Cochrane · intervention · CD012432

Interventions for managing medication‐related osteonecrosis of the jaw

Beth-Tasdogan, NH, Mayer, B, Hussein, H, et al. · Cochrane Database of Systematic Reviews · 2022 · Cochrane Library

Oral Health Oral and maxillofacial surgery3 versionsAMSTAR 2: not assessed

Full textEvery question was extracted from the full review (methods and results), not only its Summary of Findings table.

Questions

current version

GRADE rated

No studies

Included studies

as reported

No studies 0 · 0%Ungraded 6 · 31.6%Very low 11 · 57.9%Low 2 · 10.5%Moderate 0 · 0%High 0 · 0%

Ungraded means an effect was reported without a GRADE rating; it is not a gap. No studies means the review found nothing to answer the question. The six categories are a display order, not a score.

Review question

Element	Planned (methods)	Found (results)
Population	(A) Prophylaxis: people treated with known risk (antiresorptive or antiangiogenic) medications who had not yet developed MRONJ before assignment to the experimental or control group. (B) Treatment: people who had developed clinically apparent MRONJ (case definition: exposure to a risk drug plus necrotic bone or fistulae that probe to bone). No restrictions on sex, age, initial health status, pre-existing conditions, or type/dose/duration of the ONJ-related drug; participants with a history of head and neck radiation therapy excluded.	1668 participants in 13 RCTs (eight new); five prophylaxis trials and eight treatment trials; sample sizes 13-700; more women than men, except one trial of men with prostate cancer; two trials also included denosumab-treated participants (n=1668).
Intervention	(A) Prophylaxis: completion of dental treatment before/soon after commencement of therapy; antibiotic prophylaxis or antiseptic mouthwash; preventive recall programme and patient information; non-traumatic surgery, reconstructive wound-closure techniques and specific dental extraction protocols; supportive measures to accelerate wound healing (PRP, PRGF); cessation of antiresorptive/antiangiogenic therapy ('drug holiday') before invasive dental procedures. (B) Treatment - non-surgical: antiseptic mouthwashes; antibiotic and antifungal therapy; parathyroid hormone and teriparatide; pentoxifylline and alpha-tocopherol; ozone therapy (OT); hyperbaric oxygen therapy (HBO); laser therapy (LLLT); platelet-derived growth-factor preparations (PRP, PRGF); recombinant human bone morphogenetic proteins (rhBMPs). Surgical: surgical debridement, sequestrectomy; jaw bone resection; extraction of teeth within exposed necrotic bone.	Dental examinations at three-month intervals and preventive treatments (n=126); PRGF inserted into the postextraction alveolus (n=91); delicate surgery and closure by primary intention (n=350); primary closure of the extraction socket with a mucoperiosteal flap (n=39); subperiosteal (SPP) wound closure (n=65); hyperbaric oxygen therapy as an adjunct to conventional therapy (n=25); autofluorescence-guided bone surgery (n=20); bone morphogenetic protein-2 with platelet-rich fibrin (n=30); autofluorescence-guided surgery (n=18); platelet-rich fibrin after bone surgery (n=24); concentrated growth factor and primary wound closure (n=14); teriparatide 20 microg daily (n=15); teriparatide 56.5 microg weekly (n=6).
Comparison	No treatment, placebo, or an active control (e.g. standard care).	Standard care (n=127); standard dental extraction protocol without PRGF (n=85); non-traumatic avulsion and closure by secondary intention (n=350); application of platelet-rich fibrin without primary closure (n=38); epiperiosteal (EPP) wound closure (n=67); conventional therapy (n=24); tetracycline fluorescence-guided bone surgery (n=20); platelet-rich fibrin alone (n=25); conventional surgery (n=15); surgery alone (n=23); primary wound closure only (n=14); placebo (n=18); teriparatide 20 microg daily (n=6).
Outcomes	Primary outcomes: (A) prophylaxis - incidence of MRONJ; (B) treatment - healing of MRONJ. Secondary outcomes: (A) quality of life, time-to-event, rate of complications and side effects of the intervention; (B) quality of life, recurrence, rate of complications and side effects of the intervention.	Incidence of MRONJ (5 prophylaxis comparisons); healing of MRONJ (8 treatment comparisons); quality of life (1 comparison, not analysable); rate of complications and side effects (3 comparisons).
Study designs	Randomised controlled trials (RCTs) comparing one modality of intervention with another for the prevention or treatment of MRONJ. Quasi-randomised and non-RCTs, case studies, case series (or case series design) and cross-sectional studies excluded. No restriction on language, publication status or date of publication.	13 RCTs (one study per comparison; eight new since PUB2).
Timing	Follow-up of at least 3 years for the prophylaxis primary outcome and at least 1 year for the treatment primary outcome was planned; the 3-year threshold was subsequently relaxed as it proved unfeasible.	Follow-up ranged from 16 weeks to 60 months: mean ~32 months (dental examinations); 24-60 months (PRGF); 90 days (mucoperiosteal flap vs PRF); 6 months (SPP/EPP; CGF; teriparatide weekly); up to 24 months (HBO); 1 year (fluorescence-guided surgery; PRF after surgery); 16 weeks (BMP-2); 52 weeks (teriparatide daily).

Search date: 2021-06. Databases: Cochrane Oral Health's Trials Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE Ovid; Embase Ovid; US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov); World Health Organization International Clinical Trials Registry Platform

Questions and results

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Dental examinations at three-month intervals and preventive treatments vs Standard care

Population: Men with metastatic prostate cancer receiving intravenous zoledronic acid (at risk of MRONJ)

2 questions

Outcome	Effect	Evidence	Status / GRADE
MRONJ (incidence proportion) mean 32 months same question in other reviews	RR 0.10 [0.02, 0.39] 233 per 1000 vs 23 per 1000	1 study · 253 participants	Very low Downgraded: risk of bias, indirectness
MRONJ (incidence rate: cases per patient-year) mean 28.8 months same question in other reviews	rate ratio 0.18 [0.04, 0.74]	1 study · 253 participants	Very low Downgraded: risk of bias, indirectness

Dental extraction protocol with plasma rich in growth factors (PRGF) inserted into the postextraction alveolus vs Standard dental extraction protocol without PRGF

Population: People with cancer treated with intravenous bisphosphonates undergoing dental extractions (at risk of MRONJ)

2 questions

Outcome	Effect	Evidence	Status / GRADE
Rate of complications and side effects of the intervention 24 to 60 months same question in other reviews	No intraoperative complications were observed in either of the groups.	1 study · 176 participants	Ungraded
MRONJ (incidence proportion) 24 to 60 months same question in other reviews	RR 0.08 [0.00, 1.51] 59 per 1000 vs 5 per 1000	1 study · 176 participants	Very low Downgraded: risk of bias, imprecision

Delicate surgery and wound closure by primary intention vs Non-traumatic tooth avulsion and wound closure by secondary intention

Population: People treated with oral bisphosphonates undergoing dental extractions (at risk of MRONJ)

2 questions

Outcome	Effect	Evidence	Status / GRADE
Rate of complications and side effects of the intervention same question in other reviews	No intraoperative complications were observed in either of the two groups.	1 study · 700 participants	Ungraded
Incidence of MRONJ same question in other reviews	In both study arms, no case of postoperative MRONJ was observed (700 participants; 1 RCT); effect not estimable.	1 study · 700 participants	Ungraded

Hyperbaric oxygen therapy (HBO) as an adjunct to conventional therapy vs Conventional therapy

Population: People with established (manifest) MRONJ

2 questions

Outcome	Effect	Evidence	Status / GRADE
Healing of MRONJ up to 24 months (at last follow-up) same question in other reviews	RR 1.56 [0.77, 3.18] 333 per 1000 vs 520 per 1000	1 study · 46 participants	Very low Downgraded: risk of bias, imprecision
Quality of life 6 months same question in other reviews	QoL measured with the Duke Health Profile; only within-group comparisons were provided; no score values, so a between-group analysis was not possible.	1 study	Ungraded

Autofluorescence-guided bone surgery vs Tetracycline fluorescence-guided bone surgery

Population: People with MRONJ referred for surgical treatment

1 question

Outcome	Effect	Evidence	Status / GRADE
Healing of MRONJ (mucosal integrity) 1 year same question in other reviews	RR 1.05 [0.86, 1.30] 889 per 1000 vs 933 per 1000	1 study · 34 participants	Very low Downgraded: risk of bias, imprecision

Primary closure of the extraction socket with a mucoperiosteal flap vs Application of platelet-rich fibrin (PRF) without primary closure

Population: People on antiresorptive treatment undergoing tooth extraction (at risk of MRONJ)

2 questions

Outcome	Effect	Evidence	Status / GRADE
Incidence of MRONJ 90 days same question in other reviews	All participants had complete mucosal coverage without any signs of MRONJ at the final control examination 90 days postoperatively (77 randomised; 1 RCT); no case of postoperative MRONJ in either group; effect not…	1 study · 77 participants	Ungraded
Rate of complications and side effects of the intervention 90 days same question in other reviews	No intraoperative complications occurred in either group. Postoperative complications: 6 participants (15.4%) in the mucoperiosteal flap group and 1 participant (2.6%) in the PRF group.	1 study · 77 participants	Ungraded

Subperiosteal prepared (SPP) wound closure after tooth extraction vs Epiperiosteal prepared (EPP) wound closure after tooth extraction

Population: People on antiresorptive therapy for cancer or osteoporosis undergoing dental extractions (at risk of MRONJ)

1 question

Outcome	Effect	Evidence	Status / GRADE
MRONJ after tooth extraction (incidence proportion) 6 months same question in other reviews	RR 0.09 [0.00, 1.56] 77 per 1000 vs 7 per 1000	1 study · 132 participants	Low Downgraded: risk of bias, imprecision

Bone morphogenetic protein-2 (BMP-2) together with platelet-rich fibrin vs Platelet-rich fibrin alone

Population: People with established (manifest) MRONJ

1 question

Outcome	Effect	Evidence	Status / GRADE
Healing of MRONJ 16 weeks same question in other reviews	RR 1.10 [0.94, 1.29] 880 per 1000 vs 968 per 1000	1 study · 55 participants	Very low Downgraded: risk of bias, imprecision

Autofluorescence-guided bone surgery vs Conventional bone surgery

Population: People with established (manifest) MRONJ

1 question

Outcome	Effect	Evidence	Status / GRADE
Healing of MRONJ 1 year same question in other reviews	RR 1.08 [0.85, 1.37] 867 per 1000 vs 933 per 1000	1 study · 30 participants	Very low Downgraded: risk of bias, imprecision

Platelet-rich fibrin after bone surgery vs Bone surgery alone

Population: People with established (manifest) MRONJ

2 questions

Outcome	Effect	Evidence	Status / GRADE
Healing of MRONJ (mucosal integrity and absence of infection) 1 year same question in other reviews	RR 1.05 [0.90, 1.22] 913 per 1000 vs 958 per 1000	1 study · 47 participants	Very low Downgraded: risk of bias, imprecision
Healing of MRONJ (mucosal integrity, absence of infection, and no re-intervention) 1 year same question in other reviews	RR 1.60 [1.04, 2.46]	1 study · 47 participants	Very low Downgraded: risk of bias, imprecision

Concentrated growth factor (CGF) and primary wound closure vs Primary wound closure only

Population: Women with osteoporosis and established MRONJ

1 question

Outcome	Effect	Evidence	Status / GRADE
Healing of MRONJ (soft tissue healing) 6 months same question in other reviews	RR 1.38 [0.81, 2.34] 521 per 1000 vs 286 per 1000	1 study · 28 participants	Very low Downgraded: risk of bias, imprecision, indirectness

Teriparatide 20 microg daily in addition to standard care vs Placebo in addition to standard care

Population: People with established (manifest) MRONJ

1 question

Outcome	Effect	Evidence	Status / GRADE
Healing of MRONJ (resolution of lesions) 52 weeks same question in other reviews	RR 0.96 [0.31, 2.95] 278 per 1000 vs 267 per 1000	1 study · 33 participants	Low Downgraded: risk of bias, imprecision

Teriparatide 56.5 microg weekly in addition to standard care vs Teriparatide 20 microg daily in addition to standard care

Population: People with established (manifest) MRONJ

1 question

Outcome	Effect	Evidence	Status / GRADE
Healing of MRONJ (remission) 6 months same question in other reviews	RR 0.60 [0.25, 1.44] 500 per 1000 vs 300 per 1000	1 study · 12 participants	Very low Downgraded: risk of bias, imprecision