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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