Rollason 2016

Cochrane Database of Systematic Reviews
Interventions for treating bisphosphonate-related

osteonecrosis of the jaw (BRONJ) (Review)
Rollason V, Laverrière A, MacDonald LCI, Walsh T, Tramèr MR, Vogt-Ferrier NB
Rollason V, Laverrière A, MacDonald LCI, Walsh T, Tramèr MR, Vogt-Ferrier NB.

Interventions for treating bisphosphonate-related osteonecrosis of the jaw (BRONJ).
Cochrane Database of Systematic Reviews 2016, Issue 2. Art. No.: CD008455.
DOI: 10.1002/14651858.CD008455.pub2.
www.cochranelibrary.com
Interventions for treating bisphosphonate-related osteonecrosis of the jaw (BRONJ) (Review)

Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . 4
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 35
Interventions for treating bisphosphonate-related osteonecrosis of the jaw (BRONJ) (Review) i

[Intervention Review]
Interventions for treating bisphosphonate-related

osteonecrosis of the jaw (BRONJ)
Victoria Rollason1 , Alexandra Laverrière1 , Laura CI MacDonald2 , Tanya Walsh3 , Martin R Tramèr4 , Nicole B Vogt-Ferrier1
1
Division of Clinical Pharmacology and Toxicology, Department APSI, Geneva University Hospitals, Geneva, Switzerland. 2 Cochrane
Oral Health Group, School of Dentistry, The University of Manchester, Manchester, UK. 3 School of Dentistry, The University of
Manchester, Manchester, UK. 4 Division of Anaesthesiology, Department APSI, Geneva University Hospitals, Geneva, Switzerland
Contact address: Nicole B Vogt-Ferrier, Division of Clinical Pharmacology and Toxicology, Department APSI, Geneva University
Hospitals, Hopital Cantonal de Geneve, Geneva, 1211, Switzerland. [email protected].
Editorial group: Cochrane Oral Health Group.

Publication status and date: Edited (no change to conclusions), published in Issue 2, 2016.
Review content assessed as up-to-date: 15 December 2015.
Citation: Rollason V, Laverrière A, MacDonald LCI, Walsh T, Tramèr MR, Vogt-Ferrier NB. Interventions for treating bisphospho-
nate-related osteonecrosis of the jaw (BRONJ). Cochrane Database of Systematic Reviews 2016, Issue 2. Art. No.: CD008455. DOI:
10.1002/14651858.CD008455.pub2.
ABSTRACT
Background
Bisphosphonate drugs can be used to prevent and treat osteoporosis and to reduce symptoms and complications of metastatic bone
disease; however, they are associated with a rare but serious adverse event: osteonecrosis of the maxillary and mandibular bones. This
condition is called bisphosphonate-related osteonecrosis of the jaw or BRONJ. BRONJ is diagnosed when people who are taking,
or have previously taken, bisphosphonates have exposed bone in the jaw area for more than eight weeks in the absence of radiation
treatment. There is currently no “gold standard” of treatment for BRONJ. The three broad categories of intervention are conservative
approaches (e.g. mouth rinse, antibiotics), surgical interventions and adjuvant non-surgical strategies (e.g. hyperbaric oxygen therapy,
platelet-rich plasma), which can be used in combination.
Objectives
To determine the efficacy and safety of any intervention aimed at treating BRONJ.
Search methods
We searched the following databases to 15 December 2015: the Cochrane Oral Health Group Trials Register, the Cochrane Breast
Cancer Group Trials Register (20 September 2011), the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE
via Ovid, EMBASE via Ovid, CancerLit via PubMed, CINAHL via EBSCO and AMED via Ovid. We scanned the references cited
in retrieved articles and contacted experts in the field, the first authors of included papers, study sponsors, other bisphosphonates
investigators and pharmaceutical companies. We searched for ongoing trials through contact with trialists and by searching the US
National Institutes of Health Trials Register (clinicaltrials.gov) and the World Health Organization Clinical Trials Registry Platform.
We also conducted a grey literature search to September 2015.
Selection criteria
Randomised controlled trials (RCTs) comparing the effects of any treatment for BRONJ with another treatment or placebo.
Interventions for treating bisphosphonate-related osteonecrosis of the jaw (BRONJ) (Review) 1
Data collection and analysis
Two review authors independently screened the search results, assessed the risk of bias in the included trials and extracted data. When
in dispute, we consulted a third review author.
Main results
One small trial at high risk of bias met the inclusion criteria. The trial randomised 49 participants, most of whom had cancer. It
compared standard care (defined as surgery, antibiotics and oral rinses at the discretion of the oral-maxillofacial surgeon) to standard
care plus hyperbaric oxygen therapy (2 atmospheres twice a day for 40 treatments). The trial measured the percentage of participants
who improved or healed at three, six, 12 and 18 months and last contact. It also measured mean weekly pain scores.
At three months, the study found that the participants in intervention group were more likely to have an improvement in their
osteonecrosis than the standard care group participants (risk ratio (RR) 1.94, 95% confidence interval (CI) 1.01 to 3.74). There was
no clear difference between the groups for the outcome ’healed’ at three months (RR 3.60, 95% CI 0.87 to 14.82). There was no clear
difference between the groups for improvement or healing when they were evaluated at six, 12 and 18 months and last contact.
The study did not give any information on adverse events.
Although the findings suggest adjunctive hyperbaric oxygen improved BRONJ, the quality of the evidence is very low since the only
study was underpowered and was at high risk of bias due to lack of blinding, cross-over of participants between groups and very high
attrition (50% at 12 months and 80% at 18 months in this study, which was designed for an intended follow-up of 24 months).
Authors’ conclusions
There is a lack of evidence from randomised controlled trials to guide treatment of bisphosphonate-related osteonecrosis of the jaw
(BRONJ). One small trial at high risk of bias evaluated hyperbaric oxygen therapy (HBO) as an adjunct to “standard” care and could not
confirm or refute the effectiveness of HBO. There are two ongoing trials of teriparatide treatment for BRONJ. We found no randomised
controlled trials of any other BRONJ treatments. High quality randomised controlled trials are needed. We provide recommendations
for their focus and design.
PLAIN LANGUAGE SUMMARY

Interventions for treating osteonecrosis of the jaw bones associated with bisphosphonate drugs
Review question
How well do treatments for bisphosphonate-related osteonecrosis of the jaw bones, or ’BRONJ’, work and how safe are they?
Background
Bisphosphonates are drugs very similar to pyrophosphate (a normal substance found in bone). They are used to lessen symptoms and
complications due to the spread of cancer to the bones, and to prevent and treat fragile bones in osteoporosis (a conditon where tiny
holes in the bones makes them brittle). These drugs can cause a rare but serious condition called bisphosphonate-related osteonecrosis
of the jaw or ’BRONJ’. BRONJ affects the healing of bone damage by interrupting the process of removing dead bone and laying
down new bone. When this happens, parts or all of the jaw bone becomes friable (a bit like chalk), and eventually this dead bone can
be exposed. This makes it difficult for people to eat, speak or brush their teeth, and it often causes severe pain.
Many different treatments are currently used for BRONJ. They can be categorised as non-invasive treatments (such as antibiotics and
mouth rinses), surgical approaches or “add-on” treatments used to enhance usual care (for example, ozone therapy or use of blood
plasma that has been enriched with platelets). Different treatments may be combined.
Study characteristics
Review authors, working with the Cochrane Oral Health Group, carried out a thorough search up to 15 December 2015 for studies
that randomly allocated participants to different treatments for BRONJ (or to a ’placebo’ condition that has no active treatment). This
type of study design is known as a ’randomised controlled trial’. We only found one relevant completed study and two ongoing studies.
The completed study compared people with BRONJ being treated with surgery, antibiotics and mouth rinses to people receiving the
same ’standard care’ with an add-on treatment called hyperbaric oxygen therapy, which is thought to increase bone renewal. There were
49 participants, most of whom had cancer.
Key results
The study found that the participants in intervention group were more likely than the standard care group participants to have an
improvement in their osteonecrosis at three months, but there was no clear difference between the groups when they were evaluated
at six, 12 and 18 months and last contact. There was no clear difference between the groups at any time point for complete healing.
These results are not reliable as the quality of the evidence is very low. The study did not assess whether there were any side effects of
the treatment.
Quality of the evidence
The study had several important flaws: for example, there was a very small number of participants, some participants changed groups
during the study and there was a loss of participants during the study.
Authors’ conclusions
There is insufficient evidence to conclude whether hyperbaric oxygen therapy is a useful add-on to standard care in the treatment of
BRONJ. There are two ongoing trials of teriparatide, a hormonal treatment for BRONJ. We found no randomised controlled trials of
any other treatments for BRONJ. As there is a lack of good quality scientific evidence to decide how best to treat BRONJ, high quality
trials are needed.

Interventions for treating bisphosphonate-related osteonecrosis of the jaw (BRONJ) (Review) S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]
Adjunctive hyperbaric oxygen therapy compared with standard care for BRONJ
Patient or population: people with bisphosphonate-related osteonecrosis of the jaw (BRONJ)

Settings: hospital
Intervention: hyperbaric oxygen therapy in addition to surgery, antibiotics and oral rinse
Comparison: surgery, antibiotics and oral rinse
Outcomes Illustrative comparative risks* (95% CI) Relative effect No of participants Quality of the evidence Comments
(95% CI) (studies) (GRADE)
Assumed risk1 Corresponding risk
Standard care Hyperbaric oxygen ther-

apy
Healing of osteonecro- 100 per 1000 360 per 1000 RR 3.60 (0.87 to 14.82) 45 (1) very low2 Only 45 of the study’s
sis (dichotomous out- (87 to 1000) ⊕ original 49 participants
come (’healed’ vs. ’im- were assessed
proved’, ’unchanged’ and
’worse’) measured at 3
months)
Im- 350 per 1000 680 per 1000 RR 1.94 (1.01 to 3.74) 45 (1) very low2 Only 45 of the study’s
provement in osteonecro- (354 to 1000) ⊕ original 49 participants
sis (dichotomous out- were assessed
come (’healed’ and ’im-
proved’ vs. ’unchanged’
and ’worse’) measured at
3 months)
Adverse effects The included study did not measure adverse effects
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the
assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio.
4
Interventions for treating bisphosphonate-related osteonecrosis of the jaw (BRONJ) (Review)
GRADE Working Group grades of evidence

High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
1. Risk in the control group.

2. Quality of the evidence was downgraded by one level for imprecision and two levels for high risk of bias.
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5
BACKGROUND 2011). Greater drug strength, longer duration of use, older age
and a history of inflammatory dental disease are associated with a
higher risk of BRONJ (Ruggiero 2009).
Description of the condition The true incidence of BRONJ is unknown. Reported rates range
from 0.028% (Solomon 2013) to 18.6% (Walter 2008), depend-
Bisphosphonates are synthetic analogues of the endogenous sub-
ing on indication for treatment, study population and sample size.
stance pyrophosphate (a normal constituent of the bone matrix),
Our review focused specifically on the treatment of BRONJ, al-
which inhibit bone resorption and thus have a hypocalcaemic ef-
though other medications (denosumab, bevacizumab, cabozan-
fect. They are an extremely effective treatment for reducing symp-
tinib, sunitinib) have also been associated with jaw osteonecrosis,
toms and complications of metastatic bone disease and for pre-
the condition then being called medication-related osteonecrosis
venting and treating osteoporosis (Stevenson 2005; Wells 2008a;
of the jaw (MRONJ) (AAOMS 2014).
Wells 2008b; Wells 2008c). Bisphosphonate analogues differ in
activity, potency and adverse effect profiles. Bisphosphonates are
associated with a serious adverse event: osteonecrosis of the max-
illary and mandibular bones. In this condition, the affected bone Description of the intervention
becomes friable, non-viable and eventually exposed. The oral com- There is currently no ’gold standard’ of treatment for BRONJ.
plications can have negative impact on quality of life by affecting Interventions used to treat this complication are diverse, contro-
eating, speaking and maintenance of oral hygiene. versial and largely empirical. Three broad categories of interven-
The first clinical descriptions of bisphosphonate-related os- tions have been described: classical ’wound-healing’ conservative
teonecrosis of the jaw (BRONJ) are attributed to Marx and Rug- treatment, diverse surgical techniques and different “add-on” treat-
giero. In 2003, Marx described 36 cases of exposed necrotic jaw ments. These three approaches are often used in combination, ei-
bone detected in people who had been treated with intravenous ther at the same time or in succession (AAOMS 2014; Ruggiero
bisphosphonates as part of cancer therapy (Marx 2003). In June 2009).
2004, Ruggiero reported 63 additional cases of osteonecrosis of • Conservative treatment:
the jaw identified by retrospective chart review of people with the ◦ disinfectant mouth rinses (saline, chlorhexidine,
diagnosis of refractory osteomyelitis and a history of chronic bis- chlorine, peroxide);
phosphonate therapy (Ruggiero 2004). ◦ antibiotic therapy (local, systemic, or both);
According to the American Association of Oral and Maxillofacial ◦ antifungal therapy.
Surgeons Position Paper on Bisphosphonate-Related Osteonecro- • Surgical techniques:
sis of the Jaw: “Patients may be considered to have BRONJ if all ◦ surgical debridement, sequestrum removal, surgical
of the following three characteristics are present: 1) current or pre- sinus drainage procedures (antrostomy);
vious treatment with a bisphosphonate; 2) exposed bone in the ◦ extraction of teeth within osteonecrotic bone,
maxillofacial region that has persisted for more than 8 weeks; and management of implants;
3) no history of radiation therapy to the jaws. It is important to ◦ bone resection;
understand that patients at risk for BRONJ or with established ◦ surgical wound closure, reconstructive surgery, grafts;
BRONJ can also present with other common clinical conditions ◦ laser-assisted surgery;
not to be confused with BRONJ. Commonly misdiagnosed con- ◦ fluorescence-assisted surgery.
ditions may include, but are not limited to, alveolar osteitis, sinusi- • Adjuvant non-surgical treatment strategies:
tis, gingivitis/periodontitis, caries, periapical pathology, and tem- ◦ hyperbaric oxygen therapy;
poromandibular joint disorders” (Ruggiero 2009). BRONJ may ◦ pentoxifylline and tocopherol (vitamin E);
be asymptomatic or present with pain, swelling, loose teeth and ◦ ozone therapy;
altered sensation (Ruggeiro 2007). ◦ low level laser therapy (LLLT) for biostimulation, pain
Intravenous bisphosphonate treatment seems to pose a greater risk relief, anti-inflammatory treatment (erbium-doped yttrium
of BRONJ than oral administration, though oral treatment longer aluminium garnet (Er:YAG); neodymium-doped yttrium
than three years may increase the risk (Ruggiero 2009). Dentoalve- aluminium garnet (Nd:YAG), natrium-doped yttrium
olar surgery is often a precipitating factor for BRONJ symptoms aluminium perovskite (Nd:YAP), etc.);
so preventive measures include maintaining good oral hygiene and ◦ platelet-rich plasma;
undertaking any necessary dental treatment before beginning a ◦ parathyroid hormone and teriparatide;
course of intravenous bisphosphonate treatment. Some clinical ◦ bone morphogenetic protein (BMP).
guidelines recommend that people at risk of BRONJ should take
a three-month break from oral bisphosphonates before and after
dental treatment (Ruggiero 2009); however, other guidelines state How the intervention might work
there is no evidence that this reduces the risk of BRONJ (SDCEP

Treatments are empirical with different modes of action hypoth- BMP belongs to a group of growth factor cytokines. It induces
esised for each modality. the differentiation of mesenchymal cells into mature bone and has
Conservative management, with no or minimal surgical interven- been used as adjunctive therapy in different oral and mandibu-
tion, aims to provide optimal local conditions for wound healing lar reconstruction surgeries to promote bone remodelling. BMPs
and, in particular, to fight super-infection and remove necrotic for clinical use are produced using recombinant deoxyribonucleic
soft tissues as well as allowing spontaneous extrusion of bone se- acid (DNA) technology (recombinant human BMPs; rhBMPs)
questra. (Moghadam 2001; Wikesjö 2009).
Surgical techniques aim to remove dead bone and accelerate
wound closure. In severe cases, removing parts of the jaw makes
it possible to insert synthetic jaw prostheses.
Hyperbaric oxygen therapy is thought to increase bone turnover Why it is important to do this review
by stimulating osteoclast differentiation, activity and viability and Although the first case series of BRONJ was described in 2003, our
thus to represent a useful adjunctive treatment (Freiberger 2012). bibliographic search in 2010 indicated that data for the treatment
Pentoxifylline and tocopherol have been used concurrently in ra- of BRONJ was essentially empirical. Before 2010, several major
diation-induced tissue necrosis. In BRONJ treatment trials, they narrative reviews had been published (Capsoni 2006; Migliorati
are also administered together. Pentoxifylline reduces blood viscos- 2006; Woo 2006), and numerous professional associations offered
ity and improves erythrocyte flexibility, microcirculatory flow and advice as to how the condition could be prevented and how to
tissue oxygen concentrations. It also has an anti-tumour necrosis manage established disease (Khan 2008; MRHA 2006; Pazianas
factor effect and may inhibit inflammatory reactions and decrease 2007; Ruggiero 2009). These recommendations were largely based
fibrosis. It most likely has an effect in decreasing pain and accelerat- on experience and opinion. Some were issued by the pharmaceuti-
ing healing in radiation-induced tissue necrosis (Delanian 1999). cal producers of bisphosphonates themselves or by other industry-
Tocopherol is an antioxidant; its effect could influence platelet ag- sponsored associations. These findings prompted our systematic
gregation. It also impairs tissue fibrosis. review. We applied stringent criteria to trial design retaining only
Ozone (O3 ) gas has strong oxidation and antimicrobial effects randomised controlled trials (RCTs). Our conclusions offer guid-
(bactericidal, viricidal and fungicidal). It has immuno-stimulat- ance for future research.
ing and analgesic properties and acts on blood cells (erythro- The Cochrane Oral Health Group undertook an extensive pri-
cytes, leukocytes, platelets and endothelial cells), thus affecting the oritisation exercise in 2014 to identify a core portfolio of titles
microcirculation and vascular system (Azarpazhooh 2008; Bocci that were the most clinically important ones to maintain on The
2004; Saini 2011). Some researchers believe that ozone stimulates Cochrane Library (Worthington 2015). This review was identified
tissue healing through its oxidant, antimicrobial and fibro-induc- as a priority title by the oral and maxillofacial surgery expert panel
ing effects and thus can be useful in treating BRONJ (Ripamonti (Cochrane OHG priority review portfolio).
2012).
LLLT consists of applying a beam of light generated by lasers (an
abbreviated term for ’light amplification by stimulated emission of
radiation’) or light-emitting diodes on the surface of wounded tis-
sue sites so as to deliver energy in the depth of the tissues. Contrary OBJECTIVES
to high-power lasers used in surgery, LLLT is thought to modify
cell function favourably by reducing pro-inflammatory cytokines To determine the efficacy and safety of any intervention aimed at
and by increasing anti-inflammatory growth factors and cytokines. treating BRONJ.
Dosage, wavelength, site and duration of treatment all contribute
to the variability of LLLT effects (Neiburger 1999; Page 2014).
Several different types of crystals are used to focalise and amplify METHODS
the light energy. In BRONJ, the materials used for LLLT have
included Er:YAG, Nd:YAG and Nd:YAP.
Platelet-rich plasma is produced by concentrating platelets from
whole blood. It contains growth factors that are thought to be Criteria for considering studies for this review
useful for tissue healing by increasing tissue vascularisation (Lai
2015; Longo 2014).
Parathyroid hormone mediates bone remodelling. Teriparatide is Types of studies
a recombinant human parathyroid hormone. Effects are dose de-
RCTs (published or unpublished). We planned to exclude split-
pendant with intermittent low doses stimulating bone formation
mouth studies of treatments that could contaminate other sites in
through osteoblast activation. (Dayisoylu 2013).
the mouth.

Types of participants resections of the affected bone and reconstructive surgery,
Study participants could be people of any age and either sex, in including use of allografts or xenografts.
any setting, with BRONJ. Exposure to bisphosphonates could be We considered the following comparisons for this review:
past or current. We included people with cancer receiving che- • any experimental intervention (surgical or non-surgical)
motherapy, corticosteroids or hormonal therapies, as well as peo- versus none (placebo; no treatment);
ple with osteoporosis. The diagnosis of BRONJ could be clinical • any experimental intervention (surgical or non-surgical)
(AAOMS 2014; Ruggiero 2009), but preferably should have been versus an active control (surgical or non-surgical);
confirmed with radiological and histological data. • any combined intervention (e.g. surgical debridement plus
We also excluded studies of people with osteonecrosis from oc- antibiotics plus antiseptic mouthwash) versus none (placebo; no
cupational hazards (fluoride or phosphate exposure), people with treatment);
radiotherapy-induced osteonecrosis of the jaw and people with • any combined intervention (e.g. surgical debridement plus
other causes of avascular necrosis of the bone (sickle cell disease or antibiotics plus antiseptic mouthwash) versus an active control
other primarily ischaemic diseases). (surgical or non-surgical or a combined intervention).
We considered any length of treatment and, for drug therapy, all
Types of interventions administration routes.
We included studies describing the outcome of surgical or non-

surgical management of BRONJ. Types of outcome measures
Primary outcome
Definitions
• Healing of the osteonecrosis as indicated by one or more of
• By non-surgical management, we mean use of topical or
the following six indicators.
systemic interventions.
• By surgical management, we mean surgical debridement, ◦ Improvement in the clinical grade of the lesions
including necrotic bone resection, sequestrum removal or dental according to the American Academy of Oral and Maxillofacial
extraction within osteonecrotic bone, as well as more extensive Surgeons staging of BRONJ (AAOMS 2014; Ruggiero 2009).
Stage* Description*
At risk No apparent exposed/necrotic bone in people treated with oral or intravenous bisphosphonates
0 No clinical evidence of necrotic bone but non-specific clinical findings and symptoms
1 Exposed/necrotic bone in people who were asymptomatic and had no evidence of infection
2 Exposed/necrotic bone associated with infection as evidenced by pain and erythema in the region of the exposed bone with
or without purulent drainage
3 Exposed/necrotic bone in people with pain, infection and 1 of the following: pathological fracture, extraoral fistula or
osteolysis extending to the inferior border
◦ Wound healing (yes or no).

◦ Improvement in exposed bone quality (judged techniques such as: X-ray examination (improvement of sclerotic
clinically on inspection of the mouth by a dentist or a dental/oral changes, mottling and bone fragmentation, improvement of
surgeon as exposed bone that is less friable, less devitalised, less formed sequestrum or persistent extraction sockets), computed
necrotic). tomography (CT) scan, magnetic resonance imaging (MRI)
◦ Halt in bone disease progression as per imaging (surface area of the bone disease, localisation, evidence of bone

marrow disease), positron emission tomography (PET)/CT Electronic searches
imaging (decreased abnormal focal uptake) (Raje 2008). We searched the following databases:
◦ Halt in bone disease progression as visualised with • the Cochrane Oral Health Group Trials Register (to 15
doxycycline viable bone fluorescence (surface area of the bone December 2015) (see Appendix 2);
disease, localisation, evidence of bone marrow disease) (Pautke • the Cochrane Breast Cancer Group Trials Register (to 20
2009). September 2011) (see Appendix 2);
◦ Healing of sinus tract or deep periodontal pockets. • the Cochrane Central Register of Controlled Trials
(CENTRAL) (2015, Issue 1) (see Appendix 3);
• MEDLINE via Ovid (1946 to 15 December 2015) (see
Secondary outcomes Appendix 1);
• EMBASE via Ovid (1980 to 15 December 2015) (see
• Mortality rate and cause of death.
Appendix 4);
• Pain: presence and level of pain, use of analgesia during the
• CancerLit via PubMed (1950 to 15 December 2015) (see
first two weeks after intervention, use of analgesics, duration of
Appendix 5);
pain, per cent pain relief.
• CINAHL via EBSCO (1937 to 15 December 2015) (see
• Improvement of pre-existing accompanying symptoms
Appendix 6);
other than pain, such as mucosal oedema, super-infection,
• AMED via Ovid (1985 to 15 December 2015) (see
purulent discharges, fistulae to skin, or inflammatory reactions
Appendix 7);
including fever.
• the Database of Randomised Controlled Trials in
• Improvement in nutritional intake or in the ability of eating
Hyperbaric Medicine (1966 to 15 December 2015) (see
different types of food (normal diet, blended or pureed foods,
Appendix 8).
liquid diets).
• Quality of life.
• Health economic measures, such as effect on healthcare
Language
consumption, number or length of hospitalisations, health
resource use. The search attempted to identify all relevant studies irrespective
of language or alphabet. We translated papers in alphabets other
than latin.
Adverse events
• Any effect not listed as an outcome and reported as an Searching other resources
adverse effect by the authors or deemed as such by us. Two review authors (NV, VR) searched the following databases
• New or worsening signs of infection, intraoperative for ongoing trials (see Appendix 9 for the search terms used):
bleeding, medication adverse effects. • US National Institutes of Health Trials Register (
clinicaltrials.gov) (to 15 December 2015);
We decided to classify the time points for outcome measurement • The World Health Organization International Clinical
as: immediate (less than 24 hours after intervention); early (one Trials Registry Platform (apps.who.int/trialsearch/default.aspx)
to eight days after intervention) and long term (more than eight (to 15 December 2015).
days after intervention).
We conducted a cited reference search through Web of Science
and Scopus to see where our included and excluded studies had
Search methods for identification of studies been cited, to attempt to identify further clinical trials. We re-
We developed detailed search strategies for each database. These trieved the articles citing the single identified RCT from Web of
were based on the search strategy developed for MEDLINE but re- Science and Scopus and 12 non-randomised comparative studies
vised appropriately for each database to take account of differences (see Characteristics of excluded studies table) previously identified
in controlled vocabulary and syntax rules. The initial searches were from MEDLINE via Ovid and evaluated them for inclusion.
performed without an RCT filter, but subsequent top-up searches Two review authors (NV, VR) sought grey literature to 15 Septem-
combined the subject search with the Cochrane Highly Sensitive ber 2015 in the following (see Appendix 10 for the search terms):
Search Strategy for identifying randomised trials (as published in • the Grey Literature Report in Public Health of The New
Box 6.4.c in the Cochrane Handbook for Systematic Reviews of In- York Academy of Medicine (www.greylit.org);
terventions) (Higgins 2011) (Appendix 1). The search strategy was • GreyNet International (www.greynet.org);
applied without an RCT filter up to March 2013 and with the • Grey Literature for Dentistry (guides.library.utoronto.ca/
RCT filter from April 2013 to December 2015. dentistrygreylit);

• Grey Literature in the Health Sciences ( Data extraction and management
guides.library.upenn.edu/healthgreylit?hs=a); Two review authors (from NV, VR, LM, TW) selected the studies
• Open Grey (www.opengrey.eu); and extracted data independently. We resolved differences in data
• National Technical Information Service (www.ntis.gov). extraction coding by discussion. We used Review Manager soft-
To identify additional studies and results, two review authors (NV, ware (RevMan 2014).
VR) scanned the references cited in the retrieved grey literature We recorded the following data if available.
(mainly doctorate theses), but did not find any additional experi- • General characteristics - year of publication, language of
mental trials on BRONJ treatment. publication, country of origin and source of study funding.
Using email addresses on abstracts and articles, we contacted: • Trial design - sample size, method of allocation, blinding
• experts in the field; and comparative group characteristics.
• the first author of the included RCT; • Details of the participants including demographic
• study sponsors; characteristics, age, any orodental disease diagnoses, radiograph
• other bisphosphonates investigators; examinations, edentulous or not, presence of other stated
• pharmaceutical companies. medical conditions, medications and smoking habits. We
accounted for drop-outs whenever possible.
As BRONJ has only recently been more widely recognised, we • Details of exposure to bisphosphonates: ever, current or
found that much of the medical literature focused on incidence, past. Dose, route of administration.
risk factors and other epidemiological data and that trials reporting • Details on the type of intervention (see Types of
on BRONJ treatment are still in their infancy (March 2015). interventions).
• Details of the outcomes reported (see Types of outcome
measures), including method of assessment (where measurement
Data collection and analysis scales were used, we recorded whether or not they were
validated), and time intervals.
• Reported results of the interventions.
Selection of studies
Two review authors (NV, VR) sorted the identified publications by
Assessment of risk of bias in included studies
type (primary versus secondary literature) on the basis of article ti-
tle and abstract if available. We further classified primary literature Two review authors (NV, VR) appraised the risk of bias in the in-
reports according to design and applied inclusion/exclusion crite- cluded study with the tool recommended by the Cochrane Hand-
ria to select articles describing the effects of interventions designed book for Systematic Reviews of Interventions as appropriate for RCTs
to treat BRONJ. The review authors were unblinded regarding (Higgins 2011, Chapter 8.5). We referred instances of disagree-
the study author(s), their institutional affiliations and the site of ment in risk of bias assessments to one of the other members of
publication of reports. We obtained the full article for all studies the review team (MT) and resolved them by discussion.
appearing to meet the inclusion criteria or in instances where there
was insufficient information from the title, keywords and abstract
to make a decision. Two review authors independently assessed all Measures of treatment effect
studies for eligibility. We referred instances of uncertainty in the We analysed the data using standard Cochrane systematic review
study selection process to the other members of the review team methods as outlined in Higgins 2011. For dichotomous outcomes,
and ultimately resolved disagreements by mutual discussion. we expressed the estimate of effect as risk ratio (RR); for contin-
At the preliminary stage triage, the exclusion criteria were: uous outcomes, we expressed the estimate of effect as the mean
• not a primary study (e.g. guidelines, reviews, expert difference (MD) if studies reported an outcome using the same
opinions); scales, or standardised mean difference (SMD) if studies reported
• not the population of interest (e.g. cellular or animal an outcome using different scales. We calculated the 95% con-
studies, not on BRONJ and not on people with BRONJ but on fidence interval (CI) alongside the effect estimate. Where insuf-
their doctors); ficient information was reported to enable these effect measures
• other (e.g. not on BRONJ treatment). to be calculated, we provided a narrative report of the summary
measures.
This left us with interventional observations including case re-
ports, case series (separating studies with individual patient data
and studies in which results had been pooled), non-randomised
clinical trials and RCTs. Unit of analysis issues
For this publication, we included RCTs only. The unit of analysis was the individual participant.

Dealing with missing data Subgroup analysis and investigation of heterogeneity
We planned to contact study authors when necessary for clarifica- We planned to assess clinical heterogeneity by considering the
tion of data or to obtain missing data. types of bisphosphonate, participants and interventions in each
study. Such sources of heterogeneity may include, but are not
limited to:
• type and indication of the bisphosphonate therapy (people
Assessment of heterogeneity with cancer versus people with osteoporosis), route of
We planned to assess clinical heterogeneity on the basis of the par- administration (oral versus parenteral), duration of therapy;
ticipants and the interventions in the included studies. We planned • participant characteristics (age, socioeconomic status,
to undertake a meta-analysis when there were studies with suffi- setting, ethnicity, general health status, smoking);
cient similarities in the participants, interventions and outcomes. • orodental co-morbidities (prior interventions, edentulous,
We would have assessed statistical heterogeneity using the Chi2 periodontal status - type and severity of disease);
test for heterogeneity (P value < 0.1) and the I2 statistic. The I • location of the osteonecrosis (maxilla, mandible, palate,
2 values range from 0% (may not be important) to 100% (con- unilateral, bilateral);
siderable heterogeneity). The importance of the observed value of • type, duration and intensity of interventions (extent of
the I2 statistic depends on: magnitude and direction of effects and surgical excisions, length of therapy, type and route of drug
strength of evidence for heterogeneity (e.g. P value from the Chi administration, alterations in ambient pressures and length of
2 test) (Higgins 2011). exposure for hyperbaric oxygen therapy, etc.).
If we had identified other important sources of heterogeneity dur-

ing the course of the review, we would have explored and identified
Assessment of reporting biases them as post-hoc analyses.
If there had been more than 10 studies for meta-analysis, we would
have assessed possible publication bias by visually inspecting a
Sensitivity analysis
funnel plot for asymmetry. If detected, we would have carried
out further investigation using the methods described by Egger If there had been sufficient RCTs, we planned to conduct sen-
1997 for continuous outcomes and Rücker 2008 for dichotomous sitivity analyses to assess the robustness of our review results by
outcomes. repeating the analysis with the following adjustments: exclusion
We planned to assess time lag bias by comparing the dates of pub- of studies with unclear or inadequate allocation concealment and
lication of studies showing a particular intervention being effec- incomplete follow-up.
tive against the dates of publication of those studies showing no
or insignificant effect. We would also have considered multiple
publication bias and location bias and contacted study authors for Summarising results and assessing the quality of the
further details where these were suspected. evidence
We planned to verify whether effect size of the interventions was We created a ’Summary of findings’ table for each comparison and
related to publication in English language journals, MEDLINE presented summary information for the main outcomes: healing
accessibility, impact factor size, or a combination of these, but this and adverse events. Two review authors (LM, TW) assessed the
was not necessary (only one RCT identified). quality of the evidence as high, moderate, low or very low in
We planned to check for citation bias by looking at the number of accordance with GRADE criteria for study design, consistency,
times a study has been cited (Web of Science, Scopus) and whether precision and directness of results, and publication bias (GRADE
this number was influenced by the nature and direction of the 2004; Higgins 2011).
results.
Data synthesis
RESULTS
We planned to carry out a meta-analysis when pooling of the
data was clinically and statistically appropriate. We would have
used random-effects or fixed-effect meta-analyses as appropriate to
combine quantitative data. For comparisons where a meta-analysis
Description of studies
could not be carried out, we provided a narrative reporting of the See Characteristics of included studies; Characteristics of excluded
summary measures and treatment effects. studies; Characteristics of ongoing studies tables.

Results of the search pers, we excluded 12 of them because they were not randomised
Our broad search strategy retrieved 3224 articles. Two re- (see Characteristics of excluded studies table).
view authors (NV, VR) excluded those that were not primary One study met the pre-specified inclusion criteria of this review.
studies, not the population, disease or intervention of inter- This study was an unblinded, RCT on the effect of standard care
est, or where there was no intervention or no reported out- defined as surgery, antibiotics and oral rinses at the discretion of
come of the intervention. We identified two ongoing clin- the oral-maxillofacial surgeon (control group) compared to the
ical trials (ACTRN12612000950864; UMIN000009132; see same treatment and hyperbaric oxygen as an adjunct. We found
Characteristics of ongoing studies table). The 403 remaining ar- no RCTs on the therapies (conservative and surgical approaches)
ticles were classified by study design. Of these, we gave detailed recommended in the guidelines issued by most professional asso-
consideration to 13 studies with comparison groups that were po- ciations.
tentially eligible for inclusion, but after inspection of the full pa- Figure 1 shows the study flow diagram.

Figure 1. Study flow diagram.

the authors presented the data based on the treatment that was
Included studies
received rather than treatment allocated.
Only one study was eligible for inclusion in this review. The study
had 49 randomised participants (45 participants contributed data
for first analysis at three months and 18 contributed data at 18 Ongoing trials
months’ follow-up). Novartis funded the study. See Characteristics We identified two ongoing trials:
of included studies table for study details. Briefly, it was an inter- • ACTRN12612000950864 is a randomised, double-blind,
ventional, unblinded, RCT. The enrolment period was July 2006 placebo-controlled trial comparing subcutaneous teriparatide
to December 2010. The trial screened 133 participants for eligi- injections (20 µg/day) plus calcium (600 mg/day tablet) plus
bility, 49 of whom were included in the trial. vitamin D (1000 IU/day tablet) supplementation to placebo
Participants were randomised into two groups. saline injections plus calcium (600 mg/day tablet) plus vitamin
• Control group: standard care defined as surgery, antibiotics D (1000 IU/day tablet) supplementation for eight weeks in
and oral rinses at discretion of oral-maxillofacial surgeon. people treated with bisphosphonates or denosumab. The trial is
• Hyperbaric oxygen therapy group: standard care plus being conducted in Australia. The target sample is 68
hyperbaric oxygen therapy (2 atmospheres twice a day for 40 participants and follow-up will be one year. Primary outcomes
treatments). are clinical staging of osteonecrosis of the jaw and radiological
staging of osteonecrosis of the jaw. Secondary outcomes are bone
There were 27 participants in the control group and 22 in the formation and resorption markers (P1NP, beta-CTX), jaw
hyperbaric oxygen therapy plus standard care group. The partici- osteoblast activity, as measured by 18F-sodium fluoride (NaF)-
pants were outpatients (Duke referral area of central North Car- PET imaging and quality of life, as measured by Oral Health
olina and participants recruited through the internet) that had Impact Profile 14 questionnaire.
BRONJ as described by the Task Force of the American Society for • UMIN000009132 is a parallel, open, active RCT
Bone and Mineral Research (Khosla 2007). They had been treated comparing two different commercialised teriparatide
with bisphosphonates for multiple myeloma (39.6% of total sam- preparations (Forteo® versus Teribone®) for efficacy and safety
ple), breast cancer (25% of total sample), osteoporosis (14.6% of outcomes. The trial is being conducted in Japan. It will include
total sample) or another indication (20.4% of total sample). The females only and has a target sample size of 15.
mean age was 66.3 years in the control group and 66.1 years in the
standard care plus hyperbaric oxygen therapy group. At baseline,
15/27 (56%) people in the control group were women, and 13/ Excluded studies
22 (60%) people in the hyperbaric oxygen therapy group were We considered 13 abstracts to be potentially eligible for inclusion,
women. but after inspection of the full papers, we excluded 12 of them be-
The RCT reported four outcomes for a follow-up duration of up cause they were not RCTs. See Characteristics of excluded studies
to 24 months: table.
• change from baseline in oral lesion size and number
(translated into a binary outcome variable, i.e. healed or Risk of bias in included studies
improved versus unchanged or worse);
• time to improvement;
• pain;
Allocation
• quality of life.
The generation of the randomisation sequence was not reported.
The trial authors reported that two outcomes would be reported Concealment of allocation was done using opaque envelopes. Se-
in a separate publication: lection bias may be present, so we judged the level of risk to be
• serum measurements of bone turnover; unclear.
• bone turnover signalling.
Time points for collection of the oral lesion data were baseline, Blinding
three, six, 12, 18 and 24 months (or at last contact). Pain was We assessed the risk of performance and detection bias as high.
assessed weekly. Quality of life was assessed at baseline and six Study personnel were not blinded to therapy. In regards to change
months. There was some cross-over of participants from their al- from baseline in oral lesions size and number, the oral-maxillofacial
located treatment arm to the alternative trial arm. For this reason, surgeon was not told the participants’ assignments before the initial

staging examination. On subsequent assessments, the evaluators with no exposed bone) or otherwise and healed or improved (de-
were not blinded to treatment group. The participants were not crease in size or number of baseline lesions) or otherwise). Scores
blinded to therapy. were based on direct observation by the study’s oral-maxillofacial
surgeon. However, if a participant died, was unable to return to
Duke University Medical Center or was lost to follow-up, lesion
Incomplete outcome data
scores were based on the notes of the last scheduled or unsched-
We assessed the risk of attrition bias as high. The last contact was uled Duke University Medical Center contact or on reports from
intended to be 24 months after consent; however, if a person died, local or referring physicians in the person’s home town. The study
was unable to return to the investigation site or was lost to follow- investigators assessed only two of our secondary outcomes of in-
up, lesion scores were based on the notes of the last contact or on terest, pain and quality of life. Pain was self assessed using a 0-
reports from physicians in the person’s home town. The attrition to 10-point Likert scale. Quality of life was self assessed using the
rate was very high. At the 12-month evaluation, 50% of partici- Duke Health Profile, a 17-question instrument with six health do-
pants were lost to follow-up and at 18 months, only approximately mains (physical, mental, social, general, perceived health and self
20% of participants were available for analysis. Thirteen out of 49 esteem) and four dysfunction measurements (anxiety, depression,
participants did not complete all follow-up visits. At the end of pain and disability).
the study, 15/49 participants had died (three early deaths). The Outcomes based on the change in lesion scores were measured at
missing outcome data were not balanced between the intervention each time point. Visits were scheduled at baseline, three, six, 12
groups (at the end of the follow-up period, there were six partic- and 18 months. Pain was measured weekly and quality of life was
ipants left in the standard care group and 12 in the hyperbaric measured at baseline and six months.
oxygen therapy plus standard care group). Except for one participant in the standard care group who contin-
ued bisphosphate administration for one month after the initial
Selective reporting evaluation, all participants discontinued bisphosphonates before
or at the time of consent.
All clinical data mentioned in ClinicalTrials.gov were reported
in the trial publication. However, some laboratory results (serum
measurements of bone turnover and bone turnover signalling) were
Primary outcome
withheld. As these were not primary outcomes and the trial authors
stated that they would be reported in a separate publication, we
assessed the risk of reporting bias as low.
Healing of the osteonecrosis
The RCT reported healing of osteonecrosis as change from base-
Other potential sources of bias
line in oral lesion size and number, and clinical severity (Freiberger
Five participants crossed over from the standard care group to the 2012).
hyperbaric oxygen therapy plus standard care group (especially Possible outcomes were:
three late cross-overs) and one participants crossed over from the • healed (gingival coverage with no exposed bone);
hyperbaric oxygen therapy plus standard care group to the standard • improved (decrease in size or number of baseline lesions);
care group. Analysis of data was done by treatment group and • unchanged (no change in size or number of baseline
not by intention-to-treat. We assessed the risk of other potential lesions);
sources of bias as high. • worse (increase in size or number of baseline lesions
compared with their condition at the time of consent).
Effects of interventions There was some evidence of a beneficial effect of hyperbaric oxy-
gen therapy for ’improvement’ (’healed’ plus ’improved’ versus
See: Summary of findings for the main comparison Adjunctive
’unchanged’ and ’worse’) at the first time point evaluated (three
hyperbaric oxygen therapy compared with standard care for
months: RR 1.94, 95% CI 1.01 to 3.74), but this was not demon-
BRONJ
strated at any other time points. For the outcome ’healed’ (’healed’
We identified only one eligible study with a single comparison
versus ’improved’, ’unchanged’ and ’worse’), the range of effects
(hyperbaric oxygen as an adjunct to standard care (surgery and
contained within the CIs included both no effect of the interven-
antibiotics)) (Freiberger 2012), and presented this data at multiple
tion and some effect of the intervention for all time points. Table
time points as an additional table (Table 1). The study was at high
1 details the effect estimates and 95% CIs.
risk of bias.
Our primary outcome, healing of the osteonecrosis, was reported
as a change from baseline in oral lesion size and number (trans-
Secondary outcomes
lated into a binary outcome variable, i.e. healed (gingival coverage

Pain reports, as they have not been investigated in RCTs. The only com-
The study authors recorded pain scores weekly using a 0- to 10- pleted RCT of BRONJ treatment investigated an adjunctive ther-
point Likert scale (0 = no pain) and calculated the change ref- apy, hyperbaric oxygen therapy. Two RCTs evaluating teriparatide
erenced to the initial value (Freiberger 2012). Sixteen of the 42 are ongoing.
participants evaluated for pain did not report any pain at baseline.
There was no difference in baseline pain scores between the two
treatment groups before hyperbaric oxygen therapy. This outcome
was incompletely reported, presented as figures and a narrative Overall completeness and applicability of
only; it reported no numerical summary statistics for pain, mean- evidence
ing that we could not carry out a re-analysis for this outcome.
The only eligible RCT was an evaluation of adjunctive therapy
The authors of the study reported that “subjects with pain who
(hyperbaric oxygen) for people undergoing surgery (Freiberger
received hyperbaric oxygen therapy exhibited a rapid decrease in
2012). It was unblinded and loss to follow-up was substantial.
pain within the first three weeks of therapy. Pain scores decreased
We could draw no definitive conclusions as to the efficacy of hy-
from baseline for 2 groups over the course of the study” and “the
perbaric oxygen therapy. There are only two ongoing RCTs, one
change in average weekly pain score in the hyperbaric oxygen ther-
evaluating teriparatide treatment for BRONJ versus placebo and
apy and control groups differ (P < 0.01, linear regression) from
the other comparing two types of teriparatide treatment. There
week 1 to week 16 (P not significant at >16 weeks)”.
is no blinded RCT on any other treatment applied at present to
people with BRONJ, although we know that there are thousands
of these iatrogenic cases treated worldwide.
Quality of life
The study investigators measured self reported quality of life at
baseline and six months’ follow-up using the generic Duke Health
Profile (Freiberger 2012). They reported only within-group com-
Quality of the evidence
parisons for each of the domains. As summary statistics were not
reported, we were unable to present or re-analyse the data to pro- Extensive review of the literature on BRONJ treatment identified
vide between-group comparisons. only one completed RCT, which constitutes the body of evidence
of this review. Overall evidence from this trial of hyperbaric oxy-
gen adjunctive therapy for people undergoing surgery is under-
Other secondary outcomes mined by its unblinded design, low number of participants and
high attrition rate. A serious concern is the underpowered nature
The trialists did not measure our other secondary outcomes (mor-
of the study (they did not meet the required sample size of 70 par-
tality rate and cause of death, improvement of pre-existing accom-
ticipants and the proportion of cross-over). Therefore, we down-
panying symptoms other than pain, improvement in nutritional
graded the quality of the evidence to very low. We could draw
intake or in the ability of eating different types of food, health
no definite conclusions regarding the effectiveness of hyperbaric
economic measures) (Freiberger 2012).
oxygen therapy as an add-on therapy for BRONJ treatments. No
other treatment modalities can be reported upon.
Adverse events
The study reported no information on adverse events (Freiberger
2012).
Potential biases in the review process
Finding only one RCT raises the question of potential selection
bias. Since the initial publication of the protocol for this review in
2010 (Vogt-Ferrier 2010), the review process has been extensive
DISCUSSION and systematic. The Cochrane Oral Health Group Trials Search
Co-ordinator (Anne Littlewood) performed all searches in the
databases, apart from those for grey literature and the hyperbaric
oxygen therapy database (carried out by NV and VR) and the
Summary of main results search strategy was intentionally very wide. We applied no lan-
Classical ’wound-healing’ conservative treatments and surgery are guage restriction. Alexandra Laverrière contacted about 200 ex-
the two treatments most frequently used for BRONJ. These treat- perts and authors in hopes of getting additional data. We believe
ments are employed empirically, drawing on the many case-series that selection bias was avoided.

Agreements and disagreements with other • Diagnosis and staging of the disease should be assessed with
studies or reviews standardised reproducible scales. Included participants should be
registered in a centralised pharmacovigilance database, such as
Recently, there have been several other systematic and literature
the World Health Organization Vigibase or Eudravigilance and
reviews of treatments for BRONJ (Fliefel 2015; Khan 2015; Rupel
the worldwide unique number available to identify participants
2014; Silva 2016; Spanou 2015). These reviews included all types
included in several treatment trials.
of trial designs while our review focused on RCTs. Our litera-
• Randomisation should be carried out and described in
ture search was more comprehensive with 12 different databases
sufficient detail to allow an assessment of whether it produced
searched, a wide time span, a thorough grey literature search, con-
comparable groups. The participant should be the unit of
tact with authors and experts, identification of ongoing trials and
randomisation and analysis, rather than individual BRONJ sites
no language restriction. All reviews agree that management of
(Jull 2015).
BRONJ remains controversial and that there is no definitive stan-
• Allocation concealment should be carried out and described
dard of care for this disease. All conclude that controlled studies
in sufficient detail to determine whether intervention allocations
should be performed.
could have been foreseen in advance of, or during, enrolment.
• Blinding of participants or personnel (preferably both)
should be done. While it may be very difficult to blind
participants and medical professionals with regard to surgical
AUTHORS’ CONCLUSIONS interventions, as well as to certain aspects of minimally invasive
conservative management (such as wound exudate removal, or
Implications for practice necrotic tissue debridement), it is possible to blind outcome
assessors, or to use photography and computer programmes to
There is a lack of evidence from randomised controlled trials to
measure wound size. The methods used for blinding the
guide treatment of bisphosphonate-related osteonecrosis of the jaw
outcome assessors should be described providing information to
(BRONJ). Treatment should be determined for each individual
whether the proposed blinding was effective.
situation based on clinical judgement and patient preference.
• Common, quantifiable and clinically relevant endpoints
(time to complete wound healing, pain, treatment acceptability
Implications for research
and participant satisfaction), including objective measurements
The Freiberger 2012 randomised controlled trial on hyperbaric if possible, should always be used. When continuous or
oxygen therapy as an adjunct to standard surgical care involved categorical data are synthesised in binary outcomes, the
a small number of participants and was at high risk of perfor- procedure should be clearly described and justified.
mance, detection and attrition bias. Therefore, it cannot be used • Research must adopt a survival approach for the analysis of
to support or refute a benefit for adjunctive hyperbaric oxygen time-to-event data, such as time to healing.
therapy in treating BRONJ. Two trials are currently underway to • A sufficiently long follow-up period of at least six months is
evaluate teriparatide treatment for BRONJ. This systematic re- essential if treatment effects on indolent, often long-standing
view has identified the need for well-designed, adequately powered BRONJ sites are to be detected. This can be difficult in people
randomised controlled trials to assess the benefits of all proposed with cancer with short life expectancy.
treatments for BRONJ. • When working with people with cancer, attrition bias can
weaken treatment protocols. The completeness of outcome data
The implications for further research arising from this review fall
for each main outcome, including attrition and exclusions from
into two categories: improving the conduct and reporting of future
the analysis must be fully described.
research, and specifying important research questions.
• A systematic collecting and thorough reporting of adverse
events is required. Structured questionnaires should be designed
Improving the conduct and reporting of future with a standardised terminology such as MedDRA (Medical
research Dictionary for Regulatory Activities).
• An estimation of costs should complete the clinical
Most treatment centres offer multimodal treatments combining
evaluation of treatments.
conservative treatment with surgical techniques and sometimes
more innovative non-surgical treatments. Therefore, it has been Apart from the above general recommendations, the following rec-
impossible to establish the efficacy of individual treatment options. ommendations are specific for multimodal treatment modalities.
In general, for all BRONJ treatment research protocols, either sin- • Studies should be clearly presented as being multimodal
gle or combined modalities, the following rules should be applied that is multicomponent and multilevel interventions. The
(Higgins 2011). putative underlying mechanisms of action of combined
interventions, the elements identified as the “active” intervention

of this combined healthcare programme, and the factors that We have found few data on which antibiotics are given, at what
mediate and moderate its effectiveness should be described as dose, by which route, for how long and to which participants.
precisely as possible. The following two examples illustrate this Comparisons of the effectiveness of various antibiotics and their
general principal and were weaknesses we found in actual studies risks are mostly lacking.
on BRONJ treatment: in a study on the distinctive role of How important is stopping bisphosphonates once BRONJ is
teriparatide on intractable BRONJ, all participants received present in view of the long “half-life” of these drugs?
“conventional care with or without sequestrectomies” but no No-one appears to have made an inventory of the various mouth
description of this management (e.g. which antibiotics were rinses used throughout the world and how they are applied un-
given, at which dose and duration) and which participants der such commonly used terms as ’good oral hygiene’ or ’standard
underwent surgery was available. Another example could be conservative management’ (Fernandez 2012). We do not know
when a multicentric study offers a certain treatment to all whether disinfectant mouth rinses are better than saline mouth-
participants but follow-up is entrusted to different local washes or just frequent rinses with tap water for improving the
healthcare settings to avoid long-distance travelling to sick oral status of the mouth. Regardless of the liquid solution used, is
participants, the effect of the setting (in which the follow-up care the volume or temperature of the mouth rinse important? We do
is given), as a contextual factor, should also be explored and not know how often people use them at home. Should it be done
described. daily? Less or more?
• Investigators planning complex interventions should As for antifungal treatments, are they formulated simply as mouth
include a graphical description of the important elements and rinses? Are they swallowed? Which ones are prescribed? How do
relationships between the different components of the they compare? When should they be prescribed? For how long?
management strategy. Is nutritional state an important factor to promote healing of
• A means to bypass the problems associated with BRONJ? Many people have cancer or are elderly, or both, and the
multimodal intervention studies, especially when exploring the mouth lesion can in itself impair adequate feeding either because
efficacy of new treatment modalities, could be to standardise the of the pain, or the dysguesia or through loss of appetite. How
conservative care and the surgery in order to show the efficacy of do well-nourished people with BRONJ compare to malnourished
the added intervention only. people with BRONJ?
• Multimodal studies should be built as to include multiple Moreover, does immunosuppression state make a difference to the
treatment arms, with stratification by BRONJ staging and BRONJ healing outcome?
participant co-morbidities.
Such research can only be accomplished by multicentric collabora-

Surgical techniques
tion or referral to a single designated specialised centre with a very
large geographic recruitment. In these conditions, randomised Surgery has been defined as a medical speciality that uses opera-
controlled trials exploring single modalities are more simple to tive manual and instrumental techniques. Timing, type of partic-
design and could bring clearer answers but are farther from the ipants, type of procedure, degree of invasiveness and instruments
(complex) clinical reality (Petticrew 2013). used are all differentiating features of surgical operations. Most
publications do not give sufficient detail on the procedures used
for other surgeons to reproduce the technique.
Important research questions Very broadly, answers to such basic questions as the following
could be useful.
There is currently no ’gold standard’ of treatment for BRONJ.
• Is it better to operate early or later? Should surgery be
Three broad categories of interventions have been described: clas-
reserved for cases failing conservative management?
sical conservative wound healing management, surgery and “add-
• Do people who receive preoperative anti-infective
on” adjuvant treatments.
preparation do better than those who do not?
• Does the type of anaesthesia or analgesia affect outcome?
• When is debridement sufficient? How long should one wait
Conservative treatment for spontaneous extrusion of the diseased bone (sequestrum)?
Classical ’wound-healing’ conservative management mainly im- • As in other types of resective oral surgery, do nerves and
plies minimising environmental factors that are known to impair other tissue parts need particular care? (Coulthard 2014).
tissue healing and fighting infection. In BRONJ treatment, this • Should surgeons endeavour to remove only BRONJ-
includes promoting oral hygiene, using topical treatments (’mouth affected bone or can more extensive removal of bone facilitate
rinses’, disinfectant or not) and systemic anti-infective therapy. prosthetic reconstruction of the jaw and healing?
Many aspects of these conservative treatments would be interest- • What instruments should be used? Does laser-assisted or
ing to research. fluorescent-assisted surgery improve the outcome? If so, what

protocols are effective? We wish to acknowledge the financial support and encouragement
• Does perioperative drainage, placement of drains or delayed provided by the 2007 IADR Evidence-Based Dentistry Network
closure affect the incidence of bleeding, swelling, pain or Systematic Review Award received for the development of the
infection? protocol of this systematic review.
• How to best close the surgical site (flaps, types of sutures)?
• What is the best treatment for fistulae or other We thank the editorial team at the Cochrane Oral Health
complications (sinus drainage)? Group, especially Anne Littlewood, Janet Lear, Helen Worthing-
ton, Jan Clarkson, Ruth Floate, Philip Riley and Luisa Fernandez
Mauleffinch. We thank Prof Mikako Hayashi and Asaf Achiron for
Innovative non-surgical adjuvant treatments
translating records that were in Japanese and Hebrew. We thank
The following treatments have been used as adjuvant treatments Ian Needleman, Samantha Rutherford and Bosun Hong for useful
in people with BRONJ: feedback and Anne Lawson for copy editing the review.
• hyperbaric oxygen therapy;
• pentoxifylline and tocopherol (vitamin E); We thank the following authors for their kind response to our re-
• ozone therapy; quests for additional information: Prof M. Baciut, Dr S. Abi Najm,
• low level laser therapy for biostimulation, pain relief, anti- Dr P. Chaturvedi, Dr M. Curi, Prof P. Vescovi, Dr A. Villa, Dr F.
inflammatory treatment (erbium-doped yttrium aluminium Saad, Dr O. Nicolatou-Galitis, Dr A. Bedogni, Dr M. Knezevic,
garnet (Er:YAG); neodymium-doped yttrium aluminium garnet Dr S. Pozzi, Dr C. Pigrau, Dr M. Vieillard, Dr J. Fellows, Dr C.
(Nd:YAG), natrium-doped yttrium aluminium perovskite (Nd: Ortega, Dr B. Stack, Dr D. Aguiar-Bujanda, Prof P. Da Silva San-
YAP), etc.); tos, Dr N. La Verde, Dr M. Mozzati, Dr V. Fucsco, Dr S. Hoefert,
• platelet-rich plasma; Dr I. Kaplan, Dr A. Badros, Dr B. Balla, Prof M. Dimopoulos,
• parathyroid hormone and teriparatide; Dr T. Fehm, Dr J. Toro, Prof G. Campisi, Dr Y Ohbayashi and
• bone morphogenetic protein. Prof P Ebeling.
Researchers designing trials for adjuvant treatments should fol-
low the recommendations for multimodal treatments as described We thank Laura MacDonald and Tanya Walsh for joining the
above. author team in December 2015.
We thank Dr Brigitte Uebelhart and Dr M Hugentobler for their

support and advice in the initial phase of this project and their par-
ticipation in writing the protocol. Brigittte taught us about bone
ACKNOWLEDGEMENTS
metabolism and bisphosphonates and Max shared his first-hand
We thank Prof M Richter, R Rizzoli, J Desmeules and P Dayer for clinical knowledge of this disease. Both convinced us that endeav-
their support of our academic work. ouring to improve its prevention and treatment was important.
REFERENCES
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∗
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∗
evaluation of alendronate, etidronate, risedronate, raloxifene Indicates the major publication for the study

CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Freiberger 2012
Methods Interventional, prospective, unblinded, randomised controlled trial
Participants 133 participants assessed; 49 consented (84 excluded or declined to participate); 27

control (standard care), 22 experimental (HBO and standard care)
Outpatients (Duke referral area of central North Carolina and participants recruited
through internet)/university medical centre; USA
Mean age: control group 66.3 years/HBO group 66.1 years
Sex: control group 55.6% female/HBO group 59.1% female
Condition treated with bisphosphonates: multiple myeloma (39.6% of total sample),
breast cancer (25% of total sample), osteoporosis (14.6% of total sample), other indica-
tion (20.4% of total sample)
Interventions Group 1: standard care defined as surgery, antibiotics and oral rinses as needed at dis-
cretion of oral-maxillofacial surgeon
Group 2: standard care + HBO (2.0 atmospheres for 2 hours twice a day for 40 treatments)
Outcomes 4 outcomes reported:

• change from baseline in oral lesion size and number (translated into a binary
outcome variable, i.e. healed or improved vs. unchanged or worse)
• time to improvement
• pain
• quality of life
2 to be reported in a separate publication:
• serum measurements of bone turnover
• bone turnover signalling
Time points for main outcome of healing were at 0, 3, 6, 12, 18 and 24 months (or at
last contact)
Pain levels were assessed weekly through telephone or email contact from study co-
ordinator
Quality of life was assessed at baseline and 6 months
Notes Participants were enrolled from July 2006 to December 2010. Study duration was not
mentioned but participants were followed-up for 2 years
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection Unclear risk Generation of randomisation sequence not
bias) reported
Allocation concealment (selection bias) Low risk Concealment of allocation using opaque
envelopes

Freiberger 2012 (Continued)
Blinding of participants and personnel High risk Participants and staff not blinded to ther-
(performance bias) apy
All outcomes
Blinding of outcome assessment (detection High risk In regards to change from baseline in oral
bias) lesion size and number, the oral-maxillofa-
All outcomes cial surgeon was not told the participants’
assignments before the initial staging ex-
amination. On subsequent assessments, the
evaluators were not blinded to treatment
group
Incomplete outcome data (attrition bias) High risk The attrition rate was very high. At the
All outcomes 12-month evaluation, 50% of participants
were lost to follow-up and at 18 months,
only about 20% of participants were avail-
able for analysis. 13/49 participants did not
complete all follow-up visits. At the end of
the study, 15/49 participants had died (3
early deaths). The missing outcome data
were not balanced between the interven-
tion groups (at the end of the follow-up pe-
riod, there were 6 participants in the stan-
dard care group and 12 participants in the
standard care + HBO group)
Selective reporting (reporting bias) Low risk All collected clinical data mentioned in
ClinicalTrials.gov were reported in the pub-
lication. However, some laboratory results
(serum measurements of bone turnover and
bone turnover signalling) were withheld.
These were not primary outcomes and the
authors clearly stated that they would be
reported in a separate publication
Other bias High risk 5 cross-overs from standard care group to

standard care + HBO group (especially 3
late cross-overs) and 2 cross-over from stan-
dard care + HBO to standard care group.
Analysis of data was done by treatment
group and not by intention-to-treat
HBO: hyperbaric oxygen therapy.

Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Atalay 2011 Not an RCT
Gasparini 2010 Not an RCT
Graziani 2012 Not an RCT

Duplicated subject-per-report bias
Kim 2014 Not an RCT
Lee 2014 Not an RCT
Manfredi 2011 Not an RCT

Pelaz 2014 Not an RCT
Vescovi 2007 Not an RCT


Vescovi 2012a Not an RCT

Vescovi 2012b Not an RCT


RCT: randomised controlled trial.
Characteristics of ongoing studies [ordered by study ID]
ACTRN12612000950864
Trial name or title Does Teriparatide Reverse Osteonecrosis of the Jaw in Patients Treated with Either Bisphosphonates or
Denosumab? A Randomised, Controlled Trial
Methods Prospective, randomised, double-blind, placebo-controlled study

ACTRN12612000950864 (Continued)
Participants Men and women 18 years or older. Target sample size = 68

Exclusion criteria:
• previous craniofacial radiotherapy
• pregnancy
• hypercalcaemia or pre-existing primary hyperparathyroidism
• severe renal impairment (eGFR < 30)
• Known metabolic bone disease, excluding osteoporosis or metastatic bone disease
• Growth hormone deficiency
• Secondary hyperparathyroidism with parathyroid hormone greater than 2-fold above upper limit of
reference range
Interventions Group 1: subcutaneous teriparatide injections (20 µg/day) + calcium (600 mg/day tablet) + vitamin D (1000
IU/day tablet) supplementation
Group 2: placebo saline injections + calcium (600 mg/day tablet) + vitamin D (1000 IU/day tablet) supple-
mentation for 8 weeks
Outcomes Primary outcomes: clinical staging of osteonecrosis of the jaw and radiological staging of osteonecrosis of the
jaw, as assessed by cone beam CT
Secondary outcomes: bone formation and resorption markers (P1NP, beta-CTX), jaw osteoblast activity, as
measured by NaF-PET imaging and quality of life, as measured by Oral Health Impact Profile 14 questionnaire
1-year follow-up
Starting date 11 September 2012
Contact information [email protected]
Notes We contacted the trial author (Peter Ebeling) and he responded to let us know that the trial will be completed
in April 2016 and the data submitted for publication in second half of 2016
Conducted in University of Melbourne, Australia
UMIN000009132
Trial name or title Study to the Effect of Teriparatide Formulation Forteo versus Teribon on Bisphosphonate-Related Osteonecro-
sis of the Jaw in Osteoporosis Patients
Methods Parallel, randomised, open study
Participants Women, aged ≥ 20 years; target sample size = 15

Inclusion criteria: female outpatients with bisphosphonate-related osteonecrosis of the jaw who require con-
tinued treatment for osteoporosis and whose stage of bisphosphonate-related osteonecrosis of the jaw is ≥ 2.
Signed informed consent forms must be obtained
Exclusion criteria:
• hypercalcaemic disorders
• potential risk of osteosarcoma
• people with Paget’s disease of bone
• unexplained elevations of alkaline phosphatase
• young adults with open epiphyses
• people with prior external beam or implant radiation involving the skeleton

UMIN000009132 (Continued)
• people with bone metastases, history of skeletal malignancies

• metabolic bone diseases other than osteoporosis
• pregnancy or women with suspected pregnancy
• people with hypersensitivity to teriparatide or to any of its excipients
• serious cardiac disease, serious hepatic disorder, renal disease
• use of active vitamin D3 or digoxin
• no informed consent
• unsuitability for the trial based on clinical judgement
Interventions Teriparatide as Forteo® vs. teriparatide as Teribone®
Outcomes Efficacy and safety (pain and bone formation)
Starting date 28 August 2012
Contact information [email protected]
Notes We contacted the trial author (Yumiko Ohbayashi) who confirmed that the study still has another 1-2 years
to run
Conducted in Kagawa university in Japan
CT: computed tomography; eGFR: estimated glomerular filtration rate; NaF-PET: 18F-sodium fluoride positron emission tomography.

DATA AND ANALYSES
This review has no analyses.
ADDITIONAL TABLES
Table 1. Effects of interventions - healing
Time point Improved HBO Total HBO Improved standard care Total standard care RR (95% CI)
3 months 17 25 7 20 1.94 (1.01 to 3.74)
6 months 16 23 9 17 1.31 (0.78 to 2.22)
12 months 11 15 4 9 1.65 (0.75 to 3.64)
18 months 7 12 2 6 1.75 (0.51 to 5.98)
Last contact 17 25 8 21 1.78 (0.97 to 3.28)
Time point Healed HBO Total HBO Healed standard care Total standard care RR (95% CI)
3 months 9 25 2 20 3.60 (0.87 to 14.82)
6 months 9 23 7 17 0.95 (0.44 to 2.04)
12 months 6 15 3 9 1.20 (0.39 to 3.65)
18 months 4 12 2 6 1.00 (0.25 to 4.00)
Last contact 13 25 7 21 1.56 (0.77 to 3.18)

CI: confidence interval; HBO: hyperbaric oxygen therapy; RR: risk ratio.

APPENDICES
Appendix 1. MEDLINE via Ovid search strategy

1. Osteonecrosis/
2. (osteonecro$ or “bone necrosis”).mp. [mp=title, original title, abstract, name of substance word, subject heading word]
3. osteochemonecro$.mp. [mp=title, original title, abstract, name of substance word, subject heading word]
4. or/1-3
5. exp Jaw/
6. Jaw Diseases/ci [Chemically Induced]
7. Alveolar Bone Loss/ci [Chemically Induced]
8. (jaw$ or jawbone$ or mandib$ or maxill$ or (alveolar adj4 bone)).mp. [mp=title, original title, abstract, name of substance
word, subject heading word]
9. or/5-8
10. 4 and 9
11. exp Diphosphonates/
12. (diphosphonate$ or bisphosphonate$ or aminobisphosphonate$ or alendronate or risedronate or pamidronate or “zoledronic
acid” or ibandronate).mp. [mp=title, original title, abstract, name of substance word, subject heading word]
13. (“etidronate disodium” or didronel or “clodronate disodium” or Bonefos or “Tiludronate disodium” or Skelid or Fosamax or
Aredia or Actonel or Zometa or Boniva).mp. [mp=title, original title, abstract, name of substance word, subject heading word]
14. or/11-13
15. 10 and 14
The searches were done without an RCT filter up to April 2013, a top-up search was performed with the RCT filter below in January
2015.
The Cochrane Highly Sensitive Search Strategy (CHSSS) for identifying randomised trials in MEDLINE: sensitivity maximising
version (2008 revision) as referenced in Chapter 6.4.11.1 and detailed in box 6.4.c of The Cochrane Handbook for Systematic Reviews
of Interventions, Version 5.1.0 [updated March 2011].
1. randomized controlled trial.pt.
2. controlled clinical trial.pt.
3. randomized.ab.
4. placebo.ab.
5. drug therapy.fs.
6. randomly.ab.
7. trial.ab.
8. groups.ab.
9. or/1-8
10. exp animals/ not humans.sh.
11. 9 not 10
Appendix 2. The Cochrane Oral Health Group Trials Register/the Cochrane Breast Cancer Group
Trials Register search strategy
(osteonecros* or “bone necrosis” or osteochemonecros*)

Appendix 3. The Cochrane Central Register of Controlled Trials (CENTRAL) search strategy
#1 MeSH descriptor Osteonecrosis this term only
#2 (osteonecro* in All Text or “bone necrosis” in All Text)
#3 osteochemonecro* in All Text
#4 (#1 or #2 or #3)
#5 MeSH descriptor Jaw explode all trees
#6 MeSH descriptor Jaw Diseases this term only
#7 MeSH descriptor Alveolar Bone Loss this term only
#8 (alveolar in All Text near/4 bone* in All Text)
#9 (jaw* in All Text or mandibl* in All Text or maxill* in All Text)
#10 (#5 or #6 or #7 or #8 or #9)
#11 (#4 and #10)
#12 MeSH descriptor Diphosphonates explode all trees
#13 (diphosphonate* in All Text or bisphosphonate* in All Text or
aminobisphosphonate* in All Text or alendronate in All Text or risedronate in All Text or pamidronate in All Text or “zoledronic acid”
in All Text or ibandronate in All Text)
#14 (“etidronate disodium” in All Text or didronel in All Text or “clodronate disodium” in All Text or Bonefos in All Text or “Tiludronate
disodium” in All Text or Skelid in All Text or Fosamax in All Text or Aredia in All Text or Actonel in All Text or Zometa in All Text or
Boniva in All Text)
#15 (#12 or #13 or #14)
#16 (#11 and #15)
Appendix 4. EMBASE (Ovid) search strategy

1. Osteonecrosis/
2. (osteonecro$ or “bone necrosis”).mp. [mp=title, original title, abstract, name of substance word, subject heading word]
3. osteochemonecro$.mp. [mp=title, original title, abstract, name of substance word, subject heading word]
4. or/1-3
5. exp Jaw/
6. Jaw Diseases/
7. Alveolar Bone Loss/
8. (jaw$ or jawbone$ or mandib$ or maxill$ or (alveolar adj4 bone)).mp. [mp=title, original title, abstract, name of substance
word, subject heading word]
9. or/5-8
10. 4 and 9
11. exp Diphosphonates/
acid” or ibandronate).mp. [mp=title, original title, abstract, name of substance word, subject heading word]
Aredia or Actonel or Zometa or Boniva).mp. [mp=title, original title, abstract, name of substance word, subject heading word]
14. or/11-13
15. 10 and 14
2015.
1. random$.ti,ab.
2. factorial$.ti,ab.
3. (crossover$ or cross over$ or cross-over$).ti,ab.
4. placebo$.ti,ab.
5. (doubl$ adj blind$).ti,ab.
6. (singl$ adj blind$).ti,ab.
7. assign$.ti,ab.
8. allocat$.ti,ab.
9. volunteer$.ti,ab.
10. CROSSOVER PROCEDURE.sh.
11. DOUBLE-BLIND PROCEDURE.sh.
12. RANDOMIZED CONTROLLED TRIAL.sh.
13. SINGLE BLIND PROCEDURE.sh.
14. or/1-13
15. (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.)
16. 14 NOT 15
Appendix 5. CancerLit (PubMed) search strategy

#1 Search Osteonecrosis [mh:noexp]
#2 Search osteonecro* or “bone necrosis”
#3 Search osteochemonecro*
#4 Search #1 or #2 or #3
#5 Search Jaw [mh:exp]
#6 Search Jaw Diseases [mh:noexp]
#7 Search Alveolar Bone Loss [mh:noexp]
#8 Search jaw* or jawbone* or mandib* or maxill*
#9 Search “alveolar bone”
#10 Search #5 or #6 or #7 or #8 or #9
#11 Search Diphosphonates [mh:exp]
#12 Search diphosphonate* or bisphosphonate* or aminobisphosphonate* or alendronate or risedronate or pamidronate or “zoledronic
acid” or ibandronate
#13 Search “etidronate disodium” or didronel or “clodronate disodium” or Bonefos or “Tiludronate disodium” or Skelid or Fosamax
or Aredia or Actonel or Zometa or Boniva
#14 Search #11 or #12 or #13
#15 Search #4 and #10
#16 Search #14 and #15
2015. The Cochrane Highly Sensitive Search Strategy (CHSSS) for identifying randomised trials in MEDLINE: sensitivity maximising
version (2009 revision) as referenced in Chapter 6.4.11.1 and detailed in box 6.4.a of The Cochrane Handbook for Systematic Reviews
of Interventions, Version 5.0.2 [updated September 2009]:
#1 randomized controlled trial [pt]
#2 controlled clinical trial [pt]
#3 randomized [tiab]
#4 placebo [tiab]
#5 drug therapy [sh]
#6 randomly [tiab]
#7 trial [tiab]
#8 groups [tiab]
#9 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8
#10 animals [mh] not humans [mh]
#11 #9 NOT #10

Appendix 6. CINAHL (EBSCO) search strategy
S1 MH “Osteonecrosis”
S2 osteonecro* or “bone necrosis”
S3 osteochemonecro*
S4 S1 or S2 or S3
S5 MH “Jaw+”
S6 MH “Jaw Diseases”
S7 jaw* or jawbone* or mandib* or maxill*
S8 alveolar N4 bone
S9 S5 or S6 or S7 or S8
S10 S4 and S9
S11 MH “Diphosphonates+”
S12 diphosphonate* or bisphosphonate* or aminobisphosphonate* or alendronate or risedronate or pamidronate or “zoledronic acid”
or ibandronate
S13 “etidronate disodium” or didronel or “clodronate disodium” or Bonefos or “Tiludronate disodium” or Skelid or Fosamax or Aredia
or Actonel or Zometa or Boniva
S14 S11 or S12 or S13
S15 S10 AND S14
The searches were done without an RCT filter up to April 2013, a top-up search was performed with the addition of the Cochrane
Oral Health Group filter for identifying RCTs in CINAHL via EBSCO in January 2015:
S1 MH Random Assignment or MH Single-blind Studies or MH Double-blind Studies or MH Triple-blind Studies or MH Crossover
design or MH Factorial Design
S2 TI (“multicentre study” or “multicenter study” or “multi-centre study” or “multi-center study”) or AB (“multicentre study” or
“multicenter study” or “multi-centre study” or “multi-center study”) or SU (“multicentre study” or “multicenter study” or “multi-
centre study” or “multi-center study”)
S3 TI random* or AB random*
S4 AB “latin square” or TI “latin square”
S5 TI (crossover or cross-over) or AB (crossover or cross-over) or SU (crossover or cross-over)
S6 MH Placebos
S7 AB (singl* or doubl* or trebl* or tripl*) or TI (singl* or doubl* or trebl* or tripl*)
S8 TI blind* or AB mask* or AB blind* or TI mask*
S9 S7 and S8
S10 TI Placebo* or AB Placebo* or SU Placebo*
S11 MH Clinical Trials
S12 TI (Clinical AND Trial) or AB (Clinical AND Trial) or SU (Clinical AND Trial)
S13 S1 or S2 or S3 or S4 or S5 or S6 or S9 or S10 or S11 or S12
Appendix 7. AMED (Ovid) search strategy

1. Osteonecrosis/
2. (osteonecro$ or “bone necrosis”).mp.
3. osteochemonecro$.mp.
4. or/1-3
5. exp Jaw/
6. Jaw Diseases/
7. Alveolar Bone Loss/
8. (jaw$ or jawbone$ or mandib$ or maxill$ or (alveolar adj4 bone)).mp.
9. or/5-8
10. 4 and 9
acid” or ibandronate).mp.
Aredia or Actonel or Zometa or Boniva).mp.
13. 11 or 12
14. 10 and 13
Appendix 8. Database of Randomised Controlled Trials in Hyperbaric Medicine

osteonecrosis OR bisphosphonates
Appendix 9. US National Institutes of Health Trials Register (ClinicalTrials.gov) and the World
Health Organization International Clinical Trials Registry Platform search strategy
osteonecrosis AND jaw AND bisphosphonates
Appendix 10. Grey literature searches

osteonecrosis OR osteoporosis OR bisphosphonates
WHAT’S NEW
Last assessed as up-to-date: 15 December 2015.
Date Event Description
29 February 2016 Amended Minor edit to Summary of findings table
HISTORY
Protocol first published: Issue 4, 2010
Review first published: Issue 2, 2016
Date Event Description
13 April 2010 Amended Minor edits to protocol.

CONTRIBUTIONS OF AUTHORS
Co-ordinated the review: Nicole Vogt (NV).
Developed the protocol: NV, Victoria Rollason (VR), Martin Tramèr (MT).
Wrote the protocol: NV, VR.
Developed the search strategy: NV, VR (with Anne Littlewood (ALi) of the Oral Health Group).
Searched for trials: NV, VR, ALi.
Selected the trials: NV, VR, MT, Laura MacDonald (LM), Tanya Walsh (TW).
Assessed trial for risk of bias: NV, VR, MT.
Assessed quality of the evidence: LM, TW.
Co-ordinated contact with BRONJ experts: Alexandra Laverrière (AL).
Contacted authors of ongoing RCTs: LM
Extracted trial data: NV, VR, MT, AL, LM, TW.
Analysed and interpreted the data: NV, VR, MT, LM, TW.
Wrote Results and Discussion: NV, VR, AL, LM, TW.
Produced ’Summary of findings’ table: LM, TW.
Provided clinical perspective, expert advice: MT.
DECLARATIONS OF INTEREST
Victoria Rollason: none known.
Alexandra Laverrière: none known.
Laura MacDonald: none known.
Tanya Walsh: none known.
Martin Tramèr: none known.
Nicole B Vogt-Ferrier: none known.
SOURCES OF SUPPORT
Internal sources
• School of Dentistry, The University of Manchester, UK.
• Division of Clinical Pharmacology and Toxicology, Department APSI, Geneva University Hospitals, Switzerland.

External sources
• National Institute for Health Research (NIHR), UK.
This project was supported by the NIHR, via Cochrane Infrastructure funding to the Cochrane Oral Health Group. The views and
opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR,
National Health Service (NHS) or the Department of Health.
• Cochrane Oral Health Group Global Alliance, Other.
Through our Global Alliance (ohg.cochrane.org/partnerships-alliances), the Cochrane Oral Health Group has received support from:
British Association for the Study of Community Dentistry, UK; British Association of Oral Surgeons, UK; British Orthodontic
Society, UK; British Society of Paediatric Dentistry, UK; British Society of Periodontology, UK; Canadian Dental Hygienists
Association, Canada; Mayo Clinic, USA; National Center for Dental Hygiene Research & Practice, USA; New York University
College of Dentistry, USA; and Royal College of Surgeons of Edinburgh, UK.
• 2007 International Association for Dental Research (IADR) Evidence-Based Dentistry Network Systematic Review Award, UK.
Financial support
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

We changed the title of the review from Interventions for treating osteonecrosis of the jaw associated with bisphosphonates (Vogt-Ferrier
2010) to Interventions for treating bisphosphonate-related osteonecrosis of the jaw (BRONJ).
We edited the Background to describe the intervention more thoroughly, particularly current practice and how the intervention might
work.
We decided not to include studies other than randomised controlled trials in the review. We modified the sections that referred to non-
randomised studies (objectives, types of studies and assessment of risk of bias) accordingly. We modified the search strategy, adding an
“RCT only” filter from April 2013 to December 2015.
We added quality of life as a secondary outcome.


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Cochrane Database of Systematic Reviews

Interventions for treating bisphosphonate-related

Rollason V, Laverrière A, MacDonald LCI, Walsh T, Tramèr MR, Vogt-Ferrier NB

Rollason V, Laverrière A, MacDonald LCI, Walsh T, Tramèr MR, Vogt-Ferrier NB.

Interventions for treating bisphosphonate-related osteonecrosis of the jaw (BRONJ) (Review)

Interventions for treating bisphosphonate-related osteonecrosis of the jaw (BRONJ) (Review) i

Interventions for treating bisphosphonate-related

Editorial group: Cochrane Oral Health Group.

PLAIN LANGUAGE SUMMARY

Interventions for treating bisphosphonate-related osteonecrosis of the jaw (BRONJ) (Review) 3

Patient or population: people with bisphosphonate-related osteonecrosis of the jaw (BRONJ)

Assumed risk1 Corresponding risk

Standard care Hyperbaric oxygen ther-

GRADE Working Group grades of evidence

1. Risk in the control group.

Interventions for treating bisphosphonate-related osteonecrosis of the jaw (BRONJ) (Review) 6

Interventions for treating bisphosphonate-related osteonecrosis of the jaw (BRONJ) (Review) 7

We included studies describing the outcome of surgical or non-

◦ Wound healing (yes or no).

Interventions for treating bisphosphonate-related osteonecrosis of the jaw (BRONJ) (Review) 8

Interventions for treating bisphosphonate-related osteonecrosis of the jaw (BRONJ) (Review) 9

Interventions for treating bisphosphonate-related osteonecrosis of the jaw (BRONJ) (Review) 10

If we had identified other important sources of heterogeneity dur-

Interventions for treating bisphosphonate-related osteonecrosis of the jaw (BRONJ) (Review) 11

Interventions for treating bisphosphonate-related osteonecrosis of the jaw (BRONJ) (Review) 12

Interventions for treating bisphosphonate-related osteonecrosis of the jaw (BRONJ) (Review) 13

Interventions for treating bisphosphonate-related osteonecrosis of the jaw (BRONJ) (Review) 14

Interventions for treating bisphosphonate-related osteonecrosis of the jaw (BRONJ) (Review) 15

Interventions for treating bisphosphonate-related osteonecrosis of the jaw (BRONJ) (Review) 16

Interventions for treating bisphosphonate-related osteonecrosis of the jaw (BRONJ) (Review) 17

Such research can only be accomplished by multicentric collabora-

Interventions for treating bisphosphonate-related osteonecrosis of the jaw (BRONJ) (Review) 18

We thank Dr Brigitte Uebelhart and Dr M Hugentobler for their

Interventions for treating bisphosphonate-related osteonecrosis of the jaw (BRONJ) (Review) 21

Interventions for treating bisphosphonate-related osteonecrosis of the jaw (BRONJ) (Review) 22

Characteristics of included studies [ordered by study ID]

Methods Interventional, prospective, unblinded, randomised controlled trial

Participants 133 participants assessed; 49 consented (84 excluded or declined to participate); 27

Outcomes 4 outcomes reported:

Bias Authors’ judgement Support for judgement

Interventions for treating bisphosphonate-related osteonecrosis of the jaw (BRONJ) (Review) 23

Other bias High risk 5 cross-overs from standard care group to

HBO: hyperbaric oxygen therapy.

Interventions for treating bisphosphonate-related osteonecrosis of the jaw (BRONJ) (Review) 24

Study Reason for exclusion

Atalay 2011 Not an RCT

Gasparini 2010 Not an RCT

Graziani 2012 Not an RCT

Kim 2014 Not an RCT

Lee 2014 Not an RCT

Manfredi 2011 Not an RCT

Pelaz 2014 Not an RCT

Vescovi 2007 Not an RCT

Vescovi 2010 Not an RCT

Vescovi 2012a Not an RCT

Vescovi 2012b Not an RCT

Vescovi 2014 Not an RCT

RCT: randomised controlled trial.

Characteristics of ongoing studies [ordered by study ID]