Mai Xiong, D.D.S.,
Andrew Pearson, D.D.S.,
Ma'Ann Sabine, D.D.S., Ph.D.
and Lance Svoboda, D.D.S.
Hennepin County Medical Center
General Practice Residency
Oral and Maxillofacial Surgery
Bisphosphonates are a class of compounds with known effects on bone metabolism. In recent decades, much attention has focused on the dental implications related to bisphosphonate use. Oral bisphosphonates are considered the most effective therapy for management of osteoporosis and osteopenia, disorders characterized by decreased bone density that, if left untreated, may result in fractures and an impaired quality of life. Other indications for oral bisphosphonate use include Paget’s disease of bone and osteogenesis imperfecta.
Oral bisphosphonates exert their action by inhibition of the mevalonate pathway necessary for osteoclast survival. The osteoclast therefore loses its ability to form functional osteoclasts necessary for bone resorption. From a therapeutic standpoint, this stabilizes and/or improves the patient’s bone density and therefore quality of life.
The basic chemical structure and a list of oral bisphosphonates available in the U.S. market which are approved by the FDA are shown in the figure and table. The potency of each drug is related to the R2 arm of the structure. Note that recently, intravenous zolendronic acid (Reclast ®, Novartis) was approved for treatment of postmenopausal osteoporosis. Unlike intravenous bisphosphonates used to treat skeletal malignancies and metastases, this formulation is only given once a year.
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a well known complication associated with bisphosphonate use and is characterized by necrosis of the bones of the maxilla and mandible. Although dental procedures have been shown to increase the development of BRONJ, BRONJ may also occur spontaneously without an inciting event. Many studies have been undertaken to assess the risk for developing BRONJ in patients taking oral bisphosphonates for non-malignant skeletal conditions such as osteoporosis and steopenia.
Estimates of BRONJ prevalence related to ORAL bisphosphonates range from 0.001%- 0.1% and 0.2% for IV zoledronic acid (Reclast ® (Black, DM et al, 2007; Lo JC et al, 2010; Mavrokokki, T et al, 2007). The risk for developing BRONJ appears to be related to the potency of drug, duration of exposure, and co-morbidities such as steroid use and immunocompromised status. This risk increases approximately eight-fold with dental extractions (Mavrokokki, T et al, 2007). While other dentoalveolar procedures such as endodontic therapy and periodontal surgery have been listed as inciting events, no cases of BRONJ have been reported in patients receiving orthodontic therapy.
Definition and Treatment Recommendations for BRONJ from ORAL BPs
The currently accepted definition of bisphosphonate-related osteonecrosis of the jaw (BRONJ) as adopted by
the American Association of Oral and Maxillofacial Surgeons (AAOMS) (Ruggiero SL, et al, JOMS, 67:2-12,
2009, suppl1) is:
a. Exposed bone in the maxillofacial region that has persisted for MORE THAN EIGHT WEEKS
b. Patient must have CURRENT or PREVIOUS EXPOSURE to a bisphosphonate
c. No history of radiation therapy to the jaws
The risk for developing BRONJ in patients on oral bisphosphonates is considerably lower than that for patients exposed to the IV form for skeletal malignancies. However, studies suggest the risk of developing BRONJ increases when exposure to oral bisphosphonates exceeds three years. Therefore, the current recommendations for management of patients on oral bisphosphonates are as follow:
Asymptomatic patients receiving oral bisphosphonates for < three years, no clinical risk factors:
Elective dentoalveolar surgery is not contraindicated in this group. While the risk for developing BRONJ is minimal, informed consent is necessary to discuss the potential for development following any surgical procedure.
There is scant data on development of BRONJ following dental implant procedures. While implant surgery is not contraindicated, informed consent including potential failure to heal and possible osteonecrosis should be discussed.
Finally, the clinician should consider communicating with the prescribing physician to determine if any of the following would be appropriate:
(1) alternating dosing schedule,
(2) drug holiday, or
(3) alternative to bisphosphonate therapy.
Asymptomatic patients receiving oral bisphosphonates for < three years, concomitant steroid use:
These patients are considered at greater risk than the previous group due to exposure to steroids, a known clinical risk factor. Therefore, the clinician is advised to contact the prescribing physician to consider discontinuation of oral bisphosphonate for at least three months if systemic conditions permit. Restarting oral bisphosphonate should be done once osseous healing is complete.
Asymptomatic patients receiving oral bisphosphonates > three years, with or without concomitant steroid use:
Because of the increased risk for developing BRONJ with exposure to oral BPs > three years, the clinician is advised to contact the prescribing physician to consider discontinuation of oral bisphosphonates for at least three months if systemic conditions permit. The bisphosphonate should not be restarted until osseous healing is complete.
Patients With BRONJ
Patients with established BRONJ should avoid elective dentoalveolar surgery. Management objectives are primarily geared towards elimination of pain, control of ongoing infection, and minimizing progression of exposed necrotic bone. Treatment strategies are primarily based on stage of BRONJ, as follow:
Stage 0 - non-specific symptoms or clinical/radiologic abnormalities that might be due to bisphosphonate
exposure. No evidence of exposed bone. This stage may also be present in patients who were previously Stage
1, 2, or 3 who have healed and have no evidence of exposed bone.
Stage 1 - exposed and necrotic bone in patients who are ASYMPTOMATIC and have NO EVIDENCE of INFECTION.
Stage 2 - exposed and necrotic bone in patients with PAIN and clinical evidence of INFECTION.
Stage 3 - exposed and necrotic bone in patients with PAIN, INFECTION, and one or more of the following:
• exposed bone extending beyond the region of alveolar bone (i.e., to inferior border of mandible, maxillary sinus, and/or zygoma in the maxilla).
• pathologic fracture
• extraoral fistula
• oral antral/oral nasal communication
• osteolysis extending to the inferior border of the mandible or sinus floor.
Observational studies demonstrate that BRONJ lesions from oral bisphosphonates are generally less severe in nature and respond better to stage-specific treatment strategies and discontinuation of the drug. Regardless of stage, bony sequestra should be removed as atraumatically as possible. Extensive surgical treatment such as resection and reconstruction is generally reserved for Stage 3 disease.
Use of Bone Turnover Markers to Assess BRONJ Risk
Bone turnover markers have been used to assess clinical efficacy of antiresorptive compounds in patients with osteolytic processes such as osteoporosis and bone cancers. One specific marker of bone resorption that has received attention in BRONJ patients is CTX, or collagen type I cross-linked C-telopeptide (Marx RE et al, 2007). Recommendations for its use are based on observational studies from a single institution, and unfortunately, no well-controlled trials exist that demonstrate its utility and predictability. Therefore, its use in predicting BRONJ susceptibility is not currently accepted or recommended by the American Dental Association or the American Association of Oral and Maxillofacial Surgeons (Edwards, BE et al, 2008; Ruggiero SL et al, 2009).
A fifty-four-year-old Caucasian male was referred for evaluation of an asymptomatic non-restorable tooth #29 due to caries.
Medical history was significant for scleroderma, pulmonary hypertension, chronic obstructive pulmonary disease, CREST syndrome, seizure disorder, osteoporosis, anemia, gastroesophageal reflux disorder, and
degenerative joint diseases.
Medications include: alendronate (Fosamax®), which he has been on for nine years), Neurontin®, Combivent®, Keppra®, Flomax®, and oxycodone.
Due to patient’s > three-year exposure to an oral bisphosphonate, treatment options offered included:
(1) three-month drug holiday, then extraction of #29 vs.
(2) atraumatic extrusion of #29 following root canal therapy using orthodontic elastics. Orthodontic extrusion of teeth in bisphosphonate-treated patients has been described recently as an alternative treatment strategy
(Regev E et al, 2008). Twenty percent of the patient population studied were on oral bisphosphonates for treatment of osteoporosis.
Following the treatment protocol, the patient underwent caries excavation and root canal therapy. Orthodontic elastic bands were then placed around the tooth root subgingivally once every week. Periapical radiographs were taken intermittently throughout the three and-one-half month period to assess for periapical pathology and to monitor extrusion. Once a grade 3+ mobility was achieved, the tooth was removed using forceps. The patient recovered well with good mucosal and osseous healing two weeks postextraction.
Oral bisphosphonate treatment has been shown in animal models to inhibit orthodontic movement of teeth. However, no cases of BRONJ due to orthodontic treatment have been described (Karras, JC et al, 2009). While it is still premature to present long term effects in this case, we were able to achieve our primary goal of good osseous and mucosal healing. Placement of the elastics subgingivally may have caused a low grade inflammatory response that allowed for slow degradation of the periodontal ligaments attached to the tooth and its extrusion without exposing bone. This low grade inflammation was also sufficient to cause granulation tissue to form periapically that ensured no bone exposure. Minor complaints related to this treatment included pain which was managed with narcotic analgesics. No systemic antibiotics were used. However, chlorhexidine mouthrinse (Peridex®) was prescribed. Close observation with weekly visits and patient cooperation are imperative for the success of this treatment strategy.
Orthodontic extrusion of teeth may be considered a treatment option in patients at risk for developing BRONJ secondary to prolonged exposure to oral bisphosphonates.
Black DM et al. N Eng J Med, 2007, 356:18.
Edwards BE et al. JADA, 2008, 139(12):1,674.
Karras, JC et al. Am J Orthod Dentofacial Orthop 2009, 136:843-7.
Lo JC et al. J Oral Maxillofac Surg 2010, 68:243.
Marx RE et al. J Oral Maxillofac Surg 2007,65(12):2,397.
Mavrokokki T et al. J Oral Maxillofac Surg 2007, 65:44.
Regev E et al. J Oral and Maxillofac Surg 2008, 66:1,157.
Ruggiero SL et al. J Oral and Maxillofac Surg 2009, 67:2. suppl 1.
Emerson Ehlis, D.D.S.
VA Medical Center
With more than 20 million extractions performed annually, and an ever increasing prevalence of implant supported prostheses, there is a widespread potential for the application of socket preservation.1 Involvement of a specialist in all potential immediate and future implant placement sites may not be feasible for various reasons, including accessibility, finances, emergent infectious risk, and intolerable pain. Thus, general practitioners are extracting millions of teeth annually, with a tremendous impact on the patient’s future treatment course. The question then presents itself: When and how can the general practitioner best preserve all treatment options in a post-extraction socket?
In order for a patient to provide informed consent prior to an extraction, a practitioner is legally obligated to provide full disclosure. This consists not only of the laundry list of peri-operative risks such as damage to adjacent structures, but must include the potential for postextraction bony resorption in the edentulous site. Bone resorption has been shown to be unpredictable and often rapid, with a 25% decrease in width of the alveolus in the first year, and up to 60% in the subsequent two years.2,3 And vertical bone loss can range from 1 mm in a single extraction site to 4 mm when multiple teeth are removed.2-4
A literature review was conducted and specialists were consulted.
Maintaining adequate bone volume for delayed dental implant placement is the objective of most socket preservations. While an immediate implant placement is most predictable for maintaining bone levels, a suitable five-wall alveolus may not be present. Situations such as a traumatic extraction, a socket fenestration, previous apicoectomy, or other bony defects due to root fracture, periodontal disease, or abscesses may necessitate a graft. Additionally, lack of apical bone for immediate implant stability can be addressed through a preservation and delayed implant surgery.
Beyond maintaining bone volume for implants, socket preservation can also offer predictability in esthetics and function for prosthetic cases. In the case of a maxillary anterior incisor extraction prior to fabrication of a fixed partial denture, a preservation can be beneficial, especially in a high esthetic risk patient. This anatomical area often has prominent root form and thin buccal plates of bone, with a high propensity for resorption. A socket preservation increases predictability of the soft tissue esthetics, prevents horizontal bone loss of adjacent tooth abutments, and allows for expedited fabrication of a definitive prosthesis, by minimizing the necessary healing time through reduced remodeling. Christensen endorses the making of a final impression for the anterior maxilla as soon as six to eight weeks after incisor extraction, when a preservation is performed with an alloplast.10
Multiple bone grafting materials are present for performing a socket preservation. They can be categorized largely into four categories, including autograft, allograft, xenograft, and alloplast. Each of these donor sources have different mechanisms, such as containing bone-generating cells (osteogenic), stimulating bone-generating cells in the host (osteoinductive), and simply maintaining a space for the host cells to infiltrate (osteoconductive). As Figure 1 shows, the autograft provides the greatest potential bone replacement. However, as the harvest of such bone often requires a separate surgical incision on the patient, its application should be used only when other materials are unsuitable.
Several factors should be considered when selecting a graph material.6 Again, with autografts serving as the gold standard for bone growth, the autogenous bone provides the highest predictability. However, it has a limited biologic availability, and carries a greater operative risk, when a second harvest site is necessary. All other graft materials offer essentially unlimited availability, but carry other concerns. For instance, patient acceptance would a deterring factor for use of a xenograft, amongst certain cultures.
The allograft also carries a very limited but inherent risk of disease transmission. Though the cadaver bone can be treated with various methods, to date, there have been three documented cases of Hepatitis C transmission, a Hepatitis B transmission, and estimates of HIV transmission in one case for every 1.6 million grafts.6-8
Alloplasts avoid many risks in their synthetic nature, but also may not be accepted by patients who tolerate only all-natural substances. Alloplasts have also historically offered the lowest potential for bone regeneration, simply serving as osteoconductive matrices. More recently, a subset known as growth-factor-based alloplasts have shown osteoinductive effects at the alveolar cell walls. Bone morphogenic protein (BMP) in particular has been demonstrated to be a highly potentiating material, but its clinical feasibility is still limited, as it adds thousands of dollars in cost to every grafting case.
Principles in Preservation
Regardless of the case, certain principles apply for all ridge preservations. As recommended by Misch, goals for regeneration of a ridge include:
(1) atraumatic tooth removal
(2) asepsis and debridement of all soft tissue
(3) ensuring adequate blood supply for healing
(4) soft-tissue closure
(5) adequate healing time.
As we will see in case selection, the number of remaining bony walls remaining postextraction drives the technique and prognosis for ridge regeneration. Providers should refer extraction cases in which they do not have a clear plan to removal.
Asepsis. During and after tooth removal, care should be taken not to introduce contaminants into the socket. Should a periapical lesion be observed pre-operatively, consideration should be given to a course of antibiotics, with analgesic pain management, to diminish the bacterial load in the area prior to socket preservation. The socket should also be debrided, not only to remove any soft tissue pathoses,which could lead to a fibrous defect in the regenerating bone, but also to inspect the remaining socket walls in order to determine the technique for preservation.
Blood Supply. While soft tissue bleeding near the graft site can be helpful during graft placement, the regeneration phase of healing requires osteoprogenitor cells, which are only provided by the surrounding bone or torn periodontal ligament vessels. Bleeding from the bony walls should be verified prior to a graft placement to ensure success. Decortication of the alveolar walls is indicated if no bleeding is observed. If devascularized bone is suspected pre-operatively, due to a history of smoking or dry sockets, the socket may benefit from addition of Protein Rich Plasma (PRP). However, given the cost of the additional materials for isolating PRP, patients with risk for non-bleeding sockets should likely be referred to a specialist.
Soft Tissue Closure.
Numerous authors have reported success in fivewall socket preservations with only a resorbable collagen plug for graft retention, in lieu of primary tissue closure.3,12 However, a barrier membrane is indicated for a fourwall or less socket preservation, and soft-tissue primary closure will further reduce the potential for bacterial contamination of the site.
Adequate Healing Time. In general, the healing time for a graft is four to six months, but one radiographic indicator is the loss of the cortical lining of the socket walls on a periapical film.9
When determining if a general practitioner should treat or refer an extraction, with the intent of future implant placement, the paramount concern should be predicting the number of bony walls that will be present post-extraction. Accordingly, the indications and treatment can be best discussed as three classes of defects:
(1) thick five-wall
(2) thin five-wall and four-wall
(3) three-wall and two-wall.
As Misch reports9, the greater the number of maintained bony walls, the less technique-intensive the graft procedure. Inversely, as the number of walls decreases to three or below, the need for autogenous bone in the graft. Therefore, unless the general practitioner feels comfortable harvesting a graft, he or she should likely refer cases where bony wall regeneration is required.
The thick five-wall bony defect provides the simplest preservation case. Indeed, many of these sockets will fill with bone independent of any grafting material placement. An important distinction is the thickness of the facial bony wall. If greater than 1.5 mm of facial bone is preserved without deformation, the socket can be expected to fill with bone without a defect. However if the facial bone is < 1.5 mm, it has been reported that only one out of five maxillary incisor sockets maintained adequate 6 mm bone width for implant placement.11 This same study reported placement of a xenograft with primary tissue closure only, maintained of adequate thickness in four out of five maxillary incisor sockets with a thin facial plate. What’s more, when the study asked experienced specialists to predict resorption outcomes based upon pictures of the post-extraction sockets, all experts displayed poor predictive capability. Therefore, without the ability to predict the sockets which will resorb, all sockets for potential implants should be preserved.
In addition to maintaining width, another indication for preservation is increasing buccal bone height in both the four-wall defect and the five-wall defect with facial recession. Placement of a non-autogenous bone graft alone as been shown to provide little bone height formation.12 Addition of a barrier membrane to grafting has been shown to better maintain bone width and height at six months.13 A collagen membrane may be used for this purpose, but an acellular dermal matrix should be used when soft tissue augmentation is desired, which is often a case for referral to a surgeon.14,15 If a membrane is placed, reflection of the surrounding tissue must be performed to insert at least 8 mm of membrane subperiosteally, from the margins of the tissue.9 An important point is that primary tissue closure is not necessary for a four-or five-wall defect, and flap advancement often leads to an unaesthetic tissue redundancy that creates tension on the graft.9 Short term antibiotic coverage has been recommended for a non-union healing socket open to contaminants.16
Resorption prognosis of a postextraction alveolar ridge is unpredictable, even with years of experience. Most ridges will regenerate without significant bony loss if 1.5 mm of the facial bony plate is preserved. However, the prognosis for bony regeneration is improved in all sockets via a preservation graft material, unless a contraindication exists. Atraumatic tooth removal is paramount for preserving the ridge.
The prognosis worsens and the ease of preservation techniques is inversely related to the number of remaining bony walls post-extraction. If a provider is uncertain about his or her ability to remove a tooth or perform the necessary ridge preservation, the individual should contact a local specialist.
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17. Misch CE. Contemporary Implant Dentistry. 2nd ed. St. Louis, Mo: Mosby; 1999:462.