biphosphonates

MEDICATION-RELATED OSTEONECROSIS OF THE JAW – MRONJ – CASE STUDIES 
Bisphosphonates (BP) are a group of medications affecting bone metabolism. Oral BP has been successfully used to prevent and treat osteoporosis as well as in the treatment of Paget’s disease, osteogenesis imperfecta, in the management of giant cell lesions of the jaws has also been recommended.

Intravenous BP has an important role in the management of hypercalcemia of malignancy, skeletal related events associated with bone metastasis from solid tumors and in the treatment of multiple myeloma. Newer indications for intravenous BP medications include their use in osteoporosis as alternatives to oral BP.

No doubt the quality and often the length of life of patients with many types of bone diseases, is enhanced in patients treated with BP medications.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a complication of BP reported only in the jaws, in which necrosis of bone is followed by exposure to the oral cavity. Inflammation suppuration and pain are typical, with a chronic course. It is a debilitating condition, which is often resistant to treatment.

Until approximately 2003 cases of osteonecrosis were primarily noted in patients with osteomyelitis and osteoradionecrosis.

In 2003 OMFS first recognized and reported cases of nonhealing exposed bone in the maxillofacial region in patients treated with IV BPs.

In 2004 Novartis notified healthcare professionals of additions in the labelling of these products that 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 BPs.

Approximately 90% of patients reported with BRONJ were treated by IV BP, and the remaining 10% oral BP.

The National Institute of Health has provided funding opportunities for research on the pathophysiology of MRONJ. The main areas of investigations include: a. the effect of BPs on intraoral soft tissue wound healing, b. the treatment in patients who developed MRONJ disease, and c. the development of valid MRONJ risk assessment tools.

The purpose of this paper is to provide perspectives on the risk of development BRONJ and the risk of benefits of BPS to facilitate medical decision-making of both the treating physician and the patients. Furthermore to provide guidance to clinicians on possible BRONJ prevention measures and treatment of patients with BRONJ according to the presenting stage of the disease.


Indications and Benefits of Bisphosphonate therapy:

Bisphosphonates:

  • Hypercalcemia of malignancy
  • Bone metastasis of solid tumors
  • Osteolytic lesions of Multiple myeloma
  • Osteoporosis

Oral Bisphosphonates:

  • Osteoporosis / Osteopenia
  • Paget’s disease
  • Osteogenesis imperfecta
  • Multifocal osteomyelitis
  • Central giant cell tumor
  • Histiocytosis
  • B Thalassemia
  • Fibrous dysplasia

Patients benefit from the use of BPs they have had a significant positive effect of the quality of life controlling the pain and preventing the possibility of fractures. They prevent from 40% to 70% of fractures of the hip and the spine.

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The AAOMS position paper from 2006 and its modification from 2009 suggested a set of criteria for diagnosis and treatment of BRONJ. The requirements for diagnosis of BRONJ include:

  1. Current or previous treatment with a bisphosphonates
  2. Exposed bone in the maxillofacial region that has persisted for more than 8 weeks
  3. No history of radiation therapy to the jaws

According to case series, case controlled studies and cohort studies, IV BPs exposure, estimates  of the cumulative incidence of BRONJ have ranged from 0,8% to 12%

A prevalence of 0.10% has been recently reported among oral BP users, more frequently in patients using the medications for over 3 years.


Risk factors associated with development of BRONJ

  1. Drug related risk factors include BP potency and the duration of therapy. Zometa is more potent than Fosamax and the IV route of administration results in greater drug exposure than the oral route, increasing the risk of developing of BRONJ disease. A longer duration of therapy appears to be associated with increase risk.
  1. Local risk factors include dentoalveolar surgery like extractions, dental implant placement, periapical surgery, periodontal surgery involving osseous injury.

Cancer patients treated with IV BPs who undergo dentoalveolar procedures have a 5 – to 21- fold increase risk of BRONJ compared with cancer patients treated with IV BPs who do not undergo dentoalveolar procedures. It has been observed that lesions are found more commonly in the mandible than the maxilla (2:1 ratio) and more commonly in areas with thin mucosa overlying bony prominences such as tori, bony exostoses and the mylohyoid ridge.

Cancer patients exposed to IV BPs with a history of inflammatory dental disease are at the 7- fold increased risk of developing BRONJ.

  1. Demographic and systemic factors

Older and white patients have an increased risk of BRONJ compared with younger and blacks. Systemic factors or conditions such as renal dialysis, anaemia, obesity, diabetes, smoking and the use of steroids were variably reported to increase the risk of BRONJ.

  1. Genetic factors

It is demonstrated that single nucleotide polymorphisms, in the cytochrome P450-2c gene were associated with an increased risk of BRONJ among multiple myeloma patients treated with IV BPs.

  1. Preventing factors

The AAOMS Taskforce on BRONJ recommended that patients undergo dental evaluations and receive necessary treatment before initiating BP therapy.  In addition given the long-term biologic activity of IV BPs, one could hypothesize that different dosing regimens might be equally effective and decrease the risk of BRONJ.

Several studies suggest that although BRONJ is not eliminated, dental evaluations and treatment before initiating IV BP therapy among cancer patients reduces the BRONJ risk. The risk of developing associated with oral BPs, although exceedingly small, appears to increase when the duration of therapy exceeds 3 years.

If systemic conditions permit, the clinician might consider discontinuation of oral BP for 3 months period before and 3 months period after elective invasive dental surgery to lower the risk of BRONJ. Modification or cessation of oral BP therapy should be done in consultation with the treating physician and the patient.

The Morning Fasting CTX Test is critical to predictably successful reconstructive survey including dental implant placements in patients who have received oral BP therapy and who have not taken prednisone or methotrexate. The CTX test measures an octapeptide  fragment of collagen cleaved by the collagenase of osteoclasts during bone resorption. Therefore, this test represents an index of osteoclast function and bone turnover.

Normal values are over 350 pg/ml. Lower numbers represent greater degress of bone turnover suppression. Less than 100pg/ml= high risk, 100 pg/ml to 150 pg/ml= moderate risk, and greater than 150pg/ml= little or no risk.


The treatment goals for patients are risk of developing or who have BRONJ are preservation of quality of life through:

  1. Patient education
  2. Control of pain
  3. Control of secondary infection
  4. Prevention of extension of lesion and development of new areas of necrosis

The treatment strategies have been determined from published studies.

Patients about to initiated IV BP treatment: if systemic conditions permit, initiation of BP therapy should delayed until the dental health has been optimized. This decision must be made in conjunction with the treating physician and dentist and other specialist involved in the case of a patient. It appears advisable that BP therapy should be delayed for 14 to 21 days until the extraction side has mucosalized. It is critical that patients be educated as to the importance of dental hygiene in order to prevent the disease. Medical Oncologist should evaluate and treat patients scheduled to receive IV BP similarly to those patients scheduled to initiate radiotherapy of the head and neck.


Asymptomatic patients receiving IV BP

Procedures that involve direct osseous injury should be avoided as well as placement of dental implants in the oncology patient exposed to the more potent IV BP medications on a frequent dosing schedule 4 to 12 times annually. Reclast administered once annually for the treatment of osteoporosis suggests a low risk of BRONJ. The efficacy of a drug holiday for patients receiving yearly zoledronic acid therapy is unknown and requires additional study.


Asymptomatic patients receiving Oral BP therapy

Patients receiving oral BP are also at risk of developing BRONJ but to a much lesser degree than those treated with IV BP.

BRONJ can develop spontaneously or after minor trauma. In general these patients seem to have less severe manifestations of necrosis and respond more readily to stage-specific treatment regimens. Patients has to be adequately informed of the small risk of compromised bone healing.

No information is available to suggest that monthly dosing of oral BP is associated with the risk of BRONJ. The risk of developing BRONJ associated with oral BP increased when the duration of therapy exceeded 3 years and the patients are divided in 3 categories:

  • For individuals who have taken an oral BP for fewer than 3 years and have no clinical risk factors, no alteration or delay in the planned surgery is necessary. Patients with dental implants should be informed that possible future implant failure and possible osteonecrosis of the jaw if the patient continues to take an oral BP and should be placed on a regular recall schedule.
  • For the patients who have taken an oral BP for fewer than 3 years and have also taken corticosteroids concomitantly, the prescribing provider should be contacted to consider discontinuation of the oral BP for at least 3 months before oral surgery, if systemic conditions permit. The BP should not be restarted until osseous healing has occurred.
  • For those patients who have taken an oral BP for more than 3 years with or without any concomitant prednisone or other steroid medication, the prescribing provider should be contacted to consider discontinuation of the oral BP for 3 months before oral surgery if systemic conditions permit. The BP should not be restarted until osseous healing has occurred.
  • Patients with BRONJ

The treatment objectives for patients with an established diagnosis of BRONJ are to eliminate pain, control infection of the soft and hard tissue, and minimized the progression or occurrence of bone necrosis. These patients respond less predictably to the established surgical treatment algorithms for osteomyelitis or osteoradionecrosis.

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AAOMFS-Position Paper on BRONJ-2009 Update             

J Oral Maxillofacial Surg 67:2-12,2009,Suppl 1

Regardless of the disease stage, mobile segments of bony sequestrum should be removed without exposing uninvolved bone. The extraction of symptomatic teeth within exposed, necrotic bone should be considered since it is unlikely that the extraction will exacerbate the established necrotic process. Treatment modalities suggested differ according to the clinical stage, and include prolonged antibiotic treatment, sequestrectomy, surgical debridement, and even resection in certain cases. Hyperbaric oxygen treatment may also be indicated, however, there is not enough information in the literature nor are there well-established protocols regarding management of BRONJ.

The therapeutic effect of parathyroid hormone or BMP is under investigation.

Patients at risk no apparent necrotic bone in asymptomatic patients who have been treated with IV oral BP. These patients should be informed of the risks of developing BRONJ as well as the signs and symptoms of this disease process.

Stage 0: patients with no clinical evidence of necrotic bone, but who present with nonspecific symptoms or clinical and radiographic findings, including odontalgia, dull, aching bone pain, sinus pain, altered neurosensory functions. Systemic management can include the use of medication for chronic pain and the control of infection with antibiotics when indicated.

Stage 1: exposed and necrotic bone in patients who are asymptomatic and have no evidence of infection. These patients benefit from the use of oral antimicrobial rinses, such as chlorhexidine o, 12%.

Stage 2: exposed and necrotic bone in patients with pain and clinical evidence of infection. These patients benefit from the use of oral antimicrobial rinses, combined with antibiotic therapy. It has been hypothesized that the pathogenesis of BRONJ might be related to factors adversely influencing bone remodelling. Additionally BRONJ is not due to a primary infectious etiology. Most of the isolated microbes have been sensitive to the penicillin group of antibiotics. Quinolones, metronidazole, clindamycin, doxycycline and erythromycin have been used with success in those patients allergic to penicillin. In cases with Actinomycosis the antibiotic regimen and the duration of treatment should be adjusted accordingly.

Pain control and surgical debridement are necessary.

Stage 3: exposed and necrotic bone in patients with pain, infection and exposed necrotic bone extending beyond the region of alveolar bone or pathologic fracture or extraoral fistula or oral antral/ oral nasal communication or osteolysis extending to the inferior border of the mandible or sinus floor.

These patients benefit from debridement, including resection, combined with antibiotic therapy, which might offer long term palliation with resolution of acute infection and pain.

Oncology patients benefit greatly from the therapeutic effects of BP because they control bone pain and the incidence of pathologic fractures. Discontinuation of IV BP offers no short term benefit. However if systemic conditions permit long term discontinuation might be beneficial in treatment of BRONJ and reducing clinical symptoms.

The risk and benefits of continuing BP therapy should be determined only by the treating oncologist in consultation with the Oral & Maxillofacial surgeon and the patient.

Discontinuation of oral BP therapy in patients with BRONJ has been associated with gradual improvement in clinical disease. Discontinuation of oral BP from 6 to 12 months can result in either spontaneous sequestration or resolution after debridement surgery. If systemic conditions permit modification or cessation of oral BP therapy should be done in consultation with the treating physician and the patient.


Cases Treated in our Clinic

Case 1

Case 1

 

69 year old lady came to our clinic for the first time in 2007, citing in her medical history rheumatoid arthritis and osteoporosis. She did not smoke or made alcohol use. For 22 years (since 1991) she was receiving alendronate orally. In her dental history it is indicated removal of wisdom tooth No.28 in 2005 without healing. Her biggest complaint was pain and swelling in the left maxilla. During the clinical examination, swelling and pain on the left upper jaw with erythema mucosa, suppuration, intraoral communication and granulation tissue was identified

Patient was diagnosed with osteomyelitis actinomycosis consistent with BRONJ disease stage 3.

Immediate discontinuation of bisphosphonate was effected, surgical debridement, washes with chlorhexidine and antibiotics by mouth for seven months. The wound was completely closed two months later. Patient presented recurrent pain, swelling, and suppuration intraoral fistula. Surgical debridement was effected and antibiotics from the mouth was given. Also hyperbaric oxygen therapy (30 dives) was effected. Due to persistence of the disease hemimaxillectomy was effected in October 2010 and close of the wound in two layers using fat graft. Since then patient presents complete cure as seen in clinical and radiographic picture 2½ years later. The Patient presented clinical and radiological features of BRONJ disease stage 3 and made use of bisphosphonates orally. Initially with conservative treatment, outcomes were poor, based on treatment protocols for stage 3 disease. The disease was fired after three years of drug discontinuation. This case shows that the risk for appearance of BRONJ disease increases with the duration of oral therapy. There is a correlation between the initial duration of use of bisphosphonates BP and the time required for healing after stopping the drug (in this case three years).

This incident presented unusual BRONJ disease after tooth extractions because of oral bisphosphonate use that required treatment similar with that required in severe BRONJ due to intravenous bisphosphonate use.

 


Case 2

 

Case 2

Lady 70 years old came to our clinic for the first time in February 2016 complaining of pain and necrosis in the anterior and left mandible. Patient is suffering from multiple myeloma in the last seven years (2009) and amyloidosis and takes Revlimin, Dexamed, Calcium and Zometa IV systematically. She does not smoke nor consume alcohol. Dental findings indicate automatic necrosis in the lower jaw and mobility of teeth 31, 41 is indicated . In the panoramic radiograph inflammation around the teeth 31, 41 and bone necrosis are apparent .

BRONJ disease stage 2 was diagnosed. Zometa was stopped and tooth removal of teeth 31, 41 was effected as well as surgical debridement of the dead bone. Antibiotic (Dalacin 300mg x 4 daily) was administered followed by washes with chlorhexidine 2% for weeks. After five weeks the area showed healing while it did not present any recurrence 6 months later.

 


Case 3

Case 3

 

Male 63 years old was admitted to hospital for the first time in February 2016 complaining of intense pain in the jaw and weakness in chewing. Medical history included lung cancer with metastases in the liver and bones is indicated. He was granted Zometa IV for a year, and the administration of Zometa IV was paused in February 2015. During the clinical examination intraoral fistula with suppuration and granulomatous tissue in the upper jaw right and necrotic bone in the upper jaw left were identified . In the mandible, patient presents bilateral necrosis and extraoral fistula left. In the panoramic radiography and 3D Cone Beam tomography bone necrosis is observed, along with pathological fracture in the left mandible and turbidity in the right maxillary antrum.

BRONJ disease stage 3 was diagnosed and debridement was held, as well as closure of the intraoral fistulaPatient showed complete cure 4 months later.

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