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Review

Current Trends in Adjuvant Therapies for Medication-Related Osteonecrosis of the Jaw

by
Gyu-Jo Shim
1,
Joo-Young Ohe
2,*,
Young-Jae Yoon
2,
Yong-Dae Kwon
2,* and
Deog-Yoon Kim
3
1
Department of Oral and Maxillofacial Surgery, Graduate School, Kyung Hee University Dental Hospital, Seoul 02447, Korea
2
Department of Oral and Maxillofacial Surgery, School of Dentistry, Kyung Hee University, Seoul 02447, Korea
3
Department of Nuclear Medicine, Kyung Hee University Hospital, Kyung Hee University School of Medicine, Seoul 02447, Korea
*
Authors to whom correspondence should be addressed.
Appl. Sci. 2022, 12(8), 4035; https://0-doi-org.brum.beds.ac.uk/10.3390/app12084035
Submission received: 7 March 2022 / Revised: 11 April 2022 / Accepted: 14 April 2022 / Published: 16 April 2022
(This article belongs to the Special Issue Medication-Related Osteonecrosis of the Jaw: Prevention, Diagnosis and Treatment)
Review Reports Versions Notes

Abstract

:
Medication-related osteonecrosis of the jaw (MRONJ) is a refractory disease, and a standard protocol for its treatment has not yet been established. In addition, owing to the old age of MRONJ patients and various complications, treatment goals focus on relieving the symptoms and improving the quality of life. For this reason, different treatments such as conservative, surgical, and adjunctive treatments have been attempted. In particular, adjunctive treatment, which is effective for promoting healing and reducing recurrence, is gaining increasing interest, and several studies and clinical trials related to it have been published. Representative adjuvant therapies include teriparatide, recombinant human bone morphogenetic protein-2, hyperbaric oxygen, photobiomodulation and platelet concentrates. All have generally shown beneficial effects; however, no standard protocol for adjunctive treatment exists. Therefore, in this literature review, we briefly summarized the different adjuvant therapies and reviewed clinical reports to help decide whether to use adjuvant therapies in treating patients with MRONJ.

1. Introduction

Medication-related osteonecrosis of the jaw (MRONJ) is a rare disease induced by antiresorptive agents, such as bisphosphonates, denosumab, or antiangiogenic therapies. It can also be provoked by other types of medications, such as tyrosine kinase inhibitors, monoclonal antibodies, mammalian target of rapamycin inhibitors, radiopharmaceuticals, selective estrogen receptor modulators, and immunosuppressants [1]. Several diagnostic criteria for MRONJ exist: (1) current or previous treatment with antiresorptive or antiangiogenic agents, (2) exposed bone or bone that can be probed through an intraoral or extraoral fistula in the maxillofacial region that has persisted for more than eight weeks, and (3) no history of radiation therapy to the jaw or obvious metastatic disease of the jaw [2,3].
In osteoporosis patients, the incidence rate of MRONJ is approximately 0.001–0.1%, which is marginally higher than that in the general population (<0.001%). In oncology patients, by contrast, it has dramatically risen (1–15%) due to high-dose antiresorptive therapy [4]. The risk of developing MRONJ is higher in patients with cancer-related conditions (<5%) than in those with osteoporosis (<0.05%) [3]. In addition, the incidence is considerably high in elderly patients who have undergone surgical treatments such as tooth extraction and dental implants. Because MRONJ is a refractory disease that mainly affects the elderly and has a poor prognosis, proper management is crucial for improving the quality of life.
Ever since the first case of MRONJ was described in 2003, attempts have been made to clarify its pathophysiological mechanisms. The evidence-based mechanisms include infection or inflammation, inhibited bone remodeling, altered angiogenesis, soft tissue toxicity, and decreased immune resilience [5]. Furthermore, local jaw infections play a major role in MRONJ development [6]. Chronic exposure to bisphosphonates significantly reduces osteogenic differentiation and impairs stem cell viability, increasing predisposition to MRONJ [7]. Although various underlying mechanisms have been proposed, they remain unclear. Thus, the management of MRONJ remains controversial.
Several therapeutic strategies ranging from conservative treatment to surgical approaches have been recommended for MRONJ. The conservative treatment involves maintaining good oral hygiene, medication, and antibacterial mouth rinse for patients at stages 0–II [2]. Although conservative treatment stabilizes the patient’s condition, the condition improves minimally [8]. Moreover, most patients with MRONJ exhibit infection-related symptoms that do not show improvement with conservative treatment; thus, this treatment is a valid option only for reducing the symptoms and controlling the infection [9]. Surgical treatment may provide better outcomes for all stages of the disease [10,11]. Debridement, sequestrectomy, and resection are recommended for stage III or stage II patients unresponsive to conservative treatment. Conservative surgery may also confer better outcomes for patients at stages I and II of the disease [12,13]. Surgery provides better mucosal healing and aids in relieving symptoms, including bone necrosis [9].
A good surgical outcome requires adjuvant therapy, such as administration of teriparatide, recombinant human bone morphogenetic protein-2, hyperbaric oxygen, photobiomodulation, or platelet concentrates. This therapy is given concurrently with or after surgical treatment but sometimes alone. Although adjuvant therapies promote the recovery of patients with MRONJ [14,15], their exact role in alleviation of MRONJ has never been demonstrated, and a standard protocol is lacking. Here, we discussed the latest understanding of adjuvant therapies for MRONJ.

2. Methods

This review focused on popular adjuvant therapies for MRONJ: teriparatide, recombinant human bone morphogenetic protein-2 (rhBMP-2), hyperbaric oxygen, photobiomodulation, and platelet concentrates. Case and clinical reports spanning the last decade were discussed to assess the latest trends in using adjuvant treatments. Each was classified and summarized in tables.
The literature search was done using the PubMed database with the following keywords:
(1)
Medication-related osteonecrosis of the jaw
(2)
Bisphosphonate-related osteonecrosis of the jaw
(3)
Teriparatide/parathyroid hormone level
(4)
Recombinant human bone morphogenetic protein-2
(5)
Hyperbaric oxygen
(6)
Photobiomodulation/low-lever laser therapy
(7)
Platelet concentrates

3. Results and Discussion

3.1. Teriparatide

Teriparatide (TPTD) is a human recombinant peptide consisting of the first 34 amino acids, or the bioactive part, of the human parathyroid hormone. It stimulates osteoblastic bone formation, improving bone quality and mass [14]. Because of this property, it was approved as the first anabolic agent for treating osteoporosis in men and postmenopausal women. Intermittent administration of TPTD causes an early decrease in mRNA levels of the receptor activator of nuclear factor-kappa B ligand, and an increase in osteoprotegerin mRNA, enhancing bone formation in vitro [16]. A case study showed that by promoting bone reformation and anabolic activity, the physiologic mechanism of TPTD, although unknown, is effective in treating MRONJ [17]. The effects of TPTD on MRONJ were also evaluated in a rat model. Better bone formation and density were observed in the TPTD-treated group versus the control, suggesting that TPTD is a beneficial treatment modality for MRONJ [18]. Other animal studies also support TPTD as an effective treatment for the disease [19,20].
Although the positive effects of TPTD in treating MRONJ are unequivocal, inadequate dosage, duration, and timing of TPTD administration can cause unpredictable side effects. For example, the continuous administration of TPTD increases the incidence of osteosarcoma in rats [21,22]. Although concerning, it is questionable whether this result applies to humans due to interspecific and dosing (timing, duration, or level) differences between humans and rats. Temporary adverse events such as nausea, malaise, and renal dysfunction were reported in some patients who received TPTD [23], increasing attention to the proper dosage, duration, and timing of TPTD treatment. Low dosage and intermittent administration of TPTD promote the maturation of osteoblast precursors and the differentiation of lining cells into osteoblasts. Moreover, this dosage and type of administration helps increase bone turnover via stimulation of new bone generation as a part of bone metabolism [24]. Administering TPTD before or after surgery positively affects the prevention of MRONJ and recovery [25,26].
Therefore, appropriate low-dose TPTD before or after surgery is an effective adjuvant treatment for MRONJ. Although there is no standard protocol for TPTD administration, low-dose TPTD appears to improve prognosis as reported in the known case reports, which are summarized in Table 1.

3.2. Recombinant Human Bone Morphogenetic Protein-2

Recombinant human bone morphogenetic protein-2 (rhBMP-2) is a protein belonging to the transforming growth factor-β superfamily. It is currently the only Food and Drug Administration-approved osteoinductive growth factor used as a bone graft substitute. Owing to its osteoinductive properties, rhBMP-2 has been used for clinical applications requiring bone tissue regeneration in orthopedic and oral-maxillofacial surgery [37]. It promotes osteoblast differentiation through BMP receptors present in osteoclasts. Thus, rhBMP-2 shows osteoclast activity and promotes favorable bone remodeling [37]. Oversuppression of bone remodeling is considered central in the pathogenesis of MRONJ, arising from pharmacologic inhibition of osteoclast activity [38]. Therefore, the positive effect of rhBMP-2 on bone remodeling in MRONJ patients might involve relieving oversuppression.
Appropriate scaffolds are necessary for the long-term application of rhBMP-2 to the defect area to maximize the bone remodeling effect. These include tricalcium phosphate, demineralized bone matrix, hydroxyapatite, and absorbable collagen sponges (ACS). The collagen sponges are versatile, highly biocompatibile, easy to use, relatively inexpensive, and the least immunogenic scaffolds. The release period of rhBMP-2 in combination with ACS (rhBMP-2/ACS) is twice faster than without ACS [39]. In addition, rhBMP-2/ACS promotes faster bone formation than rhBMP-2 combined with tricalcium phosphate or platelet-rich fibrin-mixed tricalcium phosphate [40]. The bone regenerative effect of rhBMP-2/ACS has been demonstrated in patients with MRONJ. Following surgical treatment, rhBMP-2/ACS increases the rate of new bone formation [41]. Moreover, rhBMP-2/ACS and miniplates are associated with a good prognosis in MRONJ patients [42]. Recent human studies on using rhBMP-2/ACS in MRONJ are summarized in Table 2.
Since MRONJ patients are mostly elderly and have comorbidities, carefully deciding the treatment plan based on the patient’s condition is of paramount importance. Although rhBMP-2 is the only approved bone graft substitute, it provokes side effects such as swelling, seroma, inflammation, and carcinogenicity [43]. Therefore, further studies are needed to evaluate its efficacy and safety for MRONJ treatment. Likewise, the collagen sponges lack structural stability and are not ideal for delivering rhBMP-2 to the defect area. Some studies have used mechanical protectors to stabilize and improve ACS as scaffolds. However, these protectors cannot prevent soft tissue migration, and secondary surgery for their removal is imminent. Thus, additional research is required to develop an ideal carrier with sufficient stability and release efficiency.
Table
Table 2. Human studies of recombinant human bone morphogenetic protein-2(rhBMP-2) administration for MRONJ treatment in the past 10 years.
Table 2. Human studies of recombinant human bone morphogenetic protein-2(rhBMP-2) administration for MRONJ treatment in the past 10 years.
ReferenceTotal PtMedical ConditionBP RouteDuration
(Years)		Trigger
Event		StageAdditional Adjuvant UsedOutcome
Cicciù et al. (2012) [44]20OP/BMOral/IVNANA3NoneFavorable
Kim et al. (2016) [45]1OPOral4Ext3L-PRFFavorable
Jung et al. (2017) [33]10OPOral0.5–15NA2 or 36 pt (TPTD)Favorable
Park et al. (2017) [46]30OP/BMOral/IV1–15Ext/Imp/Perio
/Spon		1–3L-PRFFavorable
Min et al. (2020) [41]16OP/BMOralNANA2 or 3NoneFavorable
Kim et al. (2020) [42]3OPOral/IV5 to 10Ext/perio3NoneFavorable
Pt, patient; BP, bisphosphonate; Tx, treatment; OP, osteoporosis; TPTD, teriparatide; BM, bone metastasis; NA, not available; IV, intravenous; L-PRF, leukocyte- and platelet-rich fibrin; Spon, spontaneous; Ext, extraction; Imp, implant; Perio, periodontitis.

3.3. Hyperbaric Oxygen

Hyperbaric oxygen (HBO) is a treatment in which patients breathe 100% oxygen in a hyperbaric chamber. The inhaled oxygen dissolves in the blood serum, and its concentration increases in arterial flow and tissues. Therefore, HBO promotes wound healing by maintaining a consistently high oxygen concentration in patients. Elevated oxygen concentration enhances the production of reactive oxygen and nitrogen species, which play important roles in signaling pathways that promote neovascularization, boost matrix formation, and reduce inflammation.
Numerous indications exist for HBO treatment: embolism, poisoning, myositis, anemia, abscess, necrotizing soft tissue infections, and refractory osteomyelitis [47]. Dauwe et al. reported that HBO has a positive effect on treating necrotizing infections and ulcers [48]. Because HBO treatment promotes wound healing progression, it is considered an effective adjunctive modality in conditions involving impaired bone healing, such as osteoradionecrosis and chronic osteomyelitis of the jaw.
Several studies have investigated the utility of HBO for MRONJ treatment. One case series and one randomized controlled trial reported the effect of HBO in patients with MRONJ [49,50]. Their findings suggest that HBO is beneficial as an adjunct therapy for MRONJ in combination with a surgical approach and systemic antibiotic treatment. Other studies showed HBO alone is effective in stages 1 and 2 of the disease; however, in advanced stages, it is effective only when combined with surgical treatment [51]. In addition, HBO is successful when used as an adjunct therapy before and after surgery, emphasizing the importance of treatment timing [52]. Recent human studies on HBO therapy for MRONJ are summarized in Table 3.
Barotrauma, myopia, seizures, and pulmonary edema are minor complications of HBO and generally show minor and reversible symptoms. In rare cases, serious complications, including seizures, congestive heart failure exacerbation, pulmonary edema, and retinal changes, may occur after HBO therapy. As elderly MRONJ patients typically have comorbidities, HBO therapy requires cautious planning. In particular, it should be carefully considered for treating patients who have experienced seizures, hyperthyroidism, or pulmonary disease.

3.4. Photobiomodulation

Photobiomodulation (PBM) is a light therapy that uses nonionizing light sources in the visible and near-infrared spectrum. Many fields of medicine and dentistry use PBM because of its beneficial effects such as good wound healing, tissue generation, and analgesic and anti-inflammatory effects [56]. In dentistry, for example, PBM protects oral tissues by improving wound healing and enhancing epithelization. In addition, it stimulates cell proliferation and regeneration of bone, lymphatic, and blood vessels [56]. Owing to its antibacterial and biostimulating effects on soft and hard tissues, PBM is becoming a popular, non-invasive adjuvant therapy for MRONJ treated with conservative or surgical approaches. Furthermore, it is considered an attractive alternative approach to aggressive surgical treatment in elderly patients prone to surgical issues and relatively slow recovery. Recently, its role in patients who underwent conservative or surgical treatment of MRONJ has been investigated, and several clinical studies and systemic reviews have been published.
Conservative or surgical treatment combined with PBM shows better results than either treatment alone in patients with MRONJ [57]. Early laser-assisted conservative surgical treatment with PBM is a better approach than conservative medical therapy [58]. A systematic review of laser therapy in MRONJ reported that PBM combined with conventional surgical/medical therapy has superior results over either treatment alone [59]. Preoperative PBM combined with surgery and medical therapy offers better clinical outcomes than the conventional treatment for MRONJ [60]. Interestingly, PBM therapy after invasive dental treatments such as tooth extraction prevents MRONJ [61]. Because prevention is better than treatment, further studies on the role of PBM in MRONJ prevention are needed. Published human studies on PBM in MRONJ are summarized in Table 4.
Although several studies have shown clinically favorable results of PBM in treating patients with MRONJ, they included only a few patients at stage 3 of the disease with severe symptoms. Therefore, the lack of evidence hinders using PBM in the later stages of the disease. As no randomized controlled trial related to PBM in MRONJ exists, careful decision-making and operator experience are detrimental to PBM treatment. In addition, setting a standard protocol for PBM is challenging due to various variables that have to be considered, such as laser type, application time, output power and frequency, laser distance from applied tissue, and treatment period. Follow-up studies should address these shortcomings and aim to establish a standard protocol.

3.5. Platelet Concentrates

Platelet concentrates (PC) are autologous products which are obtained from patients. PC contain several growth factors, such as transforming growth factor, vascular endothelial growth factor, platelet-derived growth factor and endothelial growth factors [70]. Because they contain these various factors, they can accelerate epithelial wound healing, improve the regeneration of bone and soft tissues, promote vascularization and decrease tissue inflammation. In addition to these effects, PC can be made easily in a clinic or operating room, so can be used in many fields of medicine and dentistry. PC are composed of four groups (platelet-rich plasma, leukocyte-and platelet-rich plasma, platelet-rich fibrin, leukocyte- and platelet-rich fibrin) by the fibrin and leukocyte contents [71].
Among them, platelet-rich plasma (PRP) and leukocyte-and platelet-rich fibrin are mainly used in the treatment of MRONJ. Since Adornato et al. reported a clinical report using PRP for the treatment of MRONJ, several papers have reported about the effect of PC in MRONJ treatment [72]. Generally, PC have been used alone or in combination with other adjuvant therapies. When the surgical defect site was filled with PRP after surgical treatment, better soft tissue and bone healing was achieved with a good prognosis [73,74]. In addition, application of PRP was effective after surgical treatment by the Er,Cr:YSGG laser [75]. On the other hand, Park et al. reported that wound healing was better achieved when L-PRF was used with rhBMP-2 rather than L-PRF alone [46]. Other clinical reports suggested that the combined approach using surgery, PBM, and PC was effective [60,65]. Currently published human studies about PC in MRONJ are summarized in Table 5.
Application of PC as a membrane is effective in soft tissue recovery, but there remains a question whether it will have a direct effect on the recovery of bone defect. Blatt et al. found that PRF as an adjunct did not significantly optimize wound healing [76]. Moreover, two systemic reviews reported that the use of PC was clinically effective, but it was insufficient to have scientific evidence [77,78]. Similarly, there was no significant difference in long-term follow-up between the group with PC or not [79]. From these results, it seems that additional research is needed to find scientific evidence about the use of PC in MRONJ treatment. In addition, as with other adjuvant therapies, further studies are needed because there is no standard protocol.
Table
Table 5. Human studies of platelet concentrates (PC) administration for MRONJ treatment in the past 10 years.
Table 5. Human studies of platelet concentrates (PC) administration for MRONJ treatment in the past 10 years.
ReferenceTotal Pt.Medical ConditionBP RouteDuration
(Years)		Trigger
Event		StageAdditional material.Outcome
Bocanegra et al. (2012) [80]8OP/MMOral/IVNAExt2NoneFavorable
Kim et al. (2014) [81]34OP/BMOral/IVNASpon/Ext/
Imp		1 to 3NoneFavorable
Dinca et al. (2014) [82]10CA/MMIVNAExt2NoneFavorable
Longo et al. (2014) [83]34CA/MMIV1 to 5Ext/Perio0 to 3NoneFavorable
Nørholt et al. (2016) [84]15OP/CAOral/IV1 to 20NA2, 3NoneFavorable
Park et al. (2017) [46]55OP/BMOral/IV1 to 15Spon/Ext/
Imp		1 to 3rhBMP-2
(30 of 55)		Favorable
Mauceri et al. (2018) [75]10CA/MMOral1 to 5NA1, 2 NoneFavorable
Merigo et al. (2018) [65]21OP/BMOral1 to 14NA1 to 3PBMFavorable
Giudice et al. (2018) [79]24OP/CAOral/IVNANA2 to 3NoneFavorable
Lopez et al. (2019) [73]3OP/CAOral/IV3 to 6Ext/Imp2NoneFavorable
Valente et al. (2019) [85]15OP/CAOral/IV2 to 6Ext/SPon0 to 3NoneFavorable
Mourao et al. (2020) [86]11OPOral3 to 7NA2NoneFavorable
Pt, patient; BP, bisphosphonate; Tx, treatment; OP, osteoporosis; BM, bone metastasis; CA, cancer; MM, multiple myeloma; IV, intravenous; NA, not available; Spon, spontaneous; Ext, extraction; Imp, implant; Perio, periodontitis; rhBMP-2, recombinant human bone morphogenetic protein-2; PBM, photobiomodulation.

4. Conclusions

Since no standard protocol for MRONJ treatment is available, various adjuvant therapies have been attempted along with surgical treatment to increase the treatment success rate. They were applied for weeks to months, depending on the treatment, and were effective in improving the success rate. Among the different adjuvant therapies, photobiomodulation is effective even when applied alone, without surgery. Although no standard protocol for each adjuvant therapy is available, they seem efficient when used in MRONJ patients. Additional studies on the mechanism of the adjuvant therapies for MRONJ should help develop a standardized treatment.

Author Contributions

Conceptualization: G.-J.S., J.-Y.O., Y.-D.K. and D.-Y.K.; methodology, G.-J.S., J.-Y.O. and Y.-D.K.; investigation, G.-J.S.; original draft preparation, G.-J.S. and Y.-J.Y. review and editing, J.-Y.O. and Y.-D.K.; visualization, G.-J.S.; supervision, J.-Y.O. and Y.-D.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

ACSAbsorbable collagen sponge
HBOHyperbaric oxygen
MRONJMedication-related osteonecrosis of the jaw
PBMPhotobiomodulation
RhBMP-2Recombinant human bone morphogenetic protein-2
TPTDTeriparatide
PCPlatelet concentrates

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Table
Table 1. Human studies of teriparatide administration for medication-related osteonecrosis of the jaw (MRONJ) treatment in the past 10 years.
Table 1. Human studies of teriparatide administration for medication-related osteonecrosis of the jaw (MRONJ) treatment in the past 10 years.
ReferenceTotal PtMedical ConditionBP RouteDuration (Years)Trigger
Event		StageSurgical TxTPTD Duration (Months)Outcome
Kwon et al. (2012) [27]6OPOral3–8NA2 or 3100%1–3Favorable
Narvarez et al. (2013) [28]1OPNA2.7SponNSNone8Favorable
Yoshiga et al. (2013) [29]2NAOral4.5Spon350%3Favorable
Kim et al. (2014) [30]15OPOral/IV3Ext/Imp/Spon2 or 380%6Favorable
Kakehashi et al. (2015) [26]10NAOral4.3Ext/Perio2 or 3100%4–24Favorable
Yao et al. (2016) [31]1OPOral2Ext3100%18Favorable
Zushi et al. (2017) [32]1OPOral6Imp3100%5Favorable
Jung et al. (2017) [33]6OPOral0.5–15NA2 or 3100%1–4Favorable
Kim et al. (2019) [34]1OPOral4Imp3None2Favorable
Morishita et al. (2020) [23]29OPOral/IV0.8–7.3Ext/Perio1–338%0.3–26Favorable
Ohbayashi et al. (2020) [35]12OPOral1–10NA2 or 3None6Favorable
Sim et al. (2020) [36]34OP/CA/MMNANAExt/Imp/Spon0–340%2Favorable
Pt, patient; BP, bisphosphonate; Tx, treatment; TPTD, teriparatide; OP, osteoporosis; CA, cancer; MM, multiple myeloma; IV, intravenous; NA, not available; Spon, spontaneous; Ext, extraction; Imp, implant; Perio, periodontitis.
Table
Table 3. Human studies of hyperbaric oxygen (HBO) administration for MRONJ treatment in the past 10 years.
Table 3. Human studies of hyperbaric oxygen (HBO) administration for MRONJ treatment in the past 10 years.
ReferenceTotal PtMedical ConditionBP RouteDuration
(Years)		Trigger
Event		StageSurgical TxOutcome
Freiberger et al. (2012) [50]25OP/BMNA2–8NANA83%Favorable
Fatema et al. (2015) [53]1OPOral2Ext2100%Favorable
Lin et al. (2020) [54]1NANANANA0100%Favorable
Youn et al. (2020) [55]1MMIV1Ext2100%Favorable
Watanabe et al. (2021) [52]143OP/BMOral/IV1–5Spon/Ext/
Imp/Perio		2 or 376%Favorable
Pt, patient; BP, bisphosphonate; Tx, treatment; OP, osteoporosis; BM, bone metastasis; MM, multiple myeloma; NA, not available; IV, intravenous; Spon, spontaneous; Ext, extraction; Imp, implant; Perio, periodontitis.
Table
Table 4. Recent human studies on photobiomodulation (PBM) therapy for MRONJ.
Table 4. Recent human studies on photobiomodulation (PBM) therapy for MRONJ.
ReferenceTotal PtMedical ConditionBP RouteDuration
(Years)		Trigger
Event		StageSurgical TxOutcome
Vescovi et al. (2012) [58]128OP/BM/MMNA1–8NA1–361%Favorable
Vescovi et al. (2012) [57]190OP/BM/MMNA112NA1–358%Favorable
Altay et al. (2014) [62]11CA/MMIV1–5Ext2–3100%Favorable
Minamisako et al. (2016) [63]1OPOral8Ext2100%Favorable
Momesso et al. (2017) [64]1OPOral5Imp2NoneFavorable
Merigo et al. (2018) [65]21OP/BMOral1–14NA1–3100%Favorable
Torres et al. (2020) [66]1BMIV2Ext3100%Favorable
Sanchez et al. (2020) [67]1NAOral1Ext3100%Favorable
Tenore et al. (2020) [68]26OP/CA/MMOral/IV1–8NA1–250%Favorable
Almeida et al. (2021) [69]1CAIVNANA2NoneFavorable
Nica et al. (2021) [60]241OP/CAOral/IV1–7NA0–345%Favorable
Pt, patient; BP, bisphosphonate; Tx, treatment; OP, osteoporosis; BM, bone metastasis; CA, cancer; MM, multiple myeloma; IV, intravenous; NA, not available; Ext, extraction; Imp, implant.
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Shim, G.-J.; Ohe, J.-Y.; Yoon, Y.-J.; Kwon, Y.-D.; Kim, D.-Y. Current Trends in Adjuvant Therapies for Medication-Related Osteonecrosis of the Jaw. Appl. Sci. 2022, 12, 4035. https://0-doi-org.brum.beds.ac.uk/10.3390/app12084035

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Shim G-J, Ohe J-Y, Yoon Y-J, Kwon Y-D, Kim D-Y. Current Trends in Adjuvant Therapies for Medication-Related Osteonecrosis of the Jaw. Applied Sciences. 2022; 12(8):4035. https://0-doi-org.brum.beds.ac.uk/10.3390/app12084035

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Shim, Gyu-Jo, Joo-Young Ohe, Young-Jae Yoon, Yong-Dae Kwon, and Deog-Yoon Kim. 2022. "Current Trends in Adjuvant Therapies for Medication-Related Osteonecrosis of the Jaw" Applied Sciences 12, no. 8: 4035. https://0-doi-org.brum.beds.ac.uk/10.3390/app12084035

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