Background: We studied 265 men (mean age 56.4. years; range 18-83. years), among patients enrolled in two arms of a double-blind, 1-year study comparing the effects of zoledronic acid (ZOL) with risedronate (RIS) in patients either commencing (prednisolone 7.5. mg/day or equivalent) (prevention arm, n = 88) or continuing glucocorticoid therapy (treatment arm, n = 177). Methods: Patients received either a single ZOL 5. mg infusion or RIS 5. mg oral daily at randomization, along with calcium (1000. mg) and vitamin D (400-1200. IU). Primary endpoint: difference in percentage change from baseline in bone mineral density (BMD) at the lumbar spine (LS) at 12. months. Secondary endpoints: percentage changes in BMD at total hip (TH) and femoral neck (FN), relative changes in bone turnover markers (β-CTx and P1NP), and overall safety. Findings: In the treatment subpopulation, ZOL increased LS BMD by 4.7% vs. 3.3% for RIS and at TH the percentage changes were 1.8% vs. 0.2%, respectively. In the prevention subpopulation, bone loss was prevented by both treatments. At LS the percentage changes were 2.5% vs. -0.2% for ZOL vs. RIS and at TH the percentage changes were 1.1% vs. -0.4%, respectively. ZOL significantly increased lumbar spine BMD more than RIS at Month 12 in both the prevention population (p = 0.0024) and the treatment subpopulation (p = 0.0232) in men. In the treatment subpopulation, ZOL demonstrated a significantly greater reduction in serum β-CTx and P1NP relative to RIS at all time-points. In the prevention subpopulation, ZOL significantly reduced β-CTx[U+F020] at all time-points, and P1NP at Month 3 (p = 0.0297) only. Both treatments were well tolerated in men, albeit with a higher incidence of influenza-like illness and pyrexia events post-infusion with ZOL. Interpretation: Once-yearly ZOL preserves or increases BMD within 1. year to a greater extent than daily RIS in men receiving glucocorticoid therapy. © 2011.