Treatment of osteoporosis in people with beta thalassaemia

Review question

We reviewed the evidence on the effects and safety of different treatments of osteoporosis in people with beta-thalassaemia.

Background

Osteoporosis affects bone density over time and leads to an increased risk of fractures. It is an important cause of illness in people with beta-thalassaemia. We wanted to find the most effective available treatment for treating osteoporosis and improving quality of life.

Search date

The evidence is current to: 04 February 2016.

Trial characteristics

The review included four trials with 211 people with beta-thalassaemia aged between 10 years and 58 years of age. Trials compared bisphosphonates (alendronate, clodronate and neridronate and pamidronate) and zinc sulphate to either control groups or, as in one trial a different dose of treatment, with people selected for one treatment or the other randomly. Three trials were carried out for two years, with one currently only reporting 12-month data and one trial was carried out for 12 months.

Key results

Three trials assessed bisphosphonate therapy, in one trial (118 volunteers) there was an increase (in favour of the treatment group) in bone mineral density at the lumbar spine and hip at six and 12 months and at the femoral neck only after 12 months. In a second trial (25 volunteers), bone mineral density at the lumbar spine increased after two years of treatment with alendronate and clodronate. In the 12-month trial comparing different doses of pamidronate (26 volunteers), the 60 mg group reported a larger increase in bone mineral density at the lumbar spine and forearm than the 30 mg group, but this was not the case at the femoral neck.

In a zinc sulphate supplements trial (42 volunteers), bone mineral density increased at the lumbar spine and hip after 12 and 18 months.

It was stated that there were no fractures in one trial and this outcome was not reported in three trials.

There were no major adverse effects reported in either of the trials comparing bisphosphonates to control; although in the neridronate trial there were fewer painkillers used and a lower score for back pain reported in the bisphosphonate group. Adverse effects were not reported in the bisphosphonate trial comparing different doses or in the zinc sulphate supplements trial.

Therefore, evidence indicates an increase in bone mineral density at the femoral neck, lumbar spine and forearm after giving bisphosphonates. This is also true for the lumbar spine and hip after zinc sulphate supplementation. The authors recommend that further long-term randomised controlled trials looking at different treatments with bisphosphonates and zinc supplementation are carried out on people with beta-thalassaemia who have osteoporosis.

Quality of the evidence

The quality of the included trials was mixed. Specifically, although all the trials stated that people received different treatments at random, two of them did not describe exactly how they did this. Also, none of the four trials described how they stopped people knowing which group they were going to be put into.

Authors' conclusions: 

There is evidence to indicate an increase in bone mineral density at the femoral neck, lumbar spine and forearm after administration of bisphosphonates and at the lumbar spine and hip after zinc sulphate supplementation. The authors recommend that further long-term randomised control trials on different bisphosphonates and zinc supplementation therapies in people with beta-thalassaemia and osteoporosis are undertaken.

Read the full abstract...
Background: 

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. Osteoporosis represents an important cause of morbidity in people with beta-thalassaemia and its pathogenesis is multifactorial. Factors include bone marrow expansion due to ineffective erythropoiesis, resulting in reduced trabecular bone tissue with cortical thinning; endocrine dysfunction secondary to excessive iron loading, leading to increased bone turnover; and lastly, a predisposition to physical inactivity due to disease complications with a subsequent reduction in optimal bone mineralization.

A number of therapeutic strategies have been applied to treat osteoporosis in people with beta-thalassaemia, which include bisphosphonates, with or without, hormone replacement therapy. There are various forms of bisphosphonates, such as clodronate, pamidronate, alendronate and zoledronic acid. Other treatments include calcitonin, calcium, zinc supplementation, hydroxyurea and hormone replacement therapy for preventing hypogonadism.

Objectives: 

To review the evidence on the efficacy and safety of treatment for osteoporosis in people with beta-thalassaemia.

Search strategy: 

We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group’s Haemoglobinopathies Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.

Date of most recent search: 04 February 2016.

Selection criteria: 

Randomised, placebo-controlled trials in people with thalassaemia with a bone mineral density z score of less than -2 standard deviations for: children less than 15 years old; adult males (15 to 50 years old); and all pre-menopausal females above 15 years and a bone mineral density t score of less than -2.5 standard deviations for post-menopausal females and males above 50 years old.

Data collection and analysis: 

Two review authors assessed the eligibility and risk of bias of the included trials, extracted and analysed data and completed the review. We summarised results using risk ratios or rate ratios for dichotomous data and mean differences for continuous data. We combined trial results where appropriate.

Main results: 

Four trials (with 211 participants) were included; three trials investigated the effect of bisphosphonate therapies and one trial investigated the effect of zinc supplementation. Only one trial was judged to be of good quality (low risk of bias); the remaining trials had a high or unclear risk of bias in at least one key domain.

One trial (data not available for analysis) assessing the effect of neridronate (118 participants) reported significant increases in favour of the bisphosphonate group for bone mineral density at the lumbar spine and hip at both six and 12 months. For the femoral neck, a significant difference was noted at 12 months only. A further trial (25 participants) assessed the effect of alendronate and clodronate and found that after two years, bone mineral density increased significantly in the alendronate and clodronate groups as compared to placebo at the lumbar spine, mean difference 0.14 g/cm2 (95% confidence interval 0.05 to 0.22) and at the femoral neck, mean difference 0.40 g/cm2 (95% confidence interval 0.22 to 0.57). One 12-month trial (26 participants) assessed the effects of different doses of pamidronate (30 mg versus 60 mg) and found a significant difference in bone mineral density in favour of the 60 mg dose at the lumbar spine and forearm, mean difference 0.43 g/cm2 (95% CI 0.10 to 0.76), mean difference 0.87 g/cm2 (95% CI 0.23 to 1.51), respectively, but not at the femoral neck.

In a zinc sulphate supplementation trial (42 participants), bone mineral density increased significantly compared to placebo at the lumbar spine after 12 months (37 participants), mean difference 0.15 g/cm2 (95% confidence interval 0.10 to 0.20) and after 18 months (32 participants), mean difference 0.34 g/cm2 (95% confidence interval 0.28 to 0.40). The same was true for bone mineral density at the hip after 12 months, mean difference 0.15 g/cm2 (95% confidence interval 0.11 to 0.19) and after 18 months, mean difference 0.26 g/cm2 (95% confidence interval 0.21 to 0.31).

Fractures were not observed in one trial and not reported in three trials. There were no major adverse effects reported in two of the bisphosphonate trials; in the neridronate trial there was a reduction noted in the use of analgesic drugs and in the reported back pain score in favour of bisphosphonate treatment. Adverse effects were not reported in the trial of different doses of pamidronate or the zinc supplementation trial.

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