Abstract

Background: Beta-thalassemia is an inherited disorder of hemoglobin synthesis with many associated morbidities. Osteoporosis is an important cause of morbidity in these patients. Bisphosphonates are potent inhibitors of osteoclast activity and have been recently used for the treatment of osteoporosis in beta-thalassemia. Several studies have indicated that the vitamin D receptor (VDR) gene has a role in the regulation of bone mineral density (BMD) and bone metabolism, but the results are very controversial. The aim of this study is to assess the effectiveness and safety of zoledronic acid in Lebanese thalassemics with osteoporosis.

Methods: We studied 23 patients with beta-thalassaemia major (14 patients) and intermedia (9 patients). Thirteen patients were male and 10 were female, with a mean (+/− standard deviation) age of 25 +/− 9 years. All patients had severe osteoporosis and were receiving calcium and vitamin D supplements prior to and during the study. Zoledronic acid was given i.v. at a dose of 4 mg every 3 months over 12 months. The effects were monitored by assessing pain score, analgesic score and performance score. The BMD of the hip and lumbar spine, osteocalcin, bony alkaline phosphatase and pyrrolidine crosslinks were also measured. To gain more insight into the genetic basis of osteoporosis in thalassemia and to correlate this with the response to zoledronic acid, we analysed the polymorphism of the VDR gene in three polymorphic sites (Bsm I, Taq I and Apa I) using restriction enzymes digestion.

Results: We have given two doses of zoledronic acid uptil now. The most common adverse event was joint pain in 12 patients (52.2%) lasting for 1–3 days and responding to analgesics. Four patients had perioral numbness and five had fever. These adverse events were markedly reduced after the 2nd dose; only two patients had joint pain. No patients discontinued the study until now. The pain scores, analgesic score and performance score were all improved compared to baseline values. The difference in pain index score was significant (p=0.004), and the reduction in the number of painful sites was slightly significant (p=0.097). There was significant difference in the baseline z score of the spine between transfusion dependent patients (15 patients) and transfusion non-dependent patients (8 patients) (p = 0.042).

The distributions of VDR alleles in Bsm I polymorphism were 30.4% for BB, 52.3% for Bb, and 17.3% for bb; in the Apa I polymorphism 17.4% for AA, 47.8% for Aa, and 34.8% for aa; in Taq I polymorphism 30.4% for TT, 52.3% for Tt, and 17.3% for tt. We found no significant differences in baseline BMD between the three groups of Bsm I polymorphism at all sites. Apa I was not associated with significant differences in BMD. The BMD of the Ward’s triangle was higher in patients with the Tt-genotype compared with individuals with the tt-genotype and the difference was almost significant (p=0.089, ANOVA).

Conclusions: In Lebanese thalassemics with osteoporosis zoledronic acid (a dose of 4 mg) is well tolerated and the clinical response is quite impressive. However, the response to treatment needs to be assessed by follow-up BMDs and blood bone markers.

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