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 (thrombosis), a known cause of bone infarct and ischaemia. Exogenous estrogens, also called hormonal disruptors, have 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 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 blood 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. Bisphosphonates The first three reported cases of bisphosphonate-associated<unk>  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<unk>  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 adverse drug reaction were reported to the manufacturers and to the FDA. By December 2006, 3607 cases of people with this ADR had been reported to the FDA and 2227 cases had been reported to the manufacturer of intravenous bisphosphonates. Rise in reported cases of<unk>  from 1988 through 2007 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,<unk>  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<unk> , 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<unk>  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<unk>  rates that were much lower. Although the majority of cases of<unk>  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<unk>  in oral bisphosphonate users are stage 1–2 and tend to progress to resolution with conservative measures such as oral chlorhexidine rinses. Owing to prolonged embedding of bisphosphonate drugs in the bone tissues, the risk for BRONJ is high even after stopping the administration of the medication for several years. 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 ossification. Diseased or damaged bone is resorbed through the osteoclasts mediated process while osteoblasts 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 causes and contributing factors, and bisphosphonates do not address these factors at all. In 2011, a proposal incorporating both the reduced bone turnover and the infectious elements of previous theories has been put forward. It cites the impaired functionality of affected macrophages as the dominant factor in the development of<unk> . In a systematic review of cases of bisphosphonate-associated<unk>  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<unk> , 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 glucocorticoids are at increased risk. Matrix metalloproteinase 2 may be a candidate gene for bisphosphonate-associated<unk> , since it is the only gene known to be associated with bone abnormalities and atrial fibrillation, both of which are side effects of bisphosphonates.
Osteonecrosis of the jaw
Osteomyelitis of the jaws
Alveolar osteitis
Acroosteolysis
Osteomyelitis
Osteoradionecrosis
Medication-related osteonecrosis of the jaw
Osteolysis