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American Association of Oral and Maxillofacial Surgeons Osteonecrosis Guidelines

Lecture 46-Bisphosphonates. American Association of Oral and Maxillofacial Surgeons Osteonecrosis Guidelines. Biochemical and molecular mechanisms of action of bisphosphonates Michael J. Rogers , Julie C. Crockett , Fraser P. Coxon , Jukka Mönkkönen. Bone, 49, 34-41 (2011)

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American Association of Oral and Maxillofacial Surgeons Osteonecrosis Guidelines

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  1. Lecture 46-Bisphosphonates American Association of Oral and Maxillofacial Surgeons Osteonecrosis Guidelines Biochemical and molecular mechanisms of action of bisphosphonates Michael J. Rogers , Julie C. Crockett , Fraser P. Coxon , Jukka Mönkkönen. Bone, 49, 34-41 (2011) (Please read it in News and Views on my website) “Position Paper on Bisphosphonate Related Osteonecrosis of the Jaws” JOMS 65 : 369 -376, 2007 www. aaoms.org Bisphosphonates-kumar

  2. Bisphosphonates-Mechanismof Action : Summary Inorganic pyrophosphates analogs Affinity for hydroxyapatite crystals Inhibitor of osteoclast activity Bone resorption inhibition Calcification inhibition Bisphosphonates-kumar

  3. Mechanism of Action : Summary Osteoclast Inhibition Antiangiogenic* Antineoplasic* Bisphosphonates-kumar

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

  5. Pyrophosphate (PPi) (ATP = AMP + PPi) Bisphosphonate (P-C-P) Chemical Structure HO R1 OH O - O - P P O O C P P O O O OH HO O - O - R2 Bisphosphonates-kumar

  6. Bisphosphonate Structure P-C-P acts as ‘bone hook’ and is essential for binding tohydroxyapatite HO R1 OH When R1 is an OH group binding to hydroxyapatiteis enhanced P P O O C OH HO R2 The R2 sidechain determinespotency The P-C-P group is essential for biological activity Bisphosphonates-kumar

  7. Bisphosphonate Structure HO R1 OH P P O O C Non Nitrogen Side Chain Etidronate (Didronel) Clondronate (Bonefos) Tiludronate (Skelid) Nitrogen Side Chain Alendronate (Fosamax) Risedronate (Actonel) Ibandronate (Bonviva) Zolendronate (Zometa) Pamidronate (Aredia) OH HO R2 Bisphosphonates-kumar

  8. Increasing Potency of Bisphosphonates Bisphosphonates-kumar

  9. HAP: hydroxyapatite CAP: carbonated hydroxyapatite Bisphosphonates-kumar

  10. Normal Bone Remodelling Osteoclast Osteoblast Bone Formation Bone Resorption GrowthFactors Resorption Formation 160 days 20 days Bisphosphonates-kumar

  11. Bone Metabolism Bisphosphonates-kumar

  12. Cellular Mechanism of Action • Osteoclast actively reabsorbs bone matrix • BISPHOSPHONATE ( ) binds to bone mineral surface • BISPHOSPHONATE is taken up bythe osteoclast • Osteoclast is inactivated • Osteoclast becomes apoptotic (‘suicidal’) and dies Bisphosphonates-kumar

  13. Mechanism of action by non-nitrogenous BPs Bisphosphonates-kumar

  14. Inhibitory action by nitrogen containing BPs Bisphosphonates-kumar

  15. Fig. 5 Bisphosphonates-kumar

  16. Osteonecrosis BRONJ Bisphosphonate Related OsteoNecrosis of the Jaw Osteochemonecrosis (Flint et al, 2006) Bisphosphonates-kumar

  17. Marx, JOMS December 200730 cases BRONJ, Oral Bisphosphonates 27 Fosamax (Alendronate), 3 Actonel (Residronate) Posterior Mandible 98% Spontaneous 50% Post Surgery 50% Mean Duration Tx 5 years Bisphosphonates-kumar

  18. 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 Bisphosphonates-kumar

  19. 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) Bisphosphonates-kumar

  20. MWRH Bisphosphonate Retrospective Study (n = 79) Bisphosphonates-kumar

  21. Treatment Goals in BRONJ Eliminate pain Control infection Minimise progression Bisphosphonates-kumar

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

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

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

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

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

  27. Serum CTX and BRONJ Risk Serum LevelRisk BRONJ < 100 pg / ml High 100 – 150 pg / ml Moderate > 150 pg /ml Low Bisphosphonates-kumar

  28. What you should understand from lecture 46? Understand structure-function relationship among various bisphosphonates. Be aware of the differences between the mechanism of action for non-nitrogen and nitrogen containing bisphosphonates. Understand what is BRONJ and what likely causes it? Must be cognizant of the risk factors for developing BRONJ? Should know the best method of treating BRONJ? Given the information should be able to point out the markers for bone turnover. Should know what serum component is indicative of BRONJ risk? Bisphosphonates-kumar

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