Treatment for osteoporosis in people with ß-thalassaemia

  • Protocol
  • Intervention

Authors


Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To compare treatments of osteoporosis in people with ß-thalassaemia.

Background

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.

Objectives

To compare treatments of osteoporosis in people with ß-thalassaemia.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs).

Types of participants

All people with thalassaemia with:

  • a BMD z score of < -2 standard deviations (SD) for: children less than 15 years old; adult males (15 to 50 years old); and all pre-menopausal females above 15 years;

  • a BMD t score of < -2.5 SD for post-menopausal females and males above 50 years old.

Types of interventions

Any treatment for osteoporosis in people with ß-thalassaemia. The interventions include, but are not limited to, bisphosphonates, HRT, calcitonin, blood transfusion or hydroxyurea, versus controls who receive either placebo, another intervention, or the same intervention with a different dosing regimen, or with an adjuvant therapy, or both.

Types of outcome measures

Primary outcomes
  1. Absolute or per cent change in a real or volumetric BMD z score for the hip joint, spine and wrist (as measured by dual X-ray absorptiometry (DXA) or computerized tomography (CT))

  2. Incidence of fracture (clinical or radiographic)

Secondary outcomes
  1. Mobility (as reported by patients, using a validated score if possible)

  2. Quality of life (as reported in the individual trials)

  3. Adverse effects of treatment (as reported by the patient) (e.g. upper gastro-intestinal symptoms)

  4. Bone pain (intensity, frequency, duration)

Search methods for identification of studies

Electronic searches

We will identify relevant studies from the Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register using the terms: osteoporosis AND (thalassaemia OR haemoglobinopathies general).

The Haemoglobinopathies Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue) and quarterly searches of MEDLINE. Unpublished work is identified by searching the abstract books of four major conferences: the European Haematology Association conference; the American Society of Hematology conference; the Caribbean Health Research Council Meetings; and the National Sickle Cell Disease Program Annual Meeting. For full details of all searching activities for the register, please see the relevant section of the Cochrane Cystic Fibrosis and Genetic Disorders Group Module.

We will also search PubMed, Google Science and ongoing trials registers such as the WHO ICTRP.

Searching other resources

Reference lists of the identified studies will be scrutinized for additional citations. We will contact organizations and researchers working in this field. We will also cross check references from obtained studies to identify more studies.

Data collection and analysis

Selection of studies

The authors (AB and KM) will independently assess study eligibility and screen all available titles and abstracts for inclusion using an eligibility form designed in accordance with the specified inclusion criteria. If they cannot ascertain the relevance by screening the title and abstract, they will retrieve and review the full text of the article. The authors plan to resolve disagreements by discussion or, if required, by consultation with a third review author. The authors will display studies excluded from the review in the form of a table along with the reason for exclusion.

Data extraction and management

Two authors (KM and AB) will independently collect and record data, then compare their results and correct any errors. They aim to resolve any disagreements through discussion, and if required by consultation with the third review author. In the event that published reports contain unclear information, they will attempt to contact the trial authors for further details. The authors plan to analyse and present the different interventions separately. They also plan to analyse the BMD scores across the different sites (hip joint, spine, wrist) separately.

Assessment of risk of bias in included studies

Two review authors (KM, IO) will independently assess the risk of bias of the included studies by using the criteria outlined in the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2011). They will assess sequence generation, allocation concealment, blinding, incomplete outcome data, and selective outcome reporting and other potential sources of bias. They will judge each domain as having a ‘low risk’, ‘high risk, or ‘unclear risk’ of bias. The two authors will resolve any disagreements by discussion, or, if required, by consultation with a third author.

Measures of treatment effect

For dichotomous data, the authors will present results as relative risks (RR) with 95% confidence intervals (CI). For continuous data, if outcomes are measured in the same way between trials, they will use the mean difference (MD), with 95% CIs. They will use the standardized mean difference (SMD) to combine trials that measure the same outcome, but use different methods (Higgins 2011). For count data they plan to calculate the MD with corresponding CIs.

Unit of analysis issues

The unit of analysis will be the treated patient. The authors will include data from cluster-randomised trials if the information is available. For cluster-randomised trials, they will calculate the intracluster correlation coefficient (ICC) according to Donner (Donner 2001). If cross-over studies are identified, the authors plan to analyse data from such studies using an approach as recommended by Elbourne (Elbourne 2004).

Dealing with missing data

Where studies have been published in abstract form only or presented at meetings, the review authors will contact the trial authors for any available full reports or further information. For any studies where information is missing or unclear, they will contact the trial authors for further details.

Assessment of heterogeneity

The authors plan to use the Chi2 test for statistical heterogeneity (significance level P < 0.1) and quantify the degree of heterogeneity by means of the I2 statistic. For the interpretation of the I2 values, they will use the following guidelines (Higgins 2011):

  • 0% to 40%: might not be important;

  • 30% to 60%: may represent moderate heterogeneity;

  • 50% to 90%: may represent substantial heterogeneity;

  • 75% to 100%: considerable heterogeneity.

Where the I2 value is at 50% or more, the authors will regard this as significant heterogeneity.

Assessment of reporting biases

Two authors will undertake comprehensive searches in an attempt to minimize publication and reporting biases and consider the likelihood that these biases will affect the study results. Within studies, the authors will consider selective outcome reporting as part of the risk of bias assessment. They will compare the 'Methods' section of the full published paper to the 'Results' section to ensure that all outcomes which were measured, were reported. They will assess publication bias by constructing and assessing the symmetry of a funnel plot. If they detect asymmetry, they will explore causes other than publication bias.

Data synthesis

Where studies are clinically and methodologically comparable, the authors will carry out meta-analysis using the Review Manager software (RevMan 2011). If there is no significant heterogeneity (as defined above) and trials are sufficiently similar, they will use a fixed-effect meta-analysis model for combining data. If they find significant heterogeneity, they will use a random-effects model.

Subgroup analysis and investigation of heterogeneity

If the authors find substantial or considerable heterogeneity (as defined above), they plan to carry out the following subgroup analyses:

  1. sex and age (females: less than 15 years old; compared to 15 years and older to 45 years old; post-menopausal) (males: less than 15 years old; 15 years to 50 years old; above 50 years of age);

  2. routes (oral, intravenous infusion and intra-muscular injection) and doses of treatments;

  3. treatment duration (less than one year, more than one year to two years, three years, five years).

Sensitivity analysis

The authors will carry out a sensitivity analysis to explore the effect of the risk of bias (assessed by concealment of allocation), by excluding studies with a high risk of bias.

Appendices

Appendix 1. Glossary of terms

TermExplanation
arthropathydisease of a joint
chelationthe removal of metal (in this case iron) poisoning using agents which separate the metal from organs or tissues and bind it firmly with a new compound which can be eliminated from the body
cirrhosiswidespread disruption of normal liver structure by fibrosis and the formation of regenerative nodules that is caused by any of various chronic progressive conditions affecting the liver
cortical thinningthe thinning of the outer shell of bone
erythropoiesisprocess by which red blood cells (erythrocytes) are produced
extramedullary hematopoiesislocated or taking place outside the bone marrow
femoralto do with the femur (thigh bone)
hematopoiesisthe process by which immature precursor cells develop into mature blood cells
hepatocellular carcinomathe most common type of liver cancer
heterozygoushaving inherited different forms of a particular gene from each parent
hyperplasiaincrease in number of cells/proliferation of cells
hypogonadisma medical condition characterized by abnormally high levels of reproductive hormones such as oestrogen or testosterone
leucopeniaa decrease in the number of total white blood cells found in blood
lumbarto do with the lower abdominal region or lower spine
malocclusionmisalignment of teeth or incorrect relation between the teeth of the two dental arches
maxillary bonesbones that form the upper jaw
osteoblasta cell that is responsible for bone formation
osteoclastic activityactivities by cells to breakdown and reabsorb bone tissue
phagocytosisprocess of engulfing particles by the cell
pulmonary hypertensionabnormally high blood pressure in the arteries of the lungs
siderosisdeposition of iron in tissue
splenomegalyenlargement of the spleen 
thrombocytopeniareduced platelet count
trabecular bone

a type of bone typically occurring at the ends of long bones near to joints and within the interior of vertebrae; it is highly 

vascular and frequently contains red bone marrow, where the production of blood cells occurs

Contributions of authors

Preliminary database searchDr Amit, Dr Kye Mon
Develop and run the search strategiesDr Kye Mon and the Group's Trials Search Co-ordinator will perform these
BackgroundDr Amit ,Dr Kye Mon, Dr Osunkwo, Dr Sinha
ObjectivesDr Amit ,Dr Kye Mon, Dr Osunkwo
MethodologyDr Kye Mon, Dr Amit, Dr Osunkwo, Dr Sinha

Declarations of interest

None known.