Homozygous beta-thalassemia represents a serious hemoglobinopathy, in which an amazing prolongation in the survival rate of patients has been achieved over recent decades. A result of this otherwise positive evolution is the fact that bone problems have become a major issue in this group of patients. Through an in-depth review of the related literature, the purpose of this study is to present and comment on the totality of the data that have been published to date pertaining to the prevention and treatment of thalassemia bone-disease, focusing on: the contribution of diet and lifestyle, the treatment of hematologic disease and its complications, the management of hypercalciuria, the role of vitamins and minerals and the implementation of anti-osteoporosis medical regimen. In order to comprehensively gather the above information, we mainly reviewed the international literature through the PubMed database, searching for the preventive and therapeutic data that have been published pertaining to thalassemia bone-disease over the last twenty-nine years. There is no doubt that thalassemia bone-disease is a complication of a multi-factorial etiopathology, which does not follow the rules of classical postmenopausal osteoporosis. Bisphosphonates have been the first line of treatment for many years now, with varied and usually satisfactory results. In addition, over the last few years, more data have arisen for the use of denosumab, teriparatide, and other molecules that are in the clinical trial phase, in beta-thalassemia.