IAOMT ACCREDITATION-- Checklist for Completing Unit 10: Jawbone Osteonecrosis

Transcription

1 IAOMT ACCREDITATION-- Checklist for Completing Unit 10: Jawbone Osteonecrosis INTRODUCTION TO UNIT 10 Take the Unit 10 Pre-test. Click here to go to page 3. Read the Unexplained Dental Pain Explained: Tooth Extractions, Cavitations and the Periodontal Ligament article by Rehme. Click here to go to pages 4-5. REQUIRED (MANDATORY) CONTENT OF UNIT 10 Read the Cavitational Osteonecrosis article by Warwick and Warwick. Click here to go to pages 6-8. View the IAOMT online learning module Hidden Pathogens at Click here to go to page 9. Read the Incidence Levels and Chronic Health Effects Related to Cavitations by Windham. Click here to go to pages Read the Position Paper on Human Jawbone Osteonecrosis by the IAOMT. Click here to go to pages Read the Systematic Review: Bisphosphonates and Osteonecrosis of the Jaws review by Woo, Hellstein, and Kalmar. Click here to go to pages UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 1

2 TEST FOR UNIT 10 Take the Post-Test for Unit 10 at Click here to go to page 45. If you are interested in learning more about any of the topics in this unit, explore the readings in the OPTIONAL Unit 10 PDF file. Note that these are not required materials. Continue on to the post-course requirements! Click here to go to UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 2

3 PRE-TEST FOR UNIT 10 TO BE TAKEN BEFORE STUDYING JAWBONE OSTEONECROSIS *This is a pre-test, and the results are for your records only. You are not expected to know the answers since you have not studied this material yet. The pre-test is simply designed to assist you in recognizing some of the important information that will be presented in this unit. There is no time limit for this test. Choose the option that BEST answers each question. 1. Technically, jawbone osteonecrosis is also known as. A. cavitation B. cavitational osteonecrosis C. ischemic osteonecrosis D. neuralgia inducing cavitational osteonecrosis E. all of the above 2. In the 1860 s, Noel broke down the label of pathological jawbone as either dead or. A. alive B. reduced vitality C. non-invasive D. treatable E. all of the above 3. Jaw cavitations can trigger pain in the face, head, and other parts of the body, and osteonecrosis may also occur asymptomatically for years before symptoms show up. A. True B. False 4. When gutta percha used in root canaled teeth cools, there is shrinkage, which allows for the entrance of bacteria. A. True B. False 5. A 2006 study by Woo, Hellstein, and Kalmar identifies as a major predispositional factor in the development of bisphosphonate-associated jawbone osteonecrosis. A. the type and total dose of bisphosphonate B. dental surgery C. dental infection D. history of trauma E. all of the above Answers: 1. E; 2. B; 3. A; 4. A; 5. E UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 3

4 Unexplained Dental Pain Explained: Tooth Extractions, Cavitations and the Periodontal Ligament 2014 By Michael Rehme, DDS, CCN, FIAOMT [For access to all of Dr. Rehme s articles, visit ] Removing a tooth is certainly an unfortunate event for a patient both physically and emotionally. However, having the tooth properly extracted may prevent health related complications from occurring in years to come. There are two important steps to follow when removing a tooth: First, it is imperative to remove the entire tooth. Avoid leaving any root tips behind. These can lead to chronic, low grade infections that can fester within the jawbone. Second, once the tooth is extracted, thoroughly remove the periodontal ligament. This is a group of specialized connective tissue fibers that essentially attach a tooth to the alveolar bone within which it sits. A surgical round bur is used to remove one millimeter of bone as thoroughly as possible from the entire bony socket area, excluding the apex. If the periodontal ligament is not carefully removed from the socket after the extraction, the surrounding bone receives no notification that the tooth is gone. The continued presence of any portion of the ligament gives the biological message to the surrounding jawbone that all is well and no new bone growth is needed. This void that occurs within the surrounding bone is called a cavitation. A cavitation refers to a toxin-containing hole in the jawbone that often develops because of incomplete healing after a routine tooth extraction. The contents of cavitations are always necrotic, dead or dying material. Cavitations have many scientific names such as ischemic osteonecrosis, chronic non-superative osteomyelitis, and neuralgia inducing cavitational osteonecrosis (NICO). This is not so much an infection in the bone, as a necrosis or gangrene (dead tissue) in the bone marrow, as a result of impaired blood flow (ischemia). Although the term cavitation is not commonly used in conventional dentistry today, it was initially described in 1915 by Dr. G.V. Black, who is considered the godfather of modern dentistry. He described a cavitation as bone necrosis, or chronic osteitis, resulting in hollowed-out lesions found at the sites of old extractions. The bone was usually softened initially by the progressive cellular death of cancellous bone, until an actual hole resulted. He even went on to describe the appropriate way to treat such lesions, which was essentially a surgical debridement. UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 4

5 During the next 60 years, Black s findings were either ignored, forgotten, or not given proper acceptance. They were never integrated into dentistry nor taught in any dental institutions in this country. In the 1970s, however, cavitations were re-discovered and correlations with previously unexplained pain syndromes were suggested. Patients with atypical facial neuralgia and trigeminal neuralgia of unknown cause were often found to have cavitations at the sites of previous extractions, and the pathology was as Black had already described. Such cavities would be subjected to curettage and, upon complete healing with new bone, the pain syndromes would frequently subside. Other symptoms associated with these boney defects include: deep bone pain and pressure; a sour, bitter taste which often causes gagging and bad breath; sharp, shooting pain from the jaws which can elude a doctor s diagnostic attempts; chronic maxillary sinusitis, congestion and pain; a history of large dental fillings followed by pain, root canal therapy, and ultimately, removal of the tooth; difficult tooth extraction, including wisdom teeth, several years earlier; post-operative complications, especially the development of a dry socket. If you re faced with a situation that requires the removal of a tooth, remember to follow the biological approach. Being an educated dentist can help prevent your patients from experiencing years of unexplained pain, discomfort or compromised health conditions later in life. UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 5

6 WHAT IS IT? Cavitational Osteonecrosis By David Warwick, DDS, FIAOMT, and Robin Warwick, DDS, IAOMT Hanna Dental Clinic, Alberta Canada Neuralgia Inducing Cavitational Osteonecrosis (NICO) is basically a hollow place in bone that produces pain. A cavitation (another word for NICO that literally means hole ) contains dead or starved bone resulting from poor blood flow following some kind of initiating factor. Pathogens ( bugs ) are also present in these cavitations which release highly toxic waste products that can have detrimental effects to the heart, kidney, uterus, immune, nervous, and endocrine systems. Some investigations have found reservoirs of heavy metals (eg. mercury) present as well, especially in patients with mercury amalgam fillings in their mouths. Although this phenomenon is difficult to diagnose because it doesn t always appear on a dental x-ray and can be asymptomatic for years, the disease has been around for a long time under many different names such as Ratner bone cavities and maxillofacial osteonecrosis. In 1915, G. V. Black first described these jawbone lesions as follows: An osteomyelitis-like bone disease which seemed not to be a true infection, but rather a slow, progressive, unexplained death of cancellous bone and marrow, cell by cell. UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 6

7 WHY DOES IT OCCUR? NICO most likely occurs due to a combination of initiating events, predisposing factors, and risk factors. Initiating events: o Physical trauma (such as a tooth extraction, vasoconstrictors in dental freezing, root canal treatment) o Bacterial trauma (such as periodontal disease, abcesseses, or root canal bacteria) o Toxic trauma (such as dental materials or bacterial toxins) Predisposing factors: such as blood clotting disorders (eg. thromophilia, hypofibrinolysis), age (arteries in the jaw tend to decrease in size with age), chemotherapy or radiation treatment for cancer, rheumatoid arthritis, bone dysplasia, changes in atmospheric pressures, osteoporosis, thyroid dysfunction, systemic lupus erythematosis, sickle cell anemia, gout and physical inactivity Risk factors: such as smoking, pregnancy, alcoholism, and long-term cortisone usage When an initiating event occurs, the body responds by creating a mild inflammation in the bone and marrow which releases chemicals to increase local blood clotting. This design works well under normal circumstances to deal with trauma (eg. if you cut your finger); however, when there is already a compromised blood flow, the clotting can lead to painful infarction and marrow death. Some dental freezing contains a vasoconstrictor which decreases blood flow and may worsen the situation even more. WHERE DOES IT OCCUR? NICO may occur in any bone in the body but hips, knees, and jaws are most common. The majority of cavitational lesions in the jaw tend to occur at wisdom teeth extraction sites (top or bottom) and these lesions can spread to other areas to initiate further cavities. WHAT ARE THE SYMPTOMS? Jaw cavitations can be asymptomatic or may trigger pain in other parts of the face and head or even distant parts of the body. Osteonecrosis (bone death) may be occurring asymptomatically for years before symptoms show up. If there is pain present, it is often difficult to describe and localize. It may be a dull ache or there will be symptoms that mimic atypical facial neuralgia, trigeminal neuralgia, headache, sinusitis, phantom toothache pain or chronic fatigue. Although the pain is usually intermittent and variable, it seems to increases in intensity, area and frequency slowly over time. The typical NICO patient has pain for about 6 years before a proper diagnosis is made. Some patients describe an occasional sour taste in the mouth. UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 7

8 WHO DOES IT AFFECT? NICO in the jaws may occur with men or women at any age; however, it tends to occur more commonly in middle-aged women. HOW IS IT TREATED? Currently, there is no known treatment that is completely and consistently effective; however, there are several therapies that may reduce or eliminate symptoms in some patients, but these treatments may need to be performed several times every few weeks. NICO tends to recur and/or spread to other jawbone sites even after treatment. Methods for preventing routine extractions from becoming osteonecrotic lesions are in early development. UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 8

9 YOU NOW NEED TO VISIT IAOMT S ONLINE LEARNING CENTER TO WATCH THE HIDDEN PATHOGENS VIDEO AT IF CLICKING ON THE LINK ABOVE DOES NOT WORK, THE VIDEO IS LOCATED ON THE IAOMT WEBSITE ( ON THE TAB FOR MEDIA AND RESOURCES, AND ON THE SUB- TAB FOR ONLINE LEARNING CENTER. ONCE IN THE ONLINE LEARNING CENTER, CLICK ON FREE ONLINE LEARNING, AND THEN VIEW THE HIDDEN PATHOGENS VIDEO. UPON COMPLETION OF THE HIDDEN PATHOGENS VIDEO, YOU WILL NEED TO CONTINUE WITH THE ADDITIONAL REQUIREMENTS FOR UNIT 10, WHICH INCLUDE MORE READINGS AND COMPLETING THE UNIT 10 TEST. UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 9

10 INCIDENCE LEVELS AND CHRONIC HEALTH EFFECTS RELATED TO CAVITATIONS Reproduced by kind permission of: Bernard Windham (Editor) President & Research Director DAMS International UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 10

11 CAVITATIONS Edited by: B. Windham What Are Cavitations? A cavitation is a hole in the bone, often where a tooth has been removed and the bone has not filled in properly. In the last several years, the term cavitation has been used to describe various bone lesions which appear both as empty holes in the jawbones and holes filled with dead bone and bone marrow (5). Dead, cavitational areas, which produce pain, are now called NICO (Neuralgia Inducing Osteonecrosis) lesions (6). Cavitations are often a result of either ischemic osteonecrosis, due to poor blood flow in the marrow, or a traumatic bone cyst. In his book on oral pathology, Dr. G.V. Black, one of the early experts on cavitations, suggested surgical removal of these dead bone areas. Other less traumatic measures are now first used and surgery with curetting is used primarily where the patient has significant health effects not resolved by other means. When a tooth is being extracted, in what has been normal dental procedure, the surrounding periodontal membrane is usually left behind. Theoretically, when a tooth has been pulled, the body will eventually fill in the space in the bone where the tooth once was. But when the membrane is left behind, an incomplete healing commonly takes place which leaves a hole or a spongy place inside the jaw bone. Experts speculate that perhaps this is because the bone cells on either side sense the presence of the periodontal membrane and "think" that the tooth is still there. This appears to be one common cause of cavitations (1, 2, 3, 4, 5, 16, 17, 18, 19, 20, 21, 22, 29, 30, 31, 32, 45). Ondodontic cysts are also commonly occurring usually in the gums at the tip of a tooth, that have pockets of bacterial infection that can cause inflammation and pain in some cases similar to cavitations (33, 48, 49). Bacterial infections are also known to have systemic effects. A cavitation can form in any bone in the body, not just in the jaw bones. There are also other reasons that cavitations form, some of which are localized traumas, poor circulation to the area, clotting disorders, and the use of steroids. On X-ray of an extracted tooth site, this membrane can form an image that appears to be a shadow of a tooth. Almost always, this is indicative of a cavitation. Most dentists are aware of this phantom tooth image, but they do not recognize it as a site of potential problems. Other means of locating or identifying cavitational areas include sonic imaging (CAVITAT) (3, 68), local anaesthesia, Spect Scan (65), pressure to determine trigger points, Computer Electro Dermal System (67), etc. While 2 UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 11

12 CAVITATIONS Edited by: B. Windham positive Spect Scans were found in 19 of 20 patients with jaw pain, several control patients with no pain also had positive scans- often finding previous jaw pathoses. Thus the Spect Scan was not sensitive at differentiating painful from non-painful conditions. Some of the other methods had more success at such differentiation. What s Hiding Inside? Inside a cavitation, bacteria flourish and deviant cells multiply. Cavitations act as a breeding ground for bacteria and their toxins. Research has shown these bacterial waste products to be extremely potent (7, 8). Cavitations can also cause blockages on the body's energy meridians and can exert far-reaching impact on the overall system. Investigation has revealed that some cavitations are reservoirs of huge amounts of mercury and other toxic substances. Cavitations may be a source of low level or high level stress on the entire body. (1-73) How Toxic Are Cavitations And What Type Of Effects Are Caused By Cavitations? The results of recent research of Dr. Boyd Haley (former Chairman, Department of Chemistry, University of Kentucky) show that ALL cavitation tissue samples he's tested contain toxins, which significantly inhibit one or more of the five basic body enzyme systems necessary in the production of energy (7, 8). These toxins, which are most commonly likely to be metabolic waste products of anaerobic bacteria (bacteria which don't live in oxygen), may produce significant systemic effects, as well as play an important role in localized disease processes, which negatively affect the blood supply in the jawbone. There are indications that other types of toxins also accumulate in cavitations, and when these toxins combine with certain chemicals or heavy metals (for example, mercury), much more potent toxins may form (5-15). High levels of mercury are commonly found in some cavitations and in general in the jawbone of those with mercury amalgam fillings and to have significant local and systemic effects (79). Mercury is known to be extremely toxic and to commonly cause chronic adverse local and systemic health effects (70). Yeast and fungi have also been found to accumulate in cavitations, and to have significant systemic effects (10-14). Accurate tests for cavitation-related bacterial toxins have been developed by the Affinity Laboratory in Kentucky, based on research by Chemists from the University 3 UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 12

13 CAVITATIONS Edited by: B. Windham of Kentucky Department of Chemistry (7, 8). The toxins released by anaerobic bacteria in cavitations have been found to be extremely toxic, and to have major effects on necessary body enzymes and the immune system. Cavitations Are Very Common One study (1, 20) of cavitation incidence involved an analysis of 112 randomly selected dental patient charts who had been tested for cavitations, with patient age ranging from 19 to 83 years among 40 males and 72 females. The cavitations were tested for using exploratory drilling. Cavitations were found at approximately 75% of all extraction sites examined. The most commonly extracted teeth, the third molars ("wisdom teeth"), produced CVs that were found by clinical exploration in 313 out of 354 extraction sites (88%). Cavitations were found in 35 of 50 second molar extraction sites (70%), and for first molars, 60 of 73 extraction sites showed cavitations (82%). They were found in 441 of the total number of 517 molar extraction sites explored (85%). For the maxillary non-molars, CVs were found in 72 of 123 extraction sites (58%), and for mandibular non-molars, 23 of 51 extraction sites were affected (45%). For all non-molars, the cavitation rate was 55%, representing 95 of 174 extraction sites. Note that the cavitations found were not all related to pain or known chronic conditions, and dental patients who had been tested for cavitations is not the same as the general population, so the general population likely has a somewhat lower cavitation incidence. Bob Jones is the inventor of the CAVITAT an ultrasound instrument designed to detect and image cavitations that has been approved for testing for cavitations by the FDA after undergoing FDA clinical trials (2b). He found cavitations of various sizes and severity in approximately 94% of several thousand wisdom teeth sites scanned (2a). He also found cavitations under or located near over 90% of root canal teeth scanned in both males and females of various ages from several different geographic areas of the United States. Note again that the population being tested for cavitations in these trials is not the same as the general population, which might have a somewhat lower incidence of cavitations. But its clear that the occurrence is very common. Confirmation of cavitation necrosis and toxicity is commonly by 2 or the leading labs in the U.S. with technology for performing such tests, the Maxifillial Center in West Virginia and the Affinity Laboratory in Kentucky.(5-8). Analysis typically finds clear evidence of chronic intraosseous inflammation often with dense marrow fibrosis or 4 UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 13

14 CAVITATIONS Edited by: B. Windham non-resorbing necrotic bone flakes with very little healing or new bond formation (6). It has also been found that these lesions often spread to other areas to initiate further cavities. Root Canals And Cavitations Research has demonstrated that virtually all root canals result in residual infection due to the imperfect seal that allows bacteria to penetrate. The most commonly used material in root canals is gutta percha, which is soaked with chloroform and heated. But when the chloroform evaporates and the gutta percha cools, there is significant shrinkage in all such root canal fillings, which allows entrance of bacteria (18, 19, 20, 21, 22, 50). A condition that commonly occurs with root-canalled teeth is a radicular or periapical cyst or apical periodontis, which is a pocket of bacterial inflammation that often forms in the gums at the tip of root-canalled teeth (48, 49, 52, 53) due to bacteria inhabiting the tooth. These are the most common type of cysts that form in the gums and can also be a factor in formation of cavitations in the neighboring jawbone. Once established, non-mutans streptococci, enterococci and lactobacilli appear to survive commonly following endodontic root-canal treatment of teeth with clinical and radiographical signs of apical periodontitis (51). Large scale tests found cavitations under or located near approximately 90% of root canal teeth scanned in both males and females of various ages from several different geographic areas of the United States (2). The general population could be somewhat different from this sample as the sample was not a random sample. In tests of 745 randomly chosen root-canalled teeth at a dental school, done at least 1 year prior to test, 33% were found to have apical periodontitis (53). The toxins given off by these bacteria are often even more toxic than mercury (7, 8, 9, 10). The bacterial toxins from root-canalled teeth and associated cavitations can cause systemic diseases of the heart, kidney, uterus, immune, nervous and endocrine systems (see later). A useful and commonly used test to assess the cause of toxic related chronic health conditions is the urinary fractionated porphyrin test, which measures the degree that toxic exposures have blocked digestive enzymatic processes necessary to the function of the body, by looking at the level of various waste porphyrins in the urine caused by these blockages. The level of such toxic related porphyrins in the urine of people with chronic conditions including Parkinson s have been found to decline in some patients after cavitation treatment (or amalgam removal) (20). This is also 5 UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 14

15 CAVITATIONS Edited by: B. Windham been found for many cases of Lupus and MS (38, 78). Lupus symptoms are often associated with blockage and resulting high levels in urine of Uriporphyrin, while MS is more commonly associated with high Coproporphyrin. Cavitation Treatment Usually Results In Significant Pain Improvement Cavitations commonly cause adverse health effects, and many thousands of cavitations have been treated. They are commonly tested or biopsed by labs having the expertise to provide these services, and virtually all that have been tested or biopsed were found to be associated with dead, necrotic tissue and extreme toxicity (3, 5, 6, 7, 8, 9). The types of conditions that cavitations have been most commonly related to are atypical facial neuralgia, trigeminal neuralgia, chronic sinusitis, phantom toothache pain, and headaches including migraines. Dr. Briener, DDS, and others recommend two primary methods of treatment for their patients (33, 40, 54, etc.). First is a procedure where special homeopathic medications called Sanum remedies are injected into the cavitation site, and then a modified form of infrared light or low level laser light therapy is applied to the area. In some cases the light therapy alone has been sufficient to resolve the problem (54). This is often successful in cases related to smaller cavitations with primarily poor blood flow or bacterial toxin effects. Cavitations have also been treated successfully using oxygen/ozone therapy (74). Although cavitations are very common, they should only be treated surgically if there is indication of a relation to pain or chronic health effects not resolved by other means. There are various ways to assess this. If this method is not successful, the alternative is to surgically open the area and clean the remaining ligament and resultant debris from the bone. Every biopsy of bone material he has collected from cavitation surgeries has shown osteonecrosis, or dead bone material. In all studies reviewed, the majority of those undergoing surgery for NICO pain had significant pain relief after surgery [3(Table 1), 40, 42, 43, 44, 45, 55, 56, 57, 58, 59, 60, 61, 62, 63, 70, 71, etc.). Clinical experience indicates that delays in treatment can lead to further infections (44), and the majority of patients have long term pain relief (45). However as much as 30% may have reoccurrence or new cavitations that lead to reoccurrence of pain. Prior to bone marrow biopsy the average NICO patient has been in pain for 6 years (up to 32 years), usually diagnosed as atypical facial neuralgia/pain, but also diagnosed as trigeminal neuralgia, chronic sinusitis, phantom toothache/pain, and 6 UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 15

16 CAVITATIONS Edited by: B. Windham various headaches, including migraine headache (3). However treatment has also been successful at eliminating rheumatoid arthritic pain (18, 26, 27, 43). French and German oral surgeons have developed an alternative method of minimally invasive cavitation surgery (41). Due to the nature of the mechanisms related to cavitation formation, it is not uncommon for cavitation sites that are treated to become re-infected or to accumulate other toxins that can cause a relapse of symptoms. Such cases may require retreatment using either surgery or other options. Chronic Health Conditions Other Than Pain Related To Cavitations And Oral Bacteria Levels Many researchers today believe that NICO lesions, like periodontal disease, is the focus of various infections which may spread throughout the body and have systemic effects. In the last few years, some of the most surprising medical news has been the discovery that bacteria from the mouth appear to be very influential in causing various heart, liver, kidney, and immune problems (68). Researchers from New York University found that certain bacteria from the mouth may be related to preterm delivery and low birth weight according to a study in the Journal of Periodontology (JOP) (68b). The presence of specific bacteria and combinations of bacteria in periodontal pockets also appears to be responsible for the relationship between periodontal disease and acute coronary syndrome (ACS), according to a new study published in the Journal of Periodontology (68c). Dr. Weston Price was a prominent dental researcher leading a medical research team on the relation between root-canal teeth and chronic health conditions (70). Through a long series of well documented clinical cases and experiments his team found that root-canals accumulate bacteria that give off extreme toxins sufficient to cause serious health conditions, including cancer (22, 25, 28, 29, 36, 37, 38, 46, 47, 70, etc.), cardiovascular conditions (19, 20, 21, 22, 29, 36, 38, 70, 72, 73), arthritis (22, 27, 29, 36, 38, 43, 70, etc.), neurological conditions (3, 5, 42, 56, 70, 71, 72, etc.) kidney conditions, etc. Dr. Meinig, one of the founders of the endodontic association has reviewed the research of Dr. Price and others and is in agreement with their findings (18, 20, 26). Many doctors and dentists through their experience with patients have reached similar conclusions (18, 19, 20, 21, 22, 23, 24, 25, 26, 28, 29, 32, 33, 34, 35, 36, 37, 7 UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 16

17 CAVITATIONS Edited by: B. Windham 38, 39, 45-65, 71, 73). They have had large numbers of patients who have had such health conditions significantly improve after treatment of root canals or cavitations along with other detoxification measures. A collaborative study by the North Carolina Institute of technology using advanced tests developed by Affinity Laboratory has demonstrated the mechanisms by which cavitations can cause cancer (47). Modern experiences also support this theory. Dr. Issels, a German physician, recommends extraction of root canal teeth as part of his protocol for terminal cancer patients. Over the last 40 years with 16,000 patients, he has observed a 24% total remission rate (25, 46). Dr. Florian Kubitzek, a physician and dentist in Munich, Germany, uses the CT scan to study the teeth and jaw. His scanning technique has been invaluable in diagnosing jaw abscesses below the teeth that have been inadequately treated by standard dentistry. Conventional dental X-rays have entirely missed the jaw abscesses known as cavitations. Kubitzek treats many cancer patients who have dental cavitations as a collaborative approach in the overall treatment of metastatic and primary cancer (37). Dr. John Diamond (MD) says that all patients with breast cancer that he has tested had root canals on the tooth related to the breast area on the associated energy meridian." (25) Other clinics that treat cancer have similarly found that most of their patients with cancer have root-canalled teeth or cavitations and that treating these is an important part in success at treating cancer (38, 39). Research and clinical cases have found cavitations to be related to many chronic health conditions which have improved after cavitation treatment, including cancer, congestive heart failure and other cardiovascular problems, lupus, rheumatoid arthritis, and autoimmune conditions- perhaps related to cavitations major effects on the immune system. If you have a joint implant or mitral valve prolapse, your dentist must prescribe an antibiotic before any dental treatment. Why? Because bacteria from the mouth can spread through the blood to cause serious problems elsewhere in the body. There is growing evidence that the toxins from NICO lesions do the same. 8 UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 17

18 CAVITATIONS Edited by: B. Windham References (1) Routine Dental Extractions Routinely Produce Cavitations, Thomas E. Levy, MD, FACC, and Hal A. Huggins, DDS, MS, Journal of Advancement in Medicine Volume 9, Number 4, Winter 1996, Human Sciences Press, Inc, (2) Bob's Dental Awareness Page, Occurrence of Cavitations- CAVITAT, (b) Cavitat Medical Technologies, (3) (a) Maxillofacial Osteonecrosis (NICO), Dr. J.E. Bouquot, Maxillofacial center, Dr. J. E. Bouquot's Biographical Information, (4) Clinical Features of Maxillofacial Osteonecrosis (NICO), The MF Center, (5) NICO And Cavitations, TMJ & Facial Pain Clinic, Dr. Wesley Shankland, (6) Neuralgia-Inducing cavitational osteonecrosis (NICO), Osteomyelitis in 224 jawbone samples from patients with facial neuralgia, Bouquot JE, Roberts,AM Person P, Christian J, Dept. of Oral Surgery, West Virginia Univ. School of Dentistry, Oral Surg Oral Med Oral Pathol 1992, 73(3): (7) In Vitro Toxicity Testing of Oral Samples, (a) The TOPAS I Toxicity Prescreening Assay. A chair-side test for the detection of bacterial toxins, bacterial proteins and human inflammatory proteins in gingival crevicular fluid (GCF). (8) Toxins Produced by Oral Microorganisms and Their Toxic Effects on Critical Enzymes in the Human Body, ALT, (9) Do Infected Endodontically Treated Teeth and Osteomyelitic Lesions Constitute an Unrecognized Toxic Burden Potentially Contributing to Systemic Diseases? (10) Root Canals - Infected vs. Toxic. Is There A Difference? (10) Published Studies on Infections Caused By Yeast and Fungi and the Mycotoxins They Produce (11) Do Mycotoxins Produced by Pathogenic Yeast and Fungi Contribute to Oral Toxicity and Potentially to Systemic Diseases? (12) Selected Studies on the Toxicity Caused Oral Microorganisms Published in Peer Reviewed Scientific, Dental and Medical Journals, ALT, (13) Oral Toxicity Abstracts UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 18

19 CAVITATIONS Edited by: B. Windham (14) Oral Toxicity Hyperlinks (15) Ostemyeolitic and Osteonecrotic Lesions of the Jaw, Affinity Laboratory Technologies, (16) JAWBONE CAVITATIONS: Infarction, Infection & Systemic Disease, By Suzin Stockton, (17) Stockton, Susan. Beyond Amalgam: The Health Hazard Posed by Jawbone Cavitations. Power of One Publishing: Aurora, CO, (18) ROOT CANAL COVERUP by George E. Meinig, D.D.S., (19) The Roots of Disease: Connecting Dentistry and Medicine, Dr. Robert Kulacz & Dr. Thomas Levy (20) Uninformed Consent- Dr. Hal Huggins & Dr. Thomas Levy (21) Tooth Truth, Dr. Frank Jerome (22) Elements of Danger, Dr. Morton Walker (23) Chronic Fatigue: Cavitations and Root Canals, (24) Root Canal Therapy - Does Saving a Tooth Effect Your Health, Robert Gammal, DDS, (25) Root Canals & Cancer- Dr. Hal Huggins, (b) Dental Problems may Contribute to Cancer, Dr. John Diamond, in Alternative Definitive Guide to Cancer, Dr. Burton Goldberg,MD (26) Cavitations & Root Canals, Laura Lee Interview with George Meinig, DDS & Dr. M. LaMarche, Townsend Letter for Doctors and Patients (27) Arthritis: The dental amalgam and root-canal connection, Gary Null, (28) Cancer: Dental Risk, expert opinions, (29) Root Canal - Roots of Disease Dr. John Roberts, (30) THE DANGERS OF ROOT CANAL (& APICOECTOMY)-DENTAL TREATMENT by Theresa Dunford, mercury%20amalgam.htm (31) CAVITATIONS - (from Issue #1 of Cavitations Plus Quarterly newsletter) by Karen Evans, EdD, UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 19

20 CAVITATIONS Edited by: B. Windham (32) Root Canal Experience: Melanie Yarbough (33) Whole Body Dentistry, Mark Breiner, DDS, Root Canals and Cavitations: (34) NICO and Chronic Jaw Pain Forum (35) Bio-Compatible Dentistry (36) Chronic conditions caused by cavitations: (37) Cancer Conquest Edited by Burton Goldberg, (38) Source: Dr. Clark's e-newsletter, received May 03, 2002 A Cure of All Cancers, Dr. Hulda Clark, A Cure of Advanced Cancers, 2005, A Cure of All Diseases, 2003, Dr. Hulda Clark, (39) Gerson, Max A Cancer Therapy: Results of Fifty Cases (Third Edition, 1977) Del Mar, CA: Totality Books, & Gerson Patient's Problems + Cavitations (1999) (40) Treatment Options, Dr. Briener, DDS, (41) S. Siervo et al, Piezoelectric surgery. An alternative method of minimally invasive surgery, Schweiz Monatsschr Zahnmed. 2004;114(4): Clinical cases and studies: (42)Trigeminal Neuralgia and Atypical Facial Neuralgia- CAVITATIONS, DAMS Intl Newsletter: (43) 6-year remission of rheumatoid arthritis after unusually vigorous treatment of closed dental foci. Breebaart AC, Bijlsma JW, van Eden W. Department of Ophthalmology, University of Amsterdam, The Netherlands. acb@euronet.nl, Clin Exp Rheumatol 2002 Jul-Aug;20(4): ed.pubmed_resultspanel.pubmed_rvdocsum (44) Neuralgia-inducing cavitational osteonecrosis (NICO). Osteomyelitis in 224 jawbone samples from patients with facial neuralgia. Bouquot JE, Roberts AM, Person P, Christian J. Oral Surg Oral Med Oral Pathol Mar;73(3): (45) Long-term effects of jawbone curettage on the pain of facial neuralgia. Bouquot JE, Christian J. J Oral Maxillofac Surg Apr;53(4):387-97; discussion (46) Phillip Sukel, Midwest Integrative Dentistry, Root Canals Treatment is UNSAFE Viewpoint, (b) Dr. J.M Issels, MD, (detox and immunology) UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 20

21 CAVITATIONS Edited by: B. Windham (c) More Cures for Cancer, Translation from the German by Dr Josef Issels, Helfer Publishing E. - Schwabe, Bad Homburg FRG, (47) The Cancer/Cavitation Connection, North Carolina Institute of Technology, (48) Odontogenic Cysts and Tumors, Grand Rounds Presentation, UTMB, Dept. of Otolaryngology; Michael Underbrink, MD, MBA, Anna Pou, MD, (49) Maxillary odontogenic keratocyst A common and serious clinical misdiagnosis MOHAMMAD ALI, D.D.S.; RONALD A. BAUGHMAN, D.D.S., M.S.D. (50) Implant Failures Associated With Asymptomatic Endodontically Treated Teeth, David L. Brisman, D.M.D.; Adam S. Brisman, D.M.D.; Mark S. Moses, D.D.S. JADA February 2001, page 191, (51) Bacteria recovered from teeth with apical periodontitis after antimicrobial endodontic treatment. Chavez de Paz LE, Dahlen G, Molander A, Moller A, Bergenholtz G. Int Endod J Jul; 36(7): (52) Cultivable microbial flora associated with persistent periapical disease and coronal leakage after root canal treatment, Adib V, Spratt D, Ng YL, Gulabivala K, Int Endod J Aug;37(8): (53) Periapical health related to the quality of coronal restorations and root fillings. Hommez GM, Coppens CR, De Moor RJ. Int Endod J Aug;35(8): (54) Dr. Charles McGee(MD), Healing Energies of Heat and Light, MediPress, 2000, p117; & Lumen Photon Therapy, Inc (55) Microbiology and Management of Deep Facial Infections and Lemierre Syndrome, Itzhak Brook, Georgetown Univ. School of Medicine, Washington, D.C., ORL- Journal for Oto-Rhino-Laryngology, 2003, Vol 65, No. 2. (56) Jawbone cavities and trigeminal and atypical facial neuralgias, Ratner DJ et al, Oral Surg. Oral Med Oral Pathol, 1979, 48(1):3-20. (57) Osteocavitation lesions: a case report, Shankland,WE, Cranio,1993, 11(3): (58) Further Observations on dental parameters of trigeminal and atypical facial neuralgias, Roberts AM, et al, Oral Surg Oral Med Oral Pathol, 1984, 58(2): (59) Unhealed extraction sites mimicking TMJ pain, Dupont JD, Gen Dent 2000, 48(1): UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 21

22 CAVITATIONS Edited by: B. Windham (60) A modified protocol for early treatment of osteomyelitis and osteoradionecrosis of the mandible. Aitasalo K, et al, Head Neck, 1998, 20(5): (Finland). (61) Osteomyelitis, Laughlin RT et al, Wright Univ. School of Medicine, Curr Opin Rheumatol, 1995, 7(4): (62) Osteomyelitis, A commonsense approach to antibiotic and surgical treatment, Bamberger DM, Univ. of Missouri-Kansas City School of Medicine, Postgrad Med, 1993, 94(5): (63) Complications of routine extractions - osteomyelitis, Tomeo C, Sadowsky D, Friedman JM, NY State Dent J, 1981, 47(7): (64) Trigeminal neuralgia: typical or atypical? Shankland, WE. Cranio, 1993, 11(2): (65) The Use of SPECT bone scans to evaluate patients with idiopathic jaw pain, Denucci DJ et al, NIH, Oral surg Oral Med Oral Pathol Oral Radiol Endod, 2000, 90(6): (66) NICO Ultrasonic Imaging (67) Location of Atypical Facial Pain or Neuralgia Inducing Cavitational Osteonecrosis and non-vial teeth with local anesthetic, X-ray evaluation or the use of the Computer Electro Dermal System(CEDS), DL Cook(DDS), (68) The Mouth-Body Connection, The American Academy of Periodontology, (a) (b) Preterm deliveries and infant weight & (c) Periodontal Disease and Cardiovascular Disease: (69) Informational Webpages About NICO (70)Dental Infections Oral and Systemic,: Volume I and Dental Infections and the Degenerative Diseases, Vol II, Weston Price, DDS, (71) Bone Cavities, Trigeminal Neuralgia, Atypical Facial Pain, Robert E Mc Mahon DDS. (72) Dental Infections Foci and Diseases of the Nervous System, Tore Patrick Stortebecker, Neural Focal Dentistry, Dental Interference Fields and NICO. & Stortebecker P "Chronic dental infections in the etiology of Glioblastomas. 8th int congress" Neuropathy. Washington D.C. Sept 1978 J Neuropth. Exp. Neurology 37(s) 1978, (73) Mouth Infections and the Relation to Systemic Diseases, Vol I and II, Malcolm Graeme MacNevin, MD, F.A.C.P; Harold Sterns Vaughn, M.C. DACS (74) Of metalicized mouths, mycotoxicosis, and oxygen, Townsend Letter for Doctors and Patients, June, 2005 by Philip Mollica, Robert Harris 13 UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 22

23 CAVITATIONS Edited by: B. Windham (78) The beneficial effect of amalgam replacement on health in patients with autoimmunity. Prochazkova J, Sterzl I, Kucerova H, Bartova J, Stejskal VD; Neuro Endocrinol Lett Jun;25(3): (79) Mercury levels in the oral cavity of people with amalgam fillings and oral effects of mercury accumulation in the oral cavity, DAMS review paper, (80) Chronic health effects caused by mercury, documentation of mechanisms of causality and incidence, DAMS review papers, UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 23

24 The International Academy of Oral Medicine and Toxicology IAOMT Position Paper on Human Jawbone Osteonecrosis July 27, 2014 The International Academy of Oral Medicine and Toxicology (IAOMT) is founded upon the belief that Science should be the basis upon which all diagnostic and treatment modalities be based. In following that philosophy, this position paper is written utilizing the available information found in textbooks, research papers, and peer reviewed journal articles published throughout the world. History A review of the literature relating to the topic of Human Jawbone Osteonecrosis (JON) reveals that information has been researched and presented since the 1860 s with Barrett 1 and Noel 2 describing noticeable defects in the jawbone. Noel broke down even further the label of pathological jawbone as either dead or the less damaged reduced vitality. G. V. Black in his 1915 textbook set aside an entire section to describe the usual appearance and treatment of JON. 3 It is unfortunate that this information was seemingly forgotten until the 1970 s when others began researching the topic again including information regarding JON in sections of modern oral pathology textbooks. 4, 5 Since that time, articles relative to JON have appeared in peerreviewed journals including the Journal of Endodontics, the Journal of Periodontics, Oral Surgery-Oral Medicine- Oral Pathology, the AGD s General Dentistry, and the Journal of Craniomandibular Practice, and others. Unfortunately, the topic of JON remains controversial in some dental circles. 6 Controversy It is acknowledged that clinically observable and histologically confirmed cases of osteonecrosis pathology exist in almost all other bones in the human body, yet some clinicians still doubt that the same disease occurs in the alveolar processes of the human maxilla and / or mandible. 7 It is our hope that a Pennsylvania action taken against a dentist providing treatment of JON which was later overturned by a hearing examiner for the Pennsylvania State Board of Dentistry will be helpful to advancing the issue. It was the finding of the examiner that 1) JON is accepted as a pathological entity by the majority of dental pathologists, 2) Treatment of the entity is within the standards of care of the State of Pennsylvania, 3) The use of the thru-transmission ultrasonography device known Cavitat is helpful in the diagnosis of this osseous pathology. 8 The reality that the most widely used oral pathology textbook in the world describes the JON lesion and the treatment thereof, propels the diagnoses and treatment of this disease from a controversial theory to a scientifically recognized fact. 9 The IAOMT hopes national and state UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 24

25 dental regulating entities that have jurisdiction, licensing, and enforcement powers will become familiar with the current body of research regarding JON and base their opinions upon these facts ( Science ), rather than personal opinion or some other agency dictated agenda. In order to fulfill the mission of educating the practitioner and patients about JON, it is essential to acknowledge the existence of the disease. Also known as Cavitations, Cavitational Osteonecrosis, Ischemic Osteonecrosis, NICO s, and various other labels, the presence of necrotic, or dying bone in the jawbones is well established as a known pathology of mankind. 10 With application of the scientific method, it is clear that pathologically observed areas of JON are found in human jawbones. These bony defects when observed clinically present themselves in numerous ways. Some report that over 75% of lesions are completely hollow or filled with soft, grayish-brown and mushy tissue, often with yellowish oily material (oil cysts) found in the defective areas with surrounding normal bone anatomy. 11 Others report the presence of cavities having varying overlying cortical bone density that upon opening appear to have linings with fibrous black, brown or grey filamentous materials. 12 Still others report gross changes variously described as gritty, like sawdust, hollow cavities, and dry with occasional sclerotic, tooth-like hardness of the cavity walls. These lesions upon histological examination appear similar to the necrosis in other bones of the body and are histologically different from Osteomyelitis. 13 It is therefore the position of the IAOMT that JON is a diseased state that exists in human jawbones. Recently, DNA analysis of the biopsied contents from JON lesions has become available. Although as yet unpublished, the DNA data clearly demonstrates that JON is colonized with a broad range of potent anaerobic bacteria. Diagnosis Diagnosis is difficult due to the fact that some JON is almost invisible on standard radiographic films commonly used in dentistry. Ratner and others have stated that since 40% or more of the bone needs to be altered to show changes on standard dental radiographs, the disease state is UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 25

26 sometimes referred to as undetectable on dental films. 14 The interpretation of dental films is subjective and it is not uncommon for many trained researchers and clinicians to review identical films and come away with different interpretations. 15 For these reasons, Tech 99 scans, MRI with filters, CAT scans, digital radiography, thru transmission ultrasonography (Cavitat ), 16 and other methods to visualize these lesions may be necessary. It should be mentioned that although the Cavitat ultrasound has been used as a diagnostic aid by some clinicians for many years, it is no longer manufactured. Cone-Beam Computed Tomography (CBCT) has proven to be a reliable method of identifying and estimating the size and extent of intra-bony defects in the jaws. 17 It also helps to overcome a major limitation of two-dimensional (periapical and panoramic) imaging; the inability to distinguish anatomy in three dimensions. This limitation inherently leads to the superimposition of anatomical structures, which can mask areas of interest and decrease the diagnostic value of an image. In the case of defects or pathology specifically in the mandible, the masking effect of the dense cortical bone on the underlying structures can be significant. Also, CBCT provides the practitioner with a significantly higher diagnostic accuracy (less distortion, less magnification, etc.) than two-dimensional imaging. It also has the ability to view a lesion of interest in three dimensions (frontal, sagittal, coronal), and it employs highly accurate measurement tools and it utilizes advanced software which allows for image manipulation that will further aid in recognition of intra-bony defects. 18,19 Other clinical studies have shown CBCT images are also helpful in determining the contents of a lesion (fluid-filled, granulomatous, solid, etc.), possibly helping to distinguish between inflammatory lesions, odontogenic or non-odontogenic tumors, cysts, and other benign or malignant lesions. 20, 21 Such an image can prove useful in the diagnosis and treatment of JON, in areas such as: 1) Identifying the size, extent and threedimensional position of a lesion, proximity of a lesion to other nearby vital anatomical structures such as the inferior alveolar nerve, maxillary sinus, or adjacent tooth roots, 2) Determining a UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 26

27 conservative approach to surgical or non-surgical treatment, and 3) Follow-up imaging to determine the possible need to re-treat a lesion. Although there are a lack of clinical studies regarding the use of CBCT specifically for JON lesions, it is clear that using this technology for diagnosis and assessment of other maxillofacial conditions, many of which share very similar physical characteristics to JON, is quickly becoming a valuable diagnostic tool. Techniques as described by Ratner utilizing digital palpation and pressures, diagnostic local anesthetic injections, history and location of radiating pain if present and other manual testing procedures are needed. Complicating the issue is the fact that some JON lesions cause pain, hence the term neuralgia induced cavitational osteonecrosis (NICO) that describes a neuralgia component, and other JON lesions do not cause unprovoked pain, swelling, redness, or even fever. 22 The histological markers are the same but the symptoms differ. We believe that systemic illness previously not attributed to JON needs to be further evaluated. 23 Systemic Implications Recent research by Lechner and von Baehr confirm that JON lesions have high levels of inflammatory chemical messengers primarily regulated upon activation, normal T cell expressed, and secreted (RANTES) and fibroblast growth factor (FGF-2). Studies have shown RANTES to be implicated in many systemic illnesses such as arthritis, atopic dermatitis, nephritis, colitis, promotion of multiple sclerosis and Parkinson s disease, alopecia, thyroid disorders, and RANTES has been shown to cause an acceleration of tumor growth. FGF-2 has been shown in prostate cancer to promote tumor and cancer progression. Also, FGF-2 levels have shown direct correlation to the progression, metastasis and prognosis for survival of colorectal cancer patients. Also patients with gastric carcinoma have significantly higher levels of FGF-2 in their serum than that of cancer-free patients. Lechner and von Baehr conclude that RANTES deriving from JON might act as a low level inflammatory signal that leads to up-regulation of RANTES levels in specific organs with deleterious biological effects over the long term. JON can therefore be defined as a sort of inflammatory focus. Both inflammatory messengers are implicated in many serious illnesses. The excessive levels of RANTES/FGF-2 in JON lesions was compared by Lechner and von Baehr to the levels of these inflammatory messengers that have been observed in other systemic illnesses like amyotrophic lateral sclerosis, multiple sclerosis, rheumatoid arthritis and breast cancer. The levels of these messengers detected in the JONs are higher than in the serum and cerebrospinal fluid of amyotrophic lateral sclerosis and multiple sclerosis patients. Current research by Lechner and von Baehr has demonstrated a five-fold increase in RANTES in the jawbone osteonecrotic lesions of breast cancer patients. They suggest that the JON derived RANTES may serve as an expediter of breast cancer progression. The most striking discovery of the study was the high levels of RANTES and FGF-2 found in 97% of the tissues investigated. Correlations between levels of RANTES and FGF-2 in NICO tissue were statistically significant. The high levels of RANTES/FGF-2 in JON patients indicate that JON can be described as a derailed metabolic pattern, causing similar and mutually reinforcing pathogenic signaling pathways to other organs. The immune system seems to be UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 27

28 activated in response to danger signals, which evoke various innate molecular pathways that culminate in inflammatory cytokine production and possible activation of the adaptive immune system. The study suggests that JON might serve as a fundamental cause of inflammatory diseases, through RANTES/FGF-2 production. Thus, JON and implicated messengers represent an integrative aspect of inflammatory diseases and serve as a potential etiology of the disease. Removing JONs may be a key to reversing these and other inflammatory diseases. NICO is a chronic, insidious and subtle process. The absence of acute inflammation or symptoms is supported by the fact that acute pro-inflammatory cytokines, such as TNF-alpha and IL-6 are not seen in increased numbers in the JONs. The absence of acute inflammation denotes that the proliferation of chronic immunological processes associated with JONs are under the guidance of 24, 25, 26, 27 RANTES/FGF-2. Treatment Once the location and size of the lesions are determined, treatment modalities are needed. The IAOMT believes that it is generally unacceptable to leave dead bone in the human body. It is believed that JON lesions can be the foci for systemic toxins to begin the process for degrading a patient s overall health. Hydrogen sulfide has long been regarded as the most toxic material the human body can produce. Yet the Affinity Labeling Technologies Lab Corporation has found substances that are far more toxic to five essential mammalian enzymes than hydrogen sulfide in JON biopsy samples. 28 Biopsy to confirm the diagnosis of JON and rule out other disease states including cancer is important. Then, treatment to remove or eliminate the involved pathology and stimulate the regrowth of normal, vital bone is necessary. At this time in the peer- reviewed literature, surgical therapy consisting of excising the affected non-vital bone appears to be the favored treatment for JON. The use of epinephrine containing local anesthetics should be avoided due to the already compromised blood flow associated with JON. Following a thorough surgical decortication and curettage 29 of the lesion and irrigation with sterile normal saline, 30, 31, healing is enhanced by placement of platelet-rich fibrin (PRF) grafts into the osseous void. 32, 33 The use of platelet-rich fibrin concentrates in surgical procedures is not only beneficial from a clotting standpoint, but also from the aspect of releasing growth factors over a period of up to fourteen days following surgery. 34 Prior to the use of PRF grafts, relapse of the jawbone osteonecrotic lesion after surgery has been observed to occur in 40% of cases. 35 It should be noted that the 40% rate of surgical failures occurred when no adjunctive healing therapies such as PRF grafts were included as part of the treatment protocol. Alternative techniques that are used in Europe and other parts of the world as primary or supportive therapies should also be evaluated. These include homeopathy, electrical stimulation, radiation such as laser and infrared, medical grade oxygen/ozone, hyperbaric oxygen, anticoagulation modalities, Sanum remedies, nutrition and nutriceuticals, energy treatments, and others. The IAOMT believes these forms of treatment should be evaluated and confirmed to be viable forms of treatment or shown ineffective and eliminated from use. 36 Standards of care to ensure proper healing and detoxification should be established. Techniques for evaluating success should be tested and standardized. Protocols or procedures to help determine when UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 28

29 treatment is appropriate and when it is not should be put forth for evaluation. Researchers have shown that JON is a disease associated with reduced blood flow. 37 The sluggish medullary blood flow coupled with the fact that JON lesions maintain a pressure two to four times that of normal marrow challenge the delivery of antibiotics and the delivery of the body s own immune defenses. Genetic predisposition, effects of certain medications, trauma and infections, and other factors like smoking and atmospheric extremes lead to the formation of JON. 38 In no other bone is the potential for trauma and infections as great as in the jawbones. Those with reduced immune function are at increased risk for developing JON. 39 JON As It Relates To Bisphosphonate Drugs Of special interest and concern recently pertaining to JON is the increased use of a category of drugs called Bisphosphonates. These drugs are commonly prescribed for osteoporosis and for other diseases such as multiple myeloma and cancers that have metastasized to bone. The bisphosphonate-induced osteonecrosis of the jaw (BIJON) is characterized by exposure of bone in the mandible or maxilla for more than eight weeks in a patient who has taken or currently is taking a bisphosphonate and who has no history of radiation therapy to the jaws. 40 The fundamental biologic action of all bisphonates is to inhibit bone resorption and hence bone turnover and renewal, which of course reduces serum calcium levels as well. The reason for this anti-osteoclastic or anti-resorption effect is the inhibition and/or irreversible cell death of the osteoclast. All bisphosphonates have a half-life in bone of more than eleven years and are perhaps even lifelong. 41 Although all bones are affected by bisphosphonates, the maxilla and mandible have a greater uptake of bisphonates due to the accelerated turnover rate of alveolar bone. Dixon et al. documented the remodeling rate of bone at various sites and found that the alveolar crest remodels at ten times the rate of the tibia. 42 Prolonged use of oral bisphosphonates, the most common of which is alendronate (Fosamax), or short-term use of intravenous bisphosphonates, the most potent of which is zolendronate (Zometa), become lethally toxic to osteoclasts and result in necrotic bone. According to Marx et al. Zometa, when administered at the recommended dose of four milligrams per month, may produce exposed bone within three to twelve months. 43 Once the toxicity of the bisphosphonate has overwhelmed the osteoclasts, necrosis of the bone occurs. The avascular nature of the necrotic bone leads to subsequent necrosis of the overlying tissue, resulting in exposed dead bone. Initially the exposed bone is not painful because it is necrotic and lacks innervation. However, once the bone becomes infected it often progresses to a painful lesion. Marx details the treatment regimens for various stages of BIONJ involvement. These regimens range from daily oral 12% Chlorhexidine rinses, to long-term antibiotic coverage, to resection of the alveolar bone. 44 Most often the best management practice for treating patients with early stage BIONJ is to leave the exposed bone undisturbed except for removing superficial sharp edges. In cases where patients are able to discontinue bisphosphonate therapy for up to one year, enough osteoclastic activity resumes adjacent to the necrotic bone that fifty percent of patients experience sequestration of the exposed bone with subsequent healing of the soft tissue. In order to expedite UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 29

30 the exfoliation of the diseased bone some practitioners have successfully incorporated the use of oxygen-ozone therapy. 45, 46, 47 Treatments have consisted of injecting oxygen ozone in surrounding tissues on a weekly to monthly basis. In addition, others have encouraged the use of topical applications of ozone that are delivered via ozonated oils. The IAOMT believes that the findings associated with bisphosphonates should be a major concern for the dental profession. Having this knowledge is essential so that dentists will be cognizant of the need to be thorough in checking the medical and pharmacological history of patients prior to performing invasive surgical procedures. Education Education of our professional peers is necessary in order to understand the necessity for testing our patients for genetic predisposition of reduced osseous blood flow. Dissemination of information regarding laboratories such as Hemex (Phoenix, Arizona), Thrombocare (Dallas, Texas), and research facilities such as Dr Glueck s lab at the University of Cincinnati Medical Center that provide testing to determine risk factors for increased blood clotting tendencies in the osseous tissues is necessary. 48 Knowing and reviewing risk factors from the environment, medicines, and genetics, as well as previous medical and dental treatments is essential. The need for proper pre and post surgical therapy and proper techniques to be used in performing extractions and other osseous surgeries is indicated. Providing information to the patients regarding post surgical nutrition, blood flow maintenance, and prevention is also needed. Educating our dental boards and national dental agencies regarding the current state of research in JON is essential. If decisions are made using out of date information thus holding practitioners to dated standards of care, then no basis for continuing research, understanding, or treatments will be forth coming for our patients. The IAOMT urges the dental, medical, and research communities to continue applying the scientific method in order to diagnose, treat, educate, and ultimately prevent the occurrence of Human Jawbone Osteonecrosis (JON). Summary In summary, jawbone osteonecrosis, whether it is a result of bisphosphonate drugs, use of epinephrine containing local anesthetics, genetic predisposition, or systemic factors, is an insidious disease process. The broad array of DNA verified anaerobic pathogens and their toxins are risk factors for systemic disease. Although most JON lesions are difficult to diagnose with routine radiographs and most are not painful, one should never assume that the disease process does not exist. There are many disease processes that are difficult to diagnose, and many that are not painful. If we used pain as an indicator for treatment, periodontal disease, diabetes and most cancers would go untreated. Today s dental practitioner has a broad spectrum of modalities to successfully treat jawbone osteonecrosis and failure to acknowledge the disease and recommend treatment is no less serious than failure to diagnose and treat periodontal disease. A paradigm shift is in order for the dental profession to follow the lead of the medical profession in the recognition of JON for the health and welfare of its trusting patients. UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 30

31 1 Barrett WC: Oral Pathology and Practice. Philadelphia, PA, S.S. White Dental Mfg. Co, Noel HR: A lecture on caries and necrosis of bone. Am J Dent Sci (series 3):189, Black GV: A work on special dental pathology. Chicago: Medico-Dental Co, 1915; Ratner EJ, Person P, Kleinman DJ, et al: Jawbone cavities and trigeminal neuralgia and atypical facial neuralgias. Oral Surg Oral Med Oral Pathol 1979; 48: Neville BW, Damm DD, Allen CM, Bouquot JE. Oral and Maxillofacial Pathology. Philadelphia: WB Saunders Co; 2009: Donlon, WC: Invited Commentary on Neuralgia-inducing Cavitational Osteonecrosis. Oral Surg Oral Med Oral Pathol March 1992; 73, no.3: Freedman PD, Reich, FR, Steinlauf AF: Letters to the editor. Oral Surg Oral Med Oral Pathol, July 1998; 86 no. 1: Hearing Examiner s Proposed Adjudication and Order, Commonwealth of Pennsylvania, Bureau of Professional and Occupational Affairs v. Stephen R. Evans, DDS, May 10, IBID 5 10 Bouquot JE, Roberts, AM, Person P: Neuralgia-inducing Cavitational Osteonecrosis (NICO): Osteomyelitis in 224 jawbone samples from patients with facial neuralgias. Oral Surg Oral Med Oral Pathol 1992; 73: Shankland WE, et al: Medullary and Odontogenic Disease in the Painful Jaw: Clinicopathologic Review of 500 Consecutive Lesions. Cranio 2002; 20, no. 4: Ratner EJ, Person P, Kleinman DJ, Shklar G, Socranksy SS: Jawbone cavities and trigeminal and atypical facial neuralgias. Oral Surg 19790, 48, no. 1: Bouquot JE, Roberts AM, Person P: Neuralgia-inducing cavitational Osteonecrosis (NICO): Osteomyelitis in 224 jawbone samples from patients with facial neuralgias. Oral Surg Oral Med Oral Pathol 1992; 73: Ratner EJ, Person P, Kleinman DJ, et al: Jawbone cavities and trigeminal and atypical facial neuralgias. Oral Surg Oral Med Oral Pathol 1079; 48, mo. 1: Cohen S: Diagnostic procedures. In: Pathways of the pulp. 6 th ed. Cohen S. Burns RC (eds). St. Louis: CV Mosby Co; 1994:10. UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 31

32 16 Imbeau J: Introduction to Through-Transmission Alveolar Ultrasonography (TAU) in Dental Medicine. Cranio April 2005, Vol. 23, No.2: Esposito SA, et al. A Novel Method to Estimate the Volume of Bone Defects Using Cone- Beam Computer Tomography; an In Vitro Study. JOE 2013 Sept; 39(9): M. Joujeim, T.J. Prihoda, et al. Evaluation of high-resolution cone-beam computed tomography in the detection of simulated inter-radicular bone lesions. Dentomaxillofacial Radiology (2009) 38, B. Felipe, et al. Comparison between cone-beam and multi-slice computed tomography for identification of simulated bone lesions. Braz. oral res. [online]. 2011, vol.25, n.4, pp ISSN Tyndall DA, Rathore S. Cone-Beam CT Diagnostic Applications: Caries, Periodontal Bone Assessment, and Endodontic Applications. Dent Clin N Am 52 (2008) Patil NA, Gadda R, Salvi R. Cone Beam Computed Tomography: Adding the Third Dimension. J Contemp Dent 2012;2(3): Bouquot JE, LaMarche MG: Ischemic Osteonecrosis under fixed partial denture pontics: Radiographic and microscopic features in 38 patients with chronic pain. J Prosthetic Dent 81: Bouquot JE: Characterization and identification of chemical toxicants isolated from cavitational material and infected root canalled teeth; in situ testing of teeth for toxicity and infection. Proceedings of Annual Meeting, International Academy of Oral Medicine and Toxicology; San Diego, CA; Lechner J, VonBaehr V. Rantes and fibroblast growth factor in jawbone cavitations; Triggers for systemic disease? International Journal of Medicine 2013: 6, Lechner J, Mayer W. Immune messengers in neuralgia inducing cavitational osteonecrosis (NICO) in jawbone and systemic interference. European Journal of Integrative Medicine. 2 (2010) Lechner J. Chronic osteonecrosis of jawbone (NICO): Unknown trigger for systemic disease and a possible new integrative approach? J Altern Med Res 2013;5(3): Lechner J., von Baehr V. Hyperactive signaling pathways of chemokine RANTES/CCL5 in osteopathies of jawbone in breast cancer patients case report and research. Breast Cancer: Basic and Clinical Research 2014: 8, Haley B. Characterization and identification of chemical toxicants isolated from cavitational UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 32

33 material and infected root canalled teeth; in situ testing of teeth for toxicity and infection; Proceedings of Annual meeting, International Academy of Oral medicine and Toxicology; San Diego, California; IBID 5 30 L. He, Y. Lin, X. Hu, Y. Zhang, and J. We, A comparative study of platelet-rich fibrin (PRF) and platelet-rich plasma (PRP) on the effect of proliferation and differentiation of rat osteoblasts in vitro. Oral Surg Oral Med Oral Pathol Oral Radiol Endod Nov;108(5): M. Thorat, A.R. Pradeep, and B. Pallavi, Clinical effect of autologous platelet-rich fibrin in the treatment of intra-bony defects; a controlled clinical trial, Journal of Clinical Periodontology, vol. 38, no, 10, pp , D.M. Dohan, J. Choukroun, A. Diss et al., Platelet-rich fibrin (PRF): a second-generation platelet concentrate. Art I: technological concepts and evolution, Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology, vol. 101, no 3, pp J.M. Karp, F. Sarraf, M.S. Shoichet, and J. E. Davies, Fibrin filled scaffolds for bones-tissue engineering: an in vivo study, Journal of Biomedical Materials Research A, vol. 71, no. 1, pp , D.M.S. Ehrenfest, G. M. de Peppo, P. Doglioli, and G. Sammartino, Slow release of growth factors and thrombospondin-1 in Choukroun s platelet-rich fibrin (PRF): a gold standard to achieve for all surgical platelet concentrates technologies, Growth Factors, vol. 27, no. 1, pp , Bouquot, J.E, and McMahon, R.E. Ischemic osteonecrosis in facial pain syndromes; a review of NICO (neuralgia-inducing cavitational osteonecrosis) based on experience with more than 2,000 patients TM Diary 1996; 8:32-39). 36 Ali M, et al. Curriculum for Doctorate of Integrative Medicine. Capital University of Integrative Medicine: Washington DC: Glueck CJ, McMahon RE, Bouquot JE, Rabinovich B: Thrombophilia, hypofibrinolysis, and osteonecrosis of the jaws. Oral Surg Oral Med Oral Path 1996; 81: Bouquot, JE, McMahon RE: Neuropathic pain in maxillofacial osteonecrosis. J Oral Maxillofac Surg 2000; 58: Brown P, Cran L: Avascular necrosis of bone in patients with human immunodeficiency virus infection: report of 6 cases and review of the literature. Clinical Infectious Diseases 2001; 32: UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 33

34 40 Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, Mehotra B (Task Force on Bisphophonate-Related Osteonecrosis of the Jaws, American Association of Oral and Maxillofacial Surgeons). American Association of Oral and Maxillofacial Surgeons position pater on bisphosphonate-related osteonecrosis of the jaw-2009 update. Aust Endod J 2009; 35: Marx, R.E. Oral and Intravenous bisphosphonate-induced osteonecrosis of the jaws. Chicago: Quintessence. 2011: Dixon RB, Tricker ND, Garetto LP. Bone turnover in elderly canine mandible and tibia [abstract 2579]. J Dent Res 1997; 76: Marx RE, Swatari Y, Fortin M, Broumand V. Bisphophonate-induce exposed bone (osteonecrosis/osteopetrosis) of the jaws: Risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 2005;63: Marx, R.E. Oral and Intravenous bisphosphonate-induced osteonecrosis of the jaws. Chicago: Quintessence. 2011: Cole, G. Treatment of bisphosphonate related osteonecrosis of the jaw (BRONJ) with oxygenozone therapy: a case report. J of Implant and Advanced Clinical Dentistry, Vol 5, No. 5, May Ripamonti, CI, Maniezzo M, Pessi, MA, Boldini, S. Treatment of osteonecrosis of the jaw (ONJ) by medical ozone gas insufflation. A case report. Tumori May-June; 98(3): Agrillo, A et al. Bisphosphonate-related osteonecrosis of the jaw (BRONJ): five year experience in the treatment of 131 cases with ozone therapy. Eur Rev Med Pharmacol Sci Nov:16(2): Bick RL: Disorders of Thrombosis and Hemostasis. Clinical and Laboratory Practice. Roger Bick (ed). Third ec., Philadelphia, PA: Lippincott Williams and Williams; 2002 UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page 34

35 Annals of Internal Medicine Review Systematic Review: Bisphosphonates and Osteonecrosis of the Jaws Sook-Bin Woo, DMD; John W. Hellstein, DDS, MS; and John R. Kalmar, DMD, PhD Osteonecrosis of the jaws is a recently described adverse side effect of bisphosphonate therapy. Patients with multiple myeloma and metastatic carcinoma to the skeleton who are receiving intravenous, nitrogen-containing bisphosphonates are at greatest risk for osteonecrosis of the jaws; these patients represent 94% of published cases. The mandible is more commonly affected than the maxilla (2:1 ratio), and 60% of cases are preceded by a dental surgical procedure. Oversuppression of bone turnover is probably the primary mechanism for the development of this condition, although there may be contributing comorbid factors. All sites of potential jaw infection should be eliminated before bisphosphonate therapy is initiated in these patients to reduce the necessity of subsequent dentoalveolar surgery. Conservative débridement of necrotic bone, pain control, infection management, use of antimicrobial oral rinses, and withdrawal of bisphosphonates are preferable to aggressive surgical measures for treating this condition. The degree of risk for osteonecrosis in patients taking oral bisphosphonates, such as alendronate, for osteoporosis is uncertain and warrants careful monitoring. Ann Intern Med. 2006;144: For author affiliations, see end of text. Bisphosphonates are used to treat osteoporosis, Paget disease of bone and other metabolic bone diseases, multiple myeloma, and skeletal events associated with metastatic neoplasms. Their primary mechanism of action is inhibition of osteoclastic resorption of bone. Within the past 2 years, an increasing body of literature has suggested that bisphosphonate use, especially intravenous preparations, may be associated with osteonecrosis of the jaws. We briefly review the action of bisphosphonates, outline the clinical manifestations of bisphosphonate-associated osteonecrosis of the jaws, summarize current treatment strategies, discuss possible mechanisms of etiopathogenesis, and suggest avenues of research. METHODS We performed MEDLINE and PubMed searches of English- and foreign-language literature (1966 to 31 January 2006) using the following Medical Subject Headings (MeSH) and terms: osteonecrosis, avascular necrosis, phosphorous necrosis, bisphosphonates, and diphosphonates. We then crossed the same terms with the terms jaw diseases, myeloma, breast cancer, and metastatic cancer. Other references were obtained from citations from retrieved articles. Similar terms were used to search abstracts from meetings of the American Society of Clinical Oncology. We specifically reviewed all case reports and case series of patients with bisphosphonate-associated osteonecrosis of the jaws. We included any report that provided acceptable documentation of disease and use of bisphosphonates, regardless of whether it included information on the sex of patients, the site of the lesions, and the bisphosphonate used. Several authors published more than 1 paper describing patients with osteonecrosis. Through direct communication with these authors, we confirmed that some of the same patients were included in multiple reports. When this occurred, we used and cited data only from the larger, more recent publication. No funding was received for this study. ACTIONS OF BISPHOSPHONATES Bisphosphonates are powerful inhibitors of osteoclastic activity. They are analogues of inorganic pyrophosphates with low intestinal absorption, are excreted through the kidneys without metabolic alteration, and have a high affinity for hydroxyapatite crystals (1, 2). Because they are incorporated into the skeleton without being degraded, they are remarkably persistent drugs; the estimated half-life for alendronate is up to 12 years (3). Alendronate, risedronate, pamidronate, zoledronic acid, and ibandronate, which are called aminobisphosphonates, have much higher potency because they contain nitrogen in a side chain (Table 1). The nonaminobisphosphonates are metabolized by osteoclasts to inactive nonhydrolyzable adenosine triphosphate analogues that are directly cytotoxic to the cell and induce apoptosis (1, 2). The newer aminobisphosphonates have 2 actions (4): induction of another adenosine triphosphate analogue that induces apoptosis, and inhibition of farnesyl diphosphonate synthase, which is part of the mevalonate pathway of cholesterol synthesis. Such inhibition results in dysregulation of intracellular transport, cytoskeletal organization, and cell proliferation, leading to inhibition of osteoclast function. In addition, aminobisphosphonates reduce recruitment of osteoclasts and induce osteoblasts to produce an osteoclast-inhibiting factor (5, 6). Aminobisphosphonates exert several antitumor effects, including induction of tumor cell apoptosis, inhibition of tumor cell adhesion to the extracellular matrix, and inhibition of tumor invasion (4, 7). Bisphosphonates also have See also: Print Key Summary Points Web-Only CME quiz Conversion of figures and tables into slides UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; Page American College of Physicians 753

36 Review Bisphosphonates and Osteonecrosis of the Jaws antiangiogenesis properties (8, 9) and can activate T cells (10, 11). The use of bisphosphonates in patients with multiple myeloma and metastatic cancer to the bones, such as breast, prostate, lung, and renal cell carcinomas, has resulted in a statistically significant reduction in skeletal complications, including pathologic fractures, spinal cord compression, hypercalcemia of malignant disease, and the need for subsequent radiotherapy or surgery to bone (12 14). Intravenous bisphosphonates have improved bioavailability and do not produce gastrointestinal side effects, resulting in better patient adherence. They have become standard therapy in the management of patients with multiple myeloma and metastatic cancer. POTENTIAL ADVERSE EFFECTS OF BISPHOSPHONATE ACTIONS In normal bone homeostasis, osteoclastic resorption is tightly linked to osteoblastic bone deposition and both functions are essential for repair of physiologic microdamage. Prolonged use of bisphosphonates may suppress bone turnover to the point that such microdamage persists and accumulates (15). The result is hypodynamic bone with decreased biomechanical competence. Although osteoblastic function is also reduced during bisphosphonate therapy, continued mineralization yields a hard, brittle bone with an osteopetrotic appearance and an increased risk for fracture (16 18). Thus, some experts caution that the benefits of prolonged use of bisphosphonates must be carefully weighed against the potential negative effects of oversuppression of bone metabolism (1, 19, 20). Other experts argue that although long-term use of bisphosphonates may retard fracture healing or slow callus remodeling, it may not affect bone mineralization or mechanical properties (21, 22). ORAL COMPLICATIONS OF BISPHOSPHONATE THERAPY Although oral bisphosphonates may cause oral mucosal lesions (purportedly arising from direct contact injury) (23, 24), we focus our review on bisphosphonate-associated osteonecrosis of the jaw. Table 2 summarizes 368 reported cases of bisphosphonate-associated osteonecrosis of the jaw (25 54). Reported cases manifested as exposure of portions of the bone of the mandible only (65%), maxilla only (26%), or both (9%). Approximately one third of lesions were painless (27), and there was a slight female predilection in a ratio of 3:2 among all reported cases. Multifocal or bilateral involvement was slightly more common in the maxilla than in the mandible (31% vs. 23%). Most lesions were on the posterior lingual mandible near the mylohyoid ridge. Of importance, 60% of cases occurred after a tooth extraction or other dentoalveolar surgery and the remaining cases occurred spontaneously. The latter cases often involved patients wearing dentures, a possible source of local trauma. Marx and colleagues (27) reported that 39% of cases that occurred spontaneously were located on bony exostoses that were easily traumatized. There is 1 case report of dental implant failure associated with bisphosphonate use (55). Most patients (94%) were treated with intravenous bisphosphonates (primarily pamidronate and zoledronic acid), and most patients (85%) had multiple myeloma or metastatic breast cancer (Table 3). The remaining patients Table 1. Bisphosphonate Formulations* Generic Name Brand Name Manufacturer and Location Dosage Forms Nitrogen- Containing FDA Approval Date Etidronate disodium Didronel Procter & Gamble Pharmaceuticals, Cincinnati, Ohio 200- and 400-mg tablets No 1 September 1977 Clodronate disodium Bonefos (Canada) Schering AG, Berlin, Germany 400- and 800-mg tablets; 60 mg/ml No Not approved ampule Tiludronate disodium Skelid Sanofi-Synthelabo Inc., New York, 200-mg tablet No; sulfur 7 March 1997 New York moiety Alendronate sodium Fosamax Merck & Co. Inc., Whitehouse Station, New Jersey 5-, 10-, 35-, 40-, and 70-mg tablets; 70 mg/75 ml oral solution Yes 29 September 1995 Alendronate sodium Fosamax plus D Merck & Co. Inc., Whitehouse 70-mg and 2800-U cholecalciferol Yes 7 April 2005 plus vitamin D 3 Station, New Jersey tablet Pamidronate disodium Aredia Novartis Pharmaceuticals, East 30-, 60-, and 90-mg vials Yes 31 October 1991 Hanover, New Jersey Risedronate sodium Actonel Procter & Gamble Pharmaceuticals, 5-, 30-, and 35-mg tablets Yes 27 March 1998 Cincinnati, Ohio Risedronate sodium Actonel with calcium Procter & Gamble Pharmaceuticals, 35-mg and 500-mg calcium tablets Yes 12 August 2005 plus calcium Cincinnati, Ohio Zoledronic acid Zometa Novartis Pharmaceuticals, East 4-mg vial Yes 20 August 2001 Hanover, New Jersey Ibandronate sodium Boniva Roche Laboratories Inc., Nutley, 2.5-mg tablet Yes 16 May 2003 New Jersey 150-mg tablet 24 March mg/3 ml 6 January 2006 * This table shows the most common brand names. Generic forms, other names, and other doses may be available outside the United States. Clodronate is included because of its common use in Canada and Europe. FDA Food and Drug Administration. Drug is administered intravenously UNIT May REQUIRED Annals of Internal IAOMT Medicine Accreditation Volume 144 Materials Number 10as of December 18, 2017; Page 36

37 Bisphosphonates and Osteonecrosis of the Jaws Review Table 2. Reports of Cases of Bisphosphonate-Associated Osteonecrosis of the Jaws* Study, Year (Reference) Ruggiero et al., 2004 (25) Estilo et al., 2004 (26) Marx et al., 2005 (27) Migliorati et al., 2005 (28) Purcell and Boyd, 2005 (29) Bagan et al., 2006 (30) Pires et al., 2005 (31) Bamias et al., 2006 (32) Melo and Obeid, 2005 (33) Zarychanski et al., 2006 (34) Summary of studies with fewer than 10 patients (35 54) Patients, n Sex, n Primary Diagnosis Sites Previous Surgical Male Female Procedure, n (%) Myeloma (n 29) Breast cancer (n 21) Prostate cancer (n 3) Lung cancer (n 1) Uterine leiomyosarcoma (n 1) Leukemia (n 1) Osteoporosis (n 7) Breast cancer (n 9) Myeloma (n 4) 119 NS NS Myeloma (n 62) Breast cancer (n 50) Prostate cancer (n 4) Osteoporosis (n 3) Breast cancer (n 10) Myeloma (n 3) Prostate cancer (n 2) Ovarian cancer (n 1) Ovarian/breast cancer (n 1) Osteoporosis (n 1) Breast cancer (n 5) Prostate cancer (n 4) Myeloma (n 3) Osteoporosis (n 1) Breast cancer (n 10) Myeloma (n 9) Prostate cancer (n 1) Breast cancer (n 6) Myeloma (n 4) Prostate cancer (n 1) Lung cancer (n 1) Myeloma (n 11) Prostate cancer (n 3) Breast cancer (n 2) Other neoplasm (n 1) Breast cancer (n 3) Myeloma (n 7) Lung cancer (n 1) Myeloma (n 10) Breast cancer (n 1) Renal cancer (n 1) Myeloma (n 29) Breast cancer (n 26) Prostate cancer (n 5) Paget disease (n 3) Osteoporosis (n 3) Lung cancer (n 2) Lymphoma (n 1) Mesothelioma (n 1) Mandible (n 39) Maxilla (n 23) Both (n 1) Mandible (n 6) Maxilla (n 5) Both (n 2) Mandible (n 81) Maxilla (n 33) Both (n 5) Mandible (n 8) Maxilla (n 2) Both (n 1) Unknown (n 7) Mandible (n 4) Maxilla (n 2) Unknown (n 7) Mandible (n 11) Maxilla (n 1) Both (n 8) Mandible (n 8) Maxilla (n 3) Both (n 1) Mandible (n 14) Maxilla (n 3) Mandible (n 8) Maxilla (n 2) Both (n 1) Mandible (n 10) Maxilla (n 1) Both (n 1) Mandible (n 30) Maxilla (n 14) Both (n 9) Not assigned (n 17) Medications 54 (86) Pamidronate (n 34) Zoledronic acid (n 9) Pamidronate and zoledronic acid (n 13) Alendronate (n 5) Risedronate (n 1) Alendronate and zoledronic acid (n 1) 9 (69) Intravenous forms, not specified 55 (46) Zoledronic acid (n 48) Pamidronate and zoledronic acid (n 36) Pamidronate (n 32) Alendronate (n 3) 6 (33) Zoledronic acid (n 8) Pamidronate and zoledronic acid (n 6) Pamidronate (n 3) Alendronate (n 1) 5 (38) Zoledronic acid (n 9) Pamidronate (n 2) Pamidronate and zoledronic acid (n 1) Alendronate (n 1) 11 (55) Zoledronic acid (n 9) Pamidronate and zoledronic acid (n 6) Pamidronate (n 5) 8 (67) Pamidronate and zoledronic acid (n 5) Pamidronate (n 4) Zoledronic acid (n 3) 13 (76) Pamidronate and zoledronic acid (n 9) Zoledronic acid (n 7) Zoledronic acid and ibanronate (n 1) 9 (82) Zoledronic acid (n 4) Pamidronate (n 4) Pamidronate and zoledronic acid (n 3) 7 (58) Pamidronate (n 12) 44 (63) Zoledronic acid (n 27) Pamidronate and zoledronic acid (n 21) Pamidronate (n 14) Alendronate (n 5) Alendronate and zoledronic acid (n 1) Pamidronate, zoledronic acid, and alendronate (n 1) Oral ibandronate (n 1) * NS not stated. Sex was not reported for 9 patients in these studies. were taking oral bisphosphonates for osteoporosis or Paget disease of bone (25, 27 29, 40, 50, 51). Clinically, intraoral lesions appear as areas of exposed yellow-white, hard bone with smooth or ragged borders (Figures 1 and 2). Extraoral or intraoral sinus tracts may be present (Figure 3). Painful ulcers may develop in soft tissues that impinge on the ragged bony margins. Results of radiographic evaluation may be negative in early cases. Although some investigators have noted subtle changes, such as widening of the periodontal ligament, UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; 16 MayPage Annals of Internal Medicine Volume 144 Number

38 Review Bisphosphonates and Osteonecrosis of the Jaws Table 3. Primary Diagnoses and Types of Bisphosphonates in Reported Cases of Osteonecrosis of the Jaws Variable Patients, n (%)* Primary diagnosis Multiple myeloma 171 (46.5) Metastatic breast cancer 143 (38.8) Metastatic prostate cancer 23 (6.2) Osteoporosis 15 (4.1) Other metastatic disease 13 (3.5) Paget disease of bone 3 (0.8) Total 368 (100) Bisphosphonate medications Zoledronic acid 124 (35) Pamidronate 110 (31) Pamidronate and zoledronic acid 100 (28) Oral alendronate 15 (4.2) Alendronate and zoledronic acid 2 (0.6) Oral risedronate 1 (0.3) Oral ibandronate 1 (0.3) Ibandronate and zoledronic acid 1 (0.3) Pamidronate, zoledronic acid, and alendronate 1 (0.3) Total 355 (100) Intravenous bisphosphonates, not specified 13 Patients with osteoporosis 15 Receiving alendronate 13 (87) Receiving risedronate 1 (7) Receiving alendronate and zoledronic acid 1 (7) * Percentages may not sum to 100% because of rounding. Five patients had lung tumors. Other diseases were leiomyosarcoma, leukemia, ovarian/breast cancer, ovarian cancer, renal cancer, lymphoma, mesothelioma, and other. Nine of 11 cases were in the mandible, and 2 of 11 cases were in the maxilla. The remaining 2 cases were not specified. All cases were in the mandible. these findings are indistinguishable from chronic periodontal infection, a predisposing factor for osteonecrosis (27). Advanced cases show a moth-eaten, poorly defined radiolucency, with or without radio-opaque sequestra. In 1 series, 5 of 63 patients developed pathologic jaw fractures (25). Cultures of exposed bone may identify Actinomyces species, but care must be taken to distinguish between a true suppurative infection and mere surface colonization by Actinomyces, because such organisms are a common component of dental plaque. Patients with bisphosphonate-associated osteonecrosis may present similarly to those with osteoradionecrosis of the jaws. Osteoradionecrosis is a complication of radiotherapy. It is thought to result from osteocyte and microvascular damage after the jaws are exposed to ionizing radiation and also frequently occurs after tooth extraction (56). Osteoradionecrosis, however, infrequently involves the maxilla ( 5% of cases) and is more common in men than in women (57, 58). the jaws are the type and total dose of bisphosphonate and history of trauma, dental surgery, or dental infection. Ninety-four percent of patients with osteonecrosis received pamidronate or zoledronic acid. The doses for oncologic indications are often up to 12 times higher than those used for osteoporosis (13, 59). Of interest, clodronate, a nonaminobisphosphonate, has not been implicated in the development of osteonecrosis (60). The risk for osteonecrosis of the jaws is substantially higher for patients taking zoledronic acid and increases over time, probably because of the long half-life of these drugs. Although oral lesions may develop after as few as 4 months of bisphosphonate therapy, the median duration of drug use ranged from 22 to 39 months (32, 38, 48) and the mean ranged from 9 to 14 months (27, 33). The cumulative hazard was 1% within the first year and 21% at 3 years of treatment with zoledronic acid. In contrast, it was 0% in the first year and 4% in the third year for patients receiving pamidronate alone or with subsequent zoledronic acid (32). Another study showed that 10% of 211 patients receiving zoledronic acid developed osteonecrosis compared with 4% of 413 patients receiving pamidronate (61). A few cases have been reported in patients taking alendronate (10 mg/d) for osteoporosis (25, 27 29, 50, 51). One patient had taken alendronate for only 2 years (27). The concern is that with more women aging and taking bisphosphonates for longer periods of time, more cases of osteonecrosis may develop even in patients receiving alendronate or ibandronate therapy. Trauma to oral tori is also associated with osteonecrosis (27) (Figure 2). Furthermore, 60% of patients had some form of dentoalveolar surgery resulting in nonhealing of the surgical site and necrosis of bone. Because most dentoalveolar surgeries are performed to treat dental infection, the contribution of each to the development of osteo- Figure 1. Osteonecrosis of the right mandible after tooth extraction in a patient taking zoledronic acid for metastatic breast cancer. RISK FACTORS AND ETIOPATHOGENESIS The most important predisposing factors for the development of bisphosphonate-associated osteonecrosis of UNIT May REQUIRED Annals of Internal IAOMT Medicine Accreditation Volume 144 Materials Number 10as of December 18, 2017; Page 38

39 Bisphosphonates and Osteonecrosis of the Jaws Review Figure 2. Osteonecrosis of the palatal torus in a patient with osteoporosis taking alendronate. necrosis is unclear, although it is likely that together they compound the problem. Patients with myeloma tend to be prothrombotic and are often treated with other antiangiogenic agents, such as glucocorticoids, thalidomide, and the new proteasome inhibitors, such as bortezomib, in addition to bisphosphonates (62, 63). Although neither corticosteroids nor thalidomide has been shown to be associated with additional risk for osteonecrosis of the jaws, prospective studies are needed to more fully address this issue (32, 61). The impact of local factors, such as smoking, and of underlying medical conditions, such as diabetes or peripheral vascular diseases, remains to be determined. SUSCEPTIBILITY OF THE JAWS TO OSTEONECROSIS The question often asked is Why the jaws? First, the jaw bones are separated from a trauma-intense and microbiologically diverse oral environment by thin mucosa and periosteum. The fragility of this barrier is reflected by the condition known as lingual mandibular sequestration, which occurs in healthy adults yet resembles mild cases of bisphosphonate-associated osteonecrosis of the jaws (64). In this condition, 1- to 3-mm slivers of bone are sequestrated in the area of the protuberant mylohyoid ridge with spontaneous resolution. It is thought that minor trauma causes local damage to the thin mucosa and underlying periosteum, leading to bone necrosis. Because the posterior lingual mandible is also a frequent site for osteonecrosis, it seems probable that the hypodynamic bone in patients receiving bisphosphonate therapy may turn this typically innocuous process into chronic bone exposure. Trauma to the periosteum may also serve to initiate osteonecrosis in patients wearing dentures or dental prostheses or in patients with prominent exostoses. Second, teeth are readily infected by bacteria that cause caries and periodontal disease, 2 common infectious diseases. Because the teeth are separated from bone by no more than 2 mm of periodontal connective tissue, such infections have easy access to the underlying bone. A case of osteonecrosis in the ear of a patient taking zoledronic acid for multiple myeloma was reported recently (44). The lesion occurred after removal of exostoses in the external auditory canal, and the patient had concurrent osteonecrosis of the maxilla. We suggest that bisphosphonate-associated osteonecrosis of the jaws results from marked suppression of bone metabolism that results in accumulation of physiologic microdamage in the jawbones, compromising biomechanical properties. Trauma and infection increase demand for osseous repair that exceeds the capacity of the hypodynamic bone, resulting in localized bone necrosis. The antiangiogenic property of bisphosphonates and other medications and the presence of other comorbid factors may promote the risk for or persistence and progression of this condition. PREVALENCE OF BISPHOSPHONATE-ASSOCIATED OSTEONECROSIS OF THE JAWS A Web-based survey conducted by the International Myeloma Foundation resulted in 1203 respondents, 904 with myeloma and 299 with breast cancer. Seven percent and 4% of patients with myeloma and breast cancer, respectively, reported osteonecrosis, and 6% and 8% of patients with myeloma and breast cancer, respectively, reported lesions suspicious for osteonecrosis (61). In a singlecenter study of 252 patients who had received intravenous bisphosphonates since January 1997, 10% of 111 patients with myeloma and 3% of 46 patients with breast cancer developed osteonecrosis (32). In another study of 124 patients with myeloma or breast cancer who were treated with intravenous bisphosphonates in a dental clinic in a cancer center, 4 and 9 patients with myeloma and breast Figure 3. Extraoral fistula in a patient with intraoral osteonecrosis. UNIT 10 REQUIRED IAOMT Accreditation Materials as of December 18, 2017; 16 MayPage Annals of Internal Medicine Volume 144 Number