This document summarizes osteonecrosis of the jaw (ONJ) associated with antiresorptive agents. It defines ONJ and stages its severity. It discusses the pathogenesis of ONJ and risk factors like underlying disease, treatment duration, and dental procedures. Cancer patients on intravenous bisphosphonates have the highest ONJ risk of 1-8% due to higher drug doses and worse oral/general health. Management involves conservative measures like mouthwashes for early stages and surgery with antibiotics for later stages. Discontinuing antiresorptives may help healing but risks fractures. Teriparatide may help healing in some cases but its use in cancer is uncertain. More research is needed on preventing and treating established ON

1. Osteonecrosis of the jaw and
antiresorptive agents in benign and
malignant diseases: a critical review
IWO, 19 november 2022
Carola Zillikens, internist-endocrinoloog
Erasmus MC Botcentrum
Rotterdam
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Prof. Dr. M.C. Zillikens

2. (potentiële) belangenverstrengeling Geen
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4. • Definition and staging
• Pathogenesis, risk factors and incidence
• Management
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5. • One or more necrotic bone lesions in the maxillofacial region
• That are exposed or can be probed through an intraoral or
extraoral fistula
• And persist for at least 8 weeks without response to
appropriate therapy
• Without history of radiation therapy or metastatic disease to
the jaws.
• Mostly cases after a dental procedure
Definition
Anastasilakis A et al JCEM 2022
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6. Staging
Ruggiero SL et al J Oral Maxillofac Surg.2014 Update 2022
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7. • At risk: any patient treated with antiresorptives
• Stage 0: non-specific symptoms (sinus or tooth pain) or
clinical/radiographic findings - no necrotic bone
• Stage 1: Exposed and necrotic bone, or fistulae that probe to bone –
asymptomatic. No evidence of adjacent/regional inflammation/infection
• Stage 2: Exposed and necrotic bone, or fistulae that probe to bone with
infection, evident by pain and adjacent
or regional soft-tissue inflammatory swelling
Staging
Ruggiero SL et al J Oral Maxillofac Surg.2014
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Prof. Dr. M.C. Zillikens

8. • Stage 3: in addition at least one of the following: (1)
pathologic fracture, (2) extra-oral fistula, (3) oral-
antral fistula, or (4) radiographic evidence of
osteolysis extending to the inferior border of the
mandible or floor of the maxillary sinus
Staging
Ruggiero SL et al J Oral Maxillofac Surg.2014
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Prof. Dr. M.C. Zillikens

9. X-rays: (OPG)
• Early signs: thickening of the lamina dura, widening of the
periodontal ligament space, increased trabecular density of the
alveolar bone, or even sequestration
• Later stages: high bone density, dense woven bone, thickening of
the periosteum, opacities, radiolucencies, and osteolysis and even
pathologic fracture of the mandible in stage 3 of ONJ
CT and MRI: more sensitive.
Imaging
Ruggiero SL et al J Oral Maxillofac Surg.2014
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10. • Inhibition of bone resorption and turnover, ↓ repair of microdamage
• Local inflammation/bacterial infection (periodontal/periapical disease)
• Angiogenesis inhibition (BPs only, glucocorticoids))
• Immune system dysfunction (production of proinflammatory cytokines)
• Soft-tissue toxicity (BPs only, toxic to epithelium)
• Genetic predisposition
Pathogenesis
Anastasilakis A et al JCEM 2022
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Prof. Dr. M.C. Zillikens

11. • Higher remodeling rate in the jaws
• Repetitive microtraumas from chewing
• Jaw osteoclasts may absorb higher amounts of BPs than long
bone osteoclasts
Predeliction for alveolar jaw bone
Anastasilakis A et al JCEM 2022
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Prof. Dr. M.C. Zillikens

12. Terminology
• ONJ: OsteoNecrosis of the Jaw
• BRONJ: Bisphosphonate Related ONJ
• DRONJ: Denosumab Related ONJ
• ARONJ: Antiresorptive agent Related ONJ
• MRONJ: Medication Related ONJ
Anastasilakis A et al JCEM 2022
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Prof. Dr. M.C. Zillikens

13. Nonantiresorptive medications associated with ONJ development
Glucocorticoids
VEGF inhibitors bevacizumab, aflibercept
TKIs sunitinib, imatinib, cabozantinib, sorafenib, regorafenib,
axitinib, pazopanib, dasatinib
mTOR inhibitors everolimus, temsirolimus
BRAF inhibitors dabrafenib, trametinib
MonoclonalAbs against CD20 rituximab
Immune checkpoint inhibitors Nivolumab, monoclonal Abs against CTLA-4 (ipilimumab)
Lenalidomide
Leflunomide
Anti-TNF agents adalimumab
Chemotherapy regimens
cytarabine, idarubicin, and daunorubicin; gemcitabine,
vinorelbine, and doxorubicin; doxorubicin
and cyclophosphamide; 5-azacitidine
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14. Regimen of antiresorptive agents according to
underlying bone disease
Osteoporosis CTIBL Bone metastases
Dose Frequency Dose Frequency Dose Frequency
Alendronate 70mg Pos weekly 70mg Pos weekly - -
Risedronate
35mg (75mg)
Pos
weekly
(2
consecutiv
e d/mo)
35mg Pos weekly - -
Ibandronate
150mg Pos monthly 150mg Pos monthly 50mg Pos Daily
3mg iv every 3 mo 3mg iv every 3 mo 6mg iv every 3-4 wk
Pamidronate - - 60mg iv every 3 mo 90mg iv every 3-4 wk
Zoledronate 5mg iv yearly 4mg iv every 3-6 mo 4mg iv every 3-4 wk
Denosumab 60mg sc every 6 mo 60mg sc every 6 mo 120mg sc every 4 wk
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15. ONJ incidence
• Depending on the underlying condition
– Osteoporosis: 0,01-0,06%
– Cancer treatment induced bone loss (CTIBL): 0,1-1,8%
– Bone metastases: 1-8%
Anastasilakis A et al JCEM 2022
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16. Predominance in cancer patients
• Higher and more frequent (and iv) dosing of antiresorptives (12-15x
Zol for bone metastases)
• Concurrent therapies (glucocorticoids, chemotherapy, antiangiogenic
agents, immunomodulators)
• Decreased oral and general health in cancer patients
Anastasilakis A et al JCEM 2022
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Prof. Dr. M.C. Zillikens

17. Risk factors
• Underlying disease
– dose/frequency of administration
– other medications
– oral & general health status
• Treatment duration
• Tooth extraction
• Pre- or coexisting periodontal/periapical inflammation/infection
• Concomitant therapies (chemo, glucocorticoids, antiangiogenics)
• Smoking
• Diabetes
• Obesity
Anastasilakis A et al JCEM 2022
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18. Antiresorptive agents associated with ONJ
• Bisphosphonates (BPs)
• Denosumab (Dmab)
• Raloxifene: scarce incidents
• Bazedoxifene, lasofoxifene: 0
• Romosozumab: 2 incidents
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19. ONJ risk – differences among BPs
• i.v. BPs > oral BPs
– disease / dose / frequency
• Cancer: mostly Zol > PAM
• Breast Ca: only reported with Zol (not with PAM, RIS, ΙΒΝ,
CLO)
• Osteoporosis: mostly ALN (>> RIS, IBN, PAM) 77%
Anastasilakis A et al JCEM 2022
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Prof. Dr. M.C. Zillikens

20. ONJ risk – BPs vs Dmab
• In most studies & meta-analyses: Dmab > BPs
• In cancer patients transition from Zol to Dmab ⇢ ↑ risk
• Dmab
– earlier manifestation
– faster resolution
Anastasilakis A et al JCEM 2022
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21. ONJ risk – BPs vs Dmab 2015-2019
ONJ incidence Dmab 28.3 per 100.000 and BP: 4.5 Risk ratio 6.3
Everts-Graber J et al JBMR.2021
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22. Management
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23. Anastasilakis A et al JCEM 2022
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24. *In the absence of RCT
Anastasilakis A et al JCEM 2022
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25. Patients at low risk of ONJ
Antiresorptive treatment management:
Osteoporotic patients:
Do not discontinue bisphosphonates
Do not discontinue denosumab – perform procedure preferably 5-6
months
following the last injection
Lower doses of antiresorptives? – no supporting evidence
Cancer patients:
Do not discontinue bisphosphonates
Do not discontinue denosumab
2
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26. BPs discontinuation
residual effect of BPs
questions the effect of
discontinuation on
ONJ
in osteoporotic patients
tooth extraction safely
performed without BPs
(ALN & Zol)
discontinuation
suspension of BPs not
beneficial in animals1
& humans2,3 who
developed ONJ
1Hadaya et al, J Dent Res. 2021
2Hasegawa et al, Osteoporos Int. 2017;28(8):2465-73
3Yoshida et al, J Oral Maxillofac Surg, Med, Pathol 2021;33(2):115-9
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27. Denosumab discontinuation
Anastasilakis A et al JCEM 2022
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28. Anastasilakis A et al JCEM 2022
Patients at high risk of ONJ
Antiresorptive treatment management:
Osteoporotic patients:
Bisphosphonates could be discontinued (at least 1 week before and until surgical site healing –
usually 2-4 weeks after the procedure)
Do not discontinue denosumab – perform procedure preferably 5-6 months following the last
injection – perform next denosumab injection 4-6 weeks after the procedure but not > 4 weeks
later than it should be done
Consider replacing antiresorptives with teriparatide
No data on romosozumab
Cancer patients:
Personalized decision in agreement with the treating oncologist,
weighing the risk of ONJ against the risks of SREs
Bisphosphonates could be discontinued
Short-term denosumab discontinuation e.g. 3 weeks before and 4-6 weeks
after dental procedure has been advised – no clear benefit
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29. Conservative management: mainly in earlier ONJ stages
• At-risk patients: no need for intervention. Patients must be
informed and be able to early identify signs and symptoms
• Stage 0: Since symptoms are not specific, the objective is to
symptomatically control pain and infections, and closely
monitoring for signs of progression
• Stage 1: Management with chlorhexidine mouthwash and
regular follow-up. No antibiotic nor surgical intervention
• Stage 2: Due to necrosis and associated infection,
antimicrobial mouthwash and oral antibiotics
Anastasilakis A et al JCEM 2022
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Prof. Dr. M.C. Zillikens

30. Surgical management: mostly in later ONJ stages
• Stage 2: Besides the antibiotic regimen, debridement is often
needed
• Stage 3: Surgical management is indicated (and antibiotics)
varying from limited debridement to complete resection with
possible immediate reconstruction
Anastasilakis A et al JCEM 2022
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Prof. Dr. M.C. Zillikens

31. Table 4.Adjuvant therapies applied in the management of ONJ
During
conservative
management
During surgical management
• bone marrow stem cell
intralesional
transplantation
• laser
‐
assisted surgical debridement
• leukocyte and platelet
rich
fibrin membrane placement
• pre-operative antibiotic treatment
followed by laser and wound
local treatment with platelet-rich
plasma applications
• ozone • surgical debridement in combination
with platelet
‐
derived growth factor
(PDGF)
• pentoxifylline • intraoperative fluorescence guidance
• vitamin E • longer
‐
term preoperative antibiotics
• hyperbaric oxygen therapy • adjunctive therapy with
hyperbaric oxygen combined with
Anastasilakis A et al JCEM 2022
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Prof. Dr. M.C. Zillikens

32. Antiresorptives when ONJ occurs
• Consider discontinuing antiresorptives in stage 2 and 3 until complete
soft-tissue closure after carefully weighing risk of ongoing ONJ with
risk of fractures or SREs
• Some experts consider continuing denosumab
• Healing time in 12 patients with ONJ under Dmab of 4.5 months
(interquartile range [IQR], 2–14), which was shorter than that in
patients with BP-related ONJ (6 months; IQR, 5–33)
• Evidence is lacking!
Anastasilakis A et al JCEM 2022; Everts-Graber J et al JBMR 2022
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Prof. Dr. M.C. Zillikens

33. Teriparatide
• Helpful in ONJ management in several case reports
• RCT: 8 weeks treatment with TPTD vs pcb ⇢ more lesions healed and
reduced bone defects at 52 weeks
• Cancer patients?
– theoretically contraindicated in cancer patients but a brief
exposure (e.g., of 8 weeks) should not activate quiescent
malignant cells
• Concerns: limited duration of teriparatide treatment;
temporary decrease of hip BMD; uncertain effect
on the rebound phenomenon after stopping Dmab
Anastasilakis A et al JCEM 2022
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Prof. Dr. M.C. Zillikens

34. Cochrane review 2022
• Five RCTs examined different interventions to prevent ONJ occurrence
• One open-label RCT: some evidence that dental examinations at 3-
month intervals and preventive treatments may be more effective than
standard care for reducing MRONJ incidence of MRONJ in with i.v. BPs
for advanced cancer (evidence very low)
• Eight RCTs examined different interventions for the treatment of
established MRONJ; that is, the effect on MRONJ cure rates.
• Available evidence insufficient to either claim or refute a benefit, in
addition to standard care, of any of the interventions for treatment of
MRONJ (including 2 RCTs with TPT with 33 and 12 participants)
Beth-Tasdogan NH et al Cochrane Database of Systematic Reviews 2022,
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35. Take home
• Risk for ONJ largely depends on the underlying bone disease and the
relevant antiresorptive regimen applied
• Risk is much higher in patients with advanced malignancies because
of the higher doses and more frequent administration of
antiresorptives and possibly compromised general health and co-
administration of other medications that predispose to ONJ
• Risk appears higher with denosumab, possible partly because of pre-
treatment with BP
• Physicians and dentists should keep in mind that the benefits of
antiresorptive therapy far outweigh the risk for ONJ development
• Uncertain if TPT may fasten healing
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36. Thank you!
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