Cara B. Gonzales, DDS, PhD. Assistant Professor Department of Comprehensive Dentistry UTHSCSA Dental School

Transcription

1 Cara B. Gonzales, DDS, PhD Assistant Professor Department of Comprehensive Dentistry UTHSCSA Dental School

2 March 30, st annual STOHN Convocation 16 Community Clinicians 15 Investigators Bisphosphonate-associated Osteonecrosis of the Jaw (BONJ) identified as top research priority of STOHN members.

3 Introduced in 1990s to prevent loss of bone mass: Osteoporosis: Fosamax (Alendronate)-oral Increase bone mass Decrease non-traumatic fractures Bone metastasis (breast and prostate cancer): Zometa (Zoledronate)-IV Reduce tumor invasion of bone Reduce corresponding bone pain and fractures Paget s disease of the bone Multiple myeloma Sept million prescriptions for oral BP.

4 Primary Mechanism of Action: Inhibit bone resorptionby inducing apoptosis of osteoclasts. Disrupts homeostasis of bone turnover. Accumulates in the bone via Ca 2+ binding. Half-life is unknown. Highest concentration in mandible. Can be taken in by osteoclasts for an unknown period of time, thus risk of adverse side effects don t diminish with discontinuation.

5 AAOMS Definition of BONJ: Exposed bone in maxillofacial region Persists>8weeks Current or previous bisphosphonate use Nohxofradiationtherapy Extremely rare with 3000 cases worldwide BONJ associated mostly with: IV bisphosphonates highdoses longerdurationoftherapy(lowdoseoral>2yrs) More frequent in mandible Associated with: Pre-existing dental disease Tobacco Diabetes Denture wearing

6 Most cases occur following dental extractions 1/10,000 to 1/100,000 but increases to 1/300 following extractions May occur spontaneously No known pathogens Treatment: Supportive and preventive i.e. pain management and antibiotics to prevent secondary infections. In severe cases debridement and other surgical interventions are warranted. Major concern for dental practitioners due to its severity and limited management options. Prevention is key!

7 BONJ Subcommittee 2 General Dentists 2 Oral Surgeons 1 Periodontist 1 Pharmacist 1 Statistician Review of Literature 38 Item Survey(9 knowledge based and 29 perception based) Knowledge Perceptions Practice behaviors 88 Participants completed the survey Demographics: practitioner s specialty, year completed highest level of training, and STOHN membership.

8 Participants classified based on knowledge score: High Knowledge: 7-9 knowledge questions answered correctly Low Knowledge: 0-6 knowledge questions answered correctly Associations between survey response and knowledge score category were assessed using Fisher s exact test.

9 Survey Question Correct Answer Reference BONJ occurs at a higher frequency in the True [3, 4] mandible than in the maxilla a INTRAVENOUS use of bisphosphonates True [1, 5, 12, 13, 25] is correlated with higher risk of BONJ than ORAL use a. Sources of infection should be eliminated True [6, 25] prior to beginning INTRAVENOUS bisphosphonate therapy a Elective invasive dental treatment should True [1, 4, 6, 25] be avoided during and after INTRAVENOUS bisphosphonates therapy a Sound oral hygiene practices and regular Strongly Agree/Agree [1, 6, 25] dental care can reduce the risk of BONJ b. There is evidence linking BONJ with Agree /Neutral/Disagree c [23, 24] alcohol and tobacco use b. There is evidence linking BONJ with preexisting Strongly Agree/Agree [6, 25] dental disease b. The risk of BONJ increases with Strongly Agree/Agree [1, 5, 12, 13, 25] duration/dose of bisphosphonate therapy b. Risk of BONJ decreases to normal after discontinuing bisphosphonate therapy b. Agree/Neutral/Disagree c Unknown a Response choices: True, False, or Don t Know. b Response choices: Strongly agree, Agree, Neutral, Disagree, or Strongly disagree. c We translated limited or inconclusive evidence as correctly answered by the less definitive responses of agree/neutral/disagree.

10 90% of all participants had adequate knowledge levels answering 6/9 knowledge questions correctly. High Knowledge: 7-9 correct answers(n=64) Low Knowledge: 0-6 correct answers (n=24) 51% of participants were aware that BONJ is linked to untreated/pre-existing dental disease. The majority (86% High and 79% Low) of participants correctly believe that elective invasive procedures should not be given during and after IV bisphosphonate use.

11 78% of high knowledge and 54% of low knowledge categories reported that they were well informed about BONJ. 76% of high knowledge and 58% of low knowledge categories report that they are confident that they couldidentifyacaseofbonj. None are comfortable in managing a case of BONJ.

12 94% with high knowledge scores will ASK if their patients are taking BP(p<0.01). 71% with low knowledge scores ASK(p<0.01). If practitioner is already aware that a patient is on BP then 93% of all practitioners will discuss the risk of developing BONJ. 63% of all practitioners report not having informed-consent forms outlining the risk of developing BONJ. Regardless of BONJ knowledge score, most participants make the following changes in their practice: Avoid elective invasive procedures on ANY form of BP. Patients on BP requiring invasive treatment will be referred to a specialist.

13 80% of all practitioners will modify treatment recommendations for patients on oral BP therapy. 97% with high knowledge scores modify treatment for patients on IV BP while only 79% with low knowledge scores report modifying their treatments for these patients. Low knowledge category participants report modifying treatment fororalandivbpuseequally(80%). What does this imply? DoparticipantsaskhowlongptshavetakenoralBP? Are high knowledge participants more informed about increasedbonjriskwithivbpvs.oralbpuse? Are some low knowledge participants not aware of the different risks related to rout and duration of BP therapy?

14 Type I collagen is degraded allowing small fragments (CTX) to enter the bloodstream. C-terminal cross-linking telopeptide (CTX) is a biological index used to measure bone remodeling and, indirectly, osteoclastic activity. CTX testing is used to measure bone turnover in Paget s disease. Current studies indicate CTX levels are not predictive of risk for developing BONJ following invasive dental procedures. 30% with high knowledge scores routinely order blood work to evaluate CTX levels prior to invasive treatments. 9% with low knowledge scores report evaluating CTX levels.

15 65% of all practitioners perceive that their patients are not well informed about BONJ and 47% report that their patients are not concerned about developing BONJ. Where are patients getting their information? 55% of all practitioners report that their patients will choose to delay dental care due to pre-existing BP use. 42% of high knowledge and 21% of low knowledge categories report that their patients will elect to delay initiation of BP therapy until completion of dental care.

16 85% of all practitioners are concerned about their patients developing BONJ and would like more guidelines regarding BONJ identification, risk and management.

17 VARIABLE Before therapy < 2 years CONSIDERATIONS FOR MANAGING PATIENTS ORAL HEALTH Prevention Strategies for Patients Receiving Anti-resorptive Therapy Optimal time to establish lifetime oral health awareness, as the long-term nature of anti-resorptive therapy is associated with ever-increasing BONJ risk Optimal period to remove unsalvageable teeth and perform invasive dentoalveolar procedures, although a less stringent requirement than that for patients being treated with these drugs as part of cancer therapy Risk during this period is very low; however, a few cases of BONJ have been reported Dentoalveolar procedures involving periosteal penetration or intramedullary bone exposure (for example, extractions, apicoectomies, periodontal surgeries, implants or biopsies) seem to carry a minimal risk of the patient s developing BONJ Chlorhexidine rinses are advised whenever periosteal or medullary bone exposure is anticipated or observed In patients with multiple surgical needs, a trial segmental approach may be helpful in assessing a specific patient s risk of developing osteonecrosis and in reducing the likelihood of developing multifocal BONJ 2 years Continue as above while advising the patient and physician who prescribes antiresorptive drugs that the risk of developing ARONJ continues to increase with extended drug use The dentist should discuss antiresorptive therapy with the patient s physician as it relates to the patient s oral health Any length of therapy Risk Assessment Emergency Dental Therapy Routine Dental Care Discontinuation of antiresorptive therapy should be a medical decision based primarily on the risk of experiencing skeletally related events (for example, fractures) secondary to low bone density, not the potential risk of developing BONJ No oral or maxillofacial surgical procedures are strictly contraindicated, although it is the opinion of the expert committee that treatment plans that minimize periosteal and/or intrabony exposure or disruption are preferred Serum C-terminal telopeptide levels have not shown reliability or accuracy in predicting risk of developing ARONJ; therefore, serum testing is not recommended to predict risk Although the trial segmental or sextant approach to surgical procedures has not been studied in a prospective fashion, this approach should help limit the extent of ARONJ in a given All extractions or dentoalveolar surgeries required on the basis of dental or medical emergencies are appropriate, regardless of the number of extractions or surgeries and multifocality Good oral health and routine dental care always are recommended ADA Council on Scientific Affairs Executive Summary Recommendations for managing care of patients receiving anti-resorptive therapy for prevention and treatment of osteoporosis; 2011.

18 1) Anti-resorptive therapy for low bone mass puts osteoporosis patients at a very low risk (0.10%) of developing BONJ. 2) The low risk can be minimized but not eliminated. 3) Sound oral hygiene and routine dental care may be the best approach for minimizing risk of BONJ. 4) Currently, there are no diagnostic tests that determine which patients are at risk of developing BONJ. 5) Discontinuing bisphosphonate therapy may not eliminate risk of developing BONJ, but may have a negative impact on their osteoporosis. 6) Importantly, there is no data that illustrates a drug holiday is useful in reducing the risk of developing BONJ. Furthermore, discontinuation of treatment should be a medical decision based on the risk of skeletally related events (bone fractures) and not the potential risk of developing BONJ.

19 AAOMS Recommended Staging and Treatment Strategies for BONJ* *This table is modified from AAOMS 2009 position paper update [20]. BONJ Stage Description Treatment Strategies At Risk Category Stage 0 Stage 1 No apparent necrotic bone in patients who have been treated with either oral or IV bisphosphonates. No clinical evidence of necrotic bone, but nonspecific clinical findings and symptoms. Exposed and necrotic bone in asymptomatic patients without evidence of infection. No treatment indicated. Systemic management, including use of pain medication and antibiotics. Antibacterial mouth rinse Clinical follow-up on quarterly basis. Patient education and review of indications for continued bisphosphonate therapy. Stage 2 Exposed and necrotic bone associated with infection as evidenced by pain and erythema in region of exposed bone with or without purulent drainage. Symptomatic treatment with oral antibiotics. Oral antibacterial mouth rinse Pain Control Stage 3 Exposed and necrotic 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 or the sinus floor. Superficial debridement to relieve soft tissue irritation. Antibacterial mouth rinse Antibiotic therapy and pain control. Surgical debridement/resection for longer term palliation of infection and pain.

20 Incorporate more specific knowledge questions PotencyofBP DurationofBPTherapy Physicians knowledge and perceptions related to BONJ Do physicians refer patients for dental care prior to initiation of BP? Do pharmacists discuss BONJ with pts on BP therapy?

21 Thank you PBRN members and STOHN! ThisCTSAworkissupportedbyNIHawardULIRR025767

22 1. Almazrooa, S.A. and S.B. Woo, Bisphosphonate and nonbisphosphonate-associated osteonecrosis of the jaw: a review. J Am Dent Assoc, (7): p Assael, L.A., Oral bisphosphonates as a cause of bisphosphonate-related osteonecrosis of the jaws: clinical findings, assessment of risks, and preventive strategies. J Oral Maxillofac Surg, (5 Suppl): p Ruggiero, S.L., et al., Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg, (5): p Hellstein, J.W., et al., 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. J Am Dent Assoc. 142(11): p Black, D.M., et al., Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA, (24): p Brown, J.E., et al., Prolonged efficacy of a single dose of the bisphosphonate zoledronic acid. Clin Cancer Res, (18 Pt 1): p Rosen, L.S., et al., Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J, (5): p American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg, (3): p Nussbaum, S.R., et al., Single-dose intravenous therapy with pamidronate for the treatment of hypercalcemia of malignancy: comparison of 30-, 60-, and 90-mg dosages. Am J Med, (3): p Major, P., et al., Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol, (2): p Hortobagyi, G.N., et al., Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. Protocol 19 Aredia Breast Cancer Study Group. N Engl J Med, (24): p Hortobagyi, G.N., et al., Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. Protocol 19 Aredia Breast Cancer Study Group. J Clin Oncol, (6): p Hillner, B.E., et al., American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol, (21): p Saad, F., et al., A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst, (19): p Saad, F., et al., Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst, (11): p Rosen, L.S., et al., Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, Phase III, double-blind, placebo-controlled trial. Cancer, (12): p

23 17. Berenson, J.R., et al., Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group. N Engl J Med, (8): p Berenson, J.R., et al., Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group. J Clin Oncol, (2): p Berenson, J.R., et al., American Society of Clinical Oncology clinical practice guidelines: the role of bisphosphonates in multiple myeloma. J Clin Oncol, (17): p Ruggiero, S.L., et al., American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws update. J Oral Maxillofac Surg, (5 Suppl): p Thumbigere-Math, V., et al., Bisphosphonate-related osteonecrosis of the jaw: clinical features, risk factors, management, and treatment outcomes of 26 patients. J Oral Maxillofac Surg, (9): p Fantasia, J.E., Bisphosphonates--what the dentist needs to know: practical considerations. J Oral Maxillofac Surg, (5 Suppl): p McClung, M.R., et al., Denosumab in postmenopausal women with low bone mineral density. N Engl J Med, (8): p Lopez-Jornet, P., et al., Bisphosphonate-associated osteonecrosis of the jaw. Knowledge and attitudes of dentists and dental students: a preliminary study. J Eval Clin Pract. 16(5): p Aghaloo, T.L., A.L. Felsenfeld, and S. Tetradis, Osteonecrosis of the jaw in a patient on Denosumab. J Oral Maxillofac Surg. 68(5): p Wessel, J.H., T.B. Dodson, and A.I. Zavras, Zoledronate, smoking, and obesity are strong risk factors for osteonecrosis of the jaw: a casecontrol study. J Oral Maxillofac Surg, (4): p Rustemeyer, J. and A. Bremerich, Bisphosphonate-associated osteonecrosis of the jaw: what do we currently know? A survey of knowledge given in the recent literature. Clin Oral Investig. 14(1): p Ruggiero, S.L. and S.B. Woo, Biophosphonate-related osteonecrosis of the jaws. Dent Clin North Am, (1): p , ix. 29. Cartsos, V.M., S. Zhu, and A.I. Zavras, Bisphosphonate use and the risk of adverse jaw outcomes: a medical claims study of 714,217 people. J Am Dent Assoc, (1): p Morag, Y., et al., Bisphosphonate-related osteonecrosis of the jaw: a pictorial review. Radiographics, (7): p Raje, N., et al., Clinical, radiographic, and biochemical characterization of multiple myeloma patients with osteonecrosis of the jaw. Clin Cancer Res, (8): p Davis, D.A., et al., Accuracy of physician self-assessment compared with observed measures of competence: a systematic review. JAMA, (9): p Marx, R.E., J.E. Cillo, Jr., and J.J. Ulloa, Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg, (12): p O'Connell, J.E., O. Ikeagwani, and G.J. Kearns, A role for C-terminal cross-linking telopeptide (CTX) level to predict the development of bisphosphonate-related osteonecrosis of the jaws (BRONJ) following oral surgery? Ir J Med Sci. 181(2): p Cheng, A., et al., The dental implications of bisphosphonates and bone disease. Aust Dent J, (4 Suppl 2): p. S4-13.

24 2005 NIDCR launched the practice-based initiative with seven-year Regional Dental PBRN grants. 1,719 practitioners enrolled in 43 states Conducted 51 research studies Generated 87 journal articles Preventive and restorative dentistry Pain management and smoking cessation 2012 NIDCR $66.8 Million, Seven-year grant to consolidate the DPBRN initiative into a unified nationally coordinated effort. Renamed the National Dental Practice-Based Research Network (NDPBRN) Headquartered at the University of Alabama at Birmingham School of Dentistry

25 This study demonstrates the importance of practitioner s knowledge and their ability to communicate with their patients when making treatment recommendations. Example of practice based evidence directing evidence based practice. Reinforces the value in disseminating and translating these findings to you, the practitioners in the community.