Which med is most likely to cause osteonecrosis of the jaw?

October 11, 2025 •

5 min read

Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious side effect, with the risk significantly higher for patients on specific high-dose, intravenous medications compared to those on oral alternatives. Understanding which med is most likely to cause osteonecrosis of the jaw involves looking at antiresorptive drugs like bisphosphonates and denosumab, particularly in an oncology setting.

Quick Summary

High-dose, intravenous bisphosphonates, particularly zoledronic acid, and the RANKL inhibitor denosumab carry the highest risk for medication-related osteonecrosis of the jaw (MRONJ). This risk is compounded by factors like cancer diagnosis, treatment duration, and invasive dental procedures. Oral antiresorptive medications pose a much lower risk.

Key Points

Highest Risk Medications: The highest risk of osteonecrosis of the jaw is associated with high-dose intravenous bisphosphonates (like zoledronic acid) and the RANKL inhibitor denosumab, primarily in cancer treatment settings.
Oral vs. Intravenous Risk: Oral bisphosphonates for osteoporosis carry a much lower risk of MRONJ compared to the intravenous versions used for cancer-related conditions.
Denosumab's Half-Life: Unlike bisphosphonates, denosumab has a shorter half-life and does not accumulate in the bone, meaning its effects are more transient, though it carries a risk of rebound fractures upon discontinuation.
Role of Dental Procedures: Invasive dental procedures like tooth extractions are the most common trigger for MRONJ in patients on high-risk medications.
Preventive Dental Care is Key: Pre-treatment dental evaluation and maintaining excellent oral hygiene are the most effective strategies for preventing MRONJ.
Multiple Risk Factors: The development of MRONJ is multifactorial, influenced by medication, dose, duration, dental health, and comorbidities like cancer, diabetes, and use of corticosteroids.

Understanding Medication-Related Osteonecrosis of the Jaw (MRONJ)

Medication-related osteonecrosis of the jaw (MRONJ) is a condition characterized by areas of bone in the jaw that die and become exposed through the gums, failing to heal after more than eight weeks. While numerous medications have been implicated, antiresorptive agents are the most significant culprits. These drugs inhibit the activity of osteoclasts, the cells that break down bone tissue, a process known as bone resorption. This suppression of bone remodeling, especially in the highly active jawbone, impairs the bone's ability to repair itself after trauma or infection, leading to necrosis.

High-Risk Medications for MRONJ

Among the medications known to cause MRONJ, the highest risk is consistently associated with high-dose, intravenous antiresorptive therapy, primarily used in cancer patients. However, the risk profiles and characteristics differ between the main drug classes.

Antiresorptive Agents: Bisphosphonates and Denosumab

Intravenous Bisphosphonates: Certain potent, nitrogen-containing bisphosphonates administered intravenously carry the highest documented risk. Zoledronic acid (Zometa, Reclast) and pamidronate (Aredia) are particularly linked to a higher incidence of MRONJ, especially when used to treat bone metastases or multiple myeloma in cancer patients. The incidence can range from 1% to 12% in this high-risk population.
Denosumab: The RANKL inhibitor denosumab (Xgeva, Prolia) is also a major contributor to MRONJ, with some reports suggesting a comparable or even higher risk than intravenous bisphosphonates in cancer patients. Denosumab also affects osteoclast function, inhibiting bone resorption. A key difference from bisphosphonates is its shorter half-life and non-incorporation into bone, though its discontinuation can carry other risks.
Oral Bisphosphonates: Oral bisphosphonates (e.g., alendronate, risedronate, ibandronate) are mainly used for osteoporosis and carry a much lower risk of MRONJ compared to their intravenous counterparts. The risk is extremely low, estimated at less than 0.04%, but it increases with longer duration of use, often beyond four years.

Antiangiogenic Drugs and Other Targeted Therapies

As the name 'medication-related' suggests, other drug classes can also be involved in MRONJ development. Antiangiogenic drugs, which interfere with the formation of new blood vessels, impair the bone's healing capabilities. These are primarily used in cancer treatment and include medications like bevacizumab and sunitinib. Other drugs with potential links include immunosuppressants like methotrexate, mTOR inhibitors, and even corticosteroids, especially when used in combination with antiresorptive therapy.

Comparison: Denosumab vs. Bisphosphonates


Feature	Denosumab (Prolia®, Xgeva®)	Bisphosphonates (e.g., Zometa®, Fosamax®)
Mechanism	Human monoclonal antibody inhibiting RANKL, which is essential for osteoclast formation.	Inhibit osteoclast activity by inducing apoptosis and interfering with cell function.
Pharmacokinetics	Shorter half-life (around 25–32 days) and does not permanently bind to bone.	Long half-life (up to 10+ years for some) and accumulates in the bone matrix.
Route of Administration	Subcutaneous injection, typically every 6 months for osteoporosis (Prolia) or monthly for cancer (Xgeva).	Oral tablets for osteoporosis; monthly or yearly intravenous infusions for cancer.
MRONJ Risk (Cancer)	High risk, potentially comparable to or higher than IV bisphosphonates, though studies vary.	High risk with intravenous formulations like zoledronic acid.
MRONJ Risk (Osteoporosis)	Low risk with osteoporosis dosage (Prolia).	Very low risk with oral formulations, but increases after several years of use.
Post-Discontinuation Risk	Risk can decrease relatively quickly, but there is a risk of rebound fractures. Requires careful monitoring.	Risk persists for years due to drug accumulation in bone.

Risk Factors and Prevention

While medication is the primary trigger, a constellation of systemic and local risk factors influences the likelihood of developing MRONJ.

Key Risk Factors

Type, dose, and duration of medication: High-dose, intravenous administration, particularly for cancer, carries a much greater risk. Prolonged use (over 2-4 years) is also a significant factor.
Dentoalveolar surgery: Invasive procedures like tooth extractions, dental implants, or oral surgery, especially if they expose the jawbone, are the most common trigger for MRONJ.
Poor oral hygiene and infection: Pre-existing periodontal disease, dental infections, or ill-fitting dentures that cause trauma can increase risk.
Comorbidities: Conditions like cancer (multiple myeloma, breast, prostate), diabetes, renal failure, and heart disease are associated with higher MRONJ risk.
Concomitant medications: Use of chemotherapy, corticosteroids, or antiangiogenic agents alongside antiresorptives amplifies the risk.
Lifestyle factors: Smoking and alcohol use are also contributing risk factors.

Preventive Measures for Patients at Risk

Prevention is paramount, as there is currently no consistently effective treatment for established MRONJ. The following steps can significantly reduce the risk:

Pre-treatment dental evaluation: All patients who are about to start high-risk antiresorptive therapy, especially for cancer, should have a complete dental examination. Any necessary dental work, including extractions of compromised teeth, should be completed and healed before beginning drug therapy.
Optimal oral hygiene: Maintaining excellent oral health is critical for all patients on these medications. This includes regular dental check-ups, meticulous home care, and a consistent regimen of antiseptic oral rinses.
Minimally invasive dentistry: When dental procedures are necessary, a conservative approach is preferred. Non-invasive treatments like fillings and root canals are lower risk than extractions or implant placement.
Patient education: Patients should be made fully aware of the risks and symptoms of MRONJ, as well as the importance of reporting any non-healing sores or bone exposure in the jaw.

Conclusion

While bisphosphonates and denosumab are vital treatments for conditions like osteoporosis and cancer, they are also the primary medications linked to osteonecrosis of the jaw. The risk is highest with high-dose, intravenous formulations used for cancer, though prolonged use of oral bisphosphonates also carries a low but present risk. Denosumab presents its own distinct risk profile and pharmacological considerations. Prevention, through proactive dental care and risk management, remains the most effective strategy for mitigating this serious side effect. Patients should work closely with their medical and dental professionals to manage their treatment and maintain optimal oral health. For more detailed information on managing MRONJ risk, consulting guidelines from professional organizations like the American Association of Oral and Maxillofacial Surgeons (AAOMS) is recommended.

Expert Resources

American Association of Oral and Maxillofacial Surgeons (AAOMS) Position Paper on Medication-Related Osteonecrosis of the Jaw (MRONJ). [Outbound Link to be inserted once AAOMS guideline is sourced]

Risk Categories and Impact

The risk of developing MRONJ varies dramatically depending on the specific medication, dosage, and duration. For patients with osteoporosis taking oral bisphosphonates, the risk is very low, often less than 1 in 10,000, and is a significant consideration only with long-term use. In stark contrast, cancer patients receiving high-dose intravenous bisphosphonates or denosumab face a much higher risk, potentially ranging from 1% to over 10%. This highlights that the indication for treatment is a crucial factor in assessing the potential for MRONJ. The overall benefits of these life-saving cancer therapies must be carefully weighed against the risk of jaw necrosis, which can significantly impact quality of life but is often less severe than the underlying malignancy.

Pathophysiology of MRONJ

The exact pathophysiology is still under investigation, but several mechanisms are thought to play a role:

Suppressed Bone Remodeling: Antiresorptive drugs suppress osteoclast activity, slowing down the natural bone turnover process. This leaves micro-damaged bone unable to be repaired, leading to an accumulation of dead bone tissue.
Antiangiogenic Effects: Many of these drugs, especially newer cancer agents, have antiangiogenic properties, which restrict blood vessel formation. This reduces the blood supply to the jawbone, impairing healing.
Chronic Inflammation/Infection: The jawbone is constantly exposed to trauma and microorganisms, particularly after dental procedures. In patients with suppressed healing and bone remodeling, this can lead to chronic infection and inflammation that progresses to necrosis.

By understanding these underlying mechanisms and risk factors, clinicians and patients can collaborate to create a robust prevention strategy, emphasizing proactive dental care and careful monitoring during therapy.

Frequently Asked Questions

Bisphosphonates and denosumab are antiresorptive medications used to treat conditions involving excessive bone breakdown. This includes osteoporosis, to strengthen bones and prevent fractures, and in cancer, to manage complications associated with bone metastases.

For oral bisphosphonates, the risk of MRONJ is very low in the first couple of years but may increase significantly after four years of continuous use. For high-dose intravenous antiresorptives, the risk is higher from the start and increases with the cumulative dose and treatment duration.

Symptoms can include exposed bone in the jaw, jaw pain, swelling, soft tissue infection, numbness in the jaw, loose teeth, or non-healing sores after dental work.

Invasive dental procedures like tooth extractions should ideally be completed and fully healed before starting high-risk antiresorptive therapy. While on treatment, conservative dental procedures are preferred. For high-risk procedures, a discussion with your doctor and dentist about potentially delaying treatment or a 'drug holiday' is necessary, although the effectiveness of drug holidays is debated.

No, the risk is not the same. Cancer patients typically receive much higher doses and more frequent administrations of antiresorptive medications, particularly intravenously, which places them at a significantly higher risk of MRONJ compared to osteoporosis patients on oral medications.

In addition to the medication itself, other factors include systemic conditions like cancer, diabetes, and hypertension, and local factors such as poor oral hygiene, pre-existing dental disease, and ill-fitting dentures.

There is currently no single, consistently effective cure for MRONJ. Treatment focuses on conservative management to control symptoms, reduce infection, and minimize disease progression. This may involve antimicrobial rinses, antibiotics, and conservative debridement, with more aggressive surgery reserved for severe cases.