Advanced Peri-Implantitis and Implant Removal as Risk Factors for Osteonecrosis of the Jaw in Patients on Oral Bisphosphonate Therapy

Currently, peri-implant disease is a significant issue in dentistry. According to a systematic review, the prevalence of peri-implant mucositis and peri-implantitis was 46.8% and 19.8%, respectively,¹  which indicates that dentists encounter peri-implant diseases frequently in clinical settings.

The worst case scenario in patients with peri-implant disease is the loss of dental implants. Many cases necessitate implant removal because of severe bone destruction with various degrees of inflammation around the dental implant. This may lead to potential adverse events associated with certain systemic conditions, especially when patients are on antiresorptive drugs, such as bisphosphonates.

Presently, many dentists are well aware of complications posed by bisphosphonate-related osteonecrosis of the jaw (BRONJ) or medication-related osteonecrosis of the jaw (MRONJ) in the context of oral surgery. Thus, prior to implant surgery and/or bone augmentation surgery, a history of relevant medication use should be acquired for patient safety. Clinical guidelines for a patient with bisphosphonate medication scheduled for an oral surgery propose a drug holiday before the implant surgery or a treatment option other than dental implant.²  However, limited data are available to validate and support this guideline.

In a clinical setting, dental practitioners encounter the following situations: after successful osseointegration of the dental implant, peri-implantitis develops and progresses with time. This further leads to implant removal despite the attempts to treat the disease. In the meantime, some of the patients start (or restart) therapy with antiresorptive drugs after osseointegration of the dental implant. This situation is complicated because the peri-implantitis affects the bone tissue, leading to a potentially increased risk of osteonecrosis of the jaw (ONJ) associated with antiresorptive drugs. Conceivably, dental implant removal in such cases results in an increased risk of developing ONJ.

Hence, this case report aimed to present cases of BRONJ associated with advanced peri-implantitis and implant removal. This report hopes to improve awareness among dentists on the increasing incidence of this newly emerging complication.

A 70-year-old woman underwent dental implant treatment in the right mandibular posterior region in 2002 (#29: Zimmer TSV, 3.8 mm × 10 mm and #31: Steri-Oss, 6.0 mm × 10 mm). After final prosthesis insertion, she visited the dental clinic on a yearly basis for follow-up. In 2017, the patient complained of pain in the right mandibular posterior region and an inability to chew food on this side. She had been on a prolonged regimen of corticosteroid therapy for chronic arthritis, and before the corticosteroid therapy, she was on alendronate therapy (Fosamax; per os) for >5 years for osteoporosis.

On radiographic and clinical examination, the #31 implant was diagnosed with peri-implantitis and implant removal was scheduled. Prophylactic antibiotic (amoxicillin, 2 g) was administered 1 hour before the implant removal. The area between the #30 pontic and #29 implant prosthesis was cut with a bur and the #31 implant was easily removed with dental forceps, without resistance. Gentle debridement was performed using a surgical curette. An antibiotic (Cefaclor, 375 mg; Yuhan Pharmaceutical Co.) was prescribed and instructions were provided for mouth gargle with 0.12% chlorhexidine solution.

One week later, the patient presented with persistent pain and swelling in the affected region. On examination, wound healing was found to be delayed. Antibiotic administration and chlorhexidine mouth gargle were repeated approximately for 8 weeks, but without any symptomatic improvement and further worsening of the symptoms. The patient developed numbness in the lip, and subsequently, was referred to a university hospital for further treatment. The patient was advised an antibiotic treatment, and a surgical curettage was performed. Eventually, she died 4 months thereafter.

A 73-year-old woman underwent dental implant treatment in 2003 (Steri-Oss Inc.). She visited the dental clinic once a year for follow-up. In 2019, she presented with implant mobility (#30 and #31) in the right posterior mandibular region. On radiographic and clinical examination, a peri-implant lesion was observed. She had been on alendronate therapy (Fosamax; per os) since 2017 for vertebral osteoporosis. An implant removal surgery and post-operative pharmacotherapy, similar to that described in case 1, were performed. The patient presented with mucosal swelling and pain after 1 week, with pus discharge after 2 weeks, and with a burning sensation after 2 months postoperatively. Antibiotic treatment was ineffective during these 2 months. Cone-beam computed tomography was performed, which revealed extensive bone destruction reaching the inferior alveolar canal. The bony sequestrum was removed surgically under local anesthesia. However, delayed wound healing was found and the patient was referred to a university hospital. Histopathological examination of the retrieved sequestrum exhibited necrotic bone with a number of inflammatory cells.

A 57-year-old woman underwent dental implant treatment in the left mandibular posterior region in 2008 (HA-coated Zimmer TSV implants, Zimmer Biomet). She did not attend regular dental follow-ups. In 2014, she visited the dental clinic with chief complaints of dental implant mobility and pus discharge. Panoramic radiographs revealed progressive bone resorption up to the apical end of the implants. Since 2012, the patient had been on alendronate therapy (Fosamax; per os) for osteoporosis. The implant removal surgery and postoperative regimen was similar to that described in case 1. The patient's symptoms persisted, and the antibiotic regimen was further extended for 4 weeks, but without any improvement.

Hence, the patient was referred to a university hospital and was treated with surgical curettage under general anesthesia, followed by another 4 weeks of antibiotic therapy. Thereafter, the patient's symptom progressively alleviated. Panoramic radiograph performed 5 months postoperatively revealed bone filling in the implant removal site.

A 75-year-old woman underwent dental implant treatment in the anterior region of the mandible (hydroxy-apatite-coated Zimmer TSV implants, Zimmer Biomet) in 2012. She did not attend regular dental follow-ups after the insertion of the final prosthesis. Five years later, the patient visited the dental clinic with a chief complaint of pus discharge. Panoramic radiograph revealed moderate bone resorption on the #25 implant. She had controlled hypertension and diabetes mellitus. The patient had started alendronate therapy (Fosamax; per os) 2 years ago for the prevention of osteoporosis.

Three consecutive non-surgical treatments were performed; however, the pus discharge persisted, and the patient insisted on implant removal. An implant removal surgery, as described in case 1, was performed; presently, however, a trephine bur was used for implant removal. Antibiotic was prescribed for 6 weeks postoperatively. However, the pus discharge persisted. Panoramic radiographs acquired at 4 months after implant removal showed increased bone destruction with bony sequestrum. The bony sequestrum and granulation tissue were removed surgically under local anesthesia. Thereafter, the patient's symptom gradually improved, and mucosal and bony healing occurred.

This report described the cases of 4 patients who developed BRONJ in relation with implant removal because of peri-implantitis. The distinct findings of this study are as follows: (1) peri-implantitis-derived implant removal could be a significant contributor to BRONJ; (2) initiation of bisphosphonate therapy during the implant functioning period could induce the risk of BRONJ in patients who were previously not at risk during the implant surgery; and (3) oral bisphosphonate therapy, even for short duration, could precipitate BRONJ in patients with peri-implantitis.

BRONJ was first reported by Marx in 2003,³  followed by a number of reports demonstrating the risk of ONJ not only by bisphosphonates but also by other antiresorptive drugs. The reported prevalence of BRONJ in patients on antiresorptive drugs ranged between 0.1% and 20%.⁴  The risk factors for BRONJ include dental extraction, irritation due to dentures, and prominent bony structures with thin overlying mucosa. Spontaneous occurrence of BRONJ has also been reported.⁵  The risk of BRONJ increase with the following conditions: intravenous administration,⁶  high dose,⁷  and longer duration of bisphosphonate medication,^8,9  and cases of malignant/metastatic cancers.⁴ 

Most of the studies on dental implants have focused on the success rate of the implant (or implant loss) and incidence of BRONJ after implant surgery in the patients on bisphosphonate medication; however, limited data are available on the correlation between peri-implantitis and BRONJ,¹⁰  although the mere presence of a dental implant is considered to trigger BRONJ.^6,11  Nonetheless, peri-implantitis, as “a breach,” could initiate BRONJ because the inflammatory connective tissue lesion in peri-implantitis cases is relatively large; moreover, the lesion is close to the alveolar bone, and includes a higher number of osteoclasts and neutrophils.¹²  Hence, implant removal in patients with peri-implantitis could be detrimental for BRONJ when compared with tooth extraction. Previous studies have reported cases of BRONJ after implant removal;^13–16  however, peri-implantitis was identified as the cause in only 2 cases of implant removal. In other implant removal cases, peri-implantitis was not specified or reported. However, in this case report, it is possible that the BRONJ developed first and the lesion, which resembled peri-implantitis, was detected later. Alternatively, the removal of the implant with peri-implantitis might have caused BRONJ; this aspect needs to be investigated further (Table 1).

Currently, many dental practitioners are well aware of BRONJ, and possibly about MRONJ, in relation with implant surgery. However, some of the patients who received implant may start bisphosphonate medication or other antiresorptive drugs after the implant placement. Because of prolonged life expectancy, development of BRONJ is highly possible and the number of such patients could increase. In this case report, all patients started the intake of alendronate per os after 3–14 years of post-implant osseointegration, indicating that constant update of medical status is important. Especially, cases 3 and 4 did not follow up at the clinic after final prosthesis delivery. Hence, for these patients, updated medical status was not available; thus, information regarding bisphosphonate medication and potential complications could not be acquired.

According to the position paper by the American Association of Oral and Maxillofacial Surgeons, there is no clear evidence to support the benefits of drug holiday for osteoporotic patients, except for those with extended bisphosphonate exposure (>4 years).²  This finding was further verified in a systematic review by the fifth European Association for Osseointegration, which concluded that low dose of oral bisphosphonate, administered for the management of osteoporosis, generally does not deteriorate implant treatment.¹⁰  However, all patients in this case report, except patient 1, were on alendronate per os for less than 3 years. No other contributory medical history was reported in these patients. As described earlier, this could indicate that peri-implantitis modifies the local environment around the dental implant, resulting in high susceptibility to BRONJ following surgical interventions, such as implant removal.

The treatment protocol for BRONJ/MRONJ is yet to be established. Generally, conservative treatment with antibiotics is initiated first; thereafter, surgical interventions, such as necrotic bone removal and sequestrectomy, are performed in patients with persistent pain, pus discharge, and radiographic findings of sequestrum formation.^2,14  All patients in this study followed this treatment sequence, but none of the patients were managed with conservative treatment. All of them eventually required surgical intervention, and only 1 patient could be treated in the clinical setting of the private practitioner. The reasons for this variation could be due to varying clinical experience in BRONJ management, such as long period with medication, delay in surgical intervention, and the choice of surgical method.

Peri-implantitis-associated BRONJ should be carefully monitored, particularly in the environment having medical and social conditions similar to those prevalent in South Korea. South Korea has the highest number of dental implants placed per 10 000 patients globally.¹⁷  Moreover, 2 implants are financially supported by the national insurance system for senior citizens aged ≥65 years in their lifetime, which may drive senior citizens with various systemic conditions to undergo dental implant treatment. Further, there is a high preference for prescribing bisphosphonates for the management of osteoporotic condition in South Korea.¹⁸  High incidence of BRONJ was found in a multicenter survey in South Korea,¹⁹  and oral bisphosphonate was related to approximately 80% of BRONJ cases.²⁰ 

This study demonstrated that peri-implantitis and implant removal could precipitate BRONJ even in patients on oral bisphosphonate therapy. Owing to the initiation of bisphosphonate medication in a patient's later life and because of an increasing number of patients fitted with dental implant, constant update of the medical status should be performed to prevent detrimental BRONJ.

Abbreviations

BRONJ:

bisphosphonate-related osteonecrosis of the jaw

MRONJ:

medication-related osteonecrosis of the jaw

ONJ:

osteonecrosis of the jaw

The authors report no conflicts of interest.