Bisphosphonate Related Jaw Osteonecrosis


Continuing Education Activity

Bisphosphonates are synthetic pyrophosphate analogs used to treat hypercalcemia secondary to conditions affecting bone resorption such as malignancy, osteoporosis, multiple myeloma, Paget disease, osteosclerosis, and fibrous dysplasia. Infrequent side effects associated with bisphosphonate use include pyrexia, renal function impairment, hypocalcemia, and, more recently recognized, avascular osteonecrosis of the jaw. According to the American Society of Bone and Mineral Research, bisphosphonate-related jaw osteonecrosis is described as exposed bone in the maxillofacial region that does not heal within 8 weeks of being identified by a healthcare provider in a patient that is currently or has been on bisphosphonates who does not have a history of radiation therapy in the craniofacial region. This activity describes the evaluation and management of patients with bisphosphonate-related jaw osteonecrosis and highlights the role of the interprofessional team in improving care for affected patients.

Objectives:

  • Identify the pathological mechanism of action involved in bisphosphonate-related osteonecrosis of the jaw.
  • Describe the examination and evaluation procedures necessary to diagnose bisphosphonate-related jaw necrosis.
  • Summarize the various treatment strategies available, both conservative and invasive, for treating bisphosphonate-related jaw osteonecrosis.
  • Explain why careful planning and discussion amongst interprofessional team members involved in the management of patients with bisphosphonate jaw necrosis could improve outcomes.

Introduction

Widespread bisphosphonate (BP) use to treat various medical conditions led to increased recognition of their possible association with osteonecrosis (ON) of the jaw.[1] BPs are synthetic pyrophosphate analogs used to treat hypercalcemia secondary to malignancy, osteoporosis, multiple myeloma, Paget disease, osteosclerosis, fibrous dysplasia, and other bone diseases in which bone resorption is involved.[2] Infrequent side effects with BP use include pyrexia, renal function impairment, hypocalcemia, and recently recognized avascular ON of the jaw. The American Society of Bone and Mineral Research defined BP-related jaw ON as current or previous treatment with BPs that leads to exposed bone in the maxillofacial region that does not heal within 8 weeks of identification by a healthcare provider, and the patient has no history of radiation therapy in the craniofacial region.[3] Eight weeks is considered because most surgical and infectious sites heal in this time frame even if complications such as postsurgical infection, chemotherapy, or systemic diseases are present.

Etiology

Mechanism of Action of Bisphosphonate

BPs disrupts the bone remodeling cycle by reducing osteoclast survival and function.[4] BPs accumulate at the site of active bone formation and get internalized by osteoclasts, which makes bone resistant to dissolution by osteoclast, reduce osteoclast survival, and modulate the signaling from osteoblast to osteoclast.[5] 

Bone Remodeling Cycle

  1. Osteoclasts have a lifespan of 150 days.
  2. Osteoclasts resorb bone mineral matrix and release bone morphogenic protein(BMP) and insulin-like growth factors.
  3. Induces stem cells to differentiate into osteoblast and form a new bone matrix.

Without resorption and new bone formation, old bone survives beyond its lifespan, and capillary network in bone is not maintained, leading to avascular necrosis of the jaw. Also, high potency BPs can lead to necrosis by the toxicity of soft tissue along with cells of bone which is further complicated by infection.[6] Due to altered wound healing, delayed epithelial closure of a mucosal opening in the mouth leads to chronic infection and the necrosis of bone.[7] So far, there is no evidence from prospective controlled trials to show the relationship between BPs and ON of the jaw.

Epidemiology

The prospective data on the incidence of BP associated ON of jaw is limited and is mostly based on retrospective studies and case reports with limited sample sizes because of the lower frequency of events and only recent widespread attention of the condition. The probability of BP associated ON of jaw depends upon BP kind, duration and dosage of BP involved, baseline condition for which BP therapy is given and the location involved.

Intravenous (IV) versus oral BPs

ON of jaw is mostly reported with the use of more potent nitrogen-containing BPs like zoledronic acid and pamidronate. Incidence is higher with zoledronic acid due to a greater reduction of collagen type-1 degradation products (N-telopeptide) causing stronger antiresorptive activity leading to a decrease in bone turnover.[8]

Oral BP induced ON is rare, less aggressive and respond better to treatment compared to iv BP induced ON. The difference is due to low lipid solubility of oral BPs that limits small intestinal absorption and much more slower accumulation in bone.[9]

Dose and duration

The incidence of ON is related to dose and duration of BPs and increases with a higher dose of potent BPs being administered for a longer duration.[10][11][12][13][14] As per reported data, cautious use of zoledronic acid and pamidronate is required after 2 years. Risk of bone necrosis with BP therapy ranged from greater than 1% at 12 months to 11% at 4 years and with zoledronic acid alone, the risk from within 1% in the first-year rise to 21% at 3 years. Due to slower accumulation of oral BPs, no clinically exposed bone appear until after 3-year exposure and incidence and severity increases with each additional year of drug use.

Osteoporosis and oncology patients 

As per current data, the incidence of BP-induced ON in osteoporosis patients is very low, ranging from 0.15% to less than 0.001% person-years of exposure and may be only slightly higher than the general population. The incidence of BP-induced ON in oncology patient with bone metastasis is much higher as they are exposed to more intensive osteoclast inhibition and bone necrosis have mostly occurred due to use of high dose IV BPs. Also, the frequency varies with the underlying condition being treated. Wang et al. did a 5-year retrospective study of 292 patients who were treated with IV BPs for the incidence of ON of the jaw and found 3% to 8% patient with multiple myeloma, 2% to 5% with breast cancer and 2.9% with prostate cancer developed ON.[15] Also, Abu-Id et al. did a retrospective study on the development of BP-induced ON of the jaw and found it occurred in 2% to 11% of multiple myeloma patients, 1% to 7% of breast cancer patients and 6% to 15% of prostate cancer patients.[16]

Location

BPs induced ON of jaw occurs more frequently in the mandible than maxilla and almost always began in alveolar bone due to it’s greater bone turnover rate. It results from greater reliance on osteoclast related remodeling due to occlusion and denture wearing pressure and tension forces.[17] Most common sites are nonhealing dentoalveolar sites, traumatized palatal & mandibular tori and exposed portions of the mylohyoid ridge.

Incidence of BP-induced ON of the jaw increases with:

  1. More potent nitrogen-containing IV BPs
  2. High dosage and longer duration
  3. Oncology patients with bone metastasis
  4. Areas with a high bone turnover rate like the alveolar bone of the mandible

Pathophysiology

Risk Factors

Several factors increase the risk of developing ON with BP use.

  • Invasive surgical procedures as tooth extractions, periodontal surgery, apicoectomy, oral implant placement, abscess, hyper occlusion, periodontal inflammation and use of dentures increase the rate of bone turnover and risk of ON.[18]
  • Comorbidities like cancer, patients treated with chemotherapy, low hemoglobin levels, diabetes mellitus, renal dialysis, hypertension, hyperlipidemia, and hypercholesterolemia.[19]
  • Concomitant medications like corticosteroids use, H2 blocking drugs causing increased BP absorption, antiangiogenic agents particularly sunitinib and bevacizumab, erythropoietin, and cyclophosphamide therapy.[20]
  • Infection: It is still unclear if ON precedes or follows the infection. Presence of bacteria and polymorphonuclear aggregates and bacterial microfilm in surrounding tissue has been associated with active osteoclastic resorption of bone and necrosis.[21][22] BPs inhibit proliferation and viability of oral keratinocytes that damages the integrity of oral mucosa and increase the risk of infection.[23][24][25] Also, BPs activate gamma, delta T-cells stimulating the production of pro-inflammatory cytokines and later depletion of T cells impairing the immune response to infection.
  • Genetic predisposition: It is observed that polymorphism in farnesyl pyrophosphate synthase or CYP2C8 coding for a cytochrome P450 enzyme predisposes some individuals to BPs associated ON of jaw in multiple myeloma.[26][27][28] CYP2C8 is hence involved in the biological pathway of this adverse drug reaction. As BPs are not metabolized and excreted intact, the involvement of drug-metabolizing enzymes in undesirable drug reaction is a blow.
  • Other risk factors include increasing age, alcohol, and tobacco use.

BP-Induced ON of Jaw Risk Factors

  1. Invasive dental procedures like tooth extraction, apical and periodontal surgeries, implant placement
  2. Use of prosthesis/dentures
  3. Co-morbidities like cancer, diabetes mellitus, among others
  4. Concomitant medications like corticosteroids and H2 blocking drugs
  5. Infection
  6. Genetic predisposition

History and Physical

The necrotic bone may remain asymptomatic for a prolonged period or may become symptomatic mostly due to localized inflammation of soft tissue.[29] The most common symptoms are pain, surrounding tissue swelling, erythema, necrotic bone infection, suppuration, and lose teeth. Comorbidities include tissue ulceration, intra-and extraoral sinus tracts, and fistula formation and in few cases, it is associated with impairment of nerve function.[30] Some patients presented with altered nerve sensation due to compression of the neurovascular bundle. Paresthesia or even anesthesia of the associated branch of the trigeminal nerve can occur.[31][32] An important early symptom of BP-induced ON of the jaw that can be easily detected is hypoesthesia or anesthesia of the lower lip. Chronic maxillary sinusitis in patients with maxillary bone involvement and pathological fracture in edentulous patients with oral implants can be other complication associated with it.[33]

Radiographically, BP induced ON of jaw can range from no alterations to varying radiolucencies or radio-opacities. Frequently seen osteolytic lesions may appear less or more radiodense providing similar radiographic appearance as in bone metastasis. Radiographic appearance of ON of the jaw may include altered bone morphology, increased bone density, sequestration, or periosteal bone formation. Symptoms may be spontaneous or following dentoalveolar surgery, in edentulous regions of the jaw or at sites of exostoses in oncology patients.[34][35][36][37][38]

Signs and Symptoms

  1. None/asymptomatic
  2. Pain
  3. Soft tissues infection with inflammation, ulceration, and suppuration
  4. Formation of intra-and extraoral sinus tracts and fistulas
  5. Paresthesia or anesthesia of an associated nerve
  6. Pathological fracture
  7. Chronic maxillary sinusitis
  8. A radiographic appearance from no alterations to varying radiolucencies and radiopacities

Evaluation

Early identification of BP associated ON can be very challenging but is important for disease prevention and patient care. 

Clinical Presentation

Patient history and clinical finding of exposed bone for 8 weeks or longer that does not respond to appropriate treatment is the diagnostic hallmark of BP associated ON of jaw. Symptoms may vary from patient being asymptomatic in the early phase to presence of symptoms like pain, soft tissue inflammation, erythema, ulceration, paraesthesia as the disease progress and in advanced cases sequestration, the formation of sinus tracts and fistula along with pathological fractures can be seen. 

Histological Findings

Resected necrotic bone from BP associated ON patients does not demonstrate any unique features of the disease/[29][39] Most frequently found microorganisms in the exposed bone sites are Actinomyces, Veillonella, Eikenella, and Moraxella species and all of them are penicillin-sensitive organisms. Presence of sulfur granules in deeper tissue and drainage areas supports the diagnosis of actinomycosis and requires appropriate treatment.[40] 

Blood Test Finding

It measures C-terminal telopeptide (CTX) value which depicts the level of octapeptide fragment released due to osteoclastic bone resorption from type I bone collagen.[41] Its levels are related to the number of ON of jaw lesions, stage of disease, and is an index of bone turnover.[42] A lower value represents a high-risk patient with suppressed bone turnover and reduced healing capacity. CTX less than 100 pg/ml equals high risk, 100 to 150 pg/ml equal moderate risk, and greater than 150 pg/ml equal minimal or no risk.

Radiographic Appearance

It is very similar to that observed in bone metastasis. Osteolytic lesions are frequently seen that may vary in radiodensity than unaffected bone. Early radiographic signs along alveolar bone may include widened periodontal ligament space and sclerosis of lamina dura.

Imaging Modalities and Diagnostic Tests

Due to nonspecific radiographic features of BP associated ON of jaw, imaging provides a good evaluation of the area involved and can assist in identifying the extent of bone and soft tissue disease but do not provide any definitive differentiation of ON of the jaw from other conditions.[43]

  1. Conventional radiographs: Intraoral and panoramic radiographs are easy to acquire, inexpensive, deliver low radiation, and provide a good view. They are useful to assess early features including thickening of lamina dura, increased trabecular density, incomplete healing of extraction socket, widening of periodontal ligament space, sinus floor cortication, periosteal bone, and sequestrum formation. Also, osteonecrotic and metastatic lesions can be distinguished in the presence of radio-opaque sequestra and are useful with a combination of osteolysis and osteosclerosis. Poor quality images do not demarcate clearly between necrotic and healthy bone. Disease at early stages can be frequently missed. Despite limitations, they form the first line of routine radiological investigation.[44]
  2. CT and cone beam CT CBCT ): CT scan provides the 3-dimensional imaging of the involved cancellous and the cortical bone and can identify both osteosclerotic and osteolytic regions.[44] The CT scan can evaluate presence of sequestrum and periosteal bone reaction and the integrity of the vital adjacent structures.[45][46] Potential fistula tract, cortical erosion, and incomplete extraction socket healing can also be seen.[45][47][48][49] The early stage of ON of the jaw may not be detected, but evaluation of cortical and trabecular bone differences at the symptomatic site can aid in disease diagnosis. CBCT has similar findings of the osteonecrotic areas as the CT scan but imparts lower radiation and has higher spatial resolution with better image quality, particularly for the cancellous bone in a small field of view.[50][51] The major limitation is poor soft tissue details due to low contrast resolution. CBCT imaging findings include increased cortical bone density and erosions, sequestrum formation, periosteal bone reaction, and osteolysis.[52][53]
  3. MRI: MRI currently may be the method of choice to detect the early bone marrow and soft tissue changes surrounding the osteonecrotic area. Osseous change evaluation by MRI is similar to CT imaging. One of the consistent MRI findings is the decreased bone marrow signal intensity on T-1 weighted images resulting from progressive cell death and host response through repair, i.e., edema.[46][54][55][47] Irregular gadolinium enhancement around osteolytic lesions is observed. Non-enhancement in regions of ischemia, especially in T-1 weighted sequences, low signal intensity in areas of fibrosis and sclerosis on both T-1 and T-2 weighted images and increased signal intensity along the unexposed diseased bone.[54][56] However, MRI may not demonstrate the full extent of bony changes and may give a false-positive diagnosis.
  4. Nuclear imaging with bone scintigraphy: Technetium-99 radioisotope scintigraphy has high sensitivity for diagnosing early disease and ischemic ON. Its sensitivity depends on the stage of osteonecrotic lesion and change in vascularity.[44] It shows increased radionuclide uptake in surrounding areas with increased perfusion and blood pool, providing the more precise location of osteonecrotic areas. Primary drawbacks include significant radiation exposure, lengthy procedure, and low resolution, which sometimes make it difficult to distinguish between inflammatory & metastatic processes and between healing osteolytic lesions & progressing osteoblastic lesions.
  5. Positron emission tomography: PET using F-18 fluoride and F-18 fluorodeoxyglucose (FDG) tracers is used for patient assessment. This technique is not considered useful due to poor resolution and high radiation dosage associated.
  6. Optical coherence tomography: This technique uses the light of different wavelengths to dictate penetration depth[57] and resolution.[58][59] It does not use ionizing radiations, but the depth of penetration and birefringence cause image artifacts which is a major drawback.

Combinational approaches as use of CBCT with scintigraphy for diagnosing osteomyelitis[51] or use of contrast agents with MRI, sequential imaging and the manipulation of image planes can all be helpful measures to diagnose early or preclinical stages of BP-induced ON.

Treatment / Management

Treatment is dependent upon many variables like age, gender, disease stage and lesion size, comorbidities present, medication exposure among others, but since their influence on disease course and treatment response is not known, clinical judgment guides the treatment approach. Other important factors are prognosis, life quality and expectancy and ability of an individual to cope with the disease. No evidence-based guidelines for treatment of BP-induced ON of the jaw are currently available, but the treatment goal is to alleviate pain, control infection and stabilize the progression of exposed bone.

Conservative Therapy

It is the mainstay of care and may provide long-term symptomatic relief.[60][38] 

  1. Pain control and optimal oral hygiene including diligent home care and regular dental visits
  2. Elimination of infection and active dental disease, use of 0.12% chlorhexidine digluconate oral antimicrobial rinses and systemic antibiotic therapy[61][62][63] Penicillin VK, 500 mg, 4 times daily is the antibiotic of choice as this formulation of penicillin is non-toxic and can be used long-term without superinfection and development of candidiasis. If long-term antibiotic usage is a concern, then it can be used only during episodes of pain. If the patient is allergic to penicillin, then levofloxacin, 500 mg, once daily is the best alternative. Other alternatives include doxycycline, 100 mg daily or azithromycin, 250 mg daily. However, Levaquin and Zithromax should be used for only 21 days or less due to their potential to raise the liver enzymes and other potential side effects. If this antibiotic protocol doesn’t work well, then adding 500 mg of metronidazole 3 times daily for 10 days adds further control.
  3. It is reported that the osseous wound healing in the oral cavity is facilitated by teriparatide.[64] Teriparatide is not recommended for a patient at low risk of ON of jaw or fracture but adding it to the treatment regimen of the osteoporotic patient with established ON may benefit them.[65][66][67] Same approach not recommended for a cancer patient or who received skeletal radiation or for the one who has active bone metastasis as these patients have a risk of development or advancement of bone malignancies.
  4. Reduce the contact of the oral prosthesis, for example, artificial dentures with the exposed bone.
  5. CTX test and the drug holiday after weighing the risk-benefit ratio. Repeat CTX test results are obtained after 6 months of the drug holiday. Some cases resolve with CTX value rising above 150 pg/ml, and many show clinical and radiographic signs of improvement as separation of necrotic bone from healthy bone occurs, which is followed by sequestration and debridement. Most of the oral BP induced ON cases are resolved by CTX guided protocol. Regular follow up is required to keep the CTX value above 150 pg/ml using incremental drug schedules and alternative drugs.

Surgical Therapy 

Lack of symptomatic or radiographic improvement with various treatment modalities indicate permanent bone defect and need surgical intervention.

  1. Affected area ostectomy with resection margins extending into the adjacent healthy bone along with tension-free soft tissue closure with no underlying sharp edges that could lead to mucosal breakdown.[68]
  2. In patients with pathological fractures or disease extending to sinus or inferior border of the mandible or if ostectomy lead to discontinuity defect, microvascular composite tissue grafting and reconstruction procedures should be considered.

Experimental Therapy

The various treatment approaches included are use of hyperbaric oxygen,[69][70] bone marrow stem cell intralesional transplantation[71], local application of platelet-derived growth factor,[72] low-level laser therapy,[73][74] or using them in combination with conservative and/or surgical debridement but their effect on the treatment outcome needs further substantiation.

Most recent recommendations advocate non-surgical treatment approach due to impaired wound healing, but few studies included radical resection to viable bone and hermetic wound closure with soft tissue being the only curative approach.[16] Combination of various approaches like marginal resection along with the use of platelet-derived growth factor had been advocated by many studies.[75]

Treatment Approach Review

  1. Conservative and supportive therapy for pain and infection control
  2. Surgical therapy for permanent bone defects and sequestration
  3. Experimental therapy consisting of hyperbaric oxygen, bone marrow stem cell intralesional transplantation, platelet-derived growth factor, low-level laser therapy

Differential Diagnosis

The presence of exposed bone characterizes BP associate ON of the jaw. In the absence of exposed bone, the differential diagnosis includes conditions such as periodontal and periapical pathosis, sinusitis, gingivitis or mucositis, temporomandibular disorders, osteomyelitis, metastatic bone tumors, osteonecrosis induced by neuralgia and osteoradionecrosis. The differential diagnosis for conditions including exposed bone but without the BP use are cement osseous dysplasia with secondary sequestration, trauma, infectious osteomyelitis, osteonecrosis following Herpes zoster infection or HIV associated necrotizing ulcerative periodontitis.

Staging

Very little evidence is reviewed for the staging of BP associated ON of jaw. So staging recommendations should be considered as consensus statements. The current staging system is developed by Ruggiero and colleagues[76] and is adopted by AAOMS.[77][78] Stage system is important to identify stage characteristics and provide appropriate diagnosis and management.

Stage 1 patients have exposed bone and are asymptomatic with no localized soft tissue infection. Stage 2 patients have exposed bone and have pain and regional soft tissue inflammation or infection. Stage 3 patients have exposed bone with associated pain, localized soft tissue inflammation, or secondary infection along with pathologic fracture, the formation of extraoral or oral-antral fistula and radiographically have osteolysis extending to the inferior mandibular border or maxillary sinus floor. Recently, AAOMS added stage 0 to the staging system that has patients who take BPs and present with non-specific clinical findings and symptoms. Term stage 0 can lead to overdiagnosis that can have detrimental effects on the patient’s skeletal health if modification of anti-resorptive medication regimen is done as similar presenting symptoms may lead to a different diagnosis.[79]

Deterrence and Patient Education

Prevention is the best approach and requires good communication among dentist, oral surgeon, physicians, nurse practitioners, and oncologists to develop measures aimed at preventing the development of BP-induced ON of the jaw.

Recommendations Before Initiating BP Therapy

Around 4 to 6 monthly doses are required to have significant effects on bone healing in jaws; it is recommended to take preventive measures during this period. 

  1. Prophylactic dental examination along with maintenance of good oral hygiene and regular dental visits
  2. Patient education regarding risk of BP therapy including ON of jaw, its signs and symptoms, and the risk factors of developing ON of jaw.
  3. Developing a dental treatment plan focused on correcting pathological conditions and stabilizing dentition to prevent the need for invasive procedures after the BP therapy is initiated.
  4. Unrestorable, abscessed and periodontally compromised teeth along with those with failing root canal fills should be extracted.
  5. Treat periodontal disease and inflammation and salvage treatable teeth.
  6. Educate patients regarding home hygiene and self-maintenance.
  7. Restorative and prosthodontics procedures can be later accomplished, but dental implant placement and orthodontic treatment are not recommended. However, patients on BP for osteoporosis are currently not contraindicated for implant placement, but appropriate informed consent and documentation is recommended. 

Recommendations for Patients Receiving BP Therapy

After 4 to 6 doses of BP, bone turnover is significantly suppressed, making bone healing unpredictable and risky for ON.

  1. Maintaining good oral hygiene and regular dental visits and educating patients regarding the risk of developing BP associated ON of jaw.
  2. Oral surgical procedures like extractions, bone contouring, grafting, periodontal, and apical surgeries should be avoided.[17]
  3. If possible, endodontic treatment is preferred over extractions and periapical surgery.
  4. Noninvasive restorative procedures like crowns, bridges, removable partial, and complete dentures are recommended to prevent future surgical procedures.
  5. Orthodontic procedures are not recommended
  6. Elective dentoalveolar surgical procedures like asymptomatic teeth extraction, implant placement, tori reduction are not recommended.
  7. Unrestorable teeth preferably should be treated with root canal fill and crown amputation; mobile teeth are best splinted, failed root canal fills should be retreated but if extraction is unavoidable patient should be educated regarding the risk of developing BP induced ON of jaw and informed consent should be signed.
  8. Antibiotics before and/or after the dental procedure and antimicrobial mouth rinsing may prevent the occurrence of ON of the jaw.[80][81][82]
  9. It is necessary to stratify the risk for patients on BP requiring extensive invasive oral surgery as well as for patients with accompanying multiple risk factors like periodontal disease, immunodeficiencies and steroid treatment, diabetes, smoking, among others. If it is advisable, withhold the BP therapy and put the patient on drug holiday until soft tissue closure with well-epithelialized mucosa is achieved. Although since BPs have long halftime, there is little supporting evidence that withholding BP therapy will affect the treatment outcomes.[83]

Pearls and Other Issues

  • BP associated ON of the jaw is characterized by the presence of exposed bone in the oral cavity that does not heal within 8 weeks after identification by a healthcare provider in patients on current or previous treatment with bisphosphonates who have no history of radiation therapy in the craniofacial region.
  • BP disrupts the bone remodeling cycle by reducing osteoclast survival and function. Without resorption and new bone formation, old bone accumulates leading to avascularity and necrosis of bone.
  • The incidence of BP-induced ON of the jaw is high among oncology patients taking more potent nitrogen-containing IV BPs like zoledronic acid and pamidronate, and the occurrence increases with dosage and duration of therapy.
  • BP induced ON of jaw occurs more frequently in the mandible than maxilla due to greater bone turnover rate.
  • Factors that increase the risk of BP-induced ON of the jaw include the invasive dental procedures, comorbidities, and concomitant medications like corticosteroids.
  • Patients may be asymptomatic or present with an infection, pain, localized soft tissue inflammation, suppuration and/or ulceration, the formation of extra and intraoral sinus tracts and fistulas, pathological fractures, paresthesia, and even anesthesia of the associated nerve.
  • Radiographic appearance of BP-induced ON of the jaw can range from no alternations to varying radiolucencies and radio-opacities.
  • Early identification and diagnosis of BP-induced ON of the jaw can be very challenging. Prevention is the key to reduce the risk of ON in patients on BPs.
  • Treatment is mostly supportive and is aimed at pain and infection control. Surgical intervention is indicated for permanent bone defects and sequestration.

Enhancing Healthcare Team Outcomes

Prompt recognition of osteonecrosis by the interprofessional team is important for improving outcomes. Prescribing providers include primary care providers, dentists, orthopedists, rheumatologists, and oncologists. Pharmacists provided education to patients and their families, monitor compliance, and provide feedback to the team. Specialty care nurses including infusion nurses, orthopedic nurses, and otolaryngology provide education, monitor patients, and inform the team about status changes or issues. Good communication among the team, patient education, appropriate preventive measures, and treatment aimed at pain and infection control can enhance the patient care outcomes for patients on bisphosphonates who are at the risk of developing or having established osteonecrosis of the jaw. [Level 5]



(Click Image to Enlarge)
Jaw Osteonecrosis
Jaw Osteonecrosis
Image courtesy S Bhimji MD
Article Details

Article Author

Mohit Gupta

Article Editor:

Neha Gupta

Updated:

7/2/2020 8:35:07 PM

References

[1]

Shane E,Goldring S,Christakos S,Drezner M,Eisman J,Silverman S,Pendrys D, Osteonecrosis of the jaw: more research needed. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2006 Oct     [PubMed PMID: 16995804]

[2]

McClung MR, Bisphosphonates. Endocrinology and metabolism clinics of North America. 2003 Mar     [PubMed PMID: 12699302]

[3]

Khosla S,Burr D,Cauley J,Dempster DW,Ebeling PR,Felsenberg D,Gagel RF,Gilsanz V,Guise T,Koka S,McCauley LK,McGowan J,McKee MD,Mohla S,Pendrys DG,Raisz LG,Ruggiero SL,Shafer DM,Shum L,Silverman SL,Van Poznak CH,Watts N,Woo SB,Shane E, Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2007 Oct     [PubMed PMID: 17663640]

[4]

Lehenkari PP,Kellinsalmi M,Näpänkangas JP,Ylitalo KV,Mönkkönen J,Rogers MJ,Azhayev A,Väänänen HK,Hassinen IE, Further insight into mechanism of action of clodronate: inhibition of mitochondrial ADP/ATP translocase by a nonhydrolyzable, adenine-containing metabolite. Molecular pharmacology. 2002 May     [PubMed PMID: 11961144]

[5]

Rogers MJ,Gordon S,Benford HL,Coxon FP,Luckman SP,Monkkonen J,Frith JC, Cellular and molecular mechanisms of action of bisphosphonates. Cancer. 2000 Jun 15     [PubMed PMID: 10898340]

[6]

Reid IR,Bolland MJ,Grey AB, Is bisphosphonate-associated osteonecrosis of the jaw caused by soft tissue toxicity? Bone. 2007 Sep     [PubMed PMID: 17572168]

[7]

Rizzoli R,Burlet N,Cahall D,Delmas PD,Eriksen EF,Felsenberg D,Grbic J,Jontell M,Landesberg R,Laslop A,Wollenhaupt M,Papapoulos S,Sezer O,Sprafka M,Reginster JY, Osteonecrosis of the jaw and bisphosphonate treatment for osteoporosis. Bone. 2008 May     [PubMed PMID: 18314405]

[8]

Rosen LS,Gordon D,Kaminski M,Howell A,Belch A,Mackey J,Apffelstaedt J,Hussein M,Coleman RE,Reitsma DJ,Seaman JJ,Chen BL,Ambros Y, Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer journal (Sudbury, Mass.). 2001 Sep-Oct     [PubMed PMID: 11693896]

[9]

Marx RE,Cillo JE Jr,Ulloa JJ, Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons. 2007 Dec     [PubMed PMID: 18022461]

[10]

Cartsos VM,Zhu S,Zavras AI, Bisphosphonate use and the risk of adverse jaw outcomes: a medical claims study of 714,217 people. Journal of the American Dental Association (1939). 2008 Jan     [PubMed PMID: 18167381]

[11]

Fellows JL,Rindal DB,Barasch A,Gullion CM,Rush W,Pihlstrom DJ,Richman J, ONJ in two dental practice-based research network regions. Journal of dental research. 2011 Apr     [PubMed PMID: 21317245]

[12]

Lyles KW,Colón-Emeric CS,Magaziner JS,Adachi JD,Pieper CF,Mautalen C,Hyldstrup L,Recknor C,Nordsletten L,Moore KA,Lavecchia C,Zhang J,Mesenbrink P,Hodgson PK,Abrams K,Orloff JJ,Horowitz Z,Eriksen EF,Boonen S, Zoledronic acid and clinical fractures and mortality after hip fracture. The New England journal of medicine. 2007 Nov 1     [PubMed PMID: 17878149]

[13]

Powell D,Bowler C,Roberts T,Garton M,Matthews C,McCall I,Davie M, Incidence of serious side effects with intravenous bisphosphonate: a clinical audit. QJM : monthly journal of the Association of Physicians. 2012 Oct     [PubMed PMID: 22753670]

[14]

Sieber P,Lardelli P,Kraenzlin CA,Kraenzlin ME,Meier C, Intravenous bisphosphonates for postmenopausal osteoporosis: safety profiles of zoledronic acid and ibandronate in clinical practice. Clinical drug investigation. 2013 Feb     [PubMed PMID: 23184667]

[15]

Wang EP,Kaban LB,Strewler GJ,Raje N,Troulis MJ, Incidence of osteonecrosis of the jaw in patients with multiple myeloma and breast or prostate cancer on intravenous bisphosphonate therapy. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons. 2007 Jul     [PubMed PMID: 17577497]

[16]

Abu-Id MH,Warnke PH,Gottschalk J,Springer I,Wiltfang J,Acil Y,Russo PA,Kreusch T,     [PubMed PMID: 18234504]

[17]

Marx RE,Sawatari Y,Fortin M,Broumand V, Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons. 2005 Nov     [PubMed PMID: 16243172]

[18]

Mellal A,Wiskott HW,Botsis J,Scherrer SS,Belser UC, Stimulating effect of implant loading on surrounding bone. Comparison of three numerical models and validation by in vivo data. Clinical oral implants research. 2004 Apr     [PubMed PMID: 15008937]

[19]

Hess LM,Jeter JM,Benham-Hutchins M,Alberts DS, Factors associated with osteonecrosis of the jaw among bisphosphonate users. The American journal of medicine. 2008 Jun     [PubMed PMID: 18501224]

[20]

Jadu F,Lee L,Pharoah M,Reece D,Wang L, A retrospective study assessing the incidence, risk factors and comorbidities of pamidronate-related necrosis of the jaws in multiple myeloma patients. Annals of oncology : official journal of the European Society for Medical Oncology. 2007 Dec     [PubMed PMID: 17804475]

[21]

Sedghizadeh PP,Kumar SK,Gorur A,Schaudinn C,Shuler CF,Costerton JW, Microbial biofilms in osteomyelitis of the jaw and osteonecrosis of the jaw secondary to bisphosphonate therapy. Journal of the American Dental Association (1939). 2009 Oct     [PubMed PMID: 19797556]

[22]

Lesclous P,Abi Najm S,Carrel JP,Baroukh B,Lombardi T,Willi JP,Rizzoli R,Saffar JL,Samson J, Bisphosphonate-associated osteonecrosis of the jaw: a key role of inflammation? Bone. 2009 Nov     [PubMed PMID: 19631301]

[23]

Hikita H,Miyazawa K,Tabuchi M,Kimura M,Goto S, Bisphosphonate administration prior to tooth extraction delays initial healing of the extraction socket in rats. Journal of bone and mineral metabolism. 2009     [PubMed PMID: 19436946]

[24]

Landesberg R,Woo V,Cremers S,Cozin M,Marolt D,Vunjak-Novakovic G,Kousteni S,Raghavan S, Potential pathophysiological mechanisms in osteonecrosis of the jaw. Annals of the New York Academy of Sciences. 2011 Feb     [PubMed PMID: 21291478]

[25]

Ravosa MJ,Ning J,Liu Y,Stack MS, Bisphosphonate effects on the behaviour of oral epithelial cells and oral fibroblasts. Archives of oral biology. 2011 May     [PubMed PMID: 21146154]

[26]

Marini F,Tonelli P,Cavalli L,Cavalli T,Masi L,Falchetti A,Brandi ML, Pharmacogenetics of bisphosphonate-associated osteonecrosis of the jaw. Frontiers in bioscience (Elite edition). 2011 Jan 1     [PubMed PMID: 21196316]

[27]

English BC,Baum CE,Adelberg DE,Sissung TM,Kluetz PG,Dahut WL,Price DK,Figg WD, A SNP in CYP2C8 is not associated with the development of bisphosphonate-related osteonecrosis of the jaw in men with castrate-resistant prostate cancer. Therapeutics and clinical risk management. 2010 Nov 19     [PubMed PMID: 21151627]

[28]

Sarasquete ME,García-Sanz R,Marín L,Alcoceba M,Chillón MC,Balanzategui A,Santamaria C,Rosiñol L,de la Rubia J,Hernandez MT,Garcia-Navarro I,Lahuerta JJ,González M,San Miguel JF, Bisphosphonate-related osteonecrosis of the jaw is associated with polymorphisms of the cytochrome P450 CYP2C8 in multiple myeloma: a genome-wide single nucleotide polymorphism analysis. Blood. 2008 Oct 1     [PubMed PMID: 18594024]

[29]

Allen MR,Ruggiero SL, Higher bone matrix density exists in only a subset of patients with bisphosphonate-related osteonecrosis of the jaw. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons. 2009 Jul     [PubMed PMID: 19531405]

[30]

Otto S,Hafner S,Grötz KA, The role of inferior alveolar nerve involvement in bisphosphonate-related osteonecrosis of the jaw. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons. 2009 Mar     [PubMed PMID: 19231785]

[31]

Sharma D,Ivanovski S,Slevin M,Hamlet S,Pop TS,Brinzaniuc K,Petcu EB,Miroiu RI, Bisphosphonate-related osteonecrosis of jaw (BRONJ): diagnostic criteria and possible pathogenic mechanisms of an unexpected anti-angiogenic side effect. Vascular cell. 2013 Jan 14     [PubMed PMID: 23316704]

[32]

Fedele S,Porter SR,D'Aiuto F,Aljohani S,Vescovi P,Manfredi M,Arduino PG,Broccoletti R,Musciotto A,Di Fede O,Lazarovici TS,Campisi G,Yarom N, Nonexposed variant of bisphosphonate-associated osteonecrosis of the jaw: a case series. The American journal of medicine. 2010 Nov     [PubMed PMID: 20851366]

[33]

Pogrel MA, Bisphosphonates and bone necrosis. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons. 2004 Mar     [PubMed PMID: 15015179]

[34]

Ferlito S,Puzzo S,Liardo C, Preventive protocol for tooth extractions in patients treated with zoledronate: a case series. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons. 2011 Jun     [PubMed PMID: 21316136]

[35]

Scoletta M,Arduino PG,Pol R,Arata V,Silvestri S,Chiecchio A,Mozzati M, Initial experience on the outcome of teeth extractions in intravenous bisphosphonate-treated patients: a cautionary report. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons. 2011 Feb     [PubMed PMID: 21129835]

[36]

Barasch A,Cunha-Cruz J,Curro FA,Hujoel P,Sung AH,Vena D,Voinea-Griffin AE,Beadnell S,Craig RG,DeRouen T,Desaranayake A,Gilbert A,Gilbert GH,Goldberg K,Hauley R,Hashimoto M,Holmes J,Latzke B,Leroux B,Lindblad A,Richman J,Safford M,Ship J,Thompson VP,Williams OD,Yin W, Risk factors for osteonecrosis of the jaws: a case-control study from the CONDOR dental PBRN. Journal of dental research. 2011 Apr     [PubMed PMID: 21317246]

[37]

Schubert M,Klatte I,Linek W,Müller B,Döring K,Eckelt U,Hemprich A,Berger U,Hendricks J, The saxon bisphosphonate register - therapy and prevention of bisphosphonate-related osteonecrosis of the jaws. Oral oncology. 2012 Apr     [PubMed PMID: 22130456]

[38]

Saad F,Brown JE,Van Poznak C,Ibrahim T,Stemmer SM,Stopeck AT,Diel IJ,Takahashi S,Shore N,Henry DH,Barrios CH,Facon T,Senecal F,Fizazi K,Zhou L,Daniels A,Carrière P,Dansey R, Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Annals of oncology : official journal of the European Society for Medical Oncology. 2012 May     [PubMed PMID: 21986094]

[39]

Allen MR,Pandya B,Ruggiero SL, Lack of correlation between duration of osteonecrosis of the jaw and sequestra tissue morphology: what it tells us about the condition and what it means for future studies. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons. 2010 Nov     [PubMed PMID: 20869151]

[40]

Sawatari Y,Marx RE, Bisphosphonates and bisphosphonate induced osteonecrosis. Oral and maxillofacial surgery clinics of North America. 2007 Nov     [PubMed PMID: 18088900]

[41]

Rosen HN,Moses AC,Garber J,Iloputaife ID,Ross DS,Lee SL,Greenspan SL, Serum CTX: a new marker of bone resorption that shows treatment effect more often than other markers because of low coefficient of variability and large changes with bisphosphonate therapy. Calcified tissue international. 2000 Feb     [PubMed PMID: 10652955]

[42]

Yamazaki T,Yamori M,Ishizaki T,Asai K,Goto K,Takahashi K,Nakayama T,Bessho K, Increased incidence of osteonecrosis of the jaw after tooth extraction in patients treated with bisphosphonates: a cohort study. International journal of oral and maxillofacial surgery. 2012 Nov     [PubMed PMID: 22840716]

[43]

Morag Y,Morag-Hezroni M,Jamadar DA,Ward BB,Jacobson JA,Zwetchkenbaum SR,Helman J, Bisphosphonate-related osteonecrosis of the jaw: a pictorial review. Radiographics : a review publication of the Radiological Society of North America, Inc. 2009 Nov     [PubMed PMID: 19926757]

[44]

Store G,Larheim TA, Mandibular osteoradionecrosis: a comparison of computed tomography with panoramic radiography. Dento maxillo facial radiology. 1999 Sep     [PubMed PMID: 10490748]

[45]

Bianchi SD,Scoletta M,Cassione FB,Migliaretti G,Mozzati M, Computerized tomographic findings in bisphosphonate-associated osteonecrosis of the jaw in patients with cancer. Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics. 2007 Aug     [PubMed PMID: 17560140]

[46]

Stockmann P,Hinkmann FM,Lell MM,Fenner M,Vairaktaris E,Neukam FW,Nkenke E, Panoramic radiograph, computed tomography or magnetic resonance imaging. Which imaging technique should be preferred in bisphosphonate-associated osteonecrosis of the jaw? A prospective clinical study. Clinical oral investigations. 2010 Jun     [PubMed PMID: 19513765]

[47]

Bedogni A,Blandamura S,Lokmic Z,Palumbo C,Ragazzo M,Ferrari F,Tregnaghi A,Pietrogrande F,Procopio O,Saia G,Ferretti M,Bedogni G,Chiarini L,Ferronato G,Ninfo V,Lo Russo L,Lo Muzio L,Nocini PF, Bisphosphonate-associated jawbone osteonecrosis: a correlation between imaging techniques and histopathology. Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics. 2008 Mar     [PubMed PMID: 18280968]

[48]

Elad S,Gomori MJ,Ben-Ami N,Friedlander-Barenboim S,Regev E,Lazarovici TS,Yarom N, Bisphosphonate-related osteonecrosis of the jaw: clinical correlations with computerized tomography presentation. Clinical oral investigations. 2010 Feb     [PubMed PMID: 19603201]

[49]

Phal PM,Myall RW,Assael LA,Weissman JL, Imaging findings of bisphosphonate-associated osteonecrosis of the jaws. AJNR. American journal of neuroradiology. 2007 Jun-Jul     [PubMed PMID: 17569974]

[50]

Schulze D,Blessmann M,Pohlenz P,Wagner KW,Heiland M, Diagnostic criteria for the detection of mandibular osteomyelitis using cone-beam computed tomography. Dento maxillo facial radiology. 2006 Jul     [PubMed PMID: 16798917]

[51]

Guerrero ME,Jacobs R,Loubele M,Schutyser F,Suetens P,van Steenberghe D, State-of-the-art on cone beam CT imaging for preoperative planning of implant placement. Clinical oral investigations. 2006 Mar     [PubMed PMID: 16482455]

[52]

Torres SR,Chen CS,Leroux BG,Lee PP,Hollender LG,Santos EC,Drew SP,Hung KC,Schubert MM, Mandibular cortical bone evaluation on cone beam computed tomography images of patients with bisphosphonate-related osteonecrosis of the jaw. Oral surgery, oral medicine, oral pathology and oral radiology. 2012 May     [PubMed PMID: 22668629]

[53]

Wilde F,Heufelder M,Lorenz K,Liese S,Liese J,Helmrich J,Schramm A,Hemprich A,Hirsch E,Winter K, Prevalence of cone beam computed tomography imaging findings according to the clinical stage of bisphosphonate-related osteonecrosis of the jaw. Oral surgery, oral medicine, oral pathology and oral radiology. 2012 Dec     [PubMed PMID: 23159120]

[54]

Chiandussi S,Biasotto M,Dore F,Cavalli F,Cova MA,Di Lenarda R, Clinical and diagnostic imaging of bisphosphonate-associated osteonecrosis of the jaws. Dento maxillo facial radiology. 2006 Jul     [PubMed PMID: 16798918]

[55]

Krishnan A,Arslanoglu A,Yildirm N,Silbergleit R,Aygun N, Imaging findings of bisphosphonate-related osteonecrosis of the jaw with emphasis on early magnetic resonance imaging findings. Journal of computer assisted tomography. 2009 Mar-Apr     [PubMed PMID: 19346864]

[56]

Popovic KS,Kocar M, Imaging findings in bisphosphonate-induced osteonecrosis of the jaws. Radiology and oncology. 2010 Dec     [PubMed PMID: 22933918]

[57]

Colston BW Jr,Everett MJ,Sathyam US,DaSilva LB,Otis LL, Imaging of the oral cavity using optical coherence tomography. Monographs in oral science. 2000     [PubMed PMID: 10949834]

[58]

Hall A,Girkin JM, A review of potential new diagnostic modalities for caries lesions. Journal of dental research. 2004     [PubMed PMID: 15286130]

[59]

Baumgartner A,Dichtl S,Hitzenberger CK,Sattmann H,Robl B,Moritz A,Fercher AF,Sperr W, Polarization-sensitive optical coherence tomography of dental structures. Caries research. 2000 Jan-Feb     [PubMed PMID: 10601786]

[60]

Ji X,Pushalkar S,Li Y,Glickman R,Fleisher K,Saxena D, Antibiotic effects on bacterial profile in osteonecrosis of the jaw. Oral diseases. 2012 Jan     [PubMed PMID: 21883710]

[61]

Woo SB,Hellstein JW,Kalmar JR, Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws. Annals of internal medicine. 2006 May 16     [PubMed PMID: 16702591]

[62]

Ruggiero SL,Mehrotra B,Rosenberg TJ,Engroff SL, Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons. 2004 May     [PubMed PMID: 15122554]

[63]

Melo MD,Obeid G, Osteonecrosis of the jaws in patients with a history of receiving bisphosphonate therapy: strategies for prevention and early recognition. Journal of the American Dental Association (1939). 2005 Dec     [PubMed PMID: 16383049]

[64]

Bashutski JD,Eber RM,Kinney JS,Benavides E,Maitra S,Braun TM,Giannobile WV,McCauley LK, Teriparatide and osseous regeneration in the oral cavity. The New England journal of medicine. 2010 Dec 16     [PubMed PMID: 20950166]

[65]

Harper RP,Fung E, Resolution of bisphosphonate-associated osteonecrosis of the mandible: possible application for intermittent low-dose parathyroid hormone [rhPTH(1-34)]. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons. 2007 Mar     [PubMed PMID: 17307613]

[66]

Lau AN,Adachi JD, Resolution of osteonecrosis of the jaw after teriparatide [recombinant human PTH-(1-34)] therapy. The Journal of rheumatology. 2009 Aug     [PubMed PMID: 19671824]

[67]

Cheung A,Seeman E, Teriparatide therapy for alendronate-associated osteonecrosis of the jaw. The New England journal of medicine. 2010 Dec 16     [PubMed PMID: 20950167]

[68]

Wilde F,Heufelder M,Winter K,Hendricks J,Frerich B,Schramm A,Hemprich A, The role of surgical therapy in the management of intravenous bisphosphonates-related osteonecrosis of the jaw. Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics. 2011 Feb     [PubMed PMID: 20674411]

[69]

Bedogni A,Saia G,Bettini G,Tronchet A,Totola A,Bedogni G,Ferronato G,Nocini PF,Blandamura S, Long-term outcomes of surgical resection of the jaws in cancer patients with bisphosphonate-related osteonecrosis. Oral oncology. 2011 May     [PubMed PMID: 21439892]

[70]

Freiberger JJ,Padilla-Burgos R,McGraw T,Suliman HB,Kraft KH,Stolp BW,Moon RE,Piantadosi CA, What is the role of hyperbaric oxygen in the management of bisphosphonate-related osteonecrosis of the jaw: a randomized controlled trial of hyperbaric oxygen as an adjunct to surgery and antibiotics. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons. 2012 Jul     [PubMed PMID: 22698292]

[71]

Cella L,Oppici A,Arbasi M,Moretto M,Piepoli M,Vallisa D,Zangrandi A,Di Nunzio C,Cavanna L, Autologous bone marrow stem cell intralesional transplantation repairing bisphosphonate related osteonecrosis of the jaw. Head     [PubMed PMID: 21849044]

[72]

Mozzati M,Gallesio G,Arata V,Pol R,Scoletta M, Platelet-rich therapies in the treatment of intravenous bisphosphonate-related osteonecrosis of the jaw: a report of 32 cases. Oral oncology. 2012 May     [PubMed PMID: 22265335]

[73]

Vescovi P,Manfredi M,Merigo E,Meleti M,Fornaini C,Rocca JP,Nammour S, Surgical approach with Er:YAG laser on osteonecrosis of the jaws (ONJ) in patients under bisphosphonate therapy (BPT). Lasers in medical science. 2010 Jan     [PubMed PMID: 19543768]

[74]

Vescovi P,Merigo E,Meleti M,Manfredi M,Guidotti R,Nammour S, Bisphosphonates-related osteonecrosis of the jaws: a concise review of the literature and a report of a single-centre experience with 151 patients. Journal of oral pathology     [PubMed PMID: 21958312]

[75]

Adornato MC,Morcos I,Rozanski J, The treatment of bisphosphonate-associated osteonecrosis of the jaws with bone resection and autologous platelet-derived growth factors. Journal of the American Dental Association (1939). 2007 Jul     [PubMed PMID: 17606496]

[76]

Ruggiero SL,Fantasia J,Carlson E, Bisphosphonate-related osteonecrosis of the jaw: background and guidelines for diagnosis, staging and management. Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics. 2006 Oct     [PubMed PMID: 16997108]

[77]

Ruggiero SL,Dodson TB,Assael LA,Landesberg R,Marx RE,Mehrotra B, American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaw - 2009 update. Australian endodontic journal : the journal of the Australian Society of Endodontology Inc. 2009 Dec     [PubMed PMID: 19961450]

[78]

American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons. 2007 Mar     [PubMed PMID: 17307580]

[79]

Khan AA,Sándor GK,Dore E,Morrison AD,Alsahli M,Amin F,Peters E,Hanley DA,Chaudry SR,Dempster DW,Glorieux FH,Neville AJ,Talwar RM,Clokie CM,Al Mardini M,Paul T,Khosla S,Josse RG,Sutherland S,Lam DK,Carmichael RP,Blanas N,Kendler D,Petak S,St-Marie LG,Brown J,Evans AW,Rios L,Compston JE, Canadian consensus practice guidelines for bisphosphonate associated osteonecrosis of the jaw. The Journal of rheumatology. 2008 Jul     [PubMed PMID: 18528958]

[80]

Dimopoulos MA,Kastritis E,Bamia C,Melakopoulos I,Gika D,Roussou M,Migkou M,Eleftherakis-Papaiakovou E,Christoulas D,Terpos E,Bamias A, Reduction of osteonecrosis of the jaw (ONJ) after implementation of preventive measures in patients with multiple myeloma treated with zoledronic acid. Annals of oncology : official journal of the European Society for Medical Oncology. 2009 Jan     [PubMed PMID: 18689864]

[81]

Ripamonti CI,Maniezzo M,Campa T,Fagnoni E,Brunelli C,Saibene G,Bareggi C,Ascani L,Cislaghi E, Decreased occurrence of osteonecrosis of the jaw after implementation of dental preventive measures in solid tumour patients with bone metastases treated with bisphosphonates. The experience of the National Cancer Institute of Milan. Annals of oncology : official journal of the European Society for Medical Oncology. 2009 Jan     [PubMed PMID: 18647964]

[82]

Montefusco V,Gay F,Spina F,Miceli R,Maniezzo M,Teresa Ambrosini M,Farina L,Piva S,Palumbo A,Boccadoro M,Corradini P, Antibiotic prophylaxis before dental procedures may reduce the incidence of osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates. Leukemia     [PubMed PMID: 19021059]

[83]

Hellstein JW,Adler RA,Edwards B,Jacobsen PL,Kalmar JR,Koka S,Migliorati CA,Ristic H, Managing the care of patients receiving antiresorptive therapy for prevention and treatment of osteoporosis: executive summary of recommendations from the American Dental Association Council on Scientific Affairs. Journal of the American Dental Association (1939). 2011 Nov     [PubMed PMID: 22041409]