Testable Concepts‌

Section 1 Orthopaedic Tissues

I.Bone

 

 

Question 1

What do Haversian canals carry?

• Nerves and blood vessels
• Nutrients
• Oxygen
• Carbon dioxide

Question 2

What do Volkmann canals do?

• They carry nerves and blood vessels longitudinally in bone.
• They connect different haversian canals.
• They provide nutrients to the bone.
• They provide oxygen to the bone.

Question 3

What are osteoblasts?

• Cells that break down bone
• Cells that build up bone
• Cells that transport nutrients to bone
• Cells that control the extracellular calcium and phosphorous concentration

Question 4

What is RUNX2?

• A transcription factor that directs the differentiation of osteoblasts
• A protein that inhibits the differentiation of osteoblasts
• A protein that promotes the differentiation of osteoblasts
• A protein that controls the extracellular calcium and phosphorous concentration

Question 5

What are Wnt/Beta-catenin pathways?

• Pathways that are involved in osteoblast differentiation
• Pathways that inhibit osteoblast differentiation
• Pathways that promote osteoblast differentiation
• Pathways that control the extracellular calcium and phosphorous concentration

Question 6

What are sclerostin and Dkk-1?

• Proteins that inhibit the differentiation of osteoblasts
• Proteins that promote the differentiation of osteoblasts
• Proteins that control the extracellular calcium and phosphorous concentration
• Proteins that are involved in bone remodeling

Question

Osteocytes are former osteoblasts surrounded by newly formed matrix. They are important for control of extracellular calcium and phosphorous concentration, and are less active in matrix production than are osteoblasts.

• Haversian canals carry nerves and blood vessels longitudinally in bone, and Volkmann canals connect different haversian canals.

• Cellular biology:

  • Osteoblasts are derived from undifferentiated mesenchymal stem cells, and RUNX2 is the multifunctional transcription factor that directs this process.

  • Wnt/Beta-catenin (B-catenin) pathways are involved in osteoblast differentiation.

  • Sclerostin and Dkk-1 inhibit binding of the Wnt molecule to LRP5/6.

  • Inhibition of sclerostin or Dkk-1 will lead to increased bone mass.

  • BMPs work through SMAD to cause osteoblastic differentiation.

  • Osteoblasts produce type I collagen (i.e., bone), alkaline phosphatase, osteocalcin, bone sialoprotein, and RANKL.

  •  

  • Osteoclasts are derived from hematopoietic cells in the macrophage lineage. RANKL is produced by osteoblasts, binds to immature osteoclasts, and stimulates differentiation into active, mature osteoclasts that result in an increase in bone resorption. OPG inhibits bone resorption by binding and inactivating RANKL.

  • Denosumab is a monoclonal antibody that targets and inhibits binding of RANKL to the RANK receptor, which is found on osteoclasts.

  • Osteoclasts bind to bone surfaces by means of integrins (vitronectin receptor), effectively sealing the space below, and then create a ruffled border and remove bone matrix by proteolytic digestion through the lysosomal enzyme cathepsin K.

  • Bisphosphonates directly inhibit osteoclastic bone resorption. Nitrogen-containing bisphosphonates are up to 1000-fold more potent than non–nitrogen-containing bisphosphonates. Bisphosphonates function by inhibiting farnesyl pyrophosphate synthase in the mevalonate pathway. They are associated with osteonecrosis of the jaw, and in animal models, they have reduced the rate of spinal fusion.

• Bone matrix is 60% inorganic (mineral) components and 40% organic components. Calcium hydroxyapatite Ca10(PO4)6(OH)2 constitutes the majority of

  the inorganic matrix. Type I collagen is 90% of the organic component, and osteocalcin is the most abundant noncollagenous protein in bone.

• Wolff ’s law: Remodeling occurs in response to mechanical stress. Hueter-Volkmann law: Compressive forces inhibit growth, whereas tension stimulates it.

• There are three major types of bone formation. In enchondral formation, bone replaces a cartilage model. Intramembranous formation occurs without a cartilage model; aggregates of undifferentiated mesenchymal differentiate into osteoblasts, which form bone. In appositional formation, osteoblasts lay down new bone on existing bone; the groove of Ranvier supplies the chondrocytes.

• There are three stages of fracture repair: inflammation, repair, and remodeling. Fracture healing type varies with treatment method. In closed treatment, healing occurs through periosteal bridging callus and interfragmentary enchondral ossification. In compression plate treatment, primarily cortical healing occurs.

• BMP-2 is used for acute open tibia fractures; BMP-7 is used for tibial nonunions. BMP-3 has no osteogenic activity.

• NSAIDs adversely affect healing of fractures as well as of lumbar spinal fusions. COX-2 activity is required for normal enchondral ossification during fracture healing.

• Bone grafts have three properties. Osteoconduction acts as a scaffold for bone growth; osteoinduction involves growth factors that stimulate bone formation; osteogenic grafts contain primitive mesenchymal cells, osteoblasts, and osteocytes.

• Calcium phosphate–based grafts are capable of osteooconduction and osteointegration. They have the highest compressive strength of any graft material. Calcium sulfate is osteoconductive but rapidly resorbed.

• The primary homeostatic regulators of serum calcium are PTH and 1,25(OH)2D3.

  PTH results in increased serum Ca2+ level and decreased inorganic phosphate level.

• Bone mass peaks between 16 and 25 years of age. Physiologic bone loss affects trabecular bone more than cortical bone.

• Both urinary hydroxyproline and pyridinoline cross-links are elevated when there is bone resorption.

• Serum alkaline phosphatase increases when bone formation increases.

• The most common cause of hypercalcemia is malignancy. Initial treatment is with hydration, which causes a saline diuresis, along with loop diuretics.

• Renal osteodystrophy is a spectrum of disorders observed in chronic renal disease. The majority of cases are caused by phosphorous retention and secondary hyperparathyroidism.

• Rickets (in children) and osteomalacia (in adults) are caused by a failure of mineralization. In rickets, the width of the zone of provisional calcification is increased, which causes physeal widening and cupping.

• Premature arrest following growth plate injury is attributed to vascular invasion across the physis.

• Osteoporosis is a quantitative defect in bone. It is defined as a lumbar bone density of 2.5 or more standard deviations less than the peak bone mass of a healthy 25-year old (T-score).

• Loss of function of the OPG gene results in osteoporosis.

• Treatment of osteoporosis includes calcium supplements of 1000–1500 mg/day as well as bisphosphonates.

• Scurvy results from ascorbic acid deficiency, which causes a decrease in chondroitin sulfate synthesis and ultimately defective collagen growth and repair. Widening in the zone of provisional calcification is observed.

• Osteogenesis imperfecta is caused primarily by a mutation in genes responsible for metabolism and synthesis of collagen type I.

 

I.Cartilage and Joint

• Cartilage is viscoelastic (properties vary depending on rate of force application).

• Composed of water (75%), collagen (25% wet weight, 90%–95% is type II), and proteoglycans (10% wet weight)

• Collagen contributes to viscoelastic behavior in that it restrains “swelling” of aggrecan.

• Aggrecan is most common proteoglycan.

  • Increases osmotic pressure and is responsible for ECM’s hydrophilic behavior

• Chondrocytes are only cell in cartilage.

  • BMP-2 and the transcriptional factor SOX-9 important in regulating differentiation and formation.

  • Have cilia that serve as mechanosensory organs or “antennae.”

• Cartilage layers:

  • Zone 1 (superficial) has highest concentration of collagen and lowest of PG.

  • Zone 2 (middle or transition) has high levels of PG and water

  • Zone 3 (deep) has highest concentration of PG

  • Zone 4 (calcified cartilage) contains type X collagen

• Growth factors:

  • IL-1 stimulates MMP, COX-2, and nitric oxide synthetase, which degrades cartilage

  • TGF-β stimulates synthesis of ECM and decreased activity of IL-1 and MMPs

• Changes with aging:

  • Fewer chondrocytes but larger

  • Decreased chondroitin but increased keratin

  • Smaller PG molecules (less able to hold water)

  • Increased advanced glycosylation end products

  • Increased stiffness (modulus of elasticity)

• Changes with arthritis:

  • Decreased keratin but increased chondroitin/keratan ratio

  • Increased water content and permeability initially followed by decreased water content in later stages

  • Decreased stiffness (modulus of elasticity)

  • Osteophyte formation due to pathologic activation of endochondral ossification by periarticular chondrocytes through Indian hedgehog (Ihh) mechanism

• Lubricin is a mucinous glycoprotein that binds to hyaluronic acid and contributes to boundary lubrication.

• Major mode of lubrication in joints is elastohydrodynamic (lubricant pressure causes elastic deformation of the opposing surfaces which increases conformity).

• Rheumatoid arthritis:

  • Rheumatoid factor is antibody (IgM) against the Fc portion of IgG

  • Anti-CCP test more sensitive and specific, and presence of antibodies linked to aggressive disease

  • DMARDs:

  • Target TNF-α: etanercept, infliximab, adalimumab

  • Target IL-1: anakinra

  • Target CD20: rituximab

  • Risks of opportunistic infection and lymphoma

• Crystalline arthropathies:

  • Gout: monosodium urate (strongly negatively birefringent, needle-shaped crystals)

  • Pseudogout: calcium pyrophosphate dehydrate (CPP) (weakly positive birefringent, rhomboid-shaped crystals)

 

I.Muscle

• A-band represents thick filaments composed of myosin.

• I-band represents thin filaments composed of actin.

• Z-disk represents terminus of sarcomere.

• Motor unit is composed of the α-motoneuron and the myofibers it innervates.

• Contraction:

  • ACh diffuses across the synaptic cleft and binds to postsynaptic receptors on sarcolemma, which begin depolarization.

  • Myasthenia gravis is due to IgG antibodies to the AcH receptor. Manifests initially as ptosis and diplopia. Weakness worse with use.

  • Botulinum A reduces spasticity by blocking presynaptic acetylcholine release.

• Following muscle injury, TGF-β stimulates proliferation of myofibroblasts and increases fibrosis.

• Delayed-onset muscle soreness more common after eccentric exercises and may

be associated with changes in I-band.

 

1. Tendon

   • Composed of water (50%–60%), collagen (75% dry weight, 95% is type I), PG, and elastin

   • Elastin is a highly elastic protein than is responsible for “toe region” of stress-strain curve.

   • Decorin is most predominant PG, regulates fibril diameter, and inhibits TGF-β1.

   • Sheathed tendons have vincula (extensions of synovium), which carry blood supply.

   • Following injury, the inflammatory stage is weakest stage of repair and is characterized by production of collagen type III.

      

2. Ligament

   • Similar in composition to tendon but (1) more water, (2) less total collagen but more type III, and (3) higher PG content.

   • Following injury, healing ligament demonstrates increased collagen fibers but fewer mature cross-links at 1 year.

   • Like tendons, ligaments have direct or indirect (Sharpey fibers) insertions.

      

3. Neural Tissue and Intervertebral Disc

   • Myelin sheath composed of galactocerebroside and speeds wave propagation (thicker sheath increases speed).

   • Action potential created when neurotransmitters cross synapse and trigger

     voltage-gated Na+ channels.

   • Intervertebral disc:

     • Nucleus pulposus derived from notochord and has a high concentration of proteoglycan

     • Annulus fibrosis derived from mesoderm

     • Avascular; nutrients and fluid diffuse from vertebral end plates

   • Early degenerative disc disease is an irreversible process, with IL-1β stimulating the release of MMPs, NO, IL-6, and PGE2.

   • Aging disc has decreased water content as a result of fewer large PGs.

     • Fibronectin cleavage and fragmentation associated with degeneration

 

Section 2 Orthopaedic Biology

I.Cellular and Molecular Biology

• Antibodies against nuclear content (ANAs) are implicated in several conditions,

  including scleroderma (scl-70) and CREST syndrome.

• Alterations in ploidy occur during mitosis and gametogenesis, resulting in conditions such as trisomy-21.

• Marfan syndrome and malignant hyperthermia are examples of disorders with autosomal dominant inheritance.

• Duchenne muscular dystrophy is an example of a disorder with X-linked recessive inheritance.

• Fluorescent in situ hybridization is used to examine chromosomes for translocations predictable of diseases, including:

  • t(X;18): synovial sarcoma

  • t(11;22): in Ewing sarcoma

  • t(12;22): in clear cell sarcoma

• Bacterial LPS is recognized by TLRs on innate immune system cells.

• Adaptive immunity is conferred with the production of antibodies.

• Cell-mediated hypersensitivity (type IV) causes reaction to orthopaedic implants.

 

I.Infection and Microbiology

• Roughly 80% of orthopaedic infections are due to Staphylococcus.

• CA-MRSA at-risk groups: athletes, IV drug abusers, homeless persons, military recruits, prisoners

• C-reactive protein is the most sensitive monitor of the course of infection; it has a short half-life and dissipates about 1 week after effective treatment.

• Necrotizing fasciitis is most commonly polymicrobial and associated with diabetes.

  • Requires early débridement/amputation above level of infection.

• Only 100 bacteria are required to cause infection in the presence of a foreign object; fibronectin increases adhesion, and glycocalyx-biofilm-slime-polysaccharide capsule inhibits phagocytosis.

• Three basic mechanisms of antibiotic resistance have been identified: avoidance, decreased susceptibility, and inactivation. Biofilm formation is an example of avoidance; the biofilm creates a physical barrier.

• Superantigens like TSS toxin-1 trigger cytokine release from T cells.

• Smoking leads to two to four times more infections/osteomyelitis.

• Hyperglycemia impairs wound healing and decreases ability to fight infection.

• Lyme arthritis can be treated effectively with oral antibiotics. Adults can be given amoxicillin, doxycycline, or cefuroxime for 4 weeks.

• Clostridium tetani produces an exotoxin leading to tetanospasm. Td vaccine is recommended every 10 years.

• Sequestrum is the dead bone nidus with surrounding granulation tissue. Involucrum is periosteal new bone formation.

• MRI is the best method to show early osteomyelitis but may overestimate extent of disease.

• Kingella kingae can be difficult to culture; PCR should be considered in the toddler with a septic knee.

• Staphylococcus epidermidis is the most common organism in implant-associated infections.

• Antibiotic therapy according to Gustilo classification of open fractures:

  • Gustilo I and II: first-generation cephalosporins the treatment of choice

  • Gustilo IIIA: first-generation cephalosporin plus an aminoglycoside

  • Gustilo IIIB (grossly contaminated): first-generation cephalosporin plus aminoglycoside plus penicillin

• Antibiotics:

  • Aminoglycosides inhibit translation through irreversible binding of the 30S ribosomal subunit, inhibiting translation of proteins.

  • Cephalosporins inhibit cell-wall production by preventing peptidoglycan cross-linkage.

  • Glycopeptides, such as vancomycin, inhibit cell-wall production by interfering with the addition of cell-wall subunits.

  • Rifamycin inhibits DNA-dependent RNA polymerase F and displays excellent biofilm penetration. Bacteria develop rapid resistance to rifampin used as monotherapy.

  • Macrolides, like erythromycin, bind the 50S ribosomal subunits.

  • Fluoroquinolones, such as ciprofloxacin, inhibit DNA gyrase.

  • Beta-lactam antibiotics, like penicillin, work by inhibiting peptidoglycan synthesis by binding to the bacterial cell membrane surface penicillin-binding proteins.

 

Section 3 Perioperative and Orthopaedic Medicine

I.Thromboprophylaxis

 

• Virchow triad: endothelial damage, stasis or decreased blood flow, and hypercoagulability.

• Aspirin irreversibly binds and inactivates COX enzyme in platelets, reducing thromboxane A2.

• Warfarin can be reversed with fresh frozen plasma and vitamin K.

• Heparin and low-molecular-weight heparin act through ATIII and can be reversed by protamine sulfate.

• Rivaroxaban is a direct factor Xa inhibitor.

• Lactate is an indirect marker of tissue hyperperfusion and serves as best measure of resuscitation.

 

I.Perioperative Disease and Comorbidities

• Ratio of 1:1:1 blood product resuscitation is superior to saline fluid.

• Fat embolism syndrome classical triad = petechial rash, neurologic symptoms, respiratory decline.

• Malignant hyperthermia is autosomal dominantly inherited defect in ryanodine receptor.

  • Caused by an uncontrolled release of calcium

  • Triggered by volatile anesthetics (and succinylcholine)

  • Early sign is increasing end-tidal CO2

  • Treatment is 100% O2 and dantrolene (stabilizes sarcoplasmic reticulum).

 

Section 4 Other Basic Principles

I.Imaging and Special Studies

• Increased radiation exposure associated with:

  • Imaging of larger body parts

  • Positioning the extremity closer to the x-source

  • Use of large C-arm rather than mini C-arm

• 3.0 T MRI has 9 times greater proton energy than 1.5T.

 

I.Biomaterials and Biomechanics

• Work is the product of force and the displacement it causes (Joule).

• Energy is the ability to perform work.

  • Potential energy is stored

  • Kinetic energy is energy caused by motion: 1/2 mv 2.

• Stress is the internal resistance of body to a load (force/area).

• Strain is relative measure of deformation = change in length/original length (no units).

• Young’s modulus of elasticity (E) = stress/strain.

  • Unique for every material

  • High E to low E: ceramic, cobalt chrome, stainless steel, titanium, cortical bone, PMMA, polyethelene, cancellous bone, tendon/ligament, cartilage

• Viscoelastic materials have a stress-strain behavior that is time/rate dependent.

• Isotropic materials have mechanical properties that are the same for all directions loaded (golf ball).

• Anisotropic materials have mechanical properties that vary with the direction of the applied load (bone is stronger in axial load than with bending moment).

• Corrosion:

  • Galvanic corrosion occurs when dissimilar metals are in direct contact (cobalt chrome and stainless steel).

  • Crevice corrosion occurs in fatigue cracks with low oxygen tension.

  • Fretting corrosion comes from small movements abrading the outside

    layer.

  • Stress corrosion occurs in areas with high stress gradients.

• Joint arthrodesis:

  • Hip: 25–30 degrees of flexion; 0 degrees of abduction/rotation

  • Knee: 0–7 degrees of valgus; 10–15 degrees of flexion

  • Ankle: 5 degrees of hindfoot valgus; 5–10 degrees of external rotation; neutral dorsiflexion

  • Shoulder: 15–20 degrees of abduction; 20–25 of forward flexion; 40 degrees of internal rotation

  • Elbow: 90 degrees of flexion if unilateral; if bilateral, one at 65 degrees and one at 110 degrees

  • Wrist: 10–20 degrees of dorsiflexion; if bilateral, then the opposite should be in 10 degrees of palmarflexion.

MCQs on Haversian canals and Volkmann canals

Question 1

What do Haversian canals carry?

• Nerves and blood vessels
• Nutrients
• Oxygen
• Carbon dioxide

Question 2

What do Volkmann canals do?

• They carry nerves and blood vessels longitudinally in bone.
• They connect different haversian canals.
• They provide nutrients to the bone.
• They provide oxygen to the bone.

Question 3

What are osteoblasts?

• Cells that break down bone
• Cells that build up bone
• Cells that transport nutrients to bone
• Cells that control the extracellular calcium and phosphorous concentration

Question 4

What is RUNX2?

• A transcription factor that directs the differentiation of osteoblasts
• A protein that inhibits the differentiation of osteoblasts
• A protein that promotes the differentiation of osteoblasts
• A protein that controls the extracellular calcium and phosphorous concentration

Question 5

What are Wnt/Beta-catenin pathways?

• Pathways that are involved in osteoblast differentiation
• Pathways that inhibit osteoblast differentiation
• Pathways that promote osteoblast differentiation
• Pathways that control the extracellular calcium and phosphorous concentration

Question 6