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Tooth Extraction Socket Healing in Pediatric Patients Treated with Intravenous Pamidronate
Tooth Extraction Socket Healing in Pediatric Patients Treated with Intravenous Pamidronate CAROL CHAHINE, MD, MOIRA S. CHEUNG, MD, TIMOTHY W. HEAD, MD, STÉPHANE SCHWARTZ, MD, FRANCIS H. GLORIEUX, MD, PHD, AND FRANK RAUCH, MD
Osteonecrosis of the jaw (ONJ) has been described as a complication of bisphosphonate therapy in adults. In the present study, we did not find a case of ONJ among 278 pediatric patients who had received intravenous pamidronate during childhood or adolescence. (J Pediatr 2008;153:719-20)
yclical intravenous therapy with pamidronate is used to strengthen the bones of children and adolescents with skeletal fragility, particularly those with osteogenesis imperfecta.1 However, several reports suggest that osteonecrosis of the jaw (ONJ)— clinically visible as exposed bone in the maxillofacial area— can be a complication of bisphosphonate therapy in adults.2-7 A working diagnosis of ONJ is made when there is no evidence of healing after 6 to 8 weeks of appropriate dental care and no evidence of metastatic disease or osteoradionecrosis in the jaw.8 In adults, a high incidence of ONJ (0.8% to 12%) has been reported in patients who received bisphosphonates intravenously in the context of treatment for oncologic disorders.3-5,9 ONJ seems to be much rarer in patients who receive oral or intravenous bisphosphonates to treat postmenopausal osteoporosis (0.00038% to 0.04%).5,10 Nevertheless, it appears that a dental extraction during bisphosphonate therapy increases the risk of ONJ by 8- to 10-fold.5 Even though ONJ has been described only in adults to date, it is our experience that many dentists are reluctant to perform dental extractions in children and adolescents who receive intravenous pamidronate therapy. Consequently, we assessed the frequency of ONJ in children and adolescents who were treated with pamidronate at our institution.
C
METHODS Between October 1992 and December 2006, 338 pediatric patients received at least 1 cycle of intravenous pamidronate at the Shriners Hospital for Children in Montreal. For the purpose of the present study, we were able to contact 278 of these patients (142 females; 136 males). The majority of the patients had a diagnosis of osteogenesis imperfecta (n ⫽ 221); other diagnoses included fibrous dysplasia (n ⫽ 20), idiopathic juvenile osteoporosis (n ⫽ 14), neuromuscular disorders (n ⫽ 11), bone dysplasias (n ⫽ 8), rheumatologic disorders (n ⫽ 3), and Crohn’s disease (n ⫽ 1). The From the Faculty of Dentistry, Division of patients had received cyclical pamidronate infusions over a median period of 4.6 years Oral and Maxillofacial Surgery, Montréal, (range of pamidronate exposure, 1 infusion to 11.2 years of regular infusions). The median (C.C., T.H., S.S.) and Genetics Unit, Shriners age at follow up for this study was 14.7 years (range, 0.7 to 32 years). Hospital for Children and McGill University, Montréal, Québec, Canada (M.C., F.G., F.R.). The patients who had undergone dental extraction were asked for permission to Supported by the Shriners of North Amerobtain information from their dentists’ records. The study design was approved by McGill ica and the Fonds de la Recherche en Santé University’s Institutional Review Board. Informed written consent was obtained from all du Québec. F.G. is a consultant for Novartis, Inc. F.R. is a Chercheur-Boursier Clinician patients and/or legal guardians, as appropriate. of the Fonds de la Recherche en Santé du All patients had received pamidronate intravenously in cycles of 3 consecutive days, Québec. as described previously.1 The total annual pamidronate dose was 9 mg/kg body weight. No reprints are available from the authors. Submitted for publication Mar 6, 2008; last For each patient who had undergone dental extractions, his or her chart was consulted for revision received Apr 3, 2008; accepted information on pamidronate therapy related to the extraction procedure. In addition, the May 1, 2008. treating dentist was contacted to obtain information on the extraction procedure and Correspondence: Frank Rauch, Genetics Unit, Shriners Hospital for Children, 1529 follow-up observations. Assessment of extraction socket healing was based on the treating Cedar Ave, Montréal, Québec H3G 1A6, dentist’s clinical notes on postoperative visits. Canada. E-mail: [email protected].
ONJ
Osteonecrosis of the jaw
0022-3476/$ - see front matter Copyright © 2008 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2008.05.003
719
RESULTS None of the 278 patients who could be contacted had a history of ONJ. Dental extractions had been performed on 113 patients during or after pamidronate treatment. None of the patients or their parents recalled postoperative complications after these extractions. Chart data from the treating dentist could be obtained for 66 patients (25 females, 41 males; median age at follow up, 14.0 years; range, 2 to 30 years). The median cumulative dose of pamidronate before dental extraction was 40 mg/kg body weight (range, 2.5 to 81 mg/kg). The median duration of pamidronate treatment before dental extraction was 4.6 years (range, 0.3 to 9.0 years). These 66 patients had undergone a total of 250 tooth extractions (178 primary teeth, 72 permanent teeth). Indication for the dental extractions included impacted teeth (n ⫽ 35), fractured teeth (n ⫽ 13), decay or odontogenic abscess (n ⫽ 45), retained primary teeth (n ⫽ 80), bony ankylosis (n ⫽ 1), and ectopic eruption or preorthodontic therapy (n ⫽ 76). For 40 of the teeth, surgical extraction with flap elevation, bone removal, and tooth sectioning was required. Prophylactic antibiotic use was implemented for 41 dental extractions in 12 patients. A total of 163 teeth were extracted during active pamidronate treatment. The median intervals between the last pamidronate dose before dental extraction and the first pamidronate dose after dental extraction were 63 and 69 days, respectively. A total of 87 teeth were extracted a median of 2.0 years after the last dose of pamidronate. For 225 of these extractions, the dentist’s follow-up data could be retrieved, with a median postoperative follow-up period of 86 days (range, 3 to 1370 days). In addition, follow-up by telephone was performed a median of 908 days (range, 45 to 3790 days) after dental extraction. Adequate healing was noted on postoperative visits in all patients, with no evidence of delayed healing, exposed bone, or ONJ.
DISCUSSION In this study, we found no cases of ONJ among 278 patients who had received pamidronate at our institution, even though this group of patients had a number of risk factors for developing ONJ, such as dental extraction and prolonged exposure to intravenous pamidronate at relatively high doses. This exposure profile is similar to that of adult
720
Chahine et al
cancer patients who developed ONJ;5 however, a large majority of those adult patients also received treatment with chemotherapy and other concomitant medications, such as steroids, which are known risk factors for osteonecrosis.11,12 It is also possible that other factors, such as age, periodontal disease, and the underlying oncologic disease itself, may have played a role in the development of ONJ in those patients. The patient population in the present study did not have such comorbid conditions. Thus, our findings are compatible with the hypothesis that bisphosphonate therapy is only 1 of several factors that contribute to the development of ONJ. In conclusion, we found no cases of ONJ in a pediatric population with pamidronate exposure. Our data do not suggest that dental extraction should be withheld because of previous pamidronate treatment in this population.
REFERENCES 1. Rauch F, Glorieux FH. Osteogenesis imperfecta. Lancet 2004;363:1377-85. 2. Badros A, Weikel D, Salama A, Goloubeva O, Schneider A, Rapoport A, et al. Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol 2006;24:945-52. 3. Bamias A, Kastritis E, Bamia C, Moulopoulos LA, Melakopoulos I, Bozas G, et al. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 2005;23:8580-7. 4. Durie BG, Katz M, Crowley J. Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 2005;353:99-102. 5. 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: 415-23. 6. Migliorati CA, Schubert MM, Peterson DE, Seneda LM. Bisphosphonateassociated osteonecrosis of mandibular and maxillary bone: an emerging oral complication of supportive cancer therapy. Cancer 2005;104:83-93. 7. Weitzman R, Sauter N, Eriksen EF, Tarassoff PG, Lacerna LV, Dias R, et al. Critical review: updated recommendations for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in cancer patients, May 2006. Crit Rev Oncol Hematol 2007;62:148-52. 8. Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D, 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;22:1479-91. 9. American Association of Oral and Maxillofacial Surgeons. Position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 2007;65: 369-76. 10. Grbic JT, Landesberg R, Lin SQ, Mesenbrink P, Reid IR, Leung PC, et al. Incidence of osteonecrosis of the jaw in women with postmenopausal osteoporosis in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once-Yearly Pivotal Fracture Trial. J Am Dent Assoc 2008;139:32-40. 11. Mirzai R, Chang C, Greenspan A, Gershwin ME. The pathogenesis of osteonecrosis and the relationships to corticosteroids. J Asthma 1999;36:77-95. 12. Schwartz HC. Osteonecrosis of the jaws: a complication of cancer chemotherapy. Head Neck Surg 1982;4:251-3.
The Journal of Pediatrics • November 2008
Osteonecrosis of the jaw (ONJ) has been described as a complication of bisphosphonate therapy in adults. In the present study, we did not find a case of ONJ among 278 pediatric patients who had received intravenous pamidronate during childhood or adolescence. (J Pediatr 2008;153:719-20)
yclical intravenous therapy with pamidronate is used to strengthen the bones of children and adolescents with skeletal fragility, particularly those with osteogenesis imperfecta.1 However, several reports suggest that osteonecrosis of the jaw (ONJ)— clinically visible as exposed bone in the maxillofacial area— can be a complication of bisphosphonate therapy in adults.2-7 A working diagnosis of ONJ is made when there is no evidence of healing after 6 to 8 weeks of appropriate dental care and no evidence of metastatic disease or osteoradionecrosis in the jaw.8 In adults, a high incidence of ONJ (0.8% to 12%) has been reported in patients who received bisphosphonates intravenously in the context of treatment for oncologic disorders.3-5,9 ONJ seems to be much rarer in patients who receive oral or intravenous bisphosphonates to treat postmenopausal osteoporosis (0.00038% to 0.04%).5,10 Nevertheless, it appears that a dental extraction during bisphosphonate therapy increases the risk of ONJ by 8- to 10-fold.5 Even though ONJ has been described only in adults to date, it is our experience that many dentists are reluctant to perform dental extractions in children and adolescents who receive intravenous pamidronate therapy. Consequently, we assessed the frequency of ONJ in children and adolescents who were treated with pamidronate at our institution.
C
METHODS Between October 1992 and December 2006, 338 pediatric patients received at least 1 cycle of intravenous pamidronate at the Shriners Hospital for Children in Montreal. For the purpose of the present study, we were able to contact 278 of these patients (142 females; 136 males). The majority of the patients had a diagnosis of osteogenesis imperfecta (n ⫽ 221); other diagnoses included fibrous dysplasia (n ⫽ 20), idiopathic juvenile osteoporosis (n ⫽ 14), neuromuscular disorders (n ⫽ 11), bone dysplasias (n ⫽ 8), rheumatologic disorders (n ⫽ 3), and Crohn’s disease (n ⫽ 1). The From the Faculty of Dentistry, Division of patients had received cyclical pamidronate infusions over a median period of 4.6 years Oral and Maxillofacial Surgery, Montréal, (range of pamidronate exposure, 1 infusion to 11.2 years of regular infusions). The median (C.C., T.H., S.S.) and Genetics Unit, Shriners age at follow up for this study was 14.7 years (range, 0.7 to 32 years). Hospital for Children and McGill University, Montréal, Québec, Canada (M.C., F.G., F.R.). The patients who had undergone dental extraction were asked for permission to Supported by the Shriners of North Amerobtain information from their dentists’ records. The study design was approved by McGill ica and the Fonds de la Recherche en Santé University’s Institutional Review Board. Informed written consent was obtained from all du Québec. F.G. is a consultant for Novartis, Inc. F.R. is a Chercheur-Boursier Clinician patients and/or legal guardians, as appropriate. of the Fonds de la Recherche en Santé du All patients had received pamidronate intravenously in cycles of 3 consecutive days, Québec. as described previously.1 The total annual pamidronate dose was 9 mg/kg body weight. No reprints are available from the authors. Submitted for publication Mar 6, 2008; last For each patient who had undergone dental extractions, his or her chart was consulted for revision received Apr 3, 2008; accepted information on pamidronate therapy related to the extraction procedure. In addition, the May 1, 2008. treating dentist was contacted to obtain information on the extraction procedure and Correspondence: Frank Rauch, Genetics Unit, Shriners Hospital for Children, 1529 follow-up observations. Assessment of extraction socket healing was based on the treating Cedar Ave, Montréal, Québec H3G 1A6, dentist’s clinical notes on postoperative visits. Canada. E-mail: [email protected].
ONJ
Osteonecrosis of the jaw
0022-3476/$ - see front matter Copyright © 2008 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2008.05.003
719
RESULTS None of the 278 patients who could be contacted had a history of ONJ. Dental extractions had been performed on 113 patients during or after pamidronate treatment. None of the patients or their parents recalled postoperative complications after these extractions. Chart data from the treating dentist could be obtained for 66 patients (25 females, 41 males; median age at follow up, 14.0 years; range, 2 to 30 years). The median cumulative dose of pamidronate before dental extraction was 40 mg/kg body weight (range, 2.5 to 81 mg/kg). The median duration of pamidronate treatment before dental extraction was 4.6 years (range, 0.3 to 9.0 years). These 66 patients had undergone a total of 250 tooth extractions (178 primary teeth, 72 permanent teeth). Indication for the dental extractions included impacted teeth (n ⫽ 35), fractured teeth (n ⫽ 13), decay or odontogenic abscess (n ⫽ 45), retained primary teeth (n ⫽ 80), bony ankylosis (n ⫽ 1), and ectopic eruption or preorthodontic therapy (n ⫽ 76). For 40 of the teeth, surgical extraction with flap elevation, bone removal, and tooth sectioning was required. Prophylactic antibiotic use was implemented for 41 dental extractions in 12 patients. A total of 163 teeth were extracted during active pamidronate treatment. The median intervals between the last pamidronate dose before dental extraction and the first pamidronate dose after dental extraction were 63 and 69 days, respectively. A total of 87 teeth were extracted a median of 2.0 years after the last dose of pamidronate. For 225 of these extractions, the dentist’s follow-up data could be retrieved, with a median postoperative follow-up period of 86 days (range, 3 to 1370 days). In addition, follow-up by telephone was performed a median of 908 days (range, 45 to 3790 days) after dental extraction. Adequate healing was noted on postoperative visits in all patients, with no evidence of delayed healing, exposed bone, or ONJ.
DISCUSSION In this study, we found no cases of ONJ among 278 patients who had received pamidronate at our institution, even though this group of patients had a number of risk factors for developing ONJ, such as dental extraction and prolonged exposure to intravenous pamidronate at relatively high doses. This exposure profile is similar to that of adult
720
Chahine et al
cancer patients who developed ONJ;5 however, a large majority of those adult patients also received treatment with chemotherapy and other concomitant medications, such as steroids, which are known risk factors for osteonecrosis.11,12 It is also possible that other factors, such as age, periodontal disease, and the underlying oncologic disease itself, may have played a role in the development of ONJ in those patients. The patient population in the present study did not have such comorbid conditions. Thus, our findings are compatible with the hypothesis that bisphosphonate therapy is only 1 of several factors that contribute to the development of ONJ. In conclusion, we found no cases of ONJ in a pediatric population with pamidronate exposure. Our data do not suggest that dental extraction should be withheld because of previous pamidronate treatment in this population.
REFERENCES 1. Rauch F, Glorieux FH. Osteogenesis imperfecta. Lancet 2004;363:1377-85. 2. Badros A, Weikel D, Salama A, Goloubeva O, Schneider A, Rapoport A, et al. Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol 2006;24:945-52. 3. Bamias A, Kastritis E, Bamia C, Moulopoulos LA, Melakopoulos I, Bozas G, et al. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 2005;23:8580-7. 4. Durie BG, Katz M, Crowley J. Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 2005;353:99-102. 5. 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: 415-23. 6. Migliorati CA, Schubert MM, Peterson DE, Seneda LM. Bisphosphonateassociated osteonecrosis of mandibular and maxillary bone: an emerging oral complication of supportive cancer therapy. Cancer 2005;104:83-93. 7. Weitzman R, Sauter N, Eriksen EF, Tarassoff PG, Lacerna LV, Dias R, et al. Critical review: updated recommendations for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in cancer patients, May 2006. Crit Rev Oncol Hematol 2007;62:148-52. 8. Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D, 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;22:1479-91. 9. American Association of Oral and Maxillofacial Surgeons. Position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 2007;65: 369-76. 10. Grbic JT, Landesberg R, Lin SQ, Mesenbrink P, Reid IR, Leung PC, et al. Incidence of osteonecrosis of the jaw in women with postmenopausal osteoporosis in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once-Yearly Pivotal Fracture Trial. J Am Dent Assoc 2008;139:32-40. 11. Mirzai R, Chang C, Greenspan A, Gershwin ME. The pathogenesis of osteonecrosis and the relationships to corticosteroids. J Asthma 1999;36:77-95. 12. Schwartz HC. Osteonecrosis of the jaws: a complication of cancer chemotherapy. Head Neck Surg 1982;4:251-3.
The Journal of Pediatrics • November 2008