We determined the comparative efficacy of vitamin D, calcitonin, fluoride, and bisphosphonates for the management of corticosteroid-induced osteoporosis using meta-regression models. A systematic search for trials was conducted using MEDLINE, bibliographic references, abstracts from national meetings, and contact with pharmaceutical companies and content experts. We included all randomized controlled trials, lasting at least 6 months, of adult patients on oral corticosteroids that evaluated treatment comparisons between vitamin D, calcitonin, bisphosphonates, or fluoride either with no therapy/calcium or with each other and that reported extractable results. The outcome measure of interest was change in lumbar spine bone mineral density (BMD). We identified 45 eligible trials, which provided 49 eligible treatment comparisons (some trials had three arms or more). Our results indicated that bisphosphonates were the most effective class (effect size 1.03; 95% CI: 0.85, 1.17); results were similar even when newer generations of nitrogen-containing bisphosphonates were excluded from analysis. We found the efficacy of bisphosphonates was enhanced further when used in combination with vitamin D (effect size, 1.31; 95% CI: 1.07, 1.50). Vitamin D and calcitonin were more effective than no therapy/calcium (effect size, 0.46; 95% CI: 0.27, 0.62; and effect size, 0.51; 95% CI: 0.33, 0.67, respectively) and were of similar efficacy, but both were significantly less effective than bisphosphonates. Fluoride appeared effective, but there were too few studies (n = 5) to draw robust conclusions regarding its efficacy compared with the other three therapies. In summary, bisphosphonates are the most effective of evaluated agents for managing corticosteroid-induced osteoporosis. The efficacy of bisphosphonates is enhanced further with concomitant use of vitamin D.