Background: Interactions between metastatic prostate cancer cells, osteoblasts, osteoclasts, and other participants in bone metabolism are complex and result in pathologic bone physiology. Ra-223, a targeted alpha therapy, accumulates at sites of bone metastases and prolongs survival. Ra-223 and docetaxel (D), acting through different mechanisms of action, may have beneficial effects on bone pathophysiology and tumor microenvironment. Prior data suggest treatment with Ra-223 results in favorable alterations in bone biomarkers that are associated with survival. Methods: 53 patients with progressing CRPC and ≥ 2 bone metastases were randomized 2:1 to Ra-223 (55 kBq/kg q6wk × 5) + D (60 mg/m² q3wk × 10) versus D (75 mg/m² q3wk with step-down option to 60 mg/m²). Bone resorption (CTX-1, ICTP) and formation (P1NP, bALP) markers, tALP, and PSA were analyzed at wk 19 (after 3 Ra-223 injections) and 3 wk after end of treatment (EOT). Results: Mean % change at wk 19 and EOT are shown (Table). tALP, bALP, P1NP, and PSA declined early during treatment, reaching an average of > 30% decline from baseline by wk 19 in both arms. Mean % declines were greater in the Ra-223 + D versus the D-alone arm at wk 19 and EOT. Bone resorption markers CTX-1 and ICTP showed little decline at wk 19. Conclusions: Ra-223 + D patients had greater % decline in tALP and in bone formation markers bALP and P1NP. Due to small patient numbers and preliminary data, further analysis and correlation with clinical outcomes in a larger study is warranted. Clinical trial information: NCT01106352