Osteonecrosis of the jaw

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Osteonecrosis of the jaws
Osteonecrosis of the jaw of the upper left jaw in a patient diagnosed with chronic venous insufficiency
ICD-10 M87.1
DiseasesDB 1174
eMedicine derm/816 

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alonso Alvarado, M.D. [2]

Synonyms and keywords: ONJ

Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating Osteonecrosis of the jaw from other Diseases

Epidemiology and Demographics

Risk Factors

Natural History, Complications and Prognosis

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History and Symptoms | Physical Examination | Laboratory Findings | Other Imaging Findings | Other Diagnostic Studies

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Case#1


Overview

Osteonecrosis of the jaws (ONJ) is a severe bone disease that affects the jaws, including the maxilla and the mandible. Jaw bone (osteo-) damage and death (-necrosis) occurs as a result of reduced local blood supply (ischemia). The condition is thus included in the general category of ischemic or avascular osteonecrosis (literally "dead bone from poor blood flow.").

Various forms of ONJ have been described over the last 160 years, and a number of causes have been suggested in the literature. In recent years, an increased incidence of ONJ has been associated with the use of high dosages of bisphosphonates, required by some cancer treatment regimens, especially when the patient undergoes subsequent dental procedures. The possible risk from lower oral doses of bisphosphonates, taken by patients to prevent or treat osteoporosis, remains uncertain.[1]

Various treatment options have been explored, however severe cases of ONJ still require surgical removal of the affected bone.[2] Careful anamnesis (patient history) and assessement of pre-existing systemic problems and possible sites of dental infection are required to help prevent the condition, especially if bisphosphonate therapy is considered.[1]

Etiology

Histopathological alterations

Persons with ONJ may have either necrotic bone or bone marrow that has been slowly strangulated or nutrient-starved. Bone with chronically poor blood flow develops either a fibrous marrow since fibres can more easily live in nutrient starved areas, a greasy, dead fatty marrow (wet rot), a very dry, sometimes leathery marrow (dry rot), or a completely hollow marrow space (osteocavitation), also typical of ONJ. The blood flow impairment occurs following a bone infarct, a blood clot forming inside the smaller blood vessels of cancellous bone tissue.

Under ischemic conditions numerous pathological changes in the bone marrow and trabeculae of oral cancellous bone have been documented. Microscopically, areas of "apparent fatty degeneration and/or necrosis, often with pooled fat from destroyed adipose cells (oil cysts) and with marrow fibrosis (reticular fatty degeneration)" are seen. These changes are present even if "most bony trabeculae appear at first glance viable, mature and otherwise normal, but closer inspection demonstrates focal loss of osteocytes and variable micro cracking (splitting along natural cleavage planes). The microscopic features are similar to those of ischemic or aseptic osteonecrosis of long bones, corticosteroid-induced osteonecrosis, and the osteomyelitis of caisson (deep-sea diver’s) disease".[3]

In the cancellous portion of femoral head it is not uncommon to find trabeculae with apparently intact osteocytes which seem to be "alive" but are no longer synthetizing collagen. This appears to be consistent with the findings in alveolar cancellous bone.[4]

Osteonecrosis can affect any bone, but the hips, knees and jaws are most often involved. Pain can often be severe, especially if teeth and/or a branch of the trigeminal nerve is involved, but many patients do not experience pain, at least in the earlier stages. When severe facial pain is involved, the term NICO, for Neuralgia-Inducing Cavitational Osteonecrosis, is frequently used.

ONJ, even in its mild or minor forms, creates a marrow environment that is conducive to bacterial growth. Since many individuals have low-grade infections of the teeth and gums, this probably is one of the major mechanisms by which the marrow blood flow problem can worsen; any local infection / inflammation will cause increased pressures and clotting in the area involved. No other bones have this mechanism as a major risk factor for osteonecrosis. A wide variety of bacteria have been cultured from ONJ lesions. Typically, they are the same microorganisms as those found in periodontitis or devitalized teeth. However, according to special staining of biopsied tissues, bacterial elements are rarely found in large numbers. So while ONJ is not primarily an infection, many cases have a secondary, very low-level of bacterial infection and chronic non-suppurative osteomyelitis can be associated with ONJ. Fungal infections in the involved bone do not seem to be a problem, but viral infections have not been studied. Some viruses, such as the smallpox virus (no longer existent in the wild) can produce osteonecrosis.

The effects of persistent ischemia on bone cells

Cortical bone is well vascularized by the surrounding soft tissues thus less susceptible to ischemic damage. Cancellous bone, with its mesh like structure and spaces filled with marrow tissue is more susceptible to damage by bone infarcts, leading to anoxia and premature cell apoptosis.[5][6][7][8] The mean life-span of osteocytes has been estimated to be 15 years in cancellous bone,[9] and 25 years in cortical bone.[10] while the average lifespan of human osteoclasts is about 2 to 6 weeks and the average lifespan of osteoblasts is approximately 3 months.[11] In healthy bone these cells are constantly replaced by differentiation of bone marrow mesenchymal stem cells (MSC).[12] However in both non-traumatic osteonecrosis and alcohol-induced osteonecrosis of the femoral head, a decrease in the differentiation ability of mesenchymal stem into bone cells has been demonstrated,[13][14] and altered osteoblastic function plays a role in ON of the femoral head.[15] If these results are extrapolated to ONJ the altered differentiation potential of bone marrow mesenchymal stem cells (MSC) combined with the altered osteoblastic activity and premature death of existing bone cells would explain the failed attempts at repair seen in ischemic-damaged cancellous bone tissue in ONJ.

The rapidity with which premature cell death can occur depends on the cell type and the degree and duration of the anoxia. Hematopoietic cells , in bone marrow, are sensitive to anoxia and are the first to die after reduction or removal of the blood supply. In anoxic conditions they usually die within 12 hours. Experimental evidence suggests that bone cells composed of osteocytes, osteoclasts, and osteoblasts die within 12-48 hours, and marrow fat cells die within 120 hours.[16] The death of bone does not alter its radiographic opacity nor it’s mineral density. Necrotic bone does not undergo resorption; therefore, it appears relatively more opaque.

Attempts at repair of ischemic-damaged bone will usual occur in 2 phases. First, when dead bone abuts live marrow, capillaries and undifferentiated mesenchymal cells grow into the dead marrow spaces, while macrophages degrade dead cellular and fat debris. Second, mesenchymal cells differentiate into osteoblasts or fibroblasts. Under favorable conditions, layers of new bone form on the surface of dead spongy trabeculae. If sufficiently thickened, these layers may increase the radiopacity of the bone; therefore, the first radiographic evidence of previous osteonecrosis may be patchy sclerosis resulting from repair. Under unfavorable conditions repeated attempts at repair in ischemic conditions can be seen histologically and are characterized by extensive delamination or microcracking along cement lines as well as the formation of excessive cement lines.[17] Ultimate failure of repair mechanisms due to persistent and repeated ischemic events is manifested as trabecular fractures that occur in the dead bone under functional load. Later followed by cracks and fissures leading to structural collapse of the area involved (osteocavitation).[16]

Other contributing factors

Other factors such as toxicants can adversely impact bone cells. Infections, chronic or acute, can affect blood flow by inducing platelet activation and aggregation, contributing to a localized state of excess coagulability (hypercoagulability) that may contribute to clot formation (thrombosis), a known cause of bone infarct and ischemia. Exogenous estrogens, also called hormonal disruptors, have also been linked with an increased tendency to clot (thrombophilia) and impaired bone healing.[18]

Heavy metals such as lead and cadmium have been implicated in osteoporosis. Cadmium and lead also promotes the synthesis of plasminogen activator inhibitor-1 (PAI-1) which is the major inhibitor of fibrinolysis ( the mechanism by which the body breaks down clots ) and shown to be a cause of hypofibrinolysis.[19] Persistent blot clots can lead to congestive blood flow (hyperemia) in bone marrow, impaired blood flow and ischemia in bone tissue resulting in lack of oxygen (hypoxia), bone cell damage and eventual cell death (apoptosis). Of significance is the fact that the average concentration of cadmium in human bones in the 20th century has increased to about 10 times above the pre-industrial level.[20]

Ethanol both from exogenous and endogenous sources and, its more toxic metabolite, acetaldehyde, have also been implicated in both osteoporosis and osteonecrosis. Acetaldehyde, a highly toxic metabolite of ethanol, can play a role in hypoxia and inhibit the osteoblastogenic potential of the bone marrow.[21] Ethanol has been shown to alter the epithelial barrier through ethanol oxidation into acetaldehyde by the colonic microflora and downstream mast cell activation. Such alterations that remain for longer periods could result in excessive endotoxin passage into the vascular network.[22] Intracolonic acetaldehyde may also be an important determinant of the blood acetaldehyde level and a possible hepatotoxin.[23] High serum antibody titers against acetaldehyde-protein adducts have been found not only in alcoholics but also in patients with nonalcoholic liver disease, suggesting a contribution of acetaldehyde derived from sources other than exogenous ethanol.[24] In a study on rats the role of intestinal bacterial overgrowth on the production and metabolism of ethanol, rats with a jejunal self-filling diverticulum (blind-loop) were compared to controls with a self-emptying diverticulum. Both endogenous ethanol and acetaldehyde were found in the blind-loop contents. Intragastric administration of sucrose produced a marked increase in acetaldehyde and acetate in the portal venous blood, with only a modest elevation of ethanol. It was concluded that the resulting high concentrations of acetaldehyde, both in the intestinal lumen and the portal blood, may have deleterious effects on the gastrointestinal(GI) mucosa and the liver.[25] Another experimental in-vitro study showed the potential of certain bacteria representing normal human colonic flora to produce acetaldehyde under various atmospheric conditions that may prevail in different parts of the GI tract. This bacterial adaptation may be an essential feature of the bacteriocolonic pathway to produce toxic and carcinogenic acetaldehyde from either endogenous or exogenous ethanol.[26] Many species of gut bacteria, yeast and fungal organisms such as Candida albicans found in the human GI tract and involved in gut dysbiosis, an imbalance in the microbial flora, have been shown to significantly increase blood ethanol levels, post-mortem, in individuals who had not consumed any alcohol before death.[27][28]

The effects of chronic gut dybiosis and long term exposure to low levels of endogenous acetaldehyde on bone tissue and hepatic function is not yet fully understood. However Cordts et al suggested in 2001 that gut dysbiosis (as indicated by stool yeast) and hepatic detoxification challenge pathway exhaustion may lead to subclinical, systemic inflammation and chronic venous insufficiency (CVI). CVI is a pathological condition caused either by the congenital absence of or damage to venous valves in the superficial and communicating systems. Venous incompetence due to thrombi and formation of thrombi favoured by the Virchow triad (venous stasis, hypercoagulability, endothelial trauma) also can cause CVI.[29]

Bisphosphonates may alter the disease process

In the past few years, thousands of cases of ONJ in patients on bisphosphonate therapy have been diagnosed usually following lack of healing after a dental extraction but also in cases of spontaneous exposure of the cortical bone tissue through the gingiva and mucosa.[30][31]

The recent increase of such cases has been linked with a major emphasis on the therapeutic use of bisphosphonates for osteoporosis, especially since hormone replacement therapy has been shown to increase the risk of breast cancer, clots and cardiovascular disease in women following the 2003 findings of the U.S. Women’s Health Initiative study.[32] Two classes of bisphosphonates are presently prescribed:

The nitrogen containing bisphosphonates are the most potent inhibitors and no case of ONJ associated with etidronate has been reported yet. The main pharmacological action of bisphosphonates is inhibition of the osteoclast driven bone resorption. This is achieved by shortening osteoclast lifespan via apoptosis and by inhibiting osteoclast activity and recruitment on the bone surface (61). When a bisphosphonate binds to bone mineral, osteoclast resorb both bone and the bound bisphosphonate. During bone formation, if any, bisphosphonate remaining on the surface of the bone is covered and remains there until future osteoclastic bone resorption at the site. This explains why inhibition of bone resorption continues long after bisphosphonate treatment has been discontinued.[33]

This form of therapy has been shown to prevent loss of bone mineral density (BMD) as a result of a reduction in bone turnover. However bone health is a lot more than BMD.

In healthy bone tissue there is a homeostasis between bone resorption and bone apposition. Diseased or damaged bone is resorbed through the osteoclasts mediated process while osteoblasts form new bone to replace it, thus maintaining healthy bone density. A process commonly called remodelling.

However osteoporosis is essentially the result of a lack of new bone formation in combination with bone resorption in reactive hyperemia, related to various etiological and contributing factors, and bisphosphonates do not address these factors at all.

An individual who is already having problems with osteoporosis/ osteonecrosis of the jaws due to the effects of these etiological factors will be more susceptible to the adverse effects of bisphosphonates. In theory, by suppressing osteoclastic activity and bone resorption, any ischemic-damaged bone will be left in situ instead of being resorbed. The damaged bone will not be repaired either if the factors already inhibiting osteoblastic activity are still present. Therefore the amount of osteonecrotic tissue should be expected to increase until it reaches a level when any trauma or insult to this necrotic bone will result in extremely poor healing, exposed necrotic bone to the oral environment, development of pain, and increased risks of microbial infection, as effectively seen in bisphosphonates associated cases of ONJ.

In a systematic review of cases of bisphosphonates associated ONJ up to 2006, it was concluded that the mandible is more commonly affected than the maxilla (2:1 ratio), and 60% of cases are preceded by a dental surgical procedure. According to Woo, Hellstein and Kalmar, oversuppression of bone turnover is probably the primary mechanism for the development of this form of ONJ, although there may be contributing co-morbid factors (as discussed elsewhere in this article). It is recommended that all sites of potential jaw infection should be eliminated before bisphosphonate therapy is initiated in these patients to reduce the necessity of subsequent dentoalveolar surgery. The degree of risk for osteonecrosis in patients taking oral bisphosphonates, such as alendronate (Fosamax®), for osteoporosis is uncertain and warrants careful monitoring.[1]

History in Dental Medicine

ONJ is not a new disease, around 1850 various forms of "chemical osteomyelitis" resulting from environmental pollutants, such as lead and the white phosphorus used in early (non-safety) matches (Phossy jaw), as well as from popular medications containing mercury, arsenic or bismuth, were reported in the literature.[34][35][36][37][38][39][40] This disease apparently did not often occur in individuals with good gingival health, and usually targeted the mandible first.[35]It was associated with localized or generalized deep ache or pain, often of multiple jawbone sites. The teeth often appeared sound and suppuration was not present. Even so, the dentist often began extracting one tooth after another in the region of pain, often with temporary relief but usually to no real effect.[36]

Today a growing body of scientific evidence indicate that this disease process, in the cancellous bone and bone marrow, is caused by bone infarcts mediated by a range of local and systemic factors. Bone infarcts as well as damage to the deeper portion of the cancellous bone is an insidious process. It is certainly not visible clinically and routine imaging techniques such as radiographs are not effective for that sort of damage. "An important and often incompletely understood principle of radiography is the amount of bone destruction that goes undetected by routine x-rays procedures; this has been demonstrated by numerous investigators. Destruction confined to the cancellous portion of the bone cannot be detected radiographically, ad radiolucencies appear only when there is internal or external erosion or destruction of the bone cortex."[41] In fact no radiographic findings are specific for bone infarction / osteonecrosis. A variety of pathologies may mimic bone infarction, including stress fractures, infections, inflammations, and metabolic and neoplastic processes. The limitations apply to all imaging modalities, including plain radiography, radionuclide studies, CT scans, and magnetic resonance imaging (MRI). Through-transmission alveolar ultrasound, based on quantitative ultrasound (QUS) in combination with panoramic dental radiography (orthopantomography) is helpful in assessing changes in jawbone density.[42][43] When practitioners have an up to date understanding of the disease process and a good anamnesis is combined with detailed clinical findings and course of events, the diagnosis, with the help of various imaging modality, can be achieved earlier, in most patients.

In the modern dental profession, it is only recently when severe cases associated with bisphosphonates came to light, that the issue of ONJ has been brought to the attention of a majority of dentists. At present, the focus is mostly on bisphosphonates associated cases, and is sometimes referred to colloquially as "phossy jaw", a similar, earlier occupational disease.[44][45] However, the pharmaceutical manufacturers of bisphosphonates drugs such as Merck and Novartis have stated that ONJ in patients on this class of drug, can be related to a pre-existing condition, coagulopathy, anemia, infection, use of corticosteroids, alcoholism and other conditions already known to be associated with ONJ in absence of bisphosphonate therapy. The implication is that bisphosphonates may not be the initiating cause of ONJ and that other pre-existing or concurrent systemic and/or local dental factors are involved.[46][47]

Since ONJ has been diagnosed in many patients who did not take bisphosphonates, it is thus logical to assume that bisphosphonates are not the only factor in ONJ While the oversuppression of bone turnover seems to play a major role in aggravating the disease process, other factors can and do initiate the pathophysiological mechanisms responsible for ONJ. In non-bisphosphonate cases of ONj, it is mainly the cancellous portion of the bone and it’s marrow content that are involved in the disease process. The first stage is an oedema of the bone marrow initiated by a bone infarct, which is itself modulated by numerous etiological factors, leading to myelofibrosis as a result of hypoxia and gradual loss of mineral bone density characteristic of ischemic osteoporosis. Further deterioration can be triggered by additional bone infarcts leading to anoxia and a localized areas of osteonecrosis within the osteoporotic cancellous bone. Secondary events such as dental infection, injection of local anesthetics with vasoconstrictors, such as epinephrine, and trauma can add further complications to the disease process and chronic non-pus forming bone infection osteomyelitis can also be associated with ONJ. [48][49][50]

However, in patients on bisphosphonates, the cortical bone is also frequently involved as well. Spontaneous exposure of necrotic bone tissue through the oral soft tissues or following non-healing bone exposure after routine dental surgery, characteristics of this form of ONJ may be the result of late diagnosis of a disease process that has been masked by the oversuppression of osteoclastic activity, allowing pre-existing etiological factors to further aggravate bone damage.

Classification[51][52]

  • Stage 0: Patients who present with unspecific symptoms or radiographic findings but without clinical evidence of necrosis.
  • Symptoms:
  • Dull pain in the mandible body which can radiate to the temporomandibular joint
  • Unexplained odontalgia
  • Maxillary sinus pain
  • Altered mental status
  • Clinical findings
  • Not caries associated periapical or periodontal fistula
  • Unexplained loosening of the teeth
  • Radiographic findings
  • Trabecular pattern changes
  • Thickening of the periodontal ligament
  • Osteosclerosis regions which involves alveolar bone and the basilar bone
  • Alveolar bone loss or resorption
  • Stage 1: Asymptomatic patients, without infection evidence who present an exposed necrotic bone or fistula. Radiographic findings mentioned above can be found in patients with stage 1
  • Stage 2: Patients with exposed necrotic bone or fistula and signs of infection, usually symptomatic. Radiographic findings mentioned above can be found in patients with stage 2
  • Stage 3: Patients with the characteristics of stage 2 plus one or more of the following conditions:
  • Pathologic fracture
  • Osteolisis which reaches the sinus floor or the external border of the mandible
  • Orocutaneos fistula
  • Comunication with the maxillary sinus (oroantral) or the nose (oronasal) Normal 0 21 false false false ES-PE X-NONE X-NONE

Treatment

The treatment should be tailored to the individual patient according to the etiological factors involved and the severity of the disease process. With oral osteoporosis the emphasis should be on educating the patient to achieve good nutrient absorption and metabolic wastes elimination through a healthy gastro-intestinal function, effective hepatic metabolism of toxicants such as exogenous estrogens, endogenous acetaldehyde and heavy metals, a balanced diet, healthy lifestyle, assessment of factors related to potential coagulopathies, and treatment of periodontal diseases and other oral and dental infections.

In cases of advanced oral ischemic osteoporosis and/or ONJ that are not bisphosphonates related, clinical evidence has shown that surgically removing the damaged marrow, usually by curettage and decortication, will eliminate the problem (and the pain) in 74% of patients with jaw involvement.[2] Repeat surgeries, usually smaller procedures than the first, may be required, and almost a third of jawbone patients will need surgery in one or more other parts of the jaws because the disease so frequently present multiple lesions, i.e. multiple sites in the same or similar bones, with normal marrow in between. In the hip, at least half of all patients will get the disease in the opposite hip over time; this pattern occurs in the jaws as well. Recently, it has been found that some osteonecrosis patients respond to anticoagulation therapies alone. The earlier the diagnosis the better the prognosis. Research is ongoing on other non-surgical therapeutic modalities that could alone or in combination with surgery further improve the prognosis and reduce the morbidity of ONJ. A greater emphasis on minimizing or correcting known etiological factors is necessary while further research is conducted on chronic ischemic bone diseases such as oral osteoporosis and ONJ.

In patients with bisphosphonates-associated ONJ, the response to surgical treatment is usually poor.[53] Conservative debridement of necrotic bone, pain control, infection management, use of antimicrobial oral rinses, and withdrawal of bisphosphonates are preferable to aggressive surgical measures for treating this form of ONJ.[54] Although an effective treatment for bisphosphonate-associated bone lesions has not yet been established,[55] and this is unlikely to occur until this form of ONJ is better understood, there as been clinical reports of some improvement after 6 months or more of complete cessation of bisphosphonate therapy.[56]

Staging and Recommended Management[51]

Stage Recommended Management
Stage 0 Antibiotic treatment and pain management
Stage 1 Patient education, antibiotic mouth rinse, consider discontinuing biphosmonate therapy
Stage 2 Debridement, oral antibiotic therapy plus antibiotic mouth rinse and pain management
Stage 3 Debridement or resection for better infection control, oral antibiotic therapy plus antibiotic mouth rinse and pain management

Antibiotic Therapy

  • Patients who have exposed necrotic bone associated with superimposed infection and disrupted bone remodeling may benefit from the use of antiseptic mouthwash (such as 0.12% chlorhexidine gluconate) in combination with antibiotic therapy. Most of the isolated flora are susceptible to the beta-lactams. For patients that are allergic to penicillins, clindamycin, doxycycline, erythromycin, azithromycin, quinolones, and metronidazole have been used with success.[57][58][59]
  • Long-term maintenance antibiotics and a course of intravenous therapy according to the culture and sensitivity data may be considered for refractory cases.
  • The table below describes the recommended antimicrobial regimens for the treatment of secondary infection in the osteonecrosis of the jaw.[60]
Bacterial Infection
Preferred Regimen
▸ Penicillin VK 500 mg PO q6–8h for 7–10 days (maintenance: 500 mg PO bid)
OR
▸ Amoxicillin 500 mg PO q8h for 7–10 days (maintenance: 500 mg PO bid)
Alternative Regimen (If Allergic to Penicillin)
▸ Clindamycin 150–300 mg PO qid
OR
▸ Doxycycline 100 mg PO qd
OR
▸ Erythromycin 400 mg PO tid
OR
▸ Azithromycin 500 mg PO for 1 dose, then 250 mg PO qd for 4 days
OR
▸ Levofloxacin 500 mg PO qd
OR
▸ Moxifloxacin 400 mg PO qd
Fungal Infection
Preferred Regimen
▸ Nystatin oral suspension 5–15 mL swish qid
OR
▸ Fluconazole 200 mg PO qd, then 100 mg q24h
OR
▸ Clotrimazole 10 mg PO tid for 7–10 days
Viral Infection
Preferred Regimen
▸ Acyclovir 400 mg PO bid
OR
▸ Valacyclovir 0.5–2.0 g PO bid

Antimicrobial regimen

  • 1. Bacterial Infection [61]
  • Preferred regimen (1): Penicillin VK 500 mg PO q6–8h for 7–10 days (maintenance: 500 mg PO bid)
  • Preferred regimen (2): Amoxicillin 500 mg PO q8h for 7–10 days (maintenance: 500 mg PO bid)
  • Alternative regimen (1): Clindamycin 150–300 mg PO qid
  • Alternative regimen (4): Azithromycin 500 mg PO single dose THEN 250 mg PO qd for 4 days
  • 2. Fungal Infection
  • Preferred regimen (1): Nystatin oral suspension 5–15 mL swish qid
  • Preferred regimen (2): Fluconazole 200 mg PO qd THEN 100 mg q24h
  • Preferred regimen (3): Clotrimazole 10 mg PO tid for 7–10 days
  • 3. Viral Infection
  • Preferred regimen (1): Acyclovir 400 mg PO bid

References

  1. ↑ 1.0 1.1 1.2 Woo S, Hellstein J, Kalmar J (2006). "Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws". Ann Intern Med. 144 (10): 753–61. PMID 16702591.
  2. ↑ 2.0 2.1 Bouquot JE, Christian J. Long-term effects of jawbone curettage on the pain of facial neuralgia. J Oral Maxillofac Surg 1995; 53:387-397. PMID: 7699492
  3. ↑ Neville BW, Damn D, Allen C, Bouquot JE. Facial pain and neuromuscular diseases. In Oral and maxillofacial pathology: W.B Saunders Co, 1995: 631-632.
  4. ↑ Arlet J, Durroux R, Fauchier C, Thiechart M. Histophatology of the nontraumatic necrosis of the femoral head : topographic and evolutive aspects. In Arlet J, Ficat PR, Hungerford DS. (eds).
  5. ↑ Kanus JA. Textbook of osteoporosis. Osford: Blackwell Science Ltd.; 1996.
  6. ↑ Marcus R, Feldman D, Kelsey J. Osteoporosis. San Diego: Academic Press; 1996.
  7. ↑ Bullough PG. Orthopaedic pathology, 3rd ed. Baltimore: Wolfe-Mosby; 1997.
  8. ↑ Vigorita VJ. Orthopaedic pathology. Philadelphia: Lippincott Williams & Wilkins; 1999.
  9. ↑ Parfitt AM. Osteonal and hemi-osteonal remodeling: the spatial and temporal framework for signal traffic in adult human bone. J Cell Biochem 55:273–286. 1994 PMID: 7962158
  10. ↑ Parfitt, A M.; Kleerekoper, M.; Villanueva, A R. Increased bone age: mechanisms and consequences;. Osteoporosis. Osteopress; Copenhagen: pp. 301–308.1987
  11. ↑ Frost, H M. Charles C. Thomas; Springfield, IL: Bone Remodeling Dynamics. 1963.
  12. ↑ Owen M, Friedenstein AJ Stromal stem cells: marrow- derived osteogenic precursors. Ciba Found Symp 136:42–60. 1988.
  13. ↑ Lee JS, Lee JS, Roh HL, Kim CH, Jung JS, Suh KT. Alterations in the differentiation ability of mesenchymal stem cells in patients with non-traumatic osteonecrosis of the femoral head: comparative analysis according to the risk factor. J Orthop Res. 2006 Apr;24(4):604-9.
  14. ↑ Suh KT, Kim SW, Roh HL, Youn MS, Jung JS. Decreased osteogenic differentiation of mesenchymal stem cells in alcohol-induced osteonecrosis. Clin Orthop Relat Res. 2005 Feb;(431):220-5.
  15. ↑ Gangji V, Hauzeur JP, Schoutens A, Hinsenkamp M, Appelboom T, Egrise D. Abnormalities in the replicative capacity of osteoblastic cells in the proximal femur of patients with osteonecrosis of the femoral head. J Rheumatol. 2003 Feb;30(2):348-51.
  16. ↑ 16.0 16.1 Khan A, Chandramohan M, Turnbull I, Macdonald S, Hutchinson C.E. (July 28, 2005). "Bone infarct". E-Medicine, Web MD. Retrieved 2006-05-21.
  17. ↑ Adams WR, Spolnik KJ, Bouquot JE. Maxillofacial osteonecrosis in a patient with multiple "idiopathic" facial pains. J Oral Pathol Med 1999; 28:423-432. PMID: 10535367
  18. ↑ Glueck C, McMahon R, Bouquot J, Triplett D (1998). "Exogenous estrogen may exacerbate thrombophilia, impair bone healing and contribute to development of chronic facial pain". Cranio. 16 (3): 143–53. PMID 9852807.
  19. ↑ Yamamoto C (2000). "[Toxicity of cadmium and lead on vascular cells that regulate fibrinolysis]". Yakugaku Zasshi. 120 (5): 463–73. PMID 10825810. Unknown parameter |month= ignored (help)
  20. ↑ Jaworowski Z, Barbalat F, Blain C, Peyre E. Heavy metals in human and animal bones from ancient and contemporary France. Sci Total Environ. 1985 May; 43(1-2) : 103-126 PMID: 4012292
  21. ↑ Giuliani N, Girasole G, Vescovi P, Passeri G, Pedrazzoni M (1999). "Ethanol and acetaldehyde inhibit the formation of early osteoblast progenitors in murine and human bone marrow cultures". Alcohol Clin Exp Res. 23 (2): 381–5. PMID 10069572. Unknown parameter |month= ignored (help)
  22. ↑ Ferrier L, Berard F, Debrauwer L, Chabo C, Langella P, Bueno L, Fioramonti J. Impairment of the intestinal barrier by ethanol involves enteric microflora and mast cell activation in rodents. Am J Pathol. 2006 Apr;168(4):1148-54.
  23. ↑ Salaspuro M. Bacteriocolonic pathway for ethanol oxidation: characteristics and implications. Ann Med. 1996 Jun;28(3):195-200.
  24. ↑ Ma XL, Baraona E, Hernandez-Munoz R, Lieber CS. High levels of acetaldehyde in nonalcoholic liver injury after threonine or ethanol administration. Hepatology. 1989 Dec;10(6):933-40.
  25. ↑ Baraona E, Julkunen R, Tannenbaum L, Lieber CS. Role of intestinal bacterial overgrowth in ethanol production and metabolism in rats. Gastroenterology. 1986 Jan;90(1):103-10.
  26. ↑ Salaspuro V, Nyfors S, Heine R, Siitonen A, Salaspuro M, Jousimies-Somer H. Ethanol oxidation and acetaldehyde production in vitro by human intestinal strains of Escherichia coli under aerobic, microaerobic, and anaerobic conditions. Scand J Gastroenterol. 1999 Oct;34(10):967-73. PMID: 10563665
  27. ↑ Lewis RJ, Johnson RD, Angier MK, Vu NT. Ethanol formation in unadulterated postmortem tissues. Forensic Sci Int. 2004 Nov 10;146(1):17-24.
  28. ↑ Yajima D, Motani H, Kamei K, Sato Y, Hayakawa M, Iwase H. Ethanol production by Candida albicans in postmortem human blood samples: Effects of blood glucose level and dilution. Forensic Sci Int. 2006 Jan 19.
  29. ↑ Cordts PR, Kaminski MV, Raju S, Clark MR, Woo KM. Could gut-liver function derangements cause chronic venous insufficiency? Vasc Surg. 2001 Mar-Apr;35(2):107-14.
  30. ↑ Fosamax does more harm then good. Accessed 21 May 2006.
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  50. ↑ Gruppo R, Glueck C, McMahon R, Bouquot J, Rabinovich B, Becker A, Tracy T, Wang P (1996). "The pathophysiology of alveolar osteonecrosis of the jaw: anticardiolipin antibodies, thrombophilia, and hypofibrinolysis". J Lab Clin Med. 127 (5): 481–8. PMID 8621985.
  51. ↑ 51.0 51.1 "http://www.aaoms.org/docs/position_papers/mronj_position_paper.pdf?pdf=MRONJ-Position-Paper" (PDF). External link in |title= (help)
  52. ↑ Bedogni, A.; Fusco, V.; Agrillo, A.; Campisi, G. (2012). "Learning from experience. Proposal of a refined definition and staging system for bisphosphonate-related osteonecrosis of the jaw (BRONJ)". Oral Dis. 18 (6): 621–3. doi:10.1111/j.1601-0825.2012.01903.x. PMID 22353421. Unknown parameter |month= ignored (help)
  53. ↑ Zarychanski R, Elphee E, Walton P, Johnston J. Osteonecrosis of the jaw associated with pamidronate therapy. Am J Hematol. 2006 Jan;81(1):73-5.
  54. ↑ Abu-Id MH, Acil Y, Gottschalk J, Kreusch T. [Bisphosphonate-associated osteonecrosis of the jaw.] [Article in German]. Mund Kiefer Gesichtschir. 2006 Mar;10(2):73-81.
  55. ↑ Merigo E, Manfredi M, Meleti M, Corradi D, Vescovi P. Jaw bone necrosis without previous dental extractions associated with the use of bisphosphonates (pamidronate and zoledronate): a four-case report. J Oral Pathol Med. 2005 Nov;34(10):613-7 PMID: 16202082
  56. ↑ Simon D J Gibbs, John O'Grady, John F Seymour, H Miles Prince. Bisphosphonate-induced osteonecrosis of the jaw requires early detection and intervention. MJA 2005; 183 (10): 549-550
  57. ↑ Woo, SB.; Hellstein, JW.; Kalmar, JR. (2006). "Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws". Ann Intern Med. 144 (10): 753–61. PMID 16702591. Unknown parameter |month= ignored (help)
  58. ↑ Ruggiero, SL.; Fantasia, J.; Carlson, E. (2006). "Bisphosphonate-related osteonecrosis of the jaw: background and guidelines for diagnosis, staging and management". Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 102 (4): 433–41. doi:10.1016/j.tripleo.2006.06.004. PMID 16997108. Unknown parameter |month= ignored (help)
  59. ↑ Marx, RE.; Sawatari, Y.; Fortin, M.; Broumand, V. (2005). "Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment". J Oral Maxillofac Surg. 63 (11): 1567–75. doi:10.1016/j.joms.2005.07.010. PMID 16243172. Unknown parameter |month= ignored (help)
  60. ↑ Ruggiero S, Gralow J, Marx RE, Hoff AO, Schubert MM, Huryn JM; et al. (2006). "Practical guidelines for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in patients with cancer". J Oncol Pract. 2 (1): 7–14. PMC 2794643. PMID 20871729.
  61. ↑ Gilbert, David (2015). The Sanford guide to antimicrobial therapy. Sperryville, Va: Antimicrobial Therapy. ISBN 978-1930808843.

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