Oncology Agents and Medication-Related Osteonecrosis of the Jaw

Key points

  • Cancer metastases to the bone and hypercalcemia of malignancy are typically managed with antiresorptive agents (i.e., IV bisphosphonates, denosumab); a rare but serious adverse effect of these therapies is medication-related osteonecrosis of the jaw (MRONJ).
  • Antiangiogenic agents used for oncology indications include monoclonal antibodies, tyrosine kinase inhibitors, mTOR pathway inhibitors, and immunomodulatory agents; these agents have also been rarely associated with MRONJ.
  • In 2014, the American Association of Oral and Maxillofacial Surgeons (AAOMS) updated their definition of MRONJ to include all of the following criteria: (1) current or previous treatment with antiresorptive 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 obvious metastatic disease to the jaws.
  • Patients at increased risk of MRONJ include those:
    • receiving antiresorptive agents at dosages and treatment schedules associated with cancer-related indications;
    • receiving antiresorptive drugs for more than 2 years;
    • receiving antiresorptive therapy in conjunction with antiangiogenic drugs for cancer;
    • with periodontitis or dentures.
  • Although MRONJ is associated with bone-invasive dental procedures such as tooth extraction, it can also occur without dental intervention.
  • Potential strategies for managing dental patients undergoing antiresorptive and/or antiangiogenic therapies for oncology indications include a thorough oral examination with radiographs and optimization of oral health and, as clinically possible, completion of necessary invasive dental procedures, including dental extractions or implants, prior to initiation of antiresorptive and/or antiangiogenic therapy.
Bone Metastasis and Hypercalcemia of Malignancy

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

Medication-Related Osteonecrosis of the Jaw

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 In 2014, the American Association of Oral and Maxillofacial Surgeons (AAOMS) updated their definition of MRONJ to include all of the following criteria: (1) current or previous treatment with antiresorptive 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 obvious 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.
Management Approaches for Dental Patients Receiving Antiresorptive and/or Antiangiogenic Medications for Cancer Indications

In 2014, AAOMS published a position paper on MRONJ;8  this has not been updated as of July 2021. The position paper was based on a literature review and expert opinion/observations of a multidisciplinary committee including surgeons, pathologists, and oncologists. Although the authors cautioned that the position paper was informational in nature and not intended to set any standards of care, they did provide suggestions for potential prevention strategies for patients based on limited evidence, including implementation of dental screening and appropriate dental interventions before initiating antiresorptive and/or antiangiogenic therapies.8 In patients receiving antiresorptive and/or antiangiogenic medications for cancer-related indications, increased awareness, preventive dental care, and early recognition of the signs and symptoms of MRONJ may result in earlier detection.

The AAOMS committee outlined the following measures as part of early treatment planning:

  • thorough examination of the oral cavity and a radiographic assessment when indicated;
  • identification of acute infection and sites of potential infection to prevent future sequelae that could be exacerbated once drug therapy begins;
  • patient motivation and patient education regarding dental care.

The AAOMS paper states that if “systemic conditions permit, initiation of antiresorptive therapy should be delayed until dental health is optimized” and that “This decision must be made in conjunction with the treating physician and dentist and other specialists involved in the care of the patient.” Regarding antiangiogenic therapy, the AAOMS states, “There are no data to support or refute the cessation of antiangiogenic therapy in the prevention or management of MRONJ; therefore, continued research in the area is indicated.”

A systematic review and international consensus paper from the International Task Force on Osteonecrosis of the Jaw published in early 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 systematic review and clinical practice guideline from the American Society of Clinical Oncology (ASCO) specifically addressing the role of bone-modifying agents in metastatic breast cancer included consensus-based recommendations regarding dental therapy in these patients.21, 22 The primary recommendation is that patients maintain good oral hygiene, have preventive dental examinations before initiating therapy, and avoid invasive dental procedures whenever possible. The Update Committee consensus opinion also suggests that “in the setting of invasive dental procedures, it is advisable, whenever possible to delay the starting of therapy with bone-modifying agents until the initial bone healing process of the tooth socket bone has taken place” and that “If an invasive manipulation of the bone underlying the teeth is clinically indicated before starting bone-modifying agent therapy…initiation of bone-modifying agent therapy should be ideally delayed for 14 to 21 days to allow for wound healing, if the clinical situation permits.”

Antiresorptive Medications in Oncology

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®)23 and zoledronic acid (Zometa®)24 are FDA approved for various cancer indications (e.g., hypercalcemia of malignancy, Table 1).

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 (Table 1).25 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).25

Table 1. Antiresorptive Medications Approved by FDA for Oncology Indications
Drug Generic Name (Trade Name); Route of Administration
 FDA-approved Oncology Indications (Dosages)
 Bisphosphonates
 Pamidronate disodium23 (Aredia®, generics); IV
  • Hypercalcemia of malignancy with or without bone metastases
    (60 mg to 90 mg as a single dose infused over 2 hours to 24 hours for moderate hypercalcemia,
    or 90 mg as a single dose infused over 2 hours to 24 hours for severe hypercalcemia.; if warranted, re-treat after a minimum of 7 days)
  • Osteolytic bone metastases of breast cancer (90 mg as a 2-hour infusion every 3 to 4 weeks; re-treat after recovery of renal function)
  • Osteolytic bone lesions of multiple myeloma (90 mg as a 4-hour infusion once every 4 weeks; re-treat after recovery of renal function)
 Zoledronic acid24 (Zometa®); IV
  • Hypercalcemia of malignancy (4 mg as a single-use IV infusion over no less than 15 minutes; 4 mg as retreatment after a minimum of 7 days)
  • Patients with multiple myeloma and patients with documented bone metastases from solid tumors,
    in conjunction with standard antineoplastic therapy (4 mg as a single-use intravenous infusion over no less than
    15 minutes every 3-4 weeks for patients with creatinine clearance of greater than 60 mL/min)

NOTE: Prostate cancer should have progressed after treatment with at least one hormonal therapy.

 RANK Ligand Inhibitor
 Denosumab25 (Xgeva®); SC
  • Prevention of skeletal-related events in patients with multiple myeloma or with bone metastases from solid tumors (120 mg every 4 weeks)
  • Treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to
    result in severe morbidity (120 mg every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy)
  • Treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy
    (120 mg every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy)

IV: intravenous; SC: subcutaneous;

Antiangiogenic Medications in Oncology

Angiogenesis, or the development of new blood vessels, is a key factor in the growth and metastasis of certain solid tumors.8, 26  These tumors secrete proangiogenic factors, such as vascular endothelial growth factor (VEGF) to stimulate new vessel development via downstream signaling pathways.26, 27 Various inhibitors of angiogenesis (antiangiogenic agents) have been developed and introduced into oncology practice (Table 2).26, 28-38  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).32

Table 2. Antiangiogenic Medications Approved by FDA for Oncology Indications
 Drug Generic Name (Trade Name); Route of Administration
 FDA-approved Oncology Indications
 Monoclonal Antibody
Bevacizumab33 (Avastin®); IV
  • Metastatic colorectal cancer (1st or 2nd line)
  • Unresectable, locally advanced, recurrent, or metastatic nonsquamous
    non-small cell lung cancer (1st line)
  • Progressive glioblastoma in adults following previous treatment
  • Metastatic renal-cell carcinoma
  • Cervical cancer (persistent, recurrent, or metastatic disease)
  • Platinum-resistant, recurrent epithelial ovarian, fallopian tube or
    primary peritoneal cancer
 Tyrosine Kinase Inhibitors
 Sunitinib maleate36 (Sutent®); oral
  • Gastrointestinal stromal tumor (GIST) after disease progression on
    or intolerance to imatinib
  • Advanced renal-cell carcinoma
  • Progressive, well-differentiated pancreatic neuroendocrine tumors in
    patients with unresectable locally advanced or metastatic disease
 Sorafenib28 (Nexavar®); oral
  • Unresectable hepatocellular carcinoma
  • Advanced renal cell carcinoma
  • Locally recurrent or metastatic, progressive,
    differentiated thyroid carcinoma refractory to radioactive iodine treatment
 Panzopanib34 (Votrient®); oral
  • Advanced renal cell carcinoma
  • Advanced soft tissue sarcoma treated with prior chemotherapy
 Axitinib37 (Inlyta®); oral
  • Advanced renal cell carcinoma after failure of one prior systemic therapy
 mTOR Inhibitors
 Everolimus35 (Afinitor®); oral
  • Advanced hormone receptor-positive, HER2-negative breast cancer
    following prior therapy
  • Adults with progressive unresectable, locally advanced or metastatic
    neuroendocrine tumors of pancreatic origin
  • Adults with advanced renal cell carcinoma after prior therapy
 Temsirolimus,38 (Torisel®); IV
  • Advanced renal cell carcinoma
 Immunomodulatory agents
 Thalidomide29 (Thalomid®); oral
  • Patients with newly diagnosed multiple myeloma
 Lenalidomide30 (Revlimid®); oral
  • Multiple myeloma
  • Anemia due to myelodysplastic syndrome
  • Relapsed or progressive mantle cell lymphoma after prior therapy
 Pomalidomide31 (Pomalyst®); oral
  • Patients with multiple myeloma who have received at least two prior
    therapies including lenalidomide and a proteasome inhibitor and have demonstrated
    disease progression on or within 60 days of completion of the last therapy

HER: human epidermal receptor; IV: intravenous; mTOR: mammalian target of rapamycin

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ADA Resources

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

For the Patient page:  What is MRONJ? (August 2021)

Search JADA for articles related to osteonecrosis or MRONJ

ADA Library Services
 

Other Resources
Cochrane Database of Systematic Reviews:  Interventions for Managing Medication-related Osteonecrosis of the Jaw (2017)

U.S. Food & Drug Administration MedWatch Program. If a practitioner suspects a patient to have MRONJ, they may contact the FDA’s MedWatch program online or by calling 800-FDA-1088 to file a voluntary report.

The National Osteonecrosis Foundation
Last Updated: July 28, 2021

Prepared by:

Department of Scientific Information, Evidence Synthesis & Translation Research, ADA Science & Research Institute, LLC.


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