Bisphosphonate Related Osteonecrosis of the Jaws

1. Bisphosphonate Related Osteonecrosis of the Jaws Nik Desai, DMD, MD Division of Oral & Maxillofacial Surgery Department of Plastic Surgery Kaiser Permanente Medical Group Santa Clara, CA 04/28/2010

2. Objectives • Bisphosphonates • Clinical applications • Drug chemistry • Biologic action • BRONJ • Pathogenesis • Treatment of BRONJ • Latest management recommendations • Updates in the literature • Case Presentations

3. Bisphosphonates – what are they? Class of drugs High affinity for calcium Binds to bone surfaces Nitrogen: increased affinity, potency Prevent bone resorption and remodeling IV and oral formulations IV: tx for bone resorption 2° metastatic tumors, osteolytic lesions Oral: tx for osteoporosis, osteopenia

4. Bisphosphonates: Common uses Prevention and treatment of osteoporosis in postmenopausal women Increase bone mass in men with osteoporosis Tx of glucocorticoid-induced osteoporosis Tx of Paget’s disease of bone Hypercalcemia of malignancy Bone metastases of solid tumors breast and prostate carcinoma; other solid tumors Osteolytic lesions of multiple myeloma

5. History of Bisphosphonate Development • Mid-19th Century German chemists • Anti-corrosive in pipelines • 20th Century - Clinical applications • Tc99 Bone scans • Toothpaste • Anti-tartar, anti-plaque effects • Osteopathies • Anti-resorptive effect

6. Basic Chemical Composition • Pyrophosphate compound • Substitution of Carbon for Oxygen • Resistance to hydrolysis • Bone matrix accumulation • Extremely long half-life • Nitrogen-containing side chain • Increases potency, toxicity • Direct link to BRONJ cases

7. Antiresorptive Potency of BPs in Observed Human Clinical Trials

8. Biologic Action of Bisphosphonates • Osteoclastic toxicity • Apoptosis • Inhibited release of bone induction proteins • BMP, ILG1, ILG2 • Reduced bone turnover, resorption • Reduced serum calcium* • Hypermineralization* • “sclerotic” changes in lamina dura of alveolar bone * = goal of medicinal use

9. Normal Osteoclastic Function

10. Medical Indications for IV BPs • Bone metastasis, hypercalcemia • RANKL-mediated osteoclastic resorption • Multiple myeloma, breast CA, prostate CA • Paracrine-like effect • PTH-like peptide osteoclastic resorption • Small cell carcinoma, oropharyngeal cancers • Endocrine-like effect

11. Medical Indications for Oral BPs • Paget’s Disease of bone • Accelerated bone turnover • Reduced compressive strength, increased vascularity • Bone pain • Elevated AP levels • Osteoporosis • Effects of estrogen loss: • Decreased bone turnover/renewal • Adipocyte differentiation > osteoblastic differentiation • increased fibrofatty marrow • Progressively porotic bone • DEXA scan for BMD values

12. Drug Administration and Dosage

13. Pharmacokinetics • Oral BP’s • Absorbed in small intestine • Less if taken with meal • 1-10% available to bone • Circulating half-life: 0.5-2 hrs • Rapid uptake into bone matrix • 30-70% of IV/oral dose accumulates in bone • Remainder excreted in urine • Repeated doses accumulate in bone • Removed only by osteoclast-mediated resorption • “Biologic Catch 22”

14. Etidronate (Didronel) • Available in both oral and IV preparations • Oral: FDA approved for Paget’s disease • Dose: 5 mg/kg per day • IV: approved for use in hypercalcemia of malignancy • Dose: 7.5 mg/kg per day for 3 days • Risk of osteomalacia w/ prolonged therapy • do not treat >2 yrs • No documented cases of BRONJ

15. Pamidronate (Aredia) • Available only as IV preparation b/c of poor GI absorption and high freq of GI symptoms • Approved for tx of hypercalcemia of malignancy • one-time dose of 60-90 mg • Also used for Paget’s disease • Also used for osteoporosis pt’s who are unable to tolerate other bisphosphonates

16. Zolendronate (Zometa) • Only available in IV preparation • Approved for tx of hypercalcemia of malignancy • 4mg IV over no less than 15 mins

17. Alendronate (Fosamax) • Available as oral preparation • Osteoporosis • Treatment dose: 10 mg/day or 70 mg weekly • Prevention dose : 5 mg/day or 25 mg weekly • Less inhibition of bone mineralization • More suitable for long-term administration

18. Risedronate (Actonel) • Also available as oral preparation • Approved for tx of osteoporosis • 5 mg daily and 35 mg weekly • Dose for prevention of osteoporosis is same as for treatment

19. Ibandronate (Boniva) • Most recently approved for tx and prevention of osteoporosis • 2.5mg daily or 150 mg monthly

20. Bisphosphonate Side Effects • Upset stomach • Inflammation/erosions of esophagus • Fever/flu-like symptoms • Slight increased risk for electrolyte disturbance • Uveitis • Musculoskeletal joint pain • And of course…………………

21. BRONJ Exposed, devitalized bone in maxillofacial region Prior history or current use of BP Vague pain, discomfort Spontaneous occurrence, or… 2° surgery or trauma to oral soft tissue/bone

22. BRONJ: Clinical Presentation • Exposed alveolar bone • Open mucosal wound • Necrotic bone • Spontaneous or Traumatic • Extractions, periodontal surgery, apicoectomy, implant placement • Infection • Purulence, bone pain • Orocutaneous fistula

23. BRONJ: Clinical Presentation Subclinical Form asymptomatic radiographic signs Sclerosis of lamina dura Widening of PDL space

24. Clinical Presentation (cont)… Soft tissue abrasions Tissues rubbing against bone AND………

25. Pathologic Fracture

26. Staging of BRONJ Proposed by AAOMS: Patients at risk (Subclinical) No apparent exposed/necrotic bone in pts treated w/ IV or oral BPs Patients with BRONJ Stage 1: Exposed/necrotic bone, asymptomatic, no infection Stage 2: Exposed/necrotic bone, pain, clinical evidence of infection Stage 3: Exposed/necrotic bone, pain, infection, one or more of the following: Pathologic fracture, extra-oral fistula, osteolysis extending to inferior border

27. BRONJ: IV BPs • More frequently • Lesions more extensive • All stages • II, III more common • Lower success with Tx • Patients generally sicker

28. Stage I Lesions

29. Stage II Lesions

30. Stage III Lesions

31. Stage 0 Lesions Spontaneous onset numbness and pain No exposed bone No prior dental antecedent Positive image findings: Sclerosis Positive bone scan

32. BRONJ: Historical Context • Rare reports prior to 2001 • 2003: Marx reported 36 patients • 2004: Ruggiero et al reported 63 pts (from 2001-2003) • 2005: Migliorati reported 5 cases • 2005: Estilo et al reported 13 cases • Sept. 2004: Novartis (manufacturer of Aredia & Zometa) altered labeling to include cautionary language concerning osteonecrosis of the jaws • 2005: FDA issued warning for entire drug class (including oral bisphosphonates)

33. Phossy-Jaw: A Historical Entity • Lorinser, 1845: first reported cases • Industrial laborers working w/ white phosphorus powder • Matchmaking, fireworks factories • Missile factories • Clinical presentation • Nonhealing mucosal wound following extraction • Pain • Fetid odor • Suppuration • Necrosis w/ bony sequestra • Extra-oral fistulae • Miles, Hunter: 20% mortality due to infections • Pre-antibiotic era • Conservative treatment • Selective debridement • Minimal mucosal manipulation • Topical agents: copper sulfate

34. Similar Clinical Entities • Closely resembles Osteopetrosis • Loss of osteoclastic function • Hypermineralization • Fractures, nonunions, open oral wounds • Endpoint: bone necrosis, +/- infection

35. NOT to be confused with these other entities: Osteoradionecrosis (ORN): avascular bone necrosis 2° radiation Osteomyelitis: thrombosis of small blood vessels leading to infection within bone marrow Steroid-induced osteonecrosis: more common in long bones exposed bone very rare

36. BRONJ: Model of Pathogenesis

37. Estimated Incidence of BRONJ 2° IV BPs • Limited to retrospective studies with limited sample sizes • Marx: • Zometa: exposed bone within 6-12 months • Aredia: 10-16 months • Estimates of cumulative incidence of BRONJ range from 0.8% to 12% • Marx: 5-15% • Including Subclinical osteonecrosis • Incidence will rise: • Increased recognition • Increased duration of exposure • Increased followup

38. Estimated Incidence of BRONJ 2° Oral BPs • >190 million oral BP prescriptions dispensed worldwide • Much lower risk for BRONJ vs IV administration • Marx: • BRONJ development after 3 years of Alendronate usage • Merck study: • incidence with Alendronate usage = 0.7/100,000 person/years of exposure • Estimated incidence of BRONJ w/ weekly administration of alendronate: • 0.01% to 0.04% • After extractions, increased to 0.09% to 0.34%

39. Estimated Incidence/Prevalence of BRONJ 2° Oral BPs Australian, German Studies: .001% to .01% prevalance Lo, O’Ryan: PROBE study, Kaiser Permanente Survey of 13,000 pts using oral BP Prevalence of BRONJ: 0.06% (1:1,700)

40. low numbers, so…what’s all the hoopla for? Physicians prescribing these meds Endocrinologists, Oncologists, PCPs, OB-Gyns,etc Not well informed of adverse oral effects Hygienists, dentists diagnosing and managing the problem Lack of communication between Medicine and Dentistry likelihood of many cases unreported We are the “experts”…time to bridge the gap Effects of oral BPs lagging behind IV BPs Another few years for BRONJ to reveal itself among the oral BP population

41. Why Only in the Jaws? • Dixon et al 1997 • Alveolar crest has high remodeling rate • 10x tibia • 5x mandible at level of IA canal • 3.5x mandible at inferior border • Greater uptake of Tc 99m in bone scans • Occlusal forces • Compression at root apex and furcations • Tension on lamina dura and periodontal ligament • Remodeling of lamina dura in response • Reduced remodeling with BP uptake  hypermineralization • Sclerotic appearance of Lamina dura • Widening of periodontal ligament space

42. BRONJ Case Definition • AAOMS Position Paper (updated September 2009): • Patients considered to have BRONJ if all 3 characteristics met: • Current or previous treatment with a bisphosphonate • Exposed, necrotic bone in maxillofacial region persisting > 8 weeks • No history of radiation therapy to jaws

43. Risk Factors for Development of BRONJ • Drug-related factors • Potency of BP • Zoledronate > pamidronate > oral BPs • Duration of therapy • Local factors • Dentoalveolar surgery • Extractions, implants, periapical surgery, periodontal surgery w/ osseous injury • 7-fold risk for BRONJ with IV BPs • 5 to 21-fold risk in some studies • Local anatomy • lingual tori, mylohyoid ridge, palatal tori • Mandible > maxilla (2:1) • Concomitant oral disease • 7-fold risk for BRONJ with IV BPs

44. Risk factors (continued) • Demographic/systemic factors • Age: 9% increased risk for every passing decade • Multiple myeloma patients treated w/ IV BPs • Race: Caucasian • Cancer diagnosis • multiple myeloma > breast cancer > other cancers • Osteopenia/osteoporosis diagnosis concurrent w/ cancer diagnosis • Additional risk factors: • Corticosteroid therapy • Diabetes • Smoking • EtOH • Poor oral hygiene • Chemotherapeutic drugs

45. Subclinical Risk Assessment • Early signs of BP toxicity: • Radiographs • Panoramic, PA films • Sclerosis of alveolus, lamina dura • Widening of PDL space • Clinical exam • Tooth mobility • Unrelated to alveolar bone loss • Deep bone pain with no apparent etiology

46. Risk Assessment: Bone Turnover Markers • Bone Turnover Markers • Most assess bone formation • AP, osteocalcin • Marx: Serum CTX marker • Bone resorption • Oral BP risk • Type I collagen telopeptide assay • ELISA/RIA – Quest Diagnostics • Cleaved at carboxyl end by osteoclast in bone resorption • NTX – marker cleaved at amine end • Requires 1 mL whole blood – fasting

47. Serum CTX Peptide • Low values = high risk • Little osteoclastic function • Marx, et al 2007 (JOMS) • 17 pts on oral BPs > 5 years • CTX before/after drug holiday (6mos) • Before drug holiday: • CTX range 30-102 pg/mL • After drug holiday: • CTX range 162-343 pg/mL over 6 months • Improved mucosal healing • Drug holiday allows for osteoclast recovery • 4-6 months: reasonable, safe, and minimizes risk of BRONJ

48. Preserve Quality of Life Pain Control Treat 2° infection Prevent extension Treatment Goals

49. What this means for you as a practitioner Routine dental care a MUST for BRONJ pts and Non-BRONJ pts taking BPs dental prophylaxis nonoperative periodontal care restorative procedures conventional fixed and removable prosthodontics Invasive procedures on case-by-case basis Elective oral surgery apical surgery periodontal bone recontouring implants orthodontic tooth movement

50. Treatment Strategies • Patients about to initiate IV bisphosphonate tx • Objective: minimize risk of developing BRONJ • Dental prophylaxis, caries control, conservative restorative dentistry • Adjustment of denture flanges to minimize mucosal trauma • Extraction of nonrestorable teeth • Completion of elective dentoalveolar surgery • If systemic conditions permit: • Delay Bisphosphonate therapy until dental health optimized • 14-21 days after extractions