Periodontal disease, dental implants, extractions and medications related to osteonecrosis of the jaws

MRONJ: Diagnosis, aetiology, epidemiology and risk factors

The diagnosis of MRONJ is based on the presence of exposed bone or bone that can be probed through an intra-oral or extra-oral fistula(e) in the maxillofacial region that has persisted for more than eight weeks in the absence of radiotherapy or obvious metastatic disease to the jaw, on a background of current or previous treatment with anti-resorptive or anti-angiogenic agents.2 The AAOMS have produced a recommended staging system for MRONJ (Table 1).

The first case of ONJ-related to bisphosphonate use (BRONJ) was reported in 2003,7 though the full pathophysiological mechanism(s) of MRONJ is (are) yet to be fully understood. Current theories are centred on the drug's inhibitory role on osteoclastic bone resorption that affects bone remodeling, endothelial cell angiogenesis (certain drugs) and the presence of infection and/or inflammation.8

MRONJ is more commonly associated with the mandible compared to the maxilla (2:1) but can also affect both jaws in any one particular patient.9^,10 The published incidence of MRONJ varies (Table 2). Oncology patients are at a higher risk for MRONJ than those treated for osteoporosis since the anti-resorptive drugs used in this group are administered at higher doses, more frequently (ie monthly in oncology versus yearly or 6-monthly in osteoporosis indications) and parenteral administration allows greater drug exposure^11,12,13 (Table 2). Increased duration of the drug therapy has been reported as a risk factor for ONJ related to denosumab,14^,15 IV N-BPs14 and oral N-BP use,^16,17,18 as has concomitant corticosteroid use.15 Information on the association of ONJ with anti-angiogenic agents (in the absence of bisphosphonate therapy) is limited to case reports, and the incidence from a large analysis of patients treated with bevacizumab has been quoted in Table 2. The presence of certain genes19 and other medical co-morbidities, such as anaemia and diabetes,15 have been mentioned as risk factors, however further research is needed in these areas.

In addition to these systemic factors, local risk factors include denture wearing23 (Figure 1a and 2), the presence of inflammation or infection in the structures supporting the teeth4^,30 and procedures stimulating the bone around the teeth, such as extractions (Figure 3), implant placement, and periodontal treatment; all of which are procedures commonly carried out in general dental practice. The second part of this article addresses the risk of ONJ for these procedures in patients on anti-resorptive drugs, predominantly N-BPs.

Extractions (and other dento-alveolar surgery)

Dental extractions have been used in animal ONJ models31 and dento-alveolar surgery has been suggested as an inciting event for the development of ONJ in patients on anti-resorptive drugs.9^,15^,23^,30^,32 In one example, in a case control study of cancer patients exposed to anti-resorptive drugs, patients with a history of tooth extraction were associated with a 16-fold increased risk for ONJ when compared to cancer patients without ONJ,30 implicating the tooth extraction as a risk factor itself in addition to the IV use of the anti-resorptive agent. In addition to the extraction process causing local trauma, the presence and contribution of dental infection to the development of ONJ should not be excluded from the equation, as most dental extractions are carried out on teeth with periodontal disease or periapical pathology.

Although the risk of ONJ is much smaller in patients on oral N-BPs, there have been numerous cases of ONJ in patients taking oral BPs33 and, as previously discussed, other systemic and/or local factors can increase this risk, such as greater than 4 years of BP therapy or concomitant corticosteroid or anti-angiogenic medication use. Recommendations by AAOMS for oral surgery in patients on oral BPs have been summarized in Table 3.

Patients with a background of intravenous administration of anti-resorptive or anti-angiogenic agents, especially cancer patients, should be treated with extreme caution and careful planning, often with multidisciplinary input. For this group of patients, AAOMS recommend:

In many circumstances, dento-alveolar surgery cannot be avoided. Studies have looked at other factors such as pre- and post-operative antibiotic treatment, antibacterial mouthwashes, drug holidays and alternative methods of exodontia that could potentially reduce the risk of ONJ in patients undergoing dento-alveolar surgery whilst taking BPs.

MRONJ and periodontal disease

MRONJ and dental implants

Implants are an increasingly common treatment requiring careful surgical planning. For dental patients, costly treatment such as this carries expectations for success and longevity. Amongst other factors, the process of osseointegration of the dental implant is critical to the implant's survival. For this reason, questions arise when considering dental implants on patients who are taking medications that affect bone remodelling, ie anti-resorptives: does placing implants in patients taking anti-resorptive medications increase risk of ONJ and, furthermore, is the success rate of the implant affected? Since the placement of a dental implant is a traumatic procedure with bone removal at the osteotomy site, similarly to dento-alveolar surgery, it is contra-indicated in patients who have taken anti-resorptives for cancer by numerous expert panels.2^,3^,58 The incidence of ONJ associated with dental implants and anti-resorptive drugs for osteoporosis, however, remains uncertain within the literature. A summary of the papers cited in this article is shown in Table 4.

A systematic review of one prospective and three retrospective human studies by Madrid and Sanz concluded that there was no evidence that placement of implants in patients on oral BPs (< 4 years) was associated with ONJ in the short follow-up period.59 Some of the studies included were, however, of poor quality; one study had no control group;60 another followed patients up by questionnaires rather than clinical examination.61 The success rates of implants placed in the oral BP groups were high (95–100%), comparable to the control groups with no N-BP treatment (96.5–100%), however, the studies were unable to report on the long-term outcome of both implant success or development of ONJ. Crestal bone changes at the second stage of implant placement were compared in oral BPs users and a control group by Memon et al, with no significant differences seen between the groups.62

Case reports and case series have reported a spectrum of complications associated with implant placement in bisphosphonate patients, such as delayed wound healing at site of placement,63 failure to osseointegrate64 and subsequent failure of the implant post-osseointegration.^65,66,67 Several studies have looked into possible mechanisms for failure of dental implants in patients taking BPs, concluding that BPs significantly reduce alveolar bone turnover and wound healing, thereby increasing the risk for ONJ and implant failure.68 However, only a few studies take into consideration the role of co-existing conditions, such as hypertension, corticosteroid use and smoking status. As previously discussed, the presence of infection has been indicated as a risk factor for ONJ, however, authors describing ONJ associated with dental implants do not mention peri-implant disease, a potential source of infection. A study looking at failed implants in middle-aged women found a significant odds ratio of 2.5 for a history of oral BP use.64 Failure was defined by unsuccessful osseointegration or mobility once the implant had osseointegrated. In a case series of 27 patients, ONJ presenting less than 6 months from the time of implant placement (classified as surgically related) was observed in six patients (22.2%).69 ONJ occurred in patients with oral BPs as well as IV treatment. ONJ took longer to present (mean: 68 months) following implant placement in patients on oral BPs (alendronic acid) compared to patients who had a history of IV zolendronic acid use (mean: 16.4 months), emphasizing the need for long-term follow-up for any patient on BPs. In their cohort, four patients developed ONJ even though BP use commenced after implant placement. Notably, in this group, two patients had already had implant(s) in situ for over 9 years but developed BRONJ within 4 months of commencing IV BPs; rapid progression compared to one of the other patients whose BRONJ took longer to develop (156 months) after starting oral BPs.

With limited knowledge on the long-term affects of oral BPs on dental implants, when considering treatment patients should be warned of the risks of ONJ prior to implant treatment, and cases should be selected carefully, taking into consideration other systemic and local factors. AAOMS have suggested an informed consent process should be undertaken prior to implant placement in patients on oral BPs (Table 3) owing to the long-term possibility of implant failure and low risk of developing ONJ if the anti-resorptive is continued. This advice is based on a study evaluating the effects of intravenously administered BPs on bone healing after tooth extraction and osseointegration of dental implants in a rabbit model, where the experimental group demonstrated good initial stability at 4 weeks but impaired healing around the implants at 8 weeks compared to the control.70 The conclusions we are able to draw from this study are limited.

Interestingly, studies involving local application of BP to implant surfaces have been carried out with positive results in animal^71,72,73 and human74 models without causing ONJ. The local delivery of the anti-resorptive agents have shown improved early fixation, increased bone density, both close to and further away from the screw.75 The long-term clinical outcome of BP coatings on dental implants is an area of future research.

Conclusion

Medication-related ONJ is a complex, multi-factorial process. The key to the management of patients at risk for ONJ in primary care involves taking a thorough medical history and understanding the indications and nature of any anti-resorptive or anti-angiogenic therapy, which will subsequently determine their dental management. Cancer patients are at a higher risk of ONJ than patients with osteoporosis and should be managed with caution, however, oral health screening and preventive care would benefit any patient receiving these agents. Dentists should familiarize themselves with the names and indications of newer agents associated with ONJ to help identify those patients at higher risk for the disease. Dental extractions and periodontal disease have been identified as risk factors for ONJ, especially in high risk patients, and the long-term success rates of implants in oral BP users is yet to be determined, as does the long-term outcomes of locally applied BPs in animal and human models.