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 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 increased 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 at-risk 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".
