Medication-related osteonecrosis of the jaw (MRONJ) is a serious complication that occurs in patients currently or previously treated with antiresorptive agents such as bisphosphonates, denosumab, or anticancer agents including traditional chemotherapy agents, tyrosine kinase inhibitors, rapamycin pathway inhibitor, and immunotherapeutic agents [1,2]. MRONJ is defined as exposed bone or fistula in the oral and maxillofacial region for at least 8 weeks with a history of anti-resorptive therapy alone or in combination with immune modulators or anti-angiogenic medication, but without any history of radiation [3].

The staging suggested by the American Association of Oral and Maxillofacial Surgeons (AAOMS), most recently updated in 2022, is as follows [3]:

1. Stage 0: no clinical evidence of necrotic bone, but nonspecific clinical findings, radiographic changes, and symptoms.

2. Stage 1: exposed and necrotic bone/fistulae that can be probed to the bone, asymptomatic, no evidence of infection.

3. Stage 2: exposed and necrotic bone/fistula that can be probed to the bone, associated with infection.

4. Stage 3: exposed and necrotic bone/fistula that can be probed to the bone, associated with infection and additional complications.

In the early stages, the treatment mostly focuses on conservative treatment, including oral hygiene, 0.12% chlorhexidine rinses, and administration of antibiotics and anti-inflammatory medications. In more advanced stages, surgical interventions such as debridement and sequestrectomy may become required [1,3,4]. Despite further research on diagnosis and treatment of MRONJ, an evidence-based standard treatment for MRONJ remains controversial [3].

Conservative treatment is recommended in the early stages (stages 0 and 1). Surgical treatment should be restricted to advanced stages (stages 2 and 3) or when conservative treatment has failed. Surgical treatment has been reported to have better results than conservative treatment in most patients with advanced-stage MRONJ [5]. In some cases, patients have systemic diseases, are elderly, or have anatomic limitations that make surgical treatment difficult. In such cases, conservative management may be the most appropriate treatment for MRONJ patients.

Teriparatide, a synthetic polypeptide hormone that contains the 1–34 amino acid of recombinant human parathyroid hormone [6], is a bone anabolic agent indicated for the treatment of osteoporosis. Adjuvant administration of teriparatide is recommended in addition to surgical treatment for the treatment of MRONJ [7]. However, there are few cases of monotherapy with teriparatide without surgical treatment in advanced MRONJ. The purpose of this case report is to show that the single administration of teriparatide without surgical treatment can be an effective treatment for patients with advanced-stage MRONJ. This study was approved by the Institutional Review Board of Chosun University Dental Hospital (CUDH IRB 2401001).

Case 1

An 80-year-old female with chief complaints of pain and purulent discharge was referred to the Department of Oral and Maxillofacial Surgery. She underwent extraction of a right mandibular first molar 5 months previously. She had hypertension and severe osteoporosis and had been taking ibandronate for 5 years. The lingual bone exposure, gingival swelling, and fistula were observed on clinical examination. On radiographs, osteolysis was observed up to the inferior alveolar nerve (Fig. 1, 2). She was diagnosed with stage 2 MRONJ and was treated with chlorhexidine rinse and antibiotics. She was referred to her physician for a drug holiday on ibandronate, but she did not stop taking ibandronate. After 2 months, osteolysis extended vertically to the inferior border of the mandible (Fig. 3). She was referred to her physician about a drug holiday of ibandronate and a prescription for teriparatide again. Her T-score on bone mineral density (BMD) was –4.8 and teriparatide administration was started, and antibiotics were continued. The inflammatory condition was improved, and the symptoms subsided after 1 month. After 3 months of teriparatide administration, the sequestrum gradually separated from the surrounding bone (Fig. 4). The necrotic bone was removed spontaneously without surgical intervention, and healed without bone exposure or infection signs. After 8 months, the osteolysis that had progressed to the inferior border of the mandible disappeared, and significant bone regeneration and cortical ossification of the alveolar bone were observed (Fig. 5).

Fig. 1. Initial panoramic view showing osteonecrosis of the mandibular body extending to the inferior alveolar canal.

Fig. 2. (A) Axial and (B) coronal computed tomography scans demonstrating extensive destruction of buccal and lingual cortical bone and osteosclerosis of the surrounding bone at first visit.

Fig. 3. Panoramic radiograph depicting osteolysis extending beyond the inferior alveolar canal to the mandibular border 2 months later.

Fig. 4. Panoramic view showing progressive separation of sequestrum and reduced osteolysis after 3 months of teriparatide administration.

Fig. 5. Panoramic radiograph demonstrating complete bony healing 8 months after teriparatide administration.

Case 2

A 70-year-old woman was referred to the Department of Oral and Maxillofacial Surgery with a chief complaint of pain following the extraction of the right mandibular second molar 3 months ago. She had a past medical history of hypertension, hyperlipidemia, stage IV chronic renal disease, and osteoporosis. She had received alendronate for 9 years. At the clinical examination, bone exposure was observed in the extraction socket, and pus was discharged. No sequestrum was observed on radiographs, and the lamina dura was still observed (Fig. 6). Stage 2 MRONJ was diagnosed, and alendronate administration was discontinued. Antibiotics were administered, and chlorhexidine was used. After 3 months, sequestrum was observed, and vertical osteolysis was observed to extend to the inferior border of the mandible (Fig. 7, 8). Because the patient’s serum creatinine level was high (1.6 mg/dL), the physician decided to reduce the dose of augmentin 375 mg to twice a day. Teriparatide administration was also started. Sequestration of necrotic bone was observed one month after starting teriparatide treatment (Fig. 9). After two months, the sequestrum resolved spontaneously without surgical intervention. After four months, signs of infection or bone exposure were not observed, and bone formation was observed on radiographs (Fig. 10).

Fig. 6. Initial panoramic photograph showing the extraction socket of the right mandibular second molar without sequestrum.

Fig. 7. Panoramic view demonstrating osteolysis progressing to the mandibular border with the sequestrum and osteosclerosis of the surrounding bone 3 months later.

Fig. 8. (A) Axial and (B) coronal computed tomography scans showing lingual cortical bone destruction and osteonecrosis with sequestrum.

Fig. 9. Panoramic photograph showing separation of the sequestrum and cessation of osteolysis after 1 month of teriparatide administration.

Fig. 10. Panoramic view demonstrating the disappearance of the sequestrum and new bone formation 4 months after teriparatide administration.

Periodic administration of parathyroid hormone (PTH) has been shown to promote osteogenesis through a multifaceted mechanism. This process involves PTH enhancing calcium absorption in the gastrointestinal tract, which is achieved by augmenting the renal capacity for calcium reabsorption [7-9] and consequently stimulating increased production of active vitamin D [10]. The N-terminal segment comprising the initial 34 amino acid residues of the PTH sequence is designated as PTH (1-34), also known as teriparatide. Regulatory bodies, including the Food and Drug Administration and the European Medicines Agency, have approved the clinical application of PTH (1-34) in the management of osteoporosis and glucocorticoid-induced bone destruction [11]. The temporal sequence in which biomarkers of osteogenesis exhibit elevation prior to the rise in osteoclastic activity indicators defines a phenomenon known as the ‘anabolic window’ [12]. This initial surge in biochemical parameters associated with bone formation may predict subsequent enhancements in skeletal microarchitecture and BMD.

Teriparatide’s unique properties have led to its official approval as an anabolic agent for osteoporosis management. In contrast to antiresorptive agents, key mechanisms of teriparatide are that it enhances the bone-building activity of osteoblasts, directly stimulates new bone formation, increases the body’s ability to reabsorb calcium, and modulates phosphate excretion improves overall bone mineralization [13]. These combined effects increase bone density and mass, distinguishing teriparatide from other osteoporosis treatments that primarily prevent bone loss.

Teriparatide has been approved for use at a dose of 20 mcg/day and no longer than 24 months [14]. While teriparatide administration may potentially yield therapeutic benefits in the management of MRONJ, its application is contraindicated in specific patients [11]. These include individuals with osseous metastases or primary skeletal malignancies, those afflicted with metabolic bone disorders, patients presenting with hypercalcemia or pre-existing hypercalciuria, and cases involving drug interactions, particularly with digoxin [14]. Furthermore, recipients of teriparatide therapy frequently reported additional adverse effects, predominantly including appendicular pain, nausea, cephalalgia, and vertigo [15].

Previous studies have reported that combined treatment with teriparatide as an adjunct to surgical intervention is beneficial for MRONJ patients [16]. These studies indicate that the synergistic effect of surgical and pharmacological treatments can lead to significant improvements in MRONJ patients. While surgery addresses the necrotic bone immediately, teriparatide may support the healing process by stimulating new bone formation [13,17].

AAOMS has established a classification system and treatment guideline for MRONJ according to the stage [18]. For the early stages, conservative treatments may be considered [3]. These encompass systemic antibiotic administration, analgesic management, and antimicrobial oral irrigation. Nonetheless, some cases of early-stage MRONJ may be therapeutically resistant to conservative management. In this case, the lesions will continue to expand and worsen, as in these patients. It requires extensive resection and reconstruction. Surgical treatment is more effective than conservative treatment in advanced-stage MRONJ [19]. The conservative treatment should not be expected to induce significant remission or regeneration of necrotic bone [1]. On the other hand, teriparatide may be a solution in cases where MRONJ worsens despite conservative treatment or when surgical intervention is not possible [16]. In general, drug holidays are recommended for MRONJ due to antiresorptive agents [3], and the duration varies [20]. However, in cases with severe osteoporosis, such as case 1, drug holidays may worsen osteoporosis.

The establishment of standardized protocols and long-term outcomes for teriparatide single administration for MRONJ are not yet clear. Nevertheless, these cases suggest that teriparatide monotherapy is an effective treatment option even in cases where MRONJ has worsened with conservative treatment, suggesting its potential as a monotherapy as well as adjuvant therapy. This is particularly noteworthy in patients with severe systemic disease who may not be amenable to surgical intervention. Conservative treatment through teriparatide administration has a dual therapeutic effect that can effectively treat osteoporosis and MRONJ.

This study was supported by research fund from Chosun University Dental Hospital, 2023.

The authors declare that they have no competing interests.