1. 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-kumar1 Lecture 46-Bisphosphonates

2. Bisphosphonates-Mechanism of Action : Summary Inorganic pyrophosphates analogs Affinity for hydroxyapatite crystals Inhibitor of osteoclast activity Bone resorption inhibition Calcification inhibition Bisphosphonates-kumar2

3. Mechanism of Action : Summary Osteoclast Inhibition Antiangiogenic* Antineoplasic* Bisphosphonates-kumar3

4. History of Bisphosphonates Industrial anticorrosive1865 Bone mineralization1968 Metabolic bone disease1980 (Pagets Disease, Osteoporosis) Malignant bone disease2000 (Metastatic, Hypercalcaemia) Bisphosphonates-kumar4

5. Chemical Structure Pyrophosphate (PPi) (ATP = AMP + PPi) Bisphosphonate (P-C-P) O O O P P O - O R1R1R1R1 O C P P HO OH OH HO R2R2R2R2 Bisphosphonates-kumar5

6. O R1 O C P P HO OH OH HO R2 When R 1 is an OH group binding to hydroxyapatite is enhanced The P-C-P group is essential for biological activity The R2 side chain determines potency Bisphosphonate Structure P-C-P acts as ‘bone hook’ and is essential for binding to hydroxyapatite Bisphosphonates-kumar6

7. O R1 O C P P HO OH OH HO R2 Nitrogen Side Chain Alendronate (Fosamax) Risedronate (Actonel) Ibandronate (Bonviva) Zolendronate (Zometa) Pamidronate (Aredia) Bisphosphonate Structure Non Nitrogen Side Chain Etidronate (Didronel) Clondronate (Bonefos) Tiludronate (Skelid) Bisphosphonates-kumar7

8. 8 Increasing Potency of Bisphosphonates

9. HAP: hydroxyapatite CAP: carbonated hydroxyapatite Bisphosphonates-kumar9

10. Normal Bone Remodelling 160 days Bone Resorption Growth Factors Resorption 20 days Formation Osteoclast Osteoblast Bone Formation Bisphosphonates-kumar10

11. Bone Metabolism Bisphosphonates-kumar11

12. Cellular Mechanism of Action 1.Osteoclast actively reabsorbs bone matrix 2.BISPHOSPHONATE ( ) binds to bone mineral surface 3.BISPHOSPHONATE is taken up by the osteoclast 4.Osteoclast is inactivated 5.Osteoclast becomes apoptotic (‘suicidal’) and dies Bisphosphonates-kumar12

13. Mechanism of action by non-nitrogenous BPs Bisphosphonates-kumar13

14. Bisphosphonates-kumar14 Inhibitory action by nitrogen containing BPs

15. Bisphosphonates-kumar15 Fig. 5

16. Osteonecrosis BRONJ Bisphosphonate Related OsteoNecrosis of the Jaw Osteochemonecrosis (Flint et al, 2006) Bisphosphonates-kumar16

17. Marx, JOMS December 2007 30 cases BRONJ, Oral Bisphosphonates 27 Fosamax (Alendronate), 3 Actonel (Residronate) Posterior Mandible98% Spontaneous 50% Post Surgery 50% Mean Duration Tx 5 years Bisphosphonates-kumar17

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-kumar18

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-kumar19

20. MWRH Bisphosphonate Retrospective Study (n = 79) GroupI n = 52 II n = 27 BisphosphonateOralIntravenous DiagnosisOsteoporosisMetastatic n=17 Myeloma n=10 Dentoalveolar144 BRONJ05 Bisphosphonates-kumar20

21. Treatment Goals in BRONJ Eliminate pain Control infection Minimise progression Bisphosphonates-kumar21

22. Risk Factors Potency of Bisphosphonate /Duration of Tx Dentoalveolar Surgery / Local Infection Local Anatomy (Mandible > Maxilla) Steroids, Chemotx, Diabetes, Smoking, ETOH Bisphosphonates-kumar22

23. BRONJ : Stage 1 CLINICAL Exposed bone Asymptomatic TREATMENT Antimicrobial rinse Regular follow up Education Continued need for BP ? Bisphosphonates-kumar23

24. BRONJ : Stage 2 CLINICAL Exposed bone Infection TREATMENT Antibiotics (Broad Spectrum) Antimicrobial rinse Pain control Minimal debridement Bisphosphonates-kumar24

25. BRONJ : Stage 3 CLINICAL Exposed bone Infection, Fracture, Fistula TREATMENT Antibiotics based on culture Antimicrobial rinse Pain control Surgical debridement Bisphosphonates-kumar25

26. Biochemical Markers Bone Turnover Bone Formation (Osteoblast) Alkaline Phosphatase Osteocalcin Collagen propeptide (PINP) Bone Resorption (Osteoclast) CTX (C terminal telopeptide) Type I collagen degradation Bisphosphonates-kumar26

27. Serum CTX and BRONJ Risk Serum Level Risk BRONJ < 100pg / ml High 100 – 150pg / mlModerate > 150pg /mlLow Bisphosphonates-kumar27

28. What you should understand from lecture 46? 1.Understand structure-function relationship among various bisphosphonates. 2.Be aware of the differences between the mechanism of action for non- nitrogen and nitrogen containing bisphosphonates. 3.Understand what is BRONJ and what likely causes it? 4.Must be cognizant of the risk factors for developing BRONJ? 5.Should know the best method of treating BRONJ? 6.Given the information should be able to point out the markers for bone turnover. 7. Should know what serum component is indicative of BRONJ risk? Bisphosphonates-kumar28