Biology, Genetics & Bone Healing MCQs

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 Answersin 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).

The first stage of osteoarthritis is marked by an increase in water content secondary to disruption of the matrix framework. This is followed by an increase in chondrocyte anabolic and catabolic activity in response to tissue damage. Wnt-induced signal protein 1 increases chondrocyte protease expression. Failure to restore tissue balance ultimately leads to continued destruction and osteoarthritis. One hallmark of osteoarthritic cartilage is a reduced repair mechanism attributable to decreased chondrocyte response to growth factor stimulation (transforming growth factor-alpha and insulin-like growth factor-1). Mitochondrial dysfunction and increased production of reactive oxygen species may promote cell senescence, a progressive slowing of cellular activity. Microscopic evidence of cartilage degeneration begins with fibrillation of the superficial and transition zones, followed by disruption of the tidemark by subchondral blood vessels and eventual subchondral bone remodeling. This process ultimately leads to cartilage degradation with decreased water content in the late and terminal phases of osteoarthritis.

Based on the signs and symptoms, Paget's disease is the most likely diagnosis. In Paget's disease, an elevated alkaline phosphatase level and high output heart failure may be seen. Hearing loss can be seen when there is involvement of the skull, and malignant degeneration is uncommon but recognized as a risk. Patients are often treated with bisphosphonate medications during the active disease process to help control osteoclastic activity and pain. Vitamin D and calcium are more appropriate for treatment of osteoporosis. Methotrexate is not indicated for the treatment of Paget's disease. NSAIDs may be helpful to treat pain associated with Paget's disease but will not alter the clinical course.

Bone morphogenetic proteins (BMPs) are extracellular proteins belonging to the TGF-beta superfamily of molecules. Members of this family include BMPs, growth and differentiation factors (GDFs), anti-mnllerian hormone (AMH), activin, Nodal, and TGF-beta. These proteins exert their action by binding to cell surface receptors of the serine-threonine kinase class to activate intracellular signaling pathways. The other kinase participate in various cell signaling functions, but are not associated with BMP.

DISCUSSION: Bisphosphonates are indicated in the treatment of osteoporosis. They have been shown to reduce the incidence of vertebral and extremity fractures in patients with a T-score of less than -1. REFERENCE: Gass M, Dawson-Hughs B: Preventing osteoporosis-related fractures: An overview. Am J Med 2006;119:S3-S11.

DISCUSSIONThe patient’s MR images are consistent with transient hip osteoporosis. No signs suggest avascular necrosis. She has no joint narrowing. Transient osteoporosis of the hip is characterized by bone marrow edema in the femoral head and neck. This condition affects more men than women and is sometimes seen in the third trimester of pregnancy but can be seen in women who are not pregnant as well. This is a self-limiting condition, and the treatment is limited weight-bearing activity until the symptoms resolve. Core decompression is rarely used in these cases. There is no indication for arthroplasty or osteotomy in this scenario.

DISCUSSION: Children with vitamin D-resistant rickets are short in stature and have genu varum, physeal widening, and generalized osteopenia. The abnormality in inherited vitamin D-resistant rickets is the renal tubule’s inability to resorb phosphate leading to hypophosphatemia. Laboratory findings in the condition are normal or near normal serum calcium values, significantly decreased serum phosphate levels, elevated alkaline phosphatase levels, and normal PTH and vitamin-D levels. The most common form is inherited as an X-linked dominant trait. Nutritional rickets has a normal or low serum phosphate levels, normal or low serum calcium values, and decreased levels of 25(OH) vitamin D and 1,25-dihydroxyvitamin D. Hypophosphatasia is a rare condition characterized by a deficiency of alkaline phosphatase in the serum and tissues, leading to generalized abnormal mineralization of bone. Primary hyperparathyroidism usually is caused by a parathyroid adenoma, and the child generally has abdominal problems and hypercalcemic crisis. Laboratory findings include elevated serum calcium values, alkaline phosphatase levels, and PTH levels, and decreased serum phosphate levels. Children with renal osteodystrophy tend to have genu valgum, and laboratory findings include elevated serum phosphate, alkaline phosphatase, and PTH levels, and low serum calcium values. Findings of renal disease include elevated BUN and creatinine.

The patient has degenerative disk disease with diskogenic back pain. Several studies in both humans and animals have implicated TNF-a, IL-1, and MMP in extracellular matrix degeneration and disk degradation. TGF-ß, BMP-2, latent membrane protein 1, and growth and development factor-5 are all postulated to play anabolic roles in the intervertebral disk. Biglycan is a small leucine-rich proteoglycan that regulates extracellular matrix assembly within the disk. Noggin and gremlin are biochemical factors not involved in disk degradation.

DISCUSSION: Risk factors can suggest the existence of osteoporosis. However, definitive testing, based on the use of bone densitometry measurements, uses the T score in which an average score is taken from a normal population of young women. The presence of increased osteoid in lamellar bone is seen in osteomalacia but not osteoporosis. The presence of fractures is evidence of a risk factor for osteoporosis and can predict future fractures, but it does not definitively confirm the diagnosis. The Singh index is a radiographic finding that is not as accurate as bone mineral density scores.

Use of teriparatide in association with fracture fixation promotes healing because these fractures are associated with delayed healing. The other responses are not associated with healing of these fractures.

The radiograph demonstrates thickened trabeculae and thickened cortices in the left proximal femur compared to the right, and the bone scan shows increased uptake in this area. The MRI scans show thickened trabeculae with normal marrow signal. These findings are diagnostic of Paget’s disease. Medical treatment, including bisphosphonates and calcitonin, is indicated for painful bone lesions.

Integrins are groups of molecules essential for osteoclast attachment to the bone surface. Specifically, aVß3 is a type of integrin found on osteoclasts that attaches to bone by coupling with vitronectin.

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.

DISCUSSION: The diagnosis is severe osteoporosis because this patient's T-score is lower than -2.5 on DEXA scan and her fragility fracture involves the T12 vertebra. Osteoporosis may be associated with polymorphisms of the COL1A1 gene. EXT1 is associated with multiple hereditary exostoses, and translocation X:18 is associated with synovial sarcoma. The gene p53 is associated with Li-Fraumeni syndrome and osteosarcoma. RECOMMENDED READINGS: Masoodi TA, Alsaif MA, Al Shammari SA, Alhamdan AA. Evaluation and identification of damaged single nucleotide polymorphisms in COL1A1 gene involved in osteoporosis. Arch Med Sci. 2013 Oct 31;9(5):899-905. Kurt-Sirin O, Yilmaz-Aydogan H, Uyar M, Seyhan MF, Isbir T, Can A. Combined effects of collagen type I alpha1 (COL1A1) Sp1 polymorphism and osteoporosis risk factors on bone mineral density in Turkish postmenopausal women. Gene. 2014 May 1;540(2):226-31.

DISCUSSION: Alendronate is a second-generation bisphosphonate, and it can cause epigastric distress in up to 30% of patients. This side effect can be minimized by gradually building up to therapeutic doses over a period of 4 to 8 weeks. REFERENCES: Marshall JK, Rainsford KD, James C, et al: A randomized controlled trial to assess alendronate-associated injury of the upper gastrointestinal tract. Aliment Pharmacol Ther 2000;14:1451-1457. Lane JM, Sandhu HS: Osteoporosis of the spine, in Garfin SR, Vaccaro AR (eds): Orthopaedic Knowledge Update: Spine. Rosemont, IL, American Academy of Orthopaedic Surgeons, 1997, pp 227-234.

The differential diagnosis of genu varum includes physiologic genu varum, Blount's disease, skeletal dysplasia, and metabolic bone disease. Children with Blount's disease are generally in the 95th percentile for height and weight, and usually multiple family members are not affected. The radiographs show widening of the physis and metaphyseal flaring. In Blount's disease, the characteristic radiographic changes involve only the tibia, and at this age, most commonly show beaking of the medial metaphysis. Skeletal dysplasias, such as chondrometaphyseal dysplasia, are associated with short stature, and the radiographic changes are similar to those seen here. However, laboratory studies in these children will be within normal limits. Children with chronic renal disease will often be of short stature, and the radiographic findings are again similar to those shown here. However, BUN and creatinine levels are elevated and phosphate levels are elevated rather than decreased in children with renal disease. The absence of dietary deficiencies and positive family history rules out vitamin D-deficient rickets. There are four types of vitamin D-resistant rickets: failure of production of 1,25-dihydroxy vitamin D, phosphate diabetes (hypophosphatemic rickets), end organ insensitivity to vitamin D, and renal tubular acidosis. All types of vitamin D-resistant rickets are resistant to treatment with physiologic doses of vitamin D. The patient’s clinical picture, family history, laboratory studies, and radiographs are most consistent with hypophosphatemic rickets. This entity is inherited as a sex-linked dominant trait.

Osteogenesis imperfecta (OI) is a genetically determined disorder of type I collagen synthesis that is characterized by bone fragility. This patient has had three fractures of the long bones by age 2 years, with the last one occurring after relatively minor trauma. The patient’s history and clinical features are consistent with a diagnosis of Sillence type IA OI. Cells from individuals with type I OI largely demonstrate a quantitative defect of type I collagen; they synthesize and secrete about half the normal amount of type I procollagen.

Women older than age 50 years should receive daily supplementation with calcium and vitamin D to help preserve bone density. Bone mineral density testing is recommended for women age 65 years or older and postmenopausal women with at least one risk factor for osteoporotic fractures: prior fragility fracture, low estrogen levels, premature menopause, long-term secondary amenorrhea, glucocorticoid therapy, maternal history of hip fracture, or low body mass index. Hormone therapy is not approved for the treatment of osteoporosis.

The working distance is defined as the distance between the 2 screws closest to the fracture. Decreasing the working distance increases the stiffness of the plate fixation construct. An example of the working distance is provided in Illustrations A and B from Hak's review article. Changing the screw position from A to B results in a less rigid construct that is more suitable for secondary bone healing.Stoffel et al review the biomechanics of locking bridge plate constructs. The working distance is the most important determinant of axial stiffness and torsional rigidity.Decreasing the distance from the plate to the bone, using a longer plate, and increasing the number of screws used also increased stiffness.Egol et al reviews and compares the biomechanics of locked plates and conventional nonlocked plates. Locked plates are most indicated for diaphyseal- metaphyseal junction fractures in osteoporotic bone, severely comminuted fractures, indirect fracture reduction, and fractures where anatomical constraints prevent plating on the tension side of the bone. Conventional nonlocked plates are the fixation of choice for periarticularfractures that require anatomic reduction, and nonunions that require compression to enhance healing.A 47-year-old man complains of long standing pain involving the right index, middle, and ring fingers. A clinical image is shown in Figure A. A radiograph is provided in Figure B. Which of the following is the most likely diagnosis?GoutOsteoarthritisRheumatoid arthritisSeptic arthritisPsoriatic arthritisThe clinical presentation and radiograph are consistent with psoriatic arthritis. Figure A shows a swollen "sausage digit" (dactylitis) and nail pitting (onychodystrophy)characteristic of this condition. Figure B demonstrates the classic "pencil-in-cup" radiographic deformity seen in DIP arthritis, a common orthopaedic manifestation of psoriatic arthritis. Psoriatic arthritis affects 5 to10% of patients with psoriasis of the skin. However, the spectrum ofsymptoms varies greatly from mild and self-limiting to destructive arthritis. It most commonly affects the hands and feet, but can also involve the spine and sacroiliac joints. Primary treatment is medicinal with NSAIDS, methotrexate, and TNF-alpha inhibitors.High infection rates have been reported with surgical intervention. Illustration A is an closer image depicting psoriatic onychodystrophyis. Illustration B illustrates a "pencil-in- cup" deformity.Which of the following study designs represent a level III evidence study?Prospective, randomized controlled trialRetrospective case-control studyRetrospective case seriesProspective cohort studyExpert opinionThe practice of evidence based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research. Therapeutic study hierarchy of evidence has been established to better analyze studies in a reproducible fashion. Level I studies include well- designed randomized controlled prospective studies (RCT). Level II includelower quality designed prospective RCT as well as prospective cohort studies. Level III include retrospective cohort studies and case-control studies. Level IV include case series. Level V include case reports, expert opinion, and personal observation. This is summarized in illustration A. The referenced article by Brighton et al is a review of how the level of evidence has evolved and how the different levels can carry varied amounts of impact on clinical treatments and future research.A prosthetic polycentric knee with hydraulic swing control is chosen for a very active 63-year-old transfemoral amputee. All of the following appropriately describe the features of this prosthesis EXCEPT:Flexes in a controlled mannerVariable cadenceAbility to walk at a moderately fast paceKnee center of rotation is fixed anterior to the line of weight bearingWeighs more than a constant friction knee that has a manual extension locking mechanismA polycentric knee has a variable, not fixed, center of rotation. When the center of rotation is posterior to the line of weight bearing it allows control in the stance phase, but makes flexion more difficult. However, when the center of rotation is anterior to the line of weight bearing, flexion is improved but control is sacrificed. An example of this prosthesis is shown in illustration A.The piston mechanism in the hydraulic knee allows variable cadence by changing resistance to knee flexion. This prosthesis also flexes in a controlled manner by limiting excessive flexion and by extending earlier in the gait cycle.The polycentric knee with hydraulic swing control is best for active patients who prefer greater utility and variability but it does weigh more than the constant-friction knee hinge that has a manual extension locking mechanism.The review articles by Michael and Friel review the prescription options for lower extremity prostheses.Level 1 evidence has shown vitamin C reduces the incidence of reflex sympathetic dystrophy (RSD) or complex regional pain syndrome type I (CRPS) in patients with which of the following?Tarsal tunnel syndromeDistal radius fracturesCarpal tunnel syndromeCervical radiculopathy from herniated nucleus pulposisAnkle fracturesCorrent answer: 2Two different prospective, double-blind studies performed by the same institution have shown that vitamin C administration is associated with a lower risk of RSD (i.e CRPS) after wrist fractures. Vitamin C is thought to reducelipid peroxidation, scavenge free hydroxyl radicals, protect the capillary endothelium, and inhibit vascular permeability.The first trial by Zollinger was published in Lancet and included 115 adults with 119 fractures treated with conservative management. They found that RSD/CRPS occurred in four (7%) wrists in the vitamin C group (500mg daily for 50 days) and 14 (22%) in the placebo group.The second trial by Zollinger published in JBJS included 317 adult patients sustaining 328 distal radius fractures treated conservatively. They had allocated treatment groups to 200mg, 500mg, or 1500mg vitamin C dosagesfor 50 days. RSD/CRPS occurrence was 4.2% in the 200mg group, 1.8% in the 500mg group, and 1.7% in the 1500mg group and thus the 500mg dosage for50 days was recommended at the conclusion of the study. Patients making early cast- related complaints to their provider had a higher incidence of developing RSD/CRPS.It should also be noted that a recent double blinded randomized controlled trial by Ekrol et al found no statistical significant benefit of Vitamin C on the outcome of distal radius fractures.Which of the following best describes the mechanism by which osteoprotegerin (OPG) plays a role in RANKL-mediated osteoclast bone resorption?inhibits RANKL-mediated osteoclast bone resorption by directly binding to RANKLinhibits RANKL-mediated osteoclast bone resorption by directly binding to the RANK receptor on osteoclastsstimulates RANKL-mediated osteoclast bone resorption by directly binding to RANKLstimulates RANKL-mediated osteoclast bone resorption by directly binding to theRANK receptor on osteoclastsstimulates RANKL-mediated osteoclast bone resorption by directly binding to PTHOsteoclastic bone resorption is the final common mechanism for osteolysis, whether due to a pathologic lytic lesion, macrophage activation in particle wear, or normal remodeling. The RANKL mechanism controls the coupling of osteoblast and osteoclast activation.RANKL is expressed from osteoblasts and bone-marrow stromal cells. When RANKL binds to the RANKL receptor (receptor/activator of NF-[kappa]B) on the cell membrane of osteoclasts) itstimulates differentiation from osteoclast progenitor cells to mature osteoclasts. Mature osteoclasts proceed with osteoclastic bone resporption. Osteoprotegerin (OPG) acts as a decoy receptor by binding to RANKL and blocking the interaction between RANKL and the RANK-receptor and consequently inhibiting osteoclast formation and activation.The reference by Clohisy et al reviews recent developments in our understanding of the cellular and molecular events regulating osteoclast- mediated bone resorption and discusses the role of the RANKL pathway in several disease states, including osteolysis associated with inflammatory arthritis and cancer-induced bone loss.The reference by Goater et al studied the potential of OPG gene therapy by evaluating the ability of transfected synoviocytes expressing OPG to prevent wear debris-induced osteoclastogenesis. They found a decrease in the amount of bone resorption in mice with the transfected OPG gene. The RANKL pathway is shown in Illustration A below and further described in the linked video.Level 1 evidence has shown Low-intensity Pulsed Ultrasound Stimulation (LIPUS) decreased the time to fracture union in all of the the following injuries EXCEPT?Radius shaft fractureDistal radius fractureTibia shaft fracture treated with castingTibia shaft fracture treated with reamed intramedullary nailingScaphoid fractureTibia shaft fractures treated with reamed intramedullary nailing do not have Level 1 evidence supporting adjunctive LIPUS treatment. Low-intensity pulsed ultrasound (LIPUS) "bone stimulators" deliver 30mW/cm2 pulsed-waves via an external device over the fracture site.The meta-analysis by Busse et al found 6 randomized, controlled trials evaluating LIPUS. They concluded that low-intensity pulsed ultrasound treatment may significantly reduce the time to fracture healing for fractures treated nonoperatively.The metanalysis cites that Emami et al found no benefit to LIPUS treatment on intramedullary fixed tibial fractures. Injuries described in the metaanalysis as having positive benefits from LIPUS include radius shaft(Cook et al), distal radius(Kristiansen et al), scaphoid(Mayr et al), and tibia treated with casting (Heckman et al).The Level 1 study by Heckman et al of 67 patients found a significant decrease in the time to clinical healing in tibia fractures treated with casting and no serious complications with its use.A 58-year-old Jehovah's Witness male presents with severe right hip pain due to osteoarthritis. He has failed exhaustive physical therapy, steroid injections, and activity modifications, and now wishes to proceed with a right total hip arthroplasty. During the procedure, there is profound blood loss with associated hypotension. Which of the following is generally the most preferred method for treating the patient's acute intraoperative anemia?Iron supplementationSubcutaneous erythropoietin administrationABO-matched allogeneic blood transfusionContinuous tranexamic acid infusionUse of cell salvageThe patient has experienced a greater than expected blood loss during the procedure and has developed hemodynamic instability as a result. Given that the patient is a Jehovah's Witness, the use of a cell salvage (Cell Saver) is most preferred method for treating the patient's acute blood loss anemia.Signficant intraoperative blood loss is a risk associated with major orthopedic procedures such as joint arthroplasty, and spine, tumor, and trauma surgeries. The most effective method of mitigating this risk is by maintaining good hemostasis during the procedure.Tranexamic acid (TXA), cell saver, and allogeneic blood transfusion are adjunctive modalities to limit and address excessive intraoperative blood loss. Patients who are Jehovah's Witnesses are generally not amenable to allogeneic blood transfusions but can often be transfused with their own blood. The use of intraoperative cell saver allows for the recycling of the patient's own blood that is obtained with suction, and this can then be used later to transfuse the patient. However, this should be discussed with the patient pre- operatively, as some Jehovah's witnesses may be amenable to allogenic blood transfusion or conversely be opposed to cell saver.Moonen et al. reviewed perioperative blood management in elective orthopedic surgery procedures. The authors stated that the gold standard for preventing intraoperative blood loss was by maintaining adequate hemostasis and dissecting through anatomically correct tissue planes. They proposed the useof pre-operative erythropoietin and iron supplementation, pre-operative autologous blood donation, platelet-rich plasmapheresis, hypotensive epidural anesthesia, and intra- operative cell saving as adjunctive blood loss management modalities. The authors concluded that allogenic blood transfusion should be based on physiologic variables, risks of disease transmission, and patient preference.Imai et al. performed a retrospective study of intraoperative and postoperative blood loss in patients undergoing primary total hip arthroplasty that were treated with either a control or TXA at various time points in the perioperative period. They found that patients who received TXA either 10 minutes prior to surgery or 6 hours after the original dose had a significant decrease in periopreative blood loss. Postoperative blood loss was significantly decreasedin all patients that received TXA. The authors concluded that TXA is an effective adjunct for minimizing blood loss during arthroplasty procedures.Incorrect Answers:According to the 2008 National Osteoporosis Foundation Guidelines for Pharmacologic Treatment of Osteoporosis, when are bisphosphonates indicated for the treatment or prevention of osteoporosis?DEXA T-score between -1.0 and -2.5FRAX calculated 10-year hip fracture risk of >3%FRAX calculated 10-year risk of major osteoporosis-related fracture of>10%The 2008 National Osteoporosis Foundation Guidelines for Pharmacologic Treatment of Osteoporosis suggests that pharmacologic treatment should be considered for a DEXA T-score between -1.0 and -2.5 at the femoral neck/spine AND 10-year risk of hip fracture ≥ 3%.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 Caucasian woman has an estimated10% 10-year risk of a fragility fracture. 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 fragilityfracture, parental history of hip fracture, use of oral glucocorticoids, secondary osteoporosis and alcohol use to calculate 10-year risk of fracture.Unnanuntana et al. discussed the utility of the FRAX tool as an assessment modality for prediction of fracture risk. The authors advocated for treatment with osteopenia (T-score of-1.0 to -2.5) combined with either a ten-year risk of hip fracture >= 3% or a ten-year risk of major osteoporosis-related fractureof >= 20% as calculated by FRAX. They also discussed biochemical markers of bone formation and resorption, which are useful for monitoring the efficacy of antiresorptive therapy and may help identify patients at high risk for fracture.Cosman et al. review the 2008 National Osteoporosis Foundation guidelines and support that pharmacologic treatment for osteoporosis should be considered if patients are postmenopausal women or men > 50 years of age AND meet one of the following criteria: have a prior hip or vertebral fracture, a T score -2.5 or less at the femoral neck or spine, OR a T score between -1.0 and -2.5 at the femoral neck or spine AND a 10-year risk of hip fracturegreater than 3% or 10-year risk of major osteoporosis-related fracture greater than 20%. They conclude that DEXA scans should be repeated every 1-2 years if patients are undergoing pharmacologic treatment.Gass et al. review the epidemiology and tiered management strategy for osteoporosis. They discuss the first line prevention, treatment of secondary causes of osteoporosis, and finally pharmacologic interventions, all in an effort to mitigate fracture risk and the burden that osteoporotic fractures on the health care system.Illustrations:Illustration A outlines the variables taken into account in the FRAX score calculator.Incorrect answers:ADDITIONALLY has either a ten-year risk of hip fracture >= 3% or a ten-year risk of major osteoporosis-related fracture of >= 20% (or both) as calculated by the FRAX tool.>20% as calculated by the FRAX tool in order to meet the criterion set forth in the 2008 National Osteoporosis Foundation guidelines. Combined with documented osteopenia (T- score of -1.0 to -2.5), bisphosphonate therapy would be indicated.>20% as calculated by the FRAX tool in order to meet the criterion set forth in the 2008 National Osteoporosis Foundation guidelines.Which of the following bone graft substitutes has the fastest resorption characteristics?Calcium sulfateTricalcium phosphateHydroxyapatiteFibular allograftCortical iliac crest autograftOf the three bone graft substitutes listed (calcium sulfate, tricalcium phosphate, and hydroxyapatite), calcium sulfate has the fastest resorption characteristics. Fibular allograft and cortical iliac crest autograft are not considered bone graft substitutes.Calcium sulfate, tricalcium phosphate, and hydroxyapatite are all "osteoconductive" bone graft substitutes, meaning that these implants provide a surface and structure that facilitates the attachment, migration, proliferation, differentiation and survival of osteogenic stem and progenitor cells. Each has different chemical, macro- and microstructural properties. Calcium sulfate (plaster of Paris) is a low-molecular weight soluble compound that must be implanted adjacent to viable periosteum to work. It is reabsorbed by aprocess of dissolution over a period of 5-7 weeks.Jamali, et al., found that calcium sulphate was completely reabsorbed by 6 weeks. Tricalcium phosphate has compressive strength similar to cancellous bone, but is brittle and weak under tension and shear. It undergoes reabsorbtion via dissolution and fragmentation over 6-18 months; unfortunately less bone volume is produced than tricalcium phosphate absorbed. For this reason, it is used clinically as an adjunct with other lessabsorbable substitutes.Moore et al discuss that hydroxyapatite forms the principle mineral content of bone. Synthetically, it is available in ceramic and non-ceramic forms as porous or solid, blocks or granules. HA has good compressive strength, but is weak in tension and shear and brittle making it fracture-prone in shock loading. Ceramic HA preparations are resistant to absorption in vivo, which occurs at 1-2% per year. Non-ceramic HA is more readily absorbed.Which of the following techniques increases strength and stability to an external fixation construct?Unicortical pin fixationDecreasing total pin separation distanceIncreased working distance from the pin to fracture siteDecreasing the distance between the bone and the constructUsing smaller diameter pinsThere are several methods that can be used to increase the strength of an external fixation construct. Decreasing the distance from the bar to the bone increases stability and strengthens the construct. Some other methods to increase stability include: good bone- to-bone fracture end apposition, using an increased number of pins, using larger pins, small distance from the near pins to the fracture site (smaller working distance), increased spacing between the near and far pins, and bicortical pin fixation.Tencer et al looked at biomechanical aspects of external fixation systems. They demonstrated that system rigidity could be increased by maximizing pin separation distance in the fracture component and the number of pins used while minimizing pin separation distance across the fracture site and the sidebar offset distance from bone.Incorrect Answers: Answer choices 1,2,3, and 5 all act to decrease external fixation construct strength.A 62-year-old woman with Paget’s disease is started on a non- nitrogen containing bisphosphonate for treatment of her condition.What is the mechanism of action of this drug?Inhibition of farnesyl diphosphate synthaseConversion of drug into a non-functioning ATP-analogueInterference of isoprenylation of small GTPasesInhibition of geranylgeranyl diphosphate synthase (GGPPS)Downregulation of the undecaprenyl diphosphate synthase (UPPS) pathwayBisphosphonates are a class of antiresorptive agents used to treat diseases characterized by osteoclast-mediated bone resorption. Non-nitrogen containing bisphosphonates (such as etidronate) are metabolized into non-functioningATP analogues which cause eventual osteoclast apoptosis. Nitrogen containing bisphsphonates (alendrolate/Fosamax and Zoledronic acid/Zometa) act by inhibiting farnesyl diphosphate synthase (FPPS), resulting in decreased prenylation of small GTPases.Reszka et al reviewed nitrogen containing bisphosphonates. They outlined the mechanism of action on farnesyl diphosphate synthase in the cholesterol biosynthesis pathway.Guo et al also reviewed the mechanism of nitrogen-containing bisphosphonates. In addition to showing the decrease in prenylation of GTPase, they were shown to inhibit geranylgeranyl diphosphate synthase (GGPPS), as well as undecaprenyl diphosphate synthase (UPPS).Morris et al reviewed the bisphosphonates currently approved by the FDA. They outlined their use in the treatment of Paget disease, metastatic bone disease and widening applications in OI and fibrous dysplasia.Incorrect answers:1,3,4,5: Mechanism of nitrogen-containing bisphosphonates.A 58-year-old female falls and sustains the injury shown in Figures A and B. Following surgical treatment of the fracture, which of the following is the most appropriate additional investigation?MRI of the pelvisUrine electrophoresisCT scan of the pelvisBone scanDEXA scanFigures A and B depicts a femoral neck fracture. Medical management of postmenopausal women with fragility fractures (distal radius, femoral neck, vertebral compression fractures) includes dual-energy x-ray absorptiometry (DEXA) testing.Following the diagnosis of osteoporosis, bisphosphonates, calcitonin or other medical treatments may be initiated.Oyen et al examined 1794 patients with fractures of the distal radius. As one- third of the men and half of the women had bone mineral density (BMD) suggesting osteoporosis, they concluded that all patients aged 50 or above should have bone densitometry testing.Freedman et al reviewed 1162 women with distal radius fractures. They determined that the rate of diagnostic workup and medical treatment decreases as patient age increases at the time of fracture.A 52-year old woman who is not on any hormone replacement therapy (HRT) falls from standing height and sustains the injury seen in Figure A. Review of her medical history reveals that she carries a diagnosis of osteoporosis, and that her latest T-score was -3.0. How much calcium should she have been consuming on a daily basis prior to sustaining her injury?

Hybrid locked plating refers to the use of nonlocked and locked screws in the same fixation construct. Hybrid plating offers the advantages of both traditional plating and locked plating. Nonlocked screws are inserted first to "lag" the bone to the plate, thereby using the plate as a reduction tool. After fixation with nonlocked screws in both the proximal and distal fragments, locked screws can be added. Locked screws in the distal fragment create a fixed angle device that is resistant to varus collapse. Locked screws in the diaphyseal fragment are indicated when there is associated osteoporosis.