Why Endodontic Therapy is the Treatment of Choice in Patients on Anti-Resorptive Drug Therapy

The most common odontogenic infection is that of the periapical tissues most frequently caused by dental caries, a deep restoration, or failed root canal treatment.¹ Apical periodontitis (AP) has been found to have a prevalence of 50% in patients under the age of 50, and the prevalence and risk of AP has been found to be directly correlated with increasing age.² While the risk of apical periodontitis increases with age, so too does the prevalence of bone pathologies, such as bone metastases and osteoporosis.^3,4 Thus, it is not uncommon to see patients presenting with apical periodontitis, who are also currently being medicated with antiresorptive medications. It has been reported in the literature that patients medicated with antiresorptive medications assume a 50 to 100 times greater risk of development of osteonecrosis of the jaw, and this risk is exacerbated by surgical procedures, such as extractions and the placement of implants.⁵ This phenomenon should be judiciously evaluated by clinicians when presenting treatment options to patients to avoid the development of the intractable condition known as medication-related osteonecrosis of the jaw (MRONJ). This debilitating condition is associated with largely detrimental effects upon patients’ quality of life, and as such, all measures should be taken to avoid its development. While extraction of an implicated tooth followed by implant placement may be a viable option for a medically stable patient, endodontic therapy should be the treatment of choice in patients with periapical pathologies who are concurrently taking antiresorptive medications.

Prevalence of Bone Pathologies

According to the World Health Organization, the global population is increasingly aging.³ It is estimated that by the year 2050, 1 out of every 6 people will be over the age of 65.³ While the physiological process of aging has an impact upon several organ systems, it has been found to have an especially deleterious effect upon the dynamic organ of bone. Bone homeostasis in health is dynamically maintained through an intricate balance of osteoclastic resorption and osteoblastic deposition of bone.

Associated with aging, however, are several pathological processes, such as cellular senescence and DNA damage that are induced by oxidative stress—these result in a dysregulation of homeostatic mechanisms resulting in a shift in the balance that favors bone resorption over bone formation.^3,4

The impact upon bone mineral density with age occurs due to several effects within the cellular components of bone— the following are impacts of aging on bone cells:³

• Increased apoptosis of osteoblasts leading to a decrease in deposition of calcium and phosphate ions.
• Increased proliferation and activity of osteoclasts leading to increased resorptive mechanisms in bone and a decrease in bone mineral density (BMD)
• Decrease in the number of osteocytes, the main source of receptor activator of nuclear factor-kappa B (RANKL) which regulates the survival and function of osteoclasts.

Considering the increasingly aging population over the next 30 years, and the effects that aging exerts upon bone homeostasis, the prevalence of bone-related diseases, such as osteoporosis and osteopenia, are similarly expected to be associated with a globally higher prevalence.

As conditions impacting bone metabolism are associated with increased morbidity, decreased quality of life, and increased risk of osteoporotic fractures, it is not uncommon for patients to be medicated with antiresorptive drugs(ARD).^3,6

Similarly, older age is a risk factor for bone metastases, alongside other negative prognostic factors, such as prostate and breast cancers, male sex, and previous chemotherapy.⁷ With an increasingly aging population, the prevalence of bone metastases, commonly treated with antiresorptive medications, were found to increase from 2010 to 2019 by more than 40%, again emphasizing an increasing proportion of the population being medicated with antiresorptive drugs.

It is axiomatic therefore that clinicians are well-informed regarding antiresorptive medications, especially in light of the increased risk of osteonecrosis of the jaw that has been attributed in the literature to the use of these medications.^8–12

Antiresorptive and Antiangiogenic Medications

Antiresorptive and antiangiogenic medications are the mainstay in treatment of bone-related pathologies, as their mechanism of action revolves around reducing bone turnover and thus increasing BMD. They are used in the treatment of several conditions, such as cancer-related conditions, including metastatic bone tumors associated with prostate, breast, and lung cancers, hypercalcemia of malignancy, multiple myeloma, as well as bone diseases such as osteoporosis, osteopenia, and Paget’s disease.^5,13

The most commonly used medications for bone pathologies are bisphosphonates, human monoclonal antibody Denosumab, and antiangiogenics—cases of osteonecrosis of the jaw have been found in patients taking drugs from each of these three drug classes.¹⁴

Bisphosphonates

Bisphosphonates have been at the forefront of pharmacological therapy for bone pathologies for over 50 years.¹⁵ These drugs prove highly effective due to the fact that they possess a high affinity for bone.¹⁵ This strong affinity, however, is also problematic in that the impact of bisphosphonates on bone remains active for a long duration, even after discontinuation of drug therapy—thus, a drug holiday prior to surgical therapy would not prove fully effective in diminishing the risk of MRONJ.¹⁵

Nitrogenous bisphosphonates, such as alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid exert their bone-preserving effects through triggering apoptosis of osteoclasts through interruption of the mevalonate pathway.¹⁵

Non-nitrogenous bisphosphonates, including etidronate and clodronate, accumulate within osteoclast cytosol and again contribute to apoptosis of osteoclasts.¹⁵ Bisphosphonates have also been found to inhibit the development of osteoclast precursor cells, impairing proper bone healing and remodelling.¹⁶

Denosumab

Human monoclonal antibody Denosumab has also become increasingly utilized in the therapy of osteoporosis and other bone pathologies. It possesses a high affinity for RANKL, a transmembrane protein found in osteoclasts and osteoblasts integral in bone metabolism processes.¹⁵

In order for osteoclasts to exert their bone-resorbing abilities, RANKL must first bind to its receptor, RANK, and trigger a series of processes that allow osteoclasts to mature and become capable of resorbing bone tissue.^15,16 Denosumab exerts its bone-preserving function through inhibition of the RANK/RANKL interaction, which ultimately inhibits osteoclastic function – this prevents effective bone remodelling.^9,15

Antiangiogenics

Another common class of drugs frequently associated with the development of MRONJ are antiangiogenics.^14,17,18 Antiangiogenics, including bevacizumab, sunitinib, imatinib, everlimus, ipilimumab, and azacitidine are commonly used in the treatment of malignancies. Their association with MRONJ, especially after surgical procedures, is due to the fact that proper healing requires unimpaired revascularization.¹⁷

Additionally, it is not uncommon for patients with bone pathologies to be treated simultaneously or sequentially with anti-resorptive drugs.^6,12 Several patients, for example are treated with sequential bisphosphonate-denosumab therapy, and the risk of MRONJ was found to be further increased in these patients.^6,12,17

Medication Related Osteonecrosis of the Jaw

Medication-related osteonecrosis of the jaw (MRONJ) comprises of bisphosphonate-related osteonecrosis of the jaw (BRONJ), denosumab-related osteonecrosis of the jaw, and osteonecrosis of the jaw induced by anti-angiogenic medications.¹⁸

It is a condition that entails the following characteristics:

• The patient is currently being treated, or was in the past, with anti-resorptive or antiangiogenic medications¹¹
• The presence of exposed non-healing bone in the maxillofacial region^9,15
• The exposed bone can be probed through an intraoral or extraoral fistula¹¹
• The patient has an absence of history of head or neck radiation treatment¹¹
• The condition lasts for at least eight weeks.^9,15

Patients impacted with this condition are not only burdened with pain, but also with an unpleasant smell and a difficulty eating.¹⁵ The complex pathogenesis of this disease with a relatively recent discovery is still not fully understood and as such, there still remains to be a standardized treatment for patients inflicted with MRONJ—it is therefore integral that absolutely all preventive efforts are exercised by clinicans.¹⁵

Risk Factors for MRONJ: Osteoporosis VS. Cancer

The incidence of MRONJ varies from 0.028% to 18.6% depending upon several different factors, such as the dosing regimen of the anti-resorptive drug.¹⁷

It is important to make the distinction in the risk of MRONJ development in osteoporotic patients versus cancer patients. While the risk for MRONJ exists for both conditions, it has been found to be significantly higher in oncology patients.¹⁷

It was established by Yanni et al. that the majority of cases of MRONJ have been found in oncology patients who are treated with high doses of intravenous bisphosphonates or subcutaneous denosumab in comparison to patients receiving lower doses of oral bisphosphonates; thus, the dosage, the means of administration, as well as the duration of anti-resorptive drug therapy are influential in the risk of development of MRONJ.¹⁷

There are many other factors that can predispose patients to the development of MRONJ, such as the presence of periodontal disease, smoking, diabetes, and chemotherapy.¹⁷

Additionally, in light of periapical infections and the commonly presented treatment options, oral surgical procedures such as extractions or implants are both risk factors that lead to an increased likelihood of the development of MRONJ.¹⁷

Extractions

In patients on antiresorptive drug therapy, oral surgical procedures pose a risk to the development of MRONJ due to several different factors. When an extraction is performed due to a periapical infection, bony remodeling of the infected alveolar bone is hindered due to osteoclast apoptosis and inhibition of osteoblasts exerted by the ARD.¹⁵

This lack of bone turnover not only contributes to the development of microfractures within the alveolus15, but also causes the bone to necrose, presenting with empty lacunae upon histological examination.¹⁶

The microcracks within bone have been described as the initial stage of MRONJ and are a largely contributing factor in the progression of the disease.¹⁶

Bacteria from the oral cavity may also invade the necrotic bone, and contribute to the inflammation and infection associated with the condition.¹⁵ The antiangiogenic effect of these medications hinders bone from remodeling and triggers apoptosis of endothelial cells, preventing their survival and differentiation.¹⁵

Soft tissue is also affected as bisphosphonates are detrimental to keratinocytes and fibroblasts, impairing their viability.15 It has been reported that extractions in patients receiving IV bisphosphonates are associated with a 15% risk of developing MRONJ.¹⁸

Considering the burden that MRONJ imposes on affected patients, as well as the lack of a standardized treatment for the condition, extractions in patients on antiresorptive therapy should be avoided.

This clinical recommendation is especially of importance in oncology patients due to the larger risk of MRONJ that they possess due to drug therapy.

Implant Therapy

In the evaluation of the association between implants and MRONJ development,^11,19,20 one can make the distinction between implant-presence vs. implant-surgery triggered osteonecrosis.¹¹ This distinction was discovered by Giovannacci et al.²⁰ with the important takeaway that not only does the surgical procedure of implant placement into a patient subjected to bisphosphonate therapy pose a risk for MRONJ, but the mere presence of an implant in bone is a risk factor for MRONJ development.

A literature review by Escobedo et al.¹¹ discovered that the cases of MRONJ were significantly higher in the implant-presence compared to the implant-surgery patients, emphasizing that osteonecrosis is especially likely to occur when implants are under load.¹¹

It has also been found that implants are more likely to fail in patients who have been on oral bisphosphonates for a long duration of time (over 2 years).²¹

Finally, in a recent study by Pichardo et al. performed to evaluate if implants pose a risk for MRONJ development, 180 patients with MRONJ were evaluated, of which 22 patients had dental implants.¹⁹

Despite a low overall incidence of the rare condition MRONJ, as a condition that is very difficult to treat, any surgical procedures that subject patients to a greater risk of the condition should be avoided.

Treatment Options for Patients with Periapical Pathologies

Half of the adult population worldwide has at least one tooth with a diagnosis of apical periodontitis.²² In order to prevent the potential spread of periapical infections to other tissues, organs and potential spaces in the oral and maxillofacial region,²³ patients are presented with the following treatment options: to retain their tooth via root canal therapy, or to extract the implicated tooth with or without a replacement.²⁴

While there has been a recent shift towards extraction and replacement with an implant-supported crown,²⁴ in light of the evidence surrounding MRONJ, it seems prudent that less-invasive alternatives to extraction, such as endodontic therapy, should be the recommended treatment for patients on anti-resorptive drugs.²⁵

Non-Surgical Endodontic Therapy in Patients on Anti-Resorptive Drug Therapy

The effectiveness of root canal therapy in patients on ARD therapy with compromised teeth revolves around the ability to remove infected tissue from the root canal, and prevent dissemination of bacteria through a non-invasive and non-surgical manner.²⁵

A recent study performed by Zamparini et al.²⁵ evaluated the effectiveness of root canal therapy in 65 patients with 109 endodontically treated teeth in patients taking bisphosphonates, and found that the tooth survival rate was 85%.

Similarly, a 74% 12-month healing rate was reported by Hsaio et al.²⁶ Aside from the satisfactory peri-radicular healing rates, the largest clinical benefit of endodontic therapy is the absence of risk for development of MRONJ.¹⁸ The American Association of Endodontics has not identified non-surgical root canal treatment (NSRCT) as a risk factor in MRONJ development, and thus, it is the favored treatment of choice.²⁷

While root canal therapy is a viable option for patients on ARD therapy, on the contrary, a literature review by Schwech et al. reported that the MRONJ incidence after extractions of compromised teeth has been reported to be between 11% and 50% at the patient level. ²⁸ This is in comparison to an incidence of 3.4-9.3% in patients also taking bisphosphonates, but who did not undergo an extraction.²⁸

Apical Surgery in Patients on Anti-Resorptive Drug Therapy

While initial NSRCT has not been identified as a risk factor for MRONJ in patients taking anti-resorptive drugs, the same was found by Andersen et al. when evaluating the risk of MRONJ associated with retrograde surgical endodontic therapy in cases of primary treatment failure.²⁹

A 2021 study involving seventeen teeth in fourteen patients who had received apical surgery all but one presented as asymptomatic with evidence of periradicular healing.²⁹

Additionally, none of the patients developed MRONJ. There should, however, be exercise of caution when performing apicoectomies on oncology patients receiving high doses of IV bisphosphonates due to the higher risk of MRONJ that they possess, and non-surgical re-treatment in cases of primary endodontic failure would be advised.

There is a lack of research regarding this topic, however, and additional research is required to make clinical recommendations based upon indisputable evidence.

Conclusion

In an increasingly aging population within which an increased prevalence of patients on anti-resorptive drug therapy is observed, caution must be exercised by clinicians when it comes to the presented treatment options in the therapy of periapical infections, especially in oncology populations.

While the commonly recommended treatment option presented to patients is an extraction followed by implant placement, it is indicated in the literature that not only does performance of these surgical procedures put patients at an increased risk for MRONJ, but also, the mere presence of an implant under load in a patient on anti-resorptive drug therapy similarly increases the risk for MRONJ development.

As a condition renowned for its difficulty to treat, it is in clinicians’ best interest to recommend non-invasive endodontic therapy for patients with periapical infections on antiresorptive drugs – especially for oncology patients receiving IV bisphosphonates. Not only can patients and clinicians expect satisfactory outcomes with periradicular healing after root canal therapy, but also, the risk for MRONJ development will be avoided. 

Oral Health welcomes this original article.

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About the Authors

David Muller is a fourth-year dental student at the University of Toronto. He is currently balancing providing care to his own patients at the Faculty, while also being actively involved in patient care at UofT’s Graduate Endodontic Clinic. He aims to join UofT’s Graduate Endodontic specialty program after obtaining his DDS.

Dr. Gary Glassman graduated from the University of Toronto, Faculty of Dentistry in 1984 and from the Endodon-tology Program at Temple University in 1987. The author of numerous awards and publications, Dr. Glassman lectures globally on endodontics, is on staff at the University of Toronto, Faculty of Dentistry in the graduate department of endodontics.