A dental student’s guide to…medication-related osteonecrosis of the jaw

MRONJ

In this month’s dental student’s guide, Hannah Hook explores medication-related osteonecrosis of the jaw (MRONJ) and signs to look out for.

What is MRONJ?

Medication-related osteonecrosis of the jaw (MRONJ) is a rare side effect of anti-resorptive and anti-angiogenic medications.

It is the progressive necrosis (tissue death) of the bone in the maxilla or mandible. It presents in a patient who has received anti-angiogenic or anti-resorptive medications and does not have a history of radiation therapy.

Whilst some cases occur spontaneously, the majority of cases of MRONJ occur following dental treatment. It is defined as exposed bone or bone that the clinician can probe through a extraoral or also intraoral fistula in the maxilla or mandible persisting for more than eight weeks (Ruggiero et al, 2014; Frazer-Cox, 2020).

It was previously termed bisphosphonate-related osteonecrosis of the jaw (BRONJ). However, two classes of non-bisphosphonate drugs – RANK ligand inhibitors and anti-angiogenics – were found to also cause cases of osteonecrosis.

Signs and symptoms

As explained above, MRONJ is the formation of areas of necrotic bone that persist for a prolonged period of time (>eight weeks).

Such clinical findings paired with a patient’s medical history documenting the use of anti-angiogenic or anti-resorptive medications should also indicate the possibility of MRONJ.

According to guidance from the SDCEP, common signs and symptoms associated with the diagnosis of MRONJ include:

  • Delayed healing following a dental extraction or other oral surgery
  • Soft tissue infection and swelling
  • Numbness
  • Paraesthesia
  • Exposed bone.

Whilst listed above are common signs and symptoms of MRONJ, some patients may present asymptomatically. Furthermore, some cases may occur spontaneously.

How is MRONJ caused?

At present, the pathophysiology of the disease has not been fully determined. There is much debate about the mechanisms by which these drugs induce necrosis in the maxilla and mandible.

It has been speculated that the events that lead to bone necrosis are the suppression of bone turnover, toxic effects on the soft tissue, inhibition of angiogenesis, infection or inflammation (Ruggiero et al, 2014).

However, it is extremely likely that this disease is multifactorial, incorporating immunological and genetic elements.

Medications that cause MRONJ

The two main classes of drugs resulting in the development of MRONJ are known as anti-resorptive or anti-angiogenic medications.

Anti-resorptives

This class of drugs inhibit the resorption of bone. As the jaw has an increased turnover rate of bone, it is more likely than other bones to be adversely affected by these medications.

Bisphosphonates

Types: alendronic acid, risedronate sodium, zoledronic acid.

Mechanism: inhibition of enzymes essential for osteoclast differentiation and function. Results in increased osteoclast apoptosis and reduced bone remodelling and resorption. Bisphosphonates bind directly to bone and persist for a significant amount of time, with alendronate (alendronic acid) having a half-life of 10 years (Khan et al, 1997).

Prescribed for: patients with metastatic bone diseases, such as those associated with multiple myeloma, breast cancer and prostate cancer. They can also be prescribed for patients with osteoporosis, paget’s disease, fibrous dysplasia or osteogenesis imperfecta.

RANKL inhibitors

Types: denosumab.

Mechanism: a human monoclonal antibody that prevents bone turnover. It does this by blocking RANKL from activating the RANK receptor on the osteoclast surface. The obstruction in RANKL/RANK signalling leads to inhibition of osteoclast formation, function and survival.

Unlike bisphosphonates, RANKL inhibitors don’t bind to bone, therefore their half-life is significantly shorter at around 25-32 days (Qaisi et al, 2016). Following completion of treatment their effects diminish after six months.

Prescribed for: patients with metastatic bone disease, osteoporosis.

Anti-angiogenics

Types: bevacizumab, sunitinib, aflibercept.

Mechanism: these medications target vascular endothelial growth factor (VEGF), a protein which plays a role in the formation of new blood vessels. Inhibition of the formation of new blood vessels (angiogenesis) results in restriction of tumour growth as it cannot develop a blood supply to provide it with oxygen and nutrients.

Risk factors

The greatest risk factor for MRONJ is the underlying health condition for which the patient is being treated.

Patients are generally deemed high risk if they have been receiving these medications for the treatment of cancer, and low risk for the treatment of osteoporosis. A patient is also deemed high risk if they have had a previous episode of MRONJ, regardless of the condition they are receiving treatment for.

Low risk (0.001-0.01%)

Patients are deemed to be at low risk of developing MRONJ if they:

  • Are receiving bisphosphonates for treatment of osteoporosis or paget’s
  • Have been taking oral bisphosphonates for <five years
  • Are not being concurrently treated with systemic glucocorticoids
  • Bisphosphonates are taken orally or given as quarterly or yearly intravenous infusions.

High risk (1-10%)

Patients with a high risk of developing MRONJ are those who:

  • Have been receiving bisphosphonates for >five years
  • Are receiving concomitant (associated) systemic steroid therapy with glucocorticoids alongside bisphosphonates or denosumab
  • Are being treated with both anti-resorptive and anti-angiogenic medications for cancer management
  • Have had a previous diagnosis of MRONJ.

Prevention

Prevention is essential in patients at an increased risk of MRONJ.

Therefore, the clinician should place focus on getting the patient’s mouths stable and ensuring their oral hygiene is excellent. Their diet should be investigated, and cariogenic risk factors reduced.

Give smoking cessation where appropriate and reduce alcohol intake. Increasing the recall frequency of patients at a high risk of MRONJ will enable frequent assessments of the patient’s oral and dental health.

Carry out any invasive treatment such as extractions, where possible, before the commencement of the patients anti-resorptive or anti-angiogenic therapy.

Management

If preventative measures do not work and the patient requires treatment such as extractions, the SDCEP recommends that any such procedures are carried out in a primary care setting as there is no benefit in referring to the hospital where the same care will be provided.

However, many dental schools may have their own policies regarding referral of patients at an increased risk of MRONJ. Be sure to check this first.

The risk for developing MRONJ is fairly low. One systematic review finds the incidence of it occurring at 0.15% in osteoporosis patients and 2.9% in cancer patients (Gaudin et al, 2015). However, in 60% of cases MRONJ occurred following tooth extractions (Saad et al, 2012).

Generally, if any treatment such as extractions are required, the following steps should be taken:

  • Ensure that valid consent is gained by discussing the risks and benefits with the patient
  • Carry out treatment as clinically indicated, trying to ensure the procedure is carried out as atraumatically as possible
  • Remove any sharp bits of residual bone
  • Antibiotics or antiseptic prophylaxis is not required unless indicated for other reasons
  • Recommend that the patient contact the dentist if they have any concerns or unexpected side effects
  • Review the patient after eight weeks, if the extraction site has not healed and you suspect MRONJ, then refer to the hospital following local guidelines.

Summary

  • MRONJ is a rare side effect of anti-resorptive and anti-angiogenic medications
  • It is defined as exposed bone, which is present for more than eight weeks
  • Patients are classified as either low risk or high risk, depending on how long they have been taking the anti-resorptive/anti-angiogenic medications, whether they are taking it with glucocorticoids, and if they have had a previous diagnosis of MRONJ
  • Prevention is key. Make all efforts to help at risk patients maintain a healthy and stable oral environment
  • If intervention is required, any procedures that are a risk factor for MRONJ, such as extractions, should be carried out as atraumatically as possible
  • If healing does not occurr after eight weeks and you suspect MRONJ, then refer to secondary care.

References

ADA Science Instiute. Osteoporosis Medications and Medication-Related Osteonecrosis of the Jaw. March 27 2019; 1.

Frazer-Cox C (2020) New MRONJ guidance. Br Dent J 229: 151

Gaudin E, Seidel L, Bacevic M, Rompen E and Lambert F (2015) Occurrence and risk indicators of medication-related osteonecrosis of the jaw after dental extraction: A systematic review and meta-analysis. J Clin Periodont 42: 922-32

Khan SA, Kanis JA, Vasikaran S, Kline W, Matuszewski B, McCloskey E, Beneton M, Gertz B, Sciberras D, Holland S, Orgee J, Coombes G, Rogers S and Porras A (1997) Elimination and biochemical responses to intravenous alendronate in postmenopausal osteoporosis. J Bone Miner Res 12: 1700-7

Qaisi M, Hargett J, Loeb M, Brown J and Caloss R (2016) Denosumab Related Osteonecrosis of the Jaw with Spontaneous Necrosis of the Soft Palate: Report of a Life Threatening Case. Case Rep Dent Epub ahead of print 2016

Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B and O’Ryan F (2014) American association of oral and maxillofacial surgeons position paper on medication-related osteonecrosis of the jaw – 2014 update. J Oral Maxillofac Surg 72: 1938-56

Saad F, Brown JE, Van Poznak C, Ibrahim T, Stemmer S, Stopeck A, Diel I, Takahashi S, Shore N, Henry D, Barrios C, Facon T, Senecal F, Fizazi K, Zhou L, Daniels A, Carrière P and Dansey R (2012) Incidence, risk factors, and outcomes of osteonecrosis of the jaw: Integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol 23: 1341-7

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