Orthopedic Ob Basic Review | Dr Hutaif Basic Science Re -...

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siRNA functions by causing mRNA to be broken down after transcriptions, resulting in an inability to undergo translation.
siRNA are short (usually 20 to 24-bp) double-stranded RNA (dsRNA) sequences with phosphorylated 5' ends and hydroxylated 3' ends. Because of their ability to block a gene of interest, they have been generating interest in the treatment of disease processes that involve gene expression.
Noh et al. study the affects of PD98059, an extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor, on osteosarcoma. They found that blocking the ERK1/2 pathway with PD98059 induces osteosarcoma cell death by inhibiting a potential drug-resistance mechanism.
Illustration A shows how siRNA works to block translation of mRNA. Incorrect Answers:

: This is the function of a Western blot.
Answer 2: siRNA have not been shown to block transcription of DNA. Answer 3: This is the function of a gel electrophoresis.
Answer 5: This is the function of a Southern blot.

**Regarding bone erosion in rheumatoid arthritis, which of the following statements is true?**

1) Interference with Wnt signalling may reduce bone erosion

2) TNF and IL-6 blockade leads to slowing of bone erosion

3) The extent of bone erosion is independent of the extent of synovitis

4) M-CSF and RANKL stimulate bone resorption by synovial fibroblasts

5) The presence of serum anti-citrullinated protein antibodies is predictive of the extent of synovitis but not bone erosion
**
TNF, IL1 and IL-6 receptor blockade helps to slow/arrest bone erosion in RA and is also effective in reducing synovitis.
Cytokines TNF, IL-1 and IL-6 are key players in RA. TNF stimulates migration of osteoclast precursors from the bone marrow into the periphery, and stimulates expression of surface receptors to facilitate differentiation. In the joint, M-CSF and RANKL stimulate differentiation towards osteoclasts. Final differentiation into bone- resorbing osteoclasts is achieved following contact with the bone surface.
Schett et al. reviewed bone erosions in RA. They state that the main triggers
of bone erosion are synovitis, RANKL, and anti-citrullinated protein antibodies. In RA, there is an abundance of osteoclasts in bone erosions, but a paucity of mature osteoblasts, suggesting the presence of molecules that block osteoblast differentiation.
Ideguchi et al. investigated whether repair of erosions occurs in patients with rheumatoid arthritis (RA) treated with conventional disease-modifying anti- rheumatic drugs (DMARDs). They detected repair of erosions in 10.7% of RA patients treated with DMARDs. They recommend the use of DMARDs to reduce disease activity and thus reduce erosions.
Illustration A shows the action of antirheumatic drugs on osteoclast differentiation and bone erosion.
Answer 1: Interference with Wnt signalling impairs bone formation, thus INCREASING bone erosion. The Wnt signaling pathway is a bone anabolic pathway. TNF induces expression of Dickkopf-related protein 1( Dkk-1) in synovial fibroblasts. Dkk-1 interferes with Wnt signalling and blocks new bone formation. Other Wnt antagonists Frizzled- related protein-1 and sclerostin also inhibit bone formation and inhibit repair of bone erosion.
Answer 3: The greater the synovitis, the more extensive the bone erosive process. Some anti-rheumatic drugs (steroids, methotrexate, leflunomide) are bone sparing simply because they reduce synovitis.
Answer 4: M-CSF and RANKL stimulate osteoclast differentiation from monocyte-lineage cells. Blockage of RANKL by denosumab slows bone erosion (but does not retard inflammation).
Answer 5: Anti-citrullinated protein antibodies (ACPA) are produced by plasma cells and can appear long before the onset of synovitis, and independently predicts bone erosion. ACPA bind to citrullinated vimentin in osteoclasts, stimulating TNF release, and enhancing differentiation into mature osteoclasts.

**A patient undergoing joint arthroplasty is put on a drug that competitively inhibits the activation of an enzyme that breaks down Factor Ia. The drug is**

1) Dabigatran

2) Tranexamic acid

3) Rivaroxaban

4) Fondaparinux

5) Heparin
**
Factor Ia is fibrin. The enzyme that breaks down fibrin is plasmin. Tranexamic acid (TXA) is an antifibrinolytic that prevents the activation of plasmin from the inactive zymogen plasminogen.
Tranexamic acid competitively inhibits the activation of plasminogen to plasmin by binding to specific sites on both plasminogen and plasmin. Tranexamic acid has roughly eight times the antifibrinolytic activity of an older analogue, e-aminocaproic acid. It is used during joint replacement surgery to reduce blood loss and the need for transfusion.
Watts et al. review strategies for minimizing blood loss and transfusion. They recommend 1g of TXA prior to incision, and 1g at wound closure. They also recommend giving fluids for symptoms of anemia, rather than transfusion, as even high risk patients do well with sufficient intravascular volume even with low hemoglobin levels.
Imai et al. evaluated TXA in 107 patients undergoing THA. They found that intraoperative blood loss after preoperative TXA administration was lower than both control and postoperative TXA administration groups. They recommend using 1 g of TXA 10 minutes before surgery and 6 hours after the first administration to best reduce blood loss during THA.
Gillette et al. retrospectively reviewed 2046 patients receiving TXA for THA or TKA together with either aspirin, warfarin or dalteparin. They found that the rates of symptomatic DVT (0.35%, 0.15%, and 0.52%, respectively) and nonfatal PE were similar (0.17%, 0.43%, and 0.26%, respectively) for the 3 drugs respectively. They recommend TXA to decrease blood loss and transfusion.
Illustration A shows the role of tranexamic acid in the fibrinolytic cycle and the clotting cascade.
Incorrect Answers:
Answer 1: Dabigatran is an oral direct thrombin inhibitor.
Answer 3: Rivaroxaban is an oral direct factor Xa inhibitor. It is FDA approved for hip and joint arthroplasty DVT prophylaxis.
Answer 4: Fondaparinux is an indirect factor Xa inhibitor that works through antithrombin
III. Unlike heparin, it is selective for factor X and does not have effect on thrombin. Answer 5: Heparin is an anticoagulant that binds and activates antithrombin
III. Activated antithrombin III then inactivates thrombin and factor Xa.

**Figure A demonstrates the molecular structure of a cell membrane protein**
**important in propagating the action potential of a neuron. Which of the following medications acts by binding to the**
**location marked with an X in the illustration?**
1) Phentolamine

2) Rocuronium

3) Bupivacaine

4) Midazolam

5) Fentanyl
**
Bupivacaine exerts its actions through blockade of the voltage gated sodium channel.
Local anesthetics of the amide family (lidocaine, bupivacaine) bind to the intracellular portion of voltage-gated sodium channels to block sodium influx. This prevents depolarization and the initiation or conduction pain. Lidocaine and bupivacaine have a duration of action of 2 and 4 hours, respectively (4 and 8 hours with epinephrine), and maximum doses are 4.5mg/kg and
2.5mg/kg, respectively (7mg/kg and 3mg/kg with epinephrine respectively). Both are metabolized in the liver, and excreted by the kidneys.
Phillips et al. review specific analgesics. Agents used to manage chronic pain include tricyclic antidepressants, anticonvulsants, GABA agonists, local anesthetic analogs, and NMDA antagonists. Opiates may trigger tolerance and lack of efficacy may develop. In those with refractory chronic pain, centrally administered analgesics may be considered, including opiates, dilute local anesthetic, NMDA receptor antagonists, clonidine, midazolam, baclofen, or calcium channel blockers. Single agents may be less effective than analgesic combinations.
Scholz discussed the function of local anesthetics and sodium channels. There are 3 states to sodium channels: (1) The closed state at potentials below
-70mV. In this state, Na+ ions cannot pass from 1 side to another. (2) The open state, initiated by depolarization of the membrane to above -40mV. The channel opens to allow
Na+ ions to diffuse through the pore, causing an inward current, depolarizing the membrane further. (3) The inactivated state follows activation during prolonged depolarization. In this state, inactivation is seen in macroscopic currents.
Figure A shows the voltage gated sodium channel. Local anesthetics such as lidocaine and bupivacaine act at the binding site marked "X".
Incorrect Answers:
Answer 1: Phentolamine competitively blocks alpha-adrenergic receptors and leads to vasodilatation. It antagonizes circulating epinephrine and/or norepinephrine.
Answer 2: Rocuronium is a non-depolarizing neuromuscular blocking agent. It acts by competitively blocking the binding of acetylcholine to its receptors.
Answer 4: Midazolam increases the efficiency of GABA to decrease the excitability of neurons. GABA receptors contain a chloride ion channel. By binding to the GABA receptor, midazolam increases the influx of chloride ions, hyperpolarizing the neuronal cell membrane, decreasing its excitability. Answer 5: Fentanyl exerts its activity through binding to µ and kappa receptors. The supraspinal analgesic properties are mediated by the µ1 receptor, respiratory depression and physical dependence by the µ2 receptor, and sedation and spinal analgesia by the kappa receptor.

**Which of the following defines the incidence of a disease?**

1) The total number of cases of a disease in a city

2) The number of new cases of a disease diagnosed during a specific time period

3) The average number of cases of a disease per year over the last 10 years

4) The number of existing cases of a disease divided by total population in a city

5) The variability in the total number of disease cases between major US cities
**
As described in the review by Kocher and Zurakowski, incidence is defined as the number of NEW cases of a disease diagnosed during a specific time period per unit measurement of population. This is different from the prevalence of a disease, which is defined as the total number of cases of the disease in the population at a given time. The variance of a disease is an estimate of the variability of each individual data point from the mean, so how each patient with a disease differs from the mean of patients with that disease (e.g. length of symptoms of patients with a disease may differ for individual patients, but a mean duration of symptoms exists for all patients with that disease).
Kocher and Zurakowski present a Level 5 review article that is referenced often and discusses basic biostatistic principles.

**Which of the following cells are NOT components of the innate immune system?**

1) Dendritic cells

2) Natural killer cells

3) Basophils

4) CD8+ T lymphocytes

5) Neutrophils
**
CD8+ T lymphocytes are not part of the innate immune system.
Innate immunity refers to nonspecific defense mechanisms that come into play immediately or within hours of an antigen's appearance in the body. The cells of this system include natural killer cells, mast cells, eosinophils, basophils and phagocytic cells (macrophages, neutrophils, and dendritic cells). Metal-on- metal bearing reactivity is related to the innate immune response (cell mediated). Adaptive immunity refers to antigen-specific immune response.
The adaptive immune response is more complex as the antigen must first be processed and recognized. After antigen recognition, the adaptive immune system creates an army of immune cells specifically designed to attack that antigen. Adaptive immunity includes "memory" that makes future responses against the same antigen more efficient. The cells of this system include CD8+ T lymphocytes, T helper cells, delta gamma T cells, B cells and plasma cells.
Landgraeber et al. review the pathology of orthopaedic implant failure. They found that aseptic loosening is primarily mediated by the innate immune system. Macrophages respond to wear debris with both damage (DAMP, damage associated molecular pattern) and pathogen (PAMP, pathogen associated molecular pattern) cytokine signalling. Macrophage cytokines
include IL-1a, IL-1ß, IL-6, IL-10, IL-11, IL-15, TNF-a, TGF-a, GM-CSF, M-CSF), PDGF and EGF.
Illustration A shows the innate immune system. Incorrect Answers:
Answers 1, 2, 3, 5: These cells belong to the innate immune system.

**What is the main biologic effect of aggrecan in cartilage?**

1) Extracellular matrix protein involved in the organization of collagen

2) Proteoglycan involved in the hydrophilic behaviour of cartilage

3) Cartilage matrix protein that plays a role in cartilage tissue organization

4) Collagen component responsible for stability

5) Non-collagenous extracellular matrix protein that regulates chondrocyte proliferation
**
Aggrecan binds hyaluronic acid to attract water, which accounts for its hydrophilic property.
Aggrecan is the predominant proteoglycan in cartilage. It contains a large number of negatively charged sequences that attract water called sulfated glycosaminoglycan (GAG) chains. Its the N-terminal globular domain of aggrecan that binds hyaluronan to form huge aggregates. Together with its chondroitin sulfate chains, they help to create a hydrophilic viscous gel that decreases the coefficient of friction as well as to help absorb compressive loads.
Ulrich-Vinthe et al. reviewed the biology of articular cartilage. They report that
matrix metalloproteinases and aggrecanases play a major role in aggrecan degradation and their production is upregulated by mediators associated with joint inflammation and overloading.
Illustration A shows a depiction of the function of aggrecan in articular cartilage. In the relaxed state, the aggregates draw water into cartilage. With compressive loads, the water is displaced to cushion the load. Upon removal of the load, the water content is restored.
Incorrect Answers:
Answer 1: This describes the biological effect of Decorin. Answer 3: This describes the biological effect of Matrilin 1. Answer 4: This describes the biological effect of Type IX collagen
Answer 5: This describes the biological effect of Cartilage oligomeric matrix protein.

**Which of the following places materials in order of increasing Young's modulus of elasticity (from least stiff to most stiff)?**

1) Titanium
2) Cortical bone
3) Titanium
4) Stainless Steel
5) Stainless Steel
**
An increasing Young's modulus of elasticity is seen in order going from cortical bone, to titanium, to stainless steel, to cobalt-chromium alloy, to ceramic (AL2O3).
Material properties are an important consideration in orthopaedic implants. One such property is the Young's modulus of elasticity, which is a
measurement designed to quantify the stiffness of materials. The formula used to calculate Young's modulus is, "stress" (force applied) divided by "strain" (degree of displacement).
Thus, a material may have a higher Young's
module, and be considered "more stiff", when a greater amount of stress is needed to produce a similar amount of strain in other materials that are considered "less stiff".
Mann et al. looked at the properties of common orthopaedic implants. Titanium is notable for having the most similar Young's modulus compared to cortical bone. Stainless steel is more stiff than titanium and also commonly used in orthopaedic implants. Cobalt- chromium alloys are known for being the most stiff among metals found in orthopedic implants, and are known for
being highly resistant to corrosion. Ceramic is even more stiff than cobalt- chromium alloy.
Illustration A represents the formula for calculating Young's modulus of elasticity. Illustration B is a list of materials encountered in orthopaedic surgery in order of their Young's modulus.
Incorrect Answers:
Answer 1: Titanium has a higher Young's modulus than cortical bone
Answer 3: Ceramic has a higher Young's modulus than cobalt-chromium alloy Answer 4: Stainless steel has a higher Young's modulus than titanium Answer 5: Stainless steel has a higher Young's modulus than titanium

**Type I collagen fibers in peripheral nerves are primarily responsible for which of the following?**

1) Conduction strength

2) Tensile strength

3) Conduction velocity

4) Compressive strength

5) Cross-linkage
**
Type I collagen fibers are most responsible for the tensile strength of a peripheral nerve.
Type I collagen is the most abundant collagen of the human body which forms large, eosinophilic fibers known as collagen fibers. It is present in scar tissue, the end product when tissue heals by repair, as well as tendons, ligaments, the endomysium of myofibrils, the organic part of bone, the dermis, the dentin and organ capsules.
The COL1A1 gene produces a component of type I collagen, called the pro- alpha1(I) chain. This chain combines with another pro-alpha1(I) chain and also with a pro- alpha2(I) chain (produced by the COL1A2 gene) to make a molecule of type I procollagen. These triple-stranded, rope-like procollagen molecules must be processed by enzymes outside the cell. Once these molecules are processed, they arrange themselves into long, thin fibrils that cross-link to one another in the spaces around cells. The cross-links result in the formation of very strong mature type I collagen fibers.
Wong et al. provide a review of the basic science behind nerve healing and the recovery after nerve repair. They note the importance of minimizing additional surgical insult and careful handling of nerve tissue during repair to optimize outcomes.
Pertici et al. noted that autologous nerve implantation to bridge a long nerve gap presents the greatest regenerative performance in spite of substantial drawbacks. They were able to show improved nerve guided regrowth with a type I collagen matrix conduit as compared to a conduit made of a mix of type I and type III collagen.
Illustration A shows a diagram of type I collagen, showing the rope-like characteristics behind the tensile strength.
Incorrect Answers:
Answer 1: Strength of nerve conduction is not dependant on collagen, but is polyfactorial, with contributions from patient age, sex, nerve temperature, and myelin sheath condition.
Answer 3: Type I collagen does not significantly affect the velocity of nerve conduction, as this is also polyfactorial, as explained in Answer I immediately above.
Answer 4: Type I collagen can be compressed, but is more responsible for the tensile strength through the cross-linkages.
Answer 5: Peripheral nerves do not have cross-linkages.

**According to patients and colleagues surveyed, orthopaedic surgeons are given the highest ratings for their skills in which of the following areas?**

1) Medical knowledge

2) Social gatherings

3) Technical skills

4) Communication

5) Empathy
**
Orthopaedic surgeons are given high ratings by patients and colleagues for their technical skills in the operating room. Patients and colleagues however think orthopaedic surgeons listening and communication skills could be improved upon and they could show more empathy for their patients. Communication affects patient satisfaction, adherence to treatment, physician satisfaction, and is the most common factor in the initiation of malpractice suits.
Tongue et al. review these specific communication data as well as other common communication issues seen in the field of orthopaedic surgery.

**Your colleague, a general surgeon in your practice, brings his mother-in-law to see you for hip pain. You diagnose her with end- stage hip osteoarthritis and wish to discuss surgical options. She does not speak English. Interpretation should be provided by**

1) certified translator

2) patient's husband

3) your colleague

4) patient care advocate fluent in the same language as the patient

5) nurse fluent in the same language as the patient
**
Family members should not be involved with translation for reasons of confidentiality. This is especially true if the patient specifically requests professional translation services.
For patients who have limited English proficiency, translation can be performed by employees fluent in English and a second language, commercial telephonic services, professional translators, or volunteer translators. It is inappropriate for family members to act as translator for reasons of confidentiality, unless
the patient offers or agrees. For medico-legal reasons, certified translators (telephonic or on-site) are preferred.
Tongue et al. reviewed communication skills. They state that the Office for Civil Rights requires physicians who received reimbursement from Medicaid and Medicare Part A to have competent translation services for all patients who have limited English proficiency, and this constitutes "federal financial assistance".
Kaz et al. defined 3 communication barriers between orthopedists and patients: (1) Everyday communication skills must be acquired to effectively interact with patients, (2) There is a growing language divide between patients and physicians who do not share a common language, and (3) Cultural competency issues lead to distrust that can adversely affect patient outcomes.
Incorrect Answers
Answers 2-5: For medico-legal reasons, certified translators (telephonic or on- site) are preferred to other sources.

**Which of the following fractures (Figures A through F) is representative of a fracture that may be related to long term biphosphonate use?**
1) Figure A

2) Figure B

3) Figure C

4) Figure D

5) Figure E
**
Figure E is a bisphosphonate-related subtrochanteric fracture.
Bisphosphonate-related subtrochanteric and femoral shaft fractures are characterized by (1) focal lateral cortical thickening, (2) transverse fracture orientation, (3) medial spike ("beaking") and (4) simple pattern with lack of comminution.
Lenart et al. performed a retrospective case-control study on 41 subtrochanteric fractures. They found that more patients in the subtrochanteric/femoral shaft fracture group were likely to be on bisphosponates than the intertrochanteric/femoral neck group. They identified a common x-ray pattern in 10/15 subtrochanteric fractures on bisphosphonates and called it "simple with thick cortices."
Schilcher et al. reviewed the radiographs of 5342 women and found 172 atypical fractures. The risk was higher with alendronate (relative risk 1.9) than risedronate. Risk increased with duration of use (RR 126 at 4 years).
Compared with men, women had 3.6x greater risk (RR 3.6). They conclude that oral bisphosphonates might do more harm than good if given to patients without indication, and the evidence for prolonged treatment is weak.
Incorrect Answers:
Answers 1 and 2: Figures A and B are non-bisphosponate related subtrochanteric fractures. There is no cortical thickening or fracture site beaking, and these are spiral fractures with more comminution.
Answer 3: Figure C is a comminuted subtrochanteric fracture. The proximal fragment is abducted and the lesser trochanter is fractured and separated from the femur.
Answer 4: Figure D shows a pathological subtrochanteric fracture that is posteriorly displaced and mildly impacted, with lateral angulation of the proximal fragment. There is a lytic lesion at the fracture site from a myelomatous deposit.

**A 6-year-old girl presents with a lower extremity deformity. Her standing AP radiograph is shown in Figure 1. Her parents report that she has been prescribed vitamin supplements by her prior physician with no improvement in her condition. Calcium, PTH and Vitamin D lab values return within normal limits. What is the most likely inheritance pattern of her disease?**
1) Autosomal dominant

2) Autosomal recessive

3) X-linked dominant

4) X-linked recessive

5) Mitochondral
**
The patient most likely presents with X-linked hypophosphatemic rickets, which is inherited in an X-linked dominant pattern.
This inherited disorder is also known as Vitamin D resistant rickets (VDRR), of which the X-linked dominant form is most common. It involves a defect in the absorption of phosphorus by the renal tubules. It is characterized by short stature, genu varum, windswept deformity, physeal widening, low serum phosphorus, elevated alkaline phosphatase, and normal or low normal serum calcium. Other forms of VDRR may be associated with conversion disorders of
25-hydroxyvitamin D to 1,25-hydroxyvitamin D (Type II Vitamin D dependent rickets), in which patients have high 1,25-OH vitamin D, low calcium, and high PTH.
Sharkey et al present a review paper of the management of X-linked hypophosphatemic rickets. They review the medical management as a mainstay which focuses on oral phosphate and vitamin D supplementation, as well as the surgical management which remains somewhat unstandardized, ranging from guided growth to osteotomy with immediate fixation, nailing, or gradual correction with external fixators. Ultimately, the patient's deformity and symptoms guide the specific surgical plan, with most patients being treated medically.
Popkov et al review a series of 47 cases treated with bilateral deformity correction of
femur and tibia with ring fixators and compare this approach to a prior cohort of the same surgeon with staged correction. They found that simultaneous correction reduced the overall duration of treatment with fewer complications and saw no recurrence of any corrections that were ultimately stabilized with intramedullary nailing.
Figure A is a standing AP radiograph of a child with genu varum, physeal widening, and an overall ricketic picture on imaging.
Incorrect Answers:
Answer 1: While a form of VDRR can be inherited as autosomal dominant, this is much rarer than the X-linked dominant form.
Answer 2, 4, 5: The most common form of inheritance of this type of hypophosphatemic rickets is X-linked dominant.

**Which of the following contributes to the differentiation of mesenchymal progenitor cells towards adipose tissue?**

1) Bone morphogenic protein (BMP)

2) Peroxisome proliferator-activated receptor gamma (PPAR-gamma)

3) Runt-related transcription factor 2 (RUNX2)

4) Sex determining region-Y-box 9 (SOX9)

5) Wnt-beta-catenin
**
PPAR-gamma is a regulator of mesenchymal progenitor cell that induces apidocyte formation.
Mesenchymal progenitor cells, often referred to as mesenchymal stem cells (MSCs), are upstream cells that can form myoblasts, chondrocytes, adipocytes, and osteoblasts amongst other tissue types. Numerous regulatory pathways have been explored to understand and manipulate these differentiation pathways. PPAR-gamma has been known for many years to influence adipogenic differentation, most likely at the pre- adipocyte to adipocyte phase. It is inhibited by the Wnt5a pathway which encourages osteoblastic differentiation.
Takada, Suzawa, Matsumoto et al present a basic science paper in which they demonstrate osteoblastic differentiation instead of adipogenic by two different forms of PPAR-gamma repression. The first was through TNF-a and IL-1, with activated NF-kappa beta blocking PPAR-gamma binding to DNA. The second was Wnt-5a repression of PPAR-gamma. Both demonstrated a change from the adipogenic induction typical of PPAR-gamma to osteogenic.
Illustration A from Takada, Kouzmenko, and Kato displays known regulators of MSC differentiation.
Incorrect Answers:
Answer 1 - BMP induces OSTEOGENIC differentiation Answer 3
/- RUNX2 induces OSTEOGENIC differentiation Answer 4 - SOX9
induces CHONDROGENIC differentiation
Answer 5 - Wnt-beta-catenin induces OSTEOGENIC differentiation

**What is the most likely mechanism for failure of a modular revision total hip arthroplasty femoral implant at the mid-stem junction?**

1) Electrochemical destruction due to the association of dissimilar metals

2) Fatigue cracks due to differences in oxygen tension

3) Micromotion at the contact site between two components

4) Pit formation causing a decrease in thickness at affected sites

5) Selective attack at the grain boundaries within the metal
**
Fretting corrosion, which describes a mode of destruction from the relative micromotion of two materials, is the most common cause for mid-stem implant failure after total hip arthroplasty (THA) using a modular, revision- type stem.
Fretting is a type of corrosion and wear caused by load and repeated relative micromotion of two implants or implant components. Though an uncommon complication, arthroplasty involving modular implants are at risk for such motion between the components of the final implant because of the increased number of interfaces between the various components. Any of these interfaces can be the site of increased wear and implant failure.
Lakstein et al. analyzed six mid-stem modular implant failures, comparing them to 165 controls. They found evidence of fretting fatigue as well as a bending moment. They also note elevated BMI and inadequate proximal bone stock as risk factors for such failure.
Buttaro et al. present a case of fatigue fracture in a proximally modular, distally tapered fluted implant with diaphyseal fixation. They concluded that fatigue failure was the cause of this complication, emphasizing the reduced proximal femoral bone stock in this patient.
Illustrations A and B, from Lakstein et al, show an AP radiograph and clinical image, respectively, of a modular revision THA with fracture at the mid-stem junction.
Incorrect Answers:
Answer 1 - This describes Galvanic corrosion Answer 2 - This describes Crevice corrosion Answer 4 - This describes Pitting corrosion Answer 5 - This describes Intergranular corrosion

**Which of the follow medications activates antithrombin III?**

1) Warfarin

2) Aspirin

3) Rivaroxaban

4) Dabigatran

5) Heparin
**
Activation of antithrombin (AT) III is the mechanism of action of heparin.
Heparin works by binding to and enhancing the ability of antithrombin III to inhibit factors IIa, III, Xa. It is metabolised by the liver. The risks associated with its use include bleeding and heparin induced thrombocytopenia (HIT). The reversal agent is protamine sulfate.
Brown et al. performed a pooled analysis of 14 randomized controlled trials (RCTs) on VTE rates. They showed that VTE rates with aspirin were not significantly different than the rates for vitamin K antagonists (VKA), low molecular weight heparins (LMWH), and pentasaccharides. They concluded that aspirin may be used for VTE prophylaxis after major orthopaedic surgery.
Murphy et al. reviewed VTE prophylaxis in pediatric patients. Using public health data over 10 years, 285 611 clinical encounters were reported as lower extremity orthopaedic trauma. The incidence of VTE events was 0.058 %. Adolescents and polytrauma patients with injuries of the femur/femoral neck, tibia/ankle, and pelvis are more commonly affected.
Roehrig et al. first examined the coagulation enzyme Factor Xa (FXa) as a target for antithrombotic therapy. This study contributed to the development of rivaroxaban, which is commonly used as an oral antithrombotic agent.
Illustration A shows the interaction between anticoagulant drugs and the coagulation cascade.
Incorrect Answers:
Answer 1: Warfarin inhibits vitamin K 2,3-epoxide reductase, thereby limiting the production of vitamin K-dependent clotting factors (II, VII, IX, X) as well as Protein C and Protein S.
Answer 2: Aspirin inhibits the production of prostaglandins and thromboxanes through irreversible inhibition of cyclooxygenase (COX, 1 and 2) and thus inhibits platelet aggregation.
Answer 3: Rivaroxaban is a direct inhibitor of factor Xa. Answer 4: Dabigatran is a direct thrombin inhibitor.

**Decorin is a major controlling molecule for:**

1) Myelin diameter

2) Non-mineralized bone matrix density

3) Tendon collagen fiber size

4) Elastic cartilage thickness

5) Axon branching pattern
**
Decorin is a proteoglycan molecule that regulates the assembly of collagen fibrils in tendons.
Tendons are composed organized bundles of uniaxially arranged collagen fibrils, which are assembled together to generate force from muscles to bone. However, the variability in tendon morphology is multifactorial. At the microscopic level, decorin is an important regulator of tendon structure as it acts as a mediator of fibril growth. Variations in expression of decorin has shown to correlate with both size and density of collagen fibrils and organisation.
Robinson et al. measured the mechanical properties of multiple tendon tissues in mice with knock-out models of decorin. They found that the loss of decorin affected the posterior tibialis causing an increase in modulus and stress relaxation, but had little effect on the flexor digitorium longus. They concluded
that tendons likely are uniquely tailored to their specific location and function at the microscopic level.
Zhang et al. performed a biomechanical study on tendon function. They showed that decorin-deficient mice demonstrate altered fibril structure and significantly reduced strength and stiffness. They concluded that decorin is a key regulatory molecule in tendon development.
Incorrect Answer:
Answer 1: Myelin diameter is organized by Schwann cells
Answer 2: Non-mineralized bone matrix is formed by osteoblasts. This includes alkaline phosphatase, osteonectin, osteocalcin, etc.
Answer 3: Elastic cartilage is formed from elastic microfibril, which consist of numerous proteins such as microfibrillar-associated glycoproteins, fibrillin, fibullin, and elastin.
Answer 5: Laminin, fibronectin, tenascin, and perlecan are molecules shown to be associated with axonal growth and assembly. Decorin in not a major controlling molecule in the branching pattern.

**Which of the following medications inhibits release of neurotransmitters by binding to presynaptic calcium channels?**

1) Denosumab

2) Sertraline

3) Tramadol

4) Gabapentin

5) Linezolid
**
Gabapentin acts by inhibiting presynaptic calcium channels, thus preventing the release of neurotransmitters.
Gabapentin (also known as Neurontin) is a medication that is commonly used to treat neuropathic pain. It acts by binding the alpha2delta subunit of
voltage-dependent calcium channels on the presynaptic membrane. This serves to increase GABA synthesis, as well as inhibit the release of excitatory neurotransmitters. These neurotransmitters are believed to be part of the pathway leading to neuropathic pain.
Bennett et al. provide a review of the pharmacology of gabapentin for the use of neuropathic pain. They note effective antihyperalgesic and antiallodynic
properties of gabapentin but not significant anti-nociceptive action. Among patients with neuropathic pain they found an average pain score reduction of
2.05 points on an 11 point Likert scale, which compared favorably to placebo.
Mehta et al. explored outcomes of gabapentin and pregabalin (Lyrica) for use in patients with spinal cord injury. Both agents were found to decrease pain and secondary conditions such as sleep disturbance. They did not directly compare these agents to other analgesic medications.
Guy et al. present a meta-analysis of the use of anticonvulsants (such as gabapentin) to treat pain in patients with spinal cord injury. Large effect size was seen in 4 of 6 studies looking at the effectiveness of gabapentin.
Illustration A show the mechanism of currently available antiepileptic drugs (AEDs) that target several molecules at the excitatory synapse. Gabapentin and pregabalin bind to the a2d subunit of voltage-gated Ca2+ channels, which is thought to be associated with a decrease in neurotransmitter release.
Incorrect Answers
Answer 1: Denosumab works by inhibiting the receptor activator of nuclear factor kappa beta ligand (RANK-L)
Answer 2: Sertraline is a selective serotonin reuptake inhibitor (SSRI). It increases concentrations of serotonin in the synaptic cleft by inhibiting it's reuptake.
Answer 3: Tramadol acts as a mu-opioid receptor agonist.
Answer 5: Linezolid is a bacteriostatic antibiotic medication that acts by disrupting translation of mRNA

**A researcher experimenting with limb patterning removes some tissue from 1 part of the limb bud (which we shall call Site A) and transplants it along the anteroposterior (AP) axis to create a mirror- hand duplication. Which of the following is true?**

1) Site A is the apical ectodermal ridge (AER). Site A tissue expresses Shh protein.

2) Site A is the AER. Site A tissue expresses FGF8.

3) Site A is the zone of polarizing activity (ZPA). Site A tissue expresses Shh protein.

4) Site A is the zone of polarizing activity (ZPA). Site A tissue expresses FGF8 protein.

5) Site A is non-AER ectoderm. Site A tissue expresses WNT7a.
**
The ZPA is located on the posterior (ulnar) margin of the limb bud. It expresses Shh protein. When tissue from ZPA is added to the anterior (radial) margin of the limb bud, ulnar dimelia, or mirror hand duplication, occurs.
The ZPA controls AP (radioulnar) growth. The signaling molecule is Shh, which is dose dependent. Higher Shh doses lead to posterior (ulnar) digits ulnar
sided polydactyly. The extent of duplication is dose dependent (higher dose = more replication). Reduced Shh leads to loss of digits. Posterior elements (little finger/ulna) are formed EARLY prior to anterior elements which are formed LATE (radius/thumb).
Disruption of AP patterning will result in loss of later forming elements (radius/thumb).
Al-Qattan et al. reviewed embryology of the upper limb. They summarized that embryology of the upper limb can be viewed in 2 distinct ways: the steps of limb development and the way that the limb is patterned along its 3 spatial axes. Cell signaling plays a major role in regulating growth and patterning of the vertebrate limbs. Signaling cell dysfunction results in congenital
differences according to the affected signaling axis.
Illustration A shows an experiment to create ulnar dimelia by adding ZPA tissue to the anterior limb bud. The video shows development of the limb.
Incorrect Answers:
Answers 1 and 2: Site A is the ZPA. The AER controls proximal to distal patterning.
Answer 4: The ZPA expresses Shh. The AER expresses FGF8.
Answer 5: Non-AER ectoderm controls dorsoventral patterning. Dorsal tissue express WNT7a and ventral tissue express en-1 protein.

**A 71-year-old caucasian woman was the passenger in a low speed motor vehicle accident. She complained of acute back pain and was evaluated in the emergency department. On exam, she has point tenderness about her lower thoracic region and has no neurologic symptoms. Radiographs were obtained (Figures A). Which of the**
**following is true about this patient's condition?**
1) Her T score is likely -2.0

2) Vertebroplasty has not been shown to be beneficial for the treatment of this injury in randomized controlled trials

3) A CT scan is needed for further evaluation the patient's condition

4) Distal radius fractures are a more common fragility fracture than the patient's current injury

5) The patient's injury is most likely secondary to an underlying neoplastic condition
**
The patient in the above question has underlying osteoporosis and has suffered from a vertebral compression fracture (VCF). In randomized controlled trials (RCT), vertebroplasty has been shown to be of no benefit in the treatment of VCFs.
Osteoporosis affects more than 12 million Americans per year, with the burden falling heaviest on postmenopausal women. Because of decreased bone strength, patients with osteoporosis are susceptible to fragility fractures. With no additional risk factors, a 65- year-old white woman has a 10% 10-year risk of a fragility fracture. VCFs are the most common type of fragility fracture. Though most of these fractures will heal, many patients will have residual pain and disability despite conservative therapy. Vertebroplasty was once considered a good surgical method of treating these patients. However, vertebroplasty has been shown in RTCs to have limited efficacy and is no
longer considered an indicated procedure in this clinical scenario. If the patient continues to have pain, other options such as kyphoplasty are considered.
Buchbinder et al. investigated the efficacy of pain reduction by vertebroplasty in patients with painful osteoporotic vertebral fractures. They performed a double-blinded, randomized control trial with 78 patients comparing vertebroplasty with sham surgery and found that there was no statistically significant reduction in pain between groups at 1 week, 1 month, 3 months, or
6 months. The authors concluded that vertebroplasty provided no beneficial effect in patients with painful osteoporotic vertebral fractures and they questioned its utility as a treatment for these patients.
The U.S. Preventive Services Task Force (USPSTF) updated their guidelines and recommendations about screening for osteoporosis in both men and women. They discussed current screening methods and tools for predicting risk of osteoporotic fractures, and medical management to decrease the risk for osteoporotic fractures. The update is different from the 2002 recommendation as they address screening for osteoporosis in men and they recommended screening all women whose 10-year fracture risk is equal to or
greater than that of a 65-year-old white woman with no additional risk factors.
Figure A is a lateral radiograph of a vertebral compression fracture at the level of L4 with height loss and anterior wedging.
Incorrect Answers:
Answer 1: Her T score will likely be below -2.5.
Answer 3: A CT scan in a neurologically intact patient with adequate plain films is not indicated.
Answer 4: The order of fragility fractures are as follows from most common to least- VCFs> hips> distal radius
Answer 5: The patient's cause of the VCF is mostly likely osteoporosis with this demographic and mechanism.

**Which of the following treatments for osteoporosis is a direct inhibitor of RANK ligand (RANK-L)?**

1) Romosozumab

2) Zoledronic acid

3) Denosumab

4) Teriparatide

5) Blosozumab
**
Prolia, or denosumab, is a newly approved drug used to treat osteoporosis and has a mechanism of action similar to osteoprotegerin (inhibits binding of
RANKL to RANK).
RANKL (Receptor activator of nuclear factor kappa-B ligand) is a key molecule for osteoclast differentiation and activation. Inhibition of RANKL activity with anti-RANKL
antibody reduces osteoclastogenesis, resulting in inhibition of bone resorption.
Capozzi et al. author a review article on denosumab. They state the medication confers improved bone mineral density and prevents new fragility fractures similar to alendronate. However, denosumab presents less risk of atypical femoral fractures and osteonecrosis of the jaw.
Yasuda et al. present a review that details the creation of three elegant animal models to mimic metabolic bone disease and how the animal models can
create a template to help cure human metabolic bone disease. These enable modeling of osteoporosis, hypercalcemia, and osteopetrosis by treating normal mice with soluble RANKL (sRANKL), adenovirus expressing sRANKL, and anti- mouse RANKL neutralizing antibody, respectively. They report that these animal models can be established in about 14 days using normal mice.
Illustration A demonstrates the mechanism of action of bisphosphonates and denosumab.
Incorrect Answers:
1: Romosozumab is the first humanized anti-sclerostin monoclonal antibody that has been demonstrated to increase bone formation.
2: Zoledronic acid (Reclast) is a nitrogen containing bisphosphonates that inhibits osteoclast resorption by inhibiting the enzyme farnesyl diphosphate synthase.
4: Teriparatide (Forteo) comprises the first 34 amino acids of the 84 amino acid parathyroid hormone (PTH) and can reproduce the primary effects of PTH by activating adenyl cyclase.
5: Blosozumab is an investigational monoclonal anti-sclerostin antibody showing osteoanabolic properties with the potential to improve clinical
outcomes in patients with osteoporosis.

**Which of the following functions by inhibiting osteoblastogenesis in order to decrease bone formation?**

1) RANKL

2) Interleukin 1 (IL-1)

3) WNT signaling

4) Sclerostin

5) Osteoprotegrin
**
Sclerostin is a negative regulator of bone formation by inhibiting osteoblastogenesis.
Sclerostin is a glycoprotein expressed by osteocytes as a potent regulator of bone formation. Sclerostin impedes osteoblast proliferation and function by inhibiting the Wnt signaling pathways and thus inhibits bone formation.
Suen et al. performed a lab experiment with 120 rats that underwent femur fractures. The subjects were given Sclerostin monoclonal antibody (Scl-Ab) treatment or placebo. The Scl-Ab treatment group showed showed significantly higher ultimate load during mechanical testing and increased fracture healing with histologic testing. They concluded that an antibody to inhibit sclerostin
will have a net positive effect on fracture healing by allowing osteoblastogenesis.
Illustration A depicts how inhibition of sclerostin stimulates bone formation, and antibodies to sclerostin are potentially beneficial in the management of osteoporosis and some other skeletal diseases.
Incorrect Answers:
1: RANKL is secreted by osteoblasts and binds to the RANK receptor on osteoclast precursor and mature osteoclast cells
2: Interleukin 1 (IL-1) stimulates osteoclast differentiation and thus bone resorption 3: WNT signaling promotes osteoblast formation. In addition to increasing osteoblast
formation, the pathway upregulates osteoprotegrin (OPG) and OPG works by blocking osteoclastogenesis.
5: Osteoprotegrin is a decoy receptor produced by osteoblasts and stromal cells that binds to and sequesters RANKL and thus inhibits osteoclast
differentiation, fusion, and activation.

**Which of the following most accurately describes stainless steel?**

1) Composed of iron-carbon alloy, modulus of elasticity less stiff than bone

2) Composed of cobalt-chrome-molybdenum alloy, modulus of elasticity more stiff than bone

3) Composed of iron-carbon alloy, modulus of elasticity more stiff than titanium

4) Composed of cobalt-chrome-molybedenum alloy, modulus of elasticity less stiff than titanium

5) Composed of iron-carbon alloy, modulus of elasticity is more stiff than bone, cobalt- chrome, and aluminum-oxide (ceramic)
**
Stainless steel is primarily an iron-carbon alloy with other elements including molybdenum, chromium, and manganese. Illustration A demonstrates Young's modulus of elasticity for multiple orthopaedic biomaterials. Stainless steel is stiffer than bone and titanium but less stiff than ceramics and cobalt-chrome. Titanium most closely emulates the modulus of elasticy of bone. Friedman, et al reviews the basic sciences of orthopaedic biomaterials.

**A 60-year-old man undergoes bilateral total hip arthroplasty under a single anesthetic. Which intervention will best reduce postoperative anemia and the need for allogeneic blood transfusion?**

1) Normotensive epidural anesthesia

2) Spinal anesthesia

3) Hypotensive epidural anesthesia

4) Hypotensive total intravenous anesthesia

5) General anesthesia
**
In this patient, hypotensive epidural anesthesia (HEA) will best reduce postoperative anemia and the need for transfusion.
HEA creates an epidural block up to T2 to block cardio-acceleratory fibers of the thoracic sympathetic chain, and allow intraoperative mean arterial pressure (MAP) of 50mmHg.
Resultant bradycardia (and excessive hypotension) is treated with low-dose intravenous epinephrine. Other measures to lower the transfusion trigger include preoperative erythropoietin (EPO), preoperative autologous blood donation (ABD), and postoperative cell saving. Preoperative ABD can be used with acute normovolemic hemodilution (ANH) where 2-3 units of blood is exchanged for crystalloid/colloid during surgery, and retransfused back after surgery.
Moonen et al. reviewed perioperative blood management. For EPO, they state that 600 IE/kg weekly starting 3 weeks prior, or 300IE/kg daily for 14 days prior. They also recommend COX2 inhibitors to avoid the COX1-mediated antiplatelet effects of NSAIDS.
Morris et al. compared bipolar vs standard monopolar electrocautery in anterior THA. They found similar transfusion rates, postoperative hemoglobin and postoperative drop in hemoglobin between groups, although the bipolar group had average of 12.5cc more blood loss (140cc vs 127.5cc, p=0.03). They concluded that the utilization of hypotensive anesthesia explained the low blood loss. They discontinued routine use of bipolar cautery with anterior THA.
Incorrect Answers
Answers 1: Hypotension (reduced MAP of 50mmHg) is necessary to reduce intraoperative bleeding.
Answer 2: HEA results in reduced blood loss (because of hypotension) and postoperative transfusion compared with spinal anesthesia
Answer 4: Although hypotensive total intravenous anesthesia produces similar MAP levels compared with HEA, HEA results in less intraoperative blood loss. It is hypothesized that this is because HEA is associated with non-positive pressure ventilation (unlike HTIVA), better distribution of blood flow, and lower mean intraoperative central venous pressure.
Answer 5: Unlike general anesthesia, regional anesthesia (epidural and spinal) results in lower arterial blood pressure, lower central venous pressure, and lower peripheral venous blood pressure, resulting in lower blood loss.

**A researcher studies growth factors that have positive effects on cartilage healing. In vivo and in vitro experiments are performed with Growth Factor A. The properties of Growth Factor A include (1) it is the most widely investigated growth factor in cartilage repair, (2) it**
**increases extracellular matrix synthesis in cartilage and mesenchymal stem cells, and (3) it also triggers synovial proliferation and fibrosis. Which of the following is most likely to be Growth Factor A?**

1) Interleukin-1 (IL-1)

2) Tumor necrosis factor-alpha (TNF-alpha)

3) Fibroblast growth factor (FGF)

4) Transforming growth factor-beta 1 (TGF-beta1)

5) Platelet-derived growth factor (PDGF)
**
TGF-beta 1 stimulates the synthesis of extracellular matrix (ECM) and causes synovial proliferation and fibrosis.
TGF-beta is the most thoroughly investigated member of the TGF-beta superfamily. This group includes TGF-beta1, BMP-2, and BMP-7. Besides the above activities, TGF-beta1 also stimulates chondrocyte synthetic activity and decreases the catabolic activity of IL-1.
Fortier et al. reviewed the role of growth factors in cartilage repair and modification of osteoarthritis. They found that members of the TGF-beta superfamily, FGF family, IGF1, and PDGF have all been investigated as possible treatment augments in the management of chondral injuries and early arthritis. They concluded that more research was necessary before routine application.
Illustration A shows a summary of the different growth factors and their effects on cartilage.
Incorrect Answers:
Answer 1: IL-1 is catabolic and leads to cartilage breakdown rather than synthesis. Answer 2: TNF-alpha is a proinflammatory cytokine. It does not lead to cartilage synthesis.
Answer 3: Although FGF-2 increases proteoglycan synthesis and cell proliferation, it also increases inflammation and osteophyte formation and does not aid in healing of cartilage defects. FGF-18 is less well studied. Answer 5: PDGF has no adverse or positive effects on cartilage when used in vivo. Much evidence on its role is extrapolated from the effects of PRP.

**Passage of a sodium ion through a voltage-gated channel leads to which of the following?**

1) Apoptosis of gram negative bacteria

2) Binding of RANKL to osteoblasts

3) Inhibition of micturition

4) Generation of a nerve action potential

5) Deposition of salts in adipose tissue
**
Passage of sodium through a voltage-gated channel will lead to generation of a nerve action potential.
Voltage-gated channel are shut when the membrane potential is near the resting potential of the cell, but they rapidly begin to open if the membrane potential increases to a precisely defined threshold value. When the channels open (in response to depolarization in transmembrane voltage), they allow an inward flow of sodium ions, which changes the electrochemical gradient, which in turn produces a further rise in the membrane potential. This then causes more channels to open, producing a greater electric current across the cell membrane, and so on.
Lee et al. present a review article on nerve conduction and needle electromyography studies. They note that the three types of nerve conduction study are motor, sensory, and mixed, of which motor is the least sensitive. In
addition, they report that peripheral nerve entrapment initially results in focal demyelination; thus, nerve conduction velocity slows across the site. However, with radiculopathy and nerve root compression, the nerve conduction study may be normal.
Catterall presents a review article covering an overview of structural models of voltage- dependent activation, sodium selectivity and conductance, drug block and both fast and slow inactivation. He notes that voltage-gated sodium channels initiate action potentials in nerve, muscle and other excitable cells.
Illustration A is a diagram that shows the electrical recordings of an action potential, along with labels of each section of the process.

**Metastatic disease of several cancers create lytic lesions because these cancers:**

1) directly produce osteoprotegerin

2) stimulate osteoblasts to produce osteoprotegerin

3) directly produce receptor activator of nuclear factor kappa beta ligand (RANKL)

4) stimulate osteoclasts to produce receptor activator of nuclear factor kappa beta ligand (RANKL)

5) directly produce an analog to calcitonin

Several cancers directly produce receptor activator of nuclear factor kappa beta ligand (RANKL) which leads to bone resorption and the lytic lesions seen on radiographs.
Cancers that originate or metastasize to bone can be blastic, lytic, or mixed when viewed on radiographs. Lytic lesions appear radiolucent due to bone resorption that occurs around the cancer cells. This is secondary to direct production and release of RANKL by the cancer cells themselves. RANKL then stimulates osteoclastogenesis and an increase in local bone resorption. Denosumab is a monoclonal antibody against RANKL that has been shown to decrease rates of pathologic fractures.
Lynch et al. review the progression of metastatic disease. They note that cancer cells can stimulate both osteogenesis and osteolysis, and that this pathologic increase in bone matrix turnover is what allows the cancer to progressively expand or metastasize to distant sites. They discuss the role of matrix metalloproteinases as primary regulators of this process.
Illustration A is a diagram illustrating how the binding of RANKL to receptors on the surface of osteoclast precursors activates them and begins the process of bone resorption. Cancer cells can directly produce RANKL thus increasing the rate of local bone resorption.
Incorrect Answers:
Answers 1 and 2- Osteoprotegerin acts by sequestering RANKL as a decoy receptor and causes a decrease in bone resorption.
Answer 4- Osteoclasts do not secrete RANK-ligand, rather they express the receptor (RANK) for the ligand.
Answer 5- Calcitonin acts directly on osteoclasts to inhibit bone resorption.

**A postmenopausal patient comes to your office for follow-up after a dual- energy x-ray absorptiometry (DEXA) test. The T-score is**
**-0.7SD. The Z score is -0.4SD. By World Health Organization (WHO) criteria, these DEXA findings would merit a diagnosis of**

1) Normal

2) Osteopenia based on Z-score findings

3) Osteopenia based on T-score findings

4) Osteopenia based on T- and Z-score findings

5) Osteoporosis
**
By WHO classification, her findings (T-score of -0.7SD) would merit a diagnosis of Normal bone mineral density (BMD).
The WHO classifies bone density in postmenopausal women based on T- scores. Patients are classified based on the lowest T score of the spine, femoral neck, trochanter, or total hip. The classification should not be used with peripheral measurements. Z-scores are used for premenopausal women,
younger men, and in children. The Z score compares a patient with age-, sex-, and race- matched norms.
Blake and Fogelman reviewed the role of central DEXA in treatment of osteoporosis, compared with quantitative CT, peripheral DEXA and quantitative ultrasound. The advantages of central DEXA include results that can be interpreted using WHO T-score definitions, ability to predict fracture risk, and effectiveness at targeting antifracture treatments.
Templeton reviewed secondary osteoporosis. In women with osteoporosis, the most common causes of secondary osteoporosis include hypercalciuria, malabsorption, hyperparathyroidism, vitamin D deficiency, and exogenous hyperthyroidism. In men with osteoporosis, the most common causes of secondary osteoporosis include hypogonadism, corticosteroid use and alcoholism.
Unnanuntana et al. reviewed the assessment of fracture risk. The FRAX (World Health Organization Fracture Risk Assessment Tool) calculates 10-year risk of fracture based on the following variables: age, sex, race, height, weight, BMI, history of fragility fracture, parental history of hip fracture, use of oral glucocorticoids, secondary osteoporosis and alcohol use to calculate 10-year risk of fracture. They also discussed biochemical markers of bone formation
and resorption, which are useful for monitoring the efficacy of antiresorptive / anabolic therapy, and may help identify patients at high risk for fracture.
Illustration A shows the WHO classification. Illustration B shows a comparison between central DEXA and other methods of BMD measurement.
Incorrect Answers:
Answers 2, 3, 4: In a postmenopausal woman, only the T-score is used for classification. Osteopenia is defined as T score of between 1 and 2.5 standard deviations below the norm.
Answer 5: Osteoporosis is defined as a T-score of more than 2.5 standard deviations below the norm.

**You are staffing the prison clinic in a large public hospital when a 55-year-old African American male presents complaining of severe**
**right hip pain. His pain has been ongoing for the past five years and limits his ambulation. He has never used medications for pain control or physical therapy. A radiograph is shown in figure A. When formulating his treatment plan, it is important to:**
1) Guarantee the success of total hip arthroplasty

2) Recommend simultaneous bilateral total hip arthroplasty

3) Understand the role of implicit bias as a determinant of health care delivery disparity

4) Request the patient reveal the reason for his incarceration

5) Suggest referral to a pain management clinic
is not appropriate at this time.

**Which of the following genetic disorders has an X-linked recessive inheritance pattern?**

1) Gaucher disease

2) Prader-Willi Syndrome

3) Diastrophic Dysplasia

4) Hemophilia A

5) Hypophosphatemic rickets
**
Hemophilia A is inherited in an X-linked recessive fashion.
X-linked recessive disorders occur when a mutation occurs on the X chromosome that causes the phenotype to be expressed in males and in females who are homozygous for the gene mutation. These disorders are much more common in males since they only have one X chromosome. Other X-linked recessive disorders include: Duchenne muscular dystrophy, Becker's muscular dystrophy, Hunter's syndrome, and spondyloepiphyseal dysplasia (SED) tarda.
Vanderhave et al. reviewed the orthopaedic consideration in patients with hemophilia. Amongst other things, they discuss arthroplasty in patients with this condition. While they are at higher risk for stiffness and acute hemarthrosis following total knee arthroplasty, ~90-95% of patients have good or excellent results.
Illustration A shows how hemophilia is inherited through a punnett square. Illustration B shows how a weak clotting mechanism causes increased bleeding in patients with hemophilia.
Incorrect Answers:
Answer 1: Gaucher disease is an autosomal recessive condition.
Answer 2: Prader-Willi Syndrome is inherited through imprinting. Imprinting is a genetic phenomenon by which certain genes are expressed in a parent-of- origin-specific manner. Answer 3: Diastrophic dysplasia is an autosomal recessive condition. Answer 5: Hypophosphatemic rickets is a sex-linked dominant condition.

**Which of the following best describes the process of transcription?**

1) Reading DNA information to synthesize and replicate during the S phase of the cell cycle

2) Generating a haploid product with a genotype that differs from both haploid genotypes that constituted the meiotic diploid cell.

3) Generating a polypeptide whose amino acid sequence is derived from the codon sequence of an mRNA molecule.

4) Exchanging of two nonhomologous chromosomes resulting in chromosomal rearrangement mutations

5) Reading DNA information by RNA polymerase to make specific complementary mRNA
**
The process of reading DNA information by RNA polymerase to make specific complementary mRNA is known as transcription.
Transcription relies on the complementary pairing of bases to create mRNA from DNA. The two strands of the double helix separate, and one of the separated strands serves as a template. Then, free nucleotides are arranged on the DNA template by their complementary ribonucleotide bases in the template. The free ribonucleotide A aligns with T in the DNA, G with C, C with G, and U with A.
Musgrave et al discuss orthopaedic surgery related gene therapy and tissue engineering topics. Specific sectors of musculoskeletal medicine where gene therapy and tissue engineering have shown promise and early treatment success include the areas of bone healing, cartilage repair, intervertebral disk pathology, and skeletal muscle injuries.
Incorrect Answers:
1: This is the definition of replication.

**
Etanercept is a biochemically designed tumor necrosis factor receptor immunoglobulin G fusion protein, which binds to TNF-alpha and is thus a TNF- alpha antagonist.
TNF-alpha is considered to be one of the major cytokines involved in rheumatoid arthritis pathology. As a result, many biologic agents used to treat rheumatoid arthritis (RA) are manufactured to block TNF-alpha or its
receptors. This has been shown to reduce inflammation and stop disease progression. In the USA, Etanercept is approved to treat rheumatoid arthritis, juvenile rheumatoid arthritis and psoriatic arthritis, plaque psoriasis and ankylosing spondylitis. The route of administration is subcutaneous.
Bongartz et al. used a randomized control trial to asses the risk of infection and
malignancy rates in RA treated with TNF-alpha antagonist. Overall, patients with RA appear to have an approximately 2-fold increased risk of serious infection compared to the general population and non-RA controls, irrespective of TNF-alpha antagonist use. The pooled odds ratio for malignancy was 3.3 (95% confidence interval [CI], 1.2-9.1) and for serious infection was
2.0 (95% CI, 1.3-3.1) with use of TNF-alpha antagonist.
Howe et al. review the medical management of patients with RA who underwent orthopaedic procedures. They state that while there is conflicting information regarding TNF-alpha antagonists, they recommend holding them prior to major orthopaedic interventions.
Incorrect Answers:

: Rituximab is a monoclonal antibody to CD20 antigen (inhibits B cells). It is often used with good clinical outcomes as monotherapy in patients who are intolerant of methotrexate or have contraindications to methotrexate or other DMARDs.
Answer 3: Abatacept is a selective costimulation modulator that binds to CD80 and CD86 (inhibits T cells). It is often prescribed for treatment of moderate to severe rheumatoid arthritis, or after failure of a disease-modifying anti- rheumatic agent (DMARD), like methotrexate but it can be used as first-line therapy.
Answer 4: Methotrexate is a folic acid analogue. It binds dihydrofolate reductase and prevents synthesis of tetrahydrofolate. It is usually a first line treatment for moderate to severe rheumatoid arthritis.
Answer 5: Leflunomide is an inhibitor of pyrimidine synthesis. It is approved to treat adult moderate to severe rheumatoid arthritis, usually as a monotherapy or failure of other DMARDs.

**Cortical bone demonstrates viscoelastic behavior as its mechanical properties are sensitive to strain rate and duration of applied load. Regarding longitudinal strain in cortical bone, which of the following statements regarding this characteristic is true?**

1) As strain rate increases, both elastic modulus and ultimate strength increase

2) As strain rate increases, elastic modulus remains unchanged but ultimate strength increases

3) As strain rate increases, elastic modulus increases but ultimate strength decreases

4) As strain rate increases, both elastic modulus and ultimate strength decrease

5) As strain rate increases, elastic modulus increases but ultimate strength remains unchanged
**
As strain rate increases, both elastic modulus and ultimate strength increase. For LOW strain rates typical of normal activity (physiological strain rates of
0.1/s, high impact trauma), bone is VISCOELASTIC and BRITTLE (low ultimate strain with increasing strain rate). Bone also becomes stronger and stiffer (higher modulus, steeper slope of stress- strain plot) as strain rate increases. This viscoelastic property helps in damping muscle contracture.
Natali and Meroi reviewed studies examining mechanical properties of bone. Mechanical properties are correlated with moisture, deformation rate, density and region of bone.
Mechanical adaptation of bone is affected by strain rate (rate at which bone is deformed), strain mode (tension, compression, shear), strain direction (direction of strain relative to bone surface), strain frequency (cycles/second), stimulus duration (period over which deformation cycles are applied), strain distribution (pattern of strain magnitude across bone section) and strain energy (energy stored during deformation).
Illustration A shows the mechanical properties of bone with increasing strain rates. Illustration B shows that the ultimate strength and elastic modulus increase with rapid loading or deformation. The ultimate strength increases by roughly a factor of 3, while the elastic modulus increases by a factor of
approximately 2 over the strain rate range.
Incorrect Answers:
Answers 2, 3, 4, 5: As strain rate increases, elastic modulus and ultimate strength increase. During normal activity, as strain rate increases, bone is more ductile. With high impact trauma, bone is more brittle.

**In regards to a genetic disorder, which of the following is an example of "anticipation?"**

1) Gene characteristics more severe and earlier in onset in subsequent generations

2) A disorder inherited from a genetic mutation specific to maternal DNA

3) Gene characteristics expressed to varying degrees in different individuals

4) Variation in the relative frequency of a genotype due to chance

5) The presence of an extra copy of a chromosome
**
Genetic anticipation is a phenomenon in which a genetic disorder becomes progressively more severe and earlier in onset with each generation. Examples of disorders exhibiting anticipation include Huntington's disease and myotonic dystrophy.
Genetic anticipation is an important concept in understanding the development and genetic implications of many heritable disorders. It is a common phenomenon in trinucleotide repeat expansion disorders. These disorders are due to unstable microsatellite trinucleotide repeats that expand beyond the normal threshold. In subsequent generations these expansions become longer and thus express disease characteristics at a younger age of onset, and often with greater severity.
Martorell et al. investigated the development of CTG trinucleotide repeats in patients with myotonic dystrophy type 1 (DM1) and their relatives. They discovered unaffected individuals carry a pre-mutation sequence which can lead to trinucleotide repeat expansion in subsequent generations and thus produce offspring with the disorder.
Kamsteeg et al. compare the characteristics of DM1 and DM2. Both are due to trinucleotide repeat expansions. However, while DM1 can present with earlier onset and increasing severity in each generation, DM2 does not exhibit this genetic anticipation.
Incorrect Answers
Answer 2: "Genomic imprinting" is when a disorder is linked to a parent- specific origin. An example of maternal genomic imprinting is Angelman Syndrome. An example of paternal genomic imprinting is Prader Willi.
Answer 3: "Variable penetrance" is when gene characteristics are expressed in varying degrees.
Answer 4: "Genetic drift" is the chance variation in the relative frequency of a genotype within a population.
Answer 5: "Trisomy" is the presence of an extra copy of a chromosome. Down Syndrome is trisomy 21, which is due to an extra copy of chromosome 21.

**A researcher is working on Medication A, a drug FDA-approved for the treatment of osteoporosis in men and women. It is an anti- resorptive agent that inhibits the formation, function and survival of osteoclasts. It does not bind to calcium hydroxyapatite. At 1-year after the initial dose, tissue levels are non- detectable. It can be used in the presence of cancer metastases to bone. What is Medication A?**

1) Denosumab

2) Alendronate

3) Abaloparatide

4) Teriparatide

5) Strontium ranelate
**
Denosumab is FDA-approved for the treatment of osteoporosis in men and women. It inhibits the formation, function and survival of osteoclasts (OC). It does not bind to calcium hydroxyapatite. At 1-year after the initial dose, tissue levels are non-detectable.
Denosumab is a human monoclonal antibody against RANKL. By binding RANKL, it prevents interaction of RANKL with RANK (on OC and osteoclast precursors, OCP), and inhibits OC-mediated bone resorption, and the formation, function and survival of OC. In contrast, bisphosphonates bind to calcium hydroxyapatite in bone, and decrease resorption by decreasing function and survival (but not formation) of OC.
Vaananen et al. reviewed the cell biology of OC. During bone resorption, 3 membrane domains appear: ruffled border, sealing zone and functional secretory domain. The resorption cycle starts with migration, bone attachment, polarization (formation of membrane domains), dissolution of hydroxyapatite, degradation of organic matrix, removal of degradation
products from resorption lacuna, and apoptosis of the OC or return to the non- resorbing stage.
Boyce et al. reviewed the regulation of osteoclasts and their functions. OCPs are held in bone marrow by chemokines e.g. stroma-derived factor-1 (SDF1) and attracted to blood by sphingosine-1 phosphate (S1P) (increased in synovial fluid of patients with RA). All aspects of osteoclast formation and functions are regulated by M-CSF and RANKL. More recent studies indicate that osteoclasts and their precursors regulate immune
responses and
osteoblast formation and functions by means of direct cell-cell contact through ligands and receptors, such as ephrins and Ephs, and semaphorins and
plexins, and through expression of clastokines.
Warriner and Saag reviewed the diagnosis and treatment of osteoporosis. They defined osteoporosis as T-score of = -2.5 or a history of fragility fracture. Incident hip and vertebral fractures increase future risk of these fractures (hazard ratio 7.3 and 3.5, respectively).
Cummings et al. compared subcutaneous denosumab (60mg every 6mths) vs placebo in prevention of fractures in 7868 osteoporotic (T-score -2.5 to -4.0) postmenopausal women. They found that denosumab reduced risk of vertebral fracture by 68% (risk ratio, 0.32), hip fracture by 40% (hazard ratio 0.6), nonvertebral fracture by 20% (hazard ratio 0.8). There was no increased risk of cancer, infection, delayed fracture healing, cardiovascular disease, osteonecrosis of the jaw or adverse reactions. They concluded that it was useful for reduction of fractures in osteoporotic women.
The video shows the action of denosumab (prolia). Illustration A shows the different osteoclast zones.
Incorrect Answers:
Answers 2: Alendronate (and other bisphosphnates) inhibit resorption of bone, decrease function and survival of osteoclasts. Because of binding to calcium hydroxyapatite, they are detectable years after dosing. They reduce function and survival of OC, but do not affect the formation of osteoclasts.
Answer 3: Abaloparatide is a PTH analog that has completed phase III trials for osteoporosis. As of mid-2016, it is not yet approved for treatment of osteoporosis. Answer 4: Teriparatide (recombinant PTH 1-34) is the only anabolic (not antiresorptive) agent approved for osteoporosis treatment. It is administered by daily subcutaneous injection. Osteosarcoma, cancer metastases to bone and Paget's disease are contraindications.
Answer 5: Strontium ranelate (marketed as Protelos or Protos) both increases deposition of new bone by osteoblasts and reduces the resorption of bone by osteoclasts ("dual action bone agent", DABA). It is not FDA approved for use in the United States. Increased risk of myocardial infarction has been detected.

**Which specific legislative Act in the United States was created to require reporting of annual monetary gifts or compensation of more than $10 by orthopaedic implant companies to physicians?**

1) Patient Protection and Affordable Care Act

2) Medicare Payment Reform Act

3) Physician Financial Transparency Act

4) Physician Payments Sunshine Act

5) Health Insurance Portability and Accountability Act
**
The Physician Payments Sunshine Act requires all payments by corporations to physicians beyond $10 per year to be reported to the Centers for Medicare and Medicaid Services.
Under this Act, all manufacturers of drugs and devices covered under Medicare, Medicaid, and SCHIP are obliged to federally report payments beyond $10 annually to physicians and academic centers. The Act was first introduced in 2007, enacted in 2010, and in 2014 the first data (from 2012) was reported publicly online in the Open Payment Program of the Centers for Medicare and Medicaid Services website.
Samuel et al analyze orthopedic surgeons available data from the Sunshine Act regarding industry payments and find over 110 million USD paid to approximately 15,000 orthopedic surgeons over the 5-month study period. No long term data exists to determine if these payments have any affect in healthcare.
Incorrect Answers:
Answers 1: The Patient Protection and Affordable Care Act (PPACA), known also by its shorter name of the Affordable Care Act (ACA) or it's nickname
"Obamacare", was passed in March 2010. The Sunshine Act was one of many provisions passed within the PPACA (after the Sunshine Act failed to pass on its own in prior years), but the PPACA focused primarily on improving the quality and affordability of healthcare insurance and lowering the costs of healthcare.
Answer 2: The Medicare Payment Reform Act of 1983 was a quickly drafted revision to the way Medicare payments were made, changing from fee-for- service to prospective payments allowing Medicare to determine payment amount rather than providers/hospitals.
Answer 3: This is a fictitious act.
Answer 5: HIPPA is the 1996 legislation defining standards and protections for patient private health information and electronic exchange of records.

**Which of the following materials best approximates the Young's modulus of elasticity of cortical bone?**

1) Titanium

2) Cobalt-chrome alloy

3) Alumina

4) Zirconia

5) Stainless steel
**
Of the materials listed titanium (100GPa) has an elastic modulus closest to cortical bone (approximately 18GPa) as well as cancellous bone (approximately 2GPa).
Titanium is a material that is light, highly ductile, strong and corrosion resistant. However, titanium has poor wear resistance and is notch sensitive. It is commonly used as an orthopaedic implant materials because it has torsional and axial stiffness (moduli) that most closely mimics bone. Young’s modulus is constant and different for each material and represents the material's ability to maintain shape under external loading.
Rho et al found that the average Young's modulus for trabecular bone measured ultrasonically and mechanically was 14.8 GPa (S.D. 1.4) and 10.4 (S.D. 3.5), respectively. The average Young's modulus of microspecimens of cortical bone measured ultrasonically and mechanically was 20.7 GPa (S.D.
1.9) and 18.6 GPa (S.D. 3.5), respectively.
Illustration A depicts a stress vs. strain curve. The slope of the line in the elastic zone represents the Young Modulus of Elasticity.
Incorrect Answers:
Answer 2: Cobalt-chrome alloy is approximately 240 GPa Answer 3: Alumina is approximately 340 GPa
Answer 4: Zirconia (Ceramic) = 248 GPa
Answer 5: Stainless steel is approximately 240 GPa

**The difference between vitamin D-dependent rickets type I (VDDR I) and vitamin D-dependent rickets type II (VDDR II) is**

1) VDDR I is caused by an inactivating mutation of the receptor for 1,25 (OH)2 vitamin D3. VDDR II is a deficiency of an enzyme predominantly found in the kidney.

2) VDDR I is caused by an activating mutation of the receptor for 1,25 (OH)2 vitamin D3. VDDR II is a deficiency of an enzyme predominantly found in the kidney.

3) VDDR I is a deficiency of an enzyme predominantly found in the kidney. VDDR II is caused by an inactivating mutation of the receptor for 1,25 (OH)2 vitamin D3.

4) VDDR I is a deficiency of an enzyme predominantly found in the kidney. VDDR II is caused by an activating mutation of the receptor for 1,25 (OH)2 vitamin D3.

5) VDDR I is a deficiency of an enzyme predominantly found in the liver. VDDR II is caused by an inactivating mutation of the receptor for 1,25 (OH)2 vitamin D3.

VDDR I is a deficiency of an enzyme predominantly found in the kidney. VDDR II is caused by an inactivating mutation of the receptor for 1,25 (OH)2 vitamin D3.
VDDR I is a deficiency of 1a-hydroxylase [converts 25(OH)D to
1a,25(OH)2D3]. Lab tests show hypocalcemia, secondary hyperparathyroidism, elevated alkaline phosphatase (ALP) and low or undetectable calcitriol in the presence of adequate 25(OH)D levels. VDDR II or hereditary vitamin D resistant rickets (HVDRR) (autosomal recessive) is an inactivating mutation in the vitamin D receptor (VDR). Lab tests show low serum calcium and phosphate, elevated ALP and secondary hyperparathyroidism. Serum 25(OH)D values are normal and the 1,25(OH)2D levels are elevated (key difference from VDDR I).
Malloy et al. reviewed genetic disorders in vitamin D action. They state that VDDR I is an inborn error of vitamin D metabolism coded by the gene CYP27B1. Children with VDDR I present with joint pain/deformity, hypotonia, muscle weakness, growth failure, and hypocalcemic seizures or fractures in early infancy. Treatment is with calcitriol or 1a-hydroxyvitamin D (NOT cholecalciferol). Children with VDDR II present with bone pain, muscle weakness, hypotonia, hypocalcemic convulsions, growth retardation, severe dental caries or teeth hypoplasia. Affected children are resistant to therapy and supra-physiologic doses of all forms of vitamin D.
Illustration A shows the differences between VDDR I and VDDR II. Incorrect Answers
Answers 1, 2, 4, 5: VDDR I is a deficiency of 1a-hydroxylase (predominantly
found in the kidney). The liver enzyme vitamin D 25-hydroxylase (found in hepatocytes) is not responsible for VDDR. VDDR II is caused by an inactivating mutation (rather than an activating mutation).

**A 73-year-old female sustains a left hip fracture that is treated with hemiarthroplasty. She has continued pain two months after surgery, and comes to you for a second opinion. Her radiograph is shown in Figure A. Which of the following best describes your responsibility in disclosing to the patient that the pain may be from a medical error?**
1) You do not need to disclose this information

2) You legally must disclose this information to the patient

3) You legally must disclose this information to the original hospital's peer review panel

4) You ethically must disclose this information to the patient

5) You ethically must disclose this information to the original surgeon
**
As a practicing orthopaedic surgeon, you ethically are required to disclose the potential impact of medical errors on patient outcome.
The orthopaedic surgeon is bound ethically but not legally to give his or her best medical opinion, regardless of whether the orthopaedist is the treating physician or the physician who is asked to render a second or additional medical opinion. The best interest of the patient should clearly remain the guiding principal. It is illegal to slander the original physician if the slanderous
information is known or can be proven to be false.
Bhattacharyya et al. review the importance of documentation and ethical treatment of patients when providing second opinions. They note that it is unethical for the consulting orthopaedic surgeon to solicit care of the patient. However, at the sole discretion of the patient, the patient ethically may choose to terminate his or her relationship with his or her treating physician and then enter into another treatment relationship with the consulting
orthopaedic surgeon.
Figure A shows a left hip hemiarthroplasty with the distal component perforated through the medial proximal femur.
Incorrect Answers:
1) This information must be disclosed per ethical recommendations. 2 and 3) There is no legal requirement to disclose this information.
5) There is no documented ethical requirement to disclose this to the original surgeon.

**A patient is consented for a right wrist open reduction and internal fixation. After the patient is prepped and draped, a skin incision is made. It is recognized intra-operatively, however, that a skin incision was made on the incorrect side (left). Subsequent right wrist open reduction and internal fixation goes uneventfully. What is the next best course of action?**

1) do not tell the patient or family

2) contact the Risk Management department

3) immediately discuss the situation with the patient and family

4) alter the medical record

5) only discuss the situation with the patient if he or she brings it up.

**
Patients should be approached after a medical error and all errors must be promptly and completely disclosed. The physician should take the lead in the disclosure and not wait for the patient to ask. Risk management should be called as well, but the patient and family should be informed first. It is never appropriate to alter the medical record.

**A 14-year-old female has anal hemorrhoids. The General Surgical team has asked for a consultation in regards to her history of hand, wrist, and ankle joint pain and swelling over the past 3 years. Her physical examination reveals a swollen left wrist, right knee and left ankle. Lab work shows low hemoglobin, low albumin, elevated erythrocyte sedimentation rate (ESR), elevated antinuclear antibody (ANA) count, and a negative rheumatoid factor. Radiography of the affected joints are normal. What additional work up is required prior**
**to her rectal surgery?**

1) C-reactive protein (CRP)

2) Synovial fluid analysis of affected joints

3) Blood cultures

4) Cervical radiographs

5) Bethesda assay
**
This patient has a diagnosis of Juvenile Idiopathic Arthritis (JIA). Flexion- extension c-spine radiographs should be ordered to rule out atlantoaxial instability prior to surgery.
JIA is a persistent autoimmune inflammatory arthritis lasting more than 6 weeks in a patient younger than 16 years of age. Serologic testing for this condition will usually show elevated ESR/CRP, low hemoglobin, low albumin and an elevated anti-nuclear antibody (ANA) count, as well as negative rheumatoid factor and positive HLA-B27. Radiographs of the c-spine should be considered in patients undergoing intubation as cervical kyphosis, facet ankylosis, and atlantoaxial subluxation is associated with this condition.
Punaro et al. reviewed rheumatologic conditions in children. The typical patient with oligoarticular JIA is a white female (5:1, F:M), with a peak onset between ages 1 and 3 years. Nearly half of patients have monoarticular involvement, with the knee and ankle being most commonly involved. Uveitis is typically chronic, bilateral, and asymptomatic.
Borchers et al. reviewed juvenile idiopathic arthritis (JIA). They state that no laboratory test can conclusively establish a rheumatic diagnosis. They state that laboratory tests will be negative for systemic inflammation and antinuclear antibody (ANA) test has no use in screening for JIA, as it has a high false positive rate.
Incorrect Answers:
Answer 1: Both ESR and CRP are usually elevated in this condition and provide no further benefit for the operative management of this patient.
Answer 2: This patient has chronic joint swelling and pain. Joint aspirates and synovial fluid analysis would not be required.
Answer 3: There is no suspicion for an acute infection. Therefore, blood cultures are not required.
Answer 5: A Bethesda assay is used to measure the amount of factor VIII or IX antibody in the blood, for patients with hemophilia.

**Induction coupling stimulates bone growth through all of the following direct effects EXCEPT:**

1) Increased proliferation of osteoblasts

2) Decreased osteoclast differentiation

3) Increase release of TGF-beta1

4) Increased expression of BMP2

5) Increased expression of BMP7
**
Induction coupling stimulates bone growth by increasing expression of BMP7, BMP2, TGF-beta1, and by increasing osteoblasts proliferation. Induction coupling has not been shown to have the effect of decreasing osteoclast differentiation.
In basic science studies, electrical stimulation (i.e. induction coupling), has been shown to promote bone healing via release of growth factors that induce osteoblast differentiation/proliferation. Electrical current can be placed around bone in various ways, creating a current to stimulate growth factor release and subsequent osteoblast proliferation.
Aaron et al. summarized, in a systematic review, the effects of various types of electrical stimulation on bone and bone healing. Regardless of type (i.e. inductive coupling, capacitive coupling, direct current), they report electricity and/or electromagnetic fields promote gene expression of growth factors that promote an osteogenic environment.
Illustration A depicts a cathode placed directly to allograft with a subcutaneously placed electrical stimulator. Illustration B depicts cathodes placed anteriorly and posteriorly around the hip, connected to an outside power source to create the necessary current. Illustration C depicts an inductive coil placed laterally on the skin in order to create an electrical current.
Incorrect answers:
Answers 1,3-5: All are true effects of electrical stimulation on bone.

**Two patients are discharged from a surgicenter after upper extremity procedures. The surgeon gives them prescriptions for oral opioid analgesics. Patient A had open reduction and internal fixation of a distal radius fracture. Patient B had cubital tunnel release without transposition. Which of the following is most likely true regarding analgesic use?**

1) Patient A will use more medication than Patient B

2) Patient A will use less medication than Patient B

3) Analgesic use will be similar between Patients A and B

4) Both patients will consume more than 30 pills

5) A reasonable prescription is 40 pills with 1 refill for Patient A, and 40 pills with no refills for Patient B
**
A patient that has had ORIF will require MORE oral analgesia than a patient who has had a cubital tunnel release.
Patients undergoing bony procedures (e.g. ORIF and arthroplasty) require more analgesia than patients undergoing soft tissue procedures (e.g. carpal/cubital tunnel release, trigger finger release, elbow or shoulder arthroscopy). Overprescribing of opioid analgesia is a common problem. Many opioids are unused in the postoperative period by the patients for whom they were prescribed.
Rodgers et al. reviewed opioid use (oxycodone, hydrocodone, propoxyphene) after outpatient upper extremity surgery. Patients undergoing bony procedures used the most analgesia (14 pills) while those undergoing soft tissue
procedures used the least (9 pills). Half took medication for =
**What property of titanium alloys accounts for their high corrosion resistance in vivo?**

1) Self-passivation

2) Ductility

3) Hardness

4) Modulus of elasticity

5) Conductivity
**
In both room temperature air and physiologic fluids, titanium alloys self- passivate or spontaneously form a layer of titanium oxide very rapidly. This layer makes titanium alloys resistant to surface breakdown.

**Embolic material generated during total knee arthroplasty (TKA) shown in Figure 29 is composed of which of the following substances?**
1) Fat only

2) Fat and air

3) Fat and marrow

4) Fat and cement

5) Fat and bone
**
Emboli are created during TKA. Usually there is an increased incidence with
the use of intramedullary rods that disrupt the marrow contents. These are not fat emboli per se. They are material composed of fat cells and marrow that act like pulmonary emboli
to obstruct small arterioles in the lung. They are different from free fat emboli that are seen in fractures and that lead to chemical injury to the lung rather than obstructive injury.

**There is increasing concern about the ethical relationship of orthopaedists to the orthopaedic equipment industry. Which of the following describes the most appropriate relationship?**

1) Industry-paid travel, hotel (for the surgeon and spouse), and registration at a university- sponsored CME course

2) Industry-paid travel and hotel for a faculty member at an industry- sponsored meeting that is not CME approved

3) Consultation agreement ($50,000/annum) between the surgeon and the company for evaluation of the implant system with required oral reporting of impressions

4) A restricted grant from a company to an orthopaedic residency program with the stipulation that the third year residents be sent to an industry- sponsored course

5) Industry-paid dinner at a premium restaurant ($200/person) for surgeon and office staff at which a new set of surgical instrumentation is presented
**
It is appropriate for orthopaedic surgeons to have relationships with industry as long as the relationship is for the good of the patient and no “quid pro quo” intent exists. A grant to cover registration at a CME event is appropriate but travel and hotel for a spouse is not.
For orthopaedists who are faculty at a meeting sponsored by industry, it is appropriate for travel and expenses to be covered for that faculty member. Care must be exercised that the faculty member contributes in an amount appropriate for the expenses paid. The faculty member must ensure that information presented is unbiased and based on reasonable data and opinion. Consulting agreements should spell out specifically the duties of the agreement and payment should be appropriate for the time spent. There should be a defined work product for the consulting. Agreements that are thinly veiled payments for use of a company’s products must be avoided. In all cases, the agreements must stand up to public
scrutiny. Restricted grants for specific industry-sponsored programs aimed at residents are not appropriate. Unrestricted grants intended for attendance at approved CME courses are appropriate. Dinners at which information is presented about topics that can aid in patient care are appropriate as long as the expense is reasonable ($100 or less/person) and the guest list includes individuals who can use the information in a patient case. Clearly a “premium” dinner for office staff to review new surgical instrumentation would not pass this test.

**Figure 33 shows the venogram of a patient who has a long history of alcohol abuse. Warfarin should be used cautiously because of the interaction with which of the following factors?**
1) IV

2) V

3) VI

4) VII

5) VIII
**
Warfarin acts by inhibiting clotting factors II, VII, IX, X. The actual mechanism of action is by inhibition of hepatic enzymes, vitamin K epoxide, and perhaps vitamin K reductase.
This inhibition results in lack of carboxylation of vitamin
K-dependent proteins (II, VII, IX, X). The anticoagulant effect of warfarin can be reversed with vitamin K or fresh-frozen plasma. The use of alcohol may lead to liver dysfunction and an even more limited margin of available factors.

**Familial (Leiden) thrombophilia is of importance in joint arthroplasty because of an abnormality in the clotting cascade. Which of the following statements best describes the condition?**

1) It is a disease caused by an abnormality of platelets that leads to increased blood clotting.

2) It is a disease caused by an abnormality of vascular endothelium that leads to increased blood clotting.

3) It is a disease caused by an abnormality of hepatic metabolism that leads to decreased production of factor V and decreased blood clotting.

4) It is a disease caused by an abnormality of factor V that leads to decreased inactivation of factor Va by activated protein C (aPC) and increased blood clotting.

5) It is a familial, genetic disease that requires placement of a Greenfield filter in all
individuals who have the abnormality, prior to surgery.
**
Factor V Leiden is a disease caused by an abnormality of factor V in which a single amino acid substitution of glutamine for arginine in the protein C cleavage region leads to decreased inactivation of factor V and thus a greater tendency to form clots. More than half of all individuals with Factor V Leiden will develop deep venous thrombosis in the presence of a single additional risk factor such as long bone fracture or total joint arthroplasty.

**Which of the following terms best describes the probability of finding a significant association in a research study when one truly exists?**

1) Type-1 (alpha) error

2) Type-2 (beta) error

3) Power

4) Alpha level

5) Relative Risk
**
The power of a study is an estimate of the probability of finding a significant association in a research study when one truly exists.
The

Scientific References

by Kocher and Wojtys are excellent reviews of basic biostatistic principles. Incorrect Answers:
Answer 1: The power is defined by 1 - probability of type-II (beta) error, and is often set at 80%. For example, a power of 80% means that if the
intervention works, the study has an 80% chance of detecting this and a 20% chance of randomly missing it.
Answer 2: A type-II or beta error occurs when one falsely concludes that there is no significant association when there actually is an association (resulting in
a false-negative study that rejects a true alternative hypothesis). The type-II or beta error can be determined if Type I error rate and sample size are known. A type-I or alpha error occurs when a significant association is found when there is no true association (resulting in a false-positive study that rejects a true null hypothesis).
Answer 4:The alpha level refers to the probability of a type-I (alpha) error and is usually set for most studies at 0.05.
Answer 5:The relative risk is a term used in prospective cohorts studies and is the risk of developing disease for people with known exposure compared to risk of developing disease without exposure.

**Which of the following substances makes up the majority by weight of the extracellular matrix for articular cartilage?**

1) Keratin sulfate

2) Collagen type II

3) Water

4) Protein

5) Chondroitin sulfate
**
The extracellular matrix consists of water, proteoglycans, and collagen. Water makes up the majority (approximately 65% to 80%) of wet weight; 95% of the collage is type II with much smaller amounts of other collagens, including types IV, VI, IX, X, and XI. The exact functions of these other collagens are unknown, but they are believed to be important in matrix attachment and stabilization of the diameter of collagen fibrils.

**A pediatric orthopaedic surgeon refers a child to a neurologist. The neurologist’s office requests the office records of the pediatric orthopaedic surgeon. To maintain Health Insurance Portability and Accountability Act (HIPAA) compliance, what must the surgeon obtain from the parent(s) prior to sending records?**

1) No additional consent needed

2) Verbal approval

3) Written approval

4) Written approval with notarization

5) Telephone consent witnessed by a nurse
**
The privacy rules do not require an individual’s written authorization for certain permitted or required uses and disclosures of the medical records. Patient or parental authorization is not required for disclosures for certain purposes related to treatment, payment, or health care operations. Specifically, HIPAA does not require a covered entity to obtain patient authorization for many of the health care industry’s most fundamental activities such as providing care.

**What is the most important consideration in the preoperative evaluation of a child with polyarticular or systemic juvenile rheumatoid arthritis (JRA)?**

1) Cervical spine assessment

2) Temporomandibular joint (TMJ)/jaw assessment

3) Dental assessment

4) Stress dosing with corticosteroids

5) Opthalmology examination
**
The cervical spine may be involved in a child with polyarticular or systemic JRA; fusion or instability can occur. Radiographic assessment of the cervical spine should include lateral flexion-extension views. The potential exists for spinal cord injury during intubation or positioning in t
he presence of an unstable cervical spine. Limitations of the TMJ and micrognathia may affect ease of intubation and administration of anesthesia via a mask. If the TMJ and jaw are involved, some patients may have dental findings such as dental caries and even abscesses which can affect surgery. Some children, particularly those with systemic arthritis, may be taking corticosteroids long- term and may need stress dosing with complex surgeries. Although it is important to routinely check for uveitis and iritis in children with JRA, this usually is not needed preoperatively. Uveitis and iritis are less likely in a child with systemic JRA.

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