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  • Given that strategies to avoid ONJ are likely to be

    2019-04-28

    Given that strategies to avoid ONJ are likely to be more effective than treating the condition once it occurs, it also seems sensible to reduce bisphosphonate exposure as much as possible. This can be accomplished by using less potent agents or less intensive infusion schedules, particularly in those patients who have been on bone-targeted agents for protracted periods of time. In multiple myeloma patients most guidelines recommend stopping bisphosphonates after two years. Recently emerging data in multiple myeloma patients suggests that the incidence of ONJ might be lowered by a reduced dosing schedule without affecting the incidence of skeletal-related events [47]. The risk of ONJ was eight-fold lower with the reduced schedule (monthly injection during the first year and every 3 months thereafter) than with the standard monthly schedule. However, this small retrospective study is not conclusive regarding the efficacy of less frequent dosing or its impact on the development of ONJ. However, a number of ongoing studies are investigating the efficacy of less intensive regimens of bisphosphonates in metastatic bone disease (NCT00320710, NCT00424983). The ZOOM trial, comparing a standard 4 weeks versus 12 weeks schedule of zoledronic Puromycin for the prevention and delay of skeletal related events in metastatic breast cancer patients was presented at the ASCO meeting 2012 and showed equivalent results for these two regimens [48].
    How do you manage patients on intravenous bone-targeted agents who require dental work? For patients who are on IV bisphosphonate therapy and require dento-alveolar procedures there is a suggestion that prophylactic antibiotic use around the procedure may be helpful in reducing ONJ risk [45,49]. A recent study by Lopez-Jornet et al. showed a statistically significant reduction of ONJ with pre and postoperative antibiotics for extraction procedures in an animal model [50]. If a surgical procedure is unavoidable, conservative surgical intervention is preferred in an attempt to minimize trauma to bone tissue. The procedure should be performed by experienced clinicians familiar with ONJ, ensuring that a minimally invasive, efficient procedure be performed with minimal morbidity.
    Should patients on a bone-targeted agent requiring dental work stop their bone-targeted agent? Recommendations on need of discontinuation of bisphosphonates in patients requiring dental work have not been created yet. Given the very long half-life of bisphosphonates in bone, with a 12-year terminal half-life even for oral agents like alendronate, effects of temporary cessation of the agents is questionable [31,46]. On the other hand, temporary discontinuation of bisphosphonates may remove their acute toxic effect on soft tissue and could facilitate the healing process [5]. AAOMS recommends withholding oral bisphosphonates for up to 3 months before a surgical procedure and for up to 3 months thereafter [5]. This strategy also supported by a correlation of the level of the bone turnover marker, C-terminal telopeptide (CTX) with risk of development of ONJ. According to Marx et al. morning fasting serum CTX levels correlated with the duration of oral bisphosphonate use, with increased values for each month of a drug holiday when the oral bisphosphonate was discontinued, suggesting a recovery of bone remodelling during this time. A rising of CTX was associated with reduced risk of ONJ after surgical dental procedures [51]. On the other hand, other trials failed to show a correlation between level of biochemical markers (i.e. CTX, N-terminal telopeptide (NTX), or bone specific alkaline phosphatase) and risk of development of ONJ [52–54]. It however must be recognized that inter individual variability, gender, age, physical activity, and seasonal variation exist that can result in difficulty in interpreting these assays, hence more research is needed.
    Management of patients with established osteonecrosis of the jaw This section will deal with the care of patients on bone-targeted agents who then develop ONJ (Fig. 4). Although a number of clinical guidelines for management of patients with ONJ have been released by various oncology, oral surgical organizations and bisphosphonate manufacturers, there is no established gold standard, since most recommendations are based on case-control studies, retrospective analyses and expert opinions. For patients with established ONJ, treatment objectives are elimination of pain, control of infection in the soft and bone tissue, and minimization of the progression or occurrence of bone necrosis. In general, patients with ONJ should be evaluated and managed by a team including an oral and maxillofacial surgeon and an oncologist [5,46]. Several staging systems of ONJ have been developed by different dental and oncology organizations to help facilitate treatment decisions. The most useful system had been proposed by Ruggiero and subsequently revised by the American Association of Oral and Maxillofacial Surgeons (Table 4 and Fig. 1). According to this classification, Stage 0 defines patients presenting with non-specific symptoms such as tooth pain, sinus pain, and unexplained tooth mobility but without significant clinical findings on examination. For these patients conservative management with topical mouth rinses (chlorhexidine gluconate or hydrogen peroxide) and analgesia is recommended. This is to decrease and prevent further progression of infection in the exposed bone [5,11].