Please see glossary for explanation of terms (Appendix 1).
Description of the condition
Osteoporosis is a systemic skeletal disease characterized by low bone mass and micro-architectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture (WHO 1994). Osteoporosis represents an important cause of morbidity in people with beta (ß)-thalassaemia.
The ß-thalassaemias are a group of hereditary blood disorders characterized by anomalies in the synthesis of the ß-chains of hemoglobin resulting in variable phenotypes ranging from severe anemia to clinically asymptomatic individuals (Galanello 2010). It has been estimated that about 1.5% of the global population (80 to 90 million people) are carriers of ß-thalassaemia, with about 60,000 symptomatic individuals born annually, the great majority in the developing world. The total annual incidence of symptomatic individuals is estimated at 1 in 100,000 throughout the world and 1 in 10,000 people in the European Union (Vichinsky 2005).
In ß-thalassaemia, a reduced rate of synthesis of one or more ß-globin chains leads to: an imbalance in the globin chain synthesis; defective haemoglobin production; and damage to red cells (or their precursor) from the effects of alpha (α)-globin subunits that are produced in excess. This disorder is extremely heterogeneous at the molecular level with over 100 different mutations. These fall into deletional and non-deletional mutations that may affect the transcription, processing, or translation of ß-globin messenger ribonucleic acid (RNA). Deletional mutations are rare and there have been approximately 15 identified to date, whereas there are approximately 200 non-deletional mutations which have been characterized.
The most clinically severe form of ß-thalassaemia is thalassaemia major which is characterized by the complete absence of ß-globin chain production. A milder form which requires no or fewer transfusions is known as ß-thalassaemia intermedia. A further form, ß-thalassaemia minor (also known as ß-thalassaemia-trait), is a heterozygous carrier state for ß-thalassaemia. The affected infants with ß-thalassaemia major are well at birth but develop progressive anaemia in the first few months of life.
The course of the disease in childhood depends almost entirely upon whether the child is maintained on an adequate transfusion program. An inadequately transfused child with ß-thalassaemia develops stunted growth, bossing of the skull, overgrowth of maxillary bones and evidence of extramedullary hematopoiesis (Galanello 2010). Spontaneous fractures commonly occur as the result of expansion of the marrow cavity with thinning of long bones and skull. In addition to this, maxillary deformity often leads to dental problems from malocclusion; liver and spleen are enlarged, splenomegaly leads to thrombocytopenia and leucopenia (resulting in an increased tendency to infection and to bleeding); and chronic leg ulceration may also occur.
Children who have grown and developed normally throughout the first 10 years of life, due to regular blood transfusions, begin to develop the symptoms of iron loading as they enter puberty. The first indication of iron loading is usually the absence of a pubertal growth spurt and the failure of menarche. Over the years, a variety of endocrine problems may develop, in particular diabetes mellitus and adrenal insufficiency. Towards the end of the second decade of life, cardiac complications arise and cardiac siderosis may result in death in the second or third decade. Additional complications of iron overload include pulmonary hypertension and restrictive lung disease, liver cirrhosis and hepatocellular carcinoma, diabetes, defective phagocytosis and degenerative arthropathy (Weatherall 1995).
The pathogenesis of osteoporosis in ß-thalassaemia is multifactorial. This includes bone marrow expansion due to ineffective erythropoiesis, resulting in reduced trabecular bone tissue with cortical thinning (Vichinsky 1998). Endocrine dysfunction secondary to excessive iron loading (De Sanctis 1996) also occurs, which leads to increased bone turnover (Wonke 1998). Lastly, there is a predisposition to physical inactivity due to disease complications with a subsequent reduction in optimal bone mineralization (Athanasios 2007). Additional genetic factors, such as the COLIA 1 gene polymorphism seem to play an important role in the development of low bone mass in these patients. Osteoclastic activity is elevated and osteoblasts are deregulated in people with thalassaemia suffering from osteoporosis (Vokaridou 2004).
The prevalence of osteoporosis in people with thalassaemia varies depending on the site (lumbar and femoral). Lumbar osteoporosis was found to vary from 50.7 % to 74.1%, whereas femoral osteoporosis was reported to vary between 10.8 % and 37.9 % in different studies (Scacchi 2008; Shamshirsaz 2007). The prevalence of fractures in people with thalassaemia is reported to vary from 12.1% to 35.1 % (Basanagoudar 2001; Ruggierol 1998; Sutipornpalangkul 2010; Vogiatzi MG 2006).
Description of the intervention
There are various therapeutic strategies that have been applied to either prevent or to treat osteoporosis in patients with ß-thalassaemia. Optimizing transfusions to maintain higher pre-transfusion hemoglobin levels reduces bone marrow hyperplasia from ineffective erythropoiesis. Regular blood transfusion to maintain haemoglobin (Hb) levels between 9 g/dl and 10 g/dl with adequate chelation particularly during childhood and adolescence, are critical to ensure normal growth and puberty and to prevent bone deformities and endocrine complications (Athanasios 2007). Aggressive iron chelation therapy reduces the risk of endocrine dysfunction thus minimizing bone loss and supporting normal lumbar bone mineral density (BMD) (Christoforidis 2007). Calcium and vitamin D supplementation, weight-bearing physical activity and stopping smoking are also recommended to reduce the risk of osteoporosis (Vokaridou 2004).
Bisphosphonates, with or without, hormonal replacement therapy (HRT), are regarded as the most effective treatment for osteoporosis (Akesson 2003). There are various forms of bisphosphonates, such as clodronate, pamidronate, alendronate and zolidronic acid. Other treatments include calcitonin, which is a potent inhibitor of osteoclasts and is used in combination with the daily administration of calcium. Hydroxyurea has also shown promising results in treating osteoporosis (Angastiniotis 1998). However, the most effective way of preventing osteoporosis and other bone deformities in this population seems to be HRT for preventing hypogonadism (Jensen 1998a; Lindsay 1993).
How the intervention might work
All interventions listed above are aimed to increase BMD, markers of bone formation and decrease the markers for bone resorption. Increased BMD will reduce the risk of fracture and bone pain, thus improving the quality of life of people with thalassaemia suffering from osteoporosis.
Bisphosphonates are potent inhibitors of osteoclastic bone resorption and 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 (Suda 1997). There is an increase in calcium balance and mineral content of bone and a decrease of bone resorption with bisphosphonate treatment (Fleisch 1997). Clodronate reduces bone resorption markers (deoxypyrydinoline and pyrydinoline) and inhibits bone loss, but does not demonstrate a substantial increase in bone mineral density (BMD) (Morabito 2002; Pennisi 2003). Alendronate normalizes the rate of bone turnover and results in a rise in BMD of the spine and the hip. Alendronate further decreases bone resorption markers (pyridinium crosslink) (Morabito 2002). Pamidronate, a second generation amino-bisphosphonate has also shown a significant improvement in BMD in this population (Wonke 2001). Zoledronic acid is the most potent third generation bisphosphonate which increases BMD and is used in patients with transfusion-dependent ß-thalassaemia and severe osteoporosis (Perifanis 2004). Bisphosphonates have the greatest efficacy with few side-effects, however, more trials must be conducted in order to clarify the exact role of each bisphosphonate, and to assess the long-term benefit and side-effects (Gaudio 2008; Vokaridou 2004).
Calcitonin inhibits osteoclasts and, in combination with the daily administration of calcium, results in a marked decrease in bone pain and number of fractures and also improved radiological findings of osteoporosis (Canatan 1995).
Hydroxyurea acts by reducing marrow hyperplasia and bone pain (Angastiniotis 1998). It may be an effective alternative to chronic blood transfusion It is initiated to decrease the frequency of painful crises, of acute chest syndrome and decrease the need for blood transfusion and to improve quality of life (Mokhtar 2011)
Regular blood transfusion reduces haemopoiesis, which is the major reason for marked bone deformities. It not only prevents deformity but may even regress established deformity (Borgna-Pignatti 2007; Jensen 1998b).
It has been reported that the continuous HRT, with transdermal oestrogen for females or human chorionic gonadotrophin for males, improves bone density parameters (Anapliotou 1995).
Why it is important to do this review
Currently there are a number of treatment guidelines for treating osteoporosis in people with ß-thalassaemia. We aim to find the most effective available treatment in terms of bone remodeling parameters and BMD in this population, thus, improving the quality of life in these individuals.