medical Society Duodecim, Reino Lathikari Foundation and by Leiras Clinical Research."

Methods

Recruitment period:

• January 2004 to April 2010.

End points:

• overall survival, disease progression, pain response adverse events.

Pain assessment tool:

• PPI scale.

Randomization:

• intervention vs control.

Participants

Eligibility criteria:

• men with castration‐resistant prostate cancer;

• age ≥ 18 years;

• ECOG performance status ≤ 2;

• adequate hepatic, renal and hematologic function;

• people with disease‐related pain with ≥ 1 week on stable analgesic regimen.

Exclusion criteria:

• prior use of bisphosphonates;

• radiation therapy within 4 weeks of enrolment;

• CNS involvement or other serious illness.

Participants randomized:

• 592 randomized, 291 intervention, 301 control.

Mean age:

• intervention: 68 years;

• control: 69 years.

Country of participants:

• the Netherlands and Norway.

Interventions

Previous interventions:

• LHRH analogues for some participants.

Interventions during study period:

• intervention: risedronate 30 mg PO daily, docetaxel 75 mg/m² IV every 3 weeks, prednisone 5 mg PO daily;

• control: docetaxel 75 mg/m² IV every 3 weeks, prednisone 5 mg PO daily.

Outcomes

Reported and analyzed in this review:

• overall survival;

• PFS and disease progression;

• pain response;

• adverse events.

Funding sources

Funding sources:

• Sanofi‐Aventis, Gouda, the Netherlands.

Declarations of interest

Conflicts of interest:

• senior author received honoraria and research funding from Sanofi‐Aventis, Gouda, the Netherlands.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information on sequence generation.

Allocation concealment (selection bias)

Unclear risk

Insufficient information on allocation concealment.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "This randomised, open label, phase II/III trial [...]."

Blinding of outcome assessment (detection bias)
Objective outcomes

Unclear risk

Quote: "This randomised, open label, phase II/III trial [...]."

Blinding of outcome assessment (detection bias)
Subjective outcomes

High risk

Quote: "This randomised, open label, phase II/III trial [...]."

Incomplete outcome data (attrition bias)

Low risk

All participants with bone metastasis from prostate cancer were included in the analysis of efficacy and safety.

Selective reporting (reporting bias)

Low risk

Protocol available (ISRCTN22844568), prespecified outcomes reported.

Other bias

Unclear risk

Quote: "Funding was provided by Grants from Sanofi‐Aventis."

Methods

Recruitment period:

• June 2008 to April 2010.

End points:

• overall survival, SREs, disease progression, pain response, adverse events.

Pain assessment tool:

• 10‐cm VAS.

Randomization:

• intervention vs control.

Participants

Eligibility criteria:

• men with histologically confirmed castration‐resistant prostate cancer (defined by 3 sequential rises in serum PSA level with castrate levels of serum testosterone (50 ng/dL) or increase in cancer‐related pain or new metastatic lesions on hormonal therapy, or a combination of these);

• age > 18 years;

• ECOG performance status ≤ 2;

• life expectancy > 3 months;

• evidence of bone metastases by 2 radiographic methods.

Exclusion criteria:

• previous use of bisphosphonates within 1 year prior to study enrolment;

• previous chemotherapy;

• radiation therapy or surgery to metastatic bone lesions within 1 month at time of study enrolment;

• brain metastasis;

• psychological symptoms;

• significant renal, hepatic or non‐malignant‐related disease.

Participants randomized:

• 105 randomized, 53 intervention, 52 control.

Mean age:

• intervention: < 71 years: 34%, > 71 years: 66%;

• control: < 71 years: 38.5%, > 71 years: 61.5%.

Country of participants:

• China.

Interventions

Previous interventions:

• not reported.

Interventions during study period:

• intervention: zoledronic acid 4 mg IV every 3 weeks, 75 mg/m² docetaxel IV on day 1 of a 21‐day cycle, prednisone 10 mg daily, supplemental calcium 500 mg PO daily, supplemental vitamin D 400 IU PO daily;

• control: saline (placebo) IV every 3 weeks, 75 mg/m² docetaxel IV on day 1 of a 21‐day cycle, prednisone 10 mg daily, supplemental calcium 500 mg PO daily, supplemental vitamin D 400 IU PO daily.

Outcomes

Reported and analyzed in this review:

• overall survival;

• SREs;

• PFS and disease progression;

• pain response;

• adverse events;

• analgesic consumption.

Funding sources

Funding sources:

• Wenzhou science bureau project.

Declarations of interest

Conflicts of interest:

• none of the authors had a conflict of interest.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient report on sequence generation.

Allocation concealment (selection bias)

Unclear risk

Insufficient information on allocation concealment.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Placebo‐controlled trial.

Blinding of outcome assessment (detection bias)
Objective outcomes

Unclear risk

Insufficient report on blinding of outcome.

Blinding of outcome assessment (detection bias)
Subjective outcomes

Unclear risk

Insufficient report on blinding of outcome.

Incomplete outcome data (attrition bias)

Low risk

No participants lost to follow‐up.

All participants were included in the ITT analysis.

Selective reporting (reporting bias)

Unclear risk

No study protocol available.

Other bias

Low risk

No further information provided.

Methods

Recruitment period:

• June 1994 to July 1998.

End points:

• overall survival, SREs, disease progression, adverse events, analgesic consumption.

Pain assessment tool:

• not reported.

Randomization:

• intervention vs control.

Participants

Eligibility criteria:

• response to initial hormone therapy (orchiectomy, LHRH analogues, cyproterone acetate, flutamide or androgen blockade);

• normocalcemia;

• WHO performance status ≤ 2;

• serum creatinine level less than the upper local limit.

Exclusion criteria:

• previous or current use of bisphosphonates;

• other active malignancy within the past 5 years;

• acute severe inflammation of the gastrointestinal tract;

• serious concomitant physical or psychiatric disease;

• previous use of long‐term hormone therapy;

• use of any investigational drug within 12 months of the first dose of study tablets.

Participants randomized:

• 311 randomized, 155 intervention, n = 156 control.

Median age:

• intervention: 71 years;

• control: 71 years.

Country of participants:

• UK and New Zealand.

Interventions

Previous interventions:

• not reported.

Interventions during study period:

• intervention: clodronate 2080 mg PO daily up to a maximum of 3 years and standard hormone therapy;

• control: placebo PO daily and standard hormone therapy.

Outcomes

Reported and analyzed in this review:

• overall survival;

• PFS and disease progression;

• pain response;

• adverse events;

• analgesic consumption.

Funding sources

Quote: "This trial was sponsored by the U.K. Medical Research Council (MRC)."

"The trial was initiated with the support of Boehringer Mannheim. The company provided trial tablets (Loron 520 and matching placebo) free of charge, plus financial support (£250) on a per patient basis, which was sufficient to contribute toward the administrative costs of the trial. The financial support was distributed proportionately between the participating clinicians and the coordinating center [...] During the trial, Boehringer Mannheim was taken over by Roche Products Ltd., which honored all commitments regarding this trial."

Declarations of interest

Insufficient report on potential conflicts of interest.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information on sequence generation.

Allocation concealment (selection bias)

Low risk

Quote: "Randomization was performed centrally at the MRC CTU [...] No patient information, other than their drug number and hospital, was revealed to the pharmaceutical companies."

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Placebo‐controlled trial.

Blinding of outcome assessment (detection bias)
Objective outcomes

Unclear risk

Insufficient information on blinding of outcome assessment.

Blinding of outcome assessment (detection bias)
Subjective outcomes

Unclear risk

Insufficient information on blinding of outcome assessment.

Incomplete outcome data (attrition bias)

Low risk

All participants were included in the ITT analysis.

Selective reporting (reporting bias)

Low risk

Study protocol available. All prespecified outcomes were reported.

Other bias

Unclear risk

Quote: "The trial was initiated with the support of Boehringer Mannheim. The company provided trial tablets (Loron 520 and matching placebo) free of charge, plus financial support (£250) on a per patient basis, which was sufficient to contribute toward the administrative costs of the trial. The financial support was distributed proportionately between the participating clinicians and the coordinating center.[...] During the trial, Boehringer Mannheim was taken over by Roche Products Ltd., which honored all commitments regarding this trial."

Methods

Recruitment period:

• June 1998 to January 2001.

End points:

• overall survival, SREs, disease progression, QoL, adverse events.

Pain assessment tool:

• not reported.

Randomization:

• intervention vs control.

Participants

Eligibility criteria:

• ≥ 1 bone metastasis currently or in the participant's history;

• 3 consecutive increases in serum PSA levels despite hormone therapy;

• serum testosterone < 50 ng/dL;

• ECOG performance status ≤ 2;

• written informed consent.

Exclusion criteria:

• previous or current use of bisphosphonates;

• bone pain requiring strong narcotic therapies;

• cytotoxic chemotherapy;

• radiation within 3 months;

• severe cardiovascular disease, refractory hypertension, symptomatic coronary artery disease;

• serum creatinine level > 3 mg/dL;

• corrected serum calcium < 8 mg/dL or > 11.6 mg/dL.

Participants randomized:

• 643 randomized, 214 intervention I, 221 intervention II, 208 control.

Mean age:

• intervention I: 71.8 years;

• intervention II: 71.2 years;

• control: 72.2 years.

Country of participants:

• Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, France, Germany, Italy, New Zealand, Peru, Sweden, Switzerland, UK, Uruguay, US.

Interventions

Previous interventions:

• not reported.

Interventions during study period:

• intervention I: zoledronic acid 4 mg IV every 3 weeks for 15 months and calcium 500 mg and vitamin D 400‐500 IU;

• intervention II: zoledronic acid 8 mg IV every 3 weeks for 15 months (dose reduction from 8 mg to 4 mg due to renal toxicity) and calcium 500 mg and vitamin D 400‐500 IU;

• control: placebo IV every 3 weeks for 15 months and calcium 500 mg and vitamin D 400‐500 IU.

Outcomes

Reported and analyzed in this review:

• overall survival;

• SREs;

• pain response;

• adverse events;

• QoL.

Funding sources

Quote: "Supported by a grant from Novartis Pharmaceuticals Corporation, East Hanover, NJ."

Declarations of interest

Quote: "The following have conducted or are currently conducting research sponsored by Novartis Pharmaceuticals Corp.: F. Saad, D. M. Gleason, R. Murray, L. Lacombe, J. L. Chin, and J. J. Vinholes. F. Saad is a consultant on an advisory board to Novartis Pharmaceuticals Corp."

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The 643 patients who met the inclusion criteria after the screening visit were randomly assigned to treatment according to a computer‐generated list of randomization numbers provided to each center."

Allocation concealment (selection bias)

Unclear risk

Insufficient report on allocation concealment.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Placebo‐controlled trial.

Blinding of outcome assessment (detection bias)
Objective outcomes

Unclear risk

Insufficient report on blinding of outcome assessment.

Blinding of outcome assessment (detection bias)
Subjective outcomes

Unclear risk

Insufficient report on blinding of outcome assessment.

Incomplete outcome data (attrition bias)

Low risk

All participants were included in ITT analysis.

Selective reporting (reporting bias)

Unclear risk

No study protocol available.

Other bias

Low risk

No further information provided.

Methods

Recruitment period:

• February 1998 to November 1999.

End points:

• pain response, SREs, adverse events, analgesic consumption.

Pain assessment tool:

• numeric 11‐point rating scale as part of BPI, 0 = no pain to 10 = pain as severe as can be imagined.

Randomization:

• intervention vs control.

Participants

Eligibility criteria:

• men age ≥ 18 years;

• prostate cancer with bone or skeletal metastases confirmed by radiology review;

• bone pain due to bone or skeletal metastases;

• life expectancy ≥ 6 months;

• progressive systemic disease despite androgen deprivation.

Exclusion criteria:

• white blood cell count ≤ 3 × 10⁹/L;

• platelet count < 50 × 10⁹/L;

• total bilirubin > 2.5 mg/dL;

• serum magnesium ≤ 0.9 mg/dL;

• corrected serum calcium ≥ 11.0 mg/dL or ≤ 8.4 mg/dL;

• serum creatinine ≥ 5.0 mg/dL;

• untreated brain metastases;

• prior use of bisphosphonates;

• clinically significant abnormal ECG;

• ascites;

• impending spinal cord compression or spinal orthosis;

• SRE (pathologic fracture, radiation to bone, surgery to bone) within 1 month before randomization;

• drugs or therapies affecting osteoclast activity.

Only CGP 032:

• change in chemotherapy or hormone therapy regimen within 6 weeks before randomization.

Participants randomized:

• 378, INT‐05: 138, CGP 032: 240; 182 in intervention group, 196 in control group.

Median age:

• intervention: 72 years;

• control: 71 years.

Country of participants:

• CGP 032: US;

• INT‐05: not reported.

Interventions

Previous interventions:

• CGP 032: all participants underwent prior androgen deprivation:

• • 46 in intervention group and 53 in control group received prior chemotherapy;

• INT‐05: all but 1 participant underwent prior androgen deprivation.

Interventions during study period:

• intervention: pamidronate disodium 90 mg IV every 3 weeks for 27 weeks;

• control: 5% dextrose IV every 3 weeks for 27 weeks.

Outcomes

Reported and analyzed in this review:

• SREs;

• pain response;

• adverse events;

• analgesic consumption;

• QoL.

Funding sources

Funding sources:

• not reported.

Declarations of interest

Conflicts of interest:

• owns stock (not including shares held through a public mutual fund): John Seaman, Novartis Pharmaceuticals; Mildred Kowalski, Novartis Pharmaceuticals; Stephanie Petrone, Novartis Pharmaceuticals;

• acted as a consultant within the last 2 years: Matthew Smith, Novartis Pharmaceuticals; Eric Small, Novartis Pharmaceuticals;

• received more than USD 2000 a year from a company for either of the last 2 years: John Seaman, Novartis Pharmaceuticals; Mildred Kowalski, Novartis Pharmaceuticals; Matthew Smith, Novartis Pharmaceuticals.

Notes

2 multicenter, randomized, double‐blind, placebo‐controlled trials (INT‐05 as international trial and CGP 032 as national trial in the US)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient report on sequence generation.

Allocation concealment (selection bias)

Unclear risk

Insufficient information on allocation concealment.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Placebo‐controlled trial.

Blinding of outcome assessment (detection bias)
Objective outcomes

Unclear risk

Insufficient report on blinding of outcome assessor.

Blinding of outcome assessment (detection bias)
Subjective outcomes

Unclear risk

Insufficient report on blinding of outcome assessor.

Incomplete outcome data (attrition bias)

High risk

Quote: "Because of protocol violations, 350 patients were included in the intent‐to‐treat efficacy analysis (169 patients in the pamidronate group and 181 patients in the placebo group)."

Selective reporting (reporting bias)

Unclear risk

No study protocol available.

Other bias

Unclear risk

Quote: "The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Owns stock (not including shares held through a public mutual fund): John Seaman, Novartis Pharmaceuticals; Mildred Kowalski, Novartis Pharmaceuticals; Stephanie Petrone, Novartis Pharmaceuticals. Acted as a consultant within the last 2 years: Matthew Smith, Novartis Pharmaceuticals; Eric Small, Novartis Pharmaceuticals. Received more than $2,000 a year from a company for either of the last 2 years: John Seaman, Novartis Pharmaceuticals; Mildred Kowalski, Novartis Pharmaceuticals; Matthew Smith, Novartis Pharmaceuticals."

Methods

Recruitment period:

• not reported.

End points:

• bone pain, analgesia consumption.

Pain assessment tool:

• numerical analogue scales;

• linear analogue scales;

• bone pain rating scale (investigator).

Randomization:

• intervention vs control.

Participants

Eligibility criteria:

• prostate cancer metastatic to bone documented by bone scan;

• 1 site of bone pain requiring analgesics caused by bone metastasis;

• no radiation therapy within 1 month before study enrollment and during treatment period.

Exclusion criteria:

• serum creatinine > 2.5 mg/dL.

Participants randomized:

• 57 randomized, 14 intervention I (etidronate IV and etidronate PO), 14 intervention II (etidronate IV and placebo PO), 15 intervention III (placebo IV and etidronate PO), 14 control (placebo IV and placebo PO).

Mean age:

• not reported.

Country of participants:

• not reported.

Interventions

Previous interventions:

• all participants underwent hormonal therapy with no chance of hormonal therapy within 2 months before study enrollment.

Interventions during study period:

• intervention I: sodium etidronate 7.5 mg/kg IV daily for 3 days following sodium etidronate 200 mg PO twice a day;

• intervention II: sodium etidronate 7.5 mg/kg IV daily for 3 days following 1 placebo tablet PO twice a day;

• intervention III: placebo IV daily for 3 days following sodium etidronate 200 mg PO twice a day;

• control: placebo IV daily for 3 days following 1 placebo tablet PO twice a day.

Outcomes

Reported and analyzed in this review:

• analgesic consumption.

Funding sources

Funding sources:

• not reported.

Declarations of interest

Conflicts of interest:

• not reported.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information on sequence generation.

Allocation concealment (selection bias)

Unclear risk

Insufficient information on allocation concealment.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Placebo‐controlled trial.

Blinding of outcome assessment (detection bias)
Objective outcomes

Unclear risk

No information on blinding of investigated outcome.

Blinding of outcome assessment (detection bias)
Subjective outcomes

Unclear risk

No information on blinding of investigated outcome.

Incomplete outcome data (attrition bias)

High risk

Quote: "Six patients [...] were considered unevaluable because they failed to complete 1 month of treatment."

Selective reporting (reporting bias)

Unclear risk

No study protocol available.

Other bias

High risk

No statistical analysis of observed results.

Methods

Recruitment period:

• June 1993 to May 1995.

End points:

• bone pain.

Pain assessment tool:

• 10‐cm VAS.

Randomization:

• intervention vs control.

Participants

Eligibility criteria:

• primary or secondary hormone refractory prostate cancer with persisting pain > 2 cm on VAS caused by bone metastasis;

• life expectancy > 3 months.

Exclusion criteria:

• impaired renal function;

• use of bisphosphonates or other drugs affecting calcium metabolism within 3 weeks before study enrollment;

• palliative radiation therapy within 3 weeks before study enrollment.

Participants randomized:

• 55 randomized but only 52 participants evaluable for efficacy analysis, 25 intervention (clodronate IV and clodronate PO), 27 control (placebo IV and placebo PO).

Mean age:

• intervention: 71 years;

• control: 74 years.

Country of participants:

• not reported.

Interventions

Previous interventions:

• not reported.

Interventions during study period:

• intervention: clodronate 300 mg IV daily for 3 days following clodronate 3200 mg PO daily for 4 weeks;

• control: isotonic saline IV daily for 3 days following placebo tablets PO daily for 4 weeks.

Outcomes

Reported and analyzed in this review:

• pain response.

Funding sources

Funding sources:

• Leiras OY Finland;

• ASTRA Lakemedel Sweden.

Declarations of interest

Conflicts of interest:

• not reported.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient report on sequence generation.

Allocation concealment (selection bias)

Unclear risk

Insufficient information on allocation concealment.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Placebo‐controlled trial.

Blinding of outcome assessment (detection bias)
Objective outcomes

Unclear risk

Insufficient report on blinding of outcome assessor.

Blinding of outcome assessment (detection bias)
Subjective outcomes

Unclear risk

Insufficient report on blinding of outcome assessor.

Incomplete outcome data (attrition bias)

High risk

Different report on number of randomized participants. In the text, 55 participants were randomized and, according to Table 1, 52 participants were randomized.

Selective reporting (reporting bias)

Unclear risk

No study protocol available.

Other bias

High risk

Quote: "The study had to be prematurely terminated before the planned number of patients were included in secondary to difficulties finding enough patients according to inclusion and exclusion criteria."

"The work was supported by Leiras OY Finland and ASTRA Lakemedel Sweden."

Methods

Recruitment period:

• 2005‐2012.

End points:

• safety, PFS, pain response, overall survival, QoL.

Pain assessment tool:

• not reported.

Randomization:

• intervention I vs intervention II vs control I vs control II.

Participants

Eligibility criteria:

• men age ≥ 18 years;

• histologically or cytologically confirmed prostate adenocarcinoma or multiple sclerotic bone metastases with PSA ≥ 100 ng/mL without histologic confirmation;

• radiologic evidence of bone metastases;

• life expectancy ≥ 3 months;

• prior hormonal therapy (bilateral orchiectomy or LHRH agonist);

• disease progression (defined as progression after discontinued hormonal therapy, 2 consecutive increases in serum PSA, PSA > 5 ng/mL, progression of any measurable malignant lesion, ≥ 1 new lesion on bone scan;

• ECOG performance status ≤ 2;

• Hb ≥ 10 g/dL;

• neutrophil count ≥ 1500/mm³;

• platelet count ≥ 100,000/mm³;

• serum creatinine ≤ 1.5 times of ULN;

• ALT or AST ≤ 1.5 times of ULN;

• serum bilirubin ≤ 1.5 times of ULN.

Exclusion criteria:

• brain of leptomeningeal metastases;

• any malignant disease within the past 5 years other than basal cell carcinoma;

• symptomatic peripheral neuropathy ≥ grade 2;

• known hypersensitivity to bisphosphonates;

• prior treatment with any other investigational compound within 30 days;

• prior cytotoxic chemotherapy other than estramustine;

• prior radionuclide therapy for hormone‐resistant prostate cancer;

• prior radiation therapy to whole pelvic or ≥ 25% of bone marrow.

Participants randomized:

• 757 in total in a 2 × 2 factorial design;

• intervention: 188;

• control: 191.

Median age:

• 68 years.

Country of participants:

• not clearly reported.

Interventions

Previous interventions:

• all participants underwent prior hormonal therapy (bilateral orchiectomy or LHRH agonist, or both);

• 337 participants underwent prior radiotherapy.

Interventions during study period:

• intervention: zoledronic acid 4 mg IV and docetaxel 75 mg/m² IV every 3 weeks (21 days/cycle, 10 cycles in total), prednisolone 10 mg daily PO;

• intervention II: zoledronic acid 4 mg IV and docetaxel 75 mg/m² IV every 3 weeks (21 days/cycle, 10 cycles in total), prednisolone 10 mg daily PO and a single dose 150‐MBq strontium chloride Sr89 IV on day 28;

• control: docetaxel 75 mg/m² IV every 3 weeks (21 days/cycle, 10 cycles in total), prednisolone 10 mg daily PO;

• control II: docetaxel 75 mg/m² IV every 3 weeks (21 days/cycle, 10 cycles in total), prednisolone 10 mg daily PO and a single dose 150‐MBq strontium chloride Sr89 IV on day 28.

Outcomes

Reported and analyzed in this review:

• overall survival/mortality;

• adverse events;

• SREs;

• PFS and disease progression.

Funding sources

Funding sources:

• Sanofi Aventis, Novartis Pharmaceuticals and GE Healthcare.

Declarations of interest

Conflicts of interest:

• James ND:

  • honoraria: Astellas Pharma; Bayer; Janssen Pharmaceuticals; Oncogenex; Pierre Fabre; Sanofi;

  • consulting or advisory role: Astellas Pharma; Bayer; Janssen Pharmaceuticals; Merck; Sanofi;

  • speakers' bureau: Astellas Pharma; Ferring; Pierre Fabre; Sanofi;

  • research funding: Astellas Pharma (Inst); Janssen Pharmaceuticals (Inst); Pfizer (Inst); Sanofi (Inst).

• Parker C:

  • consulting or advisory role: Bayer Schering Pharma; BN ImmunoTherapeutics; Janssen Pharmaceuticals;

  • research funding: Bayer Schering Pharma (Inst);

  • travel, accommodations, expenses: Bayer Schering Pharma; Janssen Pharmaceuticals.

• Brown JE:

  • consulting or advisory role: Amgen; Novartis;

  • speakers' bureau: GlaxoSmithKline;

  • research funding: Novartis (Inst);

  • patents, royalties, other intellectual property: patent pending for biomarker for bone metastasis (Inst).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Patients were stratified by investigation center and ECOG performance status at trial entry in a 1:1:1:1 allocation ratio using a computerized minimization algorithm accessed by telephone to the trials unit."

Allocation concealment (selection bias)

Low risk

Quote: "Patients were stratified by investigation center and ECOG performance status at trial entry in a 1:1:1:1 allocation ratio using a computerized minimization algorithm accessed by telephone to the trials unit."

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "TRAPEZE was a randomized, open‐label, phase 3 trial using a 2 × 2 factorial design."

Blinding of outcome assessment (detection bias)
Objective outcomes

Unclear risk

Insufficient report on blinding of outcome assessment.

Blinding of outcome assessment (detection bias)
Subjective outcomes

High risk

Quote: "TRAPEZE was a randomized, open‐label, phase 3 trial using a 2 × 2 factorial design."

Incomplete outcome data (attrition bias)

Unclear risk

Insufficient report on outcome data.

Selective reporting (reporting bias)

High risk

No report on all prespecified outcomes (e.g. QoL).

Other bias

Low risk

No further information provided.

Methods

Recruitment period:

• July 2006 to June 2011.

End points:

• SREs, disease progression, adverse events.

Pain assessment tool:

• not reported.

Randomization:

• intervention vs control.

Participants

Eligibility criteria:

• histologically confirmed prostate cancer and bone metastases present in bone scintigraphy;

• non‐therapy prostate cancer (possible inclusion of men with hormone therapy for < 1 month);

• ECOG performance status ≤ 3;

• leukocyte count > 3000/mm³;

• platelet count > 100,000/mm³;

• Hb level > 9 mg/dL;

• serum ALT ≥ 3 times the institutional reference;

• BUN < 30 mg/dL, ≥ 3 times the institutional reference;

• serum creatinine < 3.0 mg/dL;

• serum calcium 8.5‐11.5 mg/dL.

Exclusion criteria:

• prior use of bisphosphonates;

• radiation therapy within 3 months of therapy initiation;

• serum correction calcium values < 8.0 mg/dL or in active cancer ≥11.6 mg/dL;

• other active malignancy within 3 years prior to therapy initiation;

• grave complications;

• planed invasive dental treatment or a treatment within 6 months prior to study entry;

• anaphylactic medical history regarding bisphosphonates.

Participants randomized:

• 60 randomized, 29 intervention, 31 control.

Mean age:

• intervention: 71.1 years;

• control: 71.8 years.

Country of participants:

• Japan.

Interventions

Previous interventions:

• participants had no prior intervention.

Interventions during study period:

• intervention: zoledronic acid 4 mg IV infusion every 4 weeks (started 1 month after combined androgen blockade), combined androgen blockade with bicalutamide 80 mg and an LHRH agonist;

• control: combined androgen blockade with bicalutamide 80 mg and an LHRH agonist.

Outcomes

Reported and analyzed in this review:

• SREs;

• overall survival;

• adverse events.

Funding sources

Funding sources:

• not reported.

Declarations of interest

Conflicts of interest:

• not reported.

Notes

Inclusion of "bone pain" in SREs.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information on sequence generation.

Allocation concealment (selection bias)

Unclear risk

Insufficient information on allocation concealment.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "This study was under a still ongoing randomized multicenter collaborative open‐labeled project [...]."

Blinding of outcome assessment (detection bias)
Objective outcomes

Unclear risk

Insufficient information on blinding of the outcome assessor.

Blinding of outcome assessment (detection bias)
Subjective outcomes

High risk

Quote: "This study was under a still ongoing randomized multicenter collaborative open‐labeled project [...]."

Incomplete outcome data (attrition bias)

Low risk

All participants were included in statistical analysis.

Selective reporting (reporting bias)

High risk

No report on survival data (planned per protocol).

Other bias

Low risk

No further information provided.

Methods

Recruitment period:

• May 2008 to December 2010.

End points:

• overall survival, SREs, disease progression, adverse events.

Pain assessment tool:

• not reported.

Randomization:

• intervention vs control.

Participants

Eligibility criteria:

• men age ≥ 20 years;

• histopathologically or cytologically confirmed prostate cancer;

• bone metastasis on bone scan;

• sensitivity to androgen blockade therapy;

• ECOG performance status ≤ 2;

• PSA level ≥ 30 ng/mL;

• leukocyte count ≥ 3000/µL;

• Hb ≥ 9.0 g/dL;

• platelet count 7.5 × 10⁴/µL;

• serum creatinine level ≤ 3.0 mg/dL;

• corrected serum calcium ≥ 8.5 mg/dL and ≤ 11.5 mg/dL;

• total bilirubin ≤ 1.8 mg/dL;

• AST level ≤ 90 IU/L;

• ALT level ≤ 100 IU/L.

Exclusion criteria:

• poorly controlled dental caries;

• poorly controlled hypertension or cardiovascular disease;

• double cancer requiring treatment;

• systematical use of steroid drugs;

• active HIV or hepatitis virus infections;

• prior androgen blockade therapy;

• prior or concurrent other anticancer therapy;

• prior or concurrent immunologic adjuvant therapy;

• prior or concurrent use of bisphosphonates (excluding zoledronic acid);

• prior systemic chemotherapy.

Participants randomized:

• 227, 115 intervention, 112 control.

Median age:

• 72.0 years, 73.0 years intervention, 71.5 years control.

Country of participants:

• Japan.

Interventions

Previous interventions:

• all participants were treatment‐naive.

Interventions during study period:

• intervention: zoledronic acid 4 mg IV every 4 weeks from study entry and androgen blockade therapy with LHRH analogue + bicalutamide for 2 years;

• control: androgen blockade therapy with LHRH analogue + bicalutamide for 2 years.

Outcomes

Reported and analyzed in this review:

• none.

Funding sources

Funding sources:

• "The ZAPCA trial was supported by Grant for Urologic Research No. 200040700148 from Kyoto University Hospital."

Declarations of interest

Conflicts of interest:

• Tomomi Kamba: honorarium from Astellas Pharma;

• Toshiyuki Kamoto: research funding and honoraria from Astellas Pharma;

• Fuminori Sato: research funding from Janssen Pharmaceutical and Astellas Pharma;

• Naoya Masumori: honoraria from Novartis Pharma and Daiichi Sankyo, and research funding from Daiichi Sankyo;

• Shin Egawa: research funding from Astellas Pharma and Takeda Pharmaceutical;

• Hideki Sakai: research funding from Astellas Pharma and Takeda Pharmaceutical, and honoraria from Astellas Pharma and AstraZeneca;

• Osamu Ogawa: honorarium from Astellas Pharma.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Computer‐based randomization was conducted at the Translational Research Informatics Center (TRI; Kobe, Japan) with stratification according to the treatment institution, baseline PSA concentration (<200 or ≥200 ng/mL), baseline extent of disease (EOD) grade [13] (≤2 or ≥3), and biopsy Gleason score (≤7 or ≥8). [...] The system automatically evaluated the eligibility of each patient and randomly assigned participants to each group."

Allocation concealment (selection bias)

Low risk

Quote: "Computer‐based randomization was conducted at the Translational Research Informatics Center (TRI; Kobe, Japan) with stratification according to the treatment institution, baseline PSA concentration (<200 or ≥200 ng/mL), baseline extent of disease (EOD) grade [13] (≤2 or ≥3), and biopsy Gleason score (≤7 or ≥8). [...] The system automatically evaluated the eligibility of each patient and randomly assigned participants to each group."

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label trial.

Blinding of outcome assessment (detection bias)
Objective outcomes

Unclear risk

Insufficient information on blinding of outcome assessor.

Blinding of outcome assessment (detection bias)
Subjective outcomes

High risk

Open‐label trial.

Incomplete outcome data (attrition bias)

Low risk

Quote: "All 224 patients who received at least one dose of LH–RH agonist were included in the Safety Assessment Set (SAS)."

Selective reporting (reporting bias)

High risk

Study investigators initially planned to analyze QoL and pain as outcomes, but the authors did not provide any data on these end points in their publications.

Other bias

Unclear risk

Quote: "The ZAPCA trial was supported by Grant for Urologic Research No. 200040700148 from Kyoto University Hospital. [...] Tomomi Kamba accepted an honorarium from Astellas Pharma. Toshiyuki Kamoto accepted research funding and honoraria from Astellas Pharma. Fuminori Sato accepted research funding from Janssen Pharmaceutical and Astellas Pharma. Naoya Masumori accepted honoraria from Novartis Pharma and Daiichi Sankyo, and research funding from Daiichi Sankyo. Shin Egawa accepted research funding from Astellas Pharma and Takeda Pharmaceutical. Hideki Sakai accepted research funding from Astellas Pharma and Takeda Pharmaceutical, and honoraria from Astellas Pharma and AstraZeneca. Osamu Ogawa accepted an honorarium from Astellas Pharma."