MRONJ & Oral Surgery

Medications & Osteo-Necrosis of the Jaw (‘Dead Jaw Syndrome’)

Medication-Related Osteo-Necrosis of the Jaw (MRONJ) is a rare side effect of anti-resorptive and anti-angiogenic drugs (these medications are given for osteoporosis or bone manifestations in different types of cancer, to reduce skeletal complications of these conditions, achieving a reduction in pain and typical bone fractures, as well as an improvement in the life quality of these patients).

BRONJ, ARONJ & MRONJ

Bisphosphonate-induced Osteo-Necrosis of the Jaw (BRONJ)
Anti-Resorptive agent-induced Osteo-Necrosis of the Jaw (ARONJ)
Medication-induced Osteo-Necrosis of the Jaw (MRONJ)

This covers the Osteo-Necrosis of the Jaw 2^nd to use of Anti-Resorptive & Anti-Angiogenesis medications. These include the following medications:

Bisphosphonates
Denosumab
Bevacizumab
Sunitinib & Aflibercept

I always presume with female patients > 55 – 60 years of age, that they may be on bisphosphonates unless proved otherwise. If they have annual infusions, patients tend to forget. I specifically question, if patients have problems with osteoporosis, if they have annual or weekly infusions for the osteoporosis. If unsure, write to the patient’s GMP.

For historical reasons, most cases would have been seen with bisphosphonates. With increased use of the RANKL-inhibitors & tyrosine kinase receptor inhibitors, may start to see more cases of MRONJ.

What is MRONJ?

Exposed bone or bone that can be probed through an intra-oral or extra-oral fistula, in the maxillo-facial region that has persisted for more than 8 weeks in patients with a history of treatment with anti-resorptive or anti-angiogenic drugs and where there has been no history of radiation therapy to the jaw or no obvious metastatic disease to the jaws.

Ætiology of MRONJ

At present, the patho-physiology of the disease has not been fully determined & there is much debate about the mechanisms by which these drugs induce necrosis in the jaw bone.
Current hypotheses for the causes of necrosis include suppression of bone turnover, inhibition of angio-genesis (blood vessel formation), toxic effects on soft tissue, inflammation or infection.
It is likely that the cause of the disease is multi-factorial, with both genetic & immunological elements.

Incidence of MRONJ

Risk Factors – Local & General

Use of high-dose IV bis-phosphonate
Longer duration of treatment with bis-phosphonate
Steroid use (Prednisolone, Dexamethasone)
Alcohol abuse and tobacco use
People suffering from cancer
Poor dental hygiene and those who undergo a dental procedure such as dental extraction
Diabetes mellitu

Local risk factors

Lower jaw molar extractions: ²/₃’s of BRONJ cases have been reported in the mandible (lower jaw)
All dento-alveolar surgery
Periodontitis / poor oral hygiene: the bacterial bio-film present in periodontal disease (gum disease) is responsible for gingival (gum) inflammation and alveolar bone resorption. This pathology, together with the interactions between bacteria themselves and bisphosphonates can increase the possibility of BRONJ
Trauma related to dentures
Thin mucosal coverage, lingual (tongue-side) to lower molars and bony

General risk factors

Concomitant therapies: corticosteroids, other immunosuppressants (eg methotrexate, thalidomide), chemotherapeutic agents (eg hormone antagonists)
Systemic conditions affecting bone turnover: immunocompromised patients, rheumatoid arthritis, poorly controlled diabetes
Smoking
Socio-demographic characteristics: extreme of age (over 6th decade), gender

Previous Treatment with MRONJ Drugs

Denosumab diminishes over 6 months. After completion of treatment, the risk is negligible (ie same risk as a non-treated patient)
Anti-angiogenic drugs are not thought to remain in the body for extended periods of time. After completion of treatment, the risk is negligible (ie same risk as a non-treated patient)
Bisphosphonates are known to persist in bone (and have an effect) even though the patient may be on a drug holiday or have stopped taking the medications. Soft tissues recover faster than hard. Still at risk (though this gets less slowly with time).

MRONJ Discussions with patients

Important that patients are not discouraged from taking their medication or having dental treatment
Due to medication, small / rare risk of MRONJ
Discuss the benefits of these medications & why it is important for them to continue taking them
Discuss the overall risk of MRONJ with the patient, based on the medical condition for which they are being treated, using language that they are able to understand
Stress that the disease is rare, is an adverse effect of the medication & is not caused by dental treatment
Discuss with the patient the steps you will take to reduce their risk of MRONJ
Discuss with the patient the steps that they can take to reduce their risk of MRONJ
All to be written in the notes & confirmed by patient

What are the symptoms of BRONJ?

These symptoms may occur spontaneously or more often, following tooth extraction.

Although most cases of MRONJ occur following a dental intervention which impacts on bone, some can occur spontaneously.
Signs and symptoms include delayed healing following a dental extraction or other oral surgery, pain, soft tissue infection & swelling, anæsthesia, paræsthesia or exposed bone.
Loosening of teeth and exposed bone
Patients may also complain of pain or altered sensation in the absence of exposed bone.
However, be aware that some patients may be asymptomatic at presentation, with MRONJ lesions an incidental finding.
A history of anti-resorptive or anti-angiogenic drug use in these patients should alert to the possibility of MRONJ.

Staging of MRONJ

Exposed necrotic bone in the anterior left maxilla related to use of Bisphosphonates

Exposed_necrotic_bone_in_the_anterior_left_maxilla-2

Stage I Bisphosphonate-Related Osteo-Necrosis of the Jaw (BRONJ) of the right mylohyoid ridge area

Stage_I_bisphosphate-related_osteonecrosis_of_the_jaw_BRONJ_of_the_right_mylohyoid_ridge_area-2

Extensive stage III BRONJ of the mandible in a patient treated with intravenous bisphosphonate therapy

Extensive_stage_III_bisphosphonate-related_osteonecrosis_of_the_jaw_BRONJ_of_the_mandible_in_a_p-3

GDP Treatment of Patients

Give personalised preventive advice to help the patient optimise their oral health, emphasising the importance of:

having a healthy diet & reducing sugary snacks & drinks
maintaining excellent oral hygiene
using fluoride toothpaste / fluoride mouthwash
stopping smoking
limiting alcohol intake
regular dental checks
reporting any symptoms such as loose teeth, numbness or altered sensations, pain or swelling as soon as possible

Prioritise care that will reduce mucosal trauma or may help avoid future extractions or any oral surgery or procedure that may impact on bone

extract any teeth of poor prognosis without delay
undertake any remedial dental work
focus on reducing periodontal / dental infection or disease
adjust / replace poorly fitting dentures to minimise future mucosal trauma
consider prescribing high fluoride toothpaste

For higher risk, medically complex patients who are being treated with anti-resorptive or anti-angiogenic drugs for the management of cancer & for whom you would normally seek advice, consider consulting an oral (& maxillofacial) surgery / special care dentistry specialist with regards to clinical assessment & treatment planning

MRONJ Treatment Considerations

Low Risk

Patients being treated for osteoporosis or other non-malignant bone diseases with:
- Oral / annual infusions of bisphosphonates < 5 years or
- RANKL inhibitors
Who are not taking concurrent systemic corticosteroids or other immuno-suppressants
Perform extractions & procedures that may impact on bone
Do not prescribe antibiotics or antiseptic mouth rinses

High Risk

Patients being treated for osteoporosis or other non-malignant bone diseases with:
- Oral / annual infusions of bisphosphonates > 5 years or
- Oral / annual infusions of bisphosphonates or RANKL inhibitors for any length of time who are taking concurrent systemic corticosteroids or other immuno-suppressants
Patients taking anti-resorptive / anti-angiogenic drugs (or both) as part of cancer management
Patients with previous diagnosis of MRONJ

Explore all possible alternatives to extraction where teeth could potentially be retained

If extraction remains the most appropriate treatment, proceed as for low risk patients

If patient is diagnosed with MRONJ, surgery & exodontia should be avoided. Oral hygiene measures should be reassessed & reinforced
This conditions requires a team approach & regular communication between GP, hospital specialist (such as endocrinologist), dentist & oral (and maxillofacial) surgeon
“BRONJ Networks”
The main aim is to conserve the teeth & maintain good oral hygiene

Some fundamental treatment steps to be used are:

Daily irrigation & antiseptic mouth rinses
Antibiotics to control acute infection
Surgical treatment to remove the necrotic bone may be advisable in more advanced cases
In some patients, a removable appliance to cover & protect the exposed bone is necessary (though a protective stent may damage the surrounding soft tissues or makes normal function difficult)
If dentures are worn, minimise irritation of the soft-tissues, particularly for patients who are receiving IV bisphosphonate therapy. Dentures should be removed & thoroughly cleaned at night

MRONJ & Antibiotic Prophylaxis

Due to increased incidence of bacterial resistance & numerous side-effects associated with antibiotic therapy, antibiotics should only be prescribed where there is clear evidence that patients will benefit from them (cf. NICE Antibiotic Stewardship & FGDP (UK))
Currently insufficient evidence to support the use of antibiotic or topical antiseptic prophylaxis to reduce the risk of MRONJ following exodontia or procedures that impact on bone

Can MRONJ be treated?

There is no cure for MRONJ to date. This is possibly a case of prevention is better than cure. Regardless though, there are a number of treatment pathways and network can ameliorate MRONJ if it develops.

Useful Articles & Websites

Bandolier – Evidence-Based Healthcare

http://www.bandolier.org.uk/band149/b149-3.html

Journal of the American Dental Association

https://jada.ada.org/article/S0002-8177(21)00310-X/fulltext

Journal of the Royal College of Surgeons of Edinburgh and Ireland

https://www.sciencedirect.com/science/article/abs/pii/S1479666X11001259

Dentistry Today.com

link not working

Royal College of Physicians

https://www.rcplondon.ac.uk/guidelines-policy/medication-related-osteonecrosis-jaw-guidance-oncology-multidisciplinary-team

American Association of Oral and Maxillofacial Surgeons

https://www.aaoms.org/docs/govt_affairs/advocacy_white_papers/mronj_position_paper.pdf

Dental Protection

https://www.dentalprotection.org/uk/articles/an-update-on-mronj-and-the-successful-defence-of-a-difficult-claim

American Association of Endodontists

link not working

NHS England

https://www.england.nhs.uk/mids-east/wp-content/uploads/sites/7/2015/03/bisphosphonates-guidelines-2015.pdf

Journal of Research in Medical & Dental Science

https://www.jrmds.in/articles/clinical-practice-guidelines-in-dental-management-of-medication-related-osteonecrosis-of-jaw-mronj-61370.html

British Association of Oral Surgery

https://www.baos.org.uk/wp-content/uploads/2019/03/MRONJ-website-text.pdf

Cochrane Reviews

https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD012432.pub2/full?highlightAbstract=mronj

BMJ

https://www.bmj.com/content/365/bmj.l1733

Useful Articles:

J Am Dent Assoc 2005. Managing the Care of Patients with Bisphosphonate-Associated Osteonecrosis – An American Academy of Oral Medicine Position Paper

Dental Update 2006. BONJ – A Guide for the GDP

British Dental Journal 2007. Bisphosphonate osteonecrosis of the jaws; an increasing problem for the dental practitioner

Dental Update 2008. Recent Recommendations on BONJ

Journal of Rheumatology 2008. Guidelines for bisphosphonate-associated osteonecrosis of the jaw

American Academy of Oral Medicine 2008. Patient Information Sheet. Bisphosphonate Therapy & the Oral Cavity

British Dental Journal 2009. Dental extractions and bisphosphonates – the assessment, consent and management, a proposed algorithm

J Oral Maxillofac Surg 2009. Bisphosphonates – What the Dentist Needs to Know. Practical Considerations.

J Oral Maxillofac Surg 2009. American Association of Oral & Maxillofacial Surgeons Position Paper on BONJ. Update.

British Medical Journal 2009 – Battle over Fosamax bursts into court

British Medical Journal 2010 – Osteonecrosis of the Jaw and Bisphosphonates – Low Doses for Osteoporosis seem to be safe

Oral Surgery 2010. Reviewing the efficacy of changing prophylactic measures for the prevention of Bisphosphonate Related Osteonecrosis of the Jaws (BRONJ) in the management of oral surgery patients

J Oral Maxillofac Surg 2010. Occurrence of Bisphosphonate-Related Osteonecrosis of the Jaw After Surgical Tooth Extraction

JOMS 2010. Dental extractions in patients receiving Bisphosphonate therapy

J Oral Maxillofac Surg 2011. Nationwide Survey for Bisphosphonate-Related Osteonecrosis of the Jaws in Japan

BJOMS 2011. Leading Article. Bisphosphonate Osteonecrosis of the Jaw – A Literature Review of UK Policies versus International Policies on the Management of Bisphosphonate Osteonecrosis of the Jaw

Dental Update 2011. A Current Update on Osteonecrosis of the Jaw & Bisphosphonates

BJOMS 2011. Leading Article. Bisphosphonate Osteonecrosis of the Jaw — A Literature Review of UK policies vs. International Policies on Bisphosphonates, Risk Factors & Prevention

BJOMS 2011. Treatment of BONJ – Presentation of a Protocol & an Observational Longitudinal Study of an Italian Series of Cases

BJOMS 2011. Short communication. Non-surgical management of stage 3 biphosphonate-related oro-antral fistula

Dental Update 2011. Practical Considerations for Treatment of Patients taking Bisphosphonate Medications – An Update

JADA 2011. For The Dental Patient…Osteoporosis Medications & your Dental Health

Scottish Dental Clinical Effectiveness Programme. Oral Health Management of Patients Prescribed Bisphosphonates Dental Clinical Guidance

Scottish Dental Clinical Effectiveness Programme 2011. Advice for Patients Prescribed Bisphosphonates

The Surgeon, J RCS Edinburgh & Ireland 2012. Review. Bisphosphonate Osteonecrosis of the Jaw. A Historical & Contemporary Review

BDJ 2012. Letter to Editor. Bisphosphonate Considerations

BDJ 2012. Bisphosphonate-Related Osteonecrosis of the Jaw is Rare

Bisphosphonates and Osteonecrosis of the Jaw – A Multidisciplinary Approach (2012)

FGDP (UK). December 2012. National study on Avascular Necrosis of the Jaws including Bisphosphonate-Related Necrosis

JOMS 2013. Tooth Extractions in Intravenous Bisphosphonate-Treated Patients – A Refined Protocol

JOMS 2013. Osteonecrosis of the Jaw Onset Times are based on the Route of Bisphosphonate Therapy

Dent Update 2013. The Characteristics of Bisphosphonate Patients Developing BRONJ Attending an OMFS Department

Dent Update 2013. The Risk of BRONJ in Children. A Case Report & Literature Review

BDJ 2014. Legal liability in bisphosphonate-related osteonecrosis of the jaw

Dent Update 2015. Case Report. Beware the Silver Nitrate Stick. A Risk Factor for BRONJ

Medication-Related Osteonecrosis of the Jaws – Bisphosphonates, Denosumab & New Agents ( 2015)

Dent Update 2016. Relevance of Bisphosphonate Therapy in Osteoporosis & Cancer − No Cause for Alarm

Scottish Dental Clinical Effectiveness Programme (SDCEP) 2017. Oral Health Management of Patients at Risk of Medication-related Osteonecrosis of the Jaw – Dental Clinical Guidance

Dental Update 2018. Dental Update 2018. Medication-Related Osteo-Necrosis of the Jaw (MRONJ) – Realities, Risks & Responsibilities

BMJ Open 2019. General dental practitioners’ perceptions of, and attitudes towards, improving patient safety through a multidisciplinary approach to the prevention of medication-related osteonecrosis of the jaw (MRONJ): a qualitative study in the North East of England

Medication-related osteonecrosis of the jaw. Guidance for the oncology multidisciplinary team. Report of a working party on behalf of the UK Chemotherapy Board. 2019

Oral Surg Oral Med Oral Pathol Oral Radiol 2019. Medication-Related Osteonecrosis of the Jaw – Definition and Best Practice for Prevention, Diagnosis & Treatment

BDJ 2020. New MRONJ Guidelines. Letter to Editor

Clin Exp Dent Res 2020. Conservative Non-Surgical Management in Medication Related Osteonecrosis of the Jaw. A Retrospective Study

Medicina 2021. Infection as an Important Factor in Medication-Related Osteonecrosis of the Jaw (MRONJ).

Appl Sci 2021. 18 Years of Medication-Related Osteonecrosis of the Jaw (MRONJ) Research. Where Are We Now? – An Umbrella Review.

Dent J 2022. Medication-Related Osteonecrosis of the Jaw in Dental Practice. A Retrospective Analysis of Data from the Milan Cohort

Eur J Dent Oral Health 2022. Medication-Related Osteonecrosis of the Jaw. A Reflection of Current Preventative and Therapeutic Guidelines. A Review.

Oral 2022. ONJ (MRONJ) Update 2021 – Osteonecrosis of Jaw Related to Bisphosphonates and Other Drugs – Prevention, Diagnosis, Pharmaco-vigilance, Treatment: A 2021 Web Event

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