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

β-thalassemia major (TM) is often accompanied by osteopenia or osteoporosis. 1,2 Bisphosphonates have been used in the management of TM-induced bone loss. [3][4][5][6][7] We report here the results of the long-term follow-up of our TM patients with osteoporosis who participated in a randomized, placebo-controlled trial with zoledronic acid (ZOL), the results of which at 12 months had been previously reported. 5 According to that study, 66 patients with TM-induced osteoporosis (21M/45F; median age 35.5 years) were studied. Patients were blindly randomized to receive 4 mg ZOL, iv, in 15 min. infusion, every six months (group A, n=23) or every three months (group B, n=21), or to receive placebo every three months (group C, n=22), for a period of one year.Patients of groups A and B then discontinued ZOL treatment, while patients of group C were given 4 mg ZOL, every three months, for 12 months, and subsequently stopped ZOL therapy. 5 Informed consent was obtained from all patients prior to inclusion in the study. The study was conducted with the approval of the Greek National Drug Organization Committee (Ref. No Aα-K∆-79/01/03) in keeping with the guidelines of Helsinki. Bone Mineral Density of the lumbar spine (L1-L4), femoral neck (FN) and wrist was evaluated in all patients prior to starting therapy and then after 12 and 36 months, using DEXA. 5 Serum markers of bone remodeling [C-telopeptide of collagen type-I (CTX) and bonespecific alkaline phosphatase (bALP)] were measured in patients and in a control group of 40, age and gendermatched, healthy blood donors, as previously described. 5 Patients were asked to quantify their degree of bone pain on Huskisson's visual analog scale (VAS) and the McGill-Melzack scoring system before entering the trial, and then every six months for 36 months. Statistical analysis was described in our initial report. 5 Patients of groups A and C showed no differences in BMD of all evaluated sites at the 12 th month, while patients of group B achieved a significant increase only in their L1-L4 BMD 5 (Figure 1A-1C). ZOL also reduced bone pain in groups A+B, while there was no pain relief in the placebo group after 12 months of therapy (Table 1). Similar results have been described in two subsequent trials where ZOL was given in TM patients with osteoporosis for 12 months 6,7 confirming the beneficial effect of ZOL in this setting. However, the treatment duration has not been clarified in any trial.Our patients were followed for 24 months after discontinuation of ZOL for groups A and B, and for 12 months for group C. Interestingly, at the 36 th month, patients of both groups A and B showed a significant increase in BMD of all studied sites compared with baseline values (p<0.01) (Figure 1A-1B). Patients of group C, who had received ZOL for 12 months after the placebo period, also increased their BMD of all studied sites at the 36 th month (p<0.01; Figure 1C), while they also reduced bone pain scores (Table 1). Furthermore, there was no more difference in BMD T-values of L1-L4 and forearm b...

Talasemi Osteoporozunda Zoledronik Asit Kullanımı: İki Olgu Sunumu ve Literatürün Gözden Geçirilmesi

“…Voskaridou ve arkadaşlarının (16) çalışmasında 1 yıl süreyle bir gruba 6 ayda bir İV 4 mg zoledronat, diğer gruba 3 ayda bir İV 4 mg zoledronat, bir diğer gruba ise 3 ayda bir plasebo tedavisi verilmiş, 3 ayda bir İV 4 mg zoledronat alan hastaların lomber omurga KMY'lerinin arttığı, plasebo grubunda ise değişmediği bulunmuştur. Takip eden bir yayınlarında zoledronatın kesilmesinden sonra da etkisinin devam ettiğini bildirmişlerdir (17). Perifanis ve arkadaşlarının (18) yaptığı çalışmada 12 ay boyunca her 3 ayda bir 1 mg İV zoledronat tedavisi uygulanmış ve lomber omurga KMY'sinde artış tespit edilmiştir.…”

“…Olguların lomber KMY ölçümlerinde belirgin düzelme saptanmış ve tedaviye başlandıktan sonra yeni kırık oluşmamıştır. Birinci olguda tedavi aralıklarının daha sık olmasının sebebi sık kırık öyküsü olmasıdır ve bu konu ile ilgili yapılan yayınlarda da farklı aralıklarla uygulamalar yapılmıştır (2,(16)(17)(18)(19).…”

“…Zoledronat tedavisinin eritropoietik aktiviteyi arttırdığı (23) ve bunun da tedavi kesildikten sonra bile KMY'de uzun dönem artmaya neden olduğu gösterilmiştir (17). Tedavi ile kemik rezorbsiyon ve formasyon belirteçlerinin azalması ilacın kemik döngüsünü azaltarak etki gösterdiğini düşündürmektedir (6).…”

Serum Dickkopf-1 is increased and correlates with reduced bone mineral density in patients with thalassemia-induced osteoporosis. Reduction post-zoledronic acid administration

“…The characteristics of the patients and the study protocol have been previously described. 4,5 In summary, patients were blindly randomized to receive ZOL at a dose of 4 mg, iv, in 15 min infusion, every six months (group A, n=23) or every three months (group B, n=21), or to receive placebo every three months (group C, n=22) for a 12-month period.…”

“…1 Osteoclast activity is elevated in thalassemia osteoporosis, 2 and thus bisphosphonates have been used for its management. [3][4][5] Moreover, osteoblasts are also deregulated in thalassemia osteoporosis 1,6 but there is very limited data for the underlying mechanisms of this deregulation.…”