A HOT REVIEW OF BASIC BIOMECHANICS....................................................................................................................................................................................................................................... 2

MATRIX MOLECULES ........................................................................................................................................................................................................................................................................ 2

STRUCTURE AND FUNCTION OF BONE ................................................................................................................................................................................................................................................... 3

BONE DEGRADATION ........................................................................................................................................................................................................................................................................ 4

STRUCTURE AND FUNCTION OF CARTILAGE, LIGAMENTS, TENDONS, DIARTHRODIAL JOINTS ...................................................................................................................................................... 5

JOINT DISEASE ................................................................................................................................................................................................................................................................................. 6

LIGAMENTS AND TENDONS ................................................................................................................................................................................................................................................................. 6

CONTROL OF CONNECTIVE TISSUE (BONE) METABOLISM .............................................................................................................................................................................................................. 6

BONE METABOLISM ......................................................................................................................................................................................................................................................................... 7

PATHOPHYSIOLOGY ........................................................................................................................................................................................................................................................................ 8

GOUT ............................................................................................................................................................................................................................................................................................ 8

ANKYLOSING SPONDYLITIS .................................................................................................................................................................................................................................................................. 9

LYME DISEASE ............................................................................................................................................................................................................................................................................... 10

TEMPORAL ARTERITIS (GIANT CELL ARTERITIS)...................................................................................................................................................................................................................................... 11

JUVENILE IDIOPATHIC ARTERITIS (JIA) ................................................................................................................................................................................................................................................. 12

SYSTEMIC LUPUS ERYTHEMATOUS (SLE) ............................................................................................................................................................................................................................................. 13

MARFAN SYNDROME ...................................................................................................................................................................................................................................................................... 15

REACTIVE ARTHRITIS ....................................................................................................................................................................................................................................................................... 15

SJOGREN SYNDROME .................................................................................................................................................................................................................................................................... 16

SALIVARY GLAND AND SALIVA REVIEW ................................................................................................................................................................................................................................................ 16

SJOGRENS SYNDROME ..................................................................................................................................................................................................................................................................... 16

OSTEOMALACIA, IMPLANTS, BONE GRAFTING AND MRONJ ........................................................................................................................................................................................................ 18

OSTEOMALACIA ............................................................................................................................................................................................................................................................................. 18

BONE GRAFTING AND IMPLANTS ........................................................................................................................................................................................................................................................ 19

IMPLANTS .................................................................................................................................................................................................................................................................................... 19

MEDICATION-RELATED OSTEONECROSIS OF THE JAW (MRONJ) ............................................................................................................................................................................................................... 20

MUSCULOSKELETAL PHARMACOLOGY ......................................................................................................................................................................................................................................... 21

MUSCLE RELAXANTS ....................................................................................................................................................................................................................................................................... 21

RHEUMATOLOGY AND OSTEOPOROSIS DRUGS....................................................................................................................................................................................................................................... 25

PBL 1 – ANNA WRIGHT .................................................................................................................................................................................................................................................................. 29

PHYSIOLOGIC CHANGES DURING PREGNANCY ........................................................................................................................................................................................................................................ 29

MORNING SICKNESS VS. ORAL HEATH ................................................................................................................................................................................................................................................ 30

FETAL RISK WITH DRUGS.................................................................................................................................................................................................................................................................. 30

DENTAL CONSIDERATIONS ................................................................................................................................................................................................................................................................ 31

PBL 2 – SIGMA CHI-GUY ................................................................................................................................................................................................................................................................ 32

BRUXISM ..................................................................................................................................................................................................................................................................................... 32

TEMPOROMANDIBULAR DYSFUNCTION ................................................................................................................................................................................................................................................ 32

TRISMUS ...................................................................................................................................................................................................................................................................................... 34

PBL 3 - BETTINA ............................................................................................................................................................................................................................................................................. 34

SMART BMI ................................................................................................................................................................................................................................................................................. 34

BONES......................................................................................................................................................................................................................................................................................... 35

ELDERLY INJURIES ........................................................................................................................................................................................................................................................................... 35

MANDIBLE FRACTURE ..................................................................................................................................................................................................................................................................... 36

STAGES OF FRACTURE HEALING ......................................................................................................................................................................................................................................................... 37

AFTER-CARE TREATMENT OF FRACTURES .............................................................................................................................................................................................................................................. 38

BONE REMODELLING ...................................................................................................................................................................................................................................................................... 38

PBL 4 – JACKIE FALLS ..................................................................................................................................................................................................................................................................... 39

OSTEOPOROSIS .............................................................................................................................................................................................................................................................................. 39

POLYMYALGIA RHEUMATICA ............................................................................................................................................................................................................................................................. 41

MRONJ (MEDICATION RELATED OSTEONECROSIS OF THE JAW) ............................................................................................................................................................................................................... 41

PBL 5 – MRS. STEPHANIE CURRY ................................................................................................................................................................................................................................................... 42

RADIOGRAPHS OF TMJ ................................................................................................................................................................................................................................................................... 42

ARTHRITIS .................................................................................................................................................................................................................................................................................... 42

GENETIC PREDISPOSITION ............................................................................................................................................................................................................................................................. 44

VARIATIONS IN THE GENOME ............................................................................................................................................................................................................................................................ 45

DENTAL TRAITS WITH GENETIC BASIS .................................................................................................................................................................................................................................................. 46

PHARMAGOGENOMICS .................................................................................................................................................................................................................................................................... 46

EPIGENETICS ................................................................................................................................................................................................................................................................................. 46

A Hot review of Basic Biomechanics

Matrix Molecules

- Cellular receptors for the Matrix (Integrins, Hyaluronan receptors) transduce mechanical signals which influence gene expression in

connective tissue cells

o Use it or lose it! -> Wolff’s Law

o Cells perceive surroundings, bind extracellular signalling molecules, mechanically modify matrix, and respond biosynthetically

to mechanical signals

o Matrix binding leads to changes in gene expression and structure of the ECM

Integrin Hyaluronan Receptor (CD44)

Transmembrane receptors. α and β subunits dictate specificity of ligand binding

- High affinity adhesion -> allows cells to alter shape of tissue (muscle contraction) and not tear apart

Extracellular Ligands - Collagens - Fibronectin (Would heling) - Vitronectin (Wound healing) - Laminin (Basal lamina attachment)

Intracellular Ligands

- Actin - Focal contact

Adhesion Kinase - Talin - Plectin - Alpha - Actinin

Involved in cell migration and adhesion in proteoglycan rich matrices - Low affinity (allows cells to move) - Important in development, nervous system, inflammation

and wound healing

Molecule Function Analogy

Collagens - Tendon - Ligament - Type I Collagen - Bone (Type 1 Collagen mineralized

with calcium phosphate)

Provide Tensile Strength

Elastics - Elastin - Blood Vessels (not a molecule but

whatever)

Provide Elasticity/stretch

Proteoglycans - Cartilage (type II collagen mesh w/

aggrecan/proteoglycans)

Resistance to compressive forces

Structure and Function of Bone Cell Function

Osteoblasts Deposit bone matric

Osteocytes Mechanical sensors (deem whether or not to degrade or build bone)

Osteoclasts Degrade bone

Step 1: Collagen - All fibrillar collagens are 1/3 glycine -> Smallest and simplest amino acid, the only one that will fit within the center of a triple helix

- High content of proline -> Puts a kink in chain to create the helical shape

- Hydroxyproline and hydroxylysine -> presumably also contribute to the shape?

- Long sequences of (Gly-X-Y)n -> Frequently (Gly-Pro-Hydroxypro)n

- Red = Glycine. It’s a constant, regardless of the polypeptide on the outside.

- Every 3rd residue is always glycine. Many genetic disorders in collagen involve a glycine mutation,

making the proteins fold incorrectly

- Pretty self-explanatory depiction of collagen formation…seen it 100 times

- If folding fucks up (step 5) then the proteins are exported to cytosol and recycled -> if everything

works fine, then it wont get secreted.

- Different genes code for alpha chains in different tissues -> How we get different types of

cartilage.

Step 2: Mineralization - Collagen laid down and is mineralized by osteoblasts

a. Proteoglycanases degrade proteoglycan to create a gap in between collagen rods

b. Phosphoproteins with 3 phosphates fill in the gap created

c. Osteoblasts secrete alkaline phosphatase -> Cleaves phosphates from the

phosphoproteins = ↑ free phosphate

d. Ca++ binds the phosphate and crystalizes = CaPO4 -> Matures into hydroxyapatite

- Osteoblast matrix vesicles (cellular processes) are covered in membrane bound alkaline phosphatase to start the mineralization reaction

Bone Degradation - Controlled by Osteoclasts, occurs at the ruffled border of these cells

a. ATP dependent proton pump creates a low pH -> Dissolves the mineralized bone

o pH creates protection from inhibitors that would stop the demineralization

o 10% of serum proteins are designed and dedicated to neutralizing the low pH

in the ruffled border to control the process

b. High content of lysosomal proteinases to degrade collagen once the acid has

demineralized

During bone remodeling a Degradation/Formation effort is balanced together:

- Regulated by the mechanical censorship of osteocytes -> influence osteoblasts which influence osteoclast proliferation and activity

- At the leading edge are the osteoclasts, moving forward and eating through old bone

- Behind the osteoclasts blood vessels form which contain stem cells needed to follow the bone cell lineage -> Forms pre-osteoblast and

osteoblasts

- Pre-osteoblasts mature into osteoblasts behind the osteoclasts and synthesize sheets of type 1 collagen that will be the starting point of

lamellae ring formation around the osteon.

- Osteocytes sense mechanical stimulation to regulate the remodelling

- Osteoblasts then mineralize the lamellae

Endochondral Bone Formation Intramembranous Bone Formation

- Cartilage model is made first - Perichondrial cells develop into osteoblasts which mineralize the cartilage template - Extension predominantly occurs at growth plate

- No cartilage model - Compact and spongy bone develops directly from sheets of

mesenchymal (undifferentiated) connective tissue. - Flat bones of the face, most of the cranial bones, and the

clavicles (collarbones) are formed via intramembranous ossification

Mandible

- Both Endochondral and Intramembranous Formation Endochondral

- Entire body of the mandible (Except Anterior portion) - Ramus of the Mandible up to mandibular Foramen

Intramembranous

- Anterior portion of the mandible (symphysis) - Coronoid process - Condylar Process

Trabecular bone stores calcium -> can be readily released under the control of parathyroid hormone

- Inside of the mandible surrounded by a layer of compact bone

Structure and Function of cartilage, ligaments, tendons, diarthrodial joints Proteoglycan = glycoprotein containing glycosaminoglycans

Aggrecan

- Aggregating proteoglycan of cartilage -> Forms large aggregates with hyaluronan (a polysaccharide)

o Hyaluronic acid is extruded through a pore (strange) and can by mm long! Very important

molecule for cartilage

- Core is covalently linked to >100 chondroitin sulphate chains (VERY –‘ve charge)

o Chondroitin sulfate imparts the –‘ve charge. Up to 3 –‘ve charges per molecule!

o Marketed as Tx for oseoarthritis, but there is no evidence of it working directly

o –‘ve charge attracts +’ve ions = creates osmotic pressure = water surrounds molecule =

provides cushing effect

- Entrapped in a matrix of Type II collagen, within the “bag” hydrated glycosaminoglycan-rich matrix

provides resistance to compression

- Blue = hyaline cartilage -> Providing

the impact resistance for the joint.

Collagen is actually highly organized and non-random

- Attached to the subchondral bone with woven vertical fibers (Tide mark = attachment site)

- At the “artificial split line” the vertical collagen fibers transition to a horizontal orientation

o Can peel off the layer above artificial split line -> Lamina Splendens (Its so splendid)

TMJ

- Considered a synovial joint

- Articulating surfaces are considered fibrocartilage, have more collagen than a

typical diarthrodial joint

Joint Disease Osteoarthritis – Involves spicules in the joint and bony enlargement

- Age related wear and tear mostly -> Inability of cartilage to accurately repair damage

- Hyaline cartilage is replaced with fibrocartilage -> Picks up CaPO4 and mineralizes = find bony bits within a joint (calcification)

Inflammatory Arthritis

- Joint inflammation leading to cartilage degradation and skeletal remodelling

Ligaments and Tendons - Type I collagen -> very high tensile strength

- Depending on the ligament or tendon might contain elastic fibers or cartilage-like regions.

- Collagen fibers contain small proteoglycans considered as “spacers” during assembly (This is the starting point for bone formation as well)

Control of Connective Tissue (Bone) Metabolism Wolff’s Law -> If you don’t use it you lose it!

- Bones grow and remodel throughout life to adapt to mechanical environment. Bone is able to sense stress and respond to mechanical

loads.

Review of terms

Axial Skeleton Head, Neck, Trunk (Spine and Ribcage)

Appendicular Skeleton Bone of limbs (includes Pelvis and Clavicle)

Skeleton Cartilage AND Bone, surrounded by perichondrium and periosteum

Intramembranous Ossification Mesenchymal bone DIRECTLY formed during embryonic and prenatal periods - Cranial Bones - Growth at sutures (& Periosteal surface) -> Osteoid synthesized and mineralized directly w/o

cartilage model - Flat Bones

Endochondral Ossification Cartilage models formed during the fetal period -> Bone replaces cartilage after birth - Long Bones

Osteoid Type I collagen-rich matrix that will later mineralize to form bone - Analogous to Pre-Dentin

Bone Function Mechanical support Movement Storage (Calcium) Synthesis of blood cells (RBC, WBC etc)

Bone Metabolism = Balance between bone synthesis and bone degradation

- Involves regulation of activity and generation of osteoblasts and osteoclasts

- Osteoblasts produce and express RANKL to Osteoclast precursors

- RANKL binding to RANK on the precursor = initiates gene transcription for

osteoclastogenic genes -> Creates/activates osteoclasts

- Osteoprotegerin (OPG) is also created by Osteoblasts in presence of growth factors and

cytokines

- OPG intercepts RANKL and prevents it from binding to RANK -> ↓ Osteoclast activation,

↑ bone formation

Regulation of Bone Metabolism

** Osteoclasts controlled mostly by signals from osteoblasts**

Parathyroid Hormone regulation of Ca++

↑ PTH = ↑ RANKL production, ↓ OPG production by osteoblasts = ↑ RANKL binding and ↓ OPG regulation of osteoclasts

o ↑ Osteoclasts = ↑ dissolution of bone = ↑ Ca++ release into blood

Catabolic Signals (Degrades Bone)

M-CSF and TNF11 - Activate and Proliferate osteoclasts - Synergistic with RANKL, but it is not inhibited by OPG

Excessive catabolism -> Osteoporosis

Anabolic Signals (Builds bone)

Osteoprotegerin (OPG) - Blocks RANKL and osteoclast activation -> protects bone

TGF β - Stimulates new matrix synthesis and OPG synthesis - Released from bone matrix during remodelling as a feedback mechanism to stimulate re-synthesis after

degradation. Excessive anabolic signals -> Osteopetrosis

Hormones Estrogen, Androgen, Leptin - Estrogen blocks osteoblast production of IL-6 (pro-inflammatory chemokine that stims osteoclast activity) =

↓ bone resorption - After menopause = no estrogen = ↑ risk of osteoporosis for women. Can treat with estrogen replacement

or low dose bisphosphonates In both genders, ↑ adipose cells in marrow with age at the expense of osteoblast production

Pharmacological Bisphosphonates = anti-catabolic. - Binds to bone to kill and/or inhibit osteoclasts

Mechanical Sensing Integrins sense mechanical stress experienced in the ECM to ↑ bone density

Inflammatory Signals Tumour Necrosis Factor- α (TNF-α) 2 Mechanisms of Action:

1. Activate osteoclasts 2. Inhibit Osteoblast formation and activity

TNF Inhibitors ↓ symptoms of rheumatoid arthritis/inflammation -> Biologics

- Adalimumab (Humira) - Infliximab (Remicade)

Pathophysiology

Gout - Type of arthritis characterized by transient attacks of acute arthritis due to crystallization of monosodium urate with/around joints

o Repeat bouts of arthritis = main clinical feature

Pathogenesis Purines = nitrogen containing organic compounds -> metabolised into uric acid Systemic uric acid (hyperuricemia) ↑ by:

1. ↑ purine ingestion - Diet (soft drinks, fructose, meat, seafood, low dairy)

2. ↑ production from purine metabolism - ↑ cellular turnover during chemo = ↑ purine production (chemo induced gout) - Alcohol ↑ purine catabolism in liver, and urate synthesis

3. ↓ excretion from kidneys - Loop or Thiazide Diuretics ↑ water excretion which ↑ relative concentration of urate in blood - Low dose Aspirin inhibits renal secretion of uric acid (patients with cardiac concerns) - Alcohol ↓ urate secretion in renal tubules - ↓ GFR = ↓ uric acid excretion

Alcohol: - Beer has strongest association > Spirits have moderate association >Wine has no association -> Gout = Wine Drunk Wednesdays

Pathophysiology Hyperuricemia -> Monosodium urate crystals precipitate -> MSU deposited in joints tendons etc -> activates immune system -> Inflammation + pain Immunologically: MSU phagocytosed by macrophages (indigestible) -> ↑ IL-1 -> attracts more immune cells (B,T, Macro) -> ↑ inflammation = damage to joint (bony erosion, cartilage degradation, synovial hypertrophy)

4 Stages of Gout 1. Asymptomatic Hyperuricemia - Common, not clinically significant - >6.8mg/dL starts to precipitate out

2. Acute Gout - Rapid Inflammation (Erythema, edema, heat, pain) starting at night or early morning -> peaks within 24-48 hours) - Spontaneous resolution in 3-14 days - Frequently monoarticular, affecting big toe (first metatarsophalangeal joint) -> Uncommon in Axial joint - In severe attacks skin desquamation may occur over affected joint with pyrexia, chills, malaise Tx: - NSAIDs, Corticosteroids (symptomatic relief) 3. Asymptomatic Inter Critical Period - Sometimes lasts forever Tx:

- Allopurinol (↓ uric acid formation by inhibiting xanthine oxidase) - Probenecid (↑ uric acid excretion in urine)

4. Chronic Tophaceous Gout (TOEphaceous) -> crippling disease - Tophy present in big toe - about 12 years after initial attack - Joints permanently stiff and swollen from chronic inflammation - Bony erosions evident on radiographs (osteoclastic activity) Tophy = deposite of crystaline uric acid

Epidemiology - More prevalent in Males (3.6:1 Male:Female) -> most common inflammatory arthritis in males - Mean Age: 40-60 (later for women) - 35% ↑ risk if 1st degree relative has gout - 50% ↑ in incidence in 2010 vs 1990

Associated Condition

- Cardiovascular Disease - Renal Disease - Diabetes Mellitus - Dyslipidemia - Metabolic Syndrome - Alcoholism

**Gout attack can occur before these are diagnosed. The association with gout helps the Dx**

Dental Implications Joint pain impairs oral hygiene -> Helps to tape tennis ball to toothbrush so it’s easier to grab Chair position is important -> Muchos pillows Short Appointments (No electrive treatment during acute attacks) Can Affect TMJ Drug Interactions:

- NSAIDS -> Prolonged bleeding - Corticosteroids -> Immunosuppression (↑ infection risk) - Allopurinol -> Dysguesia, oral paresthesia, altered drug metabolism in liver, oral erythema multiforme, erosion from vomit

Exam Q on this:

Ankylosing Spondylitis = Chronic, Progressive, Painful inflammatory arthritis causing arthritic pain in sacroiliac joints and spine

- Associated with HLA-B27 genetic marker

- No cure!

Back Pain:

- Insidious onset with dull quality radiating to the glutes -> worse in the AM, gets better as you

move

Axial arthritis progresses from sacroiliac joints up the spine until the whole thing is involved

3 results of limited spinal mobility:

1. Flattening of lumbar lordosis

2. Exaggerated thoracic kyphosis

3. Hyperextension of cervical spine

Pathogenesis Occurs at attachment between tendon, ligament, capsule and bone in 3 processes: 1. Inflammation

- Tumor Necrosis Factor (TNF) plays big role 2. Bone Erosion

- Occurs at corners of vertebral bodies early in disease 3. Spur formation

- Syndesmophytes (spurs) appear as tissue is replaced by ossified fibrocartilage -> eventually fuse making spine look like 1 piece (Bamboo spine)

Pathophysiology Mostly unclear - Multiple genes/gene variants are involed - HLA-B27 -> codes MHC molecule presenting Ag to CD8 T cells (Cytotoxic T-cell)

- 90% of patients with AS have this varient, but only 5% of people with the variant have AS Hypothesis:

- Misfolded, dysfunctional, or autoimune against HLA B-27 = Inflammation Trigger:

- Bacteria travel from GI -> Bloodstream -> SI Joints -> Inflammation -> Chronic inflammation -> Pain & Ossification -> Erosion of vertebrae + syndesmophyte formation -> fused vertebrae -> ↓ flexibility and difficulty breathing

Epidemiology 4-8x more common in men - Average starts at 23 years old

Risk Factors: Family Hx

- Ankylosing Spondylitis - IBD (inflammation starts in GI and spreads to spine) - Frequent GI infections

HLA-B27 (encondes MHC I) -> regulates immune system

Clinical Presentation

Pain and Stiffness - Acute pain in SI joint, lumbar vertebrae, costal cartilage, hip joint, and shoulder joint

Fused Vertebrae and ribs - Results in stiffness and difficulty breathing (ribcase can fuse together as well)

Osteopenia/Osteoporosis - ↓ bone density from chronic inflammation -> ↑ risk of compression fractures

Kyphosis - Hunched forward posture

Uveitis/Iritis - Rapid-onset red, inflammed painful eyes

Cardiac problems - Inflamed aorta -> aortic valve insufficiency

Fever and ↓ apetite

Treatment Non-Pharma: - Patient Education and regular exercise, Physical therapy interventions

Pharma: - NSAIDs - TNF inhibitors (biologic) - DMARDS - Cortocosteroids

Dental Implications

- Secondary Osteoporosis - May affect TMJ and Mandible -> ↑ risk of TMJ, trismus and clicking

- Assess cervical bone erosion and ankylosis prior to surgery - Rule out spinal fracture before to avoid lawsuit

- Tipping the head too far back can cause spinal cord compression - Difficulty intubating during general anaesthesia - Kyphosis can make it difficult to get to the dentist = ↓ oral hygiene - Associations with secondary sjogrens (↑ caries and fungal infections) - Need lots of pillows and short appointments for patient comfort - Difficult breathing with rubber dam due to limited chest expansion

Medications:

- NSAIDs -> ↑ bleeding risk - DMARDS (methotrexate) -> Ulcerative stomatitis, gingivitis, glossitis, mucositis, Aplastic anemia (with NSAIDs) - TNF blockers (Infliximab) -> immunosuppression - Corticosteroids -> immunosupporession - Xerostomia from most meds

Lyme Disease Systemic inflammatory condition caused by Boriella burgdorferi spirochete bacteria

- Bacteria live in saliva of deer ticks -> tick falls off infected deer into grass -> jump onto us when we walk through tall grass - Nymph ticks responsible for most infections because they are hard to spot on skin

Pathophysiology (Largely unknown)

Large mammals + rodents = reservoirs for Borrelia burgdorferi -> Tick feeds on blood of reservoir and takes up microbe -> Tick bites human, if stays on for 24-48 hours can transmit bacteria -> Tick saliva disturbs our immune system at bite -> bacteria can multiply in dermis safely -> 3-32 days later invades surrounding skin (erythema migrans bullseye rash) -> Bacteria enters lymphatics (inflammatory adenopathy) and blood (heart, nervous system, skin, joints) = neurologic, cardiac and joint issues

Erythema Migrans Pathagnomic of Lyme disease (found in 75% of patients) -> absence of rash however does not rule out lyme disease

- Bullseye rash, can be up to 30cm in diameter, no pain or itch - Goes away after 1 month (but still have disease)

3 Phases 1. Early Localized (3-32 days post bite) - Erythema migrans appear

2. Early Disseminated - Bacteria spreads to blood and lymphatics - Flu like symptoms, Arthralgia/joint pain (most common presentation of lyme disease) - Cardiac Issues -> Arrhythmia, Myopericarditis - Neurologic Issues -> cranial nerve palsy, meningitis, neurologic pain (1-2 months after initial bite)

3. Late Stage (months – years post bite) - Lyme Arthritis -> inflamed, swollen, painful joints (including TMJ) - Late neurological symptoms -> Encephalopathy, Neurocognitive dysfunction, peripheral neuropathy (↓

sensation, movement, gland function)

Autoimmune disorders linked with HLA-B27

- Ankylosing spondylitis

- Reactive Arthritis

- Rheumatoid Arthritis

- Psoriasis

- Enthesitis Related JIA

- SLE

- MS

- Type 1 DM

- Narcolepsy

- Celiac Disease

DMARDS – Disease-modifying Antirheumatic Drugs:

- Powerful anti-inflammatories

- Used to prevent joint damage (↓ cartilage and bone destruction)

Non-biologic DMARDs: Methotrexate, leflunomide, sulfasalazine

Biologic DMARDs: Abatacept (T-cell modulator), Etanercept, Adalimumab (TNF

antagonist), Canakinumab (IL-1 antagonist), Toxilizumab (IL-6 antagonist)

Treatment Antibiotics - Early Lyme -> Doxycycline, Amoxicillin orally 1-2weeks - Early Disseminated -> Cefotaxime IV - Late Lyme -> 2-4 weeks of antibiotics

Dental Implications TMJ Inflammation Dental Neuralgia (Facial palsy resembling Bell’s Palsy) -> Be aware of before delivering LA or might be sued

- Twitching muscles might make Tx challenging

Temporal Arteritis (Giant Cell Arteritis) **Medical Emergency! -> 50% of cases end up going blind**

Subtype of Giant Cell Arteritis -> chronic systemic vasculitis of large/medium arteries - Can lead to ischemia, blindness, stroke, MI - Most common systemic vasculitis >50yrs old - Amaurosis Fugax (transient blindness) = warning sign of permanent vision loss (involvement of ophthalmic artery or posterior ciliary

artery

Pathophysiology T-cell dependent and antigen driven (inflammatory condition) -> TNF and IL-6 have a major role Environmental : –> Seasonal with cyclic patterns with geographic variation Genetic -> TNF, ↑ IL-6 (proinflammatory), IFδ, ↓ IL-10 (anti-Inflammatory), Vascular endothelial growth factor

1. Exposure to exogenous antigen 2. T-cells recruited to vessel wall -> release cytokines to act upon macrophages 3. Matrix Metalloproteinases (MMP) degrade collagen in the vessel walls allowing access to macrophages at the basement

membrane 4. In the Adventitia (outer layer), macrophages release cytokine IL-6 to ↑ inflammatory response. 5. In the Media (middle layer), macrophages produce free radicals and MMP’s to degrade the arterial wall and break down

elastic lamina (Inner most layer) 6. Migrating fibroblasts add more ECM to the intima which thickens the vessel walls -> narrows the lumen = ischemia and ↑ prevalence of cranial pain, blindness, TIA and stokes.

Clinical Presentation - New-onset unilateral headache -> noticed which brushing hair, head on pillow or wearing hat -> If not treated has serious implications - Pain in muscles of mastication on chewing - Intermittent claudication of jaw and tongue - Visual Disturbance - ↑ erythrocyte sedimentation rate (inflammation = sticky RBC, sediment together) - ↑ C-reactive protein

Treatment Early initiation of high-dose corticosteroid therapy for 2-4 weeks until reversible signs are gone - Adding DMARDS (Methotrexate) to corticosteroids ↓ relapse rate

Pt’s treated for 1-2 years

Juvenile Idiopathic Arteritis (JIA) = Chronic arthritides involving 1+ joint for at least 6 weeks in patient < 16 years old

- Influenced by Genetic and environmental factors

*Systemic JIA = autoinflammatory condition, all other

types are autoimmune**

Epidemiology - Ages 6 months – 16 years (no primary age). Issues for 6 weeks+ - Boys and girls equally affected - More common if European ancestry

Differential Dx Infection Reactive - Viral (parvovirus, toxic synovitis) - Post-streptococcal rheumatic fever - Bacterial (Lyme, Osteomyelitis, Septic Joints)

Inflammation Malignancy - SLE - Leukemia/Bone tumor - Serum Sickness - IDB

Laboratory Tests No Dx tests - Do CBC -> check Rheumatoid Factor (RF), Cyclic Citrullinated Peptide Ab (CCP), Antinuclear Ab (ANA),

Erythrocyte sedimentation Rate (ESR), and C-reactive protein (CRP) Eliminate other causes of arthritis

Treatment - No cure, but with aggressive Tx and early Dx remission is possible Non-Pharma: Physical and occupational therapy + collaboration among healthcare team = best results Pharma: DMARDS (methotrexate, leflunomide, sulfasalazine) Biologics -> cytokine inhibitors are 1st line therapy

- IL-1 and IL-6 inhibitors - IL-1 and IL-6 antagonists (anakinra, tocilizumab) - TNF antagonists (etanercept, adalimumab) - T-cell modulator (abatacept)

Systemic Corticosteroids -> should be limited to allow regular growth of kid Injected Corticosteroids -> Selected joints to relieve inflammation NSAIDs

Dental Implications TMJ - 25-43% of JIA’s have TMJ issues - Pain on palpation - Trismus - Mandible deviation when opening - Ankylosis of joint - Facial asymmetry

Other issues: - Prolonged morning stiffness -> book late morning appointments - Avoid neck hyperextension in case C1-C2 subluxation and spinal compression

Autoinflammatory Autoimmune

Problems in innate immune system Characterized by neutrophils, macrophages, and NK cells releasing cytokines

Problems in adaptive immune system B & T cells lose ability to differentiate self from non-self

7 Types of JIA -> Focus on the main differences between them, not the little details

Systemic JIA (Still’s Disease if in

adults)

Autoinflammatory disease (the rest are autoimmune), arthritis in 1+ joints preceded by daily high-grade fever associated with at least one of:

- Erythematous rash (salmon coloured) - Generalized lymphadenopathy - Hepatomegaly - Splenomegaly - Serositis (pericarditis, pleuritis, peritonitis)

Inflammatory synovitis -> leads to pannus formation w/ cartilage and bone erosions

- Abnormal thickening of synovial tissue (membrane of granulation tissue w/ mesenchyme + bone marrow derived cells)

- Synovium migrates along articular cartilage, eroding it as it goes - Stimulates release of IL-1, IL-6, and TNF, prostaglandins, Substance P by macrophages = destruction +

erosion of cartilage and bone Abnormal cytokine levels (↑ TNF, ↑ IL-6)

Oligoarticular JIA -Most common form

Arthritis in <4 joints in 1st 6 months of disease 2 subtypes:

1. Persistent -> <4 joints throughout disease 2. Extended -> <4 joints for 6 months then > 4 joints after 6 months

↑ risk of uveitis (eye inflammation) vs other subtypes - Positive test for antinuclear antibody (ANA) = risk of uveitis and blindness

Polyarticular JIA (Rheumatoid Factor –‘ve)

Arthritis in >5 joints AND negative for RF - Found typically in weight bearing joints and TMJ

Polyarticular JIA (Rheumatoid Factor +’ve)

Arthritis in >5 joints AND positive for RF - Anti-cyclic citrullinated (CCP) antibodies may also be present - Most similar to adult rheumatoid arthritis = ↑ risk of progression

More severe than RF –‘ve

Psoriatic JIA Psoriasis AND Arthritis, OR arthritis and 2+ of: - Dactylitis (inflammation of fingers/toes) - Nail pitting - Onycholysis (separation of fingernail from nail bed) - Psoriasis in a 1st degree relative (Erythematous plaques covered by silvery scales)

Enthesitis-Related JIA Arthritis or enthesitis AND 2+: - Sacroiliac tenderness - Acute anterior uveitis - HLA-B27 +’ve - 1st degree relative with HLA-B27 related disease - Male and >6 yrs

Tenderness (enthesitis) where bone beets a tendon, ligament or CT -> typically hips, knees, feet

Undifferentiated Arthritis

Fulfills criteria of 2+ of the other 6 categories, or none of them

Systemic Lupus Erythematous (SLE) 2 Types of Lupus -> Systemic and Discoid

Systemic more serious and affects more organs:

- Skin (Discoid only affects skin)

- Joints

- CNS

- Kidneys (causes highest mortality)

- Lung

- Heart

- GI

- Hematologic System

= Multisystem, autoimmune disorder of the connective tissue Characterised by:

- Antinuclear antibodies (autoantibodies targeting nuclear ag) - Remissions and flares - Variable presentation, disease course and prognosis

Pathophysiology Not completely understood (classic) Thought to be genetically determined immune issue triggered by environmental factors:

- Infectious agents - Stress - Diet - Toxins - Drugs - Sunlight

Strongest genetic risk = deficiency in Complement protein (C1q deficiency)

Auto-immune antibodies form pro-inflammatory immune complexes that deposit onto tissues - Complexes clog up kidneys = kidney failure = death - Immune cells and Complement recruited to complexes and damage tissues

Main immune pathways affected 1. ↓ clearance of nucleic acid-containing debris and immune complexes (ANA antibodies) 2. ↑ innate immune activation 3. Abnormal T and B cell activation

Clinical Presentation Renal - Main cause of mortality (60% of people afflicted renally) - Range from asymptomatic proteinuria -> glomerulonephritis -> renal failure - Renal status is prognostic indicator

Musculoskeletal - 1st symptom of SLE is arthralgia in 50% of patients with SLE - Non-erosive arthritis of hands, wrists, and knees, TMJ involved in 67% cases - Corticosteroid therapy can cause avascular bony necrosis

CNS - Cerebral vasculitis or neuronal damage (Stroke, Seizures, Psychosis, neuropathy, headaches,

numbness/tingling, vision problems) Cardiovascular

- Vasculitis, pericarditis, endocardial damage, myocarditis, arrhythmia - ↑ risk of MI, heart failure, stroke

Pulmonary - Dyspnea, Pleurisy (60% of SLE patients), Hemoptysis - Pulmonary hypertension

Gastrointestinal - Abdominal pain, nausea and vomiting

Skin - Butterfly rash across face/bridge of nose (worse when in sunlight), upper truck and/or exposed skin - Raynaud Syndrome -> vasospasm causing ↓ blood flow to extremities

Miscellaneous - Anemia, Leukopenia, thrombocytopenia -> Pancytopenia - Flu-like symptoms

Risk Factors - ↑ in Women vs men (especially 15-45 child bearing years) - ↓ Complement proteins = biggest genetic risk factor -> Family Hx has a role - Current smoking (not Hx of smoking though)

Medications - Oral contraceptives and Hormone replacement therapy

Environmental - Viral infection (EBV) - UV light - Pesticides

Treatment - Antimalarials (Hydroxychloroquine, Chloroquine) - Corticosteroids - DMARDS (methotrexate) - Biologics (belimumab) - NSAIDs (caution with chronic use)

Oral Manifestations Oral Lesions -> ulcerations or mucosal inflammation - Transient, waxes and wanes - Resemble lichen planus, leukoplakia, candidiasis, Erythroplakia - Ulcerated lesions are hard to distinguish from common aphthous ulcer - Discoid Lupus lesion has white striae

Xerostomia (from meds and secondary sjogrens) Dysgeusia Glossodynia TMJ issues

Dental Implications Medications can cause immunosuppression and eventually adrenal insufficiency Antimalarials can cause lichenoid like reactions or oral hyperpigmentation If have renal failure

- May be on blood thinners, have an AV fistula, or may be taking cyclosporine (gingival hyperplasia)

Marfan Syndrome = connective tissue disease

- Autosomal Dominant mutation of FBN1 gene (encodes fibrillin = structural weakness of CT) - Fibrillin-1 = glycoprotein in microfibrils essential for elastic fiber formation in CT potential issues with heart and aortic aneurysm/dissection

- Fibrillin -1 also involved in TGF-β signalling and is found in ciliary zones, aorta, and ligaments (Skeleton, Eyes, CV system affected)

Systemic Problems Cardiovascular - Thoracic aortic aneurysm, aortic regurgitation, aortic dissection, mitral valve prolapse and regurgitation - No antibiotic prophylaxis though!

Vision - Spontaneous retinal detachment, early onset glaucoma, cataracts, myopia, abnormal cornea

Musculoskeletal - Back pain, kyphoscoliosis, scoliosis

Respiratory - Spontaneous pneumothorax - Cystic lung disease

Presentation Tall, thin stature -> long limbs (arm span exceeds height, legs longer than torso) Disproportionally long fingers Inward or outward displacement of sternum Joint hypermobility Diaphragmatic and inguinal hernias Kyphoscoliosis (anterior and lateral curved spine) Facial/Oral features

- Long thin face (dolichocephaly) - Downward sloping palpebral features - Malar hypoplasia - Strabismus - Retrognathia - High, narrow palate (crowding, posterior cross-bite, malocclusion, TMD)

Quick Test:

- Thumb overlaps pinky finger when held around wrist - Can see thumb nail when closed in a fist

Treatment Early diagnosis can save lives -> Notice oral facial features! Restrict high intensity activity (or risk aortic dissection or aneurysm)

Dental Implications ↑ TMD -> painful mastication, headache, clicking, trismus May need orthodontic treatment for crowded jaw, posterior crossbite and disproportionate arches

- Kids should see ortho at 7 years old

Reactive Arthritis Aseptic arthritis triggered by infectious agent outside the joint -> Asymmetric polyarthritis, mostly in lower extremities

- Begins 1-5 weeks after genitourinary or GI infection Unknown if autoimmune or a response to infection

Presentation Axial inflammation and damage Peripheral arthritis Enthesopathy Extra-articular issues:

- IBD - Psoriasis - Uveitis -> can progress to blindness - Urethritis - Cervicitis - Dysentery

Etiology 20-40 years old - More men than women following UTI, but equally Men:Women following GI

Pathophysiology Triggered by GI or UTI infection spreading to joints - Strong association with HLA-B27

Self-limited and spontaneously resolves w/o Tx after 3-12 months Defined by a triad of: Arthritis, Nongonococcal urethritis or cervicitis, and conjunctivitis

1. Primary Infection -> Genitourinary (chlamydia); GI Tract (Salmonella, Yersinia, Shigella, Campylobacter)

2. Infection disseminates to synovial joints 3. Viable bacteria or bacterial antigens in the joints 4. Host Immune reaction -> Can lead to bacterial elimination, bacterial persistence (tolerated) or autoimmune synovitis (leading to arthritis) 5. Aberrant immune response or persistent microbial infection leads to prolonged inflammation

Treatment NSAIDs for acute phase -> indomethacin (25-50 PO tid) Corticosteroids if inflammation severe DMARDS -> pt’s where NSAIDs are insufficient -> methotrexate infliximab NO Antibiotics, ↑ risk of GI adverse effects -> the bacteria arnt in the joints, so won’t help the arthritis

Sjogren Syndrome

Salivary Gland and Saliva Review Salivary glands are organized like grapes with a functional acinar unit at the bottom, can be 1 type of acinus or a mix of

both types

Acinar units can be of 2 types:

1. Serous -> flowable and liquidy

2. Mucinous -> Thicker and viscous

Saliva

Function Lubricate Aid in Swallowing Digestion Antimicrobial Buffering against acid Tooth remineralization Mediation of taste

Volume 600-1500mL/day - 5% during sleep (0.1mL/min) - 80-90% response to stimuli (4-5mL/min) -> Parotid and Submandibular produce same amount when stim. - Resting (0.3mL/min) -> Submandibular produces most at rest

Control Parasympathetic Stimulation -> High levels of watery Serous flow Sympathetic Stimulation -> Low flow of mucinous protein rich flow Masticatory Salivary Reflex -> Mechanical receptors in periodontal ligament and in masticatory muscle fibers Gustatory Salivary Reflex -> Taste bud activated chemoreceptors, use CN VII, IX and X to bring signal to Medulla Oblongata

Aging Salivary function DOES NOT naturally ↓ with age - ↑ number of drugs taken with ↑ age though can contribute to ↓ salivary flow (usually will find this if on 5+ drugs)

Sjogrens Syndrome Epidemiology Slowly progressive autoimmune disease with wide range of organ specific and systemic manifestations

9:1 Female:Male ratio -> WAY more in females (as it is with most autoimmune issues) Onset: 40-50yrs old ↑ Malignancy Risk

Etiology Primary: No other connective Tissue Disorder Secondary: Secondary to accompanying autoimmune disorder

- Rheumatoid Arthritis - Systemic Lupus Erythematosus - Systemic Sclerosis

Pathophysiology Affects Lacrimal Glands and mucosal exocrine glands of respiratory and GI tracts - Salivary glands = main targets -> they are a local source of autoantigens and signal for lymphocyte organization

1. Salivary gland epithelial cells secrete cytokines to activate T-cells 2. CD4 T cells and dendritic cells infiltrate -> Produce Type 1 IFN 3. ↑ in B cells occurs during course of the disease, and correlates to onset

of systemic manifestations 4. Immune complexes form and stimulate further inflammation (loops) 5. Over time 20% of patients developt germinal centers within the

lymphocytic foci located around the parotid gland (germinal centers associated with B-cell Lymphoma development)

Major Salivary Glands

Parotid -> mostly Serous (helps swallowing and lubricating food) Submandibular -> Most important! Mixed Mucinous and Serous Saliva

- Important for taste, protection, lubrication, remineralizing teeth Sublingual -> Mostly mucinous, no major roles

Minor Salivary Glands

More radioresistant than major glands -> ↑ change of surviving during radiotherapy

Clinical Presentation

Hyposalivation Parotid gland enlargement Difficulty speaking, eating, swallowing Keratoconjunctivitis Sicca (Dry Eyes) Skin and vaginal dryness Orally

- Candidiasis - Angular Cheilitis - Caries - Halitosis - Gingivitis - Mucosal Atrophy - Mouth Soreness

**Periodontitis NOT associated w/ hyposalivation, because it’s not directly associated with bacteria. It’s an immune reaction Musculoskeletal

- Intermittent polyarticular arthropathy of small joints - 53% get arthralgia - 23% get myalgia

Dermatological - Dry Skin - Some with mild Reynaud Syndrome - Vasculitis - Palpable purpura

Pulmonary, GI, Renal involvement usually rare Neurologic

- Sensory neuropathy - CNS rarely involved

Hematologic

- 44x ↑ risk of lymphoma -> Especially around parotid gland, and B-cells (low grade and mostly curable

Clinical Predictors of lymphoma - Persistent parotid enlargement - Splenomegaly - Lymphadenopathy - Palpable Purpura - Leg Ulcers

Diagnosis Ocular Tests - Schirmer Test -> Stick some filters under eyelids, if after 5 mins <5mm of wetting = Sjrogens - Rose Bengal Scoring -> Rose Bengal solution stains eyes for something - Slit Lamp exam -> detects destroyed conjunctiva

Salivary Tests - Sialometry -> is <1.5mL in 15 mins = Sjorgrens - Minor salivary gland biopsy -> 1.2-2cm incision middle of the lower lip. Looking for foci of 50

lymphocytes/4mm2 Lab Work CBC, CRP, TSH, T4, Fasting Glucose/HbA1C, ANA, SS-A, SS-B, RF

- Auto-antibodies precede clinical disease, but prophylactic Tx doesn’t prevent development. Its inevitable

Consensus DX Dry Eyes -> Symptoms, and Test confirmed Dry Mouth -> Symptoms and test confirmed Minor salivary gland biopsy Autoantibodies -> SS-A and SS-B

Treatment Hyposalivation - ↑ H2O, ↓ sugar - ↓ alcohol, tobacco, caffiene - Saliva Substitutes (Xylimelt tablets) - Meticulous oral hygiene (F- mouthrinses and toothpastes) - 3 month recalls - Pilocarpine (5mg tid, 30 mins before meals)

- Parasympathetic agent (muscarinic agonist) - Can cause GI upset, sweating, bradycardia, ↑ pulmonary secretions, ↑ smooth muscle tone, Blurred vision - Tabs not covered under insurance…but eye drops are. Can Px the drops and get them to mix with water!

- Cevimeline (30mg, tid) - Specific paraympathetic agent (muscarinic agonist that doesn’t act on heart or lungs)

Dry Eyes - Artificial Tears - Pilocarpine (↑ production of tears) - Punctal plugs (↓ removal of tears)

Systemic - NSAIDs -> Hydrocychloroquine -> Methotrexate -> Corticosteroids -> Leflunomide -> Sulfalazine -> Azathioprine ->

Cyclosporin - Exercise for MSK pain - Biologics: Rituximab can be used for many symptoms

Osteomalacia, Implants, Bone Grafting and MRONJ Wolff’s Law: Bone will adapt to the loads of stress than it is placed under.

- Surfers get thicker outgrowths of bone on tops of their feet for example

Distraction Osteogenesis = application of Wolff’s Law

- Used to reconstruct skeletal deformities and lengthen long bones

o (micrognathia, midface and fronto-orbital hypoplasia)

- Corticotomy performed to fracture bone in 2 segments, the 2 segments are gradually

moved apart as bone repairs during the distraction phase = new bone fills gap

- Rate of distraction is very important:

o Too Fast = Fibrous union connecting pieces not osseous tissue.

o Too Slow = Early bone consolidation

o Ideal = 1mm/day keeps the micrognathia away

Osteomalacia = Defective mineralization of bone -> Affects quality, not quantity or density

Vitamin D Deficiency

- Most common nutritional deficiency (Sun avoidance, using sun protection, ↑ pigmentation, ↓ dietary supplementation, Obesity,

Medication)

- Usually Asymptomatic, but if severe and prolonged can cause:

o Growth Retardation

o Rickets (in kids)

o Osteomalacia

o Osteopenia

o Osteoporosis

Rickets

- In children, before epiphyseal plate fusion -> results in bowed legs and growth retardation

- Costochondrial junctions enlarged and growth plates are widened and irregular

10 clinical features:

1 Delayed Fontanelle Closure 2 Wide Sutures

3 Frontal Bossing

4 Craniotabes

5 Dental hypoplasia

6 Pectus carnatum

7 Rachitic rosary

8 Harrison’s Sulcus

9 Wrist and ankle swelling

10 Bowing of the legs

Causes Deficiency in: - Vitamin D - Phosphate - Alkaline phosphatase

Drugs: - Glucocorticoids (↓ bone formation) - Thiazolidenediones (↓ bone formation) - Unfractionated Heparin (↓ formation, ↑ resorption) - Excessive thyroid hormone replacement (↑ resorption) - Proton Pump Inhibitors (↓ Ca++ absorption)

Clinical Manifestations

Bone Pain Muscle Weakness Waddling Gait ↓ bone mass detectable on x-ray and bone densitometry Pseudo-fracture -> Clinical Hallmark

Pathogenesis Early Stage: - ↓ Ca++ absorption causes secondary hyperparathyroidism -> prevents hypocalcaemia but ↑ renal phosphate excretion = hypophosphataemia

Late Stage: - Hypocalcaemia + Hypophosphataemia

Osteomalacia vs Osteoporosis Osteomalacia Osteoporosis

↓ ratio of mineral to matrix (too much matrix relative to bone), but normal bone mass

- Affects Quality of the bone Clinical Features:

- Soft bones, bow legs

↓ bone mass and normal mineral to matrix ratio “normal bone, but not enough of it”

- Affects the Quantity of bone Clinical Features:

- Fractures from minimal trauma

Bone Grafting and Implants

Implants Osseointegration = formation of direct interface btwn implant and bone without intervening soft tissue

Screw threads on implants are more to ↑ surface area for better osseointegration

Material: Titanium - High biocompatibility - Good Resistance to Corrosion - No toxicity to macrophages or fibroblasts - No inflammatory response - Oxide layer of titanium allows it to repair itself by reoxidizing when damaged

-> That’s some Wolverine shit… (except Adamantium)

Implant Properties

Mechanical - Wear related to strength and surface roughness - Must be strong -> ion implantation minimizes wear

Topographical - Degree of roughness is related to surface and orientation of surface irregularities - Chemical composition of implant interface on surface affects initial cell attachment

Surface Roughness (sand blasting, acid etching) 1. ↑ Surface Energy 2. ↓ grain size = ↑ surface energy = better cell adherence

- Can cause peri-implantitis and ion leakage - Roughened surfaces though have ↑ ↑ success rates, better bone-implant contact, and ↑ stability

Bone Grafting = Surgical procedure to replace missing bone with material from patients’ body, artificial, synthetic, or another natural source/animal

- Bone can completely regenerate -> Replaces the graft material completely until the region is fully integrated new bone

Types of Grafts

Type Description

Allograft Bone from another individual (different genotype) but of the same species

Factor-based Natural and recombinant growth factors - TGF-β, Platelet derived growth factor (PDGF), Fibroblast growth factors (FGF), Bone Morphogenic Protein (BMP)

Cell-based Cells generate a new tissue alone or from on top of support matrix

Ceramic-based Ca(PO)4, Ca(SO)4 and Bioglass

Polymer- based Degradable or non-degradable polymers (open porosity polyacctic acid polymer)

Osteoconduction Osteoinduction Osteopromotion Osteogenesis

Definition Graft material acts as scaffold for new bone growth

Stimulation of osteoprogenitors to differentiate into osteoblasts and make new bone Bone Morphogenic Proteins = most studied osteoinducer Can have a material be both conductive and indictive

↑ osteoinduction without having osteoinductive properties itself

Vital osteoblasts from bone graft contribute to new bone growth

Examples Calcium Sulphate Ceramics Calcium Phosphate cements Collagen Bioactive Glass Synthetic Polymers

Demineralized bone matrix Bone morphogenic proteins (BMP) Growth Factor Gene Therapy

Enamel Matrix Derivative - Emdogain = amelogenin from

pigs. Used successfully to repair bony defects in periodontal disease

Bone Marrow Aspirate - Taken from iliac crest

bone

Medication-Related Osteonecrosis of the Jaw (MRONJ) Definition Adverse drug reaction consisting of progressive bone destruction (of jaw) in patients under current or previous

treatment with antiresorptive and antiangiogenic meds - Very challenging to treat

Diagnosis if ALL are present:

1. Current or previous Tx with antiresorptive or antiangiogenic agents 2. Exposed bone, or bone probable through intra/extraoral sinus/fistula for > 8weeks

- Sinus = internal to external surface communication - Fistula = 2 outside surfaces communicating

3. No Hx of radiation therapy to jaws or obvious metastasis to the jaw (Osteoradionecrosis of jaw is different)

Avascular Necrosis

= Death of bone tissue due to lack of blood supply (aka osteonecrosis) -> leads to tiny breaks in bone until it eventually collapses

- Blow flow can be interrupted from bone fracture or dislocation

Phossy Jaw -> Historical, not really a thing anymore

= Chronic exposure of phosphorus vapour = phosphorous deposition in the jaw -

> Bone dies, painful toothache and gum swelling

- Jaws rot away and glow green in the dark (not sure if the glow in the

dark jaws is Matthews fucking with us…but just in case)

Management: Excision of affected jaw, otherwise death

MRONJ Staging Treatment

At Risk - No apparent necrotic bone

No tx Patient Education

Stage 0 - No clinical evidence of necrotic bone, but non-

specific clinical findings exist, radiographic changes & symptoms

Systemic management: Pain meds and antibiotics

Stage 1 - Exposed necrotic bone or fistulae that probes

to bone - Asymptomatic and no infection

Antibacterial rinses (Chlorhexidine) Quarterly clinical follow ups Patient education Review indications for continued bisphosphonate use

Stage 2 - Exposed necrotic bone or fistulae that probes

to bone - Infection evidenced by pain and erythema in

region of exposed bone - W or W/O purulent drainage

Symptomatic Tx with antibiotics + Mouth rinses Pain Control Debridement to relieve soft tissue irritation Infection control

Stage 3 - Exposed necrotic bone or fistulae that probes

to bone - Infection evidenced by pain and erythema in

region of exposed bone and one of the following:

- Necrotic bone beyond alveolar bone resulting in pathologic fracture

- Extra-oral fistula - Oral nasal communication - Osteolysis extending to inferior border of

mandible or sinus floor

Mouth Rinses and antibiotic therapy Pain control Surgical debridement/resection for long term palliation of infection and pain

Musculoskeletal Pharmacology

Muscle Relaxants

1. Choline + Acetyl CoA = Acetylcholine

2. Action Potential stimulates Ach containing vesicles to release

contents into synapse.

3. 2 Ach molecules bind muscarinic receptor to cause conformational

change

-> Allows Na+ to flow in and depolarize muscle cell

4. Depolarization of the muscle cell propagates AP and stimulates

contraction pathway

Neuromuscular Blocker - Produce paralysis by being structurally similar to acetylcholine

2 Types:

1. Depolarizing Blockers

2. Non-depolarizing Blockers

Depolarizing Blocker

Drug Succinylcholine (only clinically useful one)

MOA Agonist at nicotinic acetylcholine receptors -> Open channel, enzymes have issues breaking it down -> Prolonged Depol. Phase I Block (depolarizing):

- Succinylcholine binds to nic. Receptor to open ion channel -> Na enters cell -> transient muscle contraction (twitching)

- Not metabolized well @ synapse -> prolonged depolarization -> unresponsive to nerve impulses = flaccid paralysis - Cholinesterase inhibitors prolongs depol. even longer

Phase II Block (Desensitizing): - After prolonged succinylcholine exposure, depol ↓ and membrane can repolarize - Subsequent depol is hard to achieve -> has become desensitized (possibly refractory period)

Clinical Uses Surgery (relaxes muscles to make suturing easier) Tetanus Electroconvulsive therapy -> drug prevents spasm Laryngospam

Adverse Effects

Arrythmias Hyperkalemia Transient ↑ in intra-abdominal and intraocular pressure Post-op myalgia Malignant Hyperthermia

Special Considerations

Has NO anaesthetic or analgesic effects - Make SURE anesthetic is working before using -> Won’t be able to see pain reflex twitching if anesthetic isn’t

working

Malignant Hyperthermia

Potential side effect when undergoing general anesthesia, can occur from Succinylcholine. - From genetic disorder of skeletal muscle

Many mutations associated: - RyR1 (Skeletal muscle ryanodine receptor) -> calcium release channel in Sarcoplasmic Reticulum - Mutated a1 subunit of skeletal muscle L-type voltage-dependent Ca channel

Clinical Findings - Muscle rigidity - Hyperthermia - Rapid onset tachycardia - Hypercapnia - Hyperkalemia - Metabolic acidosis

What is happening

↑ free cytosolic calcium concentration w/I skeletal muscle cells = Severe muscle contraction and ↑ Body temp

Treatment Dantrolene -> ↓ Ca release from sarcoplasmic reticulum -> via RyR1 receptor Control body temperature Restore electrolyte and acid-base balance

Centrally Acting Muscle Relaxation Drugs Clonazepam

Cyclobenzaprine

Dental Use ↓ Facial pain from muscle spasms associated with TMD Treatment of Trismus Muscle relaxation in General anesthesia

Adverse Effects Don’t give to elderly - Acts within the CNS -> can cause ataxia (↓ muscle coordination) = falling -> Thrombus -> Stroke -> Death

Non-depolarizing Blockers

Drug (-curonium)

Pancuronium Rocuronium Vecuronium d-tubocurarine

MOA Reversible competitive inhibitor of Nicotinic acetylcholine receptor - Experiences co-operative binding: ↑ concentration = more bind = more blocking - 2 Ach binding sites on the Ach Receptor

Effects Prevents depolarization by Ach - Causes flaccid paralysis

Clinical Application

Prolonged muscle relaxation for surgical procedures Relaxation of respiratory muscles to facilitate intubation and mechanical ventilation

Spasmolytics Spasticity = disordered sensorimotor control from upper motor neuron lesion

- Presents as intermittent or sustained involuntary activation of muscles - Causes stiffness or tightness of the muscles and can interfere with normal movement, speech and gait

Pathophysiology Stretch reflex arc involved - Upper motor neuron lesion causes damage to the descending pathway in

spinal cord (inhibitory/Excitatory interneuron) - Hyperexcitability of the α-motor neurons in the spinal cord

= ↑ in tonic stretch reflexes and flexor muscle spasm + Muscle weakness

Pharmacological Treatment Goal

↓ spinal “polysynapse” arc

Dental Uses Relieve Anxiety Treat post-procedure trismus Treat muscle spasms of head and neck

Spinal Cord Reflex Arc GABA Receptors in Spinal Cord

Monosynaptic arc Polysynaptic arc (withdrawl reflex)

Regulates speed and extent of muscle stretch Sensory muscle spindle fiber fires and sends signal through Ia Sensory neurons

- Signal transferred through gamma and alpha motor neurons

- Gamma transmits back to muscle spindle to moderate sensitivity to stretching

- Alpha transmits to striated muscle fiber to contract

This is what happens when the doc bangs your tendon with the little hammer and you kick up

1. Signal (pain) sensed with sensory receptor 2. Signal sent through afferent neuron to

integration center in spinal chord 3. Afferent synapses on Interneuron which

transmits signal through Efferent motor neuron to muscle (bicep for example) to cause contraction (pulling hand up off burner)

4. Interneuron also synapses on inhibitory neuron which sends signal through motor efferent to other muscles to cause relaxation (allowing recoil, tricep for example)

5. Interneuron also synapses on efferents sent to the brain so you can remember to not burn your hand off ** Inhibitory Interneurons release GABA to regulate the muscle contraction from the Efferent

Some good instruction

https://www.youtube.com/watch?v=6noV8AHcM6E

GABAergic Agents -> Acts on Efferent Neuron

Benzodiazepine (Diazepam, Midazolam, Lorazepam)

MOA GABAA Agonist

(Ligand gated Cl channel) - Binds to allosteric site on GABAA ↑ ability of GABA ligand to bind and cause change in shape - Cl- flows in causing hyperpolarization with its –‘ve charge - ↓ response to action potential

Effect Potentiates neural inhibition mediated by GABA -> still need GABA to bind and cause effect though

Baclofen

MOA GABAB Agonist (G-protein coupled linked to K channels)

- Binds GABAB causes signal to open up K+ channels

- K+ flows out of the cell causing hyperpolarization - ↓ response to action potential

Results in Hyperpolarization by: 1. Closure of pre-synaptic Ca channels 2. ↑ post synaptic K conductance 3. ↓ dendritic Ca++ influx **Causes a ↓ in excitatory transmitter release**

Effect Suppression of la sensory afferents, spinal interneurons, motor neurons

Common Uses Alleviating spasticity of MS and spinal cord injury Treatment for trigeminal neuralgia

Drug Interactions ↑ Effect of Baclofen - Benzodiazepines - Antihypertensives - Opioid analgesics

↓ Effects of Baclofen - Lithium

Considerations May ↑ seizures in epileptic patients -> slowly taper off drug Use cautiously in renal impaired patients Can cause drowsiness, ataxia, and confusion -> caution with elderly Sudden withdrawal associated with hallucination and tachycardia

Tizanidine -> Acts on Afferent Neuron

MOA Adrenergic α2 agonist (mechanism unknown)

Effects Reinforces pre- and post-synaptic inhibition within spinal cord to ↓ spasticity - Inhibits nociceptive transmission in spinal dorsal horn (↓ release of Ach and Norepinephrine)

-> Pain reflex (recoil after putting your hand on hot thing)

Uses Treatment of myofascial pain in head and neck

Dental consideration Additive effects when used with other CNS depressants Oral contraceptives -> ↓ tizanidine clearance by 50% (↑ duration of effects) ↑ levels of antihypertensive drugs DON’T USE with other Adrenergic α2 agonist

Other Centrally Acting Anti-Spasmolytics

Dantrolene

MOA Acts on skeletal muscle by ↓ Ca released from the SR (blocks RyR1 ryanodine receptor) - Doesn’t act in the CNS (unlike the others mentioned above)

Clinical uses Treats malignant hyperthermia Treats spasm from cerebral palsy, spinal cord injury and MS

Cyclobenzaprine (Flexeril)

MOA Unknown (thought to act in the brainstem) - Structurally related to tricyclic antidepressants -> produces anti-muscarinic effects

Dental Use Treats muscle spasm associated with TMJ pain

Adverse Effects Drowsiness and malaise, Tachycardia/dysrhythmia ↑ effects of alcohol, barbituates and CNS depressants

Contraindications DO NOT TAKE with - Monoamine oxidase inhibitors, - Hyperthyroidism - CHF - Recent MI - Dysrhythmias

Musculoskeletal Toxins Botulinum Toxin - Botox

The heck is it? Neurotoxin from Clostridium botulinum

MOA Cleaves fusion proteins in nerve endings - Prevents Ach release by interfering with vesicle fusion - No Ach = no contraction

Effects Flaccid paralysis

Clinical use Treatment of spams from cerebral palsy, MS, overactive bladder, migraine

Others

Mg2+ ions, Co2+ ions, aminoglycosides, Hemichollrium

Rheumatology and Osteoporosis Drugs

Osteoarthritis and RA Osteoarthritis Rheumatoid Arthritis

What is it Progressive disorder affecting weight bearing, diarthrodial joints

Chronic progressive inflammatory disorder

Characterizations Deterioration of articular cartilage Osteophyte formation Pain Limited mobility and disability Deformity Usually Unilateral

Polyarticular symmetric joint involvement Systemic manifestation Usually Bilateral

Pathophysiology 1. Tissue damage from mechanical injury 2. Inflammatory mediators first stimulate chondrocyte

repair (↑ proteoglycans and collagen) 3. Prolonged inflammation stimulates enzymes to degrade

cartilage: - Joint space ↓ with pain and deformity - Exposed bone becomes sclerotic - Bony repair causes subchondral sclerosis and

osteophytes at joint margin - Periarticular tendons and ligaments become

stressed = tendinitis - ↓ mobility in joints and ↓ muscle support

Autoimmune reaction within joint - Chronic inflammation causing erosion of cartilage and bone

Trigger causes inflammation (unknown)

-> Macrophasges release pro-inflammatory cytokines (TNF, Il1, TL6)

-> Cytokines also stimulate the Fibroblast-Like Synoviocytes (FLS) liking the

joint to proliferate and activate.

• FLS secrete RANKL to stim. Osteoclast = bone erosion, and Proteases to

break down cartilage

• FLS migrate between joints -> this is how it is symmetrical

-> T-Cells recruited to joint and release proinflammatory cytokines

-> Plasma Cells also release inflammatory cytokines and Ab

-> Neutrophils in synovial fluid release proteases and reactive oxygen

species -> damage cartilage

Find Angiogenesis in these joints -> increases the delivery of WBC to area

Predisposition to the disease found in:

- Genes (HLA) - Inflammation in Joints

- Smoking

Predispositions -> Modify auto-antigens (Citrullination) = now seen as foreign

= activates immune system. Plasma cells produce auto-antibodies.

• Rheumatoid Factor: IgM antibody (targets Fc portion of IgG) -> immune

complexes deposit in joint

• Anti-Citrullinated Protein Antibody: Target Citrullinated proteins

(created as above) -> Specific for RA Dx

Treatment Non-Pharma: - Educate & Weight Loss - Physical therapy (heat or cold + exercise) - Assistive devices - Surgery (osteotomy, arthroplasty)

Pharma: Oral Analgesics

- Acetaminophen (1st line), NSAIDs, Opioids Topical Analgesics

- Capsaicin cream (0.025% or 0.075%) - NSAIDs (diclofenac gel/patch)

Intra-articular corticosteroids - Triamcinolone - Methylprednisolone acetate

Antidepressants - Duloxetine (SNRI, not sure how helps pain

though)

_____________________DMARDS____________________ Methotrexates

- Cytotoxic folate antagonist (cancer tx) with immunosuppressant action. Inhibits Dihydrofolate Reductase in the production of folate during DNA repair or replication

- Associated with bone marrow suppression Sulfazaline

- Unknown MOA, thought to scavenge Toxic oxygen metabolites from neutrophils

- Bacterial in colon aid in activation through metabolism - Used in IBD and RA

Penicillamine - Hydrolysed penicillin - MOA unknown, thought to ↓ immune response and IL-1 production - Prevents maturation of collagen

Gold Salts - MOA unclear, anti-inflammatory effect develops over 3-4 months

_________________Immunosuppressants____________ Cyclosporine

- Found in fungi, has immunosuppressive action - ↓ Tcell activities by inhibiting Transcription and release of IL-2

Tacrolimus - Macrolide Ab from fungi - Similar mechanism to cyclosporine but ↑ potency

Azathioprine

- ↓ Purine synthesis -> ↓ clonal proliferation during immune response - Mercaptopurine (metabolite) = inhibits DNA synth.

Cyclophosphamide - Used in cancer tx mostly - Crosslinks DNA double helix to prevent cell division

Mycophenolate mofetil - Derived from fungi -> converted to mycophenolic acid = inhibit inosine

monophosphate dehydrogenase (needed for purine synthesis) - Inhibits proliferation of T and B cells

Leflunomide - Inhibits T cell activation

Glucocorticoids - Inhibits transcription factors = ↓ genes for IL-1, IL-2, TNFα and IFNγ

______________________Biologics_____________________ Infliximab and Adalimumab

- Anti TNF α to ↓ proinflammatory effects - Used when pt doesn’t respond to at least 2 DMARDs

Anakinra - Anti IL-1 - ANAKINra is an anti- interLUKEin 1

Basiliximab - IL-2 receptor antagonist on T-cells = ↓ T-cell

proliferation - Basilisk was an antagonist in Harry Potter 2

Dental Considerations

NSAIDs - ↑ Bleeding Risk

Gold Salts - Oral ulcers - ↓ WBC and platelets - Review lab tests prior to surgery

Penicillamine D - ↓ WBC and platelets - Drug induced pemphigus with oral lesion or nephrotic syndrome - Dysgeusia

Infliximab - Thrombocytopenia - Anemia - Hemolytic anemia

Gout What is it? Abnormality in uric acid processing = ↑ Uric acid = precipitation of uric acid crystals in joints

Characterization Hyperuricemia Recurrent attacks of acute arthritis w/ mono-sodium urate deposition in tissues and joints Interstitial renal disease

Non-Pharma Treatment Ice ↓ weight Dietary change to ↓ purine intake ↑ water ↓ alcohol (beer is worse, then spirits, wine is fineeee)

Pharma Treatment Acute Management - NSAIDs (NOT ASPIRIN) -> Aspirin ↓ renal excretion of uric acid - Corticosteroids - Colchicine

-> disrupts cytoskeletal function by inhibiting β-tubulin polymerization into microtubules = prevents activation and migration of neutrophils Side Effects: GI hemorrhage, kidney damage, bone marrow depression, peripheral neuropathy

Prophylaxis Management Allopurinol

- Competitive inhibitor of xanthine oxidase (enzyme involved in production of uric acid) Side Effects: - GI disturbance, Stevens-Johnson syndrome

Febuxostat - Similar to Allopurinol

Probenecid and Sulfinpryazone - Uricosuric agents -> ↑ renal excretion of uric acid by inhibiting its reabsorption - Must drink ↑ water - Less effective and more toxic than allopurinol (only for patients who can’t handle allo)

Pegloticase and Rasburicase - Recombinant urate-oxidase enzyme -> converts uric acid to allantoin = non-reactive metabolite - Allantoin excreted more readily

Myopathies What is it? Neuromuscular disorder resulting in muscle weakness from dysfunctional muscle fibres

Signs and Symptoms Muscle Cramps Stiffness Spasms

Etiology Inherited - Muscular dystrophies - Inherited biochemical defects

Acquired - Immunologically mediated (SLE, RA) - Non-inflammatory (Hyperthyroidism, diabetes, electrolyte imbalance) - Toxic myopathies (Alcohol induced, protein malnutrition, drug induced) - Infection (HIV, Coxsackie virus, influenza)

Treatment Non-Pharma - Genetic counseling - Surgery - Physical aids - Family support - Dietary advice

Pharma For spasity

- Baclofen For Cramps

- Phenytoin Idiopathic Inflammatory

- Glucocorticoid - DMARDs - Biologics

Osteoporosis Bone disorder characterized by:

- ↓ density

- Impaired bone architecture

- Compromised bone strength predisposing to fragility fractures

Pathophysiology = Bone resorption > Bone formation

- Starts at 35 years old

- Estrogen deficiency during menopause ↑ osteoclast activity -> accelerates OP 10 fold

- Age related OP comes from ↓ Ca, ↓ Vit. D. -> ↓ Osteoblast

Tx:

Non-Pharma Pharma

- ↑ Ca and Vitamin D - Limit alcohol to 1 drink/ day women, and 2/day men - Limit Caffeine - Stop Smoking - ↑ weight bearing aerobic and strengthening activities

Anti-resorptive Bisphosphonates Selective Estrogen Receptor mods Denusomab (Biological) Calcitonin

Anabolic Agents Parathyroid hormone and teriparatide Strontium

Bisphosphonates

Drugs (-dronate)

Alendronate Ibandronate Risedronate Zoledronic Acid

Effects Bind with Ca2+ in bone and release when bone is resorbed by osteoclasts -> creates high [local] of bisphosphonates

- ½ life: 10 years! -> hard to get out of patients body

MOA 1st Gen: - Similar to pyrophosphate = promotes apoptosis of osteoclasts

2nd Gen: - ↑ potency over 1st gen - Bind cell surface proteins of osteoclasts -> prevents osteoclast attachment to bone - Also induces apoptosis

Estrogen

Effects

Raloxifene (Selective estrogen receptor Modulator)

Stim osteoblast and inhibit osteoclast - Straight E is antagonist on mammary tissues and uterus though -> ↑ risk of endometrial and breast

cancer ↑ bone density w/o risk of endometrial or breast cancer

- ↓ total and LDL cholesterol too!

Parathyroid Hormone (Teriparatide)

Effects Stimulate and proliferate Osteoblasts to ↑ bone formation

Side Effects Nausea Dizziness Headache Arthralgias Mild hypercalcemia Transient orthostatic hypotension Leg Cramps

Biologics (Denosumab)

MOA Monoclonal Ab -> Targets RANKL - Inhibits osteoclast formation and activation

Side Effects Altered Bowel Habits Dermatological reactions (rash) Hypocalcaemia Osteonecrosis of the Jaw ↑ infection risk

Calcitonin

What is it? Peptide hormone from thyroid follicles -> C cells

MOA Inhibits bone resorption by binding to inhibitory receptors on osteoclasts

Strontium

Effects - Inhibit bone resorption AND stimulate bone formation - Prevents vertebral and non-vertebral fractures in old ladies

MOA Stimulates Ca-sensing receptor -> ↑ Pre-osteoblasts differentiating into osteoblasts - ↓ osteoclasts

Medication Related ONJ (Osteonecrosis of the Jaw from Bisphosphonates/meds)

Drugs of Concern IV or Oral bisphosphonates Denosumab (biologic) – RANKL inhibitor

Pathophysiology Inhibits Osteoclastic remodeling of bone (healing bone from surgery or damage) -> ↓ clearance of damage and infection - Mandible affected the most -> ↓ blood in cortical bone so it’s harder to heal

Risk Factors - Many variables makes it hard to

predict

Concomitant use with corticosteroids, or chemo Dental extraction, trauma or infection Being female Clotting disorders Arthritis Alcohol abuse Smoking Malnutrition Bony exostosis Periodontal disease

May have MRONJ if ALL are present:

1. Current or previous tx w/ antiresorptive or antiangiogenic agents 2. Exposed bone, or probable bone through intra or extra oral fistulae for 8+ weeks 3. No Hx of radiation therapy to jaws or obvious metastatic disease in jaw

Avoiding MRONJ Avoid elective Tx that will require bone healing Provide routine clinical dental exams Perform invasive procedures PRIOR to bisphosphonate therapy begins Perform dental prophylaxis, caries control and stabilize restorative care Oral hygiene education is very important NO ANTIBIOTIC PROPHYLAXIS NEEDED

Management Consult with oral surgeon Minimal bony debridement -> reduce sharp edges to ↓ trauma on tissues Removable appliance to protect exposed bone

AAOMA Recommendations

Exposure to oral Bisphosphonates Recommendation

< 4 years, No clinical risk factors No alteration or delay in surgery needed

< 4 years, taken with corticosteroids or antiangiogenic meds Consider drug holiday for 2 months prior to surgery -> Physician has to make the call, consult

> 4 years, w/ or w/o other meds Consider drug holiday for 2 months prior to surgery -> Physician has to make the call, consult

- Anti-resorptive drugs should not be restarted until osseous healing occurred

Staging Treatment

At Risk - No apparent necrotic bone

No tx Patient Education

Stage 0 - No clinical evidence of necrotic bone, but non-specific clinical

findings exist, radiographic changes & symptoms

Systemic management: Pain meds and antibiotics

Stage 1 - Exposed necrotic bone or fistulae that probes to bone - Asymptomatic and no infection

Antibacterial rinses (Chlorhexidine) Quarterly clinical follow ups Patient education Review indications for continued bisphosphonate use

Stage 2 - Exposed necrotic bone or fistulae that probes to bone - Infection evidenced by pain and erythema in region of exposed

bone - W or W/O purulent drainage

Symptomatic Tx with antibiotics + Mouth rinses Pain Control Debridement to relieve soft tissue irritation Infection control

Stage 3 - Exposed necrotic bone or fistulae that probes to bone - Infection evidenced by pain and erythema in region of exposed

bone and one of the following: - Necrotic bone beyond alveolar bone resulting in pathologic

fracture - Extra-oral fistula - Oral nasal communication - Osteolysis extending to inferior border of mandible or sinus

floor

Mouth Rinses and antibiotic therapy Pain control Surgical debridement/resection for long term palliation of infection and pain

PBL 1 – Anna Wright

Physiologic Changes during Pregnancy System Change In Short

Cardiovascular - ↑ Blood volume to meet both maternal and fetal demands - Enlarged cardiac chambers & myocardial hypertrophy

- ↑ HR and Stroke Volume = ↑ Cardiac output (by up to 50%) - ↓ BP in 2nd and 3rd trimester

Dental Implication: - Hypotension may occur when patient is supine -> fetus compresses inferior vena cava and aorta

-> Left Lateral Decubitus position - ↑ Distribution Volume = ↑ dose of hydrophilic drugs to reach therapeutic concentrations - ↓ serum albumin = Other drugs may have to ↓ dosage b/c ↑ free drug concentrations

Eclampsia: - Only occurs during pregnancy and causes seizures late in pregnancy - Follows pre-eclampsia ↑ BP (can ↓ oxygenated blood to fetus)

↑ CO ↑ SV ↑HR ↓ BP

Respiratory - Diaphragm moves 3-4cm upwards (make space for fetus) - ↑ O2 consumption by 15%-20% - Progesterone stimulates ventilation by ↑ sensitivity to CO2 in respiratory center

- ↑ tidal volume to eliminate CO2 = ↑ minute volume - Nasal breathing may become difficult = mouth breathing = ↑ xerostomia

↑ Tidal Volume ↑ / Same Vital Capacity ↓ Residual Volume

Circulatory - ↑ Total blood volume (Plasma, WBC, RBC) - ↑ blood clotting (↑ all coagulation factors except ↓ factor XI, XIII)

-> ↑ D-dimer b/c clotting

↑ plasma volume ↑ RBC ↑ WBC ↑ Clotting

Gastrointestinal - ↓ esophageal tone = ↓ gastric emptying and intestinal motility -> ↑ gastric pressure - -> GERD - ↑ vomiting - ↑ heartburn - ↑ salivation when suffer from nausea and vomiting - ↑ estrogen = ↑ serum cholesterol globulins etc = altered pharmacokinetics - ↑ gastric pH = ↓ drug absorption

↓ Gastric Emptying ↓ GI motility ↑ Heartburn ↑ Vomiting ↑ Salivation

Renal - ↑ renal blood flow and glomerular filtration rate by 50-60% - ↑ creatinine clearance up to 50% - ↑ RAAS system = ↑ aldosterone

↑ Renal Blood flow ↑ GFR ↑ Creatinine clearance

Oral Lesions Associated with Pregnancy

Description Image

Aphthous Stomatitis (canker sore)

- Mostly during 3rd trimester -> exacerbation after delivery - Occurrence during menstruation suggests hormonal cause - Worsens when smoking is stopped (worth it doeeee)

Pyogenic granuloma - Red nodular overgrowth of granulation tissue - Typically, on gingivae, lips, tongue, buccal mucosa, palate,

vestibule - Most common is interdental papilla -> can cause diastema - Bleeds A LOT when cut out

Plaque -induced gingivitis

- ↑ by pregnancy and puberty

Morning Sickness Vs. Oral Heath - ↑ Vomiting, gagging, overheating

o Encourage to drink electrolyte rich fluids

o Provide fluoride treatment (varnish)

- Edema of the nose, oral cavity and larynx during pregnancy

o May lead to congestion resulting in mouth breathing -> Xerostomia

Fetal Risk with Drugs Drug Category

Description

A No risk at all in any trimester

B No risk to the fetus in any trimester

C Potential risk to fetus, but benefit of drug may outweigh risk

D Positive evidence of fetal risk, but benefit of drug may outweigh risk

X Definite evidence of fetal abnormalities, drug DOESN’T outweigh risk

N Unclassified drug

Dental Considerations Procedure Recommendation

Radiographs THEY ARE FINE (with usual precautious: lead shield, thyroid guard etc) - We don’t take radiographs low enough to be cause for concern - Most concerned in 1st trimester, but again our dose and location don’t pose risk - ALARA principle is the gospel!

Local Anesthetic ALSO FINE (unless other contraindications with the patient exist of course)

IV Sedation Benzodiazepines - Px for: Anxiety, insomnia, seizures, muscle spasms, alcohol withdrawal etc - Category D drug -> Avoid during pregnancy

- Implicated in cleft lip and palate

Nitrous Oxide - Used for conscious sedation - ↓ Folate production -> Vital for DNA production in fetus - AVOID during 1st trimester (Safe in 2nd and 3rd trimester though)

General Anaesthesia - Can cross placental circulation - AVOID near time of delivery -> impairs infant’s breathing

Analgesics for the Pregnant

Drug FDA Class Recommendations

Aspirin C Short Duration use Avoid in 1st and 3rd trimester and if breastfeeding

Acetaminophen (Tylenol)

B Choice analgesic!

Ibuprofen B/D Short Duration use (no longer than 48-72hrs) Avoid in 1st and 3rd trimester Ok with breastfeeding Category D in 3rd trimester

Naproxen B Short Duration use (no longer than 48-72hrs) Avoid in 1st and 3rd trimester Ok with breastfeeding

Codeine C Ok with breastfeeding In high maternal doses can cause infant drowsiness and depression

Morphine B/D Category D with prolonged use In high maternal doses can cause infant drowsiness and depression

Meperidine B/D Ok with breastfeeding Category D with prolonged use

Percocet C Opioids may cause physical dependence in neonates Respiratory depression may occur in newborn if opioids used prior to delivery

PBL 2 – Sigma Chi-Guy

Bruxism = involuntary habitual grinding of teeth.

2 circadian manifestations:

Sleep Bruxism Awake Bruxism

- More common than awake - 5-8% in adults, 10-20% in children, 3% in elderly - In children develops during “teething” when first teeth erupt

Risk Factors:

- Smoking - Caffeine - Illicit Drugs (cocaine or other stimulants) - Anxiety

Clinical Features based on self-report, partner report, clinical observation

- Possibly from emotions: Anxiety, Stress, Anger, Frustration

- Coping strategy or habit during deep concentration

Underlying Issues

Issue Description

Stress Sometimes not even consciously done or recognized. Making them aware can often help during awake bruxism (STAY WOKE)

Anxiety 70% of cases associated with stress or anxiety (affects people during sleep)

Sleep Disorders Obstructive Sleep Apnea = ↑ risk of grinding

Drug Induced Linked to Selective Serotonin Reuptake Inhibitor (SSRI) use -> Anti-anxiety/depression

Lifestyle Drinking and smoking ↑ risk Recreational drug use (ecstasy and cocaine, crystal meth. especially) Caffeine (6+ cups a day)

Psychological and Psychiatric disorders

Associated with ADHD

Demographic Young age = ↑ prevalence

Temporomandibular Dysfunction Masseteric Hypertrophy

- = most probably congenital, genetically determined anomaly

- Doesn’t necessarily need to be treated, unless for esthetic concerns

- Treated mostly with Botox

- Associated with TMD and bruxism, but not necessarily cause and effect

Symptom Differential Dx

Teeth Grinding Odontogenic infection

Persistent Headache Migraine Tension headache Temporal arteritis

Jaw/ear discomfort Ear infection Gout/pseudogout Mandible dislocation Mandible fracture

Tension/discomfort in neck, shoulders, upper back

Myopathy

Signs and Symptoms of Bruxism:

- Teeth grinding/clenching - Indentations on Tongue

- Flattened, fractured, chipped or loose teeth - Dull Headache in temples

- Worn enamel - Earache-type pain (no ear probs)

- ↑ sensitivity - Tired/Tight jaw muscles

- Jaw or facial soreness

Muscles of Mastication and Facial Expression

Muscle Origin Insertion Innervation Function

Mastication

Temporalis Temporal fossa and fascia Medial side of coronoid process and

anterior side of the ramus of mandible

Mandibular nerve V3

Elevation

Retraction

Masseter Zygomatic arch Lateral surface of the ramus of

mandible

Elevation

retraction

Medial pterygoid Deep head: medial surface of

lateral plate of pterygoid process

Superficial head: maxilla and

palatine bone

Medial surface of angle of mandible

Elevation

Side to

side

Lateral pterygoid Upper head: greater wing of

sphenoid bone

Lower head: lateral surface of

lateral plate of pterygoid process

Articular disc of TMJ and pterygoid

fovea on neck of mandible

Protrusion

Side to

side

Digastric

Muscle Origin Insertion Innervation Function

Facial Expression

Frontalis Galea aponeurosis Galea aponeurosis Facial (temporal branch)

Orbicularis Oculi Frontal and maxillary bone

Facial

Orbicularis Oris Fibers from other mouth muscles

(buccinatory)

Skin along the mouth Facial (buccal and

mandibular branches)

Zygomaticus major Zygomatic bone

Facial

Zygomaticus minor Zygomatic bone Lateral upper lip

Buccinator

Platysma

Pterygomandibular raphe

Alveolar margins of the maxilla and

mandible

Subcutaneously near clavicle

Some fibers blend and provide origin

for the orbicularis oris

Some fibers blend into the upper and

lower lips

Inferior border of mandible

Facial

Facial

Trismus = Limited Mouth Opening

Causes Info or something

Infection Odontogenic - Pulpal, Periodontal, Pericoronal

Non-odontogenic - Tetanus, Meningitis, Parotid abscess, Peritonsillar abscess, Septic arthritis

Dental Treatment Inflammation to muscles of mastication Trauma to TMJ during extractions Injection of LA into Medial Pterygoid

Trauma Fractures - (mandible, zygomatic arch especially)

TMJ Disorders Extra-capsular disorders - (myofascial pain dysfunction syndrome)

Intra-capsular problems - (Disk displacement, arthritis, fibrosis)

Acute closed locked conditions (displaced meniscus)

Cancer Rare but possible

Drugs Succinylcholine (strange…this is a muscle relaxant) Phenothiazines Tricyclic anti-depressants known to cause trismus

Radiotherapy Fibrosis of muscles of mastication when within field of radiation

Medial Ptyerygoid Haematoma

- Caused by damage to medial pterygoid muscle (bent needle tip in this case)

- More common in older patients. 2-5 days after mandibular block given

- LA injection directly into MP muscle can cause myotoxic reaction leading to necrosis

- Hematoma in the muscle can lead to fibrosis -> trismus

- Management: Hot packs (20mins every hour), stretching with wooden spatulas, analgesics as required

Osteomyelitis

= infection of the bone

Radiographic findings Initially soft tissue changes: - Muscle swelling and blurring of soft tissue planes

1st changes in bone indicate infectious process present for 2-3 weeks + - Extends 1cm and compromises 30-50% to produce noticeable changes in radiographs - Early changes not obvious until 5-7 days in kids or 10=-14 days in adults

Bony changes:

- Periosteal thickening - Lytic lesions - Endosteal scalloping - Osteopenia - ↓ trabeculations

** If patient doesn’t feel right, need to see them right away or could have a lawsuit**

PBL 3 - Bettina

Smart BMI Differs from the traditional BMI in 3 ways:

1. Takes Age and Sex into account in addition to the weight and height

2. Purely comparative (no physical units) on a scale /70

3. Can relate to your health whereas BMI cannot

SBMI Assessment Risk Level

0/70 – 9/70 Extreme Anorexia Red

10/70 – 19/70 Anorexia to underweight Orange

20/70 – 29/70 Moderate to slight underweight Yellow

30/70 – 39/70 Normal Weight Green

40/70 – 49/70 Slight to Moderate Overweight Yellow

50/70 – 59/70 Overweight to obese Orange

60/70 – 70/70 Extreme Overweight Red

Bones Functions Facial Skeleton

- House and protect brain, organs of smell, sight, and taste - Provide framework for muscles of mastication, facial expression, breathing, and speech to function on

In General: - Haematopoiesis -> Red bone marrow (Axial Skeleton, Pectoral Girdle, Pelvic Girdle, Proximal of humerus and

femur bones) - Lipid and Mineral storage - Shape and framework for the body - Resist compressive forces

Characterizations

Appearance Bone Type

Gross Appearance Flat - Skull, Pelvis, Scapula

Long - Axial Skeleton

Macroscopic Appearance

Compact/Cortical - Mature bone, Flat bones, Shaft of long bones - Dense and solid, surrounds marrow space - Entire mandible is bicortical

Spongy/Trabecular

- Early bone, interior of extremities/epiphysis of long bone - Honeycombed network of trabecular plates and rods within the marrow component

Development/ Formation Intramembranous - Direct formation of mesenchyme - Flat Bones

Endochondral - From a cartilage model - Long Bones

Regions Diaphysis - Shaft

Metaphysis - Transition of shaft leading to growth plate zone

Epiphysis - Extremities of long bones

Microstructure Embryonic/Woven - Irregular collagen network

Lamellar - Collagen arranged in concentric layer (like rings of a tree)

Disposition of lamellae Circumferential - Periosteal and industrial surfaces

Osteonic - Concentric lamellae forming osteons (new bone)

Interstitial - Residual fragments between newly forming osteons (older bone)

Types of Osteons Primary - 1st formed Haversion systems consisting of poorly organized lamellae

Definitive - Higher ordered osteons after the remodelling of primary osteons

Elderly Injuries Falling Hypertension Drugs are common causes of falling

- Vasodilators, diuretics, certain CCB’s exacerbate postural blood pressure changes -> orthostatic hypotention = light headedness and falling

β-blockers, ACE inhibitors, Angiotensin-receptor antagonists are safer to prevent falling

Bruising/Contusion Occurs when there is a subcutaneous or submucosal haemorrhage without breaking the skin - From trauma or body damage rupturing blood vessels under skin

Elderly prone to bruising (↓ force required to cause one) - ↓ elasticity of the vasculature making vessels more fragile

Saggy/wrinkly skin -yummm

Moisture retention of skin ↓ making it dry, scaly and wrinkled Skin loses elasticity also = sagging

Mandible Fracture Types

Simple Closed linear fractures (condyle, coronoid, ramus, edentulous body of the mandible) - Single break, no bone exposure

Compound

Fractures of the tooth bearing portions of the mandible, protruding into the mouth via periodontal membrane - Rare, but can also expose through the skin - May cause a step in the arch

Comminuted

Often a compound fracture, but with multiple pieces of broken bone, not 1 single break

Pathological A break resulting from a weakened mandible (ONJ, Bone Cysts etc)

Condyle is most frequently broken > Angle / Body > Parasymphysis > Ramus > Coronoid Process

Favorable Fractures Occur in a direction where the pull of the muscle of mastication do not displace the 2 ½’s of the break. - Horizontal: In relation to the upward pull of the masseter - Vertical: In relation to the medial pull of the mylohyoid, digastric etc.

Unfavorable Fractures Occurs in a direction thast the pull of the muscles of mastication separates the 2 halves of the break - Horizontal: In relation to the upward pull of the masseter - Vertical: In relation to the medial pull of the mylohyoid, digastric etc.

A: Horizontally Unfavorable B: Horizontally Favorable C: Vertically Unfavorable D: Vertically Favorable **The “vertical and horizontal” classifications seem counter intuitive. The name doesn’t refer to the direction of favourability as much as it refers to the plane at which the fracture is viewed** - A and B are viewed from the side (horiz.) - C and D are usually viewed from above (Vert)

Management of the fracture

Reduction Placing the fractured fragments in the correct alignment - Closed Reduction: No surgical intervention. The tissues remained closed - Open Reduction: Surgical access used to expose the bone. Tissues were opened

Essential to place in relation to the mandible to recreate the normal occlusal relationship Approximated reduction puts the fragments close to each other, but not directly in contact to allow “indirect fracture healing”

- Both endochondral and intramembranous bone healing occurs, enhanced by micro-motion and weight bearing

Fixation Holding/fixing the bony fragments in position once reduction is complete Maxillomandibular Fixation:

- Wiring the Max. and Man. together - Good to keep occlusal relationship - Very uncomfortable for the patient - Liquids only - Must educate the patient on how to cut the wires or elastics off in case of vomiting!

Rigid Internal Fixation: - Screws and PLastes - If the direction of the break allows, the 2 pieces can be screwed together - An overlying plate can be screwed on to hold pieces together -> Used in comminuted fractures with many fragments.

Stages of Fracture Healing

Secondary Bone Healing -> Micro movement present, bones not screwed or fixed solidly in place, large gap between segments

Immediately after break

Haematoma formed (cells of peripheral and intramedullary blood, bone marrow cells) - Initiates inflammatory response -> Clot forms between and around the fracture pieces and within the medulla

= Template for callus formation

Within 48 Hours Chemotactic molecules attract more inflammatory cells Blood clot provides fibrin mesh to seal fracture site & provide framework for inflammatory cells fibroblasts and new capillaries Platelets + Inflammatory cells -> release PDGF, TGF-β̛, FGF etc = Activates osteoprogenitor cells and stimulate osteoblasts and osteoclasts

Early Fibroplastic Stage

Occurs if fractured ends are >1mm apart - Large amounts of collagen have to be laid down to bridge the gap first

Osteoprogenitors differentiate and proliferate into osteoblasts, clasts and chondroblasts, capillary budding begins

End of Week 1 Matrix production in adjacent tissues and fractured ends of bone start remodeling Fibroblasts and chondroblasts produce ECM of fibrous tissue and cartilage where woven bone can be deposited by osteoblasts -> Soft Tissue Callus

- Provides anchorage between ends of bone (but isn’t rigid for weight bearing)

End of Week 2 Soft Tissue Callus turns into bony callus - Woven bone is first to be laid down - Mesh of woven bone replaced by lamellar bone organized parallel to the axis of bone

Osteoprogenitor cells deposit subperiosteal trabeculae of woven bone (perpendicular to cortical axis) within the medullary cavity

Late Fibroplastic Stage

Osteoclasts resorb necrotic bone - Areas of ↑ O2 tension: Osteoblasts deposit bone - Areas of ↓ O2 tension: Chondroblasts lay down cartilage

Capillary and Callus growth continues

End of Week 3 Bony callus reaches largest girth -> helps stabilize fracture - Will be able to feel for 3-4 months until the fragments are firmly united by new bone

New cartilage along fracture line undergoes endochondral ossification to form bone w/ trabeculae in medulla and beneath periosteum

Final Stages Bony union is achieved when fracture site is completely bridge with woven bone (the first bone to go down) - w/ functional stresses (Wolff’s law) callus is remodelled to form mature lamellar bone

Fully healed Initial stages of bony healing lasts about 6 weeks

Primary Bone Healing -> Absolute Rigidity of 2 pieces is achieved by screwing or plating the 2 pieces together is tight approximation

- <200nm -> Lamellar bone is directly formed in gap

- >200nm – Woven bone fills gap and is replaced with lamellar bone

A good video!

https://www.youtube.com/watch?v=MNkI6Of2PRs

After-care treatment of fractures Emergency Release of Wires Teach patient how to release the MMF in case starts choking or vomiting

- Can give wire cutters or use elastics instead of wires

Radiographs Postop radiographs taken within first days post-surgery and prior to removing MMF

Follow-up Check stability of occlusion and infection 1 week after surgery - Periodically check oral hygiene and signs of infection

Physiotherapy Mandible will be hypomobile after MMF with atrophic and tight muscle - Opening and excursive exercises should be Rx - If has trismus can use a Therabite device (super expensive), or

just stack popsicle sticks between teeth to force mouth open

Speech Patient should speak as freely as possible to ↑ range of jaw motion and provide the micro-motion necessary to ↑ healing of the jaw

Oral Hygiene Rx Chlorhexidine rinse used 3x/day Use a waterpik and sulcabrush to clean between teeth and toothbrush for buccal surface

Bone Remodelling Complex process controlled by hormones (Leptin and serotonin) from the CNS and by mechanically induced micro-damage

- Depends on Basic Multicellular Unit of Bone (Osteoblast, Osteoclast, Osteocyte) -> BMU

Wnt family of molecules/genes regulates differentiation of pluripotent mesenchymal stem cells into the osteoblastic lineage and ↑ osteoblastic

bone formation

Factors Influencing Remodeling

Type of fracture Displaced, or comminuted fractures have delayed union because must bridge a larger gap during healing. - Any soft tissue trapped between bone ends can prevent union completely

↑ Mobility at fracture site Too much mobility interferes with vascularization of the fracture haematoma -> ↑ strain and disturbing bridging callus

Age Kids bones remodel and unite faster than older patients

Nutrition and Drugs ↓ nutrition, long term corticosteroids and NSAIDs can impair inflammatory response and delay fracture healing

Infection ↓ healing due to prolonged inflammatory phase

Smoking This is generally always bad…just don’t do it…you don’t look cool...and no one wants to kiss you

Response to loading occurs via mechano-transduction where mechanical forces are converted to biochemical signals (Integrins do the sensing of

the ECM)

- Trabecular bone first resorbed by osteoclasts -> creates a shallow pit called “Howship’s Lacuna”

- Osteoblasts then deposit compact bone within the lacuna

Stages

Phase Description

Resorptive Phase

Osteoclasts from bone marrow monocytes resorb discrete area of bone matrix

Reversal Phase Osteoprogenitor cells proliferate and differentiate into osteoblasts

- Migrate to the resorption lacuna to stop osteoclast activity

Formative Phase

Osteoblasts deposit new bone -> initially unmineralized and called “ostia weight”

- Eventually mineralizes and surrounds osteoblast into an osteoid

Resting Phase Once embedded in osteoid osteoblasts mature into osteocytes - Osteoblasts lying on the surface lay dormant until

activated

PBL 4 – Jackie Falls

Osteoporosis Overview Primary Secondary

Females predominantly - ↓ estrogen after menopause - Faster bone loss in general

Caused by chronic medical conditions - Endocrine disorders (hyperthyroidism) - Intestinal Disorders (↓ Vit. D and Ca++ absorption) - COPD - Hypogonadism - Multiple Myeloma

Risk Factors Modifiable Non-Modifiable

↓ Estrogen/Testosterone ↓ Ca++ & Vitamin D Inactive Lifestyle Excessive Alcohol Cigarette Smoking Hyperparathyroidism Hyperthyroidism Malnutrition (Malabsorption or Diet) Steroids or Cushing’s Syndrome Proton Pump Inhibitors (↓ Ca++ absorption)

↑ Age Low BMI Ethnicity (White>Asian>Black) Family Hx Rheumatoid Arthritis

Secondary Causes

Misc. -> Most common causes - Alcoholism - Smoking - Organ transplant - COPD - End-stage renal disease - Immobilisation

Endocrine - Hypogonadism - Type 1 Diabetes - Cushing’s Syndrome (Excess steroid) - Hyperthyroidism

Ca++ imbalance - ↓ Ca intake - ↓ Vitamin D - Hyperparathyroidism

GI - Coeliac disease - Bariatric surgery (stomach/intestine weight loss

surgery) - IBD - Malabsorption - End-stage liver disease

Haematological - Multiple Myeloma - Sickle-cell - Thalassaemia - Haemophlia - Leukaemia - Lymphoma

Genetic - Osteogenesis imperfecta - Ehlers-Danlos (Collagen disorders) - Marfan syndrome - Cystic fibrosis

Medications - Glucocorticoids - Anticonvulsants (phenytoin) - Heparin - Cytotoxic drugs (methotrexate) - Immunosuppressants (tacrolimus, cyclosporin)

Rheumatological - Ankylosing spondylitis - Rheumatoid Arthritis

Screening DEXA scan - Dual Energy X-ray Absorptiometry -> 2 photons released from X-ray tube to give precise measurements at important sites - Measures bone mineral density and is the best predictor of fracture risk - Woman 65+ should get this scan done and men 70+

T-score - Post menopausal women - Determine if has OP Normal T-score: > -1.0 Osteopenia: -1.0 - -2.5 Osteoporosis: <-2.5 Z-Score

- Premenopausal Women - Determines BMD relative to healthy young controls FRAX – Fracture Risk Assessment X

- Assesses Age, Gender, BMI, Fracture Hx, Current Smoking, Glucocorticoid use, and Rheumatoid Arthritis Hx

Prevention Adequate Nutrition (Ca and Vitamin D specifically) Weight Bearing exercise Stopping Smoking Discourage Alcohol Abuse ↓ Falling risks Hip Protectors

Treatments Bisphosphonates Denosumab (Biologic, anti-RANKL antibody) Teriparatide (Synthetic Parathyroid Hormone -> Stimulates osteoblasts) Selective Estrogen Receptor Modulators (SERMs) Hormone Replacement Therapy

Fragility Fracture

= Any fall from standing height or less that causes a fracture (when it shouldn’t normally)

- Commonly Hip, Spine, Wrist

Factors Leading to Fracture

Vertebral Fractures Compression fractures can vary from Mild Wedge fractures to complete compression - Varying degrees of pain, can be almost asymptomatic is a slow insidious onset

Dorsal Kyphosis (Dowager’s Hump)

- Occurs with exaggerated lordosis -> Outward curve of stomach. Makes old ladies think they are getting fat.

- Can be result of multiple compression fractures

Calcium Homeostasis

↓ Ca++ (Hypocalcaemia) ↑ Ca++ (Hypercalcaemia)

Voltage gated ion channels open spontaneously - Nerve and muscle cells become hyperactive - Involuntary muscle spasms potentially leading to hypocalcaemic

tetany

Ion channels have a hard time opening - ↓ nervous system functioning - Ca combines with PO4 = deposits of Ca(PO4) in vessels and kidneys

Influenced by dietary intake, Ca++ absorption in small intestine and excretion of Ca++ in urine - Bones are reservoir of Ca++ used to maintain homeostasis

Endocrine Regulation

Parathyroid hormone (PTH) Secretion stimulated by hypocalcaemia to ↑ Ca++ - Stimulates bone resorption - ↓ urinary loss = ↑ Ca++ reabsorption in kidneys - Stimulates synthesis of Vitamin D -> ↑ Ca++ absorption from small intestine

Vitamin D [1,25(OH)2D ]

↑ Ca++ absorption from the small intestine

Thyroid Hormone Act directly on osteoblasts -> important for skeletal growth in children - Hypothyroidism = ↓ bone growth, short stature - Hyperthyroidism = ↑ bone loss (osteoclastic), suppression of PTH, ↓ Vitamin D metabolism, ↓ Ca++

absorption

Polymyalgia Rheumatica - Inflammatory Rheumatic (non-articular) condition characterised by aching and morning stiffness in the shoulders, hip girdle, and neck

o Closely related to Giant Cell Arteritis (GCA)

o No muscle weakness

MRONJ (Medication Related Osteonecrosis of the Jaw) Risk Factors Concomitant use of estrogen

Prolonged use of bisphosphonates Age >65 Smoking Alcohol Use Poor Oral Hygiene Chemotherapeutic drugs

IV vs Oral bisphosphonates

IV - 6 doses (monthly) ↑ risk of MRONJ -> 6 months before effects

Oral - 156 continuous weekly doses (3 years) ↑ risk of MRONJ -> 3 years before effects - ↓ lipid solubility = ↓ absorption in small intestine, need to take with milk to ↑ absorption - Accumulate in bone slowly -> Doesn’t show clinically exposed bone until 3 years after drug

** Important for dentist to evaluate all teeth before start of treatment and complete all work before the risk of MRONJ ↑ (6 months if IV, 3 years if Oral)**

Clinical Presentation - Exposed bone (varying amounts from pinpoint to extensive) -> necrotic bone beneath - Alveolar bone extending into inferior border of mandible Rami and zygoma or maxillary sinus walls

-> high bone turnover & Greater reliance on osteoclast-mediated remodeling - Pressure and tension forces ↑ in alveolar bone by occlusion or dentures - Deep Bone Pain -> painful when infected with microbes - Tooth Mobility unexplained by dental or other pathologies

Radiographic Signs Widened periodontal ligament space (not Dx of MRONJ) Sclerosis of Lamina Dura (not Dx of MRONJ) Ill-defined diffuse radiolucency/opacity

Causes Over-eruption of teeth Periodontal Inflammation Failing root canal fills Abscess Formation Trauma

- Extractions - Periodontitis - Spontaneous

**All ↑ rate of bone turnover in alveolar bone**

Prevention Before IV Bisphosphonates - Have 6 months to prepare oral cavity - Eliminate pathology ASAP so you don’t need to do invasive procedures while on Bisphosphonates - Remove teeth that are non-restorable, abscessed, periodontally compromised, or with failing root canals - Perio care to ↓ inflammation, save treatable teeth, educate patient - Restore restorable teeth

During IV Bisphosphonates

- Avoid invasive surgical procedures affecting the bone - Restorative procedures not affecting bone are ok (crowns, bridges, Removable partial and full dentures) - Non-restorative teeth give root canals instead of extraction - Splint mobile teeth

-> D-Pyd Test - Deoxypyridinium cross links organic matrix in Type I collagen of the bone -> ↑ amounts in urine indicate rapid bone loss/turnover

-> Can predict the possibility of developing MRONJ if patient has been on it for 3 years Concomitant use with:

- Prednisone and Methotrexate ↑ risk of MRONJ and its severity - Ranitidine and other H2 blockers ↑ risk of MRONJ

Treatment of MRONJ Self-maintenance will ↓ possibility of developing multiple more sites Follow up every 4 months Bone resection may be needed for severe cases Antibiotics:

- Exposed bone w/o pain (Stage 1) -> 0.12% chlorhexidine 30mL 3x/day - Pain + Infection (Stage 2) – 0.12% Chlorhexidine + Penicillin VI 300mg QID

-> If allergic to penicillin: Levofloxacin 500mg 1x/day; Doxycycline 100mg 1x/day; or Zithromycin 250mg 1x/day - Metronidazole 500mg TID for 10 days adds control for gram –‘ve anaerobes

PBL 5 – Mrs. Stephanie Curry

Radiographs of TMJ - Hard to evaluate TMJ with conventional radiographs -> Many structures in front of it superimposed makes clear image not possible

o Need advanced imaging to see mild bony changes

Cone Beam Computed Tomography (CBCT) -> High-res multiplanar images allowing 3D examination of the TMJ without superimposition or

distortion

- Allows us to evaluate bone morphology, Joint Space, Dynamic Function

Magnetic Resonance Imaging (MRI) also a good diagnostic tool for the TMJ

CBCT Cephalometric Radiograph

Seeing: -Erosions of the condylar head -Sclerosis -Osteophyte formation -↓ joint space

Really hard to see anything here because of all the superimposition infront of the TMJ, but we can see a pretty major anterior open bite - This is caused by significant erosions to the Condylar head making its relationship in the TMJ different

Arthritis Primary Arthritis

- Joint pain is main feature of disease Secondary Arthritis

- Joint pain is a symptom of another disease

Osteoarthritis Rheumatoid Arthritis Gout Pseudo-gout Ankylosing spondylitis Juvenile idiopathic arthritis Adult Still’s Disease (Systemic JIA in adults) Septic Arthritis

Psoriatic Arthritis SLE Lyme Disease Sjogren’s Syndrome Reactive Arthritis Fibromyalgia Raynaud’s Syndrome Scleroderma Behcet’s Disease (Systemic Vasculitis)

Osteoarthritis

- Characterized by articular cartilage loss, bone remodeling, and periarticular muscle weakness resulting in knee pain and instability

o Most common source of pain in older adults

Risk Factors Age >50 Female ↑ BMI Prior knee injury Joint laxity Overuse (occupational or recreational) Family Hx

Lab Tests CBC with diff - Measurement of RBC, Hemoglobin, hematocrit, Total and individual WBC, platelet levels

ESR (Erythrocyte Sedimentation Rate) - Non-specific marker for inflammation, neoplasm and autoimmune diseases - Blood placed in tube and erythrocytes allowed to settle (measure distance fallen in 1hr) - Cells clump during inflammation -> faster sedimentation rate

CRP (C-Reactive Protein) - Non-specific marker for inflammation, ↑ with IL-6 secretion by macrophages and T-cells

Comprehensive Metabolic Panel (CMP) - Tests blood glucose, electrolyte and fluid balance, kidney function and Liver function

Rheumatoid Factor (RA Factor) - Pentameric IgM Autoantibody against IgG (Fc portion) -> form immune complex and contributes to

disease process Antinuclear Antibody (ANA)

- Autoantibodies binding to contents of the nucleus - SLE and JIA

Cyclic Citrullinated Peptide (CCP) - Autoantibodies against citrullinated peptides present in RA - Very specific to RA

Rheumatoid Arthritis

Definition Chronic, systemic, autoinflammatory disorder of the synovial membrane within joints bilaterally

Clinical Presentation

- Joint Inflammation - Erosive properties - Symmetric multiple joint involvement - Weight Loss - Fever - Fatigue - TMJ involvement - Limited joint movement - Joint stiffness - Muscle Spasms

Chronic inflammation leads to ↓ cartilage, erosion and weakness of the bone -> joint deformity, destruction and ↓ function - Swan Neck deformity, Z-thumb, Ulnar Deviation of the fingers

Etiology Not known for sure - Complex interplay of environmental and genetic factors -> Combo of: Infection, Autoimmunity, Genetics

Rheumatoid Factor

Autoantibody produced by B-cells - IgG targeted against Fc portion of IgG’s -> Form complexes and activate complement system = ↑ inflammation and

persistent synovitis Found in:

- Rheumatoid Arthritis - Systemic Lupus Erythematous (SLE) - Sjogren’s Syndrome - Hepatitis B - Chronic Liver disease and hepatitis

Pathogenesis Initial triggering event causes proliferation of synovial macrophages and fibroblasts (Fibroblast- Like Synvocytes) - Lymphocytes infiltrate perivascular regions and angiogenesis ↑ vascular access to area - Blood vessels affected in joint become occluded with clots and inflammatory cells

Inflamed synovial tissue grows irregularly and forms pannus which invades and destroys cartilage and bone

- Pannus = thickened synovial tissue -> stimulates release of IL-1, IL-6, TNF, PDGF, Prostaglandins, Substance P by macrophages = cartilage destruction and bone erosion

RA of the TMJ Affects 50% of RA patients -> correlated to severity and duration of disease 1. Intra-articular Osteopenia w/ soft tissue swelling 2. Erosions and joint space loss

Affected bilaterally often quite late in disease progression - Pain - Swelling - ↓ Movement (opening and lateral) - Crepitus - Morning stiffness (lasting >30mins)

Symptoms are usually transient but if severe enough can lead to: - Bilateral destruction of condyle - Anterior Open bite - Malocclusion - Micrognathia in JIA patients

Treatment Complex and non-curative -> just trying to maintain function and keep disease from progressing 1st Line:

- NSAIDs and cortisone -> fast acting to ↓ pain and inflammation 2nd Line:

- DMARDs (Methotrexate and hydroxychloroquine) -> promote remission and prevent progression - Biologics (Infliximab, Adalimumab etc)

Methotrexate

- Antimetabolite targeted against dihydrofolate reductase -> Prevents folate synthesis = prevents DNA replication and repair in replicating cells

- Indicated in cancer (Lymphoma, Breast cancer, Leukaemia, Head and Neck cancer) - HIGHLY toxic when combined with NSAIDs, Corticosteroids and Penicillin’s

Drug Side Effects

NSAIDS -> Prolonged Bleeding DMARDS

- Methotrexate -> Ulcerative stomatitis, gingivitis, glossitis, mucositis - Anti-malarial -> Lichenoid reactions, Oral hyperpigmentation - Use with NSAIDS can cause bone marrow suppression and aplastic anemia

TNF Blockers (infliximab)

- Immunosuppression - Consult with physician re: drug holiday or elective surgery

Corticosteroids - Immunosuppression - Adrenal insufficiency

Genetic Predisposition Genome = ALL the genetic material in the cells (Gene coding exons and non-coding introns)

Pregenomic = Crude mapping of trains to certain chromosomal regions

- Based on phenotypic associations -> Blue eyes and blonde hair are closely associated so it is likely they are close on a chromosome

Genomic = Precision mapping of DNA sequence variations

Mutations

Hereditary Passed down to offspring through germ line mutations in egg or sperm Can be de novo mutation occurring for the first time and still be considered hereditary, just needs to be a germ line mutation.

Non-Hereditary

Occurs in cells outside of the germ line Cancer

Mutation Types

Silent Single base change in a codon, but the amino acid encoded is the same -> no effect to the protein

Missense Single Base change to encode a different amino acid

Non-sense Early Stop codon

Frameshift Many different codons completely changes the protein

** Non-sense and Frameshift mutations are most likely to cause disease**

Micro-mutations

Deletion Base is deleted, changing the reading frame

Insertion Base added, changing the reading frame

Substitution 1 base replaces another, possibly changes the amino acid

Macro-mutations

Deletion Whole sections of the chromosome are deleted/removed

Duplication Whole sections of the chromosome are duplicated

Inversion Section of the chromosome is flipped upside down

Substitution Section of 1 chromosome moved to another chromosome

Translocation 2 sections from 2 chromosomes are switched

- Can act at many levels to alter protein synthesis and function

o Regulatory areas (non-coding)

o Cause splicing errors in the exons

o Affect RNA stability

o Alter protein expression and stability

Inheritance patterns Autosomal Dominant: 50% chance of inheriting trait

- With 2 generations having the trait, can find the causative mutation within the 3 billion base pairs!

Amelogenesis Imperfecta

Inheritance Patterns of the AMELX gene

All 3! Autosomal Dominant

- Can be found in every generation

Autosomal Recessive - If there is consanguinity can lose the normal copy of the gene and have

2 mutated versions (That’s why you don’t sleep with your cousins!) X-Linked

- Males will express mutated genes on X chromosomes (only have 1) if they inherit a bad one from the mom

- Females can present also if X-inactivation occurs on the normal chromosome

Genes that can cause AI Fam83H Enamelin Ameloblastin Amelogenin Mmp-20

Dentinogenesis Imperfecta

Presentation Translucent, amber discoloration of the teeth Rough surface prone to wear Enamel is sheered off leaving exposed dentin

Inheritance Pattern Autosomal Dominant

Oligodontia

Whats going on >6 teeth missing (not including 8’s) - Usually a single gene mutation that causes agenesis of multiple teeth

Variations in the Genome Ways that we can get normal variation:

Independent Assortment Randomly sorts which copies of the gene go into the individual sperm or eggs during Meiosis

Cross Over Mixing of the mother and father’s DNA during Meiosis - Homologous chromosomes can swap sections of genes to create new variants

Random fertilization 1 sperm fertilizes 1 egg -> completely random which egg and which sperm will fertilize

Single Nucleotide Polymorphisms (SNP)

Variation at a single position in a DNA sequence among individuals - May not directly cause a disorder but are associated with certain diseases

-> Can asses genetic predisposition to certain disease development! To be called a SNP -> >1% of the population have the variant

- No disease-causing variants are this common Challenging to know if SNP contributes to a disease

- Can be in a gene desert with nothing around, but may affect a long range enhancer! Can’t say for sure in SNP is disease causing or pathogenic

- Can change protein function, BUT not considered a mutation if it is commonly found in population = variant

Dental Traits with Genetic Basis Strong Basis

- Few genes affecting the trait

Toot Agenesis Many genes needed for tooth initiation, a few are associated with agenesis - WNT10A - AXIN2 - EDA

Posterior Agenesis - PAX9 - MSX1 - AXIN2

Aggressive Periodontal Disease

…I guess there is nothing much to say here?

Cleft Palate Only Whole-Exome Sequencing (WES) used to identify 2/26 candidate genes with association - GRHL3 - CREBBP

Weak Genetic Links - Dozens of genes involved

Cleft lip w/ or w/o cleft palate

- Need HUGE data to find genes with significant contribution to clefting - Deep phenotyping needed to find more affected family members acting as carriers

Facial Appearance Genome-Wide Association study found multiple loci influencing normal human facial morphology! - MAFB - PAX9 - MIPOL1 - ALX3 - HDAC8 - PAX1

One step closer to true designer babies

Malocclusion Especially class III - ADAMTS1

Pain Sensitivity

Drug Sensitivity

Pharmagogenomics = how genes affect a person’s response to drugs

- Used to develop safe and effective meds with doses tailored to persons genetic profile. Can also be used to predict if a person will have a

good or bad response to a drug

Pharmacogenetics = inherited differences in drug metabolism

**Once again we can use SNP’s do determine certain variants associated with good or bad responses to a drug

Cytochrome Enzymes Strong players in drug metabolism - Affected by genetic variation to affect its function with certain drugs

CYP2D6 variants lead to ↑ levels of morphine for a particular dose of codiene: ↑ risk of opioid induce respiratory depression

- Rapid Metabolizer phenotype: overactive system caused by gene duplication - Poor metabolizer phenotype: Enzyme inhibition or defect in one of the 2 alleles

Redheads MC1R gene variants = ↑ dental anxiety and fear of dental pain - Found specifically in females, Males are unaffected by this variant

MC1R ↓ expression with pheomelanin (molecule that causes redheads to be readheads)

Epigenetics = Environmental changing of the genome (methylation, histone packing via acetylation)