Dento-Alveolar Surgery, Bisphosphonates, and MRONJ

Dento-alveolar surgery forms a core component of oral and maxillofacial practice and includes procedures such as tooth extraction, surgical removal of teeth, alveoloplasty, and minor bone surgery. While these interventions are routine in the general population, they become significantly more complex in patients receiving medications that alter bone metabolism and vascularity. Among the most clinically significant of these drugs are bisphosphonates, denosumab, and anti-angiogenic agents. These medications, widely used in the management of osteoporosis, metastatic malignancy, and other systemic conditions, are strongly associated with medication-related osteonecrosis of the jaw (MRONJ).

MRONJ is a potentially devastating complication characterized by exposed, non-healing bone in the maxillofacial region. Although relatively uncommon, its impact on quality of life can be profound, causing pain, infection, pathological fractures, and difficulty with mastication and speech. Importantly, MRONJ is often precipitated by dento-alveolar surgery, particularly tooth extractions, making the dental management of patients on these drugs a subject of critical importance.

Bisphosphonates: Mechanism of Action and Clinical Use

Bisphosphonates represent a large and heterogeneous group of drugs that act primarily by inhibiting osteoclast-mediated bone resorption. Chemically analogous to pyrophosphate, bisphosphonates bind strongly to hydroxyapatite crystals in bone, particularly at sites of active remodeling. Once incorporated into bone, they can remain for many years, exerting prolonged biological effects.

Their principal mechanism involves the suppression of osteoclast activity. Nitrogen-containing bisphosphonates, such as alendronate, zoledronic acid, and pamidronate, inhibit the mevalonate pathway within osteoclasts, leading to impaired cytoskeletal function and apoptosis. The net effect is a reduction in bone turnover and increased bone mineral density.

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Clinically, bisphosphonates are used extensively in:

 

In these conditions, bisphosphonates reduce fracture risk, alleviate bone pain, and stabilize skeletal architecture. However, their potent inhibition of bone remodeling underlies the pathogenesis of MRONJ.

 

Denosumab and Anti-Angiogenic Agents

Denosumab is a monoclonal antibody that inhibits receptor activator of nuclear factor kappa-B ligand (RANKL), a key mediator of osteoclast differentiation and survival. Unlike bisphosphonates, denosumab does not bind to bone but exerts a reversible anti-resorptive effect while present in the circulation. Despite this pharmacological difference, denosumab carries a similar risk of MRONJ, particularly in oncology patients receiving high doses.

Anti-angiogenic medications, including agents that inhibit vascular endothelial growth factor (VEGF), interfere with blood vessel formation. Adequate vascularity is essential for bone healing and mucosal repair. By impairing angiogenesis, these drugs compromise wound healing and increase susceptibility to necrosis following surgical trauma.

The common endpoint shared by all these medications is impaired bone healing, altered immune response, and increased vulnerability of the jawbones, which are uniquely susceptible due to their high remodeling rate and exposure to the oral microbial environment.

 

Pathophysiology of Medication-Related Osteonecrosis of the Jaw

The exact pathogenesis of MRONJ remains multifactorial and incompletely understood. However, several key mechanisms are widely accepted:

  1. Suppressed Bone Remodeling
    Normal bone repair requires a balance between osteoclast-mediated resorption and osteoblast-mediated formation. Anti-resorptive drugs disrupt this balance, leading to microdamage accumulation and reduced capacity for healing after trauma.
  2. Local Infection and Inflammation
    The oral cavity harbors a diverse microbial population. Following tooth extraction or mucosal breakdown, bacteria can access bone that lacks adequate remodeling capacity, leading to chronic infection.
  3. Impaired Angiogenesis
    Reduced blood supply limits oxygen delivery, nutrient exchange, and immune cell migration, all of which are essential for healing.
  4. Soft Tissue Toxicity
    Some evidence suggests that these drugs may directly impair oral mucosal cell function, increasing the likelihood of wound breakdown and bone exposure.

The mandible is more commonly affected than the maxilla, likely due to its relatively poorer blood supply and higher mechanical loading.

 

Rendering a Patient “Dentally Fit” Prior to Drug Initiation

One of the most effective strategies for preventing MRONJ is comprehensive dental assessment and treatment before anti-resorptive or anti-angiogenic therapy begins. When a clinician is asked to render a patient “dentally fit,” the objective is to minimize the future need for invasive dental procedures.

This approach parallels that used for patients undergoing head and neck radiotherapy. Ideally, all teeth with a poor long-term prognosis should be addressed before medication initiation. This may include:

  • Extraction of non-restorable teeth
  • Definitive management of advanced periodontal disease
  • Completion of necessary restorative and endodontic treatment
  • Adjustment or replacement of ill-fitting prostheses

 

However, a careful balance must be struck. Over-zealous extraction leading to unnecessary edentulism is undesirable and can negatively impact function and quality of life. Conversely, a passive “watch-and-wait” approach may leave the patient vulnerable to future dental emergencies that necessitate extraction once medication therapy has begun.

Risk stratification is essential. Patients receiving oral bisphosphonates for osteoporosis generally carry a lower risk than those receiving intravenous agents for malignancy. This distinction should guide the aggressiveness of pre-treatment dental intervention.

 

Tooth Removal in Patients Already on Bisphosphonates

Despite best efforts, situations frequently arise where a patient already receiving bisphosphonates or related drugs requires tooth removal. The clinician must then decide whether extraction is unavoidable and, if so, how to minimize risk.

Alternatives to Extraction

Whenever possible, non-surgical alternatives should be prioritized. These may include:

  • Endodontic treatment in preference to extraction
  • Coronectomy for impacted teeth where the roots are asymptomatic
  • Occlusal adjustment or restorative stabilization

 

If the tooth can be retained without ongoing infection or pain, this is generally preferable.

Risk Communication

If extraction cannot be avoided, the patient must be fully informed of the risks. The incidence of MRONJ varies widely depending on the drug type, dose, duration, and underlying condition. Reported risk ranges from less than 1% in low-risk osteoporosis patients to as high as 30% in long-term survivors of multiple myeloma receiving intravenous bisphosphonates.

Informed consent should include discussion of:

  • The possibility of delayed healing
  • Risk of exposed bone and infection
  • Potential need for further surgical or specialist care

 

Surgical Principles for Minimizing Risk

When extraction is undertaken, meticulous surgical technique is critical. The goal is to reduce trauma, eliminate sharp bone edges, and achieve primary soft tissue closure.

Key principles include:

  1. Atraumatic Extraction
    Excessive force, bone removal, and flap reflection should be minimized. Sectioning of teeth may reduce the need for forceful elevation.
  2. Alveolar Septoplasty
    Smoothing and contouring of the alveolar bone ensures that no sharp edges remain and that all bone lies well below the gingival margin.
  3. Primary Mucosal Closure
    Achieving tension-free closure of the mucosa is essential. Vascularized soft tissue coverage protects underlying bone from oral bacteria and reduces the risk of superinfection.
  4. Antimicrobial Prophylaxis
    Use of chlorhexidine mouthwash pre- and post-operatively is commonly recommended. Broad-spectrum antibiotics may be prescribed, although their routine use remains debated and should be tailored to individual risk.

The rationale for these measures lies in the belief that well-vascularized mucosal coverage prevents infection of bone that lacks the capacity to remodel effectively.

 

Management of Established MRONJ

Once MRONJ has developed, management becomes challenging. To date, there is no universally accepted, evidence-based treatment protocol.

Conservative Management

Initial management often focuses on symptom control and infection suppression. This may include:

  • Antimicrobial mouth rinses
  • Systemic antibiotics for secondary infection
  • Analgesia
  • Avoidance of further surgical trauma

 

While conservative measures may stabilize early disease, they rarely result in complete resolution.

Surgical Intervention

Surgical strategies used successfully for osteoradionecrosis do not appear to translate effectively to MRONJ. Extensive resection often leads to poor healing and disease progression.

Limited sequestrectomy, involving removal of loose necrotic bone, may be beneficial in selected cases, particularly when combined with soft tissue coverage. The aim is not aggressive eradication but rather reduction of irritation and infection.

Various adjunctive therapies have been proposed, including:

  • Hyperbaric oxygen
  • Platelet-rich plasma
  • Teriparatide
  • Laser therapy

 

However, none currently possess a robust evidence base, and their use remains experimental.

 

Referral and Multidisciplinary Care

Given the complexity and potential severity of MRONJ, referral to an oral and maxillofacial surgery department is strongly recommended for established cases. Management often requires coordination between dentists, surgeons, oncologists, and physicians to balance oral health needs with systemic disease control.

 

Conclusion

Dento-alveolar surgery in patients receiving bisphosphonates, denosumab, or anti-angiogenic medications presents unique and significant challenges. While these drugs play a crucial role in managing serious systemic conditions, their impact on bone healing necessitates careful dental planning and surgical caution.

Prevention remains the most effective strategy, emphasizing the importance of rendering patients dentally fit before therapy begins. When surgery is unavoidable, atraumatic technique, meticulous soft tissue management, and thorough patient counseling are essential. For established MRONJ, treatment options remain limited, underscoring the need for ongoing research and specialist care.

For dental practitioners, understanding these principles is vital to minimizing harm, optimizing patient outcomes, and navigating the complex intersection of dental and medical care.

 

References

  1. Ruggiero SL, Dodson TB, Fantasia J, et al.
    American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw—2014 update.
    J Oral Maxillofac Surg. 2014;72(10):1938–1956.
  2. Ruggiero SL, Dodson TB, Aghaloo T, Carlson ER, Ward BB, Kademani D.
    Medication-related osteonecrosis of the jaw—2022 update.
    J Oral Maxillofac Surg. 2022;80(5):920–943.
  3. Marx RE.
    Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic.
    J Oral Maxillofac Surg. 2003;61(9):1115–1117.
  4. Khan AA, Morrison A, Hanley DA, et al.
    Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus.
    J Bone Miner Res. 2015;30(1):3–23.
  5. Hellstein JW, Adler RA, Edwards B, et al.
    Managing the care of patients receiving antiresorptive therapy for prevention and treatment of osteoporosis.
    J Am Dent Assoc. 2011;142(11):1243–1251.
  6. McGowan K, McGowan T, Ivanovski S.
    Risk factors for medication-related osteonecrosis of the jaws: a systematic review.
    Oral Dis. 2018;24(4):527–536.
  7. Yarom N, Shapiro CL, Peterson DE, et al.
    Medication-related osteonecrosis of the jaw: MASCC/ISOO/ASCO clinical practice guideline.
    J Clin Oncol. 2019;37(25):2270–2290.
  8. Khosla S, Burr D, Cauley J, et al.
    Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research.
    J Bone Miner Res. 2007;22(10):1479–1491.
  9. Migliorati CA, Siegel MA, Elting LS.
    Bisphosphonate-associated osteonecrosis: a long-term complication of bisphosphonate treatment.
    Lancet Oncol. 2006;7(6):508–514.
  10. Reid IR.
    Effects of bisphosphonates on bone quality.
    Osteoporos Int. 2008;19(6):717–725.
  11. Patel V, McLeod NMH, Rogers SN, Brennan PA.
    Bisphosphonate osteonecrosis of the jaw—A literature review of UK policies versus international policies on bisphosphonates, risk factors and prevention.
    Br J Oral Maxillofac Surg. 2011;49(4):251–257.
  12. Scottish Dental Clinical Effectiveness Programme (SDCEP).
    Oral Health Management of Patients at Risk of Medication-related Osteonecrosis of the Jaw.
    Dundee: SDCEP; 2017 (updated 2022).
  13. Marx RE, Cillo JE, Ulloa JJ.
    Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment.
    J Oral Maxillofac Surg. 2007;65(12):2397–2410.
  14. Woo SB, Hellstein JW, Kalmar JR.
    Systematic review: bisphosphonates and osteonecrosis of the jaws.
    Ann Intern Med. 2006;144(10):753–761.
  15. Peterson LJ, Ellis E, Hupp JR, Tucker MR.
    Contemporary Oral and Maxillofacial Surgery. 7th ed.
    St. Louis: Elsevier; 2019.