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Bisphosphonate-associated osteonecrosis of the jaws: The limits of a conservative approach

Bisphosphonate-associated osteonecrosis of the jaws: The limits of a conservative approach
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  BISPHOSPHONATE-RELATED JAW NECROSIS: A CASE REPORT  ARTICLE Spec Care Dentist 30(2) 2010 77 ©2010 Special Care Dentistry Association and Wiley Periodicals, Inc.doi: 10.1111/j.1754-4505.2009.00128.x  ABSTRACT  This paper reports the case history of apatient who had bisphosphonate-associ-ated osteonecrosis of the jaw (ONJ) inwhich adjunctive treatment with teri-paratide was used. The patient wastreated for 5 years with alendronate forosteoporosis and developed ONJ afterextraction of maxillary teeth. An implantwas placed at the site of the extractedteeth. The pathology report confirmedthe clinical diagnosis of ONJ; treatmentwas changed from alendronate to teri-paratide and the ONJ resolved.To ourknowledge, this is the third case historyreported in the literature in which teri-paratide was successfully used asadjunct therapy in ONJ because it hasan anabolic effect and presumed role inaccelerating bone healing. ONJ is aserious but infrequent condition that hasbeen recently associated with nitrogen-containing bisphosphonate therapy. Teriparatide may be a useful adjunctivetherapy when ONJ develops. Bisphosphonate-associated osteonecrosisof the jaw,with healing after teriparatide:a review of the literatureand a case report Pongthorn Narongroeknawin, MD; 1 Maria I. Danila, MD, MSc; 1 Lewis G.Humphreys Jr., DMD; 2  Andrei Barasch, DMD, MDSc; 3 Jeffrey R. Curtis, MD, MPH 1 * 1 Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham,Birmingham, AL; 2 Private Practice, Dothan, AL; 3 Department of Diagnostic Sciences, University of Alabama at Birmingham, Birmingham, AL.*Corresponding author e-mail: Spec Care Dentist 30(2): 77-82, 2010 The prevalence of ONJ appears tovary widely depending on the underlyingindication for, and potency and durationof, the bisphosphonate treatment.Various study designs and methodologieshave been used to determine the epi-demiology of ONJ, 5,7 including Web-based surveys, 8 reports from clinicaltrials, 9 retrospective chart reviews, 10 andpopulation-based studies. 11 It is impor-tant to recognize that these individualstudies used different diagnostic criteriaand study designs which may contributeto the heterogeneity of the results.Recent postmarketing reports of twooral bisphosphonates used for patientswith osteoporosis showed an ONJ inci-dence of less than 1.2 per 100,000patient-years for risedronate use, and of less than 0.5–2.5 per 100,000 patient-years for alendronate. 7,12,13 The criteriaused to confirm the diagnosis of ONJ inthese studies were heterogeneous. Incontrast, the frequency of ONJ inpatients with multiple myeloma, breastcancer, and prostate cancer who havebeen treated with intravenous bisphos-phonates varied between 1% and15%. 8,14-18 ONJ prevalence seems to be relatedto the duration of bisphosphonate ther-apy in most subjects. 7 In 2004–2005, Introduction Osteonecrosis of the jaw (ONJ) associated with bisphosphonate therapy was initiallydescribed 1 in 2003 among patients receiving parenteral bisphosphonates for lytic bonelesions and cancer-associated hypercalcemia. Since then, at least 865 case reports of bisphosphonate-associated ONJ involving the use of oral and parenteral bisphospho-nates have been reported in the English-language literature. 2 The rise in the number of published cases can be explained not only by the increased recognition of this conditionby clinicians, 3 but also by cumulative doses of bisphosphonates over time. 4 Althoughmost reports of ONJ involve patients receiving intravenous aminobisphosphonates forhypercalcemia of malignancy and for the prevention and treatment of bone metastases,data are accumulating regarding lesions in patients treated with oral bisphosphonatesfor osteoporosis. 5,6 KEY WORDS: osteonecrosis, ONJ,bisphosphonate, teriparatide, osteoporosis  78 Spec Care Dentist 30(2) 2010 Bishphosphonate-related jaw necrosis: a case report  BISPHOSPHONATE-RELATED JAW NECROSIS: A CASE REPORT a postal survey 11 of Australian Oral andMaxillofacial Surgeons identified 158cases of ONJ among patients taking bis-phosphonates for multiple indications.The frequency of ONJ in patients withosteoporosis, most of them on weeklyalendronate, was 1 in 2,260 to 1 in8,470, approximately 100 times lowerthan in patients on IV bisphosphonatesbut still much higher than previous esti-mates among patients with osteoporosis. When dental extractions were done inthis population, the calculated frequencyof ONJ is estimated to be between1 in296 and 1 in 1,130. The median time toonset of ONJ was 12 months for zole-dronate and 24 monthsin the case of pamidronate and alendronate. However,the diagnosis of ONJ in this study wasnot accompanied by formal validation of a case definition. 11 Sedghizadeh et al. 19 conducted anextensive search in the electronic medicalrecord system of a single center forpatients with a history of alendronate usewho were also being treated for ONJ inthe Oral Surgery clinic and the OrofacialPain and Oral Medicine clinic at theUniversity of Southern California.Inclusion criteria were that subjects hadclinical features of ONJ, had a bisphos-phonate history consistent with adiagnosis of ONJ which was defined asexposed necrotic bone (sequestra) insubjects with pain, infection, and apathological fracture; extraoral fistula; or osteolysis extending to the inferiorborder of the mandible or floor of thesinonasal cavity—stage 2 or 3 in the ONJ staging system according to Ruggiero et al . 20 The authors found that prevalenceof ONJ secondary to oral alendronatetherapy was approximately 4% and morecommon than previously suggested. 19 A key limitation of this 4% prevalenceestimate is that the study population wasfrom a tertiary care referral center of patients receiving dental services and istherefore not population based. However,in a large controlled trial, the HealthOutcomes and Reduced Incidence withZoledronic Acid Once Yearly (HORI-ZON) Pivotal Fracture Trial, 9 almost4,000 osteoporotic women were treatedwith 5 mg of zoledronate annually for 3 years, and a similar number received aplacebo. Despite a rigorous search forany potential cases of bisphosphonate-associated ONJ—defined as an exposedbone with delayed healing despite 6 weeks of appropriate medical care andadjudicated by a blinded panel of experts—only two possible cases werefound: one in the placebo group and onein the treatment group (a case of osteomyelitis that preceded any treat-ment with zoledronate). 9,21 No ONJlesions were seen in the HORIZONRecurrent Fracture Trial, 22 whichincluded more than 2,000 subjects whohad suffered hip fracture. Both of thesestudies were funded by the maker of zoledronate and the patients’ follow-upwas relatively short (3 years).The risk of developing ONJ whiletaking intravenous pamidronate or zole-dronate in cancer patients was furtherevaluated in a population-based cohortstudy 23 using data from the Surveillance,Epidemiology and End Results (SEER)program linked to Medicare claims.Because there was no billing diagnosiscode specific for ONJ, surrogateInternational Disease Classification, 9thedition (ICD9) and Current ProceduralTerminology (CPT) codes thought torepresent ONJ lesions were used in theclaims data. These ICD9 and CPT codesidentified diagnoses of inflammatoryconditions or osteomyelitis of the jaw orfacial bone surgery. 23 This study included14,349 intravenous bisphosphonateusers. The use of pamidronate and zole-dronate was associated with an increasedrisk for facial bone surgery (hazard ratio[HR] 3.15, 95% CI 1.86–5.32) and anincreased risk for diagnosis of inflamma-tory conditions or osteomyelitis of the jaw (HR 11.48, 95% CI 6.49–20.33). 23 Predisposing factors Both oral and systemic factors arethought to predispose individuals todevelop ONJ. 24-27 The oral risk factorsinclude dental and periodontal disease,dental surgery, oral trauma, and poordental hygiene. Systemic factors includedose, duration and type of bisphospho-nate therapy, concomitant therapies(chemotherapy, corticosteroids), alcoholuse, smoking, advanced age, and otherunderlying medical conditions (diabetesmellitus or peripheral vascular disease). Pathogenesis Bisphosphonates are pyrophosphate ana-logues characterized by their ability tolocalize to the bone where they inhibitosteoclast function. 28 After being takenin by the skeleton, they continue to per-sist in the bone, due to their very longhalf-lives related to their strong mineralbinding affinity. 29 The precise molecularmechanism by which bisphosphonatesmay predispose to the development of ONJ is not well understood. Similarly,the effect of bisphosphonates on dentalimplant osseointegration is still underdebate. Although dental implant failuresassociated with oral bisphosphonatetherapy have been reported in the literature, 30 both animal and humanstudies have shown no adverse effect of bisphosphonates on dental implantosseointegration. 31-33 A longitudinalsingle-blind controlled study 34 comparedimplant success in 25 postmenopausalwomen receiving oral bisphosphonate(102 implants) to 25 age-matched women(108 implants). At the end of the 3-yearobservation period, there were no cases of ONJ and the implant success was greaterthan 99% in both groups. Currently, theAmerican Society for Bone and MineralResearch (ASBMR) does not considerprior oral bisphosphonate therapy as acontraindication to dental implant place-ment, nor are routine dental examinationsrecommended before beginning oral bis-phosphonate therapy for osteoporosis. 7 Clinical manifestations An ASBMR task force panel defined ONJas the presence of exposed bone in themaxillofacial region that does not healfor at least 8 weeks after its identificationby a clinician in a patient exposed to bisphosphonates, but without prior radi-ation therapy to the craniofacial region. 7 Patients with ONJ may be asympto-matic and the diagnosis often is made bythe serendipitous discovery of exposed  Narongroeknawin et al.Spec Care Dentist 30(2) 2010 79 BISPHOSPHONATE-RELATED JAW NECROSIS: A CASE REPORT bone in the oral cavity during a regulardental examination. 35 If sites become sec-ondarily infected or there is trauma tothe soft tissue by the sharp edges of exposed bone, symptoms such as pain,soft tissue swelling and infection, looseteeth, and purulent drainage maydevelop. Atypical complaints mayinclude numbness, jaw heaviness, anddysesthesias. Less-specific signs andsymptoms that could herald the develop-ment of clinical osteonecrosis are suddenchanges in the health of periodontal andoral tissues, failure of oral mucosa toheal, undiagnosed oral pain, loose teeth,and soft tissue infections.In three published case series 24,25,36 that included at least 50 patients withONJ, the mandible was involved in 50%to 68% of the cases, the maxilla exclu-sively in 24% to 37% of the patients, andboth the mandible and the maxilla in 4%to 13% of the cases. Both the mandibleand the maxilla can be unilaterally orbilaterally involved. 24 To our knowledge,there is only a single report 37 of bisphos-phonate-related osteonecrosis involving asite outside the oral cavity, which was inthe auditory canal. Diagnosis The diagnosis of ONJ is primarily clinical, consisting of clinical signs andsymptoms in relation to treatment withbisphosphonates. Radiography, computedtomography, or functional imaging suchas bone scans are not necessary for diagnosis but may be used to excludeother conditions such as cysts orimpacted teeth, depending on thepatient’s symptoms. 35 Two expert panels, one convened bythe American Dental Association 35 andanother multidisciplinary team of medicaloncologists, hematologists, urologists,and stomatologists from Spain, 38 recom-mended that tissue biopsy should beperformed only if metastatic disease wassuspected. Management Management strategies need to considerboth prevention and treatment for thiscondition. For patients with malignancy,pretreatment dental examinations areimportant. In a retrospective survey of patients treated with zoledronate,Ripamonti et al. 39 showed that a dentalexamination and the application of pre-ventive measures led to a sustainedreduction in occurrence of ONJ from7.8% to 1.7% (  p = 0.016). Reducing bisphosphonate dose could be a preven-tive measure in oncology practice, andearly results suggest that administrationof intravenous bisphosphonate every 3 months is safer than monthly adminis-tration. 40 Avoidance of invasive dentalprocedures is also an important preventivestrategy. In addition, recent research 41 suggests that antibiotic prophylaxisbefore dental procedures in patients withmultiple myeloma treated with bisphos-phonates may prevent the occurrence of ONJ after dental procedures.However, recent recommendationsfor managing the care of patients receiv-ing oral bisphosphonate therapy by theAmerican Dental Association (ADA)Council on Scientific Affairs 42 indicatedthat risk of developing ONJ apparentlyremained low for patients receiving oralbisphosphonates. Therefore, routinedental treatment should not be modifiedsolely because the patient is taking oralbisphosphonates. Furthermore, given themorbidity and mortality associated withosteoporosis and the proven benefits of oral bisphosphonate therapy, patientsshould not alter their use of these med-ications without first consulting theirphysicians. In contrast to the AmericanSociety for Bone and Mineral Research(ASBMR) guidelines, 7 the ADA guide-lines 42 recommend that all patients whoare prescribed oral bisphosphonatesshould receive routine dental examina-tions before or during the early portionof their bisphosphonate therapeutic regi-men. Oral healthcare providers should beinformed if any problems develop in theoral cavity during oral bisphosphonatetherapy.The standard of care for the manage-ment of ONJ includes symptompalliation, treatment of dental and peri-odontal infections, and conservativesurgical intervention. 7  Wide surgicaldebridement is not recommended,although sharp bone edges and sequestrashould be removed to prevent trauma tosoft tissues. 7 Some investigators haveadvocated the use of hyperbaric oxygen,but its efficacy appears doubtful. 7 Thevalue of stopping bisphosphonate ther-apy remains unclear, given the longhalf-life of these compounds, althoughsome experts believe that it could helphasten healing. 7 However, the optimalduration of bisphosphonate discontinua-tion lacks any evidence at this time.Recently, teriparatide was reported asan adjunctive treatment modality forONJ. 43,44 Teriparatide contains the 1–34N-terminal amino acid residues of thehuman parathyroid hormone and isapproved for treatment of osteoporosis inmen and postmenopausal women. 45 Unlike bisphosphonates, which areantiresorptive agents, teriparatide hasanabolic effects and promotes osteoblastdifferentiation and activity. 45,46 The inter-mittent delivery of parathyroid hormoneleads to an early decrease of receptoractivator of nuclear factor-kappa B ligandmRNA and increase of osteoprotegerinmRNA, 47 resulting in an increase in boneformation. If indeed bisphosphonate-associated ONJ results fromoversuppression of bone turnover, teri-paratide would seem to be beneficial byexerting its physiologic effect to promotebone formation and anabolic activityagainst a background of the suppressedturnover common to long-term bisphos-phonate use. Recently, a prospectivetrial 48 examined the early anabolic effectsof teriparatide in postmenopausal womenwith osteoporosis previously treated withalendronate or risedronate. Boneturnover markers including N-terminalpropeptide (P1NP), bone-specific alka-line phosphatase activity (BAP),osteocalcin (OC), serum C telopeptide(CTX), and N-telopeptide to urine creati-nine ratio (NTX) were measured atbaseline, 0.5, 1–6, and 12 months. Allbone turnover markers increased frombaseline for both groups as early as 2 weeks after beginning teriparatidetherapy. The results from these studiessupport the hypothesis that administra-tion of parathyroid hormone after  80 Spec Care Dentist 30(2) 2010 Bishphosphonate-related jaw necrosis: a case report  BISPHOSPHONATE-RELATED JAW NECROSIS: A CASE REPORT discontinued bisphosphonate treatmentcan stimulate bone formation and mayhelp restore the bone tissues in the oralcavity. However, there is no specific evi-dence for the benefit of teriparatidetherapy on the course of bisphospho-nate-associated ONJ except for a fewanecdotal reports of benefit such as thisone.This review was based on a search of PubMed for English language paperspublished from 1966 to October 2008using these keywords: osteonecrosis of  jaw, bisphosphonate, teriparatide, osteo-porosis, malignancy, epidemiology,pathogenesis and treatment. In thisoverview paper, we also present a patientwith osteoporosis who was treated withalendronate who developed ONJ follow-ing a surgical procedure. The necroticbone showed significant healing aftertreatment with teriparatide for fourmonths. Case report A 63-year-old Caucasian male physicianpresented to a periodontist complainingof pain in the maxillary right second pre-molar and maxillary left first premolarand requested extraction of the sympto-matic teeth and placement of dentalimplants. His medical history was signifi-cant for osteoporosis and erosiveosteoarthritis of the hands. He had awrist fracture at age 53 and also had sev-eral thoracic spine fractures. Hismedications included calcium citrate, amultivitamin, and alendronate, which hehad been taking orally for five years. Healso reported the following list of med-ications: esomeprazole, glucosamine,chondroitin, atorvastatin, aspirin, andmirtazapine. He denied a history of glu-cocorticoid exposure and did not usetobacco products or alcohol.Fifteen months after the teeth wereextracted, the patient underwent one-stage titanium tooth implants placed atboth sites (Figure 1A). Four days later,the patient returned, complaining of painin the area of the maxillary left canine.An assessment of the intraoral radi-ograph revealed possible impingement of the adjacent maxillary left first premolarimplant body on the periodontal liga-ment of the maxillary left canine. Theimplant was removed and a collagen plugwas placed in the osteotomy site. Onemonth later, the maxillary left first pre-molar implant site had not healed andthe surrounding tissue was inflamed. Theimplant at the maxillary right secondpremolar site was asymptomatic, butprobing depths around it were 12 mminstead of the normal 2–3 mm. An evalu-ation of the intraoral radiograph showedbone loss around the implant body(Figure 1B). Three weeks later, theremaining implant was removed and thearea thoroughly degranulated. Aroundthe implant, we noted advanced boneloss that extended through the buccalcortical plate to the adjacent premolartooth. During the procedure, the maxil-lary left first premolar implant was alsodegranulated and specimens were sentfor histopathologic examination. Afterdebridement, bone allografts were placedin both sites and covered with resorbablecollagen membranes. Chlorhexidinerinse was prescribed and utilized bothbefore and after implant removal.The biopsy report stated that therewas nonvital bone and focal inflamma-tion at the implant sites. With thepatient’s lack of symptoms, the radi-ographic appearance, and the history of alendronate use, a clinical and pathologicdiagnosis of bisphosphonate-associatedONJ was made. The large amount of bone loss precluded the possibility of delayed healing, whereas absence of painand new hyperostosis made primaryosteomyelitis unlikely.The patient was referred to ourrheumatology/osteoporosis clinic for fur-ther management. The patient’s previousdiagnosis of osteoporosis complicated byprior wrist and vertebral fractures andthe histopathologic evidence of bisphos-phonate-associated ONJ were taken intoconsideration and the patient was startedon teriparatide 20 µg subcutaneouslydaily and alendronate was discontinued.Four months after the teriparatide infu-sions were started, an evaluation of theintraoral radiographs of the implant sitesshowed osseous regeneration withincreased bone density (Figure 1C). Thepatient is currently awaiting replacementof the dental implants at these sites. Discussion In our patient, given the history of osteo-porosis with multiple fragility fractures,the decision was made to switch fromalendronate to teriparatide. His alveolarbone showed significant healing 4 monthsafter the start of teriparatide treatment.Although bone healing may haveoccurred with discontinuation of bisphosphonate therapy and surgeryalone, based on our patient, intermittentadministration of teriparatide might beuseful in the clinical setting of osteo-porosis and ONJ.A critical evaluation of the currentliterature and on the published casereports shows that the risk of developingONJ as a result of oral bisphosphonatetherapy is significantly lower comparedwith the risk associated with intravenousbisphosphonate therapy in patients withcancer. 42 Multiple risk factors such asdental and periodontal disease, dentalsurgery, poor dental hygiene, durationand type of bisphosphonate therapy, and Figure 1. (A) Maxillary right second premolar immediately after implant placement. (B) Failingimplant, maxillary right second premolar. Notice the radiolucent area around the metal. (C) Healedimplant site 8 months after implant removal and 4 months after teriparatide infusions were started.  Narongroeknawin et al.Spec Care Dentist 30(2) 2010 81 BISPHOSPHONATE-RELATED JAW NECROSIS: A CASE REPORT underlying medical conditions may alsoplay a role. The diagnosis of ONJ ismostly based on clinical findings.Although some experts recommend stop-ping bisphosphonate therapy in patientswho develop ONJ, there is insufficientevidence to support this practice. Ourpatient’s necrotic bone showed signifi-cant healing 4 months after the start of teriparatide treatment. It is likely thatbecause of its anabolic effects on thebone, administration of this medicationmay be useful in the clinical setting of osteoporosis and ONJ. Clinical trials areneeded to test this hypothesis. Financial disclosures Pongthorn Narongroeknawin, Maria I.Danila, Lewis G. Humphreys, and AndreiBarasch: none; Jeffrey R. Curtis: consul-tancies, speaking fees, and honorariafrom Roche, Eli Lilly, Merck, Novartis,Procter, and Gamble. References 1. Marx RE. Pamidronate (Aredia) and zole-dronate (Zometa) induced avascularnecrosis of the jaws: a growing epidemic.  J Oral Maxillofac Surg 2003;61:1115-7.2. Brooks JK, Gilson AJ, Sindler AJ, et al .Osteonecrosis of the jaws associated withuse of risedronate: report of 2 new cases. Oral Surg Oral Med Oral Path Oral RadiolEndod 2007;103:780-6.3. Malden NJ, Pai AY. Oral bisphosphonateassociated osteonecrosis of the jaws: threecase reports. Br Dent J  2007;203:93-7.4. Bilezikian JP. Osteonecrosis of the jaw—dobisphosphonates pose a risk? N Engl J Med 2006;355:2278-81.5. Khan AA, Sándor GK, Dore E, et al .Bisphosphonate associated osteonecrosis of the jaw.  J Rheumatol 2009;36:478-90.6. Silverman SL, Landesberg R. Osteonecrosisof the jaw and the role of bisphosphonates:a critical review.  Am J Med 2009;122:S33-45.7. 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