Recommendations from the American Dental Association Council on Scientific Affairs Hellstein JW, Adler RA, Edwards B, Jacobsen PL, Kalmar JR, Koka S, Migliorati CA, Ristic H* November 2011 1.0 INTRODUCTION 1.1 Goals and rationale This report is a narrative review on the subject of osteonecrosis of the jaw in low bone mass patients taking antiresorptive agents. It is based on an appraisal of the available literature identified using a systematic computer-aided search by an advisory committee of the American Dental Association (ADA) Council on Scientific Affairs. This review demonstrates where there is evidence, where evidence is lacking, and what topics future research should target in order to improve the dental management of patients on antiresorptive therapy. The purpose of this report is to help dentists make treatment decisions based on the current best evidence when available, and expert opinion when necessary, for patients taking antiresorptive agents. In an effort to improve the quality and efficiency of oral health care, this report is intended as an educational tool to assist dentists when discussing oral health with patients on antiresorptive therapy, and when treating these patients. The report focuses on patients on antiresorptive therapy for low bone mass rather than patients on antiresorptive therapy for cancer management. This focus was chosen because patients with low bone mass are routinely seen by the general dentist, and, dosing, apparent risk and patient management are different for patients on antiresorptive therapy for cancer management. The clinical recommendations in this report, which are based on critical evaluation of relevant scientific evidence, do not represent a standard of care. The clinical recommendations should be integrated with the practitioner‟s professional judgment and individual patient‟s needs and preferences. Treatments and procedures appropriate to the individual patient rely on mutual communication between patient, dentist and other healthcare practitioners. This report updates the 2008 advisory statement from the ADA Council on Scientific Affairs.  1.2 Nomenclature Osteonecrosis is defined by Dorland‟s Medical Dictionary2 as “necrosis of bone due to obstruction of its blood supply”. Osteonecrosis of the jaw (ONJ) can result from radiation therapy of the head and neck, chronic corticosteroids therapy, herpes zoster virus infection in immunocompromised patients, anti-angiogenesis medications,3 uncontrolled infections and major trauma.4 By convention, the etiologic agents serve as a modifier for a specific case of osteonecrosis (e.g. radiation osteonecrosis) although spontaneous or idiopathic examples are recognized. Osteonecrosis of the jaw (ONJ) associated with antiresorptive therapy deserves distinction from other causes and diseases/medications associated with the development of osteonecrosis. Various terminologies have been applied to ONJ secondary to bisphosphonates, including: “bisphosphonate-related osteonecrosis of the jaw” (BRONJ), “bisphosphonate-induced osteonecrosis of the jaw” (BIONJ), and “bisphosphonateassociated osteonecrosis of the jaw” (BONJ). Bisphosphonate-associated osteonecrosis (BON) originated in a paper published in the Journal of the American Dental Association, but nomenclature of the condition has continued to evolve.5 Non-bisphosphonate antiresorptive agents are now available. Denosumab (ProliaTM) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of women with postmenopausal osteoporosis. Denosumab reduces bone resorption by inhibiting osteoclast function. The osteoclast targeting and end result is similar to bisphosphonates.6 ONJ has been reported in a cancer patient taking denosumab.7 Other antiresorptive agents, including cathepsin K inhibitors (discussed later), could also prove to be associated with ONJ. Therefore, we propose that all cases of ONJ related to the administration of antiresorptive therapeutic agents be termed „„antiresorptive agent-induced ONJ” (ARONJ). This term will encompass bisphosphonate associated/induced cases as well as cases associated with the use of other antiresorptive agents. The term ARONJ will be used preferentially throughout this manuscript unless denoting a specific antiresorptive agent is more appropriate. The panel acknowledges that this condition has a history of variable and confusing terminology. The panel also acknowledges that there is limited information about denosumab and cathepsin K inhibitors. In addition, to our knowledge no cases of ONJ have been reported in patients taking the antiresorptive medications known as SERMS, selective estrogen receptor modulators, now called estrogen agonists/antagonists. 2.0 OSTEOPOROSIS Increasingly prevalent in older adults, osteoporosis is responsible for considerable morbidity and mortality.8-13 The characteristic bone fragility of osteoporosis often results in skeletal fractures, including wrist, spine and extremity fractures, of which hip fracture is the most serious. A woman is more likely to suffer an osteoporotic fracture than she is to suffer a heart attack, stroke or breast cancer.14 Osteoporotic fractures have been associated with functional decline leading to disability, increased subsequent vertebral and hip fractures and increased mortality.12, 15-17 There are approximately 10 million Americans over the age of 50 with osteoporosis and an additional 34 million with low bone mass or “osteopenia,” which puts them at risk for osteoporosis.18 The bone health status of Americans will deteriorate due primarily to aging of the US population. By 2020, there will be 14 million cases of osteoporosis and 47 million cases of low bone mass. It is expected that the number of hip fractures in the US will double or triple by 2040.19 Fractures are common and have become a chronic and costly burden on individuals and society. An estimated 1.8 million individuals suffer a bone disease-related fracture each year.20, 21 In the US, four out of every 10 white women age 50 or older will experience a hip, spine, or wrist fracture in their lifetime; at least 13 percent of white men will suffer a similar fate.22 The risk of sustaining a fracture increases exponentially after menopause. Wrist fractures often occur in relatively independent women during the sixth decade of life, vertebral fractures during the seventh decade and hip fractures during the eighth decade of life. In men, osteoporotic fractures occur at a more advanced age but have worse prognosis with a mortality of 30% within a short time after fracture.22-25 While the lifetime risk for men and non-white women is decreasing, it is rising in certain populations, such as Hispanic women.26 2.1 Therapies for osteoporosis Therapy for osteoporosis has been shown to reduce the risk of fracture. Medications may be considered antiresorptive or anabolic. Antiresorptives, e.g., bisphosphonates, exert their effect by reducing bone resorption while anabolic agents, e.g. teriparatide, promote bone formation. The most commonly used medications for osteoporosis are the antiresorptive bisphosphonates, which reduce bone resorption by inhibiting osteoclast function. Bisphosphonates (alendronate, risedronate, ibandronate and zoledronic acid) are effective in reducing vertebral and non vertebral fractures.27-30 Alendronate, the first modern bisphosphonate was FDA-approved in 1995, and all drugs in this class are considered generally safe and effective. Therapy is continued for at least 5 years, and some patients need treatment for longer periods.31 Bisphosphonates remain in bone and their effect to decrease bone resorption markers can be detected many months later.32, 33 The only available anabolic agent, teriparatide enhances osteoblast (bone-forming cell) activity and has not been associated with ARONJ. Clinical trials have shown efficacy in reducing vertebral and non-vertebral fractures.34 Teriparatide appears to be a superior medication in glucocorticoid-induced osteoporosis.35 Teriparatide, however, is FDAapproved only for up to 2 years of treatment and thus must be followed by another agent after 2 years. 2.2 New agents Denosumab. Denosumab is a human monoclonal antibody that targets the receptor activator of nuclear factor-kappa B ligand (RANKL). RANKL is a cytokine member of the tumor necrosis factor family that is the principal final mediator of osteoclastic bone resorption. It plays a major role in the pathogenesis of postmenopausal osteoporosis, as well as bone loss associated with rheumatoid arthritis, metastatic cancer, multiple myeloma, aromatase inhibitor therapy and androgen deprivation therapy.36 Denosumab prevents RANKL from binding to its receptor on the surface of osteoclasts and their precursors.37 This inhibits osteoclast formation, function, and survival leading to a decrease in bone resorption and an increase in mass and strength of both cortical and trabecular bone. Clinical trials have also shown great clinical efficacy reducing fracture risk.38 Denosumab increases bone mass and prevents fractures in women with postmenopausal osteoporosis39- 42 and in men on androgen deprivation therapy for prostate cancer. 43 It is administered as a subcutaneous injection twice yearly. Randomized controlled trials in postmenopausal women show a 68% and 20% reduction in spine and hip fractures, with no increase in the risk of cancer, infection, cardiovascular disease, delayed fracture healing, or hypocalcemia. Longer term surveillance of this medication is needed to confirm general safety. In the trials, there was one reported case of osteonecrosis of the jaw.7 Denosumab has been tested to prevent bone events in patients with cancer. Using higher doses, given more often than in osteoporosis, investigators have identified more cases of osteonecrosis of the jaw.7, 44 Denosumab is FDA-approved for postmenopausal osteoporosis, and in Europe is also approved for men on androgen deprivation therapy. Unlike bisphosphonates, denosumab does not become incorporated into bone, and bone resorption markers return to baseline six months after the last injection.45 Other antiresorptive drugs. Cathepsin K, a cysteine protease expressed in osteoclasts, degrades type 1 collagen. Inhibition of cathepsin K (CatK) is a potential new treatment approach for osteoporosis. Odanacatib selectively and reversibly inhibited cathepsin K and rapidly decreased bone resorption in preclinical and phase I studies. Pharmacokinetic analysis revealed a long half-life (t1/2 = 66-93 hours) consistent with once-weekly dosing. Odanacatib exhibits robust and sustained suppression of bone resorption biomarkers Cterminal telopeptide (CTx) and N-terminal telopeptide (NTx) at weekly doses above 25 mg.46 A 1-year dose-finding trial with a 1-year extension on the same treatment assignment was performed in postmenopausal women with low bone mineral density (BMD). Women with BMD T scores of -2.0 or less at lumbar spine or femoral sites were randomly assigned to receive placebo or one of four doses of odanacatib. With a 50-mg dose of odanacatib, lumbar spine and total-hip BMD increased 5.5% and 3.2%. The safety and tolerability of odanacatib generally were similar to placebo.47 Unlike bisphosphonates, odanacatib appears to have less effect on bone formation markers. The influence on side effects of this new drug is unknown at this time. The drug is undergoing further phase 3 studies. Anabolic agents. A monoclonal antibody to sclerostin (AMG 785) has been evaluated in healthy men and postmenopausal women. Sclerostin is a bone morphogenetic protein (BMP) antagonist that decreases osteoblast activity and suppresses the differentiation of osteoprogenitors.48 The mechanism of action of sclerostin is expressed in modeling and remodeling. In remodeling, sclerostin produced and secreted by newly embedded osteocytes may be transported to the bone surface where it inhibits osteoblastic bone formation and prevents overfilling of the bone modeling unit (BMU). In modeling, sclerostin may serve two actions. First, it may keep bone lining cells in a state of quiescence and prevent, consequent initiation of de novo bone formation. In addition, sclerostin produced and secreted by newly embedded osteocytes may inhibit osteoblastic bone formation, as in a BMU.49 The sclerostin antibody AMG 785 induces dose-related increases in the bone formation markers procollagen-1 N-peptide (PINP), bone alkaline phosphatase (BAP), and osteocalcin, along with a dose-related decrease in the bone resorption marker serum CTx (sCTx), resulting in a large anabolic window. AMG 785 has been reported to increase bone mineral density up to 5.3% at the lumbar spine and 2.8% at the total hip compared with placebo.50, 51 This drug is still in development. Strontium ranelate is an orally active treatment able to decrease the risk of vertebral and hip fractures in osteoporotic postmenopausal women. Strontium 2 g/day treatment for 3 years decreased the risk of both vertebral and nonvertebral fractures. The decrease in risk of vertebral fractures was 37% in women <70 years, 42% for those 70-80 years of age, and 32% for those ≥ 80 years.52 The mechanism of action of strontium ranelate is unclear at this time, but there is some evidence of an anabolic effect.53 This agent is not available in the United States. 3.0 REVIEW OF ARONJ LITERATURE A search of Medline was conducted using PubMed for literature published between May 2008 (the end date of the last advisory statement search) and February 2011. The following search strategy was employed: (“Osteonecrosis”[Mesh] OR osteonecrosis) AND (“Diphosphonates”[Mesh] OR “bisphosphonate*” OR “denosumab”) AND (“Jaw”[Mesh] OR “jaw”) NOT “Addresses”[Publication Type] NOT “News”[Publication Type] NOT “Newspaper Article”[Publication Type] AND (English[lang]). The Cochrane Central Register of Controlled Trials was also searched using the following strategy: (Osteonecrosis OR “avascular necrosis” OR chemonecrosis) AND (Diphosphonate* OR bisphosphonate* OR denosumab) AND (jaw). Since 2003, reports of ARONJ related to antiresorptive agents in the bisphosphonate drug class (initially associated with use of zoledronic acid, (Zometa™), and pamidronate, (Aredia™) have appeared in the literature.54,55 Zoledronic acid and pamidronate are bisphosphonates administered intravenously as often as every three to four weeks to treat skeletal metastasis or hypercalcemia of malignancy, and yearly to treat Paget‟s disease of bone. Other uses include treatment of children and young adults with osteogenesis imperfecta, although cases of ARONJ have yet to be reported in children.56, 57 More recently, annual and quarterly intravenous infusions have been used for the treatment of osteoporosis Regardless of the route of administration, or underlying disease, ONJ has primarily occurred in patients taking nitrogen-containing bisphosphonates. Nitrogen-containing bisphosphonates are significantly more potent than the first generation of bisphosphonates such as etidronate. Information about available bisphosphonates and other antiresorptive agents is presented in Table 1. While the non-nitrogen-containing bisphosphonates are associated with a much lower risk for ONJ compared to the nitrogen-containing bisphosphonates, the former cannot be considered risk-free. On the other hand, the vast majority of low bone density and cancer patients in the U.S. are using nitrogen-containing bisphosphonates. As a result, most studies referenced in this report primarily involve the nitrogen-containing bisphosphonates. In general, the panel concluded that some level of ARONJ risk may be associated with any antiresorptive agent, and varies by type, delivery method, dose, dosing protocol and duration of therapy. Despite uncertainty regarding absolute risk for each agent with a given patient, this report will generally consider all antiresorptive medication for low bone mass as a single group. TABLE 1. ANTIRESORPTIVE AGENTS 3.1 Estimates of ARONJ risk The risk for developing ARONJ remains unknown despite attempts at quantification. Study limitations such as small sample size, retrospective design, inadequate study duration, and issues associated with voluntary reporting of cases have hindered accurate estimation of incidence and prevalence in the general population. The studies that have attempted to estimate the risk for ARONJ are summarized in Table 2. Several potential risk factors and comorbidities have been reported in the literature, including: diabetes mellitus,59 clinically and radiographically apparent periodontitis,60 tooth extractions,61 denture wearing62, 63 and smoking.64 Corticosteroid use was not consistently found to be a risk factor.61, 65-67 Median duration of exposure to oral nitrogen-containing bisphosphonates in individuals who developed ARONJ was reported in two survey studies to be 24 months (range 3 to 87)68 and 42 months (interquartile range 30 to 56).69 The results of studies performed by three Dental Practice-based Research Networks found that for all ONJ cases identified (excluding cancer), bisphosphonate use for less than two years, two to five years, and more than five years was associated with odds ratios of 5.2 (1.2 – 22.5), 11.4 (3.2 – 40.2, and 26.6 (5.3 – 133.6), respectively.67 While many cases of ARONJ have been associated with an invasive dental procedure such as tooth extraction, ARONJ also occurs spontaneously or in patients with minor mucosal irritation such as those who wear dentures. It may take many years to develop a thorough understanding of ARONJ, its risk factors and possible co-factors. At present, the best available data come from health databases. Earlier reports did not have the benefit of utilizing the American Association of Oral and Maxillofacial Surgeons (AAOMS) or American Society for Bone and Mineral Research (ASBMR) definitions; and, therefore, were not able to rigorously identify true cases of ARONJ. The authors of a Canadian study used a risk ratio to describe the probability of what they termed aseptic osteonecrosis (AON) occurring in patients taking oral bisphosphonates as compared with patients not taking oral bisphosphonates.70 The study utilized the administrative health databases of 87,837 patients and reported a risk ratio of 2.87 (95 percent confidence interval 1.17-5.05) for AON in past or present users of alendronate, etidronate and risedronate. Another study, which analyzed the United States medical claims data of 714,217 patients, found a four-fold increased risk of inflammatory conditions and surgical procedures of the jaw for users of intravenous bisphosphonates related to cancer therapy, but not for users of oral bisphosphonates.71 Both these studies are limited by their use of medical claims information, which can pose methodological challenges for accurate data reporting. In an earlier report, Mavrokokki and colleagues reported on the frequency of ARONJ in Australia.68 The authors utilized a mail survey of Australian oral and maxillofacial surgeons and other specialists as well as data from the Australia Adverse Drug Reaction Committee. One hundred and fifty eight cases of ARONJ were reported with nearly three-quarters occurring in cancer patients. A dental extraction was considered the precipitating factor in 73% of the cases. When investigating patients receiving bisphosphonate therapy for the treatment of osteoporosis, the frequency of ARONJ was observed to range from 1 in 2,260 (0.04%) to 1 in 8,470 (0.01%). However, when focusing on the population that underwent a dental extraction, the frequency of ARONJ was observed to range from 1 in 1,130 (0.09%) to 1 in 296 (0.34%). More recently, Lo and colleagues investigated the prevalence of ARONJ, using the AAOMS definition, in patients with a history of chronic oral bisphosphonate use treated within a large US health care delivery system.69 Of the 8,572 survey respondents, 2,159 reported pertinent dental symptoms and of these 2,159, 1,005 received a dental examination and 536 permitted review of their dental records. Nine cases of ARONJ were identified with a dental extraction reported to be a common initiating event in four of the nine cases. Overall, the data indicate a prevalence of ARONJ in this population of 1 in 952 bisphosphonate users, or approximately 0.10%. Because previous estimates68, 72 had ranged from 0.001% to 0.01% among oral bisphosphonate users, these data represent the highest current estimate of ARONJ in a population of oral bisphosphonate users. In the study by Sedghizadeh et al.,73 nine of 208 patients taking oral bisphosphonates for low bone density and being treated in dental school clinics, had active ONJ. A corresponding prevalence of over four percent ARONJ has not been duplicated by other investigators and may, in part, be attributable to a relatively small sample size. A Dental Practice-based Research Network study74 estimated ONJ incidence and odds ratios for bisphosphonate exposure of all individuals in two large health-care organizations by searching the electronic records and charts. Fellows and colleagues reported an ONJ incidence of 0.63 per 100,000 person-years for all individuals. Individuals taking oral bisphosphonates were 15.5 (confidence interval, 6.0 – 38.7) times more likely to have ONJ than individuals who were not exposed to bisphosphonates. Novartis sponsored a randomized controlled trial that studied the effect of once yearly zoledronate administered intravenously for treatment of osteoporosis in 7,714 postmenopausal subjects. Study results demonstrated clinical efficacy in preventing vertebral and hip fractures. In the three-year study, no ARONJ cases were reported. However, patients were not evaluated for jaw problems. A retrospective search of the adverse events database identified two possible cases of ONJ (defined as the presence of exposed bone for more than six weeks), one case in the treatment and one incidence in the placebo group.75 Currently, there are insufficient data to determine the risk for ARONJ associated with yearly zoledronic acid infusion for treating osteoporosis. The prevalence of ARONJ is higher in cancer patients. A 2010 systematic review in cancer patients revealed that the prevalence of ARONJ varies depending on the type and quality of studies. Analysis of 22 studies examining data from 39,124 individuals resulted in a mean weighted prevalence of 6.1% cases of ARONJ. However, when selecting studies with comprehensive and well-documented follow-up, the total sample included 927 individuals and the mean weighted prevalence was 13.3%. Other studies that reviewed medical records of 8,829 individuals showed a mean weighted prevalence of 0.7% and epidemiological studies that included 29,386 individuals showed a mean weighted prevalence of 1.2%.76 Therefore, prospective, well-controlled studies are needed to better determine the true prevalence of ARONJ worldwide. TABLE 2. SUMMARY OF PUBLISHED STUDIES ESTIMATING RISK FOR ARONJ IN PATIENTS ON ANTIRESORPTIVE THERAPY FOR TREATMENT OF OSTEOPOROSIS New antiresorptive agents and ARONJ risk. Denosumab, a new non-bisphosphonate antiresorptive agent, was recently approved by the FDA for the treatment of women with postmenopausal osteoporosis and for the prevention of skeletal-related events in patients with bone metastasis. Denosumab inhibits bone resorption by binding to receptor activator of nuclear factor kappa-B ligand (RANKL), a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts, the cells responsible for bone resorption. Following a single subcutaneous dose, the median time to maximum denosumab serum concentration was 10 days (range: 3 to 21 days). Denosumab concentrations declined over a period of 4 to 5 months with a mean half-life of 25.4 days (SD = 8.5 days; n = 46).77 No residual effect on bone was noted after six months, and markers of bone turnover rose to normal postmenopausal levels. In completed osteoporosis clinical trials representing 16,348 patient-years of follow-up, using 60 mg of denosumab every six months, no potential cases of ONJ were positively adjudicated. A total of five years of follow-up has been completed for all subjects who initially participated in the three-year pivotal fracture study39 and are now participating in the seven-year open-label extension. ONJ was positively adjudicated in two subjects during the first two years of the extension study (H. Varav, Amgen, personal communication, September 2010). This represents a prevalence of ARONJ of 0.061%. For comparison in cancer patients, a study examining denosumab versus zoledronic acid for the treatment of bone metastases, found no significant difference in the occurrence of ARONJ (2.0%, denosumab; 1.4%, zoledronic acid; P=0.39).78 3.2 Pharmacology In 2005, Novartis and the FDA issued drug precautions regarding ARONJ, a condition observed in cancer patients receiving intravenous bisphosphonate treatment.79 The precautions also raised concerns about patients who receive invasive dental treatment while taking oral bisphosphonates for other conditions. Zometa ™ (zoledronic acid) is used for cancer therapy, while Reclast™ (zoledronic acid) is used for osteoporosis and metabolic bone disease. Intravenous infusion is used for both therapies, however the dose used for cancer therapy is approximately 48 mg per year as compared to 5 mg per year for osteoporosis therapy. It is believed that the higher concentration of zoledronic acid, skeletal issues associated with cancer therapy and steroid use, as well as intravenous route with greater bioavailability contribute to a higher incidence of ARONJ. In general, less than one percent of the dose of an oral bisphosphonate is absorbed by the gastrointestinal tract, whereas more than 50 percent of the dose of an intravenous bisphosphonate is available for incorporation into the bone matrix.80 Though it is early in the investigative stage, the relationship between bisphosphonate exposure and the occurrence of ONJ appears to be consistent with Bradford Hill‟s criteria for causality as shown in the Table 3. 81 Bisphosphonates have shown benefit in the short-term treatment (fewer than six months) of periodontal disease and avascular necrosis of the hip.88, 89, 94, 95 However, the median time to onset of ARONJ in patients taking alendronate is reportedly more than two years.68 Also, two of the studies reporting a benefit used topical rather than systemic bisphosphonate administration. Recent animal studies (rodent models) have provided preliminary evidence that alendronate and zoledronic acid impair angiogenesis and delay bone formation, resulting in reduced healing after dental extraction. 96, 97 Prolonged bisphosphonate use in humans (more than three years) may result in poorly functional, highly multinucleated osteoclasts with nuclear condensation and poor adhesion to bone surface.98 A recent study in dogs found that three years of daily oral bisphosphonate treatment significantly reduced bone turnover and increased the incidence of matrix necrosis in the mandible.99 TABLE 3. ANTIRESORPTIVE THERAPY AND OSTEONECROSIS OF THE JAW – ASSOCIATION OR CAUSATION? To date, studies have consistently shown that the risk for developing ARONJ is higher for cancer patients on intravenous bisphosphonate therapy than for patients on oral bisphosphonate therapy for low bone density. Therefore, clinical recommendations are specific to the type of bisphosphonate therapy administered. Recommendations for cancer patients on intravenous therapy were initially developed by an expert panel and were published in 2006.100 The American Academy of Oral Medicine and the American Association of Oral and Maxillofacial Surgeons have also published position papers on managing the care of patients with ARONJ.5, 101 Readers should refer to these documents to obtain recommendations for the management of cancer patients on intravenous bisphosphonate therapy and patients with ARONJ. The American Dental Association, the American Academy of Oral and Maxillofacial Pathology, the American Association of Oral and Maxillofacial Surgeons and the American Society for Bone and Mineral Research also have published papers on ARONJ.1, 102-104 The National Osteoporosis Foundation,105 the American Association of Endodontists106 and the American College of Rheumatology107 among others, also have addressed these issues. 3.3 Clinical presentation of ARONJ AAOMS uses the following case definition to describe bisphosphonate-related osteonecrosis of the jaw: exposed bone in the maxillofacial region persisting for more than eight weeks in a patient who is taking, or has taken, a bisphosphonate and has not had radiation therapy to the head and neck.101 This advisory committee also accepts the 2009 AAOMS staging criteria described in Table 4, but extends the criteria to patients taking any antiresorptive agent, rather than being restricted to a bisphosphonate. Clinical signs and symptoms of ARONJ typically include variable reports of pain, soft-tissue swelling and infection, loosening of teeth, halitosis, drainage, and exposed bone. Symptoms spontaneously may occur in the bone; or, more commonly, at a non-healing site following tooth extraction. In some cases, clinical features of osteonecrosis may not be obvious or even clinically detectable. In other cases, patients may present with pain, clinical swelling and/or purulent drainage in the absence of visible exposed necrotic bone.108 An asymptomatic patient can have ARONJ for weeks or months before exposed alveolar bone is detected by routine examination. Some patients may seek care because of oral pain or other non-specific symptoms but in the absence of signs of infection or bone exposure. In other patients, symptoms of ARONJ can mimic dental or periodontal disease; however, these symptoms do not typically resolve following routine dental and periodontal treatment. In challenging presentations such as these, involving a patient known to be receiving or to have previously received bisphosphonate therapy, stage 0 ARONJ should be considered in the differential diagnosis. If a practitioner suspects a patient to have ARONJ, they should contact the FDA‟s MedWatch program at http://www.fda.gov/Safety/MedWatch/HowToReport/default.htm or 800-FDA-1088 . 4.0 PANEL CONCLUSIONS Based on a review of the available scientific literature and expert opinion, the panel reached the following conclusions: A non-cancer patient‟s risk of developing ARONJ appears to be low with the highest prevalence estimate in a large sample of about 0.10%.69 At present there are no studies that adequately address incidence. The few studies to date use a wide range of methods, all with potential shortcomings, and come to varied estimates. Without good information on the incidence of ARONJ, it is difficult to predict risk in general, and impossible to predict an individual patient‟s risk. ARONJ can occur spontaneously, but is more commonly associated with specific medical and dental conditions, including dental procedures or conditions that increase the risk for bone trauma. Most commonly, ARONJ is associated with invasive bone procedures such as dental extractions.55 Older age (over 65 years), periodontitis, prolonged use of bisphosphonates (more than two years), smoking, denture wearing and diabetes have been associated with an increased risk for ARONJ.59, 62-64, 109 Corticosteroid use was not consistently found to be a risk factor.61, 65-67 One study (that controlled for the effects of several known or potential confounders) found that smoking and obesity were risk factors for developing ARONJ in cancer patients receiving intravenous zoledronic acid.110 If a physician prescribes or is planning to prescribe an antiresorptive agent, it is important for the patient and the patient‟s dentist to be informed. The panel advises that clinicians ask questions about osteoporosis, osteopenia and the use of one of the various antiresorptive agents, during the health history interview process. Both medical and dental communities continue to study ways to prevent and treat ARONJ to ensure the safest possible result for dental patients taking antiresorptive agents. The physician serves as the best source of information regarding the need for antiresorptive therapeutic agents. Given the significant benefits of these medications, and the significant skeletal and psychosocial complications of  osteoporosis, a physician will likely recommend continued antiresorptive treatment despite the slight risk of developing ARONJ. While neither the physician nor the dentist can eliminate the possibility of ARONJ development, regular dental visits and maintaining excellent oral hygiene are essential parts of risk management for the patient. Open communication regarding treatment options is a fundamental requirement for all members of the healthcare team, but particularly in patients with significant dental concerns or active ARONJ. 5.0 PANEL RECOMMENDATIONS FOR THE DENTAL MANAGEMENT OF NONCANCER PATIENTS RECEIVING ANTIRESORPTIVE THERAPY These recommendations focus on conservative surgical procedures, proper infection control technique, appropriate use of oral antimicrobials and the principle of effective antibiotic therapy when indicated. Because of a paucity of clinical data on the dental management of patients on antiresorptive therapy, these recommendations primarily are based on expert opinion. They are intended to help dentists make clinical decisions and should be considered with the practitioner‟s professional judgment and the patient‟s preferences. Dentists are encouraged to visit http://www.ada.org/2594.aspx?currentTab=2 before treating patients taking antiresorptive agents. As new information becomes available, these recommendations will be updated, as appropriate. 5.1 General treatment recommendations Routine dental treatment generally should not be modified solely due to use of antiresorptive agents. All patients should receive routine dental examinations. Patients who are prescribed antiresorptive agents and are not receiving regular dental care would likely benefit from a comprehensive oral examination before or early in their treatment. Informing patients prior to dental care. A discussion of the risks and benefits of dental care with patients on antiresorptive therapy is appropriate. When informing a patient about the risk of ARONJ, the dental care provider must keep in mind that the patient may not be aware of this risk.111 This may raise patient concerns about the continuation of dental treatment. Points that could be discussed with the patient when informing about risks of bisphosphonate therapy include: Antiresorptive therapy for low bone mass use places them at low risk for developing ARONJ (the highest prevalence estimate in a large sample is 0.10%). The low risk for developing ARONJ can be minimized but not eliminated. An oral health program consisting of sound oral hygiene practices and regular dental care may be the optimal approach for lowering the risk for developing ARONJ. There is no validated diagnostic technique currently available to determine which patients are at increased risk for developing ARONJ. Discontinuing bisphosphonate therapy may not eliminate any risk for developing ARONJ. However, discontinuation of bisphosphonate therapy may have a negative impact on the outcomes of low bone mass treatment. Therefore, significant dental risks need to be present to consider cessation of antiresorptive therapy for low bone mass, cancer or other off-label therapies. Discussion with all members of the healthcare team is recommended prior to discontinuing therapy. The patient should be informed of the dental treatment needed, alternative treatments, how any treatment relates to the risk of ARONJ, other risks associated with various treatment options, and the risk of foregoing treatment, even temporarily. The patient should be encouraged to consult with his/her physician about health risks associated with discontinuation of antiresorptive therapy. All decisions with respect to utilization of drugs prescribed for medical conditions should be discussed with the prescribing physician. Misinformation and misunderstandings can lead to severe and preventable adverse events. Therefore, efforts should be made to present to the patient a balanced assessment of the current information.112 Patients taking antiresorptive agents should be instructed to contact their dentist if any problem develops in the oral cavity. Making treatment decisions. The dental provider may face the decision of whether or not to treat a patient who has been exposed to antiresorptive agents. As discussed above, the risk for ARONJ is lower for a patient who is not taking these drugs for cancer therapy. The panel recommends that a patient with active dental or periodontal disease should be treated in spite of the risk for ARONJ because the risks and consequences of no treatment likely outweigh the risks of developing ARONJ. Leaving active dental pathology (caries, periodontal disease, extensive periapical abscesses or granulomas) untreated can lead to future complications that may require more extensive and risky treatments. Prior to starting therapy, patients should be informed to the fullest extent possible. The dentist should consider documenting the discussion of risks, benefits and treatment options with the patient (see discussion above) and obtaining the patient‟s written acknowledgment of that discussion and consent for the chosen course of treatment. The dentist should retain in the patient‟s record the acknowledgment and consent for treatment. Dentists are advised to review the above discussion on the risks associated with low-bone density so that an appropriate informed consent is obtained. Prevention and treatment planning. Strategies for managing the oral health of patients on antiresorptive therapy in an effort to prevent ARONJ are described in Table 5. A major goal in the prevention of ARONJ is to limit the possibility of extensive or multifocal involvement. Despite limited supporting evidence, a localized clinical approach to dentoalveolar surgery in patients on antiresorptive therapy for low bone density may help the practitioner to assess risks on an individual basis and before putting multiple quadrants at risk. Common scenarios include, but are not limited to, a patient needing full mouth extractions for dentures or a patient needing full mouth periodontal surgery. For example, a single tooth extraction or one sextant of alveolar surgery could be performed initially while treating the patient with chlorhexidine, or another topical antiseptic.113 Patient healing response may be assumed to be adequate once normal healing of the surgical site(s) is observed. Antiseptic agents may be used longer if the area remains inflamed, irritated or erythematous. After establishing the patient‟s apparent adequate healing response a more accelerated surgical treatment plan involving multiple (or all) sextants at a single appointment could be considered. Because periapical pathoses, sinus tracts, purulent periodontal pockets, severe periodontitis and active abscesses that already involve the medullary bone, may exacerbate osteonecrosis and are themselves risk factors for ARONJ, they should be treated expeditiously. When dental pathoses are not evident, the trial sextant approach may be applicable. The sextant by sextant approach does not apply to emergency cases, even if multiple quadrants are involved. TABLE 5. PREVENTION STRATEGIES FOR PATIENTS ON ANTIRESORPTIVE THERAPY* (ABSENT EVIDENCE OF STAGE 1, 2 OR 3 ARONJ**) 5.2 Treatment recommendations for specific conditions Management of periodontal diseases. Individuals on antiresorptive therapy who have active chronic periodontal diseases should generally receive appropriate forms of nonsurgical therapy, which should be combined with the commonly recommended reevaluation at four to six weeks. This is not to say that surgical procedures are contraindicated in these patients, only that minimization of dento-alveolar manipulation is generally preferred. Because dental extractions constitute a risk factor for ARONJ, patients should be regularly monitored and treated with the goal of preventing progression of periodontal disease to the point where dental extractions are necessary. The goal of surgical periodontal treatment should be to obtain access to root surfaces, and preference should be placed on the use of atraumatic techniques when possible. There are no published studies that evaluate the risk of ARONJ or the success of implant treatment following periodontal procedures such as guided tissue regeneration or bone replacement grafts. Use of such techniques should be judiciously considered based on patient need. Primary soft tissue closure following periodontal surgical procedures is desirable, when feasible, though extended periosteal bone exposure for the sake of primary closure may increase, rather than decrease, the risk of ARONJ. Patients without periodontal disease should receive preventive therapy or instruction for prevention of periodontal disease. Implant placement and maintenance. The risk of ARONJ and/or implant failure in female patients with a history of bisphosphonate use has been examined in several relatively small, short-term studies. Although there are case reports of ARONJ at implant osteotomy sites, the relative scarcity of ARONJ and dental implant failure in bisphosphonate users despite the large number of these patients receiving dental implants is reassuring. Indeed, Fugazzotto and colleagues noted no ARONJ post-operatively in 61 patients with an average duration of bisphosphonate use of 3.3 years.114 None of the implants failed in this population. In a population of 101 implants placed in 42 bisphosphonate users (range 6 months to 11 years duration of use prior to implant placement), Bell and Bell observed no ARONJ and a 95% implant success rate.115 Using phone and e-mail surveys, Grant and colleagues noted no ARONJ associated with 468 implants placed in 115 bisphosphonate users with a 99.6% success rate.116 Koka and colleagues compared 121 implants placed in 55 bisphosphonate users (approximately one third over 5 years of use) with 166 implants placed in 82 non-users.117 No ARONJ was observed in either group and the implants in the two groups showed similar profiles with a 99.2% success rate in bisphosphonate users and a 98.2% in non-users. Taken together, these data are encouraging. Patients may be informed that the risk of ARONJ as a result of antiresorptive therapy is low, and that the success rates of implants placed in bisphosphonate users appears to be no different than the success rates of implants placed in patients without a history of bisphosphonate use in the short-term. Presently, antiresorptive therapy does not appear to be a contraindication for dental implant placement. However, larger and longer-term studies are needed to determine if implants do as well in patients exposed to antiresorptive agents in comparison to those who have not been exposed to these agents. Oral and maxillofacial surgery. When treatment of dental and/or periodontal diseases has failed, surgical intervention may be the best alternative. Patients receiving antiresorptive therapy who are undergoing invasive surgical procedures should be informed of the risk, albeit small, of developing ARONJ. Alternative treatment plans should be discussed with the patient, which include: endodontics (including endodontic treatment followed by removal of the clinical crown), allowing the roots to exfoliate (instead of extraction), and use of fixed and removable partial dentures. If extractions or bone surgery are necessary, conservative surgical technique with primary tissue closure, when feasible, should be considered. Placement of semipermeable membranes over extraction sites may also be appropriate if primary closure is not possible. In addition, before and after any surgical procedures involving bone, the patient should gently rinse with a chlorhexidine-containing rinse until healed. The regimen may be extended based on the patient‟s healing progress but use twice daily for 4-8 weeks would be a common regimen. There is some evidence that antibiotic prophylaxis starting one day before and extending 3 to 7 days after dental procedures may be effective in preventing ARONJ.118 In addition, use of chlorhexidine and systemic antibiotics pre and post tooth extraction appeared to reduce the risk of ARONJ in a small study of 23 patients undergoing tooth extraction.119 In patients who already have ARONJ, there is limited evidence that teriparatide, a recombinant form of parathyroid hormone, may be helpful in the treatment of ARONJ.120, 121 Endodontics. In patients with elevated risk of ARONJ, endodontic treatment is preferable to surgical manipulation if a tooth is salvageable. Routine endodontic technique should be used and manipulation beyond the apex is not recommended. There is limited evidence that periapical healing after endodontic therapy is similar regardless of whether a patient has a history of bisphosphonate use.122 Endodontic surgical procedures should be guided by the same recommendation as is used for any oral and maxillofacial surgical procedure described above. Restorative dentistry and prosthodontics. There is no evidence that malocclusion or masticatory forces increase the risk for ARONJ. All routine restorative procedures should be performed with the goal to minimize the impact on bone, so as not to increase the risk of infection. Prosthodontic appliances in patients should be promptly adjusted for fit in order to avoid ulceration and possible bone exposure. Orthodontics. There are no published studies examining the effect of bisphosphonates on orthodontia. Case reports have recounted inhibited tooth movement in patients taking bisphosphonates.123, 124 Patients should be advised of this potential complication. Orthodontics is unique in the dental specialties in that its very existence is based on the delicate balance between osteoclast and osteoblast function. While orthodontic treatment occurs predominantly in children and early adolescent patients, one in five orthodontic patients in the US is an adult.125 There have been sporadic reports in the orthodontic literature on the differences of treating post-menopausal patients. The orthodontic literature concerning bisphosphonates concentrates primarily in the ability of these drugs to stabilize teeth post-treatment or with focal topical application to a localized area during therapy.126 But now with the advent of antiresorptive bone agents there are potentially 44 million Americans where orthodontic movement may be compromised by the medication. The potential problem of ARONJ and the alteration of the bone physiology caused by antiresorptive therapy need to be recognized by orthodontists.95, 124, 127 The orthodontist should remain vigilant that the tooth movement is proportional to the amount of force being applied. It is possible that orthodontic treatment duration will be longer in bisphosphonate users. 6.0 CTX TESTING AND DRUG HOLIDAYS Serum-based bone turnover markers are biochemical markers of bone remodeling. Two such markers are CTx and NTx. These markers together represent each end of the three strands of type 1 collagen and each is used in tests that monitor bone turnover. Some studies advocate the use of sCTx for predicting the risk of developing ARONJ,101, 128-132 while others question its utility.133-137 Because some recommendations address the use of sCTx, this section will examine the limitations of sCTx as a risk predictor for ARONJ; and will discuss why the panel does not recommend the use of sCTx for ARONJ risk assessment. First, the wide variability of sCTx (values vary throughout any give 24-hour period) and the wide range of reference values makes individual test results unreliable and difficult to extrapolate from a given study population or test group.129, 130, 133 In addition, a general lack of baseline sCTx levels in patients prior to beginning antiresorptive therapy makes it difficult to assess the significance of values obtained following the start of treatment. Total sCTx is a mixture of four distinct forms of the molecule. The forms represent a maturation of bone ages: αL reflects the youngest bone, followed by βL, βD and, finally, αD, which reflects the oldest bone. Assays may detect one, two, three or four of these agerelated CTx isoforms. But most often, either only one form or an unknown combination of these forms is assayed. The interested reader of CTx literature is warned that most studies fail to identify the CTx form being assayed. Also comparisons between papers are difficult if the assayed form(s) is not identified, and the reference ranges by age and gender are unknown.133, 138-146 Only one laboratory performs sCTx analyses for patient samples in the United States (Quest Diagnostics, Nichols Institute, San Juan Capistrano, CA). The laboratory analyzes specimens for type 1 collagen by conducting assays for the βL subtype, the second youngest bone (M. Caufield, Quest Diagnostics, personal communication, September 2010). The reference ranges of the laboratory’s test results vary widely as shown in Table 6. Type 1 collagen is found in soft tissues and cartilage, as well as in bone. Therefore, sCTx laboratory results are not solely representative of bone. More than one sCTx measurement is needed to assess what, if any, of the sCTx level is related to bone. Consideration should also be given to baseline values, antiresorptive agent accumulation, and dosing patterns. In one of the first articles to recommend the use of sCTx for predicting patient risk for the development of ARONJ by Marx et al,128 the study population was small (n=30) and all of the study subjects had ARONJ. At the time initial laboratory values obtained, roughly half of the subjects were on bisphosphonate therapy and the other half were not. Furthermore, the picogram level selected as the predictive level for patient risk (150 picograms) was within the reference ranges (as indicated above). It is noteworthy that there is no reference range for women aged 50 years or older nor for men or women over 68. A 2009 study131 found that in individuals with a history of receiving bisphosphonate therapy, sCTx values varied from 100 pg/ml to more than 300 pg/ml. In addition, based on the results of a small study comparing radiographic markers to CTX, Fleisher et al. reported that the radiographic findings of sclerotic change may be a more sensitive predictor of ARONJ risk compared to sCTx levels.135 The wide ranging values of these data and the lack of reference values in significant patient segments suggest that sCTx levels would have limited use for assessing risk for ARONJ in the individual patient or guiding treatment decisions. Marx et al.128 noted that sCTx levels rose in patients with ARONJ after their oral bisphosphonate therapy was discontinued. In a 2009 position paper,101 the AAOMS recommended a drug “holiday” three months before and after surgical intervention, concluding that the Marx paper showed that the drug holiday invariably raised sCTx levels. In the Marx study all subjects had ARONJ. There are no published studies that demonstrate that either drug holidays or higher sCTx levels reduce the incidence of ARONJ. It is also unclear how drug holidays will affect the risk for fracture. There has been a study on fracture risk that compared discontinuing alendronate after five years to continuing alendronate for ten years.147, 148 The results suggest that for women not at high risk of clinical vertebral fractures, discontinuation of alendronate after five years does not significantly increase fracture risk. However, there is no data on the effect of discontinuing antiresorptive therapy before five years, ARONJ can occur in patients on antiresorptive therapy for less than five years, and studies on whether alendronate findings can be extrapolated to other bisphosphonates have yet to be performed. The panel believes the following concerns should be addressed before recommendations can be made: 1. The release/expression of CTx/NTx relies on bone turnover129, 130 and osteoclast function is specifically inhibited by increased deposition of bisphosphonate in the bone.149, 150 2. CTx/NTx serum levels measure total body expression/release, and, therefore, do not measure the release from the alveolar processes of the jaws specifically. 3. Bisphosphonates are not equally deposited (throughout the skeleton). Due to the high bone turnover rate in the jaws, bisphosphonates are particularly  concentrated within the alveolar processes due to the „homing in” effect of bisphosphonates.150 4. How osteoclasts function (and therefore how CTx/NTx is released from jaw) with the above mentioned local increases in antiresorptive agent levels, has yet to be studied. 5. Systemic measurements may identify localized release of CTx in cancer patients.151 Such measurement, however, does not differentiate the site of bone turnover (i.e. not jaw specific). 6. The rate of bone turnover in the alveolar process in the jaw is several times higher than skeletal sites such as the femur and vertebral column; but with the concentration effect of bisphosphonates noted above (point 3) local CTx/NTx release may be different due to higher bisphosphonate concentrations in the jaw. 7. The jaw bones are at most risk of developing ARONJ, and they may have been affected by antiresorptive agents for a long duration. Measuring βL form, the second youngest of the type 1 collagen breakdown products, as is done in the currently available commercial test may, therefore, not be adequate or appropriate for risk assessment.150 For an excellent review of CTx and the many limitations associated with its use as a predictive test, the article by Baim and Miller may provide additional information.133 The article reviews many of the points above and provides a detailed look at sCTx use in a clinical setting. Notably, the authors state that the process of mailing samples to a central laboratory invites a host of uncontrolled variables involved with specimen collection, handling, temperature and storage. While there have been limited studies on stopping antiresorptive drugs (drug holidays) for treatment of ARONJ, currently there have yet to be studies to confirm drug holidays are effective in prevention of ARONJ without increasing the skeletally related risks of low bone mass. At present, there is insufficient evidence to recommend serum tests, such as sCTX as a predictor of ARONJ risk. In addition, there is insufficient evidence to recommend an antiresorptive “drug holiday” or waiting periods for prevention of ARONJ. 7.0 ARONJ STAGING AND TREATMENT STRATEGIES Using the AAOMS staging criteria, Table 7 presents treatment strategies for patients at risk for, and who present with, different stages of ARONJ. This report does not provide guidance on specific treatment strategies for managing patients with ARONJ. Treatment should be generally conservative while at the same time realizing that some severe cases will need large segments of necrotic bone removed and will leave large defects. Treatment will vary by individual case with secondary infection, necrosis and fracture often being difficult, but necessary, to address. There is limited evidence that conservative surgical intervention with the ER:YAG laser leads to clinical improvement.152-154 There is weak evidence to support discontinuation of antiresorptive therapy to promote healing when ARONJ is present.128, 155- 157 The decision to stop antiresorptive therapy must be weighed with the risks associated with the underlying systemic disease for which the antiresorptive agent is prescribed. Several studies have postulated a role of actinomyces spp. in ARONJ as well as in osteoradionecrosis (ORN).158, 159 The actinomyces are anaerobic gram-positive microorganisms considered to be early colonizers of the oral cavity and occasionally reported as the principal infectious agent of ARONJ lesions.160 In a histopathological study, 42/45 patients with the diagnosis of actinomycosis were found to have ARONJ (58.7%) and ORN (35.6%) of the oral cavity. These findings have led to speculation that actinomyces are opportunistic microorganisms that can infect bone already altered by medications or radiotherapy. 158, 161 Nevertheless, a pathogenic role for actinomyces as a single-organism in the pathobiology of ARONJ remains controversial. This can be further disputed because authors have demonstrated that the formation of a multiorganism biofilm in ARONJ lesions could participate in the pathogenesis of this type of osteonecrosis.162, 163 Because of difficulties related to isolating actinomyces, it is not always clear if their presence is due to surface colonization or a deep infection that contributes to the pathogenesis of osteonecrosis.159 In a case report of a patient with an advanced case of Actinomycesinfected ARONJ, the lesion was treated with intravenous penicillin G (18 MU/day) in combination with intravenous metronidazole (1.5 g/day) for 6 weeks, followed by oral administration of oral amoxicillin (1.5 g/day) for 6 months. The aggressive treatment controlled infection and purulent drainage, but did not affect the necrotic bone area that continued to be exposed to the oral cavity.160 At this point, the panel suggests that intravenous therapy should be reserved for advanced stages (stage 3 OMFS) where there is supportive evidence (culture plus clinical evidence of purulence) for active actinomycotic infection of ARONJ lesions. It has been recently shown that chlorhexidine has a positive effect in controlling surface based actinomycotic colonizations such as are seen in oral biofilms.164 For the more common lower stage cases where only actinomycotic surface colonization is suspected, chlorhexidine mouth rinses can be used with oral amoxicillin/penicillin added if indicated. 8.0 RECOMMENDATIONS FOR RESEARCH Based on the current literature on ARONJ pathophysiology, and based on the lack of knowledge of the factors that place patients at risk for developing ARONJ, the panel recommends that research be conducted on a number of topics identified below. 8.1 Basic research Researchers should investigate the molecular mechanisms that lead to development of ARONJ, the role of antiresorptive drugs in altering bone remodeling, and its effects on ARONJ. Research on pharmacogenetic factors that place patients at risk for ARONJ may be helpful for identifying patients at increased risk. 8.2 Clinical research Researchers should continue or initiate adequately designed studies that: • better define risks associated with routine dental therapy, placing dental implants and bone augmentation, orthodontic treatment, and tooth extraction in patients on antiresorptive therapy • concomitant risk factors (e.g. oral and systemic disease) • address the dental management of patients with ARONJ • collaborate with bone specialists in order to establish whether ARONJ is a localized or systemic condition. Bone biopsy and histomorphometric assessment will provide insights into the underlying bone pathology • evaluate the effect of discontinuing antiresorptive therapy and relevance to healing • evaluate the use of surrogate bone markers relative to risk for, and treatment of, ARONJ • evaluate screening and diagnostic tests In addition, it would be desirable to have a national registry that would allow systematic study of cases of ARONJ related to antiresorptive therapy and the effect of co-morbidities and concurrent therapies. REFERENCES 1. Edwards B, Hellstein J, Jacobsen P, Kaltman S, Mariotti A, Migliorati C. Updated recommendations for managing the care of patients receiving oral bisphosphonate therapy: an advisory statement from the American Dental Association Council on Scientific Affairs. J Am Dent Assoc. 2008;139(12):1674-1677. 2. Newman Dorland WA. Dorland’s Illustrated Medical Dictionary. Vol 31st ed. Philadelphia: Saunders Elsevier; 2007:1368. 3. Greuter S, Schmid F, Ruhstaller T, Thuerlimann B. Bevacizumab-associated osteonecrosis of the jaw. Ann Oncol. December 2008;19(12):2091-2092. 4. Almazrooa SA, Woo SB. Bisphosphonate and nonbisphosphonate-associated osteonecrosis of the jaw: a review. J Am Dent Assoc. 2009;140(7):864-875. 5. Migliorati CA, Casiglia J, Epstein J, Jacobsen PL, Siegel MA, Woo S-K. Managing the care of patients with bisphosphonate-associated osteonecrosis. J Am Dent Assoc. 2005;136:1658-1668. 6. Bekker P, Holloway D, Rasmussen A, et al. A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res. Jul 2004;19(7):1059-1066. 7. Aghaloo TL, Felsenfeld AL, Tetradis S. Osteonecrosis of the Jaw in a Patient on Denosumab. J Oral Maxillofac Surg. May 2010;68(5):959-963. 8. Abrahamsen B, van Staa T, Ariely R, Olson M, Cooper C. Excess mortality following hip fracture: a systematic epidemiological review. Osteoporos Int. 2009;20(10):1633- 1650. 9. Braithwaite RS, Col NF, Wong JB. Estimating hip fracture morbidity, mortality and costs. J Am Geriatr Soc. Mar 2003;51(3):364-370. 10. Browner WS, Pressman AR, Nevitt MC, Cummings SR. Mortality following fractures in older women. The study of osteoporotic fractures. Arch Intern Med. Jul 22 1996;156(14):1521-1525. 11. Caliri A, De Filippis L, Bagnato GL, Bagnato GF. Osteoporotic fractures: mortality and quality of life. Panminerva Med. . Mar 2007;49(1):21-27. 12. Cauley JA, Thompson DE, Ensrud KC, Scott JC, Black D. Risk of mortality following clinical fractures. Osteoporos Int. . 2000;11(7):556-561. 13. Ensrud KE, Thompson DE, Cauley JA, et al. Prevalent vertebral deformities predict mortality and hospitalization in older women with low bone mass. Fracture Intervention Trial Research Group. J Am Geriatr Soc. . Mar 2000;48(3):241-249. 14. Cauley JA, Wampler NS, Barnhart JM, et al. Incidence of fractures compared to cardiovascular disease and breast cancer: the Women’s Health Initiative Observational Study. Osteoporos Int. Dec 2008;19(12):1717-1723. 15. Browner WS, Pressman AR, Nevitt MC, Cummings SR. Mortality following fractures in older women. The study of osteoporotic fractures. Arch Intern Med. . Jul 22 1996;156(14):1521-1525. 16. Cauley JA, Hochberg MC, Lui LY, et al. Long-term risk of incident vertebral fractures. JAMA. Dec 19 2007;298(23):2761-2767. 17. Edwards BJ, Song J, Dunlop DD, Fink HA, Cauley JA. Functional decline after incident wrist fractures–Study of Osteoporotic Fractures: prospective cohort study. BMJ. Jul 8 2010;341:c3324. 18. National Osteoporosis Foundation. Osteoporosis Review of the Evidence for Prevention, Diagnosis and Treatment, and Cost Effectiveness Analysis. Osteoporos Int. 1998;Suppl 4:S1-S85. 19. Schneider EL, Guralnik JM. The aging of America: Impact on health care costs. JAMA. 1990;263:2335-2350. 20. Riggs BL, ed Epidemiology of Osteoporosis. Philadelphia: Lippincott-Raven Publishers; 1995. Melton LJ, III, ed. Osteoporosis: Etiology, Diagnosis, and Management. 21. Chrischilles EA, Butler CD, Davis CS, Wallace RB. A model of lifetime osteoporosis impact. . Arch Intern Med. 1991;151:2026-2032. 22. Cummings SR, Melton LJ. Epidemiology and outcomes of osteoporotic fractures. Lancet Oncol. 2002;359:1761-1767. 23. Melton L, Amadio PC, Crowson CS, O’Fallon WM. Long-term trends in the incidence of distal forearm fractures. Osteoporos Int. 1998;8(4):341-348. 24. Melton LJ, Atkinson EJ, Cooper C, O’Fallon WM, Riggs BL. Vertebral fractures predict subsequent fractures. Osteoporos Int. 1999;10:214-221. 25. Melton LJ, Therneau TM, Larson DR. Long term trends in hip fracture prevalence: the influence of hip fracture incidence and survival. Osteoporos Int. 1998;8:68-74. 26. Zingmond DS, Melton LJ, Silverman SL. Increasing hip fracture incidence in California Hispanics, 1983-2000. Osteoporos Int. 2004;15:603-610. 27. Bauer DC, Black DM, Garnero P, et al. Change in bone turnover and hip, non-spine, and vertebral fracture in alendronate-treated women: the fracture intervention trial. J Bone Miner Res. 2004;19(8):1250-1258. 28. Silverman SL, Watts NB, Delmas PD, Lange JL, Lindsay R. Effectiveness of bisphosphonates on nonvertebral and hip fractures in the first year of therapy: the risedronate and alendronate (REAL) cohort study. Osteoporos Int. Jan 2007;18(1):25- 34. 29. McClung MR, Geusens P, Miller PD, et al. Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med. Feb 1 2001;344(5):333-340. 30. Reginster JY, Adami S, Lakatos P, et al. Efficacy and tolerability of once-monthly oral ibandronate in postmenopausal osteoporosis: 2 year results from the MOBILE study. Ann Rheum Dis. 2006;65(5):654-661. 31. Watts NB, Diab DL. Long-term use of bisphosphonates in osteoporosis. J Clin Endocrinol Metabolism. Apr 2010;95(4):1555-1565. 32. Ravn P, Weiss SR, Rodriguez-Portales JA, et al. Alendronate in early postmenopausal women: effects on bone mass during long-term treatment and after withdrawal. Alendronate Osteoporosis Prevention Study Group. J Clin Endocrinol Metabolism. Apr 2000;85(4):1492-1497. 33. Johnson DA, Williams MI, Petkov VI, Adler RA. Zoledronic Acid Treatment of Osteoporosis: Effects in Men. Endocr Pract. 2010;16(6):960-967. 34. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;344(19):1434-1441. 35. Saag KG, Zanchetta JR, Devogelaer JP, et al. Effects of teriparatide versus alendronate for treating glucocorticoid-induced osteoporosis: thirty-six-month results of a randomized, double-blind, controlled trial. Arthritis Rheum. Nov 2009;60(11):3346-3355. 36. Lewiecki EM. RANK ligand inhibition with denosumab for the management of osteoporosis. Expert Opin Biol Ther. Oct 2006;6(10):1041-1050. 37. Morony S, Warmington K, Adamu S, et al. The inhibition of RANKL causes greater suppression of bone resorption and hypercalcemia compared with bisphosphonates in two models of humoral hypercalcemia of malignancy. Endocrinology. Aug 2005;146(8):3235-3243. 38. Reddy GK, Nadler E, Jain VK. Denosumab (AMG 162), a Fully Human Monoclonal Antibody Against RANK Ligand Activity. Support Cancer Ther. Oct 1 2005;3(1):14- 15. 39. Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. Aug 20 2009;361(8):756-765. 40. McClung MR, Lewiecki EM, Cohen SB, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. Feb 23 2006;354(8):821-831. 41. Lewiecki EM, Miller PD, McClung MR, et al. Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low BMD. J Bone Miner Res. Dec 2007;22(12):1832-1841. 42. Bone HG, Bolognese MA, Yuen CK, et al. Effects of denosumab on bone mineral density and bone turnover in postmenopausal women. J Clin Endocrinol Metab. Jun 2008;93(6):2149-2157. 43. Smith MR, Egerdie B, Hernández Toriz N, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med. Aug 20 2009;361(8):745-755. 44. Kyrgidis A, Toulis KA. Denosumab-related osteonecrosis of the jaws. Osteoporos Int. Mar 20 2010. 45. Miller PD, Bolognese MA, Lewiecki EM, et al. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone. Aug 2008;43(2):222-229. 46. Stoch SA, Zajic S, Stone J, et al. Effect of the cathepsin K inhibitor odanacatib on bone resorption biomarkers in healthy postmenopausal women: two double-blind, randomized, placebo-controlled phase I studies. Clin Pharmacol Ther. Aug 2009;86(2):175-182. 47. Bone HG, McClung MR, Roux C, et al. Odanacatib, a cathepsin-K inhibitor for osteoporosis: a two-year study in postmenopausal women with low bone density. J Bone Miner Res. May 2010;25(5):937-947. 48. Sutherland MK, Geoghegan JC, Yu C, et al. Sclerostin promotes the apoptosis of human osteoblastic cells: a novel regulation of bone formation. Bone. Oct 2004;35(4):828-835. 49. Moester MJ, Papapoulos SE, Lowik CW, van Bezooijen RL. Sclerostin: Current Knowledge and Future Perspectives. Calcif Tissue Int. May 15 2010. 50. Ominsky MS, Vlasseros F, Jolette J, et al. Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength. J Bone Miner Res. May 2010;25(5):948-959. 51. Padhi D, Jang G, Stouch B, Fang L, Posvar E. Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J Bone Miner Res. Jun 30 2010. 52. Roux C, Reginster JY, Fechtenbaum J, et al. Vertebral fracture risk reduction with strontium ranelate in women with postmenopausal osteoporosis is independent of baseline risk factors. J Bone Miner Res. Apr 2006;21(4):536-542. 53. Hamdy NA. Strontium ranelate improves bone microarchitecture in osteoporosis. Rheumatology (Oxford). Oct 2009;48(Suppl 4):iv9-13. 54. Marx RE. Pamidronate (Aredia) and zoledronic acid (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003;61:1115- 1117. 55. Migliorati C. Bisphosphonates and oral cavity avascular bone necrosis. J Clin Oncol. 2003;21:4253-4254. 56. Panigrahi I, Das RR, Sharda S, Marwaha RK, Khandelwal N. Response to zoledronic acid in children with type III osteogenesis imperfecta. J Bone Miner Metab. 2010;28:451-455. 57. Malmgren B, Astrom E, Soderhall S. No osteonecrosis in jaws of young patients with osteogenesis imperfecta treated with bisphosphonates. J Oral Pathol Med. 2008;37(4):196-200. 58. Landesberg R, Eisig S, Fennoy I, Siris E. Alternative indications for bisphosphonate therapy. J Oral Maxillofac Surg. May 2009;67(5 Suppl):27-34. 59. Khamaisi M, Regev E, Yarom N, et al. Possible association between diabetes and bisphosphonate-related jaw osteonecrosis. J Clin Endocrinol Metabolism. 2007;92(3):1172-1175. 60. Bagan JV, Murillo J, Jimenez Y, et al. Avascular jaw osteonecrosis in association with cancer chemotherapy: series of 10 cases. J Oral Pathol Med. 2005;34:120-123. 61. Boonyapakorn T, Schirmer I, Reichart PA, Sturm I, Massenkeil G. Bisphosphonateinduced osteonecrosis of the jaws: Prospective study of 80 patients with multiple myeloma and other malignancies. Oral Oncol 2008;44(9):857-869. 62. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: A review of 63 cases. J Oral Maxillofac Surg. 2004;62:527-534. 63. Vahtsevanos K, Kyrgidis A, Verrou E, et al. Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. J Clin Oncol. 2009;27(32):5356-5362. 64. Yarom N, Yahalom R, Shoshani Y, Hamed W, Regev E, Elad S. Osteonecrosis of the jaw induced by orally administered bisphosphonates: incidence, clinical features, predisposing factors and treatment outcome. . Osteoporos Int. 2007;18(10):1363- 1370. 65. Marx RE, Sawatari Y, Fortin M, Broumand V. Bisphosphonate-Induced Exposed Bone (Osteonecrosis/Osteopetrosis) of the Jaws: Risk Factors, Recognition, Prevention, and Treatment. J Oral Maxillofac Surg. 2005;63:1567-1575. 66. Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CY. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metabolism. 2005;90:1294-1301. 67. Barasch A, Cunha-Cruz J, Curro FA, et al. Risk Factors for Osteonecrosis of the Jaws: a Case-Control Study from the CONDOR Dental PBRN. J Dent Res. 2011;90(4):439-444. 68. Mavrokokki T, Cheng A, Stein B, Goss A. Nature and Frequency of BisphospnonateAssociated Osteonecrosis of the Jaws in Australia. J Oral Maxillofac Surg. 2007;65:415-423. 69. Lo JC, O’Ryan FS, Gordon NP, et al. Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure. J Oral Maxillofac Surg. Feb 2010;68(2):243-253. 70. Etminan M, Aminzadeh K, Matthew IR, Brophy JM. Use of Oral Bisphosphonates and the Risk of Aseptic Osteonecrosis: A Nested Case-Control Study. J Rheumatol 2008;35:1-5. 71. Cartsos VM, Zhu S, Zavras AI. Bisphosponate use and the risk of adverse jaw outcomes J Am Dent Assoc. 2008;139:23-40. 72. Felsenberg D, Hoffmeister B, Amling M. Bisphosphonattherapie assoziierte. Kiefernekrosen Deutsches Arzteblatt. 2006;46:A3078-A3080. 73. Sedghizadeh PP, Stanley K, Caligiuri M, Hofkes S, Lowry B, Shuler CF. Oral bisphosphonate use and the prevalence of osteonecrosis of the jaw: an institutional inquiry. J Am Dent Assoc. 2009;140(1):61-66. 74. Fellows JL, Rindal DB, Barasch A, et al. ONJ in Two Dental Practice-Based Research Network Regions. J Dent Res. 2011;90(4):433-438. 75. Grbic JT, Landesberg R, Lin S-Q, et al. Incidence of osteonecrosis of the jaw in women with postmenopausal osteoporosis in the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Pivotal Fracture Trial. J Am Dent Assoc. 2008;139:32-40. 76. Migliorati CA, Woo SB, Hewson I, et al. Bisphosphonate Osteonecrosis Section, Oral Care Study Group, Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO). A systematic review of bisphosphonate osteonecrosis (BON) in cancer. Support Care Cancer. 2010;18(8):1099-1106. 77. Amgen. Prescribing information for ProliaTM (denosumab). June 2010. 78. Stopeck AT, Lipton A, Body JJ, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010;28(35):5132-5139. 79. US Food and Drug Administration. Safety Alerts. MedWatch [2005; http://www.fda.gov/medwatch/SAFETY/2005/safety05.htm. Accessed Dec 2010. 80. Ezra A, Golomb G. Administration routes and delivery systems of bisphosphonates for the treatment of bone resorption. Adv Drug Deliv Rev. 2000;42:175-195. 81. Bradford Hill A. The Environment and Disease: Association or Causation? Proc Royal Soc Medicine. 1965;58:295-300. 82. Dimopoulos MA, Kastritis E, Anagnostopoulos A, et al. Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: evidence of increased risk after treatment with zoledronic acid. Hematologica. 2006;91:968-971. 83. Bamias A, Kastritis E, Bamia C, et al. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol. 2005;23:8580-8587. 84. Badros A, Weikel D, Salama A, et al. Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol. 2006;20:945-952. 85. Bagan JV, Jimenez Y, Murillo J, et al. Jaw osteonecrosis associated with bisphosphonates: Multiple exposed areas and its relationship to teeth extractions. Study of 20 cases. Oral Oncol 2006;42:327-329. 86. Wang J, Goodger NM, Pogrel MA. Osteonecrosis of the jaws associated with cancer chemotherapy. J Oral Maxillofac Surg. 2003;61:1104-1107. 87. Jeffcoat MK, Cizza G, Shih WJ, Genco R, Lombardi A. Efficacy of bisphosphonates for the control of alveolar bone loss in periodontitis. . J Int Acad Periodontol. 2007;9(3):70-76. 88. Reddy MS, Weatherford TW, Smith CA, III, West BD, Jeffcoat MK, Jacks TM. Aledronate treatment of naturally occurring periodontitis in beagle dogs. J Periodontol. 1995;66:211-217. 89. Little DG, McDonald M, Sharpe IT, Williams P, McEvoy T. Zoledronic acid improves femoral head sphericity in a rat model of perthes disease. J Orthop Res. 2005;23:862-868. 90. Shane E, Burr D, Ebeling PR, et al. Atypical subtrochanteric and diaphyseal femoral fractures: Report of a task force of the American Society for Bone and Mineral Research J Bone Miner Res. Nov 2010;25(11):2267-2294. 91. Edwards BJ, Gounder M, McKoy JM, et al. Pharmacovigilance and reporting oversight in US FDA fast-track process: bisphosphonates and osteonecrosis of the jaw. Lancet Oncol. Dec 2008;9(12):1166-1172. 92. Bi Y, Gao Y, Ehirchiou D, et al. Bisphosphonates cause osteonecrosis of the jaw-like disease in mice. Am J Pathol. Jul 2010;177(1):280-290. 93. Allen MR, Kubek DJ, Burr DB. Cancer treatment dosing regimens of zoledronic acid result in near-complete suppression of mandible intracortical bone remodeling in beagle dogs. J Bone Miner Res. 2010;25(1):98-105. 94. Adachi H, Igarashi K, Mitani H, Shinoda H. Effects of topical administration of a bisphosphonate (risedronate) on orthodontic tooth movements in rats. J Dent Res. 1994;73:148-184. 95. Liu L, Igarashi K, Haruyama N, Seeki S, Shinoda H, Mitani H. Effects of local administration of clodronate on orthodontic tooth movement and root resorption in rats. Eur J Orthod. 2004;26:469-473. 96. Aguirre JI, Altman MK, Vanegas SM, Franz SE, Bassit AC, Wronski TJ. Effects of alendronate on bone healing after tooth extraction in rats. Oral Dis. Oct 2010;16(7):674-685. 97. Kobayashi Y, Hiraga T, Ueda A, et al. Zoledronic acid delays wound healing of the tooth extraction socket, inhibits oral epithelial cell migration, and promotes proliferation and adhesion to hydroxyapatite of oral bacteria, without causing osteonecrosis of the jaw, in mice. J Bone Miner Metab. Mar 2010;28(2):165-175. 98. Weinstein RS, Roberson PK, Manolagas SC. Giant osteoclast formation and longterm oral bisphosphonate therapy. N Engl J Med. 2009;360(1):53-62. 99. Allen MR, Burr DB. Mandible matrix necrosis in beagle dogs after 3 years of daily oral bisphosphonate treatment. J Oral Maxillofac Surg. 2008;66:987-994. 100. Ruggiero S, Gralow J, Marx RE, et al. Practical Guidelines for the Prevention, Diagnosis, and Treatment of Osteonecrosis of the Jaw in Patients With Cancer. J Oncol Prac 2006;2:7-14. 101. Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, Mehrotra B. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaw – 2009 update. J Oral Maxillofac Surg. 2009;67:2-12. 102. Khosla S, Burr D, Cauley J, et al. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2007;22(10):1479-1491. 103. Advisory Task Force on Bisphosphonate-Related Ostenonecrosis of the Jaws, American Association of Oral and Maxillofacial Surgeons. Position Paper on Bisphosphonate-Related Osteonecrosis of the Jaw. J Oral Maxillofac Surg. 2007;65:369-375. 104. Woo SB, Hellstein JW, Kalmar JR. Bisphosphonates and Osteonecrosis of the Jaws. J Ann Intern Med. 2006;144:753-761. 105. Science and Research Committee of the National Osteoporosis Foundation. Osteonecrosis of the Jaw. 2006; http://www.nof.org/node/67. Accessed Oct 27, 2010. 106. American Association of Endodontists. Position Statement. Endodontic Implications of Bisphosphonate-associated Osteonecrosis of the Jaw. 2006; http://www.aae.org/ManagedFiles/pub/0/Pulp/bisphosonatesstatement.pdf. Accessed Dec 20, 2010. 107. Clarke B, Koka S. Bisphosphonate-associated osteonecrosis of the jaw. Hotline [2006; http://www.rheumatology.org/publications/hotline/0606onj.asp. Accessed Dec 20, 2010. 108. Mawardi H, Treister N, Richardson P, et al. Sinus tracts–an early sign of bisphosphonate-associated osteonecrosis of the jaws? J Oral Maxillofac Surg. 2009;67(3):593-601. 109. Mavrokokki T CA, Stein B, Goss A. Nature and Frequency of BisphospnonateAssociated Osteonecrosis of the Jaws in Australia. J Oral Maxillofac Surg. 2007;65:415-423. 110. Wessel JH, Dodson TB, Zavras AI. Zoledronate, smoking, and obesity are strong risk factors for osteonecrosis of the jaw: a case-control study. J Oral Maxillofac Surg. 2008;66(4):625-631. 111. Migliorati CA, Mattos K, Palazzolo MJ. How patients’ lack of knowledge about oral bisphosphonates can interfere with medical and dental care. J Am Dent Assoc. 2010;141(5):562-566. 112. Sambrook PN, Chen JS, Simpson JM, March LM. Impact of adverse news media on prescriptions for osteoporosis: effect on fractures and mortality. Med J Aust. 2010;193(3):154-156. 113. Vescovi P, Nammour S. Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) therapy. A critical review. Minerva Stomatol. 2010;59(4):181-203. 114. Fugazzotto P, Lightfoot WS, Jaffin R, Kumar A. Implant placement with or without simultaneous tooth extraction in patients taking oral bisphosphonates: Postoperative healing, early follow-up, and the incidence of complications in two private practices. J Periodontology. 2007;78:1664-1669. 115. Bell BM, Bell RE. Oral bisphosphonates and dental implants: a retrospective study. J Oral Maxillofac Surg. 2008;66(5):1022-1024. 116. Grant BT, Amenedo C, Freeman K, Kraut RA. Outcomes of placing dental implants in patients taking oral bisphosphonates: a review of 115 cases. J Oral Maxillofac Surg. 2008;66:223-230. 117. Koka S, Babu NM, Norell A. Survival of dental implants in post-menopausal bisphosphonate users. Prosthodont Res. 2010;54:108-111. 118. Montefusco V, Gay F, Spina F, et al. Antibiotic prophylaxis before dental procedures may reduce the incidence of osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates. Leuk Lymphoma. Nov 2008;49(11):2156- 2162. 119. Lodi G, Sardella A, Salis A, Demarosi F, Tarozzi M, Carrassi A. Tooth extraction in patients taking intravenous bisphosphonates: a preventive protocol and case series. J Oral Maxillofac Surg. Jan 2010;68(1):107-110. 120. Narongroeknawin P, Danila MI, Humphreys LG, Jr., Barasch A, Curtis JR. Bisphosphonate-associated osteonecrosis of the jaw, with healing after teriparatide: a review of the literature and a case report. Spec Care Dentist. Mar-Apr 2010;30(2):77- 82. 121. Lee JJ, Cheng SJ, Jeng JH, Chiang CP, Lau HP, Kok SH. Successful treatment of advanced bisphosphonate-related osteonecrosis of the mandible with adjunctive teriparatide therapy. Head Neck. Mar 22 2010. 122. Hsiao A, Glickman G, He J. A retrospective clinical and radiographic study on healing of periradicular lesions in patients taking oral bisphosphonates. J Endod 2009;35:1525-1528. 123. Schwartz JE. Ask us: Some drugs affect tooth movement. Am J Orthod Dentofacial Orthop. 2005;127:644. 124. Rinchuse DJ, Sosovicka MF, Robison JM, Pendleton R. Orthodontic treatment of patients using bisphosphonates: A report of 2 cases. Am J Orthod Dentofacial Orthop. 2007;131:321-326. 125. American Association of Orthodontists. Myths and Facts. 2010; http://www.braces.org/mythsandfacts/index.cfm. Accessed January 12, 2010. 126. Iglesias-Linares A, Yáñez-Vico RM, Solano-Reina E, Torres-Lagares D, González Moles MA. Influence of bisphosphonates in orthodontic therapy: Systematic review. J Dent. 2010;38(8):603-611. 127. Zahrowski JJ. Optimizing orthodontic treatment in patients taking bisphosphonates for osteoporosis. Am J Orthod Dentofacial Orthop. 2009;135(3):361-374. 128. Marx RE, Cillo JE, Jr., Ulloa JJ. Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg. 2007;65:2397-2410. 129. Hannon RA, Eastell R. Bone markers and current laboratory assays. Cancer Treat Rev. 2006;32 Suppl 1:7-14. 130. Leeming DJ, Alexandersen P, Karsdal MA, Qvist P, Schaller S, Tanko LB. An update on biomarkers of bone turnover and their utility in biomedical research and clinical practice. Eur J Clin Pharmacol. 2006;62:781-792. 131. Kunchur R, Need A, Hughes T, Goss A. Clinical investigation of C-terminal crosslinking telopeptide test in prevention and management of bisphosphonate-associated osteonecrosis of the jaws. J Oral Maxillofac Surg. 2009;67:1167-1173. 132. Lazarovici TS, Mesilaty-Gross S, Vered I, et al. Serologic bone markers for predicting development of osteonecrosis of the jaw in patients receiving bisphosphonates. J Oral Maxillofac Surg. 2010;68:2241-2247. 133. Baim S, Miller PD. Assessing the clinical utility of serum CTX in postmenopausal osteoporosis and its use in predicting risk of osteonecrosis of the jaw. J Bone Miner Res. 2009;24:561-574. 134. Avolio G, Brandao C, Marcucci M, Alonso G. Use of the plasma CTX for assessing the bone activity of the mandible among osteopenic and osteoporotic patients. Braz Oral Res. 2010;24:250-255. 135. Fleisher KE, Welch G, Kottal S, Craig RG, Saxena D, Glickman RS. Predicting risk for bisphosphonate-related osteonecrosis of the jaws: CTX versus radiographic markers. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. Oct 2010;110(4):509- 516. 136. Lee CY, Suzuki JB. CTX biochemical marker of bone metabolism. Is it a reliable predictor of bisphosphonate-associated osteonecrosis of the jaws after surgery? Part I: biological concepts with a review of the literature. Implant Dent. 2009;18:492-500. 137. Lee CY, Suzuki JB. CTX biochemical marker of bone metabolism. Is it a reliable predictor of bisphosphonate-associated osteonecrosis of the jaws after surgery? Part II: a prospective clinical study. Implant Dent. 2010;19:29-38. 138. Gineyts E, Cloos PA, Borel O, Grimaud L, Delmas PD, Garnero P. Racemization and isomerization of type I collagen C-telopeptides in human bone and soft tissues: assessment of tissue turnover. Biochem J. Feb 1 2000;345 Pt 3:481-485. 139. Garnero P, Borel O, Delmas PD. Evaluation of a fully automated serum assay for Cterminal cross-linking telopeptide of type I collagen in osteoporosis. Clin Chem. 2001;47:694-702. 140. Garnero P, Cloos P, Sornay-Rendu E, Qvist P, Delmas PD. Type I collagen racemization and isomerization and the risk of fracture in postmenopausal women: the OFELY prospective study. J Bone Miner Res. 2002;17:826-833. 141. Garnero P, Mulleman D, Munoz F, Sornay-Rendu E, Delmas PD. Long-term variability of markers of bone turnover in postmenopausal women and implications for their clinical use: the OFELY study. J Bone Miner Res. 2003;18:1789-1794. 142. Crofton PM, Evans N, Taylor MR, Holland CV. Serum CrossLaps: pediatric reference intervals from birth to 19 years of age. Clin Chem. 2002;48:671-673. 143. Cloos PA, Fledelius C. Collagen fragments in urine derived from bone resorption are highly racemized and isomerized: a biological clock of protein aging with clinical potential. Biochem J. 2000;345 Pt 3:473-480. 144. Cloos PA, Fledelius C, Christgau S, et al. Investigation of bone disease using isomerized and racemized fragments of type I collagen. Calcif Tissue Int. 2003;72:8- 17. 145. Christgau S, Bitsch-Jensen O, Hanover Bjarnason N, et al. Serum CrossLaps for monitoring the response in individuals undergoing antiresorptive therapy. Bone. 2000;26:505-511. 146. Bergmann P, Body JJ, Boonen S, et al. Evidence-based guidelines for the use of biochemical markers of bone turnover in the selection and monitoring of bisphosphonate treatment in osteoporosis: a consensus document of the Belgian Bone Club. Int J Clin Pract. 2009;63:19-26. 147. Bone HG, Hosking D, Devogelaer JP, et al. Ten years’ experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med. 2004;350:1189-1199. 148. Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006;296:2927-2938. 149. Fleisch H. Bisphosphonates: mechanisms of action. 1998;19:80-100. 150. Vignery A, Baron R. Comparative effects of APD and Cl2MDP on bone in the rat: In vivo and in vitro studies. Metab Bone Dis Relat Res. 1980;2:381-387. 151. Leeming DJ, Delling G, Koizumi M, et al. Alpha CTX as a biomarker of skeletal invasion of breast cancer: immunolocalization and the load dependency of urinary excretion. Cancer Epidemiol Biomarkers Prev. 2006;15:1392-1395. 152. Vescovi P, Manfredi M, Merigo E, et al. Surgical approach with Er:YAG laser on osteonecrosis of the jaws (ONJ) in patients under bisphosphonate therapy (BPT). Lasers Med.Sci. Jan 2010;25(1):101-113. 153. Stubinger S, Dissmann JP, Pinho NC, Saldamli B, Seitz O, Sader R. A preliminary report about treatment of bisphosphonate related osteonecrosis of the jaw with Er:YAG laser ablation. Lasers Surg.Med. 2009;41(1):26-30. 154. Angiero F, Sannino C, Borloni R, Crippa R, Benedicenti S, Romanos GE. Osteonecrosis of the jaws caused by bisphosphonates: evaluation of a new therapeutic approach using the Er:YAG laser. Lasers Med.Sci. 2009;24(6):849-856. 155. Assael LA. Oral bisphosphonates as a cause of bisphosphonate-related osteonecrosis of the jaws: clinical findings, assessment of risks, and preventive strategies. J Oral Maxillofac Surg. May 2009;67(5 Suppl):35-43. 156. Kwon YD, Kim YR, Choi BJ, Lee DW, Kim DY. Oral bisphosphonate-related osteonecrosis of the jaws: Favorable outcome after bisphosphonate holiday. Quintessence Int. Apr 2009;40(4):277-278. 157. Van den Wyngaert T, Claeys T, Huizing MT, Vermorken JB, Fossion E. Initial experience with conservative treatment in cancer patients with osteonecrosis of the jaw (ONJ) and predictors of outcome. Ann Oncol. 2009;20(2):331-336. 158. Hansen T, Kunkel M, Springer E, et al. Actinomycosis of the jaws–histopathological study of 45 patients shows significant involvement in bisphosphonate-associated osteonecrosis and infected osteoradionecrosis. Virchows Arch. Dec 2007;451(6):1009-1017. 159. Hall V. Actinomyces–gathering evidence of human colonization and infection. Anaerobe. 2008;14:1-7. 160. Naik NH, Russo TA. Bisphosphonate-related osteonecrosis of the jaw: the role of actinomyces. Clin Infect Dis. 2009;49:1729-1732. 161. Kos M, Brusco D, Kuebler J, Engelke W. Clinical comparison of patients with osteonecrosis of the jaws, with and without a history of bisphosphonates administration. Int J Oral Maxillofac Surg. 2010;39:1097-1102. 162. Sedghizadeh PP, Kumar SK, Gorur A, Schaudinn C, Shuler CF, Costerton JW. Identification of microbial biofilms in osteonecrosis of the jaws secondary to bisphosphonate therapy. J Oral Maxillofac Surg. 2008;66(4):767-775. 163. Sedghizadeh PP, Kumar SK, Gorur A, Schaudinn C, Shuler CF, Costerton JW. Microbial biofilms in osteomyelitis of the jaw and osteonecrosis of the jaw secondary to bisphosphonate therapy. J Am Dent Assoc. 2009;140(10):1259-1265. 164. Haffajee AD, Roberts C, Murray L, et al. Effect of herbal, essential oil, and chlorhexidine mouthrinses on the composition of the subgingival microbiota and clinical periodontal parametersperiodontal parameters. J Clin Dent. 2009;20(7):211- 217.