Neridronate (NE) for the Treatment of Osteoporosis In Patients with β-Thalassemia: Results from an Italian Multicenter Randomized, Open Label, Phase II Trial

Abstract 4282

A high percentage (90%) of patients with β- Thalassemia Major suffers from osteopenia or osteoporosis. The aim of this study was to evaluate the effect of NE on Thalassemia-induced osteoporosis. NE is an aminobisphosfonate which has been proved to inhibit osteoclast-mediated bone resorption. It has been already used in the treatment of several bone disorders such as Paget's disease and Osteogenesis Imperfecta. This trial is registered with ClinicalTrials.gov. NTC01140321. Male and female patients (> 18 years) with transfusion dependent β- Thalassemia who had a BMD Z score <-2 at the level of the femoral neck or of the lumbar column and received regular transfusions in order to maintain pre-transfusional Hb values >9 g/dl were eligible. Exclusion criteria were: Thalassemia Intermedia if not regularly transfused; pregnancy and breast feeding; impaired renal function (creatinine > 1.5 mg/dl); neoplastic disease; mean levels of alanine aminotransferase (ALT) > 300 U/l and variations of aspartate aminotransferase (AST) or AST of 300% within the year before randomization (at least 4 assessments over 12 months); systemic cardiovascular, renal, hepatic disease which would prevent the patient from undergoing the study treatment; hypoparathyroidism; Thalassemia Intermedia occasionally transfused; known hypersensibility to bisphosphonates. If di-bisphosphonates iv within the past 2 years or of bisphosphonates per os had been administered, a wash out period (1 year if >8 weeks <48 weeks; 6 months if > 2 weeks and <8 weeks) was necessary before entering the trial. The trial was approved by the Coordinating Centre Ethics Committee (EC) at E.O. Ospedali Galliera in Genoa, Italy and the local EC at each participating Centre. All participants gave written informed consent before entering the study. 118 patients (51 males and 67 females) were randomized in two groups: group A (n=54) treated with NE 100 mg iv every 90 days plus 500 mg of calcium/400 UI of vitamin D daily; group B (n=64) treated with 500 mg of calcium/400 UI of vitamin D daily. The 2 groups were homogeneous at baseline with respect to age and gender. Efficacy and safety of NE were monitored via monthly Blood Cells Count, creatinine, BUN, AST, ALT, Ca, P, proteins electrophoresis, total protein readings. Bone Mineral Density (BMD) of the lumbar spine, total hip and femoral neck was performed at baseline and at month 6 and 12. Serum levels of bone alkaline phosphatase (bALP) and C-telopeptide of collagen type-I (CTX) and pain scores (questions 7 and 8 of SF-36 Questionnaire) were assessed at baseline and 3, 6 and 12 months after the start of the treatment. The mean increase of the lumbar spine BMD after 12 months was 3.3 % in group A and 0.2 % in group B, with an highly significant difference (p=0.003). After 6 months, the mean changes in lumbar spine BMD were 3.2 % and 0.1 % in group A and B respectively (p<0.001). The comparison between group A and group B showed a significant mean percent increase of the BMD in total hip and in the femoral neck (p<0.01 and p<0.05, respectively). Changes in bALP and CTX became significant as early as 3 months after the first administration in group A (p=0.015 and p<0.001, respectively), while in group B there was a borderline significance only for CTX (p = 0.048) after 3 months. Concerning question 7 of the SF-36 (physical pain in the last 4 weeks), the reduction was statistically significant after 6 months in group A (p=0.008). This result was confirmed after 12 months (p=0.001). Question 8 (pain that has hindered the usual work in the last 4 weeks) showed earlier significant reduction from the third month. One patient of group A dropped out after 6 months because of multiple fractures as a result of a traffic accident. Finally, hematologic and haematochemical and biochemical analyses did not show any clinically relevant variations. Statistically significant changes, although within the normal range, were reported for PTH, calcemia and calciuria in group A, and PTH and BUN in group B. This is the largest randomized trial designed to treat Thalassemia induced osteoporosis. NE, at the dose of 100 mg, iv, every 3 months was shown to be safe and effective both in reducing bone resorption and increasing BMD. Moreover it was shown to be effective in reducing back pain and it has a clinically manageable safety profile at a very affordable price and, being administered once every three months does not interfere with the life of patients already burdened with many treatments.