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Pathogenesis of osteomyelitis

Pathogenesis of osteomyelitis
Literature review current through: Jan 2024.
This topic last updated: Jul 26, 2022.

INTRODUCTION — Osteomyelitis is an infection involving bone.

The pathogenesis and pathology of osteomyelitis will be reviewed here. The clinical manifestations, diagnosis, and treatment of osteomyelitis are discussed separately. (See "Nonvertebral osteomyelitis in adults: Clinical manifestations and diagnosis" and "Approach to imaging modalities in the setting of suspected nonvertebral osteomyelitis" and "Osteomyelitis associated with open fractures in adults" and "Clinical manifestations, diagnosis, and management of diabetic infections of the lower extremities" and "Vertebral osteomyelitis and discitis in adults".)

CLASSIFICATION — Osteomyelitis may be divided into two major categories based upon the pathogenesis of infection: (1) hematogenous osteomyelitis and (2) nonhematogenous osteomyelitis, which develops adjacent to a contiguous focus of infection or via direct inoculation of infection into the bone [1-3]. (See "Nonvertebral osteomyelitis in adults: Clinical manifestations and diagnosis", section on 'Classification'.)

Either hematogenous or contiguous-focus osteomyelitis can be classified as acute or chronic. Acute osteomyelitis evolves over several days to weeks and can progress to a chronic infection [1]. The hallmark of chronic osteomyelitis is the presence of dead bone (sequestrum). Other common features of chronic osteomyelitis include involucrum (reactive bony encasement of the sequestrum), local bone loss, and, if there is extension through cortical bone, sinus tracts.

Brodie abscess is a form of subacute osteomyelitis that is usually hematogenous in origin but can occur as a the result of trauma; the classic presentation of Brodie abscess consists of a cavity filled with suppurative and/or granulation in a long bone metaphysis, surrounded by dense fibrous tissue and sclerotic bone [4].

PATHOGENESIS — Normal bone is highly resistant to infection. Osteomyelitis develops when there is a large inoculation of organisms, presence of bone damage, and/or presence of hardware or other foreign material.

The pathogenesis of osteomyelitis is multifactorial and poorly understood; important factors include the virulence of the infecting organism(s), the host immune status, and the bone vascularity.

Bacteria have a number of virulence determinants that may contribute to development of osteomyelitis in the appropriate clinical setting. Staphylococcus aureus, the most common cause of osteomyelitis, has been used extensively as a model to study pathogenesis and is therefore discussed in detail in this section. It is an important cause (though not the only cause) of hematogenous and contiguous focus osteomyelitis. S. aureus produces several extracellular and cell-associated factors that may contribute to virulence by promoting bacterial adherence, resistance to host defense mechanisms, and proteolytic activity.

Bacterial adherence — Adherence appears to play a central role in the early stages of S. aureus-induced osteomyelitis or arthritis. S. aureus adheres to a number of components of bone matrix including fibrinogen, fibronectin, laminin, collagen, bone sialoglycoprotein, and clumping factor A [5-9]. Adherence is mediated by expression of specific adhesins, called microbial surface components recognizing adhesive matrix molecules [5,10].

The potential importance of adhesins was illustrated in a study in which mice were inoculated with positive and negative mutants for the collagen adhesin gene: septic arthritis occurred with greater frequency in the mutant-positive compared with mutant-negative strains (>70 versus 27 percent) [11]. The adhesin-positive strains were also associated with the production of high levels of immunoglobulin G (IgG) and interleukin 6. In other experimental studies, S. aureus adhesion was blocked by antibodies directed against the collagen receptor [12]. It has been speculated that bone and other invasive S. aureus infections might be prevented by an adhesin-derived vaccine [13].

Collagen-binding adhesin (CNA) of S. aureus is a virulence factor for arthritis in several animal models [14,15]. The expression of CNA permits the attachment of pathogen to cartilage [16]. How CNA contributes to virulence and whether it is important in humans are unclear.

Fibronectin-binding protein rapidly coats implanted foreign bodies in vivo and adheres to biomaterials coated with host proteins. It may be particularly important in infections associated with prosthetic joints [7]. Atomic-force microscopy has demonstrated that fibronectin-binding proteins A and B (FnBPA and FnBPB) form bonds with host fibronectin and may play a key role in binding S. aureus to implants [17]. (See "Prosthetic joint infection: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

Resistance to host defense — The ability of microorganisms to resist host defense mechanisms at the cellular and matrix levels presents difficulties in the management of osteomyelitis.

Persistence of intracellular pathogens within osteoblasts may be an important factor in the pathogenesis of osteomyelitis and may partially explain the high relapse rate when antimicrobials are given for a short period of time [2,18]. As an example, osteoblast persistence of S. aureus in chronic osteomyelitis has been described [19,20]. S. aureus can survive intracellularly by undergoing phenotypic alteration which renders the organism more resistant to the action of antimicrobials. Electron microscopy of S. aureus-infected long-bone tissue in mice has identified the organism within live cortical bone and showed that the organism changes shape to migrate along canaliculi into the osteocytic lacunae, ultimately leading to biofilm formation within the osteocyte-rich lacunae [21].

Arachidonic acid metabolites, such as prostaglandin E2, a strong osteoclast agonist, decrease the bacterial inoculum needed to produce infection.

S. aureus expresses a 42-kDa protein, protein A, which is bound covalently to the outer peptidoglycan layer of their cell walls. Protein A binds to the Fc portion of IgG on polymorphonuclear leukocytes, interfering with opsonization and phagocytosis of S. aureus [22]. Loss of protein A activity reduces virulence [23].

S. aureus secretes two toxins, exotoxin and toxic shock syndrome toxin (TSST-) 1, which exert important effects on the immune system when administered parenterally. The toxins act as superantigens and suppress plasma cell differentiation; they also stimulate production of cytokines, such as interleukin 1 [24], interferon-gamma, and tumor necrosis factor-alpha [25]. Animals infected with strains of S. aureus isogenic for TSST-1 develop frequent and severe arthritis [26]. Staphylococcal enterotoxin and TSST-1 subvert the cellular and humoral immune system, which may determine whether a local infection is eliminated or develops into osteomyelitis or septic arthritis.

HISTOPATHOLOGY

Overview — Acute osteomyelitis demonstrates suppurative infection with acute inflammatory cells, accompanied by edema, vascular congestion, and small vessel thrombosis (picture 1 and picture 2). In early acute disease, the vascular supply to the bone is compromised by infection extending into the surrounding soft tissue. When both the medullary and periosteal blood supplies are compromised, large areas of dead bone (sequestra) may form [27]. Within this necrotic and ischemic tissue, bacteria can be difficult to eradicate even in the setting of an intense host response, surgery, and antibiotic therapy.

Clinically and histologically, acute osteomyelitis blends into chronic osteomyelitis. Pathologic features of chronic osteomyelitis include necrotic bone, the formation of new bone, and polymorphonuclear leukocyte exudation joined by large numbers of lymphocytes, histiocytes, and occasional plasma cells (picture 3).

Necrosis of normal tissue is an important feature of osteomyelitis. Dead bone is absorbed by the action of granulation tissue developing at its surface. Absorption takes place earliest and most rapidly at the junction of living and necrotic bone. If the area of the dead bone is small, it is entirely destroyed by granulation tissue, leaving a cavity behind. The necrotic cancellous (trabecular) bone in localized osteomyelitis, even though extensive, is usually absorbed. Some of the dead cortical bone is gradually detached from living bone to form a sequestrum [3,28].

Host defense and mesenchymal cells, mainly the polymorphonuclear leukocytes, macrophages, and the osteoclasts, elaborate proteolytic enzymes that break down organic elements in the dead bone (picture 2). Because of lost blood supply, dead bone appears whiter than living bone. Cancellous bone is absorbed rapidly and may be completely sequestrated or destroyed in two to three weeks, but necrotic cortex may require two weeks to six months for separation. After complete separation, the dead bone is slowly eroded by granulation tissue and absorbed.

New bone formation is another characteristic feature of osteomyelitis. New bone forms from the surviving fragments of periosteum, endosteum, and the cortex in the region of the infection and is produced by a vascular reaction to the infection. New bone may be formed along the intact periosteal and endosteal surfaces and may also arise when the periosteum forms an encasing sheath of live bone (involucrum) surrounding the dead bone. Involucrum is irregular and is often perforated by openings through which pus may track into the surrounding soft tissues and eventually to the skin surfaces through a sinus tract. The involucrum can gradually increase in density and thickness to form part or all of a new shaft.

New bone increases in amount and density for weeks or months, according to the size of the bone and the extent and duration of infection. Endosteal new bone may proliferate and obstruct the medullary canal. After host defense removal or surgical removal of the sequestrum, the body, especially in children, may fill the remaining cavity with new bone. However, in adults, the cavity may persist or the space may be filled with fibrous tissue that may connect with the skin surface via a sinus tract.

The surviving bone in the osteomyelitis field usually becomes osteoporotic during the active period of infection. Osteoporosis is the result of the inflammatory reaction and atrophy disuse. After the infection subsides, bone density increases partially from reuse (eg, of a limb); the bone may undergo extensive transformation to conform to areas of new mechanical stresses. It may be difficult to distinguish between the old living bone and the newly formed bone as time passes. All traces of osteomyelitis can disappear in children and, to a lesser extent, in adults.

Differences by age — There are basic differences in the pathology of osteomyelitis in infants, children, and adults.

In neonates, small capillaries cross the epiphyseal growth plate and permit extension of infection into the epiphysis and joint space. The cortical bone of the neonate and infant is thin and loose, consisting predominantly of woven bone, which permits escape of the pressure caused by infection, but promotes rapid spread of the infection directly into the subperiosteal region. A large sequestrum is not produced because extensive infarction of the cortex does not occur; however, a large subperiosteal abscess can form [29,30].

In children older than one year, infection presumably starts in the metaphyseal sinusoidal veins and is contained by the growth plate. Dye injection experiments described in the 1920s have depicted metaphyseal vessels as a series of capillary loops terminating adjacent to the growth plate and expanding into dilated venous sinusoids resulting in sluggish blood flow, thus predisposing to bacterial deposition [31]. Subsequently, electron micrographic studies have described rapidly growing vessels with a single layer of discontinuous endothelium at their tips, through which bacteria may pass during an episode of bacteremia, thus initiating osteomyelitis [32,33]. An experimental avian model confirmed that bacteria are deposited initially at the end of metaphyseal tunnels that provide a framework for the rapidly growing metaphyseal vessels. The presence of endothelial gaps in the tips of metaphyseal vessels, regardless of blood flow rates, may play a critical role in the initiation of osteomyelitis [34]. The joint is spared unless the metaphysis is intracapsular. The infection spreads laterally where it breaks through the cortex and lifts the loose periosteum to form a subperiosteal abscess [30,35].

In adults, the growth plate has resorbed, and the infection may again extend to the joint spaces as in infants. In addition, the periosteum is firmly attached to the underlying bone; as a result, subperiosteal abscess formation and intense periosteal proliferation are less frequently seen. The infection can erode through the periosteum, forming a draining sinus tract(s) [36].

CLINICAL FORMS — Issues related to clinical manifestations and diagnosis of osteomyelitis are discussed separately. (See "Nonvertebral osteomyelitis in adults: Clinical manifestations and diagnosis".)

Hematogenous osteomyelitis — Hematogenous osteomyelitis is the most common form of osteomyelitis in infants and children [1]. The pathogenesis is discussed separately. (See "Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology".)

In adults, vertebral osteomyelitis is the most common form of hematogenous osteomyelitis; the pathogenesis is discussed separately. (See "Vertebral osteomyelitis and discitis in adults", section on 'Pathogenesis'.)

Other sites of hematogenous osteomyelitis in adults include the long bones, pelvis, and clavicle. (See "Nonvertebral osteomyelitis in adults: Clinical manifestations and diagnosis", section on 'Hematogenous osteomyelitis'.)

In people who inject drugs (PWID), osteomyelitis assumes an axial distribution involving vertebral column, especially the lumbar spine; the reason for the axial distribution in this patient population is uncertain. Osteomyelitis can also occur in the sternum, extremities, and sacroiliac joints. Common microbiologic causes include S. aureus, Pseudomonas spp, and Candida spp. In addition, osteomyelitis due to oral flora can occur among PWID who lick the needle tip or skin before injection [37].

Tuberculous osteomyelitis usually occurs from reactivation of tuberculous bacilli lodged in bone during the mycobacteremia occurring at the time of the primary infection. (See "Bone and joint tuberculosis", section on 'Spondylitis (Pott disease)'.)

Nonhematogenous osteomyelitis — Nonhematogenous osteomyelitis, which develops adjacent to a contiguous focus of infection or via direct inoculation of infection into the bone (via trauma, surgery or hardware placement). The clinical manifestations and diagnosis of nonhematogenous osteomyelitis are discussed separately. (See "Nonvertebral osteomyelitis in adults: Clinical manifestations and diagnosis", section on 'Nonhematogenous osteomyelitis'.)

Skull base osteomyelitis can occur as a complication of otogenic, sinogenic, odontogenic, or rhinogenic infections [38]. The pathogenesis is not fully understood; it may include a combination of factors including hypoperfusion and diminished immune response. In addition, use of water irrigation for cerumen disimpaction may reduce the cerumen lysozyme content, leading to alkaline pH and increased susceptibility to Pseudomonas infection [39]. Malignant otitis externa can spread from the external auditory canal to the skull base [40,41]. Potential complications include involvement cranial nerves, the parotid gland, the temporomandibular joint, the carotid artery, and the jugular vein.

Osteomyelitis involving the hand can occur as a result of animal or human bite. Pathogens include aerobic and anaerobic bacteria; streptococcal and staphylococcal species are most commonly reported [42-44]. (See "Animal bites (dogs, cats, and other mammals): Evaluation and management" and "Human bites: Evaluation and management".)

Contiguous osteomyelitis associated with vascular insufficiency occurs most commonly in the setting of diabetes mellitus and/or peripheral vascular disease. Inadequate tissue perfusion predisposes to development of osteomyelitis following minor foot trauma [36].

SUMMARY

Classification of osteomyelitis – Osteomyelitis can be classified as acute or chronic. Clinically and histologically, acute osteomyelitis can evolve into chronic osteomyelitis. (See 'Classification' above.)

Acute osteomyelitis – Acute osteomyelitis is an acute suppurative infection of the bone that progresses over several days to weeks. In untreated acute disease, the vascular supply to the bone is progressively compromised, which ultimately causes chronic osteomyelitis.

Chronic osteomyelitis – The hallmark of chronic osteomyelitis is the presence of dead bone (sequestrum). Other common features of chronic osteomyelitis include involucrum (reactive bony encasement of the sequestrum), local bone loss, and, if there is extension through cortical bone, sinus tracts.

Pathogenesis of osteomyelitis – The pathogenesis of osteomyelitis is multifactorial and poorly understood. Some important factors include virulence of the infecting organism(s); underlying immune status of the host; and the type, location, and vascularity of the bone. (See 'Pathogenesis' above.)

Persistence of intracellular pathogens within osteoblasts may be an important factor in the pathogenesis of osteomyelitis. Bacterial proliferation occurs during canalicular invasion. When digested by osteoblasts, organisms such as S. aureus undergo phenotypic alteration, which renders them resistant to the action of many antimicrobials. This may explain in part the high relapse rate of osteomyelitis treated with antimicrobials for a short duration. (See 'Resistance to host defense' above.)

Histopathology – Acute and chronic osteomyelitis have different histopathologic findings, although many cases have evidence of both. (See 'Histopathology' above.)

Acute osteomyelitis – Acute osteomyelitis demonstrates suppurative infection with acute inflammatory cells, accompanied by edema, vascular congestion, and small vessel thrombosis (picture 1 and picture 2).

Chronic osteomyelitis – Pathologic features of chronic osteomyelitis include necrotic bone, the formation of new bone, and polymorphonuclear leukocyte exudation joined by large numbers of lymphocytes, histiocytes, and occasional plasma cells (picture 3). New bone forms from the surviving fragments of periosteum, endosteum, and the cortex in the region of the infection and is produced by a vascular reaction to the infection.

Histopathology after treatment – The surviving bone in the osteomyelitis field usually becomes osteoporotic during the active period of infection. Osteoporosis is the result of the inflammatory reaction and atrophy disuse. (See 'Histopathology' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges LiYan Yin, MD, and Jason Calhoun, MD, who contributed to earlier versions of this topic review.

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