Medication-Related Osteonecrosis of the Jaws in Patients on Antiresorptive Medication With Dental Implants. A Scoping Review.

Introduction

Antiresorptive medication (AR) is often prescribed to patients with osteoporosis or cancer to prevent skeletal‐related events (SRE), such as pathologic fractures, pain, hypercalcemia, and metastatic spread of cancer (Black et al. 1996 ; Bundred 2012 ). AR is clinically well documented to reduce the risk of SRE, delay SRE, and alleviate pain (Cummings et al. 1998 ; Saad et al. 2004 ).

Patients taking AR, either due to cancer or osteoporosis, have a risk of developing medication‐related osteonecrosis of the jaws (MRONJ) (Marx 2003 ). MRONJ is defined and staged according to the latest position paper from the American Association of Oral and Maxillofacial Surgeons (AAOMS) where MRONJ is diagnosed when the following criteria are met (Ruggiero et al. 2022 ). Current or previous treatment with ARs alone or in combination with immune modulators or antiangiogenic medications. Exposed bone or bone that can be probed through an intraoral or extraoral fistula(e) in the maxillofacial region that has persisted for more than 8 weeks. No history of radiation therapy to the jaws or metastatic disease to the jaws.

Patients with osteoporosis often receive low‐dose AR (LDAR), whereas patients with cancer often receive high‐dose AR (HDAR) (Al‐Nawas et al. 2023 ). AR can be administered orally as tablets, as subcutaneous injections, or as intravenous infusions in different doses, treatment periods, and intervals depending on the patient's diagnosis (Body 2001 ; Bone et al. 2017 ). The risk of MRONJ is closely related to the AR dose, interval, and duration of treatment. The risk has previously been associated with the route of administration, with intravenous administration being linked to a higher risk compared to oral administration. However, today the risk of MRONJ is rather suspected to be related to the accumulative exposure and the potency of ARs (Moon et al. 2024 ; Persson et al. 2024 ). The 100‐fold lower prevalence of MRONJ in patients with osteoporosis compared to patients with cancer may be partially explained by the 10‐fold lower accumulative annual dose of these agents used for the treatment of osteoporosis (Coropciuc et al. 2023 ). Furthermore, numerous local and systemic risk factors have been identified, with dental implants (DI) being a particularly notable local factor (Ruggiero et al. 2022 ).

The differentiation and stimulation of osteoclasts are essential processes in bone remodeling and osseointegration of DIs involving the removal of mineralized bone by resorption, followed by the formation and subsequent mineralization of new bone matrix through the action of osteoblasts (Schaffler 2003 ). In several conditions, such as osteoporosis, osteopenia, and osteolytic tumor metastases, osteoclasts resorb more bone than osteoblasts can replace during formation, leading to progressive bone loss, increased fragility, and a higher risk of fractures or skeletal complications (Baron et al. 2011 ). AR, including BPs and denosumab, is used to counteract this imbalance by inhibiting the differentiation and normal function of osteoclasts, thus preventing potential fractures and limiting pain and metastatic spread (Coleman et al. 2014 ). AR significantly improves patients' quality of life; however, as previously mentioned, it can have the adverse effect of delayed wound healing, potentially resulting in MRONJ (Sher et al. 2021 ).

The first report regarding bisphosphonates (BPs) causing osteonecrosis of the jaws was published in 2003 (Marx 2003 ). In 2014, the American Association of Oral and Maxillofacial Surgeons (AAOMS) changed the term bisphosphonate‐related osteonecrosis of the jaw to MRONJ to include other drugs besides bisphosphonates that cause osteonecrosis (Ruggiero et al. 2014 ).

Although the risk of developing MRONJ after DI placement in patients on AR remains unknown (McGowan and Ivanovski 2018 ), it has been reported to be 0.68% after an invasive dental procedure (such as tooth extraction and DI surgery) among osteoporosis patients treated with low‐dose denosumab for up to 10 years (Watts et al. 2019 ). The AAOMS position paper from 2022 cautions against DI placement in patients with cancer treated with ARs and recommends osteoporosis patients be well informed about the potential risk of early and late DI failure before any procedure is carried out (Ruggiero et al. 2022 ). The 2023 ITI consensus report generally found the available documentation insufficient to frame clear consensus statements regarding the influence of low‐dose denosumab. Likewise, data were insufficient to assess the outcome of DI placement and failure of existing DIs in patients receiving HDAR. Additionally, there was a lack of evidence on DI‐supported rehabilitation following resection and healing of patients diagnosed with MRONJ (Al‐Nawas et al. 2023 ).

Additionally, MRONJ has been observed around existing, formerly successful DIs after initiation of AR. In otherwise healthy patients, DI therapy is considered a predictable treatment option, with 10‐year DI survival rates of 98% (Adell et al. 1990 ; Albrektsson et al. 1986 ; Buser et al. 1997 ; Esposito et al. 1998 ; Gotfredsen and Wiskott 2012 ; Hämmerle et al. 2015 ). Several published case reports and studies have shown that DIs may be associated with the development of MRONJ in patients taking ARs, and it has been reported as a risk factor regardless of the DI being placed before or after initiating AR (Giovannacci et al. 2016 ; Kwon et al. 2023 ; Shin et al. 2010 ; Shirota et al. 2009 ).

The majority of existing case series and case reports described the development of MRONJ due to DI operations or the development of MRONJ due to peri‐implantitis (Li and Leung 2024 ; Ottesen et al. 2022 ; Pichardo et al. 2020 ). In contrast, recent studies indicate that DI therapy may be successful if conservative placement protocols are followed (Hjortholt et al. 2024 ; Otto et al. 2023 ). Furthermore, there are studies suggesting that the loading of DIs may be the main risk factor for the development of MRONJ in these patients on AR (Kwon et al. 2023 ).

Studies often report the difference in MRONJ incidence in relation to DIs associated with the administration of ARs (oral, subcutaneous, or intravenous), low‐dose or high‐dose therapy, and reason for AR treatment (osteoporosis or cancer), and not the accumulation of ARs (Chappuis et al. 2018 ; Li and Leung 2024 ; Sher et al. 2021 ). It is known that the incidence of MRONJ increases with longer duration and higher doses of ARs, i.e., the accumulative dose (Moon et al. 2024 ; Persson et al. 2024 ). However, to the best of our knowledge, no previous review has focused on the accumulated dose of AR in patients developing MRONJ related to DIs.

The aim of this scoping review is, therefore, to evaluate the occurrence of MRONJ in relation to DIs placed before or after initiation of AR, with respect to the type, dose, and duration of ARs, with emphasis on the accumulated dose of AR. The hypothesis is that the risk of developing MRONJ in relation to DI is related to the accumulated dose of AR.

Secondly, we aim to characterize patients with MRONJ in relation to DIs to potentially identify local and systemic risk factors.

Materials and Methods

The present review was conducted as a scoping review, and the guideline for Preferred Reporting Items for Systematic Reviews and Meta‐Analyses extension for Scoping Reviews (PRISMA‐ScR) was followed (Tricco et al. 2018 ).

Focused Research Question

To comprehensively characterize patients on AR developing MRONJ related to DIs compared to those not developing MRONJ based on the available clinical scientific evidence (randomized controlled trials, cohort studies, case–control studies, case series, and case reports).

The PCC (population, concept, and context) framework was followed using the PRISMA‐ScR (Tricco et al. 2018 ).

P: Patients with DI receiving AR due to osteoporosis or cancer.

C: Characterization of DI patients on AR developing MRONJ compared to those who do not develop MRONJ.

C: Success of DI treatment and development of MRONJ.

Eligibility Criteria

The present review included studies on patients treated with ARs receiving DIs before or after the start of AR. Since the literature in this field is scarce, no specific criteria based on study design were established. Hence, case series and case reports were also included.

Inclusion criteria were human trials that provided information on the type, dose, and duration of AR as well as the site and follow‐up period of the DIs. Exclusion criteria were osteonecrosis in locations other than the jaws and MRONJ in locations other than the DI site, bone diseases other than MRONJ, such as osteomyelitis or osteoradionecrosis, MRONJ due to anti‐angiogenesis, animal studies, in vitro studies, editorials, commentaries, conference, and review papers. Furthermore, clinical studies with insufficient information on ARs and/or DIs and DIs placed with simultaneous bone augmentation or in areas with previous bone augmentation were excluded.

Literature Search Protocol

A comprehensive, systematic, computerized database search was conducted using the National Centre for Biotechnology Information (NCBI) literature resource to search MEDLINE (PubMed), Cochrane Library, and Embase. The search strategy was developed in collaboration with a research librarian (TLK) and followed the Population, Concept, and Context (PCC) framework as recommended by the Johanna Briggs Institute (JBI) for scoping reviews. The search included all articles published in any language before 13 April 2024, with no restrictions on the initial publication date. Articles written in languages other than English or Danish were translated using Google Translate. The search used the Medical Subject Headings (MeSH), Embase Subject Headings (Emtree), and text words were combined using Boolean operators (AND/OR). The complete search strategy, including keywords and Boolean logic, is detailed in Appendix S1 . Furthermore, grey literature was systematically searched, which included bibliographies of identified relevant publications and Clinical.Trials.gov .

Literature Selection and Data Extraction Protocol

Screening was conducted by two independent examiners (SWM and NVH) according to the inclusion and exclusion criteria. Disagreements were resolved by discussion between the authors. In cases where consensus could not be reached, a third author, SSJ, was consulted. Initially, headlines and abstracts were screened for inclusion and exclusion criteria using Covidence systematic review software. If the article was included, or if an article had an incomplete abstract, the full article was reviewed.

Data from the articles were extracted in Covidence with regard to author, year, study design, number of participants, age, sex, primary disease, use of corticosteroids, current smoking, diabetes, drug holiday, type of AR, AR dose, period of AR treatment before and/or after DI placement, number of DI installed before and/or after the start of AR, development of MRONJ, period of AR treatment before MRONJ, estimated accumulated dose at DI placement and at MRONJ diagnosis, total observation period after DI placement, dropouts, cured previous MRONJ, immediate DI procedure, information about other medication, period of DI loading before MRONJ development, and DI position.

As in the 2023 ITI consensus papers (Al‐Nawas et al. 2023 ), LDAR and HDAR were defined in terms of dose and treatment interval rather than the route of administration. LDAR may include, for example, tablet alendronate (35–70 mg once weekly) subcutaneous denosumab (60 mg every 6 months), or intravenous zoledronic acid (5 mg every 12 months). Whereas HDAR may include subcutaneous denosumab (120 mg monthly), intravenous zoledronic acid (4 mg monthly), or oral ibandronate (50 mg daily).

Quality Assessment and Risk of Bias

To assess the level of agreement between reviewers, inter‐rater reliability was measured using Cohen's kappa (McHugh 2012 ). To ensure the methodological quality of studies included in this review, the two reviewers employed the JBI critical appraisal tool to assess the risk of bias in case reports, case series, and cohort studies. The possible responses for each criterion were “Yes,” “No,” “Unclear,” or “Not/Applicable.” A response of “No” to any question was considered to impact the overall quality of the study negatively (Munn et al. 2020 ). Unclear responses were excluded from the final calculation. Only criteria for which a clear “Yes” or “No” answer was provided were included in the appraisal score. As a result, the overall percentage reflects the proportion of “Yes” responses relative to the number of applicable criteria.

Statistical Analyses

Due to the small number of included patients and high variation in variables, only descriptive statistical analyses were performed and presented using tables, figures, and thematic summaries, following the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses for Scoping Reviews (PRISMA‐ScR) framework.

Results

Study Selection

The study selection was performed according to the PRISMA‐ScR flow diagram, and the initial search resulted in 2101 articles published up to 13 April 2024 (Figure 1 ). After the removal of 851 duplicates, two reviewers (SWM and NVH) independently screened the titles and abstracts of 1250 articles for papers related to the research question. A total of 173 articles were assessed for eligibility, and full‐text articles were reviewed. Due to various reasons, 145 studies did not meet the inclusion criteria and were thus excluded, the majority due to missing information on AR or DIs (Appendix S2 ). Finally, 28 studies published between 2009 and 2023 were included in the review, consisting of one cohort study (Andersen et al. 2023 ), two case series (Longoni et al. 2014 ; Zahid et al. 2011 ) and 25 case reports (Bayani et al. 2019 ; Bedogni et al. 2010 ; Caicedo‐Rubio et al. 2017 ; Favia et al. 2011 ; Fernández Ayora et al. 2015 ; Flichy‐Fernández et al. 2012 ; Gil et al. 2019 ; Goker et al. 2023 ; Gupta 2012 ; Junquera et al. 2011 , 2014 ; Kim et al. 2016 , 2019 ; Ottesen et al. 2022 ; Petropoulos et al. 2016 ; Povsic et al. 2023 ; Rugani et al. 2015 ; Ruocco‐Vetucci et al. 2019 ; Seki et al. 2021 ; Shin et al. 2010 ; Subramanian et al. 2012 ; Sverzut et al. 2012 ; Torres et al. 2009 ; Valente and Andreana 2017 ; Zadik et al. 2012 ) (Table 1 ).

The inter‐rater reliability between the two reviewers was calculated to be 0.70 at the abstract level and 0.68 at the full‐text level, indicating a substantial agreement (McHugh 2012 ) (Figure 2 ).

Population and Study Characteristics

Table 2 presents a summary of outcome measures, demographic, and health‐related data for all the included studies. In total, the studies involved 76 patients. The population in 22 of the included studies (Bedogni et al. 2010 ; Caicedo‐Rubio et al. 2017 ; Fernández Ayora et al. 2015 ; Flichy‐Fernández et al. 2012 ; Gil et al. 2019 ; Goker et al. 2023 ; Gupta 2012 ; Junquera et al. 2014 ; Kim et al. 2016 ; Kim et al. 2019 ; Longoni et al. 2014 ; Petropoulos et al. 2016 ; Povsic et al. 2023 ; Rugani et al. 2015 ; Ruocco‐Vetucci et al. 2019 ; Seki et al. 2021 ; Shin et al. 2010 ; Subramanian et al. 2012 ; Torres et al. 2009 ; Valente and Andreana 2017 ; Zadik et al. 2012 ; Zahid et al. 2011 ), comprising 44 patients, received LDAR. Of these, 18 studies (Bedogni et al. 2010 ; Fernández Ayora et al. 2015 ; Flichy‐Fernández et al. 2012 ; Gil et al. 2019 ; Goker et al. 2023 ; Gupta 2012 ; Junquera et al. 2014 ; Kim et al. 2016 ; Kim et al. 2019 ; Petropoulos et al. 2016 ; Povsic et al. 2023 ; Rugani et al. 2015 ; Ruocco‐Vetucci et al. 2019 ; Seki et al. 2021 ; Shin et al. 2010 ; Subramanian et al. 2012 ; Zadik et al. 2012 ; Zahid et al. 2011 ) reported treatment due to osteoporosis, one due to osteoporosis or Paget's disease (Longoni et al. 2014 ), two due to either Paget's disease or osteogenesis imperfecta (Caicedo‐Rubio et al. 2017 ; Torres et al. 2009 ), and one due to breast cancer (Valente and Andreana 2017 ). In six studies (Andersen et al. 2023 ; Bayani et al. 2019 ; Favia et al. 2011 ; Junquera et al. 2011 ; Ottesen et al. 2022 ; Sverzut et al. 2012 ), the population, comprising 32 patients, received HDAR due to cancer. Out of these, 15 patients were treated for multiple myeloma, 10 for breast cancer, six for prostate cancer, and one for colon cancer.

One study (Zahid et al. 2011 ), including 10 patients receiving LDAR, did not report age or gender; however, in the remaining studies, the mean ages ranged from 48 to 88 years, with 47 females and 19 males.

Of the included studies, eight studies reported whether the patient received corticosteroids in adjunct to AR or not (Andersen et al. 2023 ; Fernández Ayora et al. 2015 ; Gil et al. 2019 ; Goker et al. 2023 ; Junquera et al. 2011 ; Longoni et al. 2014 ; Rugani et al. 2015 ; Torres et al. 2009 ). In two studies (Andersen et al. 2023 ; Junquera et al. 2011 ), participants were administered corticosteroids; one case study presented a DI‐related MRONJ case (Junquera et al. 2011 ), while the other study did not present DI‐related MRONJ (Andersen et al. 2023 ). Junquera et al. presented one patient treated with two DI, where one DI developed MRONJ, whereas Andersen et al. presented three patients with four DI, without any MRONJ development (Andersen et al. 2023 ; Junquera et al. 2011 ).

Smoking habits were described in 12 studies (Andersen et al. 2023 ; Bayani et al. 2019 ; Caicedo‐Rubio et al. 2017 ; Fernández Ayora et al. 2015 ; Goker et al. 2023 ; Longoni et al. 2014 ; Ottesen et al. 2022 ; Seki et al. 2021 ; Subramanian et al. 2012 ; Torres et al. 2009 ; Zadik et al. 2012 ; Zahid et al. 2011 ), of which four, including one case series and three case reports, involved smokers (Caicedo‐Rubio et al. 2017 ; Subramanian et al. 2012 ; Zadik et al. 2012 ; Zahid et al. 2011 ). Among them, two patients developed MRONJ (Subramanian et al. 2012 ; Zadik et al. 2012 ). Both were patients with osteoporosis. In two case reports (Ottesen et al. 2022 ; Seki et al. 2021 ), patients diagnosed with diabetes were included, and both patients developed MRONJ. In one of the cases, the patient was diagnosed with osteoporosis and lost all four DIs placed prior to AR treatment (Seki et al. 2021 ). The other case presented a patient with prostate cancer (Andersen et al. 2023 ), who developed MRONJ around two out of four DIs placed after the start of AR treatment.

In total, 215 DI were placed, 154 in patients receiving LDAR and 61 in patients receiving HDAR. In four patients, 15 DI were placed before LDAR, of which MRONJ developed around 11 DI in three patients (Goker et al. 2023 ; Povsic et al. 2023 ; Seki et al. 2021 ; Subramanian et al. 2012 ). In the group of patients receiving HDAR, one patient had two DIs placed before the initiation of AR (Junquera et al. 2011 ) where MRONJ developed around one DI.

A drug holiday was described in eight studies, five studies on patients receiving LDAR (Flichy‐Fernández et al. 2012 ; Gil et al. 2019 ; Goker et al. 2023 ; Kim et al. 2016 ; Ruocco‐Vetucci et al. 2019 ) and three studies on patients receiving HDAR (Andersen et al. 2023 ; Bayani et al. 2019 ; Favia et al. 2011 ).

MRONJ related to DIs was presented in 15 of 22 studies in patients receiving LDAR (Bedogni et al. 2010 ; Fernández Ayora et al. 2015 ; Flichy‐Fernández et al. 2012 ; Gil et al. 2019 ; Goker et al. 2023 ; Gupta 2012 ; Junquera et al. 2014 ; Kim et al. 2016 ; Kim et al. 2019 ; Petropoulos et al. 2016 ; Seki et al. 2021 ; Shin et al. 2010 ; Subramanian et al. 2012 ; Valente and Andreana 2017 ; Zadik et al. 2012 ) and in four of six studies including patients on HDAR (Favia et al. 2011 ; Junquera et al. 2011 ; Ottesen et al. 2022 ; Sverzut et al. 2012 ).

Type, Dose, and Dental Implant Placement— LDAR

Table 3 highlights the type and accumulated dose of AR for the 44 patients treated with LDAR. Alendronate was the most frequently administered LDAR (25 patients) (Bedogni et al. 2010 ; Flichy‐Fernández et al. 2012 ; Gil et al. 2019 ; Goker et al. 2023 ; Junquera et al. 2014 ; Kim et al. 2016 ; Longoni et al. 2014 ; Petropoulos et al. 2016 ; Ruocco‐Vetucci et al. 2019 ; Seki et al. 2021 ; Shin et al. 2010 ; Subramanian et al. 2012 ; Zadik et al. 2012 ; Zahid et al. 2011 ) and the overall estimated mean accumulated dose before DI placement ranged from 1517 mg to 25,480 mg. Of the 154 DIs placed in patients treated with LDAR, 86 were placed in the maxilla and 68 in the mandible, Table 4 . In total, 31 DIs placed in 15 patients developed MRONJ, 11 in the maxilla and 20 in the mandible. The DI survival rate was 100% in seven studies (Caicedo‐Rubio et al. 2017 ; Longoni et al. 2014 ; Povsic et al. 2023 ; Rugani et al. 2015 ; Ruocco‐Vetucci et al. 2019 ; Torres et al. 2009 ; Zahid et al. 2011 ), 80% in one study (Petropoulos et al. 2016 ), 62.5% in one study (Goker et al. 2023 ), 50% in eight studies (Flichy‐Fernández et al. 2012 ; Gil et al. 2019 ; Gupta 2012 ; Junquera et al. 2014 ; Kim et al. 2016 ; Kim et al. 2019 ; Seki et al. 2021 ; Zadik et al. 2012 ), and 0% in 5 studies (Bedogni et al. 2010 ; Fernández Ayora et al. 2015 ; Shin et al. 2010 ; Subramanian et al. 2012 ; Valente and Andreana 2017 ).

In patients who developed MRONJ, the estimated mean accumulated dose of bisphosphonates at the time of diagnosis ranged from 3640 mg to 31,546 mg. The mean duration of AR administration before DI placement was 41 months (range 5–114 months), whereas the mean duration from DI placement to development of MRONJ was 23 months (range 0–73 months) (Figure 3 ).

No studies involving LDAR with denosumab fulfilled the inclusion criteria, except for a single case report that examined DI survival following exposure to both alendronate and denosumab. The study reported a 100% DI survival rate (Povsic et al. 2023 ).

With respect to drug holiday, 26 DIs were placed in patients receiving LDAR, of which MRONJ developed around nine DIs, four in the mandible (one premolar and three molars) (Flichy‐Fernández et al. 2012 ; Gil et al. 2019 ; Goker et al. 2023 ) and five in the maxilla (three molars, one premolar, and one canine) (Goker et al. 2023 ; Kim et al. 2016 ).

Type, Dose, and Dental Implant Placement— HDAR

HDAR was administered to 32 patients, primarily in the form of intravenous zoledronate (17 patients) and pamidronate (4 patients), either alone or in combination with other bisphosphonates, while eight patients received denosumab Table 5 . The mean accumulated bisphosphonate dose at DI placement ranged from 46 to 78,042 mg, including oral intake of ibandronate. For denosumab, the estimated mean dose ranged between 1420 and 2669 mg. Only one patient had a DI placed before the initiation of AR therapy (Junquera et al. 2011 ). A total of 69 DIs were placed in these 32 patients, 19 in the maxilla region and 50 in the mandible Table 4 . DI survival was 100% in two studies (Andersen et al. 2023 ; Bayani et al. 2019 ), 50% in two studies (Junquera et al. 2011 ; Ottesen et al. 2022 ), and 0% in two studies (Favia et al. 2011 ; Sverzut et al. 2012 ).

Overall, eight cases of MRONJ were reported in four patients, with two cases occurring in the maxilla and six in the mandible, including one case in the mandible associated with a patient receiving corticosteroid therapy. The estimated accumulated dose at the time of MRONJ diagnosis was 68 and 268 mg of zoledronate, 36,000 mg of clodronate, and 2160 mg of denosumab. The mean duration of AR administration before DI placement was 35 months (range 13–60 months), whereas the mean duration from DI placement to development of MRONJ was 9 months (range 4–17 months) (Figure 4 ).

With respect to the drug holidays, 52 DIs were placed in patients receiving HDAR, of which MRONJ developed around two DIs, both located in the mandibular molar region (Favia et al. 2011 ).

Quality Assessment

Quality assessment of the included studies is presented in Tables 6 , 7 , 8 . Overall, the quality of the included studies can be categorized as moderate, with the cohort study being of high quality with limited risk of bias. In general, case series and especially case reports are positioned low in the hierarchy of evidence (Howick et al. 2011 ). However, within their categories, the case series and case reports showed moderate to high quality of evidence, but with variability across individual studies, leading to a higher risk of bias. In case reports, the variability and high risk of bias primarily arise from patient history and timeline, demographic characteristics, key takeaways, and adverse events. In the case series, the variability and high risk of bias primarily arose from the inclusion of participants, demographic and clinical reporting, and site/clinic information.

Discussion

This scoping review focused on the accumulated dose of different ARs and not only on the form of administration, low‐dose or high‐dose therapy, and the reason for AR treatment. Our hypothesis was that the risk of MRONJ development is related to a higher accumulated dose of AR. This hypothesis could not be confirmed, based on the limited number of included studies with heterogeneous reporting. The available evidence did not allow us to identify a specific dose or duration of AR below which DI therapy can be safely performed or above which patients on AR are at increased risk of DI failure or development of MRONJ. We observed that MRONJ occurred across a very wide range of accumulated doses in both the LDAR and HDAR groups.

Although we were unable to confirm the hypothesis, recent studies indicate that the accumulated dose and the potency of the ARs play significant roles in the risk of MRONJ development (Moon et al. 2024 ; Persson et al. 2024 ). As shown in Tables 3 and 5 , AR is not necessarily administered in standard doses or intervals. Therefore, it is crucial to report detailed information on the actual dose, treatment duration, and intervals to enable accurate analysis and comparison of previously published results. This will aid in understanding the relationship between accumulated doses and the risk of MRONJ in patients receiving DIs.

Whether it is safe to place DI in patients receiving AR with respect to the development of MRONJ cannot be determined solely from this review. Success and failure have been presented in the literature, both in patients on LDAR and HDAR. The review, based on 28 studies, demonstrated that the survival rate for DI placement in patients receiving ARs varied considerably, ranging from 0% to 100%. It should be noted that neither of the studies described cases of failed osseointegration, which is known to account for 2%–3% in healthy patients receiving DIs (Brizuela‐Velasco et al. 2021 ).

Patients Receiving LDAR

The majority of studies focused on patients receiving alendronate, followed by risedronate, with no studies included involving patients exclusively treated with denosumab. When comparing the accumulated dose at the time of DI placement within the LDAR group, there was no evidence of a threshold dose value for the development of MRONJ. There was considerable variation in the accumulated dose (Table 3 ) among both patients who developed MRONJ and those who did not. Furthermore, no correlation was identified between local and systemic risk factors (Table 2 ). Due to a lack of data in published studies, it was not possible to draw any conclusions regarding patients undergoing denosumab treatment.

Patients Receiving HDAR

In the HDAR group, comparing the accumulated dose in patients who developed MRONJ was not feasible. This was primarily due to the limited number of studies on patients receiving HDAR and DIs, as well as significant variability in the type of AR, dosage, and treatment period (Table 5 ). Additionally, no correlation was identified with local or systemic risk factors (Table 2 ).

Accumulated Dose—LDAR and HDAR

In general, patients who developed MRONJ had a higher accumulated dose in the LDAR group compared to the HDAR group (Tables 3 and 5 ). Furthermore, the treatment duration was longer for patients in the LDAR group (Figures 3 and 4 ) than for those in the HDAR group, but with smaller individual doses. This was observed both at the time of DI placement and from DI placement to the development of MRONJ. These findings align with published studies on risk factors for the development of MRONJ, which are known to include the AR dose, duration of treatment, and treatment intervals (Bedogni et al. 2024 ; Ruggiero et al. 2022 ). The treatment periods of AR, whether in LDAR or HDAR, before and/or after DI placement, did not reveal any specific pattern associated with the development of MRONJ in relation to DIs.

Drug Holiday— LDAR and HDAR

The role of a drug holiday in the treatment and prevention of MRONJ remains widely debated, with no established consensus and a lack of high‐level evidence to support or refute its use (Ruggiero et al. 2022 ). Similarly, the ITI consensus report found insufficient evidence to draw definitive conclusions regarding the potential effect of a drug holiday on DI failure or the development of MRONJ following DI insertion (Al‐Nawas et al. 2023 ). However, the report recommended against a drug holiday and advised planning the DI operation within the therapeutic window, considering the general effects and pharmacokinetics of AR. In this scoping review, comparing the development of MRONJ around DIs in patients undergoing a drug holiday was not feasible. Likewise, the duration of the drug holiday was inconsistently reported in the included articles.

Implant Location and Development of MRONJ

The survival rate of DIs appeared to be higher in patients receiving HDAR compared to those on LDAR (Table 4 ). However, it should be noted that more DI were placed in patients on LDAR than in those receiving HDAR, and fewer studies have been published on HDAR (Table 2 ).

The distribution of DIs between the mandible and maxilla was nearly equal in both groups, yet MRONJ occurred almost twice as often in the mandible. This aligns with previously published findings, which report the mandible being involved in 75% of cases and both jaws affected in 4.5% (Ruggiero et al. 2022 ). Other studies have reported that the mandible is affected by MRONJ in 60% of cases, with both jaws involved in 5% (Frutuoso et al. 2024 ).

This scoping review indicated that the survival rate was higher for DI placed in the maxilla than in the mandible. This may potentially be due to differences in bone density and vascularization between the maxilla and mandible, as previously reported in studies examining DI outcomes in patients on AR (Jacobsen et al. 2013 ; Lazarovici et al. 2010 ). Furthermore, the study confirms that the survival rate was highest for DI placed in the anterior maxilla (83.3%), followed by the posterior maxilla (78.7%), the posterior mandible (75.3%), and the anterior mandible (68.2%), consistent with the findings in the systematic review by Li and Leung (Li and Leung 2024 ). It should be noted, however, that information regarding the anterior or posterior placement of the DI was only available for 164 DIs, of which less than a quarter were placed anteriorly.

Local and Systemic Risk Factors

Surgical procedures in the oral cavity are widely recognized as the most significant local risk factor for developing MRONJ. According to the literature, tooth extraction is the triggering event in 62% to 82% of cases (Aljohani et al. 2017 ; Hallmer et al. 2018 ; Saad et al. 2012 ).

It is not possible in this scoping review to conclude whether the DI surgery itself was the primary cause of MRONJ development. However, two studies involving patients treated with alendronate reported exposed bone in relation to the DIs within 2 weeks of the DI operation (Flichy‐Fernández et al. 2012 ; Gil et al. 2019 ). Late DI failure may be attributed to insufficient osseointegration, likely caused by the loss of primary stability of the DI (Guglielmotti et al. 2019 ).

Local infection is a known risk factor for the development of MRONJ (Bedogni et al. 2024 ; Ruggiero et al. 2022 ), and similarly, local infection around DIs is known to correlate with DI survival (Roccuzzo et al. 2018 ). However, no conclusions could be drawn in this area, as no studies specifically described local infections.

Systemic risk factors for MRONJ development include diabetes, smoking, and systemic use of corticosteroids PEVuZE5vdGU (Bedogni et al. 2024 ; Ruggiero et al. 2022 ). These factors similarly impact the survival and success rates of DIs. DIs placed in smokers face a 140.2% higher risk of failure compared to those placed in non‐smokers (Mustapha et al. 2021 ). Regarding systemic steroid use, a study demonstrated an approximately five‐fold increase in DI failure among patients taking steroids compared to those not taking steroids, independent of smoking or diabetes (Zou et al. 2023 ). Furthermore, a systematic review and meta‐analysis concluded that DIs placed in diabetic patients present a statistically significant higher risk of failure and greater marginal bone loss compared to DIs placed in non‐diabetic patients (Al Ansari et al. 2022 ).

There was insufficient data in the included studies to determine the relative significance of systemic risk factors like diabetes, concurrent corticosteroid treatment, and smoking and the association of DI‐related MRONJ.

Limitations and Bias

The present review was planned as a systematic review and therefore initially followed the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines for systematic reviews (Page et al. 2021 ). However, since the identified scientific evidence was too sparse and heterogeneous, eventually, a scoping review approach was selected, and the guideline for the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses extension for Scoping Reviews (PRISMA‐ScR) was hence followed (Tricco et al. 2018 ).

The main limitation of the present review is the potential for bias due to the quality of the included studies. The majority were case reports (89.3%) published over a time period of 14 years. This suggests that there may be significant variation in surgical techniques, both due to the temporal differences and the numerous surgeons involved in DI placements. Variation in surgical competencies must be assumed.

Several of the included case reports were retrospective, meaning that patients were enrolled at the time of MRONJ diagnosis. Consequently, the survival rate for DI is likely biased, as studies documenting successful DI placements in patients receiving ARs are underrepresented. Selection bias may arise because the included articles may not be representative of the general population of patients receiving AR and undergoing DI procedures. This could be influenced by Berkson's bias, as studies are more likely to include patients who have developed MRONJ following DI placement, while those who received DIs without complications may be underreported. This overrepresentation of cases with adverse outcomes could lead to an overestimation of the association between AR therapy and MRONJ. Furthermore, the included studies may also be influenced by selection bias due to the preferential publication of cases with complications. Furthermore, the inclusion criterion requiring the specification of AR dosage and duration has led to the exclusion of studies describing uncomplicated DI placements in the target population (Otto et al. 2023 ).

The follow‐up period varies significantly, with the longest observed period in patients receiving LDAR. However, the rationale for the follow‐up period is not consistently reported. A short follow‐up period may result in an underestimation of MRONJ incidence, as it primarily documents early DI failure and initial MRONJ development. Consequently, this may result in an overestimation of DI survival rates.

Given the observational nature of the included studies, confounding by indication is of particular concern. As patients receive different doses of AR due to varying underlying diseases over different time periods, no direct comparisons can be made. Additionally, patients have different baseline risk factors that may influence the development of MRONJ.

There have also been challenges in calculating the exact accumulated dosage of AR, which is not typically reported in studies on MRONJ. As a result, the stated accumulated dose is an estimation based on dosage and treatment duration, without accounting for potential treatment pauses or variations in intervals for individual patients.

The key strength of this study is that it is the first to report specific doses, rather than focusing solely on the route of administration.

Conclusion

Based on the limited and heterogeneous available evidence, this scoping review could not confirm the hypothesis that the risk of development of MRONJ in relation to DI is related to the accumulated dose of AR. Furthermore, no specific local or systemic risk factors could be identified as contributing to an increased risk of MRONJ development.

The reported survival rates for DIs in patients on AR varied significantly and indicated an increased but unpredictable risk of DI failure. The results underline the need for more standardized reporting of DI therapy in this complex group of patients. Systematic and detailed information on the type of AR, doses, duration of treatment, and intervals is needed for enabling detailed analyses of patients on AR with existing DIs or planned to undergo DI therapy to provide an individualized risk assessment. Until such evidence‐based guidelines can be set up, it is recommended that DI therapy in patients on HDAR and long‐term LDAR be restricted to specialized centers.

Author Contributions

Sanne Werner Moeller Andersen: conceptualization, investigation, writing – original draft, methodology, visualization, formal analysis, project administration, data curation, validation, software, resources. Nishma Vandvig Hindocha: investigation, writing – review and editing, data curation, validation, formal analysis. Iben Poulsen: writing – review and editing, formal analysis. Henning Schliephake: supervision, writing – review and editing. Simon Storgård Jensen: conceptualization, validation, supervision, resources, writing – review and editing, methodology.

Ethics Statement

The authors have nothing to report.

Consent

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Appendix S1 Search history 13 April 2024.

Appendix S2 Excluded studies based on full‐text evaluation.

Acknowledgements

We would like to acknowledge Trine Lecoppidan Kæstel (TLK) for her contributions as a research librarian and Liezl Dawson for English grammar, spelling, and typo corrections.

Data Availability Statement

The data that support the findings of this study are available in Appendix S1 of this article.

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