Antiresorptive and Antiangiogenic Drugs

Antiresorptive and Antiangiogenic Drugs

Section I: Clinical Scenario and Dental Considerations

Clinical Scenario

A 73‐year‐old man presents to the dental clinic with an ulcer on the right side of the tongue which is particularly painful when speaking and eating. He feels that it may be related to an adjacent rough area on the lower jaw which he first became aware of approximately 2 months ago.

Medical History

  • Prostate cancer diagnosed 8 years earlier
    • Intermediate‐risk, Gleason score of 7
    • Bone metastases recently confirmed
    • Previous treatment has included various combinations of androgen‐deprivation agents (bicalutamide), gonadotropin‐releasing hormone superagonist (goserelin) and cytostatic drugs (leuprorelin)
  • Arterial hypertension (with target organ impairment)


  • Denosumab (for the last 2 years, every 6 months, last given 2 months ago)
  • Prednisone (5–10 mg for the last 5 years)
  • Docetaxel (antineoplastic agent)
  • Calcium
  • Vitamin D
  • Candesartan/hydrochlorothiazide

Dental History

  • Irregular dental visit attender
  • Stopped going due to ongoing treatment and side‐effects related to his oncological disease
  • Often feels tired and forgets to brush his teeth

Social History

  • Widowed, lives alone
  • Son lives nearby and is next of kin
  • Care‐giver support daily
  • Reduced mobility; relies on a walking aid and can only manage short distances

Oral Examination

  • Poor oral hygiene with multiple soft and hard deposits all quadrants
  • Chronic periodontal disease in relation to all the remaining teeth
  • An area > 1 cm of bony exposure in the region of the right mandibular alveolar crest, painful on probing; no purulent discharge (Figure 16.2.1)
  • An ulcer > 1 cm in the right lateral border of the tongue adjacent to the exposed area of bone
  • Extensive caries in #44
  • Partially edentate with missing posterior teeth: #14–17, #24–26, #35–37 and #45–47
  • Overlying trauma from a poorly fitting lower partial denture
Photo depicts exposed bone right lingual surface of the mandible and traumatic tongue ulceration (S).

Figure 16.2.1 An area > 1 cm of exposed bone on the right lingual surface of the mandible, and adjacent traumatic tongue ulceration.

Radiological Examination

  • An orthopantomogram was undertaken and demonstrated scarce and irregular bone trabeculation in the region of the exposed bone area and adjoining areas
  • Computed tomography confirmed the presence of a sequestrum in the lower right mandibular region

Structured Learning

  1. What is your provisional diagnosis for the exposed area of bone?
    • Whilst it is important to exclude bone metastasis secondary to prostate cancer, the appearance of bone coupled with the patient’s history of taking an antiangiogenic drug suggests that the area of exposed bone is due to medication‐related osteonecrosis of the jaw (MRONJ)
    • This patient has associated pain on probing, suggestive of infection; hence this would be described as Stage 2 MRONJ
  2. What MRONJ risk factors does this patient have?
    • Related to the antiresorptive drug: denosumab (high‐potency drug)
    • Related to other drugs: chemotherapy and corticosteroids
    • Patient‐related: older age
    • Local factors: poorly fitting lower partial denture causing trauma to the mandibular crestal ridge, poor oral health/existing periodontal disease
  3. What are the treatment options for managing this lesion?
    • Antimicrobial treatment with a 0.12–0.2% chlorhexidine mouthwash (twice per day)
    • Antibiotics, e.g. doxycycline (200 mg/day) from 7 days prior to the surgery until 3 weeks after the procedure (or an alternative antibiotic regime)
    • Removal of sequestrum
    • Reduce trauma to the tongue (gently smooth the exposed bone)
    • Pain relief for the tongue ulcer (anaesthetic gel/anti‐inflammatory mouthwash)
    • Reduce trauma from the denture (avoid wearing it, adapt by adjusting it so that there is no contact, and/or replace with once the area has stabilised)
  4. What factors are considered important in assessing the risk of managing this patient?
    • Social
      • Reduced mobility
      • Requires escort/support for attending appointments
    • Medical
      • Poor prognosis (metastasised prostate cancer)
      • Risk of acute adrenal insufficiency/crisis due to systemic steroids (see Chapter 12.1)
      • Local and distant infection risk, delayed wound healing and bleeding tendency due to adverse effects of the antineoplastic agent (see Chapter 12.2)
      • Risk of a hypertensive crisis (see Chapter 8.1)
      • Risk of complications due to hypertension‐related target organ involvement (see Chapter 8.1)
    • Dental
      • Poor oral hygiene
      • Periodontal disease
      • Lack of posterior occlusal support and hence increased risk of continued denture‐associated trauma may trigger further MRONJ
      • Extensive caries in #44: dental extraction can trigger further MRONJ; preferable to undertake endodontic treatment and seal the root surface; this also maintains support for the denture as an overdenture abutment
  5. Would you advise the patient to discontinue denosumab in view of the MRONJ?
    • There is insufficient evidence to support or refute the discontinuation of bone‐modifying agents such as denosumab
    • Administration of denosumab may be deferred at the discretion of the treating physician, in conjunction with the patient and with input from the dentist regarding the oral findings
    • However, careful consideration should be given to the risks of discontinuation as the systemic complications in relation to the bony metastases in this patient are significant
    • As denosumab has a shorter half‐life than bisphosphonates, it has been suggested that if an oral surgical procedure is planned, this should be conducted no sooner than 1 month after the last injection and when there are at least 6 weeks until the next injection to allow for adequate healing (although there is some controversy on this matter)
  6. What circumstances would justify referring the patient to a hospital‐based maxillofacial surgery department?
    • Medical comorbidities and frailty related to cancer diagnosis and the arterial hypertension (close liaison with the physician/oncologist required)
    • Significant haematological abnormalities due to the antineoplastic chemotherapy
    • If the sequestrum is large (greater than 3 cm) and/or if primary closure appears impossible
  7. What antibiotics are indicated during the perioperative period?
    • Maxillofacial/oral surgeons mostly prefer penicillin‐based antibiotics plus beta‐lactamase inhibitor or metronidazole for MRONJ surgery
    • Based on empirical experience, doxycycline has also shown satisfactory results

General Dental Considerations

Oral Findings: Medication‐Related Osteonecrosis of the Jaw (MRONJ)

  • MRONJ is an adverse effect of antiresorptive and antiangiogenic drugs and can appear spontaneously, although it is generally triggered by a dental procedure that involves bone manipulation (Figure 16.2.2)
  • Signs and symptoms include delayed healing following a dental extraction or other oral surgical procedure, as well as pain, soft tissue infection and swelling, numbness, paraesthesia and exposed bone
  • Patients might also complain of pain or altered sensation in the absence of exposed bone
  • MRONJ can be spontaneous and also present as an incidental finding in the absence of any symptoms, appearing either as areas of radiopacity or radiolucency in the jaw bones

Dental Management

  • For patients who are administered antiresorptive or antiangiogenic agents, the recommendation is to implement a protocol that includes preventive and procedural measures, mainly applicable when performing surgical procedures in the dentoalveolar area (Table 16.2.1)
  • A risk assessment is required to ensure a specific informed consent is undertaken before any invasive dental procedure (Table 16.2.2)
Photo depicts spontaneous bone exposure following periodontal treatment, suggestive of medication-related osteonecrosis of the jaw (M).

Figure 16.2.2 Spontaneous bone exposure following periodontal treatment, suggestive of medication‐related osteonecrosis of the jaw.

Table 16.2.1 Recommended clinical protocol before starting antiresorptive treatment.

  • Collect information on the drug product, dosage, envisaged treatment duration and concomitant administration of other drugs
  • Provide verbal and written information to the patient about the risk of medication‐related osteonecrosis of the jaw (informed consent)
  • Extract the non‐restorable teeth
  • Perform restorative and prosthodontic treatment for the teeth with good prognoses
  • Diagnose and treat periodontal disease
  • Assess the risk of caries and periodontal disease
  • Teach the patient oral hygiene techniques and implement an individual maintenance protocol
  • For patients with cancer, close liaison with the oncologist is required to ensure adequate healing in relation to the timing of cancer therapy

Section II: Background Information and Guidelines


Medication‐related osteonecrosis of the jaw is a rare side‐effect of antiresorptive and antiangiogenic drugs (Table 16.2.3). It is defined as exposed bone or bone that can be probed through an intraoral or extraoral fistula in the maxillofacial region, that has persisted for more than 8 weeks in patients with a history of treatment with antiresorptive or antiangiogenic drugs but no history of radiation therapy to the jaw and no obvious metastatic jaw disease.

The incidence of MRONJ increases with the duration of antiresorptive or antiangiogenic therapy, with notable differences observed with respect to drug type and potency, route of administration and underlying disease. MRONJ can develop in approximately 7% of patients with cancer who take high‐potency bisphosphonates or high‐dose denosumab and about 0.001–0.01% of those with osteoporosis using low‐potency oral bisphosphonates or low‐dosage denosumab.

More recently, novel targeted chemotherapy drugs have been implicated in MRONJ (see Chapter 12.2) and the risk may be compounded further if given in conjunction with bisphosphonates or denosumab (Table 16.2.4).


  • The aetiopathogenesis of MRONJ has not been fully determined and is likely to be multifactorial, with both genetic and immunological components
  • Several genes (e.g. CP2C8
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Nov 6, 2022 | Posted by in Implantology | Comments Off on Antiresorptive and Antiangiogenic Drugs

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