phossy jaw

Phossy jaw

Phossy jaw also known as phosphorus necrosis of the jaw, is a deadly occupational hazard for those who work with white phosphorus in an environment without proper safeguards. Phossy jaw is  disease of the poor. Workers in match factories developed unbearable abscesses in their mouths, leading to facial disfigurement and sometimes fatal brain damage. In addition, the gums developed an eerie greenish white ‘glow’ in the dark. Phossy jaw was most commonly seen in workers in the match industry in the 19th and early 20th century. Modern industrial hygiene practices have eliminated the conditions which lead to this affliction.

Chronic exposure to white phosphorus vapour, the active ingredient of most matches from the 1840s to the 1910s, caused a deposition of phosphorus in the jaw bones. It also caused serious brain damage. Workers afflicted would begin suffering painful toothaches and swelling of the gums. Over time, the jaw bone would begin to abscess, a process which was both extremely painful and disfiguring to the patient, and repellent to others, since drainage from the dying bone tissue was exceedingly foul-smelling. The jawbones would gradually rot away and would actually glow a greenish-white color in the dark. Surgical removal of the afflicted jaw bones might save the sufferers’ life at this point—otherwise, death from organ failure would invariably follow. This epidemic of osteonecrosis produced pain, swelling, debilitation, and a reported mortality of 20% and was linked to “yellow phosphorous,” the key ingredient in “strike-anywhere” matches. In match-making factories, workers called “mixers,” “dippers,” and “boxers” were exposed to heated fumes containing this compound 1.

Today, a related condition, osteonecrosis of the jaw, has been described as a side-effect of bisphosphonates, called “bis-phossy jaw” (bisphosphonate-induced osteonecrosis of the jaw) has surfaced with pathologic fractures and other features common to its predecessor, “phossy jaw” 2. Bisphosphonates is a class of phosphorus-based drugs that inhibit bone resorption, and are used widely for treating osteoporosis, bone disease in cancer and some other situations 3. Osteoporosis, bone metastasis (breast and prostate), multiple myeloma, and Paget primary disease of bone (osteitis deformans) are but a few of the human disorders profoundly improved when bisphosphonates are used, either as a preventive or as treatment 4.

The majority of patients suffering from osteonecrosis of the jaw (73%) had been treated with some form of dentoalveolar surgery prior to the onset of osteonecrosis of the jaw 5. This corresponds well to what Filleul et al 6 reported in a review of about 2400 osteonecrosis of the jaw cases, where disease onset was preceded by tooth extraction in 67%. Only 20% had no record of dentoalveolor surgery/trauma or dentures, which can be compared to the 26% that Filleul et al 6 reported as spontaneous cases.

The mechanism of action of bisphosphonates remains uncertain 2. Bench research to date, however, suggests bisphosphonates throttle the osteoclast (warranting dysfunction without triggering cell death) and (in ways not yet certain) disallow inherent angiogenic repair 2. Migliorati et al 7 and Lam et al 8, it follows, speculate side effects of bisphosphonates that lead to osteonecrosis are the result of a combination of (1) inhibition of bone remodeling and (2) decreased endosteal blood flow.

The clinical effects of bisphosphonates, like the experience in factory workers exposed to white phosphorous, persist for prolonged periods of time (decades), even in cases in which treatment has been discontinued 9.

The biomechanism by which mandibular bone and its microvasculature is singled out as an end point of toxicity requires much further study, although the suspected sequence and pathogenesis of bis-phossy jaw can be depicted, as it is in Figure 1. Future clinical and bench studies might include angiography of the endosteal vasculature during and after bisphosphonate administration; serial biennial cone-beam CT monitoring of the mandible in patients consuming bisphosphonate; and the viability of bone grafts despite patients having discontinued bisphosphonates.

Clinical research would do well to explain the proclivity of the jaws and the adjacent soft tissue to osteonecrosis compared with skull and long bones 10.

Savvy dental practitioners continue to be aware of unrelenting pain as a marker of compromised bone and cognizant of tardy healing of gingiva in patients consuming bisphosphonates. They would astutely offer preventive care early and weigh extraction and surgical intervention according to perceived risk.

Phossy jaw key points

  • Bisphosphonate associated osteonecrosis 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.
  • Bisphosphonate 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 bisphosphonate-induced osteonecrosis of the jaw is high among oncology patients taking more potent nitrogen-containing IV bisphosphonates like zoledronic acid and pamidronate, and the occurrence increases with dosage and duration of therapy.
  • Bisphosphonate induced osteonecrosis of jaw occurs more frequently in the mandible than maxilla due to greater bone turnover rate.
  • Factors that increase the risk of bisphosphonate-induced osteonecrosis 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 bisphosphonate-induced osteonecrosis of the jaw can range from no alternations to varying radiolucencies and radio-opacities.
  • Early identification and diagnosis of bisphosphonate-induced osteonecrosis of the jaw can be very challenging. Prevention is the key to reduce the risk of osteonecrosis in patients on bisphosphonates.
  • Treatment is mostly supportive and is aimed at pain and infection control. Surgical intervention is indicated for permanent bone defects and sequestration.

Figure 1. Pathophysiology of bisphosphonate-induced toxicity

Pathophysiology of bisphosphonate-induced toxicity
[Source 2 ]

Phossy jaw cause

Bisphosphonates disrupts the bone remodeling cycle by reducing osteoclast survival and function 11. Bisphosphonates 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 12.

Bone Remodeling Cycle

  • Osteoclasts have a lifespan of 150 days.
  • Osteoclasts resorb bone mineral matrix and release bone morphogenic protein (BMP) and insulin-like growth factors.
  • 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 13. Also, high potency bisphosphonates can lead to necrosis by the toxicity of soft tissue along with cells of bone which is further complicated by infection 14. Due to altered wound healing, delayed epithelial closure of a mucosal opening in the mouth leads to chronic infection and the necrosis of bone 15. So far, there is no evidence from prospective controlled trials to show the relationship between bisphosphonates and osteonecrosis of the jaw 13.

The prospective data on the incidence of bisphosphonate associated osteonecrosis 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 bisphosphonate associated osteonecrosis of jaw depends upon bisphosphonate kind, duration and dosage of bisphosphonate involved, baseline condition for which bisphosphonate therapy is given and the location involved.

Intravenous (IV) versus oral bisphosphonates

Osteonecrosis of jaw is mostly reported with the use of more potent nitrogen-containing bisphosphonates 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 16.

Oral bisphosphonate induced osteonecrosis is rare, less aggressive and respond better to treatment compared to iv bisphosphonate induced osteonecrosis. The difference is due to low lipid solubility of oral bisphosphonates that limits small intestinal absorption and much more slower accumulation in bone 17.

Dose and duration

The incidence of osteonecrosis is related to dose and duration of bisphosphonates and increases with a higher dose of potent bisphosphonates being administered for a longer duration 18. As per reported data, cautious use of zoledronic acid and pamidronate is required after 2 years. Risk of bone necrosis with bisphosphonate 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 bisphosphonates, 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 bisphosphonate-induced osteonecrosis 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 bisphosphonate-induced osteonecrosis 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 bisphosphonates. 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 bisphosphonates for the incidence of osteonecrosis 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 osteonecrosis 19. Also, Abu-Id et al. did a retrospective study on the development of bisphosphonate-induced osteonecrosis 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 20.

Location

Bisphosphonates induced osteonecrosis 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 21. Most common sites are nonhealing dentoalveolar sites, traumatized palatal and mandibular tori and exposed portions of the mylohyoid ridge.

Incidence of bisphosphonate-induced osteonecrosis of the jaw increases with:

  1. More potent nitrogen-containing IV bisphosphonates
  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 for phossy jaw

Several factors increase the risk of developing osteonecrosis with bisphosphonate 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 osteonecrosis 22.
  • Comorbidities like cancer, patients treated with chemotherapy, low hemoglobin levels, diabetes mellitus, renal dialysis, hypertension, hyperlipidemia, and hypercholesterolemia 23.
  • Concomitant medications like corticosteroids use, H2 blocking drugs causing increased bisphosphonate absorption, antiangiogenic agents particularly sunitinib and bevacizumab, erythropoietin, and cyclophosphamide therapy 24.
  • Infection: It is still unclear if osteonecrosis 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 25. Bisphosphonates inhibit proliferation and viability of oral keratinocytes that damages the integrity of oral mucosa and increase the risk of infection 26. Also, bisphosphonates 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 bisphosphonates associated osteonecrosis of jaw in multiple myeloma 27. CYP2C8 is hence involved in the biological pathway of this adverse drug reaction. As bisphosphonates 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.

Bisphosphonate-induced osteonecrosis of jaw risk factors

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

Phossy jaw prevention

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 bisphosphonate-induced osteonecrosis of the jaw.

Recommendations before Initiating bisphosphonate 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 bisphosphonate therapy including osteonecrosis of jaw, its signs and symptoms, and the risk factors of developing osteonecrosis 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 bisphosphonate 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 bisphosphonate for osteoporosis are currently not contraindicated for implant placement, but appropriate informed consent and documentation is recommended.

Recommendations for patients receiving bisphosphonate therapy

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

  1. Maintaining good oral hygiene and regular dental visits and educating patients regarding the risk of developing bisphosphonate associated osteonecrosis of jaw.
  2. Oral surgical procedures like extractions, bone contouring, grafting, periodontal, and apical surgeries should be avoided 28.
  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 bisphosphonate induced osteonecrosis 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 osteonecrosis of the jaw 29.
  9. It is necessary to stratify the risk for patients on bisphosphonate 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 bisphosphonate therapy and put the patient on drug holiday until soft tissue closure with well-epithelialized mucosa is achieved. Although since bisphosphonates have long halftime, there is little supporting evidence that withholding bisphosphonate therapy will affect the treatment outcomes 30.

Phossy jaw symptoms

The American Society of Bone and Mineral Research defined bisphosphonate-related osteonecrosis of the jaw as current or previous treatment with bisphosphonates 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 31. 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.

The majority of all osteonecrosis of the jaw lesions (60%) occurred in the mandible, which is in line with other studies. Filleul et al 6 reported that 65% of all osteonecrosis of the jaw lesions were localized to the mandible, whereas Hoff et al 32 and Otto et al 33 reported that 70% and 71% of all lesions, respectively, occur in the mandible. Previous studies reported the highest occurrence of osteonecrosis of the jaw among patients who received intravenous bisphosphonates due to a malignant condition 34.

Phossy jaw signs and symptoms:

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

The necrotic bone may remain asymptomatic for a prolonged period or may become symptomatic mostly due to localized inflammation of soft tissue 35. 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 36. 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 37. An important early symptom of bisphosphonate-induced osteonecrosis 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 38.

Radiographically, bisphosphonate induced osteonecrosis 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 osteonecrosis 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 39.

Phossy jaw diagnosis

Early identification of bisphosphonate associated osteonecrosis 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 bisphosphonate associated osteonecrosis 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 bisphosphonate associated osteonecrosis patients does not demonstrate any unique features of the disease 40. 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 41.

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 42. Its levels are related to the number of osteonecrosis of jaw lesions, stage of disease, and is an index of bone turnover 43. A lower value represents a high-risk patient with suppressed bone turnover and reduced healing capacity. C-terminal telopeptide (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 bisphosphonate associated osteonecrosis 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 osteonecrosis of the jaw from other conditions 44.

  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 45.
  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 45. The CT scan can evaluate presence of sequestrum and periosteal bone reaction and the integrity of the vital adjacent structures 46. Potential fistula tract, cortical erosion, and incomplete extraction socket healing can also be seen 47. The early stage of osteonecrosis of the jaw may not be detected, but evaluation of cortical and trabecular bone differences at the symptomatic site can aid in disease diagnosis. Cone beam CT (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 48. 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 49.
  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. 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 50. 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 osteonecrosis. Its sensitivity depends on the stage of osteonecrotic lesion and change in vascularity 45. 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): 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 51 and resolution 52. 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 cone beam CT (CBCT) with scintigraphy for diagnosing osteomyelitis 53 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 bisphosphonate-induced osteonecrosis.

Phossy jaw treatment

Prevention is better than treatment, and the establishment of meticulous oral hygiene and surgical procedures prior to commencing bisphosphonate treatment is important for preventing bisphosphonate-induced osteonecrosis of the jaw.

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

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 bisphosphonate-induced osteonecrosis 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 39.

  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 54. 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 55. Teriparatide is not recommended for a patient at low risk of osteonecrosis of jaw or fracture but adding it to the treatment regimen of the osteoporotic patient with established osteonecrosis may benefit them 56. 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. C-terminal telopeptide (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 bisphosphonate induced osteonecrosis 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 57.
  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 58, bone marrow stem cell intralesional transplantation 59, local application of platelet-derived growth factor 60, low-level laser therapy 61, 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 20. Combination of various approaches like marginal resection along with the use of platelet-derived growth factor had been advocated by many studies 62.

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