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| ==Overview==
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| {{Infobox_Disease | | | {{Infobox_Disease | |
| Name = Osteonecrosis of the jaws | | | Name = Osteonecrosis of the jaws | |
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| {{SI}} | | __NOTOC__ |
| '''[[Osteonecrosis]] of the [[jaw]]s''' ('''ONj''') is a severe [[bone]] disease that affects the jaws, including the [[maxilla]] and the [[mandible]]. Jaw bone (''[[bone|osteo]]-'') damage and death (''-[[necrosis]]'') occurs as a result of reduced local blood supply ([[ischaemia]]). The condition is thus included in the general category of ischaemic or [[Avascular necrosis|avascular osteonecrosis]] (literally "dead bone from poor blood flow."). | | {{Osteonecrosis of the jaw}} |
| | | '''For patient information on this page, click [[Osteonecrosis of the jaw (patient information)|here]]''' |
| 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 [[bisphosphonate]]s, 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.<ref name="Woo2006">{{cite journal | author = Woo S, Hellstein J, Kalmar J | title = Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws. | journal = Ann Intern Med | volume = 144 | issue = 10 | pages = 753-61 | year = 2006 | id = PMID 16702591}}</ref>
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| Various treatment options have been explored, however severe cases of ONj still require surgical removal of the affected bone.<ref name="Bouquot1995"> Bouquot JE, Christian J. Long-term effects of jawbone curettage on the pain of facial neuralgia. J Oral Maxillofac Surg 1995; 53:387-397. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=7699492&query_hl=24&itool=pubmed_docsum PMID: 7699492]</ref> 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.<ref name="Woo2006">{{cite journal | author = Woo S, Hellstein J, Kalmar J | title = Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws. | journal = Ann Intern Med | volume = 144 | issue = 10 | pages = 753-61 | year = 2006 | id = PMID 16702591}}</ref>
| | {{CMG}}; {{AE}} {{Alonso}} |
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| ==Aetiology==
| | {{SK}} ONJ |
| ===Histopathological alterations===
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| 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.
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| Under ischaemic 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 cell]]s (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 [[osteocyte]]s and variable micro cracking (splitting along natural cleavage planes). The microscopic features are similar to those of ischaemic or aseptic osteonecrosis of long bones, [[corticosteroid]]-induced osteonecrosis, and the osteomyelitis of caisson (deep-sea diver’s) disease"''.<ref> 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. </ref>
| | ==[[Osteonecrosis of the jaw overview|Overview]]== |
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| In the cancellous portion of femoral head it is not uncommon to find [[trabeculae]] with apparently intact [[osteocyte]]s which seem to be "alive" but are no longer synthetizing [[collagen]]. This appears to be consistent with the findings in alveolar [[cancellous bone]].<ref> 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).</ref>
| | ==[[Osteonecrosis of the jaw historical perspective|Historical Perspective]]== |
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| 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. | | ==[[Osteonecrosis of the jaw classification|Classification]]== |
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| 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 [[biopsy|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.
| | ==[[Osteonecrosis of the jaw pathophysiology|Pathophysiology]]== |
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| ===The effects of persistent ischaemia on bone cells=== | | ==[[Osteonecrosis of the jaw causes|Causes]]== |
| [[Cortical bone]] is well vascularized by the surrounding soft tissues thus less susceptible to ischaemic 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]].<ref> Kanus JA. Textbook of osteoporosis. Osford: Blackwell Science Ltd.; 1996.</ref><ref>Marcus R, Feldman D, Kelsey J. Osteoporosis. San Diego: Academic Press; 1996.</ref><ref> Bullough PG. Orthopaedic pathology, 3rd ed. Baltimore: Wolfe-Mosby; 1997.</ref><ref>Vigorita VJ. Orthopaedic pathology. Philadelphia: Lippincott Williams & Wilkins; 1999.</ref> The mean life-span of osteocytes has been estimated to be 15 years in cancellous bone,<ref> 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 [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=7962158&query_hl=27&itool=pubmed_docsum PMID: 7962158]</ref> and 25 years in cortical bone.<ref> Parfitt, A M.; Kleerekoper, M.; Villanueva, A R. Increased bone age: mechanisms and consequences;. Osteoporosis. Osteopress; Copenhagen: pp. 301–308.1987 </ref> while the average lifespan of human osteoclasts is about 2 to 6 weeks and the average lifespan of [[osteoblast]]s is approximately 3 months.<ref> Frost, H M. Charles C. Thomas; Springfield, IL: Bone Remodeling Dynamics. 1963.</ref> In healthy bone these cells are constantly replaced by differentiation of bone marrow [[mesenchymal stem cells]] (MSC).<ref> Owen M, Friedenstein AJ Stromal stem cells: marrow- derived osteogenic precursors. Ciba Found Symp 136:42–60. 1988.</ref> 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,<ref> 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.</ref><ref> 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.</ref> and altered osteoblastic function plays a role in ON of the femoral head.<ref> 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.</ref> 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 ischaemic-damaged cancellous bone tissue in ONj. | |
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| The rapidity with which premature cell death can occur depends on the cell type and the degree and duration of the [[anoxia]]. [[pluripotential hemopoietic stem cell|haematopoietic 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.<ref name="eMedicine">{{cite web | author=Khan A, Chandramohan M, Turnbull I, Macdonald S, Hutchinson C.E. | title=Bone infarct. | url=http://www.emedicine.com/radio/topic86.htm | publisher=E-Medicine, Web MD | date=July 28, 2005 | accessdate=2006-05-21}}</ref> 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.
| | ==[[Osteonecrosis of the jaw differential diagnosis|Differentiating Osteonecrosis of the jaw from other Diseases]]== |
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| Attempts at repair of ischaemic-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 ischaemic conditions can be seen [[Histology|histologically]] and are characterized by extensive delamination or microcracking along cement lines as well as the formation of excessive cement lines.<ref> Adams WR, Spolnik KJ, Bouquot JE. Maxillofacial osteonecrosis in a patient with multiple "idiopathic" facial pains. J Oral Pathol Med 1999; 28:423-432. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=10535367&query_hl=2&itool=pubmed_docsum PMID: 10535367 ]</ref> Ultimate failure of repair mechanisms due to persistent and repeated ischaemic 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).<ref name="eMedicine">{{cite web | author=Khan A, Chandramohan M, Turnbull I, Macdonald S, Hutchinson C.E. | title=Bone infarct. | url=http://www.emedicine.com/radio/topic86.htm | publisher=E-Medicine, Web MD | date=July 28, 2005 | accessdate=2006-05-21}}</ref>
| | ==[[Osteonecrosis of the jaw epidemiology and demographics|Epidemiology and Demographics]]== |
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| ===Other contributing factors=== | | ==[[Osteonecrosis of the jaw risk factors|Risk 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 ischaemia. Exogenous estrogens, also called hormonal disruptors, have also been linked with an increased tendency to clot ([[thrombophilia]]) and impaired bone healing.<ref> {{cite journal | author = Glueck C, McMahon R, Bouquot J, Triplett D | title = Exogenous estrogen may exacerbate thrombophilia, impair bone healing and contribute to development of chronic facial pain. | journal = Cranio | volume = 16 | issue = 3 | pages = 143-53 | year = 1998 | id = PMID 9852807}}</ref>
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| [[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.<ref>{{cite journal | author = Yamamoto C | title = [Toxicity of cadmium and lead on vascular cells that regulate fibrinolysis] | journal = Yakugaku Zasshi | volume = 120 | issue = 5 | pages = 463-73 | year = 2000 | month=May | id = PMID 10825810}}</ref> Persistent blot clots can lead to congestive blood flow ([[hyperemia]]) in bone marrow, impaired blood flow and ischaemia in bone tissue resulting in lack of oxygen ([[hypoxia (medical)|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.<ref> 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 [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=4012292&query_hl=8&itool=pubmed_docsum PMID: 4012292]</ref> | | ==[[Osteonecrosis of the jaw natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
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| [[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.<ref>{{cite journal | author = Giuliani N, Girasole G, Vescovi P, Passeri G, Pedrazzoni M | title = Ethanol and acetaldehyde inhibit the formation of early [[osteoblast]] progenitors in murine and human bone marrow cultures. | journal = Alcohol Clin Exp Res | volume = 23 | issue = 2 | pages = 381-5 | year = 1999 | month=Feb | id = PMID 10069572}}</ref> 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.<ref> Ferrier L, Berard F, Debrauwer L, Chabo C, Langella P, Bueno L, Fioramonti J. Impairment of the [[Intestine|intestinal]] barrier by ethanol involves [[enteric]] microflora and mast cell activation in rodents. Am J Pathol. 2006 Apr;168(4):1148-54.</ref> Intracolonic acetaldehyde may also be an important determinant of the blood acetaldehyde level and a possible [[hepatotoxin]].<ref> Salaspuro M. Bacteriocolonic pathway for ethanol oxidation: characteristics and implications. Ann Med. 1996 Jun;28(3):195-200.</ref> 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.<ref> 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.</ref> 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]].<ref> 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.</ref> 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.<ref> 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. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=10563665&query_hl=5&itool=pubmed_docsum PMID: 10563665]</ref> 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.<ref> Lewis RJ, Johnson RD, Angier MK, Vu NT. Ethanol formation in unadulterated postmortem tissues. Forensic Sci Int. 2004 Nov 10;146(1):17-24.</ref><ref> 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. </ref>
| | ==Diagnosis== |
| | | [[Osteonecrosis of the jaw history and symptoms| History and Symptoms]] | [[Osteonecrosis of the jaw physical examination | Physical Examination]] | [[Osteonecrosis of the jaw laboratory findings|Laboratory Findings]] | [[Osteonecrosis of the jaw other imaging findings|Other Imaging Findings]] | [[Osteonecrosis of the jaw other diagnostic studies|Other Diagnostic Studies]] |
| 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 [[Vein|venous valves]] in the superficial and communicating systems. Venous incompetence due to [[Thrombus|thrombi]] and formation of thrombi favoured by the Virchow triad (venous stasis, hypercoagulability, endothelial trauma) also can cause CVI.<ref> 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.</ref>
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| ===Bisphosphonates may alter the disease process===
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| 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.<ref> [http://www.lawyersandsettlements.com/articles/fosamax.html Fosamax does more harm then good. ] Accessed 21 May 2006.</ref><ref> Hay KD, Bishop PA. Association of osteonecrosis of the jaws and bisphosphonate pharmacotherapy: dental implications. NZ Dent J. 2006 Mar;102(1):4-9.</ref>
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| 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.<ref> Wassertheil-Smoller S. et al. Effect of Estrogen Plus Progestin on Stroke in Postmenopausal Women The Women's Health Initiative: A Randomized Trial. JAMA. 2003;289:2673-2684. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=12771114&query_hl=10&itool=pubmed_docsum PMID: 12771114]</ref> Two classes of [[bisphosphonate]]s are presently prescribed:
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| *Non-[[nitrogen]] containing bisphosphonates such as [[etidronic acid|etidronate]] (Didronel®, [[Procter & Gamble|Procter & Gamble Pharmaceuticals]])
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| *Nitrogen containing such as [[alendronate]] (Fosamax®, [[Merck & Co.|Merck]]), [[pamidronic acid|pamidronate]] (Aredia®, [[Novartis]]), [[zoledronate]] (Zometa®, Novartis), [[risedronate]] (Actonel®, Procter & Gamble) and [[ibandronic acid|ibandronate]] (Boniva®, [[Hoffmann-La Roche|Roche Laboratories]]).
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| 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.<ref> Rodan G, Reszka A. Osteoporosis and bisphosphonates. The Journal of Bone and Joint Surgery. 2003;85-A (Suppl. 3)8-12.</ref>
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| 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.
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| In healthy bone tissue there is a [[homeostasis]] between [[bone resorption]] and bone apposition. Diseased or damaged bone is resorbed through the [[osteoclast]]s mediated process while [[osteoblast]]s form new bone to replace it, thus maintaining healthy [[bone density]]. A process commonly called remodelling.
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| 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.
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| 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 ischaemic-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.
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| 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]] [[factor]]s (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.<ref name="Woo2006">{{cite journal | author = Woo S, Hellstein J, Kalmar J | title = Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws. | journal = Ann Intern Med | volume = 144 | issue = 10 | pages = 753-61 | year = 2006 | id = PMID 16702591}}</ref>
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| ==History in dental medicine==
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| 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 (element)|mercury]], [[arsenic]] or [[bismuth]], were reported in the literature.<ref> Bond TE Jr. A practical treatise on dental medicine. Philadelphia: Lindsay & Blakiston, 1848.</ref><ref name="ONj_Lucifer matches"> Anonymous. Necrosis of the lower jaw in makers of Lucifer matches. Am J Dent Science 1867; 1 (series 3):96-97.</ref><ref name="MCDR-HistoryONJ"> [http://www.maxillofacialcenter.com/NICOhistory.html Bouquot J.E. The history of maxillofacial osteonecrosis. Maxillofacial Center for Diagnostics and Research.] Accessed 22 May 2006.</ref><ref> Ferguson W. New treatment of necrosis. Am J Dent Science 1868; 1 (series 3):189.</ref><ref> Noel HR. A lecture on caries and necrosis of bone. Am J Dent Science 1868; 1 (series 3):425, 482. </ref><ref> Barrett WC. Oral pathology and practice. Philadelphia, S.S. White Dental Mfg Co, 1898. </ref><ref> Black GV. A work on special dental pathology (2nd ed). Chicago, Medico_Dental Publ Co, 1915 </ref>
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| This disease apparently did not often occur in individuals with good gingival health, and usually targeted the mandible first.<ref name="ONj_Lucifer matches"> Anonymous. Necrosis of the lower jaw in makers of Lucifer matches. Am J Dent Science 1867; 1 (series 3):96-97.</ref>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.<ref name="MCDR-HistoryONJ"> [http://www.maxillofacialcenter.com/NICOhistory.html Bouquot J.E. The history of maxillofacial osteonecrosis. Maxillofacial Center for Diagnostics and Research.] Accessed 22 May 2006.</ref>
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| Today a growing body of scientific evidence indicate that this disease process, in the cancellous bone and bone marrow, is caused by bone [[infarct]]s 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."''<ref> Cohen S, Burns R. Pathways of the pulp. ed. 2, St-Louis, 55-57, 1980. C.V. Mosby </ref> 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.<ref>{{cite journal | author = Imbeau J | title = Introduction to through-transmission alveolar ultrasonography (TAU) in dental medicine. | journal = Cranio | volume = 23 | issue = 2 | pages = 100-12 | year = 2005 | id = PMID 15898566}}</ref><ref> Bouquot J, Margolis M, Shankland WE, Imbeau J. Through-transmission alveolar sonography (TTAS) – a new technology for evaluation of medullary diseases, correlation with histopathology of 285 scanned jaw sites. Presented at the 56th annual meeting of the American Academy of Oral and Maxillofacial Pathology. April 2002.</ref> 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.
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| 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.<ref>PM Purcell, IW Boyd, [http://www.mja.com.au/public/issues/182_08_180405/pur10144_fm.html Bisphosphonates and osteonecrosis of the jaw], ADRAC Report, MJA 2005; 182 (8): 417-418</ref><ref> J Carreyrou, [http://www.gatago.com/misc/headlines/9744680.html Fosamax Drug Could Become Next Merck Woe], Dow Jones (THE WALL STREET JOURNAL), Apr. 12, 2006 </ref> 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.<ref> [http://www.merck.com/newsroom/press_releases/product/fosamax_statement.html Statement by Merck on Fosamax and rare cases of osteonecrosis of the jaws.]- Accessed 21 May 2006.</ref><ref> [http://www.us.novartisoncology.com/info/coping/dental_health.jsp?usertrack.filter_applied=true&NovaId=7852773730358657033 Information on osteonecrosis of the jaws on the Novartis web site.]- Accessed 21 May 2006.</ref>
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| 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 [[Pathophysiology|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 ischaemic 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 anaesthetics]] with [[vasoconstrictor]]s, 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. <ref> Bouquot J, Wrobleski G, Fenton S. The most common osteonecrosis? Prevalence of maxillofacial osteonecrosis (MFO). J Oral Pathol Med 2000; 29:345. (abstract)</ref><ref> Glueck CJ, McMahon RE, Bouquot JE, et al. Thrombophilia, hypofibrinolysis and osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol; 81:557-566, 1996. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=8734702&query_hl=15&itool=pubmed_docsum PMID: 8734702]</ref><ref>{{cite journal | author = Gruppo R, Glueck C, McMahon R, Bouquot J, Rabinovich B, Becker A, Tracy T, Wang P | title = The pathophysiology of alveolar osteonecrosis of the jaw: anticardiolipin antibodies, thrombophilia, and hypofibrinolysis. | journal = J Lab Clin Med | volume = 127 | issue = 5 | pages = 481-8 | year = 1996 | id = PMID 8621985}}</ref>
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| 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]] [[factor]]s to further aggravate bone damage.
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| ==Treatment== | | ==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 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 [[Coagulopathy|coagulopathies]], and treatment of periodontal diseases and other oral and dental infections.
| | [[Osteonecrosis of the jaw medical therapy|Medical Therapy]] | [[Osteonecrosis of the jaw surgery|Surgery]] | [[Osteonecrosis of the jaw primary prevention|Primary Prevention]] | [[Osteonecrosis of the jaw secondary prevention|Secondary Prevention]] | [[Osteonecrosis of the jaw future or investigational therapies|Future or Investigational Therapies]] |
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| In cases of advanced oral ischaemic 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.<ref name="Bouquot1995"> Bouquot JE, Christian J. Long-term effects of jawbone curettage on the pain of facial neuralgia. J Oral Maxillofac Surg 1995; 53:387-397.</ref> 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 ischaemic bone diseases such as oral osteoporosis and ONj.
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| In patients with bisphosphonates-associated ONj, the response to surgical treatment is usually poor.<ref>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. </ref> 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.<ref> 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.</ref> Although an effective treatment for bisphosphonate-associated bone lesions has not yet been established,<ref> 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 [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16202082&query_hl=18&itool=pubmed_docsum PMID: 16202082]</ref> 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.<ref> 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 </ref>
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| ===Antibiotic treatment<SMALL><SMALL><SMALL><SMALL><SMALL>Adapted from ''JOP January 2006 vol. 2 no. 1 7-14.''<ref name="pmid20871729">{{cite journal| author=Ruggiero S, Gralow J, Marx RE, Hoff AO, Schubert MM, Huryn JM et al.| title=Practical guidelines for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in patients with cancer. | journal=J Oncol Pract | year= 2006 | volume= 2 | issue= 1 | pages= 7-14 | pmid=20871729 | doi= | pmc=PMC2794643 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20871729 }} </ref></SMALL></SMALL></SMALL></SMALL></SMALL>===
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| | style="padding: 0 5px; font-size: 90%; background: #F5F5F5;" align=center | '''''Preferred Regimen'''''
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| | style="font-size: 90%; padding: 0 5px; background: #DCDCDC" align=left | ▸ '''''[[Penicillin VK]] 500 mg PO q6-8h for 7 to 10 days, mantainance: 500 mg PO bid'''''<BR> OR <BR>'''''[[Amoxicillin]] 500 mg PO q8h for up to 7 to 10 days, mantainance: 500 mg PO two bid'''''
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| | style="padding: 0 5px; font-size: 90%; background: #F5F5F5;" align=center | '''''Allergic to penicillin'''''
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| | style="font-size: 90%; padding: 0 5px; background: #DCDCDC" align=left | ▸ '''''[[Doxycycline]] 100 mg PO q24h '''''<BR> OR <BR>'''''[[Clindamycin]] 150-300 mg PO q6h '''''<BR> OR <BR>'''''<BR> OR <BR> ▸ '''''[[Azithromycin]] 500 mg PO q24h for 1 day, then 250 mg PO q24h for 4 days'''''<BR> OR <BR>'''''[[Erythromycin]] 400 mg PO q8h'''''
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| ! style="height: 30px; line-height: 30px; background: #4479BA; border: 0px; font-size: 100%; text-shadow: 0 -1px 0 rgba(0, 0, 0, 0.5);" align=center | {{fontcolor|#FFF|Fungal infection}}
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| | style="padding: 0 5px; font-size: 90%; background: #F5F5F5;" align=center | '''''Preferred Regimen'''''
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| | style="font-size: 90%; padding: 0 5px; background: #DCDCDC" align=left | ▸ '''''[[Nystatin oral suspention]] 5-15 ml q6h '''''<BR> OR <BR>'''''[[Fluconazole]] 200 mg every two days, lower the dose to 100 mg q24h'''''<BR> OR <BR>'''''[[Clotrimazole]] 10 mg PO q8h for7 to 10 days'''''
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| {| style="float: left; cellpadding=0; cellspacing= 0; width: 400px;"
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| ! style="height: 30px; line-height: 30px; background: #4479BA; border: 0px; font-size: 100%; text-shadow: 0 -1px 0 rgba(0, 0, 0, 0.5);" align=center | {{fontcolor|#FFF|Viral infection}}
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| | style="padding: 0 5px; font-size: 90%; background: #F5F5F5;" align=center | '''''Preferred Regimen'''''
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| | style="font-size: 90%; padding: 0 5px; background: #DCDCDC" align=left | ▸ '''''[[Acyclovir]] 400 mg q12h '''''<BR> OR <BR>'''''[[Valacyclovir]] 0.5-2 g PO q12h'''''
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| ===Staging of Patients with Osteonecrosis of the Jaw<SMALL><SMALL><SMALL><SMALL><SMALL>Adapted from ''JOP January 2006 vol. 2 no. 1 7-14.''<ref>{{Cita web | apellido = | nombre = | título = http://www.aaoms.org/docs/position_papers/mronj_position_paper.pdf?pdf=MRONJ-Position-Paper | url = http://www.aaoms.org/docs/position_papers/mronj_position_paper.pdf?pdf=MRONJ-Position-Paper | obra = | fecha = | fechaacceso = 16 de mayo de 2014 }}</ref></SMALL></SMALL></SMALL></SMALL></SMALL>===
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| | ==Case Studies== |
| | [[Osteonecrosis of the jaw case study one|Case#1]] |
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| * Stage 0: Patients who present with unspecific symptoms or radiografic findings but without clinical evidence of necrosis.
| | [[Category:Disease]] |
| :* Symptoms:
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| ::* Dull pain in the mandible body which can radiate to the temporomandibular joint
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| ::* Unexplained odontalgia
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| ::* Maxillary sinus pain
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| ::* Altered mental status
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| :* Clinical findings
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| ::* Not caries associated periapical or periodontal fistula
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| ::* Unexplained losening of the theeth
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| :* Radiografic findings
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| ::* Trabecular pattern changes
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| :* Thickening of the periodontal ligament
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| ::* Osteosclerosis regions which involves alveolar bone and the basilar bone
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| ::* Alveolar bone loss or resortion
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| * 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
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| * Stage 2: Patients with exposed nectrotic bone or fistula and signs of infection, usually symptomatic. Radiographic findings mentioned above can be found in patients with stage 2
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| * Stage 3: Patients with the characteristics of stage 2 plus one or more of the following conditions:
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| :* Pathilogic fracture
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| :* Osteolisis which reaches the sinus floor or the externar border of the madible
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| :* Orocutaneos fistula
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| :* Comunication with the maxillary sinus (oroantral) or the nose (oronasal)
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| ==Footnotes==
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| <div class="references-small"><references/></div>
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| ==External links== | | ==External links== |
| *[http://www.maxillofacialcenter.com/indexNICO.htm The Maxillofacial Center for Education & Research] | | *[http://www.maxillofacialcenter.com/indexNICO.htm The Maxillofacial Center for Education & Research] |
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| [[Category:Skeletal disorders]] | | [[Category:Skeletal disorders]] |
| [[Category:Dentistry]] | | [[Category:Dentistry]] |
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