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Scott S. De Rossi, DMDChairman, Oral Health & Diagnostic Sciences

Professor of Oral MedicineProfessor of Otolaryngology/Head & Neck Surgery

Professor of DermatologyGeorgia Regents University, Augusta GA

THE ORAL-SYSTEMIC CONNECTION:A DIFFERENT ANGLE

Scott S. De Rossi, DMD


• Oral & Maxillofacial PathologyBiopsy Service

– Dr. Rafik Abdelsayed, Director

– Dr. Zoya Kurago

• Oral & Maxillofacial Radiology3D Imaging Center

– Dr. Sajitha Kalathingal, Director

– Dr. Allison K. Hunter


• Oral MedicineMucosal Disease, Facial Pain,

Salivary Gland Disease

– Dr. Scott S. De Rossi, Director

– Dr. Katharine N. Ciarrocca

– Dr. Wayne Herman

– Dr. Ilanit Stern


What is Oral Medicine?

• The specialty of dentistry that includes the diagnosis and primarily non-surgical management of:– Oral mucosal disease– Orofacial pain and TMD– Salivary gland disorders/Xerostomia

Prescription drug use (CDC)

• Percent of persons using at least one prescription drug in the past 30 days: 48.5% (2007-2010)

• Percent of persons using three or more prescription drugs in the past 30 days: 21.7% (2007-2010)

• Percent of persons using five or more prescription drugs in the past 30 days: 10.6% (2007-2010)


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Physician office visits

• Number of drugs ordered or provided: 2.6 billion

• Percent of visits involving drug therapy: 75.1%

• Most frequently prescribed therapeutic classes:– Analgesics

– Antihyperlipidemic agents

– Antidepressants


Clinical Pearl

• In the presence of oral lesions and dry mouth, consider medication use a potential cause

• Carefully explore the temporal relationship of signs and symptoms with medication use (new use, dose change, generic/brand)



A review of adverse oral reactions to systemic medicationScott S. De Rossi, DMD and Elliot V. Hersh, DMD, MS, PhD

Potential oral manifestations of cardiovascular drugs.

• The frequency of potential oral manifestations in patients receiving cardiovascular agents was 14.1%.

• The occurrence and character of the oral manifestations had no significant relation with individual cardiac drugs, although there was a trend for oral manifestations to be likely with increasing number of drugs.

• Oral symptoms and/or signs were recorded in 75 (14.1%) patients with xerostomia being the most common (7.5%), followed by lichenoid (lichen planus-like) lesions (3.6%) and dysgeusia (1.9%).

– Xerostomia was significantly more frequent in patients with a history of diabetes mellitus and in female patients (P < 0.05).

– There were no statistically significant differences (P > 0.05) between patients with or without oral manifestations when age, gender, cardiovascular risk factor, cardiac disease, type of cardiac drug used or the number of medications were assessed.

Scott S. De Rossi, DMD Habbab KM1, Moles DR, Porter SR.Oral Dis. 2010 Nov;16(8):769-73.


Introduction

• Many commonly prescribed medications have adverse oral sequelae

• Little scientific data as to the prevalence

• Dental and oral manifestations are often nonspecific and vary in significance

• Manifestations may mimic many disease processes (e.g. EM) while others are very characteristics (drug-induced gingival enlargement)


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Introduction

• Many commonly prescribed medications have adverse oral sequelae

• Little scientific data as to the prevalence

• Dental and oral manifestations are often nonspecific and vary in significance

• Manifestations may mimic many disease processes (e.g. EM) while others are very characteristics (drug-induced gingival enlargement)



Oral manifestations of drugs are dependent on:

1. The type of drug

2. The drug dose

3. The chronicity of dosing

4. The variability in patient response

• Reactions may be immediate or develop over several weeks


Etiology and pathogenesis of drug-induced oral reactions

Reactions generally result from one of two mechanisms:• Immune-mediated

– IgE-mediated reactions when the drug reacts with IgEantibodies bound to mast cells

– Drug-related cytotoxic reactions when antibodies bind to a drug attached to a cell surface

– Circulation of antigens for extended periods allowing for sensitization and antibody production

• Non-immune-mediated

– Drugs that directly affect cells leading to chemical mediator release and inflammation and cell death

Drug Actions/Interactions

• Therapeutic (desired) effects and adverse (unwanted) effects

• 81% of Americans take at least 1 medication routinely and many take >1

• 42% use at least 1 OTC medication

• 49% use at least 1 dietary supplement

• 29% use at least 5 medications concurrently


Kauffman DW, et al. JAMA 2002.


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Scott S. De Rossi, DMD Scott S. De Rossi, DMD


Angioedema

• Common clinical presentation of a group of allergic conditions

• Previously known as “angioneurotic edema” because of a presumed psychologic or CNS stimulation

• Defined as rapid, painless swelling of the lips and adjacent structures after contact with an allergen or medication


Angioedema

• Very concerning when posterior structures are involved (airway compromise)

• Upon cessation of contact with the suspected allergen, swelling subsides within 24-48 hrs

• Two forms: – Hereditary

– Acquired


Hereditary Angioedema

• Rare autosomal dominant disorder• Deficiency in C1 esterase inhibitor (C1INH) of

the complement cascade – This innate immune response is the first line of

defense against invading microorganisms. This system is not specific for a given pathogen, but can aid in the induction of cell-mediated immunity (antibody and specific killer cells)

• Unlike the acquired form, swellings usually result from mild trauma


Acquired Angioedema

• More common form and frequently the result of recent ingestion of a new medication or exposure to a chemical– May affect 10-20% of US population

• Although it can occur after long-term therapy

• Most cases are mediated by an IgE immune reaction (antibiotics)

• Some cases are non-immune mediated (NSAIDs)

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Airway compromise with angioedema

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Drugs commonly associated with angioedema

Drug Class Common Drug Names Drug Indication

ACE Inhibitors (1%) BenazeprilCaptoprilEnaloprilFosinoprilLisinoprilMoexiprilPerindoprilQuiniprilRamiprilTrandolapril

Hypertension, Congestive heart failure

Anxiolytics Midazolam Anxiety

Antifungal Agents Ketoconazole Yeast infections

Cholinesterase Inhibitors Donezipil, Tacrine Alzheimer’s disease

ACE Inhibitors

• Angiotensin-converting enzyme (ACE) inhibitors induce angioedema in 0.1 to 0.7 percent of recipients

• The incidence of ACE inhibitor-induced angioedema is up to five times greater in people of African descent

• More than 40 million patients in the United States are taking these agents

– Comparative risk for angioedema associated with the use of drugs that target the renin-angiotensin-aldosterone system. Arch Intern Med. 2012;172(20):1582



Treatment of angioedema

• Standard management: – airway protection, supportive treatment,

antihistamines and/or corticosteroids

• Epinephrine and early intubation or cricothyroidotomy may be necessary– Diphenhydramine (50) mg po or IM or IV

– Hydrocortisone (200 mg) or Solu-Medrol (40-60 mg) IV may reduce the possibility of relapse

– Epinephrine (1:1000) should be administrated intramuscularly at 0.01 mg/kg or 0.3 mg repeated every 10-15 min, if necessary


Color changes of the oral mucosa and teeth

• Occurs via direct contact with or ingestion of a medication

• Medications containing metals such as silver, bismuth, gold, lead, mercury, zinc, and copper

• These ingested pigments extravasate from vessels in foci of increased capillary permeability (gingival margin – via formation of metallic sulphides)

• Withdrawal of medication can lead to resolution or these lesions may be permanent

Heavy Metal Staining


Color changes of the oral mucosa and teeth: Drug-induced melanosis• Flat pigmented areas usually without

nodularity• Flat, macular, localized or multifocal areas• Areas most frequently affected

– Palate– Tongue– Buccal mucosa

• Quinilone, hydroxyquinilone, amiodoquine, minocycline, doxycycline

• Pigmentation can remain after withdrawal of the incriminated drug

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Hairy or Coated Tongue

• Elongation and staining of filiform papillae

• Often a response to infections, fever, xerostomia, antibiotic, tobacco

• Occasionally idiopathic

• Usually asymptomatic

• Dx via history and examination

• Tx via elimination of causes and debridement (mechanical/chemical)

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Elongation of filiform papillae


Black/Brown Hairy Tongue

• Common condition of unknown etiology affecting the tongue dorsum

• Elongated papilla become pigmented by the colonization of chromogenic bacteria and extrinsic stains

• Can occur after ingestion of antibiotics or anti-diarrheals

• Treatment involves tongue brushing and scraping; eliminations of offending agent; and Dakin’s solution



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Drugs commonly associated with color changes in the oral cavity


Antidiarrheals Bismuth subsalicylate Acute diarrheaH. Pylori treatments

Centrally acting antihypertensives

Methyldopa Hypertension

Antibiotics Minocycline Bacterial infectionsPeriodontal diseasePemphigoidAcne

Oral Contraceptives Ethinyl estradiol/progestin combos

Birth controlDysmenorhhea

Antidysrythmics Quinidine Atrial fibrillation/flutterVentricular/supraventricular arrhythmia

Antivirals Zidovudine HIV infection


Taste Disturbances

• Many medications induce abnormalities in taste by a yet to be understood process– Blunting or decreased taste (Hypoguesia)

– Total loss of taste (Aguesia)

– Distortion in the perception of a correct taste (Dysguesia)

• May manifest as an unusual, bitter, metallic, or change in taste perception or distaste


Taste Disturbances

• Proposed mechanisms: – Interference with the chemical

composition or flow of saliva

– Direct effects on taste receptor function or signal transduction

• It does appear to be dose related

• Usually resolves with drug discontinuation

• May benefit from Zinc supplementation (220mg/day)


Medications

• 0.12% chlorhexidine rinse has been reported to produce a reversible impairment of peripheral taste receptors

• Some medications cause alterations of specific tastes (sweet, bitter, salty, sour)

• Some increase taste or recognition thresholds

Medications

• Several drugs have been associated with total loss of taste:– local anesthetics (lidocaine), antineoplastics

(bleomycin), and antirheumatics(penicillamine)

• The mechanisms behind these effects are complex and not yet clearly defined, but medication-induced taste dysfunction can occur at any of the transport, sensory, or neuronal levels of the gustatory system


AntibioticsAmpicillinAzithromycin (Zithromax)Ciprofloxacin (Cipro)Clarithromycin (Biaxin)Griseofulvin (Grisactin)Metronidazole (Flagyl)Ofloxacin (Floxin)Tetracycline

AntidepressantsAmitriptyline (Elavil)Clomipramine (Anafranil)Desipramine (Norpramin)Doxepin (Sinequan)Imipramine (Tofranil)Nortriptyline (Pamelor)

Antihistamines and decongestantsChlorpheniramineLoratadine (Claritin)Pseudoephedrine

Antihypertensives and cardiac medicationsAcetazolamide (Diamox)Amiloride (Midamor)Betaxolol (Betoptic)Captopril (Capoten)Diltiazem (Cardizem)Enalapril (Vasotec)Hydrochlorothiazide (Esidix) and combinationsNifedipine (Procardia)NitroglycerinPropranolol (Inderal)Spironolactone (Aldactone)

AnticonvulsantsCarbamazepine (Tegretol)Phenytoin (Dilantin)

Anti-inflammatory agentsAuranofin (Ridaura)ColchicineDexamethasone (Decadron)Gold (Myochrysine)HydrocortisonePenicillamine (Cuprimine)

Antimanic drugLithium

AntineoplasticsCisplatin (Platinol)Doxorubicin (Adriamycin)Methotrexate (Rheumatrex)Vincristine (Oncovin)

Antiparkinsonian agentsLevodopa (Larodopa; with carbidopa: Sinemet)

AntipsychoticsClozapine (Clozaril)Trifluoperazine (Stelazine)

Antithyroid agentsMethimazole (Tapazole)Propylthiouracil

Lipid-lowering agentsFluvastatin (Lescol)Lovastatin (Mevacor)Pravastatin (Pravachol)

Muscle relaxantsBaclofen (Lioresal)Dantrolene (Dantrium)

Drugs that cause Taste Disorders

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Erythema Multiforme

• An acute inflammatory disease of the skin and mucous membranes

• Can cause a variety of lesions• Oral lesions – inflammation accompanied by

rapidly rupturing vesicles and bullae• Immune mediated process

– Initiated by deposition of immune complexes in the superficial microvasculature

– Direct cell-mediated toxicity


Erythema Multiforme

• Skin lesions in 50% of cases

• Acute, multiple, ulcers involving any oral surface but usually sparing gingiva

• Lip crusting and “target lesions”

• Oral lesions– erythematous patches, necrosis,

erosions/ulcers

– hemmorhagic crusting of vermillion zone


Erythema Multiforme

• Erythema multiforme major– Stevens-Johnson

– mortality = 2-10%

• Toxic epidermal necrolysis– older people with female predilection

– mortality = 34%


Erythema Multiforme: diagnosis and treatment

• Non-specific histopathology

• Must be differentiated from HSV, lichen planus, pemphigoid, pemphigus

• Treatment– avoid known/suspected trigger

– supportive measures (analgesia, hydration, etc.)

– high dose steroids (prednisone 60-90mg/day)

– HSV prophylaxis for recurrent episodes


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Medications associated with erythema multiforme


Antiarthritic agents Allopurinol Gouty arthritisLeukemia associated gout

Antibiotics ClindamycinPenicillin V potassiumTetracycline

Bacterial infections

Anticonvulsant agents Carbamazepine Seizure disordersDepressionTrigeminal neuralgia

Antiviral agents Acyclovir Herpes infection/suppression

Barbituates PentobarbitalPhenobarbitalSecobarbital

Antianxiety/sedative hypnoticsAnticonvulsant

Non Steroidal Antiinflammatory Drugs

Phenylbutazone Pain and inflammation

Sulfonamides SulfacytineSulfamethizoleSulfamethoxazoleSulfisoxazole

Bacterial infections


Medication-induced Gingival Enlargement/Overgrowth

• Formerly known as “gingival hyperplasia”

• Diffuse enlargement due to increase of the fibrous component of the gingiva

• Associated with normal color usually

• Local factors are ALWAYS an etiologic factor– Fibroblasts in non-inflamed tissue are less

likely to respond to circulating drugs

Histology



Medication-induced Gingival Enlargement

• Phenytoin– mast cell mediated androgen activity

• Calcium channel blockers– inhibit adherence and lipopolysaccharide-

stimulated/macrophage-induced fibroblast death

• Cyclosporine– increases fibroblast production of collagen

and matrix


Treatment of drug-induced gingival enlargement

• Lesions do not resolve with drug withdrawal

• Aggressive oral hygiene

• Frequent recall maintenance

• Treatment with gingivectomy

• Explore alternative drug therapy

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Mild nifedipine induced GH



Moderate



Severe


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Medications known to cause gingival overgrowth


Anticonvulsants Phenytoin Epilepsy/seizures

Calcium channel blockers DiltiazemFelodipineNifedipineNisoldipineVerapamil

HypertensionRaynaud’s phenomenon

Immunosuppressive agents Cyclosporin AMycophenelate mofetil

Organ transplant rejectionMucocutaneous disease


Lichen Planus/Lichenoid Rxn

• Common dermatologic disease of skin and mucous membranes

• Middle-aged adults; 60% women• Prevalence of oral LP = 0.1-2.2%• Chronic, multiple lesions• Various forms:

– Reticular/Wickham’s striae - asymptomatic– Plaque-like - asymptomatic– Bullous/erosive/ulcerative - symptomatic


Lichenoid drug reactions

• Exhibit similar clinical and histological findings as ‘idiopathic’ LP

• Usually two distinguishing factors– The association with the administration of a

drug, contact with metal, foodstuff, or systemic disease

– Their resolution when the offending agent is eliminated


Etiology of Lichen Planus

• Immune mediated - T cell mediated degeneration of the basal cell layer of epithelium

• Associated with stress, drug hypersensitivity (lichenoid drug reaction), or infection (HCV)– NSAIDs, allopurinol, sulfonamides, tetracyclines, ACE

inhibitors, HCTZ, lorazepam, sulfonylureas

– dental materials• amalgam and resins

– idiopathic


EPITHELIUM

CONNECTIVETISSUE

PRIMARYRESPONSE

SECONDARYRESPONSE

LYMPH NODE

LC

CAPILLARIES

HYPERSENSITIVITYREACTIONS

CYTOKINERELEASE

T-CELLRECIRCULATION

T-CELLSENSITIZATION


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Topical Corticosteroids Preparations: treatment of lichenoid reactions

• Flucinonide gel (Lidex) 0.05%

• Betamethasone (Diprolene) gel 0.05%

• Clobetasol(Temovate) gel 0.05%

• Dexamethasone rinse 0.5mg/5cc

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Intralesional GCS injection

Triamcinolone 5-40mg/cc - inject 0.1cc per cubic cm



Medications known to induce lichenoid reactions


Antiarthritic agents Allopurinol Gouty arthritisLeukemia associated gout

Beta adrenergic antagonists Propranolol HypertensionCongestive heart failureMigraine prophylaxisDysrhthymia

ACE Inhibitors Captopril HypertensionCongestive heart failure

Oral hypoglycemic agents Chlorpropamide Type 2 diabetes

Centrally acting agents Methyldopa Hypertension

Duiretics FurosemideThiazides

HypertensionPeripheral edema

Non-Steroidal Anti-inflammatory Drugs

DiflusinalFlurbiprofenIbuprofen

PainInflammation

Medication-induced Xerostomia

• 80% of the most commonly prescribed medications have been reported to cause xerostomia

• Xerostomic drugs can be found in 42 drug categories and 56 sub-categories

• Most drugs do not cause damage to glands• DIX is a transient symptom• Inhibitory effects can be overcome with

gustatory stimulation

Medication-induced Xerostomia

• Drugs which directly damage salivary glands (e.g. anti-neoplastics)

• Drugs with anticholinergic activity (e.g. antihistamines)

• Drugs acting on sympathetic system (e.g. alpha 1 antagonists)

• Drugs that deplete fluid (e.g. diuretics)

Myth Vs. Reality

• TCAs are potent inhibitors of salivation that act on muscarinic-cholinergic receptors

• Alpha adrenergic antagonists consistently cause hyposalivation

• Beta blockers and ACE inhibitors cause neither hyposalivation nor xerostomia

• Diuretics cause xerostomia but not hyposalivation

Scott S. De Rossi, DMDNapenas J. Odonotol 2009.

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Medication-induced xerostomia

• Common and significant side effect of many medications (over 1500 listed)

• Few drugs have been shown to objectively reduce salivary function

• Increased risk with increased drugs taken• Older people are more likely to be affected

– 75% of people over 65yo are on at least 1 medication

– Known synergistic effects of medications– May interfere with chewing and swallowing

• Altered nutrition and increased DMR scores



Medication-induced xerostomia

• Principal mechanism of action is an anticholinergic or sympathomimetic action

• Close temporal relationship between drug initiation and dryness; return to normal with withdrawal

• Medication-induced dryness affects unstimulated output, leaving stimulated function intact– Results in complaints of dryness at baseline resting

levels, but normal flow to stimuli (eating, etc.)


Dry mouth due to muscarinicacetylcholine receptor

blockade


Medications known to cause oral dryness


Amphetamines DextroamphetamineMethamphetamine

Attention deficitNarcolepsy

Anticholinergics AtropineBenztropineDicyclomineOxybutyninScopolamineTolterodine

Motion sicknessOveractive bladder

Antihistamines AzelastineCetirizineClemastine fumarateDiphenhydramineHydroxyzineMeclizine

Allergic rhinitis

Anti-HIV protease inhibitors

AmprenavirIndinavirNelfinavirRitonavirSaquinavir

HIV disease

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Medications known to cause oral dryness


Selective serotonin reuptake inhibitors

CitalopramFluoxetineParoxetineSertraline

Depressions/anxietyPanic disorderObsessive compulsiveEating disorder

Tricyclic antidepressants AmitriptylineDesipramineDoxepinImipramineNortriptyline

Depressions/anxietyNocturnal enuresisChronic pain/TMDBurning mouth syndrome

Add lobulated tongue image



Diagnosing dry mouth


Navazesh M. JADA 2003

Some Simple Questions

• Does the amount of saliva in your mouth seem to be too little? Too much? Don’t notice?

• Do you have any difficulty swallowing?

• Does your mouth feel dry when eating a meal?

• Do you sip liquids to aid in swallowing dry food?– Fox P. et al 1997


A simple clinical test to assess dryness – the ‘tongue blade test’• Place dry tongue

blade on against buccal mucosa

• Adherence of the tissue to the blade indicates tissue dryness and reduced salivary secretion

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Complications of xerostomia

• Caries

• Periodontal and gingival disease

• Mucosal abnormalities

• Halitosis

• Candidiasis

• Poor quality of life

Management of Dry Mouth

• After establishing a diagnosis, a step-wise management approach is implemented

• Five goals of management:1. Alleviating symptoms

2. Instituting preventive measures

3. Treating oral conditions

4. Improving salivary function (if possible)

5. Managing underlying systemic conditions



Systemic Strategies: Cholinergic drugs

• Parasympathomimetic stimulating agents to increase salivary production

• Require functioning glands

• GI, sweat, and cardiac side effects

• May alter cardiac conduction and should be avoided in patients with significant heart disease, asthma, and narrow angle glaucoma


CevimelinePilocarpine


Drug-induced Pemphigus

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Types of Pemphigus

• Vulgaris

• Vegetans

• Foliaceus

• Erythematosus

• Paraneoplastic pemphigus

• Drug-induced pemphigus


Drug-induced pemphigus

• A drug origin should be considered with all new pemphigus patients

• Pemphigus foliaceous and vulgaris are the most common drug induced types

• Causative drugs can be classified intotwo groups:– Thiol drugs – Non-thiol drugs


Drug-induced pemphigus

• Proposed mechanism:– Drugs induce antibody formation, resulting in

acantholysis via a mechanism identical to idiopathic pemphigus (non-thiol drugs)

– Other drugs induce acantholysis directly in the absence of antibody formation

• Although eosinophilic spongiosis is often present, it is not possible to distinguish them based on histologic features alone


Binding of IgG autoantibodies to Desmoglein 3 on desmosomes.

Steric hindrance leads to loss of cell-to-cell adhesion resulting in blister formation.

Epithelial changes occur as a result of intercellular cement, widening of intercellular spaces, demosome destruction and cellular degeneration.


Clinical Manifestations

• Classic lesion - thin-walled bulla arising on otherwise normal skin or mucosa

• Applying pressure to an intact area results in new lesion formation = Nikolsky sign

• 80-90% of patients develop oral lesions• 60% develop oral lesions as first sign • Shallow, irregular ulcers because of rapid

bullae rupture


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Treatment

• Removal of the offending drug

• Most, but not all patients go into remission once the offending agent is stopped

• Systemic corticosteroids– Prednisone (0.5-2 mg/kg/day)

– Immunosuppressive therapy• Mycophenelate mofetil, azathioprine,

cyclophosphamide


Antiresorptive Related Osteonecrosis (ARONJ):

• Since 2003 reports of BON associated with the use of zoledronic acid (Zometa) and pamidronate (Aredia) have appeared in the literature– intravenous bisphosphonates administered

every three to four weeks to treat certain cancers (primarily multiple myeloma and metastatic bone, breast or prostate cancer) and Paget’s disease of bone

• Some reports of BON related to po drugs

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Bisphosphonate-associated osteonecrosis

• Complication of cancer treatment

• Oral lesions similar in appearance to ORN

• Appear as ragged oral ulcerations that expose underlying bone

• Occasionally extremely painful

• Persistent and do not respond to traditional treatments


Bisphosphonate-Induced Jaw Osteonecrosis

Ruggiero SL et al, J Oral Maxillofac Surg. 2004;62:527-34

Bisphosphonates - For the treatment of:• Hematological malignancies• Cancer metastasis to bone• Osteoporosis

Long term I.V Bisphosphonates ( Aredia™ and Zometa™)

Jaw osteonecrosis•Chronic bone devitalization•Tissue dehiscence•Radiolucency •Hypocellularity


Bisphosphonates

• Used to treat osteoporosis, Paget’s disease of bone, and hypercalcemia of malignancy

• Goal: to arrest bone loss and increase bone density and reduce risk of pathologic fracture

• PO bisphosphonates are mostly used with osteoporosis

• Injectable bisphosphonates are used in cancer patients with primary or metastatic bone lesions

• More than 150 million prescriptions were dispensed to outpatients between 2005 and 2009– Whitaker M. NEJM 2102.



Bisphosphonates

• Potent inhibitors of osteoclast activity

• Accumulate in mineralized bone matrix

• Physiologic bone deposition and remodelling are severely compromised

Denosumab (Prolia, Xgeva)

• Monoclonal antibody with high affinity to RANK ligand which prevents the interaction of RANK ligand with its receptor, RANK, which is present on the surface of osteoclasts and their precursors.

• Denosumab thus inhibits osteoclast activity, thereby decreasing bone resorption in trabecular and cortical bone.

• Cases of ONJ develop quickly – within a few weeks


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Antiangiogenics

• Indirectly affect bone remodeling

• Sunitinib– Advanced renal cell Ca, pancreatic neuroendocrine

tumors

• Sorafenib – no cases reported yet– Hepatocellular Ca, advanced renal cell Ca

• Bevaacizumab– VEGF pathway inhibitor

– Metastatic colorectal;, advanced nonsquamous small-cell lung, metastatic kidney, glioblastoma


Saad F et al. Ann Oncol 2011;annonc.mdr435

© The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]

Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases

Cumulative incidence of ONJ. The crude incidence of ONJ reported for month 0–12, 0–24, and 0–36.

Saad F et al. Ann Oncol 2011;annonc.mdr435

© The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]

Efficacy of Antiresorptives

• Very effective

• Life saving medications

• Cut vertebral fracture rate by 70% and the hip fracture rate by 50%


Rev. Bras. Reumatol. vol.51 no.4 São

Paulo July/Aug. 2011

Long-Term Efficacy against Fracture for Three Bisphosphonates in Core Registration and Extension Studies.

Whitaker M et al. N Engl J Med 2012;366:2048-2051.


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Drug Design: Bisphosphonates

•Drug design of bisphosphonate→ Pyrophosphate•Different bisphosphonates: Change in the side radicals


Chemical structure of bisphosphonates demonstrating that the manipulation of the basic structure will change the

biological activity and the potency of the drug

• Resemble naturally occurring polyphosphates

• Parachlorophenol moiety is essential for hydroxyapatite binding an affinity to skeleton

• The exact mechanism of BON is unknown

The presence of either an amino-terminal group or a cyclic nitrogen-containing side

chain increases the resorptive potency


This image cannot currently be displayed.

Mechanism of Action of Bisphosphonates

Inhibit bone resorption

Directly on osteoclasts Indirectly through osteoblasts

Inhibit osteoclast activation Inhibit osteoclast recruitment

They inhibit osteoclasts formation, migration, osteolytic activity and promotes apoptosis. They also modulate signalling from

osteoblasts to osteoclasts.



Risk factors for induction of BON

RISK FACTORS ASSOCIATED WITH BISPHOSPHONATE-ASSOCIATED OSTEONECROSIS

Extent of Risk Factor Risk Factor

Systemic Intravenous use of bisphosphonates

Multiple myeloma

Cancer metastatis to bone such as breast, lung, and prostate

Local Dental extraction

Surgical bone manipulation*

Trauma from dentures

Presence of oral infection*

Poor oral health*

* While these possibly participate in the process, the mechanisms by which they might do so have not yet been completely identified.

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Clinical signs and symptoms of BON

• Absent or delayed hard- and soft-tissue healing following extraction or trauma induced by prosthodontic appliances

• No radiographic changes early!• Severe pain as necrotic bone becomes secondarily

infected• Progressive – leading to extensive areas of bony

exposure and dehiscence• Can occur spontaneously!




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Questions I need to ask

• What is the risk?

• Can I prevent ONJ?

• Can routine dental therapy be performed?

• Is a drug holiday recommended?

• Do I need any preoperative tests?

• If ONJ is present or if it has been successfully treated can antiresorptivetherapy be started agin?


What is the risk?

• Very low for oral drugs

• Fourfold increase with extractions compared to other dental procedures

• No reported cases in 7-10 year clinical trials of risedronate and alendronate

• Median time to onset of BON is greater than 2 years for alendronate; most cases occur following 5 years of therapy

What is the Risk?

• The risk for developing BON remains unknown despite attempts to quantify it.

• Study limitations such as retrospective design, inadequate study durations, and issues associated with voluntary reporting of cases have limited estimates of incidence in the general population.

• An approximate frequency of 1 in 140,000 person-life years of exposure associated with the orally administered drugs was originally based on BON cases reported to pharmaceutical companies.

• Currently, there are insufficient data to determine the risk for BON associated with yearly zoledronate infusion for treating osteoporosis.


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Oral Bisphosphonate use and the prevalence of osteonecrosis

of the jaw• Sedghizadeh PP, et al in J Am Dent Assoc

2009

• Queried EHR to determine number of patients with h/o alendronate use and all patients receiving alendronate who were receiving Tx for ONJ

• 208 patients with h/o alendronate use

• 9 patients with active ONJ

• 1 in 23 (4%)

Can patients with ONJ on denosumabheal faster that those on BP?

• No information as of yet

• Mechanism of action is different.– BPs incorporate in bone and accumulate in skeleton

– Denosumab does not

• Effects of denosumab on bone remodeling reverse more rapidly. This may lead to a quicker resolution of ONJ with drug discontinuation– Malan J. OOOO 2012


Incorporate specific questions into your health history form



From ADA Council on Scientific Affairs Document

• 5-10% for patients with cancer receiving IV drugs

• 0-.34% for patients taking oral drugs– Fewer than 5 percent of BON cases are

associated with patients taking orally administered bisphosphonate drugs.

Can ONJ be prevented?

• Ideal: stabilization or elimination of oral disease prior to starting therapy

• Oral disease appears to be inportant for the development of ONJ

• Protocols that have instituted oral hygience in which dental treatment was done prior to starting therapy have demonstrated a decrease in ONJ– Rimpamonti C, Ann Oncol 2009

– Dimopoulos M. Ann Oncol 2009

– Heufelder M. OOOO 2012


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Predicting Risk

• A major goal in the prevention of BON is to limit the possibility of extensive or multifocal involvement.

• OK to proceed conservatively in some cases– Determine how a patient will heal in a relatively small region

before putting multiple quadrants at risk.

• After establishing the patient’s apparent adequate healing response a more accelerated surgical treatment plan involving multiple sextants at a single appointment could be considered.


CTX testing and drug holidays

• Recently, the use of serum levels of the collagen breakdown product, C-terminal cross-linking telopeptide of type I collagen (CTX), has been advocated as a risk predictor for developing BON.

• Serum CTX and urinary N telopeptide of type I collagen (NTX) are considered markers for bone resorption.

• Higher levels of these markers are associated with active bone turnover.

• Reports suggest that dental treatment decisions should be based on the results of serum CTX/NTX levels.


CTX testing and drug holidays

• These recommendations are derived from clinical observations at one institution that have not been validated. – It remains to be seen if these recommendations will be

corroborated by well-controlled, randomized clinical trials.

• Recognized value of predicting and mitigating the risk for developing BON in individual patients.

• Until objective research studies document and correlate specificity, predictive value and reliability of such tests, no recommendations can be made.


Laboratory Assessment

• CTx: serum test to evaluate bone turnover• C-terminal cross-linked telopeptide• Limited scientific data regarding its use as

a predictor of adverse events– R. Marx (1 study – 25 patients)

• CTx < 100pg/ml = high risk of BIONJ• CTx 100-150pg/ml = moderate risk• CTx > 150pg/ml = minimal to no risk

• Not a validated test to predict risk!

CTX biochemical marker of bone metabolism. Is it a reliable predictor of bisphosphonate-associated

osteonecrosis of the jaws after surgery? Implant Dent. 2009 Dec;18(6):492-500.

• Lee, et al. examine the scientific basis (validity) of the morning fasting serum CTX test in 163 consecutive patients who underwent various oral surgery procedures in the office.

• The authors also review the laboratory test results and the recommended protocol based on the test values.

• One hundred sixty-three patients (mean age, 75.9 years) were divided into 2 groups.

• Group I was the control group that consisted of 109 patients taking oral BPs who did not take the CTX test preoperatively. Group 2 consisted of 54 patients taking BPs and who elected to have the CTX test performed to assess their level of risk of developing ONJ, preoperatively.

• Both groups of patients were observed for a period of 8 weeks for signs and symptoms of BP-associated ONJ after surgery. The clinical data at 8 weeks and beyond revealed that there was no evidence of BP-associated ONJ in all participants.

• We conclude that the serum CTX is not a valid preoperative test to accurately assess the level of risk of developing ONJ and is not indicated in the oral surgery patient.

Serologic bone markers for predicting development of osteonecrosis of the jaw in patients receiving

bisphosphonatesJ Oral Maxillofac Surg. 2010 Sep;68(9):2241-7.

• Lazarovici TS, etal.• Data on the demographics, comorbidities, and BP

treatment were collected from 78 patients scheduled for dentoalveolar surgery. Of the 78 patients, 51 had been treated with oral BPs and 27 had been treated with frequent intravenous infusions of BPs. Blood samples for CTX, bone-specific alkaline phosphatase, and parathyroid hormone measurements were taken preoperatively. Surgery was performed conservatively, and antibiotic medications were prescribed for 7 days.

• Conclusion: The measurement of serum levels of CTX is not a definitive predictor of the development of BRONJ

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Is a drug holiday a valid alternative?

• What is the rationale?

• Does the type of antiresorptive matter?Mostpatients now come to us for ONJ treatment when drug has been discontinued

• Risk of skeletal complications versus benefit of oral treatment

• Discontinuation of BP did not affect outcomes– Vrade M. JOMS 2011


General Recommendations

• Routine dental care should not be modified solely based on use of bisphosphonates

• Comprehensive examination prior to initiation of bisphosphonate therapy

• Inform patients BON can occur in response to dental disease or dental therapy


Patients should be informed that:


AAOMS Staging Criteria


People taking bisphosphonates are often unfamiliar with the drug and its side effects

Bisphosphonate information provided by patients

YES NO or UNSURE

Reason for taking bisphosphonate? 84% 16%

How long are you going to be on therapy? 20% 80%

Informed about the risks or side effects? 18% 82%

Informed about bone densityimprovement?

30% 70%


Miglorati CA, et al. JADA 2010

Dentists must be prepared to educate patients about the risks of developing oral complications from bisphosphonate use and the need for appropriate dental care!

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