Table 3.

Clinical Trials Evaluating Bisphosphonates for the Prevention of Skeletal Complications in Prostate Cancer Patients With Bone Metastases

Study/Regimen*	Primary Endpoint	Comments and AEs
Dearnaley 200343
Clodronate	BPFS time†	No significant difference in BPFS time (HR = 0.79; 95% CI, 0.61−1.02; P = .066) or overall survival time (HR = 0.8; 95% CI, 0.62−1.03; P = .082) between groups Median time to SRE: 23.6 vs 19.3 mo (95% CI, 0.8−11.5 mo) BPFS at 2 y: 49.3% vs 41%; absolute difference, 8.3% (95% CI, −1%−18%) 29% reduction in risk of worsening WHO performance status in clodronate group (95% CI, 8%−44%; P = .008) AEs: more frequent in patients receiving clodronate‡ (P = .02); dose-modifying AEs more common in clodronate group (P < .0001)
2080 mg PO q d
× 3 y
(n = 155)
vs
placebo
(n = 156)
Ernst 200344
Clodronate	Reduction in pain and/or analgesic use§	Achievement of primary endpoint: 45% vs 39% (P = .54) Median duration of response, symptomatic PFS time, overall survival time, QOL similar between groups AEs: serious AEs were infrequent and similar in both treatment groups
1500 mg IV
q 3 wk
(n = 104)
vs
placebo
(n = 105)
Saad 2002,41 200442
Zoledronic acid	Proportion of patients having at least 1 SRE∥	15-month analysis At least 1 SRE in significantly fewer patients receiving zoledronic acid 4 mg vs placebo (33.2% vs 44.2%, P = .021) Fewer fractures in patients receiving zoledronic acid vs placebo (4 mg, 13.1% vs 22.1%, P = .015; 8/4 mg, 14.9% vs 22.1%, P = .054) Time to first SRE not reached by end of study (day 420) in patients receiving zoledronic acid 4 mg; median time to first SRE was 321 d in placebo group Mean skeletal-related morbidity# rates lower for all SREs in patients receiving zoledronic acid 4 mg vs placebo (P = .006) Similar time to disease progression, survival time, and QOL scores among groups AEs: fatigue, anemia, myalgia, fever, and lower-limb edema 5% more common in both zoledronic acid groups vs placebo; renal function deterioration slightly more common in patients receiving zoledronic acid 8/4 mg vs placebo (RR 1.76 [95% CI, 0.79−3.93; P = 165]); no zoledronic acid-related renal failure or ONJ 24-month analysis At least 1 SRE in significantly fewer patients receiving zoledronic acid 4 mg vs placebo (38% vs 49%, P = .028) by 24 mo; between 15 and 24 mo, 19% vs 38% of patients experienced at least 1 SRE (P = .017) Annual SRE incidence lower in zoledronic acid 4 mg group vs placebo (0.77 vs 1.47, P = .005) Time to first SRE longer in zoledronic acid 4 mg group vs placebo (488 vs 321 d, P = .009) AEs: similar to AEs observed in 15-month analysis
4 mg IV q 3 wk
× 20
(n = 214)
vs
zoledronic acid
8/4 mg¶ IV q 3 wk
× 20
(n = 221)
vs
placebo
(n = 208)
Small 200345
Pamidronate	Reduction in pain and/or analgesic use**	Changes in baseline pain scores and analgesic use similar between groups at 9 and 27 wk Number of SREs†† at wk 9 (12% vs 11%) and wk 27 (25% for both groups) similar between pamidronate and placebo groups, respectively AEs: no between-group differences; no pamidronate-related renal failure or ONJ
90 mg IV q 3 wk
× 9
(n = 169)
vs
placebo
(n = 181)

^*Patients (n) evaluable for efficacy analysis.

^†Defined as either time to development of symptomatic bone metastases requiring intervention or PC-related death; does not include asymptomatic disease progression (eg, asymptomatic vertebral fracture) often included in the definition of skeletal-related event.

^‡Most common AEs included gastrointestinal problems, increased lactate dehydrogenase levels, cardiovascular problems, joint pain.

^§Pain reduction defined as PPI of 0 or reduction by 2 points in PPI scale; a decrease in analgesic use defined as 50% reduction.

^∥Defined as pathologic bone fracture, spinal cord compression, bone surgery, radiation therapy of bone, change in antineoplastic therapy to treat bone pain.

^¶To reduce renal toxicities, zoledronic acid dose decreased to 4 mg for all patients per protocol amendment.

^#Defined as number of SREs divided by years at risk.

^**Pain measured using a self-administered numeric rating scale and categorized as “least,” “average,” or “worst” pain at each study visit; analgesic use self-recorded daily and assigned oral morphine equivalents.

^††Defined as radiation therapy of bone for pain relief, radiation therapy of bone to prevent fracture or spinal cord compression, pathologic fracture, spinal cord compression, bone surgery, hypercalcemia, or a need for a spinal orthotic brace.

AE, adverse event; BPFS, bone progression-free survival; CI, confidence interval; HR, hazard ratio; IV, intravenous; ONJ, osteonecrosis of the jaw; PFS, progression-free survival; PPI, present pain index; QOL, quality of life; RR, relative risk; SRE, skeletal-related event; WHO, World Health Organization.