The natural history of beta thalassemia major (TM) has significantly changed during the last 2 decades. At present TM patients survive over their thirties and forties, but they have considerable morbidity. Bone demineralization is an important cause of morbidity in older patients; the etiology is multifactorial and partially unknown. We examined cross-sectionally 111 adult TM patients (66 females and 45 males, 32.6 ± 6 years), regularly transfused, properly chelated and replaced for endocrine defects. Bone demineralization was detected in 92.7% of patients, with different severity according to gender and site: osteopenia was the prominent finding at the femur, osteoporosis at lumbar spine (p<0.001), more evident in males. The femoral site was more influenced by biochemical and clinical factors; despite adequate replacement, femoral T-score was lower in the hypogonadic than in the eugonadic group (p =0.047). A significant correlation was found between bone mass and body mass index (BMI), alkaline phosphatase (ALP) and pre-transfusional Hb levels. Multivariate analysis indicated as significant regressors ALP, BMI and hypoparathyroidism (T-score: p=0.005, 0.035, 0.002; Z-score: 002, 0.009, 0.003, respectively) at femur, only ALP at lumbar spine (p= 0.008 and 0.045 for T and Z scores, respectively). Statistical significance was reached more frequently by T-score, while Zscore demonstrated to have a lower sensitivity. Despite best care facilities, bone demineralization in thalassemic patients remains a challenge; further exploration of the relationships between bone loss and endocrine, biochemical and hematologic variables is warranted to find effective measures to reduce bone pain and fracture risk.Response to Reviewers: We are grateful for the useful suggestions of the reviewers. We have revised our paper following their recommendations.Reviewers' comments: 1) In the Discussion session they comment that "....the correlation between alkaline phosphatase and bone mineralization indicates a prevalent role of reduced deposition over increased reabsorption, as reported by other Authors, at variance with others. We could not confirm the same relationship with osteocalcin, another marker of osteoblastic activity.".First of all the authors have not measured any of the markers of bone resorption. I believe that it is important for the paper and for the the discussion to include at least NTX or CTX measurements. I hope that they have available serum for such measurement. I suggest that CTX is more sensitive than NTX in the serum.-In the original paper, we did not include any marker of bone resorption because we had only partial data (different markers, incomplete series). It seems now evident that the importance of these indices to our work has been understated. In effect, we had available serum of most patients, so we decided to measure CTX following the useful suggestion of the reviewer; we recognize that this adjunct increases the scientific interest of our results. As pointed out in the revised paper (page 8, l...