Bisphosphonate Related Jaw Osteonecrosis

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.

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.

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

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

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

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 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

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.

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]

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]

• 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.

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]