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Referencias

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Freiberger JJ, Padilla‐Burgos R, McGraw T, Suliman HB, Kraft KH, Stolp BW, et al. What is the role of hyperbaric oxygen in the management of bisphosphonate‐related osteonecrosis of the jaw: a randomized controlled trial of hyperbaric oxygen as an adjunct to surgery and antibiotics. Journal of Oral and Maxillofacial Surgery 2012;70(7):1573‐83. [DOI: 10.1016/j.joms.2012.04.001; PUBMED: 22698292]CENTRAL
NCT00462098. Randomized controlled trial of hyperbaric oxygen in patients who have taken bisphosphonates. clinicaltrials.gov/show/NCT00462098 (first received 10 April 2007). CENTRAL

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Mozzati M, Arata V, Gallesio G. Tooth extraction in patients on zoledronic acid therapy. Oral Oncology 2012;48(9):817‐21. [DOI: 10.1016/j.oraloncology.2012.03.009; PUBMED: 22483860]CENTRAL
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Mozzati 2013 {published data only}

Mozzati M, Arata V, Gallesio G. Tooth extraction in osteoporotic patients taking oral bisphosphonates. Osteoporosis International 2013;24(5):1707‐1. [DOI: 10.1007/s00198‐012‐2239‐8; PUBMED: 23288026]CENTRAL
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Mücke T, Deppe H, Hein J, Wolff KD, Mitchell DA, Kesting MR, et al. Prevention of bisphosphonate‐related osteonecrosis of the jaws in patients with prostate cancer treated with zoledronic acid ‐ a prospective study over 6 years. Journal of Cranio‐maxillo‐facial Surgery 2016;44(10):1689‐93. [DOI: 10.1016/j.jcms.2016.07.026; 27555374]CENTRAL

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Ristow O, Otto S, Geiß C, Kehl V, Berger M, Troeltzsch M, et al. Comparison of auto‐fluorescence and tetracycline fluorescence for guided bone surgery of medication‐related osteonecrosis of the jaw: a randomized controlled feasibility study. International Journal of Oral and Maxillofacial Surgery 2017;46(2):157‐66. [DOI: 10.1016/j.ijom.2016.10.008; PUBMED: 27856150]CENTRAL

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Asaka T, Ohga N, Yamazaki Y, Sato J, Satoh C, Kitagawa Y. Platelet‐rich fibrin may reduce the risk of delayed recovery in tooth‐extracted patients undergoing oral bisphosphonate therapy: a trial study. Clinical Oral Investigations 2016 Nov 11 [Epub ahead of print]. [DOI: 10.1007/s00784‐016‐2004‐z]CENTRAL

Bonacina 2011 {published data only}

Bonacina R, Mariani U, Villa F, Villa A. Preventive strategies and clinical implications for bisphosphonate‐related osteonecrosis of the jaw: a review of 282 patients. Journal (Canadian Dental Association) 2011;77:b147. CENTRAL

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Bramati A, Girelli S, Farina G, Dazzani MC, Torri V, Moretti A, et al. Prospective, mono‐institutional study of the impact of a systematic prevention program on incidence and outcome of osteonecrosis of the jaw in patients treated with bisphosphonates for bone metastases. Journal of Bone and Mineral Metabolism 2015;33(1):119‐24. CENTRAL

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Coviello V, Peluso F, Dehkhargani SZ, Verdugo F, Raffaelli L, Manicone PF, et al. Platelet‐rich plasma improves wound healing in multiple myeloma bisphosphonate‐associated osteonecrosis of the jaw patients. Journal of Biological Regulators and Homeostatic Agents 2012;26(1):151‐5. CENTRAL

DE Iuliis 2014 {published data only}

DE Iuliis F, Taglieri L, Amoroso L, Vendittozzi S, Blasi L, Salerno G, et al. Prevention of osteonecrosis of the jaw in patients with bone metastases treated with bisphosphonates. Anticancer Research 2014;34(5):2477‐80. CENTRAL

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Dimopoulos MA, Kastritis E, Bamia C, Melakopoulos I, Gika D, Roussou M, et al. Reduction of osteonecrosis of the jaw (ONJ) after implementation of preventive measures in patients with multiple myeloma treated with zoledronic acid. Annals of Oncology 2009;20(1):117‐20. CENTRAL

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Lee LW, Hsiao SH, Chen LK. Clinical treatment outcomes for 40 patients with bisphosphonates‐related osteonecrosis of the jaws. Journal of the Formosan Medical Association 2014;113(3):166–72. CENTRAL

Montebugnoli 2007 {published data only}

Montebugnoli L, Felicetti L, Felicetti L, Gissi DB, Pizzigallo A, Pelliccioni GA, et al. Biphosphonate‐associated osteonecrosis can be controlled by nonsurgical management. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics 2007;104(4):473‐7. CENTRAL

Pelaz 2014 {published data only}

Pelaz A, Junquera L, Gallego L, García‐Consuegra L, Junquera S, Gómez C. Alternative treatments for oral bisphosphonate‐related osteonecrosis of the jaws: apilot study comparing fibrin rich in growth factors and teriparatide. Medicina Oral, Patologia Oral y Cirugia Bucal 2014;19(4):e320–6. CENTRAL

Vescovi 2010 {published data only}

Vescovi P, Manfredi M, Merigo E, Meleti M, Fornaini C, Rocca JP, et al. Surgical approach with Er:YAG laser on osteonecrosis of the jaws (ONJ) in patients under bisphosphonate therapy (BPT). Lasers in Medical Science 2010;25(1):101–13. CENTRAL

Vescovi 2012 {published data only}

Vescovi P, Merigo E, Meleti M, Manfredi M, Fornaini C, Nammour S. Surgical approach and laser applications in BRONJ osteoporotic and cancer patients. Journal of Osteoporosis 2012;2012:Article ID 585434, 8 pages. [DOI: 10.1155/2012/585434]CENTRAL

ACTRN12612000950864 {unpublished data only}

ACTRN12612000950864. Does teriparatide reverse osteonecrosis of the jaw in patients treated with either bisphosphonates or denosumab? A randomised, controlled trial.. anzctr.org.au/Trial/Registration/TrialReview.aspx?id=362988 (first received 9 September 2012). CENTRAL

NCT01526915 {unpublished data only}

NCT01526915. Assessment of Platelet Rich Fibrin Efficiency on Healing Delay and on Jawbone Osteochemonecrosis Provoked by Bisphosphonates (OCN/PRF). clinicaltrials.gov/ct2/show/record/NCT01526915 (first received 31 January 2012). CENTRAL

NCT02198001 {unpublished data only}

NCT02198001. Prospective Randomized Study: Assessment of PRF Efficacy in Prevention of Jaw Osteonecrosis After Tooth Extraction (PRF). clinicaltrials.gov/ct2/show/record/NCT02198001 (first received 15 July 2014). CENTRAL

UMIN000009132 {unpublished data only}

UMIN000009132. Study to the effect of teriparatide formulation Forteo versus Teribon on bisphosphonate‐related osteonecrosis of the jaw in osteoporosis patients. upload.umin.ac.jp/cgi‐open‐bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000010706&language=E (first received 17 October 2012). CENTRAL

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Bone 2017

Bone HG, Wagman RB, Brandi ML, Brown JP, Chapurlat R, Cummings SR, et al. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open‐label extension. The lancet. Diabetes & endocrinology 2017;5(7):513‐23. [DOI: 10.1016/S2213‐8587(17)30138‐9; PUBMED: 28546097]

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Boquete‐Castro A, Gómez‐Moreno G, Calvo‐Guirado JL, Aguilar‐Salvatierra A, Delgado‐Ruiz RA. Denosumab and osteonecrosis of the jaw. A systematic analysis of events reported in clinical trials. Clinical Oral Implants Research 2016;27(3):367‐75. [DOI: 10.1111/clr.12556; PUBMED: 25639776]

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Chen F, Pu F. Safety of denosumab versus zoledronic acid in patients with bone metastases: a meta‐Analysis of randomized controlled trials. Oncology Research and Treatment 2016;39(7‐8):453‐9. [DOI: 10.1159/000447372; PUBMED: 27487236]

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Martins MA, Martins MD, Lascala CA, Curi MM, Migliorati CA, Tenis CA, et al. Association of laser phototherapy with PRP improves healing of bisphosphonate‐related osteonecrosis of the jaws in cancer patients: a preliminary study. Oral Oncology 2012;48(1):79‐84.

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Petrucci MT, Gallucci C, Agrillo A, Mustazza MC, Foà R. Role of ozone therapy in the treatment of osteonecrosis of the jaws in multiple myeloma patients. Haematologica 2007;92(9):1289‐90.

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Qi WX, Tang LN, He AN, Yao Y, Shen Z. Risk of osteonecrosis of the jaw in cancer patients receiving denosumab: a meta‐analysis of seven randomized controlled trials. International Journal of Clinical Oncology 2014;19(2):403‐10. [DOI: 10.1007/s10147‐013‐0561‐6; PUBMED: 23605142]

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Vescovi P, Merigo E, Meleti M, Manfredi M. Bisphosphonate‐associated osteonecrosis (BON) of the jaws: a possible treatment?. Journal of Oral and Maxillofacial Surgery 2006;64(9):1460‐2.

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

Freiberger 2012

Methods

  • Trial design: single‐centre, interventional, prospective, unblinded, randomised controlled trial

  • Duration of study: enrolment period from July 2006 to December 2010

  • Follow‐up: per protocol 2 years

  • Sample size calculation: quote: "The target study sample size was calculated based on the primary outcome variable (change in oral lesion size and number) and indicated a requirement for 33 to 37 subjects with MRONJ per group. This assumed a spontaneous remission rate of 5% to 10% for the study to detect at least a 25% difference in cure rates between HBO‐treated patients and non‐treated controls. The authors used a value equal to 0.05 and a power equal to 0.80 for these calculations."

  • Country of origin: USA

  • Year of publication: 2012

  • Language of the original publication: English

  • Category: treatment of MRONJ, non‐surgical

  • Funding: quote: "This work was supported by a grant from Novartis Healthcare."

  • Registration in a public trials registry: NCT00462098

Participants

  • 49 participants with MRONJ randomised into 2 groups: 27 control (standard care), 22 experimental (standard care + hyperbaric oxygen [HBO])

  • Mean age: control 66 yr, HBO 66 yr

  • Sex: control 56% female, HBO 59% female

  • Condition treated with bisphosphonates: osteoporosis (15% of total sample), cancer and other indications (85% of total sample)

  • Inclusion criteria:

    • Able to consent

    • Has taken bisphosphonates

    • Presence of exposed bone in the maxillofacial area with no evidence of healing after 6 weeks of appropriate evaluation and dental care

    • no radiation history of the affected area

  • Exclusion criteria:

    • Unable to consent

    • Ineligible for HBO

    • Taking protease inhibitors for HIV

    • Any past history of radiation to the jaw

    • Metastatic or recurrent malignant disease of the jaw or oropharynx

    • Life expectancy less than 12 months

    • Tobacco use

    • Pregnancy

Interventions

  • Control: standard care (antiseptic rinses, antibiotics, and surgery, if indicated by the participant's individual conditions)

  • Experimental: standard care plus 40 sessions of 100% oxygen at 2 atmospheres of pressure for 2 hours each, twice a day

Outcomes

  • Primary:

    • Change from baseline in oral lesion size and number

  • Secondary:

    • Pain (0‐ to 10‐point Likert scale)

    • Quality of life (Duke Health Profile, a 17‐question generic self‐reporting instrument)

    • Serum measurements of bone turnover (data collected but not reported)

    • Molecular measures of osteoclast signalling (data collected but not reported)

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of sequence generation not reported

Allocation concealment (selection bias)

Low risk

Quote: "The randomization of patients with MRONJ to treatment groups was performed after informed consent, but before the initial staging examination using a series of 70 opaque envelopes containing the assignment."

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "The subjects and staff were not blinded to therapy because of the impracticality of providing sham HBO; however, the oral‐maxillofacial surgeon was not told the subjects’ assignments before the initial staging examination."

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: "Lesion scores at the time of last contact were assigned by the study team, including the oral‐maxillofacial surgeon."

No blinding of outcome assessment

Incomplete outcome data (attrition bias)
All outcomes

High risk

High attrition rate: at the 12‐ and 18‐month evaluations 50% and 63%, respectively, of participants were lost to follow‐up.

High and unbalanced rate of crossovers: after randomization 5 participants switched from the control to the HBO group; 1 participant assigned to the HBO group declined HBO treatment and was switched to the control group.

Data analysis: as‐treated, not by intention‐to‐treat

Selective reporting (reporting bias)

Low risk

Serum measurements of bone turnover and molecular measures of osteoclast signalling were not reported. These are not primary outcomes and will be "reported separately". All other outcome variables listed in the Methods and the study protocol were reported.

Mozzati 2012

Methods

  • Trial design: single‐centre, interventional, prospective, unblinded, randomised controlled trial

  • Duration of study: January 2005 to December 2009

  • Follow‐up: between 24 and 60 months

  • Sample size calculation: not provided

  • Country of origin: Italy

  • Year of publication: 2012

  • Language of the original publication: English

  • Category: prophylaxis of MRONJ

  • Funding: not reported

  • Registration in a public trials registry: not reported

Participants

  • 176 participants randomised into 2 groups: 85 control, 91 experimental (plasma rich in growth factors [PRGF])

  • Age 44‐60 yr: control 27, PRGF 22

  • Age 60‐70 yr: control 36, PRGF 43

  • Age 70‐83 yr: control 22, PRGF 26

  • Sex: control 54% female, PRGF 60% female

  • Condition treated with intravenous (IV) bisphosphonate (zoledronic acid): breast cancer, prostate cancer, ovarian cancer, lung cancer, and multiple myeloma

  • Inclusion criteria:

    • Current IV bisphosphonate therapy

    • The necessity for removal of strongly compromised dental elements

  • Exclusion criteria

    • Any previous history of irradiation to the maxillofacial area

    • Dental extractions before the study period

Interventions

  • Control: standardised medical (professional oral hygiene session 1 week before surgery; antibiotics for 6 days starting the evening before surgery) and surgical care (anaesthesia by alveolar nerve block, no intraligamentous or intrapapillary infiltrations; mucosal flap and suturing to enable healing via primary intention)

  • Experimental: standardised medical and surgical care plus PRGF fraction inserted into the postextraction alveolus

Outcomes

  • Postoperative bisphosphonate‐associated osteonecrosis

Follow‐up examinations: mucosal healing was monitored at 3, 7, and 14 days postoperatively; monitoring for MRONJ was continued at 21, 30, 60, 90, and 120 days, and 6 months, followed by visits every 6 months

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "The study cohort was divided randomly into two groups of 50 subjects"

Generation of randomisation sequence not reported

Allocation concealment (selection bias)

Unclear risk

Concealment of allocation not reported

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, the personnel were not blinded. Because an extra 15 mL blood sample was obtained from the participants in the PRGF group, the participants were most likely not blinded.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

It is not reported whether outcome was monitored by an independent and blinded outcome assessor. Outcome was most likely assessed by the surgeon who had performed the dental extraction.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Completeness or loss to follow‐up was not reported.

Selective reporting (reporting bias)

Low risk

The outcomes mentioned in the Methods were all reported.

Mozzati 2013

Methods

  • Trial design: single‐centre, interventional, prospective, unblinded, two‐arm randomised controlled trial

  • Duration of study: from January 2005 to April 2011

  • Follow‐up: between 12 and 72 months

  • Sample size calculation: not provided

  • Country of origin: Italy

  • Year of publication: 2013

  • Language of the original publication: English

  • Category: prophylaxis of MRONJ

  • Funding: not reported

  • Registration in a public trials registry: not stated

Participants

  • 700 participants receiving oral bisphosphonates: tooth extractions were performed in 334 participants with protocol A (delicate surgery and closure by primary intention), in 366 participants with protocol B (non‐traumatic avulsion and closure by secondary intention).

  • Age 50‐60 yr: protocol A 85, protocol B 93.

  • Age 60‐70 yr: protocol A 185, protocol B 179.

  • Age 70‐80 yr: protocol A 64, protocol B 94.

  • Sex: protocol A 96% female, protocol B 98% female.

  • Condition treated with bisphosphonates: osteoporosis, rheumatoid arthritis, Paget disease

  • Inclusion criteria:

    • Current oral bisphosphonate therapy

    • Treatment with oral bisphosphonates for more than 24 months

    • The necessity for the removal of compromised dental elements

  • Exclusion criteria:

    • Any previous history of irradiation to the maxillofacial area

    • Dental extractions before the study period

Interventions

All participants: professional oral hygiene session 1 week before surgery; antibiotics for 6 days starting the evening before surgery

  • Protocol A: the surgical extractions were carried out by intrasulcular incisions and detachment of full thickness flaps to allow wound healing via primary intention.

  • Protocol B: the extractions were carried out without detachment of full thickness flaps; sockets were filled with absorbable gelatin sponge haemostatic to allow wound healing via secondary intention.

Outcomes

  • Intraoperative complications

  • Success rate (absence of postoperative MRONJ)

Follow‐up examinations: mucosal healing was monitored at 3, 7, and 14 days postoperatively; monitoring for MRONJ was continued at 21, 30, 60, and 90 days, and 6 months, followed by visits every 6 months.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Each patient was assigned by a computer‐randomization program to one of two groups."

Allocation concealment (selection bias)

Unclear risk

Concealment of allocation not reported

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Due to the nature of the intervention, the personnel and participants were not blinded.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

At least during the mucosal healing period, due to the nature of the intervention, blinding of outcome assessors is not possible.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Completeness or loss to follow‐up was not reported.

Selective reporting (reporting bias)

Low risk

The outcomes mentioned in the Methods were all reported.

Mücke 2016

Methods

  • Trial design: single‐centre, prospective, unblinded, two‐arm, randomised controlled trial

  • Duration of study: enrolment period from 2008 to 2014

  • Follow‐up: quote: "The mean application period of zolendronic acid was 28.8 months"

  • Sample size calculation: not provided

  • Country of origin: Germany

  • Year of publication: 2016

  • Language of the original publication: English

  • Category: prophylaxis of MRONJ

  • Funding: no extramural funding; quotation: "The study was not funded"

  • Registration in a public trials registry: not stated

Participants

  • 253 men with prostate cancer with planned zoledronic acid for treatment of bone metastases were randomised into 2 groups: 127 in group A and 126 in group B

  • Mean age: group A 69 yr, group B 72 yr

  • Sex: male

  • Condition treated with IV zoledronic acid: metastatic adenocarcinoma of the prostate with bone metastases

  • Inclusion criteria

    • Metastatic adenocarcinoma of the prostate with bone metastases

    • Not yet treated with IV zoledronic acid

  • Exclusion criteria

    • Kidney failure (creatinine clearance < 30 mL/min)

Interventions

  • Group A (control): participants received an initial examination at the study centre and were monitored and treated where deemed necessary by the individual's dentist, and were re‐evaluated once a year.

  • Group B (experimental): participants received an initial examination and were treated if needed at the study centre. Participants were monitored and treated where necessary by the authors at 12‐week intervals. Extractions were performed under prophylactic antibiotic treatment and wound closure was carried out without tension on the local flap

Outcomes

  • Incidence rate per year for MRONJ

  • Incidence proportion for MRONJ

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "All patients were prospectively examined before the start of therapy with zoledronic acid and were randomly allocated into two groups."

Generation of randomisation sequence not reported

Allocation concealment (selection bias)

Unclear risk

Concealment of allocation not reported

Blinding of participants and personnel (performance bias)
All outcomes

High risk

"treatment was not possible to be blinded"

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Not blinded

Incomplete outcome data (attrition bias)
All outcomes

High risk

High and unbalanced rate of crossovers: "36 patients, who were randomized to participate in group B did not want to be part of a close follow‐up and were then regrouped in group A."

"At the end of this study, 153 (93.3%) patients of group A and 79 (87.8%) patients from group B have died."

Data analysis: as‐treated, not by intention‐to‐treat.

Selective reporting (reporting bias)

Low risk

The outcomes mentioned in the Methods were all reported.

Ristow 2016

Methods

  • Trial design: single‐centre, prospective, unblinded, two‐arm, randomised controlled trial

  • Duration of study: quote: "patients [...] were recruited over a time period of 12 months and followed up for 12 months"

  • Follow‐up: one year

  • Sample size calculation: not provided; quote: "Because of the preliminary ‘proof‐of‐concept’ character of this study, the sample size estimation was disclaimed"

  • Country of origin: Germany

  • Year of publication: 2016

  • Language of the original publication: English

  • Category: treatment of established MRONJ

  • Funding: quote: "There was no source of funding for this research"

  • Registration in a public trials registry: not stated

Participants

  • 40 participants with MRONJ randomised into 2 groups: 20 control (tetracycline fluorescence‐guided bone surgery [TF]), 20 experimental (autofluorescence‐guided bone surgery [AF])

  • Mean age: control 67 yr, AF 71 yr

  • Sex: control 69% female, AF 70% female

  • Condition treated with antiresorptive medication: cancer (85% of total sample), osteoporosis (15% of total sample)

  • Inclusion criteria

    • History of antiresorptive drug treatment (bisphosphonates or denosumab, or both) in the absence of radiotherapy to the head and neck region

    • Exposed osteonecrosis of the jaw, defined as the long‐standing (more than 8 weeks) transmucosal exposure of necrotic bone in the jaw

  • Exclusion criteria

    • History of head and neck irradiation

    • Metastatic bone disease of the maxillofacial region

    • Contradictions to surgery under general anaesthesia

Interventions

  • Control (TF group): participants received 100 mg doxycycline twice a day for at least 7 days preoperatively. Incorporation of doxycycline into vital bone and absence of doxycycline in necrotic bone was detected by a fluorescent light source (VELscope fluorescence lamp; LED Dental, White Rock, British Columbia, Canada). Doxycycline fluorescence was used for intraoperative identification of bone resection margins and guided debridement of necrotic bone.

  • AF group: participants received antibiotic prophylaxis with ampicillin/sulbactam 2000 mg/1000 mg (or clindamycin 600 mg in case of hypersensitivity to penicillin or a penicillin allergy) before operation. Autofluorescence of vital bone, induced with the VELscope fluorescence lamp (LED Dental, White Rock, British Columbia, Canada) was used for intraoperative identification of bone resection margins and guided debridement of necrotic bone.

In all participants, a tension‐free wound closure was achieved using mucoperiostal flaps. All participants remained in hospital for 4 days after the operation. Participants received routine postoperative instructions and the same postoperative analgesic drug therapy. Antibiotic treatment involved the administration of ampicillin/sulbactam 2000 mg/1000 mg (or clindamycin in case of hypersensitivity to penicillin or a penicillin allergy) intravenously while in hospital and then orally for a further 6 days after discharge from the hospital.

Outcomes

  • Primary

    • Success rate: absence of a MRONJ site (i.e. maintenance of full mucosal coverage) at 8 weeks (T2) after surgery

  • Secondary

    • Mucosal integrity at 10 days (T1), 6 months (T3), and 1 year (T4) after surgery

    • Loss of sensitivity (numbness) of the alveolar nerve (Vincent sign) at 10 days (T1), 8 weeks (T2), 6 months (T3), and 1 year (T4) after surgery

    • Subjective pain at 10 days (T1), 8 weeks (T2), 6 months (T3), and 1 year (T4) after surgery

    • Signs of infection at 10 days (T1), 8 weeks (T2), 6 months (T3), and 1 year (T4) after surgery

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Over a period of 12 months, the study population was prospectively referred for the treatment of MRONJ and divided randomly into two study groups"

Generation of randomisation sequence not reported

Allocation concealment (selection bias)

Unclear risk

Concealment of allocation not reported

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Not blinded

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Not blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

4 participants (2 each in the TF and the AF group) died after T2 (8 weeks after the operation) and 2 participants in the AF group failed to attend the 1‐year follow‐up (T4).

No participant was lost for assessment of the primary endpoint at T2 (8 weeks after the operation).

Selective reporting (reporting bias)

Low risk

The outcomes mentioned in the Methods were all reported.

Characteristics of excluded studies [author‐defined order]

Study

Reason for exclusion

Asaka 2016

Not an RCT

Bonacina 2011

Not an RCT

Bramati 2015

Not an RCT

Coviello 2012

Not an RCT

DE Iuliis 2014

Not an RCT

Dimopoulos 2009

Not an RCT

Lee 2014

Not an RCT

Montebugnoli 2007

Not an RCT

Pelaz 2014

Not an RCT

Vescovi 2010

Not an RCT

Vescovi 2012

Not an RCT

RCT: randomised clinical 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

Interventional, randomised, parallel assignment, blinded

Participants

Target sample size: 68

All sexes eligible for study, 18 years and older

Inclusion criteria:

  • Osteonecrosis of the jaw

  • Previous/current treatment with either bisphosphonates or denosumab

Exclusion criteria:

  • Previous craniofacial radiotherapy

  • Pregnancy

  • Hypercalcaemia or pre‐existing primary hyperparathyroidism

  • Known metabolic bone disease, excluding osteoporosis or metastatic bone disease

  • Growth hormone deficiency

  • Secondary hyperparathyroidism with parathyroid hormone greater than two‐fold above upper limit of reference range

  • Severe renal impairment (estimated glomerular filtration rate < 30 mL/min)

Interventions

Experimental: subcutaneous teriparatide injections (20 μg daily), plus calcium (600 mg tablet daily) and vitamin D (1000 IU tablet daily) supplementation for 8 weeks

Control: placebo saline injections, plus calcium (600 mg tablet daily) and vitamin D (1000 IU tablet daily) supplementation for 8 weeks

Outcomes

Primary outcome:

  • Clinical staging of osteonecrosis of the jaw ‐ described by the American Association of Oral and Maxillofacial Surgeons position paper

  • Radiological staging of osteonecrosis of the jaw, as assessed by cone beam computed tomography

Secondary outcome:

  • Bone formation and resorption markers (P1NP1, beta‐CTX2)

  • Jaw osteoblast activity, as measured by NaF‐positron emission tomography imaging

  • Quality of life

Starting date

September 2012

Contact information

[email protected]

Notes

Prof. Ebeling was contacted. The study results will be available in the second half of 2017.

NCT01526915

Trial name or title

Assessment of platelet rich fibrin efficiency on healing delay and on jawbone osteochemonecrosis provoked by bisphosphonates (OCN/PRF)

Methods

Interventional, randomised, parallel assignment, open label

Participants

270 participants are required to validate the expected objectives in this study

All sexes eligible for study, 18 years and older

Inclusion criteria:

  • Adults (male or female)

  • Documented indication at the initial visit at day 0 (JO) for a maximum extraction of 3 teeth

  • Treatment with nitrogenous or non‐nitrogenous bisphosphonate (BP) by intravenous injection or oral administration whatever the reason for this drug prescription:

    • ongoing BP treatment

    • individual having received a previous treatment with BPs (irrespective of the duration and withdrawal date of this treatment

  • Individual having received the specific information letter regarding the study and having signed the clarified consent form

Exclusion criteria:

  • Individual having a maxillary or mandibulary OCN3 at day 0 (JO)

  • Positive HIV serology at Day 0 (for participants belonging to the platelet‐rich fibrin (PRF) group)

  • Previous history of maxillocervicofacial radiotherapy

  • Individual with estimated survival expectancy shorter than one year

  • Lack of social security cover

  • Inability of the individual to respect the study follow‐up

  • Individual having reached his/her majority and under tutelage, trusteeship or protection of the court

  • Individual whose diagnosis could not be revealed to him/her (especially when the individual or the family expressed this wish)

Interventions

Experimental: bone curettage + PRF insertion

Control: bone curettage alone without PRF insertion

Outcomes

Primary outcome measures:

  • Delay in cicatrisation4 at week 8

  • The appearance of osteochemonecrosis during the follow‐up period

Secondary outcome measures:

  • The characteristics of the received BP treatment: starting date of ongoing treatment, accumulated dose, type of BP, administration route

  • The precise location of the extraction site according to the tooth classification number

Starting date

September 2011

Contact information

e.gerard@chr‐metz‐thionville.fr

Notes

NCT02198001

Trial name or title

Prospective randomized study: assessment of PRF efficacy in prevention of jaw osteonecrosis after tooth extraction (PRF)

Methods

Interventional; randomised; parallel assignment, blinded

Participants

Cohort of 100 participants: control group 50 participants and experimental 50 participants

All sexes eligible for study; 50 years and older

Inclusion criteria:

  • Individuals taking bisphosphonates whatever the indication, the type, the administration and the duration of treatment (we include those taking or having taken bisphosphonates, even several years ago)

  • Individuals who need tooth extraction (not recoverable in conservative dentistry and symptomatic tooth: dental and periodontal infections, symptomatic traumatic tooth fracture)

Exclusion criteria:

  • Pregnant women

  • Younger than 50 years old

  • Aw's radiotherapy

  • History of jaw osteonecrosis

  • Aw metastasis from another cancer

Interventions

Experimental: tooth extraction and insertion of PRF (non‐traumatic tooth extraction with antibiotics (amoxicillin clavulanate combination). Insertion of PRF membrane in tooth‐extraction site)

Control: no PRF (non‐traumatic extraction with antibiotic without PRF insertion)

Outcomes

Number of participants with jaw osteonecrosis after tooth extraction

Starting date

January 2014

Contact information

[email protected], [email protected]

Notes

UMIN000009132

Trial name or title

Study to the effect of teriparatide formulation Forteo versus Teribone on bisphosphonate‐related osteonecrosis of the jaw in osteoporosis patients

Methods

Interventional, parallel, randomised, open study

Participants

15 female participants >= 20 years of age

Inclusion criteria:

  • Individuals who require continued treatment for osteoporosis

  • Females with bisphosphonate‐related osteonecrosis of the jaw

  • Bisphosphonate‐related osteonecrosis of the jaw stage 2 or more

  • Outpatients

  • Signed informed consent forms obtained

Exclusion criteria:

  • Hypercalcaemic disorders

  • Potential risk of osteosarcoma

  • Individuals with Paget's disease of bone

  • Unexplained elevations of alkaline phosphatase

  • Young adults with open epiphyses

  • Individuals with prior external beam or implant radiation involving the skeleton

  • Individuals with bone metastases, history of skeletal malignancies

  • Metabolic bone diseases other than osteoporosis

  • Pregnancy or women with suspected pregnancy

  • Individuals 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

  • Individuals who could not provide informed consent

  • Unsuitability for the trial based on clinical judgement

Interventions

Forteo (teriparatide) vs Teribone (teriparatide)

Outcomes

  • pain

  • bone formation

Starting date

August 2012

Contact information

[email protected]‐u.ac.jp

Notes

1. P1NP, N‐terminal propeptide of type 1 collagen Procollagen I Intact N‐Terminal

2. Beta‐CTX, Beta‐carboxy‐terminal telopeptide of type 1 collagen (beta‐CrossLaps)

3. OCN: osteochemonecrosis

4. Cicatrisation: formation of scar tissue at a wound site by fibroblasts

Data and analyses

Open in table viewer
Comparison 1. Dental examinations at three‐month intervals and preventive treatments (experimental) versus standard care (control) for prophylaxis of MRONJ

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 MRONJ (incidence proportion) Show forest plot

1

253

Risk Ratio (M‐H, Fixed, 95% CI)

0.10 [0.02, 0.39]

Analysis 1.1

Comparison 1 Dental examinations at three‐month intervals and preventive treatments (experimental) versus standard care (control) for prophylaxis of MRONJ, Outcome 1 MRONJ (incidence proportion).

Comparison 1 Dental examinations at three‐month intervals and preventive treatments (experimental) versus standard care (control) for prophylaxis of MRONJ, Outcome 1 MRONJ (incidence proportion).

2 MRONJ (incidence rate: MRONJ cases per patient‐year) Show forest plot

1

Rate ratio (Fixed, 95% CI)

0.18 [0.04, 0.74]

Analysis 1.2

Comparison 1 Dental examinations at three‐month intervals and preventive treatments (experimental) versus standard care (control) for prophylaxis of MRONJ, Outcome 2 MRONJ (incidence rate: MRONJ cases per patient‐year).

Comparison 1 Dental examinations at three‐month intervals and preventive treatments (experimental) versus standard care (control) for prophylaxis of MRONJ, Outcome 2 MRONJ (incidence rate: MRONJ cases per patient‐year).

Open in table viewer
Comparison 2. A dental extraction protocol with plasma rich in growth factors (PRGF) (experimental) versus a standard dental extraction protocol without PRGF (control) for prophylaxis of MRONJ in people treated with IV bisphosphonates who need dental extractions

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 MRONJ (incidence proportion) Show forest plot

1

176

Risk Ratio (M‐H, Random, 95% CI)

0.08 [0.00, 1.51]

Analysis 2.1

Comparison 2 A dental extraction protocol with plasma rich in growth factors (PRGF) (experimental) versus a standard dental extraction protocol without PRGF (control) for prophylaxis of MRONJ in people treated with IV bisphosphonates who need dental extractions, Outcome 1 MRONJ (incidence proportion).

Comparison 2 A dental extraction protocol with plasma rich in growth factors (PRGF) (experimental) versus a standard dental extraction protocol without PRGF (control) for prophylaxis of MRONJ in people treated with IV bisphosphonates who need dental extractions, Outcome 1 MRONJ (incidence proportion).

Open in table viewer
Comparison 3. Hyperbaric oxygen as an adjunct to conventional therapy (experimental) versus conventional therapy (control) for treatment of MRONJ

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Healing of MRONJ at last contact Show forest plot

1

46

Risk Ratio (M‐H, Fixed, 95% CI)

1.56 [0.77, 3.18]

Analysis 3.1

Comparison 3 Hyperbaric oxygen as an adjunct to conventional therapy (experimental) versus conventional therapy (control) for treatment of MRONJ, Outcome 1 Healing of MRONJ at last contact.

Comparison 3 Hyperbaric oxygen as an adjunct to conventional therapy (experimental) versus conventional therapy (control) for treatment of MRONJ, Outcome 1 Healing of MRONJ at last contact.

Open in table viewer
Comparison 4. Autofluorescence‐guided bone surgery (experimental) versus tetracycline fluorescence‐guided bone surgery (control) for treatment of MRONJ

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Healing of MRONJ (defined as mucosal integrity) at 1 year Show forest plot

1

34

Risk Ratio (M‐H, Fixed, 95% CI)

1.05 [0.86, 1.30]

Analysis 4.1

Comparison 4 Autofluorescence‐guided bone surgery (experimental) versus tetracycline fluorescence‐guided bone surgery (control) for treatment of MRONJ, Outcome 1 Healing of MRONJ (defined as mucosal integrity) at 1 year.

Comparison 4 Autofluorescence‐guided bone surgery (experimental) versus tetracycline fluorescence‐guided bone surgery (control) for treatment of MRONJ, Outcome 1 Healing of MRONJ (defined as mucosal integrity) at 1 year.

Study flow diagram. Results of the search strategy for inclusion of studies in this review
Figuras y tablas -
Figure 1

Study flow diagram. Results of the search strategy for inclusion of studies in this review

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study
Figuras y tablas -
Figure 2

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study

Comparison 1 Dental examinations at three‐month intervals and preventive treatments (experimental) versus standard care (control) for prophylaxis of MRONJ, Outcome 1 MRONJ (incidence proportion).
Figuras y tablas -
Analysis 1.1

Comparison 1 Dental examinations at three‐month intervals and preventive treatments (experimental) versus standard care (control) for prophylaxis of MRONJ, Outcome 1 MRONJ (incidence proportion).

Comparison 1 Dental examinations at three‐month intervals and preventive treatments (experimental) versus standard care (control) for prophylaxis of MRONJ, Outcome 2 MRONJ (incidence rate: MRONJ cases per patient‐year).
Figuras y tablas -
Analysis 1.2

Comparison 1 Dental examinations at three‐month intervals and preventive treatments (experimental) versus standard care (control) for prophylaxis of MRONJ, Outcome 2 MRONJ (incidence rate: MRONJ cases per patient‐year).

Comparison 2 A dental extraction protocol with plasma rich in growth factors (PRGF) (experimental) versus a standard dental extraction protocol without PRGF (control) for prophylaxis of MRONJ in people treated with IV bisphosphonates who need dental extractions, Outcome 1 MRONJ (incidence proportion).
Figuras y tablas -
Analysis 2.1

Comparison 2 A dental extraction protocol with plasma rich in growth factors (PRGF) (experimental) versus a standard dental extraction protocol without PRGF (control) for prophylaxis of MRONJ in people treated with IV bisphosphonates who need dental extractions, Outcome 1 MRONJ (incidence proportion).

Comparison 3 Hyperbaric oxygen as an adjunct to conventional therapy (experimental) versus conventional therapy (control) for treatment of MRONJ, Outcome 1 Healing of MRONJ at last contact.
Figuras y tablas -
Analysis 3.1

Comparison 3 Hyperbaric oxygen as an adjunct to conventional therapy (experimental) versus conventional therapy (control) for treatment of MRONJ, Outcome 1 Healing of MRONJ at last contact.

Comparison 4 Autofluorescence‐guided bone surgery (experimental) versus tetracycline fluorescence‐guided bone surgery (control) for treatment of MRONJ, Outcome 1 Healing of MRONJ (defined as mucosal integrity) at 1 year.
Figuras y tablas -
Analysis 4.1

Comparison 4 Autofluorescence‐guided bone surgery (experimental) versus tetracycline fluorescence‐guided bone surgery (control) for treatment of MRONJ, Outcome 1 Healing of MRONJ (defined as mucosal integrity) at 1 year.

Summary of findings for the main comparison. Dental examinations at three‐month intervals and preventive treatments (experimental) compared to standard care (control) for prophylaxis of MRONJ

Dental examinations at three‐month intervals and preventive treatments (experimental) compared to standard care (control) for prophylaxis of MRONJ

Population: prophylaxis of MRONJ
Setting: hospital
Intervention: dental examinations at three‐month intervals and preventive treatments (experimental)
Comparison: standard care (control)

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with standard care (control)

Risk with dental examinations at three‐month intervals and preventive treatments (experimental)

MRONJ (incidence proportion)
Diagnostic criteria for MRONJ: non‐healing exposed bone in mandible or maxilla for longer than 8 weeks without any change of the stage of disease

(follow‐up: mean 32 months)

233 per 1000

23 per 1000
(5 to 91)

RR 0.10
(0.02 to 0.39)

253
(1 RCT)

⊕⊕⊝⊝
LOW1

Participants: high‐risk ( i.e. individuals with cancer exposed to intravenous zoledronic acid

The outcome MRONJ was also reported as number of cases per patient‐year (incidence rate) rate ratio 0.18 (95% CI 0.04 to 0.74)

*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio; OR: odds ratio

GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1. We downgraded the quality of the evidence by two levels due to very serious risk of bias (high and unbalanced rate of crossovers after randomisation, high drop‐out rates due to high mortality, failure to adhere to the intention‐to‐treat principle, the mean follow‐up differed between experimental and control group).

MRONJ = medication‐related osteonecrosis of the jaw

RCT = randomised controlled trial

Figuras y tablas -
Summary of findings for the main comparison. Dental examinations at three‐month intervals and preventive treatments (experimental) compared to standard care (control) for prophylaxis of MRONJ
Summary of findings 2. A dental extraction protocol with plasma rich in growth factors (PRGF) (experimental) compared to a standard dental extraction protocol without PRGF (control) for prophylaxis of MRONJ in people treated with IV bisphosphonates who need dental extractions

A dental extraction protocol with plasma rich in growth factors (PRGF) (experimental) compared to a standard dental extraction protocol without PRGF (control) for prophylaxis of MRONJ in people treated with IV bisphosphonates who need dental extractions

Population: people treated with IV bisphosphonates who need dental extractions
Setting: hospital
Intervention: a dental extraction protocol with PRGF (experimental)
Comparison: a standard dental extraction protocol without PRGF (control)

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with a standard dental extraction protocol without PRGF (control)

Risk with a dental extraction protocol with PRGF (experimental)

MRONJ (incidence proportion)
Diagnostic criteria of MRONJ: pain, swelling, and non‐healing exposed necrotic bone or fistulae, or both, with connection to the bone
(follow‐up: 24‐60 months)

59 per 1000

5 per 1000
(0 to 89)

RR 0.08
(0.00 to 1.51)

176
(1 RCT)

⊕⊝⊝⊝
VERY LOW1

Participants: high risk, i.e. individuals with cancer exposed to IV zoledronic acid

*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio; OR: odds ratio

GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1. We downgraded the quality of the evidence by three levels due to imprecision and very serious risk of bias (high or unclear risk of selection bias, performance bias, detection bias, and attrition bias).

IV = intravenous

MRONJ = medication‐related osteonecrosis of the jaw

RCT = randomised controlled trial

Figuras y tablas -
Summary of findings 2. A dental extraction protocol with plasma rich in growth factors (PRGF) (experimental) compared to a standard dental extraction protocol without PRGF (control) for prophylaxis of MRONJ in people treated with IV bisphosphonates who need dental extractions
Summary of findings 3. Hyperbaric oxygen therapy as an adjunct to conventional therapy (experimental) compared to conventional therapy (control) for treatment of MRONJ

Hyperbaric oxygen therapy as an adjunct to conventional therapy (experimental) compared to conventional therapy (control) for treatment of MRONJ

Population: treatment of MRONJ
Setting: hospital
Intervention: hyperbaric oxygen therapy as an adjunct to conventional therapy (experimental)
Comparison: conventional therapy (control)

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with conventional therapy (control)

Risk with hyperbaric oxygen therapy as an adjunct to conventional therapy (experimental)

Healing of MRONJ
Diagnostic criteria for healing of MRONJ: gingival coverage with no exposed bone

(follow‐up: up to 24 months (outcome was measured at last follow‐up))

333 per 1000

520 per 1000
(257 to 1000)

RR 1.56
(0.77 to 3.18)

46 participants included in the analysis
(1 RCT)

⊕⊝⊝⊝
VERY LOW1

*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio; OR: odds ratio

GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1. We downgraded the quality of the evidence by three levels due to imprecision and very serious risk of bias (unclear and high risk of selection bias, performance bias, detection bias, and attrition bias; failure to adhere to the intention‐to‐treat principle).

MRONJ = medication‐related osteonecrosis of the jaw

RCT = randomised controlled trial

Figuras y tablas -
Summary of findings 3. Hyperbaric oxygen therapy as an adjunct to conventional therapy (experimental) compared to conventional therapy (control) for treatment of MRONJ
Summary of findings 4. Autofluorescence‐guided bone surgery (experimental) compared to tetracycline fluorescence‐guided bone surgery (control) for treatment of MRONJ

Autofluorescence‐guided bone surgery (experimental) compared to tetracycline fluorescence‐guided bone surgery (control) for treatment of MRONJ

Population: treatment of MRONJ
Setting: hospital
Intervention: autofluorescence‐guided bone surgery (experimental)
Comparison: tetracycline fluorescence‐guided bone surgery (control)

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with tetracycline fluorescence‐guided bone surgery (control)

Risk with autofluorescence‐guided bone surgery (experimental)

Healing of MRONJ
Criteria for healing of MRONJ: mucosal integrity

(follow‐up: 1 year)

889 per 1000

933 per 1000
(764 to 1000)

RR 1.05
(0.86 to 1.30)

34 participants included in the analysis
(1 RCT)

⊕⊝⊝⊝
VERY LOW1

*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio; OR: odds ratio

GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1. We downgraded the quality of the evidence by three levels due to imprecision and very serious risk of bias (unclear and high risk of selection bias, performance bias, and detection bias).

MRONJ = medication‐related osteonecrosis of the jaw

RCT = randomised controlled trial

Figuras y tablas -
Summary of findings 4. Autofluorescence‐guided bone surgery (experimental) compared to tetracycline fluorescence‐guided bone surgery (control) for treatment of MRONJ
Table 1. Clinical staging of MRONJ

MRONJ stage

Description

AT RISK

No apparent necrotic bone in patients who have been treated with oral or intravenous bisphosphonates

STAGE 0

No clinical evidence of necrotic bone but nonspecific clinical findings, radiographic changes, and symptoms

STAGE 1

Exposed and necrotic bone or fistulas that probes to bone in patients who are asymptomatic and have no evidence of infection

STAGE 2

Exposed and necrotic bone or fistulas that probes to bone associated with infection as evidenced by pain and erythema in the region of exposed bone with or without purulent drainage

STAGE 3

Exposed and necrotic bone or a fistula that probes to bone in patients with pain, infection, and ≥ 1 of the following: exposed and necrotic bone extending beyond the region of alveolar bone (i.e. inferior border and ramus in mandible, maxillary sinus, and zygoma in maxilla) resulting in pathologic fracture, extraoral fistula, oral antral, or oral nasal communication, or osteolysis extending to inferior border of the mandible or sinus floor

From the American Association of Oral and Maxillofacial Surgeons position paper on medication‐related osteonecrosis of the jaw‐‐2014 update (Ruggiero 2014)

Figuras y tablas -
Table 1. Clinical staging of MRONJ
Comparison 1. Dental examinations at three‐month intervals and preventive treatments (experimental) versus standard care (control) for prophylaxis of MRONJ

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 MRONJ (incidence proportion) Show forest plot

1

253

Risk Ratio (M‐H, Fixed, 95% CI)

0.10 [0.02, 0.39]

2 MRONJ (incidence rate: MRONJ cases per patient‐year) Show forest plot

1

Rate ratio (Fixed, 95% CI)

0.18 [0.04, 0.74]

Figuras y tablas -
Comparison 1. Dental examinations at three‐month intervals and preventive treatments (experimental) versus standard care (control) for prophylaxis of MRONJ
Comparison 2. A dental extraction protocol with plasma rich in growth factors (PRGF) (experimental) versus a standard dental extraction protocol without PRGF (control) for prophylaxis of MRONJ in people treated with IV bisphosphonates who need dental extractions

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 MRONJ (incidence proportion) Show forest plot

1

176

Risk Ratio (M‐H, Random, 95% CI)

0.08 [0.00, 1.51]

Figuras y tablas -
Comparison 2. A dental extraction protocol with plasma rich in growth factors (PRGF) (experimental) versus a standard dental extraction protocol without PRGF (control) for prophylaxis of MRONJ in people treated with IV bisphosphonates who need dental extractions
Comparison 3. Hyperbaric oxygen as an adjunct to conventional therapy (experimental) versus conventional therapy (control) for treatment of MRONJ

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Healing of MRONJ at last contact Show forest plot

1

46

Risk Ratio (M‐H, Fixed, 95% CI)

1.56 [0.77, 3.18]

Figuras y tablas -
Comparison 3. Hyperbaric oxygen as an adjunct to conventional therapy (experimental) versus conventional therapy (control) for treatment of MRONJ
Comparison 4. Autofluorescence‐guided bone surgery (experimental) versus tetracycline fluorescence‐guided bone surgery (control) for treatment of MRONJ

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Healing of MRONJ (defined as mucosal integrity) at 1 year Show forest plot

1

34

Risk Ratio (M‐H, Fixed, 95% CI)

1.05 [0.86, 1.30]

Figuras y tablas -
Comparison 4. Autofluorescence‐guided bone surgery (experimental) versus tetracycline fluorescence‐guided bone surgery (control) for treatment of MRONJ