Table 2.

Notable completed clinical trials of osteoclast inhibition in advanced prostate cancer

Study	N	Population	Study Arms	Endpoints	Outcome/Notes
National Cancer Institute of Canada (NCIC) Clinical Trials Group (CTG) Pr06⁸⁸	209	CRPC with symptomatic bone metastases	All received mitoxantrone (12 mg/m² every 3 weeks) 1:1 randomization to clodronate (1,500 mg IV) or placebo every 3 weeks	Primary: palliative response as assessed by present pain intensity index Secondary: symptomatic PFS, overall survival, quality of life	No significant difference in palliative response (46% with clodronate vs. 39% with placebo, p = 0.54) or in secondary endpoints such as symptomatic PFS, overall survival, and quality of life
CGP 032 & INT-05 (combined analysis)⁸⁹	378	CRPC with symptomatic bone metastases	1:1 randomization to pamidronate (90 mg IV) or placebo every 3 weeks for 27 weeks	Self-reported pain score, analgesic use, incidence of SREs, mobility	No significant difference in pain, analgesic use, or skeletal-related events. Urinary bone resorption markers such as NTx were significantly suppressed with therapy.
Trial 039^{7, 8}	643	CRPC with bone metastases	1:1:1 randomization to zoledronic acid (4 mg or 8 mg) or placebo every 3 weeks	Proportion of patients with SREs, time to first SRE, skeletal morbidity rate, pain and analgesic scores, and disease progression	Significant decrease in skeletal related events (33.2 % with zoledronic acid 4 mg vs. 44.2% with placebo), trend toward improved survival. Zoledronic acid 8 mg was modified due to nephrotoxicity.
Trial 103⁴¹	1,904	CRPC with bone metastases	1:1 randomization to denosumab (120 mg SC) vs. zoledronic acid (4 mg IV) every 4 weeks	Primary: time to first on-study SRE and was assessed for non-inferiority Secondary: superiority in time to first SRE, overall survival	Denosumab lengthened time to first on-study SRE (20.7 months vs. 17.1 months, hazard ratio or HR 0.82, 95% CI 0.71 to 0.95; p = 0.0002 for non-inferiority, p = 0.008 for superiority).
Medical Research Council (MRC) Pr05^{43, 44}	311	Prostate cancer with bone metastases, starting or responding to first-line ADT	1:1 randomization to oral clodronate (2,080 mg) vs. placebo daily; maximum 3 years treatment	Primary: symptomatic bone progression free survival Secondary: overall survival, performance status	Non-significant trend toward improved bone progression-free survival (HR 0.70, 95% CI 0.61 to 1.02; p = 0.066). Long term follow-up revealed an improvement in overall survival with clodronate treatment (HR 0.77, 95% CI 0.60 to 0.98; p = 0.032)⁴³, currently regarded as hypothesis-generating.
MRC Pr04^{43, 45}	508	Nonmetastatic prostate cancer, within 3 years of diagnosis	1:1 randomization to oral clodronate (2.080 mg) vs. placebo daily for up to 5 years	Symptomatic bone metastasis-free survival	There was no improvement in symptomatic bone metastasis free survival (HR 1.22; 95% CI 0.88 to 1.68) or survival (HR 1.02; 95% CI 0.80 to 1.30).
Trial 704⁴⁶	201 (closed early)	Nonmetastatic CRPC	1:1 randomization to zoledronic acid (4 mg IV) or placebo every 4 weeks	Bone metastasis-free survival	Halted early for futility due to lower-than-expected rate of bone metastases. With placebo, median bone metastasis-free survival was 30 months; PSA > 10 ng/mL and PSA doubling time were significantly associated with risk.
Trial 147⁴⁸	1,432	Nonmetastatic CRPC with PSA ≥ 8 μg/L or PSA doubling time ≤10.0 months	1:1 randomization to denosumab (120 mg SC) or placebo every 4 weeks	Bone metastasis-free survival	Denosumab increased bone-metastasis-free survival by 4.2 months (median 29.5 months with denosumab vs. 25.2 months with placebo; HR 0.85, 95% CI 0.73 to 0.98, p = 0.028). It is not approved for this indication.