Bisphosphonates are potent inhibitors of bone resorption, widely used for the management of osteoporosis and fracture prevention. Recent evidence suggests that bisphosphonates may have beneficial effects in the treatment of thalassemia-associated osteoporosis, a complex and multifactorial condition. Here we summarise available data about the efficacy and tolerability of bisphosphonates in beta--thalassemic patients. Randomised controlled trials (RCTs) of bisphosphonates in beta-thalassemia were identified searching PubMed. Studies were reviewed to retrieve relevant clinical information. The following variables were considered to assess the safety and efficacy of bisphosphonates-bone mineral density (BMD), markers of bone turnover, incidence of fragility fracture, bone pain, back pain, and clinical adverse events. Five RCTs were identified, investigating alendronate, clodronate, zoledronic acid and neridronate. All bisphosphonates produced a significant decrease of the markers of bone turnover. Alendronate, neridronate, and zoledronic acid significantly improved BMD at the lumbar spine, femoral neck and total hip. Zoledronic acid and neridronate were also shown to reduce bone and back pain. Probably due to the small sample sizes and to the short duration of the trials, it was not possible to establish the anti-fracture efficacy of bisphosphonates; however, they were well tolerated and adverse events were rare but expected on the basis of previous studies. Sufficient evidence exists to support the use of bisphosphonates in the management of thalassemia-associated osteoporosis (to prevent bone loss and improve the BMD). Further research is warranted to establish their anti-fracture efficacy and long-term safety.