Rheumatology Advance Access originally published online on May 11, 2007
Rheumatology 2007 46(7):1049-1051; doi:10.1093/rheumatology/kem106
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EDITORIALS |
Bisphosphonates and osteonecrosis of the jaw
Department of Rheumatology, The Royal London Hospital, Bancroft Road, London E1 4DG, UK
Correspondence to: Dr Nicholas G Shenker, E-mail: mpxns{at}bath.ac.uk; alismjawad1{at}hotmail.com
There are concerns regarding osteonecrosis of the jaw (ONJ) in patients who take aminobisphosphonates. This is a relatively newly recognized complication of a therapy from which hundreds of thousands of patients in the UK currently benefit, a number which is currently increasing. What is the evidence linking these drugs with ONJ? Which bisphosphonates are implicated? What patients are at risk? And finally, what are the implications of this new insight for the management and safety of patients under the care of rheumatologists?
ONJ is a rare but often intractable disease. Patients with ONJ present with exposed bone related to the oral cavity which is necrotic and often complicated by secondary infection with the bacteria that typically cause periodontitis, including actinomycetes [1]. Patients usually present in pain which is sometimes severe although a significant proportion, up to a third, have no pain at all [2]. Other manifestations include loose teeth or a draining fistula. It more commonly involves the mandible rather than the maxilla and lesions are non-healing, or slow to heal. Histological appearance reflects this underlying avascular necrosis usually with superadded infection [2]. ONJ has previously been associated with osteopetrosis and phosphorous poisoning (‘phossy jaw’). The main risk factors already known to be associated with ONJ are corticosteroids, dental surgery, radiotherapy and poor oral hygiene. Other risks that have been recognized include alcohol abuse, smoking, poor nutrition, infection, chemotherapy, hormonal treatments, anaemia, thalidomide and previous organ transplant [1–5].
Currently, there are no effective treatments for ONJ. It is important to note that surgical debridement can make the condition worse and patients should avoid this if at all possible [3]. Should surgery be contemplated, then a referral should be made to an experienced oral and maxillofacial surgeon. Patients may be treated non-invasively with antibiotics (such as penicillin or clindamycin) and antimicrobial mouth rinses (such as chlorhexidine or hydrogen peroxide) to limit the extent of the damage. Because of the recent association it is recommended that any bisphosphonate should be stopped when ONJ has been identified although the long half-life of such treatment precludes an immediate impact on the course of the disease. Hyperbaric oxygen has not been shown to be effective. Sadly, most lesions are non-healing or show only slow improvements and close follow-up should be made [2, 3].
ONJ is hypothesized to occur as the direct result of micro-trauma on bone that is both hypovascular and hypodynamic and thus less able to meet an increased demand for repair and remodelling. The jaw is particularly prone to ONJ as it is regularly exposed to physiologic stress (e.g. mastication), iatrogenic damage (e.g. tooth extraction or denture injury) or tooth infection. The anti-angiogenic properties of some coexisting risk factors contributes to this hypothesis. These include medications (glucocorticoids, thalidomide and bortezomib in patients with myeloma), diabetes mellitus, irradiation of the jawbone, peripheral vascular disease and hyperviscosity syndromes.
Bisphosphonates are synthetic analogues of cellular inorganic pyrophosphates. The first generation of bisphosphonates (etidronate, tiludronate and clodronate) are not nitrogen containing and these compounds have not been considered to cause ONJ [3]. Multiple mechanisms effect their actions on bone but the primary mechanism of action is likely to be a direct osteoclastic cytotoxicity once they are converted to a non-hydrolysable adenosine triphosphate analogue. Alendronate, risedronate, pamidronate, zoledronic acid and ibandronate all contain nitrogen within a side chain. These aminobisphosphonates, as well as inducing apoptosis via another adenosine triphosphate analogue, also inhibit farnesyl diphosphonate synthase which is part of the mevalonate pathway of cholesterol synthesis [6]. This has the effect of disrupting osteoclast function. All bisphosphonates also appear to reduce the recruitment of osteoclasts, and aminobisphosphonates in particular have been demonstrated to have anti-tumour effects and have therefore become standard therapy for patients with multiple myeloma and bone metastases [7].
Aminobisphosphonate usage in post-menopausal osteoporosis has gradually superseded the older bisphosphonates as they are more efficacious with respect to bone mineral density and fracture prevention, and the weekly and intravenous preparations are better tolerated. Other indications for their rheumatological use include Paget's disease and steroid-induced osteoporosis and they are used in other diseases associated with altered bone turnover including ankylosing spondylitis, childhood disorders of bone metabolism and complex regional pain syndromes [8].
The nitrogen-containing bisphosphonates, and especially the intravenous forms (zoledronate and pamidronate) have been associated with ONJ. At oncological doses the incidence ranges from 4–13%, with a median onset of between 22 and 39 months from the first administration [5]. Oral bisphosphonates given to rheumatology patients however carry an ONJ incidence <0.1% and likely to be about 1 in 100 000 [9]. Twenty-two cases of ONJ occurred in patients who were taking oral bisphosphonates for either osteoporosis or Paget's disease, a further six cases being associated with the intravenous forms. This is dwarfed by more than 900 cases occurring in patients with cancers who were treated with intravenous bisphosphonates which are given at doses up to 12 times greater than those for osteoporosis or Paget's disease.
In 2003, Marx [10] reported that there may be an association between ONJ and aminobisphosphonate use. In a recent review, 368 published cases of ONJ in relation to the use of bisphosphonates were identified although the true number of cases is much higher [3]. Novartis, at an FDA review in 2005, reported 875 cases of jaw osteonecrosis out of 2.9 million patients treated with intravenous bisphosphonates. Six cases (4056 patients) had previously been identified in all controlled clinical trials and the first post-marketing report was made in December 2002.
From the published cases, 94% are related to intravenous zoledronate and/or pamidronate for the treatment of metastatic or bony cancers [3]. Sixty percent of all cases occurred following dental procedures. Despite this, some cases occurred spontaneously and were associated with oral bisphosphonates. Alendronate was implicated in 13 cases compared to one case involving risedronate.
Novartis’ data broadly support Woo et al's summary although are restricted to oncology patients. The majority of cases had had recent dental surgery and most (74%) had another risk factor aside from cancer and aminobisphosphonate prior to developing ONJ. These included corticosteroids, chemotherapy, radiotherapy, hormonal treatments, anaemia, thalidomide and previous organ transplant.
Novartis has already circulated memoranda to all doctors in the US in 2005 advising on the risk of ONJ in patients about to start zoledronate or pamidronate infusions and who have cancer or other risk factors. They have changed the medication information leaflet to reflect this risk. They recommend that patients about to commence such treatment for bone cancers should be considered to have a dental examination with appropriate preventive dentistry and, once commenced, should avoid invasive dental procedures. Woo et al. recommended in their review that all patients (including those with osteoporosis) prior to starting aminobisphosphonate treatment (alendronate and risedronate included) should have oral infections actively treated; should have routine restorative care of carious teeth and should have invasive procedures for non-salvageable teeth. In addition, biannual oral examinations with dental cleaning should be performed.
Both of these recommendations would appear heavy handed when applied to patients about to start bisphosphonate treatment for osteoporosis and Paget's disease. Grey and Cundy [11] highlighted the distinction between patients with cancer who receive much higher bisphosphonate doses and have multiple other risk factors for ONJ (chemotherapy, radiotherapy, poor nutrition) and those with osteoporosis. They emphasized that the recommended approach runs the risk of denying potentially beneficial treatments for patients with osteoporosis and Paget's disease with poor dentition as well as potentially beneficial dental surgery for those patients already on treatment [11, 12]. More recent advice from the American Dental Association concerning patients who are about to start an oral bisphosphonate are perhaps more appropriate [9]. This report recommends that the benefits of treatment should be emphasized but the patient should also be informed of the very low risk of ONJ. A screen for oral risk factors should be performed (e.g. poor dental hygiene, oral infection, recent and proposed dental surgery). A risk-benefit analysis should then be performed for each patient. Should there be significant doubt, then a referral to an appropriate dental professional might be considered and alternative treatments, including bisphosphonate therapy with the non-amino category of bisphosphonates, can be considered.
What advice should be given to non-cancer patients already taking bisphosphonates? It is important that patients who are at high risk, especially those who are to undertake dental surgery whilst on therapy, should be made aware of the risk of ONJ. Following this there is uncertainty and little guidance exists. The American Dental Association's advice is still pertinent to this group of patients. Vigilance, education and good oral care with the avoidance of unnecessary dental surgery would be appropriate ‘take-home’ messages.
ONJ is the latest in a number of new side effects associated with bisphosphonates. Nephrotic syndrome, renal insufficiency and ophthalmic inflammation have also been described as well as the well-recognized upper gastrointestinal symptoms, hypocalcaemia and the myalgic self-limiting illness that occurs around the time of intravenous administration [13].
Further areas for discussion include the role of a drug holiday. Does the ONJ-bisphosphonate association affect the risk-benefit analysis when considering the implementation of a drug holiday? There is animal evidence to suggest that micro fractures increase and may accumulate as a result of the hypodynamicity of the bone caused by bisphosphonates [14]. This is controversial, however, and not generally accepted at this point. The delayed development of ONJ adds further evidence to the suggestion that continued bisphosphonate administration may be harmful. More work is needed to see if ONJ incidence peaks at any one time, or the medians quoted above are artefactual due to patient factors. Studying populations longitudinally over many years will provide the answer to this question. With respect to a bisphosphonate holiday, the major benefit in terms of fracture risk reduction occurs in the first year following treatment and then tails off, although it is clear that fractures remain at a lower level for at least 5 yrs since starting treatment with alendronate. Interestingly this reduction is maintained for the following 5 yrs when the alendronate is stopped, although bone turnover markers and BMD are seen to drop when compared with patients who continue to take the alendronate [15]. Bone mineral density is preserved 1 yr after stopping chronic alendronate use before then diminishing in subsequent years. Presumably BMD may be preserved for longer in patients exposed to the bisphosphonates with longer half-lives such as zoledronic acid. The benefits and risks of a bisphosphonate holiday will continue to be debated and the information concerning ONJ and its relationship to these drugs will influence this.
We recommend that patients about to start oral and intravenous bisphophonates should have an oral inspection by the rheumatologist, and if there are any doubts then the patient should be referred to an appropriate dental surgeon for further advice. Secondly, we recommend that patients who are already taking oral bisphosphonates should not stop these when they go for dental surgery as the risk of ONJ is very small and the half-life of the bisphosphonates long. Thirdly, we recommend that in patients who are already having intravenous bisphosphonates and who have planned dental surgery, the administration of the bisphosphonates should be delayed until after healing has been completed.
In conclusion, ONJ has been linked with high-dose intravenous bisphosphonate use in patients with bony cancers and the observation has been extended at a much lower incidence to patients on oral bisphosphonates taken for rheumatological conditions. The benefit-risk ratio is still heavily weighted towards therapy but rheumatologists need to be aware of this link. The risk is greatest in those with poor oral health who are undergoing dental surgery. If there is doubt, then a review by an experienced oral surgeon is appropriate. Finally, given the paucity of NHS dentists in the UK, there is a role for a wider debate on the links between rheumatology and oral surgeons in the management of this potentially disabling, costly and increasingly common problem.
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  N. G. Shenker and A. S. M. Jawad Comment on: Bisphosphonates and osteonecrosis of the jaw: reply Rheumatology, March 1, 2008; 47(3): 383 - 384. [Full Text] [PDF]
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M. L. Bianchi, C. Limonta, J. Frasunkiewicz, M. Biggioggero, and S. Vai Comment on: Bisphosphonates and osteonecrosis of the jaw Rheumatology, March 1, 2008; 47(3): 383 - 383. [Full Text] [PDF]
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