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

ORAL MEDICINE
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
594
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
temic antibiotics owing to purulence, before initiation 1. Migliorati CA, Siegel MA, Elting LS. Bisphosphonate-associ- of the PT. Chlorhexidine rinses were provided to all ated osteonecrosis: a long-term complication of bisphosphonatetreatment. Lancet Oncol 2006;7:508-14.
patients during the treatment with PT and the antibiot- 2. Michaelson MD, Smith MR. Bisphosphonates for treatment and ics that were started before PT treatment were contin- prevention of bone metastases. J Clin Oncol 2005;23:8219-24.
ued in 3 patients. Five patients were female and 1 was 3. Cartsos VM, Zhu S, Zavras AI. Bisphosphonate use and the risk male, with a mean age of 75 years. Four patients had a of adverse jaw outcomes: a medical claims study of 714,217 history of cancer and 2 had a history of severe osteo- people. J Am Dent Assoc 2008;139:23-30.
4. Grbic JT, Landesberg R, Lin SQ, Mesenbrink P, Reid IR, Leung porosis, and all but one was treated with intravenous PC, et al. Health outcomes and reduced incidence with BP. For those maintained on oral agents, the mean zoledronic acid once yearly pivotal fracture trial research group.
duration of oral alendronate was 62 months. In those Incidence of osteonecrosis of the jaw in women with postmeno- receiving intravenous (IV) BP, the duration on drug pausal osteoporosis in the health outcomes and reduced inci- ranged from 19 months to 126 months (mean, 71 dence with zoledronic acid once yearly pivotal fracture trial.
J Am Dent Assoc 2008;139:32-40.
months). Four of these patients had an extensive history 5. Badros A, Weikel D, Salama A, Goloubeva O, Schneider A, of years of fluctuating symptomatic BON. Of the 6 Rapoport A, et al. Osteonecrosis of the jaw in multiple myeloma patients, 1 remained stable, 4 improved with a decrease patients: clinical features and risk factors. J Clin Oncol 2006;24: in bone exposure along with improvement in symp- toms, and 1 case resolved. One had a small sequestrum 6. Khamaisi M, Regev E, Yarom N, Avni B, Leitersdorf E, Raz I, easily mobilized and removed before resolution. In one et al. Possible association between diabetes and bisphosphonate-related jaw osteonecrosis. J Clin Endocrinol Metab 2007;92: case, symptoms and bone exposure increased following initial improvement on PT and ␣-tocopherol when 7. Advisory Task Force on Bisphosphonate-Related Ostenonecrosis these agents were discontinued for 3 months, and im- of the Jaws, American Association of Oral and Maxillofacial proved upon resuming these agents. The mean reduc- Surgeons. American Association of Oral and Maxillofacial Sur- tion in area of exposed bone in all patients was 74%, at geons position paper on bisphosphonate-related osteonecrosis ofthe jaws. J Oral Maxillofac Surg. 2007;65:369-76.
a mean follow-up of 10 months. All patients were 8. Migliorati CA, Casiglia J, Epstein J, Jacobsen PL, Siegel MA, without pain, erythema, or purulence following initia- Woo SB. Managing the care of patients with bisphosphonate- tion of treatment with PT. The improved clinical out- associated osteonecrosis: an American Academy of Oral Medi- comes should be compared with the history of fluctu- cine position paper. J Am Dent Assoc 2005;136:1658-68.
ating symptoms and progression in lesion size before 9. Edwards BJ, Hellstein JW, Jacobsen PL, Kaltman S, Mariotti A, Migliorati CA; American Dental Association Council on Scien- the addition of PT. The medications were well tolerated tific Affairs Expert Panel on Bisphosphonate-Associated Osteo- with no adverse effects identified. Potential comorbid necrosis of the Jaw. Updated recommendations for managing the risk factors were present in 4 patients and included use care of patients receiving oral bisphosphonate therapy: an advi- of tobacco, prednisone, lenalidomide, and lack of oral sory statement from the American Dental Association Council on Scientific Affairs. J Am Dent Assoc 2008;139:1674-7.
10. Edwards BJ, Hellstein JW, Jacobsen PL, Kaltman S, Mariotti A, The primary goal is prevention of BON by expert Migliorati CA, et al. Updated recommendations for managing the dental assessment and dental management before the care of patients receiving oral bisphosphonate therapy: an advi- initiation of BP For patients who present sory statement from the American Dental Association Council on with painful exposed bone, nonsurgical care using a Scientific Affairs. J Am Dent Assoc 2008;139:1674-7.
regimen of 0.12% chlorhexidine mouth rinse, systemic 11. Teng MS, Futran ND. Osteoradionecrosis of the mandible. Curr Opin Otolaryngol Head Neck Surg 2005;13:217-21.
antibiotics (in the presence of secondary infection), 12. Delanian S. Kinetics of response to long-term treatment combin- pain management, and cessation of tobacco and alcohol ing pentoxifylline and tocopherol in patients with superficial radiation-induced fibrosis. J Clin Oncol 2005;23:8570-9.
596
13. Delanian S, Depondt J, Lefaix JL. Major healing of refractory omide on alveolar bone loss in short-term experimental mandible osteoradionecrosis after treatment combining pentoxifyl- periodontal disease in rats. J Periodontol 2004;75:162-8.
line and tocopherol: a phase II trial. Head Neck 2005;27:114-23.
22. Delanian S, Lefaix JL. The radiation-induced fibroatrophic pro- 14. Altenburg A, Abdel-Naser MB, Seeber H, Abdallah M, Zoubou- cess: therapeutic perspective via the antioxidant pathway. Ra- lis CC. Practical aspects of management of recurrent aphthous stomatitis. J Europ Acad Dermatol Venereol 2007;21:1019-26.
23. Tousoulis D, Antoniades C, Vassiliadou C, Toutouza M, Pitsa- 15. Delanian S, Lefaix JL. Complete healing of severe osteoradio- vos C, Tentolouris C, et al. Effects of combined administration necrosis with treatment combining pentoxifylline, tocopherol of low dose atorvastatin and vitamin E on inflammatory markers and clodronate. Br J Radiol 2002;75:467-9.
and endothelial function in patients with heart failure Eur J Heart 16. Delanaian S, Balla-Mekias S, Lefaix J-L. Striking regression of chronic radiotherapy damage in a clinical trial of combined 24. Han SN, Wu D, Ha WK, Beharka A, Smith DE, Bender BS, et pentoxifylline and tocopherol. J Clin Oncol 1999;17:3283-90.
al. Vitamin E supplementation increases T helper 1 cytokine 17. Lyons A, Ghazali N. Osteoradionecrosis of the jaws: current production in old mice infected with influenza virus. Immunol understanding of its pathophysiology and treatment. Br J Oral 25. Mol MJ, de Rijke YB, Demacker PN, Stalenhoef AF. Plasma 18. Futran ND, Trotti A, Gwede C. Pentoxifylline in the treatment of levels of lipid and cholesterol oxidation products and cytokines radiation-related soft tissue injury: preliminary observations. La- in diabetes mellitus and cigarette smoking: effects of vitamin E treatment. Atherosclerosis 1997;129:169-76.
19. Fernandes JL, de Oliveira RT, Mamoni RL, Coelho OR, Nicolau 26. Houwing R, Overgoor M, Kon M, Jansen G, van Asbeck BS, JC, Blotta MH, et al. Pentoxifylline reduces pro-inflammatory Haalboom JR. Pressure-induced skin lesions in pigs: reperfusioninjury and the effects of vitamin E. J Wound Care 2000;9:36-40.
and increases anti-inflammatory activity in patients with coro-nary artery disease-a randomized placebo-controlled study. Ath-erosclerosis 2008;196:434-42.
20. Dion M, Hussey D, Doornbos J, Vigliotti A, Wen B, Anderson Joel Epstein, DMD, MSD, FRCD(C), FDS RCS (Ed) B. Preliminary results of a pilot study of pentoxifylline in the treatment of late radiation soft tissue necrosis. Int J Radiat Oncol Department of Oral Medicine and Diagnostic Sciences 21. Lima V, Vidal FD, Rocha FA, Brito GA, Ribeiro RA. Effects of tumor necrosis factor-alpha inhibitors pentoxifylline and thalid-

Source: http://oralmedicinepacific.com/docs/whats-new/BON-Trental-ARTICLE-Nov-2010.pdf

Classificafinale.xls

25° LAKE GARDA MEETING OPTIMIST CLASS 5 - 8 APRIL 2007 RESULTS AFTER TEN RACES (TWO DISCARDS) - JUNIORES www.fragliavelariva.it Helmsman M 1993 SOCIETA' CANOTTIERI GARDA - SEZ. VELAM 1992 SOCIETA' VELICA DI BARCOLA - GRIGNANOM 1993 CIRCOLO VELA TORBOLE S.C.R.L. M 1992 CIRCOLO VELA TORBOLE S.C.R.L. F 1993 SOCIETA' VELICA DI BARCOLA - GRIGNANOM 1994 CIRCOLO VELA TORBOLE S.C.R.

Microsoft word - today's therapist knock-on effect pain relief nov-dec06.doc

Today’s Therapist International Trade Journal - Issue 43 Nov Dec 2006 The Bowen Technique Knock on effects of pain relief The effects of sorting out one physical problem can often have other happy consequences in a person’s state of health 13 April 2006: one week later, he came for his second Bowen and well being. This was illustrated very well in the case of treatment. He rep

Copyright ©2018 Sedative Dosing Pdf