Osteonecrosis of the jaw pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Pathophysiology

Histopathological Alterations

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

Under ischemic conditions numerous pathological changes in the bone marrow and trabeculae of oral cancellous bone have been documented. Microscopically, areas of "apparent fatty degeneration and/or necrosis, often with pooled fat from destroyed adipose cells (oil cysts) and with marrow fibrosis (reticular fatty degeneration)" are seen. These changes are present even if "most bony trabeculae appear at first glance viable, mature and otherwise normal, but closer inspection demonstrates focal loss of osteocytes and variable micro cracking (splitting along natural cleavage planes). The microscopic features are similar to those of ischemic or aseptic osteonecrosis of long bones, corticosteroid-induced osteonecrosis, and the osteomyelitis of caisson (deep-sea diver’s) disease".[1]

In the cancellous portion of femoral head it is not uncommon to find trabeculae with apparently intact osteocytes which seem to be "alive" but are no longer synthetizing collagen. This appears to be consistent with the findings in alveolar cancellous bone.[2]

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

The Effects of Persistent Ischemia on Bone Cells

Cortical bone is well vascularized by the surrounding soft tissues thus less susceptible to ischemic damage. Cancellous bone, with its mesh like structure and spaces filled with marrow tissue is more susceptible to damage by bone infarcts, leading to anoxia and premature cell apoptosis.[3][4][5][6] The mean life-span of osteocytes has been estimated to be 15 years in cancellous bone,[7] and 25 years in cortical bone.[8] while the average lifespan of human osteoclasts is about 2 to 6 weeks and the average lifespan of osteoblasts is approximately 3 months.[9] In healthy bone these cells are constantly replaced by differentiation of bone marrow mesenchymal stem cells (MSC).[10] 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,[11][12] and altered osteoblastic function plays a role in ON of the femoral head.[13] If these results are extrapolated to ONJ the altered differentiation potential of bone marrow mesenchymal stem cells (MSC) combined with the altered osteoblastic activity and premature death of existing bone cells would explain the failed attempts at repair seen in ischemic-damaged cancellous bone tissue in ONJ.

The rapidity with which premature cell death can occur depends on the cell type and the degree and duration of the anoxia. Hematopoietic cells , in bone marrow, are sensitive to anoxia and are the first to die after reduction or removal of the blood supply. In anoxic conditions they usually die within 12 hours. Experimental evidence suggests that bone cells composed of osteocytes, osteoclasts, and osteoblasts die within 12-48 hours, and marrow fat cells die within 120 hours.[14] The death of bone does not alter its radiographic opacity nor it’s mineral density. Necrotic bone does not undergo resorption; therefore, it appears relatively more opaque.

Attempts at repair of ischemic-damaged bone will usual occur in 2 phases. First, when dead bone abuts live marrow, capillaries and undifferentiated mesenchymal cells grow into the dead marrow spaces, while macrophages degrade dead cellular and fat debris. Second, mesenchymal cells differentiate into osteoblasts or fibroblasts. Under favorable conditions, layers of new bone form on the surface of dead spongy trabeculae. If sufficiently thickened, these layers may increase the radiopacity of the bone; therefore, the first radiographic evidence of previous osteonecrosis may be patchy sclerosis resulting from repair. Under unfavorable conditions repeated attempts at repair in ischemic conditions can be seen histologically and are characterized by extensive delamination or microcracking along cement lines as well as the formation of excessive cement lines.[15] Ultimate failure of repair mechanisms due to persistent and repeated ischemic events is manifested as trabecular fractures that occur in the dead bone under functional load. Later followed by cracks and fissures leading to structural collapse of the area involved (osteocavitation).[14]

Other Contributing Factors

Other factors such as toxicants can adversely impact bone cells. Infections, chronic or acute, can affect blood flow by inducing platelet activation and aggregation, contributing to a localized state of excess coagulability (hypercoagulability) that may contribute to clot formation (thrombosis), a known cause of bone infarct and ischemia. Exogenous estrogens, also called hormonal disruptors, have also been linked with an increased tendency to clot (thrombophilia) and impaired bone healing.[16]

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.[17] Persistent blot clots can lead to congestive blood flow (hyperemia) in bone marrow, impaired blood flow and ischemia in bone tissue resulting in lack of oxygen (hypoxia), bone cell damage and eventual cell death (apoptosis). Of significance is the fact that the average concentration of cadmium in human bones in the 20th century has increased to about 10 times above the pre-industrial level.[18]

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.[19] 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.[20] Intracolonic acetaldehyde may also be an important determinant of the blood acetaldehyde level and a possible hepatotoxin.[21] 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.[22] 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.[23] 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.[24] 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.[25][26]

The effects of chronic gut dybiosis and long term exposure to low levels of endogenous acetaldehyde on bone tissue and hepatic function is not yet fully understood. However Cordts et al suggested in 2001 that gut dysbiosis (as indicated by stool yeast) and hepatic detoxification challenge pathway exhaustion may lead to subclinical, systemic inflammation and chronic venous insufficiency (CVI). CVI is a pathological condition caused either by the congenital absence of or damage to venous valves in the superficial and communicating systems. Venous incompetence due to thrombi and formation of thrombi favoured by the Virchow triad (venous stasis, hypercoagulability, endothelial trauma) also can cause CVI.[27]

References

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