Application of monoclonal antibodiesin primary chronic osteomyelitis of the mandible in children

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Introduction

Primary Chronic Osteomyelitis (PCO) is a rare autoinflammatory disorder mostly affecting children and adolescents and lacks a bacterial origin. The term «Chronic Non-bacterial Osteomyelitis» was first introduced by Bjorksten et al. in 1980 to describe a clinical state marked by the persistent occurrence of chronic sterile osteomyelitis [1–3].

This disease, along with any other autoimmune disease, is characterized by the spontaneous activation of the innate immune system, which results in bone inflammation [4–7]. This phenomenon is evident through recurrent cycles of remission and exacerbation, manifesting as episodes of pain and fever accompanied by sterile cultures that do not respond to antibiotic treatment [8, 9].

The suspicion of PCO arises in the absence of clear indicators of bone infection, such as pus, fistula formation, or sequestrum. Consequently, the diagnostic process is challenging and typically involves the exclusion of other bone pathologies through radiographic imaging and, when necessary, biopsy [10, 11].

In the absence of placebo-controlled trials, treatment of PCO relies on personal experience, case collections, and expert opinion. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as Ibuprofen and Naproxen, are regarded as the first-line treatment, demonstrating efficacy in pain management and inducing remission in approximately 43% to 83% of patients. In patients who are refractory to NSAID or in individuals with vertebral lesions, more aggressive treatment is commonly applied, including corticosteroids, sulfasalazine (SSZ), methotrexate (MTX), or TNF-α inhibitors [12, 13].

Due to the pivotal involvement of RANK and its ligand RANKL in the primary pathophysiological mechanisms associated PCO, Denosumab as a monoclonal antibody that specifically targets RANKL, an acronym for Receptor Activator of Nuclear Factor-Kappa B Ligand [14, 15], has recently been employed as a therapeutic intervention. By inhibiting the activation of RANKL on the surface of osteoclasts, Denosumab subsequently influences the RANK receptor. This blockade of the interaction between RANKL and RANK effectively hinders osteoclast differentiation, functionality, and longevity, thereby leading to a reduction in bone resorption [16–20].

Material and methods

At the Department of Maxillofacial Surgery of the Russian Children’s Clinical Hospital (RDKB), a branch of the Federal State Autonomous Educational Institution of Higher Education at the Russian National Research Medical University named after N.I. Pirogov, under the Ministry of Health of the Russian Federation in Moscow, 45 children received inpatient treatment for primary chronic osteomyelitis (PCO) from 2015 to 2023.

Among these patients, a 9‑year-old girl with a persistently relapsing course was selected for this article. In her clinical case, debridement and decortication were performed, involving the resection of granulomatous fibro-osseous tissue from the affected area. Subsequent culture and morphological analysis verified the aseptic characteristics of the inflammatory condition. Following this, a single administration of the monoclonal antibody Denosumab was performed. Prior to the administration of the monoclonal antibodies, the patient underwent standard biochemical assessments of blood and urine to exclude the possibility of renal dysfunction, and informed consent was secured for the off-label application of the medication.

The patient’s parents provided informed voluntary consent to participate in the study according to the Helsinki Declaration of the World Medical Association (WMA Declaration of Helsinki — Ethical Principles for Medical Research Involving Human Subjects, 2013) and personal data processing.

Clinical case description

Description of the clinical case: A 9‑year-old female patient had been ill since February 2020, when she first exhibited facial asymmetry accompanied by pain in the lower jaw. A lower jaw anomaly was identified through multi-slice computed tomography (MSCT) conducted at her place of residence. Subsequently, a surgical procedure was performed, during which a biopsy was obtained, leading to a diagnosis of fibrous dysplasia of the left half of the lower jaw.

Over the following year, the patient experienced recurrent episodes of her condition, necessitating her admission to RDKB hospital in January 2021 for further evaluation and treatment. Upon her admission, notable asymmetry of the lower jaw was observed, attributed to bone deformation in the left body of the lower jaw (Figure 1).

Fig 1. Patient’s visual evaluation when admitted to the hospital for the first time

Diagnosis

The MSCT imaging reveals edema and deformity in the left segment of the mandible. The affected osseous structure exhibits uneven compaction resembling a «ground glass» appearance, accompanied by localized areas of softening and disruption of the cortical layer. Notably, there is a periosteal thickening along the anterior surface of the altered bone, measuring up to 2.5 mm. Additionally, the mandibular canal demonstrates widening, and the compaction of bone extends into the right segment over a distance of 10 mm. The left masseter muscle appears slightly hypertrophied, and the surrounding soft tissues exhibit edema, with linear compaction extending to the skin (Figure 2).

Fig. 2. MSCT scan in January 2021 shows the affected area that includes the body, angle and the ramus of the left half of the mandible. It can also be noted the widening of the mandibular canal on the left side

Treatment

In light of the clinical and radiographic findings, a surgical intervention was conducted involving the excision of fibrously altered tissues using Volkmann spoon and a bur until the sclerotic margins of the cavity were palpated. In the area corresponding to tooth 3.8, the cortical layer was excised, and the rudimentary structure of tooth 3.8 was extracted. The excised tissue was subsequently sent for culture and histopathological analysis. The postoperative course was uneventful, during which antibacterial and symptomatic therapies were administered, along with a single dose of 60 mg of the monoclonal antibody Denosumab.

Histological analysis of the provided bone material revealed fragments of spongy bone with areas of osteolysis and reactive bone formation. The intertrabecular spaces were occupied by loose fibrous connective tissue, which contained minimal foci of productive, non-granulomatous inflammation. The results from the culture did not demonstrate any microbial growth, thereby conforming the sterilized status of the PCO. Following an improvement in the patient’s condition, the child was discharged under the care of specialists at their place of residence.

Observation

Throughout the subsequent year, no relapses were observed; however, in the month prior to the second admission which was in April 2022, the patient experienced mild pain on the right side of the lower jaw, necessitating readmission to the RDKB. A MSCT scan conducted upon admission revealed a softening focus measuring up to 5 mm in depth and 1 cm in diameter located at the angle of the right half of the lower jaw, accompanied by a cystic cavity in the vicinity of the roots of tooth 3.5. Additionally, an irregular structure of the body of the left half of the lower jaw was noted (Figure 3).

Fig. 3. MSCT scan in April 2022 exhibits the extension of the bone destruction on both halves of the mandible

Consequently, a decision was made to perform decortication on both sides and to excise the fibrous-altered tissues utilizing Volkmann spoons until the sclerotic margins of the cavity were palpated. Since the patient’s general condition and radiological findings before the second admission were not as serious as her condition when she was first admitted, and since we had already given the patient a dose of 60 mg of denosumab, which is considered a rather high dose, and for fear of complications of this drug such as osteonecrosis of drug use, it was decided not to repeat the dose in the postoperative period, which was uneventful, and the patient received antibacterial treatment (Medaxone, Metrogyl) along with symptomatic therapy.

Discussion

Monitoring the patient’s condition in the year following reveals that the regions of bone destruction were filled, despite the retention of the irregular morphology of the external contour of the mandible. Notably, the child remained pain free throughout this period (Figure 4).

Fig. 4. MSCT scan in May 2023 showing the recovering process of the mandible with the remaining of uneven contour of the left half of the mandible

Similarly, a MSCT scan conducted in June 2024, one year later, revealed evidence of bone regeneration, with the external contour of the mandible returning to its typical dimensions and morphology (Figure 5).

Fig. 5. MSCT scan in June 2024 exhibiting the evidence of bone regeneration and positive dynamic of the treatment protocol. It can be clearly seen the positive effect of adding Denosumab to the treatment protocol in keeping the good outcome of the operation

Although Denosumab is most commonly used to treat osteoporosis in the elderly and postmenopausal women, it is now being considered as a first-line treatment for primary chronic osteomyelitis. We can see the added benefit of using Denosumab in the treatment plan in achieving stable remission, extending the time period between relapses and consolidating resorption zones. This is illustrated by comparing the patient’s condition prior to hospitalization, marked by frequent relapses within a single year, to the following year, during which the patient experienced no pain.

Conclusion

The therapeutic interventions used in this clinical case effectively enhanced the density of the impacted region. Nevertheless, in instances where minor cystic elements were not completely removed and the decontamination of the granulated tissues was inadequate, a recurrence ensued, prompting the need for additional surgical intervention. The utilization of Denosumab postoperatively contributed to the maintenance of disease remission. The most commonly used doses among adult patients are 120 or 60 mg. However, since our patients are children and their anthropometric parameters differ from adults, it was decided to adjust the dose based on the weight and height of the children. This decision was made to choose smaller doses to prevent the risk of osteonecrosis as it is known as the most common complication after using the Anti-resorptive drugs, while ensuring effective rehabilitation and prolonging the periods between relapses.

The inquiry regarding the differential response to Denosumab treatment among patients persists as a topic for future discussion and scientific investigation. Specifically, it remains unclear why certain individuals achieve satisfactory outcomes with a single dose, while others require multiple doses to attain the desired therapeutic effect.

It is essential to determine the correct dosage, treatment duration, and administration frequency of these medications to achieve optimal results and minimize the risk of postoperative complications typically associated with this class of drugs. Consequently, a comprehensive strategy for managing PCO should include antiresorptive therapy. The incorporation of monoclonal antibodies represents an innovative approach to PCO management, aimed at enhancing treatment efficacy.

About the authors

Alexander Yu. Kugushev

N.I. Pirogov Russian National Research Medical University

Email: suzandager@yandex.com
ORCID iD: 0000-0002-6881-7709
SPIN-code: 3045-0722
Moscow, Russian Federation

Andrey V. Lopatin

RUDN University; Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology

Email: suzandager@yandex.com
ORCID iD: 0000-0003-0043-9059
SPIN-code: 6341-8912
Moscow, Russian Federation

Suzan Dagher

RUDN University

Author for correspondence.
Email: suzandager@yandex.com
ORCID iD: 0009-0004-1950-4011
Moscow, Russian Federation

References

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