The document attached has been archived with permission from the editor of the Medical Journal of Australia. An external link to the publisher’s copy is included.Glen Carter, Alastair N Goss and Chris Doeck

Carter, Glen

Doecke, Christopher

Goss, Alastair Norman

The Medical Journal of Australia

Adelaide Research &amp; Scholarship

PUBLISHED VERSION   Carter, Glen; Goss, Alastair Norman; Doecke, Christopher  Bisphosphonates and avascular necrosis of the jaw: a possible association Medical Journal of Australia, 2005; 182(8):413-415  This article is available from the Medical Journal of Australia at:      http://www.mja.com.au/public/issues/182_08_180405/car10429_fm.html       PERMISSIONS   This document has been archived with permission from the editor of the Medical Journal of Australia, 26 April 2007.         http://hdl.handle.net/2440/41581 NOTABLE CASESBisphosphonates and avascular necrosis of the jaw: a possible associationThe Medical Journal of Australia ISSN: 0025-729X 18 April 2005 182 8 413-415©The Medical Journal of Australia 2005www.mja.com.auNotable casestions involve gastrointestinal symptoms. Bone-marrowand thrombocytopenia are also reported rarely.The second- and third-generation bisphosphonatescantly more potent than their first-generation predecesnate, clodronate and tiludronate). They inhibit bone rosteoclastic inhibition, through selective concentrationface of the active osteoclast and the bone-resorption ereasssevH  we present five cases of osteonecrosis of the jawociated with bisphosphonate use. In North America,eral preliminary reports have been published of unu-sual cases of avascular necrosis of the jaw in patients using second-and third-generation nitrogen-containing bisphosphonates.1-4These included pamidronate, alendronate, risedronate andzoledronic acid.2,3In Australia, bisphosphonates have been available for severalyears and are commonly prescribed for a range of conditions,including osteoporosis, Paget’s disease, multiple myeloma,5,6 hyper-calcaemia of malignancy, and bone metastases of malignancies suchas breast and prostate cancer. An estimated 200 000 patients inAustralia receive these drugs. Commonly reported adverse reac- depression are signifi-sors, (etidro-esorption by at the inter-surface. Thespecific mechanism of this inhibition is unknown, but there isevidence for several actions, including inhibition of osteoclastdevelopment from precursor cells, increase in osteoclast apoptosis,7stimulation of osteoclast inhibitory factor, reduction of osteoclastactivity, and down-regulation of matrix metalloproteinases. Theresulting reduction in osteoclastic activity reduces bone resorption,supporting the use of bisphosphonates for the above indications.However, osteoclastic function is part of the cycle of boneturnover; osteocytes have a life span of about 150 days, after whichosteoclasts resorb the mineral matrix of bone and release bonemorphogenetic protein and insulin-like growth factors, which inturn induce local stem cells to differentiate into osteoblasts andform new bone. This cycle is critical to maintaining bone stocks andbone viability. If osteoclastic function is too severely impaired, deadand dying osteocytes are not replaced, and the capillary network inthe bone is not maintained, resulting in avascular bone necrosis.Dental disease and denture-wearing are ubiquitous. Studiesinvolving larger patient numbers have shown that nearly 80% ofcases were initiated by tooth removal.3 Patients who have beenusing potent bisphosphonates for more than 6 months appear to beat highest risk.2 Other apparent risk factors are residual multiplemyeloma or other malignancy, hypoproteinaemia, renal impairmentfrom disease or drugs, and chemotherapy.1 Necrosis of the maxilla in a 57-year-old man receiving pamidronate for multiple myelomaThe oral cavity showing exposed necrotic maxillary bone and a large oro-antral communication.Computed tomography showing significant bone destruction in the right maxilla (outlined).Clinical recordsIn 2003, five patients presented to the Oral and Maxillofacial Surgery Unit at Royal Adelaide Hospital, South Australia, with painful exposed bone in the maxilla, or both the maxilla and mandible (Box 1 and Box 2).All patients were receiving either pamidronate (Aredia [Novartis]) or alendronate (Fosamax [Merck Sharp & Dohme]). Pamidronate was being given intravenously monthly at a dose of 60 mg (one patient) or 90 mg (three patients). The patient taking alendronate received a daily oral dose of 40 mg. Duration of bisphosphonate therapy was 6 months to 6 years. Associated risk factors for the development of avascular necrosis included renal impairment in one patient and hypoproteinaemia in another.Initial management of these patients comprised surgical debridement of the exposed bone. Histopathological assessment of surgical specimens showed no histological evidence of myelomatous deposits or Paget’s disease from the affected sites in the jaws in any of the patients. None had exposed bone elsewhere in the body. SEE ALSO PAGE 417MJA • Volume 182 Number 8 • 18 April 2005 413NOTABLE CASESAlthough a definite cause-and-effect relationship is yet to beestablished, the association between bisphosphonate therapy andosteonecrosis of the jaw appears strong.2-4,8-10 The incidence of thepotential complication appears low. In South Australia in 2003,about 14 000 patients received prescriptions for the potent second-and third-generation nitrogen-containing bisphosphonates, withabout 10% having intravenous administration. Our five patientsprobably represented all cases of the complication, as our Depart-ment is the only oral and maxillofacial surgery service in SA andreceives referrals from around the state.8,9 Checking with colleaguesand related hospital services has not revealed further cases in SA,but we are aware of other cases in all states of Australia. Indeed, theAdverse Drug Reactions Advisory Committee recently reportedanother nine cases.10At present, there is no effective treatment for the condition.Patients are usually referred to oral and maxillofacial surgeons, butsurgical intervention is difficult as it often exposes further bone,and, as bisphosphonates affect the whole skeleton, locating viablebone margins may be impossible. Furthermore, removal of painfulteeth, while initially alleviating pain, also further exposes bone,causing more pain. Covering exposed bone with tissue flaps hasbeen found ineffective because of the development of fistulaearound the flaps and possible complete dehiscence (Box 1).Compounding the problem, some patients must continue withbisphosphonate therapy and/or other chemotherapies to controlhypercalcaemia. Hyperbaric oxygen therapy is not useful inbisphosphonate-induced necrosis, and antibiotics are indicatedonly to treat secondary infection.Because of the lack of effective treatment for the condition,second- and third-generation bisphosphonates should be used onlywhen benefits clearly outweigh risks. When intravenous or high-dose oral bisphosphonates are considered appropriate, referral forfull dental assessment and treatment before the start of therapyshould be considered. Once bisphosphonate therapy has begun,there should be regular clinical monitoring of oral health. Avoidingtooth removal and dental implants, non-surgical control of perio-dontal disease, and use of soft liners on dentures also seem prudent.In addition, major debridement surgeries should be avoided if at allpossible.In established cases, the primary goals are palliation andcontrol of osteomyelitis. In most cases, progression has beencontrolled with long-term or intermittent courses of dicloxacillinor cephalexin (to treat any secondary infection), chlorhexidinemouthwash (Savacol), and periodic minor debridement of soft-textured sequestrating bone and wound irrigation.The rapid expansion of indications for bisphosphonates hasresulted in their widespread use across many medical disciplines,including endocrinology, rheumatology, medical oncology, hae-matology and general practice. Most medical practitioners areunaware of this serious and potentially permanent complication.Before prescribing bisphosphonates, medical practitionersshould analyse the risks versus benefits for the individual patient,consider alternative drugs, and obtain informed consent afterdiscussing this potential adverse reaction. We also encouragevigilant surveillance of patients who are using a bisphosphonate.Glen Carter,* Alastair N Goss,† Chris Doecke‡* Senior Registrar, † Professor and Director, Oral and MaxillofacialSurgery Unit, ‡ Associate Professor and Director of Pharmacy ServicesRoyal Adelaide Hospital and University of Adelaide, SAoral.surgery@adelaide.edu.au1 Assael LA. New Foundation in understanding osteonecrosis of thejaws. J Oral Maxillofac Surg 2004; 62: 125-126.2 Ruggiero S, Rosenberg TJ. Osteonecrosis of the jaws associated with theuse of bisphosphonates. J Oral Maxillofac Surg 2004; 62: 527-534.3 Marx RE. Pamidronate (Aredia) and Zoledronate (Zometa) induced avas-cular necrosis of the jaws: A growing epidemic [letter]. J Oral MaxillofacSurg 2003; 61: 115-118.2 Clinical details of five patients with avascular necrosis of the jaw in South Australia, 2003 Age,sex Presentation PrecipitantBisphosphonate [indication] Other medications Treatment Outcome57, M Painful exposed bone in maxilla and mandibleTooth extractionPamidronate (90 mg IV monthly for 6 years) [multiple myeloma]Dexamethasone, methotrexate, warfarin, folic acid, ranitidine, metformin, hydroxychloroquine, verapamil, sertraline, morphineHyperbaric oxygen, Le Fort I level maxillectomy, bisphosphonate continued Persistent necrosis of midface and mandible64, M Ulcer in right hard palate with bone sequestrumTooth extractionPamidronate (90 mg IV monthly for 2 years) [multiple myeloma]Prednisolone, cyclosporin, itraconazole, sulfamethoxazole–trimethoprim, ranitidine, penicillinSequestrectomy, local debridement, bisphosphonate continuedResolution73, M Pain, swelling of anterior maxillary alveolusTooth extractionsAlendronate (40 mg orally daily for 5 years) [Paget’s disease]Amlodipine, tramadol, perindoprilLocal debridement, sequestrectomies, primary flap closure, bisphosphonate ceased Resolution78, F Painful exposed bone in maxillaDenture pressurePamidronate (90 mg IV monthly for 18 months) [Paget’s disease]None Hyperbaric oxygen, local debridement, denture reline, bisphosphonate ceased Persistent areas of exposed bone84, F Non-healing extraction site in left maxillaryalveolusTooth extractionPamidronate (60 mg IV monthly for 6 months) [Paget’s disease]Diltiazem, simvastatin, ferrous sulfate, aspirin, bendrofluazideWide intraoral resection with primary flap closure, bisphosphonate ceasedPersistent fistulaIV = intravenous.414 MJA • Volume 182 Number 8 • 18 April 2005NOTABLE CASES4 Wang J, Goodger NM, Pogrel MA. Osteonecrosis of the jaws associatedwith cancer chemotherapy. J Oral Maxillofac Surg 2003; 61: 1104-1107.5 Ashcroft AJ, Davies FE, Morgan GJ. Aetiology of bone disease and the roleof bisphosphonates in multiple myeloma. Lancet Oncol 2003; 4: 284-292.6 Djulbegovic B, Whetley K, Ross J, et al. Bisphosphonates in multiplemyeloma (Cochrane Review). Cochrane Database Syst Rev 2002 (3):CD003188.7 Luckman SP, Hughes DE, Coxon FP, et al. Heterocycle-containingbisphosphonates cause apoptosis and inhibit bone resorption by pre-venting protein prenylation: evidence from structure activity relationshipsin J774 macrophages. J Bone Miner Res 1998; 13: 1668-1678.8 Carter GD, Goss AN. Bisphosphonates and avascular necrosis of the jaws[letter]. Australian Prescriber 2004; 27: 32-33.9 Carter GD, Goss AN. Bisphosphonates and avascular necrosis of the jaws[letter]. Aust Dent J 2003; 48: 268.10 Adverse Drug Reactions Advisory Committee (ADRAC). Bisphosphonatesand osteonecrosis of the jaw. Aust Adv Drug Reactions Bull 2005; 24: 3.(Received 15 Jun 2004, accepted 18 Feb 2005) ❏Summary• Five patients presented to the Royal Adelaide Hospital, South Australia, in 2003 with painful exposed bone in the maxilla, or both the maxilla and mandible.• All had been receiving potent second- or third-generation bisphosphonate therapy — monthly intravenous pamidronate in four cases and daily oral alendronate in the other.• These cases are among the earliest reported occurrences of this condition in association with bisphosphonate therapy in Australia.• The condition presented after tooth extraction in four cases and denture pressure in the other.• Osteonecrosis continued for more than a year in three patients despite treatment.MJA • Volume 182 Number 8 • 18 April 2005 415

Bisphosphonates and avascular necrosis of the jaw: a possible association

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Bisphosphonates and avascular necrosis of the jaw: a possible association

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Bisphosphonates and avascular necrosis of the jaw: a possible association

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Adelaide Research & Scholarship