Widespread bisphosphonate (BP) use to treat various medical conditions led to increased recognition of their possible association with osteonecrosis (ON) of the jaw. 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. 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. 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. 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.
Bone Remodeling Cycle
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. Due to altered wound healing, delayed epithelial closure of a mucosal opening in the mouth leads to chronic infection and the necrosis of bone. 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.
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.
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. 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. 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.
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. 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:
Several factors increase the risk of developing ON with BP use.
BP-Induced ON of Jaw Risk Factors
The necrotic bone may remain asymptomatic for a prolonged period or may become symptomatic mostly due to localized inflammation of soft tissue. 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. 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. 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.
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.
Signs and Symptoms
Early identification of BP associated ON can be very challenging but is important for disease prevention and patient care.
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.
Resected necrotic bone from BP associated ON patients does not demonstrate any unique features of the disease/ 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.
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. Its levels are related to the number of ON of jaw lesions, stage of disease, and is an index of bone turnover. 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.
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.
Combinational approaches as use of CBCT with scintigraphy for diagnosing osteomyelitis 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.
Lack of symptomatic or radiographic improvement with various treatment modalities indicate permanent bone defect and need surgical intervention.
The various treatment approaches included are use of hyperbaric oxygen, bone marrow stem cell intralesional transplantation, local application of platelet-derived growth factor, low-level laser therapy, 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. Combination of various approaches like marginal resection along with the use of platelet-derived growth factor had been advocated by many studies.
Treatment Approach Review
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 and is adopted by AAOMS. 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.
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.
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.
Prompt recognition of ON by the interdisciplinary 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]
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