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Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
Bisphosphonate Related Osteonecrosis: Update
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Bisphosphonate Related Osteonecrosis: Update

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  • 1. Nik Desai, DMD, MD Division of Oral & Maxillofacial Surgery Department of Plastic Surgery Kaiser Permanente Medical Group Santa Clara, CA 04/28/2010 Bisphosphonate Related Osteonecrosis of the Jaws
  • 2. Objectives <ul><li>Bisphosphonates </li></ul><ul><li>Clinical applications </li></ul><ul><li>Drug chemistry </li></ul><ul><li>Biologic action </li></ul><ul><li>BRONJ </li></ul><ul><li>Pathogenesis </li></ul><ul><li>Treatment of BRONJ </li></ul><ul><li>Latest management recommendations </li></ul><ul><li>Updates in the literature </li></ul><ul><li>Case Presentations </li></ul>
  • 3. Bisphosphonates – what are they? <ul><li>Class of drugs </li></ul><ul><li>High affinity for calcium </li></ul><ul><ul><li>Binds to bone surfaces </li></ul></ul><ul><ul><li>Nitrogen: increased affinity, potency </li></ul></ul><ul><li>Prevent bone resorption and remodeling </li></ul><ul><li>IV and oral formulations </li></ul><ul><ul><li>IV : tx for bone resorption 2° metastatic tumors, osteolytic lesions </li></ul></ul><ul><ul><li>Oral : tx for osteoporosis, osteopenia </li></ul></ul>
  • 4. Bisphosphonates: Common uses <ul><li>Prevention and treatment of osteoporosis in </li></ul><ul><li>postmenopausal women </li></ul><ul><li>Increase bone mass in men with osteoporosis </li></ul><ul><li>Tx of glucocorticoid-induced osteoporosis </li></ul><ul><li>Tx of Paget’s disease of bone </li></ul><ul><li>Hypercalcemia of malignancy </li></ul><ul><li>Bone metastases of solid tumors </li></ul><ul><ul><li>breast and prostate carcinoma; other solid tumors </li></ul></ul><ul><li>Osteolytic lesions of multiple myeloma </li></ul>
  • 5. History of Bisphosphonate Development <ul><li>Mid-19 th Century German chemists </li></ul><ul><ul><li>Anti-corrosive in pipelines </li></ul></ul><ul><li>20 th Century - Clinical applications </li></ul><ul><ul><li>Tc99 Bone scans </li></ul></ul><ul><ul><li>Toothpaste </li></ul></ul><ul><ul><ul><li>Anti-tartar, anti-plaque effects </li></ul></ul></ul><ul><ul><li>Osteopathies </li></ul></ul><ul><ul><ul><li>Anti-resorptive effect </li></ul></ul></ul>
  • 6. Basic Chemical Composition <ul><li>Pyrophosphate compound </li></ul><ul><li>Substitution of Carbon for Oxygen </li></ul><ul><ul><li>Resistance to hydrolysis </li></ul></ul><ul><ul><li>Bone matrix accumulation </li></ul></ul><ul><ul><li>Extremely long half-life </li></ul></ul><ul><li>Nitrogen-containing side chain </li></ul><ul><ul><li>Increases potency, toxicity </li></ul></ul><ul><ul><li>Direct link to BRONJ cases </li></ul></ul>
  • 7. Antiresorptive Potency of BPs in Observed Human Clinical Trials
  • 8. Biologic Action of Bisphosphonates <ul><li>Osteoclastic toxicity </li></ul><ul><ul><li>Apoptosis </li></ul></ul><ul><ul><li>Inhibited release of bone induction proteins </li></ul></ul><ul><ul><ul><li>BMP, ILG1, ILG2 </li></ul></ul></ul><ul><ul><li>Reduced bone turnover, resorption </li></ul></ul><ul><ul><li>Reduced serum calcium* </li></ul></ul><ul><ul><li>Hypermineralization* </li></ul></ul><ul><ul><ul><li>“ sclerotic” changes in lamina dura of alveolar bone </li></ul></ul></ul><ul><ul><ul><li>* = goal of medicinal use </li></ul></ul></ul>
  • 9. Normal Osteoclastic Function
  • 10. Medical Indications for IV BPs <ul><li>Bone metastasis , hypercalcemia </li></ul><ul><ul><li>RANKL-mediated osteoclastic resorption </li></ul></ul><ul><ul><ul><li>Multiple myeloma, breast CA, prostate CA </li></ul></ul></ul><ul><ul><ul><li>Paracrine-like effect </li></ul></ul></ul><ul><ul><li>PTH-like peptide osteoclastic resorption </li></ul></ul><ul><ul><ul><li>Small cell carcinoma, oropharyngeal cancers </li></ul></ul></ul><ul><ul><ul><li>Endocrine-like effect </li></ul></ul></ul>
  • 11. Medical Indications for Oral BPs <ul><li>Paget’s Disease of bone </li></ul><ul><ul><li>Accelerated bone turnover </li></ul></ul><ul><ul><ul><li>Reduced compressive strength, increased vascularity </li></ul></ul></ul><ul><ul><ul><li>Bone pain </li></ul></ul></ul><ul><ul><ul><li>Elevated AP levels </li></ul></ul></ul><ul><li>Osteoporosis </li></ul><ul><ul><li>Effects of estrogen loss: </li></ul></ul><ul><ul><ul><li>Decreased bone turnover/renewal </li></ul></ul></ul><ul><ul><ul><ul><li>Adipocyte differentiation > osteoblastic differentiation </li></ul></ul></ul></ul><ul><ul><ul><ul><li>increased fibrofatty marrow </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Progressively porotic bone </li></ul></ul></ul></ul><ul><ul><li>DEXA scan for BMD values </li></ul></ul>
  • 12. Drug Administration and Dosage
  • 13. Pharmacokinetics <ul><li>Oral BP’s </li></ul><ul><ul><li>Absorbed in small intestine </li></ul></ul><ul><ul><ul><li>Less if taken with meal </li></ul></ul></ul><ul><ul><li>1-10% available to bone </li></ul></ul><ul><li>Circulating half-life: 0.5-2 hrs </li></ul><ul><ul><li>Rapid uptake into bone matrix </li></ul></ul><ul><ul><li>30-70% of IV/oral dose accumulates in bone </li></ul></ul><ul><ul><li>Remainder excreted in urine </li></ul></ul><ul><li>Repeated doses accumulate in bone </li></ul><ul><ul><li>Removed only by osteoclast-mediated resorption </li></ul></ul><ul><ul><li>“ Biologic Catch 22 ” </li></ul></ul>
  • 14. Etidronate (Didronel) <ul><li>Available in both oral and IV preparations </li></ul><ul><li>Oral: FDA approved for Paget’s disease </li></ul><ul><ul><li>Dose: 5 mg/kg per day </li></ul></ul><ul><li>IV: approved for use in hypercalcemia of malignancy </li></ul><ul><ul><li>Dose: 7.5 mg/kg per day for 3 days </li></ul></ul><ul><li>Risk of osteomalacia w/ prolonged therapy </li></ul><ul><ul><li>do not treat >2 yrs </li></ul></ul><ul><li>No documented cases of BRONJ </li></ul>
  • 15. Pamidronate (Aredia) <ul><li>Available only as IV preparation b/c of poor GI absorption and high freq of GI symptoms </li></ul><ul><li>Approved for tx of hypercalcemia of malignancy </li></ul><ul><ul><li>one-time dose of 60-90 mg </li></ul></ul><ul><li>Also used for Paget’s disease </li></ul><ul><li>Also used for osteoporosis pt’s who are unable to tolerate other bisphosphonates </li></ul>
  • 16. Zolendronate (Zometa) <ul><li>Only available in IV preparation </li></ul><ul><li>Approved for tx of hypercalcemia of malignancy </li></ul><ul><li>4mg IV over no less than 15 mins </li></ul>
  • 17. Alendronate (Fosamax) <ul><li>Available as oral preparation </li></ul><ul><li>Osteoporosis </li></ul><ul><ul><li>Treatment dose: 10 mg/day or 70 mg weekly </li></ul></ul><ul><ul><li>Prevention dose : 5 mg/day or 25 mg weekly </li></ul></ul><ul><li>Less inhibition of bone mineralization </li></ul><ul><li>More suitable for long-term administration </li></ul>
  • 18. Risedronate (Actonel) <ul><li>Also available as oral preparation </li></ul><ul><li>Approved for tx of osteoporosis </li></ul><ul><li>5 mg daily and 35 mg weekly </li></ul><ul><ul><li>Dose for prevention of osteoporosis is same as for treatment </li></ul></ul>
  • 19. Ibandronate (Boniva) <ul><li>Most recently approved for tx and prevention of osteoporosis </li></ul><ul><li>2.5mg daily or 150 mg monthly </li></ul>
  • 20. Bisphosphonate Side Effects <ul><li>Upset stomach </li></ul><ul><li>Inflammation/erosions of esophagus </li></ul><ul><li>Fever/flu-like symptoms </li></ul><ul><li>Slight increased risk for electrolyte disturbance </li></ul><ul><li>Uveitis </li></ul><ul><li>Musculoskeletal joint pain </li></ul><ul><li>And of course………………… </li></ul>
  • 21. BRONJ <ul><li>Exposed, devitalized bone in maxillofacial region </li></ul><ul><li>Prior history or current use of BP </li></ul><ul><li>Vague pain, discomfort </li></ul><ul><li>Spontaneous occurrence, or… </li></ul><ul><li>2° surgery or trauma to oral soft tissue/bone </li></ul>
  • 22. BRONJ: Clinical Presentation <ul><li>Exposed alveolar bone </li></ul><ul><ul><li>Open mucosal wound </li></ul></ul><ul><ul><li>Necrotic bone </li></ul></ul><ul><ul><li>Spontaneous or Traumatic </li></ul></ul><ul><ul><ul><li>Extractions, periodontal surgery, apicoectomy, implant placement </li></ul></ul></ul><ul><li>Infection </li></ul><ul><ul><li>Purulence, bone pain </li></ul></ul><ul><ul><li>Orocutaneous fistula </li></ul></ul>
  • 23. BRONJ: Clinical Presentation <ul><li>Subclinical Form </li></ul><ul><ul><li>asymptomatic </li></ul></ul><ul><ul><li>radiographic signs </li></ul></ul><ul><ul><ul><li>Sclerosis of lamina dura </li></ul></ul></ul><ul><ul><ul><li>Widening of PDL space </li></ul></ul></ul>
  • 24. Clinical Presentation (cont)… <ul><li>Soft tissue abrasions </li></ul><ul><ul><li>Tissues rubbing against bone </li></ul></ul><ul><li>AND……… </li></ul>
  • 25. Pathologic Fracture
  • 26. Staging of BRONJ <ul><li>Proposed by AAOMS: </li></ul><ul><ul><li>Patients at risk (Subclinical) </li></ul></ul><ul><ul><ul><li>No apparent exposed/necrotic bone in pts treated w/ IV or oral BPs </li></ul></ul></ul><ul><ul><li>Patients with BRONJ </li></ul></ul><ul><ul><ul><li>Stage 1: Exposed/necrotic bone, asymptomatic, no infection </li></ul></ul></ul><ul><ul><ul><li>Stage 2: Exposed/necrotic bone, pain, clinical evidence of infection </li></ul></ul></ul><ul><ul><ul><li>Stage 3: Exposed/necrotic bone, pain, infection, one or more of the following: </li></ul></ul></ul><ul><ul><ul><ul><li>Pathologic fracture, extra-oral fistula, osteolysis extending to inferior border </li></ul></ul></ul></ul>
  • 27. BRONJ: IV BPs <ul><li>More frequently </li></ul><ul><li>Lesions more extensive </li></ul><ul><li>All stages </li></ul><ul><ul><li>II, III more common </li></ul></ul><ul><li>Lower success with Tx </li></ul><ul><li>Patients generally sicker </li></ul>
  • 28. Stage I Lesions
  • 29. Stage II Lesions
  • 30. Stage III Lesions
  • 31. Stage 0 Lesions <ul><li>Spontaneous onset numbness and pain </li></ul><ul><li>No exposed bone </li></ul><ul><li>No prior dental antecedent </li></ul><ul><li>Positive image findings: </li></ul><ul><ul><li>Sclerosis </li></ul></ul><ul><ul><li>Positive bone scan </li></ul></ul>
  • 32. BRONJ: Historical Context <ul><li>Rare reports prior to 2001 </li></ul><ul><li>2003: Marx reported 36 patients </li></ul><ul><li>2004: Ruggiero et al reported 63 pts (from 2001-2003) </li></ul><ul><li>2005: Migliorati reported 5 cases </li></ul><ul><li>2005: Estilo et al reported 13 cases </li></ul><ul><li>Sept. 2004: Novartis (manufacturer of Aredia & Zometa) altered labeling to include cautionary language concerning osteonecrosis of the jaws </li></ul><ul><li>2005: FDA issued warning for entire drug class (including oral bisphosphonates) </li></ul>
  • 33. Phossy-Jaw : A Historical Entity <ul><li>Lorinser, 1845: first reported cases </li></ul><ul><li>Industrial laborers working w/ white phosphorus powder </li></ul><ul><ul><li>Matchmaking, fireworks factories </li></ul></ul><ul><ul><li>Missile factories </li></ul></ul><ul><li>Clinical presentation </li></ul><ul><ul><li>Nonhealing mucosal wound following extraction </li></ul></ul><ul><ul><li>Pain </li></ul></ul><ul><ul><li>Fetid odor </li></ul></ul><ul><ul><li>Suppuration </li></ul></ul><ul><ul><li>Necrosis w/ bony sequestra </li></ul></ul><ul><ul><li>Extra-oral fistulae </li></ul></ul><ul><li>Miles, Hunter: 20% mortality due to infections </li></ul><ul><ul><li>Pre-antibiotic era </li></ul></ul><ul><li>Conservative treatment </li></ul><ul><ul><li>Selective debridement </li></ul></ul><ul><ul><li>Minimal mucosal manipulation </li></ul></ul><ul><ul><li>Topical agents: copper sulfate </li></ul></ul>
  • 34. Similar Clinical Entities <ul><li>Closely resembles Osteopetrosis </li></ul><ul><ul><li>Loss of osteoclastic function </li></ul></ul><ul><ul><li>Hypermineralization </li></ul></ul><ul><ul><li>Fractures, nonunions, open oral wounds </li></ul></ul><ul><ul><li>Endpoint: bone necrosis, +/- infection </li></ul></ul>
  • 35. NOT to be confused with these other entities: <ul><ul><li>Osteoradionecrosis (ORN) : </li></ul></ul><ul><ul><ul><li>avascular bone necrosis 2° radiation </li></ul></ul></ul><ul><ul><li>Osteomyelitis: </li></ul></ul><ul><ul><ul><li>thrombosis of small blood vessels leading to infection within bone marrow </li></ul></ul></ul><ul><ul><li>Steroid-induced osteonecrosis : </li></ul></ul><ul><ul><ul><li>more common in long bones </li></ul></ul></ul><ul><ul><ul><li>exposed bone very rare </li></ul></ul></ul>
  • 36. BRONJ: Model of Pathogenesis
  • 37. Estimated Incidence of BRONJ 2° IV BPs <ul><li>Limited to retrospective studies with limited sample sizes </li></ul><ul><li>Marx: </li></ul><ul><ul><li>Zometa: exposed bone within 6-12 months </li></ul></ul><ul><ul><li>Aredia: 10-16 months </li></ul></ul><ul><li>Estimates of cumulative incidence of BRONJ range from 0.8% to 12% </li></ul><ul><ul><li>Marx: 5-15% </li></ul></ul><ul><ul><ul><li>Including Subclinical osteonecrosis </li></ul></ul></ul><ul><li>Incidence will rise: </li></ul><ul><ul><li>Increased recognition </li></ul></ul><ul><ul><li>Increased duration of exposure </li></ul></ul><ul><ul><li>Increased followup </li></ul></ul>
  • 38. Estimated Incidence of BRONJ 2° Oral BPs <ul><li>>190 million oral BP prescriptions dispensed worldwide </li></ul><ul><ul><li>Much lower risk for BRONJ vs IV administration </li></ul></ul><ul><li>Marx: </li></ul><ul><ul><li>BRONJ development after 3 years of Alendronate usage </li></ul></ul><ul><li>Merck study: </li></ul><ul><ul><li>incidence with Alendronate usage = 0.7/100,000 person/years of exposure </li></ul></ul><ul><li>Estimated incidence of BRONJ w/ weekly administration of alendronate: </li></ul><ul><ul><ul><li>0.01% to 0.04% </li></ul></ul></ul><ul><ul><ul><li>After extractions, increased to 0.09% to 0.34% </li></ul></ul></ul>
  • 39. Estimated Incidence/Prevalence of BRONJ 2° Oral BPs <ul><ul><li>Australian, German Studies: </li></ul></ul><ul><ul><ul><li>.001% to .01% prevalance </li></ul></ul></ul><ul><ul><li>Lo, O’Ryan: </li></ul></ul><ul><ul><ul><li>PROBE study, Kaiser Permanente </li></ul></ul></ul><ul><ul><ul><ul><li>Survey of 13,000 pts using oral BP </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Prevalence of BRONJ: 0.06% (1:1,700) </li></ul></ul></ul></ul>
  • 40. low numbers, so…what’s all the hoopla for? <ul><li>Physicians prescribing these meds </li></ul><ul><ul><li>Endocrinologists, Oncologists, PCPs, OB-Gyns,etc </li></ul></ul><ul><ul><li>Not well informed of adverse oral effects </li></ul></ul><ul><li>Hygienists, dentists diagnosing and managing the problem </li></ul><ul><ul><li>Lack of communication between Medicine and Dentistry </li></ul></ul><ul><ul><li>likelihood of many cases unreported </li></ul></ul><ul><ul><li>We are the “experts”…time to bridge the gap </li></ul></ul><ul><li>Effects of oral BPs lagging behind IV BPs </li></ul><ul><ul><li>Another few years for BRONJ to reveal itself among the oral BP population </li></ul></ul>
  • 41. Why Only in the Jaws? <ul><li>Dixon et al 1997 </li></ul><ul><ul><li>Alveolar crest has high remodeling rate </li></ul></ul><ul><ul><ul><li>10x tibia </li></ul></ul></ul><ul><ul><ul><li>5x mandible at level of IA canal </li></ul></ul></ul><ul><ul><ul><li>3.5x mandible at inferior border </li></ul></ul></ul><ul><li>Greater uptake of Tc 99m in bone scans </li></ul><ul><ul><li>Occlusal forces </li></ul></ul><ul><ul><ul><li>Compression at root apex and furcations </li></ul></ul></ul><ul><ul><ul><li>Tension on lamina dura and periodontal ligament </li></ul></ul></ul><ul><ul><ul><li>Remodeling of lamina dura in response </li></ul></ul></ul><ul><ul><ul><li>Reduced remodeling with BP uptake  hypermineralization </li></ul></ul></ul><ul><ul><ul><ul><li>Sclerotic appearance of Lamina dura </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Widening of periodontal ligament space </li></ul></ul></ul></ul>
  • 42. BRONJ Case Definition <ul><li>AAOMS Position Paper ( updated September 2009 ): </li></ul><ul><ul><li>Patients considered to have BRONJ if all 3 characteristics met: </li></ul></ul><ul><ul><ul><li>Current or previous treatment with a bisphosphonate </li></ul></ul></ul><ul><ul><ul><li>Exposed, necrotic bone in maxillofacial region persisting > 8 weeks </li></ul></ul></ul><ul><ul><ul><li>No history of radiation therapy to jaws </li></ul></ul></ul>
  • 43. Risk Factors for Development of BRONJ <ul><li>Drug-related factors </li></ul><ul><ul><li>Potency of BP </li></ul></ul><ul><ul><ul><li>Zoledronate > pamidronate > oral BPs </li></ul></ul></ul><ul><ul><li>Duration of therapy </li></ul></ul><ul><li>Local factors </li></ul><ul><ul><li>Dentoalveolar surgery </li></ul></ul><ul><ul><ul><li>Extractions, implants, periapical surgery, periodontal surgery w/ osseous injury </li></ul></ul></ul><ul><ul><ul><li>7-fold risk for BRONJ with IV BPs </li></ul></ul></ul><ul><ul><ul><li>5 to 21-fold risk in some studies </li></ul></ul></ul><ul><ul><li>Local anatomy </li></ul></ul><ul><ul><ul><li>lingual tori, mylohyoid ridge, palatal tori </li></ul></ul></ul><ul><ul><ul><li>Mandible > maxilla (2:1) </li></ul></ul></ul><ul><ul><li>Concomitant oral disease </li></ul></ul><ul><ul><ul><li>7-fold risk for BRONJ with IV BPs </li></ul></ul></ul>
  • 44. Risk factors (continued) <ul><li>Demographic/systemic factors </li></ul><ul><ul><li>Age: 9% increased risk for every passing decade </li></ul></ul><ul><ul><ul><li>Multiple myeloma patients treated w/ IV BPs </li></ul></ul></ul><ul><ul><li>Race: Caucasian </li></ul></ul><ul><ul><li>Cancer diagnosis </li></ul></ul><ul><ul><ul><li>multiple myeloma > breast cancer > other cancers </li></ul></ul></ul><ul><ul><li>Osteopenia/osteoporosis diagnosis concurrent w/ cancer diagnosis </li></ul></ul><ul><li>Additional risk factors: </li></ul><ul><ul><li>Corticosteroid therapy </li></ul></ul><ul><ul><li>Diabetes </li></ul></ul><ul><ul><li>Smoking </li></ul></ul><ul><ul><li>EtOH </li></ul></ul><ul><ul><li>Poor oral hygiene </li></ul></ul><ul><ul><li>Chemotherapeutic drugs </li></ul></ul>
  • 45. Subclinical Risk Assessment <ul><li>Early signs of BP toxicity: </li></ul><ul><ul><li>Radiographs </li></ul></ul><ul><ul><ul><li>Panoramic, PA films </li></ul></ul></ul><ul><ul><ul><ul><li>Sclerosis of alveolus, lamina dura </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Widening of PDL space </li></ul></ul></ul></ul><ul><ul><li>Clinical exam </li></ul></ul><ul><ul><ul><li>Tooth mobility </li></ul></ul></ul><ul><ul><ul><ul><li>Unrelated to alveolar bone loss </li></ul></ul></ul></ul><ul><ul><ul><li>Deep bone pain with no apparent etiology </li></ul></ul></ul>
  • 46. Risk Assessment: Bone Turnover Markers <ul><li>Bone Turnover Markers </li></ul><ul><ul><li>Most assess bone formation </li></ul></ul><ul><ul><ul><li>AP, osteocalcin </li></ul></ul></ul><ul><li>Marx: Serum CTX marker </li></ul><ul><ul><li>Bone resorption </li></ul></ul><ul><ul><li>Oral BP risk </li></ul></ul><ul><ul><li>Type I collagen telopeptide assay </li></ul></ul><ul><ul><ul><li>ELISA/RIA – Quest Diagnostics </li></ul></ul></ul><ul><ul><li>Cleaved at carboxyl end by osteoclast in bone resorption </li></ul></ul><ul><ul><ul><li>NTX – marker cleaved at amine end </li></ul></ul></ul><ul><ul><li>Requires 1 mL whole blood – fasting </li></ul></ul>
  • 47. Serum CTX Peptide <ul><li>Low values = high risk </li></ul><ul><ul><li>Little osteoclastic function </li></ul></ul><ul><li>Marx, et al 2007 (JOMS) </li></ul><ul><ul><li>17 pts on oral BPs > 5 years </li></ul></ul><ul><ul><li>CTX before/after drug holiday (6mos) </li></ul></ul><ul><ul><li>Before drug holiday: </li></ul></ul><ul><ul><ul><li>CTX range 30-102 pg/mL </li></ul></ul></ul><ul><ul><li>After drug holiday: </li></ul></ul><ul><ul><ul><li>CTX range 162-343 pg/mL over 6 months </li></ul></ul></ul><ul><ul><ul><li>Improved mucosal healing </li></ul></ul></ul><ul><ul><li>Drug holiday allows for osteoclast recovery </li></ul></ul><ul><ul><li>4-6 months: reasonable, safe, and minimizes risk of BRONJ </li></ul></ul>
  • 48. Treatment Goals <ul><li>Preserve Quality of Life </li></ul><ul><ul><li>Pain Control </li></ul></ul><ul><ul><li>Treat 2° infection </li></ul></ul><ul><ul><li>Prevent extension </li></ul></ul>
  • 49. What this means for you as a practitioner <ul><li>Routine dental care a MUST for BRONJ pts and Non-BRONJ pts taking BPs </li></ul><ul><ul><ul><li>dental prophylaxis </li></ul></ul></ul><ul><ul><ul><li>nonoperative periodontal care </li></ul></ul></ul><ul><ul><ul><li>restorative procedures </li></ul></ul></ul><ul><ul><ul><li>conventional fixed and removable prosthodontics </li></ul></ul></ul><ul><li>Invasive procedures on case-by-case basis </li></ul><ul><ul><ul><li>Elective oral surgery </li></ul></ul></ul><ul><ul><ul><li>apical surgery </li></ul></ul></ul><ul><ul><ul><li>periodontal bone recontouring </li></ul></ul></ul><ul><ul><ul><li>implants </li></ul></ul></ul><ul><ul><ul><li>orthodontic tooth movement </li></ul></ul></ul>
  • 50. Treatment Strategies <ul><li>Patients about to initiate IV bisphosphonate tx </li></ul><ul><ul><li>Objective: minimize risk of developing BRONJ </li></ul></ul><ul><ul><li>Dental prophylaxis, caries control, conservative restorative dentistry </li></ul></ul><ul><ul><li>Adjustment of denture flanges to minimize mucosal trauma </li></ul></ul><ul><ul><li>Extraction of nonrestorable teeth </li></ul></ul><ul><ul><li>Completion of elective dentoalveolar surgery </li></ul></ul><ul><ul><li>If systemic conditions permit: </li></ul></ul><ul><ul><ul><li>Delay Bisphosphonate therapy until dental health optimized </li></ul></ul></ul><ul><ul><ul><li>14-21 days after extractions </li></ul></ul></ul>
  • 51. Treatment Strategies <ul><li>Asymptomatic patients receiving IV BPs </li></ul><ul><ul><li>Maintenance of good oral hygiene, dental care </li></ul></ul><ul><ul><li>Avoid invasive procedures </li></ul></ul><ul><ul><ul><li>Nonrestorable teeth: </li></ul></ul></ul><ul><ul><ul><ul><li>Remove crowns </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Endodontic treatment of remaining roots </li></ul></ul></ul></ul><ul><ul><ul><li>Avoid placement of implants </li></ul></ul></ul>
  • 52. Treatment Strategies <ul><li>Asymptomatic patients receiving oral BPs </li></ul><ul><ul><li>Less than 3 years with no clinical risk factors: </li></ul></ul><ul><ul><ul><li>No alteration or delay in elective surgery </li></ul></ul></ul><ul><ul><ul><li>Implants permitted </li></ul></ul></ul><ul><ul><ul><ul><li>Discuss risks </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Regular recall schedule </li></ul></ul></ul></ul><ul><ul><ul><li>Discuss with PCP re: alternate dosing, drug holidays, BP alternatives </li></ul></ul></ul>
  • 53. Treatment Strategies <ul><li>Asymptomatic patients receiving oral BPs (continued) </li></ul><ul><ul><li>Less than 3 years , concomitant steroid use </li></ul></ul><ul><ul><ul><li>Contact PCP re: drug holiday for at least 3 months prior to surgery </li></ul></ul></ul><ul><ul><ul><li>Restarted after osseous healing complete (3 months) </li></ul></ul></ul><ul><ul><li>More than 3 years , with/without concomitant steroid use </li></ul></ul><ul><ul><ul><li>Contact PCP re: drug holiday for 3 months prior to oral surgery </li></ul></ul></ul><ul><ul><ul><li>Restarted after osseous healing complete </li></ul></ul></ul><ul><ul><li>CTX??? </li></ul></ul>
  • 54. Treatment Strategies <ul><li>Patients with Established Diagnosis of BRONJ </li></ul><ul><ul><li>Objectives: eliminate pain, control infection, minimize progression/occurrence of necrosis </li></ul></ul><ul><ul><li>Marx: </li></ul></ul><ul><ul><ul><li>debridement may worsen condition </li></ul></ul></ul><ul><ul><li>Removal of bone serving as soft tissue irritant, loose bony sequestra </li></ul></ul><ul><ul><ul><li>Without exposure of uninvolved bone </li></ul></ul></ul><ul><ul><li>Extraction of teeth within exposed, necrotic bone </li></ul></ul><ul><ul><li>Avoid elective dentoalveolar surgery </li></ul></ul>
  • 55.  
  • 56.  
  • 57.  
  • 58. Treatment Strategies <ul><li>Stage III disease </li></ul><ul><ul><li>Pathologic fractures, refractory cases </li></ul></ul><ul><ul><ul><li>Preservation of function </li></ul></ul></ul><ul><ul><ul><ul><li>Airway, speech compromise with large mandible resections </li></ul></ul></ul></ul><ul><ul><ul><li>Segmental resections, titanium plate reconstruction, external fixation. </li></ul></ul></ul><ul><ul><ul><ul><li>All infections must be cleared first </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Delay reconstruction up to 3 months </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><li>Avoid bone grafting </li></ul></ul></ul></ul>
  • 59. Summary of Treatment Strategies
  • 60. Summary <ul><li>BPs are associated with BRONJ </li></ul><ul><ul><li>Direct causal relationship not established </li></ul></ul><ul><ul><li>Increased potency (nitrogen), dosing frequency, duration associated w/ increase risk </li></ul></ul><ul><li>No recommended duration to be on drug </li></ul><ul><li>For Asymptomatic patients taking BPs: </li></ul><ul><ul><li>Review AAOMS Guidelines </li></ul></ul><ul><ul><li>Thorough medication history – don’t just ask if they take BPs </li></ul></ul><ul><ul><li>Routine dental care a necessity to maintain optimal oral health </li></ul></ul><ul><ul><li>Elective surgery - Review on case-by-case basis </li></ul></ul><ul><ul><ul><ul><li>CTX, drug holiday </li></ul></ul></ul></ul>
  • 61. Summary <ul><li>Pts with BRONJ : </li></ul><ul><ul><li>Review AAOMS guidelines: </li></ul></ul><ul><ul><li>Stage I, II lesions – early recognition, conservative mgmt </li></ul></ul><ul><ul><ul><li>No debridement unless loose bony sequestrum </li></ul></ul></ul><ul><ul><li>Stage III lesions – resection and reconstruction most predictable tx outcome </li></ul></ul><ul><ul><li>Routine dental care a necessity </li></ul></ul><ul><ul><li>No Elective surgery </li></ul></ul><ul><ul><li>There is a Stage 0 – bone pain, paresthesia, no open wound. Get Xray, bone scan! </li></ul></ul><ul><li>BRONJ 2° Oral BP better success rate than IVBP </li></ul><ul><li>Discontinuing BP improves healing over long-term </li></ul><ul><li>TALK to the Medicine folks….share your knowledge!!!!! </li></ul>

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