Management of bisphosphonate-associated osteonecrosis: pentoxifylline and tocopherol in addition to antimicrobial therapy. an initial case series

Management of bisphosphonate-associated osteonecrosis:
pentoxifylline and tocopherol in addition to antimicrobial
therapy. An initial case series

Matthew S. Epstein, BS,a Fredrick W. Wicknick, DMD,bJoel B. Epstein, DMD, MSD, FRCD(C), FDS RCS (Ed),c James R. Berenson, MD,d andMeir Gorsky, DMD,e Seattle and Bellingham, WA, Chicago, IL, W. Hollywood, CA,Tel Aviv, IsraelUNIVERSITY OF WASHINGTON, UNIVERSITY OF ILLINOIS, INSTITUTE FOR MYELOMA AND BONECANCER RESEARCH, TEL AVIV UNIVERSITY Background. Studies of the use of pentoxifylline and ␣-tocopherol in osteoradionecrosis of the jaw have suggested
their efficacy in this condition. We report an initial case series of pentoxifylline and ␣-tocopherol for patients with
bisphosphonate-associated osteonecrosis (BON).
Methods. Six cases referred for management of BON were provided pentoxifylline and ␣-tocopherol in addition to
antimicrobial therapy, and followed for a mean of 10 months.
Results. A 74% decrease in area of bony exposure and symptom control was achieved in these cases.
Discussion. Pentoxifylline with ␣-tocopherol may represent a strategy for management of BON. Controlled trials in
cases of BON appear warranted. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010;110:593-596)
Bisphosphonate-associated osteonecrosis (BON) is a mellitus, concurrent immunosuppressive therapy, med- recently recognized oral complication with hundreds of ications with antiangiogenic effects, and ongoing can- among cancer patients treated with potent bisphospho- veloped for the prevention and care of patients nates (BP), including zoledronic acid, pamidronate, and prescribed BP, primarily based on expert It is strongly recommended that all patients planned to treated with oral BP for osteoporosis, BON is a rare receive BP treatment, and those already undergoing potential complication.A significant correlation has treatment, receive thorough dental assessments and ap- been reported between the administered dose and du- propriate preventive dental management before initia- ration of BP and BON in cancer patients.Comorbid risk factors identified include tobacco use, diabetes Osteoradionecrosis (ORN) and other late radiation complications have been associated with radiation-in- duced fibrosis (RIF), which has led to studies that focus Senior Dental Student, University of Washington.
bOral and Maxillofacial Surgery, Bellingham, WA.
on a fibro-atrophic mechanism in the pathogenesis of cProfessor, Oral Medicine and Otolaryngology and Head and Neck pentoxifylline and ␣-tocopherol (PT) significantly re- Institute for Myeloma and Bone Cancer Research, W. Hollywood, duce modulating fibroblast activity, perhaps be- CA.
eProfessor, Oral Medicine, Tel Aviv University, Tel Aviv, Israel.
cause of their impact on cytokine production. A phase Received for publication Feb 4, 2010; returned for revision May 27, II clinical trial with PT induced a 66% regression of the 2010; accepted for publication May 28, 2010.
RIF surface area after 12 months of These results were confirmed in an experimental RIF model 2010 Published by Mosby, Inc.
doi:10.1016/j.tripleo.2010.05.067 where a 70% regression of RIF volume was observed 593
after 6 months of These results were rep-licated in a phase II trial of uterine and breast cancer patients showed long-term benefits with a 68% reduction of RIF in breast tissue 2 years after treatment with PT Based on these findings and the similar pathogenesis to radiation-induced fibro-sis in ORN, trials of PT were conducted. Case series and a phase II trial of patients treated for mandibular ORN with PT and antibiotic therapy document im- Pentoxifylline improves peripheral blood flow, re- duces viscosity of blood, increases flexibility of red blood cell membranes, improves microcirculation, and line has anti–tumor necrosis factor alpha (anti-TNF␣) effects, inhibits dermal fibroblasts, and increases colla- genase Decreased levels of TNF␣ and re- duced production of interleukin (IL)-12 have been ob- served among patients with acute coronary syndromes treated with pentoxifylline compared with Decrease in the anti-inflammatory cytokine IL-10 and increase in transforming growth factor beta (TGF␤) have also been Pentoxifylline also reduces the synthesis of proinflammatory cytokines, including TNF␣ crease in the duration of soft tissue necrosis was re-ported in radiation-associated In a study of experimental periodontitis in rats, bone loss was de- A number of mechanisms of action of ␣-tocopherol may decrease inflammation and stimulate healing. ␣-To- copherol impairs tissue fibrosis and is a potent oxygen radical scavenger that may reduce damage caused by free radicals impacting ␣-Tocopherol scavenges re- active oxygen species generated during oxidative stress, thereby protecting cell membranes, and inhibits TGFh1 proves endothelial function in patients with hypercholes- reported to produce a proinflammatory effect induced by low-dose atrovastatin among patients with ischemic heart Studies of dietary ␣-tocopherol supplementation resulted in significantly lower TNF␣ production in ani- reduced inflammation in patients with diabetes or who smoked, and prevention of the early signs of dermal Studies of PT in RIF and ORN prompted us to assess the utility of this combination in addition to standard antimicro- bial therapy in a series of cases of BON of the jaws.
Consecutive patients with persisting BON of the jaws were referred for management. Pentoxifylline and 595
␣-tocopherol were both prescribed at 400 mg twice where control of bone destruction or infection is not daily with chlorhexidine rinses. Four of the 6 patients possible, or in cases of pathologic fracture, alveolec- had used chlorhexidine rinse (0.12%) before treatment tomy or resection of affected bone may be necessary.
with PT. All of the patients used chlorhexidine (10-15 The findings in the 6 patients who were treated with PT mL rinsed more than 30 seconds, twice daily) with PT.
here suggest that this drug combination with antimicro- Outcomes assessed included symptoms, signs, and bial agents may have utility in the medical management measure of the area of exposed bone. All patients of BON. The patients in this series improved with the introduction of PT and ␣-tocopherol without noticeableadverse effects. Future studies of potential therapeutic RESULTS AND DISCUSSION
and prophylactic efficacy of this therapy for high-riskpatients should be considered.
A summary of the patients is presented in Of the patients presented in this series, 4 of 6 were previ-ously treated with chlorhexidine rinses and 4 with sys- REFERENCES
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