Osteonecrosis of the jaw sounds terrifying. Terrifying for the patient and potentially terrifying for the practitioner who is not prepared for it. We have known that bisphosphonates can cause necrosis of the jaws since the early 2000’s¹. We also have an idea how these drugs work: they inhibit osteoclastic activity, thus improving bone density. This is exceedingly important for someone who may have osteoporosis, osteopenia, Paget’s disease, osteogenesis imperfecta, and other diseases that affect metabolism of bone including metastatic cancers^2,3.

As described in the Journal of the American Dental Association: “Bisphosphonate-related osteonecrosis of the jaw is defined as exposed necrotic bone in patients receiving Bisphosphonates that persists for at least eight weeks. Risk factors include dental extractions, inflammation and poor oral hygiene, and a number of medications prescribed in oncologic treatment such as steroids, antiangiogenics and various other chemotherapeutics¹⁵“.

Knowledge about medication-related osteonecrosis of the jaw (MRONJ) and its management among dentists does not appear to be well versed⁴. So enhancing our knowledge about how to avoid complications, and how to treat is imperative.

It is absolutely critical to first probe all new and existing patients if they have ever taken or been prescribed Oral or IV Bisphosphonates. Some forms of these drugs may linger around in the human body for decades⁵. And while these drugs remain in the body, the potential for MRONJ is there.

Oral or PO drugs:

0. Alendronate:
   • Fosamax®, Fosamax Plus D™, Binosto®
1. Risedronate
   • Actonel®, Atelvia™
2. Ibandronate
   • Boniva®
3. Tildudronate
   • Skelid

Intravenous Drugs:

1. Zoledronic Acid
   • Reclast®
2. Ibandronate
   • Boniva®

Notice that some drugs can be administered Orally or via IV. May not be an exhaustive list.

Risk Factors: according to the American Association of Oral and Maxillofacial Surgeons

1. Cancer patients with IV Zoledronic acid
2. IV or Oral Bisphosphonate treatment for Osteoporosis
3. Patients who were on long-term Bisphosphonate therapy, IV or oral administration, 4+ years
4. Tooth Extraction
   • 0.5% of patients who took oral bisphosphonates contract MRONJ after singular tooth extraction⁶
   • Estimates for developing ONJ after tooth extraction among cancer patients exposed to intravenous BPs ranges from 1.6 to 14.8%⁷
5. Concomitant use of Corticosteroids⁸
6. Patients who are receiving antiresorptive therapy in conjunction with antiangiogenic drugs for cancer⁹
7. Ill-fitting dentures after bisphosphonate therapy

Prevention:

Prevention starts with a THOROUGH MEDICAL HISTORY. Radiographs, vitality tests, and a detailed clinical exam all need to be completed. In the ideal world, hopeless teeth should be extracted and any bone-invasive procedures should be completed before bisphosphonate therapy begins⁹.

Once Bisphosphonate treatment begins: “Dental prophylaxis, caries control and conservative restorative dentistry are critical to maintaining functionally sound teeth. This level of care must be continued indefinitely”. Dentures need to be inspected for accurate fit, especially the lingual flanges of mandibular dentures. This is essential to avoid undue rubbing on the tissues which may incite a necrotic event. Patients should also be instructed to alert their dental provider immediately if they begin to feel any excessive wear or pain ⁷.

For Osteoporosis/Osteopenia patients:

Previously, a drug holiday was advocated for oral bisphosphonate therapy prior to any invasive procedures. This stance has been changed and no drug holidays are necessary, especially for patients who have had lower cumulative doses. The benefits of continuing the drug therapy outweighs the very low risk of MRONJ for bisphosphonates^{7,10,11,16,17}.

For Cancer Patients:

These patients are much more likely to be prescribed IV bisphosphonates along with other concomitant therapies which will elevate their risk of MRONJ¹³ It has been proven that these IV drugs have a higher risk of causing MRONJ¹⁸. Again in the ideal world, for individuals receiving monthly IV bisphosphonates for cancer, extractions should be avoided. A great option for a non-restorable tooth would be to remove the crown, complete Endodontic therapy, and bury the tooth under the gingiva¹².

Staging and Treatment: according to the American Association of Oral and Maxillofacial Surgeons

Stage 0:

• No clinical evidence of necrotic bone, but non-specific clinical findings, radiographic changes and symptoms
• Treatment: Systemic management, including the use of pain medication and antibiotics, Close Monitoring

Stage 1:

• Exposed and necrotic bone, or fistulae that probes to bone, in patients who are asymptomatic and have no evidence of infection, dull, aching bone pain in the body of the mandible, loosening of teeth not explained by chronic periodontal disease
• Treatment: Antibacterial mouth rinse, Quarterly follow-ups, review precautions with patient

Stage 2:

• Exposed and necrotic bone, or fistulae that probes to bone, associated with infection as evidenced by pain and erythema in the region of the exposed bone with or without purulent drainage
• Treatment: Antibiotic mouth rinse, oral antibiotic regimen, pain control, and debridement of necrotic tissue and bone, reapproximation of tissue

Stage 3:

• Exposed and necrotic bone or a fistula that probes to bone in patients with pain, infection, and one or more of the following: exposed and necrotic bone extending beyond the region of alveolar bone,(i.e., inferior border and ramus in the mandible, maxillary sinus and zygoma in the maxilla) resulting in pathologic fracture, extra-oral fistula, oral-antral/oral nasal communication, or osteolysis extending to the inferior border of the mandible of sinus floor
• Treatment: Antibacterial mouth rinse, Antibiotic therapy, surgical debridement and resection of necrotic tissues⁷.

If there is a symptomatic tooth (Pulpal involvement, PDL loss, PA pathology) within necrotic bone, it should be extracted as this does not seem to exacerbate the ongoing necrosis. During any stage, if there are areas of necrosis with bone that is irritating soft tissue or bony sequestra that is loose; removal and recontouring of the bone is necessary. “Treatment objectives for patients with an established diagnosis of MRONJ are to eliminate pain, control infection of the soft and hard tissue, and minimize the progression or occurrence of bone necrosis”^7,14.

Before the initiation of therapy, patients should be aware of all of the possible dental complications that can occur. Signed informed consent should be mandatory for patients undergoing extractions or implant placement, after bisphosphonate therapy⁷.

Summary: IV bisphosphonates carry more risk than Oral. Corticosteroid use along with either form of bisphosphonates elevates the risk. The longer the usage of either oral or IV therapy increases the risk, as does the reason they are prescribed, e.g., osteoporosis vs. cancer therapy. Drug holidays are not recommended anymore. Implants can be placed, but extreme caution and preventive measure should be taken; consult newer research. Prevention is better than treatment in all cases.

IF IN DOUBT, REFER OUT

1. Ruggiero, S. L., Mehrotra, B., Rosenberg, T. J., & Engroff, S. L. (2004). Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons, 62(5), 527–534. https://doi.org/10.1016/j.joms.2004.02.004
2. Kanis JA, Gertz BJ, Singer F, Ortolani S (1995) Rationale for the use of alendronate in osteoporosis. Osteoporos Int 5:1–13
3. Nase, J. B., & Suzuki, J. B. (2006). Osteonecrosis of the jaw and oral bisphosphonate treatment. Journal of the American Dental Association (1939), 137(8), 1115–1170. https://doi.org/10.14219/jada.archive.2006.0350
4. Al-Eid, R., Alduwayan, T., Bin Khuthaylah, M., & Al Shemali, M. (2020). Dentists’ knowledge about medication-related osteonecrosis of the jaw and its management. Heliyon, 6(7), e04321. https://doi.org/10.1016/j.heliyon.2020.e04321
5. Susan M. Ott, Long-Term Safety of Bisphosphonates, The Journal of Clinical Endocrinology & Metabolism, Volume 90, Issue 3, 1 March 2005, Pages 1897–1899, 
6. Kunchur R, Need A, Hughes T, et al: Clinical investigation of C-terminal cross-linking telopeptide test in prevention and man- agement of bisphosphonate-associated osteonecrosis of the jaws. J Oral Maxillofac Surg 67:1167, 2009.
7. Ruggiero, S. L., Dodson, T. B., Fantasia, J., Goodday, R., Aghaloo, T., Mehrotra, B., O’Ryan, F., & American Association of Oral and Maxillofacial Surgeons (2014). American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw–2014 update. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons, 72(10), 1938–1956. https://doi.org/10.1016/j.joms.2014.04.031
8. 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.
9. Department of Scientific Information, Evidence Synthesis & Translation Research, ADA Science & Research Institute, LLC.
10. Hellstein, J. W., Adler, R. A., Edwards, B., Jacobsen, P. L., Kalmar, J. R., Koka, S., Migliorati, C. A., Ristic, H., & American Dental Association Council on Scientific Affairs Expert Panel on Antiresorptive Agents (2011). Managing the care of patients receiving antiresorptive therapy for prevention and treatment of osteoporosis: executive summary of recommendations from the American Dental Association Council on Scientific Affairs. Journal of the American Dental Association (1939), 142(11), 1243–1251. https://doi.org/10.14219/jada.archive.2011.0108
11. Morrato, E. H., & Ling, S. B. (2012). The Drug Safety and Risk Management Advisory Committee: a case study of meeting frequency, content, and outcomes before and after FDAAA. Medical care, 50(11), 970–986. https://doi.org/10.1097/MLR.0b013e31826c872d
12. Endodontic Implications of Bisphosphonate-Associated Osteonecrosis of the Jaws. Chicago, IL: American Association of Endodontists; 2010:4.
13. Lo, J. C., O’Ryan, F. S., Gordon, N. P., Yang, J., Hui, R. L., Martin, D., Hutchinson, M., Lathon, P. V., Sanchez, G., Silver, P., Chandra, M., McCloskey, C. A., Staffa, J. A., Willy, M., Selby, J. V., Go, A. S., & Predicting Risk of Osteonecrosis of the Jaw with Oral Bisphosphonate Exposure (PROBE) Investigators (2010). Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons, 68(2), 243–253. https://doi.org/10.1016/j.joms.2009.03.050
14. Kademani, D., Koka, S., Lacy, M. Q., & Rajkumar, S. V. (2006). Primary surgical therapy for osteonecrosis of the jaw secondary to bisphosphonate therapy. Mayo Clinic proceedings, 81(8), 1100–1103. https://doi.org/10.4065/81.8.1100
15. Cartsos, V. M., Zhu, S., & Zavras, A. I. (2008). Bisphosphonate use and the risk of adverse jaw outcomes: a medical claims study of 714,217 people. Journal of the American Dental Association (1939), 139(1), 23–30. https://doi.org/10.14219/jada.archive.2008.0016
16. Goodchild, J. H., & Donaldson, M. (2018). What do you really need to know about bisphosphonates?. General dentistry, 66(2), 23–26.
17. Hasegawa, T., Kawakita, A., Ueda, N. et al. A multicenter retrospective study of the risk factors associated with medication-related osteonecrosis of the jaw after tooth extraction in patients receiving oral bisphosphonate therapy: can primary wound closure and a drug holiday really prevent MRONJ?. Osteoporos Int 28, 2465–2473 (2017). https://doi.org/10.1007/s00198-017-4063-7
18. Zahrowski J. J. (2010). Osteonecrosis of the jaws is associated with high-dose bisphosphonate treatment in patients with cancer. Journal of the American Dental Association (1939), 141(7), 887–888. https://doi.org/10.14219/jada.archive.2010.0288

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