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Morphology of Fracture Nonunion and Osteomyelitis
Fracture Complications
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Morphology of Fracture Nonunion and Osteomyelitis
]. Carroll Woodard, DVM, PhD,* and Wayne H. Riser, DVM, MS, DrVetMed, MAt
SUMMARY OF NORMAL FRACTURE HEALING
After injury of sufficient magnitude to cause fracture, blood vessels in the area rupture, and there is soft-tissue contusion. The magnitude of the injury determines the severity of tissue damage. The site of trauma, including the fractured bone, becomes a special sphere of influence that enhances normal biologic processes and accelerates physiologic mechanisms. This acceleration of the bone's biologic processes is termed a general metabolic shift or the regional acceleratory phenomenon (RAP). It is this physiologic acceleration that permits bone healing to proceed at such a rapid pace, even in cortical bone locations in adult animals that have low bone turnover. The RAP is responsible for scintograms showing increased deposition of radiobisphosphonate as much as 1 year or longer after injury. Hemorrhage into the injured area clots in the same manner as any other extravasation, and mesenchymal cells migrate into the clot along the fibrinous scaffolding (Fig. 1). Soon the clot organizes, and the formation of granulation tissue aids bone repair because of neovascularization (Fig. 2). After fracture, the ruptured periosteum initially contracts, but soon cells of the cambium layer with primitive mesenchymal cells of the soft-tissue reactive zone begin to divide. They differentiate to form fibroblasts, chondroblasts, and osteoblasts in varying proportions and make the provisional callus that encircles the fracture site (Fig. 3). It is during this first week of the initial granulation tissue and inflammatory phase that systemic and local factors cause cell recruitment and differentiation. These mediators direct the amount, location, and cellular nature of the future bone callus. The proliferating mesenchymal cells differentiate into fibrous tissue, hyaline From the Department of Comparative and Experimental Pathology, University of Florida College of Veterinary Medicine, Gainesville, Florida *Professor t Adjunct Professor Veterinary Clinics of North America: Small Animal Practice- Vol. 21, No. 4, July 1991
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Figure l. Initial injury leads to necrosis of cortical bone and hemorrhage and sets into motion the regional acceleratory phenomenon.
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Figure 2. As in injury in other tissues , there is an acute inflammatory response that leads to organization of the hematoma.
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Fibrous tissue
Figure 3. A provisional callus is formed in the region of the organized clot by mesenchymal cell division and differentiation into fibrous tissue, cartilage, and woven bone. The necrotic bone of the cortex is replaced by longitudinal vascular tunneling.
cartilage, and bone. Osteoid trabeculae mostly form by intramembranous bone formation. They may be formed to a lesser degree by endochondral ossification of cartilage. Trabeculae of the provisional callus mineralize as true callus develops. This bony callus not only fills the gaps of the broken structure but also fills the marrow cavity. The callus protrudes outwardly, forming a considerably larger mass than the original bone. The newly formed bone trabeculae merge or meld into the original bone of the cortices and are separated by cement lines. For some months or even years afterward, this bone undergoes repeated sequences of remodeling, removal by osteoclasts, and replace ment by lamellar bone. The remodeling reduces the size of the callus, makes normal secondary haversian systems, and more nearly duplicates the original bone structure (Fig. 4). In young animals that are still in the growth phase, bone modeling through formation and resorption drifts straighten crooked bones (Fig. 5). If there is mobility at the fracture site, a cartilage union often precedes formation of bone. In excessive mobility, delayed union or nonunion may develop, and fibrous tissue may be the predominant tissue of the callus site. On the other hand, little callus or little or no cartilage is form ed if there is sufficient immobility to cause osteosynthesis.
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Fine trabeculae
Figure 4. After the provisional callus becomes mineralized, there is remodeling of the woven bone and necrotic cortex. This activity reduces the size of the callus and creates osseous tissue of a mature character and structural orientation.
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Figure 5. In the young animal, macromodeling usually straightens crooked bones. Striped = resorption, dotted area = formation.
FAILURE OF FRACTURES TO HEAL Types Delayed union occurs when a fracture requires a healing time longer than the generally accepted average period for such cases. Nonunions do . not heal without treatment, and infrequently they may progress to a synovial nonunion or pseudoarthrosis. A true pseudoarthrosis (Figs. 6, 7, and 8) is characterized by having a true joint space and a joint capsule that is lined by synovial cells. Synovial villi also may be present. In the classic pseudoarthrosis, the fractured bone ends are round and covered by hyaline cartilage so perfect that one might question whether the false joint resulted from fracture (Fig. 6). Before the devel6pment of a pseudoarthrosis, the opposing surfaces of a nonunion may be joined by fibrous tissue or fibrocartilage (Fig. 8), or excessive abrasion may erode the adjoining surfaces and cause eburnation (Fig. 7). In long bones, the pseudoarthrosis may resemble a ball and socket joint. The end of the longest bone elemen t becomes convex, and the end of the shorter element is concave (Figs. 7 and 8). Fracture healing frequently is impaired after pathologic fracture. The pathologic process causing the fracture is responsible for the delayed union. In bone tumors (Fig. 9), bone fracture is common, because tumor Text continued on page 823
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Figure 6. A 3-year-old male feral Florida panther was hit by a car and died. Necropsy exam ination revealed evidence of recent trauma. In addition, there was atrophy of the muscles of the right thigh and pseudarthrosis of the right femur, presumably from a previous automobile accident. A, False joint, femoral head within acetabulum (upper), fractured neck (lower). Note the articulating surfaces are rounded, and fractured bone ends are covered with cartilage. B, Acetabulum contains remnant of fractured femoral head that has hyaline cartilage on all articulating surfaces. C, Femur. The surface of the fractured neck is covered with hyaline cartilage.
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Figure 7. Six-month-old Wirehaired Terrier, pseudarthrosis of cervical fracture, proximal femur. Bone ends between fracture fragments are eburnated, and regional trabeculae are thick. Subperiosteal reactive bone (R), region of bone necrosis and resorption (N).
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Figure 8. After three months, a distal humoral fracture failed to heal following intramedullary pinning. A plate was placed across the fracture site, but an additional pin was inserted after the screws loosened. A, Pin tract occupies one half of the marrow space and extends through the cortex. Area of nonunion can be seen at the fracture site. B, Section lateral to that shown in A. C, Higher magnification of B, pseudarthrosis surrounded by joint capsule with synovial villi. Fibrocartilage separates the fracture surfaces.
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Figure 9. Fibrosarcoma (12 X 6 X 6 em) and pathologic fracture of the proximal tibia of a large mixed-breed dog . Increased bone porosity and tumor invasion through the cortex.
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growth causes increased focal bone remodeling and resorption. This possibly may occur because intramedullary tumor growth produces a RAP effect. Some tumors such as lymphosarcomas may secrete lymphokines that activate remodeling; the nonparathyroid peptide lymphokines are believed to cause bone resorption in multiple myeloma. 22 Tumor cells, particularly canine apocrine gland carcinomas of the anal sack, produce parathyroid hormone-related peptide, which causes hypercalcemia of malignancy. 20 Secondary hyperparathyroidism causes fibrous osteodystrophy and can lead to pathologic fracture of long bones or vertebra (Fig. 10). When fracture occurs in the vertebra, osteophytes may bridge the intervertebral space and aid the development of nonunion by decreasing intervertebral movement and increasing motion between fracture fragments (Fig. 11). However, not all metabolic bone diseases cause delayed union; in some types of osteoporosis, healing of fractures occurs in a normal fashion. Pathogenesis The pathogenesis of non unions can be divided into two basic categories: (1) primary or biologic failures in which proper conditions for healing are created, but the biologic mechanism fails to heal the bone properly, and (2) nonunions that develop because there is failure to create proper conditions for the normal healing process (secondary or technical failure). 6 · 7 In both veterinary and human medicine, most nonunions fall in the second category. As surgical techniques, immobilization methods, and antibacterial agents improve, however, the primary or biologic failures will take on added importance. Primary or Biologic Failure. Nutritional osteodystrophy or other metabolic bone diseases that interfere with bone mineralization (Fig. 12) are the most commonly recognized type of biologic failure in veterinary medicine. In young dogs and cats, feeding an all-meat diet is a common cause of nutritional osteodystrophy. With this exception, little attention is given to this aspect of the pathogenesis of nonunion because it usually is assumed that the failure was secondary or due to some technical difficulty. Each aspect of the normal bone healing process can go astray and lead to nonunion. 6 Thus, failure to make callus, inadequate RAP, failure to mineralize callus, maldifferentiation in which the fracture space fills with fibrous tissue and fat rather than callus, remodeling stage malfunctions in which there is delayed replacement of callus with normal bone, and modeling malfunctions in which there are inadequate modeling drifts are conditions that potentially can cause biologic failure. The mechanisms and cellular cascade associated with biologic failures have been discussed in light of recent laboratory investigations of various connective-tissue growth factors. 22 In the future, these biologic failures will be the cause of a greater percentage of nonunions in veterinary medicine. It is important to recognize biologic failures so that animal models can be developed to test therapeutic regimens that might prevent their occurrence. The cause of nonunions in adult animals in which conditions are optimum for healing should be investigated. Primary failure can be suspected when inadequate callus forms or when cortical bone shows little longitudinal tunneling that is normally caused by
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Figure 10. Three-month-old Persian kitten developed multiple limb fractures while being fed a ground-beef diet. Folding or green-stick fracture (between arrows) of vertebral body has caused injury to the spinal cord and hemorrhage (H).
Figure 11. Vertebral fracture in a cat resulting from a car accident. Osteophyte beneath the intervertebral disk space transfers joint motion laterally where fibrocartilage remains. A fibrous nonunion is present between vertebral body fragments.
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Figure 12. Delayed union in a 9-week-old Doberman Pinscher. Pathologic fracture following nutritional osteodystrophy. Exuberant amount of cartilage in the fracture callus.
the RAP and disuse. The rates of nonunion are higher in small-breed dogs. Sixty percent of nonunions in the dog occur in the radius and ulna. Some fractures of the distal radius and ulna of small-breed dogs show little callus formation and poor longitudinal tunneling of cortical bone (Fig. 13). The distal third of the radius and ulna has little muscle tissue, and nonunion in this region may be related to the lack of revascularization of the fracture site. Biologic failure also may play a role in these cases, because microangiography has shown that the medullary arterial supply dominates the pattern in rapid fracture healing. 19 Secondary or Technical Failure. Secondary or technical failures represent over 80% of non unions in veterinary medicine. These may be caused by infection, poor fracture reduction in which the bone ends are imperfectly aligned, distraction in which the bone ends are too far apart to permit healing, too much motion at the fracture site, or loss of blood supply and necrosis of bone. 6 Excessive motion of the fracture ends is probably the most important factor. Open fractures are a frequent cause of osteomyelitis, and contamination during open reduction surgery is the most important
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Figure 13. A well-formed nonunion 2. 5 em above the distal end of the radius and ulna of a terrier. Little callus has formed, and there is little evidence of activated remodeling of the cortex. A few osteoclasts were found associated with a limited amount of necrotic cortical tissue .
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cause of osteomyelitis. If suppurative osteomyelitis becomes sufficient, bone necrosis and sequestration occur (Fig. 14). A sheath or involucrum develops around the necrotic fragments. Small amounts of suppurative exudate may prevent healing by resulting in bone necrosis (Fig. 15). The placement of an intramedullary pin causes medullary vascular disruption, but this seems tolerated surprisingly well with only slight reduction of endosteal callus (Fig. 16). If periostitis complicates intramedullary pinning, necrosis of the bone cortex follows, because these factors compromise both the endosteal and periosteal vascular components of the dual supply (Fig. 17). More movement of the fracture ends can be tolerated in classic healing by callus formation than in primary union by osteosynthesis, because large gaps permit more motion before tissue disruption occurs. After intramedullary pinning, excessive motion can lead to nonunion and pseudarthrosis (see Fig. 8). Movement also can create a fibrous nonunion after fracture across an apophysis (Fig. 18). 13 A pseudarthrosis requires resection of the cartilage, because the cartilage and synovial fluid are a barrier that prevents ossification. Bone grafts are used in the treatment of delayed unions and nonunions. The most successful grafts are vital bone grafts transferred from donor to recipient bone sites with circulation still intact. 17 This type of preparation keeps the bone's mediator mechanisms intact. All other kinds of grafts represent dead bone (Fig. 19). 2 The graft matrix contains growth factors, and success depends upon competence of mediator mechanisms in the recipient site. Treatment of nonviable grafts with bone morphogenetic protein improves the incorporation of the graft into bone. 24
Figure 14. Postfracture humoral amputation, osteomyelitis . A large sequestrum (S) is surrounded by suppurative exudate (E) and involucrum (I ).
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Figure 15. Failure to develop an osteosynthesis following bone plating. Only a small amount of chronic active inflammation was found at the site of nonunion. However, cortical bone (C) is necrotic along the distance from the fracture site to the arrows . Large amount of subperiosteal reactive bone (P) and endosteal trabeculae (E) appear around screw holes.
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Figure 16. Nonunion of femur after intramedullary pinning. Little external callus is present because of limited motion. Reactive bone fills the medullary cavity and abuts the space where the pin was removed.
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Figure 17. Fracture repaired with an intramedullary pin. Amputations performed after development of osteomyelitis. Clear space (P) is where the pin was removed. Reactive bone (R) surrounds suppurative exudate (E) and necrotic bone cortex (N).
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Figure 18. Nonunion, fractured anconeal process (ununited anconeal process) of ulna.
Bone Inflammation
The inflammatory reaction in bone (osteitis) is confined to connective tissue spaces forming periosteum and marrow and filling haversian canals. The inflammatory process may be confined to marrow (osteomyelitis) or periosteum (osteoperiostitis), but the dividing line between these processes seldom is well defined. Osteitis occurs whenever there is significant tissue damage or whenever mediators of the inflammatory response are liberated, but it occurs in its most conspicuous form in association with infectious agents. Spondylitis, that is, inflammation of the vertebrae, may follow penetrating wounds, may be of hematogenous origin, or may occur by retrograde spread through the vertebral venous plexus. Diskospondylitis occurs when there is contiguous involvement of the vertebral body and disk. Ankylosing spondylitis is a special form of vertebral inflammation rarely seen in animals other than humans, and the early histologic lesions resemble rheumatoid arthritis. Calcific and osseous changes in the annulus fibrosus are particularly characteristic of the condition; these changes produce the so-called "bamboo spine." The use of the term ankylosing
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Figure 19. Cross-section of canine fibular autograft after continuous intravital tetracycline labeling. A , Microradiograph, B, fluorescence photomicrograph. Newly formed subperiosteal bone is less dense and shows fluorescence compared to the nonlabeled necrotic grafted bone. Bone surrounding vessels (a and b) has the same density, but fluorescence shows b to be a completed remodeling site. (Courtesy of Dr. H. Burchardt.)
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spondylitis to indicate noninflammatory ankylosing spinal lesions characterized by vertebral osteophytosis is inappropriate and should not be continued. Osteochondritis is inflammation at the osteochondral junction and occurs most frequently beneath articular cartilage or the growth plate in young animals. Another term, epiphysitis, refers to inflammation of the epiphysis or the growth-plate cartilage that separates it from the main bone. Osteochondritis also may designate a joint lesion characterized by dissection of articular cartilage (osteochondritis dissecans). This lesion is classified as a type of osteochondrosis, because inflammation does not play a prominent pathogenetic role. ACUTE OSTEOMYELITIS AND CAUSE AND PATHOGENESIS OF HEMATOGENOUS DISEASE Bone infection most commonly follows open fracture, and infection can follow orthopedic surgical procedures. Orthopaedic implant materials increase the likelihood of osteomyelitis after instillation of bacterial organisms. 9• 18 Also, hematogenous bone infections occur more frequently after bone trauma. 16 • 26 Hematogenous osteomyelitis occurs most often in young animals, because the presence or absence of epiphyseal fusion is a factor that influences the localization of blood-borne infection. It has been shown experimentally that staphylococci produce osteomyelitis in the young (epiphysis unfused) but arthritis without osteomyelitis in adults (epiphysis fused). 14 Staphylococci and streptococci are the most frequent aerobic bacteria found in hematogenous infections, but even microorganisms of low pathogenicity, such as Escherichia coli, cause bone infections. 1 Infections with anaerobic bacteria or mixed aerobic and anaerobic infection are common. 25 Peptostreptococcus anaerobicus is a frequent anaerobic isolate, and the most frequently isolated genus is the obligate anaerobe, Bacteroides, usually Bacteroides asaccharolyticus. Hematogenous osteomyelitis starts in the primary spongiosa of the metaphysis just below the growth plate or in the secondary ossification center of the epiphysis beneath the articular-cartilage growth area. This is because of the unique vascular supply in these areas. Arterioles form a loop at the growth plate-bone junction and then drain into the medullary cavity without forming a capillary bed. Bacteria lodge in this region and attach to trabecular bone or cartilage matrix surfaces, 3 • 4 • 10• 15• 23 but do not attach to adjacent vascular linings or erythrocytes. Staphylococci and P. aeruginosa attach to matrix surfaces and grow in a biofilm that serves as a barrier against hostile environmental agents such as host defense mechanisms and antibiotics. S. aureus binds sialoprotein selectively, and the major binding site residues are in the sialoprotein core protein, not in the carbohydrate side chains. An average of 1000 bone-sialoprotein-binding sites are found per bacterial cell. 21 The adherence of staphylococci stimulates the organism to exude a glycocalyx that becomes progressively more dense and buries the organism in a dense, coccoid-studded biofilm. Liberated bacterial toxins and ischemia lead to bone necrosis; the necrotic areas coalesce into an avascular zone permitting further bacterial
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proliferation. With some bacterial infections, there may be bone sequestration. If infection is contained, the bone end grows away from the inflammatory focus, and the distance between the focus and the growth zone increases. If the condition progresses, exudation may be extensive and results in osteolysis of metaphyseal trabeculae (Fig. 20A). Puriform softening of bone is the result of liberation of lysosomal enzymes from polymorphonuclear leukocytes and macrophages, but there may be activation of resorption cavities with osteoclasts. 8 Tissue destruction may be so extensive that it interrupts the vascular supply to the growth plate (Fig. 20B). Focal lesions resembling rickets develop because inflammation prevents normal vascular invasion of the mineralized growth-plate cartilage. Suppurative exudate and bacteria may spread into the endosteal, haversian, and Volkmann vascular channels that supply the cortex. Suppurative exudate forming beneath the periosteum shears off the perforating arteries, which further devitalizes the cortex. The exudate flows between the periosteum and the cortex, isolating more bone from its blood supply, and may cause complete necrosis of the cortex. The exudate may escape from the bone's interior at the periosteal surface of the growth plate-cortical bone junction. As the extruded exudate dissects between the bone cortex and the periosteum, it
Figure 20. A, Suppurative exudate with puriform softening of metaphyses. B, Metaphyseal inflammation caused focal growth-plate thickening and reactive metaphyseal bone surrounding central suppurative exudate. Some of the exudate was lost during processing.
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Figure 21. Metaphyseal exostosis of distal ulna secondary to creeping periostitis and seeping of exudate from the marrow at the growth plate--metaphyseal junction, canine hypertrophic osteodystrophy.
causes reactive bone to be formed (Fig. 21). The suppurative exudate outside the bone may invade the joint, leading to a secondary suppurative arthritis. The growth plate and the articular cartilage normally act as a barrier to prevent direct extension of the osteomyelitis into the joint. Eventually, the purulent exudate penetrates the periosteum and the skin to form a draining sinus. The hole formed in the bone during this process is termed a cloaca. Periosteal new bone formation and reactive bone formed within the marrow cavity tend to wall off the infection. If the infection is somewhat limited, a Brodie's abscess is formed. When the infection is extensive, the periosteal new bone forms a sheath around the necrotic sequestrum, causing an involucrum (Fig. 14). The involucrum may be a microscopic fibrous membrane or may consist of the entire cortex. Whenever there is bone inflammation, a RAP is induced, and normal physiologic healing and defense processes are accelerated. The RAP may increase vascular flow, bone turnover, or longitudinal bone growth. In chronic inflammation, intermittent periods of bone resorption and formation (bone remodeling) may lead to trabeculae with a cement-line mosaic pattern (Fig. 22). Although the trabecular pattern is similar to the lesion found in
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Figure 22. Prominent cement-line mosaic pattern (reversal lines) in bone inflammation caused by increased remodeling activity in canine craniomandibular osteopathy.
osteitis deformans, proved cases of this disease have not been described in animals other than humans. Besides accelerating biologic processes, local factors may be liberated that interact with disuse to decrease the amount of bone. Inflammatory cells, particularly lymphocytes and macrophages, may liberate cytokines that activate bone resorption (remodeling). On the other hand, elevation of the periosteum by dissecting periostitis causes subperiosteal proliferation of reactive bone. The periosteal new bone formed in creeping periostitis remains delimited from the underlying original bone for some time. The distinction gradually becomes obliterated, and eventually the thickened bones consist entirely of coarsely compacted cancellous osseous tissue (Fig. 23). Creeping periostitis that causes increased thickness and disfigures craniofacial bones in a bilaterally symmetric manner is known as leontiasis ossea. Sometimes, the changes start in the interior of the bone and replace the compact structure of the cortex. Suppurative periostitis can spread steadily from one bone to another causing thickening of the affected bones through subperiosteal new bone deposition. Suppuration and bone sequestration only seem to occur as rare complications. 11 CLASSIFICATION OF OSTEOMYELITIS AND CHRONIC OSTEOMYELITIS
Osteomyelitis usually is classified according to the histology of the inflammatory reaction. Acute suppurative osteomyelitis is the most common form. Sometimes, the inflammatory reaction is characterized by lesser
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Figure 23. Mandibles from (A) a dog with craniomandibular osteopathy and (B) a normal West Highland White Terrier. Activated remodeling increases cortical porosity and produces a trabecular bone pattern. Delineation between newly formed subperiosteal bone and the original cortex gradually diminishes following periostitis.
numbers of neutrophils and is termed subacute or chronic depending upon the extent to which macrophages, lymphocytes, or plasma cells predominate. Chronic cystic osteomyelitis occurs when suppurative inflammation subsides and when the inflammatory cystic spaces previously occupied by exudate contain xanthochromic proteinaceous fluid surrounded by a reparative reaction. Infections with Actinomyces, Actinobacilli, and Nocardia organisms often have pathologic features similar to a low-grade, slowly progressive, chronic infection. Indurated, connective tissue granulomas; some degree of suppuration; and the presence of grains in the exudate characterize actinomycosis. Eosinophilic clavate deposits surround organisms. Destruction of the jaw bones coupled with compensatory apposition of surface bone is characteristic. Pyogranulomatous inflammation also is characteristic of mycetomas that occur as localized swollen lesions involving subcutaneous tissue, fascia, and bone (Fig. 24A). There are multiple diverse causative agents in mycetomas, including both higher fungi and actinomycetes. The characteristic bone lesion is an exophytic proliferation of bone trabeculae that may surround colonies of organisms. Like actinomycosis,
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Figure 24. Mycetoma of the shoulder involves the scapula. A , Pyogranulomatous myositis and osseous proliferation. Tissue granules appear dark. B, Characteristic tissue granules within bone, little inflammatory exudate. Tissue reaction covers pigmented, broad, septate, and branched hyphae. Terminal portions of hyphae near the periphery of granule are greatly expanded.
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colonies of organisms form characteristic tissue grains in which eosinophilic hyaline material surrounds fungi within microscopic granules (Fig. 24B). The inflammatory reaction may not be as severe when organisms locate within the bone. Chronic granulomatous osteomyelitis rather than a pyagranulomatous reaction is characteristic of certain microorganisms. Granulomatous osteomyelitis can be caused by Brucella or Mycobacteria. These lesions are not often seen in dogs and cats, but Brucella infections have been reported in dogs after hip replacement. 12 Usually, a fungal agent causes granulomatous osteomyelitis. Coccidioidomycosis is the most notorious infection in the southwestern United States. Biopsy specimens of bone lesions may not reveal many organisms, and yeast phases do not always contain endospores. Aspergillosis probably is the most common cause of canine granulomatous osteomyelitis in the coastal southern states (Fig. 25). The condition may start as a nasal infection, but it also may be found as a disseminated disease without a preceding rhinitis. In endemic regions, one third of dogs with blastomycosis have bone lesions. Histoplasmosis also causes bone and joint lesions to a lesser extent. Cryptococcus is another fungus that causes granulomatous bone and joint lesions, but the inflammatory response may be less granulomatous and more histiocytic. A granulomatous reaction occurs in association with fat necrosis of bone marrow; this condition may accompany acute hemorrhagic pancreatitis, chronic relapsing pancreatitis, or metastatic pancreatic carcinoma. Viruses affect bone and its connective tissue, but inflammation is not the predominating reaction. Parasites in bone are uncommon but are reported with echinococcosis. 11 In dogs, periostitis associated with Hepatozoon canis infection of muscles causes exostoses. 5
IDIOPATHIC BONE INFLAMMATIONS Craniomandibular Osteopathy
Craniomandibular osteopathy ("lion jaw") is a bone disease of unknown cause mainly affecting Terriers. The disease begins when puppies of 2 to 3 months of age show clinical signs of extreme soreness during mastication or when the mouth is opened. The condition is characterized by enlargement of the mandible and tympanic bullae of the temporal bone. If the bulla and posterior mandible fuse, the jaw will not open, and the animal has difficulty eating and drinking. If symptomatic treatment prevents bone fusion, the condition subsides after growth-plate closure at 9 to 11 months of age, and some of the excessive bone is resorbed. The microscopic lesions in the mandible consist of bony proliferation on the periosteal surface and internal replacement of cortical bone with osseous trabeculae (Fig. 23). Often, active areas of ossification or bone remodeling are associated with foci of suppurative inflammation (Fig. 26). In other regions, trabeculae may be separated by highly vascular fibrous stroma that contains a mixed population of inflammatory cells composed of macrophages, neutrophils, lymphocytes, and plasma cells. Sometimes, few if any inflammatory cells are seen. A mosaic pattern of irregular cement lines (reversal lines) is
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Figure 25. Granulomatous osteomyelitis. A , Distal humerus, bone marrow replaced by inflammatory tissue with loss of distal bone cortex and secondary subperiosteal proliferation of reactive bone. B, Chronic inflammation and granuloma within the marrow cavity.
characteristic of the newly produced trabeculae (Fig. 22). Sometimes, inflammatory cells are sparse, but the prominent cement-line pattern in trabeculae of the enlarged bone gives evidence of previous intense remodeling activity. Necrotic bone is observed in some trabeculae. Hypertrophic Osteodystrophy Canine hypertrophic osteodystrophy (metaphyseal osteopathy) is an inflammatory bone disease of unknown cause that affects young dogs. Although the disease affects a number of the large-dog breeds, it is particularly common in Great Danes and Irish Setters. Early microscopic lesions are those of acute inflammation in which large numbers of neutrophils infiltrate the intertrabecular tissue of the primary spongiosa. Inflammation results in necrosis of mesenchymal components of the primary spongiosa, and necrosis of osteoblasts leads to a failure of ossifications of cartilaginous trabeculae. The thin, elongated , mineralized cartilaginous trabeculae may fracture and cause infraction beneath the growth plate (Fig. 27). Interruption in the metaphyseal vessels prevents normal growth-plate cartilage resorption and leads to elongation of the zonal depth of mineralized hypertrophic cartilage. Inflammation of osteochondral junctions (osteochondritis) is evident in many locations where there are no gross or radiographic
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Figure 26. Canine craniomandibular osteopathy, focally severe acute suppurative inflammation with osteoclasts.
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Figure 27. Distal radius, recurrent hypertrophic osteodystrophy in a 4-month-old Great Dane . Suppurative exudate and infraction beneath the growth plate (*).
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lesions. Osteomyelitis may be evident in the mandible, particularly in the dental sac, and the incisor and molar teeth may have a grey-brown color. Soft-tissue lesions may include focal suppurative inflammation in the skin, heart, and stomach. Hemorrhages probably are related to prolongation in blood clotting. Soft-tissue mineralization in heart, spleen, lung, stomach, and kidney also is common. Panosteitis Panosteitis is a noncontagious, self-limiting canine inflammatory bone disease of unknown cause. It occurs in 6- to 10-month-old large- or giantbreed dogs. The condition is known to occur in pups from previously affected bitches, but it is not an inherited condition. Usually, a single bone of the appendicular skeleton is affected, and the animal may be lame before a lesion can be detected radiographically. There is extreme tenderness of the tissues around the affected bone. Within 2 weeks, radiographic changes are evident, and the initial lesion begins within the medullary cavity in the region of the nutrient foramen. As the density within the medullary cavity expands, the cortex may become rarefied with production of subperiosteal reactive bone. Usually, only a single bone is involved at a particular time. One exception is the ulna and radius, where a single vessel divides to form the nutrient artery of each bone. The condition may vacillate from one bone to another.
Figure 28. A, Initial lesion of panosteitis, nidus of bone proliferation in the region of the nutrient foramen. B, Higher magnification illustrates hyperemia, scant inflammatory cells and fibrinous exudate.
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Histologically, the first lesion is seen in the region of the nutrient foramen where increased vascularity and edema are observed. There is proliferation of the adventitial cells accompanying the small medullary vessels, and a small central area composed of woven bone trabeculae is formed (Fig. 28A). Vascular congestion and an intratrabecular fibrinous exudate are prominent at this stage. Plasma cells and other mononuclear cells may be seen within the lesion, but inflammatory cell infiltration is not a predominant feature (Fig. 28B). After formation of the initial nidus, satellites develop along the vascular system. The newly formed osseous trabeculae spread centrifugally within the marrow cavity, eventually stopping at the metaphysis. At the late phase, inflammation is absent. There is an increase in bone maturity from the periphery to the center of the more developed lesion. When a trabecular network fills most of the marrow, there is subperiosteal osteophyte formation. As the lesion begins to resolve, the more mature central bone disappears first.
REFERENCES 1. Andersen BC, Bulgin MS: Blood culture of the canine patient. J Am Vet Med Assoc 184:175-178, 1984 2. Burchardt H: The biology of bone graft repair. Clin Orthop 174:28, 1983 3. Buxton TB, Horner J, Hinton A, et a!: In vivo glycocalyx expression by Staphylococcus aureus phage type 52/52A/80 in S. aureus osteomyelitis. J Infect Dis 156:942-946, 1987 4. Costerton JW: The etiology and persistence of cryptic bacterial infections: A hypothesis. Rev Infect Dis 6:S608-S616, 1984 5. Craig TT, Smallwood JE, Knauer KE, eta!: Hepatozoon canis infection in dogs: Clinical, radiologic and hematologic findings. JAm Vet Med Assoc 173:967-972, 1978 6. Frost FM: The biology of fracture healing. An overview for clinicians. Part II. Clin Orthop 248:293-309, 1989 7. Frost HM: The Biology of fracture healing. An overview for clinicians. Part I. Clin Orthop 248:283-293, 1989 8. Gillespie WJ, Allardyce RA: Mechanisms of bone degradation in infections: A review of current hypotheses. Orthopedics 13:407-410, 1990 9. Grewe SR, Stephens BO, Perlino C, et a!: Influence of internal fixation on wound infections. J Trauma 27:1051-1054, 1987 10. Cristina AG, Costerton JW: Bacterial adherence and the glycocalyx and their role in musculoskeletal infection. Orthop Clin North Am 15:517-535, 1984 11. Jaffe HL: Metabolic, Degenerative, and Inflammatory Diseases of Bone and Joints. Philadelphia, Lea & Febiger, 1972, pp 278-281 12. Lamb CR: Brucella canis osteomyelitis in two dogs with total hip replacements. JAm Vet Med Assoc 191:986-990, 1987 13. Lenehan TM, Van Sickle DC: Ununited anconeal process, ununited medial coronoid process, ununited medial epicondyle, patella cubiti, and sesamoidal fragments of the elbow. In Newton CD, Nunamaker DM (eds): Textbook of Small Animal Orthopaedics. Philadelphia, JB Lippincott, 1985, pp 999-1012 14. Lindberg L: Experimental staphylococcal arthritis in golden hamsters (Mesocriceturs auratus). Acta Pathol Microbiol Scand 76:117-125, 1969 15. Mayberry-Carson KJ, Tober-Meyer B, Smith JK, eta!: Bacterial adherence and glycocalyx formation in osteomyelitis experimentally induced with Staphylococcus aureus. Infect Immun 43:825-833, 1984 16. Morrissy RT, Haynes DW: Acute hematogenous osteomyelitis: A model with trauma as an etiology. J Pediatr Orthop 9:447-456, 1989 17. Osterman AL, Bora FW: Free vascularized bone grafting for large-gap nonunions oflong bones. Orthop Clin North Am 15:131-142, 1984
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18. Petty W, Spanier S, Shuster JJ, et al: The influence of skeletal implants on incidence of infection. Experiments in a canine model. J Bone Joint Surg Am 67:1236-1234, 1985 19. Rhinelander FW, Barogry RA: Microangiography of bone healing: Undisplaced closed fractures. J Bone Joint Surg 44A:1273-1298, 1962 20. Rosol TJ, Capen CC: Pathogenesis of humoral hypercalcemia of malignancy. Domest Aniin Endocrinol 5:1-21, 1988 21. Ryden C, Yacoub AI, Maxe I, et al: Specific binding of bone sialoprotein to Staphylococcus aureus isolated from patients with osteomyelitis. Eur J Biochem 184:331-336, 1989 22. Simmons OJ: Biology offracture healing in normal and metabolic bone disease: Molecularcell concepts. In Takahashi HE (ed): Bone Morphometry. Niigata, Japan, Nishimura, 1990, pp 82-87 23. Speers OJ, Nade SM: Ultrastructural studies of adherence of Staphylococcus aureus in experimental acute hematogenous osteomyelitis. Infect Immunol 49:443-446, 1985 24. Urist MR, Huo YK, Brownell AG, et al: Purification of bovine bone morphogenetic protein by hydroxyapatite chromatography. Proc Nat! Acad Sci USA 81:371-375, 1984 25. Walker AD, Richardson CC, Bryant MJ, et al: Anaerobic bacteria associated with osteomyelitis in domestic animals. JAm Vet Med Assoc 182:814-816, 1983 26. Whalen JL, Fitzgerald RH, Morrissy RT: A histological study of acute hematogenous osteomyelitis following physeal injuries in rabbits. J Bone Joint Surg Am 70:1383-1392, 1988
Address reprint requests to J. Carroll Woodard, DVM, PhD Department of Comparative and Experimental Pathology University of Florida College of Veterinary Medicine Gainesville, FL 32610
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Morphology of Fracture Nonunion and Osteomyelitis
]. Carroll Woodard, DVM, PhD,* and Wayne H. Riser, DVM, MS, DrVetMed, MAt
SUMMARY OF NORMAL FRACTURE HEALING
After injury of sufficient magnitude to cause fracture, blood vessels in the area rupture, and there is soft-tissue contusion. The magnitude of the injury determines the severity of tissue damage. The site of trauma, including the fractured bone, becomes a special sphere of influence that enhances normal biologic processes and accelerates physiologic mechanisms. This acceleration of the bone's biologic processes is termed a general metabolic shift or the regional acceleratory phenomenon (RAP). It is this physiologic acceleration that permits bone healing to proceed at such a rapid pace, even in cortical bone locations in adult animals that have low bone turnover. The RAP is responsible for scintograms showing increased deposition of radiobisphosphonate as much as 1 year or longer after injury. Hemorrhage into the injured area clots in the same manner as any other extravasation, and mesenchymal cells migrate into the clot along the fibrinous scaffolding (Fig. 1). Soon the clot organizes, and the formation of granulation tissue aids bone repair because of neovascularization (Fig. 2). After fracture, the ruptured periosteum initially contracts, but soon cells of the cambium layer with primitive mesenchymal cells of the soft-tissue reactive zone begin to divide. They differentiate to form fibroblasts, chondroblasts, and osteoblasts in varying proportions and make the provisional callus that encircles the fracture site (Fig. 3). It is during this first week of the initial granulation tissue and inflammatory phase that systemic and local factors cause cell recruitment and differentiation. These mediators direct the amount, location, and cellular nature of the future bone callus. The proliferating mesenchymal cells differentiate into fibrous tissue, hyaline From the Department of Comparative and Experimental Pathology, University of Florida College of Veterinary Medicine, Gainesville, Florida *Professor t Adjunct Professor Veterinary Clinics of North America: Small Animal Practice- Vol. 21, No. 4, July 1991
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Figure l. Initial injury leads to necrosis of cortical bone and hemorrhage and sets into motion the regional acceleratory phenomenon.
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Figure 2. As in injury in other tissues , there is an acute inflammatory response that leads to organization of the hematoma.
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Fibrous tissue
Figure 3. A provisional callus is formed in the region of the organized clot by mesenchymal cell division and differentiation into fibrous tissue, cartilage, and woven bone. The necrotic bone of the cortex is replaced by longitudinal vascular tunneling.
cartilage, and bone. Osteoid trabeculae mostly form by intramembranous bone formation. They may be formed to a lesser degree by endochondral ossification of cartilage. Trabeculae of the provisional callus mineralize as true callus develops. This bony callus not only fills the gaps of the broken structure but also fills the marrow cavity. The callus protrudes outwardly, forming a considerably larger mass than the original bone. The newly formed bone trabeculae merge or meld into the original bone of the cortices and are separated by cement lines. For some months or even years afterward, this bone undergoes repeated sequences of remodeling, removal by osteoclasts, and replace ment by lamellar bone. The remodeling reduces the size of the callus, makes normal secondary haversian systems, and more nearly duplicates the original bone structure (Fig. 4). In young animals that are still in the growth phase, bone modeling through formation and resorption drifts straighten crooked bones (Fig. 5). If there is mobility at the fracture site, a cartilage union often precedes formation of bone. In excessive mobility, delayed union or nonunion may develop, and fibrous tissue may be the predominant tissue of the callus site. On the other hand, little callus or little or no cartilage is form ed if there is sufficient immobility to cause osteosynthesis.
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Fine trabeculae
Figure 4. After the provisional callus becomes mineralized, there is remodeling of the woven bone and necrotic cortex. This activity reduces the size of the callus and creates osseous tissue of a mature character and structural orientation.
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Figure 5. In the young animal, macromodeling usually straightens crooked bones. Striped = resorption, dotted area = formation.
FAILURE OF FRACTURES TO HEAL Types Delayed union occurs when a fracture requires a healing time longer than the generally accepted average period for such cases. Nonunions do . not heal without treatment, and infrequently they may progress to a synovial nonunion or pseudoarthrosis. A true pseudoarthrosis (Figs. 6, 7, and 8) is characterized by having a true joint space and a joint capsule that is lined by synovial cells. Synovial villi also may be present. In the classic pseudoarthrosis, the fractured bone ends are round and covered by hyaline cartilage so perfect that one might question whether the false joint resulted from fracture (Fig. 6). Before the devel6pment of a pseudoarthrosis, the opposing surfaces of a nonunion may be joined by fibrous tissue or fibrocartilage (Fig. 8), or excessive abrasion may erode the adjoining surfaces and cause eburnation (Fig. 7). In long bones, the pseudoarthrosis may resemble a ball and socket joint. The end of the longest bone elemen t becomes convex, and the end of the shorter element is concave (Figs. 7 and 8). Fracture healing frequently is impaired after pathologic fracture. The pathologic process causing the fracture is responsible for the delayed union. In bone tumors (Fig. 9), bone fracture is common, because tumor Text continued on page 823
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Figure 6. A 3-year-old male feral Florida panther was hit by a car and died. Necropsy exam ination revealed evidence of recent trauma. In addition, there was atrophy of the muscles of the right thigh and pseudarthrosis of the right femur, presumably from a previous automobile accident. A, False joint, femoral head within acetabulum (upper), fractured neck (lower). Note the articulating surfaces are rounded, and fractured bone ends are covered with cartilage. B, Acetabulum contains remnant of fractured femoral head that has hyaline cartilage on all articulating surfaces. C, Femur. The surface of the fractured neck is covered with hyaline cartilage.
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Figure 7. Six-month-old Wirehaired Terrier, pseudarthrosis of cervical fracture, proximal femur. Bone ends between fracture fragments are eburnated, and regional trabeculae are thick. Subperiosteal reactive bone (R), region of bone necrosis and resorption (N).
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Figure 8. After three months, a distal humoral fracture failed to heal following intramedullary pinning. A plate was placed across the fracture site, but an additional pin was inserted after the screws loosened. A, Pin tract occupies one half of the marrow space and extends through the cortex. Area of nonunion can be seen at the fracture site. B, Section lateral to that shown in A. C, Higher magnification of B, pseudarthrosis surrounded by joint capsule with synovial villi. Fibrocartilage separates the fracture surfaces.
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Figure 9. Fibrosarcoma (12 X 6 X 6 em) and pathologic fracture of the proximal tibia of a large mixed-breed dog . Increased bone porosity and tumor invasion through the cortex.
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growth causes increased focal bone remodeling and resorption. This possibly may occur because intramedullary tumor growth produces a RAP effect. Some tumors such as lymphosarcomas may secrete lymphokines that activate remodeling; the nonparathyroid peptide lymphokines are believed to cause bone resorption in multiple myeloma. 22 Tumor cells, particularly canine apocrine gland carcinomas of the anal sack, produce parathyroid hormone-related peptide, which causes hypercalcemia of malignancy. 20 Secondary hyperparathyroidism causes fibrous osteodystrophy and can lead to pathologic fracture of long bones or vertebra (Fig. 10). When fracture occurs in the vertebra, osteophytes may bridge the intervertebral space and aid the development of nonunion by decreasing intervertebral movement and increasing motion between fracture fragments (Fig. 11). However, not all metabolic bone diseases cause delayed union; in some types of osteoporosis, healing of fractures occurs in a normal fashion. Pathogenesis The pathogenesis of non unions can be divided into two basic categories: (1) primary or biologic failures in which proper conditions for healing are created, but the biologic mechanism fails to heal the bone properly, and (2) nonunions that develop because there is failure to create proper conditions for the normal healing process (secondary or technical failure). 6 · 7 In both veterinary and human medicine, most nonunions fall in the second category. As surgical techniques, immobilization methods, and antibacterial agents improve, however, the primary or biologic failures will take on added importance. Primary or Biologic Failure. Nutritional osteodystrophy or other metabolic bone diseases that interfere with bone mineralization (Fig. 12) are the most commonly recognized type of biologic failure in veterinary medicine. In young dogs and cats, feeding an all-meat diet is a common cause of nutritional osteodystrophy. With this exception, little attention is given to this aspect of the pathogenesis of nonunion because it usually is assumed that the failure was secondary or due to some technical difficulty. Each aspect of the normal bone healing process can go astray and lead to nonunion. 6 Thus, failure to make callus, inadequate RAP, failure to mineralize callus, maldifferentiation in which the fracture space fills with fibrous tissue and fat rather than callus, remodeling stage malfunctions in which there is delayed replacement of callus with normal bone, and modeling malfunctions in which there are inadequate modeling drifts are conditions that potentially can cause biologic failure. The mechanisms and cellular cascade associated with biologic failures have been discussed in light of recent laboratory investigations of various connective-tissue growth factors. 22 In the future, these biologic failures will be the cause of a greater percentage of nonunions in veterinary medicine. It is important to recognize biologic failures so that animal models can be developed to test therapeutic regimens that might prevent their occurrence. The cause of nonunions in adult animals in which conditions are optimum for healing should be investigated. Primary failure can be suspected when inadequate callus forms or when cortical bone shows little longitudinal tunneling that is normally caused by
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Figure 10. Three-month-old Persian kitten developed multiple limb fractures while being fed a ground-beef diet. Folding or green-stick fracture (between arrows) of vertebral body has caused injury to the spinal cord and hemorrhage (H).
Figure 11. Vertebral fracture in a cat resulting from a car accident. Osteophyte beneath the intervertebral disk space transfers joint motion laterally where fibrocartilage remains. A fibrous nonunion is present between vertebral body fragments.
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Figure 12. Delayed union in a 9-week-old Doberman Pinscher. Pathologic fracture following nutritional osteodystrophy. Exuberant amount of cartilage in the fracture callus.
the RAP and disuse. The rates of nonunion are higher in small-breed dogs. Sixty percent of nonunions in the dog occur in the radius and ulna. Some fractures of the distal radius and ulna of small-breed dogs show little callus formation and poor longitudinal tunneling of cortical bone (Fig. 13). The distal third of the radius and ulna has little muscle tissue, and nonunion in this region may be related to the lack of revascularization of the fracture site. Biologic failure also may play a role in these cases, because microangiography has shown that the medullary arterial supply dominates the pattern in rapid fracture healing. 19 Secondary or Technical Failure. Secondary or technical failures represent over 80% of non unions in veterinary medicine. These may be caused by infection, poor fracture reduction in which the bone ends are imperfectly aligned, distraction in which the bone ends are too far apart to permit healing, too much motion at the fracture site, or loss of blood supply and necrosis of bone. 6 Excessive motion of the fracture ends is probably the most important factor. Open fractures are a frequent cause of osteomyelitis, and contamination during open reduction surgery is the most important
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Figure 13. A well-formed nonunion 2. 5 em above the distal end of the radius and ulna of a terrier. Little callus has formed, and there is little evidence of activated remodeling of the cortex. A few osteoclasts were found associated with a limited amount of necrotic cortical tissue .
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cause of osteomyelitis. If suppurative osteomyelitis becomes sufficient, bone necrosis and sequestration occur (Fig. 14). A sheath or involucrum develops around the necrotic fragments. Small amounts of suppurative exudate may prevent healing by resulting in bone necrosis (Fig. 15). The placement of an intramedullary pin causes medullary vascular disruption, but this seems tolerated surprisingly well with only slight reduction of endosteal callus (Fig. 16). If periostitis complicates intramedullary pinning, necrosis of the bone cortex follows, because these factors compromise both the endosteal and periosteal vascular components of the dual supply (Fig. 17). More movement of the fracture ends can be tolerated in classic healing by callus formation than in primary union by osteosynthesis, because large gaps permit more motion before tissue disruption occurs. After intramedullary pinning, excessive motion can lead to nonunion and pseudarthrosis (see Fig. 8). Movement also can create a fibrous nonunion after fracture across an apophysis (Fig. 18). 13 A pseudarthrosis requires resection of the cartilage, because the cartilage and synovial fluid are a barrier that prevents ossification. Bone grafts are used in the treatment of delayed unions and nonunions. The most successful grafts are vital bone grafts transferred from donor to recipient bone sites with circulation still intact. 17 This type of preparation keeps the bone's mediator mechanisms intact. All other kinds of grafts represent dead bone (Fig. 19). 2 The graft matrix contains growth factors, and success depends upon competence of mediator mechanisms in the recipient site. Treatment of nonviable grafts with bone morphogenetic protein improves the incorporation of the graft into bone. 24
Figure 14. Postfracture humoral amputation, osteomyelitis . A large sequestrum (S) is surrounded by suppurative exudate (E) and involucrum (I ).
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Figure 15. Failure to develop an osteosynthesis following bone plating. Only a small amount of chronic active inflammation was found at the site of nonunion. However, cortical bone (C) is necrotic along the distance from the fracture site to the arrows . Large amount of subperiosteal reactive bone (P) and endosteal trabeculae (E) appear around screw holes.
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Figure 16. Nonunion of femur after intramedullary pinning. Little external callus is present because of limited motion. Reactive bone fills the medullary cavity and abuts the space where the pin was removed.
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Figure 17. Fracture repaired with an intramedullary pin. Amputations performed after development of osteomyelitis. Clear space (P) is where the pin was removed. Reactive bone (R) surrounds suppurative exudate (E) and necrotic bone cortex (N).
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Figure 18. Nonunion, fractured anconeal process (ununited anconeal process) of ulna.
Bone Inflammation
The inflammatory reaction in bone (osteitis) is confined to connective tissue spaces forming periosteum and marrow and filling haversian canals. The inflammatory process may be confined to marrow (osteomyelitis) or periosteum (osteoperiostitis), but the dividing line between these processes seldom is well defined. Osteitis occurs whenever there is significant tissue damage or whenever mediators of the inflammatory response are liberated, but it occurs in its most conspicuous form in association with infectious agents. Spondylitis, that is, inflammation of the vertebrae, may follow penetrating wounds, may be of hematogenous origin, or may occur by retrograde spread through the vertebral venous plexus. Diskospondylitis occurs when there is contiguous involvement of the vertebral body and disk. Ankylosing spondylitis is a special form of vertebral inflammation rarely seen in animals other than humans, and the early histologic lesions resemble rheumatoid arthritis. Calcific and osseous changes in the annulus fibrosus are particularly characteristic of the condition; these changes produce the so-called "bamboo spine." The use of the term ankylosing
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Figure 19. Cross-section of canine fibular autograft after continuous intravital tetracycline labeling. A , Microradiograph, B, fluorescence photomicrograph. Newly formed subperiosteal bone is less dense and shows fluorescence compared to the nonlabeled necrotic grafted bone. Bone surrounding vessels (a and b) has the same density, but fluorescence shows b to be a completed remodeling site. (Courtesy of Dr. H. Burchardt.)
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spondylitis to indicate noninflammatory ankylosing spinal lesions characterized by vertebral osteophytosis is inappropriate and should not be continued. Osteochondritis is inflammation at the osteochondral junction and occurs most frequently beneath articular cartilage or the growth plate in young animals. Another term, epiphysitis, refers to inflammation of the epiphysis or the growth-plate cartilage that separates it from the main bone. Osteochondritis also may designate a joint lesion characterized by dissection of articular cartilage (osteochondritis dissecans). This lesion is classified as a type of osteochondrosis, because inflammation does not play a prominent pathogenetic role. ACUTE OSTEOMYELITIS AND CAUSE AND PATHOGENESIS OF HEMATOGENOUS DISEASE Bone infection most commonly follows open fracture, and infection can follow orthopedic surgical procedures. Orthopaedic implant materials increase the likelihood of osteomyelitis after instillation of bacterial organisms. 9• 18 Also, hematogenous bone infections occur more frequently after bone trauma. 16 • 26 Hematogenous osteomyelitis occurs most often in young animals, because the presence or absence of epiphyseal fusion is a factor that influences the localization of blood-borne infection. It has been shown experimentally that staphylococci produce osteomyelitis in the young (epiphysis unfused) but arthritis without osteomyelitis in adults (epiphysis fused). 14 Staphylococci and streptococci are the most frequent aerobic bacteria found in hematogenous infections, but even microorganisms of low pathogenicity, such as Escherichia coli, cause bone infections. 1 Infections with anaerobic bacteria or mixed aerobic and anaerobic infection are common. 25 Peptostreptococcus anaerobicus is a frequent anaerobic isolate, and the most frequently isolated genus is the obligate anaerobe, Bacteroides, usually Bacteroides asaccharolyticus. Hematogenous osteomyelitis starts in the primary spongiosa of the metaphysis just below the growth plate or in the secondary ossification center of the epiphysis beneath the articular-cartilage growth area. This is because of the unique vascular supply in these areas. Arterioles form a loop at the growth plate-bone junction and then drain into the medullary cavity without forming a capillary bed. Bacteria lodge in this region and attach to trabecular bone or cartilage matrix surfaces, 3 • 4 • 10• 15• 23 but do not attach to adjacent vascular linings or erythrocytes. Staphylococci and P. aeruginosa attach to matrix surfaces and grow in a biofilm that serves as a barrier against hostile environmental agents such as host defense mechanisms and antibiotics. S. aureus binds sialoprotein selectively, and the major binding site residues are in the sialoprotein core protein, not in the carbohydrate side chains. An average of 1000 bone-sialoprotein-binding sites are found per bacterial cell. 21 The adherence of staphylococci stimulates the organism to exude a glycocalyx that becomes progressively more dense and buries the organism in a dense, coccoid-studded biofilm. Liberated bacterial toxins and ischemia lead to bone necrosis; the necrotic areas coalesce into an avascular zone permitting further bacterial
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proliferation. With some bacterial infections, there may be bone sequestration. If infection is contained, the bone end grows away from the inflammatory focus, and the distance between the focus and the growth zone increases. If the condition progresses, exudation may be extensive and results in osteolysis of metaphyseal trabeculae (Fig. 20A). Puriform softening of bone is the result of liberation of lysosomal enzymes from polymorphonuclear leukocytes and macrophages, but there may be activation of resorption cavities with osteoclasts. 8 Tissue destruction may be so extensive that it interrupts the vascular supply to the growth plate (Fig. 20B). Focal lesions resembling rickets develop because inflammation prevents normal vascular invasion of the mineralized growth-plate cartilage. Suppurative exudate and bacteria may spread into the endosteal, haversian, and Volkmann vascular channels that supply the cortex. Suppurative exudate forming beneath the periosteum shears off the perforating arteries, which further devitalizes the cortex. The exudate flows between the periosteum and the cortex, isolating more bone from its blood supply, and may cause complete necrosis of the cortex. The exudate may escape from the bone's interior at the periosteal surface of the growth plate-cortical bone junction. As the extruded exudate dissects between the bone cortex and the periosteum, it
Figure 20. A, Suppurative exudate with puriform softening of metaphyses. B, Metaphyseal inflammation caused focal growth-plate thickening and reactive metaphyseal bone surrounding central suppurative exudate. Some of the exudate was lost during processing.
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Figure 21. Metaphyseal exostosis of distal ulna secondary to creeping periostitis and seeping of exudate from the marrow at the growth plate--metaphyseal junction, canine hypertrophic osteodystrophy.
causes reactive bone to be formed (Fig. 21). The suppurative exudate outside the bone may invade the joint, leading to a secondary suppurative arthritis. The growth plate and the articular cartilage normally act as a barrier to prevent direct extension of the osteomyelitis into the joint. Eventually, the purulent exudate penetrates the periosteum and the skin to form a draining sinus. The hole formed in the bone during this process is termed a cloaca. Periosteal new bone formation and reactive bone formed within the marrow cavity tend to wall off the infection. If the infection is somewhat limited, a Brodie's abscess is formed. When the infection is extensive, the periosteal new bone forms a sheath around the necrotic sequestrum, causing an involucrum (Fig. 14). The involucrum may be a microscopic fibrous membrane or may consist of the entire cortex. Whenever there is bone inflammation, a RAP is induced, and normal physiologic healing and defense processes are accelerated. The RAP may increase vascular flow, bone turnover, or longitudinal bone growth. In chronic inflammation, intermittent periods of bone resorption and formation (bone remodeling) may lead to trabeculae with a cement-line mosaic pattern (Fig. 22). Although the trabecular pattern is similar to the lesion found in
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Figure 22. Prominent cement-line mosaic pattern (reversal lines) in bone inflammation caused by increased remodeling activity in canine craniomandibular osteopathy.
osteitis deformans, proved cases of this disease have not been described in animals other than humans. Besides accelerating biologic processes, local factors may be liberated that interact with disuse to decrease the amount of bone. Inflammatory cells, particularly lymphocytes and macrophages, may liberate cytokines that activate bone resorption (remodeling). On the other hand, elevation of the periosteum by dissecting periostitis causes subperiosteal proliferation of reactive bone. The periosteal new bone formed in creeping periostitis remains delimited from the underlying original bone for some time. The distinction gradually becomes obliterated, and eventually the thickened bones consist entirely of coarsely compacted cancellous osseous tissue (Fig. 23). Creeping periostitis that causes increased thickness and disfigures craniofacial bones in a bilaterally symmetric manner is known as leontiasis ossea. Sometimes, the changes start in the interior of the bone and replace the compact structure of the cortex. Suppurative periostitis can spread steadily from one bone to another causing thickening of the affected bones through subperiosteal new bone deposition. Suppuration and bone sequestration only seem to occur as rare complications. 11 CLASSIFICATION OF OSTEOMYELITIS AND CHRONIC OSTEOMYELITIS
Osteomyelitis usually is classified according to the histology of the inflammatory reaction. Acute suppurative osteomyelitis is the most common form. Sometimes, the inflammatory reaction is characterized by lesser
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Figure 23. Mandibles from (A) a dog with craniomandibular osteopathy and (B) a normal West Highland White Terrier. Activated remodeling increases cortical porosity and produces a trabecular bone pattern. Delineation between newly formed subperiosteal bone and the original cortex gradually diminishes following periostitis.
numbers of neutrophils and is termed subacute or chronic depending upon the extent to which macrophages, lymphocytes, or plasma cells predominate. Chronic cystic osteomyelitis occurs when suppurative inflammation subsides and when the inflammatory cystic spaces previously occupied by exudate contain xanthochromic proteinaceous fluid surrounded by a reparative reaction. Infections with Actinomyces, Actinobacilli, and Nocardia organisms often have pathologic features similar to a low-grade, slowly progressive, chronic infection. Indurated, connective tissue granulomas; some degree of suppuration; and the presence of grains in the exudate characterize actinomycosis. Eosinophilic clavate deposits surround organisms. Destruction of the jaw bones coupled with compensatory apposition of surface bone is characteristic. Pyogranulomatous inflammation also is characteristic of mycetomas that occur as localized swollen lesions involving subcutaneous tissue, fascia, and bone (Fig. 24A). There are multiple diverse causative agents in mycetomas, including both higher fungi and actinomycetes. The characteristic bone lesion is an exophytic proliferation of bone trabeculae that may surround colonies of organisms. Like actinomycosis,
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Figure 24. Mycetoma of the shoulder involves the scapula. A , Pyogranulomatous myositis and osseous proliferation. Tissue granules appear dark. B, Characteristic tissue granules within bone, little inflammatory exudate. Tissue reaction covers pigmented, broad, septate, and branched hyphae. Terminal portions of hyphae near the periphery of granule are greatly expanded.
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colonies of organisms form characteristic tissue grains in which eosinophilic hyaline material surrounds fungi within microscopic granules (Fig. 24B). The inflammatory reaction may not be as severe when organisms locate within the bone. Chronic granulomatous osteomyelitis rather than a pyagranulomatous reaction is characteristic of certain microorganisms. Granulomatous osteomyelitis can be caused by Brucella or Mycobacteria. These lesions are not often seen in dogs and cats, but Brucella infections have been reported in dogs after hip replacement. 12 Usually, a fungal agent causes granulomatous osteomyelitis. Coccidioidomycosis is the most notorious infection in the southwestern United States. Biopsy specimens of bone lesions may not reveal many organisms, and yeast phases do not always contain endospores. Aspergillosis probably is the most common cause of canine granulomatous osteomyelitis in the coastal southern states (Fig. 25). The condition may start as a nasal infection, but it also may be found as a disseminated disease without a preceding rhinitis. In endemic regions, one third of dogs with blastomycosis have bone lesions. Histoplasmosis also causes bone and joint lesions to a lesser extent. Cryptococcus is another fungus that causes granulomatous bone and joint lesions, but the inflammatory response may be less granulomatous and more histiocytic. A granulomatous reaction occurs in association with fat necrosis of bone marrow; this condition may accompany acute hemorrhagic pancreatitis, chronic relapsing pancreatitis, or metastatic pancreatic carcinoma. Viruses affect bone and its connective tissue, but inflammation is not the predominating reaction. Parasites in bone are uncommon but are reported with echinococcosis. 11 In dogs, periostitis associated with Hepatozoon canis infection of muscles causes exostoses. 5
IDIOPATHIC BONE INFLAMMATIONS Craniomandibular Osteopathy
Craniomandibular osteopathy ("lion jaw") is a bone disease of unknown cause mainly affecting Terriers. The disease begins when puppies of 2 to 3 months of age show clinical signs of extreme soreness during mastication or when the mouth is opened. The condition is characterized by enlargement of the mandible and tympanic bullae of the temporal bone. If the bulla and posterior mandible fuse, the jaw will not open, and the animal has difficulty eating and drinking. If symptomatic treatment prevents bone fusion, the condition subsides after growth-plate closure at 9 to 11 months of age, and some of the excessive bone is resorbed. The microscopic lesions in the mandible consist of bony proliferation on the periosteal surface and internal replacement of cortical bone with osseous trabeculae (Fig. 23). Often, active areas of ossification or bone remodeling are associated with foci of suppurative inflammation (Fig. 26). In other regions, trabeculae may be separated by highly vascular fibrous stroma that contains a mixed population of inflammatory cells composed of macrophages, neutrophils, lymphocytes, and plasma cells. Sometimes, few if any inflammatory cells are seen. A mosaic pattern of irregular cement lines (reversal lines) is
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Figure 25. Granulomatous osteomyelitis. A , Distal humerus, bone marrow replaced by inflammatory tissue with loss of distal bone cortex and secondary subperiosteal proliferation of reactive bone. B, Chronic inflammation and granuloma within the marrow cavity.
characteristic of the newly produced trabeculae (Fig. 22). Sometimes, inflammatory cells are sparse, but the prominent cement-line pattern in trabeculae of the enlarged bone gives evidence of previous intense remodeling activity. Necrotic bone is observed in some trabeculae. Hypertrophic Osteodystrophy Canine hypertrophic osteodystrophy (metaphyseal osteopathy) is an inflammatory bone disease of unknown cause that affects young dogs. Although the disease affects a number of the large-dog breeds, it is particularly common in Great Danes and Irish Setters. Early microscopic lesions are those of acute inflammation in which large numbers of neutrophils infiltrate the intertrabecular tissue of the primary spongiosa. Inflammation results in necrosis of mesenchymal components of the primary spongiosa, and necrosis of osteoblasts leads to a failure of ossifications of cartilaginous trabeculae. The thin, elongated , mineralized cartilaginous trabeculae may fracture and cause infraction beneath the growth plate (Fig. 27). Interruption in the metaphyseal vessels prevents normal growth-plate cartilage resorption and leads to elongation of the zonal depth of mineralized hypertrophic cartilage. Inflammation of osteochondral junctions (osteochondritis) is evident in many locations where there are no gross or radiographic
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Figure 26. Canine craniomandibular osteopathy, focally severe acute suppurative inflammation with osteoclasts.
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Figure 27. Distal radius, recurrent hypertrophic osteodystrophy in a 4-month-old Great Dane . Suppurative exudate and infraction beneath the growth plate (*).
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lesions. Osteomyelitis may be evident in the mandible, particularly in the dental sac, and the incisor and molar teeth may have a grey-brown color. Soft-tissue lesions may include focal suppurative inflammation in the skin, heart, and stomach. Hemorrhages probably are related to prolongation in blood clotting. Soft-tissue mineralization in heart, spleen, lung, stomach, and kidney also is common. Panosteitis Panosteitis is a noncontagious, self-limiting canine inflammatory bone disease of unknown cause. It occurs in 6- to 10-month-old large- or giantbreed dogs. The condition is known to occur in pups from previously affected bitches, but it is not an inherited condition. Usually, a single bone of the appendicular skeleton is affected, and the animal may be lame before a lesion can be detected radiographically. There is extreme tenderness of the tissues around the affected bone. Within 2 weeks, radiographic changes are evident, and the initial lesion begins within the medullary cavity in the region of the nutrient foramen. As the density within the medullary cavity expands, the cortex may become rarefied with production of subperiosteal reactive bone. Usually, only a single bone is involved at a particular time. One exception is the ulna and radius, where a single vessel divides to form the nutrient artery of each bone. The condition may vacillate from one bone to another.
Figure 28. A, Initial lesion of panosteitis, nidus of bone proliferation in the region of the nutrient foramen. B, Higher magnification illustrates hyperemia, scant inflammatory cells and fibrinous exudate.
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Histologically, the first lesion is seen in the region of the nutrient foramen where increased vascularity and edema are observed. There is proliferation of the adventitial cells accompanying the small medullary vessels, and a small central area composed of woven bone trabeculae is formed (Fig. 28A). Vascular congestion and an intratrabecular fibrinous exudate are prominent at this stage. Plasma cells and other mononuclear cells may be seen within the lesion, but inflammatory cell infiltration is not a predominant feature (Fig. 28B). After formation of the initial nidus, satellites develop along the vascular system. The newly formed osseous trabeculae spread centrifugally within the marrow cavity, eventually stopping at the metaphysis. At the late phase, inflammation is absent. There is an increase in bone maturity from the periphery to the center of the more developed lesion. When a trabecular network fills most of the marrow, there is subperiosteal osteophyte formation. As the lesion begins to resolve, the more mature central bone disappears first.
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Address reprint requests to J. Carroll Woodard, DVM, PhD Department of Comparative and Experimental Pathology University of Florida College of Veterinary Medicine Gainesville, FL 32610