What medication most commonly causes osteonecrosis? A look at bisphosphonates and corticosteroids

October 6, 2025 •

5 min read

According to estimates, corticosteroid-induced osteonecrosis alone accounts for over 10% of the half-million total joint replacements performed annually in the U.S. Determining what medication most commonly causes osteonecrosis is complex, as it depends on the specific drug class and the affected part of the skeleton, with bisphosphonates and corticosteroids being the two primary culprits.

Quick Summary

This article explores the two main classes of medications most commonly linked to osteonecrosis: bisphosphonates, which primarily cause jaw issues, and corticosteroids, which frequently affect the hip. It details their respective mechanisms, risk factors, and key differences in how they manifest.

Key Points

Leading culprits: The two most common medication classes causing osteonecrosis are bisphosphonates, linked primarily to jaw issues, and corticosteroids, associated mainly with hip and joint damage.
Bisphosphonate-related ONJ: Intravenous bisphosphonates, such as zoledronic acid, used for cancer treatment, carry the highest risk for osteonecrosis of the jaw (ONJ) due to suppressing bone turnover.
Corticosteroid-induced AVN: High-dose, long-term systemic use of corticosteroids like prednisone is a major cause of osteonecrosis in the femoral head (hip) by disrupting blood flow and increasing intraosseous pressure.
Risk factors differ: Bisphosphonate-related ONJ is often triggered by dental procedures and oral trauma, while steroid-induced AVN risk is directly tied to the cumulative dose and duration of therapy.
Prevention is key: For bisphosphonate users, regular dental exams and addressing oral issues before treatment are crucial. For corticosteroid users, using the lowest effective dose and monitoring for symptoms are vital preventive strategies.
Other medications: Certain antiangiogenic drugs and immunosuppressants can also contribute to osteonecrosis risk, particularly in cancer patients.

Understanding Osteonecrosis: Bone Death from Medication

Osteonecrosis, also known as avascular necrosis (AVN), is a serious condition caused by the loss of blood supply to a section of bone, leading to bone tissue death and potential collapse. While injury and other diseases can cause osteonecrosis, certain medications are significant contributing factors. Two classes, bisphosphonates and corticosteroids, are the most recognized culprits, although they typically affect different parts of the body. High-potency, long-term intravenous (IV) bisphosphonate use is overwhelmingly associated with osteonecrosis of the jaw (ONJ), whereas high-dose, systemic corticosteroid therapy is a major risk factor for osteonecrosis of the femoral head (hip).

Bisphosphonates and Osteonecrosis of the Jaw (ONJ)

Bisphosphonates are powerful antiresorptive drugs that inhibit osteoclasts, the cells responsible for breaking down old bone. This mechanism makes them highly effective in treating conditions involving excessive bone resorption, such as osteoporosis, multiple myeloma, and bone metastases associated with various cancers. However, this same action can lead to a condition known as Medication-Related Osteonecrosis of the Jaw (MRONJ), or more commonly, bisphosphonate-related ONJ (BRONJ).

The Mechanism Behind ONJ

Bisphosphonates have a high affinity for bone minerals, causing them to accumulate at sites of high bone turnover, such as the jawbone. By interfering with osteoclast function, bisphosphonates suppress bone remodeling and turnover, impairing the bone's ability to repair itself. If the jawbone is traumatized, such as during a dental extraction, this impaired healing can result in exposed, necrotic bone that fails to heal. The jaw is particularly susceptible due to its high remodeling rate and constant exposure to oral microbes.

High-risk Bisphosphonates

Intravenous (IV) Bisphosphonates: Used in high doses for cancer patients, these carry a significantly higher risk of ONJ compared to oral forms. Zoledronic acid (Zometa, Reclast) and pamidronate (Aredia) are the most frequently implicated. The incidence in cancer patients can be as high as 11% after prolonged therapy.
Oral Bisphosphonates: Used to treat osteoporosis, these have a much lower risk profile. The risk typically arises after long-term use (e.g., more than three years) and is often triggered by invasive dental procedures. Examples include alendronate (Fosamax) and risedronate (Actonel).

Related Antiresorptive Agents

Another class of antiresorptive drugs, RANK ligand inhibitors, such as denosumab (Prolia, Xgeva), also carry a risk for MRONJ. Like bisphosphonates, denosumab suppresses bone turnover, although its effect is reversible upon cessation.

Corticosteroids and Femoral Head Osteonecrosis

Systemic corticosteroids, also known as glucocorticoids (e.g., prednisone, dexamethasone), are powerful anti-inflammatory medications used to treat a wide range of conditions, including autoimmune diseases, organ transplant rejection, and severe inflammation. However, their long-term, high-dose use is a leading cause of non-traumatic osteonecrosis, most commonly affecting the hip joint (femoral head).

The Pathophysiology of Steroid-Induced Osteonecrosis

The exact mechanism is complex and multifactorial, but key processes include:

Vascular Impairment: Steroids can damage the delicate blood vessels that supply the bone, leading to reduced blood flow and ischemia.
Fat Cell Changes: They promote the enlargement of fat cells (adipocyte hypertrophy) within the bone marrow. This increases intraosseous pressure, further compressing the blood vessels and exacerbating ischemia.
Blood Clotting: Steroids can increase the risk of intravascular coagulation, leading to microthrombi that block blood supply.

Risk Factors and Presentation

The risk of steroid-induced osteonecrosis is strongly linked to the dose and duration of treatment. A cumulative prednisone-equivalent dose greater than 5.4 grams has been associated with increased risk. The condition often presents with pain in the hip, groin, or thigh, which worsens with weight-bearing activities.

Comparison Table: Bisphosphonates vs. Corticosteroids


Feature	Bisphosphonates	Corticosteroids
Primary Affected Area	Jawbone (Mandible > Maxilla)	Femoral head (Hip)
Associated Condition	Medication-Related Osteonecrosis of the Jaw (MRONJ)	Avascular Necrosis (AVN)
Main Mechanism	Suppression of bone turnover and remodeling	Impaired blood flow, fat embolism, and increased intraosseous pressure
Main Risk Factor	High dose, IV administration (especially for cancer) and invasive dental procedures	High dose, long-term, systemic administration
Onset	Can be spontaneous but often follows dental trauma, particularly with long-term use	Typically insidious, with symptoms appearing weeks to months after therapy starts or ends
Main Patient Group	Cancer patients (higher risk) and osteoporosis patients (lower risk)	Patients with autoimmune diseases, post-transplant patients

Prevention and Management

Mitigating the risk of medication-related osteonecrosis requires careful monitoring and a multi-pronged approach.

For Bisphosphonate-Related ONJ

Before starting therapy: Patients should undergo a comprehensive dental evaluation to address any potential issues, such as tooth decay or periodontal disease.
During therapy: Maintain excellent oral hygiene and inform your dentist about your medication. Invasive procedures should be avoided or minimized if possible.
For management: Treatment is typically conservative, involving antimicrobial rinses and antibiotics to control infection, and surgical debridement only if necessary.

For Steroid-Induced Osteonecrosis

Risk assessment: Clinicians should balance the benefits of high-dose, long-term steroids with the risk of osteonecrosis.
Lowest effective dose: Always use the lowest possible dose of corticosteroids for the shortest duration necessary to achieve therapeutic effect.
Early detection: For at-risk patients with joint pain, MRI is the most effective tool for early detection, enabling conservative treatment before irreversible collapse occurs.

Conclusion: A Delicate Balance of Risk and Benefit

Determining what medication most commonly causes osteonecrosis depends heavily on the specific type of osteonecrosis and the patient population. For osteonecrosis of the jaw, high-potency intravenous bisphosphonates, particularly zoledronic acid, are the most common culprits, especially in cancer patients. In contrast, systemic high-dose corticosteroids, such as prednisone, are the primary cause of osteonecrosis in the hip and other major joints. In both cases, the risk is often cumulative and depends on the dose and duration of therapy. While these medications offer life-saving benefits, both patients and healthcare providers must be vigilant about the potential for bone necrosis and take proactive steps for prevention and early management.

For more information on bone health, consult resources from authoritative sources like the National Institutes of Health.

Frequently Asked Questions

High-potency intravenous bisphosphonates like zoledronic acid (Zometa, Reclast) and pamidronate (Aredia), typically used for cancer patients, are most frequently associated with osteonecrosis of the jaw (ONJ). Oral bisphosphonates, such as alendronate (Fosamax), carry a lower risk, especially with long-term use.

No, the risk profile is different. Oral bisphosphonates have a much lower risk of causing ONJ compared to the high doses used in intravenous therapy for cancer. For oral bisphosphonate users, the risk is higher with prolonged use and is often triggered by dental surgery.

Steroid-induced osteonecrosis, also known as avascular necrosis, most commonly affects the femoral head, which is the ball portion of the hip joint. It can also occur in other joints, including the knee and shoulder.

Good oral hygiene, regular dental checkups, and addressing any needed dental work (like extractions) before starting bisphosphonate therapy are crucial. For patients already on the medication, minimizing invasive dental procedures is recommended.

Yes. For steroid-induced osteonecrosis, symptoms can appear weeks to months after the medication has been discontinued. For bisphosphonate-related ONJ, the drugs can remain in the bone for years, so the risk can persist even after stopping the medication.

Other drugs, primarily those used for cancer treatment, have been associated with medication-related osteonecrosis of the jaw (MRONJ). These include denosumab (a RANK ligand inhibitor), certain antiangiogenic drugs, and mTOR inhibitors.

The mechanism is multifactorial, but it primarily involves impaired blood flow (vascular impairment) to the bone. Corticosteroids can also cause fat cell enlargement within the bone marrow, increasing pressure and further compressing blood vessels, leading to ischemia and bone death.