Intravenous zoledronic acid treatment in thalassemia ... - Springer Link

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Intravenous zoledronic acid treatment in thalassemia-induced osteoporosis: results of a phase II clinical trial. Received: 8 March 2006 / Accepted: 22 April 2006 ...
Ann Hematol (2006) 85: 605–609 DOI 10.1007/s00277-006-0136-y

ORIGINA L ARTI CLE

Zaher K. Otrock . Sami T. Azar . Wael A. Shamseddeen . Dany Habr . Adlette Inati . Suzane Koussa . Rami A. R. Mahfouz . Ali T. Taher

Intravenous zoledronic acid treatment in thalassemia-induced osteoporosis: results of a phase II clinical trial Received: 8 March 2006 / Accepted: 22 April 2006 / Published online: 8 July 2006 # Springer-Verlag 2006

Abstract Osteoporosis is an important cause of morbidity in beta-thalassemia patients. Bisphosphonates have been recently used for the treatment of osteoporosis in betathalassemia. This study is a prospective quasi-experimental study to assess the efficacy and safety of zoledronic acid in thalassemics with osteoporosis. Eighteen thalassemia patients with osteoporosis were given zoledronic acid 4 mg intravenously every 3 months over a period of 12 months. The efficacy of treatment was assessed by measuring bone mineral density (BMD) at the lumbar spine, femoral neck, and hip at baseline, 6, and 12 months. Z-score was used to measure the BMD. Other medical assessments included markers of bone formation and resorption (bone alkaline phosphatase (BAP), osteocalcin (OC), and urinary deoxypyridinoline), and the assessment of pain score, analgesic score, and performance score. Ten thalassemic osteoporotic patients were followed up only with serial BMDs as controls. Both groups had no Z. K. Otrock . S. T. Azar . W. A. Shamseddeen . A. T. Taher Department of Internal Medicine, American University of Beirut-Medical Center, P.O. Box 113-0236, Riad El-Solh St., 1107–2020, Beirut, Lebanon D. Habr Novartis Pharma Services, Beirut, Lebanon A. Inati . S. Koussa . A. T. Taher Chronic Care Center, Hazmieh, Lebanon R. A. R. Mahfouz Department of Pathology and Laboratory Medicine, American University of Beirut-Medical Center, Beirut, Lebanon A. T. Taher (*) Hematology–Oncology Division, Department of Internal Medicine, American University of Beirut-Medical Center, P.O. Box 113-0236 Beirut, Lebanon e-mail: [email protected] Tel.: +961-3-755669 Fax: +961-1-370814

significant difference with respect to age, gender, and baseline BMD. Patients taking zoledronic acid had a significant increase in their lumbar spine, femoral neck, trochanter, and total hip BMD measurements over the 12-month period. Patients in the control group did not have any significant change in BMD measurements. There was a significant change in the levels of OC and BAP over the 12-month follow-up period. There was also a significant decrease in the number of painful sites experienced by the patients. Treatment of thalassemic osteoporotic patients with zoledronic acid is very effective in increasing BMD at the lumbar spine and hip and in reducing pain; it is also well-tolerated. Keywords Clinical trial . Osteoporosis . Thalassemia . Zoledronic acid

Introduction Thalassemia is a hereditary disease caused by defective globin synthesis resulting in abnormal as well as decreased quantity of globin chains. The life expectancy of betathalassemia patients has markedly improved over the last years as a result of regular blood transfusions and compliance with tight iron chelation therapies [1]. However, beta-thalassemia patients still suffer from many complications of their chronic disease, including bone involvement. Bone disease in thalassemia is manifested by diffuse bone pain, spinal deformities like scoliosis, nerve compression, and various degrees of osteopenia, osteoporosis, and spontaneous fractures [2]. In fact, osteopenia and/or osteoporosis are major causes of morbidity in these patients who are surviving longer as a result of improved treatment [3]. The etiology of bone disease in thalassemia appears to be multifactorial and is still under investigation. Several factors may affect bone metabolism and turnover in betathalassemia patients, such as bone marrow expansion due to increased erythropoiesis, endocrine complications, iron overload and desferrioxamine chelation therapy, vitamins

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and trace minerals deficiencies, physical activity, and genetic factors [4]. Marrow expansion causes mechanical interruption of bone formation, leading to cortical thinning, and is considered a main reason of distortion and fragility of the bones in thalassemia patients. Despite the normalization of hemoglobin levels, adequate hormone replacement, and effective iron chelation, thalassemic patients continue to show an unbalanced bone turnover and an increased resorption resulting in seriously diminished bone mineral density (BMD) [5]. The frequency of osteopenia or osteoporosis in well-treated thalassemic patients has been reported to be approximately 40–50% [6–8]. The increased bone resorption observed in patients with thalassemia-induced osteoporosis has led to the use of bisphosphonates in these patients, as these agents represent the treatment of choice for most patients with osteoporosis. Bisphosphonates are potent inhibitors of osteoclastic bone resorption and they act by inhibiting osteoclastic recruitment and maturation, preventing the development of monocyte precursors into osteoclasts, inducing osteoclast apoptosis, and interrupting their attachment to the bone. The decrease of bone resorption due to bisphosphonates is accompanied by an increase in calcium balance and mineral content of bone [9]. In thalassemia-induced osteoporosis, almost all generations of bisphosphonates have been used to increase the BMD and improve the abnormal bone remodeling in these patients [4]. Zoledronic acid, the most potent thirdgeneration bisphosphonate available, was only used in one recent study to treat patients with transfusion-dependent beta-thalassemia and severe osteoporosis at a dose of 1 mg intravenously every 3 months over a 12-month period [10]. The present paper reports a clinical study of the efficacy and safety of zoledronic acid, administered at a dose of 4 mg intravenously every 3 months over 12 months to 18 patients with beta-thalassemia and osteoporosis.

Materials and methods Eighteen thalassemic patients (13 thalassemia major and 5 intermedia) with osteoporosis defined as z-score