Osteonecrosis

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Osteonecrosis of the jaw: A serious byproduct of bisphosphonates usage10/3/2007By: Shalmali PalIf Sally Field is to be believed, then she really, really likes Boniva, thebone loss drug that she currently shills for in TV commercials. And ifCheryl Ladd is considered a reliable source, then having Fosamax in her lifeis almost as good as being one of "Charlie's Angels."What these two actresses don't mention in their ads is the less glamorousside of bisphosphonates, the main ingredient in drugs that build bone massand stem bone loss: the association between bisphosphonates andosteonecrosis of the jaw.Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is a relatively newcondition, first brought to the attention of the medical community (anddentists in particular) in the early 21st century. But with the graying ofthe population, and the reliance on bisphosphonates to battle osteoporosisand other bone-related diseases, BRONJ has become a serious problem in needof an effective management solution, according to a presentation last weekat the 2007 American Dental Association (ADA) meeting in San Francisco.BRONJ "has developed very rapidly," said Dr. Kalmar, Ph.D. "We'retalking about a (disease) history back to 2003. So in four years, it'sadvanced pretty fast and we're still flying with very little concreteinformation. There are lot of questions about where we are withbisphosphonates and dental care.""We can manage these patients, but are we managing them effectively?" addedKalmar, who is the program director in the department of oral andmaxillofacial pathology at Ohio State University in Columbus.In the ADA talk, Kalmar, along with Dr. Hellstein, offered an overviewof BRONJ. While the role of imaging in BRONJ was not a major part of theirpresentation, two recent papers have taken a closer look at how radiologicstudies can be a key factor in making the differential diagnosis."The bottom line is that this is a disease that intrinsically alters the(bone remodeling process)," said Hellstein, who is a clinical professor oforal pathology and radiology at the University of Iowa in Iowa City.Bisphosphonates background"The skeleton is not a static entity," Kalmar noted. "We know that there isa very fine interplay between the osteoclasts, the large multinucleatedcells that can resorb bone and bring calcium into the system as is needed.This (process) loosens up the bone. It's stimulated by, and controlled by,the other cells on the skeleton, the osteoblasts. These osteoclasts andosteoblasts interact with one another, and you cannot affect one withoutaffecting the other."Basically, bisphosphonates do their job by suppressing bone turnover.Unfortunately, bisphosphonates can suppress bone turnover a little too much,resulting in long-term interference with the osteoclasts and theirbone-building capabilities.Bisphosphonates currently on the marketDidronel (etidronate disodium) and Actonel with and withoutcalcium (risendronate sodium/risendronate sodium plus calcium), Procter & Gamble Pharmaceuticals, CincinnatiFosamax and Fosamax plus D (alendronate sodium with and withoutvitamin D3), Merck & Co., Whitehouse, NJBonefos (clodronate disodium), Bayer Schering Pharma, BerlinSkelid (tiludronate disodium), Sanofi-Synthelabo, New York CityAredia (pamidronate disodium), and Zometa and Reclast(zoledronic acid), Novartis Pharmaceuticals, East Hanover, NJBoniva (ibandronate sodium), Roche Laboratories, Nutley, NJAll but Didronel and Skelid are nitrogen-based bisphosphonates. Aredia,Zometa, and sometimes Boniva are administered intravenously, most commonlyin multiple myeloma and other cancer patients (breast, prostate, lung) withbone metastases, Kalmar explained.On the upside for these patients, co-therapy with IV bisphosphonates canreduce skeletal complications, reduce pain, extend survival, and improvequality of life. However, 50% of the total IV-administered bisphosphonatebecomes integrated with the skeleton, and the predominance of BRONJ caseshave been in cancer patients, he added.In addition to osteoporosis, oral bisphosphonates are prescribed for Paget'sdisease of the bone and hyperparathyroidism, Hellstein said. Kalmar stressedthat less than 1% of the total dose in oral bisphosphonate is absorbed intothe skeleton.Still, bisphosphonates have a very long half-life in the skeletal system --10 to12 years, Kalmar stated. And because bone itself turns over about 10%every year, the nitrogen-based bisphosphonates are not only embedded in thebone, but are not readily metabolized by the body.Defining BRONJThe first report of BRONJ came in 2003 when Dr. Marx from theUniversity of Miami in Florida submitted a letter to the Journal of Oral andMaxillofacial Surgery about the growing epidemic of induced avascularnecrosis of the jaws (September 2003, Vol. 61:9, pp. 1115-1117).A year later, Dr. Salvatore Ruggiero from the division of oral andmaxillofacial surgery at Long Island Jewish Medical Center in New Hyde Park,NY, reported on an additional 63 cases of BRONJ, while Marx detailed another119 cases of exposure in a subsequent article (Journal of Oral andMaxillofacial Surgery, May 2004, Vol. 62:5, pp. 527-534; November 2005, Vol.63:11, pp. 1567-1575).Four years later, the dental community has moved beyond case reports and isworking toward establishing guidelines for diagnosing and treating BRONJ.Kamar, Hellstein, and Dr. Sook-Bin Woo of Brigham and Women's Hospital inBoston offered a systematic review of BRONJ in a paper in the ls ofInternal Medicine (May 16, 2006, Vol. 144:10, pp. 753-761).Ruggiero's group also published background and guidelines for diagnosis,staging, and management of BRONJ (Oral Surgery, Oral Medicine, OralPathology, Oral Radiology, and Endodontology, October 2006, Vol. 102:4, pp.433-441).Kalmar and Hellstein referred several times to a paper by Dr. R. Graham, Ph.D., published earlier this year that discussed the pharmacologyand mode of action used by bisphosphonates. is from the BotnarResearch Centre and Oxford University Institute of Musculoskeletal Sciencesin Oxford, U.K. (Pediatrics, March 2007, Vol. 199: supplement 2, pp.S150-S162).In March 2007, the American Association of Oral and Maxillofacial Surgeons(AAOMS) issued a position paper on BRONJ, setting out the following diseaseparameters: Patients who are currently on, or were previously treated with,bisphosphonates must have exposed necrotic bone of the maxillofacial regionthat has persisted for more than eight weeks and no history of radiationtherapy to the jaws (Journal of Oral and Maxillofacial Surgery, March 2007,Vol. 65:3, pp. 369-376).In the same paper, the AAOMS also laid out a staging system for BRONJ, withthe most advanced stage III disease defined as "exposed/necrotic bone inpatients with pain, infection, and one or more of the following: pathologicfracture, extraoral fistula, or osteolysis extending to the inferiorborder."More recently, the American Society for Bone and Mineral Research (ASBMR)task force put out a similar definition of BRONJ: "The presence of exposedbone in the maxillofacial region that did not heal within eight weeks afteridentification by a healthcare provider" (Journal of Bone and MineralResearch, July 31, 2007).Bisphosphonates affect the jaws (and the mandible in particular) sodramatically for various reasons, Kalmar and Hellstein said. First,bisphosphonates are drawn to areas that are metabolically active: the jawbones have higher bone turnover than long bones, they explained. Also, thejaws, as well as the oral cavity, are microbial-rich regions that arefrequently subjected to minor injury and infection.Imaging BRONJThe ASBMR's definition of BRONJ came from a set of guidelines on themanagement of the disease. In this report, a multidisciplinary group, led byDr. Sundeep Khosla from the endocrine research unit at the Mayo Clinic inRochester, MN, made several recommendations for imaging BRONJ:Panoramic radiography can distinguish between osteonecrosis andmetastatic lesions, and is useful when there is a combination of osteolysisand osteosclerosis. However, as much as 50% bone mineral loss is necessaryfor optimal x-ray detection.CT has the potential to detect cancellous and cortical boneinvolvement, and can aid in differentiating cortical bone involvement fromtrabecular involvement. But studies have shown that CT cannot contribute tox-ray in asymptomatic patients with osteonecrosis.MRI depicts histopathologic changes of necrotic bone. In chroniccases, fibrosis and sclerosis of the bone will result in low signalintensity on T1- and T2-weighted imaging.Technetium-99m scintigraphy could be useful as a screening tool with asensitivity that is tied to the stage of osteonecrotic lesion. The imagingexam is often done in metastatic cancer patients as part of the routineworkup.PET offers poor resolution with high radiation dose and will mostlikely not have any role in BRONJ examination.Optical coherence tomography (OCT) could be used to image smalllesions in the alveolar bone; imaging artifacts are a serious problem.Ultimately, the task force suggested that patients who present with "overtclinical evidence of ONJ" do not require imaging. However, radiographsshould be the first-line imaging study, with other modalities reserved fordifferential diagnosis. Research continues on the way to optimize ONJimaging, such as combining anatomic and functional modalities (conebeam CTand scintigraphy) and using contrast agents, the group wrote.In an e-mail to AuntMinnie.com, Kalmar stated that the role of imaging inBRONJ should be determined on a case-by-case basis. "I think it truly has tobe ... reserved for IV bisphosphonate patients or oral drug users with stageII or III presentations," he explained. "Besides the issue of differentialdiagnosis, use of CT to exclude areas of 'cortical fragmentation' ... may behelpful in predicting sites of exposure or sequestra formation. I wish thatthe new conebeam CT units were sensitive enough for this duty, but I havenot seen enough data to unequivocally support them as a good alternate toregular CT imaging."In the second paper, an international multidisciplinary group strongly urgedhead and neck specialists to consider imaging as an alternative to moreinvasive methods."Cases of exposed bone are not always associated with pain (and) it ispreferable to avoid biopsy in patients taking bisphosphonates because ofproblems with healing postsurgical intervention," wrote Dr. Pramit Phal andcolleagues. "It is important for radiologists to recognize (BRONJ), becauseimaging is likely to play an increasing role in confirming the diagnosis"(American Journal of Neuroradiology, June-July 2007, Vol. 28:6, pp.1139-1145).Phal is from the department of radiology at Royal Melbourne Hospital inAustralia; his co-authors are from the departments of oral and maxillofacialsurgery, otolaryngology, and ophthalmology, as well as the School ofDentistry at Oregon Health & Science University in Portland.In this retrospective study, Phal's group included 15 patients onbisphosphonates who developed osteonecrosis of the jaws. Among the 11 femalesubjects, six had breast cancer, three had osteoporosis, and two hadmultiple myeloma. Among the four male patients, there were two cases ofprostate cancer, one of multiple myeloma, and one of osteoporosis.Based on clinical data, 10 of the 15 patients had a degree of osseoussclerosis involving the alveolar margin. Other clinical conditions includedsclerotic changes on the mandibular canal, osteolysis, and widening of theperiodontal ligament space.Of the 15, all but one patient had orthopantomograms. Five patients had CTscans and one patient had a radionuclide bone scan. Nine patients underwentsequential imaging. All images were reviewed in consensus by tworadiologists.According to the imaging results, osseous sclerosis was the most commonlyencountered x-ray finding in all 15 patients. In those who underwentsequential imaging, these sclerotic changes were often progressive, whichcan act as a hallmark for BRONJ, the authors stated. Osseous sclerosis"varied from subtle thickening of the lamina dura and alveolar crest toattenuated osteopetrosis-like sclerosis," they explained.They also stated that they found CT more sensitive than orthopantomographyfor deciphering soft-tissue swelling, periosteal new bone, and sequestrum.ManagementA major challenge that the healthcare community faces with BRONJ is that ofunder-reporting, Kalmar and Hellstein said. Most primary care physicians arenot likely to check the jaws and oral cavity of their patients onbisphosphonates, they said, so it is up to dental professionals to keep alookout.To that end, they recommended that the individual patient is the bestpredictor of future BRONJ. "In an individual patient, a single extraction orsingle sextant surgery will likely provide the best predictor of risk inother sextants/quadrants," Hellstein said. In these patients, the best betis minimizing the need for, and the extent of surgery, because their abilityto heal is retarded, he added.The duo offered the following treatment paradigm:Obtain a comprehensive medical history, asking specifically aboutbisphosphonates use.Minimize trauma and infection by being conservative with dentoalveolarsurgery.Minimize bone and/or soft-tissue manipulation with conservativedebridement.Treat with topical, alcohol-free chlorhexidine.If BRONJ persists, then systemic treatment may be necessary. They suggestedcombining topical treatment with systemic antibiotics (penicillin oramoxicillin).While informing patients of the ongoing BRONJ risk is important, Hellsteinurged ADA attendees not to scare patients. "What's the best thing that theycan do? Visit their dentist twice a year and practice good oral hygiene," hesaid. "It's that simple."Finally, Kalmar and Hellstein stressed that dental professionals shouldnever advise a patient to go off bisphosphonates."No studies have shown that discontinuing bisphosphonates, particularly oralbisphosphonates ... will improve the healing of (BRONJ)," Kalmar noted."Bisphosphonates should never be stopped without physician consultation. Therisks associated with cancer or osteonecrosis almost always outweigh therisk of BRONJ."By Shalmali PalAuntMinnie.com staff writerOctober 3, 2007http://www.auntminnie.com/index.asp?Sec=sup & Sub=cto & Pag=dis & ItemId=77751

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