Kamis Gaballah, IJSID, 2013, 3 (1), 11-21

ISSN:2249-5347

IJSID

International Journal of Science Innovations and Discoveries

Research Article
Kamis Gaballah1

An International peer Review Journal for Science

Available online through www.ijsidonline.info

BISPHOSPHONATE RELATED OSTEONECROSIS OF JAWS: AN OVER-REVIEW FOR GENERAL DENTAL PRACTITIONERS Assistant Professor in Oral and Maxillofacial Surgery and Oral Medicine. Ajman University. PO Box 5069 Ajman, UAE

Received: 26.01.2013 Accepted: 14.02.2013

*Corresponding Author

management of such diseases as osteoporosis, Pagets disease of bone, multiple myeloma

bone disease, metastatic cancers and breast carcinoma. Since their approval in 2002 the drugs were widely prescribed in US, Europe and Australia and wont be long before the intravenous forms. Both preparations showed excellent clinical results for most of their therapeutic uses. However, sporadic case reports followed by several controlled studies be refractory to most of available treatment modalities because of the systemic nature of managing such complications. showed that BPs can cause significant necrosis to the patients jaw bones. This disease can agent be populated in the rest of the world. These agents are available in both oral and

Bisphosphonates (BPs) are important pharmacological agents in the clinical ABSTRACT

Address: Name: Kamis Gaballah Place: Ajman University, Ajman, USE E-mail: kamisomfs@yahoo.co.uk

the problem. This review aims to introduce the problems associated with increased use of the BPs and will also outline the role of the Dental professionals in minimising and Key words: Bisphosphonates, Metastasis, bone resorption, osteoclasts, Osteoporosis, Osteonecrosis, Jaws, Dentistry,

International Journal of Science Innovations and Discoveries, Volume 3, Issue 1, January-February 2013

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Kamis Gaballah, IJSID, 2013, 3 (1), 11-21 anti- angiogenic and anti-neoplastic properties; they are predominantly used in the treatment of numerous disorders that affect bone, including osteoporosis, cancer metastases to bone, hypercalcemia of malignancy, and multiple myeloma. quality of life in affected patients. Currently, the pathogenesis of ONJ is poorly understood and clinical and robust treating the condition. Lessons from History Bisphosphonates (BPs) are a u n i q u e class of pharmaceuticals that have a p o w e r f u l anti- bone resorption, INTRODUCTION

significant morbidity such impaired eating ability, pain, altered sensation and compromised esthetics, resulting in poor epidemiologic studies are lacking, therefore no well-established and evidence-based therapeutic protocols exist for

Osteonecrosis of the jaws (ONJ) owed to BP therapy is an emerging health change that may be associated with

century as anticorrosive and antiscaling agents owed their ability to inhibit the formation of calcium deposits on different surfaces . In the early 1960s, Scientists at Procter & Gamble discovered the mechanism of action offluoride on enamel and dentin as a therapeutic approach to preventing dental caries. They also showed that compounds such as the quaternary ammonium fluoride salts and polyphosphates, including pyrophosphate, were very effective in inhibiting the crystal growth crystals which led to the prediction that they might retard bone resorption(2). On the same year the Lancet has published the first clinical use of BP was in a treatment of the child with myositis ossificans progressia (3). in significantly increased bone d e n s i t y and reduced the rate of vertebral fractures in such patient (4). the prevention and treatment of the surface calcium fluoride and result in an ultra-thin layer of phosphates protecting the surface from etch damaged In the mid-1980s, a clinical investigation determined the efficacy and safety of a cyclical regimen of etidronate The BPs can be divided into two generation; the first generation was non-nitrogen based agents like etidronate that

Pyrophosphate , the analogue for the medical BP. have been used in the industry since the end of eighteenth

surface of enamel(1). Another key observation reported on 1969 was that the BPs blocked the dissolution of hydroxyapatite of postmenopausal osteoporosis. These early studies demonstrated that the drug

was earlier used for the management of patient with osteoporosis despite the lack of Food and Drug Administration (FDA) at those with multiple myeloma (5) and Pagets disease of bone (6)(7)(8).

that time. The second generation appeared in early 1990s was the nitrogen-containing agents like Pamidronate that has a different mechanism of action and show higher affinity to bone tissue and hence a powerful anti-resorptive efficiency. This j a w b o n e s . A c o n d i t i o n a t t r i b u t e d t o o c c u p a t i o n a l exposure of elemental phosphorus in matches-making industry was described as phossy jaw. The disease was similar to the presentation of bisphosphonate related osteonecrosis of jaw (BRONJ) and was described as necrosis of the jaw bone and recurrent osteomyelitis and soft tissue infection and as the condition appeared on the pre-antibiotic era the mortality rate was as high as 50% (9). unhealed socket and subsequentRefractory Osteomyelitis The second striking
(1).

group of BPs has shown to reduce the incidence of skeletal metastasis in patients with breast cancer (5) , the bony disorders in The ends of eighteenth century have s h o w n t h e r e p o r t o f f i r s t u n w a n t e d e f f e c t s o f p h o s p h a t e o n

oncological indications. The first suspicion of the condition was in 2001 due the growing number of patients presented with presentation to osteoradionecrosis, none of the reported patient has received radiotherapy to their head and neck region. International Journal of Science Innovations and Discoveries, Volume 3, Issue 1, January-February 2013

The currently known BRONJ was not identified before at least a decade of a wide spread use of the BPs for various observation was that all these patient had received an anticancer medications including BPs.

Despite the close similarity of the clinical and radiological

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Concomitantly, more cases of Osteomyelitis were accumulated in individuals with osteoporosis who were treated with BPsbased medications for the last few years. All these observations have led to serious investigation by various groups as well among the same group of patients over 12 month period (10). by one of the major manufacturer of BPs Novartis Pharmaceuticals. Although the records of the manufacturer showed that any report of jaw problems among the participant patients, other investigators have reported around 30 cases of BRONJ

Kamis Gaballah, IJSID, 2013, 3 (1), 11-21

the clinical trials throughout their phases I,II and III that had done to approve the clinical use of their BPs did not disclose

of Clinical Oncology, which they hoped would alert the oncology community to this new potential complication(11). Later on the same year, a letter t o the editor of Journal of Oral and Maxillofacial Surgery presenting experience of 36 cases with Potential BRONJ(12). F e w m o n t h s l a t e r , t h e s a m e g r o u p ha s published with over 63 cases of BRONJ. This of these reports of BRONJ in addition to cases reported to the FDA and directly to the manufacturer, Novartis recommended appropriate dental surveillance (1). Pharmaceuticals has included in September 2004 to include a warning insert of in the zolendronic acid and pamidronate States. The warning letters cautioned against performing dentoalveolar surgery in these patients at risk, strongly BRONJ. By December 2006, the FDA was aware of a t l e a s t 3,607 cases of BRONJ diagnosed in United States Subsequently, the FDA has issued a universal warning against the use of BPs including the oral preparations. By the end of By April 2006 FDA survey showed that 1257 oral surgeons have examined or treated over 4,700 patients with

In early 2003, there was a single case report published as an abstract in the proceedings of the American Society

case series represented the first peer- reviewed case series report of this problem in the literature (13). The publication packages and Dear Health Professional letters w e r e circulated to oncologists and oral surgeons throughout the United
(14).

2006, the adverse effects of the BPs were the material for media in United States. This resulted in significant rise of the public awareness of the problem and triggered lawsuit cases against the manufacturer of the medications. Furthermore, a oral and intravenous BPs. This year, the Federal courts in United Sates estimated that about 900 pending cases against Fosamax only (15). Pharmacology of the current Bisphosphonates: specialized Bisphosphonates Lawyer practices have been established to seek compensation for patients claimed BPs-related problems. The availability of such widely advertised practices has dramatically increased the number court cases against both

mineralized tissues. The backbone of the all BPs is the phosphonate-carbon-phosphonate (P-C-P) structure which is responsible for their ability to bind divalent metal ions such as calcium circulation and bind to bone mineral surfaces at sites of active bone remodeling, with more affinity to areas undergoing extended periods (18).
(17).

Bisphosphonates are pharmaceutically-stable analogues of inorganic pyrophosphate that regulate the calcification of
(16).When

osteoclastic resorption(17). The widely understood route through which BPs inhibit bone resorption is by their direct effects on neighboring cells (i.e., osteoblasts, bone marrow cells, or tumor cells), particularly with repeated administrations over

osteoclasts. However, other investigators have raised the possibility that small amounts of these drugs are also internalized by converted through an intracellular pathway to non-hydrolyzable of adenosine-triphosphate , which are toxic for these cells International Journal of Science Innovations and Discoveries, Volume 3, Issue 1, January-February 2013 In the presence of a nitrogen, BP act either by direct toxicity to osteoclasts while Non-nitrogen-containing BPs are

absorbed BPs are rapidly cleared from the

Nitrogen-containing BPs include Pamidronate, Alendronate, and Risedronate . The non-nitrogen containing BP include

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Etidronate, Didronel and Tiludronate. Table 1 shows examples of different BPs along with their classification, availability and their relative potency in bone resorption. some embryonic bone marrow cells. Osteoblasts enhance osteoclast recruitment and activation by interaction of osteoblast cell surface-receptor activator with hematopoietic osteoclast precursor cells. The drug can inhibit these receptor functions and resorption (19). cells by affecting the mevalonate pathway on animal osteosarcoma cell lines of capillary formation and a decrease in the blood flow BRONJ.
(22). (20).They

Kamis Gaballah, IJSID, 2013, 3 (1), 11-21

thus the production by bone marrow stromal cells and osteoblasts is disrupted resulting in further inhibition of bone adhesion of these cells to bone matrix, local invasion and distant metastasis in preclinical investigations (21). Bisphosphonates have also showed direct cytoxicity against neoplastic cells through induction of apoptosis in tumor

Bisphosphonates may also inhibit osteoclastic activity indirectly by interfering with the functions of osteoblasts and

Other important effects of BPs are their ability to interfere with blood supply of the affected bone through the inhibition of the capacity of the alveolar bone complicate the effectiveness of any treatment approach may be considered for treatment of Agent Table 1. The pharmacological properties of the commonly prescribed BPs. Presence of No No No Nitrogen Atom Route of administration Oral/IV Oral IV IV Oral Oral IV Oral The later effect in addition to the inhibition of bone remodeling

endothelial proliferation and the capillary formation. In jaw alveolar bone, the selective accumulation of BPs can cause a lack

also have the ability to inhibit the

Generic(Brand name) Clodronate (Bonefos) Tiludronate (Skelid)

from 20 min and 23 h, while the terminal bone elimination half-life of this drug group is variable and can be extremely long (e.g., ibandronate, 1060 h; zoledronic acid, 146 h; risedronate, 480 h; pamidronate, 300 days; and alendronate, more than 10 years) remodeling if the drug is totally eliminated from tissue. Furthermore it is equally important to recognize that the bone turn humans (24).
(23).It

Bisphosphonates are absorbed, stored, and excreted unchanged from the body. The plasma half-life is short, ranging is important to estimate the half-life of the specific agents as this may indirectly indicate the ability of the bone

Zoledronate (Zometa)

Ibandronate (Boniva) Risedronate(Actonel)

Pamidronate (Aredia)

Etidronate (Didronel)

Alendronate (Fosamax)

Yes Yes Yes Yes Yes

Oral/ IV

over and half-life periods obtained from animal and human studies are highly variable. For instance at a given site on the surface of trabecular bone, a human undergoes remodeling once every 2 years vs. once every month in rats. On the other hand gastrointestinal tract, and 50 percent of the a b s o r b e d dose or that administered intravenously is bioavailable for International Journal of Science Innovations and Discoveries, Volume 3, Issue 1, January-February 2013 It is important to appreciate that less than 10 percent of the dose of BP taken orally is absorbed by the the terminal bone half-life of alendronate, which has been reported to be 200 days in rats, 3 years in dogs, and 12 years in incorporation into the bone matrix (25).This may account for the higher number of cases of BRONJ in patients taking the IV

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preparation.

Kamis Gaballah, IJSID, 2013, 3 (1), 11-21

Therapeutic indications

bone mineral density and reduce the risk of fractures in patients with osteoporosis. Bisphosphonate therapy has also made a multiple myeloma, breast cancer, and other solid tumors has been proved by several clinical studies summarizes the clinical indication of the modern BPs. -Osteoporosis - Bone metastasis (with or without hypercalcaemia) - Multiple myeloma - Paget's disease of the bone. -Postmenopausal women with vertebral compression fractures - Elderly men with non-traumatic fractures and with bone fragility Definition and Incidence of BRONJ: bisphosphonate-related osteonecrosis of the jaw (BRONJ) if each of the following 3 characteristics are present: 1) current or and 3) no history of radiation therapy to the jaws (30). On other hand, task force of the American Society for Bone and Mineral Research divided the cases of BRONJ into Table 2.Clinical indications of bisphosphonates (modified from 40).
(26)(27)(28).

significant impact in the alleviation of cancer morbidity. Its role in decreasing osteoclast-mediated lysis of bone secondary to Society of Clinical Oncology recommend the use of BP in the treatment of moderate to severe hypercalcemia associated with

Bisphosphonates work as potent suppressors of osteoclast and thus slow down the remodeling process. They increase

malignancy and also for metastatic osteolytic lesions associated with breast cancer and multiple myeloma (29). Table (2) Clinical Indications of Bisphosphonates:

The American

previous treatment with BPs, 2) exposed, necrotic bone in the maxillofacial region that has persisted for more than 8 weeks,

The American Association of Oral and Maxillofacial Surgeons (AAOMS) implies patients may be considered to have

confirmed or suspected cases. A confirmed case was defined as an area of exposed bone in the maxillofacial region that did not trauma, extractions, and oral surgical procedures would have resulted in soft tissue closure, and exposed bone would no to determine whether they ultimately meet the definition of a confirmed case (30). longer be present. A suspected case was defined as an area of exposed bone in the maxillofacial region that had been identified by a health care provider and had been present for less than 8 weeks in a patient who was receiving or had been exposed to a According to the advisory task force on BRONJ, American Association of Oral and Maxillofacial Surgeons, the

heal within 8 wk after identification by a health care provider, in a patient who was receiving or had been exposed to a BP and had not had radiation therapy to the craniofacial region. The 8-week duration is consistent with a time frame where most BP and had not had radiation therapy to the craniofacial region. Suspected cases of BRONJ should receive follow-up evaluation cumulative incidence of the disease has been reported to be between 0.8 to 12% in patients using intravenous BPs. However, BPs. Given the widespread use of BPs in clinical practice, even a very low incidence of BRONJ should be considered a public emergency. an increase in this incidence is expected with a wider recognition of the disease and the close follow-up of the patients using

International Journal of Science Innovations and Discoveries, Volume 3, Issue 1, January-February 2013

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receiving orally administered alendronate for a long period of time was estimated to be 0.7 per 100,000 person years of exposure (31). Incidence rates for BRONJ were found to be related to 1) length of exposure to the drug, 2) history of dental extraction, oral

The American Dental Association Council on Scientific Affairs reported that the incidence of BRONJ for patients

Kamis Gaballah, IJSID, 2013, 3 (1), 11-21

bone manipulating surgery, poor fitting dental appliances, intraoral trauma, 3) number of treatment cycles, 4) route of administration, 5) cancer and anticancer therapy, 6) steroid therapy, 7) Alcohol and/or tobacco abuse and 8) Pre-existing dental or periodontal disease (30) (32).

Prevention and Management of BRONJ

to their patient, but the preventive measures should be thought about even after the patient has started or completed the BP treatment course. preventing BRONJ should be the main aim of all medical, dental and surgical personnel as there are no sound evidences prove the effectiveness of any available treatment modalities for this condition. Preventive measures before initiating BP therapy All patients who may require BP therapy should be referred to an expert General Dental Practitioner or Oral Surgeon

The prevention of BRONJ should be planned when the treating Physician or Oncologist consider the BP prescription

Figure (1): Various effects of bisphosphonates on bone.

for comprehensive clinical oral and dental examination and investigations. The prime objective of this step is to remove all potential source of infection and equally important to eliminate the need for any invasive or surgical oral procedures while International Journal of Science Innovations and Discoveries, Volume 3, Issue 1, January-February 2013

the patient taking their BP treatment. The investigation must include panoramic dental radiograph and peri-apical films

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where indicated to exclude any ambiguous dental or osseous pathologies. It should also be emphasis that the patients who are the surgical removal of impacted teeth that are communicated with the oral cavity through partial eruption or deep connecting periodontal pocket or those covered by thin rim of bone or oral mucosa where the tooth may penetrate those of large bony tori, exostosis or prominent myelohyoid ridge that are covered by thin oral mucosa as the later may torn and

Kamis Gaballah, IJSID, 2013, 3 (1), 11-21

potentially to receive intravenous BPs should not have any dental implant work at this stage. The oral surgeon may consider tissues exposed to the contaminated oral environment. Of interest the Oral surgeon should also consider the surgical removal the underlying bone is exposed, traumatized or infected resulting in osteonecrosis. If any of this surgical procedure is carried removable complete or partial dentures should be examined for areas of mucosal trauma, particularly along the lingual and patients oral health should be closely monitored every three to six months. Preventive measures for patients on BP therapy out the BP therapy should be delayed for at least one month to allow healthy soft tissue healing. Individual wearing

buccal flange regions. The soft reline should also be considered to minimize any potential future mucosal trauma. At this stage the General Dental Practitioner should stress out to their patient the importance of maintain meticulous oral hygiene in preventing future dental and periodontal diseases that may significantly contribute to development BRONJ. Finally, the

examinations or receive an examination and investigations if they have not previously been seen by a dentist prior to the onset of treatment. The patients who start taking BP orally for a period less than three years should continue to receive the same measures outlined for patient about to start their BP treatment. surgical procedures when indicated but they should warn about the risk of future BRONJ if dental implant work is considered. Should the patient presented to their General Dental Practitioner or Oral Surgeon after taking the oral preparation for more bones may reach comparable levels to those receiving injectable BPs. Some authors suggested that discontinuation of oral BRONJ (29) (33-36). planned in quadrants or sextants, the dentist should treat one part or tooth first, according to the clinical priorities. months after surgery as the majority of cases of BRONJ arise within two months of a dental procedure (37). Orthodontic treatment considerations than three years they must be regarded as patient receiving intravenous BPs. This is due to the accumulated BPs in their relates to the risk of BRONJ, other risks associated with various treatment options. This group may still undergo oral The patient also should be informed of the dental treatment needed, alternative treatments, how any treatment

Patients without e vi d e nc e BRONJ but who are receiving BP therapy should continue to receive dental

BPs for a period of three months prior to and three months following elective invasive dental surgery may lower the risk of

that point, the dentist should allow for a two-month disease-free follow-up and provide the patient with antimicrobials, before other parts or teeth are treated. T he expert panelists recommend the use of chlorhexidine rinse twice daily for two The BP treatment poses a significant challenge for orthodontic planning and treatment as the successful orthodontic

When the oral treatment may involve periosteum and/or medullary bone manipulation the treatment should be

At

movement is solely based on healthy bone remodeling in form of resorption on pressure side and bone formation on the patient undergoing BP treatment (39).

tension side. Evidence from animal studies suggested that the tooth movement is slowed downed by 40% when the injectable BP treatment was initiated(38). Several case reports shown significant difficulties with orthodontic tooth movements on International Journal of Science Innovations and Discoveries, Volume 3, Issue 1, January-February 2013

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locally in the jaws. Although no studies have directly attributed orthodontic treatment to increased osteonecrosis risks, orthodontic treatment may increase the potential for BRONJ. It is unlikely that many patients with advanced malignant disease would seek orthodontic treatment, But for those

evidence from previous studies noting retarded tooth movement in patients receiving BP therapy suggests that prolonged who do, the decision to commence such treatment should carefully considered based critical evaluation of the benefits vs. the movement or more serious medical complications such as BRONJ. considered appropriate, plans should be assessed and modified to include compromises such as avoiding or minimizing treatment. risks of orthodontic treatment by first assessing whether the patient is at high or low risk for inhibition of orthodontic tooth elective surgery and extractions, favoring proximal stripping over dental extractions, minimizing tooth movement, minimizing pressures on tissues during treatment and retention, avoiding any soft tissue wounds and irritation that may result to Management of BRONJ: For low-risk patients, if orthodontic treatment is

Orthodontic tooth movement causes increased alveolar bone turnover and might further increase the uptake of BP

Kamis Gaballah, IJSID, 2013, 3 (1), 11-21

exposure of underlying alveolar bone and finally limiting treatment to facilitate the possible need for early discontinuation of

infection, without jeopardizing the ongoing oncologic or osteoporotic treatment. It is also crucial to limit the extension of existing areas of bone necrosis and the development of new lesions. patients presented with asymptomatic exposed bone with no evidence of any significant adjacent or regional soft tissue inflammatory swelling or infection. This group requires no intervention other than regular antimicrobial mouthwashes bone should be considered, since it is unlikely that the extraction will exacerbate the established necrotic process(33)(40). and close clinical monitoring. No surgical procedure should be considered unless areas of exposed bone cause significant Many authors suggested stage-specific treatment strategies for the management of patient with BRONJ .Stage 1

Treatment of patients with BRONJ aimed at preserving the quality of life by controlling the pain and subsequent

irritation to the surrounding soft tissue. The removal of grossly mobile or symptomatic teeth within exposed, necrotic Patients with Stage 2 BRONJ usually show an exposed necrotic bone that is painful and now secondarily

infected. This g r o u p requires both oral antimicrobial rinses and systemic antibiotic therapy. The most commonly antibiotics reported in BRONJ publication with variable success are Penicillin, Quinolones, metronidazole, clindamycin, doxycycline, and erythromycin. Surface smoothening of the exposed bone may help in pain relive. Mobile bony sequestrum should be removed without undue exposure of vital bone. pathologic jaw fracture, or refractory maxillary sinusitis. The management of patient with advanced disease represents a determine the healthy bony border where surgeon can limit their surgical intervention to. microorganisms directly or through the ulceration of adjacent soft tissues antibiotics. Limited sequestrumectomy may be indicated to reduce the pain the infection as the dead bone act as portal for oral significantly affect the quality of life. These cases may be complicated by the presence facial or cervical f i s t u l a e , major challenge to oral and maxillofacial surgeon due the generalized effect of the drug on jaw bone and the difficulty to contamination. This may be followed by an attempt to achieve primary mucosal closure especially if the patient may receive chemotherapy or steroids for their primary morbidity. All these interventions should be accompanied with oral or parental International Journal of Science Innovations and Discoveries, Volume 3, Issue 1, January-February 2013 Patients with Stage 3 disease have pain and infection associate with large or multiple areas of exposed bone that

forming another gateway for microbial

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further increase of the osseous breakdown and wound dehiscence. Before any surgical procedure is planned, patients should be fully informed of the possible risks and benefits. residual bony fragments with a reconstruction plate. The bone grafting and the free transfer composite flap are not generally manipulation and exposure of affected jaw bone. recommended for patients with advanced disease due to the increased morbidity at both donor and recipient surgical sites. Similarly, the pathologically fractured jaw may be fixed using an external pin apparatus without the need for periosteal Dental Care of patients with established BRONJ:

It is worth mentioning that any surgical manipulation may not lead to the coverage of the necrotic bone site but to Patients with widespread mandibular necrosis may require segmental resection along with stabilization of the

Kamis Gaballah, IJSID, 2013, 3 (1), 11-21

following some dental and surgical oral procedures. Therefore, extra care must be taken while planning the routine and and prophylaxis should be carried out as a traumatically as possible, with minimal soft-tissue manipulation. Generally, all sorts of dento-alveolar surgery should be avoided if possible. The teeth must not be extracted unless they are very mobile (grade rinse margin.

emergency dental for such individuals. Routine restorative care may be normally provided and the local analgesic can be administered as required. However, excessive infiltration of solution containing vasoconstrictor should be avoided. Scaling 3). The healing of extraction socket should be monitored for at least 8 weeks and may be assisted with chlorhexidine mouth and oral antibiotic when indicated. Teeth with extensive unrestorable caries should s t i l l be considered for Bisphosphonates are important drugs that reduce the morbidity and mortality in patientswith diseases CONCLUSION OR RECOMMENDATIONS

Patients with an established diagnosis of BRONJ are certainly at the highest risk of developing osteonecrosis

endodontic therapy. They should be prepared as over denture abutments. The crown should be cut off at the gingival that affect bone including osteoporosis metastatic bone cancers. Patients who are on intravenously administered BPs appear to have the greatest risk for BRONJ (between 1 percent and 10 percent prevalence). The prevalence of orally administered BPs is dramatically lower (between 0.00007 percent and 0.04 percent). The BRONJ is The disease may appear spontaneously but is more frequently associated with local trauma to the jaw, especially following tooth extraction.The effective and efficient management of patients with BRONJ has not adequately characterized. Presently, the management of BRONJ usually involves simple measures that include diagnosed when persistent exposed area of jaw bone is reported for at least eight weeks in patients taking a BP.

local antimicrobial rinses, antibiotic therapy, and improved oral home care. Even though surgical debridement and attempted wound closure can worsen BRONJ, surgical treatment is required when pathologic features continue to expose the jaw to further destruction. In patients taking BPs who do not exhibit BRONJ, prevention is program that emphasizes meticulous and routine oral hygiene practices. Furthermore, prior to BPs therapy, interventions once BPs therapy is initiated. Finally, during the drug therapy, patient education, the preferred method for patient management and involves the establishment of a customized oral home care preventative treatment that involves periodontal, prosthetic, and endodontic therapy, combined with essential and minimally invasive dental extractions should be considered to reduce the amount of dental surgical periodontal maintenance, and review of oral hygiene practices are vital to avoid any invasive dental intervention and the possible appearance of BRONJ. International Journal of Science Innovations and Discoveries, Volume 3, Issue 1, January-February 2013

been

regular

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Kamis Gaballah, IJSID, 2013, 3 (1), 11-21

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, Mehrotra B. American Association of Oral and Maxillofacial Surgeons

REFERENCES

position paper on bisphosphonate-related osteonecrosis of the jaw: 2009 update. J Oral Maxillofac Surg 2009; 67:2-12. vivo. Science 1969; 165:1262-1264. Lancet 1969; 2:845.

Fleisch H, Russell RGG, Francis MD. Diphosphonates inhibit hydroxyapatite in vitro and bone resorption in tissue culture and in Bassett CAL, Donath A, Macagno F, Preisig R, Fleisch H, Francis MD. Diphosphonates in the treatment of myositis ossificans. discontinuation of risedronate. Osteoporos Int. 2008 Mar;19(3):365-372. cancer and myeloma with pamidronate.Eur J Cancer. 1991;27(1):37-41 disease of bone. Ann Rheum Dis. 1991 Dec;50(12):930-933. disease. Lancet. 1993 Dec 11;342(8885):1459-1460. 8;312(7044):1476-1477. MaxilloFac Surg. 2004;62:1563-1565. Quintessence Pub. Co., 2006. Watts NB, Chines A, Olszynski WP, McKeever CD, McClung MR, Zhou X, Grauer A. Fracture risk remains reduced one year after

Thibaud D, Leyvraz S, von Fliedner V, Perey L, Cornu P, Thibaud S, Burckhardt P. Treatment of bone metastases from breast

Gallacher SJ, Boyce BF, Patel U, Jenkins A, Ralston SH, Boyle IT. Clinical experience with pamidronate in the treatment of Paget's Chakravarty K, Merry P, Scott DG. Disodium pamidronate has beneficial effect in Paget's disease of bone. BMJ. 1996 Jun Marx R. Oral & intravenous bisphosphonate-induced osteonecrosis of the jaws: history, etiology, prevention, and treatment. Mehrotra B. Fantasia J. Nissel-Horowitz S, et al. Osteonecrosis of the maxilla:An unusual complication of prolonged bisphosphonatc therapy. A case report. Proc Am Soc Clin Oncol 2003;22:795. review of 63 cases. J Oral Maxillofac Surg. 2004 May;62(5):527-534. 2520234.html. accessed 3 June, 2010. necrosis of the jaws: A growing epidemic. J Oral Maxillofac Surg 2003;61:1115-1117. FDA: Bisphosphonates and Oral Osteonecrosis. Washington,DC. FDA. 2007. bisphosphonates. Cancer. 2000 Jun 15;88(12 Suppl):2961-2978. Res. 2006 Oct 15;12(20 Pt 2):6222s-6230s Dec;2(6):538-543. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a Marx R. Pamidronate (Aredia) and zolendronate (Zometa) induced vascular

Adamson BB, Gallacher SJ, Byars J, Ralston SH, Boyle IT, Boyce BF. Mineralisation defects with pamidronate therapy for Paget's Hellstein j, Marek C: Bis-phossy jaw. phossy jaw and the 21st century. Bisphosphonate-associated complication of the jaws. J Oral

Rogers MJ, Gordon S, Benford HL, Coxon FP, Luckman SP, Monkkonen J, Frith JC. Cellular and molecular mechanisms of action of

Susan Ardizzoni. Fosamax Lawsuit. 2010 available at: http://www.articlesbase.com/womens-health-articles/fosamax-lawsuit

Roelofs AJ, Thompson K, Gordon S, Rogers MJ. Molecular mechanisms of action of bisphosphonates: current status. Clin Cancer

Boivin G, Meunier PJ. Effects of bisphosphonates on matrix mineralization. J Musculoskelet Neuronal Interact. 2002 Sarin J, DeRossi SS, Akintoye SO. Updates on bisphosphonates and potential pathobiology of bisphosphonate-induced jaw osteonecrosis. Oral Dis. 2008 Apr;14(3):277-285. Mackie PS, Fisher JL, Zhou H, Choong PF. Bisphosphonates regulate cell growth and gene expression in the UMR 106-01 clonal rat osteosarcoma cell line. Br J Cancer. 2001 Apr 6;84(7):951-958.

International Journal of Science Innovations and Discoveries, Volume 3, Issue 1, January-February 2013

20

22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41.

Lin Brown JE, Neville-Webbe H, Coleman RE. The role of bisphosphonates in breast and prostate cancers. Endocr Relat Cancer. 2004 Jun;11(2):207-224. Fournier P, Boissier S, Filleur S, et al. Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res 2002;62:65386544. elimination half-lives of bisphosphonates. Clin Drug Investig. 2005;25(2):107-114. Fleisch H. Development of bisphosphonates. Breast Cancer Res. 2002;4(1):30-34. Drug Deliv Rev 2000;42:175-195. Lasseter KC, Porras AG, Denker A, Santhanagopal A, Daifotis A. Pharmacokinetic considerations in determining the terminal

Kamis Gaballah, IJSID, 2013, 3 (1), 11-21

G.R. Mundy and T. Yoneda, Bisphosphonates as anticancer drugs, N Engl J Med 1998; 339:398400. 4935.

Watts NB. Treatment of osteoporosis with bisphosphonates. Endocrinol Metab Clin North Am 1998; 27:41939.

Ezra A, Golomb G. Administration routes and delivery systems of bisphosphonates for the treatment of bone resorption. Adv

R.E. Coleman, P. Major, A. Lipton, J.E. Brown, K.A. Lee and M. Smith et al. Predictive value of bone resorption and formation 2006;144(10):753761.

markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J Clin Oncol 2005; 23:4925 Woo S-B, Hellstein JW, Kalmar JR. Systematic review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med Advisory Task Force on Bisphosphonate-Related Ostenonecrosis of the Jaws, American Association of Oral and Maxillofacial the jaws. J Oral Maxillofac Surg. 2007 Mar;65(3):369-376. Oral Maxillofac Surg 67: Suppl. 1; 71-74, 2009,. Med. 2006 May 16;144(10):753-761. Approved by the Board of Trustees, September 25, 2006. J Oral Maxillofac Surg 2007;65(3):369376. Surgeons. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of

American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. Ruggiero SL, Fantasia J, Carlson E. Bisphosphonate-related osteonecrosis of the jaw: background and guidelines for diagnosis, staging and management. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006 Oct;102(4):433-441. Quintessence Publishing (IL) 2006.pp.77-95.

Gliklich R and Wilson j. Epidemiology of Bisphosphonate-Related Osteonecrosis of the Jaws: The Utility of a National Registry. J Woo SB, Hellstein JW, Kalmar JR. Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Giuseppe Ficarra and Francesco Beninati Bisphosphonate related osteonecrosis of the jaws: the point of view of the oral pathologist. Clin Cases Miner Bone Metab. 2007 Jan Apr; 4(1): 5357. in rats. Am J Orthod Dentofacial Orthop 1994;106:279289. Igarashi K, Mltani H, Adachi H, Shinoda H. Anchorage and retentive effects of a bisphosphonates (AHBuBP) on tooth movements Schwartz JE. Ask us: some drugs affect tooth movement. Am J Orthod Dentofacial Orthop 2005;127:644. aminobisphosphonates. Endocr Relat Cancer. 2006 Mar;13(1):7-26. S.L. Ruggiero and S.J. Drew, Osteonecrosis of the jaws and bisphosphonate therapy, J Dent Res 2007; 86 (11):10131021. Marx RE. Oral & Intravenous Bisphosphonate-Induced Osteonecrosis of the Jaws: History, Etiology, Prevention, and Treatment.

Caraglia M, Santini D, Marra M, Vincenzi B, Tonini G, Budillon A. Emerging anti-cancer molecular mechanisms of

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