Medication-related osteonecrosis of the jaw (MRONJ) is a serious concern for dentists as well as maxillofacial surgeons. Therefore, the safety of dental implant placement in patient receiving antiresorptive drugs (ARDs) has been the subject of controversial debate for several years and remains a source of uncertainty for surgeons and patients. This consecutive case series assessed the clinical and radiographic outcomes of dental implants placed in patients under antiresorptive therapy. Patients who received at least one dental implant at the Department of Oral and Maxillofacial Surgery, Ludwig Maximilian University (LMU), Munich, Germany, between 2010 and 2019 with a history of current or past antiresorptive medication were included the study. The main outcomes were occurrence of MRONJ, implant success, and survival rate. A total of 16 patients were treated with 39 implants. No implant loss or MRONJ occurred in the respective patients. The reasons for antiresorptive intake were osteoporosis, malignancy, edema of bone marrow, or diffuse sclerosing osteomyelitis (DSO). MRONJ occurred neither around implants nor in other locations. Cumulative implant success was 92.6% (25 of 27). No subjective complaints or postoperative complications were documented. Mean bone loss was 0.60 ± 0.98 mm. The prevalence of peri-implantitis was 30% on patient level and 29.6% on implant level. None of the patients had failed implants. No major complications after implant placement under antiresorptives could be detected. As long as implant surgery follows a specific protocol, implant placement in patients treated with antiresorptive therapy seems to be safe and predictable.
Medication-related osteonecrosis of the jaw (MRONJ) is a well-known and potential side effect in patients receiving antiresorptive drugs (ARDs) as bisphosphonates or denosumab for various skeletal diseases.1,2 These drugs increase quality of life of those patients by significantly preventing fractures and other skeletal related events3–5 by inhibiting osteoclast activity and reducing bone turnover.2,6,7 In acidic environments such as inflammatory processes, the locally destructive effects of ARDs are strengthened.6,8 The potential risks factors of MRONJ are high doses of the drug, long-term application, certain comorbidities, poor oral hygiene, periodontitis, and ill-fitting prostheses.2,9 Initially, surgical trauma has also been reported as one of the most important possible risk factors for the development of MRONJ.10,11 Therefore, the safety of dental implant placement in these patients has been the subject of controversial debate for several years and remains an ongoing source of uncertainty for dental as well as oral and maxillofacial surgeons.
As osteoporosis predominantly occurs in older patients, the combination of an aging population and the rising interest in dental implants should be incentive to clear the uncertainty surrounding dental implant safety. Furthermore, tooth loss and complete edentulism might be in the decline,12 but still limit the oral health related quality of life of those concerned.13,14 Currently, dental implants are a common and safe therapeutic option in healthy patients with a survival rate of up to 97%15,16 and offer high patient satisfaction.12 However, for patients under antiresorptive medication, there were reviews with sparse literature and low levels of evidence.17,18
A few studies have correlated dental implant surgery with a higher risk of MRONJ19–21 while several others found no increased risk.22,23 Current German guidelines warned of dental implant surgery in patients treated with ARDs, especially in osteoporosis patients.24 An individual risk assessment is recommended regarding the underlying disease, the respective ARDs including their application mode or dosage, and other risk factors such as co-medications.25 The individual risk of MRONJ should be discussed with the patient before getting their consent.
Therefore, the purpose of this study was to investigate the clinical outcome of dental implant surgery in patients treated with antiresorptive therapy and determine whether it is possible to place the dental implants safely in those patients.
Materials and Methods
This study was a consecutive case series and conducted according to the fundamental principles of the World Medical Association Declaration of Helsinki. The study was approved by the Local Ethics Committee of Ludwig Maximilian University, Munich, Germany (EK18-690, LMU Munich). All patients were enrolled in the study after they had been informed of the study objectives and had signed a consent form. Patients took part in routine follow-up examinations including radiographic imaging and consented to anonymous use of the obtained data for the purpose of this study. This study was reported according to the STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) guidelines.26 The methodology was reviewed by an independent statistician.
Inclusion and exclusion criteria
The records of the 16 consecutive patients who had undergone implant surgery between 2010 and 2019 at the Department of Oral and Maxillofacial Surgery and Facial Plastic Surgery, Ludwig Maximilian University, Munich, Germany, were screened thoroughly.
Inclusion criteria were: (1) partially or completely edentulous patients with a history of current or past antiresorptive medication, (2) received at least 1 dental implant, (3) a follow-up of at least 1 year.
In accordance with the updated MRONJ definition by the American Association of Oral Maxillofacial Surgeons,27 exclusion criteria included the following: (1) history of radiation therapy to the head and neck area, (2) obvious metastatic infiltration of the jaw, (3) bone exposure or fistula at the time of intended implant surgery. No control group was included.
Surgical and postsurgical protocol
Preoperative orthopantomogram (OPG) or cone beam computerized tomography (CBCT) radiographs were performed. If necessary, extractions and periodontal treatment or scaling were performed at least 10 weeks before implant surgery.
The surgical procedures were performed following a standardized protocol by experienced oral or maxillofacial surgeons (SO and MT). The intervention was performed minimizing the soft tissue and bone trauma and under antibiotic coverage. Briefly, prophylactic systemic antibiotics (amoxicillin/clavulanic acid 875 mg/125 mg or, in case of allergy, clindamycin, 600 mg) were administered 1 day preoperatively and continued for 5–7 days postoperatively. An antiseptic mouthwash of 0.2% chlorhexidine (Dynexidin Forte solution, Chemische Fabrik Kreussler & Co, Wiesbaden, Germany) was used immediately before surgery and for 2 weeks after the surgery. An intraoral incision was performed with atraumatic reflection of a full-thickness mucoperiosteal flap under local anesthesia (Articain hydrochlorid and 1:200.000 Epinephrinhydrochlorid, Ultracain D-S, Sanofi-Aventis, Germany). The implant site was prepared in accordance with the protocol recommended by the respective implant company. In hard bone, a pilot drill was used for guidance of the drills before implant insertion to minimize lateral force on the bone. The inserted implants were placed submerged with the shoulder at the alveolar crest level. Finally, tension-free primary wound closure was performed by repositioning and suturing of the mucoperiosteal flap using Seralon 4/0 sutures (SERAG-WIESSNER, Naila, Germany) or Serafit 4/0 (SERAG-WIESSNER, Naila, Germany). All patients received routine postoperative instructions and the same postoperative analgesic drug (ibuprofen 600 mg) were administered for 2–3 days (1-1-1) and then on demand.
Final wound inspection and suture removal were performed 10 days after surgery. The implants were exposed at a minimum of 2 months after placement. Prosthodontic treatment was executed by the referring dentists according to general tooth condition and patient needs.
The follow-up examinations were performed initially at 1, 3, and 6 months and then once per year and the results were documented in the patient charts. Early follow-up included subjective complaints and wound healing. At a later stage, implants were assessed for bleeding on probing, probing pocket depths, gingival recession, implant mobility, sensitivity to percussion, overall oral hygiene, and further parameters. All occurring complications were treated by experienced oral maxillofacial surgeons.
Standardized radiographic images (OPG) were taken for each implant at day of implant insertion or at suture removal and at the regular follow-up.
The data retrieved from medical records were demographic data, history of bisphosphonate/antiresorptive medication therapy, underlying disease, as well as other systemic illnesses and risk factors.
Marginal bone loss was evaluated under standardized conditions with newly calibrated imaging software (SIDEXIS XG, Version 2.63, Sirona Dental Systems, Bensheim, Germany). Implant measurements were used as a reference for calibration. The standardized radiographic images (OPG or periapical) taken after implant insertion served as initial radiographs for this study. The most recent panoramic radiographs were used to measure the current bone level. Bone loss was calculated by marginal bone level changes mesial and distal to the dental implant using the initial and the most recent radiograph. The larger difference of both calculations, mesial and distal, of the implant was used as the bone loss for this implant.
The primary outcome of the study was onset of MRONJ defined according to the American Association of Oral and Maxillofacial Surgeons (AAOMS) position paper on MRONJ in 2014.27 Staging of the disease was also performed according to AAOMS criteria: implant loss and other specified implant failure (eg, material fracture, prosthetic failure) were assessed. The Health Scale for Dental Implants (HSDI) suggested by Misch et al28 (Table 1) was used to rate implant success.
Secondary outcome variables are subjective complaints (eg, prolonged or persisting pain), postoperative complications (eg, wound dehiscence), bone loss, and peri-implant health were further assessed outcome variables. Peri-implantitis was diagnosed as (1) presence of bleeding on gentle probing or exudation and (2) radiographic bone loss exceeding 0.5 mm.
The data was presented as qualitative data expressed as percentages or quantitative data expressed as mean values including standard error of the mean and range. Descriptive statistical analysis was performed using SPSS (IBM SPSS Statistics for Windows, Version 26.0; IBM Corp, Armonk, NY).
Results were reviewed by an independent statistician where 16 patients (15 female, 1 male) with a mean age of 70.8 ± 7.48 years at the time of implant placement with 39 implants were assessed. Duration of the 39 implants in each patient's mouth was 2.66 ± 2.13 years (minimum: 3.5 months; maximum: 9.33 years). None of the patients complained of pain, peri-implantitis, or implant loss. Six patients (37.5%) with 12 implants (7 Straumann, 4 Thommen, 1 Camlog) were lost in follow-ups due to compromised general health or no complaint from the placed implant.
Ten patients (9 female, 1 male) were finally included in the study with a mean age of 69.40 ± 7.06 years at the time of implant placement. The reasons for antiresorptive medication intake in the patients were osteoporosis (n = 11), malignancies (breast cancer, n = 2; and multiple myeloma, n = 1), edema of bone marrow (n = 1), or diffuse sclerosing osteomyelitis (DSO; n = 1). Different types of ARDs have been administrated to the patients. Ibandronate was administrated in 7 patients, zoledronate in 5 patients, alendronate in 2 patients, denosumab in 3 patients, and risedronate in 1 patient. The mean cumulative dose for ARDs intake was 56.1 ± 55.8. Besides intake of antiresorptive medication, demographic data and risk factors were documented in Table 2.
Twenty-seven implants were placed in 10 patients (17 Straumann, 8 Thommen, 2 Camlog), where 21 implants in the mandible and 6 implants in the maxilla were assessed at the last follow-up. Implant specifications were described in Table 3.
For patients who attended the last follow-up, the mean age was 71.42 ± 7.01 years. Mean follow-up time for dental implants was 2.01 ± 1.03 years, ranging from 0.73 to 3.86 years.
No cases of MRONJ around implants or elsewhere were recorded.
None of the assessed patients had a failed or lost implant.
Cumulative implant success according to HSDI was 92.6% (25 of 27 assessed implants). The other 2 implants showed satisfactory survival of 7.4% while there was no compromised survival or failure of the implants documented.
No subjective complaints (prolonged or persisting pain) or postoperative complications (wound dehiscence) were documented. There was no spontaneous bleeding, exudation, pain on percussion around the dental implants, or tenderness upon function. Implants had no sign of mobility.
Mean bone loss between implant placement and follow-up was 0.60 ± 0.98 mm (minimum: 0 mm; maximum 3.8 mm).
Two patients (20%) had no signs of peri-implantitis. However, prevalence of peri-implantitis was 30% in 3 out of 10 patients. Nine of 27 implant sites (33.3%) showed neither bleeding on gentle probing nor exudation, while 8 out of 27 (29.6%) implant sites showed peri-implantitis. Prevalence of peri-implant mucositis was 50% on patient level (5 of 10 patients) and 37% on implant level (10 of 27 implant sites).
Impact of ARDs on osseointegration and survival of dental implants has not been comprehensively studied. Thus, the purpose of this study was to investigate the clinical outcome of dental implants in patients treated with ARDs and determine whether it is possible to place implants safely in those patients.
There were no cases of MRONJ documented in this study after 2.01 ± 1.03 years of dental implant placement in patients with history of antiresorptive therapy. Furthermore, none of the 39 implants was lost within the observation time. This was compliant with the results presented by Al-Sabbagh et al, where none of the 20 patients exhibited MRONJ,23 as well as Bell and Bell, who reached a 95% survival rate with 5 lost implants22 in patients who reported a history of oral bisphosphonate use.
In this study the HSDI as suggested by Misch et al28 was consulted to rate the actual state of the implant and health of peri-implant tissue, as the absence of MRONJ and implant survival are not sufficient implant outcome variables. The high success rate of 92.6% in the present cohort is in line with cohorts without antiresorptive drug intake, where implant success rates were 76.04% in 56 implants after 60 months29 and 97.1% success and 2.9% satisfactory survival in 208 immediately loaded implants after 24 months.16
Results were satisfying as the documented bone loss was 0.60 ± 0.98 mm after implant insertion. The overall patient satisfaction on a scale of 1 to 10 was 9.80 ± 0.63.
Though several studies had correlated dentoalveolar surgery in general and in particular dental implant surgery with a higher risk of osteonecrosis,19–21 peri-implant MRONJ in most reported cases occurred not in conjunction with implant placement but related to previously osseointegrated implants placed prior to antiresorptive medication.30–32 As inflammatory processes play an important role in the etiology of MRONJ,6,8 several authors concluded that peri-implantitis may be a possible risk factor for peri-implant MRONJ occurrence.18,21,33
Seemingly, peri-implantitis but not dentoalveolar surgery might lead to MRONJ. Results of this study indicated the possibility of a safe and predictable implant placement not only in patients who received low dosage for osteoporosis but also in patients who received antiresorptive medication with oncological diseases in general as approved by the current German guidelines.34 Results of this study also indicated that a critical indication, strict surgical protocol including antibiotic prophylaxis, as well as submerged healing and a close recall system allowed safe and predictable implant placement in patients who received antiresorptive medication.
Still, individual risk of MRONJ after implant placement should be discussed carefully with the patient before getting their consent. Besides, life expectancy and prognosis in case of malignancy should be considered. Patients should be motivated to improve their oral hygiene and informed about potential risk factors for the development of MRONJ such as poor oral hygiene,35 periodontal diseases,36 and local infections,6,8 as well as peri-implantitis.33 As the clinical presentation and level of pain in case of MRONJ can vary to a great extent,37 close recall intervals are recommended. The results of treatment in early stages of MRONJ are good,38–40 in particular in cases with oral BP intake.41
Peri-implantitis is a common complication in implant dentistry. Zitzmann and Bergludh reported peri-implantitis in 28% and 56%–77% of patients, respectively, and in 12% and 43% of implants,42 respectively, while Mombelli et al estimated a 10% and 20% prevalence of peri-implantitis on implant and patient level, respectively, 5–10 years after implant insertion on the basis of 29 publications.43 As prevalence of peri-implantitis in this study was 30% on patient level (3 of 10) and 29.6% on implant level (8 of 27 implant sites), the present cohort did not seem to have a higher risk regarding peri-implantitis.
Particular attention should be made to a good cleaning ability for the patient also in the case of postimplant definitive prosthetic rehabilitation. Single-tooth restorations or fixed dental prostheses with adequate interdental basal separation are suitable for this purpose in the case of a definitive fixed restoration. In the case of removable implant-supported dentures, locators, telescopes, and bars with sufficient distance from the alveolar ridge provide an opportunity to clean the area around the implants with interdental brushes, toothbrushes, and dental floss. A sufficient compliance of the patients is necessary.
The patients' quality of life could be highly improved by benefit from implant-retained crowns or prosthesis as oral health strongly affects proper nutrition and even morbidity. The dental implant placement might offer a possibility to prevent MRONJ in edentulous patients by use of implant-retained prosthesis, thus a potential denture-related mucosal lesions can be prevented.
A limitation of our study is the nature of the study as a retrospective monocentric study with a small number of participants. As implant placement in patients under antiresorptive medication is relatively new, no long-term results can be presented at this point. Though results of our patient cohort are promising, surgeons are advised to ponder carefully risks and benefits of dental implant placement for each patient. Further prospective studies are needed to confirm these results.
This study's results indicate it might be helpful for patients taking antiresorptive drugs to have prophylactic antibiotics and more frequent follow-up periods to allow safe implant placement.
American Association of Oral and Maxillofacial Surgeons
cone beam computerized tomography
diffuse sclerosing osteomyelitis
Health Scale for Dental Implants
Ludwig Maximilian University
medication-related osteonecrosis of the jaw
The authors report no conflict of interest. No source of funding was provided for this study.