3. Bisphosphonate Related OsteoNecrosis of Jaws (BRONJ)

4. Case Reports BRONJ Marx R, JOMS, 2003 “Pamidronate (Aredia) and Zoledronate (Zometa) induced avascular necrosis of the Jaws” Ruggiero S et al JOMS, 2004 “Osteonecrosis of the Jaws associated with the use of Bisphosphonates a review of 63 cases”

5. Marx, JOMS, Nov 2003Intravenous Bisphosphonates 36 patients with osteonecrosis 28 following extraction, 8 spontaneous

6. Tarasoff (Novartis Pharma) JOMS, 2003 Letter to the Editor “Avascular Necrosis of the Jaws : Risk Factors in Metastatic Cancer Patients” No causal relationship between ONJ and BP Other risk factors for ONJ are present 3. BP used to treat Osteonecrosis

7. Ruggiero, JOMS, Jan 2004(56 Intravenous, 7 Oral Bisphosphonates) 63 patients with osteonecrosis 54 following extraction, 9 spontaneous

8. 27 Fosamax (Alendronate), 3 Actonel (Residronate) Posterior Mandible 98% Spontaneous 50% Post Surgery 50% Mean Duration Tx 5 years

9. Kraut, JOMS, Jan 2008Implants / Oral Bisphosphonates 115 patients oral bisphosphonates 468 implants placed, 466 integrated No osteonecrosis “Review guidelines on Oral Bisphosphonates”

10. Overview 1. BRONJ Relevance to Dentist Bisphosphonates Limerick Experience 5. Guidelines / Strategies

11. Bisphosphonate Related OsteoNecrosis of Jaws (BRONJ)

12. Osteonecrosis BRONJ Bisphosphonate Related OsteoNecrosis of the Jaw Osteochemonecrosis (Flint et al, 2006)

13. Relevance of BRONJ to Dental Practitioner Diagnosis Treatment Causation

14. Pathogenesis of BRONJ Who is at risk ? Oral Bisphosphonates (Osteoporosis) IV Bisphosphonates (Malignant Bone Disease) Comorbidities (eg) Chemotherapy Diabetes, Steroids What precipitates BRONJ ? Dentoalveolar Surgery (Extraction, Implant, Scaling) Dental Abscess (Pulpal, Periodontal) Spontaneous

15. Why does this happen ?

17. History of Bisphosphonates Industrial anticorrosive 1865 Bone mineralization 1968 Metabolic bone disease 1980 (Pagets Disease, Osteoporosis) Malignant bone disease 2000 (Metastatic, Hypercalcaemia)

18. Bisphosphonates Inorganic pyrophosphates analogs Affinity for hydroxyapatite crystals Inhibitor of osteoclast activity Bone resorption inhibition Calcification inhibition

19. Chemical Structure Pyrophosphate (PPi) (ATP = AMP + PPi) Bisphosphonate (P-C-P)

20. Bisphosphonate Structure Treatment and prevention (36) The chemical moiety at the R1 position is instrumental for the binding of bisphosphonate to bone mineral. The relative affinity for bone mineral decreases according to the group at the R1 position: OH>H>no group>Cl (van Beek et al. 1994). The chemical moiety at the R2 position is instrumental for in-vivo antiresorptive potency. Following the development of the non-nitrogen-containing bisphosphonates etidronate and clodronate (R2 moieties CH3 and Cl, respectively), the R2 moiety evolved by the elongation of the alkyl chain and introduction of a primary nitrogen (e.g. alendronate, pamidronate). Later, a tertiary nitrogen (e.g. Bonviva) or a nitrogen-containing hetercyclic ring (e.g. risedronate and zoledronate) were added. Bisphosphonates with a nitrogen atom at the R2 position have greater antiresorptive potency than non-nitrogen-containing bisphosphonates. Treatment and prevention (36) The chemical moiety at the R1 position is instrumental for the binding of bisphosphonate to bone mineral. The relative affinity for bone mineral decreases according to the group at the R1 position: OH>H>no group>Cl (van Beek et al. 1994). The chemical moiety at the R2 position is instrumental for in-vivo antiresorptive potency. Following the development of the non-nitrogen-containing bisphosphonates etidronate and clodronate (R2 moieties CH3 and Cl, respectively), the R2 moiety evolved by the elongation of the alkyl chain and introduction of a primary nitrogen (e.g. alendronate, pamidronate). Later, a tertiary nitrogen (e.g. Bonviva) or a nitrogen-containing hetercyclic ring (e.g. risedronate and zoledronate) were added. Bisphosphonates with a nitrogen atom at the R2 position have greater antiresorptive potency than non-nitrogen-containing bisphosphonates.

21. Bisphosphonate Structure Treatment and prevention (36) The chemical moiety at the R1 position is instrumental for the binding of bisphosphonate to bone mineral. The relative affinity for bone mineral decreases according to the group at the R1 position: OH>H>no group>Cl (van Beek et al. 1994). The chemical moiety at the R2 position is instrumental for in-vivo antiresorptive potency. Following the development of the non-nitrogen-containing bisphosphonates etidronate and clodronate (R2 moieties CH3 and Cl, respectively), the R2 moiety evolved by the elongation of the alkyl chain and introduction of a primary nitrogen (e.g. alendronate, pamidronate). Later, a tertiary nitrogen (e.g. Bonviva) or a nitrogen-containing hetercyclic ring (e.g. risedronate and zoledronate) were added. Bisphosphonates with a nitrogen atom at the R2 position have greater antiresorptive potency than non-nitrogen-containing bisphosphonates. Treatment and prevention (36) The chemical moiety at the R1 position is instrumental for the binding of bisphosphonate to bone mineral. The relative affinity for bone mineral decreases according to the group at the R1 position: OH>H>no group>Cl (van Beek et al. 1994). The chemical moiety at the R2 position is instrumental for in-vivo antiresorptive potency. Following the development of the non-nitrogen-containing bisphosphonates etidronate and clodronate (R2 moieties CH3 and Cl, respectively), the R2 moiety evolved by the elongation of the alkyl chain and introduction of a primary nitrogen (e.g. alendronate, pamidronate). Later, a tertiary nitrogen (e.g. Bonviva) or a nitrogen-containing hetercyclic ring (e.g. risedronate and zoledronate) were added. Bisphosphonates with a nitrogen atom at the R2 position have greater antiresorptive potency than non-nitrogen-containing bisphosphonates.

22. Bone Metabolism

23. Normal Bone Remodelling Pathophysiology of osteoporosis (2) Source: Rosen C. In: Marcus R, et al. Ed. Osteoporosis, Atlas of Clinical Endocrinology, volume 3. Blackwell Science Publisher 2000. Bone remodelling is the process whereby bone is continuously renewed and restructured, a process that involves the selective resorption and formation of bone. Bone formation takes place at the same site as bone resorption. There is, therefore, no net growth, the process instead replaces old and damaged bone with new. In adulthood, bone remodelling becomes the predominant metabolic activity of the skeleton. It is a process that is critical to the overall health of bone tissue (American Medical Association, 2000b) and serves two major purposes by renewing bone continuously, daily wear and tear on the skeleton does not compromise its biomechanical integrity mineral homeostasis is maintained by transferring calcium and other ions in and out of bone (Peel, et al. 1995). Pathophysiology of osteoporosis (2) Source: Rosen C. In: Marcus R, et al. Ed. Osteoporosis, Atlas of Clinical Endocrinology, volume 3. Blackwell Science Publisher 2000. Bone remodelling is the process whereby bone is continuously renewed and restructured, a process that involves the selective resorption and formation of bone. Bone formation takes place at the same site as bone resorption. There is, therefore, no net growth, the process instead replaces old and damaged bone with new. In adulthood, bone remodelling becomes the predominant metabolic activity of the skeleton. It is a process that is critical to the overall health of bone tissue (American Medical Association, 2000b) and serves two major purposes by renewing bone continuously, daily wear and tear on the skeleton does not compromise its biomechanical integrity mineral homeostasis is maintained by transferring calcium and other ions in and out of bone (Peel, et al. 1995).

24. Normal Bone Remodelling Pathophysiology of osteoporosis (2) Source: Rosen C. In: Marcus R, et al. Ed. Osteoporosis, Atlas of Clinical Endocrinology, volume 3. Blackwell Science Publisher 2000. Bone remodelling is the process whereby bone is continuously renewed and restructured, a process that involves the selective resorption and formation of bone. Bone formation takes place at the same site as bone resorption. There is, therefore, no net growth, the process instead replaces old and damaged bone with new. In adulthood, bone remodelling becomes the predominant metabolic activity of the skeleton. It is a process that is critical to the overall health of bone tissue (American Medical Association, 2000b) and serves two major purposes by renewing bone continuously, daily wear and tear on the skeleton does not compromise its biomechanical integrity mineral homeostasis is maintained by transferring calcium and other ions in and out of bone (Peel, et al. 1995). Pathophysiology of osteoporosis (2) Source: Rosen C. In: Marcus R, et al. Ed. Osteoporosis, Atlas of Clinical Endocrinology, volume 3. Blackwell Science Publisher 2000. Bone remodelling is the process whereby bone is continuously renewed and restructured, a process that involves the selective resorption and formation of bone. Bone formation takes place at the same site as bone resorption. There is, therefore, no net growth, the process instead replaces old and damaged bone with new. In adulthood, bone remodelling becomes the predominant metabolic activity of the skeleton. It is a process that is critical to the overall health of bone tissue (American Medical Association, 2000b) and serves two major purposes by renewing bone continuously, daily wear and tear on the skeleton does not compromise its biomechanical integrity mineral homeostasis is maintained by transferring calcium and other ions in and out of bone (Peel, et al. 1995).

25. Cellular Mechanism of Action

26. Zometa inhibits the mevalonic acid pathway. This blocks the synthesis of molecules essential to the action of signaling proteins – Rho & Ras. By interfering with these intracellular signals the action of osteoclasts and osteoblasts is inhibited, and apoptosis (programmed cell death) induced. Thus bone resorbtion is reduced.Zometa inhibits the mevalonic acid pathway. This blocks the synthesis of molecules essential to the action of signaling proteins – Rho & Ras. By interfering with these intracellular signals the action of osteoclasts and osteoblasts is inhibited, and apoptosis (programmed cell death) induced. Thus bone resorbtion is reduced.

27. Mechanism of Action : Summary Osteoclast Inhibition Antiangiogenic* Antineoplasic*

29. Who takes Bisphosphonates ? Non Malignant Bone Disease Post Menopausal Osteoporosis Steroid Related Osteoporosis Pagets Disease Malignant Bone Disease Malignant Hypercalcaemia Multiple Myeloma Metastatic Bone Disease (Breast, Prostate, Lung Ca)

30. Osteoporosis (WHO,1994) Low bone mass Architectural deterioration Increase in bone fragility Susceptibility to fracture Bone mineral density (BMD T-score <–2.5);

31. Who gets Osteoporosis ? 30 million females affected 25 - 30% of females aged >50 yrs 50% females > 50 yrs will have an osteoporotic fracture 15% with osteoporosis are males

32. Costs of Osteoporosis: Financial and Social Osteoporosis Cost 412 million euro 2008 530 million euro 2010 Hip Fracture 20% ‘other cause’ mortality 50% never walk again 25% supervised care

33. Osteoporosis Treatment Treatment and prevention (11) Adapted from: Nguyen TV, et al. Med J Aust 2004;180:S18–22 Based on current evidence (Seeman, et al. 2004) Hormone replacement therapy (HRT) is used to prevent bone loss in early postmenopausal women with menopausal symptoms, although side effects now limit its extensive use Selective oestrogen receptor modulators (SERMs) are an alternative for reducing the risk of vertebral fractures in middle-to-late postmenopausal women without osteoporosis Bisphosphonates are the first-line therapy in the treatment of osteoporosis Teriparatide (recombinant parathyroid hormone) is used in patients with severe osteoporosis, i.e., those who have had multiple fractures.Treatment and prevention (11) Adapted from: Nguyen TV, et al. Med J Aust 2004;180:S18–22 Based on current evidence (Seeman, et al. 2004) Hormone replacement therapy (HRT) is used to prevent bone loss in early postmenopausal women with menopausal symptoms, although side effects now limit its extensive use Selective oestrogen receptor modulators (SERMs) are an alternative for reducing the risk of vertebral fractures in middle-to-late postmenopausal women without osteoporosis Bisphosphonates are the first-line therapy in the treatment of osteoporosis Teriparatide (recombinant parathyroid hormone) is used in patients with severe osteoporosis, i.e., those who have had multiple fractures.

34. Malignant Bone Disease Intravenous Bisphosphonates Pamidronate (Aredia) Zolendronic Acid (Zometa)

35. Malignant Bone Disease

36. Skeletal Related Events Metastatic Cancer Signs and Symptoms Bone Pain Hypercalcaemia Spinal Compression Pathological Fractures

38. MWRH BRONJ Experience

39. MWRH Bisphosphonate Retrospective Study (n = 79)

40. Osteonecrosis Group II (n = 27) BRONJ 5(18%) patients Extraction 4 patients Spontaneous 1 patients Pamidronate 3/10 patients (Multiple Myeloma) Zolendronate 2/17 patients (Prostate, Breast)

42. American Association of Oral and Maxillofacial Surgeons Osteonecrosis Guidelines “Position Paper on Bisphosphonate Related Osteonecrosis of the Jaws” JOMS 65 : 369 -376, 2007 www. aaoms.org

43. Treatment StrategiesIV Bisphosphonates Commencing Treatment Treat as patients for DXT 2-3 weeks healing before Tx Asymptomatic (IV BP) Avoid dentoalveolar surgery Regular dental visits / prevention

44. Treatment StrategiesOral Bisphosphonates Post Menopausal Females (Osteoporosis) Avoid empirical Bisphosphonate Tx Osteoporosis diagnosed on Dexa Scan Dental consultation prior to treatment Complete elective treatment before Tx Regular dental review

45. Treatment StrategiesOral Bisphosphonates Treatment < 3 Years No alteration in planned surgery Treatment > 3 Years “Drug Holiday” Discontinue 3 months before Resume 3 months after elective suregry

46. Treatment Goals in BRONJ Eliminate pain Control infection Minimise progression

47. BRONJ : Stage 1 CLINICAL Exposed bone Asymptomatic TREATMENT Antimicrobial rinse Regular follow up Education Continued need for BP ?

48. BRONJ : Stage 2 CLINICAL Exposed bone Infection TREATMENT Antibiotics (Broad Spectrum) Antimicrobial rinse Pain control Minimal debridement

49. BRONJ : Stage 3 CLINICAL Exposed bone Infection, Fracture, Fistula TREATMENT Antibiotics based on culture Antimicrobial rinse Pain control Surgical debridement

50. Discontinue Bisphosphonates ? Intravenous No short term benefit Long term may be beneficial Oral Discontinuation for 6 -12 months May provide resolution BRONJ

51. Risk Factors Potency of Bisphosphonate /Duration of Tx Dentoalveolar Surgery / Local Infection Local Anatomy (Mandible > Maxilla) Steroids, Chemotx, Diabetes, Smoking, ETOH

52. BRONJ : What’s important ? Education in Medical / Dental Specialties Bisphosphonate half life Comorbidities in development of BRONJ Biochemical markers

53. Biochemical Markers Bone Turnover Bone Formation (Osteoblast) Alkaline Phosphatase Osteocalcin Collagen propeptide (PINP) Bone Resorption (Osteoclast) CTX (C terminal telopeptide) Type I collagen degradation

54. Serum CTX and BRONJ Risk Serum Level Risk BRONJ < 100 pg / ml High 100 – 150 pg / ml Moderate > 150 pg /ml Low

55. Summary Increasing age profile population Increasing Bisphosphonate use Potential for increasing BRONJ Need for increased awareness Future studies for specific risk factors