Bisphosphonates-related osteonecrosis of the jaw (BRONJ) is a serious dental-medical complication that is seen among individuals undergoing invasive dental procedures such as extractions, implant placement, or other procedures involving bone surgery. In 2003, Marx1 identified bisphosphonate treatment as a possible contributor to osteonecrosis, and many studies demonstrating a correlation between chronic biphosphonate consumption and osteonecrosis onset have appeared in the literature since then.2–7 The risk of BRONJ rises if the patient is taking other drugs such as chemotherapeutic agents, steroids, and antiangiogenic therapies,7 and it has been hypothesized that rheumatoid arthritis can be a risk factor on its own.8 In 2014, the term medication-related osteonecrosis of the jaw (MRONJ) was introduced, replacing the common expression BRONJ, as this condition can also result from treatment with other antiresorptive (denosumab) and antiangiogenic therapies. The American Association of Oral and Maxillofacial Surgeons (AAOMS) defines MRONJ as a condition of exposed or probable bone in the maxillofacial region without resolution for greater than 8 weeks in patients treated with an antiresorptive and/or an antiangiogenic agent who have not received radiation therapy to the jaws.9
For patients who have taken an oral bisphosphonate for fewer than 4 years and have also taken corticosteroids or antiangiogenic medications concomitantly or for those who have taken an oral bisphosphonate for more than 4 years with or without associated steroid therapy, the AAOMS guidelines recommend considering discontinuation of the oral bisphosphonate (drug holiday) for at least 2 months before oral surgery, if systemic conditions permit. The antiresorptive should not be restarted until osseous healing has occurred.9
Marx et al, in 2007,5 found a direct exponential relationship between the size of the exposed bone and the duration of oral bisphosphonate use, which was also correlated to the morning fasting serum C-terminal cross-linking telopeptide (CTX) test results; CTX is a bone turnover biomarker, and a stratification of relative risk was seen, with CTX values of less than 100 pg/mL representing high risk, CTX values between 100 and 150 pg/mL representing moderate risk, and CTX values greater than 150 pg/mL representing minimal risk.5,10 In addition, drug holidays associated with CTX values rising above the 150-pg/mL threshold were observed to correlate either with spontaneous bone healing or a complete healing response after an office-based debridement procedure.10
Several clinical protocols have been suggested to treat ONJ, and good results have been shown for the use of blood derivates,11,12 such as plasma rich in growth factors (PRGF). PRGF seems to permit achievement of better and faster healing, due to the high concentration of platelets and growth factors in the PRGF. This is why its use has been proposed in many different fields of surgery.13
The aim of this report was to show how a strict protocol based on recording CTX values and using PRGF to enhance healing processes enabled implant-supported prosthetic rehabilitation of a patient with a high risk of MRONJ.
A 65-year-old man affected by rheumatoid arthritis who was a chronic consumer of bisphosphonates and methylprednisolone was referred to the authors seeking restoration of his mandible with a full-arch prosthesis. Clinical and radiographic examinations were carried out to determine the condition of his residual dentition and bone volume (Figures 1 and 2). The patient previously had been rehabilitated with a full removable prosthesis in the upper jaw and removable partial dentures in the lower jaw.
Clinical evaluation revealed an unfavorable prognosis for the anterior mandibular residual teeth, which were affected by caries and advanced periodontal disease. The radiographic evaluation showed severe bone atrophy of the posterior regions, so a rehabilitation supported by 4 implants was proposed. A postextraction immediate implant approach was chosen to limit the surgical interventions and thus reduce the risk of MRONJ caused by exposure of the bone.
As suggested by Marx et al,5 CTX, which is the marker for bone turnover, was recorded after the patient's first visit. The value was 120 pg/mL, under the threshold for minimizing MRONJ (150 pg/mL). For this reason, with the agreement of the patient's physician, a decision was made to suspend bisphosphonate consumption and repeat the CTX analysis every 3 months until the CTX exceeded the 150-pg/mL threshold.
After 9 months of monitoring, the marker value reached 210 pg/mL (the Table). This was considered a good level for proceeding with surgery. Antibiotic prophylaxis consisted of amoxicillin + clavulanic acid 3 g/day for 6 days, starting with 2 g at 1 hour before surgery.
After blood was drawn from the patient and centrifuged (PRGF System, BTI Biotechnology Institute, Milan, Italy), PRGF was prepared according to the centrifuge manufacturer's instructions.
Under local anesthesia, a crestal incision was made from the left mandibular molar region to the right one, without releasing incisions. A full-thickness buccal flap was raised while paying careful attention to the mental nerves. All teeth were extracted in a nontraumatic manner, and the sockets were cleared of soft-tissue remnants and cleaned to avoid infection (Figure 3).
The implant sites were prepared to place 2 medial straight implants and 2 distal tilted ones in the intraforaminal region, avoiding the mental foramens; the site preparation and implant placement followed standard procedures, according to the manufacturer's instructions (Figure 4). Pretapping was performed for all sites to prevent excessive bone compression, and the implants were inserted 1 mm under the alveolar ridge. A PRGF solution was applied to all the implant sites and implant surfaces to enhance the osseointegration process (Figures 5 through 7).
Passive positioning of the buccal and lingual flaps was achieved by means of a periosteal incision to allow for first intention closure of the extraction sites. To hasten the soft-tissue healing, PRGF clot membranes were positioned above the alveolar ridge and under the surgical flaps before they were sutured with 4-0 resorbable sutures (Figures 8 through 10). After an uneventful period of 4 months, the patient underwent re-entry surgery, and 6 months after implant surgery, the prosthesis was delivered, thus permitting the patient to resume his normal masticatory function (Figure 11).
Clinical evaluation was performed monthly during the first 3 months following definitive restoration and then every 3 months thereafter. No signs or symptoms of MRONJ were detected during the healing period. Little ulceration (<5 mm) was visible at the 1-month follow-up due to temporary mobile prosthesis compression, but it completely healed after prosthesis relining (Figure 12).
During the 1-year follow-up period, no other complications occurred, and no signs or symptoms of MRONJ were detected. Both clinical and radiographic examinations showed bone-tissue healing of the extraction sites and implants, soft-tissue contours with no significant changes, and stable perio-implant bone levels (Figures 11 and 13).
Bisphosphonate consumption and corticosteroid therapy have been found to be significant contraindications for oral surgical procedures because of the risk of osteonecrosis, superinfection, and healing problems.7,8 Although implant placement under such medical conditions is challenging, it is possible.14,15
To avoid MRONJ and other complications, many protocols have been suggested, generally based on antibiotic prophylaxis and first intention healing to limit bone exposure and devascularization. The protocol described in the present report is based on antibiotic prophylaxis, monitoring of CTX values, immediate implant placement after tooth extraction, PRGF application, and first intention healing of the soft tissue.
The CTX value was first proposed by Marx et al,5 but it is important to note that the threshold values of the original protocol (150 pg/mL) were empirically established without a control group. Considering the absence of scientific evidence regarding CTX values and concomitant consumption of bisphosphonates and corticosteroids, the authors chose to wait until the value exceeded 200 pg/mL (the Table).
The PRGF was used in this case because of its encouraging results in oral surgery for soft-tissue healing, bone reconstruction, and MRONJ treatment itself.11,16,17 The PRGF solution was applied to the bone-implant interface to improve osseointegration, whereas PRGF membranes were positioned under the flaps to guarantee their immediate closure and minimize the risk of infection. The implants were placed immediately after tooth extraction to reduce the number of surgeries and further reduce the risk of MRONJ and limit bone exposure.
After 1 year of follow-up, the crestal bone levels seemed stable with no signs of bone resorption or necrosis, and all implants were successful according to the criteria proposed by Albrektsson and Zarb.18
The protocol described in this report can be a viable solution for preventing MRONJ in a patient who is consuming bisphosphonates and corticosteroids and undergoes implant surgery. Its purpose is to reduce the risk of infection and hasten the healing of bone and soft tissue.