Oral bisphosphonates are commonly used to improve bone density in patients who suffer from a variety of pathologies. However, they have also been known to cause bisphosphonate-related osteonecrosis of the jaws (BRONJ). The aim of this clinical case presentation is to (1) determine whether the currently recommended length of time that oral bisphosphonates should be discontinued, before performing dental implant surgery, is sufficient to prevent BRONJ and (2) to describe an alternative treatment for BRONJ. A 65-year-old female patient developed BRONJ after receiving mandibular dental implants 5 months after discontinuing alendronic acid (Fosamax). The BRONJ was treated by surgical osteotomy and plasma rich in growth factors (PRGF), and the patient was followed up with biweekly examinations, which included 0.2% chlorhexidine mouthwashes and removal of any remaining necrotic bone. The dental implants were loaded 41 weeks after surgery and followed up with periapical radiographs and implant stability quotient measurements at 3, 6, 12, and 24 months postloading. Although the Association of Oral and Maxillofacial Surgeons protocols for suspension of presurgical oral bisphosphonates were followed, this patient still developed BRONJ after implant surgery. While a multitude of treatments have been described in the literature, there is not enough scientific evidence to support any one treatment. Based on this clinical case, it can be concluded that the potential adverse effects of oral bisphosphonates on the jaws could be greater than expected and that treatment with PRGF produces promising results, although more long-term studies are necessary to confirm these findings.
Introduction
Bisphosphonates are a group of pyrophosphate analogues that have been shown to reduce vertebral fractures and those of the peripheral skeleton. They have a carbon atom to which 2 phosphorus atoms are attached, which allows them to fix efficiently and quickly to the hydroxyapatite crystals that are found on the bone mineral surface.1–5 The indications for bisphosphonates have increased in recent years. They can be classified according to their chemical composition, with their bioavailability depending on the mode of administration.6
Nowadays, they are used in pathologies involving increased bone resorption, including hypercalcemia of tumor origin, bone metastasis, osteoporosis type I, and Paget's disease. Moreover, they can also be used in osteogenesis imperfecta, hypertrophic osteopathy, systemic mastocytosis, fibrous dysplasia, and sternocostoclavicular hypertosis.1–3,6
The main complication associated with bisphosphonate intake in the field of oral surgery is the appearance of osteonecrosis of the jaws.7 However, it was only in 2003 that the phenomenon of osteonecrosis of the jaws associated with bisphosphonates was first described in the literature.7 In 2007, the American Association of Oral and Maxillofacial Surgeons (AAOMS) established a clear definition of the process, denominating the entity as bisphosphonate-related osteonecrosis of the jaws (BRONJ).8,9 As a consequence of the growing number of cases of osteonecrosis and antiresorptive and antiangiogenic therapies, the AAOMS has since changed the name BRONJ to medication-related osteonecrosis of the jaw (MRONJ).10,11
Because of the increasing number of patients receiving bisphosphonates, clinicians' concerns regarding MRONJ as an oral surgery–related complication have led to the description of several treatment protocols, although no clear standard has been defined.10,11
This clinical case description has 2 objectives: (1) to offer an alternative treatment for osteonecrosis of the jaws associated with bisphosphonates (MRONJ) and (2) to assess the need to increase the length of time for which bisphosphonates should –be avoided prior to treatment.
Case Report
Medical history
In July 2014, a 65-year-old white woman was referred to the dental office for rehabilitation of the lower left mandibular first and second molars (Nos. 18 and 19) and upper left maxillary first premolar and first molars with dental implants (Nos. 12 and 14). The patient's medical history included osteoporosis type I, hypertension, and primary epilepsy, respectively, treated with the following drugs: alendronic acid (10 mg 1-0-0), nifedipine (10 mg 1-0-0), and valproate (900 mg). The patient had been taking alendronic acid (10 mg 1-0-0) since January 2013, a 20-month period prior to the consultation. The patient had excellent oral hygiene with no unhealthy habits and had no other significant medical conditions reported.
The patient's dental history included composite resin and silver amalgam restorations, completed 20 years ago, and the extraction of the lower left mandibular first and second molars (Nos. 18 and 19) and upper left maxillary first premolar and first molars (Nos. 12 and 14) 5 years ago. To carry out a complete analysis of the clinical case, a radiologic study was performed, which included periapical radiographs, an orthopantomography, and a computerized axial tomography. This was followed by a clinical analysis using photographs and study models assembled in a semi-adjustable articulator (Figure 1). No pathology associated with the dentition was found during the radiologic and clinical analyses.
Although the patient had been taking oral bisphosphonates for less than a 3-year period, her physician advised her to temporarily discontinue the medication at least 3 months prior to the surgery. The patient stopped taking the medication in September 2014, and the surgery was performed 5 months later in February 2015.9 Twelve months after restoring the dental implants and completing treatment, the patient restarted the oral bisphosphonate treatment with authorization from her physician.
Surgery for placement of dental implants Nos. 12, 14, 18, and 19
Before the surgery, the patient was informed of the possible risks and complications of the implant treatment and signed an informed consent form.
The patient was instructed to rinse her mouth using mouthwash containing 0.2% chlorhexidine (Oraldine Perio, Johnson and Johnson, Madrid, Spain) for 1 minute prior to surgery. This was followed by a crestal incision with an intrasulcular extension to the adjacent tooth without discharge, and subsequently, a mucoperiosteal flap was raised. With the help of a surgical splint from the diagnostic wax up, Implant-Guide Biomet 3i (West Palm Beach, Fla), to place dental implants in type II bones, was used, leaving a distance of more than 3 mm between the implant of the first lower left molar (Biomet 3i NT510, with stability of 40 Ncm) and the second lower left molar implant (Biomet 3i NT510, with stability of 35 Ncm).12 The same surgical protocol was employed in type III–IV bones to dental implants of the first upper left premolar (Biomet 3i INT411.5, with stability of 35 Ncm) and the first upper left molar (Biomet 3i INT510, with stability of 35 Ncm), leaving a distance of more than 1.5 mm to adjacent teeth.
All dental implants were placed juxtacrestal and sutured with a synthetic nonabsorbable polyamide suture, Supramid 4/013 (Figure 2). The patient received amoxicillin/clavulanic acid 875/125 mg as a prophylactic antibiotic on the day before surgery and 6 days after the surgery and ibuprofen 600 mg 1 hour before the surgery and for 2 days after the surgery, 3 times a day.
The patient arrived to the clinic with an emergency episode 6 days after surgery, experiencing discomfort in the lower surgical area without any complications and excellent healing in the maxilla. After the clinical evaluation, an open flap exploratory surgery was carried out. Bone exposure was observed; therefore, the antibiotic treatment was continued for 4 more days, and the edges of the flap were sutured together. At the 15th day postsurgery follow-up visit, the patient presented symptoms suggestive of osteonecrosis without suppuration in the interimplant lingual area; therefore, the following treatment was prescribed: chlorhexidine 0.2% (Oraldine Perio, Johnson and Johnson) mouthwash 3 times per day combined with topical application of chlorhexidine gel (Oraldine Perio, Johnson and Johnson). At the fourth week postsurgery control, a bony lingual exposure of 7 mm in length and 3 mm in width was present with no other symptoms. A periapical control radiography was performed, antibiotic treatment with amoxicillin/clavulanic acid 875/125 mg was prescribed for 7 days, and the chlorhexidine protocol was continued (Figure 3). A blood test was performed to determine, among other parameters, the blood level of carboxyl terminal telomere of type I collagen (CTX). At the eighth week postsurgery control, the lesion presented with the same clinical signs. The wound was disinfected with gauze, impregnated with 0.2% chlorhexidine, and the antibiotic treatment was continued. The blood test showed CTX values of 0.150 pg/mL, which were within the appropriate parameters.14
Osteotomy surgery and Plasma Rich in Growth Factors
After periodic reviews at the 9th and 10th weeks postsurgery, it was decided to interrupt the antibiotic treatment and continue with 0.2% chlorhexidine mouthwash. Twelve weeks after surgery, necrotic bone osteotomy surgery was performed using a tungsten drill and handpiece. plasma rich in growth factors (PRGF) activated with calcium chloride was then applied in the surgical area and stabilized with suture type Surgicryl 5/0 (Figure 4).15,16
The patient was recalled 15 weeks after initial surgery and 3 weeks after necrotic bone removal to remove the suture. At the 18th, 28th, 32nd, and 38th week follow-up visits, the patient presented with lingual soft-tissue dehiscence and a 3-mm exposure of necrotic bone that gradually decreased until it disappeared completely on week 38 (Figure 5). During the follow-up visits, the remaining necrotic bone was removed using a 7/8 Gracey curette, and the wound was disinfected with 0.2% chlorhexidine. Forty weeks after initial surgery, a periapical radiograph was performed that showed bone loss distal to implant No. 19 up to the third thread and mesial loss at implant No. 18 up to the second thread. Prior to loading the implants, the implant stability quotient (ISQ) was measured using the Osstell system (Gothenburg, Sweden) to evaluate the stability of the dental implants (Nos. 12, 14, 18, and 19). The ISQ was determined on 2 occasions on the fourth week after the second surgery, with values between 67 and 70 obtained for all dental implants.
Throughout this long period of time, the maxillary dental implants showed no complications, with excellent healing and no bone loss.
Therefore, definitive impressions were taken to start the prosthodontics rehabilitation of the maxilla and mandible. The semiprecious metal milled metal structure was tested to verify the passive adjustment and the design of all crowns. After the color determination and final ceramics manufacturing, the rehabilitation was fixed to 25 Ncm with a hexagonal head screw, as indicated by the implant manufacturer.17 Finally, the occlusion was adjusted with respect to its antagonist following the appropriate procedures18 (Figure 6).
Once the definitive prosthesis was placed in the mouth, the torque was checked again after 15 days, and clinical reviews were carried out at the 3, 6, 12, and 24 months postload. Periapical radiographs were also taken to evaluate the bone remodeling at each appointment. Peri-implant bone stability was observed in all reviews, and ISQ values were between 66 and 69 (Figure 7).
Discussion
Oral bisphosphonates are used as a treatment option in many entities that cause an increase in bone resorption. However, there have been several reported cases of the presence of osteonecrosis of the jaw associated with oral surgery following the use of bisphosphonates.1–3,6 For this reason, the AAOMS established the term BRONJ, meaning any persistent bone exposure or intra- or extraoral fistula in the maxillofacial region for more than 8 weeks, in a patient under current or previous treatment with antiresorptive or antiangiogenic drugs and without any history of radiotherapy or bone metastasis in the jaws. BRONJ can be divided into 3 grades: grade 0, no exposure of any necrotic bone but nonspecific clinical symptoms; grade 1, exposure of necrotic bone, asymptomatic and without signs of acute infection; grade 2, exposure of necrotic bone associated with pain and signs of infection; and grade 3, exposure of necrotic bone associated with pain, signs of infection, cutaneous fistula, and clinical or radiographic evidence of bone sequestration or another complication.
To reduce the prevalence of this type of complication, the AAOMS established a protocol of action when performing any oral surgery, depending on the time that the patient has been taking oral bisphosphonates: less than 3 years: if they do not present any risk factor, they can undergo any surgical intervention without the need to stop the pharmacologic treatment, and more than 3 years: in 2014, the AAOMS recommended suspending the drug 2 months before and 2 months after surgery, providing that the systemic conditions allow this.10,11
Starck and Epcker19 were the first to report the possible association between implant therapy and the development of osteonecrosis of the maxilla in patients treated with bisphosphonates. The risk of suffering BRONJ is considered to decrease when the bisphosphonates are administered orally; however, the prevalence of BRONJ increases if bisphosphonates are used for long periods.20–23 However, there are articles reporting that BRONJ can develop after periods of less than 3 years with the placement of dental implants.24 To the authors' knowledge, there are no studies with described cases of BRONJ after less than 3 years of treatment with bisphosphonates and with suspension of the drugs 5 months before implant surgery, as is the clinical case described in this article.
Although following the AAOMS recommendations decreases the risk of BRONJ, its occurrence is still a possibility. If this happens, there are many possible treatments: medical treatment, minimally invasive surgery, medical treatment + minimally invasive surgery, medical treatment + minimally invasive surgery + major surgery, laser light therapy, growth factors (PRGF or bone morphogenetic protein–2), ozone treatment, hyperbaric oxygen therapy, teriparatide, and major surgery. However, there is no clear scientific evidence establishing which treatment to use depending on the size of the lesion, location, type of bisphosphonate (oral or intravenous), other associated pathologies, or periodontitis.25–27
In the clinical case presented herein, the complication was solved with a combination of treatments: medical treatment, surgical resection, and the use of PRGF. Medical treatment was carried out by antibiotic and chlorhexidine therapy. We considered the short-term use of chlorhexidine necessary in this study for its antiseptic effects, despite the fact that previous studies demonstrated that it has an inhibitory effect on the proliferation and migration of fibroblasts and osteoblasts.28 Another possible intervention is surgical resection of the necrotic bone with primary closure, which has been used in several studies with promising results.15,16 However, there are no randomized clinical trials comparing all of the different techniques.
The action potential of oral bisphosphonates on the maxilla may be much more aggressive than previously thought, given the clinical case described herein in which osteonecrosis developed in the jaw after the placement of dental implants following the use of oral bisphosphonates (alendronic acid) for 20 months and suspension of the drugs for 5 months prior to implant treatment. On the other hand, necrotic bone resection therapy, which maintained the perilesional soft tissue without raising a flap and was associated with autologous growth factors and antibiotic medical treatment and topical antiseptic (chlorhexidine), led to good results in our case. Randomized clinical trials are needed to establish a clear protocol of action to prevent and treat this type of complication of oral or implant surgery.
Abbreviations
Acknowledgment
We would like to thank John Lindberg, DMD candidate, University of Pennsylvania, for assistance in proofreading the manuscript.
