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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