High Prevalence of Bone Pain and Fractures in Young Transfusion Dependent Patients with �-Thalassemia at Southern Pakistan

Special Article - Thalassemia

Ann Hematol Oncol. 2019; 6(2): 1234.

High Prevalence of Bone Pain and Fractures in Young Transfusion Dependent Patients with β-Thalassemia at Southern Pakistan

Moiz B*, Khan HA, Raheem A and Shariq M

Department of Pathology and Laboratory Medicine, Aga Khan University, Pakistan

*Corresponding author: Bushra Moiz, Department of Pathology & Laboratory Medicine, Section of Hematology and Transfusion Medicine, Aga Khan University, Karachi, Pakistan

Received: December 31, 2018; Accepted: February 01, 2019;Published: February 08, 2019


Standard thalassemia management is focused primarily on blood transfusions and iron chelation. Thalassemia caregivers grossly underestimate chronic pain due to bone and mineral related disorders. This study aimed to determine the frequency of bone pain, fractures, performance status and biochemical bone markers in children having transfusion dependent β-thalassemia major. We recruited 367 patients between 5 to 17 years of age from Fatimid Foundation Karachi, Pakistan. A questionnaire regarding clinical details such as demography, frequency of transfusion, iron chelation and fractures was administered. Wong-Baker Faces® pain rating scale and Eastern Cooperative Oncology Group Performance Status were used for assessment of bone pain and performance status respectively. Biochemical bone-health markers estimated included vitamin D, corrected calcium, intact parathyroid hormone, phosphorous, magnesium, zinc and ferritin levels. Among 367 children, 33.5% (n=123) were taking regular chelation and 50% (n=184) were on calcium and or vitamin D supplements. Eighty-two percent (n=303) patients experienced variable intensity of recurrent bone pain in past two years, which increased in frequency with advancing age. Forty-six patients (12.5%) reported multiple or recurrent fractures. Median 25OHD level was deficient (13.09ng/ ml IQR 18.6-8.56) with normal corrected calcium (8.81mg/dl IQR 9.4-7.97) while serum phosphate was at upper limit of reference range (5.1 IQR 5.9-4.3). Logistic regression analysis showed significant association of pain with age (OR 1.1 95% CI 1.0-1.2 p 0.001).

The patients with and without fractures showed significant differences in age, corrected calcium, ferritin and zinc levels. Higher median phosphorus and iPTH were noted in patients with fractures but the difference was not significant. Binary logistic regression analysis showed statistically significant association with low levels of corrected calcium (OR 0.77% CI 0.6-0.9 p<0.04) and zinc (OR 0.08% CI 0.97-1.0 p<0.04). High prevalence of bone pains, fractures and biochemical abnormalities including hypovitaminosis D, hypocalcaemia and hyperphosphatemia were noted in patients with thalassemia. We need more studies to determine the impact on peak bone mass, prevalence of osteopenia and osteoporosis so that preventive intervention strategies can be planned in addition to adherence with optimum care for improving bone health in thalassemia.

Keywords: Thalassemia; Musculoskeletal pain; Fractures; Vitamin D


β-thalassemia major (β-TM) is the most frequent single gene disorder worldwide. The mainstay of treatment is blood transfusion for maintaining hemoglobin concentration at 9.5 to 10.5 g/dl with adequate iron chelation. Complications involving heart, endocrine glands, liver and spleen were described in these patients due to iron overload [1]. Recent literature shows abnormalities of vitamin D, calcium and phosphorous and low bone mass at an early age. These abnormalities are multifactorial due to iron deposition, drug therapy, abnormal mineral homeostasis, bone turnover, and endocrine abnormalities [2,3]. In addition, dysregulation of OPG/RANKL system, resulting in increased expression of RANKL by stromal or osteoblastic cells with increased bone loss are described at cellular level [4,5]. Abnormalities in bone metabolism can be prevented by adequate iron chelation, maintaining target hemoglobin, optimal calcium and vitamin D levels, and life style modification [6]. Adding therapies like bisphosphonates or gonadal hormones helps in prevention of morbidity associated with metabolic bone diseases.

β-TM is widely prevalent in Pakistan with an estimated frequency of 5000-9000 children born with β-TM each year in Pakistan and a carrier rate of 9.8 million [7]. Local literature reports a high prevalence of endocrine dysfunction [8], hepatic siderosis, cardiomyopathies [9], hypocalcaemia, hypovitaminosis D in patients with TM [10] and a high prevalence of transfusion transmitted infections [11]. These studies anticipate presence of chronic bone pain in such patients in Pakistan. Moreover as treating physicians, we frequently observe patients complaining of bone pain during the course of disease. Except for a single report of multiple fractures in an eight-year old girl with thalassemia [12], the systematic data to objectively assess frequency of bone pain or fractures in young patients with thalassemia is not available.

We performed a cross-section evaluation of bone health status in pre-pubertal and adolescents patients with transfusion dependent β-TM using biochemical markers of bone metabolism.

Material and Methods

Study setting and patient recruitment

Study setting, patient selection and anthropometric measurements were described previously [13]. Briefly 367 pediatric patients (age 5 to 17 years) with transfusion dependent β-TM were enrolled from a notfor profit organization-Fatimid Foundation Karachi.

Data collection

An on-site research officer collected demographic, anthropometric and clinical details from patients and/or their guardians. Medical records of patients were reviewed for clinical information.

Bone pain was evaluated through Wong-Baker Faces Pain rating. This is a ten-point scale (marked 0 to 10) with a series of six faces ranging from “no hurt’ to “crying’ with pain. Patient chose the face that best described intensity of his/her pain. A score of 1-3, 4-6 and 7-10 was considered as mild, moderate and severe pain respectively.

Performance status was assessed through a six-point Eastern Cooperative Oncology Group Performance Status scale (ECOG) ranging from fully functional (scored 1) to dead (scored 5) [14].

Biochemical analysis for bone profile

Blood samples for serum calcium, albumin, phosphorous, creatinine, magnesium, ALT and 25OHD were collected in gel tubes and for intact parathyroid hormone (iPTH) and zinc in EDTA and heparin vacutainer respectively. All the samples were centrifuged, aliquoted and refrigerated at 2 to 8°C. Sample for PTH was frozen at -20°C and transported in dry ice to the laboratory on the same day as of collection.

Analysis was performed using standard protocols on Elecsys auto analyzer (Roche Diagnostic, Mannheim USA). Reference range of >30ng/ml (sufficient) 20-30 ng/ml (insufficient) <20ng/ml (deficient) for 25OHD and 15-65 pg/ml for iPTH was used. Serum ferritin was measured on Architect system B7K590 (Abbott Ireland Diagnostic, USA). Reference interval of 21-274 ng/ml for male and 4.6-204 ng/ml for female was used. Zinc testing was performed on atomic absorption spectrophotometer on Agilent technologist 200 series AA (Agilent technologies) and a reference range of 50-150 ug/dl was used.

Data analysis

Data analysis was performed using SPSS v 20. Shapiro-wilk test for normality for all quantitative variables was significant so median (IQR) were reported. Frequency (percentage) were computed for qualitative variables. Univariate analysis was performed by Mann-whitney U test. Multivariate linear regression was applied to determine the relation of fracture and pain between the significant variables with other confounder variables of the study. P-value =0.05 was considered as significant.

Ethical challenges and measures to address them

Ethics Review Committee of Aga Khan University approved the study [ERC no # 2305-Pat-ERC12]. Informed consent was taken from parents/guardians. On-site research assistants collected clinical data and re-coded it removing patient identification prior to statistical analysis.

Financial support

University research council of Aga Khan University [URC # 1112012 P& M] provided financial support for conducting this study.


Details on demographics, anthropometry, blood transfusion history, iron chelation, last pre transfusion hemoglobin, and last serum ferritin levels have been described previously [13]. Chelation therapy was prescribed in 96% of patients. However, only 33% of patients were taking chelation regularly.

Clinical details of patients with β-tm

Table 1 shows the characteristics of 367 patients with β-TM recruited in the study.