ALACHUA COUNTY DENTAL SOCIETY LECTURE OBJECTIVES CASE STUDY BISPHOSPHONATE INDUCED OSTEOCHEMONECROSIS NOVEMBER 3, 2006

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1 ALACHUA COUNTY DENTAL SOCIETY NOVEMBER 3, 2006 INDUCED DONALD M COHEN DMD MS MBA SECTION HEAD ORAL PATHOLOGY, UFCOD DCOHEN@DENTAL.UFL.EDU LECTURE OBJECTIVES Learn the diagnostic features of osteochemonecrosis. The etiology and pathogenesis will also be elucidated and why the jaws are the only target. Participants will also learn how to treat and prevent it. CASE STUDY 56 year old diabetic black female is an adult onset diabetic taking HCTZ for HBP, metformin and glyburide for diabetes & Fosomax for osteoporosis. She had a tooth extraction 6 months ago but area failed to heal. She has intense pain, exposed bone, swelling and purulence in the extraction site.. 1

2 DIAGNOSIS Fosamax Induced Osteochemonecrosis (Osteopetrosis) DEFINITION: Painless(31%) or painful(69%) exposure of avascular bone, mand(80%), max(15%) both(5%) Pain is indication of infection Present at least weeks No response to Tx No history of radiation 2

3 CLINICAL MANIFESTATIONS EXPOSED BONE +/- PAIN- 100% MOBILE TEETH -24% FISTULA MUCOSAL OR SKIN -18% OSTEOLYSIS + SCLEROSIS -83% INCREASE BONE THICKNESS ESPECIALLY PERIOSTEAL %?? In both radio- and chemo- necrosis: Increased subperiosteal bone deposition Increased thickness of the jaw (radiated area or wide spread) I.e. altered bone remodeling 3

4 Necrosis seen mostly with iv meds(96%) Potency of drugs may be similar but absorption is 1% for oral preparations and 50% for i.v. 2.5% of cases seen with oral bisphosphonates (Fosomax) S Lesions developed after months on meds Zometa average 9 months Aredia 14 months Fosomax average 46 months (+/- 30) earliest 2 years Fosomax has a 10 year half life INCIDENCE I.V. 0.6% - 12% breast cancer patients 1.5%( months)-7.7%(37 7.7%(37-48 months) multiple myeloma and boney metastasis 12.8% multiple myeloma IV Zolendronate(10%) >Pamidronate(4%) INCIDENCE I.V. Patients receiving IV bisphosphonates and undergoing dentoalveolar surgery are at least 7-times more likely to develop BON than patients who are not having dentoalveolar surgery. ORAL FOSAMAX Fosamax first introduced million on oral forms of bisphosphonate (190 million world wide) Only 93 documented and 378 undocumented cases reported to manufacturer of Fosamax FOSAMAX(ALENDRONATE) & 37.7 million patient years of treatment Reporting rate per 100,00 patient years exposure( %).01%) But many cases misdiagnosed or unreported/ unrecognized Incidence %, in Australia Following extractions, %. 4

5 Trigger 1. None- spontaneous bone necrosis, mylohyoid ridge etc. - 25% 2. Tooth extraction -38%(56%) 3. Periodontal disease & Surgery 40%(most common trigger) 4. Implants 3.4%(9) and apico <1% Many cases are silent, or mimic dental disease TOOTH EXTRACTION PERIO SURGERY EARLIEST SIGNS Widened PDL Sclerosis of lamina dura Incipient bifurcation involvement Mobile teeth Pain 5

6 Other possible associated risk factors LT steroid use(22%) Shorten time to development don t cause OCN RED HERRING CASE HISTORY 44 y/o male supposedly developed spontaneous bony sequestrum in the mylohyoid ridge area associated with rapid bone loss, pain, purulence etc. Resembles osteochemonecrosis. RED HERRING CASE RED HERRING CASE RED HERRING CASE HISTORY But not on bisphosphonate and history reveals periodontal surgery in area 1-21 years ago. Biopsy results osteomyelitis associated with Actinomycosis. 6

7 RED HERRING CASE HISTORY 2 66 Y/o female painful ulcer lingual retromolar area present for months. Taking Fosamax for 5 years. Patient is a smoker & drinker. Lesion appeared spontaneously. No history of trauma. Incisional biopsy done to rule out carcinoma but doesn't look like Ca. RED HERRING CASE HISTORY 2 RED HERRING CASE HISTORY 2 RED HERRING CASE HISTORY 2 Diagnosis??? Squamous cell carcinoma Therefore add 2 clinical criteria for ONJ diagnosis Histologic examination Radiograph (osteosclerosis( +/- lucency) S Endogenous regulator of bone mineralization (bone resorption inhibitors) which accumulate in hydroxyapatite in mineralized bone S Prevents bone metastasis (breast & prostate Ca, myeloma,) & treats metabolic bone diseases (high turnover) i.e. osteoporosis, hypercalcemia of malignancy & Paget s disease 7

8 S Dramatically improves quality of life, reduce skeletal complications and pain Does not significantly extend life S Zometa and Aredia i.v. drugs most associated with avascular intraoral bone necrosis Together account for 96% of cases of ONJ ZOMETA & AREDIA These along with Fosamax are newer generation, extremely potent, nitrogen containing, nonmetabolizable pyrophosphates Stays in bone a long time (12 years) Necrosis due to anti-osteoclastic and (anti-angiogenesis) angiogenesis) effects of drug ZOMETA & AREDIA Powerful inhibitor of osteoclastic activity Cytotoxic especially to osteoclast precursors and irreversibly inhibits recruitment and activation and shortens life span of osteclasts MECHANISM OF ACTION 8

9 ZOMETA & AREDIA Bone resorption essential for bone viability Without resorption after 150 days (life span of osteocyte) osteon becomes non-vital ONJ WHY NOW?? Nitrogen containing (more potent, newer generation) are only bisphosphonates that cause ONJ Continuous dose accumulates in bone Risk increases proportionally each year More patients on more potent drugs continuously, = more cases WHY ONLY THE JAWS??? Alveolar bone remodeling depends more on osteoclasis than any other bone. Remodeling rate of mandible is 10x that of any other bone and alveolus remodels 2-3x 2 faster than the rest of the mandible. WHY ONLY THE JAWS??? Local lesions (ulcers, plaque, trauma) cause need for bone remodeling to increase significantly WHY ONLY THE JAWS??? Bacterial lipolysaccharides and inflammation increase bone remodeling and concentration of bisphosphonates in bone Fosamax localizes to area where osteoclasts are remodeling bone 8x more than normal bone S I.V. bisphosphonates produce irreversible ONJ however, if systemic conditions permit, long-term discontinuation may be beneficial in stabilizing BRON, reducing risk of new site development, and reducing symptoms. 9

10 NEWEST RECOMMENDATIONS PATIENTS ON ORAL BISPHOSHONATES Lesions less severe from oral meds (Fosomax) may respond better to local therapy More predictable, reversible and amenable to surgery NEWEST RECOMMENDATIONS PATIENTS ON ORAL BISPHOSHONATES If systemic conditions permit, modification or cessation of oral bisphosphonate in consultation with the physician and patient. After 5 years on Fosamax a one year drug holiday is usually no problem TREATMENT Spontaneous resolution can occur Discontinuation of oral bisphosphonates for 6-12 months may result in spontaneous sequestration or resolution following debridement Conservative sequestrectomy may help but no surgery!!! The effectiveness of hyperbaric oxygen therapy is undetermined. TREATMENT For elective surgery discontinue oral bisphosphonate for 3 months, do necessary surgery then allow 3 more months for healing. Antibiotic therapy and chlorhexidine rinses may be helpful for prevention. POST FOSOMAX HEALING POST FOSOMAX HEALING 10

11 BONY SEQUESTRUM 11

12 CONSERVATIVE SEQUESTRECTOMY SEQUESTRUM Position Paper on Bisphosphonate- Related Osteonecrosis of the Jaws BRON Case Definition American Association of Oral and Maxillofacial Surgeons Approved by the Board of Trustees September 25, Current or previous treatment with a bisphosphonate 2. Exposed bone in the maxillofacial region persisting for more than eight weeks 3. No history of radiation therapy to the jaws. Management Strategies for Patients Treated with Bisphosphonates Prevention of BRON Prior to treatment with IV bisphosphonate, patient should have thorough oral examination, any unsalvageable teeth should be removed, all invasive dental procedures should be completed, and optimal periodontal health should be achieved. Prevention (BEFORE I.V.Bisphosphonates Bisphosphonates) Complete invasive dental procedures and let heal for weeks (extractions, perio, endo) Caries Control and Fluoride Trays Restorative Dentistry No Implants, make sure dentures fit/soft reline Remove all sources of infection Remove large tori 12

13 Management Strategies for Patients Treated with Bisphosphonates Prevention of BRON Therefore, if systemic conditions permit, initiation of bisphosphonate therapy should be delayed until dental health is optimized. This decision must be made in conjunction with the treating physician and oncologist PREVENTION AND TREATMENT Pre-medication dental evaluation BEFORE start bisphosphonate Extraction avoidance AFTER to prevent or reduce problem Prevention AFTER Bisphosphonates Dental evaluation every 4 months Prophy and Fluoride Trays Endo and crown abscessed teeth (Cut off crown at gingival level if it is not restorable) Splint 1+ and 2+ mobile teeth Remove abscessed and 3+ mobile teeth EXPERT PANEL RECOMMENDATIONS PATIENTS ON ORAL BISPHOSHONATES Non-surgical endodontics is preferred to extraction. Periodontal disease, conservative perio first EXPERT PANEL RECOMMENDATIONS PATIENTS ON ORAL BISPHOSHONATES Conservative surgery if unresolved avoid guided bone regeneration If extractions necessary conservative approach with primary closure Immediate pre and post surgery use peridex rinse (gentle) and then rinse 2x/day for two months. TREATMENT Inform patient of diagnosis and that this is permanent Avoid debridement of bone (can round sharp edges of bone) or dental implants 13

14 TREATMENT 90%+ patients pain free (but with continued exposed bone) if use antibiotics and 0.12% chlorhexidine mouth rinse (3-4x/day) Strategies: At risk category No exposed/necrotic bone in patients who have been treated with either oral or IV bisphosphonates No treatment indicated Patient education Strategies: Stage 1 Exposed/necrotic bone in asymptomatic patients who have no evidence of infection Antibacterial mouth rinse Strategies: Stage 1 Clinical follow-up on a quarterly basis Patient education and review of indications for continued bisphosphonate therapy Strategies: Stage 2 Infected exposed/necrotic bone with pain and erythema in the region of the exposed bone +/-purulent drainage Symptomatic treatment with broadspectrum oral antibiotics, e.g. penicillin, cephalexin, clindamycin, or 1st generation fluoroquinolone Strategies: Stage 2 Microbial cultures For Actinomyces Treat pain with Pen VK 500mg Q.I.D. and chlorhexidine mouth rinse until pain free and Add Flagyl 500mg T.I.D. if pain persists 14

15 Strategies: Stage 2 Oral antibacterial mouth rinse Pain control Only superficial debridements to relieve soft tissue irritation Strategies: Stage 3 Exposed/necrotic bone in patients with pain, infection, and one or more of the following: pathologic fracture, extraoral fistula, or osteolysis extending to the inferior border Antibacterial mouth rinse Strategies: Stage 3 Antibiotic therapy and pain control Surgical debridement/resection for longer term palliation of infection and pain Strategies: Stage 3 Surgical debridement has been variably effective in eradicating the necrotic bone. Surgical treatment should be delayed if possible. Strategies: Stage 3 Loose segments of bony sequestrum should be removed without exposing uninvolved bone. Symptomatic patients with pathologic mandibular fractures may require segmental resection and immediate reconstruction with a reconstruction plate. Strategies: Stage 3 The extraction of symptomatic teeth within exposed, necrotic bone should be considered since unlikely that the extraction will exacerbate the necrotic process. Patients with established BRON should avoid elective dentoalveolar surgical procedures 15

16 STAGING & MANAGEMENT Refractory cases Combination antibiotic therapy Long-term antibiotic maintenance therapy IV antibiotic therapy Quinolones, metronidazole, clindamycin, doxycycline, and erythromycin patients who are allergic to penicillin. CASE HISTORY This 66 Y/O AFA with multiple myeloma, third partial remission, was sent to the Oral & Maxillofacial Surgery service to rule out a dental abscess/osteomyelitis. Patient is about to under go high dose chemo followed by autologous stem cell transplant. CASE HISTORY Patient has a small hypertrophic soft tissue growth in area of previous extraction. No pain or bad taste or suppuration and extractions done in left side of mandible 1+ year ago. A Panorex shows multiple areas of lucency/opacity,? Sequestrum,, mainly in the area of previous extractions. CASE HISTORY Medications include: Diflucan, Florinef, Tequin, K-Dur, K Flagyl, Protonix, prednisone, Valtrex, Pamidronate, Amikacin, Cefeprine, Digoxin, Activase, Insulin, Ambien, and Oxycodone 16

17 TREATMENT??? Why treat?? Why not treat?? TREATMENT Consult with oncology Most likely fistulous tract and sequestrum. This lesion appears localized. Did incisional biopsy and found boney fragments encapsulated in soft tissue Base of lesion was solid bone HISTOLOGIC DIAGNOSIS SEPTIC BONEY SEQUESTRUM WITH ACTINOMYCOTIC AND OTHER BACTERIAL COLONIES, ABSCESS, AND GRANULATION TISSUE What about the rest of his mouth?? 4 th Annual Oral Pathology and Medicine Update Dates: Feb , 2007 (Friday and half-day Saturday) Location: Hilton in the Walt Disney World Resort at Orlando, FL CEUs: 12 contact hours Faculty: University of Florida Faculty Registration Fees: $595 Dentists, $395 Auxiliaries Call toll-free or visit for more information or to register. CASE STUDIES IN ORAL MEDICINE Announcing Case of the Month!!! Be a life long learner! Study each month for free!!! Get monthly pathology updates and alerts. 17