Healthy alveolar bone is an essential component of an intact dentition. Chronic periodontitis, which leads to progressive destruction of alveolar bone, is the most common cause of tooth loss in the over fifties.1,2 Once the teeth are lost the alveolar bone disappears. Alveolar bone is subject to a number of local and systemic conditions which will result in its progressive loss. Consideration of the complex interplay of most of these factors is beyond the scope of this paper but is covered elsewhere in the supplement.3 An important systemic factor is generalized bone diseases and their treatment, with some, such as osteoporosis, being very common.4
Five per cent of all Australians suffer from osteoporosis and the involvement will increase with age, particularly in females. It is estimated that over 50 per cent of all females over the age of 60 suffer osteoporosis. A number of preventive and therapeutic strategies exist to medically manage osteoporosis.5 A key drug group involved is the bisphosphonates which are effective in stabilizing osteoporosis and reducing the risk of low impact fractures in the elderly. An unfortunate complication of these drugs is the development of osteonecrosis of the jaws (ONJ) particularly following alveolar bone invasive dental treatment. Accordingly, given the large number of patients being treated for osteoporosis, there is a strong likelihood of dentists and periodontists treating a patient at risk for this complication.
This review examines the key elements of the interaction between alveolar bone, the bisphosphonates and ONJ.
Alveolar bone exists to support the teeth. Its structure varies between individuals and generally it gets denser with age.6 Broadly, there is a dense bone wall near the gingivae and then the middle portion of the tooth root. There are larger marrow spaces near the tooth apex.7 The alveolar bone walls at the attachment of the periodontal membrane have a cribiform structure with open channels. The bone structure follows that of bone structure throughout the body with cortical bone containing osteons and Haversian systems. New bone is formed in a lamellar structure by osteoblasts with the osteocytes being incorporated within the bone. Older bone, or bone in the path of erupting or moving teeth is resorbed by osteoclasts. In keeping with all bone in the body, alveolar bone is a dynamic structure with the bone constantly remodelling and adapting to functional needs.
The key question however, is whether alveolar bone is exactly the same as the long bones or whether it is subtly different. Alveolar bone develops as a membrane bone whereas the limbs and vertebrae develop as endochondral bones. The mandible is of neural crest origin whereas the limbs and vertebral column are of mesodermal origin.8 There are minor phenotypic differences between osteoblasts depending on their site of origin and anatomical location, which can be demonstrated biochemically.9 Membrane bone osteoblasts also have an increased rate of cell division as compared to iliac crest osteoblasts.10
Osteoclasts are derived from mononuclear precursor cells which migrate from the bone marrow via the vasculature to the bone site. Their function is dictated largely by interaction with the osteoblasts in the area. There are biochemical differences between osteoclasts of membrane bone origin and long bone origin.11 There are also differences in behaviour between giant cell tumours of the jaws and of the long bones.12 The overall rate of turnover of alveolar bone is 10 times greater than that of the long bones.13
Thus, there are key differences in behaviour between the alveolar bones and the long bones. This is summarized in Table 1.
|Tissue||Long bone||Alveolar bone||Bisphosphonate effect on alveolar bone|
|Osteoblasts9,10||Divide slowly||Divide faster|
|Increased bone depression|
|Osteocytes8||Respond slowly to mechanical stress||Respond faster to mechanical stress||Increased bone depression|
|Osteoclasts11,12||Site dependent differences|
Some osteoblast fusion
Less resorptive activity
Giant cell tumours rarer but aggressive
|Site dependent differences|
? more osteoblast fusion
Greater resorptive activity
Giant cell tumours common and less aggressive
|Increased bone depression|
|Bone turnover13||Slow||x10 faster than long bones||Increased bone depression|
|Protection from injury||Deeply covered in soft tissue|
|Mucoperiosteal cover only|
|Alveolus more prone to exposure to bacterial contamination|
|Angiogenesis32,33||Low vascular||High vascular||Decreased healing capacity|
|Keratinocytes34||Not involved in bone healing||Involved in mucoperiosteal healing||Decreased healing capacity|
Systemic bone diseases and alveolar bone
The most common bone disease is osteoporosis.4,5 This occurs most frequently in post-menopausal females but also occurs in men and younger individuals on steroids.14 It is a chronic progressive disorder in which bone resorption exceeds formation. The resulting decreased bone mass and loss of microarchitecture results in increased susceptibility to bone fractures. The bone fractures may be spontaneous or low impact types.15 There are community impacts with resulting financial burdens for the state and families as well as the affected individuals. For example, females over the age of 70 years with an osteoporotic hip fracture have a 25 per cent chance of being dead within 12 months.
Osteoporosis is primarily diagnosed by a bone mineral density (BMD) test which compares the bone density of the lumbar vertebrae and hip to standard values obtained from young white American females. One standard deviation from the mean is normal, two standard deviations is osteopenia and three standard deviations is osteoporosis. The presence or absence of fractures also contributes to the diagnostic stage.16 BMD is not a sensitive test and requires a minimum of 12 months between tests to show effect. A serum assay for the presence of C-telopeptide fragments of collagen-I which are generated by osteoclastic activity (CTX test or serum cross laps assay) is a measure of bone turnover which can also be employed, particularly to show the effects of the hormones and the bisphosphonates on bones.17 It will show changes within six weeks with higher activity during active bone loss. Prevention and management of osteoporosis is multifactorial and has recently been reviewed in Australia by the National Prescribing Service.5 A key element is the bisphosphonates which are a group of anti-resorptive drugs. Oral bisphosphonates, most commonly alendronate and risedronate, are extensively used with over 300 000 prescriptions issued for oral bisphosphonates in 2007.
Most bone physicians are of the view that “osteoporosis does not occur in the head and neck”. This is clinically true as spontaneous or low impact fractures of the facial bones do not present to bone physicians. Maxillofacial surgeons usually ascribe facial fractures in the elderly to general frailty, poor balance and advanced alveolar resorbtion rather than primarily to osteoporosis. However, a number of studies have looked at the associations between osteoporosis and periodontal disease. These show generalized osteoporosis is associated with tooth loss in otherwise healthy post-menopausal females.18–20 However, a reciprocal study which examined tooth loss as a predictor of osteoporosis, found no direct association.21 Similarly, generalized osteoporosis is associated with alveolar resorption in the edentulous.22
Paget’s disease is a common metabolic disease of bone which mainly affects the middle-aged and elderly. It is mostly asymptomatic but may present as pain, bone enlargement and low impact fractures. Imaging, particularly by CT, is valuable with bone scans showing areas of activity. A CTX test will show high levels when active resorption is occurring. Oral or intravenous bisphosphonates are useful for controlling the symptoms.
Paget’s disease involves the jaws in approximately 20 per cent of advanced cases, mainly the maxilla, sometimes the maxilla and mandible and only occasionally the mandible alone. The main feature is alveolar enlargement with spreading of the teeth in dentate individuals and broader large alveolar processes in the edentulous, where the patient’s dentures no longer fit. Radiographically, there is a mixed radiopacity and radiolucency or “cotton wool” appearance. Histologically, there is a wide variation ranging from dense inactive cortical bone to rapid bone turnover and vascularization. A typical “mosaic bone” pattern is seen in both the alveolus and other bony sites reflecting the histological changes caused by the increased turnover.23
Malignancies which metastasize to the bones such as the adenocarcinomas of the breast, prostate and gut will result in osteolytic activity, both from direct effects of invading malignant cells and from paracrine secretion of factors which activate osteoclasts. These can be imaged radiographically, by a CT or bone scan. The CTX level is high. Treatment is by chemotherapeutic agents, steroids and intravenous bisphosphonates. Multiple myeloma is a primary malignant neoplasm of bone marrow. The tumour consists of neoplastic plasma cells which destroy the bones, particularly of the axial skeleton. In addition, there is increased bone resorption from paracrine secretion of cytokines such as IL-6. The CTX level is high. Treatment is by chemotherapeutic drugs, steroids, intravenous bisphosphonates, localized radiotherapy and bone marrow transplants.
Metastatic tumours to the bones and multiple myeloma do not primarily involve the alveolus but settle in the marrow, commonly near the mandibular angle.23 Metastasis may enlarge to involve the alveolus, hence any loosening of teeth, mandibular sensory change and radiographic bone changes, particularly in patients with known adenocarcinomas, must be treated with suspicion that they are a metastatic deposit. It is uncommon that the jaws are involved alone with widespread bone involvement being the norm.
In brief, the nitrogen containing agents come as both oral and intravenous preparations. The most common oral preparations are alendronate (Fosamax) and risedronate (Actonel) which are primarily used for osteoporosis. These are usually taken weekly. The intravenous preparations, pamidronate (Aredia, Pamisol) and zoledronate (Zometa, Aclasta) are considerably more potent and are used mainly to manage bony metastatic disease and multiple myeloma. These are usually administered monthly. Both oral and intravenous agents are used as indicated for Paget’s disease. Intravenous bisphosphonates are used in a single dose to reverse hypercalcaemia, usually secondary to bone metastatic malignancy, hyperparathyroidism or the humoral effects of neoplasia. Recently, an intravenous form of zoledronic acid (Aclasta) has been introduced to the Australian market for the treatment of osteoporosis, and is now approved as an annual treatment.
The mechanisms of action of the bisphosphonates in bone metabolism are complex and multifactorial. They act almost exclusively on bone because of their specific affinity to bone where they are deposited in newly formed bone and close to osteoclasts. Although the time in the circulation is short, 30 to 180 minutes, once incorporated into bone they can persist for up to 10 years.26,27 Different types of bisphosphonates have differing affinities to bone with the rank order from greatest to least being zoledronate, alendronate, ibandronate, risedronate, etidronate and clodronate.28
Once in the bone they directly affect mononuclear activity, which is the parent cell of osteoclasts, they disrupt osteoclast mediated, bone resorption and increase apoptosis of osteoclasts.29,30 This in turn reduces bone deposition by osteoblasts.31 The net effect of this is to reduce bone resorption and bone turnover.
Angiogenesis is reduced by depression of blood flow and a marked decrease in vascular endothelial growth factor.32,33 Epithelial keratinocytes are also inhibited.34 The net effect of these actions is to reduce healing capacity.
The bisphosphonates were extensively tested before they were released onto the market with a wide margin of safety. However, in 2003 the first reports of the severe complication of osteonecrosis of the jaws was reported in America31,35–37 and Australia.38 More recently, a wide range of other complications including atrial fibrillation,39 severe and incapacitating bone pain40 and spontaneous femur fracture41 have been reported.
Bisphosphonate associated osteonecrosis of the jaws
Bisphosphonate associated osteonecrosis of the jaws (ONJ) has been reviewed in detail in the Medications in Dentistry supplement to the Australian Dental Journal.24 Since the initial descriptions of the condition, and more detailed reviews, there have been numerous reports of ONJ with the condition becoming increasingly well characterized. Usually, ONJ commences in the alveolar bone and then spreads into the jaws. By definition, ONJ is an area of exposed bone in the jaws of more than eight weeks duration. Important exclusions are presence of malignancy at the site and that the jaws have not been irradiated.42 The condition is most common in elderly, medically compromised patients on intravenous bisphosphonates but may occur in medically well patients on oral bisphosphonates. The key concern with ONJ is that once established it is usually longstanding, debilitating to the patient and refractory to treatment.43
When ONJ was first described in 2003, it was thought to be rare, an avascular necrosis of jaw bone which related to the underlying bone disease and other jaw bone necroses and somewhat indirectly to the bisphosphonates. Considerable research both clinical and basic since that time has focused on the true nature of ONJ.
Firstly, it is not rare, although compared to the very large numbers of patients on the bisphosphonates, it is not common either. There is a difference between the relatively small number of patients on intravenous bisphosphonates for malignancy where the risk is high and the very large numbers of patients on oral bisphosphonates where the risk is much lower. However, a small percentage of a very large number is a large number of affected individuals. Estimates of risk for the oral bisphosphonate vary from 1 in 10 000 to 1 in 100 000.42 However, both of these estimates are overall population estimates and don’t take into account the role of trigger factors. The most common trigger is a dental extraction and if this is taken into account then the risk increases to the order of 1 in 1000.44 The more detailed the capture of all cases of ONJ, then the higher the risk. In South Australia, where it is straightforward to capture all cases of ONJ then the risk of ONJ was of the order of 1 in 296 for patients having an extraction.44 In more recent studies with good capture, the overall risk was reported as 0.03 per cent or 1 in 3333 but this did not factor in the extraction risk.45 The extraction risk was factored into a San Diego study which had the highest reported rate at 4 per cent to date.46 Thus, for patients on oral bisphosphonates having dental extractions there is an identifiable risk, probably of the order of 1 in 300 which given the very large number of patients on oral bisphosphonates, means large numbers of ONJ sufferers.
With intravenous bisphosphonates though there is less discussion of the risk, it is agreed it is high. Estimate range is 1 to 10 per cent of dental extractions for patients on intravenous bisphosphonates.44 Once established the condition is usually longstanding and refractory.
The triggers for the development of ONJ are sometimes spontaneous but usually involve bone invasive procedures, particularly tooth extractions. The various published estimates of the percentage involvement of trigger factors are presented in Table 2. There is controversy as to the involvement of periodontal factors and it is difficult to determine whether it is the presence of periodontal disease or the effect of bone-exposing periodontal treatment, such as periodontal surgery. In the authors’ experience, periodontal disease was commonly present but this was the indication for extractions, which was the trigger.47 We have not seen any cases initiated by periodontal treatment such as scaling or root planing but have seen cases relating to dental implants.48
|Author||Spontaneous||Extraction||Advance periodontitis||Periodontal flap surgery||Implants||Endodontics||Dentures|
|Marx et al.67|
n = 119
|Carter, Doeke, Goss68|
n = 5
n = 11
|Mavrokokki et al.44|
n = 91
The nature of ONJ is now considered not an area of avascular necrosis nor an osteomyelitis but an inability of the alveolar bone to respond to injury. When a tooth is extracted there is a deep and narrow wound in the bone which is contaminated by bacterially infested saliva. Normally, the local immune reaction and the bone react swiftly to repair the wound. Macrophages and other inflammatory cells counter the bacterial contamination, osteoclasts remove any damaged bone, osteoblasts form new bone and the epithelium regrows over the wound. The bisphosphonates inhibit all of these functions with a greater effect on alveolar bone (with its high bone turnover, increased vascularity, more susceptible osteoclasts, osteoblasts, mononuclear cells and keratinocytes) as compared to the endochondral bones. This increased effect in the alveolus has been neatly encapsulated in the statement that “the correct dose of bisphosphonate for the long bones is an overdose for the alveolar bone of the jaws”43 (Table 1).
The dose of bisphosphonates varies with the rate of administration and type with zoledronic acid being the most potent and highest affinity to bone and thus not surprisingly the highest rate of ONJ.44 The median dose to onset was 12 months and the authors have seen cases occurring following three injections at monthly intervals.44 The two main oral bisphosphonates are alendronate and risedronate. Different rates of development of ONJ have been reported with more risk with alendronate. This is more than the difference in market share. Alendronate has a greater bone affinity than risedronate.28 The recommended weekly dose of alendronate at 70 mg weekly is almost double the potency of the recommended dose of 35 mg risedronate. It was also initially felt that the oral bisphosphonate needed to have been prescribed for a considerable time for the cumulative dose to have built up to where ONJ may occur, commonly a window period of three years was suggested. However, the median period for the onset of ONJ from alendronate was 24 months in the large Australia-wide study.44 Thus, ONJ can and will occur in a shorter period. The shortest time seen by the authors was with a dental implant which lost integration within 12 weeks of commencement of alendronate.48
An insight as to why there is such variable time of onset from commencement of oral bisphosphonates to ONJ was gained from the recent CTX study.49 There was wide variation in the degree of decreased bone turnover in 215 patients presenting for tooth extractions; some (37 per cent) had very low bone turnover, which put them in the risk zone for ONJ, some (35 per cent) were in a more appropriate therapeutic range for the bisphosphonates and the remainder were in the normal range. This would appear to be beyond just a matter of compliance and didn’t correlate with age, gender, medical comorbidity, bone disease or duration of treatment. Thus not surprisingly, different individuals have different dose and duration drug requirements. There is also good evidence that many osteoporotic patients don’t need to be on bisphosphonates forever. The results of five years therapy and ceasing were similar to 10 years continuance of therapy.50
Lastly, and most importantly, there is the issue of whether bisphosphonates cause ONJ. Initially, the association was considered weak and this view is still supported by some medical authorities and parts of the pharmaceutical industry. Clinically however, ONJ has a unique presentation and only occurs in patients on bisphosphonates with the only exception being the historical condition of “phossy jaw”. The chemistry of the phosphorous agents used in the munitions and match industry in the late 1800s and early 1900s has been compared to the chemistry of the bisphosphonates. Essentially the yellow phosphorous, to which patients with “phossy jaw” were exposed to, is converted to potent amino bisphosphonates by natural chemical reactions in the body. These amino bisphosphonates are almost identical to current pharmaceutical bisphosphonates.51 Animal studies have shown that dogs on oral alendronate for three years show increased bone matrix necrosis as compared to controls. These animal studies, however, did not have extractions so ONJ was not seen.52 The corresponding author developed a research protocol for a sheep model with intravenous bisphosphonates with staged extractions but could not obtain funding for the bisphosphonates.
Thus, currently the direct association between ONJ and the bisphosphonates is indisputable but the precise mechanism of causation is suggested but not fully documented.