Edited by: Heike Wulff, University of California, Davis, United States
Reviewed by: Blaine A. Christiansen, UC Davis Health, United States; Rosane Vianna-Jorge, Instituto Nacional de Câncer (INCA), Brazil
This article was submitted to Pharmaceutical Medicine and Outcomes Research, a section of the journal Frontiers in Pharmacology
†These authors have contributed equally to this work and as first authors.
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Warfarin is a traditional oral anticoagulant for preventing thrombotic events in patients with atrial fibrillation (AF) and venous thromboembolism. Along with the widespread clinical use, the potential association between warfarin use and fracture risk have been addressed gradually. Non-vitamin K antagonist oral anticoagulants (NOACs), targeting thrombin or Xa factor, have been recommended as an optimal alternative due to their favorable property of thromboembolism prophylaxis and reduced bleeding risk. However, evidence of the fracture risk with NOACs use is limited. Therefore, the present study investigated this issue by a meta-analysis. Medline, Embase, Cochrane Library and the ClinicalTrials.gov Website were searched for randomized controlled trials (RCTs) that reported the fracture data of NOACs and warfarin. The primacy outcome was a composite of any fracture. Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated using random- or fixed-effects models according to between-study heterogeneity. Heterogeneity was assessed through
Fracture is becoming more frequent than before with the aging of the world's population (Cummings and Melton,
Non-vitamin K Antagonist Oral Anticoagulants (NOACs)—dabigatran, apixaban, rivaoxaban, and edoxaban—that are either thrombin inhibitors or Xa factor inhibitors have been demonstrated to be non-inferior or superior to warfarin in terms of thromboprophylaxis and bleeding risk in phase III RCTs. Owing to their favorable net clinical benefit, international updated clinical guidelines have now issued a class I recommendation for the use of NOACs for stroke prevention in non-valvular atrial fibrillation (NVAF) patients (Kirchhof et al.,
Interestingly, dabigatran had a better safety profile of bone than warfarin by increasing trabecular size and mineralization in rats (Fusaro et al.,
This study was reported in consist with standards that were outlined in the Cochrane Handbook and the PRISMA Statement for Systemic Reviews (Hutton et al.,
Studies were included if they met the following criteria: (1) Only RCTs were included; (2) treatment had to involve NOACs and warfarin, and reported the fracture events. The primacy outcome was a composite of any fracture, combining any fracture events reported in the trial. The secondary outcomes included (1) fragility fracture by merging data of vertebral, hip, rib, and wrist fracture; (2) vertebral fracture by merging data of spinal compression fracture, lumbar vertebral fracture, thoracic vertebral fracture, cervical vertebral fracture, spinal fracture, fractured coccyx, and fractured sacrum; (3) all fracture sites. Two reviewers (Z.G. and L.Z.) independently evaluated all study titles and abstracts for determining eligibility. Thereafter, full text was retrieved and assessed the relevant possibility according to the inclusion. All discrepancies were resolved by consulting a third author (X.L.).
Information were extracted using a pre-specified form, including trial name, publication year, condition, sample size, mean age, sex, creatinine clearance, intervention groups, study duration, and reported fracture sites. Detailed fracture data that was not reported in the publications was further extracted from the ClinicalTrials.gov website. It included acetabulum fracture, ankle fracture, avulsion fracture, cervical vertebral fracture, clavicle fracture, compression fracture, facial bones fracture, femoral neck fracture, femur fracture, fibula fracture, foot fracture, forearm fracture, fracture, fractured coccyx, fractured sacrum, hand fracture, hip fracture, humerus fracture, jaw fracture, lower limb fracture, lumbar vertebral fracture, multiple fractures, open fracture, patella fracture, pelvic fracture, pubis Fracture, radius fracture, rib fracture, scapula fracture, skull fracture, spinal compression fracture, spinal fracture, sternal fracture, thoracic vertebral fracture, tibia fracture, upper limb fracture, and wrist fracture. Traumatic fracture was excluded from the analyses. The methodological quality of included RCTs was evaluated using Cochrane Collaboration Risk of Bias Tool (Higgins et al.,
Relative ratios (RRs) and their 95% confidence intervals (CIs), according to fracture site, were calculated using a random- or fixed-effects model on the basis of between-study heterogeneity. Heterogeneity, defined as variation beyond chance, was assessed through
In total, 8,245 records were identified from the initial database search. After the removal of 1,642 duplicates, 6,483 records were excluded for various reasons through title and abstract screening. The remaining 120 records were full-text articles, of which 108 proved ineligible due to the unavailability of fracture data, single arm studies, or not warfarin as comparison. Finally, 12 eligible RCTs were included in the analyses (Figure
Flow diagram for the selection of eligible randomized controlled trials.
Summarized Characteristics.
RE-LY, 2009 | AF/24 | Dabigatran 150 mg twice daily | 6,059 | 71.5/63.2 | NA/20.4 | Ankle fracture; Cervical vertebral fracture; Clavicle fracture; Compression fracture; Facial bones fracture; Femoral neck fracture; Femur fracture; Fibula fracture; Foot fracture; Forearm fracture; Fracture; Hand fracture; Hip fracture; Humerus fracture; Lower limb fracture; Lumbar vertebral fracture; Multiple fractures; Patella fracture; Pelvic fracture; Pubis Fracture; Radius fracture; Rib fracture; Scapula fracture; Skull fracture; Spinal compression fracture; Spinal fracture; Sternal fracture; Thoracic vertebral fracture; Tibia fracture; Upper limb fracture; Wrist fracture |
Dabigatran 110 mg twice daily | 5,983 | 71.4/64.3 | NA/20.1 | |||
Warfarin | 5,998 | 71.6/63.3 | NA/18.9 | |||
ROCKET AF, 2011 | AF/23 | Rivaroxaban 20 mg daily | 7,111 | 73.0/60.3 | NA/ 21.0 | Ankle fracture; Avulsion fracture; Cervical vertebral fracture; Clavicle fracture; Compression fracture; Facial bones fracture, Femoral neck fracture; Femur fracture; Fibula fracture; Foot fracture; Fracture; Hand fracture; Hip fracture; Humerus fracture; Lower limb fracture; Lumbar vertebral fracture; Multiple fractures; Patella fracture; Pelvic fracture; Pubis Fracture; Radius fracture; Rib fracture; Spinal compression fracture; Spinal fracture; Thoracic vertebral fracture; Tibia fracture; Upper limb fracture; Wrist fracture |
Warfarin | 7,125 | 73.0/60.3 | NA/ 20.6 | |||
J-ROCKET, 2012 | AF/30 | Rivaroxaban 15 mg daily | 639 | 71.0/82.9 | NA/22.1 | Femur fracture; Fibula fracture; Patella fracture; Radius fracture; Rib fracture; Skull fracture; Spinal compression fracture; Tibia fracture; Ulna fracture |
Warfarin | 639 | 71.2/78.2 | NA/22.4 | |||
ARISTOTLE, 2011 | AF/21 | Apixaban 5 mg twice daily | 9,088 | 70.0/64.5 | NA/15.0 | Acetabulum fracture; Ankle fracture; Cervical vertebral fracture; Clavicle fracture; Facial bones fracture; Femoral neck fracture; Femur fracture; Fibula fracture; Foot fracture; Forearm fracture; Fracture; Hand fracture; Hip fracture; Lower limb fracture; Lumbar vertebral fracture; Open fracture; Patella fracture; Pelvic fracture; Pubis Fracture; Radius fracture; Rib fracture; Scapula fracture; Skull fracture; Spinal compression fracture; Spinal fracture; Sternal fracture; Thoracic vertebral fracture; Tibia fracture; Ulna fracture; Upper limb fracture; Wrist fracture |
Warfarin | 9,052 | 70.0/65.0 | NA/15.2 | |||
ENGAGE AF-TIMI 48, 2013 | AF/33 | Edoxaban 60 mg daily | 7,012 | 72.0/62.1 | NA/19.6 | Acetabulum fracture; Ankle fracture; Cervical vertebral fracture; Clavicle fracture; Compression fracture; Facial bones fracture; Femoral neck fracture; Femur fracture; Fibula fracture; Foot fracture; Forearm fracture; Fracture; Fractured coccyx; Hand fracture; Hip fracture; Humerus fracture; Jaw fracture; Lower limb fracture; Lumbar vertebral fracture; Multiple fractures; Patella fracture; Pelvic fracture; Pubis Fracture; Radius fracture; Rib fracture; Scapula fracture; Skull fracture; Spinal compression fracture; Spinal fracture; Sternal fracture; Thoracic vertebral fracture; Tibia fracture; Ulna fracture; Upper limb fracture; Wrist fracture |
Edoxaban 30 mg daily | 7,002 | 72.0/61.2 | NA/19.0 | |||
Warfarin | 7,012 | 72.0/62.5 | NA/19.3 | |||
RE-COVER, 2009 | VTE/6 | Dabigatran 150 mg twice daily | 1,273 | 56.0/58.0 | 105.8/NA | Femur fracture; Hip fracture; Lower limb fracture; Radius fracture; Rib fracture; Tibia fracture |
Warfarin | 1,266 | 55.0/58.9 | 104.4/NA | |||
RE-COVER II, 2014 | VTE/6 | Dabigatran 150 mg twice daily | 1,280 | 54.7/61.0 | 108.2/NA | Femoral neck fracture; Hip fracture; Humerus fracture; Multiple fractures; Upper limb fracture |
Warfarin | 1288 | 55.1/60.2 | 107.1/NA | |||
RE-MEDY, 2013 | VTE/6-36 | Dabigatran 150 mg twice daily | 1,430 | 55.4/60.9 | 104.2/NA | Acetabulum fracture; Ankle fracture; Femoral neck fracture; Femur fracture; Fibula fracture; Foot fracture; Hand fracture; Hip fracture; Humerus fracture; Lower limb fracture; Radius fracture; Tibia fracture; Upper limb fracture |
Warfarin | 1,426 | 53.9/61.1 | 106.6/NA | |||
EINSTEIN, 2010 | VTE/3, 6, or 12 | Rivaroxaban 15 mg twice daily for 3 weeks, followed by 20 mg daily | 1,718 | 55.8/57.4 | NA/6.6 | Ankle fracture; Clavicle fracture; Femoral neck fracture; Femur fracture; Humerus fracture; Radius fracture; Rib fracture; Spinal compression fracture; Thoracic vertebral fracture; Ulna fracture |
Warfarin | 1,711 | 56.4/56.3 | NA/7.0 | |||
EINSTEIN-PE, 2012 | PE/3, 6, or 12 | Rivaroxaban 15 mg twice daily for 3 weeks, followed by 20 mg daily | 2,412 | 57.9/54.1 | NA/8.6 | Ankle fracture; Cervical vertebral fracture; Facial bones fracture; Femoral neck fracture; Femur fracture; Fibula fracture; Foot fracture; Hip fracture; Humerus fracture; Lumbar vertebral fracture; Rib fracture; Spinal compression fracture; Sternal fracture; Thoracic vertebral fracture; Tibia fracture; Upper limb fracture |
Warfarin | 2,405 | 57.5/51.7 | NA/7.9 | |||
AMPLIFY, 2013 | VTE/6 | Apixaban 10 mg twice daily for 7 days, followed by 5 mg twice daily | 2,676 | 57.2/58.3 | NA/6.0 | Ankle fracture; Cervical vertebral fracture; Facial bones fracture; Femur fracture; Hip fracture; Humerus fracture; Lower limb fracture; Lumbar vertebral fracture; Pelvic fracture; Radius fracture; Spinal compression fracture; Upper limb fracture; Wrist fracture |
Warfarin | 2,689 | 56.7/59.1 | NA/5.5 | |||
Hokusai-VTE, 2013 | VTE/12 | Edoxaban 60 mg daily | 4,118 | 55.7/57.3 | NA/6.5 | Acetabulum fracture; Ankle fracture; Clavicle fracture; Compression fracture; Facial bones fracture; Femoral neck fracture; Femur fracture; Fibula fracture; Foot fracture; Forearm fracture; Fractured sacrum; Hand fracture; Hip fracture; Humerus fracture; Jaw fracture; Lower limb fracture; Lumbar vertebral fracture; Multiple fractures; Pelvic fracture; Pubis Fracture; Radius fracture; Rib fracture; Spinal compression fracture; Spinal fracture; Thoracic vertebral fracture; Tibia fracture; Upper limb fracture; Wrist fracture |
Warfarin | 4,122 | 55.9/57.2 | NA/6.6 |
Patient demographics and clinical characteristics of included studies.
RE-LY, 2009 | 18,040 | 71.5 | 63.6 | 82.7 | NA | 20.0 | 32.0 | 23.3 | 78.9 | NA | 19.8 | NA |
ROCKET AF, 2011 | 14,236 | 73.0 | 60.3 | NA | NA | 54.7 | 62.4 | 39.9 | 90.6 | NA | 20.8 | NA |
J-ROCKET, 2012 | 1,278 | 71.1 | 80.6 | NA | NA | 63.6 | 40.8 | 38.1 | 79.5 | NA | 22.3 | NA |
ARISTOTLE, 2011 | 18,140 | 70.0 | 64.7 | 82.0 | NA | 19.4 | 35.5 | 25.0 | 87.4 | NA | 15.1 | NA |
ENGAGE AF-TIMI 48, 2013 | 21,026 | 72.0 | 38.1 | 28.3 | NA | NA | 57.4 | 36.1 | 93.6 | NA | 19.3 | NA |
RE-COVER, 2009 | 2,539 | 54.7 | 58.4 | 84.9 | NA | NA | NA | NA | NA | 105.1 | NA | 4.8 |
RE-COVER II, 2014 | 2,568 | 54.9 | 60.6 | 83.0 | NA | NA | NA | NA | NA | 107.6 | NA | 3.9 |
RE-MEDY, 2013 | 2,856 | 54.7 | 61.0 | 86.1 | NA | NA | NA | 9.1 | 38.6 | 105.4 | NA | 4.2 |
EINSTEIN, 2010 | 3,429 | 56.1 | 56.9 | NA | 14.2 | NA | NA | NA | NA | NA | 6.8 | 6.0 |
EINSTEIN-PE, 2012 | 4,817 | 57.7 | 52.9 | NA | 14.6 | NA | NA | NA | NA | NA | 8.3 | 4.6 |
AMPLIFY, 2013 | 5,365 | 56.9 | 58.7 | 84.6 | 19.3 | NA | NA | NA | NA | NA | 5.7 | 2.7 |
Hokusai-VTE, 2013 | 8,240 | 55.8 | 57.2 | NA | 15.4 | NA | NA | NA | NA | NA | 6.6 | 9.4 |
A total of 1,139 (1.3%) developed fracture, of which 515 (1.1%) were NOACs users and 624 (1.4%) were warfarin users. Consequently, NOACs significantly reduced the risk of fracture by 18% (RR: 0.82, 95%CI: 0.73–0.93,
Risk of any fracture with Non-vitamin K antagonist oral anticoagulants and warfarin. RR indicates relative risk; 95%CI indicates 95% confidence interval.
Risk of fracture at different site was presented in Table
Relative risk of fracture at different skeletal site.
Fragility fracture |
12 | 212/44816(0.47%) | 240/44733(0.54%) | 0.88 | 0.73–1.06(0.18) |
Vertebral fracture |
9 | 78/40833(0.19%) | 99/40753(0.24%) | 0.79 | 0.59–1.06(0.11) |
Hip fracture | 10 | 78/42459(0.18%) | 79/42383(0.19%) | 0.99 | 0.72–1.34(0.93) |
Femur fracture | 11 | 64/43536(0.15%) | 79/43445(0.18%) | 0.82 | 0.59–1.13(0.22) |
Rib fracture | 9 | 44/39430(0.11%) | 51/39330(0.13%) | 0.87 | 0.58–1.29(0.48) |
Femoral neck fracture | 9 | 44/40228(0.11%) | 44/40139(0.11%) | 1.00 | 0.66–1.51(1.00) |
Spinal compression fracture | 9 | 39/40883(0.10%) | 42/40753(0.10%) | 0.93 | 0.60–1.43(0.74) |
Humerus fracture | 9 | 31/33816(0.09%) | 24/33776(0.07%) | 1.27 | 0.76–2.12(0.36) |
Ankle fracture | 9 | 29/41624(0.07%) | 37/41540(0.09%) | 0.79 | 0.49–1.27(0.33) |
Upper limb fracture | 9 | 19/41186(0.05%) | 28/41117(0.07%) | 0.7 | 0.40–1.22(0.21) |
Lumbar vertebral fracture | 7 | 13/38476(0.03%) | 20/38403(0.05%) | 0.69 | 0.36–1.31(0.26) |
Lower limb fracture | 8 | 13/38767(0.03%) | 18/38690(0.05%) | 0.75 | 0.38–1.46(0.40) |
Pelvic fracture | 6 | 14/36064(0.04%) | 15/35998(0.04%) | 0.93 | 0.46–1.91(0.85) |
Facial bones fracture | 7 | 13/38476(0.03%) | 15/38403(0.04%) | 0.88 | 0.43–1.78(0.72) |
Tibia fracture | 9 | 15/39142(0.04%) | 16/39045(0.04%) | 0.95 | 0.50–1.80(0.87) |
Foot fracture | 7 | 14/37230(0.04%) | 11/37140(0.03%) | 1.23 | 0.59–2.55(0.58) |
Pubis Fracture | 5 | 11/33388(0.03%) | 12/33309(0.04%) | 0.92 | 0.41–2.05(0.84) |
Thoracic vertebral fracture | 7 | 7/37518(0.02%) | 16/37425(0.04%) | 0.50 | 0.22–1.11(0.09) |
Wrist fracture | 6 | 12/36064(0.03%) | 11/35998(0.03%) | 1.08 | 0.49–2.37(0.84) |
Radius fracture | 10 | 10/41124(0.02%) | 13/41040(0.03%) | 0.82 | 0.40–1.68(0.58) |
Cervical vertebral fracture | 6 | 6/34358(0.02%) | 13/34281(0.04%) | 0.52 | 0.21–1.25(0.14) |
Spinal fracture | 5 | 11/33388(0.03%) | 8/33309(0.02%) | 1.35 | 0.56–3.28(0.51) |
Fibula fracture | 8 | 6/37869(0.02%) | 7/37779(0.02%) | 0.89 | 0.35–2.25(0.81) |
Clavicle fracture | 6 | 3/35106(0.01%) | 10/35020(0.03%) | 0.42 | 0.15–1.18(0.10) |
Hand fracture | 6 | 4/34818(0.01%) | 9/34735(0.03%) | 0.52 | 0.19–1.47(0.22) |
Patella fracture | 5 | 6/29909(0.02%) | 6/29826(0.02%) | 1.00 | 0.36–2.75(1.0) |
Forearm fracture | 4 | 3/26277(0.01%) | 6/26184(0.02%) | 0.54 | 0.15–1.97(0.35) |
Multiple fractures | 5 | 3/25580(0.01%) | 7/25545(0.03%) | 0.56 | 0.19–1.66(0.29) |
Ulna fracture | 4 | 3/18457(0.02%) | 4/18414(0.02%) | 0.82 | 0.23–2.84(0.75) |
Acetabulum fracture | 4 | 4/21648(0.02%) | 3/21612(0.01%) | 1.22 | 0.35–4.24(0.75) |
Skull fracture | 4 | 1/22798(0.00%) | 6/22701(0.03%) | 0.29 | 0.06–1.37(0.12) |
Sternal fracture | 4 | 1/24571(0.00%) | 7/24467(0.03%) | 0.25 | 0.05–1.18(0.08) |
Compression fracture | 4 | 3/24300(0.01%) | 3/24257(0.01%) | 1.00 | 0.25–4.00(1.00) |
Fracture | 4 | 4/29270(0.01%) | 1/29187(0.00%) | 1.99 | 0.50–7.98(0.33) |
Jaw fracture | 2 | 4/11130(0.04%) | 0/11134(0.00%) | 5.00 | 0.58–42.81(0.14) |
Scapula fracture | 3 | 1/22159(0.00%) | 2/22062(0.01%) | 0.60 | 0.08–4.53(0.62) |
Avulsion Fracture | 1 | 1/7111(0.01%) | 0/7125(0.00%) | 3.01 | 0.12–73.77(0.50) |
Fractured COCCYX | 1 | 1/7012(0.01%) | 0/7012(0.00%) | 3.00 | 0.12–73.63(0.50) |
Open fracture | 1 | 0/9088(0.00%) | 1/9052(0.01%) | 0.33 | 0.01–8.15(0.50) |
Fractured sacrum | 1 | 1/4118(0.02%) | 0/4122(0.00%) | 3.00 | 0.12–73.69(0.50) |
According to each NOACs, as shown in Table
Subgroup analyses.
0.33 | |||||||||
Dabigatran | 4 | 54/10042(0.5%) | 53/9978(0.5%) | 1.01 | 0.69–1.48(0.96) | 15.6 | 0.31 | — | |
Rivaroxaban | 4 | 110/11880(0.9%) | 142/11880(1.2%) | 0.78 | 0.61–0.99(0.04) | 15.5 | 0.31 | 333 | |
Apixaban | 2 | 105/11764(0.9%) | 149/11741(1.3%) | 0.70 | 0.55–0.90(0.01) | 55.0 | 0.14 | 250 | |
Edoxaban | 2 | 246/11130(2.2%) | 280/11134(2.5%) | 0.88 | 0.74–1.04(0.13) | 0.0 | 0.64 | — | |
1.00 | |||||||||
Atrial fibrillation | 5 | 436/29909(1.5%) | 528/29826(1.8%) | 0.82 | 0.73–0.93(<0.01) | 28.7 | 0.23 | 333 | |
VTE | 7 | 79/14907(0.5%) | 96/14907(0.6%) | 0.82 | 0.61–1.11(0.20) | 18.2 | 0.29 | — | |
0.74 | |||||||||
>1 year | 5 | 436/29909(1.5%) | 528/29826(1.8%) | 0.82 | 0.73–0.93(<0.01) | 28.7 | 0.23 | 333 | |
<1 year | 6 | 73/13477(0.5%) | 84/13481(0.6%) | 0.87 | 0.64–1.19(0.38) | 18.5 | 0.29 | — |
The overall outcomes failed to identify any individual trials as having influenced the results to a significant extent (Table
Visual inspection of funnel plots for the analyses showed that all plots exhibited fairly symmetrical inverted funnel shapes, suggesting that publication bias was not a concern (Figure
Previous studies have stated the potential link between warfarin use and increased fracture risk. At present, NOACs provide an improved clinical net benefit compared with warfarin, and are recommended by international clinical guideline. With the widespread use of NOACs in elderly people, fracture risk is becoming a key clinical issue. However, the risk of fracture in patients receiving NOACs or warfarin is unclear. For this reason, we have performed the first systematic review to pool current evidence for analyzing the risk of fracture in patients with NOACs therapy. The results indicated that the use of NOACs was associated with a lower fracture risk when compared to warfarin, but with a relatively low absolute risk reduction.
Several reasons might explain the reason of relatively lower fracture risk in NOACs than warfarin. Firstly, recent studies have investigated the effects of NOACs on bone biology. An
Secondly, in order to achieve a satisfied anticoagulation effect, dietary restrictions of vitamin K rich foods was frequently adopted in patients receiving warfarin. In our included RCTs, good control of anticoagulation (as reflected by average time in therapeutic range, TTR) may be related to dietary limitation. Vitamin K1, mainly provided by leafy and green vegetables, is involved in multiple stages on bone metabolism and poor vitamin status is linked to low bone mass and high fracture risk (Pearson,
Although several animal studies have provided the positive effects of NOACs on bone biology. No similar studies have been conducted in humans. In addition, vitamin K1 concentrations were not detected in warfarin-treated patients who had been strictly limited in consumption of Vitamin K rich foods. Thus, the exact mechanism of NOACs on human bones is still necessary to be explored.
Up to now, only one study has described the fracture risk with NOACs vs. warfarin (Lau et al.,
Given that many risk factors for fracture (old age, stroke, previous fracture, etc.,) are also risk factors for thromboembolism among patients taking anticoagulation. The use of warfarin is at even greater risk of fracture in this fragile population. Thus, screening for the risk of fracture should be considered before initiating anticoagulation treatment and NOACs may represent a preferable alternative to warfarin in patients who are at high risk of fracture or expected long-term anticoagulation treatment.
Several limitations need to be considered. Firstly, four studies of NOACs were excluded from the analysis owing to the unavailable fracture data, which might reduce the power of statistics. Secondly, fracture data is notoriously difficult to ascertain, differently collected method of fracture data across trials might introduce certain bias. Thirdly, we have not get access to patient-level data in relation to relevant clinical characteristics, making powerful subgroup analysis unavailable. Whereas, we have performed a meta-regression analysis to assess potential effect modifiers in baseline characteristics, and the results failed to identify any potential confounding on fracture risk. Undeniably, residual confounding effects between included studies cannot be excluded absolutely. Fourthly, the mean duration of follow up was insufficiently long, which may underestimate the fracture risk of warfarin. Finally, included RCTs were not especially designed to assess the fracture risk of NOACs. Therefore, further RCTs as well as long-term observational studies are necessary to be conducted.
The use of NOACs conferred a relatively lower risk of fracture compared to warfarin, with a very low absolute risk reduction. Hence, NOACs may represent a preferable alternative to warfarin in patients who are at high risk of fracture.
X-YL, H-WL, and JP are the guarantors of the entire manuscript. Z-CG and L-YZ contributed to the study conception and design; data acquisition, analysis, and interpretation; drafting of the manuscript; critical revision of the manuscript for important intellectual content; and final approval of the version to be published. LS and CZ contributed to the data acquisition, analysis, and interpretation.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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