Learning objectives
- •
The definition, diagnosis, and staging of osteonecrosis of the Jaw (ONJ).
- •
Factors increasing the risk of ONJ.
- •
Developing a management plan tailored to individual circumstances of the patient.
The case study
Reasons for seeking medical help
- •
DD, 68 years old, has been diagnosed with osteoporosis about 12 years ago. She was prescribed alendronate and is taking it as directed. She has not experienced any adverse effect.
- •
Her dentist is concerned because she has a nonhealing cavity where a tooth was extracted about 4 months ago. DD is asymptomatic and did not know she had this cavity. Her dentist recommends multiple teeth extraction in the very near future.
Past medical and surgical history
- •
Natural menopause at 47 years, no HRT.
- •
Always enjoyed good health.
Lifestyle
- •
Daily dietary calcium intake about 1200 mg.
- •
No excessive sodium/caffeine intake.
- •
Observes meticulous dental hygiene.
- •
Exercises regularly: aerobic/resistive exercises, about 60 min, three times a week.
Medication(s)
- •
Risedronate 75 mg once a week. Good adherence.
Family history
- •
Positive: her mother sustained a fragility hip fracture.
Clinical examination
- •
Weight 152 pounds, steady; height 64″.
- •
A cavity is present in the left mandible where the tooth was extracted, bone is visible, no signs of inflammation.
- •
No other relevant clinical signs.
Laboratory result(s)
- •
CBC, CMP, serum 25-hydroxy-vitamin D: all within normal limits.
DXA and radiologic result(s)
- •
T-scores: lumbar vertebrae −1.2, left femoral neck −1.1, left total hip −1.1.
- •
VFA: no evidence of vertebral compression fractures.
- •
FRAX scores: 1.3% and 9% for the 10-year risk of sustaining an osteoporotic hip or major fracture, respectively.
Multiple choice questions
- 1.
DD’s clinical presentation is suggestive of osteonecrosis of the jaw:
- A.
Stage 0.
- B.
Stage I.
- C.
Stage II.
- D.
Stage III.
- E.
None of the above; she has a posttooth extraction: a dry socket.
Correct answer: B.
Comment:
The hallmark of ONJ is exposed mandibular or maxillary bone for at least 8 weeks as observed and recorded by a health care professional in a patient who has been on long-term antiresorptive medication (including bisphosphonates and denosumab), has not received radiation therapy to the craniofacial region, and does not have neoplastic lesions in the jaw.
The American Association of Oral and Maxillofacial Surgeons developed a staging classification:
- •
Stage I: Exposed bone, no pain, no signs of inflammation.
- •
Stage II: Exposed bone, pain, and evidence of inflammation/infection.
- •
Stage III: Exposed bone, pain, and evidence of purulent discharge, fistulae and/or sinuses, and fractures.
- •
Stage 0 includes patients on bisphosphonates, with no exposed bone, but with nonspecific symptoms, clinical and/or radiological findings.
The main underlying cause of ONJ is suppression of bone turnover by antiresorptive medications, inhibition of osteoclast activity, and apoptosis in conditions uniquely found in the mandible and maxilla. These include first, a very thin, easily breached mucosal barrier separating the mandible and maxilla from the oral cavity and the surrounding microflora. Second, infections, albeit superficial, frequently affecting the jaws. Third, surgery is often undertaken in this area, to extract teeth and manage periodontal infection.
Fourth, the rate of bone turnover may be higher in the mandible and maxilla than the rest of the skeleton. As a result, the jaw bones are exposed to a higher concentration of antiresorptive medication than the rest of the skeleton. In addition, the direct toxic effect on the epithelium and antiangiogenic properties of bisphosphonates may further interfere with wound healing.
- A.
- 2.
At this stage, the following investigation(s) is/are recommended:
- A.
Panoramic X-ray, MRI, or CT scan of the mandible.
- B.
Technetium bone scan.
- C.
Bone markers.
- D.
A, B, or C.
- E.
None of the above.
Correct answer: A
Comment:
At this stage, although the diagnosis and staging are clinically obvious, it is possible that other lesions are present, hence the need for imaging studies of the mandible and maxilla. The absence of symptoms and leukocytosis makes an infectious process unlikely. The final diagnosis is therefore ONJ, stage I. ONJ affects the mandible more frequently than the maxilla. Radiological findings include :
- •
Thickening of the lamina dura.
- •
Regional increased trabecular density of the alveolar bone.
- •
Alveolar bone loss not attributable to chronic periodontal disease.
- •
Widening of the periodontal space.
- •
The presence of a sequestrum.
CT scans allow the assessment of the following:
- •
Cortical integrity of the maxilla and mandible.
- •
Cortical and trabecular architecture of the maxilla and mandible.
- •
Thickening of the cortical outline.
- •
Periosteal bone reaction.
- •
Sequestrum formation.
- •
Early fistula track formation.
- •
Diffuse osteosclerosis and increased trabecular bone density.
Magnetic resonance imaging identifies early features of ONJ before the development of clinical features and includes a decrease in bone marrow signal intensity on T1-weighted images and increased signal intensity due to bone edema. Although markers of bone resorption are sometimes assayed prior to undertaking dental work, especially invasive dental work, there is still no consensus as to their clinical usefulness.
- A.
- 3.
At this stage the following therapeutic intervention(s) is/are recommended:
- A.
Discontinue bisphosphonate.
- B.
Prescribe teriparatide.
- C.
Prescribe denosumab.
- D.
A and B.
- E.
A and C.
Correct answer: A
Comments:
Although there is evidence to support that long-term oral bisphosphonate therapy is associated with delayed healing after tooth extraction, and a positive association has been documented between risk of ONJ and the dose and duration of bisphosphonate therapy, it is debatable whether the discontinuation of bisphosphonate or antiresorptive therapy significantly alters the course of ONJ in patients with osteoporosis, especially given the very long half-life of bisphosphonates. On the other hand, several cases reported document that patients on antiresorptive therapy for osteoporosis who have developed ONJ (Stages 0, I, and II) heal spontaneously, even when the patients continue to take the bisphosphonates.
Notwithstanding, in DD’s case, given her present marginally low T-scores (−1.1, −1.1, and −1.3), therefore low risk of sustaining a hip or major fracture and the duration of alendronate therapy (about 12 years), the oral bisphosphonate should be discontinued. There is no indication to prescribe denosumab. Although teriparatide or abaloparatide may be useful in ONJ, they are not recommended at this stage given DD’s T-scores and low risk of sustaining a fracture or ONJ.
- A.
- 4.
Factors increasing the risk of ONJ include:
- A.
Dental procedures.
- B.
Alcohol abuse.
- C.
Cigarette smoking.
- D.
A and B.
- E.
A, B, and C.
Correct answer: E
Comment:
Osteonecrosis of the jaw is believed to be due to a defect in the finely orchestrated bone remodeling process, whereby osteocytes send signals to the osteoclasts and osteoblasts to modulate bone resorption and bone formation. Two main sets of factors increase the risk of ONJ: first, high doses of antiresorptive therapy and second, invasive dentoalveolar procedures especially in cancer patients. Although routine dental procedures are not associated with an increased risk of ONJ, they are the main triggers for ONJ in over 70% of the cases, and dental implants should be avoided in cancer patients exposed to high doses of bisphosphonates. Dentures also increase the rate of ONJ in cancer patients. There is no evidence that malocclusion increases the risk of ONJ in patients on bisphosphonates. There is evidence that cigarette smoking and alcohol abuse increase the risk of ONJ in cancer patients treated with zoledronic acid.
As much as possible, all invasive planned dental procedures should be completed before the initiation of bisphosphonate therapy, especially in the large doses needed by patients with neoplastic lesions.
- A.
- 5.
Medications predisposing to ONJ include:
- A.
Bisphosphonates.
- B.
Denosumab.
- C.
Teriparatide.
- D.
A and B.
- E.
A, B, and C.
Correct answer: D
Comments:
Although a definite causative relationship between bisphosphonates and ONJ has not yet been established, the circumstantial evidence is compelling, especially in cancer patients who receive larger doses of bisphosphonates. Bisphosphonate therapy increases the risk of ONJ in a dose- and duration-dependent manner. The mean time to developing ONJ in patients on denosumab is 23.83 ± 12.84 months. For oral bisphosphonates that period is 21.9 months, and for zoledronic acid it is 33.8 months. The incidence of ONJ among cancer patients prescribed intravenous bisphosphonates varies between 1% and 15%. On the other hand, the risk in patients on bisphosphonates for osteoporosis varies between 1 in 10,000 and less than 1 per 100,000 patients.
The increased risk of ONJ with bisphosphonates begins about 2 years after initiation of therapy and increases fourfold in the following 2 years.
As bisphosphonates are not the only medications associated with an increased risk of ONJ, the American Association of Oral and Maxillofacial Surgeons adopted the term: MRONJ (Medication-Related Osteonecrosis of the Jaw). The association of denosumab with ONJ suggests that ONJ is not a specific adverse event of bisphosphonates but of antiresorption therapy.
As ONJ also may occur spontaneously, as in patients on placebo in clinical trials, antiresorptive therapy per se is therefore but one factor increasing the risk of ONJ. Glucocorticoids and cyclophosphamide also increase the risk of ONJ.
- A.
- 6.
Diseases increasing the risk of ONJ:
- A.
Neoplasia.
- B.
Diabetes mellitus.
- C.
Obesity.
- D.
All of the above.
- E.
A and B.
Correct answer: D
Comment:
Many patients who develop ONJ have an underlying neoplastic condition treated with high doses of bisphosphonates. A number of other diseases also increase the risk of ONJ such as anemia, diabetes mellitus, hypertension, hypothyroidism, hypovitaminosis D, lupus erythematosus, malnutrition, obesity, pancreatitis, renal impairment, and renal dialysis. Advanced age is another risk factor: it is estimated that the risk of ONJ is increased by about 10% for each decade. Of interest, no case of ONJ has been reported in pediatric patients on iv bisphosphonates for osteogenesis imperfecta.
- A.
- 7.
The risk of ONJ may be reduced by:
- A.
Avoiding antiresorptive medication if the patient has evidence of gum disease.
- B.
Educating the patient about ONJ and the importance of meticulous oral hygiene
- C.
Anticipating dental interventions and, if possible, completing them prior to initiating antiresorptive therapy.
- D.
B and C.
- E.
A, B, and C.
Correct answer: E
Comment:
All listed are useful measures to prevent ONJ. Several preventive protocols have been developed to reduce the risk of ONJ and enhance its management. Teriparatide has been shown to have a positive effect on MRONJ. The sequential administration of antiresorptives: pamidronate/zoledronate and bisphosphonate/denosumab appears to increase the risk of MRONJ when compared to single antiresorptive therapy .
Thorough examination of the patient’s gums prior to prescribing an antiresorptive medication is essential and can be done by the prescribing clinician. The need for good oral hygiene should be emphasized. If possible, dental procedures including tooth extraction should be performed and allowed to heal before prescribing antiresorptives. For patients who are on antiresorptives and need to have a dental procedure done, it should be done by dental specialists with expertise in this area. Also, although there is no hard evidence, it is prudent to discontinue the antiresorptive therapy before the procedure and ideally until it heals. It is also important to ensure patients are vitamin D sufficient.
- A.
- 8.
Long-term bisphosphonate therapy may increase the risk of ONJ by inhibiting:
- A.
Bone angiogenesis.
- B.
Osteoclastic activity.
- C.
Formation of new bone.
- D.
A and B.
- E.
A, B, and C.
Correct answer: E
Comment:
Several mechanisms explain the increased risk of ONJ in patients on long-term antiresorptive therapy including:
- •
The antiresorptive effect leads to reduced bone turnover, reduced bone formation, and suppression of bone turnover. As a result, microdamage, mature cross-links, and advanced glycation end products accumulate in the bone leading to an altered microarchitecture, impaired mechanical strength, and increased brittleness leading to microfractures and localized increased blood flow which attracts bisphosphonates, thus triggering a vicious cycle culminating in bone necrosis.
- •
The previously mentioned changes are possibly further aggravated by local inflammatory processes and associated pH changes which may trigger the release of bisphosphonates stored in the bones.
- •
Bisphosphonates also have an antiangiogenic effect which is not limited to bone tissue but also affects endothelial cells.
- •
Because of the jaw vascularity and exposure to repeated microtrauma, bisphosphonates are more concentrated in the jaw bones, especially when given parenterally in high doses.
- •
Bisphosphonates also enhance the pathogenicity of periodontal bacteria through the promotion of interleukin-1-B.
- •
There also may be a genetic susceptibility to developing ONJ with polymorphisms in cytochrome P450, CYP2C8 gene, or the farnesyl pyrophosphate synthase gene.
- •
Vitamin D deficiency additionally may play a role in the development of ONJ: the resulting low serum calcium levels and elevated parathyroid hormone levels may trigger an immune response that leads to soft tissue destruction and interferes with bone healing.
- A.
- 9.
The management of ONJ includes:
- A.
Scrupulous dental hygiene.
- B.
Frequent oral rinses with local antiseptic solution.
- C.
Surgical debridement/
- D.
A and B.
- E.
A, B, and C.
Correct answer: E
Comment:
In addition to discontinuing the antiresorptive medication, scrupulous dental hygiene, and frequent rinses with an oral antimicrobial solution such as chlorhexidine (0.15%), is recommended for all stages of ONJ. Long-term systemic antibiotics are recommended in ONJ stages II and III. Penicillin, quinolones, clindamycin, doxycycline, erythromycin, and metronidazole are good first choices. Microbial cultures and sensitivity tests should modulate the choice of antimicrobials. Analgesics are often required.
Debridement by clinicians experienced in ONJ is sometimes needed, and protocols for the surgical management of ONJ have been developed. In stage III hyperbaric oxygen, medical ozone and resection of the affected area with reconstruction may be useful.
- A.
- 10.
Match the following:
- (a)
Inside-out theory.
- (b)
Outside-in theory.
- (c)
Both.
- (d)
Neither.
- A.
Infection starts in the oral mucosa and spreads to submucosa and bone.
- B.
Process starts with bone necrosis and spreads to surrounding soft tissue.
- C.
Supported by the microbiology of the oral cavity.
- D.
Explains the increased risk among patients with neoplasia.
- E.
Explains increased risk among cigarette smokers.
Correct answers: A (b); B (a); C (a); D (c); E (b)
Comment:
Two main hypotheses have been put forward to explain the development of ONJ. The outside-in hypothesis speculates that the oral mucosa sustains abrasions; infection sets in and gradually spreads to deeper tissue reaching the bones. Bisphosphonates also inhibit oral mucosal cell proliferation and healing.
The inside-out hypothesis speculates that the process is initiated in the bone as a direct result of antiresorptive therapy and then spreads to surrounding soft-tissues. It is likely that the 2 mechanisms interact and potentiate each other leading to ONJ.
- A.
- (a)
Case summary
Analysis of data
DD presents with a cavity where a tooth was extracted. She has been on oral bisphosphonates for about 12 years and her present T-score is higher than −2.5. She has taken the medication as directed and now bone is visible at the bottom of the cavity. There is no evidence of inflammation. Her dentist states that the cavity has been evident for the past 4 months. This is compatible with Stage I osteonecrosis of the jaw.
Diagnosis
- •
Osteonecrosis of the jaw, stage I, posttooth extraction.
Management recommendations
Treatment recommendation(s)
- •
Discontinue oral bisphosphonate.
- •
Given the degree of her bone demineralization, there is no need for any other medication for her low bone mass.
- •
Given the lack of inflammation or infection, there is no need for antibiotics or antiinflammatory medications.
Diagnostic test(s)
- •
None at this stage: there is no clinical evidence of inflammation, and her CBC is within normal limits.
Lifestyle
- •
Maintain scrupulous oral hygiene.
- •
Frequent mouth wash with oral antiseptics.
- •
Regular follow-up by dentist to ensure there is no inflammation/infection in the cavity.
DXA and radiological
- •
DXA scan in 2 years’ time to monitor bone mass and fine-tune management strategy.
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