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Effect of Pamidronate on osteoporosis in patients with β-thalassemia major

Article · January 2014

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 ORIGINAL ARTICLE

IJBC 2014;6(3): 149-153

Effect of Pamidronate on Osteoporosis in Patients

with β-Thalassemia Major
Naderi M 1, Zakeri Z 2*, Dorgalaleh A 3, Alizadeh SH 3 , Tabibian SH 3, Bamedi T 1
1. Genetics of Non-Communicable Disease Research Center, Zahedan University of Medical Sciences, Zahedan, Iran.
2. Clinical Research and Development Center, Ali Ebn-e Abitaleb Hospital, Zahedan University Of Medical Sciences,
Zahedan, Iran.
3. Allied Medical School, Tehran University of Medical Sciences, Tehran, Iran.

*Corresponding Author: Zakeri Z , Email: naderifactorxiii@yahoo.com

Submitted: 04-12-2013 , Accepted: 29-04-2014

Abstract
Background: β-thalassemia major is a hereditary life threatening anemia which requires regular blood transfusion.
Clinical symptoms of the disease are growth retardation, pallor, jaundice and skeletal alternations. The variety of bone
disease in thalassemia major is manifested by diffuse bone pain or deformity, spontaneous and pathologic fractures
and osteopenia or osteoporosis. This study aimed to evaluate the effect of Pamidronate on beta thalassemia major
induced osteoporosis.
Patients and Methods: This cross sectional study was conducted on 20 patients with β-thalassemia major with
osteoporosis. Patients received Pamidronate injections (30 mg in equal intervals of one month) for one year. At the
beginning and the end of study period (after twelve months of treatment) patients’ BMD and Z score of lumbar spine
and Hip were determined.
Results: The mean baseline BMD of lumbar spine and hip among patients were 097/0±720/0(gr/cm²) and 083/0±684/0
(gr/cm²) respectively which at the end of the study these numbers reached to 100/0±783/0(gr/cm²) (p<0.001) and
097/0±713/0(gr/cm²) (p=0.015) respectively. The mean baseline Z score of lumbar spine and hip for patients were
/0±98/2-956 and 727/0±96/1- before treatment (one full year of treatment) that reached 886/0±44/2- (p=0.001) and
856 /0±47/1- (p=0.003) respectively. The baseline alkaline phosphatase was 94/89±85/385 µg/dl and after treatment
this value decreased to 66/113±95/251µg/dl (p<0.001).
Conclusion: The Pamidronate is effective in increasing the bone mineral density and improving the osteoporosis
condition in patients with β-thalassemia major.
Keywords: Osteoporosis, BMD (Bone Mineral Density), β-thalassemia major, Pamidronate.

Introduction
The term thalassemia stems from the Greek, major occurs between 6 and 24 months after the
thalassa (sea) and hemia (blood).This disorder birth and affected infants are identified by growth
is classified into two major types, α-thalassemia retardation, pallor, jaundice, hepatosplenomegaly,
and β-thalassemia. β-thalassemia syndromes progression of masses from extra medullary
are a group of hereditary blood dysfunctions hematopoiesis, and skeletal alternations resulting
characterized by unbalanced β-globin chain from expansion of the bone marrow 5. The variety
synthesis, resulting in decreased Hb, diminished of bone diseases in thalassemia major patients
RBC production and anemia with ineffective are manifested by diffuse bone pain or deformity,
erythropoiesis and increased peripheral hemolysis. fail to thrive, scoliosis, nerve compression, spinal
It consists of three main forms: thalassemia major, deformities, spontaneous and pathologic fractures
thalassemia intermedia and thalassemia minor 1, 2. and osteopenia or osteoporosis 6, 7.
β-thalassemia major (TM) is a hereditary Osteopenia and osteoporosis are one of
hemolytic anemia that requires regular blood the common complications, especially in adult
transfusions and most affected people are TM patients and they are prominent causes
Mediterranean 3, 4. Clinical symptoms of thalassemia of morbidity in patients of both genders who
IRANIAN JOURNAL OF BLOOD AND CANCER Volume 6 Issue 3 Spring 2014 149
Naderi et al.
survive longer as a result of better treatment with high affinity for bone minerals that attach to
methods 8, 9. The pathogenesis of osteoporosis in sites of elevated bone resorption or production
TM is very complicated and several genetic and and act by inhibiting osteoclastic recruitment,
acquired factors are implicated in the incidence intercepting the development of monocyte
of bone diseases among TM patient, including precursors into osteoclasts, evolving osteoclast
hypogonadism, growth hormone (GH) and insulin apoptosis and discontinuing of their attachment to
growth factor-(IGF)-1 deficiency, hypothyroidism, the bone and thus, increasing the BMD , diminishing
ineffective haemopoiesis with progressive marrow the markers of bone resorption and prevention of
expansion and direct iron toxicity on osteoblasts 10. bone fractures 15.
Among these factors are hypogonadism and Along with previous studies this investigation
delayed puberty causing enhanced resorption of aimed to evaluate the effect of Pamidronate on
bone and interference with bone reconstruction by thalassemia major-induced osteoporosis.
inhibiting osteoblast activation and/or increasing
osteoclast function 11. Neoplastic disorders, Patients and Methods
gastrointestinal disorders, inflammatory conditions, Study population
and drugs may also cause osteoporosis 9. Genetic This clinical trial study was conducted on 20
factors seem to play an important role in the patients with thalassemia major disease during
pathogenesis of postmenopausal osteoporosis and April 2012 to May 2013. Written consent was
osteoporotic fractures. In TM patients, heightened obtained from each participant and the study
markers of bone resorption such as serum alkaline was approved by the medical ethics committee of
phosphatase (sALP), osteocalcin (OC), serum levels Zahedan University of Medical Science.
of tartrate-resistant acid phosphatase isoform 5b
(TRACP-5b), pyridinoline, deoxypyridinoline, urinary Study protocol
levels of N-telopeptides of collagen type I (NTX) Inclusion criteria for the present study were
and elevated ratio of (receptor activator of nuclear having B-thalassemia major, BMD< -2.5, serum
factor-kappa B ligand)/OPG (osteoprotegerin) that ferritin level > 1000 mg/dl, more than 10 sessions
seem to account for increased osteoclastic activity, of blood transfusion or having received more
diminished bone mineral density and consequently than 100 cc/kg of blood up to the study time,
bone diseases, are observed 12, 13. normal serum creatinine level and also normal
Pamidronate, a second generation of amino complete blood count (CBC). Exclusion criteria
bisphosphonates has been used intravenously at were history of bone diseases, leukemia or other
a monthly dose of 30 mg depending on patient’s neoplastic disorders, gastrointestinal disorders or
condition with minimal side effects for prevention inflammatory conditions during the study.
and treatment of osteoporosis 14. Bisphosphonates All patients were first interviewed by a trained
are strong inhibitors of osteoclastic bone resorption staff to complete a detailed questionnaire regarding

Table 1: Comparison of the BMD and Z score of the lumbar spine and hip before and after treatment.

Region Analysis Before After twelve Change P Value

treatment months of
treatment
Lumbar BMD(gr/cm²) 0.720±0.097 0.783±0.100 -06/0 <0.001

spine Z score -2.98±0.956 -2.44±886 -0.53 0.001

Hip BMD(gr/cm²) 0.684±0.083 0.713±0.097 -0.029 0.015

Z score -1.96±0.727 -1.47±0.856 -0.48 0.003

150 IRANIAN JOURNAL OF BLOOD AND CANCER

 Effect of Pamidronate on Osteoporosis …
demographic data and previous medical history (p=0.001) (Table 1).
including age, gender, height, weight, duration The baseline BMD of hip was 083/0±684/0(gr/
and frequency of blood transfusion. In addition, all cm²) that after treatment, reached to
participants were questioned about any symptoms 097/0±713/0(gr/cm²) (p=0.015) (Table 1). The base
like bone pain and life quality changes during clinical line Z scores of the hip region was 727/0±96/1-
examinations every two months. Selected patients which reached to 856/0±47/1- (p=0.003) (Table 1).
were under regular blood transfusion once about The baseline alkaline phosphatase was
every 3 to 4 weeks and all were on chelation therapy 94/89±85/385 µg/dl that after treatment this value
by standard protocol. Patients with BMD score decreased to 66/113±95/251µg/dl (p<0.001).
(measured by dual energy X-ray absorptiometry
(DXA) method) of less than -2.5, at the beginning Discussion
of study, were considered osteoporotic. All patients Osteoporosis in TM patients is a prominent
regularly received three-hour intravenous (IV) cause of morbidity in both genders 16. The etiology
infusion of Pamidronate (Caspian Pharmaceutical of the bone disease in these patients is very complex
Companies, Tehran, Iran) in doses of 30 mg in equal and multifactorial. It is commonly accepted that its
intervals of one month for one year. All patients main causes include factors primarily interfering
also received calcium and vitamin D supplementary with bone reconstruction, such as aging, genetic
treatment and patients with hypogonadism also abnormalities of osteogenesis especially COLIA1
underwent hormone replacement therapy (HRT). gene polymorphism, defective certain nutritional
During the entire period of the study, patients were elements including vitamin D deficiency or physical
regularly checked by physical examination and also activity, elevated iron stores, desferrioxamine
by hematological (CBC) and biochemistry (Alkaline toxicity and endocrine disorders mainly estrogen
phosphatase, ferritin and serum iron) laboratory deficiency which cause increased resorption 17.
analysis. For evaluation of treatment efficacy, BMD The primary disease, itself may make a mechanical
and Z-score of patients’ hip and lumber regions interruption of bone production through bone
were measured at the beginning and at the end of marrow expansion, leading to cortical thinning,
the study. The Z-score is the number of standard augmented distortion and fragility of the bones.
deviations above or below the average for age- and Moreover, changes in the RANK/RANKL/OPG
sex-matched control subjects. system in favor of osteoclasts seem to have a
serious influence on the impaired bone metabolism
Statistical analyses in the bone disease. Patients show an enhanced
Data was collected during the entire period of resorptive phase resulting in seriously decreased
the study and analyzed by SPSS statistical software. bone mineral density (BMD), indirectly indicating
Paired-t test was applied to compare variable an increase in osteoclastic activity 18. One of the
changes before and after treatment. Statistical therapeutic approaches, which have so far been
significance was based on two-sided design-based suggested to prevent or manage osteoporosis in
tests evaluated at the 0.05 level of significance. thalassemia, and aims to emend one or more of the
above disturbances, is Pamidronate. This medicine
Results results in increased bone mineral density and
For a total of 20 patients (all women) the mean prevention of bone fractures through inhibiting
age was 23.1±3.3 years (range 18-31 years). The osteoclastic recruitment and maturation 19.
mean weight and height were 42±8 kg and 152±5 In this study we evaluated the effect of
cm respectively. Pamidronate treatment on thalassemia major-
The mean baseline BMD of lumbar spine induced osteoporosis by determination of BMD
was 097/0±720/0(gr/cm²) that after one year of and Z score of the lumbar spine and the hip
treatment with Pamidronate reached 100/0±783/0 region. There are a few similar studies which have
(gr/cm²) (p<0.001) (Table 1). assessed the effect of this drug on improvement of
The baseline mean of the Z score for lumbar osteoporosis in patients with thalassemia.
region was 956/0±98/2- that at the end of study In our study, prescription of Pamidronate
period of 12 months reached 886/0±44/2- injections with a dose of 30 mg/month caused

Volume 6 Issue 3 Spring 2014 151

Naderi et al.
significant increase of BMD that showed the 3. Arisal O, Deviren A, Fenerci E, Hacihanefioglu S,
effectiveness of this drug in improving the Ulutin T, Erkmen S, et al. Polymorphism analysis
osteoporosis among thalassemia patients. Our in the COLIA1 gene of patients with thalassemia
results also indicated that Pamidronate causes major and intermedia. Haematologia (Budap).
significant change in Z score of β-thalassemia major 2002;32(4):475-82.
patients with osteoporosis. Measurement of serum 4. Gaudio A, Morabito N, Xourafa A, Macri I, Meo
alkaline phosphatase also revealed a decrease after A, Morgante S, et al. Bisphosphonates in the
administration of Pamidronate that itself was an treatment of thalassemia-associated osteoporosis.
indicator of osteoporosis improvement. J Endocrinol Invest. 2008;31(2):181-4.
In a similar study, Terpos et al. have shown 5. Haidar R, Musallam KM, Taher AT. Bone disease and
the effect of 15 mg of Pamidronate injection per skeletal complications in patients with β thalassemia
month on increasing the BMD in TM patients with major. Bone. 2011;48(3):425-32.
osteoporosis 16. In another evaluation, Voskaridou 6. Bielinski B, Darbyshire P, Mathers L, Boivin C,
et al. in 2003 indicated the effect of Pamidronate Shaw N. Bone density in the Asian thalassaemic
in thalassemia major-induced osteoporosis and population: a cross‐sectional review. Acta Paediatr.
postmenopausal women through increased 2001;90(11):1262-6.
BMD and diminishing the markers of osteoclast 7. Arjmandi Rafsanjani K, Razzaghy-Azar M, Zahedi-
function including TRACP-5b, NTX, OPG, and Shoolami L, Vossough P, Modarres A, Taheri N.
RANKL 12. In another study Brumsen et al. in 2002 Bone Mineral Density in β Thalassemia Major and
have shown that Pamidronate administration Intermedia, Correlation with Biochemical and
causes the increase of BMD and decrease of Hormonal Profiles. Iranian Journal of Blood and
bone fractures in postmenopausal and steroid- Cancer. 2009;1(4):121-7.
induced osteoporosis 20. Also Viereck et al. in 2002 8. Voskaridou E, Kyrtsonis MC, Terpos E, Skordili M,
demonstrated that Pamidronate can enhance the Theodoropoulos I, Bergele A, et al. Bone resorption
production of OPG by primary human osteoblasts, is increased in young adults with thalassaemia
thus antagonizing the osteoclast genetic activity major. Br J Haematol. 2001;112(1):36-41.
of RANKL and finally increase the BMD 21. Skeletal 9. Di Stefano M, Chiabotto P, Roggia C, Garofalo F,
assessment is important to determine the risk of Lala R, Piga A, et al. Bone mass and metabolism in
fracture in transfusion dependent thalassemia thalassemic children and adolescents treated with
patients18-23. The etiology of increased bone turn different iron-chelating drugs. J Bone Miner Metab.
over are multifactorial, but bisphosphonates such 2004;22(1):53-7.
as alendronate, pamidronate, and zolendronic 10. Lasco A, Morabito N, Gaudio A, Crisafulli A, Meo A,
acid are effective in repairing the bone mineral Denuzzo G, et al. Osteoporosis and beta-thalassemia
density20-24. Our study did not have a big sample major: role of the IGF-I/IGFBP-III axis. J Endocrinol
size and more trials are necessary to compare the Invest. 2002;25(4):338-44.
efficacy of these products in reducing fracture risks 11. Anapllotou MLG, Kastanias IT, Psara P, Evangelou
and to produce national guidelines in treatment of EA, Liparaki M, Dimitriou P. The contribution of
osteoporosis among thalassemic patients. hypogonadism to the development of osteoporosis
in thalassaemia major: new therapeutic approaches.
Conclusion Clin Endocrinol (Oxf). 1995;42(3):279-87.
The Pamidronate is effective in increasing 12. Voskaridou E, Terpos E, Spina G, Palermos J,
the bone mineral density and improving Rahemtulla A, Loutradi A, et al. Pamidronate
the osteoporosis condition in patients with is an effective treatment for osteoporosis in
β-thalassemia major. patients with betathalassaemia. Br J Haematol.
2003;123(4):730-7.
References 13. Morabito N, Gaudio A, Lasco A, Atteritano M,
1. Schrier SL. Pathobiology of thalassemic erythrocytes. Pizzoleo MA, Cincotta M, et al. Osteoprotegerin and
Curr Opin Hematol. 1997;4(2):75-8. RANKL in the Pathogenesis of Thalassemia Induced
2. Olivieri NF. The β-thalassemias. N Engl J Med. Osteoporosis: New Pieces of the Puzzle. J Bone
1999;341(2):99-109. Miner Res. 2004;19(5):722-7.

152 IRANIAN JOURNAL OF BLOOD AND CANCER

 Effect of Pamidronate on Osteoporosis …
14. Bekheirnia R, Shamshirsaz AA, Kamgar M, Bouzari
N, Erfanzadeh G, Pourzahedgilani N, et al. Serum
zinc and its relation to bone mineral density in
β-thalassemic adolescents. Biol Trace Elem Res.
2004;97(3):215-24.
15. Fleisch H. Bisphosphonates: mechanisms of action.
Endocr Rev. 1998;19(1):80-100.
16. Terpos E, Voskaridou E. Treatment options for
thalassemia patients with osteoporosis. Ann N Y
Acad Sci. 2010;1202:237-43.
17. Ralston SH. The genetics of osteoporosis. QJM.
1997;90(4):247-51.
18. Toumba M, Skordis N. Osteoporosis syndrome in
thalassaemia major: an overview. J Osteoporos.
2010;2010:537673.
19. Mehrvar A, Azarkeivan A, Faranoush M,
Mehrvar N, Saberinedjad J, Ghorbani R, et al.
Endocrinopathies in patients with transfusion-
dependent beta-thalassemia. Pediatr Hematol
Oncol. 2008;25(3):187-94.
20. Brumsen C, Papapoulos SE, Lips P, Geelhoed
Duijvestijn PHLM, Hamdy NAT, Landman JO, et
al. Daily Oral Pamidronate in Women and Men
With Osteoporosis: A 3 Year Randomized Placebo
Controlled Clinical Trial With a 2 Year Open
Extension. J Bone Miner Res. 2002;17(6):1057-64.
21. Viereck V, Emons G, Lauck V, Frosch KH, Blaschke
S, Gründker C, et al. Bisphosphonates pamidronate
and zoledronic acid stimulate osteoprotegerin
production by primary human osteoblasts. Biochem
Biophys Res Commun. 2002;291(3):680-6.
22. Faranoush M, Rahiminejad MS, Karamizadeh Z,
Ghorbani R, Owji SM. Zinc Supplementation Effect
on Linear Growth in Transfusion Dependent β
Thalassemia. Iranian Journal of Blood and Cancer.
2008;1(1), 29-32.
23. Shamshirsaz AA, Bekheirnia MR, Kamgar M, Pakbaz
Z, Tabatabaie SM, Bouzari N,et al. Bone mineral
density in Iranian adolescents and young adults
with beta-thalassemia major. Pediatr Hematol
Oncol. 2007;24(7):469-79.26.
24. Izadyar S, Fazeli M, Izadyar M, Salamati P,
Gholamrezanezhad A. Bone mineral density in adult
patients with major thalassaemia: our experience
and a brief review of the literature. Endokrynol Pol.
2012;63(4):264-9.

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