Bisphosphonates are antiresorptive medications commonly used to treat osteoporosis, Paget's disease, and cancer-related bone disease. These medications have been shown to reduce the incidence of pathological fractures associated with multiple myeloma and metastatic bone involvement. Additionally, bisphosphonates can reduce the risk of spine and hip fractures in women with osteoporosis by approximately 30–70%.¹ 

Despite their therapeutic benefits, osteonecrosis of the jaw (ONJ) is a rare but serious complication of bisphosphonate therapy. Formally called bisphosphonate-related osteonecrosis of the jaw (BRONJ), the term medication-related osteonecrosis of the jaw (MRONJ) refers to ONJ associated with antiresorptive agents (e.g., bisphosphonates) and antiangiogenic therapies.¹ 

Reference

1. Alaranji, G., Reilly, E. Bisphosphonate Toxicity. (2025, December 13). StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK562331/

While the underlying mechanisms aren't fully understood, MRONJ is believed to occur through multiple interacting mechanisms, one of which is the inhibition of bone remodeling.¹ 

Bisphosphonates increase bone density by slowing bone resorption, primarily through the suppression of osteoclast activity. Due to their strong affinity for bone mineral, particularly hydroxyapatite, these drugs are internalized by osteoclasts, leading to cell death (apoptosis).^1,2 Because osteoclasts are responsible for normal bone turnover and also release the cytokines necessary to promote osteoblast maturation, their suppression indirectly impairs the bone remodeling cycle.¹ While this process increases bone density, it is suggested that prolonged suppression may lead to excessive inhibition of bone remodeling. This disruption is hypothesized to eventually impair the bone's natural ability to heal, increasing the risk of osteonecrosis.^1,2

The maxilla and mandible are thought to be especially vulnerable because the alveolar crest undergoes a higher rate of remodeling than most other bones in the skeleton. This elevated turnover may increase local exposure to bisphosphonates, contributing to the development of MRONJ.¹

References

1. Lee, E.S., Tsai, M.C., Lee, J.X., et al. Bisphosphonates and Their Connection to Dental Procedures: Exploring Bisphosphonate-Related Osteonecrosis of the Jaws. Cancers (Basel). 2023; 15(22): 5366. https://pmc.ncbi.nlm.nih.gov/articles/PMC10670230/ 

2. Alaranji, G., Reilly, E. Bisphosphonate Toxicity. (2025, December 13). StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK562331/

Beyond inhibition of bone remodeling, angiogenesis inhibition and inflammation or infection are other proposed mechanisms that contribute to MRONJ. Bisphosphonates are known to interfere with angiogenesis, the formation of new blood vessels. Because healthy blood flow is essential for tissue repair, reduced blood supply may impede healing and increase susceptibility to infection and necrosis.¹

Additionally, the immunosuppressive effects of bisphosphonates are believed to reduce the body's ability to respond effectively to bacterial challenges in the oral cavity, leading to inflammation and infection. This increased susceptibility to infection may further contribute to the development of MRONJ.¹

Reference

1. Lee, E.S., Tsai, M.C., Lee, J.X., et al. Bisphosphonates and Their Connection to Dental Procedures: Exploring Bisphosphonate-Related Osteonecrosis of the Jaws. Cancers (Basel). 2023; 15(22): 5366. https://pmc.ncbi.nlm.nih.gov/articles/PMC10670230/

Although MRONJ is most often associated with tooth extractions, it does not appear to depend solely on the procedure itself. Some research suggests that infection and inflammation associated with extraction, rather than the extraction itself, are contributing factors in the development of MRONJ. The risk appears to increase with more invasive extractions involving greater bone trauma, particularly in the mandible. Preexisting infections, such as osteomyelitis or periapical periodontitis, have also been suggested to play a role. Given this risk, avoiding extraction is recommended when possible, provided that infections or lesions can be managed conservatively through alternatives such as endodontic treatment.¹

Reference

1. Lee, E.S., Tsai, M.C., Lee, J.X., et al. Bisphosphonates and Their Connection to Dental Procedures: Exploring Bisphosphonate-Related Osteonecrosis of the Jaws. Cancers (Basel). 2023; 15(22): 5366. https://pmc.ncbi.nlm.nih.gov/articles/PMC10670230/

Minimizing the risk of MRONJ begins with addressing oral health issues before bisphosphonate therapy begins. Prior to initiating therapy, patients should:

• Complete a comprehensive dental evaluation.
• Delay bisphosphonate therapy if possible until oral health concerns are addressed, especially before IV therapy.
• Treat infection or potential infection sites.
• Complete necessary dental surgeries (e.g., extractions) 4 to 6 weeks before starting bisphosphonates to allow for adequate osseous healing.¹

Once bisphosphonate therapy begins, patients should maintain regular dental appointments. Dental hygiene should be prioritized, as periodontal disease is associated with the development of MRONJ. Research indicates that 41%–84% of patients with MRONJ had periodontal disease. Periodontal pathogens have also been isolated from MRONJ lesions. The American Association of Oral and Maxillofacial Surgeons (AAOMS) identified preexisting inflammatory dental disease, such as periodontal disease, as a risk factor for MRONJ in its 2022 position paper.¹

Reference

1. Lee, E.S., Tsai, M.C., Lee, J.X., et al. Bisphosphonates and Their Connection to Dental Procedures: Exploring Bisphosphonate-Related Osteonecrosis of the Jaws. Cancers (Basel). 2023; 15(22): 5366. https://pmc.ncbi.nlm.nih.gov/articles/PMC10670230/