JBMR
REPLY
Bisphosphonate Exposure and Osteonecrosis of the Jaw Gelsomina L Borromeo,1 Caroline Brand,2,3 John G Clement,1 Michael McCullough,1 Lisa Crighton,4 Graham Hepworth,5 and John D Wark6 1
Melbourne Dental School, The University of Melbourne, 720 Swanston Street, Victoria, Australia 3010 Centre for Research Excellence in Patient Safety (CREPS), Monash University, Commercial Road Melbourne, Vic 3004 3 Melbourne EpiCentre, University of Melbourne and Melbourne Health, Parkville, Australia 3050 4 Department of Oral and Maxillofacial Surgery, Royal Melbourne Hospital, Parkville, Victoria, Australia 3050 5 Statistical Consulting Centre, The University of Melbourne, Victoria, Australia 3010 6 Department of Medicine, and Bone and Mineral Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Australia 3050 2
Dear Dr. Compston, We thank the Editor for this opportunity to respond to this letter which questions the magnitude of the association that we have reported between bisphosphonate use, delayed dental healing and osteonecrosis of the jaw after a dental precipitant. Further, this letter asks if we have any insight whether our findings should change clinical decision making. First, the letter questions our reported odds ratios (OR). All the ORs reported in our study were based on conditional logistic regression, which is the appropriate analysis technique for data with a matched design. As Rothman (1986, p250) states, “the main task in a matched case-control analysis is to stratify by the matching factors”, which in our study were age, sex, and clinic. The unadjusted “crude” ORs are potentially misleading, and may be quite discrepant from those arising from the conditional analysis. We therefore did not see the need to report the crude ORs; it was certainly not due to avoiding transparency. Nor was there need to describe the statistical methods in more detail – conditional logistic regression is fully covered in classic epidemiology texts such as Rothman(1) or Breslow & Day.(2) As specifically requested, we also provide the relevant SPSS commands below: COXREG DDH12 /STATUS ¼ DDH(1) /STRATA ¼ group /CONTRAST (BPTherapy) ¼ Indicator /METHOD ¼ ENTER BPTherapy /PRINT ¼ CI(95). DDH12 ¼ 1 for cases, 2 for controls DDH ¼ case or control group ¼ matched set of 1 case and 4 controls BPTherapy ¼ yes or no
There is a straightforward explanation for the discrepancy between adjusted and unadjusted ORs observed in our study. There were 40 matched groups, each comprising 1 case and 4 controls. 15 of the groups were concordant in regard to bisphosphonate exposure, in that all 5 individuals were not exposed. Concordant groups are uninformative about the association between bisphosphonate use and delayed dental healing. If they are omitted, it leaves 4 cases and 77 controls that were not exposed, which gives a crude OR of 17.6. The adjusted OR of 13.1 is no longer surprising. Note too that on the log-odds scale, which is arguably more appropriate for comparisons, the discrepancy is not as marked, with 95% confidence intervals of (1.47, 3.67) and (1.12, 2.65) for adjusted and unadjusted ORs respectively. The current case-control study was retrospective in nature and as such some data were not available for analysis. However, it was known from chart review that all patients at the time of their dental treatment were taking bisphosphonates. Information on any previous bisphosphonate use was obtained by complete examination of the available clinical record. It is acknowledged that such records may be incomplete or subject to bias. Likewise, although we knew patients’ other medication and type of dental intervention, and have reported these data in the published study, it was not possible to know from the records the patients’ plaque control. Attached please find a table describing the basic demographics of the sample, as requested (Table 1). There are unfortunately problems encountered when undertaking a retrospective study by chart review. Nevertheless, we do not believe that this limitation detracts significantly from the strong statistical association found between patients currently taking bisphosphonate and the development of delayed dental healing/osteonecrosis of the jaw as reported. Finally, we respectfully contend that the findings of our study should be considered in clinical practice. We have clearly demonstrated an important association between bisphosphonate
Received in original form December 5, 2014; accepted December 5, 2014. Accepted manuscript online Month 00, 2015. Journal of Bone and Mineral Research, Vol. 30, No. 4, April 2015, pp 749–750 DOI: 10.1002/jbmr.2428 © 2014 American Society for Bone and Mineral Research
749
Table 1. Basic Demographics of the Sample Cases Age, years n (mean SD)
Controls n
Female 30 66.3 10.1 120 Male 10 63.6 9.0 40 Total 40 65.6 9.8 160
Total
Age, years (mean SD)
n
Age, years (mean SD)
65.9 9.9 62.5 9.1 65.0 9.9
150 50 200
65.9 9.9 62.7 9.0 65.1 9.8
use and delayed dental healing in the setting of benign bone disease. Although it is sometimes difficult to discuss with patients the meaning of a specific OR for their individual clinical situation, a more appropriate statistic would be to discuss the rate at which an adverse outcome has been reported in apparently similar clinical circumstances. Within the confines of our reported study, assuming that the percentage bisphosphonate use in the recruited control group (14.4%) is representative of the whole cohort, then it can be estimated that, in patients over the age of 50 who are taking bisphosphonates, attending a dental specialist and
750
undergoing an invasive dental procedure, there was a prevalence of 3.46% (21/607 100) at a rate of 1 in 28.9 patients. Almost all of the cases we reported had a dental intervention (tooth extraction, 89.5%) as the dental precipitant. Thus to gain informed consent, a dental specialist prior to an extraction of a tooth for a patient over 50 years on bisphosphonates, should explain that, according to the best evidence currently available, osteonecrosis of the jaw may occur in 1 in 30 patients. While highest-level evidence would be highly desirable, that evidence is currently unavailable, so we must be guided by the best information at hand. This surely is a worthwhile guide to good clinical practice and we anticipate that those preparing future clinical guidelines would base those guidelines on the best available scientific evidence, as provided by our study. To ignore this evidence would fail to adequately inform our patients.
References 1. Rothman KR. Modern Epidemiology. Little, Brown & Co, Boston. 1986. 2. Breslow N, Day NE. Statistical Methods in Cancer Research, Volume 1. The Analysis of Case-Control Studies. IARC, Lyon. 1980.
Journal of Bone and Mineral Research
REPLY
Bisphosphonate Exposure and Osteonecrosis of the Jaw Gelsomina L Borromeo,1 Caroline Brand,2,3 John G Clement,1 Michael McCullough,1 Lisa Crighton,4 Graham Hepworth,5 and John D Wark6 1
Melbourne Dental School, The University of Melbourne, 720 Swanston Street, Victoria, Australia 3010 Centre for Research Excellence in Patient Safety (CREPS), Monash University, Commercial Road Melbourne, Vic 3004 3 Melbourne EpiCentre, University of Melbourne and Melbourne Health, Parkville, Australia 3050 4 Department of Oral and Maxillofacial Surgery, Royal Melbourne Hospital, Parkville, Victoria, Australia 3050 5 Statistical Consulting Centre, The University of Melbourne, Victoria, Australia 3010 6 Department of Medicine, and Bone and Mineral Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Australia 3050 2
Dear Dr. Compston, We thank the Editor for this opportunity to respond to this letter which questions the magnitude of the association that we have reported between bisphosphonate use, delayed dental healing and osteonecrosis of the jaw after a dental precipitant. Further, this letter asks if we have any insight whether our findings should change clinical decision making. First, the letter questions our reported odds ratios (OR). All the ORs reported in our study were based on conditional logistic regression, which is the appropriate analysis technique for data with a matched design. As Rothman (1986, p250) states, “the main task in a matched case-control analysis is to stratify by the matching factors”, which in our study were age, sex, and clinic. The unadjusted “crude” ORs are potentially misleading, and may be quite discrepant from those arising from the conditional analysis. We therefore did not see the need to report the crude ORs; it was certainly not due to avoiding transparency. Nor was there need to describe the statistical methods in more detail – conditional logistic regression is fully covered in classic epidemiology texts such as Rothman(1) or Breslow & Day.(2) As specifically requested, we also provide the relevant SPSS commands below: COXREG DDH12 /STATUS ¼ DDH(1) /STRATA ¼ group /CONTRAST (BPTherapy) ¼ Indicator /METHOD ¼ ENTER BPTherapy /PRINT ¼ CI(95). DDH12 ¼ 1 for cases, 2 for controls DDH ¼ case or control group ¼ matched set of 1 case and 4 controls BPTherapy ¼ yes or no
There is a straightforward explanation for the discrepancy between adjusted and unadjusted ORs observed in our study. There were 40 matched groups, each comprising 1 case and 4 controls. 15 of the groups were concordant in regard to bisphosphonate exposure, in that all 5 individuals were not exposed. Concordant groups are uninformative about the association between bisphosphonate use and delayed dental healing. If they are omitted, it leaves 4 cases and 77 controls that were not exposed, which gives a crude OR of 17.6. The adjusted OR of 13.1 is no longer surprising. Note too that on the log-odds scale, which is arguably more appropriate for comparisons, the discrepancy is not as marked, with 95% confidence intervals of (1.47, 3.67) and (1.12, 2.65) for adjusted and unadjusted ORs respectively. The current case-control study was retrospective in nature and as such some data were not available for analysis. However, it was known from chart review that all patients at the time of their dental treatment were taking bisphosphonates. Information on any previous bisphosphonate use was obtained by complete examination of the available clinical record. It is acknowledged that such records may be incomplete or subject to bias. Likewise, although we knew patients’ other medication and type of dental intervention, and have reported these data in the published study, it was not possible to know from the records the patients’ plaque control. Attached please find a table describing the basic demographics of the sample, as requested (Table 1). There are unfortunately problems encountered when undertaking a retrospective study by chart review. Nevertheless, we do not believe that this limitation detracts significantly from the strong statistical association found between patients currently taking bisphosphonate and the development of delayed dental healing/osteonecrosis of the jaw as reported. Finally, we respectfully contend that the findings of our study should be considered in clinical practice. We have clearly demonstrated an important association between bisphosphonate
Received in original form December 5, 2014; accepted December 5, 2014. Accepted manuscript online Month 00, 2015. Journal of Bone and Mineral Research, Vol. 30, No. 4, April 2015, pp 749–750 DOI: 10.1002/jbmr.2428 © 2014 American Society for Bone and Mineral Research
749
Table 1. Basic Demographics of the Sample Cases Age, years n (mean SD)
Controls n
Female 30 66.3 10.1 120 Male 10 63.6 9.0 40 Total 40 65.6 9.8 160
Total
Age, years (mean SD)
n
Age, years (mean SD)
65.9 9.9 62.5 9.1 65.0 9.9
150 50 200
65.9 9.9 62.7 9.0 65.1 9.8
use and delayed dental healing in the setting of benign bone disease. Although it is sometimes difficult to discuss with patients the meaning of a specific OR for their individual clinical situation, a more appropriate statistic would be to discuss the rate at which an adverse outcome has been reported in apparently similar clinical circumstances. Within the confines of our reported study, assuming that the percentage bisphosphonate use in the recruited control group (14.4%) is representative of the whole cohort, then it can be estimated that, in patients over the age of 50 who are taking bisphosphonates, attending a dental specialist and
750
undergoing an invasive dental procedure, there was a prevalence of 3.46% (21/607 100) at a rate of 1 in 28.9 patients. Almost all of the cases we reported had a dental intervention (tooth extraction, 89.5%) as the dental precipitant. Thus to gain informed consent, a dental specialist prior to an extraction of a tooth for a patient over 50 years on bisphosphonates, should explain that, according to the best evidence currently available, osteonecrosis of the jaw may occur in 1 in 30 patients. While highest-level evidence would be highly desirable, that evidence is currently unavailable, so we must be guided by the best information at hand. This surely is a worthwhile guide to good clinical practice and we anticipate that those preparing future clinical guidelines would base those guidelines on the best available scientific evidence, as provided by our study. To ignore this evidence would fail to adequately inform our patients.
References 1. Rothman KR. Modern Epidemiology. Little, Brown & Co, Boston. 1986. 2. Breslow N, Day NE. Statistical Methods in Cancer Research, Volume 1. The Analysis of Case-Control Studies. IARC, Lyon. 1980.
Journal of Bone and Mineral Research
