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Improved periodontal disease and prevention of tooth loss in osteoporosis patients receiving once-yearly zoledronic acid

a randomized clinical trial

Taguchi, Akira DDS, PhD1; Shiraki, Masataka MD, PhD2; Tanaka, Satoshi BS3; Ohshige, Hideyo BS3; Nakamura, Toshitaka MD, PhD4

doi: 10.1097/GME.0000000000001393
Original Articles
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Objective: This randomized, clinical trial investigated whether zoledronic acid combined with oral health maintenance can improve periodontal disease associated with osteoporosis, thus reducing the risk of tooth loss.

Methods: Participants were those of the ZONE (ZOledroNate treatment in efficacy to osteoporosis) study. None of the participants had symptomatic periodontal disease at baseline. Participants received either zoledronic acid (5 mg; n = 333 [male 21, female 312]) or placebo (n = 332 [male 19, female 313]) once yearly for 2 years, and their age was 74.0 ± 5.3 (65-88) and 74.3 ± 5.4 (65-87) years, respectively. Participants were instructed to maintain good oral hygiene at baseline and every 3 months. Participants with signs or symptoms involving their oral cavity at the monthly visit with their physician were referred to dentists for examination of oral disease. All cases were included to analyze adverse events in this study. Testing for significance was conducted using Fisher exact test (P < 0.05).

Results: The incidence of oral adverse events was significantly higher in the control group (67 cases, 20.2%) than in the zoledronic acid group (47 cases, 14.1%; P = 0.04). The frequency of symptomatic periodontal disease observed during the study was significantly higher in the control group (40 cases, 12.0%) than in the zoledronic acid group (18 cases, 5.4%; P = 0.002). Loss of teeth was more frequent in the control group (36 cases, 10.8%) than in the zoledronic acid group (24 cases, 7.2%), although the difference was not significant.

Conclusions: Zoledronic acid effectively prevented symptomatic periodontal disease in patients with osteoporosis who maintained good oral hygiene.

Video Summary: Supplemental Digital Content 1,

1Department of Oral and Maxillofacial Radiology, Matsumoto Dental University, Nagano, Japan

2Research Institute and Practice for Involutional Diseases, Nagano, Japan

3Asahi Kasei Pharma Corporation, Tokyo, Japan

4Touto Sangenjaya Rehabilitation Hospital, Tokyo, Japan.

Address correspondence to: Akira Taguchi, DDS, PhD, Department of Oral and Maxillofacial Radiology, School of Dentistry, Department of Hard Tissue Research, Graduate School of Oral Medicine, Matsumoto Dental University, 1780 Gobara, Hirooka, Shiojiri, Nagano 399-0781, Japan. E-mail:

Received 18 February, 2019

Revised 30 April, 2019

Accepted 30 April, 2019

Funding/support: This study was funded by Asahi-Kasei Pharma.

Financial disclosures/conflicts of interest: A.T. has received consulting fees and lecture fees from Asahi-Kasei Pharma, Daiichi-Sankyo, MSD, Ono Pharmaceutical, Takeda Pharmaceutical, Chugai Pharmaceutical, and Teijin Pharma. M.S. has received consulting fees from Asahi Kasei Pharma, MSD, and Teijin Pharma and received lecture fees from Astellas Pharma, Chugai Pharmaceutical, Daiichi-Sankyo, Eisai, Eli Lilly Japan, Ono Pharmaceutical, and Pfizer. S.T. and H.O. are employees of Asahi Kasei Pharma. T.N. has received consulting fees from Asahi-Kasei Pharma, Amgen, Chugai Pharmaceutical, Daiichi-Sankyo, Eli Lilly Japan, MSD, Taisho Toyama Pharmaceutical, and Teijin Pharma.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (

Clinical trial registration number: NCT01522521 (

Online date: August 19, 2019

This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

The dynamic process of bone remodeling is maintained through a well-controlled balance between bone formation and bone resorption, but bone resorption exceeds bone formation in patients with osteoporosis, leading to enhanced bone fragility and an increased risk of fracture.1 In periodontal disease, on the contrary, resorption of alveolar bone is induced by inflammatory reactions that occur in response to localized infection caused by poor oral hygiene. Several studies conducted worldwide have indicated a close association between osteoporosis and periodontal disease.2 In other words, patients with osteoporosis have severe periodontal disease and a greater risk of tooth loss.3

Zoledronic acid (Reclast, Novartis Pharmaceuticals, Tokyo, Japan, and Asahi Kasei Pharma, Tokyo Japan; Aclasta, Novartis Pharma, Basel, Switzerland) is a third-generation bisphosphonate (BP) with a potent antiresorptive effect when given by once-yearly intravenous infusion. In an international multicenter trial (HORIZON-PFT), administration of zoledronic acid over a 3-year period reduced the risk of new vertebral fractures by 70% and of hip fractures by 41%.4 Similarly, in a clinical trial (ZOledroNate treatment in Efficacy to osteoporosis; the ZONE study) that evaluated the effects of zoledronic acid on the risk of fracture in Japanese patients, 2-year administration of this drug reduced the incidence of new vertebral fractures by 66%.5

Several small-scale, randomized, clinical trials in participants who maintained good oral health with and without use of a BP drug have been conducted to demonstrate the synergistic effect of BP use on the improvement of periodontal disease.6,7 The results indicated that, when combined with proper oral hygiene management, this drug can improve chronic inflammatory disorder, periodontal disease, more than proper oral hygiene management alone. However, it has yet to be determined whether BP use in combination with proper oral hygiene management can improve symptomatic periodontal disease that clinically shows gingival swelling, bleeding, pain, and/or tooth mobility, although clinical assessment parameters of periodontal disease improved in previous studies.6,7 Periodontal disease is basically a silent disease; however, the risk of osteonecrosis of the jaw (ONJ), a severe side effect in osteoporosis patients with BP therapy, has been shown to increase considerably in the presence of a tooth with clinical symptoms in both osteoporosis and oncology patients using BPs.8-10 If BP use in combination with proper oral hygiene management can improve symptomatic periodontal disease, it is likely that the risk of ONJ may decrease during BP therapy. In addition, the risk of tooth loss associated with symptomatic periodontal disease may decrease. In the ZONE study, all participants received professional oral hygiene care and dental treatments before and during the trial. The aim of the present study was to determine whether once-yearly zoledronic acid in combination with proper oral hygiene management can improve symptomatic periodontal disease and reduce the risk of tooth loss compared with placebo.

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Study design and procedure

The participants of this study were the participants of the ZONE study. Specifically, they had been diagnosed with primary osteoporosis based on the Diagnostic Criteria for Primary Osteoporosis (2000 revision) of the Japanese Society for Bone and Mineral Research.11 In addition, they had between one and four fractures from the fourth thoracic vertebra to the fourth lumbar vertebra. Patients whose bone metabolism was potentially altered by complications they had developed or by medications they had been taking were excluded. In addition, patients who had impaired renal function were excluded, including patients whose serum creatinine levels increased by >0.5 mg/dL during the pretreatment assessment period, and patients whose creatinine clearance was <35.0 mL/min or urinary protein was ≥2+ at the time of consent or treatment initiation. After a survey using an oral health interview form (Table 1), the participants were randomly assigned to two groups and given either zoledronic acid (5 mg) or placebo once yearly for 2 years via a 15-minute intravenous infusion. All participants received daily oral supplements of calcium (610 mg), vitamin D3 (400 IU), and magnesium (30 mg). The ZONE study was conducted in accordance with the ethical principles set forth in the Declaration of Helsinki and the Good Clinical Practice guidelines. Before recruiting patients, the protocol was approved by an institutional review board at each study site. Written, informed consent was obtained from all participants before enrollment. The clinical trial registration number at is NCT01522521.



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Dental survey and maintenance of oral health

To exclude patients with poor dental status, such as symptomatic periodontal disease, ill-fitting denture use, and/or dental peri-implantitis, from the study, participating physicians conducted a survey using an oral health interview form (Table 1) at the time of consent. Based on this survey, the physicians excluded certain patients considered unsuitable for the study drug before randomization.

Patients were excluded from the study if they were being treated with or had a plan for invasive dental treatment of the jaw at the time of informed consent. Patients were also excluded from the study if they answered either “less than 3 months” to Question 4-1 or answered “yes” to Questions 4-2 through 12 of the Oral Health Interview Form (Supplementary Fig. 1, This questionnaire was similarly administered before the second injection. The condition in the oral cavity was strictly confirmed in each patient by a dentist, and the aim was to include only patients with good oral condition. Furthermore, after the initiation of treatment, the physicians verified the lack of dental health issues approximately once every 3 months. Using a questionnaire similar to the above interview form, they asked patients about their oral conditions and if they had undergone invasive dental procedures affecting the jaw bone, including tooth extractions.

In addition, if the participants had some dental symptoms such as pain in the oral cavity at the time when they visited their physicians to take vitamin D and calcium every month, the physicians referred the participants to their dentists to carefully examine the oral cavity.

After written, informed consent was obtained, the participants received dental care manuals, toothbrushes, and dental floss and were educated and instructed to maintain good oral hygiene at baseline. Maintenance of oral hygiene of all participants was reconfirmed at routine oral health check-ups (approximately once every 3 months).

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Population characteristics

Informed consent was obtained from 1,311 patients. Of these, 665 who did not have symptomatic dental disease symptoms based on the oral health interview were randomized and given either zoledronic acid (333 patients) or placebo (332 patients). The participants’ characteristics are shown in Table 2. There were no significant differences in sex, age, body mass index, postmenopausal years, drinking habits, mean bone mineral density value, and 25-hydroxyvitamin D value between the zoledronic acid group and the placebo group. Participants in the zoledronic acid group had a significantly higher prevalence of smoking than those in the placebo group (P = 0.040). After the initiation of treatment, more participants in the zoledronic acid group discontinued the study (75 in the zoledronic acid group vs 48 in the placebo group). In addition, only three participants from each group were excluded from the study before the second injection based on their responses to the oral health interview form. A total of 542 participants (258 and 284 patients in the zoledronic acid and placebo groups, respectively) completed the study (Fig. 1). Adverse events and voluntary withdrawal of consent were notable reasons for discontinuation, and these were observed more frequently in the zoledronic acid group than in the placebo group.



FIG. 1

FIG. 1

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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.

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Statistical analyses

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).

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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.



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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.

FIG. 2

FIG. 2

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.



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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.

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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.

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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.

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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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