Osteonecrosis Associated with Long-Term Bone-Active Medications: Clinical Review and Evidence-Based Insights

Abstract

Osteonecrosis associated with long-term use of bone-active medications, particularly antiresorptive agents such as bisphosphonates and denosumab, has emerged as a significant complication in the management of osteoporosis, metastatic bone disease, and other skeletal conditions. This review synthesizes current evidence on incidence, pathophysiology, risk factors, clinical presentation, diagnosis, and management strategies, with a focus on medication-related osteonecrosis of the jaw (MRONJ). Recent advances, guideline recommendations, and practical implications for clinicians are discussed to enhance prevention, early recognition, and optimized patient care.

Introduction

The use of bone-active medications, including bisphosphonates, denosumab, and selective estrogen receptor modulators, has revolutionized the treatment of osteoporosis, metastatic bone disease, and other skeletal disorders. Despite their proven efficacy in fracture reduction and skeletal stabilization, these agents are associated with rare but serious adverse effects, most notably osteonecrosis, particularly of the jaw. Medication-related osteonecrosis of the jaw (MRONJ) is defined as exposed bone or bone that can be probed through a fistula in the maxillofacial region, persisting for more than eight weeks in patients with a history of antiresorptive or antiangiogenic therapy, in the absence of prior radiation to the craniofacial region. With increasing use of these therapies, awareness and understanding of osteonecrosis as a clinical entity have become vital for healthcare professionals managing at-risk populations.

Epidemiology / Disease Burden

The true incidence of MRONJ varies based on medication type, dose, route, and underlying patient population. In osteoporosis patients receiving oral bisphosphonates, the incidence is estimated at 1–90 per 100,000 patient-years, whereas in oncology patients treated with high-dose intravenous bisphosphonates or denosumab for bone metastases, the incidence can exceed 1%. MRONJ remains rare but is associated with substantial morbidity, impaired quality of life, and increased healthcare utilization. Non-jaw sites of osteonecrosis related to bone-active medications are exceedingly rare but may occur, particularly in patients on prolonged high-dose therapy. The rising use of these agents in aging populations and cancer care underscores the clinical significance of this complication.

Pathophysiology

The pathogenesis of osteonecrosis associated with bone-active medications is multifactorial. Inhibition of osteoclastic bone resorption impairs normal bone remodeling, particularly in the jaw, where high turnover is required to repair microdamage and respond to infection or trauma. Bisphosphonates bind to hydroxyapatite and persist in bone, leading to prolonged suppression of bone turnover. Denosumab, a RANKL inhibitor, also suppresses osteoclast function but without skeletal accumulation. Additional mechanisms include impaired angiogenesis, altered immune response, and soft tissue toxicity, all contributing to the risk of bone necrosis. The jaw is uniquely vulnerable due to its high remodeling rate, frequent exposure to microtrauma, and the presence of oral flora, which can precipitate infection and exacerbate necrosis.

Risk Factors

Risk factors for medication-related osteonecrosis include cumulative dose and duration of antiresorptive therapy, intravenous administration, concomitant use of corticosteroids or antiangiogenic agents, underlying malignancy, poor oral hygiene, invasive dental procedures (e.g., extractions), pre-existing dental disease, advanced age, and comorbid conditions such as diabetes or immunosuppression. Oncology patients, particularly those with multiple myeloma or metastatic breast/prostate cancer, are at highest risk due to higher cumulative drug exposure. Genetic predispositions and lifestyle factors such as smoking may further increase susceptibility.

Clinical Features

MRONJ typically presents as persistent exposed bone in the maxillofacial region, often accompanied by pain, swelling, local infection, fistula formation, and, in advanced cases, pathologic fracture or extraoral fistulas. Early lesions may be asymptomatic or present as non-healing extraction sites. Non-jaw osteonecrosis is rare but may manifest as bone pain, edema, or radiographic changes in affected sites. Prompt recognition of early clinical signs is critical for minimizing progression and optimizing outcomes.

Diagnosis

Diagnosis of MRONJ is primarily clinical, based on the presence of exposed or probeable bone in a patient with a relevant medication history and absence of prior craniofacial radiation. Imaging modalities, including panoramic radiographs and cone-beam CT, assist in determining the extent of bone involvement and excluding alternative diagnoses. Biopsy is reserved for cases where malignancy or metastatic disease is suspected. Laboratory studies are generally of limited value but may aid in assessing infection or systemic factors.

Treatment & Management

Management of MRONJ is stage-dependent and multidisciplinary. Conservative approaches, including antimicrobial mouth rinses, systemic antibiotics, and pain management, are first-line for early-stage disease. Surgical interventions, such as sequestrectomy or resection, may be required for advanced, refractory, or symptomatic cases. Optimization of oral hygiene, avoidance of invasive dental procedures during therapy, and collaboration with dental professionals are essential preventive measures. Temporary or permanent discontinuation of bone-active medications ("drug holiday") may be considered on a case-by-case basis, particularly in oncology patients, although robust evidence supporting this practice is limited.

Recent Advances / Emerging Therapies

Recent research has focused on risk stratification, improved diagnostic algorithms, and novel therapeutics. Local application of platelet-rich fibrin, low-level laser therapy, and use of teriparatide in select patients have shown potential in enhancing healing. Advances in oral health screening, patient education, and integrated care pathways have improved early detection and prevention. Ongoing trials are evaluating the role of alternative dosing regimens and novel antiresorptive agents with potentially lower MRONJ risk profiles.

Guideline Recommendations

International and national guidelines, including those from the American Association of Oral and Maxillofacial Surgeons (AAOMS), emphasize risk assessment prior to initiating bone-active therapy, baseline dental evaluation, and regular dental surveillance. Patients should be counseled on oral hygiene, and invasive dental procedures should ideally be completed prior to therapy initiation. In established MRONJ, a stage-based approach to management is recommended, with escalation from conservative to surgical interventions as indicated. Multidisciplinary collaboration among oncologists, endocrinologists, dentists, and maxillofacial surgeons is critical for optimal patient outcomes.

Conclusion

Osteonecrosis associated with long-term bone-active medications, while rare, poses significant clinical challenges, particularly in oncology and high-risk populations. Understanding the pathophysiology, identifying at-risk patients, and implementing evidence-based preventive and management strategies are essential for minimizing morbidity. Ongoing research and evolving guidelines continue to inform best practices, underscoring the need for multidisciplinary care and clinician vigilance in patients receiving antiresorptive therapy.