Continuous Improvement of Bone Mineral Density Two Years Post Zoledronic Acid Discontinuation in Patients with Thalassemia-Induced Osteoporosis: Long-Term Follow-Up of a Randomized, Placebo-Controlled Trial.

Abstract Zoledronic acid is a third generation aminobisphosphonate with proven efficacy in patients with thalassemia major (TM) and osteoporosis. We report here the results of the long-term follow-up (36 months) of our TM patients with osteoporosis who participated in a randomized, placebo-controlled, trial with zoledronic acid. Sixty-six patients with TM-induced osteoporosis (21M/45F; median age 35.5 years) were studied. The majority of patients had pathological fractures and/or bone pain due to osteoporosis. Patients were blindly randomized to receive zoledronic acid at a dose of 4 mg, iv, in 15 min infusion, every 6 months (group A, n=23) or every 3 months (group B, n=21), or to receive placebo every 3 months (group C, n=22) for a period of one year. There was no difference in terms of gonadal dysfunction between the three studied groups. All patients were under oral calcium (500 mg) administration during study period, while hypogonadic patients were allowed to continue their hormonal replacement therapy. After the first 12 months of therapy, patients of groups A and B discontinued zoledronic acid treatment, while patients of group C were allowed to receive zoledronic acid at a dose of 4 mg, every 3 months, for 12 months and then to stop zoledronic acid therapy. Effects were monitored by measuring BMD of the lumbar spine, femoral neck and forearm using DEXA, at baseline, and then after 12 and 36 months post zoledronic acid administration. Patients were also asked to quantify their degree of bone pain on Huskisson’s visual analogue scale and the McGill-Melzack scoring system at baseline, and then every 6 months for 36 months. Patients of groups A and C showed no differences in terms of BMD of all three evaluated sites after 12 months of therapy, while patients of group B achieved a significant increase in their lumbar spine BMD (p=0.028), and a borderline increase in their femoral neck BMD. Zoledronic acid reduced bone pain in groups A+B, while there was no bone pain relief in placebo group after 12 months of therapy. Interestingly, after 36 months, patients of both groups A and B showed a dramatic increase in BMD of all studied sites compared with baseline values (p=0.001, p=0.001, and <0.001 for BMD of lumbar spine, femoral neck, and forearm, respectively). Patients of group C who received zoledronic acid for 12 months after the placebo period showed also a dramatic increase in BMD of all studied sites at 36 month (p=0.008, p=0.018, and <0.001 for BMD of lumbar spine, femoral neck, and forearm, respectively), while they also reduced significantly bone pain scores (p<0.001). At 36 month, there was no difference in terms of BMD of lumbar spine and forearm between patients of groups A and B, while BMD of the femoral neck continued to be higher in group B (either as a T-score absolute value or as a T-score percentage change; p=0.01). No skeletal related events were observed during the study period. This study suggests that zoledronic acid is an effective treatment in increasing BMD in TM-induced osteoporosis. Its effect seems to be continued even 24 months after the discontinuation of the drug. Studies with larger number of patients are required to clarify the best dose and treatment duration of zoledronic acid for the management of TM-induced osteoporosis.

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