|Year : 2013 | Volume
| Issue : 2 | Page : 78-82
Bisphosphonate-related osteonecrosis of the jaw: An insight
Shalini Kapoor1, Geetanjali Sikka1, Pallak Arora2, Pradeep Chaudhary3
1 Department of Periodontology, Sri Gobind Tricentenary Dental College, Gurgaon, Haryana, India
2 Department of Oral Medicine and Radiology, Kalka Dental College, Meerut, Uttar Pradesh, India
3 Rajasthan Dental College, Jaipur, Rajasthan, India
|Date of Web Publication||3-Jan-2014|
Department of Periodontology, Sri Gobind Tricentenary Dental College, Gurgaon - 123 505, Haryana
Source of Support: None, Conflict of Interest: None
Bisphosphonates are potent inhibitors of osteoclast activity that reduce bone turnover and re-establish the balance between bone resorption and formation. They are effective in multiple clinical settings including postmenopausal osteoporosis, low bone mass in men, and drug-induced bone loss. Bisphosphonate-associated osteonecrosis of jaws (BRONJ) may result in serious oral complications, such as osteomyelitis and chronic exposure of necrotic bone. Dentists must be familiar with this disorder and pay special attention to all patients on bisphosphonate therapy due to their defective osteoclast function and reduced osseous tissue vascularity, leading to impaired wound healing and progressive necrosis of jaw bones. The purpose of this article is to review the history and pathogenesis of BRONJ, provide guidance to dentists on possible measures to prevent and manage patients with BRONJ.
Keywords: Bisphosphonates, osteoporosis, periodontal, radionecrosis
|How to cite this article:|
Kapoor S, Sikka G, Arora P, Chaudhary P. Bisphosphonate-related osteonecrosis of the jaw: An insight. J Orofac Sci 2013;5:78-82
|How to cite this URL:|
Kapoor S, Sikka G, Arora P, Chaudhary P. Bisphosphonate-related osteonecrosis of the jaw: An insight. J Orofac Sci [serial online] 2013 [cited 2020 Oct 31];5:78-82. Available from: https://www.jofs.in/text.asp?2013/5/2/78/124248
| Introduction|| |
Bisphosphonates (also called diphosphonates) are a class of drugs that suppress bone turnover and are commonly prescribed to prevent skeletal-related events in malignancy and for benign bone diseases such as osteoporosis. They are called bisphosphonates because they have two phosphonate (PO 3 ) groups and are similar in structure to pyrophosphate. Bone undergoes constant turnover and is kept in balance (homeostasis) by osteoblasts creating bone and osteoclasts destroying bone. The drug inhibit the digestion of bone by encouraging osteoclasts to undergo apoptosis or cell death, thereby, slowing bone loss. 
| History|| |
Bisphosphonates were first introduced in 1960's for use in disorders of bone metabolism. Their non-medical use was to soften water in irrigation systems used in orange groves. The initial rationale for their use in humans was their potential in preventing the dissolution of hydroxyapatite, the principal bone mineral, thus arresting bone loss. Reports of osteonecrosis (also called "osteochemonecrosis" and "bisphosphonate-associated osteonecrosis") of the jaw associated with the use of the bisphosphonates zoledronic acid (Zometa, Novartis, East Hanover, NJ) and pamidronate (Aredia, Novartis), began to surface in 2003. 
| Chemistry|| |
All bisphosphonate drugs share a common P-C-P "backbone": The two PO 3 (phosphonate) groups covalently linked to carbon determine both the name "bisphosphonate" and the function of the drugs. Bis refers to the fact that there are two such groups in the molecule.
The long side-chain [R 2 ] determines the chemical properties, the mode of action, and the strength of bisphosphonate drugs.
The short side-chain (R 1 ), often called the 'hook', mainly influences chemical properties and pharmacokinetics.
| Generations of Bisphosphonate|| |
There are different generations of bisphosphonate: The N-containing and Non-N-containing bisphosphonates. The three types of bisphosphonates work differently in killing osteoclast cells. ,
First generation bisphosphonates
These are short chain molecules, which inhibit the Krebs cycle.  They are metabolized in the cell to compounds forming a nonfunctional molecule that competes with adenosine triphosphate (ATP) in the cellular energy metabolism. The osteoclast initiates apoptosis and dies, leading to an overall decrease in the breakdown of bone  e.g. Etidronate, Clodronate.
Second generation (nitrogenous)
These are long chain molecules, which inhibit fatty chain pathways. They act on bone metabolism by binding and blocking the enzyme farnesyl diphosphate synthase (FPPS) in the 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase pathway (also known as the mevalonate pathway) , e.g. pamidronate-available in intravenous (IV) form-alendronate.
These are available in IV form, which can be given on an annual basis e.g. risedronate, zolendronate.
| Bronj-Bisphosphonate-Associated Osteonecrosis of the Jaw|| |
Bisphosphonate-associated osteonecrosis of the jaw, often abbreviated BRONJ, is a recently discovered dental phenomenon that may lead to surgical complication in the form of impaired wound healing following oral or periodontal surgery or endodontic therapy. BRONJ, defined as Osteonecrosis or localized death of bone tissue of the jaws, is a rare potential complication in cancer patients receiving treatments including radiation, chemotherapy, or in patients with tumors or infectious embolic events. In 2003, , reports surfaced of the increased risk of osteonecrosis in patients receiving these therapies concomitantant with and an IV bisphosphonate. 
| Diagnosis|| |
A diagnosis of BRONJ relies on three criteria 
- The patient possesses an area of exposed bone in the jaw persisting for more than 8 weeks.
- The patient must present with no history of radiation therapy to the head and neck.
- The patient must be taking or have taken bisphosphonate medication.
According to the updated 2009 BRONJ Position Paper published by the American Association of Oral and Maxillofacial Surgeons, both the potency and the length of exposure to bisphosphonates are linked to the risk of developing BRONJ. 
| Mode of Action|| |
Classically, bisphosphonates are taken up by bone tissue in relatively high concentrations and inhibit osteoclast formation and function. The accumulation of high levels of bisphosphonates in the bone could potentially make them available to the surrounding tissue. They have proved to be very powerful inhibitors of bone resorption when assessed under a variety of conditions, both in culture and in vivo. It is thought that bisphosphonates bind to the bone surface and act directly on osteoclasts to inhibit their resorptive activity and to promote their apoptosis. 
Effects of bisphosphonates on osteoclasts
Because of the high affinity of bisphosphonates for hydroxyapatite bone mineral, these drugs are targeted to areas of bone turnover and are especially concentrated to sites of osteoclastic bone resorption. Therefore, the most likely route by which bisphosphonates could inhibit bone resorption is by a direct effect on resorbing osteoclasts.
There have been many reports supporting the view that bisphosphonates have direct effects on osteoclasts, with the majority of studies having been performed with rodent or avian osteoclasts but also more recently with human osteoclast-like cells. 
Effects of bisphosphonates on osteoblasts
In vitro , bisphosphonates can both inhibit and stimulate the proliferation of osteoblast-like cells and other connective tissue cells. However, the anti-proliferative effect of bisphosphonates has been observed with a variety of other cell types in vitro (including macrophages, tumor cells, and slime mold amoebae) and probably is not of physiologic significance because bisphosphonates do not inhibit bone formation. Of more interest is the observation that bisphosphonates may have more subtle effects on osteoblasts, causing the release of a factor that subsequently inhibits osteoclast activity or osteoclast formation. 
Effects of bisphosphonates on osteoclast formation
As well as affecting mature osteoclasts that have resorbed osteoclast-coated bone, several studies have suggested that some bisphosphonates also may inhibit bone resorption indirectly by affecting osteoclast precursors, thereby preventing osteoclast formation. 
| Calcification|| |
The mechanism of the inhibition of both normal and ectopic mineralization is most likely due, in part if not entirely, to a physicochemical mechanism. There is a close relationship between the ability of an individual bisphosphonate to inhibit calcium phosphate in vitro and its effectiveness on calcification in vivo; therefore, the mechanism is likely to be a physicochemical one. It is of interest that, in contrast to what occurs in bone resorption, the bisphosphonate must be continuously present to exert this effect both in vitro and in vivo.
| Bone Resorption|| |
Possible Biochemical Action of Bisphosphonates on the Osteoclast
It is known that bisphosphonates have a strong affinity to the surface of solid phase calcium phosphate. This union culminates in the inhibition of hydroxyapatite aggregation, dissolution, and crystal formation. Yet, the mode of action of bisphosphonate on bone resorption in vivo is likely not mediated by their physicochemical effects on crystal growth regulation. In fact, bisphosphonate effects on osteoclasts and other bone cells are probably more direct, and expressed at the molecular level. Bisphosphonates bound to bone mineral are released during bone resorption by osteoclasts. This could lead to a localized accumulation of bisphosphonate, which could directly perturb osteoclastic activity or indirectly target osteoblasts and macrophages, resulting in decreased osteoclastic chemotaxis and activity. 
| Pathogenesis and Clinical Presentation|| |
The exact pathogenesis remains obscure but some possible factors have been into play, inhibition of osteoclasts leads to impaired natural remodeling process being critical for bone healing. The bone becomes over-aged and self-healing capacity is decreased. Besides this, decreased angiogenesis leads to avascular necrosis  or a response to infection which are known to modulate the immune response of different cell types. ,
Another factor, genetic variations among individuals confer susceptibility or resistance to BRONJ development, since BRONJ occurs only in a certain percentage. 
All factors could play a role in the pathogenesis of BRONJ; however, none of them (in isolation or combination) is able to explain why the jawbone is the exclusive target. Also, the current concept do not offer a plausible explanation as to why nitrogen-containing BPs, which do not overly accumulate in the jawbone compared with other bones,  result in an increased risk of developing BRONJ. The risk factors for BRONJ can be (PM3: The factors which increase risk for BRONJ) if they are with malignant disease receiving IV BP therapy (PM4: Bisphosphonate) in high doses or with a history of chemotherapy, or concomitant medications of systemic corticosteroids or anti-angiogenic agents. A history of diabetes mellitus seems to mildly increase the risk. 
Clinically patients may be considered to have BRONJ if the following three characteristics are present: 1. Current or previous treatment with a bisphosphonate; 2. Exposed, necrotic bone in the maxillofacial region that has persisted for more than 8 weeks; and 3. No history of radiation therapy to the jaws. Signs and symptoms that may occur before the development of clinically detectable osteonecrosis include pain, tooth mobility, mucosal swelling, erythema, and ulceration.
Although, it would seem that the most important clinical use for bisphosphonate would be related to inhibition of bone loss, their affinity for newly mineralizing bone. This makes these drugs ideal for diagnostic purpose as well as when combined with radiolabels a field known as "Nuclear Medicine".
| Clinical Recommendations for Managing Patients Receiving Oral Bisphosphonate Therapy|| |
- Routine dental examinations are recommended.
- A comprehensive oral assessment should be carried out for all patients about to begin therapy with oral bisphosphonates (or as soon as possible after beginning therapy).
- The dentist should inform the patient taking oral bisphosphonates that:
- There is a very low risk (estimated at 0.7 cases per 100,000 person-years' exposure) of developing BRONJ.
- There are ways to minimize the risk, but not to eliminate the already low risk.
- The best way to lower risk is that good oral hygiene along with regular dental care.
- There are no diagnostic techniques to identify those at increased risk of developing BRONJ. Therefore, patients taking oral bisphosphonates should be instructed to contact their dentist if any problem develops in the oral cavity.
- Non-surgical management of BRONJ may consist of the following:
- Antimicrobial rinses
- Systemic antibiotics
- Systemic or topical antifungals
- Discontinuation of bisphosphonate therapy
Before undergoing any invasive procedure the risk of developing osteonecrosis of the jaw is considered very small, and that the vast majority of patients taking an oral bisphosphonate do not develop any oral complications.
When the treatment plan dictates the medullary bone or periosteum is going to be involved in multiple sextants, the dentist should treat one sextant or tooth first, if dentally possible. At that point, the dentist should allow for a 2-month disease-free follow-up, treating the patient with antimicrobials, before other sextants are treated with similar therapy. Typically, chlorhexidine is used two times per day for two months after surgery.  Given success at two months (or longer if the area remains inflamed, irritated or erythematous) with the first sextant, treatment may accelerate to a more normal multisextant treatment and follow-up schedule.
Periapical pathoses, sinus tracts, and active abscesses already involve the medullary bone and may cause osteonecrosis by themselves. These areas should be treated immediately, because the medullary bone already is involved in the pathologic process. The sextant-by-sextant approach does not apply to emergency cases, even if there is involvement of multiple quadrants.
Once general recommendations are discussed with the patient taking an oral bisphosphonate, specific clinical questions situations regarding speciality treatment should be considered.
| Management Strategy in Periodontal Diseases|| |
Patients with destructive periodontal diseases who are receiving oral bisphosphonate therapy should receive appropriate forms of nonsurgical therapy, which should be combined with a prolonged phase of initial therapy for observation.
If the disease does not resolve, surgical treatment should be aimed primarily at obtaining access to root surfaces, with modest bone recontouring being considered when necessary.
Guided tissue regeneration should be judiciously considered, in view of the fact that bisphosphonates have been shown to decrease the vascularity of tissues,  which may have a negative effect on grafted sites.
Despite the untoward effects of bisphosphonate therapy, the periodontal literature has suggested that these drugs may be beneficial in modulating host response for management of periodontal diseases. ,
| Role of Oral and Maxillofacial Surgeons in Bronj|| |
Patients taking oral bisphosphonates who are undergoing invasive surgical procedures should be informed of the risk, albeit small, of developing BRONJ. Alternative treatment plans consisting of endodontics instead of extraction and bridges and partial dentures versus implant reconstruction should be discussed with the patient. 
If extractions or bone surgery are necessary, conservative surgical technique with primary tissue closure should be considered, when possible. In addition, immediately before and after surgical procedures involving bone, the patient should rinse gently with a chlorhexidine-containing rinse. Typically, chlorhexidine is used two times per day for 2 months after surgery. 
Prophylactic antibiotics may be utilized during the healing/wound closure phase for procedures that involve extensive manipulation of the bone (for instance, extractions, periodontal recontouring, sinus lifts)
| Recent Advances|| |
Implant placement and maintenance
In recent years, rehabilitation of patients with dental implants for edentulous areas, or for whom tooth prognosis was considered hopeless, has been successful. At this time, there are limited data regarding the effects of implant placement in patients taking bisphosphonates. Therefore, treatment plans for patients taking bisphosphonates should be considered carefully, since implant placement requires the preparation of the osteotomy site. ,
The patient may be at increased risk of developing BRONJ when extensive implant placement or guided bone regeneration to augment the deficient alveolar ridge before implant placement is necessary. Before implant placement, the dentist and the patient should discuss the risks, benefits and treatment alternatives, which may include but are not limited to periodontal, endodontic, or non-implant prosthetic treatments.
Maintenance of implants should follow accepted mechanical and pharmaceutical methods to prevent peri-implantitis, with regular monitoring of the patient.
Appropriate forms of nonsurgical therapy combined with a prolonged phase of initial therapy should be considered for patients with peri-implantitis. If the disease does not resolve, surgical revision of soft tissues around the implant (s) may be appropriate and, when necessary, modest bone recontouring may be considered. 
| Conclusion|| |
Bisphosphonate therapy corrects the imbalance in bone remodeling that causes loss of bone, prevents bone loss, and preserves the integrity of bone structure. Convenient dosing regimens now exist. On the basis of these attributes, bisphosphonates have become important treatment option for the prevention and treatment of various forms of osteoporosis.
| Future Directions|| |
Bisphosphonates are an important adjunct to systemic biological and chemotherapeutic management of multiple myeloma. They clearly provide an important enhancement in the quality of life by reducing skeletal related events and reducing pain; however, now with widespread use, post-marketing experience suggests caution toward monitoring for toxicities. Osteonecrosis of the jaw and renal toxicities can lead to significant morbidity and impairment in quality of life. Future trials must evaluate the optimal dosing, duration of treatment, potency of agent used, frequency of administration, and quality of life end points to enable clinicians to make evidence-based recommendations in the management of their patients with symptomatic malignant bony disease.
| References|| |
|1.||Woo SB, Hellstein JW, Kalmar JR. Narrative [corrected] review: Bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 2006;144:753-61. |
|2.||Fleisch H. Development of bisphosphonates. Breast Cancer Res 2002;4:30-4. |
|3.||van beek E, Lowik C, van der Pluijm G, Papapoulos S. The role of geranylgeranylation in bone resorption and its suppression by bisphosphonates in fetal bone explants in vitro: A clue to the mechanism of action of nitrogen-containing bisphosphonates. J Bone Miner Res 1999;14:722-9. |
|4.||Lehrer S, Montazem A, Ramanathan L, Pessin-Minsley M, Pfail J, Stock RG, et al. Bisphosphonate-induced osteonecrosis of the jaws, bone markers, and a hypothesized candidate gene. J Oral Maxillofac Surg 2009;67:159-61. |
|5.||Green J, Czanner G, Reeves G, Watson J, Wise L, Beral V. Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum: Case-control analysis within a UK primary care cohort. BMJ 2010;341:c4444. |
|6.||Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, et al. HORIZON Pivotal Fracture Trial. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007;356:1809-22. |
|7.||Weinstein RS, Roberson PK, Manolagas SC. Giant osteoclast formation and long-term oral bisphosphonate therapy. N Engl J Med 2009;360:53-62. |
|8.||Gnant M, Mlineritsch B, Schippinger W, Luschin-Ebengreuth G, Postlberger S, Menzel C, et al. ABCSG-12 Trial Investigators. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 2009;360:679-91. |
|9.||Fleisch H. Bisphosphonates: Mechanisms of action. Endocr Rev 1998;19:80-100. |
|10.||Santini D, Vincenzi B, Avvisati G, Dicuonzo G, Battistoni F, Gavasci M, et al. Pamidronate induces modifications of circulating angiogenetic factors in cancer patients. Clin Cancer Res 2002;8:1080-4. |
|11.||Wolf AM, Rumpold H, Tilg H, Gastl G, Gunsilius E, Wolf D. The effect of zoledronic acid on the function and differentiation of myeloid cells. Haematologica 2006;91:1165-71. |
|12.||Roelofs AJ, Jauhiainen M, Monkkonen H, Rogers MJ, Monkkonen J, Thompson K. Peripheral blood monocytes are responsible for gammadelta T cell activation induced by zoledronic acid through accumulation of IPP/DMAPP. Br J Haematol 2009;144:245-50. |
|13.||Katz J, Gong Y, Salmasinia D, Hou W, Burkley B, Ferreira P, et al. Genetic polymorphisms and other risk factors associated with bisphosphonate induced osteonecrosis of the jaw. Int J Oral Maxillofac Surg 2011;40:605-11. |
|14.||McDonald MM, Dulai S, Godfrey C, Amanat N, Sztynda T, Little DG. Bolus or weekly zoledronic acid administration does not delay endochondral fracture repair but weekly dosing enhances delays in hard callus remodeling. Bone 2008;43:653-62. |
|15.||Kos M, Kuebler JF, Luczak K, Engelke W. Bisphosphonate-related osteonecrosis of the jaws: A review of 34 cases and evaluation of risk. J Craniomaxillofac Surg 2010;38:255-9. |
|16.||Brookler K. Medical treatment of osteosclerosis: Rationale for use of bisphosphonates. Int Tinnitus J 2008;14:92-6. |
|17.||Sayed-Noor AS, Kadum BK, Sjoden GO. Bisphosphonate-induced femoral fragility fractures: What do we know? Orthop Res Rev 2010;2:27-34. |
|18.||Van Beek ER, Cohen LH, Leroy IM, Ebetino FH, Lowik CW, Papapoulos SE. Differentiating the mechanisms of antiresorptive action of nitrogen containing bisphosphonates. Bone 2003;33:805-11. |
|19.||Lenart BA, Lorich DG, Lane JM. Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate. N Engl J Med 2008;358:1304-6. |