Bisphosphonate and Bisphosphonate Induced Osteonecrosis of the Jaws, i.e. BIONJ Review. September , 2009.
- Brian Whitley
Bisphosphonates are powerful inhibitors of bone turnover, particularly osteoclast function. The most common use is in osteoporosis but they are also used in metastatic bone disorders, such as Paget's disease and cancers which affect the bone. Cancer treatment is usually high dose and an IV infusion. Bisphosphonates absorb to bone hydroxyapatite and become absorbed into the bone. They have an estimated half-life of ten years.
(Australian Dental Journal : Vol 50, 4, Supp 2 Dec, 2005)
There are currently two main types of bisphosphonates; nitrogen containing (Fosamax, Actonel, Aredia, Pamisol, Zometa) and non-nitrogen containing (Etidronate, Clodronate and Tiludronate).
The AAOMS Taskforce definition of BIONJ is "the presence of non-healing, exposed bone in the maxilla or mandible that has persisted for more than eight weeks in a patient who has received systemic bisphosphonate but has not received local radiation therapy". BIONJ is histologically similar to osteopetrosis but different to osteomyelitis where there is evidence of repair. The most common cause are dental extractions (70%). The symptoms include odontalgia of non-odontogenic cause, a dull aching bone pain in the mandible, sinus pain and neuropathy. Clinical findings include loosening of teeth in the absence of chronic periodontitis, peri-apical / peri-odontal fistulae not associated with pulpal necrosis due to caries. The radiographic findings include alveolar bone loss or resorption, changes to the trabecular pattern - dense woven pain and persistence of un-modelled bone in extraction sites and a thickening or obscuring of periodontal ligament and inferior alveolar canal narrowing. The relative potency of Etidronate (Didronel) which is a non-nitrogen containing bisphosphonate used in the management of Paget's disease, is 1. By comparison, Alendronate (Fosamax) used primarily for the management of osteoporosis and containing nitrogen is 1000. Pamidronate (Aredia) and Zolendronate (Zometa) both of which are intravenous preparations used in the management of bone metastases have a relative potency to that of Etidronate of 1000-5000 in the case of Pamidronate and 10,000+ in the case of Zolendronate.
The risks for developing BIONJ for patients taking Fosamax is between 1:100, and 1:1000. For patients on the IV nitrogen containing preparations, the risk is in the order of between 10 and 25%. Risks increase with patient age, co-morbidities and the greater total dose.
With respect to dental implants, Goss (2005) reported five patients in Australia who had successful dental implants and were then placed on bisphosphonates subsequently developed loss of integration around some implants. Dental implants are contra-indicated for patients having had intravenous bisphosphonates and relatively contra-indicated for patients receiving Fosamax, considering other risk factors. Bisphosphonate induced osteonecrosis affects the jaws more than other bones because alveolar bone has ten times the turnover of long bones, and is frequently traumatised, for instance during extractions. There is also the added issue of contamination. Risk factors for the development of BIONJ include increasing age, total dose, the duration, for instance with oral bisphosphonates more than three years, and decreased bone turnover.
Marx RE et al (2005) presented data from thirty cases of oral BIONJ contrasting it to data accumulated in 116 cases of IV BIONJ related to risk factors, prevention recommendations and treatment recommendations. The article also introduced morning fasting serum C-terminal telopeptide (CTX) bone turnover marker as a useful clinical tool to assess risk and guide decisions. The CTX specifically measures a specific cross link peptide of type 1 collagen in bone. Type 1 collagen is the structural organic component of bone and accounts for 98% of the total bone protein. The telopeptide fragment is cleaved from the main chains of collagen by the osteoclast during bone resorption. Thus, the level of CTX in fasting morning serum is proportional to the amount of osteoclast resorption occurring at the time the blood is drawn.
C-terminal telopeptide is a bone suppressor marker and the blood test measures bone turnover. It is more sensitive than a bone mineral density test. A high reading would be 1000+ pg/ml, a normal reading would be 400 pg/ml, a low reading 150 - 250 pg/ml, and a reading of < 70 pg/ml would indicate bone turnover has ceased. The risks of BIONJ based on the CTX blood test results would therefore be high risk : 100 pg/ml, moderate risk : below 150 pg/ml, minimal risk : above 150 pg/ml.
The results of Marx's study are as follows:
- 29 out of 30 cases occurred in the mandible, and 1 case occurred in the maxilla
- There was 94.7% predilection for the posterior mandible, and 50% of cases occurred spontaneously
- The remaining 50% occurred as a result of an oral surgical procedure, mostly dental extraction
- Two cases (6.7%) were as a result of dental implant placement, and one case (3.3%) from harvesting a palatal connective tissue graft
The findings in this report indicate that drug holidays of four to six months are reasonable, safe and could be expected to minimise the risk of BIONJ associated with oral surgical procedures. This is due to an anticipated rise in CTX due to an increase in osteoclast function. Bone mass density (BMD) values are maintained in fractures related to osteoporosis prevented.
In terms of prevention, patients first diagnosed with osteopaenia or osteoporosis who are prescribed a bisphosphonate should see the dental team to obtain optimum oral health and repair of the dentition and monitoring. Dental implants are likely safe and will osseo-integrate during this period. However, informed consent should be provided as to an increased risk of implant failure or osteonecrosis about the implants once the oral bisphosphonate exposure exceeds three years. Substitute drugs used for osteoporosis might include Raloxifene (Evista), Calcitonin Salmon (Miacalcin), and Recombinant Human 1-34 parathyroid hormone (rh-1-34PTH-Forteo). FDA clearance has been obtained for these three preparations.
Management strategies for patients receiving Fosamax include the following :
- Fosamax less than three years - no clinical risk factors - no alteration or delay in surgery
- Fosamax less than three years and taking steroids - three month "drug holiday" before surgery
- Fosamax greater than three years - "drug holiday" for three months then CTX prior to surgery
- IV bisphosphonates - CTx; if systemic conditions permit, discontinue and repeat CTX
For cases of established BIONJ, the treatment objectives include the elimination of pain, the control of infection of hard and soft tissue and to minimise the progression or recurrence of bone necrosis.
Staging and Treatment Strategies
| BIONJ Staging | Treatment Strategies |
| At risk category – no apparent exposed / necrotic bone in patients who have been treated with either oral or IV bisphosponates |
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| Stage 1 – exposed / necrotic bone in patients who are asymptomatic and have no evidence of infection |
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| Stage 2 – exposed / necrotic bone associated with infection as evidenced by pain and erythema in the region of the exposed bone with/without purulent drainage |
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Stage 3 – exposed / necrotic bone in patients with pain, infection and one or more of the following:
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In papers by Lee C et al (2007) and Curie M et al (2007), the use of platelet rich plasma has shown promise in the management of oral bisphosphonate induced osteonecrosis of the jaws. Platelet rich plasma (PRP) is a rich source of growth factors involved in wound healing. The main growth factors involved include platelet derived growth factor (PDGF), transforming growth factor-beta (TGF-b), vascular endothelial growth factor (VEGF), Insulin like growth factor 1 and epidermal growth factor (EGF). These growth factors recruit undifferentiated mesenchymal stem cells to the site of injury and stimulate mitosis. They stimulate osteoblast differentiation with formation of new bone and also stimulate osteogenesis. In these case reports, combined with marginal resection of the affected area ± hyperbaric oxygen therapy, PRP reduces the treatment time of avascular osteonecrosis and improves patient comfort. It produces bone re-modelling with no evidence of wound dehiscence or breakdown at six months. Clearly, further larger randomised prospective studies are needed to confirm the findings of these case reports.
In terms of genetic risk factors for the development of BIONJ, Sarasquete ME et al (2008) reported a single nucleotide polymorphism in the cytochrome P 450 – 2C gene (CYP 2C8). This was associated with an increased risk of BIONJ among multiple myeloma patients treated with IV bisphosphonates.
Marx RE (2009) reported on reconstruction of defects caused by BIONJ of the jaws. He recommended implant placement following debridement provided there was sufficient alveolar bone and the CTX remains > 150 pg/ml. There was a higher incidence of implant failure and bone loss in cases of oral bisphosphonate use for several years and without a CTX or a CTX of < 100 pg/ml. A drug holiday of between four months and one year to gain a CTX of > 150 pg/ml has been demonstrated to have proven negligible effects on osteoporosis / osteopaenia and clinical safety by randomised clinical trials. Predictable outcomes using drug holiday / CTX testing has been found for alveolar grafts for site preparations, ridge augmentations, maxillary sinus augmentations and cancellous cellular marrow grafts for continuity defects following resection for BIONJ.
Kuncher R et al (2009) reported on a clinical investigation of C-terminal cross linking telopeptide test in the prevention and management of bisphosphonate associated osteonecrosis of the jaws. The aim of the study was to determine, in a clinical setting, the effectiveness of the C-terminal cross linking telopeptide test (CTX) in the prevention and management of osteonecrosis of the jaws (ONJ) in patients taking biphosphonates. A total of 348 patients underwent a fasted morning CTX test. Of these, 222 were patients at risk of ONJ who had been referred for extractions, 15 had ONJ, and 113 were controls.
The 215 patients taking long term oral bisphosphonates were older (71± 11.6 years), were predominantly women with osteoporosis, and were medically compromised – cardiovascular, renal or respiratory disease. The average CTX value was 238 ± 144 pg/ml, with 98 having a value less than 200 pg/ml. One patient with a CTX value of 126 pg/ml developed ONJ after extraction. 7 intravenous bisphosphonate patients underwent extractions with no cases of ONJ developing. The CTX values were 329 ± 354, with 4 less than 200 pg/ml. 15 patients developed ONJ, 12 after extractions and 3 spontaneously. Of these, 7 who were still taking a bisphosphonate at presentation, had a CTX value of 116 pg/ml.
A CTX value of < 150 pg/ml did not correlate with the clinical risk factors of age, gender, co-morbidities, bone disease or bisphosphonate duration. A statistically significant difference in the CTX value was found for those taking Alendronate (Fosamax) compared with those taking Risedronate (P < 0.001). If the bisphosphonate was ceased, the CTX value increased at approximately 25 pg/ml per month. The authors concluded that the CTx test is not predictive of the development of ONJ for an individual patient, but does identify those in the “risk zone”, which is a value of < 150 – 200 pg/ml. If medically appropriate, the bisphosphonate can be ceased so that the CTX value increased to bring the patient out of the “risk zone”.
References:
- Bisphosphonate Therapy: Implications for the Oral and Maxillofacial Surgery Patient,
Journal of Oral and Maxillofacial Surgery 67 (5) May 2009, Supplement 1 - Curie M, Cossolin G, Koga D et al
Treatment of Avascular Necrosis of the Mandible in Cancer Patients with a History of Bisphosphonate Therapy by Combining Bone Resection and Autologous Platelet Rich Plasma: Report of Three Cases.
J Oral Maxillofac Surg 65 : 349 – 355, 2007 - Goss A
ANZAOMS Update Newsletter March 2007 - Kuncher R, Need A, Hughes T, Goss A
Clinical Investigation of C-Terminal Cross Linking Telopeptide Test in Prevention and Management of BAOJ
J. Oral Maxillofac Surg 67 : 1167 – 1173, 2009 - Lee C, David T, Nishime M
Use of Platelet Rich Plasma in the Management of Oral Bisphosphonate – Associated Osteonecrosis of the Jaw : A Report of Two Cases.
J. Oral Implant. 6; 371 – 382, 2007 - Marx RE, Cillo JE, Ulloa J.
Oral Bisphosphonate Induced Osteonecrosis : Risk Factors, Prediction of Risk Using Serum CTX Testing, Prevention, and Treatment
J. Oral Maxillofac Surg 65 : 2397, 2007 - Marx RE
Reconstruction of Defects Caused by Bisphosphonate Induced Osteonecrosis of the Jaws
J. Oral Maxillofac Surg 67 : 107 – 119, 2009, Suppl. 1 - Sarasquete ME, Garcia-Sanz R, Marin L, et al
Single Nucleotide Polymorphism in the Cytochrome P450 – 2C Gene (CYP 2C8) Associated with an Increased Risk of BRONJ Among Multiple Myeloma Patients Treated with IV Bisphosphonates
Blood 112 : 2709, 2008