PRESENTED BY:

DR. YOGENDER SINGH

PG II

• 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

• Bisphosphonates (also called diphosphonates)are a class of drugs that prevent the loss of bonemass.

• 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.)

• The “bis” prefix is a term indicating two -phosphonate groups, attached to a commoncarbon atom.

• These are structurally similar to naturalpyrophosphate (PP), which is a normalproduct of human metabolism that has acalcium chelating property.

Rodan GA. Mechanisms of action of bisphosphonates. AnnuRev Pharmacol Toxicol 1998; 38:375-88.

• These drugs have a high attraction forhydroxyapatite crystals and thus rapidly includedinto all parts of the skeleton.

• They are used as inhibitors of osteoclastic activityto alleviate bone pain that results from therelease of biochemical mediators in metastaticbone disease.

(Shinozaki T, Pritzker KP. Regulation of alkaline phosphatase: Implications for calcium pyrophosphate dehydrate crystaldissolution 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.)

• In 1897, Von Baeyer and Hoffman reportedthe synthesis of the first bisphosphonates.

• Initially used in chemical industry asanticorrosive & anti-scaling agent by virtue oftheir ability to inhibit formation of calcium onsurfaces.

• In 1960, Fleisch et al. first reported theirability to inhibit hydroxyapetite dissolution inbone.

• First human use of a bisphosphonate,etidronate, was reported by Bassett et al. in1969 for the treatment of Myositis OssificansProgressiva (MPO).

• Smith et al.(1971) were the first to report theevidence of effectiveness of thebisphosphonates for the treatment of Paget’sdisease of bone.

NON-NITROGENOUS

Olpadronate

NITROGENOUS

Tiludronate

Clodronate

Etidronate (Didronel)

Alendronate (Fosamax)

Neridronate

Pamidronate

Risedronate (Actonel)

Ibandronate (Boniva)

Zoledronate (Zometa, Aclasta)

• Minimally modified sidechains (R1 R2) contain achlorophenyl group.

• Metabolized into a non-hydrolyzable ATP analogthat accumulates withinosteoclasts and inducesapoptosis. which accountfor its antiresorptive effect.

• Least potent.

Etidronate

Medronate

Clodronate

Tiludronate

• Contains nitrogen group (aminoterminal) in the side chain.

• Primarily inhibits bone resorption.

• Antiresorptive activity involvesinhibition of multiple steps in thepathway from mevalonate tocholesterol and isoprenoid lipidsthat are required for theprenylation of proteins that areimportant for osteoclast function.

• They are 10-100 times morepotent than 1st generation BPs.

Alendronate

Pamidronate

Ibandronate

• Contain nitrogen atom within a heterocyclic ring.

• These are upto 10,000 times more potent than 1st generation.

Risedronate,

Zoledronate

• Inverse relation exists between pharmacologic activity and oralbioavailability

• Absorption by passive diffusion from gut

• Milk and other dairy products, orange juice, coffee and calcium andiron 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)

• Bisphosphonates are used to inhibit boneresorption & they act through different modeof actions:

1. Inhibit development of osteoclasts. (Hughes DE et al.1995)

2. Induction of osteoclast apoptosis. (Sato M et al. 1990)

3. Reduction of osteoclast activity. (Hughes DE et al.1989)

4. Prevention of development of osteoclasts fromhematopoietic precursors. (Vitte C et al. 1996)

5. Stimulation of production of an osteoclastinhibitory factor. (Coluccis S et al. 1998)

• There are 2 classes of BPs which have differentmechanisms of action:

• Non nitrogen containing BPs are taken up by the osteoclastand cause cell apoptosis through activation of capsasepathway. (Benford HL et al. 2001)

• Nitrogen containing BPs are not metabolised and affectprotein prenylation of osteoclast by inhibiting farnesyldiphosphate (FPP) synthase, a key enzyme of the mevalonatepathway .

(Luckman SP et al. 1998)

• The physicochemical effects are very similar topyrophosphate.

• Inhibit the formation and aggregation of calcium phosphatecrystals , even at very low concentrations.

• Block the transformation of amorphous calcium phosphateinto Hydroxyapetite, and delay the aggregation of apetitecrystals.

• Bisphosphonates also delays the dissolution of calciumphosphate crystals.

(Fleisch H, Russell RGG, Bisaz S, Mu¨ hlbauer RC, Williams DA 1970 The inhibitory effect of phosphonates on the formation ofcalcium phosphate crystals in vitro and on aortic and kidney calcification in vivo. Eur J Clin Invest 1:12–18)

• All of these effects are related to the markedaffinity of BPs for the surface of calciumphosphate where they bind onto the calciumby chemisorption.

• BPs chiefly act as a crystal poison on bothgrowth and dissolution.

• The inhibition of bone resorption can be explainedlargely by cellular mechanisms.

• Can be considered at three levels: tissue, cellular,and molecular.

• The effect may be directly on the osteoclasts andmay be mediated, via other cells such as osteoblasticlineage cells and macrophages.

• At this level, the action of the activebisphosphonates appears to be the same for all, i.e.,a reduction in bone turnover.

• This is shown by a decrease in both bone resorptionand bone formation, as assessed in humans bycalcium-45 kinetics, biochemical markers andmorphology.

• Under normal conditions, destroyed bone isreplaced by bone formation.

• In adults this occurs mostly at the trabeculae andthe cortex.

• The morphological dynamic unit of the turnoveris the BMU.

• The remodeling process in this unit starts withthe erosion of a certain amount of bone throughosteoclasts on the surface of the trabeculae, aswell as on the surface or the interior of thecortex.

• The resorption follows a linear path, forming a canalwithin the cortex and a trench on the surface.

• The destruction is followed by a refilling of theexcavation by the osteoblasts.

• The final morphological entity is called the bonestructural unit (BSU).

• It corresponds to an osteon within the cortex and hasbeen termed a hemiosteon when it is at the surfaceof the bone.

• The total bone resorption and formation will thereforedepend upon the number of BMUs present at any timewhich, in turn, will depend upon both the number ofBMUs formed and the length of time they are active.

• Under normal conditions, the amount of bone formed ineach BMU equals the amount destroyed, so that thebalance is zero.

• In osteoporosis, however, a greater amount of bone isresorbed than formed, leading to a negative balance.

• The bisphosphonates act at the individualBMU level by decreasing the depth of theresorption site .

• Since the amount of new bone formed in theBMU is not decreased, but possibly evenincreased .

• The local and consequently the whole bodybone balance will be less negative or mighteven be positive.

• The effect both on the general turnover andthe local balance will lead to:

Less trabecular thinning.

A decreased number of trabecularperforations

A smaller erosion of the cortex.

Thus slowing down the decrease in bonestrength and the occurrence of fractures.

• Reasons to accept that bisphosphonates can lead to apositive calcium and bone balance, both in animals and inhumans.

1. One is inherent to bone turnover.

A decrease in bone resorption is not immediately followedby the diminution of formation, so that a temporaryincrease in balance through a reduction in the remodeling.

2. After the decrease in turnover, the new BSU formed will beremodeled later than it would be normally. It therefore hasmore time to finish the lengthy process of mineralization.

This will lead to a higher calcium content and, therefore, ahigher bone mineral density and content.

3. If the decrease in resorption depth at individualremodeling sites is not matched by a decrease information in the individual BMU, the local bonebalance in the BMU will be positive.

4. The last possibility is an increase in the amountbone formed at the level of the BMU.

• At this level the final target of bisphosphonateaction 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.

• The first three mechanisms will lead to a decrease inthe number of osteoclasts. (observed in humans)

• All four effects could be due either to a direct actionon the osteoclast or its precursors.

Hwang and Wang, 2007

• 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)

• Patients may be considered to have BONJ ifthey have exposed bone in the maxillofacialregion for at least 8 weeks, are currently on orhave taken bisphosphonates and have nohistory of radiotherapy to the jaws . (AAOMS )

Osteonecrosis of the right mandible aftertooth extraction in a patient takingzoledronic acid for metastatic breast cancer.

Osteonecrosis of the palatal torus in apatient with osteoporosis takingalendronate.

Generalized osseous sclerosis of uniform thickness involving the

cortical plates and the lamina dura.

BP reduces vascularity of bone due to their antiangiogenic properties.

Suppression of bone turnover

Soft tissue toxicity

Compounding effects such as:• presence of infection• medications• pathologiesmay suppress bone or soft tissue healing.

• 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

• For patients about to start a course of i.v. BPs,the goal of treatment is to minimize the risk ofdeveloping 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 tomucosalized.

• Examine prostheses for sharp edges.

• If there is exposed bone but no signs ofinfection (AAOMS Stage 1) the treatment isCHX rinses and analgesics.

• Where there is exposed bone and localizedinfection (AAOMS Stage 2) . Antibiotics areprescribed.

• The goal of surgical treatment is the removal ofnecrotic bone and to create soft tissue coverageover healthy bone.

• Most commonly symptomatic bony sequestrumare removed with minimal soft tissuedisturbance.

• If there are large segments of necrotic bone moreradical surgical approaches are advocated.

• It is suggested that cessation of the BPs allowsregeneration of osteoclasts and some improvement inbone turnover.

• For a patient who has been taking an oral BP longerthan 3years, it should be discontinued, 3 monthsbefore and 3 months after the surgical procedure, ifapproved by the patient’s physician.

• Serum C-telopeptide (CTx) levels should be greaterthan 150 pg/mL before any surgical procedure, andrechecked at the time of surgery.

(Lam DK, Sandor GKB 2007)

• 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.)

• In early 1990’s an increased application ofBPs as host modulating agents was seen forthe treatment of periodontal disease.

• Many animal studies proved their high clinicalefficacy in inhibiting the progression ofexperimentally induced periodontitis.

• These improvements, especially alveolar bonegain, were also achieved in many humanclinical trials.

• In spite of these improvements in periodontal statusshown by BPs, they could never reach the stage ofgeneral periodontal use as host modulating agentsdue to their adverse effects.

• YAFFE A et al. (2003) found that in local drugdelivery of tetracycline in combination withalendronate showed significant reduction inalveolar bone loss.

• A R PRADEEP et al. (2012) in two different studiesfound significant reduction in PD and CAL andalso more percentage of bone fill after using 1 %of Alendronate gel in the treatment of bothchronic as well as aggressive periodontitis.

•As these human studies indicate, local drug deliveryof BPs show a ray of hope to be used as local hostmodulating agents in periodontal therapy.

•This mode of application can overcome the adverseeffects associated with systemic administration of BPs,while at the same time retaining the property of bonesparing.

• In experimentally induced periodontitis in monkeys showedthat Alendronate when given I/v biweekly at a dose of0.05mg/kg could retard bone loss around affected teethwhen compared with controls but had no effect over pocketdepth . ( Burnsvold LA et al. 1992)

• Another study shows a dose of 0.05mg/kg of alendronatecould inhibit bone loss but no effect is seen at higherdosages(0.25mg/Kg). Which coincides with the finding thatalendronate is released in acidic environment (inflamedperiodontal pocket) from hydroxyapetite and has locallycytotoxic effects to other stromal cells. (Sato M et al. 1991)

• Finding indicate that alendronate is a valuabletherapeutic medicine which can be used for thetreatment of periodontal disease either alone orin combination with regenerative componentslike anti-inflammatory drug, bone graft, materialand guided tissue regeneration or even withdental implants. (Kaynak D et al. 2003)

• Lane et al. 2005 suggested that BPs treatmentimproves the clinical outcome of non-surgicalperiodontal therapy and may be an appropriateadjunctive treatment to severe periodontal boneloss.

• A newely developed BPs, TRK-530 (disodiumdihydrogen [4-(methylthio) phenylthio]methanebisphosphonate), has recently beenshown to have anti-inflammatory, anti-boneresorbing activity as well as dose dependentlocal anticalculogenic action.

(Sikder MNH et al. 2004)

• Topically administered BPs reduces the rootresorption associated with orthodontic toothmovement and alveolar bone resorptionfollowing periodontal surgery.

(Igarashi K 1996) (Yaffe A 2000)

• BPs also reported to modulate cementoblastbehavior through the regulation of geneexpression, and thus has the potential forcementum formation and mineralizationmodifiers. (Chun Y-HP, Foster BL 2005)

• Alendronate found to inhibit bone resorption,induced or as result of flap elevation &RAP(The phenomenon is a transient burst oflocalized remodeling process followingsurgical wounding of cortical bone).

(Yaffe A et al. 1994)

• 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)

• Studies shows the potential of topical BPs application toenhance osseointegration of dental implants.

(Borromeo GL et al. 2011)

• Its application on dental implants, with or withoutcalcium phosphate layer promoted implant-bone contactand increased the amount of bone peripheral to implantsin dogs. (Jeffcoat MK. 2006)

• Zuffetti et al.2009 reported that bisphosphonate-treatedimplant showed more contact with newly formed bonethan the control implant.

• However, despite of these potential benefits, it maycontribute the development of BON.

• Implant patient who has been taking an oral BPs forosteoporosis is the possible risk of developingosteonecrosis of jaw after implant placement.

• Oral BPs have been reported to be associated withimplant failure.

• Cheng et al. 2009 reported this risk to be 0.88% of thepatients receiving oral BPs.

• It is likely that the length of time a patient has beentaking oral bisphosphonates is important indetermining the level of risk.

• Since oral bisphosphonates slowly accumulate inbone with time, an osteoporosis patient who hasbeen taking the drug for one year is at a lowerrisk of developing osteonecrosis of jaw or implantfailure than someone who has been on the drugfor many years.

• In general, it is not recommended that implantsbe placed in patients who have been on the drugfor more than 3 years.

• Prolonged use of bisphosphonates is acontraindication to implant placement.

(Starck WJ, Epker BN 1985)

• Implants- “Currently not contra-indicated iftaking bisphosphonates but prudent to gaininformed consent which should bedocumented (risk assessment)”

• Physicians and dentists should be fully updatedregarding the potential complications in themanagement of patients on BPs.

• Effective communication process between prescribingphysicians, dentists and patients on BPs, is needed.

• BON is much lower in patients receiving oral BPs ascompared with patients receiving intravenous BPtherapy and good oral hygiene, accompanied byregular dental care using non-invasive procedures, isthe best way to minimize this risk, if it exists.

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Related Osteonecrosis of the Jaw—2009 Update.