1 s2.0 S8756328220304567 Main

Bone 141 (2020) 115676
Contents lists available at ScienceDirect
Bone
journal homepage: www.elsevier.com/locate/bone
Review Article
Adjuvant therapies for MRONJ: A systematic review T

a,b a,b a a,b
Dries Govaerts , Frederik Piccart , Anna Ockerman , Ruxandra Coropciuc ,
Constantinus Politisa,b, Reinhilde Jacobsa,c,
⁎
a
OMFS–IMPATH Research Group, Department of Imaging and Pathology, Faculty of Medicine, Catholic University Leuven, Belgium
b
Department of Oral and Maxillofacial Surgery, University Hospitals Leuven, Leuven, Belgium
c
Department of Dental Medicine, Karolinska Institute, Stockholm, Sweden
ARTICLE INFO ABSTRACT
Keywords: Objective: Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse reaction caused by the use of
Osteonecrosis antiresorptive antiangiogenic medication. Treating MRONJ is difficult and besides standard treatments, which
Medication-related osteonecrosis of the jaw are conservative medical and surgical approaches, there are some adjuvant therapies that might further sti
Therapy mulate healing. The aim of this systematic review is to compare outcome and effectiveness of currently available
laser ablation
adjuvant therapies for MRONJ.
LPRF
Bisphosphonates
Methods: This systematic review was conducted following the PRISMA guidelines. Articles focusing on mucosal
Denosumab healing in patients treated with an adjuvant therapy for MRONJ were selected and analysed. Inclusion was not
limited to randomized controlled trials to present a complete review of the current literature.
Results: A search was performed in Pubmed, Embase, Web of Science and Cochrane Central Register of
Controlled Trials. Thirty articles out of 3297 were included. Laser ablation had a success of 60–95% for complete
healing. The controlled trials of leukocyte- and platelet-rich-fibrine (LPRF) showed 60–100% success for the
same outcome. Fluorescence guided surgery had a complete healing percentage of 85–90%.
Conclusions: The results suggest that laser ablation, LPRF and fluorescence guided surgery might have a potential
in improving the healing process. Interpreting the results should however be done with great care and a critical
point of view, as most articles had a medium to high risk of bias. More randomized controlled trials are necessary
to define the most beneficial therapy protocols.
Clinical relevance: It seems that adjuvant surgical therapies for treating MRONJ are beneficial for mucosal
healing, but there is only low scientific evidence.
1. Introduction 6.7% or 1.9% when zoledronate or denosumab are administered re

spectively [11]. Based on the current literature, for osteoporotic pa
Bisphosphonates (BP) inhibit osteoclastic activity, thereby sup tients, the MRONJ risk goes up to 0.21% when exposed to oral BP for
pressing bone turnover. Next to antiresorption, BP also have an anti longer than four years and up to 0.04% receiving intravenous (IV) BP or
angiogenic and anticancer activity [1]. Antiresorptive medications play denosumab [11].
an important role in the treatment of various bone resorptive diseases. The current definition of MRONJ is based on three characteristics:
Medication-related osteonecrosis of the jaw (MRONJ) was reported for 1) current or previous treatment with antiresorptive or antiangiogenic
the first time in 2003 by Marx [2] and clearly acknowledged in the agents, 2) exposed jaw bone or bone that can be probed through an
following years [3–5]. intraoral or extra-oral fistula in the maxillofacial region that has per
Next to BP, denosumab [6,7] (RANKL inhibitor), bevacizumab [8,9] sisted for longer than 8 weeks, 3) no history of radiation therapy to the
(monoclonal antibody; inhibitor of VEGF-A, avascular growing factor), jaws or obvious metastatic disease to the jaws [11]. It is important to
sunitinib [9,10] (tyrosine kinase inhibitor) and temsirolimus [8] (spe keep in mind that patients at risk can present with other clinical con
cific mTOR inhibitor) are other risk factors for MRONJ. As more and ditions not to be confused with MRONJ. Common misdiagnosed con
more anti-resorptive and antiangiogenic drugs are being developed, ditions include, but are not limited to, osteitis, fibro-osseous lesions and
there is a risk that these new drugs will increase the incidence of chronic sclerosing ostemyelitis [11].
MRONJ. The risk of developing MRONJ in cancer patients goes up to MRONJ is divided in five stages, which are the following: At risk
⁎
Corresponding author at: Omfsimpath Research Group, Department of Imaging and Pathology, KU Leuven, Kapucijnenvoer 33, Leuven 3000, Belgium.
E-mail address: [email protected] (R. Jacobs).
https://doi.org/10.1016/j.bone.2020.115676
Received 29 June 2020; Received in revised form 29 September 2020; Accepted 1 October 2020
Available online 03 October 2020
8756-3282/ © 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
D. Govaerts, et al. Bone 141 (2020) 115676
stage, no apparent necrotic bone in patients treated with antiresorptive (Preferred Reporting items for Systematic Reviews and Meta-Analysis)
treatment. Stage 0 is defined as no clinical evidence of necrotic bone guidelines to ensure the quality, transparency and comprehensiveness
but present with nonspecific symptoms or clinical and radiographic of the review. A search strategy was specified in advance and registered
findings. Stage 1 is defined as exposed and necrotic bone or a fistula at PROSPERO (International prospective register of systematic reviews;
that probes to bone in patients who are asymptomatic and have no registration number: CRD42019124062).
evidence of infection. Stage 2 is defined as exposed and necrotic bone or
a fistula that probes to bone with evidence of infection. These patients
are symptomatic Stage 3 is defined as exposed and necrotic bone or 2.2. Eligibility criteria
fistulas that probe to bone with evidence of infection and at least 1 of
the following: exposed necrotic bone extending beyond the region of The following criteria were employed for inclusion of papers in this
alveolar bone (ie, inferior border and ramus in the mandible, maxillary review:
sinus, and zygoma in the maxilla), pathologic fracture, extraoral fistula,
oral antral or oral nasal communication or osteolysis extending to the Type of studies: Since we were searching for unconventional
inferior border of the mandible or sinus floor [11]. therapies for MRONJ, which is a recent pathology due to the use of
The most controversial topic about MRONJ is its management. The bisphosphonates or denosumab, we were all-inclusive and con
current main treatment styles for MRONJ are medical conservative sidered case-controls, cohort studies, non-randomized trials and
(long term antibiotics and antiseptics) and surgical (ranging from randomized controlled trials. There was no exclusion based on the
debridement to segmental resection to free flap reconstruction). The follow-up period, but we are aware that the follow-up period was
guidelines state that therapy should be stage specific, suggesting a important for a potential risk of bias. Accordingly, we assessed the
medical conservative approach for stage 0 and I, a minimally invasive follow-up in the risk of bias and provided information in the risk of
surgical approach for stage II and a radical surgical approach for stage bias table.
III [11]. Type of participants: Studies evolving patients diagnosed with
According to some studies, both medical conservative and surgical MRONJ and treated with a non-standardized, adjuvant treatments
approaches might be optimized by adding an unconventional but ad were included.
juvant therapy to improve the healing process [12–15]. Several recent Type of intervention and comparisons: All possible unconventional
studies proposed their alternative protocol to prove their effectiveness. treatments to manage MRONJ, such as bone morphogenetic protein-
As treating MRONJ can be challenging, preventive approaches, surgery 2, geranylgeraniol, hyperbaric oxygen therapy, bovine lactoferrin,
and adjuvant therapy should be considered. laser ablation, low-level laser therapy, mesenchymal stem cells,
A wide variety of adjuvant therapies exist, which we describe in leukocyte-platelet rich fibrin or platelet-rich plasma, ozone therapy,
short hereafter. For example, Hyperbaric Oxygenation Therapy (HBO) pentoxifylline and tocopherol, unconventional surgical techniques,
augments the availability of reactive oxygen in the body and signalling teriparatide and more.
for bone turnover may be increased [16]. Also, necrotic bone can be Type of outcome measures: Studies evaluating the improvement or
vaporized by Laser Ablation and is linked to a faster bone healing completion of mucosal healing and the length of follow up.
without risk for thermal increase [17]. While Low Level Laser Therapy
(LLLT) stimulates cell proliferation and bone formation through in The overall overview of the inclusion criteria:
duction of cell-cycle regulatory proteins [17,18]. Leukocyte- and Pla
telet Rich Fibrin (LPRF) and its variations (Platelet Rich Fibrin (PRF), • The use of an adjuvant therapy for the treatment of MRONJ
Platelet Rich Plasma (PRP) or Leukocyte- and Platelet Rich Plasma • Detailed information of the adjuvant therapy
(LPRP)) are used for the amelioration of bone healing and showed a • Outcome measures described by mucosal healing
significant improvement of terms of quality of life [19]. To stimulate
the antioxidant system and increasing of red blood cells and hae An adjuvant therapy is a treatment that is complementary to the
moglobin concentration, Ozone Therapy can be used [20]. An adjuvant standard medical conservative or surgical care and improves healing of
surgical technique is called Fluorescence Guided Surgery which high MRONJ.
lights the transition from necrotic to vital bone during debridement Studies were excluded on basis of the following criteria: articles
[21]. Teriparatide (TPTD) can reactivate bone formation by stimulation describing only standard conservative (antibiotics and antiseptics) and
osteoblasts and osteoclasts [22] and Bovine Lactoferrin (bLf) contains standard surgical (debridement or sequestrectomy) therapy, systematic
an anti-inflammatory effect [23], whereas recombinant human bone reviews, case-reports, case series, ex vivo/in vitro studies, animal stu
morphogenetic protein-2 (rhBMP-2) has osteoconductive effects and dies and articles on osteoradionecrosis.
increases bone remodeling [24]. The toxicity of bisphosphonates may
be reversed by Geranylgeraniol (GGOH) [25]. While Mesenchymal stem 2.3. Information sources
cells (MSC) owns the potential to differentiate into different cell
lineages [26]. Last, Pentoxifylline and tocopherol (PENTO) are widely The search strategy was developed for Pubmed and appropriately
used for treatment of osteoradionecrosis, by inhibiting inflammation modified for Embase, Web of Science and Cochrane Central Register of
and protecting cell membranes, thus possible improving healing of Controlled Trials, which we accessed through the University of Leuven.
MRONJ lesions [27]. The databases were screened on the 1st of April 2020 for eligible arti
Despite the variety of available reports on different adjuvant cles. In addition, the reference lists of all included full-text articles were
therapies, their differential indications and potential therapeutic effects screened manually for potential useful articles.
have not yet been contrasted and compared. Therefore, the aim of this
systematic review is to determine the differences in outcome and to
evaluate the effectiveness of various adjuvant therapies for MRONJ. 2.4. Search
2. Methods The search strategy was based on a combination of Medical Subject

Headings (MeSH) and free text terms. No filter, nor a time limit or other
2.1. Protocol and registration data restrictions were used when searching the electronic bibliographic
databases. The search strategy used for Pubmed can be found in
This systematic review was performed following the PRISMA Appendix A.
2
Fig. 1. PRISMA flow chart outlining the study selection process.
2.5. Study selection concerning authors of potentially eligible articles were contacted for
clarification.
Two reviewers (D.G. and F.P.) independently screened the titles and
abstracts and obtained a consensus about the inclusion of articles. If 2.7. Data items
they disagreed about inclusion or exclusion, a third (senior) reviewer
(R.J.) was consulted, who decided about the matter. In case of articles The following data were collected:
concerning extension of an original sample, only one article with the
most recent data and the most relevant information (P-values) was Methods: study design, level of evidence by Cochrane Library [29]
considered for inclusion. adapted from Oxman [30], year of publication, recruitment period.
Participants: Number of participants and demographics (mean age,
women/men ratio, ratio of initial diagnoses, ratio of ONJ staging as
2.6. Data collection process applicable and bisphosphonates ratio).
Intervention: Details regarding the adjuvant treatment, subgroups
The data extraction and collection process was performed by a per article, use of antiseptics, antibiotics and conservative surgery.
single author (D.G.) according to the Cochrane data extraction form Outcome: Outcome measures (mucosal healing) and follow-up (in
[28] and supervised by the other authors (R.C. and R.J.). If data was terval).
missing or when a possibility of misinterpreting the data existed, the
3
Mucosal healing was divided in three categories (complete healing, included [50] while the other were excluded to prevent double re
improvement of healing, no improvement of healing) following the porting.
categories of healing in the majority of the included articles. Complete
healing was considered when mucosal coverage of the lesion was
3.2. Study characteristics
achieved. Improvement of healing is defined as partial healing or as the
transition from a higher to a lower stage of MRONJ. No improvement
Four of the 28 included studies were Randomized Controlled Trials
covers a stabile lesion, meaning no change in MRONJ-staging, or a
(RCT) [16,19,24,69]. Three studies had a prospective controlled design
progression of the lesion.
[23,53,63] while seven studies had a retrospective controlled design
In the majority of included articles, results of mucosal healing were
[21,50,51,54,64,67,70]; seven studies [17,55,57,58,61,62,65] had a
stated in text form or in tables as defined in this systematic review.
prospective uncontrolled design and seven studies
When the results of a category were absent, they were calculated as
[20,52,56,59,60,66,68] had a retrospective uncontrolled design.
possible or the author was contacted. The three categories were con
Based on the level of evidence tool adapted from Oxman [30], one
verted to a percentage ratio to allow a more homogenous and com
study had level I [24]; four studies had level II [16,19,21,69]; nine
parative overview, with results of mucosal healing presented in a
studies had level III [23,50,51,53,54,63,64,67,70]; no study had level
summary table.
IV (non-randomized historical cohort studies) and fourteen studies had
level V [17,20,52,55–62,65,66,68]. Level I represents the highest level
2.8. Risk of bias in individual studies of evidence.
Adjuvant treatments proposed in the papers were either HBO
Given the heterogeneity of the study designs, the Newcastle-Ottawa [16,68], a combination of laser ablation and LLLT [17,50,69,70], only
Scale (NOS) was used for evaluation of the risk of bias of the included LLLT [51,52,65], LPRF and its variations [19,24,53–58,66,67], Ozone
studies [31,32]. Two authors (D.G. and F.P.) independently performed [20,59,60], Fluorescence guided surgery [21,61,62], Teriparatide
risk of bias assessment. Any disagreement was resolved by discussion [63,64] and Bovine Lactoferrin [23]. One study combined laser abla
and seeking consensus or consultation of a third author (R.J.) for a tion and LPRF [58], one study combined laser ablation, LLLT and LPRF
conclusive decision. The risk of bias of all studies was judged via a star [17] and one study combined BMP-2 and LPRF [24] as adjuvant
ranking system. The NOS is divided in a selection domain, a compar therapy.
ability domain and an outcome domain. The three domains together Between 7 and 151 patients were selected for each study with a
reflect the overall risk of bias, and are based on assigning a rank of zero median of 25 patients. The mean age of subjects in the study samples
to nine stars. Studies were categorized as ‘Low risk’ (6–9 stars), ranged from 55 to 76 years old. Two studies did not report the mean age
‘Medium risk’ (3–5 stars) and ‘High risk’ (0–2). [23,68]. Gender distribution ranged from 38%–93% (male) and 7–62%
(female). Two studies only reported on outcome in women [63,66].
3. Results Most of the studies included patients with oncologic as non-onco
logic primary diagnoses. Seven studies reported only oncologic primary
3.1. Study selection diagnoses [23,54,56,58,61,62,69]; two studies only multiple myeloma
[53,59]. Two studies, both focusing on teriparatide, had only osteo
The flow diagram resuming the selection process is presented in porosis as primary diagnosis [63,64].
Fig. 1. Through searching the databases mentioned above, 3294 records Stage I, II and III MRONJ were presented in 12 studies
were identified. In addition, 3 records were added trough manual [16,17,21,24,50–52,54,62,65,66,70], three papers focused on stage II
searching. After removing the duplicates, titles and abstracts of 1994 MRONJ [23,55,56], two studies had only patients with stage I or II
unique articles were screened, and 332 articles were included for full- MRONJ [58,69] and another five studies had stage II or III MRONJ
text analysis. Finally, 45 articles were assessed for eligibility based on patients [19,57,61,64,67]. Six studies [20,53,59,60,63,68] didn't
the inclusion criteria. Seventeen articles [33–49] did not met inclusion mention the staging of their study sample. Three out of these six studies
criteria (Table 1), resulting in 28 studies [16,17,19–21,23,24,50–70] [20,59,68] were published in 2007, before any position paper was
included for a qualitative synthesis. It must be noted that Vescovi et al. written [5].
[34,42,43,46,47,50] reported broadly on adjuvant treatments using a In all but five articles, patients were treated with only bispho
sample that extended over time. Solely the most recent article was sphonates for their primary diagnosis. Three studies selected patients
Table 1
Articles discarded not meeting the inclusion criteria.
Author, year Reason for exclusion
Agrillo et al., 2006 [33] Providing a protocol in treatment of MRONJ, no report of results
Vescovi et al., 2007 [34] Same study sample as Vescovi et al. [50]
Sweeny et al., 2012 [44] No MRONJ patient population
Andriani et al., 2012 [45] No detailed information on the complementary therapy, combining 2 subgoups with different coplementary therapies (HBO and Ozone) as one
subgroup
Franco et al., 2014 [48] Reporting on overall healing, no therapy-specific subgroup results
Vescovi et al., 2015 [49] Reporting on healing of tooth sockets after extraction in a MRONJ population
Fleisher et al., 2016 [35] No specifications or results on patient subgroup treated with complementary therapy
Mücke et al., 2016 [36] Reporting on overall healing, no therapy-specific subgroup results, no adjuvant treatment
Jung et al., 2017 [37] No outcome of mucosal healing
Asaka et al., 2017 [38] Reporting on healing of tooth sockets after extraction in a MRONJ population
Hadaya et al., 2018 [39] variation on post-operative wound care, no complementary therapy
Valente et al., 2019 [40] Multiple treatments until complete healing, no outcome of mucosal healing
Tartaroti et al., 2020 [41] No outcome of mucosal healing
4
Table 2
Overview of included studies with outcome presented as complete, improvement or no improvement for healing. The level of evidence, intervention and control groups, use of antiseptics, antibiotics or conservative
surgery, healing outcomes and significance are shown.
Author, year LOE Patient groups (n (sites)) AS? AB? CS? HEALING (in general) Significance What is significant?
D. Govaerts, et al.
Complete healing Improvement No improvement
HBO
Freiberger et al., 2012 [16] II G1: HBO (25) ✓ ✓ ✓ 52% 16% 32% P = 0,203 Complete healing G1 vs G2
G2: medical + conservative surgery (21) ✓ ✓ ✓ 33% 5% 62% P = 0,043⁎ Improvement G1 vs G2
Freiberger et al., 2007 [68] V G1: HBO (16) N/A N/A N/A 44% 50% 6% P < 0,001 Clinical size (before vs after)
Laser ablation + LLLT

Atalay et al., 2011 [69] II G1: laser ablation + LLLT (10) ✓ ✓ ✓ 70% 30% – P = 0,370 Complete healing G1 vs G2
G2: medical + conservative surgery (10) ✓ ✓ ✓ 40% 60% –
Angiero et al., 2009 [70] III G1: laser ablation + LLLT (10) ✓ ✓ ✓ 60% 40% – N/A –
G2: medical (19) ✓ ✓ ✗ – 74% 26%
G3: conservative surgery (20) ✓ ✗ ✓ – – 100%
Vescovi et al., 2012 [50] III G1: laser ablation + LLLT (29) ✓ ✓ ✓ 90% 7% 3% P < 0,0001⁎ Complete healing G1 vs G2
G2: medical (28) ✓ ✓ ✗ 18% 7% 75% P < 0,0001⁎ Complete healing G2 vs G5
G3: medical + conservative surgery (17) ✓ ✓ ✓ 65% – 35% P = 0,058 Complete healing G3 vs G1
G4: medical + LLLT (32) ✓ ✓ ✗ 28% 44% 28% P < 0,0001⁎ Complete healing G4 vs G1
G5: medical + conservative surgery + LLLT (33) ✓ ✓ ✓ 73% 9% 18% P = 0,1161 Complete healing G5 vs G1
Merigo et al., 2018 [17] V G1: laser ablation + PRP + LLLT (21) N/A ✓ ✓ 95% 5% N/A –
LLLT
Favia et al., 2018 [51] III G1: LLLT (21 (24)) ✓ ✓ ✗ – 8% 92% N/A –
G2: medical + conservative surgery (85 (107)) ✓ ✓ ✓ 95% 5% –
⁎
Scoletta et al., 2010 [65] V G1: LLLT (20) N/A N/A N/A 20% 40% 40% P = 0,0034 Clinical size (before vs after)
Romeo et al., 2011 [52] V G1: LLLT + conservative surgery (12) ✓ ✓ ✗ 17% 75% 8% N/A –
5
LPRF
Park et al., 2017 [24] I G1: BMP-2 + LPRF (30) ✓ ✓ ✓ 60% 37% 3% P = 0,028⁎ General healing G1 vs G2
G2: medical + conservative surgery + LPRF (25) ✓ ✓ ✓ 36% 52% 12%
⁎
Giudice et al., 2018 [19] II G1: PRF (24) ✓ ✓ ✓ 96% 4% – P < 0,05 Complete healing at 1 m G1 vs G2
G2: medical + conservative surgery (23) ✓ ✓ ✓ 91% 9% –
Coviello et al., 2012 [53] III G1: PRP (3) N/A ✓ ✓ 100% – – N/A –
G3: conservative surgery (4) N/A ✓ ✓ – 50% 50%
Longo et al., 2014 [54] III G1: PRP (34) ✓ ✓ ✓ 94% 6% – P = 0,003⁎ General healing G1 vs G3
G2: medical (23) ✓ ✓ ✗ 32% 68% –
G3: conservative surgery (15) ✓ ✓ ✓ 53% 47% –
Szentpeteri et al., 2020 [67] III G1: PRF (73) N/A ✓ ✓ 82% 18% – P = 0,022⁎ General healing G1 vs G2
G2: conservative surgery (28) N/A ✓ ✓ 58% 19% 23% P = 0,005⁎ Improvement G1 vs G2
Bocanegra-Pérez et al., 2012 [55] V G1: LPRP (8) ✓ ✓ ✓ – 100% – N/A –
Dincă et al., 2014 [56] V G1: PRF (10) ✓ ✓ ✓ 100% – – N/A –
Nørholt et al., 2016 [57] V G1: LPRF (15) ✓ ✓ ✓ 93% – 7% N/A –
Mauceri et al., 2018 [58] V G1: laser ablation + PRP (10) ✓ ✓ ✓ 30% 50% 20% P = 0,012⁎ CH + I at pre-op vs 12 months
Ozone
Petrucci et al., 2007 [59] V G1: ozone (12) ✓ N/A ✓ 67% 33% – N/A –
Agrillo et al., 2007 [20] V G1: ozone (33) ✓ ✓ ✓ 54% 30% 16% N/A –
Agrillo et al., 2012 [60] V G1: ozone (94) ✓ ✓ ✓ 60% 30% 10% P < 0,001⁎ CH vs I vs NI
Fluorescence guided surgery
Ristow et al., 2017 [21] II G1: auto-fluorescence-guided (20) ✓ ✗ ✓ 90% – 10% P > 0,05 Complete healing G1 vs G2
G2: tetracycline-fluorescence-guided (20) ✓ ✗ ✓ 85% – 15%
Pautke et al., 2011 [61] V G1: auto-fluorescence-guided (15 (20)) N/A ✓ ✓ 85% 15% 0% N/A –
Otto et al., 2016 [62] V G1: auto-fluorescence-guided (54 (65)) N/A ✓ ✓ 87% 11% 2% N/A –
Teriparatide
Kim et al., 2014 [64] III G1: TPTD + Cal + VitD (15) N/A ✓ ✗ 38% 63% – P < 0,05⁎ General healing G1 vs G2
G2: Cal + VitD (9) N/A ✓ ✗ – 60% 40%
Bone 141 (2020) 115676
(continued on next page)

Level of Evidence, N number, AS Antiseptics, AB Antibiotics, CS Conservative Surgery, N/A Not Available, G Group, HBO Hyperbaric Oxygenation Therapy, LLLT Low Level Laser Therapy, LPRF leukocyte-platelet rich
Table 2: Level of evidence, intervention and control groups, use of antiseptics, antibiotics or conservative surgery, healing outcomes and significance of the included studies. Subdivision based on adjuvant therapies. LOE
treated with bisphosphonates or denosumab or a combination of both
antiresorptive medications [19,21,51,57,62].
The follow-up period ranged from 1 to 39 months. Only 2 studies
had a follow-up of less than six months; following the patient sample for
30 days [56] and 3 months [53].
What is significant?
All the patient characteristics are presented in Appendix B. The

table is ordered based on the adjuvant treatment and the level of evi
dence. Number of patients (or sites), the mean age, women/men ratio,
primary diagnoses, stage of MRONJ, antiresorptive medication ad
ministered, location of the lesion and details on follow up (mean and
–
interval) of the included studies are presented in the table.

Other collected data related to treatment is presented in Table 2.
Significance
The table is ordered based on the adjuvant treatment and the level of
evidence. The patient groups within each article are shown as G1–5.
N/A
The adjuvant therapy is always group 1 (G1). Some articles use an

adjuvant treatment partly or fully as their control groups (G2-G5)
No improvement
[24,50,64]. Info on the use of antiseptics, antibiotics or a conservative

surgical approach is given per patient group. The healing outcome
(mucosal coverage) is presented. The P-values (if available) and if the
study results were significant are showed in the last 2 columns.
25%
–
3.3. Adjuvant therapies

Improvement
The different adjuvant therapies are discussed in detail in Table 3.

50%
–
3.3.1. HBO
HEALING (in general)
Freiberger et al. [16,68] studied an HBO therapy after surgical

Complete healing
debridement. This adjuvant therapy consisted of 40 sessions at 2.0 atm

(atm) for 2 h twice per day.
100%
25%
3.3.2. Laser ablation + LLLT

Atalay et al. [69] performed the debridement with laser ablation
technique (Er:YAG; 2940 nm) following LLLT (Nd:YAG; 1064 nm) for
CS?
1 min in 5 sessions every two days. Angiero et al. [70] removed necrotic
✗
bone with laser ablation (Er:YAG; 2940 nm), subsequently they applied
AB?
biostimulation with the same device, but with a fifth of the power
✓
✓
setting, 3 times for 1 min. In the article of Vescovi et al. [50], the laser
N/A
N/A
AS?
ablation (Er:YAG; 2940 nm) was followed by irrigation with povidone

iodine solution and LLLT (Nd:YAG; 1064 nm), 5 times for 1 min, once a
week for 2 months. Merigo et al. [17] started with piezosurgery to re
move the necrotic bone, laser ablation (Er:YAG; 2940 nm) was used
until bleeding of the bone. They added platelet rich plasma (PRP;
180 rpm; 10 min) as a gel consistency directly on the wound on a fibrin
sponge or with a syringe after suturing, following LLLT (diode laser;
808 nm), 5 times for 1 min, twice a week until suture removal or
complete mucosal coverage.
fibrin, CH Complete Healing, I Improvement, NI No Improvement.
Patient groups (n (sites))
3.3.3. LLLT
Favia et al. [51] reported on LLLT (diode laser; 800 nm) that was
applied monthly (they gave no further specifications) without any
G1: TPTD (4)
G2: PRF (5)
surgical intervention in the intervention group (G1). Romeo et al. [52]

first performed a debridement, following LLLT (double diode laser;
650 nm & 904-910 nm) for 15 min every 3 days for 2 weeks. Scoletta
et al. [65] applied LLLT (diode laser; 904 nm) for 15 min in 10 sessions
LOE
over 20 days, performing a debridement or conservative surgery was

III
not mentioned in the study.
3.3.4. LPRF
Significant P < 0,05.
Park et al. [24] performed a debridement following application of

rhBMP-2 (0.5 ml and a collagen sponge as a carrier) and added L-PRF
Pelaz et al., 2014 [63]
Table 2 (continued)
(3000 rpm; 10 min). Giudice et al. [19] performed a debridement and

added PRF (1300 rpm; 8 min). Coviello et al. [53] performed a se
Author, year
questrectomy and applied PRP as proposed by Marx et al. [71]. Longo

et al. [54] performed a debridement and added PRP (firstly 180 rpm for
10 min to separate the erythrocytes, secondly 1800 rpm for 10 min to
⁎
separate platelet concentrate). Szentpeteri et al. [67] performed a
6
Table 3
Details on the adjuvant therapy of the included studies.
Author, year Details on adjuvant therapy
HBO
Freiberger et al., 2012 [16] 40 HBO treatments at 2.0 ATM for 2 h twice per day
Freiberger et al., 2007 [68] 40 HBO treatments at 2.0 ATM for 2 h twice per day

Atalay et al., 2011 [69] Laser ablation (Er:YAG, 2940 nm, 200 mJ) + LLLT (Nd:YAG; 1064 nm) for 1 min, per 2 days, during 5 sessions
Angiero et al., 2009 [70] Laser ablation (Er:YAG, 2940 nm, 200-250 mJ) + LLLT (Er:YAG, 2940 nm, 50 mJ) 3 times for 1 min
Vescovi et al., 2012 [50] Laser ablation (Er:YAG; 2940 nm) + irrigation with povidone iodine solution + LLLT (Nd:YAG; 1064 nm) 5 times for 1 min, once a week, for
2 months
Merigo et al., 2018 [17] Piezotome and Laser Ablation (Er:YAG; 2940 nm, 200 mJ) + PRP (180 rpm; as a gel) + LLLT (diode laser; 808 nm) 5 times for 1 min, twice a
week
LLLT
Favia et al., 2018 [51] LLLT (800 nm) once a month
Romeo et al., 2011 [52] LLLT (GaAs, double diode, 650 nm & 904-910 nm) for 15 min, per 3 days, for 2 weeks
Scoletta et al., 2010 [65] LLLT (GaAs, 904 nm) for 15 min, per 2 days, during 10 sessions
LPRF
Park et al., 2017 [24] rhBMP-2 (0,5 ml, collagen sponge as carrier, direct contact with bone) + L-PRF (3000 rpm, 10 min)
Giudice et al., 2018 [19] PRF (1300 rpm, 8 min)
Coviello et al., 2012 [53] PRP (as proposed by Marx et al. [71])
Longo et al., 2014 [54] PRP (180 rpm, 10 min, to separate erythrocytes; 1800 rpm, 10 min, to separate platelet concentrate)
Szentpeteri et al., 2020 [67] PRF (3000 rpm, 8 min, as membranes, multilayer)
Bocanegra-Pérez et al., 2012 [55] L-PRP (1 ml thrombin/3 ml plasma, as a gel)
Dincă et al., 2014 [56] PRF (1300 rpm, 14 min, clots & membranes)
Nørholt et al., 2016 [57] LPRF (1300 rpm, 14 min, as membranes, multiple layers)
Mauceri et al., 2018 [58] PRP (180 rpm, 10 min, to separate erythrocytes; 1800 rpm, 10 min, to separate platelet concentrate)
Kim et al., 2014 [66] LPRF (3000 rpm, 10 min)
Ozone
Petrucci et al., 2007 [59] Ozone (7 days pre-operative, 2 sessions during surgery, 7 days post-operative, N/S)
Agrillo et al., 2007 [20] Ozone (5 cycles of 8 sessions for 3 min, twice a week)
Agrillo et al., 2012 [60] Ozone (4 cycles of 8 sessions for 3 min, twice a week)

Ristow et al., 2017 [21] Preoperative administration of doxycycline (or tetracycline in control group), debridement until a homogenous greenish bone fluorescence
was observed using the VELscope system
Pautke et al., 2011 [61] Preoperative administration of doxycycline, debridement until a homogenous greenish bone fluorescence was observed using the VELscope
system
Otto et al., 2016 [62] Preoperative administration of doxycycline, debridement until a homogenous greenish bone fluorescence was observed using the VELscope
system
Teriparatide
Kim et al., 2014 [64] Teriparatide (20 μg, once daily, subcutanous selfadministration, maximum 6 months) with Calcium and Vitamin D supplement
Pelaz et al., 2014 [63] Teriparatide (20 μg, once daily, subcutanous selfadministration, maximum 10 months) vs PRF (vivostat PRF system)
Bovine lactoferrin
Calvani et al., 2018 [23] Bovine lactoferrin (100 mg/2 ml, gauze application on surgical site) + bLf tablets (50 mg, locally dissolved, 2 times a day)
Table 3: Details on adjuvant therapy of the included studies, subdivision based on adjuvant therapy. HBO Hyperbaric Oxygenation Therapy, ATM atmosphere,
Er:YAG erbium-doped yttrium aluminum garnet, nm nanometer, mJ microJoule, LLLT Low Level Laser Therapy, Nd:YAG neodymium-doped yttrium aluminum
garnet, min minute, PRP platelet rich plasma, rpm rounds per minute, GaAs Gallium arsenide, LPRF leukocyte-platelet rich fibrin, rhBMP-2 recombinant human bone
morphogenetic protein-2, ml milliliter, PRF platelet rich fibrin, N/S not specified, μg microgram, bLf bovine lactoferrin.
debridement and added PRF (3000 rpm; 8 min) as membranes in a 3.3.6. Fluorescence guided surgery
multilayer technique. Bocanegra-Pérez et al. [55] performed a debri In 2017, Ristow et al. [21] performed a debridement using auto-
dement and applied L-PRP as a gel (1 ml thrombin/3 ml plasma). Dincă fluorescence-guided surgery versus tetracycline-fluorescence-guided
et al. [56] performed a debridement and added LPRF (3000 rpm; surgery to identify the better adjuvant therapy among these examples.
14 min and clot- & membrane-shaped). Nørholt et al. [57] performed a The VELscope system (VELscope fluorescence lamp; LED Dental, White
sequestrectomy or a debridement and added LPRF (1300 rpm; 14 min; Rock, British Columbia, Canada) was used for auto-fluorescence. Pautke
membrane-shaped; multiple layers). Mauceri et al. [58] performed a et al. [61] and Otto et al. [62] only performed a debridement based on
debridement with laser ablation (Er,Cr:YSGG; 2780 nm) and applied auto-fluorescence-guided surgery.
PRP (firstly 180 rpm for 10 min to separate the erythrocytes, secondly
1800 rpm for 10 min to separate platelet concentrate). Kim et al. [66] 3.3.7. Teriparatide
performed a debridement and added LPRF (3000 rpm; 10 min) to the Pelaz et al. [63] administered only TPTD (subcutane; 20 μg) daily
wound. during 4 to 10 months as intervention. The control group had a deb
ridement combined with application of PRF (no further details). Kim
et al. [64] administered TPTD (subcutane; 20 μg) daily during 6 months
3.3.5. Ozone and added Calcium and Vitamin D supplementation.
Petrucci et al. [59] performed a debridement and applied ozone
7 days pre-operatively, 2 times locally during surgery and 7 days post- 3.3.8. Bovine Lactoferrin
operatively (no further details). Agrillo et al. [20,60] performed a Calvani et al. [23] performed a debridement and applied bLf
debridement and applied ozone in 4 or 5 cycles (pre- and post-opera (100 mg/2 ml, gauze application, 10 min) combined with tablets of bLf
tive), each cycle were 8 sessions of ozone therapy, twice a week. (at home, tablets locally dissolved, 50 mg, 2×/day). The control group
7
had application of sterile gauzes combined with the same tablets as the [57,74,75]. The use of adjuvant BMP may even enhance healing be
intervention group. cause of its osteoconductive effects [24,76,77].
Two articles [23,66] included in this systematic review but absent Regarding ozone therapy, none of the reported studies had a control
in Table 2, presented their results differently from the majority of the group and all of them had a medium to high risk of bias. A reserved
papers. Kim et al. [66] presented the results of their LPRF study based interpretation is certainly appropriate given that there are no controlled
on mucosal coverage over time instead of a fixed follow-up period. papers published yet on this subject.
Seventy-seven percent had a complete resolution (mucosal coverage at Fluorescence-guided bone surgery is a way to objectify the surgeon's
1 month), 18% had a delayed resolution (mucosal coverage between 1 intraoperative control of the transition of necrotic to vital bone and
and 4 months) and 6% had no resolution (persistence of the lesion at thereby standardizes the technique. This can limit the MRONJ resection
4 month follow-up). There was a significant association between re to a minimum and optimize the healing process as such. No significant
sponse to treatment and stage of MRONJ (p = 0.002); the higher the difference was reported between the auto-fluorescence-guided and
stage of MRONJ, the worse the response to treatment. All patients in the tetracycline-fluorescence-guided surgery [21]. No study compared the
study of Calvani et al. [23] on bLf had mucosal coverage, but obtained fluorescence-guided surgery to standard surgery techniques.
this point of healing at different levels of the follow up. The interven Literature on teriparatide is scarce. Only two articles with a non-
tion group had 31% and 100% complete healing at 1 and 2 weeks. The surgical intervention group were identified [63,64]. The complete
control group had 15% and 100% complete healing at 2 and 3 months healing outcome was low (25–38%), with selection bias further low
respectively. ering the clinical evidence. Both articles only included osteoporosis
cases, with MRONJ stages II and III.
3.4. Risk of bias within studies As to lactoferrin as adjuvant treatment option for MRONJ.
According to Calvani et al. [23] the difference in the healing time when
The Newcastle-Ottawa Scale [31,32] was used to determine the risk using lactoferrin versus conservative medical therapy was a few weeks
of bias for the included studies. Table 4 provides a breakdown of the and up to three months respectively. More research on this matter is
components of this bias tool. recommended to promote this adjuvant treatment.
More adjuvant therapies, such as pentoxifylline and tocopherol
4. Discussion [27,78], geranylgeraniol [25,79] or BMP alone [80], are reported in
literature, but these articles did not meet the inclusion criteria. Further,
The purpose of this study was to give an overview of all existing therapies that might gain importance in the future aremesenchymal
adjuvant therapies for treating MRONJ and the evaluate the effective stem cells (MSCs) [26,81], the use of dental pulp MSCs [82] and the use
ness and the differences in outcome of these therapies. Publications on of human amniotic membrane [83].
this matter have greatly increased the last decade since MRONJ is a It is difficult to draw firm conclusions from this systematic review.
recently discovered pathology [2]. The adjuvant therapy is often combined with either the standard sur
Performing a meta-analysis on the subject appeared impossible be gical or medical conservative treatment. Both approaches can influence
cause of the high variation in study designs, protocols and reports on the result and thus be a confounding factor with respect to each other.
outcome [72]. Additionally, the majority of the included articles had a For this reason, the results in this systematic review must be interpreted
medium to high risk of bias, so that results should be interpreted with with the necessary precautions.
caution. This systematic review was not limited to only RCTs to present As stated above, the heterogeneity, lack of control group in some of
a complete review of the literature. the studies and the high number of articles with a medium to high risk
Based on this review, we can cautiously state the following re of bias also limit the conclusions that can be drawn of this systematic
garding the adjuvant therapies. review. Most of the articles were non-randomized retrospective studies
HBO therapy showed a significantly improved healing based on a which make the articles susceptible for all forms of bias. Combining
RCT with a low risk of bias [16]. Yet clinical success seems rather low data of heterogeneous articles can be misleading so that wrong con
(44–52% complete healing) and no further research has been conducted clusions could be drawn. A statement could be made to standardize the
on HBO therapy. outcome measures since comparing the results of different experimental
The combination of Laser Ablation and LLLT gave a success of treatments is often impossible to a high variety of parameters. To
60–95% for complete healing. Yet, it might be that the success is rather evaluate the effectiveness of an adjuvant treatment more well-con
related to laser ablation alone or surgical treatment in general. Indeed, trolled studies are necessary. Some of the included articles had a major
a non-randomized study concluded that LLLT is inferior to a surgical discrepancy in treatment of the intervention and control groups
approach [51] which was confirmed by other articles using only LLLT, [51,63]. It is evident that in further studies, a medical or surgical ad
reporting complete healing with only 0–20% of the patients [51,52,65]. juvant treatment should always be compared to either a standard
Vescovi et al. [50] used several control groups, with a conservative or a medical or surgical therapy respectively to minimize the intrinsic dif
surgical approach, and showed that minimal invasive surgery had the ference in the results between a medical and surgical therapy.
best healing results in the general population of MRONJ. A subdivision
based on MRONJ stages was not reported. Unfortunately, this article
had a high risk of bias according to the NOS scale. 5. Conclusions
The first report of treating MRONJ with platelet derived growth
factors was published in 2007 [73]. The overall success of LPRF as an The results of this systematic review suggest that an adjuvant
adjuvant treatment may be due to the surgical component since all therapy concomitant with the standard surgical or medical conservative
interventions were combined with a surgical approach. Longo et al. approach may offer an advantage to a standard surgical or medical
[54] and Szentpeteri et al. [67] stated a significant difference in healing conservative approach solely. Yet, the present outcomes should be in
between the LPRF group and the control group. However, both studies terpreted cautiously because of bias and low evidence study designs.
had a medium risk of bias. Giudice et al. could only show a significant There seem to be some indications that laser ablation, LPRF and
difference between L-PRF and control at one month of follow-up [19]. fluorescence guided surgery might present interesting options for
This study results are trustworthy given the low risk of bias and the treating MRONJ. There is an urgent need for conducting more rando
randomized controlled trial design. LPRF might thus be useful to fasten mized well-controlled trials before implementing these adjuvant
the healing process. The reason for this might be that L-PRF acts as a therapies in a standard treatment protocol of MRONJ.
membrane, thus avoiding direct contact between bone and oral mucosa
8
Table 4
Newcastle-Ottawa Quality Assessment.
Author, year Representativeness of the Selection of the non- Ascertainment of Demonstration that Comparability of Assessment of Was follow up long Adequacy of Stars (n) Overall
intervention cohort intervention cohort intervention outcome of interest was cohorts on the basis of outcome enough for follow up of risk of bias
D. Govaerts, et al.
not present at start of the design or analysis outcomes to occur cohorts

study
HBO
Freiberger et al., Low (★) Low (★) Low (★) Yes (★) High: no control of High: assessment Yes (★) Loss < 20% 6 Low
2012 [16] potential confounding done by the (★)
variable study's surgeon
Freiberger et al., High: no MRONJ staging N/A Low (★) Yes (★) N/A Unclear: no Yes (★) Complete 4 Medium
2007 [68] discription follow up (★)

Atalay et al., High: mostly stage II ONJ Low (★) Low (★) Yes (★) High: no control of Unclear: no Yes (★) Complete 5 Medium
2011 [69] potential confounding discription follow up (★)
variable
Angiero et al., High: no MRONJ staging High: no MRONJ staging Low (★) Yes (★) High: no control of Unclear: no Yes (★) Loss < 20% 4 Medium
2009 [70] potential confounding discription (★)
variable
Vescovi et al., High: only staging, no further High: only staging, no Low (★) Yes (★) High: no control of Unclear: no Unclear: no Unclear: no 2 High
2012 [50] information further information potential confounding discription discription discription
variable
Merigo et al., Low (★) N/A Low (★) Yes (★) N/A Unclear: no Yes (★) Complete 5 Medium
LLLT
Favia et al., High: treatment based on Low (★) Low (★) Yes (★) High: no control of Unclear: no Yes (★) Complete 5 Medium
2018 [51] general health potential confounding discription follow up (★)
9
variable
Scoletta et al., Low (★) N/A Low (★) Yes (★) N/A Low: Single Yes (★) Complete 6 Low
2010 [65] skilled examiner follow up (★)
(★)
Romeo et al., Low (★) N/A Low (★) Yes (★) N/A Unclear: no Yes (★) complete 5 Medium
LPRF
Park et al., 2017 Low (★) Low (★) Low (★) Yes (★) High: no control of Unclear: no yes (★) Complete 6 Low
[24] potential confounding discription follow up (★)
variable
Giudice et al., Low (★) Low (★) Low (★) Yes (★) High: no control of Low: same Yes (★) Complete 7 Low
2018 [19] potential confounding indepedent follow up (★)
variable resident (★)
Coviello et al., High: no MRONJ staging High: no MRONJ staging Low (★) Yes (★) High: no control of Low: same No: only 3 months complete 4 Medium
2012 [53] potential confounding calibrated follow up (★)
variable examiner (★)
Longo et al., High: surgical treatment if High: surgical treatment if Low (★) Yes (★) High: no control of Unclear: no Yes (★) Complete 5 Medium
2014 [54] medical therapy was medical therapy was potential confounding discription follow up (★)
insufficient insufficient variable
Szentpeteri High: only stage II or III High: based on the Low (★) Yes (★) High: no control of Unclear: no Yes (★) Complete 4 Medium
et al., 2020 duration of treatment potential confounding discription follow up (★)
[67] variable
Bocanegra-Pérez High: only stage II MRONJ N/A Low (★) Yes (★) N/A Unclear: no Yes (★) Complete 4 Medium
et al., 2012 discription follow up (★)
[55]
Dincă et al., High: only stage II MRONJ N/A Low (★) Yes (★) N/A Unclear: no No: only 30 days Complete 3 High
(continued on next page)
Bone 141 (2020) 115676
Table 4 (continued)
Author, year Representativeness of the Selection of the non- Ascertainment of Demonstration that Comparability of Assessment of Was follow up long Adequacy of Stars (n) Overall
intervention cohort intervention cohort intervention outcome of interest was cohorts on the basis of outcome enough for follow up of risk of bias
not present at start of the design or analysis outcomes to occur cohorts
D. Govaerts, et al.
study
Nørholt et al., High: only stage II or III and N/A Low (★) Yes (★) N/A Unclear: no Yes (★) Complete 4 Medium
2016 [57] intervention after failure of discription follow up (★)
medical therapy
Mauceri et al., High: only stage I & II N/A Low (★) Yes (★) N/A Unclear: no Yes (★) Complete 4 Medium
Kim et al., 2014 High: only women (★) N/A Low (★) Yes (★) N/A Unclear: no Yes (★) Complete 5 Medium
[66] discription follow up (★)
Ozone
Petrucci et al., High: no MRONJ staging N/A Low (★) Yes (★) N/A Unclear: no Unclear: no Complete 3 High
2007 [59] discription discription follow up (★)
Agrillo et al., High: no MRONJ staging N/A Low (★) Yes (★) N/A Unclear: no Yes (★) Complete 4 Medium
Agrillo et al., High: no MRONJ staging N/A Low (★) Yes (★) N/A Unclear: no Yes (★) Complete 4 Medium

Ristow et al., Low (★) Low (★) Low (★) Yes (★) High: no control of Unclear: no Yes (★) Complete 6 Low
2017 [21] potential confounding discription follow up (★)
variable
Pautke et al., High: stage II and III MRONJ N/A Low (★) Yes (★) N/A Unclear: no Unclear: no Complete 3 High
2011 [61] discription discription; follow up (★)
preliminary results
Otto et al., 2016 Low (★) N/A Low (★) Yes (★) N/A Unclear: no yes (★) Complete 5 Medium
10
[62] discription follow up (★)
Teriparatide
Kim et al., 2014 High: only osteoporisis, stage High: only osteoporisis, Low (★) Yes (★) High: no control of Unclear: no Yes (★) Complete 4 Medium
[64] II and III MRONJ stage II and III MRONJ, potential confounding discription follow up (★)
refusing TPTD treatment variable
(repulsing to self-injection)
Pelaz et al., High: no surgery possible due High: previous surgeries Low (★) Yes (★) High: no control of Unclear: no Yes (★) Complete 4 Medium
2013 [63] general condition with adverse outcome potential confounding discription follow up (★)
variable
Bovine Lactoferrin
Calvani et al., High: only stage II ONJ, only High: previous surgeries Low (★) Yes (★) High: no control of Unclear: no Yes (★) Complete 4 Medium
2018 [23] carcinomas as primary with adverse outcome potential confounding discription follow up (★)
diagnoses variable
Table 4: Newcastle-Ottawa Quality Assessment Scale for included studies.

Bone 141 (2020) 115676
Declaration of competing interest Funding
None. None.
Acknowledgements
None.
Appendix A
The search strategy used for Pubmed: (“Osteonecrosis”[Mesh] OR Osteonecros*[tiab] OR “Bisphosphonate-Associated Osteonecrosis of the
Jaw”[Mesh] OR ONJ[tiab] OR BRONJ[tiab] OR MRONJ[tiab] OR ARONJ[tiab]) AND (“Jaw”[Mesh] OR Jaw*[tiab] OR Alveolar process*[tiab] OR
tooth socket*[tiab] OR dental arch*[tiab] OR mandible[tiab] OR maxilla[tiab] OR palate[tiab]) (((“Therapeutics”[Mesh] OR “Disease
Management”[Mesh] OR Treatment*[tiab] OR Therap*[tiab] OR Disease Management[tiab]) AND (new[tiab] OR novel[tiab] OR alternative[tiab]
OR modern[tiab] OR recent[tiab] OR complementary[tiab] OR supplementary[tiab] OR adjuvant[tiab] OR accessory[tiab] OR additional[tiab])) OR
“complementary therapies”[MeSH] OR “Biological Control Agents”[Mesh] OR Biological molecule*[tiab] OR bFGF[tiab] OR BMP*[tiab] OR LPRF
[tiab] OR PRP[tiab] OR APC[tiab] OR PDGF[tiab] OR PRGF[tiab] OR PRF[tiab] OR PRT[tiab] OR “platelet-rich plasma”[tiab] OR “platelet rich
plasma”[tiab] OR “platelet concentrate*”[tiab] OR “Platelet-derived growth factor*”[tiab] OR “Platelet derived growth factor*”[tiab] OR “platelet-
rich growth factor*”[tiab] OR “platelet rich growth factor*”[tiab] OR “platelet-rich fibrin”[tiab] OR “platelet rich fibrin”[tiab] OR “leukocyte- and
platelet-rich fibrin”[tiab] OR “leukocyte and platelet rich fibrin”[tiab] OR “autologous platelet concentrate”[tiab] OR “Platelet-rich therap*”[tiab]
OR “Platelet rich therap*”[tiab] OR “Pentoxifylline”[Mesh] OR Pentoxifylline[tiab] OR Oxpentifylline[tiab] OR “Tocopherols”[Mesh] OR
Tocopherol*[tiab] OR “Ultrasonic Therapy”[Mesh] OR “Ultrasound therap*” OR “Ultrasonic therap*”[tiab] OR “Low-Level Light Therapy”[Mesh]
OR “Low-Level Light Therapy”[tiab] OR “Low Level Light Therapy”[tiab] OR “Low-level laser therapy”[tiab] OR “Low level laser therapy”[tiab] OR
LLLT[tiab] OR “Osteogenesis, Distraction”[Mesh] OR “Distraction osteogenesis”[tiab] OR “Ozone”[Mesh] OR Ozone[tiab] OR trioxygen[tiab] OR
“geranylgeraniol” [Supplementary Concept] OR geranylgeraniol[tiab] OR lactoferrin[tiab] OR lactotransferrin[tiab] OR “Hyperbaric
Oxygenation”[Mesh] OR “Hyperbaric oxygen*”[tiab] OR HBO[tiab]).
Appendix B
Details on the included studies. Level of evidence (LOE), details of the patient characteristics (number of patients (sites), mean age, women/men
ratio, primary diagnoses, stages of MRONJ, antiresorptive medication administered, location of the lesion) and details on follow-up (mean and
interval) of the included studies.
Author, year LOE Patients Mean Women/men Primary diagnoses Stages Antiresorptive Location Follow-up Follow-up interval
(sites) age ratio (%) MRONJ medication
HBO
Freiberger et al., II 46 66,2y 57,2%/ MM (39,6%) All stages BP (100%) N/A 2y 3;6;12;18;24 m
2012 [16] 42,8% BreastCa (25%) (N/S)
Other (20,4%)
Osteoporosis (14,6%)
Freiberger et al., V 16 N/A 37,5%/ MM (62,5%) N/A BP (100%) Man 1 m to post-HBO; any visit with relapse;
2007 [68] 62,5% BreastCa (18,8%) (75%) 24 m at least 1 m after therapy
ProstateCa (6,3%) Max
(12,5%)
Sarcoidosis (6,3%) Both
Waldenstrom's macro (12,5%)
globulinemia (6,3%)

Atalay et al., 2011 II 20 55,4y 65%/35% MM (55%) Stage I BP (100%) Man 6 months 2;4;6;8;10d, 1;2;3;4;5;6 m
[69] BreastCa (35%) (30%) (45%)
ProstateCa (5%) Stage II Max
NET (5%) (70%) (55%)
Angiero et al., 20 III 49 69,8y 67,3%/ MM (57,1%) Stage I BP (100%) Man 39 m N/A
09 [70] 32,7% BreastCa (16,3%) (2%) (77,6%) (mean)
ProstateCa (4,1%)
RenalCa (4,1%) Stage II
LaryngCa (2,0%) (N/S) Max
Paget (4,1%) Stage III (22,4%)
LungCa (4,1%) (N/S)
Osteoporosis (8,2%)
Vescovi et al., 20 III 151 66,9y 72,8%/ MM (37,1%) Stage I BP (100%) Man N/A N/A
12 [50] (139) 27,2% (15,9%) (62,9%)
Bone metastasis (43%) Stage II Max
(67,5%) (27,8%)
Osteoporosis (19,9%) Stage III Both
(16,6%) (9,3%)
11
Merigo et al., 2018 V 21 72,6y 76,2%/ BreastCa (33,3%) Stage I BP (100%) Man 9,6 m N/A
[17] 23,8% ProstateCa (9,5%) (9,6%) (71,4%) (mean)
PancreasCa (4,8%) Stage II
RenalCa (4,8%) (71,4%) Max
Reu Art (4,8%) Stage III (28,6%)
Osteoporosis (42,9%) (19%)
LLLT
Favia et al., 2018 III 106 70,4y 69,8%/ Oncologic (72,5%) Stage I BP (79,2%) Man 18 m 1;2;3;4w, 3;6;12 m
[51] (131) 30,2% (8,4%) (64,9%) (mean)
Non-oncologic (27,5%) Stage II Denosumab Max
(49,6%) (15,4%) (35,1%)
Stage III Both (5,4%)
(42%)
Romeo et al., 2011 V 12 62y 58%/42% MM (33,4%) Stage I BP (100%) Man 6m 1;2;3;4;5;6 m
[52] BreastCa (25%) (16,7%) (83,4%)
LungCa (8,3%) (66,6%) (8,3%)
Osteoporosis (8,3%) Stage III Both
(16,7%) (8,3%)
Scoletta et al., 20 V 20 71,3y 70%/30% MM (30%) Stage I BP (100%) N/A 8m 1;2;3;6;9;12;15 m; every 3 m
10 [65] (10%) (mean) further one
BreastCa (30%) Stage II
ProstateCa (15%) (80%)
Osteoporosis (25%) Stage III
(10%)
LPRF
Park et al., 2017 I 55 75,2y 93%/7% Bone metastasis Stage I BP (100%) Man 10 m 1;2;3;4w, 2;3;4;5;6 m
[24] (12,7%) (14,5%) (67,3%) (mean)
Osteoporosis (87,3%) Stage II Max
(78,2%) (29,1%)
Stage III Both
(7,3%) (3,6%)
Giudice et al., 20 II 47 74,7y 51%/49% MM (2,1%) Stage II BP (78,7%) Man 1 year 1;6 m, 1y
18 [19] BreastCa (23,4%) (57,4%) (74,5%)
RenalCa (10,6%) Stage III Denosumab (10,6%)
LungCa (6,4%) (42,6%) (21,3%) Both
Osteoporosis (25,5%) (14,9%)
Coviello et al., 20 III 7 75,6y 71,4%/ MM (100%) N/A BP (100%) Man 3m 15d, 1;2;3 m
12 [53] 28,6% (71,4%)
Max
(0%)
Both
(28,6%)
Longo et al., 2014 III 72 59y 83,3%/ MM (1,4%) Stage 0 BP (100%) N/A 6 m to Regular follow-up (N/S)
[54] 16,7% (6,9%) 94 m
BreastCa (75%) Stage I
(15,3%)
ProstateCa (12,5%) Stage II
(56,9%)
LungCa (11,1%) Stage III
(20,8%)
Szentpeteri et al., III 101 65,9y 73,3%/ MM (11,9%) Stage II BP (100%) Man 1y 1;2w, 1;3;6;12 m
2020 [67] 26,7% BreastCa (40,6%) (76,2%) (67,3%)
RenalCa (3,0%) Stage III (26,7%)
Other (11,9%) (23,8%) NA
Bocanegra-Pérez V 8 66y 75%/25% MM (50%) Stage II BP (100%) Man 14 m 2;4;6;10;14w
et al., 2012 [ BreastCa (25%) (100%) (87,5%) (mean)
55] Osteoporosis (25%) Max
(12,5%)
Dincă et al., 2014 V 10 59y 60%/40% MM (20%) Stage II BP (100%) Man 30d 3;5;10;30d
[56] BreastCa (30%) (100%) (70%);
ProstateCa (30%)
RenalCa (10%) Max
BowelCa (10%) (30%)
Nørholt et al., 20 V 15 68,5y 73%/27% MM (6,7%) Stage II BP (73,3%) Man 7 m to At least 6 m
16 [57] BreastCa (26,7%) (86,7%) (73,3%) 20 m
RenalCa (13,3%) Stage III Denosumab (20%)
Osteoporosis (46,7%) (13,3%) (26,7%) Both
(6,7%)
Mauceri et al., 20 V 10 75,2y 70%/30% MM (40%) Stage I BP (100%) Man 12 m 15d, 1;3;6;12 m
18 [58] BreastCa (30%) (60%) (90%)
(40%) (10%)
12
Kim et al., 2014 [ V 34 71y 100%/0% Bone metastasis (5,9%) Stage I BP (100%) Man 6m 1;2;3;4;5;6w, 2;3;4;5;6 m
66] (20,6%) (79,4%)
Osteoporosis (94,1%) Stage II
(61,8%)
Stage III Max
(17,6%) (20,6%)
Ozone
Petrucci et al., 20 V 12 72y 75%/25% MM (100%) N/A BP (100%) NA N/A N/A
07 [59]
Agrillo et al., 2007 V 33 64y 67,2%/ MM (65,6%) N/A BP (100%) Man 7m N/A
[20] 32,8% BreastCa (27,6%) (55%)
RenalCa (1,7%) (28%)
BladderCa (1,7%) Both
Rheu Art (1,7%) (17%)
Agrillo et al., 2012 V 94 57y 62,8%/ MM (43,3%) N/A BP (100%) Man 6,5 m N/A
[60] 37,2% BreastCa (31,5%) (55%)
RenalCa (6,3%) (33%)
LungCa (7,9%) Both
Osteoporosis & other (12%)
(5,5%)

Ristow et al., 2017 II 40 (51) 71,8y 65%/35% MM (10%) Stage I BP (80%) Man 1y 10d, 8w, 6 m, 1y
[21] BreastCa (45%) (7,8%) (64,7%)
ProstateCa (25%) Stage II Denosumab
RenalCa (2,5%) (80,4%) (0%) Max
LiverCa (2,5%) Stage III Both (20%) (35,3%)
Osteoporosis (15%) (11,8%)
Pautke et al., 2011 V 15 (20) 63,2y 66,7%/ MM (26,7%) Stage II BP (100%) Man 4w 2;4w, every 3 m further on
[61] 33,3% (75%) (65%)
BreastCa (53,3%) Stage III Max
ProstCa (20%) (25%) (35%)
Otto et al., 2016 V 54 (65) 71,4y 59,3%/ MM (7,4%) Stage 0 BP (87%) Man 12,9 m 1;2;3;4w,
[62] 40,7% BreastCa (37%) (1,5%) (61,5%) (mean) 2;3;4;5;6;7;8;9;10;11;12 m
ProstateCa (29,6%) Stage I
ThyroidCa (3,7%) (21,5%) Denosumab
SquamousCellCa (1,9%) Stage II (5,6%) Max
BronchialCa (1,9%) (64,6%) (38,5%)
EndometrialCa (1,9%) Stage III Both (7,4%)
Teriparatide
Kim et al., 2014 [ III 24 75,9y 91,7%/8,3% Osteoporosis (100%) Stage II BP (100%) Man 6m 1;3;6 m
64] (91,7%) (70,8%)
Stage III Max
(8,3%) (29,2%)
Pelaz et al., 2014 III 9 73,2y 100%/0% Osteoporosis (100%) NA BP (100%) Man 16,6 m 15;30;45;60;75;90d
[63] (88,9) (mean)
Max
(11,1%)
Bovine lactoferrin
Calvani et al., 20 III 26 N/A 80,8%/ BreastCa (73,1%) Stage II BP (100%) N/A 6m 1;2;3;4d, 1;2;4;8;12w, 6;12;24 m
18 [23] 19,2% ProstateCa (11,5%) (100%)
LungCa (7,7%)
LiverCa (7,7%)
Appendix A: Level of evidence (LOE), details of the patient characteristics (number of patients (sites), mean age, women/men ratio, primary diagnoses, stages of
MRONJ, antiresorptive medication administered, location of the lesion) and details on follow-up (mean and interval) of the included studies. Subdivision based on
complemntary therapy. HBO Hyperbaric Oxygenation Therapy, LLLT Low Level Laser Therapy, LPRF leukocyte-platelet rich fibrin, N/A Not available, N/S Not
specified, MM Multiple Myeloma, Ca Carcinoma, NET Neuro Endocrine Tumor, Reu Art Reumathoid Artritis, BP Bisphosphonates, Man Mandible, Max Maxilla, d
Days, w Weeks, m Months, y Year.
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Bone 141 (2020) 115676

Contents lists available at ScienceDirect

Adjuvant therapies for MRONJ: A systematic review T

ARTICLE INFO ABSTRACT

1. Introduction 6.7% or 1.9% when zoledronate or denosumab are administered re­

2. Methods The search strategy was based on a combination of Medical Subject

Fig. 1. PRISMA flow chart outlining the study selection process.

Complete healing Improvement No improvement

Laser ablation + LLLT

(continued on next page)

All the patient characteristics are presented in Appendix B. The

interval) of the included studies are presented in the table.

The adjuvant therapy is always group 1 (G1). Some articles use an

[24,50,64]. Info on the use of antiseptics, antibiotics or a conservative

3.3. Adjuvant therapies

The different adjuvant therapies are discussed in detail in Table 3.

Freiberger et al. [16,68] studied an HBO therapy after surgical

debridement. This adjuvant therapy consisted of 40 sessions at 2.0 atm

3.3.2. Laser ablation + LLLT

ablation (Er:YAG; 2940 nm) was followed by irrigation with povidone

surgical intervention in the intervention group (G1). Romeo et al. [52]

over 20 days, performing a debridement or conservative surgery was

not mentioned in the study.

Park et al. [24] performed a debridement following application of

(3000 rpm; 10 min). Giudice et al. [19] performed a debridement and

questrectomy and applied PRP as proposed by Marx et al. [71]. Longo

separate platelet concentrate). Szentpeteri et al. [67] performed a

Laser ablation + LLLT

Fluorescence guided surgery

not present at start of the design or analysis outcomes to occur cohorts

Laser ablation + LLLT

Fluorescence guided surgery

Table 4: Newcastle-Ottawa Quality Assessment Scale for included studies.

Declaration of competing interest Funding

Laser ablation + LLLT

Fluorescence guided surgery

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1. Introduction 6.7% or 1.9% when zoledronate or denosumab are administered re