Mandible / maxilla
Osteomyelitis
Medication related osteonecrosis of the jaw (MRONJ)




Topic Completed: 1 January 2015

Revised: 8 February 2019

Copyright: 2004-2018, PathologyOutlines.com, Inc.

PubMed Search: Medication related osteonecrosis [title] jaw

Page views in 2018: 1,181
Page views in 2019 to date: 241
Cite this page: Morrison A. Osteomyelitis: medication related osteonecrosis of the jaw (MRONJ). PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/mandiblemaxillaMRONJ.html. Accessed February 18th, 2019.
Definition / general
  • Medication related osteonecrosis of the jaw (MRONJ) is an adverse drug reaction consisting of progressive bone destruction in the maxillofacial region of patients under current or previous treatment with antiresorptive and antiangiogenic medications
  • In 2014, the American Association of Oral and Maxillofacial Surgeons suggested a nomenclature change from Bisphosphonate related osteonecrosis of the jaw (BRONJ) to MRONJ to accommodate the growing number of gnathic osteonecrosis cases associated with other antiresorptive (denosumab) and antiangiogenic therapies
Terminology
  • Synonyms, some still in use:
    • Bisphosphonate related osteonecrosis of the jaw (BRONJ)
    • Bisphosphonate induced osteonecrosis of the jaws (BIONJ)
    • Osteochemonecrosis (OCN)
    • Osteonecrosis of the jaw (ONJ)
    • Antiresorptive agent induced osteonecrosis of the jaw (ARONJ)
    • Bisphosphonate associated osteonecrosis (BON)
  • 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 to 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
        • Although initially thought to be an obscure infectious process, the clinical presentation is similar to 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 a history of parafunctional complaints
        • Palpation of the temporal, masseter, medial pterygoid and the digastric muscles reveals tenderness in one or more of locations
        • 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 recurrent multifocal osteomyelitis (CRMO)
    • 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
    • Characterized by 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
    • Lesions occur mainly in metaphyses of long tubular bones, as well as clavicles, spine, and pelvis; lesions are sometimes symmetrically distributed
    • 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
  • 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 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
  • 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 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
  • Osteoradionecrosis (ORN)
    • Exposed, devitalized bone in radiated field with no healing for 3 months and no evidence of tumor recurrence
    • Osteoradionecrosis (ORN) is considered a late effect of a radiation induced fibroatrophic process but is not considered as primary osteomyelitis
    • Is more similar to aseptic / avascular necrosis of bone than primary infection of bone, although infection or bacterial colonization can occur
  • Periapical granuloma
    • Acute and / 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
  • 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 unspecific and inconclusive when considered by themselves; however, tissue examinations of biopsies are irreplaceable for confirmation of the diagnosis, in cases of unclear and atypical clinical and radiological appearance, and moreover in excluding 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 tertiary classification criteria
    • These tertiary criteria are helpful in determining the necessary therapeutic strategies which may differ somewhat among the subgroups
Sites
  • Tooth bearing sites of maxilla and mandible
  • Rarely described in other locations
Pathophysiology
  • Pathophysiology of the disease has not been fully elucidated but theories include:
    • Inhibition of osteoclastic bone resorption and remodeling:
      • Antiresorptive drugs inhibit osteoclast differentiation and function and increase apoptosis, all leading to decreased bone resorption and remodeling
    • Inflammation and infection:
      • Early studies identified bacteria, especially Actinomyces species, in biopsied specimens of necrotic bone removed from patients with ONJ
      • The presence of bacteria has prompted studies to evaluate the possibility of a complex biofilm on exposed bone
    • Inhibition of angiogenesis:
      • Osteonecrosis is classically considered an interruption in vascular supply or avascular necrosis; it is the leading hypothesis in ONJ pathophysiology
    • Soft Tissue Toxicity:
      • Multiple cell types have exhibited increased apoptosis or decreased proliferation after exposure to bisphosphonate medications in vitro
    • Immune Dysfunction
Etiology
  • Associated with multiple groups and classes of medications, primarily those with anti-resorptive and those with anti-angiogenic properties
Clinical features
  • Variable depending on the underlying reason associated with the putative medication / drug
  • In general, older adults, female > male
  • Many with antecedent dental trauma (oral surgery, tooth extraction)
  • Clinical features: pain, swelling, oral bone exposure, orocutaneous fistula, malocclusion
Clinical images

Images hosted on other servers:
Missing Image Missing Image Missing Image Missing Image

Various cases

Missing Image

Osseous involvement


Missing Image

Due to prosthesis

Missing Image

After tooth extraction

Missing Image

Maxillary involvement

Missing Image

Osteolytic lesion in mandible

Diagnosis
  • Patients may be considered to have MRONJ if ALL these characteristics are present:
    • Current or previous treatment with antiresorptive or antiangiogenic agents
    • Exposed bone or bone that can be probed through an intraoral or extraoral fistula in the maxillofacial region that has persisted for > 8 weeks
    • No history of radiation therapy or obvious metastatic disease to the jaws
  • Staging of disease: (J Oral Maxillofac Surg 2014;72:1938)
  • Use of these criteria helps to distinguish MRONJ from other clinical mimics (dental disease such as periapical granuloma, osteomyelitis, etc.), treatment complications (ex: osteoradionecrosis) and forms of delayed healing such as alveolar osteitis
  • Exposed bone or sequestra can occur in patients not treated with antiresorptive or antiangiogenic agents; thus all the above criteria are important
Radiology description
  • Plain films such as intraoral dental films or extraoral Panoramic radiography may be utilized to evaluate relation to dentition
  • Depending on disease stage, computed tomography (CT) or magnetic resonance imaging (MRI) may show cancellous or cortical bone destruction, sequestration and osteosclerosis
  • Periosteal new bone formation tends to favor higher stage disease
Case reports
Treatment
  • Management remains controversial and may be variable based on these clinical scenarios:
    • Patients about to initiate antiresorptive or antiangiogenic treatment for cancer therapy or osteoporosis
    • Asymptomatic patients receiving antiresorptive or antiangiogenic treatment for cancer therapy or osteoporosis
    • Patients with established MRONJ
  • Since universally accepted guidelines are unavailable, position papers based on expert opinion and existing evidence are often cited (Oral Oncol 2014;50:1049)
  • Staging of disease: J Oral Maxillofac Surg 2014;72:1938
Gross description
  • Biopsies to confirm diagnosis of osteomyelitis are often minute
  • Evaluate bone margins with mandibular (see gross image below) or maxillary resection because malignancy may later be noted
Gross images

Images hosted on other servers:
Missing Image

Segmental mandibulectomy
and surgical defect

Micro description of bone lesions
  • In patients taking medications associated with MRONJ for malignancy, metastatic foci admixed with MRONJ may represent a diagnostic pitfall
  • Histological features of MRONJ may overlap with osteomyelitis and osteoradionecrosis
  • Histologic findings are variable and likely influenced by specimen presentation (segmental resection of jaw will have a spectrum of changes vs. debridement of long-standing exposed bone will represent non-viable tissue)
  • Bone necrosis, empty Haversian systems, sequestrum formation, possible areas of viable bone
  • May observe osteoclastic detachment, thought to be related to medication effect
  • Empty Howship lacunae and viable osteoblasts possible
  • Also variable increased trabecular thickness, pseudoepitheliomatous hyperplasia, acute or chronic inflammation
Microscopic (histologic) images

Images hosted on other servers:
Missing Image

Osteolytic pattern

Missing Image

Destruction of alveolar bone process

Missing Image

Mandibular alveolar bone exposed

Missing Image

Right maxillary exposed bone

Missing Image

Generalized sclerotic changes