Management of Tooth Extraction in Patients Taking Antiresorptive Drugs: An Evidence Mapping Review and Meta-Analysis
Abstract
:1. Introduction
2. Materials and Methods
2.1. Eligibility Criteria
- Participants/population: patients taking antiresorptive drugs, immune modulators, or antiangiogenic drugs who needed tooth extractions.
- Intervention/exposure: tooth extraction with any unlimited intervention.
- Comparator/control: tooth extraction with any unlimited comparator, including blank control and placebo control.
- Outcomes: primary outcomes were the prevalence or incidence of MRONJ or the delayed healing of extracted sockets, all-cause mortality (crude death rate) and MRONJ-related mortality (death rate with MRONJ); secondary outcomes were complications after tooth extraction (such as pain, swelling, and skeletal-related events), and quality of life (QoL) after tooth extraction.
- Study design: (1) primary controlled studies, including randomized controlled trials (RCTs) and nonrandomized controlled studies (NRSs), such as historical controlled trials and cohort studies; (2) secondary studies, including systematic reviews and scoping reviews; and (3) tertiary studies, including umbrella reviews (overviews of reviews) and meta-epidemiological studies.
2.2. Search Methods
2.3. Selection and Data Collection of Studies
2.4. Assessment of Risk of Bias in Included Studies
2.5. Effect Measures
2.6. Data Synthesis Methods
2.7. Assessment of Publication Bias
2.8. Assessment of Certainty
3. Results
3.1. Selection of Studies
3.2. Evidence Map, Characteristics and Risk-of-Bias of Included Studies
3.2.1. Characteristics of Included Secondary and Tertiary Studies
3.2.2. Characteristics of Included Primary Studies
3.2.3. Risk of Bias in Included Studies
3.3. Results of Syntheses
- Autologous platelet concentrates (APC) versus control, including platelet-rich fibrin (PRF), plasma rich in growth factors (PRGF) and platelet-rich plasma (PRP) (four primary studies: Asaka 2017 [32], Mauceri 2020 [33], Mozzati 2012 [27] and Poxleitner 2020 [30]; three reviews: Beth-Tasdogan 2022 [25], Del Fabbro 2015 [26] and Sacco 2021 [24]);
3.3.1. Comparison 1: Drug Holiday versus Drug Continuation
3.3.2. Comparison 2: APC versus Control
3.3.3. Comparison 3: Different Surgical Techniques
3.3.4. Comparison 4: Antibacterial Prophylaxis versus Control
3.4. Certainty of Evidence
4. Discussion
4.1. Interventions of Tooth Extraction in Patients at Risk of MRONJ
4.1.1. Drug Holiday
4.1.2. APC
4.1.3. Surgical Techniques
4.1.4. Antibacterial Prophylaxis
4.2. Limitations
4.2.1. Internal Validity of Included Primary Studies
4.2.2. External Validity of Included Primary Studies
4.2.3. Reliability of Included Primary Studies
4.2.4. Limitations of This Evidence Mapping Review
4.3. Implications for Future Research
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Generic Name | Brand Name | Primary Indication | Common Dose | Route |
---|---|---|---|---|
Bisphosphonates, first-generation (non-nitrogen-containing) | ||||
Clodronate | Bonefos | malignant tumors | 300 mg per day | intravenous |
Clasteon/Clastoban/Ostac | malignant tumors | 400 mg per day | oral | |
Etidronate | Didronel | Paget’s disease | 300–750 mg per day | oral |
Tiludronate | Skelid | Paget’s disease | 400 mg per day | oral |
Bisphosphonates, second-generation (nitrogen-containing, with an amino terminal group) | ||||
Alendronate | Binosto/Fosavance | osteoporosis | 70 mg per week | oral |
Fosamax | osteoporosis | 10 mg per day | oral | |
Neridronate * | Nerixia | Investigational ** | - | - |
Pamidronate | Aredia/Pamidria/Pamidonat/Pamifos/Pamisol | malignant tumors | 90 mg every 3 weeks | intravenous |
Bisphosphonates, third-generation (nitrogen-containing, with a cyclic side-chain or a tertiary amino group) | ||||
Ibandronate | Boniva | osteoporosis | 2.5 mg per day | oral |
Bondenza/Bonviva/Boniva | osteoporosis | 150 mg per month | oral | |
Bondenza/Bonviva/Boniva | malignant tumors | 3 mg every 3 months | intravenous | |
Bondronat/Iasibon | malignant tumors | 2–6 mg every 3 months | intravenous | |
Bondronat/Iasibon | malignant tumors | 50 mg per day | oral | |
Minodronate | Bonteo/Onobis/Recalbon | Investigational ** | - | - |
Risedronate | Actonel | osteoporosis | 5 mg per day | oral |
Actonel/Atelvia | osteoporosis | 35 mg per week | oral | |
Zoledronate | Aclasta/Reclast | osteoporosis | 5 mg per year | intravenous |
Zomera/Zometa | malignant tumors | 4 mg every 3 weeks | intravenous | |
Humanized monoclonal antibody | ||||
Denosumab | Prolia | osteoporosis | 60 mg every 6 months | subcutaneous |
Xgeva | bone metastases | 120 mg every 4 months | subcutaneous |
Mechanism of Action | Generic Name | Brand Name |
---|---|---|
Tyrosine kinase inhibitors (TKI) | Axitinib | Inlyta |
Cabozantinib | Cabometyx/Cometriq | |
Dasatinib | Sprycel | |
Erlotinib | Tarceva | |
Imatinib | Gleevec/Glivec | |
Pazopanib | Votrient | |
Regorafenib | Stivarga | |
Sorafenib | Nexavar | |
Sunitinib | Sutent | |
B-Raf inhibitors | Dabrafenib | Tafinlar |
Trametinib | Mekinist | |
Mammalian target of rapamycin (mTOR) inhibitors | Rapamycin/Sirolimus | Rapamune |
Temsirolimus | Torisel | |
Everolimus | Afinitor/Certican/Votubia/Zortress | |
Vascular endothelial growth factor (VEGF) inhibitors | Aflibercept | Eylea/Zaltrap |
Bevacizumab | Abevmy/Alymsys/Avastin/Aybintio/Bambevi/Equidacent/ Mvasi/Onbevzi/Oyavas/Zirabev | |
Monoclonal antibodies used in immunotherapy | Ipilimumab | Yervoy |
Nivolumab | Opdivo | |
Rituximab | Blitzima/Mabthera/Riabni/Ritemvia/Rituxan/Rixathon/ Riximyo/Ruxience/Truxima |
Study ID | Methods | Findings | |
---|---|---|---|
Outcomes and Relative Effect | Certainty | ||
Beth-Tasdogan 2022 [25] | Design: systematic review Registration: Cochrane protocol Included studies: 13 RCTs | Intervention: extraction with PRGF Control: extraction without PRGF Incidence proportion of MRONJ RR 0.08 (95% CI 0.00 to 1.51) from one RCT | Very low * Very low # |
Intervention: sub-periosteal wound closure Control: epi-periosteal wound closure Incidence proportion of MRONJ RR 0.09 (95% CI 0.00 to 1.56) from one RCT | Very low * Very low # | ||
Cabras 2021 [16] | Design: systematic review Registration: PROSPERO Included studies: 17 primary studies | Intervention: antibacterial prophylaxis Control: no antibacterial prophylaxis Efficacy not reported | Not reported * Very low # |
Del Fabbro 2015 [26] | Design: systematic review Registration: not reported Included studies: 18 primary studies | Intervention: extraction with PRGF Control: extraction without PRGF Incidence proportion of MRONJ OR 0.08 (95% CI 0.00 to 1.47) from one RCT | Not reported * Very low # |
Ottesen 2020 [15] | Design: systematic review Registration: PROSPERO Included studies: 14 primary studies | Intervention: drug holiday Control: drug continuation Efficacy reported as uncertain | Not reported * Very low # |
Sacco 2021 [24] | Design: umbrella review Registration: INPLASY Included studies: 25 systematic reviews | All comparisons of interventions Efficacy not reported | Very low * Very low # |
Study ID | Methods | Participants | Outcomes |
---|---|---|---|
Asaka 2017 [32] | Design: HCT Region: Japan Period: 2013 to 2015 | 102 patients (Male/Female = 9/93; none withdrawn), median age 69, range from 24 to 88 Systemic conditions: metabolic bone diseases (all 102) Drugs *: alendronate (53), etidronate (5), minodronate (12), risedronate (49) | Follow-up: 3 months Primary: MRONJ, delayed healing |
Bodem 2015 [35] | Design: PCS Region: Germany Period: Not reported | 61 patients (Male/Female = 19/42; none withdrawn), mean age 65.65, ranged from 34 to 87 Systemic conditions: malignant tumors (all 61) Drugs: ibandronate (17), pamidronate (6), zoledronate (38) | Follow-up: 3 months Primary: MRONJ |
Hasegawa 2017 [37] | Design: multicenter RCS Region: Japan Period: 2008 to 2015 | 1175 patients (Male/Female = 161/1014; none withdrawn), mean age 70.7, ranged from 23 to 102 Systemic conditions *: malignant tumors, metabolic bone diseases Drugs *: alendronate (742), risedronate (334), minodronate (129), other bisphosphonates (10), unknown (11) | Follow-up: more than 2 months Primary: MRONJ |
Hasegawa 2019 [38] | Design: multicenter RCS Region: Japan Period: 2008 to 2016 | 85 patients (Male/Female = 34/51; none withdrawn), mean age 64.5, ranged from 39 to 90 Systemic conditions: malignant tumors (all 85) Drugs *: zoledronate (52), alendronate (1), risedronate (1), denosumab (39) | Follow-up: more than 2 months Primary: MRONJ |
Hasegawa 2021 [39] | Design: multicenter RCS Region: Japan Period: 2008 to 2019 | 72 patients (Male/Female = 31/41; none withdrawn), mean age 65.2, ranged from 41 to 85 Systemic conditions: malignant tumors (all 72) Drugs: denosumab (all 72) | Follow-up: more than 2 months Primary: MRONJ |
Kang 2020 [40] | Design: RCS Region: Korea Period: 2008 to 2017 | 465 patients (Male/Female = 45/420; none withdrawn), mean age 68.8 Systemic conditions: malignant tumors (6), metabolic bone diseases (458), unknown (1) Drugs *: alendronate (439), ibandronate (56) | Follow-up: more than 2 months Primary: MRONJ |
Mauceri 2020 [33] | Design: HCT Region: Italy Period: 2015 to 2016 | 20 patients (prospective; none withdrawn) and 905 patients (retrospective from literature), age not reported Systemic conditions in prospective: malignant tumors (6), metabolic bone diseases (14) Drugs in prospective: alendronate (6), clodronate (4), ibandronate (2), risedronate (2), zoledronate (6) | Follow-up: 24 months in prospective Primary: MRONJ, delayed healing |
Montefusco 2008 [48] | Design: multicenter RCS Region: Italy Period: till 2006 | 24 patients Systemic conditions: malignant tumors (all 24) Drugs *: pamidronate, zoledronate | Follow-up: more than 2 months Primary: MRONJ |
Mozzati 2012 [27] | Design: RCT Region: Italy Period: 2005–2009 | 176 patients (Male/Female = 75/101; none withdrawn), age ranged from 44 to 83 Systemic conditions: malignant tumors (all 176) Drugs: zoledronate (all 176) | Follow-up: 24 to 60 months Primary: MRONJ, delayed healing |
Mozzati 2013 [28] | Design: RCT Region: Italy Period: 2005–2011 | 700 patients (Male/Female = 23/677; none withdrawn), age ranged from 52 to 79 Systemic conditions: metabolic bone diseases (all 700) Drugs: alendronate (all 700) | Follow-up: 12 to 72 months Primary: MRONJ, delayed healing |
Ottesen 2022 [29] | Design: Single-blind RCT Region: Denmark Period: 2018–2019 | 23 patients (Male/Female = 11/12; three withdrawn but evaluated in ITT analysis), age ranged from 56 to 78 Systemic conditions: malignant tumors (all 23) Drugs: bisphosphonates (pamidronate or zoledronate) (10), denosumab (13) | Follow-up: 6 months Primary: MRONJ, mortality Secondary: complications, QoL |
Poxleitner 2020 [30] | Design: RCT Region: Germany Period: 2017–2019 | 77 patients (Male/Female = 1/76; none withdrawn), median age 78, ranged from 44 to 88 Systemic conditions: metabolic bone diseases (all 77) Drugs: alendronate (28), ibandronate (9), pamidronate (1), risedronate (8), zoledronate (7), denosumab (24) | Follow-up: 3 months Primary: MRONJ Secondary: complications |
Ristow 2021 [31] | Design: Double-blind RCT Region: Germany Period: 2016–2018 | 160 patients (Male/Female = 43/117; 28 withdrawn but evaluated in ITT analysis), mean age 68.1 Systemic conditions: malignant tumors (87), metabolic bone diseases (73) Drugs *: bisphosphonates (130), denosumab (46) | Follow-up: 6 months Primary: MRONJ, mortality |
Sanchis 2014 [36] | Design: PCS Region: Spain Period: 2009–2011 | 36 patients (Male/Female = 16/20; two withdrawn and not evaluated), mean age 63.81 Systemic conditions: malignant tumors (33), Crohn’s disease (1) Drugs: zoledronate (all 36) | Follow-up: 4 months Primary: MRONJ |
Scoletta 2013 [34] | Design: HCT Region: Italy Period: 2010–2011 | 127 patients (Male/Female = 38/89; none withdrawn), mean age 65.31 Systemic conditions: malignant tumors (117), metabolic bone diseases (10) Drugs *: ibandronate (5), pamidronate (11), zoledronate (116) | Follow-up: 4 to 12 months Primary: MRONJ |
Study ID | Incidence of MRONJ among Different Surgical Techniques | ||||
---|---|---|---|---|---|
(Study Design) | A | B | C | D | E |
Hasegawa 2017 [37] (RCS, 3-armed) | 0/105 extractions | 18/1470 extractions | 23/855 extractions | ||
Hasegawa 2019 [38] (RCS, 3-armed) | 0/2 extractions | 22/85 extractions | 17/57 extractions | ||
Hasegawa 2021 [39] (RCS, 3-armed) | 1/5 patients (2/15 extractions) | 12/40 patients (20/71 extractions) | 12/27 patients (17/50 extractions) | ||
Mozzati 2013 [28] (RCT, 2-armed) | 0/334 patients (0/620 extractions) | 0/366 patients (0/860 extractions) | |||
Ristow 2021 [31] (RCT, 2-armed) | 5/82 patients | 11/78 patients | |||
Scoletta 2013 [34] (HCT, 2-armed) | 1/63 patients | 5/64 patients |
Study ID | Antibiotic | Dose and Frequency | Route | Duration of Antibiotic Schedule | |
---|---|---|---|---|---|
Asaka 2017 [32] | Preferred | Amoxicillin | 250 mg q 8 h | Not reported | 7 days, starting from the morning of the surgery |
Alternative | Clindamycin | 150 mg q 6 h | Not reported | ||
Bodem 2015 [35] | Preferred | Ampicillin/sulbactam | 1.5 g tid | Intravenous | ≥6 days, starting at least 24 h before the surgery, and continuing 5 days after the surgery |
Alternative | Clindamycin | 600 mg tid | Intravenous | ||
Montefusco 2008 [48] | Preferred | Amoxicillin/clavulanate | 1 g bid | Oral | 4 days, starting from 1 day before the surgery, and continuing 3 days after the surgery |
Alternative | Levofloxacin | 500 mg qd | Oral | ||
Mozzati 2012 [27] | Preferred | Amoxicillin/clavulanate potassium | 1 tablet (1 g) q 8 h | Oral | 6 days, starting from the evening before the surgery |
Alternative | Erythromycin | 1 tablet (600 mg) q 8 h | Oral | ||
Mozzati 2013 [28] | Preferred | Amoxicillin/clavulanatic acid | 1 tablet q 12 h | Oral | 6 days, starting from the evening before the surgery |
Alternative | Erythromycin | 1 tablet q 8 h | Oral | ||
Ottesen 2022 [29] | Preferred | Amoxicillin/clavulanatic acid | 1000/250 mg for the first time before the surgery; 500/125 mg tid after the surgery | Oral | 10 days, starting from 1 h before the surgery |
Alternative | Erythromycin | 600 mg for the first time before the surgery; 300 mg tid after the surgery | Oral | ||
Poxleitner 2020 [30] | Preferred | Penicillin | 10,000,000 IU qd | Intravenous | 2 days, starting from 1 day before the surgery, and continuing 1 day after the surgery |
Alternative | Clindamycin | 600 mg tid | Intravenous | ||
Ristow 2021 [31] | Preferred | Sultamicillin | 375 mg (frequency not reported) | Oral | ≥7 days, starting on the week before the surgery, and continuing 1 week after surgery |
Alternative | Clindamycin | 600 mg (frequency not reported) | Oral | ||
Sanchis 2014 [36] | Preferred | Amoxicillin/clavulanatic acid | 875/125 mg mg q 8 h | Not reported | 17 days, starting from 2 days before the surgery, and continuing 15 days after surgery |
Alternative | Clindamycin | 300 mg q 8 h | Not reported | ||
Scoletta 2013 [34] | Preferred | Amoxicillin/clavulanate potassium | 1 tablet (1 g) q 8 h | Oral | 6 days, starting from the evening before the surgery |
Alternative | Erythromycin | 1 tablet (600 mg) q 8 h | Oral |
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Liu, C.; Xiong, Y.-T.; Zhu, T.; Liu, W.; Tang, W.; Zeng, W. Management of Tooth Extraction in Patients Taking Antiresorptive Drugs: An Evidence Mapping Review and Meta-Analysis. J. Clin. Med. 2023, 12, 239. https://doi.org/10.3390/jcm12010239
Liu C, Xiong Y-T, Zhu T, Liu W, Tang W, Zeng W. Management of Tooth Extraction in Patients Taking Antiresorptive Drugs: An Evidence Mapping Review and Meta-Analysis. Journal of Clinical Medicine. 2023; 12(1):239. https://doi.org/10.3390/jcm12010239
Chicago/Turabian StyleLiu, Chang, Yu-Tao Xiong, Tao Zhu, Wei Liu, Wei Tang, and Wei Zeng. 2023. "Management of Tooth Extraction in Patients Taking Antiresorptive Drugs: An Evidence Mapping Review and Meta-Analysis" Journal of Clinical Medicine 12, no. 1: 239. https://doi.org/10.3390/jcm12010239