medication related osteronecrosis of the jaw

1. MEDICATION-RELATED
OSTEONECROSIS OF THE
JAW (MRONJ)
BY: DR.HASSAN HAFEEZ KHAN
FCPS RESIDENT OMFS
DIKIOHS,DUHS

2. LEARNING OBJECTIVES
• Brief description of antiresorptive and antiangiogenic medications
• Diagnostic criteria.
• Different theories about pathophysiology.
• Risk estimates of developing MRONJ.
• Preventive measures and management strategies based on the disease
stage.

3. ANTIRESORPTIVE MEDICATIONS
BISPHOSPHONATES (BPs):
• Attach to hydroxyapatite binding sites on bony surfaces, especially
surfaces undergoing active resorption, thereby, inhibiting osteoclastic
bone resorption.
1. INTRAVENOUS BPs are used to manage cancer-related conditions
including
• hypercalcemia of malignancy.
• skeletal-related events (SRE) associated with bone metastases and
• for management of osteolytic lesions in case of multiple myeloma.
2. ORAL BPs are commonly used to treat osteopenia and osteoporosis.
• And also for less common conditions like Paget’s disease of bone, and
osteogenesis imperfecta

4. 3. RANK LIGAND INHIBITOR (DENOSUMAB):
• It exists as a fully humanized antibody against Receptor Activator of Nuclear
factor Kappa-Β Ligand (RANK-L), also known as tumor necrosis factor, and
inhibits osteoclast function and associated bone resorption.
• Denosumab (Prolia®) administered subcutaneously every 6 months reduces
the risk of vertebral, non-vertebral, and hip fractures in osteoporotic patients.
(Cummings SR, San Martin J, McClung MR, et al: Denosumab for prevention of fractures in postmenopausal women
with osteoporosis. N Engl J Med 361:756, 2009.)
• Denosumab (Xgeva®) is also effective in reducing SRE related to metastatic
bone disease from solid tumors when administered monthly.
(Stopeck A, Body JJ, Fujiwara Y, et al: Denosumab versus zolendronic acid for the treatment of breast cancer patients
with bone metastases: results of a randomized phase 3 study. Eur J Cancer Supplements [EJC supplements] 7:2, 2009.)

6. ANTIANGIOGENIC MEDICATIONS
• Interferes with the formation of new blood vessels by binding to
various signaling molecules disrupting the angiogenesis-signaling
cascade.
• Includes:
• Tyrosine kinase inhibitors (TKIs)
• Monoclonal antibodies targeting Vascular Endothelial Growth
Factor (VEGF)
• Mammalian target of rapamycin pathway.

8. DIAGNOSTIC CRITERIA
• Patient’s history and clinical examination continues to be the most
sensitive diagnostic tools for this condition.
• A diagnosis of MRONJ should be considered if a patient presents with
all of the following criteria:
• Current or previous treatment with antiresorptive and/or
antiangiogenic agents
• Exposed bone or bone that can be probed through an intraoral or
extraoral fistula(e) in the maxillofacial region that has persisted
for more than 8 weeks
• No history of radiation therapy to the jaws or obvious metastatic
disease to the jaws

9. PATHOPHYSIOLOGY
• Pathophysiology of the disease has not been fully elucidated.
• Proposed hypotheses that attempt to explain the unique localization of
MRONJ exclusively to the jaws include:
• Inhibition of osteoclastic bone resorption and remodeling
• Inflammation/Infection
• Inhibition of Angiogenesis
• Soft tissue toxicity
• Innate or acquired immune dysfunction

10. RISK FACTORS
• Medication-related risk factors
• Among cancer patients
• Among osteoporotic patient
• Local risk factors
• Dentoalveolar surgery
• Concomitant oral disease
• Local anatomic factors
• Demographic and systemic factors
• Genetic factors

11. A. MEDICATION RELATED RISK FACTORS
1. MRONJ risk among cancer patients
• The risk for ONJ among cancer patients assigned to placebo groups ranges from
0% to 0.019% (0-1.9 cases per 10,000 cancer patients)
Qi WX, Tang LN, He AN, et al: Risk of osteonecrosis of the jaw in cancer patients receiving denosumab: a meta-analysis of
seven randomized controlled trials. Int J Clin Oncol, 2013.
• The risk of MRONJ in subjects exposed to zolendronate approximates 1% (100
cases per 10,000 patients).
Coleman R, Woodward E, Brown J, et al: Safety of zoledronic acid and incidence of osteonecrosis of the jaw (ONJ) during
adjuvant therapy in a randomised phase III trial (AZURE: BIG 01-04) for women with stage II/III breast cancer. Breast
Cancer Res Treat 127:429, 2011
• Beuselink, et al, reported an overall incidence of ONJ to be 10% in renal cell
carcinoma patients with bone metastasis treated with oral TKIs and concomitant
bisphosphonates.
Beuselinck B, Wolter P, Karadimou A, et al: Concomitant oral tyrosine kinase inhibitors and bisphosphonates in advanced
renal cell carcinoma with bone metastases. Br J Cancer 107:1665, 2012.

12. 2. MRONJ risk among osteoporosis patients exposed to ORAL BPs
• Malden, et al, derived an incidence of 0.004% (0.4 cases per 10,000 patient
exposed to alendronate)
Malden N, Lopes V: An epidemiological study of alendronate related osteonecrosis of the jaws. A case series from the south-
east of Scotland with attention given to case definition and prevalence. Bone Miner Metab 30:171, 2012.
3. MRONJ risk among osteoporotic patients exposed to IV BPs or RANK-L
inhibitors
• Patients with osteoporosis exposed to yearly zolendronate therapy for 3 years
reported a risk for MRONJ of 0.017% (1.7 cases per 10,000 subjects).
Grbic JT, Black DM, Lyles KW, et al: The incidence of osteonecrosis of the jaw in patients receiving 5 milligrams of
zoledronic acid: data from the health outcomes and reduced incidence with zoledronic acid once yearly clinical trials
program. J Am Dent Assoc 141:1365, 2010.
• Patients exposed to denosumab, the risk for MRONJ is 0.04% (4 cases per
10,000 subjects).
Papapoulos S, Chapurlat R, Libanati C, et al: Five years of denosumab exposure in women with postmenopausal
osteoporosis: Results from the first two years of the FREEDOM extension. J Bone Miner Res 27:694, 2012.

13. 4. Duration of medication therapy:
• Among cancer patients exposed to
zolendronate or denosumab, the incidence of
developing ONJ was, respectively, 0.6 and
0.5% at 1 year, 0.9 and 1.1% at 2 years, and
1.3 and 1.1% at 3 years.
Henry DH, Costa L, Goldwasser F, et al: Randomized, double-
blind study of denosumab versus zoledronic acid in the treatment
of bone metastases in patients with advanced cancer (excluding
breast and prostate cancer) or multiple myeloma. J Clin Oncol
29:1125, 2011.
• For osteoporotic patients receiving oral
bisphosphonate therapy, the prevalence of
ONJ increases over time from near 0 at
baseline to 0.21% after four or more years of
BP exposure.

14. B. LOCAL RISK FACTORS
1. Dentoalveolar surgery
• In cancer patients exposed to intravenous BPs (predominately zolendronate),
tooth extraction was associated with a 33-fold increased risk for ONJ.
Vahtsevanos K, Kyrgidis A, Verrou E, et al: Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-
related osteonecrosis of the jaw. J Clin Oncol 27:5356, 2009
• The best current estimate for the risk of ONJ among patients exposed to oral
BPs following tooth extraction is 0.5%, while it ranges from 1.6 to 14.8% for
patients receiving IV BPs.
Yamazaki T, Yamori M, Ishizaki T, et al: Increased incidence of osteonecrosis of the jaw after tooth extraction in patients treated with
bisphosphonates: a cohort study. Int J Oral Maxillofac Surg 41:1397, 2012.

15. 2. Concomitant oral disease
• Pre-existing inflammatory dental disease was a risk factor among 50% of the
cases.
Saad F, Brown JE, Van Poznak C, et al: 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,
2012.
3. Anatomic factors
• MRONJ is more likely to appear in the mandible (73%) than the maxilla
(22.5%) but can appear in both jaws (4.5%).
• In a study by Vahtsevanos, et al, a sample of 1,621 cancer patients treated with
intravenous BPs, there was a 2-fold increased risk for ONJ among denture
wearers.
Vahtsevanos K, Kyrgidis A, Verrou E, et al: Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-
related osteonecrosis of the jaw. J Clin Oncol 27:5356, 2009

16. C. DEMOGRAPHIC, SYSTEMIC AND OTHER MEDICATION FACTORS
• The higher prevalence of this complication in the female population is likely a
reflection of the underlying disease for which the agents are being prescribed (i.e.
osteoporosis, breast cancer).
• Corticosteroids and tobacco use are associated with an increased risk for MRONJ
• Among cancer patients anemia (hemoglobin < 10g/dL) and diabetes are
inconsistently reported to be associated with an increased risk for MRONJ.
Tsao C, Darby I, Ebeling PR, et al: Oral health risk factors for bisphosphonate-associated jaw osteonecrosis. J Oral
Maxillofac Surg 71:1360, 2013
D. GENETIC FACTORS
• Nicoletti reported that patients with a single nucleotide polymorphisms (SNP) in the
RBMS3 gene (associated with bone density and collagen formation) were 5.8 times
more likely to develop ONJ.
Nicoletti P, Cartsos VM, Palaska PK, et al: Genome wide pharmacogenetics of bisphosphonate-induced osteonecrosis of
the jaw: the role of RBMS3. Oncologist 17:279, 2012.

17. CLINICAL STAGING

18. STAGE 1: ASYMPTOATIC,
EXPOSED NECROTIC
BONE
STAGE 2: SYMPTOMATIC, EXPOSED
NECROTIC BONE

19. STAGE 3: EXTENSIVE MRONJ OF THE RIGHT
HEMIMAXILLA, RIGHT INFERIOR TURBINATE, AND
ORBITAL FLOOR.

20. PREVENTIVE MEASURES
• For patients who may be prescribed antiresorptive or antiangiogenic
therapy comprise a thorough clinical and radiographic assessment
including:
• Patient motivation, patient education regarding dental care, fluoride
application, chlorhexidine rinses, tooth mobility, periodontal disease,
presence of root fragments, caries, periapical pathology, edentulism,
and denture stability
• Bonacina did not report any new cases of ONJ in patients who received
dental screening and necessary dental treatment before initiating IV
bisphosphonate treatment.
Bonacina R, Mariani U, Villa F, et al: Preventive strategies and clinical implications for bisphosphonate-related osteonecrosis
of the jaw: a review of 282 patients. J Can Dent Assoc 77:b147, 2011

21. CESSATION OF AT-RISK MEDICATION THERAPY PRIOR TO TOOTH
EXTRACTION OR OTHER PROCEDURES
• Damm and Jones proposed several alternatives to a drug holiday in BP-
exposed patients who require invasive dental treatment. They proposed a 2-
months drug free period prior and 3-months after an invasive dental
procedure.
Damm DD, Jones DM: Bisphosphonate-related osteonecrosis of the jaws: a potential alternative to drug holidays. Gen
Dent 61:33, 2013
• ADA council recommendations:
• Patients receiving BP or denosumab for < 2years can undergo invasive
dental treatment without prior drug holiday
• Patients with exposure > 4 years or with comorbid risk factor such as
rheumatoid arthritis, glucocorticoid exposure, diabetes and smoking;
should have a drug holiday.

22. MANAGEMENT STRATIGIES
• Treatment objectives:
• Eliminate pain
• Control infection of the soft and hard tissue
• Minimize the progression or occurrence of bone necrosis.
• Can be divided into:
• MEDICAL THERAPY
• SURGICAL THERAPY

23. MEDICAL THERAPY
• Employed for patients with less severe disease, those who decline surgery,
or those whose comorbidities preclude them from surgery.
1. ANTIMICROBIALS
• Topical antimicrobials: Chlorhexidine gluconate 0.12%
• Oral antimicrobials: Penicillin remains first antibiotic choice.
Alternates: clindamycin, fluoroquinolones, and/or metronidazole.
Generally prescribe a 2-week course for patients with persistent stage 1
disease and up to a 4- to 6-week course for more severe cases.
• Intravenous antimicrobials: When all available oral agents have been
exhausted and no less invasive option exists, employ long-term (6
weeks) intravenous antimicrobials.

24. 2. PENTOXIFYLLINE AND VITAMIN E:
• The recommended dose of pentoxifylline is 400 mg sustained release twice daily
and 1000 IU vitamin E daily for 2-3 years or till the resolution of disease.
3. TERIPARATIDE:
• (Forteo) is a subcutaneously administered drug used primarily in the treatment
of osteoporosis. It promotes bone remodeling, stimulate effectively osteoblast
function and activates osteoclasts.
4. HYPERBARIC OXYGEN THERAPY (HBO):
• HBO is seldom used as a singular treatment modality, but is more commonly
used as a surgical adjunct.
• Provides greater oxygen to tissues with impaired vascularization, and
contributes to improved wound healing and bone turnover.
• HBO therapy is a controversial, costly, and time-intensive treatment whose
efficacy deserves further study.

25. SURGICAL MANAGEMENT
• INCLUDES
• Surgical debridement/sequestrectomy
• Marginal or segmental resection
• Adjunctive treatments including autologous platelet-rich plasma and
low-level laser therapy, parathyroid hormone and bone morphogenic
protein, have been used in conjunction with surgical debridement to
improve postoperative healing.

27. SUMMARY
• Our understanding of the pathogenesis of MRONJ and how it influences the
clinical presentation continues to evolve.
• Obtaining a complete patient history and clinical examination remains the
most effective mode of establishing a timely diagnosis of MRONJ.
• Treatment of MRONJ presents a challenging clinical dilemma. Based on
current evidences, the best treatment is that which achieves the patient’s
goals and provides the best quality of life.
• Use of topical and oral antimicrobials, Pentoxifylline and vitamin E, with or
without surgery leads to satisfactory outcomes.
• However, continued research and investigations are required in this area in
order to have a more accurate judgments about risk, prognosis, treatment
selection, and outcomes for patients with MRONJ.

28. • REFERENCES FROM:
Position Paper of American Association of Oral and Maxillofacial
Surgeons: Medication-Related Osteonecrosis of the Jaw—2014 Update