Methods

Three randomized single‐blinded controlled studies
Quality score (1/0/0)
Outcomes: pain and analgesic consumption
Pain assessment tool: 20cm VAS
Pain response definition: not specified
Analgesic consumption definition: daily consumption of analgesic drugs (ketoprofen)
Pain assessment schedule: 0,1,2,4 week.

Participants

Prostatic carcinoma. Bone metastasis (radiographic). Pain requirement: not specified.
Cointerventions: orchidectomy at least 8 months before study (n=16), extramustine but disease refractory (n=16), distribution not specified.
Randomized 56 patients.
Baseline pain (mean 20cm VAS): active 16/20, control 12/20

Interventions

Study 1: Placebo (n=6) versus Clodronate i.v. infusion 300mg /day x 2 weeks (n=7)
Study 2: Clodronate oral 1200mg/day x 2 weeks (n=11) versus Clodronate i.m. 100mg/day x 2 weeks (n=12)
Study 3: Clodronate i.v. x 2 weeks then stop (n=13) versus Clodronate i.v. x 2 weeks then clodronate oral 1200mg/day x at least 6 weeks (n=18)

Outcomes

Study 1: Mean pain score and analgesic consumption at 0,1,2,4 week. No S.D. provided.
Study 2: Mean pain score and analgesic consumption at 0,1,2,4 week. No S.D. provided.
Study 3: Mean percentage change in pain score at 1,2,4,6,8 week. No S.D. provided.
No haematological toxicity reported.

Notes

Methods

Randomized double‐blind placebo‐controlled study
Quality score (2/2/1)
Primary outcome: symptomatic bone progression‐free survival (osseous disease requiring increase analgesic, radiotherapy, change in hormonal therapy, pathological fracture or spinal cord compression)
Secondary outcomes: overall survival, toxicity, bone events, type of progressive disease, analgesic consumption, WHO performance status, PSA, alkaline phosphatase levels.
Pain assessment criteria: nil
Definition of pain response:
Analgesic: time to first regular use of analgesics of any strength.
Follow‐up schedule: 4 week, 3,6,9,12,15,18,21,24 months, then every 6 months (median follow up 59 months).

Participants

Prostate cancer bone metastases.
Pain not required.
Commencing or responding to hormonal therapy; no previous use of long‐term hormone therapy; normocalcaemia; WHO performance status 2 or less; bisphosphonates naive; serum creatinine less than 2 x ULN; no other active malignancy; no acute severe bowel inflammatory conditions; no serious concomitant disease; no drug trial within 12 months.
Randomized 311 patients: active 155, control 156, analysed active 155, control 156.

Interventions

Active: Clodronte oral 2080mg/day up to 3 years
Control: Placebo up to 3 years

Outcomes

Longer time to first regular use of analgesics in active group, HR = 1.12 (95%CI = 0.86‐1.45, P=0.41, data not shown)
Longer Symptomatic BPFS in active group, HR = 0.79 (0.61‐1.02, p.066)
Number of SBP events: active 94/155, control 103/156
Any death: active 111/155, control 124/156
Prostate cancer death: active 91/155 control 105/156
Bone progression as first event: active 89/155, control 98/156.
Disease progression: 106/155, 112/156.
Patients with adverse effects: active 78/155, control 53/156
Bone disease progression: 86/155, 98/156
Higher risk of adverse effects in active group, HR = 1.71 (1.21‐1.41, P 0.002),
Number of adverse events: Total active 123/155, control 82/156, including gastrointestinal (active 31/155 control 21/156), cardiovascular, joint pain, dyspnoea, urinary, skin, second primary malignancy, tiredness, central nervous system, bone pain/fracture, sweats, dizziness, headaches, abnormal blood counts (active 2/155 control 3/156) or biochemistry, paresthesia, sleep, hepatic, memory, gastrointestinal bleeding, etc.
Change in WHO performance status (HR 0.71, CI=0.56‐0.92, p.008).
Sustained deterioration of WHO performance status: active 79/155 control 98/156
Worsened WHO performance status, HR = 0.71, 95%CI = 0.56‐0.92, P=0.008, favours active.
Improved WHO performance before reaching primary endpoint: active 22/155, control 17/156.
Estimated median PSA during first 2 years: active 5.0, control 10.4 (P=0.053, data not shown).

Notes

Methods

Randomized placebo‐controlled parallel study. Blinding not mentioned.
Quality score 1/0/1
Primary outcome: pain
Secondary outcomes: performance status, bone pain, analgesic use, serum biochemical markers, side effects.
Pain assessment criteria: presence or absence of bone pain evaluated by patient and doctor
Pain response definition: no pain
Analgesic consumption assessment: not specified.
Analgesic response definition: no analgesic.
Pain assessment schedule: 0,1,3,6 month.

Participants

Prostate cancer refractory to at least one hormonal therapy. Bone metastases required. Pain required (with daily use of analgesics).
Life expectancy at least 3 months.
RT not allowed.
Randomized 75 patients: active 36, placebo 39

Interventions

Active arm: Clodronate oral 3.2g/day for 1 month then 1.6g/day for 5 months. Total 6 months.
Control arm: Placebo
Cointervention: All patient received estramustine 280mg bid

Outcomes

No pain (doctor evaluation) at 0, 1, 3, 6 months: clodronate 0/36 9/29 5/22 3/11; placebo 0/39 5/34 1/24 1/13.
No pain (patient evaluation) at 0, 1, 3, 6 months: clodronate 0/36 10/29 6/21 2/11; placebo 0/39 6/34 1/23 2/13
No analgesic at 0, 1, 3, 6 months: clodronate 0/36 11/29 5/22 2/11; placebo 0/39 6/34 3/24 3/13
Median survival and survival rates: no difference
All death: active 12/36, control 10/39.
Cancer death: active 9/36, control 6/39.
Performance status: ambulatory rate at 1, 3 month: active 30%, 40%, control 20%, 40%
Biochemical markers and blood count: no difference
Patients discontinued trial at 1,3,6 months: active 2,3,1, control 3,4,2.
Side effects uncommon.

Notes

Methods

Randomized double‐blind controlled study
Quality score (1/2/1)
Primary outcome: palliative response, defined as either 2‐point reduction in PPI (present pain intensity score, six‐point, 0‐5) or >50% decrease in analgesic score.
Secondary outcomes: time to symptomatic progression, duration of palliative response, PSA response (>50% decrease from baseline), morbid skeletal events (hypercalcaemia, pathologic fractures, palliative radiotherapy), toxicity, HRQOL. Urine biochemical markers.
Pain assessment: six‐point PPI scale 0‐5 (Present pain intensity scale of the McGill‐Melzack Pain Questionnaire)
Analgesic assessment: Analgesic score defined by total number of analgesics units (1 unit = standard doses of non‐opioid, 2 units = morphine 10‐mg equivalents).
Pain assessment schedule: every 3 week.

Participants

Prostate cancer. Progressive bone disease. Castration testosterone levels. Hormonal treatment stopped before randomization.
Pain required: PPI = 1 or more. Stable analgesic intake required.
ECOG performance status < 3, adequate baseline cardiac, haematologic and biochemical function, able to complete pain and QOL scores.
Exclusion: prior malignancy, more than one previous chemotherapy regimen or a previous regimen containing mitoxantrone or an anthracycline, precious bisphosphonate therapy, treatment with radiotherapy within the previous 4 weeks or radioisotopes within the previous 8 weeks, radicular or back pain suggestive of epidural metastases, potential spinal cord or nerve root compression, impending pathological fracture, and uncontrolled cardiac failure or active infection.
Randomized 227 patients: active 115, control 112; ineligible: active 11, control 7; analysed: active 104, control 105.
Baseline pain, PPI 1‐2, active 78/104, control 82/105; PPI 3‐4, active 26/104, control 23/105.

Interventions

Active arm (n=115): clodronate 1500mg i.v. q3w until disease progression in responding patients.
Control arm(n=112): placebo q3w
Cointervention: mitoxantrone 12mg/m2 iv q3w and prednisolone 5mg po bid.

Outcomes

Palliative response: active 49/115, control 41/112.
Pain response: active 34/115 control 27/112.
Analgesic response: active 34/115 control 32/112.
No need for analgesic: active 33/115 control 27/112.
Any death: active 87/115 control 89/112. All except one caused by disease progression.
PSA response: active 30/115 control 30/112
Disease progression: 58/115 control 68/112
Requirement of local radiotherapy: active 18/115 control 16/112
Morbid skeletal events: results not reported.
Adverse effects (grade3/4) (active:control): granulocytopenia 14/115 14/112, anaemia 8/115 5/112, thrombocytopenia 2/115 4/112, cardiovascular 0/115 3/112 nausea/vomiting 9/115 7/112 headache 4/115 1/112 dyspnoea 4/115 7/112 infection 7/115 3/112.
QOL response: active 39/115 control 44/112
Withdraws: active 11/115, 7/112

Notes

Methods

Randomized controlled study
Quality score (1/0/1)
Primary outcome: type I collagen metabolites.
Other outcomes: pain, analgesic use, bone scan changes, serum calcium, phosphate, acid phosphatase, PSA, creatinine, transaminase.
Pain assessment criteria: presence or absence of bone pain
Definition of pain response: absence of pain.
Analgesic measurement: with or without analgesic
Pain assessment schedule: not stated, diagrams suggests this followed the assessment schedule for other parameters i.e. 0,1,3,6 months

Participants

Prostate cancer, hormone refractory.
Bone metastases required. Pain required. Analgesic consumption required.
Radiotherapy not allowed in preceding 2 months and during trial.
Life expectancy at least 3 months.
Randomized 99 patients: active 50, placebo 49.

Interventions

Active arm: oral clodronate 3.2g/day x 1 month then 1.6g/day x 5 months; extramustine 280mg twice daily
Control arm: open control with extramustine 280mg twice daily

Outcomes

Percentage of patient free from bone pain: no significant difference, SD not reported.
Percentage of patient without analgesic: no significant difference, SD not reported.
Trial discontinuation: active 31/50, control 31/49 (nausea and diarrhoea: active 6/50, control 7/49, progression: active 10/50, control 14/49, death: active 15/50, control 10/49)
No significant difference in median survival and survival rate at 6 month between active and control group.
No significant difference in number of sites of bone metastases at 0 and 6 month between active and control group.
Mean (SD) PSA at 0,1,3,6 months: active 335(563), 192(225), 213(280), 448(708), control 240(297), 201(263), 254(704), 214(229). P not significant between active and control group.

Notes

Methods

Randomized double‐blind placebo‐controlled study
Quality score (1/2/0)
Primary outcome: pain
Other outcomes: use of analgesics, performance status, clinical response (i.e. better, same, worse by doctor), imaging response, PSA response, biochemical markers, side‐effects.
Pain assessment criteria: verbal ordinal scale 0‐4 by doctor and visual analogue scale by patient.
Definition of pain response: not defined.
Analgesic measurement: 3 point scale (0 none, 1 non‐narcotics < tid, 2 non‐narcotic > tid, 3 narcotic).
Pain assessment schedule: 0,1,3,6,12 months

Participants

Prostate cancer (failed hormonal therapy). Bone metastases required. No pain required.
Life expectancy 6 months or more.
Exclusion radiotherapy within 2 weeks.
Hormonal/ chemotherapy allowed.
Randomized 57 patients: active 28, placebo 29, analysed: active 28, control 27
Baseline pain (grade 0,1,2,3,4): active 6,13,5,3,0/28 control 2,12,12,1,0/29

Interventions

Active arm: clodronate (i.v. 300mg/day x 5days followed by oral 1.6g/day x 12 months)
Control arm: placebo
All received estramustine 280mg twice daily.

Outcomes

Pain: no significant different in any pain score. Proportion of patient with no pain at 1 month: active 10/28, control 6/29.
Analgesic: proportion of patient without analgesic at 1 month: active 13/28, control 8/29.
Performance status: proportion of patients asymptomatic at 1 month: active 4/28 control 1/29.
Clinical response: no significant difference.
Radiological response at 6 months: active 15/28 (5SD, 9PR, 1CR), control 14/29 (6SD, 7PR, 1CR)
Mean(SE) PSA at 0,1,3 months: active 161(52) 138(54) 226(70) control 214(104) 258(197) 331(204).
Adverse effects:
Nausea at 1 month: active 33% placebo 40%.
No renal failure

Notes

Methods

Randomized double blind placebo‐controlled study.
3 arm study: 2 active arms, 1 placebo arm.
Quality score (2/2/1)
Primary outcome: skeletal‐related event (pathologic fracture, spinal cord compression, change in anti‐neoplastic therapy for bone pain, bone surgery or radiotherapy).
Secondary outcomes: time to first skeletal‐related event, skeletal morbidity rate, proportion of patients with skeletal‐related events, time to disease progression, bone lesion response, bone biochemical markers, quality of life parameters.
Pain assessment: Brief Pain Inventory pain score
Analgesic assessment: analgesic score 0‐4
Pain assessment schedule: 3,6,9,12,15 months

Participants

Prostate cancer (hormone refractory). Bone metastases required. Pain not required.
ECOG performance status of 0,1,2.
Cointervention: Antineoplastic therapy allowed.
Exclusion: bone pain requiring strong narcotic therapy, chemotherapy (except estramustine), RT within 3 months, previous bisphosphonate treatment, severe heart disease or hypertension, a serum creatinine of more than 3mg/dL or calcium less than 8mg/dL or greater than 11.6mg/dL.
Randomized 643 patients: active arm‐1 214, active arm‐2 221, control 208
Baseline pain, Mean BPI, active1 = 2 +/‐ 2, active2 = 2.5 +/‐ 2.1, control 2.1 +/‐ 2.0

Interventions

Active arm 1: zoledronic acid 4mg, 214 patients
Active arm 2: zoledronic acid 8mg, 221 patients
Control arm: placebo q3w x 20 cycles (15 months), 208 patients..
Ca supplement and vit D.

Outcomes

Pain score, mean change (95% confidence intervals) at 3 months: active1 ‐0.028 (0.22), active2 ‐0.04 (0.21), control 0.42 (0.22)
Analgesic score: No statistically significant difference (scores not included).
Patients having skeletal‐related events: active1 71/214, active2 85/221, control 92/208, pathologic fractures 28/214 33/221 46/208, vertebral fractures 8/214, 8/221, 17/208, non‐vertebral fractures 22/214, 22/221, 33/208, bone radiotherapy 49/214 53/221 61/208, bone surgery 5/214 6/221 7/208, spinal cord compression 9/214, 11/221, 14/208.
Time to first skeletal‐related event: active1 but not active2 is significantly longer than control.
Patients with radiological bone response: active1 56/214 (CR0,PR9,SD47), active2 52/221 (CR0,PR6,SD46), control 43/208 (CR0,PR8,SD35)
Patients with adverse events: bone pain (active1 108/214, active2 133/218, placebo 127/208), nausea (active1 77/214, active2 115/218, placebo 77/208), constipation, fatigue, anaemia (active1 57/214, active2 60/218, placebo 37/208), myalgia, vomiting (active1 46/214, active2 115/218 placebo 43/208), weakness, anorexia, fever, lower limb edema, dizziness, diarrhoea, weight increase.
ECOG performance scores, FACT‐GQoL and EURO‐QOL scores: No statistically significant difference.
Medican time to cancer progression = 84 days in all treatment groups.
PSA, percent change from baseline, no statistically significant difference.
Median survival (days) (active1, active2, placebo): 546, 407, 464
P = 0.091 (active1 vs placebo), P = 0.386 (active2 vs placebo).

Notes

Methods

Randomized double‐blind, placebo‐controlled trial.
Quality score (1/2/1)
Primary outcomes: pain and analgesic use
Pain assessment: Brief Pain Inventory (11 point numeric rating scale 0‐10) (least, average and worst pain since last visit)
Analgesic assessment: Oral morphine equivalent (OME)
Definition of pain and analgesic responses: mean change from baseline BPI and OME scores
Pain assessment schedule: 9 and 27 weeks. Study end at 27 weeks.
Secondary: skeletal related event, skeletal morbidity rate, mobility, bone imaging, PSA and other biochemical markers and disease progression (stage, clinical and pain).

Participants

Prostate cancer (hormone refractory). Bone metastases. Pain required.
Life expectancy 6 months or above. RT and radio‐isotope allowed.
Exclusion: leucopenia, thrombocytopenia, serum Cr 5mg/dL or above, corrected serum Ca 11mg/dL or above or 8.4mg/dL or below, magnesium 0.8mg/dL or below, or total bilirubin more than 2.5mg/dL. Patient with untreated brain metastases, prior bisphosphonate therapy, abnormal ECG, ascites, impending spinal cord compression or spinal orthosis, or skeletal event within 1 month. Change in chemotherapy or hormone therapy within 6 weeks. Receiving drugs that affected osteoclast activity.
Randomized 378 patients: active 182, control 196
Analyzed patients: active 169, control 181
Baseline pain, mean BPI, active 4.3 +/‐ 2.1, control 4.5 +/‐ 2.1

Interventions

Active arm: Pamidronate 90mg in 250ml D5 iv infusion over 2h q3w x 27 weeks.
Control arm: placebo

Outcomes

Mean Pain change (average BPI) at week 9: active ‐0.61 SE 0.17, n=147; placebo: ‐0.44 SE 0.16 n=154
OME score, week 9: active +16.6 SE 6.8, n=147; placebo: +10.2 SE 6.6 n=154
Decreasing or stable analgesic use at week 9: active 53/147, control 68/154; week 27: active 46/110, control 52/108.
Patients having SRE, week 9: active 20/169 control 20/181; week 27: active 42/169 control 46/181
Patients having RT for bone pain, week 9: active 11/169 control 10/181; week 27: active 25/169 control 29/181
Patients having RT to prevent fracture, week 9: active 6/169 control 3/181; week 27: active 8/169 control 7/181
Patients with nonvertebral fractures, week 9: active 6/169 control 6/181; week 27: active 14/169 control 12/181
Patients with vertebral fractures, week 9: active 5/169 control 2/181; week 27: active 11/169 control 10/181
Patients with spinal cord compression, week 9: active 3/169 control 0/181; week 27: active 5/169 control 3/181
Patients with surgery to bone, week 9: active 2/169 control 3/181; week 27: active 5/169 control 6/181
Patients with hypercalcaemia, week 9: active 0/169 control 1/181; week 27: active 1/169 control 2/181
Patients with adverse effects: bone pain (active 77/180, control 75/194); nausea (active 50/180, control 43/194); fatigue, anorexia, constipation, vomiting (active 31/180, control 31/194), anaemia (active 38/180, control 39/194), fever, weight decrease, asthenia, diarrhoea, dyspnoea, urinary tract infection, dizziness.
Mean PSA increase from baseline (data not shown)
All deaths: active 22 control 26 (primarily due to progressive disease)

Notes

Data pooled from two trials

Methods

Randomized double‐blind placebo‐controlled study
3 active arms, 1 placebo arm
Quality score (1/1/0)
Outcomes: pain relief and analgesic requirement.
Pain assessment: numerical and linear analogue scales, rated by patient and investigator.
Definition of pain response: minor and major improvement, details not described.
Analgesic requirement: daily assessment, details not described.
Pain assessment schedule: daily pain diary by patient.

Participants

Prostate cancer (previous hormone therapy). Bone metastases required (documented by bone scan). Pain required.
Cointervention: hormonal therapy as clinically indicated. RT not allowed.
Exclusion: renal dysfunction
Randomized 57 patients: active1 14, active2 14, active3 15, control 14; evaluable: active1 13, active2 12, active3 14, control 12.

Interventions

Active 1 ‐ sodium etidronate 7.5mg/kg x 3 days then oral sodium etidronate 200mg bid
Active 2 ‐ sodium etidronate 7.5mg/kg x 3 days then placebo bid
Active 3 ‐ i.v. placebo then oral sodium etidronate 200mg bid
Control ‐ i.v. and oral placebo
Duration of treatment at least 1 month up to 6 month if responding.

Outcomes

Major pain improvement: active1 0/14, active2 2/14, active3 1/15, control 1/14
Minor pain improvement: active1 2/14, active2 2/14, active3 1/15, control 1/14
Decrease analgesic requirement: active 4/43, control 3/14.
Discontinued (2 due to nausea and vomiting): active1: 1/13, active2 2/12, active3 1/14, control 2/12
No serious adverse effects observed.
Mild stomach cramp and nausea: active 7/43, control 3/14.

Notes

Methods

Randomized double‐blind placebo‐controlled study
Quality score (1/0/0)
Outcomes: pain intensity and analgesic consumption.
Pain assessment: mean pain, least pain, worst pain with 10cm VAS
Pain response definition: not specified
Analgesic consumption definition: not specified
Pain assessment schedule: Day 0,1,2,3,4,11,18,25,32.

Participants

Prostate cancer, hormone refractory, bone metastases.
Pain required, > 20mm VAS.
Conintervention: none described.
Life expectancy > 3m
Exclusion: renal dysfunction, bisphosphonate within previous 30 days, RT within previous 3 weeks.
Included 55 patients, randomized 52 patients (active 25, control 27), 46 patients valid for efficacy (meaning not defined, active 22, control 24).
Baseline pain, mean VAS (mm), active 39 +/‐ 19, control 53 +/‐ 21

Interventions

Active arm: Clodronate 300mg/day iv x 3 days then Clodroate 1600mg bd oral for 4 weeks
Control arm: isotonic saline for 3 days then placebo capsules

Outcomes

Baseline mean overall pain and mean pain during the best and worst period reported.
No significant changes in mean pain intensity and in pain intensity during best and worst period. Data not included.
Subgroup analysis (patients with baseline mean pain > 50mm VAS): also not significant pain reduction compared with control.
Analgesic consumption not reported.
Withdraws: not reported.

Notes

Study closed early due to lack of accrual.