Osteonecrosis of the Jaw in Sweden Associated With the Oral Use of Bisphosphonate

PATHOLOGY

Osteonecrosis of the Jaw in Sweden Associated With the Oral Use of Bisphosphonate Mattias Ulmner, DDS,* Fredrik Jarnbring, DDS,y and Ove T€ orring, MD, PhDz Purpose:

To estimate the incidence of bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ) associated with the use of oral BPs and osteonecrosis of the jaw (ONJ) not associated with current or previous medication with a BP or radiotherapy to the head and neck region (background ONJ) in Sweden.

Materials and Methods:

A survey was sent to all oral and maxillofacial surgery clinics and hospital dental clinics in Sweden. They were requested to report all new cases of BRONJ and background ONJ during 2007 and 2008.

Results:

The response rate was 61%. The oral BRONJ incidence for patients aged 45 years or older was 67 cases/100,000 patient-years of BP medication in 2007 (1 case/1,500 patient-years). In 2008, 69 cases/ 100,000 patient-years (1 case/1,445 patient-years) were reported. The mean age at the development of oral BRONJ was 76.5  10.8 years (median age 79, range 49 to 96) for 2007 and 79.8  7.6 years (median 79, range 67 to 94) for 2008. Women were primarily affected (22 of 26 in 2007 and 25 of 29 in 2008). The incidence of background ONJ was low: 0.14 and 0.09/100,000 person-years for those aged 45 years or older in 2007 and 2008, respectively (3 cases in 2007 and 2 in 2008).

Conclusions: The BRONJ incidence has been estimated to be more than 100-fold greater than the incidence of background ONJ. However, an average Swedish dental practice (1,234 patients) will only encounter 1 patient with new oral BRONJ every 62nd year. Ó 2014 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 72:76-82, 2014

The risk of developing bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ) associated with oral use of BPs is uncertain. The incidence among users of oral BPs has been reported to be 1 case/100,000 person-years and has been proposed to be similar to the occurrence of osteonecrosis of the jaw (ONJ) in the background population.1-3 The first report of BRONJ was published in 2003 and has since been reported by several groups.4-8 The guidelines for treating BRONJ have been published by the American Association of Oral and Maxillofacial Surgeons (AAOMS), the American Society for Bone and Mineral Research (ASBMR), and the Canadian Association of Oral and Maxillofacial Surgeons.9-11

The intravenous use of BPs, in particular zoledronic acid and pamidronate, in patients with cancer has been associated with an increased risk of developing ONJ and has been seen in about 5% of high-dose users.2 The first series of BRONJ in association with oral BPs reported on 7 of 63 patients who had received oral BPs.8 Since then, other investigators have also reported jaw necrosis associated with the oral use of BPs.3,12,13 Recently, ONJ has also been reported in cancer patients in association with the use of another potent antiresorptive drug, denosumab.13-15 An increased awareness of BRONJ among dentists has, in some cases, even led to an unwillingness to undertake any dental procedure in oral BP-treated patients. Still, the

*Consultant, Department of Oral and Maxillofacial Surgery,

Hospital, S-141 86, Stockholm Sweden; e-mail: mattias.ulmner@

Karolinska University Hospital, Stockholm, Sweden.

karolinska.se

yConsultant, Department of Oral and Maxillofacial Surgery,

Received March 6 2013

Karolinska University Hospital, Stockholm, Sweden. zAssociate Professor, Department of Clinical Research and

Ó 2014 American Association of Oral and Maxillofacial Surgeons

Education, S€ odersjukhuset, Karolinska Institute, Stockholm, Sweden.

0278-2391/13/00828-8$36.00/0

Accepted June 28 2013

Address correspondence and reprint requests to Dr Ulmner:

http://dx.doi.org/10.1016/j.joms.2013.06.221

Department of Oral and Maxillofacial Surgery, Karolinska University

76

€ ULMNER, JARNBRING, AND TORRING

77

pathogenesis of BRONJ is unknown and BP’s causative role uncertain. Using the AAOMS and ASBMR task force criteria, we aimed to estimate the incidence of BRONJ in patients who had currently or previously been treated orally with BPs. In addition, we explored the occurrence of background ONJ.

population. In addition, the data for all reported drug adverse reactions in 2007 and 2008 from BP use were obtained from the MPA. All reported cases were compared by gender, birth year, and medication type to exclude any patient who could possibly have received treatment at more than 1 center.

Materials and Methods

Results

In the present cross-sectional survey, a questionnaire was sent to all 95 oral and maxillofacial surgery clinics and hospital dental clinics in Sweden (see the Appendix). These were referral centers and received all cases of ONJ within their region. They were asked to report all new patients with BRONJ during 2007 and 2008. The definitions of BRONJ as established by the ASBMR task force and AAOMS position paper were enclosed and required to be as follows: 1) current or previous treatment with a BP; 2) exposed bone in the maxillofacial region that had persisted for more than 8 weeks; and 3) no history of radiotherapy to the jaws.9,10 The corresponding center representative used the local ONJ registry, if available, or searched the center’s digital medical records ‘‘International Classification of Disease, 10th revision’’ (ICD-10) code registry. The receivers of the survey were also asked to supply information on the extent of background population in their region and to state all new cases of background ONJ in 2007 and 2008 in the same manner as for the BRONJ cases. Two reminder letters were sent out to nonresponders, the last in late summer 2010. An exemption from the local ethics committee (etikpr€ ovningsn€amnderna, EPN) was granted (EPN nr 2013/68-31/2).

Of the 95 Swedish departments of oral and maxillofacial surgery and hospital dental clinics, 58 responded. The answers from 2 centers lacked contact information to the corresponding center representative, but all other information was given correctly and therefore was included in the analyses. Double reporting of patients was checked and did not occur. A total of 26 and 29 cases with newly developed BRONJ associated with the use of oral BPs was reported in 2007 and 2008, respectively (Table 1). According to the MPA, a total of 72,234 patient-years and 77,622 patient-years of oral BPs were sold at Swedish pharmacies during 2007 and 2008 to patients 45 years old or older, respectively. The background population in the reporting regions was very close to 5.0 million, corresponding to 54% of Sweden’s total population by the end of 2008.15 The total BP prescription in the participating areas also approximated 54% of the total BP prescription in Sweden. In the geographic area of the reporting centers, 39,006 patient-years and 41,916 patient-years of BP were administered in 2007 and 2008 to patients 45 years old or older, respectively. The oral BRONJ incidence was 67 cases/100,000 patient-years in 2007, or 1 case/1,500 patient-years of medication, and 69 cases/100,000 patient-years in 2008, or 1 case/1,445 patient-years of medication (Table 2). In 2007 and 2008, 3 and 2 patients had a diagnosis of new background ONJ, corresponding to an incidence of background ONJ of 0.06/100,000 person-years and 0.04/100,000 person-years for all ages in 2007 and 2008, respectively. Excluding inhabitants younger than 45 years old, the incidence was 0.14/100,000 personyears in 2007 and 0.09/100,000 person-years in 2008. The age of the patients at the diagnosis of BRONJ associated with oral BP use was reported for 16 of the 26 cases in 2007, giving a mean age of 76.5  10.8 years (median 79, range 49 to 96). In 2008, patient age was reported for 21 of the 29 cases, corresponding to a mean age of 79.8  7.6 years (median 79, range 67 to 94 years). Women accounted for 22 of the 26 oral BRONJ cases in 2007 and 25 of the 29 cases in 2008. The oral BRONJ incidence was slightly greater among men (85 cases/ 100,000 patient-years in 2007 and 79 cases/100,000 patient-years in 2008) compared with the incidence

STATISTICAL ANALYSIS

From the Swedish Medical Products Agency (MPA), the official statistics of the prescribed BPs, the total amount of oral BPs used by those older than 30 years, the prescription patterns in Sweden’s 21 counties, and the total amount of intravenous BP used by all ages in 2007 and 2008 were obtained. The MPA reports the prescribed medication as the defined daily dose (DDD).14 The statistics on the oral BPs presented by the MPA as the DDD/1,000 individuals (DDD/TIND) were transformed to the number of patient-years using the formula: DDD/TIND  number of citizens/1,000. The incidence rate in 2007 and 2008 was calculated by dividing the number of new BRONJ cases by the number of patient-years of oral BP use, adjusted for the background population reported in the survey. The incidence rate in 2007 and 2008 for background ONJ was calculated by dividing the number of new background ONJ cases by the reported background

78

OSTEONECROSIS OF THE JAW IN SWEDEN

Table 1. INDIVIDUAL BRONJ CASES DUE TO ORAL USE OF BISPHOSPHONATES IN 2007 AND 2008

2007

Gender M F F F F F F F F M F F M F F F F F F F F F F F F M

2008

Age (yr)

BP

Site

Duration of BP Use (yr)

49 64 66 71 73 73 73 79 79 80 81 81 82 83 88 89 ? ? ? ? ? ? ? ? ? ?

RIS IB ? IB ALN ALN ALN ALN ALN IB ? RIS ? ALN ALN ALN ALN ? ? ALN ? ? ? ALN ALN ALN

Mandible Mandible Mandible Maxilla Maxilla Mandible Mandible Mandible Mandible Mandible Mandible Mandible Maxilla Mandible Bimaxillary Maxilla Mandible Mandible Maxilla Mandible Bimaxillary Mandible Mandible Mandible Mandible Mandible

1-3 >3 >3 <1 >3 1-3 ? ? <1 >3 >3 >3 >3 >3 >3 >3 >3 >3 >3 >3 ? ? ? >3 >3 >3

Gender

Age (yr)

BP

Site

Duration of BP Use (yr)

F F F M F M F F F F F F M F F F F F F F F M F F F F F F F

67 69 69 72 73 73 77 77 77 78 79 80 81 84 85 85 88 88 88 92 94 ? ? ? ? ? ? ? ?

ALN ALN ALN ALN ALN ALN RIS ALN ALN ? ALN IB ALN ALN ALN ALN ALN ALN ALN ALN ALN ALN ALN ALN ? ? ? ALN ALN

Mandible Bimaxillary Mandible Mandible Mandible Maxilla Mandible Mandible Maxilla Mandible Mandible Mandible Maxilla Mandible Maxilla Mandible Mandible Mandible Mandible Mandible Mandible Mandible Mandible Mandible Bimaxillary Mandible Mandible Mandible Maxilla

>3 ? >3 ? >3 ? ? ? 1-3 >3 >3 >3 ? >3 ? <1 ? ? >3 ? ? 1-3 >3 >3 ? ? ? >3 >3

Abbreviations: ALN, alendronic acid; BP, bisphosphonate; BRONJ, bisphosphonate-related osteonecrosis of the jaw; F, female; IB, ibandronic acid; M, male; RIS, risedronic acid; ?, no information provided by the reporting center. Ulmner, Jarnbring, and T€ orring. Osteonecrosis of the Jaw in Sweden. J Oral Maxillofac Surg 2014.

for women (63 cases/100,000 patient-years in 2007 and 69 cases/100,000 patient-years in 2008); however, the men were too few for a valid determination of the male incidence. Women were prescribed BPs 7.5 times more frequently than were men during 2007 and 2008 in Sweden. Alendronate was the most frequent reported BP associated with the development of BRONJ (Table 3). The mandible was affected to a greater degree than the maxilla. In 2007, 19 of 26 patients (73%) had a lesion in the mandible, 5 had a lesion in the maxilla (19%), and 2 had lesions in both (8%). In 2008, the data were almost identical, with 22 of 29 patients having mandibular engagement (76%), 5 with maxillary (17%), and 2 with bimaxillary involvement (7%). The duration of oral BP medication before the diagnosis of BRONJ was predominantly more than 3 years (Table 4).

Of the reported 55 cases with BRONJ associated with oral BPs, the lesions had healed in 15 patients at the point of the survey (ie, approximately 1 to 2 years after the diagnosis of BRONJ). Most healed lesions were in the mandible of a female patient. In 2007, 73 new cases of BRONJ associated with intravenous BPs were reported, with 63 cases reported in 2008. Of these, 1 case each year had resulted from zoledronic acid in preventing osteoporotic fractures (1 dose/year of treatment). However, it was not possible in our survey to calculate the incidence of BRONJ associated with intravenous BP use owing to the different treatment regimens, varying doses, and so forth. The survey reported a total of 191 reported new BRONJ cases (oral and intravenous) in Sweden during 2007 and 2008, with a response rate of 61%. The MPA

€ ULMNER, JARNBRING, AND TORRING

79

Table 2. INCIDENCE OF BRONJ DUE TO ORAL USE OF BISPHOSPHONATES IN SWEDEN STRATIFIED BY AGE

Age $ 30 yr

Age $ 45 yr

Age $ 60 yr

Year

Patient-Years/ BRONJ Case

BRONJ/100,000 Patient-Years

Patient-Years/ BRONJ Case

BRONJ/100,000 Patient-Years

Patient-Years/ BRONJ Case

BRONJ/100,000 Patient-Years

2007 2008

1,529 1,464

65.4 68.3

1,500 1,445

66.6 69.2

1,357 1,300

73.7 76.9

Abbreviation: BRONJ, bisphosphonate-related osteonecrosis of the jaw. Ulmner, Jarnbring, and T€ orring. Osteonecrosis of the Jaw in Sweden. J Oral Maxillofac Surg 2014.

received 47 reports of patients with BRONJ during the same period. The MPA’s statistics on drug sales showed that 2% of the population aged 45 years or older was prescribed BPs in 2007 and in 2008. For those aged 60 years or older, the proportion was 3% in 2007 and 2008, and for those aged 80 years or older, it was 5%. Extending the reports of BRONJ cases to the total Swedish background population aged 45 years or older (ie, also including inhabitants without any use of BPs) resulted in an incidence of 1.2 BRONJ cases/ 100,000 person-years in 2007 and 1.3 cases/100,000 person-years in 2008. For the population aged 60 years or older, the corresponding data were 2.1 cases/ 100,000 person-years in 2007 and 2.4 cases/100,000 person-years in 2008.

Data on the background incidence of ONJ have been missing, despite the number of published reports of BRONJ associated with the use of oral BPs published.4,8-10 We found an incidence of background ONJ in persons aged 45 years or older of 0.14/100,000 person-years in 2007 and 0.09/100,000 person-years

in 2008. In contrast, the incidence of BRONJ associated with oral BP use was almost equal in 2007 and 2008: 67 and 69 cases/100,000 patient-years, respectively. This corresponds to 1 case of BRONJ/1,500 patient-years in 2007 and 1 case/1,445 patient years in 2008 for those aged 45 years or older. The incidence of background ONJ, therefore, seems to be more than 100-fold lower than the incidence of BRONJ associated with oral BP treatment. The number of confirmed background ONJ cases was small, and an under- or overestimation could not be ruled out because the ICD-10 diagnosis used in the medical records could be the same as for other bone diseases (eg, osteomyelitis of the jaw). To identify the cases of background ONJ in the medical records, however, would be time-consuming. Therefore, the risk of under- or overreporting could not be ruled out. This also applies to the BRONJ diagnosis when local hospital ONJ registries were not available. Given a decent reliability of our estimation of incidence, however, the suggestion that BRONJ associated with oral BP treatment most likely represents background ONJ does not seem reasonable in Sweden.2,3 Our incidence data of BRONJ were considerably greater than the previous report of 1 case/100,000 patient-years.1 The greater incidence of BRONJ we

Table 3. BRONJ CASES IN RELATION TO PRESCRIBED ORAL BISPHOSPHONATES AND CORRESPONDING PERCENTAGE OF TOTAL SALE OF BISPHOSPHONATES IN SWEDEN FOR 2007 AND 2008 COMBINED

Table 4. DURATION OF ORAL BISPHOSPHONATE TREATMENT AT DIAGNOSIS OF BRONJ PER CASE AND PERCENTAGE OF TOTAL (N = 55) FOR 2007 AND 2008 COMBINED

Discussion

BP Type Alendronic acid Ibandronic acid Risedronic acid Unknown Total

Part of National Sale (%)

BRONJ Cases in 2007 and 2008

71 8 21

36 (66) 4 (7) 3 (5) 12 (22) 55 (100)

100

Duration of BP Treatment (yr) <1 1-3 >3 Unknown Total

BRONJ Cases in 2007 and 2008 3 (5) 4 (7) 29 (53) 19 (35) 55 (100)

Data in parentheses are percentages. Abbreviation: BRONJ, bisphosphonate-related osteonecrosis of the jaw.

Data in parentheses are percentages. Abbreviation: BRONJ, bisphosphonate-related osteonecrosis of the jaw.

Ulmner, Jarnbring, and T€ orring. Osteonecrosis of the Jaw in Sweden. J Oral Maxillofac Surg 2014.

Ulmner, Jarnbring, and T€ orring. Osteonecrosis of the Jaw in Sweden. J Oral Maxillofac Surg 2014.

80 observed could have several explanations. A contributing factor might be that Sweden has a very high prevalence of osteoporosis compared with other countries, and one third of all women aged 70 to 79 years have been diagnosed with osteoporosis.16 Oral BPs were approved by the Swedish MPA for the prevention of osteoporotic fractures in Sweden by 1994. BPs are the first-line treatment of osteoporosis in Sweden according to the guidelines provided by the MPA in 2007 and more recently by the Swedish National Board of Health and Welfare.17,18 In addition, it is possible that an increased awareness among dentists of the BRONJ issue could have led to a more accurate registration of the condition at the questionnaire survey in 2007 and 2008. Even if weaknesses are present in the questionnaire design of the study, the BRONJ incidence might not be that different from the actual occurrence in Sweden. The BRONJ incidence of 67 to 69/100,000 patientyears might seem high, but these numbers should be considered in a broader perspective. From the total population aged 45 years or older in the reporting regions, the incidence of BRONJ associated with oral BP treatment was only 1.2 cases/100,000 inhabitants in 2007 and 1.3/100,000 inhabitants in 2008. In addition, we had 81 practicing general dentists per 100,000 inhabitants in Sweden in 2008.19 Our observed incidence, considering an average Swedish dentist’s patient stock (1,234 patients), therefore, would correspond to only 0.016 patient/year with a new diagnosis of BRONJ from the oral use of a BP. The likelihood that a Swedish dentist would encounter 1 patient with new BRONJ due to oral BP, therefore, would be only 1 patient each 62nd year. The prevalence of BRONJ according to a postal survey from Australia varied from 1 case/2,260 patient-years to 1 case/8,470 patient-years.20 The Kaiser Permanente of Northern California survey found a prevalence of 0.1% for patients who had received chronic BP therapy in 2006.21 Another retrospective study using the medical record system from the University of Southern California School of Dentistry identified all patients with current or previous oral BP treatment and reported a BRONJ prevalence of 4%.22 The Swedish BRONJ prevalence is still to be estimated, we hope through future national registries instead of local ones. The mean age at BRONJ diagnosis in our study (77 to 80 years) was older than that in previous reports (66.8 years and 64.8 years).12,20 Differences in the patterns of the prescription of osteoporosis drugs could be a likely explanation, because the mean age for pharmacologic treatment in Sweden during the survey period was 71 years.23 We also found that the prescription of oral BPs increased with age (3% of all inhabitants aged 60 years or older and 5% in those aged 80 years or older in both 2007 and 2008). In addition, BRONJ related to oral BP

OSTEONECROSIS OF THE JAW IN SWEDEN

use takes some time to develop and is most frequent after more than 3 years of medication use.12,21 Differences in life expectancy would be an unlikely explanation, because they are quite similar in the United States, Australia, and Sweden.24 Alendronic acid was by far the most frequent BP associated with BRONJ in our study and was also the most prescribed BP in Sweden in 2007 and 2008. The percentage of alendronic acid’s market sale was in accordance with the frequency that alendronic acid was reported to be associated with BRONJ in our study. Our finding has corroborated earlier studies reporting that alendronic acid was the most frequent oral BP associated with BRONJ.3,7,8,12,13 In accordance with other studies, it seems to be more prevalent for BRONJ to develop after more than 3 years of BP use.9,10,12 However, 3 patients in our study had used an oral BP for less than 1 year at the diagnosis of BRONJ. This could even be an underestimation, because we lacked information for 19 of 55 patients with BRONJ regarding the duration of their BP treatment. Our study has also shown underreporting to the MPA, because they, nationwide, received reports of only 47 cases of osteonecrosis in association with BP use (intravenous and oral administration) during 2007 and 2008. During the same period, 191 new cases of BRONJ were reported through our survey, with a response rate of 61%. The present cross-sectional survey study had several limitations. Adjudication by an independent dentist of the patients’ dental and medical chart was not possible. In addition, we were unable to calculate the incidence of BRONJ resulting from intravenous use of BPs for the same reason. Centers with no patients with BRONJ and centers with patients with BRONJ might have chosen not to respond to the questionnaire for unknown reasons. The participation bias was difficult to estimate; however, 19 of 58 respondents did not report any patients with newly diagnosed BRONJ. Furthermore, our estimate of the incidence was determined by the prescription data from the MPA; however, the patients’ adherence to their prescription was unknown. As much as 49% of a Swedish cohort have been reported to discontinue the treatment after 1 year.23 It would be difficult to apply those data to the survey material because we did not know the median duration of medication use for the whole Swedish population of oral BP users. However, the estimated incidence should be greater, with adjustments for compliance. No information on dental procedures, such as tooth extraction and dental infection, was obtained, but has been reported previously as a possible inciting event preceding BRONJ.3,7,9,10,12,20 In addition, questions on comorbidity, comedications, the reason for BP treatment, and so forth, were left out of the

€ ULMNER, JARNBRING, AND TORRING

survey to increase the centers, compliance with responding. In conclusion, the incidence of BRONJ associated with oral BP use seemed to be greater than the incidence of background ONJ. The likelihood that a dentist with an average practice of 1,234 patients will encounter 1 patient with new BRONJ due to oral BP use would be only 1 patient every 62nd year, including patients of all ages. Therefore, we have concluded that the incidence and potential influence of BRONJ associated with oral BP use on dental practice is still so low that the AAOMS recommendation for the dental regimen seems adequate. Acknowledgments We thank Karin Klingberg, of the Swedish MPA, for help with the statistics on BP use.

References 1. Khan AA, Rios LP, Sandor GK, et al: Bisphosphonate-associated osteonecrosis of the jaw in Ontario: A survey of oral and maxillofacial surgeons. J Rheumatol 38:1396, 2011 2. Reid IR, Cornish J: Epidemiology and pathogenesis of osteonecrosis of the jaw. Nat Rev Rheumatol 8:90, 2012 3. Assael LA: Oral bisphosphonates as a cause of bisphosphonaterelated osteonecrosis of the jaws: Clinical findings, assessment of risks, and preventive strategies. J Oral Maxillofac Surg 67(5 Suppl):35, 2009 4. Marx RE: Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: A growing epidemic. J Oral Maxillofac Surg 61:1115, 2003 5. Kumar SK, Meru M, Sedghizadeh PP: Osteonecrosis of the jaws secondary to bisphosphonate therapy: A case series. J Contemp Dent Pract 9:63, 2008 6. 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 23:8580, 2005 7. Filleul O, Crompot E, Saussez S: Bisphosphonate-induced osteonecrosis of the jaw: A review of 2,400 patient cases. J Cancer Res Clin Oncol 136:1117, 2010 8. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL: Osteonecrosis of the jaws associated with the use of bisphosphonates: A review of 63 cases. J Oral Maxillofac Surg 62:527, 2004 9. 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 22:1479, 2007 10. Ruggiero SL, Dodson TB, Assael LA, et al: American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws—2009 update. J Oral Maxillofac Surg 67(5 Suppl):2, 2009 11. Campisi G, Fedele S, Colella G, et al: Canadian consensus practice guidelines for bisphosphonate associated osteonecrosis of the jaw. J Rheumatol 36:451, 2009 12. Marx RE, Cillo JE Jr, Ulloa JJ: Oral bisphosphonate-induced osteonecrosis: Risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg 65:2397, 2007 13. Jarnbring F, Ulmner M, Blomlof J, Ljungman P: [Diphosphonates can cause necrosis of the jaw: Patients with malignant skeletal diseases are at risk]. Lakartidningen 103:1741, 2006 14. WHO Collaborating Centre for Drug Statistics Methodology. Oslo, Norway: Norwegian Institute of Public Health, 2009. Available at: http://www.whocc.no/ddd/definition_and_general_considera/ 15. Press release From Statistics Sweden 2009-02-17, 09:30, no. 2009:39, 2009. Available at: http://www.scb.se/Pages/ PressRelease____262430.aspx. Accessed February 17, 2009.

81 16. Bacon WE, Maggi S, Looker A, et al: International comparison of hip fracture rates in 1988-89. Osteoporos Int 6:69, 1996 17. Medical Products Agency: [Treatment of osteoporosis], in [Information from MPA]. Uppsala, Sweden: Medical Products Agency, 2007, pp 19–29 [Swedish]. 18. National Board of Health and Welfare: [National Guidelines for Musculoskeletal Disorders. Osteoporosis.]. Stockholm, Sweden: National Board of Health and Welfare, 2012 [Swedish]. 19. National Board of Health And Welfare: [National Planning Support. Annual report 2011: An Analysis of Midwives, Nurses, Doctors, Dental Hygienists and Dentists Labor Market.] National Board of Health and welfare, Stockholm, Sweden. 2011[Swedish] 20. Mavrokokki T, Cheng A, Stein B, Goss A: Nature and frequency of bisphosphonate-associated osteonecrosis of the jaws in Australia. J Oral Maxillofac Surg 65:415, 2007 21. Lo JC, O’Ryan FS, Gordon NP, et al: Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure. J Oral Maxillofac Surg 68:243, 2010 22. Sedghizadeh PP, Stanley K, Caligiuri M, et al: Oral bisphosphonate use and the prevalence of osteonecrosis of the jaw: An institutional inquiry. J Am Dent Assoc 140:61, 2009 23. Landfeldt E, Strom O, Robbins S, Borgstrom F: Adherence to treatment of primary osteoporosis and its association to fractures—the Swedish Adherence Register Analysis (SARA). Osteoporos Int 23:433, 2012 24. Central Intelligence Agency: Country comparison: Life expectancy at birth, in The World Factbook. 2012. Available at: https://www .cia.gov/library/publications/the-world-factbook/rankorder/2102 rank.html#top. Accessed July 13, 2012.

Appendix Survey on Bisphosphonate-Related Osteonecrosis of the Jaws Questions concerning osteonecrosis of the jaw associated with oral administration of bisphosphonate. 1. Has your clinic treated any new patients with BRONJ associated with oral administrated bisphosphonates in 2007 and 2008? Yes (go to question 2) No (go to question 5) 2. State all the patients diagnosed and treated at your clinic for newly discovered osteonecrosis of the jaw associated with orally administrated bisphosphonates during the following years (to avoid duplication of registration, we would like you to enter the patient’s initials and year of birth below ‘‘Patient ID’’). Patient ID 2007

2008

.... .... .... .... .... .... .... ....

Gender Bisphosphonate .... ..... ..... ..... ..... ..... ..... ..... .... ..... ..... ..... ..... ..... ..... .....

Maxilla/ Mandible ..... .... .... .... ..... .... .... ....

82

OSTEONECROSIS OF THE JAW IN SWEDEN

3. For how long have the above patients been treated with bisphosphonates before osteonecrosis developed?

<1 year 1-3 years >3 years Unknown

Patients (n) ...... ...... ...... ......

4. Has healing of BRONJ occurred in the patients stated in question 2, and, if so, in how many of the cases? Yes No

Patients (n) ...... ......

Questions concerning osteonecrosis of the jaw associated with intravenously administrated bisphosphonate. 5. How many new patients have been treated at your clinic during the following years because of osteonecrosis of the jaw associated with the bisphosphonate zoledronate (Aclasta) that was given once/year intravenously to treat osteoporosis?

2007 2008

Number of patients diagnosed in ...... ......

6. How many new patients treated with intravenous bisphosphonate for malignant disease were diagnosed with BRONJ during the following years?

2007 2008

Number of patients diagnosed in ...... ......

7. How many patients have been treated at your clinic because of newly discovered osteonecrosis of the jaw that was not associated with bisphosphonate or radiotherapy to the head or neck region, but with exposed jaw bone for more than 8 weeks?

2007 2008

Number of patients diagnosed in ...... ......

8. State the background population in your region? .................................... Enter the name of your clinic together with all contact details below. .................................... Thank you for your cooperation!