Osteonecrosis of the jaw
Encyclopedia
Osteonecrosis of the jaw
(ONJ) is a severe bone
disease that affects the maxilla
and the mandible. 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.
Various treatment options have been explored, however severe cases of ONJ still require surgical removal of the affected bone. A thorough 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.
Osteonecrosis of the jaw is classified based on severity, number of lesions, and lesion size. Osteonecrosis of greater severity is given a higher grade, with asymptomatic ONJ designated as grade 1, and severe ONJ designated as grade 4.
ry bone through lesions in the gingiva
that do not heal. Pain, inflammation of the surrounding soft tissue, secondary infection or drainage may or may not be present. The development of lesions is most frequent after invasive dental procedures, such as extractions, but is also known to occur spontaneously. There may be no symptoms for weeks or months, until lesions with exposed bone appear. Lesions are more common on the mandible than the maxilla.
), 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.
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. 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
), 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.
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. 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. Intracolonic acetaldehyde may also be an important determinant of the blood acetaldehyde level and a possible hepatotoxin
. 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. 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
. 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. 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.
The effects of chronic gut dysbiosis 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.
The International Myeloma Foundation's web-based survey included 1203 respondents, 904 patients with myeloma and 299 with breast cancer and an estimate that after 36 months, osteonecrosis of the jaw had been diagnosed in 10% of 211 patients on zoledronate and 4% of 413 on pamidronate. A population based study in Germany identified more than 300 cases of osteonecrosis of the jaw, 97% occurring in cancer patients (on high-dose intravenous bisphosphonates), and 3 cases in 780,000 patients with osteoporosis for an incidence of 0.00038%. Time to event ranged from 23–39 months and 42–46 months with high dose intravenous and oral bisphosphonates. A prospective, population based study by Mavrokokki et al. estimated an incidence of osteonecrosis of the jaw of 1.15% for intravenous bisphosphonates and 0.04% for oral bisphosphonates. Most cases (73%) were precipitated by dental extractions. In contrast, safety studies sponsored by the manufacturer reported bisphosphonate-associated osteonecrosis of the jaw rates that were much lower.
Although the majority of cases of ONJ have occurred in cancer patients receiving high dose intravenous bisphosphonates, almost 800 cases have been reported in oral bisphosphonate users for osteoporosis or Pagets disease. In terms of severity most cases of ONJ in oral bisphosphonate users are stage 1-2 and tend to progress to resolution with conservative measures such as oral chlorhexidine rinses.
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.
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. Two classes of bisphosphonate
s 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, osteoclasts 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.
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 entails quite a bit more than just BMD. There are many other factors to consider.
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
. This process is 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 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 bisphosphonate-associated cases of ONJ. Recently, a proposal incorporating both the reduced bone turnover and the infectious elements of previous theories has been put forward, which cites the impaired functionality of affected macrophages as the dominant factor in the development of ONJ.
In a systematic review of cases of bisphosphonate-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. Patients taking dexamethasone
and other glucocorticoid
s are at increased risk.
Matrix metalloproteinase
2 may be a candidate gene for Bisphosphonate-associated osteonecrosis of the jaw, since it is the only gene known to be associated with bone abnormalities and atrial fibrillation, both of which are side effects of bisphosphonates.
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 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 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 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".
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.
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.
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 Hypoxia (medical)
and premature cell apoptosis
. The mean life-span of osteocytes has been estimated to be 15 years in cancellous bone, and 25 years in cortical bone. while the average lifespan of human osteoclasts is about 2 to 6 weeks and the average lifespan of osteoblast
s is approximately 3 months. In healthy bone these cells are constantly replaced by differentiation of bone marrow mesenchymal stem cells (MSC). 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, and altered osteoblastic function plays a role in ON of the femoral head. 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.
The rapidity with which premature cell death can occur depends on the cell type and the degree and duration of the anoxia
. 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. The death of bone does not alter its radiographic opacity nor its mineral density. Necrotic bone does not undergo resorption; therefore, it appears relatively more opaque.
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 decrease the radiodensity
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 histologically
and are characterized by extensive delamination or microcracking along cement lines as well as the formation of excessive cement lines. 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).
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 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. 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.
In patients with bisphosphonates-associated ONJ, the response to surgical treatment is usually poor. 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. Although an effective treatment for bisphosphonate-associated bone lesions has not yet been established, 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.
), as well as from popular medications containing mercury
, arsenic
or bismuth
, were reported in the literature.
This disease apparently did not often occur in individuals with good gingival health, and usually targeted the mandible first. 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.
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." 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. 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. 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.
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 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 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.
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.
Jaw
The jaw is any opposable articulated structure at the entrance of the mouth, typically used for grasping and manipulating food. The term jaws is also broadly applied to the whole of the structures constituting the vault of the mouth and serving to open and close it and is part of the body plan of...
(ONJ) is a severe bone
Bone
Bones are rigid organs that constitute part of the endoskeleton of vertebrates. They support, and protect the various organs of the body, produce red and white blood cells and store minerals. Bone tissue is a type of dense connective tissue...
disease that affects the maxilla
Maxilla
The maxilla is a fusion of two bones along the palatal fissure that form the upper jaw. This is similar to the mandible , which is also a fusion of two halves at the mental symphysis. Sometimes The maxilla (plural: maxillae) is a fusion of two bones along the palatal fissure that form the upper...
and the mandible. 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
Bisphosphonate
Bisphosphonates are a class of drugs that prevent the loss of bone mass, used to treat osteoporosis and similar diseases...
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
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
, remains uncertain.
Various treatment options have been explored, however severe cases of ONJ still require surgical removal of the affected bone. A thorough 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.
Classification
| Grade | Size (diameter*) |
|---|---|
| 1A | Single lesion, <0.5 cm |
| 1B | Multiple lesions, largest <0.5 cm |
| 2A | Single lesion <1.0 cm |
| 2B | Multiple lesions, largest <1.0 cm |
| 3A | Single lesion, ≤2.0 cm |
| 3B | Multiple lesions, largest ≤2.0 cm |
| 4A | Single lesion >2.0 cm |
| 4B | Multiple lesions, largest >2.0 cm |
| *Lesion size measured as the largest diameter | |
| Grade | Severity |
|---|---|
| 1 | Asymptomatic |
| 2 | Mild |
| 3 | Moderate |
| 4 | Severe |
Osteonecrosis of the jaw is classified based on severity, number of lesions, and lesion size. Osteonecrosis of greater severity is given a higher grade, with asymptomatic ONJ designated as grade 1, and severe ONJ designated as grade 4.
Signs and symptoms
The definitive symptom of ONJ is the exposure of mandibular or maxillaMaxilla
The maxilla is a fusion of two bones along the palatal fissure that form the upper jaw. This is similar to the mandible , which is also a fusion of two halves at the mental symphysis. Sometimes The maxilla (plural: maxillae) is a fusion of two bones along the palatal fissure that form the upper...
ry bone through lesions in the gingiva
Gingiva
The gingiva , or gums, consists of the mucosal tissue that lies over the mandible and maxilla inside the mouth.-General description:...
that do not heal. Pain, inflammation of the surrounding soft tissue, secondary infection or drainage may or may not be present. The development of lesions is most frequent after invasive dental procedures, such as extractions, but is also known to occur spontaneously. There may be no symptoms for weeks or months, until lesions with exposed bone appear. Lesions are more common on the mandible than the maxilla.
Toxic agents
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 (thrombosisThrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
), 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
Thrombophilia
Thrombophilia is an abnormality of blood coagulation that increases the risk of thrombosis . Such abnormalities can be identified in 50% of people who have an episode of thrombosis that was not provoked by other causes...
) and impaired bone healing.
Heavy metals
Heavy metals
A heavy metal is a member of a loosely-defined subset of elements that exhibit metallic properties. It mainly includes the transition metals, some metalloids, lanthanides, and actinides. Many different definitions have been proposed—some based on density, some on atomic number or atomic weight,...
such as lead
Lead
Lead is a main-group element in the carbon group with the symbol Pb and atomic number 82. Lead is a soft, malleable poor metal. It is also counted as one of the heavy metals. Metallic lead has a bluish-white color after being freshly cut, but it soon tarnishes to a dull grayish color when exposed...
and cadmium
Cadmium
Cadmium is a chemical element with the symbol Cd and atomic number 48. This soft, bluish-white metal is chemically similar to the two other stable metals in group 12, zinc and mercury. Similar to zinc, it prefers oxidation state +2 in most of its compounds and similar to mercury it shows a low...
have been implicated in osteoporosis. Cadmium and lead also promotes the synthesis of plasminogen activator inhibitor-1
Plasminogen activator inhibitor-1
Plasminogen activator inhibitor-1 also known as endothelial plasminogen activator inhibitor or serpin E1 is a protein that in humans is encoded by the SERPINE1 gene....
(PAI-1) which is the major inhibitor of fibrinolysis
Fibrinolysis
Fibrinolysis is a process that prevents blood clots from growing and becoming problematic. This process has two types: primary fibrinolysis and secondary fibrinolysis...
( the mechanism by which the body breaks down clots ) and shown to be a cause of hypofibrinolysis. 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
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
), bone cell damage and eventual cell death (apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
). 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.
Ethanol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
both from exogenous and endogenous sources and, its more toxic metabolite
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
, acetaldehyde
Acetaldehyde
Acetaldehyde is an organic chemical compound with the formula CH3CHO or MeCHO. It is one of the most important aldehydes, occurring widely in nature and being produced on a large scale industrially. Acetaldehyde occurs naturally in coffee, bread, and ripe fruit, and is produced by plants as part...
, 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. Ethanol has been shown to alter the epithelial barrier through ethanol oxidation into acetaldehyde by the colonic microflora and downstream mast cell
Mast cell
A mast cell is a resident cell of several types of tissues and contains many granules rich in histamine and heparin...
activation. Such alterations that remain for longer periods could result in excessive endotoxin
Endotoxin
Endotoxins are toxins associated with some Gram-negative bacteria. An "endotoxin" is a toxin that is a structural molecule of the bacteria that is recognized by the immune system.-Gram negative:...
passage into the vascular network. Intracolonic acetaldehyde may also be an important determinant of the blood acetaldehyde level and a possible hepatotoxin
Hepatotoxin
A hepatotoxin is a toxic chemical substance that damages the liver.It can be a side-effect of medication, or found naturally, as microcystins, or in laboratory environments....
. High serum antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
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. 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
Diverticulum
A diverticulum is medical or biological term for an outpouching of a hollow structure in the body. Depending upon which layers of the structure are involved, they are described as being either true or false....
(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
Sucrose
Sucrose is the organic compound commonly known as table sugar and sometimes called saccharose. A white, odorless, crystalline powder with a sweet taste, it is best known for its role in human nutrition. The molecule is a disaccharide composed of glucose and fructose with the molecular formula...
produced a marked increase in acetaldehyde and acetate
Acetate
An acetate is a derivative of acetic acid. This term includes salts and esters, as well as the anion found in solution. Most of the approximately 5 billion kilograms of acetic acid produced annually in industry are used in the production of acetates, which usually take the form of polymers. In...
in the portal venous blood
Venous blood
Venous blood is deoxygenated blood in the circulatory system. It runs in the systemic veins from the organs to the heart. Deoxygenated blood is then pumped by the heart to lungs via the pulmonary arteries, one of the few arteries in the body that carries deoxygenated blood .Venous blood is...
, 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
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
. 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. Many species of gut bacteria, yeast and fungal organisms such as Candida albicans
Candida albicans
Candida albicans is a diploid fungus that grows both as yeast and filamentous cells and a causal agent of opportunistic oral and genital infections in humans. Systemic fungal infections including those by C...
found in the human GI tract and involved in gut dysbiosis
Dysbiosis
Dysbiosis refers to a condition with microbial imbalances on or within the body. Dysbiosis is most prominent in the digestive tract or on the skin, but can also occur on any exposed surface or mucous membrane such as the vagina, lungs, nose, sinuses, ears, nails, or eyes...
, 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.
The effects of chronic gut dysbiosis 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
Vein
In the circulatory system, veins are blood vessels that carry blood towards the heart. Most veins carry deoxygenated blood from the tissues back to the heart; exceptions are the pulmonary and umbilical veins, both of which carry oxygenated blood to the heart...
in the superficial and communicating systems. Venous incompetence due to thrombi
Thrombus
A thrombus , or blood clot, is the final product of the blood coagulation step in hemostasis. It is achieved via the aggregation of platelets that form a platelet plug, and the activation of the humoral coagulation system...
and formation of thrombi favoured by the Virchow triad (venous stasis, hypercoagulability, endothelial trauma) also can cause CVI.
Bisphosphonates
The first three cases of bisphosphonate-associated osteonecrosis of the jaw were spontaneously reported to the FDA by an oral surgeon in 2002, with the toxicity being described as a potentially late toxicity of chemotherapy. In 2003 and 2004, three oral surgeons independently reported to the FDA information on 104 cancer patients with bisphosphonate-associated osteonecrosis of the jaw seen in their referral practices in California, Florida, and New York. These case series were published as peer-reviewed articles- two in the Journal of Oral and Maxillofacial Surgery and one in the Journal of Clinical Oncology. Subsequently, numerous instances of persons with this ADR were reported to the manufacturers and to the FDA. By December 2006, 3607 cases of persons with this ADR had been reported to the FDA and 2227 cases had been reported to the manufacturer of intravenous bisphosphonates.The International Myeloma Foundation's web-based survey included 1203 respondents, 904 patients with myeloma and 299 with breast cancer and an estimate that after 36 months, osteonecrosis of the jaw had been diagnosed in 10% of 211 patients on zoledronate and 4% of 413 on pamidronate. A population based study in Germany identified more than 300 cases of osteonecrosis of the jaw, 97% occurring in cancer patients (on high-dose intravenous bisphosphonates), and 3 cases in 780,000 patients with osteoporosis for an incidence of 0.00038%. Time to event ranged from 23–39 months and 42–46 months with high dose intravenous and oral bisphosphonates. A prospective, population based study by Mavrokokki et al. estimated an incidence of osteonecrosis of the jaw of 1.15% for intravenous bisphosphonates and 0.04% for oral bisphosphonates. Most cases (73%) were precipitated by dental extractions. In contrast, safety studies sponsored by the manufacturer reported bisphosphonate-associated osteonecrosis of the jaw rates that were much lower.
Although the majority of cases of ONJ have occurred in cancer patients receiving high dose intravenous bisphosphonates, almost 800 cases have been reported in oral bisphosphonate users for osteoporosis or Pagets disease. In terms of severity most cases of ONJ in oral bisphosphonate users are stage 1-2 and tend to progress to resolution with conservative measures such as oral chlorhexidine rinses.
In the past few years, thousands of cases of ONJ in patients on bisphosphonate
Bisphosphonate
Bisphosphonates are a class of drugs that prevent the loss of bone mass, used to treat osteoporosis and similar diseases...
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.
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. Two classes of bisphosphonate
Bisphosphonate
Bisphosphonates are a class of drugs that prevent the loss of bone mass, used to treat osteoporosis and similar diseases...
s are presently prescribed:
- Non-nitrogenNitrogenNitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...
containing bisphosphonates such as etidronateEtidronic acidEtidronic acid or 1-hydroxyethane 1,1-diphosphonic acid is a bisphosphonate used in detergents, water treatment, cosmetics and pharmaceutical treatment....
(Didronel, Procter & Gamble PharmaceuticalsProcter & GambleProcter & Gamble is a Fortune 500 American multinational corporation headquartered in downtown Cincinnati, Ohio and manufactures a wide range of consumer goods....
) - Nitrogen containing such as alendronateAlendronateAlendronic acid or alendronate sodium — sold as Fosamax by Merck — is a bisphosphonate drug used for osteoporosis and several other bone diseases. It is marketed alone as well as in combination with vitamin D . Merck's U.S...
(Fosamax, MerckMerck & Co.Merck & Co., Inc. , also known as Merck Sharp & Dohme or MSD outside the United States and Canada, is one of the largest pharmaceutical companies in the world. The Merck headquarters is located in Whitehouse Station, New Jersey, an unincorporated area in Readington Township...
), pamidronatePamidronic acidPamidronic acid or pamidronate disodium , pamidronate disodium pentahydrate is a nitrogen containing bisphosphonate, used to prevent osteoporosis. It is marketed by Novartis under the brand name Aredia.-Uses:...
(Aredia, NovartisNovartisNovartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...
), zoledronateZoledronateZoledronic acid or zoledronate is a bisphosphonate. Zometa is used to prevent skeletal fractures in patients with cancers such as multiple myeloma and prostate cancer, as well as for treating osteoporosis...
(Zometa, Novartis), risedronateRisedronateRisedronic acid or risedronate sodium is a bisphosphonate used to strengthen bone, treat or prevent osteoporosis, and treat Paget's disease of bone. It is produced and marketed by Warner Chilcott, Sanofi-Aventis, and in Japan by Takeda under the trade names Actonel, Atelvia, and Benet...
(Actonel, Procter & Gamble) and ibandronateIbandronic acidIbandronic acid or ibandronate sodium , marketed under the trade names Boniva, Bondronat and Bonviva, is a potent bisphosphonate drug used in the prevention and treatment of osteoporosis....
(Boniva, Roche LaboratoriesHoffmann-La RocheF. Hoffmann-La Roche Ltd. is a Swiss global health-care company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on the SIX Swiss Exchange....
).
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, osteoclasts 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.
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 entails quite a bit more than just BMD. There are many other factors to consider.
In healthy bone tissue there is a homeostasis
Homeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
between bone resorption
Bone resorption
Bone resorption is the process by which osteoclasts break down bone and release the minerals, resulting in a transfer of calcium from bone fluid to the blood....
and bone apposition. Diseased or damaged bone is resorbed through the osteoclast
Osteoclast
An osteoclast is a type of bone cell that removes bone tissue by removing its mineralized matrix and breaking up the organic bone . This process is known as bone resorption. Osteoclasts were discovered by Kolliker in 1873...
s mediated process while osteoblast
Osteoblast
Osteoblasts are mononucleate cells that are responsible for bone formation; in essence, osteoblasts are specialized fibroblasts that in addition to fibroblastic products, express bone sialoprotein and osteocalcin.Osteoblasts produce a matrix of osteoid, which is composed mainly of Type I collagen...
s form new bone to replace it, thus maintaining healthy bone density
Bone density
Bone density is a medical term normally referring to the amount of mineral matter per square centimeter of bones. Bone density is used in clinical medicine as an indirect indicator of osteoporosis and fracture risk.This medical bone density is not the true physical "density" of the bone, which...
. This process is 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 ischaemic-damaged bone will be left in situ
In situ
In situ is a Latin phrase which translated literally as 'In position'. It is used in many different contexts.-Aerospace:In the aerospace industry, equipment on board aircraft must be tested in situ, or in place, to confirm everything functions properly as a system. Individually, each piece may...
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 bisphosphonate-associated cases of ONJ. Recently, a proposal incorporating both the reduced bone turnover and the infectious elements of previous theories has been put forward, which cites the impaired functionality of affected macrophages as the dominant factor in the development of ONJ.
In a systematic review of cases of bisphosphonate-associated ONJ up to 2006, it was concluded that the mandible is more commonly affected than the maxilla
Maxilla
The maxilla is a fusion of two bones along the palatal fissure that form the upper jaw. This is similar to the mandible , which is also a fusion of two halves at the mental symphysis. Sometimes The maxilla (plural: maxillae) is a fusion of two bones along the palatal fissure that form the upper...
(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
Alendronate
Alendronic acid or alendronate sodium — sold as Fosamax by Merck — is a bisphosphonate drug used for osteoporosis and several other bone diseases. It is marketed alone as well as in combination with vitamin D . Merck's U.S...
(Fosamax), for osteoporosis is uncertain and warrants careful monitoring. Patients taking dexamethasone
Dexamethasone
Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant...
and other glucocorticoid
Glucocorticoid
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
s are at increased risk.
Matrix metalloproteinase
Matrix metalloproteinase
Matrix metalloproteinases are zinc-dependent endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs belong to a larger family of proteases known as the metzincin superfamily....
2 may be a candidate gene for Bisphosphonate-associated osteonecrosis of the jaw, since it is the only gene known to be associated with bone abnormalities and atrial fibrillation, both of which are side effects of bisphosphonates.
Histopathological alterations
Persons with ONJ may have either necrotic bone or bone marrowBone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
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 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 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 osteocyte
Osteocyte
An osteocyte, a star-shaped cell, is the most abundant cell found in compact bone. Cells contain a nucleus and a thin ring of cytoplasm. When osteoblasts become trapped in the matrix they secrete, they become osteocytes...
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
Corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...
-induced osteonecrosis, and the osteomyelitis of caisson (deep-sea diver’s) disease".
In the cancellous portion of femoral head it is not uncommon to find trabeculae with apparently intact osteocyte
Osteocyte
An osteocyte, a star-shaped cell, is the most abundant cell found in compact bone. Cells contain a nucleus and a thin ring of cytoplasm. When osteoblasts become trapped in the matrix they secrete, they become osteocytes...
s which seem to be "alive" but are no longer synthetizing collagen
Collagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
. This appears to be consistent with the findings in alveolar cancellous bone.
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
Trigeminal nerve
The trigeminal nerve contains both sensory and motor fibres. It is responsible for sensation in the face and certain motor functions such as biting, chewing, and swallowing. Sensory information from the face and body is processed by parallel pathways in the central nervous system...
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
Neuralgia-inducing cavitational osteonecrosis
Neuralgia-inducing cavitational osteonecrosis refers to presence of cavitations in jaw bones in conjunction with chronic facial neuralgia. The concept implies direct and causal relationship between the bone pathology and pain itself. Pain in this setting is commonly described as atypical facial...
, 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
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
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
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
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
Biopsy
A biopsy is a medical test involving sampling of cells or tissues for examination. It is the medical removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...
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
Osteomyelitis
Osteomyelitis simply means an infection of the bone or bone marrow...
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
Smallpox
Smallpox was an infectious disease unique to humans, caused by either of two virus variants, Variola major and Variola minor. The disease is also known by the Latin names Variola or Variola vera, which is a derivative of the Latin varius, meaning "spotted", or varus, meaning "pimple"...
virus (no longer existent in the wild) can produce osteonecrosis.
The effects of persistent ischaemia on bone cells
Cortical boneCortical bone
Cortical bone, synonymous with compact bone, is one of the two types of osseous tissue that form bones. Cortical bone facilitates bone's main functions: to support the whole body, protect organs, provide levers for movement, and store and release chemical elements, mainly calcium. As its name...
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 Hypoxia (medical)
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
and premature cell apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. The mean life-span of osteocytes has been estimated to be 15 years in cancellous bone, and 25 years in cortical bone. while the average lifespan of human osteoclasts is about 2 to 6 weeks and the average lifespan of osteoblast
Osteoblast
Osteoblasts are mononucleate cells that are responsible for bone formation; in essence, osteoblasts are specialized fibroblasts that in addition to fibroblastic products, express bone sialoprotein and osteocalcin.Osteoblasts produce a matrix of osteoid, which is composed mainly of Type I collagen...
s is approximately 3 months. In healthy bone these cells are constantly replaced by differentiation of bone marrow mesenchymal stem cells (MSC). 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, and altered osteoblastic function plays a role in ON of the femoral head. 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.
The rapidity with which premature cell death can occur depends on the cell type and the degree and duration of the anoxia
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
. haematopoietic cells
Pluripotential hemopoietic stem cell
Hematopoietic stem cells , also spelled Hæmatopoietic stem cells, are multipotent stem cells that give rise to all the blood cell types from the myeloid , and lymphoid lineages...
, 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. The death of bone does not alter its radiographic opacity nor its mineral density. Necrotic bone does not undergo resorption; therefore, it appears relatively more opaque.
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 decrease the radiodensity
Radiodensity
Radiodensity refers to the relative inability of electromagnetic radiation, particularly X-rays, to pass through a particular material. Radiolucency indicates greater transparency or "transradiancy" to X-ray photons...
of the bone; therefore, the first radiographic evidence of previous osteonecrosis may be patchy sclerosis
Sclerosis (medicine)
In medicine, sclerosis refers to the stiffening of a structure, usually caused by a replacement of the normal organ-specific tissue with connective tissue.Types include:...
resulting from repair. Under unfavorable conditions repeated attempts at repair in ischaemic conditions can be seen histologically
Histology
Histology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining cells and tissues commonly by sectioning and staining; followed by examination under a light microscope or electron microscope...
and are characterized by extensive delamination or microcracking along cement lines as well as the formation of excessive cement lines. 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).
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 nutrientNutrient
A nutrient is a chemical that an organism needs to live and grow or a substance used in an organism's metabolism which must be taken in from its environment. They are used to build and repair tissues, regulate body processes and are converted to and used as energy...
absorption and metabolic wastes elimination through a healthy gastro-intestinal function, effective hepatic metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
of toxicants such as exogenous estrogens, endogenous acetaldehyde and heavy metals, a balanced diet, healthy lifestyle, assessment of factors related to potential coagulopathies
Coagulopathy
Coagulopathy is a condition in which the blood’s ability to clot is impaired. This condition can cause prolonged or excessive bleeding, which may occur spontaneously or following an injury or medical and dental procedures.The normal clotting process depends on the interplay of various proteins in...
, and treatment of periodontal diseases and other oral and dental infections.
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
Curettage
Curettage, in medical procedures, is the use of a curette to remove tissue by scraping or scooping.Curettages are also a declining method of abortion. It has been replaced by vacuum aspiration over the last decade....
and decortication, will eliminate the problem (and the pain) in 74% of patients with jaw involvement. 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.
In patients with bisphosphonates-associated ONJ, the response to surgical treatment is usually poor. 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. Although an effective treatment for bisphosphonate-associated bone lesions has not yet been established, 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.
History
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 jawPhossy jaw
Phossy jaw, formally phosphorus necrosis of the jaw, is an occupational disease of those who work with white phosphorus, also known as yellow phosphorus, without proper safeguards. It was most commonly seen in workers in the match industry in the 19th and early 20th century...
), as well as from popular medications containing mercury
Mercury (element)
Mercury is a chemical element with the symbol Hg and atomic number 80. It is also known as quicksilver or hydrargyrum...
, arsenic
Arsenic
Arsenic is a chemical element with the symbol As, atomic number 33 and relative atomic mass 74.92. Arsenic occurs in many minerals, usually in conjunction with sulfur and metals, and also as a pure elemental crystal. It was first documented by Albertus Magnus in 1250.Arsenic is a metalloid...
or bismuth
Bismuth
Bismuth is a chemical element with symbol Bi and atomic number 83. Bismuth, a trivalent poor metal, chemically resembles arsenic and antimony. Elemental bismuth may occur naturally uncombined, although its sulfide and oxide form important commercial ores. The free element is 86% as dense as lead...
, were reported in the literature.
This disease apparently did not often occur in individuals with good gingival health, and usually targeted the mandible first. 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.
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." 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
Radiography
Radiography is the use of X-rays to view a non-uniformly composed material such as the human body. By using the physical properties of the ray an image can be developed which displays areas of different density and composition....
, radionuclide
Radionuclide
A radionuclide is an atom with an unstable nucleus, which is a nucleus characterized by excess energy available to be imparted either to a newly created radiation particle within the nucleus or to an atomic electron. The radionuclide, in this process, undergoes radioactive decay, and emits gamma...
studies, CT scans, and magnetic resonance imaging
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
(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. 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. 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.
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
Pathophysiology
Pathophysiology is the study of the changes of normal mechanical, physical, and biochemical functions, either caused by a disease, or resulting from an abnormal syndrome...
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
Myelofibrosis
Myelofibrosis, also known as myeloid metaplasia, chronic idiopathic myelofibrosis, osteomyelofibrosis and primary myelofibrosis is a disorder of the bone marrow...
as a result of hypoxia and gradual loss of mineral bone density
Bone density
Bone density is a medical term normally referring to the amount of mineral matter per square centimeter of bones. Bone density is used in clinical medicine as an indirect indicator of osteoporosis and fracture risk.This medical bone density is not the true physical "density" of the bone, which...
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 vasoconstrictors, such as epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...
, and trauma can add further complications to the disease process and chronic non-pus forming bone infection osteomyelitis
Osteomyelitis
Osteomyelitis simply means an infection of the bone or bone marrow...
can also be associated with ONJ.
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.