Effect of Denosumab Therapy on Pain Level in Diffuse Sclerosing Osteomyelitis of the Mandible: a Case Report

Abstract

This is the first case report where two patients were under uniform denosumab administration protocol in diffuse sclerosing osteomyelitis (DSO) treatment and were closely monitored for 18 months. Objectives: This study aimed to describe the beneficial effects of denosumab in DSO treatment as well as pain relief and the significant lack of long-term use due to poorer outcomes after repeated use. DSO of the jaw is a poorly understood rare chronic disease the treatment of which is still very challenging despite a rapid development of medicine. Different medical treatments have been proposed without any significant long-lasting success. Bisphosphonates have offered substantial clinical benefit in DSO therapy, but due to harmful pharmacodynamic properties, denosumab therapy has been used to replace bisphosphonate therapy. Patients had a reduction in pain intensity with each subsequent application of denosumab but with less success than the first administration of denosumab. This case report has shown that denosumab could be a promising conservative treatment option for pain treatment in patients suffering from DSO.

Abstract

Introduction

Diffuse sclerosing osteomyelitis (DSO) of the mandible is a poorly understood rare chronic disease characterized by recurrent cheek swelling, trismus, and severe mandibular pain with the absence of fistula formation or suppuration in clinical examination (1-3).

In addition to clinical finding, it has a striking radiological finding characterized by partial osteolytic and osteosclerotic processes at the initial stage of the disease. Over time, bone sclerosis becomes more prominent with noticeable subperiosteal bone formation, periosteal reaction, lamina dura spreading, and mandibular canal boundary loss (3, 4).

Despite the development of medicine, treating this disease is still very challenging. Attempts have been made with long-term steroid, analgesic and antibiotics therapy, hyperbaric oxygen therapy and aggressive oral surgery procedures, all without significant long-lasting success (3, 5, 6).

Promising results have been reported concerning the treatment of DSO with bisphosphonates, mainly with intravenously administered ibandronate (7, 8).

By inhibiting the osteoclasts, the bisphosphonates inhibit bone resorption and remodeling. Although intravenous bisphosphonates show promising results in therapy DSO, their noticeable deficiency is a very long half-life in bone (approximately ten years) and the possibility of developing bisphosphonate-related osteonecrosis of the jaw (BRONJ).

Denosumab, a monoclonal antibody used in this case report, has some favorable characteristics compared to ibandronate. Denosumab inhibits the receptor activator of nuclear factor-kB ligand (RANKL) and potently inhibits osteoclast differentiation, function, and survival, thus decreasing bone resorption and remodeling. Furthermore, unlike bisphosphonates, denosumab does not accumulate in bone, and its effect on modelling is reversible and lasts for approximately six months (9-11).

We showed two cases where denosumab was used to treat mandibular pain in DSO since other conservative treatments were not successful and did not have long-lasting satisfactory effects.

Case reports

DSO was diagnosed after clinical and radiological examination, bone biopsy, and histological analysis with no bacterial colonization in microbiological testing. Both patients were conservatively treated with analgesics (diclofenac, ibuprofen), corticosteroids and antibiotics, and hyperbaric oxygen therapy, but without significant long-lasting success.

Written informed consent was obtained from the patient, and a routine blood testing (differential blood count, complete blood count, renal function test, a 25-hydroxy vitamin D test, and ionized calcium test) was performed on each patient before every denosumab application. All complications, symptoms related to the disease and mandibular pain levels on the VAS scale were recorded every day for 18 months. The level of pain was evaluated on a scale from 0 to 10 according to the visual analogue scale (VAS), where the endpoints were marked as zero, meaning "no pain", and ten meaning "unbearable pain". The pain level was measured the day after the denosumab application and for the following six months. The 25-hydroxy vitamin D test blood levels were within normal as patients were under supplementation during the treatment. Before each denosumab application, a detailed clinical examination, new multislice computed tomography (MSCT) and scintigraphic imaging were performed (Figure 1, Figure 3).

Figure 1.

An orthopantomograph before the treatment with Prolia® 60 mg showed sclerosis of the right side of the mandible of a 59-year-old woman.

Figure 3.

Comparison of pain level on VAS scale during six months after first, second and third denosumab administration in first clinical case

Clinical case 1

A 59-year-old woman visited the Department of Maxillofacial and Oral Surgery 90 days after the first right molar and the second premolar were extracted, and mandibular pain and swelling were still present. The patient stated that the post extraction wound took a long time to heal, while the intraoral examination showed a normal-looking mucosa without signs of acute odontogenic or other infections that could explain her present symptoms. A panoramic radiograph and an MSCT showed an expansion of the mandibular buccal and lingual cortical bone on the right side, pronounced bony sclerosis of the mandibular right side, which was more voluminous than the contralateral side of the mandible, Figures 1 and 2. DSO was identified considering clinical, radiological examination, microbiological testing, and biopsy with histology diagnosis. This DSO was treated with antibiotics, NSAID, corticosteroids, and HBO but without pain relief for three years. Then, the surgical and other conservative treatment modalities were explained, and denosumab therapy started after explaining the possible risks of developing MRONJ.

Figure 2.

Scintigraphy with increased metabolic activity in the right mandible before the first denosumab administration (a1). Unchanged metabolic activity after last denosumab therapy (a2). Coronal and axial radiological examinations (MSCT) of a 59‐year‐old woman with diffuse sclerosing osteomyelitis show a discretely increased bone sclerosis of the right corpus of the mandible with the noticeable subperiosteal bone formation during denosumab therapy, before denosumab therapy (b1, b2), before a second dose (c1, c2), before third dose (d1, d2) and six months after the third dose of denosumab therapy (e1, e2).

The patient was administered subcutaneously with the first injection of 60 mg of denosumab (Prolia® 60 mg) in August 2019. Intermittent mild mandibular pain occurred and lasted for ten days, hence taking analgesics was unnecessary. After that, there was a pain-free period for about four months, after which severe pain occurred. Six months after the first administration, the subcutaneous 60mg denosumab was repeated due to the re-onset of pain, after which, in the next thirty days, the pain was characterized as severe decrease in a pain-free period that lasted for the next three months. Again, after a pain-free period, severe pain occurred. Six months after the second, the third injection of 60 mg of denosumab was administered. The pain gradually decreased, and after six weeks, it completely disappeared, which lasted only two days. After that, the pain gradually increased, with short-term remissions, and at week 19 it became almost unbearable. The reduction or disappearance of mandibular swelling followed the reduction in pain. Each subsequent application of denosumab was less successful than the previous one, Figure 3. A one-way repeated measures ANOVA was performed to compare VAS scores on the first, second and third subcutaneous denosumab administration. The mean values of VAS were 2.935±3.938, 4.609±4.337 and 5.516±2.760 for the first, second and third denosumab administration, respectively. There was a significant effect in VAS scores among administrations, Wilks' Lambda=0.515, F (2, 182) =85.718, p< 0.001. In addition, the post-doc test with Bonferroni adjustment for multiple comparisons showed a statistically significant difference in VAS scores among pairs of three administrations (p<0.001).

Clinical case 2

A 66-year-old woman was referred to the Department of Maxillofacial and Oral Surgery because of jaw swelling, and the mandibular pain was classified as "cannot be worst". Between May 2018 and May 2019, she was treated with different analgesics (diclofenac, ibuprofen), steroids and antibiotics, but without any significant long-lasting success. She was also treated with hyperbaric oxygen therapy, which did not show clinically significant improvement. Panoramic radiograph and MSCT revealed bone sclerosis of the right mandible with noticeable subperiosteal bone formation, Figures 4 and 5. Clinical and radiological examination excluded odontogenic and temporomandibular etiology, and DSO was diagnosed. The diagnosis was confirmed by bone biopsy, histological analysis and no bacterial colonization in microbiological testing.

Figure 4.

An orthopantomograph before the treatment with Prolia® 60 mg showed sclerosis of the right side of the mandible of a 66-year-old woman.

Figure 5.

Scintigraphy with increased metabolic activity in the right mandible before first denosumab administration (a1) and (a2) unchanged metabolic activity after last denosumab therapy. Coronal and axial radiological examinations (MSCT) of a 66‐year‐old woman with diffuse sclerosing osteomyelitis show less pronounced bone sclerosis of the right mandible during the denosumab therapy period: before denosumab therapy (b1, b2), before a second dose (c1, c2), before third dose (d1,d2) and six months after the third dose of denosumab therapy (e1, e2).

She was offered surgical treatment for the DSO, which she refused, and after being informed about the risk of the development of MRONJ, she agreed to treatment with denosumab.

In October 2019, she received an injection of 60 mg of denosumab (Prolia® 60 mg) subcutaneously, and two days later, she was pain-free. With no analgesics, the pain-free period lasted over five months. At week 24, after the denosumab application, severe pain occurred with one episode of mild relief. The second injection of 60 mg of denosumab subcutaneously was given, and the pain decreased during the day of application; then, in the ninth week, moderate pain appeared, which disappeared after a few days, and reappeared in the 20th week. It was more pronounced to the point of severe pain and it did not decrease. A significant effect on pain reduction in the third application of 60 mg of denosumab was achieved at the end of the second week, while the pain completely disappeared at the end of the third week. The tolerable state lasted until the 18th week when the pain began to increase to unbearable at 25 week. The reduction or disappearance of jaw swelling also followed the reduction in mandibular pain. Each subsequent application of denosumab was less successful than the previous one (Figure 6). A one-way repeated measures ANOVA was performed to compare VAS scores on the first, second and third subcutaneous denosumab administration. The mean values of VAS were 1.016±2.517, 1.272±2.359 and 3.777±3.708 for the first, second and third denosumab administration, respectively. There was a significant effect in VAS scores among administrations, Wilks'Lambda = 0.557, F (2, 182) = 72.377, p<0.001. Post-Hoc test with Bonferroni adjustment for multiple comparisons showed a statistically significant difference in VAS scores between the first and third administrations and second and third administrations (p<0.001).

Figure 6.

Comparison of pain level on VAS scale during six months after first, second and third denosumab administration in second clinical case

Discussion

Although it significantly affects the quality of life due to recurrent swelling, trismus, and severe mandibular pain, the pathophysiology remains largely unknown, and DSO treatment is still unsuccessful. Given the current methods of DSO treatment, it was necessary to explore another conservative, non-surgical treatment (3, 6-8). The first studies using bisphosphonates in the treatment of DSO have been conducted since 2001. They have shown a relatively successful treatment option but with inconsistent protocols, routes of administration, types, and doses of bisphosphonates (3, 7). To the best of our knowledge, only two scientific papers with three cases reported the treatment of DSO with denosumab (1, 12), and this is the first case report that closely followed patients for 18 months with three denosumab administration. A dose of 60 mg denosumab was used because it is the most commonly used dose in osteoporosis and is safe and reliable (12).

Our findings have shown significant results of mandibular pain regression and reducing swelling in both patients after they had previously been on different conservative treatment methods: antibiotics, hyperbaric oxygen therapy, and steroids, which did not show significant long-lasting success.

Similarly, positive results have been established in a study by Otto et al. where 11 patients with DSO were successfully treated with bisphosphonate ibandronate. In contrast, after the recurrence of symptoms characteristic of DSO, one year after initial therapy with bisphosphonates, and one patient was treated with a subcutaneous administration of 60 mg denosumab, resulting in the disappearance of all symptoms and inflammatory activity (7). Hallmer et al. (1) obtained similar results when using denosumab subcutaneously, in contrast to Otto et al. (12), but without prior intravenous use of bisphosphonates, resulting in the complete disappearance of pain symptoms in both treated patients. Doses of denosumab in the first clinical case administered subcutaneously were significantly higher than in our cases. During the first three months, 120 mg were given every month and then two times 120 mg in the following eleven months. In the second clinical case, the denosumab administration protocol was similar to ours.

There were also some differences in our report on the success of therapy compared to Otto et al. (12) and Hallmer and al. (1). In our cases, patients were closely monitored for a more extended period, and the patients had a reduction in the intensity of pain with each subsequent application of denosumab following reducing of swelling, but with less success than the first administration of denosumab. After every next denosumab application, the average rated pain on the VAS scale was higher. After the first denosumab administration was VAS 2.934; after the second, VAS was 4.608; and after the third, VAS was 5.516. In the second clinical presentation, moderate pain on the VAS scale was rated after the first administration, VAS 1.016; after the second, VAS 1.571; and after the third, VAS 3.777.

The exact pathophysiological mechanism of action of antiresorptive drugs in the treatment of DSO and mandibular pain reduction is unclear. There are several theories about the aforementioned. Otto et al. consider that disrupting the RANK / RANKL / OPG system affects the osteoclastic and osteoblastic activity. The mechanism of that system is considered to impact the emergence of the DSO. Excessive activity of osteoclasts or inaccuracy in interaction and coupling between osteoclasts and osteoblasts will eventually cause an increase in osteoblast activity and, consequently, bone sclerosis.

Consequently, the inhibition of osteoclasts may reduce osteoclastic pain mediator excretion, pain levels and swelling (12). However, antiresorptive therapy, which is used in DSO therapy, has some limitations associated with developing MRONJ. Therefore, we decided on conservative denosumab therapy to treat our patients because compared to bisphosphonates, they have a shorter half-life (~26 days) and have no bone accumulation, i.e. they are eliminated six months after administration (9, 10).

Conclusions

In conclusion, these case reports show the benefits of denosumab in DSO pain with short-term intake. However, there is a significant reduction in success with each subsequent dose. Therefore, in our cases, a fourth denosumab administration was planned, with a dose twice as large as the previous or alternative surgical resection. Furthermore, it is unknown whether higher doses and more frequent administration of denosumab, different routes, and administration protocols would be more effective and lead to a longer duration of the complaint-free interval. However, further research is needed with control groups and longer follow-ups to confirm the aforementioned statements.