Bisphosphonates in Dentistry and Osteonecrosis of the Jaws
Osteonecrosis of the jaws is a rising issue of multidisciplinary medical interest, unknown until the last decade of the 20th century, that has also had great resonance in the field of dentistry in recent years. This phenomenon is a potential adverse reaction to drugs of the bisphosphonate class containing nitrogen (aminobisphosphonates). Although the present scientific evidence does not support the existence of a cause-effect relation between the use of the drug and the onset of the disease, many epidemiological and experimental studies confirm the strong association between IV bisphosphonates (injectable solution) pharmacological treatment and the development of osteonecrosis of the jaws. IV bisphosphonates are thought to be the major risk factors for the onset of the disease: the cumulative incidence is estimated to be between 0.8% and 12%.
The overall risk to develop that condition for the patients undergoing aminobisphosphonate therapy is not yet clearly assessed; it is nonetheless possible to state, on the basis of epidemiological studies and clinical observations, that the risk is higher for the patients that have been administered the drug intravenously rather than orally.
The diagnostic criteria introduced by the American Association of Oral and Maxillofacial Surgeons for bisphosphonates-related osteonecrosis of the jaws require the concurrence of three factors: current or previous treatment with the drug, exposure of bone tissue in the maxillofacial area for more than eight weeks and absence of positive anamnesis for radiation therapy to the jaws.
Bisphosphonates, and particularly aminobisphosphonates, are drugs that present a high affinity for circulating calcium and calcium that is present on the bone surface: moreover, they remain present in the bone tissue for many years. They are strong inhibitors of bone resorption and remodeling since they stop the osteoclasts’ differentiation and their enzymatic activity (collagen degradation). At high concentrations they are able to induce the osteoclasts’ apoptosis.
|Brand Name||Active Ingredient||Route of administration|
|Boniva||Ibandronate sodium||Oral, intramuscular|
|Aredia||Pamindronate disodium||Intravenous, intramuscular|
|Zometa||Zoledronic acid||Intravenous, intramuscular|
|Reclast||Zoledronic acid||Intravenous, intramuscular|
- Osteoporosis treatment
- Paget’s disease
- Bone metastases from solid tumors
- Multiple myeloma
- Malignant Hypercalcemia
Some aminobisphosphonates administered in specific concentrations are able to inhibit angiogenesis and thus have direct antitumor effect.
RISK FACTORS FOR THE APPEARANCE OF OSTEONECROSIS:
DRUG DEPENDENT RISK FACTORS
|Brand name||Active Principle||Relative Potency|
- Length of the therapy
A longer duration of the therapy is associated with an increasing risk, especially if the therapy exceeds three years. The risk for the patients is 1% during the first year of treatment and rises to 11% after 4 years. The risk for the patients taking zoledronate only is 21% after 3 years.
- Combining two or more aminobisphosphonates
Combined administration of zoledronate and pamindronate shows a ten-fold increased risk.
LOCAL RISK FACTORS
- Dentoalveolar surgery (extractions, implants’ insertion, periapical surgery)
Patients treated with IV bisphosphonates present a risk at least 7 times higher to develop osteonecrosis if they undergo dentoalveolar surgery.
- Local anatomy (mandibular tori, mylohyoid line, palatal tori)
The mandibular structures appear to suffer twice as much as the maxillary from osteonecrosis and especially by the mucous areas covering the bony growths.
- Concurring oral diseases (dental and periodontal abscesses)
Patients suffering from cancer and treated with IV bisphosphonates with positive anamnesis for oral lesions present a risk to develop osteonecrosis 7 times higher.
DEMOGRAPHIC AND SYSTEMIC RISK FACTORS
Patients suffering from osteonecrosis are generally older than 40 since bisphosphonates are prescribed to people suffering from diseases that are mostly age-related. However, it is worth remembering that the risk of osteonecrosis increases with age.
- Systemic diseases (diabetes, obesity, kidney failure, anaemia)
The presence of these diseases increases the risk of osteonecrosis.
- Concurrent pharmacological therapies (glucocorticoids, cyclophosphamide, erythropoietin, IV ranitidine).
They increase the risk of osteonecrosis . Chronic use of glucocorticoids, in particular, inhibits the laying down of osteoid matrix by osteoblasts and induces their apoptosis. This results in secondary osteoporosis. Prednisone increases alendronate’s bioavailability between 20 and 44%. The use of chemotherapy drugs, on the other hand, induces a neutropenia responsible for increased possibilities of mouth infections. IV ranitidine increases the bioavailability of alendronate by 100% and ibandronate by 20%.
It increases the risk of osteonecrosis.
GENETIC RISK FACTORS
The polymorphism of a single nucleotide of cytochrome P450-2C gene is associated with an increased risk of osteonecrosis in patients suffering from multiple myeloma treated with IV bisphosphonates.
CLINICAL DIAGNOSIS OF OSTEONECROSIS
The clinical aspects of osteonecrosis of the jaws result from the exposure of non-vital white-yellowish bone tissue surrounded by inflamed and edematous mucosa in the mouth: this situation can be anticipated by a vague sensation of pain or discomfort in the affected area. In case there is no clinical and radiographic evidence of inflammatory, metabolic, cystitis or neoplasic reactions the differential element for an early diagnosis is the very sensation of pain by dental elements or edentulous areas of the jaws reported by the patients who had undergone, also earlier in time, bisphosphonate therapy. Osteonecrosis generally shows itself after manoeuvres that can cause traumas to the bone (e.g. dental extractions); episodes of spontaneous onset (40%) have been observed and documented especially by palatal and mandibular tori. The most frequently affected area is the mandible. However, the upper jaw can be affected and some patients can show multifocal osteonecrosis of the jaws. Before reaching bone necrosis it is possible to identify signs and symptoms that are typical of any odontogenous infection (pain, edema and ulceration of the mucosa, dental mobility): these symptoms should alert the specialist and address him towards an early diagnosis. In an advanced stage of the disease it is possible to observe the presence of inflammatory and infectious foci (suppurative osteomyelitis), pathological fractures, skin fistulas, oral and nasal antral fistulas that contribute to worsen the symptomatology.
|At risk||Absence of clinical evidence and symptoms in patients treated with bisphosphonates (via oral, intravenous or intramuscular route)|
|Stage 0||Absence of clinical evidence and presence of aspecific symptoms and clinical or dubious radiological reports|
|Stage 1||Presence of bone exposure without symptoms|
|Stage 2||Presence of bone exposure and concurring pain, inflammation or tissue infection|
|Stage 3||Presence of bone exposure and concurring pain, inflammation or tissue infection along with one or more of the following clinical reports: pathological fractures of the alveolar bone, extraoral fistulas, oro-nasal antral communication, osteolysis of the inferior section of the mandible or of the maxillary sinus floor|
During the initial stages of osteonecrosis of the jaws it is possible to observe slight or insignificant changes of the bone architecture when a panoramic or periapical endo-oral X-ray scan is performed. The effects of the pharmacological therapy result in a systemic increase of the bone mineral density that affects the maxillary bones evenly. It is thus impossible to notice an increased radio-opacity of single bone segments radiographically, as it is possible in the case of the most common focal diseases. As the disease progresses and the bone exposure in the mouth becomes more evident, the bacterial superinfection and the bone local demineralization processes may result in a specific radiographic discontinuous aspect due to the presence of alternating radiopaque and radiotransparent areas: this feature may raise the issue of a possible osteolitic process on (osteomyelitis, bone metastases, bone lymphoma). In the advanced states of the disease the process of osteonecrosis can lead to the formation of bone sequestrum recognizable by means of X-rays for the typical sclerotic or streaked aspect of a bone section surrounded by a radiotransparent halo. Two important elements for an early radiographic diagnosis are finding an alveolus that does not fill up with bone in the expected amount of time after the extraction of a tooth and an evident residual lamina dura: these findings should alert the dentist for the presence of a possible growing risk of osteonecrosis not yet clinically determinable.
Necrotic bone devoid of osteocytes and osteoclasts surrounded by granulation tissue with or without abscess collections. Metastases by the osteonecrotic bone and the surrounding soft tissues have never been observed but in the case of multiple myeloma: it is worth remembering that multiple myeloma is considered a malignant primitive bone tumor and not a metastatic lesion.
Studying biochemical markers of bone turnover makes it possible to evaluate non invasively both bone metabolism variations and the patient’s response to the pharmacologic therapy and the variation in markers’ concentration in case the drug is discontinued. The markers to be taken into account are:
- Osteoblastic activity markers (they show the amount of bone deposition):
1. Serum osteocalcine (synthesised by osteoblasts and odontoblasts)
2. Bone serum alkaline phosphatase (isoenzyme present on the osteoblasts membrane)
3. Serum bone sialoprotein
- Osteoclastic activity markers (they show bone resorption)
1 C-telopeptide of collagen type I CTX (collagen degradation product due to osteoclasts) from serum and urine
2. N-telopeptide of collagen type I NTX from serum and urine
3. Urine deoxypyridinoline
Other markers of bone resorption, such as urine pyridinoline, urine hydroxyproline, serum tartrate-resistant acid phosphatase, are not bone-specific since they can be found in other tissues as well and thus they are not reliable markers of bone metabolism. Bone resorption markers are very useful when monitoring patients undergoing bisphosphonates therapy since they are effective indicators both of the effectiveness of the therapy and the risk of osteonecrosis of the jaws.
MANAGEMENT OF PATIENTS TREATED WITH BISPHOSPHONATES
Granted that the exposure to bisphosphonates and dentoalveolar procedures are the two major risk factors for the development of osteonecrosis of the jaws, a way of preventing the disease can be having the patients undertake an accurate oral and extra-oral exam – inclusive of X-ray scan – and perform all the necessary dental treatments to restore mouth, soft and hard tissues’ health before starting the pharmacologic therapy. Recent studies have shown that this kind of therapeutic approach can effectively reduce – but not get rid of – the risk of osteonecrosis. In the case of bisphosphonates oral therapies, if general health conditions permit and the patient needs dentoalveolar surgery, a discontinuation of the drug 3 month prior and 3 month following the dental treatment could be hypothesized in order to reduce the risk of osteonecrosis. Although the effectiveness of discontinuing the drug (drug holiday) is yet to be assessed by long term prospective studies, the results of the study of the fluctuations in the osteoclastic function in relation to bisphosphonates administration have suggested the possibility to give credit to this kind of approach.
- Preserve a good quality of life by means of:
1. Control of pain
2. Hard and soft tissues secondary infections control
3. Prevention of the development of new areas of necrosis
- Not to stop oncologic cures in patients treated with IV bisphosphonates that are able to control well bone pain and reduce the onset of skeletal complications.
PATIENTS THAT HAVE TO START IV BISPHOSPHONATES
The aim of the therapy is to reduce the risk of osteonecrosis of the jaws. If the general health conditions of the patient permit, the start of the pharmacologic treatment should be postponed until overall oral health (the health of all the dental elements, periodontal tissues and soft tissues) is at its best. Unsalvageable teeth and those with uncertain prognosis should be extracted. In the case of dental extractions, it would be better to wait for the complete re-epithelization of the extraction site (14-21 days) or an adequate bone healing before starting the pharmacologic therapy. Patients with total or partial prosthesis should be carefully examined to detect possible mucous areas subject to traumatism and the necessary treatments to reduce those strains should be performed. Preventive treatment, caries control, preservative dentistry and patient motivation are fundamental instruments to preserve the health of the remaining dental elements.
PATIENTS UNDER TREATMENT WITH BISPHOSPHONATES WITHOUT SYMPTOMS
Dentoalveolar surgery can be performed on these patients who must be made aware of the risk – tough very light – to develop osteonecrosis of the jaws. The patients belonging to this group present a much lower risk of developing osteonecrosis of the jaws than those in therapy with IV bisphosphonates: moreover, in case they develop osteonecrosis, the lesions are smaller and they quickly respond to stage-specific therapy. The study of bone turnover markers and the temporary discontinuation of the pharmacologic treatment can be of further help during the decision phase. In these patients osteonecrosis can occur spontaneously or after a light trauma and the risk tends to increase for therapies that last more than 3 years. The guidelines to manage these patients contemplate two different therapeutic strategies:
- Patients in therapy for less than 3 years and without clinical risk factors can undergo any kind of oral, periodontal and maxillofacial surgery. In case titanium implants are placed, the patient must be informed of the possibility of osteonecrosis or failure of the very operation.
- The patients in therapy for less than 3 years that takes corticosteroids and the patients in therapy for more than 3 years, whether or not taking corticosteroid, must discontinue the therapy for at least 3 months prior the oral surgery, if the general conditions permit, until complete bone healing.
PATIENTS IN THERAPY WITH IV BISPHOSPHONATES WITHOUT SYMPTOMS
An adequate oral hygiene regimen and non-invasive dental therapies are the best compromise to prevent oral and periodontal diseases that may later lead to surgery. All the procedures that may directly cause trauma to the bone should be avoided. Non-restorable teeth should be treated by removal of the crown and devitalized. Implant operations should be avoided.
PATIENTS IN THERAPY WITH ORAL BISPHOSPHONATES WITH OSTEONECROSIS
Oral bisphosphonates-related osteonecrosis is a less common and less severe adverse reaction: the lesions spontaneously resolve in 50% of the cases treated with the pharmacological therapy discontinuation protocol (drug holiday) associated with the serum terminal C-telopeptide of collagen type I CTX test. This test measures the bone turnover suppression testing a fragment of collagen type I (main component of the organic bone matrix) made up of eight amino acids, that is broken down by osteoclastic collagenasis in the bone resorption phase. It is thus an index of osteoclastic function and bone remodeling. The normal range is higher than 350 pg/mL. A range below 100 pg/mL indicates a high risk, a range between 100 and 150 pg/mL indicates a moderate risk, a range higher than 150 pg/mL indicates a low risk or no risk at all. The CTX test is only valid for non oncologic patients and for oncologic patients without bone metastases: it is not reliable if the patients who undergo it suffer from rheumatic disease and are in therapy with methotrexate, prednisone or raloxifene. The remaining 50% of the cases requires debridement of the necrotic tissue.
PATIENTS IN THERAPY WITH IV BISPHOSPHONATES WITH OSTEONECROSIS
IV (intravenous) bisphosphonates-related osteonecrosis of the jaws is a more common and larger adverse reaction causing more loss of soft tissues and harder to treat than oral bisphosphonates-related osteonecrosis of the jaws. This is due to the higher potency of IV bisphosphonates that bind faster with calcium and build up more in the bone tissue. It is also worth remembering that the subjects treated with these drugs are oncologic patients that also take corticosteroids and chemotherapy drugs that make the bone tissue more vulnerable to the effects of bisphosphonates. Some cases of osteonecrosis have been treated with success by means of a non surgical approach, i.e. using a protocol that contemplates cycles of systemic antibiotic therapy and local antiseptic therapy in order to keep the bone exposure stable and achieve a good control of pain. Nonetheless, in some cases, ranging from 3 to 10%, that are refractory to non-surgical procedures or prone to pathologic fractures, surgical debridement of the necrotic bone becomes compulsory. As a general rule, the surgical approach should be reserved to the patients belonging to the third clinical stage, i.e. those presenting bone exposure, pain, inflammatory phenomena in the surrounding tissues and bacterial superinfection or when the limits of bone sequestrum are clearly defined. The surgical debridement of the necrotic bone segment must be performed under adequate antibiotic coverage and taking great care of the healthy tissues surrounding the lesion.
CLINICAL STAGING AND THERAPEUTIC STRATEGIES
|Clinical stage||Therapeutic strategies|
|At risk||No treatment|
|Stage 0||Management of systemic aspects and use of painkillers and antibiotics if necessary. Conservative approach for local risk factors (cavities and periodontal insults)|
|Stage 1||Antibacterial therapy of the mouth (chlorhexidine 0.12%) and quarterly check-ups|
|Stage 2||Systemic therapy with antibiotics and anti-inflammatory drugs, antibacterial therapy for the mouth, superficial debridement of necrotic bone to relieve soft tissue irritation|
|Stage 3||Systemic therapy with antibiotics and painkillers, antiseptic therapy for the mouth. Surgical debridement of the necrotic bone in order to reduce pain and the risk of bacterial infection|
Osteonecrosis of the jaws is a severe complication that may be induced by bisphosphonates therapy, drugs prescribed for the treatment of metabolic and oncologic skeletal diseases. The risk factors that may induce the onset of the disease are many and are dependent both on systemic and local factors.
In 70-80% of the cases osteonecrosis manifests itself as a failed healing or a delay of the healing process after a dental extraction or any other type of oral surgery. In fewer cases the disease can develop spontaneously.
The early stages are mostly asymptomatic and do not present clinical or radiographic changes. As the disease progresses the symptom most commonly reported by the patients is that of an unpleasant feeling of mouth numbness and burning. A scrupulous exploration of the oral mucosa and the skin region of the inferior third of the face – supported by X-ray investigation for the patients having positive anamnesis to bisphosphonates – helps the clinician recognize small hints that may arouse the suspicion of an osteonecrotic process on. This phase comes before proper osteonecrosis and for this reason it is fundamental for an early diagnosis and prevention of the disease.
The dental management for the patients that are about to start IV bisphosphonates therapy requires an accurate odontostomatologic evaluation and the carrying out of an appropriate conservative treatment, periodontal and prosthetic, aimed at getting rid of possible local risk factors that might lead to the development of osteonecrosis.
In case there is need of surgery and the systemic conditions of the patient permit, the bisphosphonates therapy should be postponed after the healing processes of bone and mucosa are complete.
The management of patients that come to our observation in therapy with IV bisphosphonates is based on a conservative approach and aims at avoiding in any possible way any operation that may trigger bone remodelling. Osteonecrosis risk assessment in patients in therapy with oral bisphosphonates is definitely lower (especially if the therapy has been going on for less than three years and there is no concurrent corticosteroid use): this lets the dentist handle the cure of oral and periodontal diseases better. The therapy of choice in the case of patients presenting signs and symptoms of osteonecrosis is, finally, aimed at preserving the quality of life of these subjects by means of control of pain and of infective and dysfunctional complications.
The medical protocol contemplates cycles of broad-spectrum antibiotic therapy and concurring use of painkillers. In case of need, conservative surgical debridement of the necrotic bone is performed. In conclusion, it is our belief that, although many questions on the pathogenesis, epidemiology, individual susceptibility, etc. are still unresolved, a close cooperation among dentist, general practitioner, oncologist and orthopaedic may create the conditions to be able to effectively prevent and cure stage-specifically bisphosphonates related-osteonecrosis of the jaws.
R. Marx: Reconstruction of Defects Caused by Bisphosphonate-Induced Osteonecrosis of the Jaws. Journal of Oral and Maxillofacial Surgery, Volume 67, Issue 5, Pages 107-119, 2009.
S. Ruggiero, T.B. Dodson, L.A. Assael , R. Landesberg, R.E. Marx, B. Mehrotra: American Association of Oral and Maxillofacial Surgeons Position Paper on Bisphosphonate-Related Osteonecrosis of the Jaws?2009 Update.
S. Ruggiero :Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ): Initial Discovery and Subsequent Development. Journal of Oral and Maxillofacial Surgery, Volume 67, Issue 5, pag. 13-18, 2009.
S. Ruggiero, B. Mehrotra, T. J. Rosenberg, S. L. Engroff: Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases.Journal of Oral and Maxillofacial Surgery, Volume 62, Issue 5, Pages 527-534, 2004.
A. Bamias, E. Kastritis, C. Bamia, L. A. Moulopoulos: Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 23:8580, 2005.
S. Ruggiero, J. Fantasia, E. Carlson: Bisphosphonate-related osteonecrosis of the jaw: background and guidelines for diagnosis, staging and management.Oral Surg Oral Med Oral Path Oral Radiol Endod 102(4):433-41, 2006.
M. A. Dimopoulos, E. Kastritis, C. Bamia, I. Melakopoulos, D. Gika, M. Roussou, M. Migkou, E. Eleftherakis-Papaiakovou, D. Christoulas, E. Terpos, A. Bamias: Reduction of osteonecrosis of the jaw (ONJ) after implementation of preventive measures in patients with multiple myeloma treated with zoledronic acid. Annals of Oncology 2009 20(1):117-120.
E. R. Carlson, J. D. Basile: The Role of Surgical Resection in the Management of Bisphosphonate-Related Osteonecrosis of the Jaws. J Oral Maxillofacial Surg 67:85, 2009.
J.E. Fantasia: Bisphosphonates—What the Dentist Needs to Know: Practical Considerations. J Oral Maxillofacial Surg 67: 53-60, 2009.
S. B. Woo, J.W. Hellstein, J.R. Kalmar: Systematic Review: Bisphosphonates and Osteonecrosis of the Jaws Ann Intern Med. 2006;144:753–761
D.B. Kimmel: Mechanism of Action, Pharmacokinetic and Pharmacodynamic Profile, and Clinical Applications of Nitrogen-containing Bisphosphonates. Journal of Dental Research, Vol. 86, No. 11, 1022-1033, 2007.
S.L. Ruggiero, S.J. Drew: Osteonecrosis of the Jaws and Bisphosphonate Therapy. Journal of Dental Research, Vol. 86, No. 11, 1013-1021, 2007