Osteopenia-osteoporosis syndrome (OOS) causes considerable morbidity in 60-80% β-thalassemia major (β-TM) patients. We evaluated the effect of sex hormone replacement therapy (HRT) in β-TM patients with hypogonadism presenting with OOS using premature ovarian failure (POF) for comparative purposes. We undertook a 10-year prospective study of in 50 β-TM and 375 patients with POF and OOS. All were treated with HRT for 2-5 years. We used dual X-ray absorptiometry (DEXA), and plasma type 1-collagen markers of bone turnover for monitoring of response to therapy. Our results suggest that prior to HRT, both groups had comparable degrees of OOS. Both groups had significant improvement but the POF group had normalization of spinal T scores following HRT in contrast to the β-TM patients. Femoral T scores did not normalize in both groups. These data indicate for the first time from comparative POF control studies that hypogonadism is not the only cause of OOS in β-TM.