Post on 16-Jan-2016
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
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Lecture 46-Bisphosphonates
Bisphosphonates-Mechanism of Action : Summary
Inorganic pyrophosphates analogs
Affinity for hydroxyapatite crystals
Inhibitor of osteoclast activity
Bone resorption inhibition
Calcification inhibitionBisphosphonates-kumar 2
Mechanism of Action : Summary
Osteoclast Inhibition
Antiangiogenic*
Antineoplasic*
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History of Bisphosphonates
Industrial anticorrosive 1865
Bone mineralization 1968
Metabolic bone disease 1980(Pagets Disease, Osteoporosis)
Malignant bone disease 2000(Metastatic, Hypercalcaemia)
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Chemical Structure
Pyrophosphate (PPi)
(ATP = AMP + PPi)
Bisphosphonate
(P-C-P)
OO OOOO PPPP
O -O - O -O -
O -O -O -O -
OO
RR11
OOCC PPPP
HOHO OHOH
OHOHHOHO
RR22
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OO
R1R1
OOCC PPPP
HOHO OHOH
OHOHHOHO
R2R2
When RWhen R11 is an OH is an OH group binding to group binding to hydroxyapatitehydroxyapatite
is enhancedis enhanced
The P-C-P groupThe P-C-P groupis essential is essential
for biological activityfor biological activity
The R2 sideThe R2 sidechain determineschain determines
potencypotency
Bisphosphonate Structure
P-C-P acts as P-C-P acts as ‘bone hook’ ‘bone hook’
and is essential and is essential for binding tofor binding to
hydroxyapatitehydroxyapatite
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OO
R1R1
OOCC PPPP
HOHO OHOH
OHOHHOHO
R2R2
Nitrogen Side ChainNitrogen Side Chain
Alendronate (Fosamax)Alendronate (Fosamax)
Risedronate (Actonel)Risedronate (Actonel)
Ibandronate (Bonviva)Ibandronate (Bonviva)
Zolendronate (Zometa)Zolendronate (Zometa)
Pamidronate (Aredia)Pamidronate (Aredia)
Bisphosphonate Structure
Non Nitrogen Side ChainNon Nitrogen Side Chain
Etidronate (Didronel)Etidronate (Didronel)
Clondronate (Bonefos)Clondronate (Bonefos)
Tiludronate (Skelid)Tiludronate (Skelid)
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Increasing Potency of Bisphosphonates
HAP: hydroxyapatiteCAP: carbonated hydroxyapatite
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Normal Bone Remodelling
160 days160 days
Bone ResorptionBone Resorption GrowthGrowthFactorsFactors
ResorptionResorption20 days20 days
FormationFormation
OsteoclastOsteoclast OsteoblastOsteoblast
Bone FormationBone Formation
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Bone Metabolism
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Cellular Mechanism of Action
1.1. Osteoclast actively reabsorbs bone Osteoclast actively reabsorbs bone matrixmatrix
2.2. BISPHOSPHONATE ( ) binds to BISPHOSPHONATE ( ) binds to bone mineral surfacebone mineral surface
3.3. BISPHOSPHONATE is taken up byBISPHOSPHONATE is taken up bythe osteoclastthe osteoclast
4.4. Osteoclast is inactivatedOsteoclast is inactivated
5.5. Osteoclast becomes apoptotic Osteoclast becomes apoptotic (‘suicidal’) and dies (‘suicidal’) and dies
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Mechanism of action by non-nitrogenous BPs
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Inhibitory action by nitrogen containing BPs
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Fig. 5
Osteonecrosis
BRONJ
Bisphosphonate
Related OsteoNecrosis
of the Jaw
Osteochemonecrosis
(Flint et al, 2006)
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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
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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
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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)
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MWRH Bisphosphonate Retrospective Study (n = 79)
Group I
n = 52
II
n = 27
Bisphosphonate Oral Intravenous
Diagnosis Osteoporosis Metastatic n=17
Myeloma n=10
Dentoalveolar 14 4
BRONJ 0 5Bisphosphonates-kumar 20
Treatment Goals in BRONJ
Eliminate pain
Control infection
Minimise progression
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Risk Factors
Potency of Bisphosphonate /Duration of Tx
Dentoalveolar Surgery / Local Infection
Local Anatomy (Mandible > Maxilla)
Steroids, Chemotx, Diabetes, Smoking, ETOH
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BRONJ : Stage 1
CLINICAL
Exposed bone
Asymptomatic
TREATMENT
Antimicrobial rinse
Regular follow up
Education
Continued need for BP ?Bisphosphonates-kumar 23
BRONJ : Stage 2
CLINICAL
Exposed bone
Infection
TREATMENT
Antibiotics (Broad Spectrum)
Antimicrobial rinse
Pain control
Minimal debridement
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BRONJ : Stage 3
CLINICAL
Exposed bone
Infection, Fracture, Fistula
TREATMENT
Antibiotics based on culture
Antimicrobial rinse
Pain control
Surgical debridementBisphosphonates-kumar 25
Biochemical Markers Bone Turnover
Bone Formation
(Osteoblast)
Alkaline Phosphatase
Osteocalcin
Collagen propeptide (PINP)
Bone Resorption
(Osteoclast)
CTX(C terminal telopeptide)
Type I collagen degradation
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Serum CTX and BRONJ Risk
Serum Level Risk BRONJ
< 100 pg / ml High
100 – 150 pg / ml Moderate
> 150 pg /ml Low
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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?
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