Medication-Related Osteonecrosis of the Jaw Subsequent to Peri-Implantitis: A Case Report and Literature Review

Bisphosphonates (BPs) are drugs that inhibit bone resorption by suppressing osteoclasts. They have been widely used to treat osteoporosis, malignancy-associated hypercalcemia, and osteodynia associated with bone metastasis of a solid cancer (eg, breast cancer), multiple myeloma-associated bone diseases, Paget's disease of bone, and osteogenesis imperfect¹ BP-related osteonecrosis of the jaw (BRONJ), which has serious side effects in the jawbone. This was first reported by Marx in 2003.²  Subsequently, osteonecrosis of the jawbone associated with the anti-receptor activator of nuclear factor-kappaB ligand antibody denosumab and angiogenesis inhibitors was reported and has been renamed medication-related osteonecrosis of the jaw (MRONJ) in a recent position paper of the American Association of Oral Maxillofacial Surgeons.¹  MRONJ onset after starting a BP was slower in osteoporosis patients than in cancer patients.^1,3,4  It was also reported that the incidence of ONJ in patients prescribed oral BPs for the treatment of osteoporosis ranged from 1.04 to 69.0/100 000 patient-years, whereas the incidence in patients with prescribed intravenous BPs ranged from 0 to 90/100 000 patient-years.⁵  The number of patients taking oral BPs for osteoporosis treatment has been increasing in recent years, and it is predicted to create serious dental problems.

Local risk factors that cause MRONJ have been identified as dental infections, such as apical lesions and untreated periodontal disease. In addition to surgical invasion due to tooth extraction, it has been reported that implant surgery during and after BP treatment is a risk factor for MRONJ.^6–8  There have been only a few reports on the pathogenesis of MRONJ that develops around the already osseointegrated implants or that has been subsequent to peri-implantitis, and the details have not been clarified. We present a rare case of MRONJ subsequent to peri-implantitis in a patient who had been taking alendronate sodium hydrate, an oral BP, during long-term implant maintenance.

A 73-year-old woman presented at our Nihon University School of Dentistry dental hospital in May 2017 with a chief complaint of discomfort around the maxillary implant. The patient had medical histories of type 1 diabetes, subtotal gastrectomy for a gastric ulcer in 1998, and colorectal cancer in 2003. The patient did not have a smoking habit and was in good health. She had experienced menopause in her mid-50s.

The patient was first referred to our periodontology department in 2006 for periodontal disease treatment. She was diagnosed with generalized chronic severe periodontitis (stage IV, in the molar area, grade B according to the diagnostic criteria of the American Academy of Periodontology & European Federation of Periodontology^9,10) (Figure 1). After the initial 7 months of periodontal treatment, with her type 1 diabetes stable, 2-stage implant surgery was planned. The implants were placed according to the manufacturer's recommended protocol under intravenous sedation (Micro Thread 4.5ST; Astra Tech AB; #14: 11 mm, #16: 9 mm, #35: 11 mm, #36: 9 mm). The superstructures were created using porcelain fused to both metal crown and bridge. Subsequently, they were fixed with a side-screw system (Figure 2). It is worth noting that the patient did not request prosthetic treatment of all second molars owing to financial reasons. After confirming that periodontal and peri-implant tissue were stable, maintenance treatment began in June 2007 (Figure 3).

The patient's papillary thyroid carcinoma was diagnosed in 2012, and hemithyroidectomy and conservative neck dissection were performed at a university hospital. Postoperative thyrotropin-suppression therapy with levothyroxine sodium hydrate (Thyradin-S tablets 75 μg; ASKA Pharmaceutical Co, Ltd) once daily was prescribed to prevent recurrence. Additionally, oral BP was prescribed for hypercalcemia and osteoporosis due to hyperparathyroidism. Alendronate sodium hydrate (Fosamac tablets, 35 mg; Merck & Co) once for a week was also prescribed and not stopped until she was seen by us in 2017.

The patient complained of discomfort in the right upper molar region during maintenance in April 2016. Intraoral examination revealed diffuse redness and swelling in the #14 and #16 peri-implant mucosa. Purulent discharge from the pocket of #14 implant was also recognized (Figure 4a). To simplify our evaluation, we removed the superstructure, during which the depth of the probing was 6 mm all around it, resulting in bleeding (Figure 4b). Radiological findings showed diffuse vertical bone resorption extending one-third of the implant length at mesial and distal sites (Figure 4c). These findings led to a diagnosis of peri-implantitis.¹¹  Later, the superstructure was again removed to make it easier to access the implant surface for non-surgical debridement using a titanium hand scaler. After healing had been ensured via systemic antibacterial therapy, the cleaned superstructure was reset, and maintenance treatment began.

One year after treatment for peri-implantitis of the maxillary right molar (May 2017), the patient contacted us because the implant superstructure had detached from its abutment. Clinical findings were redness, mucosal swelling around the implant, and #16 implant mobility. The #16 implant was easily and painlessly removed using a finger. It was observed that bone-like tissue was attached to the implant's rough surface (Figure 5). Dental cone-beam computerized tomography (CBCT) revealed that the alveolar bone around the #16 implant was largely absorbed, with partial rupture of cortical bone continuity, and reaching the sinus with thickening of the sinus mucosa. Additionally, a rough, opacity resembling sequestrum was seen around the #14 implant (Figure 6). The necrotic bone tissue was sent for pathological examination. The results showed lamellar bone with an empty osseous lacuna and necrotic tissue with a bacterial clot in the area of the bone marrow cavity. Granulation tissue with partial epithelialization was also found (Figure 7). MRONJ (stage 2) subsequent to peri-implantitis was diagnosed.

The #14 implant was removed prior to sequestrectomy to increase mobility. Clarithromycin, 200 mg (Clarith tablets 200; Taisho Pharmaceutical Co, Ltd) was prescribed for 14 days twice a day because right maxillary sinusitis occurred simultaneously with ONJ progression, although the patient's nasal symptoms and thickening of the sinus mucosa were alleviated. Because of the spreading bone necrosis, including the removed #14 implant, sequestrectomy of the area was planned.

The patient was informed that resection might worsen the MRONJ, but it was necessary to remove the infection site early, while continuing the osteoporosis treatment. She agreed to the proposed measures. Hence, the alendronate sodium hydrate, which she had been taking continuously for about 4 years (since 2013 after thyroid surgery), was changed to raloxifene hydrochloride (Evista, 60 mg tablets; Eli Lilly) once a day in May 2017. It was discontinued once before the sequestrectomy surgery 4 months later. Serum calcium levels remained constant within the standard range (8.2–8.7 mg/dL) throughout these drug changes. In contrast, control of her type 1 diabetes had gradually worsened since 2014 when she had started using insulin injections (Humalog injection, 100 units/mL) via insulin pump therapy. There had been no complications (eg, retinopathy, neuropathy), and her HbA1c level at the preoperative examination was 8.4%.

A plan was made to remove the insulin pump device during the operation because acute attacks are manageable by intravenous injection. Clarithromycin was given twice a day for 9 days as antimicrobial prophylaxis.

Sequestrectomy and maxillary sinus lavage were performed under general anesthesia in September 2017. The area to undergo sequestrectomy was determined from preoperative CT images. The bone resection area included only sites where bleeding could be confirmed intraoperatively. The wound was completely closed using a mucoperiosteal flap because vertical bone resorption had extended to the bottom of the maxillary sinus.

The postoperative course was considered good, and the stitches were removed 1 week postoperatively with no observed recurrence of inflammatory symptoms. Oral administration of raloxifene hydrochloride (Evista, 60 mg tablets, once a day) was resumed postoperatively. To date (October 2019), there have been no findings to support relapse of the MRONJ. The treatment course and the patient's condition were classified as good, and there have been no unpleasant events for a year after the sequestrectomy. A removable partial denture has been adopted, and gradual progress has ensued (Figure 8).

Since the concept of osseointegration (wherein titanium is directly connected to bone tissue) has been accepted,¹²  dental implants have made great progress and have become beneficial to oral health. Because of their structure, however, implants also pose the risk of allowing bacterial invasion into internal tissues, such as connective and alveolar bone tissue, wherever implants exist in the oral epithelium. Peri-implantitis is a nonspecific, suppurative inflammation in the peri-implant tissue due to an oral bacterial infection. Clinical symptoms are characterized by pus drainage, peri-implant tissue bleeding, and alveolar bone resorption. If the infection becomes severe, the implant must be removed, thereby impairing the patient's quality of life.¹¹  There are many unknowns about peri-implantitis despite its having an onset mechanism and clinical symptoms similar to those of periodontitis, which is mainly caused by plaque infection.

BPs are bone resorption inhibitors. Once deposited in bone, BPs are specifically taken in by osteoclasts, and later released into the serum in an acidic environment. Bone resorption and remodeling are suppressed, leading to apoptosis by the osteoclasts, which contain BPs.¹³  Although the pathophysiological pathogenesis mechanism of MRONJ that develops characteristically in the jawbone has not been clarified, the involvement of inflammation and infection has been discussed, as have changes in the bone remodeling response, excessive bone resorption, inhibition of angiogenesis, continuous minor trauma, immunodeficiency, vitamin D deficiency, and the toxicity of BP to soft tissue.^1,14,15  Because the peri-implant environment is considered prone to chronic inflammatory conditions, it is speculated that peri-implant MRONJ is more likely to develop because the immune function is weaker than when natural teeth are in place, and a strong occlusal force tends to act.

Risk factors for developing MRONJ are generally linked to the following factors: drugs; local and/or systemic factors; and genetic factors. Drug-related MRONJ often occurs in patients medicated with oral alendronate as a bone resorption inhibitor for hypercalcemia and osteoporosis associated with hyperparathyroidism. Alendronate, a second-generation BP, contains nitrogen and is estimated to be 10–1000 times more active than first-generation BPs. The third-generation zoledronate is even more potent at inhibiting bone resorption.¹⁶  Generally, BP injection used as cancer treatment has high absorption efficiency. Thus, at high doses, the risk of osteonecrosis of the jaw is estimated to be greater with an injected BP than when it is given orally. The number of osteoporosis patients in Japan, a super-aging society, has risen to 1,280,000, and oral BP users will likely increase as well.¹⁷  In the future, we must pay attention to any further increase in MRONJ patients who are taking an oral BP given its current lower incidence.

Regarding the administration period of oral BPs, the risk of developing MRONJ has previously increased from 3 years to 4 years, as reported in a recent position paper.¹  A previous study of 13 000 people using long-term oral BPs reported that BRONJ prevalence was 0.1% but, when calculated over a 4-year period, the incidence increased to 0.21%.¹⁸  In our patient, MRONJ developed 4 years after starting an oral BP, implying that the cumulative use of BPs over a long period might have had an effect.

Local factors leading to MRONJ include invasive dental treatment, such as tooth extraction and implant surgery. It is difficult to regard implant surgery as a local factor in the present case, however, because the implant treatment was completed several years before the patient started taking the oral BP. It was previously reported that the incidence of MRONJ was low after implant surgery on healthy jawbone.¹⁹  Likewise, inflammatory lesions appearing as apical and marginal periodontitis has been proposed to have a greater effect on MRONJ development than the surgical invasion of tooth extraction in recent years.²⁰  In our patient, the implant treatment was performed after we confirmed clinical improvement of periodontal tissue in response to the initial periodontal treatment. Although the patient was constantly undergoing maintenance treatment, peri-implantitis developed in the #14–#16 area during the 8 years after maintenance began. Active surgical therapy was not performed to alleviate peri-implant inflammation despite recognizing bleeding in ∼6-mm pockets and redness of the peri-implant tissue due to the patient having taken oral BPs at that time. Fortunately, clinical improvement was obtained by cleaning out the removed superstructure and non-surgical therapy. Frequent maintenance was planned with the patient's grateful approval.

Histopathological examination revealed bacterial accumulations in the sequestrum, but we did not identify the bacterial genus and species. A wide variety of oral bacterial infections have been reported due to the bacterial flora of peri-implantitis.²¹ Coriobacterium, the major genus of actinomycetes, is one of the bacterial species specific to peri-implantitis. Some studies have detected actinomycetes in MRONJ lesions,²²  suggesting that similar bacterial species may be involved in the development of both peri-implantitis and MRONJ. As for MRONJ having a relatively low incidence despite the increase in BP users, it may be because of the differences in the bacterial infections in the oral cavity.

Although the present patient does not suffer from bruxism, it has been noted that implants at the most distal location are subjected to excessive bite force, thus implying that the inflammatory response may worsen due to excessive occlusal force acting on peri-implant tissues, which could be harmful as a modifier after endogenous infection of dental plaque. In our case, the symptoms of peri-implant inflammation were identified in the #16 implant located at the most distal point, suggesting that it might be related to an occlusal load.

Considering the aforementioned suppositions, it was hypothesized that certain factors in MRONJ development contribute to chronic inflammation, and, subsequently, that occlusal force activated remodeling of the bone tissue. Thus, it became easy to accumulate BP in the local environment.

Considering the systemic factors and that MRONJ developed at age 72 years, previous cohort surveys reported an increased risk of onset at age 65 years and older.²³  It is surmised that the risk of developing breast cancer and osteoporosis increases with age even if aging is currently not a definitive systemic factor for MRONJ. Whether diabetes is a risk factor for developing MRONJ has not reached a consensus,^5,24  although an immunocompromised state due to diabetes has been speculated to be a risk factor for peri-implantitis.²⁵  In the present patient, it was implied that type 1 diabetes affected MRONJ development at the site that had been locally infected. Regarding concomitant drugs, the patient was not medicated on corticosteroids, angiogenesis inhibitors, or immunosuppressants, which have been reported associated with an increased risk for developing MRONJ. However, levothyroxine sodium hydrate to diminish thyroid hormone and ethyl icosapentate for hyperlipidemia were administered.

Genetically, an association of single nucleotide polymorphisms (SNPs) during MRONJ onset has been reported,²⁶  although no further genetic diagnostic tests were performed because none of the relatives of the patients had a history of this disease.

The present study searched for articles published until 2019. The databases Medline via PubMed was searched. As a result, from all 67 articles that fit these circumstances, hand search was performed for cases that MRONJ was developed in functioning implants. Five case reports were hit in the past 10 years. Most of the previous patients with peri-implant-related MRONJ who were operated on because of the onset of jawbone necrosis while using BPs had their MRONJ triggered by an implant surgical procedure.^27,28  However, as in the present rare case studies, there have been a few reports of patients who developed peri-implant MRONJ after beginning oral BP treatment^29–33  (Table 1). The results of other studies are shown in Table 2. It is anticipated that many cases involving BP intake that started after implants were already functioning will be reported in the future.

A recent systematic review showed that a history of oral or intravenous BP use is not an absolute contraindication for dental implant placement, and osseointegration can be achieved even among those patients.³⁶  Another review reported that implant treatment is possible if it can meet 3 criteria: (1) preoperative antibiotics are administered; (2) bone augmentation is avoided; (3) satisfactory oral hygiene is maintained.³⁷ 

In this case presentation, it was suggested that MRONJ development was caused by multiple factors attributable to BP accumulation released during a previous bout of local inflammation with persistent peri-implantitis after local infection in an environment where the immune function was depressed by type 1 diabetes. In situations where implant maintenance is prolonged with widespread implant treatment, cases of BP intake for treatment of osteoporosis may increase in the future. The risk of developing peri-implant MRONJ in patients taking BPs should be recognized. Moreover, such patients' implants should be carefully monitored. Similarly, one must keep in mind that the incidence of systemic diseases will increase in our super-aging society. It is therefore suggested that more attention must be paid to local infection control during implant maintenance.

We documented a case of peri-implant MRONJ in a 73-year-old woman. The patient underwent implant removal and sequestrectomy, with no postoperative recurrence. The conditions of this case imply that the local infection around the already osseointegrated implant and type 1 diabetes are factors in MRONJ development. We summarized the case and included a literature review on the pathogenesis of MRONJ.

Abbreviations

BPs:

bisphosphonates

MRONJ:

medication-related osteonecrosis of the jaw