Introduction

At the time of writing bisphosphonates are enjoying widespread and increasing use in the treatment of a number of conditions. In their publication Russell and Rogers1 provide an historical perspective citing the clinical applications of these agents as far back as the early 1960s. The action of the most potent nitrogen containing bisphosphonates in the inhibition of the mevalonate pathway is described. This action may explain the potent inhibitory action of these drugs on osteoclast activity. The anti-angiogenic effect of these drugs has also been demonstrated in animal2 and human3 studies. This action may well explain the great reduction in vascularity of bone as well as the tumouricidal effect. The common uses of these drugs include the management of Paget's disease of bone, hypercalcaemia of malignancy, multiple myeloma, metastatic breast and prostate cancer.

The most prolific use of these drugs is in the treatment of post-menopausal and cortico-steroid induced osteoporosis.4 In children it is limited to specialist use in the treatment of hypercalcaemia of unknown cause and also of malignancy, osteoporosis, and osteogenesis imperfecta.5 It is interesting that until the beginning of this century researchers considered 'significant side effects of these drugs to be minimal'.1 In the case of oral administered drugs, associated oesophageal and oral ulceration have been well documented in relation to poor patient compliance.6,7 However, in 2003 Marx published evidence of an association with an avascular necrosis of the jaws.8 The jaw bones affected by this drug appear similar to those of osteoporotic bone, the bone having less capability of repair when stressed from masticatory physiological forces. It is theorised that the resulting unrepaired micro damage sets the stage for osteonecrosis.9 The bone is also more vulnerable to infection if exposed to the oral environment. A number of co-morbidity factors have been suggested as possibly linked to the establishment of what is now termed bisphosphonate associated osteonecrosis of the jaws (BONJ). Other abbreviations used to describe the condition include BON and ONJ. Co-morbidities have included poorly controlled diabetes and other immuno compromised states, concurrent use of cortico-steroids, chemotherapeutic drugs, advanced age, alcohol abuse and smoking.10

Local factors contributing to establishment of the condition have been sited and include periodontal and periapical disease, anatomical variations including mandibular tori and the lingual area of the mandibular molar region. Recent trauma, ie tooth extraction, is the commonest local risk factor.10 Cases with no obvious co-morbidity factors have also been reported.9,10,11 The condition has been compared to osteo-radio necrosis (ORN) which almost exclusively affects the posterior mandible. BONJ also has a marked predilection for the mandible, 68% (Marx);10 66% (Woo),12 but also affects the maxilla in isolation as well as in combination with the mandible. In fact any part of the jaws can be affected in a variety of site combinations. The incidence of the condition has recently been claimed to be highest when the intravenous preparations are used in the management of multiple myeloma, prostate and breast metastases.13

The incidence in patients receiving alendronic acid so far appears to be very low.14 This orally administered drug is less potent than its intravenous counterparts but is the most commonly prescribed drug due to its use in the management of post-menopausal and steroid induced osteoporosis. Risedronate is a less commonly prescribed oral bisphosphonate licensed for use in Paget's disease and osteoporotic conditions. The oral drug clodronate has also been reported in association with BONJ but in all cases has been given in conjunction or following the use of a potent intravenous bisphosphonate (personal communication from the Medicines and Healthcare Products Regulatory Agency (MHRA)). We are now seeing, however, the increased use of the oral bisphosphonate, ibandronic acid, in the treatment of metastatic breast disease15 and reports of BONJ in relation to this drug are on the increase.

Three case reports are presented of BONJ associated with the administration of alendronic acid, risedronate and ibandronic acid. In all three cases the extraction of a tooth preceded development of the condition.

Case 1

A 56-year-old woman was referred to the Department of Oral Surgery by her general dental practitioner following the failure to heal of an extraction socket of the upper left first premolar. At 11 months post extraction and following repeated courses of antibiotics, pain was beginning to become a feature.

A medical history included steroid resistant rheumatoid arthritis. Drugs being taken included leflunomide, prednisolone, alendronic acid, diclofenac, iron supplements and omeprazole. The patient had not smoked for 15 years. Intra-oral exam revealed a non-healing socket in the 25 region. The 22 and 23 were slightly tender and dull to percussion with associated inflamed gingival tissues which the patient felt were receding. An orthopantomogram was unremarkable except for the suspicion of a thickening of the left sinus floor and a suggestion of a retained root in the upper left second premolar region. Surgical exploration and debridement was performed in the premolar region and discoloured grey/black bone was removed. A histological report did not demonstrate a retained root but instead sclerotic and necrotic bone. Further extractions were required in this lady's case. In liaison with the patient's prescribing specialist bisphosphonate treatment was discontinued and an oral systemic antibiotic (phenoxymethylpenicillin 250 mg six-hourly) prescribed with chlorhexidine gluconate 0.2% mouth rinsing. Extraction of the upper left first molar was performed with an attempt at primary closure. Wound healing was slow and some exposure of bone was noted. An oroantral communication (OAC) persisted for some time post extraction (Fig. 1). Curettage of soft bone was performed and soft tissue closure again attempted. At the time of writing her oral condition continues to show improvement with her 22 and 23 remaining vital and demonstrating improved periodontal health.

Figure 1: Post extraction of 24 and more recently surgical removal of 26.
figure 1

Exposure of bone 24 region and an oro-antral communication 26 region. 22 and 23 dull to percussion with signs of periodontal breakdown

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She continues to receive treatment for her underlying systemic disease but has not as yet been considered for further treatment with bisphosphonates.

Case 2

A 64-year-old lady was referred by her general dental practitioner with repeated sepsis with drainage in the areas of previous extraction sites of 34 and 36. Previous medical history revealed treatment with risedronate prescribed for osteoporosis. The lady was a heavy smoker for many years (> 20 per day for > 20 years). Previous dental history was significant for periodontal disease and extraction of teeth at regular intervals. The patient was also complaining of a progressive painful altered sensation in the distribution of the left inferior dental nerve.

Extra-oral examination revealed a swelling with tender left submandibular lymphadenopathy. Intra-orally, the presence of a non-healing extraction site 36 with purulent discharge was noted. An orthopantomogram demonstrated a mixed picture showing areas of osteosclerosis and osteolysis (Fig. 2). A provisional diagnosis of osteomyelitis of the jaw was made. Surgical exploration revealed granulation tissue with areas of necrotic bone which was confirmed histologically. Although surgery appeared to give some initial relief painful symptoms returned. Further teeth were required to be extracted in the quadrant and following a number of courses of antibiotics, including clindamycin, some relief from symptoms was again achieved.

Figure 2: Moth eaten appearance of bone.
figure 2

Areas of osteosclerosis and osteolysis with loss of definition of ID canal in the 35, 36 region. Pain moderate to severe indicative of established osteomyelitis

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Three months later, however, the patient re-presented in considerable pain with associated left ID nerve deficit. Only at this point was a diagnosis of bisphosphonate osteonecrosis made. A long-term antibiotic regime was prescribed and a referral to maxillofacial surgery made. After failure to control symptoms using conservative means the patient accepted a partial mandibulectomy sacrificing the left inferior dental nerve. Her management is on-going.

Case 3

A 66-year-old lady was referred by her general dental practitioner with a suspected case of bisphosphonate associated osteonecrosis of the jaw. The lady had been receiving oral ibandronate for the previous six months following diagnosis of metastatic breast malignancy, the primary lesion being diagnosed 13 years previously. Approximately one month into treatment with the bisphosphonate (ibandronic acid), she required the extraction of a lower right molar tooth.

The socket failed to heal and occasional courses of amoxycillin and metronidazole were given which gave temporary relief. The situation continued for a three month period before referral to our department.

Other relevant medical history included irradiation to her shoulder one month prior to the prescribing of a bisphosphonate. The hormone antagonist letrozole was being taken and a smoking habit of five cigarettes a day was noted. (This represented quite a reduction on her previous smoking habit of 10-15 per day since the age of 16.)

On intra-oral examination the previous extraction site did have soft tissue cover but on closer examination a purulent exudate could be expressed through multiple sinus tracts. On exploration non-vital bone was probe-able beneath the surface (Fig. 3). Intra and extra-oral radiography demonstrated what appeared to be an extraction socket with poor bony fill-in around the 47 area. A provisional diagnosis of BONJ was made and initial treatment involved the prescription of amoxycillin 250 mg eight-hourly with chlorhexidine gluconate 0.2% mouth rinsing. Review appointments were made to allow regular irrigation through the sinus tracts using normal saline twice weekly. Over a period of two to three weeks the patient's symptoms reduced and it was decided to discontinue the antibiotic regime. Also at this stage a bone biopsy was performed at the site, histology of which confirmed evidence of osteonecrosis. A decision was also reached with the patient's oncologist, to discontinue the ibandronate (a total of seven months of drug therapy having been completed). There then followed a period of conservative management, which lasted approximately three months consisting of regular irrigation of debris from the site, using normal saline and the patient using daily chlorhexidine gluconate 0.2% mouth rinsing. During this three month period the patient suffered two infective episodes involving painful facial swellings, which were treated blindly with amoxycillin and metronidazole. Bacterial sampling (as deep into the wound as practicable) demonstrated the main cultures of organisms to be sensitive to metronidazole in one instance and to penicillin in the second incidence. Both these infective episodes resolved quickly under these antibiotic regimes and once painful symptoms, and swelling were resolved the antibiotics were discontinued. One further surgical reduction of the buccal bone was performed during this three month period under amoxycillin surgical antibiotic prophylaxis. Healing was observed to be relatively uneventful and soft tissue coverage of the site with absence of sinus tracts ensued.

Figure 3: Inflamed, oedematous soft tissues covering site of previous extraction of 47.
figure 3

De-sensitised bone easily probed via soft tissue clefts and sinus tracts providing exit for purulent discharge. Regular flushing an aid to relief of symptoms

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Management of the patient's underlying malignancy during this three-month period included haematological investigation to monitor for signs of hypercalcaemia. By the end of this three month period the patient was also beginning to suffer some painful symptoms from known metastatic disease sites and a bone scan was performed. At the time of writing the patient remains orally symptom-free but is receiving further treatment for her metastatic bone disease. The patient is not being considered at present for further bisphosphonate treatment and at time of writing is five months post-discontinuation of the drug ibandronate.

Discussion

Reports of osteonecrosis of the jaw in relation to oral administered bisphosphonates are becoming more common. Alendronate and most recently ibandronate generating the most reports [Committee for safety of medicines (CSM) circa October 2006]. In contrast only a few reports worldwide of the condition in relation to oral risedronate have been documented. The increase in reporting of BONJ may be purely as a result of an increase in recognition and pharmacovigilance. In any voluntary reporting system under reporting is accepted as the norm and therefore data so collected can give no reliable information as to prevalence or incidence of the condition. However, the sudden appearance of reported cases of ibandronic acid associated ONJ does appear to coincide with the drug's most recent introduction. Being a potent nitrogen containing oral bisphosphonate such an association might be expected to be in the same incidence as experienced with zoledronic acid. The potency of ibandronate is demonstrated anecdotally in Case 3, the drug being taken only for one month prior to the extraction of the tooth and subsequent development of BONJ. It may be noted that the mandible was not considered to be in the field of radiation during radiation to the patient's spine.

In the other Case reports 1 and 2, the bisphosphonate regimes had been administered for periods over and above a year and other co-morbidity factors were noted, ie long-term corticosteroid use and a heavy smoking habit. Dental extractions appear to have played a role in initiating BONJ in all three cases. The role of surgery in the management of the established condition if the aim is to remove affected bone back to a healthy margin, may well prove counterproductive. Such surgery, which might otherwise prove useful in cases of osteomyelitis, is more likely to encourage progression of established BONJ.10 Mandibular hemi section was however performed in case three to alleviate severe distressing symptoms of pain and purulent discharge.

The discontinuation of bisphosphonates in suspected cases of ONJ is suggested by a number of authors and in a recent systemic review discontinuation is considered an important therapeutic tool.12 Cases of alendronic acid associated osteonecrosis have been described and a resolution has been noted within one year of discontinuation of the drug. resolution has also been described after longer periods of discontinuation and more severe cases.16 Preventative measures have been described and endorsed by a number of expert groups. However in established cases effective management protocols have yet to find international agreement or acceptance. Evidence does, however, exist and newly suspected cases and antibiotic regimes should be initiated and where practicable bacteriological sample taken for culture and sensitivity. Irrigation of exposed bone and use of Chlorhexidine antiseptic mouth rinsing should be encouraged. Antibiotics of first choice for blind use should be penicillin based or metronidazole. If these are contra-indicated then tetracycline or erythromycin can be considered. If microbial analysis has been successful, adjustment of the antibiotic regime can be considered. The common reporting of 'actinomycetes like' bacteria may suggest why penicillin and metronidazole are regularly effective in controlling symptoms in this condition.14 However, there is little evidence to suggest that BONJ is a form of orofacial actinomycosis. It is the authors' opinion that if symptoms have been controlled antibiotic regimes can cease but if symptoms are not being controlled then long-term or intravenous antibiotic regimes may be considered.12

At slight variance with the ADA,14 who appear to support the 'blind' use of clindamycin, the authors suggest that this drug be used, in primary care, only when previous regimes have proved ineffective or when directed by a microbiologist.

Surgical debridement of bone will be of some merit in most cases and in known cases of metastatic disease a bone biopsy should always be taken to rule out the presence of secondary jaw deposits. More extensive resection should be reserved for symptomatic cases who do not respond to conservative management. Monitoring of the patient's underlying disease process in these cases will involve the reporting of changes in patient's symptoms, blood sampling to observe the development of hypercalcaemia and bone scanning. Should resolution of the condition be achieved re-administration of a bisphosphonate has been proposed by some authors.17 It is accepted that in individual cases the patient may best be served by remaining on bisphosphonate therapy regardless of the development and continued presence of BONJ.

Conclusion

Bisphosphonates represent a group of life improving and, in some cases, life prolonging drugs. Osteonecrosis has become a known complication of treatment with bisphosphonates and must not now be considered rare. It is important for the dental surgeon to identify the risk factors and provide appropriate dental care to these patients.

Bisphosphonate associated osteonecrosis of the jaw is reported most commonly with the intravenously administered drugs but recent reports have also shown its association with the orally administered bisphosphonates. These are used in the management and prevention of osteoporosis, in post-menopausal women and patients receiving long-term or high dose corticosteroids. Ibandronate is a newer potent oral preparation used in the management of metastatic bone disease. If osteomyelitis is diagnosed early in these cases conservative management including discontinuation of the drug may provide an environment conducive to resolution of the condition.