Bisphosphonate therapy: a "bone-afide" problem.

As the "Baby-Boomer" generation ages, efforts have been concentrated on health maintenance and preventive care. Osteoporosis, characterized by a decrease in bone mass and bone density with increased risk of fractures, has received significant and warranted attention. While exercise and diet can have positive impacts on osteoporosis, increased incidence of the disorder is associated with obesity, diabetes, smoking and chronic steroid therapy. Add to this metastatic bone cancers, and the difficulty of patient management is only magnified.

It has become increasingly clear over the last few years that our medical colleagues and the pharmaceutical companies that court them have unknowingly produced a modern-day dilemma for the dental community. The development of bisphosphonate-related osteonecrotic lesions of the jaw (BRONJ) is a clinical problem where spontaneous exposure of alveolar bone occurs or, much worse, the patient presenting for routine dental extractions or periodontal curettage, develops an area of necrotic bone that does not respond to conservative treatment or surgical management. The burden now falls on the dental provider to consider the ramifications of bisphosphonate therapy in our patient population carefully before undertaking what may seem to be routine dental care.

What Are Bisphosphonates and How Do They Work?

The bisphosphonates are a class of compounds used for the treatment of many different medical conditions. These compounds localize to bone and inhibit osteoclast-mediated bone resorption. Since bisphosphonates are not metabolized, high concentrations are maintained within bone for a long time, the exact duration remains unknown at this time.

The efficacy of these agents in reducing bone pain, hypercalcemia and skeletal complications has been extensively documented in patients with metastatic breast cancer, multiple myeloma and other tumors that metastasize to bone. Bisphosphonates are also widely used for the treatment of postmenopausal osteoporosis and steroid (glucocorticoid) induced osteoporosis. In this group of patients, bisphosphonate therapy can increase bone mineral density resulting in a decreased incidence of skeletal complications associated with osteoporosis.

There are a variety of bisphosphonates approved for clinical use in the United States (Table I). The potent intravenous bisphosphonates, pamidronate (Aredia[R], Novartis Oncology) and zoledronic acid (Zometa[R], Novartis Oncology), are typically administered monthly in patients with metastatic bone disease. Except for ibandronate (Boniva[R], GlaxoSmithKline), all of the other bisphosphonates approved for the treatment of osteoporosis are dosed orally on a daily or weekly schedule. Only Fosamax[R], (Merck&Co., Inc.), Actonel[R] (Procter & Gamble Pharmaceuticals, Inc.), and Boniva are the nitrogen-containing oral bisphosphonates that are most likely to cause this condition. Given their proven efficacy, these drugs are extensively utilized by oncologists, endocrinologists and other medical professionals. Since their introduction into the global marketplace, over 190 million prescriptions for these medications have been dispensed. (1) Introduced in April 2006, Boniva is the latest member of this chemical class, and patients currently using it are starting to be studied to assess sufficient exposure to the drug to formulate BRONJ risk profiles. Zoledronic acid (Reclast[R], Novartis) administered once per year for the treatment of osteoporosis, was approved by the U.S. Food and Drug Administration (FDA) in August 2007. Only two cases of osteonecrosis of the jaw were reported, one each in the treatment and control groups, suggesting a low risk of BRONJ with this treatment modality through three years. The efficacy of a drug holiday for patients receiving yearly zoledronic acid therapy and the appropriate timing of dentoalveolar surgery (if required) are unknown and therefore require further study. (2)

BRONJ as a Patient Clinical Presentation

In 2003 and 2004, oral and maxillofacial surgeons were the first clinicians to recognize and report cases of nonhealing exposed bone in the maxillofacial region in patients treated with IV bisphosphonates. Since these initial reports, several case series and reviews have been published, including some cases in patients taking the less potent oral bisphosphonates. In September 2004, Novartis, the manufacturer of the IV bisphosphonates pamidronate (Aredia) and zoledronic acid (Zometa), notified health care professionals of additions to the labeling of these products, which provided cautionary language related to the development of osteonecrosis of the jaws. This was followed in 2005 by a broader drug class warning of this complication for all bisphosphonates, including the oral preparations. (1)

These lesions may remain asymptomatic for many weeks or months and may be recognized only by the presence of pain or exposed bone in the oral cavity. Lesions are most frequently symptomatic when sites become secondarily infected or there is trauma to the soft tissues via the sharp edges of the exposed bone. Typical signs and symptoms include pain, soft tissue swelling and infection, loosening of teeth, drainage and exposed bone. The necrosis may occur spontaneously or, more commonly, at the site of previous dentoalveolar trauma or extractions (Figures 1-7).

In order to distinguish BRONJ from other delayed healing conditions, the American Association of Oral and Maxillofacial Surgeons has adopted the following working definition of BRONJ. (1)

Patients may be considered to have BRONJ if all of the following three characteristics are present:

1. Current or previous treatment with a bisphosphonate.

2. Exposed bone in the maxillofacial region that has persisted for more than eight weeks.

3. No history of radiation therapy to the jaws.

It is important to understand that patients at risk for BRONJ or with established BRONJ can also present with other common clinical conditions that should not be confused as BRONJ. Commonly misdiagnosed conditions may include, but are not limited to, alveolar osteitis (dry sockets), sinusitis, gingivitis/periodontitis, caries, periapical pathology and temporomandibular joint disorders.

The extent of symptoms and clinical disease can vary despite similar disease processes, bisphosphonate dosage and treatment duration. These patients have been classified based on their presenting symptoms and clinical exam (Table II).

Why the Jaws Are at an Increased Risk

The apparent selective involvement of the maxilla and mandible may be a reflection of the unique environment of the oral cavity. Typically, healing of an open bony wound (e.g., extraction socket) in the presence of normal oral microflora occurs quickly and without infection. However, when the healing potential of the mandible or maxilla is compromised, minor injury or disease in these sites is much more likely to progress to widespread necrosis and osteomyelitis.

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It appears that the pathogenesis of this process is most consistent with a defect in jawbone remodeling. The mechanism by which bisphosphonates can have this effect may be related to their effect on osteoclasts. With significant impairment of osteoctast function, normal bone turnover and resorption are inhibited. This could result in decreased new bone formation and diminished capillary ingrowth. Also, bisphosphonates are preferentially deposited in bones with high turnover rates; given the maxilla and mandible are sites of significant remodeling, it is possible that the levels of bisphosphonate within the jaw are selectively elevated. (3)

Dental Risk Factors

Recent retrospective clinical studies have identified several potential risk factors associated with the development of BRONJ. These include a history of dentoalveolar trauma, duration of bisphosphonate exposure, and the type of bisphosphonate. In the vast majority of BRONJ cases reported to date, recent dentoalveolar trauma was the most prevalent and consistent risk factor. This underscores the importance of maintaining good oral health and avoiding extractions in this population. The duration of bisphosphonate therapy also appears to be related to the development of necrosis with longer treatment regimens associated with a higher likelihood of developing disease. (4) In addition, the more potent intravenous bisphosphonares, such as pamidronate (Aredia) and especially zolendronate (Zometa), appear to be significantly more problematic as compared with the oral preparations. Based on retrospective studies, the estimate of the cumulative incidence of BRONJ in patients receiving intravenous bisphosphonates ranges from 0.8% to 12%. (4) Patients under treatment with oral bisphosphonate therapy are at a considerably lower risk for BRONJ than patients treated with IV bisphosphonates, weighing in around 0.01% of all bisphosphonate cases reported. (5) However, reliable incidence data of BRONJ in this patient population is lacking. In general, these patients seem to have a less severe manifestation of BRONJ and respond more readily to conservative treatment. Although we do not consider oral bisphosphonate therapy an absolute contraindication in patients who require elective dentoalveolar surgery, we do suggest that patients be adequately informed of the small potential risk of compromised bone healing. If systemic conditions permit, it has been proposed that discontinuation of oral bisphosphonates for a period of three months prior to and three months following elective invasive dental surgery may lower the risk of BRONJ. (1) The potential for complications in patients with a history of oral bisphosphonate treatment is probably related to the duration of exposure (greater than three years) and surely requires further analysis. In patients who have undergone relatively routine dental treatment, the incidence of iatrogenic (treatment-induced) BRONJ was reported as follows: spontaneous bone exposures, 25.2%; dental extractions, 37.8%; advanced periodontitis, 28.6%; periodontal surgery, 11.2%; dental implants, 3.4% and root canal surgery, 0.8%. (4) If suspected, appropriate imaging with computed tomography or panoramic imaging should be performed.

If osteonecrosis is suspected, panoramic and tomographic imaging may be performed; however, radiographic changes are not evident until there is significant bone involvement (Figure 5). It is recognized that patients may have symptoms of pain prior to the development of radiographic changes suspicious for osteonecrosis or clinical evidence of exposed bone. A thorough history and intraoral clinical exam is the most effective way to establish the diagnosis.

Diagnostic Testing: The CTX Blood Test

The breakthrough in prevention as well as management was the identification that the C-terminal telopeptide level in blood was correlated with osteo-clastic activity and with clinical healing or response to surgical debridement. (6) The serum test, C-terminal cross-linking telopeptide (CTX), is a morning fasting blood test requiring only 1 ml of blood. It measures an octapeptide fragment of type I bone collagen that is released into circulation upon osteoclastic bone resorption. It has been demonstrated that a CTX value of 100 pg/mL or less represents a high risk for oral bisphosphonate-induced osteonecrosis, a CTX value between 100 pg/mL and 150 pg/mL a moderate risk, and a CTX value of greater than 150 pg/mL a minimal risk.

Based on the CTX levels in the study reported by Dr. Robert E. Marx of the University of Miami School of Medicine (34 with bisphosphonate-induced osteonecrosis of the jaw and more than 100 patients who were on oral bisphosphonates when a surgical procedure was indicated), the following recommendations are made:

Prevention in patients about to start on an oral bisphosphonate or those who have taken one for less than three years: The accumulation of an oral bisphosphonate in bone is slowed by its minimal gastrointestinal absorption. Thus, during the first three years of bisphosphonate consumption, dental practitioners should strive to achieve optimum oral health. Inflammatory conditions should be eliminated during this period so that the need for oral surgical procedures after three years of drug exposure can be reduced or eliminated. This translates into the initial removal of unsalvageable teeth followed by periodontal therapy and comprehensive restorative and prosthodontic dentistry. Dental implants may be placed in this time period. However, informed consent about an increased risk of implant failure after three years of drug exposure should be provided.

Prevention in patients who have received an oral bisphosphonate for three years or more and require a periodontal or oral surgical procedure: For these patients, it is advisable to obtain a reference CTX value. If the CTX value is below 150 pg/mL, use of the drug should be discontinued temporarily. Such a suspension, also known as a "drug holiday," is usually acceptable to the prescribing physician due to studies that have documented the continued control of osteoporosis and prevention of fractures with long-term discontinuation of Fosamax. (4) If the prescribing physician is concerned about progression of the osteoporosis without ongoing drug therapy, nonbisphosphonate alternatives can be suggested. These include raloxifene (Evista[R], Eli Lilly and Company), teriparatide (Forteo[TM], Eli Lilly and Company), or calcitonin-salmon (Miacalcin[R], Novartis). After a four- to six-month drug holiday, another CTX test is advised. If the CTX value remains below 150 pg/mL, then the drug holiday should be extended for another four months. The CTX serum test should then be repeated. The rate of osteoclast recovery as measured by the CTX has been 25 pg/mL per month. In all cases observed, the level of CTX in the blood has recovered to a value in excess of 150 pg/mL in six to nine months.

Management

If systemic conditions permit, patients who are about to initiate intravenous bisphosphonate treatment should have their oral health optimized prior to therapy. Medical oncologists should evaluate and manage patients scheduled to receive IV bisphosphonates similarly to patients scheduled to initiate radiation therapy to the head and neck. The osteoradionecrosis prevention protocols are guidelines familiar to most oncologists and general dentists. (1) While this approach is not necessary for patients who are about to begin oral bisphosphonate therapy, the importance of regular dental care should be stressed, and the patient should be educated as to the signs and symptoms of BRONJ. It is important to understand that routine dental care that does not involve dentoalveolar trauma (i.e., caries control, prosthetic procedures, periapical endodontic therapy, plaque removal) is not contraindicated in any of these patients.

The goals of therapy in patients with established BRONJ are to eliminate pain and infection and minimize the progression of necrosis (Table III). Maintaining a good level of oral hygiene is important for all patients receiving bisphosphonate therapy (at-risk category) to minimize the potential for therapeutic dentoalveolar trauma. Most patients with limited areas of exposed bone who are asymptomatic (Stage 1) can be managed with irrigations alone and close follow-up. Patients with symptomatic areas of exposed bone that are infected (Stage 2) will require oral antibiotic rinses and oral antibiotic therapy for pain relief and infection control. Areas of necrotic bone that are a constant source of soft tissue irritation should be removed without exposing additional bone. However, it is likely that the margin of the debridement will remain exposed. Symptomatic patients with large areas of infected necrotic bone or with pathologic mandibular fractures (Stage 3) require surgical resection.

Discontinuation of IV bisphosphonates offers no short-term benefit. However, if systemic conditions permit, long-term discontinuation may be beneficial in stabilizing established sites of BRONJ, reducing the risk of new site development and reducing clinical symptoms. (7) Decisions regarding the risks and benefits of continuing bisphosphonate therapy should be made only by the treating oncologist in consultation with the oral and maxillofacial surgeon and the patient. Discontinuation of oral bisphosphonate therapy in patients with BRONJ has been associated with gradual improvement in clinical disease following adequate treatment. Modification or cessation of oral bisphosphonate therapy should be done in consultation with the treating physician and the patient.

In 50 percent of the oral bisphosphonate-induced osteonecrosis of the reported jaw cases treated, the exposed bone was spontaneously sequestered or resorbed four to nine months after discontinuation of the drug. (4) Spontaneous recovery was correlated with the CTX value exceeding 150 pg/ml. The remaining cases were resolved with an office-based debridement surgery four to nine months after discontinuation of the drug (again, once the patient's CTX value exceeded 150 pg/ml).

It is recommended that exposed bone due to an oral bisphosphonate be initially managed with 0.12% chlorhexidine if it is nonpainful and there are no signs of infection. If pain or signs of infection are present, penicillin VK 500 mg four times daily is recommended in addition to chlorhexidine. For the penicillin-allergic patient, Levaquin[R] (Ortho-McNeiI-Janssen Pharmaceuticals, Inc.) 500 mg once daily is the best alternative.

At the initial visit, a CTX test should be accomplished and a drug holiday suggested to the prescribing physician. The CTX should be repeated four months later and at four-month intervals thereafter. Once the CTX value exceeds 150 pg/ml, office-based debridement can be considered. If the exposed bone shows radiographic signs of sequestration and the involucrum or exposed bone becomes mobile, the drug holiday may be extended in anticipation of a spontaneous sequesterectomy.

In summary, with common dental procedures, knowledge of bone turnover, and CTX blood testing, bisphosphonate-induced osteonecrosis of the jaw can be prevented in most cases, and in those cases in which osteonecrosis is already present, it can be resolved in a straightforward manner. It is incumbent on the dental practitioner, be they a dental hygienist, general dentist or surgical specialist, to adequately evaluate and manage the bisphosphonate patient. Assessment should include a staging and assignment of the risk group to the patient, and then managing the patient within the published guidelines of care. This should also include consultation with the patient's primary medical care provider or oncologist where staging of the risk and treatment strategies requires clarification.

Additional Reading

AAOMS: American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. Available at: http://www. aaoms.org/docs/position_papers/osteonecrosis.pdf

Marx RE. Oral and intravenous bisphosphonate induced osteonecrosis of the jaws: history, etiology, prevention, and treatment. Chicago: Quintessence, 2006: 77-95.

References

(1.) American Association of Oral and Maxillofacial Surgeons Advisory Task Force on Bisphosphonate-Related Osteonecrosis of the Jaws. Position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 2007 65:369.

(2.) Black DM, Delmas PD, Eastell R et al. HORIZON pivotal fracture trial: once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007; 356: 1809.

(3.) Pozzi S, Marcheselli R, Sacchi S et al. Analysis of frequency and risk factors for developing bisphosphonate associated necrosis of the jaw. Blood (American Society of Hematology Annual Meeting Abstracts) 2005; 106:5057.

(4.) Marx RE, Sawatari Y, Fortin M, Broumand V. Bisphosphonate-induced exposed bone (osteonecrosis osteopetrosis) of the jaws: risk factors, recognition, prevention and treatment. J Oral Maxillofac Surg 2005; 63:1567.

(5.) Dodson TB. Intravenous bisphosphonate therapy and bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 2009; 67 (in publication).

(6.) Ruggiero SL, Fantasia J, Carlson E: Bisphosphonate related osteonecrosis of the jaw: background and guidelines for diagnosis, management and staging. Oral Surg Oral Med Oral Path Oral Rad Endo 2006; 102: 433.

(7.) Ruggiero SL, Mehrotra B, Rosen-berg TJ, et al: Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004; 62:527.

By David A. Salmassy, DMD 

David Salmassy, DMD, is an oral and maxillofacial surgeon, He is a member of the California Dental Association, American Dental Association, American Association of Oral and Maxillofacial Surgeons, and the California Association of Oral and Maxillofacial Surgeons, and International Congress of Oral Implantologists, He maintains a private practice in Auburn, California.

Table 1. Bisphosphonate Preparations Currently Available in the U.S.

                            Primary           Nitrogen
                            Indication        Containing   Dose

Etidronate (Didronel [R])   Paget's Disease   No           300-750 mg
Procter & Gamble                                           daily for
Pharmaceuticals                                            6 months

Tiludronate (Skelid [R])    Paget's Disease   No           400 mg daily
Sanofi-aventis U.S. LLC                                    for 3 months

Alendronate (Fosamax [R])   Osteoporosis      Yes          10 mg/day
Merck                                                      70 mg/week

Risedronate (Actonel [R])   Osteoporosis      Yes          5 mg/day
Procter & Gamble                                           35 mg/week
Pharmaceuticals, Inc.

Ibandronate (Boniva [R])    Osteoporosis      Yes          2.5 mg/day
GlaxoSmithKline                                            150 mg/month
                                                           3 mg every
                                                           3 months

Pamidronate (Aredia [R])    Bone Metastases   Yes          90 mg/3
Novartis                                                   weeks

Zoledronate (Zometa [R])    Bone Metastases   Yes          4 mg/3 weeks
(Reclast [R])               Osteoporosis                   5 mg/year
Novartis

                                    Relative
                            Route   Potency *

Etidronate (Didronel [R])   Oral    1
Procter & Gamble
Pharmaceuticals

Tiludronate (Skelid [R])    Oral    50
Sanofi-aventis U.S. LLC

Alendronate (Fosamax [R])   Oral    1,000
Merck

Risedronate (Actonel [R])   Oral    1,000
Procter & Gamble
Pharmaceuticals, Inc.

Ibandronate (Boniva [R])    Oral    1,000
GlaxoSmithKline             IV

Pamidronate (Aredia [R])    IV      1,000-5,000
Novartis

Zoledronate (Zometa [R])    IV      10,000 +
(Reclast [R])               IV
Novartis

* Potencies are relative to etidronate.

Table II. Staging of BRONJ

Stage 1:   Disease characterized by exposed bone that is
           asymptomatic with no evidence of any significant
           adjacent or regional soft tissue inflammatory
           swelling or infection.

Stage 2:   Disease characterized by exposed bone with
           associated pain, adjacent or regional soft tissue
           inflammatory swelling, or secondary infection.

Stage 3:   Disease characterized by exposed bone associated
           with pain, adjacent or regional soft tissue
           inflammatory swelling, or secondary infection
           and the presence of an extraoral cutaneous fistula
           or a pathologic fracture.

Table III. Risk Profiles and Treatment Strategies

BRONJ * Staging                         Treatment Strategies

Stage 0    No apparent exposed/         No treatment indicated
           necrotic bone in             Patient education
           patients who have been
           treated with either oral
           or IV bisphosphonates

Stage 1    Exposed/necrotic bone in     Antibacterial mouth rinse
           patients who are             Clinical follow-up on a
           asymptomatic and have          quarterly basis
           no evidence of infection     Patient education and
                                          review of indications
                                          for continued
                                          bisphosphonate therapy

Stage 2    Exposed/necrotic bone        * Symptomatic treatment
           associated with infection      with broad-spectrum oral
           as evidenced by pain and       antibiotics, e.g.,
           erythema in the region         penicillin, cephalexin,
           of the exposed bone            clindamycin, or first
           with or without                generation
           purulent drainage              fluoroquinolone
                                        * Oral antibacterial
                                          mouth rinse
                                        * Pain control
                                        * Only superficial
                                          debridement to relieve
                                          soft tissue irritation

Stage 3    Exposed/necrotic bone in     * Antibacterial mouth
           patients with pain,            rinse
           infection, and one or        * Antibiotic therapy
           more of the following:         and pain control
           pathologic fracture,         * Surgical debridement/
           extraoral fistula, or          resection for longer
           osteolysis extending to        term palliation of
           the inferior border            infection and pain

* Exposed bone in the maxillofacial region without resolution
in 8 to 12 weeks in persons treated with a bisphosphonate who
have not received radiation therapy.