Introduction Fracture healing involves a complex and sequential set of events to restore injured bone to pre-fracture condition stem cells are crucial to the fracture repair process the periosteum and endosteum are the two major sources Fracture stability dictates the type of healing that will occur the mechanical stability governs the mechanical strain when the strain is below 2%, primary bone healing will occur when the strain is between 2% and 10%, secondary bone healing will occur Modes of bone healing primary bone healing (strain is < 2%) intramembranous healing occurs via Haversian remodeling occurs with absolute stability constructs secondary bone healing (strain is between 2%-10%) involves responses in the periosteum and external soft tissues. enchondral healing occurs with non-rigid fixation, as fracture braces, external fixation, bridge plating, intramedullary nailing, etc. bone healing may occur as a combination of the above two process depending on the stability throughout the construct Type of Fracture Healing with Treatment Technique Cast treatment Secondary: enchondral ossification External fixation Secondary: enchondral ossification IM nailing Secondary: enchondral ossification Compression plate Primary: Haversian remodeling Secondary Bone Healing Stages of Fracture Healing Inflammation Hematoma forms and provides source of hemopoieitic cells capable of secreting growth factors. Macrophages, neutrophils and platelets release several cytokines this includes PDGF, TNF-Alpha, TGF-Beta, IL-1,6, 10,12 they may be detected as early as 24 hours post injury lack of TNF-Alpha (ie. HIV) results in delay of both enchondral/intramembranous ossification Fibroblasts and mesenchymal cells migrate to fracture site and granulation tissue forms around fracture ends during fracture healing granulation tissue tolerates the greatest strain before failure Osteoblasts and fibroblasts proliferate inhibition of COX-2 (ie NSAIDs) causes repression of runx-2/osterix, which are critical for differentiation of osteoblastic cells Repair Primary callus forms within two weeks. If the bone ends are not touching, then bridging soft callus forms. the mechanical environment drives differentiation of either osteoblastic (stable enviroment) or chondryocytic (unstable environment) lineages of cells Enchondral ossification converts soft callus to hard callus (woven bone). Medullary callus also supplements the bridging soft callus cytokines drive chondocytic differentiation. cartilage production provides provisional stabilization Type II collagen (cartilage) is produced early in fracture healing and then followed by type I collagen (bone) expression Amount of callus is inversely proportional to extent of immobilization primary cortical healing occurs with rigid immobilization (ie. compression plating) enchondral healing with periosteal bridging occurs with closed treatment Remodeling Begins in middle of repair phase and continues long after clinical union chondrocytes undergo terminal differentiation complex interplay of signaling pathways including, indian hedgehog (Ihh), parathyroid hormone related peptide (PTHrP), FGF and BMP these molecules are also involved in terminal differentiation of the appendicular skeleton type X collagen types is expressed by hypertrophic chondrocytes as the extraarticular matrix undergoes calcification proteases degrade the extracellular matrix cartilaginous calcification takes place at the junction between the maturing chondrocytes and newly forming bone multiple factors are expressed as bone is formed including BMPs, TGF-Betas, IGFs, osteocalcin, collagen I, V and XI subsequently, chondrocytes become apoptotic and VEGF production leads to new vessel invasion newly formed bone (woven bone) is remodeling via organized osteoblastic/osteoclastic activity Shaped through Wolff's law: bone remodels in response to mechanical stress piezoelectic charges : bone remodels is response to electric charges: compression side is electronegative and stimulates osteoblast formation, tension side is electropostive and simulates osteoclasts Variables that Influence Fracture Healing Internal variables blood supply (most important) initially the blood flow decreases with vascular disruption after few hours to days, the blood flow increases this peaks at 2 weeks and normalizes at 3-5 months un-reamed nails maintain the endosteal blood supply reaming compromises of the inner 50-80% of the cortex looser fitting nails allow more quick reperfusion of the endosteal blood supply versus canal filling nails head injury may increase osteogenic response mechanical factors bony soft tissue attachments mechanical stability/strain location of injury degree of bone loss pattern (segmental or fractures with butterfly fragments) increased risk of nonunion likely secondary to compromise of the blood supply to the intercalary segement External variables Low Intensity Pulsed Ultrasound (LIPUS) exact mechanism for enhancement of fracture healing is not clear alteration of protein expression elevation of vascularity development of mechanical strain gradient accelerates fracture healing and increases mechanical strength of callus (including torque and stiffness) the beneficial ultrasound signal is 30 mW/cm2 pulsed-wave healing rates for delayed unions/nonunions has been reported to be close to 80% bone stimulators four main delivery modes of electrical stimulation direct current decrease osteoclast activity and increase osteoblast activity by reducing oxygen concentration and increasing local tissue pH capacitively coupled electrical fields (alternating current, AC) affect synthesis of cAMP, collagen and calcification of carilage pulsed electromagnetic fields cause calcification of fibrocartilage combined magnetic fields they lead to elevated concentrations of TGF-Beta and BMP COX-2 promotes fracture healing by causing mesenchymal stem cells to differentiate into osteoblasts radiation (high dose) long term changes within the remodeling systems cellularity is diminished Patient factors diet nutritional deficiencies vitamin D and calcium as high as 84% of patients with nonunion were found to have metabolic issues greater than 66% of these patients had vitamin D deficiencies in a rat fracture model protein malnourishment decreases fracture callus strength amino acid supplementation increases muscle protein content and fracture callus mineralization gastric bypass patients calcium absorption is affected because of duodenal bypass with Roux-en-Y procedure leads to decreased Ca/Vit D levels, hyperparathyroidism (secondary) & increased Ca resportion from bone treat these patients with Ca/Vit D supplementation gastric banding does not lead to these abnormalities because the duodenum is not bypassed diabetes mellitus affects the repair and remodeling of bone decreased cellularity of the fracture callus delayed enchondral ossification diminished strength of the fracture callus fracture healing takes 1.6 times longer in diabetic patients versus non-diabetic patients nicotine decreases rate of fracture healing inhibits growth of new blood vessels as bone is remodeled increase risk of nonunion (increases risk of pseudoarthrosis in spine fusion by 500%) decreased strength of fracture callus smokers can take ~70% longer to heal open tibial shaft fractures versus non-smokers HIV higher prevalence of fragility fractures with associated delayed healing contributing factors anti-retroviral medication poor intraosseous circulation TNF-Alpha deficiency poor nutritional intake medications affecting healing bisphosphonates are recognized as a cause of osteoporotic fractures with long term usage recent studies demonstrated longer healing times for surgically treated wrist fractures in patients on bisphosphonates long term usage may be associated with atypical subtrochanteric/femoral shaft fractures systemic corticosteroids studies have shown a 6.5% higher rate of intertrochanteric fracture non unions NSAIDs prolonged healing time becaue of COX enzyme inhbition quinolones toxic to chondrocytes and diminishes fracture repair
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Take This Question Anyway (OBQ10.41) In rat models looking at the effect of malnutrition on fracture healing, amino acid supplementation in a nutritionally deprived rat increases all of the following EXCEPT Review Topic | Tested Concept QID: 3129 Type & Select Correct Answer 1 Serum albumin 4% (108/2964) 2 Body mass 14% (425/2964) 3 Quadriceps total protein content 9% (255/2964) 4 Fracture callus mineralization 36% (1081/2964) 5 Insulin-like growth factor 1 (IGF-1) mRNA expression 36% (1064/2964) L 4 Question Complexity D Question Importance Select Answer to see Preferred Response SUBMIT RESPONSE 5 You have 100% on this question. Just skip this one for now. Take This Question Anyway (OBQ10.273) 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? Review Topic | Tested Concept QID: 3361 Type & Select Correct Answer 1 Radius shaft fracture 8% (207/2656) 2 Distal radius fracture 10% (276/2656) 3 Tibia shaft fracture treated with casting 10% (255/2656) 4 Tibia shaft fracture treated with reamed intramedullary nailing 53% (1404/2656) 5 Scaphoid fracture 19% (507/2656) L 4 Question Complexity D Question Importance Select Answer to see Preferred Response SUBMIT RESPONSE 4 You have 100% on this question. Just skip this one for now. Take This Question Anyway (OBQ09.84) What is the mechanism of action of capacitive coupling (CC) stimulation when used as an adjunctive therapy for bone healing? Review Topic | Tested Concept QID: 2897 Type & Select Correct Answer 1 Reduces oxygen concentration and increases local tissue pH 8% (167/2120) 2 Stimulates transmembrane calcium translocation via voltage-gated calcium channels 65% (1369/2120) 3 Upregulates TNF alpha 2% (32/2120) 4 Transmits mechanical energy to stimulate bone formation 24% (503/2120) 5 Upregulates osteoclast activity 2% (35/2120) L 3 Question Complexity D Question Importance Select Answer to see Preferred Response SUBMIT RESPONSE 2 Sorry, this question is for PEAK Premium Subscribers only Upgrade to PEAK You have 100% on this question. Just skip this one for now. Take This Question Anyway (OBQ08.44) Which of the following statements regarding COX-2 is FALSE? Review Topic | Tested Concept QID: 430 Type & Select Correct Answer 1 It causes mesenchymal stem cells to differentiate into osteoblasts 28% (867/3050) 2 COX-2 knockout mice heal fractures more quickly than control mice 57% (1738/3050) 3 COX-2 is an enzyme which converts arachidonic acid to prostaglandin endoperoxide H2 4% (116/3050) 4 Most NSAIDS non-specifically inhibit both COX-1 and COX-2 enzymes 6% (193/3050) 5 The expression of COX-2 is upregulated in several human cancers 4% (117/3050) L 4 Question Complexity C Question Importance Select Answer to see Preferred Response SUBMIT RESPONSE 2 You have 100% on this question. Just skip this one for now. Take This Question Anyway (OBQ06.27) The nonunion as seen in Figure A will most likely unite by what intervention? Review Topic | Tested Concept QID: 138 FIGURES: A Type & Select Correct Answer 1 Increased mechanical stability 94% (1823/1949) 2 Decreased mechanical stability 2% (35/1949) 3 Increased biology at the fracture site 2% (46/1949) 4 Decreased biology at the fracture site 0% (6/1949) 5 Antibiotics and resection of pseudoarthrosis 1% (19/1949) L 1 Question Complexity C Question Importance Select Answer to see Preferred Response SUBMIT RESPONSE 1 You have 100% on this question. Just skip this one for now. Take This Question Anyway (OBQ06.262) Which of the following is a mechanism by which low-intensity pulsed ultrasound is reported to stimulate fracture healing? Review Topic | Tested Concept QID: 273 Type & Select Correct Answer 1 decreasing intracellular calcium concentration 4% (50/1121) 2 decreasing temperature 1% (7/1121) 3 produces nanomotion at the fracture site 91% (1024/1121) 4 decreases proteoglycan synthesis 2% (19/1121) 5 inhibits integrins 1% (13/1121) L 1 Question Complexity D Question Importance Select Answer to see Preferred Response SUBMIT RESPONSE 3 You have 100% on this question. Just skip this one for now. Take This Question Anyway (OBQ05.64) Which of the following is most often implicated as an etiology for a hypertrophic nonunion? Review Topic | Tested Concept QID: 950 Type & Select Correct Answer 1 Malreduction with open plating 2% (16/850) 2 Smoking 2% (15/850) 3 Inadequate mechanical stability 93% (793/850) 4 Open injury with significant soft tissue stripping 1% (6/850) 5 Infection 2% (16/850) L 1 Question Complexity C Question Importance Select Answer to see Preferred Response SUBMIT RESPONSE 3 You have 100% on this question. Just skip this one for now. Take This Question Anyway (OBQ05.1) What type of fracture healing occurs in a femoral shaft fracture treated with an intramedullary nail? Review Topic | Tested Concept QID: 38 Type & Select Correct Answer 1 Primary fracture healing 5% (92/1984) 2 Secondary fracture healing 91% (1811/1984) 3 Extramembranous ossification 2% (39/1984) 4 Haversian remodelling 1% (13/1984) 5 "Cutting cone" remodelling 1% (14/1984) L 1 Question Complexity D Question Importance Select Answer to see Preferred Response SUBMIT RESPONSE 2 You have 100% on this question. Just skip this one for now. Take This Question Anyway (OBQ04.180) During fracture healing, granulation tissue tolerates the greatest strain before failure so that mature bone can eventually bridge the fracture gap during healing. What is the definition of strain? Review Topic | Tested Concept QID: 1285 Type & Select Correct Answer 1 Amount of force an object can withstand until plastic deformation is lost 9% (244/2681) 2 Change in length / original length of an object due to an external force 79% (2116/2681) 3 Relationship of stiffness to time-dependent loading 3% (78/2681) 4 Force intensity / volume 1% (19/2681) 5 Force intensity / cross sectional area 8% (205/2681) L 2 Question Complexity B Question Importance Select Answer to see Preferred Response SUBMIT RESPONSE 2 You have 100% on this question. Just skip this one for now. Take This Question Anyway (OBQ04.109) Type X collagen expression by hypertrophic chondrocytes is characteristic of which of the following aspects of fracture healing? Review Topic | Tested Concept QID: 1214 Type & Select Correct Answer 1 Inflammation 2% (10/597) 2 Granulation tissue formation 10% (59/597) 3 Cartilage callus formation and calcification 80% (475/597) 4 Bone deposition 2% (9/597) 5 Bone remodeling 6% (35/597) L 1 Question Complexity B Question Importance Select Answer to see Preferred Response SUBMIT RESPONSE 3
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