Oncology Agents and Medication-Related Osteonecrosis of the Jaw

Bone metastases are a frequent cancer complication, occurring in up to 70% of patients with advanced breast or prostate cancer and 15% to 30% of patients with other common cancers (e.g., lung, thyroid, or kidney cancer).¹ Although metastases can occur in any bone in the body, they are most commonly seen in the spine, pelvis, and limbs.² Symptoms of bone metastases include pain, fracture, spinal cord compression, and hypercalcemia (high levels of blood calcium from increased bone resorption).² In addition, adverse hormonal effects of some anticancer medications (e.g., androgen suppression in prostate cancer) may also have a detrimental effect on bone integrity.³

Bone remodeling relies on a balance of osteoclastic (cells that resorb bone) and osteoblastic (cells that build bone) activity.^{1, 4} Disruptions in bone remodeling in metastasis may be caused by systemic or locally acting factors such as parathyroid hormone, prostaglandins, or interleukins,¹ and usually result in a mix of disordered osteoblastic and osteoclastic activity.^{1, 2}

Osteonecrosis is broadly defined as necrosis of bone due to obstruction of blood supply.⁵ Osteonecrosis of the jaw (ONJ) is an oral lesion involving exposed mandibular or maxillary bone, which usually manifests with pain and purulent discharge, although it may be asymptomatic;⁵ ONJ typically occurs following tooth extractions or other dentoalveolar surgeries, but in some cases, it can occur spontaneously.^{6, 7} ONJ associated with use of antiresorptive or antiangiogenic drugs is referred to as “medication-related ONJ” or MRONJ.⁸ The definition of MRONJ from the American Association of Oral and Maxillofacial Surgeons (AAOMS) includes all of the following elements: (1) current or previous treatment with antiresorptive therapy alone or in combination with immune modulators or antiangiogenic agents; (2) exposed bone or bone that can be probed through an intraoral or extraoral fistula(e) in the maxillofacial region that has persisted for more than 8 weeks; and (3) no history of radiation therapy to the jaws or metastatic disease to the jaws.^{8, 9}

The mechanism(s) by which these drugs cause MRONJ has not been clearly elucidated; however, there are several hypotheses.^{8, 10} It has been suggested that suppression of bone turnover and remodeling by the antiresorptive agents impairs the body’s ability to repair microfractures in the maxilla and mandible.^8-11 Because osteonecrosis is classically considered an interruption in vascular supply, inhibition of angiogenesis by the antiangiogenic agents or the bisphosphonate zoledronic acid is considered a likely contributing risk factor.^{8, 10} Systemic and local oral risk factors have also been implicated in MRONJ pathogenesis; several studies have implicated coincident dental disease, inflammation, or bacterial infection.^{8, 10}

The reported incidence of MRONJ varies, but it is generally considered to be between 1% and 10% of patients taking IV bisphosphonates for the management of bone metastatic disease and between 0.001% and 0.01% in patients taking oral bisphosphonates for the management of osteoporosis.⁶

Higher-dose parenteral bisphosphonates and denosumab, as well as teriparatide or other antiresorptive or anabolic agents, are also used off-label for the management of osteogenesis imperfecta, a rare inherited metabolic bone disorder resulting in bone fragility (also known as “brittle bone disease”).^{12, 13} Although treatment with bisphosphonates has shown increases in bone mass, vertebral reshaping, and decreases in long-bone fracture, fractures and scoliosis can still occur.¹³ No cases of osteonecrosis of the jaw have been reported in persons receiving antiresorptive agents for osteogenesis imperfecta.^13-15 A 2014 systematic review¹⁶ reviewing 4 retrospective cohort studies and one case series concluded that, “There is no evidence to support hypothesis of causal relationship between bisphosphonates and osteonecrosis of the jaw in children and adolescents with osteogenesis imperfecta.”

The differential diagnosis of MRONJ includes other conditions such as alveolar osteitis, sinusitis, gingivitis/periodontitis, or periapical pathosis.^{8, 9} According to a 2015 systematic review and international consensus paper,⁹ patient history and clinical examination remain the most sensitive diagnostic tools for MRONJ. While it is not possible to identify who will develop MRONJ and who will not, research suggests the following as risk factors:^{6, 8, 11, 17-20}

• age older than 65 years;
• periodontitis;
• dentoalveolar surgery, including tooth extraction;
• high dose and/or prolonged use of antiresorptive agents (more than 2 years); 
• receiving antiresorptive therapy in conjunction with antiangiogenic drugs for cancer;
• smoking;
• malignant disease (multiple myeloma, and breast, prostate, and lung cancer);
• chemotherapy, corticosteroid therapy, or treatment with antiangiogenic agents;
• denture wearing;
• diabetes.

In 2022, AAOMS published an updated position paper (PDF) on MRONJ.8 The purpose of the 2022 position paper was to provide updates regarding:

1. Risk estimates for developing MRONJ.
2. Comparisons of the risks and benefits of medications related to osteonecrosis of the jaw in order to facilitate medical decision-making for the treating physician, dentist, dental specialist, and patient with the establishment of algorithms.
3. Guidance to clinicians regarding:

a. the differential diagnosis of MRONJ in patients with a history of exposure to antiresorptive medications.
b. MRONJ prevention measures (Table) and management strategies for patients with MRONJ based on the disease stage.

Table. MRONJ Prevention Strategies in Malignant Disease from the 2022 AAOMR Position Paper⁸

Pretherapy

• Educate patients about the higher risk of MRONJ and the importance of regimented dental care.
• Optimization of the dental health prior to the initiation of [antiresorptive therapies] if systemic conditions permit (extraction of nonrestorable teeth or teeth with a poor prognosis).

During antiresorptive therapy/targeted therapies

• Educate patients about the higher MRONJ risk in the setting of malignant disease.
• Educate the patient about the importance of regimented dental care and prevention.
• Avoid dentoalveolar surgery if possible.
• Consider root retention techniques to avoid extractions.
• Dental implants are contraindicated.
• Drug holidays are controversial.

A systematic review and international consensus paper from the International Task Force on Osteonecrosis of the Jaw published in 2015⁹ also suggests that key prevention strategies for MRONJ include elimination or stabilization of oral disease prior to initiation of antiresorptive agents, as well as maintenance of good oral hygiene. For patients whose cancer management includes  treatment with denosumab or IV bisphosphonates, the Task Force recommends that “a thorough dental examination with dental radiographs should be ideally completed prior to the initiation of antiresorptive therapy in order to identify dental disease before drug therapy is initiated” and that “Any necessary invasive dental procedure including dental extractions or implants should ideally be completed prior to initiation of [bisphosphonate] or [denosumab] therapy.”

The Task Force⁹ also states that, “Non-urgent procedures should be assessed for optimal timing because it may be appropriate to complete the non-urgent procedure prior to osteoclast inhibition, delay it until it is necessary, or perhaps plan for it during a drug holiday; however, there are no compelling data to guide these decisions.”

A 2022 guideline update from the American Society of Clinical Oncology (ASCO)-Ontario Health (Cancer Care Ontario [CCO]) specifically addressing the role of bone-modifying agents in metastatic breast cancer included consensus-based recommendations regarding dental therapy in these patients.²¹ The dental recommendations are as follows:

• A dental assessment is recommended, where feasible, before commencement of bisphosphonates, and any pending dental or oral health problems should be dealt with before starting treatment, if possible.
• Patients should be informed of the risk of developing ONJ, especially with tooth extractions and other invasive dental procedures.
• Patients should inform their dental practitioner of their treatment.
• Patients with suspected ONJ should be referred to a dental practitioner with expertise in treating this condition.

Antiresorptive agents suppress bone resorption by binding to active sites of bone remodeling and inhibiting osteoclasts.⁶ There are two classes of antiresorptive drugs approved by the U.S. Food and Drug Administration (FDA) for use in cancer: bisphosphonates and RANKL (receptor activator for nuclear factor-kappa B ligand) inhibitors.⁶ Two parenteral bisphosphonates, pamidronate (Aredia®)²² and zoledronic acid (Zometa®)²³ are FDA approved for various cancer indications (e.g., hypercalcemia of malignancy).

Denosumab is a monoclonal antibody against RANKL, a ligand required for osteoclastic precursors to differentiate into mature osteoclasts.⁶ For cancer-related indications (i.e., solid cancer metastatic to bone, giant cell tumor of bone, and hypercalcemia of malignancy), denosumab is marketed under the trade name Xgeva® and is administered at doses of 120 mg subcutaneously every 4 weeks.²⁴ Both the drug dose and the frequency of administration are more intense than denosumab marketed for osteoporosis indications (Prolia®; 60 mg subcutaneously every 6 months).²⁴ 

Angiogenesis, or the development of new blood vessels, is a key factor in the growth and metastasis of certain solid tumors.^{8, 25} These tumors secrete proangiogenic factors, such as vascular endothelial growth factor (VEGF) to stimulate new vessel development via downstream signaling pathways.^{25, 26} Various inhibitors of angiogenesis (antiangiogenic agents) have been developed and introduced into oncology practice.^{25, 27-37} These include monoclonal antibodies against VEGF (e.g., bevacizumab), tyrosine kinase inhibitors (e.g., sorafenib, sunitinib), mammalian target of rapamycin (mTOR) pathway inhibitors (e.g., everolimus), and immunomodulatory agents (e.g., thalidomide, lenalidomide).³¹

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ADA Oral Health Topics: Osteoporosis Medications and Medication-Related Osteonecrosis of the Jaw

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