Dental adverse events
Oral adverse events were identified from among all of the adverse events recorded for the safety evaluation of zoledronic acid, and their rates were compared between the zoledronic acid and placebo groups. Incidentally, symptomatic periodontal disease, including both marginal and apical periodontitis, was diagnosed by a dentist before, during, and after this study. Symptomatic periodontal disease was confirmed using dental x-rays in each participant.
The safety evaluation was conducted using the safety analysis set that consisted of participants who received at least one infusion. As a post hoc analysis, characteristics including oral conditions that developed in the participants who had been included in the safety evaluation were collected and analyzed.
Periodontal diseases were classified as apical periodontitis and marginal periodontitis. In addition, loss of teeth included spontaneous tooth loss and tooth extraction.
Categorical data are presented as numbers and percentages, and they were compared using Fisher exact test. Numeric variables are presented as means ± standard deviation (SD), and they were compared using Student t test. The significance level was <0.05.
Adverse events during the study period were coded using the ICH Medical Dictionary for Regulatory Activities (MedDRA) Terminology (MedDRA/J Version 17.1). Marginal and apical periodontitis and spontaneous tooth loss were classified without using MedDRA into two types based on periodontal disease adverse events described in the case report form.
Testing for significance was conducted using Fisher exact test. All P values were two-sided (two-tailed significance level of 5%). Data analyses were conducted with SAS version 9.3 (SAS Institute Inc, Cary, NC).
Summary of adverse events
The adverse events are summarized in Table 3. The overall rates of adverse events in the treatment and control groups were similar (P = 0.216), with 315 cases (94.6%) and 306 cases (92.2%) in the zoledronic acid and placebo groups, respectively.
Dental adverse events
Dental adverse events in the oral cavity during the study are shown in Table 3 and Figure 2. The incidence of oral adverse events was significantly higher in the control group (P = 0.04), with 67 cases (20.2%), than in the zoledronic acid group with 47 cases (14.1%). The frequency of symptomatic periodontal disease was approximately twice as high in the control group than in the treatment group (18 cases [5.4%] in the zoledronic acid group vs 40 cases [12.0%] in the placebo group), with a significant (P = 0.002) difference.
As for the classification of periodontal disease, marginal periodontitis was seen in 29 (8.7%) patients in the placebo group and 16 (4.8%) in the zoledronic acid group, with a significant (P = 0.046) difference. The cause of all spontaneous tooth loss was marginal periodontitis.
On the contrary, apical periodontitis was seen in 11 (3.3%) patients in the placebo group and 2 (0.6%) in the zoledronic acid group. Participants in the placebo group had a significantly higher risk of apical periodontitis than those in zoledronic acid group (P = 0.012).
Loss of teeth including spontaneous tooth loss and tooth extraction was not significantly different, affecting 24 (7.2%) participants in the zoledronic acid group and 36 (10.8%) participants in the placebo group. Furthermore, during the 2-year treatment period, 23 participants (6.9%) and 32 participants (9.6%) in the zoledronic acid and placebo groups, respectively, underwent tooth extraction. When these data were examined for each year individually, tooth extraction was performed in 13 (3.9%) zoledronic acid–treated participants and 15 (4.5%) placebo-treated participants during the first year of the study. In the second year, these numbers changed to 11 (4.1%) and 19 (6.6%), respectively. The numbers of participants who underwent tooth extractions in both the first and second years were one and three in the zoledronic acid and placebo groups, respectively (Table 4). The most common reason for tooth extraction was periodontitis.
In this study, zoledronic acid was significantly more effective than placebo in preventing symptomatic periodontal disease, provided that oral hygiene was properly maintained with the assistance of oral questionnaires. The rate of smoking, which contributes greatly to aggravation of marginal periodontitis, was significantly higher in the zoledronic acid group than in the placebo group at baseline (P = 0.040). More significant improvement of marginal periodontitis might be observed in the zoledronic acid group if smoking was to be similar between the groups at baseline.
BPs show their effects by directly suppressing bone resorption in osteoporosis patients.12 Thus, these drugs were also considered to suppress bone resorption caused by periodontal disease.
In a periodontal disease model in rats, alendronate maintained alveolar bone resorption and showed anti-inflammatory activity.13-15 It is likely that BPs slow progression of apical periodontitis, because postmenopausal women with osteopenia/osteoporosis tended to have an increased risk of apical periodontitis compared to women with normal bone mineral density.16 In addition, we previously demonstrated that maintaining the oral health condition in patients who had marginal periodontitis normalized serum concentrations of C-reactive protein and interleukin-6 and endothelial function, in addition to diminishing local infection foci in the oral cavity.17 It is likely that the synergistic effect obtained by BP use and maintenance of good oral hygiene may have contributed to the significant difference in marginal and apical periodontitis between the placebo and zoledronic acid groups in the present study.
Khosla and Shane18 noted that the patient with osteoporosis is in a critical situation in which adequate treatment has not been received because, fearing rare side effects, ONJ and atypical femoral fractures, of BPs, and millions take their chances with osteoporosis. Suppurative oral disease, such as symptomatic periodontal disease, is a major risk factor for developing ONJ.19 Reports of cancer patients from Australia20 and Germany21 imply that oral infection control achieved by a collaborative effort between the medical and dental communities is important in combating ONJ. Based on the present results, it appears possible that the combination of zoledronic acid with excellent oral hygiene management may prevent ONJ.
Because this was a post hoc analysis, dental safety was not a prespecified endpoint for the ZONE study. However, a baseline questionnaire to exclude those who had pre-existing symptomatic dental disease such as periodontal diseases was administered. During the study, symptomatic dental diseases of each participant were basically recorded every 3 months. Also, if the participants reported some symptoms in the oral cavity at the time when they visited their physicians to take vitamin D and calcium every month, they were referred to their dentists for careful examination of their oral cavity. In addition, all participants were encouraged to maintain good dental hygiene during the study. Therefore, the data used in this post hoc analysis appear reliable.
The present study involved a relatively homogeneous group of participants that undertook oral care in particular; thus, they were not truly representative of all patients receiving zoledronic acid treatment. In addition, the ZONE study was designed to assess the safety of zoledronic acid over a 2-year intervention period. This short time frame was not sufficient to detect the effects of this drug on the jaw bones. Patients with good oral condition were included, but it was not possible to evaluate patients’ pretreatment dental conditions, since their oral hygiene was not evaluated before study drug administration. Diagnosis of periodontal disease was not standardized among the dentists in the randomized study. In addition to the above limitations, marginal periodontitis was not determined using precise periodontal measurements, such as periodontal depth, clinical attachment loss, and tooth mobility, in all participants. However, it is doubtful whether small significant changes of these periodontal parameters during a 2-year trial are clinically important. Furthermore, it is very difficult for many examiners to measure these parameters accurately in a large number of participants, both longitudinally and cross-sectionally.22 The incidence of symptomatic periodontal disease and tooth loss was simply estimated as the true outcome in this study.
The results of the present study clearly demonstrate that zoledronic acid was more effective than placebo in preventing symptomatic periodontal disease in osteoporosis patients who maintained good oral hygiene. These results also showed that zoledronic acid might be more effective than placebo in preventing tooth loss. Because zoledronic acid can prevent symptomatic periodontal disease when combined with good oral hygiene management, it is possible that the procedures performed in this study could eventually suppress the development of ONJ.
The authors would like to thank the investigators of the study and acknowledge Novartis Pharma AG for editorial assistance with this manuscript. The study was jointly designed by the authors and the sponsor, Asahi-Kasei Pharma Corporation. The authors discussed the interpretation of the data and the conclusions of the manuscript with the sponsor. Data analyses for publication were the responsibility of the sponsor. The corresponding author had full access to all of the data in the study and had responsibility for the decision to submit for publication. The study was sponsored by Asahi-Kasei Pharma Corporation, Tokyo, Japan. The sponsor had responsibility for quality control.
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Antiresorptives; Clinical trials; Osteoporosis; Periodontal disease; Tooth loss
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