Bisphosphonates

Role of bisphosphonates in periodontology

1. BISPHOSPHONATES PRESENTED BY : DR. YOGENDER SINGH PG II

2. CONTENTS Introduction History Chemical Structure Types Of Bisphosphonates Pharmacokinetics Mechanism Of Action Drug Administration And Dosage Common Uses Of Bisphosphonates Contraindications Of Bisphosphonates BRONJ Bisphosphonates and Periodontology Conclusion

3. INTRODUCTION Bisphosphonates (also called diphosphonates ) are a class of drugs that prevent the loss of bone mass. Used in the treatment of many skeletal disorders- Bone metastases, osteoporosis, Paget’s disease etc. ( Walia MS, Arora S, Singal B. Jaw Osteonecrosis a Risk Factor in Bisphosphonate Therapy - A Dental Concern. J Oral Health Comm Dent 2010; 4: 72-7.)

4. The “ bis ” prefix is a term indicating two - phosphonate groups, attached to a common carbon atom. These are structurally similar to natural pyrophosphate (PP), which is a normal product of human metabolism that has a calcium chelating property. Rodan GA. Mechanisms of action of bisphosphonates. AnnuRev Pharmacol Toxicol 1998; 38: 375-88.

5. These drugs have a high attraction for hydroxyapatite crystals and thus rapidly included into all parts of the skeleton . They are used as inhibitors of osteoclastic activity to alleviate bone pain that results from the release of biochemical mediators in metastatic bone disease. (Shinozaki T, Pritzker KP. Regulation of alkaline phosphatase : Implications for calcium pyrophosphate dehydrate crystal dissolution and other alkaline phosphatase functions. J Rheumatol 1996; 23:677-83.) ( Armitage GC, Lundgren T. Risk Assessment of the Implant Patient. Clin Periodontol Implant Dent 2008; 5: 634-51.)

6. HISTORY In 1897, Von Baeyer and Hoffman reported the synthesis of the first bisphosphonates. Initially used in chemical industry as anticorrosive & anti-scaling agent by virtue of their ability to inhibit formation of calcium on surfaces.

7. In 1960 , Fleisch et al. first reported their ability to inhibit hydroxyapetite dissolution in bone. First human use of a bisphosphonate, etidronate , was reported by Bassett et al. in 1969 for the treatment of Myositis Ossificans Progressiva (MPO). Smith et al.(1971) were the first to report the evidence of effectiveness of the bisphosphonates for the treatment of Paget’s disease of bone.

8. TYPES OF BISPHOSPHONATES NON-NITROGENOUS Olpadronate   NITROGENOUS Tiludronate Clodronate   Etidronate   ( Didronel ) Alendronate  ( Fosamax ) Neridronate   Pamidronate   Risedronate   ( Actonel ) Ibandronate  ( Boniva ) Zoledronate   ( Zometa , Aclasta )

9. 1 ST GENERATION – ORAL BISPHOSPHONATES Minimally modified side chains (R1 R2) contain a chlorophenyl group. Metabolized into a non- hydrolyzable ATP analog that accumulates within osteoclasts and induces apoptosis. which account for its antiresorptive effect. Least potent. Etidronate Medronate Clodronate Tiludronate

10. 2 ND GENERATION – IV BISPHOSPHONATES Contains nitrogen group (amino terminal) in the side chain. Primarily inhibits bone resorption. Antiresorptive activity involves inhibition of multiple steps in the pathway from mevalonate to cholesterol and isoprenoid lipids that are required for the prenylation of proteins that are important for osteoclast function. They are 10-100 times more potent than 1st generation BPs. Alendronate Pamidronate Ibandronate

11. 3 RD GENERATION – IV BISPHOSPHONATES Contain nitrogen atom within a heterocyclic ring. These are upto 10,000 times more potent than 1st generation. Risedronate , Zoledronate

12. PHARMACOKINETICS Inverse relation exists between pharmacologic activity and oral bioavailability Absorption by passive diffusion from gut Milk and other dairy products, orange juice, coffee and calcium and iron products reduce absorption ( Form insoluble complexes) Bound to plasma proteins 20-80% of the absorbed dose is rapidly taken up by bone. Remainder is rapidly excreted in urine Long skeletal retention (half life up to 10 years)

13. MECHANISM OF ACTION Bisphosphonates are used to inhibit bone resorption & they act through different mode of actions: Inhibit development of osteoclasts. (Hughes DE et al.1995) Induction of osteoclast apoptosis. (Sato M et al. 1990) Reduction of osteoclast activity. (Hughes DE et al.1989) Prevention of development of osteoclasts from hematopoietic precursors. ( Vitte C et al. 1996) Stimulation of production of an osteoclast inhibitory factor. ( Coluccis S et al. 1998)

14. There are 2 classes of BPs which have different mechanisms of action: Non nitrogen containing BPs are taken up by the osteoclast and cause cell apoptosis through activation of capsase pathway. ( Benford HL et al. 2001) Nitrogen containing BPs are not metabolised and affect protein prenylation of osteoclast by inhibiting farnesyl diphosphate (FPP) synthase , a key enzyme of the mevalonate pathway . ( Luckman SP et al. 1998)

15. The differential effects of statins and BPs in the mevalonate pathway,showing how tissue selectivity of uptake determines their pharmacological specificity.

16. CALCIFICATION The physicochemical effects are very similar to pyrophosphate. Inhibit the formation and aggregation of calcium phosphate crystals , even at very low concentrations. Block the transformation of amorphous calcium phosphate into Hydroxyapetite, and delay the aggregation of apetite crystals. Bisphosphonates also delays the dissolution of calcium phosphate crystals. (Fleisch H, Russell RGG, Bisaz S, Mu¨ hlbauer RC, Williams DA 1970 The inhibitory effect of phosphonates on the formation of calcium phosphate crystals in vitro and on aortic and kidney calcification in vivo. Eur J Clin Invest 1:12–18)

17. All of these effects are related to the marked affinity of BPs for the surface of calcium phosphate where they bind onto the calcium by chemisorption. BPs chiefly act as a crystal poison on both growth and dissolution.

18. BONE RESORPTION The inhibition of bone resorption can be explained largely by cellular mechanisms. Can be considered at three levels: tissue, cellular, and molecular. The effect may be directly on the osteoclasts and may be mediated, via other cells such as osteoblastic lineage cells and macrophages.

19. TISSUE LEVEL At this level, the action of the active bisphosphonates appears to be the same for all, i.e., a reduction in bone turnover. This is shown by a decrease in both bone resorption and bone formation, as assessed in humans by calcium-45 kinetics, biochemical markers and morphology.

20. Under normal conditions, destroyed bone is replaced by bone formation. In adults this occurs mostly at the trabeculae and the cortex. The morphological dynamic unit of the turnover is the BMU. The remodeling process in this unit starts with the erosion of a certain amount of bone through osteoclasts on the surface of the trabeculae , as well as on the surface or the interior of the cortex.

21. The resorption follows a linear path, forming a canal within the cortex and a trench on the surface. The destruction is followed by a refilling of the excavation by the osteoblasts. The final morphological entity is called the bone structural unit (BSU). It corresponds to an osteon within the cortex and has been termed a hemiosteon when it is at the surface of the bone.

22. The total bone resorption and formation will therefore depend upon the number of BMUs present at any time which, in turn, will depend upon both the number of BMUs formed and the length of time they are active. Under normal conditions, the amount of bone formed in each BMU equals the amount destroyed, so that the balance is zero . In osteoporosis, however, a greater amount of bone is resorbed than formed, leading to a negative balance .

23. The bisphosphonates act at the individual BMU level by decreasing the depth of the resorption site . Since the amount of new bone formed in the BMU is not decreased, but possibly even increased . The local and consequently the whole body bone balance will be less negative or might even be positive .

24. The effect both on the general turnover and the local balance will lead to: Less trabecular thinning. A decreased number of trabecular perforations A smaller erosion of the cortex. Thus slowing down the decrease in bone strength and the occurrence of fractures.

25. Reasons to accept that bisphosphonates can lead to a positive calcium and bone balance, both in animals and in humans. One is inherent to bone turnover. A decrease in bone resorption is not immediately followed by the diminution of formation, so that a temporary increase in balance through a reduction in the remodeling. 2. After the decrease in turnover, the new BSU formed will be remodeled later than it would be normally. It therefore has more time to finish the lengthy process of mineralization. This will lead to a higher calcium content and, therefore, a higher bone mineral density and content.

26. If the decrease in resorption depth at individual remodeling sites is not matched by a decrease in formation in the individual BMU, the local bone balance in the BMU will be positive. The last possibility is an increase in the amount bone formed at the level of the BMU.

27. CELLULAR LEVEL At this level the final target of bisphosphonate action is the osteoclast. Four mechanisms appear to be involved: 1) Inhibition of osteoclast recruitment; 2) Inhibition of osteoclastic adhesion; 3) Shortening of the life span of osteoclasts; 4) Inhibition of osteoclast activity.

28. The first three mechanisms will lead to a decrease in the number of osteoclasts . (observed in humans) All four effects could be due either to a direct action on the osteoclast or its precursors.

29. MOLECULAR LEVEL

30. Hwang and Wang, 2007

31. MECHANISM OF ACTION

32. BISPHOSPHONATE FORMULATIONS

33. BISPHOSPHONATE SIDE EFFECTS Upset stomach Inflammation/erosions of esophagus Fever/flu-like symptoms Slight increased risk for electrolyte disturbance Uveitis Musculoskeletal joint pain Bisphosphonate related osteonecrosis of jaw (BRONJ)

34. BISPHOSPHONATE RELATED OSTEONECROSIS OF THE JAW (BRONJ) Patients may be considered to have BONJ if they have exposed bone in the maxillofacial region for at least 8 weeks, are currently on or have taken bisphosphonates and have no history of radiotherapy to the jaws . (AAOMS )

35. CLINICAL PICTURE Osteonecrosis of the right mandible after tooth extraction in a patient taking zoledronic acid for metastatic breast cancer. Osteonecrosis of the palatal torus in a patient with osteoporosis taking alendronate.

36. RADIOGRAPHIC SIGNS Generalized osseous sclerosis of uniform thickness involving the cortical plates and the lamina dura .

37. PATHOPHYSIOLOGY OF BONJ BP reduces vascularity of bone due to their anti angiogenic properties. Suppression of bone turnover Soft tissue toxicity Compounding effects such as: presence of infection medications pathologies may suppress bone or soft tissue healing.

38. WHY DOES BONJ ONLY AFFECT THE MAXILLOFACIAL SKELETON BPs accumulate in high turnover areas like mandible than elsewhere. As a result of trauma or infection bone cannot respond adequately. Masticatory Forces Chronic Low Grade Trauma Unable to repair micro-fractures Necrotic Bone Bony sequestrum

39. MANAGEMENT For patients about to start a course of i.v. BPs, the goal of treatment is to minimize the risk of developing BONJ. If systemic conditions permit, initiation of i.v. BPs is delayed until dental health is optimized, i.e. 14-21 days for extraction site to mucosalized . Examine prostheses for sharp edges.

40. NON SURGICAL MANAGEMENT If there is exposed bone but no signs of infection (AAOMS Stage 1) the treatment is CHX rinses and analgesics. Where there is exposed bone and localized infection (AAOMS Stage 2) . Antibiotics are prescribed.

41. SURGICAL TREATMENT The goal of surgical treatment is the removal of necrotic bone and to create soft tissue coverage over healthy bone. Most commonly symptomatic bony sequestrum are removed with minimal soft tissue disturbance. If there are large segments of necrotic bone more radical surgical approaches are advocated.

42. THE “DRUG HOLIDAY” It is suggested that cessation of the BPs allows regeneration of osteoclasts and some improvement in bone turnover. For a patient who has been taking an oral BP longer than 3years, it should be discontinued, 3 months before and 3 months after the surgical procedure, if approved by the patient’s physician. Serum C- telopeptide ( CTx ) levels should be greater than 150 pg/ mL before any surgical procedure, and rechecked at the time of surgery. (Lam DK, Sandor GKB 2007)

43. PERIODONTAL DISEASE AS A RISK FACTOR FOR BISPHOSPHONATE-RELATED OSTEONECROSIS OF THE JAW BRONJ patients have fewer teeth, greater CAL, and less alveolar bone support compared with controls after adjusting for number of BP infusions. ( Vivek Thumbigere -Math,* Bryan S. Michalowicz ,* James S. Hodges,† Michaela L. Tsai, Karen K. Swenson,‡ Laura Rockwell,‡ and Rajaram Gopalakrishnan§J Periodontol2014;85:226-233.)

44. ROLE IN PERIODONTAL THERAPY: In early 1990’s an increased application of BPs as host modulating agents was seen for the treatment of periodontal disease. Many animal studies proved their high clinical efficacy in inhibiting the progression of experimentally induced periodontitis. These improvements, especially alveolar bone gain , were also achieved in many human clinical trials.

45. In spite of these improvements in periodontal status shown by BPs, they could never reach the stage of general periodontal use as host modulating agents due to their adverse effects.

46. TO OVERCOME THESE SIDE EFFECTS, THE LOCAL DELIVERY OF BISPHOSPHONATES HAS BEEN PROPOSED. YAFFE A et al. (2003) found that in local drug delivery of tetracycline in combination with alendronate showed significant reduction in alveolar bone loss. A R PRADEEP et al. (2012) in two different studies found significant reduction in PD and CAL and also more percentage of bone fill after using 1 % of Alendronate gel in the treatment of both chronic as well as aggressive periodontitis.

47. As these human studies indicate, local drug delivery of BPs show a ray of hope to be used as local host modulating agents in periodontal therapy. This mode of application can overcome the adverse effects associated with systemic administration of BPs, while at the same time retaining the property of bone sparing.

48. USE OF BPs IN DIAGNOSIS AND MANAGEMENT OF PERIODONTITIS Management Of Periodontal Bone Loss In experimentally induced periodontitis in monkeys showed that Alendronate when given I/v biweekly at a dose of 0.05mg/kg could retard bone loss around affected teeth when compared with controls but had no effect over pocket depth . ( Burnsvold LA et al. 1992) Another study shows a dose of 0.05mg/kg of alendronate could inhibit bone loss but no effect is seen at higher dosages(0.25mg/Kg). Which coincides with the finding that alendronate is released in acidic environment (inflamed periodontal pocket) from hydroxyapetite and has locally cytotoxic effects to other stromal cells. (Sato M et al. 1991)

49. Finding indicate that alendronate is a valuable therapeutic medicine which can be used for the treatment of periodontal disease either alone or in combination with regenerative components like anti-inflammatory drug, bone graft, material and guided tissue regeneration or even with dental implants. ( Kaynak D et al. 2003) Lane et al. 2005 suggested that BPs treatment improves the clinical outcome of non-surgical periodontal therapy and may be an appropriate adjunctive treatment to severe periodontal bone loss.

50. A newely developed BPs, TRK-530 (disodium dihydrogen [4-( methylthio ) phenylthio ] methanebisphosphonate ), has recently been shown to have anti-inflammatory, anti-bone resorbing activity as well as dose dependent local anticalculogenic action. ( Sikder MNH et al. 2004)

51. Topically administered BPs reduces the root resorption associated with orthodontic tooth movement and alveolar bone resorption following periodontal surgery . (Igarashi K 1996) ( Yaffe A 2000) BPs also reported to modulate cementoblast behavior through the regulation of gene expression, and thus has the potential for cementum formation and mineralization modifiers. (Chun Y-HP, Foster BL 2005)

52. EFFECTS OF BP IN RELATION TO REGIONAL ACCELERATED PHENOMENON (RAP) Alendronate found to inhibit bone resorption, induced or as result of flap elevation & RAP(The phenomenon is a transient burst of localized remodeling process following surgical wounding of cortical bone). ( Yaffe A et al. 1994)

53. DIAGNOSIS OF PERIODONTAL BONE LOSS In nuclear medicine when combined with radio-labeled BPs, can be used to detect periodontal bone loss . (Kaplan ML et al. 1978), ( Jeffcoat ML et al. 1982, 1985), (Nicolay OF et al. 1986)

54. BISPHOSPHONATE AND IMPLANTS Studies shows the potential of topical BPs application to enhance osseointegration of dental implants . ( Borromeo GL et al. 2011) Its application on dental implants, with or without calcium phosphate layer promoted implant-bone contact and increased the amount of bone peripheral to implants in dogs. ( Jeffcoat MK. 2006) Zuffetti et al.2009 reported that bisphosphonate-treated implant showed more contact with newly formed bone than the control implant.

55. However, despite of these potential benefits, it may contribute the development of BON. Implant patient who has been taking an oral BPs for osteoporosis is the possible risk of developing osteonecrosis of jaw after implant placement. Oral BPs have been reported to be associated with implant failure. Cheng et al. 2009 reported this risk to be 0.88% of the patients receiving oral BPs. It is likely that the length of time a patient has been taking oral bisphosphonates is important in determining the level of risk.

56. Since oral bisphosphonates slowly accumulate in bone with time, an osteoporosis patient who has been taking the drug for one year is at a lower risk of developing osteonecrosis of jaw or implant failure than someone who has been on the drug for many years. In general, it is not recommended that implants be placed in patients who have been on the drug for more than 3 years . Prolonged use of bisphosphonates is a contraindication to implant placement . ( Starck WJ, Epker BN 1985)

57. British Dental Association Fact file Recommendations Implants- “Currently not contra-indicated if taking bisphosphonates but prudent to gain informed consent which should be documented (risk assessment)”

58. CONCLUSION Physicians and dentists should be fully updated regarding the potential complications in the management of patients on BPs. Effective communication process between prescribing physicians, dentists and patients on BPs, is needed. BON is much lower in patients receiving oral BPs as compared with patients receiving intravenous BP therapy and good oral hygiene, accompanied by regular dental care using non-invasive procedures, is the best way to minimize this risk, if it exists.

59. Herbert Fleisch . Bisphosphonates: Mechanisms of Action. Endocrine Reviews 19(1): 80–100. M.D. Francis,D.J . Valent J. Historical perspectives on the clinical development of bisphosphonates in the treatment of bone diseases. Musculoskelet Neuronal Interact 2007; 7(1):2-8. Angelo Mariotti . Bisphosphonates and Osteonecrosis of the Jaws. Carol Tekavec , CDA, RDH. Bisphosphonates. Journal of the American Dental Association in August 2006. Howard C Tenenbaum et al . Bisphosphonates and periodontics : potential applications for regulation of bone mass in the periodontium and other therapeutic/ diagnostic uses. JOP 2002;73:813-822. R. G. G. Russell, N. B. Watts, F. H. Ebetino , M. J. Rogers. Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int (2008) 19:733–759. American Association of Oral and Maxillofacial Surgeons. Position Paper on Bisphosphonate-Related Osteonecrosis of the Jaw—2009 Update. REFERENCES