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. 2023 May 9;5(5):CD010429.
doi: 10.1002/14651858.CD010429.pub3.

Treatment for osteoporosis in people with beta-thalassaemia

Amit Bhardwaj  1 , Kye Mon Min Swe  2 , Nirmal K Sinha  3
Affiliations

Treatment for osteoporosis in people with beta-thalassaemia

Amit Bhardwaj et al. Cochrane Database Syst Rev. .

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.

PubMed Disclaimer

Conflict of interest statement

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.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
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)
1.2
1.2. Analysis
Comparison 1: Bisphosphonates versus placebo or no treatment, Outcome 2: Bone mineral density at the lumbar spine (Z score)
1.3
1.3. Analysis
Comparison 1: Bisphosphonates versus placebo or no treatment, Outcome 3: Adverse effects – clodronate versus placebo
1.4
1.4. Analysis
Comparison 1: Bisphosphonates versus placebo or no treatment, Outcome 4: Adverse effects – alendronate versus placebo
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)
2.2
2.2. Analysis
Comparison 2: Different doses of bisphosphonates compared, Outcome 2: Bone mineral density at the lumbar spine (Z score)
2.3
2.3. Analysis
Comparison 2: Different doses of bisphosphonates compared, Outcome 3: Bone mineral density at the forearm (Z score)
3.1
3.1. Analysis
Comparison 3: Zinc versus placebo, Outcome 1: Bone mineral density at the total hip/femoral neck (Z score)
3.2
3.2. Analysis
Comparison 3: Zinc versus placebo, Outcome 2: Bone mineral density at the lumbar spine (Z score)
4.1
4.1. Analysis
Comparison 4: Denosumab (DNB) versus placebo, Outcome 1: Bone mineral density at the total hip/femoral neck (Z score)
4.2
4.2. Analysis
Comparison 4: Denosumab (DNB) versus placebo, Outcome 2: Bone mineral density at the lumbar spine (Z score)
4.3
4.3. Analysis
Comparison 4: Denosumab (DNB) versus placebo, Outcome 3: Bone mineral density at the wrist (Z score)
4.4
4.4. Analysis
Comparison 4: Denosumab (DNB) versus placebo, Outcome 4: Pain score (Huskisson's VAS)
4.5
4.5. Analysis
Comparison 4: Denosumab (DNB) versus placebo, Outcome 5: Pain score (McGill–Melzack scoring system)
5.1
5.1. Analysis
Comparison 5: Strontium ranelate (SrR) versus placebo, Outcome 1: Back pain score (VAS)
See this image and copyright information in PMC

Update of

References

References to studies included in this review

Forni 2012 {published data only}
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Fung 2013 {published data only}
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Morabito 2002 {published data only}
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Voskaridou 2018 {published data only}
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References to studies excluded from this review

Balachandar 2012 {published data only}
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Canartan 1995 {published data only}
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Chae 2009 {published data only}
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Chatterjee 2012 {published data only}
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Darvish‐Khezri 2018 {published data only}
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Gilfillan 2006 {published data only}
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Gurkan 2005 {published data only}
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Krishnan 1994 {published data only}
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Olgun 2019 {published data only}
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Otrock 2006 {published data only}
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Pennisi 2003 {published data only}
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Skordis 2008 {published data only}
    1. Skordis N, Ioannou YS, Kyriakou A, Savva SC, Efstathiou E, Savvides I, et al. Effect of bisphosphonate treatment on bone mineral density in patients with thalassaemia major. Pediatric Endocrinology Reviews: PER 2008;6 Suppl 1:144-8. [CENTRAL: 699706] [PMID: ] - PubMed
Voskaridou 2008 {published data only}
    1. Voskaridou E, Christoulas D, Antoniadou L, Tsaftaridis P, Plata E, Terpos E. Zoledronic acid increases bone mineral density in patients with thalassemia intermedia-induced osteoporosis despite the continuous bone marrow expansion. Haematologica 2007;92 Suppl 1:342. [CENTRAL: 625349] [CFGD REGISTER: TH96c]
    1. Voskaridou E, Christoulas D, Antoniadou L, Tsaftaridis T, Plata E, Terpos E. Zoledronic acid increases bone mineral density in patients with thalassemia intermedia-induced osteoporosis regardless of the incessant bone marrow expansion. Blood 2007;110(11):3813. [ABSTRACT NO.: 3813] [CENTRAL: 625484] [CFGD REGISTER: TH96a]
    1. Voskaridou E, Christoulas D, Antoniadou L, Terpos E. Continuous increase in erythropoietic activity despite the improvement in bone mineral density by zoledronic acid in patients with thalassemia intermedia-induced osteoporosis. Acta Haematologica 2008;119(1):40-4. [CFGD REGISTER: TH96b] - PubMed
Voskaridou 2009 {published data only}TH74
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    1. Voskaridou E, Anagnostopoulos A, Konstantopoulos K, Stoupa E, Spyropoulou E, Kiamouris C, et al. Zoledronic acid for the treatment of osteoporosis in patients with beta-thalassemia: results from a single-center, randomized, placebo-controlled trial. Haematologica 2006;91(9):1193-202. [CFGD REGISTER: TH74b] - PubMed
    1. Voskaridou E, Christoulas D, Konstantinidou M, Tsiftsakis E, Alexakos P, Terpos E. Continuous improvement of bone mineral density two years post zoledronic acid discontinuation in patients with thalassemia-induced osteoporosis: long-term follow-up of a randomized, placebo-controlled trial. Haematologica 2008;93(10):1588-90. [CFGD REGISTER: TH74i] - PubMed
    1. Voskaridou E, Christoulas D, Konstantinidou M, Tsiftsakis E, Spyropoulou E, Alexakos P, et al. Continuous improvement of bone mineral density two years post zoledronic acid discontinuation in patients with thalassemia-induced osteoporosis: long-term follow- up of a randomized, placebo-controlled trial. Blood 2007;110(11):2768. [ABSTRACT NO.: 2768] [CFGD REGISTER: TH74c] - PubMed
    1. Voskaridou E, Christoulas D, Pantelaros T, Varvagiannis K, Xirakia C, Papatheodorou A, et al. Serum Dickkopf-1 is increased and correlates with bone mineral density in patients with thalassemia-induced osteoporosis. Reduction post-zoledronic acid administration. Blood 2008;112(11):3889. [ABSTRACT NO.: 3889] [CFGD REGISTER: TH74e] - PMC - PubMed
Yassin 2020 {published data only}
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References to studies awaiting assessment

Eid 2021 {published data only}
    1. Eid MA, Aly SM. Effect of whole body vibration training on bone mineral density and functional capacity in children with thalassemia. Physiotherapy Theory and Practice 2021;37(2):279-86. [CFGD REGISTER: TH231b] - PubMed
    1. PACTR201804003248173. Effect of whole body vibration training on bone mineral density and functional capacity in children with thalassemia. trialsearch.who.int/Trial2.aspx?TrialID=PACTR201804003248173 (first registered 24 March 2018). [CFGD REGISTER: TH231a]
TCTR20201223008 {published data only}
    1. TCTR20201223008. Effects of melatonin on bone metabolism in thalassemia patients with low bone mineral density (randomized controlled study). trialsearch.who.int/Trial2.aspx?TrialID=TCTR20201223008 (first registered 23 December 2020). [CFGD REGISTER: TH233]

References to ongoing studies

CTRI/2019/04/018764 {published data only}
    1. CTRI/2019/04/018764. Trial to study the role of zoledronate in the prevention of early bone loss in patients undergoing bone marrow transplant. in prevention of early bone loss in patients undergoing bone marrow transplant. trialsearch.who.int/Trial2.aspx?TrialID=CTRI/2019/04/018764 (first registered 24 April 2019). [CFGD REGISTER: TH232]
IRCT2017070420258N51 {published data only}
    1. IRCT2017070420258N51. Evaluation of intravenous pamidronate & oral alendronate on bone marrow density in patients with major and intermedia thalassemia. trialsearch.who.int/Trial2.aspx?TrialID=IRCT2017070420258N51 (first registered 16 July 2017). [CFGD REGISTER: TH230]
NCT01016093 {published data only}
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Piriyakhuntorn 2019 {published data only}
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