JBMR
LETTER TO THE EDITOR
Bisphosphonate Exposure and Osteonecrosis of the Jaw Randy C Hatton,1 Priti Patel,2 and Wei Liu3 1
Clinical Professor, Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, PO Box 100486, Gainesville, FL 32610-0486 2 Clinical Associate Professor, Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida 3 Research Associate, Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida
To the Editor: In their case-control study, Borromeo and colleagues report an association between the use of bisphosphonates, primarily alendronate, and delayed dental healing and osteonecrosis of the jaw (ONJ) after a dental precipitant.(1,2) We question the magnitude of their association. The reported “adjusted” odds ratio (OR) of 13.1 (95% confidence interval [CI] 4.4 to 39.3, p < 0.001) is difficult to understand considering the unadjusted (crude) OR. Using the data that 21 cases were exposed to bisphosphonate, while 19 cases were not exposed and that 23 of the controls were exposed to bisphosphonate, while 137 controls were not exposed, we calculated an OR of 6.6 (95% CI 3.1 to 14.1). If we interpret their analysis correctly, they used a multivariate logistic model adjusting for age (dichotomized to age older or younger than 70 years), sex, clinic type, duration of exposure, relevant co-morbidities, concurrent treatment, and other potential confounders.(1,2) Age, sex, and clinic type was “automatically incorporated” into their statistical model. When they adjusted for smoking, the OR decreased to 11.6. It is not clear whether the OR was for a matched study design. A clear explanation of the multivariate models and the methods used for the ORs for their primary and secondary analyses would be beneficial. Unlike most case-control studies, the report by Borromeo and colleagues did not provide a demographic table that would show the distribution of possible confounders for this observational study. More details about bisphosphonate exposure in the cases is needed like duration of exposure, total dose, and proximity of use to the dental procedure. We would also like to see additional demographic information for the cases exposed to bisphosphonates, the cases not exposed to bisphosphonates, and the controls like the patients’ dental hygiene as assessed in their dental charts, other drug use, alcohol use, and types of dental interventions. This information
could potentially draw attention to confounders that could explain the large increase in the adjusted OR compared with the unadjusted crude OR. One could argue that the 13.1 OR, the 11.6 OR [when adjusted for smoking], and the 6.1 unadjusted crude OR we calculated are all “statistically” significant. While a matched or stratified analysis is preferred for matched designs from a statistical perspective, both matched and unmatched analyses can be reported and sometimes the two analytic approaches can lead to significantly different findings.(3) We suggest authors of future case control studies increase transparency in reporting of their data and findings. At least, a detailed demographic table showing patient characteristics, rationale for the matching variables, and the detailed statistical methods used to calculate the ORs should be reported in papers. Further, it would helpful to provide insight as to whether the relative differences found in a case-control study should change clinical decision making. Since we do not know absolute risks, we cannot calculate number-needed-to-harm (NNH). This is a known disadvantage case-control studies. Borromeo and colleagues found a statistically significant association between bisphosphonate use and ONJ; however, it is difficult to use their finding to guide clinical practice.
References 1. Borromeo GL, Brand C, Clement JG, et al. A large case-control study reveals a positive association between bisphosphonate use and delayed dental healing and osteonecrosis of the jaw. J Bone Miner Res. 2014;29:1363–1368. doi: 10.1001/jbmr.2178. 2. Borromeo GL, Brand C, Clement JG, et al. Is bisphosphonate therapy for benign bone disease associated with impaired dental healing? A case-controlled study. BMC Musculoskelet Disord. 2011;12:71. doi: 10.1186/1471-2474-12-71. 3. Feinstein AR. Quantitative ambiguities in matched versus unmatched analyses of the 22 table for a case-control study. Int J Epidemiol. 1987;16:128–134.
Received in original form October 17, 2014; accepted December 5, 2014. Accepted manuscript online Month 00, 2015. Address corresdondence to: Randy C Hatton, BPharm, PharmD, FCCP, BCPS, Clinical Professor, Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, PO Box 100486, Gainesville, FL 32610-0486. E-mail: [email protected] The authors have no conflicts of interest. Journal of Bone and Mineral Research, Vol. 30, No. 4, April 2015, p 748 DOI: 10.1002/jbmr.2429 © 2014 American Society for Bone and Mineral Research
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LETTER TO THE EDITOR
Bisphosphonate Exposure and Osteonecrosis of the Jaw Randy C Hatton,1 Priti Patel,2 and Wei Liu3 1
Clinical Professor, Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, PO Box 100486, Gainesville, FL 32610-0486 2 Clinical Associate Professor, Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida 3 Research Associate, Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida
To the Editor: In their case-control study, Borromeo and colleagues report an association between the use of bisphosphonates, primarily alendronate, and delayed dental healing and osteonecrosis of the jaw (ONJ) after a dental precipitant.(1,2) We question the magnitude of their association. The reported “adjusted” odds ratio (OR) of 13.1 (95% confidence interval [CI] 4.4 to 39.3, p < 0.001) is difficult to understand considering the unadjusted (crude) OR. Using the data that 21 cases were exposed to bisphosphonate, while 19 cases were not exposed and that 23 of the controls were exposed to bisphosphonate, while 137 controls were not exposed, we calculated an OR of 6.6 (95% CI 3.1 to 14.1). If we interpret their analysis correctly, they used a multivariate logistic model adjusting for age (dichotomized to age older or younger than 70 years), sex, clinic type, duration of exposure, relevant co-morbidities, concurrent treatment, and other potential confounders.(1,2) Age, sex, and clinic type was “automatically incorporated” into their statistical model. When they adjusted for smoking, the OR decreased to 11.6. It is not clear whether the OR was for a matched study design. A clear explanation of the multivariate models and the methods used for the ORs for their primary and secondary analyses would be beneficial. Unlike most case-control studies, the report by Borromeo and colleagues did not provide a demographic table that would show the distribution of possible confounders for this observational study. More details about bisphosphonate exposure in the cases is needed like duration of exposure, total dose, and proximity of use to the dental procedure. We would also like to see additional demographic information for the cases exposed to bisphosphonates, the cases not exposed to bisphosphonates, and the controls like the patients’ dental hygiene as assessed in their dental charts, other drug use, alcohol use, and types of dental interventions. This information
could potentially draw attention to confounders that could explain the large increase in the adjusted OR compared with the unadjusted crude OR. One could argue that the 13.1 OR, the 11.6 OR [when adjusted for smoking], and the 6.1 unadjusted crude OR we calculated are all “statistically” significant. While a matched or stratified analysis is preferred for matched designs from a statistical perspective, both matched and unmatched analyses can be reported and sometimes the two analytic approaches can lead to significantly different findings.(3) We suggest authors of future case control studies increase transparency in reporting of their data and findings. At least, a detailed demographic table showing patient characteristics, rationale for the matching variables, and the detailed statistical methods used to calculate the ORs should be reported in papers. Further, it would helpful to provide insight as to whether the relative differences found in a case-control study should change clinical decision making. Since we do not know absolute risks, we cannot calculate number-needed-to-harm (NNH). This is a known disadvantage case-control studies. Borromeo and colleagues found a statistically significant association between bisphosphonate use and ONJ; however, it is difficult to use their finding to guide clinical practice.
References 1. Borromeo GL, Brand C, Clement JG, et al. A large case-control study reveals a positive association between bisphosphonate use and delayed dental healing and osteonecrosis of the jaw. J Bone Miner Res. 2014;29:1363–1368. doi: 10.1001/jbmr.2178. 2. Borromeo GL, Brand C, Clement JG, et al. Is bisphosphonate therapy for benign bone disease associated with impaired dental healing? A case-controlled study. BMC Musculoskelet Disord. 2011;12:71. doi: 10.1186/1471-2474-12-71. 3. Feinstein AR. Quantitative ambiguities in matched versus unmatched analyses of the 22 table for a case-control study. Int J Epidemiol. 1987;16:128–134.
Received in original form October 17, 2014; accepted December 5, 2014. Accepted manuscript online Month 00, 2015. Address corresdondence to: Randy C Hatton, BPharm, PharmD, FCCP, BCPS, Clinical Professor, Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, PO Box 100486, Gainesville, FL 32610-0486. E-mail: [email protected] The authors have no conflicts of interest. Journal of Bone and Mineral Research, Vol. 30, No. 4, April 2015, p 748 DOI: 10.1002/jbmr.2429 © 2014 American Society for Bone and Mineral Research
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