- Email: [email protected]
METHODOLOGY QUESTIONED
L E T T E R S
Tufts University Boston
Shao Zhu, MD, PhD Medical Analyst Ingenix—i3 Drug Safety Basking Ridge, N.J.
Athanasios I. Zavras, DMD, MS, DMSc Associate Professor and Director of Dental Public Health Department of Oral Health Policy and Epidemiology Harvard School of Dental Medicine Boston 1. Zavras AI, Wilkinson GS. Signal detection in the evaluation of bisphoshonateassociated osteonecrosis of the jaw. Poster presented at: 22nd International Conference on Pharmacoepidemiology & Therapeutic Risk Management; Aug. 22, 2005; Lisbon, Portugal. 2. Wessel JH, Dodson TB, Zavras AI. Zoledronate, smoking and obesity are strong risk factors of osteonecrosis of the jaw. A case control study. J Oral Maxillofac Surg 2008; 66(4):625-631. 3. Clarke BM, Boyette J, Vural E, Suen JY, Anaissie EJ, Stack BC Jr. Bisphosphonates and jaw osteonecrosis: the UAMS experience. Otolaryngol Head Neck Surg 2007;136(3): 396-400. 4. Corso A, Varettoni M, Zappasodi P, et. al. A different schedule of zoledronic acid can reduce the risk of the osteonecrosis of the jaw in patients with multiple myeloma. Leukemia 2007;21(7):1545-1548. 5. Etminan M, Aminzadeh K, Matthew IR, Brophy JM. Use of oral bisphosphonates and the risk of aseptic osteonecrosis: a nested casecontrol study (published online ahead of print Jan. 15, 2008). J Rheumatol 2008; 35(4):691-695. 6. Pazianas M, Blumenthals WA, Miller PD. Lack of association between oral bisphosphonates and osteonecrosis using jaw surgery as a surrogate marker (published online ahead of print Nov. 13, 2007). Osteoporos Int 7. Jeffcoat MK. Safety of oral bisphosphonates: controlled studies on alveolar bone. Int J Oral Maxillofac Implants 2006;21(3): 349-353. 8. Grbic JT, Landesberg R, Lin SQ 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. JADA 2008;139(1):32-40.
METHODOLOGY QUESTIONED
While Dr. Cartsos and colleagues are to be commended for their January JADA study of adverse jaw outcomes in a medical claims database of 15 million lives, the study methodology renders many of their
conclusions problematic (“Bisphosphonate Use and the Risk of Adverse Jaw Outcomes: A Medical Claims Study of 714,217 People” (JADA 2008; 139[1]:23-30). The authors set out to define the risk of developing osteonecrosis of the jaw (ONJ) among 714,217 people who were receiving oral or intravenous (IV) bisphosphonates. The diagnostic and procedure codes used as a basis for their findings are far too broad to allow any conclusions to be drawn about ONJ as an entity. Because no International Classification of Diseases, Ninth Revision, code for ONJ is available, they used codes for inflammatory conditions of the jaws, major jaw surgery necessitated by necrotic or inflammatory indications, and jaw surgeries necessitated by a malignant process. dInflammatory conditions of the jaws may include ONJ but also many other conditions, including infections such as osteomyelitis. Accepted definitions of ONJ put forth by expert panels from the American Association of Oral and Maxillofacial Surgeons1 and the American Society for Bone and Mineral Research2 are far narrower and more exclusive. dMajor surgeries for a necrotic or inflammatory process of the jaw are problematic for capturing ONJ cases for a similar reason. The conditions necessitating such surgeries encompass a broader range of processes than what most experts would consider ONJ. dJaw surgeries necessitated by a malignant process is a category that would be explicitly excluded under all accepted definitions of ONJ. Patients with cancers of the jaw or who have
received radiotherapy for head and neck cancers should be excluded from consideration as true ONJ cases because the malignant process itself, or the radiotherapy itself, may have caused the lesion. Because the authors are unable to confirm diagnoses by chart review, it is impossible to validate the frequency estimates for the occurrence of ONJ using accepted definitions in patients receiving IV versus oral bisphosphonates or in patients with cancer compared with patients with osteoporosis. Without being able to apply accepted definitions of ONJ systematically to each case reviewed in this study, one cannot use these study findings to inform clinical treatment decisions in patients considered to be at risk of developing ONJ owing to their disease state or the type of bisphosphonate they are receiving. The database used studied patients from 2000 to 2006, when no U.S. Food and Drug Administration–approved IV bisphosphonate was available for treatment of osteoporosis; yet they found 1,800 patients treated with IV bisphosphonates for osteoporosis, raising concerns that some of these patients may have had osteoporosis and cancer. Looking at the diagnoses and medications of these patients in the six months prior to the prescription for bisphosphonates may be helpful in further understanding the authors’ results. The authors conclude that use of oral bisphosphonates had a protective effect on ONJ. Unfortunately, the authors did not correct for multiple comparisons. Although the authors are careful to apply their findings to
JADA, Vol. 139
http://jada.ada.org
Copyright © 2008 American Dental Association. All rights reserved.
May 2008
537
L E T T E R S
“adverse jaw outcomes” in patients treated with bisphosphonates, the data should not be misread as applying to ONJ. Because the role of bisphosphonates in the development of ONJ is not well-understood, and because the risk factors for ONJ are multifactorial in nature, it is even more difficult to surmise the role, if any, that bisphosphonates may have had in contributing to any of the adverse jaw outcomes reported in this retrospective database review. Stuart L. Silverman, MD Attending Physician Cedars-Sinai Medical Center and Clinical Professor of Medicine and Rheumatology David Geffen School of Medicine at UCLA and Medical Director Osteoporosis Medical Center Clinical Research Center Beverly Hills, Calif. 1. American Association of Oral and Maxillofacial Surgeons. Position paper on bisphosphonate-related osteonecrosis of the jaws. “www.aaoms.org/docs/position_papers/ osteonecrosis.pdf”. Accessed Dec. 11, 2006. 2. 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(10):1479-1491.
Authors’ response: We appreciate Dr. Silverman’s interest and thoughtful comments. The aim of this project was descriptive, to inform the discussion on the frequency of surrogate measures of osteonecrosis of the jaw (ONJ) in a large unselected population. Because this work has presented preliminary descriptive information on adverse jaw outcomes and surrogate markers of ONJ (known to epidemiologists as “crude statistics”), we explicitly mentioned several study limitations, including the fact that the codes used (ICD9 and Current
538
JADA, Vol. 139
http://jada.ada.org
Procedural Technology codes) are not specific for ONJ. In fact, we dedicated more than one page in the Discussion section of the article, discussing most comments presented in this letter. With regard to the inclusion of codes for jaw surgeries necessitated by a malignant process, we agree with the spirit of the comment, and in essence have chosen to include these CPT codes as a quality control measure. Stratifying by indication in two categories and analyzing them to see if the method is able to distinguish risks adds valuable information. If bisphosphonates were found to be significantly associated with surgeries owing to a malignant process, one could hypothesize that intravenous (IV) bisphosphonates are not effective in controlling malignant spread. In contrast, our analytic strategy identified significant differences between the two surgical categories (see Tables 2 and 3), adding validity to our work and possibly reaffirming the clinical benefits of IV bisphosphonates in oncology, which seem to come with some increased risk of having surgery owing to necrosis or some other inflammatory condition. Dr. Silverman correctly noted an increased frequency of IV bisphosphonate use among the patients with osteoporosis. It is possible that some of the patients with osteoporosis may have had osteoporosis plus cancer. While not representative of all patients with osteoporosis, this group still allows an evaluation of the association between IV bisphosphonates and the main outcomes. A second plausible explanation of the in-
creased use of IV bisphosphonates among the osteoporosis group is the fact that several patients with osteoporosis may have received pamidronate, an IV bisphosphonate in use since 1994, which to our knowledge has been used in the off-label control of osteoporosis. Descriptive studies do not answer the question of causality, but instead raise several interesting hypotheses. The letters serve as a proof and a source of ideas for future analytic studies. Funding permitting, our plan for the future is to move from claims-based analyses to the longitudinal evaluation of atrisk patients with osteoporosis. We also pursue a pharmacogenetic study to identify markers of genetic susceptibility, and we work toward developing an animal model to test findings from our human studies. Because more needs to be done, we invite interested colleagues to collaborate with us in our studies of osteonecrosis of the jaw, more details of which may be found at “www.hsdm. harvard.edu/news/HSDM_ONJ_ site.pdf”. Vassiliki M. Cartsos, DMD, MS Assistant Professor Department of Orthodontics School of Dental Medicine Tufts University Boston
Shao Zhu, MD, PhD Medical Analyst Ingenix—i3 Drug Safety Basking Ridge, N.J.
Athanasios I. Zavras, DMD, MS, DMSc Associate Professor and Director of Dental Public Health Department of Oral Health Policy and Epidemiology Harvard School of Dental Medicine Boston
May 2008
Copyright © 2008 American Dental Association. All rights reserved.
Tufts University Boston
Shao Zhu, MD, PhD Medical Analyst Ingenix—i3 Drug Safety Basking Ridge, N.J.
Athanasios I. Zavras, DMD, MS, DMSc Associate Professor and Director of Dental Public Health Department of Oral Health Policy and Epidemiology Harvard School of Dental Medicine Boston 1. Zavras AI, Wilkinson GS. Signal detection in the evaluation of bisphoshonateassociated osteonecrosis of the jaw. Poster presented at: 22nd International Conference on Pharmacoepidemiology & Therapeutic Risk Management; Aug. 22, 2005; Lisbon, Portugal. 2. Wessel JH, Dodson TB, Zavras AI. Zoledronate, smoking and obesity are strong risk factors of osteonecrosis of the jaw. A case control study. J Oral Maxillofac Surg 2008; 66(4):625-631. 3. Clarke BM, Boyette J, Vural E, Suen JY, Anaissie EJ, Stack BC Jr. Bisphosphonates and jaw osteonecrosis: the UAMS experience. Otolaryngol Head Neck Surg 2007;136(3): 396-400. 4. Corso A, Varettoni M, Zappasodi P, et. al. A different schedule of zoledronic acid can reduce the risk of the osteonecrosis of the jaw in patients with multiple myeloma. Leukemia 2007;21(7):1545-1548. 5. Etminan M, Aminzadeh K, Matthew IR, Brophy JM. Use of oral bisphosphonates and the risk of aseptic osteonecrosis: a nested casecontrol study (published online ahead of print Jan. 15, 2008). J Rheumatol 2008; 35(4):691-695. 6. Pazianas M, Blumenthals WA, Miller PD. Lack of association between oral bisphosphonates and osteonecrosis using jaw surgery as a surrogate marker (published online ahead of print Nov. 13, 2007). Osteoporos Int 7. Jeffcoat MK. Safety of oral bisphosphonates: controlled studies on alveolar bone. Int J Oral Maxillofac Implants 2006;21(3): 349-353. 8. Grbic JT, Landesberg R, Lin SQ 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. JADA 2008;139(1):32-40.
METHODOLOGY QUESTIONED
While Dr. Cartsos and colleagues are to be commended for their January JADA study of adverse jaw outcomes in a medical claims database of 15 million lives, the study methodology renders many of their
conclusions problematic (“Bisphosphonate Use and the Risk of Adverse Jaw Outcomes: A Medical Claims Study of 714,217 People” (JADA 2008; 139[1]:23-30). The authors set out to define the risk of developing osteonecrosis of the jaw (ONJ) among 714,217 people who were receiving oral or intravenous (IV) bisphosphonates. The diagnostic and procedure codes used as a basis for their findings are far too broad to allow any conclusions to be drawn about ONJ as an entity. Because no International Classification of Diseases, Ninth Revision, code for ONJ is available, they used codes for inflammatory conditions of the jaws, major jaw surgery necessitated by necrotic or inflammatory indications, and jaw surgeries necessitated by a malignant process. dInflammatory conditions of the jaws may include ONJ but also many other conditions, including infections such as osteomyelitis. Accepted definitions of ONJ put forth by expert panels from the American Association of Oral and Maxillofacial Surgeons1 and the American Society for Bone and Mineral Research2 are far narrower and more exclusive. dMajor surgeries for a necrotic or inflammatory process of the jaw are problematic for capturing ONJ cases for a similar reason. The conditions necessitating such surgeries encompass a broader range of processes than what most experts would consider ONJ. dJaw surgeries necessitated by a malignant process is a category that would be explicitly excluded under all accepted definitions of ONJ. Patients with cancers of the jaw or who have
received radiotherapy for head and neck cancers should be excluded from consideration as true ONJ cases because the malignant process itself, or the radiotherapy itself, may have caused the lesion. Because the authors are unable to confirm diagnoses by chart review, it is impossible to validate the frequency estimates for the occurrence of ONJ using accepted definitions in patients receiving IV versus oral bisphosphonates or in patients with cancer compared with patients with osteoporosis. Without being able to apply accepted definitions of ONJ systematically to each case reviewed in this study, one cannot use these study findings to inform clinical treatment decisions in patients considered to be at risk of developing ONJ owing to their disease state or the type of bisphosphonate they are receiving. The database used studied patients from 2000 to 2006, when no U.S. Food and Drug Administration–approved IV bisphosphonate was available for treatment of osteoporosis; yet they found 1,800 patients treated with IV bisphosphonates for osteoporosis, raising concerns that some of these patients may have had osteoporosis and cancer. Looking at the diagnoses and medications of these patients in the six months prior to the prescription for bisphosphonates may be helpful in further understanding the authors’ results. The authors conclude that use of oral bisphosphonates had a protective effect on ONJ. Unfortunately, the authors did not correct for multiple comparisons. Although the authors are careful to apply their findings to
JADA, Vol. 139
http://jada.ada.org
Copyright © 2008 American Dental Association. All rights reserved.
May 2008
537
L E T T E R S
“adverse jaw outcomes” in patients treated with bisphosphonates, the data should not be misread as applying to ONJ. Because the role of bisphosphonates in the development of ONJ is not well-understood, and because the risk factors for ONJ are multifactorial in nature, it is even more difficult to surmise the role, if any, that bisphosphonates may have had in contributing to any of the adverse jaw outcomes reported in this retrospective database review. Stuart L. Silverman, MD Attending Physician Cedars-Sinai Medical Center and Clinical Professor of Medicine and Rheumatology David Geffen School of Medicine at UCLA and Medical Director Osteoporosis Medical Center Clinical Research Center Beverly Hills, Calif. 1. American Association of Oral and Maxillofacial Surgeons. Position paper on bisphosphonate-related osteonecrosis of the jaws. “www.aaoms.org/docs/position_papers/ osteonecrosis.pdf”. Accessed Dec. 11, 2006. 2. 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(10):1479-1491.
Authors’ response: We appreciate Dr. Silverman’s interest and thoughtful comments. The aim of this project was descriptive, to inform the discussion on the frequency of surrogate measures of osteonecrosis of the jaw (ONJ) in a large unselected population. Because this work has presented preliminary descriptive information on adverse jaw outcomes and surrogate markers of ONJ (known to epidemiologists as “crude statistics”), we explicitly mentioned several study limitations, including the fact that the codes used (ICD9 and Current
538
JADA, Vol. 139
http://jada.ada.org
Procedural Technology codes) are not specific for ONJ. In fact, we dedicated more than one page in the Discussion section of the article, discussing most comments presented in this letter. With regard to the inclusion of codes for jaw surgeries necessitated by a malignant process, we agree with the spirit of the comment, and in essence have chosen to include these CPT codes as a quality control measure. Stratifying by indication in two categories and analyzing them to see if the method is able to distinguish risks adds valuable information. If bisphosphonates were found to be significantly associated with surgeries owing to a malignant process, one could hypothesize that intravenous (IV) bisphosphonates are not effective in controlling malignant spread. In contrast, our analytic strategy identified significant differences between the two surgical categories (see Tables 2 and 3), adding validity to our work and possibly reaffirming the clinical benefits of IV bisphosphonates in oncology, which seem to come with some increased risk of having surgery owing to necrosis or some other inflammatory condition. Dr. Silverman correctly noted an increased frequency of IV bisphosphonate use among the patients with osteoporosis. It is possible that some of the patients with osteoporosis may have had osteoporosis plus cancer. While not representative of all patients with osteoporosis, this group still allows an evaluation of the association between IV bisphosphonates and the main outcomes. A second plausible explanation of the in-
creased use of IV bisphosphonates among the osteoporosis group is the fact that several patients with osteoporosis may have received pamidronate, an IV bisphosphonate in use since 1994, which to our knowledge has been used in the off-label control of osteoporosis. Descriptive studies do not answer the question of causality, but instead raise several interesting hypotheses. The letters serve as a proof and a source of ideas for future analytic studies. Funding permitting, our plan for the future is to move from claims-based analyses to the longitudinal evaluation of atrisk patients with osteoporosis. We also pursue a pharmacogenetic study to identify markers of genetic susceptibility, and we work toward developing an animal model to test findings from our human studies. Because more needs to be done, we invite interested colleagues to collaborate with us in our studies of osteonecrosis of the jaw, more details of which may be found at “www.hsdm. harvard.edu/news/HSDM_ONJ_ site.pdf”. Vassiliki M. Cartsos, DMD, MS Assistant Professor Department of Orthodontics School of Dental Medicine Tufts University Boston
Shao Zhu, MD, PhD Medical Analyst Ingenix—i3 Drug Safety Basking Ridge, N.J.
Athanasios I. Zavras, DMD, MS, DMSc Associate Professor and Director of Dental Public Health Department of Oral Health Policy and Epidemiology Harvard School of Dental Medicine Boston
May 2008
Copyright © 2008 American Dental Association. All rights reserved.