Mandible & maxilla

Osteomyelitis and inflammatory conditions

Chronic recurrent multifocal

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PubMed Search: Chronic recurrent multifocal osteomyelitis [title]

Annie S. Morrison, M.D.
Kelly Magliocca, D.D.S., M.P.H.
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Cite this page: Morrison A. Chronic recurrent multifocal. website. Accessed February 22nd, 2024.
Definition / general
  • Chronic recurrent multifocal osteomyelitis (CRMO) is a relapsing inflammatory disease and is considered a type of seronegative spondyloarthropathy characterized by periods of exacerbations and remissions over many years
  • Characterized by an inflammatory process presenting with findings similar to infectious osteomyelitis; however, no infectious source is identifiable
  • Most often characterized by the insidious onset of low grade fever, local swelling and bone pain
  • Radiologic findings may suggest osteomyelitis, and bone seeking isotopes reveal other asymptomatic sites of involvement
  • The lesions occur mainly in the metaphyses of long tubular bones, as well as the clavicles, spine, and pelvis; the lesions are sometimes symmetrically distributed
  • The precise relationship between primary chronic osteomyelitis, diffuse sclerosing osteomyelitis, CRMO and SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) is highly debated and not clear at this time
    • Some consider CRMO and SAPHO as primary chronic osteomyelitis with additional extragnathic manifestations
    • Whether CRMO in juvenile patients and SAPHO syndrome are the same disorder in different age groups remains to be determined
  • Acute suppurative osteomyelitis:
    • Early phase of osteomyelitis and usually a suppurative (pus forming) condition
    • Exists when an acute inflammatory process moves away from the site of initial infection and spreads through the medullary space of the bone and, in most cases, insufficient time has passed for the body to react to the presence of the inflammatory infiltrate
    • Acute phase may lead to the chronic phase which has been arbitrarily defined as an osseous infection lasting at least 1 month
  • Alveolar osteitis / fibrinolytic alveolitis:
    • After extraction of a tooth, a blood clot is formed at the extraction site with eventual organization of this clot by granulation tissue and gradual replacement by bone
    • Destruction of the initial clot is thought to delay the aforementioned additional series of steps required for uneventful extraction site healing and leads to clinical condition known as alveolar osteitis
    • Clot is lost secondary to transformation of plasminogen to plasmin with subsequent lysis of fibrin and formation of kinins which are potent pain mediators
  • Biofilm:
    • Collection of microorganisms often embedded in a self produced extracellular polymeric matrix which allows them to adhere to or coat the surface of a living or inanimate structure
  • Chronic osteomyelitis:
    • May be classified as primary or secondary and as suppurative or non-suppurative
      • Secondary chronic osteomyelitis (SCO)
      • Primary chronic osteomyelitis (PCO)
      • Chronic tendoperiostitis
        • Initially thought to be an obscure infectious process, the clinical presentation is similar to that of primary chronic osteomyelitis
        • May represent a reactive alteration of bone initiated and exacerbated by chronic overuse of the masticatory muscles, predominantly the masseter and digastric
        • Patients usually present with parafunctional complaints
        • Palpation of the temporal, masseter, medial pterygoid and the digastric muscles reveals tenderness
        • Radiographically, may be very similar to primary chronic osteomyelitis with diffuse sclerosing of the marrow and the cortical plate in the absence of pus formation or sequestration
  • Chronic sclerosing osteomyelitis / diffuse sclerosing osteomyelitis:
    • Although the term is usually used synonymously with primary chronic osteomyelitis, it represents a description of a strictly radiological appearance that can be caused by several similar processes including:
      • Primary and secondary chronic osteomyelitis
      • Chronic tendoperiostitis
      • Ossifying periostitis or Garrè's osteomyelitis
      • Medullary osseous infection, probably bacterial, which induces the complete sclerosis
        • Favors young women, is painful and appears radiographically as medullary sclerosis
        • Therapy includes antibiotics, and surgical debridement and hyperbaric oxygen therapy in refractory cases
  • Condensing osteitis:
    • Localized areas of radiographic bone sclerosis associated with the apices of inflamed dead or dying teeth (pulpitis or pulpal necrosis) are termed condensing osteitis
    • The association with an area of inflammation, usually a neighboring tooth, is critical because these lesions can resemble several other intrabony processes that produce a somewhat similar pattern
    • Is not considered a true osteomyelitis in the classical sense
  • Cortical bone:
    • Cortical bone, synonymous with compact bone, is one of the two types of osseous tissue that forms bone
    • As its name implies, cortical bone forms the cortex, or outer shell, of most bones
    • Compact bone, as its name implies, is much denser than cancellous bone which is the other type of osseous tissue
    • Furthermore, it is harder, stronger and stiffer than cancellous bone
  • Garrè's sclerosing osteomyelitis:
    • In 1893, a Swiss physician, Carl Garrè, reported on patterns of acute osteomyelitis
    • Garrè did not have any pathologic specimens for microscopic examination nor radiographs to augment his descriptions
    • Nonetheless, his name is often associated with the condition in which periosteal duplication, or an "onion-skinning" pattern of periostitis, leads to enlargement of the jaw, usually mandible
  • Involucrum:
  • Medullary bone / medullary cavity / marrow cavity:
    • The medullary cavity (medulla, innermost part) of bone is the central cavity where red bone marrow or yellow bone marrow (adipose tissue) is stored; hence, the medullary cavity is also known as the marrow cavity
    • The medullary cavity has walls composed of spongy bone (cancellous bone) and is lined by endosteum, which are osteoprogenitor cells
  • Osteochemonecrosis of Jaws:
    • Synonyms: bisphosphonate related osteonecrosis of the jaws, bisphosphonate induced osteonecrosis of the jaw, osteonecrosis of jaw, bisphosphonate osteonecrosis, bis-phossy jaw
    • Necrosis of bone related to long term use of antiresorptive medications such as bisphosphonate medications and altered bone metabolism
    • Osteoclasts are thought to be qualitatively impaired, particularly with intravenous forms of bisphosphonate medication which leads to inadequate remodeling of bone, necrosis
  • Osteoradionecrosis (ORN):
    • Clinically, a chronic non-healing wound of the affected jaw (most commonly mandible), typically with exposure of bone, in a patient with a history of radiation therapy to the head and neck region
    • Radiation injury to jaw that leads to ORN results from chronic hypovascularity, hypocellularity of marrow space and ultimately hypoxemia
    • Is more similar to avascular necrosis of bone than primary infection of bone, although infection or bacterial colonization can occur
  • Periapical granuloma:
    • Acute or chronic inflammation admixed with fibrous or granulation tissue locally at the apical or periapical region of a tooth
    • Is devoid of epithelium (i.e. no cyst lining) which distinguishes it from a periapical cyst
    • Periapical granuloma is located at the apex of a necrotic or partially necrotic tooth root
  • Periosteum:
    • Connective tissue membrane lining the outer / external surface bones, except at the joints of long bones
    • Is composed of an outer fibrous layer and an inner cambium / osteogenic layer (Wikipedia: Periosteum [Accessed 1 June 2018] )
  • Proliferative periostitis:
    • Represents a periosteal reaction to the presence of inflammation
    • The affected periosteum forms several rows of reactive vital bone that parallel each other and expand the surface of the altered bone
  • SAPHO syndrome:
    • SAPHO syndrome is an acronym for a complex clinical presentation that includes synovitis, acne, pustulosis, hyperostosis and osteitis
    • The osseous lesions mirror primary chronic osteomyelitis and CRMO
    • Unknown cause but thought to arise in genetically predisposed individuals who develop an autoimmune disturbance secondary to exposure to dermatologic bacteria
    • Increased prevalence of HLA-27
    • SAPHO and CRMO are distinguished from other forms of osteitis / osteomyelitis as these two diseases may have extragnathic skeletal involvement
  • Sequestrum:
  • Zurich Classification of Osteomyelitis:
    • The Zurich classification system of osteomyelitis is primarily based on clinical course and features of imaging of the disease
    • Histopathology is considered a secondary classification criterion, taking into account that findings are mostly nonspecific and inconclusive by themselves; however, tissue examinations of biopsies are irreplaceable for confirmation of the diagnosis if the clinical and radiological appearance is unclear or atypical and to exclude possible differential diagnoses
    • The three major classifications are: (Baltensperger, Osteomyelitis of the Jaws: Definition and Classification (Figure 2.2))
      • Acute Osteomyelitis (AO)
      • Secondary Chronic Osteomyelitis (SCO)
      • Primary Chronic Osteomyelitis (PCO)
    • Further subclassification of these major osteomyelitis groups is based on presumed etiology and pathogenesis of disease
    • These criteria are therefore considered a tertiary classification criteria
    • These tertiary criteria help determine the necessary therapeutic strategies which may differ somewhat among the subgroups
  • Rare, estimated frequency of 1:1,000,000
  • 2 - 5% of all osteomyelitis cases
  • Primarily affects children, median age 10 years, with female / male ratio of 5:1
  • Mainly affects the metaphyses of the long bones
  • The spine, pelvis, and shoulder girdle may also be affected
  • When involves the jaws, predominantly involves the mandible and the prevalence of mandibular involvement is 2 – 8%
  • The neurocranium is thought to be spared
  • A number of causes have been proposed, such as dysregulated innate immune or other altered immune response, but no single theory has received widespread acceptance
Clinical features
  • Characterized by periods of intermittent exacerbations and improvements over a period of years
  • Some patients have associated recurrent skin lesions (pustulosis palmoplantaris) that closely parallel the exacerbations of the bone lesions and makes distinction from SAPHO challenging
  • Clinical diagnosis may be challenging because the clinical picture and course of the disease may vary significantly
  • Therefore, the diagnosis is collectively based on clinical, radiologic, pathological and longitudinal findings
  • When attempting to provide a specimen for culture material, it is of the utmost importance for the surgeon to avoid contamination when harvesting a bone biopsy from a lesion for microbiological analysis
  • While lesions of CRMO in the mandible may be easier to access, a transoral approach may induce microbial contamination and a specimen from another part of the skeleton may therefore be of more diagnostic value for cultures
  • CRMO is a diagnosis of exclusion since the clinical presentation and laboratory findings are not disease specific and vary between affected individuals
Radiology description
  • Inflammatory bone lesions may be detected in plain radiographs presenting as radiolucent, osteolytic or sclerotic lesions, depending on the disease stage
  • In early phases of CRMO, radiographs may remain normal
  • Diffuse bone radiopacity is the prominent finding in patients with mandibular manifestations
  • While radiopacity governs the quiet phase of CRMO, areas of mottled cortical and cancellous bone osteolysis prevail during recurrence
  • Small osteolytic lacunae that contain lymphocytes and plasma cells are potential sites of exacerbation leading to cortical erosion and periosteal reaction
  • Scintigraphy aids in detecting synchronous or metachronous involvement of multiple bones such as the clavicle, humerus, radius, femur or tibia
  • Whole body imaging techniques, including MRI and Tc-99 m labeled methylene bone scintigraphy, represent novel and valuable diagnostic tools
    • CRMO represents a systemic disease with potentially multiple inflammatory lesions, therefore whole body imaging techniques should be performed at least at the time of diagnosis to exclude asymptomatic lesions, such as in the vertebral column
    • MRI is especially sensitive during early stages since it can detect bone edema even before erosions or sclerosis become apparent
    • At diagnosis, gadolinium enhanced T1 or strongly T2 weighted sequences with fat saturation may be superior to conventional radiographs or scintigraphy
  • Radiographic Differential Diagnosis (will be influenced by age of patient, clinical history):
    • Acute osteomyelitis
      • Cases of secondary chronic osteomyelitis with a predominant sclerosing character are particularly difficult, if not impossible, to distinguish from primary chronic osteomyelitis, if the disease is only viewed at a certain point in time and the whole course of the disease is neglected
      • Theoretically, a coincidence of primary chronic osteomyelitis with secondary chronic osteomyelitis may occur when a "superimposed" putrid bacterial infection is manifested in the impaired sclerotic bone
    • SAPHO syndrome
    • Tendoperiostitis
    • Chronic sclerosing osteomyelitis / diffuse sclerosing osteomyelitis / Garrè's sclerosing osteomyelitis
      • These terms merely describe radiological features which may be demonstrated in primary and secondary chronic osteomyelitis, with extensive sclerosis, variable osteolysis and periosteal reaction on diagnostic imaging
    • Osteochemonecrosis of the Jaws
    • Osteoradionecrosis
    • Cemento osseous dyplasia (COD)
      • Has often been confused with primary chronic osteomyelitis in the literature
      • It may be seen as a predisposing factor for bone infection
      • Florid cemento osseous dysplasia appears on radiographs as sclerosing opaque and dense masses
      • The bone changes are often adjacent to the apices of the teeth and are restricted to the alveolar process in either or both jaws
    • Malignancy or benign aggressive intraosseous neoplasms inducing proliferative periostitis
      • Osteosarcoma
      • Ewing sarcoma
      • Leukemia / lymphoma
      • Metastatic disease to the jaws
      • Langerhans cell histiocytosis
    • Paget disease (deforming ostitis)
      • Disease of disturbed bone metabolism of unknown origin
      • Usually occurs in advanced age and affects the spine, pelvic skeleton, cranial vault
      • Long bones and the facial skeleton are rarely involved
      • If the jaws are affected, the maxilla is somewhat more often involved than the mandible
    • Osteopetrosis (Albers-Schonberg disease)
      • Osteopetrosis is a genetically inherited disease which involves all bones
      • Two major types are differentiated: (a) autosomal recessive malignant form with anemia which manifests at birth; (b) autosomal dominant benign form
      • Malignant form is dramatic, with severe impairment and systemic complications, patients die by age 10; benign form is much more common
      • The jawbone in osteopetrosis cases shows massive sclerosis (Figure 2.32)
      • Disturbed physiology of bone due to reduced osteoclast function causes osteopetrotic bone to be resorbed inadequately and sclerosis increases with time jeopardizing bone perfusion
      • Secondary infection of the bone is common and the clinical picture resembles primary or secondary chronic osteomyelitis with predominant sclerosis
      • Because bone physiology is generally disturbed, both jaws may be completely affected by the pathology, contrary to primary chronic osteomyelitis which generally just affects the mandible
Prognostic factors
  • Often a prolonged course and difficult to predict
Case reports
  • NSAID are commonly used as first line treatment of CNO/CRMO in less to moderately severe cases
  • NSAIDs provide pain control in most cases and most likely alter the disease course since prostaglandins are centrally involved in osteoclast activation and bone remodeling
  • Other reported nonsurgical treatments include: corticosteroids, sulfasalazine, methotrexate (MTX), anti-TNF agents (usually etanercept or infliximab), or bisphosphonates (usually pamidronate) but consistent data regarding success is not available
  • Surgical decortication has been reported for refractory cases but in young, growing patients the associated risks must be considered since the results from surgical intervention have been inconsistent (Oral Surg Oral Med Oral Pathol 1970;29:641)
  • Obtain cultures for organism identification and antibiotic sensitivity to exclude a primary or superimposed secondary treatable infectious process

Diagrams / tables

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Treatment of CNO/CRMO

Clinical images

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Expansion of left ramus

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"Bone-on-bone" pattern

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Swelling of left masseter muscle

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Uptake of radionucleotide

Gross description
  • If a biopsy is performed to confirm a diagnosis of osteomyelitis and to rule out neoplasia, often only a minute sample is received
Microscopic (histologic) description
  • While histological analysis of bone lesions may help to exclude malignant processes, the histologic appearance of CRMO may mimic acute and secondary chronic osteomyelitis caused by microbiological infection
  • Therefore, an extensive microbiological workup of the biopsy, including culture (see Diagnosis section) and PCR techniques, may be considered
  • Cellular infiltrates are highly dependent on the disease stage
    • Early phases: neutrophils are the predominant cell subset
    • Later phases: monocytes, macrophages, lymphocytes, and plasma cells; also osteolysis and concomitant sclerosis or fibrosis
  • The cellular distribution in inflammatory lesions reflects the immunological reaction at the time
  • Unfortunately, very little is known about the kinetics of inflammatory responses
  • Histologic examination does not allow distinction of CRMO from acute or subacute bacterial osteomyelitis
Microscopic (histologic) images

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Early and late stages of CRMO

Differential diagnosis
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