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Meta-Analysis
. 2023 May 2:381:e068033.
doi: 10.1136/bmj-2021-068033.

Fracture risk reduction and safety by osteoporosis treatment compared with placebo or active comparator in postmenopausal women: systematic review, network meta-analysis, and meta-regression analysis of randomised clinical trials

Mina Nicole Händel  1   2 , Isabel Cardoso  1 , Cecilie von Bülow  1   3 , Jeanett Friis Rohde  1 , Anja Ussing  1 , Sabrina Mai Nielsen  1   4 , Robin Christensen  1   4 , Jean-Jacques Body  5 , Maria Luisa Brandi  6 , Adolfo Diez-Perez  7 , Peyman Hadji  8 , Muhammad Kassim Javaid  9 , Willem Frederik Lems  10 , Xavier Nogues  11 , Christian Roux  12 , Salvatore Minisola  13 , Andreas Kurth  14 , Thierry Thomas  15 , Daniel Prieto-Alhambra  9   16 , Serge Livio Ferrari  17 , Bente Langdahl  18 , Bo Abrahamsen  2   9   19
Affiliations
Meta-Analysis

Fracture risk reduction and safety by osteoporosis treatment compared with placebo or active comparator in postmenopausal women: systematic review, network meta-analysis, and meta-regression analysis of randomised clinical trials

Mina Nicole Händel et al. BMJ. .

Abstract

Objective: To review the comparative effectiveness of osteoporosis treatments, including the bone anabolic agents, abaloparatide and romosozumab, on reducing the risk of fractures in postmenopausal women, and to characterise the effect of antiosteoporosis drug treatments on the risk of fractures according to baseline risk factors.

Design: Systematic review, network meta-analysis, and meta-regression analysis of randomised clinical trials.

Data sources: Medline, Embase, and Cochrane Library to identify randomised controlled trials published between 1 January 1996 and 24 November 2021 that examined the effect of bisphosphonates, denosumab, selective oestrogen receptor modulators, parathyroid hormone receptor agonists, and romosozumab compared with placebo or active comparator.

Eligibility criteria for selecting studies: Randomised controlled trials that included non-Asian postmenopausal women with no restriction on age, when interventions looked at bone quality in a broad perspective. The primary outcome was clinical fractures. Secondary outcomes were vertebral, non-vertebral, hip, and major osteoporotic fractures, all cause mortality, adverse events, and serious cardiovascular adverse events.

Results: The results were based on 69 trials (>80 000 patients). For clinical fractures, synthesis of the results showed a protective effect of bisphosphonates, parathyroid hormone receptor agonists, and romosozumab compared with placebo. Compared with parathyroid hormone receptor agonists, bisphosphonates were less effective in reducing clinical fractures (odds ratio 1.49, 95% confidence interval 1.12 to 2.00). Compared with parathyroid hormone receptor agonists and romosozumab, denosumab was less effective in reducing clinical fractures (odds ratio 1.85, 1.18 to 2.92 for denosumab v parathyroid hormone receptor agonists and 1.56, 1.02 to 2.39 for denosumab v romosozumab). An effect of all treatments on vertebral fractures compared with placebo was found. In the active treatment comparisons, denosumab, parathyroid hormone receptor agonists, and romosozumab were more effective than oral bisphosphonates in preventing vertebral fractures. The effect of all treatments was unaffected by baseline risk indicators, except for antiresorptive treatments that showed a greater reduction of clinical fractures compared with placebo with increasing mean age (number of studies=17; β=0.98, 95% confidence interval 0.96 to 0.99). No harm outcomes were seen. The certainty in the effect estimates was moderate to low for all individual outcomes, mainly because of limitations in reporting, nominally indicating a serious risk of bias and imprecision.

Conclusions: The evidence indicated a benefit of a range of treatments for osteoporosis in postmenopausal women for clinical and vertebral fractures. Bone anabolic treatments were more effective than bisphosphonates in the prevention of clinical and vertebral fractures, irrespective of baseline risk indicators. Hence this analysis provided no clinical evidence for restricting the use of anabolic treatment to patients with a very high risk of fractures.

Systematic review registration: PROSPERO CRD42019128391.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare support from UCB and Amgen for the submitted work: MNH, IC, CvB, JFR, AU, SMN, and RC report grants from UCB and Amgen paid to the Parker Institute to conduct the study; J-JB reports personal fees from UCB during the conduct of the study and personal fees from UCB and Sandoz outside the submitted work; MLB reports fees as honorarium, speaker, grants, and consultant from Amgen, Bruno Farmaceutici, Calcilytix, Kyowa Kirin, UCB, Abiogen, Alexion, Echolight, Eli Lilly, Kyowa Kirin, SPA, Theramex, and Amolyt outside the submitted work; AD-P has received speaker fees from Amgen, Lilly, and Theramex and is a shareholder of Active Life; PH reports personal fees from UCB during the conduct of the study and personal fees from UCB, Amgen, Gedeon Richter, Stada, and Theramex outside the submitted work; MKJ reports personal fees and non-financial support from UCB during the conduct of the study, and grants, personal fees, and non-financial support from Amgen and UCB outside the submitted work; MKJ was also supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre and the views expressed are those of the author and not necessarily those of the NHS, the NIHR, or the Department of Health; WFL reports speakers fee/advisory board from UCB, Amgen, Pfizer, and Lilly; XN has received fees for consulting from UCB and Amgen and for lectures from UCB, Amgen, and Lilly; CR reports personal fees from UCB during the conduct of the study, and grants and personal fees from Alexion, Regeneron, Sanofi, and Amgen outside the submitted work; SM reports fees as speaker and advisory board from Abiogen, Amgen, Bruno Farmaceutici, Diasorin, Eli Lilly, Shire, Sandoz, Takeda, Abiogen, Kyowa Kirin, Pfizer and UCB outside the submitted work; TT reports personal fees from UCB during the conduct of the study, personal fees from Amgen, Arrow, and Biogen, personal fees from Grunenthal, Jansen, LCA, Lilly, MSD, Nordic, Novartis, Pfizer, Sanofi, Thuasne, and Theramex, grants and personal fees from Chugai and UCB, and grants from Bone Therapeutics outside the submitted work; SLF reports grants from Amgen, consulting and lecture honorarium from UCB, consulting honorarium from Radius, and grants and consulting honorarium from Agnovos outside the submitted work; DP-A's department received consultancy fees related to this work, DP-A reports grants and fees for speaker services and advisory board membership from Amgen, grants, non-financial support, and fees for consultancy services from UCB Biopharma, grants from Les Laboratoires Servier and UCB outside the submitted work, DP-A is an HTA Funding Committee membership, and Janssen, on behalf of Innovative Medicines Initiative (IMI) funded European Health Data and Evidence Network (EHDEN) and European Medical Information Framework (EMIF) consortiums, and Synapse Management Partners, have supported training programmes organised by DP-A's department that are open to external participants; BL reports personal fees from UCB during the conduct of the study and BL has received funding to her institution from Amgen and Novo Nordisk and personal fees from Amgen, UCB, Eli Lilly, Gedeon-Richter, and Gilead outside the submitted work; BA reports personal fees from UCB during the conduct of the study, grants and personal fees from UCB and Kyowa-Kirin UK, personal fees from Amgen, grants from Novartis, and grants and personal fees from Pharmacosmos outside the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Figures

Fig 1
Fig 1
Flowchart of included studies. Numbers=number of records; k=number of distinct trials
Fig 2
Fig 2
Network plot of studies included in network meta-analysis on clinical fractures. Each circle represents an intervention and is referred to as a node. Nodes are sized proportionally to the number of trials that included each intervention. Lines between nodes represent direct comparisons, and their thickness is proportional to the number of trials contributing to each comparison. Number of trials for each direct comparison is shown. No connecting line between two treatments indicates no direct comparison
Fig 3
Fig 3
Network meta-analysis for clinical, vertebral, hip, and major osteoporotic fractures. PTHR=parathyroid hormone receptor agonists; SERM=selective oestrogen receptor modulators; CI=confidence interval
Fig 4
Fig 4
Network meta-analysis for safety outcomes. PTHR=parathyroid hormone receptor agonists; SERM=selective oestrogen receptor modulators; CI=confidence interval
Fig 5
Fig 5
Forest plot illustrating the result of node splitting, comparing direct, indirect, and network estimates. CI=confidence interval
Fig 6
Fig 6
Meta-regression on risk of clinical fractures with baseline mean age as risk indicator, for antiresorptive agents (selective oestrogen receptor modulators, bisphosphonates, and denosumab) versus placebo. Based on restricted maximum likelihood based meta-regression for association between (log risk ratio) clinical fractures and mean age. Bisphosphonates versus placebo are indicated by purple dots and selective oestrogen receptor modulators versus placebo by yellow dot; colours do not reflect the applied model and are only for illustrative purposes. Meta-regression was done on log risk ratio scale, but for ease of interpretation, the back transformed risk ratio is shown. Identification number in figure, trial name, and reference: 3=FIT1 (Fracture Intervention Trial 1); 4=HORIZON-PFT (Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial); 7=FIT2 (Fracture Intervention Trial 2); 11=ZEST (Zoledronic acid in frail Elders to STrengthen bone); 12=ACTRN12607000576426; 15=Hosking 1998; 18=IBAN IV; 20=ACTRN1260900593235; 50=ACTRN12605000278639; 51=Hosking 2003; 52=Greenspan 2003; 53=Downs 2000; 55=Miller 2008; 78=Bell 2002; 79=Bone 2000; 82=McClung 2009; 93=NCT00271713
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