Review question
How effective and safe are different treatments for 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 (a blood disorder that reduces the production of haemoglobin).
There are several possible treatments for osteoporosis in people with beta-thalassaemia, including bisphosphonates (medicines that help to slow bone loss), calcitonin, calcium, zinc supplementation, hydroxyurea, hormone replacement therapy (HRT), denosumab (which inhibits bone resorption and increases bone mineral density (BMD)), and strontium ranelate (which promotes bone formation and inhibits bone resorption).
We wanted to find the most effective way of treating osteoporosis in people with beta-thalassaemia. Our key outcomes were BMD at the lower back, hip, and wrist (higher is better); fractures; mobility; quality of life; and unwanted effects of treatment. This is an update of a previously published Cochrane Review.
Search date
The evidence is current to 4 August 2022.
Trial characteristics
The review included six trials in which 298 people with beta-thalassaemia aged between 10 and 78 years of age were randomly allocated to a treatment group. Trials investigated bisphosphonates (alendronate, clodronate, neridronate, and pamidronate), zinc sulphate supplementation, denosumab, and strontium ranelate. Five studies compared active treatment to dummy treatment (placebo) or no treatment, while one trial compared two different doses of bisphosphonates. Four trials were scheduled to last two years (though at the time of writing, one of these trials only had 12-month data published), and two trials lasted 12 months.
Key results
Bisphosphonates versus placebo or no treatment
One trial, which enrolled 25 people, found that alendronate and clodronate may increase BMD at the lower back and hip compared with placebo after two years. One trial, which enrolled 118 people, reported increased BMD at the lower back and femoral neck (the part of the thigh bone that connects to the pelvis) at six and 12 months with neridronate compared with no treatment, but only at 12 months for the whole hip joint (there were no data to analyse).
One person in the neridronate trial (118 participants) reported fractures following a road traffic accident. We are uncertain of the effects of neridronate on quality of life. We are also uncertain whether bisphosphates have unwanted effects. No trials reported BMD at the wrist or mobility.
Pamidronate 60 mg versus pamidronate 30 mg
One 12-month trial, which enrolled 26 people, compared different monthly doses of pamidronate (30 mg versus 60 mg). We are uncertain of the effect of the different doses on BMD at the lower back, hip, and forearm. This trial did not report fractures, mobility, quality of life, or unwanted effects of treatment.
Zinc versus placebo
One trial, which enrolled 42 people, showed that zinc supplementation compared to placebo probably increases BMD at the lower back and hip after 12 months and after 18 months. This trial did not report BMD at the wrist, fractures, mobility, quality of life or unwanted effects of treatment.
Denosumab versus placebo
One trial, which enrolled 63 people, compared denosumab 60 mg to placebo. We are unsure about the effect of denosumab on BMD at the lower back, hip, and wrist after 12 months compared to placebo. The trial did not report fractures, mobility, quality of life, or unwanted effects of treatment, but it did report a reduction in bone pain with denosumab after 12 months.
Strontium ranelate versus placebo
One trial, which enrolled 24 people, narratively reported an increase in BMD at the lower back after 24 months in people taking strontium ranelate, but no change in those taking the placebo. The trial also reported a decrease in back pain with strontium ranelate, which we considered representative of improved quality of life, through the results were very uncertain.
Limitations of the evidence
We are moderately confident in some results, but have little or very little confidence in others. There were not many participants in any individual trial and we had some concerns about the trial methods. Specifically, although all the trials stated that people received different treatments at random, two trials did not describe exactly how they decided who was given which treatment. In addition, only two trials described how they stopped people knowing which group they were in.
Bisphosphonates may increase BMD at the femoral neck, lumbar spine, and forearm compared to placebo after two years' therapy. Zinc supplementation probably increases BMD at the lumbar spine and hip after 12 months. Denosumab may make little or no difference to BMD, and we are uncertain about the effect of strontium on BMD.
We recommend further long-term RCTs on different bisphosphonates and zinc supplementation therapies in people with beta-thalassaemia-associated osteoporosis.
Osteoporosis is characterized by low bone mass and micro-architectural deterioration of bone tissue leading to increased bone fragility. In people with beta-thalassaemia, osteoporosis represents an important cause of morbidity and is due to a number of factors. First, ineffective erythropoiesis causes bone marrow expansion, leading to reduced trabecular bone tissue with cortical thinning. Second, excessive iron loading causes endocrine dysfunction, leading to increased bone turnover. Lastly, disease complications can result in physical inactivity, with a subsequent reduction in optimal bone mineralization.
Treatments for osteoporosis in people with beta-thalassaemia include bisphosphonates (e.g. clodronate, pamidronate, alendronate; with or without hormone replacement therapy (HRT)), calcitonin, calcium, zinc supplementation, hydroxyurea, and HRT alone (for preventing hypogonadism). Denosumab, a fully human monoclonal antibody, inhibits bone resorption and increases bone mineral density (BMD). Finally, strontium ranelate simultaneously promotes bone formation and inhibits bone resorption, thus contributing to a net gain in BMD, increased bone strength, and reduced fracture risk.
This is an update of a previously published Cochrane Review.
To review the evidence on the efficacy and safety of treatment for osteoporosis in people with beta-thalassaemia.
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group’s Haemoglobinopathies Trials Register, which includes references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched online trial registries.
Date of most recent search: 4 August 2022.
Randomized controlled trials (RCTs) in people with beta-thalassaemia with: a BMD Z score below −2 standard deviations (SDs) for children aged under 15 years, adult males (aged 15 to 50 years) and premenopausal females aged over 15 years; or a BMD T score below −2.5 SDs for postmenopausal females and males aged over 50 years.
Two review authors assessed the eligibility and risk of bias of the included RCTs, and extracted and analysed data. We assessed the certainty of the evidence using GRADE.
We included six RCTs (298 participants). Active interventions included bisphosphonates (3 trials, 169 participants), zinc supplementation (1 trial, 42 participants), denosumab (1 trial, 63 participants), and strontium ranelate (1 trial, 24 participants). The certainty of the evidence ranged from moderate to very low and was downgraded mainly due to concerns surrounding imprecision (low participant numbers), but also risk of bias issues related to randomization, allocation concealment, and blinding.
Bisphosphonates versus placebo or no treatment
Two RCTs compared bisphosphonates to placebo or no treatment. After two years, one trial (25 participants) found that alendronate and clodronate may increase BMD Z score compared to placebo at the femoral neck (mean difference (MD) 0.40, 95% confidence interval (CI) 0.22 to 0.58) and the lumbar spine (MD 0.14, 95% CI 0.05 to 0.23). One trial (118 participants) reported that neridronate compared to no treatment may increase BMD at the lumbar spine and total hip at six and 12 months; for the femoral neck, the study found increased BMD in the neridronate group at 12 months only. All results were of very low-certainty.
There were no major adverse effects of treatment. Participants in the neridronate group reported less back pain; we considered this representative of improved quality of life (QoL), though the certainty of the evidence was very low. One participant in the neridronate trial (116 participants) sustained multiple fractures as a result of a traffic accident. No trials reported BMD at the wrist or mobility.
Different doses of bisphosphonate compared
One 12-month trial (26 participants) assessed different doses of pamidronate (60 mg versus 30 mg) and found a difference in BMD Z score favouring the 60 mg dose at the lumbar spine (MD 0.43, 95% CI 0.10 to 0.76) and forearm (MD 0.87, 95% CI 0.23 to 1.51), but no difference at the femoral neck (very low-certainty evidence). This trial did not report fracture incidence, mobility, QoL, or adverse effects of treatment.
Zinc versus placebo
One trial (42 participants) showed zinc supplementation probably increased BMD Z score compared to placebo at the lumbar spine after 12 months (MD 0.15, 95% CI 0.10 to 0.20; 37 participants) and 18 months (MD 0.34, 95% CI 0.28 to 0.40; 32 participants); the same was true for BMD at the hip after 12 months (MD 0.15, 95% CI 0.11 to 0.19; 37 participants) and 18 months (MD 0.26, 95% CI 0.21 to 0.31; 32 participants). The evidence for these results was of moderate certainty. The trial did not report BMD at the wrist, fracture incidence, mobility, QoL, or adverse effects of treatment.
Denosumab versus placebo
Based on one trial (63 participants), we are unsure about the effect of denosumab on BMD Z score at the lumbar spine, femoral neck, and wrist joint after 12 months compared to placebo (low-certainty evidence). This trial did not report fracture incidence, mobility, QoL, or adverse effects of treatment, but the investigators reported a reduction in bone pain measured on a visual analogue scale in the denosumab group after 12 months of treatment compared to placebo (MD −2.40 cm, 95% CI −3.80 to −1.00).
Strontium ranelate
One trial (24 participants) only narratively reported an increase in BMD Z score at the lumbar spine in the intervention group and no corresponding change in the control group (very low-certainty evidence). This trial also found a reduction in back pain measured on a visual analogue scale after 24 months in the strontium ranelate group compared to the placebo group (MD −0.70 cm (95% CI −1.30 to −0.10); we considered this measure representative of improved quality of life.