Bisphosphonate-Induced Osteonecrosis of the Jaw - International ...

Controversies in Oncology: 

Bisphosphonate-Induced 

Osteonecrosis of the Jaw 

Rowena N. Schwartz, PharmD, BCOP 

Associate Professor of Pharmacy and Therapeutics 

University of Pittsburgh School of Pharmacy 

University of Pittsburgh Cancer Institute



Bisphosphonates: 

• synthetic analogs of naturally occurring 

pyrophosphonate 

• accumulate to sites of active bone formation 

• more potent bisphosphonates have been 

incorporated into clinical practice 

• increasing number of reports in the oncology 

and dental literature of avascular osteonecrosis 

of the jaw



Bisphosphonates: 

• induce osteoclasts to self destruct 

• associated with osteoporosis when they carve 

out bone cavities causing excessive loss of 

calcium ⇒ decrease rate of bone resorption and 

indirect increase in bone mineral density



Reports of Osteonecrosis of the Jaw: 

• case report of osteonecrosis of the maxillas as a 

complication of chemotherapy 

Sung EC, et al. Spec Care Dentist 2002:142 

• case reports (n = 3) of osteonecrosis of the jaw among 

patients with metastatic breast cancer undergoing 

treatment with chemotherapy and steroids ⇒ later 

reported that patients were receiving pamidronate 

Wang J, et al. J Oral Maxillofac Surg 2003: 1104 

Pogrel MA. J Oral Maxillofac Surg 2004: 391



Reports of Osteonecrosis of the Jaw: 

• case reports (n = 36) of painful bone exposure 

in cancer patients treated with 

bisphosphonates. 

• multiple myeloma and breast cancer 

• pamidronate or zolendronic acid or both 

• many of the cases of ONJ were initiated by 

surgery to remove teeth 

Marx RE. J Oral Maxillofac Surg 2003:1115

Bisphosphonate-Induced Osteonecrosis: 

Necrosis of Maxilla 

Carter G, et al. MJA 2005

Bisphosphonate-Induced Osteonecrosis: 

Necrosis of Maxilla 

Carter G, et al. MJA 2005



• Clinical characteristics: 

• non-healing extraction socket or exposed jaw 

bone with progression to sequestration with 

purulent discharge 

• trauma induced by prosthodontic appliances 

• secondary infection 

• peripheral nerve compression 

• Radiologic characteristics: similar to infected 

osteoradionecrosis (IORN)



• Histologic Comparison: 

• 8 cases of BON of the jaw 

• 10 cases with infected osteoradionecrosis (IORN) 

• Results: 

• Non vital bone tissue in all cases 

• gross pattern of necrosis differed between IORN and 

BON 

• inflammatory infiltrates in all cases 

• fibrosis of medullary spaces in most cases 

• increase cellularity in the intima and media of the 

artery in BON vs. hyalinization in IORN 

• actinomyces colonies found in all cases 

• osteoclasts detected in tissue specimen 

Hansen et al. J Oral Pathol Med 2006





• 10 cases with infected osteoradionecrosis (IORN) 

• Results: 

• BON 

- ⇑ multifocality (maxilla and mandible) 

- areas of osteonecrosis patchier 

• IORN 

- area of necrosis is typically larger 

• BON and IORN 

- Actinomyces colonies in close contact to necrotic 

bone 






• 10 cases with infected osteoradionecrosis 

(IORN) 

• Results: 

• BON and IORN 

- Actinomyces colonies in close contact to 

necrotic bone ⇒ ? organism involved in 

non-healing inflammatory process 




Proposed Pathologic Mechanism: 

• inhibition of osteoclastic function 

• inhibition of osteoblastic-mediated osteoclastic 

resorption 

• antiangiogenic effects (NBPs) 

• suppression of bone turnover and physiologic 

remodeling 

• stress of normal jaw use ⇒ microdamage and 

microfractures not repaired 

• chronic non-healing inflammation

Proposed Pathobiological Model for 

Bisphosphonate-Associated Osteonecrosis (BON) 

Bisphosphonates 

+ 

Infection and 

trauma 

Bisphosphonate 

Bone Resorption 

Bisphosphonates 

And 

Chemotherapy 

Activation of Basic Multicellular Unit 

Bone Cellularity and Blood Flow 

Cell Necrosis and Apoptosis 

Dental Extraction 

Trauma 

Infection 

Bone Manipulation 

igliorati CA, et al. Cancer 2005 

BON



Bisphosphonate Associated Risk Factors: 

• Which bisphosphonates? 

• Dose effect? 

• Duration effect? 

• Route of administration?

Bisphosphonates: Antiresorptive Potency 

Structure 

agent 

Short Alkyl or Halide Side Chain 

etidronate 

Cyclic chloro side chain 

tiludronate 

Aminoterminal group 

pamidronate 

alendronate 

Cyclic Nitrogen-Containing side 

chain 

risedronate 

ibandronate 

zolendronic acid 

Antiresorptive 

Relative Potency 

1 

10 

100 

100 - 1000 

1000 – 10000 

1000 – 10000 

> 10000 

Route of 

Administration 

IV and oral 

oral 

IV 

oral 

oral 

IV and oral 

IV



Potential Patient Associated Risk Factors: 

• Cancer 

• overall tumor burden 

• stage of disease 

• extent of skeletal involvement 

• Comorbidities 

• diabetes mellitus 

• immunocompetency 

• oral health 

• Concurrent medication 

• immunosuppression 

• anti-angiogenic agents (e.g. lenolidamide, thalidomide)



Estimating the incidence of OJN: 

• Estimated incidence of 4.6% in one series of cancer 

patients receiving bisphosphonates. 

Maerevoet M, et al. NEJM 2005:100 

• Survey by the International Myeloma Foundation 

designed to asses the risk factors for OJN: 

10% risk of OJN in patients receiving zolendronic acid 

4.6% risk of OJN in patients receiving pamidronate 

Durie BG, et al. NEJM 2005:99

Bisphosphonate-Associated Osteonecrosis 

American Academy of Oral Medicine Position Paper 

• Position paper that addresses: 

• prevention of bisphosphonate-associated 

osteonecrosis (BON) 

• recommendation for management of BON 

• “Recommendations are based on expert opinion 

as there are not available randomized controlled 

trials that support any effect on patient 

management and outcomes.” 

Migliorati CA, et al. JADA 2005:1658

Bisphosphonate-Associated Osteonecrosis 

American Academy of Oral Medicine Position Paper 

• “Recommendations are based on expert opinion 

as there are not available randomized controlled 

trials that support any effect on patient 

management and outcomes.” 

• treatment is prevention 


Risk Factors Associated with Bisphosphonate- 

Associated Osteonecrosis 

• IV use of bisphosphonates such as pamidronate 

and zoledronic acid 

• multiple myeloma 

• metastatic cancer to the bone associated with 

breast cancer, prostate cancer and lung cancer 

• dental extractions 

• surgical bone manipulations 

• trauma from dentures 

• presence of oral infection 

• poor oral health 




Management considerations: 

• Dental examination for patient prior to 

initiation of bisphosphonate therapy 

- assessment of risk 

- procedures prior to therapy (e.g. 

extraction, restorative dentistry ) 

- management of potential sites of infection 

- education for oral hygiene 





• Routine dental treatment for patients receiving 

bisphosphonates: 

“ There are no prospective scientific studies to 

support specific recommendations regarding 

whether providing dental treatment for patients 

taking bisphosphonate places the patient at any 

risk of developing BON.” 





• Management of dental care for patient with BON: 

- Minimization of trauma 

- Avoid dental extractions (close follow up) 

- Endodontic procedures if needed 

- Surgical removal of bone 

- Soft vinyl appliances to cover necrotic bone 

- Infections ⇒ antibiotics

Bisphosphonate-Induced Osteonecrosis of the Jaw - International ...

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