Treatment for osteoporosis in people with beta‐thalassaemia

Abstract

Background

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.

Objectives

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

Search methods

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.

Selection criteria

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.

Data collection and analysis

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.

Main results

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.

Authors' conclusions

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.

Plain language summary

Treatment of osteoporosis in people with beta‐thalassaemia

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.

Summary of findings

Summary of findings 1. Summary of findings – bisphosphonates versus placebo or no treatment.

Bisphosphonates compared with placebo or no treatment for treating osteoporosis in people with β‐thalassaemia
Patient or population: adults with β‐thalassaemia and osteoporosis Settings: outpatients Intervention: bisphosphonatesa Comparison: placebo (Morabito 2002) or no treatment (Forni 2012)
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No. of participants (trials)	Certainty of the evidence (GRADE)	Comments
	Assumed risk (placebo/no treatment)	Corresponding risk (bisphosphonates)
BMD Z score (total hip/femoral neck) Follow‐up: 2 years	Oral bisphosphonates					The trial included in this outcome was a 3‐arm trial that compared oral alendronate against placebo and IM clodronate against placebo. The participants in the placebo group were the same for each of the interventions, so we could not combine the results.
	The mean Z score in the control group was −2.55.	The mean Z score was 0.46 higher in the intervention group (0.30 higher to 4.01 higher).	MD 0.46 (0.30 to 0.62)	17 (1)	⊕⊝⊝⊝ Very lowb,c
	IM bisphosphonates
	The mean Z score in the control group was −2.55.	The mean Z score was 0.33 higher in the intervention group (0.08 higher to 0.58 higher).	MD 0.33 (0.08 to 0.58)	16 (1)	⊕⊝⊝⊝ Very lowb,c
BMD Z score (lumbar spine) Follow‐up: 2 years	Oral bisphosphonates					The trial included in this outcome was a 3‐arm trial that compared oral alendronate against placebo and IM clodronate against placebo. The participants in the placebo group were the same for each of the interventions, so we could not combine the results.
	The mean Z score in the control group was −2.83.	The mean Z score was 0.18 higher in the intervention group (0.09 higher to 0.27 higher).	MD 0.18 (0.09 to 0.27)	17 (1)	⊕⊝⊝⊝ Very lowb,c
	IM bisphosphonates
	The mean Z score in the control group was −2.83.	The mean Z score was 0.09 higher in the intervention group (0.06 lower to 0.24 higher).	MD 0.09 (−0.06 to 0.24)	16 (1)	⊕⊝⊝⊝ Very lowb,c
BMD Z score (wrist)	No trials measured BMD Z score at the wrist.					—
Incidence of fractures Follow‐up: 1 year	The only fractures during the trial period were reported 1 participant in the neridronate group who discontinued the trial at 6 months after a road traffic accident (Forni 2012).			118 (1)	⊕⊕⊕⊝ Moderatec	The fact that the trial is open‐label is unlikely to affect this outcome.
Mobility	No trials measured mobility.					—
Quality of life (change in mean back pain) Follow‐up: 1 year	1 trial reported that the mean back pain scale value was significantly higher (better) in the neridronate group compared with the placebo group at 3 months (P < 0.042), 6 months (P = 0.008), and 12 months (P = 0.002).			118 (1)	⊕⊝⊝⊝ Very lowc,d,e	—
Adverse effects of treatment Follow‐up: 1–2 years	1 trial reported no relevant side effects to treatment with clodronate or alendronate (Morabito 2002). The most common adverse event in the clodronate group was local pain at the injection site, reported by 7/8 participants versus no participants in the placebo group (RR 15.00, 95% CI 1.00 to 225.33). 1 participant on alendronate reported abdominal pain versus no participants in the placebo group (RR 2.70, 95% CI 0.13 to 58.24). In the trial of neridronate, 3 participants reported acute‐phase reaction after infusion of the active treatment, characterized by flu‐like symptoms; these were controlled with paracetamol (Forni 2012).			143 (2)	⊕⊝⊝⊝ Very lowc,f	—
*The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). β‐thalassaemia: beta‐thalassaemia; BMD: bone mineral density; CI: confidence interval; IM: intramuscular; MD: mean difference; RR: risk ratio.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

^a One trial used neridronate 100 mg every 90 days (Forni 2012), and the second (three‐arm) trial used alendronate 10 mg oral daily or clodronate 100 mg IM every 10 days (Morabito 2002).
^b Downgraded twice for risk of bias in the single included trial for this outcome. The randomization and allocation concealment process was unclear, and the trial was open‐label.
^c Downgraded once for imprecision due to small numbers and low event rates.
^d Downgraded once for risk of bias in the single included trial for this outcome. Allocation concealment was unclear, and the trial was open‐label.
^e Downgraded once for indirectness, as back pain is a surrogate measure for quality of life.
^f Downgraded twice for risk of bias in both trials, particularly across the domains of randomization, allocation concealment, and blinding.

Summary of findings 2. Summary of findings – different doses of bisphosphonates compared.

Pamidronate 60 mg compared with pamidronate 30 mg for treating osteoporosis in people with β‐thalassaemia
Patient or population: people with β‐thalassaemia and osteoporosis Settings: outpatients Intervention: pamidronate 60 mg IV Comparison: pamidronate 30 mg IV
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No. of participants (trials)	Certainty of the evidence (GRADE)	Comments
	Assumed risk (pamidronate 30 mg)	Corresponding risk (pamidronate 60 mg)
BMD Z score (total hip/femoral neck) Follow‐up: 12 months	The mean Z score in the control group was −1.85 (SD 0.6).	The mean Z score in the intervention group was 0.08 lower (0.38 lower to 0.22 higher). P = 0.61.	MD −0.08 (95% CI −0.38 to 0.22)	26 (1)	⊕⊝⊝⊝ Very lowa,b	—
BMD Z score (lumbar spine) Follow‐up: 12 months	The mean Z score in the control group was −2.13 (SD 0.69).	The mean Z score in the intervention group was 0.43 higher (0.10 higher to 0.76 higher). P = 0.01.	MD 0.43 (95% CI 0.10 to 0.76)	26 (1)	⊕⊝⊝⊝ Very lowa,b	—
BMD Z score (wrist)	No trials measured BMD Z score for the wrist.					Voskaridou 2003 reported BMD Z score at the forearm and found that 60 mg produced an improvement in Z score compared to the 30 mg dose (MD 0.87, 95% CI 0.23 to 1.51; P = 0.008).
Incidence of fractures	No trials measured incidence of fractures.					—
Mobility	No trials measured mobility.					—
Quality of life	No trials measured quality of life.					—
Adverse effects of treatment	No trials measured adverse effects of treatment.					—
*The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). β‐thalassaemia: beta‐thalassaemia; BMD: bone mineral density; CI: confidence interval; IV: intravenous; MD: mean difference; SD: standard deviation.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

^a Downgraded twice for risk of bias within the single trial included for this outcome. There was unclear risk of bias across the domains of randomization, allocation concealment, and blinding.
^b Downgraded once for imprecision (very few participants).

Summary of findings 3. Summary of findings – zinc versus placebo.

Zinc versus placebo for treating osteoporosis in people with β‐thalassaemia
Patient or population: children and adults with β‐thalassaemia major and low bone mass Settings: outpatients Intervention: zinc (25 mg/day as zinc sulphate) Comparison: placebo
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of participants (trials)	Certainty of the evidence (GRADE)	Comments
	Assumed risk (placebo)	Corresponding risk (zinc sulphate)
BMD Z score (total hip/femoral neck) Follow‐up: 12 months	The mean Z score in the control group was −1.52 (SD 0.06).	The mean Z score in the intervention group was 0.15 points higher (0.11 higher to 0.19 higher).	MD 0.15 (95% CI 0.11 to 0.19)	37 (1)	⊕⊕⊕⊝ Moderatea	Results were also reported at 18 months, favouring zinc (MD 0.26 points, 95% CI 0.21 to 0.31; 32 participants).
BMD Z score (lumbar spine) Follow‐up: 12 months	The mean Z score in the control group was −2.26 (SD 0.08).	The mean Z score in the intervention group was 0.15 points higher (0.10 higher to 0.20 higher).	MD 0.15 (95% CI 0.10 to 0.20)	37 (1)	⊕⊕⊕⊝ Moderatea	Results were also reported at 18 months, favouring zinc (MD 0.34 points, 95% CI 0.28 to 0.40; 32 participants).
BMD Z score (wrist)	No studies reported BMD Z score at the wrist.					—
Incidence of fractures	No studies reported incidence of fractures.					—
Mobility	No studies reported mobility.					—
Quality of life	No studies reported quality of life.					—
Adverse effects of treatment	No studies reported adverse effects of treatment.					—
*The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). β‐thalassaemia: beta‐thalassaemia; BMD: bone mineral density; CI: confidence interval; MD: mean difference; SD: standard deviation.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

^a Downgraded once for imprecision (few participants).

Summary of findings 4. Summary of findings – denosumab versus placebo.

Denosumab versus placebo for treating osteoporosis in people with β‐thalassaemia
Patient or population: adults with β‐thalassaemia and low bone mass Settings: outpatients Intervention: denosumab 60 mg oral Comparison: placebo
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of participants (trials)	Certainty of the evidence (GRADE)	Comments
	Assumed risk (placebo)	Corresponding risk (denosumab)
BMD Z score (total hip/femoral neck) Follow‐up: 12 months	The mean Z score in the control group was −0.9 (SD 2.59).	The mean Z score in the intervention group was 0.05 points higher (1.23 lower to 1.33 higher).	MD 0.05 (95% CI −1.23 to 1.33)	63 (1)	⊕⊕⊝⊝ Lowa,b	—
BMD Z score (lumbar spine) Follow‐up: 12 months	The mean Z score in the control group was −1.5 (SD 3.33).	The mean Z score in the intervention group was 0.10 points lower (1.95 lower to 1.75 higher).	MD −0.10 (95% CI −1.95 to 1.75)	63 (1)	⊕⊕⊝⊝ Lowa,b	—
BMD Z score (wrist) Follow‐up: 12 months	The mean Z score in the control group was −2.65 (SD 6.29).	The mean Z score in the intervention group was 0.30 points lower (4.07 lower to 3.47 higher).	MD −0.30 (95% CI −4.07 to 3.47)	63 (1)	⊕⊕⊝⊝ Lowa,b	—
Incidence of fractures	No studies reported incidence of fractures.					—
Mobility	No studies reported mobility.					—
Quality of life	No studies reported quality of life.					—
Adverse effects of treatment	No studies reported adverse effects of treatment.					—
*The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). β‐thalassaemia: beta‐thalassaemia; BMD: bone mineral density; CI: confidence interval; MD: mean difference; SD: standard deviation.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

^a Downgraded once for imprecision (few participants).
^b Downgraded once for indirectness as the trial only included adults.

Summary of findings 5. Summary of findings – strontium ranelate versus placebo.

SrR versus placebo for treating osteoporosis in people with β‐thalassaemia
Patient or population: women with low bone mass and β‐thalassaemia Settings: outpatient Intervention: SrR 2 mg daily together with calcium carbonate (1000 mg) and vitamin D (800 IU) Comparison: placebo together with calcium carbonate (1000 mg) and vitamin D (800 IU)
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of participants (trials)	Certainty of the evidence (GRADE)	Comments
	Assumed risk (placebo)	Corresponding risk (SrR)
BMD Z score (total hip/femoral neck)	No studies measured BMD Z score at the hip.					—
BMD Z score (lumbar spine)	See comments.			24 participants  (1 trial)	⊕⊝⊝⊝ Very lowa,b	Morabito 2016 reported narratively and illustrated in a graph that after 24 months, BMD at the lumbar spine did not change in the placebo group but did increase significantly in the SrR group.
BMD Z score (wrist)	No studies measured BMD Z score at the wrist.					—
Incidence of fractures	No studies measured incidence of fractures.					—
Mobility	No studies measured mobility.					—
Quality of life (back pain VAS score in cm) Follow up: 24 months	The mean VAS score for back pain in the placebo group was 3.2 (SD 0.7) cm.	The mean VAS score in the SrR group was 0.7 cm lower (1.30 lower to 0.10 lower).	—	24 participants (1 trial)	⊕⊝⊝⊝ Very lowa,c	Back pain was reported as a surrogate marker of QoL. Lower VAS score represents less pain. This outcome was also reported at 18 months, but there was no difference between groups (MD −0.60 cm, 95% CI −1.25 to 0.05)
Adverse effects of treatment	No studies measured adverse effects of treatment.					—
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). β‐thalassaemia: beta‐thalassaemia; BMD: bone mineral density; CI: confidence interval; SD: standard deviation; SrR: strontium ranelate; VAS: visual analogue scale.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

^a Downgraded twice for risk of bias within the single trial included for this outcome. Risk of bias was unclear across the domains of randomization, allocation concealment, and blinding.
^b Downgraded once for imprecision (no analysable data and few participants).
^c Downgraded once for imprecision (few participants).

Background

See the glossary for an 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 (β)‐thalassaemia.

The β‐thalassaemias are a group of hereditary blood disorders characterized by anomalies in the synthesis of the β‐chains of haemoglobin (Hb), resulting in variable phenotypes ranging from severe anaemia to clinically asymptomatic individuals (Galanello 2010). An estimated 1.5% of the global population (80 to 90 million people) are carriers of β‐thalassaemia, with about 60,000 symptomatic individuals born annually, the great majority in low‐income countries. The total annual incidence of symptomatic β‐thalassaemia is estimated at one in 100,000 people worldwide and one in 10,000 people in the European Union (Galanello 2010).

In β‐thalassaemia, a reduced rate of synthesis of one or more β‐globin chains leads to an imbalance in the globin chain synthesis, defective Hb 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 β‐globin messenger ribonucleic acid (RNA). Deletional mutations are rare (approximately 15 have been identified to date), whereas researchers have characterized approximately 200 non‐deletional mutations.

The most clinically severe form of β‐thalassaemia is thalassaemia major, which is characterized by the complete absence of β‐globin chain production. A milder form, which requires no or fewer transfusions, is known as β‐thalassaemia intermedia. Another form, β‐thalassaemia minor (also known as β‐thalassaemia‐trait), is a heterozygous carrier state for β‐thalassaemia. Infants with β‐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 on whether the child is maintained on an adequate transfusion programme. An inadequately transfused child with β‐thalassaemia develops stunted growth, bossing of the skull, overgrowth of maxillary bones, and evidence of extramedullary haematopoiesis (Galanello 2010). Spontaneous fractures commonly occur as the result of expansion of the marrow cavity with thinning of long bones and skull. In addition, maxillary deformity often leads to dental problems from malocclusion; the liver and spleen are enlarged, with splenomegaly leading to thrombocytopenia and leukopenia (resulting in an increased tendency to infection and to bleeding); and chronic leg ulceration may also occur.

Children who have grown and developed normally during the first 10 years of life owing 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 failure of menarche. 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). Hypozincaemia is common in people with β‐thalassaemia and has been associated with low bone mass (Sanctis 2013).

The pathogenesis of osteoporosis in β‐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 also occurs (De Sanctis 1996), 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 individuals. Osteoclastic activity is elevated and osteoblasts are deregulated in people with β‐thalassaemia who also have osteoporosis (Voskaridou 2004).

The prevalence of osteoporosis in people with β‐thalassaemia varies depending on the site (lumbar or femoral). Different studies have reported lumbar osteoporosis prevalences of 50.7% to 74.1%, and femoral osteoporosis prevalences ranging from 10.8% to 37.9% (Scacchi 2008; Shamshirsaz 2007). The reported prevalence of fractures in people with β‐thalassaemia ranges from 12.1% to 35.1% (Basanagoudar 2001; Ruggierol 1998; Sutipornpalangkul 2010; Vogiatzi 2006).

Description of the intervention

There are various therapeutic strategies for preventing or treating osteoporosis in people with β‐thalassaemia. Optimizing transfusions to maintain higher pretransfusion Hb levels reduces bone marrow hyperplasia from ineffective erythropoiesis. Regular blood transfusion to maintain 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 smoking cessation are other recommended measures to reduce the risk of osteoporosis (Voskaridou 2004).

Bisphosphonates (e.g. clodronate, pamidronate, alendronate, zoledronic acid), with or without hormone replacement therapy (HRT), are a class of drugs that prevent the loss of bone density and are considered the most effective treatment for osteoporosis (Akesson 2003). They may be given either orally or intravenously.

Other treatments include calcitonin, a hormone naturally produced in the thyroid gland and available as a supplement (oral or intramuscular injection). It is a potent inhibitor of osteoclasts and is used in combination with the daily administration of calcium. Hydroxyurea is an oral medication originally used to treat cancer and prevent pain crises in sickle cell disease; it has also shown promising results in treating osteoporosis (Angastiniotis 1998). However, the most effective way of preventing osteoporosis and other bone deformities in people with β‐thalassaemia seems to be preventing hypogonadism through HRT (Jensen 1998a; Lindsay 1993).

Zinc is an essential micronutrient in humans that plays an important role in growth and development. It is present in all tissues, fluids, and secretions in the body and is critical to cellular metabolism, physical growth, immune competence, reproductive functions, integrity of intestinal mucosa, and neuro‐behavioural development (Mahyar 2010). Zinc deficiency is observed in pathological conditions including haemoglobinopathies. People with β‐thalassaemia major suffer from zinc deficiency, which may be one of the causes of delayed maturity. In cases of β‐thalassaemia, zinc supplementation corrects the risk of zinc deficiency from various causes, including desferrioxamine injections. Zinc supplements may be given orally or intravenously. 

Denosumab (DNB) is a fully human monoclonal antibody given by subcutaneous injection. It has shown efficacy in both men and postmenopausal women with osteoporosis (Cummings 2009; Papapoulus 2015; Sugimoto 2015).

Strontium ranelate (SrR) is a current oral treatment option for postmenopausal and male osteoporosis. 

How the intervention might work

All the interventions listed in Description of the intervention aim to increase BMD and markers of bone formation and decrease markers of bone resorption. Increased BMD will reduce the risk of fracture and bone pain, thus improving the quality of life (QoL) of people with β‐thalassaemia and 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 (deoxypyridinoline and pyridinoline) and inhibits bone loss, but does not cause a substantial increase in 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; it increases BMD and is used in people with transfusion‐dependent β‐thalassaemia and severe osteoporosis (Perifanis 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 improves radiological findings of osteoporosis (Canatan 1995).

Hydroxyurea acts by reducing marrow hyperplasia and bone pain (Angastiniotis 1998). It is an effective alternative to chronic blood transfusion and improves QoL by decreasing the need for blood transfusion (Bordbhar 2014; 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).

Studies have found that continuous HRT (transdermal oestrogen for females or human chorionic gonadotrophin for males) improves bone density parameters (Anapliotou 1995).

Studies have shown that zinc supplementation increases bone mass, improves linear growth, and corrects immunodeficiency and growth delay (Fung 2013). In young people with β‐thalassaemia, zinc supplementation may lead to a greater gain in BMD and help to improve anthropometry measurements (Arcasoy 1987; Swe 2013). Additionally, it works to correct zinc deficiency in people taking iron chelating agents such as desferrioxamine (Al‐Refaie 1994).

Studies have shown that circulating RANKL, the most potent osteoclast activator, is elevated in people with transfusion‐dependent β‐thalassaemia and is associated with low BMD. DNB is a monoclonal antibody that binds to RANKL, thus preventing the stimulation of osteoclasts, which are responsible for bone resorption (Voskaridou 2018).

SrR acts by simultaneously promoting bone formation and inhibiting bone resorption; it contributes to a net gain in BMD, an increase in bone strength, and a reduction in fracture risk (Morabito 2016).

Why it is important to do this review

There are a number of treatment guidelines for treating osteoporosis in people with β‐thalassaemia. We aim to find the most effective available treatment in terms of bone remodelling parameters and BMD to improve QoL in this population. This is an update of a previously published Cochrane Review (Bhardwaj 2016).

Objectives

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

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials (RCTs).

Types of participants

People with β‐thalassaemia with either a BMD Z score of under −2 standard deviations (SDs) for children aged under 15 years, adult males (aged 15 to 50 years) and all premenopausal females aged over 15 years; or a BMD T score of under −2.5 SD for postmenopausal females and males aged over 50 years.

Types of interventions

Any treatment for osteoporosis in people with β‐thalassaemia. Eligible interventions included, but were not limited to, bisphosphonates, HRT, calcitonin, blood transfusion or hydroxyurea, zinc, DNB, and SrR. Eligible controls were placebo; no treatment; another intervention; or the same intervention with a different dosing regimen, an adjuvant therapy, or both.

Types of outcome measures

Primary outcomes

1. Absolute or percentage change in a real or volumetric BMD Z score, as measured by dual X‐ray absorptiometry (DXA) or computerized tomography (CT), at the following sites

   1. Total hip or femoral neck

   2. Spine

   3. Wrist

2. Incidence of fracture (clinical or radiographic)

Secondary outcomes

1. Mobility (as reported by participants, using a validated score if possible)

2. QoL (as reported in the individual trials)

3. Adverse effects of treatment (e.g. upper gastro‐intestinal symptoms, as reported by participants)

4. Bone pain (intensity, frequency, duration)

Search methods for identification of studies

There were no restrictions regarding language or publication status.

Electronic searches

We identified potentially relevant trials from the Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register using the terms: (thalassaemia OR (haemoglobinopathies AND general)):kw AND osteoporosis:kw

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

Date of the most recent search of the Cochrane Cystic Fibrosis and Genetic Disorders Haemoglobinopathies Trials Register: 4 August 2022.

We also searched the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (apps.who.int/trialsearch). See Appendix 2 for details of the search strategy.

Searching other resources

We scrutinized the reference lists of the identified trials for additional citations. We also contacted organizations and researchers working in the field.

Data collection and analysis

Selection of studies

Two review authors (AB and KM) independently screened all available titles and abstracts for inclusion using an eligibility form designed in accordance with the specified inclusion criteria. If we could not ascertain the relevance by screening the title and abstract, we retrieved and reviewed the full text of the article. We resolved disagreements by discussion or, if required, by consulting a third review author. We displayed studies excluded from the review, together reasons for exclusion, in a Characteristics of excluded studies table.

Data extraction and management

Two review authors (KM and AB) independently collected and recorded data, then compared results and corrected any errors. The review authors resolved any disagreements through discussion, and would have consulted the third review author if required. Where published reports contained unclear information, we attempted to contact the trial authors for further details.

The bisphosphonate trials assessed different types of drug therapies; we presented these data together. For the three‐arm trial, we presented the individual bisphosphonates compared to control as well as the combined data for alendronate and clodronate therapies (Morabito 2002). We followed guidance in the Cochrane Handbook for Systematic Reviews of Interventions when calculating the means and SDs for the combined BMD results at the lumbar spine and femoral neck (Deeks 2022).

For the DNB versus placebo trial (Voskaridou 2018), as we found the data distribution to be symmetrical, we entered the medians directly into the meta‐analysis and calculated the SDs with the formula SD = interquartile range (IQR)/1.35 (Deeks 2022).

For the SrR versus placebo trial, we estimated the placebo group back pain score at 18 months from the graph presented in figure 3 in the main paper; we assumed the SD was the same as baseline, given "a significant pain reduction was detected only in the SrR group" (Morabito 2016).

Assessment of risk of bias in included studies

Two review authors (KM, IO) independently assessed the risk of bias of the included trials by using the criteria outlined in the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2017). We assessed sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other potential sources of bias. We judged each domain as having a ‘low risk’, ‘high risk, or ‘unclear risk’ of bias. We resolved any disagreements by discussion or by involving a third review author where necessary.

Measures of treatment effect

For dichotomous data, we presented results as risk ratios (RRs) with 95% confidence intervals (CIs). For continuous data, where outcomes were measured in the same way between trials, we used mean differences (MDs), with 95% CIs. In future updates, we will use the standardized mean difference (SMD) to combine data from any trials that measure the same outcome with different methods (Deeks 2022). For count data, we plan to calculate the MD of the mean number of events per person with corresponding CIs.

Unit of analysis issues

The unit of analysis was the treated participant. If, in future updates, we include cluster‐randomized trials that do not provide intracluster correlation coefficients (ICCs), we will calculate ICCs according to the method of Donner and colleagues (Donner 2001). If we identify cross‐over trials, we plan to analyse data using the approach recommended by Elbourne and colleagues (Elbourne 2002).

Dealing with missing data

For future updates of the review, where trials have been published in abstract form only or presented at meetings, we plan to contact the trial authors for any available full reports or further information. For any trials where information is missing or unclear, we will contact the trial authors for further details. If the authors do not reply, and we are unable to assess eligibility based on the published information, we will exclude the trial because of insufficient data.

For Forni 2012, there were insufficient data to include in an analysis; we therefore reported results narratively. We plan to contact the trial authors for future updates in an effort to access further information.

Assessment of heterogeneity

We assessed the presence of statistical heterogeneity using the Chi² test (significance level P < 0.1) and quantified the degree of heterogeneity using the I² statistic. For the interpretation of the I² values, we used the following guidelines (Deeks 2022).

1. 0% to 40%: might not be important

2. 30% to 60%: may represent moderate heterogeneity

3. 50% to 90%: may represent substantial heterogeneity

4. 75% to 100%: considerable heterogeneity

We regarded an I² value of 50% or more to represent significant heterogeneity.

Assessment of reporting biases

Two review authors undertook comprehensive searches in an attempt to minimize publication and reporting biases. Within trials, we considered selective outcome reporting as part of the risk of bias assessment. We compared the methods section of the full published papers to the results section to ensure that all prespecified outcomes were reported. If we include 10 or more trials in future updates, we plan to assess publication bias by constructing and assessing the symmetry of a funnel plot. If we do detect asymmetry, we plan to explore possible causes other than publication bias.

Data synthesis

Where trials were clinically and methodologically comparable, we carried out meta‐analysis using Review Manager software (RevMan 2014). As we found no significant statistical heterogeneity (as defined above), and trials were sufficiently similar, we used a fixed‐effect meta‐analysis model for combining data. If we find significant heterogeneity in future updates, we will use a random‐effects model. We analysed the BMD scores separately across the different sites (total hip/femoral neck, lumbar spine, wrist).

Subgroup analysis and investigation of heterogeneity

For future updates of the review, if we find substantial or considerable heterogeneity (as defined in Assessment of heterogeneity), we plan to carry out the following subgroup analyses.

1. Sex and age (females: younger than 15 years, 15 to 45 years, postmenopausal; males: younger than 15 years, 15 to 50 years, older than 50 years)

2. Routes (oral, intravenous (IV) infusion, intramuscular (IM) injection) and doses of treatments

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

Sensitivity analysis

If we include more trials in future updates, we plan to carry out a sensitivity analysis to explore the effect of risk of bias (assessed by allocation concealment) by excluding trials with a high risk of bias.

Summary of findings and assessment of the certainty of the evidence

For this update, in line with current Cochrane guidance, we added a summary of findings table for each comparison presented in the review (Table 1; Table 2; Table 3; Table 4; Table 5). We reported the following outcomes in the summary of findings tables (chosen based on relevance to clinicians and consumers).

1. BMD Z score at the total hip or femoral neck

2. BMD Z score at the spine

3. BMD Z score at the wrist

4. Incidence of fracture

5. Mobility

6. QoL

7. Adverse effects of treatment

We judged the certainty of the evidence using the GRADE approach, downgrading for concerns related to risk of bias, indirectness of the evidence, unexplained heterogeneity or inconsistency, imprecision of results, or high probability of publication bias. We downgraded evidence by one level if we considered the limitation to be serious and by two levels if very serious.

Results

Description of studies

For details of all studies, refer to the relevant tables (Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification; Characteristics of ongoing studies).

Results of the search

We identified 83 records through database searches and six through other searches. From this list, we removed 29 duplicates, leaving 60 references. At the screening stage, we excluded one reference based on the title, and then retrieved the full texts of the remaining 59 references. Following the assessment of these full‐text articles, we included six trials (17 references), excluded 17 trials (33 references), listed two trials (three references) as awaiting classification (Eid 2021; TCTR20201223008), and listed four trials (six references) as ongoing (CTRI/2019/04/018764; IRCT2017070420258N51; NCT01016093; Piriyakhuntorn 2019). Figure 1 presents the flow of studies in a PRISMA diagram.

1.

Study flow diagram.

Included studies

Six trials met our inclusion criteria (Forni 2012; Fung 2013; Morabito 2002; Morabito 2016; Voskaridou 2003; Voskaridou 2018). Active interventions included second‐ and third‐generation bisphosphonates with established efficacy in metabolic bone disease (Forni 2012; Morabito 2002; Voskaridou 2003), zinc supplementation (Fung 2013), the monoclonal antibody DNB (Voskaridou 2018), and SrR (Morabito 2016).

Methods

All six trials were described as RCTs of parallel design. Five trials randomized participants to one of two treatment arms, and one was a three‐arm trial (Morabito 2002). Trial duration ranged from 12 months (Voskaridou 2003; Voskaridou 2018) to two years (Morabito 2002; Morabito 2016). The planned duration of Forni 2012 was 24 months; however, an interim analysis was scheduled and performed at 12 months, and we used these data. Two trials were multicentre RCTs (Forni 2012; Fung 2013), while four trials were conducted in a single centre (Morabito 2002; Morabito 2016; Voskaridou 2003; Voskaridou 2018). Three trials took place in Italy (Forni 2012; Morabito 2002; Morabito 2016), two in Greece (Voskaridou 2003; Voskaridou 2018), and one in the USA (Fung 2013).

Participants

The number of participants in each trial ranged from 24 (Morabito 2016) to 118 (Forni 2012). All trials had more female than male participants, and one trial included only females (Morabito 2016). In total, there were 114 males and 184 females. Average ages ranged from 10 years (Fung 2013) to 78 years (Voskaridou 2018). Three trials stated that participants had β‐thalassaemia major and were transfusion‐dependent (Morabito 2002; Morabito 2016; Voskaridou 2018). A further trial published as an abstract did not describe transfusion status but stated that participants had β‐thalassaemia major; we assumed participants were transfusion‐dependent (Voskaridou 2003). Voskaridou 2003 also included a control group of 45 healthy participants who were ineligible for inclusion in this review. Fung 2013 described participants as having β‐thalassaemia and low bone mass and stated that 81% were transfusion‐dependent (Fung 2013). One trial randomized participants with either β‐thalassaemia major or severe β‐thalassaemia intermedia, but all were transfusion‐dependent (Forni 2012).

Interventions

Three trials assessed bisphosphonates: Forni 2012 compared neridronate 100 mg IV infusion every 90 days to no treatment (though both groups also received calcium 500 mg and vitamin D 400 IU daily); Morabito 2002 (the three‐arm trial) evaluated clodronate 100 mg IM every 10 days versus oral alendronate 10 mg daily versus placebo (all participants also took elemental calcium 500 mg and cholecalciferol 400 IU in the evenings at meal time); and Voskaridou 2003 compared pamidronate 60 mg IV to pamidronate 30 mg IV. Fung 2013 evaluated zinc sulphate 25 mg daily versus placebo, Morabito 2016 evaluated SrR 2 g daily versus placebo (all participants also took calcium carbonate 1000 mg and vitamin D 800 IU), and Voskaridou 2018 evaluated monoclonal antibody DNB 60 mg every six months versus placebo (Voskaridou 2018).

Outcomes

All six trials measured BMD Z score; five trials took measurements at the lumbar spine (Forni 2012; Fung 2013; Morabito 2002; Morabito 2016; Voskaridou 2003), all six at the total hip/femoral neck (Forni 2012; Fung 2013; Morabito 2002; Morabito 2016; Voskaridou 2003; Voskaridou 2018), one at the forearm (Voskaridou 2003), and one at the wrist (Voskaridou 2018). 

Four trials measured bone turnover or remodelling (Forni 2012; Morabito 2002; Morabito 2016; Voskaridou 2018), and Fung 2013 also measured bone mineral content. Three trials assessed blood test parameters: serum levels of bone‐specific isoenzyme of alkaline phosphatase (BALP) and carboxy‐terminal collagen (CTX) in Forni 2012 plasma zinc in Fung 2013; and insulin‐like growth factor‐1 (IGF‐1), sclerostin, and Dickkopf‐1 (DKK‐1) in Morabito 2016. Three trials measured pain, through the use of analgesics (Forni 2012) or scoring systems (Morabito 2016; Voskaridou 2018). Forni 2012 also evaluated QoL using the SF‐36 self‐administered questionnaire, and Morabito 2002 reported safety and tolerability.

Excluded studies

We excluded 17 trials (Balachandar 2012; Canartan 1995; Chae 2009; Chatterjee 2012; Darvish‐Khezri 2018; Gilfillan 2006; Gurkan 2005; Krishnan 1994; Naithani 2018; Noroozi 2022; Olgun 2019; Otrock 2006; Pennisi 2003; Skordis 2008; Voskaridou 2008; Voskaridou 2009; Yassin 2020). Ten trials were not RCTs (Canartan 1995; Chatterjee 2012; Chae 2009; Darvish‐Khezri 2018; Krishnan 1994; Naithani 2018; Noroozi 2022; Olgun 2019; Otrock 2006; Skordis 2008), five reported BMD results as T scores instead of Z scores (Gilfillan 2006; Gurkan 2005; Pennisi 2003; Voskaridou 2008; Voskaridou 2009), and one investigated the effects of vitamin D on calcium excretion (Balachandar 2012). One trial was terminated early as investigators were unable to recruit eligible people (Yassin 2020).

Studies awaiting classification

Two trials are awaiting classification pending further information (Eid 2021; TCTR20201223008).

Eid 2021 was an RCT that aimed to investigate the effectiveness of whole body vibration (WBV) on BMD and functional capacity in 39 children with β‐thalassaemia major. Participants (23 boys and 16 girls) ranged in age from six to 10 years. The children all had a β‐thalassaemia major diagnosis, and their baseline BMD Z scores were below −1 SD at the lumber spine, femoral neck, and the total body. The intervention group (n = 19) received medical treatment together with a conventional physical therapy programme and WBV training; the control group (n = 20) received the medical treatment and the conventional physical therapy programme. Investigators measured BMD and functional capacity at baseline and after 24 weeks. 

The second trial awaiting classification was also an RCT (TCTR20201223008). Participants were males or premenopausal females aged 19 to 50 years, diagnosed with β‐thalassaemia and with a BMD Z score below −2 SDs. The trial duration was 12 months, and the intervention group received a dietary supplement and melatonin, while the control group received placebo. The primary outcome of the study was MD in BMD at the lumbar spine. Secondary outcomes were MD in BMD at proximal femur, serum bone turnover marker, and pain score. 

Ongoing studies

Four RCTs are listed as ongoing (CTRI/2019/04/018764; IRCT2017070420258N51; NCT01016093; Piriyakhuntorn 2019). 

CTRI/2019/04/018764 is an RCT being conducted at the Postgraduate Institute of Medical Education and Research, Chandigarh, India. It began enrolling participants with a target sample size of 120 in 2019 and is still recruiting. It has a parallel design and is open‐label. The inclusion criteria state that participants must be over 18 years of age, have pre‐existing osteopenia with T scores below −1.5 and be undergoing allogeneic hematopoietic stem cell transplant. The intervention group will receive a single dose of IV zoledronate 4 mg/100 mL normal saline as a 15‐minute infusion before the transplant, and control groups will be observed for prevention of early bone loss. Investigators will assess BMD by DXA on day 100 and day 365 of transplant.

IRCT2017070420258N51 is a double‐blind, parallel‐group RCT being conducted at the Amirkabir Hospital in Arak, Iran. Participants must be aged over 10 years of age, diagnosed with major or intermedia thalassaemia, and have been referred to the hospital. A target of 40 participants will be randomised to receive either alendronate 70 mg once weekly (20 participants) or a three‐day course of IV pamidronate 0.5 mg/kg (20 participants). After 12 months, investigators will report on clinical symptoms (by observation) and BMD at the spine and femoral neck (using X‐ray).

NCT01016093 is being conducted at the Hematology‐Oncology and SCT Research Centre, Tehran University of Medical Sciences in Iran. In November 2009, the RCT began enrolling participants aged over 18 years of age with a diagnosis of β‐thalassaemia major and who were scheduled for allogenic bone marrow transplantation. The intervention group will receive IV zoledronic acid (Zometa) 4 mg (dose adjusted based on renal function) as a 15‐minute infusion every three months for a total of one year (four doses), while the control group will receive placebo. The primary outcome is the percentage change in BMD at the lumbar spine (L1 to L4) measured by DXA at 12 months. Secondary outcomes are the percentage change in BMD at total hip at 12 months; percentage change in BMD at lumbar spine (L1 to L4) and total hip at six months; changes in bone turnover markers at three, six and 12 months; incidence rate of all clinical fractures at one year; and the general safety of zoledronic acid.

Piriyakhuntorn 2019 enrolled the first participant in February 2018, and the registry entry states that the trial is still recruiting. It is a single‐centre trial taking place in Thailand. The investigators aim to recruit 100 participants of either sex diagnosed with β‐thalassaemia (either transfusion‐dependent or non‐transfusion‐dependent) and osteoporosis. Participants should be between 18 and 50 years of age. The trial is comparing oral alendronate (70 mg/tablet) to placebo (round white tablet). All participants will take one tablet per week 30 minutes before a meal. The primary outcome is BMD at one year measured by DXA. Secondary outcomes include serum bone turnover markers, pain scores on a visual analogue scale (VAS), vitamin D deficiency and insufficiency, prevalence of endocrinopathy, vertebral fracture or deformity (measured by DXA), and serum iron levels.

Risk of bias in included studies

For a graphical representation of the risk of bias judgements, see Figure 2 and Figure 3.

2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Random sequence generation

Three trials explained the randomization process clearly and we assessed these three trials as having a low risk of bias for this domain (Forni 2012; Fung 2013; Voskaridou 2018). Forni 2012 randomized participants (approximately 1:1) using a random number sequence generated by computer software. Fung 2013 stratified participants according to sex and pubertal stage and randomly assigned them (1:1) using a block randomization table. Voskaridou 2018 used block randomization to improve comparability of the treatment arms and ensure nearly equal size. The remaining three trials did not clearly describe the random sequence generation process, so we judged them at unclear risk of bias for this domain (Morabito 2002; Morabito 2016; Voskaridou 2003).

Allocation concealment

Voskaridou 2018 reported that an independent authorized person had exclusive access to the randomization list (low risk of bias). None of the remaining included trials described allocation concealment, so we judged them at unclear risk of bias for this domain (Forni 2012; Fung 2013; Morabito 2002; Morabito 2016; Voskaridou 2003).

Blinding

Blinding of participants and personnel

Forni 2012 was open‐label and therefore at high risk of performance bias. Three trials provided no details of blinding of participants, so we judged them at unclear risk of performance bias (Morabito 2002; Morabito 2016; Voskaridou 2003). We judged the remaining two trials at low risk of bias for the blinding of participants and personnel (Fung 2013; Voskaridou 2018). Fung 2013 described the use of a double‐blinding procedure. The placebo capsule was indistinguishable from the zinc capsule, and the two groups were given capsules according to the same dosing schedule. Voskaridou 2018 was described as a double‐blinded trial; neither the participants nor investigator knew the which group each participant belonged to.

Blinding of outcome assessors

Forni 2012 was open‐label and therefore at high risk of detection bias. Three trials provided no details of blinding of outcome assessors, so we judged them at unclear risk of detection bias (Morabito 2002; Morabito 2016; Voskaridou 2003). 

Two trials had a low risk of detection bias (Fung 2013; Voskaridou 2018). Fung 2013 reported that the investigators remained blinded to the intervention group until completion of the project. Voskaridou 2018 was a double‐blinded trial with an independent assessor, and all relevant files and documents were filed securely with encryption to maintain blinding throughout the trial.

Incomplete outcome data

All six trials were at low risk of attrition bias (Forni 2012; Fung 2013; Morabito 2002; Morabito 2016; Voskaridou 2003; Voskaridou 2018). In Forni 2012, there were exclusions due to errors in the imaging outcome, but these appear to be numerically balanced between the groups. Fung 2013 reported that there were 42 participants at the beginning of the trial, with 37 remaining after 12 months (11.9% attrition) and 32 remaining after 18 months (23.80% attrition), which we considered an acceptable level of attrition; there were reported reasons for all withdrawals, most of which were unrelated to the treatment (e.g. death of a sibling). Three trials had no missing data (Morabito 2002; Morabito 2016; Voskaridou 2003). There were three discontinuations in Voskaridou 2018 specifically, one participant from the placebo group was lost to follow‐up after day 272, and two participants from the DNB group withdrew consent on day 0; we considered this an acceptable level of attrition.

Selective reporting

No trials showed any evidence of selective reporting; we therefore judged them all at low risk of reporting bias.

Other potential sources of bias

We identified no other potential sources of bias in any of the trials.

Effects of interventions

See: Table 1; Table 2; Table 3; Table 4; Table 5

We graded the certainty of the evidence for the outcomes reported in the summary of findings tables, with justifications for downgrading in footnotes (Table 1; Table 2; Table 3; Table 4; Table 5).

Bisphosphonates versus placebo

Two trials (143 participants) evaluated bisphosphonates: Forni 2012 (118 participants) and Morabito 2002 (25 participants). We calculated the means and SDs for the combined BMD results at the lumbar spine and femoral neck for the three‐arm trial (Morabito 2002), according to guidance in the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2022). For this trial, we presented the individual bisphosphonates compared to control as well as the combined data for alendronate and clodronate therapies. 

Primary outcomes

1. Absolute or percentage change in a real or volumetric bone mineral density

Both trials reported change in BMD Z score (Forni 2012; Morabito 2002). Forni 2012 compared neridronate (100 mg IV infusion) to no treatment, while Morabito 2002 assessed the effect of clodronate 100 mg IM and alendronate 10 mg oral versus placebo. Forni 2012 reported percentage change but not means and SDs after baseline; we therefore provided a narrative report of the results.

Total hip/femoral neck

Both trials reported the effect of bisphosphonates on femoral neck BMD; Forni 2012 presented six‐ and 12‐month data for treatment with neridronate, and Morabito 2002 presented two‐year data for treatment with alendronate and clodronate.

Forni 2012 reported an increase in the mean femoral neck BMD in the neridronate group at six and 12 months and a decrease in the no treatment group, but these were "non‐significant" changes. When the trial authors compared the groups, they found a higher mean percentage change in femoral neck BMD in the neridronate group at 12 months (P = 0.041), but not at six months. Forni 2012 also reported narratively that at six months, there were significant increases in the mean total hip BMD in the neridronate group but not in the no treatment group. There were no data available for analysis, but the trial authors stated that compared with no treatment, neridronate resulted in a higher mean percentage change in total hip BMD at six months (P < 0.001) and at 12 months (P = 0.004).

In Morabito 2002, there was a difference in BMD Z score in favour of the alendronate group over the placebo group (MD 0.46, 95% CI 0.30 to 0.62; 17 participants; very low‐certainty evidence; Analysis 1.1) and in favour of the clodronate group over the placebo group (MD 0.33, 95% CI 0.08 to 0.58; 16 participants; very low‐certainty evidence; Analysis 1.1). As discussed in the Data extraction and management section, we followed Cochrane guidance to combine the results from the two bisphosphonate arms, finding that combined bisphosphonate treatment led to a higher BMD Z score compared to placebo (MD 0.40, 95% CI 0.22 to 0.58; 1 trials, 25 participants; Analysis 1.1).

1.1. Analysis.

Comparison 1: Bisphosphonates versus placebo or no treatment, Outcome 1: Bone mineral density at the total hip/femoral neck (Z score)

Lumbar spine

Forni 2012 reported increases in BMD at the lumbar spine in both the neridronate and the no treatment group after six months. The trial authors described the mean percentage change in lumbar spine BMD from baseline as "significantly higher" in the neridronate group (3.1%) compared with the no treatment group (0.5%), with a P value of 0.002. They noted similar changes from baseline after 12 months of therapy (3.6% with neridronate versus 0.3% with control; P = 0.001%).

At two years, Morabito 2002 reported a higher BMD Z score in the alendronate group compared with the placebo group (MD 0.18, 95% CI 0.09 to 0.27; 17 participants; very low‐certainty evidence; Analysis 1.2), but no difference between clodronate and placebo (MD 0.09, 95% CI −0.06 to 0.24; 16 participants; very low‐certainty evidence; Analysis 1.2).

1.2. Analysis.

Comparison 1: Bisphosphonates versus placebo or no treatment, Outcome 2: Bone mineral density at the lumbar spine (Z score)

When we combined these data in the same way as for the total hip/femoral neck results, we found that bisphosphonate treatment led to a higher BMD Z score compared to placebo at two years (MD 0.14, 95% CI 0.05 to 0.23; 1 trial, 25 participants; Analysis 1.2).

Wrist

Neither trial reported change in BMD Z score at the wrist.

2. Incidence of fracture

In Forni 2012, only one participant reported fractures during the trial period; the participant was in the neridronate group and discontinued the trial at six months after a road traffic accident (moderate‐certainty evidence). Morabito 2002 did not report incidence of fractures.

Secondary outcomes

1. Mobility

No trials reported mobility.

2. Quality of life

Forni 2012 presented QoL data in relation to back pain assessed on a numeric scale of 0 to 100, where higher scores indicated less back pain. Participants in the neridronate group had a "statistically significant increase" on the mean back pain scale (i.e. less pain) after three months (P = 0.02) and six months (P = 0.002), which persisted to 12 months (P < 0.001). The paper states that the absolute mean back pain scale value was significantly higher (more favourable) in the neridronate group compared with the placebo group at three months (P < 0.042), six months (P = 0.008), and 12 months (P = 0.002). A "significant reduction" in the use of analgesic drugs was noted starting from the third month (Forni 2012). We graded the certainty of this evidence as very low.

3. Adverse effects of treatment

Morabito 2002 recorded no relevant adverse effects. After two years, the most commonly noted adverse effects of treatment for the clodronate group were of local pain at the injection site (seven out of eight participants in the intervention group; RR 15.00, 95% CI 1.00 to 225.33; 16 participants; very low‐certainty evidence; Analysis 1.3). During two years of alendronate therapy, only 1/9 participants reported upper gastrointestinal symptoms (mainly abdominal pain) versus none in the placebo group (RR 2.70, 95% CI 0.13 to 58.24; 17 participants; very low‐certainty evidence; Analysis 1.4). All participants completed the trial.

1.3. Analysis.

Comparison 1: Bisphosphonates versus placebo or no treatment, Outcome 3: Adverse effects – clodronate versus placebo

1.4. Analysis.

Comparison 1: Bisphosphonates versus placebo or no treatment, Outcome 4: Adverse effects – alendronate versus placebo

Reported adverse reactions in Forni 2012 included acute‐phase reaction (characterized by flu‐like symptoms after the first dose of bisphosphonates infusion), decreased serum phosphate (after three months, P = 0.04), increased urinary calcium levels (after three months, P = 0.02), increased blood urea nitrogen (BUN) levels (after nine months, P = 0.007), and a reduction from baseline to six months in alanine transaminase (ALT; P = 0.008) and aspartate aminotransferase (AST; P = 0.03), which persisted at 12 months for AST (P = 0.03).

4. Bone pain

Forni 2012 only reported back pain, which we considered a surrogate marker for QoL.

Different doses of bisphosphonates compared

One trial (26 participants) evaluated pamidronate 60 mg versus pamidronate 30 mg (Voskaridou 2003).

Primary outcomes

1. Absolute or percentage change in a real or volumetric bone mineral density Z score

Total hip/femoral neck

Voskaridou 2003 found no difference in BMD Z score between dose groups at the femoral neck after 12 months (MD −0.08, 95% CI −0.38 to 0.22; 26 participants; very low‐certainty evidence; Analysis 2.1).

2.1. Analysis.

Comparison 2: Different doses of bisphosphonates compared, Outcome 1: Bone mineral density at the total hip/femoral neck (Z score)

Lumbar spine

Voskaridou 2003 reported an increase in BMD A score at the lumbar spine in favour of the 60 mg group over the 30 mg group (MD 0.43, 95% CI 0.10 to 0.76; 26 participants; very low‐certainty evidence; Analysis 2.2).

2.2. Analysis.

Comparison 2: Different doses of bisphosphonates compared, Outcome 2: Bone mineral density at the lumbar spine (Z score)

Wrist

Voskaridou 2003 did not report change in BMD Z score at the wrist, but did find increased BMD Z score at the forearm in favour of the 60 mg group (MD 0.87, 95% CI 0.23 to 1.51; 26 participants; Analysis 2.3).

2.3. Analysis.

Comparison 2: Different doses of bisphosphonates compared, Outcome 3: Bone mineral density at the forearm (Z score)

2. Incidence of fracture

Voskaridou 2003 did not report incidence of fracture.

Secondary outcomes

1. Mobility

Voskaridou 2003 did not report mobility.

2. Quality of life

Voskaridou 2003 did not report QoL.

3. Adverse effects of treatment

Voskaridou 2003 did not report adverse effects of treatment.

4. Bone pain

Voskaridou 2003 did not report bone pain.

Zinc versus placebo

One trial (42 participants) evaluated zinc sulphate supplementation versus placebo (Fung 2013).

Primary outcomes

1. Absolute or percentage change in a real or volumetric bone mineral density Z score

Total hip/femoral neck

Fung 2013 found an increase in BMD Z score in the zinc sulphate group compared to the placebo group at 12 months (MD 0.15, 95% CI 0.11 to 0.19; 37 participants; moderate‐certainty evidence; Analysis 3.1) and at 18 months (MD 0.26, 95% CI 0.21 to 0.31; 32 participants; moderate‐certainty evidence; Analysis 3.1).

3.1. Analysis.

Comparison 3: Zinc versus placebo, Outcome 1: Bone mineral density at the total hip/femoral neck (Z score)

Lumbar spine

Fung 2013 found an increase from baseline in BMD Z score in the zinc sulphate group compared to the placebo group at 12 months (MD 0.15, 95% CI 0.10 to 0.20; 37 participants; moderate‐certainty evidence; Analysis 3.2) and at 18 months (MD 0.34, 95% CI 0.28 to 0.40; 32 participants; moderate‐certainty evidence; Analysis 3.2).

3.2. Analysis.

Comparison 3: Zinc versus placebo, Outcome 2: Bone mineral density at the lumbar spine (Z score)

Wrist

Fung 2013 did not report change in BMD Z score at the wrist.

2. Incidence of fracture

Fung 2013 did not report incidence of fracture.

Secondary outcomes

1. Mobility

Fung 2013 did not report mobility.

2. Quality of life

Fung 2013 did not report QoL.

3. Adverse effects of treatment

Fung 2013 did not report adverse effects of treatment.

4. Bone pain

Fung 2013 did not report bone pain.

Denosumab versus placebo

One trial (63 participants) evaluated DNB 60 mg versus placebo (Voskaridou 2018).

Primary outcome

1. Absolute or percentage change in a real or volumetric bone mineral density

Total hip/femoral neck

Voskaridou 2018 found no difference in BMD Z score at the femoral neck between the DNB group and the placebo group after 12 months (MD −0.05, 95% CI −1.23 to 1.33; 63 participants; low‐certainty evidence; Analysis 4.1).

4.1. Analysis.

Comparison 4: Denosumab (DNB) versus placebo, Outcome 1: Bone mineral density at the total hip/femoral neck (Z score)

Lumbar spine

Voskaridou 2018 found no difference between DNB and placebo in BMD Z score at the lumbar spine at 12 months (MD −0.10, 95% CI −1.95 to 1.75; 63 participants; low‐certainty evidence; Analysis 4.2).

4.2. Analysis.

Comparison 4: Denosumab (DNB) versus placebo, Outcome 2: Bone mineral density at the lumbar spine (Z score)

Wrist

Voskaridou 2018 found no difference in BMD Z score at the wrist between the DNB group and the placebo group at 12 months (MD −0.30, 95% CI −4.07 to 3.47; 63 participants; low‐certainty evidence; Analysis 4.3).

4.3. Analysis.

Comparison 4: Denosumab (DNB) versus placebo, Outcome 3: Bone mineral density at the wrist (Z score)

2. Incidence of fracture

Voskaridou 2018 did not report incidence of fracture.

Secondary outcomes

1. Mobility

Voskaridou 2018 did not report mobility.

2. Quality of life

Voskaridou 2018 did not report QoL.

3. Adverse effects of treatment

Voskaridou 2018 did not report adverse effects of treatment.

4. Bone pain

Voskaridou 2018 showed a reduction in bone pain at 12 months in favour of the DNB group compared to the placebo group when measured using both Huskisson's VAS (MD −2.40 cm, 95% CI −3.80 to −1.00; 63 participants; Analysis 4.4) and the McGill‐Melzack scoring system* (MD −2.00 points, 95% CI −2.82 to −1.18; 63 participants; Analysis 4.5). 

4.4. Analysis.

Comparison 4: Denosumab (DNB) versus placebo, Outcome 4: Pain score (Huskisson's VAS)

4.5. Analysis.

Comparison 4: Denosumab (DNB) versus placebo, Outcome 5: Pain score (McGill–Melzack scoring system)

*The McGill–Melzack scoring system is a verbal scale with six levels ranging from 0 to 5, where 0 is no pain and 5 is excruciating pain.

Strontium ranelate versus placebo

One trial (24 participants) evaluated SrR versus placebo (Morabito 2016).

Primary outcome

1. Absolute or percentage change in a real or volumetric bone mineral density

Total hip/femoral neck

Morabito 2016 assessed the effects of SrR on BMD Z score by DXA densitometry at the femoral neck. The trial authors reported narratively and illustrated in a graph that after 24 months, there was no "significant BMD change" at the femoral neck in either group, but that BMD Z score values had increased in the SrR group and decreased in the placebo group.

Lumbar spine

Morabito 2016 assessed the effects of SrR on BMD Z score by DXA densitometry at the lumbar spine (L1 to L4) in anterior‐posterior projection. The trial authors reported narratively and illustrated in a graph that after 24 months, BMD Z score at the lumbar spine had not changed in the placebo group but had increased significantly in the SrR group.

Wrist

Morabito 2016 did not report change in BMD Z score at the wrist.

2. Incidence of fracture

Morabito 2016 did not report incidence of fracture.

Secondary outcomes

1. Mobility

Morabito 2016 did not report mobility.

2. Quality of life

Morabito 2016 assessed the effect of SrR on back pain, which we considered a surrogate marker for QoL. Morabito 2016 measured back pain on a VAS at 18 and 24 months. There was no difference between groups in reported reduction in back pain at 18 months (MD −0.60 cm, 95% CI −1.25 to 0.05; P > 0.05; 24 participants; very low certainty evidence; Analysis 5.1). However, there was a reduction in back pain at 24 months in favour of the SrR group compared to the placebo group (MD −0.70 cm, 95% CI −1.30 to −0.10; P = 0.02; 24 participants; Analysis 5.1).

5.1. Analysis.

Comparison 5: Strontium ranelate (SrR) versus placebo, Outcome 1: Back pain score (VAS)

Note: for the 18‐month placebo data, we estimated the placebo group back pain score at 18 months from the graph presented in Figure 3 in the main paper, and we assumed the SD was the same as baseline, given "a significant pain reduction was detected only in the SrR group" (Morabito 2016).

3. Adverse effects of treatment

Morabito 2016 did not report adverse effects of treatment.

4. Bone pain

Morabito 2016 assessed the effect of SrR on back pain, which we considered a surrogate marker for QoL.

Discussion

Summary of main results

We identified six trials for inclusion in the review and all contributed some useful outcome data (Forni 2012; Fung 2013; Morabito 2002; Morabito 2016; Voskaridou 2003; Voskaridou 2018).

Bisphosphonates

Two trials (143 participants) compared a bisphosphonate to placebo or no treatment, assessing outcomes at 12 months (Forni 2012) or two years (Morabito 2002). In Forni 2012 (the 12‐month trial of neridronate), there were increases in BMD Z score at the total hip (at six and 12 months) and femoral neck (at 12 months only) and lumbar spine compared to no treatment. In Morabito 2002 (the two‐year, three‐arm trial of alendronate, clodronate, and placebo), BMD Z score at the femoral neck increased in the combined group and both individual groups compared to placebo (Analysis 1.1). BMD Z score at the lumbar spine increased in the combined bisphosphonate group and in the individual alendronate group compared to placebo, but not in the clodronate group (Analysis 1.2). Only one trial reported a single fracture in bisphosphonate arm (after a road traffic accident; Forni 2012). Both trials reported no major adverse effects (Forni 2012; Morabito 2002). Morabito 2002 reported local pain at the injection site in nearly all participants in the clodronate group and upper gastrointestinal symptoms in one of nine participants in the alendronate group. In Forni 2012, three participants reported acute‐phase reaction characterized by flu‐like symptoms after first infusion and controlled by paracetamol. Only Forni 2012 reported bone pain, finding that participants in the neridronate group had less back pain throughout the 12‐month trial and a significant reduction in the use of analgesic drugs from the third month. Neither trial reported mobility or undertook a formal QoL assessment (Forni 2012; Morabito 2002).

One trial compared different doses of pamidronate (60 mg versus 30 mg; Voskaridou 2003). After 12 months, BMD Z score increased at the lumbar spine and forearm in the 60 mg group compared to the 30 mg group, although there was no difference between doses at the femoral neck. This trial did not report any of our other outcome measures (fracture incidence, mobility, QoL, adverse effects, or bone pain).

Zinc sulphate

In the zinc sulphate supplementation trial, BMD Z score increased at the hip and the lumbar spine in the supplemented group after 12 months and after 18 months (Fung 2013). This trial did not report any of our other outcome measures (fracture incidence, mobility, QoL, adverse effects, or bone pain).

DNB

One 12‐month trial compared DNB 60 mg to placebo (Voskaridou 2018). There were no differences in BMD Z score between DNB and placebo at the lumbar spine, femoral neck, or wrist. There was less bone pain with 60 mg DNB compared to placebo when measured using Huskisson's VAS and the McGill‐Melzack scoring system. The trial did not report any of our other outcome measures (fracture incidence, mobility, QoL, or adverse effects).

SrR

One trial compared 2 g SrR to placebo over two years (Morabito 2016). The trial narratively reported an increase in BMD at the lumbar spine with no corresponding change to the placebo group (also illustrated on a graph in the paper). Investigators also reported no difference in back pain between groups at 18 months, but back pain was less in the SrR group compared to the placebo group at 24 months (Analysis 5.1). The trial did not report any of our other outcome measures (fracture incidence, mobility, QoL, or adverse effects).

Overall completeness and applicability of evidence

There are a number of therapeutic strategies for treating osteoporosis in people with β‐thalassaemia. In this review, we examined the effect of bisphosphonates (clodronate, pamidronate, alendronate, neridronate), DNB, SrR, and zinc supplementation to improve BMD Z score, increase bone strength and reduce fracture risk.

The included trials do not cover all types of β‐thalassaemia. Nearly all participants were transfusion‐dependent; only 19% of participants in a single trial were non‐transfusion‐dependent (Fung 2013). One trial randomized some participants with β‐thalassaemia intermedia, but they were transfusion‐dependent (Forni 2012). No trials included participants with non‐transfusion‐dependent β‐thalassaemia intermedia or β‐thalassaemia minor. We were only able to include some of the currently available treatments in this review; some trials of other interventions were ineligible according to our inclusion criteria.

The available evidence suggests an increase in BMD Z score in the intervention groups compared to placebo or no treatment groups, but the trials had some limitations (e.g. number of participants, trial duration, use of adjuvant therapies such as calcium, vitamin D, and HRT).

To fully answer our review question, there is a need for long‐term RCTs investigating different treatments with bisphosphonates and zinc supplementation in people with β‐thalassaemia and osteoporosis.

Quality of the evidence

The quality of the trials was mixed. Of the six included trials, two described double‐blinding procedures (Fung 2013; Voskaridou 2018), one was open‐label (Forni 2012), and the remaining three provided insufficient information on blinding (Morabito 2002; Morabito 2016; Voskaridou 2003). There was low risk of attrition bias for all trials, although one trial reported overall attrition greater than 20% (Fung 2013). All trials were based in hospitals, with active mechanisms in place to promote adherence to the intervention. However, although all trials reported the use of randomization methods, three trials did not provide details of the method used (Morabito 2002; Morabito 2016; Voskaridou 2003), and only Voskaridou 2003 reported how allocation was concealed.

The certainty of the evidence ranged from moderate to very low due to issues surrounding the risk of bias judgements and imprecision due to low participant numbers, low event rates and indirectness (the DNB trial only included adults).

Potential biases in the review process

We took care in all the steps of the review process to minimize bias, starting from trial identification using comprehensive search strategies, independent assessment of risk of bias in the included trials, and independent data extraction.

Agreements and disagreements with other studies or reviews

Two previous reviews found that bisphosphonates were efficacious in the management of thalassaemia‐associated osteoporosis and had few side effects (Gaudio 2008; Voskaridou 2004). However, both concluded that more trials are needed to clarify the exact role of each bisphosphonate and to assess the long‐term benefit and side effects. These findings and conclusions are consistent with ours.

Authors' conclusions

Implications for practice.

The available evidence is limited, as it is based on few trials and there are some concerns around selection bias (we judged there to be an unclear risk of bias from the randomisation procedure in half of the included trials and an unclear risk of bias regarding the concealment of allocation in five of the six included trials). The overall conclusion is that bisphosphonates (neridronate, alendronate, clodronate, pamidronate; with or without co‐interventions), zinc sulphate supplements, and strontium ranelate (SrR) increase bone mineral density (BMD) in people with beta (β)‐thalassaemia. There is some evidence that bisphosphonates, denosumab (DNB), and SrR may reduce episodes of back pain.

Implications for research.

Initial results seem to show increased BMD with bisphosphonate therapy, zinc sulphate supplementation, and SrR compared with a placebo or no treatment; however, further trials are needed to improve the validity of our findings. Future trials should involve more participants and have a longer duration of treatment than those reported in this review.

What's new

Date	Event	Description
9 May 2023	New search has been performed	The searches identified 32 new potentially relevant references. Included studies We included two new trials (eight references) with a total 87 participants (Morabito 2016; Voskaridou 2018). One reference (by Catalano) was previously listed in 'Studies awaiting classification' and is now an additional reference to a newly included trial (Morabito 2016). We added three new references to two already included studies (Forni 2012; Fung 2013). Excluded studies We excluded seven new trials (nine references) (Chae 2009; Chatterjee 2012; Darvish‐Khezri 2018; Naithani 2018; Noroozi 2022; Olgun 2019; Yassin 2020). We added four new references to an already excluded study (Voskaridou 2009). We excluded one study (one reference) previously listed as 'Awaiting classification' (Gurkan 2005).  Studies awaiting classification We listed two new trials (three references) as awaiting classification (Eid 2021; TCTR20201223008). Ongoing studies We listed four new trials (six references) as ongoing (CTRI/2019/04/018764; IRCT2017070420258N51; NCT01016093; Piriyakhuntorn 2019).
9 May 2023	New citation required but conclusions have not changed	Despite the inclusion of two new trials with 87 participants, our conclusions remain the same. One author (Ify Osunkwo) stepped down at the update published in 2023.

History

Protocol first published: Issue 3, 2013
Review first published: Issue 3, 2016

Appendices

Appendix 1. Glossary of terms

Term	Explanation
Adjuvant therapy	Treatment of a disease with substances that enhance the action of drugs, especially drugs that promote the production of antibodies
Apoptosis	A pathway of cell death in which cells activate enzymes that degrade the cells' own nuclear DNA and nuclear and cytoplasmic proteins
Arthropathy	Disease of a joint
Chelation	The removal of metal (in this case iron) poisoning using agents that separate the metal from organs or tissues and bind it firmly with a new compound that can be eliminated from the body
Cirrhosis	Widespread disruption of normal liver structure by fibrosis and the formation of regenerative nodules caused by any of various chronic progressive conditions affecting the liver
Cortical thinning	Thinning of the outer shell of bone
Erythropoiesis	Process by which red blood cells (erythrocytes) are produced
Extramedullary haematopoiesis	Located or taking place outside the bone marrow
Femoral	Related to the femur (thigh bone)
Gonadotropin	A hormone that stimulates the growth and activity of the gonads, especially any of several pituitary hormones that stimulate the function of the ovaries and testes
Haematopoiesis	The process by which immature precursor cells develop into mature blood cells
Hepatocellular carcinoma	The most common type of liver cancer
Heterozygous	Having inherited different forms of a particular gene from each parent
Hyperplasia	Increase in number of cells/proliferation of cells
Hypogonadism	A medical condition characterized by abnormally high levels of reproductive hormones such as oestrogen or testosterone
Hypozincaemia	Reduced serum zinc level
Lacunae	A hollow within a structure, especially bony tissue, where osteocytes are located
Leukopenia	A decrease in the number of total white blood cells found in blood
Lumbar	Related to the lower abdominal region or lower spine
Malocclusion	Misalignment of teeth or incorrect relation between the teeth of the two dental arches
Maxillary bones	Bones that form the upper jaw
Monocyte	A large, circulating, phagocytic white blood cell that has a single well‐defined nucleus and very fine granulation in the cytoplasm and that constitutes 3%–8% of white blood cells in humans
Osteoblast	A cell that is responsible for bone formation
Osteoclastic activity	Activities by cells to break down and reabsorb bone tissue
Phagocytosis	Process of engulfing particles by the cell
Pulmonary hypertension	Abnormally high blood pressure in the arteries of the lungs
Siderosis	Deposition of iron in tissue
Splenomegaly	Enlargement of the spleen
Thrombocytopenia	Reduced 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.

Appendix 2. Electronic search strategies

Database	Search strategy	Date last searched
Clinicaltrials.gov (www.clinicaltrials.gov)	'thalassaemia OR thalassemia AND osteoporosis'	13 February 2022
WHO International Clinical Trials Registry Platform (ICTRP; www.who.int/ictrp/en/)	'thalassaemia OR thalassemia AND osteoporosis'	13 February 2020

Data and analyses

Comparison 1. Bisphosphonates versus placebo or no treatment.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Bone mineral density at the total hip/femoral neck (Z score)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.1.1 At 2 years (alendronate)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.1.2 At 2 years (clodronate)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.1.3 At 2 years (combined bisphosphonate treatment)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.2 Bone mineral density at the lumbar spine (Z score)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.2.1 At 2 years (alendronate)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.2.2 At 2 years (clodronate)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.2.3 At 2 years (combined bisphosphonate treatment)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.3 Adverse effects – clodronate versus placebo	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.3.1 Pain at injection site	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.4 Adverse effects – alendronate versus placebo	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.4.1 GI symptoms	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 2. Different doses of bisphosphonates compared.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Bone mineral density at the total hip/femoral neck (Z score)	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
2.1.1 12 months	1	26	Mean Difference (IV, Fixed, 95% CI)	‐0.08 [‐0.38, 0.22]
2.2 Bone mineral density at the lumbar spine (Z score)	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
2.2.1 12 months	1	26	Mean Difference (IV, Fixed, 95% CI)	0.43 [0.10, 0.76]
2.3 Bone mineral density at the forearm (Z score)	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
2.3.1 12 months	1	26	Mean Difference (IV, Fixed, 95% CI)	0.87 [0.23, 1.51]

Comparison 3. Zinc versus placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Bone mineral density at the total hip/femoral neck (Z score)	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
3.1.1 12 months	1	37	Mean Difference (IV, Fixed, 95% CI)	0.15 [0.11, 0.19]
3.1.2 18 months	1	32	Mean Difference (IV, Fixed, 95% CI)	0.26 [0.21, 0.31]
3.2 Bone mineral density at the lumbar spine (Z score)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.2.1 12 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.2.2 18 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Comparison 4. Denosumab (DNB) versus placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Bone mineral density at the total hip/femoral neck (Z score)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.2 Bone mineral density at the lumbar spine (Z score)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.2.1 12 months	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.3 Bone mineral density at the wrist (Z score)	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
4.3.1 12 months	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
4.4 Pain score (Huskisson's VAS)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.5 Pain score (McGill–Melzack scoring system)	1	63	Mean Difference (IV, Fixed, 95% CI)	‐2.00 [‐2.82, ‐1.18]

Comparison 5. Strontium ranelate (SrR) versus placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Back pain score (VAS)	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
5.1.1 18 months	1	24	Mean Difference (IV, Fixed, 95% CI)	‐0.60 [‐1.25, 0.05]
5.1.2 24 months	1	24	Mean Difference (IV, Fixed, 95% CI)	‐0.70 [‐1.30, ‐0.10]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Forni 2012.

Study characteristics
Methods	Open‐label, parallel‐group RCT Duration: 12 months Location: Italy (multicentre)
Participants	118 adults with transfusion‐dependent β‐thalassaemia (thalassaemia major or severe β‐thalassaemia intermedia, defined as regular transfusion requirement for ≥10 years) with BMD Z scores < −2.0. Age: group A: mean 32.4 (SD 7.4) years (range 18–58 years); Group B: mean 33.1 (SD 8.8) years (range 19–61 years) Sex: 51 males, 67 females
Interventions	Intervention (n = 54; 45.8%): neridronate 100 mg IV infusion every 90 days Control (n = 64; 54.2%): no treatment Co‐interventions: calcium 500 mg with vitamin D 400 IU daily (all participants)
Outcomes	Increase in BMD at femoral neck, total hip, and lumbar spine (measured by DXA expressed in g/cm²) Decrease in bone turnover (changes in serum levels of BALP and CTX, decrease in use of analgesics) Quality of life evaluated by the SF‐36 self‐administered questionnaire
Notes	1 participant in Group A discontinued the trial at 6 months after sustaining multiple fractures in a road traffic accident.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants randomized approximately 1:1 using a random number sequence generated a computer software.
Allocation concealment (selection bias)	Unclear risk	Not discussed.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label trial: both the researchers and participants were aware of allocated treatment.
Blinding of outcome assessment (detection bias) All outcomes	High risk	Open‐label trial: both the researchers and participants were aware of allocated treatment.
Incomplete outcome data (attrition bias) All outcomes	Low risk	There were exclusions due to errors in the imaging outcome. These appear to be numerically balanced between the groups.
Selective reporting (reporting bias)	Low risk	All the outcomes specified in the methods were reported in the results.
Other bias	Low risk	No indication of other potential bias.

Fung 2013.

Study characteristics
Methods	Double‐blind, placebo‐controlled, parallel‐group RCT Duration: 18 months Location: USA (multicentre)
Participants	42 participants with β‐thalassaemia (81% transfusion‐dependent) and a DXA‐derived aBMD Z score < −1.0 at the spine, hip, or whole body within the previous 2 years. Age: all participants: range 10–30 years; intervention group: mean 17.4 (SD 4.7) years; control group: mean 17.5 (SD 5.7) years Sex: 21 males, 21 females
Interventions	Intervention: zinc sulphate 25 mg daily Control: placebo capsule Co‐interventions: none reported
Outcomes	BMC and aBMD assessed by using DXA (Discovery A Quantitative Digital Radiography bone densitometer) at spine (L1–L4, posterior‐anterior and lateral), left proximal femur (hip) and whole body Fasting blood was collected for the measurement of plasma zinc at 0, 12, and 18 months.
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomly assigned by block randomization method. They were recruited and stratified according to sex and pubertal stage (Tanner 1 and 2 compared with Tanner 3, 4, and 5), and randomly assigned (1:1) using a block randomization table.
Allocation concealment (selection bias)	Unclear risk	All investigators and participants were blinded to treatment group. A randomization code was provided to the principal investigator by the clinical pharmacy after the last participant completed the 18‐month time point.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	All participants were blinded. The placebo capsule was indistinguishable from the zinc capsule and dispensed from the clinical pharmacy.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	The investigators were blinded. Although 1 error occurred in relation to 1 participant with zinc supplementation, the participant and investigator remained blinded to the intervention group until completion of the project.
Incomplete outcome data (attrition bias) All outcomes	Low risk	The trial started with 42 participants, with 37 participants remaining after 12 months (11.9% attrition) and 32 participants after 18 months (23.80% attrition). Reasons were given for all dropouts and most were unrelated to the treatment (e.g. death of a sibling).
Selective reporting (reporting bias)	Low risk	All outcomes specified in the methods were reported in the results.
Other bias	Low risk	No indication of other potential bias.

Morabito 2002.

Study characteristics
Methods	3‐arm, parallel‐group RCT Duration: 2 years Location: single‐centre study at University Hospital of Messina, Italy
Participants	25 young participants, both male and female, taking HRT for β‐thalassaemia major (transfusion‐dependent) and osteoporosis (BMD Z score < −2.5 SD) Age: all participants: mean 26.6 (SD 7.1) years, range 18–35 years; alendronate group: mean 25 (SD 6) years, clodronate group: mean 28 (SD 8) years, placebo group: mean 27 (SD 6) years Sex: 6 males, 19 females
Interventions	Group A (n = 9, 2 males): alendronate 10 mg oral daily Group B (n = 8, 2 males): clodronate 100 mg IM every 10 days Group C (n = 8, 2 males): placebo Co‐interventions: all participants took 500 mg of elemental calcium and 400 IU cholecalciferol in the evening at meal time. All participants were also taking HRT; males were taking methyltestosterone 100 mg IM every 28 days and females were taking oestrogen‐progestogen.
Outcomes	Bone remodelling parameters BMD at spine and femoral neck Safety and tolerability
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomly divided but method of randomization not mentioned.
Allocation concealment (selection bias)	Unclear risk	Not reported.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	No details of blinding procedure.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No details of blinding procedure.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No incomplete outcome data.
Selective reporting (reporting bias)	Low risk	All outcomes specified in the methods were reported in the results.
Other bias	Low risk	No indication of other potential bias.

Morabito 2016.

Study characteristics
Methods	Parallel‐group RCT Duration: 2 years Location: single‐centre study at University Hospital of Messina, Italy
Participants	24 women aged > 18 years with β‐thalassaemia major (transfusion‐dependent) and low bone mass, as defined by the 1994 WHO guidelines using Z scores (WHO 1994) Age: mean 40.4 (SD: 4.4) years Sex: all females
Interventions	Intervention: SrR 2 mg daily for 24 months Control: placebo daily for 24 months Co‐interventions: calcium carbonate 1000 mg and vitamin D 800 IU (all participants)
Outcomes	BMD, assessed by DXA densitometry at the lumbar spine (L1–L4) in AP projection and at the femoral neck Serum levels of CTX and BSAP were measured to evaluate bone resorption and bone formation Back pain on a VAS (0 cm = no pain, 10 cm = unbearable pain) at baseline and every 6 months Standard clinical and biochemical evaluations were carried out at baseline and then every 6 months to rule out a any possible and detectable side‐effects due to treatment
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Recruited participants were randomized into 2 groups, but there are no details of the method of randomization.
Allocation concealment (selection bias)	Unclear risk	Not reported.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not reported.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No incomplete outcome data.
Selective reporting (reporting bias)	Low risk	All outcomes specified in the methods were reported in the results.
Other bias	Low risk	No indication of other potential bias.

Voskaridou 2003.

Study characteristics
Methods	Parallel‐group RCT Duration: 12 months Location: Thalassaemia centre, Athens, Greece (single‐centre study)
Participants	26 participants with β‐thalassaemia major (not stated in abstracts but presumably transfusion‐dependent) and osteoporosis or osteopenia Age: median 35.5 years Sex: 6 males, 20 females The study analysed a further control group of 45 healthy participants, but we did not include them in our analysis.
Interventions	Group A (n = 18): pamidronate 30 mg IV each month for 12 months. Group B (n = 18): pamidronate 60 mg IV each month for 12 months.
Outcomes	BMD at lumber spine, femoral neck, and forearm
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Two intervention groups were "randomly assigned", but there are no details on the randomization method.
Allocation concealment (selection bias)	Unclear risk	Not mentioned in text.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not mentioned in text.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not mentioned in text.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No incomplete outcome data.
Selective reporting (reporting bias)	Low risk	All outcomes specified in the methods were reported in the results.
Other bias	Low risk	No indication of other potential bias.

Voskaridou 2018.

Study characteristics
Methods	Double‐blind, parallel‐group RCT (phase 2b) Duration: 12 months Location: thalassaemia reference centre at Laiko General Hospital, Athens, Greece (single‐centre study)
Participants	63 participants with β‐thalassaemia major (transfusion‐dependent; skeletally mature) and low bone mass (T score between −2.5 and −4.0 in at least 1 of the 3 examined sites (lumbar spine, femoral neck, wrist))  Age: intervention group: median 52.5 years (range 34–70 years); control group: median 56.0 years (range 36–78 years) Sex: intervention group: 14 males,18 females; control group: 16 males, 15 females
Interventions	Intervention (n = 32): DNB 60 mg in a capsule every 6 months for 12 months Control (n = 31): placebo capsule every 6 months for 12 months
Outcomes	BMD (g/cm2), % increase measured with DXA at 3 sites (lumbar spine L1‐L4, femoral neck, wrist) Bone pain according to Huskisson's VAS (0 cm = no pain; 10 cm = worst pain possible) and the McGill‐Melzack scoring system (verbal scale with 6 levels ranging from 0 to 5; 0 = no pain, 5 = excruciating pain) 4 categories of markers of bone remodelling (assessed on day 0 and then every 3 months up to 12 months so that every participant had 5 measurements)
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Block randomization was used in order to increase the comparability of the treatment groups and to provide a better guarantee of nearly equal size. PROC PLAN procedure with ordered selection was used. This procedure allocated patient numbers, randomized eligible patients to one of the two treatment arms in a 1:1 ratio."
Allocation concealment (selection bias)	Low risk	"An independent authorized person, with exclusive access to the study randomization list."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind clinical trial; participants and investigators were unaware of treatment allocation. An independent authorized person with exclusive access to the study randomization list was responsible for providing the allocated medication kit numbers when drug administration was requested by the investigator. All relevant files and documents were filed securely with encryption to maintain blinding throughout the trial.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Participants and investigators were unaware of treatment allocation
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants received the allocated treatment and were included in the analyses. 3 discontinuations occurred: 1 participant from the placebo group was lost to follow‐up after day 272, and 2 participants from the DNB group withdrew consent on day 0.
Selective reporting (reporting bias)	Low risk	All outcomes specified in the methods were reported in the results.
Other bias	Low risk	No indication of other potential bias.

aBMD: areal bone mineral density; AP: anterior‐posterior; BALP: bone alkaline phosphatase; β‐thalassaemia: beta‐thalassaemia; BMC: bone mineral content; BMD: bone mineral density; BSAP: bone‐specific alkaline phosphatase; CTX: C‐terminal telopeptide; DNB: denosumab; DXA: dual X‐ray absorptiometry; HRT: hormone replacement therapy; IM: intramuscular; IU: international units; IV: intravenous; RCT: randomized controlled trial; SD: standard deviation; SrR: strontium ranelate; VAS: visual analogue scale; WHO: World Health Organization.

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Balachandar 2012	Trial on effects of vitamin D on calcium excretion.
Canartan 1995	Case‐control study.
Chae 2009	Not an RCT.
Chatterjee 2012	Diagnostic study, not an RCT.
Darvish‐Khezri 2018	Retrospective study.
Gilfillan 2006	Participants' eligibility based on BMD T score (rather than Z score); given participants were aged 18–43, this does not fulfil our predefined eligibility criteria.
Gurkan 2005	Eligibility criteria based on BMD T score (rather than Z score); given the age group included, this does not fulfil our predefined eligibility criteria.
Krishnan 1994	Diagnostic study, not an RCT.
Naithani 2018	Not an RCT; open‐label, single‐arm trial.
Noroozi 2022	Single arm study, not an RCT.
Olgun 2019	Case‐control study, not an RCT.
Otrock 2006	Case‐control study. not an RCT.
Pennisi 2003	Participants (males aged 21 to 35 years) eligibility assessed as per BMD T score (rather than the appropriate Z score for this participant group, as per our inclusion criteria).
Skordis 2008	Retrospective study and no control group for the trial.
Voskaridou 2008	Eligibility criteria assessed based on BMD T score (rather than the appropriate Z score, as per our inclusion criteria).
Voskaridou 2009	Eligibility criteria assessed based on BMD T score (rather than the appropriate Z score, as per our inclusion criteria).
Yassin 2020	Trial terminated. Failed to recruit eligible people.

BMD: bone mineral density; RCT: randomized controlled trial.

Characteristics of studies awaiting classification [ordered by study ID]

Eid 2021.

Methods	RCT (cohort randomly divided using computer‐generated random numbers; stratified according to age and sex) Duration: 24 weeks Location: single centre in Egypt
Participants	39 children (23 boys and 16 girls) with confirmed diagnosis of β‐thalassaemia major and baseline BMD Z‐score < −1 at the lumber spine, femoral neck, and total body, and no treatment with bisphosphonates in previous 12 months Age: 6–10 years Sex: 23 boys, 16 girls All children completed trial.
Interventions	Intervention group (n = 19; 12 boys, 7 girls): medical treatment plus conventional physical therapy programme (gentle stretching exercises, strengthening exercises, balance and proprioceptive training for 1 hour/day, 3 days a week) plus whole body vibration training (unilateral vibration applied alternately to the right and left feet; the Power Plate platform produces vertical synchronous vibration where both legs are vibrated as the plate moves in the vertical direction). Control group (n = 20; 11 boys, 9 girls): medical treatment plus conventional physical therapy programme as above
Outcomes	Adherence rate BMD (lumbar spine, femoral neck, total body) 6MWT
Notes	Sample size calculation undertaken; 39 participants required.

TCTR20201223008.

Methods	RCT Duration: 1 year Location: Thailand
Participants	Males or premenopausal females aged 19–50 years, with TDT or NTDT confirmed by haemoglobin typing (High Performance Liquid Chromatography method) or PCR for thalassaemia gene result, iron overload defined as serum ferritin > 1000 ng/ml in TDT or 800 ng/ml in NTDT, axial BMD Z score < −2.0, with ECOG performance status 0–1
Interventions	Intervention: melatonin time‐release 10 mg/tab, 2 tablets once daily at bedtime Control: 2 placebo tablets once daily at bedtime.
Outcomes	Primary outcome Mean difference in BMD at lumbar spine at 12 months Secondary outcomes  Mean difference in BMD at proximal femur at 12 months Serum bone turnover marker at 6 and 12 months Pain score using a questionnaire at 6 and 12 months Change in blood analysis (serum non‐transferrin‐bound iron, hepcidin, plasma F2‐isoprostanes, melatonin, calcitonin, FGF21 levels) at 6 and 12 months Adverse events measured by questionnaire at 3, 6, 9, and 12 months
Notes	Not yet recruiting Target sample size: 64

6MWT: 6‐minute walk test; β‐thalassaemia: beta‐thalassaemia; BMD: bone mineral density; ECOG: Eastern Cooperative Oncology Group; IV: intravenous; NTDT: non‐transfusion‐dependent thalassaemia; PCR: polymerase chain reaction; RCT: randomized controlled trial; TDT: transfusion‐dependent thalassaemia.

Characteristics of ongoing studies [ordered by study ID]

CTRI/2019/04/018764.

Study name	The role of zoledronate in the prevention of early bone loss in patients undergoing bone marrow transplant
Methods	RCT (randomization using random number table) Parallel design Location: India
Participants	Inclusion criteria Age > 18 years Undergoing allogeneic haematopoietic stem cell transplant Able to understand and provide informed signed consent Pre‐existing osteopenia with T scores > −1.5 Health condition: aplastic and other anaemias and other bone marrow failure syndromes; idiopathic aplastic anaemia; leukaemia of specified cell type or unspecified cell type; lymphoid leukaemia; monocytic leukaemia; myeloid leukaemia; other leukaemias of specified cell type; thalassaemia. Exclusion criteria Renal failure with eGFR > 30 mL/min by diethylenetriamine pentaacetate method History of hypersensitivity to bisphosphonates Dental extraction within past 4 weeks Pre‐existing metabolic bone disease including individuals with osteoporosis on BMD and those with osteopenia, with T < −1.5 at either of the femoral neck or lumbar spine
Interventions	Intervention: IV zoledronate 4 mg/100 mL normal saline over 15 minutes once before the transplant Control: observation only
Outcomes	Primary outcome T score < −1.5 at any site (femoral neck or lumber spine) as assessed by DXA on day 100 of transplant Secondary outcomes ≥ 5% decrease in BMD in femoral neck and lumbar spine at day 100  T score < −1.5 at any site (femoral neck or lumber spine) as assessed by DXA on day 365
Starting date	Registered April 2019
Contact information	Niranjan Khaire and Deepesh Lad (deepesh.kem@gmail.com) Address: Room no. 28, Internal Medicine, PGIMER Chandigarh 160012 Chandigarh, CHANDIGARH India Telephone: 9417770112
Notes	Open to recruitment Institutional funding

IRCT2017070420258N51.

Study name	Evaluation of intravenous pamidronate & oral alendronate on bone marrow density in patients with major and intermedia thalassemia
Methods	Double‐blind, parallel‐group RCT Duration: 1 year Location: single centre, Iran
Participants	Target sample size of 40 participants, 20 in each group. Inclusion criteria Age > 10 years Major or intermedia thalassaemia Referral to Amirkabir Hospital Exclusion criteria Gastrointestinal intolerance for oral medication Drug allergy Heart failure Liver failure Hypoparathyroidism.
Interventions	Group 1: alendronate 70 mg once weekly  Group 2: pamidronate 0.5 mg/kg IV for 3 days
Outcomes	Clinical symptoms (observation) BMD at spine and femoral neck (X‐ray)
Starting date	First enrolment 2 August 2017
Contact information	Dr Aziz Eghbali and Dr Fatahibayat (mahmoud.nahremiany@gmail.com) Address: Amirkabir Hospital, Parastar Square 3814957558 Arak Iran (Islamic Republic of) Telephone: +98 86 3222 2003 Affiliation: Arak University of Medical Sciences
Notes	Sample size calculation, 40 participants needed

NCT01016093.

Study name	Zoledronic acid for the prevention of bone loss post‐bone marrow transplantation for thalassemia major patients
Methods	Double‐blind, parallel‐group RCT Duration: 1 year. Location: single centre, Iran
Participants	Inclusion criteria Diagnosis of β‐thalassaemia major Age ≥ 18 years Scheduled allogenic bone marrow transplantation Exclusion criteria Any clinical or radiological evidence of existing fracture in the lumbar spine or total hip History of fracture with low‐density or no associated trauma Osteoporotic with T‐score ≤ −2.5 Previous treatment with a bisphosphonate Abnormal renal function as evidenced by either a serum creatinine determination ≤ 1.5 times above the upper limit of normal or by a calculated creatinine clearance ≤ 30 mL/minute Pregnancy and lactation Women of childbearing potential not on a medically recognized form of contraception Participants who, in the opinion of the investigator, are unlikely to co‐operate fully during the study Simultaneous participation in studies with unapproved drugs, indications, or treatment regimens Known hypersensitivity to zoledronic acid or bisphosphonates Prior exposure to anabolic steroids, growth hormone, PTH or other drugs known to affect the skeleton Serious intercurrent illness History of metabolic bone diseases History of corticosteroid treatment for other causes History of antiepileptic drug treatment History or surgery at the lumbosacral spine, with or without implantable devices Any disease of the spine that would preclude the proper acquisition of a lumbar spine DXA Mental illness that precludes the participant from giving informed consent Current active dental problems, including infection of the teeth or jawbone (maxilla or mandibular); dental or fixture trauma; or a current or prior diagnosis of osteonecrosis of the jaw, of exposed bone in the mouth, or of slow healing after dental procedures Recent (within 6 weeks) or planned dental or jaw surgery (e.g. extraction, implants)
Interventions	Intervention: IV zoledronic acid 4 mg (dose adjusted based on renal function) 15‐minute infusion every 3 months for a total of 1 year (4 doses), beginning as soon as possible after randomization Control: placebo
Outcomes	Primary outcome % change in lumbar spine (L1 to L4) BMD, as measured by DXA at 12 months Secondary outcomes % change in total hip BMD at 12 months Changes in bone turnover markers at 3, 6, and 12 months Incidence rate of all clinical fractures at 12 months General safety of zoledronic acid at 12 months % change in lumbar spine (L1 to L4) BMD and total hip BMD at 6 months when available
Starting date	Registered 18 November 2009
Contact information	Collaborators: Tehran University of Medical Sciences, Novartis Contact: Mahdi Jalili MD, Hematology‐Oncology and SCT Research Center, Tehran University of Medical Sciences, Iran
Notes	Estimated enrolment 50 participants. Active not recruiting.

Piriyakhuntorn 2019.

Study name	Efficacy of alendronate in treatment of thalassemia‐associated osteoporosis: a randomized controlled trial
Methods	Phase 3 RCT Duration: 1 year Location: single centre in Thailand.
Participants	Inclusion criteria Age 18–50 years Diagnosed thalassaemia disease (both transfusion‐dependent and non‐transfusion‐dependent) BMD at hip or lumbar spine or total body Z score < −2.0 SD by DXA or vertebral deformity/fracture seen from vertebral fracture analysis ECOG performance status 0–2 Exclusion criteria Current or previous use of any bisphosphonate drug Creatinine clearance less than 35 mL/min/1.73 m² Hypocalcaemia Oesophageal disorder or abnormality, or inability to maintain upright position for 30 minutes after taking the drug Uncorrected dental problem Pregnancy Herb use
Interventions	Intervention: alendronate (70 mg/tablet), 1 tablet/week 30 minutes before meal Control: placebo tablet (white colour, round shape), 1 tablet/week 30 minutes before meal
Outcomes	Primary outcome BMD at 1 year measured by DXA Secondary outcomes Serum bone turnover markers: P1NP, CTX at 6 months and 1 year measured by blood tests Back pain and bone pain at 6 months and 1 year measured by a VAS Prevalence of vitamin D deficiency and insufficiency Prevalence of endocrinopathy  Prevalence of vertebral fracture or deformity measured by vertebral fracture analysis using DXA Non‐transferrin‐bound iron, labile plasma iron, hepcidin measured by blood test
Starting date	Initial enrolment 8 Feb 2018
Contact information	Primary sponsor: Faculty of Medicine, Chiang Mai University Contact: Adisak Tantiworawit (atantiwo@yahoo.com), Muang 50200 Chiang Mai, Thailand Contact: Pokpong Piriyakhuntorn (pk_mac@hotmail.com), Muang 50200 Chiang Mai, Thailand
Notes	Target sample size: 100 participants Described both as currently recruiting and having been completed on May 31 2019

β‐thalassaemia: beta‐thalassaemia; BMD: bone mineral density; CTX: carboxy‐terminal collagen; DXA: dual energy X‐ray absorptiometry; ECOG: Eastern Cooperative Oncology Group; eGFR: estimated glomerular filtration rate; IV: intravenous; P1NP: procollagen type I N propeptide; PTH: parathyroid hormone; RCT: randomized controlled trial; SD: standard deviation; VAS: visual analogue scale.

Differences between protocol and review

There are no differences between the protocol and the review (Bhardwaj 2013).

Contributions of authors

Preliminary database search	AB, KMMS
Development and running of search strategies	KMMS, Cochrane Group's Information Specialist
Background	AB, KMMS, NKS, IO
Objectives	AB, KMMS, IO
Methodology	AB, KMMS, NKS, IO

Sources of support

Internal sources

• No sources of support provided

External sources

• National Institute for Health Research, UK

  This systematic review was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to the Cochrane Cystic Fibrosis and Genetic Disorders Group.

Declarations of interest

AB: none known
KMMS: none known
NKS: none known
IO: served on the speakers bureau for Novartis pharmaceuticals for Exjade and Jadenu, providing disease education on sickle cell disease and education to providers and patients on managing iron overload.

New search for studies and content updated (no change to conclusions)