Practical considerations for treatment of patients taking bisphosphonate medications: an update

Indications for the use of bisphosphonates

Bisphosphonates are frequently prescribed, with alendronate being the 43rd most prescribed drug in the United States in 2009, with a greater number of prescriptions written than for omeprazole or Viagra.11 They are most commonly indicated in the management of osteoporosis,12 but also have therapeutic benefit in the control of skeletal complications and bony metastases in malignancies such as multiple myeloma and breast cancer. Infrequent indications include Paget's disease, ankylosing spondylitis and osteogenesis imperfecta (Table 1). Continuous bisphosphonate administration appears to result in a staged change in bone physiology from health to an end-stage necrosis, although the rate at which this develops varies dramatically with site, pharmacodynamics and pharmacokinetics.

The various types of bisphosphonate (Table 2) can lead to confusion amongst patients and clinicians. Although there are differences in potency, bone affinity and mode of action, the critical issue until recently has been regarded as whether the bisphosphonate is administered orally or intravenously. This is based on the logic that IV bisphosphonates are significantly more potent, given at higher doses, and are therefore associated with a much greater likelihood of ONJ-BR. However, drug manufacturers are continually refining administration methods and the advent, since our last update, of intravenously administered high potency bisphosphonates at significantly lower doses (than doses required for the management of malignancy), for the treatment of osteoporosis has somewhat confused the previously accepted dichotomy. For example, a single, annual IV administration of 5 mg zoledronic acid for patients diagnosed with osteoporosis is in contrast with the same drug being infused in 4 mg doses at 3-weekly intervals for the management of bone metastases. Evidence is emerging to suggest that tailored high potency yet low dose, low frequency IV regimens for osteoporosis have similar reduced risks to lower potency oral preparations.13 A general practitioner's initial assessment of a patient with regard to risk for ONJ-BR should therefore be based on the condition that the patient is taking a bisphosphonate for, with oncology patients being considered as high risk.14

Definition

Patients may be considered to have ONJ-BR if there is:

Patients at risk for ONJ-BR or with established ONJ-BR can also present with other common clinical conditions not to be confused with ONJ-BR. Commonly misdiagnosed conditions may include, but are not limited to, alveolar osteitis (dry socket), sinusitis, gingivitis/periodontitis, caries, periapical pathology and temporomandibular joint disorders.6

Incidence

Since our last paper, there have been several publications providing further incidence data for ONJ-BR.15–19

Under-reporting and a large number of unconfirmed (yet reported) cases have confused these data, although the clear consensus is that patients under treatment with oral bisphosphonate therapy are at a considerably lower risk for ONJ-BR than oncology patients treated with monthly IV bisphosphonates. The incidence of ONJ-BR from recent Australian surveillance data estimated a risk of 0.01–0.04% for those patients on weekly oral alendronate medication for osteoporosis,15 whereas an institutional study from a cohort of patients at the University of Southern California School of Dentistry (that appears at present as an outlier) reports an incidence following dental extractions of 4%.19 One factor that is not fully elucidated in the United States study is the influence that comorbidities such as corticosteroid therapy may have on the risk of ONJ-BR development. Nevertheless, these figures may prove to be more accurate than earlier lower estimates as practitioners' awareness of the condition is raised, patient compliance improves with weekly oral dosing, and longer term follow-up of patient cohorts is reported. There is emerging evidence, for example, that a cumulative dose effect is present and therefore duration of oral therapy exceeding two to three years may increase the risk of developing ONJ-BR.6,15 Importantly, the calculated frequency from the Australian data increased by up to a factor of seven when dental extractions were carried out, indicating that an awareness of patients' current medication is crucial as oral bisphosphonates for osteoporosis are commonly used and, although ONJ-BR remains a rare complication, vigilance is necessary to ensure that appropriately informed pre-operative consent is provided and that healing progresses satisfactorily following an extraction or surgical procedure.

Estimates of the cumulative incidence of ONJ-BR for patients receiving IV medication range from 0.8–12%,6 although the sample sizes, comorbidities, interventions (such as extractions) and awareness factors as for oral bisphosphonate administration provide for this wide distribution. Nevertheless, the overwhelming evidence is that risk is significantly greater for these patients who, until recently, have been on IV therapy for hypercalcaemia of malignancy, bony metastases and multiple myeloma. As discussed above, novel administration regimens for osteoporosis with IV bisphosphonates at low frequency and dose appear to be associated with a lower risk that may be comparable with lower potency oral preparations, although to date it is too early for data analysis. The reason for this reduced risk is assumed to be related to the effective systemic drug dose that is delivered (dependent on dose, potency, frequency of administration and bioavailability) rather than simply its potency.20

There are very little data from patients in the UK, although a recent survey of consultant oral and maxillofacial surgeons reported that nearly two-thirds had seen new cases of ONJ-BR from IV bisphosphonates in the last year, with one-quarter having seen three or more cases.21

Risk factors

The aetiology of ONJ-BR is multifactorial. Several risk factors have been recognized;6,7,8,16,17 to date there is no formal consensus to risk stratification, although management algorithms have been proposed and doubtlessly will be refined as the clinical and biological knowledge base improves.14 This is important if we are to identify and advise ‘at risk’ patients effectively. Future research will help quantify the relative risks and a new, prospective case cohort series linked with national registration would be very useful. The recently updated position paper published by the American Association of Oral and Maxillofacial Surgeons lists drug-related factors, local factors, systemic factors, genetic factors and preventive factors as key themes;6 the following comments provide updated information from a number of sources.

Prevention of ONJ-BR

Management of patients with established ONJ-BR is difficult as a cure is unlikely and options for management are limited. Therefore, prevention of ONJ-BR is the mainstay of existing management. Currently, there is lack of clarity on how best to prevent and manage ONJ-BR. Guidelines are based on clinical experience and those established for prevention of osteoradionecrosis, as randomized controlled studies and substantial observational studies, are lacking.1,6,8,9 Knowledge regarding key risk factors and confounding variables is also limited, such that these guidelines require a pragmatic approach and will be reviewed and altered in the light of ongoing patient care and experience and an increasing body of published literature.

Increased awareness on the part of the oncologist, dentist and patient is an important aspect in the prevention of ONJ-BR. Patients need to be informed by the treating oncologist prior to commencement of IV treatment about the risk of ONJ-BR. In a recent survey, only 41% of haematologists/oncologists always warned patients of the risk of ONJ-BR before commencing with IV bisphosphonate medications,28 although best practice would suggest that, as a minimum, all patients, before beginning IV bisphosphonates, have timely access to dental treatment. For patients that do not have a general dental practitioner, alternative arrangements should be made for them to be seen either in the primary care sector, in the community setting, or through cancer networks as a matter of urgency.

Patients with osteoporosis and other non-malignant bone conditions who have been taking oral bisphosphonate therapy for many years should be made aware of the low risk of developing ONJ-BR following an ‘invasive’ dental procedure, such as an extraction, and should be encouraged to see their dentist for regular check-ups. The risk of developing ONJ-BR associated with oral medications appears to be due to cumulative exposure; therefore, dental assessment prior to commencement of oral medication is not necessary and routine dental treatment should not be altered or delayed.8

The issue of antibiotic cover is contentious; currently there are no controlled studies to support surgical antibiotic prophylaxis for invasive dental procedures in bisphosphonate patients. Considering the paucity of evidence, the low incidence of ONJ-BR in patients being treated for osteoporosis and the potential reaction to antibiotics, the authors do not recommend routine use of antibiotic prophylaxis in this group of patients.

Those patients receiving IV bisphosphonates may, however, benefit from antibiotic prophylaxis prior to treatment. A recent survey of British oral and maxillofacial surgeons found that there was considerable variation in management of these patients. A questionnaire was mailed to 322 consultants working at 154 hospitals in the summer of 2008. There was a 57% response rate with at least one consultant responding from 72% (111/154) of hospitals. Screening patients prior to starting IV bisphosphonates was uncommon (15%) and relatively few would stop bisphosphonate administration. Almost all consultants would prescribe antibiotics for molar extractions, two-thirds of whom would provide this both pre- and post-extraction.21

If antibiotic prophylaxis is to be considered, it is important that a suitable antibiotic is administered. Current recommendations indicate that penicillin V may be the most applicable antibiotic to administer, with doxycycline or metronidazole use for penicillin-allergic patients.6,14

Patient management advice

In dental practice, all patients should be queried about conditions for which bisphosphonates are commonly prescribed, such as osteoporosis, a history of metastatic cancer to bone, long-term steroid use, multiple myeloma and bone diseases, such as Paget's disease. Dentists are aware that patients frequently do not remember the medications they are taking and this is particularly true for the recent introduction of annual bisphosphonate infusions. As discussed, the dentist must not assume that physicians will have clearly discussed the potential risks of ONJ-BR development prior to medication administration.

Case studies

Case study 1 (Figure 1)

This patient presented with an asymptomatic upper left lateral incisor. Medical history-taking established that the patient was due to begin IV bisphosphonate therapy for a skeletal metastasis (most commonly from breast or prostate cancer).

Treatment options would therefore be to:

Leave, with or without subsequent monitoring, given the periapical radiolucency;

Extract the tooth with adequate time for healing;

Provide endodontic retreatment – either a retrograde or orthograde approach.

Treatment recommendation

In view of the indications for this patient's impending IV bisphosphonate therapy, the risk of retaining a tooth with periapical pathology outweighed the benefit of attempting retreatment. Following careful discussion and gaining informed consent, the tooth was therefore extracted prior to intravenous bisphosphonate therapy commencing, mucosal healing achieved and a temporary, well-fitting removable prosthesis (with tooth support where feasible) placed with subsequent review of the restorative options depending on the response to chemotherapy and the patient's preference.

Case study 2 (Figure 2)

A 77-year-old male with osteoporosis, complicated with chronic obstructive airways disease (COAD), began oral bisphosphonate medication six years prior to presentation. His lower right third molar was asymptomatic but carious.

Treatment options were therefore to:

Leave;

Plan for surgical extraction;

Provide root canal treatment (RCT) and subsequent restoration of the tooth.

Treatment recommendation

Unlike Case 1, this patient was taking long-term oral bisphosphonates for osteoporosis rather than management of malignancy. In light of recent reports, his COAD warranted inhaled corticosteroids, the dose and duration of which may also have had a bearing on risk assessment, in conjunction with consideration for the surgical extraction of a mandibular molar. Furthermore, bisphosphonate medication had been provided for significantly longer than recent data, showing an increased incidence of ONJ-BR beyond two years' administration.11 There was therefore considerable concern about the potential for ONJ-BR development following extraction.

RCT and restoration, or a ‘drug holiday’ (cessation of the oral bisphosphonate for 2–3 months in consultation with the patient's physician) followed by surgical extraction with antibiotic cover were the two most contemporaneous options in light of current evidence. Oral bisphosphonate medication could then have been resumed once healing was complete. Access difficulty for root canal therapy ruled this more conservative option out. Unfortunately, this patient underwent a surgical extraction in mid-2005 without stopping medication or being given antibiotic cover, and subsequently developed intractable ONJ-BR.

Case study 3 (Figure 3)

A 63-year-old, partially dentate female prescribed IV bisphosphonates for multiple myeloma, presented complaining of generalized discomfort from her mobile, periodontally involved maxillary teeth. At presentation, bisphosphonate infusions had been administered for approximately 3 years.

Treatment options were therefore to:

Leave, monitor and allow the teeth to exfoliate spontaneously;

Extract her teeth with antibiotic prophylaxis.

Treatment recommendation

Given the indications for this patient's IV bisphosphonate therapy, discussion with, or referral to the local maxillofacial/oral surgery department would be prudent if this scenario presented in general practice; cessation of therapy is also extremely unlikely.

Following careful discussion of the risks and benefits of each option, this patient's preference was to allow the upper teeth to exfoliate naturally; mucosal healing was complete approximately 12 months later. A complete denture with maximum mucosal support and a resilient lining was subsequently constructed. This conservative approach seemed prudent, although high risk in that any acute pain or swelling may have necessitated extractions. The panoral radiograph hints at the potential risk with extractions – note the anticipated bone fill of previous left maxillary extraction sockets that has not taken place and a thickened lamina dura outlining the same sites.

Case study 4 (Figure 4)

A 70-year-old gentleman presented to our Oral Surgery department in 2006 with generalized dental neglect He had completed chemotherapy for myeloma in 2004 and had been prescribed monthly Zoledronate infusions for over five years prior to presentation. In 2006, he was asymptomatic; although radical intervention to secure oral health would have been the usual course of events, this patient's myeloma history and, in particular, his long-term prescription of high potency intravenous bisphosphonates made this plan extremely high risk. Following discussion of the risks and benefits of possible treatment, it was agreed to adopt a conservative management approach with no active intervention other than treatment of symptomatic teeth when necessary.

In 2010, extractions of the upper right canine and lower right first premolar proved necessary. Peri-operative antibiotic cover was provided in conjunction with chlorhexidine mouthwash. Whilst the mandibular extraction site healed successfully, the upper right canine socket showed no evidence of epithelialization eight weeks post-extraction, and a diagnosis of ONJ-BR was made (Figure 4d). Fortunately, the patient remains asymptomatic and is therefore being managed conservatively with twice daily chlorhexidine mouthwashes at present.

Conclusion

As prescription of both IV and oral bisphosphonates increases, the general dental practitioner is more likely to encounter patients taking these medications. The above contemporaneous advice will be reviewed as more research data and clinical experience is forthcoming. As the mainstay of treatment is currently prevention, it is important that protocols are implemented in dental practices to minimize the risk of ONJ-BR. Routine dental care, including tailored oral hygiene advice, non-surgical periodontal therapy and orthograde endodontics should be considered the mainstay of prevention in a primary care setting, in addition to conventional fixed and removable prosthodontics, where appropriate. Elective surgical procedures should be subjected to risk-benefit assessment on an individual basis, with referral for advice or treatment where appropriate.