Interventions dans la prise en charge de l'ostéonécrose de la mâchoire liée aux médicaments
Résumé scientifique
Contexte
L'ostéonécrose de la mâchoire (ONM) liée aux médicaments est une réaction indésirable grave à certains médicaments couramment utilisés dans le traitement du cancer et de l'ostéoporose (par exemple, les bisphosphonates, le dénosumab et les agents antiangiogéniques), qui entraîne la destruction progressive de l'os de la mandibule ou du maxillaire. En fonction du médicament, de sa posologie et de la durée d'exposition, cet effet indésirable pourrait survenir rarement (par exemple, après l'administration orale de bisphosphonates ou de dénosumab pour le traitement de l'ostéoporose ou le traitement du cancer par des agents antiangiogéniques) ou fréquemment (par exemple, après l'administration intraveineuse de bisphosphonates pour le traitement du cancer). La ONM liée aux médicaments est associée à une morbidité importante, affecte négativement la qualité de vie (QoL) et est difficile à traiter. Il s'agit d'une mise à jour de notre revue publiée pour la première fois en 2017.
Objectifs
Évaluer les effets des interventions par rapport à l'absence de traitement, au placebo ou à un contrôle actif pour la prophylaxie de l’ONM liée aux médicaments chez les personnes exposées à des médicaments antirésorptifs ou antiangiogéniques.
Évaluer les effets d'interventions chirurgicales ou non chirurgicales (seules ou combinées) par rapport à l'absence de traitement, à un placebo ou à un contrôle actif dans le traitement des personnes souffrant d'une ONM manifeste liée aux médicaments.
Stratégie de recherche documentaire
Le coordinateur de recherche documentaire du groupe Cochrane sur la Santé Bucco‐dentaire a effectué des recherches dans quatre bases de données bibliographiques jusqu'au 16 juin 2021 et a utilisé des méthodes de recherche supplémentaires pour identifier les études publiées, non publiées et en cours.
Critères de sélection
Nous avons inclus des essais contrôlés randomisés (ECR) comparant une modalité d'intervention à une autre pour la prévention ou le traitement de l’ONM liée aux médicaments. Pour la « prophylaxie de l’ONM liée aux médicaments », le critère de jugement principal d'intérêt était l'incidence de l’ONM liée aux médicaments ; les critères de jugement secondaires étaient la qualité de vie, le délai de survenue et le taux de complications et d'effets secondaires de l'intervention. Pour le « traitement d'une ONM liée aux médicaments établie », le critère de jugement principal d'intérêt était la guérison de la l’ONM liée aux médicaments ; les critères de jugement secondaires étaient la qualité de vie, la récurrence et le taux de complications et d'effets secondaires de l'intervention.
Recueil et analyse des données
Deux auteurs de la revue ont indépendamment examiné les résultats de la recherche, extrait les données et évalué le risque de biais dans les études incluses. Pour les critères de jugement dichotomiques, nous avons rapporté le risque relatif (RR) (ou rapport de taux) et les intervalles de confiance (IC) à 95 %.
Résultats principaux
Nous avons inclus 13 ECR (1668 participants) dans la mise à jour de cette revue, dont huit étaient de nouveaux ajouts. Les études étaient cliniquement diverses et portaient sur des interventions très différentes, de sorte que des méta‐analyses n'ont pas pu être réalisées.
Le niveau de confiance des données probantes disponibles est faible ou très faible concernant les interventions pour la prophylaxie ou le traitement de l’ONM liée aux médicaments.
Prophylaxie de l’ONM liée aux médicaments
Cinq ECR ont examiné différentes interventions visant à prévenir la survenue de l’ONM liée aux médicaments.
Un ECR a comparé les soins standard avec des examens dentaires réguliers à trois mois d'intervalle et des traitements préventifs (notamment des antibiotiques avant les extractions dentaires et l'utilisation de techniques de fermeture des plaies évitant l'exposition et la contamination de l'os) chez les hommes atteints d'un cancer de la prostate métastatique et traités par l'acide zolédronique. L'intervention a semblé réduire le risque de l’ONM liée aux médicaments (RR 0,10, IC à 95 % 0,02 à 0,39, 253 participants). Les critères de jugement secondaires n'ont pas été évalués.
La chirurgie dentoalvéolaire est considérée comme un événement prédisposant communément à l'apparition de l’ONM liée aux médicaments et cinq ECR ont testé diverses mesures préventives pour réduire le risque de l’ONM liée aux médicaments postopératoire. Les études ont évalué le plasma riche en facteurs de croissance inséré dans l'alvéole post‐extraction en plus des soins médicaux et chirurgicaux standardisés par rapport aux soins médicaux et chirurgicaux standardisés seuls (RR 0,08, IC à 95 % 0,00 à 1.51, 176 participants) ; la chirurgie délicate et la fermeture par intention primaire par rapport à l'avulsion dentaire non traumatique et la fermeture par intention secondaire (aucun cas de microtraumatisme répété après l'opération dans les deux groupes) ; la fermeture primaire de l'alvéole d'extraction avec un lambeau mucopériosté par rapport à l'application de fibrine riche en plaquettes sans fermeture primaire de la plaie (aucun cas de microtraumatisme répété après l'opération dans les deux groupes) ; et la fermeture de la plaie sous‐périostée par rapport à la fermeture de la plaie épipériostée (RR 0,09, IC à 95 % 0,00 à 1,56, 132 participants).
Traitement de l’ONM liée aux médicaments
Huit ECR ont examiné différentes interventions pour le traitement de l’ONM liée aux médicaments établie, c'est‐à‐dire l'effet sur les taux de guérison de l’ONM liée aux médicaments.
Un ECR a analysé le traitement à l'oxygène hyperbare (OHB) utilisé en plus des soins standard (rinçages antiseptiques, antibiotiques et chirurgie) par rapport aux soins standard seuls (lors du dernier suivi: RR 1,56, IC à 95 % 0,77 à 3,18, 46 participants).
Les taux de guérison de l’ONM liée aux médicaments n'étaient pas significativement différents entre la chirurgie osseuse guidée par autofluorescence et la chirurgie osseuse conventionnelle (RR 1,08, IC à 95 % 0,85 à 1,37, 30 participants). Un autre ECR qui a comparé la séquestrectomie guidée par autofluorescence et celle guidée par fluorescence de tétracycline pour le traitement chirurgical de l’ONM liée aux médicaments n'a pas trouvé de différence significative (lors du suivi d'un an) : RR 1,05, IC à 95 % 0,86 à 1,30, 34 participants).
Trois ECR ont étudié l'effet des facteurs de croissance et des concentrés plaquettaires autologues sur les taux de cicatrisation de l’ONM liée aux médicaments: fibrine riche en plaquettes après chirurgie osseuse par rapport à la chirurgie seule (RR 1,05, IC à 95 % 0,90 à 1.22, 47 participants), la protéine morphogénétique osseuse‐2 associée à la fibrine riche en plaquettes par rapport à la fibrine riche en plaquettes seule (RR 1,10, IC à 95 % 0,94 à 1,29, 55 participants), et le concentré de facteur de croissance et la fermeture primaire de la plaie par rapport à la fermeture primaire de la plaie uniquement (RR 1,38, IC à 95 % 0,81 à 2,34, 28 participants).
Deux ECR ont porté sur le traitement pharmacologique par tériparatide: le tériparatide 20 μg par jour par rapport au placebo associé aux soins standard (RR 0,96, IC à 95 % 0,31 à 2,95, 33 participants) et le tériparatide 56,5 μg par semaine par rapport au tériparatide 20 μg par jour associé aux soins standard (RR 1,60, IC à 95 % 0,25 à 1,44, 12 participants).
Conclusions des auteurs
Prophylaxie de l'ostéonécrose de la mâchoire liée aux médicaments
Un ECR ouvert a fourni quelques données probantes suggérant que les examens dentaires à intervalles de trois mois et les traitements préventifs pourraient être plus efficaces que les soins standard pour réduire l'incidence de l'ostéonécrose de la mâchoire (ONM) liée aux médicaments chez les personnes prenant des bisphosphonates par voie intraveineuse pour un cancer avancé. Nous avons évalué le niveau de confiance des données probantes comme étant très faible.
Les données probantes sont insuffisantes pour affirmer ou réfuter un bénéfice des interventions testées pour la prophylaxie de l’ONM liée aux médicaments chez les patients sous traitement antirésorptif subissant une chirurgie dentoalvéolaire. Bien que certaines interventions aient suggéré un effet potentiel important, les études n'étaient pas assez puissantes pour montrer une signification statistique, et la reproduction des résultats dans des études plus importantes est en attente.
Traitement de l'ostéonécrose de la mâchoire liée aux médicaments
Les données probantes disponibles sont insuffisantes pour affirmer ou réfuter un bénéfice, en plus des soins standards, de l'une ou l'autre des interventions étudiées pour le traitement de l’ONM liée aux médicaments.
PICO
Résumé simplifié
Interventions dans la prise en charge de l'ostéonécrose (lésions osseuses graves) de la mâchoire liée aux médicaments
Problématique de la revue
Quels sont les effets des différentes interventions visant à prévenir ou à traiter l'ostéonécrose de la mâchoire liée à la médication, les unes par rapport aux autres ou par rapport à l'absence de traitement ou à une intervention inactive (placebo) ?
Contexte
L'ostéonécrose de la mâchoire liée aux médicaments (l’ONM liée aux médicaments) est une lésion osseuse grave de la mâchoire qui survient chez certaines personnes en réaction à certains médicaments couramment utilisés dans le traitement du cancer et de l'ostéoporose (une maladie qui fragilise les os). Il s'agit d'une affection douloureuse qui peut être difficile à traiter. l’ONM liée aux médicaments survient rarement chez les personnes prenant certains médicaments contre l'ostéoporose. Cependant, chez les personnes recevant ces médicaments à des doses plus élevées pour des affections liées au cancer, le risque de l’ONM liée aux médicaments pourrait être plus élevé et a été signalé comme pouvant survenir chez cinq personnes sur 100. Il est important d'identifier des mesures préventives efficaces pour réduire le risque de l’ONM liée aux médicaments, et de meilleurs traitements pour ceux qui en sont atteints.
Il s'agit d'une mise à jour de notre revue publiée pour la première fois en 2017. Elle est basée sur une recherche d'articles effectuée pour la dernière fois en juin 2021.
Caractéristiquesdes études
En collaboration avec le groupe Cochrane sur la Santé Bucco-dentaire, nous avons recherché les études qui avaient été publiées jusqu'en juin 2021. Nous avons trouvé cinq études qui portaient sur la prévention de l’ONM liée aux médicaments et huit études qui testaient les traitements de l’ONM liée aux médicaments. Les études ont porté sur 1668 adultes, la plus petite étude comptant 13 participants et la plus grande 700. La plupart des participants à l'étude étaient des femmes, mais une étude portait sur des hommes atteints d'un cancer de la prostate et recevant des perfusions de bisphosphonates (administrés au goutte à goutte dans une veine). Toutes les études, sauf deux, ne comprenaient que des participants traités aux bisphosphonates (utilisés pour soutenir le traitement et réduire le risque de fracture et de douleur osseuse), bien que plusieurs autres médicaments soient également connus pour induire l’ONM liée aux médicaments. Deux essais ont également inclus des patients traités par bisphosphonates ou dénosumab.
Principauxrésultats
Une étude a fourni des données probantes d’un niveau de confiance très faible suggérant que les examens dentaires à intervalles de trois mois et les traitements préventifs (antibiotiques avant les extractions dentaires et utilisation de techniques de fermeture des plaies qui évitent l'exposition et la contamination de l'os) sont plus efficaces que les soins standard pour réduire le nombre de cas de l’ONM liée aux médicaments dans un groupe de personnes recevant des bisphosphonates par voie intraveineuse pour des pathologies liées au cancer. Dans le groupe expérimental, qui a reçu des soins préventifs consistant en des antibiotiques et une fermeture spécifique des plaies, moins de personnes ont développé une ONM liée aux médicaments: deux participants sur 100 ayant fait l'objet d'une surveillance étroite ont développé une ONM liée aux médicaments, contre 23 participants sur 100 dans le groupe témoin (soins standard).
Les données probantes étaient insuffisantes pour conclure que l'utilisation des autres interventions étudiées réduirait le risque d’ONM liée aux médicaments ou améliorerait la guérison de l’ONM liée aux médicaments.
Niveau de confiance des données probantes
Le niveau de confiance des données probantes était faible ou très faible. Cela est dû aux limites de la conception et de la réalisation des études. Par exemple, certains participants ont changé de groupe au cours de l'étude, d'autres n'ont pas terminé l'étude, et les critères de jugement ont été mesurés à des moments de suivi différents. En outre, la plupart des études ne comptaient qu'un petit nombre de participants.
Authors' conclusions
Summary of findings
| Dental examinations at three‐month intervals and preventive treatments (experimental) compared to standard care (control) for prophylaxis of MRONJ | ||||||
| Population: people at risk of MRONJ | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | Number of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with standard care (control) | Risk with dental examinations at 3‐month intervals and preventive treatments (experimental) | |||||
| MRONJ (incidence proportion)
Follow‐up: mean 32 months | 233 per 1000 | 23 per 1000 | RR 0.10 | 253 | ⊕⊝⊝⊝ | Participants: high‐risk (i.e. individuals with cancer exposed to intravenous zoledronic acid). The outcome MRONJ was also reported as number of cases per patient‐year (incidence rate): rate ratio 0.18 (95% CI 0.04 to 0.74). |
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. We downgraded the certainty of the evidence by three levels due to very serious risk of bias (high and unbalanced rate of crossovers after randomisation; high dropout rates due to high mortality; failure to adhere to the intention‐to‐treat principle; mean follow‐up differed between experimental and control groups) and very serious limitation of indirectness (all male and high‐risk patients). | ||||||
| Dental extraction protocol with plasma rich in growth factors (PRGF) (experimental) compared to a standard dental extraction protocol without PRGF (control) for prophylaxis of MRONJ in people treated with IV bisphosphonates who need dental extractions | ||||||
| Population: people treated with IV bisphosphonates who need dental extractions | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | Number of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with standard dental extraction protocol without PRGF (control) | Risk with dental extraction protocol with PRGF (experimental) | |||||
| MRONJ (incidence proportion) Follow‐up: 24‐60 months | 59 per 1000 | 5 per 1000 | RR 0.08 | 176 | ⊕⊝⊝⊝ | Participants: high risk, i.e. individuals with cancer exposed to IV zoledronic acid |
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. We downgraded the certainty of evidence by three levels due to imprecision and very serious risk of bias (high or unclear risk of selection bias, performance bias, detection bias, and attrition bias). | ||||||
| Subperiosteal wound closure versus epiperiosteal wound closure after tooth extraction for prevention of MRONJ in patients on antiresorptive treatment | ||||||
| Population: people on antiresorptive treatment | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | Number of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with epiperiosteal wound closure after tooth extraction | Risk with subperiosteal wound closure after tooth extraction | |||||
| MRONJ after tooth extraction Assessed with: absence of complete mucosal integrity
Follow‐up: 6 months | 77 per 1000 | 7 per 1000 | RR 0.09 | 132 | ⊕⊕⊝⊝ | 8 patients changed intervention from epiperiosteal wound closure to subperiosteal wound closure. |
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. We downgraded the certainty of the evidence by two levels due to imprecision and serious risk of bias (unclear selection bias, detection bias, high risk of performance bias, attrition bias and reporting bias). | ||||||
| HBO as an adjunct to conventional therapy (experimental) compared to conventional therapy (control) for treatment of MRONJ | ||||||
| Population: people with MRONJ | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | Number of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with conventional therapy (control) | Risk with HBO therapy as an adjunct to conventional therapy (experimental) | |||||
| Healing of MRONJ
Follow‐up: up to 24 months (outcome was measured at last follow‐up) | 333 per 1000 | 520 per 1000 | RR 1.56 | 46 (1 RCT) | ⊕⊝⊝⊝ |
|
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. We downgraded the certainty of the evidence by three levels due to imprecision and very serious risk of bias (unclear and high risk of selection bias, performance bias, detection bias, and attrition bias; failure to adhere to the intention‐to‐treat principle). | ||||||
| Autofluorescence‐guided bone surgery (experimental) compared to tetracycline fluorescence‐guided bone surgery (control) for treatment of MRONJ | ||||||
| Population: people with MRONJ | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | Number of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with tetracycline fluorescence‐guided bone surgery (control) | Risk with autofluorescence‐guided bone surgery (experimental) | |||||
| Healing of MRONJ
Follow‐up: 1 year | 889 per 1000 | 933 per 1000 | RR 1.05 | 34 | ⊕⊝⊝⊝ |
|
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. We downgraded the certainty of the evidence by three levels due to imprecision and very serious risk of bias (unclear and high risk of selection bias, performance bias, and detection bias). | ||||||
| Bone morphogenetic protein‐2 together with platelet‐rich fibrin (experimental) compared to platelet‐rich fibrin alone (control) for treatment of MRONJ | ||||||
| Population: people with MRONJ Settings: hospital Intervention: bone morphogenetic protein‐2 together with platelet‐rich fibrin (experimental) Comparison: platelet‐rich fibrin only (control) | ||||||
| Outcomes | Anticipated absolute risks* (95% CI) | Relative effect | Number of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with platelet‐rich fibrin only (control) | Risk with bone morphogenetic protein‐2 adjacent to platelet‐rich fibrin (experimental) | |||||
| Healing of MRONJ Defined in the study as full coverage with absence of exposed bone, mucosal swelling and erythema, purulent drainage, intra‐ and extra oral fistula and/or any pain or discomfort
Follow‐up: 16 weeks post surgery | 880 per 1000 | 968 per 1000 | RR 1.10 (0.94 to 1.29) | 55 | ⊕⊝⊝⊝
|
|
| *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% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. We downgraded the certainty of the evidence by three levels due to very serious limitations of imprecision and very serious risk of bias (unclear risk of selection bias, detection bias, high risk of performance bias, attrition bias, reporting bias). | ||||||
| Autofluorescence‐guided surgery (experimental) compared to conventional surgery (control) for treatment of MRONJ | ||||||
| Population: people with MRONJ Settings: hospital Intervention: autofluorescence guided surgery (experimental) Comparison: conventional surgery (control) | ||||||
| Outcomes | Anticipated absolute risks* (95% CI) | Relative effect | Number of Participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with conventional surgery (control) | Risk with autofluorescence guided surgery (experimental) | |||||
| Healing of MRONJ Criteria for healing: absence of bone exposure
Follow‐up: 1 year (at last follow‐up) | 867 per 1000 | 933 per 1000 | RR 1.08 (0.85 to 1.37) | 30 | ⊕⊝⊝⊝
| High drop‐out rate. 6 patients were excluded due to mortality and no show at follow‐up appointments. |
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. We downgraded the certainty of the evidence by three levels due to very serious imprecision and serious risk of bias (high selection bias, performance bias, attrition bias, unclear risk of detection bias). | ||||||
| Platelet‐rich fibrin after bone surgery (experimental) compared to surgery alone (control) for treatment of MRONJ | ||||||
| Population: people with MRONJ Settings: hospital Intervention: platelet‐rich fibrin (experimental) Comparison: conventional (control) | ||||||
| Outcomes | Anticipated absolute risks* (95% CI) | Relative effect | Number of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with surgery alone (control) | Risk with platelet‐rich fibrin after bone surgery (experimental) | |||||
| Healing of MRONJ Defined as absence of infection and mucosal integrity without fistula
Follow‐up: 1 year | 913 per 1000 | 958 per 1000 | RR 1.05 (0.90 to 1.22) | 47 | ⊕⊝⊝⊝
| The outcome healing of MRONJ was also reported as absence of infection, mucosal integrity without fistula, no need for re‐intervention: rate ratio 1.60 (95% CI 1.04 to 2.46). Follow‐up: 1 year See Analysis 8.2. |
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. We downgraded the certainty of the evidence by three levels due to very serious limitation of imprecision and serious risk of bias (unclear selection bias, detection bias, high risk of performance bias, reporting bias). | ||||||
| Concentrated growth factor and primary wound closure compared with primary wound closure only for treatment of MRONJ | ||||||
| Population: people with MRONJ | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | Number of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with primary wound closure only (control) | Risk with concentrated growth factor and primary wound closure (experimental) | |||||
| Healing of MRONJ Defined as soft tissue healing Follow‐up: 6 months | 521 per 1000 | 286 per 1000 | RR 1.38 | 28 | ⊕⊝⊝⊝ |
|
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. We downgraded the certainty of the evidence by three levels because of serious risk of bias (unclear selection bias, high risk of performance bias), very serious limitation of indirectness (only female participants with osteoporosis) and very serious limitation of imprecision (few participants). | ||||||
| Teriparatide 20 μg daily compared with placebo for treatment of MRONJ | ||||||
| Population: people with MRONJ Settings: outpatient and inpatient treatment Intervention: teriparatide 20 μg daily Comparison: placebo | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo (control) | Risk with teriparatide 20 µg daily (experimental) | |||||
| Healing of MRONJ Primary outcomes were the clinical and radiologic resolution of MRONJ lesions, as evaluated by oral examination and CBCT imaging; secondary outcomes included improvement in MRONJ stage, change in MRONJ lesion size, quality of life, bone mineral density, and evidence of osteoblastic response measured biochemically using P1NP and radiologically using 18F‐fluoride PET‐CT imaging
Last follow‐up: 52 weeks | 278 per 1000 | 267 per 1000 (87 to 819) | RR 0.96 (0.31 to 2.95) | 33 (1 RCT) | ⊕⊕⊝⊝
|
|
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. We downgraded the certainty of the evidence by two levels due to imprecision and serious risk of bias (unclear selection bias, high risk of attrition bias and reporting bias). | ||||||
| Teriparatide 56.5 μg weekly (experimental) compared with teriparatide 20 μg daily (control) in addition to standard care for treatment of MRONJ | ||||||
| Population: people with MRONJ Settings: outpatient and inpatient treatment Intervention: teriparatide 56.5 μg weekly in addition to standard care Comparison: teriparatide 20 μg daily in addition to standard care | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with teriparatide 20 μg daily (control) | Risk with teriparatide 56.5 µg weekly (experimental) | |||||
| Healing of MRONJ Measured changes in MRONJ clinical stage at 6 months after the start of the treatment as clinical course, changes in bone metabolism (using bone scintigraphy), percentage of bone formation on the osteolysis of MRONJ, and measurement of bone turnover markers)
Follow‐up: 6 months after start of treatment | 500 per 1000
| 300 per 1000 (125 to 721) | RR 0.60 (0.25 to 1.44) | 12 (1 RCT) | ⊕⊝⊝⊝
|
|
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. We downgraded the certainty of the evidence by three levels due to imprecision and very serious risk of bias (unclear selection bias and detection bias, high risk of performance bias, attrition bias and reporting bias). | ||||||
Background
Description of the condition
Medication‐related osteonecrosis of the jaw (MRONJ) is a severe adverse reaction experienced by some individuals to certain medicines commonly used in the treatment of cancer and osteoporosis (e.g. bisphosphonates, denosumab and antiangiogenic agents), and involves the progressive destruction of bone in the mandible or maxilla.
Osteonecrosis of the jaw (ONJ) associated with bisphosphonate treatment was first reported in 2003 (Marx 2003; Migliorati 2003; Ruggiero 2007; Sigua‐Rodriguez 2014). Subsequently, ONJ was observed in individuals who took denosumab, an antiresorptive medication unrelated to the bisphosphonate class (Bone 2017). A growing number of case reports currently suggest that ONJ is also associated with antiangiogenic agents such as bevacizumab, aflibercept, sunitinib, temsirolimus, and everolimus (Ruggiero 2014; Zhang 2016). The condition formerly referred to as 'bisphosphonate‐related ONJ' has been renamed 'medication‐related ONJ' due to the growing number of ONJ cases associated with non‐bisphosphonate treatments (Ruggiero 2014).
The exact mechanisms underlying MRONJ remain unknown. Interestingly, MRONJ is primarily limited to the maxillofacial region. In contrast to other skeletal bones, jaw bones (the alveolar process and periodontium) have relatively high vascularity, bone turnover, and remodelling because of continuous mechanical stress, which may make them vulnerable to the adverse effects of drugs. Proposed hypotheses that attempt to explain the localisation of MRONJ exclusively to the jaws include altered bone remodelling, angiogenesis inhibition, constant microtrauma, suppression of innate or acquired immunity, and possible effects of inflammation or infection (Ruggiero 2014).
According to the case definition provided by the American Society for Bone and Mineral Research and the American Association of Oral and Maxillofacial Surgeons, people may be considered to have MRONJ if all of the following characteristics are present: (i) current or previous treatment with antiresorptive or antiangiogenic agents, (ii) exposed or necrotic bone in the maxillofacial region that did not heal (by primary or secondary intent) within eight weeks after identification by a healthcare provider, (iii) no history of radiation therapy to the jaws, and (iv) no evidence of metastatic disease to the jaws (Ruggiero 2007; Sigua‐Rodriguez 2014). MRONJ has been divided into four stages based on clinical symptoms. Stage 0 describes individuals with prodromal disease (unexposed variant). Bone exposure is common in individuals with stage 1 to 3 MRONJ without infection (stage 1), with infection (stage 2), or with infection as well as a pathological fracture or fistula, or evidence of osteolysis extending to the inferior border of the mandible or sinus floor (stage 3) (Table 1) (Ruggiero 2007; Ruggiero 2014; Sigua‐Rodriguez 2014; Vescovi 2012a).
| MRONJ stage | Description |
| AT RISK | No apparent necrotic bone in patients who have been treated with oral or intravenous bisphosphonates |
| STAGE 0 | No clinical evidence of necrotic bone but nonspecific clinical findings, radiographic changes, and symptoms |
| STAGE 1 | Exposed and necrotic bone or fistulas that probes to bone in patients who are asymptomatic and have no evidence of infection |
| STAGE 2 | Exposed and necrotic bone or fistulas that probes to bone associated with infection as evidenced by pain and erythema in the region of exposed bone with or without purulent drainage |
| STAGE 3 | Exposed and necrotic bone or a fistula that probes to bone in patients with pain, infection, and ≥ 1 of the following: exposed and necrotic bone extending beyond the region of alveolar bone (i.e. inferior border and ramus in mandible, maxillary sinus, and zygoma in maxilla) resulting in pathologic fracture, extraoral fistula, oral antral, or oral nasal communication, or osteolysis extending to inferior border of the mandible or sinus floor |
From the American Association of Oral and Maxillofacial Surgeons position paper on medication‐related osteonecrosis of the jaw‐‐2014 update (Ruggiero 2014)
The frequency of MRONJ is highly variable and ranges from very rare (less than 1/10,000) to common (1/100 or more), depending on the drug, treatment indication (cancer versus osteoporosis), dose, and duration of treatment (Dodson 2015). For example, in randomised controlled trials (RCTs) and a meta‐analysis, the incidence of MRONJ in individuals with cancer exposed to intravenous (IV) zoledronic acid was between 0.3% and 5% (Coleman 2011; Lopez‐Olivo 2012; Mauri 2009; Morgan 2010). The reported risk of MRONJ in individuals with cancer treated with denosumab ranged from 0.7% to 1.9% (Boquete‐Castro 2016; Qui 2014; Ruggiero 2014). A meta‐analysis that compared the safety of denosumab and zoledronic acid in individuals with bone metastases did not reveal a significant difference in the risk of MRONJ between the denosumab and zoledronic acid groups (Chen 2016).
Among individuals with osteoporosis, who receive substantially lower doses of bisphosphonates or denosumab than those with cancer, MRONJ is rare and the incidence may not be substantially greater than the natural background incidence of the condition. In people receiving bisphosphonates to treat osteoporosis, incidence estimates range from less than 0.1 to 0.7 cases per 10,000 patient years of exposure (Chamizo Carmona 2013; Grbic 2010). In a recent report studying people exposed to denosumab for treatment of osteoporosis, the incidence of MRONJ was 5.2 per 10,000 patient‐years (Bone 2017). The risk for MRONJ among people with osteoporosis treated with bisphosphonates or denosumab approximates the risk for MRONJ that is observed in placebo groups (Bone 2017; Grbic 2010). The risk of MRONJ among people exposed to antiresorptive medications for the treatment of osteoporosis is approximately 100‐fold smaller than the risk in people with cancer (Ruggiero 2014).
Evidence supporting the association of antiangiogenic medications with the development of MRONJ is primarily based on case reports. The frequency of MRONJ in people receiving antiangiogenic agents is not known accurately and reliably. Analysis of the United States Food and Drug Administration’s Adverse Event Reporting System database showed that the intravenous BPs were associated with the highest risk for MRONJ, denosumab was associated with risk comparable to bisphosphonates used for osteoporosis, and the antiangiogenic agents were associated with the lowest risk for MRONJ (Zhang 2016). In a combined analysis of three phase III trials the incidence of MRONJ in people exposed to the angiogenesis inhibitor bevacizumab was 0.2% (Guarneri 2010). The incidence was substantially higher in those exposed to both zoledronic acid and bevacizumab (Guarneri 2010).
The treatment of MRONJ is challenging, and an effective and appropriate therapy that substantially improves the outcome remains to be identified. The median time to resolution of osteonecrosis symptoms may be up to 12 months and depends on the specific therapeutic intervention (Hinson 2015). Additional information on the natural history of MRONJ comes from a report of individuals with multiple myeloma who were prospectively observed for a minimum of 3.2 years following diagnosis (Badros 2008). MRONJ resolved in 62% of cases, resolved and then recurred in 12%, and did not heal in 26%.
Antiresorptive medications associated with MRONJ
Bisphosphonates are osteotropic agents with antiresorptive activity that are used in a wide spectrum of indications such as the treatment and prevention of osteoporosis, as well as the treatment of Paget's disease, multiple myeloma, and malignancy‐associated hypercalcaemia. Bisphosphonates bind to bone hydroxyapatite and specifically inhibit the activity of osteoclasts, the bone‐resorbing cells. Bone turnover is thereby reduced, which results in an increase in the mineral density of the bone and a reduction in serum calcium (Chestnut 2001; Guyatt 2002; Ruggiero 2007; Sigua‐Rodriguez 2014). Bisphosphonates have a long retention time in bone, and effects may persist for some time after treatment has been stopped. There are two major risk categories for bisphosphonate‐related ONJ: (i) low risk in individuals without cancer treated with oral bisphosphonates (e.g. alendronic acid, clodronic acid, etidronic acid, ibandronic acid, and risedronic acid), or intravenous bisphosphonates (e.g. ibandronic acid and zoledronic acid) for osteoporosis, Paget’s disease, osteopenia, and osteogenesis imperfecta; and (ii) high risk in individuals with cancer treated with intravenous bisphosphonates (e.g. zoledronic acid, pamidronic acid, and ibandronic acid) for multiple myeloma and bone metastases (Bagan 2009; Ruggiero 2014; Vescovi 2012a). Additional parameters affecting the development of bisphosphonate‐related ONJ include the duration of bisphosphonate exposure, age, comedication, comorbidity, smoking, and oral health/oral hygiene (Bamias 2005; Dimopoulos 2006; Katsarelis 2015; Ruggiero 2014; Sigua‐Rodriguez 2014).
Denosumab, a potent antiresorptive agent, is used to treat osteoporosis in postmenopausal women and in men who have an increased risk of fracture. The recommended dose is 60 mg administered as a single subcutaneous injection once every six months. Denosumab is also used to prevent bone complications in adults with bone metastases from solid tumours and to treat a type of bone cancer called giant cell tumour of bone. The recommended maintenance dose for the latter indications is much higher, 120 mg every four weeks. Denosumab is a monoclonal antibody, which has been designed to attach to an antigen called RANK ligand (RANKL). By attaching to and blocking RANKL, denosumab reduces the formation and activity of osteoclasts, the cells in the body that are involved in breaking down bone tissue (Katsarelis 2015; Pageau 2009; Ruggiero 2014; Xu 2013). The exact pathophysiological mechanisms of denosumab‐related ONJ are currently unknown.
Antiangiogenic medications associated with MRONJ
Antiangiogenic agents are increasingly used as anticancer drugs for the treatment of renal cell carcinomas, gastrointestinal tumours, and other solid tumours. The drugs interfere with the formation of new blood vessels by inhibiting angiogenesis signalling cascades, such as vascular endothelial growth factor signalling (bevacizumab and aflibercept), mechanistic target of rapamycin signalling (temsirolimus and everolimus), or receptor tyrosine kinase signalling (sunitinib). MRONJ is a known, rare side effect of these agents, possibly resulting from their interaction with wound healing or osteoclast differentiation and survival (Patel 2015; Ruggiero 2014). Drug approval authorities (US Food and Drug Administration, European Medicines Agency) have included drug safety warnings in the drug labels of bevacizumab, aflibercept, and sunitinib regarding the risk of MRONJ.
Description of the intervention
Interventions for the prevention of MRONJ in at‐risk individuals or the management of MRONJ in individuals with manifest disease may include the following.
Prophylaxis of MRONJ
A range of dental prophylactic measures may be used alone or in combination. A primary means of prevention is the completion of all dental treatment (such as restorative therapy, root canal treatment, periodontitis therapy, or tooth extraction) before the commencement of antiresorptive or antiangiogenic therapy or as soon as possible following the commencement of antiresorptive or antiangiogenic therapy to ensure that treatment is completed within the specified ‘time frame’ for the intended agent. Antibiotic prophylaxis or antiseptic mouthwash (e.g. chlorhexidine) may be used. Individuals may take part in a preventive recall programme, or be provided with information regarding antiresorptive or antiangiogenic therapy risks, professional teeth cleaning, effective oral hygiene, and the importance of limiting or ceasing oral health risk behaviours (such as smoking and drug and alcohol use), or both. Surgical interventions may use a non‐traumatic surgical technique (i.e. surgical treatment designed to minimise tissue damage). The use of plasma rich in growth factors (PRGF) may promote bone and adjacent soft tissue regeneration in post‐extraction defects, thereby reducing the risk of MRONJ. To minimise wound exposure to bacteria, reconstructive surgical techniques for wound closure can be used. Some specific dental extraction methods recommend the discontinuation of antiresorptive or antiangiogenic agents before dentoalveolar surgery.
Treatment of MRONJ
For individuals with established MRONJ, the objective is to control infection, minimise necrosis progression, and promote tissue healing (Bagan 2009; Rollason 2016; Ruggiero 2014; Sigua‐Rodriguez 2014; Vescovi 2006; Vescovi 2012a). The standard medical care of MRONJ is currently anti‐infective treatment with systemic antibiotics or oral antiseptic rinses (e.g. chlorhexidine), or both, and surgical debridement or resection (Ruggiero 2014).
Non‐surgical treatment options
Healing may be stimulated by oral pentoxifylline and α‐tocopherol (vitamin E) in addition to antimicrobial therapy. Other options are adjunct hyperbaric oxygen (HBO) therapy, which involves breathing pure oxygen in a pressurised room or tube, or topical ozone therapy (OT) to improve healing. Low‐level laser therapy (LLLT) is also considered a promising adjunctive treatment method for MRONJ. The lasers most commonly used for biomodulation in bone are argon, carbon dioxide, helium/neon, and neodymium‐doped yttrium‐aluminium‐garnet. The use of (autologous) platelet‐rich plasma (PRP) has been suggested to enhance postsurgical wound healing. PRP is commonly used in a gel formulation, which is formed by mixing PRP (derived from the centrifugation of autologous whole blood) with thrombin and calcium chloride. PRP gel contains higher amounts of fibrinogen, platelets, and growth factors than whole blood. Moreover, bone may be restored by teriparatide, a recombinant form of parathyroid hormone. Teriparatide is approved for the treatment of osteoporosis but is used off‐label for other indications such as fracture healing, dental stability, and ONJ. Recombinant human bone morphogenetic proteins (rhBMPs), which also have the ability to induce osteogenesis, are another treatment option to enhance bone healing in MRONJ. After sequestrectomy, a carrier/scaffold (absorbable collagen sponge) that contains rhBMP is placed into the defect.
Surgical treatment options
Surgical treatments include sequestrectomy, debridement, resection, immediate reconstruction. Surgical treatment may also include extraction of teeth within exposed necrotic bone.
How the intervention might work
Prophylaxis of MRONJ
Controlling risk factors for MRONJ may represent an effective prophylaxis for MRONJ. MRONJ is a complication that can develop spontaneously after dentoalveolar surgery in combination with antiresorptive agents. Therefore, the completion of necessary elective dentoalveolar surgery before the start of this therapy may help reduce the risk of MRONJ (Ruggiero 2007; Ruggiero 2014). Another known risk factor is infection (Katsarelis 2015; Ruggiero 2014). Dental prophylaxis, caries control, and conservative restorative dentistry are expected to minimise the number of bacteria and eliminate the ports of entry for bacteria, thereby reducing the risk of infection. Regular dental evaluations during antiresorptive or antiangiogenic therapy may help to recognise significant risks at an early stage and enable prompt measures to be taken to counter them (Ruggiero 2014; SDCEP 2017). If surgery is necessary, for example, during bisphosphonate therapy, wound exposure to bacteria may be controlled by antibiotic prophylaxis, antiseptic mouthwash, or both. Choosing of surgical procedures that help minimise bone exposure or trauma to the jaws may reduce the risk of MRONJ. Platelet‐derived growth‐factor preparations, such as PRP and PRGF, applied at the surgical site may accelerate wound healing and reduce the time of increased infection risk. Stopping antiresorptive drugs before an invasive dental procedure (drug holiday) could be useful for the prevention of MRONJ. Due to the pharmacokinetics, the antiresorptive effect of bisphosphonates and denosumab is maintained for several weeks or months. This would require cessation of antiresorptive therapy for at least two months to significantly reduce the risk of MRONJ during invasive dental procedures (Damm 2013; Ruggiero 2014).
Treatment of MRONJ
Treatment objectives for people with a defined diagnosis of MRONJ are to control infection of the soft and hard tissues, and minimise the progression or occurrence of bone necrosis to optimise wound healing. Stage‐dependent strategies to treat MRONJ have been proposed (Ruggiero 2014), which can be classified into non‐surgical and surgical treatment.
Non‐surgical treatment options
Non‐surgical management includes, for example, drug treatment with teriparatide, which is a recombinant form of parathyroid hormone that stimulates osteoblasts to increase bone density when used intermittently. Alternative options are treatment with pentoxifylline and α‐tocopherol in combination with anti‐microbial therapy, OT, HBO, and LLLT (Vescovi 2012a). Pentoxifylline and α‐tocopherol have been used to treat osteoradionecrosis for many years. Pentoxifylline, a methylxanthine derivative and phosphodiesterase inhibitor, improves blood flow by increasing erythrocyte flexibility and vasodilatation, and modulates immunological activity; α‐tocopherol has antioxidant properties (Epstein 2010); pentoxifylline and α‐tocopherol may play a role in encouraging wound healing and reducing scarring; ozone has antimicrobial and wound‐healing properties, and OT as an adjunct treatment has been hypothesised to induce the repair of tissues by cleansing osteonecrotic lesions, which leads to mucosal healing (Petrucci 2007; Ripamonti 2011). HBO has been shown to be effective in addition to conventional therapies to treat osteoradionecrosis (Bennett 2016). HBO has been proven to stimulate new blood vessel growth within the damaged tissues and to improve the availability of oxygen for wound healing. Thus, HBO has been hypothesised to be a useful adjunctive treatment for MRONJ (Freiberger 2009). Phototherapy with a low‐intensity laser is used as an adjunctive therapy for the treatment of various diseases including wounds. The laser light used with LLLT is in the red visible and near infrared wavelength ranges and promotes biological effects, such as inflammation and angiogenesis. It also increases the inorganic matrix, which may support wound healing (Martins 2012; Vescovi 2006). Platelet‐derived growth‐factor preparations, such as PRP and PRGF, are applied at the surgical site as an adjuvant to stimulate regeneration of osseous and epithelial tissues, thereby accelerating wound healing. Platelet‐derived growth factors are proposed to support angiogenesis and to improve bone formation by enhancing osteoblast formation and activity (Lee 2007; Lopez‐Jornet 2016). rhBMP is used in surgical procedures to improve bone formation and remodelling during bone healing by enhancing the effects of osteoblast formation and activity (Gerard 2014).
Surgical treatment options
Surgical treatments may include a more conservative approach, such as sequestrectomy and surgical debridement or aggressive therapies, such as resections of affected bone with reconstruction. One of the advantages of a more conservative surgical approach such as sequestrectomy is that a better healing can be expected because the periosteum and unaffected bone are conserved (Eckardt 2011; Stanton 2009; Comas‐Calonge 2017).
Why it is important to do this review
Cochrane Oral Health undertook an extensive prioritisation exercise in 2014 to identify a core portfolio of titles that were the most clinically important to maintain on the Cochrane Library (Worthington 2015). This review was identified as a new priority title by the oral and maxillofacial surgery expert panel (Cochrane Oral Health priority review portfolio).
Among the drugs associated with MRONJ, bisphosphonates are by far the most widely used for a wide range of clinical indications. For example, bisphosphonates can be used in breast cancer and prostate cancer, which have the highest sex‐related incidence rates worldwide. Osteoporosis, another common indication for bisphosphonates, is estimated to affect 200 million women worldwide: approximately one‐tenth of women aged 60 years, one‐fifth of women aged 70 years, two‐fifths of women aged 80 years, and two‐thirds of women aged 90 years (Kanis 2007). Moreover, several other drugs (denosumab, antiangiogenic medications) have recently been associated with MRONJ. MRONJ may occur as a common side effect, particularly in individuals with cancer, depending on the drug and the dosage used. Therefore, the population at risk for MRONJ is large and expanding, and the public health implications may be substantial.
MRONJ significantly affects the quality of life (QoL), and the decline in QoL correlates with MRONJ stage (Kyrgidis 2012; Miksad 2011). The following factors contribute to impairment of QoL: (i) infected and painful necrotic jaw bone; (ii) ulcerated, painful, and swollen oral mucosa; (iii) chronic sinus tracts and facial disfigurement; (iv) impaired speech, swallowing, and eating; and (v) frequent medical and dental evaluations and treatments (Migliorati 2010). Rehabilitation after a complete cure of MRONJ is often protracted. A further aggravating circumstance is a high risk of recurrence, which is higher than in other diseases of the jaw bone. Thus, it is important to develop strategies to prevent or manage MRONJ. Preventative dentistry may be shown to decrease the incidence of MRONJ, in which case the implementation of preventive strategies will become an important consideration for individuals, clinicians, and policy makers (Dimopoulos 2006; Ripamonti 2009). Epidemiological studies have shown that the risk of MRONJ increases with a longer duration of treatment and with higher drug doses. Effective measures to prevent and treat MRONJ may significantly improve the risk‐benefit balance, in particular for people requiring long‐term or high‐dose therapy.
However, there is uncertainty regarding how to prevent MRONJ before and during bisphosphonate therapy and how to manage manifest MRONJ (Lopez‐Jornet 2010). As a consequence, current recommendations are contradictory in certain respects (Ruggiero 2014; SDCEP 2017). This review complements and extends the previous Cochrane Review by Rollason 2016, which focused on interventions for treating ONJ associated with bisphosphonate drugs.
This review was first published in 2017 evaluating the prophylaxis and treatment of MRONJ (Beth‐Tasdogan 2017). We completed this update in 2022.
Objectives
To assess the effects of interventions versus no treatment, placebo, or an active control for the prophylaxis of medication‐related osteonecrosis of the jaw (MRONJ) in people exposed to antiresorptive or antiangiogenic drugs.
To assess the effects of non‐surgical or surgical interventions (either singly or in combination) versus no treatment, placebo, or an active control for the treatment of people with manifest MRONJ.
Methods
Criteria for considering studies for this review
Types of studies
We included randomised controlled trials (RCTs) comparing one modality of intervention with another for the prevention or treatment of MRONJ. We excluded quasi‐randomised and non‐RCTs, as well as case studies, case series (or those of case series design), and cross‐sectional studies. We did not exclude studies on the basis of language, publication status or date of publication.
Types of participants
To assess preventive strategies, we included participants who were treated with known risk medications and who had not yet developed MRONJ before assignment to the experimental or control group.
To assess interventions to treat MRONJ, we included people who had developed clinically apparent MRONJ. Case definition included exposure to risk drug and the presence of necrotic bone or fistulas that probe to bone.
We applied no restrictions regarding participant sex, age, initial health status, and pre‐existing conditions, or type of ONJ‐related drug (e.g. alendronic acid, clodronic acid, etidronic acid, ibandronic acid, incadronic acid, olpadronic acid, pamidronic acid, risedronic acid, tiludronic acid, zoledronic acid, denosumab, bevacizumab, aflibercept, sunitinib, temsirolimus, or everolimus), dose, or duration of therapy. To comply with the MRONJ case definition (Ruggiero 2014), we did not include participants with a history of head and neck radiation therapy.
Types of interventions
For prophylaxis of MRONJ
Any intervention (before or after commencement of antiresorptive or antiangiogenic drug therapy) that aims at prevention of MRONJ. Examples of interventions discussed in the literature include the following.
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Completion of all necessary dental treatment before the commencement of antiresorptive or antiangiogenic agents or as soon as possible following commencement of antiresorptive or antiangiogenic agents
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Antibiotic prophylaxis or antiseptic mouthwash
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Preventive recall programme and provision of information for patients
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Non‐traumatic surgery (i.e. surgical treatment designed to minimise tissue damage), reconstructive techniques for wound closure to minimise wound exposure to bacteria, and specific dental extraction protocols
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Supportive measures to accelerate wound healing after surgery, such as platelet‐rich plasma (PRP) and plasma rich in growth factors (PRGF)
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Cessation of therapy with antiresorptive or antiangiogenic agents (‘drug holiday’) before invasive dental procedures
For treatment of MRONJ
Any intervention (non‐surgical, surgical, or a combination of both) that aims to treat clinically manifest MRONJ. Examples of interventions discussed in the literature include the following.
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Non‐surgical
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Antiseptic mouthwashes
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Antibiotic and antifungal therapy
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Parathyroid hormone and teriparatide
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Pentoxifylline and α‐tocopherol
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Ozone therapy (OT)
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Hyperbaric oxygen therapy (HBO)
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Laser therapy (low‐level laser therapy (LLLT))
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Platelet‐derived growth‐factor preparations, such as PRP and PRGF
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Recombinant human bone morphogenetic proteins (rhBMPs)
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Surgical
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Surgical debridement, sequestrectomy
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Jaw bone resection
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Extraction of teeth within exposed necrotic bone
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Comparisons: any single or combined experimental intervention versus control. The control arm consisted of participants receiving no treatment, placebo, or an active control (e.g. standard care).
Types of outcome measures
Primary outcomes
Prophylaxis of MRONJ
Incidence of MRONJ
Two related measures are often used to describe the incidence of MRONJ: incidence proportion (cumulative incidence) and incidence rate of MRONJ. As the incidence rate of MRONJ peaks after two to four years of exposure to bisphosphonates or denosumab in individuals with cancer (Henry 2011; Nakamura 2015; Saad 2012), we had originally planned to include only trials with a follow‐up period of at least three years for the primary outcome. However, we found that the three‐year follow‐up threshold was not applicable as a strict selection criterion for the following reasons: a large proportion of individuals with metastatic cancer (i.e. those most likely to be affected by MRONJ) may die before reaching a three‐year follow‐up. Moreover, follow‐up periods were reported inconsistently between studies (mean follow‐up versus range, follow‐up period of the total study population versus that for each study arm separately, follow‐up per protocol versus follow‐up period as observed).
Treatment of MRONJ
Healing of MRONJ
There is no standardised scale for the assessment of MRONJ healing. Healing of MRONJ may be defined based on clinical examination, imaging findings, or both. Wound healing may be defined as absolute area healed per day, percentage of initial area healed per day, and advance of the wound margin towards the wound centre per day. Wound healing may also be defined as the time taken for mucosa to completely cover necrotic tissue and exposed bone (‘cure period’). The number of participants with resolution of MRONJ (defined as mucosal healing with coverage of exposed bone) within a given time period (e.g. six months) may also be used to describe the healing of MRONJ. Follow‐up time should be at least six months for this primary outcome.
Secondary outcomes
Prophylaxis of MRONJ
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Quality of life (QoL)
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Time‐to‐event
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Rate of complications and side effects of the intervention
Treatment of MRONJ
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QoL
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Recurrence
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Rate of complications and side effects of the intervention
For QoL measures, we reported whether validated scales were used. Non‐validated scales were not excluded a priori. QoL had to have been measured at baseline and at least once during follow‐up.
For the outcome 'complications', if the intervention involved interruption/delay of antiresorptive or antiangiogenic treatment or progression of the underlying disease (e.g. fracture in osteoporosis or disease progression in cancer) were considered complications of the intervention.
Search methods for identification of studies
Electronic searches
Cochrane Oral Health’s Information Specialist conducted systematic searches in the following databases for randomised controlled trials and controlled clinical trials. Due to the Cochrane Centralised Search project to identify all clinical trials on the database and add them to CENTRAL, we only searched recent years of the Embase database. Please see the searching page on the Cochrane Oral Health website for more information. We did not place any other restrictions on the language or date of publication when searching the electronic databases:
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Cochrane Oral Health’s Trials Register (searched 16 June 2021) (see Appendix 1);
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The Cochrane Central Register of Controlled Trials (CENTRAL; 2021, Issue 5) in the Cochrane Library (searched 16 June 2021) (see Appendix 2);
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MEDLINE Ovid (1946 to 16 June 2021) (see Appendix 3);
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Embase Ovid (23 May 2016 to 16 June 2021) (see Appendix 4).
Subject strategies were modelled on the search strategy designed for MEDLINE Ovid. Where appropriate, they were combined with subject strategy adaptations of the highly sensitive search strategies designed by Cochrane for identifying randomised controlled trials and controlled clinical trials (as described in the Cochrane Handbook for Systematic Reviews of Interventions, Version 6.3, (Lefebvre 2022)).
Searching other resources
The following trial registries were searched for ongoing studies:
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US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov; searched 16 June 2021) (see Appendix 5);
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World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch; 16 June 2021) (see Appendix 6).
We asked experts in the field to help identify unpublished literature and searched the reference lists of potential clinical trials in an attempt to identify any study not found by the other searches.
We searched the reference lists of included studies and relevant systematic reviews for further studies.
We checked that none of the included studies in this review were retracted due to error or fraud.
We did not perform a separate search for adverse effects of interventions used, we considered adverse effects described in included studies only.
Data collection and analysis
Selection of studies
Two review authors (NBT (for the original and updated review) and JP) independently assessed the titles and abstracts of each paper identified by the review search strategy. We excluded only clearly irrelevant records at this stage. The search was designed to be sensitive and include controlled clinical trials; these were filtered out early in the selection process if they were not randomised. Following this, we obtained the full text of potentially relevant studies and assessed these for eligibility based on the inclusion criteria as outlined above. In the event that the two review authors could not reach a consensus, another review author (OZ (for the original and updated review)) acted as arbiter. We maintained a detailed log of study eligibility and reasons for exclusion, and recorded these in 'Characteristics of excluded studies' tables.
Data extraction and management
Two review authors (NBT (for the original and updated review) and JP) independently collected details from the included trials using a structured form. If necessary, a third review author (OZ (for the original and updated review)) was consulted to resolve inconsistencies. We extracted the following details and entered them into 'Characteristics of included studies' tables in Review Manager 5 (RevMan 5) (RevMan 2014).
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Methods
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Trial design
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Duration of study
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Sample size calculation
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Country of origin
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Year of publication
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Language of the original publication
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Category (i.e. prophylaxis or treatment of MRONJ)
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Funding
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Registration in a public trials registry
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Participants
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Number of participants
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Age
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Sex
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Condition treated with antiresorptive or antiangiogenic agents
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Inclusion criteria
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Exclusion criteria
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Interventions (i.e. the type of intervention and procedural information)
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Outcomes
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Primary outcomes
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Secondary outcomes
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We planned to contact study authors to ask for further information or clarification of their data if necessary.
Assessment of risk of bias in included studies
Two review authors (NB and JP) independently assessed the risk of bias in the included studies according to guidelines in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
We assessed the included trials for risk of bias (high, low, or unclear) in the following key domains:
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random sequence generation (allocation bias);
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allocation concealment (allocation bias);
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blinding of participants and personnel (performance bias);
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blinding of outcome assessors (detection bias);
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incomplete outcome data (attrition bias);
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selective reporting (reporting bias).
'Unclear’ indicates either a lack of information or uncertainty over the potential for bias. We completed a risk of bias table for each study and presented the results graphically by study and by domain for all studies. If the risk of bias was not clear because of a lack of detail in the studies, we planned to contact the study authors to request further information.
We categorised overall risk of bias by outcome as shown in the table below.
| Risk of bias | Interpretation | Within a study | Across studies |
|---|---|---|---|
| Low risk of bias | Plausible bias unlikely to seriously alter the results | Low risk of bias for all key domains | Most information is from studies at low risk of bias |
| Unclear risk of bias | Plausible bias that raises some doubt about the results | Unclear risk of bias for one or more key domains | Most information is from studies at low or unclear risk of bias |
| High risk of bias | Plausible bias that seriously weakens confidence in the results | High risk of bias for one or more key domains | The proportion of information from studies at high risk of bias is sufficient to affect the interpretation of results |
Measures of treatment effect
We used RevMan 5 (RevMan 2014) to perform the analyses.
For continuous data, we planned to calculate the mean differences (MDS)and 95% confidence intervals (CIs). We planned to report continuous outcomes as means and standard deviations (SDs). When studies used different instruments to measure the same construct, we planned to use the standardised difference i(SMD) n means in the analysis to combine the data.
For dichotomous outcomes, we calculated risk ratios (RRs) along with 95% CIs from cumulative incidence data. In cases of reported incidence rates, the rate ratio was the effect measure of choice. In cases when no events are observed in one or both groups, RevMan automatically checks for problematic zero counts, and add a fixed value to all cells of a table where the problems occur. Studies with no events in either arm are excluded from the meta‐analysis of risk ratios (Higgins 2011).
To summarise time‐to‐event data, we planned to use methods of survival analysis and we planned to express the intervention effect as a hazard ratio (HR), along with 95% CI.
Where insufficient information was reported to enable effect measures to be calculated, we provided a narrative report of the summary measures.
Unit of analysis issues
The individual participant was the unit of analysis.
If there was a choice of time points for a primary outcome, we selected the time point closest to three years for prophylaxis and one year for treatment. We avoided multiple testing of the effect at each of the time points.
Dealing with missing data
We attempted, where feasible, to contact authors from the primary studies to obtain missing data. We used the methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions to estimate the missing standard error of the log rate ratio (Higgins 2011).
Assessment of heterogeneity
To identify and measure the statistical heterogeneity of the data, we planned to use the I² statistic (Higgins 2003). This value (percentage) defines the variability in effect estimates between studies that is beyond what would be expected by chance. The I² value can be categorised as not important heterogeneity (0% to 40%), moderate heterogeneity (30% to 60%), substantial heterogeneity (50% to 90%), and very substantial heterogeneity (75% to 100%) (Higgins 2003). We also planned to use graphical displays, such as Galbraith plots, if appropriate. Galbraith plots enable the display of several estimates of the same quantity having different standard errors; this is why they provide a useful way of checking for the presence of heterogeneity (Anzures‐Cabrera 2010; Copas 2009). Clinical diversity (i.e. variability in the participants, interventions, and outcomes studied) may contribute to statistical heterogeneity. If a sufficient number of studies was included, we planned to explore heterogeneity by conducting subgroup analyses. If there was substantial evidence for between‐study heterogeneity, we planned to use a random‐effects meta‐analysis.
Assessment of reporting biases
If there had been sufficient studies, we would have assessed publication bias using methods based on a funnel plot, such as Egger's test (Egger 1997). However, all publication bias methods were characterised by a relatively low power and could not be assumed to prove or exclude publication bias (Higgins 2011).
Data synthesis
We followed the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions for the statistical analysis of results (Higgins 2011). If the studies had been sufficiently similar with respect to the participants included, interventions compared, and outcomes and time points reported, we would have conducted meta‐analyses. We would have used a random‐effects or fixed‐effect meta‐analysis as appropriate to combine quantitative data. For comparisons in which a meta‐analysis could not be carried out, we have provided a narrative report of the summary measures and treatment effects.
Subgroup analysis and investigation of heterogeneity
Clinical heterogeneity (i.e. differences associated with the participants, interventions, or outcomes across the included studies) may contribute to statistical heterogeneity (i.e. differences in the effects of interventions). If a sufficient number of studies were included, we planned to explore heterogeneity by conducting subgroup analyses in any case (i.e. whether statistical heterogeneity was present or not). To assess the effect of particular aspects of the studies on the primary and secondary outcome variables, we had planned to conduct the following subgroup analyses: medication dose or dose intensity (i.e. unit dose of medication administered per unit time); medication type (e.g. nitrogenous or non‐nitrogenous bisphosphonate) or compound; stage and type of disease (e.g. cancer or non‐cancer); and risk factors (e.g. multimorbidity, age, smoker). If we had included at least 10 studies, we would have investigated these effects using a meta‐regression analysis.
In the case of significant statistical heterogeneity, we would have attempted to identify the source of the heterogeneity with subgroup analyses.
Sensitivity analysis
If there had been sufficient RCTs for meta‐analyses, we would have performed a sensitivity analysis to check the robustness of results when omitting studies with high or unclear risk of bias or to investigate whether the meta‐analysis result was heavily determined by outlier studies. We would have used the Galbraith plot to detect potential outliers.
Summary of findings and assessment of the certainty of the evidence
We have developed a summary of findings table for each comparison, and have presented summary information for the primary outcomes.
Following GRADE methods and using GRADEPro software (GRADEPro 2014), two review authors (NB and OZ) assessed the certainty of evidence with reference to the overall risk of bias of the included studies, directness of the evidence, consistency of the results, precision of the estimates, and risk of publication bias. Factors that may lead to downgrading of evidence in the GRADE approach are: (a) risk of bias, (b) inconsistency between studies, (c) indirectness, (d) imprecision, and (e) likely publication bias. We assessed the certainty of the body of evidence for each comparison and outcome as high, moderate, low, or very low.
Results
Description of studies
See Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies.
Results of the search
We brought forward five included studies (eight references), 11 excluded studies and four ongoing studies from the previous version of the review. For details of the study selection process for the previous version of the review, see Table 2.
| The initial electronic search of 2016 retrieved 1105 references after de‐duplication. After screening the titles and abstracts, we excluded all but 23 references from further evaluation. We examined the full text of the remaining 23 articles and found that eight references relating to five studies met the prespecified inclusion criteria and were therefore included in this review. We identified four additional studies that are ongoing and listed these under Characteristics of ongoing studies. We excluded 11 full‐text articles for reasons noted in the Characteristics of excluded studies table. |
Our searches for the update identified a total of 1047 references. After de‐duplication, two review authors NBT (for the original and updated review) and JP screened the remaining 728 references as titles and abstracts, most of which did not fulfil the inclusion criteria. Twenty‐nine articles were selected for further evaluation in full text. We excluded nine ineligible articles (see Characteristics of excluded studies), and there were nine ongoing studies (see Characteristics of ongoing studies). We identified eight new RCTs (11 references) for inclusion (see Included studies).
The flow diagram summarises the study selection process for the whole review (Figure 1).
Included studies
We included 13 studies in the review: five studies from the previous review (Freiberger 2012; Mozzati 2012; Mozzati 2013; Mücke 2016; Ristow 2016) and eight additional RCTs identified for this update (Giudice 2018a; Giudice 2018b; Ohbayashi 2020; Park 2017; Poxleitner 2020; Ristow 2020; Sim 2020; Sim 2020). Five studies focused on the prophylaxis of MRONJ (Mozzati 2012; Mozzati 2013; Mücke 2016; Poxleitner 2020; Ristow 2020), and eight trials investigated options for the treatment of MRONJ (Freiberger 2012; Giudice 2018a; Giudice 2018b; Ohbayashi 2020; Park 2017; Ristow 2016; Sim 2020; Yüce 2021). The trials varied in sample size between 13 (Ohbayashi 2020) and 700 participants (Mozzati 2013). In total, 1668 participants were included in this review. More women than men took part in the studies, with the exception of one study (Mücke 2016), which recruited only men with prostate cancer. Full details of the studies are in the Characteristics of included studies tables.
Prophylaxis of MRONJ
Characteristics of the trial designs and settings
Of the five studies concerning prophylaxis of MRONJ, three were conducted in Germany (Mücke 2016; Poxleitner 2020; Ristow 2020), and two in Italy (Mozzati 2012; Mozzati 2013). All of the five studies used a parallel‐group design and had two treatment arms.
Characteristics of the participants
The five studies focusing on prophylaxis of MRONJ involved a total of 1366 participants, ranging from 77 to 700 participants per study. All participants were scheduled for tooth extraction while receiving intravenous bisphosphonate for the treatment of cancer (Mücke 2016; Mozzati 2012), or oral bisphosphonate or subcutaneous denosumab for the treatment of osteoporosis (Mozzati 2013; Poxleitner 2020; Ristow 2020), cancer (Ristow 2020), or rheumatoid arthritis and Paget's disease (Mozzati 2013).
Characteristics of the interventions
The following interventions were used in the included studies.
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Dental examinations at three‐month intervals and preventive treatments versus standard care (Mücke 2016).
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Dental extraction protocol with plasma rich in growth factors (PRGF), which was inserted into the postextraction alveolus versus standard dental extraction protocol without PRGF. All participants had a professional oral hygiene session one week before surgery and antibiotics for six days starting the evening before surgery. Surgical care included anaesthesia by alveolar nerve block, no intraligamentous or intrapapillary infiltrations, mucosal flap, and suturing to enable healing via primary intention (Mozzati 2012).
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Surgical extractions carried out via an intrasulcular incision and mobilisation of a mucoperiosteal flap versus extractions carried out without detachment of full‐thickness flaps, and sockets were filled with absorbable haemostatic gelatine sponges (Mozzati 2013).
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Primary closure of the extraction socket with a mucoperiosteal flap versus application of platelet‐rich fibrin (PRF) without subsequent primary closure. Bisphosphonate or denosumab drug holiday prior to the tooth extraction was not required. All patients received perioperative intravenous antibiotic therapy, initiated one day before surgery and continued until one day after surgery. Prior to the extraction, all patients rinsed their mouths with chlorhexidine solution. Postoperatively, patients were instructed to consume a soft diet, to apply daily mouth rinses with chlorhexidine solution, and to refrain from wearing dentures until complete mucosal healing was achieved (Poxleitner 2020).
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Subperiosteal wound closure versus epiperiosteal wound closure after tooth extraction. All patients were pre‐treated with oral antibiotics from the week before surgery until one week after surgery and used an antimicrobial mouth rinse with chlorhexidine three times daily, starting two days before surgery and for at least five days after surgery. If a drug holiday was possible from an oncologic/osteologic perspective, antiresorptive therapy was discontinued one month before surgery until one month after surgery (Ristow 2020).
Characteristics of the outcomes
Primary outcome
The primary outcome was the development of MRONJ. The major diagnostic criterion of MRONJ was non‐healing exposed bone in the mandible or maxilla for longer than eight weeks (according to the AAOMS criteria) after surgery (Mücke 2016; Ristow 2020). Mozzati 2013 defined the success rate as the proportion of participants without clinical signs of postoperative MRONJ, such as pain, swelling, and non‐healing exposed necrotic bone or fistulas, or both, with connection to the bone. Poxleitner 2020) defined the primary outcome as complete mucosal coverage at the extraction site at the follow‐up examination 90 days postoperatively. Mücke 2016 determined the incidence of MRONJ calculated as the incidence rate (i.e. the number of people developing MRONJ per patient‐years) and incidence proportion (i.e. the number of people developing MRONJ relative to the number of people in the study group.
Secondary outcome
Intraoperative and postoperative complications were reported as secondary outcomes (Mozzati 2013). Quality of life was not investigated, except for one study that used the QoL EQ‐5D score sheet as one of the secondary study outcomes (Ristow 2020).
Treatment of MRONJ
Characteristics of the trial designs and settings
The eight included studies concerning treatment and healing of MRONJ were conducted in the USA (Freiberger 2012), in Germany (Ristow 2016), in Korea (Park 2017), two in Italy (Giudice 2018a; Giudice 2018b), in Japan (Ohbayashi 2020), in Australia (Sim 2020), and in Turkey (Yüce 2021).
All of the eight studies used a parallel‐group design and had two treatment arms.
Characteristics of the participants
The eight studies focusing on treatment of MRONJ involved a total of 302 participants ranging from 13 to 55 participants per study. All had MRONJ related to the use of antiresorptive drugs (bisphosphonates or denosumab), mainly for the treatment of cancer or osteoporosis.
Characteristics of the interventions
The interventions used in the included studies included the following.
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Standard care with hyperbaric oxygen (HBO) versus standard care without HBO. Treatment for MRONJ included surgical debridement at the discretion of the referring surgeon and antibiotics for any sign of local infection. Participants in the HBO group received 40 HBO sessions at 2 atmospheres of pressure for two hours each over four weeks (Freiberger 2012).
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Preoperative treatment with doxycycline, which is incorporated into viable bone and is visualised with a certified medical lamp intraoperatively versus treatment with ampicillin/sulbactam (or clindamycin in case of hypersensitivity to penicillin or a penicillin allergy) preoperatively without doxycycline labelling. Autofluorescence of vital bone, which was induced with a special fluorescence lamp (provided for the study by the manufacturer), was used to visualise vital bone intraoperatively (Ristow 2016).
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Single application of leukocyte rich and platelet‐rich fibrin (L‐PRF group) versus combined application of L‐PRF and recombinant human bone morphogenetic protein 2 (rhBMP‐2) (PRF plus BMP group) after surgical removal of bone sequestra and before primary wound closure. All patients received antibiotics, analgesics, 0.12% chlorhexidine for daily rinsing, and professional dental prophylaxis in the week before surgery. Postoperatively, all patients were treated with an antibacterial mouth rinse until complete healing and with intravenous antibiotics for one week and oral antibiotics for another two weeks. (Park 2017).
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Autofluorescence‐guided surgery (AF) versus the traditionally treated group (non‐AF). In the AF group resection margins were visualised using the VELscope which reveals natural autofluorescence of healthy bone by emitting high‐intensity polarised ultraviolet light. In the non‐AF group, bone resection margins of patients were removed by the surgeon according his surgical experience. Absorbable sutures were used in all patients for tension‐free wound closure, and antibiotics started three days preoperatively were continued until seven days postoperatively (Giudice 2018a).
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Removal of necrotic bone and treatment with local application of platelet‐rich fibrin (PRF) at the surgical site before primary wound closure (tension‐free with absorbable suture material) versus removal of necrotic bone and primary wound closure without treatment with PRF. Starting three days before surgery, each patient was treated with antibiotics for 10 days. All patients also received a professional oral hygiene session and a mouth rinse with 0.2% chlorhexidine one week before surgery (Giudice 2018b).
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Removal of necrotic bone and treatment with local application of concentrated growth factor (CGF) at the surgical site before primary wound closure versus removal of necrotic bone and primary wound closure without treatment with CGF (Yüce 2021).
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Eight weeks of subcutaneous teriparatide (TPTD) (20 mg/day) injections versus placebo injections. All participants received calcium and vitamin D supplementation and standard clinical care (Sim 2020).
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Injections of 1×/week 56.5‐μg TPTD for six months versus 20‐μg TPTD injections daily for six months. Participants in both groups received conventional therapy and intensive antibiotic therapy as needed (Ohbayashi 2020).
Characteristics of the outcomes
Primary outcome
The primary outcome was success rate, defined as the absence of a MRONJ site after surgery i.e. full mucosal coverage or the absence of exposed necrotic bone with full coverage at eight weeks after surgery (according to the AAOMS criteria) (Ristow 2016). Giudice and colleagues defined primary outcome as mucosal integrity at six months postoperatively (Giudice 2018a; Giudice 2018b). For the primary outcome, oral lesions were scored by size and number, and a change in lesion scores compared with the baseline condition was used to grade the primary outcome. Possible outcome categories were healed (defined as gingival coverage with no exposed bone), improved, unchanged, or worse (Freiberger 2012). Park 2017 categorised healing outcomes as complete healing, delayed healing or no resolution at four and 16 weeks post‐surgery. Ohbayashi 2020 defined the outcome as change in MRONJ stage, changes in bone metabolism (bone scintigraphy), the percentage of bone formation (axial and coronal computed tomography (CT) images of the maximum osteolysis area), and bone turnover markers (osteocalcin, procollagen type I N‐terminal propeptide, bone‐specific alkaline phosphatases, urinary cross‐linked N‐telopeptide of type I collagen, urinary deoxypiridinolin, and tartrate‐resistant acid phosphatase‐5b).
Secondary outcomes
Secondary outcomes were quality of life (QoL), laboratory measures of bone turnover, and molecular indicators of osteoclast activation, such as RANK, RANKL, OPG, and pAKt (Freiberger 2012), or osteoblastic responses as measured biochemically and radiologically (Sim 2020). Park 2017 analysed serum concentration of C‐terminal cross‐linked telopeptide of type I collagen (sCTX) of each patient with MRONJ additionally to the primary outcomes. Two studies reported mucosal integrity or full coverage at the remaining measurement time points, no signs of infection (Ristow 2016), loss of sensitivity (numbness) of the alveolar nerve, and subjective pain as secondary outcomes (Giudice 2018a).
Excluded studies
We excluded 20 studies (11 in the last version of the review and nine from the updated searches). They were all excluded because they were not RCTs (Asaka 2017; Bonacina 2011; Bramati 2015; Calvani 2018; Colapinto 2018; Coviello 2012; DE Iuliis 2014; Dimopoulos 2009; Garcia‐Martinez 2017; Giovannacci 2016; Jung 2017; Lee 2014; Montebugnoli 2007; Nica 2021; Pelaz 2014; Rodriguez 2019; Szentpeteri 2020; Vescovi 2010; Vescovi 2012; Watanabe 2021). See the Characteristics of excluded studies.
Ongoing studies
There are 12 RCTs currently in process that may be included in future iterations of this review (ChiCTR1900027382; DRKS00012888; jRCTs071200006; NCT01526915; NCT02198001; NCT03040778; NCT03269214; NCT03390777; NCT04512638; NCT04531800; UMIN000009132; UMIN000042862). See Characteristics of ongoing studies.
Risk of bias in included studies
See below and the Characteristics of included studies tables for more details about our risk of bias assessments. A graphical overview is provided in Figure 2.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
Allocation
In all 13 trials, participants were randomly divided into two groups. The method of random sequence generation was noted in only two studies: participants were assigned by a computer randomisation programme, and we judged the risk of bias to be low (Mozzati 2013; Ristow 2020). The authors of 10 trials did not mention the generation of the randomisation sequence and we therefore rated the level of risk as unclear (Freiberger 2012; Giudice 2018b; Mozzati 2012; Mücke 2016; Ohbayashi 2020; Park 2017; Poxleitner 2020; Ristow 2016; Sim 2020; Yüce 2021). In Giudice 2018a, participants were assigned to one of two groups by an independent resident senior, which we considered to be high risk of bias.
We considered the use of sealed envelopes in three studies put them at low risk of bias due to inadequate allocation concealment (Freiberger 2012; Ristow 2020; Yüce 2021). Allocation concealment was not reported for 10 studies, so we categorised the risk level as unclear (Giudice 2018a; Giudice 2018b; Mozzati 2012; Mozzati 2013; Mücke 2016; Ohbayashi 2020; Park 2017; Poxleitner 2020; Ristow 2016; Sim 2020).
Combining these possible sources of selection bias, we therefore judged only one study to be at low risk of selection bias (Ristow 2020), with one at high risk (Giudice 2018a), and the rest unclear.
Blinding
Performance bias
We considered the level of risk for performance bias to be high in all but one of study (Sim 2020) because personnel were not blinded, which in many studies was due to the nature of the intervention.
Detection bias
Detection bias was rated low for three studies where outcome assessors were blinded (Ristow 2020; Sim 2020; Yüce 2021). Therefore, we considered the level of risk for performance and detection bias to be high for all but one study (Sim 2020).
Incomplete outcome data
We judged attrition bias to be high in six studies (Freiberger 2012; Giudice 2018a; Mücke 2016; Ohbayashi 2020; Ristow 2020; Sim 2020). Although a description of losses and withdrawals was given, data analysis was performed as‐treated and not by intention‐to‐treat, or numbers of participants excluded were not balanced across intervention groups. None of the studies reported data in a format that would have enabled us to recalculate effects on an intent‐to‐treat basis.
We judged attrition bias to be low in six studies: follow‐up was complete in five studies, with all participants included in analyses (Giudice 2018b; Park 2017; Poxleitner 2020; Ristow 2016; Yüce 2021), and in Ristow 2016, although some participants were lost for the assessment of secondary endpoints; all participants were included in the assessment of the primary endpoint.
The level of risk of attrition bias was unclear in the other two studies because completeness or loss to follow‐up was not reported (Mozzati 2012; Mozzati 2013).
Selective reporting
We judged four studies to be at high risk of reporting bias (Giudice 2018b; Ohbayashi 2020; Park 2017; Sim 2020). In the report by Giudice 2018b, preoperative pain levels in control and intervention groups were not reported. (Ohbayashi 2020 presented in their publication P values of statistical analyses but did not report effect estimates of outcomes such as improvement of MRONJ. Park 2017 did not report results for all follow‐up time points. Sim 2020 did not report all outcomes; for example, quality of life survey data were missing. All of the other studies presented data for their planned outcomes and were therefore judged to be at low risk of reporting bias.
Other potential sources of bias
We identified no other sources of bias.
Effects of interventions
See: Summary of findings 1 Dental examinations at three‐month intervals and preventive treatments (experimental) compared to standard care (control) for prophylaxis of MRONJ; Summary of findings 2 Dental extraction protocol with plasma rich in growth factors (PRGF) (experimental) compared to standard dental extraction protocol without PRGF (control) for prophylaxis of MRONJ in people treated with IV bisphosphonates who need dental extractions; Summary of findings 3 Subperiosteal wound closure versus epiperiosteal wound closure after tooth extraction for prevention of MRONJ in patients on antiresorptive treatment; Summary of findings 4 Hyperbaric oxygen therapy (HBO) as an adjunct to conventional therapy (experimental) compared to conventional therapy (control) for treatment of MRONJ; Summary of findings 5 Autofluorescence‐guided bone surgery (experimental) compared to tetracycline fluorescence‐guided bone surgery (control) for treatment of MRONJ; Summary of findings 6 Bone morphogenetic protein‐2 together with platelet‐rich fibrin (experimental) compared to platelet‐rich fibrin alone (control) for treatment of MRONJ; Summary of findings 7 Autofluorescence‐guided surgery (experimental) compared to conventional surgery (control) for treatment of MRONJ; Summary of findings 8 Platelet‐rich fibrin after bone surgery (experimental) compared to surgery alone (control) for treatment of MRONJ; Summary of findings 9 Concentrated growth factor and primary wound closure (experimental) versus primary wound closure only (control) for treatment of MRONJ; Summary of findings 10 Teriparatide 20 μg daily (experimental) versus placebo (control) in addition to standard care for treatment of MRONJ; Summary of findings 11 Teriparatide 56.5 μg weekly (experimental) versus teriparatide 20 μg daily (control) in addition to standard care for treatment of MRONJ
Prophylaxis of MRONJ
Regular dental examinations at three‐month intervals and preventive treatments versus standard care for the prophylaxis of MRONJ in men with metastatic prostate cancer and intravenous zoledronic acid
We identified one study with 253 participants that explored the preventive effect of a prophylactic treatment to reduce MRONJ in men with metastatic prostate cancer treated with zoledronic acid (Mücke 2016). The study compared regular dental examinations at three‐month intervals and preventive treatments (including antibiotics before dental extractions, and the use of techniques for wound closure that avoid exposure and contamination of bone) versus standard care (i.e. monitoring and treatment if necessary at the discretion of the participant's dentist).
Incidence of MRONJ
Our primary outcome, incidence of MRONJ, was reported as incidence rate per year and incidence proportion. MRONJ was defined as the non‐healing of exposed bone in the mandible or maxilla for longer than eight weeks without any change in the stage of disease. The mean follow‐up time was 28.8 months. Regular dental examinations at three‐month intervals and preventive treatments showed a lower risk ratio (RR) for MRONJ (0.10; 95% CI 0.02 to 0.39) compared to standard care when dental extractions were performed. There was also a clinically relevant difference in the number of MRONJ cases per patient‐years (rate ratio 0.18; 95% CI 0.04 to 0.74). We rated the certainty of the evidence for the primary outcome to be very low due to very serious risk of bias (high and unbalanced rate of cross‐overs after randomisation; high dropout rates due to high mortality; failure to adhere to the intention‐to‐treat principle; mean follow‐up differed between experimental and control groups), and very serious limitation of indirectness (all male and high‐risk patients). See summary of findings Table 1, Analysis 1.1, and Analysis 1.2.
Plasma rich in growth factors inserted into the postextraction alveolus in addition to standardised medical and surgical care (experimental) versus standardised medical and surgical care alone (control) for prophylaxis of MRONJ
One RCT reported the effect of PRGF for preventing MRONJ in 176 participants with cancer undergoing dental extractions (Mozzati 2012).
Incidence of MRONJ
The diagnosis of MRONJ was based on clinical examination and radiographic examinations. Clinical signs of MRONJ were pain, swelling, and non‐healing exposed necrotic bone or fistulas, or both, with connection to the bone. The study group had a total follow‐up period of 24 to 60 months. At the last contact, no participants in the PRGF group (N = 91) but five participants in the control group (N = 85) developed MRONJ. The RR was 0.08 (95% CI 0.00 to 1.51). We rated the certainty of the evidence for the primary outcome to be very low due to imprecision and very serious risk of bias (high or unclear risk of selection bias, performance bias, detection bias, and attrition bias). See summary of findings Table 2 and Analysis 2.1.
Rate of complications and side effects of the intervention
No intraoperative complications were observed in either of the groups.
Delicate surgery and closure by primary intention (experimental) versus non‐traumatic tooth avulsion and closure by secondary intention (control) for the prophylaxis of MRONJ
One RCT with 700 participants compared wound closure by primary intention with wound closure by secondary intention after dental extractions in individuals treated with oral bisphosphonates (Mozzati 2013).
Incidence of MRONJ
The participants were regularly monitored for clinical signs of MRONJ: pain, swelling, and non‐healing exposed necrotic bone or fistulas, or both, with connection to the bone. In both study arms, no case of postoperative MRONJ was observed.
Rate of complications and side effects of the intervention
No intraoperative complications were observed in either of the two groups.
Primary closure of the extraction socket with a mucoperiosteal flap (experimental) versus application of platelet‐rich fibrin without primary closure (control) for the prophylaxis of MRONJ
One RCT, which randomised 77 participants, reported on the effects of a PRF clot inserted into the extraction socket without primary closure versus primary closure of the extraction socket with a mucoperiosteal flap after tooth extraction (Poxleitner 2020).
Incidence of MRONJ
All participants had complete mucosal coverage without any signs of MRONJ at the final control examination 90 days postoperatively.
Rate of complications and side effects of the intervention
No intraoperative complications occurred in either of the groups. Postoperative complications were found in six participants (15.4%) in the mucoperiosteal flap group and in one participant (2.6%) in the PRF group. Postoperative complications were defined as any deviation from the normal postoperative course such as delayed wound healing, inflammation at the site of extraction, postoperative hematoma/haemorrhage, exposed bone/sequestrum.
Subperiosteal prepared (SPP) mucoperiosteal flap versus epiperiosteal prepared (EPP) mucosa flap for the prevention of MRONJ in individuals treated with antiresorptive therapy for cancer or osteoporosis who underwent dental extractions
One RCT with 160 participants compared two methods of alveoplasty, namely the epiperiosteal prepared (EPP) mucosal flap and the subperiosteal prepared (SPP) mucoperiosteal flap after tooth extraction (Ristow 2020).
Incidence of MRONJ
Six months after surgery, no participant in the EPP group (N = 67) but 5 participants (7.7%) in the SPP group (N = 65) had MRONJ. Diagnosis of MRONJ was based on the absence of full mucosal integrity. The RR was 0.09 (95% CI 0.00 to 1.56). We rated the certainty of the evidence for the primary outcome to be low due to imprecision and serious risk of bias (unclear selection bias, detection bias, high risk of performance bias, attrition bias and reporting bias). See summary of findings Table 3 and Analysis 3.1.
Treatment of MRONJ
Hyperbaric oxygen as an adjunct to conventional therapy (experimental) versus conventional therapy (control) for treatment of MRONJ
One RCT with 49 participants analysed the healing of MRONJ using HBO treatment in addition to standard care (antiseptic rinses, antibiotics, surgery) (Freiberger 2012). All participants terminated bisphosphonate administration before or at the time of consent, except one who continued bisphosphonate administration for one month after the initial examination.
Healing of MRONJ
Oral lesions were graded by size and number, and staged by clinical severity. The last contact was intended to be 24 months after consent; however, only 18 participants completed the full 24‐month observation period. Healing was defined as gingival coverage with no exposed bone. HBO in addition to standard care did not improve healing from MRONJ at any of the investigated time points (at last follow‐up: RR 1.56; 95% CI 0.77 to 3.18; n = 46). We rated the certainty of the evidence for the primary outcome to be very low due to imprecision and very serious risk of bias (unclear and high risk of selection bias, performance bias, detection bias, and attrition bias; failure to adhere to the intention‐to‐treat principle). See summary of findings Table 4 and Analysis 4.1.
Quality of life
Quality of life (QoL) was measured using the Duke Health Profile, a 17‐question generic self‐reporting instrument with six health domains (physical, mental, social, general, perceived health, and self‐esteem) and four dysfunction measurements (anxiety, depression, pain, and disability) (Freiberger 2012). QoL assessments were recorded at the time of the initial interview and after six months. Only within‐group comparisons for each domain were provided based on a dichotomous classification (‘improved’, ‘no change, or worse’). Because no score values were provided, we were unable to make a between‐group analysis.
Autofluorescence‐guided bone surgery (experimental) versus tetracycline fluorescence‐guided bone surgery (control) in individuals with MRONJ referred for surgical treatment
One RCT with 40 participants compared autofluorescence‐guided and tetracycline fluorescence‐guided bone surgery for the treatment of MRONJ (Ristow 2016).
Healing of MRONJ
The primary endpoint reported by Ristow 2016 was success rate. Success was defined as the absence of a MRONJ site after surgery, specified as the maintenance of full mucosal coverage (mucosal integrity) after surgery at the time of the evaluation. All measurements were acquired at five specific time points: preoperatively, and 10 days, eight weeks, six months, and one year after surgery. There was no relevant difference between the autofluorescence‐ and the tetracycline fluorescence‐guided groups at any of the time points (at one‐year follow‐up: RR 1.05; 95% CI 0.86 to 1.30; n = 34). We rated the certainty of the evidence for the primary outcome to be very low due to imprecision and very serious risk of bias (unclear and high risk of selection bias, performance bias, and detection bias). See summary of findings Table 5 and Analysis 5.1.
Bone morphogenetic protein‐2 together with platelet‐rich fibrin (experimental) versus platelet‐rich fibrin alone (control) for treatment of MRONJ
One RCT compared the healing results of the combined use of bone morphogenetic protein‐2 (BMP‐2) and platelet‐rich fibrin (PRF) with the use of PRF alone in patients with MRONJ and bony lesions requiring surgical debridement (Park 2017). Fifty‐five patients were included, of whom 30 patients were assigned to the experimental group (PRF and rhBMP‐2) and 25 participants to the PRF control group.
Healing of MRONJ
Healing of MRONJ was defined as full mucosal coverage without clinical or radiographical evidence of MRONJ. At 16 weeks postoperatively, 29 participants (96.7%) of the PRF plus BMP group and 22 participants (88.0%) of the PRF group showed complete resolution (RR 1.10, 95% CI 0.94 to 1.29). We rated the certainty of the evidence for the primary outcome to be very low due to very serious limitations of imprecision and very serious risk of bias (unclear risk of selection bias, detection bias, high risk of performance bias, attrition bias, reporting bias). See summary of findings Table 6 and Analysis 6.1.
Autofluorescence‐guided bone surgery (experimental) versus conventional bone surgery (control) for treatment of MRONJ
An RCT with 36 participants investigated whether autofluorescence‐guided delineation of resection margins for necrotic bone results in improved MRNOJ cure rates compared with conventional bone surgery based on surgeon experience alone (Giudice 2018a).
Healing of MRONJ
Healing of MRONJ was defined as the absence of exposed necrotic bone with full mucosal coverage and no signs of residual infection (pain, purulent discharge, or numbness) at one week, one month, six months, and one year after surgery. The primary outcome as reported by Giudice 2018a was mucosal integrity six months after surgery. MRONJ cure rates were not different between both treatment arms at one‐year follow‐up (RR 1.08; 95% CI 0.85 to 1.37; n = 30) or any other time points. We rated the certainty of the evidence for the primary outcome to be very low due to very serious imprecision and serious risk of bias (high selection bias, performance bias, attrition bias, unclear risk of detection bias). See summary of findings Table 7 and Analysis 7.1.
Platelet‐rich fibrin after bone surgery (experimental) versus surgery alone (control) for treatment of MRONJ
Giudice 2018b recruited 47 participants with the diagnosis of stage II or III of MRONJ to compare the efficacy of bone surgery either with or without PRF for mucosal healing in an RCT.
Healing of MRONJ
Giudice 2018b reported mucosal integrity, absence of residual infection or cutaneous fistulas, and no re‐intervention necessary to healing as study outcomes, evaluated at one month, six months, and one year after surgery. We used a composite endpoint requiring mucosal integrity and absence of residual infection or cutaneous fistulas to define successful healing of MRONJ at 1‐year follow‐up. The RR was 1.05 (95% CI 0.90 to 1.22). We rated the certainty of the evidence for the primary outcome to be very low due to very serious limitation of imprecision and serious risk of bias (unclear selection bias, detection bias, high risk of performance bias, reporting bias). See summary of findings Table 8 and Analysis 8.1.
The need for re‐intervention may be considered a treatment failure, i.e. the endpoint of cure would likely not have been achieved without re‐intervention. Therefore, as part of a sensitivity analysis, we additionally considered the combined endpoint of mucosal integrity, absence of residual infection or cutaneous fistulas, and no re‐intervention necessary. The RR was 1.60 (95% CI 1.04 to 2.46). We rated the certainty of the evidence for the primary outcome to be very low due to very serious limitation of imprecision and serious risk of bias (unclear selection bias, detection bias, high risk of performance bias, reporting bias). See summary of findings Table 8 and Analysis 8.2.
Concentrated growth factor and primary wound closure (experimental) versus primary wound closure only (control) for treatment of MRONJ
One RCT examined the effect of concentrated growth factor (CGF) applied to the surgical site compared with a control group without CGF (Yüce 2021). Twenty‐eight patients with stage 2 or 3 MRONJ and inadequate improvement with conservative treatment who underwent surgical debridement were randomised 1:1.
Healing of MRONJ
Healing was defined as soft tissue coverage without signs of infection or necrotic bone exposure. Healing of MRONJ was observed in 11 participants (78.6%) in the CGF group and 8 participants (57.1%) in the control group at six months after surgery (RR 1.38, 95% CI 0.81 to 2.34). We rated the certainty of the evidence for the primary outcome to be very low due to serious risk of bias (unclear selection bias, high risk of performance bias), very serious limitation of indirectness (only female participants with osteoporosis) and very serious limitation of imprecision (few participants). See summary of findings Table 9 and Analysis 9.1.
Teriparatide 20 μg daily (experimental) versus placebo (control), in addition to standard care, for treatment of MRONJ
One RCT evaluated the efficacy of eight weeks of subcutaneous teriparatide (20 mg/day) versus placebo injections in addition to calcium and vitamin D supplementation and standard clinical care in 34 participants with established MRONJ (Sim 2020). Participants were observed for 12 months, with primary outcomes that included the clinical and radiologic resolution of MRONJ lesions.
Healing of MRONJ
The proportion of participants without any unresolved lesion at 52 weeks was 27.8% in the placebo group versus 26.7% in the teriparatide group (RR 0.96, 95% CI 0.31 to 2.95). We rated the certainty of the evidence for the primary outcome to be low due to imprecision and serious risk of bias (unclear selection bias, high risk of attrition bias and reporting bias). We downgraded the certainty of the evidence by two levels due to imprecision and serious risk of bias (unclear selection bias, high risk of attrition bias and reporting bias). See summary of findings Table 10 and Analysis 10.1.
Teriparatide 56.5 μg weekly (experimental) versus teriparatide 20 μg daily (control) in addition to conventional treatment of MRONJ
Ohbayashi 2020 examined the clinical outcomes of teriparatide (TPTD) treatment in 13 patients with stage II‐III bisphosphonate‐induced ONJ and compared two TPTD dosing regimens, namely 20 μg TPTD injections daily for six months versus 1×/week 56.5 μg TPTD injections for six months, in an RCT. After one dropout, 12 participants, six in each group, were analysed. The last follow‐up time point was six months after the start of teriparatide treatment.
Healing of MRONJ
The authors reported MRONJ remission as an outcome measure based on the clinical staging of MRONJ. However, the report aggregated the rates of partial remission and complete remission, leaving the cure rate, i.e. the rate of complete remission, unclear. At the end of six months of TPTD treatment, partial remission or complete remission was achieved in three of six participants in the experimental group and in five of six participants in the control group (RR 0.60, 95% CI 0.25 to 1.44). We rated the certainty of the evidence for the primary outcome to be very low due to imprecision and very serious risk of bias (unclear selection bias and detection bias, high risk of performance bias, attrition bias and reporting bias). See summary of findings Table 11 and Analysis 11.1.
Discussion
At present, the mechanisms of medication‐related osteonecrosis of the jaw (MRONJ) are not well known, and the prevention and treatment of MRONJ remains challenging. Thus, it is important to identify effective strategies for managing this well‐known complication of antiresorptive medication.
Summary of main results
For the prevention of MRONJ, we identified five randomised controlled trials (RCTs), each evaluating different interventions (Mozzati 2012; Mozzati 2013; Mücke 2016; Poxleitner 2020; Ristow 2020).
There is very low‐certainty evidence that dental examinations at three‐month intervals and preventive treatments are more effective than standard care in reducing the incidence proportion and the incidence rate of MRONJ in men taking intravenous bisphosphonates for advanced cancer and bone metastases.
Tooth extractions are considered one of the main triggers for the development of MRONJ and various preventive measures have been tested (Mozzati 2012; Mozzati 2013; Poxleitner 2020; Ristow 2020). After evaluating the available evidence, it is not possible to assert or refute a benefit of any of the interventions reviewed, such as plasma rich in growth factors (PRGF) or platelet‐rich fibrin (PRF) inserted into the postextraction alveolus or a specific surgical strategy (i.e. wound closure by primary or secondary intention) or a specific alveoplasty technique (i.e. epiperiosteal or subperiosteal wound closure) for prevention of MRONJ.
We identified eight RCTs that evaluated specific methods to improve the healing of MRONJ, namely hyperbaric oxygen (HBO) therapy (Freiberger 2012), fluorescence‐guided bone surgery (Ristow 2016; Giudice 2018a), growth factors such as PRF, concentrated growth factor or bone morphogenic protein 2 (Giudice 2018b; Yüce 2021; Park 2017), and teriparatide (Ohbayashi 2020; Sim 2020). There was insufficient evidence to either claim or refute a benefit of any of these therapies for improved healing of MRONJ. There was also insufficient evidence to support either autofluorescence‐guided bone surgery or tetracycline fluorescence‐guided bone surgery for improved healing of MRONJ. The small sample size may have contributed to a lack of measurable effect.
Overall completeness and applicability of evidence
The types of interventions evaluated in the included RCTs varied widely and so we were not able to combine data from different studies.
Most RCTs included only people with bisphosphonates for the treatment of cancer or osteoporosis, or both. Two studies included patients treated with both denosumab and bisphosphonates (Poxleitner 2020; Ristow 2020). Although another study also allowed individuals treated with denosumab to participate, only individuals treated with bisphosphonates were included (Ristow 2016). None of the trials investigated the association between MRONJ and antiangiogenic medications. Thus, the included RCTs do not cover the entire spectrum of medications associated with MRONJ.
One trial recruited a highly selective group of participants (i.e. men with prostate cancer receiving zoledronic acid for the treatment of bone metastases) (Mücke 2016). The applicability of the results of this study to other populations is unclear.
A subgroup of individuals, namely those with a history of head and neck radiation therapy, were generally excluded from the RCTs due to the widely accepted case definition of MRONJ. Although exclusion of these individuals may be useful in reducing the heterogeneity of the study populations and in controlling for an important influencing variable, this may have impaired the overall completeness of evidence.
Quality of the evidence
We judged the overall certainty of the evidence to be low or very low, meaning that we are uncertain about the estimates of effect.
All included studies were assessed to have a high risk of bias overall, as they had at least one domain rated at high risk. All trials but one (Sim 2020) were open‐label. Due to their nature, some interventions could not be blinded to participants or surgeons. In only a few studies were outcome assessors blinded (Ristow 2020; Sim 2020; Yüce 2021). Altogether, a lack of blinding confers a high risk of bias. In one trial, the length of follow‐up differed between comparison groups, which may have biased the results of the study (Mücke 2016). A high and unbalanced rate of cross‐overs after randomisation between the comparison groups in two trials may also have conferred a high risk of bias (Freiberger 2012; Mücke 2016). We also downgraded the certainty of the evidence due to imprecision. This is because most studies included relatively few participants (Freiberger 2012; Ristow 2016; Giudice 2018a; Ohbayashi 2020; Poxleitner 2020; Sim 2020; Yüce 2021) or had few or no events (Mozzati 2012; Mozzati 2013; Poxleitner 2020), making it impossible to determine the effect estimates, or the effect estimates had wide 95% confidence intervals. In two comparisons, the certainty of evidence was downgraded due to indirectness (based on Mücke 2016 and Yüce 2021); only one sex (either males or females) was included with one particular disease or the participants were high‐risk patients.
Potential biases in the review process
The methods we used in the review were established and documented in advance of the review being undertaken. We were not influenced by prior knowledge of the study results when making judgements regarding study eligibility. We made no subsequent changes to the types of studies and types of participants to be included in the review as specified in the protocol, with one exception. For trials investigating the effects of interventions for the prophylaxis of MRONJ, we originally required a follow‐up period of at least three years. The three‐year follow‐up threshold, however, turned out not to be a feasible selection criterion (see Primary outcomes). We consider this change to the inclusion criteria to be well justified, however, and we do not believe that we have introduced a relevant selection bias.
Cochrane Oral Health Information Specialist (Anne Littlewood) conducted comprehensive searches of journal and conference databases to ensure that all published and unpublished trials were identified. We did not limit the searches to a particular language. Two review authors independently extracted the trials that met the inclusion criteria. The study authors were contacted where necessary to ascertain if any newer data were available following publication.
Agreements and disagreements with other studies or reviews
In the last two years, several systematic reviews have been published addressing the prophylaxis and treatment of MRONJ (Cabras 2021; Di Fede 2021; Dos Santos Ferreira 2021; Fortunato 2020; Goker 2021; Govaerts 2020; de Souza Tolentino 2019). Unlike our work, which included only RCTs, these reviews additionally included non‐RCTs, such as case reports, case series, retrospective studies, and prospective cohort studies. The reviews investigated the efficacy of hyperbaric oxygen, low‐intensity laser, autologous platelet concentrates (platelet‐rich plasma, plasma‐rich growth factors, and platelet‐rich fibrin), teriparatide, ozone applications, or fluorescence‐guided surgery in the treatment of MRONJ (de Souza Tolentino 2019; Di Fede 2021; Dos Santos Ferreira 2021; Fortunato 2020; Goker 2021; Govaerts 2020; de Souza Tolentino 2019). Another focus of the reviews was prophylaxis of MRONJ by periprocedural administration of systemic antibiotics (Cabras 2021) or autologous platelet concentrates (Fortunato 2020) in patients under antiresorptive and/or biologic agents undergoing tooth extraction or implant surgery. All these reviews agree that high‐quality research, i.e. randomised controlled trials with large samples are required before conclusive statements can be made regarding strategies for the prevention or treatment of MRONJ.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
Comparison 1: Dental examinations at three‐month intervals and preventive treatments (experimental) versus standard care (control) for prophylaxis of MRONJ, Outcome 1: MRONJ (incidence proportion)
Comparison 1: Dental examinations at three‐month intervals and preventive treatments (experimental) versus standard care (control) for prophylaxis of MRONJ, Outcome 2: MRONJ (incidence rate: MRONJ cases per patient‐year)
Comparison 2: Plasma rich in growth factors inserted into the postextraction alveolus in addition to standardised medical and surgical care (experimental) versus standardised medical and surgical care alone (control) for prophylaxis of MRONJ, Outcome 1: MRONJ (incidence proportion)
Comparison 3: Subperiosteal wound closure versus epiperiosteal wound closure after tooth extraction for prevention of MRONJ in patients on antiresorptive treatment, Outcome 1: MRONJ after tooth extraction (assessed with: absence of complete mucosal integrity) at 6 months
Comparison 4: Hyperbaric oxygen as an adjunct to conventional therapy (experimental) versus conventional therapy (control) for treatment of MRONJ, Outcome 1: Healing of MRONJ at last contact
Comparison 5: Autofluorescence‐guided bone surgery (experimental) versus tetracycline fluorescence‐guided bone surgery (control) for treatment of MRONJ, Outcome 1: Healing of MRONJ (defined as mucosal integrity) at 1 year
Comparison 6: Bone morphogenetic protein‐2 together with platelet‐rich fibrin (experimental) compared to platelet‐rich fibrin alone (control) for treatment of MRONJ., Outcome 1: Healing of MRONJ (defined as full mucosal coverage without clinical or radiographical evidence of MRONJ) after 16 weeks
Comparison 7: Autofluorescence‐guided surgery (experimental) compared to conventional surgery (control) for treatment of MRONJ, Outcome 1: Healing of MRONJ (defined as full mucosal coverage and no signs of residual infection) at 1 year
Comparison 8: Platelet‐rich fibrin after bone surgery (experimental) compared to surgery alone (control) for treatment of MRONJ, Outcome 1: Healing of MRONJ (defined as absence of infection and mucosal integrity without fistula) at 1 year
Comparison 8: Platelet‐rich fibrin after bone surgery (experimental) compared to surgery alone (control) for treatment of MRONJ, Outcome 2: Healing of MRONJ (defined as absence of infection, mucosal integrity without fistula, and no need for re‐intervention) at 1 year
Comparison 9: Concentrated growth factor and primary wound closure (experimental) versus primary wound closure only (control) for treatment of MRONJ, Outcome 1: Healing of MRONJ (assessed with: mucosal integrity) at 6 months
Comparison 10: Teriparatide 20 μg daily (experimental) versus placebo (control), in addition to standard care, for treatment of MRONJ, Outcome 1: Healing of MRONJ (defined as absence of any unresolved lesion) at 1 year
Comparison 11: Teriparatide 56.5 μg weekly (experimental) versus teriparatide 20 μg daily (control), in addition to standard care, for treatment of MRONJ, Outcome 1: Healing of MRONJ (defined as partial or complete remission) at 6 months
| Dental examinations at three‐month intervals and preventive treatments (experimental) compared to standard care (control) for prophylaxis of MRONJ | ||||||
| Population: people at risk of MRONJ | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | Number of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with standard care (control) | Risk with dental examinations at 3‐month intervals and preventive treatments (experimental) | |||||
| MRONJ (incidence proportion)
Follow‐up: mean 32 months | 233 per 1000 | 23 per 1000 | RR 0.10 | 253 | ⊕⊝⊝⊝ | Participants: high‐risk (i.e. individuals with cancer exposed to intravenous zoledronic acid). The outcome MRONJ was also reported as number of cases per patient‐year (incidence rate): rate ratio 0.18 (95% CI 0.04 to 0.74). |
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. We downgraded the certainty of the evidence by three levels due to very serious risk of bias (high and unbalanced rate of crossovers after randomisation; high dropout rates due to high mortality; failure to adhere to the intention‐to‐treat principle; mean follow‐up differed between experimental and control groups) and very serious limitation of indirectness (all male and high‐risk patients). | ||||||
| Dental extraction protocol with plasma rich in growth factors (PRGF) (experimental) compared to a standard dental extraction protocol without PRGF (control) for prophylaxis of MRONJ in people treated with IV bisphosphonates who need dental extractions | ||||||
| Population: people treated with IV bisphosphonates who need dental extractions | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | Number of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with standard dental extraction protocol without PRGF (control) | Risk with dental extraction protocol with PRGF (experimental) | |||||
| MRONJ (incidence proportion) Follow‐up: 24‐60 months | 59 per 1000 | 5 per 1000 | RR 0.08 | 176 | ⊕⊝⊝⊝ | Participants: high risk, i.e. individuals with cancer exposed to IV zoledronic acid |
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. We downgraded the certainty of evidence by three levels due to imprecision and very serious risk of bias (high or unclear risk of selection bias, performance bias, detection bias, and attrition bias). | ||||||
| Subperiosteal wound closure versus epiperiosteal wound closure after tooth extraction for prevention of MRONJ in patients on antiresorptive treatment | ||||||
| Population: people on antiresorptive treatment | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | Number of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with epiperiosteal wound closure after tooth extraction | Risk with subperiosteal wound closure after tooth extraction | |||||
| MRONJ after tooth extraction Assessed with: absence of complete mucosal integrity
Follow‐up: 6 months | 77 per 1000 | 7 per 1000 | RR 0.09 | 132 | ⊕⊕⊝⊝ | 8 patients changed intervention from epiperiosteal wound closure to subperiosteal wound closure. |
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. We downgraded the certainty of the evidence by two levels due to imprecision and serious risk of bias (unclear selection bias, detection bias, high risk of performance bias, attrition bias and reporting bias). | ||||||
| HBO as an adjunct to conventional therapy (experimental) compared to conventional therapy (control) for treatment of MRONJ | ||||||
| Population: people with MRONJ | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | Number of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with conventional therapy (control) | Risk with HBO therapy as an adjunct to conventional therapy (experimental) | |||||
| Healing of MRONJ
Follow‐up: up to 24 months (outcome was measured at last follow‐up) | 333 per 1000 | 520 per 1000 | RR 1.56 | 46 (1 RCT) | ⊕⊝⊝⊝ |
|
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. We downgraded the certainty of the evidence by three levels due to imprecision and very serious risk of bias (unclear and high risk of selection bias, performance bias, detection bias, and attrition bias; failure to adhere to the intention‐to‐treat principle). | ||||||
| Autofluorescence‐guided bone surgery (experimental) compared to tetracycline fluorescence‐guided bone surgery (control) for treatment of MRONJ | ||||||
| Population: people with MRONJ | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | Number of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with tetracycline fluorescence‐guided bone surgery (control) | Risk with autofluorescence‐guided bone surgery (experimental) | |||||
| Healing of MRONJ
Follow‐up: 1 year | 889 per 1000 | 933 per 1000 | RR 1.05 | 34 | ⊕⊝⊝⊝ |
|
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. We downgraded the certainty of the evidence by three levels due to imprecision and very serious risk of bias (unclear and high risk of selection bias, performance bias, and detection bias). | ||||||
| Bone morphogenetic protein‐2 together with platelet‐rich fibrin (experimental) compared to platelet‐rich fibrin alone (control) for treatment of MRONJ | ||||||
| Population: people with MRONJ Settings: hospital Intervention: bone morphogenetic protein‐2 together with platelet‐rich fibrin (experimental) Comparison: platelet‐rich fibrin only (control) | ||||||
| Outcomes | Anticipated absolute risks* (95% CI) | Relative effect | Number of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with platelet‐rich fibrin only (control) | Risk with bone morphogenetic protein‐2 adjacent to platelet‐rich fibrin (experimental) | |||||
| Healing of MRONJ Defined in the study as full coverage with absence of exposed bone, mucosal swelling and erythema, purulent drainage, intra‐ and extra oral fistula and/or any pain or discomfort
Follow‐up: 16 weeks post surgery | 880 per 1000 | 968 per 1000 | RR 1.10 (0.94 to 1.29) | 55 | ⊕⊝⊝⊝
|
|
| *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% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. We downgraded the certainty of the evidence by three levels due to very serious limitations of imprecision and very serious risk of bias (unclear risk of selection bias, detection bias, high risk of performance bias, attrition bias, reporting bias). | ||||||
| Autofluorescence‐guided surgery (experimental) compared to conventional surgery (control) for treatment of MRONJ | ||||||
| Population: people with MRONJ Settings: hospital Intervention: autofluorescence guided surgery (experimental) Comparison: conventional surgery (control) | ||||||
| Outcomes | Anticipated absolute risks* (95% CI) | Relative effect | Number of Participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with conventional surgery (control) | Risk with autofluorescence guided surgery (experimental) | |||||
| Healing of MRONJ Criteria for healing: absence of bone exposure
Follow‐up: 1 year (at last follow‐up) | 867 per 1000 | 933 per 1000 | RR 1.08 (0.85 to 1.37) | 30 | ⊕⊝⊝⊝
| High drop‐out rate. 6 patients were excluded due to mortality and no show at follow‐up appointments. |
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. We downgraded the certainty of the evidence by three levels due to very serious imprecision and serious risk of bias (high selection bias, performance bias, attrition bias, unclear risk of detection bias). | ||||||
| Platelet‐rich fibrin after bone surgery (experimental) compared to surgery alone (control) for treatment of MRONJ | ||||||
| Population: people with MRONJ Settings: hospital Intervention: platelet‐rich fibrin (experimental) Comparison: conventional (control) | ||||||
| Outcomes | Anticipated absolute risks* (95% CI) | Relative effect | Number of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with surgery alone (control) | Risk with platelet‐rich fibrin after bone surgery (experimental) | |||||
| Healing of MRONJ Defined as absence of infection and mucosal integrity without fistula
Follow‐up: 1 year | 913 per 1000 | 958 per 1000 | RR 1.05 (0.90 to 1.22) | 47 | ⊕⊝⊝⊝
| The outcome healing of MRONJ was also reported as absence of infection, mucosal integrity without fistula, no need for re‐intervention: rate ratio 1.60 (95% CI 1.04 to 2.46). Follow‐up: 1 year See Analysis 8.2. |
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. We downgraded the certainty of the evidence by three levels due to very serious limitation of imprecision and serious risk of bias (unclear selection bias, detection bias, high risk of performance bias, reporting bias). | ||||||
| Concentrated growth factor and primary wound closure compared with primary wound closure only for treatment of MRONJ | ||||||
| Population: people with MRONJ | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | Number of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with primary wound closure only (control) | Risk with concentrated growth factor and primary wound closure (experimental) | |||||
| Healing of MRONJ Defined as soft tissue healing Follow‐up: 6 months | 521 per 1000 | 286 per 1000 | RR 1.38 | 28 | ⊕⊝⊝⊝ |
|
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. We downgraded the certainty of the evidence by three levels because of serious risk of bias (unclear selection bias, high risk of performance bias), very serious limitation of indirectness (only female participants with osteoporosis) and very serious limitation of imprecision (few participants). | ||||||
| Teriparatide 20 μg daily compared with placebo for treatment of MRONJ | ||||||
| Population: people with MRONJ Settings: outpatient and inpatient treatment Intervention: teriparatide 20 μg daily Comparison: placebo | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo (control) | Risk with teriparatide 20 µg daily (experimental) | |||||
| Healing of MRONJ Primary outcomes were the clinical and radiologic resolution of MRONJ lesions, as evaluated by oral examination and CBCT imaging; secondary outcomes included improvement in MRONJ stage, change in MRONJ lesion size, quality of life, bone mineral density, and evidence of osteoblastic response measured biochemically using P1NP and radiologically using 18F‐fluoride PET‐CT imaging
Last follow‐up: 52 weeks | 278 per 1000 | 267 per 1000 (87 to 819) | RR 0.96 (0.31 to 2.95) | 33 (1 RCT) | ⊕⊕⊝⊝
|
|
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. We downgraded the certainty of the evidence by two levels due to imprecision and serious risk of bias (unclear selection bias, high risk of attrition bias and reporting bias). | ||||||
| Teriparatide 56.5 μg weekly (experimental) compared with teriparatide 20 μg daily (control) in addition to standard care for treatment of MRONJ | ||||||
| Population: people with MRONJ Settings: outpatient and inpatient treatment Intervention: teriparatide 56.5 μg weekly in addition to standard care Comparison: teriparatide 20 μg daily in addition to standard care | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with teriparatide 20 μg daily (control) | Risk with teriparatide 56.5 µg weekly (experimental) | |||||
| Healing of MRONJ Measured changes in MRONJ clinical stage at 6 months after the start of the treatment as clinical course, changes in bone metabolism (using bone scintigraphy), percentage of bone formation on the osteolysis of MRONJ, and measurement of bone turnover markers)
Follow‐up: 6 months after start of treatment | 500 per 1000
| 300 per 1000 (125 to 721) | RR 0.60 (0.25 to 1.44) | 12 (1 RCT) | ⊕⊝⊝⊝
|
|
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. We downgraded the certainty of the evidence by three levels due to imprecision and very serious risk of bias (unclear selection bias and detection bias, high risk of performance bias, attrition bias and reporting bias). | ||||||
| MRONJ stage | Description |
| AT RISK | No apparent necrotic bone in patients who have been treated with oral or intravenous bisphosphonates |
| STAGE 0 | No clinical evidence of necrotic bone but nonspecific clinical findings, radiographic changes, and symptoms |
| STAGE 1 | Exposed and necrotic bone or fistulas that probes to bone in patients who are asymptomatic and have no evidence of infection |
| STAGE 2 | Exposed and necrotic bone or fistulas that probes to bone associated with infection as evidenced by pain and erythema in the region of exposed bone with or without purulent drainage |
| STAGE 3 | Exposed and necrotic bone or a fistula that probes to bone in patients with pain, infection, and ≥ 1 of the following: exposed and necrotic bone extending beyond the region of alveolar bone (i.e. inferior border and ramus in mandible, maxillary sinus, and zygoma in maxilla) resulting in pathologic fracture, extraoral fistula, oral antral, or oral nasal communication, or osteolysis extending to inferior border of the mandible or sinus floor |
| From the American Association of Oral and Maxillofacial Surgeons position paper on medication‐related osteonecrosis of the jaw‐‐2014 update (Ruggiero 2014) | |
| The initial electronic search of 2016 retrieved 1105 references after de‐duplication. After screening the titles and abstracts, we excluded all but 23 references from further evaluation. We examined the full text of the remaining 23 articles and found that eight references relating to five studies met the prespecified inclusion criteria and were therefore included in this review. We identified four additional studies that are ongoing and listed these under Characteristics of ongoing studies. We excluded 11 full‐text articles for reasons noted in the Characteristics of excluded studies table. |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 MRONJ (incidence proportion) Show forest plot | 1 | 253 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.10 [0.02, 0.39] |
| 1.2 MRONJ (incidence rate: MRONJ cases per patient‐year) Show forest plot | 1 | Rate Ratio (IV, Fixed, 95% CI) | 0.18 [0.04, 0.74] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 MRONJ (incidence proportion) Show forest plot | 1 | 176 | Risk Ratio (M‐H, Random, 95% CI) | 0.08 [0.00, 1.51] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 3.1 MRONJ after tooth extraction (assessed with: absence of complete mucosal integrity) at 6 months Show forest plot | 1 | 132 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.09 [0.00, 1.56] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 4.1 Healing of MRONJ at last contact Show forest plot | 1 | 46 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.56 [0.77, 3.18] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 5.1 Healing of MRONJ (defined as mucosal integrity) at 1 year Show forest plot | 1 | 34 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.05 [0.86, 1.30] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 6.1 Healing of MRONJ (defined as full mucosal coverage without clinical or radiographical evidence of MRONJ) after 16 weeks Show forest plot | 1 | 55 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.10 [0.94, 1.29] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 7.1 Healing of MRONJ (defined as full mucosal coverage and no signs of residual infection) at 1 year Show forest plot | 1 | 30 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.08 [0.85, 1.37] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 8.1 Healing of MRONJ (defined as absence of infection and mucosal integrity without fistula) at 1 year Show forest plot | 1 | 47 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.05 [0.90, 1.22] |
| 8.2 Healing of MRONJ (defined as absence of infection, mucosal integrity without fistula, and no need for re‐intervention) at 1 year Show forest plot | 1 | 47 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.60 [1.04, 2.46] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 9.1 Healing of MRONJ (assessed with: mucosal integrity) at 6 months Show forest plot | 1 | 28 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.38 [0.81, 2.34] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 10.1 Healing of MRONJ (defined as absence of any unresolved lesion) at 1 year Show forest plot | 1 | 33 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.96 [0.31, 2.95] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 11.1 Healing of MRONJ (defined as partial or complete remission) at 6 months Show forest plot | 1 | 12 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.60 [0.25, 1.44] |
