Background

Bisphosphonates are anti-resorptive agents and were first utilised in the nineteenth century for non-medical uses. Their first medicinal rationale came about in the 1960s where they were investigated for the use of bone loss prevention. In 1995, alendronic acid was licensed by the Food and Drug Administration Agency (FDA) for use in osteoporotic patients. Intravenous bisphosphonates, such as pamidronic acid and zolendronic acid gained FDA approval, in 1996 and 2002 respectively.1

The first reported case of medication-related osteonecrosis of the jaws (MRONJ) was presented in 2003 on a patient using bisphosphonates; since then numerous cases have been reported in the literature.2 The majority of cases were observed in patients requiring intravenous infusions of bisphosphonates used for solid tumour bone metastases, cancer-related hypercalcaemia, Paget's disease and osteolytic lesions of multiple myeloma.3,4 In 2004 Novartis, the manufacturers of pamidronic acid and zolendronic acid, informed healthcare professionals that the risk of MRONJ had been included on their labelling.2 In 2005, this was extended to all bisphosphonates including oral preparations. Warnings were also included in the British National Formulary from 2008.5 In 2015, the European Medicines Agency advised prescribers to issue patient reminder cards detailing the risk of MRONJ in relation to their bisphosphonate medication.6

Numerous theories have been proposed for the mode of action of bisphosphonates including the inhibition of osteoclast action or reduction osteoclast numbers.7,8,9,10 Some sources also state that bisphosphonates may inhibit angiogenesis.11,12,13,14

Current guidelines define medication related osteonecrosis of the jaw (MRONJ) as;15,16,17

  • Exposed bone, or bone that can be probed through an extra-oral or intra-oral fistula in the maxilla or mandible

  • Persistent for more than eight weeks

  • Current or previous treatment with anti-resorptive or anti-angiogenic agents

  • No history of radiation therapy.

Since 2003 extensive research has been carried out to determine the risk of developing MRONJ in patients exposed to bisphosphonates. It is important to consider the medication itself, the route of administration, and the disease process that the medication for which the medication is being used.

The national study performed by Faculty of General Dental Practice (UK) estimates that the incidence is 10 patients per year per million population. For females the estimated rate is 14 per million per year and for males 6 per million per year. The risk of developing MRONJ in post-menopausal women taking oral bisphosphonates is estimated to be between 1 in 1,262 and 1 in 4,419.16

In osteoporotic patients taking oral bisphosphonates, the risk of MRONJ appears to be low. The American Association of Oral and Maxillofacial Surgeons state that the incidence is between 0.004% and 0.1%.17,18,19 In patients with severe osteoporosis exposed to intravenous bisphosphonates, the risk of developing MRONJ still remains low. Figures approximate between 0.017% and 0.04%.20,21,22 This may be explained by the less frequent administration of the medication.

Evidence has shown that the risk of developing MRONJ in patients taking intravenous bisphosphonates for cancer treatment is higher than those taking the medication in an oral form or intravenously for osteoporosis. High quality evidence supports this and has suggested that the risk in cancer patients exposed to zolendronic acid is approximately 1%.20

The number of patients taking bisphosphonates is rising. Since 2010 the number of prescriptions dispensed has increased by 2.5% and the use of alendronic acid has increased by 5.5%.16 The total number of women receiving medication for osteoporosis in the UK was approximately 480,000 in 2012 and this number is increasing.16

In recent years medications other than bisphosphonates have been found to cause MRONJ both spontaneously and following extraction. These include monoclonal antibodies and tyrosine kinase inhibitors, in particular denosumab, bevacizumab and sunitinib. Denosumab, an anti-resorptive agent, is licenced for use in osteoporotic women as well as in bone-related malignancy whereas bevacizumab and sunitinib have been licenced for use in renal cell carcinomas, neuroendocrine tumours, gastro-intestinal tumours and have also been used in macular degeneration.17

Awareness of the risks associated with bisphosphonates is important to general dental practitioners (GDPs). With upcoming changes to oral surgery commissioning pathways, there will be a drive for more dento-alveolar surgery to be performed in primary care settings. The general dental workforce must therefore ensure that they are confident and competent to manage these cases and know when to refer more complex cases or suspected MRONJ lesions appropriately.

Materials and methods

This study aimed to assess the awareness of GDPs regarding MRONJ and the medications that may be implicated in its development. The study also assessed whether GDPs were willing to undertake simple exodontia on patients taking bisphosphonates and if not, what could be done to improve their confidence in treating this cohort of patients.

One hundred and fifty dentists were surveyed at the British Dental Association conference in May 2015. The proforma used for data capture (see Fig. 1) collected information on demographics and asked questions aiming to assess the understanding of osteonecrosis as a disease process. We asked GDPs to firstly define osteonecrosis of the jaw, and secondly state drugs other than bisphosphonates which could lead to osteonecrosis. In the final question we gave an example scenario outlining a patient requiring a non-surgical extraction. The patient's medical history revealed osteoporosis which was managed with oral alendronic acid which the patient had been taking for a duration of one year. Aside from this, the medical history was clear. We asked if GDPs would be comfortable carrying out the dental extraction in primary care.

Figure 1
figure 1

Proforma used for data capture

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The proformas were completed and returned immediately, thereby removing false positive answers by discussing with peers or accessing alternative information sources. All the data was analysed separately by two oral surgeons and a 10% sample was repeat reviewed after 2 weeks in order to confirm inter-rater reliability due to the 'free text' nature of the answers to certain questions. Any GDPs working in the secondary care setting who completed the survey were excluded on the assumption that this cohort may have had an increased level of confidence in treating patients on bisphosphonates and therefore our results would not have been representative of all GDPs.

Results

A total of 162 GDPs were asked to participate in the survey. Twelve refused to take part and there were no drop outs. All surveyed GDPs worked in primary dental care, with 21/150 also working in secondary care or in the community services (Fig. 2). By excluding those also working in secondary care and/or the community setting, the final sample size was 129.

Figure 2
figure 2

A graph to show the numbers of the sampled GDPs who worked in primary care, secondary and/or a community setting

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Our results revealed that the year of qualification of the sample was mixed with a range from 1965–2014. The mean year was 2002, whilst the median year of graduation was 2005 demonstrating that the sample contained a majority of GDPs who qualified in the past 10 years. There was a good mix of GDPs who qualified from all over the UK (Fig. 3). No one in the sample had qualified outside of the UK.

Figure 3
figure 3

A graph showing where the sampled GDPs gained their dental undergraduate qualification

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Of the 129 GDPs surveyed, the majority, 80/129 (62%), recorded a correct definition of osteonecrosis of the jaw stating 'dead bone' or 'death of bone'. The remaining 49/129 participants (38%), either did not provide an answer [13/49 GDPs (27%)], or cited 'infection' [28/49 GDPs (57%)] or 'delayed healing' [8/49 GDPs (16%)].

We asked whether GDPs were aware of drugs other than bisphosphonates that may lead to the development of osteonecrosis; 3/129 GDPs (2%) were aware that denosumab could lead to the development of osteonecrosis of the jaw. No antiangiogenic medications were stated. Of the 129 surveyed GDPs, 55/129 (43%) stated radiotherapy as a potential risk factor for osteonecrosis of the jaw. Although radiotherapy is a cause of osteonecrosis, our question asked which drugs could lead to osteonecrosis and hence we discounted radiotherapy as a correct answer. The remaining 71/129 GDPs (55%) were not aware of any other drugs aside from bisphosphonates that could lead to the development of osteonecrosis.

Participants were asked whether they would feel comfortable performing a nonsurgical extraction on an osteoporotic patient (with no other medical problems) who had been taking oral alendronic acid for one year. The results revealed that 54/129 GDPs (42%) felt comfortable in extracting the tooth in primary care whilst 75/129 GDPs (58%) did not (Fig. 4).

Figure 4
figure 4

A graph to show the percentage of sampled GDPs who are confident to undertake the dental extraction in the given example versus the percentage that were not confident

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The 75 GDPs (58%) who stated that they would not be confident carrying out the extraction were questioned about their reluctance to treat such patients in primary care. The most frequently cited reasons were a lack of clear protocol [21/75 GDPs (28%)] and reluctance to proceed without second opinion [21/75 GDPs (28%)]. Interestingly, 16 /75 GDPs (21%) cited litigation as a reason for not carrying out the extraction in primary care. The remaining 17/75 GDPs (23%) stated that their reluctance stemmed from being unsure of risk, a lack of confidence and an unwillingness to perform extractions (Fig. 5).

Figure 5
figure 5

A graph to show the reasons why sampled GDPs were not confident to undertake extractions of patients with a history of bisphosphonate use

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Based on the scenario provided, 54/129 GDPs (42%) stated that they would be confident to perform the required extraction. All 54 GDPs felt a post extraction review was necessary. There was however less consensus regarding the use of therapeutics, the inclusion of drug holidays, and the use of primary closure post-extraction.

The results revealed that 16/54 GDPs (30%) advocated the use of chlorhexidine mouthwash with the majority [10/16 GDPs (63%)] advising both pre and postoperative use. A total of 45/54 GDPs (83%) stated that they would prescribe antibiotics and 5 GDPs out of this cohort of 45 (11%) specified that they would utilise both pre-operative and post-operative antibiotics.

Only 2/54 GDPs (4%) advocated primary closure post-extraction and 4/54 GDPs (7%) stated that they would advise a drug holiday but did not disclose further information regarding liaison with the prescriber.

Discussion

Our results suggest that there are a large number of GDPs who are not confident in treating patients who are taking bisphosphonates. However, there are a number of points to consider when interpreting whether the data collected is representative of the UK population of working GDPs. Firstly, the cohort of GDPs in this study were mainly in the early years of their careers. The BDA's State of general dental practice in 2013 research report revealed that in England between 2012–2013, there was a higher proportion of GDPs under the age of 35 years (37%) compared to 14% of GDPs above the age of 55.23 This trend was similar in Northern Ireland, Scotland and Wales. This was a similar pattern to what was observed in our cohort of GDPs.

When we look at the place of primary qualification, it can be seen that all sample GDPs in this study qualified from the UK. However, research from the BDA in 2012 revealed that 41% of GDPs in the UK had qualified from either the European Economic Area or overseas.23 In this respect, our sample therefore may not have been fully representative of the population of general dentists working in the UK. It is also worth noting that the sample of GDPs in this study was surveyed at a national conference showing their commitment and dedication to the profession. Therefore, it could be surmised that the cohort sampled may have had an increased knowledge base, thus adding bias to the data. In addition sampling techniques were not used and the participants were selected at random; this could have affected the results.

It is important that GDPs are aware of the definition of osteonecrosis, are able to identify 'at risk' patients and know when to refer for appropriate advice or management. The majority of GDPs were familiar with the definition of osteonecrosis of the jaw although some stated that the term was synonymous with 'infection' or 'delayed healing'. Almost half of the GDPs were aware that radiotherapy can lead to osteonecrosis of the jaw, better known as osteoradionecrosis (ORN). The vast majority were unable to recall medications other than bisphosphonates which have the potential to cause osteonecrosis. It appears from this answer that GDPs may have difficulty distinguishing between ORN and MRONJ which have different causes and pathophysiology. It remains important for GDPs to be aware of anti-angiogenic and anti-resorptive drugs implicated in MRONJ as the number of these agents being prescribed is increasing and hence they are more likely to come across patients taking them.

In order to assess the confidence of GDPs in treating patients on bisphosphonates, an example scenario was given. The particular example was selected as it represented a low risk case which would likely be familiar to general dentists. The 2011 Scottish Dental Clinical Effectiveness Programme (SCDEP) document 'Oral health management of patients prescribed bisphosphonates', classifies the risk of developing osteonecrosis with bisphosphonate use into two categories; high and low risk.15 Low risk includes patients who are about to start bisphosphonate therapy for any condition or patients who are taking bisphosphonate therapy to prevent or manage osteoporosis and who do not have additional risk factors. These additional risk factors include bisphosphonate use for cancer, a previous diagnosis of osteonecrosis, non-malignant bone conditions such as Paget's, concurrent use of immunosuppressants, corticosteroids and more recently, use of other anti-resorptive drugs and/or anti-angiogenic drugs.15 Low risk patients have also been identified as those who have had fewer than four years of oral bisphosphonate therapy.15,16,17

The evidence from the SDCEP, the 2014 American Association of Oral and Maxillofacial Surgery (AAOMS) position paper and the FGDP guidelines is strong in suggesting that the patient in our given example is at a low risk of developing MRONJ taking into consideration the duration of bisphosphonate therapy, the oral route of administration and the uncomplicated medical history of the patient. Patients such as these can therefore be treated successfully in primary care for dental extractions.

The new oral surgery commissioning guidelines outline pathways for the transfer of patients requiring dentoalveolar services from secondary care into primary care; however an array of factors need to be considered.24 These include an enhancement of skills and knowledge but just as vital is the support available and clear accessible guidelines.

Our sample revealed that 16 of the GDPs feared litigation when treating patients at risk of osteonecrosis. It is known that claims against dentists are on the increase. Figures from the MDDUS annual report reveal a 19% rise in claims against GDPs and hospital dentists in 2014 compared to the previous year and a significant increase in the number of members subject to investigation by the GDC, up 37% on the previous year which mirrors the GDC's own statistics for 2014.25 However, there is no evidence of an increase in litigation or regulatory action against practitioners treating patients who are taking bisphosphonates.

The most important factor is ensuring that informed consent is gained from those at risk of MRONJ. This should include a detailed discussion of risks and benefits of all treatment options. It is important to recognise that not all clinicians will feel that they have the necessary competencies to obtain informed consent and this is where litigation concerns may arise.

The potential management strategies for treating patients at risk of osteonecrosis varied amongst the GDP cohort. Evidence pertaining to any of the stated measures such as chlorhexidine mouthwash, antibiotics and primary closure is weak. The most recent systematic review into MRONJ advises a drug holiday following extraction until soft tissue closure has occurred but again the evidence is limited.26 There is a risk, albeit small, of anaphylaxis when using chlorhexidine as detailed in the literature.27

Conclusions

There is a need to provide further education and training in order to improve GDP confidence and awareness of bisphosphonates and other medications which have the potential to cause osteonecrosis. This will mean that more of these patients can be managed appropriately in primary care provided that the risk is low.

We are aware that the number of patients receiving bisphosphonates is rising and this leads to a potential increased workload in secondary care which has an effect on efficiency and ease of care from a patient perspective. Furthermore, with the use of anti-angiogenic drugs and anti-resorptive agents, such as denosumab, also increasing, GDPs are likely to encounter more potential risk factors for MRONJ as well as established cases.

To increase primary care treatment of this cohort there is a need for national comprehensive guidelines to assist GDPs in decision making and undertaking treatment. The SDCEP guidelines, originally published in 2011, are currently under review and should improve understanding of MRONJ.15

With proposed changes to the structure of the oral surgery workforce, the ultimate aim is for a consultant-led service (including triage) in a primary care setting, which will reassure those performing extractions and ensure that patients are being treated in the most appropriate environment for their treatment needs. Along with this, the delivery of continuing professional development that encourages accredited dentoalveolar seminars and courses will hopefully raise confidence among those providing treatment. As a body of dental professionals we must also work closely with the medical practitioners who prescribe these medications so that they are aware of the potential risks they pose and are informing their patients accordingly.