Bisphosphonate associated osteonecrosis of the jaw

Journal of Rheumatology

Volumn 36, Issue 3, 2009, Pages 478-490

  Khan, Aliya A ^a   Sándor, George K B ^b,c,d,e   Dore, Edward ^a   Morrison, Archibald D ^f   Alsahli, Mazen ^z   Amin, Faizan ^g   Peters, Edmund ^g   Hanley, David A ^h   Chaudry, Sultan R ^a   Lentle, Brian ^i,j   Dempster, David W ^k,l   Glorieux, Francis H ^m,n   Neville, Alan J ^o   Talwar, Reena M ^b   Clokie, Cameron M ^b   Al Mardini, Majd ^p   Paul, Terri ^q   Khosla, Sundeep ^r   Josse, Robert G ^s,t   Sutherland, Susan ^b   Lam, David K ^b   Carmichael, Robert P ^c   Blanas, Nick ^u   Kendler, David ^i,v   Petak, Steven ^w   Ste Marie, Louis Georges ^x   Brown, Jacques ^y   Evans, A Wayne ^y   Rios, Lorena ^a   Compston, Juliet E ^y   more..

^a MCMASTER UNIVERSITY   (Canada)

^b UNIVERSITY OF TORONTO   (Canada)

^c HOSPITAL FOR SICK CHILDREN   (Canada)

^d TAMPERE UNIVERSITY OF TECHNOLOGY   (Finland)

^e UNIVERSITY OF OULU   (Finland)

^f DALHOUSIE UNIVERSITY   (Canada)

^g UNIVERSITY OF ALBERTA   (Canada)

^h Health Sciences Centre Calgary   (Canada)

ⁱ UNIVERSITY OF BRITISH COLUMBIA   (Canada)

^j Canadian Association of Radiology   (Canada)

^k Och Spine at New York Presbyterian Hospitals   (United States)

^l HELEN HAYES HOSPITAL   (United States)

^m MCGILL UNIVERSITY   (Canada)

ⁿ SHRINERS HOSPITAL FOR CHILDREN   (Canada)

^o MCMASTER UNIVERSITY   (Canada)

^p UNIVERSITY OF ROCHESTER   (United States)

^q WESTERN UNIVERSITY   (Canada)

^r MAYO CLINIC   (United States)

^s ST MICHAEL'S HOSPITAL   (Canada)

^t UNIVERSITY OF TORONTO   (Canada)

^u SUNNYBROOK RESEARCH INSTITUTE   (Canada)

^v International Society for Clinical Densitometry   (United States)

^w UNIVERSITY OF TEXAS MEDICAL SCHOOL   (United States)

^x CENTRE HOSPITALIER DE L UNIVERSITÉ DE MONTRÉAL   (Canada)

^y UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^z School of Clinical Medicine and Addenbrooke's NHS Trust ^*

more..

Author keywords

Bisphosphonates; Epidemiology; Guidelines; Osteonecrosis of the jaw; Side effects

Indexed keywords

ALENDRONIC ACID; BISPHOSPHONIC ACID DERIVATIVE; CHLORHEXIDINE; CLINDAMYCIN; CLODRONIC ACID; DOXYCYCLINE; ERYTHROMYCIN; GLUCOCORTICOID; IBANDRONIC ACID; METRONIDAZOLE; PAMIDRONIC ACID; PENICILLIN V POTASSIUM; PLACEBO; RISEDRONIC ACID; ZOLEDRONIC ACID; BONE DENSITY CONSERVATION AGENT;

BONE METASTASIS; BREAST CANCER; CONSERVATIVE TREATMENT; DRUG DOSE COMPARISON; DRUG EXPOSURE; DRUG MEGADOSE; HUMAN; INCIDENCE; JAW OSTEONECROSIS; MOUTH HYGIENE; MULTIPLE MYELOMA; NEOPLASM; ONCOLOGY; OSTEOPOROSIS; PAGET BONE DISEASE; POPULATION RESEARCH; PRIMARY TUMOR; PRIORITY JOURNAL; PROSPECTIVE STUDY; REVIEW; RISK ASSESSMENT; SYSTEMATIC REVIEW; TREATMENT DURATION; BONE NECROSIS; CHEMICALLY INDUCED DISORDER; DOSE RESPONSE; JAW DISEASE; RISK FACTOR;

BONE DENSITY CONSERVATION AGENTS; DIPHOSPHONATES; DOSE-RESPONSE RELATIONSHIP, DRUG; HUMANS; JAW DISEASES; NEOPLASMS; OSTEONECROSIS; OSTEOPOROSIS; RISK FACTORS;

EID: 65649114391     PISSN: 0315162X     EISSN: None     Source Type: Journal    
DOI: 10.3899/jrheum.080759     Document Type: Review

References (95)

1. Advisory Task Force on Bisphosphonate-Related Ostenonecrosis of the Jaws. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 2007;65:369-376
2. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: A growing epidemic. J Oral Maxillofac Surg 2003;61:1115-1117
3. Ruggiero SL, Mehrotra B, Rosenberg TJ, et al. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004;62:527-534 (Pubitemid 38542516)
4. Brown JP, Josse RG. Scientific Advisory Council of the Osteoporosis Society of Canada: 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada. Can Med Assoc J 2002;167 Suppl:S1-S34.
5. Berenson JR, Hillner BE, Kyle RA, et al. American Society of Clinical Oncology clinical practice guidelines: the role of bisphosphonates in multiple myeloma. J Clin Oncol 2002;20:19-36. (Pubitemid 34983232)
6. Berry S, Waldron T, Winquist E, et al. The use of bisphosphonates in men with hormone-refractory prostate cancer. Practice Guideline Report no. 3-14. Program in Evidence-Based Care; a Cancer Care Ontario Program. January 10, 2005. Toronto: Ontario Ministry of Health and Long-term Care; 2005
7. Berry S, Waldron T, Winquist E, et al. The use of bisphosphonates in men with hormone-refractory prostate cancer: a systematic review of randomized trials. Can J Urol 2006;13:3180-3188
8. Hillner BE, Ingle JN, Chlebowski RT, et al. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 2003;21:4042-4057
9. Kyle RA, Yee GC, Somerfield MR, et al. American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol 2007;25:2464-2472
10. Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002;94:1458-1468
11. Santini D, Vincenzi B, Dicuonzo G, et al. Zoledronic acid induces significant and long lasting modifications of circulating angiogenic factors in cancer patients. Clin Cancer Res 2003;9:2893-2899 (Pubitemid 36993246)
12. Bamias A, Dimopoulos MA. Thalidomide and immunomodulatory drugs in the treatment of cancer. Exp Opin Invest Drugs 2005;14:45-55.
13. Reid IR, Bolland MJ, Grey AB. Is bisphosphonate- associated osteonecrosis of the jaw caused by soft tissue toxicity? Bone 2007;41:318-320
14. Rubegni P, Fimiani M. Bisphosphonate-associated contact stomatitis. New Engl J Med 2006;355:E25. (Pubitemid 44837775)
15. Khan AA, Sandor GKB, Dore E, et al. Canadian consensus practice guidelines for bisphosphonate associated osteonecrosis of the jaw. J Rheumatol 2008;35:1391-1397
16. Khosla S, Burr D, Cauley J, et al. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007;22:1479-1491
17. Marx RE, Sawatari Y, Fortin M, Broumand V. Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 2005;63:1567-1575 (Pubitemid 41525412)
18. Bianchi SD, Scoletta M, Cassione FB, et al. Computerized tomographic findings in bisphosphonate-associated osteonecrosis of the jaw in patients with cancer. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;104:249-258
19. Ruggiero SL, Fantasia J, Carlson E. Bisphosphonate-related osteonecrosis of the jaw: background and guidelines for diagnosis, staging and management. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006;102:433-441
20. Pharoah M. Maxillofacial Radiology, University of Toronto. Personal communication. 2007.
21. Epstein JB, Wong FL, Dickens A, Szasz I, Lepawsky M. Bone and gallium scans in postradiotherapy osteonecrosis of the jaw. Head Neck 1992;14:288-292
22. Bisdasa S, Chambron Pinhob N, Smolarzb A, Saderb R, Vogla TJ, Macka MG. Biphosphonate-induced osteonecrosis of the jaws: CT and MRI spectrum of findings in 32 patients. Clin Radiol 2008;63:71-77 (Pubitemid 350212865)
23. Phal PM, Myall RW, Assael LA, Weissman JL. Imaging findings of bisphosphonate-associated osteonecrosis of the jaws. Am J Neuroradiol 2007;28:1139-1145 (Pubitemid 46984558)
24. Bedogni A, Blandamura S, Lokmic Z, et al. Bisphosphonateassociated jawbone osteonecrosis: a correlation between imaging techniques and histopathology. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:358-364
25. Peters E, Lovas GL, Wysocki GP. Lingual mandibular sequestration and ulceration. Oral Surg Oral Med Oral Pathol 1993;75:739-743 (Pubitemid 23184720)
26. Peters E, Daley T; American Academy of Oral and Maxillofacial Pathology. Persistent painful ulcer of the posterior lingual mandibular mucosa. J Contemp Dent Pract 2003;4:71-75
27. Farah CS, Savage NW. Oral ulceration with bone sequestration. Aust Dent J 2003;48:61-64 (Pubitemid 38011274)
28. Kessler HP. Oral and maxillofacial pathology case of the month. Lingual mandibular sequestration with ulceration. Tex Dent J 2005;122:198-9, 206-207
29. Neville HP, Damm DD, Allen CM, et al. Spontaneous sequestration (traumatic sequestration). Oral and maxillofacial pathology. Philadelphia: W.B. Saunders Co.; 2002:276-277
30. Sculley C. Oral ulceration: a new and unusual complication. Br Dent J 2002;192:139-140
31. Sonnier KE, Horning GM. Spontaneous bony exposure: a report of 4 cases of idiopathic exposure and sequestration of alveolar bone. J Periodontol 1997;68:758-762 (Pubitemid 127513257)
32. Migliorati CA, Schubert MM, Peterson DE, Seneda LM. Bisphosphonate- associated osteonecrosis of mandibular and maxillary bone: an emerging oral complication of supportive cancer therapy. Cancer 2005;104:83-93. (Pubitemid 40847755)
33. Hellstein JW, Marek CL. Bisphosphonate osteochemonecrosis (bis-phossy jaw): Is this phossy jaw of the 21st century? J Oral Maxillofac Surg 2005;63:682-689
34. Dempster DW, Zhou H, Nieves JW, et al. Unusual osteoclast morphology in teriparatide-treated patients who have been pretreated with alendronate [abstract]. J Bone Miner Res 2007;22 Suppl 1:S29.
35. Woo SB, Hellstein JW, Kalmar JR. Systematic review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 2006;144:753-761 (Pubitemid 46780635)
36. Kanat O, Ozet A, Ataergin S, et al. Bisphosphonate treatment as a cause of jaw osteonecrosis. Oral Dis 2007;13:346-347 (Pubitemid 46632683)
37. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007;356:1809-1822 (Pubitemid 46698462)
38. Mavrokokki T, Cheng A, Stein B, Goss A. Nature and frequency of bisphosphonate-associated osteonecrosis of the jaws in Australia. J Oral Maxillofac Surg 2007;65:415-423 (Pubitemid 46343586)
39. Bamias A, Kastritis E, Bamia C, et al. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 2005;23:8580-8587 (Pubitemid 46211499)
40. Dimitrakopoulos I, Magopoulos C, Karakasis D. Bisphosphonate-induced avascular osteonecrosis of the jaws: a clinical report of 11 cases. Int J Oral Maxillofac Surg 2006;35:588-593 (Pubitemid 43863136)
41. Dannemann C, Zwahlen R, Gratz KW. Clinical experiences with bisphosphonate-induced osteochemonecrosis of the jaws. Swiss Med Wkly 2006;136:504-509
42. Salesi N, Pistilli R, Marcelli V, et al. Bisphosphonates and oral cavity avascular bone necrosis: a review of twelve cases. Anticancer Res 2006;26:3111-3115 (Pubitemid 44161808)
43. Farrugia MC, Summerlin DJ, Krowiak E, et al. Osteonecrosis of the mandible or maxilla associated with the use of new generation bisphosphonates. Laryngoscope 2006;116:115-120 (Pubitemid 44383974)
44. Zarychanski R, Elphee E, Walton P, Johnston J. Osteonecrosis of the jaw associated with pamidronate therapy. Am J Hematol 2006;81:73-75 (Pubitemid 43077219)
45. Thakkar SG, Isada C, Smith J, et al. Jaw complications associated with bisphosphonate use in patients with plasma cell dyscrasias. Med Oncol 2006;23:51-56 (Pubitemid 43787117)
46. Bagan JV, Jimenez Y, Murillo J, et al. Jaw osteonecrosis associated with bisphosphonates: multiple exposed areas and its relationship to teeth extractions. Study of 20 cases. Oral Oncol 2006;42:327-329 (Pubitemid 43246766)
47. Merigo E, Manfredi M, Meleti M, et al. Bone necrosis of the jaws associated with bisphosphonate treatment: a report of twenty-nine cases. Acta Biomed 2006;77:109-117 (Pubitemid 44884943)
48. Purcell P, Boyd IW. Bisphosphonates and osteonecrosis of the jaw. Med J Austral 2005;182:417-418
49. Pires FR, Miranda A, Cardoso ES, et al. Oral avascular bone necrosis associated with chemotherapy and bisphosphonate therapy. Oral Dis 2005;11:365-369 (Pubitemid 41727234)
50. Melo M, Obeid G. Osteonecrosis of the maxilla in a patient with a history of bisphosphonate therapy. J Can Dent Assoc 2005;71:111-113 (Pubitemid 41679824)
51. Estilo CS, Van Poznak CH, Williams T, et al. Osteonecrosis of the maxilla and mandible in patients treated with bisphosphonates: a retrospective study. Proc Am Soc Clin Oncol 2004;22:1479-1491
52. Merigo E, Manfredi M, Meleti M, et al. Jaw bone necrosis without previous dental extractions associated with the use of bisphosphonates (pamidronate and zoledronate): a four-case report. J Oral Pathol Med 2005;34:613-617 (Pubitemid 41512948)
53. Sanna G, Zampino MG, Pelosi G, et al. Jaw avascular bone necrosis associated with long-term use of bisphosphonates. Ann Oncol 2005;16:1207-1208 (Pubitemid 41418326)
54. Bagan JV, Murillo J, Jimenez Y, et al. Avascular jaw osteonecrosis in association with cancer chemotherapy: series of 10 cases. J Oral Pathol Med 2005;34:120-123
55. Lugassy G, Shaham R, Nemets A, et al. Severe osteomyelitis of the jaw in long-term survivors of multiple myeloma: a new clinical entity. Am J Med 2004;117:440-441 (Pubitemid 39369551)
56. Migliorati CA. Bisphosphonates and oral cavity avascular bone necrosis. J Clin Oncol 2003;21:4253-4254
57. Carter GD, Goss AN. Bisphosphonates and avascular necrosis of the jaws [letter]. Aust Dent J 2003;48:268.
58. Wang J, Goodger NM, Pogrel MA. Osteonecrosis of the jaws associated with cancer chemotherapy. J Oral Maxillofac Surg 2003;61:1104-1107 (Pubitemid 37064708)
59. Kademani D, Koka S, Lacy MQ, Rajkumar SV. Primary surgical therapy for osteonecrosis of the jaw secondary to bisphosphonate therapy. Mayo Clin Proc 2006;81:1100-1103 (Pubitemid 44175022)
60. Pastor-Zuazaga D, Garatea-Crelgo J, Martino-Gorbea R, Etayo-Perez A, Sebastian-Lopez C. Osteonecrosis of the jaws and bisphosphonates. Report of three cases. Med Oral Patol Oral Cir Bucal 2006;11:E76-9.
61. Hansen T, Kunkel M, Weber A, James Kirkpatrick C. Osteonecrosis of the jaws in patients treated with bisphosphonates - histomorphologic analysis in comparison with infected osteoradionecrosis. J Oral Pathol Med 2006;35:155-160
62. Carter G, Goss AN, Doecke C. Bisphosphonates and avascular necrosis of the jaw: a possible association. Med J Aust 2005;182:413-415
63. Ficarra G, Beninati F, Rubino I, et al. Osteonecrosis of the jaws in periodontal patients with a history of bisphosphonates treatment. J Clin Periodontol 2005;32:1123-1128 (Pubitemid 41499467)
64. Katz H. Endodontic implications of bisphosphonate-associated osteonecrosis of the jaws: a report of three cases. J Endod 2005;31:831-834 (Pubitemid 41578797)
65. Lenz JH, Steiner-Krammer B, Schmidt W, et al. Does avascular necrosis of the jaws in cancer patients only occur following treatment with bisphosphonates? J Craniomaxillofac Surg 2005;33:395-403.
66. Durie BG, Katz M, Crowley J. Osteonecrosis of the jaws and bisphosphonates. N Engl J Med 2005;353:99-102.
67. Zervas K, Verrou E, Teleioudis Z, et al. Incidence, risk factors and management of osteonecrosis of the jaw in patients with multiple myeloma: a single-centre experience in 303 patients. Br J Haematol 2006;134:620-623 (Pubitemid 44253605)
68. Dimopoulos MA, Kastritis E, Anagnostopoulos A, et al. Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: Evidence of increased risk after treatment with zoledronic acid. Haematologica 2006;91:968-971 (Pubitemid 44023154)
69. Tosi P, Zamagni E, Cangini D. Bisphosphonates and osteonecrosis of the jaws: Incidence in a homogeneous series of patients with newly diagnosed multiple myeloma treated with zoledronic acid. Blood 2005;106:3467a.
70. Cafro AM, Barbarano LA, Andriani A. Osteonecrosis of the jaw associated with chronic bisphosphonates therapy: An Italian experience [abstract 5152]. American Society of Hematology Annual Meeting, 2005.
71. Pozzi S, Marcheselli R, Sacchi S. Analysis of frequency and risk factors for developing bisphosphonate associated necrosis of the jaw [abstract 5057]. American Society of Hematology Annual Meeting, 2005.
72. Favus MJ. Diabetes and the risk of osteonecrosis of the jaw [editorial]. J Clin Endocrinol Metab 2007;92:817-818 (Pubitemid 46465648)
73. Felsenberg D, Hoffmeister B, Amiling M. Bisphosphonattherapie assoziierte. Kiefernekrosen Deutsches Arzteblatt 2008; [abstract; in press].
74. Alendronate sodium. Merck & Co., Inc. 1995-2008. Internet. Available from: www.fosamax.com. Accessed Oct 23 2008.
75. Risedronate sodium. Procter & Gamble Pharmaceuticals. 2008. Internet. Available from: www.actonel.com. Accessed Oct 23 2008.
76. Chahine C, Cheung MS, Head TW, Schwartz S, Glorieux FH, Rauch F. Tooth extraction socket healing in pediatric patients treated with intravenous pamidronate. J Pediatr 2008;153;719-720
77. Kademani D, Koka S, Lacy MQ, Rajkumar SV. Primary surgical therapy for osteonecrosis of the jaw secondary to bisphosphonate therapy. Mayo Clin Proc 2006;81:1100-1103 (Pubitemid 44175022)
78. Hoff AO, Toth BB, Altundag K, et al. Osteonecrosis of the jaw in patients receiving intravenous bisphosphonate therapy [abstract]. ASCO Annual Meeting Proceedings. J Clin Oncol 2006;24:8528.
79. Starck WJ, Epker BN. Failure of osseointegrated dental implants after diphosphonate therapy for osteoporosis: a case report. Int J Oral Maxillofac Implants 1995;10:74-78
80. Marx RE. Oral and intravenous bisphosphonate-induced osteonecrosis of the jaws - history, etiology, prevention and treatment. Hanover Park, IL: Quintessence Publishing Co.; 2007.
81. Khamaisi M, Regev E, Yarom N, et al. Possible association between diabetes and bisphosphonate-related jaw osteonecrosis. J Clin Endocrinol Metab 2007;92:1172-1175 (Pubitemid 46465699)
82. Badros A, Weikel D, Salama A, et al. Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol 2006;24:945-952 (Pubitemid 46638849)
83. Zavras AI, Zhu S. Bisphosphonates are associated with increased risk for jaw surgery in medical claims data: Is it osteonecrosis? J Oral Maxillofac Surg 2006;64:917-923 (Pubitemid 44240236)
84. Erdogan O, Esen E, Ustun Y. Bony palatal necrosis in a diabetic patient secondary to palatal rotational flap. J Diabet Complicat 2005;19:364-367 (Pubitemid 41563021)
85. Herrod NW. Bisphosphonate-associated osteonecrosis. J Am Dent Assoc 2006;137:441-443
86. Melo M, Obeid G. Osteonecrosis of the jaws in patients with a history of receiving bisphosphonate therapy. Strategies for prevention and early recognition. J Am Dent Assoc 2005;136:1675-1681 (Pubitemid 41810029)
87. Ruggiero S, Gralow J, Marx RE, et al. Practical guidelines for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in patients with cancer. J Oncol Pract 2006;2:7-14.
88. Migliorati CA, Casiglia J, Epstein J, et al. Managing the care of patients with bisphosphonate-associated osteonecrosis: an American Academy of Oral Medicine position paper. J Am Dent Assoc 2005;136:1658-1668 (Pubitemid 41810027)
89. Magopoulos C, Karakinaris G, Telioudis Z, et al. Osteonecrosis of the jaws due to bisphosphonate use. A review of 60 cases and treatment proposals. Am J Otolaryngol 2007;28:158-163 (Pubitemid 46702356)
90. Biasotto M, Chiandussi S, Dore F, et al. Clinical aspects and management of bisphosphonates-associated osteonecrosis of the jaws. Acta Odontol Scand 2006;64:348-354 (Pubitemid 44845517)
91. Freiberger JJ, Padilla-Burgos R, Chhoeu AH, et al. Hyperbaric oxygen treatment and bisphosphonate-induced osteonecrosis of the jaw: a case series. J Oral Maxillofac Surg 2007;65:1321-1327 (Pubitemid 46907400)
92. Landesberg R, Wilson T, Grbic JT. Bisphosphonate-associated osteonecrosis of the jaw: conclusions based on an analysis of case series. Dent Today 2006;25:52, 54-57
93. Nastro E, Musolino C, Allegra A, et al. Bisphosphonate-associated osteonecrosis of the jaw in patients with multiple myeloma and breast cancer. Acta Haematol 2007;117:181-187 (Pubitemid 46496803)
94. Shimura K, Shimazaki C, Taniguchi K, et al. Hyperbaric oxygen in addition to antibiotic therapy is effective for bisphosphonate-induced osteonecrosis of the jaw in a patient with multiple myeloma. Int J Hematol 2006;84:343-345 (Pubitemid 46606576)
95. Treister N, Woo SB. Bisphosphonate-associated osteonecrosis of the jaw. N Engl J Med 2006;355:2348-2352 (Pubitemid 44837783)