Quality Resource Guide l Bisphosphonate and Other Medication-Related Jaw Necrosis Part One 6th Edition 4 www.metdental.com The mean time of developing BRON varies overall time of exposure along with the effective potency of the bisphosphonate administered. An 18-month mean time of onset associated with zoledronate (monthly dose) therapy has been reported versus a 6-year onset with pamidronate (3-4 week dose) treatment. 23 Others report a 9.9% incidence of bisphosphonate-related osteonecrosis in myeloma patients and 2.9% in breast cancer patients over an eight year period. 24 In another study of 303 myeloma patients receiving zoledronate, a two year time span was stated as a threshold when an increased level of caution was advised. 25 Chronologic estimates for jawbone necrosis development in patients taking oral bisphosphonates have been significantly longer than those associated with intravenous agents. Suffice to say that the risk of developing MRONJ in relation to the use of oral bisphosphonates is very low in comparison the risk associated with intravenous bisphosphonate therapy in the oncologic setting. On balance, the reported cases and emerging experience support the notion that MRONJ is not an unconfirmed phenomenon and must be dealt with effectively. 26 The evolution from initial discovery to sequestrum formation can be rapid, though several months are more characteristic for this to occur. Clinical data and statistics concerning the overall impact of denosumab on osteonecrosis of the jaws is being gathered, though it is clear that this agent likewise also carries a small risk of MRONJ development. Of note is the confirmed increased risk of jaw osteonecrosis development with denosumab use versus bisphosphonates in osteoporosis patients. 29 Risk Factors Risk exists for developing MRONJ when any form of bisphosphonate or similar stabilizing agent is taken. However, the specific type of agent will help determine the degree of risk. Orally ingested bisphosphonate forms demonstrate a much lower risk potential than the intravenously administered agents. The most frequently prescribed oral agent, alendronate (Fosamax ® ), has the greatest established time on the market and number of doses administered. Stated estimates of risk or incidence of developing MRONJ in association with oral alendronate administration is 0.7 per 100,000 patient years exposure. 26 Of the intravenously administered forms, zoledronate/zoledronic acid (Zometa ® ) is the dominant drug associated with development of MRONJ. The frequency of MRONJ is associated more with monthly zoledronate administration (4mg) in cancer patients than with any other type of bisphosphonate. Patients with malignant skeletal lesions such as metastatic cancer and myeloma receive overall intravenous doses that are 12-fold higher than patients with benign skeletal conditions such as osteoporosis and osteopenia. See Table 3 for Risk Factor tabulation. The total duration of bisphosphonate admin- istration is of great importance regarding risk potential. If, and when, the patient discontinued using bisphosphonates is also very important. Three years of routine alendronate administration is associated with an approximate complication risk of 2% for patients having office-based oral surgical procedures, with the level of risk rising to 4% when the patient has had 3-4 years of exposure to the drug, 6% at 4-5 years of exposure, 9% at 5-6 years of exposure and 11% with exposure beyond 6 years. 27 Given the long half-life of bisphosphonates (up to 10 years at sites of low bone turnover, but less in alveolar bone due to its known higher rate of turnover), the obtained medical history should be specific with regard to use of these agents. It should include current as well as former use, duration and type of bisphosphonate administered. Ninety-five percent of MRONJ cases occur in patients with malignant skeletal disease. The general level of risk for development of MRONJ in patients taking oral bisphosphonates for management of osteopenia, osteoporosis and Paget’s disease remains relatively low. The risk of developing MRONJ when oral bisphosphonates are used in the context of managing these non-neoplastic conditions is 0.01% to 0.04%. Tooth extraction elevates that risk to 0.09% to 0.34%. The risk of developing MRONJ in patients being managed for benign skeletal disease with typical oral bisphosphonate doses is so minimal that it has been suggested that systematic screening and prevention programs, including the withholding of dental procedures, is not justified. 27 Other risk factors for developing MRONJ include: periodontal and dentoalveolar surgery; local anatomic factors including maxillary and mandibular tori, and the mylohyoid ridge; and pre-existing inflammatory dental disease and other conditions. ( Table 4) Finally, the possibility that genetic factors may influence overall risk for development of BRON has been raised, based on single nucleotide Table 3 - MRONJ Risk Factors 1. Drug-related: Type, potency and duration of bisphosphonate used, concomitant corticosteroid therapy or chemotherapeutic drug therapy 2. Local risk factors: Dentoalveolar, periapical and osseous periodontal surgery, diabetes, alcohol use, smoking and poor oral hygiene 3. Systemic risk factors: hypercoagulability, diabetes, alcohol use, tobacco smoking 4. Local anatomic factors: Palatal and mandibular tori, exostoses and mylo- hyoid ridges that may require surgical correction in the future 5. Demographic factors: age, race, cancer type, concurrent osteopenia or osteoporosis in juxtaposition with a cancer diagnosis