Dental practitioners in every specialty will encounter patients on bisphosphonate therapy who require treatment. In some instances, the provider will be faced with asymptomatic patients that already display BRONJ. Though knowledge regarding BRONJ is evolving, a primary algorithm to treatment of these patients can be utilized in order to treat the patient’s pain and restore their function.

Algorithm for Clinical Treatment of Bisphosphonate related Osteonecrosis of the Jaw (BRONJ)

ABSTRACT

Patricia Lukasavage, DDS**; David Telles, DDS*; William Flick DDS, MS ¥; Gene Sbalchiero DDS Ұ

INTRODUCTION

Objective

Case Reports

Acknowledgements

Dr. Tarkan Sidal*** – for photos of various cases

Case #1 – Superficial debridement, long term chlorhexidine rinse and antibiotic treatment [PenVK 500 mg x 6 months]68 yo Caucasian with history of Breast CA, Zolendronate (Zometa) x 1 yr, mandibular anterior extractions, history of debridements x 4

Case #2 Chlorhexidine rinse, Long term antibiotic treatment (Amoxicillin/Metronidazole) [for approx. 4 months], sequestrectomy of exposed bone under local anesthesia

60 yo African American female with Multiple Myeloma on IV Pamidronate, had #19 removed in 2005, painful, infected, exposed bone

To demonstrate an algorithm for treatment of BRONJ that dentalprofessionals can utilize when faced with this side effect of oraland intravenous bisphosphonates based upon clinical

presentationand symptoms.

Ұ Department Head of Oral and Maxillofacial Surgery, College of Dentistry, University of Illinois-Chicago, Chicago, IL¥ Clinical Instructor of Oral and Maxillofacial Surgery, College of Dentistry, University of Illinois-Chicago, Chicago, IL,* Intern for the department of Oral and Maxillofacial Surgery, College of Dentistry, University of Illinois-Chicago, Chicago, IL, USA** 3rd year resident for the department of Oral and Maxillofacial Surgery, College of Dentistry, University of Illinois-Chicago, Chicago, IL***4th year resident/chief for the department Head of Oral and Maxillofacial Surgery, College of Dentistry, University of Illinois-Chicago,

Chicago, IL, USA

Case #4 - Treatment Extended course of Penicillin of approx 6 months, Peridex rinse, Long term follow-up.

70 yo hispanic female w/ h/o Breast CA, secondary metastases to spine, on Zolendronate >1 year She presented 3 months status post extraction of dentition in upper right quadrant with a chief complaint of a non-healing wound and inability to wear prosthesis

Discussion

Several cases of BRONJ will be presented with their clinical symptoms and manifestations as well as the treatment modalities utilized. Success of a given treatment was determined as resolution of patient’s clinical complaints and symptoms, not necessarily the resolution of the drug-related osteonecrosis itself.

Uses of bisphosphonates1

- Inhibition of bone resorption6 - Osteolytic disease (Paget’s, Multiple Myeloma) - Metastatic bone disease- Hypercalcemia associated with malignancy- Osteoporosis- Anti-tumor activity (Rosen, Theriault et.al. 2001)

Mechanism of Action- Effects on osteoclasts- Precursor cells, cytoskeleton, apoptosis4 (, Hughes et.al. 1995)- Anti-angiogenesis - Zometa study8

Intravenous vs. Oral- Ruggiero et. al. (2004) study - 63 cases oral osteonecrosis (56 on IV treatment, 7 on oral treatment) 7

This poster presentation is designed to give an overview of our clinical experiences in dealing w/ BRONJ. These techniques correspond to the guidelines set forth by an expert task force in the AAOMS position paper on BRONJ. 1 In this paper, the qualifications for BRONJ are listed as 1) current or previous treatment with bisphosphonates 2) exposed/necrotic bone that has persisted for more than 8wks and 3) no history of radiation therapy to the jaw. Local and systemic risk factors are also listed and outlined in Table 1, staging of BRONJ and proposed treatment is outlined in Table 2. Table 1 Systemic Factors Local Factors

-Potency of bisphosphonate -Length of bisphosphonate treatment -Race (usually Caucasians) -Age (usually >60) -Primary disease multiple myeloma >breast CA>other CA -Misc-steroid treatment, diabetes, smoking, alcohol, poor oral hygiene, concurrent chemo therapy

-Recent history of invasive dental surgery (dentoalveolar surgery i.e. exodontias, implants, periodontal surgery is 7x more likely to develop BRONJ) -Anatomy – tori, mylohyoid ridge, palatal tori -Concomitant oral disease – periodontal and dental abscesses are at a 7x increase for BRONJ

Table 2 Clinical Staging of BRONJ Treatment No exposed bone but history of oral/IV bisphosphonate treatment

Perceived risk, but no treatment necessary Encourage oral hygiene

Stage 1: exposed/necrotic bone in patients who have no infection/ no pain

Chlorhexidine gluconate, encourage oral hygiene, no surgery

Stage 2: exposed bone in patients with pain and evidence of infection

Chlorhexidine gluconate, antimicrobial therapy with cultures taken to determine if actinomyces species present

Stage 3:exposed bone in patients with pain and infection, and one or more of the following: pathologic fracture, extraoral fistula or osteolysis extending to the inferior border

Surgical debridement/resection in combination with antibiotics, removal of mobile segments of sequestrum -If pathologic fracture present, pt may require removal of compromised bone and reconstruction (vascularized fibular flap, Engroff et al)

It is recommended that patients beginning bisphosphonate therapy obtain a thorough dental evaluation in which all compromised teeth, implants and pre-prosthetic surgery be completed to allow for adequate tissue healing prior to initiation of therapy. Treatment for “at risk” patients is dictated by the type of bisphosphonate therapy i.e. oral vs. intravenous, duration of therapy and co-morbid conditions as outlined in Table 1 and ultimately by patient preference. Asymptomatic patients receiving IV therapy with nonrestorable teeth should have the coronal portion removed with subsequent endodontic therapy. Restoration should consist of an overlying prosthesis. Placement of implants should be avoided. If oral bisphosphonate treatment is less than 3 years and the patient remains asymptomatic, then the risk is minimal. In those receiving less than 3 years of oral bisphosphonate treatment with concomitant steroid use or those with over 3 years of treatment, it is suggested that a drug holiday of 3 months prior to dental surgery and 3 months post surgery occur to allow adequate osseous healing. This drug holiday should be coordinated with the patient’s physician as the patient’s primary health condition allows.

Conclusion

CTX (C-terminal telopeptide) – Marx5 - a breakdown product of bone resorption - used pre-operatively as a determinant for BRONJ - inverse relationship between the risk for BRONJ and the level of CTX - less than 100pg/mL pose a high risk - between 100 and 150 are at moderate risk - over 150 are minimal risk. With cessation of the drug, values increased an average of 25.9 pg/mL per month, therefore justifying the implementation of a drug holiday. In all clinical situations, well-documented informed consent should be obtained and discussed with the patient.

The rise in bisphosphonate treatment of degenerative osseous diseases is accompanied by a proportional increase in the number of reported cases of bisphosphonate related osteonecrosis of the jaw (BRONJ). BRONJ is precipitated by surgical procedures and may occur spontaneously (Marx et al.)5; the presentation of this pathology varies by route of administration. Ruggiero7 et al. demonstrated a more aggressive clinical course in cases of intravenous administration in contrast to administration per os (po). This has been correlated with a potential difference in the relative potency of the different drug forms, the intravenous suspension being more potent. Although the intravenous form is more efficacious, the relative ease of administration in oral form translates into a greater prevalence of this drug among patients. As the use of bisphosphonates increases, dental practitioners are encountering BRONJ more often. The typical clinical presentation is usually exposed bone or dehisced tissue with or without pain and swelling. In untreated cases, these sites of osteonecrosis can progress into orocutaneous fistulas which may become secondarily infected. In this clinical situation, dentists must determine how to treat BRONJ without further challenging the compromised bone. The treatment modalities range from conservative measures, such as antibiotics and antimicrobial rinses, to more involved therapy, such as superficial debridement, sequestrectomy and resection of the involved bone. The purpose of this presentation is to illustrate the different modalities in treating BRONJ and specific cases treated at this institution will be discussed.

Case #3 - Oral hygiene, Chlorhexidine gluconate mouth rinse and on long term follow up

88 yo Caucasian female, lymphoma, Zolendronate IV, multiple extractions and debridement by private dentist, currently not painful

References

1. American Association of Oral and Maxillofacial Surgeons Position Paper on Bisphosphonate-Related Osteonecrosis of the Jaws. JOMS, 65: 369-376, 2007.

2. Engroff SL. Et al Treating Bisphosphonate Osteonecrosis of the Jaws: Is there a Role for Resection and Vascularized Reconstruction? JOMS, 65:2374-2385, 2007.

3. Grant, BT, et al Outcomes of Placing Dental Implants in Patients Taking Oral Bisphosphonates: A Review of 115 Cases. JOMS. 66:223-230, 2008

4. Ito M, Chokki M, , Ogino Y, Satomi Y, Azuma Y, Ohta T, Kiyoki M. Comparison of cytotoxic effects of bisphosphonates in vitro and in vivo. Calcif Tissue Int 1998:63:143-147

5. Marx, RE. Oral Bisphosphonate-Induced Osteonecrosis: Risk Factors, Prediction of Risk Using Serum CTX Testing, Prevention and Treatment. JOMS, 65: 2397-2410, 2007.

6. Rogers MJ, Watts DJ, Russell RG. Overview of Bisphosphonates. CANCER supplement 1997;80:1652-1660

7. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: A review of 63 cases. Journal of Oram and Maxillofacial Surg 2004;62:527-534

8. Wood J, Bonjean K, Ruetz S. Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther 2002: 302: 1055-1061.

Case #5 – Surgical Debridement with Buccal fat pad advancement, primary closure , Long term pen vk, Chlorhexidine gluconate rinse 2x/day

61 yo HF, on IV Zometa 1 time per month for multiple myeloma. The pt developed BRONJ in lower right quadrant secondary to extractions performed by a private dentist. The patient experienced pain and bleeding of gums x 3-4 months after dental procedure of removal of root fragment/bone in lower right side. Afterwards, patient developed this problem on lower right quadrant, the area of necrosis became slowly worse and as a result the patient developed numbness in lower right jaw, lip and face (V3 distribution) about 3 months prior to presentation to UIC. Level of numbness at initial presentation was unchanged from initial development 3 months prior.