Glucocorticoid-induced osteoporosis (GIOP) is the most common form of secondary osteoporosis. To date, six large randomized controlled clinical trials on the efficacy of pharmaceutical treatment in GIOP have been conducted. All of these studies have focused predominately on bone mineral density outcomes, and none of them have been statistically powered to address fracture endpoints. The purpose of this review is to highlight differences in the design and results within these large randomized GIOP clinical trials, and how these differences might affect clinical decisions. Differences between studies in trial design, populations studied, and variable efficacy impact the comparability and generalizability of these findings, and ultimately should affect practitioners’ behavior. We review the clinical trials that provide the best quality evidence on comparative efficacy and safety of GIOP treatments. We also propose suggestions on the design of future GIOP clinical trials with attention to improved generalizability, and, ideally, study designs that might achieve fracture outcomes.