journal of prosthodontic research 59 (2015) 3–5
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/jpor
Letter to the editor Osteonecrosis of the jaw in patients with dental prostheses being treated with bisphosphonates or denosumab
Keywords: Medication-related osteonecrosis of the jaw (MRONJ) Bisphosphonate Denosumab Removable denture Fixed partial denture
Dear Editor, Bisphosphonates are used in the treatment of bone-resorbing diseases such as osteoporosis, malignancy-related hypercalcemia, multiple myeloma, and bone metastasis from solid cancers [1]. The treatment is administered orally for osteoporosis, and by intravenous injection for cancer metastasis cases. However, recent studies have reported instances of bisphosphonate-related osteonecrosis of the jaw (BRONJ), raising concerns for all dentists about this type of treatment. Although the developmental mechanism of BRONJ is still not fully understood, some studies have reported that BRONJ is caused by (1) apoptosis of osteoclasts [2]; (2) disturbance of osteoclast progenitor cell differentiation [2]; (3) disturbance of osteoclast enzyme activity [3]; (4) destruction of bone microstructure caused by drug deposition [4]; and (5) antineovascularization [5]. Denosumab (Ranmark1), an IgG2 monoclonal antibody that binds to receptor activator of nuclear factor-kB ligand (RANKL), is not a bisphosphonaterelated preparation, but some studies have reported complications of osteonecrosis of the jaw (ONJ) from denosumab [6]. Therefore, the ONJ has been recently termed medicationrelated ONJ (MRONJ) [7]. Although specific guidelines have been developed for treatment and prevention of ONJ [8], they are limited to symptomatic treatment or infection prevention, rather than fundamental prevention. According to the guideline, one of the risk factors of ONJ is a history of inflammatory dental disease [8]. The oral mucosal inflammation associated with ill-fitting dental prostheses is a common clinical case for prosthodontists; however, information on the occurrence of dental prosthesis-related ONJ is limited [9,10].
Indeed, no report has been found in the literature that investigates the incidence of MRONJ by denosumab in relation to dental prostheses. This gap in the literature prompted us to perform a pilot clinical study investigating the relationship between MRONJ and dental prostheses. This study was approved by the Ethics Committee of the School of Medicine, Keio University (Approval number: 20110018). Intended subjects were 424 patients (male: 125; female: 299) with a mean age of 64.8 years who were seeking treatment for dental problems at the Department of Dentistry and Oral Surgery, Keio University Hospital from June 2013 to May 2014. The subjects were already being treated with oral or intravenous bisphosphonates, or denosumab. To diagnose MRONJ, we applied the diagnostic criteria of the American Association of Oral and Maxillofacial Surgeons for definitive diagnosis of BRONJ [8]. A total of 21 cases of MRONJ were detected in the subjects (5.0%: 21/424 subjects). It should be noted that MRONJ was only found in subjects who were intravenously treated with bisphosphonates or denosumab (16.4%: 21/128 intravenous subjects). Among the 21 MRONJ cases, seven subjects were treated with zoledronic acid-hydrate (Zometa1) only, two subjects were treated with denosumab only, and 12 subjects had changed medication from zoledronic acid-hydrate to denosumab before they visited our dental clinic. Four cases of MRONJ were related to post-extraction dental sockets, and we could not explain the specific cause of MRONJ in nine cases in this study (Table 1). To examine the association between wearing a dental prosthesis and the occurrence of MRONJ, the 128 subjects who were intravenously treated with bisphosphonates or denosumab were separated into three groups: (1) no prosthesis (n = 60), (2) removable denture (RD: n = 34), and (3) fixed partial denture (FPD: n = 34). The incidence of MRONJ in the RD group was 32.4% (11/34 subjects), which is significantly higher than that in the no prosthesis group (8.3%: 5/60 subjects) (Table 1). Among the 11 MRONJ cases in the RD group, seven subjects had changed medication from zoledronic acid-hydrate to denosumab before they visited our dental clinic. These findings suggest that wearing an RD is a risk factor for MRONJ in patients being treated with bisphosphonates or denosumab intravenously. In the 11 RD-related MRONJ cases, the ONJ lesions were all observed in the tissue under the RD in the mandibular molar region. The fit of the RD was evaluated using either pressure indicator paste or a polyaddition-type silicone, and seven out of the 11 RD-related MRONJ cases were found to have an ill-fitting denture (Table 1). A
4
journal of prosthodontic research 59 (2015) 3–5
Table 1 – Clinical profile of 128 subjects being treated with intravenous bisphosphonates or denosumab. Dental prosthesis
Subjects
ONJ cases
Clinical features of ONJ With ill-fitting RD
No prosthesis RD FPD Total
60 34## 34 128
(45) (18#) (21) (84)
5 11** 5y 21
(5) (7*) (2) (14)
– 7 (5) – 7 (5)
In extraction socket 1 2 1 4
(1) (1) (1) (3)
With severe periodontitis 0 0 1 1
Undetermined cause 4 2 3 9
(4) (1) (1) (6)
ONJ: osteonecrosis of the jaw, RD: removable denture, FPD: fixed partial denture. Parentheses indicate the number of patients who were treated with denosumab only or those who had changed medication from zoledronic acid-hydrate to denosumab before they visited our dental clinic. Six (##) or three (#) of these subjects had both RD and FPD. A statistically significant difference (**p < 0.01, *p < 0.05) between ONJ cases in the RD group and the no prosthesis group, calculated with a Fisher’s exact test. yNote that all ONJ lesions in the FPD group (n = 5) were found under the pontic.
Fig. 1 – (A) A 60-year-old Japanese female who changed medication from zoledronic acid hydrate (ZAH) to denosumab for breast cancer. Osteonecrosis of the jaw (ONJ) was observed in the mandibular right molar region (left) under the ill-fitting removable denture (right). (B) A 67-year-old Japanese female being treated with ZAH for breast cancer. ONJ was observed under the pontic of the fixed partial denture associated with severe periodontitis in the maxillary first premolar region.
representative clinical case is shown in Fig. 1A. Interestingly, we found five ONJ lesions in the tissue under the FPD pontic (Table 1) in patients with breast cancer (two cases) and multiple myeloma (three cases) as the primary disease. Two of these MRONJ patients had changed medication from zoledronic acid-hydrate to denosumab before they visited our dental clinic. The incidence of MRONJ in the FPD group was 14.7% (5/34 subjects). It should be noted that all ONJ lesions in the FPD group were observed under the pontic. In one out of the five cases, the ONJ lesion was associated with severe periodontitis of the abutment tooth (Fig. 1B). Because dental extractions and a history of inflammatory dental disease are risk factors for BRONJ [8], denture use and recurrent lesions caused by ill-fitting dentures could be responsible for the occurrence of MRONJ in this study. Additionally, poor oral hygiene is thought to be a risk factor for BRONJ [8]; therefore, poor oral hygiene under the pontic may, in part, cause infection of the underlying mucosa. The mechanism by which MRONJ occurs in the region of the pontic is unclear; it would be valuable to analyze the pontic shape, distance to the gingiva, and dental hygiene in a future study. Future research should focus on factors such as bone metabolism, dental plaque retention, and mechanical trauma by the dental prosthesis to clarify the association of dental prostheses with MRONJ. In summary, this clinical survey showed that dental prostheses, such as RDs and FPDs, are a possible risk factor
for MRONJ in patients being treated intravenously with bisphosphonates or denosumab. However, the study population was relatively small, and thus the result may be specific to this study sample. Nevertheless, patients being treated with bisphosphonates or denosumab who use dental prostheses, not only RDs but also FPDs, should be encouraged to seek regular dental follow-up.
references
[1] Berenson J, Lipton A. Bisphosphonates in the treatment of malignant bone disease. Annu Rev Med 1999;50:237–48. [2] Hughes D, Wright K, Uy H, Sasaki A, Yoneda T, Roodman GD, et al. Bisphosphonates promote apoptosis in murine osteoclasts in-vitro and in-vivo. J Bone Miner Res 1995;10:1478–87. [3] Fisher J, Rogers M, Halasy J, Luckman SP, Hughes DE, Masarachia PJ, et al. Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro. Proc Natl Acad Sci U S A 1999;96:133–8. [4] Assael L. A time for perspective on bisphosphonates. J Oral Maxillofac Surg 2006;64:877–9. [5] Wood J, Bonjean K, Ruetz S, Bellahcene A, Devy L, Foidart JM, et al. Novel antiangiogenic effects of the
5
journal of prosthodontic research 59 (2015) 3–5
[6]
[7]
[8]
[9]
[10]
bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther 2002;302:1055–61. Smith M, Saad F, Coleman R, Shore N, Fizazi K, Tombal B, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet 2012;379: 39–46. Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, et al. Medication-related osteonecrosis of the jaw – 2014 update. Am Assoc Oral Maxillofac Surg 2014; 1–26. AAOMS. American association of oral and maxillofacial surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 2007;65:369–76. Kyrgidis A, Vahtsevanos K, Koloutsos G, Andreadis C, Boukovinas I, Teleioudis Z, et al. Bisphosphonate-related osteonecrosis of the jaws: a case–control study of risk factors in breast cancer patients. J Clin Oncol 2008;26: 4634–8. Vahtsevanos K, Kyrgidis A, Verrou E, Katodritou E, Triaridis S, Andreadis C, et al. Longitudinal Cohort Study of risk
factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. J Clin Oncol 2009;27:5356–62.
Kunimichi Niibe DDS, PhD* Takehito Ouchi DDS Ryotaro Iwasaki DDS, PhD Taneaki Nakagawa DDS, PhD Nobuyuki Horie DDS, PhD Department of Dentistry and Oral Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 150-8582, Japan *Corresponding author. Tel.: +81 3 3353 1211; fax: +81 3 3357 1593 E-mail address: [email protected] (K. Niibe) 18 July 2014 Available online 8 September 2014 http://dx.doi.org/10.1016/j.jpor.2014.08.001 1883-1958/# 2014 Japan Prosthodontic Society. Published by Elsevier Ireland. All rights reserved.
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/jpor
Letter to the editor Osteonecrosis of the jaw in patients with dental prostheses being treated with bisphosphonates or denosumab
Keywords: Medication-related osteonecrosis of the jaw (MRONJ) Bisphosphonate Denosumab Removable denture Fixed partial denture
Dear Editor, Bisphosphonates are used in the treatment of bone-resorbing diseases such as osteoporosis, malignancy-related hypercalcemia, multiple myeloma, and bone metastasis from solid cancers [1]. The treatment is administered orally for osteoporosis, and by intravenous injection for cancer metastasis cases. However, recent studies have reported instances of bisphosphonate-related osteonecrosis of the jaw (BRONJ), raising concerns for all dentists about this type of treatment. Although the developmental mechanism of BRONJ is still not fully understood, some studies have reported that BRONJ is caused by (1) apoptosis of osteoclasts [2]; (2) disturbance of osteoclast progenitor cell differentiation [2]; (3) disturbance of osteoclast enzyme activity [3]; (4) destruction of bone microstructure caused by drug deposition [4]; and (5) antineovascularization [5]. Denosumab (Ranmark1), an IgG2 monoclonal antibody that binds to receptor activator of nuclear factor-kB ligand (RANKL), is not a bisphosphonaterelated preparation, but some studies have reported complications of osteonecrosis of the jaw (ONJ) from denosumab [6]. Therefore, the ONJ has been recently termed medicationrelated ONJ (MRONJ) [7]. Although specific guidelines have been developed for treatment and prevention of ONJ [8], they are limited to symptomatic treatment or infection prevention, rather than fundamental prevention. According to the guideline, one of the risk factors of ONJ is a history of inflammatory dental disease [8]. The oral mucosal inflammation associated with ill-fitting dental prostheses is a common clinical case for prosthodontists; however, information on the occurrence of dental prosthesis-related ONJ is limited [9,10].
Indeed, no report has been found in the literature that investigates the incidence of MRONJ by denosumab in relation to dental prostheses. This gap in the literature prompted us to perform a pilot clinical study investigating the relationship between MRONJ and dental prostheses. This study was approved by the Ethics Committee of the School of Medicine, Keio University (Approval number: 20110018). Intended subjects were 424 patients (male: 125; female: 299) with a mean age of 64.8 years who were seeking treatment for dental problems at the Department of Dentistry and Oral Surgery, Keio University Hospital from June 2013 to May 2014. The subjects were already being treated with oral or intravenous bisphosphonates, or denosumab. To diagnose MRONJ, we applied the diagnostic criteria of the American Association of Oral and Maxillofacial Surgeons for definitive diagnosis of BRONJ [8]. A total of 21 cases of MRONJ were detected in the subjects (5.0%: 21/424 subjects). It should be noted that MRONJ was only found in subjects who were intravenously treated with bisphosphonates or denosumab (16.4%: 21/128 intravenous subjects). Among the 21 MRONJ cases, seven subjects were treated with zoledronic acid-hydrate (Zometa1) only, two subjects were treated with denosumab only, and 12 subjects had changed medication from zoledronic acid-hydrate to denosumab before they visited our dental clinic. Four cases of MRONJ were related to post-extraction dental sockets, and we could not explain the specific cause of MRONJ in nine cases in this study (Table 1). To examine the association between wearing a dental prosthesis and the occurrence of MRONJ, the 128 subjects who were intravenously treated with bisphosphonates or denosumab were separated into three groups: (1) no prosthesis (n = 60), (2) removable denture (RD: n = 34), and (3) fixed partial denture (FPD: n = 34). The incidence of MRONJ in the RD group was 32.4% (11/34 subjects), which is significantly higher than that in the no prosthesis group (8.3%: 5/60 subjects) (Table 1). Among the 11 MRONJ cases in the RD group, seven subjects had changed medication from zoledronic acid-hydrate to denosumab before they visited our dental clinic. These findings suggest that wearing an RD is a risk factor for MRONJ in patients being treated with bisphosphonates or denosumab intravenously. In the 11 RD-related MRONJ cases, the ONJ lesions were all observed in the tissue under the RD in the mandibular molar region. The fit of the RD was evaluated using either pressure indicator paste or a polyaddition-type silicone, and seven out of the 11 RD-related MRONJ cases were found to have an ill-fitting denture (Table 1). A
4
journal of prosthodontic research 59 (2015) 3–5
Table 1 – Clinical profile of 128 subjects being treated with intravenous bisphosphonates or denosumab. Dental prosthesis
Subjects
ONJ cases
Clinical features of ONJ With ill-fitting RD
No prosthesis RD FPD Total
60 34## 34 128
(45) (18#) (21) (84)
5 11** 5y 21
(5) (7*) (2) (14)
– 7 (5) – 7 (5)
In extraction socket 1 2 1 4
(1) (1) (1) (3)
With severe periodontitis 0 0 1 1
Undetermined cause 4 2 3 9
(4) (1) (1) (6)
ONJ: osteonecrosis of the jaw, RD: removable denture, FPD: fixed partial denture. Parentheses indicate the number of patients who were treated with denosumab only or those who had changed medication from zoledronic acid-hydrate to denosumab before they visited our dental clinic. Six (##) or three (#) of these subjects had both RD and FPD. A statistically significant difference (**p < 0.01, *p < 0.05) between ONJ cases in the RD group and the no prosthesis group, calculated with a Fisher’s exact test. yNote that all ONJ lesions in the FPD group (n = 5) were found under the pontic.
Fig. 1 – (A) A 60-year-old Japanese female who changed medication from zoledronic acid hydrate (ZAH) to denosumab for breast cancer. Osteonecrosis of the jaw (ONJ) was observed in the mandibular right molar region (left) under the ill-fitting removable denture (right). (B) A 67-year-old Japanese female being treated with ZAH for breast cancer. ONJ was observed under the pontic of the fixed partial denture associated with severe periodontitis in the maxillary first premolar region.
representative clinical case is shown in Fig. 1A. Interestingly, we found five ONJ lesions in the tissue under the FPD pontic (Table 1) in patients with breast cancer (two cases) and multiple myeloma (three cases) as the primary disease. Two of these MRONJ patients had changed medication from zoledronic acid-hydrate to denosumab before they visited our dental clinic. The incidence of MRONJ in the FPD group was 14.7% (5/34 subjects). It should be noted that all ONJ lesions in the FPD group were observed under the pontic. In one out of the five cases, the ONJ lesion was associated with severe periodontitis of the abutment tooth (Fig. 1B). Because dental extractions and a history of inflammatory dental disease are risk factors for BRONJ [8], denture use and recurrent lesions caused by ill-fitting dentures could be responsible for the occurrence of MRONJ in this study. Additionally, poor oral hygiene is thought to be a risk factor for BRONJ [8]; therefore, poor oral hygiene under the pontic may, in part, cause infection of the underlying mucosa. The mechanism by which MRONJ occurs in the region of the pontic is unclear; it would be valuable to analyze the pontic shape, distance to the gingiva, and dental hygiene in a future study. Future research should focus on factors such as bone metabolism, dental plaque retention, and mechanical trauma by the dental prosthesis to clarify the association of dental prostheses with MRONJ. In summary, this clinical survey showed that dental prostheses, such as RDs and FPDs, are a possible risk factor
for MRONJ in patients being treated intravenously with bisphosphonates or denosumab. However, the study population was relatively small, and thus the result may be specific to this study sample. Nevertheless, patients being treated with bisphosphonates or denosumab who use dental prostheses, not only RDs but also FPDs, should be encouraged to seek regular dental follow-up.
references
[1] Berenson J, Lipton A. Bisphosphonates in the treatment of malignant bone disease. Annu Rev Med 1999;50:237–48. [2] Hughes D, Wright K, Uy H, Sasaki A, Yoneda T, Roodman GD, et al. Bisphosphonates promote apoptosis in murine osteoclasts in-vitro and in-vivo. J Bone Miner Res 1995;10:1478–87. [3] Fisher J, Rogers M, Halasy J, Luckman SP, Hughes DE, Masarachia PJ, et al. Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro. Proc Natl Acad Sci U S A 1999;96:133–8. [4] Assael L. A time for perspective on bisphosphonates. J Oral Maxillofac Surg 2006;64:877–9. [5] Wood J, Bonjean K, Ruetz S, Bellahcene A, Devy L, Foidart JM, et al. Novel antiangiogenic effects of the
5
journal of prosthodontic research 59 (2015) 3–5
[6]
[7]
[8]
[9]
[10]
bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther 2002;302:1055–61. Smith M, Saad F, Coleman R, Shore N, Fizazi K, Tombal B, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet 2012;379: 39–46. Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, et al. Medication-related osteonecrosis of the jaw – 2014 update. Am Assoc Oral Maxillofac Surg 2014; 1–26. AAOMS. American association of oral and maxillofacial surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 2007;65:369–76. Kyrgidis A, Vahtsevanos K, Koloutsos G, Andreadis C, Boukovinas I, Teleioudis Z, et al. Bisphosphonate-related osteonecrosis of the jaws: a case–control study of risk factors in breast cancer patients. J Clin Oncol 2008;26: 4634–8. Vahtsevanos K, Kyrgidis A, Verrou E, Katodritou E, Triaridis S, Andreadis C, et al. Longitudinal Cohort Study of risk
factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. J Clin Oncol 2009;27:5356–62.
Kunimichi Niibe DDS, PhD* Takehito Ouchi DDS Ryotaro Iwasaki DDS, PhD Taneaki Nakagawa DDS, PhD Nobuyuki Horie DDS, PhD Department of Dentistry and Oral Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 150-8582, Japan *Corresponding author. Tel.: +81 3 3353 1211; fax: +81 3 3357 1593 E-mail address: [email protected] (K. Niibe) 18 July 2014 Available online 8 September 2014 http://dx.doi.org/10.1016/j.jpor.2014.08.001 1883-1958/# 2014 Japan Prosthodontic Society. Published by Elsevier Ireland. All rights reserved.
