Osteoporosis represents a prominent cause of morbidity in patients with thalassemia. The delay in sexual maturation, the presence of diabetes and hypothyroidism, the parathyroid gland dysfunction, the progressive marrow expansion, the iron toxicity on osteoblasts, the iron chelators, and the deficiency of growth hormone or insulin growth factors have been identified as major causes of osteoporosis in thalassemia. Adequate hormonal replacement, effective iron chelation, improvement of hemoglobin levels, calcium and vitamin D administration, physical activity, and smoking cessation are the main to-date measures for the management of the disease. During the last decade, novel pathogenetic data suggest that the reduced osteoblastic activity, which is believed to be the basic mechanism of bone loss in thalassemia, is accompanied by a comparable or even greater increase in bone resorption. Therefore, the role of bisphosphonates, potent inhibitors of osteoclast activation, arises as a major factor in the management of osteoporosis in thalassemia patients.